CN101677564A - (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the improvement delivery formulations and the using method thereof of 6-benzothiazole-diamines - Google Patents

Abstract

The invention discloses the improvement release of pharmaceutical compositions (controlled release, lasting release and/or prolongation release) of R-Pramipexole, and use the such combination treatment nerve degenerative diseases or the method for those diseases relevant with the oxidative stress of mitochondria dysfunction or increase.

Description

(6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the improvement delivery formulations and the using method thereof of 6-benzothiazole-diamines

B. the cross reference of related application

[0001] the application requires the U.S. Provisional Application submitted on March 14th, 2007 number 60/894,799, the U.S. Provisional Application of submitting on March 14th, 2007 number 60/894,829, the U.S. Provisional Application of submitting on March 14th, 2007 number 60/894,814, the U.S. Provisional Application of submitting on March 14th, 2007 number 60/894,835, the U. S. application of submitting on December 14th, 2007 number 11/957,157 rights and interests, described U. S. application number 11/957,157 require the U.S. Provisional Application submitted on December 14th, 2006 number 60/870,009, with the priority of the U.S. Provisional Application of submitting on October 10th, 2007 number 60/979,049, its each part is all incorporated into this paper by integral body by reference.

C. governmental interests: inapplicable

D. the participant of joint study agreement: inapplicable

E. quote material: inapplicable by on CD, submitting

The E background

[0001] compound 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole is the synthetic aminobenzothiazole that chiral carbon is arranged at 6, and exist with a pair of optics enantiomter, described optics enantiomter depends on that whether 6-propyl group amino group is with S (-) orientation or R (+) orientation.Its S (-) enantiomter, (6S)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines (PPX), generally known with its USAN name Pramipexole, and conduct

(dihydrochloride) is commercial to be got, and Pramipexole is powerful dopamine agonist, and thus, the effect of imitation neurotransmitter dopamine.Therefore, Pramipexole is considered at treatment Parkinson's disease, gathering together property headache, ekbom syndrome and anxiety disorder, only needs little every day of dosage and tolerated by the patient.Although Pramipexole is effective clinically as dopamine agonist, its R (+) enantiomter, (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines (RPPX) has the compatibility that reduces greatly to dopamine receptor, and non-useful clinically dopamine agonist.Yet two kinds of enantiomters have all shown the enforcement neuroprotective activity, and interact irrelevant with dopamine receptor.Its each enantiomter all can pass through in the cell of brain and spinal cord and; more specifically; in the mitochondria of these cells, accumulate; and give clinical neuroprotection among the patient; in the mitochondria of these cells; these two enantiomters are exercised the dopamine independent utility on nervous function, may be by suppressing liposome peroxidation, making mitochondria metabolism normalization and/or make the oxygen atomic group detoxifcation.So, these compounds can have the purposes as cell death cascade reaction and the inhibitor that observed cell viability is lost in nerve degenerative diseases.

[0002] the neuroprotective character of PPX has been considered to useful potentially at the treatment of neurological sexual disorder; but described medicine has shown that at the treatment clinical practice of dopamine defective disorder (for example PD) dosed administration (dosing) both temporarily had been subjected to the restriction of the prolonged dose titration of needs, is being restricted aspect the maximum tolerated dose (MTD) owing to the side effect relevant with dopamine agonist utterly again.At this type of dopamine-receptor stimulant, the restriction of these dosed administrations is typical.

[0003] as if every day three times (t.i.d.),

The maximum of (a kind of release composition immediately) allows that the single initial dose is 0.125mg; And the maximal allowance dose of Mirapex is 1.5mgt.i.d., if provide a maximum daily dose 4.5mg's after the titration in 7-8 week

[0004] although

These dosage levels be useful for the S﹠S of treatment PD and RLS, but PPX hangs down about 1,000 times as the usefulness (potency) of neuroprotective agent than its usefulness as dopamine agonist in neuroprotective is analyzed.This shows that using this enantiomter can not reach treatment goes up useful neuroprotective dosage.

[0005] RPPX has similar neuroprotective usefulness, but has lower dopamine receptor compatibility.Therefore, it is suggested as the treatment potential more useful compound of neurological sexual disorder.Yet that had before reported will still force at important clinically dosage restriction at the dopamine receptor affinity difference of comparing RPPX with PPX, and will still need dose titration to limit to avoid the relevant side effect of dopamine with dosage.The report that formerly RPPX is used for ALS, the dosed administration that shows RPPX are limited and require significant dose titration in the zoopery.The dose titration requirement of supposing particularly, begins dosed administration and on the period in 7-8 week dosage is increased to final treatment effective dose level with low-down dosage, has seriously limited the serviceability of the neuroprotective potential of RPPX enantiomter.In addition, the MTD that supposes will seriously limit the timely exploitation of RPPX enantiomter for the neuroprotective potential of acute and chronic neurological sexual disorder.

G. summary of the invention

[0006] embodiment of the present invention are usually at the improvement delivery formulations field of Pramipexole, especially RPPX and pharmaceutically acceptable salt thereof.Such improvement delivery formulations can be useful in the treatment of neurological sexual disorder.

[0007] the present invention by obtaining purifying clinically RPPX and determine binding affinity in its actual external and body and the patient to the tolerance of the RPPX of purifying, and opened the treatment potential of RPPX.According to embodiment of the present invention, can give more heavy dose of RPPX to the patient of needs.

[0008] the present invention also is provided at the method for treatment nerve degenerative diseases among the patient who needs, comprise and give the about 25mg of patient to about 5, the RPPX of the daily dose value of 000mg, more preferably every day, about 500mg was to about 2,100mg, most preferably every day is greater than 500mg and less than 2, the RPPX of 100mg, and preferably a kind of improvement delivery formulations with RPPX gives.

[0009] in some embodiments, the disease that treat is acute and it is chronic in other embodiments.In some embodiments, described chronic nerve degenerative diseases is selected from the primary nerve degenerative diseases, Huntington, metabolism causes neurotrosis, senile dementia Alzheimer type disease, the age cognitive disorder of being correlated with, blood vessel nature feeble-mindedness, MID, dementia with Lewy body disease, the nervus retrogression dementia, the nervus retrogression movement disorder, incoordination, the Friedrich incoordination, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, spastic disorder disease, motor neuron disorder or disease, struvite demyelinating disorder, Alzheimer's, Parkinson's disease, amyotrophic lateral sclerosis, hepatic encephalopathy and chronic encephalitis.In some embodiments, described chronic nerve degenerative diseases is an amyotrophic lateral sclerosis.In some embodiments, described patient is the patient of first treatment.

[0010] this paper has described the improvement release composition that contains RPPX.Described composition can be configured to R (+) enantiomter that comprises Pramipexole, is substantially free of its S (-) enantiomter.Described improvement release formulation can provide the blood plasma level that continues of Pramipexole during the time period that prolongs.As used herein, be substantially free of PPX, be meant such Pramipexole preparation, wherein more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, more than 99.9%, preferably more than 99.95%, be RPPX more preferably more than 99.99% Pramipexole molecule, or its R (+) enantiomter.

H. brief description of drawings

[0011] Fig. 1 has described under the fasted conditions healthy volunteer's orally give single Discharge immediately50mg, 150mg and the average blood plasma RPPX concentration behind the 300mg dosage.

[0012] Fig. 2 has described under the feeding condition healthy volunteer's orally give single Discharge immediately150mg dosage after average blood plasma RPPX concentration.

[0013] Fig. 3 has described under the fasted conditions healthy volunteer's orally give Discharge immediatelyFirst day 50mg and 100mg dosage, the 3rd to 6 day Q12H, and during the 7th day single dose, the average blood plasma RPPX concentration of the 1st day and the 7th day.

[0014] Fig. 4 has described exposure (AUC) at male and female rats and mankind's (two kinds of sexes) to dosage (mg/m ²) figure.

[0015] Fig. 5 has described average exposure (AUC) at male and female miniature pig and mankind's (two kinds of sexes) to dosage (mg/m ²) figure.

[0016] Fig. 6 has described the Cpss of the prediction of the exemplary 300mg improvement delivery formulations of orally give once a day

[0017] Fig. 7 has described release characteristics in the body of prediction of the exemplary 300mg improvement delivery formulations of orally give once a day.

I. describe in detail

[0018] the dopamine receptor compatibility that the invention provides RPPX is the more previous much lower evidence of thinking in fact, and described evidence has increased the clinical serviceability of said composition greatly. This paper also prove between PPX and the RPPX enantiomter functional affinity difference (for example 10,000-20,000 times) than previous report much bigger. These digital proofs RPPX can be dosed in a plurality of levels, thereby need not just can more fully be developed more unexpectedly by the theoretical limit of forcing about the hypothesis of the separation in the dopamine receptor compatibility between described two kinds of enantiomters the neuroprotective potential of the more low liter of compound. This dosed administration can need not dose titration and occur. These data show that also a small amount of PPX causes the active remarkable change of missing the target of described composition to the pollution of the composition of pure RPPX. This application proposes with full concentration (immediate full-strength) immediately, and/or using clinically without dose titration that the improvement of purer RPPX discharges the method that composition is used for acute and chronic neurological sexual disorder, described acute and chronic neurological sexual disorder formerly is considered to be inaccessible this medicine.

[0019] in some embodiments; the improvement release of pharmaceutical compositions that the invention provides the RPPX that comprises enough dose is realized neuroprotective, anti-oxidant, anti-apoptosis or other useful cytological effect; and do not cause simultaneously significant side effect, particularly those and the active relevant side effects of dopamine. Two basic finds to make and sends clinical effective dose and do not have the ability of dose limiting side effect to become possibility: (i) pure RPPX synthetic in the detectability discussed in this article; And (ii) RPPX have than previous report for the in essence discovery of lower compatibility of dopamine receptor. Improvement release of pharmaceutical compositions of the present invention can depend on the optical purity of employed RPPX in (in some embodiments) composition or depend on the limited dopaminergic activity one of RPPX of employed chiral purity in the composition or both.

[0020] before describing this composition and method, it should be understood that to the invention is not restricted to described detailed process, composition or methodology, because these can change. It should also be understood that employed in this manual term only is in order to describe specific version or embodiment, and be not intended to limit the scope of the invention that scope of the present invention is only limited by additional claims. All mentioned publications of this paper are all incorporated to support into the present invention by integral body by reference.

[0021] compound 2-amino-4,5,6, and 7-tetrahydrochysene-6-(propyl group is amino) benzothiazole is a synthetic amino-benzothiazole derivatives, has two kinds of enantiomters of structure shown below. Described (S) enantiomter is dopamine receptor D₂The brute force of family (potent) activator has for D₃The specific compatibility of receptor subtype. As dopamine agonist, PPX activates dopamine receptor, imitates thus the effect (effect) of neurotransmitter dopamine. The PPX stereoisomer is the powerful activator of dopamine, only needs a little daily dose and really can be tolerated by the patient. Two kinds of enantiomters all are considered to be accumulated in brain, vertebra and mitochondria by it; and do not rely on the ability of dopamine agonist activity; may be by suppressing liposome peroxidation, make mitochondrial function normalization and/or make the oxygen atomic group detoxifcation and given the neuroprotective effect. Therefore, these compounds can have the purposes as the inhibitor of cell death cascade reaction and the forfeiture of the cell viability observed in nerve degenerative diseases.

(S)-Pramipexole (R)-Pramipexole

[0022] the dosed administration degree of molecule has that evincible phenotype activity is can be thus in operation active comes the specific curative effect with expectation is worked and defines with active approaches (" (on-target) hits " activity) or passive approaches (" (off-target) misses the target " activity), described verifiable phenotype activity is to be caused by the compatibility for special receptor or other pharmacology effective protein proteins, or even when described activity be by and when causing for the compatibility of unknown target spot.For any given molecule, can discern (identify) many " missing the target " activity in theory, but " hitting " activity is subject to the curative effect of expectation.Can be measured or quantitative with regard to these activity, or make comparisons with known reference material, at these classifications (" active equivalent ", or AE) each in can generate activity index, and one or more ratio will " miss the target " and active compare with " hitting " activity, and will be useful for more intermolecular potential risk-benefit ratio.

[0023] with regard to RPPX, in this context, can define two kinds of activity.First kind at most of neurological sexual disorders activity of " missing the target ", and it is the agonist activity to human dopamine acceptor subgroup and its behaviouristics that is caused/toxicology phenotype.Because the agonist activity of dopamine receptor, this activity causes the restricted side effect of dosage, for the purpose of discussing at present, can be defined as the active equivalent of dopamine, or DAE.Run through the application, term " dopaminergic activity equivalent " (DAE) will be used in reference to and mean the PPX that the is equivalent to 1mg measurement to the activity of the dopamine receptor of the activity of dopamine receptor.For instance, the RPPX consumption with DAE of 0.01 will will have the activity of the PPX activity that is equivalent to 0.01mg to dopamine receptor.For clear, described DAE can also be relevant with various medicine terms, comprises maximum tolerated dose (MTD), no discernable ill-effect level (NOAEL), and the placebo value.For instance, exist at PPX Discharge immediatelyIn the NOAEL dose value most preferred for being lower than 0.05mg.This corresponding is lower than 0.05 DAE conversely.Therefore, the dose value with DAE of 0.01 will be lower than the DAE at the NOAEL dose value of the PPX of most preferred 0.05mg.In some embodiments, DAE is by measuring with respect to the identical parameters at 1mg PPX, to D ₂And/or D ₃Binding affinity (the IC of acceptor ₅₀) or active (EC ₅₀) and determine.In some embodiments, DAE is by measuring D ₂The binding affinity of acceptor or active and determine.In some embodiments, DAE is by measuring D ₃The binding affinity of acceptor or active and determine.In some embodiments, DAE is by measuring D ₂The binding affinity of acceptor and definite.In some embodiments, DAE is by measuring D ₃The binding affinity of acceptor and definite.In some embodiments, DAE is by suitable analyzed in vitro, for example at D ₂Or D ₃The IC of acceptor ₅₀Binding affinity is analyzed and is determined, comprises those by Schneider, C.S.; Mierau, J. at " dopamine autoreceptor activator: 2; fractionation of the aminothiazole analog of 6-diaminourea tetrahydro benzothiazol and apomorphine and pharmacological activity (Dopamine Autorecept Autoreceptor Agonists:Resolution and PharmacologicalActivity of 2; 6-Diaminotetrahydrobenzothiazole and an Aminothiazole Analogue ofApomorphine) " (1987), pharmaceutical chemistry (J.Med.Chem.) 30:494-498; Or Wong, S.K.-F.; Shrikhande, A.V., S.K.-F.Wong is " by dopamine D ₂And D ₃Acceptor pair cell external signal is modulated kinase whose activation (Activation of Extracellular Signal-Regulated Kinase by Dopamine D2 and D3 Receptors) " (2003), described in Society for Neuroscience's digest (Society For Neuroscience Abstracts).This kind will be at its enantiomter PPX activity that " hits " at " missing the target " activity of RPPX in neurological sexual disorder (except that Parkinson's disease), and described activity is used for the treatment of PD and ekbom syndrome.

[0024] we studies show that at the DAE of RPPX more much lower than what before may be familiar with.For instance, our research shown when using the RPPX of high chiral purity, at RPPX to D ₂And D ₃The binding affinity of dopamine receptor is than PPX low respectively about 290 and about 649 times.By relatively, bibliographical information at RPPX to D ₂The binding affinity of dopamine receptor than the low about 9-21 of PPX doubly, and at RPPX to D ₃The binding affinity of dopamine receptor is lower about 50 times than PPX.

[0025] more thrillingly be, we RPPX that studies show that in beasle dog is 10,000 to the MTD dosage ratio of PPX, and RPPX is 20,000 to the NOAEL dosage ratio of PPX.As bioanalysis, MTD in dog and NOAEL disclose tolerance in the complete up to now uncertain body.Because restriction in reference material and quantitative analysis, even in fact MTD and NOAEL show that the slightest 0.005% impurity also may be actually the reason that causes the relevant side effect of dopamine agonist in the body in dog.These contrast Journal of Sex Research show that DAE at RPPX is than previous be familiar with much lower.

[0026] another activity of RPPX and PPX is a neuroprotective.Neuroprotective is a kind of phenomenon that does not rely on mechanism, and therefore is classified as a class activity.This " hitting " activity at the RPPX that treats the neurological sexual disorder is measurable, and approximately suitable in two kinds of enantiomters, and can be defined as neuroprotective activity equivalent or NAE by relative terms.Described neuroprotective activity equivalent (NAE) refers to neuroprotective activity intrinsic among the PPX of 1mg.Different with DAE, in many testing in vitro, NAE is presented in two kinds of Pramipexole enantiomters and equates.In this embodiment, described DAE is regarded as the measurement unit of ill-effect potential, and described NAE is regarded as the measurement unit of treatment benefit potential.At this embodiment, RPPX and Both NAE can determine from produce the required concentration of neuroprotective analyzed in vitro.

[0027] in some embodiments, NAE can be determined by the neuroprotective activity of measuring outside standard body in the neuroprotective analysis with respect to the PPX activity of 1mg.In some embodiments; described neuroprotective activity is by measuring cell death (as non-limiting embodiment under the situation that has MPP+ and/or rotenone in dopaminergic and/or non-dopaminergic cell; see M.Gu; neurochemistry magazine (Journal of Neurochemistry), the analysis among the 91:1075-1081 (2004)) determine.

[0028] the preferred purpose of the present invention is to make the NAE maximization that is delivered to the patient, and the number of the active equivalent of prompting adverse events (adverse events) is minimized, and active equivalent described here is DAE.

[0029] owing to its high dopamine compatibility, PPX has high DAE/NAE ratio, and obviously lower at the corresponding ratio of RPPX.From the practical point of view, embodiment of the present invention provide than previous significantly higher NAE level of believing and higher NAE/DAE level, and the possibility of treatment effective dose value of the patient's that can need described neuroprotective agent is maximized.Described NAE and DAE are useful on the ratio of useful and ill-effect especially on ratio, and for useful on the scope that is defined in the particular composition that can give.

[0030] yet, the consumption of PPX (dosage) is subjected to the restriction of the dopaminergic activity of described (S) enantiomter, and this can cause adverse side effect at the consumption on " not having discernable ill-effect level " (NOAEL dose value).As used herein, NOAEL dosage refers to produce on the frequency of ill-effect or severity that non-statistical is learned or the biologically significant reactive compound that increases or the amount of pharmaceutical agent exposing between colony and its suitable contrast; On this level, may produce some effects, but that it is not considered to is bad, or is considered to the omen of ill-effect.Exposing colony can be system, tissue, animal, the individuality or human of just being treated by researcher, animal doctor, doctor or other clinicians.About PPX, exemplary ill-effect is dizzy, illusion, feel sick, low blood pressure, drowsiness, constipation, headache, tremble, backache, postural hypotension, hypertonia, depressed, stomachache, anxiety, indigestion, flatulence, diarrhoea, fash, ataxia, do a mouthful disease, the extrapyramidal system syndrome, have a cramp in the leg, twitch, pharyngitis, sinusitis, perspire, rhinitis, urinary tract infections, vasodilation, the influenza syndrome, saliva increases, odontopathy, expiratory dyspnea, cough increases, abnormal gait, frequent micturition, vomiting, allergy, hypertension, itch, hypokinesis, neurotic, dreamland is unusual, pectoralgia, cervical pain, cacesthesia, tachycardia, dizzy, sound changes, conjunctivitis, paralysis, tinnitus, shed tears, mydriasis and diplopia.

[0031] for instance, shown 1.5mg PPX discharge immediately dosage cause the human experimenter drowsiness (from European medicine evaluation administration at

Communique, the sleep rise suddenly; Boehringer Ingelheim at

The product inset show that this medicine is by 3 dosed administrations every day).In addition, pointed as this paper, the research of carrying out in dog (seeing the result shown in embodiment and the table 11) shows that it can be to be low to moderate 0.00125mg/kg that described NOAEL discharges dosage immediately, and it is equivalent to the human dosage of 0.0007mg/kg or for the 0.05mg of the individuality of 70kg.Therefore, about PPX, NOAEL releasing agent value immediately can be to be lower than 1.5mg, to be lower than 0.50mg or more preferably to be lower than the amount of 0.05mg.About DAE as herein defined, NOAEL dosage can have and is lower than 1.5, is lower than 0.5, perhaps more preferably is lower than 0.05 DAE.About the improvement release composition, the NOAEL dose value can be to be lower than 3.0mg, to be lower than 1.5mg or more preferably to be lower than the amount of 0.15mg.

[0032] usually, need the amount bigger treat the curative effect in the active disease of alleviating by dopamine agonist to have than the placebo value of PPX.Yet this amount is not supposed to when seeking neuroprotection, because it can cause described adverse side effect.As used herein " placebo value " refers to as the viewed biology that is similar to placebo or biology or the reactive compound of medical response or the amount of pharmaceutical agent of medical response of causing in the tissue, system, animal, individuality or the mankind that are being treated by researcher, animal doctor, physician or other clinicians.Therefore, as viewed in the tissue, system, animal, individuality or the mankind that are being treated by researcher, animal doctor, physician or other clinicians, " placebo value " can not cause the recognizable difference with placebo aspect positive-effect.Thus, described " placebo value " is not supposed to (1) prevent disease; For instance, in the disease that is easy to take a disease, discomfort or disorderly but also do not experience or show this disease of prevention, discomfort or disorderly in the individuality of the pathology of this disease or disease; (2) suppress disease, for instance, experiencing or is showing this disease of inhibition, discomfort or disorder in the individuality of disease, discomfort or disorderly pathology or disease (promptly stop or slow down further developing of described pathology and/or disease); (3) alleviate disease; For instance, relax this disease, discomfort or disorder (promptly reverse or alleviate described pathology and/or disease) in the individuality of disease, discomfort or disorderly described pathology or disease experiencing or show.

[0033] as an embodiment, by MPTP (1-methyl-4-phenyl-1,2,3, the 6-tetrahydropyridine) in the monkey of (a kind of known dopaminergic nerve toxin) treatment, PPX has shown that the minimum effective oral dosage that discharges immediately is 0.053mg/kg (seeing the discussion in science (Scientific Discussion) at http://www.emea.europa.eu/humandocs/PDFs/EPAR/Sifrol/059197EN6. pdf) with dosage relevant mode resisted motion defective and class op parkinson's symptom.These mankind that will be equivalent to 0.017mg/kg discharge dosage immediately, perhaps at the 1.2mg of the individuality of 70kg.In mankind test, find relative placebo in the treatment Parkinson's disease, have remarkable result PPX the minimum effectively oral dosage that discharges immediately be 1.1mg/ days.Individual patient may need to be higher than 1.1mg/ days the enough effect (from European medicine evaluation affix one's name at the initial discussion in science of ratifying Mirapex) of dosage to obtain to be higher than placebo effect.In mankind test, find in the treatment ekbom syndrome, to have minimum effective dose with respect to the remarkable result of placebo and be 0.25mg/ days (Boehringer Ingelheim at

The product inset).Therefore, about PPX, the placebo value can be to be lower than 1.0mg/ days, is lower than 0.75mg/ days, is lower than 0.5mg/ days, is lower than 0.25mg/ days, or is preferably lower than 0.125mg/ days amount.About DAE, the placebo value of every day can have and is lower than 1.0, is lower than 0.75, is lower than 0.5, is lower than 0.25, or is preferably lower than 0.125 DAE every day.

[0034] other restrictions of amount that can deliver medicine to patient's PPX also comprise maximum recommended therapeutic dose and maximum tolerated dose." maximum recommended therapeutic dose " (MRTD) refers to the CDER by FDA, the consumption that pharmacy science office formulates, maximum recommended treatment consumption with information and computationally secure analysis office worker, and as Matthews etc. described " the health-care effect evaluation of chemicals in the mankind: I; estimate (Assessment of the Health Effectsof Chemicals in Humans:I.QSAR Estimation of the Maximum Recommended TherapeuticDose (MRTD) and No Effect Level (NOEL) of Organic Chemicals Based on Clinical TrialData) " based on the maximum recommended therapeutic dose (MRTD) of the organic chemicals of clinical testing data and the QSAR of invalid level (NOEL), (contemporary medicine discovery technique (Current Drug Discovery Technologies), 2004,1:61-76).The MRTD database of FDA is quoted at 0.1mg/kg/ days of PPX or at 70 pounds people 7.0mg/ days MRTD.Matthews has estimated normally described MRTD about 1/10th of NOEL (no ill-effect level) again, and this is corresponding to 0.01mg/kg, or at 70 pounds the about 0.7mg/ of people days.

[0035] because its harmful effect for first treatment patient, PPX must be on the period of several weeks titration do not have to reach these consumptions the restricted ill-effect of dosage (for example Boehringer Ingelheim at

The product inset in write down).For instance, for ekbom syndrome, recommendation

The first day dose value of (composition of Shi Fanging immediately) is 0.125mg, and took once every day before going to bed in 2-3 hour.For the patient that the extra disease of needs is alleviated, a daily dose can increase to 0.25mg 4-7 days time period, increases to 0.5mg second time period of 4-7 days subsequently.At the treatment of Parkinson's disease, package insert (package insert) recommend following at

The titration schedule:

Week	Consumption (mg)	A total daily dose (mg)
			??1	??0.125tid	??0.375
??2	??0.25tid	??0.75
			??3	??0.5tid	??1.5
??4	??0.75tid	??2.25
			??5	??1.0tid	??3.0
??6	??1.25tid	??3.75
			??7	??1.5tid	??4.5

[0036] as used herein " maximum tolerated dose " (MTD) refers to cause the amount of the reactive compound or the pharmaceutical agent of remarkable toxicity in the tissue, system, animal, individuality or the mankind that are just being treated by researcher, animal doctor, physician or other clinicians.The research of single dose toxicity behind the PPX oral administration has been arranged in rodent, dog, monkey and the mankind.In rodent, dead (from the initial discussion in science of European medicine evaluation administration at approval Mirapex) takes place when 70-105mg/kg and above dosage.The human dosage of this and 7-12mg/kg or suitable for the about 500-850mg of the individuality of 70kg.In the human experimenter, when giving the patient of first treatment, do not tolerated greater than the first day dosage of the PPX of 0.20mg.In dog, vomit at 0.0007mg/kg and when above, and monkey shows excited significantly at 3.5mg/kg.In addition, described at

The product inset mankind's maximum tolerated dose is fixed on 4.5mg/ days, with the once used amount administration of three 1.5mg.Yet, be not the patient who described 4.5mg/ days consumption is given first treatment, but different therewith, after the titration scheme, reach (as at

The product inset in write down like that).Usually, the described first day consumption that gives the patient of first treatment is that the 0.125mg that is administered three times every day discharges dosage immediately, and the titration schedule of recommending for seven weeks is to reach the 1.5mg dosage that is administered three times every day.All species all show and the relevant toxicity sign of excessive drug effect response for PPX.For instance, it is common that the behavior that comprises hyperfunction changes, and causes many second order effects, for example loses weight and other the symptom of pressure inducement.In miniature pig and monkey, PPX moderate influence cardio-vascular parameters.In rat, the powerful prolactin depression effect of Pramipexole (for example influences reproductive organs, the corpus luteum, the pyometra that increase), and the retinal degeneration that show dose is relevant in long term exposure (affixing one's name at the initial discussion in science of ratifying Mirapex from European medicine evaluation).In dog, studies show that the MTD amount at human experimenter's PPX can be to be lower than 4.5mg/ days amount, be preferably lower than 1.5mg/ days amount.In addition, based on result of study disclosed herein, can be to be lower than the 0.3mg/ amount of releasing agent immediately at human experimenter's MTD amount, and be preferably lower than 0.2mg/ releasing agent (seeing Table 11) immediately.About DAE, described MTD measures to have and is lower than 1.5,0.9 and 0.6 DAE.

[0037] consider restriction on the amount of the PPX that can give the patient, the use of embodiment of the present invention has proposed the important clinically alternative method of the development of new neuroprotective therapy.Document had reported before that RPPX was to D ₂The binding affinity of acceptor is than little about 9 to 21 times of PPX, and RPPX is to D ₃The binding affinity of acceptor is than little about 50 times (table 10) of PPX.The relative binding affinity that these documents obtain is than showing that RPPX only can be with the consumption administration higher a little than PPX.Use RPPX because tissue, system, animal and human's class experimenter have been got rid of with the relative binding affinity of two kinds of enantiomters being obtained by described document greatly than the tolerance dose of PPX the sharp susceptibility of dopamine stirring effect than the dosage of big coefficient, this restriction can take place.

[0038] can prove apparent elimination with reference to theoretic 50mg ER tablet to the more high dose of RPPX.Suppose on binding affinity 9 times difference, 99.95% pure 50mg ER tablet will have about 5.575DAE (from the 5.55DAE of RPPX with from the 0.025DAE of PPX).Similarly, the tablet of expectation 25mg is presented 2.79 DAE (from the 2.78DAE of RPPX with from the 0.0125DAE of PPX).After the titration scheme in 7 weeks, the MTD of PPX is 4.5mg, or every day three 1.5mg, be equivalent to 4.5DAE in a day.In addition, be to be lower than 4.5mg at the NOAEL dose value of PPX, be preferably lower than 1.50mg, perhaps more preferably be lower than 0.15mg, be equivalent to DAE respectively, DAE and DAE.Suppose to have 4.5DAE, and the NOAEL of PPX has less than about 4.5DAE at the described one day MTD of PPX, the relative binding affinity that obtains by described document when independent reference than the time have the 50mg ER consumption of 5.55DAE.In addition, the use of the high chiral purity of 99.95% in these theoretical consumptions will cause unacceptable high 5.55 DAE, and described DAE has surpassed the consumption per day MTD of 4.5mg DAE, and has far surpassed the NOAEL of preferred 1.5DAE and 0.15DAE.

[0039] on the contrary, in some embodiments, one aspect of the present invention relates to the unexpectedly high chiral purity that had obtained already.These purity cause being familiar with high MTD or NOAEL at RPPX than the relative binding affinity that before obtains based on described document.In some embodiments, the invention provides the improvement release of pharmaceutical compositions, initial dose, methods of treatment, and the medicine box that comprises the RPPX of high chiral purity.According to above discussion, predictably, the improvement with 50mg of similar 99.95% chiral purity discharges consumption can be far above MTD and the NOAEL at PPX, and therefore causes perceptible adverse side effect.Yet the RPPX that studies show that described high chiral purity in dog causes the unexpected high NOAEL dose value (table 10) that may be familiar with than those.Fabulously be, do not cause perceptible effect but the 25mg/kg with the PPX (0.05% detectability) that does not contain detection limit discharges the RPPX of consumption immediately in dog, according to the binding affinity data of document, this is unexpected.

[0040] in addition, in dog, studies have shown that height at the described composition of (R)-enantiomter (near absolute) chiral purity.RPPX in research disclosed herein with the horizontal administration of high dose (be equivalent to 1,000 to 3, the human dosage of 000mg is seen embodiment), even make the PPX of minimum also will help described observed NOAEL and MTD.For instance, about based on the human DE of the data that in dog, obtain, be shown as at the MTD of (R)-enantiomter and be equivalent at the human experimenter's of 70kg about 3,000mg, and will be equivalent to only 0.30mg (table 11) at identical experimenter at the MTD of equal value of (S)-enantiomter.This is 10,000 times a difference.At the NOAEL dosage of (R)-enantiomter than big 20,000 times (table 11) of described (S)-enantiomter.Therefore, only derive from the pollution that is caused by (S)-enantiomter if suppose described observed side effect, the RPPX composition that uses in these researchs must be 99.99% pure at least.On the other hand, these digital proofs can be by the described high dose level of (the R)-enantiomter of the Pramipexole of safe administration.These data have been given prominence in various embodiments of the present invention the serviceability at the described high chiral purity of RPPX.

[0041] the present invention further provides the medicine box of improveing release of pharmaceutical compositions, initial dose, method and comprising RPPX with higher consumption and Geng Gao chiral purity.As discussed above, document before showed at D ₂And D ₃Relative binding affinity on the acceptor is about 9 to 21 and 50 (seeing embodiment 1 and following table 10) than respectively.Find unexpectedly, when using the RPPX of high chiral purity, at D ₂And D ₃Relative binding affinity on the acceptor is about 290 and 649 than PPX: RPPX.

[0042] as discussing in more detail following, this shows described relative binding affinity than be about 13 to 32 times of the relative binding affinity reported in described document.Described document has been full of the dysgenic discussion to PPX.Although the support vitro data of the present invention and the binding affinity that propose are convincing, relatively in the external and body that proposes of this paper during data, the synthetic importance of economical and effective becomes apparent.Clinical observation shows that RPPX is 10,000 to the MTD dosage ratio of PPX in the body in beasle dog, and RPPX is 20,000 to the NOAEL dosage ratio of PPX.Absolute MTD dosage ratio may be higher, because the chiral purity that this paper reported is subject to detectability (seeing embodiment 2 and table 11).Based on described chiral purity and external relative binding affinity ratio, clinical NOAEL dosage ratio, perhaps clinical MTD dosage are than (this paper " relative scale "), and the RPPX prediction DAE at setting dosage is possible now.Table 1 shows the DAE as the RPPX of the 25mg ER dosage of the function of relative scale and chiral purity.Because relative scale lower when comparing with the relative scale that document obtains described herein, can be knowable than the before much lower DAE of these data show can be unexpectedly caused by the 25mg ER formulation of RPPX.

Table 1: as % chiral purity and relative scale function at the DAERPPX's of the RPPX of 25mg ER dosage

Percentage hand 20,000 10,000 5,000 2,400 100 10

Property purity relative scale relative scale relative scale relative scale relative scale relative scale

99.9967????0.0020749????0.0033249????0.0058248????0.0112413????0.2508168????2.5007425

99.9958????0.0022999????0.0035498????0.0060498????0.0114662????0.2510395????2.5009450

99.9950????0.0024999????0.0037499????0.0062498????0.0116661????0.2512375????2.5011250

99.9933????0.0029249????0.0041783????0.0066747????0.0120909????0.2516583????2.5015075

99.9900????0.0037499????0.0049998????0.0074995????0.0129156????0.2524750????2.5022500

99.9833????0.0054248????0.0066746????0.0091742????0.0145899????0.2531333????2.5037575

99.9800????0.0062498????0.0074995????0.0099990????0.0154158????0.2549500????2.5045000

99.9750????0.0074997????0.0087494????0.0112488????0.0166641????0.2561875????2.5056250

99.9667????0.0095746????0.0108242????0.0133233????0.0187382????0.2582418????2.5074925

99.9583????0.0116745????0.0129239????0.0154229????0.0208373????0.2603208????2.5093825

99.9500????0.0137494????0.0149988????0.0174975????0.0229115????0.2623750????2.5112500

99.9333????0.0179242????0.0191733????0.0216717????0.0270847????0.2665083????2.5150075

99.9000????0.0262488????0.0274975????0.0299950????0.0354063????0.2747500????2.5225000

99.8333????0.0429229????0.0441798????0.0466666????0.0520743????0.2912583????2.5375075

99.8000????0.0512475????0.0524950????0.0549900????0.0603958????0.2995000????2.5450000

99.7500????0.0637469????0.0649938????0.0674875????0.0728906????0.3118750????2.5562500

99.6667????0.0845708????0.0858167????0.0883093????0.0937065????0.3324918????2.5749925

99.5800????0.1062448????0.1074895????0.1099790????0.1153729????0.3539500????2.5945000

99.5000????0.1262438????0.1274875????0.1299750????0.1353656????0.3737500????2.6125000

99.3333????0.1679167????0.1691583????0.1764167????0.1770222????0.4150083????2.6500075

99.0000????0.2512375????0.2524750????0.2549500????0.2603125????0.4975000????2.7250000

98.3300????0.4187291????0.4199583????0.4224165????0.4277427????0.6633250????2.8757500

98.0000????0.5102250????0.5024500????0.5049000????0.5102083????0.7450000????2.9500000

97.5000????0.62621875???0.6274375????0.629875?????0.6351563????0.86875??????3.0625

[0043] table 1 attempts illustrating the importance of purity and compatibility, even for the single oral consumption of 25mg.To get rid of in advance or even the RPPX tablet of the 25mg of high-purity (or even 100% pure) from apparent about the hypothesis of the dopaminergic activity of RPPX on described dopamine receptor.Based on disclosure of the present invention, can imagine many forms of illustrating this point immediately.Below table 1A and 1B intention by illustrating even importance at the single oral formulation purity of RPPX is illustrated in the influence of the minimum pollution of described composition by PPX.

Table 1A

" NOAEL " consumption of RPPX composition is (based on DAE ＜0.15)

50mg??????100mg?????150mg?????200mg?????250mg?????500mg

(R)-purity % 99.9000 99.9500 99.9667 99.9750 99.9800 99.9900

(S)-impurity level % 0.1000 0.0500 0.0333 0.0250 0.0200 0.0100

(S)-impurity DAE 0.05 0.05 0.05 0.05 0.05 0.05

Table 1B

The engineering noise consumption of RPPX composition (based on DAE＜0.125)

50mg??????100mg?????150mg?????200mg?????250mg?????500mg

(R)-purity % 99.7500 99.8750 99.9170 99.9380 99.9500 99.9750

(S)-impurity level % 0.2500 0.1250 0.0830 0.0620 0.0500 0.0250

(S)-impurity DAE 0.125 0.125 0.125 0.125 0.125 0.125

[0044] nobody recognizes or clearly expresses synthetic method to be essential for reaching the purity that surpasses general detectability.In addition, nobody shows that this once used amount must be 99.95% or higher its predetermined purpose that just is suitable on purity.

[0045] based on relative scale at binding affinity, NOAEL and MTD value, what prediction can administration, the amount of RPPX that is equivalent to the placebo value of PPX is possible.Table 2 shows the DAE as RPPX (left hand row) consumption and described relative scale (top line) function.Reference table 2 can select to take into account the unit dose of the amount of the RPPX with the DAE that equates with the ineffective dose amount of PPX.In fact, unless expect dual DAE/NAE effect, in pharmaceutical composition, will avoid or minimize DAE.Therefore, desirably, any ER dosage can not avoid missing the target activity and will specially being avoided by those skilled in the art greater than 25mg.If as in the present invention, relative scale surpasses 200, this is wrong.This is illustrated best by table 2.

Table 2: as the DAE (supposing the RPPX of 100% chiral purity) of RPPX and relative scale function

20,000???10,000????5,000?????2,400?????1,700?????1,300?????650???????400?????300?????200??????100??????50

2.5????0.00013??0.00025???0.0005????0.0010????0.0015????0.0019????0.0038????0.0063??0.0083??0.0125???0.0250???0.0500

5??????0.00025??0.00050???0.001?????0.0021????0.0029????0.0038????0.0077????0.0125??0.0167??0.0250???0.0500???0.1000

6.25???0.00031??0.00063???0.00125???0.0026????0.0037????0.0048????0.0096????0.0156??0.0208??0.0313???0.0625???0.1250

10?????0.00050??0.00100???0.002?????0.0042????0.0059????0.0077????0.0154????0.0250??0.0333??0.0500???0.1000???0.2000

12.5???0.00063??0.00125???0.0025????0.0052????0.0074????0.0096????0.0192????0.0313??0.0417??0.0625???0.1250???0.2500

15?????0.00075??0.00150???0.003?????0.0063????0.0088????0.0115????0.0231????0.0375??0.0500??0.0750???0.1500???0.3000

20?????0.00100??0.00200???0.004?????0.0083????0.0118????0.0154????0.0308????0.0500??0.0667??0.1000???0.2000???0.4000

25?????0.00125??0.00250???0.005?????0.0104????0.0147????0.0192????0.0385????0.0625??0.0833??0.1250???0.2500???0.5000

32.5???0.00163??0.00325???0.0065????0.0135????0.0191????0.0250????0.0500????0.0813??0.1083??0.1625???0.3250???0.6500

37.5???0.00188??0.00375???0.0075????0.0156????0.0221????0.0288????0.0577????0.0938??0.1250??0.1875???0.3750???0.7500

50?????0.0025???0.0050????0.0100????0.0208????0.0294????0.0385????0.0769????0.1250??0.1667??0.2500???0.5000???1.0000

65?????0.0033???0.0065????0.0130????0.0271????0.0382????0.0500????0.1000????0.1625??0.2167??0.3250???0.6500???1.3000

80?????0.0040???0.0080????0.0160????0.0333????0.0471????0.0615????0.1231????0.2000??0.2667??0.4000???0.8000???1.6000

81.25??0.0041???0.0081????0.0163????0.0339????0.0478????0.0625????0.1250????0.2031??0.2708??0.4063???0.8125???1.6250

85?????0.0043???0.0085????0.0170????0.0354????0.0500????0.0654????0.1308????0.213???0.283???0.425????0.850????1.700

100????0.0050???0.0100????0.0200????0.0417????0.0588????0.0769????0.1538????0.250???0.333???0.500????1.000????2.000

120????0.0060???0.0120????0.0240????0.0500????0.0706????0.0923????0.1846????0.300???0.400???0.600????1.200????2.400

130????0.0065???0.0130????0.0260????0.0542????0.0765????0.1000????0.2000????0.325???0.433???0.650????1.300????2.600

150????0.0075???0.0150????0.0300????0.0625????0.0882????0.1154????0.2308????0.375???0.500???0.750????1.500????3.000

162.5??0.0081???0.0163????0.0325????0.0677????0.0956????0.1250????0.2500????0.406???0.542???0.813????1.625????3.250

200????0.0100???0.0200????0.0400????0.0833????0.1176????0.1538????0.3077????0.500???0.667???1.000????2.000????4.000

212.5??0.011????0.021?????0.043?????0.0885????0.1250????0.1635????0.3269????0.531???0.708???1.063????2.125????4.250

250????0.013????0.025?????0.050?????0.1042????0.1471????0.1923????0.3846????0.625???0.833???1.250????2.500????5.000

260????0.013????0.026?????0.052?????0.1083????0.1529????0.2000????0.4000????0.650???0.867???1.300????2.600????5.200

300????0.015????0.030?????0.060?????0.1250????0.1765????0.2308????0.4615????0.750???1.000???1.500????3.000????6.000

325????0.016????0.033?????0.065?????0.135?????0.191?????0.250?????0.500?????0.813???1.083???1.625????3.250????6.500

340????0.017????0.034?????0.068?????0.142?????0.200?????0.262?????0.523?????0.850???1.133???1.700????3.400????6.800

350????0.018????0.035?????0.070?????0.146?????0.206?????0.269?????0.538?????0.875???1.167???1.750????3.500????7.000

400????0.020????0.040?????0.080?????0.167?????0.235?????0.308?????0.615?????1.000???1.333???2.000????4.000????8.000

500????0.025????0.050?????0.100?????0.208?????0.294?????0.385?????0.769?????1.3?????1.7?????2.5??????5.0??????10.0

600????0.030????0.060?????0.120?????0.250?????0.353?????0.462?????0.923?????1.5?????2.0?????3.0??????6.0??????12.0

625????0.031????0.063?????0.125?????0.260?????0.368?????0.481?????0.962?????1.6?????2.1?????3.1??????6.3??????12.5

650????0.033????0.065?????0.130?????0.271?????0.382?????0.500?????1.000?????1.6?????2.2?????3.3??????6.5??????13.0

850????0.043????0.085?????0.170?????0.354?????0.500?????0.654?????1.308?????2.1?????2.8?????4.3??????8.5??????17.0

1000???0.050????0.100?????0.200?????0.417?????0.588?????0.769?????1.538?????2.5?????3.3?????5.0??????10.0?????20.0

1200???0.060????0.120?????0.240?????0.500?????0.706?????0.923?????1.846?????3.0?????4.0?????6.0??????12.0?????24.0

1250???0.063????0.125?????0.250?????0.521?????0.735?????0.962?????1.923?????3.1?????4.2?????6.3??????12.5?????25.0

1300???0.065????0.130?????0.260?????0.542?????0.765?????1.000?????2.000?????3.3?????4.3?????6.5??????13.0?????26.0

1700???0.085???0.170???0.340???0.708??1.000??1.308??2.615???4.3????5.7????8.5????17.0???34.0

2000???0.100???0.200???0.400???0.833??1.176??1.538??3.077???5.0????6.7????10.0???20.0???40.0

2400???0.120???0.240???0.480???1.00???1.41???1.85???3.69????6.0????8.0????12.0???24.0???48.0

2500???0.125???0.250???0.500???1.04???1.47???1.92???3.85????6.3????8.3????12.5???25.0???50.0

3250???0.163???0.325???0.650???1.35???1.91???2.50???5.00????8.1????10.8???16.3???32.5???65.0

5000???0.250???0.500???1.000???2.08???2.94???3.85???7.69????12.5???1.67???25.0???50.0???100.0

6500???0.325???0.650???1.300???2.71???3.82???5.00???10.00???16.3???21.7???32.5???65.0???130.0

8500???0.425???0.850???1.700???3.54???5.00???6.54???13.08???21.3???28.3???42.5???85.0???170.0

10000??0.500???1.000???2.000???4.17???5.88???7.69???15.38???25.0???33.3???50.0???100.0??200.0

20000??1.000???2.000???4.000???8.33???11.76??15.38??30.77???50.0???66.7???100.0??200.0??400.0

The DAE that is equivalent to the placebo value of preferred PPX can be lower than 1.0mg, preferably is lower than 0.5mg, and more preferably is lower than 0.125mg.

[0046] similarly, can determine the amount of RPPX that can administration, described amount is equivalent to the horizontal dose value of no discernable ill-effect of described PPX.Table 3 shows the DAE as the function of RPPX (left hand row) consumption and relative scale (top line).Reference table 3 can select to take into account the unit dose of amount of the RPPX of the DAE with the NOAEL dose value that is equivalent to PPX.Although 0.125 has avoided unnecessary effect, avoided NOAEL less than 0.15.Difference in bibliographical information and the actual result is in table 3 even more surprising.

Table 3: as the DAE (supposing the RPPX of 100% chiral purity) of RPPX consumption and relative scale function

20,000????10,000????5,000?????2,400?????1,700?????1,300?????650???????400???????300???????200???????100??????50.000

2.5????0.00013???0.00025???0.00050???0.00104???0.0015????0.0019????0.0038????0.0063????0.0083????0.0125????0.025????0.050

5??????0.00025???0.00050???0.00100???0.00208???0.0029????0.0038????0.0077????0.0125????0.0167????0.0250????0.050????0.100

6.25???0.00031???0.00063???0.00125???0.00260???0.0037????0.0048????0.0096????0.0156????0.0208????0.0313????0.063????0.125

10?????0.00050???0.00100???0.00200???0.00417???0.0059????0.0077????0.0154????0.0250????0.0333????0.0500????0.100????0.200

12.5???0.00063???0.00125???0.00250???0.00521???0.0074????0.0096????0.0192????0.0313????0.0417????0.0625????0.125????0.250

15?????0.00075???0.00150???0.00300???0.00625???0.0088????0.0115????0.0231????0.0375????0.0500????0.0750????0.150????0.300

20?????0.00100???0.00200???0.00400???0.00833???0.0118????0.0154????0.0308????0.0500????0.0667????0.1000????0.200????0.400

25?????0.00125???0.00250???0.00500???0.01042???0.0147????0.0192????0.0385????0.0625????0.0833????0.1250????0.250????0.500

32.5???0.00163???0.00325???0.00650???0.01354???0.0191????0.0250????0.0500????0.0813????0.1083????0.1625????0.325????0.650

37.5???0.00188???0.00375???0.00750???0.01563???0.0221????0.0288????0.0577????0.0938????0.1250????0.1875????0.375????0.750

50?????0.0025????0.0050????0.0100????0.0208????0.0294????0.0385????0.0769????0.1250????0.1667????0.2500????0.500????1.000

65?????0.0033????0.0065????0.0130????0.0271????0.0382????0.0500????0.1000????0.1625????0.2167????0.3250????0.650????1.300

80?????0.0040????0.0080????0.0160????0.0333????0.0471????0.0615????0.1231????0.2000????0.2667????0.4000????0.800????1.600

81.25??0.0041????0.0081????0.0163????0.0339????0.0478????0.0625????0.1250????0.2031????0.2708????0.4063????0.813????1.625

85?????0.0043????0.0085????0.0170????0.0354????0.0500????0.0654????0.1308????0.2125????0.2833????0.4250????0.850????1.700

100????0.0050????0.0100????0.0200????0.0417????0.0588????0.0769????0.1538????0.2500????0.3333????0.5000????1.000????2.000

120????0.0060????0.0120????0.0240????0.0500????0.0706????0.0923????0.1846????0.3000????0.4000????0.6000????1.200????2.400

130????0.0065????0.0130????0.0260????0.0542????0.0765????0.1000????0.2000????0.3250????0.4333????0.6500????1.300????2.600

150????0.0075????0.0150????0.0300????0.0625????0.0882????0.1154????0.2308????0.3750????0.5000????0.7500????1.500????3.000

162.5??0.0081????0.0163????0.0325????0.0677????0.0956????0.1250????0.2500????0.4063????0.5417????0.8125????1.625????3.250

200????0.0100????0.0200????0.0400????0.0833????0.1176????0.1538????0.3077????0.5000????0.6667????1.0000????2.000????4.000

212.5??0.0106????0.0213????0.0425????0.0885????0.1250????0.1635????0.3269????0.5313????0.7083????1.0625????2.125????4.250

250????0.0125????0.0250????0.0500????0.1042????0.1471????0.1923????0.3846????0.6250????0.8333????1.2500????2.500????5.000

260????0.0130????0.0260????0.0520????0.1083????0.1529????0.2000????0.4000????0.6500????0.8667????1.3000????2.600????5.200

300????0.0150????0.0300????0.0600????0.1250????0.1765????0.2308????0.4615????0.7500????1.0000????1.5000????3.000????6.000

400????0.0200????0.0400????0.0800????0.1667????0.2353????0.3077????0.6154????1.0000????1.3333????2.0000????4.000????8.000

500????0.0250????0.0500????0.1000????0.2083????0.2941????0.3846????0.7692????1.2500????1.6667????2.5000????5.000????10.000

600????0.0300????0.0600????0.1200????0.2500????0.3529????0.4615????0.9231????1.5000????2.0000????3.0000????6.000????12.000

625????0.0313????0.0625????0.1250????0.2604????0.3676????0.4808????0.9615????1.5625????2.0833????3.1250????6.250????12.500

650????0.0325????0.0650????0.1300????0.2708????0.3824????0.5000????1.0???????1.6???????2.2???????3.3???????6.5??????13.0

850?????0.0425????0.0850????0.1700??0.3542????0.5000??0.6538????1.3????2.1????2.8????4.3?????8.5?????17.0

1000????0.0500????0.1000????0.2000??0.4167????0.5882??0.7692????1.5????2.5????3.3????5.0?????10.0????20.0

1200????0.0600????0.1200????0.2400??0.5000????0.7059??0.9231????1.8????3.0????4.0????6.0?????12.0????24.0

1250????0.0625????0.1250????0.2500??0.5208????0.7353??0.9615????1.9????3.1????4.2????6.3?????12.5????25.0

2000????0.1000????0.2000????0.4000??0.8333????s???????1.5385????3.1????5.0????6.7????10.0????20.0????40.0

2400????0.1200????0.2400????0.4800??1.0000????1.4118??1.8462????3.7????6.0????8.0????12.0????24.0????48.0

2500????0.1250????0.2500????0.5000??1.0417????1.4706??1.9231????3.8????6.3????8.3????12.5????25.0????50.0

3250????0.1625????0.3250????0.6500??1.3542????1.9118??2.5000????5.0????8.1????10.8???16.3????32.5????65.0

5000????0.2500????0.5000????1.00????2.08??????2.94????3.85??????7.7????12.5???16.7???25.0????50.0????100.0

6500????0.3250????0.6500????1.30????2.71??????3.82????5.00??????10.0???16.3???21.7???32.5????65.0????130.0

8500????0.4250????0.8500????1.70????3.54??????5.00????6.54??????13.1???21.3???28.3???42.5????85.0????170.0

10000???0.5000????1.0000????2.00????4.17??????5.88????7.69??????15.4???25.0???33.3???50.0????100.0???200.0

20000???1.0000????2.0000????4.00????8.33??????11.76???15.38?????30.8???50.0???66.7???100.0???200.0???400.0

The DAE that is equivalent to no discernable ill-effect level (NOAEL) dose value of preferred PPX can be lower than 1.5mg, is preferably lower than 0.15mg.

[0047] in addition, table 4 shows the DAE as RPPX (left hand row) consumption and relative scale (top line) function.Reference table 4 can select to take into account the unit dose of the RPPX dose value with specific DAE.

Table 4: as the DAE (supposing the RPPX of 100% chiral purity) of RPPX consumption and relative scale function

20,000?????10,000???5,000????2,400????1,700????1,300????650??????400??????300??????200??????100????50

2.5????0.00013????0.00025??0.00050??0.0010???0.0015???0.0019???0.0038???0.0063???0.0083???0.013????0.025??0.050

5??????0.00025????0.00050??0.00100??0.0021???0.0029???0.0038???0.0077???0.0125???0.0167???0.025????0.050??0.100

6.25???0.00031????0.00063??0.00125??0.0026???0.0037???0.0048???0.0096???0.0156???0.0208???0.031????0.063??0.125

10?????0.00050????0.00100??0.00200??0.0042???0.0059???0.0077???0.0154???0.0250???0.0333???0.050????0.100??0.200

12.5???0.00063????0.00125??0.00250??0.0052???0.0074???0.0096???0.0192???0.0313???0.0417???0.063????0.125??0.250

15?????0.00075????0.00150??0.00300??0.0063???0.0088???0.0115???0.0231???0.0375???0.0500???0.075????0.150??0.300

20?????0.00100????0.00200??0.00400??0.0083???0.0118???0.0154???0.0308???0.0500???0.0667???0.100????0.200??0.400

25?????0.00125????0.00250??0.00500??0.0104???0.0147???0.0192???0.0385???0.0625???0.0833???0.125????0.250??0.500

40?????0.00200????0.00400??0.00800??0.0167???0.0235???0.0308???0.0615???0.1000???0.1333???0.200????0.400??0.800

50?????0.00250????0.00500??0.010????0.021????0.029????0.038????0.077????0.125????0.167????0.250????0.500??1.000

60?????0.00300????0.00600??0.012????0.025????0.035????0.046????0.092????0.150????0.200????0.300????0.600??1.200

65?????0.00325????0.00650??0.013????0.027????0.038????0.050????0.100????0.163????0.217????0.325????0.650??1.300

80?????0.00400????0.00800??0.016????0.033????0.047????0.062????0.123????0.200????0.267????0.400????0.800??1.600

85?????0.00425????0.00850??0.017????0.035????0.050????0.065????0.131????0.213????0.283????0.425????0.850??1.700

100????0.00500????0.010????0.020????0.042????0.059????0.077????0.154????0.250????0.333????0.500????1.000??2.000

130????0.00650????0.013????0.026????0.054????0.076????0.100????0.200????0.325????0.433????0.650????1.300??2.600

150????0.00750????0.015????0.030????0.063????0.088????0.115????0.231????0.375????0.500????0.750????1.500??3.000

162.5??0.00813????0.016????0.033????0.068????0.096????0.125????0.250????0.406????0.542????0.813????1.625??3.250

200????0.010??????0.020????0.040????0.083????0.118????0.154????0.308????0.500????0.667????1.000????2.000??4.000

260????0.013??????0.026????0.052????0.108????0.153????0.200????0.400????0.650????0.867????1.300????2.6????5.2

300????0.015??????0.030????0.060????0.125????0.176????0.231????0.462????0.750????1.000????1.500????3.0????6.0

325????0.016??????0.033????0.065????0.135????0.191????0.250????0.500????0.813????1.083????1.625????3.3????6.5

340????0.017??????0.034????0.068????0.142????0.200????0.262????0.523????0.850????1.133????1.700????3.4????6.8

350????0.018??????0.035????0.070????0.146????0.206????0.269????0.538????0.875????1.167????1.750????3.5????7.0

400????0.020??????0.040????0.080????0.167????0.235????0.308????0.615????1.000????1.333????2.000????4.0????8.0

480????0.024??????0.048????0.096????0.200????0.282????0.369????0.738????1.200????1.600????2.400????4.8????9.6

500????0.025??????0.050????0.100????0.208????0.294????0.385????0.769????1.250????1.667????2.500????5.0????10.0

600????0.030??????0.060????0.120????0.250????0.353????0.462????0.923????1.500????2.000????3.000????6.0????12.0

850????0.043??????0.085????0.170????0.354????0.500????0.654????1.308????2.125????2.833????4.250????8.5????17.0

1000???0.050??????0.100????0.200????0.417????0.588????0.769????1.538????2.500????3.3??????5.0??????10.0???20.0

1200???0.060??????0.120????0.240????0.500????0.706????0.923????1.846????3.000????4.0??????6.0??????12.0???24.0

1250????0.063??0.125???0.250???0.521???0.735???0.962???1.923???3.125???4.2????6.3????12.5????25.0

1300????0.065??0.130???0.260???0.542???0.765???1.000???2.000???3.250???4.3????6.5????13.0????26.0

1500????0.075??0.150???0.300???0.625???0.882???1.154???2.308???3.750???5.0????7.5????15.0????30.0

1700????0.085??0.170???0.340???0.708???1.000???1.308???2.615???4.250???5.7????8.5????17.0????34.0

2000????0.100??0.200???0.400???0.833???1.176???1.538???3.077???5.000???6.7????10.0???20.0????40.0

2400????0.120??0.240???0.480???1.000???1.412???1.846???3692????6.000???8.0????12.0???24.0????48.0

2500????0.125??0.250???0.500???1.042???1.471???1.923???3.846???6.250???8.3????12.5???25.0????50.0

3250????0.163??0.325???0.650???1.354???1.912???2.500???5.000???8.125???10.8???16.3???32.5????65.0

4000????0.200??0.400???0.800???1.667???2.353???3.077???6.154???10.000??13.3???20.0???40.0????80.0

5000????0.250??0.500???1.000???2.083???2.941???3.846???7.7?????12.5????16.7???25.0???50.0????100.0

6500????0.325??0.650???1.300???2.708???3.824???5.000???10.0????16.3????21.7???32.5???65.0????130.0

8500????0.425??0.850???1.700???3.542???5.000???6.538???13.1????21.3????28.3???42.5???85.0????170.0

10000???0.500??1.000???2.000???4.167???5.882???7.692???15.4????25.0????33.3???50.0???100.0???200.0

12000???0.600??1.200???2.400???5.000???7.059???9.231???18.5????30.0????40.0???60.0???120.0???240.0

20000???1.000??2.000???4.000???8.333???11.765??15.385??30.8????50.0????66.7???100.0??200.0???400.0

25000???1.250??2.500???5.000???10.417??14.706??19.231??38.5????62.5????83.3???125.0??250.0???500.0

35000???1.750??3.500???7.000???14.583??20.588??26.923??53.8????87.5????116.7??175.0??350.0???700.0

50000???2.500??5.000???10.000??20.833??29.412??38.462??76.9????125.0???166.7??250.0??500.0???1000.0

75000???3.750??7.500???15.000??31.250??44.118??57.692??115.4???187.5???250.0??375.0??750.0???1500.0

100000??5.000??10.000??20.000??41.667??58.824??76.923??153.8???250.0???333.3??500.0??1000.0??2000.0

DAE is lower than 0.2, or is lower than 5.

[0048] higher relative scale described herein shows that further the given dose of RPPX can comprise a certain amount of PPX impurity before surpassing described acceptable DAE.For instance, suppose the RPPX of 100% chiral purity, the NOAEL ratio of PPX is shown that table 3 shows that the RPPX of 25mg dosage causes at 20,000 o'clock 0.00125DAE of relative scale as RPPX in the research of dog.In theory, can add the PPX of extra 1.4mg and be not more than DAE, and before surpassing the preferred NOAEL dose value of PPX, can add extra 0.045mg PPX at the single dose MTD of PPX.These compositions will be 96% pure and mild 99.8% pure.In contrast, adopt relative binding affinity from document than 9, the 100% pure RPPX of 25mg will cause 2.78DAE, also be not enough to avoid adverse side effect even show 100% purity.Therefore, the present invention further provides the given dose of RPPX, described given dose tolerates PPX impurity in a small amount unexpectedly.

Other fixed literary compositions

[0049] also it must be noted that as herein with the accessory claim book in employed, singulative " (a) ", " one (an) " and " one (the) " comprise plural connotation, unless clearly point out in addition in the context.Therefore, for instance, the connotation of " salt " is that one or more plant organic solvent or equivalent well known by persons skilled in the art, or the like.

[0050] as used herein, term " about " is meant that the numerical value of used number adds deduct 10%.Therefore, about 50% scope that is meant 45%-55%.Unless otherwise defined, employed all technology of this paper or scientific terminology have the identical meanings of those of ordinary skills institute common sense.

[0051] as used herein, term " binding affinity ratio relatively " is meant that RPPX is at D ₂Or D ₃Binding affinity (IC on the dopamine receptor ₅₀The value) divided by PPX at D ₂And D ₃Binding affinity (IC on the dopamine receptor ₅₀Value).In some embodiments, described relative binding affinity ratio refers at D ₂IC on the acceptor ₅₀The ratio of value.In some embodiments, described relative binding affinity ratio refers at D ₃IC on the acceptor ₅₀The ratio of value.

[0052] as used herein, it is one of following that term " relative scale " refers to: 1) at RPPX to PPX at D ₂Or D ₃IC on the acceptor ₅₀The ratio of value; 2) at the ratio of RPPX to the MTD amount of PPX; Or 3) at the ratio of RPPX to the NOAEL dose value of PPX.

[0053] as used herein, term " controlled release " refers to discharge with controlled speed the formulation of medicine during the time period that prolongs, be preferably more than about 12 hours during the time period of described prolongation, more preferably about 24 hours.

[0054] as used herein, term " a daily dose value " refers to give every day or writes out a prescription to the amount of patient's medicine.This amount can give with unit dose repeatedly or with the single unit dose, and the single moment or a plurality of moment in during described one day give.Preferably, a described daily dose value gives with the improvement release of pharmaceutical compositions.

[0055] as used herein, term " dopamine active equivalent " (DAE) refers to be equivalent to the measurement of the PPX of 1mg in the activity on described dopamine receptor of the activity on the dopamine receptor.

[0056] as used herein " dose value " usually is equal to and can gives every day once, perhaps can give absorption of active ingredient several times (for example, unit dose is the mark of a daily dose of expectation) in one day.For instance, the placebo value of 0.5mg/ days PPX can be with 1 dosage of 0.5mg, 2 dosage of every dose of 0.25mg, and perhaps 4 dosage of every dose of 0.125mg give.The discrete amount that can show the therapeutic combination of the reactive compound that comprises scheduled volume with as used herein term " unit dose ".The amount of described active component generally equals and can be administered once every day, or administration in a day described absorption of active ingredient (for example, described unit dose is the mark of a daily dose of expectation) for several times.Can also show a total daily dose with described unit dose, a described total daily dose can be administered once or can be with the administration of mark easily of this dosage (for example every day, described unit dose is total daily dose that can give in the mode that part increases progressively, for example, for instance, half of described consumption or 1/3rd).

[0057] as used herein, term " enantiomter ", " stereoisomer " and " optical isomer " can use interchangeably, and refer to and contain asymmetric or chiral centre and be the molecule of mirror image that each other can not be overlapping.As used herein, term " chiral purity " or " enantiomeric pure " can be used for showing that described compound comprises at least 99.95% single optical isomer.Term " the enantiomerism enrichment " can be used for showing that at least 51% of described material is single enantiomter, removes nonnumeric being mentioned.Term as used herein " enantiomter enrichment " refers to the increase with respect to the amount of a kind of enantiomter of another kind of enantiomter." racemic " mixture is the mixture of the equal quantities of chiral molecules (R)-and (S)-enantiomter.

[0058] as used herein " prolong and discharge " and/or " continuing to discharge " referred to discharge medicine (or multiple medicine) during the time period that prolongs, make that the frequency of administration can be than the formulation of immediate release dosage form reduction, especially, permission is than as the medicine of regular dosage form (for example as solution or immediate release drug, the conventional solid dosage forms) formulation that reduces of twice at least on the dosed administration frequency of medicine.For instance, prolong the formulation that discharges and to discharge medicine approximately greater than 12 hours during preferably about 24 hours time period.Prolong herein to discharge to put interchangeably with the gentle slow release of lasting release and use.

[0059] as used herein, " medicine box " refer to one or more plant pharmaceutical compositions and be used to give or write out a prescription described one or more plant the explanation of compositions.Described explanation can be by product inset, explanation on the packing of one or more Chinese traditional medicine compositions, or any other explanation is formed.

[0060] as used herein, term

Refer to comprise the tablet of Pramipexole dihydrochloride, described Pramipexole dihydrochloride has chemical name, (S)-2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole two hydrochloric acid monohydrates.

[0061] as used herein " improvement discharge " refer to the drug release characteristics on the time period and/or locate selected, with realize conventional dosage forms (for example solution, ointment or Expidet) the treatment that can not provide or the formulation of purpose easily.The improvement of one or more active components discharges by reducing the simplification that a daily intaking amount of recommending allows patient's administration time table, improve deferring to of patient, and weaken adverse events, as with the relevant adverse events in high blood plasma peak.Improvement discharges pharmaceutical preparations and regulates one or more active components release in time of incorporating into, and comprise have controlled, that postpone, that continue, slowly or the release that prolongs, thereby can realize traditional formulation (for example solution or Expidet) the treatment that can not provide or purpose easily.Preferably, described improvement delivery formulations can discharge the medicine of treatment effective dose, RPPX at the time durations (preferably approximately greater than 12 hours, more preferably about twenty four hours) that prolongs.Controlled release, prolongation release and sustained release forms and combination thereof are the polytypes of improvement release dosage form.Except as otherwise noted, all such terms all use interchangeably.

[0062] as used herein, term " patient of first treatment " referred to before the patient who did not receive treatment (RPPX or PPX) or do not accept the titration scheme before accepting initial dose.

[0063] as used herein, term " neuroprotective agent " refers to any reagent that can prevent or slow down neurodegenerative process and/or can prevent nerve cell death.

[0064] term " patient " and " experimenter " be can exchange and can be used with mean any can be with the organism of the work of compounds for treating of the present invention.In this way, term " patient " and " experimenter " can include, but not limited to any non-human mammal, the primate or the mankind.In some embodiments, described " patient " or " experimenter " are mammals, for example mouse, rat, other rodents, rabbit, dog, cat, pig, ox, sheep, horse, primate or the mankind.In some embodiments, described patient or experimenter are adult, children or baby.In some embodiments, described patient or experimenter are human.

[0065] as used herein, term " pharmaceutically acceptable salt " means those and falls in the correct medical judgment scope those and be applicable to the salt that contacts with the mankind or more zootic tissue and do not have toxicity, excitant, allergy or the like improperly and match with rational benefit/risk ratio.The pharmaceutically acceptable salt of compound can be synthesized by traditional chemical method from parent compound, and described parent compound can comprise alkalescence or acidic moiety.Usually, such salt can by with the suitable alkali of the free acid of these compounds or alkali form and stoichiometric amount or acid in water or in organic solvent, or in the mixture of the two, react and prepare; Usually, the non-aqueous media as Anaesthetie Ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile is preferred.The tabulation of suitable salt can be at the pharmaceutical science of Remington, and the 20th edition, Lippincott Williams ﹠amp; Wilkins, Baltimore, Md., people (1977) pharmaceutical sciences (J.Pharm.Sciences) such as 704 pages (2000) and Berge the 6th volume finds in the 1-19 page or leaf.

[0066] term " pharmaceutical composition " should mean and comprise at least a composition of active components, thus can by at specific in the mammal (for example, not adding restriction, the mankind), effectively described composition is checked in result's research.Those of ordinary skills will be understood that and recognize and are suitable for determining whether active component has some technology based on effective result of the expectation of technical staff's needs.

[0067] as used herein, term " RPPX " refers to (the R)-enantiomter of Pramipexole, perhaps its pharmaceutically acceptable salt, preferably R (+) enantiomter of Pramipexole, perhaps its pharmaceutically acceptable salt." RPPX " can also comprise the hydrate of Pramipexole (R)-enantiomter, perhaps its pharmaceutically acceptable salt.In some embodiments, RPPX is RPPX two hydrochloric acid monohydrates.

[0068] as used herein, term " PPX " refers to Pramipexole ((S)-enantiomter) or its pharmaceutically acceptable salt." PPX " also can comprise Pramipexole hydrate, perhaps its pharmaceutically acceptable salt.

[0069] as used herein, term RPPX " salt " is any acid-adducting salt, is preferably pharmaceutically acceptable acid-adducting salt, includes, but not limited to contain halate, for example, for instance, hydrobromic acid, hydrochloric acid, hydrofluoric acid and hydriodate; Inorganic acid salt, for example, for instance, nitric acid, perchloric acid, sulfuric acid and phosphate; Organic acid salt, for example, for instance, sulfonate (methanesulfonic acid, trifluoromethane sulfonic acid, ethyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid), acetic acid, malic acid, fumaric acid, succinic acid, citric acid, benzoic acid, gluconic acid, lactic acid, mandelic acid, glactaric acid, pounce on acid (Pamoicacid), pantothenic acid, oxalic acid and maleate; And amino-acid salt, for example aspartic acid or glutamate.Described acid-adducting salt can be single acid or two acid-adducting salts, for example two halogen acid salts, dithionate, diphosphate or two organic acid salts.In all cases, described acid-adducting salt all is used as achiral reagent, its selection be not based on any desired or known specific optical isomer to product of the present invention have an effect or the priority that precipitates (for example, opposite with the tartaric specific use of D (+) in the prior art, described D (+) tartaric acid can preferentially precipitate RPPX).

[0070] as used herein, term " first day dose value " refers to give every day or writes out a prescription to the amount of the patient's of beginning Pramipexole treatment Pramipexole, and described patient had not before stood Pramipexole titration scheme.This amount can be with unit dose repeatedly or with the single unit dose, the single moment during one day or during one day a plurality of moment give.

[0071] as used herein " treatment effective dose " refers to cause biological or the reactive compound of medicine response or the amount of pharmaceutical agent that researcher, animal doctor, physician or other clinicians look in tissue, system, animal, individuality and the mankind, and described biology and medicine response comprise one or more following kinds: (1) prevent disease; For example, be easy to take a disease disease, discomfort or disorderly, but also do not experiencing or show this disease of prevention, discomfort or disorderly in the individuality of the pathology of this disease or disease, (2) inhibition disease; For example, suppress this disease, discomfort or disorder (promptly stop or slow down further developing of described pathology and/or disease) in the individuality of disease, discomfort or disorderly pathology or disease experiencing or show, and (3) alleviation disease; For example, relax this disease, discomfort or disorder (promptly reverse or reduce described pathology and/or disease) in the individuality of disease, discomfort or disorderly pathology or disease experiencing or show.

[0072] can take term " treatment " to mean specific disorder, disease or uncomfortable preventive treatment, with the alleviation of specific disorder, disease or the uncomfortable symptom that is associated and/or with the prevention of specific disorder, disease or the uncomfortable symptom that is associated.In some embodiments, described term refers to slow down described disorder, disease or uncomfortable process, perhaps alleviates and described specific disorder, disease or the uncomfortable symptom that is associated.In some embodiments, described term refers to slow down described disorder, disease or uncomfortable process.In some embodiments, described term refers to alleviate and described specific disorder, disease or the uncomfortable symptom that is associated.In some embodiments, described term refers to recover owing to specific disorder, disease or the uncomfortable function of damaging or losing.

[0073] can take term " development (trituration) " to show the method that a compound is solidified.Development comprise by stir, impact or similarly method stir described compound and form crystalline solid or precipitation up to described compound.This solid can play the effect of making the kind crystalline substance of residue compound in the solution, causes it to precipitate or crystallization from solution.

[0074] although can be used for the practice or the checking of embodiment of the present invention, preferable methods, equipment and material are described now to those any methods similar or of equal value described herein and material.

The improvement release of pharmaceutical compositions

[0075] R-(+) enantiomter of the Pramipexole of the employed high chiral purity of this paper, or RPPX is allowed the therapeutic combination that can have a wide single and daily dose scope.Therefore, in first aspect, the invention provides the improvement release of pharmaceutical compositions that comprises RPPX.Described composition can further comprise pharmaceutically acceptable carrier.

[0076] embodiment at amount, chiral purity, NOAEL, NOEL, DAE, NAE and the formulation of RPPX in the described improvement release composition described separately in this article for the simple reasons can any suitable combination combination.

[0077] in some embodiments, the amount of RPPX can from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the amount of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described consumption can for 10mg/kg/ days to 1,500mg/kg/ days, more preferably be 100mg/kg/ days to about 600mg/kg/ days.The amount of RPPX can be preferably about 50mg to about 5 in the described improvement release composition, 000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, in the described improvement release composition amount of RPPX can be from about 25mg to about 5,000mg, about 50mg is to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, or from about 400mg to about 5,000mg, from about 450mg to about 5,000mg, from about 200mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, or from about 400mg to about 3,000mg, from 450mg to about 3,000mg, or from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from about 450mg to about 1,000mg.In some embodiments, the amount of described RPPX is to about 900mg from about 600mg.Preferably, these dosage can be to be preferably more than about 12 hours, and provide during more preferably about twenty four hours in the improvement release of pharmaceutical compositions of release of RPPX dosage and be given.In some embodiments, the amount of RPPX be from about 50mg to about 5,000mg.In some embodiments, the amount of RPPX be from about 100mg to about 3,000mg.In some embodiments, the amount of RPPX is to about 1500mg from about 300mg.In some embodiments, the amount of RPPX be from about 500mg to about 1,000mg.In some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described improvement release composition is a solid oral dosage form.

[0078] described improvement release composition can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity of RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described improvement release composition.

[0079] in some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described improvement release composition is a solid oral dosage form.In some embodiments, described improvement release composition is a capsule.In some embodiments, described improvement release composition is a tablet.

[0080] on the other hand, the present invention relates at RPPX is the improvement release composition of chiral purity.In some embodiments, the amount of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the amount of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described consumption can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.In some embodiments, described composition with from about 50mg to about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, or from about 500mg to about 1, the dosage of the RPPX of 000mg is given.In some embodiments, described improvement release composition with from 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, to about 5,000mg is from about 200mg from 450mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1, the dosage of the RPPX of 000mg is given.In some embodiments, the amount of RPPX is to about 900mg from about 600mg.Preferably, these dosage can be to be to be preferably more than 12 hours and more preferably to be given at least about the improvement release of pharmaceutical compositions of the release that RPPX dosage is provided during the twenty four hours.These dosage preferably have 97% or bigger chemical purity and at RPPX 99.6% or bigger, 99.7% or bigger, 99.8% or bigger, 99.9% or bigger, preferably 99.95% or bigger and more preferably 99.99% or the prepared product of bigger chiral purity in.In preferred embodiments, described improvement release composition can have the chiral purity at RPPX100%.Described improvement release composition can also comprise carrier.Improvement release composition of the present invention can be taken orally, preferably with solid oral agent with more preferably can be the solid oral agent administration of capsule or tablet.In preferred embodiments, improvement release composition of the present invention can be configured to the tablet that is used for oral administration.

[0081] on the other hand, the present invention comprises the RPPX that treats effective dose so that a kind of improvement release composition to be provided.Described composition can also comprise pharmaceutically acceptable carrier.

[0082] in some embodiments, the RPPX of described treatment effective dose can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the RPPX of described treatment effective dose can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the RPPX of described treatment effective dose can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the RPPX of described treatment effective dose can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described consumption can be 10mg/ days to 1,500mg/ days more preferably 100mg/ days to 600mg/ days.In the described improvement release composition RPPX of treatment effective dose can be preferably about 50mg arrive about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, in the described improvement release composition RPPX of treatment effective dose can be approximately from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, to about 5,000mg is from about 200mg from 450mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the amount of RPPX makes from about 600mg to about 900mg.Preferably, these dosage can be to be to be preferably more than about 12 hours and more preferably to be given at least about the improvement release of pharmaceutical compositions of the release that RPPX dosage is provided during the twenty four hours.In some embodiments, the RPPX of described treatment effective dose is to about 5000mg from about 50mg.In some embodiments, the RPPX of described treatment effective dose is to about 3000mg from about 100mg.In some embodiments, the RPPX of described treatment effective dose is to about 1500mg from about 300mg.In some embodiments, the RPPX of described treatment effective dose is to about 1000mg from about 500mg.In some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described improvement release composition is a solid oral dosage form.

[0083] described improvement release composition can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, described chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described improvement release composition.

[0084] in some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described improvement release composition is a solid oral dosage form.In some embodiments, described improvement release composition is a capsule.In some embodiments, described improvement release composition is a tablet.

[0085] in additional one side, the invention provides a kind of release composition that improves and mainly form by the RPPX of treatment effective dose, wherein the chiral purity at RPPX is 99.9%, or higher.In some embodiments, the chiral purity at RPPX is 99.95% or higher.In some embodiments, the chiral purity at RPPX is 99.99% or higher.In some embodiments, the chiral purity at RPPX is 100%.

[0086] in some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described improvement release composition is a solid oral dosage form.In some embodiments, described improvement release composition is a capsule.In some embodiments, described improvement release composition is a tablet.

[0087] in additional one side, the present invention also provides a kind of improvement release composition, comprises the RPPX that treats effective dose and the PPX of placebo value.Described composition also can comprise pharmaceutically acceptable carrier.

[0088] in some embodiments, the amount of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the amount of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described consumption can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.The amount of RPPX can be preferably about 50mg to about 5 in the described improvement release composition, 000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, in the described improvement release composition amount of RPPX can be approximately from about 25mg to about 5,000mg, from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.Preferably, these dosage can be to be to be preferably more than about 12 hours and more preferably to be given at least about the improvement release of pharmaceutical compositions of the release that RPPX dosage is provided during the twenty four hours.In some embodiments, the amount of RPPX is to about 5000mg from about 50mg.In some embodiments, the amount of RPPX is to about 3000mg from about 100mg.In some embodiments, the amount of RPPX is to about 1500mg from about 300mg.In some embodiments, the amount of RPPX is to about 1000mg from about 500mg.In some embodiments, the amount of RPPX is to about 900mg from about 600mg.In some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described composition is a solid oral dosage form.

[0089] described improvement release composition can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described improvement release composition.

[0090] in embodiments, the described placebo value of PPX is the amount that is not more than about 1.0mg.In a more preferred embodiment, the placebo value of PPX is to be not more than about 0.75mg, about 0.5mg, about 0.25mg, the perhaps amount of about 0.125mg.In some embodiments, the placebo value of PPX is the amount that is not more than about 0.125mg.

[0091] in some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described improvement release composition is a solid oral dosage form.In some embodiments, described improvement release composition is a capsule.In some embodiments, described improvement release composition is a tablet.

[0092] on the other hand, the invention provides a kind of improvement release of pharmaceutical compositions, comprise the RPPX of the treatment effective dose that gives with unit dosage form and the PPX of placebo value.Preferred unit dosage form comprises the unit dosage form that is suitable for oral administration, including but not limited to, capsule, tablet or the like.Table 5 shows various exemplary.In each row of table 5, show be as composition at the function of the chiral purity of (the R)-enantiomter of Pramipexole, can be with the amount of the PPX of placebo value co-administered.The RPPX of described treatment effective dose can be preferably about 50mg to about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, the RPPX of treatment effective dose can be approximately from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, to about 5,000mg is from about 200mg from 450mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the RPPX of described treatment effective dose is to about 900mg from about 600mg.

[0093] the placebo value of PPX can be preferably lower than 1.0mg/ days, is lower than 0.5mg/ days and is lower than 0.125mg/ days.Therefore, as non-limiting embodiment, give R (+) enantiomter that patient's 500mg/ days dosage can have at Pramipexole as the single unit dose and be at least about 99.80% chiral purity, make the PPX of described placebo value can keep below 1.0mg/ days; More preferably about 99.90%, make the PPX of placebo value can keep below 0.5mg/ days; And more preferably about 99.975%, make the PPX of placebo value can keep below 0.125mg/ days.The embodiment at the RPPX that treats effective dose that this paper lists, the placebo value of PPX and the embodiment of chiral purity can any suitable combining form make up.Reference table 5 can use the chiral purity of combination of expectation of PPX of any RPPX that takes into account the treatment effective dose as this paper stated and placebo value and the combination of unit dose.

[0094] in some embodiments, described improvement release of pharmaceutical compositions is suitable for oral administration and comprises greater than the RPPX of the amount of 100mg and less than the PPX of the placebo value of about 0.125mg.Another embodiment preferred is to comprise greater than the RPPX of the amount of 250mg and less than the improvement release of pharmaceutical compositions that is suitable for oral administration of the PPX of the placebo value of about 0.125mg.Another preferred embodiment of the present invention are to comprise greater than the RPPX of the amount of 500mg and less than the improvement release of pharmaceutical compositions that is suitable for oral administration of the PPX of the placebo value of about 0.125mg again.The improvement release of pharmaceutical compositions that preferably is suitable for oral administration comprises tablet, capsule etc.

[0095] in some embodiments, described improvement release of pharmaceutical compositions is configured to the tablet that is suitable for oral administration and comprises greater than the RPPX of the amount of 50mg with less than the PPX of the placebo value of about 0.50mg, be preferably more than 100mg amount RPPX and less than the PPX of the placebo value of about 0.50mg, and more preferably greater than the RPPX of the amount of 250mg with less than the PPX of the placebo value of about 0.50mg.Another embodiment preferred is the improvement release of pharmaceutical compositions that is formulated as the tablet that is suitable for oral administration, comprises greater than the RPPX of the amount of 500mg with less than the PPX of the placebo value of about 0.50mg.

Table 5: based on the placebo value of the preferred PPX of the chiral purity of the composition of RPPX

The placebo value of preferred PPX can be to be lower than 1.0mg; More preferably be lower than 0.5mg and more preferably be lower than 0.125mg.

[0096] another embodiment of the invention is to be formulated as the improvement release of pharmaceutical compositions that is suitable for oral tablet, comprise greater than the RPPX of the amount of 50mg with less than the PPX of the placebo value of about 0.25mg, be preferably more than 100mg amount RPPX and less than the placebo value PPX of about 0.25mg, and more preferably greater than the RPPX of the amount of 250mg with less than the PPX of the placebo value of about 0.25mg.Another embodiment preferred is the improvement release of pharmaceutical compositions that is formulated as the tablet that is suitable for oral administration, comprises greater than the RPPX of the amount of 500mg with less than the PPX of the placebo value of about 0.25mg.

[0097] on the other hand, the invention provides a kind of improvement release composition, comprise the PPX of the RPPX that treats effective dose and no discernable ill-effect level (NOAEL) dose value.Described therapeutic combination also can comprise pharmaceutically acceptable carrier.

[0098] in some embodiments, the amount of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the amount of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described consumption can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.The amount of RPPX in described improvement release composition can be preferably about 50mg to about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, the amount of RPPX in described improvement release composition can be approximately from about 25mg to about 5,000mg, from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the amount of RPPX is to about 900mg from about 600mg.In some embodiments, the amount of RPPX is to about 5000mg from about 50mg.In some embodiments, the amount of RPPX is to about 3000mg from about 100mg.In some embodiments, the amount of RPPX is to about 1500mg from about 300mg.In some embodiments, the amount of RPPX is to about 1000mg from about 500mg.In some embodiments, described composition is suitable for that oral administration works as.In some embodiments, described improvement release composition is a solid oral dosage form.

[0099] described improvement release composition can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described improvement release composition.

[00100] in some embodiments, the horizontal dose value of no discernable ill-effect of PPX is less than about 4.50mg.In some embodiments, the no discernable ill-effect level amount of described PPX is less than about 0.15mg.In some embodiments, the no discernable ill-effect level amount of described PPX is less than about 0.15mg.

[00101] in some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described improvement release composition is a solid oral dosage form.In some embodiments, described improvement release composition is a capsule.In some embodiments, described improvement release composition is a tablet.

[00102] in additional one side, the invention provides a kind of improvement release of pharmaceutical compositions, comprise the RPPX and the NOAEL dose value of the treatment effective dose that gives with unit dosage form.Preferred unit dosage form comprises those that are suitable for oral administration, including but not limited to, capsule, tablet or the like.Table 6 shows various exemplary.In each row of table 6, show be as described improvement release composition at R (+) the enantiomter chiral purity function of Pramipexole, can be with the amount of the PPX of NOAEL dose value co-administered.The treatment effective dose of RPPX can be preferably about 50mg to about 5,000mg, preferably from about 100mg to about 3,000mg, preferably from about 300mg to about 1,500mg, more preferably from about 500mg to about 1,000mg.In some embodiments, the treatment effective dose of RPPX can be approximately from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the amount of RPPX is to about 900mg from about 600mg.

[00103] the NOAEL dosage of PPX can be preferably lower than 4.5mg, is preferably lower than 1.5mg, or more preferably is lower than 0.15mg.Therefore, as non-limiting embodiment, embodiment of the present invention can be to give patient's 1 as the single unit dose, 500mg/ days dosage, described single unit dose have at R (+) enantiomter of Pramipexole at least about 99.967% chiral purity, make the no bad dosage of PPX can remain on below the 0.50mg/ agent.Alternately, give patient's 1 as 3 independent 500mg dosage, 500mg/ days dosage can have and is at least about 99.90% chiral purity at RPPX, makes the no bad dosage of PPX can remain on the 0.50mg/ agent or below 1.5mg/ days.At the treatment effective dose of RPPX, the NOAEL dose value of PPX, and the embodiment of the chiral purity enumerated of this paper can be with any suitable combination combination.Reference table 6 can adopt the combination of any chiral purity and unit dose, and its expectation that takes into account the PPX of the RPPX of the treatment effective dose of stating as this paper and no ill-effect dose value is made up.

[00104] in some embodiments, described improvement release of pharmaceutical compositions is configured to the tablet that is suitable for oral administration, and comprise greater than the RPPX of the amount of 50mg with less than the PPX of the NOAEL dose value of about 0.05mg, be preferably more than 100mg amount RPPX and less than the PPX of the NOAEL dose value of about 0.15mg, and the RPPX of preferred amount greater than 250mg and less than the PPX of the NOAEL dose value of about 0.15mg.In some embodiments, described improvement release of pharmaceutical compositions is configured to the tablet that is suitable for oral administration, and comprises greater than the RPPX of the amount of 500mg with less than the PPX of the NOAEL dose value of about 0.15mg.

Table 6: based on the horizontal dosage of no discernable ill-effect at the preferred PPX of the chiral purity of RPPX of improvement release composition

Preferred no discernable ill-effect level (NOAEL) dose value of PPX can be lower than 1.5mg; Be preferably lower than 0.15mg.

[00105] in some embodiments, the invention provides the improvement release composition that is used for as neuroprotective agent, comprise the PPX of the treatment effective dose of the RPPX that treats effective dose.Described improvement release composition can further comprise pharmaceutically acceptable carrier.Described improvement release composition can be useful on to the treatment of diseases that can be alleviated by the effect of neuroprotective agent.The embodiment that the present invention adds is the therapeutic combination as neuroprotective agent, comprises RPPX that treats effective dose and the PPX that treats effective dose.Described improvement release composition can further comprise pharmaceutically acceptable carrier.Described therapeutic combination can be useful in to the treatment of diseases relevant with nerve degeneration and nerve cell death.

[00106] in one embodiment, the improvement release composition of RPPX can be used in adult and children's recovery or improve nerve, retina and muscle function.In addition, the composition of described RPPX can be used for the treatment of nerve degenerative diseases, perhaps other diseases relevant with the oxidative stress of mitochondria dysfunction or increase.In some embodiments, the composition of described RPPX can be treated neurological dementia, nervus retrogression action disorder and incoordination, epilepsy, motor neuron disorder or disease and struvite demyelinating disorder in adult and children.Composition of the present invention also can be useful in the treatment of other disorders of not enumerating in this article, and any in the present invention enumerating of providing all only be for exemplary purpose, and right and wrong are determinate.

[00107] in some embodiments, comprise that the improvement release composition of RPPX can be effective as the inhibitor of the inhibitor of oxidative stress, lipid peroxidation in the detoxifcation of oxygen atomic group and mitochondrial function normalization.Oxidative stress may be caused by the increase of oxygen and other free radicals, and has been relevant with fatal neurological sexual disorder amyotrophic lateral sclerosis (ALS).ALS is a kind of carrying out property neurological sexual disorder, relates to cerebral cortex, the motor neuron of brain stem and spinal cord.All ALS patient's about 10% is the familial case, and wherein 20% has sudden change on superoxide dismutase 1 (SOD-1) gene.Described SOD-1 enzyme may be brought into play key effect in the morbidity of family's amyotrophic lateral sclerosis (FALS) with in carrying out.Nearest research also will be relevant with ALS too early neuronal death with cause the chondriogen of the parafunctional sudden change of production of energy approach in the mitochondria to interrelate.

[00108] the improvement release composition that comprises RPPX also may be effective in to the treatment of AMD.Therefore, embodiment of the present invention can be to be suitable for whole body administration, dosing eyes or to the improvement release composition that comprises RPPX of eyes topical.

[00109] therefore, the present invention improve the neuroprotection of release composition can be at least in part from the ability of (the R)-enantiomter of Pramipexole, by at least a prevention nerve cell death of three kinds of mechanism.The first, (the R)-enantiomter of Pramipexole may be able to reduce the formation of active oxygen in the cell that impaired mitochondria energy produces.The second, (the R)-enantiomter of Pramipexole can partly be recovered the potential of the mitochondrial membrane that reduces, described potential and alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis disease association.The 3rd, (the R)-enantiomter of Pramipexole can be blocked by alzheimer's disease, the cell death approach that the pharmacology model of Parkinson's disease and amyotrophic lateral sclerosis and injury of mitochondria produces.

[00110] the improvement release composition as the RPPX of active agent that comprises of these several embodiments can be effective as the inhibitor of oxidative stress, the inhibitor of lipid peroxidation in oxygen atomic group detoxifcation and mitochondrial function normalization.In addition, it may be that effectively described degenerative disease may influence heart flesh and striated muscle and retinal tissue in to the treatment of impaired motion function and degenerative disease.Therefore, it for example may be effective in the treatment of ALS, Parkinson's disease and alzheimer's disease and macular degeneration at nerve degenerative diseases.

[00111] another embodiment of the invention is the main improvement release composition of being made up of the PPX of RPPX that treats effective dose and placebo value.Another embodiment of the present invention is the main improvement release composition of being made up of the PPX of RPPX that treats effective dose and NOAEL dose value.The improvement release composition that another embodiment of the present invention is made up of the PPX of treatment RPPX of effective dose and placebo value.These compositions can preferably be treated or pharmaceutical composition.The improvement release composition that another embodiment of the present invention is made up of the PPX of treatment RPPX of effective dose and NOAEL dose value.These compositions can preferably be treated or pharmaceutical composition.

[00112] on the other hand, the invention provides a kind of improvement release tablet, comprise RPPX and the PPX that is not more than about 4.5mg at least about 100mg.In some embodiments, described tablet comprises the RPPX of about 150mg.In some embodiments, described tablet comprises the RPPX of about 200mg.In some embodiments, described tablet comprises the RPPX of about 250mg.In some embodiments, described tablet comprises the RPPX of about 500mg.In some embodiments, described tablet comprises the RPPX of about 1000mg.In some embodiments, described tablet comprises the PPX that is not more than 3.0mg.In some embodiments, described tablet comprises the PPX that is not more than 0.1mg.In some embodiments, described tablet comprises the PPX that is not more than 0.9mg.In some embodiments, described tablet comprises the PPX that is not more than 0.6mg.In some embodiments, described tablet comprises the PPX that is not more than 0.375mg.In some embodiments, described tablet also comprises pharmaceutically acceptable carrier.

[00113] in some embodiments, described improvement release tablet comprises the RPPX and the PPX that is not more than about 3.0mg of about 150mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.1mg of about 150mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.9mg of about 150mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.6mg of about 150mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.375mg of about 150mg.

[00114] in some embodiments, described improvement release tablet comprises the RPPX and the PPX that is not more than about 3.0mg of about 200mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.1mg of about 200mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.9mg of about 200mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.6mg of about 200mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.375mg of about 200mg.

[00115] in some embodiments, described improvement release tablet comprises the RPPX and the PPX that is not more than about 3.0mg of about 250mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.1mg of about 250mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.9mg of about 250mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.6mg of about 250mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.375mg of about 250mg.

[00116] in some embodiments, described improvement release tablet comprises the RPPX and the PPX that is not more than about 3.0mg of about 500mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.1mg of about 500mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.9mg of about 500mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.6mg of about 500mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.375mg of about 500mg.

[00117] in some embodiments, described improvement release tablet comprises the RPPX and the PPX that is not more than about 3.0mg of about 1000mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.1mg of about 1000mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.9mg of about 1000mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.6mg of about 1000mg.In some embodiments, described tablet comprises the RPPX and the PPX that is not more than about 0.375mg of about 1000mg.

[00118] described improvement release tablet can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described tablet.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described tablet.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described tablet.

[00119] on the other hand, the invention provides the agent of a kind of improvement release capsule, comprise RPPX and the PPX that is not more than about 4.5mg at least about 100mg.In some embodiments, described capsule comprises the RPPX of about 150mg.In some embodiments, described capsule comprises the RPPX of about 200mg.In some embodiments, described capsule comprises the RPPX of about 250mg.In some embodiments, described capsule comprises the RPPX of about 500mg.In some embodiments, described capsule comprises the RPPX of about 1000mg.In some embodiments, described capsule comprises the PPX that is not more than 3.0mg.In some embodiments, described capsule comprises the PPX that is not more than 0.1mg.In some embodiments, described capsule comprises the PPX that is not more than 0.9mg.In some embodiments, described capsule comprises the PPX that is not more than 0.6mg.In some embodiments, described capsule comprises the PPX that is not more than 0.375mg.In some embodiments, described capsule also comprises pharmaceutically acceptable carrier.

[00120] in some embodiments, the agent of described improvement release capsule comprises the RPPX and the PPX that is not more than about 3.0mg of about 150mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.1mg of about 150mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.9mg of about 150mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.6mg of about 150mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.375mg of about 150mg.

[00121] in some embodiments, the agent of described improvement release capsule comprises the RPPX and the PPX that is not more than about 3.0mg of about 200mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.1mg of about 200mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.9mg of about 200mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.6mg of about 200mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.375mg of about 200mg.

[00122] in some embodiments, the agent of described improvement release capsule comprises the RPPX and the PPX that is not more than about 3.0mg of about 250mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.1mg of about 250mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.9mg of about 250mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.6mg of about 250mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.375mg of about 250mg.

[00123] in some embodiments, the agent of described improvement release capsule comprises the RPPX and the PPX that is not more than about 3.0mg of about 500mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.1mg of about 500mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.9mg of about 500mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.6mg of about 500mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.375mg of about 500mg.

[00124] in some embodiments, the agent of described improvement release capsule comprises the RPPX and the PPX that is not more than about 3.0mg of about 1000mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.1mg of about 1000mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.9mg of about 1000mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.6mg of about 1000mg.In some embodiments, described capsule comprises the RPPX and the PPX that is not more than about 0.375mg of about 1000mg.

[00125] agent of described improvement release capsule can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described capsule.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described capsule.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described capsule.

[00126] in further one side, the invention provides a kind of improvement release of pharmaceutical compositions, comprise at least about the RPPX of 25mg with less than about 4.5 dopaminergic activity equivalents (" DAE ").Table 1 shows the RPPX at 25mg dosage, as the particular chiral purity of RPPX in the medicament and the DAE of the function of relative binding affinity ratio.

[00127] in some embodiments, described improvement release of pharmaceutical compositions comprises less than about 1.5 dopaminergic activity equivalents (DAE).In some embodiments, described improvement release of pharmaceutical compositions comprises less than about 0.15 dopaminergic activity equivalent.These DAE values are to be obtained by the no discernable ill-effect level as the RPPX of this paper discussion.In some embodiments, described composition has the DAE of the DAE that calculates less than the placebo value by described MTD value or PPX.With reference to the placebo value of PPX, in some embodiments, it is about 1.0 that described DAE dosage is no more than, and is no more than approximately 0.75, is no more than approximately 0.5, is no more than approximately 0.25, or is no more than about 0.125.With reference to the MTD value, described improvement release composition can have and is lower than 4.5, is lower than 0.9, perhaps is lower than 0.6 DAE.

[00128] in some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 50mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 75mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 125mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 150mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 200mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 250mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 300mg.In some embodiments, described pharmaceutical composition comprises the RPPX at least about 400mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 500mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 600mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 750mg.In some embodiments, described improvement release of pharmaceutical compositions comprises the RPPX at least about 1000mg.

[00129] in some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described composition is a solid oral dosage form.In some embodiments, described pharmaceutical composition is a tablet.In some embodiments, described pharmaceutical composition is a capsule.

[00130] in some embodiments, the amount of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the amount of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the amount of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described consumption can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.The amount of RPPX in described improvement release composition can be preferably about 50mg to about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, the amount of RPPX in described improvement release composition can be from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, to about 5,000mg is from about 200mg from 450mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the amount of RPPX is to about 900mg from about 600mg.In some embodiments, the amount of RPPX is to about 5000mg from about 50mg.In some embodiments, the amount of RPPX is to about 3000mg from about 100mg.In some embodiments, the amount of RPPX is to about 1500mg from about 300mg.In some embodiments, the amount of RPPX is to about 1000mg from about 500mg.In some embodiments, described composition is suitable for oral administration.In some embodiments, described composition is a solid oral dosage form.

[00131] described improvement release composition can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described improvement release composition.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described improvement release composition.

[00132] on the other hand, the invention provides first day dosage at least about the RPPX of the RPPX of 25mg.In some embodiments, described first day dosage comprises the RPPX at least about 50mg.In some embodiments, described first day dosage comprises the RPPX at least about 75mg.In some embodiments, described first day dosage comprises the RPPX at least about 125mg.In some embodiments, described first day dosage comprises the RPPX at least about 150mg.In some embodiments, described first day dosage comprises the RPPX at least about 200mg.In some embodiments, described first day dosage comprises the RPPX at least about 300mg.In some embodiments, described first day dosage comprises the RPPX at least about 400mg.In some embodiments, described first day dosage comprises the RPPX at least about 500mg.In some embodiments, described first day dosage comprises the RPPX at least about 600mg.In some embodiments, described first day dosage comprises the RPPX at least about 750mg.In some embodiments, described first day dosage comprises the RPPX at least about 1000mg.In some embodiments, described first day dosage comprises the RPPX from about 600mg to about 900mg.

[00133] in some embodiments, the first day dose value of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the first day dose value of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the first day dose value of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the first day dose value of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described first day dose value can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.The first day dose value of RPPX can be preferably about 50mg to about 5 in the described improvement release composition, 000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, in the described improvement release composition first day dose value of RPPX can be approximately from about 25mg to about 5,000mg, from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the first day dose value of RPPX is to about 900mg from about 600mg.In some embodiments, the first day dose value of RPPX is to about 5000mg from about 50mg.In some embodiments, the first day dose value of RPPX is to about 3000mg from about 100mg.In some embodiments, the first day dose value of RPPX is to about 1500mg from about 300mg.In some embodiments, the first day dose value of RPPX is to about 1000mg from about 500mg.

[00134] described improvement release composition can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described composition.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described composition.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described composition.

[00135] in some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described composition is a solid oral dosage form.In some embodiments, described pharmaceutical composition is a tablet.In some embodiments, described pharmaceutical composition is a capsule.

[00136] on the other hand, the invention provides and comprise from accounting for described prescription from about 20% microcrystalline cellulose to the amount of about 50% weight; Account for described prescription from about 10% mannitol to the amount of about 30% weight; Account for described prescription from about 2% Crospovidone to the amount of about 6% weight; Account for described composition and discharge pharmaceutical formulation from about 0.01% to the dolomol of the amount of about 2% weight and the improvement of RPPX.In some embodiments, described improvement release of pharmaceutical compositions comprises and accounts for described prescription from about 20% thinner to the amount of about 50% weight; Alternatively, account for second thinner of described prescription from the amount of about 10% to 30% weight; Alternatively, account for the disintegrant of about 2% to 6% the amount of described prescription; Alternatively, account for the lubricant and the RPPX of described composition from about 0.01% to about 2%.In some embodiments, described improvement release of pharmaceutical compositions comprises microcrystalline cellulose, mannitol, cross-linked carboxymethyl cellulose sodium, dolomol, or its combination.In some embodiments, described pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol or its combination, and further comprises cross-linked carboxymethyl cellulose sodium or dolomol, perhaps its combination alternatively.

[00137] described improvement release formulation can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described prescription.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described prescription.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described prescription.

[00138] in the improvement release formulation amount of RPPX can be preferably about 50mg arrive about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, in the described prescription first day dose value of RPPX can be from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, to about 5,000mg is from about 200mg from 450mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the prescription of described RPPX is to about 900mg from about 600mg.

[00139] in some embodiments, the invention provides a kind of improvement release of pharmaceutical compositions, comprise from accounting for described composition from about 20% amount microcrystalline cellulose to about 50% weight; Account for described composition from about 10% mannitol to the amount of about 30% weight; Account for described composition from about 2% Crospovidone to the amount of about 6% weight; Account for described composition from about 0.01% dolomol to the amount of about 2% weight, and the pharmaceutical composition of RPPX.In some embodiments, described improvement release composition is suitable for oral administration.In some embodiments, described composition is a solid oral dosage form.

[00140] described improvement release composition can have at RPPX and is at least 99.5%, and preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or at least 99.99% chiral purity more preferably.In some embodiments, the chiral purity at RPPX is 100%.In some embodiments, to have at RPPX be 99.9% or higher chiral purity to described composition.In some embodiments, to have at RPPX be 99.95% or higher chiral purity to described composition.In some embodiments, to have at RPPX be 99.99% or higher chiral purity to described composition.

[00141] amount of RPPX can be preferably about 50mg to about 5 in the described improvement release composition, 000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, from about 500mg to about 1,000mg.In some embodiments, in the described improvement release composition first day dose value of RPPX can be approximately from about 25mg to about 5,000mg, from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg, to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the amount of RPPX is to about 900mg from about 600mg.In some embodiments, the present invention also provides and comprises having about 25 neuroprotective activity equivalents, and less than the improvement release of pharmaceutical compositions that comprises RPPX of about 4.5 dopaminergic activity equivalents.In some embodiments, described improvement release of pharmaceutical compositions has less than about 1.5 dopaminergic activity equivalents.In some embodiments, described improvement release of pharmaceutical compositions has less than about 0.15 dopaminergic activity equivalent.

[00142] in some embodiments, described improvement release of pharmaceutical compositions has at least about 50, at least about 75, at least about 125; at least about 150, at least about 200, at least about 300, at least about 400; at least about 500, at least about 750, at least about 750, or at least about 100 neuroprotective activity equivalents.In some embodiments, described improvement release of pharmaceutical compositions has from about 50 to about 5,000, from about 100 to about 3,000; from about 300 to about 1,500, from about 500 to about 1,000; from about 25 to about 5,000, from about 100 to about 5,000; from about 200 to about 5,000, from about 250 to about 5,000; from about 300 to about 5,000, from about 400 to about 5,000; from 450 to about 5,000, from about 200, to about 3; 000, from about 250 to about 3,000, from about 300 to about 3; 000, from about 400 to about 3,000, from 450 to about 3; 000, from about 100 to about 1,000, from about 200 to about 1; 000, from about 250 to about 1,000, from about 300 to about 1; 000, from about 400 to about 1,000, from about 600 to about 1; 000, from 450 to about 1,000, or from about 600 to about 900 neuroprotective activity equivalents.

[00143] in some embodiments, described improvement release of pharmaceutical compositions has from about 50 to about 5,000 neuroprotective activity equivalents; And less than from about 1.5 dopaminergic activity equivalents.In some embodiments, described pharmaceutical composition has about 100 to about 3,000 neuroprotective activity equivalents; And less than from about 1.5 dopaminergic activity equivalents.In some embodiments, described pharmaceutical composition has about 200 to about 3,000 neuroprotective activity equivalents; And less than from about 1.5 dopaminergic activity equivalents.In some embodiments, described pharmaceutical composition has about 300 to about 1,500 neuroprotective activity equivalent; And less than from about 1.5 dopaminergic activity equivalents.In some embodiments, described pharmaceutical composition has about 500 to about 1,000 neuroprotective activity equivalent; And less than from about 1.5 dopaminergic activity equivalents.In some embodiments, described pharmaceutical composition has about 50 to about 5,000 neuroprotective activity equivalents; And less than from about 0.15 dopaminergic activity equivalent.In some embodiments, described pharmaceutical composition has about 100 to about 3,000 neuroprotective activity equivalents; And less than from about 0.15 dopaminergic activity equivalent.In some embodiments, described pharmaceutical composition has about 200 to about 3,000 neuroprotective activity equivalents; And less than from about 0.15 dopaminergic activity equivalent.In some embodiments, described pharmaceutical composition has about 300 to about 1,500 neuroprotective activity equivalent; And less than from about 0.15 dopaminergic activity equivalent.In some embodiments, described pharmaceutical composition has about 500 to about 1,000 neuroprotective activity equivalent; And less than from about 0.15 dopaminergic activity equivalent.

[00144] in some embodiments, described improvement release of pharmaceutical compositions is a solid oral dosage form.In some embodiments, described pharmaceutical composition is a tablet.In some embodiments, described pharmaceutical composition is a capsule.

[00145] prolongs delivery formulations.Many active pharmaceutical agent comprise medicine and prodrug, have been configured to the oral delivery formulation, provide effectively lasting release (or be called slow release or prolong release) of this reagent during a time period, to allow administration once a day.The known system that is used to prepare this formulation relates to and comprises that described reagent is scattered in the skeleton of hydrophilic polymer wherein (matrix); Described reagent is released to intestines and stomach with the dissolving or the corrosion of skeleton during a time period.The sustained release forms that comprises such skeleton system is prepared as compressed tablets easily, is described as " matrix tablet " usually.

[00146] in water, have high-dissolvability relatively, about for instance 10mg/ml or bigger solvability, medicine and prodrug, bring challenges for the formulator be desirable to provide sustained release forms, and the big more challenge of solvability is also big more.These challenges are illustrated in the example of Pramipexole dihydrochloride well, and the dihydrochloride of described Pramipexole has the solvability of about 200mg/ml in water.

[00147] at the Pramipexole dihydrochloride tablet that discharges immediately every day three dosed administration schemes by well tolerable, if but scheme once a day if possible, deferring to of patient will improve greatly.

[00148] described prolongation delivery formulations is prepared as diffusion or osmosis system usually, for instance, as " science of Lei Mingdun---pharmacy with put into practice (Remington-The Science and Practice of Pharmacy) " (the 20th edition, Lippincott Williams; Wilkins, Baltimore, Md., 2000) described in.Diffusion system typically is made up of two class devices, storage device and frame device, and both all are known in this area and are described.Described frame device prepares by with slow dissolved polymers carrier medicine being pressed into tablet form usually.The material of three kinds of main types that is used for the preparation of frame device is insoluble plastics, hydrophilic polymer, and aliphatic compound.Plastic skeleton comprises, but is not limited to, methyl acrylate-methylmethacrylate copolymer, polyvinyl chloride and polyethylene.Hydrophilic polymer comprises, but is not limited to, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and CARBOPOL934, and PEO.Aliphatic compound comprises, but is not limited to, and various waxes are Brazil wax (carnaubawax) and glycerol tristearate for example.

[00149] alternately, the prolongation delivery formulations can use osmosis system or prepare by using semi-transparent dressing to described formulation.In the latter's situation, the drug release characteristics of expectation can be by reaching in conjunction with hyposmosis and high infiltration coating material in the proper ratio.

[00150] an exemplary prolongation delivery formulations that can be used in some embodiment of improvement delivery formulations of RPPX of the present invention is open in the US publication 20050226926 that is entitled as " the continuous release tablet composition of Pramipexole (Sustained-release tablet composition ofpramipexole) ", but the disclosure has been described the lasting release of pharmaceutical compositions of the tablet form of oral delivery, comprise the water soluble salt that is dispersed in the PPX in the skeleton, described skeleton is included in solid portion and represents the hydrophilic polymer of described tablet and have the cm at least about 0.15kN ^-2The starch of tensile strength, the disclosure is incorporated into this paper by integral body by reference.Another the exemplary prolongation delivery formulations of some embodiment of improvement delivery formulations that can be used for RPPX of the present invention is open in the US publication 20060051419 that is entitled as " prolongation that contains Pramipexole or its pharmaceutically acceptable salt discharges piller prescription (Extended release pellet formulation containing pramipexole or a pharmaceutically acceptablesalt thereof) ", the disclosure has been described the prolongation that contains PPX or its pharmaceutically acceptable salt and has been discharged the piller prescription, its manufacturing and using method, described disclosing incorporated into this paper by integral body by reference.

[00151] it is believed that the lasting liberation port oral dosage form that provides so especially expects, described lasting liberation port oral dosage form provides drug with substantially invariable rate of release during a time period that prolongs.In this way, for many medicines, its blood concentration begins initially to rise during the time period of a weak point because of drug, and continues to keep substantially constant during a time period that prolongs with constant rate of speed because of drug then.For many medicines, this substantially invariable blood concentration is relevant with substantially invariable drug effect on lasting treatment cycle.In addition, owing to avoided initial phase peak blood concentration over the ground, side effect no longer is a problem.Correspondingly, the advantage of constant release dosage form comprises and has reduced the medicament quantity that certain hour need be given, and described medicine better expectation and non-expectation pharmacological action balance are provided.

[00152] osmotic dosage form especially, significantly success in the constant release that medicine was provided during the time period that prolongs.Osmotic dosage form, usually, utilize osmotic pressure with, pass through semipermeable wall at least in part, generation is used for the driving force of absorption fluids to the interval that forms, and described semipermeable wall allows fluid freely to spread, and does not allow medicine or one or more osmotic agent (if any) freely to spread.The substantially invariable speed of drug can be by designing described system so that relatively constant osmotic pressure to be provided, with have at the suitable mechanism of leaving away of described pharmaceutical preparation (exit methods) to allow described medicine bosom friend being released corresponding to the absorbed speed of fluid and reaching, the absorbed speed of described fluid is because constant relatively osmotic pressure.The remarkable advantage of osmosis system is that operation does not rely on pH, therefore and run through that the speed with infiltration decision (osmotically-determined) continues during time period of whole prolongation, even described formulation is through intestines and stomach and meet with the different microenvironment with significantly different pH values.

[00153] shockingly simply but efficiently permeability apparatus be known in the art, described permeability apparatus comprises the medicine with mixed with excipients, alternatively betwixt every in comprise one or more and plant osmotically active components.Although effective for many medicines, the rate of release in these devices is decay in time usually, and sending fully of described drug loading may do not taken place.The more accurate type of permeability apparatus comprises two component layers in the interval that is formed by semi-transparent wall.Component layers comprises the medicine with mixed with excipients, comprise one or more alternatively and plant the osmotically active component, but described osmotically active component will form the delivering drugs preparation in rising at interval, and second component layers comprise that one or more plant osmotically active components, and not comprise medicine.In described second component layers one or more are planted the osmotically active component and are typically comprised short osmopolymer (osmopolymerys), described short osmopolymer has macromolecule relatively, and performance " swelling " when absorption fluids, make these components that the release by the mechanism of leaving away of pharmaceutical preparation not take place.Described second component layers is called as " advancing (push) " layer, because when absorption fluids, but the short osmopolymer swelling of described one or more kinds is also pushed the delivering drugs preparation of described first component layers, discharges with substantially invariable speed to help described pharmaceutical preparation thus.Said apparatus from, for instance, below the United States Patent (USP) that has by Alza company known: U.S. Patent number 4,327,725; 4,612,008; 4,783; 337; And 5,082,668, and each of described patent is incorporated into this paper by integral body by reference.The appropriate formulations of other employings, for instance, the Oros of Alza company ^TMContinue the release tech platform and exist, for instance, U.S. Patent number 6,919,373; 6,930,129; 5,024,843; 5,091,190; 5,545413; 5,591,454; 5,674,895; 5,840,754; 5,912,268; 6,262,115; And be described in 6,919,092, described platform can be useful in the improvement delivery formulations of RPPX.

[00154] device with different pharmaceutical releasing mechanism described above can be combined into the final formulation that comprises single or multiple unit.Repeatedly the embodiment of unit comprises multilayer tablet and the capsule that contains tablet, globule (bead), particulate (granule) etc.

[00155] release portion (portion) can discharge the method that immediate release layer is used at core top (top) in described prolongation by using dressing or pressing process immediately, perhaps with unit system repeatedly, for example contain the method that prolongs and discharge the capsule of globule immediately, be added to described prolongation delivery systme.

[00156] the prolongation release tablet that contains hydrophilic polymer by this area usually known technology be produced for example directly compacting, wet granulation, or dry granulation process.Its preparation is usually incorporated polymer, thinner, adhesive and lubricant and active pharmaceutical ingredient into.Thinner commonly used comprises the inert powder material, for example many different types of starch, and powdered cellulose, crystallization and microcrystalline cellulose especially, carbohydrate is fructose, mannitol and sucrose for example, grain flour and similar edible powder any.Typical thinner comprises, for instance, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulphate, mineral salt is sodium chloride and powdered carbohydrate for example.The powdered cellulose derivative also is useful.Typical tablet binder comprises for example starch, and gelatin and carbohydrate be lactose for example, the material of fructose and sucrose.Natural with synthetic glue comprises gum Arabic (acacia), alginate (alginates), and methylcellulose, and polyvinylpyrrolidine also can be used.Polyethylene glycol, hydrophilic polymer, ethyl cellulose and wax class also can be used as adhesive.Lubricant is essential in tablet formulation, is bonded in the mould to prevent described tablet and drift.Described lubricant is selected from as talcum, dolomol and calcium stearate, the solid of the cunning of stearic acid and hydrogenated vegetable oil.

[00157] the prolongation release tablet that contains wax material uses the methods known in the art preparation usually, for example directly mixed method, congealing method, and water dispersion.In congealing method, described medicine is mixed with wax material and is congealed or congeal by spraying, sieved, and processing.

[00158] improvement or prolongation discharge preparation capable of permeating skin (transdermal formulation).The transdermal formulation is particularly useful for the timing release (timed-release) and lasting release of active agent.Be used to send the transdermal system of diversified medicine or other beneficial agents in U.S. Patent number 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,144,317; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,698,062; 4,704,282; 4,725,272; 4,781,924; 4,788,062; 4,816,258; 4,849,226; 4,904,475; 4,908,027; 4,917,895; 4,938,759; 4,943,435; 5,004,610; 5,071,656; 5,122,382; 5,141,750; 5,284,660; 5,314,694; 5,342,623; 5,411,740; 5,635,203,20080026043; And be described in 20080020028, described patent is incorporated into this paper by integral body by reference.Modal transdermal formulation is to use the diffusion-driven transdermal system form of emplastrum (especially with) of fluid reservoir (fluid reservoir) or pressure sensitive adhesive decentralized (drug-in-adhesive) shell system.Other transdermal formulation comprises, but is not limited to, topical gel, and washing lotion, ointment, mucous membrane system and device, and ion imports (electrodiffusion) delivery system.Referring to, for instance, authorize people's such as Aungst U.S. Patent number 4,626,539, disclose and it is said the useful pharmaceutical composition of transdermal delivery of opium to the mammal circulatory system; Authorize people's such as Chien U.S. Patent number 4,806,341, disclose and comprised backing layer, adhesive polymer layer, and the adjoining course that contains the solid polymer skeleton of morphinan narcotic analgesic or antagonist, and the Transdermal absorption dosage unit of skin penetration promoter; And the U.S. Patent number 5,069,909 of authorizing people such as Sharma, disclose and be used to use transdermal delivery from the continue medication method of uncle's fourth coffee of the compound emplastrum of lamination.The U.S. Patent number 5,830,497 of authorizing people such as Yamanaka discloses as the ointment composition that is used for through skin (percutaneosu) absorption type, and described composition contains (1) one alkaline drug and acidic materials; The salt of (2) one alkaline drugs and an alkaline matter; Or any of the salt of (3) one alkaline drug and alkaline drugs.The U.S. Patent number 5,804,215 of authorizing people such as Cubbage discloses the treatment system at the percutaneous sticking plaster that contains medicament, and that described medicament comprises is that sticker coats, elasticity, the anti-matrix of tearing.Thereby employed percutaneous sticking plaster it is said and is adhered to the encapsulation of described matrix and stops near percutaneous sticking plaster.The rubber-based sticker is disclosed as preferably.

[00159] described improvement delivery formulations also can additionally be given with other reactive compounds, and described reactive compound is antalgesic for example, antiphlogistic, antipyretic, antidepressant, Anti-epileptics, antihistaminic, anti-migraines medicine, antimuscarinic drug, anxiolytic, sedative, hypnotic, antipsychotic drug, bronchodilator, antasthmatic, cardiovascular drugs, alclometasone diproionate, dopaminergic or other dopamine agonists (including but not limited to): Requip IR (Ropinirole), Stalevo (carbidopa, levodopa (L-dopa), the grace Tolcapone), COMtan (grace Tolcapone), Eldepryyl (selegiline), Neupro (rotigotine), and Azilect (Rasagiline), electrolyte, gastrointestinal drug, muscle relaxant, nutritional agents, vitamin, Parasympathomimetic, analeptic, anoretics and anti-drowsiness dose.Compound of the present invention also can give with other active component combinations, described active component for example, for instance, adjuvant, protease inhibitors, or other compatible medicine or compounds, when such combination is regarded as in reaching desired effects of putting method described herein expectation or useful.Mean by auxiliary administration, compound is with same dosage form administration simultaneously, and with different dosage form administration simultaneously, and compound is individually dosed.

Make the method for improvement delivery formulations

[00160] as will be understood by those skilled in the art and as described in related text and the document, many methods can be used for preparing various drug release characteristics are provided contain medicine tablet, globule, particulate or particle.Such method comprises, but be not limited to, below: with suitable coating material coating medicine or contain pharmaceutical composition, although typically not necessarily comprise polymeric material, increase the drug particles size, medicine is positioned in the skeleton, and the compound that forms medicine with suitable complex reagent.

[00161] being used to prepare the preferable methods that prolongs release tablet is to contain the medicine blend by compacting, for example uses the blend of particles of direct blend, wet granulation or the preparation of dry granulation process.Prolonging release tablet can also begin with the wet stock that contains suitable soluble oil, is molded but not suppresses.Yet tablet preferably uses compacting but not molded manufacturing.Being used to form the preferable methods that contains the medicine blend that prolongs release is direct and one or more kind excipient blend with drug particles, and described excipient is thinner (or filler), adhesive, disintegrant, lubricant, glidant and colouring agent for example.As the replacement of direct blend, containing the medicine blend can be by using the preparation of wet granulation or dry granulation process.The globule that contains active agent also can typically disperse (fluiddispersion) from fluid by any preparation of many conventional arts.For instance, being used for preparing the typical method that contains the medicine globule relates to and active agent disperseed or is dissolved in dressing suspension or the solution that contains drug excipient (for example PVP(polyvinyl pyrrolidone), methylcellulose, talcum, metallic stearate, silica, plasticizer or analog).This admixture is used to coat the globule core, for example has the sugared ball (or so-called " non-pareil ") that is roughly 60 to 20 purpose sizes.

[00162] process that is used to prepare the replacement of medicine globule is by medicine and one or more are planted pharmaceutically acceptable mixed with excipients, described excipient is microcrystalline cellulose for example, lactose, cellulose, PVP(polyvinyl pyrrolidone), talcum, dolomol, disintegrant, or the like, push described mixture, described extrudate is round as a ball, and dry also being coated with formation alternatively discharges globule immediately.

Treatment, the method and composition that is used to use and the compound that use

[00163] on the other hand, the invention provides the method that is used for the treatment of nerve degenerative diseases by the RPPX that treats effective dose.According to this embodiment, RPPX can combine and is formulated as improvement and discharges medicine or therapeutic combination by planting pharmaceutically acceptable carrier with one or more.Embodiment comprises that the improvement that can be taken orally discharges medicine or therapeutic combination, preferably as solid oral agent, and more preferably as the solid oral agent that can be capsule or tablet.In preferred embodiments, described improvement release medicine or therapeutic combination are configured to tablet or the capsule formulation that uses in oral administration route.The amount of described composition and the non-active ingredient in such prescription can be depending on the amount of active component, and the size and dimension of described tablet or capsule.Those skilled in the art can easily recognize and understand these parameters.The RPPX of treatment effective dose is as the inhibitor of oxidative stress, the inhibitor of lipid peroxidation or in the detoxifcation of oxygen atomic group, or can be effective as the inhibitor of cell death approach.

[00164] in some embodiments, the treatment effective dose of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the treatment effective dose of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the treatment effective dose of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the treatment effective dose of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, described consumption can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.In some embodiments, the treatment effective dose of RPPX can be from about 50mg to about 5,000mg, from about 100mg to about 3,000mg, preferably from about 300mg to about 1,500mg, or more preferably from about 500mg to about 1,000mg.In some embodiments, the treatment effective dose of RPPX can be from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the treatment effective dose of RPPX is to about 900mg from about 600mg.

[00165] described embodiment can have at RPPX and is at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, at least 99.95% and more preferably at least 99.99% chiral purity preferably.In preferred embodiments, the chiral purity at R (+) enantiomter of Pramipexole can be 100%.

[00166] further, the present invention also is provided at the method for the acute nerve degenerative diseases of treatment among the patient who needs, comprise give the about 50mg of patient arrive about 5, the RPPX of the daily dose value of 000mg.In some embodiments, the invention provides to being used for medicaments preparation in the methods of treatment of the acute neurological sexual disorder of patient provides about 50mg to about 5, the use of the RPPX of the daily dose value of 000mg.On the other hand, the present invention provides about 50mg to about 5 for the use in the methods of treatment of acute neurological sexual disorder in the patient, the RPPX of the daily dose value of 000mg.

[00167] in some embodiments, described acute nerve degenerative diseases is selected from apoplexy, neurotrosis, acute dysbolism, the outbreak of brain epilepsy sequelae, status epilepticus and acute encephalitis.

[00168] in some embodiments, described patient is the patient of first treatment.

[00169] in some embodiments, the daily dose value of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the daily dose value of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the daily dose value of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the daily dose value of RPPX can be from about 3mg/1kg/ days to about 50mg/kg/ days.In some embodiments, a described daily dose value can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.In some embodiments, the daily dose value of RPPX be from about 50mg to about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, or from about 500mg to about 1,000mg.In some embodiments, the daily dose value of RPPX makes from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the daily dose value of RPPX is to about 900mg from about 600mg.In some embodiments, a described daily dose value be from about 500mg to about 1, the RPPX of 000mg.In some embodiments, a daily dose value be from about 50mg to about 5, the RPPX of 000mg.In some embodiments, a described daily dose value be from about 100mg to about 3, the RPPX of 000mg.In some embodiments, a daily dose value be from about 200mg to about 3, the RPPX of 000mg.In some embodiments, a daily dose value be from about 300mg to about 1, the RPPX of 500mg.In some embodiments, a daily dose value be from about 500mg to about 1, the RPPX of 000mg.

[00170] in some embodiments, be 99.5% at the chiral purity of RPPX, or higher.In some embodiments, be 99.6% at the chiral purity of RPPX, or higher.In some embodiments, be 99.7% at the chiral purity of RPPX, or higher.In some embodiments, be 99.8% at the chiral purity of RPPX, or higher.In some embodiments, be 99.9% at the chiral purity of RPPX, or higher.In some embodiments, be 99.95% at the chiral purity of RPPX, or higher.In some embodiments, the chiral purity at RPPX is 99.99% or higher.

[00171] in some embodiments, a described daily dose value also comprises the PPX of no discernable ill-effect level amount.In some embodiments, the no discernable effective dose value of described PPX is to be lower than 4.5mg every day, is lower than 1.5mg, or is lower than 0.15mg.

[00172] in some embodiments, a described daily dose value also comprises the PPX of placebo value.In some embodiments, the placebo value of described PPX is the value that is no more than the accumulated dose of 1.0mg every day.In some embodiments, the placebo value of described PPX is the value that is no more than the accumulated dose of 0.75mg/ days, 0.5mg/ days, 0.25mg/ days, 0.125mg/ days.In some embodiments, the placebo value of described PPX is no more than 0.125mg/ days accumulated dose.

[00173] in some embodiments of the present invention, a described order dose value is about 100mg to about 3, the RPPX of 000mg and be 99.95% or higher at the chiral purity of RPPX.

[00174] in some embodiments of the present invention, a described daily dose value is from about 200 to about 3, the RPPX of 000mg and be 99.95% or higher at the chiral purity of RPPX.

[00175] in some embodiments of the present invention, a described order dose value is from about 300 to about 1, the RPPX of 500mg and be 99.95% or higher at the chiral purity of RPPX.

[00176] in some embodiments of the present invention, a described daily dose value be from about 500mg to about 1, the RPPX of 000mg and be 99.95% or higher at the chiral purity of RPPX.

[00177] in some embodiments of the present invention, a described daily dose value is from about 100mg to 3, and the RPPX of 000mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00178] in some embodiments of the present invention, a described daily dose value be from about 200mg to about 3, the RPPX of 000mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00179] in some embodiments of the present invention, a described daily dose value is from about 300 to about 1, and the RPPX of 500mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00180] in some embodiments of the present invention, a described daily dose value be from about 500mg to about 1, the RPPX of 000mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00181] in another embodiment, the RPPX in the embodiment of each method described herein gives as the improvement release of pharmaceutical compositions.In some embodiments, described improvement release of pharmaceutical compositions is a tablet.In some embodiments, described improvement release of pharmaceutical compositions is a capsule.In some embodiments, described improvement release of pharmaceutical compositions comprises pharmaceutically acceptable carrier.

[00182] described separately for the simple reasons in this article at morbid state, patient's type (treatment or non-first treatment for the first time), a daily dose value, the horizontal dose value of no discernable ill-effect, placebo value and can be with any suitable combination combination at the embodiment of the chiral purity of the inventive method.Any embodiment that this paper describes at method also can be used at the medicament preparation in the methods of treatment of acute neurological sexual disorder, perhaps in the purposes at the RPPX that uses a daily dose in the methods of treatment of acute neurological sexual disorder.

[00183] on the other hand, the present invention further provides in the patient of needs the method for the chronic nerve degenerative diseases of treatment, comprise give the about 50mg of patient arrive about 5, the RPPX of the daily dose value of 000mg.In some embodiments, the present invention provides about 50mg to about 5 for being used for medicaments preparation in the methods of treatment of the chronic neurological sexual disorder of patient, the use of the RPPX of the daily dose value of 000mg.In some embodiments, the present invention provides about 50mg to about 5 for being used for medicaments preparation in the methods of treatment of the chronic neurological sexual disorder of patient, the RPPX of the daily dose value of 000mg.

[00184] in some embodiments, described chronic nerve degenerative diseases is selected from the primary nerve degenerative diseases, Huntington, metabolism causes neurotrosis, senile dementia Alzheimer type disease, the age cognition dysfunction of being correlated with, blood vessel nature feeble-mindedness, MID, dementia with Lewy body disease, the nervus retrogression dementia, the nervus retrogression movement disorder, incoordination, the Friedrich incoordination, multiple sclerosis, spinal muscular atrophy, primary lateral spinal sclerosis disease, epilepsy, motor neuron disorder or disease, struvite demyelinating disorder, Alzheimer's, Parkinson's disease, amyotrophic lateral sclerosis, hepatic encephalopathy and chronic encephalitis.

[00185] in some embodiments, described patient is the patient of first treatment.

[00186] in some embodiments, the daily dose value of RPPX can be from about 0.01mg/kg/ days to about 10,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 0.1mg/kg/ days to about 1,000mg/kg/ days, from about 1mg/kg/ days to about 1,000mg/kg/ days, from about 1,000mg/kg/ days to about 10,000mg/kg/ days, or from about 1mg/kg/ days to about 100mg/kg/ days.In some embodiments, the daily dose value of RPPX can be from about 3mg/kg/ days to about 70mg/kg/ days.In some embodiments, the daily dose value of RPPX can be from about 7mg/kg/ days to about 40mg/kg/ days.In some embodiments, the daily dose value of RPPX can be from about 3mg/kg/ days to about 50mg/kg/ days.In some embodiments, a described daily dose value can be 10mg/ days to 1,500mg/ days, more preferably 100mg/ days to 600mg/ days.In some embodiments, the daily dose value of RPPX be from about 50mg to about 5,000mg, from about 100mg to about 3,000mg, from about 300mg to about 1,500mg, or from about 500mg to about 1,000mg.In some embodiments, the daily dose value of RPPX be from about 50mg to about 5,000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1,000mg.In some embodiments, the daily dose value of RPPX is to about 900mg from about 600mg.In some embodiments, a described daily dose value be from about 500mg to about 1, the RPPX of 000mg.In some embodiments, a daily dose value be from about 50mg to about 5, the RPPX of 000mg.In some embodiments, a daily dose value be from about 100mg to about 3, the RPPX of 000mg.In some embodiments, a daily dose value be from about 200mg to about 3, the RPPX of 000mg.In some embodiments, a daily dose value be from about 300mg to about 1, the RPPX of 500mg.In some embodiments, a described daily dose value be from about 500mg to about 1, the RPPX of 000mg.

[00187] in some embodiments, be 99.5% at the chiral purity of RPPX, or higher.In some embodiments, be 99.6% at the chiral purity of RPPX, or higher.In some embodiments, be 99.7% at the chiral purity of RPPX, or higher.In some embodiments, be 99.8% at the chiral purity of RPPX, or higher.In some embodiments, be 99.9% at the chiral purity of RPPX, or higher.In some embodiments, be 99.95% at the chiral purity of RPPX, or higher.In some embodiments, the chiral purity at RPPX is 99.99% or higher.

[00188] in some embodiments, a described daily dose value also comprises the PPX of no discernable ill-effect level amount.In some embodiments, the no discernable effective dose value of described PPX is to be lower than 4.5mg every day, is lower than 1.5mg, or is lower than 0.15mg.

[00189] in some embodiments, a described daily dose value also comprises the PPX of placebo value.In some embodiments, the placebo value of described PPX is the value that is no more than the accumulated dose of 1.0mg every day.In some embodiments, the placebo value of described PPX is the value that is no more than the accumulated dose of 0.75mg/ days, 0.5mg/ days, 0.25mg/ days, 0.125mg/ days.In some embodiments, the placebo value of described PPX is no more than 0.125mg/ days accumulated dose.

[00190] in some embodiments of the present invention, a described daily dose value is about 100mg to about 3, the RPPX of 000mg and be 99.95% or higher at the chiral purity of RPPX.

[00191] in some embodiments of the present invention, a described daily dose value is from about 200 to about 3, the RPPX of 000mg and be 99.95% or higher at the chiral purity of RPPX.

[00192] in some embodiments of the present invention, a described daily dose value is from about 300 to about 1, the RPPX of 500mg and be 99.95% or higher at the chiral purity of RPPX.

[00193] in some embodiments of the present invention, a described daily dose value be from about 500mg to about 1, the RPPX of 000mg and be 99.95% or higher at the chiral purity of RPPX.

[00194] in some embodiments of the present invention, a described daily dose value is from about 100mg to 3, and the RPPX of 000mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00195] in some embodiments of the present invention, a described daily dose value be from about 200mg to about 3, the RPPX of 000mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00196] in some embodiments of the present invention, a described daily dose value is from about 300 to about 1, and the RPPX of 500mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00197] in some embodiments of the present invention, a described daily dose value be from about 500mg to about 1, the RPPX of 000mg and a described daily dose value also comprise the PPX less than about 0.05mg.

[00198] in another embodiment, the RPPX in the embodiment of each method described herein gives as the improvement release of pharmaceutical compositions.In some embodiments, described improvement release of pharmaceutical compositions is a tablet.In some embodiments, described improvement release of pharmaceutical compositions is a capsule.In some embodiments, described improvement release of pharmaceutical compositions comprises pharmaceutically acceptable carrier.

[00199] described separately for the simple reasons in this article at morbid state, patient's type (treatment or non-first treatment for the first time), a daily dose value, the horizontal dose value of no discernable ill-effect, placebo value and can be with any suitable combination combination at the embodiment of the chiral purity of the inventive method.Any embodiment that this paper describes at method also can be used in the medicament preparation of purposes of treatment of the chronic neurological sexual disorder of pin, perhaps in the purposes at the RPPX that uses a daily dose in the method for the chronic neurological sexual disorder of treatment.

Medicine box

[00200] on the other hand, the invention provides medicine box, described medicine box comprise one or more kinds comprise the improvement release of pharmaceutical compositions and being used to of RPPX give or write out a prescription described one or more plant the specification of pharmaceutical compositions, described specification comprise be enough to cause giving the patient at least about 50mg to about 5, the value of the first day dosage of 000mg RPPX give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.In addition, in some embodiments, the invention provides multiple medicine box, described medicine box comprise one or more plant according to the pharmaceutical composition of any embodiment the preceding of composition described herein or its any combination and be used to give or write out a prescription described one or more plant the specification of improvement release of pharmaceutical compositions, described specification comprises according to the embodiment of method described herein or its any combination, give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.

[00201] medicine box of the present invention can have at RPPX and is at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, 99.95%and at least 99.99% chiral purity more preferably at least preferably.In preferred embodiments, the chiral purity at R (+) enantiomter of Pramipexole can be 100%.In some embodiments, the chiral purity at RPPX can be 99.9% or bigger.In some embodiments, the chiral purity at RPPX can be 99.95% or bigger.In some embodiments, the chiral purity at RPPX can be 99.99% or bigger.

[00202] in some embodiments, described specification comprise be enough to cause giving from about 0.1mg/kg/ days to about 1,000mg/kg/ days or from the amount of the first day dosage of about 1mg/kg/ days to about 100mg/kg/ days RPPX give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.In some embodiments, described specification comprise be enough to cause to give from the amount of the first day dosage of about 3mg/kg/ days to about 70mg/kg/ days RPPX give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.In some embodiments, described specification comprise be enough to cause to give from the amount of the first day dosage of about 7mg/kg/ days to about 40mg/kg/ days RPPX give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.In some embodiments, described specification comprises being enough to and causes giving from about 50mg to about 5,000mg, from about 100mg to about 3,000mg, preferably from about 300mg to about 1,500mg, or more preferably from about 500mg to about 1, the amount of the first day dosage of the RPPX of 000mg give or write out a prescription described one or more plant the guidance of pharmaceutical compositions.In some embodiments, described specification comprises to be enough to cause giving from about 50mg to about 5 000mg, from about 100mg to about 5,000mg, from about 200mg to about 5,000mg, from about 250mg to about 5,000mg, from about 300mg to about 5,000mg, from about 400mg to about 5,000mg, from 450mg to about 5,000mg, from about 200mg to about 3,000mg, from about 250mg to about 3,000mg, from about 300mg to about 3,000mg, from about 400mg to about 3,000mg, from 450mg to about 3,000mg, from about 100mg to about 1,000mg, from about 200mg to about 1,000mg, from about 250mg to about 1,000mg, from about 300mg to about 1,000mg, from about 400mg to about 1,000mg, from about 600mg to about 1,000mg, or from 450mg to about 1, the amount of the first day dosage of the RPPX of 000mg gives or writes out a prescription describedly to plant the guidance of improvement release of pharmaceutical compositions to one or more.In some embodiments, the first day dose value of RPPX is to about 900mg from about 600mg.

[00203] in some embodiments, described specification comprise be enough to cause giving the patient from about 100mg to about 3, the amount of the first day dosage of the RPPX of 000mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.In some embodiments, specification comprise be enough to cause giving the patient from about 200mg to about 3, the amount of the first day dosage of the RPPX of 000mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.In some embodiments, described specification comprise be enough to cause giving the patient from about 300mg to about 1, the amount of the first day dosage of the RPPX of 500mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.In some embodiments, described specification comprise be enough to cause giving the patient from about 500mg to about 1, the amount of the first day dosage of the RPPX of 000mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.

[00204] in some embodiments, described guidance further causes giving the PPX of placebo value.In embodiments, the placebo value of PPX is the amount that is no more than 1.0mg/ days accumulated dose.In a more preferred embodiment, the placebo value of PPX be no more than 0.75mg/ days, 0.5mg/ days, 0.25mg/ days, and 0.125mg/ days the amount of accumulated dose preferably.In some embodiments, described placebo value is less than the PPX of about 0.125mg.

[00205] in some embodiments, described guidance further causes not having the PPX of discernable ill-effect level (NOAEL) dose value.In some embodiments, the PPX dosage of described no discernable effective dose value can be preferably lower than 4.5mg, is preferably lower than 1.5mg, perhaps more preferably is lower than 0.15mg.In some embodiments, the horizontal dose value of described no discernable ill-effect is less than about 0.05mg every day.In another embodiment preferred, the NOAEL dose value of described PPX is the value that is no more than per unit dosage 0.0007mg/kg.In some embodiments, described guidance further causes giving every day less than about 4.5 dopaminergic activity equivalents.In some embodiments, described guidance further causes giving every day less than about 1.5 dopaminergic activity equivalents.In some embodiments, described guidance further causes giving every day less than about 0.15 dopaminergic activity equivalent.

[00206] in some embodiments, described specification comprises being enough to causing giving the patient from about 100mg to 3, the amount of the first day dosage of the RPPX of 000mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions; And the chiral purity at described RPPX is 99.95% or bigger.

[00207] in some embodiments, described specification comprises being enough to causing giving the patient from about 200mg to 3, the amount of the first day dosage of the RPPX of 000mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions; And the chiral purity at described RPPX is 99.95% or bigger.

[00208] in some embodiments, described specification comprises being enough to causing giving the patient from about 300mg to 1, the amount of the first day dosage of the RPPX of 500mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions; And the chiral purity at described RPPX is 99.95% or bigger.

[00209] in some embodiments, described specification comprises being enough to causing giving the patient from about 500mg to 1, the amount of the first day dosage of the RPPX of 000mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions; And the chiral purity at described RPPX is 99.95% or bigger.

[00210] in some embodiments, described specification comprises being enough to causing giving the patient from about 100mg to 3, the RPPX of 000mg and less than the amount of the first day dosage of the PPX of about 0.05mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.

[00211] in some embodiments, described specification comprises being enough to causing giving the patient from about 200mg to 3, the RPPX of 000mg and less than the amount of the first day dosage of the PPX of about 0.05mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.

[00212] in some embodiments, described specification comprises being enough to causing giving the patient from about 300mg to 1, the RPPX of 500mg and less than the amount of the first day dosage of the PPX of about 0.05mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.

[00213] in some embodiments, described specification comprises being enough to causing giving the patient from about 500mg to 1, the RPPX of 000mg and less than the amount of the first day dosage of the PPX of about 0.05mg give or write out a prescription described one or more plant the guidance of improvement release of pharmaceutical compositions.

[00214] improvement of the present invention discharges medicine or therapeutic combination can be used as the single unit dose, or prepares in a large number, packs, sells as unit dose repeatedly.That described composition can be formulated as is oral, in eye, intravenous, intramuscular, intra-arterial, marrow, in the sheath, in the ventricle, in the transdermal, subcutaneous, intraperitoneal, vesicle, in the nose, through intestines, part, hypogloeeis or per rectum administration.Improvement release composition of the present invention can be oral administration, preferably as the solid oral agent administration, and more preferably is the solid oral agent administration of capsule or tablet.In some embodiments, improvement release composition of the present invention can be formulated as the tablet that is used for oral administration.

[00215] compound of the present invention can be active administration by any its in a usual manner.Administration can be whole body, the part or oral.For instance, administration can be, but be not limited in parenteral, subcutaneous, intravenous, intramuscular, the peritonaeum, the approach of transdermal, oral, cheek or eye, perhaps in the vagina, in the vesicle, by suck, by depot injection or pass through drug delivery implant.Therefore, the administration of compound of the present invention (independent or with other drug combination) pattern can be, but be not limited to, the hypogloeeis, injectable (comprise subcutaneous or intramuscular injection quick-acting, accumulate, implant and piller form) or by using vaginal cream, suppository, pessary, pesseulum, rectal suppository, intrauterine device and transdermal form, as emplastrum and emulsifiable paste.

The dosage of the patient RPPX that [00216] can need can every day about 0.1mg/kg about 1 to every day, change between the 000mg/kg.That method of administration can comprise is oral, hypogloeeis, transdermal, rectum or any accessibility parenteral route.Those of ordinary skills will be understood that and recognize the described consumption of patient's administration of needs and the arrangement of time of described consumption.The dosage and the duration of treatment can change, and can be with those of ordinary skills based on monitoring and the evaluation of improvement of measuring neural and non-nervous tissue as the basis.This evaluation can be based on the external sign of improving, the muscle control that for example improves, or make based on the physiologic character of inherence or label.Dosage can also depend on the discomfort or the disease of just treating, the discomfort of just treating or the degree of disease and further depend on patient's age and body weight.

[00217] the concrete pattern of administration will depend on index.Administration specifically by way of with the selection of dosage can be by the clinician according to the known method adjustment of clinician or titration to obtain best clinical response.The amount of the compound of administration can be an effectively amount of treatment.Consumption to be administered can depend on the experimenter's who is just being treated feature, described feature for example, by concrete animal or human's class experimenter of being treated, age, body weight, health, the treatment type of carrying out recently, if any, and the frequency of treatment, and can easily determine by those skilled in the art (for example, clinician).

[00218] to improve the preferred method of administration of release composition can be oral in the present invention, and preferred approach is to be forms such as tablet, capsule, lozenge.In preferred embodiments, composition of the present invention can be configured to the tablet that is used for oral administration.Tablet can be by suppressing or molded the manufacturing with one or more auxiliary elements alternatively.The tablet of compacting can be for example powder of free-flowing form or the active component of particle by compacting in suitable machine, prepares with adhesive, lubricant, inert diluent, lubricated, surfactant or dispersant alternatively.Molded tablet can prepare by molded mixture by the wetting ground compound of inert liquid diluent in suitable machine.

[00219] described tablet can be uncoated or it can coat by known technology, postpone disintegration and absorption in digestive tract alternatively, and be provided at the effect that continues on the long stage thus.Dressing can be suitable for predetermined form release of active compounds (for example, in order to realize the controlled release prescription) or can be suitable for not discharging described reactive compound passing through stomach (enteric coating) until it.Described dressing can be sweet tablet, film dressing (for example based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, polyethylene glycol and/or PVP(polyvinyl pyrrolidone)), perhaps enteric coating (for example, based on methacrylic acid copolymer, cellulose acetate-phthalate, Hydroxypropyl Methylcellulose Phathalate, succinic acid acetate hydroxypropyl methylcellulose, polyvinyl acetate phthalate, lac and/or ethyl cellulose).In addition, can postpone material service time, for example, glycerin monostearate or distearin.The solid tablet composition can comprise and is suitable for protecting described composition to avoid the dressing of undesirable chemical change (for example chemical degradation before discharging described active drug substance).

[00220] to discharge pharmaceutical formulation also can be the polymer of the present invention that comprises effective dose of any number or the solid formulation form of copolymer in the improvement that contains composition of the present invention and suitable carriers, described solid formulation form comprises, but be not limited to tablet, capsule, cachet, piller, pill, powder and particle; The local dose form, it includes, but not limited to solution, powder, fluid emulsion, fluid suspension, semisolid, ointment, paste, emulsifiable paste, gel and jelly, and foam; And parenteral dosage forms, it includes, but not limited to solution, suspension, emulsion and dry powder.It is also known that in this area that active component can be included in the prescription with acceptable diluent on the pharmacology, filler, disintegrant, adhesive, lubricant, surfactant, hydrophobic carrier, water-solubility carrier, emulsifier, buffer, wetting agent, wetting agent, solubilizer, preservative etc.The means and the method for administration are well known in the art, and the technical staff can be with reference to various pharmacology lists of references for instructing.For instance, can consult modern pharmacy (Modern Pharmaceutics), Banker﹠amp; Rhodes, Marcel Dekker, Inc. (1979) and Goodman ﹠amp; The pharmacy basis of the treatment of Gilman (ThePharmaceutical Basis of Therapeutics), sixth version, MacMillan Publication Co., New York (1980).

[00221] compound of the present invention can be at the parenteral preparation by injection, and described injection is for example injected or continuous infusion.Described compound can pass through continuous infusion administration on about 15 minutes to about 24 hours period.The injection prescription can exist with unit dosage forms, for example with ampoule or multi-dose container form, has the preservative of interpolation.Described improvement release composition can be taked for example form of suspension, solution or the emulsion in oil or water medium liquid, and can comprise prescription reagent for example that suspend, stable and/or dispersion reagent.

[00222] at oral administration, described compound can be easily by preparing these compounds and pharmaceutically acceptable carrier combinations well known in the art.These carriers make compound of the present invention be configured to tablet, pill, dragee (dragees), capsule, liquid preparation, gel, syrup, pulpous state agent, suspension etc. for the purpose of the patient's that will be treated orally ingestible.The medicinal prepared product that is used to orally use can if desired, grind the mixture that is produced alternatively by adding the excipient of solid, and after adding suitable adjuvant the processing granular mixture, to obtain tablet or dragee core.Suitable excipient includes, but not limited to filler, and for example sugar includes but not limited to lactose, sucrose, mannitol and sorbitol; The preparation of cellulose thing for example, but is not limited to corn starch, wheaten starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP).If desired, disintegrant be can add, for example, but crospolyvinylpyrrolidone, agar or alginic acid or its salt are not limited to, as sodium alginate.

[00223] suitable dressing is provided for the dragee core.For this purpose, can use concentrated sugar juice, described concentrated sugar juice can comprise gum Arabic, talcum, PVP(polyvinyl pyrrolidone), carbomer gel, polyethylene glycol and/or titanium dioxide alternatively, lacquer (1acquer) solution, and the organic solvent or the solvent mixture that are fit to.Dyestuff or pigment can add the various combination that tablet or dragee dressing are used for identification or distinguish active compound doses to.

[00224] pharmaceutical preparations that can orally use includes, but not limited to the capsule of slippaging made by gelatin, and the capsule of being made by the plasticizer of gelatin and for example glycerine or sorbitol soft, sealing.The described capsule of slippaging can comprise the active component with the filler fusion, described filler as, the adhesive of lactose, for example starch and/or, the lubricant of for example talcum or dolomol and alternatively, stabilizing agent.In soft capsule, reactive compound can be dissolved or suspended in the suitable liquid, for example fat oil, atoleine or liquid macrogol.In addition, can add stabilizing agent.The prescription of all oral administrations all should be in the consumption that is suitable for administration.

[00225] at oral cavity or sublingual administration, described composition can be taked tablet, fulguration body (flash melts) or the lozenge with any usual manner preparation.

[00226] at inhalation, being used for compound used according to the invention can be in easily by pressurization bag or sprayer, adopt the form of the aerosol spray that suitable propellant provides to send, described propellant is dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbonic acid gas and other suitable gas for example.Under the aerocolloidal situation of compression, consumption unit can be by providing the valve of sending metered amount to determine.For example being used for the capsule of gelatin of inhalator or insufflator or cartridge case can be configured to and contain for example mixture of powders of lactose or starch of described compound and suitable powder bodying agent.

[00227] compound of the present invention can also be formulated as the rectum composition of suppository for example or enema,retention, for example, comprises conventional suppository bodying agent for example cocoa butter or other glyceride.

[00228] except the prescription of describing before, compound of the present invention can also be formulated as and accumulate preparation (depotpreparation).Long-acting prescription like this can be by implantation (for example subcutaneous or intramuscular) administration or by the intramuscular injection administration.Depot injection can be about 1 to about 6 months or longer interval administration.Therefore, for instance, described compound can be with suitable polymerization or hydrophobic material (for example, as the emulsion in acceptable oil) or ion exchange resin, perhaps slightly molten derivative, for example slightly molten salt preparation.

[00229] in cutaneous penetration, compound of the present invention can be applied to emplastrum for instance, perhaps can be applied to the therapy system by transdermal, thereby be supplied to organism.

[00230] medicine of compound and therapeutic combination can also comprise suitable solid or gel phase carrier or excipient.The embodiment of these carriers or excipient for example includes, but are not limited to calcium carbonate, phosphate, various sugar, starch, cellulose derivatives, gelatin and polymer, for instance polyethylene glycol.

[00231] compound of the present invention can also with other active component combination medicine-feeding, described active component for example, for instance, adjuvant, protease inhibitors or other compatible medicine or compound, wherein said combination are thought conform with expectation or favourable in being realized the desired effects of method described herein.

(R) and the preparation of PPX

[00232] preparation process of Pramipexole is described in the U.S. Patent number 4,843,086 of authorizing Griss etc. and U.S. Patent number 4,886,812, and each of described patent all incorporated into this paper by integral body by reference.RPPX of the present invention can be by submitting on March 14th, 1, the U.S. Provisional Application number 60/894 that is entitled as " method of synthetic and purifying R (+) and S (-) Pramipexole (Methods of Synthesizing and Purifying R (+) and (S)-promipexole) ", 829, with on March 14th, 2007 submitted, the U.S. Provisional Application number 60/894 that is entitled as " method of enantiomerism purifying chipal compounds (Methodsof Enantiomerically Purifying Chiral Compounds) ", 814, and meanwhile submit _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ the synthetic and/or purifying of middle disclosed method, described provisional application integral body is by reference incorporated this paper into.Particularly, be that the prepared product of chiral purity can use bimolecular nucleophilic subsititution (SN2) to produce at R (+) enantiomter.In the one kettle way synthetic schemes, molecular formula is 2,6-diaminourea-4,5,6, and the diamines of 7-tetrahydrochysene-benzothiazole reacts in polar solvent with sulfonic acid propyl ester or halogenopropane, generates insoluble Pramipexole salt.Described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole salt reaction product presents above the high chemical purity of reactant and the optical purity of raising, this may be because 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt limited dissolubility in the polar solvent of reactant mixture.Therefore the final 2-amino-4 of purifying from reactant mixture, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole synthetic product comprises simple development and at the volatile solvent 2-amino-4 of washing precipitation in alcohol or the heptane for example, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt, then vacuum drying.

[00233] in some embodiments, RPPX is by being 2 with molecular formula, 6-diaminourea-4,5,6, the diamines of 7-tetrahydrochysene-benzothiazole is dissolved in the organic solvent, make described diamines and sulfonic acid propyl ester or halogenopropane be enough to produce and precipitate 2-amino-4,5,6, react under the condition of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt, and reclaim described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt.In preferred embodiments, the sulfonic acid propyl ester can be the toluenesulfonic acid propyl ester.In further embodiment, halogenopropane can be a bromo propane.The 2-amino-4,5,6 of this process, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole salt reaction product presents above the high chemical purity of reactant and the optical purity of raising.Do not wish to be entangled in theory, the optical purity of raising may be because described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole salt reaction product limited dissolubility in the polar solvent of reactant mixture.Therefore the final 2-amino-4 of purifying from reactant mixture, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product comprises simple development and at the volatile solvent 2-amino-4 of washing precipitation in alcohol or the heptane for example, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt, then vacuum drying.

[00234] in the embodiment of this process, described diamines can be R (+) diamines, or the mixture of described R (+) and S diamines.Final 2-amino-4,5,6, the chemical purity of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be at least about 97% or bigger, is preferably 98% or bigger, and more preferably 99% or bigger.The 2-amino-4,5 that this process of use generates, 6, R (+) enantiomter of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt is to generate from initial diamines, described diamines can be at least 55% optical voidness, is preferably 70% optical voidness and more preferably is higher than 90% optical voidness.Final 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product can be enriched to 99.6% optical voidness or bigger, 99.7% optical voidness or bigger is preferably 99.8% optical voidness or bigger, more preferably 99.9% optical voidness or bigger, 99.95% optical voidness or bigger, 99.99% optical voidness or bigger.In some embodiments, described optical purity can be 100%.

[00235] in the embodiment of this process, described organic solvent can be a polar aprotic solvent, for example oxolane, dimethyl formamide, dimethyl sulfoxide (DMSO), dimethylacetylamide or HMPA.Described organic solvent can also be low-molecular-weight alcohol, for example ethanol, 1-propyl alcohol or n-butanol.Further, described organic solvent can be any combination of described polar aprotic solvent and described low-molecular-weight alcohol.Described organic solvent can have about 0 water content to about 10 percentage by volumes.Preferably, the solvent that uses in the present invention's practice is standard A CS level solvent.Further, described sulfonic acid propyl ester or halogenopropane can add with about 1.0 to about 2.0 molar equivalent of described diamines.

[00236] in the further embodiment of this process, be enough to produce and precipitate described 2-amino-4,5,6, the temperature that the condition of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be included in rising heats the diamines of described dissolving, adds sulfonic acid propyl ester or halogenopropane, and described sulfonic acid propyl ester and halogenopropane can be dissolved in diisopropylethylamine and the organic solvent, to form mixture and to stir described mixture about 4 hours.Alternately, described diisopropylethylamine can be added in the reaction with diamines, and described sulfonic acid propyl ester or halogenopropane can be dissolved in the organic solvent, to form mixture, described mixture can be added in the described reaction, and stirs about 4 hours.

[00237] in this embodiment, the temperature of the rising of described reaction can be below the boiling temperature of described reaction, particularly, and below the boiling temperature of one or more organic solvents of described reactant mixture.The temperature of described rising can be to be lower than about 125 ℃, is preferably lower than about 100 ℃ and more preferably be lower than about 95 ℃ or lower.Described reaction time necessary can change with the different of reactant itself, solvent system and with selected temperature.

[00238] in alternative embodiment, be enough to produce and precipitate described 2-amino-4,5,6, the condition of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can comprise uses dimethyl formamide as organic solvent, heats the diamines of described dissolving in the temperature that raises, add sulfonic acid propyl ester or halogenopropane, described sulfonic acid propyl ester and halogenopropane can be dissolved in the dimethyl formamide, to form mixture and to stir described mixture about 4 hours.The temperature of the rising of described reaction can be below the boiling temperature of described reaction, particularly, and below the boiling temperature of one or more organic solvents of described reactant mixture.The temperature of described rising can be to be lower than about 125 ℃, is preferably lower than about 100 ℃ and more preferably be lower than about 75 ℃ or lower.Described reaction time necessary can change with the different of reactant itself, solvent system and with selected temperature.

[00239] in preferred alternative embodiment, be enough to produce and precipitate described 2-amino-4,5,6, the condition of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt comprises uses dimethyl formamide to heat the diamines of described dissolving as organic solvent with in the temperature that raises.Described sulfonic acid propyl ester or halogenopropane mixture are dissolved in the dimethyl formamide with 1.25 molar equivalents preferably, are preferably 10 times of volumes, and diisopropylethylamine, be preferably 1.25 molar equivalents, slowly added in the diamines of described heating, and stir above about 4 hours period.Alternately, the diisopropyl diamines can be added in the reaction with described diamines and described sulfonic acid propyl ester or halogenopropane can be dissolved in the dimethyl formamide to form mixture, and described mixture can be added in the reaction, and stirs about 4 hours.The reaction temperature of described rising can be below the boiling temperature of reaction, particularly, and below the boiling temperature of one or more organic solvents of reactant mixture.The temperature of described rising can be to be lower than about 125 ℃, is preferably lower than about 100 ℃ and more preferably be lower than about 65 ℃ or lower.Described reaction time necessary can be with reactant itself, solvent system different and change with selected temperature.

[00240] embodiment of this process further comprises the described temperature that is reacted to about room temperature of cooling, is approximately 25 ℃, and stirs described reaction about 2 hours.This process may further include filters described reaction, with the separating solids sediment, with pure washing precipitate and vacuum drying sediment.The 2-amino-4,5,6 of this process, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole salt reaction product can present the optical purity above the raising of reactant.

[00241] alternately, described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole sulfonate or halogen can with dense HCl for example alcohol organic solvent in, from about 0 to about 5 ℃ thermotonus.Can add for example organic solvent of methyl tertiary butyl ether (MTBE), and described reaction can be stirred extra 1 hour.RPPX dihydrochloride product can with alcohol washing and vacuum drying, reclaim from reactant mixture by filtering.

[00242] in the embodiment of this process, be called as condition A in an embodiment in table 7 neutralization, be enough to produce described 2-amino-4,5,6, the reaction condition of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product, the diamines that can comprise the Formulae II of heating for dissolving arrives the temperature that raises, and follows to continue to stir.The temperature of described rising is preferably the fusing point that is lower than selected organic solvent, is lower than about 125 ℃, is preferably to be lower than about 100 ℃, more preferably about 95 ℃.Slowly add the solution of sulfonic acid propyl ester or halogenopropane in the period of several hrs, the solution of described sulfonic acid propyl ester or halogenopropane is dissolved in diisopropylethylamine and the organic solvent to form mixture.Then, stir extra a period of time of this reactant mixture in this temperature, for example, for instance, about 4 hours.Described reaction time necessary can be with reactant itself, solvent system different and change with selected temperature, and can be understood by those skilled in the art.

[00243] in alternative embodiment, diisopropylethylamine can be added in the reaction with described diamines, and sulfonic acid propyl ester and halogenopropane can be dissolved in the organic solvent to form mixture, and described mixture can add in the reaction, and stir the period of several hrs.Then, stir extra a period of time of this reactant mixture in this temperature, for example, for instance, at least 4 hours.Described reaction proceeds to be finished time necessary and can change with the different of reactant itself and solvent system and with selected temperature, and can be understood by those skilled in the art.

[00244] in the alternative embodiment of this process, in table 7, be called as condition B, be enough to produce described 2-amino-4,5,6, the reaction condition of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product can comprise and use dimethyl formamide as organic solvent, and the diamines of the Formulae II of heating for dissolving is to the temperature that raises, and continues to stir.The temperature of described rising is preferably the fusing point that is lower than selected organic solvent, is lower than about 125 ℃, is preferably to be lower than about 100 ℃ and more preferably about 75 ℃.Can slowly add the solution of sulfonic acid propyl ester or halogenopropane in the period of several hrs, the solution of described sulfonic acid propyl ester or halogenopropane is dissolved in the dimethyl formamide.Then, under this temperature, stir extra a period of time of this reactant mixture, for example, for instance, at least 4 hours.Described reaction proceeds to be finished time necessary and can change with the different of reactant itself and solvent system and with selected temperature, and can be understood by those skilled in the art.

[00245] in the preferred alternative embodiment of this process, be called as condition C in table 7, described reaction comprises uses dimethyl formamide as organic solvent, is used to dissolve described diamines.The diamines of described Formulae II can be heated to the temperature of rising then, and continues to stir.The temperature of described rising is preferably the fusing point that is lower than selected organic solvent, is lower than about 125 ℃, is preferably to be lower than about 100 ℃ and more preferably about 65 ℃.The solution of sulfonic acid propyl ester or halogenopropane is preferably about 1.25 molar equivalents, can be dissolved in dimethyl formamide and the diisopropylethylamine, to form mixture, wherein, dimethyl formamide is preferably about 10 times of volumes, and diisopropylethylamine is preferably about 1.25 molar equivalents.This mixture can be slowly added in the diamines of described heating in the period of several hrs.Then, can under this temperature, stir extra a period of time of this reactant mixture, for example, for instance, about 4 hours.Alternately, diisopropylethylamine can be added in the reaction with described diamines, and described sulfonic acid propyl ester or halogenopropane can be dissolved in the dimethyl formamide, to form mixture, described mixture can add in the reaction, and stirs the period of several hrs.Then, under this temperature, stir extra a period of time of this reactant mixture, for example, for instance, about 4 hours.Described reaction proceeds to be finished time necessary and can change with the different of reactant itself and solvent system and with selected temperature, and can be understood by those skilled in the art.

[00246] final 2-amino-4,5,6, the purifying of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product can comprise top disclosed reaction is cooled to about 25 ℃, and stir described reaction a period of time, for example, for instance, about 2 hours.This purifying can further comprise this reaction of filtration with the separating solids sediment, with this sediment of alcohol washing, and this sediment of vacuum drying.The final products of described reaction can be analyzed chemistry and chiral purity by high performance liquid chromatography (HPLC).

[00247] further, can use ¹H NMR and ¹³C NMR is to confirm described product 2-amino-4,5,6, the structure of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole.Listed each the synthetic embodiment result who uses described several conditions in the table 7, described synthetic embodiment is an embodiment disclosed by the invention.Describe the synthetic embodiment of several Pramipexoles of open middle service condition A of the present invention and C among the embodiment 5-7 in detail.

[00248] 2-amino-4,5,6, the sulfonate of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole or halogen can use the concentrated solution of HCl to be converted into HCl salt in ethanol.P-TSA 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be dissolved in the alcohol of ethanol for example once more, and described mixture can under continuing to stir, be cooled to about 0 and about 5 ℃ between.Can add dense HCl then, then add for example solvent of methyl tertiary butyl ether (MTBE), and can about 0 and about 5 ℃ between stirred described mixture 1 hour.Described reactant mixture can be filtered then, with the washing of MTBE/ alcoholic solution, and vacuum drying.Final products are 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole dihydrochloride.This synthetic specific embodiment can find in embodiment 8.

[00249] 2-amino-4,5,6, the sulfonate of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole or halogen comprise concentrated solution and the isopropyl acetate (IPAC) that uses HCl to the alternative method of the conversion of HCl salt.2-amino-4,5,6, the sulfonate or the halogen of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole can be brought among the IPAC, and are cooled to 15 ℃.HCl (gas) can be sparging in the described slurry about 1 hour, this mixture can be filtered then, with IPAC washing and vacuum drying under room temperature, with output 2-amino-4,5,6, the dihydrochloride of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole.This synthetic specific embodiment can find in embodiment 9.

[00250] 2-amino-4,5,6, the free alkali form that the sulfonate of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole or halogen can alternately be converted into Pramipexole.P-TSA 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be dissolved in carrene (DCM) and the water.Can make the pH of the solution that obtains with NaOH then is about 11-12.Can generate two-phase, and described water can extract with DCM, by magnesium sulfate (MgSO ₄) drying, by

Filter and concentrate.Described concentration residue can be dissolved among the MTBE once more, and stir the slurry several hrs.Can cross filter solid then, with the MTBE washing, and in about 35 ℃ of temperature vacuum dryings.Final products are 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole free alkali.This synthetic specific embodiment can find in embodiment 10.

[00251] alternately, 2-amino-4,5,6, the sulphonic acid ester of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole or halogen can alternately be converted into the free alkali form of Pramipexole by second kind of process.In this second kind of process, 2-amino-4,5,6, the p-TSA salt of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole is dissolved in the water, and is cooled to about 10 ℃ temperature.Make this slurry alkalization by adding NaOH, with the salt solution dilution, and extraction is several times in DCM.The organic facies that merges with the salt water washing is passed through MgSO then ₄Drying is filtered and be concentrated into to drying.This synthetic specific embodiment can find in embodiment 11.

[00252] 2-amino-4,5,6, the free alkali form of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole can pass through to 2-amino-4,5,6, bubbling HCl gas in the solution of the cooling of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole free alkali in IPAC and be converted into 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole dihydrochloride.Alternately, 2-amino-4,5,6, the free alkali form of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole can be converted into 2-amino-4,5,6 by mixing with dense HCl to spend the night in room temperature, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole dihydrochloride.The specific embodiment of aforementioned synthetic schemes can find in embodiment 12 and 13 respectively.

[00253] alternately, 2-amino-4,5,6, the free alkali form of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole can be converted into 2-amino-4,5,6 by the fumaric acid that adds 2 molar equivalents, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole fumarate.

* condition E is not included in recycling step and dilutes among the MTBE, identical with condition C.MTBE has improved recovery (yield) from synthetic reaction, but may reduce whole chiral purity.Condition E is explained in more detail in table 9.

[00254] alternate process for preparing the raw material of enantiomer-pure from the mixture of RPPX and PPX comprises and uses sour addition and with the 2-amino-4 of enantiomer-pure, 5,6, it is insoluble in the achiral salting liquid that obtains that the development (precipitation) of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole, described development are based on described enantiomter (R (+) and S (-)).In the embodiment of this process, insoluble in the achiral salt reagent that obtains based on described multiple enantiomter, with the 2-amino-4,5,6 of enantiomer-pure, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole is developed from sour addition solution.In the present embodiment, the 2-amino-4,5 of preparation enantiomer-pure, 6, the process of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole comprises, with the 2-amino-4,5 of enantiomter enrichment, 6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole is dissolved in the organic solvent in the temperature that promotes, add selected acid, reaction is cooled to room temperature, in time of reaction one elongated segment of stirring at room cooling with reclaim the RPPX of enantiomer-pure.In preferred embodiments, selected acid can be being the 2-amino-4,5,6 of described enantiomter enrichment, being added to about 2 molar equivalents from about 1 molar equivalent of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole.

[00255] in an embodiment of this process, selected acid is p-methyl benzenesulfonic acid (p-TSA), and described organic solvent is an ethanol.In another embodiment of this process, the temperature of described lifting can be from about 65 ℃ to about 85 ℃, and cools off with per hour about 25 ℃ speed.The temperature of described lifting can also be to be lower than 125 ℃, is preferably to be lower than 100 ℃ and more preferably about 75 ℃ temperature.Described reaction time necessary can be with reactant itself, solvent system different and change with selected temperature, and can easily be familiar with by those skilled in the art.In another embodiment again of this process, reclaim the 2-amino-4,5,6 of enantiomer-pure, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole comprises that cooling is reacted to about 25 ℃ temperature, and stirs this reaction at least about 2 hours.Described recovery may further include filters described reaction with the separating solids sediment, with alcohol this sediment of washing and this sediment of vacuum drying.

[00256] in the various embodiments of this process, described organic solvent can include, but not limited to acetonitrile, acetone, ethanol, ethyl acetate, methyl tertiary butyl ether, methyl ethyl ketone, isopropyl acetate and isopropyl alcohol.In preferred embodiments, described organic solvent is an ethanol.Described acid can include, but not limited to contain hydracid, for example, for instance, hydrobromic acid, hydrochloric acid, hydrofluoric acid and hydroiodic acid; Inorganic acid, for example, for instance, nitric acid, perchloric acid, sulfuric acid and phosphoric acid; Organic acid, for example, for instance, sulfonic acid (methanesulfonic acid, trifluoromethane sulfonic acid, ethyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid), acetic acid, malic acid, fumaric acid, succinic acid, citric acid, benzoic acid, gluconic acid, lactic acid, mandelic acid, glactaric acid, pounce on acid (Pamoic), pantothenic acid, oxalic acid and maleic acid; And amino acid, for example aspartic acid or glutamic acid.Described acid can be single acid or diacid, for example two halogen acids, two sulfuric acid, diphosphonic acid or two organic acids.In all cases, described acid all is used as achiral reagent, and its selection is not the priority of having an effect or precipitating based on any desired or known specific optical isomer to disclosure product.In preferred embodiments, selected acid is p-methyl benzenesulfonic acid.

[00257] in the embodiment of this process, when comprising at described R (+) enantiomter, described starting mixt is at least 55% optically pure 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole, being preferably at described R (+) enantiomter is 80% optical voidness, being preferably at described R (+) enantiomter is 85% optical voidness, be 90% optical voidness more preferably at described R (+) enantiomter, with most preferably be when being 95% optical voidness at described R (+) enantiomter, described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be greater than 99% at the final chiral purity of R (+) enantiomter.When comprising at described S (-) enantiomter, described starting mixt is at least 55% optically pure Pramipexole, being preferably at described S (-) enantiomter is 80% optical voidness, being preferably at described S (-) enantiomter is 85% optical voidness, be 90% optical voidness more preferably at described S (-) enantiomter, with most preferably be when being 95% optical voidness at described S (-) enantiomter, described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be greater than 99% at the final chiral purity of S (-) enantiomter.Described final 2-amino-4,5,6, the chiral purity of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be preferably 99.6% or bigger, and 99.7% or bigger, be preferably 99.8% or bigger, and more preferably 99.9% or bigger.In some embodiments, described final 2-amino-4,5,6, the chiral purity of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be 100%.

[00258] in embodiments, be the temperature that promotes 2-amino-4,5 with the enantiomter enrichment, 6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole is dissolved in the organic solvent, and after adding described acid, described reaction can be cooled to room temperature with about 25 ℃/hour speed.Then, the 2-amino-4 of described enantiomer-pure, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole can be by stirring about at least 2 hours of described reaction, filtering reaction, with the alcohol described sediment of washing with described sediment vacuum drying and is recovered from described reaction solution with the separating solids sediment.Required time of described cooldown rate and extra stirring can be with different change of selected organic solvent and acid, and can easily be familiar with by those skilled in the art.In addition, reaction volume can determine described final 2-amino-4,5,6, the degree and the whole yield of the optics purifying of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product.These volumes can be understood and be familiar with by those skilled in the art.The embodiment of concrete time, temperature and volume that the present invention can implement is provided in an embodiment.

[00259] in embodiments, when described initial 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole mixture at the chiral purity of R (+) enantiomter greater than 55% o'clock, be preferably more than 70%, or more preferably greater than 90% o'clock, described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product salt can be greater than 99% at the chiral purity of R (+).Described final 2-amino-4,5,6, the chiral purity of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be 99.6% or bigger, 99.7% or bigger, be preferably 99.8% or bigger and more preferably 99.9% or bigger, more preferably 99.95% or bigger, even more preferably 99.99% or bigger.In some embodiments, described final 2-amino-4,5,6, the chiral purity of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be 100%.

[00260] the 2-amino-4 of chiral purity, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole also can be by sour addition with 2-amino-4,5,6, the process of the single enantiomter development of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole is from the mixture preparation of RPPX and PPX, and it is insoluble in the achirality salting liquid that obtains that described development is based on described enantiomter.Described process is included in the 2-amino-4 of the temperature of lifting with the enantiomter enrichment, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole is dissolved in the organic solvent, adds the selected acid from about 1.05 molar equivalents to about 2.05 molar equivalents, cools off the described room temperature that is reacted to, in time of reaction one elongated segment of the described cooling of stirring at room and reclaim the 2-amino-4 of enantiomer-pure, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole.

[00261] in embodiments, the temperature of the lifting of described reaction can be the boiling temperature that is lower than described reaction, particularly, is lower than the boiling temperature of one or more kind organic solvents of described reactant mixture.The temperature of described lifting can be to be lower than about 125 ℃, more preferably is lower than about 100 ℃ and more preferably about 75 ℃.Described reaction time necessary can be with reactant itself, solvent system different and change with selected temperature, and can be familiar with by those skilled in the art.

[00262] in embodiments, described organic solvent can include, but not limited to acetonitrile, acetone, ethanol, ethyl acetate, methyl tertiary butyl ether, methyl ethyl ketone, isopropyl acetate and isopropyl alcohol.In preferred embodiments, described organic solvent is an ethanol.In this embodiment, described acid can include, but not limited to contain hydracid, for example, for instance, hydrobromic acid, hydrochloric acid, hydrofluoric acid and hydroiodic acid; Inorganic acid, for example, for instance, nitric acid, perchloric acid, sulfuric acid and phosphoric acid; Organic acid, for example, for instance, sulfonic acid (methanesulfonic acid, trifluoromethane sulfonic acid, ethyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid), acetic acid, malic acid, fumaric acid, succinic acid, citric acid, benzoic acid, gluconic acid, lactic acid, mandelic acid, glactaric acid, pounce on acid (Pamoic), pantothenic acid, oxalic acid and maleic acid; And amino acid, for example aspartic acid or glutamic acid.Described acid can be single acid or diacid, for example two halogen acids, two sulfuric acid, diphosphonic acid or two organic acids.In all cases, described acid all is used as achiral reagent, and its selection is not the priority of having an effect or precipitating based on any desired or known specific optical isomer to disclosure product.In preferred embodiments, selected acid is p-methyl benzenesulfonic acid.

[00263] in extra embodiment, is the temperature that promotes 2-amino-4,5 with the enantiomter enrichment, 6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole is dissolved in the organic solvent, and after adding described acid, described reaction can be cooled to room temperature with about 25 ℃/hour speed.Then, the 2-amino-4 of described chiral purity, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole can be by stirring about at least 2 hours of described reaction, filtering reaction, with the alcohol described sediment of washing with described sediment vacuum drying and is recovered from described reaction solution with the separating solids sediment.Required time of described cooldown rate and extra stirring can be with different change of selected organic solvent and acid, and can be familiar with by those skilled in the art.In addition, reaction volume can determine described final 2-amino-4,5,6, the degree and the whole yield of the optics purifying of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product.These volumes can be understood by those skilled in the art and recognize.The embodiment of specific time, temperature and volume that the present invention can implement is provided in an embodiment.

[00264] in embodiments, when described initial 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole raw material has at R (+) enantiomter greater than 55%, be preferably more than 70%, or during more preferably about 90% chiral purity, the 2-amino-4,5 of described recovery, 6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be greater than 99% at the chiral purity of R (+) enantiomter.Described final 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be 99.6% or bigger at the chiral purity of R (+) enantiomter, 99.7% or bigger, be preferably 99.8% or bigger and more preferably 99.9% or bigger, more preferably 99.95% or bigger, even more preferably 99.99% or bigger.In the most preferred embodiment, described final 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be 100% at the chiral purity of R (+) enantiomter.

[00265] this process can be included in the temperature of lifting, with the 2-amino-4,5 of enantiomter enrichment, 6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole is dissolved in the organic solvent, the described room temperature that is reacted to is cooled off in the selected acid of interpolation from about 1.05 equivalents to about 2.05 equivalents, in the time of reaction one elongated segment of the described cooling of stirring at room, and the 2-amino-4 of the enantiomer-pure of recovery Formula I, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole.

[00266] in an embodiment of this process, selected acid is p-methyl benzenesulfonic acid (p-TSA), and described organic solvent is an ethanol.In another embodiment of this process, the temperature of described lifting is from about 65 ℃ to about 85 ℃, and described cooling takes place with per hour about 25 ℃ speed.The temperature of described lifting can also be to be lower than 125 ℃, is preferably to be lower than 100 ℃ and more preferably about 75 ℃ temperature.Described reaction time necessary can be with reactant itself, solvent system different and change with selected temperature, and can easily be familiar with by those skilled in the art.In another embodiment again of described process, reclaim the 2-amino-4,5,6 of enantiomer-pure, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole comprises that cooling is described and is reacted to about 25 ℃ temperature and stirred described reaction about at least 2 hours.Described recovery may further include filters described reaction with the separating solids sediment, with the alcohol described sediment of washing and with described sediment vacuum drying.

[00267] in the various embodiments of this process, described organic solvent can include, but not limited to acetonitrile, acetone, ethanol, ethyl acetate, methyl tertiary butyl ether, methyl ethyl ketone, isopropyl acetate and isopropyl alcohol.In preferred embodiments, described organic solvent is an ethanol.Described acid can include, but not limited to contain hydracid, for example, for instance, hydrobromic acid, hydrochloric acid, hydrofluoric acid and hydroiodic acid; Inorganic acid, for example, for instance, nitric acid, perchloric acid, sulfuric acid and phosphoric acid; Organic acid, for example, for instance, sulfonic acid (methanesulfonic acid, trifluoromethane sulfonic acid, ethyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid), acetic acid, malic acid, fumaric acid, succinic acid, citric acid, benzoic acid, gluconic acid, lactic acid, mandelic acid, glactaric acid, pounce on acid (Pamoic), pantothenic acid, oxalic acid and maleic acid; And amino acid, for example aspartic acid or glutamic acid.Described acid can be single acid or diacid, for example two halogen acids, two sulfuric acid, diphosphonic acid or two organic acids.In all cases, described acid all is used as achiral reagent, and its selection is not the priority of having an effect or precipitating based on any desired or known specific optical isomer to disclosure product.In preferred embodiments, selected acid is p-methyl benzenesulfonic acid.

[00268] in the embodiment of this process, when comprising at R (+) enantiomter, described starting mixt is at least 55% optical voidness, be preferably at R (+) enantiomter 80% optical voidness, be preferably at R (+) enantiomter 85% optical voidness, more preferably at R (+) enantiomter 90% optical voidness, with most preferably be at R (+) enantiomter 95% optically pure 2-amino-4,5,6, during 7-tetrahydrochysene-6-(propyl group amino) benzothiazole, described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be greater than 99% at the final chiral purity of R (+) enantiomter.When comprising at S (-) enantiomter, described original mixture is at least 55% optical voidness, be preferably at S (-) enantiomter 80% optical voidness, be preferably at S (-) enantiomter 85% optical voidness, more preferably at S (-) enantiomter 90% optical voidness, with most preferably be at S (-) enantiomter 95% optically pure 2-amino-4,5,6, during 7-tetrahydrochysene-6-(propyl group amino) benzothiazole, described 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be greater than 99% at the final chiral purity of S (-) enantiomter.Described final 2-amino-4,5,6, the chiral purity of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be preferably 99.6% or bigger, and 99.7% or bigger, be preferably 99.8% or bigger and more preferably 99.9% or bigger.In a more preferred embodiment, described final 2-amino-4,5,6, the chiral purity of 7-tetrahydrochysene-6-(propyl group amino) benzothiazolium salt can be 100%.

[00269] the embodiment purification result of each of several conditions of use embodiment of the present disclosure is listed in the table 8.

[00270] chemistry of RPPX prepared product and chiral purity can be used HPLC at least, ¹³C-NMR, ¹H-NMR and FTIR confirm.In preferred embodiments, RPPX can be synthetic by method described above, and it produces the material of enantiomer-pure.Alternately, can use on March 14th, 2007 to submit, the U.S. Provisional Application number 60/894 that is entitled as " method of synthetic and purifying R (+) and S (-) Pramipexole (Methods of Synthesizing and Purifying R (+) and (S)-pramipexole) ", on March 14th, 829 and 2007 submitted, the U.S. Provisional Application number 60/894 that is entitled as " method of enantiomerism purifying chipal compounds (Methods of Enantiomerically Purifying Chiral Compounds) ", disclosed purifying flow chart in 814, purifying RPPX from the mixture of RPPX and PPX, described provisional application integral body is by reference incorporated this paper into.

[00271] mode by explaining, and do not wish to be entangled in theory, in the described development step in synthetic and purge process, the solvability of RPPX and PPX may be identical.For instance, if building-up process is to carry out with described R (+) diamines of 90 grams and 10 described S (-) diamines that restrain, described final 2-amino-4,5,6, the solvability of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product is 10 grams to any enantiomter, the PPX product of the RPPX products of 80 grams and 0 gram will precipitate and (suppose from described diamines 100% chemical conversion and be converted into 2-amino-4 so, 5,6, molecular weight does not change during 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product).That is, the 2-amino-4,5,6 of 10 grams, every kind of enantiomter of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole may be expected to enter solution.This will obtain having at R (+) enantiomter the 2-amino-4,5,6 of 100% chiral purity, 7-tetrahydrochysene-6-(propyl group amino) benzothiazole product.The opposite ratio of initial feed in the described building-up process (R (+) diamines of S (-) diamines of 90 grams and 10 grams) may generate the PPX of 90 grams and the reactor product of 10 RPPX that restrain.From this reaction product mixture, the 2-amino-4 of 80 grams, 5,6, R (+) enantiomter of S (-) enantiomter of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole and 0 gram will be supposed to precipitate, and cause having at described S (-) enantiomter the 2-amino-4,5 of 100% chiral purity, 6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product.In this notion experiment, can imagine that the volume that reaction is used may have big potential impact to ultimate yield and chiral purity.Also be, volume will reduce yield too greatly, since more 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole enantiomter product will enter solution (but can improve chiral purity), volume is too little then can to improve yield, because less 2-amino-4,5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product will enter solution (but can reduce chiral purity).

[00272] uses the reaction volume of disclosure method and the actual limit of available optical purity, the various ratios of having tested the chiral purity of described initial diamines raw material for definition better.As shown in table 9, use the described initial R (+) and S (-) diamines of following ratio, test described synthetic and purge process, described ratio is: 80: 20,20: 80,85: 15,15: 85,90: 10,10: 90,95: 5 and 5: 95.In addition, also tested three kinds of specific reaction conditions, described three kinds of reaction conditions or on reaction volume, or on reacted recycling step, change.These evidences, 2-amino-4,5,6, two kinds of enantiomters of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole are equal to ground insoluble (or solvable) in the organic solvent that the various embodiments of building-up process disclosed herein are used.

Condition C: describedly react on 65-67 ℃, in the toluenesulfonic acid propyl ester of the DMF of 10 times of volumes and 1.25 equivalents, carry out.Then described reaction being cooled to room temperature also dilutes with the MTBE of 8 times of volumes.

Condition D: describedly react on 65-67 ℃, in the toluenesulfonic acid propyl ester of the DMF of 18 times of volumes and 1.25 equivalents, carry out.Then described reaction being cooled to room temperature also dilutes with the MTBE of 8 times of volumes.

Condition E: describedly react on 65-67 ℃, in the toluenesulfonic acid propyl ester of the DMF of 10 times of volumes and 1.25 equivalents, carry out.Then described reaction is cooled to room temperature and in MTBE, does not dilute.

[00273] the digital proof 2-amino-4,5,6 in the table 9, two kinds of enantiomters of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole have similar (if inequality) dissolubility.Further, described data show 2-amino-4,5,6, each enantiomter of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole synthetic has the efficient that is equal to.These data also prove described two kinds of enantiomters, and behavior is independent each other, and the dissolubility that is apparent in a kind of enantiomter shows to such an extent that be not subjected to the influence of the concentration of another kind of enantiomter in solution in the solution.For instance, the described various synthetic reactions of the carrying out of service condition C all have about 50% chemical yield, do not rely on the percentage that accounts for the enantiomter of leading diamines in the described initiation material.During the volume of organic solvent used in increasing described synthetic reaction, chemical yield reduces, and the chirality yield then raises.By contrasting the reaction of under condition C and D, carrying out, obviously, under the described conditions, the R (+) of 85: 15 ratios: S (-) diamines is when the organic solvent of 10 times of volumes is used in reaction, production has obtained having at described R (+) enantiomter the 2-amino-4 of 86.8% chiral purity, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product, and when the described organic solvent of 18 times of volumes is used in reaction, produce the 2-amino-4,5 that has obtained having 99.8% chiral purity at described R (+) enantiomter, 6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product.What it should further be appreciated that is, in the reaction of the organic solvent that uses more volume, chemical yield has reduced (in the condition C among 43% yield and the condition D 36% yield).

[00274] in the table 9, condition E is except that recycling step is not included among the MTBE dilution, and is identical with condition C.Observing MTBE has increased 2-amino-4,5,6 from synthetic reaction, the recovery (yield) of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole, but may reduce overall chiral purity.The R (+) of this phenomenon by contrasting 85: 15 ratios: the result of the test of carrying out in S (-) diamines draws, when described reaction comprises the MTBE organic solvent, production has obtained having at described R (+) enantiomter the 2-amino-4 of 86.8% chiral purity, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product, and when described reaction does not comprise the MTBE organic solvent, production has obtained having at described R (+) enantiomter the 2-amino-4 of 99.9% chiral purity, 5,6,7-tetrahydrochysene-6-(propyl group amino) benzothiazole product.Removing the MTBE dilution in described recycling step has reduced chemical yield; 43% yield is with respect to 39% yield among the condition E in the condition C.

[00275] can be converted into the pharmaceutically acceptable salt of RPPX by the RPPX of the chiral purity of above any one preparation of method.For instance, because it is high water-soluble, the RPPX dihydrochloride is preferred pharmaceutical salts.The RPPX dihydrochloride can be prepared in one step process by other the salt of RPPX, described one step process comprise with RPPX or RPPX salt and concentrated hydrochloric acid in the organic solvent of for example alcohol in the thermotonus that reduces.In some embodiments, the temperature of described reduction is from about 0 ℃ to about 5 ℃.Can add for example organic solvent of methyl tertiary butyl ether, and described reaction can be stirred extra one hour.RPPX dihydrochloride product can reclaim from described reactant mixture with alcohol washing and vacuum drying by filtering.

[00276] disclosed hereinly be used to make with every kind of method of purifying RPPX or its pharmaceutically acceptable salt all scalable so that plant-scale amount and yield to be provided, supply has the high chemistry and the product of chiral purity.In some embodiments, the RPPX of enantiomer-pure can be with manufacturing in enormous quantities, and is required as satisfying extensive medicinal demand.

[00277] each side of the present invention illustrates with reference to following non-limiting embodiment.

Embodiment

[00278] embodiment 1-dopamine receptor is to 2-amino-4,5,6, the mensuration of the R (+) of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole and the compatibility of S (-) enantiomter.

[00279] 2-amino-4,5,6, S (-) enantiomter of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole is characterized as at D in the past ₂(S and L isomer), D ₃And D ₄Although high-affinity dopamine receptor ligands on the acceptor is for D ₃Receptor subtype the highest visible compatibility.Will be from the dopamine receptor ligands compatibility tabulation (data are replicated in the table 10) of the PPX of periodical publication and RPPX.Although it is slightly different to carry out each research or experimental conditions, and has used different radioligands, described data show is at the comparable compatibility of different dopamine receptors.At 2-amino-4,5,6, the dopamine receptor compatibility research of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole S (-) and R (+) enantiomter also is shown in Table 10.These digital proofs 2-amino-4,5,6, two kinds of enantiomters of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole are for the unexpected big difference of the compatibility of all dopamine receptors.Table 10 shows that different with the expection according to document, document is expected to D ₂Receptor affinity on affinity, have 10-20 doubly difference and to D ₃Receptor affinity has 50 times difference on affinity, yet the value that we find is typically than higher 10 times (being respectively 290 times and 649 times) (table 10).

Table 10.2-amino-4,5,6, the comparison binding affinity data of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole enantiomter

^*Schneider, C.S.; Mierau, J., " Dopamine Autoreceptor Agonists:Resolution andPharmacological Activity of 2; 6-Diaminotetrahydrobenzothiazole and anAminothiazole Analogue of Apomorphine (dopamine autoreceptor activator: 2; fractionation and the pharmacologically active of the aminothiazole analog of 6-diaminourea tetrahydro benzothiazol and apomorphine) ", (1987) .J.Med.Chem.30:494-498

^*Wong, S.K.-F.; Shrikhande, A.V., S.K.-F.Wong, " Activation ofExtracellular Signal-Regulated Kinase by Dopamine D2 and D3 Receptors (extracellular signal-regulated kinase is through the activation of dopamine D 2 and D3 acceptor) ". (2003) Society forNeuroscience Abstracts

^{* *}Data from this research

[00280] RPPX and PPX are offered our signatory Cerep of research institution with dry powder form by the AMRI of manufacturer.The solution of RPPX and PPX is prepared by the storing solution among the DMSO.The RPPX of eight concentration of use or PPX (0.01nM, 0.1nM, lnM, 10nM, 100nM, 1mM, 10mM and 100mM) are to replace the radiolabeled dopamine agonist of standard reference.These concentration are at the clone's dopamine receptor (D that expresses the selected mankind _2S, D ₃) cell-line in test.Not significant interaction the between previous work in the document and our digital proof D1 and the D5 dopamine receptor.Be expressed as IC in the table 10 for the interactional result of group of RPPX or PPX and each acceptor ₅₀

[00281] these data show, the IC of RPPX on these acceptors ₅₀Value is the IC of PPX ₅₀The value about 290 to 649 times.Further, these data show at D ₂The IC of RPPX on the acceptor ₅₀The IC of value and PPX ₅₀The ratio of value is than ratio shown in the document, at least when its chiral purity exceeds detection limit (LOD 0.05%) (chiral purity is greater than 99.95%), greater than about 14 to 32 times.Similarly, these data show at D ₃The IC of RPPX on the acceptor ₅₀The IC of value and PPX ₅₀The ratio of value is than ratio shown in the document, and when its chiral purity exceeds detection limit (chiral purity is greater than 99.95%) at least is greater than about 13 times.These data also show if the dopamine receptor compatibility is the main contribution factor of the threshold dose tolerance of S (-) enantiomter, should the having than the maximum tolerated dose (MTD) of big at least 290 times of the MTD of S (-) enantiomter and/or NOAEL and/or do not have discernable ill-effect level (NOAEL) dosage of the prepared product of pure R (+) enantiomter.Therefore,, be low to moderate 0.5% or level still less, also may influence observed MTD and NOAEL even to the pollution of little S (-) enantiomter of RPPX composition of the present invention.

[00282] at 100% pure R (+) and S (-) enantiomter, and the IR prepared product of a mixture (R99.5%/S 0.5%) is determined research in the body of described MTD and NOAEL to embodiment 2-in dog.The form of RPPX is the two hydrochloric acid monohydrates of RPPX.

[00283] carry out in the following body in beasle dog (Beagle dog) research to test such hypothesis, promptly the observed big difference in the receptors bind affinity will change these two kinds of enantiomters at observed maximum tolerated dose (MTD) and/or there is not the observed big difference of discernable ill-effect level (NOAEL) at described R (+) and S (-) enantiomter.Give all to be prepared as the IR prepared product of each enantiomter ((in the limit of analyzing and testing limit) 100% pure prepared product) of highly purified compound to dog, perhaps by the prepared product of R (+) enantiomter of 0.5% S (-) enantiomerism body pollution.

[00284] use three groups, every group 4 to accept treatment in this research Male beasle dog.Every group of R (+) or S (-) enantiomter that all is prepared as highly purified compound, perhaps by 0.5% 2-amino-4,5,6, the various dosage of the prepared product of R (+) enantiomter of S (-) the enantiomerism body pollution of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole.Medicament is by the tube feed orally give and continue to carry out clinical observation after dosed administration: to initial 4 hours per hour once, then at the intermittence between the dosed administration or behind the dosed administration, every day, twice cage limit observed.Availability to clinical sign, lethality, damage and food and water is done observation.Allowed the animal fasting in preceding 24 hours at dosed administration.Every group dog all only is exposed to a kind of medicine, perhaps described composition; Every kind of medicament all only is administered once, and the medicament of administration subsequently is after 4 days convalescence.These data are summarized in table 11.

[00285] at R (+) enantiomter when deliver medicine to accepted the treatment dog the time, NOAEL is established as the dosage level of 25mg/kg, and the dosage level of 75mg/kg can be considered to be receiving the treatment dog in MTD.Find in the dog of accepting treatment, to be the NOAEL of 0.00125mg/kg and the MTD of 0.0075mg/kg at described S (-) enantiomter.Composition (99.5% RPPX and 0.5% PPX) for the mixture that contains described two kinds of enantiomters, find that described NOAEL is 0.25mg/kg, it is corresponding to the dosage of S (-) enantiomter of 00125mg/kg, and MTD is 1.5mg/kg, corresponding to the dosage of S (-) enantiomter of 0.0075mg/kg.These data show that in the dog of accepting treatment for 2-amino-4,5,6, greater than about 20,000 times, and MTD is greater than about 10,000 times to the NOAEL of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole R (+) enantiomter than S (-) enantiomter.

Table 11: at 2-amino-4,5,6, the clinical observation of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole composition administration in male beasle dog

^*Be subjected to number of animals/total number of animals of affect

^*The mixture of 99.5% RPPX and 0.5% PPX

[00286] data shown in the table 11 show that the receptor affinity of being identified (referring to table 10) contributes to viewed at 2-amino-4 in direct mode, 5,6, the R (+) of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole and the MTD of S (-) enantiomter and the difference of NOAEL dosage.It is excessive 99.9% that the chiral purity (reference table 5 and 6) that these data are further illustrated in Pramipexole R (+) enantiomter in the embodiment of the present composition may need, and depends on last accumulated dose, to avoid the adverse side effect of PPX.

[00287] digital proof in the further face of land 11 can directly be determined by the dosage of S (-) enantiomter in the composition for the NOAEL and the MTD of combination composition (99.5% RPPX and 0.5% PPX).Therefore, may reduce the MTD and the NOEL of described composition to the pollution of little (fractions) of RPPX composition by PPX.For instance, in these experiments, respectively, the MTD of Pramipexole is reduced to the accumulated dose (50 times) of the 1.5mg/kg of described blend compositions from the 75mg/kg at R (+) enantiomter, and NOAEL is reduced to 0.25mg/kg (100 times) from 25mg/kg.Because the change of MTD and NOAEL can be by 2-amino-4 in the mixture, 5,6, the dose prediction of S (-) enantiomter of 7-tetrahydrochysene-6-(propyl group amino) benzothiazole, change at the mixture of any the unknown can be calculated based on the percentage by the RPPX that PPX polluted, and is relevant with MTD and NOAEL at PPX.This shows that any dosed administration solution by the RPPX that PPX polluted will have measurable effect on the indicator of these dosage tolerances.

[00288] the I phase of embodiment 3.1-on toxicologic study on rat and the miniature pig and healthy adult volunteer studied.Two week and the trimestral toxicologic studies of RPPX on rat and miniature pig, have been finished.The NOAEL dosage level is established as at the 150mg/kg in two weeks of rat and trimestral 100mg/kg, and at the 75mg/kg and the trimestral 50mg/kg in two weeks of miniature pig.Healthy adult volunteer's the I phase studied has proved that RPPX is up to the single dose that increases progressively of 300mg with to 4 ¹/ ₂My god, be safety and well-tolerated every day during up to the multidose of 200mg.

Label has been specified the initial dose of 0.125mg and the maximum total daily dose of 4.5mg.Therefore, this I issue is according to proof, and RPPX in (1)

The initial dose that the initial dose height is at least 2400 times and (2) are

The stable state dosage of at least 44 times of the highest recommended dose height under to give can be safe.The form of RPPX is the two hydrochloric acid monohydrates of RPPX.

[00289] PRELIMINARY RESULTS of this clinical research and this toxicologic study has been discussed.Under the stable state, rat, it is linear that being exposed among miniature pig and the human experimenter is on the whole research dosage.Behind the dosed administration 3 months, the current no discernable ill-effect level (NOAEL) in the rat is confirmed as 100mg/kg; And the current NOAEL in miniature pig is confirmed as 50mg/kg.In rat, the average steady state AUC of the NOAEL dosage of 100mg/kg is at male and femalely be respectively 61,299 and 61,484h*ng/mL, and for miniature pig, the NOAEL dosage of 50mg/kg are then at male and femalely be respectively 91,812 and 131,731h*ng/mL.In the mankind, the average steady state AUC of 100mg Q12H dosage (the total daily dose of 200mg) is 2,574h*ng/mL.This medicine is in the healthy adult experimenter, single dose is up to 300mg and multidose during up to 100mg Q12H, be safe, well-tolerated and do not had clinically remarkable adverse events, and predict at dosed administration after 13 weeks, plan to be that the relevant mankind of 250mg Q12H expose lower greater than 13 times than seeing in the male miniature pig exposure under NOAEL with a daily dose, and than seeing in male and the female rats low about 9 times of the exposure under NOAEL.

[00290] 3.2-clinical research.In the healthy adult volunteer to RPPX 4 ¹/ ₂It 50,150 and the single IR dosage on the one of 300mg and 50 and twice on the one IR dosage of 100mg study.This medicine is safety and well-tolerated in two researchs, and serious adverse events does not all appear in arbitrary research, because of the termination of adverse events or dosage is relevant or clinically serious adverse events.The most frequent adverse events occurring is dizzy and headache, and their severity is light to moderate and has alleviated and need not to intervene.

[00291] (blind method) safety of 3.2.1-RPPX and pharmacokinetics result sum up (the single dose research that increases progressively).Three order every group of 8 experimenters of group (sequential panels) with 50,150 and the IR dosage level that increases progressively of 300mg accept the single dose of RPPX (6 experimenters) or placebo (2 experimenters).Safety is observed and is comprised vital sign, health check-up, clinical labororatory's test, ECGs and adverse events report.Collected blood and urine sample in 72 hours before dosage and behind dosage, to estimate its pharmacokinetics.Whole 24 experimenters have finished research according to plan.There is not serious adverse events; All 46% among the experimenter had at least one non-serious adverse events (AE) by report.Most of AEs are slight; The AE that the frequency of occurrences is the highest is the slight dizziness in 21% experimenter.All not having significant clinically safety on a dosage water in office is flat observes.

[00292] pharmacokinetic data shows RPPX by fast Absorption, at 50,150 and 300mg dosage group, behind dosage about 2 hours, reaches 125,360 and the average Cmax (referring to following Fig. 1 and table 12) of 781ng/mL respectively.At 50,150 and the average exposure (AUC of 300mg dosage group _0-∞) be respectively 1254,3815 and 8623h*ng/mL.C _MaxWith AUC the dosage range of whole test all with the proportional increase of dosage.At whole dosage range, the homaluria of prototype medicine accounts for about 70% of medicine elimination.Average T ¹/ ₂Be 6-7 hour, and uncorrelated with dosage.To after the single 150mg administration after the meal early of higher fatty acid/high heat with fasted conditions under mean plasma concentration (Fig. 2) after the 150mg administration and the relatively proof of average pharmacokinetic parameter (table 12), canteen is to the absorption of RPPX and eliminate and do not have in essence to influence.

[00293] the single IR oral dose of this result of study proof 50,150 and 300mg RPPX is safe and well-tolerated.This medicine is that oral biology is available, and linear pharmacokinetics.Absorbing and eliminating not influenced by higher fatty acid/high heat canteen.

Table 12: to the healthy volunteer single 50mg, 150mg under the fasted conditions and 300mg dosage and behind 150mg oral administration under the feeding condition pharmacokinetic parameter at RPPX sum up

¹Mean value ± standard deviation (N) is except T _MaxThat report is median (N).

[00294] (blind method) safety of 3.2.2-RPPX and pharmacokinetics result sum up (the multidose research that increases progressively).This research is being carried out and the treatment task is not being taken off blindly as yet, only has clinical observation and pharmacokinetic data to get to preceding two groups.Up to the present, 2 order every group of 8 experimenters of group are registered the multidose of accepting IR RPPX (6 experimenters) or placebo (2 experimenters).First group gives the single IR dosage of 50mg, after 48 hours, 4 ¹/ ₂During it with 50mg Q12 hour IR dosed administration (twice of every day) repeatedly.Second group gives the single IR dosage of 100mg, after 48 hours, during 41/2 day with 100mg Q12 hour IR dosed administration (twice of every day) repeatedly.Safety is observed and is comprised vital sign, health check-up, clinical labororatory's test, ECGs and adverse events report.Collected blood sample in turn to estimate single medicament pharmacokinetics in 48 hours before the 1st day dosage and behind the dosage.Before the 5th, 6 and 7 day dosage, collect blood sample confirming to reach stable state, and at the 7th day dosage after collected blood sample in 72 hours in turn to estimate the stable state pharmacokinetics of RPPX.After quantitative administration in the 7th day, collect urine sample 12 hours the time to estimate homaluria.

[00295] up to the present whole 16 experimenters of registration finish this research according to plan.Occur dead, serious adverse events report in the research or end because of adverse events.Two kinds of average well-tolerated of dosage water.In group 1, the intensity of all adverse events is slightly, removes and reports that in 2 experimenters the moderate headache is arranged.In group 2, the intensity of all adverse events is slightly, removes and reports that in 1 experimenter moderate " back is stiff " (stiffness in back) and the reaction of the moderate blood vessel fan property walked are arranged.Main researcher is reported in 8 experimenters of group 1 (50mg group) dosed administration 1, and heart rate is slightly accelerated (no blood pressure) when having 2 experimenters asymptomatic standing to occur in 8 experimenters of group 2 (100mg group) dosed administration.All not occurring significant clinically safety on arbitrary dosage level observes.

[00296] pharmacokinetic data is shown among table 3 and Fig. 3.To accepting the several experimenters of 50mg Q12H, from the 1st day to the 7th day, C _MaxAnd AUC _(0-12)Increased by 37% and 40% respectively, and T _MaxDo not change in essence.To 50mgQ12H dosage group, the 7th day average exposure AUC _(0-12)Be 1449h*ng/mL.To accepting the several experimenters of 100mg Q12H, from the 1st day to the 7th day, C _MaxAnd AUC _(0-12)Increased by 24% and 38% respectively, and T _MaxDo not change in essence.To 100mg Q12H dosage group, the 7th day average exposure AUC _(0-12)Be 2465h*ng/mL.The repeatedly oral dose of 50 and 100mg RPPX of twice administration every day of this result of study proof is safe and well-tolerated.This medicine be available and its pharmacokinetics of oral biology in stable state for linear, do not have significantly accumulation.

Table 13 couple healthy volunteer under fasted conditions the 1st day 50mg and 100mg dosage, the 3rd to 6 day

The pharmacokinetic parameter of RPPX is summed up during the oral administration of Q12H and the 7th day single dose

¹Mean value ± standard deviation (N) is except T _MaxThat report is median (N).

[00297] 3.3-toxicologic study.In 2 all repeated doses toxicologic studies in rat, through 14 days, 50,150 and the 500mg/kg IR dosage of animals received RPPX.RPPX causes death when the high dose of 500mg/kg, and observes animal to two kinds of sexes all statistics occurs on weight increase and food consumption and change significantly in the animal of putting to death to whole latter stage that survives.The target organ toxicity that equal inorganization pathological examination is confirmed on the dosage in office.The NOAEL of the 2 week research of this in rat is confirmed as 150mg/kg.This research after, finished 30,100 and 300mg/kg dosage on 3 months and 6 months repeated doses toxicologic study.The result of research in these 3 months is included in the target organ toxicology of some histopathological examinations of maximum dose level (300mg/kg), except that taking place in the high dose rat, several examples continue about 2 minutes convulsions, the not death relevant with test sample does not have significant clinical observation yet.As if the health of described animal be not subjected to the harmful effect of these convulsions.Liver (the atomic level cholestasia relevant), ileum small intestine (atomic level mineralising) and thymus gland with the total bilirubin that increases (with the control group atomic grade of relevant lymph atrophy of low group thymic weight of comparing) in observe the trickle variation of being correlated with test sample.The NOAEL of research in these 3 months is considered to 100mg/kg in rat.During the 13rd week, at the systemic exposure (AUC of the NOAEL of 100mg/kg dosage _0-last) be in male 61,299h*ng/mL and in female 61,484h*ng/mL.The survival vegetative period of 6 months toxicologic study, " in-life phase " finished in the recent period in rat, was about to carry out histopathological examination.During the execution in 13 weeks and 26 weeks, all do not have dead on arbitrary dosage level.

[00298] in 2 all repeated doses toxicologic studies to miniature pig, through 14 days, the IR dosage of 7.5,25 and the 75mg/kg of animals received RPPX.The target organ toxicity that equal inorganization pathological examination is confirmed on the dosage in office.Clinical observation comprises salivary secretion, the movable minimizing, and vomiting and apocleisis (inappetance) are wherein vomitted the more male height of generation in female, and are organized at 75mg/kg mostly.The generation of vomiting in 75mg/kg group (in 5 of 8 animals of dosed administration 75mg/kg at least one routine incident of having merely hit) shows that this dosage is near the tenability limit of RPPX chronic dosing regimen in miniature pig.Do not change owing to when this high dose, observe the toxicology relevant, think that therefore the NOAEL of this 2 week research is greater than or equal to 75mg/kg with test sample.Based on this research, in miniature pig, the repeated doses research of 3 months, 6 months of RPPX and 9 months is originated in 7.5,25 and the dosage level of 75mg/kg.Because in the death of 75mg/kg level,, dosage level is reduced to 7.5,25 and 50mg/kg at 2nd month.The repeated doses research of these 3 months and 6 months 7.5,25 and the dosage level of 50mg/kg finish, and 9 months repeated doses research is carried out.After exposing three months, after the sacrifice of animal, carry out histopathological examination, the average target organ toxicity unconfirmed of a dosage water in office.The NOAEL of research in these 3 months is considered to 50mg/kg in miniature pig.NOAEL dosage at 50mg/kg/ days, the systemic exposure (AUC0-24) in the 13rd when week be in male 91,812h*ng/mL and in female 131,731h*ng/mL.The survival of 6 months toxicologic studies is finished vegetative period in the recent period in miniature pig, is about to carry out histopathological examination.During the execution in 13 weeks and 26 weeks, arbitrary dosage water does not on average have the dead or significant clinical observation that causes because of test sample.Ongoing 9 months toxicologic study is now through 7 months in miniature pig, and the dead or significant clinical observation that causes because of test sample does not on average take place a dosage water in office.

[00299] the human consumption of 3.4..The development that RPPX is used for the treatment of ALS is based on the maximum tolerated dose strategy, tolerance or data of safety that this strategy or come is studied among the comfortable mankind, or from the result of animal toxicology research.Up to the present, in the mankind, also there is not the observation of dosage restriction tolerance.Therefore, in the mankind, carrying out dosed administration, be necessary to check closely the exposure of in rat and miniature pig, observing toxicity.The pharmacokinetic data that obtains so far shows that the pharmacokinetics among the mankind still can be directly proportional with dosage when higher consumption, and its accumulation factor will be constant.Safety that draws from 3 months toxicologic study rat and miniature pig and poison show for kinetic results, in rat up to 100mg/kg and in miniature pig the chronic dosing regimen up to 50mg/kg do not have ill-effect.Therefore, it is about 7 that the analysis of the margin of safety that exposes at RPPX between the NOAEL of miniature pig and the human exposure plan is supported among the mankind that the RPPX stable state as the total daily dose of 500mg of 250mg Q12H administration up to the process plan of the total daily dose of 500mg at least exposes, 000h*ng/mL, this value is lower more than 13 times in the exposure of NOAEL than seeing the male miniature pig of dosed administration after 13 weeks, hangs down about 9 times than seeing the male and female rats of dosed administration after 13 weeks in the exposure of NOAEL.

[00300] Figure 4 and 5 are respectively to compare the variation diagram of the exposure of rat and miniature pig with dosage with the mankind.Each figure is presented in 2 weeks and two evaluations in 13 weeks exposure on each dosage level of every kind of species administration and the relation between the dosage, wherein exposes the expression with AUC (h*ng/mL), and dosage is represented (mg/m with corpus surface area ²).The individual data point that has error bar is this mean value ± SD.The dotted line horizontal line that is arranged in the bottom on two charts show the stable state AUC the 250mgQ12H dosage mankind of deduction (7,000h*ng/mL).Table 17A and table 17B sum up for the integration that all human pharmacokineticss that obtain in studying two I phases are estimated.

The summary that the human pharmacokinetics that table 17A obtains in twice I phase of healthy volunteer studied is estimated

Research	Dosage (mg)	The dosed administration scheme	Food	??Cmax??(ng/mL)	??Tmax??(h)	??AUC(0-t)??(h*ng/mL)	??AUC(inf)??(h*ng/mL)	??AUC(0-12)??(h*ng/mL)
									??CL001	??50	??SD	Fasting	??125??±22.0(6)	??2.04(6)	??989??±295(6)	??1,245±347(6)	??--
	??150	??SD	Fasting	??360??±60.4(6)	??2.04(6)	??3,387??±746(6)	??3,815±972(5)	??--
										??300	??SD	Fasting	??781??±158(6)	??1.96(6)	??8,339??±3,202(6)	??8,623±3,262(6)	?--
	??150	??SD	Fasting	??315??±062(6)	??2.58(6)	??3,099??±920(6)	??3,397±944(6)	??--
									??CL002	??50	Q12H (the 1st day)	Fasting	??139??±15.3(6)	??1.83(6)	??1,463??±280(6)	??1,502±280(6)	??1,035±121(6)
		(the 7th day)	Fasting	??191??±20.9(6)	??1.75(6)	??-	??-	??1,449±221(6)
										??100	Q12H (the 1st day)	Fasting	??248??±30.4(6)	??1.92(6)	??2,545??±497(6)	??2,574±505(6)	??1,776±260(6)
		(the 7th day)	Fasting	??306??±055(6)	??2.00(6)	??-	??-	??2,465±299(6)
										??250	Q12H (the 1st day)	Fasting	??-	??-	??-	??-	??-
		(the 7th day)	Fasting	??-	??-	??-	??-	??-

Mean value ± standard deviation (N), except the Tmax report is median (N).

The SD=single dose

The summary (continuing) that the human pharmacokinetics that table 17B obtains in twice I phase of healthy volunteer studied is estimated

Mean value ± standard deviation (N) is except T _MaxThat report is median (N).

The SD=single dose

[00301] stable state in rat, miniature pig and human experimenter is exposed to and is linear on the whole research dosage.Behind the dosed administration 3 months, the NOAEL in the rat is confirmed as 100mg/kg; And the NOAEL in the miniature pig is confirmed as 50mg/kg.In the rat at the average A UC of NOAEL at male and femalely be respectively 61,299 and 61,484h*ng/mL, in the miniature pig then at male and femalely be respectively 91,812 and 131,731h*ng/mL.In the mankind, the average A UC of stable state 100mg Q12H dosage (the total daily dose of 200mg) is 2,574h*ng/mL.

[00302] embodiment 4-contains the preparation of the capsule of RPPX.RPPX two hydrochloric acid monohydrates are not added excipient to be inserted in the hard gelatin capsule.This capsule that is used for medicine is the opaque gelatine capsule of #00 blueness from Huo Jinsi chemicals group (Hawkins ChemicalGroup).The dose intensity of producing is 50 and 500mg.The Cebo-Caps that is complementary is filled with microcrystalline cellulose.By weighing empty capsule and write down its weight (W separately _e) prepare capsule.The active drug substance of specified amount is weighed separately and is used

Fill the manual capsule bottom that is filled into of funnel.The purity of use 1.0638 is adjusted the weight (hydration) that coefficient is adjusted water in this salt form, and for example, 50mg dosage should have the target of 50 * 1.0638=53.16mg and fill.The capsule top is combined with the capsule bottom of filling.The capsule that to fill is weighed then, and writes down this weight (W _f).Calculated weight (the W of capsule Chinese traditional medicine material _f-W _e) also be recorded.If this calculated weight nominal weight+/-5% scope in, then this capsule is cleaned, and polishes and place the container of suitable mark.If this calculated weight exceeds specified scope, then this capsule is dropped.Free alkali in each capsule (free-base) weight (in every mg capsule in the material weight of free alkali multiply by filling weight) is 90% to 100% of the label amount calculated.Total impurities≤2%.Outward appearance is to contain the blue capsule of adularescent to pale powder.

[00303] embodiment 4B-contains the preparation of the tablet of RPPX.Has the preparation of compositions shown in the capsule employing table 17 of 125mg dose intensity.Capsule prepares under 60 to 74, relative moisture are 30 to 60% condition usually.Microcrystalline cellulose, mannitol, Crospovidone, dolomol and RPPX (grinding) weigh according to the amount shown in " amount/criticize " row in the table 14.Then microcrystalline cellulose, mannitol, Crospovidone and RPPX were sieved #20 purpose stainless steel mesh by hand, and transferred in the Maxiblend V-blender with 4 quarts of housings (shell).Then this material was mixed 10 minutes with Maxiblend V-blender.Again with dolomol with the manual mesh screen mistake of 30 purpose stainless steels, and move in the blender.Mixed this powder then five minutes.Afterwards final blend is emptied in the double-deck PE lining drum of label, and gross weight, tare weight and the net weight of record mixture.

[00304] tablet uses and to have 5 pair 3/8 " circular punch die, standard, concave surface cutter and gravity supplies with the MinipressII B preparation of frame.Final blend is placed hopper, and the tablet press machine is provided with running according to the concrete specification in the table 15.

Table 14: tablet and batch composition

Composition	Percentage	Amount/unit (mg)	Amount/crowd (g)
				RPPX (grinding)	??40.00	??125.00	??400.000
Microcrystalline cellulose (Avicel PH102) (thinner)	??35.25	??110.16	??352.512
				Mannitol (Pearlitol SD100) (thinner)	??20.00	??62.50	??200.000
Crospovidone (Polyplasdone XL) (disintegrant)	??4.00	??12.50	??40.000
				Dolomol (plant origin, 905-G level) (lubricant)	??0.75	??2.34	??7.488
Add up to	??100.00	??312.50	??1000.000

Table 15: the tablet press machine is provided with

Parameter	Target (scope)
		Average tablet quality (10)	(3.125g 3.031g is to 3.219g) (+/-3%)
Target weight (monolithic)	(312.5mg 296.9mg is to 328.1mg) (+/-5%)
		Target hardness	12Kp (6Kp is to 18Kp)
Pressing speed	20rpm (10 to 30rpm)

[00305] preparation of embodiment 5-RPPXp-TSA salt: condition A: all reagent are all available from CNH technologies, Fisher, and Aldrich, G.J.Chemicals, Puritan, TCI and Spectrum, and directly use.Proton NMR spectrum records in 300MHz on Bruker AC 300 spectrometers.HPLC to chiral purity analyzes

The IA post (5M, on 250 * 4.6mm), in 30 ℃, (80: 20: carried out to use normal heptane/ethanol/diethylamine by flowing phase 2v/v/v).HPLC to chemical purity analyzes

(3.5M on 150 * 4.6mm), in 30 ℃, uses two kinds of flowing phase (TFA aqueous solution of A-0.5% to post; TFA methanol solution with B-0.5%) carries out.Use 5%B to the gradient separations diamines of 80%B and the peak of Pramipexole.Two HPLC analyze the detection wavelength that uses and are 265nm.

[00306] the arbitrary process that describes in detail among the embodiment 5-14 all scalable to the industrial processes scale shown in embodiment 15-17.Some embodiment is all existing detailed description the in detail to prove that its chemistry and chirality yield do not rely on synthetic scale on laboratory scale and commercial production scale.

On [00307] 2.0 liter the three-neck flask, the charging hopper of overhead type agitator, hygrosensor, heating mantles, Clarkson joint, reflux condenser and 500ml is housed.45 gram R (+)-2 are housed, 6-diaminourea-4,5,6,7-tetrahydrochysene-benzothiazole, the 750ml normal propyl alcohol of packing into subsequently in this flask.Continue to stir down, the temperature that described mixture is heated to 95 ℃ during 15 minutes generates settled solution.In this charging hopper, be enclosed in the solution of gram toluenesulfonic acid propyl ester of 74 in the 250ml normal propyl alcohol and 60ml diisopropylethylamine (diisopropylethyleamine).Continue to stir down, during 4 hours, this drips of solution is added in this flask of 2.0 liters.This reacts on 95 ℃ and under agitation proceeds extra 8 hours, afterwards this solution is brought to room temperature, and continues to stir extra 4 hours.

[00308] sediment adopts filtration method to collect, and at every turn with 100ml SILVER REAGENT alcohol washing three times.Then with pure washed precipitate cake with the washing of 100ml normal heptane, under high vacuum dry 2 hours again.The final weight of dry products is the yield of 53.2 gram expressions 52.2%.Use HPLC to determine described R (+)-2,6-diaminourea-4,5,6, the chemical purity of 7-tetrahydrochysene-benzothiazole (RPPX) is 98.2%, chiral purity surpasses 99.5%. ¹H NMR and ¹³C NMR is used to confirm its structure.

[00309] preparation of embodiment 6-racemic Pramipexole p-TSA salt: the three-neck flask of condition A:250ml is equipped with the charging hopper of magnetic stirring apparatus, hygrosensor, heating mantles, Clarkson joint, reflux condenser and 100ml.In this flask, pack into 5 the gram racemics 2,6-diaminourea-4,5,6,7-tetrahydrochysene-benzothiazole, the 80ml normal propyl alcohol of packing into subsequently.Continue to stir down, the temperature that described mixture is heated to 95 ℃ during 15 minutes generates settled solution.In described charging hopper, be enclosed in the solution of gram toluenesulfonic acid propyl ester of 10.12 in the 28ml normal propyl alcohol and 8.2ml diisopropylethylamine.Continue to stir down, during 2 hours, described drips of solution is added in the described 250ml flask.React on 95 ℃ and under agitation proceed extra 6 hours, afterwards described solution is brought to room temperature, and continue to stir extra 6 hours.

[00310] sediment adopts filtration method to collect, and uses 25ml SILVER REAGENT alcohol washed twice at every turn.Then with pure washed precipitate cake with 25ml normal heptane washing under high vacuum dry 1 hour again.The final weight of dry products is the yield of 5.12 gram expressions 45%.Use HPLC to determine described racemic 2,6-diaminourea-4,5,6, the chemical purity of 7-tetrahydrochysene-benzothiazole (racemic Pramipexole) are that 97.12% its chiral purity is shown as 1: 1 R (+) and the mixture of PPX. ¹H NMR is used to confirm its structure.

[00311] preparation of embodiment 7-RPPXp-TSA salt: on the three-neck flask of condition C: 12L, the charging hopper of overhead type agitator, hygrosensor, heating mantles, Clarkson joint, condenser and 500ml is housed.In this flask, pack into 250 the gram R (+)-2,6-diaminourea-4,5,6,7-tetrahydrochysene-benzothiazole (R (+) diamines), the 2L dimethyl formamide (DMF) of packing into subsequently.Continue to stir down, this mixture is heated to 65 ℃ temperature.In this charging hopper, be enclosed in the solution of gram toluenesulfonic acid propyl ester (1.25 molar equivalent) of 386.6 among the 500ml DMF and 322ml diisopropylethylamine (1.25 molar equivalent).This solution was added drop-wise to during 2.0 hours in this 12L flask.This reaction is by analyzing monitoring on HPLC.

[00312] this is reflected at 65 ℃ and proceeds extra 5 hours, then this solution is cooled to gradually room temperature and stirs to spend the night.Dilute this solution and stirred extra 0.5 hour with 2L MTBE.Sediment is collected with filtration method, and washs with the MTBE of 500ml, more at every turn with 500ml SILVER REAGENT alcohol washing three times.The washed precipitate cake is dry down in high vacuum.

[00313] final weight of this dry products is 317.6 grams, the yield of expression 56%.Use HPLC to determine this R (+)-2,6-diaminourea-4,5,6, the chemical purity of 7-tetrahydrochysene-benzothiazole (PPX) are that 98.4% chiral purity surpasses 99.8%. ¹H NMR and ¹³C NMR is used to confirm its structure: ¹H NMR (300MHz, DMSO-d6) δ 8.5 (br.s, 2H), 7.5 (d, 2H), 71.2 (d, 1H), 6.8 (s, 2H), 3.4 (m, 1H), 2.95 (m, 3H), 2.6 (m, 2H merge with the DMSO peak), 2.3 (s, 3H), 2.15 (m, 1H), 1.8 (m, 1H), 1.55 (m, 2H), 0.9 (t, 3H); ¹³C NMR (300MHz.DMSO-d6) δ 167.0,145.5,144.6,138.4,128.6,125.8,110.7,53.9,46.5,25.8,25.6,24.5,21.2,19.6,11.3.

[00314] embodiment 8-RPPXp-TSA salt is to the conversion of RPPX dihydrochloride: under continuing to stir with RPPXp-TSA salt (50 grams; 0.13mol) put into the absolute ethanol of 150ml, and be cooled between 0 to 5 ℃.Slowly add dense HCl (33ml) in this reaction, maintain the temperature at simultaneously between 0 to 5 ℃, and this mixture was stirred extra 15 minutes.Add MTBE (200ml) to this mixture, and under this temperature, continue to stir extra 1.5 hours.Filter this reactant mixture then,, spend the night 30 ℃ of vacuum dryings with MTBE/ ethanolic solution (2: 1,2 * 50ml wash volumes) washed twice.Final products are the RPPX dihydrochloride of 34 grams, indicate 92% yield, and the chemical purity of determining through HPLC is 97.3%.

[00315] embodiment 9-RPPXp-TSA salt to the conversion of RPPX dihydrochloride with RPPXp-TSA salt (10 grams; 0.026mol) be dissolved among the 200ml IPAC, and continuing to be cooled to 15 ℃ under the stirring.Bubbling HCl gas is 1 hour in this slurry.Filter this mixture then, with the IPAC washing, and at room temperature vacuum drying is spent the night.Final products are the RPPX dihydrochloride of 6.8 grams, the yield of indication 92%, and the chemical purity of determining through HPLC is 97%.

[00316] embodiment 10-RPPXp-TSA salt is to the conversion of RPPX free alkali: with RPPXp-TSA salt (25 grams; 0.065mol) be dissolved among the 200ml DCM and be mixed into slurry.Add 10ml water and with the NaOH of 12ml 6N make this mixture alkalize to pH be 11-12.Two-phase separately, and with 200ml DCM aqueous phase extracted.With the organic facies that merges through MgSO ₄Drying, by

Filter and concentrate.Residue is dissolved among the 100ml MTBE, and the pulp several hrs.Leach solid then, with the MTBE washing and 35 ℃ of vacuum dryings.Final products are the RPPX dihydrochloride of 9.1 grams, the yield of indication 66%, and the chemical purity of determining through HPLC is 98%.

[00317] embodiment 11-RPPX p-TSA salt is to the conversion of RPPX free alkali: being formed on the 200 gram scales of free alkali carried out.In that being housed, overhead type agitator/temperature takes into account RPPXp-TSA salt and the 1L water of the 200g (0.522mol) that packs in the 5L three neck round-bottomed flasks of charging hopper.Stir this mixture and be cooled to 10 ℃.By during 15 minutes, slowly adding the NaOH of 200ml 6N, make this slurry alkalize to pH be about 11-12.This reactant mixture with 500ml salt solution (being dissolved in the sodium chloride in the water) dilution, is used 3 * 1L dichloromethane extraction again.The organic facies that merges with the salt water washing of 1.0L is through MgSO ₄Drying is filtered and be concentrated into to drying.With this residue and 1: 1 IPAC of 1L: the normal heptane development, stirred the slurry that obtains 1 hour, filter and with filter cake with 2 * 250ml1: 1 IPAC: the normal heptane mixed liquor washs.Collect this filter cake and, obtain 94.1 gram RPPX (85.5%) white solids in dry 24 hours of 40 ℃ of high vacuums.Its chemical purity is 100%AUC through the HPLC test, and its chiral purity is 100%AUC through the HPLC test. ¹H NMR and ¹³C NMR is used to confirm its structure: ¹H NMR (300MHz, DMSO-δ 6) δ 6.6 (s, 2H), 2.8 (m, 2H), 2.5 (m, 2H merge with the DMSO peak), 2.2 (m, 1H), 1.9 (m, 1H), 1.5-1.3 (m, 4H), 0.85 (t, 3H); ¹³C NMR (300MHz, DMSO-d6) δ 166.2,144.8, and 113.6,54.2,49.1,30.0,29.6,25.2,23.5,12.3.

[00318] embodiment 12-RPPX free alkali is to the conversion of RPPX dihydrochloride: with free alkali (4.8 grams of RPPX; 0.022mol) be dissolved among the 200ml IPAC, and be cooled to 15 ℃.HCl gas bubbling was gone in this slurry 1 hour.Filter this mixture then, spend the night with the IPAC washing and in room temperature vacuum drying.Final products are the RPPX dihydrochloride of 6.4 grams, the yield of indication 100%, and the chemical purity of determining with HPLC is 97%.

[00319] embodiment 13-RPPX free alkali is to the conversion of RPPX dihydrochloride free alkali (50 grams with RPPX; 0.13mol) be dissolved among the 500ml IPAC.Continue to stir down, in 25 ℃ the temperature dense HCl of 78ml that in this mixture, slowly packs into.This mixture stirred in environmental temperature (～25 ℃) spend the night, filter and in 40 ℃ of vacuum dryings.Final products are the RPPX dihydrochloride of 68 grams, the yield of indication 95%.

[00320] embodiment 14-with the optics purifying of the RPPX of achirality acid addition will at the Pramipexole of R (+) enantiomter enantiomerism enrichment (～300mg) in 75 ℃ of selected solvents that are dissolved in 10ml (referring to the embodiment in the table 8; Ethanol or acetonitrile).All samples is all observed dissolving fully.The acid addition is in that (solvent is an ethanol at p-TSA; 2.97ml the acid of 0.5M) and MSA (solvent is an acetonitrile; 1.49ml1.0M acid) time be 1.05 molar equivalents, and (solvent is an acetonitrile at fumaric acid; 5.84ml the acid of 0.5M) and phosphoric acid (solvent is an acetonitrile; 2.90ml1.0M acid) time be to make under 2.05 molar equivalents.This reactant mixture is cooled to room temperature with 25 ℃/hour speed, and extra 19 hours of stirring at room.The solid by filtration that obtains in this development step is separated, and in room temperature high vacuum drying.These products employings HPLC, ¹H NMR, thermogravimetric analysis, differential scanning calorimetric, X-ray powder diffraction (XPRD), Fourier transform infrared spectroscopy and the analysis of wet absorption (moister-sorption) analytical method.The XPRD collection of illustrative plates shows the p-TSA of RPPX, and MSA and fumarate form are crystal, and the phos-phate forms of RPPX is amorphous.

[00321] commercial scale of embodiment 15-racemic diamines splits: it is racemic 2 to pack in the no jacketed reactor of 72L, 6-diaminourea-4,5,6,7-tetrahydrochysene-benzothiazole (racemic-diamines) (4.5kg; 26.6mol) and 58.5L water, and heat this suspension and arrive about 65 ℃ temperature for extremely about 60 ℃.By (D)-(-)-tartaric acid (3991 grams that make an addition to the monovalent in the 4.5L water; 26.6mol) realize fractionation to this enantiomter, subsequently the solution that obtains is heated to about 70 ℃ and arrives about 75 ℃ temperature, and kept about 1 hour in this temperature.Make this mixture be cooled to about 20 ℃ and arrive about 25 ℃ temperature, and stirred extra 15 hours, subsequently this mixture is filtered, and water (each 6.3L) washs three times.

[00322] the wet solid that will contain R (+) enantiomter of this diamines is packed in the reactor, the 54L water of packing into then, with this mixture be heated to about 70 ℃ to about 75 ℃ temperature, heated 2 hours.Make this mixture be cooled to about 20 ℃ to about 25 ℃ temperature and stirred 17 hours.Then this mixture is filtered, and with solid water (each 4.5L) washed twice.The solid transfer that should wet is to jacketed reactor, and the 8.1L water of packing in reactor.This mixture is cooled to about 0 ℃ arrives about 5 ℃ temperature, and the 1.625L concentrated hydrochloric acid of carefully packing into, and then the NaOH of the 1.155L 50% that packs into, make the pH value reach about 9-10.Maintain the temperature at about 0 ℃ to about 5 ℃ in the adition process, and under this temperature, stirred one extra hour.Then the mixture that obtains is filtered, and wash solid twice with cold (0 ℃ to 5 ℃) water (each 1.125L).With this solid transfer to jacketed reactor, and with 4.5L water at 0 ℃ to 5 ℃ reslurry.With this solid filtering, and down dry at warm air (40 ℃ to 45 ℃), obtain the white solid of 1940 gram products (R (+) diamines), be 86% at the yield of R (+) enantiomter.

[00323] S (-) enantiomter that contains described diamines in the mother liquor of first splitting step concentrates this mother liquor that to obtain can be 95.5% diamines at S (-) enantiomter yield.

[00324] commercial scale of embodiment 16-toluenesulfonic acid propyl ester preparation: 1-propyl alcohol (2.098kg packs in the jacketed reactor of the glass of 100L; 34.9mol), triethylamine (4.585kg; 45.3mol; 1.3 equivalent) and DCM (20.1L).This mixture is cooled to about 5 ℃ arrives about 15 ℃ temperature, and the paratoluensulfonyl chloride (6kg that during 30 minutes, carefully packs into; 31.47mol; 0.9 DCM equivalent) (10.5L) solution.In case add and to finish, be about to this mixture be warmed to about 18 ℃ to about 22 ℃ temperature and stirred 12 hours.This reactant mixture passes through ¹H NMR is (at CDCl ₃In) check and be considered as finishing.Keeping temperature to be lower than in 25 ℃, HCl (6N carefully packs into; 2.98L).Remove water, and, use MgSO organic facies water (each 21L) washing 2 times ₄Drying, and pass through

Filter.The solid that this is leached washs with DCM (4L) then, and is concentrated into residue.Be dissolved in the heptane this residue also concentrated once more so that final toluenesulfonic acid propyl ester product (6.385kg, productive rate 95%) can be provided.

[00325] the invention provides the in fact more previous much lower evidence of being familiar with of dopamine receptor compatibility of RPPX.In the research of the use beasle dog that this paper proposes, shown that the functional separation (functional separation) (10,000 to 20,000 times) between PPX and the RPPX enantiomter is far longer than before desired.These data show that also the PPX of little known quantity causes the predictable change of the MTD of said composition to the pollution of the composition of pure PPX.These digital proofs RPPX can be dosed in a plurality of ranks, thereby need not the theoretical MTD limit of previous hypothesis, also need not the neuroprotective ability that dose titration just can more fully be developed the more low liter of compound more unexpectedly.This application proposes formerly to be difficult near in the acute and chronic neurological sexual disorder of this medicine and immediately with the full concentration of no dose titration and the pure method for compositions of the following RPPX of use of high theoretical MTD.In addition, the pure composition of data show RPPX can mix with the PPX of known quantity and produce can by the contribution of this (S)-enantiomter separately decision the dopamine-receptor stimulant effect therefore these data be used for being subjected to the application of neurological sexual disorder of (as the PD) of dopamine-receptor stimulant treatment and neuroprotective effect to get ready for the composition of the mixture that uses pure (R) that comprise known quantity-and (S)-enantiomter.

[00326] commercial scale of embodiment 17-RPPXp-TSA salt preparation: condition C: 1.84kg (10.87mol) R (+)-2 packs in 72 liters no jacketed reactor, 6-diaminourea-4,5,6,7-tetrahydrochysene-benzothiazole (R (+) diamines), the 14.7L dimethyl formamide (DMF) of packing into subsequently.Continue to stir down, this mixture is heated to temperature between 65 ℃ to 68 ℃.During 2 hours, slowly be added on the solution of gram toluenesulfonic acid propyl ester of 2926 among the 3.455L DMF and 1761 gram diisopropylethylamine.This is reflected at 67 ℃ and carried out extra 4 hours, afterwards this solution is cooled to gradually room temperature (18 ℃ to 22 ℃) and stirs extra 15 hours.MTBE with 14.72L during 30 minutes time period dilutes this solution, and stirs extra 1 hour.By filtration method collecting precipitation thing and with 7.32L MTBE washing, use the 3.68L washing with alcohol again three times at every turn, use the 9.2L heptane wash more once.This washed precipitate cake is dry under high vacuum in 30 ℃ to 35 ℃.The final weight of this dry products is 2090 grams, represents 50% yield.

[00327] embodiment provides the exemplary simulated of plasma concentration-time graph of KNS-760704 below 18, this simulation can obtain in stable state according to after the various scheme administrations based on segmented model (compartmental model), described segmented model is suitable for the average data from research KNS-760704-CL001, the dosage of single 50mg and 150mg is given the healthy volunteer in this research, and the target in the described exemplary simulated is to use dosed administration once a day to have the blood medicine-valley concentration of 1 μ M (211ng/mL) of the RPPX (alkali that is equivalent to 224mg) of the basic salt of 300mg conduct in the matrix type preparation that discharges for the one-level type.

[00328] Cpss-time graph of the prediction that obtains afterwards in the system change (systematic variation) of absorption rate is shown in Fig. 6.With the one-level absorption rate constant (this constant is considered to " equaling " in-vitro release rate) of tangible 0.02h-1, obtained to have the curve of the highest Cmin, this highest Cmin can use 300mg dosage, and 185ng/mL (0.9 μ M) obtains.Slower accumulation absorption ratio (input rates) causes the reduction of plasma concentration, and this is because can be by the amount that reduces of the medicine of accumulation absorption during 24 hours.Fig. 7 comprises corresponding release characteristics; Be assumed to be the A level external/interior dependency, this also will represent the external dissolution characteristic at described prescription, and be generally used for the release percentage in a plurality of moment in the dissolution test and be shown in the following table 17.

Table 17: in the body at the prediction of controlled release KNS-760704 prescription once a day/extracorporeal releasing characteristic

[00329] Cmin of 185ng/mL and the Cmax of 219ng/mL have been predicted in this modeling (modeling), a little less than surpassing 211ng/mL (1 μ M) target blood medicine-valley and relative level and smooth curve is provided with omiting.This modeling only provides an embodiment of specific prolongation release formulation.Other prescriptions as described herein, can be measured to provide/to keep other targets Cmin and Cmax by preparation.For instance, comprise that 400mg can cause the prescription of the Cmax of the Cmin of about 211ng/mL (1 μ M) and about 320ng/mL, this Cmax is far below the Cmax of observed about 479ng/mL afterwards of per 150mg prescription that gave to discharge immediately in 12 hours in KNS-760704-CL002.

[00330] although the present invention is described in detail with reference to its some embodiment preferred, other forms also are possible.Therefore the spirit and scope of the claims preferred form that should not be subject to specification and in this specification, be comprised.

Claims (102)

1. a single dose improvement release composition comprises (6R)-4,5,6 at least about 50 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines; Less than about 4.5 milligrams (6S)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines and pharmaceutically acceptable carrier.

2. composition as claimed in claim 1, wherein said composition comprise less than about 1.5 dopaminergic activity equivalents.

3. composition as claimed in claim 1, wherein said composition comprise less than about 0.15 dopaminergic activity equivalent.

4. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 75 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

5. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 125 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

6. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 150 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

7. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 200 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

8. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 300 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

9. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 400 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

10. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 500 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

11. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 600 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

12. composition as claimed in claim 1, wherein said composition comprise (6R)-4,5,6 at least about 750 milligrams, 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

13. composition as claimed in claim 1, wherein said composition have from about 50 to about 5,000 neuroprotective activity equivalent; And the dopaminergic activity equivalent between about 0.0001 and about 4.5.

14. composition as claimed in claim 13, wherein said composition have from about 100 to about 3,000 neuroprotective activity equivalent; And the dopaminergic activity equivalent between about 0.0001 and about 1.5.

15. composition as claimed in claim 13, wherein said composition have from about 175 to about 2,100 neuroprotective activity equivalent; With from about 0.0001 to about 4.5 dopaminergic activity equivalent.

16. composition as claimed in claim 13, wherein said composition have from about 200 to about 1,500 neuroprotective activity equivalent; With from about 0.0001 to about 0.375 dopaminergic activity equivalent.

17. composition as claimed in claim 13, wherein said composition have from about 50 to about 5,000 neuroprotective activity equivalent; With less than about 0.375 dopaminergic activity equivalent.

18. composition as claimed in claim 13, wherein said composition have from about 50 to about 5,000 neuroprotective activity equivalent; With less than about 0.15 dopaminergic activity equivalent.

19. composition as claimed in claim 13, wherein said composition have from about 100 to about 2,000 neuroprotective activity equivalent; With less than about 0.15 dopaminergic activity equivalent.

20. composition as claimed in claim 13, wherein said composition have from about 200 to about 2,000 neuroprotective activity equivalent; With less than about 0.15 dopaminergic activity equivalent.

21. composition as claimed in claim 13, wherein said composition have from about 300 to about 1,500 neuroprotective activity equivalent; With less than about 0.15 dopaminergic activity equivalent.

22. composition as claimed in claim 13, wherein said composition have from about 500 to about 1,000 neuroprotective activity equivalent; With less than about 0.15 dopaminergic activity equivalent.

23. composition as claimed in claim 1, wherein said composition is a solid oral dosage form.

24. composition as claimed in claim 1, wherein said composition is a tablet.

25. composition as claimed in claim 1, wherein said composition is a capsule.

26. composition as claimed in claim 1, wherein said composition is a preparation capable of permeating skin.

27. one kind the improvement release of pharmaceutical compositions, comprise from about 50 milligrams to about 5,000 milligrams (6R)-4; 5,6,7-tetrahydrochysene-N6-propyl group-2; 6-benzothiazole-diamines, described composition have the neuroprotection on the acology and do not have the ill-effect level, and described ill-effect level is attributable to (6R)-4; 5,6,7-tetrahydrochysene-N6-propyl group-2; 6-benzothiazole-diamines or any (6S)-4,5,6; 7-tetrahydrochysene-N6-propyl group-2, any of 6-benzothiazole-diamines.

28. composition as claimed in claim 27, wherein said no ill-effect level does not have observable ill-effect level in the mankind.

29. composition as claimed in claim 27, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

30. composition as claimed in claim 27, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

31. composition as claimed in claim 27, wherein, in detection limit, at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines is 100%.

32. composition as claimed in claim 27, comprise from about 100 milligrams to about 2,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

33. composition as claimed in claim 32, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

34. composition as claimed in claim 32, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

35. composition as claimed in claim 27, comprise from about 175 milligrams to about 3,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

36. composition as claimed in claim 35, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

37. composition as claimed in claim 35, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

38. composition as claimed in claim 27, comprise from about 300 milligrams to about 1,500 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

39. composition as claimed in claim 38, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

40. composition as claimed in claim 38, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

41. composition as claimed in claim 27, comprise from about 500 milligrams to about 1,000 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

42. composition as claimed in claim 41, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

43. composition as claimed in claim 41, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

44. composition as claimed in claim 27, wherein said pharmaceutical composition is a solid oral dosage form.

45. composition as claimed in claim 27, wherein said pharmaceutical composition is a tablet.

46. composition as claimed in claim 27, wherein said pharmaceutical composition is a capsule.

47. composition as claimed in claim 27, wherein said pharmaceutical composition is a preparation capable of permeating skin.

48. the method for a treatment acute illness in the patient of needs, comprise give described patient improvement in the release of pharmaceutical compositions about 50 milligrams to about 5,000 milligrams of (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, a daily dose value of 6-benzothiazole-diamines.

49. method as claimed in claim 48, wherein said disorder are acute nerve degenerative diseases.

50. method as claimed in claim 49, wherein said acute nerve degenerative diseases are selected from apoplexy, neurotrosis, acute dysbolism, the outbreak of brain epilepsy sequelae, status epilepticus and acute encephalitis.

51. method as claimed in claim 48, wherein said patient is the patient of first treatment.

52. method as claimed in claim 48, a wherein said daily dose value be from about 100 milligrams to about 3,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

53. method as claimed in claim 48, a wherein said daily dose value be from about 200 milligrams to about 3,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

54. method as claimed in claim 48, a wherein said daily dose value be from about 300 milligrams to about 1,500 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

55. method as claimed in claim 48, a wherein said daily dose value be from about 500 milligrams to about 1,000 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

56. method as claimed in claim 48, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.9% or higher.

57. method as claimed in claim 48, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

58. method as claimed in claim 48, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

59. the method for a treatment chronic disorder in the patient of needs, comprise give improvement in the release of pharmaceutical compositions about 50 milligrams to about 5,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, a daily dose value of 6-benzothiazole-diamines.

60. method as claimed in claim 59, wherein said chronic disorder are chronic nerve degenerative diseases.

61. method as claimed in claim 59, wherein said patient is the patient of first treatment.

62. method as claimed in claim 60, wherein said chronic nerve degenerative diseases is selected from the primary nerve degenerative diseases, Huntington, metabolism causes neurotrosis, senile dementia Alzheimer type disease, the age cognition dysfunction of being correlated with, blood vessel nature feeble-mindedness, MID, dementia with Lewy body disease, the nervus retrogression dementia, the nervus retrogression movement disorder, incoordination, the Friedrich incoordination, multiple sclerosis, spinal muscular atrophy, primary lateral spinal sclerosis disease, epilepsy, motor neuron disorder or disease, struvite demyelinating disorder, Alzheimer's, Parkinson's disease, amyotrophic lateral sclerosis, hepatic encephalopathy and chronic encephalitis.

63. method as claimed in claim 60, wherein said chronic nerve degenerative diseases are selected from nervus retrogression movement disorder, incoordination, epilepsy, motor neuron disorder or disease, struvite demyelinating disorder, Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis.

64. method as claimed in claim 60, wherein said chronic nerve degenerative diseases is an amyotrophic lateral sclerosis.

65. method as claimed in claim 59, a wherein said daily dose value be from about 100 milligrams to about 3,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

66. method as claimed in claim 59, a wherein said daily dose value be from about 200 milligrams to about 3,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

67. method as claimed in claim 59, a wherein said daily dose value be from about 300 milligrams to about 1,500 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

68. method as claimed in claim 59, a wherein said daily dose value be from about 500 milligrams to about 1,000 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

69. method as claimed in claim 59, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.9% or higher.

70. method as claimed in claim 59, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

71. method as claimed in claim 59, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

72. one kind the improvement release tablet, comprise from about 50 milligrams to about 500 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines and pharmaceutically acceptable carrier.

73. as the described tablet of claim 72, wherein said (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines are about 50 milligrams.

74. as the described tablet of claim 72, wherein said tablet has greater than about 25 neuroprotective activity equivalent with less than about 0.375 dopaminergic activity equivalent.

75. as the described tablet of claim 72, wherein said tablet has the dopaminergic activity equivalent less than about 0.15.

76. as the described tablet of claim 72, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, dolomol or its combination.

77. one kind the improvement release tablet, comprise from about 100 milligrams to about 500 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines and pharmaceutically acceptable carrier.

78. as the described tablet of claim 77, wherein said (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines are about 100 milligrams.

79. as the described tablet of claim 77, wherein said tablet has greater than about 25 neuroprotective activity equivalent with less than about 0.375 dopaminergic activity equivalent.

80. as the described tablet of claim 77, wherein said tablet has the dopaminergic activity equivalent less than about 0.15.

81. as the described tablet of claim 77, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, dolomol or its combination.

82. one kind the improvement release tablet, comprise from about 150 milligrams to about 500 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines and pharmaceutically acceptable carrier.

83. as the described tablet of claim 82, wherein said (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines are about 150 milligrams.

84. as the described tablet of claim 82, wherein said tablet has greater than about 25 neuroprotective activity equivalent with less than about 0.375 dopaminergic activity equivalent.

85. as the described tablet of claim 82, wherein said tablet has the dopaminergic activity equivalent less than about 0.15.

86. as the described tablet of claim 82, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, dolomol or its combination.

87. an improvement release tablet comprises greater than about 168 milligrams and less than about 2,000 milligrams (6R)-4,5,6 7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines and pharmaceutically acceptable carrier.

88. as the described tablet of claim 87, wherein said (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines are about 200 milligrams.

89. as the described tablet of claim 87, wherein said tablet has greater than about 25 neuroprotective activity equivalent with less than about 0.375 dopaminergic activity equivalent.

90. as the described tablet of claim 87, wherein said tablet has the dopaminergic activity equivalent less than about 0.15.

91. as the described tablet of claim 87, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, dolomol or its combination.

92. the method for a treatment nerve degenerative diseases in the patient of needs, comprise give described patient improvement in the release of pharmaceutical compositions about 50 milligrams to about 5,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the initial dose of 6-benzothiazole-diamines.

93. as the described method of claim 92, wherein said nerve degenerative diseases is selected from apoplexy, neurotrosis, acute dysbolism, brain epilepsy outbreak sequelae, status epilepticus, acute encephalitis, the primary nerve degenerative diseases, Huntington, metabolism causes neurotrosis, senile dementia Alzheimer type disease, the age cognition dysfunction of being correlated with, blood vessel nature feeble-mindedness, MID, dementia with Lewy body disease, the nervus retrogression dementia, the nervus retrogression movement disorder, incoordination, the Friedrich incoordination, multiple sclerosis, spinal muscular atrophy, primary lateral spinal sclerosis disease, epilepsy, motor neuron disorder or disease, struvite demyelinating disorder, Alzheimer's, Parkinson's disease, amyotrophic lateral sclerosis, hepatic encephalopathy and chronic encephalitis.

94. as the described method of claim 92, wherein said nerve degenerative diseases is an amyotrophic lateral sclerosis.

95. as the described method of claim 92, wherein said patient is the patient of first treatment.

96. as the described method of claim 92, wherein said initial dose be from about 100 milligrams to about 3,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

97. as the described method of claim 92, wherein said initial dose be from about 200 milligrams to about 3,000 milligrams (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

98. as the described method of claim 92, wherein said initial dose be from about 300 milligrams to about 1,500 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

99. as the described method of claim 92, wherein said initial dose be from about 500 milligrams to about 1,000 milligram (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2,6-benzothiazole-diamines.

100. as the described method of claim 92, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.9% or higher.

101. as the described method of claim 92, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.95% or higher.

102. as the described method of claim 93, wherein at described (6R)-4,5,6,7-tetrahydrochysene-N6-propyl group-2, the chiral purity of 6-benzothiazole-diamines are 99.99% or higher.

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