STERIC ISOMERS OF FUSED TROPANE DERIVATIVES AND THEIR USE AS MONOAMINE NEUROTRANSMITTER RE-UPTAKE INHIBITORS
TECHNICAL FIELD
This invention relates to steric isomers of fused tropane-derivatives. More specifically the invention provides optically active isomers of (1S,3S,4S,8R)-3-(3,4- dichlorophenyl)-7-azatricyclo[5.3.0.0]decan-5-ol. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the optically active isomer of the invention.
BACKGROUND ART
WO 97/16451 describes fused tropane-derivatives and their use as mixed monoamine neurotransmitter re-uptake inhibitors.
SUMMARY OF THE INVENTION
While working with the compounds described in WO 97/16451 , a particular compound, i.e. Compound 13 of WO 97/16451 , has attracted attention. First it has turned out that when produced as described in Example 11 of WO 97/16451 , the product obtained consists almost exclusively of the 5S-isomer. While the 5S isomer has valuable properties, it was found that the 5R isomer possesses distinct pharmacokinetic and pharmacological properties. Such properties may include enhanced efficacy, improved selectivity, or improved safety. In addition the 5R isomer may have excellent physical properties, that aid formulation or adsorption, and organoleptic properties. Therefore, in its first aspect, the invention provides an optically active isomer of (IS.SS^S.δRJ-S^S^-dichloropheny ^-azatricyclofδ.S.O.OJdecan-δ-ol, which is
(1 S,3S,4S,5R,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0]decan-5-ol; or a pharmaceutically-acceptable salt thereof.
In its second aspect the invention provides a pharmaceutical composition comprising a therapeutical ly effective amount of the optically active isomer of the invention together with at least one pharmaceutically-acceptable carrier or diluent, for the treatment, prevention or alleviation of a disease or a disorder or a condition that is responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system.
In a further aspect the invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system (CNS), which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of the optically active isomer of the invention.
Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.
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DETAILED DISCLOSURE OF THE INVENTION
The (1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0]decan-5-ol described in WO 97/16451 exists in two optically active configurations, the 5S isomer 15 and the 5R isomer. The method of preparing the (1S,3S,4S,8R)-3-(3,4- dichlorophenyl)-7-azatricyclo[5.3.0.0]decan-5-ol that is described in WO 97/16451 leads almost exclusively to the 5S isomeric compound. This 5S isomer therefore is inherently disclosed in WO 97/16451.
The present invention provides an optically active isomer of (1S,3S,4S,8R)- 20 3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0]decan-5-ol, which is the 5R isomer, i.e. (IS.SS^S.δR.SRJ-S-CS^-dichloropheny ^-azatricyclofδ.S.O.OJdecan-δ-ol, or a pharmaceutically-acceptable salt thereof.
The 5R isomer can be provided in pure form or substantially pure form.
Thus, the ratio 5R:5S isomer may be at least 80:20, such as at least 95:5 or at least
25 99:1. Preferably the 5R isomer is provided having an isomeric purity of at least 99.5%.
Pharmaceutically Acceptable Salts
The optically active isomer of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e.
30 physiologically) acceptable salts, and pre- or prodrug forms of the compound of the invention.
Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from
35 hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the
benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulphonate derived from methane sulphonic acid, the naphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the succinate derived from succinic acid, the tartrate derived from tartaric acid, the toluene-p-sulphonate derived from p-toluene sulphonic acid, and the like. Such salts may be formed by procedures well known and described in the art.
Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a compound of the invention and its pharmaceutically acceptable acid addition salt.
Metal salts of a compound of the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group. In the context of this invention the "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
The compound of the invention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
Labelled Compounds
The optically active isomer of the invention may be used in its labelled or unlabelled form. In the context of this invention "label" stands for the binding of a marker to the compound of interest that will allow easy quantitative detection of said compound.
The labelled isomer of the invention may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging.
The labelled isomer of the invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is prefereably selected from 2H (deuterium), 3H (tritium), 13C, and 14C.
The physical method for detecting the labelled isomer of the present invention may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.
Methods of Preparation
The optically active isomer of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
Also one compound of the invention can be converted to another compound of the invention using conventional methods.
The end product of the reaction described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
Biological Activity
The optically active isomer of the invention has been tested for its ability to inhibit the reuptake of the monoamine neurotransmitters in synaptosomes. Based on the balanced activity observed in these tests the compound of the invention is considered useful for combating diseases, disorders or conditions associated with the dopaminergic, noradrenalinergic and/or serotonergic neural system.
The diseases, disorders or conditions contemplated in this context are eating disorders, obesity, anorexia nervosa, disorders of sleep, panic disorders, social phobia, dementia, senile dementia, pre-senile dementia, memory deficits, memory loss, Alzheimer's disease, chronic fatigue syndrome, anxiety, pseudodementia, Ganser's syndrome, narcolepsy, drug addiction or misuse, alcoholism, tobacco abuse, panic disorder, post-traumatic syndrome, migraine, pain, attention deficit hyperactivity disorder, autism, mutism, trichotillomania, Parkinson's disease, depression, attention, alertness, arousal, vigilance, premature ejaculation, and erectile dysfunction.
The isomer of the invention is considered particularly useful for the treatment, prevention or alleviation of depression, pseudodementia, Ganser's
syndrome, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety and eating disorders.
Pharmaceutical Compositions In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the optically active isomer of the invention.
While the compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
In a preferred embodiment, the invention provides pharmaceutical compositions comprising the optically active isomer of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients, know and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the optically active isomer of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules. The optically active isomer of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may
contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
The optically active isomer of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either an optically active isomer of the invention or a pharmaceutically acceptable salt of an optically active isomer of the invention.
For preparing pharmaceutical compositions from an optically active isomer of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from five or ten to about seventy percent of the optically active isomer. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the optically active isomer with encapsulating material as carrier providing a capsule in which the optically active isomer, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection
liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
The optically active isomer according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
For topical administration to the epidermis the optically active isomer of the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions
may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the optically active isomer in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the optically active isomer will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micron ization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).
A therapeutically effective dose refers to that amount of active ingredient which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, e.g. ED5o and LD50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic
effects is the therapeutic index and may be expressed by the ratio LD50 ED50. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.
The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
The actual dosage depend on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
The active ingredient may be administered in one or several doses per day. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10 mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.
Methods of Therapy
In another aspect the invention provides a method for the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system (CNS), and which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of the optically active isomer of the invention.
In a more preferred embodiment the invention provides a method of combating depression, pseudodementia, Ganser's syndrome, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety and eating disorders.
It is at present contemplated that suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of the dosage range is about 10 mg/kg i.v. and 100 mg/kg p.o.
Preferred ranges are from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about 10 mg/kg p.o.
EXAMPLES
The invention is further illustrated with reference to the following examples which are not intended to be in any way limiting to the scope of the invention as claimed.
Example 1
(1S.3S,4S,5R.8R)-3-(3.4-Dichlorophenvh-7-azatricvclo-r5.3.0.0 44,'8°ηl-decan-5-ol
(Compound A)
To a -10°C stirred solution of triphenylphosphine (4.71 g; 18 mmol) in THF
(125 ml), a solution of diethylazodicarboxylate (2.82 ml) in THF (25 ml) was added drop-wise, during which reaction the temperature was kept at -10°C by external cooling.
Solid (1S,3S,4S,5S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.04'8]- decan-5-ol (Compound 13, obtained according to Example 11 of WO 97/16451) (4.45 g) was now added in one portion. Stirring was continued for two hours, during which period the temperature was allowed to rise to 0°C.
Benzoic acid (2.19 g) was added, and stirring was continued overnight at room temperature. The reaction mixture was evaporated in vacuo, and the residue treated with diethylether/1 N HCI (100 ml). The organic phase was discharged, and the aqueous phase was basified with aqueous ammonia. This afforded a precipitate of the crude product which was subsequently extracted with diethyl ether. The organic phase was dried and evaporated to dryness.
Yield: 5 g of crude intermediate benzoate.
This intermediate was purified by Si02 column purification in
EtAc:MeOH:acetone (4:1 :1), and subsequently treated with EtOH/4N NaOH for 3 hours at room-temperature. Addition of water to the reaction mixture gave a precipitate of (1 S,3S,4S,5R,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.04,8]- decan-5-ol, which could be recrystallised from EtOH to give a crystalline product with a melting point of 220-221 °C.
Elemental analysis
NMR Determination
"5S" "5R"
ROE observations from NMR-investigations carried out on the "5S compound" ((1S,3S,4S,5S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.04'8]-decan- 5-ol; Compound 13, obtained according to Example 11 of WO 97/16451) shows ROE's between H8, H5; and H8, H9endo and H8, H4. This observation combined with the lack of ROE between H8, H2eXo; H8, H 2 and H8) H16, indicates that the hydroxy substituent occupies the exo position.
When Compound A (the 5R compound) of this invention is subjected to NMR-investigations, ROE's are observed between H8, H2eχo; H8, H4; H8, H9eχo; H8, Hgendo,' H8, Hι2 and H8, H16, which, combined with the lack of ROE between H8, H5, indicates that the hydroxy substituent occupies the endo position, so the compound is (1S,3S,4S,5R,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.04'8]-decan-5-ol.
Example 2
Pharmaceutical Compositions
The chemical compound of the invention may be put on any desirable form of composition, and may be dosed in any desired amount. This example shows the preparation of a standard capsule formulation, a standard tablet formulation, and a standard injection solution formulation, respectively.
As active pharmaceutical ingredient (API), Compound A of Example 1 has been used.
Standard Capsule Formulation Capsules containing 1 mg active pharmaceutical ingredient per capsule may be obtained using the following composition:
The calculated amount of drug substance and filler corresponding to 1 mg of active drug substance and 117 mg of filler per capsule are weighed out and dry- mixed.
The blend is subsequently filled into the calculated number of capsules (size 4).
Standard Tablet Formulation
Tablets containing 1.585 mg active pharmaceutical ingredient per tablet may be obtained using the following composition:
The active ingredient is dissolved in a Granulation Solvent, which is composed of methyl cellulose and water, and subsequently used for granulation of the Microcrystalline Cellulose. The granulate was left to dry on a tray.
The granulate from above containing the active pharmaceutical ingredient, the Microcrystalline Cellulose, the Lactose, and the Crosscarmellose Sodium are weighed out, screened into a mixer and blended.
Magnesium stearate is weighed out and screened into a mixer together with a specimen of the blend from above, and blended.
The resulting blend is then compressed into tablets.
Standard Injection Solution Formulation
An injection solution containing 1 mg/ml of active pharmaceutical ingredient may be obtained using the following composition:
The calculated amount of active ingredient is weighed out, dissolved in sterile purified water, added the prescribed amount of sodium chloride and sodium citrate, and pH of the solution is subsequently adjusted to the desired value, usually in the range of from about pH 6.5 to about pH 8.