CA2136008C - Substituted (arylalkylaminobenzyl)amino-propionamide derivatives and process for their preparation - Google Patents
Substituted (arylalkylaminobenzyl)amino-propionamide derivatives and process for their preparation Download PDFInfo
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- CA2136008C CA2136008C CA002136008A CA2136008A CA2136008C CA 2136008 C CA2136008 C CA 2136008C CA 002136008 A CA002136008 A CA 002136008A CA 2136008 A CA2136008 A CA 2136008A CA 2136008 C CA2136008 C CA 2136008C
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- aminopropanamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The invention provides new compounds of formula (I) wherein o is an integer of 1 to 4; each of R and R1, which may be the same or different, is hydrogen, halogen, trifluoromethyl or C1-C4 alkoxy; R2 is hydrogen or C1-C4 alkyl;
and a pharmaceutically acceptable salt thereof;
and wherein when, at the same time, R is hydrogen, R1 is hydrogen or halogen and n is one, then R2 is other than hydrogen or methyl; and of formula (IA) wherein R3 is halogen, and a pharmaceutically acceptable salt thereof, which are active on the central nervous system (CNS) and can be used in therapy as anti-epileptics, anti-Parkinson, neuroprotective, antidepressant, anti-spastic anal hypnotic agents.
and a pharmaceutically acceptable salt thereof;
and wherein when, at the same time, R is hydrogen, R1 is hydrogen or halogen and n is one, then R2 is other than hydrogen or methyl; and of formula (IA) wherein R3 is halogen, and a pharmaceutically acceptable salt thereof, which are active on the central nervous system (CNS) and can be used in therapy as anti-epileptics, anti-Parkinson, neuroprotective, antidepressant, anti-spastic anal hypnotic agents.
Description
SUBSTITUTED (ARYLALKYLAMINOBENZYL) AMINOPROPIONAMIDE DERIVATIVES, THEIR PREPARATION AND USE ANTI-EPILEPTIC, NEUROPROTECTI11E
AND ANTIDEPRESSANT AGENTS
The present invention relates to substituted (phenyl-alkylaminobenzyl)aminopropanamide derivatives, to their use as therapeutic agents, to a process for their preparation and to pharmaceutical compositions containing them. Other N-substituted d,-amino carboxamide derivati-ves are known as having pharmacological properties, for instance those described by British patent No. 1140748.
The compounds according to this prior art document are useful in the treatment and prophylaxis of such diseases as coronary artery disease and atherosclerosis; moreover they are useful in the treatment of inflammatory condi-tions such as rheumatoid arthritis.
Further substituted amino acid derivatives are known as enkephalinase inhibitors, analgesics and hypotensives from EP-A-0038758.
Still other substituted glycine and alanine derivatives are disclosed by US-A-4049663. The compounds according to this document have utility as oral analgesics.
International patent application WO-90/14334 discloses N-phenylalkyl substituted o(-amino carboxamide derivati-ves active on the central nervous system.
It has now been found that new substituted ( arylalkylami-nobenzyl)aminopropanamide derivatives, which are a ~13~~f18~
selected class of those disclosed in WO-90/14334 by the present applicants, have valuable biological properties, in particular as anti-epileptic, anti-Parkinson, neuro protective, antidepressant, antispastic, and/or hypnotic agents.
Accordingly the present invention provides a new compound of formula (I) R
-(CH2)n-NH CH2-NH-CH-CONH2 CI) R
wherein n is an integer of 1 to 4;
each of R and R1, which may be the same or different, is hydrogen, halogen, trifluoromethyl or C1-Ca alkoxy;
Rs is hydrogen or C1-CQ alkyl; or a pharmaceutically acceptable salt thereof; and wherein when, at the same time, R is hydrogen, R1 is hydrogen or halogen and n is one, then R2 is other than hydrogen or methyl.
A halogen atom is preferably fluorine, chlorine or bromi-ne, in particular fluorine or chlorine.
A -(CHs)n - group may be a branched or straight alkylene chain.
A C1-CQ alkoxy group may be a branched or straight group, typically methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy, preferably methoxy or ethoxy.
A C1-CQ alkyl group may be a branched or straight group, typically methyl, ethyl, propyl, isopropyl, butyl or tert-butyl, preferably methyl or ethyl.
Preferred compounds of the invention a~ the compounds of formula (I) wherein, subject to the above proviso, n is 1, 2, 3 or 4;
R is hydrogen; R1 is hydrogen, halogen, Cl-C4 elkoxy or trifluoromethyl;
R2 is C1-C4 alkyl; and the pharmaceutically acceptable salts thereof.
Specific examples of preferred compounds of the Inv~entim are:
AND ANTIDEPRESSANT AGENTS
The present invention relates to substituted (phenyl-alkylaminobenzyl)aminopropanamide derivatives, to their use as therapeutic agents, to a process for their preparation and to pharmaceutical compositions containing them. Other N-substituted d,-amino carboxamide derivati-ves are known as having pharmacological properties, for instance those described by British patent No. 1140748.
The compounds according to this prior art document are useful in the treatment and prophylaxis of such diseases as coronary artery disease and atherosclerosis; moreover they are useful in the treatment of inflammatory condi-tions such as rheumatoid arthritis.
Further substituted amino acid derivatives are known as enkephalinase inhibitors, analgesics and hypotensives from EP-A-0038758.
Still other substituted glycine and alanine derivatives are disclosed by US-A-4049663. The compounds according to this document have utility as oral analgesics.
International patent application WO-90/14334 discloses N-phenylalkyl substituted o(-amino carboxamide derivati-ves active on the central nervous system.
It has now been found that new substituted ( arylalkylami-nobenzyl)aminopropanamide derivatives, which are a ~13~~f18~
selected class of those disclosed in WO-90/14334 by the present applicants, have valuable biological properties, in particular as anti-epileptic, anti-Parkinson, neuro protective, antidepressant, antispastic, and/or hypnotic agents.
Accordingly the present invention provides a new compound of formula (I) R
-(CH2)n-NH CH2-NH-CH-CONH2 CI) R
wherein n is an integer of 1 to 4;
each of R and R1, which may be the same or different, is hydrogen, halogen, trifluoromethyl or C1-Ca alkoxy;
Rs is hydrogen or C1-CQ alkyl; or a pharmaceutically acceptable salt thereof; and wherein when, at the same time, R is hydrogen, R1 is hydrogen or halogen and n is one, then R2 is other than hydrogen or methyl.
A halogen atom is preferably fluorine, chlorine or bromi-ne, in particular fluorine or chlorine.
A -(CHs)n - group may be a branched or straight alkylene chain.
A C1-CQ alkoxy group may be a branched or straight group, typically methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy, preferably methoxy or ethoxy.
A C1-CQ alkyl group may be a branched or straight group, typically methyl, ethyl, propyl, isopropyl, butyl or tert-butyl, preferably methyl or ethyl.
Preferred compounds of the invention a~ the compounds of formula (I) wherein, subject to the above proviso, n is 1, 2, 3 or 4;
R is hydrogen; R1 is hydrogen, halogen, Cl-C4 elkoxy or trifluoromethyl;
R2 is C1-C4 alkyl; and the pharmaceutically acceptable salts thereof.
Specific examples of preferred compounds of the Inv~entim are:
2-~4-(2-methoxybenzyl)aminobenzyl]aminopropanamide;
2- ~4-(3-methoxybenzyl)aminobenzyl~jaminopropanamide;
2- [4-( 2-trifluoromethylbenzyl )aminobenzyl~ eNrnpropenaraide;
2- (4-( 3-trifluoromethylbenzyl ) a~ainobenzyl] arntnoprapan,~~;
2-t4- [2-(2-fluorophenyl )ethyl]aminobenzyl ~a~cdr~opro~aide;
2-{4- [2-( 3-fluorophenyl )ethyl] aminobenzyl} arnirx7pr~nide;
2-{ 4- [3-( 2-fluorophenyl )propyl~ aminobenzyl}arnirnpr~opan,emide;
2- { 4- ~3-( 3-fluorophenyl )oropyl] aminobenzyl)abr~opropasamide;
2- { 4- [4- ( 3-fluorophenyl ) butyl] sminobenzyl }erdr~opropa~emide;
2-~4-(3-phenylpropyl)aminobenzyl~aminopropanamide;
2-[4-(2-phenylethyl)aminobenzyl~aminopropanamide;
2-{4- [4-( 2-fluorophenyl )butyl aminobenzyl}art~inoprap~r~aaide;
2-[4-(4-phenylbutyl)aminobenzyl~aminopropanamide;
if the case, either as single (S) or (R) isomer or as a mixture thereof and the pharmaceutically acceptable salts thereof.
213f X08 The present invention also provides a new compound of formula (IA) (H3 -CH2-NH -CH2-NH-CH-CONH2 (IA) wherein R3 is halogen: or a pharmaceutically acceptable salt thereof .
Compounds of formula (IA) are a further selected class of compounds according to WO-90/14334.
Specific examples of preferred compounds of formula. (IA) are the following:
2-[4-(4-fluorobenzyl)aminobenzyllaminopropanamide;
2-[4-(4-chlorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(4-bromobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-chlorobenzyl)aminobenzyl]aminopropanamide;
2-~4-(2-bromobenzyl)aminobenzyl~aminopropanaraide;
2-[4-(2-chlorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(2-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-bromobenzyl)aminobenzyl]aminopropanamide; if the case, either as single (S) or (R) isomer or as a mixture thereof, and the pharmaceutically acceptable salts thereof.
The compounds of formula (I) and (IA) and their salts are hereafter referred to as the "active compounds"
WO 94/22809 PCT/EP94/00$25 and as the "compounds of the invention".
The present invention includes all the possible optical isomers of the compounds of formulae (I) and (IA) and their mixtures, as well as the metabolites thereof.
The present invention also includes within its scope pharmaceutically acceptable bioprecursors and prodrugs of the compounds of formulae (I) and (IA) i.e. compounds, which have a formula different to formula (I) and (IA), respectively, but which nevertheless are directly or indirectly converted in vivo into a compound of formula (I) or (IA), respectively, upon administration to a human being.
Pharmaceutically acceptable salts of the compounds of formulae (I) and (IA) include acid addition salts with inorganic acids, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric, and phosphoric acid, or organic acids, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, benzoic, cinnsmic, mandelic, methanesulfonic and salicylic acids.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can be obtained by a process comprising e) reacting a compound of formula (II) R
-(CH2)n-NH ~ ~ -CHO (II) ~l~~~fl8 wherein R, R1 and n are as defined above, with a compound of formula (III) H2N-CH-CONH2 (III) wherein R2 is as defined above; or b) reacting a compound of formula (IV) or a reactive derivative thereof -(CH2)n-NH -CH2-NH-CH-COOH (IV) R
wherein R, R1, R2 and n are as defined above, with ammonia; or c) reacting a compound of formula (V) R
-(CH2)n-NH- ~ / -CH2-NH2 (V) -wherein R, R1 and n are as defined above; with a compound of formula (VI) W-CH-CONH2 (VI) wherein W is a halogen atom and R2 as defined above; and, if desired converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of the invention into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers of compounds of the invention into the single isomers.
All the processes described hereabove are analogy pro-cesses and can be carried out according to well known methods in organic chemistry.
The reaction of a compound of formula (II) with a com-pound of formula (III) is a reductive amlnation reac-tion which can be carried out according to well known methods. According to a preferred embodiment of the invention it may be performed under nitrogen atmosphere, in a suitable organic solvent, such as an alcohol, e.g.
a lower elkanol, in particular methanol, or in aceto-nitrile, at a temperature ranging from about 0°C, to about 40°C, in the presaxe of a reducing agent, the most appropriate z~~soas _ g _ being sodium cyanoborohydride. Occasionally molecular sieves can be added to the reaction mixture for fa~ili-tating the reaction.
A reactive derivative of a compound of formula (IV) may be for instance an alkyl ester thereof e.g. a C1-C6 alkyl ester such as a Cl-CQ alkyl ester and, in particular a methyl, ethyl or propyl ester, which may be unsubstituted or substituted by a phenyl ring optionally substituted by a nitro group.
Preferably an alkyl ester of a compound of formula (IV) is used.
The reaction of a compound of general formula (IV) or a reactive derivative thereof, with ammonia can be performed using an excess of ammonia, optionally in the presence of water or of an organic solvent, such as dimethylformamide. The temperature of the reaction may range from about 20°C to about 100°C.
In a acompound of formula (VI) W is preferably bromine or chlorine. The reaction of a compound of general formula (V) with a compound of general formula (VI) can be carried out in a suitable organic solvent, such as an alcohol , a . g . ethanol , or in dimethylf ormamide , at a tem perature ranging from about 40°C to about 140°C in the presence of a suitable acid acceptor e.g. anhydrous potassium carbonate.
A compound of the invention can be converted, as stated _ g _ above, into another compound of the invention by known methods.
Also the optional salification of a compound of the in-vention as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.
The compounds of formulae (II) to (VI) are either known compounds or may be obtained according to known methods, e.g, as described in WO-90/14334, and in the Examples which follow.
The compounds of formula (IA) and the pharmaceutically acceptable salts thereof can be obtained by any one of process variants a) to c) described above for the prepa-ration of compounds of formula (I).
The compounds of formula (IA) and the pharmaceutically acceptable salts thereof are preferably obtained by a process comprising reacting a compound of formula (VII) / -CH2-NH- ~ -CHO (VII) wherein R3 is as defined above, with a compound of formula (VIII) H2 N-CH-CONH2 (VIII) ~~~eoo~
and, if desired converting a compound of formila (IA) into another compound of formula (IA), and/or, it' desired converting a compound of formula (IA) into a pharmaceutically acceptable salt and/or, if desi-red, converting a salt into a free compound, and/or, 1f desired, separating a mixture of isomers of acarpo~nd of formula (IA) into the single isomers.
The reaction of a compound of formula (VII) with~a com-pound of formula (VIII) can be carried out by following the same reaction conditions described above in connec-tion with the reaction of a compound of formula (II) with a compound of formula (III).
Also the additional optional steps described above, as well as the salification of a compound of formula (IA), can be performed according to known methods.
The compounds of formula (VII) and (VIII) on either known or can be obtained by known methods.
When 1n the compounds of the present invention and in the intermediate-products thereof, groups are present, which need to be protected before submitting them to the here above illustrated reactions, they may be protect-ed before being reacted and then deprotected, according to methods well known in organic chemistry.
The intermediate compounds, according to the processes herein described for the preparation of the compounds of the invention, may be either in the form of a single isomer or as a mixture thereof. Preferably they are in the form of a single isomer.
WO 94/22809 ~ PCT/EP94/00825 PHARMACOLOGY
The compounds of he invention are active on the central nervous system (CNS) and can be used in therapy, for example, as anti-epileptics, in the treatment of Parkinson's disease and as neuroprotective agents in degenerative processes associated with normal ageing or pathological situations, such as brain ischemia; they can also be used as antidepressants, hypnotics and antispa-stic agents.
The activity on the CNS of the compounds of the invention was evaluated on the basis of pharmacological methods, such as, for example, the antagonism of convulsions and lethality induced by intravenous injection of bicuculline in mice (Antiepileptic Drugs, D.M. Woodbury et al. eds., 2nd edition, Raven Press, New York, 1982), or the anta-gonism of maximal electroshock seizures (MES) (Woodbury, L.A. and Davenport V.D., Arch. Int. Pharmacodyn. Ther.
92; 97-104, 1952).
The neurotoxicity of the compounds and of the reference anticonvulsants was assessed with the rotorod test (Dunan and Miye, J. Am. Pharm. Ass. Sci. Ed., 1957, 46, 208;
Kinnard et al. J. Pharmacol. Exp. Ther. 1957, 121, 354;
Horowitz, Nature, 1963, 200, 369).
For instance, fallowing Table 1 summarizes the activity and neurotoxicity data obtained in the MES test and in the rotorod test, respectively, for a representative group of compounds according to the present invention, in comparison with the prior art compound 2-(4-benzyl-aminobenzyl)aminopropanamide, dihydrochloride (internal code FCE 26749) which is known from WO-90/14334.
Internal code MES - ED,o ROTOROD-TDSO TI
FCE (mg/kg) (mg/kg) 28622 18.7 1642 88 28623 17.1 917 54 28639 29.1 1902 65 28640 26.5 1676 63 28714 11.3 663 59 26749 9.5 217 23 wherein:
EDso means effective dose in 50% of treated animals TDso means toxic dose in 50% of treated animals TI means therapeutic index (TD,o / EDSO) FCE 28622 means ~-[4-(4-chlorobenzyl)aminobenzyl)amino-propanamide;, dihydrochloride;
FCE28623means2-[4-(2-phenylethyl)aminobenzyl]aminopro-panamide~ dihydrochloride;
FCE28639means~-[4-(4-bromobenzyl)aminobenzyl]aminopro-panamide, dihydrochloride;
FCE 28640 means 2-[4-(4--fluox,obenzyl)aminobenzyl]amino-propanamide~, dihydrochloride;
FCE 28714 means 2-[4-(3-chlor.obenzyl)aminobenzyl]amino-propanamide~ dihydrochloride.
From the comparative test data it is evident that the compounds of the present invention are endowed with a better therapeutic index than the prior art compound.
A patient is treated according to the present invention by a method comprising administering to the patient an effective amount of one of the compounds of the invention.
In this way the present compounds can be used to treat disorders of the central nervous system, for example epilepsy or Parkinson's disease, or as neuroprotective agents, anti-depressants, hypnotics or anti-spastic agents.
The condition of a patient may thus be improved.
z~.~~oQs - i4 -The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions; rectally, in the form of suppositories; paren-terally, e.g. intramuscularly or by intravenous in~ec-tion or infusion.
The therapeutic regimen for the different clinical syn-dromes must be adapted to the type of pathology taking into account as usual, also the route of administration, the form in which the compound is administered and the age, weight and conditions of the subject involved.
The oral route is employed, in general, for all condi-tions requiring such compounds. In emergency situations preference is given to intravenous infection.
For these purposes the compounds of the invention can be administered orally at doses ranging e.g. from about 20 to about 1500 mg/day. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic res-ponse.
The nature of the pharmaceutical compositions containing the compounds of this invention in association with phar-maceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration.
The compositions may be formulated in the conventional manner with the usual ingredients. For example, the com-pounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatine capsules, syrups, drops or suppositories.
Thus, for oral administration, the pharmaceutical compo-sitions containing the compounds of this invention are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as star-ches, gelatine, methylcellulose, carboxymethylcellulose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggre-gating agents, such as starches, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; ~restuf~'s;
sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharma-cologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coatlng processes.
The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
The syrups may contain as carrier, for example, saccha-rose or saccharose with glycerine and/or mannitol end/
or sorbitol.
The suspensions and the emulsions may contain as carrier, 21~6~~~
for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
The suspensions or solutions for intramuscular in~ec-tions may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g, propylene glycol, and if desired, a suitable amount of lidocaine hydro-chloride.
The solutions for intravenous infection or infusion may contain as carrier, for example, sterile water or pre-ferably they may be in the form of sterile aqueous iso-tonic saline solutions.
The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g.
cocoabutter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
The following examples illustrate but do not limit the invention.
Example 1 a) Methyl 4-(3-fluorobenzyl)aminobenzoate (1) 41 g (0.219 mol) of methyl 4-aminobenzoate hydrochloride are suspended in 500 ml of dry methanol and 10 g (0.159 mol) of sodium cysnoborohydride are added, while stirring under nitrogen. After ten minutes, 34.3 g (0.199 mol) of 3-fluorobenzaldehyde are added in a single portion.
The reaction mixture is stirred seven hours at room temperature and then allowed to stand 16 hours. The solution is filtered and evaporated, taken up with water and extracted three times with a~ethylene chloride. After drying and evaporating, the crude residue is chromato-graphed on silica gel (eluant: cyclohexane/ethyl acetate 4/1) to give methyl 4-(3-fluorobenzyl)aminobenzoate (27 g; 52%; m.p. 107-110°C).
b) Methyl 4-LN-t-butyloxycarbonyl-N-(3-fluorobenzyl~
aminobenzoate (2) (1), (16 g; 0.0617 mol) is dissolved in dichloromethane (350 ml) and treated with 4-dimethylaminopyridine (10.8 g; 0.0617 mol), di-t-butyldicarbonate (26.9 g; 0.123 mol) and triethylamine (12.4 ml) at room temperature for three hours. After evaporation and purification of the residue on silica gel (eluant: cyclohexane/ethyl acetate 7/3), 19 g (86%) of (2) are obtained, as a colorless oil.
~~~~~as c ) 4-[ I~t-butyloxycnrbonyl-N-( 3-fluorobenzyl )] 8minobenzyl-alcohol(3) The N-BOC- aminoester (2), (19 g; 0.0528 mol) is dissolv-ed in 500 ml of ethyl ether under nitrogen and kept to -70°C, while stirring. To this solution, a 1.2 M solu-tion of diisobutyl aluminumhydride (DIBAH) (110 ml;
0.132 mol) is dropped slowly while temperature is main-tained between -70 and -60°C. After 30' minutes at -70°C, ethyl acetate (31 ml) is dropped and temperature allow-ed to raise to -20°C; then, water (15 ml) is cautiously added and the resulting mixture kept to room temperature for 1 hour. After filtration and washing of the residue with ethyl acetate, extraction and drying over sodium sulfate and evaporation, (3) (16.1 g; 92%) is obtained as an oil.
d) 4-~N-t-butyloxycarbonyl-N-(3-fluorobenzyl)]amino-benzaldehyde (4) To a mixture of DMSO (8.2 ml; 0.116 mol) in 250 ml of dichloromethane, 10.2 ml (0.0724 mol) of trifluoroacetic anhydride in 50 ml of dichloromethane are added, under nitrogen and stirring, at -70°C. After 15 minutes, a solution of 4-[N-t-butyloxycarbonyl-N-(3-fluorobenzyl)]
aminobenzylalcohol in 100 ml of dichloromethane is drop-ped within an hour. After 30 minutes at -70°C, the tarpe-rature is raised to -20°C and 65 ml of triethylamine are added while stirring. The mixture is allowed to stand 1 hour at room temperature, then brine is added and the organic layer separated, dried on sodium sulfate and evaporated to give an oily residue which is purified by flash chromatography (eluant: cyclohexane/ethyl acetate 4/1) to give (4) as a white solid (7.5 g; 47% ; m.p. 87-90°C).
Example 2 a) (S)-2-[4-(N-t-butyloxycarbonyl-N-(3-fluorobenzyl)-aminobenzyl)]aminopropanamide (S)-(+) 2-aminopropanamide hydrochloride (2.7 g; 0.0217 mol) is dissolved in methanol (70 ml) under nitrogen, while stirring; to this solution, 2.7 g of 4~, molecular sieves are added. The suspension formed is treated with sodium cyanoborohydride (1 g; 0»0157 mol) in a single portion at room temperature. To this mixture, 6.5 g (0.0197 mol) of 4-[N-t-butyloxycarbonyl-N-(3-fluoro-benzyl)]amino-benzaldehyde (4) are added and the reaction kept 3 hours at room temperature. After filtration and evaporation, the crude oil obtained is purified by flash chromatography (eluant: dichloromethane/methanQ,l/300 NHQOH 190/10/1 to give (S)-2-[4-(N-t-butyloxycarbonyl-N--(3-fluoro-benzyl)aminobenzyl)]aminopropanamide as an oil (5 g; 640).
b) (S)-2-[4-(3-fluorobenzyl)aminobenzyl]amino-propanamide dihydrochloride [FCE 27232A]
g (0.0124 mol) of 2-[4-(N-t-butyloxycarbonyl-N-(3-fluorobenzyl)aminobenzyl)]aminopropanamide are dissolved 5 in 3.5 N HC1 in ethanol and the mixture stirred at room temperature for 3.5 hours. After completion of the deprotection, the solution is evaporated, taken up with abs. ethanol, evaporated. The solid residue is triturated in ethyl ether, filtered, washed with ether and dried at 50°C/3 torr for 3 hours. 3.1 g (67%) of white plates of the title compound are obtained (m. p. 170°C dec.), [ol ] D 2 5 + 3 .1 ( C = 1 . 2 DMF ) .
Analogously, starting from (4) and (R)-(-)-2-aminopropa-namide, the R-enantiomer can be obtained (m.p. 170°C
dec.), [off]D25 - 3.0 (C = 1.1 DMF).
Analogously, the following compounds can be obtained, either in R or S-enantiomeric form, starting from the corresponding aldehyde and the appropriate oC-aminoamide.
2-[4-(2-fluorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 135°C (dec.);
2-[4-(2-chlorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(3-chlorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 180°C (dec.);
2-[4-(2-bromobenzyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(3-bromobenzyl)aminobenzyl)aminopropanamide, dihydrochloride, m.p. 180°C (dec.);
2-[4-(4-fluorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 195°C (dec.);
2-[4-(4-bromobenzyl)aminobenzyl)aminopropanamide, dihydrochloride, m.p. 170°C (dec.);
2-[4-(4-chlorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 150°C (dec.);
2- 4-[2-(2-fluorophenyl)ethyl]aminobenzyl aminopropa-namide, dihydrochloride;
2- 4-[2-(3-fluorophenyl)ethyl]aminobenzyl aminopropana-mide, dihydrochloride;
2- 4-[3-(2-fluorophenyl)propyl]aminobenzyl aminopropana-mide, dihydrochloride;
2- 4-[3-(3-fluoraphenyl)propyl)aminobenzyl aminopropana-mide, dihydrochloride;
2-[4-(2-phenylethyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 145°C (dec.);
2-[4-(3-phenylpropyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(4-phenylbutyl)aminobenzyl)aminopropanamide, dihydrochloride;
2- 4-[4-(2-fluorophenyl)butyl]aminobenzyl aminopropana-mide, dihydrochloride;
~~.360~8 2- .~-[4-(3-fluorophenyl)butyl]aminobenzyl aminopropana-mide, dihydrochloride;
2-[4-(2-methoxybenxyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(3-methoxybenzyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(2-trifluoromethylbenzyl)aminobenzyl]aminopropana-mide, dihydrochloride; and 2-[4-(3-trifluoromethylbenzyl)aminobenzyl]aminopropana-mide, dihydrochloride.
Example 3 Tablets, each weighing 300 mg and containing 100 mg of the active substance can be manufactured as follows:
Compositions (for 500 tablets) 2-[4-(3-fluorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride 500 g Lactose 710 g Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15 g 2-[4-(3-fluorobenzyl)aminobenzyl~aminopropanamide, dihydrochloride, methanesulfonate, lactose and half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml).
The resulting paste is used to granulate the powder.
The granules are dried, comminuted on a sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium is added, carefully mixed, and processed into tablets.
2- ~4-(3-methoxybenzyl)aminobenzyl~jaminopropanamide;
2- [4-( 2-trifluoromethylbenzyl )aminobenzyl~ eNrnpropenaraide;
2- (4-( 3-trifluoromethylbenzyl ) a~ainobenzyl] arntnoprapan,~~;
2-t4- [2-(2-fluorophenyl )ethyl]aminobenzyl ~a~cdr~opro~aide;
2-{4- [2-( 3-fluorophenyl )ethyl] aminobenzyl} arnirx7pr~nide;
2-{ 4- [3-( 2-fluorophenyl )propyl~ aminobenzyl}arnirnpr~opan,emide;
2- { 4- ~3-( 3-fluorophenyl )oropyl] aminobenzyl)abr~opropasamide;
2- { 4- [4- ( 3-fluorophenyl ) butyl] sminobenzyl }erdr~opropa~emide;
2-~4-(3-phenylpropyl)aminobenzyl~aminopropanamide;
2-[4-(2-phenylethyl)aminobenzyl~aminopropanamide;
2-{4- [4-( 2-fluorophenyl )butyl aminobenzyl}art~inoprap~r~aaide;
2-[4-(4-phenylbutyl)aminobenzyl~aminopropanamide;
if the case, either as single (S) or (R) isomer or as a mixture thereof and the pharmaceutically acceptable salts thereof.
213f X08 The present invention also provides a new compound of formula (IA) (H3 -CH2-NH -CH2-NH-CH-CONH2 (IA) wherein R3 is halogen: or a pharmaceutically acceptable salt thereof .
Compounds of formula (IA) are a further selected class of compounds according to WO-90/14334.
Specific examples of preferred compounds of formula. (IA) are the following:
2-[4-(4-fluorobenzyl)aminobenzyllaminopropanamide;
2-[4-(4-chlorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(4-bromobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-chlorobenzyl)aminobenzyl]aminopropanamide;
2-~4-(2-bromobenzyl)aminobenzyl~aminopropanaraide;
2-[4-(2-chlorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(2-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-bromobenzyl)aminobenzyl]aminopropanamide; if the case, either as single (S) or (R) isomer or as a mixture thereof, and the pharmaceutically acceptable salts thereof.
The compounds of formula (I) and (IA) and their salts are hereafter referred to as the "active compounds"
WO 94/22809 PCT/EP94/00$25 and as the "compounds of the invention".
The present invention includes all the possible optical isomers of the compounds of formulae (I) and (IA) and their mixtures, as well as the metabolites thereof.
The present invention also includes within its scope pharmaceutically acceptable bioprecursors and prodrugs of the compounds of formulae (I) and (IA) i.e. compounds, which have a formula different to formula (I) and (IA), respectively, but which nevertheless are directly or indirectly converted in vivo into a compound of formula (I) or (IA), respectively, upon administration to a human being.
Pharmaceutically acceptable salts of the compounds of formulae (I) and (IA) include acid addition salts with inorganic acids, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric, and phosphoric acid, or organic acids, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, benzoic, cinnsmic, mandelic, methanesulfonic and salicylic acids.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can be obtained by a process comprising e) reacting a compound of formula (II) R
-(CH2)n-NH ~ ~ -CHO (II) ~l~~~fl8 wherein R, R1 and n are as defined above, with a compound of formula (III) H2N-CH-CONH2 (III) wherein R2 is as defined above; or b) reacting a compound of formula (IV) or a reactive derivative thereof -(CH2)n-NH -CH2-NH-CH-COOH (IV) R
wherein R, R1, R2 and n are as defined above, with ammonia; or c) reacting a compound of formula (V) R
-(CH2)n-NH- ~ / -CH2-NH2 (V) -wherein R, R1 and n are as defined above; with a compound of formula (VI) W-CH-CONH2 (VI) wherein W is a halogen atom and R2 as defined above; and, if desired converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of the invention into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers of compounds of the invention into the single isomers.
All the processes described hereabove are analogy pro-cesses and can be carried out according to well known methods in organic chemistry.
The reaction of a compound of formula (II) with a com-pound of formula (III) is a reductive amlnation reac-tion which can be carried out according to well known methods. According to a preferred embodiment of the invention it may be performed under nitrogen atmosphere, in a suitable organic solvent, such as an alcohol, e.g.
a lower elkanol, in particular methanol, or in aceto-nitrile, at a temperature ranging from about 0°C, to about 40°C, in the presaxe of a reducing agent, the most appropriate z~~soas _ g _ being sodium cyanoborohydride. Occasionally molecular sieves can be added to the reaction mixture for fa~ili-tating the reaction.
A reactive derivative of a compound of formula (IV) may be for instance an alkyl ester thereof e.g. a C1-C6 alkyl ester such as a Cl-CQ alkyl ester and, in particular a methyl, ethyl or propyl ester, which may be unsubstituted or substituted by a phenyl ring optionally substituted by a nitro group.
Preferably an alkyl ester of a compound of formula (IV) is used.
The reaction of a compound of general formula (IV) or a reactive derivative thereof, with ammonia can be performed using an excess of ammonia, optionally in the presence of water or of an organic solvent, such as dimethylformamide. The temperature of the reaction may range from about 20°C to about 100°C.
In a acompound of formula (VI) W is preferably bromine or chlorine. The reaction of a compound of general formula (V) with a compound of general formula (VI) can be carried out in a suitable organic solvent, such as an alcohol , a . g . ethanol , or in dimethylf ormamide , at a tem perature ranging from about 40°C to about 140°C in the presence of a suitable acid acceptor e.g. anhydrous potassium carbonate.
A compound of the invention can be converted, as stated _ g _ above, into another compound of the invention by known methods.
Also the optional salification of a compound of the in-vention as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.
The compounds of formulae (II) to (VI) are either known compounds or may be obtained according to known methods, e.g, as described in WO-90/14334, and in the Examples which follow.
The compounds of formula (IA) and the pharmaceutically acceptable salts thereof can be obtained by any one of process variants a) to c) described above for the prepa-ration of compounds of formula (I).
The compounds of formula (IA) and the pharmaceutically acceptable salts thereof are preferably obtained by a process comprising reacting a compound of formula (VII) / -CH2-NH- ~ -CHO (VII) wherein R3 is as defined above, with a compound of formula (VIII) H2 N-CH-CONH2 (VIII) ~~~eoo~
and, if desired converting a compound of formila (IA) into another compound of formula (IA), and/or, it' desired converting a compound of formula (IA) into a pharmaceutically acceptable salt and/or, if desi-red, converting a salt into a free compound, and/or, 1f desired, separating a mixture of isomers of acarpo~nd of formula (IA) into the single isomers.
The reaction of a compound of formula (VII) with~a com-pound of formula (VIII) can be carried out by following the same reaction conditions described above in connec-tion with the reaction of a compound of formula (II) with a compound of formula (III).
Also the additional optional steps described above, as well as the salification of a compound of formula (IA), can be performed according to known methods.
The compounds of formula (VII) and (VIII) on either known or can be obtained by known methods.
When 1n the compounds of the present invention and in the intermediate-products thereof, groups are present, which need to be protected before submitting them to the here above illustrated reactions, they may be protect-ed before being reacted and then deprotected, according to methods well known in organic chemistry.
The intermediate compounds, according to the processes herein described for the preparation of the compounds of the invention, may be either in the form of a single isomer or as a mixture thereof. Preferably they are in the form of a single isomer.
WO 94/22809 ~ PCT/EP94/00825 PHARMACOLOGY
The compounds of he invention are active on the central nervous system (CNS) and can be used in therapy, for example, as anti-epileptics, in the treatment of Parkinson's disease and as neuroprotective agents in degenerative processes associated with normal ageing or pathological situations, such as brain ischemia; they can also be used as antidepressants, hypnotics and antispa-stic agents.
The activity on the CNS of the compounds of the invention was evaluated on the basis of pharmacological methods, such as, for example, the antagonism of convulsions and lethality induced by intravenous injection of bicuculline in mice (Antiepileptic Drugs, D.M. Woodbury et al. eds., 2nd edition, Raven Press, New York, 1982), or the anta-gonism of maximal electroshock seizures (MES) (Woodbury, L.A. and Davenport V.D., Arch. Int. Pharmacodyn. Ther.
92; 97-104, 1952).
The neurotoxicity of the compounds and of the reference anticonvulsants was assessed with the rotorod test (Dunan and Miye, J. Am. Pharm. Ass. Sci. Ed., 1957, 46, 208;
Kinnard et al. J. Pharmacol. Exp. Ther. 1957, 121, 354;
Horowitz, Nature, 1963, 200, 369).
For instance, fallowing Table 1 summarizes the activity and neurotoxicity data obtained in the MES test and in the rotorod test, respectively, for a representative group of compounds according to the present invention, in comparison with the prior art compound 2-(4-benzyl-aminobenzyl)aminopropanamide, dihydrochloride (internal code FCE 26749) which is known from WO-90/14334.
Internal code MES - ED,o ROTOROD-TDSO TI
FCE (mg/kg) (mg/kg) 28622 18.7 1642 88 28623 17.1 917 54 28639 29.1 1902 65 28640 26.5 1676 63 28714 11.3 663 59 26749 9.5 217 23 wherein:
EDso means effective dose in 50% of treated animals TDso means toxic dose in 50% of treated animals TI means therapeutic index (TD,o / EDSO) FCE 28622 means ~-[4-(4-chlorobenzyl)aminobenzyl)amino-propanamide;, dihydrochloride;
FCE28623means2-[4-(2-phenylethyl)aminobenzyl]aminopro-panamide~ dihydrochloride;
FCE28639means~-[4-(4-bromobenzyl)aminobenzyl]aminopro-panamide, dihydrochloride;
FCE 28640 means 2-[4-(4--fluox,obenzyl)aminobenzyl]amino-propanamide~, dihydrochloride;
FCE 28714 means 2-[4-(3-chlor.obenzyl)aminobenzyl]amino-propanamide~ dihydrochloride.
From the comparative test data it is evident that the compounds of the present invention are endowed with a better therapeutic index than the prior art compound.
A patient is treated according to the present invention by a method comprising administering to the patient an effective amount of one of the compounds of the invention.
In this way the present compounds can be used to treat disorders of the central nervous system, for example epilepsy or Parkinson's disease, or as neuroprotective agents, anti-depressants, hypnotics or anti-spastic agents.
The condition of a patient may thus be improved.
z~.~~oQs - i4 -The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions; rectally, in the form of suppositories; paren-terally, e.g. intramuscularly or by intravenous in~ec-tion or infusion.
The therapeutic regimen for the different clinical syn-dromes must be adapted to the type of pathology taking into account as usual, also the route of administration, the form in which the compound is administered and the age, weight and conditions of the subject involved.
The oral route is employed, in general, for all condi-tions requiring such compounds. In emergency situations preference is given to intravenous infection.
For these purposes the compounds of the invention can be administered orally at doses ranging e.g. from about 20 to about 1500 mg/day. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic res-ponse.
The nature of the pharmaceutical compositions containing the compounds of this invention in association with phar-maceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration.
The compositions may be formulated in the conventional manner with the usual ingredients. For example, the com-pounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatine capsules, syrups, drops or suppositories.
Thus, for oral administration, the pharmaceutical compo-sitions containing the compounds of this invention are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as star-ches, gelatine, methylcellulose, carboxymethylcellulose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggre-gating agents, such as starches, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; ~restuf~'s;
sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharma-cologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coatlng processes.
The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
The syrups may contain as carrier, for example, saccha-rose or saccharose with glycerine and/or mannitol end/
or sorbitol.
The suspensions and the emulsions may contain as carrier, 21~6~~~
for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
The suspensions or solutions for intramuscular in~ec-tions may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g, propylene glycol, and if desired, a suitable amount of lidocaine hydro-chloride.
The solutions for intravenous infection or infusion may contain as carrier, for example, sterile water or pre-ferably they may be in the form of sterile aqueous iso-tonic saline solutions.
The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g.
cocoabutter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
The following examples illustrate but do not limit the invention.
Example 1 a) Methyl 4-(3-fluorobenzyl)aminobenzoate (1) 41 g (0.219 mol) of methyl 4-aminobenzoate hydrochloride are suspended in 500 ml of dry methanol and 10 g (0.159 mol) of sodium cysnoborohydride are added, while stirring under nitrogen. After ten minutes, 34.3 g (0.199 mol) of 3-fluorobenzaldehyde are added in a single portion.
The reaction mixture is stirred seven hours at room temperature and then allowed to stand 16 hours. The solution is filtered and evaporated, taken up with water and extracted three times with a~ethylene chloride. After drying and evaporating, the crude residue is chromato-graphed on silica gel (eluant: cyclohexane/ethyl acetate 4/1) to give methyl 4-(3-fluorobenzyl)aminobenzoate (27 g; 52%; m.p. 107-110°C).
b) Methyl 4-LN-t-butyloxycarbonyl-N-(3-fluorobenzyl~
aminobenzoate (2) (1), (16 g; 0.0617 mol) is dissolved in dichloromethane (350 ml) and treated with 4-dimethylaminopyridine (10.8 g; 0.0617 mol), di-t-butyldicarbonate (26.9 g; 0.123 mol) and triethylamine (12.4 ml) at room temperature for three hours. After evaporation and purification of the residue on silica gel (eluant: cyclohexane/ethyl acetate 7/3), 19 g (86%) of (2) are obtained, as a colorless oil.
~~~~~as c ) 4-[ I~t-butyloxycnrbonyl-N-( 3-fluorobenzyl )] 8minobenzyl-alcohol(3) The N-BOC- aminoester (2), (19 g; 0.0528 mol) is dissolv-ed in 500 ml of ethyl ether under nitrogen and kept to -70°C, while stirring. To this solution, a 1.2 M solu-tion of diisobutyl aluminumhydride (DIBAH) (110 ml;
0.132 mol) is dropped slowly while temperature is main-tained between -70 and -60°C. After 30' minutes at -70°C, ethyl acetate (31 ml) is dropped and temperature allow-ed to raise to -20°C; then, water (15 ml) is cautiously added and the resulting mixture kept to room temperature for 1 hour. After filtration and washing of the residue with ethyl acetate, extraction and drying over sodium sulfate and evaporation, (3) (16.1 g; 92%) is obtained as an oil.
d) 4-~N-t-butyloxycarbonyl-N-(3-fluorobenzyl)]amino-benzaldehyde (4) To a mixture of DMSO (8.2 ml; 0.116 mol) in 250 ml of dichloromethane, 10.2 ml (0.0724 mol) of trifluoroacetic anhydride in 50 ml of dichloromethane are added, under nitrogen and stirring, at -70°C. After 15 minutes, a solution of 4-[N-t-butyloxycarbonyl-N-(3-fluorobenzyl)]
aminobenzylalcohol in 100 ml of dichloromethane is drop-ped within an hour. After 30 minutes at -70°C, the tarpe-rature is raised to -20°C and 65 ml of triethylamine are added while stirring. The mixture is allowed to stand 1 hour at room temperature, then brine is added and the organic layer separated, dried on sodium sulfate and evaporated to give an oily residue which is purified by flash chromatography (eluant: cyclohexane/ethyl acetate 4/1) to give (4) as a white solid (7.5 g; 47% ; m.p. 87-90°C).
Example 2 a) (S)-2-[4-(N-t-butyloxycarbonyl-N-(3-fluorobenzyl)-aminobenzyl)]aminopropanamide (S)-(+) 2-aminopropanamide hydrochloride (2.7 g; 0.0217 mol) is dissolved in methanol (70 ml) under nitrogen, while stirring; to this solution, 2.7 g of 4~, molecular sieves are added. The suspension formed is treated with sodium cyanoborohydride (1 g; 0»0157 mol) in a single portion at room temperature. To this mixture, 6.5 g (0.0197 mol) of 4-[N-t-butyloxycarbonyl-N-(3-fluoro-benzyl)]amino-benzaldehyde (4) are added and the reaction kept 3 hours at room temperature. After filtration and evaporation, the crude oil obtained is purified by flash chromatography (eluant: dichloromethane/methanQ,l/300 NHQOH 190/10/1 to give (S)-2-[4-(N-t-butyloxycarbonyl-N--(3-fluoro-benzyl)aminobenzyl)]aminopropanamide as an oil (5 g; 640).
b) (S)-2-[4-(3-fluorobenzyl)aminobenzyl]amino-propanamide dihydrochloride [FCE 27232A]
g (0.0124 mol) of 2-[4-(N-t-butyloxycarbonyl-N-(3-fluorobenzyl)aminobenzyl)]aminopropanamide are dissolved 5 in 3.5 N HC1 in ethanol and the mixture stirred at room temperature for 3.5 hours. After completion of the deprotection, the solution is evaporated, taken up with abs. ethanol, evaporated. The solid residue is triturated in ethyl ether, filtered, washed with ether and dried at 50°C/3 torr for 3 hours. 3.1 g (67%) of white plates of the title compound are obtained (m. p. 170°C dec.), [ol ] D 2 5 + 3 .1 ( C = 1 . 2 DMF ) .
Analogously, starting from (4) and (R)-(-)-2-aminopropa-namide, the R-enantiomer can be obtained (m.p. 170°C
dec.), [off]D25 - 3.0 (C = 1.1 DMF).
Analogously, the following compounds can be obtained, either in R or S-enantiomeric form, starting from the corresponding aldehyde and the appropriate oC-aminoamide.
2-[4-(2-fluorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 135°C (dec.);
2-[4-(2-chlorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(3-chlorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 180°C (dec.);
2-[4-(2-bromobenzyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(3-bromobenzyl)aminobenzyl)aminopropanamide, dihydrochloride, m.p. 180°C (dec.);
2-[4-(4-fluorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 195°C (dec.);
2-[4-(4-bromobenzyl)aminobenzyl)aminopropanamide, dihydrochloride, m.p. 170°C (dec.);
2-[4-(4-chlorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 150°C (dec.);
2- 4-[2-(2-fluorophenyl)ethyl]aminobenzyl aminopropa-namide, dihydrochloride;
2- 4-[2-(3-fluorophenyl)ethyl]aminobenzyl aminopropana-mide, dihydrochloride;
2- 4-[3-(2-fluorophenyl)propyl]aminobenzyl aminopropana-mide, dihydrochloride;
2- 4-[3-(3-fluoraphenyl)propyl)aminobenzyl aminopropana-mide, dihydrochloride;
2-[4-(2-phenylethyl)aminobenzyl]aminopropanamide, dihydrochloride, m.p. 145°C (dec.);
2-[4-(3-phenylpropyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(4-phenylbutyl)aminobenzyl)aminopropanamide, dihydrochloride;
2- 4-[4-(2-fluorophenyl)butyl]aminobenzyl aminopropana-mide, dihydrochloride;
~~.360~8 2- .~-[4-(3-fluorophenyl)butyl]aminobenzyl aminopropana-mide, dihydrochloride;
2-[4-(2-methoxybenxyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(3-methoxybenzyl)aminobenzyl]aminopropanamide, dihydrochloride;
2-[4-(2-trifluoromethylbenzyl)aminobenzyl]aminopropana-mide, dihydrochloride; and 2-[4-(3-trifluoromethylbenzyl)aminobenzyl]aminopropana-mide, dihydrochloride.
Example 3 Tablets, each weighing 300 mg and containing 100 mg of the active substance can be manufactured as follows:
Compositions (for 500 tablets) 2-[4-(3-fluorobenzyl)aminobenzyl]aminopropanamide, dihydrochloride 500 g Lactose 710 g Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15 g 2-[4-(3-fluorobenzyl)aminobenzyl~aminopropanamide, dihydrochloride, methanesulfonate, lactose and half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml).
The resulting paste is used to granulate the powder.
The granules are dried, comminuted on a sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium is added, carefully mixed, and processed into tablets.
Claims (17)
1. A compound of formula (I) wherein n is an integer of 1 to 4;
each of R and R1, which may be the same or different, is hydrogen, halogen, trifluoromethyl or C1-C4 alkoxy;
R2 is hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof; and wherein when, at the same time, R is hydrogen, R1 is hydrogen or halogen and n is one, then R2 is other than hydrogen or methyl.
each of R and R1, which may be the same or different, is hydrogen, halogen, trifluoromethyl or C1-C4 alkoxy;
R2 is hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof; and wherein when, at the same time, R is hydrogen, R1 is hydrogen or halogen and n is one, then R2 is other than hydrogen or methyl.
2. A compound of formula (I), according to claim 1, wherein n is 1, 2, 3 or 4;
R is hydrogen; R1 is hydrogen, halogen, C1-C4 alkoxy or trifluoromethyl; and R2 is C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.
R is hydrogen; R1 is hydrogen, halogen, C1-C4 alkoxy or trifluoromethyl; and R2 is C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.
3. A compound which is 2-[4-(2-methoxybenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-methoxybenzyl)aminobenzyl]aminopropanamide;
2-[4-(2-trifluoromethylbenzyl)aminobenzyl]aminopropana-mide;
2-[4-(3-trifluoromethylbenzyl)aminobenzyl] aminopropanamide;
2-{4-[2-(2-fluorophenyl)ethyl] aminobenzyl} aminopropanamide;
2-{4-[2-(3-fluorophenyl)ethyl] aminobenzyl} aminopropanamide;
2-{4-[3-(2-fluorophenyl)propyl] aminobenzyl} aminopropanamide;
2-{4-[3-(3-fluorophenyl)propyl] aminobenzyl} aminopropanamide;
2-{4-[4-(3-fluorophenyl)butyl] aminobenzyl} aminopropanamide;
2-[4-(3-phenylpropyl)aminobenzyl]aminopropanamide;
2-[4-(2-phenylethyl)aminobenzyl]aminopropanamide;
2-{4-[4-(2-fluorophenyl)butyl] aminobenzyl aminopropanamide;
2-[4-(4-phenylbutyl)aminobenzyl]aminopropanamide; if the case, either as single (S) or (R) isomer or as a mixture thereof or a pharmaceutically acceptable salt thereof.
2-[4-(3-methoxybenzyl)aminobenzyl]aminopropanamide;
2-[4-(2-trifluoromethylbenzyl)aminobenzyl]aminopropana-mide;
2-[4-(3-trifluoromethylbenzyl)aminobenzyl] aminopropanamide;
2-{4-[2-(2-fluorophenyl)ethyl] aminobenzyl} aminopropanamide;
2-{4-[2-(3-fluorophenyl)ethyl] aminobenzyl} aminopropanamide;
2-{4-[3-(2-fluorophenyl)propyl] aminobenzyl} aminopropanamide;
2-{4-[3-(3-fluorophenyl)propyl] aminobenzyl} aminopropanamide;
2-{4-[4-(3-fluorophenyl)butyl] aminobenzyl} aminopropanamide;
2-[4-(3-phenylpropyl)aminobenzyl]aminopropanamide;
2-[4-(2-phenylethyl)aminobenzyl]aminopropanamide;
2-{4-[4-(2-fluorophenyl)butyl] aminobenzyl aminopropanamide;
2-[4-(4-phenylbutyl)aminobenzyl]aminopropanamide; if the case, either as single (S) or (R) isomer or as a mixture thereof or a pharmaceutically acceptable salt thereof.
4. A compound of formula (IA) wherein R3 is halogen,or a pharmaceutically acceptable salt thereof.
5. A compound which is:
2-[4-(4-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(4-chlorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(4-bromobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-chlorobenzyl)aminobenzyl] aminopropanamide;
2-[4-(2-bromobenzyl)aminobenzyl]aminopropanamide;
2-[4-(2-chlorobenzyl)aminobenzyl] aminopropanamide;
2-[4-(2-fluorobenzyl)aminobenzyl] aminopropanamide;
2-[4-(3-bromobenzyl)aminobenzyl] aminopropanamide; if the case, either as single (S) or (R) isomer or as a mixture thereof, or a pharmaceutically acceptable salt thereof.
2-[4-(4-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(4-chlorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(4-bromobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-fluorobenzyl)aminobenzyl]aminopropanamide;
2-[4-(3-chlorobenzyl)aminobenzyl] aminopropanamide;
2-[4-(2-bromobenzyl)aminobenzyl]aminopropanamide;
2-[4-(2-chlorobenzyl)aminobenzyl] aminopropanamide;
2-[4-(2-fluorobenzyl)aminobenzyl] aminopropanamide;
2-[4-(3-bromobenzyl)aminobenzyl] aminopropanamide; if the case, either as single (S) or (R) isomer or as a mixture thereof, or a pharmaceutically acceptable salt thereof.
6. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, the process comprising a) reacting a compound of formula (II) wherein R, R1 and n are as defined in claim 1, with a compound of formula (III) wherein R2 is as defined in claim i; or b) reacting a compound of formula (IV) or s reactive derivative thereof wherein R, R1, R2 and n are as defined in claim 1, with ammonia; or c) reacting a compound of formula (V):
wherein R, R1 and n are as defined in claim 1 with a compound of formula (VI):
wherein W is a halogen atom and R2 as defined in claim 1;
and, where required, conducting at least one further step selected from:
(d) converting a compound of formula (I) thus formed into another compound of formula (I);
(e) converting a compound of formula (I) thus formed into a pharmaceutically acceptable salt;
(f) converting a salt of a compound of formula (I) thus formed into a free compound; and (g) separating a mixture of isomers of compounds of formula (I) thus formed into the single isomers.
wherein R, R1 and n are as defined in claim 1 with a compound of formula (VI):
wherein W is a halogen atom and R2 as defined in claim 1;
and, where required, conducting at least one further step selected from:
(d) converting a compound of formula (I) thus formed into another compound of formula (I);
(e) converting a compound of formula (I) thus formed into a pharmaceutically acceptable salt;
(f) converting a salt of a compound of formula (I) thus formed into a free compound; and (g) separating a mixture of isomers of compounds of formula (I) thus formed into the single isomers.
7. A process for the preparation of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, as defined in claim 4, the process comprising reacting a compound of formula (VII):
wherein R3 is as defined in claim 4, with a compound of formula (VIII):
and, where required, conducting at least one further step selected from:
(i) converting a compound of formula (IA) thus formed into another compound of formula (IA);
(ii) converting a compound of formula (IA) thus formed into a pharmaceutically acceptable salt;
(iii) converting a salt of a compound of formula (IA) thus formed into a free compound; and (iv) separating a mixture of isomers of a compound of formula (IA) into the single isomers.
wherein R3 is as defined in claim 4, with a compound of formula (VIII):
and, where required, conducting at least one further step selected from:
(i) converting a compound of formula (IA) thus formed into another compound of formula (IA);
(ii) converting a compound of formula (IA) thus formed into a pharmaceutically acceptable salt;
(iii) converting a salt of a compound of formula (IA) thus formed into a free compound; and (iv) separating a mixture of isomers of a compound of formula (IA) into the single isomers.
8. The compound (S)-2-[4-(3-fluorobenzyl)aminobenzyl]aminopropanamide or a pharmaceutically acceptable salt thereof.
9. The compound 2-[4-(4-chlorobenzyl)aminobenzyl]aminopropanamide or a pharmaceutically acceptable salt thereof.
10. The compound 2-[4-(2-phenylethyl)aminobenzyl]aminopropanamide or a pharmaceutically acceptable salt thereof.
11. The compound 2-[4-(4-bromobenzyl)aminobenzyl]aminopropanamide or a pharmaceutically acceptable salt thereof.
12. The compound 2-[4-(4-fluorobenzyl)aminobenzyl]aminopropanamide or a pharmaceutically acceptable salt thereof.
13. The compound 2-[4-(3-chlorobenzyl)aminobenzyl] aminopropanamide or a pharmaceutically acceptable salt thereof.
14. The compound 2-[4-(3-fluorobenzyl)aminobenzyl] aminopropanamide or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising:
a pharmaceutically acceptable carrier or diluent and, the compound or salt as defined in any one of claims 1 to 5 or any one of claims 8 to 14.
a pharmaceutically acceptable carrier or diluent and, the compound or salt as defined in any one of claims 1 to 5 or any one of claims 8 to 14.
16. The pharmaceutical composition according to claim 15, which is an anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic or hypnotic agent.
17. The use of the compound or salt as defined in any one of claims 1 to 5 or any one of claims 8 to 14, in the preparation of a pharmaceutical composition for use as an anti-epileptic, anti-Parkinson, neuroprotective, anti-depressant, antispastic or hypnotic agent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939306899A GB9306899D0 (en) | 1993-04-01 | 1993-04-01 | Substituted (arylalkylaminobenzyl) aminopropionamide derivatives and process for their preparation |
| GB9306899.7 | 1993-04-01 | ||
| PCT/EP1994/000825 WO1994022809A1 (en) | 1993-04-01 | 1994-03-15 | Substituted (arylalkylaminobenzyl)aminopropionamide derivatives, their preparation and use anti-epileptic, neuroprotective and antidepressant agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2136008A1 CA2136008A1 (en) | 1994-10-13 |
| CA2136008C true CA2136008C (en) | 2005-06-14 |
Family
ID=10733226
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002136008A Expired - Fee Related CA2136008C (en) | 1993-04-01 | 1994-03-15 | Substituted (arylalkylaminobenzyl)amino-propionamide derivatives and process for their preparation |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5449692A (en) |
| EP (1) | EP0648202B1 (en) |
| JP (1) | JP3542600B2 (en) |
| KR (1) | KR950701905A (en) |
| CN (1) | CN1035939C (en) |
| AT (1) | ATE152442T1 (en) |
| AU (1) | AU667169B2 (en) |
| CA (1) | CA2136008C (en) |
| DE (1) | DE69402935T2 (en) |
| DK (1) | DK0648202T3 (en) |
| ES (1) | ES2104370T3 (en) |
| FI (1) | FI945582A0 (en) |
| GB (1) | GB9306899D0 (en) |
| GR (1) | GR3024150T3 (en) |
| HU (1) | HUT70944A (en) |
| IL (1) | IL108970A0 (en) |
| NZ (1) | NZ263183A (en) |
| PL (1) | PL306538A1 (en) |
| RU (1) | RU94046144A (en) |
| WO (1) | WO1994022809A1 (en) |
| ZA (1) | ZA941964B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9515412D0 (en) * | 1995-07-27 | 1995-09-27 | Pharmacia Spa | 2-(4-substituted)-benzylamino-2-methyl-propanamide derivatives |
| IT1283489B1 (en) * | 1996-07-23 | 1998-04-21 | Chiesi Farma Spa | AMIDES OF ALPHA-AMINO ACIDS, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
| WO1999026614A1 (en) | 1997-11-21 | 1999-06-03 | Euro-Celtique S.A. | Substituted 2-aminoacetamides and the use thereof |
| GB9727523D0 (en) | 1997-12-31 | 1998-02-25 | Pharmacia & Upjohn Spa | Alpha-aminoamide derivatives useful as analgesic agents |
| US6281211B1 (en) | 1999-02-04 | 2001-08-28 | Euro-Celtique S.A. | Substituted semicarbazides and the use thereof |
| WO2000061188A1 (en) * | 1999-04-09 | 2000-10-19 | Euro-Celtique S.A. | Sodium channel blocker compositions and the use thereof |
| IL160523A0 (en) | 2001-09-03 | 2004-07-25 | Newron Pharm Spa | PHARMACEUTICAL COMPOSITION COMPRISING GABAPENTIN OR AN ANALOGUE THEREOF AND AN alpha-AMINOAMIDE AND ITS ANALGESIC USE |
| EP1438956A1 (en) | 2003-01-16 | 2004-07-21 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful as antimigraine agents |
| CN101018546B (en) * | 2004-09-10 | 2013-06-12 | 纽朗制药有限公司 | (halobenzyloxy) benzylamino-propanamides as sodium and/or calcium channel selective modulators |
| BRPI0617891A2 (en) * | 2005-10-26 | 2011-08-09 | Boehringer Ingelheim Int | (hetero) aryl compounds having mch antagonist activity, physiologically acceptable salts thereof, composition, pharmaceutical composition as well as use and preparation of said compounds |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1140748A (en) * | 1966-06-23 | 1969-01-22 | Ici Ltd | New carboxylic acid derivatives |
| US4049663A (en) * | 1972-06-06 | 1977-09-20 | Allen & Hanburys Limited | Ethylene diamine derivatives |
| DE3050800C2 (en) * | 1979-03-22 | 1989-06-22 | Continental Pharma Inc., Bruessel/Bruxelles, Be | |
| FR2480747A1 (en) * | 1980-04-17 | 1981-10-23 | Roques Bernard | AMINO ACID DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
| US4725619A (en) * | 1985-04-16 | 1988-02-16 | Usv Pharmaceutical Corporation | Aryl and heteroaryl ethers as agents for the treatment of hypersensitive ailments |
| US4728668A (en) * | 1985-04-16 | 1988-03-01 | Usv Pharmaceutical Corporation | Aryl and heteroaryl ethers as agents for the treatment of hypersensitive ailments |
| US4631287A (en) * | 1985-04-16 | 1986-12-23 | Usv Pharmaceutical Corp. | Aryl and heteroaryl ethers as agents for the treatment of hypersensitive ailments |
| US4839369A (en) * | 1985-04-16 | 1989-06-13 | Rorer Pharmaceutical Corporation | Aryl and heteroaryl ethers as agents for the treatment of hypersensitive ailments |
| IL94466A (en) * | 1989-05-25 | 1995-01-24 | Erba Carlo Spa | Pharmaceutical compositions containing n-phenylalkyl substituted alpha-amino carboxamide derivatives, some such novel compounds and their preparation |
-
1993
- 1993-04-01 GB GB939306899A patent/GB9306899D0/en active Pending
-
1994
- 1994-03-14 IL IL10897094A patent/IL108970A0/en not_active IP Right Cessation
- 1994-03-15 WO PCT/EP1994/000825 patent/WO1994022809A1/en active IP Right Grant
- 1994-03-15 CN CN94190169A patent/CN1035939C/en not_active Expired - Fee Related
- 1994-03-15 RU RU94046144/04A patent/RU94046144A/en unknown
- 1994-03-15 PL PL94306538A patent/PL306538A1/en unknown
- 1994-03-15 KR KR1019940704344A patent/KR950701905A/en not_active Application Discontinuation
- 1994-03-15 CA CA002136008A patent/CA2136008C/en not_active Expired - Fee Related
- 1994-03-15 ES ES94911181T patent/ES2104370T3/en not_active Expired - Lifetime
- 1994-03-15 AU AU63776/94A patent/AU667169B2/en not_active Ceased
- 1994-03-15 NZ NZ263183A patent/NZ263183A/en unknown
- 1994-03-15 DK DK94911181.9T patent/DK0648202T3/en active
- 1994-03-15 EP EP94911181A patent/EP0648202B1/en not_active Expired - Lifetime
- 1994-03-15 DE DE69402935T patent/DE69402935T2/en not_active Expired - Fee Related
- 1994-03-15 HU HU9403809A patent/HUT70944A/en unknown
- 1994-03-15 AT AT94911181T patent/ATE152442T1/en not_active IP Right Cessation
- 1994-03-15 JP JP52143094A patent/JP3542600B2/en not_active Expired - Fee Related
- 1994-03-21 ZA ZA941964A patent/ZA941964B/en unknown
- 1994-03-22 US US08/215,694 patent/US5449692A/en not_active Expired - Lifetime
- 1994-11-28 FI FI945582A patent/FI945582A0/en unknown
-
1997
- 1997-07-16 GR GR970401800T patent/GR3024150T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0648202A1 (en) | 1995-04-19 |
| KR950701905A (en) | 1995-05-17 |
| DK0648202T3 (en) | 1997-10-27 |
| RU94046144A (en) | 1996-09-27 |
| AU6377694A (en) | 1994-10-24 |
| CN1104018A (en) | 1995-06-21 |
| CN1035939C (en) | 1997-09-24 |
| GB9306899D0 (en) | 1993-05-26 |
| WO1994022809A1 (en) | 1994-10-13 |
| EP0648202B1 (en) | 1997-05-02 |
| HUT70944A (en) | 1995-11-28 |
| NZ263183A (en) | 1996-02-27 |
| JP3542600B2 (en) | 2004-07-14 |
| ES2104370T3 (en) | 1997-10-01 |
| ZA941964B (en) | 1994-10-19 |
| GR3024150T3 (en) | 1997-10-31 |
| DE69402935T2 (en) | 1997-11-20 |
| FI945582A (en) | 1994-11-28 |
| PL306538A1 (en) | 1995-04-03 |
| DE69402935D1 (en) | 1997-06-05 |
| HU9403809D0 (en) | 1995-02-28 |
| US5449692A (en) | 1995-09-12 |
| FI945582A0 (en) | 1994-11-28 |
| ATE152442T1 (en) | 1997-05-15 |
| CA2136008A1 (en) | 1994-10-13 |
| IL108970A0 (en) | 1994-06-24 |
| AU667169B2 (en) | 1996-03-07 |
| JPH08504828A (en) | 1996-05-28 |
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