Patent EA-002401-B1 (EA)
Title: N-linked ureas and carbamates of heterocyclic thioesters
Inventor: HAMILTON GREGORY S
IPC: A61K31/40
Filed: 1997-12-23
Abstract: 1. A compound of formula IV:   or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2, forming a 5 member heterocyclic ring; Y is a direct bond to Z, or a C1-C6 straight or branched chain alkylene, Z is a C1-C6 straight or branched chain alkylene, C and D are independently: hydrogen, Ar, or C6 cycloalkyl or C1-C6 alkyl, substituted with Ar; where Ar is 3-pyridyl, adamantyl, naphtyl or phenyl, optionally substituted in one or three position(s) with methoxy, C1-C6 alkyl, fluoro or chloro; W is oxygen or sulfur; R1 and R2 are selected independently from the group consisting of hydrogen, Ar, C3-C6 cycloalkyl, optionally substituted with phenyl, C1-C6 straight or branched alkyl or or C1-C8 straight or branched alkyl optionally substituted in one or more positions with Ar; or or R1 and R2 may be taken together to form pyrrolidine or morpholine. 2. The compound of claim 1, wherein the compound is selected from the group consisting of: 3-Phenylpropyl (2S)-1-(1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothiate (17); Phenethyl (2S) -N-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothiate (18); 3-(2,3,5-Trimethylphenyl)propyl 1-(1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (19); 3-(2,3,5-Trimethylphenyl)propyl 1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (20); 3-(3-Fluorophenyl-propyl (2S)-1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (21); 3-(2-Fluorophenyl)propyl (2S)-1-1adamantylcarbamoyl)-2-pyrrolidinecarbothioate (22); 3-(2-Fluorophenyl-propyl (2S)-1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (23); 3-(4-Methylphenyl)propyl (2S)-1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (24); 3-(4-Methylphenyl)propyl (2S)-1-1adamantylcarbamoyl)-2-pyrrolidinecarbothioate (25); 3-(4-Methylphenyl)propyl (2S)-1-tertbutylcarbamoyl)-2-pyrrolidinecarbothioate (26); 3-(2-Chlorophenyl)propyl (2S)-1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate 27); 3-(3,5-Dimethoxyphenyl)propyl (2S)-1-{[(1S)-1-(1-naphthyl)ethyl]-carbamoyl}-2-pyrrolidinecarbothioate (28); 3,3-Diphenylpropyl (2S)-1-[(1,1,3,3-tetramethylbutyl)carbamoyl]-2-pyrrolidinecarbothioate (29); 3-Cyclohexylpropyl (2S)-1-[2,6-diisopropylphenyl)carbamoyl]-2-pyrrolidinecarbothioate (31); 3-Cyclohexylpropyl (2S)-1-(hexylcarbamoyl)-2-pyrrolidinecarbothioate (32); 3,3-Diphenylpropyl (2S)-1-[(2,4-dimethoxyphenyl)carbamoyl]-2-pyrrolidinecarbothioate (33); 3-(3,5-Dimethoxyphenyl)propyl (2S)-1-{[(1S,2R)-2-phenyl-cyclopropyl]carbamoyl]-2-pyrrolidinecarbothioate (34); 3-Phenylpropyl (2S)-1-[(2,4-Dimethoxyphenyl)carbamoyl]-2-pyrrolidinecarbothioate (35); 3-Phenylpropyl (2S)-1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (36); 3-Phenylpropyl (2S)-1-(1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (37); 3-Phenylpropyl (2S)-1-[1-adamantylamino) (thioxo)-methyl]-2-pyrrolidinecarbothioate (38); 3-(3,4,5-Trimethoxyphenyl)propyl (2S)-1-(hexylcarbomoyl)-2-pyrrolidinecarbothioate (39); 3-(3,4,5-Trimethoxyphenyl)propyl (2S)-1-(benzylcarbamoyl)-2-pyrrolidinecarbothioate (40); 3-Phenylpropyl (2S)-1-(dimethylcarbamoyl)-2-pyrrolidinecarbothioate (41); 3-Phenylpropyl (2S)-1-(1-pyrrolidinylcarbonyl)-2-pyrrolidinecarbothioate (42); 3-Phenylpropyl (2S)-1-(morphilinocarbonyl)-2-pyrrolidinecarbothioate (43); 3-Phenylpropyl (2S)-1-(diisopropylcarbamoyl)-2-pyrrolidinecarbothioate (44); 3. A pharmaceutical composition comprising a neurotrophically effective amount of the compound of any claims 1 and 2 and a pharmaceutically acceptable carrier. 4. A method of effecting a neuronal activity in an animal, comprising administering to the animal a neurotrophically effective amount of the compound of any claims 1 and 2. 5. The method of claim 4, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder. 6. The method of claim 5, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration. 7. The method of claim 6, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.