Patent EA-002774-B1 (EA)
Title: Use of new neurotrophic compounds for stimulating growth and neuron regeneration for treating neurologic disorder and for neurodegeneration prevention and in manufacturing of medicine
Inventor: HAMILTON GREGORY S
IPC: A61P21/00
Filed: 1996-06-05
Abstract: 1. A neurotrophic compound of the formula:   or pharmaceutically acceptable salt or hydrate thereof, wherein R1 is a C1-C9 alkyl or C2-C9 alkenyl group with straight or branched chain optionally substituted with C3-C8 cycloalkyl, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, where said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, or hydroxy, or Ar1 where Ar1 is selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, straight or branched C1-C6 alkyl or C2-C6 alkenyl, C1-C4 alkoxyl or C2-C4 alkenyloxyl, phenoxy, benzyloxy, and amino group; X is oxygen or sulfur; Y is oxygen or NR2, where R2 is hydrogen or C1-C6 alkyl; and Z is C2-C6 alkyl or alkenyl with straight or branched chain, wherein the alkyl or alkenyl chain is substituted in one or more positions with Ar1 as defined above, C3-C8 cycloalkyl, cycloalkyl connected by a C1-C6 alkyl or C2-C6 alkenyl straight or branched chain, or Ar2 where Ar2 is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or C2-C9alkenyl, C1-C4alkoxy or C2-C4alkenyloxy, phenoxy, benzyloxy, and amino; the fragment:   where R3 is selected from the group consisiting of straight or branched alkyl C1-C8 optionally substituted with C3-C8cycloalkyl, or Ar1 as defined above and unsubstituted Ar1; X2 is O or NR5, where R5 is selected, from the group consisting of hydrogen, C1-C6 straight or branched alkyl and C2-C6alkenyl; R4 is selected from the group consisting of phenyl, benzyl, straight or branched C1-C5alkyl or C2-C5 alkenyl, and straight or branched C1-C5 alkyl or C2-C5 alkenyl substituted with phenyl; for stimulating growth and neuron regeneration, for treating neurologic disorders or for neurodegeneration prevention. 2. The use according to Claim 1, for stimulating growth of damaged peripheral nerves. 3. The use according to Claim 1, whrein neurologic disorder is selected from the group consisting of peripheral neuropathy and neurodegeneration-related neurologic pathologies. 4. The method of Claim 3, wherein the neurological neurodegeneration-related disorder is Alzheimer's disease. 5. The method of Claim 3, wherein the neurological neurodegeneration-related disorder is Parkinsons's disease. 6. The method of Claim 3, wherein the neurological neurodegeneration-related disorder is amyotrophic lateral sclerosis. 7. The use according to Claim 1, where Z and R1 are lipophilic groups. 8. The use according to Claim 1, wherein the compound is selected from the group consisting of: 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-(3-pyridyl)-1-propyl-(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-(3,4,5-trimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-(4,5-dichlorophenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-(4,5-dichlorophenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-cyclohexyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, (1R)-1,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, (1R)-1,3-diphenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (1R)-1-cyclohexyl-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, (1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, (1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate, 1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate, 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester, 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethyl ester, 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglicine ethyl ester, 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenyl ester, 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl ester, and 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester. 9. The use of neurotrophic compound of formula   or pharmaceutically acceptable salts or hydrates thereof. wherein R1 is a C1-C9 alkyl or C2-C9 alkenyl group with straight or branched chain optionally substituted with C3-C8 cycloalkyl, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, where said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, or hydroxy, or Ar1 where Ar1 is selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, straight or branched C1-C6 alkyl or C2-C6 alkenyl, C1-C4 alkoxyl or C2-C4 alkenyloxyl, phenoxy, benzyloxy, and amino group; Z is C2-C6 alkyl or alkenyl with straight or branched chain, wherein the alkyl or alkenyl chain is substituted in one or more positions with Ar1 as defined above, C3-C8 cycloalkyl, cycloalkyl connected by a C1-C6 alkyl or C2-C6 alkenyl straight or branched chain, or Ar2 where Ar2 is selected from the group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or C2-C9alkenyl, C1-C4alkoxy or C2-C4alkenyloxy, phenoxy, benzyloxy, and amino; for stimulating growth and neuron regeneration, for treating neurologic disorders or for neurodegeneration prevention. 10. The use according to Claim 9, wherein R1 is selected from the group consisting of C1-C9 straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl. 11. The use according to Claim 9, for stimulating growth of damaged peripheral nerves. 12. The use according to Claim 9, whrein neurologic disorder is selected from the group consisting of peripheral neuropathy and neurodegeneration-related neurologic pathologies. 13. The method of Claim 9, wherein the neurological neurodegeneration-related disorder is Alzheimer's disease. 14. The method of Claim 9, wherein the neurological neurodegeneration-related disorder is Parkinsons's disease. 15. The method of Claim 9, wherein the neurological neurodegeneration-related disorder is amyotrophic lateral sclerosis. 16. The use according to Claim 9, where Z and R1 are lipophilic groups. 17. The use of neurotrophic compound of the formula:   or pharmaceutically acceptable salts or hydrates thereof; wherein Z is the fragment:   where R3 is selected from the group consisting of straight or branched alkyl C1-C8 optionally substituted with C3-C8 cycloalkyl, or Ar1 as defined above, and unsubstituted Ar1; X2 is O or NR5, where R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched alkyl and C2-C6alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched alkyl or C2-C5alkenyl, and C1-C5 straight or branched alkyl or C2-C5alkenyl substituted with phenyl; for stimulating growth and neuron regeneration, for treating neurologic disorders or for neurodegeneration prevention. thienyl, 2-thiazolyl, and 4-hydroxybutyl. 18. The use according to Claim 17, for stimulating growth of damaged peripheral nerves. 19. The use according to Claim 17, whrein neurologic disorder is selected from the group consisting of peripheral neuropathy and neurodegeneration-related neurologic pathologies. 20. The method of Claim 17, wherein the neurological neurodegeneration-related disorder is Alzheimer's disease. 21. The method of Claim 17, wherein the neurological neurodegeneration-related disorder is Parkinsons's disease. 22. The method of Claim 17, wherein the neurological neurodegeneration-related disorder is amyotrophic lateral sclerosis. 23. The use according to Claim 17, where Z and R1 are lipophilic groups. 24. The use of a neurotrophic N-glyoxyl prolyl ester compound of the formula:   or pharmaceutically acceptable salts or hydrates thereof; w