Claims
- 1. A method for inhibiting β-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of β-amyloid peptide wherein said compounds are represented by formula I:
9
- 2. A method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:
11
- 3. A method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:
13
- 4. The method according to claim 1, 2 or 3 wherein R1 is phenyl, 2-naphthyl, quinolin-3-yl, benzothiazol-6-yl, and 5-indolyl.
- 5. The method according to claim 1, 2 or 3 wherein R1 is a substituted phenyl group of the formula:
15wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb′ are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb′ are either both hydrogen or both substituents other than hydrogen.
- 6. The method according to claim 1, 2 or 3 wherein R1 is a substituted 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl.
- 7. The method according to claim 1, 2 or 3 wherein R1 is a substituted heteroaryl containing 1 to 3 substitlents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the —NH group.
- 8. The method according to claim 7 wherein R1 is a 4-substituted, a 3,5-disubstituted or 3,4-disubstituted phenyl.
- 9. The method according tu claim 8 wherein R1 is a 3,5-disubstituted phenyl.
- 10. The method according to claim 9 wherein the 3,5-disubstituted phenyl is selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)phenyl and 3,5-dimethoxyphenyl.
- 11. The method according to claim 8 wherein R1 is a 3,4-disubstituted phenyl.
- 12. The method according to claim 11 wherein the 3,4-disubstituted phenyl is selected from the group consisting of 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3,4-methylenedioxyphenyl.
- 13. The method according to claim 8 wherein R1 is a 4-substituted phenyl.
- 14. The method according to claim 13 wherein the 4-substituted phenyl is selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, and 4-(1-ethoxy)ethylphenyl.
- 15. The method of claims 1, 2 or 3 wherein R1 is 2-methylquinolin-6-yl.
- 16. The method according to claims 1, 2 or 3 wherein R2 is selected from the group consisting of alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms and aryl.
- 17. The method according to claim 16 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, —CH2CH2SCH3 and phenyl.
- 18. The method according to claims 1, 2 or 3 wherein R3 is an alkyl group.
- 19. The method according to claim 18 wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl.
- 20. The method according to claims 1, 2 or 3 wherein R3 is a substituted alkyl group.
- 21. The method according to claim 20 wherein the substituted alkyl group is selected from the group consisting of α-hydroxyethyl, —CH2-cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-diiodo-4-hydroxybenzyl, —CH2-indol-3-yl, —(CH2)4—NH—BOC, —(CH2)4—NH2, —CH2—(1—N-benzyl-imidazol-4-yl), —CH2-imidazol-4-yl, —CH2CH2SCH3, —(CH2)4NHC(O)(CH2)3CH3, and —(CH2)yC(O)OR5 where y is 1 or 2 and R5 is hydrogen, methyl, or tert-butyl. 22. The method according to claims 1, 2 or 3 wherein X is —C(O)Y wherein Y is selected from the group consisting of alkoxy and thioalkoxy.
- 23. The method according to claim 22 wherein Y is alkoxy selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, and tert-butoxy.
- 24. The method according to claims 1, 2, or 3 wherein X is —C(O)Y and Y is —NR′R″ where R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups.
- 25. The method according to claim 24 wherein Y is selected from the group consisting of amino (—NH2), N-(iso-butyl)amino, N-methylamino, N,N-dimethylamino, and N-benzylamino.
- 26. The method according to claims 1, 2 or 3 wherein X is —CH2OH.
- 27. The method according to claims 1, 2 or 3 wherein the compound of formula I is selected from the group consisting of:
N-[N-(3,4-dichlorophenyl)alanyl]valine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine N-iso-butyl amide N-[N-(3,4-dichlorophenyl)alanyl]threonine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine ethyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine tert-butyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine amide N-(3,4-dichlorophenyl)alanine N-(1-hydroxy-3-methyl-2-butyl) amide N-[N-(3,4-dichlorophenyl)alanyl]valine NN-dimethyl amide N-[N-(3,4-dichlorophenyl)alanyl]valine N-methyl amide N-[N-(3,4-dichlorophenyl)alanyl]alanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]leucine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]isoleucine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]tryptophan methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid β-(tert-butyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-N-BOC-lysine methyl ester N-[N-benzothiazol-6-yl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]lysine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]tyrosine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]alanine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester N-[N-(3,5-dichlorophenyl)alanyl]phenylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid β-(methyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-1-benzylhistidine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid γ-(tert-butyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]leucine amide N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-(3,5-diiodo)tyrosine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-(3-iodo)tyrosine methyl ester N-[N-(3,5-dichlorophenyl)glycyl]-2-aminopentanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-Nε-(hexanoyl)lysine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine amide N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]-β-cyclohexylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanamide N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]methionine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide N-[N-(3,5-dichlorophenyl)alanyl-2-aminohexanamide N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]histidine methyl ester N-[N-(quinolin-3-yl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(benzothiazol-2-yl)-L-alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,5-difluorophenyl)alanyl]alanine methyl ester N-[N-(3,5-difluorophenyl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)-L-alanyl]-S-2-aminohexanamide N-[N-(3,4-dichlorophenyl alanyl-2-aminohexan-(N-benzyl)-amide N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-2-amino-2-phenylethanol N-[N-(3,5-dichlorophenyl)phenylglycinyllalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanol N-[N-(3,5-dichlorophenyl)alanyl]-2-amino-2-phenylethanol N-[N-(3,5-dichlorophenyl)-L-alanyl]-L-phenylglycine tert-butyl ester N-[N-(3,5-di-(trifluoromethyl)phenyl)-L-alanyl]-L-phenylglycine tert-butyl ester N-[N-(3,5-dimethoxyphenyl)-L-alanyl]-2-aminohexanoic acid methyl ester and pharmaceutically acceptable salts thereof.
- 26. A pharmaceutical composition comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of formula I:
16
- 27. The pharmaceutical composition according to claim 26 wherein R1 is phenyl, 2-naphthyl, quinolin-3-yl, benzothiazol-6-yl, and 5-indolyl.
- 28. The pharmaceutical composition according to claim 26 wherein R1 is a substituted phenyl group of the formula:
18wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb′ are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb′ are either both hydrogen or both substituents other than hydrogen.
- 29. A. The pharmaceutical composition according to claim 26 wherein R1 is a substituted 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl.
- 30. The pharmaceutical composition according to claim 26 wherein R1 is a substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the —NH group.
- 31. The pharmaceutical composition according to claim 30 wherein R1 is a 4-substituted, a 3,5-disubstituted or 3,4-disubstituted phenyl.
- 32. The pharmaceutical composition according to claim 31 wherein R1 is a 3,5-disubstituted phenyl.
- 33. The pharmaceutical composition according to claim 32 wherein the 3,5-disubstituted phenyl is selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)phenyl and 3,5-dimethoxyphenyl.
- 34. The pharmaceutical composition according to claim 31 wherein R1 is a 3,4-disubstituted phenyl.
- 35. The pharmaceutical composition according to claim 34 wherein the 3,4-disubstituted phenyl is selected from the group consisting of 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3,4-methylenedioxyphenyl.
- 36. The pharmaceutical composition according to claim 31 wherein R1 is a 4-substituted phenyl.
- 37. The pharmaceutical composition according to claim 36 wherein the 4-substituted phenyl is selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, and 4-(1-ethoxy)ethylphenyl.
- 38. The pharmaceutical composition according to claim 26 wherein R1 is 2-methylquinolin-6-yl.
- 39. The pharmaceutical composition according to claim 26 wherein R2 is selected from the group consisting of alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms and aryl.
- 40. The pharmaceutical composition according to claim 39 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, —CH2CH2SCH3 and phenyl.
- 41. The pharmaceutical composition according to claim 26 wherein R3 is an alkyl group.
- 42. The pharmaceutical composition according to claim 41 wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl.
- 43. The pharmaceutical composition according to claim 26 wherein R3 is a substituted alkyl group.
- 44. The pharmaceutical composition according to claim 43 wherein the substituted alkyl group is selected from the group consisting of α-hydroxyethyl, —CH2-cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-diiodo-4-hydroxybenzyl, —CH2-indol-3-yl, —(CH2)4—NH—BOC, —(CH2)4—NH2, —CH2—(1-N-benzyl-imidazol-4-yl), —CH2-imidazol-4-yl, —CH2CH2SCH3, —(CH2)4NHC(O)(CH2)3CH3, and —(CH2)yC(O)OR5 where y is 1 or 2 and R5 is hydrogen, methyl, or tert-butyl.
- 45. The pharmaceutical composition according to claim 26 wherein X is —C(O)Y wherein Y is selected from the group consisting of alkoxy and thioalkoxy.
- 46. The pharmaceutical composition according to claim 45 wherein Y is alkoxy selected from the group consisting of methoxy, ethyoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, and tert-butoxy.
- 47. The pharmaceutical composition according to claim 26 wherein X is —C(O)Y and Y is —NR′R″ where R′ and R′ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups.
- 48. The pharmaceutical composition according to claim 47 wherein Y is selected from the group consisting of amino (—NH2), N-(iso-butyl)amino, N-methylamino, N,N-dimethylamino, and N-benzylamino.
- 49. The pharmaceutical composition according to claim 26 wherein X is —CH2OH.
- 50. The pharmaceutical composition according to claim 26 wherein the compound of formula I is selected from the group consisting of:
N-[N-(3,4-dichlorophenyl)alanyl]valine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine N-iso-butyl amide N-[N-(3,4-dichlorophenyl)alanyl]threonine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine ethyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine tert-butyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine amide N-(3,4-dichlorophenyl)alanine N-(1-hydroxy-3-methyl-2-butyl) amide N-[N-(3,4-dichlorophenyl)alanyl]valine N,N-dimethyl amide N-[N-(3,4-dichlorophenyl)alanyl]valine N-methyl amide N-[N-(3,4-dichlorophenyl)alanyl]alanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]leucine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]isoleucine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]tryptophan methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid β-(tert-butyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-N-BOC-lysine methyl ester N-[N-benzothiazol-6-yl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]lysine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]tyrosine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]alanine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester N-[N-(3,5-dichlorophenyl)alanyl]phenylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid β-(methyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-1-benzylhistidine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid γ-(tert-butyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]leucine amide N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-(3,5-diiodo)tyrosine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-(3-iodo)tyrosine methyl ester N-[N-(3,5-dichlorophenyl)glycyl]-2-aminopentanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-Nε-(hexanoyl)lysine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine amide N-[N-(3,4-dichlorophenyl)alanyl-2-aminohexan-(N-methyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]-β-cyclohexylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanamide N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]methionine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexanamide N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]histidine methyl ester N-[N-(quinolin-3-yl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(benzothiazol-2-yl)-L-alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,5-difluorophenyl)alanyl]alanine methyl ester N-[N-(3,5-difluorophenyl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)-L-alanyl]-S-2-aminohexanamide N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N-benzyl)-amide N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-2-amino-2-phenylethanol N-[N-(3,5-dichlorophenyl)phenylglycinyl]alanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanol N-[N-(3,5-dichlorophenyl)alanyl]-2-amino-2-phenylethanol N-[N-(3,5-dichlorophenyl)-L-alanyl]-L-phenylglycine tert-butyl ester N-[N-(3,5-di-(trifluoromethyl)phenyl)-L-alanyl]-L-phenylglycine tert-butyl ester N-[N-(3,5-dimethoxyphenyl)-L-alanyl]-2-aminohexanoic acid methyl ester and pharmaceutically acceptable salts thereof.
- 51. A compound of formula III:
19
- 52. The compound according to claim 51 wherein R1 is phenyl, 2-naphthyl, quinolin-3-yl, benzothiazol-6-yl, and 5-indolyl.
- 53. The compound according to claim 51 wherein R1 is a substituted phenyl group of the formula:
21wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb′ are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb′ are either both hydrogen or both substituents other than hydrogen.
- 54. The compound according to claim 51 wherein R1 is a substituted 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl.
- 55. The compound according to claim 51 wherein R1 is a substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the —NH group.
- 56. The compound according to claim 55 wherein R1 is a 4-substituted, a 3,5-disubstituted or 3,4-disubstituted phenyl.
- 57. The compound according to claim 56 wherein R1 is a 3,5-disubstituted phenyl.
- 58. The compound according to claim 57 wherein the 3,5-disubstituted phenyl is selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)phenyl and 3,5-dimethoxyphenyl.
- 59. The compound according to claim 56 wherein R1 is a 3,4-disubstituted phenyl.
- 60. The compound according to claim 59 wherein the 3,4-disubstituted phenyl is selected from the group consisting of 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3,4-methylenedioxyphenyl.
- 61. The compound according to claim 56 wherein R1 is a 4-substituted phenyl.
- 62. The compound according to claim 61 wherein the 4-substituted phenyl is selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, and 4-(1-ethoxy)ethylphenyl.
- 63. The compound according to claim 51 wherein R1 is 2-methylquinolin-6-yl.
- 64. The compound according to claim 51 wherein R2 is selected from the group consisting of alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms and aryl.
- 65. The compound according to claim 64 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, —CH2CH2SCH3 and phenyl.
- 66. The compound according to claim 51 wherein R3 is an alkyl group.
- 67. The compound according to claim 66 wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl.
- 68. The compound according to claim 51 wherein R3 is a substituted alkyl group.
- 69. The compound according to claim 68 wherein the substituted alkyl group is selected from the group consisting of α-hydroxyethyl, —CH2-cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-diiodo-4-hydroxybenzyl, —CH2-indol-3-yl, —(CH2)4—NH—BOC, —(CH2)4—NH2, —CH2—(1-N-benzyl-imidazol-4-yl), —CH2-imidazol-4-yl, —CH2CH2SCH3, —(CH2)4NHC(O)(CH2)3CH3, and —(CH2)yC(O)OR5 where y is 1 or 2 and R5 is hydrogen, methyl, or tert-butyl.
- 70. The compound according to claim 51 wherein X is —C(O)Y wherein Y is selected from the group consisting of alkoxy and thioalkoxy.
- 71. The compound according to claim 70 wherein Y is alkoxy selected from the group consisting of methoxy, ethyoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, and tert-butoxy.
- 72. The compound according to claim 51 wherein X is —C(O)Y and Y is —NR′R″ where R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing i to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups.
- 73. The compound according to claim 72 wherein Y is selected from the group consisting of amino (—NH2), N-(iso-butyl)amino, N-methylamino, N,N-dimethylamino, and N-benzylamino.
- 74. The compound according to claim 51 wherein X is —CH2OH.
- 75. The compound according to claim 51 wherein the compound of formula I is selected from the group consisting of:
N-[N-(3,4-dichlorophenyl)alanyl]valine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine N-iso-butyl amide N-[N-(3,4-dichlorophenyl)alanyl]threonine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine ethyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine tert-butyl ester N-[N-(3,4-dichlorophenyl)alanyl]valine amide N-(3,4-dichlorophenyl)alanine N-(1-hydroxy-3-methyl-2-butyl) amide N-[N-(3,4-dichlorophenyl)alanyl]valine N,N-dimethyl amide N-[N-(3,4-dichlorophenyl)alanyl]valine N-methyl amide N-[N-(3,4-dichlorophenyl)alanyl]alanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]leucine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]isoleucine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]tryptophan methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid β-(tert-butyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-N-BOC-lysine methyl ester N-[N-benzothiazol-6-yl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]lysine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]tyrosine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]alanine methyl ester N-[N-(3,5-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester N-[N-(3,5-dichlorophenyl)alanyl]phenylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid 3-(methyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-1-benzylhistidine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid γ-(tert-butyl ester) α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]leucine amide N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid α-methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-(3,5-diiodo)tyrosine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-(3-iodo)tyrosine methyl ester N-[N-(3,5-dichlorophenyl)glycyl]-2-aminopentanoic acid methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-Nε-(hexanoyl)lysine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine amide N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]-β-cyclohexylalanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanamide N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]methionine methyl ester N-[N-(3,5-dichlorophenyl)alanyl-2-aminohexan-(N,N-dimethyl)-amide N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexanamide N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide N-[N-(3,4-dichlorophenyl)alanyl]histidine methyl ester N-[N-(quinolin-3-yl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(benzothiazol-2-yl)-L-alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,5-difluorophenyl)alanyl]alanine methyl ester N-[N-(3,5-difluorophenyl)alanyl]-2-aminohexanoic acid methyl ester N-[N-(3,4-dichlorophenyl)-L-alanyl]-S-2-aminohexanamide N-[N-(3,4-dichlorophenyl)alanyl-2-aminohexan-(N-benzyl)-amide N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-2-amino-2-phenylethanol N-[N-(3,5-dichlorophenyl)phenylglycinyl]alanine methyl ester N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanol N-[N-(3,5-dichlorophenyl)alanyl]-2-amino-2-phenylethanol N-[N-(3,5-dichlorophenyl)-L-alanyl]-L-phenylglycine tert-butyl ester N-[N-(3,5-di-(trifluoromethyl)phenyl)-L-alanyl]-L-phenylglycine tert-butyl ester N-[N-(3,5-dimethoxyphenyl)-L-alanyl]-2-aminohexanoic acid methyl ester and pharmaceutically acceptable salts thereof.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 60/______, which was converted pursuant to 37 C.F.R. §1.53(b)(2)(ii) from U.S. patent application Ser. No. 08/755,334, filed Nov. 22, 1996, which is incorporated herein by reference in its entirety.
Continuations (1)
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Number |
Date |
Country |
Parent |
08976191 |
Nov 1997 |
US |
Child |
09280966 |
Mar 1999 |
US |