The invention concerns cholecystokinin (CCK) antagonists useful in the treatment of cognitive disorders. Especially useful are CCKB antagonists such as CI-988.

Cholecystokinin (CCK) is a neuropeptide with a widespread distribution in brain. CCK receptors are classified into two types; CCKA and CCKB, both of which are present in brain (Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol. 31, 469-501).
CI-988, the chemical name is: [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino)-4-oxobutanoic acid, and the structure is:
It is a potent CCKB antagonist with high selectivity for CCKB receptors (Hughes, J., et al, 1990, Proc. Natl. Acad. Sci., USA, 87 6728-6732). CCKB antagonists have been shown to have anxiolytic-like activity in animal models of anxiety (Hughes, J., et al, Proc. Natl. Acad. Sci., USA, 87, 6728-6732; Singl, L., Lewis, A. S., Field, M. J., Hughes, J., and Woodruff, G. N., 1991, Proc. Natl. Acad. Sci., USA, 88, 1130-1133), suggesting a physiological role for CCK in anxiety. It has also been suggested that CCK may be involved in the control of food intake and in analgesic responses (Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol. 31, 469-501).
The above compound and other CCK antagonists have been described in EPA 0405537. These antagonists are also described in U.S. application Ser. No. 07/629,809, filed Dec. 19, 1990, now U.S. Pat. No. 5,278,316 the disclosure of which is hereby incorporated by reference.
Other CCK antagonists have been described in U.S. application Ser. No. 07/726,656, now U.S. Pat. No. 5,331,006; Ser. No. 07/726,655, now abandoned; application Ser. Nos. 07/839,647; 07/726,654 now U.S. Pat. Nos. 5,244,915, 5,397,788, and 5,523,306; Ser. No. 07/726,653 now U.S. Pat. No. 5,340,825; Ser. No. 07/726,652 now U.S. Pat. No. 5,264,419; and, Ser. No. 07/726,651 now U.S. Pat. No. 5,244,905, the disclosures of which are also hereby incorporated by reference.
The above patents and applications cover the compounds of the instant invention, methods for preparing them, and several uses thereof.
The above references do not disclose the use of CCKB antagonists for treating cognitive disorders.
The present invention concerns medical methods of treatment. More particularly, the invention concerns the use of CCK-B ligands for the treatment of the symptoms of cognitive decline or deficiencies such as in the loss of memory or in an elderly patient suffering from Alzhemier""s disease.
Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well known. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least ten percent of persons over sixty years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
The present invention relates to a novel therapeutic use of known compounds, CCKB antagonists, their derivatives, and pharmaceutically acceptable salts. The present invention concerns a method for treating cognitive disorders in a mammal in need of such treatment.
This invention provides a method of treating disorders of cognition using CCKB receptor antagonists. The results presented herein indicate that such compounds improve basal cognition and inhibit the impairments in performance caused by cholinergic deficits. Thus the compounds with CCK-B receptor antagonist activity are expected to be useful in diseases such as senile cognitive decline, Alzheimer""s disease, myasthenia gravis, tardive dyskinesia and dementia associated with Down""s syndrome or Parkinson""s disease.
The treatment comprises administering in unit dosage form an amount effective to treat the cognitive disorder of a CCKB antagonist or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.
Preferred compounds include but are not limited to:
1. [1S-[1xcex1,2xcex2[S*[S*(E)]],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
2. [1S-[1xcex1,2xcex2[S*(S*)],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]methylamino]-1-phenylethyl]amino]-4-oxobutanoic acid,
3. [1S-[1xcex1,2xcex2[S*(S*)],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]-hept-2-yl)amino]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
4. [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[188.8.131.52,7]dec-2-ylsulfonyl)amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
5. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[22.214.171.124,7]dec-2-ylsulfonyl)amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
6. [1R-[1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)],2xcex2]]-4-[[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
7. [1R-(1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)],2xcex2]]-4-[[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
8. [1R-[1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)],2xcex2]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexyl]oxy]carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
9. [1R-[1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)],2xcex2]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexyl]oxy]carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
10. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
11. [1S-[1xcex1,2xcex2[S*(R*)],4xcex1]]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-1-(phenylmethyl)ethyl]amino]ethyl]carbamic acid, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester,
12. [1S-[1xcex1,2xcex2[S*,R*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl]amino]ethyl]carbamic acid, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester,
13. N-[2-methyl-N-[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanylglycine,
14. N-[2-methyl-N-[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl-xcex2-alanine, and
15. (R)-tricyclo[22.214.171.124,7]dec-2-yl [1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl(2-phenylethyl)amino]-2-oxo-ethylcarbamate.
In addition preferred compounds of the instant invention are:
16. (xc2x1)-trans-2-chlorocyclohexyl [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
17. 2-chorocyclohexyl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
18. 2-[[2-[[[(2-chlorocyclohexyl]oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl)amino]-3-phenylpropyl butanedioate,
19. 2-[[2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropyl butanedioate,
20. (xc2x1)-tricyclo[126.96.36.199,7]dec-2-yl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethylcarbamate,
21. tricyclo[184.108.40.206,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
22. 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl butanedioate,
23. 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl butanedioate,
24. [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
25. [1S-[[1xcex1,2xcex2[S*(S*)],4xcex1]]-4-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
26. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl) amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
27. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
28. (R)-tricyclo[188.8.131.52,7]dec-2-yl [1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl(2-phenylethyl)amino]-2-oxoethylcarbamate,
29. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid, ethyl ester,
30. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetic acid, ethyl ester,
31. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid,
32. [R-[R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
33. [R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]acetic acid,
34. [1S-[1xcex1,2xcex2[S*[S*(E)]],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, methyl ester, (Bicyclo system is 1S-endo),
35. [1S-[1xcex1,2xcex2[S*[S*(E)]],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, (Bicyclo system is 1S-endo),
36. [R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-3-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)]carbonyl]amino]propyl]amino)-1-phenylethyl]amino]-3-oxopropanoic acid,
37. [R-(R*,S*))-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxo-8-thia-2,5-diazatridecanoic acid, tricyclo[18.104.22.168,7]dec-2-yl or ester,
38. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]benzenebutanoic acid,
39. [R-(R*,S*))-N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-4-phenylbutyl]glycine,
40. (R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo[3.3.1]non-9-yloxy)carbonyl]amino]-1-oxopropyl]amino]-4-oxo-2-butenoic acid,
41. mono[R-(R*,R*)]-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]-1-phenylethyl butanedioate,
42. 3-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-oxo-2-phenylprophl]amino]propanoic acid (TRP is R, other center is RS),
43. [1R-[1xcex1(R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid, (xe2x88x92)-Isomer,
44. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid, (xe2x88x92)-Isomer,
45. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, (xe2x88x92)-Isomer,
46. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid, (xe2x88x92)-Isomer,
47. 2-methylcyclohexyl-[1R-[1xcex1[R*(S*)]],2xcex2]-[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
48. [R-[R*,S*-(E,E)]]-6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-7-phenyl-2,4-heptadienoic acid,
49. [R-(R*,R*)]-[2-[[2-[[1,4-dioxo-4-(1H-tetrazol-5-ylamino)butyl]amino]-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamic acid,
50. tricyclo[220.127.116.11,7]dec-2-yl-[S-[R*,S*-(E)]]-12-(1H-indol-3-ylmethyl)-12-methyl-3,11-dioxo-9-(phenylmethyl)-2-oxa-7,10,13-triazatetradec-4-en-14-oate,
51. [R-(R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-3-oxopropanoic acid,
52. ethyl [R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]acetate,
53. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl) -2-methyl-1-oxo-2-[[tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-4-iodo-benzenebutanoic acid,
54. [R-(R*,R*)]-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(1(tricyclo[[(18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethoxy]acetic acid,
55. [[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-3-[[tricyclo(18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]acetic acid (TRP center is R, other center is RS),
56. (R)-[[[2-[[3-(1H-indol-3-yl)-1-oxo-2-methyl-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethylidene]amino]oxy]acetic acid,
57. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]benzenebutanoic acid,
58. [R-(R*,S*)]-N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]propyl]amino]-4-phenylbutyl)glycine,
59. 2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino)-1-phenylethyl]amino]carbonyl]cyclopropanecarboxylic acid (cyclopropane ring is trans-(xc2x1), other centers are R),
60. carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl]amino]ethyl-, tricyclo[220.127.116.11,7]dec-2-yl ester, [R,(R*,S*)]-,
61. benzeneheptanoic acid, xcex1-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-,[R-(R*,S*)]-,
62. methyl-(xc2x1)-xcex2-[[(2-phenylethyl)amino]carbonyl]-1xcex2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]-1H-indole-3-butanoate,
63. [R-(R*,S*)]-4-[[2-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[18.104.22.168,7]dec-2-yloxycarbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
64. bicyclo[2.2.1]heptane-2-acetic acid, 3-[[[[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]amino]carbonyl)oxy]-4,7,7-trimethyl-, [1R-[1xcex1,2xcex2,3xcex1[R*(S*)],4xcex1]]-,
65. butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino)-1-phenylethyl]amino]-4-oxo-[1R-1xcex1[R*(R*)]2xcex2]]-((xe2x88x92)-isomer),
66. 2-butenoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-, [1R-[1xcex1[R*(R*))],2xcex2]]-((xe2x88x92) -isomer),
67. butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-[1R-[1xcex1[R*(S*)],2xcex2]]-((xe2x88x92)-isomer), and
68. 2-butenoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-[IR[1xcex1[R*(S*)],2xcex2]]-((xe2x88x92)-isomer).
Additionally preferred are the compounds:
69. [[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]acetic acid,
70. [R-(R*,R*)]-[2-([3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethoxy]acetic acid,
71. [1R-(1xcex1,2xcex2[R*(R*)]]]-2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7)]dec-2-yloxy)carbonyl]amino]propyl]amino)-1-phenylethyl]amino]carbonyl]cyclopropane carboxylic acid,
72. [1S-[1xcex1,2xcex2[S*(S*)]]]-2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl)amino]carbonyl]cyclopropane carboxylic acid,
73. pR-R*,R*)]-3-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethoxy]propanoic acid,
74. [R-(R*,R*)]-mono 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]-1-phenylethyl butanedioic acid,
75. 3-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyllamino]propanoic acid,
76. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-4-iodobenzenebutanoic acid,
77. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
78. [1R-[1xcex1[R*(S*)],2xcex2]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid, ((xe2x88x92)-isomer),
79. [1R -[1xcex1[R*(R*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
80. 1R-[1xcex1[R*(R*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid, ((xe2x88x92)-isomer),
81. [R-(R*,S*)]-lg/-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]benzeneheptanoic acid,
82. 2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]-cyclopropanecarboxylic acid (cyclopropyl ring is trans-(xc2x1), other centers are R),
83. 2-methylcyclohexyl [1R-[1xcex1[R*(S*)]],2xcex2]-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl]carbamate,
84. [R-[R*,S*-(E less than E)[[-6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-7-phenyl-2,4-heptadienoic acid,
85. tricyclo[126.96.36.199,7]dec-2-yl [2-[[1-(hydroxymethyl)-2-hydroxy-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl]carbamate,
86. tricyclo[22.214.171.124,7]dec-2-yl [R-(R*,R*)]-[1-(1H-indol-3-ylmethyl) -1-methyl-2-oxo-2-[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl]amino]ethyl]carbamate,
87. [R-(R*,S*)]-2-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid,
88. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetic acid,
89. ethyl (R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetate,
90. 2-chlorocyclohexyl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl carbamate.
Isomer II
Ring Centers are trans, trp center is D, other center is S, ((xe2x88x92) or (+) form)
91. [R-[R*,R*(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-ylamino)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
92. [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
93. [R-(R*,S*)-mono[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]butanedioate,
94. tricyclo[188.8.131.52,7]dec-2-yl [R-(R*,S*)-[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
95. [1S-[1xcex1,2xcex2[S*[S(E)]],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
96. [1S-[1xcex1,2xcex2[S*(S*)],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-[[[(1,7,7-trimethylbicyclo[2.2.1]-hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, (bicyclo system is 1S-endo),
97. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
98. N-[2-methyl-N-[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanylglycine,
99. [R-(R*,S*)[-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
100. [R-(R*,R*)]-2-[[2-[[1,4-dioxo-4-(1H-tetrazol-5-ylamino)butyl]amino]-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamic acid,
101. [R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-3-oxopropanoic acid,
102. [R-(R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-3-oxopropanoic acid,
103. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo[3.3.1]non-9-yloxy)carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
104. [R-(R*,S*)]-5-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-5-oxopentanoic acid,
105. ethyl [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]-sulfinyl]acetate,
106. [R-[R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
107. [R-(R*,S*)]-N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-4-phenylbutyl]-xcex2-alanine,
108. N-[N-[xcex1-methyl-N-[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]-D-tryotophyl]-L-phenylalanyl]-L-alanine,
109. [R-R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]propanoic acid,
110. [R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amion]-3-phenylpropyl]thio]acetic acid,
111. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]benzenebutanoic acid,
112. tricyclo[22.214.171.124,7]dec-2-yl [R-(R*,S*)]-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxa-8-thia-2,5-diazatridecanoic acid,
113. [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-(hydroxymethyl)-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-, tricyclo[184.108.40.206,7]dec-2-yl ester,
114. N-[xcex1-methyl-N-[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]-L-tryptophyl)-D-3-(phenylmethyl)-xcex2-alanine,
115. (1R-trans)-N-[xcex1-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]-L-tryptophyl]-D-3(phenylmethyl) ((1R,2R)-N-[[(2-methylcyclohexyl)oxy]carbonyl]) ((xcex1/-Me)LTrp-(D-3-Bzl)bAla-xcex2-alanine ((xe2x88x92)-isomer), and
116. (1S-trans)-N-[xcex1-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-xcex2-alanine.
The more preferred compound is CI-988.
The most preferred compound is the N-methylglucamine salt of CI-988.
Pharmaceutical compositions of a compound of the present invention or its salts are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma, propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions of the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents.
The percentage of the active ingredient in the foregoing compositions can be varied within wide limits but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The more satisfactory compositions are those in which a much higher proportion of the active ingredient is present.
Routes of administration of a subject compound or its salts are oral or parenteral. For example, a useful intravenous dose is between 100 and 800 mg and a useful oral dosage is between 200 and 800 mg.
A unit dosage form of the instant invention may also comprise other compounds useful in the therapy of depression.
A typical dose is, for example, from 600 to 2400 mg per day given in three individual doses.
A skilled physician will be able to determine the appropriate situation in which subjects are in need of such medication suffering from a cognitive disorder and will determine the appropriate route for administration by methods of the present invention.
The advantages of using the compounds of the invention are the compounds are well tolerated, are easily administered IV, are not metabolized in the body, do not cause sedation, and do not cause a withdrawal reaction. There are no cardiovascular side effects and the compounds do not potentiate the action of alcohol or of barbiturates.
Compounds useful in the method of treating cognitive disorders of the instant invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cycloalkyl or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents each independently selected from the group consisting of a straight or branched alkyl of from one to about six carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, and xe2x80x94(CH2)nOR5 wherein R* is hydrogen or a straight or branched alkyl of from one to six carbon atoms, R5 and R6 are each independently hydrogen or alkyl of from one to about six carbon atoms and n is an integer from zero to six;
A is xe2x80x94(CH2)nCOxe2x80x94,xe2x80x94SO2xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94NHCOxe2x80x94,
HOxe2x80x94SCOxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nCOxe2x80x94 or xe2x80x94HCxe2x95x90CHCOxe2x80x94 wherein n is an integer from zero to six;
R2 is a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94HCxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94(CH2)nAr, xe2x80x94(CH2)nOR*, (CH2)nOAr, xe2x80x94(CH2)nCO2R*, or xe2x80x94(CH2)nNR5R6 wherein n, R*, R5 and R6 are as defined above and Ar is as defined below;
R3 and R4 are each independently selected from hydrogen, R2 and xe2x80x94(CH2)n,xe2x80x94Bxe2x80x94D wherein:
nxe2x80x2 is an integer of from zero to three;
B is a bond,
xe2x80x94OCO(CH2)nxe2x80x94,
xe2x80x94O(CH2)nxe2x80x94,
xe2x80x94SO2NH(CH2)nxe2x80x94,
xe2x80x94NHSO2(CH2)nxe2x80x94,
xe2x80x94NHCO(CH2)nxe2x80x94,
xe2x80x94CONH(CH2)nxe2x80x94,
xe2x80x94NHCOCHxe2x95x90CHxe2x80x94,
xe2x80x94COO(CH2)nxe2x80x94,
xe2x80x94CO(CH2)nxe2x80x94,
xe2x80x94Sxe2x80x94(CH2)nxe2x80x94,
xe2x80x94S(xe2x95x90O)xe2x80x94(CH2)nxe2x80x94,
xe2x80x94SO2xe2x80x94(CH2)nxe2x80x94,
wherein R7 and R8 are independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is
xe2x80x94COOR*,
xe2x80x94CH2OR*,
xe2x80x94CHR2OR*,
xe2x80x94CH2SR*,
xe2x80x94CHR2SR*,
xe2x80x94CONR5R6,
xe2x80x94CN,
xe2x80x94NR5R6,
xe2x80x94OH,
xe2x80x94H and acid replacements tetrazole,
xe2x80x83wherein
R*, R2, R5, and R6 are as defined above;
R9 is hydrogen or a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94(CH2)nCO2R*, xe2x80x94(CH2)nOArxe2x80x2, xe2x80x94(CH2)nArxe2x80x2 or (CH2)nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from R3 and Arxe2x80x2 is taken from Ar as defined below;
R12 and R13 are each independently hydrogen or are each independently taken with R3 and R4 respectively to form a moiety doubly bonded to the carbon atom; and
Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety.
Especially useful are compounds selected from:
1. [1S-[2xcex1,2xcex2[S*[S*(E)]],4xcex1]]-4-[[2 -[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[((1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
2. [1S-[1xcex1,2xcex2[S*(S*)],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]methylamino]-3-1-phenylethyl]amino]-4-oxobutanoic acid,
3. [1S-[1xcex1,2xcex2[S*(S*)],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]-hept-2-yl)amino)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
4. [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[184.108.40.206,7]dec-2-ylsulfonyl)amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
5. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[126.96.36.199,7]dec-2-ylsulfonyl)amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
6. [1R-[1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)),2xcex2]]-4-[[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
7. [1R-[1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)],2xcex2]]-4-[[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
8. [1R-[1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)],2xcex2]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexylloxy]carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
9. [1R-[1xcex1[R*(S*)],2xcex2]] and [1S-[1xcex1[S*(R*)],2xcex2]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexyl]oxy]carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
10. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
11. [1S-[1xcex1,2xcex2[S*(R*)],4xcex1]]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-1-(phenylmethyl)ethyl]amino]ethyl]carbamic acid, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester,
12. [1S-[1xcex1,2xcex2[S*,R*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl)amino]ethyl]carbamic acid, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester,
13. N-[2-methyl-N-[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanylglycine,
14. N-[2-methyl-N-[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl-xcex2-alanine, and
15. (R)-tricyclo[126.96.36.199,7]dec-2-yl [1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl(2-phenylethyl)amino]-2-oxo-ethylcarbamate.
In addition preferred compounds of the instant invention are:
16. (xc2x1)-trans-2-chlorocyclohexyl [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
17. 2-chorocyclohexyl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
18. 2-[[2-[[[(2-chlorocyclohexyl)oxy]carbonyl]amino]-3-[1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropyl butanedioate,
19. 2-[[2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropyl butanedioate,
20. (xc2x1)-tricyclo[184.108.40.206,7]dec-2-yl[l-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethylcarbamate,
21. tricyclo[188.8.131.52,7]dec-2-yl[2-[[l-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
22. 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl butanedioate,
23. 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl butanedioate,
24. [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
25. [1S-[1xcex1, 2xcex2[S*(S*)],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
26. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
27. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4oxobutanoic acid,
28. (R)-tricyclo[188.8.131.52,7]dec-2-yl [1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl(2-phenylethyl)amino]-2-oxoethylcarbamate,
29. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid, ethyl ester,
30. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetic acid, ethyl ester,
31. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid,
32. [R-[R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
b 33. [R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]acetic acid,
34. [1S-[1xcex1,2xcex2[S*[S*(E)]],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, methyl ester, (Bicyclo system is 1S-endo),
35. [1S-[1xcex1, 2xcex2[S*[S*(E)]],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, (Bicyclo system is 1S-endo),
36. [R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-3-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-3-oxo-propanoic acid,
37. [R-(R*,S*)]-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxo-8-thia-2,5-diazatridecanoic acid, tricyclo[126.96.36.199,7]dec-2-yl or ester,
38. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]benzenebutanoic acid,
39. [R-(R*,S*)]-N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-4-phenylbutyl]glycine,
40. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo[3.3.1]non-9-yloxy)carbonyl]amino]-1-oxopropyl]amino]-4-oxo-2-butenoic acid,
41. mono [R-(R*,R*)]-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]-1-phenylethyl butanedioate,
42. 3-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-oxo-2-phenylprophl]amino]propanoic acid (TRP is R, other center is RS),
43. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid, (xe2x88x92)-Isomer,
44. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid, (xe2x88x92)-Isomer,
45. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, (xe2x88x92)-Isomer,
46. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]-amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid, (xe2x88x92)-Isomer,
47. 2-methylcyclohexyl-[1R-[1xcex1[R*(S*)]],2xcex2]-[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
48. [R-[R*,S*-(E,E))]]-6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-7-phenyl-2,4-heptadienoic acid,
49. [R-(R*,R*)]-[2-[[2-[[1,4-dioxo-4-(1H-tetrazol-5-ylamino)butyl]amino]-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamic acid,
50. tricyclo[22.214.171.124,7]dec-2-yl-[S-[R*,S*-(E)]]-12-(1H-indol-3-ylmethyl)-12-methyl-3,11-dioxo-9-(phenylmethyl)-2-oxa-7,10,13-triazatetradec-4-en-14-oate,
51. [R-(R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-3-oxopropanoic acid,
52. ethyl [R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]-acetate,
b 53. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-4-iodo-benzenebutanoic acid,
54. [R-(R*,R*)]-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(1(tricyclo[[(22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethoxy]acetic acid,
55. [[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-3-[[tricyclo(18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]acetic acid (TRP center is R, other center is RS),
56. (R)-[[[2-[[3-(1H-indol-3-yl)-1-oxo-2-methyl-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethylidene]amino]oxy]acetic acid,
57. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]benzenebutanoic acid,
58. [R-(R*,S*)]-N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]propyl]amino]-4-phenylbutyl]glycine,
59. 2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]cyclopropanecarboxylic acid (cyclopropane ring is trans-(xc2x1), other centers are R),
60. carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl]amino]ethyl-, tricyclo[184.108.40.206,7]dec-2-yl ester, [R,(R*,S*)]-,
61. benzeneheptanoic acid, xcex1-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-,[R-(R*,S*)]-,
62. methyl-(xc2x1)-xcex2-[[(2-phenylethyl)amino]carbonyl]-1xcex2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]-1H-indole-3-butanoate,
63. (R-(R*,S*)]-4-[[2-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[18.104.22.168,7]dec-2-yloxycarbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
64. bicyclo[2.2.1]heptane-2-acetic acid, 3-[[[[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]amino]carbonyl]oxy]-4,7,7-trimethyl-, [1R-[1xcex1,2xcex2,3xcex1[R*(S*)],4xcex1]]-,
65. butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-[1R-1xcex1[R*(R*)]2xcex2]]-((xe2x88x92)-isomer),
66. 2-butenoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-, [1R-[1xcex1[R*(R*)],2xcex2]]-((xe2x88x92)-isomer),
67. butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-[1R-[1xcex1[R*(S*)],2xcex2]]-((xe2x88x92)-isomer), and
68. 2-butenoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-[IR[1xcex1[R*(S*)],2xcex2]]-((xe2x88x92)-isomer).
Additionally preferred are the compounds:
69. [[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]acetic acid,
70. [R-(R*,R*)]-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethoxy]acetic acid,
71. [1R-[1xcex1,2xcex2[R*(R*)]]]-2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]cyclopropane carboxylic acid,
72. [1S-[1xcex1,2xcex2[S*(S*)]]]-2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]cyclopropane carboxylic acid,
73. pR-R*,R*)]-3-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethoxy]propanoic acid,
74. [R-(R*,R*)]-mono 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]-1-phenylethyl butanedioic acid,
75. 3-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]propanoic acid,
76. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-4-iodobenzenebutanoic acid,
77. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
78. [1R-[1xcex1[R*(S*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid, ((xe2x88x92)-isomer),
79. [1R-[1xcex1[R*(R*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
80. 1R-[1xcex1[R*(R*)],2xcex2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid, ((xe2x88x92)-isomer),
81. [R-(R*,S*)]-lg/-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]benzeneheptanoic acid,
82. 2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]cyclopropanecarboxylic acid (cyclopropyl ring is trans-(xc2x1), other centers are R),
83. 2-methylcyclohexyl [1R-[1xcex1[R*(S*)]],2xcex2]-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
84. [R-[R*,S*-(E less than E)[[-6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-7-phenyl-2,4-heptadienoic acid,
85. tricyclo[126.96.36.199,7]dec-2-yl [2-[[1-(hydroxymethyl)-2-hydroxy-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl]carbamate,
86. tricyclo[126.96.36.199,7]dec-2-yl [R-(R*,R*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl]amino]ethyl]carbamate,
87. [R-(R*,S*)]-2-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino)propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid,
88. [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetic acid,
89. ethyl [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetate,
90. 2-chlorocyclohexyl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
91. [R-[R*,R*(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-ylamino)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
92. [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo [188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
93. [R-(R*,S*)]-mono[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]butanedioate,
94. tricyclo[184.108.40.206,7]dec-2-yl [R-(R*,S*)-[2-[[1-(hydroxymethyl)-2-phenylethyl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
95. [1S-[1xcex1, 2xcex2[S*[S(E)]],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
96. [1S-[1xcex1,2xcex2[S*(S*)],4xcex1]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-[[[(1,7,7-trimethylbicyclo[2.2.1]-hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid, (bicyclo system is 1S-endo),
97. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
98. N-[2-methyl-N-[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanylglycine,
99. [R-(R*,S*)[-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
100. [R-(R*,R*)]-2-[[2-[[1,4-dioxo-4-(1H-tetrazol-5-ylamino)butyl]amino]-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamic acid,
101. [R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-3-oxopropanoic acid,
102. [R-(R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-3-oxopropanoic acid,
103. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo[3.3.1]non-9-yloxy)carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoic acid,
104. [R-(R*,S*)]-5-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-5-oxopentanoic acid,
105. ethyl [R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetate,
106. [R-[R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
107. [R-(R*,S*)]-N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-4-phenylbutyl]-xcex2-alanine,
108. N-[N-[xcex1-methyl-N-[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]-D-tryotophyl]-L-phenylalanyl]-L-alanine,
109. [R-R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]propanoic acid,
110. [R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amion]-3-phenylpropyl]thio]acetic acid,
111. [R-(R*,S*)]-xcex2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7)dec-2-yloxy)carbonyl]amino]propyl]amino]benzenebutanoic acid,
112. tricyclo[18.104.22.168,7]dec-2-yl (R-(R*,S*)]-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxa-8-thia-2,5-diazatridecanoic acid,
113. [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-(hydroxymethyl)-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-, tricyclo[18.104.22.168,7]dec-2-yl ester,
114. N-[xcex1-methyl-N-[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]-L-tryptophyl]-D-3-(phenylmethyl)-xcex2-alanine,
115. (1R-trans)-N-[xcex1-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]-L-tryptophyl]-D-3-(phenylmethyl) ((1R,2R)-N-[[(2-methylcyclohexyl)oxy]-carbonyl])(xcex1/-Me)LTrp-(D-3-Bzl)bAla-xcex2-alanine ((xe2x88x92)-isomer), and
116. (1S-trans)-N-[xcex1-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-xcex2-alanine.
Other compounds useful in the method of treating cognitive disorders of the instant invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cycloalkyl or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents each independently selected from the group consisting of a straight or branched alkyl of from one to about six carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, and xe2x80x94(CH2)nOR5 wherein R* is hydrogen or a straight or branched alkyl of from one to six carbon atoms, R5 and R6 are each independently hydrogen or alkyl of from one to about six carbon atoms and n is an integer from zero to six;
A is xe2x80x94(CH2)nCOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94NHCOxe2x80x94,
xe2x80x94Oxe2x80x94(CH2)nCOxe2x80x94, or xe2x80x94HCxe2x95x90CHCOxe2x80x94 wherein n is an integer from zero to six;
R2 is a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94HCxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH2, xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CH, xe2x80x94(CH2)nCxe2x89xa1CH, xe2x80x94(CH2)nAr, xe2x80x94(CH2)nOR*, xe2x80x94(CH2)nOAr, xe2x80x94(CH2)nCO2R*, or xe2x80x94(CH2)nNR5R6 wherein n, R*, R5, and R6 are as defined above and Ar is as defined below;
R3 and R4 are each independently selected from hydrogen, R2 and xe2x80x94(CH2)n,xe2x80x94Bxe2x80x94D wherein:
nxe2x80x2 is an integer of from zero to three;
B is a bond,
xe2x80x94OCO(CH2)nxe2x80x94,
xe2x80x94O(CH2)nxe2x80x94,
xe2x80x94NHCO(CH2)nxe2x80x94,
xe2x80x94CONH(CH2)nxe2x80x94,
xe2x80x94NHCOCHxe2x95x90CHxe2x80x94,
xe2x80x94COO(CH2)nxe2x80x94,
xe2x80x94CO(CH2)nxe2x80x94,
xe2x80x94Sxe2x80x94(CH2)nxe2x80x94,
xe2x80x94S(xe2x95x90O)xe2x80x94(CH2)nxe2x80x94,
xe2x80x94SO2xe2x80x94(CH2)nxe2x80x94,
xe2x80x94NHSO2xe2x80x94(CH2)nxe2x80x94,
xe2x80x94SO2NH(CH2)nxe2x80x94,
wherein R7 or R8 are independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is
xe2x80x94COOR*,
xe2x80x94CH2OR*,
xe2x80x94CHR2OR*,
xe2x80x94CH2SR*,
xe2x80x94CHR2SR*,
xe2x80x94CONR5R6,
xe2x80x94CN,
xe2x80x94NR5R6,
xe2x80x94OH,
xe2x80x94H and acid replacements such as tetrazole
xe2x80x83wherein
m is an integer of from 0 to 2, wherein R*, R2, R5, and R6 are as defined above;
R9 is hydrogen or a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94(CH2)nCO2R*, xe2x80x94(CH2)nOArxe2x80x2, xe2x80x94(CH2)nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from R3 and Arxe2x80x2 is taken from Ar as defined below;
R12 and R13 are each independently hydrogen or are each independently taken with R3 and R4, respectively, to form a moiety doubly bonded to the carbon atom;
Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heteroaromatic or carbo- or heterohydroaromatic moiety; and
Ar2 can be selected from Ar as defined above or the CH2Ar2 moiety of formula I is the sidechain of a biologically significant amino acid, with the proviso that Ar2 cannot be
xe2x80x83Ar2 is also xe2x80x94(CH2)2NHC(xe2x95x90NH)NHNO2, xe2x80x94(CH2)2NMe2, or xe2x80x94CH2CO2CH3.
Especially useful are compounds selected from
Tricyclo[220.127.116.11,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(9H-pyrido[3,4-b)indol-3-ylmethyl)ethyl]-carbamate (alanine center is RS, other center is S),
Tricyclo[184.108.40.206,7]dec-2-yl[1-methyl-1-[[9-(methylsulfonyl)-9H-pyrido[3,4-b]indol-3-yl]methyl]-2-oxo-2-[(2-phenylethyl)amino]ethyl]-carbamate,
Tricyclo[126.96.36.199,7]dec-2-yl[2-[[1-(hydroxymethyl) -2-phenylethyl]amino]-1-methyl-1-[[9-(methylsulfonyl) -9H-pyrido[3,4-b]indol-3-yl]methyl]-2-oxoethyl]carbamate (phenylmethyl center S, other center RS),
Tricyclo[188.8.131.52,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1-(1-naphthalenylmethyl)-2-oxoethyl]carbamate (naphthalenylmethyl center is RS, other center is S),
Tricyclo[188.8.131.52,7]dec-2-yl[2-[[1-hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1-(2-naphthalenylmethyl)-2-oxoethyl]carbamate (naphthalene center is RS, hydroxymethyl center is S),
Tricyclo[22.214.171.124,7]dec-2-yl(xc2x1)-[1-methyl-1-(1-naphthalenylmethyl)-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[126.96.36.199,7]dec-2-yl(xc2x1)-[1-methyl-1-(2-naphthalenylmethyl)-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[126.96.36.199,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1-(2-naphthalenylmethyl)-2-oxoethyl]carbamate (hydroxy center is S, other center is R or S) (Isomer I),
Tricyclo[220.127.116.11,7]dec-2-yl(xc2x1) [1-(3-benzofuranylmethyl) -1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[18.104.22.168,7]dec-2-yl[1-(3-benzofuranylmethyl)-2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxoethyl[carbamate (benzofuranylmethyl center is RS, other center is S),
Tricyclo[188.8.131.52,7]dec-2-yl[1-[(2-bromo-3-benzofuranyl)methyl]-2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxoethyl]carbamate (benzofuran center is RS, hydroxymethyl center is S),
Tricyclo[184.108.40.206,7]dec-2-yl(xc2x1)-[1-[(2-bromo-3-benzofuranyl)methyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
2-Methylpropyl 2-[[2-methyl-1-oxo-3-(3-pyridinyl)-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl carbonate (pyridine center is RS, other center is S),
Tricyclo[184.108.40.206,7]dec-2-yl[2-[[1-hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(3-pyridinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other is (xc2x1)) (Diastereomer I),
Tricyclo[18.104.22.168,7]dec-2-yl(xc2x1)-[1-methyl-2-oxo-2[(2-phenylethyl)amino]-1-(4-pyridinylmethyl)ethyl]carbamate,
Tricyclo[188.8.131.52,7]dec-2-yl [2-[[1-(hydroxymethyl) -2-phenylethyl]amino]-1-methyl-2-oxo-1-(2-pyridinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other center is R or S) (Diastereomer I),
Tricyclo[18.104.22.168,7]dec-2-yl(xc2x1)-[1-methyl-2-oxo-2-[(2-phenylethyl)amino]-1-(2-pyridinyl)methyl)ethyl]carbamate,
Tricyclo[22.214.171.124,7]dec-2-yl(xc2x1)-[-[(2-aminophenyl)methyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[18.104.22.168,7]dec-2-yl(xc2x1)-[1-[(2-hydroxyphenyl)methyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[184.108.40.206,7]dec-2-yl(xc2x1)-[1-methyl-2-oxo-2-[(2-phenylethyl)amino]-1-[(2-quinolinyl)methyl]ethyl]carbamate,
Tricyclo[22.214.171.124,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(4-quinolinylmethyl)ethyl]carbamate (hydroxymethyl center is S, other center is RS),
Tricyclo[126.96.36.199,7]dec-2-yl) (xc2x1)-[1-methyl-2-oxo-2-[(2-phenylethyl)-amino]-1-(4-quinolinylmethyl)ethyl]carbamic acid,
Tricyclo[220.127.116.11,7]dec-2-yl(xc2x1)-[1-methyl-2-oxo-2-[(2-phenylmethyl)amino]-1-(3-quinolinylmethyl)ethyl]carbamate,
Tricyclo[220.127.116.11,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(2-quinolinylmethyl)ethyl[carbamate (alanine center is RS, other center is S),
Tricyclo[188.8.131.52,7]dec-2-yl [2-[(2-amino-2-phenylethyl)amino]-1-(1H-indazol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
4-[[2-[[2-methyl-1-oxo-3-(1,2,3,4-tetrahydro-2-quinolinyl)-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol,
4-[[2-[[3-(1,2-dihydro-2-quinolinyl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol,
4-[[2-[[2-methyl-1-oxo-3-(4-quinolinyl)-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol,
Tricyclo[184.108.40.206,7]dec-2-yl(xc2x1)-[1-(1H-indazol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[18.104.22.168,7]dec-2-yl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indazol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate (hydroxymethyl center is S, other center is RS),
4-[[2-[3-(1H-indazol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid (mixture of isomers),
Tricyclo[184.108.40.206,7]dec-2-yl(xc2x1)-1-[1-(1H-benzimidazol-2-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl]amino]ethyl]carbamate,
Tricyclo[22.214.171.124,7]dec-2-yl[1-(1H-benzimidazol-2-ylmethyl)-2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxoethyl]carbamate (hydroxy center is S, other center is RS),
Tricyclo [188.8.131.52,7]dec-2-yl[1-(benzo[b]thien-3-ylmethyl)-2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxoethyl]-carbamate (benzothiophene center is RS, hydroxymethyl center is S),
Tricyclo[18.104.22.168,7]dec-2-yl(xc2x1)-[1-(benzo[b]thien-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[184.108.40.206,7]dec-2-yl-(R or S,R)-[2-[[2-(2,5-dioxo-1-pyrrolidinyl)-2-phenylethyl]amino]-1-(1H-indazol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
Tricyclo[22.214.171.124,7]dec-2-yl-(S or R,R)-[2-[[2-(2,5-dioxo-1-pyrrolidinyl)-2-phenylethyl]amino]-1-(1H-indazol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
Tricyclo[18.104.22.168,7]dec-2-yl [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]ethyl]carbamate,
Tricyclo[220.127.116.11,7]dec-2-yl [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-[(4-hydroxyphenyl)methyl]-1-methyl-2-oxoethyl]carbamate (Mixture of [1S-[1R*(R*),2R*]] and [1S-[1R*(S*),2R*]]isomers),
Tricyclo[220.127.116.11,7]dec-2-yl [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-[(4-methoxyphenyl)methyl]-1-methyl-2-oxoethyl]carbamate (Mixture of [1S-[1R*(R*),2R*)]] and [1S-[1R*(S*),2R*]]isomers),
Tricyclo[184.108.40.206,7]dec-1-yl [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]ethyl]carbamate (Mixture of [1S-[1R*(R*),2R*]] and [1S-[1R*(S*),2R*]]isomers),
Tricyclo[126.96.36.199,7]dec-2-yl (xc2x1)-[1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[220.127.116.11,7]dec-2-yl (xc2x1)-[l-[[2-(acetylamino)-4-thiazolyl]methyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[22.214.171.124,7]dec-2-yl (xc2x1)-[1-(1H-benzotriazol-1-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,
Tricyclo[22.214.171.124,7]dec-2-yl (RS,S) [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-[[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl]ethyl]carbamate,
Tricyclo[220.127.116.11,7]dec-2-yl (S or R, S)-[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-[[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl]ethyl]carbamate,
Tricyclo[18.104.22.168,7]dec-2-yl-(S or R,R)-[2-[[2-(2,5-dioxo-1-pyrrolidinyl)-2-phenylethyl]amino]-1-(1H-indazol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
4-[[2-[[2-Methyl-1-oxo-3-(4-pyridinyl)-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
4-[[2-[[3-(2,3-dihydro-1-methyl-5-phenyl-1H-benzodiazepin-2-yl)-2-methyl-1-oxo-2-[[(tricyclo-[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid compd. with 1-deoxy-1-(methylamino)-D-glucitol,
Tricyclo[184.108.40.206,7]dec-2-yl [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(2-pyridinylmethyl}ethyl]carbamate, N-oxide,
Tricyclo[126.96.36.199,7]dec-2-yl [1-[(2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-yl)methyl]-1-methyl-2-[(2-phenylethyl)amino]-2-oxoethyl]carbamate,
Tricyclo[18.104.22.168,7]dec-2-yl [2-[[1-hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(4-pyridinylmethyl)ethyl]carbamate,
Tricyclo[184.108.40.206,7]dec-2-yl (xc2x1)-[1-methyl-2-oxo-2-[(2-phenylethyl)amino]-1-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)methyl]ethyl]carbamate,
Tricyclo[22.214.171.124,77]dec-2-yl [1S-[1R*(R or S),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)ethyl]carbamate,
Tricyclo[184.108.40.206,7][1S-[1R*(S or R),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)ethyl]carbamate,
Tricyclo[126.96.36.199,7]dec-2-yl [1S-[1R*(R or S),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)ethyl]carbamate,
Tricyclo[126.96.36.199 13,7][1S-[1R*(S or R),2R*]]-[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)ethyl]carbamate,
Carbamic acid, [-[(2,3-dimethyl)-1H-pyrrol-4-ylmethyl]-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl-, tricyclo[184.108.40.206,7]dec-2-yl ester,
Carbamic acid, [1-[(2,3-dimethyl)-1H-pyrrol-4-ylmethyl]-2-[[1-(hydroxymethyl)-2-hydroxy-2-phenylethyl]amino]-1-methylethyl]-, tricyclo[18.104.22.168,7]dec-2-yl ester (mixture of isomers),
Carbamic acid, [1-(imidazo[1,5-a]pyridin-3-ylmethyl) -2-oxo-2-[(2-phenylethyl)amino]ethyl]-, tricyclo[18.104.22.168,7]dec-2-yl ester, and
Carbamic acid, [2-[[1-(hydroxymethyl)-2-hydroxy-2-phenylethyl]amino]-1-(imidazo[1,5-a]pyridin-3-ylmethyl)-1-methylethyl]-, tricyclo[22.214.171.124,7]dec-2-yl ester (mixture of isomers).
Other compounds useful in the method of treating cognitive disorders of the instant invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cyclo or polycycloalkyl hydrocarbon or mono- or polyheterocyclic moiety wherein the hetero atom(s) can be N, O, and/or S, of from 3 to 12 carbon atoms with from 0 to 4 substituents each independently selected from a straight or branched alkyl of from 1 to 6 carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, or (CH2)nOR5 wherein R*, R5, and R6 are each independently hydrogen or a straight or branched alkyl of from 1 to about 6 carbon atoms;
m, n, p, q, r, s, t, u, and v are each independently an integer of from 0 to 6 with the proviso that q, r, and s are not all 1 when m, p, t, u, and v are all 0 except when X is not CONR9 or A-E is not (CH2)nCONHxe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94S(O)NHxe2x80x94, xe2x80x94NHCONH, xe2x80x94(CH2)nxe2x80x94OCOxe2x80x94NHxe2x80x94, xe2x80x94SCONHxe2x80x94, xe2x80x94O(CH2)nCOxe2x80x94 or xe2x80x94HCxe2x95x90CHCONHxe2x80x94 wherein n is as above,
A is a bond,
O,
S,
NR*,
xe2x80x94(CH2)nCOxe2x80x94Z,
xe2x80x94SO2xe2x80x94Z,
xe2x80x94SOxe2x80x94Z,
xe2x80x94NHCOxe2x80x94Z,
xe2x80x94SCOxe2x80x94Z,
xe2x80x94Oxe2x80x94(CH2)nCOxe2x80x94Z,
xe2x80x94HCxe2x95x90CHCOxe2x80x94Z,
wherein Z is a bond, oxygen, sulphur, or xe2x80x94NR*xe2x80x94
wherein R* is as defined above;
E is a bond,
an amino acid residue,
xe2x80x94(CHR3)rxe2x80x94,
xe2x80x94(CHR3)rxe2x80x94(CHR4)sxe2x80x94,
xe2x80x94CONHxe2x80x94,
xe2x80x94NHCOxe2x80x94,
xe2x80x94OCOxe2x80x94,
xe2x80x94COOxe2x80x94,
xe2x80x94CH2N(R3)xe2x80x94,
xe2x80x94CH2Oxe2x80x94,
xe2x80x94CH2Sxe2x80x94,
xe2x80x94Cxe2x95x90Cxe2x80x94,
xe2x80x94SO2NR3xe2x80x94,
xe2x80x94NR3SO2xe2x80x94,
xe2x80x94NHCONHxe2x80x94
xe2x80x83wherein
r and s are independently as defined above and R3 and R4 are as defined above;
R2 and R20 are each independently hydrogen, a straight or branched alkyl of from 1 to 6 carbon atoms, xe2x80x94HCxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH, xe2x80x94(CH2)nCHxe2x95x90CH2, xe2x80x94(CH2)nCxe2x89xa1CH, xe2x80x94(CH2)nAr1, xe2x80x94(CH2)nAr2, xe2x80x94(CH2)nOR*, xe2x80x94(CH2)nOAr, xe2x80x94(CH2)nCO2R*, xe2x80x94(CH2)nNR5R6 wherein n,, R*, R5, and R6 are as defined above, and Ar1 and Ar2 are as defined below;
X and Y are each independently:
xe2x80x94CONHxe2x80x94,
xe2x80x94CONR9,
xe2x80x94NHCOxe2x80x94,
xe2x80x94OCOxe2x80x94,
xe2x80x94COOxe2x80x94,
xe2x80x94CH2N(R3)xe2x80x94,
xe2x80x94CH2Oxe2x80x94,
xe2x80x94CH2Sxe2x80x94,
xe2x80x94OCH2xe2x80x94,
xe2x80x94SCH2xe2x80x94,
xe2x80x94Cxe2x95x90Cxe2x80x94,
xe2x80x94SO2NR3xe2x80x94,
xe2x80x94NR3SO2xe2x80x94,
xe2x80x94NHCONHxe2x80x94,
xe2x80x94CH(OR*)CH2xe2x80x94,
xe2x80x94COCH2xe2x80x94,
xe2x80x94CH2COxe2x80x94,
xe2x80x94NR3CH2xe2x80x94,
xe2x80x83wherein
Q is O, S, or NR9;
R3 and R4 are each independently the same as R2 or xe2x80x94(CH2)n,xe2x80x94Bxe2x80x94D wherein nxe2x80x2 is an integer of from 0 to 3;
B is a bond,
xe2x80x94OCO(CH2)nxe2x80x94,
xe2x80x94O(CH2)nxe2x80x94,
xe2x80x94NHCO(CH2)nxe2x80x94,
xe2x80x94CONH(CH2)nxe2x80x94,
xe2x80x94NHCOCHxe2x95x90CHxe2x80x94,
xe2x80x94COO(CH2)nxe2x80x94,
xe2x80x94CO(CH2)nxe2x80x94,
xe2x80x94SO(CH2)nxe2x80x94,
xe2x80x94S(CH2)nxe2x80x94,
xe2x80x94SO2(CH2)nxe2x80x94,
wherein R7 and R8 are each independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5,
D is
xe2x80x94COOR*,
xe2x80x94CH2OR*,
xe2x80x94CHR2OR*,
xe2x80x94CH2SR*,
xe2x80x94CHR2SR*,
xe2x80x94CONR5R6,
xe2x80x94CN,
xe2x80x94NR5R6,
xe2x80x94OH,
xe2x80x94H, and acid replacements such as tetrazole;
wherein b is an integer of from 0 to 2, wherein R*, R2, R5, and R6 are as defined above; R9 is H, or a straight or branched alkyl of from one to six carbon atoms, xe2x80x94(CH2)nCO2R*, (CH2)nOArxe2x80x2, (CH2)nArxe2x80x2, (CH2)nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from R3 and Ar is taken from Ar1 as defined below;
R12 and R13 are each independently hydrogen or taken together form a double bond, or are xe2x80x94(CH2)nxe2x80x94Bxe2x80x94D as defined above; and
Ar1 and Ar2 are each independently a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic moiety.
Especially useful are compounds selected from:
Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)ethyl]-, tricyclo[126.96.36.199,7]dec-2-yl ester, [S-(R*,S*)]-,
Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)ethyl-, tricyclo[220.127.116.11,7]dec-2-yl ester, [S-(R*,R*)]-,
Tricyclo[18.104.22.168,7]dec-2-yl[1-[[[1-hydroxymethyl)-2-phenylethyl)carbonyl]amino]-2-(1H-indol-3-yl)ethyl]carbamate,
Carbamic acid, [2-[(2-hydroxy-2-phenylethyl)amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[220.127.116.11,7]dec-2-yl ester (hydroxy center is RS, other center is R),
Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[22.214.171.124,7]dec-2-yl ester, [R-(R*,S*)]-, 4-methylbenzenesulfonate (1:1) (salt),
Benzenepropanol,xcex2-[[2-(1H-indol-3-yl)-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-, acetate (ester), [R-(R*,S*)]-, 4-methylbenzenesulfonate (1:1) (salt),
Carbamic acid, [[2-[acetyl[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl) -1-methyllethyl]-, tricyclo[188.8.131.52,7]dec-2-yl ester, [R-(R*,S*)]-,
5,13-Dioxa-2,8-diazatetradec-10-enoic acid, 3-(1H-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7-phenyl-, tricyclo[220.127.116.11,7]dec-2-yl ester, [S-(R*,S*) ]-,
5,13-Dioxa-2,8-diazatetradecanoic acid, 3-(1H-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7-phenyl-, tricyclo[188.8.131.52,7]dec-2-yl ester, [R-(R*,R*)]-,
Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-4-phenylbutyl)amino]ethyl]-, tricyclo[220.127.116.11,7]dec-2-yl ester (R)-,
Carbamic acid, [2-(benzoylamino)-1-(1H-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[188.8.131.52,7]-dec-2-yl ester, (R)-,
Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-3-phenylpropyl]amino]ethyl]-, tricyclo[184.108.40.206,7]dec-2-yl ester, (R)-,
Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(2-phenylacetyl)amino]ethyl]-, tricyclo-[220.127.116.11,7]dec-2-yl ester, (R)-,
Carbamic acid, [2-[[3-[[1-(hydroxymethyl)-2-phenylethyl]amino]-3-oxopropyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-, [R,(R*,S*)]-,
Carbamic acid, [1-(1H-indol-3-ylmethyl)-2-[[3-[[1-(hydroxymethyl)-2-phenylethyl]amino]-3-oxopropyl]amino]-1-methyl-2-oxoethyl]-, tricyclo-[126.96.36.199,7]dec-2-yl ester, [S-(R*,R*)]-,
D-Phenylalaninamide, xcex1-methyl-N-[(tricyclo-[126.96.36.199,7]dec-2-yloxy)carbonyl]-D-tryptophyl-xcex2-alanyl-,
L-Phenylalaninamide, xcex1-methyl-N-[(tricyclo-[220.127.116.11,7]dec-2-yloxy)carbonyl]-D-tryptophyl-xcex2-alanyl-,
L-Phenylalaninamide, xcex1-methyl-N-[(tricyclo-[220.127.116.11,7]dec-2-yloxy)carbonyl]-L-tryptophyl-xcex2-alanyl-,
D-Phenylalaninamide, xcex1-methyl-N-[tricyclo-[184.108.40.206,7]dec-2-yloxy) carbonyl]-L-tryptophyl-xcex2-alanyl-,
12-Oxa-2,5,9-triazatridecanoic acid, 3-(1H-indol-3-ylmethyl)-3-methyl-4,8,11-trioxo-10-(phenylmethyl)-, tricyclo[126.96.36.199,7]dec-2-yl ester, [R,(R*,R*)]-,
L-Phenylalanine, N-[N-[xcex1-methyl-N-[(tricyclo-[184.108.40.206,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-xcex2-alanyl]-, phenylmethyl ester,
Propanoic acid, 2-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxopropyl]amino]-3-phenyl-, phenylmethyl ester, [S-(R*,R*)]-,
D-Phenylalanine, N-[N-[xcex1-methyl-N-[(tricyclo-[188.8.131.52,7]dec-2-yloxy)carbonyl]-D-tryptophyl-xcex2-alanyl]-,
L-Phenylalanine, N-[N-[xcex1-methyl-N-[(tricyclo-[220.127.116.11,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-xcex2-alanyl]-,
L-Phenylalanine, N-[N-[xcex1-methyl-N-[(tricyclo-[220.127.116.11,7]dec-2-yloxy)carbonyl]-L-tryptophyl]-xcex2-alanyl]-,
Benzenepropanoic acid, xcex1-[[3-[[3-[(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxopropyl]amino]-, [S-(R*,S*)]-,
Glycine, N-[2-methyl-N-[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-, phenylmethyl ester,
Carbamic acid, [3-(1H-indol-3-ylmethyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidinyl]-, tricyclo[18.104.22.168,7]dec-2-yl ester, (xc2x1)-,
Carbamic acid, [1-(1H-imidazol-4-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]-, 1,1-dimethylethyl ester, (xc2x1)-,
Carbamic acid, [3-(1H-indol-3-yl)-1-methyl-1-[[(2-phenylethyl)amino]carbonyl]propyl]-, tricyclo-[126.96.36.199,7]dec-2-yl ester, (xc2x1)-,
Carbamic acid, [1-[[[1-hydroxymethyl)-2-phenylethyl]amino)carbonyl]-3-(1H-indol-3-yl)-1-methylpropyl]-, tricyclo[220.127.116.11,7]dec-2-yl ester (hydroxymethyl center is S, other center is RS),
13-Oxa-2,5,xcex2-triazatetradec-10-enoic acid, 3-[2-(1H-indol-3-yl)ethyl]-3-methyl-4,5,12-trioxo-7-phenyl-, tricyclo[184.108.40.206,7]dec-2-yl ester [TRP center is R/S mixture, other center is R],
L-Phenylalaninamide, N-[[(1,1-dimethylethoxy)-carbonyl]-xcex1-methyl]-L-tryptophyl]-L-methionyl-L-xcex1-aspartyl-,
Glycine, N-[2-methyl-N-[(tricyclo-[18.104.22.168,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl-,
Carbamic acid, [1-[[[1-(hydroxymethyl)-2-phenylethyl]amino]carbonyl]-2-(1H-indol-3-yl)propyl]-, tricyclo[22.214.171.124,7]dec-2-yl ester (hydroxymethyl center S, other centers RS),
2,4-Heptadienoic acid, 6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[18.104.22.168,7]dec-2-yloxy)-carbonyl]amino]propyl]amino]-7-phenyl-, [R,R*,S*-(E,E)]]-,
Glycine, N-[2-methyl-N-[(tricyclo-[126.96.36.199,7])dec-2-yloxy)carbonyl]-D-tryptophyl]-, phenylmethyl ester, and
Tricyclo[184.108.40.206,7]dec-2-yl-R-(R*,S*)]-[1-[4,5-dihydro-4-(phenylmethyl)-2-thiazolyl]-2-(1H-indol-3-yl)-1-methylethyl]carbamate.
Other compounds useful in the method of treating cognitive disorders of the instant invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cyclo- or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents, each independently selected from the group consisting of: a straight or branched alkyl of from one to six carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, or xe2x80x94(CH2)nOR5, wherein R* is hydrogen, straight or branched alkyl of from one to six carbon atoms, R5 and R6 are each independently hydrogen or alkyl of from one to six carbon atoms; and n is an integer from zero to six;
A is xe2x80x94(CH2)nCOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94NHCOxe2x80x94,
xe2x80x94SCOxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nCOxe2x80x94 or xe2x80x94HCxe2x95x90CHCOxe2x80x94 wherein n is an integer from zero to six;
R2 is a straight or branched alkyl of from one to six carbon atoms, xe2x80x94HCxe2x95x90CH2, xe2x80x94Cxe2x89xa1xe2x80x94CH, xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CH2, xe2x80x94(CH2)nCxe2x89xa1CH, xe2x80x94(CH2)nAr, xe2x80x94(CH2)nOR*, xe2x80x94(CH2)nOAr, xe2x80x94(CH2)nCO2R*, xe2x80x94(CH2)nNR5R6 wherein n, R, R5, and R6 are as defined above and Ar is a mono or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety;
R9 is H, or a straight or branched alkyl of from one to six carbon atoms, xe2x80x94(CH2)nCO2R*, (CH2)nOArxe2x80x2, (CH2)nArxe2x80x2, (CH2)nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from R3 and Arxe2x80x2 is taken independently from Ar and w is zero or 1;
Ar2 is
wherein x and y are each independently O, S, N, CH2, xe2x80x94CHR12, xe2x80x94NR12xe2x80x94, xe2x80x94NR12COxe2x80x94, xe2x80x94Cxe2x95x90Nxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, or xe2x80x94(Cxe2x95x90O)xe2x80x94 or a bond; o, p, q, and r are each independently an integer of from 0 to 3, provided that when o, p, q, and r are all simultaneously zero, Ar2 becomes
R12, R13, and R14 are each independently halogen,
R2 as is defined above,
xe2x80x94(CH2)gxe2x80x94Bxe2x80x94D wherein g is an integer of from 0 to 6
wherein B is a bond,
xe2x80x94OCO (CH2)nxe2x80x94,
xe2x80x94O(CH2)nxe2x80x94,
xe2x80x94NHCO (CH2)nxe2x80x94,
xe2x80x94CONH(CH2)nxe2x80x94,
xe2x80x94NHCOCHxe2x95x90CHxe2x80x94,
xe2x80x94COO(CH2)nxe2x80x94,
xe2x80x94CO(CH2)nxe2x80x94,
xe2x80x94S(CH2)nxe2x80x94,
xe2x80x94SO(CH2)nxe2x80x94,
xe2x80x94SO2(CH2)nxe2x80x94,
xe2x80x94NHSO2xe2x80x94(CH2)nxe2x80x94, or
xe2x80x94SO2NHxe2x80x94(CH2)nxe2x80x94,
wherein R7 and R8 are independently selected from hydrogen and R2, or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is
xe2x80x94COOR*,
xe2x80x94CH2OR*,
xe2x80x94CHR2OR*,
xe2x80x94CH2SR*,
xe2x80x94CHR2SR*,
xe2x80x94CONR5R6,
xe2x80x94CN,
xe2x80x94NR5R6,
xe2x80x94OH,
xe2x80x94H, and acid replacements such as tetrazole,
wherein s is an integer of from 0 to 2
wherein R*, R2, R5, and R6 are as defined above.
Especially useful are compounds selected from:
carbamic acid, [2-[(2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-, 1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester (bicyclo ring is 1S-endo (+-isomer), trp center is D, indene ring centers are unknown),
carbamic acid, [2-[(2,3-dihydro-1-hydroxy-1H-inden-2-yl) amino]-1-1H-indol-3-ylmethyl)-2-methyl-2-oxoethyl]-, 1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester, [1S*[1xcex1,2xcex2[S-(trans)],4xcex2]]-(Bicyclo system is 1S-endo),
carbamic acid, [2-[(2,3-dihydro-1-hydroxy-1H-inden-2-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-, 1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester, [1S-[1xcex1,2xcex2[S*(1S*,2S*)],4xcex1]]-[Bicyclo system is 1S-endo, all other centers are R],
carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)amino]ethyl]-, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester (Bicyclo system 1S-endo; TRP center R; naphthyl center (xe2x88x92) or (+)), (Isomer II),
carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-2,3,4-tetrahydro-1-oxo-2-naphthalenyl)amino]ethyl]-, 1,7,7-trimethylbicyclo[18.104.22.168]hept-2-yl ester (Bicyclo system 1S-endo; TRP center R; naphthyl center (+) or (xe2x88x92)), (Isomer I),
carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-1-naphthalenyl)amino]ethyl]-, tricyclo[22.214.171.124,7]-dec-2-yl ester, (xc2x1)-,
carbamic acid, [1-1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-2-naphthalenyl)amino]ethyl]-, tricyclo[22.214.171.124,7]-dec-2-yl ester, (xc2x1)-,
carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl)]-, tricyclo[22.214.171.124,7]-dec-2-yl ester, (R)-,
4-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-4-oxobutanoate
tricyclo[22.214.171.124,7]dec-2-yl-[2-[(1-azido-1,2,3,4-tetrahydro-2-naphthalenyl)amino]-1(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
methyl 3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxopropanoate,
methyl 3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxopropanoate, and
methyl 1-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-4-oxo-2-butanoate.
Other compounds useful in the method of treating cognitive disorders of the instant invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cycloalkyl or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents each independently selected from the group consisting of a straight or branched alkyl of from one to about six carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, and xe2x80x94(CH2)nOR5 wherein R* is hydrogen, straight or branched alkyl of from one to six carbon atoms, xe2x80x94(CH2)nAr, xe2x80x94COAr, xe2x80x94(CH2)nOCOAr, or xe2x80x94(CH2)nNR5COAr and R* may also independently be R** as defined below,
and R** must be present at least once in formula I, and R** is attached to formula I through a metabolically labile bond and can include
R5 and R6 are each independently hydrogen or alkyl of from one to about six carbon atoms and n is an integer from zero to six;
and,R** is xe2x80x94(CH2)nNR5R6, xe2x80x94(CH2)nxe2x80x94Bxe2x80x94D* wherein D* is Oxe2x80x94COR*, CO2Ar2, (CH2)nAr2, OCOAr2, NR5COAr2, COAr2, CO2CH(R)xe2x80x94CO2R*, CO2xe2x80x94(CH2)nOCOR* where Ar2 is independently taken from Ar, where m is as defined below, CONHCH(R)CO2R* where R is a side chain of a biologically significant amino acid, R is hydrogen only when B is not a bond, xe2x80x94CO2CH2CH2N+(R*)3X1xe2x88x92 when X1xe2x88x92 is a pharmaceutically acceptable counter anion,
A is xe2x80x94(CH2)nCOxe2x80x94,xe2x80x94SO2xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94(CH)nxe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94Oxe2x80x94(CH2)nCOxe2x80x94 or xe2x80x94HCxe2x95x90CHCOxe2x80x94 wherein n is an integer from zero to six;
R2 is a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94HCxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH, xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CH2, xe2x80x94(CH2)nCxe2x89xa1CH, xe2x80x94(CH2)nAr, xe2x80x94(CH2)nOR*, xe2x80x94(CH2)nOAr, xe2x80x94(CH2)nCO2R*, or xe2x80x94(CH2)nNR5R6 wherein n, R*, R5 and R6 are as defined above and Ar is as defined below;
R3 and R4 are each independently selected from hydrogen, R2 and xe2x80x94(CH2)nxe2x80x2xe2x80x94Bxe2x80x94D wherein:
nxe2x80x2 is an integer of from zero to three; B is a bond,
xe2x80x94OCO(CH2)nxe2x80x94,
xe2x80x94O(CH2)nxe2x80x94,
xe2x80x94NHCO (CH2)nxe2x80x94,
xe2x80x94CONH (CH2)nxe2x80x94,
xe2x80x94NHCOCHxe2x95x90CHxe2x80x94,
xe2x80x94COO(CH2)nxe2x80x94,
xe2x80x94CO(CH2)nxe2x80x94,
xe2x80x94Sxe2x80x94(CH2)nxe2x80x94,
xe2x80x94S(xe2x95x90O)xe2x80x94(CH2)nxe2x80x94,
xe2x80x94SO2xe2x80x94(CH2)nxe2x80x94,
xe2x80x94NHSO2xe2x80x94(CH2)nxe2x80x94,
xe2x80x94SO2NHxe2x80x94(CH2)nxe2x80x94,
wherein R7 and R8 are each independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is hydrogen,
xe2x80x94COOR*,
xe2x80x94CH2NR5R*,
xe2x80x94CHR2NR5R*,
xe2x80x94CH2OR*,
xe2x80x94CHR2OR*,
xe2x80x94CH2SR*,
xe2x80x94CHR2SR*,
xe2x80x94CONR5R6,
xe2x80x94CONR5R*,
an acid replacement selected from
wherein m is an integer of from 0 to 2 wherein R*, R2, R5, and R6 are as defined above;
R9 is hydrogen or a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94(CH2)nCO2R*, xe2x80x94(CH2)nNR5R*, wherein n, R*, and R5 are as defined above or taken from R3;
R12 and R13 are each independently hydrogen or are each independently taken with R3 and R4, respectively, to form a moiety doubly bonded to the carbon atom; and
Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heteroaromatic or carbo- or heterohydroaromatic moiety.
Especially useful are compounds selected from:
L-Aspartic acid, N-[N-[xcex1-methyl-N-[(tricyclo[220.127.116.11,7]-dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl]-,
L-Glutamic acid, N-[N-[xcex1-methyl-N-[(tricyclo[220.127.116.11,7]-dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl]-,
L-Glutamic acid, N-[N-[xcex1-methyl-N-[(tricyclo-[184.108.40.206,7]-dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl]-, dimethyl ester,
2-[[3-(1H-Indol-3-yl)-2-methyl-1-oxo-2[[tricyclo-[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]-amino]-3-phenylpropyl[R-(R*,S*)]-1,4-dihydro-1-methyl-3-pyridinecarboxylate,
2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[(tricyclo-[126.96.36.199,7]dec-2-yloxy)carbonyl]amino]propyl]-amino]-3-phenylpropyl[R-(R*,S*)]-trigonelline iodide
2-[3-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo-[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl[R-(R*,S*)]-3-pyridinecarboxylate,
butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-, (2,2-dimethyl-1-oxopropoxy)methyl ester, [R-(R*,R*)]-,
butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]ethyl]amino]-4-oxo-, chloromethyl ester, [R-(R*,R*)]-,
Pentanedioic acid, [4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[184.108.40.206,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-1,4-dioxobutoxy]methyl ester, [R-(R*,R*)]-,
butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2,3-dihydro-1H-inden-5-yl ester, [R-(R*,R*)]-, and
butanoic acid, 4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-, [R-(R*,R*)]-.
Other compounds useful in the method of treating cognitive disorders of the instant invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
R1 is a cyclo- or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents, each independently selected from the group consisting of: a straight or branched alkyl of from one to six carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, or xe2x80x94(CH2)nOR5, wherein R* is hydrogen, straight or branched alkyl of from one to six carbon atoms, R5 and R6 are each independently hydrogen or alkyl of from one to six carbon atoms; and n is an integer from zero to six;
A is xe2x80x94(CH2)nCOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94NHCOxe2x80x94,
xe2x80x94SCOxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nCOxe2x80x94 or xe2x80x94HCxe2x95x90CHCOxe2x80x94 wherein n is an integer from zero to six;
R2 is a straight or branched alkyl of from one to six carbon atoms, xe2x80x94HCxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94(CH2)nCxe2x89xa1CH, xe2x80x94(CH2)nAr, xe2x80x94(CH2)nOR*, xe2x80x94(CH2)nOAr, xe2x80x94(CH2)nCO2R*, xe2x80x94(CH2)nNR5R6 wherein n, Rxe2x80x2 R5 and R6 are as defined above and Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety;
E is xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94(CH2)mNR3xe2x80x94, xe2x80x94(CH2)mOxe2x80x94, xe2x80x94(CH2)mSxe2x80x94, xe2x80x94Cxe2x95x90C,
xe2x80x94SO2NR3xe2x80x94, xe2x80x94NR3SO2xe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94CH2COxe2x80x94, xe2x80x94COCH2xe2x80x94, xe2x80x94(CH2)mNHCOxe2x80x94, xe2x80x94(CH2)m CONHxe2x80x94 wherein m is an integer of from 1-5,
F is a bond, xe2x80x94CH(R)COxe2x80x94 wherein R is xe2x80x94(CHR3)pxe2x80x94(CHR4)q-D, wherein D is as defined below, wherein p and q are each independently 0, 1, or 2 and wherein F is a desamino biologically significant amino acid, excluding Tyr, Phe, Trp, His;
R3 and R4 are each independently selected from R2 and xe2x80x94(CH2)nxe2x80x2xe2x80x94Bxe2x80x94D wherein:
nxe2x80x2 is an integer of from zero to three;
B is a bond,
xe2x80x94OCO(CH2)nxe2x80x94,
xe2x80x94O(CH2)nxe2x80x94,
xe2x80x94NHCO(CH2)nxe2x80x94,
xe2x80x94CONH(CH2)nxe2x80x94,
xe2x80x94NHCOCHxe2x95x90CHxe2x80x94,
xe2x80x94COO(CH2)nxe2x80x94,
xe2x80x94CO(CH2)nxe2x80x94,
xe2x80x94Sxe2x80x94(CH2)nxe2x80x94,
xe2x80x94S(xe2x95x90O)xe2x80x94(CH2)nxe2x80x94,
xe2x80x94SO2xe2x80x94(CH2)nxe2x80x94,
xe2x80x94NHSO2xe2x80x94(CH2)nxe2x80x94,
xe2x80x94SO2NHxe2x80x94(CH2)nxe2x80x94,
wherein R7 and R8 are independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is xe2x80x94COOR*,
xe2x80x94CH2OR
xe2x80x94CHR2OR*r
xe2x80x94CH2SR*,
xe2x80x94CHR2SR*,
xe2x80x94CONR5R6,
xe2x80x94CN,
xe2x80x94NR5R6r
xe2x80x94OH,
xe2x80x94H or an acid replacement such as tetrazole, or
wherein s is an integer of from 0 to 2,
wherein R*, R2, R5, and R6 are as defined above and
G is R3 as defined above, and
G cannot be hydrogen when F is a bond.
Especially useful are compounds selected from:
(R)-N-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]amino]propyl]glycine,
(R)-4-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]amino]propyl]amino]butanoic acid,
Methyl (R)-4-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]butanoate,
Phenylmethyl (R)-3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[220.127.116.11,7]dec-2-yloxy)carbonyl]amino]propyl]amino]propanoate,
Methyl N-[xcex1-methyl-N-[(tricyclo[188.8.131.52,7]-dec-2-yloxy)carbonyl]-D-tryptophyl]-xcex2-alanine,
Phenylmethyl N-[2-methyl-N-[(tricyclo-[126.96.36.199,7]-dec-2-yloxy)carbonyl]-D-tryptophyl]glycine,
N-[(xcex1-methyl-N-[(tricyclo[22.214.171.124,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-xcex2-alanine,
Tricyclo[220.127.116.11,7]dec-2-yl [1S-[1R*(S*),2R*]]-[2-[[1-(hydroxy-methyl)-2-methyl-butyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
Tricyclo[184.108.40.206,7]dec-2-yl [R-(R*,S*)]-[2-[[1-(hydroxymethyl)-3-methylbutyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,
Methyl N-[xcex1-methyl-N-[(tricyclo-[18.104.22.168,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-methionine,
N-[xcex1-methyl-N-[(tricyclo[126.96.36.199,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-methionine,
Methyl N-[N-[(xcex1-methyl-N-[(tricyclo-[184.108.40.206,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-methionyl]-xcex2-alanine,
N-[S-methyl-N-[xcex1-methyl-N-[(tricyclo[220.127.116.11,7]-dec-2-yloxy)carbonyl]-D-tryptophyl]-D-cysteinyl-xcex2-alanine,
S-methyl-N-[xcex1-methyl-N-[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]-D-tryptophyl-D-cysteine,
N-[xcex1-Methyl-[N-[(tricyclo[18.104.22.168,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-xcex3-(methylsulfinyl)-L-xcex1-amino-butanoic acid, and
N-[xcex1-methyl-N-[(tricyclo[188.8.131.52,7]dec-2-yloxy)carbonyl]-D-tryptophyl-xcex3-(methylsulfonyl)-L-xcex1-aminobutanoic acid.
Other compounds useful in the method of treating cognitive disorders of the instant invention are those of formula
or a pharmaceutically acceptable salt thereof wherein:
R1 is tert.-butyl, a cycloalkyl or polycycloalkyl hydrocarbon of from three to twelve carbon atoms with from zero to four substituents each independently selected from the group consisting of a straight or branched alkyl of from one to about six carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, and xe2x80x94(CH2)nOR5 wherein R* is hydrogen or a straight or branched alkyl of from one to six carbon atoms, R5 and R6 are each independently hydrogen or alkyl of from one to about six carbon atoms and n is an integer from zero to six;
A is xe2x80x94(CH2)nCOxe2x80x94,xe2x80x94SO2xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94NHCOxe2x80x94,
xe2x80x94SCOxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nCOxe2x80x94, xe2x80x94HCxe2x95x90CHCOxe2x80x94, or
wherein n is an integer from zero to six;
R2 is hydrogen, a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94HCxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94(CH2)nAr, xe2x80x94(CH2)nOR*, xe2x80x94(CH2)nAr, xe2x80x94(CH2)nCO2R*, or xe2x80x94(CH2)nNR5R6 wherein n, R*, R5 and R6 are as defined above and Ar is as defined below;
R3, R4 and R14 are each independently selected from hydrogen, R2 and xe2x80x94(CH2)nxe2x80x2-B-D wherein:
nxe2x80x2 is an integer of from zero to three;
B is a bond,
xe2x80x94OCO(CH2)nxe2x80x94,
xe2x80x94O(CH2)nxe2x80x94,
xe2x80x94NHCO(CH2)nxe2x80x94,
xe2x80x94CONH(CH2)nxe2x80x94,
xe2x80x94NHCOCHxe2x95x90CHxe2x80x94,
xe2x80x94COO(CH2)nxe2x80x94,
xe2x80x94CO(CH2)nxe2x80x94,
xe2x80x94S(CH2)nxe2x80x94,
xe2x80x94SO(CH2)nxe2x80x94,
xe2x80x94SO2(CH2)nxe2x80x94,
xe2x80x94NHSO2(CH2)nxe2x80x94,
xe2x80x94SO2NH(CH2)nxe2x80x94,
wherein R7 and R8 are independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5 and n is as defined above;
D is
xe2x80x94COOR*,
xe2x80x94CH2OR*,
xe2x80x94CHR2OR*,
xe2x80x94CH2SR*,
xe2x80x94CHR2SR*,
xe2x80x94CONR5R6,
xe2x80x94CN,
xe2x80x94NR5R6
xe2x80x94OH,
xe2x80x94H, and acid replacements such as tetrazole,
wherein R*, R2, R5, and R6 are as defined above;
R9 is hydrogen or a straight or branched alkyl of from one to about six carbon atoms, xe2x80x94(CH2)nCO2R*, xe2x80x94(CH2)nOArxe2x80x2, xe2x80x94(CH2)nArxe2x80x2 or (CH2)nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from R3 and Arxe2x80x2 is taken from Ar as defined below;
R12 and R13 are each independently hydrogen or are each independently taken with R3 and R4 respectively to form a moiety doubly bonded to the carbon atom; and
Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety.
Especially useful are compounds selected from:
(+/xe2x88x92)1,3,4,9-tetrahydro-3-methyl-3-[[2-phenylethyl)amino]carbonyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[126.96.36.199,7]dec-2-yl ester,
(R)-1,3,4,9-tetrahydro-3-methyl-3-[[2-phenylethyl)amino]carbonyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[220.127.116.11,7]dec-2-yl ester,
(S)-1,3,4,9-tetrahydro-3-methyl-3-[[2-phenylethyl)amino]carbonyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[18.104.22.168,7)dec-2-yl ester,
1,3,4,9-tetrahydro-3-[[[1-(hydroxymethyl)-2-phenylethyl]amino]carbonyl]-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo-[188.8.131.52,7]dec-2-yl ester (mixture of diastereomers),
(R)-1,3,4, 9-tetrahydro-3-[[[1-(hydroxymethyl)-2-phenylethyl]amino]carbonyl]-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid,tricyclo[126.96.36.199,7]dec-2-yl ester,
(S)-1,3,4,9-tetrahydro-3-[[[1-(hydroxymethyl)-2-phenylethyl]amino]carbonyl]-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo-[184.108.40.206,7]dec-2-yl ester,
1,3,4,9-tetrahydro-3-[[[1-(hydroxymethyl)-2-hydroxy-2-phenylethyl]amino]carbonyl]-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo-[126.96.36.199,7]dec-2-yl ester,
3-[[(2-amino-2-phenylethyl)amino]carbonyl]-1,3,4,9-tetrahydro-3-methyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[220.127.116.11,7)]dec-2-yl ester, (mixtures of diastereomers),
3-[[[2-(3-carboxy-1-oxopropyl)-amino]-2-phenylethyl]amino]carbonyl]-1,3,4,9-tetrahydro-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[18.104.22.168,7)]dec-2-yl ester, [R-(R*,R*)] and [R-(R*,S*)]-,
3-[[[2-(R)-(3-carboxy-1-oxopropyl)amino]-2-phenylethyl]amino]carbonyl]-1,3,4,9-tetrahydro-3-(S)-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[126.96.36.199,7]dec-2-yl ester,
3-[3-[3-[2-[2-[1,4-dioxo-4-(phenylmethoxy)butyl]amino]-2-phenylethyl]amino]carbonyl]-1,3,4,9-tetrahydro-3-methyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[220.127.116.11,7]dec-2-yl ester (mixture of diastereomers).
3-[[(2-hydroxy-2-phenylethyl)amino]carbonyl]-1,3,4,9-tetrahydro-3-methyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[184.108.40.206,7]dec-2-yl ester,
butanedioic acid, mono[2-[[[2,3,4,9-tetrahydro-3-methyl-2-[(tricyclo[126.96.36.199,7]dec-2-ylox)carbonyl]-1H-pyrido[3,4-b]indole-3-yl]carbonyl]amino]-1-phenethyl] ester.
3-[[[2-[(3-carboxyacetyl)amino]-2-phenethyl]amino]carbonyl]-1,3,4,9-tetrahydro-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, [tricyclo[188.8.131.52,7]dec-2-yl ester (mixture of diastereomers),
3-[[[2-[(3-carboxy-1-oxo-2-propenyl)amino]-2-phenethyl]amino]carbonyl]1,3,4,9-tetrahydro-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, [tricyclo[126.96.36.199,7]dec-2-yl ester (mixture of diastereomers),
3-[[[1-[[(3-carboxy-1-oxopropyl)amino]methyl]-1-phenethyl]amino]carbonyl]-1,3,4,9-tetrahydro-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid, [tricyclo-[188.8.131.52,7]dec-2-yl ester (mixture of diastereomers),
(+/xe2x88x92)-1,3,4,9-tetrahydro-3-[[(2-phenethyl)amino]carbonyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, [tricyclo[22.214.171.124,7]]dec-2-yl ester,
3-[[(1-carboxy-2-phenethyl)amino]carbonyl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylic acid, 1,1-dimethylethyl ester,
(+/xe2x88x92)-1,3,4,9-tetrahydro-3-methyl-N-(2-phenylethyl)-2-[(tricyclo[22.214.171.124,7])dec-2-ylamino)sulfonyl]1H-pyrido[3,4-b]indole-3-carboxamide,
3-[[[3-carboxy-1-(phenylmethyl)propyl]amino]carbonyl)-1,3,4,9-tetrahydro-3-methyl-2H-pyrido[[3,4-b]indole-2-carboxylic acid, tricyclo-[[220.127.116.11,7]dec-2-yl ester,
1,3,4,9-tetrahydro-3-methyl-3-[[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenethyl]amino]carbonyl]-2H-pyrido[3,4-b]indole-2-carboxylic acid, tricyclo[22.214.171.124,7]dec-2-yl ester, and
3-[[[2-[[(2-carboxy-1-cyclopropyl)carbonyl]amino]-2-phenethyl]amino]carbonyl)-1,3,4,9-tetrahydro-3-methyl-2H-pyrido[3,4-b]indole-2-carboxylic acid ethyl ester, tricyclo[18.104.22.168,7]dec-2-yl ester.
Other CCDB antagonists (gastrin antagonists) include but are not limited to:
L-365-091 which is 1-((3-((((4-chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)-pyrrolidine; and
(S)-5-[(10,11-dihydrodibenzo[a,d]cyclohepten-5-yl)amino]4-[(1H-indol-2yl)carbonyl]amino]-5-oxo-pentanoic acid.
L-365,260 which is (R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-Nxe2x80x2-(3-methylphenyl)urea,
LY-262,690 which is trans-1-Pyrazolidinecarboxamide, 5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4-(trifluoromethyl)phenyl]-,
LY-262,691 which is trans-5-(3-chlorophenyl)-3-oxo-4-phenyl-N-[4-(bromo)phenyl]-1-pyrazolidinecarboxamide, and
trans-1-pyrazolidinecarboxamide-N-(4-bromophenyl)-5-(2-chlorophenyl)-3-oxo-phenyl-.
Other compounds useful in the instant invention are pyrazolidinones of formula
or a pharmaceutically acceptable salt thereof wherein
R1 is 2,3-dichloro,
3,4xe2x80x94(CH2)4,
4,CF3, or
4-Br;
R2 is hydrogen,
2-chloro,
2,3-dichloro, or
CN; and
R3 is hydrogen -trans or -cis.
These are disclosed in Drugs of the Future 16(7):631-740 (1991). The compounds are made as described in Synthetic Examples 1-3 below.
Other compounds useful in the methods of treatment of the instant invention are quinazolinones disclosed in U.S. Pat. No. 5,075,313 of formula
in which
n is 1 or 2 and m is 0 or 1;
R is hydrogen, C1-C4 alkyl, benzyl, or phenyl;
Z is hydrogen or halo;
X2, X3, X4, and X5 are independently selected from the group consisting of hydrogen, halo, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylthio, and xe2x80x94NR2R3, in which R2 and R3 are independently hydrogen, C1-C4 alkyl, benzyl, or phenyl, or R2 and R3 taken together with the nitrogen atom to which they are bonded from a 5- or 6-membered ring; or
Xr and Xr+1, in which r is 2, 3, or 4,taken together from a divalent C3-C5 alkylene group or methylenedioxy; and
Y5 and Y6 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, and trifluoromethyl; and pharmaceutically acceptable salts thereof.
A test carried out using the mouse light/dark box and the rat T-maze reinforced alternation task. The results indicate that Compound 1 CI-988 improves basal cognition and inhibits the impairments in performance caused by cholinergic deficits.
On repeated exposure to the light/dark box mice habituate by moving more rapidly from the light to the dark side. The habituation occurs over a 4 to 6 day period, with a reduction in latency of movement from about 14 sec to 2 to 4 sec by the 4th day of the test. The daily administration of Compound 1 (0.01 xcexcg/kg, SC) significantly improved performance. At this dose Compound 1 showed no anxiolytic activity. The scopolamine (0.25 mg/kg) induced impairment of performance was almost completely antagonized by Compound 1 (0.01 xcexcg/kg).
In the twice daily administration of Compound 1 (0.1 mg/kg, IP) had no effect on the learning of this task. However, the deficit induced by twice daily administration of scopolamine (0.25 mg/kg) was antagonized by coadministration of Compound 1 (0.1 mg/kg, IP).
See FIGS. 1 to 5 below.
FIGS. 1 and 2 show the influence of Compound 1 on mouse habituation patterns and on acute scopolamine impairment. The compounds was administered at a dose of 0.00001 mg/kg SC once daily.
The days (1-6) are along the X axis and the time in seconds is along the Y axis (latency white to black) and Day 6 scopolamine was 0.25.
Five mice were tested
∘ p  less than 0.001 indicates improved habituation, comparison is with 1 day.
* p  less than 0.05 to p  less than 0.001 is improved performance, compared to control.
+ p  less than 0.001 is scopolamine impairment.
xcex94 p  less than 0.001 is inhibition of scopolamine impairment.
FIG. 1 is the control.
FIG. 2 is Compound 1.
FIGS. 3 and 4 show the effect of Compound 1 on the performance of a reinforced alternation task.
The X axis is the day and the Y axis is the percent correct responses.
The number of mice tested was six.
"Ovalhollow" - - - "Ovalhollow" is the control.
"Ovalsolid" - - - "Ovalsolid" is Compound 1.
In FIG. 3 Compound 1 was given at 0.01 mg/kg IP BID.
In FIG. 4 Compound 1 was given at 1.0 mg/kg IP BID.
FIG. 5 shows the effect of Compound 1 on scopolaminexe2x80x94the induced deficits in performance on a T-maze reinforced alternation task. The X axis is the day and the Y axis is the percent correct responses.
The number of mice tested was six.
"Ovalhollow" - - - "Ovalhollow" is the control vehicle.
"Ovalsolid" - - - "Ovalsolid" is scopolamine at 0.25 mg/kg IP BID.
▪ - - - ▪ is scopolamine and Compound 1 at 0.1 mg/kg IP BID.
* p  less than 0.05 to p  less than 0.001 is scopolamine impairment.
+ p  less than 0.05 to p  less than 0.001 is inhibition of scopolamine impairment.
Since the CCKB antagonist CI-988 exhibited activity in an art recognize models of CCDB receptor antagonists will be effective in the treatment of cognitive disorders in man.
Certain CCKB antagonists were tested in the antagonists will be effective in the treatment of cognitive disorders in man.