Claims for Patent: 5,387,610

Summary for Patent: 5,387,610

Title:	Peptide derivatives of collagenase inhibitor
Abstract:	This invention is directed to a collagenase inhibitor of the formula: ##STR1##
Inventor(s):	Gray; Robert D. (Louisville, KY), Spatola; Arno F. (Louisville, KY), Darlak; Krzysztof (Louisville, KY)
Assignee:	Research Corporation Technologies, Inc. (Tucson, AZ)
Application Number:	07/981,149
Patent Claims:	1. A compound of the formula: ##STR43## or pharmaceutically acceptable salts thereof wherein R and R.sub.1 are independently hydrogen, lower alkyl, aryl or aryl lower alkyl, R.sub.2 is aryl lower alkyl, said R.sub.2 being unsubstituted or mono- or di-substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, di-lower alkyl amino, mercapto, lower alkylthio or mercapto lower alkyl, B is ##STR44## CH.sub.2 SO, CH.sub.2 SO.sub.2, ##STR45## CH.sub.2 S, COCH.sub.2, CH=CH, ##STR46## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene, ##STR47## R.sub.9 and R.sub.10 are independently hydrogen, methyl or ethyl, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen or lower alkyl, D is hydrogen or lower alkyl which is unsubstituted or substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, diloweralkylamino, mercapto, lower alkyl thio, mercapto lower alkyl or aryl, m is 1, 2 or 3 with the proviso that when B is ##STR48## and X is a chemical bond or lower alkylene, then R.sub.2 is not unsubstituted benzyl or benzyl monosubstituted with hydroxy or lower alkoxy and with the further proviso that when B is ##STR49## and X is ##STR50## then R.sub.2 is not unsubstituted benzyl or benzyl substituted with hydroxy or lower alkoxy. 2. The compound according to claim 1 wherein B is CH.sub.2 S, CH.sub.2 SO, ##STR51## CH.sub.2 SO.sub.2, ##STR52## or COCH.sub.2. 3. The compound according to claim 2 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, or CH.sub.2 SO.sub.2. 4. The compound according to claim 2 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, CH.sub.2 SO.sub.2, ##STR53## 5. The compound according to claim 1 in which R.sub.2 is unsubstituted or substituted ##STR54## wherein R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl and n is 1-3 and Y is hydrogen lower alkyl or lower alkoxy and b is 1 or 2. 6. The compound according to claim 5 in which n is 1 and R.sub.2 and R.sub.4 are hydrogen. 7. The compound according to claim 1 in which R.sub.3 and R.sub.4 are hydrogen and n is 1. 8. The compound according to claim 1 in which R.sub.7 is hydrogen. 9. The compound according to claim 1 in which R is hydrogen or methyl. 10. The compound according to claim 1 in which R.sub.1 is isobutyl or sec-butyl. 11. The compound according to claim 1 in which X-D is ##STR55## 12. The compound according to claim 1 in which B is CH.sub.2 S, CH.sub.2 SO, ##STR56## CH.sub.2 SO.sub.2, ##STR57## or COCH.sub.2 and R.sub.7 is H. 13. The compound according to claim 1 in which X-D is ##STR58## and B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH or CH.sub.2 SO.sub.2. 14. The compound according to claim 12 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, CH.sub.2 SO.sub.2, ##STR59## 15. The compound according to claim 8 in which R.sub.7 is hydrogen and R.sub.2 is unsubstituted or substituted ##STR60## wherein R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl and n is 1-3 and Y is hydrogen lower alkyl or lower alkoxy and n is 1 or 2. 16. The compound according to claim 15 in which n is 1 and R.sub.3 and R.sub.4 are hydrogen. 17. The compound according to claim 1 in which R.sub.7 is hydrogen and R is hydrogen or methyl. 18. The compound according to claim 1 in which R.sub.7 is hydrogen and R.sub.1 is isobutyl or sec-butyl. 19. The compound according to claim 1 in which R.sub.7 is hydrogen and X-D is ##STR61## 20. The compound according to claim 1 in which R.sub.7 is hydrogen and R is hydrogen or methyl and R.sub.1 is isobutyl. 21. The compound according to claim 1 in which R is hydrogen or methyl, R.sub.1 is isobutyl, R.sub.7 is hydrogen and B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, CH.sub.2 SO.sub.2, ##STR62## or COCH.sub.2. 22. The compound according to claim 21 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH or CH.sub.2 SO.sub.2. 23. The compound according to claim 22 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, CH.sub.2 SO.sub.2, ##STR63## 24. The compound according to claim 1 in which R is hydrogen or methyl, R.sub.1 is isobutyl, R.sub.7 is hydrogen and R.sub.2 is ##STR64## wherein R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl, n is 1-3, and Y is hydrogen, lower alkyl or lower alkoxy and b is 1 or 2. 25. The compound according to claim 24 in which n is 1 and R.sub.2 and R.sub.4 are hydrogen. 26. The compound according to claim 1 in which R is hydrogen or methyl, R.sub.1 is isobutyl, R.sub.7 is hydrogen, and X-D is ##STR65## 27. The compound according to claim 1 in which R and R.sub.1 are independently hydrogen, lower alkyl, aryl or aryl lower alkyl, B is ##STR66## CH.sub.2 SO, CH.sub.2 SO.sub.2, ##STR67## COCH.sub.2, CH=CH, ##STR68## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene ##STR69## R.sub.9 and R.sub.10 are independently hydrogen, methyl or ethyl, D,R.sub.5, R.sub.6 and R.sub.9 are independently hydrogen or lower alkyl, m is 1, 2 or 3, and R.sub.2 is ##STR70## wherein Y is hydrogen, halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkaroyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, di-lower alkylamino, mercapto, lower alkylthio, or mercapto lower alkyl and b is 1 or 2. 28. The compound according to claim 27 in which R.sub.2 is hydrogen or lower alkyl and b is 1. 29. The compound according to claim 27 in which R.sub.2 is ##STR71## 30. The compound according to claim 27 in which B is CH.sub.2 S, CH.sub.2 SO, ##STR72## CH.sub.2 SO.sub.2, ##STR73## or COCH.sub.2. 31. The compound according to claim 30 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH or CH.sub.2 SO.sub.2. 32. The compound according to claim 27 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, CH.sub.2 SO.sub.2, ##STR74## 33. The compound according to claim 27 in which R is hydrogen or methyl. 34. The compound according to claim 27 in which R.sub.1 is isobutyl or sec-butyl. 35. The compound according to claim 27 in which X-D is ##STR75## 36. The compound according to claim 27 in which R is hydrogen or methyl, and R.sub.1 is isobutyl. 37. The compound according to claim 27 in which B is CH.sub.2 S, CH.sub.2 SO, ##STR76## CH.sub.2 SO.sub.2, ##STR77## or COCH.sub.2, R is hydrogen or methyl and R.sub.1 is isobutyl. 38. The compound according to claim 27 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, CH.sub.2 SO.sub.2, ##STR78## R is hydrogen or methyl and R.sub.1 is isobutyl. 39. The compound according to claim 1 in which R.sub.7 is hydrogen and R.sub.2 is ##STR79## wherein Y is lower alkyl, halo or lower alkoxy, and b is 1 or 2. 40. The compound according to claim 39 in which R.sub.2 is ##STR80## 41. The compound according to claim 39 in which R.sub.2 is DOPA(OMe).sub.2. 42. The compound according to claim 1 having the configuration around the chiral centers are in the S or R form. 43. The compound according to claim 1 in which the configuration around the asterisked carbon is S. 44. The compound according to claim 1 which is ##STR81## 45. The compound according to claim 1 which is HO--NH--CO--CH.sub.2 --CH--(CH.sub.2 --CH(CH.sub.3).sub.2 --CO--Nal--Pro--NH.sub.2. 46. The compound according to claim 1 which is HO--NH--CO--CH(CH.sub.3)--CH(CH.sub.2 --CH(CH.sub.3).sub.2)--CO--Nal--Ala--NH.sub.2. 47. The compound according to claim 1 which is ##STR82## 48. The compound according to claim 1 which is HO--NH--CO--CH.sub.2 --CH(CH.sub.2 CH(CH.sub.3).sub.2)--CONal--.psi.(CH.sub.2 NH)--Ala--NH.sub.2. 49. The compound according to claim 1 having the formula ##STR83## 50. The compound according to claim 1 having the formula ##STR84## 51. The compound according to claim 1 having the formula ##STR85## 52. The compound according to claim 1 having the formula ##STR86## 53. A pharmaceutical composition for the treatment of collagenase-related disorders which comprises an effective amount of a compound according to claim 1 and a pharmaceutical carrier therefor. 54. A method of treating a mammalian collagenase-related disorder which comprises administering to a mammal in need of treatment an inhibitory effective amount of a compound of claim 1. 55. The method of claim 54 wherein said mammalian collagenase-related disorder is rheumatoid arthritis. 56. The method of claim 54 wherein said mammalian collagenase-related disorder is periodontal disease. 57. The method of claim 54 wherein said mammalian collagenase-related disorder is corneal ulceration. 58. The method of claim 57 wherein said corneal ulceration is the result of alkali burning of the cornea. 59. The method of claim 57 wherein corneal ulceration is the result of said infectious keratisis. 60. The method of claim 59 wherein said infectious keratitis is induced by infection by Pseudomonas aeruginosa. 61. The method of claim 54 wherein said mammalian collagenase-related disorder is tumor metastasis. 62. A method of treating corneal ulceration resulting from infectious keratitis induced by infection by Pseudomonas aeruginosa comprising administering a corneal ulceration inhibiting amount of the compound of claim 1 to a mammal suffering from cornea ulceration resulting from infectious keratitis caused by infection by Pseudomonas aeruginosa. 63. A method of treating corneal ulceration resulting from alkali burning of the cornea comprising administering a cornea ulceration inhibiting amount of the compound of claim 1 to a mammal suffering from corneal ulceration resulting from alkali burning of the cornea. 64. The method according to claim 54 in which the callagenase related disorder is dermatitis. 65. The compound according to claim 1 in which R.sub.7 is hydrogen, R.sub.2 is aryl lower alkyl and B is CH.sub.2 SO, CH.sub.2 SO.sub.2, CH.sub.2 NH, COCH.sub.2, CH.dbd.CH or ##STR87## 66. The compound according to claim 1 in which R.sub.7 is hydrogen and R.sub.2 is naphthylalanine, DOPA or DOPA (OMe).sub.2. 67. The compound according to claim 65 in which B is CH.sub.2 S, CH.sub.2 SO.sub.2 or CH.sub.2 NH.sub.2. 68. The compound according to claim 8 in which B is ##STR88## and X is a chemical bond and R.sub.2 is ##STR89## 69. The compound according to claim 8 in which R.sub.7 is hydrogen and ##STR90## and X is ##STR91## and R.sub.2 is ##STR92## 70. The compound according to claim 69 in which R.sub.2 is ##STR93## 71. The pharmaceutical composition for the treatment of a disease caused by or made more severe by excess mammalian collagenase release which comprises a pharmaceutically effective amount of a compound according to claim 65 and a pharmaceutically acceptable carrier therefor. 72. The pharmaceutical composition for the treatment of a disease caused by or made more severe by excess mammalian collagenase release which comprises a pharmaceutically effective amount of a compound according to claim 66 and a pharmaceutically acceptable carrier therefor. 73. The pharmaceutical composition for the treatment of a disease caused by or made more severe by excess mammalian collagenase release which comprises a pharmaceutically effective amount of a compound according to claim 68 and a pharmaceutically acceptable carrier thereof. 74. The pharmaceutical composition for the treatment of a disease caused by or made more severe by excess mammalian collagenase release which comprises a pharmaceutically effective amount of a compound according to claim 69 and a pharmaceutically acceptable carrier therefor. 75. A method of treating a disease caused by or made more severe by excess mammalian collagenase release in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to claim 65. 76. A method of treating a disease caused by or made more severe by excess mammalian collagenase release in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to claim 66. 77. A method of treating a disease caused by or made more severe by excess mammalian collagenase release in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to claim 68. 78. A method of treating a disease caused by or made more severe by excess mammalian collagenase release in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to claim 69. 79. A method of treating ulceration of the cornea in a mammal which method comprises administering to a mammal in need of such treatment, an effective amount of a compound having the formula: ##STR94## or pharmaceutically acceptable salts thereof wherein R.sub.7 is H, R.sub.1 and R are independently hydrogen or lower alkyl, R.sub.2 is aryl lower alkyl, said R.sub.2 being unsubstituted or mono- or di-substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, di-lower alkyl amino, mercapto, lower alkylthio or mercapto lower alkyl, B is ##STR95## AA.sub.2 is an amino acid residue, X is a chemical bond, lower alkylene, ##STR96## R.sub.10 is methyl, ethyl or hydrogen, m is 1, R.sub.9 is hydrogen, R.sub.5, R.sub.6, and R.sub.8 are independently hydrogen or lower alkyl, D is hydrogen or lower alkyl which is unsubstituted or substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, dilower alkylamino, mercapto, lower alkyl thio, mercapto lower alkyl or aryl with the proviso that when B is ##STR97## and X is a chemical bond or lower alkylene, then R.sub.2 is not unsubstituted benzyl or monosubstituted with hydroxy or lower alkoxy and with the further proviso that when B is ##STR98## and X is ##STR99## then R.sub.2 is not unsubstituted benzyl or benzyl substituted with hydroxy or lower alkoxy. 80. The method according to claim 79 wherein R is H, R.sub.1 is lower alkyl, and B is ##STR100## 81. The method according to claim 79 wherein R.sub.2 is bicycloarylalkylene. 82. The method according to claim 81 wherein R.sub.2 is bicycloarylmethylene. 83. The method according to claim 82 wherein R.sub.2 is ##STR101## R.sub.3 and R.sub.4 are hydrogen and n is 1, b is 1 or 2, and Y is hydrogen, lower alkyl or lower alkoxy. 84. The method according to claim 83 wherein R.sub.2 is naphthylmethylene. 85. The method according to claim 79 wherein R.sub.7 is H, R is H, R.sub.1 is lower alkyl, R.sub.2 is ##STR102## B is ##STR103## R.sub.6 is hydrogen or lower alkyl and AA.sub.1 is an amino acid residue X is a chemical bond ##STR104## R.sub.10 is hydrogen, methyl or ethyl and D, R.sub.5, R.sub.6, and R.sub.8 are independently hydrogen or lower alkyl. 86. The method according to claim 79 wherein the compound is ##STR105## 87. A pharmaceutical composition for the treatment of corneal ulceration which comprises a pharmaceutically effective amount of a compound ##STR106## or pharmaceutically acceptable salts thereof wherein R.sub.7 is H, R.sub.1 and R are independently hydrogen or lower alkyl, R.sub.2 is aryl lower alkyl, said R.sub.2 being unsubstituted or mono- or di-substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, di-lower alkyl amino, mercapto, lower alkylthio or mercapto lower alkyl, B is ##STR107## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene, R.sub.9 is hydrogen, ##STR108## R.sub.10 is methyl, ethyl or hydrogen, m is 1, R.sub.5, R.sub.6, and R.sub.8 are independently hydrogen or lower alkyl, D is hydrogen or lower alkyl which is unsubstituted or substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, diloweralkylamino, mercapto, lower alkyl thio, mercapto lower alkyl or aryl with the provisos that when B is ##STR109## and X is a chemical bond or lower alkylene, then R.sub.2 is not unsubstituted benzyl or benzyl monosubstituted with hydroxy or lower alkoxy and with the further proviso that when B is ##STR110## and X is ##STR111## then R.sub.2 is not unsubstituted benzyl or benzyl substituted with hydroxy or lower alkoxy. 88. The pharmaceutical composition according to claim 87 wherein R is H, R.sub.1 is lower alkyl, and B is ##STR112## 89. The pharmaceutical composition according to claim 87 wherein R.sub.2 is bicycloarylalkylene. 90. The pharmaceutical composition according to claim 89 wherein R.sub.2 is bicycloarylmethylene. 91. The pharmaceutical composition according to claim 90 wherein R.sub.2 is ##STR113## R.sub.3 and R.sub.4 are hydrogen and n is 1. 92. The pharmaceutical composition according to claim 91 wherein R.sub.2 is naphthylmethylene. 93. The pharmaceutical composition according to claim 87 wherein R.sub.7 is H, R is H, R.sub.1 is lower alkyl, R.sub.1 is ##STR114## B is ##STR115## R.sub.6 is hydrogen or lower alkyl, AA.sub.1 is an amino acid residue, X is a chemical bond, ##STR116## R.sub.10 are independently hydrogen, methyl or ethyl, and D, R.sub.5, R.sub.6, and R.sub.8 are independently hydrogen or lower alkyl. 94. The pharmaceutical composition according to claim 87 wherein the compound is ##STR117## 95. The pharmaceutical composition according to claim 87 wherein the composition is in solution. 96. The pharmaceutical composition according to claim 87 wherein the composition is in an isotonic solution. 97. The method of treating ulceration of the cornea in a mammal according to claim 79 which method comprises administering to a mammal in need of such treatment an effective amount of HO--NH--CO--CH.sub.2 --CH--(CH.sub.2 --CH(CH.sub.3).sub.2)--CO--Nal--Pro--NH.sub.2. 98. The pharmaceutical composition for the treatment of corneal ulceration according to to claim 87 comprising a pharmaceutically effective amount of a compound HO--NH--CO--CH.sub.2 --CH--(CH.sub.2 --CH(CH.sub.3).sub.2) --CO--Nal--Pro--NH.sub.2. 99. A compound of the formula ##STR118## or pharmaceutically acceptable salts thereof wherein R.sub.7 is H, R.sub.1 and R are independently hydrogen or lower alkyl, R.sub.2 is aryl lower alkyl, said R.sub.2 being unsubstituted or mono- or di-substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, di-lower alkyl amino, mercapto, lower alkylthio or mercapto lower alkyl, R.sub.9 is hydrogen, B is ##STR119## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene, ##STR120## R.sub.10 is methyl, ethyl or hydrogen, m is 1, R.sub.5, R.sub.6 and R.sub.8 are independently hydrogen or lower alkyl; D is hydrogen or lower alkyl which is unsubstituted or substituted with halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, formyl, amino, loweralkylamino, diloweralkylamino, mercapto, lower alkylthio, mercapto lower alkyl or aryl with the provisos that when B is ##STR121## and X is a chemical bond or lower alkylene, then R.sub.2 is not substituted benzyl or benzyl monosubstituted with hydroxy or lower alkoxy and with the further proviso that when B is ##STR122## and X is ##STR123## then R.sub.2 is not unsubstituted benzyl or benzyl substituted with hydroxy or lower alkoxy. 100. The compound according to claim 99 wherein R is H, R.sub.1 is lower alkyl, and B is ##STR124## 101. The compound according to claim 99 wherein R.sub.2 is bicycloarylalkylene. 102. The compound according to claim 101 wherein R.sub.2 is bicycloarylmethylene. 103. The compound according to claim 102 wherein R.sub.2 is ##STR125## R.sub.3 and R.sub.4 are hydrogen and n is 1. 104. The compound according to claim 103 wherein R.sub.2 is naphthylmethylene. 105. The compound according to claim 99 wherein R.sub.7 is H, R is H, R.sub.1 is lower alkyl, R.sub.2 is ##STR126## B is ##STR127## R.sub.6 is hydrogen or lower alkyl, AA.sub.1 is an amino acid residue, X is a chemical bond, ##STR128## R.sub.10 are independently hydrogen, methyl or ethyl, and D, R.sub.5, R.sub.6, and R.sub.8 are independently hydrogen or lower alkyl. 106. The compound according to claim 99 wherein R.sub.1 is isobutyl, R.sub.2 is naphthylmethylene, R.sub.9 is hydrogen, R.sub.7 is hydrogen, R is hydrogen, B is ##STR129## R.sub.6 is hydrogen, R.sub.10 is hydrogen, methyl, or ethyl, R.sub.5 is hydrogen or lower alkyl, m is 1, R.sub.8 is hydrogen, D is lower alkyl which is unsubstituted or substituted with amino, lower alkylamino or dilower alkylamino. 107. The compound according to claim 106 wherein R.sub.5 is hydrogen, R.sub.10 is methyl, and D is substituted ethyl, wherein the substituent is amino. 108. The compound according to claim 106 wherein D is ethyl which is substituted with amino, R.sub.2 is 2-naphthylmethylene, R.sub.5 is hydrogen and R.sub.10 is methyl. 109. The sterioisomer of the compound claim 106 having the S configuration at each of the chiral centers. 110. The stereoisomer of the compound of claim 108 having the S configuration at each of the chiral centers. 111. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 106-110. 112. A method of treating a disease in a mammal caused by or made more severe by mammalian collagenase which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to any one of claims 106-110.

Details for Patent 5,387,610

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2012-02-07