Claims for Patent: 5,616,605

Summary for Patent: 5,616,605

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 Tech., Inc. (Tucson, AZ)
Application Number:	08/287,320
Patent Claims:	1. A compound of the formula ##STR41## 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 indolyl 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, ##STR42## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene, ##STR43## R.sub.9 and R.sub.10 are independently hydrogen, methyl or ethyl, D, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently hydrogen or lower alkyl, said lower alkyl, aryl and aryl lower alkyl groups being unsubstituted or substituted with electron donating or electron withdrawing groups, m is 1, 2 or 3. 2. The compound according to claim 1 wherein B is ##STR44## 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 ##STR45## 5. The compound according to claim 1 in which R.sub.2 is unsubstituted or substituted (CR.sub.3 R.sub.4).sub.n -indolyl, wherein R.sub.4 and R.sub.3 are independently hydrogen or lower alkyl and n is 1-3. 6. The compound according to claim 1 in which R.sub.3 and R.sub.4 are hydrogen and n is 1. 7. The compound according to claim 1 in which R.sub.7 is hydrogen. 8. The compound according to claim 1 in which R is hydrogen or methyl. 9. The compound according to claim 1 in which R.sub.1 is isobutyl or sec-butyl. 10. The compound according to claim 1 in which X-D is ##STR46## 11. The compound according to claim 7 in which B is ##STR47## 12. The compound according to claim 10 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH or CH.sub.2 SO.sub.2. 13. The compound according to claim 7 in which B is ##STR48## 14. The compound according to claim 7 in which R.sub.2 is unsubstituted or substituted (CR.sub.3 R.sub.4).sub.n -indalyl, wherein R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl and n is 1-3. 15. The compound according to claim 14 in which R.sub.3 and R.sub.4 are hydrogen and n is 1. 16. The compound according to claim 7 in which R is hydrogen or methyl. 17. The compound according to claim 7 in which R.sub.1 is isobutyl or sec-butyl. 18. The compound according to claim 7 in which X-D is ##STR49## 19. The compound according to claim 7 in which R is hydrogen or methyl and R.sub.1 is isobutyl. 20. The compound according to claim 19 wherein B is ##STR50## 21. The compound according to claim 20 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH or CH.sub.2 SO.sub.2. 22. The compound according to claim 21 in which B is ##STR51## 23. The compound according to claim 19 in which R.sub.2 is unsubstituted or substituted (CR.sub.3 R.sub.4).sub.n -indalyl, wherein R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl and n is 1-3. 24. The compound according to claim 23 in which R.sub.3 and R.sub.4 are hydrogen and n is 1. 25. The compound according to claim 19 in which X-D is ##STR52## 26. The compound according to claim 1 in which R.sub.2 is indolymethyl. 27. The compound according to claim 26 in which R.sub.2 is unsubstituted or substituted 2- or 3-indolylmethyl. 28. The compound according to claim 26 in which R.sub.2 is lower alkyl or lower alkoxy substituted indolylmethyl. 29. The compound according to claim 28 in which R.sub.2 is methyl or methoxy substituted indolylmethyl. 30. The compound according to claim 26 in which B is ##STR53## 31. The compound according to claim 26 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 26 in which B is ##STR54## 33. The compound according to claim 26 in which R is hydrogen or methyl. 34. The compound according to claim 26 in which R.sub.1 is isobutyl. 35. The compound according to claim 26 in which X-D is ##STR55## 36. The compound according to claim 26 in which R is hydrogen or methyl, and R.sub.1 is isobutyl. 37. The compound according to claim 1 having the configuration around the chiral centers are in the S or R form. 38. The compound according to claim 1 in which the configuration around the asterisked carbon is S. 39. 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. 40. 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. 41. The method of claim 40 wherein said mammalian collagenase-related disorder is rheumatoid arthritis. 42. The method of claim 40 wherein said mammalian collagenase-related disorder is periodontal disease. 43. The method of claim 40 wherein said mammalian collagenase-related disorder is corneal ulceration. 44. The method of claim 43 wherein said corneal ulceration is the result of alkali burning of the cornea. 45. The method of claim 43 wherein corneal ulceration is the result of said infectious keratisis. 46. The method of claim 45 wherein said infectious keratitis is induced by infection by Pseudomonas aeruginosa. 47. The method of claim 40 wherein said mammalian collagenase-related disorder is tumor metastasis. 48. 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. 49. 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. 50. The method according to claim 40 in which the collagenase related disorder is dermatitis. 51. The compound according to claim 7 in which B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 NH, COCH.sub.2, CH.dbd.CH or ##STR56## 52. The compound according to claim 7 in which R.sub.2 is indolylmethyl. 53. The compound according to claim 52 in which R.sub.2 is 2-or 3-indolylmethyl. 54. The compound according to claim 53 in which R.sub.2 is 3-indolylmethyl. 55. The compound according to claim 52 in which R is hydrogen or methyl. 56. The compound according to claim 1 in which R.sub.1 is isobutyl or sec-butyl, R is hydrogen or methyl, R.sub.2 is indolylmethyl; B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 SO.sub.2, COCH.sub.2, ##STR57## and R.sub.7 is hydrogen. 57. The compound according to claim 52 in which B is CH.sub.2 S, CH.sub.2 SO.sub.2 or CH.sub.2 NH.sub.2. 58. The compound according to claim 1 in which R is hydrogen or methyl, R.sub.2 is indolylmethyl; B is CH.sub.2 S, CH.sub.2 SO.sub.2, CH.sub.2 NH, COCH.sub.2, CH.dbd.CH, ##STR58## 59. The compound according to claim 1 in which R.sub.1 is isobutyl or sec-butyl, R is hydrogen or methyl, R.sub.2 indolylmethyl; B is CH.sub.2 S, CH.sub.2 SO, CH.sub.2 SO.sub.2, CH.sub.2 NH.sub.2 COCH.sub.2, ##STR59## 60. The compound according to claim 7 in which B is ##STR60## and X is a chemical bond or lower alkylene. 61. The compound according to claim 60 in which R.sub.2 is indolylmethyl. 62. The compound according to claim 60 in which R.sub.2 is 2-or 3-indolylmethyl. 63. The compound according to claim 60 in which R.sub.2 is 3-indolylmethyl. 64. The compound according to claim 7 in which B is ##STR61## 65. The compound according to claim 64 in which R.sub.2 is indolylmethyl. 66. The pharmaceutical composition for the treatment of a mammalian collagenase related disorder which comprises a pharmaceutically effective amount of a compound according to claim 51 and a pharmaceutically acceptable carrier therefor. 67. The pharmaceutical composition for the treatment of a mammalian collagenase related disorder which comprises a pharmaceutically effective amount of a compound according to claim 60 and a pharmaceutically acceptable carrier thereof. 68. The pharmaceutical composition for the treatment of a mammalian collagenase related disorder which comprises a pharmaceutically effective amount of a compound according to claim 64 and a pharmaceutically acceptable carrier thereof. 69. A method of treating a mammalian collagenase related disorder in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to claim 51. 70. A method of treating a mammalian collagenase related disorder in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to claim 60. 71. A method of treating a mammalian collagenase related disorder in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound according to claim 64. 72. The compound according to claim 1 wherein the electron donating groups are hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, diloweralkylamino, aryloxy, mercapto, lower alkyl thio, mercapto lower alkyl or lower alkyldithio, and the electron withdrawing groups are halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, monohaloloweralkyl, dihaloloweralkyl, trihaloloweralkyl, carboxyamido, formyl, sulfonyl, sulfinyl, ammonium, monoloweralkyl ammonium, diloweralkyl ammonium, triloweralkyl ammonium, tetra-lower alkyl ammonium, aryl or heterocyclic. 73. The compound according to claim 1 wherein the lower alkyl groups are unsubstituted or substituted with lower alkyl, chloro, bromo, fluoro, lower alkoxy, lower alkylamino, amino, diloweralkylamino, nitro, sulfonyl, mercapto, lower alkylthio, lower alkanoyl or trifluoromethyl. 74. 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: ##STR62## 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 indolyl 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, ##STR63## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene, ##STR64## R.sub.10 is methyl, ethyl or hydrogen, m is 1, R.sub.5, R.sub.6, R.sub.8 and D are independently hydrogen or lower alkyl, said lower alkyl groups being unsubstituted or substituted with electron donating or electron withdrawing groups. 75. The method according to claim 74 wherein R is H, R.sub.1 is lower alkyl, and B is ##STR65## 76. The method according to claim 74 where R.sub.2 is indolymethyl. 77. The method according to claim 76 wherein R.sub.2 is 2- or -3-indolylmethyl. 78. The method according to claim 76 wherein R.sub.2 is (CR.sub.3 R.sub.4).sub.n -indolyl, R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl and n is 1. 79. The method according to claim 78 wherein R.sub.2 is 3-indolylmethyl. 80. The method according to claim 74 wherein R.sub.7 is H, R is H, R.sub.1 is lower alkyl R.sub.2 is CH.sub.2 -indolyl wherein, ##STR66## R.sub.6 is hydrogen or lower alkyl and AA.sub.1 is an amino acid residue X is a chemical bond, ##STR67## 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. 81. A pharmaceutical composition for the treatment of corneal ulceration which comprises a pharmaceutically effective amount of a compound ##STR68## 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 indolyl 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 alkythio or mercapto lower alkyl, ##STR69## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene, ##STR70## R.sub.10 is methyl, ethyl, or hydrogen m is 1, R.sub.5, R.sub.6, R.sub.8 and D are independently hydrogen or lower alkyl, said lower alkyl, aryl, groups being unsubstituted or substituted with electron donating or electron withdrawing groups. 82. The pharmaceutical composition according to claim 81 wherein R is H, R.sub.1 is lower alkyl, and B is ##STR71## 83. The pharmaceutical composition according to claim 81 wherein R.sub.2 is indolymethyl. 84. The pharmaceutical composition according to claim 83 wherein R.sub.2 is 3-indolymethyl. 85. The pharmaceutical composition according to claim 83 wherein R.sub.2 is (CR.sub.3 R.sub.4).sub.n -indolyl, wherein, R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl and n is 1. 86. The pharmaceutical composition according to claim 85 wherein R.sub.2 is 3-indolylmethyl. 87. The pharmaceutical composition according to claim 81 wherein R.sub.7 is H, R is H, R.sub.1 is lower alkyl, R.sub.2 is CH.sub.2 -indolyl wherein B is ##STR72## R.sub.6 is hydrogen or lower alkyl, AA.sub.1 is an amino acid residue, X is a chemical bond, ##STR73## 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. 88. The pharmaceutical composition according to claim 81 wherein the composition is in solution. 89. The pharmaceutical composition according to claim 81 wherein the composition is in an isotonic solution. 90. A compound according to claim 1 of the formula ##STR74## 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 indolyl 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, ##STR75## AA.sub.1 is an amino acid residue, X is a chemical bond, lower alkylene, ##STR76## R.sub.10 is methyl, ethyl or hydrogen, m is 1, R.sub.5, R.sub.6, R.sub.8 and D are independently hydrogen or lower alkyl, said lower alkyl groups being unsubstituted or substituted with electron donating or electron withdrawing groups. 91. The compound according to claim 90 wherein R is H, R.sub.1 is lower alkyl, and B is ##STR77## 92. The compound according to claim 90 wherein R.sub.2 is indolylmethyl. 93. The compound according to claim 92 wherein R.sub.2 is 2- or -3-indolylmethyl. 94. The compound according to claim 92 wherein R.sub.2 is (CR.sub.3 R.sub.4).sub.n -indolyl, wherein, R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl and n is 1. 95. The compound according to claim 94 wherein R.sub.2 is 3-indolylmethyl. 96. The compound according to claim 90 wherein R.sub.7 is H, R is H, R.sub.1 is lower alkyl, R.sub.2 is CH.sub.2 -indolyl wherein, ##STR78## R.sub.6 is hydrogen or lower alkyl, AA.sub.1 is an amino acid residue, X is a chemical bond, ##STR79## R.sub.10 are independently hydrogen, methyl or ethyl, and D, R.sub.5, R.sub.6 and R.sub.8 is hydrogen or lower alkyl. 97. The method according to claim 74 wherein the electron donating groups are hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, diloweralkylamino, aryloxy, mercapto, lower alkyl thio, mercapto lower alkyl or lower alkyldithio, and the electron withdrawing groups are halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, monohaloloweralkyl, dihaloloweralkyl, trihaloloweralkyl, carboxyamido, formyl, sulfonyl, sulfinyl, ammonium, monoloweralkyl ammonium, diloweralkyl ammonium, triloweralkyl ammonium and tetraloweralkyl ammonium, aryl or heterocyclic. 98. The method according to claim 74 wherein the lower alkyl groups are unsubstituted or substituted with lower alkyl, chloro, bromo, fluoro, lower alkoxy, lower alkylamino, amino, diloweralkylamino, nitro, sulfonyl, mercapto, lower alkylthio, lower alkanoyl or trifluoromethyl. 99. The pharmaceutical composition according to claim 81 wherein the electron donating groups are hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, diloweralkylamino, aryloxy, mercapto, lower alkyl thio, mercapto lower alkyl or lower alkyldithio, and the electron withdrawing groups are halo, nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, monohaloloweralkyl, dihaloloweralkyl, trihaloloweralkyl, carboxyamido, formyl, sulfonyl, sulfinyl, ammonium, monoloweralkyl ammonium, diloweralkyl ammonium, triloweralkyl ammonium and tetraloweralkyl ammonium aryl, or heterocyclic. 100. The pharmaceutical composition according to claim 81 wherein the lower alkyl groups are unsubstituted or substituted with lower alkyl, chloro, bromo, fluoro, lower alkoxy, lower alkylamino, amino, diloweralkyl amino, nitro, sulfonyl, mercapto, lower alkylthio, lower alkanoyl or trifluoromethyl. 101. The compound according to claim 1 of the formula ##STR80## wherein R.sub.2 is indolylmethyl and R.sub.7 is hydrogen, R is hydrogen or lower alkyl, R.sub.1 is hydrogen or lower alkyl, R.sub.9 is hydrogen, B is ##STR81## R.sub.6 is hydrogen, X is a chemical bond or lower alkylene and D is hydrogen or lower alkyl. 102. The compound according to claim 1 wherein R.sub.2 is 2-indolylmethyl or 3-indolylmethyl. 103. The compound according to claim 1 wherein R.sub.2 is 3-indolylmethyl. 104. The compound according to claim 101 wherein R.sub.2 is 3-indolylmethyl, R.sub.7 is hydrogen, R is hydrogen, R.sub.1 is isobutyl, R.sub.9 is hydrogen, B is ##STR82## R.sub.6 is hydrogen and X is a chemical bond and D is lower alkyl. 105. The compound according to claim 104 wherein D is methyl. 106. The compound according to claim 101 in which the configuration around the asterisked carbon is S. 107. The compound according to claim 105 which is in the S configuration. 108. A method of treating corneal ulceration in a mammal which comprises administering to a mammal in need of such treatment an inhibiting effective amount of a compound as in one of claims 101-107. 109. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as in one of claims 101-107.

Details for Patent 5,616,605

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2014-04-01