Claims for Patent: 6,034,136

Summary for Patent: 6,034,136

Title:	Certain cyclic thio substituted acylaminoacid amide derivatives
Abstract:	Disclosed are compound of formula I wherein R represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, adamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryl)-lower alkyl, di-(lower alkyl or aryl-lower alkyl)amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl; R.sub.1 represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or (cycloalkyl, aryl or biaryl)-lower alkyl; R.sub.2 represents hydrogen, lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylamino, or (lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl); R.sub.3 represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, or C.sub.2 -C.sub.7 -alkyl interrupted by S, SO, SO.sub.2, O or N--R.sub.5 ; R.sub.4 represents hydrogen or acyl; R.sub.5 represents hydrogen, lower alkyl, aryl-lower alkyl, acyl, or (lower alkyl, aryl or aryl-lower alkyl)-sulfonyl; A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH.sub.2).sub.P which may be interrupted by S, SO, SO.sub.2, O, or N--R.sub.5 ; n represents an integer from zero to four; p represents an integer from 2 to 6; any pharmaceutically acceptable salts thereof; and disulfides corresponding to said compounds of formula I wherein R.sub.4 is hydrogen; methods for preparation thereof; pharmaceutical compositions comprising said compounds; and a method of inhibiting matrix-degrading metalloproteinases in mammals using such compounds.
Inventor(s):	Fink; Cynthia A. (Lebanon, NJ)
Assignee:	Novartis AG (Basel, CH)
Application Number:	09/040,093
Patent Claims:	1. A compound of the formula ##STR17## wherein R represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, adamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryl)-lower alkyl, di-(lower alkyl or aryl-lower alkyl)amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl; R.sub.1 represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or (cycloalkyl, aryl or biaryl)-lower alkyl; R.sub.2 represents hydrogen, lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylamino, or (lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl); R.sub.3 represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, or C.sub.2 -C.sub.7 alkyl interrupted by S, SO, SO.sub.2, O or N--R.sub.5 ; R.sub.4 represents hydrogen or acyl; R.sub.5 represents hydrogen, lower alkyl, aryl-lower alkyl, acyl, or (lower alkyl, aryl or aryl-lower alkyl)-sulfonyl; A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH.sub.2).sub.P ; n represents zero or an integer from 1 to 4; p represents an integer from 2 to 6; provided that R may not represent hydrogen or lower alkyl if R.sub.2 represents hydrogen or lower alkyl; and provided that R.sub.2 may not represent hydrogen or lower alkyl if R represents hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof; or a disulfide corresponding to said compound of formula I wherein R.sub.4 is hydrogen. 2. A compound according to claim 1 of the formula ##STR18## wherein R, R.sub.2, R.sub.3 and R.sub.4 and R.sub.5 have meaning as defined above, R.sub.1 ' represents cycloalkyl, aryl or biaryl; and Y represents CHR.sub.2. 3. A compound according to claim 1 of the formula III ##STR19## wherein R is carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl or lower alkyl; R.sub.1 ' is carbocyclic or heterocyclic aryl, or biaryl; R.sub.2 is lower alkoxy; R.sub.3 is hydrogen, lower alkyl or carbocyclic aryl-lower alkyl; and R.sub.4 is hydrogen, lower alkanoyl, aryl-lower alkanoyl or aroyl. 4. A compound according to claim 2 wherein the configuration of the asymmetric carbon atom of the terminal amino acid amide moiety corresponds to that of an L-amino acid precursor and is assigned the (S)-configuration. 5. A compound according to claim 3 wherein R.sub.2 is at the 4-position of the cyclohexane ring. 6. A compound according to claim 3 of the formula ##STR20## wherein R.sub.2 and the amide chain are cis to each other, and R, R.sub.1 ', R.sub.2, R.sub.3 and R.sub.4 have meaning as defined in said claim; and wherein the configuration of the asymmetric carbon atom of the terminal amino acid amide is assigned the (S)-configuration. 7. A compound according to claim 6 wherein R is monocyclic carbocyclic or heterocyclic aryl; R.sub.1 ' is monocyclic carbocyclic aryl; R.sub.2 is lower alkoxy; R.sub.3 is hydrogen; and R.sub.4 is hydrogen or lower alkanoyl. 8. A compound according to claim 3 which is 2-[N-(1-mercaptomethyl-4-ethoxycyclohexanecarbonyl)amino]-3-phenylpropioni c acid N-methylamide. 9. A compound according to claim 3 which is (S)-2-[N-(1-mercaptomethyl-cis-4-methoxycyclohexanecarbonyl)amino]-3-pheny lpropionic acid N-phenylamide. 10. A compound according to claim 3 which is (S)-2-[N-(1-mercaptomethyl-cis-4-ethoxycyclohexanecarbonyl)amino]-3-phenyl propionic acid N-methylamide. 11. A pharmaceutical composition comprising an effective matrix-degrading metalloproteinase inhibiting amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers. 12. A pharmaceutical composition comprising an effective matrix-degrading metalloproteinase inhibiting amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers. 13. A pharmaceutical composition comprising an effective matrix degrading metallaproteinase inhibiting amount of a compound of claim 3 in combination with one or more pharmaceutically acceptable carriers. 14. A method of inhibiting matrix-degrading metalloproteinases in mammals which comprises administering to a mammal in need thereof an effective matrix-degrading metalloproteinase inhibiting amount of a compound of claim 1. 15. A method of inhibiting matrix-degrading metalloproteinases in mammals which comprises administering to a mammal in need thereof an effective matrix-degrading metalloproteinase inhibiting amount of a compound of claim 3. 16. A method according to claim 15 wherein the metalloproteinase is collagenase. 17. A method of inhibiting matrix-degrading metalloproteinases in mammals which comprises administering to a mammal in need thereof an effective matrix-degrading metalloproteinase inhibiting amount of a compound of the formula ##STR21## wherein R represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, adamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryl)-lower alkyl, di-(lower alkyl or aryl-lower alkyl)amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl; R.sub.1 represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or (cycloalkyl, aryl or biaryl)-lower alkyl; R.sub.2 represents hydrogen, lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylamino, or (lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl); R.sub.3 represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, or C.sub.2 -C.sub.7 -alkyl interrupted by S, SO, SO.sub.2, O or N--R.sub.5 ; R.sub.4 represents hydrogen or acyl; R.sub.5 represents hydrogen, lower alkyl, aryl-lower alkyl, acyl, or (lower alkyl, aryl or aryl-lower alkyl)-sulfonyl; A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH.sub.2).sub.P ; n represents zero or an integer from 1 to 4; p represents an integer from 2 to 6; or a pharmaceutically acceptable salt thereof; or a disulfide corresponding to said compound of formula I wherein R.sub.4 is hydrogen. 18. A method according to claim 17 wherein the metalloproteinase is collagenase. 19. A method according to claim 17 which comprises the administration of a compound of the formula ##STR22## wherein R is carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl or lower alkyl; R.sub.1 ' is carbocyclic or heterocyclic aryl, or biaryl; R.sub.2 is hydrogen, lower alkyl or lower alkoxy; R.sub.3 is hydrogen, lower alkyl or carbocyclic aryl-lower alkyl; and R.sub.4 is hydrogen, lower alkanoyl, aryl-lower alkanoyl or aroyl.

Details for Patent 6,034,136

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2017-03-20