Claims for Patent: 5,672,615

Summary for Patent: 5,672,615

Title:	Arylsulfonamido-substituted hydrodxamic acids
Abstract:	Disclosed are the compounds of formula I ##STR1## wherein R and R.sub.1 together with the chain to which they are attached or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a ring; pharmaceutically acceptable prodrug derivatives and pharmaceutically salts thereof; methods of preparation thereof; pharmaceutical compositions comprising said compounds; and a method of inhibiting matrix-degrading metalloproteinase and of treating matrix-degrading metalloproteinase dependent conditions in mammals using such compounds.
Inventor(s):	MacPherson; Lawrence J. (Hampton, NJ), Parker; David Thomas (Livingston, NJ)
Assignee:	Novartis Corporation (Summit, NJ)
Application Number:	08/613,303
Patent Claims:	1. A compound of formula I ##STR13## (a) wherein R and R.sub.1 together with the chain to which they are attached form a 1,2,3,4-tetrahydro-isoquinoline, piperidine, oxazolidine, thiazolidine or pyrrolidine ring, each unsubstituted or substituted by lower alkyl; Ar is carbocyclic or heterocyclic aryl; and R.sub.2 is hydrogen or lower alkyl; or (b) wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a ring system selected from C.sub.3 -C.sub.7 -cycloalkane which is unsubstituted or substituted by lower alkyl; oxa-cyclohexane, thia-cyclohexane, indane, tetralin, piperidine or piperidine substituted on nitrogen by acyl, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or by lower alkylsulfonyl; Ar is carbocyclic or heterocyclic aryl; and R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, (oxa or thia)-C.sub.3 -C.sub.6 -cycloalkyl, [(oxa or thia)-C.sub.3 -C.sub.6 -cycloalkyl]-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 of formula I (a) wherein R and R.sub.1 together with the chain to which they are attached form a thiazolidine or pyrrolidine ring, each unsubstituted or substituted by lower alkyl; Ar is phenyl which is unsubstituted or mono-, di- or tri-substituted by C.sub.1 -C.sub.7 -alkoxy, hydroxy, phenyl-lower alkoxy, C.sub.3 -C.sub.7 -cycloalkyl-lower alkoxy, lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl-(sulfinyl or sulfonyl), amino, mono- or di-lower alkylamino; or on adjacent carbon atoms, by C.sub.1 -C.sub.2 -alkylenedioxy or oxy-C.sub.2 -C.sub.3 -alkylene; or Ar is thienyl, isoxazolyl or thiazolyl each of which is unsubstituted or mono- or di-substituted by lower alkyl; and R.sub.2 is hydrogen or lower alkyl; or (b) wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a ring system selected from C.sub.3 -C.sub.7 -cycloalkane which is unsubstituted or substituted by lower alkyl; oxa-cyclohexane, thia-cyclohexane, and piperidine which is unsubstituted or substituted on nitrogen by lower alkanoyl, di-lower alkylamino-lower alkanoyl, lower alkoxycarbonyl, (morpholino, thiomorpholino or piperidino)-carbonyl, lower alkyl, (phenyl or pyridyl)-lower alkyl, (carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl)-lower alkyl or by lower alkylsulfonyl; Ar is phenyl which is unsubstituted or mono-, di- or tri-subsisted by C.sub.1 -C.sub.7 -alkoxy, hydroxy, phenyl-lower alkoxy, C.sub.3 -C.sub.7 -cycloalkyl-lower alkoxy, lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl-(sulfinyl or sulfonyl), amino, mono- or di-lower alkylamino, or on adjacent carbon atoms by C.sub.1 -C.sub.2 -alkylenedioxy or oxy-C.sub.2 -C.sub.3 -alkylene; or Ar is thienyl, isoxazolyl or thiazolyl each of which is unsubstituted or mono- or di-substituted by lower alkyl; and R is hydrogen; lower alkyl; phenyl-lower alkyl; phenyl which is unsubstituted or mono-, di- or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, trifluoromethyl, or on adjacent carbon atoms by C.sub.1 -C.sub.2 -alkylenedioxy or oxy-C.sub.2 -C.sub.3 -alkylene; a heterocyclic aryl radical selected from pyridyl, thiazolyl and quinolinyl, each unsubstituted or mono- or disubstituted by lower alkyl; biphenylyl; biphenylyl-lower alkyl; (pyridyl or thienyl)-lower alkyl; trifluoromethyl; C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl; (oxa or thia)-C.sub.3 -C.sub.6 -cycloalkyl, [(oxa or thia)-C.sub.3 -C.sub.6 -cycloalkyl]-lower alkyl; hydroxy-lower alkyl; (N-lower alkyl-piperazino or N-phenyl-lower alkylpiperazino)-lower alkyl or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl; alkylpiperidyl)-lower alkyl; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 which is 4-(N-hydroxycarbamoyl)-4-[(4-methoxybenzenesulfonyl)(benzyl)amino]-tetrahy drothiopyran or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 1 which is 1-(N-hydroxycarbamoyl)-1-[(4-methoxybenzenesulfonyl)-(benzyl)amino]-cycloh exane or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 1 which is 1-(N-hydroxy-carbamoyl)-1-[(4-methoxybenzenesulfonyl)(3-picolyl)amino]-cyc lohexane or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 1 which is 4-(N-hydroxy-carbamoyl)-4-[(methoxybenzenesulfonyl)(benzyl)amino]-1-(benzy l)-piperidine or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 2 which is N-hydroxy-3-(4-methoxybenzenesulfonyl)-5,5-dimethylthiazolidine-4(S)-carbo xamide or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 2 which is N-hydroxy-1-(4-methoxybenzenesulfonyl)-pyrrolidine-2(S)-carboxamide or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 1 of the formula Ia ##STR14## wherein X represents methylene or 1,2-ethylene each unsubstituted or substituted by lower alkyl, or X represents oxygen, sulfur, or 1,2-phenylene; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 1 of the formula Ib ##STR15## wherein Y is a direct bond, C.sub.1 -C.sub.4 -straight chain alkylene optionally substituted by lower alkyl, CH.sub.2 OCH.sub.2, CH.sub.2 SCH.sub.2, 1,2-phenylene, CH.sub.2 --1,2-phenylene or CH.sub.2 N(R.sub.6)--CH.sub.2 in which R.sub.6 represents hydrogen, lower alkanoyl, di-lower alkylamino-lower alkanoyl, aryl, carbocyclic aryl-lower alkanoyl, lower alkyl, carbocyclic or heterocylic aryl-lower alkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or lower alkylsulfonyl; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 10 of the formula Ic ##STR16## in which Y' represents oxygen, sulfur, a direct bond, methylene or methylene substituted by lower alkyl, or NR.sub.6 ; R.sub.6 represents hydrogen, lower alkanoyl, di-lower alkylamino-lower alkanoyl, carbocyclic aryl-lower alkanoyl, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or lower alkylsulfonyl; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. 12. A matrix-degrading metalloproteinase inhibiting 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 method of inhibiting stromelysin or collagenase activity in mammals which comprises administering to a mammal in need thereof an effective stromelysin or collagenase inhibiting mount of a compound of claim 1. 14. A method of treating matrix-degrading metalloproteinase dependent conditions in mammals which comprises administering to a mammal in need thereof an effective matrix-degrading metalloproteinase inhibiting amount of a compound of claim 1.

Details for Patent 5,672,615

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2013-01-06