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Last Updated: September 22, 2021

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Claims for Patent: 5,672,615

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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 Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Smith And Nephew SANTYL collagenase OINTMENT;TOPICAL 101995 001 1965-06-04 ⤷  Free Forever Trial Novartis Corporation (Summit, NJ) 2013-01-06 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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