Patent US5464853A successfully refreshed from Google Patents.
US5464853A
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N-(5-isoxazolyl)biphenylsulfonamides, N-(3-isoxazolyl)biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin
Assignee: Encysive Pharmaceuticals Inc
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Filing: 1993-10-21
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Granted: 1995-11-07
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Expires: 2013-10-21
Abstract
Abstract N-(5-isoxazolyl)biphenylsulfonamides and N-(3-isoxazolyl)biphenylsulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(5-isoxazolyl)biphenylsulfonamides and N-(3-isoxazolyl)biphenylsulfonamides and methods for inhibiting the binding of an endothelin peptide to an endothelin receptor or increasing the activity of endothelin peptides by contacting the receptor with a sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.
Inventors
- 👤 Ming F. Chan
- 👤 Bore G. Raju
- 👤 Rosario S. Castillo
- 👤 Adam Kois
- 👤 Chengde Wu
- 👤 Vitukudi Balaji
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 21:28
CPC Classifications
C; C07; C07D; C07D261/00; C07D261/02; C07D261/06; C07D261/10; C07D261/14; C07D261/16; C07D261/20; C07D413/00; C07D413/02; C07D413/12; C07D413/14; C07D417/00; C07D417/02; C07D417/12
Claims Analysis
Total Claims: 26
Claim 1
Independent Claim
333 words
A compound of formula I: ##STR8## or a pharmaceutically acceptable salt of a compound of formula I, wherein: R 1 and R 2 are either (i), (ii) or (iii) as follows: (i) R 1 and R 2 are each independently selected from the group consisting of H, NH 2 , NO 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains, and the aryl portions contain from about 4 to about 16 carbons; or, (ii) R 1 and R 2 together form --(CH 2 ) n , where n is 1 to 4; or, (iii) R 1 and R 2 together form --CH═CH--; Ar 2 is a group of formula: ##STR9## ps in which (i) R 12 and R 13 are independently selected from the group consisting of H, OH NH S, NH 2 , NO 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons; or (ii) R 12 and R 13 together are O, S, or NR 14 in which R 14 is H or alkyl; and each 6-membered ring of Ar 2 in formula II is unsubstituted or substituted with one to six substituents that are each independently selected from R 12 or R 13 , as defined in (i).
Claim 2
Dependent Claim
333 words
A compound of formula I: ##STR8## or a pharmaceutically acceptable salt of a compound of formula I, wherein: R 1 and R 2 are either (i), (ii) or (iii) as follows: (i) R 1 and R 2 are each independently selected from the group consisting of H, NH 2 , NO 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains, and the aryl portions contain from about 4 to about 16 carbons; or, (ii) R 1 and R 2 together form --(CH 2 ) n , where n is 1 to 4; or, (iii) R 1 and R 2 together form --CH═CH--; Ar 2 is a group of formula: ##STR9## ps in which (i) R 12 and R 13 are independently selected from the group consisting of H, OH NH S, NH 2 , NO 2 , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons; or (ii) R 12 and R 13 together are O, S, or NR 14 in which R 14 is H or alkyl; and each 6-membered ring of Ar 2 in formula II is unsubstituted or substituted with one to six substituents that are each independently selected from R 12 or R 13 , as defined in (i).
Claim 3
Dependent Claim
46 words
The compounds of claim 1, wherein R 1 and R 2 are selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide and H; and R 12 and R 13 are selected from H, lower alkyl, haloalkyl and halide.
Claim 4
Dependent Claim
118 words
The compounds of claim 1, wherein R 1 and R 2 are independently selected from the group consisting of H, CH 3 , C 2 H 5 , H 2 C═CH, CH.tbd.C, Ph--O, Ph--CH 2 , 4--CH 3 --C 6 H 4 O, halide, CF 3 , C 2 F 5 , n--C 3 H 7 and iso-C 3 H 7 ; and R 12 and R 13 are each independently selected from the group consisting of H, halide, NH 2 , alkylamino, dialkylamino, CF 3 CH 3 , CN, CH 3 , (CH 3 ) 3 C, C 5 H 11 , CH 3 O, n--C 4 H 9 O, CO 2 H, and CH 2 ═CH.
Claim 5
Dependent Claim
66 words
The compounds of claim 1, wherein R 1 is Br, Cl, H, CH 3 , C 2 H 5 or CF 3 ; R 2 is H, CH 3 , C 2 H 5 , or CF 3 ; R 12 and R 13 are independently selected from H, CH 3 , C 2 H 5 , CF 3 , or halide; and X is O.
Claim 6
Dependent Claim
39 words
The compounds of claim 1, wherein Ar 2 has formula II: ##STR10## in which X is O, NH or S; and R 12 and R 13 are selected from the group consisting of H, lower alkyl, haloalkyl and halide.
Claim 7
Dependent Claim
113 words
The compounds of claim 5, wherein R 1 and R 2 are independently selected from the group consisting of H, CH 3 , C 2 H 5 , H 2 C═CH, CH.tbd.C, Ph--O, Ph--CH 2 , 4--CH 3 --C 6 H 4 O, halide, CF 3 , C 2 F 5 , n--C 3 H 7 and iso-C 3 H 7 ; and R 12 and R 13 are each independently selected from the group consisting of H, halide, NH 2 , CF 3 CH 3 , CN, CH 3 , (CH 3 ) 3 C, C 5 H 11 , CH 3 O, n--C 4 H 9 O and CH 2 ═CH.
Claim 8
Dependent Claim
66 words
The compounds of claim 5, wherein R 1 is Br, Cl, H, CH 3 , C 2 H 5 or CF 3 ; R 2 is H, CH 3 , C 2 H 5 , or CF 3 ; R 12 and R 13 are independently selected from H, CH 3 , C 2 H 5 , CF 3 , or halide; and X is O.
Claim 9
Dependent Claim
20 words
The compounds of claim 2, wherein Ar 2 has formula II: ##STR11## in which X is O, NH or S.
Claim 10
Dependent Claim
113 words
The compounds of claim 8, wherein R 1 and R 2 are independently selected from the group consisting of H, CH 3 , C 2 H 5 , H 2 C═CH, CH.tbd.C, Ph--O, Ph--CH 2 , 4--CH 3 --C 6 H 4 O, halide, CF 3 , C 2 F 5 , n--C 3 H 7 and iso-C 3 H 7 ; and R 12 and R 13 are each independently selected from the group consisting of H, halide, NH 2 , CF 3 CH 3 , CN, CH 3 , (CH 3 ) 3 C, C 5 H 11 , CH 3 O, n--C 4 H 9 O and CH 2 ═CH.
Claim 11
Dependent Claim
66 words
The compounds of claim 8, wherein R 1 is Br, Cl, H, CH 3 , C 2 H 5 or CF 3 ; R 2 is H, CH 3 , C 2 H 5 , or CF 3 ; R 12 and R 13 are independently selected from H, CH 3 , C 2 H 5 , CF 3 , or halide; and X is O.
Claim 12
Dependent Claim
21 words
The compounds of claim 1 that are selected from the group consisting of N-(3,4-dimethyl-5-isoxazolyl)-4-biphenylsufonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide, N-(4-methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide, N-(4-tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide, N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide and N-(3,4-dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide.
Claim 13
Dependent Claim
8 words
The compound of claim 1 that is N-(3,4-dimethyl-5-isoxazolyl)-4-biphenylsufonamide.
Claim 14
Dependent Claim
8 words
The compound of claim 1 that is N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide.
Claim 15
Dependent Claim
8 words
The compound of claim 1 that is N-(4-methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide.
Claim 16
Dependent Claim
8 words
The compound of claim 1 that is N-(4-tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide.
Claim 17
Dependent Claim
8 words
The compound of claim 1 that is N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide.
Claim 18
Dependent Claim
8 words
The compound of claim 1 that is N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide.
Claim 19
Dependent Claim
8 words
The compound of claim 1 that is N-(3,4-dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide.
Claim 20
Dependent Claim
14 words
A pharmaceutical composition, comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
Claim 21
Dependent Claim
14 words
A pharmaceutical composition, comprising a compound of claim 11 in a pharmaceutically acceptable carrier.
Claim 22
Dependent Claim
43 words
A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of claim 1 or pharmaceutically acceptable salts of the compounds of claim 1, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.
Claim 23
Dependent Claim
108 words
An article of manufacture, comprising packaging material and a compound of claim 1 or pharmaceutically acceptable salt of a compound of claim 1 contained within the packaging material, wherein the compound or salt therof is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC 50 of less than about 10 μM; and the packaging material includes a label that indicates that the compound or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.
Claim 24
Dependent Claim
8 words
The compounds of claim 1 that are 4-biphenylsulfonamides.
Claim 25
Dependent Claim
113 words
The compounds of claim 23, wherein R 1 and R 2 are independently selected from the group consisting of H, CH 3 , C 2 H 5 , H 2 C═CH, CH.tbd.C, Ph--O, Ph--CH 2 , 4--CH 3 --CH 6 H 4 O, halide, CF 3 , C 2 F 5 , n--C 3 H 7 and iso-C 3 H 7 ; and R 12 and R 13 are each independently selected from the group consisting of H halide, NH 2 , CF 3 CH 3 , CH, CH 3 , (CH 3 ) 3 C, C 5 H 11 , CH 3 O, n--C 4 H 9 O and CH 2 ═CH.
Claim 26
Dependent Claim
66 words
The compounds of claim 23, wherein R 1 is Br, Cl, H, CH 3 , C 2 H 5 or CF 3 ; R 2 is H, CH 3 , C 2 H 5 , or CF 3 ; R 12 and R 13 are independently selected from H, CH 3 , C 2 H 5 , CF 3 , or halide; and X is O.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1998-11-06 | 1999-05-08 | 1999-11-07 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2002-11-06 | 2003-05-08 | 2003-11-07 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2006-11-06 | 2007-05-08 | 2007-11-07 | $7700.00 | Window Closed / Lapsed |