US 6,294,573 B1Granted

Reverse hydroxamate inhibitors of matrix metalloproteinases

AssigneeAbbott Laboratories

InventorsMichael L. Curtin, Yujia Dai, Steven K. Davidsen, Joseph F. Dellaria, Jr., Alan S. Florjancic, Jianchun Gong, Yan Guo, Howard R. Heyman, James H. Holms, Michael R. Michaelides, Jamie R. Stacey, Douglas H. Steinman, Carol K. Wada, Lianhong Xu

Life of this patent

Estimating the term…

Abstract

Compounds having the formula are matrix metalloproteinase inhibitors. Also disclosed are matrix metalloproteinase-inhibiting compositions and methods of inhibiting matrix metalloproteinase in a mammal.

Claims17

Dependent claims

A compound of formula (I),

or a pharmaceutically acceptable salt or prodrug thereof, wherein n is zero;
R1 is selected from the group consisting of
(1) hydrogen and
(2) alkyl of one to six carbon atoms;
R3 and R4 are hydrogen;
R2 is selected from the group consisting of
(1) alkyl of one to six carbon atoms,
(2) alkoxyalkyl, wherein the alkoxyalkyl is substituted with hydroxy or silyloxy,
(3) hydroxyalkyl, wherein the alkylene group is of one to six carbon atoms,
(4) phenylalkyl, wherein the alkylene group is of one to six carbon atoms, and the phenyl can be optionally substituted with a substituent selected from the group consisting of
(a) alkyl of one to six carbon atoms,
(b) alkoxycarbonyl wherein the alkyl part is of one to six carbon atoms,
(c) alkoxycarbonylalkyl, wherein the alkylene and alkyl groups are independently of one to six carbon atoms,
(d) —C(O)OR5 wherein R5 is selected from the group consisting of hydrogen and alkyl of one to six carbon atoms, and
(e) hydroxyalkyl of one to six carbon atoms,
(5) -(alkylene)-S(O)p-heterocycle, wherein p is two, the alkylene group is of one to six carbon atoms, and the heterogycle is piperidine, wherein the piperidine can be optionally substituted with dioxolanyl,
(6) -(alkylene)-heterocycle, wherein the alkylene group is of one to six carbon atoms, and the heterocycle is selected from the group consisting of
(a) thienyl,
(b) tetrahydropyranyl,
(c) tetrahydrothiopyranyl wherein the sulfur atom is oxidized, and
(7) -(alkylene)-NR6R7, wherein the alkylene group is of one to six carbon atoms, R6 is hydrogen, and R7 is alkanoyl of one to six carbon atoms wherein the alkanoyl group is substituted with alkoxncarbonyl, or R6 and R7, taken together with the nitrogen atom to which they are attached, define a group selected from the group consisting of
(a) morpholinyl,
(b) thiomorpholinyl,
(c) piperidinyi,
(d) piperazinyl substituted with a substituent selected from the group consisting of alkyl of one to six carbon atoms, alkanoyl of one to six carbon atoms, and —SO2-alkyl wherein the alkyl is of one to six carbon atoms,
(8) heterocycle selected from the group consisting of
(a) oxazolidinonyl, wherein the oxazolidinonyl can be optionally substituted with alkyl of one to six carbon atoms,
(b) tetrahydrofuranyl,
(c) thiazolidinonyl, wherein the thiazolidinonyl can be optionally substituted with one or two alkyl of one to six carbon atom substituents,
(d) pyrrolidinyl substituted with —SO2-alkyl wherein the alkyl is of one to six carbon atoms,
(e) piperidinyl substituted with a substituent selected from the group consisting of alkanoyl of one to ten carbons and —SO2-alkyl wherein the alkyl is of one to six carbon atoms,
(9) -(alkylene)-S(O)p-NR6R7, wherein p is 2, and R6 and R7 are selected from the group consisting of alkyl one to six carbon atoms and phenyl substituted with hydroxyalkyl of one to six carbon atoms, or R6 and R7 together with the nitrogen atom to which they are attached, define a group selected from the group consisting of morpholine and pyrrolidine,
(10) cycloalkyl, wherein the cycloalkyl can be optionally substituted with dioxolanyl,
(11) (cycloalkyl)alkyl, wherein the cycloalkyl part is substituted with dioxolanyl,
(12) -carbonyl-NR6R7, wherein R6 and R7 are alkyl of one to six carbon atoms or R6 and R7 together are morpholinyl,
(13) -(alkylene)-S(O)p-phenyl, wherein the alkylene is of one to six carbon atoms, and the phenyl is substituted with halo,
(14) -(alkylene)-N(R5)SO2-alkyl, wherein the alkylene is of one to six carbon atoms, and R5 is alkyl of one to five carbon atoms, and
(15) -(alkylene)-carbonyl-NR6R7, wherein R6 and R7, together with the nitrogen atom to which they are attached, are morpholinyl;
or
R1 and R2, taken together with the carbon atom to which they are attached form a ring selected from the group consisting of
(1) spiroalkyl of three to eight carbon atoms, wherein the spiroalkyl can be optionally substituted with dioxolanyl or —CO2R5,
(2) tetrahydropyranyl,
(3) tetrahydrothiopyranyl, wherein the sulfur atom is oxidized,
(4) piperidinyl, wherein the nitrogen group is substituted with alkanoyl or —SOp-alkyl,
(5) dioxanyl, wherein the dioxanyl is substituted with alkyl, and
(6) dihydrobenzodioxepinyl;
X is selected from the group consisting of
(1) —O—and
(2) —S(O)p—;
and
Ar1 is unsubstituted phenyl;
Y is selected from the group consisting of
(1) a covalent bond and
(2) —O—;
and
Ar2 is phenyl,
wherein the phenyl is substituted with one substituent selected from the group consisting of
(a) alkyl of one to six carbon atoms,
(b) alkoxy of one to six carbon atoms,
(c) alkoxy of one to six carbon atoms substituted with alkoxy of one to six carbon atoms,
(d) cyano,
(e) cyanoalkyl of one to six carbon atoms,
(f) halo,
(g) thioalkoxy of one to six carbon atoms,
(h) perfluoroalkyl of one to six carbon atoms, and
(i) perfluoroalkoxy, wherein the perfluoroalkyl part is of one to six carbon atoms.

63 more elements

A compound selected form the group consisting of

3-(cyanomethyl)-4′-({3-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-[formyl(hydroxy)amino]propyl}sulfonyl)-1,1′-biphenyl;
hydroxy{3-(4-morpholinyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl}formamide;
4-({3-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-[formyl(hydroxy)amino]propyl}sulfonyl)-4′-fluoro-1,1-biphenyl;
4-({3-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-[formyl(hydroxy)amino]propyl}sulfonyl)-4′-(methylsulfanyl)-1,1-biphenyl;
4-({3-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-[formyl(hydroxy)amino]propyl}sulfonyl)-4′-(methoxy)-1,1-biphenyl;
4-fluoro-4′-({2-[formyl(hydroxy)amino]-4-hydroxybutyl}sulfonyl-1,1′-biphenyl;
4-chloro-4′-({2-[fozmyl(hydroxy)amino]-4-hydroxybutyl}sulfonyl-1,1′-biphenyl;
4-fluoro-4′-({2-[formyl(hydroxy)amino]-4-hydroxypentyl}sulfonyl-1,1′-biphenyl;
4-chloro-4′-({2-[formyl(hydroxy)amino]-4-hydroxypentyl}sulfonyl-1,1′-biphenyl;
4-chloro-4′-({3-(4,4-dimethyl-2,6-dioxo-1-piperididnyl)-2-[formyl(hydroxy)amino]propyl}sulfonyl)-1,1-biphenyl;
ethyl 5-({3-[4′-fluoro[1,1′-biphenyl]-4-yl)sulfonyl]-2-[formyl(hydroxy)amino]propyl}amino)-3,3-dimethyl-5-oxopentanoate;
4-({3-(4,4-dimethyl-2,6-dioxo-1-piperidinyl)-2-[formyl(hydroxy)amino]propyl}sulfonyl)-4′-fluoro-1,1′-biphenyl;
hydroxy[3-(4-morpholinyl)-1-({[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]sulfonyl}methyl)propyl]formamide;
4-chloro-4′-([2-[formyl(hydroxy)amino]-4-(4-morpholinyl)butyl]sulfonyl}-1,1′-biphenyl;
4-chloro-4′-{[2-[formyl(hydroxy)amino]-4-(1-piperidinyl)butyl]sulfonyl}-1,1′-biphenyl;
hydroxy{3-(1-piperidinyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl}formamide;
4-chloro-4′-{[2-[formyl(hydroxy)amino]-3-(1-piperidinyl)propyl]sulfonyl}-1,1′-biphenyl;
hydroxy{2-(1-piperidinyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl}formamide;
3-(4-acetyl-1-piperazinyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl(hydroxy)formamide;
hydroxy{3-(4-thiomorpholinyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl}formamide;
hydroxy{3-(4-methyl-1-piperazinyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl}formamide;
hydroxy{2-tetrahydro-2H-pyran-4-yl-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl}formamide;
hydroxy[(1R)-1-(2R)-1-(methylsulfonyl)pyrrolidinyl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formarnmide;
hydroxy[(1S)-1-[(2R)-1-(methylsulfonyl)pyrrolidinyl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl(hydroxy)formamide;
hydroxy{2-[4-(methylsulfonyl)-1-piperazinyl]-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl}formamide;
hydroxy{3-[4-(methylsulfonyl)-1-piperazinyl]-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl}formamide;
2-[4-(2,2-dimethylpropanoyl)-1-piperazinyl]-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl(hydroxy)formamide;
2,2-dimethyl-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl(hydroxy)formamide;
1-cyclopropyl-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl(hydroxy)formamide;
2-(1,4-dioxaspiro[4.5]dec-8-yl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl(hydroxy)formamide;
hydroxy[1-[(4S)-2-oxo-1,3-oxazolidin-4-yl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
hydroxy[(1S)-1-[(2R)-tetrahydro-2-furanyl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
hydroxy[(1R)-1-[(2R)-tetrahydro-2-furanyl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
hydroxy[1-[(4S)-3-methyl-2-oxo-1,3-oxazolidin-4-yl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
hydroxy[1-[(2R)-5-oxotetrahydro-2-furanyl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
hydroxy[1-[1-(methylsulfonyl)-4-piperidinyl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
hydroxy[1-(1-isobutyryl4-piperidinyl)-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl]formamide;
hydroxy{2-(4-morpholinylsulfonyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl}formamide;
hydroxy{2-methyl-2-(4-morpholinylsulfonyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl}formamide;
hydroxy{8-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}formamide;
1,1-dimethyl-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl(hydroxy)formamide;
hydroxy{2-(2-thienyl)-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl}formamide;
(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-{[4-(4-methoxyphenoxy)phenyl]sulfonyl}ethyl(hydroxy)formamide;
1,2,3-trideoxy-2-[formyl(hydroxy)amino]-4,5-O-(1-methylethylidene)-1-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)-D-threo-pentitol;
(1S)-2-{[4-(4-chlorophenoxy)phenyl]sulfonyl}-1-[(4S)-2,2-dimethyl-1,3-yl]ethyl(hydroxy)formamide;
2-[formyl(hydroxy)amino]-N,N-dimethyl-3-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)propanamide;
hydroxy{2-(4-morpholinyl)-2-oxo-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]ethyl}formamide;
N-[2-[formyl(hydroxy)amino]-3-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)propyl]-N-methylmethanesulfonamide;
(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-({4-[4-(trifluoromethyl)phenoxy]phenyl}sulfonyl)ethyl(hydroxy)formamide;
(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-({4-[4-(methylphenoxy]phenyl}sulfonyl)ethyl(hydroxy)formamide;
4-({(2S)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[formyl(hydroxy)amino]ethyl}sulfonyl)-4′-(trifluoromethyl)-1,1′-biphenyl;
methyl 4-[3-[formyl(hydroxy)amino]-4-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)butyl]benzoate;
4-[3-[formyl(hydroxy)amino]-4-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)butyl]benzoic acid;
hydroxy{3-[4-(hydroxymethyl)phenyl]-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]propyl}formamide;
2-{[4-(4-chlorophenoxy)phenyl]sulfonyl}-1-{[(4-chlorophenyl)sulfonyl]methyl}ethyl(hydroxy)formamide;
hydroxy{(1S)-4-hydroxy-1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]butyl}formamide;
hydroxy{(1R)-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)-1-[(4S)-3,5,5-trimethyl-2-oxo-1,3-thiazolidin-4-yl]ethyl}formamide;
hydroxy{1-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]cyclopentyl}formamide;
(1R)-1-[(4S)-5,5-dimethyl-2-oxo-1,3-thiazolidin-4-yl]-2-({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)ethyl(hydroxy)formamide;
1,1-dioxido-4-[({4-[4-(trifluoromethoxy)phenoxy]phenyl}sulfonyl)methyl]tetrahydro-2H-thiopyran-4-yl(hydroxy)formamide;
(1S)-2-((4-(4-chlorophenoxy)phenyl)sulfonyl)-1-((4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)methyl)ethyl(hydroxy)formamide;
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4′-(trifluoromethyl)(1,1′-biphenyl)-4-yl)sulfonyl)methyl)ethyl(hydroxy)formamide;
hydroxy(4-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)tetrahydro-2H-pyran-4-yl)formamide;
(1S)-2-(2,5-dioxo-1-imidazolidinyl)-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)ethyl(hydroxy)formamide;
1-acetyl-4-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)-4-piperidinyl(hydroxy)formamide;
hydroxy(1-(methylsulfonyl)-4-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)-4-piperidinyl)formamide;
2,2-dimethyl-5-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)-1,3-dioxan-5-yl(hydroxy)formamide;
(1S)-1-((4S)-1,3-dioxolan-4-yl)-2-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)ethyl(hydroxy)formamide;
4-(((2S)-2-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(formyl(hydroxy)amino)ethyl)sulfonyl)-4′-(2-methoxyethoxy)-1,1′-biphenyl;
(1S)-1-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-((4-(4-(2-methoxyethoxy)phenoxy)phenyl)sulfonyl)ethyl(hydroxy)formamide;
hydroxy(4-(4-morpholinyl)-4-oxo-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)butyl)formamide;
1,2,4-trideoxy-2-(formyl(hydroxy)amino)-4,4-dimethyl-3,5-O-(1-methylethylidene)-1-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sufonyl)-D-threo-pentitol;
hydroxy((2R)-2-phenyl-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)propyl)formamide;
2-(2-((tert-butyl(dimethyl)silyl)oxy)ethoxy)-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)ethyl(hydroxy)formamide;
hydroxy(2-(2-hydroxyethoxy)-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)ethyl)formamide;
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4′-methoxy(1,1′-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide;
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4′-methyl(1,1′-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide;
4-(((2S)-2-(formyl(hydroxy)amino)-3-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)propyl)oxy)-4′-(trifluoromethoxy)-1,1′-biphenyl;
hydroxy((1S,2S)-2-(4-isobutylphenyl)-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)propyl)formamide;
hydroxy(3-hydroxy-2,2-dimethyl-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)propyl)formamide;
1,2,3-trideoxy-2-(formyl(hydroxy)amino)-4,5-O-(1-methylethylidene)-1-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)-D-erythro-pentitol;
hydroxy(3-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)-3,4-dihydro-2H-1,5-benzodioxepin-3-yl)formamide;
ethyl 4-(formyl(hydroxy)amino)-4-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)cyclohexanecarboxylate;
4-(formyl(hydroxy)amino)-4-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)cyclohexanecarboxylic acid;
hydroxy(4-hydroxy-1-methyl-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)butyl)formamide;
4-cyano-4′-(((4-(forxyl(hydroxy)amino)tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)-1,1′-biphenyl;
hydroxy(4-(((4′-(trifluoromethyl)(1,1′-biphenyl)-4-yl)sulfonyl)methyl)tetrahydro-2H-pyran-4-yl)formamide;
(1R)-1-((4S)-5,5-dimethyl-2-oxo-1,3-thiazolidin-4-yl)-2-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)ethyl(hydroxy)formamide;
hydroxy(2-(1-piperidinylsulfonyl)-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)ethyl)formamide;
hydroxy(2-(1-pyrrolidinylsulfonyl)-1-(((4-(4-(trifluromethoxy)phenoxy)phenyl)sulfonyl)methyl)ethyl)formamide;
4-((3-(1,4-dioxaspiro[4.5]dec-8-yl)-2-formyl(hydroxy)amino)propyl)sulfonyl)-4′-fluoro-1,1′-biphenyl;
2-(formyl(hydroxy)amino)-N,N-dimethyl-3-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)-1-propanesulfonamide;
2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)-1-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)ethyl(hydroxy)formamide;
1-(1,4dioxaspiro[4.5]dec-8-yl)-2-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)ethyl(hydroxy)formamide;
3-(cyanomethyl)-4′-(((4formyl(hydroxy)amino)tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)-1,1′-biphenyl;
2-(formyl(hydroxy)amino)-N-(4-(hydroxymethyl)phenyl)-N-methyl-3-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)-1-propanesulfonamide;
N,N-diethyl-2-(formyl(hydroxy)amino)-3-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)-1-propanesulfonamide;
methyl (3-(2-(formyl(hydroxy)amino)-3-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl)phenyl)acetate;
(3-(2-(formyl(hydroxy)amino)-3-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl)phenyl)acetic acid;
and
1,2-dideoxy-2-(formyl(hydroxy)amino)-3,4-O-(1-methylethylidene)-1-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)-L-threo-pentitol.

99 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/492,567Filed 27 Jan 2000 · continuation in part
Priority: 6 Aug 1997
Granted: 25 Sep 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 263/04
Not condensed with other rings: having no double bonds between ring members or between ring members and non-ring members
C07D 207/09
With hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms: radicals substituted by nitrogen atoms, not forming part of…
C07D 207/48
With hetero atoms directly attached to the ring nitrogen atom: sulfur atoms
C07D 307/14
With substituted hydrocarbon radicals attached to ring carbon atoms: radicals substituted by nitrogen atoms not forming part of a nitro radical

Family

Application60/055,103Us provisional application · filed 6 Aug 1997
Application09/129,360Parent of this continuation-in-part · filed 5 Aug 1998
Application09/239,087Parent of this continuation-in-part · filed 27 Jan 1999
US 6,294,573 B1This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Reverse hydroxamate inhibitors of matrix metalloproteinases

AssigneeAbbott Laboratories

Life of this patent

Estimating the term…

Abstract

A compound of formula (I),

or a pharmaceutically acceptable salt or prodrug thereof, wherein n is zero;
R1 is selected from the group consisting of
(1) hydrogen and
(2) alkyl of one to six carbon atoms;
R3 and R4 are hydrogen;
R2 is selected from the group consisting of
(1) alkyl of one to six carbon atoms,
(2) alkoxyalkyl, wherein the alkoxyalkyl is substituted with hydroxy or silyloxy,
(3) hydroxyalkyl, wherein the alkylene group is of one to six carbon atoms,
(4) phenylalkyl, wherein the alkylene group is of one to six carbon atoms, and the phenyl can be optionally substituted with a substituent selected from the group consisting of
(a) alkyl of one to six carbon atoms,
(b) alkoxycarbonyl wherein the alkyl part is of one to six carbon atoms,
(c) alkoxycarbonylalkyl, wherein the alkylene and alkyl groups are independently of one to six carbon atoms,
(d) —C(O)OR5 wherein R5 is selected from the group consisting of hydrogen and alkyl of one to six carbon atoms, and
(e) hydroxyalkyl of one to six carbon atoms,
(5) -(alkylene)-S(O)p-heterocycle, wherein p is two, the alkylene group is of one to six carbon atoms, and the heterogycle is piperidine, wherein the piperidine can be optionally substituted with dioxolanyl,
(6) -(alkylene)-heterocycle, wherein the alkylene group is of one to six carbon atoms, and the heterocycle is selected from the group consisting of
(a) thienyl,
(b) tetrahydropyranyl,
(c) tetrahydrothiopyranyl wherein the sulfur atom is oxidized, and
(7) -(alkylene)-NR6R7, wherein the alkylene group is of one to six carbon atoms, R6 is hydrogen, and R7 is alkanoyl of one to six carbon atoms wherein the alkanoyl group is substituted with alkoxncarbonyl, or R6 and R7, taken together with the nitrogen atom to which they are attached, define a group selected from the group consisting of
(a) morpholinyl,
(b) thiomorpholinyl,
(c) piperidinyi,
(d) piperazinyl substituted with a substituent selected from the group consisting of alkyl of one to six carbon atoms, alkanoyl of one to six carbon atoms, and —SO2-alkyl wherein the alkyl is of one to six carbon atoms,
(8) heterocycle selected from the group consisting of
(a) oxazolidinonyl, wherein the oxazolidinonyl can be optionally substituted with alkyl of one to six carbon atoms,
(b) tetrahydrofuranyl,
(c) thiazolidinonyl, wherein the thiazolidinonyl can be optionally substituted with one or two alkyl of one to six carbon atom substituents,
(d) pyrrolidinyl substituted with —SO2-alkyl wherein the alkyl is of one to six carbon atoms,
(e) piperidinyl substituted with a substituent selected from the group consisting of alkanoyl of one to ten carbons and —SO2-alkyl wherein the alkyl is of one to six carbon atoms,
(9) -(alkylene)-S(O)p-NR6R7, wherein p is 2, and R6 and R7 are selected from the group consisting of alkyl one to six carbon atoms and phenyl substituted with hydroxyalkyl of one to six carbon atoms, or R6 and R7 together with the nitrogen atom to which they are attached, define a group selected from the group consisting of morpholine and pyrrolidine,
(10) cycloalkyl, wherein the cycloalkyl can be optionally substituted with dioxolanyl,
(11) (cycloalkyl)alkyl, wherein the cycloalkyl part is substituted with dioxolanyl,
(12) -carbonyl-NR6R7, wherein R6 and R7 are alkyl of one to six carbon atoms or R6 and R7 together are morpholinyl,
(13) -(alkylene)-S(O)p-phenyl, wherein the alkylene is of one to six carbon atoms, and the phenyl is substituted with halo,
(14) -(alkylene)-N(R5)SO2-alkyl, wherein the alkylene is of one to six carbon atoms, and R5 is alkyl of one to five carbon atoms, and
(15) -(alkylene)-carbonyl-NR6R7, wherein R6 and R7, together with the nitrogen atom to which they are attached, are morpholinyl;
or
R1 and R2, taken together with the carbon atom to which they are attached form a ring selected from the group consisting of
(1) spiroalkyl of three to eight carbon atoms, wherein the spiroalkyl can be optionally substituted with dioxolanyl or —CO2R5,
(2) tetrahydropyranyl,
(3) tetrahydrothiopyranyl, wherein the sulfur atom is oxidized,
(4) piperidinyl, wherein the nitrogen group is substituted with alkanoyl or —SOp-alkyl,
(5) dioxanyl, wherein the dioxanyl is substituted with alkyl, and
(6) dihydrobenzodioxepinyl;
X is selected from the group consisting of
(1) —O—and
(2) —S(O)p—;
and
Ar1 is unsubstituted phenyl;
Y is selected from the group consisting of
(1) a covalent bond and
(2) —O—;
and
Ar2 is phenyl,
wherein the phenyl is substituted with one substituent selected from the group consisting of
(a) alkyl of one to six carbon atoms,
(b) alkoxy of one to six carbon atoms,
(c) alkoxy of one to six carbon atoms substituted with alkoxy of one to six carbon atoms,
(d) cyano,
(e) cyanoalkyl of one to six carbon atoms,
(f) halo,
(g) thioalkoxy of one to six carbon atoms,
(h) perfluoroalkyl of one to six carbon atoms, and
(i) perfluoroalkoxy, wherein the perfluoroalkyl part is of one to six carbon atoms.

63 more elements

Facts

Application

09/492,567Filed 27 Jan 2000 · continuation in part

Priority

6 Aug 1997

Granted

25 Sep 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 263/04
Not condensed with other rings: having no double bonds between ring members or between ring members and non-ring members
C07D 207/09
With hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms: radicals substituted by nitrogen atoms, not forming part of…
C07D 207/48
With hetero atoms directly attached to the ring nitrogen atom: sulfur atoms
C07D 307/14
With substituted hydrocarbon radicals attached to ring carbon atoms: radicals substituted by nitrogen atoms not forming part of a nitro radical

Family

Application60/055,103Us provisional application · filed 6 Aug 1997

Application09/129,360Parent of this continuation-in-part · filed 5 Aug 1998

Application09/239,087Parent of this continuation-in-part · filed 27 Jan 1999

US 6,294,573 B1This patent

From the US filing history. Foreign family members aren’t listed.