US 6,306,873 B1Granted

Substituted β-thiocarboxylic acids

AssigneeAventis Pharmaceuticals Products Inc.

InventorsChristopher J. Burns, Richard Labaudiniere, Stephen Condon, Robert D. Groneberg, Rose M. Mathew, Joseph M. Salvino

Life of this patent

Estimating the term…

Abstract

This invention relates to compounds of general formula (I): in which Ar is a group selected from: A1, A2, B, C, D, E, Q1-Q3, R1-R9, Z1 and Z2 are as defined in the disclosure, and Y represents carboxy or an acid bioisostere. These compounds inhibit the production or physiological effects of TNF and inhibit cyclic AMP phosphodiesterase. The invention is also directed to pharmaceutical compositions comprising compounds of formula (I), their pharmaceutical use and methods for their preparation.

Claims30

Dependent claims

A compound of general formula (I):

wherein
R1 and R3 may be the same or different and each independently represents a group —L1—R5, where L1 is a direct bond, a straight or branched C1-6alkylene chain, a straight or branched C2-6alkenylene chain, a straight or branched C2-6alkylylene chain or a straight or branched C1-6alkylene chain containing an oxygen or sulfur atom, a phenylene, imino (—NH—) or alkylimino linkage, or a sulfinyl or sulfonyl group, in which each of the alkylene, alkenylene and alkynylene chains may be optionally substituted, the substituents selected from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo;
and R5 represents hydrogen, aryl, aroyl, carboxy or an acid bioisostere, cyano, cycloalkyl, cycloalkenyl, heterocyceloalkyl, heteroaryl, arylalkoxycarbonyl, —NH—C(═O)—NH2, —C═N—O—C(═O)—NH2, —C═(O)—NY1Y2, (where Y1 and Y2 are independently selected from hydrogen, alkyl, arylalkyl, and aryl, or the group NY1Y2 may form a 4-6 membered cyclic amine {which may optionally contain a further heteroatom selected from O, S, or NR6 in which R6 is hydrogen, alkyl, aryl or arylalkyl, or which may be fused to an additional aromatic ring}), —NY1SO2aryl, —NHR6, —SR6, or —OR6;
R2 and R4 may be the same or different and are each independently hydrogen or alkyl;
or
R2 and R4 together form a bond;
or
R1 and R2, or R1 and R3, or R3 and R4 together with the carbon atom(s) to which they are attached form a 3 to 8 membered cycloalkyl or cycloalkenyl ring, optionally substituted by alkyl, arylalkyl, or heteroarylalkyl, and which may optionally contain a heteroatom selected from O, S or NR6;
or
R1 and R3 together with the carbon atoms to which they are attached form a heteroaryl ring;
Y represents carboxy or an acid bioisostere;
A1 represents a direct bond, a straight or branched C1-4alkylene chain or a NR6 group;
Ar is a group selected from:
where the dotted lines indicate optional bonds between B—C, and/or C—D, and/or D—E;
R7 represents a straight- or branched-chain alkyl group of 1 to about 6 carbon atoms, optionally substituted by one or more halogen atoms, or when Z1 represents a direct bond R7 may also represent a hydrogen atom or a lower alkenyl or lower alkynyl group;
R8 represents an optionally substituted cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl or partially saturated bicycloaryl group;
R9 represents R10, —OR10, —SR10, —SOR12, —SO2R12, —SO2NR10R11, —NR10SO2R12, —NR10R11, —O(C—O)NR10R11, —NR10C(═O)R12, —N(OH)C(═O)R12, or —C(═O)N(OH)R12 (where R10 and R11, which may be the same or different, each represent a hydrogen atom, or an alkyl, alkenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group, or the group NR10R11 may also represents a 3 to 7 membered cyclic amine optionally containing one or more additional heteroatom selected from O, NR6, or S, and
R12 represents an alkyl, alkenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group);
A2 represents a direct bond;
and Z2 represents an oxygen or sulfur atom;
or
A2 represents a straight- or branched C1-6alkylene chain optionally substituted by halogen, hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl;
and Z2 represents an oxygen or sulfur atom or a direct bond;
or
A2 represents a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms which contains a double or triple carbon-carbon bond, or is interrupted by an oxygen or sulfur atom, a phenylene, imino (—NH—) or alkylimino linkage, or a sulfinyl or sulfonyl group;
and Z2 represents an oxygen or sulfur atom or a direct bond;
B, C, D, and E independently represent a carbon atom or a heteroatom selected from O, S, N, NOR13 or NR13 (where R13 is hydrogen or a C1-4straight- or branched-chain alkyl, aryl, arylC1-4alkyl, heteroaryl or heteroarylC1-4alkyl group), or three of B, C, D or E represent a carbon atom or a heteroatom as defined above and the other represents a direct bond;
but excluding compounds where two O or S atoms are in adjacent positions;
Q1, Q2 and Q3, which may be the same or different, each represents a CH or CX1 linkage or a nitrogen atom (where X1 represents a halogen atom);
and
n is 0, 1 or 2, (with the proviso that when A1 is NR6 n is 2);
and N-oxides thereof, and their prodrugs, pharmaceutically acceptable salts, and solvates (e.g. hydrates), thereof, but excluding the compound 3-[3-(4-fluorophenyl)phenylthio]propionic acid.

29 more elements

A compound selected from the group consisting of:

3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-7-phenylheptanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-phenylpentanohydroxamic acid;
3-(3-Cyclopentyloxy-4-methoxyphenylsulfonyl)-3-(thiophen-3-yl)-propionohydroxamic acid;
5-(4-butoxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphonylsulfonyl)-pentanohydroxamic acid;
3-(3-benzyoxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionohydroxamic acid;
3-(2-benzyloxyphenyl)3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionohydroxamic acid;
3-(3-benzyloxy-4-methoxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-3-(3-phenoxyphenyl)-propionohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-3-[3-(4-methoxyphenoxy)phenyl]-propionohydroxamic acid;
7-(benzo[1,3]dioxol-5-yl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-heptanohydroxamic acid;
3-(4-benzyloxyphenyl)-3-(3-cyclopentyloxy-4-methoxy phenylsulfonyl)-propionohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-methyl-hexanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsufonyl)-octanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-7-phenylheptanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsufonyl)-5-(4-phenoxyphenyl)-pentanohydroxamic acid;
5-(4-benzyloxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-pentanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphonylsufonyl)-hexanohydroxamic acid;
3-[3-(4-chlorophenoxy)phenyl]-3-(3-cyclopentyloxy-4-methoxyphenylsufonyl)-propionohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-3-[3-(3,4-dichlorophenoxy)phenyl]-propionohydroxamic acid;
3-(3-(4-t-butyl-phenoxy)phenyl]-3-(3-cyclopentloxy-4-methoxyphenylsulfonyl)-propionohydroxamic acid;
3-(3-bromo-4,5-dimethoxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsufonyl)-butyrohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-4-(N-methyl-N-benzoylamino)-pentanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-(N-methyl-N-benzoylamino)-butyrohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-(N-methyl-N-phenylcarbamoyloxy)-pentanohydroxamic acid;
5-(benzyloxycarbonyl-N-methylamino)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-pentanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-(N-methyl-N-phenylcarbamoyl)-pentanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-6-(N-methyl-N-phenylcarbamoyl)-hexanohydroxyamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-6-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-hexanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)6-(3,4-dihydro-2H-quinolin-1-yl)-7-oxo-hexanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-(3,4-dihydro-2H-quinolin-1-yl)-oxo-pentanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenyl)sulfanyl-7-phenylheptanohydroxamic acid;
3-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)sulfonyl-7-phenylheptanohydroxamic acid;
3-(7-methoxy-2-cyclopropyl-3H-benzimidazol-4-yl)sulfonyl-7-phenylheptanohydroxamic acid;
3-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-ylsulfonyl)-7-phenylheptanohydroxamic acid;
3-(7-methoxy-2-cyclopropyl-3H-benzimidazol-ylsulfonyl)-7-phenylheptanohydroxamic acid;
3-(4 methoxy-3-[trans-3-phenoxy-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[trans-3-(pyridin-2-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[trans-3-(pyridin-3-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[trans-3-(pyridin-4-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[cis-3-(pyridin-2-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[cis-3-(pyridin-3-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-[N-t-butoxycarbonylpyrrolidin-3-yloxy]-4-methoxyphenylsulphonyl)-7-pbenylheptanohydroxamic acid;
3-(4-methoxy-3-[(N-phenyl)pyrrolidin-3-yloxy]phenysulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3(2-phenyl-ethoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(4-phenyl-butoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-difluoromethoxy-3-[2-phenyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-benzyloxyethoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-phenoxyethoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(5-methoxy-4-[2-(4-methoxyphenyl)ethoxy]pyridin-2-ylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-indanyloxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[2-(pyridin-2-yl)ethoxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[3-(pyridin-4-yl)propyloxy]phenylsulplonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[3-(pyridin-3-yl)propyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(5-methoxy-4-[2-(pyridin-2-yl)ethoxy]pyridin-2-ylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-thien-2-ylethoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-{3-(4-chloropbenyl)-1,2,4-oxadiazol-5-ylmethoxy}-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-{3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-ylmethoxy}-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-ylmethoxy]-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-[2-(4-chlorophenyl)-1,3,4-oxadiazol-5-ylmethoxy]-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-phenylpentanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-3-(thiophen-3-yl)-propionic acid;
5(4-butoxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-pentanoic acid;
3-(3-benzyloxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionic acid;
3-(2-benzyloxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionic acid;
3-(3-benzyloxy-4-methoxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-3-(3-phenoxyphenyl)-propionic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-3-[3-(4-methoxyphenoxy)phenyl]-propionic acid;
7-benzo[1,3]dioxol-5-yl-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-heptanoic acid;
3-(4-benzyloxyphenyl)-3-(3-cyclopentloxy-4-methoxyphenylsulfonyl)-propionic acid;
3-(3-cyclopentyloxy-4-methoxy-phenylsulfonyl)-5-methyl-hexanoic acid;
3-(3-cyclopentyloxy-4-methoxy-phenylsulfonyl)-octanoic acid;
3-(3-cyclopentyloxy-4-methoxy-phenylsulfonyl)-7-phenylheptanoic acid;
3-(3-cyclopentyloxy-4-methoxy-phenylsulfonyl)-5-(4-phenoxyphenyl)-pentanoic acid;
5-(4-benzyloxyphenyl)-3-(3-cyclopentyloxy-4-methoxy-phenylsulfonyl)-pentanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-hexanoic acid;
3-[3-(4-chlorophenoxy)-phenyl]-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionic acid;
3-(3-cyclopentyloxy-4-methoxy-phenylsulfonyl)-3-[3-(3,4-dichlorophenoxy)phenyl]-propionic acid;
3-[3-(4-t-butylphenoxy)-phenyl]-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionic acid;
3-(3-bromo-4,5-dimethoxyphenyl)-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-propionic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-3-(N-methyl-N-benzoyamino)-butanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-4-(N-methyl-N-benzoylamino)-pentanoic acid;
5-[N-methyl-N-phenylcarbamoyloxy]-3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-pentanoic acid;
5-(benzyloxycarbonyl-N-methylamino)-[3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-pentanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-(N-methyl-N-phenylcarbamoyl)-pentanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-6-(N-ethyl-Nphenylcarbamoyl)-heptanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-hexanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxo-hexanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-5-(3,4-dihydro-2H-quinolin-1yl)5-oxo-pentanoic acid;
3-(3-cyclopentyloxy-4-methoxyphenylsulfonyl)-7-phenylheptanoic acid;
3-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)sulfonyl-7-phenylheptanoic acid;
3-(7-methoxy-2-cyclopropyl-3H-benzimidazol-4-yl)sulfonyl-7-phenylheptanoic acid;
3-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-ylsulfonyl)-7-phenylheptanohydroxamic acid;
3-(7-methoxy-2-cyclopropyl-3H-benzimidazol-4-ylsulfonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[trans-3-phenoxy-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[trans-3-(pyridin-2-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[trans-3-(pyridin-3-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[trans-3-(pyridin-4-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[cis-3-(pyridin-2-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[cis-3-(pyridin-3-yloxy)-cyclopentyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-[N-t-butoxycarbonylpyrrolidin-3-yloxy]-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[N-phenyl)pyrrolidin-3-yloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-phenyl-ethoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(4-phenyl-butoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-difluoromethoxy-3-[2-phenylethoxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-benzyloxyethoxy)phenylsulphonyl)-7-phenyltheptanohydroxamic acid;
3-(4-methoxy-3-(2-phenoxyethoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(5-methoxy-4-[2-(4-methoxyphenyl)ethoxy]pyridin-2-ylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-indanyloxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[2-(pyridin-2-yl)ethoxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[3-(pyridin-4-yl)propyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-[3-(pyridin-3-yl)propyloxy]phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(5-methoxy-4-[2-(pyridin-2yl)ethoxy]pyridin-2-ylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(4-methoxy-3-(2-thien-2-ylethoxy)phenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-{3-(4-chlorophenyl)-1,2,4-oxadiazol-5-ylmethoxy}-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-{3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-ylmethoxy}-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-ylmethoxy]-4-methoxyphenylsulphonyl)-7-phenylheptanohydroxamic acid;
3-(3-[2-(4-chlorophenyl)-1,3,4-oxadiazol-5-ylmethoxy]-4-methoxyphenylsulphonyl)-7-phenylheptnaohydroxamic acid;
and the corresponding N-oxides, and their prodrugs, pharamceutically acceptable salts, and solvates.

115 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/357,734Filed 20 Jul 1999 · continuation
Priority: GB 970126422 Jan 1997
Granted: 23 Oct 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification29 codes

C07D 209/48
Iso-indoles; Hydrogenated iso-indoles: with oxygen atoms in positions 1 and 3, e.g. phthalimide
A61P 11/00
Drugs for disorders of the respiratory system
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents

Family

Application60/041,962Us provisional application · filed 3 Apr 1997
PCT/IB98/00082Parent of this continuation · filed 21 Jan 1998
US 6,306,873 B1This patent

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

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Abstract

A compound of general formula (I):

wherein
R1 and R3 may be the same or different and each independently represents a group —L1—R5, where L1 is a direct bond, a straight or branched C1-6alkylene chain, a straight or branched C2-6alkenylene chain, a straight or branched C2-6alkylylene chain or a straight or branched C1-6alkylene chain containing an oxygen or sulfur atom, a phenylene, imino (—NH—) or alkylimino linkage, or a sulfinyl or sulfonyl group, in which each of the alkylene, alkenylene and alkynylene chains may be optionally substituted, the substituents selected from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo;
and R5 represents hydrogen, aryl, aroyl, carboxy or an acid bioisostere, cyano, cycloalkyl, cycloalkenyl, heterocyceloalkyl, heteroaryl, arylalkoxycarbonyl, —NH—C(═O)—NH2, —C═N—O—C(═O)—NH2, —C═(O)—NY1Y2, (where Y1 and Y2 are independently selected from hydrogen, alkyl, arylalkyl, and aryl, or the group NY1Y2 may form a 4-6 membered cyclic amine {which may optionally contain a further heteroatom selected from O, S, or NR6 in which R6 is hydrogen, alkyl, aryl or arylalkyl, or which may be fused to an additional aromatic ring}), —NY1SO2aryl, —NHR6, —SR6, or —OR6;
R2 and R4 may be the same or different and are each independently hydrogen or alkyl;
or
R2 and R4 together form a bond;
or
R1 and R2, or R1 and R3, or R3 and R4 together with the carbon atom(s) to which they are attached form a 3 to 8 membered cycloalkyl or cycloalkenyl ring, optionally substituted by alkyl, arylalkyl, or heteroarylalkyl, and which may optionally contain a heteroatom selected from O, S or NR6;
or
R1 and R3 together with the carbon atoms to which they are attached form a heteroaryl ring;
Y represents carboxy or an acid bioisostere;
A1 represents a direct bond, a straight or branched C1-4alkylene chain or a NR6 group;
Ar is a group selected from:
where the dotted lines indicate optional bonds between B—C, and/or C—D, and/or D—E;
R7 represents a straight- or branched-chain alkyl group of 1 to about 6 carbon atoms, optionally substituted by one or more halogen atoms, or when Z1 represents a direct bond R7 may also represent a hydrogen atom or a lower alkenyl or lower alkynyl group;
R8 represents an optionally substituted cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl or partially saturated bicycloaryl group;
R9 represents R10, —OR10, —SR10, —SOR12, —SO2R12, —SO2NR10R11, —NR10SO2R12, —NR10R11, —O(C—O)NR10R11, —NR10C(═O)R12, —N(OH)C(═O)R12, or —C(═O)N(OH)R12 (where R10 and R11, which may be the same or different, each represent a hydrogen atom, or an alkyl, alkenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group, or the group NR10R11 may also represents a 3 to 7 membered cyclic amine optionally containing one or more additional heteroatom selected from O, NR6, or S, and
R12 represents an alkyl, alkenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group);
A2 represents a direct bond;
and Z2 represents an oxygen or sulfur atom;
or
A2 represents a straight- or branched C1-6alkylene chain optionally substituted by halogen, hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl;
and Z2 represents an oxygen or sulfur atom or a direct bond;
or
A2 represents a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms which contains a double or triple carbon-carbon bond, or is interrupted by an oxygen or sulfur atom, a phenylene, imino (—NH—) or alkylimino linkage, or a sulfinyl or sulfonyl group;
and Z2 represents an oxygen or sulfur atom or a direct bond;
B, C, D, and E independently represent a carbon atom or a heteroatom selected from O, S, N, NOR13 or NR13 (where R13 is hydrogen or a C1-4straight- or branched-chain alkyl, aryl, arylC1-4alkyl, heteroaryl or heteroarylC1-4alkyl group), or three of B, C, D or E represent a carbon atom or a heteroatom as defined above and the other represents a direct bond;
but excluding compounds where two O or S atoms are in adjacent positions;
Q1, Q2 and Q3, which may be the same or different, each represents a CH or CX1 linkage or a nitrogen atom (where X1 represents a halogen atom);
and
n is 0, 1 or 2, (with the proviso that when A1 is NR6 n is 2);
and N-oxides thereof, and their prodrugs, pharmaceutically acceptable salts, and solvates (e.g. hydrates), thereof, but excluding the compound 3-[3-(4-fluorophenyl)phenylthio]propionic acid.

29 more elements

Facts

Application

09/357,734Filed 20 Jul 1999 · continuation

Priority

GB 970126422 Jan 1997

Granted

23 Oct 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification29 codes

C07D 209/48
Iso-indoles; Hydrogenated iso-indoles: with oxygen atoms in positions 1 and 3, e.g. phthalimide
A61P 11/00
Drugs for disorders of the respiratory system
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents