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US 5,326,760 AGranted
Aminobutanoic acid compounds having metalloprotease inhibiting properties
AssigneeGlaxo Inc.
InventorsAndrew B. McElroy, Peter J. Brown, David H. Drewry, James M. Salovich, Frank J. Schoenen
Life of this patent
Estimating the term…
Abstract
Aminobutanoic acids of the following formula (I): ##STR1## where R.sup.1 -R.sup.5 are a variety of substituents, novel intermediates, a pharmaceutical composition for treating inflammatory diseases, demyelinating diseases, and tumor metastasis, methods for such treatment and processes for preparing compounds of formula (I).
Claims20
Aminobutanoic acids of the following formula (I):
- ##STR9## wherein:
- A and B are independently CR where
- R is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy;
- R.sup.1 is C.sub.3-6 alkyl or C.sub.1-4 alkylthioC.sub.1-4 alkyl;
- R.sup.2 is hydrogen, C.sub.1-4 alkyl or hydroxyC.sub.1-4 alkyl;
- R.sup.3 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino, tris(hydroxymethyl)methyl, aryl, substituted aryl, arylsulfonyl, (substituted aryl)sulfonyl, benzylsulfonyl, heteroarylsulfonyl, (substituted heteroaryl)sulfonyl, heteroarylcarbonyl, (substituted heteroaryl)carbonyl or --(CH.sub.2).sub.n CHR.sup.6 R.sup.7 where
- n is the integer 0, 1, 2, 3 or 4;
- R.sup.6 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino;
- R.sup.7 is hydroxy, mono- or di-(C.sub.1-4 alkyl)amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, a saturated 5, 6, or 7 membered ring optionally interrupted by 1, 2, 3, or 4N, S, or O heteroatoms, sulfonyl or carbonyl, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, tri-, or tetrasubstituted independently with C.sub.1-4 alkyl, hydroxy, oxo, nitro, hydroxyC.sub.1-4 alkyl, aryl, substituted aryl, aminocarbonyl or acetylamino substitutents;
- or
- CHR.sup.6 R.sup.7 together form a saturated 5 to 13 membered ring optionally interrupted by 1, 2, 3, or 4N, S, or O heteroatoms, sulfonyl or carbonyl, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, or tri, or tetrasubstituted independently with C.sub.1-4 alkyl, hydroxy, oxo, nitro, hydroxyC.sub.1-4 alkyl, aryl, substituted aryl, aminocarbonyl or acetylamino substituents, a saturated 6, 7 or 8 membered bicyclic ring optionally interrupted by 1, 2, 3, or 4N, S, or O heteroatoms, with the proviso that any two O or S atoms are not bonded to each other, a 9 or 10 membered bicyclic ring which is partially aromatic, such bicyclic ring optionally mono-, di-, or trisubstituted independently with C.sub.1-4 alkyl, halogen, amino, hydroxy, (C.sub.1-2 alkylsulfonyl)amino, nitro, aminosulfonyl, carboxy, COO(C.sub.1-4 alkyl), trifluoromethyl, mono- or disubstituted (C.sub.1-2 alkyl)amino or trifluoromethylsulfonylamino substituents, a 9 or 10 membered heterobicyclic ring which is partially aromatic, interrupted by 1, 2, 3, or 4 N, S, O heteroatoms, carbonyl or sulfonyl, with the proviso that any two O or S atoms are not bonded to each other, such heterobicyclic ring optionally mono-, di-, or trisubstituted independently with C.sub.1-4 alkyl, halogen, amino, hydroxy, (C.sub.1-2 alkylsulfonyl)amino, nitro, aminosulfonyl, carboxy, COO(C.sub.1-4 alkyl), trifluoromethyl, mono- or disubstituted (C.sub.1-2 alkyl)amino or trifluoromethylsulfonylamino substituents;
- or
- NR.sup.2 R.sup.3 together form a saturated 5, 6, or 7 membered ring interrupted by 1, 2, 3, or 4 N, S, or O heteroatoms, sulfonyl or carbonyl, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, or trisubstituted independently with C.sub.1-4 alkyl, hydroxy, nitro, aryl, substituted aryl, 2,3-dihydroxypropyl, heteroaryl, substituted heteroaryl, --CH.sub.2 COO(C.sub.1-4 alkyl), COO(C.sub.1-4 alkyl), amino, carboxy, acetylamino, oxo, aminosulfonyl, aminocarbonyl, trifluoromethyl, trifluoromethylsulfonylamino, mono- or di-(C.sub.1-4 alkyl)amino, halogen or (C.sub.1-4 alkylsulfonyl)amino substituents, an 9 or 10 membered heterobicyclic ring which is partially aromatic, interrupted by 1, 2, 3, or 4N heteroatoms, such heterobicyclic ring optionally mono-, di-, or trisubstituted independently with oxo, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C.sub.1-4 alkyl, halogen, amino, hydroxy, acetylamino, (C.sub.1-4 alkylsulfonyl)amino, nitro, aminosulfonyl, aminocarbonyl, carboxy, COO(C.sub.1-4 alkyl), trifluoromethyl, mono- or disubstituted (C.sub.1-4 alkyl)amino, 2,3,-dihydroxypropyl or trifluoromethylsulfonylamino substituents;
- R.sup.4 is hydrogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or halogen;
- R.sup.5 is hydrogen, C.sub.1-6 alkyl, amino, aminoC.sub.1-4 alkyl, mono-or di-(C.sub.1-4 alkyl)amino, mono- or di-(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl, acetylamino, aryl, substituted aryl, (aryl)sulfonylamino, nitro, (C.sub.1-4 alkyl)sulfonylamino, hydroxy, C.sub.1-6 alkoxy, halogen, morpholino, piperazinyl, piperidinyl, (aryl)C.sub.1-4 alkoxy, (substituted aryl)C.sub.1-4 alkoxy, aryloxy, (substituted aryl)oxy, (aryl)C.sub.1-4 alkyl, (substituted aryl)C.sub.1-4 alkyl, heteroaryl, substituted heteroaryl, (heteroaryl)C.sub.1-4 alkyl, (substituted heteroaryl)C.sub.1-4 alkyl, (heteroaryl)C.sub.1-4 alkoxy, (substituted heteroaryl)C.sub.1-4 alkoxy, heteroaryloxy or (substituted heteroaryl)oxy;
- or
- R.sup.4 R.sup.5 together form an aryl, substituted aryl or a saturated 5 or 6 membered ring optionally interrupted by 1, 2, or 3N, S, or O heteroatoms, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, or trisubstituted independently with from C.sub.1-4 alkyl, oxo, nitro or aminosulfonyl substituents;
- wherein substituted aryl is defined as an aryl mono-, di-, or trisubstituted independently with C.sub.1-4 alkyl, halogen, amino, hydroxy, acetylamino, (C.sub.1-4 alkylsulfonyl)amino, nitro, aminosulfonyl, aminocarbonyl, carboxy, COO(C.sub.1-4 alkyl), trifluoromethyl, mono- or disubstituted (C.sub.1-4 alkyl)amino, aryl, 2,3,-dihydroxypropyl or trifluoromethylsulfonylamino substituents;
- wherein heteroaryl is defined as a 5 or 6 membered aromatic ring optionally interrupted by 1, 2, 3 or 4 N, S, or O heteroatoms, with the proviso that any two O or S atoms are not bonded to each other;
- wherein substituted heteroaryl is defined as heteroaryl mono-, di-, or trisubstituted independently with C.sub.1-4 alkyl, halogen, amino, hydroxy, acetylamino, (C.sub.1-4 alkylsulfonyl)amino, nitro, aminosulfonyl, aminocarbonyl, carboxy, COO(C.sub.1-4 alkyl), trifluoromethyl, mono- or disubstituted (C.sub.1-4 alkyl)amino, aryl, 2,3,-dihydroxypropyl, or trifluoromethylsulfonylamino substituents;
- or a pharmaceutically acceptable acid-addition or organic base-addition salt thereof.
18 more elements
Aminobutanoic acids of the following formula (I):
- ##STR10## wherein:
- A and B are independently CR where
- R is hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy;
- R.sup.1 is C.sub.3-6 alkyl or C.sub.1-3 alkylthioC.sub.1-3 alkyl;
- R.sup.2 is hydrogen, C.sub.1-4 alkyl or hydroxyC.sub.1-3 alkyl;
- R.sup.3 is C.sub.1-3 alkyl, C.sub.1-4 alkoxy, C.sub.1-3 alkylamino, tris(hydroxymethyl)methyl, aryl, substituted aryl, phenylsulfonyl, benzylsulfonyl, pyridinylsulfonyl, pyridinylcarbonyl or --(CH.sub.2).sub.n CHR.sup.6 R.sup.7 where
- n is the integer 0, 1, 2, 3 or 4;
- R.sup.6 is hydrogen, C.sub.1-3 alkyl, C.sub.1-4 alkoxy, C.sub.1-3 alkylamino;
- R.sup.7 is hydroxy, mono- or di-(C.sub.1-3 alkyl)amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, a saturated 5, 6, or 7 membered ring optionally interrupted by 1, 2, 3, or 4 N, S, or O heteroatoms, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, tri-, or tetrasubstituted independently with C.sub.1-3 alkyl, hydroxy, oxo, phenyl or aminocarbonyl substituents;
- or
- CHR.sup.6 R.sup.7 together form a saturated 5 to 13 membered ring optionally interrupted by 1, 2, 3, or 4 N, S, or O heteroatoms, sulfonyl or carbonyl, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, or tri, or tetrasubstituted independently with C.sub.1-3 alkyl, hydroxy, nitro, hydroxyC.sub.1-3 alkyl, phenyl, aminocarbonyl or acetylamino substituents, a saturated 6, 7 or 8 membered bicyclic ring optionally interrupted by 1, 2, 3, or 4 N, S, or O heteroatoms, with the proviso that any two O or S atoms are not bonded to each other, a 9 or 10 membered bicyclic ring which is partially aromatic, such bicyclic ring optionally mono- or disubstituted independently with C.sub.1-3 alkyl, halogen, amino, hydroxy, (C.sub.1-2 alkylsulfonyl)amino, nitro, aminosulfonyl, carboxy, trifluoromethyl, mono-or disubstituted (C.sub.1-2 alkyl)amino or trifluoromethylsulfonylamino substituents, a 9 or 10 membered heterobicyclic ring which is partially aromatic, interrupted by 1 or 2 N, S, O heteroatoms, carbonyl or sulfonyl, with the proviso that any two O or S atoms are not bonded to each other, such heterobicyclic ring optionally mono- or disubstituted independently with C.sub.1-3 alkyl, halogen, amino, hydroxy, (C.sub.1-2 alkylsulfonyl)amino, nitro, aminosulfonyl, carboxy, trifluoromethyl, mono- or disubstituted (C.sub.1-2 alkyl)amino or trifluoromethylsulfonylamino substituents;
- or
- NR.sup.2 R.sup.3 together form a saturated 5, 6, or 7 membered ring optionally interrupted by 1, 2, 3, or 4 N, S, or O heteroatoms, carbonyl or sulfonyl, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, or trisubstituted independently with C.sub.1-3 alkyl, hydroxy, nitro, phenyl, 2,3-dihydroxypropyl, pyridinyl, ethoxycarbonyl, amino, carboxy, acetylamino, aminosulfonyl, aminocarbonyl, trifluoromethyl, trifluoromethylsulfonylamino, mono- or di-(C.sub.1-3 alkyl)amino, halogen or (C.sub.1-3 alkylsulfonyl)amino substituents, an 9 or 10 membered heterobicyclic ring which is partially aromatic, such heterobicyclic ring interrupted by 1, 2, 3, or 4N heteroatoms, such heterobicyclic ring optionally mono-, di-, or trisubstituted independently with C.sub.1-3 alkyl, halogen, amino, (C.sub.1-2 alkylsulfonyl)amino, nitro, aminosulfonyl, carboxy, trifluoromethyl, mono- or disubstituted (C.sub.1-2 alkyl)amino or trifluoromethylsulfonylamino substituents;
- R.sup.4 is hydrogen, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy or halogen;
- R.sup.5 is hydrogen, C.sub.1-6 alkyl, amino, aminoC.sub.1-3 alkyl, mono-or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3 alkyl)aminoC.sub.1-3 alkyl, acetylamino, aryl, substituted aryl, (phenyl)sulfonylamino, nitro, (C.sub.1-3 alkyl)sulfonylamino, hydroxy, C.sub.1-6 alkoxy, halogen, morpholinyl, piperazinyl, piperidinyl, (aryl)C.sub.1-4 alkoxy, (substituted aryl)C.sub.1-4 alkoxy, aryloxy, (substituted aryl)oxy, (aryl)C.sub.1-4 alkyl, (substituted aryl)C.sub.1-4 alkyl, heteroaryl, substituted heteroaryl, (heteroaryl)C.sub.1-4 alkyl, (substituted heteroaryl)C.sub.1-4 alkyl, (heteroaryl)C.sub.1-4 alkoxy, (substituted heteroaryl)C.sub.1-4 alkoxy, heteroaryloxy or (substituted heteroaryl)oxy;
- or
- R.sup.4 R.sup.5 together form an aryl, subsituted aryl or a saturated 5 or 6 membered ring optionally interrupted by 1, 2, or 3N, S, or O heteroatoms, with the proviso that any two O or S atoms are not bonded to each other, such saturated ring optionally mono-, di-, or trisubstituted independently with from C.sub.1-3 alkyl, oxo, nitro or aminosulfonyl substituents;
- wherein substituted aryl is defined as an aryl mono-, di-, or trisubstituted independently with C.sub.1-4 alkyl, halogen, amino, hydroxy, acetylamino, (C.sub.1-3 alkylsulfonyl)amino, nitro, aminosulfonyl, aminocarbonyl, carboxy, trifluoromethyl, mono- or disubstituted (C.sub.1-4 alkyl)amino or trifluoromethylsulfonylamino substituents;
- wherein heteroaryl is defined as a 5 or 6 membered aromatic ring optionally interrupted by 1, 2, 3 or 4N, S, or O heteroatoms, with the proviso that any two O or S atoms are not bonded to each other;
- wherein substituted heteroaryl is defined as heteroaryl mono-, di-, or trisubstituted independently with C.sub.1-4 alkyl, halogen, amino, hydroxy, acetylamino, (C.sub.1-3 alkylsulfonyl)amino, nitro, aminosulfonyl, aminocarbonyl, carboxy, trifluoromethyl, mono- or disubstituted (C.sub.1-4 alkyl)amino, or trifluoromethylsulfonylamino substituents;
- or
- a pharmaceutically acceptable acid-addition or organic base-addition salt thereof.
19 more elements
Dependencies are inferred from the claim text.