US 6,673,804 B1 · Sulfonamide derivatives

Abstract

A compound of the formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof: R1 is H or NHOH. R2 is H, optionally substituted alkyl, cycloalkyl or a group —AR6. A is an alkylene which may be optionally interrupted by O, —S(O)m— or —N(R9). R6 is a group (II), (III), (IV) X is O, S, —N(R10)—, —C(R11)(R12)—. Y is O, CO, —S(O)n—, —N(R10)—, —C(R11)(R12)—. Each of R7 and R8 is H, alkyl, COOH, optionally substituted alkyl, etc. Each of R9, R10, R11, and R12 is H, alkyl, etc. Each of m and n is 0 to 2. R3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl. R4 is optionally substituted (hetero)arylene. R5 is optionally substituted alkyl, optionally substituted (hetero)aryl. These compounds have matrixmetalloproteinase—13 inhibitory activity and aglycanase inhibitory activity.

A compound of the following formula (I) or a pharmacologically acceptable salt thereof:

wherein:
R1 represents hydroxyamino groups;
R2 is a group of the formula —A—R6, wherein
A represents lower alkylene groups defined below, and
R6 represents a group of the following formula (II):
wherein
X represents a group of formula —N(R10)—,
R7 and R8 are the same or different from each other and each is selected from the group consisting of hydrogen atoms, lower alkyl groups defined below, carboxyl groups, one group from Substituent group α defined below, lower alkyl groups defined below substituted with at least one group from Substituent group α defined below, lower alkoxy groups defined below substituted with at least one group from Substituent group α defined below, lower alkylthio groups defined below substituted with at least one group from Substituent group α defined below, lower alkylsulfinyl groups defined below substituted with at least one group from Substituent group α defined below and lower alkylsulfonyl groups defined below substituted with at least one group from Substituent group α defined below, or R7 and R8 together with the carbon atoms to which they are attached form a moiety selected from the group consisting of non-aromatic hydrocarbon rings defined below which are unsubstituted, non-aromatic heterocyclic rings defined below which are unsubstituted, non-aromatic hydrocarbon rings defined below substituted with at least one group selected from the group consisting of Substituent group α defined below and Substituent group β defined below, non-aromatic heterocyclic rings defined below substituted with at least one group selected from the group consisting of Substituent group α defined below and Substituent group β defined below, aryl rings defined below which are unsubstituted, heteroaryl rings defined below which are unsubstituted, aryl rings defined below substituted with at least one group selected from the group consisting of Substituent group α defined below and Substituent group β defined below and heteroaryl rings defined below substituted with at least one group selected from the group consisting of Substituent group α defined below and Substituent group β defined below, and
R10 is selected from the group consisting of hydrogen atoms and lower alkyl groups defined below;
R3 is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, allyl, 2-butenyl, propargyl, 2-butynyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3-(4-chlorophenyl)propyl, 3-phenylpropargyl and 3-(4-chlorophenyl)propargyl-groups;
R4 represents an unsubstituted arylene group or an arylene group substituted with at least one group selected from the group consisting of Substituent group α defined below and Substituent group β defined below;
and
R5 represents a substituent selected from the group consisting of aryl groups defined below which are unsubstituted, heteroaryl groups defined below which are unsubstituted, aryl groups defined below substituted with at least one group selected from the group consisting of Substituent group α defined below and Substituent group β defined below, and heteroaryl groups defined below substituted with at least one group selected from the group consisting of Substituent group α defined below and Substituent group β defined below;
Substituent group α is selected from the group consisting of halogen atoms, cycloalkyl groups having from 3 to 7 carbon atoms, lower alkoxy groups defined below, halogeno lower alkoxy groups defined below, lower alkanoyl groups defined below, lower alkylthio groups defined below, halogeno lower alkylthio groups defined below, lower alkylsulfinyl groups defined below, lower alkylsulfonyl groups defined below, amino groups, mono-lower alkylamino groups defined below, di-(lower alkyl)amino groups defined below, cyano groups, nitro groups, aryl groups defined below which are unsubstituted, heteroaryl groups defined below which are unsubstituted, aryloxy groups defined below which are unsubstituted, heteroaryloxy groups defined below which are unsubstituted, arylthio groups defined below which are unsubstituted, heteroarylthio groups defined below which are unsubstituted, aryl groups defined below substituted with at least one group from Substituent group γ defined below, heteroaryl groups defined below substituted with at least one group from Substituent group γ defined below, aryloxy groups defined below substituted with at least one group from Substituent group γ defined below, heteroaryloxy groups defined below substituted with at least one group from Substituent group γ defined below, arylthio groups defined below substituted with at least one group from Substituent group γ defined below and heteroarylthio groups defined below substituted with at least one group from Substituent group γ defined below;
Substituent group β is selected from the group consisting of lower alkyl groups defined below and halogeno lower alkyl groups defined below;
and
Substituent group γ is selected from the group consisting of halogen atoms, lower alkyl groups defined below, halogeno lower alkyl groups defined below, lower alkoxy groups defined below, halogeno lower alkoxy groups defined below, lower alkylthio groups defined below, halogeno lower alkylthio groups defined below, nitrogroups and cyano groups;
the lower alkyl group in the definition of R5, R7, R8 and R10, Substituent group β and Substituent group γ and the lower alkyl moiety of the lower alkyl group substituted with at least one group from Substituent group α in the definition of R5, R7 and R8 is a straight or branched chain alkyl group having from 1 to 6 carbon atoms;
the lower alkylene group in the definition of A above is a straight or branched alkylene group having from 1 to 6 carbon atoms;
the lower alkoxy group in the definition of Substituent group α and Substituent group γ above and the lower alkoxy moiety of the lower alkoxy group substituted with at least one group from Substituent group α in the definition of R7 and R8 above is a group in which an oxygen atom is attached to the lower alkyl group defined above;
the lower alkylthio group in the definition of Substituent group α and Substituent group γ above and the alkylthio moiety of the lower alkylthio group substituted with at least one group from Substituent group α in the definition of R7 and R8 above is a group in which a sulfur atom is attached to the lower alkyl group defined above;
the lower alkylsulfinyl group in the definition of Substituent group α above and the lower alkylsulfinyl moiety of the lower alkylsulfinyl group substituted with at least one group from Substituent group α in the definition of R7 and R8 above is a group in which a sulfinyl moiety of the formula —SO— is attached to the lower alkyl group defined above;
the lower alkylsulfonyl group in the definition of Substituent group α above and the lower alkylsulfonyl moiety of the lower alkylsulfonyl group substituted with at least one group from Substituent group α in the definition of R7 and R8 above is a group in which a sulfonyl moiety of the formula —SO2— is attached to the lower alkyl group defined above;
the non-aromatic hydrocarbon ring which is formed by R7 and R8, together with the carbon atoms to which they are attached, and the non-aromatic hydrocarbon ring moiety of the non-aromatic hydrocarbon ring substituted with at least one group selected from the group consisting of Substituent group α and Substituent group β, which is formed by R7 and R8, together with the carbon atoms to which they are attached, is each a saturated or unsaturated hydrocarbon ring having from 3 to 7 carbon atoms;
the non-aromatic heterocyclic ring which is formed by R7 and R8, together with the carbon atoms to which they are attached, and the non-aromatic heterocyclic ring moiety of the non-aromatic heterocyclic ring substituted with at least one group selected from the group consisting of Substituent group α and Substituent group β, which is formed by R7 and R8, together with the carbon atoms to which they are attached, is each a 5- to 7-membered saturated or partially saturated heterocyclic ring containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
the aryl ring which is formed by R7 and R8, together with the carbon atoms to which they are attached and the aryl ring moiety of the aryl ring substituted with at least one group selected from the group consisting of Substituent group α and Substituent group β, which is formed by R7 and R8, together with the carbon atoms to which they are attached, is an aromatic hydrocarbon ring having from 6 to 10 carbon atoms, said ring optionally being fused with a cycloalkyl group having from 3 to 10 carbon atoms;
the heteroaryl ring which is formed by R7 and R8, together with the carbon atoms to which they are attached and the heteroaryl ring moiety of the heteroaryl ring substituted with at least one group selected from the group consisting of Substituent group α and Substituent group β, which is formed by R7 and R8, together with the carbon atoms to which they are attached is a 5- to 7-membered aromatic heterocyclic ring containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, said ring optionally being be fused with another cyclic group;
the arylene group and the arylene moiety of the arylene group substituted with at least one group selected from the group consisting of Substituent group α and Substituent group β in the definition of R4 above is a divalent aromatic hydrocarbon ring having from 6 to 10 carbon atoms, said group optionally being fused with a cycloalkyl group having from 3 to 10 carbon atoms;
the aryl group in the definition of R5 and Substituent group α above, the aryl moiety of the aryl group substituted with at least one group selected from Substituent group α and Substituent group β in the definition of R5 above and the aryl moiety of the aryl group substituted with at least one group from Substituent group γ in the definition of Substituent group α above is a monovalent aromatic hydrocarbon ring having from 6 to 10 carbon atoms, said group optionally being fused with a cycloalkyl group having from 3 to 10 carbon atoms;
the heteroaryl group in the definition of R5 and Substituent group α above, the heteroaryl moiety of the heteroaryl group substituted with at least one group selected from the group consisting of Substituent group α and Substituent group β in the definition of R5 above, and the heteroaryl moiety of the heteroaryl group substituted with at least one group from Substituent group γ in the definition of Substituent group α above is a monovalent 5- to 7-membered aromatic heterocyclic group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, said group optionally being fused with another cyclic group;
the halogeno lower alkoxy group in the definition of Substituent group α and Substituent group γ above is a group in which a halogeno lower alkyl group defined below is attached to an oxygen atom;
the lower alkanoyl group in the definition of Substituent group α above is a formyl group or a group in which a carbonyl group is attached to the lower alkyl group defined above;
the halogeno lower alkylthio group in the definition of Substituent group α and Substituent group γ above represents a group in which a halogeno lower alkyl group defined below is attached to a sulfur atom;
the mono-lower alkylamino group in the definition of Substituent group α above is a group in which one hydrogen atom of a —NH2 group is substituted with the lower alkyl group defined above;
the di(lower alkyl)amino group in the definition of Substituent group α above is a group in which the two hydrogen atoms of a —NH2 group are substituted with the above lower alkyl group, the two alkyl groups being the same or different;
the aryloxy group and the aryloxy moiety of the aryloxy group substituted with at least one group from Substituent group γ in the definition of Substituent group α above is a group in which the aryl group defined above is attached to an oxygen atom;
the heteroaryloxy group and the heteroaryloxy moiety of the heteroaryloxy group substituted with at least one group from Substituent group γ in the definition of the Substituent group α above is a group in which the heteroaryl group defined above is attached to an oxygen atom;
the arylthio group and the arylthio moiety of the arylthio group substituted with at least one group from Substituent group γ in the definition of Substituent group α above is a group in which the aryl group defined above is attached to a sulfur atom;
the heteroarylthio group and the heteroarylthio moiety of the heteroarylthio group substituted with at least one group selected from Substituent group γ in the definition of Substituent group α above is a group in which the heteroaryl group defined above is attached to a sulfur atom;
and
the halogeno lower alkyl group in the definition of Substituent group β and Substituent group γ above is a group in which a lower alkyl group defined above is substituted with at least one halogen atom.

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Sulfonamide derivatives

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Sulfonamide derivatives

Life of this patent

Abstract

Claims44