US 6,451,824 B1Granted

Sulfonylaminocarboxylic acids

AssigneeAventis Pharma Deutschland GmbH

InventorsWerner Thorwart, Wilfried Schwab, Manfred Schudok, Burkhard Haase

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Abstract

Compounds of formula (I) are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in the course of which an increased activity of matrix-degrading metalloproteinases is involved.

Claims14

Dependent claims

A compound of formula (I)

a stereoisomeric form of the compound of formula (I), or a physiologically tolerable salt of the foregoing, wherein
R1 is 1. phenyl,
2. phenyl, which is mono- or disubstituted by
2.1. (C1-C6)-alkyl,
2.2. —OH,
2.3. (C1-C6)-alkyl-C(O)—O—,
2.4. (C1-C6)-alkyl-O—,
2.5. (C1-C6)-alkyl-O—(C1-C4)-alkyl-O—,
2.6. halogen,
2.7. —CF3,
2.8. —CN,
2.9. —NO2,
2.10. HO—C(O)—,
2.11. (C1-C6)-alkyl-O—C(O)—,
2.12. methylenedioxo,
2.13. R4—(R5 )N—C(O)—, or
2.14. R4—(R5)N—;
R2 is a hydrogen atom;
R4 and R5 are identical or different, and each independently are
1. a hydrogen atom,
2. (C1-C6)-alkyl-,
3. HO—C(O)—(C1-C6)-alkyl-,
4. phenyl-(CH2)m—, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., or is substituted by —NH—C(O)—(C1-C3)-alkyl, and n is the integer zero, 1, or 2,
5. picolyl, or
6. R4—(R5)N—, where R4 and R5 together with the amino group form a radical, wherein said radical has a 4- to 7-membered ring, in which one of the carbon atoms in said ring is optionally replaced by —O—, —S—, or —NH—, wherein said radical is at least one radical selected from azetidine, pyrrole, pyrroline, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine, and pyrazine;
R3 is 1. (C2-C10)-alkenyl, in which alkenyl is linear or branched,
2. R9—S(O)n—(C1-C6)-alkyl, where n has the above defined meaning, and R9 is
9.a) a hydrogen atom,
9.b) (C1-C6)-alkyl-,
9.c) HO—C(O)—(C1-C6)-alkyl-,
9.d) phenyl-(CH2)n—, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., or is substituted by —NH—C(O)—(C1-C3)-alkyl, and n is the integer zero, 1, or 2, or
9.e) picolyl,
3. R9—S(O)(═NH)—(C1-C6)-alkyl-, wherein R9 is as defined under 9.a) to 9.e) above,
4.
in which n is the integer zero, 1, or 2, and W is a nitrogen, oxygen, or sulfur atom,
5. —(CH2)m—P(O)(OH)—(C1-C3)-alkyl, in which m is an integer zero, 1, 2, 3, 4, 5, or 6, or
6. R6—C(O)—(C1-C6)-alkyl, in which R6 is
1. (C1-C6)-alkyl-,
2. phenyl, in which phenyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14.,
3. heteroaryl, in which heteroaryl is as defined under 3.1. to 3.15.:
3.1. pyrrole,
3.2. pyrazole,
3.3. imidazole,
3.4. triazole,
3.5. thiophene,
3.6. thiazole,
3.7. oxazole,
3.8. isoxazole,
3.9. pyridine,
3.10. pyrimidine,
3.11. indole,
3.12. benzothiophene,
3.13. benzimidazole,
3.14. benzoxazole, or
3.15. benzothiazole,
and is unsubstituted, or is substituted by the radicals as defined under 2.1. to 2.14., or is substituted by —(C1-C4)-alkyl-COOH,
4. R10O—, in which R10 is
4.1 HO—C(O)—(C1-C6)-alkyl-,
4.2 phenyl-(CH2)n—, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., or is substituted by —NH—C(O)—(C1-C3)-alkyl, and n is the integer zero, 1, or 2, or
4.3 picolyl,
5. R4—(R5)N—, in which R4 and R5 are as defined above, with the proviso that R4 and R5 are not simultaneously a hydrogen atom,
6. heteroaryl-(CH2)m—NH—, in which heteroaryl is as defined under 3.1. to 3.15., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is as defined above, or is substituted by —(C1-C4)-alkyl-COOH,
7. R4—(R5)N—NH—, in which R4 and R5 are as defined above, or
8. HO—C(O)—CH(R11)—NH—, in which R11 is
1. a hydrogen atom,
2. (C1-C10)-alkyl, in which alkyl is unsubstituted, or a hydrogen atom of the alkyl radical is replaced by —OH,
3. (C2-C10)-alkenyl, in which alkenyl is linear or branched,
4. R9—O—(C1-C6)-alkyl, where R9 has the above defined meaning,
5. R9—S(O)n—(C1-C6)-alkyl, where n has the above defined meaning, and where R9 has the above defined meaning,
6. R9—S(O)(═NH)—(C1-C6)-alkyl-, where R9 has the above defined meaning,
7.
in which n is the integer zero, 1, or 2 and W is a nitrogen, oxygen, or sulfur atom,
8. phenyl-(CH2)m—, where m has the above defined meaning, —(CH2)m— is unsubstituted, or a hydrogen atom of —(CH2)m— is replaced by —OH, and phenyl is unsubstituted, or mono- or disubstituted by
8.1. the radicals as defined under 2.1. to 2.14.,
8.2. —O—(CH2)m-phenyl, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and m is as defined above,
8.3. —C(O)—(CH2)m-phenyl, in which phenyl is substituted as defined under 8.2.,
9. heteroaryl-(CH2)m—, in which heteroaryl is as defined under 3.1. to 3.15., m is as defined above, —(CH2)m— is unsubstituted, or a hydrogen atom of —(CH2)m—, is replaced by —OH, and heteroaryl is unsubstituted, or mono- or disubstituted by
9.1. the radicals as defined under 2.1. to 2.14.,
9.2. CH(O),
9.3. —SO2-phenyl, in which phenyl is unsubstituted, or is substituted as defined under 8.2., or
9.4. —O—(CH2)m-phenyl,
10. —(CH2)m—P(O)(OH)—(C1-C3)-alkyl, in which m is as defined above, or
11. R12—C(O)—(C6-C1-C6)-alkyl, in which R12 is
1. a hydrogen atom,
2. (C1-C6)-alkyl-,
3. phenyl, in which phenyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14.,
4. heteroaryl, in which heteroaryl is as defined under 3.1. to 3.15., is unsubstituted, or is substituted by the radicals as defined under 2.1. to 2.14., or is substituted by —(C1-C4)-alkyl-COOH,
5. HO—,
6. R9)O—, in which R9 has the above defined meaning,
7. R4—(R5)N—, in which R4 and R5 are as defined above,
8. heteroaryl-(CH2)m—NH—, in which heteroaryl is as defined under 3.1 to 3.15., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is as defined above, or is substituted by —(C1-C4)-alkyl-COOH,
9. R4—(R5)N—NH—, in which R4 and R5 are as defined above;
and
A is a covalent bond;
B is a) —(CH2)m—, in which m is as defined above,
b) —O—(CH2)p, in which p is an integer 1, 2, 3, 4, or 5, or
c) —CH═CH—;
and
X is —CH═CH—.

96 more elements

A compound of formula (VI)

a stereolsomeric form thereof, or a physiologically tolerable salt of the foregoing, wherein
R1 is 1. phenyl,
2. phenyl, which is mono- or disubstituted by
2.1. (C1-C6)-alkyl,
2.2. —OH,
2.3. (C1-C6)-alkyl-C(O)—O—,
2.4. (C1-C6)-alkyl-O—,
2.5. (C1-C6)-alkyl-O—(C1-C4)-alkyl-O—,
2.6. halogen,
2.7. —CF3,
2.8. —CN,
2.9. —NO2,
2.10. HO—C(O)—,
2.11. (C1-C6)-alkyl-O—C(O)—,
2.12. methylenedioxo,
2.13. R4—(R5 )N—C(O)—, or
2.14. R4—(R5 )N—;
R2 is a hydrogen atom;
R4 and R5 are identical or different, and each independently are
1. a hydrogen atom,
2. (C1-C6)-alkyl-,
3. HO—C(O)—(C1-C6)-alkyl-,
4. phenyl-(CH2)n—, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., or is substituted by —NH—C(O)—(C1-C3)-alkyl, and n is the integer zero, 1, or 2, or
5. picolyl, or
6. R4—(R5)N—, where R4 and R5 together with the amino group form a radical, wherein said radical has a 4- to 7-membered ring, in which one of the carbon atoms in said ring is optionally replaced by —O—, —S—, or —NH—, wherein said radical is at least one radical selected from azetidine, pyrrole, pyrroline, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine, and pyrazine;
R3 is 1. (C2-C10)-alkenyl, in which alkenyl is linear or branched,
2. R9—S(O)n—(C1-C6)-alkyl, where n has the above defined meaning, and where R9 is
9.a) a hydrogen atom,
9.b) (C1-C6)-alkyl-,
9.c) HO—C(O)—(C1-C6)-alkyl-,
9.d) phenyl-(CH2)n—, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., or is substituted by —NH—C(O)—(C1-C3)-alkyl, and n is the integer zero, 1, or 2, or
9.e) picolyl,
3. R9—S(O)(═NH)—(C1-C6)-alkyl, where R9 is as defined under 9.a) to 9.e) above,
4.
in which n is the integer zero, 1, or 2 and W is a nitrogen, oxygen, or sulfur atom,
5. —(CH2)m—P(O)(OH)—(C1-C3)-alkyl, in which m is an integer zero, 1, 2, 3, 4, 5, or 6, or
6. R6—C(O)—(C1-C6)-alkyl, in which R6 is
1. (C1-C6)-alkyl-, in which alkyl is linear, branched, or cyclic,
2. phenyl, in which phenyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14.,
3. heteroaryl, in which heteroaryl is as defined under 3.1. to 3.15.:
3.1. pyrrole,
3.2. pyrazole,
3.3. imidazole,
3.4. triazole,
3.5. thiophene,
3.6. thiazole,
3.7. oxazole,
3.8. isoxazole,
3.9. pyridine,
3.10. pyrimidine,
3.11. indole,
3.12. benzothiophene,
3.13. benzimidazole,
3.14. benzoxazole, or
3.15. benzothiazole,
is unsubstituted, or is substituted by the radicals as defined under 2.1. to 2.14., or is substituted by —(C1-C4)-alkyl-COOH,
4. R10O—, in which R10 is
4.1 HO—C(O)—(C1-C6)-alkyl-,
4.2 phenyl-(CH2)n—, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., or is substituted by —N—C(O)—(C1-C3)-alkyl, and n is the integer zero, 1, or 2, or
4.3 picolyl;
5. R4—(R5)N—, in which R4 and R5 are as defined above, with the proviso that R4 and R5 are not simultaneously a hydrogen atom,
6. heteroaryl-(CH2)m—NH—, in which heteroaryl is as defined under 3.1. to 3.15., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is as defined above, or is substituted by —(C1-C4)-alkyl-COOH,
7. R4—(R5)N—NH—, in which R4 and R5 are as defined above, or
8. HO—C(O)—CH(R11)—NH—, in which R11 is
8.1. a hydrogen atom,
8.2. (C1-C10)-alkyl, in which alkyl is unsubstituted, or a hydrogen atom of the alkyl radical is replaced by —OH,
8.3. (C2-C10)-alkenyl, in which alkenyl is linear or branched,
8.4. R9—O—(C1-C6)-alkyl,
8.5. R9—S(O)n—(C1-C6)-alkyl, where n has the above defined meaning,
8.6. R2—S(O)(═NH)—(C1-C6)-alkyl-,
8.7.
in which n is the integer zero, 1, or 2 and W is a nitrogen, oxygen, or sulfur atom,
8.8. phenyl-(CH2)m—, in which m is the integer zero, 1, 2, 3, 4, 5, or 6, —(CH2)m— is unsubstituted, or a hydrogen atom of —(CH2)m— is replaced by —OH, and phenyl is unsubstituted, or mono- or disubstituted by
8.8.a) the radicals as described under 2.1. to 2.14.,
8.8.b) —O—(CH2)m—phenyl, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as described under 2.1. to 2.14., and m is the integer zero, 1, 2, 3, 4, 5, or 6,
8.8.c) —C(O)—(CH2)m-phenyl, in which phenyl is substituted as defined under 8.2.,
9. heteroaryl-(CH2)m—, in which heteroaryl is as defined under 3.1. to 3.15., m is as defined above, —(CH2)m— is unsubstituted, or a hydrogen atom of —(CH2)m— is replaced by —OH, and heteroaryl is unsubstituted, or mono- or disubstituted by
9.1. the radicals as described under 2.1. to 2.14.,
9.2. CH(O),
9.3. —SO2-phenyl, in which phenyl is unsubstituted, or is substituted as defined under 8.2., or
9.4. —O—(CH2)m-phenyl,
10. —(CH2)m—P(O)(OH)—(C1-C3)-alkyl, in which m is as defined above, or
11. R12—C(O)—(C1-C6)-alkyl, in which R12 is
11.1. a hydrogen atom,
11.2. (C1-C6)-alkyl-,
11.3. phenyl, in which phenyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14.,
11.4. heteroaryl, in which heteroaryl is as defined under 3.1. to 3.15., is unsubstituted, or is substituted by the radicals described under 2.1. to 2.14., or is substituted by —(C1-C4)-alkyl-COOH,
11.5. HO—,
11.6. R9O—, in which R9 has the above defined meaning,
11.7. R4—(R5)N—, in which R4 and R5 are as defined above,
11.8. heteroaryl-(CH2)m—NH—, in which heteroaryl is as defined under 3.1 to 3.15., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is as defined above, or is substituted by —(C1-C4)-alkyl-COOH, or
11.9. R4—(R5)N—NH—, in which R4 and R5 are as defined above;
and
A is a covalent bond;
B is a) —(CH2)m—, in which m has the above defined meaning,
b) —O—(CH2)p—, in which p is an integer 1, 2, 3, 4, or 5, or
c) —CH═CH—;
X is —CH═CH—;
and
R8 is a hydrogen atom, (C1-C6)-alkyl, phenyl, or benzyl.

97 more elements

Dependencies are inferred from the claim text.

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