Sulfonylaminocarboxylic acids

Details Sulfonylaminocarboxylic acids Sulfonylaminocarboxylic acids

1998-05-08

2002-09-17

Rao, Deepak R. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S210010, C514S210170, C514S217110, C514S217120, C514S218000, C514S227500, C514S252100, C514S256000, C514S330000, C514S331000, C514S354000, C514S358000, C514S365000, C514S367000, C514S372000, C514S374000, C514S375000, C514S378000, C514S383000, C514S391000, C514S406000, C514S415000, C514S423000, C514S427000, C514S428000, C514S369000, C514S394000, C514S539000, C514S568000, C540S553000, C540S607000, C540S609000, C544S059000, C544S243000, C544S335000, C544S337000, C544S406000, C546S226000, C546S232000, C546S

Reexamination Certificate

active

06451824

ABSTRACT:

The invention relates to novel sulfonylaminocarboxylic acids, processes for their preparation and use thereof as pharmaceuticals for the treatment of connective tissue disorders.
Patent applications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonamidohydroxamic acids and their action as matrix metalloproteinase inhibitors. Specific arylsulfonamidocarboxylic acids are used as intermediates for the preparation of thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitors (EP 0 305 947). Patent application EP 0 757 037 also describes the action of sulfonylaminocarboxylic acid derivatives as metalloproteinase inhibitors. It is also known to those skilled in the art that the arylsulfonyl group has proven usefulness as an effective protective group of the amino function of &agr;-aminocarboxylic acids (R. Roemmele, H. Rapoport,
J. Org. Chem
. 53 (1988) 2367-2371).
In the attempt to find efficacious compounds for the treatment of connective tissue disorders, it has now been found that the sulfonylaminocarboxylic acids according to the invention are strong inhibitors of matrix metalloproteinases. Particular value is placed here on the inhibition of stromelysin (matrix metalloproteinase 3) and of neutrophil collagenase (MMP-8), since both enzymes are substantially involved, as important constituents of the cartilaginous tissue, in the degradation of the proteoglycans (A. J. Fosang et al.,
J. Clin. Invest
. 98 (1996) 2292-2299).
The invention therefore relates to compounds of formula (I)
or stereoisomeric forms of the compound of formula (I), or a physiologically tolerable salt of the compound or the stereoisomeric forms of the compound of formula (I), where
R
1
is 1. phenyl,
2. phenyl, which is mono- or disubstituted by
2.1. (C
1
-C
6
)-alkyl, which is linear, cyclic, or branched,
2.2. hydroxyl,
2.3. (C
1
-C
6
)-alkyl-C(O)—O—,
2.4. (C
1
-C
6
)-alkyl-O—,
2.5. (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—,
2.6. halogen,
2.7. —CF
3
,
2.8. —CN,
2.9. —NO
2
,
2.10. HO—C(O)—,
2.11. (C
1
-C
6
)-alkyl-O—C(O)—,
2.12. methylenedioxo,
2.13. R
4
—(R
5
)N—C(O)—,
2.14. R
4
—(R
5
)N—, or
3. a heteroaromatic ring structure as defined below under 3.1. to 3.15., which is unsubstituted, or substituted by the radicals as defined under 2.1 to 2.14.,
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;
R
2
, R
4
, and R
5
are identical or different and each independently are
1. a hydrogen atom,
2. (C
1
-C
6
)-alkyl-,
3. HO—C(O)—(C
1
-C
6
)-alkyl-,
4. phenyl-(CH
2
)
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)—(C
1
-C
3
)-alkyl, and n is the integer zero, 1, or 2, or
5. picolyl, or
6. R
4
and R
5
together with the ring amino group form a 4- to 7-membered ring, in which one of the carbon atoms is optionally replaced by —O—, —S—, or —NH—, or in which two adjacent carbon atoms of the 4- to 7-membered ring are part of a benzyl radical;
R
3
is 1. a hydrogen atom,
2. (C
1
-C
10
)-alkyl, in which alkyl is unsubstituted, or in which a hydrogen atom of the alkyl radical is replaced by —OH,
3. (C
2
-C
10
)-alkenyl-, in which alkenyl is linear or branched,
4. R
2
—O—(C
1
-C
6
)-alkyl-,
5. R
2
—S(O)
n
—(C
1
-C
6
)-alkyl-, where n is as defined above,
6. R
2
—S(O)(═NH)—(C
1
-C
6
)-alkyl-,
 in which n is the integer zero, 1, or 2, and W is a nitrogen, oxygen or sulfur atom,
8. phenyl-(CH
2
)
m
—, in which m is the integer zero, 1, 2, 3, 4, 5, or 6, —(CH2)
m
— is unsubstituted, or a hydrogen atom of —(CH
2
)
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—(CH
2
)
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 the integer zero, 1, 2, 3, 4, 5, or 6, or
8.3. —C(O)—(CH
2
)
m
-phenyl, in which phenyl is as defined under 8.2.,
9. heteroaryl-(CH
2
)
m
—, in which heteroaryl is as defined under 3.1. to 3.15., m is as defined above, or a hydrogen atom of the —(CH
2
)
m
— chain 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. —SO
2
-phenyl, in which phenyl is unsubstituted or is as defined under 8.2. or 8.3., or
9.4. —O—(CH
2
)
m
-phenyl,
10. —(CH
2
)
m
—P(O)(OH)—(C
1
-C
3
)-alkyl, in which m is as defined above, or
11. R
6
—C(O)—(C
1
-C
6
)-alkyl-, in which
R
6
is 1. a hydrogen atom,
2. (C
1
-C
6
)-alkyl-, in which alkyl is linear, branched or cyclic,
3. phenyl, in which phenyl is unsubstituted or substituted as described 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 described under 2.1. to 2.14., or is substituted by —(C
1
-C
4
)-alkyl-COOH,
5. HO—,
6. R
2
O—, in which R
2
is as defined above,
7. is R
4
—(R
5
)N—, in which R
4
and R
5
are as defined above,
8. heteroaryl-(CH
2
)m—NH—, in which heteroaryl is as defined under 3.1. to 3.15., or as described under 2.1. to 2.14., and m is as defined above,
9. R
4
—(R
5
)N—NH—, in which R
4
and R
5
are as defined above, or
10. HO—C(O)—CH(R
3
)—NH—, in which R
3
is as defined above; or
R
2
and R
3
together form a ring having a ring carboxyl group, composing subformula (II):
 in which r is the integer zero, 1, 2, or 3, or in which one of the carbon atoms in the ring is replaced by —O—, —S—, or —(R
7
)N—, in which
R
7
is 1. a hydrogen atom,
2. (C
1
-C
6
)-alkyl,
3. phenyl, in which phenyl is unsubstituted, or is substituted by the radicals as described under 2.1. to 2.14.,
4. benzyl, in which benzyl is unsubstituted, or substituted by the radicals as described under 2.1. to 2.14., or
5. R
2
N—C(═NH)—, where R
2
has the above defined meaning, or the carbon atoms in the ring of subformula (II) are mono- or poly-substituted by (C
1
-C
6
)-alkyl-, phenyl-, phenyl-(CH
2
)
m
— or HO—;
A is a) a covalent bond,
b) —O—,
c) —CH═CH—, or
d) —C═C—;
B is a) —(CH
2
)
m
—, in which m has the above defined meaning,
b) —O—(CH
2
)
p
, in which p is the integer from 1, 2, 3, 4, or 5
c) —CH═CH—; and
X is —CH═CH—, an oxygen atom, or a sulfur atom.
A currently preferred compound of formula (I) is where
R
1
is 1. phenyl, or
2. phenyl, which is monosubstituted by
2.1. (C
1
-C
6
)-alkyl-, in which alkyl is linear, cyclic, or branched,
2.2. —OH,
2.3. (C
1
-C
6
)-alkyl-C(O)—O—,
2.4. (C
1
-C
6
)-alkyl-O—,
2.5. (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—,
2.6. halogen,
2.7. —CF
3
, or
2.8. R
4
—(R
5
)N—;
2
R, R
4
and R
5
are identical or different and each independently are
1. a hydrogen atom, or
2. (C
1
-C
6
)-alkyl-;
R
3
is 1. (C
1
-C
10
)-alkyl-, in which alkyl is linear, branched, or cyclic, alkyl is unsubstituted, or in which a hydrogen atom of the alkyl radical is replaced by —OH,
2. R
2
—S(O)
n—(C
1
-C
6
)-alkyl-, in which R
2
is (C
1
-C
6
)-alkyl- or phenyl-(CH
2
)
n
, and n is the integer zero or 1,
3. phenyl-(CH
2
)
m
—, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as described under 2.1. to 2.14., —(CH
2
)
m
— is unsubstituted, or a hydrogen atom of —(CH
2
)
m
— is replaced by —OH, and m is the integer 1, 2, 3, 4, or 5,
4. heteroaryl-(CH
2
)
m
—, in which heteroaryl is as defined under 3.3., 3.5., 3.6., 3.9., or 3.11., is unsubstituted, or is substituted by the radicals as defined under 2.1. to 2.14., —(CH
2
)
m
— is unsubstituted, or a hydrogen atom of the —(CH
2
)
m
— chain is replaced by —OH, and m is the integer 1, 2, 3, or 4, or
5. R
6
—C(O)—(C
1
-C
6
)-alkyl-, in which
R
6
is 1. —OH,
2. R
2
O—, in which R is defined as above,
3. R
4
—(R
5
)N—, in which R
4
and R
5
are as defined above, or
4. R
4
and R
5
together with the ring amino group form a 5- to 6-membered ring in which one of the carbon atoms is optionally replaced by —O—,

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