Substituted diaminocarboxylic acids

Details Substituted diaminocarboxylic acids Substituted diaminocarboxylic acids

2000-10-18

2002-03-12

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S445000, C514S471000, C514S522000, C514S562000, C514S548000, C549S065000, C549S077000, C549S479000, C549S496000, C558S413000, C560S141000, C562S430000

Reexamination Certificate

active

06355673

ABSTRACT:

The invention relates to novel substituted diaminocarboxylic 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.
The arylsulfonyl group has furthermore proven useful 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 active compounds for the treatment of connective tissue disorders, it has now been found that the diaminocarboxylic 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 neutrophil collagenase (MMP-8), since both enzymes are substantially involved, as important constituents of the cartilaginous tissue, in particular 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 a stereoisomeric form of the compound of formula (I), or a physiologically tolerable salt of the compound or stereoisomeric form 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
7
)-alkyl, which 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
,
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)—, or
2.14. R
4
—(R
5
)N—, or
3. a heteroaromatic ring structure as defined under 3.1. to 3.16., 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,
3.15. benzothiazole, or
3.16. benzotriazole;
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
)
o
—, in which phenyl is unsubstituted, mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and o is the integer zero, 1, or 2,
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 carbonyl atoms is optionally replaced by —O—, —S—, or —NH—;
R
3
and G are identical or different and each independently are
1. a hydrogen atom,
2. (C
1
-C
6
)-alkyl-, in which alkyl is linear, branched, or cyclic,
3. (C
2
-C
6
)-alkenyl-,
4. phenyl-(CH
2
)
m
—, in which phenyl is unsubstituted, mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3,
5. heteroaryl-(CH
2
)
m
—, in which heteroaryl is as defined under 3.1. to 3.16., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3,
6. R
6
—C(O)—, in which
R
6
is
6.1. (C
1
-C
6
)-alkyl-, in which alkyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., or by (C
3
-C
6
)-cycloalkyl,
6.2. (C
3
-C
6
)-cycloalkyl, in which cycloalkyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14.,
6.3. (C
2
-C
6
)-alkenyl-, in which alkenyl is unsubstituted, or mono-, di-, or trisubstituted by
6.3.1. phenyl, in which phenyl is unsubstituted, or mono-, di-, or trisubstituted by the radicals as defined under 2.1. to 2.14.,
6.3.2. heteroaryl-, in which heteroaryl is as defined under 3.1. to 3.16., and is unsubstituted, or mono-, di- or trisubstituted by the radicals as defined under 2.1. to 2.14., or
6.3.3. the radicals as defined under 2. 1. to 2.14.,
6.4. phenyl-(CH
2
)
m
—, in which phenyl is unsubstituted, or mono-, di- or trisubstituted by the radicals as defined under 2.1. to 2.14., —O—CF
3
, —SO
2
—NH
2
, —NH—C(O)—CF
3
, or by benzyl, a hydrogen atom of the —(CH
2
)—radical is optionally substituted by the radical —COOH, and m is the integer zero, 1, 2, or 3,
6
.
5
. naphthyl,
6.6. adamantyl, or
6.7. heteroaryl-(CH
2
)
m
—, in which heteroaryl is as defined under 3.1. to 3.16., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3,
7. R
6
—O—C(O)—, in which R
6
is as defined above,
8. R
6
—CH(NH
2
)—C(O)—, in which R
6
is as defined above,
9. R
8
—N(R
7
)—C(O)—, in which
R
8
is
9.1. a hydrogen atom
9.2. (C
1
-C
6
)-alkyl-,
9.3. phenyl-(CH
2
)
m
, 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, or 3, or
9.4. heteroaryl-(CH
2
)
m
, in which heteroaryl is as defined under 3.1. to 3.16., is unsubstituted, or is substituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3, and in which
R
7
is a hydrogen atom, or (C
1
-C
6
)-alkyl, or in which
R
7
and R
8
are bonded to a nitrogen atom to form a 4- to 7-membered ring and the ring is unsubstituted, or a carbon atom in the ring is replaced by —O—, —S—, or —NH—,
10. R
6
—SO
2
—, in which R
6
is as defined above,
11. R
6
—SO
2
—N(R
7
)—C(O)—, in which R
6
and R
7
are as defined above,
12. R
6
—NH—C(═NR
7
)—, in which R
6
and R
7
are as defined above, or
12.1. (C
1
-C
6
)-alkyl-C(O)—,
12.2. —NO
2
, or
12.3. —SO
2
—(CH
2
)
q
-phenyl, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and q is the integer zero, 1, 2, or 3,
 in which m is the integer zero, 1, 2, or 3, and W is a nitrogen, oxygen, or sulfur atom; or
R
3
and G are bonded to a nitrogen atom to form a ring of subformulae (IIa) to (IIp),
 where r is the integer 1 or 2, R
10
is a radical as defined under 2.1. to 2.14., and R
7
and m are as defined above, and in subformula (IIg) a carbon atom in the ring is optionally replaced by oxygen, sulfur, SO
2
, or a nitrogen atom which is unsubstituted or substituted by R
2
;
A is
a) a covalent bond,
b) —O—,
c) —CH═CH—, or
d) —C≡C—;
B is
a) —(CH
2
)
m
—, in which m is as defined above,
b) —O—(CH
2
)
q
, in which q is the integer 1, 2, 3, 4, or 5, or
c) —CH═CH—;
D is —(CH
2
)
m
— in which m is the integer 1, 2, 3, 4, 5, or 6, and one of the chain carbon atoms is optionally replaced by an optionally substituted —NH—, —O—, or —S— atom; 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
1. halogen, in particular chlorine or fluorine, or
2. R
4
—(R
5
)N—, where R
4
and R
5
are identical or different and each independently are
2.1. (C
1
-C
3
)-alkyl, or
2.2. R
4
and R
5
together with the ring amino group form a 5- or 6-membered ring, where one of the carbon atoms is optionally replaced by —O—or —NH—;
R
2
is a hydrogen atom;
G and R
3
are different, and where
G is a hydrogen atom, or (C
1
-C
4
)-alkyl, and
R
3
is
1. phenyl-(CH
2
)
m
, in which phenyl is unsubstituted, mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and m is the integer 1,
2. heteroaryl-(CH
2
)
n
, in which heteroaryl is as defined under 3.10. and is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and n is zero,
3. is R
6
—C(O)—, in which
R
6
is
3.1. (C
1
-C
6
)-alkyl-, in which alkyl is linear, branched, or cyclic,
3.2. phenyl-(CH
2
)
r
— in which phenyl is unsubstituted, or mono- or disubstituted by the radicals

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