N-arylsulfonylamino acid omega-amides

Details N-arylsulfonylamino acid omega-amides N-arylsulfonylamino acid omega-amides

2000-12-28

2002-01-01

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S237800, C544S162000, C544S170000, C544S171000

Reexamination Certificate

active

06335333

ABSTRACT:

The invention relates to novel N-arylsulfonylamino acid omega-amides, processes for their preparation, and processes for their use as pharmaceuticals.
The publications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonaminohydroxamic 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). The publication EP 0 757 037 also describes the action of sulfonylamino acid derivatives as metalloproteinase inhibitors.
In the effort 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 (MMP-3) and neutrophil collagenase (MMP-8), as both enzymes are decisively involved in the degradation of the proteoglycans, as important constituents of the cartilaginous tissue (A. J. Fosang et al. J. Clin. Invest. 98 (1996) 2292-2299). Those enzymes which are involved in the constitutive degradation and synthesis of matrix constituents likewise belong to the protein family of the matrix metalloproteinases. For example, MMP-1 (collagenase —1) has an important vital function, since it is involved in natural collagen degradation, in particular even where morphogenetic changes take place. Medicinal active compounds which, although they are able to inhibit MMP-3 and MMP-8, at the same time leave MMP-1 largely unaffected, are thus preferred. Such an active compound can even be particularly preferred with respect to the healing of the human or animal body, which, with, all in all, only moderate inhibition of MMP-3 and -8, shows no or a weaker effect on the MMP-1.
The invention therefore relates to the compound of the formula I:
wherein,
R
1
is selected from
1) unsubstituted phenyl,
2) phenyl monosubstituted or disubstituted with at least one substituent selected from linear (C
1
-C
6
)-alkyl, branched (C
1
-C
6
)-alkyl, cyclic(C
3
-C
6
)-alkyl, hydroxyl, (C
1
-C
6
)-alkyl-C(O)—O—, (C
1
-C
6
)-alkyl-O—, (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—, halogen, CF
3
, CN, NO
2
, HO—C(O)—, (C
1
-C
6
)-alkyl-O—C(O)—, methylenedioxo, R
4
—(R
5
) N—C(O)—, and R
4
—(R
5
)N—; substituted or unsubstituted isoxazolidine, morpholine, isothiazolidine, thiomorpholine, pyrazolidine, imidazolidine, piperazine, azetidine, pyrrole, pyrroline, pyrrolidine, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine, and pyrazine; and
3) a substituted or unsubstituted heteroaromatic group selected from pyrrole, pyrazole, imidazole, triazole, thiophene, thiazole, oxazole, isoxazole, pyridine, pyrimidine, indole, benzothiophene, benzimidazole, benzoxazole and benzothiazole;
R
2
is selected from
1) hydrogen,
2) (C
1
-C
6
)-alkyl,
3) HO—C(O)—(C
1
-C
6
)-alkyl,
4) picolyl; and
5) phenyl-(CH
2
)
n
—, where phenyl is unsubstituted, or monosubstituted or disubstituted with at least one substituent selected from linear (C
1
-C
6
)-alkyl, branched (C
1
-C
6
)-alkyl, cyclic (C
3
-C
6
)-alkyl, hydroxyl, (C
1
-C
6
)-alkyl-C(O)—O—, (C
1
-C
6
)-alkyl-O—, (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—, halogen, CF
3
, CN, NO
2
, HO—C(O)—, (C
1
-C
6
)-alkyl-O—C(O), methylenedioxo, R
4
—(R
5
)NC(O), and R
4
—(R
5
)N—;
n is selected from zero, 1, and 2;
R
4
and R
5
are independently selected from
1) hydrogen,
2) (C
1
-C
6
)-alkyl,
3) HO—C(O)—(C
1
-C
6
)-alkyl,
4) picolyl; and
5) phenyl-(CH
2
)
n
—, where phenyl is unsubstituted, monosubstituted, or disubstituted with at least one substituent selected from linear (C
1
-C
6
)-alkyl, branched (C
1
-C
6
)-alkyl, cyclic (C
3
-C
6
)-alkyl, hydroxyl, (C
1
-C
6
)-alkyl-C(O)—O—, (C
1
-C
6
)-alkyl-O—, (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—, halogen, CF
3
, CN, NO
2
, HO—C(O)—, (C
1
-C
6
)-alkyl-O—C(O), methylenedioxo, R
4a
—(R
5a
)N—C(O), and R
4a
—(R
5a
)N—; where R
4a
and R
5a
are independently selected from hydrogen, (C
1
-C
6
)-alkyl, HO—C(O)—(C
1
-C
6
)-alkyl, substituted or unsubstituted phenyl-(CH
2
)
n
—, and picolyl;
n is selected from zero, 1, and 2;
 or together R
4
and R
5
, form a 4, 5, 6, or 7 membered ring with the nitrogen to which R
4
and R
5
are attached wherein at least one of the ring atoms is selected from
1) oxygen,
2) sulfur,
3) NH, and
4) carbon;
R
3
is selected from
1) —(C
1
-C
4
)-alkyl-C(O)—N(R
6
)—R
7
,
2) —(C
1
-C
4
)-alkyl-C(O)—Y, and
3) —(C
1
-C
4
)-alkyl-C(O)—N(R
9
)—(CH
2
)O—N(R
4
)—R
5
;
where R
6
and R
7
together with the nitrogen to which they are bonded form a radical selected from formulae IIa, IIb, and IIe:
q is selected from zero, 1 and 2, and
r is selected from zero and 1,
Z is selected from
1) carbon,
2) nitrogen,
3) oxygen,
4) sulfur, and
5) a covalent bond;
R
8
is selected from
1) hydrogen
2) linear (C
1
-C
6
)-alkyl,
3) branched (C
1
-C
6
)-alkyl,
4) cyclic (C
3
-C
6
)-alkyl,
5) hydroxyl,
6) (C
1
-C
6
)-alkyl-C(O)—O—,
7) (C
1
-C
6
)-alkyl-O—,
8) (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—,
9) halogen,
10) CF
3
,
11) CN,
12) NO
2
,
13) HO—C(O)—,
14) (C
1
-C
6
)-alkyl-O—C(O)—,
15) methylenedioxo,
16) R
4
—(R
5
)N—C(O)—, and
17) R
4
—(R
5
)N—,
o is selected from 2, 3, 4, and 5;
Y is selected from formulae IIc and IId:
R
9
is selected from
1) hydrogen,
2) (C
1
-C
6
)-alkyl-,
3) HO—C(O)—(C
1
-C
6
)-alkyl-,
4) picolyl,
5) phenyl-(CH
2
)
n
—, where phenyl is unsubstituted or monosubstituted or disubstituted with at least one substituent selected from linear (C
1
-C
6
)-alkyl, branched (C
1
-C
6
)-alkyl, cyclic (C
3
-C
6
)-alkyl, hydroxyl, (C
1
-C
6
)-alkyl-C(O)—O—, (C
1
-C
6
)-alkyl-O—, (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—, halogen, CF
3
, CN, NO
2
,HO—C(O)—, (C
1
-C
6
)-alkyl-O—C(O), methylenedioxo, R
4
—(R
5
)N—C(O), and R
4
—(R
5
)N—;
n is selected from zero, 1, and 2;
A is selected from a covalent bond, —O—, —CH═CH—, and —C≡C—;
B is selected from —(CH
2
)
m
—, —O—(CH
2
)
p
, and —CH═CH— where m is selected from zero, 1, 2, 3, 4, 5, and 6;
p is selected from 1, 2, 3, 4, and 5;
X is selected from —CH═CH—, oxygen and sulfur;
a stereoisomer or physiologically tolerable salt thereof.
In one embodiment, the invention provides for a compound of formula I, wherein
R
1
is selected from
1) unsubstituted phenyl and
2) phenyl monosubstitued with a substituent selected from linear (C
1
-C
6
)-alkyl-, branched (C
1
-C
6
)-alkyl-, cyclic (C
3
-C
6
)-alkyl-, —OH, (C
1
-C
6
)-alkyl-C(O)—O—, (C
1
-C
6
)-alkyl-O—, (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—, halogen, —CF
3
,or R
4
—(R
5
)N—;
R
2
is selected from hydrogen and (C
1
-C
6
)-alkyl;
R
4
and R
5
are independently selected from hydrogen and (C
1
-C
6
)-alkyl-, and
R
4
and R
5
together form a 4, 5, 6, or 7 membered ring with the nitrogen to which R
4
and R
5
are attached, wherein at least one of the ring atoms is selected from oxygen, sulfur, NH, and carbon;
R
3
is selected from
1) —(C
1
-C
4
)-alkyl-C(O)—N(R
6
)—R
7
,
2) —(C
1
-C
4
)-alkyl-C(O)—Y, and
3) —(C
1
-C
4
)-alkyl-C(O)—N(R
9
)—(CH
2
)
o
—N(R
4
)—R
5
;
R
6
and R
7
together with the nitrogen to which they are bonded form a radical of formula IIa;
q is selected from zero and 1;
Z is selected from carbon, nitrogen, oxygen, and sulfur;
R
8
is selected from hydrogen, linear (C
1
-C
6
)-alkyl, branched (C
1
-C
6
)-alkyl, cyclic (C
3
-C
6
)-alkyl hydroxyl, (C
1
-C
6
)-alkyl-C(O)—O—, (C
1
-C
6
)-alkyl-O—, (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—, halogen, CF
3
, and CN;
R
9
is a hydrogen atom;
o is selected from 2 and 3;
A is selected from a covalent bond and —O—;
B is selected from (CH
2
)
m
— and —O—(CH
2
)
p
;
m is selected from 0, 1, and 2;
p is selected from 1 and 2; and
X is —CH═CH—.
In another embodiment of the invention, in the compound of formula I,
R
1
is selected from
1) unsubstituted phenyl, and
2) phenyl monosubstituted with a substituent selected from chlorine, bromine, fluorine, pyrrolidine, and morpholine;
R
2
is a hydrogen

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