Selective inhibitors of MMP-12

Details Selective inhibitors of MMP-12 Selective inhibitors of MMP-12

1999-12-17

2002-03-05

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S019300, C514S020800, C530S331000, C562S426000

Reexamination Certificate

active

06352976

ABSTRACT:

BACKGROUND OF THE INVENTION
The discovery of different families of matrix metalloproteinases (MMPs), their relationships, and their individual characteristics have been categorized in several reports. Emonard, H. et al.,
Cell Molec. Biol.
36, 131-153 (1990); Birkedal-Hansen, H.,
J. Oral Pathol.
17, 445-451 (1988); Matrisian, L. M.,
Trends Genet.
6, 121-125 (1990); Murphy, G. J. P. et al.,
FEBS Lett.
289, 4-7 (1991); Matrisian, L. M., Bioessays 14, 455-463 (1992). Beckett, R. P. et al.,
DDT
1, 16-26 (1996).
The MMPs are a family of zinc containing endopeptidases which are capable of cleaving large biomolecules, such as the extracellular matrix they are generally secreted in latent form and require activation by proteolytic enzymes, and they are regulated by specific endogenous inhibitors. Three broad groups of MMPs have been delineated: the collagenases which have triple helical interstitial collagen as a substrate, the gelatinases which are proteinases of denatured collagen and Type IV collagen, and the stromelysins which were originally characterized as proteoglycanases but have now been identified to have a broader proteolytic spectrum. Examples of specific MMPs, include, in the collagenases, fibroblast collagenase (MMP-1); in the gelatinases 72 kDa gelatinase (gelatinase A; MMP-2); and in stromelysins include stromelysin 1 (MMP-3). Other MMPs do not fit neatly into the above groups, for example macrophage metalloelastase (MMP-12). Beckett, R. P. et al.,
DDT
1, 16-26 (1996).
The characterizing feature of diseases involving the MMP enzymes appears to be a stoichiometric imbalance between active enzymes and endogenous inhibitors, leading to excessive tissue disruption, and often degradation. McCachren, S. S.,
Arthritis Rheum.
34, inflammatory disorders, such as emphysema; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases such as gingivitis and periodontal disease; and neurological disorders such as multiple sclerosis. Chirivi, R. G. S. et al.,
Int. J. Cancer,
58, 460-464 (1994); Zucker, S., Cancer Research, 53, 140-146 (1993). In addition, a recent study indicates that MMP-12 is required for the development of smoking-induced emphysema in mice. Science, 277, 2002 (1997).
Apart from the role of these potentially very destructive enzymes in pathology, the MMPs play an essential role in cell regrowth and turnover in healthy tissue. Broad spectrum inhibition of the MMPs in the clinical setting results in musculoskeletal stiffness and pain. H. S. Rasmussen and P. P. McCann,
Pharmacol. Ther.,
75, 69-75 (1997). This side effect and others associated with broad spectrum inhibition may be enhanced in chronic administration. Thus, it would be advantageous to provide selective MMP inhibitors.
Surprisingly, we have found that the mercaptoacetylamido dipeptide carboxylic acids of the present application are selective inhibitors of MMP-12 compared to their N-methylamide derivatives. Specifically, while known broad spectrum inhibitors having an amide terminus have inhibiting activities with respect to MMP-1, MMP-2, and MMP-3 (PCT Application No. WO 96/11209, published Apr. 18, 1996) the compounds of the present invention are selective for MMP-12 over MMP-1, MMP-2, and MMP-3 compared to their N-methylamide derivatives. These selective inhibitors are useful for the treatment of smoking-induced emphysema. Because they are selective, the compounds of the present application are expected to be useful for long term therapy with less of the complications related to broad spectrum inhibition.
SUMMARY OF THE INVENTION
The present invention provides novel mercaptoacetylamido dipeptide carboxylic acids of the formula
wherein
R
1
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, —(CH
2
)
a
—CO
2
R
5
, —(CH
2
)
a
—C(O)NH
2
, —(CH
2
)
4
NH
2
, —(CH
2
)
3
—NH—C(NH)NH
2
, —(CH
2
)
2
—S(O)
b
—CH
3
, —CH
2
—OH, —CH(OH)CH
3
, —CH
2
—SH, —(CH2)
d
—Ar
1
, and —CH
2
—Ar
2
;
wherein
a is 1 or 2;
b is 0, 1, or 2;
d is an integer from 0 to 4;
R
5
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
Ar
1
is a radical selected from the group consisting of
wherein
R
6
is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, hydroxy, and C
1
-C
4
alkoxy;
R
7
is selected from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy;
Ar
2
is a radical selected from the group consisting of
R
2
is selected from the group consisting of C
1
-C
6
alkyl, —(CH
2
)
e
—CO
2
R
5′
, —(CH
2
)
e
—C(O)NH
2
, —(CH
2
)
4
NH
2
, —(CH
2
)
3
—NH—C(NH)NH
2
, —(CH
2
)
2
—S(O)
f
—CH
3
, —CH
2
—OH, —CH(OH)CH
3
, —CH
2
—SH, —(CH
2
)
g
—Ar
1′
, and —(CH
2
)—Ar
2′
;
wherein
e is 1 or 2;
f is 0, 1, or 2;
g is an integer from 1 to 4;
R
5
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
Ar
1′
is a radical selected from the group consisting of
wherein
R
6
is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, hydroxy, and C
1
-C
4
alkoxy;
R
7′
is selected from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy;
Ar
2′
is a radical selected from the group consisting of
R
3
is selected from the group consisting of C
1
-C
6
alkyl, —(CH
2
)
m
—W, —(CH
2
)
p
—Ar
3
, —(CH
2
)
k
—CO
2
R
9
, —(CH
2
)
m
—SO
2
NR
8′
—Y
1
, —(CH
2
)
m
—Z—Q
wherein
m is an integer from 2 to 8;
is an integer from 0-10;
k is an integer from 1 to 9;
W is phthalimido;
Ar
3
is selected from the group consisting of
wherein
R
23
is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy;
R
8′
is hydrogen or C
1
-C
6
alkyl;
R
9
is hydrogen or C
1
-C
6
alkyl;
Y
1
is selected from the group consisting of hydrogen, —(CH
2
)
j
—Ar
4
, —N(R
24
)
2
, or Y
1
and R
8′
are taken together with the nitrogen to which they are attached to form N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
wherein
j is 0 or 1;
R
24
is hydrogen or C
1
-C
6
alkyl;
Ar
4
is
wherein
R
25
is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy;
Z is selected from the group consisting of —O—, —NR
8
—, —C(O)NR
8
—, —NR
8
C(O)—, —NR
8
C(O)NH—, —NR
8
C(O)O—, and —OC(O)NH—;
wherein
R
8
is hydrogen or C
1
-C
6
alkyl;
Q is selected from the group consisting of hydrogen, —(CH
2
)
n
—Y
2
, and —(CH
2
)
x
Y
3
;
wherein
n is an integer from 0 to 4;
Y
2
is selected from the group consisting of hydrogen, —(CH
2
)
h
—Ar
5
and —(CH
2
)
t
—C(O)OR
27
wherein
Ar
5
is selected from the group consisting of
wherein
R
26
is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy;
h is an integer from 0 to 6;
t is an integer from 1 to 6;
R
27
is hydrogen or C
1
-C
6
alkyl;
x is an integer from 2 to 4;
Y
3
is selected from the group consisting of —N(R
28
)
2
, N-morpholino, N-piperidino, N-pyrrolidino, and N-isoindolyl;
wherein
R
28
is hydrogen or C
1
-C
6
alkyl;
R
4
is selected from the group consisting of hydrogen, —C(O)R
10
, —C(O)—(CH
2
)
q
—X and —S—G
wherein
R
10
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, phenyl, and benzyl;
q is 0, 1, or 2;
X is selected from the group consisting of
wherein
V is selected from the group consisting of a bond, —CH
2
—, —O—, —S(O)
r
—, —NR
21
—, and —NC(O)R
22
—;
wherein
r is 0, 1, or 2;
R
2
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
R
22
is selected from the group consisting of hydrogen, —CF
3
, C
1
-C
10
alkyl, phenyl, and benzyl;
R
11
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
R
11′
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
G is selected from the group consisting of
wherein
w is an integer from 1 to 3;
R
12
is

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