US 5,847,148 AGranted

Thiadiazole derivatives useful for the treatment of diseases related to connective tissue degradation

AssigneePharmacia & Upjohn Company

InventorsEric J. Jacobsen, Mark A. Mitchell, Heinrich J. Schostarez, Donald E. Harper

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Abstract

The present invention provides novel thiadiazole derivatives represented by formula I: ##STR1## or pharmaceutical acceptable salts thereof wherein the compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysins, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, and other diseases related to connective tissue degradation.

A compound of formula I

or pharmaceutical acceptable salts thereof wherein:
x is
a) O, or
b) S;
R.sub.1 is
a) H,
b) C.sub.1-6 alkyl,
c) --(CH.sub.2).sub.i -aryl,
d) --(CH.sub.2).sub.j -cycloalkyl,
e) --(C.sub.1-4 alkyl)--O--R.sub.4,
f) --(C.sub.1-4 alkyl)--S--R.sub.4,
f) --(CH.sub.2).sub.j -Het,
g) --C(.dbd.O)--O--R.sub.4,
h) --C(.dbd.O)--NR.sub.5 R.sub.5, or
i) --(CH.sub.2) --O--Si(R.sub.4).sub.3 ;
R.sub.2 is
a) --O--R.sub.5, or
b) --NR.sub.6 R.sub.7 ;
R.sub.3 is
a) H,
b) C.sub.1-6 alkyl,
c) --(CH.sub.2).sub.i -aryl,
d) --(CH.sub.2).sub.j -cycloalkyl,
e) --(C.sub.1-4 alkyl)--O--R.sub.4,
f) --(C.sub.1-4 alkyl)--S--R.sub.4, or
g) --OR.sub.4 ;
R.sub.4 is
a) H,
b) C.sub.1-6 alkyl, or
c) --(CH.sub.2).sub.i -aryl;
R.sub.5 is
a) H,
b) C.sub.1-6 alkyl, or
c) aryl;
R.sub.6 and R.sub.7 may be the same or differently
a) H,
b) C.sub.1-6 alkyl,
c) C.sub.1-6 OR.sub.4,
d) --(CH.sub.2).sub.i -aryl,
e) --(CH.sub.2).sub.j -cycloalkyl,
f) --(CH.sub.2).sub.j -Het,
g) --(CH.sub.2)--Q,
h) --(CH.sub.2) --C(.dbd.O)--OR.sub.4,
i) --(CH.sub.2).sub.j --C(.dbd.O)--NR.sub.5 R.sub.5,
j) 5-(((5-(dimethylamino)-1-naphthalenyl)sulfonyl)amino)pentyl, or
R.sub.6 and R.sub.7 taken together with the linking N-atom to form
k) azetidinyl,
l) pyrrolidinyl,
m) piperidinyl,
n) morpholino,
o) 4-thiomorpholinyl, or ##STR94## R.sub.8 is a) H,
b) C.sub.1-6 alkyl,
c) --(CH.sub.2).sub.i -aryl,
d) benzhydryl, or
e) --(CH.sub.2).sub.i -Het;
aryl is
phenyl, biphenyl, or naphthalene, optionally substituted with one to five of the following:
a) C.sub.1-4 alkyl,
b) --OR.sub.4,
c) halogen,
d) --NR.sub.5 R.sub.5,
e) --C(.dbd.O)--NR.sub.5 R.sub.5,
f) --NHC(.dbd.O)R.sub.4,
g) --SO.sub.2 NR.sub.5 R.sub.5,
h) --NHSO.sub.2 R.sub.5,
i) --NO.sub.2,
j) --CF.sub.3, or
k) --O--Si(R.sub.4).sub.3 ;
Het is
a 5-, 6-, 9-, or 10-membered heteroaromatic moiety having one or more atoms selected from the group consisting of N, O, and S;
Q is
a saturated 5-, or 6-membered heterocyclic moiety having 1-2 atoms selected from the group consisting of N, O, and S;
i is 0, 1, 2, 3, or 4;
j is 1, 2, 3, or 4;
n is 0, or 1;
with the following provisos:
a) where R.sub.1 is isobutyl, R.sub.6 and R.sub.7 are other than methyl,
b) where R.sub.1 is isobutyl, R.sub.5 is other than methyl.
c) where X is O at least one of R.sub.1 and R.sub.3 is other than H, or C.sub.1-6 alkyl
d) where R.sub.1 and R.sub.3 is C.sub.1-6 alkyl, R.sub.5 is other than H or C.sub.1-6 alkyl, and
e) where R.sub.1 and R.sub.3 is C.sub.1-6 alkyl, at least one of R.sub.6 and R.sub.7 is other than H or C.sub.16 alkyl.

78 more elements

Abstract

Claims15