Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-27
2001-09-25
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S389000, C514S425000, C514S521000, C514S522000, C514S630000, C548S319500, C548S477000, C549S321000, C558S404000, C558S417000, C564S219000
Reexamination Certificate
active
06294573
ABSTRACT:
TECHNICAL FIELD
This invention relates to compounds having activity to inhibit matrix metalloproteinases, to pharmaceutical compositions comprising these compounds and to a medical method of treatment. More particularly, this invention concerns reverse hydroxamate-containing compounds which inhibit matrix metalloproteinases, pharmaceutical compositions comprising these compounds and a method of inhibiting matrix metalloproteinases.
BACKGROUND OF THE INVENTION
The matrix metalloproteinases (MMP's) are a class of extracellular enzymes including collagenase, stromelysin and gelatinase which are believed to be involved in the tissue destruction which accompanies a large number of disease states varying from arthritis to cancer.
Typical connective tissue cells are embedded within an extracellular matrix of high molecular weight proteins and glycoproteins. In healthy tissue, there is a continual and delicately-balanced series of processes which include cell division, matrix synthesis and matrix degradation. In certain pathological conditions, an imbalance of these three processes can lead to improper tissue restructuring. In arthritis, for example, joint mobility can be lost when there is improper remodeling of load-bearing joint cartilage. With cancer, lack of coordination of cell division and the two processes of matrix synthesis and degradation may lead to conversion of transformed cells to invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries which, in turn, may lead to subsequent metastasis.
There has been heightened interest in discovering therapeutic agents which bind to and inhibit MMP's. The discovery of new therapeutic agents possessing this activity will lead to new drugs having a novel mechanism of action for combating disease states involving tissue degenerative processes including, for example, rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal, epidermal or gastric ulceration, and tumor growth and metastasis or invasion.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention provides a matrix metalloproteinase inhibitory compound of formula (I),
or a pharmaceutically acceptable salt or prodrug thereof, wherein
n is zero;
R
1
and R
3
are independently selected from the group consisting of
(1) hydrogen,and
(2) alkyl of one to six carbon atoms;
R
2
and R
4
are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl of one to six carbon atoms,
(3) alkenyl of one to six carbon atoms,
(4) alkynyl of one to six carbon atoms,
(5) alkoxyalkyl, wherein the alkoxyalkyl can be optionally substituted with hydroxy or silyloxy,
(6) alkoxycarbonylalkyl, wherein the alkylene and alkyl groups are independently of one to six carbon atoms,
(7) haloalkyl of one to six carbon atoms,
(8) hydroxyalkyl, wherein the alkylene group is of one to six carbon atoms,
(9) -(alkylene)-S(O)
p
-alkyl, wherein the alkylene is of one to six carbon atoms, p is zero to two, and the alkyl is of one to six carbon atoms,
(10) phenyl,
(11) phenylalkoxyalkyl, wherein the alkylene and alkyl groups are independently of one to six carbon atoms,
(12) phenylalkyl, wherein the alkylene group is of one to six carbon atoms,
(13) phenoxyalkyl, wherein the alkylene group is of one to six carbon atoms,
(14) -(alkylene)-N(R
5
)SO
2
-phenyl, wherein the alkylene is of one to six carbon atoms, and wherein R
5
is selected from the group consisting of
(a) hydrogen, and
(b) alkyl of one to six carbon atoms;
(15) (heterocycle)oxyalkyl, wherein the alkylene group is of one to six carbon atoms,
(16) -(alkylene)-S(O)
p
-heterocycle, wherein the alkylene group is of one to six carbon atoms,
(17) -(alkylene)-heterocycle, wherein the alkylene group is of one to six carbon atoms,
(18) -(alkylene)-NR
6
R
7
, wherein the alkylene group is of one to six carbon atoms,
(19) -heterocycle,
(20) -(alkylene)-S(O)
p
-NR
6
R
7
,
(21) -cycloalkyl, wherein the cycloalkyl can be optionally substituted with dioxolanyl,
(22) (cycloalkyl)alkyl, wherein the cycloalkyl can be optionally substituted with dioxolanyl,
(23) -carbonyl-NR
6
R
7
,
(24) -(alkylene)-S(O)
p
-phenyl,
(25) -(alkylene)-N(R
5
)SO
2
-alkyl, wherein the alkylene is of one to six carbon atoms, and
(26) -(alkylene)-carbonyl-NR
6
R
7
;
wherein for (15)-(17) and (19), the heterocycle is selected from the group consisting of
(a) pyridyl,
(b) pyrazinyl,
(c) pyridazinyl,
(d) furyl,
(e) thienyl,
(f) isoxazolyl,
(g) oxazolyl,
(h) thiazolyl,
(i) isothiazolyl,
(q) tetrahydropyranyl,
(r) pyrrolidinyl,
(s) tetrahydrothiopyranyl, wherein the sulfur atom can be optionally oxidized,
(t) oxazolidinonyl,
(u) tetrahydrofuranyl,
(v) dihydrofuranonyl,
(w) piperidinyl,
(x) morpholinyl, and
(y) thiazolidinonyl;
wherein for (10)-(17), (19), and (24), the phenyl, the phenyl parts of phenylalkoxyalkyl, phenylalkyl, -(alkylene)-N(R
5
)SO
2
-phenyl, phenoxyalkyl, and -(alkylene)-S(O)
p
-phenyl, and the heterocycle, the heterocycle parts of (heterocycle)oxyalkyl, -(alkylene)-heterocycle and -(alkylene)-S(O)
p
-heterocycle are optionally substituted with one, two, or three substituents independently selected from the group consisting of
(a) alkyl of one to six carbon atoms,
(b) alkoxy of one to six carbon atoms,
(c) alkoxyalkyl, wherein the alkyl group and the alkylene group are independently of one to six carbon atoms,
(d) halo,
(e) haloalkyl of one to six carbon atoms,
(f) hydroxy,
(g) hydroxyalkyl of one to six carbon atoms,
(h) -(alkylene)-heterocycle, wherein the alkylene group is of one to six carbon atoms,
(i) -(alkylene)-phenyl, wherein the alkylene group is of one to six carbon atoms,
(j) -N(R
5
)SO
2
-alkyl, wherein the alkyl group is of one to six carbon atoms,
(k) phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
(i) cyano,
(ii) nitro, and
(iii) halo;
(l) —C(O)OR
5
,
(m) —C(O)NR
x
R
y
, wherein R
x
and R
y
are independently selected from the group consisting of
(i) alkyl of one to six carbon atoms,
(ii) phenyl, and
(iii) phenylalkyl, wherein the alkyl group is of one to six carbon atoms;
wherein for (ii) and (iii), the phenyl and the phenyl part of phenylalkyl are optionally substituted with substituents independently selected from the group consisting of halo and alkoxy of one to six carbon atoms, and
(n) —SO
2
-alkyl,
(o) alkanoyl of one to ten carbons,
(p) dioxolanyl; and
(q) -(alkylene)-C(O)OR
5
; and
wherein for (18), (20), (23), and (26), R
6
and R
7
are independently selected from the group consisting of
(a) hydrogen,
(b) alkyl of one to six carbon atoms,
(c) cycloalkyl of three to eight carbon atoms,
(d) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms,
(e) alkanoyl of one to ten carbon atoms, wherein the alkanoyl group can be optionally substituted with alkoxycarbonyl,
(f) phenyl, and
(g) phenylalkyl, wherein the alkylene group is of three to ten carbon atoms;
wherein for (f) and (g), the phenyl and the phenyl part of phenylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of
(i) alkyl of one to six carbon atoms,
(ii) alkoxy of one to six carbon atoms,
(iii) perfluoroalkyl of one to six carbon atoms,
(iv) halo,
(v) haloalkyl of one to six carbon atoms,
(vi) hydroxyalkyl, and
(vii) alkanoyl of one to six carbon atoms; or R
6
and R
7
, taken together with the nitrogen atom to which they are attached, define a group selected from the group consisting of
(1) morpholinyl,
(2) thiomorpholinyl,
(3) thiomorpholinyl sulfone,
(4) pyrrolidinyl,
(5) piperazinyl,
(6) piperidinyl,
(7) succinimidyl,
(8) maleimidyl,
(9) glutarimidyl,
(10) phthalimidyl,
(11) naphthalimidyl,
wherein for (1)-(23), the groups defined by R
6
and R
7
, together with the nitrogen atom to which they are attached, are optionally substituted with one or two substituents independently selected from the group cons
Curtin Michael L.
Dai Yujia
Davidsen Steven K.
Dellaria, Jr. Joseph F.
Florjancic Alan S.
Abbott Laboratories
Donner B. Gregory
Gerstl Robert
Steele Gregory W.
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