Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-01-27
2001-05-22
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C548S319500, C549S373000, C562S621000
Reexamination Certificate
active
06235786
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
is hydrogen;
R
2
and R
4
are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) alkenyl,
(4) alkynyl,
(5) alkoxyalkyl,
(6) alkoxycarbonylalkyl,
(7) haloalkyl,
(8) hydroxyalkyl,
(9)-(alkylene)-S(O)
p
-alkyl, wherein p is zero to two,
(10) phenyl,
(11) phenylalkoxyalkyl,
(12) phenylalkyl,
(13) phenoxyalkyl,
(14)-(alkylene)-N(R
20
)SO
2
-phenyl, wherein R
20
is hydrogen or alkyl,
(15) (heterocycle)oxyalkyl,
(16)-(alkylene)-S(O)
p
-heterocycle,
(17)-(alkylene)-heterocycle,
(18) heterocycle,
and
(19)-(alkylene)-NR
6
R
7
,
wherein for (15)-(18), 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,
wherein X
5
is selected from the group consisting of —O—, —NR
5
SO
2
—, —S(O)
p
—, and —C(O)—, and Y
5
is selected from the group consisting of a covalent bond, —O—, alkylene of two to four carbon atoms, piperidineneyl, alkenylene of two carbon atoms, alkynylene of two carbon atoms, —S(O)
p
—, and —C(O)—,
and wherein for (10)-(18), the phenyl and the phenyl part of the phenylalkoxyalkyl, the phenylalkyl, -the (alkylene)-N(R
20
)SO
2
-phenyl, the phenoxyalkyl, and the -(alkylene)-S(O)
p
-phenyl, the heterocycle, and the heterocycle part of the (heterocycle)oxyalkyl, the -(alkylene)-heterocycle and the -(alkylene)-S(O)
p
-heterocycle are optionally substituted with one, two, or three substituents independently selected from the group consisting of
(a) alkyl,
(b) alkoxy,
(c) alkoxyalkyl,
(d) halo,
(e) haloalkyl,
(f) hydroxy,
(g) hydroxyalkyl,
(h) -(alkylene)-heterocycle,
(i) -(alkylene)-phenyl,
(j) —N(R
20
)SO
2
-alkyl,
(k) phenyl, wherein the phenyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of
(i) cyano,
(ii) nitro,
and
(iii) halo,
(l) —C(O)OR
20
,
and
(m) —C(O)NR
x
R
y
, wherein R
x
and R
y
are independently selected from the group consisting of
(i) alkyl,
(ii) phenyl,
and
(iii) phenylalkyl,
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
(a) halo,
and
(b) alkoxy,
and wherein for (19), R
6
and R
7
are independently selected from the group consisting of
(a) hydrogen,
(b) alkyl,
(c) cycloalkyl,
(d) cycloalkylalkyl,
(e) alkanoyl,
(f) phenyl,
and
(g) phenylalkyl,
wherein for (f) and (g), the phenyl and the phenyl part of the phenylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkoxy,
(iii) perfluoroalkyl,
(iv) halo,
(v) haloalkyl,
and
(vi) alkanoyl,
or
R
6
and R
7
, taken together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of
(a) morpholinyl,
(b) thiomorpholinyl,
(c) thiomorpholinyl sulfone,
(d) pyrrolidinyl,
(e) piperazinyl,
(f) piperidinyl,
(g) succinimidyl,
(h) maleimidyl,
(i) glutarimidyl,
(j) phthalimidyl,
(k) naphthalimidyl,
wherein for (a)-(w), 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 consisting of
(i) halo,
(iii) alkyl,
(iii) alkoxy,
(iv) phenoxy,
(v) phenylalkyl,
and
(vi) benzyloxy;
R
3
is selected from the group consisting of
(1) hydrogen,
(2) alkyl,
and
(3) hydroxyalkyl;
or
R
3
and R
4
, taken together with the carbon atom to which they are attached, form a dioxanyl ring;
or
R
2
and R
3
taken together with the carbon atoms to which they are attached form a 5, 6, or 7-membered saturated carbocyclic ring;
Ar
1
is phenyl, wherein the phenyl can be optionally substituted with one or two substituents independently selected from the group consisting of
(1) alkyl,
(2) perfluoroalkyl,
(3) halo,
(4) haloalkyl,
(5) alkoxy,
(6) hydroxy,
(7) hydroxyalkyl,
(8) alkoxyalkyl,
and
(9) nitro;
X is selected from the group consisting of
(1) —CH
2
SO
2
—,
(2) —SO
2
—,
and
(3) —NR
8
SO
2
—, wherein R
8
is either hydrogen or alkyl;
wherein each group is drawn with its left-hand end being the end which attaches to the carbon containing R
3
and R
4
, and its right-hand end being the end which attaches to Ar
1
;
Y is selected from the group consisting of
(1) a covalent bond,
(2) —O—,
(3) alkylene-of two to four carbon atoms,
(4) piperidineneyl,
(5) alkenylene of two carbon atoms,
(6) alkynylene of two carbon atoms,
(7) —SO
2
—,
(8) —NHC(O)—,
and
(9) —C(O)—;
Ar
2
is selected from the group consisting of
(1) phenyl,
(2) pyridyl,
(3) pyrazinyl,
(4) pyridazinyl,
(5) furyl,
(6) thienyl,
(7) isoxazolyl,
(8) oxazolyl,
(9) thiazolyl,
and
(10) isothiazolyl,
wherein (1)-(10) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(a) alkyl,
(b))alkoxy, wherein the alkoxy can be optionally substituted with alkoxy,
(c) -(alkylene)-CO
2
R
8
,
(d) -(alkylene)-NR
9
R
10
, wherein R
9
and R
10
are independently selected from the group consisting of
(i) alkyl,
(ii) phenyl,
and
(iii) phenylalkyl,
wherein for (ii) and (iii), the phenyl and the phenyl part of the phenylalkyl can be optionally substituted with one or two substituents independently selected from the group consisting of halo and alkoxy,
(e) alkoxyalkyl,
(f) cyano,
(g) cyanoalkyl,
(h) halo,
(i) haloalkyl,
(j) hydroxy,
(k) hydroxyalkyl,
(l) thioalkoxy,
(m) thioalkoxyalkyl,
(n) phenylalkoxy,
(o) phenoxy,
(p) phenoxyalkyl,
(q) (heterocycle)oxy,
(r) (heterocycle)oxyalkyl,
(s) perfluoroalkyl,
(t) perfluoroalkoxy,
(u) sulfinylalkyl,
(v) sulfonylalkyl,
wherein A is selected from the group consisting of —CH
2
—, CH
2
O— and —O—, and B
1
Dai Yujia
Davidsen Steven K.
Michaelides Michael R.
Stacey Jamie R.
Steinman Douglas H.
Abbott Laboratories
Donner B. Gregory
Gerstl Robert
Steele Gregory W.
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