Inhibitors of matrix metalloproteinases

Details Inhibitors of matrix metalloproteinases Inhibitors of matrix metalloproteinases

1999-12-14

2001-09-11

Gitomer, Ralph (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C514S239200, C514S386000, C514S568000, C514S618000, C514S709000, C562S622000

Reexamination Certificate

active

06288261

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 using the compounds.
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 into invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries which, in turn, can lead to subsequent metastasis.
Thus 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 inhibiting compound of formula I:
or a pharmaceutically acceptable salt or produrug thereof, wherein
R
1
is selected from the group consisting of (a) a covalent bond, (b) —O—, and (c) —S(O)
q
—wherein q is 0, 1, or 2;
R
2
is hydrogen or alkyl;
R
3
is selected from the group consisting of (a) —HNSO
2
—, (b) —O—, (c) S(O)
q
—, (d) —C(═O)—, and (e) —C(═NOH)—; and
n is 1, 2, or 3;
Ar
1
is phenyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of (a) alkyl, (b) perfluoroalkyl, (c) halo, (d) haloalkyl, (e) alkoxy, (f) hydroxy, (g) hydroxyalkyl, (h) alkoxyalkyl, and (i) nitro;
Y is selected from the group consisting of (a) a covalent bond, (b) —O—, (c) alkylene, (d) piperidineneyl, (e) alkenylene, (f) alkynylene, (g) —S(O)
q
—, (h) —NHC(═O)—, and (i) —C(═O)—; and
Ar
2
is selected from the group consisting of (a) phenyl, (b) pyridyl, (c) pyrazinyl, (d) pyridazinyl, (e) furyl, (f) thienyl, (g) isoxazolyl, (h) oxazolyl, (i) thiazolyl, and (j) isothiazolyl wherein the groups defining Ar
2
are substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of (1) alkyl, (2) alkoxy, (3) alkoxyalkoxy, (4) alkyloxycarbonylalkyl, (5) alkoxyalkyl, (6) cyano, (7) cyanoalkyl, (8) halo, (9) haloalkyl, (10) hydroxy, (11) hydroxyalkyl, (12) thioalkoxy, (13) thioalkoxyalkyl, (14) phenylalkoxy, (15) phenoxy, (16) —N(R
2
)SO
2
R
2′
wherein R
2
is defined previously and R
2′
is hydrogen or alkyl, (17) —SO
2
N(R
2
)(R
2′
) wherein R
2
and R
2′
are defined previously, (18) phenoxyalkyl, (19) (heterocycle)oxy, (20) (heterocycle)oxyalkyl, (21) perfluoroalkyl, (22) perfluoroalkoxy, (23) sulfinylalkyl, (24)
sulfonylalkyl, (25)
wherein X
1
is selected from the group consisting of —CH
2
—, —CH
2
O— and —O—, and Z
1
is —C(═O)— or —(C(R
2
)
2
)
v
— wherein R
2
is defined previously and v is 1-3, and (26) -alkyl-NR
x
R
y
wherein R
x
and R
y
are independently selected from the group consisting of
(i) alkyl,
(ii) phenyl substituted with 0, 1, or 2 substituents selected from the group consisting of halo and alkoxy, and
(iii) phenylalkyl wherein the phenyl group is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and alkoxy.
In another embodiment, the present invention provides a compound of formula I wherein R
1
is a covalent bond and R
3
is —O—.
In another embodiment, the present invention provides a compound of formula I wherein R
1
is —O— or a covalent bond and R
3
is —C(═O)— or —C(═NOH)—.
In another embodiment, the present invention provides a compound of formula I wherein R
1
is —O— and R
3
is —S(O)
q
— wherein q is defined previously.
In another embodiment, the present invention provides a compound of formula I wherein R
1
is a covalent bond and R
3
is —S(O)
q
— wherein q is defined previously.
In another embodiment, the present invention provides a compound of formula I wherein R
1
is a covalent bond and R
3
is —NHSO
2
—.
In another embodiment, the present invention provides a compound of formula I wherein R
1
and R
3
are —O—.
In another embodiment, the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of compound of formula I in combination with a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a method of inhibiting matrix metalloproteinases in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
As used throughout this specification and the appended claims, the following terms have the meanings specified.
The term “alkanoyl,” as used herein, refers to an alkyl group, as defined below, attached to the parent molecular moiety through a —C(═O)— group. Examples of alkanoyl groups include acetyl, propionyl, butanoyl, and the like.
The term “alkenyl,” as used herein, refers to a monovalent straight or branched chain of two to six carbon atoms containing at least one carbon-carbon double bond derived from an alkene by the removal of one hydrogen atom. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
The term “alkenylene,” as used herein, refers to a straight or branched chain hydrocarbon of two to ten carbon atoms containing at least one carbon-carbon double bond derived from an alkene by the removal of two hydrogen atoms. Examples of alkenylene groups include —CH═CH—, —CH
2
CH═CH—, —C(CH
3
)═CH—, —CH
2
CH═CHCH
2
—, and the like.
The term “alkoxy,” as used herein, refers to an alkyl group, as defined below, attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and the like.
The term “alkoxyalkoxy,” as used herein, refers to an alkoxy group, as defined above, attached to an alkoxy group, as defined above. Examples of alkoxyalkoxy groups include ethoxyethoxy, ethoxymethoxy, methoxymethoxy, and the like.
The term “alkoxyalkyl,” as used herein, refers to an alkoxy group, as defined above, attached to the parent molecular moiety through an alkyl group, as defined below. Examples of alkoxyalkyl groups include —CH
2
OCH
3
, —CH
2
CH
2
OCH
3
, —CH
2
CH
2
OCH
2
CH
3
, and the like.
The term “alkoxycarbonyl,” as used herein, refers to an alkoxy group, as defined above, which is attached to the parent molecular group through a —C(═O)— group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, and the like.
The term “alkoxycarbonylalkyl,” as used herein, refers to an alkoxycarbonyl group, as defined above, which is attached to the parent molecular group through an alkyl group as defined below. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, ethoxycarbonylpropyl, tert-butoxycarbonylbutyl, and the like.
The term “alkyl,” as used herein, refers to a monovalent group derived from a straight or branched

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