Alkyne containing metalloproteinase inhibitors

Details Alkyne containing metalloproteinase inhibitors Alkyne containing metalloproteinase inhibitors

2000-06-30

2002-05-14

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S159000

Reexamination Certificate

active

06387901

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to alkyne containing hydroxamide derivatives, and to pharmaceutical compositions and methods of treatment of inflammation, cancer and other disorders.
The compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the matrix metalloproteinase (also called MMP or matrixin) and reprolysin (also known as adamylsin) subfamilies of the metzincins (Rawlings, et al.,
Methods in Enzymology,
248, 183-228 (1995) and Stocker, et al.,
Protein Science,
4, 823-840 (1995)).
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP's are most well known for their role in regulating the turn-over of extracellular matrix proteins and as such play important roles in normal physiological processes such as reproduction, development and differentiation. In addition, the MMP's are expressed in many pathological situations in which abnormal connective tissue turnover is occurring. For example, MMP-13 an enzyme with potent activity at degrading type II collagen (the principal collagen in cartilage), has been demonstrated to be overexpressed in osteoarthritic cartilage (Mitchell, et al.,
J. Clin. Invest.,
97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also overexpressed in osteoarthritic cartilage and inhibition of some or all of these MMP's is expected to slow or block the accelerated loss of cartilage typical of joint diseases such as osteoarthritis or rheumatoid arthritis.
The mammalian reprolysins are known as ADAMs (A Disintegrin And Metalloproteinase) (Wolfberg, et al.,
J. Cell Biol.,
131, 275-278 (1995)) and contain a disintegrin domain in addition to a metalloproteinase-like domain. To date twenty-three distinct ADAM's have been identified.
ADAM-17, also known as tumor necrosis factor-alpha converting enzyme (TACE), is the most well known ADAM. ADAM-17 (TACE) is responsible for cleavage of cell bound tumor necrosis factor-alpha (TNF-&agr;, also known as cachectin). TNF-&agr; is recognized to be involved in many infectious and autoimmune diseases (W. Friers,
FEBS Letters,
285, 199 (1991)). Furthermore, it has been shown that TNF-&agr; is the prime mediator of the inflammatory response seen in sepsis and septic shock (Spooner, et al.,
Clinical Immunology and Immunopathology,
62 S11(1992)). There are two forms of TNF-&agr;, a type II membrane protein of relative molecular mass 26,000 (26 kD) and a soluble 17 kD form generated from the cell bound protein by specific proteolytic cleavage. The soluble 17 kD form of TNF-&agr; is released by the cell and is associated with the deleterious effects of TNF-&agr;. This form of TNF-&agr; is also capable of acting at sites distant from the site of synthesis. Thus, inhibitors of TACE prevent the formation of soluble TNF-&agr; and prevent the deleterious effects of the soluble factor.
Select compounds of the invention are potent inhibitors of aggrecanase, an enzyme important in the degradation of cartilage aggrecan. Aggrecanase is also believed to be an ADAM (Tortorella et al.,
Science,
284, 1664 (1999)). The loss of aggrecan from the cartilage matrix is an important factor in the progression of joint diseases such as osteoarthritis and rheumatoid arthritis and inhibition of aggrecanase is expected to slow or block the loss of cartilage in these diseases.
Other ADAMs that have shown expression in pathological situations include ADAM TS-1 (Kuno, et al.,
J. Biol. Chem.,
272, 556-562 (1997)), and ADAM's 10, 12 and 15 (Wu, et al.,
Biochem. Biophys. Res. Comm.,
235, 437-442, (1997)). As knowledge of the expression, physiological substrates and disease association of the ADAM's increases the full significance of the role of inhibition of this class of enzymes will be appreciated.
It is recognized that different combinations of MMP's and ADAM's are expressed in different pathological situations. As such, inhibitors with specific selectivities for individual ADAM's and/or MMP's may be preferred for individual diseases. For example, rheumatoid arthritis is an inflammatory joint disease characterized by excessive TNF levels and the loss of joint matrix constituents. In this case, a compound that inhibits TACE and aggrecanase as well as MMP's such as MMP-13 may be the preferred therapy. In contrast, in a less inflammatory joint disease such as osteoarthritis, compounds that inhibit matrix degrading MMP's such as MMP-13 but not TACE may be preferred.
The present inventors have also discovered that it is possible to identify inhibitors with differential metalloprotease activity. Specifically, for example, preferred compounds of the present invention selectively inhibit matrix metalloprotease-13 (MMP-13) preferentially over MMP-1.
The present inventors have also discovered that it is possible to identify inhibitors of formula I with differential metalloprotease and reprolysin activity (preferably MMP-13 inhibitory activity). One group of preferred inhibitors of formula I the inventors have been able to identify include those which selectively inhibit MMP-13 preferentially over MMP-1.
Matrix metalloproteinase and reprolysin inhibitors are well known in the literature. Specifically, European Patent Publication 606,046, published Jul. 13, 1994, refers to certain heterocyclic MMP inhibitors. U.S. Pat. No. 5,861,510, issued Jan. 19, 1999, refers to cyclic arylsulfonylamino hydroxamic acids that are useful as MMP inhibitors. PCT Publication WO 98/34918, published Aug. 13, 1998, refers to heterocyclic hydroxamic acids including certain dialkyl substituted compounds that are useful as MMP inhibitors. PCT publications WO 96/27583 and WO 98/07697, published Mar. 7, 1996 and Feb. 26, 1998, respectively, refer to arylsulfonyl hydroxamic acids. PCT publication WO 98/03516, published Jan. 29, 1998 refers to phosphinates with MMP activity. PCT publication 98/33768, published Aug. 6, 1998, refers to N-unsubstituted arylsulfonylamino hydroxamic acids. PCT Publication WO 98/08825 and WO 98 08815, both published Mar. 5, 1998, refer to certain heterocyclic MMP inhibitors. U.S. patent applications Nos. 60/096232 and 60/096256 both filed Aug. 12, 1998 also refer to heterocyclic hydroxamic acid MMP and TACE inhibitors. Each of the above referenced publications and applications is hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein X is S, O, >CH
2
or >NR
11
;
R
11
is hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl or a group of the formula
n is an integer from one to six;
R
12
and R
13
are independently selected from hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl or (C
2
-C
9
)heteroaryl or R
12
and R
13
may be taken together to form a ring of 3 to 8 atoms;
R
1
is selected from the group consisting of hydrogen, fluoro or (C
1
-C
6
)alkyl or R
1
may be taken together with anyone of R
2
through R
13
to form a ring;
R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are selected from the group consisting of hydrogen, hydroxy, (C
1
-C
6
)alkyl, amino, (C
1
-C
6
)alkylamino-, ((C
1
-C
6
)alkyl)
2
amino-, —CN, (C
2
-C
6
)alkenyl, (C
6
-C
10
)aryl(C
2
-C
6
)alkenyl, (C
2
-C
9
)heteroaryl(C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
6
-C
10
)aryl(C
2
-C
6
)alkynyl, (C
2
-C
9
)heteroaryl(C
2
-C
6
)alkynyl, (C
1
-C
6
)alkylamino, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkoxy, perfluoro(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, (C
6
-C
10
)arylamino, (C
6
-C
10
)arylthio, (C
6
-C
10
)aryloxy, (C
2
-C
9
)heteroarylamino, (C
2
-C
9
)heteroarylthio, (C
2
-C
9
)heteroaryloxy, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkyl(hydroxymethylene), piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
1
-C
6
)acylamino, (C
1
-C
6
)acylthio, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkoxy-(C═O)—, —CO
2
H, (C
1
-C
6
)alkyl-NH—(C═O)—, and &

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