Nitrile derivatives that inhibit cathepsin K

Details Nitrile derivatives that inhibit cathepsin K Nitrile derivatives that inhibit cathepsin K

2000-12-21

2003-03-11

Stockton, Laura L. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S200000, C548S201000, C548S215000, C548S468000, C548S518000, C548S526000, C548S537000, C548S538000

Reexamination Certificate

active

06531612

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The present invention relates to novel nitrile derivatives, their manufacture and use as medicaments. In particular, the invention relates to novel nitrile derivatives of formula (I)
2. Description
Cysteine proteases have been viewed as lysosomal mediators of terminal protein degradation. Several newly discovered members of this enzyme class, however, are regulated proteases with limited tissue expression, which implies specific roles in cellular physiology and thus would allow a specific targeting of these activities without interfering with the general lysosomal protein degragation. Development of inhibitors of specific cysteine proteases promises to provide new drugs for modifying immunity, osteoporosis, neurodegeneration, chronic inflammation, cancer and malaria (Brömme,
Drug News Perspect
1999, 12(2), 73-82; Chapman et al.,
Annu. Rev. Phys.
1997, 59, 63-88).
Cysteine proteases can be grouped into two superfamilies: the family of enzymes related to interleukin 1&bgr; converting enzyme (ICE), and the papain superfamily of cysteine proteases. Presently there are at least 12 human proteases of the papain family from which sequences have been obtained (cathepsin B, L, H, S, O, K, C, W, F, V(L2), Z(X) and bleomycin hydrolase). Cathepsin K was first discovered as a cDNA prominent in rabbit osteoclasts and referred to as OC-2 (Tezuka et al.,
J. Biol. Chem.
1994, 269, 1106-1109). Recent observations indicate that cathepsin K is a very potent mammalian elastase. Cathepsin K, as well as cathepsins S and L, are also potent collagenases and gelatinases. Macrophages appear capable of mobilizing the active proteases within endosomal and/or lysosomal compartments to the cell surface under special circumstances. In this case, the cell surface/substrate interface becomes a compartment from which endogenous inhibitors are excluded and can be viewed as a physiological extension of the lysosome. This type of physiology is an innate trait of osteoclasts, a bone macrophage, and may also be exploited by other macrophages or cells in the context of inflammation. The abundance of cathepsin K in osteoclasts suggests that cathepsin K plays an important role in bone resorption. Studies revealed that cathepsin K is the predominant cysteine protease in osteoclasts and is specifically expressed in human osteoclasts. A correlation between inhibition of cysteine protease activity and bone resorption has been reported (Lerner et al.,
J. Bone Min. Res.
1992, 7, 433; Everts et al.,
J. Cell. Physiol.
1992, 150, 221). Cathepsin K has been detected in synovial fibroblasts of RA patients, as well as in mouse hypertrophic chondrocytes (Hummel et al.,
J. Rheumatol.
1998, 25(10), 1887-1894.). Both results indicate a direct role of cathepsin K in cartilage erosion. P. Libby (Libby et al.,
J. Clin. Invest.
1998, 102 (3), 576-583) reported that normal arteries contain little or no cathepsin K or S whereas macrophages in atheroma contained abundant immunoreactive cathepsins K and S. Most of the elastolytic activity of tissue extracts associated with human atheroma compared to non-atherosclerotic arteries could be inhibited with E64, a non-selective cysteine protease inhibitor.
Tumor progression and metastasis are characterized by the invasion of tumors into adjacent tissues as well as by the dissociation of cancer cells from primary tumors and the infiltration of metastatic cells into organs. These processes are associated with the degragation of extracellular matrix proteins and thus require proteolytic activity. Cathepsin K has been identified in primary breast tumors, as well as in breast tumor-derived bone metastasis (Littlewood-Evans et al.,
Cancer Res.
1997, 57, 5386-5390).
Different classes of compounds, such as aldehydes, &agr;-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts, epoxy succinyl compounds, vinyl sulfones, aminoketones, and hydrazides have been identified as cysteine protease inhibitors (Schirmeister et al.,
Chem. Rev.
1997, 97, 133-171; Veber et al.,
Proc. Natl. Acad. Sci. USA
1997, 94, 14249-14254). The shortcomings these compounds suffer from include lack of selectivity, poor solubility, rapid plasma clearance and cytotoxicity. A need therefore exists for novel inhibitors useful in treating diseases caused by pathological levels of proteases, such as cysteine proteases, including cathepsins, and especially cathepsin K. Therefore, a need exists for compounds that are selective inhibitors of cathepsin K.
SUMMARY OF THE INVENTION
The subject invention provides compounds of the formula:
wherein
Y is O, S, or CH—R
2
;
R
1
and R
3
are each independently hydrogen or methyl and R
2
is hydrogen, or R
1
is hydrogen and R
2
and R
3
together are —CH
2
— thus forming a cyclopropyl ring;
R
4
, R
5
are each independently hydrogen or lower-alkyl;
R
6
is cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryl-lower-alkyl;
R
7
is —CO—R
a
, —SO
2
—R
b
or —CS—NH—R
c
, wherein
R
a
is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or R
d
—NH,
R
b
is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,
R
c
is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,
R
d
is aryl-lower-alkyl;
or a pharmaceutically acceptable salt or ester thereof.
A preferred group of compounds are of the formula:
wherein Y, R
1
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined above.
Another favored group of compounds are of the formula:
wherein
R
6′
is aryl;
R
7′
is —CO—R
a′
or —CS—NH—R
c′
, wherein
R
a′
is cycloalkyl-lower-alkyl, aryl-lower-alkyl, aryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, and
R
c′
is heteroaryl-lower-alkyl;
or a pharmaceutically acceptable salt or ester thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The present invention also relates to processes for the preparation of the compounds of formula (I).
wherein
Y represents O, S, or CH—R
2
,
R
1
and R
3
independently from each other represent hydrogen or methyl and R
2
represents hydrogen, or R
1
represents hydrogen and R
2
and R
3
together are —CH
2
— to form a cyclopropyl ring,
R
4
, R
5
independently from each other represent hydrogen or lower-alkyl,
R
6
represents cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryl-lower-alkyl,
R
7
represents —CO—R
a
, —SO
2
—R
b
or —CS—NH—R
c
, wherein
R
a
represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or R
d
—NH,
R
b
represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,
R
c
represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,
R
d
represents aryl-lower-alkyl,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
The nitriles derivatives of the present invention have an inhibitory activity on cysteine proteases, more paticulary on cysteine proteases of the papain superfamily, even more paticularly on cysteine proteases of the cathepsin family, most particularly on cathepsin K. It was surprisingly found, that this inhibiting effect on cathepsin K is selective with respect to other cathepsins. While compounds of formula (I) very efficiently inhibit cathepsin K, the inhibition of other p

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