Beta-amino acid nitrile derivatives as cathepsin K inhibitors

Details Beta-amino acid nitrile derivatives as cathepsin K inhibitors Beta-amino acid nitrile derivatives as cathepsin K inhibitors

2001-06-01

2002-10-08

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C558S430000, C558S432000, C549S469000, C549S454000, C514S465000, C514S601000, C514S613000, C514S659000

Reexamination Certificate

active

06462076

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel beta-amino acid nitrile derivatives, their manufacture and use as medicaments. In particular, the invention relates to novel beta-amino acid nitrile derivatives of formula (I)
wherein
R
1
represents hydrogen, aryl, —CO—R
a
or —SO
2
—R
b
, wherein
R
a
represents lower-alkyl, lower-alkoxy, cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, cycloalkyloxy, aryl, aryloxy, aryl-lower-alkyl, aryl-lower-alkoxy, aryloxy-lower-alkyl, aryl-S-lower-alkyl, aryl-lower-alkenyl, heteroaryl, heteroaryl-lower-alkyl, or heteroaryl-lower-alkoxy,
R
b
represents aryl, aryl-lower-alkyl, or heteroaryl
R
2
represents hydrogen or lower-alkyl
R
3
represents hydrogen or lower-alkyl
R
4
represents hydrogen or lower-alkyl.
R
5
represents hydrogen, lower-alkyl, cycloalkyl, or aryl,
n is 1 or 2,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
BACKGROUND OF THE INVENTION
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 the most potent mammalian elastase yet described. 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 leads to the suggestion 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 (Sukhova 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 (Otto et al.,
Chem. Rev
. 1997, 97, 133-171; Thompson 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, especially cysteine proteases, including cathepsins, especially cathepsin K.
SUMMARY OF THE INVENTION
The beta-amino acid nitrile derivatives of formula (I) 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 protease inhibitors such as cathepsin S, cathepsin L and cathepsin B is much weaker. Therefore the new compounds of formula (I) are useful for specifically inhibiting cathepsin K. They can accordingly be used for the treatment of disorders which are associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fuigax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. Accordingly, the present invention relates to a method for the prophylactic and/or therapeutic treatment of diseases which are associated with cystein proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease, which method comprises administering a compound of formula (I) to a human being or an animal. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant. Furthermore, the present invention relates to the use of such compounds for the preparation of medicaments for the treatment of disorders which are associated with cystein proteases. The present invention also relates to processes for the preparation of the compounds of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term “lower” is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term “alkyl” refers to a branched or straight chain monovalent s

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