NITRILE DERIVATIVES AS CATHEPSIN K INHIBITORS

Abstract: The present invention relates to compounds of formula (I), wherein R<1> to R<7> and Y are as defined in the description and claims and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. The compounds are useful for the 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.

Description: Nitrile Derivatives as Cat epsin K inhibitors The present invention relates to novel nitrile derivatives, their manufacture and use as medicaments. In particular, the invention relates to novel nitrile derivatives of general formula (I) wherein Y represents O, S, or CH-R 2 , R and R 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 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 , 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 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 represents aryl-lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. 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 (Brόmme, 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 lβ 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., /. 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., /. Bone Min. Res. 1992, 7, 433; Everts et al., /. 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., /. Rheumatol. 1998, 25(10), 1887-1894.). Both results indicate a direct role of cathepsin K in cartilage erosion. P. Libby (Libby et al., /. 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, α-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, especially cysteine proteases, including cathepsins, especially cathepsin K. 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 general 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 general formula (I) are usefull 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 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. 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). 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 saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms. The term "lower-alkyl" refers to a branched or straight chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. The term "cycloalkyl" refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred and chlorine and bromine being more preferred. The term "alkoxy" refers to the group R'-O-, wherein R' is an alkyl. The term "lower- alkoxy" refers to the group R'-O-, wherein R' is a lower-alkyl. The term "aryl" relates to the phenyl or naphthyl group which can optionally be mono- or multiply-substituted by alkyl, halogen, hydroxy, alkoxy, -O-(CH 2 ) 1-7 -O-, aryloxy, or aryl-alkoxy. Substitution in meta- or in meta- and para-position is preferred. Preferred substituents are lower-alkyl, fluorine, chlorine, bromine, lower-alkoxy, methylenedioxy, and aryl-lower- alkoxy. More preferred substituents are chlorine, bromine, methoxy, and benzyloxy. Another preferred substituted phenyl group is the benzo [ 1,3] dioxol-5-yl group. The term "heteroaryl" refers to an aromatic 5- or 6-membered ring which can contain 1 or 2 atoms selected from nitrogen, oxygen or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, with furyl and thienyl being preferred. The term "heteroaryl" further refers to bicyclic heteroaromatic ring systems such as e.g. indolyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term "aryl". An aryl-lower-alkyl group may optionally comprise a second aryl group, e.g. a phenyl group, at the lower-alkyl moiety. The term "aryloxy" relates to a group aryl-O-. The term "arylthio" relates to a group aryl-S-. The term "pharmaceutically acceptable salts" embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. The term "pharmaceutically acceptable esters" embraces esters of the compounds of formula (1), in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. In detail, the present invention refers to 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 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 represents aryl-lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. In a preferred embodiment, the present invention relates to compounds as described above, wherein 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, or R d -NH, R 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 represents aryl-lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. The compounds of formula (I) have at least 2 asymmetric carbon atoms and can exist in the form of optically pure enantiomers or as racemates. The invention embraces all of these forms. Preferred compounds of formula (I) are compounds of formula (la) which are derived from the corresponding S-proline derivatives. wherein Y, R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. Compounds of formula (I) in which Y represents CH-R 2 are preferred, with those wherein R 2 is hydrogen being particularly preferred. Compounds of formula (I) in which R 1 , R 3 , R 4 and/or R 5 represent hydrogen are also preferred. Another preferred embodiement refers to compounds of formula (I) in which R is phenyl, furanyl, thiophenyl, or pyrrolyl, optionally substituted with alkyl, halogen, hydroxy, alkoxy, -O- (CH 2 )ι -7 -O-, aryloxy, or aryl-alkoxy. Further, compounds of general formula (I) in which R 6 represents phenyl, phenyl substituted in meta-position, phenyl substituted in meta- and in para-position or benzo[l,3]dioxol-5-yl are also preferred with 3 -methoxy- phenyl, 3,4- dimethoxy-phenyl, 4-benzyloxy-3-methoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, or benzo[l,3]dioxol-5-yl being especially preferred. Compounds of formula (I) in which R 7 represents -CO-R a and R a is as defined above are preferred. Compounds of formula (I) in which R 7 represents -CO-R a and R a is benzyloxy, cyclopentyl-ethylene, or benzyloxy-methylene are especially preferred. Further, compounds of formula (I) in which R 7 represents -CO-R a and R a is 3-bromobenzyl, 4- bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, or 2-methyl-phenyloxymethylene are also especially preferred. A further preferred embodiement are compounds of formula (I) in which R 7 represents -CS-NH-R C and R c is as defined above. Compounds of formula (I) in which R 7 represents -CS-NH-R 0 and R c is benzyl, 3-fluorobenzyl, or furan-2-yl-methylene are especially preferred. Another preferred embodiement relates to compounds of formula (I), wherein R 7 represents -SO 2 -R b and R b is as defined above, with those in which R b is naphthyl being particularly preferred. Preferred compounds of formula 1 are (lRS,2RS,5SR)-2-{[(RS)- or -[(SR)-Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}- 3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester, (S)-2-[(R)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-l-carboxylic acid benzyl ester, (S)-2-[(S)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-l-carboxylic acid benzyl ester, (S)-l-(3-methyl-butyιγl)-pyrrolidine-2-carboxylic acid (R)- and (S)-(cyano-phenyl- methyl)-amide, (S)-2-{(S)- and (R)-[Cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-{(S)- and (R)-[Cyano-(3-hydroxy-phenyl)-met_hyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-[(R)- and (S)-(Cyano-cyclopropyl-methyl)-carbamoyl]-pyrrolidine-l-carboxylic acid benzyl ester, (S)-2-[(R)- and (S)-(Benzo[l,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-l- carboxylic acidbenzyl ester, (R)-4-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-thiazolidine-3- carboxylic acid benzyl ester, (2S,3R)-2-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl- pyrrolidine- 1 -carboxylic acid benzyl ester, (S)-l-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[l,3]dioxol- 5-yl-cyano-methyl)-amide, (S)-l-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[(Furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylic acid [(R)- and (S)- cyano-(3,4-dimethoxy-phenyl)-methyl]-amide, (S)-l-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro- phenyl)-cyano-methyl] -amide, (S)-l-(3-Fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3- chloro-phenyl)-cyano-methyl] -amide, (S)-2-((R)- and (S)-l-Cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester, (R)-4-{(R)- and (S)-[(4-Chloro-phenyl)-cyano-mefhyl]-carbamoyl}-thiazolidine-3- carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-[(R)- and (S)-(Cyano-o-tolyl-methyl)-carbamoyl]-pyrrolidine-l-carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[Cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[Cyano-(3-fluoro-phenyl)-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-[(R)- and (S)-(Cyano-m-tolyl-methyl)-carbamoyl]-pyrrolidine-l-carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[(4-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[Cyano-(3,4,5-trimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine- 1 -carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[Cyano-(3-phenoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[(4-Benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}- pyrrolidine-1 -carboxylic acid benzyl ester, (S)-l-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4- dimethoxy- phenyl) -methyl] -amide, (S)-l-(Naphthalene-l-sulfonyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)- benzo[ 1,3] dioxol-5-yl-cyano-methyl)-amide, (S)-l-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)- benzo[l,3]dioxol-5-yl-cyano-methyl)-amide, (S)-l-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[l,3]dioxol-5-yl- cyano-methyl) -amide, (S)-l-(5-Dimethylamino-naphthalene-l-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide, (S)-l-(Naphthalene-l-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4- dimethoxy-phenyl) -methyl] -amide, (S)-l-(Naphthalene-2-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-(Naphthalene-l-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4- dimethoxy- phenyl) -methyl] -amide, (S)-l-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-(Naphthalene-l-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro- phenyl)-cyano-methyl] -amide, (S)-l-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro- phenyl) -cyano-methyl] -amide, (S)-l-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano- methyl] -amide, (S)-l-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)- cyano-methyl] -amide, (S)-Pyrrolidine-l,2-dicarboxylic acid 2-{[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]- amide} l-[(R)-(l-naphthalen-l-yl-ethyl)-amide], (S)-l-(Naphthalene-l-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-bromo- phenyl)-cyano-methyl] -amide, (S)-l-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-bromo-phenyl)-cyano- methyl] -amide, (S)-l-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-bromo-phenyl)- cyano-methyl]- amide, (S)-Pyrrolidine-l,2-dicarboxylic acid 2-{ [(R)- and (S)-(3-bromo-phenyl)-cyano-methyl]- amide} l-[(R)-(l-naphthalen-l-yl-ethyl)-amide], (S)-l-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3- methoxy-phenyl) -methyl] -amide, (S)-l-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3-methoxy- phenyl) -methyl] -amide, (S)-l-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3-methoxy- phenyl)-methyl] -amide, 2-((R)- and (S)-l-Cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-l-(2-Phenyl-ethenesulfonyl)-pvrrolidine-2-carboxylic acid ((R)- and (S)- benzo[l,3]dioxol-5-yl-cyano-methyl)-amide, (S)-Pyrrolidine-l,2-dicarboxylic acid 2-{(R)- and (S)-[cyano-(3,4-dimethoxy-phenyl)- methyl] -amide} l-[(S)-(l-naphthalen-l-yl-ethyl)-amide], (S)-l-(2-Phenyl-ethenesulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4- dimethoxy-phenyl)-methyl] -amide, and pharmaceutically acceptable esters thereof. Other preferred compounds of formula 1 are (S)-l-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol- 5-yl-l-cyano-methyl)-amide, (S)-l-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)- 1 -cyano-methyl] -amide, (S)-l-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol- 5-yl-l-cyano-methyl)-amide, (S)-l-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-(2-o-Tolyloxy-et_hanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl-l- cyano-methyl) -amide, (S)-l-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy- phenyl) -methyl] -amide, (S)-l-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol- 5-yl-l-cyano-methyl)-amide, (S)-l-[2-(4-Bromo-phenyl)-ethanoyl]-pyτrolidine-2-carboxylic acid [l-(3-chloro- phenyl)- 1 -cyano-methyl] -amide, (S)-l-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5- yl- l-cyano-methyl)-amide, ' (S)-l-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)- 1 -cyano-methyl] -amide, (S)-l-(4-Phenyl-butanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)-l-cyano-methyl]-amide, (S)-l-(2-Benzo[ 1,3] dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl) - 1 -cyano-methyl] -amide, (S)-l-(2-Phenoxy-ethanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4-dimethoxy- phenyl) -methyl] -amide, (S)-l-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l- cyano-methyl] -amide, (S)-l-(2-Benzo[l,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid (1- benzo[l,3]dioxol-5-yl-l-cyano-methyl)-amide, (S)-l-(2-Phenoxy-ethanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l-cyano- methyl] -amide, (S)-l-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l-cyano- methyl] -amide, (S)-l-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy- phenyl) -methyl] -amide, (S)-l-(2-Benzo[l,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3 > 4- dimethoxy-phenyl)-methyl] -amide, (S)-l-(3-Phenyl-propanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid (1- benzo[l,3]dioxol-5-yl-l-cyano-methyl)-amide, (S)-l-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl) -1 -cyano-methyl] -amide, (S)-l-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l- [4-(3,4-Dimethoxy-phenyl)-butanoyl] -pyrrolidine-2-carboxylic acid [ 1-cyano- 1- (3,4-dimethoxy-phenyl)-methyl]-amide, (S)-l-(3-lH-Indol-3-yl-propanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-(4-Phenyl-butanoyl)-pvrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl-l- cyano-methyl) -amide, (S)-l-(2-Phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l- cyano-methyl] -amide, (S)-l-(4-Cyclohexyl-butanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-(3-Cyclohexyl-propanoyl)-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl- l-cyano-methyl)-amide, (S)-l-[4-(4-Nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl) -methyl] -amide, (S)-l-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)- 1 -cyano-methyl] -amide, (S)-l-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl) -1 -cyano-methyl] -amide, (S)-l-[4-(4-Nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)- 1 -cyano-methyl] -amide, (S)-l-(l-Naphthalen-l-yl-methanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)-l-cyano-methyl] -amide, (S)-l-[2-(4-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)-l-cyano-methyl] -amide, (S)-l-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1- (3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1- (3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-(4-Cydohexyl-butanoyl)-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl-l- cyano-methyl)-amide, (S)-l-{l-[l-(4-Chloro-phenyl)-cyclopentyl]-methanoyl}-pyrrolidine-2-carboxylic acid [1- cyano-l-(3,4-dimethoxy-phenyl)-methyl]-amide, (S)-l-((Z)-3-Phenyl-aUanoyl)-pyrrolidine-2-carboxylic acid [ 1-cyano- l-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-(2-Phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid [ 1-cyano- 1- (3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)-l-cyano-methyl]-amide, (S)-l-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1 -(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-(4-Phenyl-butanoyl)-pvrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l-cyano- methyl] -amide, (S)-l-[2-(3,4,5-Trimet_hoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3- chloro-phenyl)-l -cyano-methyl] -amide, (S)-l-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid [ l-cyano-l-(3,4-dimethoxy- phenyl)-methyl] -amide, (S)-l-(l-Cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid (1- benzo [ 1 ,3] dioxol-5-yl- 1 -cyano-methyl)-amide, (S)-l-[2-(4-Chloro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)- 1 -cyano-methyl] -amide, (S)-l-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l-cyano- methyl] -amide, (S)-l-(3,3-Diphenyl-propanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)- 1- [2-(3-Methoxy-phenoxy)-ethanoyl] -pyrrolidine-2-carboxylic acid ( 1- benzo [ 1,3] dioxol-5-yl- l-cyano-methyl)-amide, (S)-l-[2-(4-Ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid ( 1 -benzo [1,3] dioxol- 5-yl- l-cyano-methyl)-amide, (S)-l-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l -cyano- methyl] -amide, (S)-l-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl-l- cyano-methyl)-amide, (S)-l-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid (1- benzo[l,3]dioxol-5-yl-l-cyano-methyl)-amide, (S)-l-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid (1- benzo[l,3]dioxol-5-yl-l-cyano-methyl)-amide, (S)-l-(3-Cyclohexyl-propanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l- cyano-methyl] -amide, (S)-l-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)- 1 -cyano-methyl] -amide, (S)-l-[3-(2,3,4-Trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylic acid [l-(3- chloro-phenyl)- 1 -cyano-methyl] -amide, (S)-l-(2-Benzyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l- cyano-methyl] -amide, (S)-l-(l-Cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l- cyano-methyl] -amide, (S)-l-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)-l-cyano-methyl]-amide, (S)-l-(l-Cyclohexyl-methanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1- (3,4- dimethoxy-phenyl) -methyl] -amide, (S)-l-[3-(3,4,5-Trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylic acid [l-(3- chloro-phenyl)- 1-cyano-methyl] -amide, (S)-l-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3-phenoxy- phenyl) -methyl] -amide, (S)-l-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl-l- cyano-methyl)-amide, (S)-l-(3-Cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid [l-(3-chloro-phenyl)-l- cyano-methyl] -amide, (S)-l-(3-Cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl- l-cyano-methyl)-amide, (S)-l-(3-Fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl) -methyl] -amide, and (S) - 1 - [2- (2,4-Dimethyl-phenoxy)-ethanoyl] -pyrrolidine-2-carboxylic acid [ 1 -cyano- 1 - (3,4-dimethoxy-phenyl) -methyl] -amide. Especially preferred compounds of general formula (I) are (S)-2-[(R)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-l-carboxylic acid benzyl ester, (2S,3R)-2-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl- pyrrolidine-1 -carboxylic acid benzyl ester, (S)-2-[(R)- and (S)-(Benzo[l,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-l- carboxylic acidbenzyl ester, (S)-2-{(R)- and (S)-[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-l-Benzyloxyacetyl-pyτrolidine-2-carboxylic acid ((R)- and (S)-benzo[l,3]dioxol-5-yl- cyano-methyl)-amide, (S)-l-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)- benzo[l,3]dioxol-5-yl-cyano-methyl)-amide, (S)-2-{(R)- and (S)-[(4-Benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}- pyrrolidine-1 -carboxylic acid benzyl ester, and (S)-l-[(Furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylic acid [(R)- and (S)- cyano- (3,4-dimethoxy-phenyl)-methyl] -amide. Other especially preferred compounds of general formula (I) are (S)-l-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid ( 1 -benzo [1,3] dioxol- 5-yl- 1 -cyano-methyl)-amide, (S)-l-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl) -methyl] -amide, (S)- 1- [2-(4-Chloro-phenyl)-ethanoyl] -pyrrolidine-2-carboxylic acid [ l-(3-chloro- phenyl)-l-cyano-methyl] -amide, (S)-l-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol- 5-yl-l-cyano-methyl)-amide, (S)-l-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1-(3,4- dimethoxy-phenyl) -methyl] -amide, (S)-l-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, and (S)-l-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol- 5-yl- l-cyano-methyl)-amide. Other especially preferred compounds of general formula (I) are (S)-l-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [ 1-cyano- l-(3,4-dimethoxy- phenyl) -methyl] -amide, and (S)-l-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol-5-yl-l- cyano-methyl)-amide. The invention also relates to compounds of formula (IV) wherein Y, R 1 , R , R 4 , R 5 and R have the same significances as given for compounds of formula (I). The invention also relates to the use of compounds as defined above for the treatment or prophylaxis of diseases 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 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. In a preferred embodiement, the invention relates to the use of compounds as defined above for the treatment or prophylaxis of osteoporosis, instable angina pectoris or plaque rupture. Further, the invention relates to compounds as defined above for use as therapeutic active substances, in particular in context with diseases 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 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. In a preferred embodiement, the invention relates to compounds as defined above for use as therapeutic active substances in context with osteoporosis, instable angina pectoris or plaque rupture. The invention also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant, in particular for use in context with diseases 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 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. In a preferred embodiement, the invention relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant for use in context with osteoporosis, instable angina pectoris or plaque rupture. A further embodiment of the present invention refers to the use of compounds as defined above for the preparation of medicaments for the treatment or prophylaxis 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. In a preferred embodiement, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment or prophylaxis of osteoporosis, instable angina pectoris or plaque rupture. Such medicaments comprise a compound as defined above. An additional embodiment of the invention relates to a method for the prophylactic and/or therapeutic treatment of disorders in which cathepsin K plays a significant pathological role, 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 as defined above to a human being or an animal. A preferred embodiement of the invention relates to a method for the prophylactic and/or therapeutic treatment of osteoporosis, instable angina pectoris or plaque rupture, which method comprises administering a compound as defined above to a human being or an animal. The invention further relates to a process for the manufacture of compounds of general formula (I) which process comprises a) reacting a compound of formula (II) with a compound of formula (III) wherein Y, R 1 , R 3 , R 5 , R 6 and R 7 have the significances given above, or b) reacting a compound of formula (IV) with a compound of formula (V), (VI), (VII) or (VIII) Ft- -CI R— S-CI R— N = C = S R u - N = C = 0 II o (V) (VI) (VII) (VIII) wherein Y, R 1 , R 3 , R 4 , R 5 , R 6 , R a , R b , R c and R d have the significances given above. The invention also relates to a process as described above, which process comprises the preparation of pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. The formation of the esters and/or salts can be carried out at different stages of the process, e.g. with the compound of formula (I) or with the corresponding starting materials. The reaction of a compound of formula (II) with a compound of formula (III) can be carried out by methods known to the person skilled in the art. The reaction can conveniently be carried out by dissolving compound (II), compound (III), TPTU (O-1.2- Dihydro-2-oxo-l-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate) and Hϋnigsbase (N-Ethyldiisopropylamine) in MeCN and stirring the mixture at room temperature for 6 to 16 hours. The reaction mixture can be concentrated and the product can be obtained by methods known to the person skilled in the art, e.g. by extraction and column chromatography. Alternatively, a compound of formula (II) can be dissolved in CH 2 C1 2 and reacted for 6 to 16 hours at room temperature with a compound of formula (III) in the presence of N-methylmorpholin, HOBT and EDCI. The product can be obtained by methods known per se, e.g. by extraction and HPLC. The reaction of a compound of formula (IV) with a compound of formula (V), (VI), (VII) or (VIII) is conveniently carried out by preparing a solution of compound (IV) in CH 2 C1 2 and adding a solution of compound (V), (VI) or (VII) in CH 2 C1 2 . To this mixture, Triethylamin is added and after shaking 6 to 16 hours at room temperature formic acid is added. The product can be isolated and purified by methods known per se, e.g. by evaporation of the solvent and HPLC. In order to prepare pharmaceutically acceptable salts and/or pharmaceutically acceptable esters of compounds of formula (I), it is possible to prepare the corresponding esters and/or salts starting from the compounds of formula (I). It is also possible, to form the esters and/or salts at an earlier stage, e.g. to form the corresponding salts an/or esters of the corresponding starting materials. The methods to prepare pharmaceutically acceptable salts and/or pharmaceutically acceptable esters as defined before are known in the art. Compounds of formula (II) are prepared by methods already known to the person skilled in the art. Conveniently, the corresponding amino acid is converted to the corresponding methyl ester by reacting the amino acid in MeOH in the presence of thionylchloride. The resulting intermediate product is isolated by methods known per se, e.g. by extraction and evaporation of the solvent. The intermediate product is linked to the desired substituent R 7 analogously to the method described above. The methyl ester is then saponified to yield a compound of formula (II) by dissolving the methyl ester and 2 N NaOH in MeOH and stirring the mixture 5 to 16 hours at room temperature. The resulting compound (II) is isolated by methods known per se, e.g. by extraction and evaporation of the solvent. Compounds of formula (III) can conveniently be obtained by adding a solution of the corresponding aldehyde in CH 2 C1 2 to a solution of NH 4 C1 and NaCN in H O and MeOH at 0°C. The mixture is stirred and allowed to warm to room temperature. After addition of NH 3 solution and completion of the reaction the resulting compound of formula (III) is isolated and purified by methods known to the person skilled in the art, e.g. by extraction. The corresponding hydrochlorid can be prepared by methods known per se. Chiral compounds of formula (III) can conveniently be obtained by adding ammonia to a mixed anhydride (prepared from a suitable t-BOC protected amino acid and isobutylchloroformate) at -10°C. The reaction mixture is stirred at room temperature for 1-5 h. After completion of the reaction the resulting t-BOC protected amino acid amide is isolated and purified by methods known to the person skilled in the art, e.g. by extraction. The Boc protected amino acid amide and triethylamine are dissolved in THF and trifluoroacetic acid anhydride at 0°C. The mixture is stirred for 1-5 h at 0°C, then at room temperature for 1-2 h. After isolation and purification of the resulting intermediate product, e.g. by evaporation of the solvent and flash chromatography, the t-BOC protective group can be cleaved off with HC1 in acetic acid to yield the desired compound of formula (III). Compounds of formula (IV) can conveniently be obtained by reacting the corresponding t-BOC protected amino acid with a compound of formula (III) analogous to the method described above. After isolation and purification of the resulting intermediate product, e.g. by evaporation of the solvent and flash chromatography, the t-BOC protective group can be cleaved off with trifluoro- acetic acid to yield the desired compound of formula (IV) with trifluoro-acetic acid. Compounds of formula (V), (VI), (VII) and (VIII) are either commercially available or can be obtained by methods known in the art. The present invention relates to all compounds of formula (I), as prepared by one of the processes described above. The inhibitory activity of the compounds against cathepsin K, S, L and B was tested at room temperature in 96-wells opaque white polystyrene plates (Costar). The cathepsin K inhibitory activity was tested as follows: 5 μl of an inhibitor diluted in 5mM sodium phosphate, NaCl 15mM pH 7.4 containing 1% DMSO (final concentrations: 10-0.0001 μM) were preincubated for lOmin with 35 μl of human recombinant cathepsin K (final concentration: 1 nM) diluted in assay buffer (100 mM sodium acetate pH 5.5 containing 5mM EDTA and 20mM cysteine). After addition of 10 μl of the fluorogenic substrate Z-Leu-Arg-MCA diluted in assay buffer (final concentration: 5 μM), increase of fluorescence (excitation at 390 nm and emission at 460 nm) was measured for 7.5 min every 45 sec. The initial velocity (RFU/min) was derived from the linear fit of the 11 reading points. The cathepsin B inhibitory activity was assayed under the same conditions as the cathepsin K inhibitory activity using human liver cathepsin B (Calbiochem) at a final concentration of 1 nM. The cathepsin L inhibitory activity was assayed under the same conditions as the cathepsin K inhibitory activity using human liver cathepsin L (Calbiochem) at a final concentration of 3 nM. Cathepsin S inhibitory activity was assayed analogeously to the cathepsin K inhibitory activity, except that the buffer was 100 mM potassium phosphate, 5mM EDTA, 5mM DTT (freshly added), 0.01% Triton X-100, pH 6.5 and the fluorogenic substrate was Z-Val-Val-Arg-MCA (Bachem) (final concentration: 20 μM). Human recombinant cathepsin S (Wiederanders et al., Eur. J. Biochem. 1997, 250, 745-750) was used at a final concentration of 0.5 nM. The results are given as IC 50 values which denote the concentration of the inhibitor at which the enzymatic activity is inhibited by 50%. The IC 50 values are determined from a linear regression curve from a logit-log plot. Compound no. Cathepsin K Cathepsin S Cathepsin L Cathepsin B (Example 10) IC 50 (μMol/1) IC 50 (μMol/1) IC 50 (μMol/1) IC 50 (μMol/1) 2 0.046 >10 >10 2.8 11 0.068 >10 >10 0.6 9 0.014 >10 >10 9.5 22 0.016 >10 >10 >10 20 0.026 >10 >10 >10 33 0.027 >10 >10 2.0 32 0.037 >10 >10 0.6 28 0.045 >10 >10 >10 14 0.064 >10 >10 6.2 Compound no. (Example 11) 1 0.015 >10 7.0 2.0 2 0.018 >10 >10 0.6 10 0.026 >10 >10 4.0 It will be appreciated that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. As mentioned earlier, medicaments containing a compound of formula (I) are also an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula (I) and, if desired, one or more other therapeutically valuable substances into a galenical administration form. The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions. Furthermore, administration can be carried out sublingually or as opthalmological preparations or as an aerosol, for example in the form of a spray. For the preparation of tablets, coated tablets, dragέes or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragees or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules. For the preparation of solutions and syrups, excipients which maybe used include for example water, polyols, saccharose, invert sugar and glucose. For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils. For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols. The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they may also contain other therapeutically valuable agents. It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic. Intravenous, intramuscular or oral administration is a preferred form of use. The dosages in which the compounds of formula (I) are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, daily dosages of about 1 mg - 1000 mg, preferably 5 mg - 500 mg, per day come into consideration. The following Examples shall illustrate preferred embodiments of the present invention but are not intended to limit the scope of the invention. Other compounds of formula (I) can be prepared according to the general methods described above or in analogy to the examples. EXAMPLE 1 Preparation of (R,S -α-amino-3-bromophenylacetonitrile NH 4 C1 (2.14 g, 40 mmol) and NaCN (1.96 g, 40 mmol) are dissolved in 20 ml H 2 O and 20 ml MeOH and cooled to 0° C. A solution of 3-bromobenzaldehyde (4.68 ml, 40 mmol) in 15 ml CH 2 C1 2 and 15 MeOH is added dropwise over 30 min. The mixture is allowed to warm to RT and stirred for 0.5 h. NH 3 solution (25 % in H 2 O) (6 ml, 80 mmol) is added. The mixture is stirred for 16 h at RT. The organic solvents are evaporated and H 2 O is added (5 to 10 ml). The water layer is extracted with CH 2 C1 2 (2 x 50 ml) and the latter is washed with H 2 O (20 ml) and brine (20 ml), dried over Na 2 SO and evaporated. The oily residue is dissolved in 75 ml ether. While stirring vigorously dropwise a 4 M HC1 solution in dioxane is added. A solid precipitates and is filtered and dried. To recrystallize the solid is dissolved in as little MeOH as possible (do not heat!). Now, while stirring, ether is added until precipitation has finished. The precipitate is filtered and dried in vacuo. Yield: 40% MS: 229 (MNH4+) EXAMPLE 2 Preparation of chiral amino nitriles: (S)-(Carbamoyl-phenyl-methyO-carbamic acid tert-butyl ester 25 % aqueous ammonia (63mmol) is added to the mixed anhydride (prepared from 8 mmol (S)-BOC-phenyl glycine and 8 mmol iso-butylchloroformate) at -10 °C. The mixture is stirred for 1 h at this temperature, then over night at RT and concentrated. The residue is dissolved in 20 ml ethyl acetate, washed with saturated sodium bicarbonate, 2N HCL, brine dried over sodium sulfate and evaporated. Yield: 97 %, MS: 251 (MH+) (R)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester is prepared analogously to (S)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester Preparation of (S)-(Cyano-phenyl-methyD-carbamic acid tert-butyl ester (S)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester (1.93 g, 7.7 mmol) and triethylamine (2.4 ml, 17 mmol) are dissolved in THF (40 ml) and trifluoroacetic acid anhydride (1.2 ml, 8.5 mmol) is added at 0°C. The mixture is stirred at 0°C for 3h and evaporated. Dichloromethane and water are added. The organic phase is separated, dried over sodium sulfate and evaporated. The crude product is purified by chromatography (silica gel, ethyl acetate/hexane=8:2, R =0.3). Yield: 86 %, MS: 250 (MH+ 18) (R)-(Cyano-phenyl-methyl)-carbamic acid tert-butyl ester is prepared analogously to (S)- (Cyano-phenyl-methyl)-carbamic acid tert-butyl ester Preparation of (S)-Amino-phenyl-acetonitrile hydrochloride (S)-(Cyano-phenyl-methyl)-carbamic acid tert-butyl ester (1.5 g, 6.6 mmol) is dissolved in 30 ml ethyl acetate and 4N HCl in ethyl acetate (33 ml) is added at 0°C. The mixture is stirred at RT for 3 h and evaporated. The product is washed with dietyl ether and dried in vacuo, (silica gel, ethyl acetate, R f =0.7). Yield: 84 %, MS: 151 (MH+18) (R)-Amino-phenyl-acetonitrile hydrochloride is prepared analogously to (S)-Amino- phenyl- acetonitrile hydrochloride. EXAMPLE 3 Preparation of (IRS, 2RS, 5RS)-3-Aza-bicyclor3.1.0]hexane-2-carboxylic acid methyl ester) Trans-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (0.50 g, 3.54 mmol) is suspended in 15 ml MeOH (under argon) and cooled to 0° C. Thionylchloride (0.28 ml, 3.90 mmol) is added slowly over 10 min. The reaction mixture is refluxed for 2.5 h. The solvent is evaporated leaving an oily residue which is dissolved in CH 2 C1 2 (20 ml). The organic layer is washed with saturated Na 2 CO 3 (10 ml) and the H 2 O layer is extracted again with CH 2 C1 2 (3 x 20 ml). The collected organic layers are washed with brine (30 ml), dried over Na 2 SO 4 and evaporated, leaving a yellow oil. Yield: 98 %. Preparation of trans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid methyl ester The (IRS, 2RS, 5RS)-3-Aza-bicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (0.55 g, 3.1 mmol) is dissolved in 20 ml CH 2 C1 2 . Benzoylchloride (0.43 ml, 3.7 mmol) and N- methylmorpholine (NMM, 0.75 ml, 6.8 mmol) are added. 4-Dimethylaminopyridine (DMAP, 38 mg, 0.31 mmol) is added. The reaction mixture is stirred at RT for 16 h. The solvent is evaporated leaving an slightly yellow oil which is purified by column chromatography (silica, R f =0.5, ethyl acetate/hexane 1:1). Yield 52 %, MS: 246 (MH+) Preparation of trans-3-Benzoyl-3-aza-bicyclo [3.1.0] hexane-2-carboxylic acid Trans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (0.392 g, 1.6 mmol) and 2 N NaOH (1.6 ml, 3.2 mmol) are dissolved in 20 ml MeOH. The mixture is stirred at RT for 6 h. The solution is concentrated, the residue is dissolved in ethyl acetate (30 ml) and extracted with H 2 O (2 x 15 ml). The collected H 2 O layers are neutralized with 2 N HCl and extracted with ethyl acetate (2 x 20 ml). The collected ethyl acetate layers are washed with brine (30 ml), dried over Na 2 SO and evaporated leaving a white solid which is dried in vacuo. Yield 90 %. EXAMPLE 4 Preparation of trans-3-Benzoyl-3-aza-bicyclo[3.1.0lhexane-2-carboxylic acid [(3-bromo- phenyl) -cyano-methyll -amide Trans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (0.201 g, 0.87 mmol), DL- α-amino-3-bromophenylacetonitrile (0.215 g, 0.87 mmol), O-l,2-Dihydro-2-oxo-l- pyridyl)-N,N,N\N'-tetramethyluronium tetrafluoroborate (TPTU, 0.258 g, 0.87 mmol) and N-Ethyldiisopropylamine (0.45 ml, 2.61 mmol) are dissolved in 25 ml MeCN. The mixture is stirred at RT for 16 h. The solution is concentrated, the residue is dissolved in ethyl acetate (30 ml) and extracted with H 2 O (2 x 15 ml). The H 2 O layers are extracted with ethyl acetate (20 ml). The collected ethyl acetate layers are washed with saturated NaHCO 3 (2 x 20 ml), brine (30 ml), dried over Na 2 SO 4 and evaporated. The yellow oil is purified by preparative HPLC. column: HP-CombiHT XDB-C18, 21.2mmI.D.x50mm, Series No DN 1020 method: Flow: 40ml/min 0 min 80% water, 20% acetonitrile 0.2min 80% water, 20% acetonitrile 3.5min 5% water, 95% acetonitrile 4.7min 5% water, 95% acetonitrile 4.8min 80% water, 20% acetonitrile 4.9min 80% water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD-1, UV-1 Yield 15 %, MS: 441 (MNH4+) EXAMPLE 5 Preparation of (S)-2-l(R)- and (S)-[(3-Chloro-phenyl)-cyano-methyll-carbamoyl}- pyrrolidine- 1 -carboxylic acid benzyl ester (Mixture of epimers, METHOD F) A solution of 0.7mmol (S)-Pyrrolidine-l,2-dicarboxylic acid 1-benzyl ester (educt 1), 5.2mmol N-methylmorpholin, 0.15mmol HOBT and 1.78mmol EDCI in 12ml CH 2 C1 2 is added to 0.97mmol (R,S) -Amino- (3-chloro-phenyl)-acetonitrile-hydrochloride (educt 2). After shaking overnight the reaction mixture is extracted with 10ml IN HCl and the CH 2 C1 2 was evaporated. The compound is purified by HPLC: column: HP-CombiHT XDB-C18, 21.2mmI.D.x50mm, Series No DN 1020 method: Flow: 40ml/min 0 min 80% water, 20% acetonitrile 0.2min 80% water, 20% acetonitrile 3.5min 5% water, 95% acetonitrile 4.7min 5% water, 95% acetonitrile 4.8min 80% water, 20% acetonitrile 4.9min 80% water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD-1, UV-1 Yield: 43%, MS: 396 (M-H) EXAMPLE 6 Preparation of (S)-Pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3-chloro-phenyl)- methyll amide-trifluoroacetate (Mixture of epimers, METHOD G) To a solution of 15.7mmol (S)-Pyrrolidine-l,2-dicarboxylic acid 1-tert. butyl ester, 17.2mmol (R,S)-Amino-(3-chloro-phenyl)-acetonitrile-hydrochloride, 1.57mmol HOBT and 18.8mmol EDCI in 150ml CH 2 C1 2 is added 109.7mmol N-methylmorpholine. After stirring overnight at RT the reaction mixture is extracted with 150ml 10% KHS0 and 150ml sat. NaHCO 3 , dried over MgSO 4 , evaporated and purified by flash chromatography (4cm Glassfrit, 2cm silicagel 0.04-0.063, eluent 400ml CH 2 C1 2 ). BOC-cleavage is performed with 17ml TFA in 50ml CH 2 C1 2 within 4 hours at RT. Evaporation yields a brown oil which iss used without further purification. EXAMPLE 7 Preparation of (S)-l-(3-Cyclopentyl-propionyl) pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide (Mixture of epimers, METHOD H To a solution of 0.17mmol 1:1 mixture of Pyrrolidine-2-carboxylic acid (R)- and (S)- cyano-(3-chloro-phenyl)-methyl-amide-trifluoroacetate (educt 1) in 3ml CH 2 C1 2 is added a solution of 0.187mmol 3-Cyclopentyl propionylchloride (educt 2) in 1ml CH 2 C1 2 . To this mixture is added 0.36mmol triethylamine. After shaking overnight at RT formic acid is added, the CH 2 C1 2 is evaporated and the compound purified by HPLC: column: HP-CombiHT XDB-C18, 21.2mmI.D.x50mm, Series No DN 1020 method: Flow: 40ml/min O min 80% water, 20% acetonitrile 0.2min 80% water, 20% acetonitrile 3.5min 5% water, 95% acetonitrile 4.7min 5% water, 95% acetonitrile 4.8min 80% water, 20% acetonitrile 4.9min 80% water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD-1, UV-1 Yield: 25%, MS: 388 (MH+) EXAMPLE 8 Preparation of (S)-l-(Naphthalene-l-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl1 -amide (Mixture of epimers, METHOD H) To a solution of 0.17mmol 1:1 mixture of Pyrrolidine-2-carboxylic acid (R)- and (S)- cyano-(3,4-dimethoxy-phenyl)-methyl]-amide-trifluoroacetate (educt 1) in 3ml CH 2 C1 2 is added a solution of 0.187mmol Naphthalene- 1-sulfonyl chloride (educt 2) in 1ml CH 2 C1 2 . To this mixture is added 0.36mmol triethylamin. After shaking overnight at RT formic acid is added, the CH 2 C1 2 is evaporated and the compound purified by HPLC: column: HP-CombiHT XDB-C18, 21.2mmI.D.x50mm, Series No DN 1020 method: Flow: 40ml/min O min 80% water, 20% acetonitrile 0.2min 80% water, 20% acetonitrile 3.5min 5% water, 95% acetonitrile 4.7min 5% water, 95% acetonitrile 4.8min 80% water, 20% acetonitrile 4.9min 80% water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD-1, UV-1 Yield: 19%, MS: 497 (MNH4+) EXAMPLE 9 Preparation of (S)-Pyrroridine-1.2-dicarboxylic acid 2-1 [(R)- and (S)-(3-chloro-phenyl)- cyano-methyll -amide} l-[(R)-(l-naphthaIen-l-yl-ethyl)-amide] (Mixture of epimers, METHOD H) To a solution of 0.17mmol 1:1 mixture of Pyrrolidine-2-carboxylic acid (R)- and (S)- cyano-(3-chloro-phenyl)-methyl-amide-trifluoroacetate (educt 1) in 3ml CH 2 C1 2 is added a solution of 0.187mmol (R)-l-(l-Isocyanato-ethyl)-naphthalene (educt 2) in 1ml CH 2 C1 2 . To this mixture is added 0.36mmol triethylamin. After shaking overnight at RT formic acid is added, the CH 2 C1 2 is evaporated and the compound purified by HPLC: column: HP-CombiHT XDB-C18, 21.2mmI.D.x50mm, Series No DN 1020 method: Flow: 40ml/min 0 min 80% water, 20% acetonitrile 0.2min 80% water, 20% acetonitrile 3.5min 5% water, 95% acetonitrile 4.7min 5% water, 95% acetonitrile 4.8min 80% water, 20% acetonitrile 4.9min 80% water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD-1, UV-1 Yield: 19%, MS: 461 (MH+) EXAMPLE 10 Preparation of other compounds of general formula (I) Several additional compounds of general formula (I) have been prepared. The following table shows an overview of the products, the educts and th method used for the preparation. The following methods were used: METHOD E: Coupling of protected amino acids with amino nitriles The protected amino acid, the amino nitrile, TPTU (O-l,2-Dihydro-2-oxo-l-pyridyl)- N.N.N'.N'-tetramethyluronium tetrafluoroborate) and Hϋnigsbase (N- Ethyldiisopropylamine) are dissolved in MeCN. The mixture is stirred at RT for 6- 16 h. The solution is concentrated and the residue is dissolved in ethyl acetate and extracted with H 2 O. The H 2 O layers are extracted with ethyl acetate. The combined ethyl acetate layers are washed NaHCO 3 , brine, dried over Na 2 SO and evaporated. The crude product is purified by column chromatography. Yield 60-90%. METHOD F: Z-AS + amino nitrile A solution of leq (S)-Pyrrolidine- 1,2-dicarboxylic acid 1-benzyl ester, 7eq N- methylmorpholin, 0.2eq HOBT and 2.4eq EDCI in 7 ml CH 2 C1 2 is added to l.l-1.3eq amino nitrile-HCl. After shaking overnight the reaction mixture is extracted with IN HCl and the CH 2 C1 2 is evaporated. The compounds are purified by HPLC: column: HP-CombiHT XDB-C18, 21.2mmI.D.x50mm, Series No DN 1020 method: Flow: 40ml/min 0 min 80% water, 20% acetonitrile 0.2min 80% water, 20% acetonitrile 3.5min 5% water, 95% acetonitrile 4.7min 5% water, 95% acetonitrile 4.8min 80% water, 20% acetonitrile 4.9min 80% water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD- 1, UV- 1 METHOD H: Amino acid nitrile (educt 1 ) + (educt 2) Crude 1:1 mixture of Pyrrolidine-2-carboxylic -amide-trifluoroacetate (educt 1) + a. Carbonylchloride (educt 2) or b. sulfonylchloride (educt 2) or c. Isothiocyanate (educt 2)+ triethylamine To a solution of leq Pyrrolidine-2-carboxylic acid amide-TFA (educt 1) in CH 2 C1 2 is added a solution of l.leq carbonylchloride (educt 2) or sulfonylchloride (educt 2) or isothiocyanate (educt 2) in CH 2 C1 2 . To this mixture is added 2. leq triethylamine. After shaking overnight at RT formic acid is added, CH C1 2 is evaporated and the compound purified by HPLC: column: HP-CombiHT XDB-C18, 21.2mmI.D.x50mm, Series No DN 1020 method: Flow: 40ml/min 0 min 80% water, 20% acetonitrile 0.2min 80% water, 20% acetonitrile 3.5min 5% water, 95% acetonitrile 4.7min 5% water, 95% acetonitrile 4.8min 80% water, 20% acetonitrile 4.9min 80% water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD- 1 , UV- 1 EXAMPLE 11 Preparation of other compounds of general formula (I) The follwing compounds of general formula (I) have been prepared from the corresponding educts in analogy to example 10, method H. Example A Tablets containing the following ingredients can be manufactured in a conventional manner: Ingredients Per tablet Compound of formula I 10.0 - 100.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg Example B Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg Example C Injection solutions can have the following composition: Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water for injection solutions ad 1.0 ml

Claims: CLAIMS 1. 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 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 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 represents aryl-lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. 2. Compounds according to claim 1, wherein R 7 represents -CO-R a , -SO 2 -R b or -CS-NH-R 0 , 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, 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 represents aryl-lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. 3. Compounds according to any of claims 1 to 2, characterised by formula (la) wherein Y, R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. 4. Compounds according to any of claims 1 to 3, wherein Y represents CH-R 2 and R is as defined in claim 1. 5. Compounds according to claim 4, wherein R 2 represents hydrogen. 6. Compounds according to any of claims 1 to 5, wherein R 1 represents hydrogen. 7. Compounds according to any of claims 1 to 6, wherein R 3 represents hydrogen. 8. Compounds according to any of claims 1 to 7, wherein R 4 represents hydrogen. 9. Compounds according to any of claims 1 to 8, wherein R 5 represent hydrogen. 10. Compounds according to any of claims 1 to 9, wherein R 6 represents phenyl, furanyl, thiophenyl, or pyrrolyl, optionally substituted with alkyl, halogen, hydroxy, alkoxy, -O-(CH 2 ) 1-7 -O-, aryloxy, or aryl-alkoxy. 11. Compounds according to any of claims 1 to 10, wherein R represents phenyl, phenyl substituted in meta-position, phenyl substituted in meta- and in para-position, or benzo[l,3]dioxol-5-yl. 12. Compounds according to any of claims 1 to 11, wherein R 6 represents 3-methoxy-phenyl, 3,4-dimethoxy-phenyl, 4-benzyloxy-3-methoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, or benzo[l,3]dioxol-5-yl. 13. Compounds according to any of claims 1 to 12, wherein R 7 represents -CO-R and R a is as defined in claim 1. 14. Compounds according to claim 13, wherein R a is benzyloxy, cyclopentyl-ethylene, or benzyloxy-methylene. 15. Compounds according to claim 13, wherein R a is 3-bromobenzyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, or 2-methyl- phenyloxymethylene. 16. Compounds according to any of claims 1 to 12, wherein R 7 represents -CS-NH-R C and R c is as defined in claim 1. 17. Compounds according to claim 16, wherein R c is benzyl, 3-fluorobenzyl, or furan-2-yl-methylene. 18. Compounds according to any of claims 1 to 12, wherein R 7 represents -SO 2 -R and R is as defined in claim 1. 19. Compounds according to claim 18, wherein R b is naphthyl. 20. A compound according to any of claims 1 to 12, selected from the group consisting of (S)-2-[(R)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-l-carboxylic acid benzyl ester, (2S,3R)-2-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl- pyrrolidine- 1-carboxylic acid benzyl ester, (S)-2-[(R)- and (S)-(Benzo[l,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-l- carboxylic acidbenzyl ester, (S)-2-{(R)- and (S)-[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-2-{(R)- and (S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid benzyl ester, (S)-l-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[l,3]dioxol-5-yl- cyano-methyl)-amide, (S)-l-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)- benzo[l,3]dioxol-5-yl-cyano-methyl)-amide, (S)-2-{(R)- and (S)-[(4-Benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}- pyrrolidine- 1-carboxylic acid benzyl ester, and (S)-l-[(Furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylic acid [(R)- and (S)- cyano-(3,4-dimethoxy-phenyl)-methyl]-amide. 21. A compound according to any of claims 1 to 12, selected from the group consisting of (S)-l-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (l-benzo[l,3]dioxol- 5-yl-l-cyano-methyl)-amide, (S)-l-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1- (3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1- (3,4- dimethoxy-phenyl)-methyl] -amide, (S)-l-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-(3-chloro- phenyl)- 1 -cyano-methyl] -amide, (S)-l-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid ( 1 -benzo [1,3] dioxol- 5-yl-l-cyano-methyl)-amide, (S)-l-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [ 1-cyano- 1-(3,4- dimethoxy- phenyl) -methyl] -amide, (S)-l-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4- dimethoxy-phenyl)-methyl] -amide, and (S)-l-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid ( 1 -benzo [1,3] dioxol- 5-yl-l-cyano-methyl)-amide. 22. A compound according to any of claims 1 to 12, selected from the group consisting of (S)-l-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [l-cyano-l-(3,4-dimethoxy- phenyl) -methyl] -amide, and (S)-l-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid ( 1 -benzo [1,3] dioxol-5-yl-l- cyano-methyl)-amide. 23. A process for the manufacture of compounds according to any of claims 1 to 22, which process comprises a) reacting a compound of formula (II) with a compound of formula (III) wherein Y, R 1 , R 3 , R 5 , R 6 and R 7 have the significances given in claim 1, or b) reacting a compound of formula (IV) with a compound of formula (V), (VI), (VII) or (VIII) wherein Y, R .1 , τ R)3 , r R>4 , τ R)5 , R r>6 , π Ra a , τ R_b , π Rc c a ..nd j r R have the significances given in claim 1. 24. Process according to claim 23 comprising the preparation of a pharmaceutically acceptable salt and/or a pharmaceutically acceptable ester. 25. Compounds according to any of claims 1 to 22, prepared by the process of claim 23 or 24. 26. Compounds of formula (IV) wherein Y, R , R , R , R and R have the significances given in claim 1. 27. Compounds according to any of claims 1 to 22 for use as therapeutic active substances, in particular in context with 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. 28. Compounds according to any of claims 1 to 22 for use as therapeutic active substances in context with osteoporosis, instable angina pectoris and/or plaque rupture. 29. A pharmaceutical composition comprising a compound according to any of claims 1 to 22 and a pharmaceutically acceptable carrier and/or adjuvant. 30. The use of compounds according to any of claims 1 to 22 for the treatment or prophylaxis 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. 31. The use of compounds according to any of claims 1 to 22 for the treatment or prophylaxis of osteoporosis, instable angina pectoris and/or plaque rupture. 32. The use of compounds according to any of claims 1 to 22 for the preparation of medicaments for the treatment or prophylaxis 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. 33. The use of compounds according to any of claims 1 to 22 for the preparation of medicaments for the treatment or prophylaxis of osteoporosis, instable angina pectoris and/or plaque rupture. 34. A method for the therapeutic and/or prophylactic treatment of disorders in which cathepsin K plays a significant pathological role, in particular 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 according to any of claims 1 to 22 to a human being or animal. 35. A method for the therapeutic and/ or prophylactic treatment of osteoporosis, instable angina pectoris and/or plaque rupture, which method comprises administering a compound according to any of claims 1 to 22 to a human being or animal. 36. The novel compounds, processes and methods as well as the use of such compounds substantially as described hereinbefore.

Inventors: GABRIEL TOBIAS, PECH MICHAEL, WALLBAUM SABINE, GABRIEL, TOBIAS, PECH, MICHAEL, WALLBAUM, SABINE
Applicants: HOFFMANN LA ROCHE, F. HOFFMANN-LA ROCHE AG
Application year: 2000
Main classification: C07D209
IPC codes: A61K31, A61P9, A61P11, A61P13, A61P19, A61P27, A61P29, A61P33, A61P35, A61P37, C07D207, C07D209, C07D277, C07D403, C07D405