Title of Invention	DIPEPTIDE NITRILE CATHEPSIN K INHIBITORS AND A PROCESS FOR THE PREPARATION OF THE SAME
Abstract	Dipeptide nitrile Cathepsin K inhibitors of formula (I), and pharmaceutically acceptable salts or esters thereof, in which R<sub>1</sub> and R<sub>2</sub> are independently H or C<sub>1</sub>-C<sub>7</sub> lower alkyl, or R<sub>1</sub> and R<sub>2</sub> together with the carbon atom to which they are attached form a C<sub>3</sub>-C<sub>8</sub> cycloalkyl ring, and Het is an optionally substituted nitrogen-containing heterocyclic substituent, are provided, useful e.g. for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated.

Title of Invention

DIPEPTIDE NITRILE CATHEPSIN K INHIBITORS AND A PROCESS FOR THE PREPARATION OF THE SAME

Abstract

Dipeptide nitrile Cathepsin K inhibitors of formula (I), and pharmaceutically acceptable salts or esters thereof, in which R1 and R2 are independently H or C1-C7 lower alkyl, or R1 and R2 together with the carbon atom to which they are attached form a C3-C8 cycloalkyl ring, and Het is an optionally substituted nitrogen-containing heterocyclic substituent, are provided, useful e.g. for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated.

Full Text	PIPEPTTOE NITRILE CATHEPSIN K INHIBITORS This invention relates to inhibitors of cysteine proteases, in particular to dipeptide nitrile cathepsin K inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsin K is implicated. Cathepsin K is a member of the family of lysosomal cysteine cathepsin enzymes, e.g. cathepsins B, K, L and S, which are implicated m various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and immunologically mediated diseases (including transplant rejection). Our copending International patent application WO 99/24460 describes dipeptide nitriles which are inhibitors of cysteine cathepsins and their use for treatment of cysteine cathepsin dependent diseases or medical conditions. New dipeptide nitrile compounds have now been made which are inhibitors of cathepsin K, and which have desirable properties for pharmaceutical applications. Accordingly the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester thereof In which R1 and R2 are independently H or C1-C7lower alkyl, or R1 and R2 together with the carbon atom to which they are attached form a C3-C8cycloalkyI ring« and Het is an optionally substituted nitrogen-containing heterocyclic substituent, provided that Het is not 4-pyrrol-l-yl. The Het substituent may be at the 2- or 3-position of the phenyl ring, though is preferably at the 4-position. In the present description "nitrogen-containing heterocycle" signifies a heterocyclic ring system containing at least one nitrogen atom, from 2 to 10, preferably from 3 to 7, most preferably 4 or 5, carbon atoms and optionally one or more additional heteroatoms selected from O, S or preferably N, Het may comprise an unsaturated, e.g. an aromatic, nitrogen-containing heterocycle; though preferably comprises a saturated nitrogen-containing heterocycle. Particularly preferred saturated nitrogen-containing heterocycles are piperazinyl, preferably piperazin-l-yl, or piperidinyl, preferably piperidin-4-yl Het may be substituted by one or more substituents, e.g. by up to 5 substituents independently selected from halogen, hydroxy, amino, nitro, optionally substituted C1-4alkyl (e.g, alkyl substituted by hydroxy, alkyloxy, amino, optionally substituted alkylannino, optionally substituted dialkylamino, aryl or heterocyclyl), C1-4alkoxy. Preferably Het is substituted at a nitrogen atom, most preferably mono-substituted at a nitrogen atom. benzamide; N-[l'(Cyanomethyl-carbanK)yl)-cycIohexyI]-4-[l-(2-methoxy-ethyl)-piperidin 4-yI]-benzamide; N-[l-((Cyanomethyl-carbanoyl)-cyclohexyl]'4-(l-isopropyl-pipcri benzamide; N-[l-(Cyanoinethyl-^arbanK)yI)-cyclohexyl]-4-(l-yclopentyl-piperidin-4-yl) benzamide; N- [ 1 -(Cyanomethyl-carbamoyI)-cyclohexyl]-4-( 1 -niethyl-piperidin-4-yl)-benzamide, and N-[ 1 -(Cyanornethyl-carbamoyl)-cyclohexyl]-4-(piperidin-4-yl)-benzamide. Compounds of formula I and II and the specific compounds above are hereinafter referred to as Compounds of the Invention, Compounds of the Invention may be prepared by coupling the corresponding Het substituted benzoic acid derivative with 1-amino-cyclohexanecarboxylic acid cyanomethyl amide. For example, the benzoic acid derivative, preferably in the form of its hydrochloride, is mixed with 1-amino-cyclohexanecarboxylic acid cyanomethyl amide, e.g. in the presence of HOBT (l-hydroxybenzotriazole), WSCD and triethylamine, in solution, e.g. in DMF, and stirred, e.g. overnight at room temperature. The product may be recovered, for instance, by evaporation of the solvent, followed by washing with aqueous sodium carbonate solution, preferably under mildly basic conditions, followed by solvent extraction, e,g. with ethyl acetate, drying of the extract, e.g, over sodium sulfate, evaporation of the solvent and filtration. Alternative procedures and reagents may be used; for instance, as hereinafter described in the Examples. Thus in a further aspect the invention provides a process for the preparation of a compound of formula I which comprises coupling the corresponding Het substituted benzoic acid derivative of formula in l-Amino-cyclohexanecarboxylic acid cyanonoethyl-amide may be prepared by coupling 1-amino-cyclohexane carboxylic acid typically in appropriate amino protected form, e.g. FMOC-1-amino-cyclohexane carboxylic acid, with 2-aminoacetonitrile. For example, FMOC-1-amino-cyclohexane carboxylic acid, e.g. with HOBT and WSCD, is added to a solution of 2-aminoacetonitrile and triethylamine in DMF and the mixture stirred at 25°C overnight. 1-Amino-cyclohexanecarboxylic acid cyanonnethyl-amide may be recovered as described in the Examples. FMOC-1-amino-cyclohexane carboxylic acid may be prepared as described in the Examples, Compounds of the invention are either obtained in the free form, or as a salt thereof if salt forming groups are present. Compounds of the Invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (Cr C4)alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fiimaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (C1C4)-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen). Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances. The conpounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the invention exhibit valuable pharmacological properties in mammals and are particularly useful as inhibitors of cathepsin K. The cathepsin K inhibitory effects of the compound of the invention can be demonstrated in vitro by measuring the inhibition of e.g. recombinant human cathepsin K. The in vitro assay is carried out as follows: For cathepsin K: The assay is performed in 96 well microtiter plates at ambient temperature using recombinant human cathepsin K. Inhibition of cathepsin K is assayed at a constant enzyme (0.16 nM) and substrate concentration (54 mM ZrPhe-Arg-AMCA -Peptide Institute Inc. Osaka, Japan) in 100 mM sodium phosphate buffer, pH 7.0, containing 2 mM dithiothreitol, 20 mM Tween 80 and 1 mM EDTA. Cathepsin K is preincubated with the inhibitors for 30 min, and the reaction is initiated by the addition of substrate. After 30 min incubation the reaction is stopped by the addition of E-64 (2 mM), and fluorescence intensity is read on a multi-well plate reader at excitation and emission wavelengths of 360 and 460 nm, respectively. Compounds of the Invention typically have Kis for human cathepsin K of less than about 50nM, preferably of about 5nM or less, e.g. about InM. In view of their activity as inhibitors of cathepsin K, Compounds of the Invention are particularly useful in mammals as agents for treatment and prophylaxis of diseases and medical conditions involving elevated levels of cathepsin K. Such diseases include diseases involving infection by organisms such as Pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, crithidia fusiculata, as well as parasitic diseases such as schistosomiasis and malaria, tumours (tumour invasion and tumour metastasis), and other diseases such as metachromatic leukodystrophy, muscular dystrophy, amytrophy and similar diseases. Cathepsin K, has been implicated in diseases of excessive bone loss, and thus the Compounds of the Invention may be used for treatment and prophylaxis of such diseases, including osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, e.g, tumour-induced hypercalcemia and metabolic bone disease. Also the Compounds of the Invention may be use for treatment or prophylaxis of diseases of excessive cartilage or matrix degradation, including osteoarthritis and rheumatoid arthritis as weU as certain neoplastic diseases involving expression of high levels of proteolytic enzymes and matrix degradation. Compounds of the Invention, are also indicated for preventing or treating coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases and immunologically mediated diseases (including transplant rejection). Compounds of the Invention are particularly indicated for preventing or treating osteoporosis of various genesis (e.g. juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or by cortico-steroid therapy or inactivity). Beneficial effects are evaluated in in vitro and in vivo pharmacological tests generally known in the art, and as illustrated herein. The above cited properties are demonstrable in in vitro and in vivo tests, using advantageously mammals, e.g. rats, mice, dogs, rabbits, monkeys or isolated organs and tissues, as well as mammalian enzyme preparations, either natural or prepared by e.g. recombinant technology. Compounds of the Invention can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions or suspensions, and in vivo either enterally or parenterally, advantageously orally, e.g. as a suspension or in aqueous solution, or as a solid capsule or tablet formulation. The dosage in vitro may range between about 10-5 molar and 10-9 molar concentrations. The dosage in vivo may range, depending on the route of administration, between about 0.1 and 100 mg/kg. In accordance with the present invention it has been found that Compounds of the Invention, have good bioavailability, in particular good oral bioavailability. Thus, for example selected compounds of the Invention have absolute oral bioavailabilities of 50% or greater e.g. about 80% or more. The antiarthritic efficacy of the Compounds of the Invention for the treatment of rheumatoid arthritis can be determined using models such as or similar to the rat model of adjuvant arthritis, as described previously (R.E, Esser, et, al. J. Rheumatology, 1993,20,1176,) The efficacy of the compounds of the invention for the treatment of osteoarthritis can be determined using models such as or similar to the rabbit partial lateral meniscectomy model, as described previously (Colombo et al, Arth. Rheum 1993 26,875-886). The efficacy of the compounds in the model can be quantified using histological scoring methods, as described previously (O'Byme et al. Inflamm Resl995,44,S117-S118). The efficacy of the compounds of the invention for the treament of osteoporosis can be determined using an animal model such as the ovariectomised rat or other similar species, e.g. rabbit or monkey, in which test compounds are administered to the animal and the presence of markers of bone resorption are measured in urine or serum (e,g, as described in Osteoporos Int (1997) 7:539-543). Accordingly in further aspects the invention provides; A Compound of the Invention for use as a pharmaceutical; a pharmaceutical composition comprising a Compound of the Invention as an active ingredient; a method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated, comprising administering an effective amount of a Compound of the Invention to the patient, and the use of a Compound of the Invention for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated The present invention relates to methods of using Compounds of the Invention and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals for inhibiting cathepsin K, and for the treatment of cathepsin K dependent conditions, such as the cathepsin K dependent conditions, described herein, e.g. inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis. Particularly the present invention relates to a method of selectively inhibiting cathepsin K activity in a mammal which comprises administering to a mammal in need thereof an effective cathepsin K inhibiting amount of a Compound of the Invention-More specifically such relates to a method of treating osteoporosis, rheumatoid arthritis, osteoarthritis, and inflammation (and other diseases as identified above) in mammals comprises administering to a mammal in need thereof a correspondingly effective amount of a Compound of the Invention, The following examples axe intended to illustrate the invention and are not to be construed as being limitations thereon. Temratures are given in degrees Centrigrade. If not mentioned otherwise, all cvaporations are performed under reduced pressure, preferably between about 15 and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g. microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR), Abbreviations used are those conventional in the art. Alternatively THF may be used as the solvent and l-chloro-3,5-dimethoxytriazine (CDMT) as the activator, together with N-methylmorpholine (NMM) during the coupling reaction; in which case the product may be recovered by addition of isopropylacetate and water, separation of the organic phase followed by washing with brine, partial evaporation of the solvent, recovery of the crystallised product by filtration and drying. C* 1-Amino-cyclohexanecarfaoxvlic acid cvanomethyl-amide Example 1: Synthesis of N-[1-(Cvanomethvl-carbamovl)-cvclohexvn-4-piperazin-l-yl-benzamide A. 4-piperazin-l-vl-benzoic acid methvl ester l-(4-Cyanophenyl)-piperazine (11mmol) is dissolved in 15ml of a mixture of concentrated sulfonic acid and methanol (5N) and stirred in a sealed tube at 1 lO°C for 3 hours. After evaporation of the solvent, the residue is dissolved in water and extracted with ethyl acetate. Addition of sodium carbonate to the water phase until pH=9 results in the precipitation of a white solid which is filtered off and dried (vacuum). A white powder with RfrK).59 (CHaQa/MeOH (+NH3 3N)=9:1) is obtained. B, 4-piperazin-1-yl-benzoic acid hvdrochlorid 4-piperazin-l-yl-benzoic acid methyl ester (17mmol) is dissolved in 6N HCl (25ml) and heated under reflux for 3 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formed is filtered off, washed with acetone and dried (vacuum), A white powder with rap. >240°C is obtained. D. N-[1-(CYanoinethvl-carbamovl)-cvclohexvl1-4-(4-FMOC-Piperazin-l- vl)-benzamide 1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (8,3mmol) 4-(4-EMOC- piperazin-l-yl)-benzoic acid (8.3mmol), HOBT (8.3mmol) and WSCD (8,3mmol) are dissolved in DMF (20ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is # dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (ethylacetate/hexane=4:l) as mobile phase. The product containbg fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 192-194T, Rt=0.26 (CH2a2/MeOH=95:5) is obtained. is stirred at RT for 4 hours. 4 additional drops of piperidine are added and the mixture is stirred over night. The reaction mixture is poured into water and ethyl acetate and the suspension is filtered and the filtrate is acidified with HCl 4N and then extracted with ethyl acetate. Saturated sodium carbonate solution is added to make the water phase basic and the mixture is extracted three times with ethyl acetate. The water phase is saturated with sodium chloride and extracted three times with ethyl acetate again. The organic fractions are dried over sodium sulfate and the solvent is evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 3N NHS) =95:5 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 206-210°C, Rf=0.28 (CH2Cl2/MeOH (with 3N NH3) =9:1) is obtained. lH-NMR(d6-DMS0): 1.15-1.35 (m, 1H); 1.4-1.6 (m, 5H); 1,65-1.8 (m, 2H); 2.05-2.15 (m. 2H); 2.8 (m, 4H); 3.15 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, 1H); 7.75 (d,2H),8.15(m, 1H), C. N'ri-fCvanomethvl-carbainovl)>cvclohexvn-4-f4'inethvl-piperazin«l-vl)-benzamide 1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (l,38mmol) 4-(4-methyl-piperazin-l-yl)'benzoic acid hydrochloride (1.38mmol), HOBT (1.38mmol), WSCD (1.38mmol) and triethylamine (1.38mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp. 218-220°C, Rf=0.19 (CH2Cl2/MeOH=9:l) is obtained. IH-NMR (d6-DMS0): L15-1.35 (m, IH); 1.4-1.6 (m, 5H); 1.65-1.8 (m, 2H); 2.05-2.15 (m, 2H); 2.2 (s, 3H); 2.4 (m, 4H); 3.2 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, IH); 7,75 (d, 2H), 8.15 (m, IH). under reflux overnight. After evaporation of the solvent, the residue is dissolved in water and extracted three times with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A brownish powder with mp. 102-104'C, Rf=0.22 (CH2Cl2/MeOH=95:5) is obtained. B. 4-f4'Ethvl-piperazin-l-vl)-benzoic acid hvdrochlorid 4-(4-EthyI-piperazin-l-yl)-benzoic acid methyl ester (15mmol) is dissolved in 4N HCl (35ml) and heated under reflux for 8 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formed is filtered off, washed with acetone and dried (vacuum). A grey powder with mp. >270°C, Rf=0.08 (CH2Cl2/MeOH=9:1) is obtained. C. N-ri-fCvanomethvl-carbamovl)-cvclohexvn-4-f4-ethvl-piperazin-lvl)- benzamide 1 - Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.9mmol) 4-(4-ethyl-piperazin-l-yl)-benzoic acid hydrochloride (0,9mmol), HOBT (0.9mmol), WSCD (0,9mmol) and triethylamine (0,9mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 3N NH3) -93:7 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder is obtained, 1H-NMR (d6-DMSO): 1.0 (t, 3H), 1.15-1.35 (m, 1H); 1.4-1.6 (m. 5H); 1.65-1.8 (m, 2H); 2,05-2.15 (m, 2H); 2.35 (q, 2H); 2.45 (m, 4H); 3.2 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, 1H); 7.75 (d, 2H), 8.15 (m, 1H). CS2CO3 may be used in place of K2CO3 in the above procedure. B. 4-r4-fl-Propvn-piperazin-l-yl]-benzoic acid hvdrochlorid . 4-[4-(I-Propyl)-piperazin-l'yl]-benzoic acid methyl ester (38mmol) is dissolved in 4N HCl (60ml) and heated under reflux for 7 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formed is filtered off, washed with cold water and dried (vacuum). A pale powder with mp,270°C, Rf=0.19 (CH2C12/MeOH=9:l) is obtained. (22mmol) and triethylamine (22mmol) are dissolved in DMF (50ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=9:l) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp, 216-218°C, Rf=0,34 (CH2Cl2/MeOH=9:l) is obtained. IH-NMR (d6-DMS0): 0.85 (t, 3H), 1.2-1.3 (m, IH); L4-1.6 (m, 7H); 1.65-1.8 (m, 2H); 2.05-2.15 (m, 2H); 2.25 (t, 2H); 2.45 (m, 4H); 3.2 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, IH); 7.75 (d, 2H), 8.15 (m, IH). evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=95:5) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale-brown powder with Rf=0.23 (CH2Cl2/MeOH=95:5) is obtained. A. 4'(4-BenzYl-DiDerazin-l-vl)-benzoic acid methyl ester Tris-(dibenzylidene-acetone)-dipal]adium (0.03mmol), (2-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0,9mmol) and NaOtBu (6.5mmol) are suspended in toluene (20ml) in an oxygen-free atmosphere (N2). 4-Bromo-benzoic acid methyl ester (4.65mmol) and l-(benzyl)-piperazine (5.6nimol) are added and the stirred mixture is heated under reflux for 4 hours. After cooling, a mixture of ethylacetate and diethylether is added and the mixture is filtered. Then the solvent is evaporated and the residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp.l05-107T, Rf=0.67 (CH2Cl2/MeOH=95:5) is obtained. B. 4-(4-Benzyl-piDerazin-l-ylVbenzoic acid hydrochloride 4-(4-Benzyl-piperazin-l-yl)-benzoic acid methyl ester (0.84mmol) is dissolved in 4N HCl (2ml) and heated under reflux for 8 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formedis filtered off, washed with cold acetone and dried (vacuum). A grey powder with mp. >270°C, Rf=0.18 (CH2Cl2/MeOH=95:5) is obtained. (m, 5H), 7.65 (s, 1H); 7.75 (d. 2H), 8.15 (m, 1H). Example 7: Synthesis of N-ri-(CvanomethYl-carbamoYl)-CYclohexvll-4-r4-f2-rnethoxy-ethvl)-piperazin-l-vn»benzamide A. 4-(4-BenzYl'Piperazin-l-vl)-benzoic acid methyl ester 4-Fluoroben2oic acid methyl ester (200mmol), l-benzyl-piperazine (300mmol), and potassium carbonate (300mmol) are suspended in acetonitrile (400ml) and stirred under reflux for 6 days. After evaporation of the solvent, the residue is dissolved in water and extracted three times with diethylether. The extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatographie on silica gel with (CH2CI2 first, then CH2Cl2/MeOH-15:l) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum), A powder with mp. 105-107°C is obtained. B. 4-(Piperazin-1-yl)-benzoic acid methyl ester 4-(4-Benzyl-piperazin-l-yl)-benzoic acid methyl ester (19.4mmol) is dissolved in methanol (150ml) and Pd/charcoal is added (0.6g). The mature is stirred in a hydrogen atmosphere until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A powder with mp. 95-97°C is obtained. C. r4f2-methoxy'ethvlVpiP€razin-l-vll-benzoic acid methvl ester 4-(Piperazin-1 -yl)-benzoic acid methyl ester (19mmol), 2-bromoethylmethylether (21mmol), and potassium carbonate (22,8mmol) are suspended in acetonitrile (50ml) and stirred at 80°C for 8 hours. After evaporation of the solvent, the residue is dissolved in water and extracted three times with CH2CI2- The extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum), A powder with mp. 103-105°C is obtained. D» f4-(2-inethoxy--ethyl)-piperazin-l-vn-benzoic acid hydrochloride [4-(2-methoxy-ethyl)-piperazin-l-yl]-benzoic acid methyl ester (17mmol) is dissolved in 4N HCl (TOml) and heated under reflux for 5 hours. After cooling the solvent is evaporated and the residue is suspended in ethanol and the solid filtered of, washed with diethylether and dried (vacuum). A powder with mp. >270°C, Rf=0.35 (CH2Cl2/MeOH=9:l) is obtained. E. N-(1-(CYanomethvl-Carbamovl)'-cvclohexvn-4-[4-(2-methoxv-ethYl)- piperazin-l-vn-benzamide 1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (l.Ommol), [4-(2-methoxy-ethyl)-piperazin-1 -yl]-benzoic acid hydrochloride (1 .Ommol), HOBT (1 .Ommol), WSCT) (l.Ommol) and triethylamine (l.Ommol) are dissolved in DMF (4ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=92.5:7.5 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the' solid extracted three times with water and the water phase is extracted again with CH2CI2. The combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil with Rf=0,13 (ethyl acetate/hexane=l:l) is obtained. B. 4-Piperidin-4-vL-benzoic acid l-(4-Phenyl-piperidIN-l-yl)-ethanone (84mmol) is dissolved in CH2CI2 (250ml) and oxalylchloride (336mmol) is added dropwise at -20 to -10°C. After the oxalylchloride addition aluminium trichloride (260mmol) is added in portions at -lO°C. The mixture is stirred at -10°C for 3 hours. The cooling bath is removed and the mixture is stirred at rt overnight. The mixture is poured on ice/water (600ml) and extracted 3 times with CH2CI2. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in aqueous sodium hydroxide solution (2N, 250ml) and 6N HCl is added at O°C to acidify the solution. The precipitate formed is filtered off and washed with water. The solid material is suspended in 6N HCl (300ml) and the mbtture is heated for 18 hours under reflux. After cooling to rt the solvent is removed and the residue is suspended in ethanol. The solid material is filtered of and dried. A brown powder with mp. >270'C is obtained. dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:l as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale brown powder with Rf=0.35 (CH2Cl2/MeOH=9:l) is obtained. Example 9: Synthesis of N-fl-fCvanomethvl-carbainoyl)-cvclohexvl1^ 4-ri'f2-methoxY-ethvl)-Diperidin-4-vn-benzainide A* 4-Carboxybenzeneboronic acid methyl ester 4-Carboxybenzeneboronic acid (SOOmmol) is dissolved in methanol (400ml) and 1.5ml concentrated HCl is added to the stirred solution. The reaction is heated under reflux for 30 hours. The solvent is evaporated, the remaining residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp. 201-205^0, Rfc=0.28 (CH2Cl2/MeOH=95:5) is obtained. This powder is a mixture of 4-carboxyben2:eneboronic acid methyl ester and the dimeric anhydride of 4-carboxybenzeneboronic acid methyl ester and is used without further purification, B, 4'Pyridin4-vl'benzoic acid methvl ester 4-Carboxybenzeneboronic acid methyl ester (248mmol) from A, 4-bromopyridine (248mmoI), tetrakis-(triphenylphosphin)-palladium (2.5mmol) and potassium carbonate (744mmol) are suspended in 1,2-dimethoxyethane (1100ml). The stirred mature is heated under reflux for 8 hours. After cooling the solvent is evaporated and water is added to the residue which is then extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale-brown powder with mp. 99-lO°C, Rf=0.39 (CH2Cl2/MeOH=95:5) is obtained. in a hydrogen atmosphere at normal pressure until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is dissolved in CH2CI2 and extracted with aqueous sodium carbonate solution. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:1 as mobile phase. The product containing fractions are combined and evaporated. A pale yellow oil with Rf=0.22 (CH2Cl2/MeOH=95:5) is obtained. E. 4-(1-(2-Methoxy-ethvl)-piperidin-4'Vl1'benzoic acid hydrochloride 4-[l-(2-Methoxy-ethyl)-piperidin-4-yl]-benzoic acid methyl ester (47mmol) is dissolved in 4N HCl (80ml) and heated under reflux for 12 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A white powder with mp. >270°C is obtained. 2H); 7.35 (d, 2H); 7.8 (d. 2H); 7.9 (s, IH); 8.15 (m, IH). Example 10: N-fl-(Cvanomethv!-carbainovl)-cvclohexvn-4-(l-isoproDvl-' piperidin'4vl)-benzamide A. l-IsopropYl-4'(4-methoxvcarbonvl-phenvlVpvridiniuni; bromide 4-Pyridin-4-yl-benzoic acid methyl ester (2.3mmol) and 2-iodopropane (1.0ml) are heated for 24 hours to 90^C. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of and dried (vacuum). A pale-yellow powder with mp. 187-189°C,Rf=0.27 (CH2Cl2/MeOH=9:l) is obtained. B. 4-( l-Isopropvl-piperidin-4-vi)-benzoic acid methvl ester hvdroiodide 1-Isopropyl-4-(4-methoxycarbonyl-phenyl)-pyridinium; bromide (1.9mmol) is suspended in methanol (10ml) and platinoxide (80mg) is added. The mixture is stirred in a hydrogen atmosphere at normal pressure until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale powder with mp. 219-224°C, Rf=0.41 (CH2Cl2/MeOH =9:1) is obtained. (0.95mmol) and triethylamine (0.95mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 214-216°C, Rf=0.38 (CH2Cl2/MeOH (with 3N NH3) =9:1) is obtained. 1H-NMR (d6-DMS0): 0.95 (d, 6H); 1.2-1.3 (m, 1H); 1,4-1.8 (m, 1H); 2.05-2,25 (m, 4H); 2.55 (m, 1H); 2.7 (m, 1H); 2.85 (d, 2H); 4.0 (d, 2H), 7.35 (d, 2H); 7.8 (d, 2H). 7.9 (s,lH); 8.15 (m,lH). Example 11: N-ri-fCvanomethYl-carbamovl)-cYclohexvll-4-(l-cvclopentvl -piperidin-4-vn'benzainide A. l-Cvclopentvl -4-(4-methoxvcarbonvl»phenvl)-pvridinium; bromide 4-Pyridin-4-yl-benzoic acid methyl ester (2,35nimol) and 1-iodocyclopentane (1.0ml) are heated for 4 hours to llO°C. 1-Iodocyclopentane (0,5ml) are added and the mixture is heated for another 4 hours to 120°C. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of and dried (vacuum). The solid residue is purified by flash chromatography on silica gel with CH2Cl2/ME0H =9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum), A yellow powder with mp, 183-185X,RfM).35 (CH2Cl2/MeOH=9:l) is obtained. B. 4-(l-Cvclopentvl-piperidin-4-ylVbenzoic acid methvl ester hydro- iodide 1 -Cyclopentyl-4-(4-methoxycarbonyl-phenyl)-pyridinium; bromide (1,27iranol) is suspended in methanol (8ml) and platinoxide (50mg) is added. The mixture is stirred in a hydrogen atmosphere at normal pressure until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale powder with mp. 204-210°C, RM),27 (CH2 cL2/MeOH =95:5) is obtained. C. 4-(l-CvclopentYl-piperidin-4-vl)-benzoic acid hydrochloride 4-(l-Cyclopenlyl-piperidin-4-yl)-benzoic acid methyl ester hydroiodide (1.06mmol) is dissolved in 4N HCl (5ml) and heated under reflux for 10 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A grey-brown powder with mp. >270'C is obtained, D, N-(1-fCvanomethvl-carbamoyl)-cvclohexvn-4-(l-cvclopentvl- piperidin-4-vl)-benzamide 1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0,74mmol), 4-(1-cyclopentyl-piperidin-4-yl)-benzoic acid hydrochloride (0.74mmol), HOBT (0,74mmol), WSCD (0.74mmol) and triethylamine (0,74mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 233-234 1H)C, Rf=034 (CH2Cl2/MeOH (with 3N NH3) =9:1) is obtained. 1H-NMR (d6-DMS0):1.2-1.85 (m, 20H); 1.9-2.15 (m, 4H); 2.4-2,6 (m, 2H); 3,05 (d, 2H); 4.0 (d. 2H), 7.35 (d, 2H); 7.8 (d, 2H), 7.9 (s,11H); 8.15 (m,11H). Example 12: N-(1-(Cvanomethvl-carbamovl)-cYclohexvn-4-(l-methyl-piperidin-4'Vl)-benzamide A. 4-PhenYl-l-methvl-piperidine 4-Phenylpiperidine (12.4mmol), paraformaldehyde (24.8mmol) and tetraisopropoxy-titanium (12.4mmol) are suspended in 1,2-dimethoxyethane (20ml) and warmed to 60°C for 30 minutes and stirred at rt for one additional hour. Sodium borohydride (12.4mnK)I) is added in portions and the mixture is stirred at rt for 2 hours and at 60°C for additional 3 hours. After cooling the solvent is evaporated and the residue is dissolved in a mixture of aqueous ammonia (6QmI) and ethyl acetate and filtered carefully. The mixture is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil is obtained. B. 4-fl-MethvI-Diperidin-4'>vl)-benzoic acid methyl ester 4-Phenyl-l-methyl-piperidine (9.9mmol) is dissolved in CH2CI2 (60ml) and oxalylchloride (39,6mmol) is added dropwise at -20 to -10°C. After the oxalylchloride addition aluminium trichloride (260mmol) is added in portions at -10°C. The mixture is stirred at -10°C for 1,5 hours. Then the cooling bath is removed and the mixture is stirred at rt for another 2 hours. The mixture is cooled again to -0°C and methanol (30ml) is added dropwise. After completion of the methanol addition the cooling bath is removed and the mixture is stirred at rt overnight. The reaction mixture is poured into a mbcture of aqueous sodium carbonate (to ensure basic conditions) and ethyl acetate and the suspension is filtered carefully. The filtrate is extracted three times with ethyl acetate and the combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:1 as mobile phase. The product containing fractions are combined and evaporated. A pale yellow oil with RfeO.29 (CH2Cl2/MeOH=9:1) is obtained. C. 4-( l-MethvI-piperidin-4-vl)-benzoic acid hydrochloride 4-(l-Methyl-piperidin-4-yl)-benzoic acid methyl ester (4.55mmol) is dissolved in 4N HCl (10ml) and heated under reflux for 8 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum), A pale-brown powder with mp. >270°C is obtained. D. N"ri-fCvanomethylcarbamoyl)-cvclohexvn4fl-methvUpiperidin-4- vD-benzaroide 1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0,98mmol), 4-(l-methyl- piperidin-4-yl)-benzoic acid hydrochloride (0.98mmol), HOBT (0,98mmol), WSCD (0.98mmol) and triethylamine (0,98mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mbcture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A white powder with mp. 215-217°C. Rf=0.32 (CH2Cl2/MeOH (with 3N NH3) =9:1) is obtained. 1H-NMR (d6-DMSO): 1.2-1.3 (m, 1H); 1.4-1.8 (m, 1H); 1.85-2.0 (m, 2H); 2.05-2.2 (m, 5H); 2.55 (m, 1H); 2.95 (d, 2H); 4.0 (d, 2H), 7.35 (d, 2H); 7.8 (d, 2H), 7.9 (s, lH);8.15(m, 1H). Similarly N-[ 1 -(cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperidin-4-yl)-benzamide is obtained substantially as described above in Example 12; for instance by omitting Step A and starting the synthesis procedure at step B, using 4-phenylpiperidine as the starting material. CLAIMS 1, A compound of formula I, or a phannaceutically acceptable salt or ester thereof In which R1 and R2 are independently H or C1-C7 lower alkyl, or R1 and R2 together with the carbon atom to which they are attached form a C3-C8cycloalkyl ring, and Het is an optionally substituted nitrogen-containing heterocyclic substituent, provided that Het is not 4-pyrrol-1-yl. 2. A compound according to claim 1 of formula II, or a phannaceutically acceptable salt or ester thereof wherein X is CH or N, and R is C1-C7lower alkyl, C1-C7lower alkoxy-C1-C7lower alkyl, C5-C10 aryl-C1- C7 lower alkyl, or C3-C8 cycloalkyl. 3. A compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof, selected from N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperazin-l-yl)-benzaxnide; N- [ 1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-methyl-piperazin-1 -y])-benzamide; N- [ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-ethyl-piperazin-1 -yl)- benzamide; N-[l-(Cyanoniethyl-carbamoyl)-cyclohexyl]-4-[4-(l-propyl)-piperazin-l-yl]' benzamide; N-[ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-isopropyl-piperazin-1 -yl)- benzamide; N-[ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-benzyl-piperazin-1 -yl)- benzamide; N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[4-(2-methoxy-ethyl)-piperazin-l-yl]-benzamide; N-[l-(Cyanomethyl-carbanioyl)-cyclohexyl]-4-(l-propyl-piperidin-4-yl)-benzamide; N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[l-(2-methoxy-ethyl)-piperidin' 4-yl]-benzamide; N-[ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-( 1 -isopropyl-piperidin-4-yl)- benzamide; N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(l-cyclopentyI-piperidin-4-yl)- benzamide; N-[ 1 -(Cyanoniethyl-carbanoyl)yl)-cyclohexyl]-4-( l-methyl-piperidin-4-yl)- benzamide, or N- [ 1 -(C^anonaethyl-<:arbamoyl> 4. N-[l-(Cyanoroethyl-carbanoyl)-cyclohexyl]-4-[4-(l-propyl)-pipcrazin-l-yl)- benzamide, or a pharmaceutically acceptable salt or ester thereof 5. A compound according to claim 1 for use as a pharmaceutical. 6. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient. 7. A method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated, comprising administering an effective amount of a compound according to claim 1 to the patient. 8. The use of a compoundaccording to claim 1 for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is inplicated. 9. A process for the preparation of a compound of formula I or a salt or ester thereof which comprises coupling the corresponding Het substituted benzoic acid derivative of formula III wherein Het is as defined in claim 1, with 1-amino-cyclohexanecarboxylic acid cyanomethyl-amide. 10. A pharmaceutical composition substantially as herein described and exemplified. 11. A process for the preparation of a compound substantially as herein described and exemplified.

Full Text

PIPEPTTOE NITRILE CATHEPSIN K INHIBITORS
This invention relates to inhibitors of cysteine proteases, in particular to dipeptide nitrile cathepsin K inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsin K is implicated.
Cathepsin K is a member of the family of lysosomal cysteine cathepsin enzymes, e.g. cathepsins B, K, L and S, which are implicated m various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and immunologically mediated diseases (including transplant rejection).
Our copending International patent application WO 99/24460 describes dipeptide nitriles which are inhibitors of cysteine cathepsins and their use for treatment of cysteine cathepsin dependent diseases or medical conditions. New dipeptide nitrile compounds have now been made which are inhibitors of cathepsin K, and which have desirable properties for pharmaceutical applications.
Accordingly the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester thereof

In which
R1 and R2 are independently H or C1-C7lower alkyl, or R1 and R2 together with the
carbon atom to which they are attached form a C3-C8cycloalkyI ring« and

Het is an optionally substituted nitrogen-containing heterocyclic substituent, provided that Het is not 4-pyrrol-l-yl.
The Het substituent may be at the 2- or 3-position of the phenyl ring, though is preferably at the 4-position.
In the present description "nitrogen-containing heterocycle" signifies a heterocyclic ring system containing at least one nitrogen atom, from 2 to 10, preferably from 3 to 7, most preferably 4 or 5, carbon atoms and optionally one or more additional heteroatoms selected from O, S or preferably N,
Het may comprise an unsaturated, e.g. an aromatic, nitrogen-containing heterocycle; though preferably comprises a saturated nitrogen-containing heterocycle. Particularly preferred saturated nitrogen-containing heterocycles are piperazinyl, preferably piperazin-l-yl, or piperidinyl, preferably piperidin-4-yl
Het may be substituted by one or more substituents, e.g. by up to 5 substituents independently selected from halogen, hydroxy, amino, nitro, optionally substituted C1-4alkyl (e.g, alkyl substituted by hydroxy, alkyloxy, amino, optionally substituted alkylannino, optionally substituted dialkylamino, aryl or heterocyclyl), C1-4alkoxy.
Preferably Het is substituted at a nitrogen atom, most preferably mono-substituted at a nitrogen atom.

benzamide;
N-[l'(Cyanomethyl-carbanK)yl)-cycIohexyI]-4-[l-(2-methoxy-ethyl)-piperidin 4-yI]-benzamide;
N-[l-((Cyanomethyl-carbanoyl)-cyclohexyl]'4-(l-isopropyl-pipcri benzamide;
N-[l-(Cyanoinethyl-^arbanK)yI)-cyclohexyl]-4-(l-yclopentyl-piperidin-4-yl) benzamide;

N- [ 1 -(Cyanomethyl-carbamoyI)-cyclohexyl]-4-( 1 -niethyl-piperidin-4-yl)-benzamide, and
N-[ 1 -(Cyanornethyl-carbamoyl)-cyclohexyl]-4-(piperidin-4-yl)-benzamide. Compounds of formula I and II and the specific compounds above are hereinafter referred to as Compounds of the Invention,
Compounds of the Invention may be prepared by coupling the corresponding Het substituted benzoic acid derivative with 1-amino-cyclohexanecarboxylic acid cyanomethyl amide. For example, the benzoic acid derivative, preferably in the form of its hydrochloride, is mixed with 1-amino-cyclohexanecarboxylic acid cyanomethyl amide, e.g. in the presence of HOBT (l-hydroxybenzotriazole), WSCD and triethylamine, in solution, e.g. in DMF, and stirred, e.g. overnight at room temperature. The product may be recovered, for instance, by evaporation of the solvent, followed by washing with aqueous sodium carbonate solution, preferably under mildly basic conditions, followed by solvent extraction, e,g. with ethyl acetate, drying of the extract, e.g, over sodium sulfate, evaporation of the solvent and filtration. Alternative procedures and reagents may be used; for instance, as hereinafter described in the Examples.
Thus in a further aspect the invention provides a process for the preparation of a compound of formula I which comprises coupling the corresponding Het substituted benzoic acid derivative of formula in

l-Amino-cyclohexanecarboxylic acid cyanonoethyl-amide may be prepared by coupling 1-amino-cyclohexane carboxylic acid typically in appropriate amino

protected form, e.g. FMOC-1-amino-cyclohexane carboxylic acid, with 2-aminoacetonitrile. For example, FMOC-1-amino-cyclohexane carboxylic acid, e.g. with HOBT and WSCD, is added to a solution of 2-aminoacetonitrile and triethylamine in DMF and the mixture stirred at 25°C overnight. 1-Amino-cyclohexanecarboxylic acid cyanonnethyl-amide may be recovered as described in the Examples. FMOC-1-amino-cyclohexane carboxylic acid may be prepared as described in the Examples,
Compounds of the invention are either obtained in the free form, or as a salt thereof if salt forming groups are present.
Compounds of the Invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (Cr C4)alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fiimaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (C1C4)-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen). Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.
In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The conpounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
The compounds of the invention exhibit valuable pharmacological properties in mammals and are particularly useful as inhibitors of cathepsin K.
The cathepsin K inhibitory effects of the compound of the invention can be demonstrated in vitro by measuring the inhibition of e.g. recombinant human cathepsin K.

The in vitro assay is carried out as follows:
For cathepsin K:
The assay is performed in 96 well microtiter plates at ambient temperature using recombinant human cathepsin K. Inhibition of cathepsin K is assayed at a constant enzyme (0.16 nM) and substrate concentration (54 mM ZrPhe-Arg-AMCA -Peptide Institute Inc. Osaka, Japan) in 100 mM sodium phosphate buffer, pH 7.0, containing 2 mM dithiothreitol, 20 mM Tween 80 and 1 mM EDTA. Cathepsin K is preincubated with the inhibitors for 30 min, and the reaction is initiated by the addition of substrate. After 30 min incubation the reaction is stopped by the addition of E-64 (2 mM), and fluorescence intensity is read on a multi-well plate reader at excitation and emission wavelengths of 360 and 460 nm, respectively. Compounds of the Invention typically have Kis for human cathepsin K of less than about 50nM, preferably of about 5nM or less, e.g. about InM.
In view of their activity as inhibitors of cathepsin K, Compounds of the Invention are particularly useful in mammals as agents for treatment and prophylaxis of diseases and medical conditions involving elevated levels of cathepsin K. Such diseases include diseases involving infection by organisms such as Pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, crithidia fusiculata, as well as parasitic diseases such as schistosomiasis and malaria, tumours (tumour invasion and tumour metastasis), and other diseases such as metachromatic leukodystrophy, muscular dystrophy, amytrophy and similar diseases.
Cathepsin K, has been implicated in diseases of excessive bone loss, and thus the Compounds of the Invention may be used for treatment and prophylaxis of such diseases, including osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, e.g, tumour-induced hypercalcemia and metabolic bone disease. Also the Compounds of the Invention may be use for treatment or prophylaxis of diseases of excessive cartilage or matrix degradation, including osteoarthritis and rheumatoid arthritis as weU as certain neoplastic diseases involving expression of high levels of proteolytic enzymes and matrix degradation.
Compounds of the Invention, are also indicated for preventing or treating coronary disease, atherosclerosis (including atherosclerotic plaque rupture and

destabilization), autoimmune diseases, respiratory diseases and immunologically mediated diseases (including transplant rejection).
Compounds of the Invention are particularly indicated for preventing or treating osteoporosis of various genesis (e.g. juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or by cortico-steroid therapy or inactivity).
Beneficial effects are evaluated in in vitro and in vivo pharmacological tests generally known in the art, and as illustrated herein.
The above cited properties are demonstrable in in vitro and in vivo tests, using advantageously mammals, e.g. rats, mice, dogs, rabbits, monkeys or isolated organs and tissues, as well as mammalian enzyme preparations, either natural or prepared by e.g. recombinant technology. Compounds of the Invention can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions or suspensions, and in vivo either enterally or parenterally, advantageously orally, e.g. as a suspension or in aqueous solution, or as a solid capsule or tablet formulation. The dosage in vitro may range between about 10-5 molar and 10-9 molar concentrations. The dosage in vivo may range, depending on the route of administration, between about 0.1 and 100 mg/kg.
In accordance with the present invention it has been found that Compounds of the Invention, have good bioavailability, in particular good oral bioavailability. Thus, for example selected compounds of the Invention have absolute oral bioavailabilities of 50% or greater e.g. about 80% or more.
The antiarthritic efficacy of the Compounds of the Invention for the treatment of rheumatoid arthritis can be determined using models such as or similar to the rat model of adjuvant arthritis, as described previously (R.E, Esser, et, al. J. Rheumatology, 1993,20,1176,)
The efficacy of the compounds of the invention for the treatment of osteoarthritis can be determined using models such as or similar to the rabbit partial lateral meniscectomy model, as described previously (Colombo et al, Arth. Rheum 1993 26,875-886). The efficacy of the compounds in the model can be quantified using histological scoring methods, as described previously (O'Byme et al. Inflamm Resl995,44,S117-S118).

The efficacy of the compounds of the invention for the treament of osteoporosis can be determined using an animal model such as the ovariectomised rat or other similar species, e.g. rabbit or monkey, in which test compounds are administered to the animal and the presence of markers of bone resorption are measured in urine or serum (e,g, as described in Osteoporos Int (1997) 7:539-543).
Accordingly in further aspects the invention provides; A Compound of the Invention for use as a pharmaceutical;
a pharmaceutical composition comprising a Compound of the Invention as an active ingredient;
a method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated, comprising administering an effective amount of a Compound of the Invention to the patient, and the use of a Compound of the Invention for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated
The present invention relates to methods of using Compounds of the Invention and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals for inhibiting cathepsin K, and for the treatment of cathepsin K dependent conditions, such as the cathepsin K dependent conditions, described herein, e.g. inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.
Particularly the present invention relates to a method of selectively inhibiting cathepsin K activity in a mammal which comprises administering to a mammal in need thereof an effective cathepsin K inhibiting amount of a Compound of the Invention-More specifically such relates to a method of treating osteoporosis, rheumatoid arthritis, osteoarthritis, and inflammation (and other diseases as identified above) in mammals comprises administering to a mammal in need thereof a correspondingly effective amount of a Compound of the Invention,
The following examples axe intended to illustrate the invention and are not to be construed as being limitations thereon. Temratures are given in degrees Centrigrade. If not mentioned otherwise, all cvaporations are performed under reduced pressure, preferably between about 15 and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by

standard analytical methods, e.g. microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR), Abbreviations used are those conventional in the art.

Alternatively THF may be used as the solvent and l-chloro-3,5-dimethoxytriazine (CDMT) as the activator, together with N-methylmorpholine (NMM) during the coupling reaction; in which case the product may be recovered by addition of isopropylacetate and water, separation of the organic phase followed by washing with brine, partial evaporation of the solvent, recovery of the crystallised product by filtration and drying.
C* 1-Amino-cyclohexanecarfaoxvlic acid cvanomethyl-amide

Example 1: Synthesis of N-[1-(Cvanomethvl-carbamovl)-cvclohexvn-4-piperazin-l-yl-benzamide
A. 4-piperazin-l-vl-benzoic acid methvl ester
l-(4-Cyanophenyl)-piperazine (11mmol) is dissolved in 15ml of a mixture of concentrated sulfonic acid and methanol (5N) and stirred in a sealed tube at 1 lO°C for 3 hours. After evaporation of the solvent, the residue is dissolved in water and extracted with ethyl acetate. Addition of sodium carbonate to the water phase until pH=9 results in the precipitation of a white solid which is filtered off and dried (vacuum). A white powder with RfrK).59 (CHaQa/MeOH (+NH3 3N)=9:1) is obtained.
B, 4-piperazin-1-yl-benzoic acid hvdrochlorid
4-piperazin-l-yl-benzoic acid methyl ester (17mmol) is dissolved in 6N HCl (25ml) and heated under reflux for 3 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formed is filtered off, washed with acetone and dried (vacuum), A white powder with rap. >240°C is obtained.

D. N-[1-(CYanoinethvl-carbamovl)-cvclohexvl1-4-(4-FMOC-Piperazin-l-
vl)-benzamide
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (8,3mmol) 4-(4-EMOC-
piperazin-l-yl)-benzoic acid (8.3mmol), HOBT (8.3mmol) and WSCD (8,3mmol) are
dissolved in DMF (20ml) and stirred overnight at rt. After evaporation of the solvent,
the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly
basic conditions) and extracted three times with ethyl acetate. The combined extract is
# dried over sodium sulfate and evaporated. The residue is purified by flash
chromatography on silica gel with (ethylacetate/hexane=4:l) as mobile phase. The product containbg fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 192-194T, Rt=0.26 (CH2a2/MeOH=95:5) is obtained.

is stirred at RT for 4 hours. 4 additional drops of piperidine are added and the mixture is stirred over night. The reaction mixture is poured into water and ethyl acetate and the suspension is filtered and the filtrate is acidified with HCl 4N and then extracted with ethyl acetate. Saturated sodium carbonate solution is added to make the water phase basic and the mixture is extracted three times with ethyl acetate. The water phase is saturated with sodium chloride and extracted three times with ethyl acetate again. The organic fractions are dried over sodium sulfate and the solvent is evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 3N NHS) =95:5 as mobile phase. The product containing
fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 206-210°C, Rf=0.28 (CH2Cl2/MeOH (with 3N NH3) =9:1) is obtained.
lH-NMR(d6-DMS0): 1.15-1.35 (m, 1H); 1.4-1.6 (m, 5H); 1,65-1.8 (m, 2H); 2.05-2.15 (m. 2H); 2.8 (m, 4H); 3.15 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, 1H); 7.75 (d,2H),8.15(m, 1H),

C. N'ri-fCvanomethvl-carbainovl)>cvclohexvn-4-f4'inethvl-piperazin«l-vl)-benzamide
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (l,38mmol) 4-(4-methyl-piperazin-l-yl)'benzoic acid hydrochloride (1.38mmol), HOBT (1.38mmol), WSCD (1.38mmol) and triethylamine (1.38mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp. 218-220°C, Rf=0.19 (CH2Cl2/MeOH=9:l) is obtained.
IH-NMR (d6-DMS0): L15-1.35 (m, IH); 1.4-1.6 (m, 5H); 1.65-1.8 (m, 2H); 2.05-2.15 (m, 2H); 2.2 (s, 3H); 2.4 (m, 4H); 3.2 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, IH); 7,75 (d, 2H), 8.15 (m, IH).

under reflux overnight. After evaporation of the solvent, the residue is dissolved in water and extracted three times with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A brownish powder with mp. 102-104'C, Rf=0.22 (CH2Cl2/MeOH=95:5) is obtained.
B. 4-f4'Ethvl-piperazin-l-vl)-benzoic acid hvdrochlorid
4-(4-EthyI-piperazin-l-yl)-benzoic acid methyl ester (15mmol) is dissolved in 4N HCl (35ml) and heated under reflux for 8 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formed is filtered off, washed with acetone and dried (vacuum). A grey powder with mp. >270°C, Rf=0.08 (CH2Cl2/MeOH=9:1) is obtained.
C. N-ri-fCvanomethvl-carbamovl)-cvclohexvn-4-f4-ethvl-piperazin-l*vl)-
benzamide
1 - Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.9mmol) 4-(4-ethyl-piperazin-l-yl)-benzoic acid hydrochloride (0,9mmol), HOBT (0.9mmol), WSCD (0,9mmol) and triethylamine (0,9mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 3N NH3) -93:7 as mobile phase. The product containing
fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder is obtained, 1H-NMR (d6-DMSO): 1.0 (t, 3H), 1.15-1.35 (m, 1H); 1.4-1.6 (m. 5H); 1.65-1.8 (m, 2H); 2,05-2.15 (m, 2H); 2.35 (q, 2H); 2.45 (m, 4H); 3.2 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, 1H); 7.75 (d, 2H), 8.15 (m, 1H).

CS2CO3 may be used in place of K2CO3 in the above procedure.
B. 4-r4-fl-Propvn-piperazin-l-yl]-benzoic acid hvdrochlorid
. 4-[4-(I-Propyl)-piperazin-l'yl]-benzoic acid methyl ester (38mmol) is dissolved in 4N HCl (60ml) and heated under reflux for 7 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formed is filtered off, washed with cold water and dried (vacuum). A pale powder with mp,270°C, Rf=0.19 (CH2C12/MeOH=9:l) is obtained.

(22mmol) and triethylamine (22mmol) are dissolved in DMF (50ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=9:l) as mobile phase. The product containing fractions are combined
and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp, 216-218°C, Rf=0,34 (CH2Cl2/MeOH=9:l)
is obtained.
IH-NMR (d6-DMS0): 0.85 (t, 3H), 1.2-1.3 (m, IH); L4-1.6 (m, 7H); 1.65-1.8 (m, 2H); 2.05-2.15 (m, 2H); 2.25 (t, 2H); 2.45 (m, 4H); 3.2 (m, 4H); 4.0 (d, 2H), 6.95 (d, 2H); 7.65 (s, IH); 7.75 (d, 2H), 8.15 (m, IH).

evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=95:5) as mobile phase. The product containing fractions are
combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale-brown powder with Rf=0.23 (CH2Cl2/MeOH=95:5) is obtained.

A. 4'(4-BenzYl-DiDerazin-l-vl)-benzoic acid methyl ester
Tris-(dibenzylidene-acetone)-dipal]adium (0.03mmol), (2-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0,9mmol) and NaOtBu (6.5mmol) are suspended in toluene (20ml) in an oxygen-free atmosphere (N2). 4-Bromo-benzoic acid methyl ester (4.65mmol) and l-(benzyl)-piperazine (5.6nimol) are added and the stirred mixture is heated under reflux for 4 hours. After cooling, a mixture of ethylacetate and diethylether is added and the mixture is filtered. Then the solvent is evaporated and the residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp.l05-107T, Rf=0.67 (CH2Cl2/MeOH=95:5) is obtained.
B. 4-(4-Benzyl-piDerazin-l-ylVbenzoic acid hydrochloride
4-(4-Benzyl-piperazin-l-yl)-benzoic acid methyl ester (0.84mmol) is dissolved in 4N HCl (2ml) and heated under reflux for 8 hours. The mixture is cooled in an ice bath to 0-4°C and the solid material formedis filtered off, washed with cold acetone and dried (vacuum). A grey powder with mp. >270°C, Rf=0.18 (CH2Cl2/MeOH=95:5) is
obtained.

(m, 5H), 7.65 (s, 1H); 7.75 (d. 2H), 8.15 (m, 1H).
Example 7: Synthesis of N-ri-(CvanomethYl-carbamoYl)-CYclohexvll-4-r4-f2-rnethoxy-ethvl)-piperazin-l-vn»benzamide
A. 4-(4-BenzYl'Piperazin-l-vl)-benzoic acid methyl ester
4-Fluoroben2oic acid methyl ester (200mmol), l-benzyl-piperazine (300mmol), and potassium carbonate (300mmol) are suspended in acetonitrile (400ml) and stirred under reflux for 6 days. After evaporation of the solvent, the residue is dissolved in water and extracted three times with diethylether. The extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatographie on silica gel with (CH2CI2 first, then CH2Cl2/MeOH-15:l) as mobile phase. The product
containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum), A powder with mp. 105-107°C is obtained.
B. 4-(Piperazin-1-yl)-benzoic acid methyl ester
4-(4-Benzyl-piperazin-l-yl)-benzoic acid methyl ester (19.4mmol) is dissolved in methanol (150ml) and Pd/charcoal is added (0.6g). The mature is stirred in a hydrogen atmosphere until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A powder with mp. 95-97°C is obtained.
C. r4*f2-methoxy'ethvlVpiP€razin-l-vll-benzoic acid methvl ester
4-(Piperazin-1 -yl)-benzoic acid methyl ester (19mmol), 2-bromoethylmethylether (21mmol), and potassium carbonate (22,8mmol) are suspended in acetonitrile (50ml) and stirred at 80°C for 8 hours. After evaporation of the solvent, the residue is dissolved in water and extracted three times with CH2CI2- The extract is dried over
sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum), A powder with mp. 103-105°C is obtained.

D» f4-(2-inethoxy--ethyl)-piperazin-l-vn-benzoic acid hydrochloride
[4-(2-methoxy-ethyl)-piperazin-l-yl]-benzoic acid methyl ester (17mmol) is dissolved in 4N HCl (TOml) and heated under reflux for 5 hours. After cooling the solvent is evaporated and the residue is suspended in ethanol and the solid filtered of, washed with diethylether and dried (vacuum). A powder with mp. >270°C, Rf=0.35 (CH2Cl2/MeOH=9:l) is obtained.
E. N-(1-(CYanomethvl-Carbamovl)'-cvclohexvn-4-[4-(2-methoxv-ethYl)-
piperazin-l-vn-benzamide
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (l.Ommol), [4-(2-methoxy-ethyl)-piperazin-1 -yl]-benzoic acid hydrochloride (1 .Ommol), HOBT (1 .Ommol), WSCT) (l.Ommol) and triethylamine (l.Ommol) are dissolved in DMF (4ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=92.5:7.5 as mobile phase. The product containing fractions are
combined and evaporated. The residue is suspended in diethylether and the' solid

extracted three times with water and the water phase is extracted again with CH2CI2.
The combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil with Rf=0,13 (ethyl acetate/hexane=l:l) is obtained.
B. 4-Piperidin-4-vL-benzoic acid
l-(4-Phenyl-piperidIN-l-yl)-ethanone (84mmol) is dissolved in CH2CI2 (250ml) and
oxalylchloride (336mmol) is added dropwise at -20 to -10°C. After the oxalylchloride addition aluminium trichloride (260mmol) is added in portions at -lO°C. The mixture is stirred at -10°C for 3 hours. The cooling bath is removed and the mixture is stirred at rt overnight. The mixture is poured on ice/water (600ml) and extracted 3 times with CH2CI2. The combined organic phases are washed with water, dried over sodium
sulfate and evaporated. The residue is dissolved in aqueous sodium hydroxide solution (2N, 250ml) and 6N HCl is added at O°C to acidify the solution. The precipitate formed is filtered off and washed with water. The solid material is suspended in 6N HCl (300ml) and the mbtture is heated for 18 hours under reflux. After cooling to rt the solvent is removed and the residue is suspended in ethanol. The solid material is filtered of and dried. A brown powder with mp. >270'C is obtained.

dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:l as mobile phase. The product containing fractions are
combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale brown powder with Rf=0.35 (CH2Cl2/MeOH=9:l) is obtained.

Example 9: Synthesis of N-fl-fCvanomethvl-carbainoyl)-cvclohexvl1^ 4-ri'f2-methoxY-ethvl)-Diperidin-4-vn-benzainide
A* 4-Carboxybenzeneboronic acid methyl ester
4-Carboxybenzeneboronic acid (SOOmmol) is dissolved in methanol (400ml) and 1.5ml concentrated HCl is added to the stirred solution. The reaction is heated under reflux for 30 hours. The solvent is evaporated, the remaining residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp. 201-205*^0, Rfc=0.28 (CH2Cl2/MeOH=95:5) is obtained. This powder is a mixture of
4-carboxyben2:eneboronic acid methyl ester and the dimeric anhydride of 4-carboxybenzeneboronic acid methyl ester and is used without further purification,
B, 4'Pyridin*4-vl'benzoic acid methvl ester
4-Carboxybenzeneboronic acid methyl ester (248mmol) from A, 4-bromopyridine (248mmoI), tetrakis-(triphenylphosphin)-palladium (2.5mmol) and potassium carbonate (744mmol) are suspended in 1,2-dimethoxyethane (1100ml). The stirred mature is heated under reflux for 8 hours. After cooling the solvent is evaporated and water is added to the residue which is then extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale-brown powder with mp. 99-lO°C, Rf=0.39 (CH2Cl2/MeOH=95:5) is obtained.

in a hydrogen atmosphere at normal pressure until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is dissolved in CH2CI2
and extracted with aqueous sodium carbonate solution. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:1 as mobile phase. The product containing fractions
are combined and evaporated. A pale yellow oil with Rf=0.22 (CH2Cl2/MeOH=95:5)
is obtained.
E. 4-(1-(2-Methoxy-ethvl)-piperidin-4'Vl1'benzoic acid hydrochloride
4-[l-(2-Methoxy-ethyl)-piperidin-4-yl]-benzoic acid methyl ester (47mmol) is dissolved in 4N HCl (80ml) and heated under reflux for 12 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A white powder with mp. >270°C is obtained.

2H); 7.35 (d, 2H); 7.8 (d. 2H); 7.9 (s, IH); 8.15 (m, IH).
Example 10: N-fl-(Cvanomethv!-carbainovl)-cvclohexvn-4-(l-isoproDvl-' piperidin'4*vl)-benzamide
A. l-IsopropYl-4'(4-methoxvcarbonvl-phenvlVpvridiniuni; bromide
4-Pyridin-4-yl-benzoic acid methyl ester (2.3mmol) and 2-iodopropane (1.0ml) are heated for 24 hours to 90^C. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of and dried (vacuum). A pale-yellow powder with mp. 187-189°C,Rf=0.27 (CH2Cl2/MeOH=9:l) is obtained.
B. 4-( l-Isopropvl-piperidin-4-vi)-benzoic acid methvl ester hvdroiodide
1-Isopropyl-4-(4-methoxycarbonyl-phenyl)-pyridinium; bromide (1.9mmol) is suspended in methanol (10ml) and platinoxide (80mg) is added. The mixture is stirred in a hydrogen atmosphere at normal pressure until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale powder with mp. 219-224°C, Rf=0.41 (CH2Cl2/MeOH =9:1) is obtained.

(0.95mmol) and triethylamine (0.95mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 214-216°C, Rf=0.38 (CH2Cl2/MeOH (with 3N NH3) =9:1) is obtained.
1H-NMR (d6-DMS0): 0.95 (d, 6H); 1.2-1.3 (m, 1H); 1,4-1.8 (m, 1H); 2.05-2,25 (m, 4H); 2.55 (m, 1H); 2.7 (m, 1H); 2.85 (d, 2H); 4.0 (d, 2H), 7.35 (d, 2H); 7.8 (d, 2H). 7.9 (s,lH); 8.15 (m,lH).
Example 11: N-ri-fCvanomethYl-carbamovl)-cYclohexvll-4-(l-cvclopentvl -piperidin-4-vn'benzainide
A. l-Cvclopentvl -4-(4-methoxvcarbonvl»phenvl)-pvridinium; bromide
4-Pyridin-4-yl-benzoic acid methyl ester (2,35nimol) and 1-iodocyclopentane (1.0ml) are heated for 4 hours to llO°C. 1-Iodocyclopentane (0,5ml) are added and the mixture is heated for another 4 hours to 120°C. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of and dried (vacuum). The solid residue is purified by flash chromatography on silica gel with CH2Cl2/ME0H
=9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum), A yellow powder with mp, 183-185X,RfM).35 (CH2Cl2/MeOH=9:l) is obtained.
B. 4-(l-Cvclopentvl-piperidin-4-ylVbenzoic acid methvl ester hydro-
iodide
1 -Cyclopentyl-4-(4-methoxycarbonyl-phenyl)-pyridinium; bromide (1,27iranol) is suspended in methanol (8ml) and platinoxide (50mg) is added. The mixture is stirred in a hydrogen atmosphere at normal pressure until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale powder with mp. 204-210°C, RM),27 (CH2 cL2/MeOH =95:5) is obtained.

C. 4-(l-CvclopentYl-piperidin-4-vl)-benzoic acid hydrochloride
4-(l-Cyclopenlyl-piperidin-4-yl)-benzoic acid methyl ester hydroiodide (1.06mmol) is dissolved in 4N HCl (5ml) and heated under reflux for 10 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A grey-brown powder with mp. >270'C is obtained,
D, N-(1-fCvanomethvl-carbamoyl)-cvclohexvn-4-(l-cvclopentvl-
piperidin-4-vl)-benzamide
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0,74mmol), 4-(1-cyclopentyl-piperidin-4-yl)-benzoic acid hydrochloride (0.74mmol), HOBT (0,74mmol), WSCD (0.74mmol) and triethylamine (0,74mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 233-234 1H)C, Rf=034 (CH2Cl2/MeOH (with 3N NH3) =9:1) is obtained.
1H-NMR (d6-DMS0):1.2-1.85 (m, 20H); 1.9-2.15 (m, 4H); 2.4-2,6 (m, 2H); 3,05 (d, 2H); 4.0 (d. 2H), 7.35 (d, 2H); 7.8 (d, 2H), 7.9 (s,11H); 8.15 (m,11H).
Example 12: N-(1-(Cvanomethvl-carbamovl)-cYclohexvn-4-(l-methyl-piperidin-4'Vl)-benzamide
A. 4-PhenYl-l-methvl-piperidine
4-Phenylpiperidine (12.4mmol), paraformaldehyde (24.8mmol) and tetraisopropoxy-titanium (12.4mmol) are suspended in 1,2-dimethoxyethane (20ml) and warmed to 60°C for 30 minutes and stirred at rt for one additional hour. Sodium borohydride (12.4mnK)I) is added in portions and the mixture is stirred at rt for 2 hours and at 60°C for additional 3 hours. After cooling the solvent is evaporated and the residue is dissolved in a mixture of aqueous ammonia (6QmI) and ethyl acetate and filtered

carefully. The mixture is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil is obtained.
B. 4-fl-MethvI-Diperidin-4'>vl)-benzoic acid methyl ester
4-Phenyl-l-methyl-piperidine (9.9mmol) is dissolved in CH2CI2 (60ml) and
oxalylchloride (39,6mmol) is added dropwise at -20 to -10°C. After the oxalylchloride addition aluminium trichloride (260mmol) is added in portions at -10°C. The mixture is stirred at -10°C for 1,5 hours. Then the cooling bath is removed and the mixture is stirred at rt for another 2 hours. The mixture is cooled again to -0°C and methanol (30ml) is added dropwise. After completion of the methanol addition the cooling bath is removed and the mixture is stirred at rt overnight. The reaction mixture is poured into a mbcture of aqueous sodium carbonate (to ensure basic conditions) and ethyl acetate and the suspension is filtered carefully. The filtrate is extracted three times with ethyl acetate and the combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:1
as mobile phase. The product containing fractions are combined and evaporated. A pale yellow oil with RfeO.29 (CH2Cl2/MeOH=9:1) is obtained.
C. 4-( l-MethvI-piperidin-4-vl)-benzoic acid hydrochloride
4-(l-Methyl-piperidin-4-yl)-benzoic acid methyl ester (4.55mmol) is dissolved in 4N HCl (10ml) and heated under reflux for 8 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum), A pale-brown powder with mp. >270°C is obtained.
D. N"ri-fCvanomethyl*carbamoyl)-cvclohexvn*4*fl-methvUpiperidin-4-
vD-benzaroide
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0,98mmol), 4-(l-methyl-
piperidin-4-yl)-benzoic acid hydrochloride (0.98mmol), HOBT (0,98mmol), WSCD (0.98mmol) and triethylamine (0,98mmol) are dissolved in DMF (5ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mbcture of water and sodium carbonate (to ensure basic conditions) and extracted three times with

ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A white powder with mp. 215-217°C. Rf=0.32 (CH2Cl2/MeOH (with 3N
NH3) =9:1) is obtained.
1H-NMR (d6-DMSO): 1.2-1.3 (m, 1H); 1.4-1.8 (m, 1H); 1.85-2.0 (m, 2H); 2.05-2.2 (m, 5H); 2.55 (m, 1H); 2.95 (d, 2H); 4.0 (d, 2H), 7.35 (d, 2H); 7.8 (d, 2H), 7.9 (s, lH);8.15(m, 1H).
Similarly N-[ 1 -(cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperidin-4-yl)-benzamide is obtained substantially as described above in Example 12; for instance by omitting Step A and starting the synthesis procedure at step B, using 4-phenylpiperidine as the starting material.

CLAIMS
1, A compound of formula I, or a phannaceutically acceptable salt or ester thereof

In which
R1 and R2 are independently H or C1-C7 lower alkyl, or R1 and R2 together with the carbon atom to which they are attached form a C3-C8cycloalkyl ring, and Het is an optionally substituted nitrogen-containing heterocyclic substituent, provided that Het is not 4-pyrrol-1-yl.
2. A compound according to claim 1 of formula II, or a phannaceutically
acceptable salt or ester thereof

wherein X is CH or N, and
R is C1-C7lower alkyl, C1-C7lower alkoxy-C1-C7lower alkyl, C5-C10 aryl-C1-

C7 lower alkyl, or C3-C8 cycloalkyl.
3. A compound according to claim 1, or a pharmaceutically acceptable salt or
ester thereof, selected from
N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperazin-l-yl)-benzaxnide; N- [ 1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-methyl-piperazin-1 -y])-benzamide;
N- [ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-ethyl-piperazin-1 -yl)-
benzamide;
N-[l-(Cyanoniethyl-carbamoyl)-cyclohexyl]-4-[4-(l-propyl)-piperazin-l-yl]'
benzamide;
N-[ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-isopropyl-piperazin-1 -yl)-
benzamide;
N-[ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-benzyl-piperazin-1 -yl)-
benzamide;
N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[4-(2-methoxy-ethyl)-piperazin-l-yl]-benzamide;
N-[l-(Cyanomethyl-carbanioyl)-cyclohexyl]-4-(l-propyl-piperidin-4-yl)-benzamide;
N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[l-(2-methoxy-ethyl)-piperidin' 4-yl]-benzamide;
N-[ 1 -(Cyanomethyl-carbamoyl)-cyclohexyl]-4-( 1 -isopropyl-piperidin-4-yl)-
benzamide;
N-[l-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(l-cyclopentyI-piperidin-4-yl)-
benzamide;
N-[ 1 -(Cyanoniethyl-carbanoyl)yl)-cyclohexyl]-4-( l-methyl-piperidin-4-yl)-
benzamide, or
N- [ 1 -(C^anonaethyl-<:arbamoyl> 4. N-[l-(Cyanoroethyl-carbanoyl)-cyclohexyl]-4-[4-(l-propyl)-pipcrazin-l-yl)-
benzamide, or a pharmaceutically acceptable salt or ester thereof

5. A compound according to claim 1 for use as a pharmaceutical.
6. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient.
7. A method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated, comprising administering an effective amount of a compound according to claim 1 to the patient.
8. The use of a compoundaccording to claim 1 for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is inplicated.
9. A process for the preparation of a compound of formula I or a salt or ester thereof which comprises coupling the corresponding Het substituted benzoic acid derivative of formula III

wherein Het is as defined in claim 1, with 1-amino-cyclohexanecarboxylic acid cyanomethyl-amide.

10. A pharmaceutical composition substantially as herein described and
exemplified.
11. A process for the preparation of a compound substantially as herein
described and exemplified.

Documents:

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in-pct-2002-1215-che-abstract.pdf

in-pct-2002-1215-che-claims filed.pdf

in-pct-2002-1215-che-claims granted.pdf

in-pct-2002-1215-che-correspondence others.pdf

in-pct-2002-1215-che-correspondence po.pdf

in-pct-2002-1215-che-description complete filed.pdf

in-pct-2002-1215-che-description complete granted.pdf

in-pct-2002-1215-che-form 1.pdf

in-pct-2002-1215-che-form 19.pdf

in-pct-2002-1215-che-form 26.pdf

in-pct-2002-1215-che-form 3.pdf

in-pct-2002-1215-che-form 5.pdf

in-pct-2002-1215-che-other documents .pdf

in-pct-2002-1215-che-pct.pdf

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Patent Number

211742

Indian Patent Application Number

IN/PCT/2002/1215/CHE

PG Journal Number

52/2007

Publication Date

28-Dec-2007

Grant Date

09-Nov-2007

Date of Filing

07-Aug-2002

Name of Patentee

M/S. NOVARTIS AG

Applicant Address

Lichtstrasse 35, CH-4056 Basel,

Inventors:

#	Inventor's Name	Inventor's Address
1	MISSBACH, Martin	Hofstrasse 15, CH-5073 Gipf-Oberfrick,

PCT International Classification Number

C07D 211/34

PCT International Application Number

PCT/EP2001/001359

PCT International Filing date

2001-02-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0003111.2	2000-02-10	U.K.