AU7976400A - Novel imidazopyridine carbonitrile compounds - Google Patents

Description

WO 01/25237 PCT/SE00/01860 NOVEL IMIDAZOPYRIDINE CARBONITRILE COMPOUNDS Technical field 5 In general, the present invention relates to a selective inhibitor of mammalian osteoclast cell activity, processes for its preparation and pharmaceutical compositions comprising the same as well as methods of treatment, where said selective inhibitor is administered to a human or animal patient. More specifically, the present invention relates to a selective inhibitor of vacuolar H+-ATPase in mammalian osteoclast cells. 10 Background art Diseases associated with loss of bone mass, i.e. conditions involving bone resorption, are known to be caused by over activity of osteoclast cells. It is known that certain 15is compounds, usually structurally related to bafilomycin, are inhibitors of vacuolar H + ATPase in osteoclast cells, thereby being potentially useful for treatment of said diseases, see e.g. WO 91/06296, WO 98/01443, WO 98/01423, WO 98/01436, WO 98/01445 and WO 96/21644. Furthermore, certain quinolines and benzimidazoles are also claimed to be inhibitors of vacuolar H+-ATPase, see e.g. WO 97/14681 and WO 97/102219 and certain 20 imidazopyridines are claimed to be effective in the therapeutic treatment of diseases caused by abnormal bone metabolism, see e.g. WO96/34866. Recent evidence suggests that isoforms of the 116 kDa ("a") subunit of vacuolar H+-ATPase exist. At present, it appears that there are three subtypes of "a" in vertebrate species, and they are denoted "al", "a2" and "a3", respectively. Of these, "al" has been cloned from rat and bovine brain and may 25 represent the ubiquitous intracellular isoform of "a" (see Perin, M. S., Fried, V. A., Stone, D. K., Xie, X. S. and Sudhof, T. C., Journal of Biological Chemistry, 266(6), 3877-81 (1991) and Peng, S. B., Crider, B. P., Xie, X. S. and Stone, D. K., Journal of Biological Chemistry, 269(25), 17262-6 (1994)). Solely on the basis of its sequence homology, the subtype "a2" (TJ6 mouse immunosuppressor factor), is thought to be an isoform of "a" 30 (Lee, C., Ghoshal, K. and Beaman, K. D., Molecular Immunology, 27(11), 1137-44 (1990)). The third subtype, i.e. "a3" (EMBL accession number U45285), has been cloned from a human osteoclastoma cDNA library and suggested to be an osteoclast-specific WO 01/25237 PCT/SE00/01860 2 isoform of"a" (Li, Y. P., Chen, W. and Stashenko, P., Biochemical & Biophysical Research Communications, 218(3), 813-21 (1996)). In summary, none of the compounds disclosed in the prior art above provides sufficient 5 therapeutic efficiency in the treatment of disorders related to bone resorption. Thus, there is a demand in the art for new therapeutic agents against such disorders. Disclosure of the invention 10 Surprisingly, novel compounds with excellent therapeutical effect against physiological disorders involving inter alia bone resorption have now been found. More specifically, said compounds comprise a selective inhibitor of mammalian osteoclast cell activity, wherein said inhibitor comprises an imidazopyridine carbonitrile compound. Since the selective inhibitor of the present invention has been found to inhibit vacuolar H+-ATPase, 15 such as vacuolar H+-ATPase in osteoclast cells, it is thereby therapeutically efficient against physiological disorders involving bone resorption. According to the present invention, said imidazopyridine carbonitrile compound has the general formula I: R2 20 NC N~ N 25 7 wherein R 1 is selected from the group consisting of (a) H; (b) O-alkyl having 1-3 carbon atoms; 30 (c) R 1 + R 2 form a five membered ring containing at least one O, S and/or N; (d) alkyl having 1-3 carbon atoms and (e) S-methyl or S- ethyl; WO 01/25237 PCT/SE00/01860 3

R

2 is selected from the group consisting of (a) H; (b) straight chain, branched or cyclic saturated or unsaturated alkyl having 1-6 carbon 5 atoms; (c) NR 8

R

9 , wherein R 8 and R 9 are either independently selected from the group consisting of H; a straight chain, branched or cyclic saturated or unsaturated alkyl having 1-6 carbon atoms, optionally substituted with O-alkyl, NH-alkyl, N-dialkyl, N pyrrolidinyl, N-piperidinyl, N-morpholinyl or N-piperazinyl; and aryl selected from the 0 group consisting of phenyl, imidazolyl, pyridinyl or pyrrolyl; or together form a five or six membered saturated or unsaturated ring, optionally containing O, S, and/or N; (d) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms optionally substituted with O-alkyl, NH-alkyl, N-dialkyl, N-pyrrolidinyl, N piperidinyl, N-morpholinyl or N-piperazinyl; is (e) straight chain, branched or cyclic saturated or unsaturated S-alkyl having 1-6 carbon atoms optionally substituted with O-alkyl , NH-alkyl, N-dialkyl, N-pyrrolidinyl, N piperidinyl; R3-R 7 are selected from the group consisting of 20 (a) H (b) alkyl having 1-3 carbon atoms (c) O-alkyl having 1-3 carbon atoms (d) S-methyl or S- ethyl wherein at least one of R 1

-R

3 and R 4

-R

7 , respectively, is not H 25 or a pharmaceutically acceptable salt thereof. In another preferred embodiment, R 2 is S-Me, NR8R 9 , O-alkyl or alkyl having 1-6 carbon atoms; R 1 , R 3 and R 4 are H; and R 5 , R 6 and R 7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms. 30 SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SEOU/01860 4 In yet another preferred embodiment, R 2 is S-Me, NR 8

R

9 , O-alkyl or alkyl having 1-6 carbon atoms; R 1 , R 3 , R 4 , R 5 are H; and R 6 and R 7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms. 5 In still another preferred embodiment, R 2 is S-Me, NR 8

R

9 , O-alkyl or alkyl having 1-6 carbon atoms; R 1 , R 3 , R 5 , R 6 , R 7 are H; and R 4 is straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms. In a particularly preferred embodiment of the present invention, said imidazopyridine 10 carbonitrile compound is selected from the group consisting of: 7-(4-dimethylamino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[1,2- a]pyridine-8 carbonitrile; 5-(3,4-dimethoxy-phenyl)-7-(4-methoxy-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile; 7-(4-pyrrolidin- 1 -yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[1,2- a]pyridine-8 15 carbonitrile. The present invention also relates to a process for the preparation of an imidazopyridine carbonitrile compound according to any one of the embodiments set forth above. 20 In one embodiment of said preparation, a suitably substituted amino-nicotinonitrile is heated with an co-halosubstituted carbonyl reagent under basic conditions, optionally in the presence of a solvent, during 2-24 h. In another embodiment, a suitably substituted 1,3-diphenyl-propane-1,3-dione and a 25 suitably substituted (1H-benzimidazol-2-yl)-acetonitrile are treated with an alkali metal alkoxide and refluxed in an alcohol during 2-12 h. In the preparation of imidazopyridine carbonitrile compounds according to the present invention, the following references provide useful guidance concerning e.g. suitable 30 reaction conditions and proper selection of reagents and starting materials: Zimmermann, T., J. Prakt. Chem./Chem.-Ztg., 335(8), 717-20 (1993); Kaminski, J.J., Doweyko, A.M., J. Med. Chem., 40(4), 427-436 (1997); SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SE00/01860 5 Barlin, G.B., Davies, L.P., Harrison, P.W., Aust. J. Chem., 48(5), 1031-1038 (1995); Kambe, S., Saito, K., Synthesis, 5, 366-368 (1980); Hishmat, O.H., Micky, J.A.A., Sahleh, N.M., Pharmazie, 44(12), 823-825 (1989). 5 Scheme 1 below illustrates general synthetic pathways for the preparation of the imidazopyridine carbonitrile compounds of the present invention. By guidance of inter alia known reference literature (vide supra), the synthesis of suitable starting materials is readily accomplished by a person skilled in the art. SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SE00/01860 6 R2 Ri R 3 7 R7 R3 Procedure 1 Procedure 2 NC1 NaH 2

HC

3 NaOEt NaHC 3 NaOEt CHClz heat heat 15

R

2 Ri R3 NC' r .[ . '4(I) NC M 20 N N R4 -- 5 R6

R

7 25 Scheme 1. Synthesis of compounds with the general formula I. SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SE00/01860 7 General procedures for the synthesis of compounds represented by the formula I are outlined below. Procedure 1: 5 Appropriate amounts of a suitably substituted amino-nicotinonitrile and an ct halosubstituted carbonyl reagent are heated under basic conditions, e.g. in the presence of NaHCO3, in a suitable solvent, such as e.g. ethanol, butanol or chloroform, for about 2-24 h. After evaporation, dilution with CH 2 Cl 2 , washing with brine and drying, the solvent is removed. The residue is purified either by recrystallisation or chromatography on silica 10 gel. From this procedure, substituted 5,7-diphenyl-imidazo[1,2-a]pyridine-8-carbonitrile is isolated. Procedure 2 (especially for compounds, where R 9 and R 10 are part of a benzene ring): Appropriate amounts of a suitably substituted 1,3-diphenyl-propane-1,3-dione and a 5is suitably substituted (1H-benzimidazol-2-yl)-acetonitrile are treated with an alkali metal alkoxide, such as NaOEt, and refluxed in an alcohol for 2-12 h. The imidazopyridine carbonitrile compound is isolated as in procedure 1. Furthermore, the present invention relates to an imidazopyridine carbonitrile compound 20 with the general formula I for use as a pharmaceutical. Thus, the present invention also relates to a pharmaceutical composition comprising an imidazopyridine carbonitrile compound according to any one of the embodiments set forth above as active ingredient in association with a pharmaceutically acceptable adjuvant, 25 diluent or carrier. In said pharmaceutical composition, the amount of said active ingredient per dosage unit is generally within the range of about 1 to 1 000 mg preferably 1-300 mg. 30 Moreover, the amount of said active ingredient is typically within the range of about 0.1 to 95% by weight of said pharmaceutical composition.

WO 01/25237 PCT/SE00/01860 8 Additionally, the present invention is also related to the use of an imidazopyridine carbonitrile compound according to any one of the previously outlined embodiments in the manufacture of a medicament for use in therapeutic or prophylactic treatment of a human or animal body. 5 In a preferred embodiment, said use is related to a medicament intended for treatment involving inhibition of vacuolar H+-ATPase, preferably vacuolar H+-ATPase in osteoclast cells. 10 In another preferred embodiment of said use, the medicament is intended for treatment involving inhibition of vacuolar H+-ATPase containing the isoform a3, said vacuolar H+ ATPase preferably being present in osteoclast cells. In yet another preferred embodiment, said medicament is intended for treatment involving 15 inhibition of bone resorption, or is intended for treatment and/or prevention of diseases related to increased bone resorption, preferably osteoporosis. In still another preferred embodiment of said use, the medicament is intended for treatment of Paget's disease of bone, hyperparathyroidism, malignant neoplasms, parodontal 20 diseases, prosthetic and/or implant related bone loss, tumours, AIDS and disorders related thereto, Alzheimer's disease, angiogenesis, atherosclerosis, rheumatoid arthritis, diabetic retinopathy, psoriasis or diabetes. The present invention is also related to a method for inhibiting vacuolar H+-ATPase, 25 preferably vacuolar H+-ATPase in osteoclast cells, or to a method for inhibiting vacuolar H+-ATPase containing the isoform a3, said vaculoar H+-ATPase preferably being present in osteoclast cells, wherein any one of said methods comprises administering to a human or animal patient a therapeutically effective amount of an imidazopyridine carbonitrile compound according to any one of the embodiments outlined above. 30 Moreover, the present invention is related to a method for inhibiting bone resorption, or to a method for treatment and/or prevention of diseases related to increased bone resorption, WO 01/25237 PCT/SE00/01860 9 preferably osteoporosis, wherein any one of said methods comprises administering to a human or animal patient a therapeutically effective amount of an imidazopyridine carbonitrile compound according to any one of the embodiments set forth above. 5 Furthermore, the present invention concerns a method for treatment of Paget's disease of bone, hyperparathyroidism, malignant neoplasms, parodontal diseases, prosthetic and/or implant related bone loss, tumours, AIDS and disorders related thereto, Alzheimer's disease, angiogenesis, atherosclerosis, rheumatoid arthritis, diabetic retinopathy, psoriasis or diabetes, wherein said method comprises administering to a human or animal patient a o10 therapeutically effective amount of an imidazopyridine carbonitrile compound according to any one of the previously outlined embodiments. The typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as e.g. the individual requirement of each patient, the route of 15 administration and the disease. However, oral and parenteral doses will usually be in the range of 1 to 1000 mg, preferably 1-300 mg, per day of the active ingredient. In another aspect, the present invention relates to pharmaceutical compositions containing at least one compound according to the invention, or a therapeutically acceptable salt 20 thereof, as active ingredient. In cases where the active ingredient contains a basic nitrogen, the pharmaceutically acceptable salts include acid addition salts. Acids that form therapeutically acceptable salts are e.g. hydrohalogen acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sufphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, 25 glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbensensulphonic acid, toluenesulphonic acid and naphtalenesulphonic acid. 30 As outlined above, there is provided an imidazopyridine carbonitrile compound for use as a pharmaceutical. Thus, it may be used in pharmaceutical compositions for oral, intravenous, SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SE00/01860 10 topical, intraperitoneal or subcutaneous administration, in association with one or more pharmaceutically acceptable carriers, diluents or adjuvants that are well known in the art. The pharmaceutical composition of the invention may be administered topically, in the 5 form of solutions, suspensions or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. 10 Experimental part Preparation of compounds illustrating the invention. Example 1. 15 7-(4-Dimethylamino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-a]pyridine-8 carbonitrile 1 ml of chloroacetaldehyde (50% in water) was dissolved in 10 ml of chloroform and refluxed with water separation (Dean-Stark) until about 5 ml of chloroform/water was 20 removed. 120 mg (0.3 mmol) 2-amino-3-cyano-4-(4-dimethylamino-phenyl)-6-(3,4,5 trimethoxy-phenyl)-pyridine and 50 mg (0.6 mmol) NaHCO 3 was added, and the mixture was stirred at 60'C over night. The solvent was removed in vacuo, and the residue was dissolved in methylene chloride. The organic phase was washed with water and dried over sodium sulphate. Recrystallisation from ethanol gave 90 mg (70%) of the title compound. 25 'H NMR (400 MHz, CDCl 3 ), 6-value in ppm: 3.05 (s, 6H); 3.91 (s, 6H); 3.96 (s, 3H); 6.82 (d, 2h); 6.86 (s, 2H); 6.96 (s, 1H); 7.69 (d, 2H); 7.71 (min, 2H). CI IDOTITI ITC: CWPT II F 9R WO 01/25237 PCT/SEOU/0186U 11 Example 2. 5-(3,4-Dimethoxy-phenyl)-7-(4-methoxy-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile 5 As in example 1, albeit with 100 mg (0.28 mmol) 2-amino-3-cyano-4-(4-methoxy-phenyl) 6-(3,4,5-trimethoxy-phenyl)-pyridine and 45 mg (0.42 mmol) NaHCO 3 . The title compound (27 mg) was isolated with chromatography on silica gel using CH 2 C1 2 /MeOH as eluent. 1H NMR (600 MHz, CDCl 3 ), 8-values in ppm: 3.87 (s, 3H); 3.93 (s, 3H); 3.98 (s, 3H); 6.95 (s, 1H); 7.04 (d, 2H), 7.05 (d, 1H); 7.13 (d, 1H); 7.27 (dd, 1H); 7.67 (d, 2H); 10 7.74 (d, 1H); 7.76 (d, 1H). Example 3. 7-(4-Pyrrolidin- 1 -yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[ 1,2-a]pyridine-8 15 carbonitrile As in example 1, albeit with 100 mg (0.23 mmol) 2-amino-3-cyano-4-(4-pyrrolidin-1-yl phenyl)-5-(3,4,5-trimethoxy-phenyl)-pyridine and 38 mg (0.46 mmol) NaHCO 3 . The title compound (10 mg) was isolated by column chromatography on silica gel, using 20 heptane/EtOAc as eluent, followed by recrystallisation in ethanol. 'H NMR (400 MHz, CDCl 3 ), 8-value in ppm: 2.05 (min, 4H); 3.37 (min, 4H); 3.91 (s, 6H); 3.96 (s, 3H); 6.67 (d, 2H); 6.86 (s, 2H); 6.96 (s, 1H); 7.67 (d, 2H); 7.69 (d, 1H); 7.70 (d, 1H). BIOLOGICAL TESTS 25 In vitro experiments Preparation of membrane vesicles containing vacuolar H+-ATPase Chicken medullary bone Membrane vesicles were prepared from egg-laying hens after 14 days of calcium-deprived 30 diet, as previously described (Mattsson, J.P., Lorentzon, P., Wallmark, B., and Keeling, D.J., Biochim. Biophys. Acta., 1146(1), 106-12 (1993)), with some modifications. Briefly, the medullary bone scraped from the long bones was resuspended in isolation buffer (1 WO 01/25237 PCT/SE00/01860 12 ml/g medullary bone) containing 5 mM Hepes/Tris, pH 7.4, 250 mM sucrose and 1 mM EGTA, minced using a pair of scissors, diluted 1:10 (w/v) in isolation buffer and homogenised in a polytron homogeniser. The homogenate was filtered through a 250 pm nylon mesh. Membrane vesicles were then obtained by differential centrifugation (2000 x 5 g for 10 min, 10,000 x g for 20 min and 40,000 x g for 1 h). The final pellet was resuspended in isolation buffer (0.4 ml/g medullary bone) by 20 passes using a teflon/glass homogenizer, snap frozen in MeOH/dry ice and then stored at -70 0 C. Bovine brain o10 Fresh bovine brains were obtained from a local slaughter house. Membrane vesicles were prepared from whole brain exactly as described for the medullary bone membrane vesicles. Human osteoclastoma Human osteoclastoma tumours were obtained courtesy of Dr. Bj6rn Gunterberg s15 (Sahlgrenska hospital, Sweden). A portion of each tumour was snap frozen in liquid nitrogen and stored at -70 0 C. Membrane vesicles were prepared exactly as described for the medullary bone membrane vesicles, except that protease inhibitors (0.2 mM AEBSF, 15.4 p.M aprotinin, 3.6 pM bestatin, 8.8 pM leupeptin) were included in the isolation buffer. 20 Measurement of ATP-dependent proton transport Proton transport in membrane vesicles was measured in a 96-well plate reader using the weak base acridine orange (Mattsson, J.P., Lorentzon, P., Wallmark, B., and Keeling, D.J., Biochim. Biophys. Acta., 1146(1), 106-12 (1993)). Test substances (dissolved in DMSO) 25 or DMSO (control) were added to the wells of a 96-well plate, followed by the addition of 220 pl acridine-orange buffer (final concentrations: 5 mM Hepes/Tris, pH 7.4, 125 mM KC1, 3 mM MgSO 4 , 0.25 mM DTT, 1 pgM valinomycin and 5 pgM acridine orange) and membrane vesicles (10-50 pg protein). After 10 min incubation with mixing, reactions were started by the addition of Tris-ATP (pH 7.4) to a final concentration of 3 mM, and the 30 proton transport was monitored by measurement of acridine orange absorbance (A 4 9 0 ) quenching in a Molecular Devices plate reader for 2 minutes. The initial rate of proton transport, taken as the maximum rate decrease in acridine orange absorbance, was SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SE00/01860 13 calculated using Molecular devices Softmax software. IC 50 values were obtained from dose-response curves constructed using the 4-parameter logistic equation. Measurement of bone resorption by 45Ca release from neonatal mouse calvarial (skull) bones 5 Measurement of bone resorption by 45 Ca release from mouse calvaria was performed as described (Mattsson, J.P., Viinanen, K., Wallmark, B., and Lorentzon, P., Biochim. Biophys. Acta., 1065(2), 261-8 (1991)), albeit with some modifications. Pregnant mice were injected with a 45 Ca -solution (0.25 ml 120 gCi/ml, s.c.), day 2 and 1 before partus. o10 When the new-born mice were 5 to 8 days old, they were killed by decapitation and the calvaria were dissected out and cut into four equally sized pieces. The pieces were placed in petri dishes containing incubation medium (1 mM L-glutamine, 100 U/ml penicillin, 100 pg/ml streptomycin, 1 mg/ml albumin and 1 gM indomethacin) with or without 10 nM PTH and preincubated in a CO 2 incubator (5% CO 2 in air) for 20-24 h at 37 0 C. The 15 calvaria pieces were then transferred to a 24-well plate containing fresh incubation medium. After 24 h, an aliquot (400 pl) of the incubation medium was analysed for the content of 45 Ca in a Microbeta (Wallac) scintillation counter (Control CPM). The calvaria pieces were transferred to fresh incubation medium and incubated with or without test substance and after another 24 h incubation, an aliquot (400 p1) of the incubation medium 20 was analysed for the content of 45 Ca (Compound CPM). The resorption ratio between the control period and the compound period (compound CPM/control CPM) was calculated and dose-response curves constructed using the 4-parameter logistic equation. Protein determination 25 Protein was determined according to Bradford (Bradford, M.M., Anal. Biochem., 72, 248-54 (1976)) using Bio Rad's protein assay kit and y-globulin as a standard. SUBSTITUTE SHEET (RULE 26)

Claims (15)

1. An imidazopyridine carbonitrile compound R2 5 Rz R3 (I) NC R4 R N N s5 10 7 wherein R 1 is selected from the group consisting of (a) H; (b) O-alkyl having 1-3 carbon atoms; 15is (c) R 1 + R 2 form a five membered ring containing at least one O, S and/or N; (d) alkyl having 1-3 carbon atoms and (e) S-methyl or S- ethyl; R 2 is selected from the group consisting of 20 (a) H; (b) straight chain, branched or cyclic saturated or unsaturated alkyl having 1-6 carbon atoms; (c) NR 8 R 9 , wherein R 8 and R 9 are either independently selected from the group consisting of H; a straight chain, branched or cyclic saturated or unsaturated alkyl 25 having 1-6 carbon atoms, optionally substituted with O-alkyl, NH-alkyl, N-dialkyl, N pyrrolidinyl, N-piperidinyl, N-morpholinyl or N-piperazinyl; and aryl selected from the group consisting of phenyl, imidazolyl, pyridinyl or pyrrolyl; or together form a five or six membered saturated or unsaturated ring, optionally containing O, S, and/or N; 30 (d) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms optionally substituted with O-alkyl, NH-alkyl, N-dialkyl, N-pyrrolidinyl, N piperidinyl, N-morpholinyl or N-piperazinyl; SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SE00/01860 15 (e) straight chain, branched or cyclic saturated or unsaturated S-alkyl having 1-6 carbon atoms optionally substituted with O-alkyl, NH-alkyl, N-dialkyl, N-pyrrolidinyl, N piperidinyl; s R 3 -R 7 are selected from the group consisting of (a) H (b) alkyl having 1-3 carbon atoms (c) O-alkyl having 1-3 carbon atoms (d) S-methyl or S- ethyl o10 wherein at least one of R 1 -R 3 and R 4 -R 7 , respectively, is not H or a pharmaceutically acceptable salt thereof

2. An imidazopyridine carbonitrile compound according to claim 1, wherein R 2 is S-Me, NR 8 R 9 , O-alkyl or alkyl having 1-6 carbon atoms; R 1 , R 3 , R 4 are H; and R 5 , R 6 and R 7 15 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.

3. An imidazopyridine carbonitrile compound according to claim 1 or 2, wherein R 2 is S-Me, NR 8 R 9 , O-alkyl or alkyl having 1-3 carbon atoms; R 1 , R 3 , R 4 , R 5 are H; and R 6 20 and R 7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.

4. An imidazopyridine carbonitrile compound according to any one of claims 1-3, wherein R 2 is S-Me, NR 8 R 9 , O-alkyl or alkyl having 1-6 carbon atoms; R 1 , R 3 , R 5 , R 6 , 25 R 7 are H; and R 4 is straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.

5. An imidazopyridine carbonitrile compound according to any one of the preceding claims, wherein said compound is selected from the group consisting of: 30 7-(4-dimethylamino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[1,2- a]pyridine-8 carbonitrile; SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SEUU/0186U 16 5-(3,4-dimethoxy-phenyl)-7-(4-methoxy-phenyl)-imidazo[ 1,2-a]pyridine-8-carbonitrile;

7-(4-pyrrolidin-1-yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[1,2- a]pyridine-8 carbonitrile. 5 6. A process for the preparation of an imidazopyridine carbonitrile compound according to any one of claims 1-5, wherein a suitably substituted amino-nicotinonitrile is heated with an c-halosubstituted carbonyl reagent under basic conditions, optionally in the presence of a solvent, during 2-24 h. 10 7. A process for the preparation of an imidazopyridine carbonitrile compound according to any one of claims 1-5, wherein a suitably substituted 1,3-diphenyl-propane-1,3-dione and a suitably substituted (1H-benzimidazol-2-yl)-acetonitrile are treated with an alkali metal alkoxide and refluxed in an alcohol during 2-12 h. s15 8. An imidazopyridine carbonitrile compound according to any one of claims 1-5 for use as a pharmaceutical.

9. A pharmaceutical composition comprising an imidazopyridine carbonitrile compound according to any one of claims 1-5 as active ingredient in association with a 20 pharmaceutically acceptable adjuvant, diluent or carrier.

10. A pharmaceutical composition according to claim 9, wherein the amount of said active ingredient per dosage unit is within the range of about 1 to 1 000 mg, preferably 1-300 mg. 25 11. A pharmaceutical composition according to any one of claims 9-10, wherein the amount of said active ingredient is within the range of about 0.1 to 95% by weight of said pharmaceutical composition.

12. Use of an imidazopyridine carbonitrile compound according to any one of claims 1-5 30 in the manufacture of a medicament for use in therapeutic or prophylactic treatment of a human or animal body. SUBSTITUTE SHEET (RULE 26) WO 01/25237 PCT/SE00/01860 17

13. Use according to claim 12, wherein the medicament is intended for treatment involving inhibition of vacuolar H+-ATPase, preferably vacuolar H+-ATPase in osteoclast cells. 5 14. Use according to claim 12, wherein the medicament is intended for treatment involving inhibition of vacuolar H+-ATPase containing the isoform a3, said vacuolar H+ ATPase preferably being present in osteoclast cells.

15. Use according to claim 12, wherein the medicament is intended for treatment o10 involving inhibition of bone resorption.

16. Use according to claim 12, wherein the medicament is intended for treatment and/or prevention of diseases related to increased bone resorption, preferably osteoporosis. 15 17. Use according to claim 12, wherein the medicament is intended for treatment of Paget's disease of bone, hyperparathyroidism, malignant neoplasms, parodontal diseases, prosthetic and/or implant related bone loss, tumours, AIDS and disorders related thereto, Alzheimer's disease, angiogenesis, rheumatoid arthritis, diabetic retinopathy, psoriasis or diabetes. 20

18. A method for inhibiting vacuolar H'-ATPase, preferably vacuolar H+-ATPase in osteoclast cells, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of an imidazopyridine carbonitrile compound according to any one of claims 1-5. 25

19. A method for inhibiting vacuolar H+-ATPase containing the isoform a3, said vacuolar H+-ATPase preferably being present in osteoclast cells, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of an imidazopyridine carbonitrile compound according to any one of claims 1-5. 30 WO 01/25237 PCT/SE00/01860 18

20. A method for inhibiting bone resorption which comprises administering to a human or animal patient a therapeutically effective amount of an imidazopyridine carbonitrile compound according to any one of claims 1-5. 5 21. A method for treatment and/or prevention of diseases related to increased bone resorption, preferably osteoporosis, which comprises administering to a human or animal patient a therapeutically effective amount of an imidazopyridine carbonitrile compound according to any one of claims 1-5. 10 22. A method for treatment of Paget's disease of bone, hyperparathyroidism, malignant neoplasms, parodontal diseases, prosthetic and/or implant related bone loss, tumours, AIDS and disorders related thereto, Alzheimer's disease, angiogenesis, rheumatoid arthritis, diabetic retinopathy, psoriasis or diabetes, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of an 15is imidazopyridine carbonitrile compound according to any one of claims 1-5. SUBSTITUTE SHEET (RULE 26)