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EP1222188A1 - Novel imidazopyridine carbonitrile compounds - Google Patents

Novel imidazopyridine carbonitrile compounds

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Publication number
EP1222188A1
EP1222188A1 EP00970372A EP00970372A EP1222188A1 EP 1222188 A1 EP1222188 A1 EP 1222188A1 EP 00970372 A EP00970372 A EP 00970372A EP 00970372 A EP00970372 A EP 00970372A EP 1222188 A1 EP1222188 A1 EP 1222188A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
imidazopyridine
carbon atoms
compound according
carbonitrile
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00970372A
Other languages
German (de)
French (fr)
Inventor
Margareta HERSLÖF
Peter Nordberg
Henrik Sörensen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
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AstraZeneca AB
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Filing date
Publication date
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Publication of EP1222188A1 publication Critical patent/EP1222188A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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.
  • 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 isoform of "a” (Li, Y. P., Chen, W. and Stashenko, P., Biochemical & Biophysical Research Communications, 218(3), 813-21 (1996)).
  • novel compounds with excellent therapeutical effect against physiological disorders involving ter 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, such as vacuolar H + - ATPase in osteoclast cells, it is thereby therapeutically efficient against physiological disorders involving bone resorption.
  • said imidazopyridine carbonitrile compound has the general formula I:
  • R ⁇ is selected from the group consisting of
  • Rj+ R2 form a five membered ring containing at least one O, S and or N;
  • R2 is selected from the group consisting of (a) H;
  • Rg and R9 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 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;
  • R3-R7 are selected from the group consisting of (a) H
  • R2 is S-Me, NRgRc), O-alkyl or alkyl having 1-6 carbon atoms; R1 , R3 and R4 are H; and R5, R5 and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
  • R2 is S-Me, NRgRc), O-alkyl or alkyl having 1-6 carbon atoms; R1 , R3, R4, R5 are H; and Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
  • R2 is S-Me, NRgRtj, O-alkyl or alkyl having 1 -6 carbon atoms
  • R1 , R3, R5, R6, R7 are H
  • R4 is straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
  • said imidazopyridine carbonitrile compound is selected from the group consisting of:
  • 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.
  • a suitably substituted amino-nicotinonitrile is heated with an ⁇ -halosubstituted carbonyl reagent under basic conditions, optionally in the presence of a solvent, during 2-24 h.
  • a suitably substituted l,3-diphenyl-propane-l,3-dione and a suitably substituted (lH-benzimidazol-2-yl)-acetonitrile are treated with an alkali metal alkoxide and refluxed in an alcohol during 2-12 h.
  • Scheme 1 illustrates general synthetic pathways for the preparation of the imidazopyridine carbonitrile compounds of the present invention.
  • the synthesis of suitable starting materials is readily accomplished by a person skilled in the art.
  • Procedure 1 Appropriate amounts of a suitably substituted amino-nicotinonitrile and an ⁇ - 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 CH2CI2, washing with brine and drying, the solvent is removed. The residue is purified either by recrystallisation or chromatography on silica gel. From this procedure, substituted 5,7-diphenyl-imidazo[l,2-a]pyridine-8-carbonitrile is isolated.
  • a suitable solvent such as e.g. ethanol, butanol or chloroform
  • Procedure 2 (especially for compounds, where R 9 and Rio are part of a benzene ring): Appropriate amounts of a suitably substituted l,3-diphenyl-propane-l,3-dione and a suitably substituted (lH-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.
  • the present invention relates to an imidazopyridine carbonitrile compound with the general formula I for use as a pharmaceutical.
  • the present invention also relates to a pharmaceutical composition
  • 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, diluent or carrier.
  • 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.
  • the amount of said active ingredient is typically within the range of about 0.1 to 95% by weight of said pharmaceutical composition.
  • 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.
  • said use is related to a medicament intended for treatment involving inhibition of vacuolar H+- ATPase, preferably vacuolar H+- ATPase in osteoclast cells.
  • 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.
  • said medicament is intended for treatment involving inhibition of bone reso ⁇ tion, or is intended for treatment and/or prevention of diseases related to increased bone reso ⁇ tion, preferably osteoporosis.
  • the medicament is intended for treatment of Paget's disease of bone, hype ⁇ arathyroidism, 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.
  • the present invention is also related to a method for inhibiting vacuolar H + - ATPase, 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.
  • the present invention is related to a method for inhibiting bone reso ⁇ tion, or to a method for treatment and/or prevention of diseases related to increased bone reso ⁇ tion, 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.
  • the present invention concerns a method for treatment of Paget's disease of bone, hype ⁇ arathyroidism, 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 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 administration and the disease.
  • 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.
  • the present invention relates to pharmaceutical compositions containing at least one compound according to the invention, or a therapeutically acceptable salt thereof, as active ingredient.
  • 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, 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, halogenbenquentphonic acid, toluenesulphonic acid and naphtalenesulphonic acid.
  • 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,
  • an imidazopyridine carbonitrile compound for use as a pharmaceutical.
  • it may be used in pharmaceutical compositions for oral, intravenous, topical, intraperitoneal or subcutaneous administration, in association with one or more pharmaceutically acceptable carriers, diluents or adjuvants that are well known in the art.
  • composition of the invention may be administered topically, in the 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.
  • Membrane vesicles were prepared from egg-laying hens after 14 days of calcium-deprived 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.
  • the medullary bone scraped from the long bones was resuspended in isolation buffer (1 ml/g medullary bone) containing 5 mM Hepes/Tris, pH 7.4, 250 raM 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 ⁇ m nylon mesh. Membrane vesicles were then obtained by differential centrifugation (2000 x 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°C.
  • Bovine brain 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.
  • 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 or DMSO (control) were added to the wells of a 96-well plate, followed by the addition of 220 ⁇ l acridine-orange buffer (final concentrations: 5 mM Hepes/Tris, pH 7.4, 125 mM KC1, 3 mM MgSO4, 0.25 mM DTT, 1 ⁇ M valinomycin and 5 ⁇ M acridine orange) and membrane vesicles (10-50 ⁇ g protein).
  • 220 ⁇ l acridine-orange buffer final concentrations: 5 mM Hepes/Tris, pH 7.4, 125 mM KC1, 3 mM MgSO4, 0.25 mM DTT, 1 ⁇ M valinomycin and 5 ⁇ M acridine orange
  • membrane vesicles 10-50 ⁇ g protein.
  • mice were injected with a 45 Ca -solution (0.25 ml 120 ⁇ Ci/ml, s.c), day 2 and 1 before partus.
  • 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 ⁇ g/ml streptomycin, 1 mg/ml albumin and 1 ⁇ M indomethacin) with or without 10 nM PTH and preincubated in a CO2 incubator (5% CO2 in air) for 20-24 h at 37°C.
  • the calvaria pieces were then transferred to a 24-well plate containing fresh incubation medium. After 24 h, an aliquot (400 ⁇ l) 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 ⁇ l) of the incubation medium was analysed for the content of 4s Ca (Compound CPM).
  • the reso ⁇ tion ratio between the control period and the compound period was calculated and dose-response curves constructed using the 4-parameter logistic equation.
  • Protein determination Protein was determined according to Bradford (Bradford, M.M., Anal. Biochem., 72, 248-54 (1976)) using Bio Rad's protein assay kit and ⁇ -globulin as a standard.

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Abstract

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. Said selective inhibitor has been found to inhibit vacuolar H+-ATPase, such as vacuolar H+-ATPase in osteoclast cells, whereby it is therapeutically efficient against physiological disorders involving bone resorption. In an embodiment of the present invention, said selective inhibitor comprises an imidazopyridine carbonitrile compound with general formula (I).

Description

NOVEL IMIDAZOPYRIDINE CARBONITRILE COMPOUNDS
Technical field
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.
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 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 quino lines and benzimidazoles are also claimed to be inhibitors of vacuolar H+-ATPase, see e.g. WO 97/14681 and WO 97/102219 and certain 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 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" (Lee, C, Ghoshal, K. and Beaman, K. D., Molecular Immunology, 27(11), 1 137-44
(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 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 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
Surprisingly, novel compounds with excellent therapeutical effect against physiological disorders involving ter 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, 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:
wherein R\ is selected from the group consisting of
(a) H;
(b) O-alkyl having 1-3 carbon atoms;
(c) Rj+ R2 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; R2 is selected from the group consisting of (a) H;
(b) straight chain, branched or cyclic saturated or unsaturated alkyl having 1 -6 carbon atoms;
(c) NRgRcj, wherein Rg and R9 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 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; (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-R7 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 wherein at least one of R1 -R3 and R4-R7, respectively, is not H or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, R2 is S-Me, NRgRc), O-alkyl or alkyl having 1-6 carbon atoms; R1 , R3 and R4 are H; and R5, R5 and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms. In yet another preferred embodiment, R2 is S-Me, NRgRc), O-alkyl or alkyl having 1-6 carbon atoms; R1 , R3, R4, R5 are H; and Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
In still another preferred embodiment, R2 is S-Me, NRgRtj, O-alkyl or alkyl having 1 -6 carbon atoms; R1 , R3, R5, R6, R7 are H; and R4 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 carbonitrile compound is selected from the group consisting of:
7-(4-dimethylamino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[l,2- α]pyridine-8- carbonitrile;
5-(3,4-dimethoxy-phenyl)-7-(4-methoxy-phenyl)-imidazo[l,2-α]pyridine-8-carbonitrile;
7-(4-pyrrolidin-l-yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[l,2- α]pyridine-8- 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.
In one embodiment of said preparation, a suitably substituted amino-nicotinonitrile is heated with an α-halosubstituted carbonyl reagent under basic conditions, optionally in the presence of a solvent, during 2-24 h.
In another embodiment, a suitably substituted l,3-diphenyl-propane-l,3-dione and a suitably substituted (lH-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 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); 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).
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.
Scheme 1. Synthesis of compounds with the general formula I. General procedures for the synthesis of compounds represented by the formula I are outlined below.
Procedure 1 : Appropriate amounts of a suitably substituted amino-nicotinonitrile and an α- 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 CH2CI2, washing with brine and drying, the solvent is removed. The residue is purified either by recrystallisation or chromatography on silica gel. From this procedure, substituted 5,7-diphenyl-imidazo[l,2-a]pyridine-8-carbonitrile is isolated.
Procedure 2 (especially for compounds, where R9 and Rio are part of a benzene ring): Appropriate amounts of a suitably substituted l,3-diphenyl-propane-l,3-dione and a suitably substituted (lH-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 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, 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.
Moreover, the amount of said active ingredient is typically within the range of about 0.1 to 95% by weight of said pharmaceutical composition. 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.
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.
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 inhibition of bone resoφtion, or is intended for treatment and/or prevention of diseases related to increased bone resoφtion, preferably osteoporosis.
In still another preferred embodiment of said use, the medicament is intended for treatment of Paget's disease of bone, hypeφarathyroidism, 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.
The present invention is also related to a method for inhibiting vacuolar H+- ATPase, 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.
Moreover, the present invention is related to a method for inhibiting bone resoφtion, or to a method for treatment and/or prevention of diseases related to increased bone resoφtion, 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.
Furthermore, the present invention concerns a method for treatment of Paget's disease of bone, hypeφarathyroidism, 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 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 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 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, 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.
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, 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 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.
Experimental part
Preparation of compounds illustrating the invention.
Example 1. 7-(4-Dimethylamino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[l,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 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) NaHCO3 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. 1H NMR (400 MHz, CDC13), δ-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 (m, 2H). Example 2.
5-(3,4-Dimethoxy-phenyl)-7-(4-methoxy-phenyl)-imidazo[l,2-a]pyridine-8-carbonitrile
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 . The title compound (27 mg) was isolated with chromatography on silica gel using CH2θ2/MeOH as eluent. 1H NMR (600 MHz, CDC13), δ-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); 7.74 (d, 1H); 7.76 (d, 1H).
Example 3.
7-(4-Pyrrolidin-l-yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[l,2-a]pyridine-8- carbonitrile
As in example 1, albeit with 100 mg (0.23 mmol) 2-amino-3-cyano-4-(4-pyrrolidin-l-yl- phenyl)-5-(3,4,5-trimethoxy-phenyl)-pyridine and 38 mg (0.46 mmol) NaHCO3- The title compound (10 mg) was isolated by column chromatography on silica gel, using heptane/EtOAc as eluent, followed by recrystallisation in ethanol. !H NMR (400 MHz, CDC13), δ-value in ppm: 2.05 (m, 4H); 3.37 (m, 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 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 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 ml/g medullary bone) containing 5 mM Hepes/Tris, pH 7.4, 250 raM 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 μm nylon mesh. Membrane vesicles were then obtained by differential centrifugation (2000 x 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°C.
Bovine brain 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. Bjδrn Gunterberg (Sahlgrenska hospital, Sweden). A portion of each tumour was snap frozen in liquid nitrogen and stored at -70°C. Membrane vesicles were prepared exactly as described for the medullary bone membrane vesicles, except that protease inhibitors (0.2 mM AEBSF, 15.4 μM aprotinin, 3.6 μM bestatin, 8.8 μM leupeptin) were included in the isolation buffer.
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) or DMSO (control) were added to the wells of a 96-well plate, followed by the addition of 220 μl acridine-orange buffer (final concentrations: 5 mM Hepes/Tris, pH 7.4, 125 mM KC1, 3 mM MgSO4, 0.25 mM DTT, 1 μM valinomycin and 5 μM acridine orange) and membrane vesicles (10-50 μg 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 proton transport was monitored by measurement of acridine orange absorbance (A490) 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 calculated using Molecular devices Softmax software. IC50 values were obtained from dose-response curves constructed using the 4-parameter logistic equation. Measurement of bone resoφtion by 45Ca release from neonatal mouse calvarial (skull) bones
Measurement of bone resoφtion by 45Ca release from mouse calvaria was performed as described (Mattsson, J.P., Vaananen, K., Wallmark, B., and Lorentzon, P., Biochim. Biophys. Acta., 1065(2), 261-8 (1991)), albeit with some modifications. Pregnant mice were injected with a 45Ca -solution (0.25 ml 120 μCi/ml, s.c), day 2 and 1 before partus. 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 μg/ml streptomycin, 1 mg/ml albumin and 1 μM indomethacin) with or without 10 nM PTH and preincubated in a CO2 incubator (5% CO2 in air) for 20-24 h at 37°C. The calvaria pieces were then transferred to a 24-well plate containing fresh incubation medium. After 24 h, an aliquot (400 μl) of the incubation medium was analysed for the content of 45Ca 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 μl) of the incubation medium was analysed for the content of 4sCa (Compound CPM). The resoφtion 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 Protein was determined according to Bradford (Bradford, M.M., Anal. Biochem., 72, 248-54 (1976)) using Bio Rad's protein assay kit and γ-globulin as a standard.

Claims

1. An imidazopyridine carbonitrile compound
wherein R\ is selected from the group consisting of
(a) H;
(b) O-alkyl having 1-3 carbon atoms;
(c) R\+ R2 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;
R2 is selected from the group consisting of (a) H;
(b) straight chain, branched or cyclic saturated or unsaturated alkyl having 1 -6 carbon atoms;
(c) NR R9, wherein Rg and R9 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- pyrro lidinyl, N-piperidinyl, N-moφholinyl 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; (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-moφholinyl or N-piperazinyl; (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-R7 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 wherein at least one of 1- 3 and R4-R7, respectively, is not H or a pharmaceutically acceptable salt thereof.
2. An imidazopyridine carbonitrile compound according to claim 1, wherein R2 is S-Me, NRgR9, O-alkyl or alkyl having 1-6 carbon atoms; R\, R3, R4 are H; and R5, Rg and R7 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 R2 is S-Me, NR R9, O-alkyl or alkyl having 1-3 carbon atoms; R1 , R3, R4, R5 are H; and R and R7 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 R2 is S-Me, NR Rg, O-alkyl or alkyl having 1-6 carbon atoms; R , R3, R5, R5, R7 are H; and R4 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: 7-(4-dimethylamino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[l ,2- α]pyridine-8- carbonitrile; 5-(3,4-dimethoxy-phenyl)-7-(4-methoxy-phenyl)-imidazo[l,2-α]pyridine-8-carbonitrile; 7-(4-pyrrolidin-l-yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-imidazo[l,2- α]pyridine-8- carbonitrile.
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 α-halosubstituted carbonyl reagent under basic conditions, optionally in the presence of a solvent, during 2-24 h.
7. A process for the preparation of an imidazopyridine carbonitrile compound according to any one of claims 1-5, wherein a suitably substituted l,3-diphenyl-propane-l,3-dione and a suitably substituted (lH-benzimidazol-2-yl)-acetonitrile are treated with an alkali metal alkoxide and refiuxed in an alcohol during 2-12 h.
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 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.
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 in the manufacture of a medicament for use in therapeutic or prophylactic treatment of a human or animal body.
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.
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 involving inhibition of bone resoφtion.
16. Use according to claim 12, wherein the medicament is intended for treatment and/or prevention of diseases related to increased bone resoφtion, preferably osteoporosis.
17. Use according to claim 12, wherein the medicament is intended for treatment of
Paget's disease of bone, hypeφarathyroidism, 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.
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.
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.
20. A method for inhibiting bone resoφtion 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.
21. A method for treatment and/or prevention of diseases related to increased bone resoφtion, 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.
22. A method for treatment of Paget's disease of bone, hypeφarathyroidism, 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 imidazopyridine carbonitrile compound according to any one of claims 1-5.
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