EP1222169A1 - Novel trisubstituted pyridine compounds - Google Patents

Novel trisubstituted pyridine compounds

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Publication number
EP1222169A1
EP1222169A1 EP00970371A EP00970371A EP1222169A1 EP 1222169 A1 EP1222169 A1 EP 1222169A1 EP 00970371 A EP00970371 A EP 00970371A EP 00970371 A EP00970371 A EP 00970371A EP 1222169 A1 EP1222169 A1 EP 1222169A1
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EP
European Patent Office
Prior art keywords
alkyl
carbon atoms
compound according
atpase
vacuolar
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.)
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Application number
EP00970371A
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German (de)
French (fr)
Inventor
Margareta HERSLÖF
Patrik Holm
Henrik Sörensen
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1222169A1 publication Critical patent/EP1222169A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

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 FT-ATPase in mammalian osteoclast cells.
  • 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 activ it , wherein said inhibitor comprises a trisubstituted pyridine compound. Since the selectiv e inhibitor of the present invention has been found to inhibit vacuolar FT-ATPase, such as vacuolar H - ATPase in osteoclast cells, it is thereby therapeutically efficient against physiological disorders involving bone resorption.
  • R ⁇ is selected from the group consisting of (a) H,
  • R ⁇ + R ? form a fi membered ring containing at least one O, S and/or ⁇ .
  • alkyl hav ing 1 -3 carbon atoms and
  • R2 is selected from the group consisting of (a) H,
  • R12R-13, v herein R and R13 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-pipe ⁇ dinyl, N-morphohnyl or N-piperazinyl, and aryl selected from the group consisting of phenyl, imidazolyl, py ⁇ dinyl or pyrrolyl, or together form a five or six membered saturated or unsaturated ⁇ ng, 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-pyrrohdinyl, N- pipe ⁇ dinyl, N
  • R3-R1 1 are selected from the group consisting of
  • R2 is S-Me, NRpRp. O-alkyl or alkyl having 1-6 carbon atoms; R [ . R-;. R4 and Rg are H; and R5. Rg, R7, R9. i ⁇ and R ⁇ ⁇ are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
  • R2 is S-Me, NRpRp, O-alkyl or alkyl having 1-6 carbon atoms; R ⁇ . R3.
  • R5, Rg and R9 are H; and
  • Rg. R7, R [ Q and R are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
  • R2 is S-Me, NRpRp, O-alkyl or alkyl having 1-6 carbon atoms; Ri , R3. R5, Rg, R7, R9. R ⁇ Q, R ⁇ ⁇ are H; and R4 and Rg are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
  • said trisubstituted pyridine compound is selected from the group consisting of: 4-(4-pyrrolidin-l-yl-phenyl)-2,6-bis-(3,4,5-trimethoxy-phenyl)-pyridine;
  • the present invention also relates to a process for the preparation of a tnsubstituted pyridine compound according to any one of the embodiments set forth above.
  • a suitably substituted benzaldehyde is heated with ammonium acetate and a suitably substituted acetophenone, optionally in the presence of a solvent, during 2-24 h.
  • a suitably substituted chalcone is heated with ammonium acetate and a suitably substituted acetophenone, optionally in the presence of a solvent, during
  • a suitably substituted aromatic aldehyde or chalcone is reacted with a suitably substituted N-(d ⁇ phenylphosph ⁇ nyl)- l-phen lethane ⁇ m ⁇ ne in the presence of a base, preferably t-BuOK. in an aprotic solvent
  • a suitably substituted benz ⁇ ldehyde and a suitably substituted acetophenone (molar ratio 2.1) are heated with ammonium acetate in acetic acid for 2-24 h.
  • the desired compound may be isolated by cr stallisation or column chromatogtraphy on silica gel
  • a suitably substituted chalcone prepared by standard methods, and a suitably substituted acetophenone derivativ e (molar ratio 1 1), such as e g. phenacyl-py ⁇ dinium bromide, phenacyl-dimethylsulfomum bromide or d ⁇ methyl-(2-oxo-2-phenyl-ethyl)-sulfomum betaine), are heated with ammonium acetate in acetic acid for 2-24 h.
  • the desired compound may be isolated by crystallisation or column chromatography on silica gel.
  • N-(d ⁇ phenylphosph ⁇ nyl)-2-phenyl-l-azaallyl anion generated from N-(d ⁇ phenylphosph ⁇ n l)- l-phenylethane ⁇ m ⁇ ne under basic conditions (t-BuOK), is reacted with an aromatic aldehyde (molar ratio 2.1) or a chalcone (molar ratio 1.1)
  • the desired compound may be isolated by crystallisation or column chromatogtraphy on silica gel
  • the present inv ention relates to a trisubstituted pyridine compound with the general formula I for use as a pharmaceutical
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a trisubstituted pyridine compound according to any one of the embodiments set forth above as activ e 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 I 000 mg, preferably 1-300 mg Moreover, the amount of said activ e 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 a t ⁇ substituted pyridine 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-r-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-t-- ATPase preferably being present in osteoclast cells
  • said medicament is intended for treatment involving inhibition of bone resorption, or is intended for treatment and or prevention of diseases related to increased bone resorption, preferably osteoporosis
  • 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, 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 vacuolar H-r-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 a trisubstituted pyridine compound according to any one of the embodiments outlined above
  • 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, preferably osteoporosis, wherein any one of said methods comprises admmiste ⁇ ng to a human or animal patient a therapeutically effective amount of a trisubstituted py ⁇ dine 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, 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 ret ⁇ nopath> , psoriasis or diabetes, wherein said method comprises administering to a human or animal patient a
  • the typical daily dose of the active ingredient vanes within a wide range and will depend on various factors such as e g the individual requirement of each patient, the route of
  • 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, phospho ⁇ c acid, nitric acid, aliphatic, alicychc, aromatic or heterocyc c carboxyl or sufphonic acids, such as formic acid, acetic ac d, propionic acid, succimc acid.
  • glyco c acid lactic acid, malic acid, tarta ⁇ c acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, -hydroxybensoic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbenquentphonic acid, toluenesulphonic acid and naphtalenesulphonic acid.
  • a trisubstituted pyridine 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.
  • Example 4 Synthesis of 4-(4-Ethyl-phenyl)-2,6-b ⁇ s-(3,4,5-t ⁇ methoxy-phenyl)-py ⁇ dme was performed according to example 1 The crude compound was purified by column chromatography on silica gel.
  • Membrane vesicles were prepared from egg-laying hens after 14 days of calcium-deprived diet, as previously desc ⁇ bed (Mattsson, J.P., Lorentzon, P., Wallmark, B., and Keeling, D.J., Biochim. Biophys. Acta, 1 146( 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/T ⁇ s, pH 7.4, 250 mM sucrose and 1 mM EGTA, minced using a pair of scissors, diluted 1 : 10 (vv/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 mm, 10,000 x g for 20 mm 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 0.4 ml/g medullary bone
  • 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, 1 146(1), 106-12 (1993)).
  • Test substances dissolved in DMSO
  • DMSO control
  • 220 ⁇ l acridine-orange buffer final concentrations: 5 mM Hepes/Tris, pH 7.4.
  • the calvaria 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 CO incubator (5% CO; in air) for 20-24 h at 37°C.
  • incubation medium 1 mM L-glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin. 1 mg/ml albumin and 1 ⁇ M indomethacin
  • the calvaria pieces were then transferred to a 24-vvell plate containing fresh incubation medium.

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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 a trisubstituted pyridine compounds with general formula (I).

Description

NOVEL TRISUBSTΠ ΓΓED PYRIDINE 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 FT-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 quinolines and benzimidazoles are also claimed to be inhibitors of vacuolar FT-ATPase, see e.g. WO 97/14681 and WO 97/102219. Recent evidence suggests that isoforms of the 1 16 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 Perm, M. S., Fried, V. A., Stone. D. K., Xie, X. S. and Sudhof, T. C, Journal of Biological Chemistry, 266(6). 3S77-S 1 ( 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, . D., Molecular Immunology, 27(1 1), 1 137-44 ( 1990)). The third subtype, i.e. "a3" (EMBL accession number U45285). has been cloned from a human osteoclastoma cDNA librarv 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 efficiencv in the treatment of disorders related to bone resorption Thus, there is a demand in the an for new therapeutic agents against such disorders
Disclosure of the in ention
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 activ it , wherein said inhibitor comprises a trisubstituted pyridine compound. Since the selectiv e inhibitor of the present invention has been found to inhibit vacuolar FT-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, the trisubstituted pyπdine compounds hav e the general formula I-
wherein R\ is selected from the group consisting of (a) H,
(b) O-alkyl having 1-3 carbon atoms,
(c) R\+ R? form a fi membered ring containing at least one O, S and/or \. (d) alkyl hav ing 1 -3 carbon atoms and
(e) S-methyl or S- ethv l.
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) R12R-13, v herein R and R13 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-pipeπdinyl, N-morphohnyl or N-piperazinyl, and aryl selected from the group consisting of phenyl, imidazolyl, pyπdinyl or pyrrolyl, or together form a five or six membered saturated or unsaturated πng, 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-pyrrohdinyl, N- pipeπdinyl, N-morphohnyl or N-piperazinyl, (e) straight chain, branched or cyclic saturated or unsaturated S-alkyl having 1-6 carbon atoms optionally substituted w ith O-alk l , NH-alkyl, N-dialkyl, N-pyrrolidmyl, N- pipeπdinyl,
R3-R1 1 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- ethv l wherein at least one of R1-R3, R4-R7 and Rg-R[ 1 , respectively, is not H or a pharmaceutical acceptable salt thereof In another preferred embodiment, R2 is S-Me, NRpRp. O-alkyl or alkyl having 1-6 carbon atoms; R [ . R-;. R4 and Rg are H; and R5. Rg, R7, R9. iø and R\ \ 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, NRpRp, O-alkyl or alkyl having 1-6 carbon atoms; R\ . R3. R4. R5, Rg and R9 are H; and Rg. R7, R [ Q and R are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
In still another prefe ed embodiment, R2 is S-Me, NRpRp, O-alkyl or alkyl having 1-6 carbon atoms; Ri , R3. R5, Rg, R7, R9. R\ Q, R\ \ are H; and R4 and Rg are 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 trisubstituted pyridine compound is selected from the group consisting of: 4-(4-pyrrolidin-l-yl-phenyl)-2,6-bis-(3,4,5-trimethoxy-phenyl)-pyridine;
{4-[2,6-bis-(3,4,5-trimethoxy-phenyl)-pyridin-4-yl]-phenyl}-dimethyl-amine;
{4-[2,6-bis-(3,4-dimethoxy-phenyl)-pyridin-4-yl]-phenoxy}-propyl)-dimethyl- amine; and
4-(4-ethyl-phenyl)-2.6-bis-(3,4,5-trimethoxy-phenyl)-pyridine.
The present invention also relates to a process for the preparation of a tnsubstituted pyridine compound according to any one of the embodiments set forth above.
In one embodiment of said preparation, a suitably substituted benzaldehyde is heated with ammonium acetate and a suitably substituted acetophenone, optionally in the presence of a solvent, during 2-24 h.
In another embodiment, a suitably substituted chalcone is heated with ammonium acetate and a suitably substituted acetophenone, optionally in the presence of a solvent, during In yet another embodiment, a suitably substituted aromatic aldehyde or chalcone is reacted with a suitably substituted N-(dιphenylphosphιnyl)- l-phen lethaneιmιne in the presence of a base, preferably t-BuOK. in an aprotic solvent
In the preparation of trisubstituted pyπdine compounds according to the present invention, the following references pro ide useful guidance concerning e g suitable reaction conditions and proper selection of reagents
Weiss, J Am. Chem. Soc , 74, 200 ( 1952),
Tewaπ, R.S., Dubey, A K , Indian J. Chem. Sect. B, 19(2). 153- 154 ( 1980). obayashi, T , Kakiuchi, H , Kato, H , Bull. Chem. Soc Jpn , 64(2), 392-395 ( 1991 obayashi, T , Kawate, H , Kakiuchi, H., Kato, H , Bull Chem Soc. Jpn., 63(7),
1937-1942 (1990),
Tevvaπ, R.S , Awasthi. A K . Synthesis, 4. 314-315 ( 1981)
Scheme 1 below illustrates general synthetic pathways for the preparation of the trisubstituted pyπdine compounds of the present invention. By guidance of inter aha known reference literature (vide supra), the synthesis of suitable starting mateπals is readily accomplished by a person skilled in the art
Scheme I Svntliesis of compounds with the general formula I General procedures for the synthesis of compounds represented by the formula I are outlined below
Procedure la
A suitably substituted benzαldehyde and a suitably substituted acetophenone (molar ratio 2.1) are heated with ammonium acetate in acetic acid for 2-24 h. The desired compound may be isolated by cr stallisation or column chromatogtraphy on silica gel
Procedure lb:
A suitably substituted chalcone, prepared by standard methods, and a suitably substituted acetophenone derivativ e (molar ratio 1 1), such as e g. phenacyl-pyπdinium bromide, phenacyl-dimethylsulfomum bromide or dιmethyl-(2-oxo-2-phenyl-ethyl)-sulfomum betaine), are heated with ammonium acetate in acetic acid for 2-24 h. The desired compound may be isolated by crystallisation or column chromatography on silica gel.
Procedure 2:
A suitably substituted N-(dιphenylphosphιnyl)-2-phenyl-l-azaallyl anion, generated from N-(dιphenylphosphιn l)- l-phenylethaneιmιne under basic conditions (t-BuOK), is reacted with an aromatic aldehyde (molar ratio 2.1) or a chalcone (molar ratio 1.1) The desired compound may be isolated by crystallisation or column chromatogtraphy on silica gel
Furthermore, the present inv ention relates to a trisubstituted pyridine compound with the general formula I for use as a pharmaceutical
Thus, the present invention also relates to a pharmaceutical composition comprising a trisubstituted pyridine compound according to any one of the embodiments set forth above as activ e 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 I 000 mg, preferably 1-300 mg Moreover, the amount of said activ e 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 a tπsubstituted pyridine 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-r-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-t-- ATPase preferably being present in osteoclast cells
In yet another preferred embodiment, said medicament is intended for treatment involving 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 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 vacuolar H-r-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 a trisubstituted pyridine compound according to any one of the embodiments outlined above
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, preferably osteoporosis, wherein any one of said methods comprises admmisteπng to a human or animal patient a therapeutically effective amount of a trisubstituted pyπdine compound according to any one of the embodiments set forth above
ιo 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 retιnopath> , psoriasis or diabetes, wherein said method comprises administering to a human or animal patient a
\ -> therapeutically effective amount of a trisubstituted pyπdine compound according to any one of the previously outlined embodiments
The typical daily dose of the active ingredient vanes within a wide range and will depend on various factors such as e g the individual requirement of each patient, the route of
20 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, phosphoπc acid, nitric acid, aliphatic, alicychc, aromatic or heterocyc c carboxyl or sufphonic acids, such as formic acid, acetic ac d, propionic acid, succimc acid.
30 glyco c acid, lactic acid, malic acid, tartaπc acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, -hydroxybensoic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbensensulphonic acid, toluenesulphonic acid and naphtalenesulphonic acid.
As outlined above, there is provided a trisubstituted pyridine 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.
Synthesis of 4-(4-Pyrrolidin-l-yl-phenyl)-2,6-bis-(3,4,5-trimethoxy-phenyl)-pyridine
60 mg (0.34 mmol) 4-N-pyrrolidinyl-benzaldehyde, 144 mg (0.69 mmol) 3.4.5-trimethoxy- acetophenone and 58 mg (0.75 mmol) ammonium acetate were stirred at 80 C for 4 h. The crude product was filtered and recrystallized from warm ethanol/CH2Cl2. 42 mg of the title compound was obtained. lH NMR (400 MHz, CDC13) δ-values in ppm: 2.07 (m, 4H); 3.38 (t, 4H); 3.93 (s, 6H); 3.99 (s, 12H); 6.70 (d, 2H); 7.43 (s, 4H); 7.68 (d, 2H); 7.77 (s. 2H).
Example 2.
Synthesis of {4-[2,6-Bis-(3,4,5-trimethoxy-phenyl)-pyridin-4-yl]-phenyl}-dimethyl-amine was performed according to example 1. The crude compound was purified by column chromatography on silica gel. Η NMR (600 MHz, CDC13) δ-values in ppm: 3.06 (s, 6H); 3.93 (s, 6H); 3.99 (s, 12H); 6.86 (d, 2H); 7.43 (s, 4H); 7.68 (d, 2H); 7.77 (s. 2H). Example 3
Synthesis of {4-[2,6-Bιs-(3.4-dιmetho\y-phenyl)-pyπdιn-4-yl]-phenoxy}-propyl)- dimethyl-amine was performed according to example 1. The crude compound was purified by column chromatography on silica gel lH NMR (500 MHz, CDC ) δ-values in ppm: 2 17 (dt, 2H), 2.52 (s, 6H); 2.83 (t, 2H). 3 96 (s, 6H), 4.03 (s, 6H); 4.12 (t. 2H); 7.00 (d. 2H), 7 04 (d, 2H); 7.69 (d, 2H); 7 70 (dd. 2H), 7 75( s, 2H); 7 86 (d, 2H)
Example 4. Synthesis of 4-(4-Ethyl-phenyl)-2,6-bιs-(3,4,5-tπmethoxy-phenyl)-pyπdme was performed according to example 1 The crude compound was purified by column chromatography on silica gel.
Η NMR (400 MHz, CDC ) δ-values in ppm: 1.28 (t, 3H), 2.73 (q. 2H); 3 90 (s, 6H); 3.96 (s, 12H); 7.36 (d. 2H); 7.40 (s, 4H); 7.65 (d, 2H); 7.76 (s, 2H).
BIOLOGICAL TESTS
In vitro experiments
Preparation of membrane vesicles containing vacuolar H-r-ATPase
Chicken medullary bone
Membrane vesicles were prepared from egg-laying hens after 14 days of calcium-deprived diet, as previously descπbed (Mattsson, J.P., Lorentzon, P., Wallmark, B., and Keeling, D.J., Biochim. Biophys. Acta, 1 146( 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/Tπs, pH 7.4, 250 mM sucrose and 1 mM EGTA, minced using a pair of scissors, diluted 1 : 10 (vv/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 mm, 10,000 x g for 20 mm 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. Bjόrn 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, 1 146(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 MgSO 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 resorption by 45Ca release from neonatal mouse calvarial (skull) bones Measurement of bone resorption by 4:,Ca 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 4""Ca -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 CO incubator (5% CO; in air) for 20-24 h at 37°C. The calvaria pieces were then transferred to a 24-vvell plate containing fresh incubation medium. After 24 h, an aliquot (400 μl) of the incubation medium was analysed for the content of 4:,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 μl) of the incubation medium was analysed for the content of 3Ca (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-ρarameter 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

A trisubstituted pyridine compound comprising a structure with the general formula I:
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 rung 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) R12R13, wherein Rp and R13 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 0, 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-R1 \ 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, R4-R7 and Rg-R[ \, respectively, is not H or a pharmaceutically acceptable salt thereof
2. A trisubstituted pyridine compound according to claim 1, wherein R2 is S-Me, NRpR-13' O-alkyl or alkyl having 1-6 carbon atoms; R\, R3, R4 and Rg are H; and
R5, Rg, R7, R9, RJ Q and R\ \ are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-3 carbon atoms.
3. A trisubstituted pyridine compound according to any one of claims 1-2, wherein R2 is S-Me, NRpRp. O-alkyl or alkyl having 1-6 carbon atoms;
R\, R3, R4, R5, Rg and R9 are H; and
Rg, R7, Rio and R\ \ are straight chain, branched or cyclic saturated or unsaturated O- alkyl having 1-3 carbon atoms.
4. A trisubstituted pyridine compound according to any one of claims 1-3, wherein R2 is S-Me, NR12R13, O-alkyl or alkyl having 1-6 carbon atoms; Kh R3, R5, Rg, R7, R9, R10, R{ { are H; and R4 and Rg are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1 -3 carbon atoms
5 A trisubstituted pyridine compound according to any one of the preceding claims, wherein said compound is selected from the group consisting of 4-(4-pyrrolιdm- l -yl-phenv l)-2.6-bιs-(3,4,5-tπmethoxy-phen l)-pyπdιne, {4-[2,6-bιs-(3,4.5-tπmethoxy-phenyl)-pyπdιn-4-yl]-phenyl | -dιmethyl-amιne;{4- [2,6-bιs-(3,4-dιmethoxy-phenyl)-pyπdm-4-yl]-phenoxy] -propyl)-dιmethyl-amιne, 4-(4-ethyl-pheny l)-2,6-bιs-(3 ,4,5-tπmetho\y-phenyl)-pyπdιne
6 A process for the preparation of a trisubstituted pyπdine compound according to any one of claims 1-5, wherein a suitably substituted benzaldehyde is heated with ammonium acetate and a suitably substituted acetophenone, optionally in the presence of a solvent, during 2-24 h.
7 A process for the preparation of a trisubstituted pyπdine compound according to any one of claims 1-5, wherein a suitably substituted chalcone is heated with ammonium acetate and a suitably substituted acetophenone, optionally in the presence of a solvent, during 2-24 h.
8 A process for the preparation of a tπsubstituted pyπdine compound according to any one of claims 1-5, wherein a suitably substituted aromatic aldehyde or chalcone is reacted w ith a suitably substituted N-(dιphenylphosphιnyl)-l-phenylethaneιmme in the presence of a base, preferably t-BuOK, in an aprotic solvent.
9 A tπsubstituted pyπdine compound according to any one of claims 1-5 for use as a pharmaceutical.
10 A pharmaceutical composition comprising a tπsubstituted pyridine compound according to any one of claims 1-5 as active ingredient in association with a pharmaceutically acceptable adjuvant, dilutent or carrier. 1 1 A pharmaceutical composition according to claim 10. herein the amount of said active ingredient per dosage unit is within the range of about 1 to 1 000 mg, preferablv 1- 300 mg
12 A pharmaceutical composition according to any one of claims 10- 1 1, wherein the amount of said activ e ingredient is within the range of about 0 1 to 95% by weight of said pharmaceutical composition
13 Use of a tπsubstituted pyπdine 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
14 Use according to claim 13, wherein the medicament is intended for treatment involving inhibition of vacuolar H-r-ATPase, preferably vacuolar H-r-ATPase in osteoclast cells
15 Use according to claim 13, wherein the medicament is intended for treatment involving inhibition of vacuolar H-r-ATPase containing the isoform a3, said v acuolar H-r- ATPase preferably being present in osteoclast cells
16 Use according to claim 13, wherein the medicament is intended for treatment involving inhibition of bone resorption
17 Use according to claim 13, wherein the medicament is intended for treatment and or prevention of diseases related to increased bone resorption, preferably osteoporosis
18 Use according to claim 13, 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 19 A method for inhibiting vacuolar H~- ATPase, preferably vacuolar H~- ATPase in osteoclast cells, wherein said method compπses administering to a human or animal patient a therapeutically effecti e amount of a trisubstituted pyridine compound according to any one of claims 1-5
20 A method for inhibiting vacuolar H~- ATPase containing the isoform a3, said vacuolar H+-ATPase preferably being present in osteoclast cells, wherein said method compπses administering to a human or animal patient a therapeutically effective amount of a trisubstituted pyridine compound according to any one of claims 1-5
21 A method for inhibiting bone resorption which compπses administeπng to a human or animal patient a therapeutically effective amount of a tπsubstituted pyπdine compound according to any one of claims 1-5
22 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 a tπsubstituted pyridine compound according to any one of claims 1-5
23 A method for treatment of Paget's disease of bone, hyperparafhyroidism. 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 compπses administering to a human or animal patient a therapeutically effective amount of a trisubstituted pyridine compound according to any one of claims 1-5
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