EP1222170A1 - Novel nicotinonitrile compounds - Google Patents

Novel nicotinonitrile compounds

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Publication number
EP1222170A1
EP1222170A1 EP00970370A EP00970370A EP1222170A1 EP 1222170 A1 EP1222170 A1 EP 1222170A1 EP 00970370 A EP00970370 A EP 00970370A EP 00970370 A EP00970370 A EP 00970370A EP 1222170 A1 EP1222170 A1 EP 1222170A1
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EP
European Patent Office
Prior art keywords
phenyl
nicotinonitrile
alkyl
amino
carbon atoms
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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EP00970370A
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German (de)
French (fr)
Inventor
Margareta HERSLÖF
Henrik Sörensen
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1222170A1 publication Critical patent/EP1222170A1/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61P19/08—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
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

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.
  • 2-Am ⁇ no-4,6-b ⁇ s-(4-methoxy-phenyl)-n ⁇ cot ⁇ non ⁇ t ⁇ le (commercially available from Asinex); 2-Am ⁇ no-4-benzo[ 1 ,3]d ⁇ o ⁇ ol-5-yl-6-(4- ⁇ sopropyl-phenyl)-n ⁇ cot ⁇ non ⁇ t ⁇ le (El-Hashash, M A., Shaban. M E. and Habashy, M. M., Rev Roum Chun., 26(1), 101-8 (1981)).
  • novel compounds with excellent therapeutical effect against physiological disorders involving inter aha bone resorption have now been found More specifically, said compounds comprise a selective inhibitor of mammalian osteoclast cell activity, wherein said inhibitor comprises a nicotinonit ⁇ le 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 nicotinonitrile compound is comprising a structure with the general formula I:
  • R ⁇ is selected from the group consisting of
  • R ⁇ + R2 form a five or six membered ring containing at least one O, S and or N.
  • R2 is selected from the group consisting of
  • 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.
  • R3 is selected from the group consisting of (a) H;
  • R4 is selected from the group consisting of
  • R5 is selected from the group consisting of
  • R f 3 is selected from the group consisting of (a) H (b) straight chain, branched or cyclic saturated or unsaturated alkyl having 1 -6 carbon atoms;
  • Rg and R7 may form a five or six membered ring containing at lea_t one 0, S and or ,
  • R7 is selected from the group consisting of
  • R6 and R7 may form a five or six membered ring containing at least one O, S and/or N,
  • said mcotinonit ⁇ le compound is not 2-Am ⁇ no-6-(4-methoxy-phenyl)-4-/.-tolyl-n ⁇ cot ⁇ non ⁇ t ⁇ le, 2-Am ⁇ no-6-(3,4-d ⁇ methyl-phenyl)-4-(4-methoxy-phenyl)-n ⁇ cot ⁇ non ⁇ t ⁇ le, 2-Am ⁇ no-4-(4-methoxy-phenyl)-6-/?-tolyl-n ⁇ cot ⁇ non ⁇ tr ⁇ le, 2-Am ⁇ no-4-(3,4-d ⁇ methoxy-phenyl)-6- ?-tolyl-mcot ⁇ non ⁇ t ⁇ le,
  • R2 is S-Me, NRgR ⁇ , O-alkyl or alkyl having 1-6 carbon atoms
  • R1 , R3, and R4 are H
  • R5, Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms _
  • R2 is S-Me, NRgRc), O-alkyl or alkyl having 1 -6 carbon atoms
  • Rj , R3, R4 and R5 are H
  • Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
  • R2 is S-Me, NRgRo, O-alkyl or alkyl having 1-6 carbon atoms
  • Rj , R3, R5, Rg and R7 are H
  • R4 is straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
  • R-j is N-pyrrolidinyl or a dialkyl amino group having 1 -3 carbon atoms
  • R2 and R5-R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-4 carbon atoms;
  • R2 is straight chain, branched or cyclic saturated or unsaturated alkyl having 1-6 carbon atoms and R5-R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-4 carbon atoms, R2 is alkylthio having 1-3 carbon atoms; Rl, R3 and R4 are H.
  • said nicotinonitrile compound is selected from the group consisting of:
  • the present invention also relates to a process for the preparation of a nicotinonitrile 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 and malonitrile, optionally in the presence of a solvent, during 2-24 h.
  • a suitably substituted chalcone is heated with a nitrogen containing reagent, preferably malonitrile or 2-cyanoacetimidic acid ethyl ester, and ammonium acetate, optionally in the presence of a solvent, during 2-24 h.
  • a nitrogen containing reagent preferably malonitrile or 2-cyanoacetimidic acid ethyl ester, and ammonium acetate, optionally in the presence of a solvent, during 2-24 h.
  • a suitably substituted arylidenemalonitrile is heated with a suitably substituted acetophenone and ammonium acetate, optionally in the presence of an unpolar solvent, during 2-24 h.
  • suitable unpolar solvents can be mentioned benzene and toluene.
  • a suitably substituted l ,3-diphenylpropane- 1.3-dione and malonitrile are heated with ammonium acetate, optionally in the presence of a polar solvent, during 2-24 h.
  • a suitable polar solvent can be mentioned ethanol.
  • the chalcone prepared by standard methods, was heated with approp ⁇ ate amounts of a nitrogen i. containing reagent (e malonitrile or 2-cyano-acet ⁇ m ⁇ d ⁇ c acid ethyl ester) and ammonium acetate in a suitable solvent, such as ethanol. After 2-24 h of reflux, the product may be isolated as desc ⁇ bed in procedure 1
  • Procedure 3 0 A mixture of approp ⁇ ate amounts of the acetophenone derivative and an arylidenemalonitnle, both prepared by standard methods, and ammonium acetate was heated under reflux for 2-24 h in a suitable solvent, such as benzene or toluene. The product may be isolated as desc ⁇ bed in procedure 1.
  • the present in ention relates to a nicotinonitrile compound with the general formula I 0 for use as a pharmaceutical
  • the present inv ention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a nicotinonitrile compound according to any one of the embodiments set forth above as acti 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 1 000 mg, preferably from 1 to 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 a nicotinonitrile 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-r-ATPase in osteoclast cells.
  • the medicament is intended for treatment involving inhibition of vacuolar H-r-ATPase containing the isoform a3, said vacuolar H-r-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.
  • the present inv ention is also related to a method for inhibiting v acuolar 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+-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 nicotinonitrile 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 a nicotinonitrile 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 a nicotinonitrile compound according to any one of the previously outlined embodiments.
  • oral and parenteral doses will usually be in the range of 1 to 1000 mg, preferably from 1 to 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.
  • a nicotinonitrile compound for use as a pharmaceutical.
  • it may be used in pharmaceutical compositions for oral, intravenous, topical, lntrape ⁇ toneal or subcutaneous administration, in association with one or more pharmaceutically acceptable carriers, diluents or adjuv ants 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 tra ⁇ sdermally
  • H OEt H H OMe OMe OMe (400 MHz, CDCI 3 ): 1.48 (t, 3H); 3.90 (s,3H); 3.95 (s,6H); 4.11 (q, 2H); 5.32 (s br, 2H); 7.03 (d, 2H); 7.11 (s, IH); 7.23 (s,2H); 7.60 (d, 2H)
  • 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. 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/Tris, pH 7.4, 250 mM sucrose and 1 mM EGTA, minced using a pair of scissors, diluted 1 : 10 (w/v) in isolation buffer and homogenised in a polytron homogeniser.
  • the homogenate was filtered through a 250 ⁇ 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 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.
  • mice were injected with 4i Ca-solution (0.25 ml 120 ⁇ Ci/ml, s.c), day 2 and 1 before partus.
  • 4i Ca-solution (0.25 ml 120 ⁇ Ci/ml, s.c)
  • the pieces were placed in petri dishes containing incubation medium ( 1 mM L-glutamine, 100 U/ml penicillin, 100 ⁇ g'rnl streptomycin, 1 mg/ml albumin and 1 ⁇ M indomethacin) with or without 10 nM PTH and preincubated in a CO 2 incubator (5% CO2 in air) for 20-24 h at 37°C.
  • incubation medium 1 mM L-glutamine, 100 U/ml penicillin, 100 ⁇ g'rnl streptomycin, 1 mg/ml albumin and 1 ⁇ M indomethacin
  • 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 "Ca in a Microbeta (Wallac) scintillation counter (Control CPM).
  • 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 a nicotinonitrile compound with general formula (I).

Description

NOVEL NICOΠNONΓΓRILE 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 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 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 Chemisvy, 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( 1 1), 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)). The follow ing know n compounds are also of some relevance, albeit none of them have any repoπed biological effect associated with osteoclast cell activity:
2-Amιno-6-(4-methoxy-phenyl)-4-/.-tolyl-nιcotιnonιtπle (commercially available from Asinex),
2-Amιno-6-(3.4-dιmethyl-phenyl)-4-(4-methoxy-phenyI)-nιcotιnonιtπle (Moussa, H. and Chabaka. L M , Egypt J Chem . 26(3), 267-73 ( 1983)),
2-Amιno-4-(4-methoxy-phenyl)-6-jE.-tolyl-nιcotιnonιtπIe (Sammour, A , Akhnookh, Y., Jahine, H.,
U 4 R J Chem . 13(4), 421-37 (1970));
2-Amιno-4-(3,4-dιmetho\y-phenyl)-6-/.-tolyl-nιcotιnonιtπle (Sharma, A. K., Yadav, A. K. and
Prakash, L., Indian J. Chem. Sect. B, 34(8), 740-742 (1995)), 2-Amιno-6-(4-amιno-phenyl)-4-(3,4-dimethoxy-phenyl)-mcotιnonιtπle (Sharma, A. K.et al, vide supra);
2-Amιno-4-(3,4-dιmetho\>-phenyl)-6-(4-methoxy-phenyl)-nιcotιnonιtπle (Sharma, A. K. et al, vide supra);
2-Amιno-6-(3.4-dιmethoxy-phenyl)-4-(4-methoxy-phenyl)-nιcotιnonιtrile (commercially available from Bionet);
2-Amιno-4,6-bιs-(4-methoxy-phenyl)-nιcotιnonιtπle (commercially available from Asinex); 2-Amιno-4-benzo[ 1 ,3]dιo\ol-5-yl-6-(4-ιsopropyl-phenyl)-nιcotιnonιtπle (El-Hashash, M A., Shaban. M E. and Habashy, M. M., Rev Roum Chun., 26(1), 101-8 (1981)). 2-amιno-6-(2,4-dιmetho\>-phenyl)-4-(4-methoxy-phenyl)-nιcotιnonιtπle;( Abadi A., Al-Deeb O., Al-Afify A., El-Kashef H.. // Farmaco 54, 195-201 (1999)).
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 inter aha bone resorption have now been found More specifically, said compounds comprise a selective inhibitor of mammalian osteoclast cell activity, wherein said inhibitor comprises a nicotinonitπle 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.
In an embodiment of the present invention, said nicotinonitrile compound is 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 or six 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 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-piperidinvl;
R3 is selected from the group consisting of (a) H;
(b) O-alkyl having 1-3 carbon atoms;
(c) alkyl having 1 -3 carbon atoms and
(d) S-methyl or S- ethyl with the proviso that at least one of 1- 3 is not H,
R4 is 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
R5 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) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
(d) S-methyl or S- ethyl
Rf3 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) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
(d) straight chain, branched or cyclic saturated or unsaturated S-alkyl having 1-6 carbon atoms (e) Rg and R7 may form a five or six membered ring containing at lea_t one 0, S and or ,
R7 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) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
(d) R6 and R7 may form a five or six membered ring containing at least one O, S and/or N,
(e) S-methyl or S- ethyl with the proviso that at least one of R4-R7 is not H.
10 and with the additional proviso that said mcotinonitπle compound is not 2-Amιno-6-(4-methoxy-phenyl)-4-/.-tolyl-nιcotιnonιtπle, 2-Amιno-6-(3,4-dιmethyl-phenyl)-4-(4-methoxy-phenyl)-nιcotιnonιtπle, 2-Amιno-4-(4-methoxy-phenyl)-6-/?-tolyl-nιcotιnonιtrιle, 2-Amιno-4-(3,4-dιmethoxy-phenyl)-6- ?-tolyl-mcotιnonιtπle,
1 i 2-Amιno-6-(4-amιno-phenyl)-4-(3 ,4-dιmethoxy-phenyl)-nιcotιnonιtπle, 2-Amιno-4-(3,4-dιmethoxy-phenyl)-6-(4-methoxy-phenyl)-nιcotιnomtπle, 2-Amιno-6-(3,4-dιmethoxy-phenyl)-4-(4-methoxy-phenyl)-nιcotιnonιtπle, 2-Amιno-4,6-bιs-(4-methoxy-phenyl)-nιcotιnonιtπle, 2-Amιno-4-benzo[l,3]dιoxol-5-yl-6-(4-ιsopropyl-phenyl)-nιcoπnonιtπle, 0 2-amιno-6-(2,4-dιmethoxy-phenyl)-4-(4-methoxy-phenyl)-nιcotιnonιtπle
In another preferred embodiment, R2 is S-Me, NRgR<^, O-alkyl or alkyl having 1-6 carbon atoms, R1 , R3, and R4 are H, and R5, Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms _
In yet another preferred embodiment, R2 is S-Me, NRgRc), O-alkyl or alkyl having 1 -6 carbon atoms; Rj , R3, R4 and R5 are H, and Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
In still another preferred embodiment, R2 is S-Me, NRgRo, O-alkyl or alkyl having 1-6 carbon atoms, Rj , R3, R5, Rg and R7 are H, and R4 is straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms Among other preferred embodiments represented by the above formula I can be mentioned those, wherein
R-j is N-pyrrolidinyl or a dialkyl amino group having 1 -3 carbon atoms, R2 and R5-R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-4 carbon atoms;
R2 is straight chain, branched or cyclic saturated or unsaturated alkyl having 1-6 carbon atoms and R5-R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-4 carbon atoms, R2 is alkylthio having 1-3 carbon atoms; Rl, R3 and R4 are H.
In a particularly preferred embodiment of the present invention, said nicotinonitrile compound is selected from the group consisting of:
2-amιno-4-(4-pyrrolιdιn-l-yl-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnonιtπle, 2-amιno-4-(4-dιmethylamιno-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnonιtπle, 2-amιno-4-(4-dιethylamιno-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnonιtπle; 2-amιno-4-(4-terr-butyl-phenvl)-6-(3,4,5-tπmetho\y-phenyl)-nιcotιnonιtπle, 2-amιno-4-(4-ethyl-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnomtπle, 2-amιno-4-(4-methylthιo-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnonιtπle, 2-amιno-4-(4-ιsopropoxy-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnonιtπle, 2-amιno-4-(4-methoxy-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnonιtπle, 2-amιno-4-(4-ethoxy-phenyl)-6-(3,4,5-tπmethoxy-phenyl)-nιcotιnonιtπle; 2-amιno-4-(4-butoxy-phenyl)-6-(3,4,5-trιmethoxy-phenyl)-nιcotιnonιtπle; 2-amιno-4-[4-(3-dιmethylamιno-propoxy)-phenyl]-6-(3,4,5-tπmethoxy-phenyl)- nicotinonitrile;
2-amιno-4-[4-(2-pyrrohdιn- l-yl-ethoxy)-phenyl]-6-(3,4,5-tπmethoxy-phenyl)- nicotinonitπle,
2-ammo-6-(3,4-dιmethoxy-phenyl)-4-(4-dιmethylamιno-phenyl)-nιcotιnonιtπle, 2-amino-6-(3,4-dimetho.xy-phenyl)-4-(4-pyrrolidin- l -yl-phenyl)-mcotinonitnle, 2-amιno-6-(3,4-dιmethoxy-phenyl)-4-(4-methylthιo-phenyl)-nιcotιnonιtπle, 2-amιno-6-(3,4-dιmethoxy-phenyl)-4-[4-(3-dιmethylamιno-propoxy)-phenyl]- nicotinonitπle, 2-amino-4-(4-dimethylamιno-phenyl)-6-(2-ethoxy-phenyl)-nicotinonitrile:
2-amino-6-(2-ethoxy-phenyl)-4-(4-methoxy-phenyl)-nicotinonitrile;
2-amino-6-(2-ethoxy-phenyl)-4-(3-methoxy-phenyl)-nicotinonitrile;
2-amino-4-benzo[1.3]dioxol-5-yl-6-(2,4-dimethoxy-phenyl)-nicotinonitrile;
2-amino-6-(2,4-dimethoxy-phenyl)-4-(4-dimethylamino-phenyl)-nicotinonitrile;
2-amino-6-(2,4-dimethoxy-phenyl)-4-(4-pyrrolidin-l-yl-phenyl)-nicotinonitrile;
2-amino-6-(2,3-dihydro- lH-indol-5-yl)-4-(4-dimethylamino-phenyl)-nicotinonitrile:
2-amino-6-(2,3-dihydro-lH-indol-5-yl)-4-(4-methoxy-phenyl)-nicotinonitrile;
2-amino-4-[4-(2-pyrτolidin-l-yl-ethoxy)-phenyl]-6-(2,3,4-trimethyl-phenyl)- nicotinonitrile;
2-amino-4-(4-dimethyIamιno-phenyl)-6-(4-ethoxy-phenyl)-nicotinonitrile;
2-amino-6-(4-amino-phenyl)-4-(4-pyrrolidin-l-yl-phenyl)-nicotinonitrile;
2-amino-6-(4-amino-phenyl)-4-(3-methoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-isopropyl-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile.
The present invention also relates to a process for the preparation of a nicotinonitrile 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 and malonitrile, optionally in the presence of a solvent, during 2-24 h.
In another embodiment, a suitably substituted chalcone is heated with a nitrogen containing reagent, preferably malonitrile or 2-cyanoacetimidic acid ethyl ester, and ammonium acetate, optionally in the presence of a solvent, during 2-24 h.
In yet another embodiment, a suitably substituted arylidenemalonitrile is heated with a suitably substituted acetophenone and ammonium acetate, optionally in the presence of an unpolar solvent, during 2-24 h. As examples of suitable unpolar solvents can be mentioned benzene and toluene. In still another embodiment, a suitably substituted l ,3-diphenylpropane- 1.3-dione and malonitrile are heated with ammonium acetate, optionally in the presence of a polar solvent, during 2-24 h. As an example of a suitable polar solvent can be mentioned ethanol.
In the preparation of nicotinonitrile compounds according to the present invention, the following references provide useful guidance concerning e.g. suitable reaction conditions and proper selection of reagents:
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 nicotinonitrile 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.
Procedure 3 Procedure 4
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
A mixture of 0 5 mmol aiomatic aldehyde, 0 5 mmol acetophenone deri ati e, 0 5 mmol malonitrile and 0 75 mmol ammonium acetate was heated at 80°C overnight Other reaction times and temperatures were also used as well as addition of a small amount of a solvent, such as toluene
. Here, the solvent w as used only to facilitate the mixing of starting materials, and it was evaporated during the course of the reaction The residue was purified by flash chromatographv using methylene chloride methanol as eluent, followed by HPLC with acetonιtπle/0 1 M ammonium acetate (aq) as eluent In most cases the resulting material could be further purified by crystallisation from e g methylene chloride and ethanol or methanol The order of chromatographv ιo can generally be reversed, and in favourable cases crystallisation was used as the only means of purification From this procedure, 2-amιno-4,6-dιphenyl nicotinonitrile was isolated
Procedure 2
The chalcone, prepared by standard methods, was heated with appropπate amounts of a nitrogen i. containing reagent ( e malonitrile or 2-cyano-acetιmιdιc acid ethyl ester) and ammonium acetate in a suitable solvent, such as ethanol. After 2-24 h of reflux, the product may be isolated as descπbed in procedure 1
Procedure 3 0 A mixture of appropπate amounts of the acetophenone derivative and an arylidenemalonitnle, both prepared by standard methods, and ammonium acetate was heated under reflux for 2-24 h in a suitable solvent, such as benzene or toluene. The product may be isolated as descπbed in procedure 1.
5 Procedure 4
A mixture of appropriate amounts of a l,3-dιphenyl-propane- l,3-dιone, prepared by standard methods, malonitrile and ammonium acetate was heated in a suitable solvent, such as ethanol, for
2-24 h The product may be isolated as descπbed in procedure 1
Furthermore, the present in ention relates to a nicotinonitrile compound with the general formula I 0 for use as a pharmaceutical Thus, the present inv ention also relates to a pharmaceutical composition comprising a nicotinonitrile compound according to any one of the embodiments set forth above as acti 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 1 000 mg, preferably from 1 to 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 a nicotinonitrile 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-r-ATPase in osteoclast cells.
In another preferred embodiment of said use, the medicament is intended for treatment involving inhibition of vacuolar H-r-ATPase containing the isoform a3, said vacuolar H-r-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 arthπtis, diabetic retinopathy, psoriasis or diabetes
The present inv ention is also related to a method for inhibiting v acuolar 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+-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 nicotinonitrile 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 a nicotinonitrile 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 a nicotinonitrile 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 from 1 to 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 naphtalenesulphomc acid
As outlined above, there is provided a nicotinonitrile compound for use as a pharmaceutical. Thus, it may be used in pharmaceutical compositions for oral, intravenous, topical, lntrapeπtoneal or subcutaneous administration, in association with one or more pharmaceutically acceptable carriers, diluents or adjuv ants 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 traπsdermally
Experimental part
Preparation of compounds illustrating the present invention.
Example I
Synthesis of rrolιdιn-l-yl-phenyl)-6-(3,4,5-trιmethoxy-phenyl)-nιcotιnonιtnle
A mixture of 4-(dιmethylamιno)benzaldehyde (75 mg, 0.5 mmol), 3, 4,5-tπmethoxy acetophenone (105 mg, 0.5 mmol), malonitrile (33 mg, 0.5 mmol), and ammonium acetate (58 mg, 0.75 mmol) was heated overnight at 80°C The residue was purified first by HPLC and then by flash chromatographv on silica gel using methylene chloride/ methanol as eluent. The yield was 10 mg. 'H NMR see Table 1.
Examples 2-29
Synthesis according to example 1 See table 1 Table 1. 2-Amino-4,6-diphenyl nicotinonitriles according to formula I.
c I" m r
D)
O c
09 CO
π
3J r C m
N_ D)
2H)
H SMe H H OMe OMe OMe (400 MHz, CDC13): 2.55 (s, 3H); 3.91 (s, 3H); 3.95 (s, 6H); 7.11 (s, IH); 7.23 (s, 2H); 7.38 (d, 2H); 7.57 (d, 2H)
CO
C H O-iPr H H OMe OMe OMe (400 MHz, CDCI3): 1.39 (d, 6H); o_
CO 3.91 (s, 3H); 3,95 (s, 6H); 4.64 (m, IH); 5.31 (s br, 2H); 7.02 (d,
CO 2H);7.11 (s, lH);7.23(s, 2H); X m 7.59 (d, 2H)
H OMe H H OMe OMe OMe (400 MHz, CDCI3): 3.88 (s, 3H); c r- rπ 3.91 (s, 3H); 3.94 (s, 6H); 5.36 (s
Mn br,2H); 7.05 (d,2H); 7.11 (s, IH); 7.23 (d, 2H); 7.60 (d, 2H)
H OEt H H OMe OMe OMe (400 MHz, CDCI3): 1.48 (t, 3H); 3.90 (s,3H); 3.95 (s,6H); 4.11 (q, 2H); 5.32 (s br, 2H); 7.03 (d, 2H); 7.11 (s, IH); 7.23 (s,2H); 7.60 (d, 2H)
-
cO
CD to
π
CO
X m
c m
M
t
CO c CD CO
CO
X m
Ώ x c
S
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. 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/Tris, pH 7.4, 250 mM sucrose and 1 mM EGTA, minced using a pair of scissors, diluted 1 : 10 (w/v) in isolation buffer and homogenised in a polytron homogeniser. The homogenate was filtered through a 250 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. 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 MgS04, 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 Ca release from neonatal mouse calvarial (skull) bones.
Measurement of bone resoφtion by 3Ca 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 4iCa-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'rnl 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 "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 ^Ca (Compound CPM). The resoφtion ratio between the control period and the compound period (compound CPM/control CPM) was calculated and dose- response curves constaicted 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. Novel nicotinonitrile compounds having the general foπnula I:
wherein R\ is selected from the group consisting of
(a) H;
(b) O-alkyl having 1 -3 carbon atoms:
(c) Ri + R2 form a five or six membered ring contining 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- pyrrolidinyl, 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 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-moφhoIinyl 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 is selected from the group consisting of (a) H; (b) O-alkyl having 1-3 carbon atoms;
(c) alkyl having 1-3 carbon atoms and
(d) S-methyl or S- ethyl with the proviso that at least one of R1-R3 is not H,
R4 is 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
R5 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) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1 -6 carbon atoms (d) S-methy or S- ethyl
Rg 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) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
(d) straight chain, branched or cyclic saturated or unsaturated S-alkyl having 1-6 carbon atoms (e) Rg and R7 may form a five or six membered ring containing at least one 0, S and/or N;
R7 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) straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
(d) Rg and R7 may form a five or six membered ring containing at least one 0, S and/or N;
(e) S-methyl or S- ethyl with the proviso that at least one of R4-R7 is not H, and with the additional proviso that said nicotinonitrile compound is not 2-Amino-6-(4-metho.xy-phenyl)-4- -tolyl-nicotinonitrile; 2-Amino-6-(3,4-dimethyl-phenyl)-4-(4-methoxy-phenyl)-nicotinonitrile; 2-Amino-4-(4-metho.xy-phenyl)-6-Jσ-tolyl-nicotinonitrile; 2-Amino-4-(3,4-dimethoxy-phenyl)-6-p-tolyl-nicotinonitrile; 2-Amιno-6-(4-amιno-phenyl)-4-(3,4-dιmethoxy-phenyl)-nιcotιnonιtπle,
2-Amιno-4-(3,4-dιmethoxy-phenyl)-6-(4-methoxy-phenyl)-nιcotιnonιtπle,
2-Amιno-6-(3,4-dιmethoxy-phenyl)-4-(4-methoxy-phenyl)-nιcotιnonιtπle,
2-Amιno-4,6-bιs-(4-methoxy-phenyl)-nιcotιnonιtπle,
2-Amιno-4-benzo[l ,3]dιoxol-5-yl-6-(4-ιsopropyl-phenyl)-nιcotιnonιtπle,
2-amιno-6-(2,4-dιmethoxy-phenyl)-4-(4-methoxy-phenyl)-nιcotιnonιtπle
2. A mcotmonitπle compound according to claim 1, wherein R2 is S-Me, NR R9, O-alkyl or alkyl having 1-6 carbon atoms, Rj, R3 and R4 are H, and R5, Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms.
3 A mcotinonitπle compound according to claim 1 wherein R2 is S-Me, NRgR9, O-alkyl or alkyl having 1-6 carbon atoms; R\, R3, R4, and R5 are H; and Rg and R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms
4 A nicotinonitrile compound according to claim 1, wherein R2 is S-Me, NRgR9, O-alkyl or alkyl having 1-6 carbon atoms; R\ , R3, R5, Rg and R7 are H; and R4 is straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-6 carbon atoms.
5 A nicotinonitrile compound according to claim 1, wherein R2 and R5-R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl ha ing 1-4 carbon atoms.
6 A nicotinonitrile compound according to claim 1, wherein R2 is straight chain, branched or cyclic saturated or unsaturated alkyl having 1-6 carbon atoms and R5-R7 are straight chain, branched or cyclic saturated or unsaturated O-alkyl having 1-4 carbon atoms
7 A nicotinonitrile compound according to claim 1, wherein R2 is N-pyrrohdinyl
8. A nicotinonitrile compound according to any one of claims 1-4, wherein R2 is a dialkyl a ino group having 1-3 carbon atoms.
9. A nicotinonitrile compound according to any one of claims 1-4, wherein R2 is alkylthio having 1-3 carbon atoms.
10. A nicotinonitrile compound according to any one of claims 1-9, wherein Rj and R3 are H.
1 1. A nicotinonitrile compound according to any one of claims 1-10, wherein R4 is H.
12. A nicotinonitrile compound according to any one of the preceding claims, wherein said compound is selected from the group consisting of:
2-amino-4-(4-pyrrolidin- 1 -yl-phenyl)-6-(3 ,4,5-trimethoxy-phenyl)-nicotinonitrile; 2-amino-4-(4-dimethylamino-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-diethylamino-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-tert-butyl-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-ethyl-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-methylthio-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile; 2-amino-4-(4-isopropoxy-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-methoxy-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-ethoxy-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-butoxy-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile;
2-amino-4-[4-(3-dimethylamino-propoxy)-phenyl]-6-(3,4,5-trimethoxy-phenyl)- nicotinonitrile;
2-amino-4-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-6-(3,4,5-trimethoxy-phenyl)- nicotinonitrile;
2-amino-6-(3,4-dimethoxy-phenyl)-4-(4-dimethylamino-phenyl)-nicotinonitrile;
2-amino-6-(3,4-dimethoxy-phenyl)-4-(4-pyrrolidin-l-yl-phenyl)-nicotinonitrile: 2-amino-6-(3,4-dimethoxy-phenyl)-4-(4-methylthio-phenyl)-nicotinonitrile;
2-amino-6-(3,4-dimethoxy-phenyl)-4-[4-(3-dimethylamino-propoxy)-phenyl]- nicotinonitrile; 2-amino-4-(4-dimethylamino-phenyl)-6-(2-ethoxy-phenyl)-nicotinonitrile;
2-amino-6-(2-ethoxy-phenyl)-4-(4-methoxy-phenyl)-nicotinonitrile;
2-amino-6-(2-ethoxy-ρhenyl)-4-(3-methoxy-phenyl)-nicotinonitrile;
2-amino-4-benzo[ l ,3]dioxol-5-yl-6-(2,4-dimethoxy-phenyl)-nicotinonitrile; 2-amino-6-(2,4-dimethoxy-phenyl)-4-(4-dimethylamino-phenyl)-nicotinonitrile;
2-amino-6-(2,4-dimethoxy-phenyl)-4-(4-pyrrolidin-l-yl-phenyl)-nicotinonitrile;
2-amino-6-(2,3-dihydro-lH-indol-5-yl)-4-(4-dimethylamino-phenyl)-nicotinonitrile;
2-amino-6-(2,3-dihydro-lH-indol-5-yl)-4-(4-methoxy-phenyl)-nicotinonitrile;
2-amino-4-[4-(2-pyrrolidin- l-yl-ethoxy)-phenyl]-6-(2,3,4-trimethyl-phenyl)- nicotinonitrile;
2-amino-4-(4-dimethylamino-phenyl)-6-(4-ethoxy-phenyl)-nicotinonitrile;
2-amino-6-(4-amino-phenyl)-4-(4-pyrτolidin-l-yl-phenyl)-nicotinonitrile;
2-amino-6-(4-amino-phenyl)-4-(3-methoxy-phenyl)-nicotinonitrile;
2-amino-4-(4-isopropyi-phenyl)-6-(3,4,5-trimethoxy-phenyl)-nicotinonitrile.
13. A process for the preparation of a compound according to any one of claims 1-12, wherein a suitably substituted benzaldehyde is heated with ammonium acetate and a suitably substituted acetophenone and malonitrile, optionally in the presence of a solvent, during 2-24 h.
14. A process for the preparation of a compound according to any one of claims 1-12, wherein a suitably substituted chalcone is heated with a nitrogen containing reagent, preferably malonitrile or 2-cyanoacetimidic acid ethyl ester, and ammonium acetate, optionally in the presence of a solvent, during 2-24 h.
15. A process for the preparation of a compound according to any one of claims 1-12, wherein a suitably substituted arylidenemalonitrile is heated with a suitably substituted acetophenone and ammonium acetate, optionally in the presence of an unpolar solvent, during 2-24 h.
16. A process for the preparation of a compound according to any one of claims 1- 12, wherein a suitably substituted 1.3-diphenylpropane- l,3-dione and malonitrile are heated with ammonium acetate, optionally in the presence of a polar solvent, during 2-24 h.
5 17. A nicotinonitrile compound according to any one of claims 1-12 for use as a pharmaceutical.
18. A pharmaceutical composition comprising a nicotinonitrile compound according to any one of claims 1- 12 as active ingredient in association with a pharmaceutically iύ acceptable adjuvant, diluent or carrier.
19. A pharmaceutical composition according to claim 18, wherein the amount of said active ingredient per dosage unit is within the range of about 1 to 1 000 mg, preferably 1 to 300 mg. 5
20. A pharmaceutical composition according to any one of claims 18-19, wherein the amount of said active ingredient is within the range of about 0.1 to 95% by weight of said pharmaceutical composition.
0 21. Use of a nicotinonitrile compound according to any one of claims 1-12 in the manufacture of a medicament for use in therapeutic or prophylactic treatment of a human or animal body.
22. Use according to claim 21 , wherein the medicament is intended for treatment involving inhibition of vacuolar H+-ATPase, preferably vacuolar H+- ATPase in osteoclast cells.
23. Use according to claim 21, 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.
24. Use according to claim 21, wherein the medicament is intended for treatment involving inhibition of bone resoφtion.
25. Use according to claim 21, wherein the medicament is intended for treatment and/or prevention of diseases related to increased bone resoφtion, preferably osteoporosis.
26. Use according to claim 21, 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, atherosclerosis, rheumatoid arthritis, diabetic retinopathy, psoriasis or diabetes.
27. A method for inhibiting vacuolar H+- ATPase, preferably vacuolar HAATPase in osteoclast cells, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of a nicotinonitrile compound according to any one of claims 1-12.
28. 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 a nicotinonitrile compound according to any one of claims 1-12.
29. A method for inhibiting bone resoφtion which comprises administering to a human or animal patient a therapeutically effective amount of a nicotinonitrile compound according to any one of claims 1-12.
30. 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 a nicotinonitrile compound according to any one of claims 1-12.
31. 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 a nicotinonitrile compound according to any one of claims 1-12.
EP00970370A 1999-10-06 2000-09-26 Novel nicotinonitrile compounds Withdrawn EP1222170A1 (en)

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