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WO2001025207A1 - Nouveaux composes nicotinonitriliques - Google Patents

Nouveaux composes nicotinonitriliques Download PDF

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Publication number
WO2001025207A1
WO2001025207A1 PCT/SE2000/001857 SE0001857W WO0125207A1 WO 2001025207 A1 WO2001025207 A1 WO 2001025207A1 SE 0001857 W SE0001857 W SE 0001857W WO 0125207 A1 WO0125207 A1 WO 0125207A1
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Prior art keywords
phenyl
nicotinonitrile
alkyl
amino
carbon atoms
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Margareta HERSLÖF
Henrik Sörensen
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AstraZeneca AB
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AstraZeneca AB
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Priority to CA002385244A priority Critical patent/CA2385244A1/fr
Priority to AU79762/00A priority patent/AU7976200A/en
Priority to JP2001528153A priority patent/JP2003511368A/ja
Priority to EP00970370A priority patent/EP1222170A1/fr
Publication of WO2001025207A1 publication Critical patent/WO2001025207A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • 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

La présente invention concerne, d'une part un inhibiteur sélectif de l'activité ostéoclastique de mammifères, et d'autre part des procédés d'élaboration de cet inhibiteur, des compositions à base de cet inhibiteur, ainsi qu'un traitement impliquant l'administration de cet inhibiteur sélectif à des animaux, voire à des humains. Il s'est avéré que cet inhibiteur sélectif présente une action inhibitrice de l'H+-ATPase vacuolaire et notamment de l'H+-ATPase vacuolaire des ostéoclastes, ce qui fait qu'il est efficace contre des troubles physiologiques impliquant la résorption osseuse. Pour l'un de ses modes de réalisation, l'inhibiteur sélectif de l'invention comprend un composé nicotinonitrilique représenté par la formule générale (I).
PCT/SE2000/001857 1999-10-06 2000-09-26 Nouveaux composes nicotinonitriliques Ceased WO2001025207A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002385244A CA2385244A1 (fr) 1999-10-06 2000-09-26 Nouveaux composes nicotinonitriliques
AU79762/00A AU7976200A (en) 1999-10-06 2000-09-26 Novel nicotinonitrile compounds
JP2001528153A JP2003511368A (ja) 1999-10-06 2000-09-26 新規なニコチノニトリル化合物
EP00970370A EP1222170A1 (fr) 1999-10-06 2000-09-26 Nouveaux composes nicotinonitriliques

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SE9903609-7 1999-10-06
SE9903609A SE9903609D0 (sv) 1999-10-06 1999-10-06 Novel compounds I

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2331418C2 (ru) * 2006-05-24 2008-08-20 Государственное образовательное учреждение высшего профессионального образования "Пермская государственная фармацевтическая академия Федерального агентства по здравоохранению и социальному развитию" (ГОУ ВПО ПГФА Росздрава) Изоникотиноилгидразид фталевой кислоты как антидиабетическое средство
WO2015031718A1 (fr) * 2013-08-29 2015-03-05 Mcquade D Tyler Procédés de production de 2-halonicotinonitriles

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
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RU2331418C2 (ru) * 2006-05-24 2008-08-20 Государственное образовательное учреждение высшего профессионального образования "Пермская государственная фармацевтическая академия Федерального агентства по здравоохранению и социальному развитию" (ГОУ ВПО ПГФА Росздрава) Изоникотиноилгидразид фталевой кислоты как антидиабетическое средство
WO2015031718A1 (fr) * 2013-08-29 2015-03-05 Mcquade D Tyler Procédés de production de 2-halonicotinonitriles
CN106061258A (zh) * 2013-08-29 2016-10-26 弗吉尼亚联邦大学 制造2‑卤代烟腈的方法
US9951020B2 (en) 2013-08-29 2018-04-24 Virginia Commonwealth University Methods of making 2-halonicotinonitriles

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