WO1997022588A1 - Utilisation d'acides heteroarylacetiques en tant qu'inhibiteurs des leucotrienes - Google Patents

Utilisation d'acides heteroarylacetiques en tant qu'inhibiteurs des leucotrienes Download PDF

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Publication number
WO1997022588A1
WO1997022588A1 PCT/EP1996/005441 EP9605441W WO9722588A1 WO 1997022588 A1 WO1997022588 A1 WO 1997022588A1 EP 9605441 W EP9605441 W EP 9605441W WO 9722588 A1 WO9722588 A1 WO 9722588A1
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formula
carbon atoms
phenyl
chain
optionally
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PCT/EP1996/005441
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English (en)
Inventor
Mazen Es-Sayed
Masaru Yamamoto
Klaus Frobel
Chris Poll
Suzanna Grix
Stephen Tudhope
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Bayer Aktiengesellschaft
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Priority to AU11909/97A priority Critical patent/AU1190997A/en
Publication of WO1997022588A1 publication Critical patent/WO1997022588A1/fr

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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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • 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
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • 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
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides

Definitions

  • the invention relates to the use of hetarylacetic acid derivatives as medicaments, in particular for the treatment of airway and inflammatory diseases, new active compounds and process of their preparation
  • Leukot ⁇ enes are arachidonic acid metabolites produced by the 5-l ⁇ poxygenase pathway in activated phagocytes and are important mediators of bronchial asthma and acute inflammation
  • Alpha-Phenylpy ⁇ dineacetic acid esters are described in publication about tauto- me ⁇ sm synthesis and reactivity of 4-phenvl-6-p-tolyln ⁇ cot ⁇ non ⁇ t ⁇ ies and synthetic applications of N-N- linked heterocycles (J Chem Soc , Perkin I (1981), (9), 2476-82, Quator Univ Sci Bull (1986), 6, 93-104, Khim Geterotsikl Soedin
  • R represents a 6 membered aromatic heterocycle having up to 2 nitrogen atoms and to which a phenyl ring can be fused and wherein the rings optionally are ono substituted or disubstituted by identical or different substituents from the series comprising halogen, carboxyl, nitro, straight- chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group or the formula -(CO) a -NR 3 R 4
  • R and R are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl,
  • R ⁇ represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are substituted by halogen, carboxyl or straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or represents a group of the formula
  • D represents hydrogen, chlorine or hydroxyl
  • b and c are identical or different and denote a number 0 or 1 ,
  • R 5 and R 8 are identical or different and denote adamantyl or a residue of the formula
  • R denotes a residue of the formula -NHCH-,C 6 H ⁇
  • R 5 denotes hydrogen
  • R 6 and R 7 are identical or different and denote hydrogen, cycloalkyl having 3 to 6 carbon atoms, phenyl or the quinuhdinyl
  • straight-chain or branched alkyl having up to 8 carbon atoms which optionally is up to t ⁇ substituted by identical or different substituents from the series comprising cycloalkyl having 3 to 6 carbon atoms, py ⁇ dyl or by phenyl, which optionally is up to t ⁇ substituted by identical or different substituents from the series comprising hydroxyl, halogen, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 7 carbon atoms, or by a group of the formula -OC-NR 8 R 9 ,
  • R > ⁇ a n personallynd ⁇ t Ry have the abovementioned meaning of R J and R
  • R 1 represents isoquinolyl, pyrazinyl, py ⁇ dyl or py ⁇ midinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising fluorine, chlorine, bromine, iodine, carboxyl, nitro, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or by a group of a formula -(CO) ( -NR 3 R 4 ,
  • a denotes a number 0 or 1 ,
  • R and R 4 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, which are optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl
  • R ⁇ represents adamantyl, cyclopentyl, cyclohexyl, py ⁇ dyl, phenyl or benzyl, which optionally are substituted by fluorine, chlorine, bromine, carboxyl or straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or represents a group of a formula
  • D represents hydrogen, chlorine or hydroxyl
  • b and c are identical or different and denote a number 0 or 1 ,
  • R s and R 8 are identical or different and denote adamantyl or a residue of the formula
  • R s denotes a residue of the formula -NH-CH-,-C, 6-H A 1 5
  • R s denotes hydrogen
  • R and R are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyi, phenyl or quinulidinyl or denote straight- chain or branched alkyl having up to 6 carbon atoms, which optionally is up to t ⁇ substituted by identical or different substituents from the series comprising cyclopropyl, cvclopentyl, cyclohexyi, pyridyl, phenyl, which optionally is up to t ⁇ substituted by identical or different substituents from the series comprising hydroxyl, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms, or by a group of the formula -CO-NR 8 R 9 ,
  • R 8 and R 9 have the abovementioned meaning of R 3 and R 4
  • Particularly preferably used for controlling of airway diseases and inflammation are those compounds of the general formula (I),
  • R 1 represents pyridyl or py ⁇ midinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series com ⁇ prising fluorine, chlorine, bromine, carboxyl, nitro, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or by a group of the formula -(CO) -NR 3 R 4 ,
  • a denotes a number 0 or 1
  • R 3 and R 4 are identical or different and denote hydrogen, biphenyl, phenyl or adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which are optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl,
  • R ⁇ represents cyclopentyl, cyclohexyi, pyridyl, phenyl or benzyl, which op ⁇ tionally are substituted by fluorine, chlorine, bromine, carboxyl or straight- chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or D represents hydrogen, chlorine or hydroxyl,
  • E represents a group of the formula -(NH) b -CO 2 R 5 , -(CO) c -NR 6 R 7 or
  • b and c are identical or different and denote a number 0 or 1
  • R and R are identical or different and denote adamantyl or a residue of the formula
  • R denotes a residue of the formula -NH-CH 2 C 6 H 5
  • R 5 denotes hydrogen
  • R 6 and R 7 are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyi, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which optionally is up to trisubstituted by identical or different substituents from the series comprising cyclopropyl.
  • cyclopentyl, cyclohexyi, pyridyl, phenyl which is up to trisubstituted by identical or different substituents from the series comprising hydroxyl, fluorine, chlorine or bromine,
  • the invention additionally relates to new compounds of the general formula (I) with the abovementioned meaning of the substituents as given in the following table
  • hetarylacetic acid derivatives according to the invention can also be present in the form of their salts
  • salts with organic or inorganic bases or acids may be mentioned here
  • Physiologically acceptable salts are preferred in the context of the present in ⁇ vention
  • Physiologically acceptable salts of the arylacetic acid derivatives can be metal or ammonium salts of the substances according to the invention, which con ⁇ tain a free carboxylic group
  • Those which are particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or t ⁇ ethylamine, di- or t ⁇ ethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine
  • Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids
  • Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fuma ⁇ c acid, malic acid, citric acid, tarta ⁇ c acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedi sulphonic acid
  • the compounds according to the invention can exist in stereoisome ⁇ c forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers)
  • the invention relates both to the antipodes and to the racemate forms, as well as the diastereomer mixtures
  • the racemate forms, like the diastereomers, can be separated into the stereoisome ⁇ - cally uniform constituents in a known manner
  • R 1 , R 5 and D have the abovementioned meaning
  • R has the abovementioned meaning
  • W denotes halogen, preferably bromine
  • R , R" and D have the abovementioned meaning
  • X and Y are identical or different and denote halogen, preferably chlorine,
  • R , R and R have the abovementioned meaning
  • R , R ⁇ and D have the abovementioned meaning
  • R 10 denotes C, -C 4 -a_kyl
  • R 1 , R 2 and D have the abovementioned meaning
  • N-methylmorpholine benzylamine Suitable solvents are generally customary organic solvents which do not change under the reaction conditions These include ethers such as diethyl ether, dioxane or tetrahydrofuran, toluene, acetone, dimethylsulfoxide, dimethylformamide or al ⁇ cohols such as methanol, ethanol, propanol or halogenohydrocarbons such as di- chlormethane, tnchloromethane, tetrachloromethane or acetone Tetrahydrofurane, dimethylformamide, toluene and acetone are preferred
  • Suitable bases are generally inorganic or organic bases These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal or organic amines (t ⁇ alkyl(C 1 -C 6 )am ⁇ nes) such as t ⁇ - ethylamine, or heterocycles such as l,4-d ⁇ azab ⁇ cyclo[2 2 2]octane (DABCO), 1 ,8- d ⁇ azab ⁇ cyclo[5 4 0]undec-7-ene (DBU), or amides such as sodium amides, lithium diisopropyl amide or butyllithium, py ⁇ dine, methylpipe ⁇ dine, N-methylmorpholine or kahumhexamethyld ⁇
  • the process is in general carried out in a temperature range from 0°C to +100°C, preferably from room temperature to +60°C
  • the process is generally carried out at normal pressure However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0 5 to 5 bar)
  • the base is employed in an amount from 1 mol to 10 mol, preferably from
  • Suitable bases for the hydrolysis are the customary inorganic bases These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium hydrogen carbonate, or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert butoxide Sodium hydroxide or potassium hydroxide are particularly prefer ⁇ ably employed
  • Suitable solvents for the hydrolysis are water or the organic solvents customary for hydrolysis These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethyl ⁇ formamide, or dimethyl sulphoxide Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used It is also possible to employ mixtures of the solvents mentioned
  • the hydrolysis can also be carried out with acids such as, for example, t ⁇ fluoro- acetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric acid, preferably with t ⁇ fluoroacetic acid
  • the hydrolysis is in general carried out in a temperature range from 0°C to +180°C, preferably from +20°C to +160°C
  • the hydrolysis is carried out at normal pressure
  • reduced pressure or at elevated pressure for example from 0 5 to 5 bar
  • the base is in general employed in an amount from 1 to 3 mol, preferably from 1 to 1 5 mol, relative to 1 mol of the ester molar amounts of the reactants are particularly preferably used
  • the process is in general carried out in a temperature range from +60°C to +200°C, preferably from +100°C to +160°C
  • arylacetic acid derivatives of the general formulae (I), (la) and (lb) and the new compounds according to the invention can be employed as active compounds in medicaments
  • the substances can act as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism
  • the compounds of the general formulae (I), (la) and (lb) and the new compounds surprisingly draw a high activity as inhibitors of leukotriene synthesis, specifically they inhibit the production of leukotriene B 4 in poiymorphonuclear leucocytes (PMN)
  • senors are therefore preferably suitable for the treatment and prevention of diseases of the respiratory passages, such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and oedemas, throm ⁇ boses and thromboembolism, ischae is (disturbances in peripheral, cardiac and cerebral circulation), cardiac and cerebral infarctions, disturbances in cardiac rhythm, angina pectoris and arterioscleroris, in the event of tissue, transplants, dermatoses, such as psoriasis, inflammatory dermatoses, for example eczema, dermatophyte infection, infections of the skin by bacteria, metastases and for cytoprotection in the gastrointestinal tract.
  • diseases of the respiratory passages such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and oedem
  • Neutrophils (4 x 10 5 cells/ml) were placed in a 96 well microtitre plate and prewarmed to 37°C.
  • Compounds according to the invention were added in dimethyl sulphoxide (DMSO) Compound concentration ranged from 0 3 to 30 ⁇ M, the DMSO concentration was ⁇ 0.3% v/v
  • DMSO dimethyl sulphoxide
  • the plate was incubated for 5 mm at 37°C
  • Neutrophils were then stimulated by addition of 1 ⁇ M thapsigargin followed by 1 3 mM Ca"
  • the reaction was stopped after 5 minutes and supernatants assayed for the presence of leukotriene (LT) B 4 using an LTB 4 -spec ⁇ f ⁇ c radioimmunoassay kit supplied by Amersham Internationl pic Percentage inhibition was determined by comparison with vehicle-containing controls
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceuti- cally suitable excipients or solvents
  • the therapeutically active compound should in each case be present in a concentration of about 0 5 to 90% by weight of the total mixture, I e in amounts which are sufficient in order to achieve the dosage range indicated
  • the formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate
  • Administration is carried out in a customary manner, preferably orally or parenterally, in particular perhngually or intravenously
  • solutions of the active compound can be employed using suitable liquid vehicles
  • intravenous administration amounts from about 10 to 100 mg/kg, preferably about 10 to 50 mg/kg of body weight to achieve effective results, and on oral administration the dosage is about 10 to 100 mg/kg, preferably 10 to 50 mg/kg of body weight

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'acides hétéroarylacétiques comme inhibiteurs de la synthèse des leucotriènes et, plus particulièrement de la synthèse du leucotriène B4. Ces composés sont donc utiles pour prévenir et traiter les maladies des voies respiratoires et les maladies inflammatoires.
PCT/EP1996/005441 1995-12-18 1996-12-05 Utilisation d'acides heteroarylacetiques en tant qu'inhibiteurs des leucotrienes WO1997022588A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11909/97A AU1190997A (en) 1995-12-18 1996-12-05 Use of hetarylacetic acid derivatives as leukotriene inhibitors

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Application Number Priority Date Filing Date Title
GBGB9525828.1A GB9525828D0 (en) 1995-12-18 1995-12-18 Use of hetarylacetic acid derivatives
GB9525828.1 1995-12-18

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WO1997022588A1 true WO1997022588A1 (fr) 1997-06-26

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8927549B2 (en) 2008-11-21 2015-01-06 High Point Pharmaceuticals, Llc Adamantyl benzamide derivatives
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors

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JPS5687565A (en) * 1979-12-19 1981-07-16 Mitsui Petrochem Ind Ltd Production of alpha-arylpyridineacetic ester
US4571401A (en) * 1983-07-19 1986-02-18 Maggioni Farmaceutici S.P.A. 3-Pyridine acetic and 3-(3-pyridyl-methoxycarbonyl)-propionic acid pantetheine and pantetheine esters having hypolipemic activities
WO1993003723A1 (fr) * 1991-08-14 1993-03-04 Allergan, Inc. Complexe antagoniste de recepteur de leucotrienes-antihistamine
US5440044A (en) * 1990-03-19 1995-08-08 Schering Aktiengesellschaft Leukotriene-B4 derivatives, process for their production and their use as pharmaceutical agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5687565A (en) * 1979-12-19 1981-07-16 Mitsui Petrochem Ind Ltd Production of alpha-arylpyridineacetic ester
US4571401A (en) * 1983-07-19 1986-02-18 Maggioni Farmaceutici S.P.A. 3-Pyridine acetic and 3-(3-pyridyl-methoxycarbonyl)-propionic acid pantetheine and pantetheine esters having hypolipemic activities
US5440044A (en) * 1990-03-19 1995-08-08 Schering Aktiengesellschaft Leukotriene-B4 derivatives, process for their production and their use as pharmaceutical agents
WO1993003723A1 (fr) * 1991-08-14 1993-03-04 Allergan, Inc. Complexe antagoniste de recepteur de leucotrienes-antihistamine

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Title
CHEMICAL ABSTRACTS, vol. 114, no. 19, 13 May 1991, Columbus, Ohio, US; abstract no. 178177y, K. TANIGUCHI ET. AL.: "Inhibitory effects of Histamine H1 receptor blocking drugs on metabolic activations of neutrophils." page 49; column 2; XP002029081 *
CHEMICAL ABSTRACTS, vol. 95, no. 21, 23 November 1981, Columbus, Ohio, US; abstract no. 187088M, MITSUI PETROCHEMICAL INDUSTRIES LTD.: "alpha-Phenylpyridineacetic acid esters." page 638; column 2; XP002029080 *
JOURNAL OF PHARMACOBIOLOGICAL DYNAMICS, vol. 14, no. 2, 1991, pages 87 - 93 *

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US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors

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