WO2001002387A1 - N-imidazolylmethyl-carboxamides utilises comme inhibiteurs de la production d'oxyde nitrique - Google Patents

N-imidazolylmethyl-carboxamides utilises comme inhibiteurs de la production d'oxyde nitrique Download PDF

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Publication number
WO2001002387A1
WO2001002387A1 PCT/JP2000/004302 JP0004302W WO0102387A1 WO 2001002387 A1 WO2001002387 A1 WO 2001002387A1 JP 0004302 W JP0004302 W JP 0004302W WO 0102387 A1 WO0102387 A1 WO 0102387A1
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compound
pyridyl
salt
pharmaceutically acceptable
halogen
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PCT/JP2000/004302
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English (en)
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Ichiro Shima
Takehiko Ohkawa
Kazuhiko Ohne
Tatsuya Zenkoh
Kentaro Sato
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to EP00940882A priority Critical patent/EP1196407A1/fr
Priority to JP2001507824A priority patent/JP2003503489A/ja
Publication of WO2001002387A1 publication Critical patent/WO2001002387A1/fr

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Definitions

  • This invention relates to new amide compounds and pharmaceutically acceptable salts thereof which are useful as medicament .
  • This invention relates to new amide compounds.
  • One object of this invention is to provide the new and useful amide compounds and pharmaceutically acceptable salts thereof that possess a strong inhibitory activity on the production of nitric oxide (NO).
  • Another object of this invention is to provide a process for the preparation of the amide compounds and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said amide compound or a pharmaceutically acceptable salt thereof.
  • Still further object of this invention is to provide a use of said amide compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic and therapeutic treatment of NO-mediated diseases including respiratory diseases such as adult respiratory distress syndrome (ARDS) and asthma; cardiovascular diseases such as cardiovascular ischemia, myocarditis, heart failure, hypotension and atherosclerosis; endocrine diseases such as diabetes (e.g., insulin-dependent diabetes mellitus , etc . ) , complications of diabetes mellitus (e.g., diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc.
  • respiratory diseases such as adult respiratory distress syndrome (ARDS) and asthma
  • cardiovascular diseases such as cardiovascular ischemia, myocarditis, heart failure, hypotension and atherosclerosis
  • endocrine diseases such as diabetes (e.g., insulin-dependent diabetes mellitus , etc . ) , complications of diabetes mellitus (e.g., diabetic nephropathy, diabetic retinopathy, diabetic
  • renal diseases such as glomerulonephritis and renal failure
  • gastrointestinal diseases such as peptic ulcer and inflammatory bowel disease (e.g., ulcerative colitis , chronic colitis , etc. )
  • pancreatic diseases such as pancreatitis
  • hepatic diseases such as hepatitis and liver cirrhosis
  • diseases of bone or joint such as synovitis, arthritis, osteoarthritis , osteoporosis
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis
  • dermal diseases such as dermatitis and eczema
  • cancer such as solid tumors and metastasis
  • rejection by organ transplantation shock (e.g. , septic shock, etc. )
  • sepsis-induced systemic inflammatory response syndrome e.g., septic shock, etc.
  • the object amide compounds of the present invention are novel and can be represented by the following general formula ( I ) :
  • R 1 is benzofuranyl substituted by halogen, or styryl substituted by halogen
  • R 2 is hydrogen or lower alkyl
  • R 3 is pyridyl, optionally protected hydroxy or lower alkylsulfonylamino
  • R 4 is lower alkyl
  • R 5 and R 6 are the same or different and each is hydrogen or lower alkyl
  • X is CH or N, provided that ( i) R 1 is styryl substituted by halogen when R 2 is hydrogen, R 3 is pyridyl, R 5 and R 6 are each hydrogen and X is CH, and (ii) X is N when R 1 is benzofuranyl substituted by halogen, R 3 is pyridyl and R 5 and R 6 are each hydrogen.
  • Suitable pharmaceutically acceptable salts of the object compound ( I ) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. , sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc. ) , an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridinesalt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.
  • a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. , sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt,
  • an inorganic acid addition salt e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, gultamic acid, etc.
  • lower is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
  • Suitable "halogen” includes, for example, fluorine, bromine, chlorine and iodine.
  • Suitable "lower alkyl” and “lower alkyl moiety" in the term “lower alkylsulfonylamino” include straight or branched one having 1 to 6 carbon atom(s) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl, in which more preferred one is C j -C ⁇ alkyl.
  • Optionally protected hydroxy includes hydroxy and protected hydroxy.
  • Suitable examples of "hydroxy protective group" in the term “protected hydroxy” include acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g., acetyl, trichloroacetyl, etc.), mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4- methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri( lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldi ethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
  • acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g.,
  • “Styryl substituted by halogen” means styryl which has halogen atomas a substituent on the benzene ring. Suitable examples of “styryl substituted by halogen” include 2-(2-chlorophenyl)ethenyl, 2-(3- chlorophenyl)ethenyl, 2-(4-chlorophenyl)ethenyl, 2-(2- bromopheny1)ethenyl, 2-(3-bromopheny1)ethenyl, 2-(4- bromophenyl )ethenyl, 2-( 2-fluorophenyl)ethenyl, 2-(3- fluorophenyl)ethenyl, 2-(4-fluorophenyl)ethenyl, and the like.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are each as defined above, R 7 is lower alkyl, and R 8 is hydroxy protective group.
  • the starting compounds can be prepared by the method of Preparation mentioned below or by a process known in the art for preparing their structurally analogous compounds.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group, or a salt thereof with the compound (III) or its reactive derivative at the carboxy group, or a salt thereof.
  • Suitable reactive derivative of the compound (II) includes Schiff ' s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0- bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound ( II ) with phosphorus trichloride or phosgene.
  • Suitable reactive derivative of the compound (III) includes an acid halide, an acid anhydride and an activated ester.
  • the suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g.
  • substituted phosphoric acid e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid e.g., sulfurous acid, thiosulfuric acid, alkanesulfonic acid
  • methanesulfonic acid ethanesulfonic acid, etc.
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'- dicyclohexylcarbodiimide; N-cyclohexyl-N' - morpholinoethylcarbodiimide; N-cyclohexyl-N' - ( 4- diethylaminocyclohexyl )carbodiimide; N,N' -diisopropylcarbodiimide; N-ethyl-N' - ( 3-dimethylaminopropyl )carbodiimide; N,N-carbonyl-bis- (2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l- chloroethylene; trialkyl phosphite
  • the reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, or the like.
  • an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (i)-lora salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V).
  • the compound ( I )-3 or a salt thereof can be prepared by subjecting the compound (I)-2 or a salt thereof to protection of hydroxy group.
  • Suitable salts of the starting compounds and their reactive derivatives in Processes ( 1 ) to ( 3 ) can be referred to the ones as exemplified for the compound (I).
  • the compounds obtained by the above process can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the compound ( I ) and the other compounds may include one or more stereoisomer(s ) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
  • the object compounds (I) and pharmaceutically acceptable salts thereof include solvates [e.g., enclosure compounds (e.g., hydrate, etc . ) ] .
  • the object compounds (I) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO) .
  • the object compounds (I) and pharmaceutically acceptable salts thereof are expected to possess a nitric oxide synthase (NOS)-inhibitory activity or a NOS-production inhibitory activity.
  • NOS nitric oxide synthase
  • the object compounds (I) and pharmaceutically acceptable salts thereof are useful for prevention and/or treatment of NO-mediated diseases including respiratory diseases such as adult respiratory distress syndrome (ARDS) and asthma; cardiovascular diseases such as cardiovascular ischemia, myocarditis, heart failure, hypotension and atherosclerosis; endocrine diseases such as diabetes (e.g., insulin-dependent diabetes mellitus, etc.), complications of diabetes mellitus (e.g., diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc.) and gout; renal diseases such as glomerulonephritis and renal failure; gastrointestinal diseases such as peptic ulcer and inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.); pancreatic diseases such as pancreatitis; hepatic diseases such as hepatitis and liver cirrhosis; diseases of bone or joint such as synovitis , arthritis , osteoarthritis , osteoporosis; autoimmune diseases such as rhe
  • the object compounds (I) and pharmaceutically acceptable salts thereof are also useful for prevention and/or treatment of NO-mediated nervous diseases including central nervous system diseases such as CNS disorders, cerebrovascular diseases (e.g., cerebral infarction, cerebral ischemia, cerebral hemorrhage, etc . ) , migraine, Alzheimer ' s disease; peripheral nervous system diseases such as neuritis, pain (e.g., postherpetic neuralgia, reflex sympathetic dystrophy (RSD), causalgia, deafferentation pain syndrome, neuropathic pain, etc.), allodynia, hyperalgesia, neurological disorders and neuroprotection; Parkinson's disease; and amyotrophic lateral sclerosis.
  • central nervous system diseases such as CNS disorders, cerebrovascular diseases (e.g., cerebral infarction, cerebral ischemia, cerebral hemorrhage, etc . ) , migraine, Alzheimer ' s disease
  • peripheral nervous system diseases such as neuritis, pain (e.g., postherpetic neural
  • object compounds (I) and pharmaceutically acceptable salts thereof are useful for treatment of sexual dysfunction such as male sexual dysfunction including erectile dysfunction, and female sexual dysfunction including orgasmic dysfunction related to clitoral disturbances.
  • the object compounds (I) and pharmaceutically acceptable salts thereof are useful for prevention and/or treatment of NO-mediated ophthalmic diseases, including conjunctive diseases such as conjunctivitis (e.g., allergic conjunctivitis, vernal conjunctivitis, keratoconjunctivitis sicca, viral conjunctivitis, bacterial conjunctivitis, etc. ) ; uveal diseases such as uveitis (e.g. , Behcet disease, Harada disease, sympathetic ophthalmia, sarcoidosis, diabetic blinkis , etc .
  • conjunctivitis e.g., allergic conjunctivitis, vernal conjunctivitis, keratoconjunctivitis sicca, viral conjunctivitis, bacterial conjunctivitis, etc.
  • uveal diseases such as uveitis (e.g. , Behcet disease, Harada disease, sympathetic o
  • scleral diseases such as scleritis ; corneal diseases such as corneal neovascularization, keratitis, corneal edema, corneal opacity, corneal dystrophy, keratoconus and neuroparalytic keratitis; retinal, vitreous diseases such as diabetic retinopathy, retinal artery occlusion, retinal vein occlusion, central serous chorioretinopathy, central hemorrhagic chorioretinitis , macular degeneration (e.g., age-related macular degeneration, etc.), retinal detachment, retinal pigmentary degeneration, macular neovascularization, macular hole, proliferative vitreoretinopathy, vitreous hemorrhage and vitreous opacity; lens diseases such as cataract (e.g., senile cataract, traumatic cataract, diabetic cataract, atopic cataract, etc.
  • cataract e.g., senile cataract,
  • glaucoma such as primary open-angle glaucome, primary angle-closure glaucoma, normal tension glaucoma and neovascular glaucoma
  • ocular hypertension vision disorders such as amblyopia, color vision defect and night blindness
  • refractive errors such as astigmatism, hyperopia, myopia and presbyopia
  • lacrimal apparatus diseases such as dry eye syndromes , lacrimal duct obstruction and dacryocystitis .
  • Test 1 Assay for inhibitory activity on the production of nitric oxide
  • the murine macrophage cell line RAW264.7 (American Type Culture Collection, No. TIB71) was used in this study.
  • RAW264.7 cells were grown on F75 plastic culture flasks at 37°C, 5% in Dulbecco's modified Eagle's medium (DMEM) supplemented with L-glutamine, penicillin, streptomycin and 10% heat-inactivated fetal bovine serum. They were removed from culture flasks by rubber cell scraper and were centrifuged and resuspended in DMEMwithout phenol red. Theywere plated in 96-well microtiter plates (10 5 cells per well) and allowed to adhere over 2 hours.
  • DMEM Dulbecco's modified Eagle's medium
  • test samples were added and the cells were preincubated for 1 hour. Thereafter the cells were activated with both of lipopolysaccharide (LPS) ( ljLLgl l ) and interferon ⁇ (INF y ) (3 u/ml) for 18-24 hours.
  • LPS lipopolysaccharide
  • INF y interferon ⁇
  • An equal volume of Griess reagent 1% sulfanilamide/0.1% N-naphthylethylenediamine dihydrochloride/2.5% H 3 P0 4 ) was added and the cells were incubated at room temperature for 10 minutes. The absorbance was read at 570 nm using microplate reader and N0 2 ⁇ was measured using NaN0 2 as a standard.
  • Test 2 Protective effect of the compound (I) combined with FK 506 on rat cardiac allograft Method:
  • Rats were anesthetizedwith sodium pentobarbital (50 mg/kg, i.p.), and underwent allogeneic (Lewis donor to ACI recipient) heterotopic intra-abdominal cardiac transplantation.
  • Experimental groups were divided into single-drug group and combined-drug group.
  • Combined-drug dose was FK506 (0.32 mg/kg) + the compound (I) (10 mg/kg).
  • the grafted hearts were monitored by daily palpation where complete rejection was defined as the cessation of palpable contractile activity.
  • Each drug was suspended in a solution of 0.5% methylcellulose, and administered by daily gastric intubation in a volume of 5 ml/kg of body weight for 14 days.
  • the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee, suppository or ointment, or in a liquid form such as solution, suspension or emulsion for injection, intravenous drip, ingestion, eye drop, etc.
  • auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered in a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, body weight and conditions of the patient or administering method.
  • R 1 is benzofuranyl substituted by halogen
  • R 3 is optionally protected hydroxy or lower alkylsulfonylamino, or a pharmaceutically acceptable salt thereof.
  • R 3 is pyridyl, optionally protected hydroxy or lower alkylsulfonylamino, or a pharmaceutically acceptable salt thereof.
  • R 3 is pyridyl or optionally protected hydroxy, or a pharmaceutically acceptable salt thereof. 4 ) The compound of the formula ( I ) wherein R 1 is benzofuranyl substituted by halogen, R 3 is pyridyl, and X is N, or a pharmaceutically acceptable salt thereof.
  • the solution was refluxed for 2 hours and cooled to ambient temperature.
  • the solution was extracted with IN hydrochloric acid (100 ml) and the aqueous layer was washed with ethyl acetate ( 50 ml ) .
  • the aqueous layer was basifiedwith saturated aqueous sodium hydrogencarbonate solution and extractedwith ethyl acetate ( 100 ml ) .
  • the organic layer was washed successivelywith aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo.
  • the resulting mixture was diluted with ethyl acetate ( 75 ml) and washedwith saturated aqueous sodium hydrogencarbonate solution (40 ml) .
  • the organic layer was extracted with IN hydrochloric acid (60 ml) and the aqueous layer was basifiedwith saturated aqueous sodium hydrogencarbonate solution, and then extracted with chloroform (100 ml).
  • the organic layer was dried over magnesium sulfate and concentrated in vacuo.
  • the resulting mixture was diluted with water (40 ml) and extracted with ethyl acetate (40 ml) .
  • the organic layer was extracted with IN hydrochloric acid (25 ml) and the aqueous layer was basified with saturated aqueous sodium hydrogencarbonate solution, then extracted with ethyl acetate (40 ml).
  • the organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo.
  • the residual syrup was purified by silica gel column chromatography (eluent; 5% methanol in chloroform).
  • the syrup obtained was solidified with diisopropyl ether and the solid was collected by filtration to give l-[ (2E)-2-(4-chlorophenyl) ethenyl ]-N-[ (IS) -1-
  • 6-Chloro-N-methoxy-N-methylnicotinamide (33 g) was placed in a three neck flask. Tetrahydrofuran (300 ml) was added thereto, and the mixture was cooled to -30°C. To the mixture was added a solution (165 ml) of 1.1M methyllithium in diethyl ether dropwise over a 10-minute period. After 5 minutes, the reaction mixture was poured into saturated brine. The organic layer was separated, washed with saturated aqueous ammonium chloride solution and dried over magnesium sulfate.

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Abstract

La présente invention concerne un composé de formule (I) et les sels pharmaceutiquement acceptables dudit composé. Dans ladite formule, chaque symbole est tel que défini dans le descriptif. Le composé (I) et les sels pharmaceutiquement acceptables considérés ont un fort effet inhibiteur sur la production d'oxyde nitrique (NO) et sont donc utiles pour prévenir et/ou traiter les maladies à médiation NO, chez l'homme comme chez l'animal.
PCT/JP2000/004302 1999-07-05 2000-06-29 N-imidazolylmethyl-carboxamides utilises comme inhibiteurs de la production d'oxyde nitrique WO2001002387A1 (fr)

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EP00940882A EP1196407A1 (fr) 1999-07-05 2000-06-29 N-imidazolylmethyl-carboxamides utilises comme inhibiteurs de la production d'oxyde nitrique
JP2001507824A JP2003503489A (ja) 1999-07-05 2000-06-29 一酸化窒素産生阻害剤としてのｎ−イミダゾリルメチルカルボキサミド

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AUPQ1425A AUPQ142599A0 (en) 1999-07-05 1999-07-05 New amide compounds

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055479A1 (fr) * 2001-12-21 2003-07-10 Consejo Superior De Investigaciones Cientificas Composes et utilisation therapeutique relative a l'activite de phosphorylation de l'enzyme gsk-3
KR100469085B1 (ko) * 2002-05-23 2005-01-29 (주) 비엔씨바이오팜 3,4,5-트리플루오로피리딘 유도체, 그의 제조방법 및 이를포함하는 항바이러스용 약학적 조성물
US7626039B2 (en) 2005-12-14 2009-12-01 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, ayrlpropynamide, or arylmethylurea analogs as factor XIa inhibitors
CN105324366A (zh) * 2013-07-04 2016-02-10 日本曹达株式会社 苯基咪唑衍生物以及炎症性疾病等的治疗药或预防药

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WO1996016981A2 (fr) * 1994-12-02 1996-06-06 Fujisawa Pharmaceutical Co., Ltd. Composes peptidiques pour la prevention et/ou le traitement de maladies induites par no
DE19541146A1 (de) * 1995-10-25 1997-04-30 Schering Ag Imidazolderivate und deren Verwendung als Stickstoffmonoxid-Synthase-Inhibitoren
WO1997045425A1 (fr) * 1996-05-27 1997-12-04 Fujisawa Pharmaceutical Co., Ltd. Nouveaux carboxamides d'indolyle et de benzofuranyle utilises comme inhibiteurs de la production d'oxyde nitrique
WO1998027108A2 (fr) * 1996-12-16 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amide
WO1998037079A1 (fr) * 1997-02-19 1998-08-27 Berlex Laboratories, Inc. Derives n-heterocycliques utiles en tant qu'inhibiteurs de la no synthetase
WO1999051215A2 (fr) * 1998-04-06 1999-10-14 Fujisawa Pharmaceutical Co., Ltd. Nouvelle utilisation
WO1999057114A1 (fr) * 1998-05-04 1999-11-11 Fujisawa Pharmaceutical Co., Ltd. Derives de carboxamide heterocycliques utilisees comme inhibiteurs de la production de monoxyde d'azote
WO2000027842A1 (fr) * 1998-11-05 2000-05-18 Astrazeneca Ab Composes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016981A2 (fr) * 1994-12-02 1996-06-06 Fujisawa Pharmaceutical Co., Ltd. Composes peptidiques pour la prevention et/ou le traitement de maladies induites par no
DE19541146A1 (de) * 1995-10-25 1997-04-30 Schering Ag Imidazolderivate und deren Verwendung als Stickstoffmonoxid-Synthase-Inhibitoren
WO1997045425A1 (fr) * 1996-05-27 1997-12-04 Fujisawa Pharmaceutical Co., Ltd. Nouveaux carboxamides d'indolyle et de benzofuranyle utilises comme inhibiteurs de la production d'oxyde nitrique
WO1998027108A2 (fr) * 1996-12-16 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amide
WO1998037079A1 (fr) * 1997-02-19 1998-08-27 Berlex Laboratories, Inc. Derives n-heterocycliques utiles en tant qu'inhibiteurs de la no synthetase
WO1999051215A2 (fr) * 1998-04-06 1999-10-14 Fujisawa Pharmaceutical Co., Ltd. Nouvelle utilisation
WO1999057114A1 (fr) * 1998-05-04 1999-11-11 Fujisawa Pharmaceutical Co., Ltd. Derives de carboxamide heterocycliques utilisees comme inhibiteurs de la production de monoxyde d'azote
WO2000027842A1 (fr) * 1998-11-05 2000-05-18 Astrazeneca Ab Composes

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055479A1 (fr) * 2001-12-21 2003-07-10 Consejo Superior De Investigaciones Cientificas Composes et utilisation therapeutique relative a l'activite de phosphorylation de l'enzyme gsk-3
KR100469085B1 (ko) * 2002-05-23 2005-01-29 (주) 비엔씨바이오팜 3,4,5-트리플루오로피리딘 유도체, 그의 제조방법 및 이를포함하는 항바이러스용 약학적 조성물
US7626039B2 (en) 2005-12-14 2009-12-01 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, ayrlpropynamide, or arylmethylurea analogs as factor XIa inhibitors
US7842708B2 (en) 2005-12-14 2010-11-30 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIa inhibitors
US8252830B2 (en) 2005-12-14 2012-08-28 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIa inhibitors
US8604056B2 (en) 2005-12-14 2013-12-10 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIa inhibitors
CN105324366A (zh) * 2013-07-04 2016-02-10 日本曹达株式会社 苯基咪唑衍生物以及炎症性疾病等的治疗药或预防药
EP2998298A4 (fr) * 2013-07-04 2016-11-02 Nippon Soda Co Dérivé de phénylimidazole, et médicament thérapeutique ou médicament préventif d'une maladie inflammatoire, etc.

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