WO1995030675A1 - Diphenylcarboxamides utiles en tant qu'antagonistes de 5-ht1d - Google Patents

Diphenylcarboxamides utiles en tant qu'antagonistes de 5-ht1d Download PDF

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Publication number
WO1995030675A1
WO1995030675A1 PCT/EP1995/001578 EP9501578W WO9530675A1 WO 1995030675 A1 WO1995030675 A1 WO 1995030675A1 EP 9501578 W EP9501578 W EP 9501578W WO 9530675 A1 WO9530675 A1 WO 9530675A1
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WO
WIPO (PCT)
Prior art keywords
methyl
biphenyl
methoxy
carboxamide
hydrogen
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Application number
PCT/EP1995/001578
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English (en)
Inventor
Laramie Mary Gaster
Paul Adrian Wyman
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GB9409068A external-priority patent/GB9409068D0/en
Priority claimed from GB9409061A external-priority patent/GB9409061D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP7528640A priority Critical patent/JPH09512804A/ja
Priority to EP95918611A priority patent/EP0758330A1/fr
Publication of WO1995030675A1 publication Critical patent/WO1995030675A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel amide derivatives, processes for their preparation, and pharmaceutical compositions containing them.
  • EPA 0533 266 7/8 disclose a series of benzanilide derivatives which are said to possess 5HT ⁇ ⁇ -) receptor antagonist activity. These compounds are said to be of use in the treatment of various CNS disorders.
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • A is CONR where R is hydrogen or C- ⁇ alkyl
  • B is oxygen, S(O)q where q is 0, 1 or 2, or B is NR - where R*- 1 is hydrogen or
  • C ⁇ _6_dkyl or B is CH2 when R? and R form a group D;
  • R* is hydrogen, halogen, C ⁇ galkyl, C3_5cycloalkyl, COC ⁇ _5__lkyl, Ci-galkoxy, hydroxy, hydroxyCi-galkyl, hydroxyCi-galkoxy, Ci.galkoxyCi.galkoxy, acyl, nitro, trifluoromethyl, cyano, SR 9 , SOR 9 , SO 2 R 9 , SO2NRI-R 11 , CO 2 R 10 . CONR 10 R--,
  • R2 and R 3 are independently hydrogen, halogen, C1.5a.kyl, C3_5cycloalkyl, C3_5cycloalkenyl, C1.5a.koxy, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano,
  • R ⁇ and R ⁇ are independently hydrogen or Cj ⁇ alkyl
  • CR 14 CR- 5 CR 14 R 15 or (CR 14 R 15 )b where b is 2 or 3 and R 14 and R 15 are independently hydrogen or C1.5a.kyl; m is O, 1, 2 or 3; n is 1 or 2; and
  • R- is a group of formula (i):
  • R° is a group of formula (ii):
  • R*- is hydrogen or C1.5a.kyl.
  • C ⁇ _5-dkyl groups may be straight chain or branched.
  • R- is hydrogen, halogen, C ⁇ _5alkyl, C3.5cycloa.kyl, COC1.5a.kyl, C ⁇ _6alkoxy, hydroxy, hydroxy C ⁇ _5__lkyl, hydroxyC ⁇ _5alkoxy, C ⁇ _5alkoxyC ⁇ _5alkoxy, acyl, nitro, trifluoromethyl, cyano, SR 9 , SOR 9 , SO2R 9 , SO2NR 10 R l l , CO2R 10 , CONRiOR 11 , CO 2 NR 1( -R 1 -, CONR 1 0(CH 2 ) a CO2R 11 , (CH2) a NR 10 R 11 , (CH 2 ) a CONRl ⁇ Rl -, (CH 2 ) a NR 10 CORl-, (CH2) a CO2Ci.6alkyl, CO 2 (CH 2 ) a OR-0, NR 10 R--, NRIOCO
  • heterocyclic rings examples include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. These heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom.
  • Optional substituents for such rings include R 2 and R 3 groups defined above, preferred substituents include C1.5a.kyl-
  • R- is oxadiazolyl, most preferably a 5-methyl-l,2,4-oxadiazol-3-yl group.
  • R 2 and R 3 are independently hydrogen, halogen, C ⁇ _6alkyl, C3.5cyclo_-.kyl, C3_5cycloalkenyl, C1.5a.koxy, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R 11 , CONR 12 R 13 , NR 12 R 13 where R 11 , R 12 and R 13 are independently hydrogen or C ⁇ _6alkyl.
  • R 2 is Ci_5alkyl, in particular methyl.
  • R 3 is hydrogen.
  • R 4 and R- are independently hydrogen or C ⁇ _6alkyl.
  • R 4 and R ⁇ are both hydrogen.
  • R- is hydrogen, halogen, hydroxy, C1.5_.lkyl or C1.5a.koxy.
  • R- is C ⁇ _5alkoxy such as methoxy.
  • R ⁇ is hydrogen or C ⁇ _6_dkyl, preferably R ⁇ is hydrogen.
  • R ⁇ is a group of formula (i) or (ii).
  • R ⁇ is a group of formula (i) p, q and r are preferably 2.
  • R* is a group of formula (ii) where s is 1 and R* - is C1.5a.kyl such as methyl.
  • A is CONR where R is hydrogen or C1.5_.lkyl, that is to say A forms an amide linkage.
  • R is hydrogen.
  • R 14 and R.15 ajg Preferably D is an ethyl linkage, that is to say forms part of an indoline ring.
  • B is oxygen, S(O) q where q is 0, 1 or 2, or B is NR 10 where R 10 is hydrogen or C1.5a.kyl or B is CH2 when R ⁇ and R form a group D.
  • B is oxygen.
  • n is 1 or 2, preferably n is 1.
  • Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
  • acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms.
  • the present invention provides a process for the preparation of a compound of formula (I) which comprises. (a) for compounds where A is an amide linkage CONR9 reaction of a compound of formula (II):
  • R* 7 is an activated carboxylic acid derivative, such as an acyl halide or acid anhydride, and R* - is an amine group.
  • (DI) can also be prepared by reaction of the corresponding carboxylic acid with a coupling reagent such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazole.
  • R* 7 is a group COL where L is halo, particularly chloro.
  • a compound of formulae (II) and (HI) are typically reacted together in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as an alkali metal hydroxide, triethylamine or pyridine.
  • a base such as an alkali metal hydroxide, triethylamine or pyridine.
  • Compounds of formula (II) and (TV) are reacted together using similar reaction conditions to those for compounds (II) and (HI).
  • Certain compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.
  • 5HTi£) Antagonists and in particular the compounds of the present invention, are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal effective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa.
  • Other CNS disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
  • 5HT D Antagonists may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction.
  • the present invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy.
  • the present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
  • the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of the aforementioned disorders.
  • the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • the title compound was prepared from 2-(l-tert-butpxycarbonylazetidin-2-ylmethoxy)-4- nitroanisole (D9) using the procedure of Description 2 (100%). This material was used in the next step without purification.
  • the title compound was prepared from 3-(l-tert-butoxycarbonylazetidin-2-ylmethoxy)-4- methoxyaniline (D10) using the procedure of Description 6 (85%).
  • the title compound was prepared from 3-(l-tert.-butoxycarbonylazetidin-2-ylmethoxy)-4- methoxyaniline (D10) using the procedure of Example 1. Purification by chrorratography on silica gel eluting with 0-30% ethyl acetate/ether afforded the title compound as a pale yellow oil (51%).
  • the title compound (0.90g, 81 ) was prepared as a light brown solid from l-methyl-3-(2- me oxy-5-nitrophenoxy)pyrrolidine (D20, 1.2g, 0.005 mol), using the method of Description 2.
  • l-Methyl-3-piperidinemethanol (2.0g, 0.016 mole) in dry DMF (50 ml) was added dropwise to a suspension of sodium hydride (0.51g of an 80% dispersion in oil, 0.017 mole) in dry DMF (20 ml) under argon and the mixture stirred for 0.5 h.
  • l-Fluoro-4- nitrobenzene (2.4g, 0.018 mole) in dry DMF (20 ml) was added dropwise and the mixture stirred at ambient temperature for 18 h. Water was added dropwise until effervescence ceased and the mixture extracted into Et2 ⁇ .
  • the tide compound (0.13 g, 76%) as a brown oil was prepared from 5-methoxy-6-(2-(l- methylpyrrolidin-2-yl)ethyl)-lH-indole (D42) (0.17g, 0.7 mmol) using the method of Description 34, and used without purification in the next step.
  • the tide compound was prepared from 4-methoxy-3-((R)-l-methylpyrrolidin-2- ylmethoxy)aniline (D6) using the procedure of Example 1. Purification by chromatography on silica gel eluting with 5% methanol/chloroform followed by crystallisation from ethyl acetate/60-80 petrol afforded the tide compound as a white solid (12%) m.pt. 150-151° C.
  • the tide compound was prepared from 4-methoxy-3-(l-methylazetidin-2- ylme oxy)aniline (DI 1) using the procedure of Example 1. Purification by chromatography on silica gel eluting with 5% methanol/chloroform followed by crystallisation from ethyl acetate/60-80 petrol, afforded the tide compound as a white solid (9%) m.pt. 160-161° C.
  • the oil was purified by silica-gel chromatography (9385, 6%, MeOH/CH2Cl2 as eluant) to give the tide compound as a colourless oil (0.084g, 49%), which was converted to its oxalate salt, m.pt. 154-160°C.
  • the tide compound (0.38g, 45%) was prepared as a cream solid from 4-methoxy-3-(l- methylpyrrolidin-3-yloxy)aniline (D21, 0.38g, 0.0017 mol), using the method of Example 9.
  • the title compound was prepared from 4-med ⁇ oxy-3-(3-quinuclidinyloxy)aniline (D23) using the procedure of Example 1. Purifiation by chromatography on silica gel eluting witii 5% methanol/chloroform, followed by passage through a short basic alumina column eluting with ethyl acetate, afforded the title compound as a colourless oil. This was convened to its oxalate salt and crystallised from a mixture of methanol/acetone/ether as a white solid (27%), m.pt. 110-113°C.
  • the tide compound was prepared from 4-(l-med ⁇ ylpiperidin-3-ylmethoxy)aniline (D31) using the method of Example 1. Reciystallisation from ethyl acetate/petroleum ether gave a white solid (0.18g, 36%).
  • the tide compound was prepared from 5-chloro-2,3-dihydro-6-(l-methylpyrrolidin-2- ylmethoxy)-lH-indole (D34) using the procedure of Example 13. Purification by chromatography on silica gel eluting with methanol/chloroform afforded the tide compound as an off-white foam (10%) which was converted to the oxalate salt, m.pt. 102- 105° C.
  • the tide compound (0.067g, 25%) was prepared from 2,3-dihydro-5-methoxy-6-(2-(l- methylpyrrolidin-2-yl)ethyl)-lH-indole (D43) (0.13g, 0.5 mmol) using the method of Example 1.

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Abstract

Composés de la formule (I), leurs procédés de préparation et leur utilisation en tant qu'agents du système nerveux central grâce à leur activité d'antagonistes de récepteurs de 5HT1D. Dans cette formule, A représente CONR où R représente hydrogène ou alcoyle C1-6; B représente oxygène, S(O)q où q vaut 0, 1 ou 2, ou bien B représente NR?10 où R10¿ représente hydrogène ou alcoyle C¿1-6?, ou encore B représente CH2 lorsque R?7¿ et R forment un groupe D; R1 représente hydrogène, halogène, alcoyle C¿1-6?, cycloalcoyle C3-6, CO alcoyle C1-6, alcoxy C1-6, hydroxy, hydroxy-alcoyle C1-6, hydroxy-alcoxy C1-6, alcoxy C1-6-alcoxy C1-6, acyle, nitro, trifluorométhyle, cyano, SR?9, SOR9, SO¿2R9, SO2NR?10R11, CO¿2R?10, CONR10R11, CO¿2NR?10R11, CONR10(CH¿2)aCO2R11, (CH2)aNR?10R11, (CH¿2)aCONR?10R11, (CH¿2)aNR?10COR11, (CH¿2)aCO2alcoyleC1-6, CO2(CH2)aOR?10, NR10R11, NR10CO¿2R?11, NR10CONR10R11, CR10=NOR11, CNR10=NOR11, où R10 et R11¿ représentent indépendamment hydrogène ou alcoyle C¿1-6?, et a vaut 1 à 4, ou bien R?1¿ représente un noyau hétérocyclique possédant 5 à 7 chaînons, éventuellement substitué, contenant 1 à 3 hétéroatomes choisis parmi oxygène, azote ou soufre; R2 et R3 représentent indépendamment hydrogène, halogène, alcoyle C¿1-6?, cycloalcoyle C3-6, cycloalcényle C3-6, alcoxy C1-6, acyle, aryle, acyloxy, hydroxy, nitro, trifluorométhyle, cyano, CO2R?11, CONR12R13, NR12R13 où R11, R12 et R13¿ représentent indépendamment hydrogène ou alcoyle C¿1-6?; R?4 et R5¿ représentent indépendamment hydrogène ou alcoyle C¿1-6; R?6 représente hydrogène, halogène, hydroxy, alcoyle C¿1-6? ou alcoxy C1-6; R?7¿ représente hydrogène, ou il forme avec R un groupe D où D représente CR?14=CR15, CR14=CR15CR14R15 ou (CR14R15)¿b où b vaut 2 ou 3 et R?14 et R15¿ représentent indépendamment hydrogène ou alcoyle C¿1-6?; m vaut 0, 1, 2 ou 3; n vaut 1 ou 2, et R?8¿ représente un groupe de la formule (i) dans laquelle p, q et r représentent indépendamment des nombres entiers valant 1, 2 ou 3; ou bien R8 représente un groupe de formule (ii) dans laquelle s vaut 0, 1, 2 ou 3 et R16 représente hydrogène ou alcoyle C¿1-6?.
PCT/EP1995/001578 1994-05-06 1995-04-25 Diphenylcarboxamides utiles en tant qu'antagonistes de 5-ht1d WO1995030675A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP7528640A JPH09512804A (ja) 1994-05-06 1995-04-25 ５−ｈｔ１ｄアンタゴニストとして有用なビフェニルカルボキシアミド類
EP95918611A EP0758330A1 (fr) 1994-05-06 1995-04-25 Diphenylcarboxamides utiles en tant qu'antagonistes de 5-ht1d

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Application Number Priority Date Filing Date Title
GB9409068A GB9409068D0 (en) 1994-05-06 1994-05-06 Novel compounds
GB9409061A GB9409061D0 (en) 1994-05-06 1994-05-06 Novel compounds
GB9409068.5 1994-05-06
GB9409061.0 1994-05-06

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JP (1) JPH09512804A (fr)
WO (1) WO1995030675A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007120A1 (fr) * 1995-08-11 1997-02-27 Smithkline Beecham Plc Derives de biphenyl(thio)amide et de biphenylethan(thi)one, leur preparation et leur utilisation comme antagonistes des recepteurs 5-ht¿1d?
WO2001068585A1 (fr) * 2000-03-14 2001-09-20 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amides
US7125898B2 (en) 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
US7151118B2 (en) 2001-10-17 2006-12-19 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38-kinase inhibitors
US7166623B2 (en) 2001-10-17 2007-01-23 Glaxo Group Limited 2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7166597B2 (en) 2000-08-22 2007-01-23 Glaxo Group Limited Fused pyrazole derivatives being protein kinase inhibitors
US7183297B2 (en) 2001-10-17 2007-02-27 Glaxo Group Limited Biphenyl-derivatives as p38-kinase inhibitors
US7208629B2 (en) 2001-10-17 2007-04-24 Glaxo Group Limited 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7271289B2 (en) 2003-04-09 2007-09-18 Smithkline Beecham Corporation Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
US7384963B2 (en) 2001-10-17 2008-06-10 Glaxo Group Limited 2′-Methyl-5-(1,3,4-oxadiazol-2-yl)1, 1′-biphenyl-4-carboxaide derivatives and their use as p38 kinase
US7396843B2 (en) 2001-10-17 2008-07-08 Glaxo Group Limited 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7432289B2 (en) 2001-10-17 2008-10-07 Glaxo Group Limited 5-Acylamino-1,1′-biphenyl-4-carboxamide derivatives and their use as P38 kinase inhibitors
US7572790B2 (en) 2003-04-09 2009-08-11 Smithkline Beecham Corporation Biphenyl carboxylic amide p38 kinase inhibitors
US7626055B2 (en) 2003-04-09 2009-12-01 Smithkline Beecham Corporation Biphenyl-carboxamide derivatives and their use as p38 kinase inhibitors
US7642276B2 (en) 2002-07-31 2010-01-05 Smithkline Beecham Corporation Fused heteroaryl derivatives for use as P38 kinase inhibitors
US7838540B2 (en) 2003-08-11 2010-11-23 Glaxosmithkline Llc 3-aminocarbonyl, 6-phenyl substituted pyridine-1-oxides as p38 kinase inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
WO2020183011A1 (fr) 2019-03-14 2020-09-17 Institut Curie Inhibiteurs de htr1d et leurs utilisations dans le traitement du cancer

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US5972935A (en) * 1995-08-11 1999-10-26 Smithkline Beecham P.L.C. Biphenyl(thio)amide and bipennylethan(thi) one derivatives, their preparation and their use as 5-HT1D receptor antagonists
WO1997007120A1 (fr) * 1995-08-11 1997-02-27 Smithkline Beecham Plc Derives de biphenyl(thio)amide et de biphenylethan(thi)one, leur preparation et leur utilisation comme antagonistes des recepteurs 5-ht¿1d?
WO2001068585A1 (fr) * 2000-03-14 2001-09-20 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amides
US7166597B2 (en) 2000-08-22 2007-01-23 Glaxo Group Limited Fused pyrazole derivatives being protein kinase inhibitors
US7396843B2 (en) 2001-10-17 2008-07-08 Glaxo Group Limited 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7151118B2 (en) 2001-10-17 2006-12-19 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38-kinase inhibitors
US7166623B2 (en) 2001-10-17 2007-01-23 Glaxo Group Limited 2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7183297B2 (en) 2001-10-17 2007-02-27 Glaxo Group Limited Biphenyl-derivatives as p38-kinase inhibitors
US7208629B2 (en) 2001-10-17 2007-04-24 Glaxo Group Limited 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7432289B2 (en) 2001-10-17 2008-10-07 Glaxo Group Limited 5-Acylamino-1,1′-biphenyl-4-carboxamide derivatives and their use as P38 kinase inhibitors
US7309800B2 (en) 2001-10-17 2007-12-18 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
US7384963B2 (en) 2001-10-17 2008-06-10 Glaxo Group Limited 2′-Methyl-5-(1,3,4-oxadiazol-2-yl)1, 1′-biphenyl-4-carboxaide derivatives and their use as p38 kinase
US7514456B2 (en) 2002-02-12 2009-04-07 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors
US7125898B2 (en) 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
US7709506B2 (en) 2002-02-12 2010-05-04 Glaxosmithkline Llc Nicotinamide derivatives useful as p38 inhibitors
US7642276B2 (en) 2002-07-31 2010-01-05 Smithkline Beecham Corporation Fused heteroaryl derivatives for use as P38 kinase inhibitors
US7271289B2 (en) 2003-04-09 2007-09-18 Smithkline Beecham Corporation Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
US7572790B2 (en) 2003-04-09 2009-08-11 Smithkline Beecham Corporation Biphenyl carboxylic amide p38 kinase inhibitors
US7626055B2 (en) 2003-04-09 2009-12-01 Smithkline Beecham Corporation Biphenyl-carboxamide derivatives and their use as p38 kinase inhibitors
US7838540B2 (en) 2003-08-11 2010-11-23 Glaxosmithkline Llc 3-aminocarbonyl, 6-phenyl substituted pyridine-1-oxides as p38 kinase inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
WO2020183011A1 (fr) 2019-03-14 2020-09-17 Institut Curie Inhibiteurs de htr1d et leurs utilisations dans le traitement du cancer

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