WO2003097042A1 - Antagoniste de recepteur de pdg2 - Google Patents

Antagoniste de recepteur de pdg2 Download PDF

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Publication number
WO2003097042A1
WO2003097042A1 PCT/JP2003/006077 JP0306077W WO03097042A1 WO 2003097042 A1 WO2003097042 A1 WO 2003097042A1 JP 0306077 W JP0306077 W JP 0306077W WO 03097042 A1 WO03097042 A1 WO 03097042A1
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Prior art keywords
optionally substituted
alkyl
hydrogen
halogen
aryl
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PCT/JP2003/006077
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English (en)
Japanese (ja)
Inventor
Akinori Arimura
Junji Kishino
Norihiko Tanimoto
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Shionogi & Co., Ltd.
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Priority to AU2003231513A priority Critical patent/AU2003231513A1/en
Priority to JP2004505041A priority patent/JPWO2003097042A1/ja
Publication of WO2003097042A1 publication Critical patent/WO2003097042A1/fr

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/10—Antimycotics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates to a pharmaceutical composition used as a CRTH2 receptor antagonist and a novel compound having a CRTTH2 receptor antagonistic action.
  • Prostaglandin D 2 is a metabolite produced from arachidonic acid via PGG 2 and PGH 2 and is known to have various powerful physiological actions. For example, it is known that in the central nervous system, it is involved in sleep and hormone secretion, and in the periphery, it is involved in platelet aggregation inhibitory action, contraction of bronchial smooth muscle, dilation or contraction of blood vessels (Pharmacol). Rev. (1994) 46, 205-229). In addition, PGD 2 is a major arachidonic acid metabolite produced by mast cells, and has strong bronchoconstriction, enhanced vascular permeability and migration of inflammatory cells such as eosinophils. It is thought to be deeply involved in the pathogenesis of allergic diseases such as asthma.
  • the receptor for PGD 2 and only the conventional DP receptors are known, the receptor antagonist W No. 098/25915, WO No. 01/66520, are described in such WO01 / 79169.
  • 3- (4-fluorophenylsulfonamide) -1,2,3,4-tetrahydro-9-potassylpropionic acid is used in allergic dermatitis, dermatitis via delayed allergic reaction, and psoriasis.
  • JP-A-11-10-6337 and JP-A-11-116477 describe that they are useful as therapeutic agents.
  • JP-A-11-322600 describes that they have a chemokine production inhibitory action. Have been. Further, since the compound exhibits an inhibitory effect on PGD 2 induced onset bronchoconstriction, that there possibly having PGD 2 antagonism via the DP receptor J. Allergy Clin.
  • PGD 2 is a high concentration region ( ⁇ ⁇ or more) and coupled child to thromboxane receptor in (Eur J. Pharmacol (1992.. ) 226, 149- 156;. Br J. Pharmacol. (1991) 103, 1883-1888 etc.), 2) Other topomboxane receptor antagonistic compounds with weak affinity for DP receptor show similar inhibitory effects (Int. Arch. Allergy Immunol. 1992). , 98, 239-246), 3) selective DP receptor antagonist compounds that do not inhibit the PGD 2 induced bronchoconstriction (Br. J. Pharmacol.
  • EP 1170594 discloses four compounds that selectively bind to the CRTH2 receptor as compared to the DP receptor. However, the structure is dissimilar to that of the compound of the present invention, and the details such as binding activity are not described. Disclosure of the invention
  • the present inventors have developed a pharmaceutical composition and CR for use as a CRTH2 receptor antagonist.
  • a novel compound having a TH2 receptor antagonistic action was found.
  • R 1 R 2 , R 3 and R 4 are each independently hydrogen, halogen, haloalkyl, carboxy, alkyloxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted cycloalkyl, it may also be substituted I Ariru, optionally substituted Ararukiru formula: a S (0) p R 5 (wherein, p is 0-2 integer; R 5 is a group represented by the following formula: —NR 6 R 7 (where R 6 and R 7 are each independently hydrogen, alkyl, or an optionally substituted aryl) , An optionally substituted aralkyl or acyl), or a group represented by the formula: one OR 8 (wherein R 8 is hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl, Alkansulfoni , Optionally substituted ⁇ Li one Rusuruhoniru, it may also be substituted I ⁇ Lal Kill s
  • Y is hydrogen, alkyl, alkenyl, optionally substituted aryl or optionally substituted aralkyl
  • Ar is an optionally substituted aryl or an optionally substituted heteroaryl
  • n is an integer of 1 to 3;
  • m is 0 or 1]
  • a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, as a CRTH2 receptor antagonist containing as an active ingredient a pharmaceutical composition About.
  • the present invention relates to the following II) to IX).
  • Ar is halogen, arylthio, aryloxy, arylazo, heteroarylsulfonyl, heteroarylalkyl optionally substituted with alkyl, alkylene optionally having a benzene ring condensed, arylalkynyl Or a phenyl ring which may be substituted with one or more substituents selected from alkylenedioxy, which may be condensed, alkyl and aryl which may be substituted with halogen, or halogen, One or more substituents selected from hydroxy and aralkyl optionally substituted by one or more substituents A (substituent A: hydroxy, halogen, and alkyloxy); IV) The pharmaceutical composition according to the above, which is a heteroaryl.
  • I 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, haloalkyl, carboxy, alkyloxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl
  • Y is alkyl, alkenyl, optionally substituted aryl or optionally substituted aralkyl
  • Ar is an optionally substituted aryl or an optionally substituted heteroaryl 5
  • ⁇ is an integer of 1 to 3;
  • n 0 or 1]
  • a prodrug thereof a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition containing the compound according to VI) or VII), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient IX) As a CRTH2 receptor antagonist The pharmaceutical composition according to VIII) to be used.
  • halogen means fluorine, chlorine, bromine, and iodine. Fluorine, chlorine, and bromine are preferred as nourogens.
  • alkyl used alone or in combination with other terms includes a straight-chain or branched monovalent hydrocarbon group having 1 to 8 carbon atoms.
  • a C1-C6 alkyl is mentioned. More preferably, C 1 -C 3 alkyl is mentioned.
  • cycloalkyl used alone or in combination with other terms includes cycloalkyl having 3 to 8 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclooctyl can be mentioned.
  • Preferable one is C 3 -C 6 cycloalkyl.
  • alkylene used alone or in combination with another term includes a divalent hydrocarbon group derived from the above “alkyl”.
  • alkyl a divalent hydrocarbon group derived from the above “alkyl”.
  • a C1-C6 alkylene is mentioned. More preferably, a C1-C3 alkylene is mentioned.
  • alkylenedioxy includes methylenedioxy and the like.
  • an ⁇ alkenyl '' used alone or in combination with another term has 2 to 8 carbon atoms and has 1 or 2 or more double bonds.
  • vinyl, aryl, 1-propenyl, 2-propenyl, crotonyl, isopentenyl, various butenyl isomers and the like can be mentioned.
  • C 2 -C 6 alkenyl is used.
  • C 2 -C 4 alkenyl is used.
  • ⁇ alkynyl J '' which is used alone or in combination with other terms, has 2 to 8 carbon atoms and has 1 or 2 or more triple bonds. It includes a monovalent hydrocarbon group of a chain or a branched chain, for example, ethenyl, 1-propynyl, 2-propynyl, etc. Preferably, C 2 -C 6 alkynyl is used. No. Still more preferably, C2-C4 alkynyl is mentioned.
  • aryl used alone or in combination with another term includes a monocyclic or condensed cyclic aromatic hydrocarbon.
  • phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned.
  • aralkyl used alone or in combination with other terms includes those in which the above “alkyl” is substituted by one or more of the above “aryl”, and these include Substitutions may be made at all possible positions.
  • benzyl, phenylethyl for example, 2-phenylethyl
  • phenylpropyl for example, 3-phenylpropyl
  • naphthylmethyl for example, 1-naphthylmethyl, 2-naphthylmethyl, etc.
  • anthrylmethyl for example, , 9-anthrylmethyl, etc.
  • Preferable examples include benzyl, 2-phenylenyl, 1-naphthylmethyl and 2-naphthylmethyl. More preferred are benzyl and 2-phenylene.
  • non-aromatic heterocyclic group '' is an arbitrarily selected non-aromatic 5- to 7-membered ring containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring, or Includes two or more fused rings.
  • pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl
  • pyrrolinyl eg, 3-pyrrolinyl
  • imidazolidinyl eg, 2-imidazolidinyl
  • imidazolinyl eg, Midazolinyl
  • birazolidinyl eg, 1-virazolidinyl, 2-birazolidinyl
  • birazolinyl eg, birazolinyl
  • piperidyl eg, piperidino, 2-piperidyl
  • piperazinyl eg, 1-piperaziel
  • inn Examples include dolinyl (eg, 1-indolinyl), isoindolinyl (eg, isoindolinel), morpholinyl (eg, morpholino, 3-morpholinyl), and the like.
  • heteroaryl used alone or in combination with other terms.
  • the "rule” includes an optionally selected 5- to 6-membered aromatic ring containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring. This may be condensed with the “cycloalkyl”, the “aryl”, the “non-aromatic heterocyclic group”, or another heteroaryl at all possible positions. When the heteroaryl is a single ring or a condensed ring, it can be bonded at all possible positions.
  • pyrrolyl eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • furyl eg, 2-furyl, 3-furyl
  • chenyl eg, 2-phenyl, 3-phenyl
  • Imidazolyl eg, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pirazolyl, 3-pyrazolyl
  • isotizazolyl eg, 3-isothiazolyl
  • isoxazolyl eg, 3-isoxazolyl
  • Oxazolyl eg, 2-oxazolyl
  • thiazolyl eg, 2-thiazolyl
  • pyridyl eg,
  • Doridinyl, 6-indolinidyl isoindrill (for example, 21 isoindrill), indrill (for example, 11indrill, 2indlinyl)
  • indazolyl eg, 3-indazolyl
  • purinyl eg, 8-purinyl
  • quinolizinyl eg, 2-quinolinidinyl
  • isoquinolyl eg, 3-isoquinolyl
  • Quinolyl for example, 2-quinolyl, 5-quinolyl
  • phthalazinyl for example, 1-fufurazinyl
  • naphthyridinyl for example, 2-naphthyridinyl
  • quinolanyl for example, 2-quinolinyl
  • Quinazolinyl for example, 2-quinazolinyl
  • cinnolinyl for example, 3-cinnolinyl
  • pteridinyl for example, 2-pteridinyl
  • carpazolyl for example, 2-carbazolyl, 4-pot lpazolyl
  • frannan Tridinyl eg, 2-phenanthridinyl,
  • heteroaryl in Ar, chenyl, penzochenyl, oxosazolyl and the like are preferable.
  • heteroarylalkyl includes those wherein the above-mentioned “heteroaryl” is substituted by one or more at any position of the above “alkyl”, and these are substituted at all possible positions. Can be replaced. Chenylalkyl, furylalkyl, pyrrolylalkyl, imidazolylalkyl, pyrazolylalkyl, thiazolylalkyl, isothiazolylalkyl, isoxazolylalkyl, oxazolylalkyl, pyridylalkyl, etc. .
  • chenylmethyl eg, 2-phenylmethyl
  • chenylethyl eg, 2- (thiophen-2-yl) ethyl
  • furylmethyl eg, 2-furylmethyl
  • furylethyl eg, 2- (furan-methyl) 2- (yl) ethyl
  • pyrrolylmethyl for example, 2-pyrrolylmethyl
  • lipourylethyl for example, 2- (pyrrole-2-yl) ethyl
  • imidazolylmethyl for example, 2-imidazolylmethyl, 4) 1-imidazolylmethyl), imidazolylethyl (for example, 2— (imidazo-2-yl) ethyl), vilazolylmethyl (for example, 3—virazolylmethyl), pyrazolylethyl (for example, 2— (pyrazol-3-y) Le) ethyl), thiazolylmethyl (for example, .2-thiazolylmethyl),
  • heteroarylalkyl of the “heteroarylalkyl optionally substituted with alkyl” includes chenyl and the like.
  • examples of the “heteroarylalkyl optionally substituted with alkyl” include 5-methylthiophen-12-ylethyl.
  • alkyloxy includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and the like.
  • methyloxy, ethyloxy, n-propyloxy, isopropyloxy and n-butyloxy are mentioned.
  • Particularly preferred are C 1 -C 3 alkyloxy.
  • alkylthio includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
  • Preferable examples include methylthio, ethylthio, n-propylthio, isopropylthio, and n-butylthio.
  • Particularly preferred are C 1 -C 3 alkylthio
  • aryloxy examples include phenyloxy, naphthyloxy and the like.
  • arylthio includes phenylthio, naphthylthio and the like.
  • arylazo includes phenylazo, naphthylazo and the like.
  • alkyloxycarbonyl includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, and isopropyl Xycarbonyl, n-butyloxycarbonyl, t-butyloxycarbonyl, n-pentyloxycarbonyl and the like.
  • methyloxycarbonyl and ethyloxycarbonyl are exemplified.
  • Particularly preferred are C1-C3 alkyloxycarbonyl.
  • acyl used alone or in combination with other terms refers to an alkylcarbonyl wherein the alkyl moiety is the above “alkyl” or an arylcarbonyl wherein the aryl moiety is the above “aryl”. Is included. For example, acetyl, propionyl, ptiroyl, benzoyl and the like can be mentioned. “Alkyl” and “aryl” may each be substituted by the substituents exemplified in “optionally substituted alkyl” and “optionally substituted aryl” below.
  • haloalkyl used alone or in combination with other terms refers to the above-mentioned “alkyl” substituted at 1 to 8, preferably 1 to 5 positions by the above "halogen". Include. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl, chloromethyl and the like can be mentioned. Preferably, trifluoromethyl is used.
  • examples of "asyloxy” include acetyloxy, propionoxy, benzoyloxy and the like.
  • examples of the “alkanesulfonyl” include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, isobutanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl and the like.
  • Preferable examples include methanesulfonyl and ethanesulfonyl.
  • arylsulfonyl examples include phenylsulfonyl, naphthylsulfonyl and the like.
  • aralkylsulfonyl j includes benzylsulfonyl, And diethylsulfonyl.
  • heteroarylsulfonyl includes pyrrolylsulfonyl and the like.
  • the term “optionally substituted amino” used alone or in combination with other terms includes the above “alkyl”, the above “aryl”, the above “aralkyl”, the above “heteroaliquot” And the above-mentioned “heteroarylalkyl”, the above-mentioned “alkyloxycarbonyl”, the above-mentioned “alkanesulfonyl” or the above-mentioned “acyl” may be substituted with one or two aminos.
  • amino, methylamino, dimethylamino, ethylmethylamino, getylamino, ethylmethylamino, benzylamino, methoxycarbonylamino, methylsulfonylamino, acetylamino, benzoylamino and the like can be mentioned.
  • amino, methylamino, dimethylamino, ethylmethylamino, acetylamino, acetylamino are exemplified.
  • aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl are mentioned.
  • the term “optionally substituted ureido” refers to the aforementioned “lower alkyl j, the aforementioned“ aryl ”, the aforementioned“ aralkyl ”, the aforementioned“ heteroaryl ”, the aforementioned“ heteroarylalkyl ”, or
  • the above-mentioned “asil” includes a ured which may be replaced at one or more places.
  • examples of the substituent in the “optionally substituted alkyl” include cycloalkyl, alkenyl, alkylidene, hydroxy, alkyloxy, mercapto, alkylthio, amino, logen, nitro, cyano, carboxy, Alkyloxycarbonyl, haloalkyl, haloalkyloxy, optionally substituted amino, optionally substituted amino'nocarbonyl, acryl, acryloxy, substituted And an optionally substituted non-aromatic heterocyclic group, aryloxy (eg, phenyloxy), aralkyloxy (eg, benzyloxy), alkanesulfonyl, guanidino, azo group, and optionally substituted ureido. These may be substituted one or more times in all possible positions.
  • examples of the substituent in the “optionally substituted cycloalkyl” include alkyl, cycloalkyl, alkenyl, alkylidene, hydroxy, alkyloxy, mercapto, alkylthio, amino, logen, nitro and cyano.
  • examples of the substituent in “optionally substituted alkenyl” include alkyl, cycloalkyl, alkylidene, hydroxy, alkyloxy, mercapto, alkylthio, halogen, nitro, cyano, carboxy, and alkyloxycarbonyl.
  • substituent for the “optionally substituted alkenyl” ′ in R i, R 2 , R 3 and R 4 are preferable.
  • optionally substituted aryl In the present specification, "optionally substituted aryl”, “optionally substituted aralkyl”, “optionally substituted heteroaryl”, “optionally substituted arylarylsulfonyl”, Examples of the substituent in the “optionally substituted aralkylsulfonyl” and the “optionally substituted non-aromatic heterocyclic group” include an optionally substituted alkyl, cycloalkyl, alkenyl, and alkynyl , Hydroxy, alkyloxy, aralkyloxy, mercapto, alkylthio, halogeno, nitro, cyano, carboxy, alkyloxycarbonyl, haloalkyl, haloalkyloxy, optionally substituted amino, optionally substituted amino Carbonyl, acyl, acyloxy, optionally substituted aryl An optionally substituted heteroaryl, an optionally substituted non-aromatic heterocyclic group, an optionally substituted a
  • substituent for the “optionally substituted aryl” in Ar alkyl, alkyloxy, halogen and the like are preferable.
  • substituent for the “optionally substituted aralkyl” in II 1 , R 2 , R 3 and R 4 alkyl, halogen and the like are preferable.
  • the compound (I) of the present invention can be produced according to the following scheme.
  • R 9 is hydrogen or alkyl
  • X is halogen, optionally substituted alkansulfonyloxy, or optionally substituted arylsulfonyloxy).
  • the described sulfonamide derivative (IV) was converted to a solvent such as tetrahydrofuran (THF), ether, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitril, and toluene.
  • THF tetrahydrofuran
  • DMF N, N-dimethylformamide
  • DMSO dimethylsulfoxide
  • acetonitril acetonitril
  • toluene toluene.
  • a base such as sodium hydride, potassium hydride, t-butoxy potassium, potassium carbonate, etc.
  • the ester is hydrolyzed according to the usual hydrolysis conditions.
  • the desired compound (I) can be obtained.
  • Y is a compound other than hydrogen are not selective CRTH 2 receptor antagonist compound of TXA 2 receptor antagonistic activity.
  • compounds represented by the following formulas (II) and (III) are preferable.
  • H 2 is hydrogen, halogen, or a group represented by the formula: one OR 11 (where R 11 is hydrogen or alkyl)];
  • Y is alkyl, alkenyl, or aralkyl
  • R 1 Q is hydrogen or halogen], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 2 is hydrogen, halogen, or a group represented by the formula: one OR 11 (where R 11 is hydrogen or alkyl);
  • Y is alkyl, alkenyl, or aralkyl
  • R 1 G is hydrogen or halogen], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the medicinal compound contained in the pharmaceutical composition used as the CRTH2 receptor antagonist the compounds described in Tables 1 and 2 below are preferable.
  • solvate includes, for example, solvates with organic solvents, hydrates, and the like. .
  • organic solvent When forming a solvate with an organic solvent, it may be coordinated with any number of organic solvent molecules.
  • the compound of the present invention also includes a pharmaceutically acceptable salt or a solvate thereof.
  • a pharmaceutically acceptable salt or a solvate thereof for example, alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, etc.) Phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluene Sulfonic acid and the like). These salts can be formed by a commonly used method.
  • a prodrug is a derivative of a compound of the present invention that has a chemically or metabolically degradable group and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • Methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.
  • the compound of the present invention has a carboxyl group
  • an ester derivative produced by reacting the base acidic compound with a suitable alcohol, or the base acid compound and a suitable amine are reacted.
  • Prodrugs such as amide derivatives produced by the method are exemplified.
  • esters as prodrugs include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, N, N-getyl glycolamine Esters and the like.
  • a prodrug such as an acyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide or a suitable acid anhydride is exemplified. .
  • Particularly preferred Ashiruokishi as prodrugs ten C 0 C 2 H 5, - ⁇ C 0 (seven - B u), - OCOC 1 5 H 3 There - 0 C 0 (m- CO ON a -P h) , — 0 COCH 2 CH 2 CO ON a, —OCO CH (NH 2 ) CH 3 , —OCO CH 2 N (CH 3) 2 and the like.
  • an amino group such as an amide derivative produced by reacting a compound having an amino group with a suitable acid halide or a suitable mixed acid anhydride.
  • Prodrugs are exemplified.
  • One particularly preferred amide for pro-drugs is NHCO (CH 2 ) 2 . CH 3 , one NHC 0 CH (NH 2 ) CH 3 and the like.
  • the compounds of the present invention are not limited to specific isomers, but include all possible isomers and racemates.
  • the compound of the present invention exhibits excellent CRTH2 receptor antagonistic activity as described in the experimental examples described later. Therefore, the pharmaceutical composition of the present invention is useful for allergic diseases considered to involve eosinophils, such as asthma, allergic rhinitis, allergic dermatitis, papular dermatitis (filariasis, etc.) Vasculitis, polyarteritis, cutaneous eosinophilic granuloma, autoimmune diseases (eg, multiple sclerosis, transplant rejection, etc.), eosinophilic pulmonary disease, histiocytosis, pneumonia, pneumonitis Aspergillosis, pleurisy, sarcoidosis, idiopathic pulmonary fibrosis, eosinophilia, filarialism, schistosomiasis, trichinosis, coccidioidomycosis, tubercul
  • the compound of the present invention When the compound of the present invention is administered to humans for the treatment of the above-mentioned diseases, it is orally administered as powders, granules, tablets, capsules, pills, liquids, etc. They can be administered parenterally as suppositories, transdermal absorption agents, inhalants, and the like.
  • an excipient, a binder, a humectant, a disintegrant, a lubricant, and other pharmaceutical additives suitable for the dosage form may be mixed with the effective amount of the compound to form a pharmaceutical preparation, if necessary. Can be. In the case of injections, they should be sterilized with a suitable carrier to produce the preparation.
  • Dosages will vary depending on disease state, route of administration, patient age, or body weight, but for oral administration to adults, usually 0.1 to 10 O mg / kgZ days, preferably 1 ⁇ 20 mg / kg / day.
  • a compound ((+)-11-5) was obtained in the same manner as in Example 1 except that methyl bromide was replaced by methyl bromide.
  • a compound ((+)-11-7) was obtained in the same manner as in Example 1, except that benzyl bromide was used instead of methyl iodide.
  • a cell membrane fraction was prepared from K562 cells expressing the human CRTH2 receptor and subjected to a binding experiment. Coupling reaction (50 mM Tris / HC 1, pH 7.4, 10 mM MgC 1 2) to the membrane fraction (0.06 mg) and 3 nM 3 H - added PGD 2 (172 C i / mmol ) and 0.1 ml, The reaction was performed at room temperature for 60 minutes. Immediately after completion of the reaction, the mixture was filtered using a glass fiber filter paper, washed several times with cold physiological saline, and the radioactivity remaining on the filter paper was measured.
  • Specific binding was calculated by subtracting the non-specific binding (10 uM P GD 2 amount of radioactivity was determined in the same manner in the presence) from total binding.
  • the binding inhibitory activity of each compound was calculated as 50% by taking the specific binding amount in the absence of the compound as 100% and calculating the specific binding amount (%) in the presence of each compound to prepare a displacement curve.
  • the inhibitory concentration (IC prolongvalue) was calculated and the results are shown in Table 3.
  • the compound of the present invention has excellent CRTH 2 receptor antagonistic activity.
  • Test example 2 Antagonistic activity test for CRTH 2 receptor
  • a granule containing the following components is manufactured.
  • the compound of formula (I) and lactose are passed through a 60 mesh screen. Pass cornstarch through a 120 mesh sieve. These are mixed with a V-type mixer. Add an aqueous solution of HPC-L (low viscosity hydroxypropylcellulose) to the mixture and mix. After granulation (extrusion granulation pore diameter 0.5 ⁇ lmm), dry. The resulting dried granules are passed through a vibrating sieve (12 Z60 mesh) to obtain granules.
  • HPC-L low viscosity hydroxypropylcellulose
  • a powder for capsule filling containing the following ingredients is produced.
  • Lactose a compound represented by the formula (I)
  • Cone Yuichi is passed through a 120 mesh sieve.
  • These and magnesium stearate are mixed with a V-type mixer. Fill 100 mg of No. 10 hard gelatin capsule into No. 5 hard gelatin capsule.
  • a granule for filling forcepsel containing the following ingredients is produced.
  • Lactose a compound represented by the formula (I) is passed through a sieve of 60 mesh. Pass the cornstarch through a 120 mesh sieve. These are mixed, and an HPC-L solution is added to the mixed powder, followed by kneading, granulation and drying. After sizing the obtained dried granules, 150 mg thereof is filled into a No. 4 hard gelatin capsule. .
  • Formulation Example 4
  • a tablet is prepared containing the following ingredients:
  • 150 mg of the compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC—Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tablet making.
  • the mixed powder is directly hit to obtain tablets of 150 mg.
  • the pharmaceutical composition of the present invention and the compound of the present invention exhibit excellent CRTH2 receptor antagonism and can effectively function as an agent for treating or preventing allergic diseases.

Abstract

L'invention concerne une composition médicale à activité antagoniste contre un récepteur de CRTH2, et un nouveau composé. Ladite composition médicale comprend comme ingrédient actif, un composé représenté par la formule (I) dans laquelle R1, R2, R3 et R4 représentent chacun indépendamment hydrogène, halogéno, etc.; Y représente hydrogène, alkyle, alcényle, etc.; Ar représente un aryle ou un hétéroaryle éventuellement substitués; n est un nombre entier compris entre 1 et 3; et m est égal à 0 ou 1. L'invention concerne également un promédicament de cette composition, un sel de celle-ci pharmaceutiquement acceptable, ou un solvats de l'un quelconque de ces éléments. On utilise cette composition comme antagoniste du récepteur de CRTH2.
PCT/JP2003/006077 2002-05-16 2003-05-15 Antagoniste de recepteur de pdg2 WO2003097042A1 (fr)

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JP2004505041A JPWO2003097042A1 (ja) 2002-05-16 2003-05-15 Ｐｇｄ２受容体拮抗剤

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