WO2003097042A1

WO2003097042A1 - Pgd2 receptor antagonist

Info

Publication number: WO2003097042A1
Application number: PCT/JP2003/006077
Authority: WO
Inventors: Akinori Arimura; Junji Kishino; Norihiko Tanimoto
Original assignee: Shionogi & Co., Ltd.
Priority date: 2002-05-16
Filing date: 2003-05-15
Publication date: 2003-11-27
Also published as: JPWO2003097042A1; AU2003231513A1

Abstract

A medicinal composition having antagonistic activity against a CRTH2 receptor; and a novel compound. The medicinal composition contains as an active ingredient a compound represented by the formula (I): (I) (wherein R1, R2, R3, and R4 each independently is hydrogen, halogeno, etc.; Y is hydrogen, alkyl, alkenyl, etc.; Ar is optionally substituted aryl or optionally substituted heteroaryl; n is an integer of 1 to 3; and m is 0 or 1), a prodrug thereof, a pharmaceutically acceptable salt of either, or a solvate of any of these. The composition is used as a CRTH2 receptor antagonist.

Description

Specification

Technical field of P GD 2 receptor antagonists.

The present invention relates to a pharmaceutical composition used as a CRTH2 receptor antagonist and a novel compound having a CRTTH2 receptor antagonistic action. Background art

Prostaglandin D ₂ (P GD 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.

However, DP receptor which is a selective agonist BW- 2 4 5 C, since it can not be reproduced, such as eosinophil infiltration action by P GD _2, another receptor from the DP receptor on P GD ₂ Has been suggested previously (J. Immunol. (1992) 148, 3536-3542; Invest. Ophthalmol. Vis. Sci. (1990) 31, 138-146, Br. J. Pharmacol. 1985) 85, 367-375; J. Pharmacol. Exp. Ther. (1995) 275, 611-617, etc.). More recently, a second receptor CRTH 2 receptors of P GD _2, P GD ₂ eosinophils through the receptor, has been reported to induce the migration of basophils (J . Exp. Med. (2001) 193, 255-261).

Compounds having a similar structure to the compounds of the present invention, JP 62- 198659 as a thromboxane A ₂ antagonist Contact and platelet aggregation inhibitor, JP 3-151360, JP-A-4 234 846, JP-4- 257578, Tokudakida 8-245587, DE3909600, etc. However, not described at all PGD ₂ antagonistic activity.

In addition, 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-7-175991, WO97 / 44031. 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. Immunol. (1992 ) 89, 1119-1126. However, at present, 1) PGD ₂ is a high concentration region (Ι μΜ 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. (1989 ) 96, 291-300) are known, the Is an inhibitory effect of the thromboxane receptor-mediated reaction. ) It is not considered to have P receptor antagonism (Br. J. Pharmacol. (1989) 96, 291-300). Also, 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.

Wherein 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 sulfonyl, a group represented by haloalkyl);

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; and

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. Further, the present invention relates to the following II) to IX).

I I) The pharmaceutical composition according to I), wherein n is 2 and m is 0.

III) The pharmaceutical composition according to I) or II), wherein Y is hydrogen or alkyl.

IV) The pharmaceutical composition according to III), wherein RR ² , R ³ and R ⁴ are hydrogen.

V) 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.

V I) Equation (I):

[Wherein, I ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, haloalkyl, carboxy, alkyloxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl An optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, formula: one S (〇) p R ⁵ (where p is an integer of 0 to 2; R ⁵ is an alkyl or an optionally substituted group represented by the formula: — NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are each independently hydrogen, alkyl, or optionally substituted Aryl, an optionally substituted aralkyl or an acyl) or a group represented by the formula: -OR ⁸ , wherein R ⁸ is hydrogen, alkyl, optionally substituted aralkyl, optionally substituted aralkyl , Alkanesulfonyl, optionally substituted arylsulfonyl, optionally substituted aralkylsulfonyl, nodroalkyl);

Y is alkyl, alkenyl, optionally substituted aryl or optionally substituted aralkyl;

Ar is an optionally substituted aryl or an optionally substituted heteroaryl 5

η is an integer of 1 to 3; and

m is 0 or 1], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

VII) The compound according to (VI), wherein R i, R ² , R ³ and R ⁴ are hydrogen, Y is alkyl, n is 2 and m is 0, a prodrug thereof, a pharmaceutically acceptable salt thereof or Solvate of

VIII) 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.

X) A method for treating a disease involving a CRTH2 receptor, comprising administering the compound described in I).

XI) Use of a compound as described in I) for the manufacture of a medicament for the treatment of a disease involving the CRT H2 receptor. Hereinafter, the present invention will be described in detail.

In the present specification, “halogen” means fluorine, chlorine, bromine, and iodine. Fluorine, chlorine, and bromine are preferred as nourogens.

As used herein, the term “alkyl” used alone or in combination with other terms includes a straight-chain or branched monovalent hydrocarbon group having 1 to 8 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-II N-hexyl, isohexyl, n-heptyl, n-octyl and the like. Preferably, a C1-C6 alkyl is mentioned. More preferably, C 1 -C 3 alkyl is mentioned.

As used herein, "cycloalkyl" used alone or in combination with other terms includes cycloalkyl having 3 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclooctyl can be mentioned. Preferable one is C 3 -C 6 cycloalkyl.

In the present specification, “alkylene” used alone or in combination with another term includes a divalent hydrocarbon group derived from the above “alkyl”. For example, methylene, ethylene, n-prolene, isoprolene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neo-pentylene, n-hexylene, isohexylene, n-heptylene , N-octylene and the like. Preferably, a C1-C6 alkylene is mentioned. More preferably, a C1-C3 alkylene is mentioned.

In the present specification, “alkylenedioxy” includes methylenedioxy and the like.

In the present specification, 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. Includes linear or branched monovalent hydrocarbon groups. For example, vinyl, aryl, 1-propenyl, 2-propenyl, crotonyl, isopentenyl, various butenyl isomers and the like can be mentioned. Preferably, C 2 -C 6 alkenyl is used. Still more preferably, C 2 -C 4 alkenyl is used.

In the present specification, `` 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.

As used herein, the term “aryl” used alone or in combination with another term includes a monocyclic or condensed cyclic aromatic hydrocarbon. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned. Preference is given to phenyl, 1-naphthyl and 2-naphthyl. More preferably, phenyl is used.

In the present specification, the term "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. For example, 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.

In the present specification, the term `` 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. For example, 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.

As used herein, “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. For example, 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,

2-pyridyl, 3-pyridyl, 4-pyridinyl), birazinyl (for example, 2-pyrazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (for example, 3-pyridazinyl), Tetrazolyl (for example, 1H-tetrazolyl), oxadiazolyl (for example, 1,3,4-oxadiazolyl), thiadiazolyl (for example, 1,3,4-thiadiazolyl), indolizinyl (for example, 2-indine) Doridinyl, 6-indolinidyl), isoindrill (for example, 21 isoindrill), indrill (for example, 11indrill, 2indlinyl)

3-indolinyl), 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, 3-phenanthridinyl), acridinyl (For example, 1—Ata Linigi , 2-Acrylinidyl), dibenzozofuranyl (eg, 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (eg, 2-benzoimidazolyl), benzoisoxazolyl (eg, 3 — Benzoisoxazolyl), benzoxoxazolyl (for example, 2-benzoxazolyl), benzoxodiazolyl (for example, 4-benzobenzodiazolyl), benzoisothiazolyl ( For example, 3-benzoisothiazolyl), benzothiazolyl (for example, 2-benzothiazolyl), benzofuryl (for example, 3-benzofuryl), benzothenyl (for example, 2-benzothienyl) and the like can be given.

As the “heteroaryl” in Ar, chenyl, penzochenyl, oxosazolyl and the like are preferable.

In the present specification, “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. . For example, 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), thiazolyl Ethyl (eg, 2- (thiazolyl-2-yl) ethyl), isothiazolylmethyl (eg, 3-isothiazolylmethyl), isoxazolyl methyl (eg, 3-isoxazolylmethyl), oxazoly Rumethyl (for example, 2-oxazolylmethyl), oxazolylethyl (for example, 2- (oxazole-1-yl) ethyl), pyridylmethyl (for example, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl) And pyridylethyl (for example, 2-pyridylethyl).

In the present specification, the “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.

In the present specification, the “alkyloxy” includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and the like. Preferably, methyloxy, ethyloxy, n-propyloxy, isopropyloxy and n-butyloxy are mentioned. Particularly preferred are C 1 -C 3 alkyloxy.

In the present specification, “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

In the present specification, examples of “aryloxy” include phenyloxy, naphthyloxy and the like.

In the present specification, “arylthio” includes phenylthio, naphthylthio and the like.

In the present specification, “arylazo” includes phenylazo, naphthylazo and the like.

In the present specification, “alkyloxycarbonyl” includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, and isopropyl Xycarbonyl, n-butyloxycarbonyl, t-butyloxycarbonyl, n-pentyloxycarbonyl and the like. Preferably, methyloxycarbonyl and ethyloxycarbonyl are exemplified. Particularly preferred are C1-C3 alkyloxycarbonyl.

In the present specification, the term “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.

In the present specification, the term "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.

In the present specification, examples of "asyloxy" include acetyloxy, propionoxy, benzoyloxy and the like.

In the present specification, 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.

In the present specification, examples of “arylsulfonyl” include phenylsulfonyl, naphthylsulfonyl and the like.

In the present specification, “aralkylsulfonyl j” includes benzylsulfonyl, And diethylsulfonyl.

In the present specification, “heteroarylsulfonyl” includes pyrrolylsulfonyl and the like.

In the present specification, 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. For example, amino, methylamino, dimethylamino, ethylmethylamino, getylamino, ethylmethylamino, benzylamino, methoxycarbonylamino, methylsulfonylamino, acetylamino, benzoylamino and the like can be mentioned. Preferably, amino, methylamino, dimethylamino, ethylmethylamino, acetylamino, acetylamino are exemplified.

In the present specification, examples of the “aminocarbonyl which may be substituted” include aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, getylaminocarbonyl and the like. Preferably, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl are mentioned.

In the present specification, 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.

In the present specification, 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.

As the substituent for “optionally substituted alkyl” in R ¹ R ² , R ³ and R ⁴ , alkyloxy, hydroxy, optionally substituted amino, aryloxy and the like are preferable.

In the present specification, examples of the substituent in the “optionally substituted cycloalkyl” include alkyl, cycloalkyl, alkenyl, alkylidene, hydroxy, alkyloxy, mercapto, alkylthio, amino, logen, nitro and cyano. , Carboxyl, alkyloxycarbonyl, haloalkyl, haloalkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, acyloxy, optionally substituted non-aromatic heterocyclic group, aryloxy (Eg, phenyloxy), aralkyloxy (eg, benzyloxy), alkanesulfonyl, guanidino, azo group, ureido which may be substituted, and the like. These may be substituted one or more times in all possible positions.

As the substituent of the “optionally substituted cycloalkyl” in I ¹ , RR ³ and R ⁴ , alkyl, halogen and the like are preferable.

In the present specification, examples of the substituent in “optionally substituted alkenyl” include alkyl, cycloalkyl, alkylidene, hydroxy, alkyloxy, mercapto, alkylthio, halogen, nitro, cyano, carboxy, and alkyloxycarbonyl. , Peralkyl, haloalkyloxy, optionally substituted amino, optionally substituted aminocarbyl, acyl, acyloxy, optionally substituted non-aromatic heterocyclic group, aryl, aryloxy ( Examples include phenyloxy), aralkyl, aralkyloxy (for example, benzyloxy), alkenylsulfonyl, guanidino, azo group, and optionally substituted ureido. These may be substituted one or more times in all possible positions. As the substituent for the “optionally substituted alkenyl” ′ in R i, R ² , R ³ and R ⁴ , halogen, aryl and the like are preferable.

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 aralkyl, a lower alkanesulfonyl, a guanidino, an azo group, or an optionally substituted Good ureide and the like can be mentioned. These may be substituted one or more times in all possible positions.

As the substituent for the “optionally substituted aryl” in R ¹ R ² , R ³ and R ⁴ , alkyl, alkyloxy, halogen and the like are preferable.

As the substituent of the “optionally substituted aryl” for R ⁵ , alkyl, alkyloxy, halogen and the like are preferable.

As the substituent of the “optionally substituted aryl” in R ⁶ and R ⁷ , alkyl, alkyloxy, halogen and the like are preferable.

As the substituent of the “optionally substituted aryl” for R ⁸ , alkyl, alkyloxy, halogen and the like are preferable.

As the substituent for the "optionally substituted aryl" in Y, alkyl, alkyloxy, halogen and the like are preferable.

As the substituent for the “optionally substituted aryl” in Ar, alkyl, alkyloxy, halogen and the like are preferable. As the substituent for the “optionally substituted aralkyl” in II ¹ , R ² , R ³ and R ⁴ , alkyl, halogen and the like are preferable.

As the substituent for the “optionally substituted aralkyl” in R ⁶ and R ^7, -alkyl, halogen and the like are preferable.

As the substituent for the “optionally substituted aralkyl” for R ⁸ , alkyl, Haguchigen and the like are preferable.

As the substituent for the "optionally substituted aralkyl" for Y, alkyl, alkyloxy, nitro, halogen and the like are preferable.

As the substituent for the “optionally substituted heteroaryl” in Ar, alkyl, aralkyl and the like are preferable.

As the substituent for the “optionally substituted arylsulfonyl” for R ⁸ , alkyl and the like are preferable.

As the substituent for the “optionally substituted aralkylsulfonyl” for R ⁸ , alkyl and the like are preferable. BEST MODE FOR CARRYING OUT THE INVENTION

The compound (I) of the present invention can be produced according to the following scheme.

(IV) (l)

(Wherein, R ¹ R ² , R ³ , R ⁴ , Ar, Y, m, and n are the same as defined above)

, 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. Medium, hydrogen After reacting with Y-X in the presence of 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.

In the compound represented by formula (I), Y is a compound other than hydrogen are not selective CRTH 2 receptor antagonist compound of TXA ₂ receptor antagonistic activity. As such compounds, compounds represented by the following formulas (II) and (III) are preferable. Formula (II):

[Wherein, 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; and

R ¹ Q is hydrogen or halogen], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Equation (I I I):

Wherein 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; and

R ^{1 G} is hydrogen or halogen], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. As 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.

(table 1 )

(In the table, Me is methyl, Et is ethyl, allyl is aryl, and Bn is benzyl.)

(Table 2)

(In the table, Me is methyl, Et is ethyl, allyl is aryl, and Bn is benzyl) In the present specification, "solvate" includes, for example, solvates with organic solvents, hydrates, and the like. . When forming a solvate with an organic solvent, it may be coordinated with any number of organic solvent molecules. When forming a hydrate, it may be coordinated with any number of water molecules. Hydrates are preferred.

The term "the compound of the present invention" also includes 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. When 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. Particularly preferred 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. When the compound of the present invention has a hydroxyl group, for example, 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, -〇 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. When the compound of the present invention has 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, tuberculosis, bronchial carcinoma, lymphoma It can be used as a prophylactic and / or therapeutic agent for diseases such as Hodgkin's disease.

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. In addition, 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. Example

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

In the examples, the following abbreviations are used.

M e: Methyl

E t: ethyl

B n: benzyl

DMF: N, N—dimethylformamide THF: Tetrahid D franc

M e 0 H: methanol Example 1 (R) 13 — {3- [N- (4-fluorobenzenesulfonyl) 1-N-methylamino]-1,2,3,4—tetrahydrocarbazole-1-yl } Propionic acid ((+)-11-4)

(11-3) (11-4)

(R)-3-{3-[(4-Fluorobenzenesulfonyl) amino] — 1,2,3,4-tetrahydrocarpazole-9-yl} propionic acid ((+)-11- 3) In a DMF (3 mL) solution of (29 O mg: 0.70 mmol), add methyl iodide (0.13 mL, 2.1 mmol), potassium carbonate ( (289 mg, 2.1 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water, extracted with ethyl acetate-ether (1: 1), washed with brine, dried and concentrated. The residue was dissolved in methanol-THF (1: 1), 2 mol / L sodium hydroxide solution (0.6 mL, 1.2 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After acidification with dilute hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate, 1: 3) and further crystallized from ethyl acetate-hexane to give the compound ((+)-11-4) (187 mg). ; Yield 63%).

Melting point: 155-157 ° C

iH-NMR (CDCI3): δ 1.86-2.04 (m, 2H), 2,62-2.87 (m, 6H), 2.89 (s, 3H), 4.24- 4.36 (m, 3H), 7.05-7.34 (m, 6H), 7.87 (dd, J = 4.8, 9.0 Hz, 2H)

IR (KBr) 3422, 1713, 1590, 1491, 1467, 1333, 1237, 1165 cm " ¹

[a] _D ²⁴ + 95.0 ± 1.3 ° (c = 1.008, MeOH); Elemental analysis _{_{_{(C 22 H 23 FN 2 0}}} 4 S)

Calculated value (% ·): C, 61.38; H, 5.39; N, 6.51; F, 4.41; S, 7.45

Obtained value (%): C, 61.36; H, 5.26; N, 6.45; F, 4.43; S, 7.47 Example 2 (R) 3 — {3-[N— (4-fluorobenzenesulfonyl) 1N —Ethylamino] — 11,2,3,4—Tetrahydrocarbazole-9-yl} propionic acid ((+)-11-5)

A compound ((+)-11-5) was obtained in the same manner as in Example 1 except that methyl bromide was replaced by methyl bromide.

Melting point: 159.5-161 ° C

_{Ή-NMR (CDC1 3):} . Δ 1.34 (t, J = 7.2 Hz, 3H), 1.97-2.06 (m, 2H), 2.72-2 88 (m, 6H), 3.38 (q, J = 7.2 Hz, 2H), 4.14 (m, 1H), 4.32 (m, 2H) _; 7.05 -7.36 (m, 6H), 7.89 (dd, J = 5.1, 8.7 Hz, 2H)

[] _D ²³ + 95.2 ± 1.4. (C = 1.005, MeOH);

Elemental analysis _{_{_{(C 2S H 25 FN 2 0}}} 4 S)

Calculated (%): C, 62.14; H, 5.67; N, 6.30; F, 4.27; S, 7.21

Obtained value (%): C, 61.84; H, 5.66; N, 6.13; F, 4.12; S, 7.2 Example 3 (R) -3-{3-[N- (4-fluorobenzenesulfonyl) -1 N-benzylamino] 1,1,2,3,4-tetrahydrocarbazole-9-yl} propionic acid ((+)-11-7)

(11-3) (11-7)

A compound ((+)-11-7) was obtained in the same manner as in Example 1, except that benzyl bromide was used instead of methyl iodide.

Ή-NMR (CDCls): δ 1.72-1.94 (m, 2H), 2.61-2.76 (m, 6H), 4.18-4.29 (, 3Η) '4.48 (d, J = 15.9 Hz, 1H), 4.63 (d, J = 15.9 Hz, 1H), 7.07-7.42 (m, 11H), 7.85 (dd, J = 5.4, 8.7 Hz, 2H)

[] _D ^zs + 39.3 ± 0.8 ° (c = 1.002 _; Me OH);

Elemental analysis _{_{_{(C 28 H 27 FN 2 0}}} 4 S)

Calculated (%): C, 66.39; H, 5.37; N, 5.53; F, 3.75; S, 6.33

Obtained value (%): C, 66.12; H, 5.35; N, 5.43; F, 3.66; S, 6.14 'Example 43-{1 [N- (4-fluorobenzenesulfonyl) -N-methyl] Amino] methyl-1,2,3-trihydrocyclopenta [1,2-b] indole-4-yl} propionic acid (ΠΙ-4)

3- (1-([4-fluorobenzenesulfonyl) amino] methyl-1,2,3—trihydrocyclopentene instead of compound (II-3) [1,2—b] 4-yl} A compound (酸 -4) was obtained by the same operation as in Example 1 using propionic acid (操作 -3).

O-NMR (d ₆ -DMSO) δ 2.51 (m, 1H), 2,66-2.72 (m, 3H), 2.75 (s, 3H) _; 2.88 (m, 1H), 2.98-3.12 (m, 3H), 3,20 (m _; 1H), 4.28 (t, J = 6.9 Hz, 2H), 6.95-7.07 (m, 2H), 7.32 (d, J = 7.8 Hz , 1H), 7.40 (d, J = 7.8 Hz, IH), 7.43-7.51 (m, 2H), 7.83-7.90 (m, 2H) _; 12.39 (br, IH)

IR (KBr) 3274, 2681, 1739, 1712, 1591, 1493, 1459, 1340, 1292, 1231, 1167, 1154, 1088 cm ¹

Elemental analysis _{_{_{(C 22 H 23 FN 2 0}}} 4 S 2)

Calculated (%): C, 61.38; H, 5.39; F, 4.41; N, 6.61; S, 7.45

Actual value (%): C, 61.03; H, 5.37; F, 4.27; N, 6.32; S, 7.28 Test example 1 CR T H 2 receptor binding test

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 „value) was calculated and the results are shown in Table 3.

(Table 3)

From the results 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

Prepare K562 cells expressing human CRTH2 receptor at 2 x 10 ^f cells / ml, and add Fura-2 AM (2 μΜ) to a cell suspension (10 mM HEPES buffer, pH 7.4, 0.1% Bovine serum albumin). Was added and incubated at room temperature for 60 minutes. After washing, the cells were resuspended in a cell suspension, heated to 37 ° C, and variously diluted compounds were added. Two minutes later, PGD ₂ (50 nM ) Was added to induce a reaction, and the increase in intracellular calcium concentration was measured using an intracellular ion analyzer (CAF-110). The antagonistic activity of each compound was determined by the intracellular calcium concentration in the absence of the compound. The inhibition rate in the presence of each compound (1 μΜ) relative to the increase was calculated and evaluated. The results are shown in Table 4.

(Table 4)

Formulation example

Formulation Example 1

A granule containing the following components is manufactured.

Ingredient 10 mg of the compound represented by the formula (I)

Lactose 700 mg

Corn starch 274 mg

HPC-L 16 m

1000 mg

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. Formulation Example 2

A powder for capsule filling containing the following ingredients is produced.

Ingredient 10 mg of the compound represented by the formula (I)

Lactose 79 mg

Corn starch 10 mg

― Magnesium stearate _ ― _ _ l_m¾

100 mg Lactose, a compound represented by the formula (I), is passed through a 60-mesh sieve. 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. Formulation Example 3

A granule for filling forcepsel containing the following ingredients is produced.

Ingredient 15 mg of the compound represented by the formula (I)

Lactose 90 mg

Corn starch 42 mg

HPC-L 3

150 mg

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:

Ingredient 10 mg of the compound represented by the formula (I)

Lactose 90 mg

Microcrystalline cellulose 30 mg

CMC-Na 15 mg

Magnesium stearate _ 5 mg

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. Industrial applicability

INDUSTRIAL APPLICABILITY 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.

Claims

The scope of the claims

Wherein I ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, halogenated alkyl, carboxy, alkyloxycarbonyl, optionally substituted alkyl, or substituted Good alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, formula: one S (O) p R ^{5 wherein} p is 0-2 An integer; R ⁵ is an alkyl or an optionally substituted aryl group represented by the formula: — NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are each independently hydrogen, alkyl, or substituted. Or a group represented by the following formula: —OR ⁸ (where R ⁸ is hydrogen, alkyl, optionally substituted aryl, or optionally substituted) Good aralkyl, alkane sulfoni Or an optionally substituted arylsulfonyl, an optionally substituted aralkylsulfonyl, or a noloalkyl) group;

Ar is an optionally substituted aryl or an optionally substituted heteroaryl;

n is an integer of 1 to 3; and

m is 0 or 1], a drug used as a CRTH2 receptor antagonist containing a compound represented by the formula: a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Composition.

2. The pharmaceutical composition according to claim 1, wherein n is 2 and m is 0.

3. The pharmaceutical composition according to claim 1, wherein Y is hydrogen or alkyl.

4. R ^ ^2, R ³ and R ⁴ are pharmaceutical compositions ranging third claim of claim it is hydrogen.

5. Ar is halogen, arylthio, aryloxy, arylazo, heteroarylsulfonyl, heteroarylalkyl optionally substituted by alkyl, alkylene optionally fused by benzene ring, arylalkynyl, benzene ring fused Optionally substituted with one or more substituents selected from alkylenedioxy, alkyl, and aryl which may be substituted with halogen, or halogen, hydroxy, and It may be substituted at 1 or 2 or more places by the substituent group A. It may be substituted at 1 or 2 or more places by a substituent selected from aralkyl (Substituent A: hydroxy, halogen, and alkyloxy). 5. The pharmaceutical composition according to claim 4, which is heteroaryl.

6. Formula (I):

Wherein I 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, optionally substituted aryl, optionally substituted aralkyl, formula: —S (〇) _p R ⁵ (where p is an integer of 0 to 2;; R ⁵ is an alkyl or an optionally substituted aryl group represented by the formula: NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are each independently hydrogen, alkyl, or an optionally substituted aryl) Or a group represented by an optionally substituted aralkyl or acyl) or a group represented by the following formula: 10 R ⁸ (wherein, R ⁸ is hydrogen, alkyl, optionally substituted aryl, or optionally substituted aralkyl) , Alkanesulfonyl, optionally substituted arylsulfonyl, optionally substituted aralkylsulfonyl, haloalkyl);

Ar is optionally substituted aryl or optionally substituted heteroaryl;

n is;! An integer from to 3; and

7. The compound according to claim 6, wherein RKR ³ and R ⁴ are hydrogen, Y is alkyl, n is 2, and m is 0, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvent thereof. Japanese food.

8. A pharmaceutical composition comprising the compound according to claim 6 or 7, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

9. The pharmaceutical composition according to claim 8, which is used as a CRT H2 receptor antagonist.

10. A method for treating a disease associated with a CRTH2 receptor, comprising administering the compound according to claim 1.

11. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a disease associated with a CRT H2 receptor.