WO1998056785A1

WO1998056785A1 - Pyrazole derivatives

Info

Publication number: WO1998056785A1
Application number: PCT/JP1998/002552
Authority: WO
Inventors: Masashi Nakatsuka; Fumio Nishikaku; Takahiko Hashizuka; Shin-Ichiro Okada
Original assignee: Sumitomo Pharmaceuticals Co., Ltd.
Priority date: 1997-06-12
Filing date: 1998-06-09
Publication date: 1998-12-17
Also published as: AU7553198A

Abstract

Pyrazole derivatives represented by general formula (1) [wherein one of R?1 and R2¿ represents an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group and the other represents an optionally substituted aromatic heterocyclic group; R3 represents a hydrogen atom, an optionally substituted alkyl group or the like; and R4 represents a hydrogen atom or an optionally substituted alkyl group] or pharmacologically acceptable salts thereof useful as an immunosuppressive agent and can be used as a therapeutic agent for autoimmune diseases, allergic diseases or other diseases.

Description

Description Pyrazol derivative Technical field

The present invention relates to pyrazole derivatives useful as immunosuppressants. Background art

As the immunosuppressive agent, an antimetabolite such as methotrexet, an imnophilin inhibitor such as cyclosporin, and the like have been conventionally used. These are said to contribute to the effect of inhibiting the proliferation and activation of lymphocyte-derived cells.

In recent years, the relationship between a substance called superantigen, such as Staphylococcus enterotoxin, an exotoxin of Staphylococcus aureus, and autoimmune diseases has been revealed. Experimental allergic encephalomyelitis mouse, an animal model of multiple sclerosis; collagen arthritis mouse, an animal model of rheumatoid arthritis; NOD mice spontaneously developing inulin-dependent type I diabetes; It has been reported that administration of superantigen to MRL / lpr mice exhibiting lupus erythematosus-like symptoms rapidly worsens the condition. It has also been suggested that Spar antigen is involved in the onset and exacerbation of Kawasaki disease and atopic dermatitis. Furthermore, superantigens are known to selectively induce the proliferation of autoreactive lymphocytes and the production of autoantibodies.

Pyrazole derivatives are known to be useful as nonsteroidal contraceptives or agents for treating hypertension (US 3816437, US 3816438, US 3842088, US 3843664, US 3843665, US 3843666, US 3932430). Disclosure of the invention

The present inventors have conducted intensive studies to provide a novel immunosuppressant, and as a result, The inventors have found that razol derivatives have an immunosuppressive action, and completed the present invention.

That is, the present invention

[1] Equation 1:

[In the formula, ^one of R ¹ and R ² represents an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group, and the other represents an optionally substituted aromatic heterocyclic group.

R ³ is a hydrogen atom, an alkyl group which may be substituted, an alkoxy group which may be substituted, an alkenyl group which may be substituted, an alkenyloxy group which may be substituted, an alkynyl group which may be substituted, An optionally substituted alkynyloxy group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, an optionally substituted rubamoyl group, an optionally substituted alkoxycarbonyl group, an acyl group, an acyloxy group, and an optionally substituted Represents a aryl group or an amino group which may be substituted.

Also, R ³ combines with one of R ¹ and R ² to form one RR or one R ² — R with the formula:

(Ring A represents a monocyclic or bicyclic aromatic hydrocarbon ring which may be substituted, or a monocyclic or bicyclic aromatic heterocyclic ring which may be substituted. X represents methylene, ethylene, trimethylene one CO_CH ₂ -, one OCH ₂ -, one SCH ₂ - one N (R ⁵⁾ CH ₂ -., -CO-, oxygen atom, sulfur atom or a N represents a (R ⁵⁾ one R ⁵ is It represents a hydrogen atom or an alkyl group.) It may represent a divalent group represented by

R ⁴ represents a hydrogen atom or an optionally substituted alkyl group. ] An immunosuppressant comprising a pyrazole derivative represented by the formula or a pharmacologically acceptable salt thereof.

[2] An immunosuppressant comprising the pyrazole derivative or the pharmaceutically acceptable salt thereof according to [1], wherein R ⁴ is a hydrogen atom.

[3] One of R ¹ and R ² is an optionally substituted phenyl group or an optionally substituted monocyclic aromatic heterocyclic group, and the other is an optionally substituted monocyclic or bicyclic ring The pyrazole derivative according to [1] or [2], wherein the ring A is a benzene ring which may be substituted or a monocyclic aromatic heterocyclic ring which may be substituted. An immunosuppressant comprising a conductor or a pharmacologically acceptable salt thereof.

[4] ^one of R ¹ and R ² is phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, phenyl, furyl or a substituted group, and the other is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl or substituted R ³ represents a hydrogen atom, an optionally substituted alkyl group, a carboxy group, an optionally substituted alkoxycarbonyl group or an acyl group, or R ³ represents R ¹ And one of R ² and one R ¹ — R ³ — or one R ² — R ³ — are represented by the formula:

(X is as defined above. Ring A ¹ represents a benzene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a thiophene ring, a furan ring, or a substituted ring thereof.) An immunosuppressant comprising the pyrazolyl derivative according to [1] or [2], which is a divalent group, or a pharmaceutically acceptable salt thereof.

[5] X is methylene, ethylene, trimethylene, one CO—CH ₂ —, one OCH 2—, one SCH ₂ —, one N (R ⁵ ) CH ₂ — (R ⁵ is as defined above) or — An immunosuppressant comprising the pyrazolyl derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is CO—.

[In the formula, Y represents a halogen atom, an alkoxy group, a cyano group or an alkyl group. ζ represents a hydrogen atom, a halogen atom, an alkoxy group, a cyano group, a nitro group, an amino group or an alkyl group.

R ⁶ , R ⁷ and R ⁸ are as defined in (1) or (2) below.

(1) 1¾ ⁶ and 1¾ ⁷ both represent hydrogen atoms.

R ⁸ represents 3- or 4-monopyridyl which may be substituted.

(2) R ⁶ and R ⁷ are taken together, and one R ⁶ —R ⁷ — represents methylene, ethylene, one OCH 2— or one SCH ₂ —.

R ⁸ represents 3-pyridyl which may be substituted. ]

Or a tautomer thereof, or a pharmacologically acceptable salt thereof.

[7] Formula:

[Wherein, Y, R ⁶ and R ⁷ are as defined above.

Zeta ¹ is a hydrogen atom, a halogen atom, an alkoxy group, an Shiano group or a nitro group to the table. Zeta ² is a hydrogen atom, an alkyl group, Shiano group, a hydroxyl group or an alkoxy group to the table. ]

[6] The pyrazole derivative according to [6], a tautomer thereof, or a pharmacologically acceptable salt thereof. [8] The pyrazole derivative according to [7], wherein both ^{1 and} ² are hydrogen atoms, a tautomer thereof, or a pharmacologically acceptable salt thereof.

[9] The pyrazolyl derivative according to any one of the following [6] or a tautomer thereof, or a pharmacologically acceptable salt thereof.

· 3- (3-pyridinole) 1-5— (4-chlorophenyl) 1-pyrazol

• 6-Chloro-3- (3-pyridyl) — 4H-indeno [1,2—c] birazol

• 7-chloro-1,4,5-dihydro-3- (3-pyridyl) —2—naphtho [1,2-1c] pyrazol

[10] A medicament comprising the pyrazole derivative according to any one of [6] to [9] or a tautomer thereof, or a pharmacologically acceptable salt thereof.

[11] An immunosuppressant comprising the pyrazole derivative according to any one of [6] to [9] or a tautomer thereof, or a pharmacologically acceptable salt thereof.

[12] The immunosuppressant according to any one of [1] to [5] or [11], which is a T cell proliferation induction inhibitor.

[13] The immunosuppressant according to any one of [1] to [5] or [11], which is a therapeutic agent for an autoimmune disease.

[14] The immunosuppressant according to any one of [1] to [5] or [11], which is a therapeutic agent for rheumatoid arthritis.

[15] The immunosuppressant according to any one of [1] to [5] or [11], which is a therapeutic agent for multiple sclerosis.

[16] The immunosuppressant according to any one of [1] to [5] or [11], which is a therapeutic agent for ulcerative colitis. Hereinafter, the contents of the present invention will be described in detail.

Examples of the “aryl group” include groups having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, and anthryl. Preferably, phenyl, 1-naphthyl and 2-naphthyl are mentioned. Examples of the “monocyclic or bicyclic aromatic hydrocarbon ring” include a hydrocarbon ring having 6 to 10 carbon atoms, and specific examples include benzene and naphthalene.

As the "aromatic heterocyclic group", a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms can be mentioned. Specifically, furyl, phenyl, indolyl, isothiazolyl, benzothienyl, isobenzofuranyl, pyrrolyl, benzofuryl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzozozolyl, etc. A 2- or 5-membered aromatic heterocyclic group such as a bicyclic 5-membered aromatic heterocyclic group and a pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl group; Can be

Examples of the “heterocyclic group” include an aromatic heterocyclic group and a monocyclic or bicyclic aliphatic heterocyclic group containing 1 to 3 nitrogen, oxygen and / or sulfur atoms. Specific examples of the aliphatic heterocyclic group include monocyclic or bicyclic 5-membered aliphatic heterocyclic groups such as tetrahydrofuryl, pyrrolidinyl, and birazolidinyl; and monocyclic rings such as piperidyl, morpholinyl, and piperazinyl. Or a bicyclic 6-membered aliphatic heterocyclic group.

The “monocyclic or bicyclic aromatic heterocycle” includes a monocyclic or bicyclic aromatic heterocycle containing 1 to 3 nitrogen atoms, oxygen atoms, and phosphorus or sulfur atoms. Specifically, furan, thiophene, indoline, isothiazoline, benzothiophene, isobenzofuran, pyrrole, benzofuran, imidazole, pyrazol, isoxazole, isothiazole, thiazol, oxazole, benzimid Monocyclic or bicyclic 5-membered aromatic heterocycles such as dazols, benzothiazols and benzoxazols, and monocycles such as pyridine, pyrazine, pyrimidine, pyridazine, triazine, quinoline, isoquinoline, quinazoline and quinoxaline Or a bicyclic 6-membered aromatic heterocyclic ring. Examples of the substituted aryl group, the substituted aromatic heterocyclic group, and the substituent of the monocyclic or bicyclic substituted aromatic hydrocarbon ring or the substituted aromatic heterocyclic ring include, for example, the following groups a) to g). Any group may be mentioned, and these may be arbitrarily substituted one or more times. Preferred numbers of substituents include 1, 2 or 3.

jj_halogen atom, nitro group, cyano group, azide group, mercapto group, formyl group, hydroxyl group, hydroxyl group, optionally substituted amino group, optionally substituted hydroxyamino group, optionally substituted alkoxyamino Group, carboxyl group, optionally substituted rubamoyl group, optionally substituted rubamoyloxy group, sulfo group, optionally substituted sulfamoyl group, optionally substituted guanidino group, optionally substituted Amidino group, hydrazino group which may be substituted.

b) -R ^{^9,} -OR ^9, one C0 ₂ R ^9, one _{^{^{S0 3 R 9, -COR 9,}}} - S (0) n R 9 [ wherein, n represents 0, 1 or 2. R ⁹ represents a phenyl group or a monocyclic heterocyclic group. A phenyl group or a monocyclic heterocyclic group is, for example, a halogen atom, an alkyl group, a haloalkyl group, a cyano group, a nitro group, an azido group, a hydroxyl group, an alkoxy group, a haloalkoxy group, an amino group which may be substituted, It may be substituted with one or more groups arbitrarily selected from the group consisting of a rubamoyl group, a carboxy group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group. ]

c) Alkyl group, alkoxy group, alkoxycarbonyl group, alkoxy (thiothiol group), alkylthio group, (alkylthio) thiocarbonyl group, (alkylthio) carbonyl group, alkylcarbonyl group, alkylthioyl group, alkylsulfinyl group, alkyl Sulfonyl group, alkylcarbonyloxy group, alkylthioyloxy group, alkylsulfonyloxy group

[Each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, an amino group which may be substituted, a hydroxyl group, an acyl group, an acyloxy group, and a carboxy group. An optionally substituted sorbamoyl group, an optionally substituted sorbamoyloxy group, a sulfo group, an optionally substituted sulfamoy group —R ⁹ , —OR ⁹ , —SR ⁹ , one OCH ₂ R ⁹ , —S CH ₂ R ⁹ (R ⁹ is as defined above),

Cycloalkyl group (the cycloalkyl group is, for example, one or more groups selected from the group consisting of a halogen atom, an alkyl group, a non-alkyl group, an amino group which may be substituted, a hydroxyl group, an alkoxy group, and a haloalkoxy group; ), An alkoxy group, an alkoxycarbonyl group and an alkylthio group (an alkoxy group, an alkoxycarbonyl group and an alkylthio group are, for example, a halogen atom, a cycloalkyl group, a monocyclic heterocyclic group, a phenyl group, a cyano group) , Nitro group, hydroxyl group, alkoxy group, haloalkoxy group, amino group which may be substituted, force which may be substituted rubamoyl group, carboxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group and alkyl Sulfonyl May be substituted with one or more groups selected in the group or al any etc..) Optionally may be substituted with selection barrel (1) or more radicals from the group of the like. ]

d) alkenyl group

[Alkenyl groups include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, optionally substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, alkylthio group. R ⁹ , -OR ⁹ , _SR ⁹ , —OCH ₂ R ⁹ and —S CH ₂ R ⁹ (R ⁹ is May be substituted with one or more groups arbitrarily selected from the group of e) alkynyl group

[Alkynyl groups include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, amino group which may be substituted, hydroxyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, alkylthio group. group, § shea group, Ashiruokishi group, a carboxy group, an optionally substituted force Rubamoiru group, one R ¹ ^0, one oR ^10, one SR ^10, one OCH ₂ R ^{1 0} and one S CH ₂ R ¹⁰ (R ¹⁰ represents a phenyl group, for example, a halogen atom, an alkyl group, a haloalkyl W 7

9 group, cyano group, nitro group, azide group, hydroxyl group, alkoxy group, haloalkoxy group, optionally substituted amino group, optionally substituted rubamoyl group, carboxy group, alkylcarbonyl group, alkoxycarbonyl group, It may be substituted with one or more groups arbitrarily selected from the group of an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group. ) May be substituted with one or more groups arbitrarily selected from the group of ]

f) alkenyloxy, alkenyloxycarbonyl, alkenylcarbonyl, alkenylcarbonyloxy, alkynyloxy, alkynyloxycarbonyl

[Each group in this group may be substituted, for example, a halogen atom, an oxo group, an amino group which may be substituted, a hydroxyl group, an alkoxy group, a haloalkoxy group, an acyl group, an acyloxy group, an alkylthio group, a carboxy group. And may be substituted with one or more groups arbitrarily selected from the group consisting of a carbamoyl group, an alkoxycarbonyl group and a phenyl group. ]

Cycloalkyl group, cycloalkyloxy group, cycloalkylcarbonyl group, cycloalkylcarbonyloxy group, cycloalkyloxycarbonyl group, cycloalkenyl group, cycloalkenyloxy group, cycloalkenylcarbonyl group, cycloalkenylcarbonyloxy group , Cycloalkenyloxycarbonyl group

[Each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, an alkyl group, a haloalkyl group, a substituted or unsubstituted amino group, a hydroxyl group, an alkoxy group, It may be substituted with one or more groups arbitrarily selected from the group consisting of a haloalkoxy group, an acyl group, an acyloxy group, an alkylthio group, a carboxy group, an optionally substituted rubamoyl group and an alkoxycarbonyl group. ,. Preferred examples of the substituted aryl group, the substituted aromatic heterocyclic group, and the substituent of the monocyclic or bicyclic substituted aromatic hydrocarbon ring or the substituted aromatic heterocyclic ring include, for example, W 5

10-Any of the following groups may be mentioned, and these may be arbitrarily substituted one or more times.

Groups: optionally substituted sorbamoyl group, optionally substituted sulfamoyl group, sulfo group, halogen atom, cyano group, nitro group, carboxyl group, optionally substituted amino group, optionally substituted hydroxylamino Group, optionally substituted amidino group, optionally substituted guanidino group, optionally substituted hydrazino group, mercapto group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group An optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, —OR ⁹ , one C 0 ₂ R ⁹ , — COR ^9, one _{^{S (O) n R 9 (}} n and R ⁹ has the same meaning as defined above.), an optionally substituted alkyl group, an optionally substituted alkenyl An optionally substituted alkynyl group, an optionally substituted phenyl group or an optionally substituted monocyclic heterocyclic group, an optionally substituted alkoxycarbonyl group, an optionally substituted Alkenyloxycarbonyl group, alkynoxycarbonyl group which may be substituted;

Particularly preferred examples of such a substituent include, for example, any of the following groups, which may be arbitrarily substituted one or more times.

Group: halogen atom, cyano group, nitro group, carboxyl group, amino group which may be substituted, hydrazino group which may be substituted, alkyl group which may be substituted, alkoxy group which may be substituted, substituted A good alkoxycarbonyl group. Specific examples of the substituted aryl group, the substituted aromatic heterocyclic group, and the substituent of the monocyclic or bicyclic substituted aromatic hydrocarbon ring or the substituted aromatic heterocyclic ring include methyl, hexyl, 2-methyl-1- _Propyl, 2-propyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 6,6,6-trifluorohexyl, Hydroxymethyl, methoxymethyl, hexoxymethyl, cyclopropylmethoxymethyl, acetomethyl, N, N-dimethyl

', Methanesulfonyloxymethyl, N, N-dimethyl Rusulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2-methoxymethyl, carboxymethyl, methoxycarbonylmethyl, rubamoylmethyl, amidinomethyl, methylthiomethyl, cyanomethyl, aminomethyl, N-acetylamino Methyl, ethenyl, 2-propenyl, ethynyl, 2-propynyl, 2-methoxycarbonylethenyl, fluoro, chloro, bromo, chloride, nitro, cyano, hydroxyl, amino, N, N-dimethylamino, mercapto , Sulfo, carboxy, amidino, guanidino, hydrazino, methoxy, cyclopropylmethoxy, 2- (1-pyrrolidinyl) ethoxy, methoxycarbonylmethoxy, 2-acetoethoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 4, 4, 5, 5, 5 —pentafluoropentoxy, 2 —methanesulfinylethoxy, phenoxy, benzyloxy, 4-methoxybenzyloxy, methoxycarbonyloxy, 1-pyrrolidinyl, 3-hydroxy-1 — Pyrrolidinyl, N-acetylamino, N-acetyl-N-methylamino, N-methanesulfonylamino, N-methanesulfonyl N-methylamino, methoxycarbonyl, 2-methyl-12-propyloxycarbonyl, 2,2,2 —Trifluoroethoxycarbonyl, phorbamoyl, N, N_dimethylcarbamoyl, 2-thiazolidinyl, 2-oxosazolidinyl, 5-tetrazolyl, methanesulfinyl, sulfamoyl, N, N_dimethylsulfamoyl, acetyl, benzoyl, ethoxy Carbonyl, morpholino, vivalo Le, triflumizole Ruo b acetyl, formyl, ethylenedioxy O Kishime chill and the like.

The “alkyl group” includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2 _ Methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3,3-dimethylbutyl, etc. No. Examples of the substituent in the substituted alkyl group include, for example, any group included in each of the following groups a) to d), and these may be arbitrarily substituted one or more times.

A halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, a substituted amino group, a hydroxyl group, an acyl group, an acyloxy group, a hydroxyl group, an optionally substituted hydroxyl group, Optionally substituted sulfamoyloxy group, sulfo group, optionally substituted sulfamoyl group

_ ^ _ Cycloalkyl group, cycloalkenyl group

[Cycloalkyl group and cycloalkenyl group include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, formyl group, amino group which may be substituted, hydroxyl group, alkoxy, haloalkoxy, carboxy group, It may be substituted with a rubamoyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a phenyl group, a monocyclic heterocycle, or the like. ]

c) alkoxy group, alkoxycarbonyl group, alkylthio group

[Alkoxy group, alkoxycarbonyl group and alkylthio group include, for example, halogen atom, cycloalkyl group, substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, carboxy group, optionally substituted rubamoyl group, alkyl group It may be substituted with a hydroxyl group, an alkoxycarbonyl group, a phenyl group, a monocyclic heterocycle, or the like. ]

_d) —R ⁹ , one OR ⁹ , —SR ⁹ , one OCH ₂ R ⁹ , one SCH ₂ R ⁹ (R ⁹ is as defined above.) As the substituted alkyl group, specifically, trifluoro Methyl, 2-nitroethyl, 2-cyanopropyl, 4-mercaptobutyl, 3-oxobutyl, 2-piridinoethyl, 2-hydroxyethyl, 3-methoxypropyl, ethoxycarbonylmethyl, cyclopropylmethyl, cyclohexylmethyl , 6-cyclohexylhexyl, 3-cyclohexenylbutyl, 2-phenylbutyl, benzyl, 2-na Examples include phthylmethyl, phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-quinolylmethyl, 3-phenylphenyl, and the like.

The haloalkyl group refers to an alkyl group substituted with 1 to 5 halogen atoms.

“Alkoxy group” refers to an oxy group to which an alkyl group is bonded. Specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like.

Examples of the substituent of the substituted alkoxy group include the same substituents as those of the substituted alkyl group. Specific examples of the substituted alkoxy group include cyclopropyl methoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, benzyloxy, 2-pyridylmethoxy and the like.

Here, the haloalkoxy group refers to an alkoxy group substituted with 1 to 5 halogen atoms.

“Alkoxycarbonyl group” refers to a carbonyl group to which an alkoxy group is bonded. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like.

The substituent in the substituted alkoxy group is the same as the substituent in the substituted alkyl group.

Examples of the “alkenyl group” include a linear or branched alkenyl group having 2 to 6 carbon atoms and having 1 to 3 double bonds. Specifically, ethenyl, 1-probenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 2— Pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl and the like. Preferred alkenyl groups include, for example, ethenyl, 1-probenyl and 1-butenyl groups.

Examples of the substituent of the substituted alkenyl group include a halogen atom, a nitro group, and a cyano group. Group, mercapto group, oxo group, thioxo group, formyl group, substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, alkylthio group, acyl group, acyloxy group, carboxy group, substituted Te good force Luba moil ^{^{group, - R 9, -OR 9,}} - SR 9, - OCH 2 R 9, - SCH 2 R 9 (. R 9 has the same meaning as before SL), and the like.

Further, an alkenyl group refers to an oxy group to which an alkenyl group is bonded. Examples of the “alkynyl group” include a linear or branched alkynyl group having 2 to 6 carbon atoms and having 1 to 3 triple bonds. Specific examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl and the like. Preferred alkynyl groups include, for example, 1-propynyl, 1-butynyl and the like.

Examples of the substituent of the substituted alkynyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a formyl group, a substituted amino group, a hydroxyl group, an alkoxy group, a haloalkoxy group, and an acyl group. , Acyloxy, alkylthio, carboxy, optionally substituted rubamoyl, alkoxycarbonyl, —R ¹⁰ , —OR ¹⁰ , —SR ¹⁰ , —OCH ₂ R ¹⁰ , —S CH ₂ R ¹⁰ (R 1 ^G has the same meaning as described above.).

Further, an alkynyloxy group refers to an oxy group to which an alkynyl group is bonded. Examples of the “cycloalkyl group” include a cycloalkyl group having 3 to 7 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Further, a cycloalkyloxy group refers to an oxy group to which a cycloalkyl group is bonded.

Examples of the “cycloalkenyl group” include those having 5 to 7 carbon atoms, and specific examples include a cyclohexenyl group. Further, a cycloalkenyloxy group refers to an oxy group to which a cycloalkenyl group is bonded.

Examples of the substituent of the substituted cycloalkyl group and the substituted cycloalkenyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, Formyl group, alkyl group, haloalkyl group, substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, acyl group, acyloxy group, alkylthio group, carboxy group, carbamoyl group which may be substituted, alkoxycarbonyl group, etc. Are listed.

As the “acyl group”, for example, a compound represented by the formula —Q—R ¹¹ (wherein Q is one CO—, -CS

—, —SO— or —SO ₂ —, and R ¹¹ represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group. ) And the like. Specific examples of the acryl group include acetyl, propanol, 2-propanol, bivaloyl, trifluoroacetyl, benzoyl, nicotinyl, methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl. Preferred acetyl groups include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as an acetyl group. In addition, the term "acryloxy group" means an oxy group to which an acyl group is bonded.

Substituents Examples of the substituent in the rubamoyl group include an alkyl group which may be substituted with an aryl group or a heterocyclic group, and an aryl group, a heterocyclic group, and the like.A plurality of the same or different groups are independently substituted. May be. Specific examples of the substituting rubamoyl group include ethylcarbamoyl, dimethylcarbamoyl, phenylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl, and (3-pyridylmethyl) rubumoyl.

Examples of the substituent in the substituted sulfamoyl group include an alkyl group, an aryl group and a heterocyclic group, and the same or different plural substituents may be independently substituted. Specific examples of the substituted sulfamoyl group include ethylsulfamoyl, dimethylsulfamoyl, phenylsulfamoyl, and 2-pyridylsulfamoyl.

Examples of the substituent in the substituted amino group include an acyl group and an alkyl group, and a plurality of same or different ones may be independently substituted. Specific substituted amino groups include acetoamide, propionamide, butylamide, and 2-butylamine. Luamide, methylamino, 2-methylpropylamino, getylamino and the like.

The substituent in the substituted hydroxyamino group may be substituted with any of a nitrogen atom and an oxygen atom, and examples of the substituent include the same substituents as those in the substituted amino group.

Examples of the substituent in the substituted amidino group include an alkyl group, an aryl group and an arylalkyl group, and a plurality of the same or different groups may be independently replaced. Specific examples of the substituted amidino group include methylamidino, phenylamidino, dimethylamidino, ethylamidino, and benzylamidino. Examples of the substituent in the substituted guanidino group include, for example, an alkyl group, an aryl group and an arylalkyl group, and the same or different plural groups may be independently substituted. Specific substituted guanidino groups include methyldanidino, phenyldanidino, dimethyldanidino, ethyldanidino, benzylguanidino and the like.

Examples of the substituent in the substituted hydrazino group include an alkyl group, an aryl group and an arylalkyl group, and the same or different plural substituents may be independently substituted. Specific examples of the substituted hydrazino group include methylhydrazino, phenylhydrazino, dimethylhydrazino, ethylhydrazino, and benzylhydrazino groups.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. As used herein, R ³ is bonded to one of R] and R ² to form —R i—R ³ —or—R ² —R ³ —force \ formula: Five

17 '

In the formula, ring A or ring A ¹ is bonded to the carbon atom to which R ¹ or R ² is bonded, and X is bonded to the carbon atom to which R ³ is bonded. The tautomer of a pyrazole derivative means an isomer formed by changing a bonding position of a hydrogen atom bonded to a pyrazole ring. The present invention includes all tautomers of the pyrazol derivatives of the formula 1, and also includes a mixture of tautomers, even if not specified as tautomers. The pyrazolyl derivative can be a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acid addition salts and base addition salts. Examples of acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, etc., citrate, oxalate, acetate, and formic acid. Organic salts such as salts, propionates, benzoates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, and the like.Examples of base addition salts are sodium salts and potassium salts. And inorganic base salts such as calcium salt, magnesium salt and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. In addition, the solvate such as a hydrate thereof is also included in the biazole derivative or a pharmacologically acceptable salt thereof in the present invention. The pyrazole derivative of the formula 1 has a T cell proliferation induction inhibitory action.

The immunosuppressant of the present invention can treat, for example, the following diseases and the like.

1: Rheumatoid arthritis, systemic lupus erythematosus, diabetes, multiple sclerosis, Hashimoto Disease, hemolytic anemia, myasthenia gravis, scleroderma, ulcerative colitis, autoimmune diseases such as idiopathic thrombocytopenic purpura

2: Chronic bronchial asthma, atopic dermatitis, contact dermatitis, hay fever, allergic diseases such as allergic rhinitis

3: Graft-versus-host disease, rejection during organ transplantation

4: Acute infectious disease in which the activation of the immune system by enterotoxin is a causative factor

5: Atherosclerosis, Kawasaki disease

Its usefulness as an immunosuppressant is tested, for example, by testing the effects on the immune response elicited by superantigen, the effects on collagen arthritis, and the effects on hapten-induced ulcerative colitis model mice as shown in the test examples. Can be confirmed. The pyrazole derivative of the formula 1 can be produced, for example, by the following two production methods.

Manufacturing method 1

[Wherein, RR ² , R ³ and R ⁴ are as defined above.

One of R ¹² and R ¹³ represents an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group, and the other represents an optionally substituted aromatic heterocyclic group.

R ¹⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted An optionally substituted alkenyl group, an optionally substituted alkenyloxy group, an optionally substituted alkynyl group, an optionally substituted alkynyloxy group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, It represents an optionally substituted sorbamoyl group, an optionally substituted alkoxycarbonyl group, an acyl group, an acyloxy group, an optionally substituted aryl group or an optionally substituted amino group.

Also, R ^{1 4} is combined with R ^{1 2} to form one R ^{1 2} —R ^{1 4} —force formula:

(Rings A and X have the same meanings as described above.).

L represents a chlorine atom or a bromine atom. By halogenating the compound of formula 2, the compound of formula 3 can be produced. Examples of the halogenating agent to be used include bromine, chlorine, iodine chloride, sulfuryl chloride, copper compounds such as cuprous bromide, N-bromosuccinic acid imide, N-chlorosuccinic acid imide and the like. The amount of the halogenating agent to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to the compound of the formula 2. Examples of the solvent used for the halogenation reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; fatty acids such as acetic acid and propionic acid; and carbon disulfide. The reaction temperature is, for example, a temperature in the range of 0 ° C. to the boiling point of the solvent, and the reaction is usually performed for about 5 minutes to 20 hours.

By reacting the compound of formula 3 with the compound of formula 4 in the presence of a base, the compound of formula 5 can be produced. Examples of the base used in the reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, butyllithium, lithium pistrimethylsilylamide, and the like. Preferred bases are sodium methoxide, sodium Ethoxide and the like can be mentioned. Examples of the solvent used in the reaction include alcohols such as ethanol and methanol. And hydrocarbons such as hexane, cyclohexane, benzene and toluene, and ethers such as tetrahydrofuran (THF) and getyl ether, and preferably alcohols. Examples of the reaction temperature include a temperature in the range of 178 to 100 ° C.

By reacting the compound of the formula 5 with the compound of the formula 6, the pyrazole derivative of the formula 1 can be produced. As the amount of the compound of the formula 6, it is preferable to use an amount in the range of 1 to 1.2 equivalents to the compound of the formula 5. Examples of the solvent used in the reaction include alcohols such as ethanol and methanol, hydrocarbons such as hexane, cyclohexane, benzene, and toluene, and ethers such as THF and methyl ether, and the like. May include alcohols. The reaction can also be carried out without a solvent. In this reaction, the reaction proceeds even in the absence of an acid, but an acid may be added. Examples of the acid used include mineral acids such as hydrochloric acid and hydrobromic acid, organic acids such as toluenesulfonic acid, and Lewis acids such as boron trifluoride. Preferably, toluene sulfonic acid and boron trifluoride are used. No. The amount of the acid to be used is preferably 0.1 to 6 equivalents to the compound of the formula 5. Examples of the reaction temperature include a temperature in the range of room temperature to the boiling point of the solvent used. Manufacturing method 2

[Wherein, RR ² , R ³ , R ⁴ , R ¹² , R ¹³ and R ¹⁴ are as defined above. The compound of formula 8 can be produced by reacting the compound of formula 2 with the compound of formula 7 in the presence of a base. Examples of the base used in the reaction include lithium pistrimylsilyl amide, lithium disopropyl amide, potassium t-butoxide and the like. Is mentioned. The reaction temperature is in the range of −100 to 0 ° C., preferably in the range of 110 to 150 ° C. Examples of the solvent used in the reaction include ethers such as THF and dimethyl ether, and hydrocarbons such as hexane, cyclohexane, benzene, and toluene.

By reacting the compound of the formula 8 with the compound of the formula 6, the pyrazole derivative of the formula 1 can be produced. As the amount of the compound of the formula 6, it is preferable to use a range of 1 to 1.2 equivalents to the compound of the formula 8. Examples of the solvent used in the reaction include alcohols such as ethanol and methanol, hydrocarbons such as hexane, cyclohexane, benzene, and toluene, and ethers such as THF and methyl ether. Preferably, alcohols are used. The reaction can also be carried out without a solvent. In this reaction, the reaction can be performed under neutral conditions, but can also be performed in the presence of an acid or a base. When reacting in the presence of an acid, examples of the acid used include mineral acids such as hydrochloric acid and hydrobromic acid, organic acids such as tosylic acid, and Lewis acids such as boron trifluoride. It is preferable to use 0.1 to 6 equivalents of the acid based on the compound. When reacting in the presence of a base, examples of the base to be used include inorganic bases such as baking soda, sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine and pyridine. Therefore, it is desirable to use 1 to 6 equivalents of the base. Examples of the reaction temperature include a temperature in the range of room temperature to the boiling point of the solvent used.

The pyrazole derivatives of Formula 1 produced by Production Methods 1 and 2 are formed as a mixture of two isomers in which R ⁴ has different substitution positions. Only the isomer can be obtained with high purity.

In each of the above reactions, a highly reactive functional group such as an amino group or a hydroxyl group can be protected, deprotected, or converted with a suitable protecting group, if necessary. This protection, deprotection, or conversion of the protecting group can be performed by a general method, for example, Protective Groups in Organic synthesis, 2nd Edition, T. Greene and PGM Wuts, John Wiley and Sons, Inc. (1991). The substituent of the pyrazole derivative of the formula 1 may be subjected to various conversion reactions after the above reaction, if necessary. These conversion reactions include, for example, the conversion of sulfides to sulfoxides and sulfones by oxidation, the conversion of carbonyls to alcohols by reduction, the conversion of esters to alcohols or carboxyls by solvolysis, and the conversion of nitriles to carboxyls. Conversion, alkylation, acylation and the like. The pyrazole derivative of Formula 1 or a pharmaceutically acceptable salt thereof can be administered orally or parenterally (eg, intravenously, subcutaneously, or intramuscularly, topically, rectally, transdermally, or nasally). ) Can be administered. Formulations for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions, suspensions, and the like. Formulations for parenteral administration include, for example, aqueous injections Or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like. These preparations are prepared using conventionally known techniques, and can contain nontoxic and inert carriers or excipients usually used in the field of preparation. The dose varies depending on the patient's condition such as age and body weight, symptoms, and the administration route. Usually, the amount of the active ingredient of the compound of the present invention per adult (body weight 60 kg) is from 0.05 to 5000 mg, preferably from 0.05 to 5000 mg. With a daily dose of 0.5 to 500 mg, a continuous or intermittent dosing method, which can be administered once to three times a day, every day.

Preferred compounds are exemplified below,

Example

Examples and test examples are described below. These are only for explaining the present invention, and do not limit the present invention in any way. Example 1

3- (3-pyridyl) 1 5_ (4-fluorophenyl) 1-vinyl

Process 1:

Under a nitrogen atmosphere, 1.4 g of 4-fluoroacetophenone was dissolved in 50 ml of THF, 41 ml of a 1.0 M lithium pistrimethylsilylamide THF solution was added dropwise at -78 ° C, and the mixture was stirred for 1 hour. The reaction solution was heated to -10 ° C and stirred for 2 hours. Thereafter, to this reaction solution, a suspension of 1.81 g of nicotinyl chloride hydrochloride in 15 ml of THF at −78 ° C. was added dropwise over 3 hours with the addition of 1.03 g of triethylamine. After the reaction solution was returned to room temperature and stirred for 12 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography of the residue

(Silica gel: hexane ethyl acetate = 2 1) to give 2.24 g of the desired product as white crystals. Step 2:

3.8 g of 1- (3-pyridyl) -1,3- (4 fluorophenyl) 1,3-propanedione was dissolved in 200 ml of ethanol, 0.80 g of hydrazine monohydrate was added dropwise, and the mixture was heated under reflux for 6 hours. The reaction solution was returned to room temperature, saturated saline was added, and the mixture was extracted with black hole form. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel: hexane ethyl acetate = 11), and recrystallized from THF to which chloroform was added to obtain 2.2 g of the desired product.

! H-NMR (270MHz, CDC1 3) δ: ppm

6.84 (1H, s), 7.11-7.18 (2H, m), 7.34-7.39 (1H, m), 7.64-7.69 (2H, m), 8.60 (1H, dd, J = 4.6, 1.7Hz), 9.03 ( 1H, d, J = 1.7Hz) mp 202.0-203.0 ° C

Elemental analysis calculated value C: 70.28 H: 4.21 N: 17.56

Obtained value C: 69.95 H: 4.08 N: 17.45 Example 2

6 _Chloro-3- (3-pyridinole) — 4: H- [1,2-c] pyrazolol Process 1 CI

Process 1:

9.15 g of 5-cycloindanone was dissolved in 200 ml of acetic acid, and a solution of 3.11 ml of bromine in 20 ml of acetic acid was added dropwise over 1 hour. After stirring under nitrogen, the solvent was distilled off, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of methanol, and 7.77 ml of nicotinaldehyde was added. At 0 ° C, 27 ml of a 5N sodium methoxide nomethanol solution was added, and the mixture was stirred for 5 hours. The reaction solution is filtered, washed with methanol and water, and then filtered. Was dried to obtain 6.47 g of the desired product. Step 2:

Dissolve 6.47 g of 3 '-(3-pyridyl) spiro [5-chloroindan-1,2'-oxysilane]-1-one in 150 ml of ethanol, add 1.96 ml of hydrazine monohydrate, and heat to reflux for 1 hour did. Thereafter, 1.46 ml of boron trifluoride getyl ether complex was dropped, and the mixture was further heated under reflux for 4 hours. The reaction solution was returned to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was washed with toluene and water, and then recrystallized from THF to obtain 2.31 _g of the desired product.

_{^ -NMR (270MHz, CDC1 3)} δ ppm

3.87 (2H, s), 7.37-7.45 (2H, m), 7.55 (1H, s), 7.66 (1H, d, J = 8.1Hz), 8.03 (1H, d, J = 8.1Hz), 8.64-8.61 (1H, m), 9.01 (1H, s) mp 274.0-275.0 ° C

Elemental analysis Calculated value C: 67.30 H: 3.77 N: 15.70

Observed value C: 67.01 H: 3.89 N: 15.63

Example 3

6-Chloro-3- (3-pyridyl) 14 / -indeno [1,2-c] pyrazol hydrochloride

The compound obtained in Example 2 was dissolved in 200 ml of methanol, and 10 ml of a 4N hydrogen chloride dioxane solution was added dropwise. After stirring the reaction solution for 2 hours, the solvent was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 1.80 g of the desired product.

! H-NMR (270MHz, CDC1 3) δ ppm

3.98 (2H, s), 7.45 (1H, d, J = 7.9 Hz), 7.65-7.69 (1H, m), 7.69 (1H, s), 7.84-7.90 (1H, m), 8.56 (1H, d, J = 8.3Hz), 8.71-8.74 (1H, m),

9.13 (1H, s)

mp 300 ° C or more Examples 4 to 26

The following compounds were synthesized in the same manner as in Examples 1-3.

Example 4 Example 5

Example 6 Example 7

Example 8 Example 9

Example 1 0 Example 1 1

Example 1 2 Example 1 3

Example 15 Example 14

Example 16 Example 17

Example 1 8 Example 1 9

Example 2 0 Example 2 1

Example 2 2 Example 2 3

Example 2 4 Example 2 5

Example 26 Data such as physical property values of these compounds are shown below.

Test example 1

Effects on immune responses elicited by superantigens

It has been reported that stimulation of spleen cells with a superantigen, Staphylococcus aureus exotoxin (staphylococcal telotoxin B), causes lymphocyte proliferation (J. Immunology, 105: 1453, 1970). ). Using this cell blastogenesis reaction, the effect of pyrazole derivatives on the immune response elicited by super-antigen was examined.

Spleens were collected from BALB / c mice, and spleen cell suspensions were prepared according to a conventional method. So as to be a concentration of 10% © shea calf serum was added culture medium (RPMI1640; Nikken Biomedical Institute) in 1 X 1 0 ⁷ cell / ml splenocytes were prepared at a concentration cell suspension 25 ^ 1 to 0.12 g / 25 μl of staphylococcal enterotoxin B solution and 50 μl of a pyrazolyl derivative at a concentration of 4, 12, 37, 111, 333, {η} were added thereto, and the cells were cultured under 5% CO _{2 at} 37 ° C. for 72 hours. Five hours before the end of the culture, thymidine labeled with tritium was added, and after the end of the culture, the amount of tritiated thymidine incorporated into the cells was measured. From the obtained measured values, a concentration (IC _{50: 1} M) that inhibits cell growth by 50% was determined. The results are shown in the table below. Example 7 1 2 1 3 1 5 1 6

I C 50 0.67 0.06 0.15 0.95 0.55 1.35 0.05 1.10 0.29 Example 1 7 1 8 1 9 20 2 1 22 23 24

I c 50 0.38 0.24 0.19 1.01 1.28 1.73 0.71 0.56 Test example 2

Effects on collagen arthritis

Induction of collagen arthritis was performed according to the method of Trentham et al. (J. Exp. Med., 164, 857, 1997). Arthritis was induced by immunizing DBA / 1J mice with collagen II type II collagen. The birazol derivative of Example 6 was suspended in a 0.5% methylcellulose solution, and orally administered at a dose of 50 mg / kg for 7 weeks each day from the day of sensitization with the collagen II collagen. After the final administration, the degree of redness, edema and joint deformity was observed in each limb of the mouse, and a score of 0 to 4 shown below was assigned. The total score of the limb was defined as the arthritis score (mouse 1 The maximum score per individual is 16).

0: Normal

1: Mild (swelling of one joint only, redness)

2: Moderate (swelling and redness of 2 to 5 joints)

3: High (light swelling of the entire foot, redness)

4 _: Severe (strong swelling of the entire foot, redness of the joints) The results are shown in the table below.

Animal group Dose (mg / kg) Number of animals — Arthritis score (mean value SD) Control group 10 1 1.1 ± 3.3

Group of Example 6 50 9 4.6 ± 3.4 Test example 3

'Effect on induced ulcerative colitis model mice

Hapten-induced ulcerative colitis was induced according to the method of El son et al. (J. Immunology, 157, 2174, 1996). Rectal infusion of trinitrobenzene sulfonic acid into BALB / c mice caused chronic inflammatory bowel disease. The pyrazole derivative of Example 3 was suspended in a 0.5% methylcellulose solution, and orally administered at a dose of 50 mg / kg for two consecutive weeks from the day of sensitization of benzenesulfonic acid with trinitrate. During the test period, body weight and stool status were observed, and a score of 0 to 4 shown below was given according to the method of Murthy et al. (Digestive Disease and Science, 38, 1722, 1993).

0 Normal

1 Mild (loose stool is observed, weight loss is less than 5%)

2 Moderate (soft stool is observed, weight loss is 5% or more)

3 Altitude (diarrhea)

4 severe (with diarrhea and bleeding)

The results are shown in the table below.

Animal group Dose (mg / kg) Number of animals Maximum score (average value SD) Control group 10 3.5 ± 0.7 1

Group of Example 3 5 0 1 0 1 .5 ± 0.85 Industrial Applicability

The pyrazole derivative of the formula 1 or a pharmacologically acceptable salt thereof is useful as an immunosuppressant and can be used as a therapeutic agent for autoimmune diseases, allergic diseases and the like.

Claims

Scope of request Formula:

R ³ is bonded to one of R ¹ and R ² to form one R ¹ —R ³ — or one R ² —R ³ —

(Ring A represents a monocyclic or bicyclic aromatic hydrocarbon ring which may be substituted, or a monocyclic or bicyclic aromatic heterocyclic ring which may be substituted. X represents methylene, ethylene, trimethylene one CO- CH ₂ -, one OCH ₂ -, one SCH ₂ - one ^{_{N (R 5) CH 2 -}} , -CO-, oxygen atom, sulfur atom or - N (R ⁵⁾ -. represents an R ⁵ Represents a hydrogen atom or an alkyl group.) It may represent a divalent group represented by:

2. The immunosuppressant comprising the pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ is a hydrogen atom.

3. One of R ¹ and R ^{2 is} a phenyl group which may be substituted or a monocyclic aromatic heterocyclic group which may be substituted, and the other includes a monocyclic or bicyclic ring which may be substituted. 3. The pyrazole derivative according to claim 1 or 2, which is a nitrogen-aromatic heterocyclic group, and wherein ring A is an optionally substituted benzene ring or an optionally substituted monocyclic aromatic heterocycle, or a pharmacologically active substance thereof. An immunosuppressant comprising a salt acceptable to the subject.

4. One of R ¹ and R ² is phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, phenyl, furyl or a substituted group, and the other is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl or substituted R ³ represents a hydrogen atom, an alkyl group which may be substituted, a carboxy group, an alkoxycarbonyl group which may be substituted or an acyl group, or R ³ represents R ¹ combined with one of R ^2, one R ¹ - R ³ - or a R ² - R ³ - is of the formula:

(Has the same meaning and significance in claim 1. Ring A ¹ represents benzene ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, Chiofuen ring, a furan ring or a replacement has been the rings.) 3. The immunosuppressant comprising the pyrazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a divalent group represented by the formula:

5. X is methylene, ethylene, trimethylene, one CO—CH ₂ —, one OCH 2 —, one SCH ₂ —, —N (R ⁵ ) CH ₂ — (R ⁵ is as defined in claim 1. Or an immunosuppressant comprising the pyrazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

6. Expression

R ⁶ , R ⁷ and R ⁸ are as defined in (1) or (2) below.

(1) 1¾ ⁶ and 1 ^ ⁷ both represent hydrogen atoms.

R ⁸ represents 3- or 4-pyridyl which may be substituted.

(2) R ⁶ and R ⁷ are connected together, and RR is OCH

₂ — or one SCH ₂ —.

R ⁸ represents 3-pyridyl which may be substituted. ]

Or a tautomer thereof, or a pharmacologically acceptable salt thereof.

7. Formula:

[Wherein, Y, R ⁶ and R ⁷ have the same meaning as in claim 6].

7. The pyrazole derivative according to claim 6, which is represented by the formula: or a tautomer thereof, or a pharmacologically acceptable salt thereof.

8. The pyrazole derivative or the tautomer thereof according to claim 7, wherein Z ¹ and Z ² are both hydrogen atoms, or a pharmacologically acceptable salt thereof.

9. The pyrazole derivative according to claim 6, or a tautomer thereof, or a pharmacologically acceptable salt thereof.

■ 3- (3-pyridyl) -1-5- (4-chlorophenyl) -pyrazole

• 6-Chloro-3- (3-pyridyl) _4 / -indeno [1,2-c] birazol

• 7 _ 1,4-dihydro-3- (3-pyridyl) -12-naphtho [1,2-c] pyrazol

10. A medicament comprising the pyrazole derivative according to any one of claims 6 to 9, or a tautomer thereof, or a pharmacologically acceptable salt thereof.

1 1. An immunosuppressant comprising the pyrazolyl derivative according to claim 6 or a tautomer thereof, or a pharmacologically acceptable salt thereof.

12. The immunosuppressant according to any one of claims 1 to 5 or 11, which is an inhibitor of T cell proliferation induction.

1 3. The immunosuppressive agent according to any one of claims 1 to 5 or 11, which is a therapeutic agent for an autoimmune disease.

1 4. The immunosuppressant according to any one of claims 1 to 5 or 11, which is a therapeutic agent for rheumatoid arthritis.

1 5. The immunosuppressant according to any one of claims 1 to 5 or 11, which is a therapeutic agent for multiple sclerosis.

1 6. The immunosuppressive agent according to any one of claims 1 to 5 or 11, which is a therapeutic agent for ulcerative colitis.