JPH11240832A - Amide or amine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine useful for prevention or treatment of various inflammatory diseases, allergic diseases, autoimmune diseases, damages to tissues, proliferative diseases, or the like by including a specific amide or an amine derivative. SOLUTION: This medicine comprises an amide or amine derivative of the formula (D is an aryl, or the like, which may have a substituent group; Y is a bond, or the like; B is phenylene, or the like, which have a substituent group; X is a group of the formula NR<1> -CR<2> R<3> , or the like; R<1> is H, or the like; R<2> and R<3> are H, or the like; A is an aryl, or the like, which has a substituent group) or its pharmaceutically permissible salt e.g. 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]thiazole-5-carbo xyanilide}. The medicine is preferably administered once or in 2-4 portions at a daily dose of about 0.001-10 mg/kg per body weight usually in the case of oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicament, particularly to a calcium release-dependent calcium channel inhibitor.

[0002]

2. Description of the Related Art Since ancient times, cells in various cell activations
Calcium ion (Ca²⁺Importance of)
It has been known. Intracellular Ca in inflammatory cells²⁺Is heavy
It functions as a key regulator. However,
Ca²⁺Nifedipine known as an antagonist
Potential-dependent Ca such as²⁺Channel (hereinafter abbreviated as VOCC)
Inhibitors have an inhibitory effect on inflammatory cell activation
In addition, inflammatory cells have Ca other than VOCC²⁺Inflow mechanism exists
Was suggested to be present. Hotth et al.
In lymphocytes, Ca²⁺Triggered by store depletion
Ca²⁺Extracellular Ca²⁺Inflow mechanism
Calcium release-dependent calcium channels (Ca²⁺
 release activated Ca ²⁺ ch
annel; hereinafter abbreviated as CRACC;
Tore-dependent calcium channel (store-dep
end Ca²⁺ channel)
Mast cells and lymphocytes
Position insensitive (Pfluge
rs Arch. , 430, p315-22 (199).
5)). CRACC is a mast cell, lymphocyte, astrosa
(J. Biol. Chem., 270, p29-3)
2 (1995)) and almost all inflammatory cells
Known to produce cytokines and lipids
I understand that it is deeply involved in mediator release etc.
(J. Immunol., 155, p285-96)
(1995) and Br. J. Pharmacol. ,
144, p598-601 (1995)).

Recently, one of the mechanisms of action of tenidap, a therapeutic agent for rheumatoid arthritis, is CR.
The fact that ACC inhibitory activity was found (C
cell Calcium, 14, p1-16 (199
3)), CRACC inhibitors may have clinical utility for inflammatory diseases such as rheumatoid arthritis. Also, CR
ACC is used for endothelial cells (Am. J. Physiol., 2).
69, C733-8 (1995)) and epithelial cells (J.
Biol. Chem. , 270, p169-75 (19
95)). It has been reported that continuous calcium influx is involved when endothelial cells undergo radical damage (Am. J. Physio).
l. , 261, C889-896 (1991)), CR
It has been suggested that ACC inhibitors have a protective effect against tissue damage involving endothelial cells.

[0004] Furthermore, the fact that inhibition of calcium influx has an inhibitory effect on cell proliferation and that interleukin 2 (IL-
2) has also been reported to suppress the production (Br.
J. Pharmacol. , 133, p861-8
(1994)), CRACC inhibitors are useful as prophylactic / therapeutic agents for proliferative or progressive diseases such as malignant tumors and autoimmune diseases, and also as inhibitors for rejection during transplantation. On the other hand, excitable cells typified by smooth muscle cells and nerve cells are known to have intracellular calcium regulation by VOCC and do not involve CRACC.
Therefore, calcium channel inhibitors having CRACC selectivity for VOCC do not show an unfavorable effect on vascular smooth muscle and central nervous system, various inflammatory diseases, allergic diseases, autoimmune diseases, tissue damage, proliferative diseases It is expected to be a drug useful for the prevention or treatment of the above.

[0005] In recent years, several compounds having a CRACC inhibitory action have been reported.
No. 249 discloses a cycloalkyl-piperazinylethanol derivative, and WO 94/00435 discloses 2-cycloalkyl-piperazinylethanol derivative.
(3,4-Dihydro-1-isoquinolyl) acetamide derivatives are disclosed. In addition, the literature (J. Pharm.
Exp. Ther. , 257, p967-971 (19)
91)) discloses that a compound represented by the following formula has a CRACC inhibitory action.

Embedded image On the other hand, German Publication No. 252024 discloses 5- (heterocycloylaminophenyl)-which exhibits an anti-inflammatory effect.
1-phenylpyrazole derivatives are disclosed. However, there is no disclosure or suggestion about the CRACC inhibitory action and the IL-2 production inhibitory action.

WO95 / 18097 discloses an anthranilic acid derivative represented by the following formula having a cyclic GMP phosphodiesterase inhibitory action.
Wherein R _{1 to} R ₄ are H, a halogen atom,..., Optionally substituted pyrazolyl,...; N is 0 to 6, W is N or CH, Y is O or S,. Is indicated (refer to the gazette for details).

Embedded image

Japanese Patent Application Laid-Open No. 9-59236 discloses a method for preventing and preventing rheumatic, allergic and other inflammatory diseases.
Disclosed are R ¹ , R ² -disubstituted benzamide derivatives of the following formula useful for therapy. In the formula, R ¹ is a substituted or unsubstituted aromatic heterocyclic group, ..., R ² is a halogen atom, a nitro group, -NR ⁵ R ⁶ , ..., A is -C (= Z)
NR ³ R ⁴ or —NR ⁴ C (＝ Z) R ³ and R ³ represent a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, etc. Gazette). However, there is no disclosure about the CRACC inhibitory action and the IL-2 production inhibitory action.

Embedded image

[0008]

PROBLEM TO BE SOLVED BY THE INVENTION An effective CRACC inhibitor useful for the prevention or treatment of various inflammatory diseases, allergic diseases, tissue damage, proliferative diseases, etc., especially VO
There is a long-awaited need to create a drug having high CRACC selectivity for CC.

[0009]

Means for Solving the Problems The present inventors have developed an excellent C
As a result of earnestly searching for a compound having an RACC inhibitory action, it was found that an amide or amine derivative having a structure completely different from that of a compound in which a CRACC inhibitory action was conventionally reported has an excellent CRACC inhibitory action. Furthermore, these compounds were found to be compounds having high CRACC selectivity for VOCC, and the present invention was completed.

That is, the present invention is a calcium release-dependent calcium channel inhibitor comprising an amide or amine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. In the present specification, lower alkyl is abbreviated as Alk, and halogen atom is abbreviated as Hal.

Embedded image (The symbols in the formula represent the following meanings: D: an aryl which may have a substituent or a monocyclic or bicyclic triaryl group which may have a substituent, Y: a bond, Methylene, O, S, CO, CS, SO ₂ or SO, B: phenylene which may have a substituent, divalent group of a nitrogen-containing saturated ring or monocyclic aromatic hetero which may be substituted by Alk A ring divalent group, or D, Y and B are integrated to form

Embedded image (Wherein, Y is as defined above, B ² and D ² denotes a benzene ring which may have a substituent.) To form a group represented by, X: wherein -NR ¹ -CR ² R ^3- , -CR ² R ³ -NR ¹ -,-
A group represented by NR ¹ -SO ₂ -or -SO ₂ -NR ^1- , R ¹ : -H, -OH, -Alk, -O-Alk or -C
O-Alk, R ² , R ³ : same or different, -H or -Alk,
Or R ² and R ^{3 taken} together as ＯO or ＳS, A: aryl optionally having substituent (s); monocyclic or bi- or tricyclic heteroaryl optionally having substituent (s); A cycloalkyl optionally having a substituent; a nitrogen-containing saturated ring optionally having a substituent; a lower alkynyl optionally having a substituent; a lower alkenyl optionally having a substituent; Or Alk which may have a substituent, or X and A are integrated,

Embedded image (Wherein A ² may have a substituent, 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl A nitrogen-containing saturated heterocyclic ring selected from the group consisting of the following: The same applies hereinafter. )

[0011] The calcium release-dependent calcium channel inhibitor of the present application is based on a good CRACC inhibitory action,
It has an excellent IL-2 production inhibitory action and is useful as an IL-2 production inhibitor. In addition, CRACC and / or IL
-2 is useful as a prophylactic or therapeutic agent for allergic, inflammatory or autoimmune diseases, particularly a prophylactic or therapeutic agent for bronchial asthma or rheumatoid arthritis.
The medicament of the present invention also includes the above-mentioned IL-2 production inhibitor involving a calcium release-dependent calcium channel, an agent for preventing or treating allergic, inflammatory or autoimmune diseases, and an agent for preventing or treating bronchial asthma or rheumatoid arthritis. Include.

The general formula (I) is represented by the following (I)
A) the novel compounds defined in (A) and (IB), and (I)
The present invention includes the novel medicaments defined in A ′) and (IB ′), and the present application covers the invention relating to these novel compounds and novel medicaments. (IA): A group in which D is unsubstituted or substituted with a specific group.
A novel compound having a structural feature in that it is lazolyl In the aforementioned general formula (I), D represents -Alk, -lower alkenyl, -lower alkynyl, -halogeno lower alkyl, -Alk-cycloalkyl, -Alk-O -Al
k, -cycloalkyl, -O-Alk, -COOH,-
Pyrazolyl which may have 1 to 3 substituents selected from the group consisting of COO-Alk and -Hal, Y is methylene or a bond, B is unsubstituted phenylene, nitrogen-containing saturated A divalent group of a ring or a divalent group of a monocyclic aromatic heterocyclic ring which may be substituted by Alk, wherein X is
Wherein ^{-NR 1 -CR 2 R 3 -,} - CR 2 R 3 -NR 1 -, - NR
^{A group represented by 1} -SO ₂ -or -SO ₂ -NR ^1- ,
R ¹ is -H, -OH, -Alk, -O- Alk or -C
O-Alk, wherein R ² and R ³ are the same or different,
-H or -Alk, or R ² and R ³ are combined to form = O
Or ＳS, wherein A is an aryl which may have a substituent, a monocyclic ring which may have a substituent or
Cyclic fused heteroaryl, cycloalkyl optionally having substituent (s), nitrogen-containing saturated ring optionally having substituent (s), lower alkenyl optionally having substituent (s), having substituent (s) Or lower alkynyl or Alk which may have a substituent, or X and A are integrated to form

Embedded image (Wherein A ² may have a substituent, 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl Represents a nitrogen-containing saturated heterocyclic ring selected from the group consisting of: (1) wherein D is 3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl, n Is 0, B is 1,4-phenylene and X is NHCO, A is 4-methyl-1,2,3-thiadiazole-5
A group other than -yl, (2) D is 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl, n is 0,
When B is thiophen-2,5-diyl and X is CONH, A represents a group other than 4-chlorophenyl, (3) D represents 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl, When n is 0, B is thiophen-2,5-diyl, and X is CONH, A is a group other than benzyl, and (4) D is 4-ethoxycarbonyl-5-trifluoromethyl-1H-pyrazole-1. -Il, n is 0, B
Is 1,4-phenylene and Y is NHCO, A represents a group other than trichlorovinyl, and (5) D represents 1H-
Pyrazole-1-yl, n is 0, B is 1,4-phenylene, and when Y is NHCO, A represents a group other than 2-ethoxyvinyl, or a novel amide or amine derivative or a pharmaceutically acceptable derivative thereof. Acceptable salt.

(IB): D is unsubstituted or a specific group
A new structure with structural features in that it is a substituted phenyl
Reference compound In the above general formula (I), D is -Hal, -Al
k, -O-Alk, -OH, have 1 to 4 substituents selected from the group consisting of -NO ₂ and -CN are also phenyl, Y is, O, S, CO or CS And B is -Hal, -Alk, -O-Alk, -OH,
-NO _2, or 1 to 3 phenylene which may have a substituent group selected from the group consisting of -CN and -NH-CO-Alk, or, D, Y and B are formulas come together

Embedded image (Wherein Y is CO, B ² and D ² are each -Hal,-
Alk, -O-Alk, -OH, -NH-CO-Al
k, —NO ₂ and —CN, which means a benzene ring which may have 1 to 3 substituents selected from the group consisting of: −NR ¹
-CR ² R ³ -or -CR ² R ³ -NR ^1- , wherein R ¹ is -H, -OH, -Alk, or -OA.
lk, R ² and R ³ are the same or different, and —H or —Alk, or R ² and R ³ are integrated to form = O or =
S and A is -Hal, -Alk, -O-Alk,-
_{O-CO-Alk, -NH 2} , -NHAlk, -N (A
_{lk) 2, -NHCO-Alk,} -OH, -NO 2 and -
Phenyl optionally having 1 to 4 substituents selected from the group consisting of CN, or -Hal, -Alk,-
O-Alk, -O-CO- Alk, -NH 2, -NHA
lk, -N (Alk) ₂ , -NHCO-Alk, -O
H, have 1 to 3 substituents selected from the group consisting of -NO ₂ and -CN are also good monocyclic or 2-3 heteroaryl, or a novel amide or amine derivative Pharmaceutically acceptable salts (excluding the compounds shown in Table 2 below).

[0014]

[Table 2] (In the table, Co is an abbreviation of the compound, the number before each substituent indicates the substitution position, and when there are a plurality of substituents, for example, 2,5-dichloro is indicated as “2,5-Cl” The same applies hereinafter.)

(IA ′): D is Unsubstituted or Specific Group
Having a structural feature in that it is a pyrazolyl substituted with
In the above general formula (I), D represents -Alk, -lower alkenyl, -lower alkynyl, -halogeno lower alkyl, -Alk-cycloalkyl, -Alk-O-Al
k, -cycloalkyl, -O-Alk, -COOH,-
Pyrazolyl which may have 1 to 3 substituents selected from the group consisting of COO-Alk and -Hal, Y is methylene or a bond, B is unsubstituted phenylene, nitrogen-containing saturated A divalent group of a ring or a divalent group of a monocyclic aromatic heterocyclic ring which may be substituted by Alk, wherein X is
Wherein ^{-NR 1 -CR 2 R 3 -,} - CR 2 R 3 -NR 1 -, - NR
¹ -SO _2- or -SO ₂ -NR ^1- , wherein R ¹ is -H, -OH, -Alk, -O-Alk or -CO-Alk, and R ² , R ³ Are the same or different, -H or -Alk, or R ² and R ³ are integrally ＝ O or ＳS, and A is an aryl which may have a substituent, Monocyclic or bicyclic tricyclic fused heteroaryl which may be substituted, cycloalkyl which may have a substituent, nitrogen-containing saturated ring which may have a substituent, and which may have a substituent A good lower alkenyl, a lower alkynyl which may have a substituent, or an Alk which may have a substituent, or X and A are combined to form a group represented by the formula

Embedded image (Wherein A ² may have a substituent, 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl A amide or amine derivative or a pharmaceutically acceptable salt thereof, which forms a group represented by the following formula:

(IB ′): D is unsubstituted or specific group
Has structural features in that it is a phenyl substituted with
Novel medicament A medicament characterized by containing the novel compound defined in the above (IB).

[0017] The definition of the novel drug of the above (IA ') includes:
The following known compounds are included. (1) D: 3,5-bis (trifluoromethyl) -1H-
Pyrazol-1-yl, n: 0, B: 1,4-phenylene, Y: NHCO, and A: 4-methyl-1,2,3-
Compounds which are thiadiazol-5-yl (hereinafter referred to as Compound A
(2) D: 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl, n: 0, B: thiophene-2,5-diyl, Y: CONH, and A: 4
-A compound that is chlorophenyl (hereinafter abbreviated as compound B), (3) D: 1-methyl-3-trifluoromethyl-
1H-pyrazol-5-yl, n: 0, B: thiophen-2,5-diyl, Y: CONH, and A: benzyl (hereinafter abbreviated as compound C), (4) D: 4-
Ethoxycarbonyl-5-trifluoromethyl-1H-
A compound (hereinafter abbreviated as compound D) which is pyrazol-1-yl, n: 0, B: 1,4-phenylene, Y: NHCO, and A: trichlorovinyl; and (5) D: 1H-
A compound which is pyrazol-1-yl, n: 0, B: 1,4-phenylene, Y: NHCO, and A: 2-ethoxyvinyl (hereinafter abbreviated as compound E). However, Compounds A to D are available from MAYBRIDGE Reagent Catalog (UK, Cornwall, August 1995).
Monthly issue) to SEW04225, KM02940, KM0
3000 and GK02421,
As for its use, there is no report on other uses as well as pharmaceutical uses. Compound E is disclosed in
No. 82 discloses it as a raw material for producing pharmaceuticals, but there is no description about its pharmacological action. Therefore, medicaments containing these known compounds are novel.

In the definition of (IB), the compounds shown in Table 2 are known compounds, and compounds F1 to F21 are
Soviet Patent Nos. 807609, 1327487 and 1026420, and Med Parazi
tol Parazit Bolezni, (6) 41
−42 (1995), ibid, (4) 43-46 (1
991), and Biofizika, 26 (6) P99.
5-998 (1981) discloses a compound having an antiparasitic effect. Compounds J1 and J2 are MAN-MA
DE TEXTILES IN INDIA 287
(1988) as a compound having an ultraviolet absorbing effect. Compounds K1-K7 were obtained from Farmaco
Ed. Sci. 43 (6) 517-522 (1988)
Are described as compounds having an antifungal effect.
Compounds G1-2 are CONTACT-SERVICE
Company (Moscow Region, R
ussia), compound H1 is from Labo Test (F
Reiberg, Germany). However, there is no disclosure that these known compounds have a CRACC inhibitory action.

In the present specification, "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Preferred groups include “lower alkyl (A
lk) "include methyl, ethyl, propyl and the like, and" lower alkenyl "includes vinyl, 1-propenyl, 1,
2-dimethyl-1-propenyl and the like and "lower alkynyl" include ethynyl and the like. "Halogen atom (Hal)" includes I, Br, F and Cl.
“Halogeno lower alkyl” is Alk substituted with one or more Hal, particularly preferably trifluoromethyl. “Aryl” includes C 6 to C 1
There are four aryl groups, preferably phenyl and naphthyl. “Cycloalkyl” includes 3 carbon atoms
-8 cycloalkyls, preferably cyclopropyl and cyclohexyl. The “divalent group of a monocyclic aromatic heterocycle” is a divalent group of a 5- or 6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from N, S and O atoms. And particularly preferably furan-
2,5-diyl, thiophen-2,5-diyl, thiazol-2,5-diyl, pyridine-2,5-diyl and pyrimidine-2,5-diyl. "Phenylene" is preferably 1,4-phenylene.

The "monocyclic or bicyclic triaryl" is a 5- to 6-membered monocyclic or bicyclic tricyclic fused ring containing 1 to 5 O, S or N atoms as hetero atoms. Yes, preferably thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, isoquinolyl, quinolyl, quinoxanyl,
Phthalazinyl, imidazopyridyl, quinazolinyl and cinnolinyl. The “nitrogen-containing saturated ring” is a 5- or 6-membered nitrogen-containing saturated heterocyclic ring containing 1 to 2 N atoms as ring atoms and further containing 1 O or S atom, preferably Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl. The “divalent group of a nitrogen-containing saturated ring” is preferably piperidine-1,4-diyl. Y
Is "bond", D and B are directly bonded. The substituent of the "aryl which may have a substituent (s)" of D is preferably -Alk, -lower alkenyl, -lower alkynyl, -halogeno lower alkyl, -Alk-cycloalkyl, -Alk-O- Alk, - cycloalkyl, -O-Alk, -Hal, -OH , -NO 2 and -
CN, and a substituent selected from these groups is 1 to 4
You may have one.

Examples of the substituent of the “monocyclic or bicyclic or tricyclic heteroaryl optionally having substituent (s)” D include:
Preferably, -Alk, -lower alkenyl, -lower alkynyl, -halogeno lower alkyl, -Alk-cycloalkyl, -Alk-O-Alk, -cycloalkyl,-
O-Alk, -COOH, -COO-Alk, -Ha
l, -OH, an -NO ₂ and -CN, or may have 1 to 3 substituents selected from these groups. A "aryl optionally having substituent (s)", "monocyclic or bi- or tricyclic heteroaryl optionally having substituent (s)", "cycloalkyl optionally having substituent (s)" ,
And the substituent of the "nitrogen-containing saturated ring which may have a substituent", preferably, -Alk, - lower alkenyl, - lower alkynyl, -Hal, -NH _2, -NH
(Alk), - N (Alk ) 2, -NO 2, -CN, -O
H, -O-Alk, -O-CO-Alk, -SH, -S
-Alk, -COOH, -COO-Alk, -CO-A
_{lk, -CHO, -CONH 2, -CONH} (Al
k), - CON (Alk) 2, -SO-Alk, -SO 2
—Alk, —SO ₂ NH ₂ , —SO ₂ NH— (Alk),
_{-SO 2 N (Alk) 2,} - aryl, - cycloalkyl, -O-Alk-O -, - halogeno-lower alkyl, -
_{Alk-NH 2, -Alk-NH} (Alk), - Alk
-N (Alk) ₂ , -Alk-OH, -Alk-OA
lk, -Alk-SH, -Alk-S-Alk, -Al
k-COOH, -Alk-COO-Alk, -Alk-
CO-Alk, -Alk-CHO, -Alk-CONH
₂ , -Alk-CONH (Alk), -Alk-CON
(Alk) ₂ , -Alk-SO-Alk, -Alk-S
O ₂ -Alk, -Alk-SO ₂ NH ₂ , -Alk-SO ₂
NH (Alk), - Alk- SO 2 N (Alk) 2, -A
lk-aryl and -Alk-cycloalkyl.

Further, the substitution of “lower alkynyl optionally having substituent (s)”, “lower alkenyl optionally having substituent (s)”, and “Alk optionally having substituent (s)” of A the group, preferably, -Hal, -NH _2, -
NH (Alk), - N ( Alk) 2, -NO 2, -CN,
-OH, -O-Alk, -O-CO-Alk, -SH,
-S-Alk, -COOH, -COO-Alk, -CO
_{-Alk, -CHO, -CONH 2, -CONH} (Al
k), - CON (Alk) 2, -SO-Alk, -SO 2
—Alk, —SO ₂ NH ₂ , —SO ₂ NH— (Alk),
—SO ₂ N (Alk) ₂ , and the above-mentioned “optionally substituted aryl”, “optionally substituted monocyclic or bicyclic to tricyclic fused heteroaryl”, “ "Cycloalkyl optionally having substituent (s)" and "nitrogen-containing saturated ring optionally having substituent (s)".

In the general formula (I) of the present invention, (1) D
Is optionally substituted phenyl, an optionally substituted naphthyl group, or an optionally substituted thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,
(2) X which is a 5-membered heteroaryl selected from thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl and thiadiazolyl
Is -CONH- or -NHCO-, (3) D
Is an optionally substituted phenyl or an optionally substituted naphthyl group, and Y is O, S, CO, CS
Or SO _2, or (4) D is thienyl optionally substituted, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, 5-membered heteroaryl selected from triazolyl and thiadiazolyl And a calcium release-dependent calcium channel inhibitor comprising an amide or amine derivative or a pharmaceutically acceptable salt thereof, wherein Y is a single bond or methylene. Particularly preferred is a calcium release-dependent calcium channel inhibitor comprising the novel drug defined in (IA ') or (IB'). Preferred compounds defined in (IA) or (IA ') according to the present invention include pyrazolyl in which the pyrazolyl group of D is substituted by at least one trifluoromethyl group, especially 1H-
Pyrazol-5-yl or 1H-pyrazol-1-
A pyrazole derivative or a pharmaceutically acceptable salt thereof.

Other preferred compounds defined in (IA) or (IA ') include: 1) B is phenylene; piperidine-1,4-diyl;
Or a monocyclic aromatic selected from the group consisting of thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, pyridine, pyrazine, pyridazine and pyrimidine, which may be substituted with Alk. A heterovalent divalent group, wherein X is -NH-CO-, -NH
_{-CH 2 -, - N (OH} ) -CO -, - N (Alk) -
CO -, - CO-NH - , - CH 2 -NH -, - CO-
N (OH) -, - CO -N (Alk) -, - SO 2 NH
-Or -NHSO _2- , wherein A is aryl optionally having one or more group F substituents; thienyl, furanyl optionally having one or more group F substituents , Pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, isoquinolyl, quinolyl, quinoxanyl,
Monocyclic or bicyclic tricyclic fused heteroaryl selected from the group consisting of phthalazinyl, imidazopyridyl, quinazolinyl and cinnolinyl; cycloalkyl; pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl optionally substituted by one or more Alk A nitrogen-containing saturated ring selected from the group consisting of, piperazinyl and morpholinyl; a lower alkynyl optionally substituted by one or more Hal; a lower alkenyl optionally substituted by one or more Hal; a of which may be substituted by Hal Alk, F group, -Alk, - lower alkenyl, lower alkynyl, -Hal, -NH _2, -N
H (Alk), - N ( Alk) 2, -NO 2, -CN, -
OH, -O-Alk, -O-CO-Alk, -SH,-
S-Alk, -COOH, -COO-Alk, -CO-
_{Alk, -CHO, -CONH 2, -CONH} (Al
k), - CON (Alk) 2, -SO-Alk, -SO 2
A group consisting of —Alk, —SO ₂ NH ₂ , —SO ₂ NH— (Alk), and —SO ₂ N (Alk) ₂ , or X
And A are united, and the expression

Embedded image 2) D is -Alk, -halogeno lower alkyl, -CO
Pyrazolyl optionally having 1 to 3 substituents selected from the group consisting of OH and -COO-Alk;
B may be substituted with phenylene or Alk,
2 of a monocyclic aromatic heterocycle selected from the group consisting of thiophene, furan, thiazole, pyridine and pyrimidine
X is -NH-CO-, -N (OH) -C
O -, - CO-NH - , - CH 2 -NH- or -CO-
N (Alk)-, and A is -Alk, -Ha
_{l, -NH 2, -N (Alk} ) 2, -NO 2, -CN, -
Phenyl optionally having one or more substituents selected from the group consisting of OH, -O-Alk and -COO-Alk; thienyl, pyrrolyl, imidazolyl, thiazolyl, optionally substituted with Alk; Oxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl,
3) X is a monocyclic or bicyclic fused heteroaryl selected from the group consisting of pyrazinyl and isoquinolyl; cycloalkyl; lower alkenyl optionally substituted with one or more Hal; or Alk; Is -NH-CO- or -CO-NH-,
It is a pyrazole derivative or a pharmaceutically acceptable salt thereof. Particularly preferably, D is 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl;
Is phenyl optionally substituted with Hal, or D is 3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl, and A may be substituted with Alk; A pyrazole derivative or a pharmaceutically acceptable salt thereof, which is a monocyclic heteroaryl selected from the group consisting of thiazolyl, thiadiazolyl, thienyl and pyridyl.

Preferred compounds defined in the above (IB) or (IB ') are those wherein X is of the formula -NHCO- or-
CONH-, wherein A is -Hal, -Al
k, -halogeno lower alkyl, -O-Alk, -OC
_{O-Alk, -NH 2, -NHAlk} , -N (Al
_{k) 2, -NHCO-Alk,} -OH, -NO 2 and -C
N is a phenyl derivative optionally having 1 to 4 substituents selected from the group consisting of N, or a pharmaceutically acceptable salt thereof. Depending on the type of the substituent of the present invention, a geometric isomer or a tautomer may exist, but the present invention includes a separated form or a mixture of these isomers. Further, the compound of the present invention may have an asymmetric carbon atom.
The (S) -form optical isomer may exist. The present invention includes all the mixtures and isolated forms of these optical isomers.

The compound (I) of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent.
Such salts are pharmaceutically acceptable salts, preferably inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, and oxalic acid. Acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, acid addition salts with organic acids such as glutamic acid, sodium, potassium, Examples include inorganic bases containing metals such as magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts. Furthermore, the present invention also includes various hydrates, solvates, and polymorphs of the compound (I) of the present invention and salts thereof.

(Preparation Method) The compound of the present invention and its pharmaceutically acceptable salts can be prepared by applying various known synthetic methods by utilizing the characteristics based on the basic skeleton or the type of the substituent. Can be. At that time, depending on the type of the functional group, it is effective in the production technology to replace the functional group with an appropriate protecting group at the stage of a raw material or an intermediate, that is, a group that can be easily converted to the functional group. There is. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include a hydroxyl group and a carboxyl group, and examples of such a protective group include "Protective Groups in Organic S" by Green and Wuts.
synthesis "and the protecting groups described in the second edition, and these may be appropriately used depending on the reaction conditions.

Hereinafter, a typical method for producing the compound of the present invention will be described. First manufacturing method

Embedded image As shown in the above reaction formula, this production method has the general formula (II)
Or an amine derivative represented by (V) and a general formula (III)
Alternatively, this is a method for obtaining the compound (I-1) or (I-2) of the present invention by subjecting the carboxylic acid derivative represented by (IV) to an amidation reaction.

The carboxylic acid derivative (III) or (IV) that can be used in the first production method is a free carboxylic acid or a reactive derivative thereof. Examples of the reactive derivative include acid chloride and acid bromide. Acid halide; acid azide; active ester that can be prepared using methanol, ethanol, benzyl alcohol, optionally substituted phenol, 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc .; symmetric acid anhydride; Examples thereof include a mixed acid anhydride with toluenesulfonic acid and the like. These reactive derivatives can be used commercially or can be produced by a conventional method. The amidation reaction can be performed by a conventional method. When a free carboxylic acid is used, N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (W
Condensing agents such as SCD), or 1,1'-carbonyldiimidazole, N, N'-disuccinimidyl carbonate, diphenylphosphoryl azide, phosphorus oxychloride, phosphorus trichloride, triphenylphosphine / N-bromosuccinimide It is preferable to use a carboxylic acid activator such as

The reaction is carried out by using equimolar amounts of the amine derivative represented by the general formula (II) or (V) and the carboxylic acid derivative represented by the general formula (III) or (IV) or an excess amount thereof. Organic solvents inert to, for example, pyridine, tetrahydrofuran (THF), dioxane, ether,
The reaction is performed in a solvent such as benzene, toluene, dichloromethane, 1,2-dichloroethane (DCE), chloroform, N, N-dimethylformamide (DMF), ethyl acetate, and acetonitrile. The reaction temperature is appropriately selected depending on the type of the reaction derivative. Depending on the type of reactive derivative, triethylamine, pyridine, picoline, N, N-
Addition of a base such as dimethylaniline, potassium carbonate, sodium hydroxide or the like may be advantageous in promoting the reaction. Pyridine can also serve as a solvent.

Second manufacturing method

Embedded image (In the formula, Ra and Rb each represent H or Alk.) In this production method, a carbon atom adjacent to a ketone of the compound represented by the general formula (VI) is trifluoroacetylated, and then reacted with a hydrazine derivative. This is a method for obtaining the compound (I-3) of the present invention by cyclization. The trifluoroacetylation in the first step is carried out in the presence of a base such as sodium methoxide, sodium ethoxide, alkali metal hexamethyldisilazide, alkali metal hydride, alkyllithium, triethylamine, etc. Trifluoroacetate, trifluoroacetic anhydride, etc.) with methanol, ethanol, 1,
3-dimethylimidazolidin-2-one (DMI), T
The reaction can be carried out in a solvent such as HF and DMF at -78 ° C under heating to reflux. In the cyclization reaction in the second step, the compound obtained in the first step and the hydrazine derivative are
In a solvent such as methanol or ethanol in the presence or absence of an acid such as acetic acid or hydrochloric acid, or a Lewis acid such as titanium (IV) isopropoxide, titanium (IV) chloride or boron trifluoride-diethyl ether complex; or The reaction can be performed by reacting without a solvent. This reaction can be performed under cooling or heating to reflux.

Third manufacturing method

Embedded image As shown in the above reaction formula, this production method has the general formula (II)
Or an amine derivative represented by (V) and a general formula (VII)
Or the compound of the present invention (I-4) or (I) by a reductive amination reaction of the aldehyde derivative represented by (VIII).
-5). This reductive amination reaction
The first process is carried out by reacting both compounds in the same inert solvent as in the amidation, and isolating the Schiff base to be formed, or reducing the Schiff base without isolation. Formation of the Schiff base is carried out in the presence of an acid catalyst such as the above-mentioned Lewis acid, p-toluenesulfonic acid, adipic acid, acetic acid, hydrochloric acid, or in the presence of a dehydrating agent such as molecular sieves or potassium hydroxide, or Gene Stack (Dean-Sta).
rk) It is advantageous to use a trap to remove the water formed. The reaction temperature is appropriately set, but is preferably from room temperature to reflux. The reduction of the Schiff base can be carried out by adding a metal hydride complex (sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride or the like) or a reducing agent such as borane and heating at −20 ° C. under reflux. Alternatively, in the presence or absence of an acid such as acetic acid and hydrochloric acid, use of a reduction catalyst (eg, palladium carbon, Raney nickel, etc.)
In a solvent such as ethanol, ethyl acetate, acetic acid, etc. from normal pressure to 5
The reaction can also be carried out at a temperature of 0 ° C. to 100 ° C. in a hydrogen atmosphere of 0 kg / cm ^2.

Fourth manufacturing method

Embedded image (In the formula, W represents a conventional leaving group such as Hal or an organic sulfone residue.) In this production method, an amine derivative represented by the general formula (II) or (V) is converted into a compound represented by the general formula (IX) or By alkylating with the compound represented by (X), the compound of the present invention (I-
This is a method for obtaining 4) or (I-5). This N-alkylation reaction is carried out in the presence or absence of a base such as potassium carbonate, triethylamine, sodium hydride or the like, in the presence or absence of DM.
The reaction can be carried out in an inert solvent such as F, acetone, 2-butanone, acetonitrile or the like or without a solvent under cooling or reflux.

Fifth manufacturing method

Embedded image (In the formula, M represents Na or a trimethylsilyl group, and A ³ represents a benzene ring which may be substituted.) In this production method, a phthalic anhydride derivative represented by the general formula (XI) is passed through an acid azide. By the rearrangement reaction, the general formula (X
This is a method for obtaining the compound (I-6) of the present invention by obtaining the compound represented by II) and then amidating the compound represented by the general formula (II). The rearrangement reaction via acid azide in the first step uses sodium azide, trimethylsilyl azide or the like in the presence or absence of a base such as triethylamine in the presence or absence of a base such as acetonitrile, dichloromethane, DCE, DMF, toluene or benzene. It can be carried out under heating and reflux at -78 ° C. Second
The amidation reaction in the step can be performed in the same manner as in the first production method. Other process X is -SO ₂ -NR ¹ - or -NR ¹ -SO ₂ - the Compound is, instead of the carboxylic acid derivative, except using a sulfonic acid derivative is prepared in the same manner as in the first production method be able to. The N-alkylation of the nitrogen atom of the amino group or the amide group of X and the N-alkylation of the ring nitrogen atom can be carried out in the same manner as in the fourth production method. In addition, the introduction of a substituent to each ring, modification of the group, removal of the protecting group, and the like can be performed by a conventional method.

(Production Method of Starting Compound) The starting compound of the above-mentioned production method is commercially available or can be easily synthesized by a method known to those skilled in the art. The reaction product obtained by each of the above production methods is isolated and purified as a free compound, a salt thereof, a hydrate or various solvates. The salt can be produced by subjecting the salt to a usual salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. Optical isomers can also be synthesized from appropriate optically active starting compounds.

[0036]

The compound of the present invention is useful as an active ingredient of a pharmaceutical composition. Especially CRACC inhibitory action and IL-2
It has a production inhibitory effect, and has a CRACC inhibitor or IL
-2 It is useful as a production inhibitor. In particular, it is useful as a prophylactic or therapeutic agent for allergic, inflammatory or autoimmune diseases involving CRACC or IL-2 production.
Here, the allergic, inflammatory or autoimmune diseases include bronchial asthma, psoriasis, atopic diseases including atopic dermatitis, inflammatory bowel diseases including Crohn's disease, peptic ulcer, nephritis, hepatitis, pancreatitis, collagen Various diseases involving CRACC or IL-2 production, such as diseases, rheumatoid arthritis, osteoarthritis, rejection at the time of transplantation, etc., are included.

The usefulness of the compound of the present invention for the above-mentioned diseases is indicated by its inhibitory effects on CRACC and IL-2 production as described below.
In vitro test results, as well as various test results using animal disease models such as antigen-induced airway eosinophil infiltration model, which is a typical disease model for bronchial asthma, a disease model involving T cell activation, and a mouse collagen arthritis model It is more obvious. Further, the compound of the present invention contains IL-4 and IL-
(5) It also has a production inhibitory action, an MMP-1 production inhibitory action, a TNFα production inhibitory action, and the like, and these results support the utility for the above-mentioned diseases. On the other hand, since CRACC inhibitors have an inhibitory effect on cell proliferation, they are useful for prevention or treatment of proliferative or progressive diseases such as malignant tumors, arteriosclerosis, multi-organ sclerosis, various fibrosis and keloids in burns. is there. In addition, CRACC inhibitors suppress ischemia-reperfusion injury by inhibiting the activation of cells involved in inflammatory reactions in peripheral or central tissues such as mast cells, inflammatory cells or astrocytes.
It is also expected to have a protective effect against tissue injury such as head trauma, cerebral infarction and myocardial infarction. In particular, C for VOCC
The compound of the present invention having a selective inhibitory effect on RACC is VO
It is useful because it can exhibit CRACC inhibitory action without undesired action occurring in the central nervous system or vascular smooth muscle caused by CC inhibition.

The following test and results for proving the pharmacological action of the compound of the present invention are shown below. (1) CRACC inhibitory action 100 μl suspension of Jurkat cells (6 × 10 ⁶ / ml) loaded with calcium-indicating fluorescent dye fura-2 (1 μM)
1 was dispensed into each well to prepare a 96-well microplate. Increase in intracellular calcium concentration stimulated by a calcium pump inhibitor (sapargargine) is induced by adding 100 μl of Hanks' balanced salt solution containing twice the final concentration of the test drug and 2 μM sapargargine (final concentration, 1 μM) to each well. 30 minutes after addition, the excitation wavelength is 340 nm / 500 nm and the excitation wavelength is 380 nm /
The fluorescence intensity ratio (R) was calculated from the two fluorescence intensities obtained at 500 nm. At the time of calculating the fluorescence intensity ratio, the autofluorescence of the test drug itself was measured in the same manner using a cell-free system in advance, and the influence of the autofluorescence on the fura-2 fluorescence was corrected. Intracellular calcium concentration is 25
Maximum reaction fluorescence intensity ratio (Rmax) obtained by stimulation with μM ionomycin, 5 μM ionomycin + 1 mM
The minimum response fluorescence intensity ratio (R
min), the fluorescence efficiency (Sb ₂ ) of the calcium-binding dye at the excitation wavelength of 380 nm and the fluorescence efficiency (Sf ₂ ) of the calcium dissociation dye at the excitation wavelength of 380 nm. Calculation formula: intracellular calcium concentration (nM) = 224 × [(R
−Rmin) / (Rmax−R)] × [Sf ₂ / Sb ₂ ] The determined concentrations of the respective concentrations from the intracellular calcium concentration in the presence of the test drug and the intracellular calcium concentration of the control group determined by the solvent alone. The rate of inhibition of calcium influx into cells (CRACC inhibition) by the test drug was determined, and 50% of CRA was determined.
The concentration (IC ₅₀ value) showing CC inhibition was calculated.

[0039] (2) VOCC selective calcium indicator fluorescence dye fura-2 (1μM) PC12- h5 rats were loaded with neuroblastoma cells to inhibitory effects (2 × 10 ⁶ /
ml) A 96-well microplate was prepared by dispensing 100 μl of the suspension into each well. High calcium chloride-stimulated intracellular calcium increase was due to double the final concentration of test drug and 100 mM KCl (final concentration, 50
(mM) containing 100 μl of Hank's balanced salt solution was added to each well.
0 nm / 500 nm and excitation wavelength 380 nm / 500
The fluorescence intensity ratio (R) was calculated from the two fluorescence intensities obtained by nm. At the time of calculating the fluorescence intensity ratio, the autofluorescence of the test drug itself was measured in the same manner using a cell-free system in advance, and the influence of the autofluorescence on the fura-2 fluorescence was corrected. In the same manner as the CRACC inhibitory activity, calculated IC ₅₀ values VOCC inhibition was compared.

(Results) The CRACC inhibitory activity (IC ₅₀ value) of the representative compounds of the present invention shown in Table 3 below was 0.51 to
It was in the range of 0.050 μM. In addition, the CRACC inhibitory activity of these compounds is 12 times lower than the VOCC inhibitory activity.
It was good by 200 times or more. On the other hand,
C described in J. Pharma. Exp. Ther., 257, p967-971 (1991).
The IC ₅₀ value of the comparative compound W having RACC inhibitory activity was 7.7 μM, and its activity was several times weaker than VOCC inhibitory activity. The scope of the present invention is not limited by the following table.

[0041]

[Table 3] (In the table, Compounds A and D are from MAYBRIDGE,
Compound F6 is CONTACT-SERVICE COM.
PANY (Moscow Region, Russi)
According to a), compound L and compound M are Labo Tes
t (Freiberg, Germany). (3) IL-2 production inhibitory action Using Jurkat cells, S. Clare Chung et al., Br. J. Phar
macol., 113: 861-868, (1994).
The production inhibitory activity was tested and its IC ₅₀ value was determined. The IC ₅₀ values of Examples 1, 5, 32, 36, 38, ₅₀ , 53 and 72, and Compounds A and D were 1 μM or less.

(4) TNCB-induced contact hypersensitivity (TNCB-induced
Effects on Contact Hypersensitivity) Using 5-week-old male ICR mice (SLC),
The effect of the compounds of the present invention on TNCB-induced contact hypersensitivity was tested in much the same way as described in S. Immunology (John Wiley & Sons, Inc. 1994). The compound of the present invention showed a dose-dependent inhibitory effect on TNCB-induced contact hypersensitivity. (5) Suppression of liver injury in mouse ConA-induced liver injury model
With use 4-5 week old female Balb / c mice (SLC), G. Tieg
The test was performed using a method substantially similar to the method of J. Clin. Invest., 90: 196-203 (1992). The compound of the present invention showed a dose-dependent inhibitory effect on liver damage.

(6) For mouse collagen arthritis model
That arthritis inhibitory action 5-week-old male DBA / 1J mice using (Japan Charles River), Fumio Nishikaku and Yoshihiko Koga, Immunoph
armacology, 25, 65-74 (1993) and Fuminori Kato,
Masanao Nomura and Kyoko Nakamura, Annals of the
The arthritis inhibitory effect was tested according to the method described in Rheumatic Disease, 55, 535-539 (1996). The compound of the present invention showed a significant arthritis inhibitory effect. (7) Antigen-induced airway eosi
nophilia (rat)) Using 4-week-old female BN rats (Charles River, Japan), acidophilic acid was prepared in substantially the same manner as described in W. Elwood et al., Inflamm. Res., 44: 83-86 (1995). The inhibitory effect on sphere infiltration was tested. The drug was administered 30 minutes before antigen exposure in the case of intravenous administration, and 1 hour before and 3 hours after the antigen exposure in the case of oral administration. In the present test, the compound of the present invention reduced the total leukocyte count and the number of eosinophils, and suppressed eosinophil infiltration.

A medicament comprising the compound (I) of the present invention or a salt thereof and a pharmaceutically acceptable carrier comprises one or more of the compound represented by the general formula (I) or a salt thereof, It can be prepared by a commonly used method using pharmaceutical carriers, excipients, and other additives that are usually used for formulation. The administration is oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration by injections such as intravenous injections, intramuscular injections, suppositories, transdermals, etc. Is also good.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, For example, it contains purified water and ethanol. The composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol,
Vegetable oils such as olive oil; alcohols such as ethanol; polysorbate 80; Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose), and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used by preparing a sterile solid composition and dissolving or suspending in sterile water or a sterile injection solvent before use.

In the case of normal oral administration, the daily dose is suitably about 0.001 to 10 mg / kg per body weight, which is administered once or in 2 to 4 divided doses. When administered intravenously, the daily dose is suitably about 0.0001 to 1 mg / kg per body weight, and is administered every few days or once a day or divided into a plurality of doses. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like.

[0048]

The present invention will be described below in more detail with reference to examples. The compounds of the present invention are not limited to the compounds described in the following examples. The method for producing the starting compounds used in the examples will be described as reference examples.

Reference Example 1 Sodium methoxide was added to a mixture of 2-acetylthiazole and methanol under ice-cooling, followed by stirring at room temperature for 20 minutes. Ethyl trifluoroacetate was added to the reaction solution under ice-cooling, and the mixture was stirred for 19 hours under reflux with heating, purified by a conventional method. After stirring, the mixture was purified by a conventional method to obtain 2- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiazole. Reference Example 2 An n-butyllithium-n-hexane solution (1.6) was added to a mixture of diisopropylamine and THF at −30 ° C. or lower.
M), and the mixture was stirred at -30 to -50 ° C for 15 minutes. 2-Propionylthiophene was added to the reaction solution at -60C or lower, and the mixture was stirred at -60C or lower for 90 minutes. The reaction solution was changed to -6
The mixture was added to a mixture of trifluoroacetic anhydride and THF cooled to 0 ° C., stirred at −60 ° C. for 1 hour, and purified by a conventional method to obtain a brown oil. To this brown oil, hydrazine hydrochloride and ethanol were added, and the mixture was stirred at 50 ° C. for 2 hours and purified by a conventional method to give 4-methyl-3- (2-thienyl) -5-trifluoromethyl-1H-. Pyrazole was obtained as a brown solid.

Reference Example 3 3- (2-thienyl) -5-trifluoromethyl-1H
A mixture of pyrazole and THF, n-
A butyllithium-n-hexane solution (1.6 M) was added, and the mixture was stirred at 0 ° C for 50 minutes. Ethyl chloroformate was added to the reaction solution at -60 ° C or lower, and the mixture was stirred at -78 ° C for 1 hour.
(1-ethoxycarbonyl-5-trifluoromethyl-
1H-pyrazol-3-yl) thiophen-2-carboxylate and ethyl 5- (1-ethoxycarbonyl-
A mixture of 3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carboxylate was obtained. This mixture and sodium bicarbonate, ethanol,
After stirring the mixture of 1,4-dioxane and water at room temperature for 3 days, the mixture was purified by a conventional method to give ethyl 5- (5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxylate. Obtained as colorless powdery crystals.
This was hydrolyzed with a base by a conventional method to obtain 5- (5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxylic acid.

Reference Example 4 To a mixture of 2- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiazole and THF,
An n-butyllithium-n-hexane solution (1.6 M) was added at −50 ° C. or lower, and the mixture was stirred at −50 ° C. or lower for 90 minutes. Ethyl chloroformate was added to the reaction solution at -20 ° C or lower,
After stirring at −20 ° C. or lower for 15 minutes, purification was conducted by a conventional method to obtain ethyl 2- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiazole-5-carboxylate. This is hydrolyzed with a base by a conventional method to give 2- (1-methyl-3-trifluoromethyl-1).
(H-pyrazol-5-yl) thiazole-5-carboxylic acid was obtained. Reference Example 5 ethyl 5- (5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxylate,
A mixture of ethyl iodide, potassium carbonate and DMF was stirred at room temperature for 9 hours. The residue obtained by the usual treatment was eluted by silica gel chromatography (eluent; n-hexane: ethyl acetate = 15: 1) to give ethyl 5-
(1-Ethyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxylate was obtained as colorless needles. In the silica gel chromatography, the eluate was further treated with n-hexane:
Elute with 10: 1 ethyl acetate and elute with ethyl 5-
(1-Ethyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carboxylate was obtained as a pale yellow oil. These compounds are hydrolyzed with a base by a conventional method, and a) 5- (1-ethyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxylic acid, and b) 5- (1 -Ethyl-3-
Trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carboxylic acid was obtained.

Reference Example 6 In the same manner as in Reference Example 5, a) 5- (1-isopropyl-5)
-Trifluoromethyl-1H-pyrazol-3-yl)
Thiophene-2-carboxylic acid and b) 5- (1-isopropyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carboxylic acid were obtained. Reference Example 7 4-methyl-3- (2-thienyl) -5-trifluoromethyl-1H-pyrazole and n-butyllithium-n-
A hexane solution (1.6 M) was reacted, ethyl chloroformate was further added at -50 ° C or lower, and the mixture was stirred at -50 ° C or lower for 30 minutes, and purified by a conventional method to obtain a yellow oil.
This is hydrolyzed by a conventional method to give 5- (4-methyl-5).
-Trifluoromethyl-1H-pyrazol-3-yl)
Thiophene-2-carboxylic acid was obtained as colorless powders.

Reference Example 8 A mixture of 5- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carboxylic acid, oxalyl chloride, DMF and DCE was stirred at room temperature for 90 minutes. Then, the mixture is treated in a conventional manner to give 5- (1-
Methyl-3-trifluoromethyl-1H-pyrazole-
5-yl) thiophene-2-carbonyl chloride was obtained as a brown solid. Reference Example 9 5- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carboxylic acid,
A mixture of diphenylphosphoryl azide, triethylamine and toluene was stirred at 50 ° C. for 30 minutes. After adding tert-butanol to the reaction solution and stirring at 80 ° C. for 5 hours, the reaction solution was purified by a conventional method to obtain tert-butyl 5- (1
-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carbamate was obtained as pale yellow crystals.

Reference Example 10 tert-butyl 5- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophene-
After stirring a mixture of 2-carbamate, trifluoroacetic acid and dichloromethane at room temperature for 2 days, the mixture was purified and salt-formed by a conventional method to give 5- (5-amino-2-thienyl) -1.
-Methyl-3-trifluoromethyl-1H-pyrazole hydrochloride was obtained as pale yellow powdery crystals. Reference Example 11 Zinc dust and ammonium chloride were added to an aqueous ethanol solution of 1- (4-nitrophenyl) -3,5-bis (trifluoromethyl) -1H-pyrazole under ice-cooling, and the mixture was added at 20 ° C.
The mixture was stirred for 30 minutes below. After removing insoluble materials in the reaction solution by filtration through celite, the filtrate was treated in a conventional manner to give 1-
(4-Hydroxyaminophenyl) -3,5-bis (trifluoromethyl) -1H-pyrazole was obtained as a colorless solid.

Reference Example 12 A mixture of 5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophene-2-carboxaldehyde, silver nitrate powder and ethanol was subjected to 5N hydroxylation under ice cooling. After stirring the mixture of the aqueous sodium solution and ethanol at room temperature for 1 hour, the mixture was purified by a conventional method to give 5-
(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxylic acid was obtained as a colorless powder.

Example 1 4-methylthiazole-5-carboxylic acid (108 m
g), 4- [3,5-bis (trifluoromethyl) -1
H-pyrazol-1-yl] aniline (223 mg),
A mixture of WSCD hydrochloride (152 mg) and DCE (5 ml) was stirred at room temperature overnight. Water (10 ml) in the reaction solution
Was added, and the product was extracted with a mixed solvent of diethyl ether (5 ml) and ethyl acetate (10 ml). The extract was washed sequentially with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 3: 1 to 2: 1), and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 4-
Methyl-4 '-[3,5-bis (trifluoromethyl)
[-1H-pyrazol-1-yl] thiazole-5-carboxyanilide (143 mg) was obtained as colorless needles. Example 2 To a mixture of 4- [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] aniline (150 mg), triethylamine (57 mg) and THF (2 ml) was added 4-chloro under ice-cooling. Benzoyl chloride (88m
g) and THF (2 ml) were added, and the mixture was stirred at room temperature for 4 hours. After water was added to the reaction solution and the product was extracted with ethyl acetate, the extract was washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 4-chloro-4 ′-[3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] benzanilide (105 mg). ) Was obtained as colorless powdery crystals.

Example 3 4'-Chloro-5- (4-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-
Carboxanilide (360 mg), methyl iodide (199 mg), potassium carbonate (129 mg) and DM
A mixture of F (5 ml) was stirred at room temperature for 3 days. Water (10 ml) was added to the reaction solution, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1 to 4: 1), and recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 4 ′ -Chloro-5- (1,4-dimethyl-
5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxyanilide (13 mg)
Was obtained as colorless powdery crystals. Example 4 In the silica gel column chromatography of Example 3, the compound eluted after the compound of Example 3 was recrystallized from a mixed solvent of ethyl acetate and hexane to give 4′-
Chloro-5- (1,4-dimethyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-
Carboxanilide (86 mg) was obtained as colorless powders.

Example 5 2-chloroaniline (68 mg), pyridine (42 m
g) and dichloromethane (2 ml) to a mixture of 5- (1-methyl-3-trifluoromethyl-1H-
Pyrazol-5-yl) thiophene-2-carbonyl chloride (150 mg) and dichloromethane (1.5 ml)
Was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give 2 ′
-Chloro-5- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophen-2-carboxyanilide (80 mg) was obtained as colorless crystals. Example 6 2-amino-1-methylpyrrole hydrochloride (202 m
g), potassium carbonate (553 mg), THF (2 ml)
And a mixture of water and 4 ml of 5- (1-methyl-3-).
Trifluoromethyl-1H-pyrazol-5-yl) thiophene-2-carbonyl chloride (295 mg) and T
HF (3 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction solution and the product was extracted with ethyl acetate, the extract was washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1 to 3: 2), and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give N-
(1-methyl-2-pyrrolyl) -5- (1-methyl-3
-Trifluoromethyl-1H-pyrazol-5-yl)
Thiophene-2-carboxamide (126 mg) was obtained as pale yellow powdery crystals.

Example 7 A 70% aqueous solution of ethylamine (1 ml) and THF (2 m
l) in a mixture of 5- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophene-2
Carbonyl chloride (150 mg) and THF (2 m
l) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give N-ethyl-5- (1-methyl-3-trifluoromethyl-1H-
(Pyrazol-5-yl) thiophene-2-carboxamide (96 mg) was obtained as colorless powdery crystals. Example 8 2-aminothiazole (68 mg), saturated aqueous sodium hydrogen carbonate solution (1 ml) and dichloromethane (1 ml)
To a mixture of 5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophene-2-carbonyl chloride (100 mg) and dichloromethane (2
ml) and stirred at room temperature for 5 hours. Water was added to the reaction solution, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 4: 1 to 2: 1), washed with diethyl ether, and 5- (1-methyl-5-triethyl). Fluoromethyl-1H-pyrazol-3-yl) -N- (2-
Thiazolyl) thiophene-2-carboxamide (68 m
g) was obtained as a colorless solid.

Example 9 3'-acetyl-4-chlorobenzanilide (1.00
g) and methanol (10 ml) were added with sodium methoxide (257 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Ethyl trifluoroacetate (0.522 ml) was added to the reaction mixture under ice-cooling, and the mixture was heated under reflux for 3 hours.
Stirred for days. Water (50 ml) was added to the reaction mixture, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. After drying the organic layer over anhydrous sodium sulfate,
Concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1 to 1: 1) to obtain a pale yellow oil.
A mixture of this and methylhydrazine (0.122 ml), acetic acid (1 ml) and ethanol (10 ml) was stirred for 15 hours under reflux with heating. After allowing the reaction solution to cool, it was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution.
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 6: 1).
After recrystallization from a mixed solvent of ethyl acetate and n-hexane, 4-chloro-3 ′-(1-methyl-5-
Trifluoromethyl-1H-pyrazol-3-yl) benzanilide (60 mg) was obtained as colorless powders.

Example 10 In the silica gel column chromatography of Example 9, the compound eluted after the compound of Example 9 was recrystallized from a mixed solvent of ethyl acetate and hexane to give 4-chloro-3 ′-( 1-methyl-3-trifluoromethyl-
1H-pyrazol-5-yl) benzanilide (134
mg) as colorless powders. Example 11 5- (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl) thiophen-2-carboxaldehyde (260 mg), 4-chloroaniline (134 m
g), acetic acid (0.1 ml) and dichloromethane (3 m
To the mixture of 1), sodium triacetoxyborohydride (530 mg) was added, and the mixture was stirred at room temperature for 2 hours and 20 minutes.
A saturated aqueous solution of sodium hydrogen carbonate (10 ml) was added to the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane:
Purification with ethyl acetate = 10: 1 to 6: 1) gave 3- [5
-[(4-Chloroanilino) methyl] -2-thienyl]
-1-Methyl-5-trifluoromethyl-1H-pyrazole (313 mg) was obtained as a colorless solid.

Example 12 Ethyl 1- [4- (4-chlorobenzoylamino) phenyl] -5-trifluoromethyl-1H-pyrazole-4-carboxylate (150 mg), 1N aqueous sodium hydroxide solution (1 ml), And ethanol (2m
The mixture of 1) was stirred at 45 ° C. for 4 hours. After cooling, a 1N aqueous hydrochloric acid solution (2 ml) was added to the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give 1- [4- (4-chlorobenzoylamino) phenyl] -5-trifluoromethyl-1H-pyrazole-4.
-The carboxylic acid (91 mg) was obtained as colorless powders.

Example 13 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (198 mg), 4- [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] aniline (206 mg), WSCD A mixture of hydrochloride (172 mg) and THF (3 ml) was stirred at room temperature overnight. After adding ethyl acetate to the reaction solution, the mixture was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate, a 1N aqueous solution of hydrochloric acid, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 7:
1-5: 1) to give tert-butyl 4- [4
-[3,5-Bis (trifluoromethyl) -1H-pyrazol-1-yl] phenylaminocarbonyl] piperidine-1-carboxylate (279 mg) was obtained as a colorless amorphous solid. To a mixture of this (263 mg) and ethyl acetate (2.6 ml) was added 4N hydrochloric acid ethyl acetate solution (2.60 ml), and the mixture was stirred at room temperature for 2 hours and 45 minutes. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was concentrated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give [4 ′-[3,5-bis (trifluoromethyl)-
[1H-Pyrazol-1-yl] piperidine-4-carboxyanilide hydrochloride (201 mg) was obtained as colorless powdery crystals.

Example 14 Ethyl 1- (4-aminophenyl) -5-trifluoromethyl-1H-pyrazole-4-carboxylate (150 mg), triethylamine (76 mg) and T
Methanesulfonyl chloride (80 mg) was added to a mixture of HF (2 ml) under ice cooling, and the mixture was stirred at room temperature for 4 hours.
Thereafter, by performing the same treatment as in Example 2, ethyl 1- (4-methanesulfonylaminophenyl) -5-
Trifluoromethyl-1H-pyrazole-4-carboxylate (29 mg) was obtained as a colorless solid. Example 15 4- (1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl) piperidine (540 mg) and TH
4-Chlorophenyl isocyanate (461 mg) was added to a mixture of F (5 ml) under ice cooling, and the mixture was stirred at room temperature overnight. Water (10 ml) was added to the reaction solution, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixed solvent of acetone and diethyl ether was added to the obtained residue, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 1).
After purification in 1), the product was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 4′-chloro-4- (1-methyl-
3-trifluoromethyl-1H-pyrazol-5-yl) piperidine-1-carboxyanilide (391 m
g) was obtained as colorless powders.

Example 16 1-trityl-1H-imidazole-4-carboxylic acid (300 mg), 4- [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] aniline (20
0mg), WSCD hydrochloride (162mg), DMF
(0.5 ml) and THF (4 ml) was stirred at room temperature overnight. Water (10 ml) was added to the reaction solution, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate =
3: 1), concentrated hydrochloric acid (0.1 ml) and acetone (3 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was concentrated under reduced pressure. A mixed solvent of ethanol and diethyl ether was added to the obtained residue, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane:
After purification by ethyl acetate = 1: 1 to 2: 3), recrystallization from a mixed solvent of ethyl acetate and n-hexane gave 4′-
[3,5-Bis (trifluoromethyl) -1H-pyrazol-1-yl] -1H-imidazole-4-carboxyanilide (35 mg) was obtained as colorless powdery crystals.

Reference Example 13 A mixture of 2-fluoro-5-nitrobenzophenone, sodium methoxide and methanol was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-methoxy-5-nitrobenzophenone and 2-methoxy-5-nitrobenzophenone.
A mixture of ethoxy-5-nitrobenzophenone (abundance = about 4: 1) was obtained as a colorless solid. REFERENCE EXAMPLE 14 A mixture of 2-methoxy-5-nitrobenzophenone and 2-ethoxy-5-nitrobenzophenone obtained in Reference Example 1, a mixture of iron powder, a 1N aqueous hydrochloric acid solution and ethanol was stirred under heating and reflux overnight. And a mixture of 5-amino-2-methoxybenzophenone and 5-amino-2-ethoxybenzophenone (existence ratio =
Approx. 4: 1) was obtained as a brown oil. Reference Example 15 2,4-dichlorobenzyl alcohol, imidazole,
To a mixture of 4-dimethylaminopyridine and DMF, tert-butyldimethylsilyl chloride was added under ice-cooling, and the mixture was stirred at room temperature for 26 hours and purified by a conventional method.
tert-Butyldimethylsilyl 2,4-dichlorobenzyl ether was obtained as a colorless oil. Reference Example 16 tert-butyldimethylsilyl under an argon atmosphere
To a mixture of 2,4-dichlorobenzyl ether and THF was added an n-butyllithium-n-hexane solution (1.6 M) at -65 ° C, and the mixture was stirred at -65 ° C for 1 hour. Add 3,4-dimethoxybenzoyl chloride and THF
And stirred at -60 to -70 ° C for 3 hours.
A 1N aqueous hydrochloric acid solution and then concentrated hydrochloric acid were added to the reaction solution, and the mixture was stirred at room temperature for 18 hours.
Dichloro-3-hydroxymethyl-3 ′, 4′-dimethoxybenzophenone was obtained as a yellow amorphous solid.

Reference Example 17 Bromoacetyl bromide was added to a mixture of 2-amino-6-bromo-4-chlorophenol, sodium hydrogencarbonate, 2-butanone and water under ice-cooling, and the mixture was heated at room temperature for 1 hour and then heated to reflux. After stirring under the following conditions for 19 hours, the product was purified by a conventional method to give 8-bromo-6-chloro-3,4-dihydro-2.
H-1,4-benzoxazin-3-one was obtained as light brown powdery crystals. Reference Example 18 8-bromo-6-chloro-3,4-dihydro-2H-
1,4-benzoxazin-3-one, borane-THF
A mixture of the complex-THF solution (1.0 M) and THF was
The mixture was stirred under reflux with heating for 21 hours. Ethanol and a 1N aqueous hydrochloric acid solution were added to the reaction solution at room temperature, and the mixture was stirred at 80 ° C. for 6 hours.
3,4-Dihydro-2H-1,4-benzoxazine hydrochloride was obtained as pale red scales. Reference Example 19 2- (2-thienyl) -4-trifluoromethylthiazole and n-butyllithium-n-hexane solution (1.6
M) was stirred at -40 ° C or lower in THF. To the reaction solution
Tert-butyldimethylsilyl chloride was added at 70 ° C. or lower, and the mixture was stirred at room temperature for 4 hours and purified by a conventional method to give 5-tert-butyldimethylsilyl-2- (2-
Thienyl) -4-trifluoromethylthiazole was obtained as a yellow oil.

Reference Example 20 A solution of 5-tert-butyldimethylsilyl-2- (2-thienyl) -4-trifluoromethylthiazole and n-butyllithium-n-hexane (1.6 M) in THF was used.
The reaction was carried out at -40 ° C or lower. Ethyl chloroformate was added to the reaction solution at -70 ° C or lower, and the mixture was stirred at 0 ° C for 1 hour.
Purification by a conventional method gave a yellow oil. To a mixture of this yellow oily substance and ethanol, a 1 N aqueous solution of sodium hydroxide and 1,4-dioxane were added under ice-cooling.
After stirring for an hour, purification was conducted by a conventional method to obtain 5- (4-trifluoromethyl-2-thiazolyl) -2-thiophenecarboxylic acid as a pale yellow solid.

Example 111 (Production of a known compound) 3-bromo-5-chlorosalicylic acid (2.09 g), 5
-Amino-2-chlorobenzophenone (1.83 g),
WSCD hydrochloride (1.82 g) and THF (20 ml)
Was stirred at room temperature for 4 days. Ethyl acetate (200 ml) was added to the reaction solution, and the mixture was washed successively with water, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, a 1N aqueous solution of hydrochloric acid, and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 6: 1), and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 3′-benzoyl-3. −
Bromo-4 ', 5-dichloro-2-hydroxybenzanilide (1.53 g) was obtained as colorless needles.

Example 112 3-Bromo-5-chlorosalicylic acid (500 mg), thionyl chloride (3 ml), DCE (10 ml) and D
The mixture of MF (1 drop) was stirred at 75 ° C. for 2 hours. After concentrating the reaction solution under reduced pressure, 3-aminobenzophenone (392 mg) and triethylamine (0.
277 ml) and DCE (10 ml) were added and stirred at 75 ° C. for 2 hours, then at room temperature overnight. Chloroform was added to the reaction solution, and the mixture was washed sequentially with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 4: 1), and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 3′-benzoyl-3. -Bromo-5-chloro-2-
Hydroxybenzanilide (202 mg) was obtained as colorless powdery crystals.

Example 113 5-amino-2-chlorobenzophenone (409 m
g), triethylamine (0.370 ml) and THF
(5 ml) was mixed with 3,5-dichlorobenzoyl chloride (0.388 ml) and THF (4 ml) under ice-cooling.
l) was added and the mixture was stirred at room temperature overnight. Add water to the reaction solution,
After the product was extracted with ethyl acetate, the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 8: 1 to 1:
After purification in 1), recrystallization from ethanol gave 3′-
Benzoyl-3,4 ', 5-trichlorobenzanilide (391 mg) was obtained as colorless needles. Example 114 5-amino-2-chlorobenzophenone (370 m
g), triethylamine (0.335 ml) and THF
(5 ml), 2-acetoxybenzoyl chloride (351 mg) and THF (3 ml) were added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature overnight. After the product was extracted with ethyl acetate, the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 16: 1 to 3:
Purified in 1), 3′-benzoyl-4′-chloro-2
-Hydroxybenzanilide (40 mg) was obtained as a yellow amorphous solid.

Example 115 In the silica gel column chromatography of Example 114, 2-acetoxy-3'-benzoyl-4'-chlorobenzanilide (368 mg) eluted after the compound of Example 4 was converted to a colorless amorphous substance. Obtained as a solid. Example 116 3'-benzoyl-3-bromo-4 ', 5-dichloro-
A mixture of 2-hydroxybenzanilide (150 mg), acetyl chloride (0.024 ml), triethylamine (0.049 ml) and 2-butanone (4 ml) was stirred at room temperature for 2 days. Water was added to the reaction solution, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate =
16: 1 to 4: 1) to give 2-acetoxy-N-
Acetyl-3'-benzoyl-3-bromo-4 ', 5-
Dichlorobenzanilide 0.75 hydrate (105 mg)
Was obtained as a colorless amorphous solid. Example 117 In the silica gel column chromatography of Example 116, 2-acetoxy-3′-benzoyl-3-bromo-4 ′, 5-eluted after the compound of Example 6
Dichlorobenzanilide (25 mg) was obtained as a colorless amorphous solid.

Example 118 3′-Benzoyl-3-bromo-4 ′, 5-dichloro-
2-hydroxybenzanilide (150 mg), methyl iodide (0.200 ml), potassium carbonate (178 m
g) and 2-butanone (4 ml) was stirred at room temperature overnight. Potassium carbonate (178 mg) was added to the reaction mixture, and the mixture was further stirred at room temperature overnight, and then water was added to the reaction mixture.
The product was extracted with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate =
16: 1 to 4: 1) to give 3′-benzoyl-3
-Bromo-4 ', 5-dichloro-2-methoxy-N-methylbenzanilide (127 mg) was obtained as a colorless amorphous solid. Example 119 3-bromo-5-chlorosalicylic acid (500 mg), thionyl chloride (0.218 ml), DCE (10 m
l) and DMF (0.008 ml) was stirred at 75 ° C for 1.5 hours. After the reaction solution was concentrated under reduced pressure, a mixture of the 5-amino-2-methoxybenzophenone and 5-amino-2-ethoxybenzophenone obtained in Reference Example 2 (452 mg) and triethylamine (0.
333 ml) and DCE (12 ml) were added, and the mixture was stirred at room temperature overnight. Water and a 1N aqueous hydrochloric acid solution were added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 16: 1 to 1).
4: 1), washed with diethyl ether,
3′-Benzoyl-3-bromo-5-chloro-4′-ethoxybenzanilide (44 mg) was obtained as colorless powder.

Example 120 In the silica gel column chromatography treatment of Example 9, the compound eluted after the compound of Example 9 was recrystallized from a mixed solvent of ethyl acetate, diethyl ether and n-hexane to give 3′- Benzoyl-3-bromo-5
-Chloro-4'-methoxybenzanilide (67mg)
Was obtained as colorless powdery crystals. Example 121 3-bromo-5-chlorosalicylic acid (500 mg), triphenylphosphine (574 mg), N-bromosuccinimide (390 mg) and dichloromethane (20 m
l) to a mixture of 5-amino-2-fluorobenzophenone (514 mg) and dichloromethane (5 m
l) was added and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction solution and the product was extracted with ethyl acetate, the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a 1N aqueous solution of hydrochloric acid, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 16: 1 to 4: 1), and then recrystallized from a mixed solvent of ethyl acetate, diethyl ether and n-hexane. 3'-Benzoyl-3-bromo-5-chloro-4'-fluoro-2-hydroxybenzanilide (122 mg) was obtained as yellow powdery crystals. Example 122 In the silica gel column chromatography of Example 127, the compound eluted later from the compound of Example 127 was crystallized from n-hexane, and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2 -Amino-
3′-Benzoyl-4 ′, 5-dichlorobenzanilide (28 mg) was obtained as colorless powdery crystals.

Example 123 3-bromo-5-chlorosalicylaldehyde (341 m
g), 5-amino-2-chlorobenzophenone (310
mg) and ethanol (6 ml) was stirred under reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, sodium triacetoxyborohydride (298 mg), acetic acid (5 ml) and DCE (12 mL) were added to the obtained residue under ice cooling.
5 ml) and stirred at 0 ° C. overnight. Ethyl acetate (350 ml) was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n
-Hexane: ethyl acetate = 10: 1 to 2: 1) to give 5-[(3-bromo-5-chloro-2-hydroxybenzyl) amino] -2-chlorobenzophenone (35
5 mg) were obtained as yellow oily crystals. Example 124 3-bromo-5-chlorosalicylic acid (250 mg), 4
A mixture of -aminobenzophenone (200 mg), phosphorus trichloride (0.087 ml) and chlorobenzene (5 ml) was stirred under reflux with heating for 3 hours. After water was added to the reaction solution and the product was extracted with ethyl acetate, the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a 1N aqueous solution of hydrochloric acid, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was crystallized from a mixed solvent of 2-propanol and diethyl ether, and recrystallized from ethyl acetate to give 4′-benzoyl-3.
-Bromo-5-chloro-2-hydroxybenzanilide (46 mg) was obtained as yellow needles.

Example 125 Imidazo [1,2-a] pyridine-3-carboxylic acid (6
5 mg), 4-amino-3,4 ', 5-trichlorobenzophenone (121 mg) and pyridine (1.2 ml)
To a mixture of phosphorus oxychloride (0.05 ° C. or less).
9 ml) and stirred at -15 ° C for 90 minutes. Ice was added to the reaction solution, the product was extracted with ethyl acetate, and the extract was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 49: 1), and recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 4 ′-(4
-Chlorobenzoyl) -3,5-dichlorophenylimidazo [1,2-a] pyridine-3-carboxyanilide (27 mg) was obtained as light brown powdery crystals. Example 126 Triphenylphosphine (1.15) under an argon atmosphere
g), bromine (0.199 ml) and dichloromethane (300 ml) were stirred at room temperature for 15 minutes. 2,6-Dichloro-3-hydroxymethyl-
3 ', 4'-dimethoxybenzophenone (1.20 g)
And a mixture of dichloromethane (15 ml) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure to give crude 3
-Bromomethyl-2,6-dichloro-3 ', 4'-dimethoxybenzophenone (3.00 g) was obtained as a yellow oil. 8-bromo-6-chloro-3,4-dihydro-
2H-benzoxazine (676 mg) and DMF (3 m
l) to a mixture of sodium hydride (109
mg) and stirred at room temperature for 20 minutes. The crude 3-bromomethyl-2,6-dichloro-
3 ', 4'-dimethoxybenzophenone (3.00 g)
And DMF (3 ml) was added, and the mixture was stirred at room temperature for 4 days. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline.
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 10: 1).
3: 1), and then recrystallized from a mixed solvent of acetonitrile and chloroform to give 3-[(8-bromo-6).
-Chloro-3,4-dihydro-2H-1,4-benzoxazin-4-yl) methyl] -2,6-dichloro-
3 ', 4'-dimethoxybenzophenone (575mg)
Was obtained as colorless powdery crystals.

Example 127 4-Chlorophthalic anhydride (3.00 g), trimethylsilyl azide (8.75 ml) and acetonitrile (10
0 ml) of the mixture was stirred for 4 hours while heating under reflux. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
5-Amino-2-chlorobenzophenone (3.82 g) and toluene (200 ml) were added to the obtained residue, and the mixture was stirred under heating and reflux for 4 hours and 30 minutes. The deposited precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; n-hexane:
After purification with ethyl acetate = 5: 1), crystallization from diethyl ether and recrystallization from a mixed solvent of ethyl acetate and n-hexane gave 2-amino-3′-benzoyl-.
4,4′-Dichlorobenzanilide (164 mg) was obtained as colorless powdery crystals. Example 128 2-Amino-3'-benzoyl-4,4'-dichlorobenzanilide (130 mg), acetic anhydride (0.060 m
A mixture of 1) and pyridine (5 ml) was stirred at room temperature for 23 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate, a 1N aqueous solution of hydrochloric acid, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1 to 7: 3), and ethyl acetate and n
Recrystallization from a mixed solvent of -hexane gave 2-acetamido-3'-benzoyl-4,4'-dichlorobenzanilide (59 mg) as colorless powdery crystals.

In the same manner as in the above embodiment, Tables 6 to 21
Were obtained. Tables 4 and 5 below show the structural formulas and physicochemical properties of the reference example compounds, and Tables 6 to 21 show the structural formulas and physicochemical properties of the example compounds. In addition, the compounds whose chemical structural formulas are listed in Tables 22 to 23 are almost the same as the methods described in the above Examples and Production Methods, or by applying some modifications obvious to those skilled in the art to them. Easily manufactured. In the table, the following abbreviations are: Rex: reference example; Ex: example; Co: compound number; Sy: production method (numerals indicate the numbers of the examples, and the compounds are produced by the same method as in the above examples. It shows that you did.);
Str: structural formula; Dat: physicochemical properties (F: FAB-MS (M +
H) ⁺ ; FN: FAB-MS (MH) ^- ; E: EI-MS; M: melting point
[° C]; (d): decomposition; N1: characteristic peak of NMR (DMSO-d ₆ , TMS internal standard) δ ppm; N2: characteristic peak of NMR (CDCl ₃ , TMS internal standard) δ ppm; Anal: elemental analysis Value; c
alcd .: calculated value; found: measured value); Ac: acetyl; and *: the absence of the group, respectively.

[0079]

[Table 4]

[0080]

[Table 5]

[0081]

[Table 6]

[0082]

[Table 7]

[0083]

[Table 8]

[0084]

[Table 9]

[0085]

[Table 10]

[0086]

[Table 11]

[0087]

[Table 12]

[0088]

[Table 13]

[0089]

[Table 14]

[0090]

[Table 15]

[0091]

[Table 16]

[0092]

[Table 17]

[0093]

[Table 18]

[0094]

[Table 19]

[0095]

[Table 20]

[0096]

[Table 21]

[0097]

[Table 22]

[0098]

[Table 23]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/215 A61K 31/215 31/38 31/38 31/40 31/40 31/41 31/41 31/415 31/415 31/425 31/425 31/44 602 31/44 602 31/47 31/47 31/535 31/535 C07D 401/12 231 C07D 401/12 231 // C07C 225/22 C07C 225/22 233/64 233 / 64 233/76 233/76 235/64 235/64 235/84 235/84 237/40 237/40 237/42 237/42 C07D 207/34 C07D 207/34 213/82 213/82 215/48 215 / 48 217/26 217/26 241/14 241/14 265/36 265/36 333/38 333/38 405/04 231 405/04 231 409/04 231 409/04 231 409/14 207 409/14 207 213 213 231 231 413/14 231 413/14 231 417/04 231 417/04 231 333 333 433 417/12 231 417/12 231 417/14 231 417/14 231 471/0 4 108 471/04 108A C07F 7/08 C07F 7/08 R 7/18 7/18 E (72) Inventor Masashi Funatsu 21 Miyukigaoka, Tsukuba, Ibaraki Pref. Yamanouchi Pharmaceutical Company Limited (72) Inventor Soichiro Kawazoe 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Kei Toshima 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Intracorporate Yamanouchi Pharmaceutical Co., Ltd. (72) Yoshinori Okamoto 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Within Yamanouchi Pharmaceutical Co., Ltd. (72) Atsushi Ishikawa, 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Inside Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor, Makoto Takeuchi, 21 Miyukigaoka, Tsukuba, Ibaraki, Yamanouchi Pharmaceutical Co., Ltd.

Claims (6)

[Claims] 1. A calcium release-dependent calcium channel inhibitor comprising an amide or amine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (The symbols in the formula represent the following meanings: D: an aryl optionally having a substituent or a monocyclic or bicyclic heteroaryl group optionally having a substituent, Y: a bond, Methylene, O, S, CO, CS, SO ₂ or SO, B: phenylene which may have a substituent, divalent group of a nitrogen-containing saturated ring or monocyclic aromatic hetero which may be substituted by Alk A ring divalent group, or D, Y and B are united to form (Wherein, Y is as defined above, B ² and D ² denotes a benzene ring which may have a substituent.) To form a group represented by, X: wherein -NR ¹ -CR ² R ^3- , -CR ² R ³ -NR ¹ -,-
A group represented by NR ¹ -SO ₂ -or -SO ₂ -NR ^1- , R ¹ : -H, -OH, -Alk, -O-Alk or -C
O-Alk, R ² , R ³ : same or different, -H or -Alk,
Or R ² and R ^{3 taken} together as ＯO or ＳS, A: aryl optionally having substituent (s); monocyclic or bi- or tricyclic heteroaryl optionally having substituent (s); A cycloalkyl optionally having a substituent; a nitrogen-containing saturated ring optionally having a substituent; a lower alkynyl optionally having a substituent; a lower alkenyl optionally having a substituent; Or Alk which may have a substituent, or X and A are united to form a group represented by the formula: (Wherein A ² may have a substituent, 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl A nitrogen-containing saturated heterocyclic ring selected from the group consisting of the following: ) 2. The medicament according to claim 1, which is a prophylactic or therapeutic agent for allergic, inflammatory, autoimmune diseases, bronchial asthma or rheumatoid arthritis. 3. The method according to claim 1, wherein
Is -Alk, -lower alkenyl, -lower alkynyl,
-Halogeno lower alkyl, -Alk-cycloalkyl,
-Alk-O-Alk, -cycloalkyl, -O-Al
k, -COOH, -COO-Alk, and pyrazolyl which may have 1 to 3 substituents selected from the group consisting of -Hal, and Y is methylene or a bond;
B is an unsubstituted phenylene, a divalent group of a nitrogen-containing saturated ring or a monocyclic aromatic heterocyclic ring 2 which may be substituted with Alk;
X is a group represented by the formula —NR ¹ —CR ² R ³ —, —CR ² R
³ -NR ^1- , -NR ¹ -SO _2- , or -SO ₂ -NR ^1-
Wherein R ¹ is -H, -OH, -Alk,
An -O-Alk or -CO-Alk, R ^2, R ³ are identical or different and are -H or -Alk, or R ² and R ³ together = O or = S, A is An aryl which may have a substituent, a monocyclic or bicyclic tricyclic fused heteroaryl which may have a substituent, a cycloalkyl which may have a substituent, A nitrogen-containing saturated ring which may be substituted, lower alkenyl which may have a substituent, lower alkynyl which may have a substituent, or Alk which may have a substituent, or X and A are united to form the formula (Wherein A ² may have a substituent, 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl Represents a nitrogen-containing saturated heterocyclic ring selected from the group consisting of: (1) wherein D is 3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl, n Is 0, B is 1,4-phenylene and X is NHCO, A is 4-methyl-1,2,3-thiadiazole-5
A group other than -yl, (2) D is 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl, n is 0,
When B is thiophen-2,5-diyl and X is CONH, A represents a group other than 4-chlorophenyl, (3) D represents 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl, When n is 0, B is thiophen-2,5-diyl, and X is CONH, A is a group other than benzyl, and (4) D is 4-ethoxycarbonyl-5-trifluoromethyl-1H-pyrazole-1. -Il, n is 0, B
Is 1,4-phenylene and Y is NHCO, A represents a group other than trichlorovinyl, and (5) D represents 1H-
When pyr is 1-yl, n is 0, B is 1,4-phenylene, and Y is NHCO, A represents a group other than 2-ethoxyvinyl, an amide or amine derivative or a pharmaceutically acceptable derivative thereof. Salt. 4. The method according to claim 1, wherein
Is -Alk, -lower alkenyl, -lower alkynyl,
-Halogeno lower alkyl, -Alk-cycloalkyl,
-Alk-O-Alk, -cycloalkyl, -O-Al
k, -COOH, -COO-Alk, and pyrazolyl which may have 1 to 3 substituents selected from the group consisting of -Hal, and Y is methylene or a bond;
B is an unsubstituted phenylene, a divalent group of a nitrogen-containing saturated ring or a monocyclic aromatic heterocyclic ring 2 which may be substituted with Alk;
X is a group represented by the formula —NR ¹ —CR ² R ³ —, —CR ² R
³ -NR ^1- , -NR ¹ -SO _2- , or -SO ₂ -NR ^1-
Wherein R ¹ is -H, -OH, -Alk,
—O—Alk or —CO—Alk, wherein R ² and R ³ are the same or different, and —H or —Alk, or R ² and R ³ are 又 は O or ＳS, and R ⁴ , R ⁵ : the same or different, —H, —Hal, —halogeno lower alkyl or —Alk, wherein A is aryl optionally having substituent (s), monocyclic ring optionally having substituent (s) Or 2- or 3-cyclic fused heteroaryl, cycloalkyl which may have a substituent, nitrogen-containing saturated ring which may have a substituent, lower alkenyl which may have a substituent, substituent Or lower alkynyl which may have a substituent, or Alk which may have a substituent, or X and A
Are integrated, and the formula (Wherein A ² may have a substituent, 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl A amide or amine derivative or a pharmaceutically acceptable salt thereof, which forms a group represented by the following formula: 5. The method according to claim 1, wherein
Is -Hal, -Alk, -halogeno lower alkyl,-
O-Alk, -OH, a phenyl optionally having 1 to 4 substituents selected from the group consisting of -NO ₂ and -CN, Y is a O, S, CO or CS, B is -Hal, -Alk, -O-Alk, -OH, -N
Phenylene which may have 1 to 3 substituents selected from the group consisting of O ₂ , —CN and —NH—CO—Alk, or D, Y and B are integrated to form Formula 6 (Wherein Y is CO, B ² and D ² are each -Hal,-
Alk, -O-Alk, -OH, -NH-CO-Al
k, —NO ₂ and —CN, which means a benzene ring which may have 1 to 3 substituents selected from the group consisting of: −NR ¹
-CR ² R ³ -or -CR ² R ³ -NR ^1- , wherein R ¹ is -H, -OH, -Alk, or -OA.
lk, R ² and R ³ are the same or different, and —H or —Alk, or R ² and R ³ are integrated to form = O or =
S and A is -Hal, -Alk, -O-Alk,-
_{O-CO-Alk, -NH 2} , -NHAlk, -N (A
_{lk) 2, -NHCO-Alk,} -OH, -NO 2 and -
Phenyl optionally having 1 to 4 substituents selected from the group consisting of CN, or -Hal, -Alk,-
O-Alk, -O-CO- Alk, -NH 2, -NHA
lk, -N (Alk) ₂ , -NHCO-Alk, -O
H, -NO ₂ and 1 to 3 have a substituent is also optionally monocyclic or 2-3 heteroaryl amide or amine derivative, or a the pharmaceutically selected from the group consisting of -CN (Excluding the compounds shown in Table 1). [Table 1] (In the table, the number before each substituent indicates the substitution position, and when there are a plurality of substituents, for example, 2,5-dichloro,
Shown as "2,5-Cl". ) 6. A medicament comprising the amide or amine derivative according to claim 5 or a pharmaceutically acceptable salt thereof.