MXPA98008433A - Derivatives of amida and pharmaceutical composition that contains them, useful as caliber channel inhibitor activated by the release of cal - Google Patents

Abstract

This invention relates to a medicament, particularly an amide derivative by the following general formula (Ii) having an action to inhibit the Ca 2+ channel activated by the release of Ca 2+, and a pharmaceutical composition containing the same as an active ingredient. , particularly a Ca2 + channel inhibitor activated by the release of Ca2 +. (The symbols in the formula having the following meanings: D represents a pyrazolyl group, which may have 1 to 3 lower alkyl groups unsubstituted or substituted by halogen as a substituent (s), B represents a phenylene or thiophenediyl group, X represents a group of a formula -NH-CO-or-CO-NH-, and A represents a phenyl group, which can be substituted with one or more halo atoms, or a five or six membered monocyclic heteroaryl group, which can be substituted with one or more lower alkyl groups

Description

DERIVED FROM AMIDA ICO TECHNICAL FIELD This invention relates to a medicament, particularly an amide derivative having an action to inhibit a Ca 2+ channel activated by Ca 2+ release, and a pharmaceutical composition containing the same as an active ingredient, particularly a channel inhibitor. Ca2 + activated by Ca2 + release.

BACKGROUND OF THE ART It has long been known that calcium ion (Ca2 +) is important for a second intracellular messenger in the activation of several cells. Intracellular Ca2 + also acts as an important regulatory factor in inflammatory cells. However, it has been suggested that voltage-operated Ca2 + channel inhibitors (to be referred to hereafter as "VOCC"), such as nifedipine, do not show inhibitory activity against the activation of inflammatory cells and that there is a mechanism of influx of Ca2 + different from VOCC in inflammatory cells. Hoth et al. have reported that a Ca2 + channel activated by depletion of Ca2 + deposit and selective Ca2 +, mainly a Ca2 + channel activated by Ca2 + release (to be referred to as "CRACC" hereafter; also called Ca2 + channel dependent on the deposit ), is present in mast cells and lymphocytes, and these cells are insensitive to membrane potential (Pflugers Arch., 430, pp. 315 - 322 (1995)). It is known that CRACC is present in various inflammatory cells such as "mast" cells, lymphocytes, astrocytes (J. Biol. Chem., 270, pp. 29-32 (1995)) and the like, and that it is deeply involved in, for example, the production of cytokines and release of lipid mediator (J. Immunol., 155, pp. 285-296 (1995), and Br. J. Pharmacol., 144, pp. 598-601 (1995) ). Recently, it has been revealed that an anti-arthritis tenidap agent has a potency of CRACC inhibitor (Cell Calcium, 14, pp. 1-16 (1993)). Therefore, a CRACC inhibitor has a potential for therapeutic potency in chronic inflammatory diseases including rheumatoid arthritis. It is known that CRACC is also present in endothelial cells (Am. J. Physiol., 269, C 733-738 (1995)) and epithelial cells (J. Biol. Chem., 270, pp. 169-175 (1995)). ). Since it has been reported that the influx of sustained calcium plays a role in the radical involvement of endothelial cells (Am. J. Physiol., 261, C 889-896 (1991)), it has been suggested that a CRACC inhibitor should have efficacy Protective tissue damage involved with endothelial cells. In addition, blockages of calcium influx have been reported to inhibit cell proliferation and interleukin 2 (IL-2) production (Br. J. Pharmacol., 133, pp. 861-868 (1994)). Therefore, a CRACC inhibitor is useful as an agent for the prevention and treatment of proliferative or progressive diseases (e.g., malignant tumor and the like) and autoimmune diseases, and also as a suppressor for tissue rejection in transplants.

On the other hand, it is known that in excitable cells, such as soft muscle cells and nerve cells, intracellular calcium is regulated mainly with VOCC, not with CRACC. Accordingly, it is expected that a calcium channel blocker having CRACC selectivity against VOCC, be a useful agent for the prevention or treatment of various inflammatory diseases, allergic diseases, autoimmune diseases, tissue damage, proliferative diseases and the like, without actions undesirable in the central nervous system and cardiovascular. Recently, some compounds showing CRACC inhibitory activity have been reported, such as a cycloalkyl-piperazinyl ethanol derivative described in published German patent publication 4404249 and a described 2- (3,4-dihydro-1-isoquinolyl) acetamide derivative. in WO 94/00435. It has also been reported that 5-amino-1 - [[3,5-dichloro-4- (4-chlorobenzoyl) phenyl] methyl] -1 H-1, 2,3-triazole-4-carboxamide inhibits CRACC (J Pharm. Exp. Ther., 257, pp. 967-971 (1991)). However, there are no reports on a compound whose CRACC selectivity on VOCC has been confirmed. On the other hand, a published German patent publication 2525024 describes a derivative of 5- (heterocycloylaminophenyl) -1-phenylpyrazole, which shows an anti-inflammatory activity. However, this patent does not describe or suggest about its inhibitory activities against CRACC and the production of IL-2. WO 95/18097 describes an anthranilic acid derivative represented by the following formula (I), which inhibits a cyclic GMP phosphodiesterase. In the formula, R <; R 4 represents H, a halogen, •••, pyrazolyl, which can be substi- tuted, ••; n is 0 to 6, W represents N or CH, Y represents O or S, ••• (see said published patent application for details).

Japanese Laid-Open Patent Application 9-59236 discloses a benzamide derivative R1, R2-di-substituted represented by the following formula (1), which is useful for the prevention and treatment of rheumatic, allergic and other diseases inflammatory In the formula, R1 represents a substituted or unsubstituted aromatic heterocyclic ring, •••, R2 represents a halogen, a nitro, -NR5R6, •••, A represents -C (= Z) NR3R4 or -NR4C (= Z) R3, R3 represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring ••• (see said published patent application for details). However, there is no illustrative description of the pyrazolyl as the aromatic heterocyclic ring group. In addition, there is no description of the inhibitory activities against CRACC and / or production of IL-2. 0) DESCRIPTION OF THE INVENTION The inventors of the present invention have conducted extensive studies on the classification of compounds that have excellent inhibitory activity of CRACC. As a result of the efforts, it has been found that certain amide deposits, which have completely different structures from those of the reported CRACC inhibitors, show excellent inhibitory activity of CRACC. The present invention has been achieved by additionally finding that these compounds have high selectivity of CRACC over VOCC. According to this, this invention relates to a novel amide derivative represented by the following general formula (I) [the symbols having the following meanings in the formula: D represents a pyrazolyl group, which may have 1 to 3 lower alkyl groups unsubstituted or substituted by halogen as substituent (s), B represents a phenylene or thiophenediyl group, X represents a group of a formula -NH-CO- or -CO-N H-, and A represents a phenyl group, which can be substituted with one or more halogen atoms, or a monocyclic heteroaryl group of five or six members, which can be substituted with one or more lower alkyl groups, with the proviso that 4-methyl-4 '[3,5-bis (trifluoromethyl) -1 H -pyrazol-1 -yl] -1 are excluded , 2,3-thiadiazole-5-carboxanilide (to be referred to hereafter as "compound A") and 4'-chloro-5- (1-methyl-5-trifluoromethyl-H-pyrazol-3-yl) thiophene -2-carboxanilide (to be referred to hereafter as "Compound B"); the same should be applied hereinafter] or a pharmaceutically acceptable salt thereof. In this regard, compounds A and B are known compounds described as SEW 04225 and KM 02904 in a reagent catalog published by MAYBRIDGE (UK, Cornwall, August, 1995). However, there are no reports on these in pharmaceutical uses and other applications. A preferred compound of the general formula (I) of the present invention is an amide derivative or a pharmaceutically acceptable salt thereof, wherein D is a pyrazolyl group substituted with at least one trifluoromethyl group or D is 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl or 3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl, and A is phenyl group, which may be substituted with one or more halogen atoms, or a five or six member monocyclic heteroaryl group selected from the group consisting of thiazolyl, thiadiazolyl, thienyl and pyridyl, which may be substituted with one or more lower alkyl groups. This invention also relates to a pharmaceutical composition, which comprises an amide derivative represented by the following general formula (I '), including compounds A and B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier acceptable, particularly to a pharmaceutical composition for use in the inhibition of the Ca2 + channel activated by Ca2 + release. Preferably, it is an inhibitor of IL-2 production, an agent for use in the prevention or treatment of allergic, chronic inflammatory or autoimmune diseases, or an agent for use in the prevention or treatment of bronchial asthma or rheumatoid arthritis. [the symbols having the following meanings in the formula: D represents a pyrazolyl group, which may have 1 to 3 lower alkyl groups unsubstituted or substituted by halogen as a substituent (s), B represents a phenylene or thiophenediyl group, X represents a group of a formula -NH-CO- or -CO-NH-, and A represents a phenyl group which can be substituted with one or more halogen atoms, or a five or six membered monocyclic heteroaryl group, which can be substituted with one or more lower alkyl groups; the same should apply hereafter.] Unless otherwise noted, the term "lower" as used herein means a linear or branched carbon chain having 1 to 6 carbon atoms. The "lower alkyl group" is preferably methyl, ethyl or propyl. The "five or six membered monocyclic heteroaryl group" is a five or six monocyclic heteroaryl group members containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and preferably is thienyl, thiazolyl, thiadiazolyl or pyridyl. Preferably, the "phenylene group" is 1,4-phenylene and the "thiophenediyl group" is 2,5-thiophenediyl.The "halogen" is preferably F or Cl. The "lower alkyl group substituted by halogen" is preferably tuoromethyl The compound of this invention may exist in the form of geometric isomers or tautomers depending on the classes of substituent groups, and these isomers in separate forms or mixtures thereof are included in the present invention. invention can have asymmetric carbon atoms, so that it can exist in forms of optical isomers (R) and (S) based on such carbon atoms All mixtures and isolated forms of these optical isomers are included in the present invention. The compound (I) or (I ') of this invention can form an acid addition salt or, depending on the classes of the substituent groups, a salt with a base. are acceptable, and preferred examples thereof include acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like) or with organic acids (e.g., formic acid, acetic acid). , propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and the like) and you go out with inorganic bases (eg, sodium, potassium, magnesium, calcium, aluminum and the like) or with organic bases (eg, methylamine, ethylamine, ethanolamine, lysine, ornithine and the like), as well as ammonium salts. In addition, various hydrates and solvates and polymorphism of the compound (I) or (I ') and salts thereof are also included in this invention.

(Production method) The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by making use of the characteristics of their basic structure or the classes of their substituents and by employing various known synthesis methods. In that case, depending on the class of each functional group, sometimes it can be effective, from the point of view of production techniques, to replace said functional group with an appropriate protective group, mainly a group, which can be converted to said functional group easily, in the stage of raw materials or intermediaries. Subsequently, the compound of interest can be obtained by removing the protective group as the occasion demands. Examples of such functional groups include a hydroxyl group, a carboxyl group and the like and examples of their protecting groups include those which are described in "Protective Groups in Organic Synthesis", 2nd edition, edited by Greene and Wuts, which may optionally be used. depending on the reaction conditions. The following describes typical methods for the preparation of the compound of the present invention.

Production method 1 In this method, as shown in the above reaction formula, the compound (1-1) or (I-2) of the present invention is obtained by subjecting an amine derivative represented by the general formula (II) or (V) ) and a carboxylic acid derivative represented by the general formula (III) or (IV) to the amidation reaction. The carboxylic acid derivative (II) or (IV) which can be used in the production method 1, is a free carboxylic acid or a reactive derivative thereof, and examples of the reactive derivative include acid halides, such as acid chlorides , acid bromides and the like; azides; active esters which can be prepared using methanol; ethanol, benzyl alcohol, phenol which can be substituted, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like; asymmetric acid anhydrides; and acid anhydrides mixed with ethoxycarbonyl chloride, isobutylcarbonyl chloride, alkylcarboxylic acid, p-toluenesulfonic acid, and the like. These reactive derivatives are commercially available or can be produced by the usual methods.

The amidation reaction can be carried out by the usual methods. When the reaction is performed using a free carboxylic acid, it is necessary to use a condensing agent, such as N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSCD) or the like, or agent carboxylic acid activator, such as 1,1 '-carbonyldiimidazole, N, N'-disuccinimidyl carbonate, diphenylphosphoryl azide, phosphorus oxychloride, phosphorus trichloride, triphenylphosphine / N-bromosuccinimide or the like. The reaction is carried out using an amine derivative represented by the general formula (II) or (V) and a carboxylic acid derivative represented by the general formula (11 I) or (IV), in equimolar amounts or one thereof in excess, in an inert organic solvent of reaction, such as pyridine, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, dichloromethane, 1,2-dichloroethane (DCE), chloroform, dimethylformamide (DMF), ethyl acetate, acetonitrile Similar. The reaction temperature is optionally selected depending on the classes of reaction derivatives. Depending on the classes of reaction derivatives, the addition of a base such as triethylamine, pyridine, picoline, N, N-dimethylaniline, potassium carbonate, sodium hydroxide or the like, may be advantageous in some cases, from the point of view of acceleration of the reaction. It is possible to use pyridine also as the solvent.

Production method 2 (In the above reaction formula, each of Ra and Rb represents H or a lower alkyl group). In this production method, the compound (1-3) of the present invention is obtained by carrying out the trifluoroacetylation of the carbon atom adjacent to the ketone of a compound represented by the general formula (VI) and then effecting the cyclization by reacting it with a hydrazine derivative. The first step of trifluoroacetylation can be performed by allowing the compound to react with a trifluoroacetylating agent (eg, ethyl trifluoroacetate, trifluoroacetic acid anhydrous or the like) at a temperature from -78 ° C to reflux temperature in a solvent, such such as methanol, ethanol, 1, 3, -dimethylimidazolidin-2-one (DMI), THF, DMF or the like, in the presence of a base, such as sodium methoxide, sodium ethoxide, alkali metal hexamethyldisilazide, hydride sodium, alkyl lithium, triethylamine or similar. The second step of the cyclization reaction can be performed by allowing the compound obtained in the first step to react with a hydrazine derivative in a solvent, such as methanol, ethanol or the like, or without a solvent, in the presence or absence of an acid, such as acetic acid, hydrochloric acid or the like, or Lewis acid, such as titanium (IV) isopropoxide, titanium (IV) chloride, boron trifluoride-diethyl ether complex or the like. This reaction can be carried out at a temperature from the cooling temperature to the reflux temperature.

(Production method of starting compounds) The starting compounds of the aforementioned production methods are commercially available or can be easily produced by methods well known to those skilled in the art. Each of the reaction products obtained by the aforementioned production methods is isolated and purified as a free compound, a salt thereof, a hydrate thereof or a solvate thereof. The salt can be produced by a usual salt-forming method. Isolation and purification are carried out by using usually used chemical techniques, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography and the like. Various forms of isomers can be isolated by the usual methods, making use of the physicochemical differences between isomers. For example, the optical isomers can be separated by means of a conventional racemic resolution method, such as fractional crystallization or chromatography. In addition, an optical isomer can also be synthesized from an appropriate optically active starting compound.

INDUSTRIAL APPLICABILITY The compound of the present invention is useful as an active ingredient of pharmaceutical compositions. Since it has inhibitory activities on CRACC and the production of IL-2, it is particularly useful as a CRACC inhibitor or 1L-2 production. It is also particularly useful as an agent for use in the prevention and treatment of allergic, chronic inflammatory or autoimmune diseases, in which CRACC and / or the production of IL-2 are involved. In this regard, examples of allergic, chronic inflammatory or autoimmune diseases include various diseases in which CRACC and / or the production of IL-2 are involved, such as bronchial asthma, psoriasis, atopic diseases including atopic dermatitis, inflammatory bowel diseases including Crohn's disease, peptic ulcer, glomerular nephritis, hepatitis, pancreatitis, collagen disease, rheumatoid arthritis, osteoarthritis, rejection in transplants and the like. The applicability of the compound of the present invention to the aforementioned diseases is evident from the results of in vitro tests on inhibition of CRACC and the production of IL-2, which will be described later, as well as the results of several tests carried out using animal models for diseases such as eosinophilia of airways induced by antigens as a typical model for bronchial asthma, some models of T cell-dependent diseases and a collagen-induced arthritis in mice. In addition, since the compounds of the present reaction also have Inhibitory effects on the production of IL-4, IL-5, MMP-1 and TNFa, such results also support its applicability to the aforementioned diseases. On the other hand, the anti-proliferative effect of the CRACC inhibitor suggests that it should be useful to prevent or treat proliferative or progressive diseases such as malignant tumors, arteriosclerosis, multiple organ sclerosis, various types of fibrosis, burn keloid and the like. Furthermore, since the CRACC inhibitor inhibits the activation of inflammatory cells such as "mast" cells, leukocytes and astrocytes, which are involved with inflammation in various brain or peripheral tissues, their action can be expected to protect tissues from their damage. as a reperfusion injury due to ischemia, head injury, cerebral infarction and myocardial infarction. In particular, the compound of the present invention, which possesses CRACC selective inhibitory activity on VOCC, is useful, because it can cause the inhibition of CRACC without undesirable reactions induced by the activation of VOCC in the central nervous system and cardiovascular system and the like. . The following shows certain tests and their results in order to confirm the pharmacological actions of the compound of the present invention. (1) Inhibitory activity of CRACC A suspension of Jurkat cells (6 x 106 / ml) loaded with a fluorescent indicator dye of calcium fura-2 (1 μM) was dispensed in 100 μl portions in cavities of a 96-well microplate. The increase in intracellular calcium stimulated with a calcium pump inhibitor (thapsigargin) was induced by adding to each cavity about 100 μl of Hanks balanced salt solution, containing a drug to be tested twice as much as the concentration as the concentration. final and 2 μM thapsigargin (final concentration, 1 μM), and, subsequently 30 minutes after the addition, a fluorescent intensity ratio (R) was calculated from two fluorescent intensities obtained at excitation wavelengths of 340 nm / 500 nm and 380/500 nm, respectively. To calculate R, the self-fluorescence of the drug to be tested was measured in a cell-free system, and the effect of auto-fluorescence on the fluorescence of fura-2 was corrected. The intracellular calcium concentration was obtained by the following calculation formula based on a maximum reaction of R (Rmax) by stimulation of 25 μM of ionomycin, a minimum reaction of R (Rmin) obtained by stimulation of 5 μM ionomycin + 1 mM of EGTA, a fluorescence efficiency (Sb2) of a calcium ligation dye at an excitation wavelength of 380 nm / 500 nm and a fluorescence efficiency (Sf2) of a calcium dissociation dye at a wavelength of excitation 380 nm / 500 nm. Calculation formula: intracellular calcium concentration (nM) = 224 x [(R - Rmin) / (Rmax - R)] x [Sf2 / Sb2] Using the intracellular calcium concentration thus calculated in the presence of a predetermined concentration of each one of the medications and that of the control solvent, a proportion of inhibition calcium influx (inhibition of CRACC) to calculate its concentration to inhibit 50% CRACC (ICso value) - The IC 50 value of the compounds of Examples 1 to 6 was within the range of 0.51 to 0.050 μM. (2) Selectivity of CRACC inhibition against VOCC A suspension of rat neuroblasts PC12-h5 (2 x 106 / ml) loaded with a fluorescent indicator dye of calcium fura-2 (1 μM) was dispensed in 100 μl portions in cavities of a microplate of 96 cavities. The increase of intracellular calcium stimulated with high concentration of potassium chloride was induced by adding to each cavity about 100 μl of balanced salt solution of Hanks, containing a drug to be tested in two times more concentration than the final concentration and 100 mM of KCl (final concentration, 50 mM), and, after 30 minutes of the addition, a ratio of fluorescence intensity (R) was calculated from two fluorescence intensities obtained at excitation wavelengths of 340 nm / 500 nm and 380 nm / 500 nm, respectively, To calculate R, the auto-fluorescence of the drug to be tested was measured in a cell-free system, and the effect of auto-fluorescence on the fluorescence of fura-2 was corrected. The ICSo value of VOCC inhibition was calculated in the same manner as in the aforementioned CRACC inhibition case, and compared with that of CRACC inhibition.

The VOCC inhibition of the compounds of Examples 1 to 6 was 16 times or more weak than their inhibition of CRACC. (3) Inhibitory effect on the production of IL-2 The inhibitory effect of the compound of the invention on the production of IL-2 from Jurkat cells was tested according to the method described by S. Clare Chung et al. in Br. J. Pharmacol. , 113: 861-868, 1994, and its ICS0 value was calculated. The compounds of this invention showed IC5o values of 1 μM or less. (4) Effect in the contact hypersensitivity model induced by TNCB In ICR male mice of five weeks of age, the effect of the compound of the invention on contact hypersensitivity induced by TNCB was tested, in almost the same way as the method described in Current Protocols in Immunology (John Wiley &Sons, Inc., 1994). The compounds of this invention inhibited contact hypersensitivity induced by TNCB in a dose-dependent manner. (5) Inhibitory effect in concanavalin A-induced hepatitis (ConA) in mice This test was performed in five-week-old female Balb / c mice (SLC) using a method similar to the method reported by G. Tiegs et al. in J. Clin. Invest. , 1992, 90: 196-203. The compounds of This invention inhibited ConA-induced hepatitis in a dose-dependent manner. (6) Inhibitory effect in collagen-induced arthritis in mice The inhibitory effect in arthritis was tested in male DBA / 1J mice of five weeks of age (Charles River Japan), in a manner similar to the methods reported by Fumio Nishikaku and Yoshihiko Koga in Immunopharmacology, 25, 65-74 (1993) and by Fuminori Kato, Masanao Nomura and Kyoko Nakamura in Annals of the Rheumatic Disease, 55, 535-539 (1996). The compounds of this invention showed significant inhibition in arthritis. (7) Inhibitory effect on antigen-induced respiratory pathway eosinophilia in rats The inhibitory effect on antigen-induced airway eosinophilia was tested almost in the same way as the method reported by W. Elwood et al. in Inflamm. Res., 44: 83-86, 1995. In this regard, the drug was administered 30 minutes before exposure to the antigen in the case of intravenous injection, or 1 hour before and 3 hours after antigen exposure in the case of oral administration. In this model, the compounds of this invention inhibited numbers of infiltrated total leukocytes and those of infiltrated eosinophils in the respiratory tract.

A pharmaceutical composition, which contains the compound (I ') of the present invention or a salt thereof and a pharmaceutically acceptable carrier, can be prepared by a commonly used method, employing at least one of the compounds represented by the general formula (I ') or salts thereof and a carrier for medicinal use, a filler or other addis usually employed in pharmaceutical preparations. Its administration can be effected either by oral administration in the form of tablets, pills, capsules, granules, powders, solutions and the like, or by parenteral administration in the form of intravenous, intramuscular and similar injections, suppositories, percutaneous absorption preparations and Similar. The solid composition for use in oral administration according to the present invention is used in the form of tablets, powders, granules and the like. In such a solid composition, one or more ac substances are mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or aluminum magnesium silicate. By the usual procedures, the composition may contain other addis than the inert diluent, such as a lubricant (e.g., magnesium stearate or the like), a disintegrating agent (e.g., calcium cellulose glycolate or the like), a stabilizing agent (for example, lactose or the like) and a solubilizing assistant agent (for example, glutamic acid, aspartic acid or the like). If necessary, the tablets or pills can be coated with films of a sugar or a gastric or enteric substance, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like. The liquid composition for oral administration use includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains an inert diluent generally used, such as purified water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents, such as a wetting agent, a suspending agent and the like, as well as sweeteners, flavors, aromatics and antiseptics. Injections for parenteral administration use include non-aqueous or aqueous aseptic solutions, suspensions and emulsions. Examples of the diluent to be used in the solutions suspensions and aqueous solutions include distilled water for use in injection and physiological saline. Examples of diluents for use in suspensions and non-aqueous solutions include propylene glycol, polyethylene glycol, vegetable oil (for example, olive oil or the like), alcohol (for example, ethanol and the like), and polysorbate 80. Such a composition may additionally contain auxil agents, such as antiseptic agent. a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent (lactose, for example), and a solubilizing agent (glutamic acid or aspartic acid, for example). These compositions are sterilized by filtration through a filter that retains bacteria, mixed with a germicide or irradiation. Alternatively, they can be used by becoming first in compositions sterile solids and then dissolve them in sterile water or a sterile solvent for injection use before use. In the case of oral administration, the appropriate daily dose is usually from about 0.001 to 10 mg / kg of body weight, and the daily dose is administered once a day or divided into 2 to 4 doses per day. In the case of intravenous injection, the appropriate daily dose is usually from about 0.0001 to 1 mg / kg of body weight, and the daily dose is administered once a day or divided into a plurality of doses per day. The dose is optionally decided upon taking into consideration symptoms, age, sex and the like of each patient to be treated.

BETTER WAY OF CARRYING OUT THE INVENTION The present invention is described additionally in detail, based on the following examples. However, it should be understood that the compounds of the present invention are not limited to the compounds described in the following examples.

Example 1 A mixture of 4-methylthiazole-5-carboxylic acid (108 mg), 4- [3,5-bis (trifluoromethyl) -1 H -pyrazol-1-yl] aniline (223 mg), hydrochloride of WSCD (152 mg) and DCE (5 ml) was stirred overnight at room temperature. Water (10 ml) was added to the reaction mixture and the product formed in this manner was extracted with a mixed solvent of diethyl ether (5 ml) and ethyl acetate (10 ml). The extract was washed with 1N hydrochloric acid, aqueous solution of sodium hydrogen carbonate and saturated brine in that order. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue like this • obtained was purified by silica gel column chromatography (levigant, n-hexane: ethyl acetate = 2: 1) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane, give 4-methyl-4 '- [3,5-bis (trifluoromethyl) -1 H -pyrazol-1-yl] thiazole-5-carboxanilide (143 mg) as colorless needles.

Example 2 A mixture of 5- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophene-2-carbonyl chloride (150 mg) was added with dichloromethane (1.5 ml) to a mixture. of 2-chloroaniline (68 mg), pyridine (42 mg) and dichloromethane (2 ml) and stirred for 30 minutes at room temperature. One was added Aqueous saturated sodium carbonate aqueous solution was added to the reaction mixture, the product thus formed was extracted with ethyl acetate, and then the extract was washed with saturated brine. The organic layer The resultant was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was returned to crystallize from ethanol to give 2'-chloro-5- (1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl) thiophene-2-carboxanilide (80 mg) as colorless crystals. In this case, the above-mentioned starting compound, 5- (1-methyl-3-trifluoromethyl-1 H -pyrazol-5-yl) thiophene-2-carbonyl chloride, was obtained as a brown solid by an acid treatment. - (1-methyl-3-trifluoromethyl-1 H-pyrazol-5-yl) thiophene-2-carboxylic acid with oxalyl chloride.

Example 3 Sodium methoxide (257 mg) was added to a mixture of 4'-acetyl-4-chlorobenzanilide (1.00 g) and DMI (10 ml) at 0 ° C, and the mixture thus prepared was stirred for 2 hours at room temperature. ambient. Ethyl trifluoroacetate (0.522 ml) was added to the reaction solution and stirred for 2 days at 60 ° C. Water (50 ml) and hydrochloric acid (10 ml) were added to the reaction mixture, the product thus formed was extracted with ethyl acetate and then the extract was washed with water and saturated brine in that order. The organic layer thus obtained was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. A mixture of the residue thus obtained with methylhydrazine (0.206 ml), acetic acid (2 ml) and ethanol (20 ml) was mixed for 21 hours at room temperature. After concentration of the reaction mixture under reduced pressure, ethyl acetate (100 ml) was added to the residue thus obtained and washed with saturated aqueous sodium carbonate aqueous solution and saturated brine, in that order. The organic layer thus obtained was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (levigante); n-hexane: ethyl acetate = 3: 1) and then recrllized from a mixed solvent of ethyl acetate and n-hexane to give 4-chloro-4 '- (1-methyl-3-trif! uoromethyl-H-pyrazol-5-yl] benzanilide (440 mg) as colorless powder crls.

The compounds of Example 4: (4-methyl-4 '- [3,5-bis (trifluoromethyl) -1 H -pyrazol-1-yl] -1,2,3-thiadiazole-5-carboxynylda), Example 5: (3-Methyl-4 '- [3,5-bis (trifluoromethyl) -1 H -pyrazol-1-yl] thiophene-2-carboxanilide) and Example 6: (4' - [Sd-bistrifluoromethyl-I H -pyrazol-l ipnicotinanilide) shown in the following Table 1, were obtained respectively in the same manner as described in Example 1. The structures and physicochemical properties of the compounds of the Examples are shown in Table 1. In the table, Ex means Example No., Str means structural formula, Dat means physicochemical properties, mp. Means melting point, NMR means d ppm of nuclear magnetic resonance spectrum (DMSO-d6, internal standard TMS) and NMR (CDCI3) means d ppm of nuclear magnetic resonance spectrum (CDCI3, internal standard TMS).

Table 1

Claims (9)

1. An amide derivative represented by the following general formula (I) (the symbols in the formula having the following meanings: D represents a pyrazolyl group, which may have 1 to 3 lower alkyl groups unsubstituted or substituted by halogen as a substituent (s), B represents a phenylene or thiophenediyl group, X represents a group of a formula -NH-CO- or -CO-NH-, and A represents a phenyl group, which can be substituted with one or more halogen atoms, or a five or six membered monocyclic heteroaryl group, which can be to be substituted with one or more lower alkyl groups, with the proviso that 4-methyl-4 '[3,5-bis (trifluoromethyl) -1 H -pyrazol-1-yl] -1,2,3-thiadiazole is excluded -5-carboxanilide and 4 * -chloro-5- (1-methyl-5-trifluoromethyl-1 H -pyrazol-3-yl) thiophene-2-carboxanilide) or a pharmaceutically acceptable salt thereof.

2. The amide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein D is a pyrazolyl group substituted with at least one trifluoromethyl group.

3. The amide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein D is 1-methyl-3-trifluoromethyl-1 H-pyrazol-5-yl or 3,5-bis (trifluoromethyl) -1 H -pyrazol-1-yl, and A is a phenyl group which can be substituted with a halogen atom, or a five or six membered monocyclic heteroaryl group, selected from the group consisting of thiazolyl, thiadiazolyl, thienyl and pyridyl, the which can be substituted with a lower alkyl group.

4. A pharmaceutical composition for inhibiting the Ca2 + channel activated by Ca2 + release, which comprises an amide derivative represented by the following general formula (I ') or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (the symbols in the formula having the following meanings: D represents a pyrazolyl group, which may have 1 to 3 lower alkyl groups unsubstituted or substituted by halogen as a substituent (s), B represents a phenylene or thiophenediyl group, X represents a group of a formula -NH-CO- or -CO-N H-, and A represents a phenyl group which can be substituted with one or more halogen atoms, or a five or six membered monocyclic heteroaryl group, which can be to be substituted with one or more lower alkyl groups.

5. The pharmaceutical composition according to claim 4, wherein it is an inhibitor of IL-2 production.

6. The pharmaceutical composition according to claim 5, wherein it is an agent for the prevention or treatment of allergic, chronic inflammatory or autoimmune diseases.

7. The pharmaceutical composition according to claim 6, wherein it is an agent for the prevention or treatment of bronchial asthma.

8. The pharmaceutical composition according to claim 6, wherein it is an agent for the prevention or treatment of rheumatoid arthritis.

9. The pharmaceutical composition according to any of claims 4 to 8, wherein it comprises an amide derivative selected from the group consisting of 4-methyl-4 '- [3,5-bis (trifluoromethyl) -1H-pyrazole. -1-yl] thiazole-5-carboxanilide, 2'-chloro-5- (1-methyl-3-trifluoromethyl-1 H -pyrazol-5-yl) thiophene-2-carboxanilide, 4-chloro-4 '- (1 -methyl-3-trif luoromethyl-1H-pyrazol-5-yl] benzanidyl, 4-methyl-4 '- [3,5-bis (trifluoromethyl) -1H-pyrazole-1 [I] -1, 2 , 3-thiadiazole-5-carboxanilide, 3-methyl-4 '- [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] thiophene-2-carboxanilide and 4' - [3,5-bis] (trifluoromethyl) -1H-pyrazol-1-yl] nicotinanilide, or a pharmaceutically acceptable salt thereof.