Amide derivative and pharmaceutical composition

 

(57) Abstract:

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups. Also described pharmaceutical composition on the basis of the claimed compounds, which is designed to inhibit the excretion of CA2+channels activated by release of CA2+. The compounds may be used as a means for the prevention or treatment of various inflammatory diseases and allergic diseases. 2 c. and 7 C.p. f-crystals, 1 PL.

This invention relates to a medicinal product, in particular the amide derivative having the ability to inhibit CA2+channels, the act is of gradient, in particular inhibitor of CA2+channels activated by the release or secretion of CA2+.

Background of the invention

It has long been known that calcium ions (CA2+important for intracellular secondary mediator in the activation of different cells. Intracellular CA2+also act as an important regulatory factor in inflammatory cells. However, it has been suggested that blockers of voltage gated CA2+channels (hereinafter referred to here PSCC), such as nifedipine, do not show inhibitory activity against activation of inflammatory cells and in inflammatory cells there is another, rather than through PSCC, the mechanism of absorption of CA2+.

Hoth et al. reported that Sa2+selective and activated by depletion of CA2+calcium channels, and it is activated by release of CA2+channels (hereafter called "ABCCC", also called dependent accumulation of CA2+channels) are present in mast cells and lymphocytes, these cells are not sensitive to the membrane potential (Pflugers Arch., 430, pp. 315-322 (1955)). It is known that ABCCC have several types of cells involved in the inflammatory process, such as fat UCLA cytokines and release of lipid mediator (J. Immunol. , 155, pp. 285-296 (1995) and Br. J. Pharmacol., 114, pp. 598-601 (1995)).

It was recently discovered that anti-arthritis agent, tenidap, has activity blocker ABCCC (Cell Calcium, 14, pp. 1-16 (1933)). Therefore, there is a possibility of therapeutic action of the blocker ABCCC in chronic inflammatory diseases, including rheumatoid arthritis.

It is known that ABCCC are also present in endothelial cells (Am. J. Physiol. , 269, S. 733-738 (1995)) and epithelial cells (J. Biol. Chem., pp. 29169-29175 (1995)). As it was reported that the continuous absorption of calcium plays a role in radical effects on endothelial cells (Am. J. Physiol. , 261, C. 889-896 (1991), it is assumed that the blocker ABCCC must have protective (preventive) action in respect associated with endothelial cells tissue damage.

In addition, it was reported that the blockade of calcium absorption suppresses cell proliferation and production of interleukin 2 (IL-2) (Br. J. Pharmacol., 113, pp. 861-868 (1994)). Therefore, the inhibitor ABCCC can be used as a tool for the prevention and treatment of proliferative or progressive disease (for example, malignant tumors and the like) and autoimmune diseases, as well as with whom ageney cells, such as smooth muscle cells and nerve cells, intracellular calcium is mainly regulated through PSCC and not using ABCCC. It is therefore expected that the calcium channel blocker that has selectivity for ABCCC compared to PSCC, can be used as a means for the prevention or treatment of various inflammatory diseases, allergic diseases, autoimmune diseases, tissue injury, proliferative diseases, etc., without undesirable actions on the cardiovascular and Central nervous system.

It was recently reported on some compounds exhibiting inhibitory activity ABCCC, such as derivatives of cycloalkylcarbonyl described in the published patent application Germany 4404249, and 2-(3,4-dihydro-1-ethanolic)acetamide derivative described in WO 94/00435. It was also reported that 5-amino-1-[3,5-dichloro-4-(4-chlorobenzoyl)phenyl] methyl] -1H-1,2,3-triazole-4-carboxamide inhibits ABCCC (J. Pharm. Exp. Ther., 257, pp. 967-971 (1991)). However, the described connections, whose selectivity for ABCCC compared to PSK would be confirmed.

On the other hand, in the published patent application Germany 2525024 described 5-(literoticacom the patent is not described and not assume its inhibitory activity against ABCCC and production of IL-2.

In WO 95/18097 describes a derivative of Anthranilic acid represented by the following formula (I), which inhibits cyclic GMP-phosphodiesterase. In the formula, R1-R4represent H, halogen,..., pyrazolyl, which may be substituted,...; n is 0-6, W is N or CH, Y is O or S,... (see the mentioned published patent application).

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Not in the examined published Japanese patent application 9-59236 described R1, R2-disubstituted benzamide derivative represented by the following formula (1), which can be used for the prevention and treatment of rheumatic, allergic and other inflammatory diseases. In the formula, R1represents a substituted or unsubstituted aromatic heterocyclic ring,..., R2represents halogen, nitro, -NR5R6... , And represents-C(=Z)NR3R4or-NR4C(=Z)R3, R3represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (see the mentioned published patent application). However, there is no illustrative descriptions pyrazolidine group in cacheset ABCCC and/or production of IL-2.

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Description of the invention

The applicants in this invention have conducted extensive studies on the selection of compounds with excellent inhibitory ABCCC activity. The result of these efforts, it was discovered that certain amide derivatives, which have completely different structures than those reported as inhibitors ABCCC, exhibit excellent inhibitory activity ABCCC. This invention was completed additional discovery that these compounds possess high selectivity for ABCCC compared to PSCC.

Accordingly, the present invention relates to new amide derivative represented by the following General formula (I)

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[symbols in the formula have the following meanings:

D represents pyrazolidine group which may contain 1 to 3 of halogen or unsubstituted lower alkyl groups as a substituent(s),

In is fenelonov or topendialog group

X represents a group of formula-NH-CO - or-CO-NH-,

A represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic Goethe and, that excluded 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] -1,2,3-thiadiazole-5-carboxanilide (hereinafter listed here as "compound a") and 4'-chloro-5-(1-methyl-5-trifluoromethyl-1H-pyrazole-3-yl)thiophene-2-carboxanilide (hereinafter listed here as "compound B"); and then in the same way] or its pharmaceutically acceptable salt.

In this regard, the compounds a and B are known compounds, described as SEW 04225 and KM 02904 in the directory of chemicals, published MAYBRIDGE (UK, Cornwall, August, 1995). However, reports of their pharmaceutical use and other applications are missing.

The preferred compound of General formula (I) according to the present invention is an amide derivative or its pharmaceutically acceptable salt, in which D represents pyrazolidine group, substituted by at least one triptorelin group, or D is 1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl or 3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group selected from the group comprising thiazolyl, thiadiazolyl, thienyl and pyridyl which may be substituted by one or more allergic amide derivative, represented by the following General formula (I'), including the compounds a and B, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, in particular to pharmaceutical compositions for use in the inhibition of release of CA2+activated CA2+channels.

Preferably it is an inhibitor of the production of IL-2, a tool for use in the prevention and treatment of allergic and chronic inflammatory or autoimmune diseases or tool for use in the prevention and treatment of bronchial asthma or rheumatoid arthritis.

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[symbols in the formula have the following meanings:

D represents pyrazolidine group which may contain 1 to 3 of halogen or unsubstituted lower alkyl groups as a substituent(s),

In is fenelonov or thienylene group

X represents a group of formula-NH-CO-or-CO-NH-,

A represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more lower alkyl groups; and the branched carbon chain, containing from 1 to 6 carbon atoms. "Lower alkyl group" is preferably methyl, ethyl or propyl. "Five - or six-membered monocyclic heteroaryl group is five - or six-membered heteroaryl group containing from 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, and is preferably tanila, thiazolium, thiadiazolyl or pyridium. Preferably "fenelonov group" represents 1,4-phenylene, and tibenderana group is 2,5-topendialog.

"Halogen is preferably F or CL. "Galactosaemia lower alkyl group" is preferably a trifluoromethyl.

The connection according to this invention may exist as geometric isomers or tautomers depending on species groups substituents, and these isomers in separated form or in a mixture are included in the present invention. In addition, the compound of the present invention may have asymmetric carbon atoms, there may exist in the form of (R) and (S) optical isomers on the basis of such carbon atoms. All these compounds and certain types of these optical isomers are included in the present invention.

Soedinenie Vice salt with base. Such salts are pharmaceutically acceptable salts, and their preferred examples include salts of accession of inorganic acids (for example, chloroethanol acid, Hydrobromic acid, iodomethane acid, sulfuric acid, phosphoric acid, etc. or 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, econsultancy acid, p-toluensulfonate acid, aspartic acid, glutamic acid, etc.,) and salts with inorganic bases (e.g. sodium, potassium, magnesium, calcium, aluminum, etc.) or organic bases (for example, methylamine, ethylamine, ethanolamine, lysine, ornithine, etc.,), and ammonium salt.

In addition, this invention includes various hydrates and salt wool and polymorphism of the compound (I) or (I') or their salts.

(Production method)

The compound of the present invention and its pharmaceutically acceptable salt can be obtained by use of characteristic p the different methods of synthesis. In this case, depending on the type of each functional group can sometimes be effective from the point of view of the method for obtaining replace the specified functional group suitable protective group, namely a group which can be easily converted into a specified functional group at the stage of the original product or intermediates. Then interest can be obtained by removing the protecting group as necessary. Examples of such functional groups include hydroxyl group, carboxyl group, etc., and examples of such protective groups include those described in "Protective Groups in Organic Synthesis", 2nd edition, published by Greene and Wuts, which may not necessarily be used depending on the reaction conditions.

The following describes the typical ways of obtaining compounds of the present invention.

The method of obtaining 1

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According to this method, as shown in the above reaction scheme, compound (I-1) or (I-2) according to the present invention is obtained by implementation of the amidation reaction amine derivative represented by the General formula (II) or (V) with carboxylic acid derivative represented by the General formula (III) or (IV).

Production is oil acid or its reactive derivative, and examples of the reactive derivative include acid halides such as acid chlorides of the acids, bromohydrin acids, etc.; azides acids, active esters, which can be obtained using methanol, ethanol, benzyl alcohol, phenol which may be substituted, 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.; symmetric acid anhydrides and mixed acid anhydrides with ethoxycarbonylethyl, isobutylbarbituric, alkalicarbonate acid, p-toluensulfonate acid, etc., These reactive derivatives are commercially available or can be obtained by conventional methods.

The amidation reaction can be conducted by conventional methods.

When the reaction is carried out 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 so on, or activated carboxylic acid agent, such as 1,1'-carbonyldiimidazole, N, N'-disuccinimidyl, diphenylphosphoryl, phosphorus oxychloride, trichloride, triphenylphosphine/N-bromosuccinimide, or etc.

The reaction is carried out using the amine prey by formula (III) or (IV), in equimolar amounts, or one of them in excessive quantities in reactionnaire organic solvent, such as pyridine, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, dichloromethane, 1,2-dichloroethane (EDC), chloroform, dimethylformamide (DMF), ethyl acetate, acetonitrile or so on, the reaction Temperature is chosen arbitrarily depending on the type of reaction derived.

Depending on the type of derivative reaction in some cases it may be beneficial to add a base, such as triethylamine, pyridine, picoline, N, N-dimethylaniline, potassium carbonate, sodium hydroxide or similar, from the point of view of accelerating the reaction. It is also possible the use of pyridine as solvent.

The method of obtaining 2

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(In the above reaction scheme, each of Ra and Rb represents H or a lower alkyl group).

This method of obtaining the compound (1-3) in this invention is obtained by triptoreline adjacent to the ketone carbon atom in the compounds represented by the General formula (VI), and then cyclization by reacting it with a derivative of hydrazine.

The first stage of triptoreline can be conducted by reacting the you or etc.) at a temperature of from -78oC to the boiling point (reflux) in a solvent such as methanol, ethanol, 1,3-dimethylimidazolidin-2-he (SIAS), THF, DMF or similar , in the presence of a base such as sodium methoxide, ethoxide sodium, hexamethyldisilazide alkali metal, sodium hydride, alkylate, triethylamine or etc.

The second stage, the cyclization reaction can be conducted by reacting the compound obtained in the first stage, with a derivative of hydrazine in a solvent such as methanol, ethanol or similar, or without solvent in the presence or in the absence of acid, such as acetic acid, chloromethane acid or similar, or a Lewis acid such as isopropoxide titanium (IV) chloride titanium (IV) complex of boron TRIFLUORIDE-diethyl ether or etc., This reaction can be conducted at a temperature of from cooling temperature to the boiling temperature under reflux.

(Method of obtaining the source connections)

Starting compound for the above-mentioned methods of obtaining commercially available or can be easily obtained well-known in the art methods.

Each of the reaction products obtained by the above methods to obtain, allocate and oC conventional method of producing salt. Isolation and purification is carried out by use of commonly used chemical methods, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, etc., Various types of isomers can be isolated by conventional methods using physico-chemical differences between the isomers. For example, optical isomers can be separated by conventional separation method racemates, such as fractional crystallization or chromatography. In addition, the optical isomer can be synthesized from the corresponding optically active starting compound.

INDUSTRIAL APPLICABILITY

The connection according to the present invention can be used as an active ingredient of pharmaceutical compositions. Because it has inhibitory ABCCC and production of IL-2 activity, it is particularly useful as an inhibitor ABCCC or production of IL-2.

It is also, in particular, can be used as a tool for use in the prevention and treatment of allergic and chronic inflammatory or autoimmune diseases that are associated with ABCCC and/or the production of IL-2. Nye disease, related ABCCC and/or by producing IL-2, such as bronchial asthma, psoriasis, atopic diseases, including atopic dermatitis, inflammatory bowel disease, including Crohn's disease, peptic ulcer, glomerulonephritis, hepatitis, pancreatitis, collagen disorders, rheumatoid arthritis, osteoarthritis, transplant rejection, etc.

The applicability of the compounds of the present invention under the above diseases can be seen from the results of tests in vitro for inhibition ABCCC and produtsirovaniya IL-2, which will be described later, and also from the results of various tests conducted using animal models for diseases such as caused by antigen eosinophilia respiratory tract as a typical model of bronchial asthma, some models of diseases that are dependent on T cells and induced collagen arthritis in mice. In addition, since compounds of this invention also possess inhibitory effect on the production of IL-4, IL-5, MMP-1 and TNF, these results also confirm the applicability of the above diseases.

On the other hand, the antiproliferative effect of inhibitor ABCCC assumes that he must be Phnom tumor, arteriosclerosis, multiple sclerosis bodies, various types of fibrosis, burn scars, etc., as Well as the blocker ABCCC inhibits activation of inflammatory cells such as mast cells, white blood cells and astrocytes, which are involved in the inflammatory process in some peripheral tissues and brain tissues, we can expect its actions to protect the tissues from damage, such as a defeat in ischemia-reperfusion injury, head trauma, cerebral infarction and myocardial infarction.

In particular, the compound of the present invention, which has selective with respect PSCC inhibitory activity ABCCC, is useful because it can cause inhibition ABCCC activated without using PSCC unwanted reactions in the Central nervous system and cardiovascular system, etc.

The following are some of the tests and their results to confirm the pharmacological action of the compounds according to the present invention.

(1) ABCCC inhibiting activity

Cell suspension Turk (Jurkat) (6106/ml), saturated indicator on the fluorescent calcium dye Fura-2 (fura-2) (1 μm) was distributed in portions of 100 μl of the cell 96-cell of the blade is Inom (thapsigargin), caused by adding to each well 100 μl of a balanced salt solution Hanks, containing the study drug at a concentration two times higher final concentration of 2 μm thapsigargin (final concentration 1 mm), and 30 minutes after adding quantitatively evaluated the ratio (R) of the intensity of fluorescence obtained by excitation light with a wavelength of 340 nm/500 nm and 380 nm/500 nm, respectively. When calculating R own fluorescence investigational medicinal substance measured in a cell-free system and adjusting the effect of intrinsic fluorescence to the fluorescence of Fura-2.

Intracellular calcium concentration was determined using the following calculation formula on the basis of the maximum response R (Rmax), obtained upon stimulation with 25 μm of ionomycin, the minimum reaction R (Rmin), obtained upon stimulation with 5 μm ionomycin + 1 mm EGTA, the efficiency of fluorescence (Sb2) calcium-binding dye when the length of the excitation wavelength 380 nm/500 nm and the efficiency of fluorescence (Sf2) dye dissociation of calcium at a wavelength of excitation 380 nm/500 nm.

Calculation formula: Intracellular calcium concentration (nm)=224[(R-Rmin)/(Rmax-R)][Sf2/Sb2].

Using rasschitannyi each of the drugs and measures for the control of the solvent, received with respect to the blockade of calcium absorption (blockade ABCCC) to calculate the concentration for 50% suppression ABCCC (value IC50).

The value of the IC50for compounds according to examples 1 to 6 was in the range of 0.51 to 0,050 mm.

(2) the Selectivity of inhibition DCCC in comparison with PSCC

Suspension of neuroblastoma rat PC12-h5 (2106/ml), saturated fluorescent dye - calcium indicator fura-2 (1 mm), was distributed in portions of 100 μl of the cell 96-cell of the blade. The increase in intracellular calcium, stimulated by a high concentration of potassium chloride, caused by adding to each well 100 μl of a balanced salt solution Hanks, containing the investigational medicinal substance at a concentration of twice the final concentration, and 100 mm KCl (final concentration 50 mm) and 30 minutes after adding the expected ratio of fluorescence intensity (R) for the two fluorescence intensities obtained upon excitation at wavelengths of 340 nm/500 nm and 380 nm/500 nm, respectively. When calculating R own fluorescence medicinal substance measured in a cell-free system and adjust the effect of fluorescence on fluorescents the described inhibition ABCCC, and compared with the inhibition ABCCC.

Inhibition PSCC compounds according to examples 1 to 6 was 16 times or more weak than their inhibition ABCCC.

(3) Inhibitory effect on the production of IL-2

The inhibitory activity of the compounds according to the invention on the production of IL-2 cells Turk (Jurkat) were tested in accordance with the method described by S. Clare Chung et al. in Br. J. Pharmacol., 113: 861-868, 1994, and expected its value IC50.

The compounds of this invention show the values of the IC50equal to 1 μm or less.

(4) the Effect on the model of contact hypersensitivity caused by TNCB

The action of the compounds of this invention on the called TNCB contact hypersensitivity in five weeks of male mice ICR was determined in much the same way as the method described in Current Protocols in Immunology (John Wiley & Sons, Inc., 1994). The compounds of this invention inhibited called TNCB contact hypersensitivity in the degree of dose-dependent.

(5) Inhibitory effect on induced concanavalin A (Con A) - induced hepatitis in mice

Four five-week mice female Balb/c mice (SLC) this test was carried out by the method similar to the method described by G. Tiegs et al. in J. Clin. Invest."ptx2">

(6) Inhibitory effect on induced collagen arthritis in mice

The vast effect on arthritis in five-week mice male DBA/1J (Charles River, Japan) were determined by a method similar to the methods described Fumio Nishikaku and Yoshihiko Koda in Immunopharmacology, 25, 65-74 (1993) and Fuminori Kato, Manasao Nomura and Nakamura Kyoto in Annals of the Rheumatic Disease, 55, 535-539 (1996). The compounds of this invention show a significant inhibition of arthritis.

(7) Inhibitory effect on induced antigen eosinophilia of the respiratory tract in rats

The inhibitory effect on induced antigen eosinophilia respiratory tract at four weeks of male rats BN was determined in much the same way as according to the method described by W. Tlwood et al. in Inflamm. Res., 44, 83-86, 1995. In this regard, the drug was administered 30 minutes prior to exposure to 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 according to this invention has reduced the number of infiltrated leukocytes in General and the number of infiltrated in airway eosinophils.

Pharmaceutical composition that contains the compound (I') according to this invention or its salt and a pharmaceutically PR is, the expressed General formula (I') or its salts and a carrier for medical use, filler and other additives commonly used in pharmaceutical preparations. Its introduction can be performed either by oral administration in the form of tablets, pills, capsules, granules, powders, solutions, etc., or by parenteral administration in the form of intravenous, intramuscular and the like injections, suppositories, preparations for percutaneous absorption, etc.

Solid composition for use in oral administration in accordance with this invention is applied in the form of tablets, powders, granules, etc. In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or silicate of aluminum-magnesium. In conventional processes, the composition may contain other additives in addition to the inert diluent, such as a lubricant (e.g. magnesium stearate or similar ), dezintegriruetsja tool (for example, Cellulosics calcium or etc.), stabilizing agent (for example, Loki so p.) If necessary, tablets or pills may be coated with films of sugar or a substance soluble in the stomach or intestines, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose or etc.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. and contains a generally used inert diluent such as purified water or ethanol. In addition to the inert solvent, the composition may also contain auxiliary substances, such as humectants, suspendisse tool, etc. and sweeteners to improve the taste and smell of the tool, flavorings and preservatives.

Injectable preparations for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the solvent for use in aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the solvent for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oil (such as olive oil or etc.), alcohol (for example, this is to antiseptic, humectants, emulsifying agent, dispersing agent, stabilizing agent (e.g., lactose) and facilitate solubilization agent (for example, glutamic acid or aspartic acid). These compositions are sterilized by filtering through inhibiting bacteria filter, add bactericidal agents or irradiation. Alternatively, they can be used by the original manufacture of sterile solid compositions and dissolving in sterile water or a sterile solvent for injection before use.

In the case of oral administration the appropriate daily dose is generally from about 0.001 to 10 mg/kg of body weight, and daily dose given once daily or divided into 2 to 4 doses per day. In the case of intravenous injection, the corresponding daily dose usually ranges from about 0.0001 to 1 mg/kg body weight and the daily dose given once daily or divided into a number of injections per day. The decision to dose is taken arbitrarily, taking into account the symptoms, age, gender, etc. of each patient in need of treatment.

THE BEST WAY OF CARRYING OUT THE INVENTION

D. the data of the invention are not limited to compounds, described in the following examples.

Example 1

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

Example 2

A mixture of 5-(1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl)thiophene-2-carbonylchloride (150 mg) with dichloromethane (1.5 ml) was added to a mixture of 2-Chloroaniline (68 mg), pyridine (42 mg) and dichloromethane (2 ml) and premiserestaurant sodium, and thus obtained product was extracted with ethyl acetate and then the extract was washed with a saturated solution of salt. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 2'-chloro-5-(1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl)thiophene-2-carboxanilide (80 mg) as colorless crystals. In this case, the above source connection 5-(1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl)thiophene-2-carbonylchloride received in the form of a brown solid by treating 5-(1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl)thiophene-2-carboxylic acid oxalylamino.

Example 3

The sodium methoxide (257 mg) was added to a mixture of 4'-acetyl-4-chlorobenzamide (1,00 g) and SIAS (10 ml) at 0oWith and thus obtained mixture was stirred for 2 hours at room temperature. To the reaction solution was added ethyltryptamine (0,522 ml) and was stirred for 2 days at 60oC. To the reaction mixture were added water (50 ml) and 1N hydrochloric acid (10 ml) and the resulting product was extracted with ethyl acetate and then the extract was washed with water and saturated saline solution in this order. Palangana pressure. The mixture thus obtained residue with methylhydrazine (0,206 ml), acetic acid (2 ml) and ethanol (20 ml) was stirred for 21 hours at room temperature. After concentrating the reaction mixture under reduced pressure, the thus obtained residue was added to ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution. Thus obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Thus obtained residue was purified by column chromatography on silica gel (elgort; n-hexane: ethyl acetate = 3:1) and then recrystallized from a mixed solvent consisting of ethyl acetate and n-hexane to obtain 4-chloro-4'-(1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl) benzanilide (440 mg) as colorless crystalline powder.

Connection example 4: (4-methyl-4'[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] -1,2,3-thiadiazole-5-carboxanilide), example 5: (3-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] thiophene-2-carboxanilide) and example 6: (4'-[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] nicotinanilide), presented in the table were respectively obtained in the same manner, to the Lena in the table. In table Ex means of example, Str means the structural formula, Dat means of physico-chemical properties, ll. means melting point, NMR means spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard) M. D. and NMR (Dl3means spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard) memorial plaques, Hz=Hz, s=C, d=d, td=TD, dd=DD, m=m, brs=Shire. C., dt=dt.

1. Amide derivative represented by the following General formula I:

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the symbols in the formula have the following meanings:

D represents pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I);

In is fenelonov or topendialog group;

X represents a group of formula-NH-CO - or-CO-NH-;

A represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group containing 1-4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted by one or more lower alkyl groups, provided that excluded 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] -1,2,3-thiadiazole-5-Carbo is acceptable salt.

2. Amide derivative or its pharmaceutically acceptable salt p. 1, where D is pyrazolidine group, substituted by at least one triptorelin group.

3. Amide derivative or its pharmaceutically acceptable salt p. 1, where D represents 1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl or 3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl and a represents a phenyl group which may be substituted by a halogen atom, or a five - or six-membered monocyclic heteroaryl group selected from the group comprising thiazolyl, thiadiazolyl, thienyl and pyridyl which may be substituted by a lower alkyl group.

4. Pharmaceutical composition for the inhibition of Ca2+channels activated by release of CA2+that contains amide derivative represented by the following General formula I', or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier

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the symbols in the formula have the following meanings:

D represents pyrazolidine group that contains from 1 to 3 of halogen or unsubstituted lower alkyl groups as the Deputy(I);

In is fenelonov or topendialog group;

X represents Grecki halogen atoms, or a five - or six-membered monocyclic heteroaryl group containing 1-4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, which may be substituted by one or more lower alkyl groups.

5. The pharmaceutical composition according to p. 4, which is an inhibitor of the production of IL-2.

6. The pharmaceutical composition according to p. 5, intended for the prevention or treatment of allergic and chronic inflammatory or autoimmune diseases.

7. The pharmaceutical composition according to p. 6, intended for the prevention or treatment of bronchial asthma.

8. The pharmaceutical composition according to p. 6, intended for the prevention or treatment of rheumatoid arthritis.

9. The pharmaceutical composition according to any one of paragraphs. 4-8 containing amide derivative selected from the group comprising 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] thiazole-5-carboxanilide, 2'-chloro-5-(1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl)thiophene-2-carboxanilide, 4-chloro-4'-(1-methyl-3-trifluoromethyl-1H-pyrazole-5-yl)-benzanilide, 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] -1,2,3-thiadiazole-5-carboxanilide, 3-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl] thiophene-2-carboxanilide

 

Same patents:

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent

The invention relates to a new, more thermodynamically stable crystalline form of the hydrochloride of (R)-(-)-2-{N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-chroman

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

The invention relates to a medicinal product on the basis of derivatives of thiazole or thiadiazole of the formula I, where a denotes a linear or branched C1-C18-alkylenes group which may contain at least one group selected from the group consisting of: O, S, NR3, СОNR3, NR3CO, COO, OCO or double or triple bond; In denotes the radical of the formula II, R1denotes H, halogen JV CO2R2, NR2R3, OR SIG3, CF3or C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen; R2denotes H, C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen, or phenyl-C1-C8-alkyl; R3has the meanings given for R2or indicate СОR2or CO2R2; X represents N or CR4where R4denotes H, C1-C8-alkyl, which is not substituted or is substituted by IT, OS1-C8-alkyl or halogen, or denotes phenyl which is not substituted or substituted with halogen, CF3C1-C8-alkyl or C1-C8-alkoxy; Ar denotes phenyl, pyridyl, pyrimidyl or triazinyl,

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to a method for Cefotaxime formula I by reacting acetone compounds of the formula II with the compound of the formula III and subsequent, if necessary, converting the compounds of formula I in the presence of a source of sodium ions in a mixture of acetone and water in the sodium salt of Cefotaxime in the form of rounded agglomerates with a bulk density of 0.2-0.6 g/ml or in the form of needle-shaped crystals

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts

The invention relates to new heterocyclic compounds with valuable biological properties, in particular derived dioxide benzothiazine, the pharmaceutical compositions based on them having inhibitory receptor endothelin activity, and to a method of inhibiting endothelin receptor

The invention relates to new compounds of the formula (I)

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where AG represents a radical selected from formulas (a) and (b) below:

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R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to CIS-isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3-yl)diamines of the formula I and their salts, where a-g, i-m R=H; a-C X= 0; and n=3; b n=4; n=5; n=6; d n=7; n=8; W n=9; h R=Ac, n=6; and n=6, and X = disuccinate; X = ditartrate; X l = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; X = dichlorhydrate

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to new derivatives of azabicycloalkanes possessing biological activity, in particular to derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to benzothiophene compounds of formula I, where R1-H, - OH, -O(C1-C4alkyl), - EA6H5-, OCO(C1-C6alkyl), or-OSO2(C2-C6alkyl);

R2IS-H, -OH, -O(C1-C4alkyl), EA6H5, CCA(C1-C6alkyl) , -OSO2(C2-C6alkyl), or halogen; R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino; n = 2 or 3; Z Is-O - or-S-, or their pharmaceutically acceptable salts

The invention relates to the field of production of new heterocyclic o-dicarbonitriles formula I

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o-Dicarbonitrile can be used to obtain hexatriene-fluorophores, as a fragment of the donor to obtain hexatriene-bifluorophors besed and hexatriene-trifluoroprop
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