The method of obtaining benzopyrano compounds, intermediate compounds and methods for their production
(57) Abstract:Describes how to obtain substituted benzopyrano derivatives, including at the last stage the cyclization of the corresponding intermediate compounds with an open circuit. 7 C. and 1 C. p. F.-ly. The invention relates to a new method of preparation of some substituted benzopyrano compounds, to intermediate compounds useful in this method, and the method of production of intermediate compounds.Substituted benzopyrano compounds known from the prior art. For example, EP 0 173 516-A discloses a class of substituted benzopyrano compounds described as compounds having activity as leukotriene antagonists and are useful in therapy for the treatment of, for example, diseases caused by leukotrienes and 5-reductase.The invention relates to a new method of obtaining some of benzopyrano compounds described in EP 0 173 516-A, and in particular offers an effective way of obtaining compounds, including much less reaction stages than described so far. Reducing the number of reaction stages in obtaining the desired products results in a much more efficient way than Pte method of obtaining compounds of structure (I):
< / BR>where:
R1represents a group of the structure:
< / BR>R2represents hydrogen or C1-6alkyl;
A represents a single bond; and
X represents oxygen;
or its salt, MES or hydrate, which involves the cyclization of compounds of structure (II):
< / BR>or its salt, hydrate or MES, where R1, R2, R3, A and X have the same meaning as described for structure (I), and obtained then, if necessary, its salts, MES or hydrate.R2represents preferably hydrogen.The cyclization of compounds of structure (II) is conducted in an appropriate manner in the presence of acid. For example, the cyclization can be carried out in the presence of sulfuric acid, in methanol or in acetic acid as solvent. Preferably, the reaction is carried out in a solvent mixture of methanol/tetrahydrofuran in the presence of hydrochloric acid. Alternative conditions acid/solvent obvious to experts and include, for example, acids such as Hydrobromic or idiscovered acid, perchloric acid or toluensulfonate, ciie as ethanol or methanol, and unsaturated carbocyclic hydrocarbons, such as benzene or toluene.It should be noted that, although for convenience, the structure (II) is represented as "di-keto-form, the compounds of structure (II) may also exist in keto-enol" form and "the cyclic hydroxypropanoic" form (IIB):
< / BR>Have in mind that the structure (II) includes all tautomeric forms of the compounds of structure (II).In a preferred aspect, therefore, proposes a method of obtaining compounds of structure (IA) or its salt, MES or hydrate:
involving the cyclization of compounds of structure (IIA) or its salt, MES or hydrate:
and after not getting his salt, MES or hydrate. Most preferably, the cyclization is carried out in the presence of hydrochloric acid in methanol/tetrahydrofuran as solvent.With regard to compounds of structure (II), compounds of structure (IIA) can, of course, exist in the corresponding keto-enol and the cyclic romanovas forms, each of which is assumed to be covered by the structure (IIA).Compounds of structure (II) (and, in particular, the structure (IIA)) are new and form a further aspect yoroi R1, R2, R3, A and X have the meanings defined for structure (I) in paragraph (1 claims, with the compound of structure (IV) or its salt:
< / BR>in which Z represents a group R6O, in particular, C1-C6alkoxy.Accordingly, the reaction is carried out in an organic solvent, such as, for example, dimethylformamide, ether solvents such as tetrahydrofuran, toluene or benzene, hexane or C1-6the alkanols, such as methanol or ethanol, in the presence of a base, such as alkali metal alkoxide, such as t-piperonyl potassium, sodium methoxide or potassium methoxide, hydrides such as sodium hydride or amide base, such as potassium amide or sodium amide. Preferably, the reaction is carried out in tetrahydrofuran as a solvent in the presence of sodium methoxide as the base.The method of obtaining compounds of structure (II) is novel and represents another aspect of the invention. In particular, for use in obtaining the compounds of structure (IIA) the method is carried out by reaction of the following compounds of structure (IIIA) and a compound of structure (IVA): or its salt in the presence of sodium methoxide in tetrahydrofuran as RASO standard techniques, as is described below. For example, compounds of structure (III) are described in EP 0173516-A. Compounds of structure (IV), for example, in which Z is R6O, can be obtained from sodium azide and appropriate Olkiluoto ether cyanopyridine acid, such as ethyl ether of cyanopyridine acid by known methods or from disodium salt tetrazol-5-carboxylic acid (commercially available) by reaction with a suitable alkilany, allowin or arylalkyl ether haloalkaline acid, for example, etelcharge.com or isobutylparaben. Obtaining compounds of structure (IV) of the corresponding disodium salt tetrazol-5-carboxylic acid is novel and constitutes another aspect of the invention. It should be noted that the compounds of structure (IV) can be obtained and then allocated before the reaction with the appropriate compounds of structure (III) or can be obtained "in situ" and further described in the interaction with compounds of structure (III) without the prior allocation.The present invention particularly useful for producing compounds of structure (IA), based on the compounds (IIIA) and (IVA) to obtain the intermediate compounds of structure (IIA), which undergo cyclization in this section the art before the cyclization of compounds of structure (I) or, alternatively, as described in the examples, the reaction between the compounds of structures (III) and (IV) followed by cyclization of compounds of structure (II), formed in this way can be brought to an end "in one pot", so to speak, without the isolation of intermediate compounds formed during this.The following examples illustrate the invention. Temperatures are given in degrees Celsius (oC).Examples
1. Obtaining the ethyl ester 1H-tetrazol-5-carboxylic acid
Triperoxonane acid (24,47 g, 0.21 M) is added dropwise over 0.5 h under nitrogen to a stirred suspension of sodium azide (12,59 g 0,19 M) in 2,6-lutidine (100 ml) for 8 of the 12o. After stirring for 7 min add ethyl ether of cyanopyridine acid (20.4 g, 0.20 M) in one portion. The mixture is heated and stirred at 75ofor 6 h and then, after cooling, stirred at 20owithin 16 hours After cooling to 10othe mixture was added to ice (250 g) and II-molar hydrochloric acid (100 ml), keeping the temperature below 20o. The product is extracted into ethyl acetate (1250, 1200, 2100 ml) and the combined extracts dried over magnesium sulfate. After evaporation of the solvent under reduced pressure the oil is ristalliceski ethyl ester 1H-tetrazol-5-carboxylic acid, which is filtered off, washed with cold ether and dried air, 14,12 g (yield 52.6 per cent), so pl. 88 93o.NMR: (270 MHz, solution in CDCl3): 13,6 13,8 (s, 1H); 4.6 to 4.5 (K, 2N); 1,5 1,4 (t, 3H).Modification techniques
On a larger scale (84,4 g of sodium azide) the reaction is carried out differently to prevent any allocation of nitric acid.After stirring at 75oand 20oadd sodium nitrate (63 g) in water (300 ml) for 10 min at 20 30o. The mixture is stirred at 20 to 25ofor 20 min and then add chilled mixture of water (1.5 l) and II-molar hydrochloric acid (690 ml), keeping the temperature between 25 and 30o. Then the product is extracted in ethyl acetate and crystallized as described above.2. Getting isobutyl ester 1H-tetrazol-5-carboxylic acid
To a stirred suspension of disodium salt tetrazol-5-carboxylic acid (15,8 g, 0.1 mol) in dimethylformamide (100 ml) in a nitrogen atmosphere at 5oadd isobutyl ether of Harborview acid (13,6 g, 13 ml, 0.1 mol) dropwise within 15 minutes the Mixture is stirred at 5 to 10owithin 2 h, then at 20owithin 2 hours the Mixture was added to water (500 ml) and extracted with em (2200 ml). An ethyl acetate extracts washed with water (2200 ml), dried (MgSO4) and evaporated, obtaining the target compound in the form of resin (8.6 g, 50.5 per cent).1H NMR (CDCl3): d of 0.95 (d, 6N, CH3), 2,08 (TC, 1H, CH), 4,25 (d, 2H, CH2).3. Obtain methyl ester of 4-(4-phenylmethoxy)benzoic acid
A solution of methyl ester of 4-hydroxybenzoic acid (13,4 kg, 88 mol) in dimethylformamide (52 l) is added dropwise to the mixture aOMe (4.8 kg, 89 mole) and dimethylformamide (50 l) at room temperature under gentle stream of nitrogen. The reaction mixture is heated at 60 70owithin 1 h with stirring and then cooled to room temperature. To this mixture is added dropwise a solution of 4-phenylbutyramide (16,92 kg, 79,4 mol) in dimethylformamide (5 l). The resulting mixture is heated at 60 70ofor 1 h with constant stirring and cooled to room temperature. After adding 1 N. NaOH (110 l) the product is extracted twice with ethyl acetate (50 l 80 l). The extracts are successively washed with 1 N. NAOH (110 l) and saturated brine (20 l) and then concentrated to dryness under vacuum, obtaining the target compound with a quantitative yield.4. Getting 4-(4-phenylmethoxy)benzoic acid
To a solution of compound of example the MeOH is removed by distillation in vacuum. To the residue is added ice water (120 l) and neutral substances extracted with ether (30 L3). The combined ether extracts are washed with 2 N. NAOH (25 l). The aqueous layers are combined and adjusted to pH 2 to 3 with concentrated HCl (16 l). Precipitated precipitated solids are collected by filtration in a centrifugal field, washed with water and dried by heating at 70 to 80oin air flow, receiving the target product (17,67 kg of 65.4 mol, yield 82% of 4-hydroxybenzoate).5. Obtaining 3-/4-(4-phenylmethoxy)benzoylamine/-2-hydroxyacetophenone
To a solution of the compound from example 4 (18,1 g, 67 mmol) in CH2Cl2(45 ml) is added a catalytic amount of dimethylformamide (0.45 ml) followed by addition of thionyl chloride (6,26 ml, to 85.8 mmol) at room temperature under nitrogen atmosphere. After boiling under reflux for 2 h the mixture is cooled to room temperature and added to a solution of the hydrochloride of 3'-amino-2'-hydroxyacetophenone (12 g, 64 mmol) and pyridine (15,5 ml, 192 mmol) in CH2Cl2(90 ml), keeping the temperature between 0oand 3o. The mixture is stirred at a temperature of 0 to 3ofor 2 h and poured into 2 N. HCl (200 ml). The aqueous layers are separated. The product in aqueous layers are extracted twice CH2Cl2(150 Ml) and Annam brine (150 ml), dried over MgSO4. The resulting solution was concentrated in vacuo until a precipitate several crystals. To the residue is added ethyl acetate (150 ml) and the solution was concentrated in vacuo until it is removed about half of ethyl acetate. The mixture is cooled to approximately 0o. The precipitated crystals are collected and dried in vacuum, obtaining the target compound (21,6 g, 53.6 mmol, 90% yield).6. Getting 2-/4-(4-phenylmethoxy)benzoylamine/- 6-/1,3-dioxo-3-(tetrazol-5-yl)propylene
Under nitrogen atmosphere, dissolved under stirring tert.-piperonyl potassium (31,36 g, 0.28 mol) in dry dimethylformamide (160 ml). To the resulting solution was added the compound of hydroxyacetophenone from example 5 (16,12 g, 0.04 mol), and then 5-ethoxycarbonylmethyl example 1 (1.39 g, 0,052 mol, 1.3 EQ.) at room temperature. The reaction temperature rises to 45o. The mixture is stirred for 3 h at 40o(oil bath), then cooled to 30oand poured into cold 1 N. HCl (800 ml). The resulting precipitate is filtered off, washed with water (500 ml) and then dried at 70oin an oven with fan, obtaining the target compound (19,4 g, 97%). Spend cleaning, using any of the following procedures.Uchenie 2 hours After cooling to room temperature, the mixture is transferred into the fridge and leave for 2 hours, the Product is filtered, washed with cold ethyl acetate (15 ml) and dried at 70oin an oven with fan, receiving the purified product (8.5 g, 85%).Procedure 2
Stirred suspension of the crude product (5 g) in acetone (50 ml) is heated under reflux for 2 hours After cooling to room temperature, the mixture is transferred into the fridge and leave for 2 hours the Product is then filtered, washed with cold acetone (5 to 10 ml) and dried at 70oin an oven with fan, getting the target product (4.1 g, 82%).7. Getting 4-oxo-8-/4-(4-phenylmethoxy)benzoylamine/- 2-tetrazol-5-yl-4H-1-benzopyran hemihydrate
To a stirred suspension of purified product from example 6 (7,984 g to 0.016 mol) in methanol (72 ml) is added concentrated sulfuric acid (0.6 ml) and the reaction mixture heated under reflux for 3 hours the Mixture is allowed to cool to room temperature, and then transfer it in the refrigerator for 2 hours the Thick mixture was then filtered, washed with cold methanol (40 ml) and water (90 ml) and then with cold methanol (30 ml). The product is dried at 0oin an oven with fan and then leave to stand for 2 the RA illustrate the method of obtaining the compounds (I) of the intermediate compounds of structures (III) and (IV) "in the same vessel."8. Getting 4-oxo-8-/4-(4-phenylmethoxy)benzoylamine/- 2-tetrazol-5-yl-4H-1-benzopyran hemihydrate
To a stirred suspension of sodium methoxide (15 g, 0.28 mol) in dry tetrahydrofuran under nitrogen atmosphere add portions of the connection hydroxyacetophenone from example 5 (16 g, 0.04 mol) at approximately 25o. Then add a solution of ethyl ether tetrazol-5-carboxylic acid from example 1 (of 7.3 g, 0.05 mol) in tetrahydrofuran, while maintaining the reaction temperature at approximately 25oC. the Reaction mixture was stirred under conditions of reflux distilled for about 100 min to ensure complete formation of the diketone compounds of example 6. To the reaction mixture is added methanol, and then add concentrated hydrochloric acid (28 ml, 0.34 mol) and subsequent heating of the reaction mixture under reflux for about 2 h leads to the formation of the target compound, which crystallizes from the solution. After cooling to approximately 20othe product is separated by filtration and washed with methanol. The selected solid is purified by conversion into the sodium salt in methanol and re-deposition of target compounds hydrochloric acid. On hydratious at room temperature, receiving the target connection (18,56 g, 94%).9. Getting 4-oxo-8-/4-(4-phenylmethoxy)benzoylamine/- 2-tetrazol-5-yl-4H-1-benzopyran hemihydrate
To a stirred suspension of sodium methoxide (14,1 kg, 261 mol) in dry tetrahydrofuran under a nitrogen atmosphere are added in several portions connecting hydroxyacetophenone from example 5 (15,0 kg, 37,2 mol) at approximately 25o. Then add a solution of ethyl ether tetrazol-5-carboxylic acid from example 1 (6.8 kg, or 47.9 mol) in tetrahydrofuran, while maintaining the reaction temperature at approximately 25o. The reaction mixture was stirred at reflux distilled for about 100 min to ensure complete formation of the diketone compounds of example 6. To the reaction mixture is added methanol and then concentrated hydrochloric acid (31,4 kg, 314 mol), and subsequent heating of the reaction mixture under reflux for about 2 h leads to the formation of the target compound, which crystallizes from the solution. After cooling to approximately 20oC the product is separated by filtration and washed with methanol. Separated solid is purified by conversion into the sodium salt in methanol and re-translation into the sediment by x the rum methanol, dried and then re-hydratious at room temperature to obtain the target compound (15.5 kg, 85%). 1. The method of obtaining benzopyrano compounds of General formula I
< / BR>where R1group
< / BR>R2hydrogen or C1WITH6-alkyl;
And single bond;
X is oxygen,
or a salt, hydrate or solvate, characterized in that carry out the cyclization of compounds of General formula II
< / BR>where R1, R2, R3And X have the above values,
or its salt, hydrate or MES and, if necessary, the desired product is isolated in the form of a salt, hydrate or MES.2. The method according to p. 1, wherein the cyclization is carried out in the presence of hydrochloric acid in methanol-tetrahydrofuran as solvent.3. The compound of General formula II
< / BR>where R1, R2, R3And X are specified in paragraph 1 values
or its salt, hydrate or MES.4. 2-[4-(4-Phenylmethoxy)benzoylamine] -6-[1,3-dioxo-3-(tetrazol-5-yl)propyl]phenol.5. The method of obtaining compounds of General formula II, wherein conducting the reaction of interaction of the compounds of General formula IV
< / BR>where Z C1C6-alkoxygroup,
or its salt.6. The method of obtaining the compounds of formula IA
< / BR>or its salt, hydrate or MES, characterized in that the compounds IIIA
< / BR>subjected to interaction with the compound of the formula IVA
< / BR>or its salt with subsequent cyclization of the obtained intermediate compound of formula IIA
< / BR>or its salt, hydrate or MES.7. The method of obtaining the compounds of formula IV
< / BR>where Z1WITH6-alkoxygroup,
characterized in that the disodium salt of tetrazole-5-carboxylic acid is subjected to interaction with the corresponding alkilany ether haloalkaline acid.8. The compound of General formula III
< / BR>where R1, R2, R3, X and a are specified in paragraph 1 values.
FIELD: organic chemistry.
SUBSTANCE: invention relates to method for production of H-type nateglinide crystals. Claimed method includes addition of nateglinide-containing reaction mixture to inorganic acid(s) to produce acidic medium, wherein said reaction mixture in produced by interaction of trans-4-isopropylcyclohexylcarbonyl chloride with D-phenyl alanine in mixed solvent comprising of ketone solvent and water in water/ketone solvent ratio from 10:1 to 0.5:1 in presence of alkali followed by adjusting of mixture temperature to 58-72°C and ketone solvent concentration to 8-22 mass % to precipitate nateglinide crystals.
EFFECT: industrially advantageous methods for production of nateglinide crystals.
10 cl, 13 ex, 1 tbl
SUBSTANCE: invention relates to a method of synthesis of N-substiuted salicylamide, involving reaction of a carsalam derivative with a chloro-substituted compound of formula (III) in the presence of a catalytic amount of a source of bromine ions, where n is an integer from 1 to 8, Q denotes a protected carboxylic group, and R5 and R6 are independently selected from a group containing hydrogen, -OH, NR3R4, halogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, where R3 and R4 are each independently selected from a group containing hydrogen, -OH, C1-C4 alkyl, C1-C4 halogenalkyl, C1-C4 alkoxy and C2-C4 alkenyl. The invention also discloses a method for synthesis of a compound of general formula IV.
EFFECT: improved method for synthesis of N-substituted salicylamide enables to obtain large amounts of high-quality product.
54 cl, 3 ex
SUBSTANCE: invention relates to a method of producing acetamidine hydrochloride which is used as raw material in organic synthesis. The method involves condensation of acetonitrile with lower alcohols in the presence of hydrogen chloride, where condensation of acetonitrile with methanol takes place in a dichloroethane medium in the presence of hydrogen chloride at temperature between -2 and +3°C, and subsequent addition of the obtained acetoiminoester suspension into methanol saturated with ammonia. Acetamidine hydrochloride is extracted through filtration from ammonium chloride and distillation of the solvent mixture until formation of a suspension, filtration and washing the residue with cold alcohol. Before distillation of the solvent mixture, the mother solution and the washing alcohol are returned to the reaction mixture.
EFFECT: high output of end product (over 91%).
1 cl, 3 ex
FIELD: color-forming compositions and recording material.
SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.
EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.
21 cl, 14 tbl, 153 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):
wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.
EFFECT: valuable medicinal properties of compounds.
9 cl, 1 tbl, 3 sch, 94 ex
FIELD: organic chemistry, pharmaceutical compositions.
SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I
, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.
EFFECT: new compounds for inflammation treatment.
10 cl, 36 ex, 1 tbl
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.
EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.
10 cl, 2 tbl, 4 dwg, 9 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):
wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.
EFFECT: valuable medicinal properties of compounds and composition.
7 cl, 2 tbl, 15 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.
EFFECT: improved method for inhibition, valuable properties of compounds and composition.
25 cl, 6 tbl
FIELD: organic chemistry, chemical technology, pharmacy.
SUBSTANCE: invention relates to a method for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide. Method involves reaction of bromosalicylic aldehyde with compound of the formula (I): L-CH2-COOR1 (I) wherein L represents Cl, Br or J atoms, or reactive esterified group -OH; R1 means (C1-C6)-alkyl or benzyl followed by reaction with formamide to yield 5-L-benzofuran-2-carboxamide (II) and the following its amination with R2-piperazine wherein R2 represents hydrogen atom (H) or amino-protecting group in the presence of a catalyst based on transient metals; in case if R2 is not H then R2 is removed, and/or prepared 5-(1-piperazinyl)-benzofuran-2-carboxamide is converted to one of its salts by treatment with acid. Except for, the invention proposes two additional methods for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide and intermediate compounds of the formula (V): wherein R2 represents H or amino-protected group; R3 means H or -CH2R6; R4 and R5 in common represent carbonyl; R6 means -CN, -COOH, -COOR7 or -CONH2; R7 means (C1-C6)-alkyl, and also their salts and solvates. Invention provides a new method for preparing the valuable intermediate compound used in preparing pharmaceutical preparations and increase of the yield of the end compound.
EFFECT: improved preparing methods.
6 cl, 10 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.
EFFECT: valuable medicinal properties of compounds and composition.
7 cl, 1 tbl, 66 ex