Heterocyclic derivatives of substituted 2-acylamino-5 - thiazolo, methods for their production, derivative substituted 2 - aminothiazole, derivatives of 2-amino-4-phenylthiazole

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds as substances inhibiting the binding of cholecystokinin to receptors. The inventive product 1: heterocyclic derivatives of substituted 2-acylamino-5-thiazolo f-ly I with the corresponding values radicals. Obtaining the compounds I are the reaction of compound II with a functional derivative of the acid f-ly Z is COOH or acylation of compounds f-ly III connection f-crystals IV. Proposed new intermediate compounds f-ly V and VI. The structure of the compounds f-ly I, II, III, IV, V and VI; presented in the text description. 5 S. and 2 C. p. F.-ly.

The invention relates to new heterocyclic derivatives of substituted 2-acylamino-5-thiazolo exhibiting affinity to the receptor cholecystokinin and gastrin to a method for producing such compounds and to pharmaceutical compositions based on them.

Cholecystokinin (CCK) is a polypeptide hormone found in vivo in several forms, containing from 8 to 39 amino acids. He has numerous physiological action on the biliary tract, gastrointestinal tract, you can refer to the article J. E. Morley, Life Sciences, 1982, 30, R. 479-493, which is such antagonists; the population of type a are, in particular, in the pancreas, the gall bladder and in some areas of the Central nervous system, whereas the population type are especially in the Central nervous system.

Gastrin is a polypeptide hormone that affects, in particular, on the acid secretion of the stomach; the 5 C-terminal amino acids are identical to amino acids of CCK.

We have already described compounds, which are antagonists against gastrin and/or CCK, in particular, proglumide, p-chloro-benzoyl-L-tryptophan, or more recently, derivatives of benzo-benzodiazepines, which are specific antagonists or CCK receptors And such as 3S[-(N-2-) 1-methyl-2-oxo-5-phenyl - 2,3-dihydro-1H-1,4-benzodiazepine-3-yl] -2-endocervical - MFA ( J. Med. Chem. 1988, 31, 2235-46) or CCK receptors, such as 3R(+)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-Ben zodiazepine-3 - yl)-N'-(3-were)-urea (Eur, J. Pharmacology, 1989, 162, 273-280).

On the other hand, thiazole derivatives with formula A.

HNHCO in which AND1represents a 2,4-acid; 2,3,4-trimethoxyphenyl or heterocyclic group, such as 3,4-dihydro-7-methoxy-2,2,8-trimethylene-superan-1-2H-6-yl or 3,4-dihydro-7-methoxy-2,2-dimethylene properties

Other derivatives of thiazole with the formula IN the

NHCO-B1where1represents a hydrogen or bromine atom, described in the article Chem. Pharm. Bull. 1977, 1977, 25 (9), 2292-9 as with anti-inflammatory properties.

Other derivatives of thiazole with formula

NHCO have immunostimulating and anti-inflammatory properties, they are described in the article Arch. Immunol. Ther. Exp. 1978, 26 (1-6), 921-9.

Derivatives of 4-chinainternational with formula D

cited in Chem. Abst. 112(13), 115 h as having germicidal and disinfectant properties.

Other derivatives of thiazole, having the properties of anti-CCK described in the patent EP-A-0 432 040.

The compounds according to the invention are heterocyclic derivatives aminothiazolo with the formula I

where R1represents a hydrogen atom; alkyl group WITH1-C4or phenylalkylamine group with alkyl WITH1-C3; aminoalkylindole group with the formula Z1-NR4R5in which Z1is alkylen2-C4and R4and R5independently of one another represent H or alkyl WITH1-C4or together with the nitrogen atom to which they are linked, form a saturated alkylpiperidines cycle; carboxyaniline group, esterified, if necessary, with the formula-Z2-COOR6in which Z2is alkylen1-C4and R6represents H or alkyl WITH1-C6; cyanoaniline group2-C5; carbamylcholine group with the formula-Z3-CONR7P8in which Z3is alkylen1-C4and R7-R8independently of one another represent H or alkyl WITH1-C4or together with N form a heterocycle, such as NR4R5; hydroxyalkyloxy group2-C6or alkoxyalkyl group1-C10;

RIVrepresents cycloalkyl group3-C7, unsubstituted or substituted by one or more alkyl groups WITH1-C4; an aromatic group such as phenyl, unsubstituted or having one or more substituents selected among halogen atoms, in particular chlorine or fluorine, (C1-C6) alkyl, alkoxy - and dialkoxy1-C3nitro - and triptorelin groups, or such as a heterocycle containing at least one heteroatom chosen among O, S and N, in frequent is the case of need, alkyl group WITH1-C3or halogen atom or alkoxygroup1-C3or RIVand RVconsidered together, is a group:

connected through the carbon of the phenyl position 4 thiazolidine ring, which has values from 1 to 3 and which contains, if necessary, one or more (PR) of the substituents Xpidentical or different, selected among halogen atoms, alkyl and alkoxygroup1-C3, nitro - and triptorelin groups, and the PR has a value from 0 to S;

RVrepresents a group -(CH2)m-X, in which m is 0 to 5, and X represents;

halogen atom, preferably a bromine atom, hydroxyl, cycloalkyl3-C7, phenyl which may be substituted by one group selected among halogen atoms, alkyl or alkoxygroup1-C3, nitro-, amino-, hydroxy - or triptorelin groups;

group selected among -- COOH; -COOH1; -O-MOR1-S-COX1; (O)q-S-X1where q is 0, 1 or 2; -O-COOCH1-CO-X1where X3H or alkyl WITH1-C3; -NH--O-X1, -O--NH-X1; -NH--NHX1where W Ile S; -NH--(CH2)s-COOH, where S 2,3,4, in which the groups selected among halogen atoms, alkyl or alkoxygroup1-C3nitro-, amino-, hydroxy-, triptoreline groups; adamantly group;

a group chosen among a-CONX1X2; -NX1X2in which X1represents hydrogen, alkyl WITH1-C3or phenyl, unsubstituted or substituted by one or more groups selected from among halogen atoms, alkyl or alkoxygroup1-C3, nitro-, amino-, Hiroki-, triptoreline groups, and X2represents a hydrogen atom, alkyl WITH1-C3or X1and X2together with the nitrogen atom, to which they are bound, form a heterocycle selected among pyrrolidine or piperidine, unsubstituted or substituted by oxopropoxy or a hydroxyl group, the latter is unsubstituted or substituted by acyl, group-COOH1or NX1X2;

or more RVis alkoxygroup1-C5; a hydroxyl group; a 5 - or 6-membered cyclic amine, unsubstituted or substituted by oxopropoxy or a hydroxyl group; piperazinilnom group, unsubstituted or N-substituted by a group-Al in which Al represents alkyl WITH1- 5where t equals 2, 3 or 4 and X5represents-OH, -O-CO-R2, -NHCOR2, -NH--NR2where R2represents alkyl WITH1-C6; or the group-NR2R6where R2or R3independently from each other represents H, alkyl WITH1-C6, phenyl group, unsubstituted or substituted by one or more substituents selected among halogen atoms, alkyl groups WITH1-C3,alkoxygroup1-C3or R2and R3together with the nitrogen atom to which they are bound, form a 5 - or 6-membered heterocycle; Z represents a heterocycle containing one or more heteroatoms selected among 0, S and N, a condensed aromatic ring which may contain heteroatom chosen among O, S and N, and which may be substituted by one or more groups selected from among halogen atoms, alkyl or alkoxygroup1-C3, benzyloxy - nitro-, amino - and triptorelin groups, and the N heteroatom may be aromatic or-NH, unsubstituted or substituted (C1-C4) alkyl, a group carboxylase-Z4-COOP10where Z4is a (C1-C4) Ala is 11R12where Z5is a (C1-C4) alkylene, and R11and R12independently from each other represents H, (C1-C6) alkyl, or together with N form a saturated a heterocycle, such as morpholino or piperidinyl; the group acyl-fulfills I TS cor13where R13is a (C1-C4) alkyl or phenyl; a group alkoxycarbonyl-COOR14where R14is tert-bootrom or benzyl;

as well as salts of the Association of these compounds with mineral or organic acids and bases; and obtained a non-toxic pharmaceutically acceptable salts, but other salts used for separation or purification of compounds with formula I, are also the object of the invention.

Alkyl, alkylene, alkoxy and tricalgoxyl can be linear or branched.

Z represents, in particular, benzothiazoline, benzofuranyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indolenine, isoindolyl, indolinyl, isoindolyl, pinolillo, izohinolinove khinoksalinona, chinazolinei, indolinyl and (2,3-C)-pyridyloxy group.

When Z represents indolenine GRU is Liza, R9represents H; alkiline group1-C4; carboxyaniline group, esterified, if necessary, with the formula-Z4-COOR10in which Z4is alkylen1-C4; carbamylcholine group with the formula-Z5-CONR11R12in which R11and R12independently of one another represent H or alkyl WITH1-C6or together with N form a saturated a heterocycle selected among morpholino or piperidinyl and Z5is alkylene,1-C5; acyl group with the formula COR13in which R13represents alkyl WITH1-C4or phenyl; alkoxycarbonyl group with the formula COOR14in which R14represents tert-butyl or benzyl.

Among the compounds with formula (I) preferred are those in which R1represents hydrogen, and among the latter, in particular, those in which Z represents indolenine group, unsubstituted or substituted on the nitrogen; among the groups RIVprefer phenyl.

The object of the invention is the formation of compounds with formula (I), which are formed by the condensation reaction aminothiazol conditions acylation of aminophenol acid with the formula Z COOH, in which Z' represents or is derived Z, in which the reactive functions of Z were protected, and R1, RIV, RVand Z have the same meaning as in formula I, or with an activated form of the acid Z COOH, such as gelegenheid, such as coal anhydride, or activated ester, obtained using the reagents commonly used in peptide synthesis.

Compounds II can be protected; R1aboutin this case, represents the same substituents, and R1in which the amino group is N-protected, and RIVaand RVarepresent the same substituents, and RIVand RVin which the hydroxy or amino groups are O - or N-protected.

If the functions were protected, after condensation is carried out, if necessary, an appropriate response unprotect.

Numerous amenities to formula II are known.

New aminothiazole can be obtained by one of the methods described, in particular, article Bull. Soc. Chim. (C) 1963, 2498-2503.

In the General case will be the reaction of thiourea with an alpha halogenated ketone, preferably, with an alpha Brom, RIVand RVhave the same meaning as in the formula (II).

For various compounds II in which R1represents aminoalkyl group, described in the patent EP-a-O 283390.

Alpha-halogenated ketones and thiourea can be obtained using the methods, the principles of which are described in the General guidelines; alpha-brominated ketones IV can be obtained by the action of the RVCH2CORIVbromine in acetic acid environment or bromide of divalent copper in an organic solvent such as ethyl acetate, chlorinated solvents or mixtures thereof, a Source of aromatic ketones are obtained in General by the reaction of the Friedel -, whereas aliphatic methylketone can be obtained by the action of diazomethane to the corresponding carboxylic acid anhydrides and subsequent hydrolysis of the resulting diazoketone.

Alpha-chlorinated aromatic ketones can be obtained by the reaction of the Friedel-with a suitable acid chloride alpha-chlorinated acid.

When RVrepresents an ester group (CH2)mCOOH1then thiazole derivatives corresponding to the following formula (V)are obtained by known methods, as a result of exposure to alpha-bromoacetanilide or alpha bracketeer for thiourea in accordance with scheme 2

SCHEME 2

R X

Depending on the type of substituent RVfollowing methods are used:

a) when RVrepresents a group -(CH2)mHE, the corresponding derivative 2 aminothiazole the following formula (VI) in which m is as defined for compound (I) can be obtained according to the previous esters (V) result of restoration with the aid of alkali metal hydride, such as, for example, alumoweld lithium in an aprotic solvent such as, for example, tetrahydrofuran, resulting in aminopyrido with formula VI

and the acylation of the compound (VI) using ZCOOH leads to the compound (IB) with the formula:

for which m, RIVand Z are as defined for compound (I);

b) when Ryis a group of ester -(CH2)m-O-CO-X1or complex tiefer -(CH2)m-S-MOR1or group (OH)q-S-X1in which m, X1and q are as defined for formula (I), derivatives of 2-aminothiazole (VII), (VIIc) or (VIId), in which RIVq, m, W, and X1are as defined for formula (I) can be obtained according to the following schemes is, who and which affect the acid chloride of the acid, such as, for example, acetylchloride, in a solvent such as, for example, pyridine, to obtain esters with the formula Ic

< / BR>
for which X1; m, RIVor Z are as defined above for compound (I):

(C) when Ryis a carbamate -(CH2)m-O-CO-NHX1in which m and X1are as defined for compound (I), thiazole derivatives according to the invention receives, from the corresponding hydroxylated compounds (IB) under the action of the isocyanate with the formula X1-N C= O in an aprotic solvent, such as for example, tetrahydrofuran or dichloromethane, at a temperature that is between 20 and 100aboutWith that leads to the compound (If) with the formula:

in which X1, m, RIVand Z are as defined for formula (I);

d) when RVis an amide- (CH2)m-CONX1X2in which m, X1and X2are as defined for compound (I), thiazole according to the invention are a result of the reaction between the amine HNX1X2and corresponding complex ester with formula (V) or (Ia) in the presence of no solvent, thicki a closed vessel in the matter whether Amin volatile, which leads to the compound (VIII) or (Id) with the formula:

or

in which X1, X2, m, RIVand, if necessary, and Z are as defined for formula (I);

e) when RVrepresents an amino group -(CH2)m-N-X1X2then thiazole derivatives according to the invention receives, for example, in the recovery described amides of formula (VIII), restoring using an alkali metal hydride such as, for example, alumoweld lithium, in a solvent such as tetrahydrofuran, at a temperature that is between the 20aboutC and the boiling point of the solvent, the resulting compound with the formula IX

moreover, the acylation of compound IX using ZCOOH leads to the compound (Ih) with the formula (Ih)

in which X1, X2, m, RIVand Z are as defined for formula (I);

f) when RVis a carbonate -(CH2)m-O-COOX1in which m and X1are as defined for compound (I), thiazole according to the invention receives, from alcohols (Ib), introducing them into the reaction chloroformate Cl--OX1in the presence of a base such as triethylamine or pyridine, which leads Allow (I);

g) when RIVand RVconsidered together, represent a group:

which (Xp)CRand are as defined for formula (I), and which is connected through the carbon of the phenyl with regulation 4 of the thiazole ring; for example, the intermediate 4-bromo-2H-dihydro-3,4-(1)-benzoxazepin-5-he formula

received in accordance with article G. Fontaine et. al. C. R. Acad. Sci, 1965, 258, 4583; 2-amino-4,5-dihydro-[5,4-d]-thiazole (-1)-benzoxazepin with the formula X

the resulting cyclization with thiourea in the usual way described above, then alleroed: resulting compound with the formula Ij

in which Z is as defined for compound (I);

h) when RVrepresents an amino group-NX2X4in which X2and X4are as defined for compound (I), a derivative of thiazole according to the invention can be produced from 2-amino-5-bromothiazole with formula XI

which is obtained in accordance with article J. Chem. Soc. 1947, 1 4, followed either by acylation, for example, using the derived Z-COOH in the presence of BOP and bases, such as triethylamine, and then it received promotergene derived with the formula Ik

in which RIVand Z I is enclosed between the 20aboutC and the boiling point of the solvent, the resulting compound with the formula Il

in which X2, X4, RIVand Z are as defined for formula (I);

any substitution of the amine HNX2X4and then alleroed in position 2 of the thiazole, and both reactions are carried out in conditions identical to those described above

i) when RVrepresents a group -(CH2)m-X, in which m=0, and X represents alkoxygroup1-C5then the corresponding 2-aminothiazol obtained from 2-bromo-2-alkoxy-1-phenylethanone, substituted, if necessary, on the phenyl, which leads to a product with the formula XI'

in which RIVis the same as defined above, and X represents alkoxygroup1-C5and then alleroed, as above, which leads to compounds (Im) with the formula (Im)

in which RIVand Z are as defined for formula (I), and X is as defined above for formula (XI'), or one of their salts.

Compounds of formula XI' are the new intermediate products that form part of the invention.

Some of the acids ZCOOH or Z COOH are known and Yes>So, indolocarbazole acid, referred to below Z"COOH, with the formula:

COOH in which R9represents alkoxycarbonylmethyl group, can be obtained on the basis of indolocarbazole acids, commercial or obtained by the classical methods in accordance with reaction scheme 4 below:

SCHEME 4

(Xi)COOQ + R9HalOOQ where HaI is a halogen atom, and Q represents a benzyl group.

Benzyl esters in scheme 4 are obtained by action of the appropriate acid in benzyl alcohol in the presence of the appropriate acid in benzyl alcohol in the presence of an agent activating the acid function, which is usually used in peptide synthesis, such as:

1,1'-carbonyldiimidazole, to which you can refer to the article Synthesis, 1982, p. 833;

N, N-dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine, to which you can refer to the article J.Org. Chem, 1990, 54 (4), born 1390;

hexaphosphate benzothiazolinone-Tris-(dimethylamino-phosphonium) (BOP), to which you can refer to the article Synthesis, 1977, p. 413.

The basis used when fixing R9nitrogen benzyl ether complex, alainna compound is a polar aprotic solvent, stable in the presence of a strong base, such as dimethylformamide or dimethoxyethane; the reaction is carried out at a temperature of enclosed between about 15 and 80aboutC.

The removal of benzyl groups after N-alkylation is carried out in a classical way under the action of at least one equivalent of hydrogen in the presence of a catalyst such as palladium on charcoal, ester, dissolved in alcohol or dimethylformamide, if necessary, under slight pressure.

However, some of the acids ZCOOH are metastability or have a function that will be able to react by condensation with aminothiazolo therefore be preferable to use them in a protected form Z COOH.

Thus, the derivative (I) in which Z represents:

(Xi) where (Xi)ni represents the possible substituents, can be obtained from compounds obtained by the condensation reaction of aminothiazole connections indolocarbazoles acid Z COOH formula XII

(Xi)COOH in which Q is a group, usually used to protect groups NH2in the condensation reactions of amino acids, such as:

-COO/Trets the organisations with the formula XIII:

obtained after the condensation reaction with a derivative II, using classical methods of removing the protection.

BOF can be chipped off during pyrolysis in the absence of a solvent at a temperature that is between 180 and 200aboutC.

Indolocarbazole acid Z"COOH, in which R9is a group COOC(CH3)3or COOCH2C6H5can be obtained by the action of dicarbonate tert-butyl, chloroformiate of benzyl Z"COOH, in which R9N, in the presence of a base such as triethylamine or 4-dimethylaminopyridine, in a solvent such as acetonitrile or methylene chloride.

Acid Z"COOH, in which R9is an acyl group, can be obtained by the action of the acid chloride or anhydride, acid Z"COOH, in which R9H, in the presence of one equivalent of triethylamine and 4-dimethylaminopyridine, for example, in dichloromethane.

The acid chloride of the acid of formula ZCOCl can be obtained, in particular, under the action of SOCl2or a mixture of POCl3and R2ABOUT5the corresponding acid is usually in the absence of solvent and at a temperature of education phlegmy reaction mixture.

Among the activated esters with the formula ZCOOY", Z COOY" iloto in the presence of dicyclohexylcarbodiimide according to the method described in the article in J. Am. Chem. Soc. 1971, 93, 6318-6319 (1971), or under the action of hexaflurophosphate 1-benzothiazolylthio(dimethylamino)-Foz - phone according to the method described in the article, Synthesis, 1976, 751-752.

The reaction of condensation of aminothiazole II with the acid to form an activated complex ester can be carried out in a solvent, the nature of which is selected depending on the solubility of the compounds and on the type of activation of the acid function,

preferably in the presence of a base, e.g. a tertiary amine such as triethylamine; the reaction is usually carried out at a temperature that is between 0 and 30aboutC.

When compounds with formula (I) contains Z the group of carboxylic acids, they can be obtained by hydrolysis, complex ether, preferably in a basic medium, for example, under the action of the mineral bases such as alkali metal hydroxide, in aqueous-alcoholic medium, or as a result of acid hydrolysis in the case of the tert-butyl ether complex.

Salt accession of compounds with formula (I) with acids or bases receive the usual way by the introduction of acid or base in a solution of compounds with formula (I). Salt is allocated depending on its rastvorityelya with formula (I) and their salts inhibit the binding of cholecystokinin with their receptors. They are more or less selective with respect to the receptor type a or b, and more or less powerful antagonists against gastrin.

Their affinity for the CCK receptor And was determined in vitro using the method described below, the principle of which is the same as referred to in article Life Sciences, 1985, 37, (26), 2483-2490; it is to determine the displacement iodirovannoi CCK 8 S from their binding sites on homogenizate pancreas of rats: aliquot quantity of a suspension of the shell of the pancreas (100 μg protein per ml) in a buffer solution of Tris, HCl (50 mm), pH 7.4, containing MgCl2(5 mm), bacitracin (9.1 mg/ml), floramite methylphenylacetonitrile (0.1 mg/ml) subjected to incubation for 40 minutes at a temperature of 25aboutWith the presence iodirovannoi CCK 8 S (200 CI/mmol, i.e. 50 mm final concentration) and increasing concentrations of the substance; the reaction is terminated after 40 min in the centrifuge. After removal of the emergent phase is measured radioactivity of the residue. On the other hand, the nonspecific binding determined in the presence of CCK 8 S with a concentration of 1 μm.

Under these conditions, the concentration inhibiting on the and is of the order of 10-10M

Their affinity for CCK receptors was determined in the study of displacement iodirovannoi CCK 8's with their specific binding sites located in homogenizate from the cerebral cortex of Guinea pigs, by applying the same methodology as for CCK receptors And, but for a suspension of membranes with a concentration of 600 μg protein/ml with the buffer solution of HEPES (10 mm) at pH values of 6.5, containing NaCl (130 mm), MgCl2(5 mm), EDTA (1 mm) and bacitracin (250 mg/ml), and incubation is carried out for 2 h

At a concentration of 10-5M all products displace more than 25% labeled CCK 8 S of receptors; some have Cl50order 10-9M

The means for gastrin receptor for compounds, the most specific in relation to the CCK receptor, was studied in accordance with the method described below, the principle of which is the same as mentioned in J. Receptor, Res. 1983, 3 (5), 647-655; aliquot the number of gastric glands of Guinea pigs in a buffer solution of HEPES when the value of pH 7.4 (24,5 mm) containing NaCl (98 mm), HCl (6 mm); NaH2PO4(2.5 mm). pyruvate (5 mm), CaCl2(0.5 mm), MgCl2(1 mm), glucose (11.5 mm), glutamine (1 mm), bovine albumin (0.4 g/100 ml) were exposed to incubation) and with increasing concentrations of the studied products. The reaction was stopped in the centrifugation was then measured radioactivity of the residue after centrifugation; the nonspecific binding was determined in the presence of gastrin (2-17) at a concentration of 1 μm. Compounds according to the invention have Cl50in the interval between 10-5and 10-9M

It was also shown that the compounds according to the invention have an inhibitory effect on the activity of CCK. It was determined in vitro by measuring under the action of the tested products inhibiting the secretion of amylase by acini rats, stimulated by CCK 8 S, in accordance with the method similar to that described in the article by J. Biol. Chem. 1979, 254, (12) 5321-5327, but with a pancreatic tissues of Guinea pigs. Connections have values Cl50in the range from 10-6up to 10-9M

Finally, in mice in vivo compounds having good affinity for CCK receptors And, had an antagonistic effect on the inhibition of gastric emptying caused by subcutaneous injection of CCK 8 S in accordance with the Protocol of the experience described in the article Life Sciences, 1986, 39, 1631-1638; thus defined, DE50(dose with 50% efficiency) is strictly less than the same values for proglumide, known antag is as medicines for the treatment of physiological disorders, due to hypersecretion of these peptides or a biological disorder of hormonal systems in which they are involved at the level of intestinal sphere or in the Central nervous system depending on their specificity. You can refer to the review of therapeutic applications of antagonists of CCK and gastrin, published in "rceedings of International Symposium on Gastrin and cholecyctokinin 7-11 September 1987, Ed. J. P. Bali, J. Martines Elsevier Science Pub. B. BV.

In particular, antagonists of CCK will be useful in the treatment of intestinal dyskinesia, such as the syndrome of the irritable colon, in the treatment of acute or chronic pancreatitis or in the treatment of pancreatic carcinomas (cancerous tumors), as well as for the regulation of appetite or in combination with oppimateriaalit pain relievers in the treatment of pain.

As for the more selective antagonists Gastronom, they will be useful in the treatment or prevention of gastric ulcers, the treatment of the syndrome of Zollinger-Ellison, in the treatment of hyperplasia of cells Gr sinus (cavity) or for patients with cancer of the esophagus, stomach or intestines.

Among the antagonists of cholecystokinin on the level of receptors And prefer compounds: 2-(2-carboxymethyl-2-Indo is ASS="ptx2">

Medicinal product according to the invention contain at least one of the compounds with the formula I or one of its salts with pharmaceutically acceptable acid or base, if necessary, in combination with the usual indifferent substances to create pharmaceutical form, enter the classical way of oral, parenteral rectal route or through the mucous membrane. Input dose depend on the nature and extent of the disease, from the connection and the route of administration. They will usually be between 20 and 100 mg per day for adult oral route and from 3 to 10 mg by injection.

The pharmaceutical compositions according to the invention for oral administration may be in the form of tablets, pills, zlatanovic capsules or granules or in the form of a solution, suspension or gel. For parenteral administration of the composition according to the invention will be in the form of a solution, suspension or emulsion in a liquid or in any solvent for injection, if necessary, water-based, containing classical additives for this type of recipe.

For local injection on the skin or on the mucous membranes of the composition according to the invention will be through the skin, whereas for Richtlinie of the invention, and also ways to get some intermediate products of the synthesis of formulas II and IV. Above the melting temperature (TPL) were determined in a capillary tube. The spectra of nuclear magnetic resonance (NMR) were recorded on tetramethylsilane.

Synthesis A.

2-Aminothiazol, substituted in position 5 by a group -(CH2)mX1.

2-Amino-4-(2,4-acid)-5-Ben - diltiazem.

R1= H; RIV= OCH3; RV= -CH

A) 1-(2,4-Acid)-3-phenylpropane-1-it is obtained in accordance with article E. Thomas et. al. J. Med. Chem. 1985, 28, 442-446 by the reaction of the Friedel -.

C) 1-(2,4-Acid)-2-bromo-3-phenylpropane-1-it is in accordance with classical methods as a result, the synthesized bromine in a solvent such as dichloromethane or carbon tetrachloride.

C) 2-Amino-4-(2,4-acid)-5-benzilate.

To 10 g obtained before this prosteradlo derived dissolved in 100 ml of 95% ethanol is added 4.35 g of thiourea and heated the reaction mixture at a temperature of education phlegmy for 3 hours, Concentrate under vacuum and extract the residue in dichloromethane, then washed with saturated process is under vacuum. The residue is crystallized in 50 ml of dichloromethane.

m 7, 10,

So pl. 202-203aboutC.

Conducting syntheses, as stated above, get a 2-aminothiazole described in table 1, below.

Synthesis Century

2-Aminothiazol, substituted in position 5 by a group -(CH2)m-CO2X1or -(CH2)m-CH2OH.

A) 2-Amino-4-phenyl-5-methoxycarbonylmethylene.

(II): R1H; RIV-C5H6; RV-CH2-CO2CH3< / BR>
It turns out in accordance with article E. Knott, J. Chem. Soc. 1945, 455.

A) 2-Amino-4-phenyl-5-hydroxyethylthio.

To a suspension containing 2 g of lithium aluminum hydride in 100 ml of tetrahydrofuran, cooled to 0aboutC, add 5 g of aminecontaining of ester obtained before this, and heated the reaction mixture at a temperature of education phlegmy for 2 hours Then after cooling in an ice bath was added sequentially 2 ml of water, 1 ml of concentrated NaOH and 6 ml of water, then stirred the reaction mixture overnight. Separate the mineral precipitate by filtration and concentrate the mother liquor solutions under vacuum. The residue is extracted into dichloromethane, washed with water, the Residue chromatographically on silica gel, eluent: dichloromethane/methanol 100/3 (V:V).

Concentration of the pure fractions gives 4 g of the expected alcohol.

So pl. 121aboutC.

Conducting syntheses, as stated above, get a 2-aminothiazole described in table.2, below.

Synthesis With.

2-Aminothiazole, substituted in position 5 by a group -(CH2)m-O-C-X1or (CH2)m-S-X1< / BR>
2-Amino-5-(1-substituted-1-Carbonia-xitil)-4-phenylthiazol.

RI= H; RIV= -C6H5; RV= -(CH2)2-O-

A) 4-(1-Adamantylamine)-1-phenyl-1-butane.

Receive in accordance with article J.Org. Chem. 1977, 42, 8, 1286 cesium salt of 1-adamantylamine acid, based on 12 g of 1-adamantylamine acid, and 10,96 g of cesium carbonate. The resulting mixture was dissolved in 70 ml of DMF, then added 18 g of 4-iodine-1-phenylbutane-1-it and heated the reaction mixture at a temperature of education phlegmy during the night. DMF is evaporated under vacuum, removing the remainder of a 5% solution of Na2CO3and extracted in CH2Cl2. The organic phase is washed with water and then dried on Na2SO4. Concentrate under vacuum and chromatographic the residue on silica gel, eluent: CH2But-5-(1-substituted-1-carbonyloxy)-4-phenyl-thiazole.

Dissolve 10 g obtained this compound in 100 ml of CCl4. Added 4.9 g of bromine dissolved in 50 ml of CCl4and leave the reaction mixture under stirring for 30 minutes, Washed with water, decanted organic phase, dried on her MgSO4filter and concentrate under vacuum.

The residue is extracted with 50 ml of 95% ethanol. To the solution was added to 3.9 g of thiourea and the reaction mixture is stored overnight at ambient temperature. Concentrate the mixture under vacuum, extract the residue in CH2Cl2washed using 5% aqueous solution of NaHCO3, decanted organic phase, dried on MgSO4filter and concentrate under vacuum. The residue is extracted into ether and dried.

m 6,8,

So pl. 167aboutC.

Conducting syntheses, as stated above, get a 2-aminothiazole described in table.3, below.

Synthesis D.

2-Aminothiazole, substituted in position 5 by a group -(CH2)mX,

in which X represents a group NX1X2where X1X2H.

Obtaining 2-amino-5-amino-ethyl-4-phenylthiazole.

(II): R1H; RIV-C6H5; RV-CH2CH2NH2aboutC for 24 hours in 100 ml of DMF. Concentrate DMF under vacuum and the residue is washed sequentially with water, 1 N. NaOH solution and extracted with ethyl acetate. The organic phase decantered, dried on MgSO4, filtered and concentrated under vacuum.

m 11,

A) 2-Amino-5-phthalimidomethyl-4-phenylthiazol.

Dissolving 9.6 g is received before this compound in 50 ml of CCl480 ml of CH2Cl2. To the solution was added drop by drop a solution containing 5.6 g of bromine in 30 ml of CCl4. The reaction mixture is washed with water, the organic phase dried on MgSO4, filtered and concentrated under vacuum. The residue is extracted in 70 ml of ethanol, then added 4.5 g of thiourea and the reaction mixture is stored overnight at ambient temperature.

The mixture is cooled, bromohydrin is separated by filtration, washed with ethanol, and then intensively stirred mixture of 5% Na2CO3ethyl ester. Filtered off the crystals.

m 8,

So pl. 209aboutC.

C) 2-Amino-5-amino-ethyl-4-phenylthiazol.

Treated with 8 g obtained before product by 1.5 g of hydrazine hydrate dissolved in 100 ml of absolute ethane is used to concentrate the ethanol under vacuum, extract the residue in water, acidified by adding concentrated HCl to pH 1, separate phthalazinedione by filtration, alkalinized cooled in an ice bath, the aqueous phase by addition of concentrated NaOH to pH 9, the precipitate is filtered off, washed with water and dried in a drying Cabinet.

m 3,7,

So pl. 136-137aboutC.

Synthesis E.

2-Aminothiazole, substituted in position 5 by a group -(CH2)mX, in which X represents a group-NX1X2,

where X1N and X2-CO-CH3.

2-Amino-5-(2-acetylamino-1-ethyl)-4-Fe - diltiazem.

(II): R1H; RIV-C6H5;

RvCH3CONH(CH2)2< / BR>
Process 1 g obtained according to the synthesis of D 2-aminothiazole dissolved in 60 ml of THF in the presence of 0.7 ml of triethylamine, by means of 0.44 ml of acetic anhydride dissolved in 20 ml of THF. The reaction mixture is left at ambient temperature for 2 h and concentrated under vacuum. The residue is washed using 5% aqueous solution of NaHCO3, the precipitate was separated by filtration, washed with water and dried.

m 1.12 g

So pl. 208-209aboutC.

Ex is cnie connection described in table. 4, below.

Synthesis F.

2-Amino-4,5-dihydro-[5,4-d]-thiazole(-)1-benzoxazepin II

< / BR>
A) 4-Bromo-4-2H-3,4-dihydro-(1)-benzoxazepin-5-he receives in accordance with article G. Fontaine, P. Maite, C. R. Acad, Sci, 1964, 258, 4583.

A) 2-Amino-4,5-dihydro-[5,4-d]-thiazolo-(1)-benzoxazepin

To 0,027 mol prosteradlo derived dissolved in 100 ml of ethanol, add 2,05 g of thiourea.

The mixture is heated at a temperature of education phlegmy for 3 hours, the Ethanol is evaporated, the residue is extracted with an aqueous solution of sodium carbonate. Extracted with ethyl acetate, the organic phase is dried on Na2SO4and evaporated to dryness. Obtain 2.4 g of white crystals.

So pl. 216aboutC.

Synthesis G.

2-Aminothiazole, substituted in position 5 by a group -(CH2)m-X, in which m is 0 and X is alkoxygroup1-C5, halogen

The reaction scheme

Stage 1:

in accordance with article J.Org. Chem. 1977, 42 (4), 754.

Stage 2:

in accordance with article Synthesis, 1983, 203.

Stage 3:

H3in accordance with article J. Chem. Soc. Perkin, 1, 1981, 2435.

2-Amino-5-methoxy-4-phenylthiazol.

(II): R1H; R is chevigny in 70 ml of methanol. The reaction mixture is heated at a temperature of education phlegmy overnight, then concentrated under vacuum. The residue is extracted into 10% aqueous solution of Na2CO3, is extracted with the help of CH2Cl2separate the organic phase, which successively dried on Na2SO4, filtered and concentrated under vacuum. The remainder precrystallization from isopropyl ether.

m 7.5 g

So pl. 96aboutC.

Synthesis Of N.

Getting indolocarbazole acid:

A) 1-Tert-butyloxycarbonyl-2-carboxylic acid

a) Indole-2-carboxylate of benzil.

Enter 5 g N,N'-carbonyldiimidazole in a solution containing 5 g of indole-2 carboxylic acid in 50 ml of anhydrous tetrahydrofuran; after stirring for 12 h at ambient temperature was added 3.7 g of benzyl alcohol and heated the reaction mixture to a temperature of education of its phlegmy; the latter is maintained for 8 h before to remove the solvent by distillation under reduced pressure. The residue is dissolved in ethyl acetate, and the organic phase washed with 1 N. aqueous solution of NaOH, then dried before evaporating the solvent.

OST the>/BR>C) 1-Tert-butyloxycarbonyl-2-carboxylate-benzyl.

To a solution containing indole-2-carboxylate of benzyl (0,072 mol; 18,18 g) in 200 ml of dimethylformamide, was added in nitrogen atmosphere in portions sodium hydride (0,075 mol; 2.25 g) in liquid oil with a concentration of 80% at a temperature that is between 0 and 5aboutC. Allow the mixture to return to ambient temperature and stir the mixture for 1 h and Then added drop by drop in 10about14 g (0,072 mol) of bromoacetate tert-butyl. The reaction mixture is left for 3 h at ambient temperature. Dimethylformamide is evaporated and then extracted in water, extracted with methylene chloride, the organic phase is dried on sodium sulfate and evaporated to dryness. As a result of crystallization of the residue in diisopropyl ether get to 23.8 g of white crystals.

So pl. 95aboutC.

C) 2-Tert-butoxycarbonylamino-2-carboxylic acid.

Received before this ester (0,065 mol; 23,8 g) was dissolved in a mixture consisting of 400 ml of ethanol and 100 ml of dimethylformamide. Add 1 g of palladium deposited on activated carbon with a content of 5% and hydronaut under atmospheric pressure at a temperature of OCD is UltraVivid on the powder catalyst, evaporated until dry solvents. Receive a crystalline residue, which was washed with diisopropyl ether. Gain of 15.3 g of white crystals.

So pl. 177aboutC.

C) 1-Acetylindole-2-carboxylic acid.

A mixture of indole-2-carboxylic acid (0.06 mol; 10 g), triethylamine (0.15 mol; each holding 21.25 g), acetic anhydride (0,075 mol; 7.5 g) and 4-dimethylaminopyridine (0,006 mol; 0.8 g) in methylene chloride, stirred at ambient temperature for 18 hours Then the reaction mixture prilisaetsa to aqueous buffer solution with pH value of 2.

The formed precipitate is filtered, then dried in an oven under vacuum. Phase on the basis of methylene chloride decanted, dried on sodium sulfate and evaporated to 3/4. Precipitates second batch of 1-acetylindole-2-carboxylic acid. Both parties combine to give 9.4 g of beige crystals.

So pl. 168aboutC.

C) 1-Benzyloxycarbonylamino-2-carboxylic acid.

Dissolve 8 g of indole-2-carboxylic acid in 120 ml of dichloromethane, then add 10 g of triethylamine and 1 g of dimethylaminopyridine.

The reaction mixture was stirred, then cooled to 0-5aboutC. PR is mesheanii at night, then concentrated under vacuum. The residue is extracted with 500 ml ethyl acetate, then filtered. Royal solutions are concentrated under vacuum and extracted in 50 ml of dichloromethane. Filter and concentrate the mother liquor solutions under vacuum.

m 2.4 g of liquid oil.

NMR(DIR): 2N when 5,38 (s, CH2-C6H5); 10H between 7.0 and 8.0 (m, N aromatic. ).

D) 1-Tert-butyloxycarbonyl-2-carboxylic acid.

Enter drop by drop 30 ml of a solution containing 6 g of dicarbonate dicret-butyl in 30 ml of a mixture consisting of 4 g of indole-2-carboxylic acid, 4 ml of triethylamine and 0.4 g of 4-dimethylaminopyridine in acetonitrile. After stirring for 2 h at ambient temperature and removing the formed precipitate the acetonitrile is removed by distillation and the residue is dissolved in methylene chloride. The organic phase is washed with water, dried and concentrated to dryness.

So pl. 117aboutWITH

Exit 66%

P R I m e R 1. 2-(Indolyl-2-carbylamine)-4-(2,4-acid)-5-benzylthio evil

RIVOCH3< / BR>
Dissolve a 1.96 g of 2-amino-4-(2,4-acid)-5-benzilate received before that according to the synthesis And 1.22 g of 1-acetylindole-2-carboxylic acid, 0.85 grams of triethylamine and Krutaya environment, then prilisaetsa to the buffer solution with pH value of 2. The precipitated yellow color is separated by filtration, washed with water and dissolved in ethyl acetate. The solution is washed sequentially with buffer solution with pH value of 2, water, 5% solution of NaHCO3and water, then dried on MgSO4and concentrated under vacuum. The residue is purified by chromatography on silica gel, eluent: dichloromethane/ethyl acetate 98/2 (V/V).

Concentration of the fractions of pure product gives a residue which is treated under stirring for 24 h using 3 g of Na2CO3in 80 ml of methanol. The methanol is concentrated under vacuum and the residue extracted into a mixture of water/ether. The precipitated white color is separated by filtration and washed on the air.

m 0.97 g

So pl. 201-202aboutC.

The same way we obtain compounds according to the invention, described in table.6, below.

P R I m e R 7. 2-(1-Tert-butoxycarbonyloxyimino-2-indolyl)-carbonyl-amino-4-phenyl - 5-hydroxyethylthio. (I): RV= -(CH2)2-OH; RIV= -C6H5; RI=H; Z

Dissolve 2 g of amerosport received before that (according to the synthesis, PL. 2), of 2.75 g of 1-tert-butoxycarbonyl at ambient temperature the reaction mixture prilisaetsa to phosphate buffer solution with pH value of 2. The precipitate is separated by filtration, washed with water and dissolved in ethyl acetate. The solution is successively washed using 5% aqueous solution of NaHCO3, is separated by decantation, the organic phase is dried on MgSO4and concentrated under vacuum.

The residue is purified by chromatography on silica gel, eluent: dichloromethane/methanol 100/0,5 (V/V).

Product suirvey first meets Vallirana connection (0 - and N-acylation, So pl. 70aboutC). The expected product is eluted second.

m 1,2,

So pl. 180-181aboutC.

P R I m e R 8. 2-(1-Tert-butoxycarbonylmethyl-2-indolyl)- carbylamine-4-phenyl-5-acetoxyacetyl. (I): RI= H; Z IS C6H5< / BR>
RVCH3-COO-(CH2)2-

Dissolve 0,30 g is received before this product in 5 ml of pyridine with the formation of the suspension.

Add 1.2 ml of acetic anhydride and stirred the reaction mixture overnight at ambient temperature. The mixture is then prilisaetsa sulfate buffer solution with pH value of 2, and the precipitate is separated by filtration, washed with water, then extracted into dichloromethane. The solution consistently SUB>, filtered and concentrated under vacuum. The residue is purified by chromatography on silica gel, eluent: dichloromethane/ethyl acetate: 98/2 (V/V).

m 0,16,

NMR (DMSO): N when to 1.48 (s, tert-O2C); 3H at 2,00 (s, CH3CO2); 2H at 3,24 (t, J 7 Hz, CH2of the thiazole); 2H at 4,30 (t, J 7 Hz, CH2OA s); 2H at of 5.40 (s, CCO2-tert-Bu); 10H between 7.2 and 7.9 (m, N aromatic.); 1H at 12.8 (s, NCO).

P R I m e R 9. 2-(1-Carboxymethyl-2-indolyl)-carbylamine-4-phenyl-5-acetic-sicilliano. (I): RI= H; Z RIV= -C6H5< / BR>
RVCH3-COO-(CH2)2-< / BR>
Dissolve 0.15 g obtained this compound in 2 ml of anisole and 10 ml triperoxonane acid.

The mixture is left for 45 min at ambient temperature, then concentrated under vacuum. The obtained residue is washed with a mixture of hexane and diethyl ether (50/50), then dried.

m of 0.14 g

So pl. 117-218aboutC.

P R I m e R 10. 2-(1-Acetyl-2-indolyl)-carbylamine-4-(2,4-acid)-5-etoxycarbonyl METI (I): RI= H; Z; RIV= OCH3< / BR>
RVCH3CH2-OCO-CH2.

Dissolve 1.5 g of 2-amino-4-(2,4-acid)-5-ethoxy-carbonylmethyl is stirred over night at ambient temperature, then concentrated under vacuum. The residue is extracted in ethyl acetate, and the solution successively washed with a buffer solution with pH value of 2, 5% solution of NaHCO3and water, then the organic phase is dried on MgSO4and concentrated under vacuum. The residue is purified by chromatography on silica gel, eluent: dichloromethane/ethyl acetate-100/2,5 (V/V).

m 1.2 g

So pl. 130-135aboutC.

P R I m e R 11. 2-(2-Indolyl)-carbylamine-5-etoxycarbonyl-4-phenyl-thiazole. (I): RH RIV= -C6H5< / BR>
Carrying out the synthesis as described before this example 10, get the compound 2-(1-acetyl-2-indolyl)-carbonyl-amino-4-phenyl-5-ethoxycarbonyl evil (1.5 g) which was dissolved in 100 ml ethanol in the presence of 0.6 g of Na2CO3. The mixture was stirred at ambient temperature for 48 h, then concentrated under vacuum. The residue is converted into powder in water, then in a minimum amount of dichloromethane, filtered and dried.

m 1.1 g

So pl. 248aboutC.

P R I m e R 12. 2-(2-Indolyl)-carbylamine-4-(2,4-acid)-5-carboxy-methylthiazole. (I): RI= H; Z RIV= OCH3< / BR>
RV-CH2-COOH.

Dissolve 0.5 g of 2-(1-acetyl-2 is accordance with example 10, in 10 ml of 95% ethanol, then add 1.5 ml 2 N. NaOH. The reaction mixture is stirred over night at ambient temperature, then concentrated under vacuum. The residue is extracted in a buffer solution with pH value of 2, the precipitate is separated by filtration, washed with water, filtered, then opolaskivaetsya ether.

m 0.28 g

So pl. 284aboutC.

Conducting the synthesis in accordance with the above examples 7-12, get connections, described in table.7.

P R I m e R 31. 2-(2-Indolyl)carbylamine-4-phenyl-5-[2-(1-pyrrolidino-CT - bonyl)-1 - ethyl]-thiazole. (I): RIV= C6H5;

Add 0.5 g of ester, described in example 14, 5 ml of pyrrolidine, stirred the mixture overnight at ambient temperature, then poured to a buffer solution with pH value of 2. The precipitate is separated by filtration, then dissolved in ethyl acetate. The solution is washed with a buffer solution with pH value of 2, then with water, the organic phase is separated by decantation, dried on MgSO4and concentrated under vacuum.

m 0,48 g

So pl. 179aboutC.

Conducting the synthesis in accordance with the above example 10, receive connect the si - utiltity. (I): RI= H; Z RIV= C6H5; RV= (CH2)2-OCO-NH

A) 2-(1-Acetyl-2-indolyl)-carbylamine-5-phenyl-5-phenylenecarbonyl - utiltity.

Stirred over night at ambient temperature 0.7 g of the alcohol obtained in accordance with example 16, and 0.2 ml of phenylisocyanate in 5 ml of dichloromethane. The formed precipitate is separated by filtration, then purified by chromatography on silica gel, eluent: dichloromethane/eteltetet 95/5 (V/V).

m 0,52 g

So pl. 156aboutC.

In The Connection 52.

Dissolve 0.5 g obtained this compound in 30 ml of ethanol and 5 ml of water, then added 0.21 g of Na2CO3< / BR>
The reaction mixture is stirred over night at ambient temperature, then concentrated under vacuum. The residue is extracted in ethyl acetate and washed successively with a solution of Na2CO3and water. The organic phase is separated by decantation and concentrated under vacuum. The residue is extracted into ether.

m 0.4 g

Sopl.249aboutC.

P R I m e R 53. 2-(2-Indolyl)-carbylamine-4,5-dihydro-[5,4-d] 1H-tasavertaiseen. (I): RI= H; Z RVand RIVCH2)2- is-2-carboxylic acid and 0.46 g of triethylamine. The reaction mixture is stirred for 30 h at ambient temperature. Dimethylformamide is evaporated, remove the residue in ethyl acetate and washed with water. The organic phase is dried on sodium sulfate and evaporated. The remainder chromatographies on silica gel, eluent: dichloromethane/methanol 100/0,5 (V/V). Get 0.9 g foamy yellow substance, which is dissolved in dichloromethane with the addition of ethanol (100 ml). Add 10 ml of 2 N. NAOH and stirred the mixture at ambient temperature for 1 h After evaporation of organic solvents extract the residue with ethyl acetate and washed with buffer solution with pH value of 2. Dried the organic phase on MgSO4, filtered and evaporated. Get the yellow crystals, which are then rinsed with dichloromethane, then with ethanol.

m 0.45 g

So pl. > 260aboutC.

P R I m e R 54. 2-(2-Indolyl)-carbylamine-4-phenyl-5-(1-piperidinyl)-thiazole. (I): RI= H; Z RIV= -C6H5; RV= -N

A) 2-Amino-4-phenyl-5-(1-piperidinyl)-thiazole.

Heated at a temperature of education phlegmy within 48 h the mixture consisting of 1 g of 2-amino-4-phenyl-5-bromothiazole and 1.7 g of piperidine in 25 ml of absolute ethanol. The ethanol is concentrated phase in Na2SO4and filtered. Concentrate under vacuum and the residue is recrystallized in isopropyl ether.

m, 0,41

So pl. 135-137aboutC.

In The Connection 54.

Dissolve 0.4 g obtained before this product in 50 ml of dichloromethane. Add sequentially 0.33 g of 1-acetyl-indole-2-carboxylic acid, of 0.82 g of BOP and 0,19 g of triethylamine. The reaction mixture is stirred for 4 days at ambient temperature. Add 25 ml of water and the organic phase is separated by decantation, dried on Na2SO4and concentrate under vacuum. The residue is extracted in 50 ml of absolute ethanol was added 10 ml of 2.5 N. NaOH and stirred the mixture for 3 h at ambient temperature. Concentrate under vacuum distilling the residue in 50 ml of water, extracted with ethyl acetate, the organic phase is separated by decantation, dried on Na2SO4and concentrate under vacuum. The remainder precrystallization of ethyl acetate.

m 0.26 g

So pl. > 260aboutC.

Conducting the synthesis in accordance with example 54, receive connections 55 and 56, as described in table.9.

P R I m e R 57. 2-(2-Indolyl)-carbylamine-5-bromo-4-phenylthiazol.

(I): RI= H; Z RIV=

Add 3,26 g 1-acetylindole-2-carboxylic acid, 8.1 g of BOP, 1.85 g of triethylamine, the reaction mixture is stirred at ambient temperature for 8 days, then add 100 ml of aqueous buffer solution with pH value of 2, decanted, the organic phase is dried on Na2SO4concentrate under vacuum. Extract the residue in 100 ml of methanol, then add 5 g of Na2CO3. Stirred for 3 h at ambient temperature, concentrated under vacuum on a cold, extracted by 100 ml of aqueous buffer solution with pH 2, extracted with ethyl acetate and dried in Na2SO4the organic phase. Filter and concentrate under vacuum. Chromatografic the residue on silica gel, eluent: CH2Cl2. After removal of the head of impurities elute the expected product, which is recrystallized (after evaporation of solvent) of a mixture of CH2Cl2-/diisopropyl ether.

m 2,8,

So pl. 224-226aboutC.

P R I m e R 58. 2-(2-Indolyl)-carbylamine-5-methoxy-4-phenylthiazol. (I): RI= H; Z RIV= -C6H5; RV= -OCH3< / BR>
Dissolve 3,15 g 2-amino-5-methoxy-4-phenylthiazole in 60 ml of CH2Cl2. Add 3,26 g 1 is the temperature of the environment within one week. Add 50 ml of water, decanted organic phase, dried on Na2SO4filter and concentrate under vacuum. The residue is extracted in 100 ml of methanol, add 10 g2CO3and stirred the mixture overnight at ambient temperature. Concentrate under vacuum, extract the residue in water, separating the resulting precipitate by filtration and washed it in CH2Cl2.

m, 1,7

So pl. > 260aboutC.

Conducting the synthesis in accordance with the above example, receive connections 59-61, described in table.10.

P R I m e R 62. 2-(2-Indolyl)-carbylamine-5-hydroxy-5-phenylthiazol. (I): RI= H; Z RIV= -C6H5; RV= -OH

Dissolve of 0.58 g of thiazole obtained in accordance with example 58, in 100 ml of CH2Cl2. Added at ambient temperature to 4.98 ml of 2M solution tribromide boron in CH2Cl2and leave the reaction mixture under stirring for 24 hours Again add to 4.98 ml BBr3leave the mixture for 5 days at ambient temperature and added last to 4.98 ml BBr3leaving the reaction mixture for 48 h at ambient temperature. This mixture is then brought forth italist aqueous phase, adding 2 n HCl solution. Extracted in CH2Cl2dry the organic phase in Na2SO4filter and concentrate under vacuum, resulting in a get a residue, which crystallizes.

m 0,5 g

So pl. 237-239aboutC.

1. Heterocyclic derivatives of substituted 2-acylamino-5-thiazolo General formula I

< / BR>
where R1hydrogen;

RIVphenyl, unsubstituted or having one or more substituents selected among halogen atoms, in particular chlorine or fluorine, C1C6-alkyl or C1C3-alkoxygroup, or RIVand RVtaken together, represent a group

< / BR>
attached through the carbon of the phenyl in position 4 of the thiazole ring,

RVthe group -(CH2)m-X, where m is 0 to 5, X is halogen, preferably bromine; hydroxyl, cyclohexyl, phenyl which may be substituted C1C3-alkoxygroup, the group selected among -- COOH, -COOX1, -OCOX1, -SX1, -OCOOX1, -NHCOX1,

< / BR>
< / BR>
< / BR>
where W is oxygen or sulfur,

< / BR>
where S is 2, 3, 4, where X1C1C5-alkyl, phenyl which may be substituted by one or more C1C3-UB>X2, - NX1X2where X1hydrogen or C1C3-alkyl, X2hydrogen or C1C3-alkyl, or X1and X2together with the nitrogen atom to which they are bound, form pyrrolidine or piperidine, unsubstituted or substituted by oxopropoxy or a hydroxyl group;

or RVC1-C5-alkoxygroup, hydroxyl group, piperazinilnom group N-substituted by a group-COOAlk, where AIk - C1-C5-alkyl, a carboxylic acid group;

Z - indolyl, unsubstituted or substituted on nitrogen by carboxyaniline - Z4COOR10where Z4C1-C4-alkylen, R10hydrogen or C1-C6-alkyl, acyl COR13where R13C1-C4-alkyl, alkoxycarbonyl-COOR14where R14tert-butyl.

2. Connection on p. 1 of formula I, where Z indolyl, unsubstituted or substituted on nitrogen by carboxyaniline Z4-COOR10where Z4C1-C4-alkylen, R10hydrogen or C1-C6-alkyl, acyl COR13where R13C1-C4-alkyl, alkoxycarbonyl

COOR14where R14tert-butyl.

4COOR10where Z4- C1-C4-alkylen, R10hydrogen or C1-C6-alkyl, acyl-COR13where R13- C1-C4-alkyl, alkoxycarbonyl COOR14where R14tert-butyl.

4. A method of obtaining a heterocyclic derivatives of substituted 2-acylamino-5-thiazolo General formula I

< / BR>
where R1hydrogen;

RIVphenyl, unsubstituted or having one or more substituents selected among halogen atoms, in particular chlorine or fluorine, C1-C6-alkyl or C1-C3-alkoxygroup, or RIVand RVtaken together, represent a group

< / BR>
attached through the carbon of the phenyl in position 4 of the thiazole ring;

RVthe group -(CH2)m-X, where m is 0 to 5, X is halogen, preferably bromine, hydroxyl, cyclohexyl, phenyl which may be substituted C1-C3-alkoxygroup, the group selected among -- COOH, -COOX1, -OCOX1SX1, -OCOOX1, -NHCOX1,

< / BR>
< / BR>
< / BR>
where W is oxygen or sulfur;

< / BR>
where s is 2, 3, 4;

where X1C1-C5-alkyl, phenyl which may be substituted by one or more Cth among-CONX1X2, -NX1X2where X1is hydrogen or C1-C3-alkyl, X2hydrogen or C1-C3-alkyl, or X1and X2together with the nitrogen atom to which they are bound, form pyrrolidin or piperidine, unsubstituted or substituted by oxopropoxy or a hydroxyl group;

or RVC1-C5-alkoxygroup, hydroxyl group, piperazinilnom group, N-substituted group -- COOAlk, where Alk - C1-C5-alkyl, a carboxylic acid group,

Z indolyl, unsubstituted or substituted on nitrogen by carboxyaniline - Z4-COOR10where Z4C1-C4-alkylen, R10hydrogen or C1-C6-alkyl, acyl-COR13where R13C1-C4-alkyl, alkoxycarbonyl-COOR14where R14tert-butyl, characterized in that the substituted 2-amino-5-thiazole of General formula

< / BR>
where R1hydrogen;

RIVaand RVahave the meanings indicated for RIVand RVwhere the hydroxy - or amino groups are O - or N-substituted,

process functional derivative of the acid of General formula

Z0COOH,

where Z0is specified for the O-protected group, carry out the removal of protection and subjected, if necessary, the thus obtained product of the acylation or alkylation with the aim of raising the compounds of General formula I, where RI, RIYand RVhave the specified values.

5. A method of obtaining a heterocyclic derivatives of substituted 2-acylamino-5-thiazolo General formula I

< / BR>
where Z indolyl;

R1hydrogen;

RIVphenyl, unsubstituted or having one or more substituents selected among halogen atoms, in particular chlorine or fluorine, C1-C6-alkyl or C1-C3-CNS group, or RIYand RVtaken together, represent a group

< / BR>
attached through the carbon of the phenyl in position 4 of the thiazole ring;

RVthe group -(CH2)m-X, where m is 0 to 5, X is halogen, preferably bromine, hydroxyl, cyclohexyl, phenyl which may be substituted C1-C3-alkoxygroup; group selected among -- COOH, -COOX1, -OCOX1, -SCOX1, -OCOOX1, NHCOX1,

< / BR>
< / BR>
< / BR>
where W is oxygen or sulfur;

< / BR>
where s is 2, 3, 4; X1C1-C5-alkyl, phenyl which may be substituted by one or more Cis selected among-CONX1X2, -NX1X2where X1hydrogen or C1-C3-alkyl, X2hydrogen or C1-C3-alkyl,

or X1and X2together with the nitrogen atom to which they are bound, form pyrrolidine or piperidine, unsubstituted or substituted by oxopropoxy or a hydroxyl group, or RVC1-C5-alkoxygroup, hydroxyl group, piperazinilnom group, N-substituted group -- COOAlk, where Alk is C1-C3-alkyl, a carboxylic acid group,

characterized in that aminothiazol General formula

< / BR>
where RIVaand RVahave the meanings indicated for RIVand RVwhere the hydroxy - or amino groups are O - or N-zasidannya,

subjected to acylation with activated form of the acid formula

< / BR>
where Q is a protecting group,

and carry out the removal of the protection of nitrogen.

6. Derivative substituted 2-aminothiazole General formula

< / BR>
where RIVphenyl, unsubstituted or substituted with halogen, C1-C6-alkyl or C1-C3-alkoxyl;

X C1-C5-alkoxygroup, piperidine, unsubstituted or substituted 4-hydroxy-group.

7. Derivative 2-amino-4-phenylthiazole total

 

Same patents:

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

-d - galactopyranosides -2) - 4,5-dihydrothiazolo-4 - carboxylic acid" target="_blank">

The invention relates to carbohydrates and heterocyclic compounds and in particular to a new method of obtaining-D-galactoside D-luciferin formula I

used as a substrate for the enzyme activity determination-galactosidase, which can find application in genetic engineering, enzyme analysis and DNA probes

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

Derivative amide // 2037493

The invention relates to new derivatives substituted benzoylbenzene-, biphenyl - 2-oxazolidinone acid, which has inhibitory activity against lipoxygenase, phospholipase A2and which are leukotriene antagonists; derivatives, which are suitable for use as anti-inflammatory, antiallergic agents, but also as protectors

The invention relates to new chemical compounds derived benzothiazine responsible of General formula I

where R1lower alkyl WITH1-C4

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry.

SUBSTANCE: method relates to new method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I . Claimed compound is high effective drug and is used in medicine as myorelaxant of central action. Claimed method includes condensation of N,N-dimethyldichloromethyleneammonium chloride with 5-chloro-4-amino-1,1,3-benzothiadiazole in organic solvent followed by treatment of formed alpha-chloroformamidine of formula R-N=C(Cl)N(CH3)2, wherein R is 5-chloro-2,1,3-benzothiazol-4-yl, with ethylenediamine. Formed intermediate of formula R-N=C(NH-CH2-CH2-NH2)N(CH3)2 is treated with hydrochloric acid, heated in organic solvent and 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I is isolated.

EFFECT: simplified method for preparation of target compound directly in hydrochloride form.

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