Derivatives polyamidine 2-amido-4-phenylthiazole, the retrieval method, the intermediate synthesis and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with agonism to receptors galactokinase. Disclosed are compounds of formula (I), where Y denotes a 3-hyalinella group or 2-indole group of the formula (II) in which R denotes hydrogen, acetyl group or the group CH2COOR1and R1is hydrogen or C1- C4-alkyl; X is a (hetero)aryl radical, selected from the groups represented in the description; Z is hydrogen, C1- C4-alkyl or benzyl, as well as their salts or solvate. The invention relates also to a method for producing compounds of formula (I), intermediate compounds for the synthesis, pharmaceutical compositions on their basis and can be used in the treatment of disorders caused by cholecystokinin. 4 C. and 8 C.p. f-crystals, 4 PL.

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The present invention relates to new thiazole derivative having biological activity, and to the application of the known derivatives of thiazole, it relates to a method for their production and to their containing pharmaceutical compositions.

More specifically, the object of the present invention are new agonists of the receptors, cholecystokinin /CCK/ test the ESD brain, the striatum, the hippocampus, the ventral shell, the aperture and the hypothalamus.

CCK is also highlighted at the peripheral level of the small intestine; its effect is the stimulation of vesicular reduction, increase bile secretion, control of pancreatic enzyme secretion, the effect on the contractions of the stomach, effects on intestinal motility. In some cases it can also affect blood pressure and affect the immune system.

CCK in some Central neurons is together with dopamine. He is also involved in mechanisms associated with acetylcholine, 4-aminobutyric acid, serotonin, opioid, somatostatin, substance P and ion channel.

Its introduction leads to physiological changes, such as palapalai ptosis, hypothermia, hyperglycemia, catalepsy; and to behavioral changes, such as hippadvisory, reducing the research function, analgesia modifies learning ability, sexual behavior and satiety.

Therefore, agonists of CCK receptors can be used in the treatment of some disorders caused by diet, obesity, diabetes; disorders emo is hypoxia disorders gastrointestinal sphere (Drugs of the future, 1992, 17 (3), 197 - 206).

Agonists of CCK receptor described in the literature. For example, some products having such properties as described in European patent A-0383690, WIPO 90/06937 and European patent A-0376849.

In European patent application A-0432040 describes allumination having affinity to the receptor CCK a and CCK receptor B. Some of the compounds claimed in this application A-0432040 described as receptor antagonists of CCK a and CCK b

Now unexpectedly found that a number of acylaminoacyl, some of which are in European patent A-432040, have a strong agonistic activity towards the CCK receptors and, therefore, suitable for the preparation of medicines on the basis of agonists of CCK.

Thus, according to one aspect of the invention the subject invention is the use of N-thiazol-2-yl-indocarbocyanine or N-thiazol-2-yl-chinainternational formula I

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in which Y denotes a 3-hyalinella group or 2-indolering group of the formula

< / BR>
in which R denotes hydrogen, acetyl group or the group CH2COOR' and R' is hydrogen or C1-C4-alkyl;

X denotes a (hetero)aryl glad sipailou, 4-methyl-2,3,6-trimethoxyphenyl, 2,6-dimethoxy-4-ethylphenyl, 2,4,6-trimetoksi-5-chloraniline, 2,4,6-trimetoksi-3-pyridinyl, 2,4-dimethoxy-6-methyl-3-pyridinyl. 6-chloro-2,4-dimethoxy-5-pyrimidinyl, 2,4,6-trimetoksi-5-pyrimidinyl, 5-chloro-2,4-dimethoxyaniline: 5-chloro-2-methoxy-4-methylphenyl, 2,5-dimethoxy-4-methylphenyl, 4-trifluoromethyl-2,6-dimethoxyphenyl, 2,4-dimethoxy-5-methylphenyl, 5-ethyl-2,4-dimethoxyphenyl, 2,4-dimethoxyphenyl group;

Z represents hydrogen, C1-C4-alkyl or benzyl, provided that Z represents the necessary hydrogen when X is a phenyl radical substituted simultaneously at positions 2 and 6, or when X is 3-pyridinoline radical substituted simultaneously at positions 2 and 4, or when X is 5-pyrimidinamine radical substituted simultaneously at positions 4 and 6,

and their pharmaceutically acceptable salts and solvate as a full or partial agonist of the receptor cholecystokinin.

Of the compounds of formula (I) some are not described in the literature and, therefore, constitute another subject of the present invention.

Thus, according to another of its aspects the invention relates to new derivatives R>< / BR>
in which R denotes hydrogen, acetyl group or the group CH2COOR', and R denotes hydrogen or C1-C4-alkyl;

X' denotes a (hetero)aryl radical, selected from the group comprising 4-chloro-2,6-dimethoxyphenyl, 2,6-dimethoxy-4-methylphenyl, 2,4,5-trimethoxyphenyl, 4-methyl-2,3,6-trimethoxyphenyl, 2,4,6-trimetoksi-5-chloraniline, 2,4.6 trimethoxy-3-pyridinyl, 2,4,6-trimetoksi-5-pyrimidinyl, 2,4-dimethoxy-6-methyl-3-pyridinyl, 6-chloro-2,4-dimethoxy-5-pyrimidinyl, 5-chloro-2,4-dimethoxyphenyl, 5-chloro-2-methoxy-4-methylphenyl, 2,5-dimethoxy-4-methylphenyl, 4-trifluoromethyl-2,6-dimethoxyphenyl, 2,4-dimethoxy-5-methylphenyl, 5-ethyl-2,4-dimethoxyphenyl group;

Z is hydrogen, C1-C4-alkyl or benzyl,

provided that Z is hydrogen when X denotes a phenyl radical substituted simultaneously at positions 2 and 6, or when X is 3-pyridinoline radical substituted simultaneously at positions 2 and 4, or when X - 5-pyrimidinyl radical substituted simultaneously at positions 4 and 6,

and their salts and solvate.

Salt accession of these compounds are salts derived from inorganic or organic acids or bases; psdi compounds of formula I' are also the subject of invention.

Especially preferred compounds of formula I', in which Y represents the group (b), where R represents hydrogen or the group CH2COOH.

The compounds of formula I', in which Z is hydrogen or methyl, are particularly preferred.

Also preferred compounds of formula I', in which Y denotes a radical (b), where R represents hydrogen or the group CH2COOH, Z is hydrogen or methyl, and X' - aryl radical, selected from the group comprising 4-chloro-2,6-dimethoxyaniline; 5-chloro-2,4-dimethoxyphenyl, 5-chloro-2-methoxy-4-methylphenyl, 2,6-dimethoxy-4-methylphenyl, 2,4-dimethoxy-5-methylphenylene and 2,4,5-trimethoxyphenyl group (where Z is necessarily denotes hydrogen, when X' denotes 4-chloro-2,6-dimethoxyaniline or 2,6-dimethoxy-4-methylphenyl group).

Of the compounds of formula I, particularly preferred

- N-/4-/4-chloro-2,6-acid/thiazol-2-yl/-1-/carboxymethyl/- indol-2-carboxamide, its pharmaceutically acceptable salt and solvate, especially hydrochloride;

- N-/4-/5-chloro-2,4-acid/thiazol-2-yl/-1H-indole-2-carboxamide, its pharmaceutically acceptable salt and solvate;

- N-/4-/5-chloro-2,4-acid/-5-methylthiazole-2-yl/-1H-indole - 2-carboxamide, its pharmaceutically receiving the ID, its pharmaceutically acceptable salt and solvate, especially triptorelin;

- N-/4-/5-chloro-2-methoxy-4-were/thiazol-2-yl/-1H-indole-2 - carboxamide, its pharmaceutically acceptable salt and solvate;

- N-/4-/2,6-dimethoxy-4-were/thiazol-2-yl/-1H-indole-2 - carboxamide, its pharmaceutically acceptable salt and solvate, especially monohydratebuy hydrochloride;

- N-/4-/2,4-dimethoxy-5-were/-5-methylthiazole-2-yl/-1H-indole - 2-carboxamide, its pharmaceutically acceptable salt and solvate;

- N-/4-/2,4,5-trimethoxyphenyl/-5-methylthiazole-2-yl/-1H-indole-2 carboxamide, its pharmaceutically acceptable salt and solvate.

The subject invention also is a method of obtaining compounds of formula I', wherein the acid of formula II

Y' = COOH,

in which Y' - 3-finalininkiu radical (a)

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2-indolinyl radical (in0)

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or 2-indolinyl radical (with0)

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and R0denotes a protective or N-group or a group CH2COOR", where R"is C1-C4-alkyl;

or a functional derivative of the above acid

II condense with 2 aminothiazolo formula III

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in which

X' and Z have the above values,

in the presence of a base, with the floor, the Wallpaper is one of the radicals (a), (b0) or (c0)

then, when the compound (I" Y' denotes a radical (b0) then, if desired, the resulting product of the formula (I" b0< / BR>
< / BR>
subjected to reaction in the removal of N-protective group, or saponification or acid hydrolysis; when the compound (I" Y' denotes a radical (c0), the resulting product of the formula

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subjected to dehydration, in some cases with prior removal of the N-protective group, saponification or acid hydrolysis, to obtain the compounds of formula I', in which Y denotes a radical (b), where R represents hydrogen or the group CH2COOR', where Z, X' and R' have the above meanings, and produce the product of formula I' as is, or in the form of a solvate, or one of its pharmaceutically acceptable salts.

As a functional derivative of the acid II can be used the acid, in certain cases activated, its anhydride, one of her mixed anhydrides or activated complex esters.

Condensation of aminothiazole III with the acid II in the form of a complex of activated ester, obtained, for example, by exposure to I-hydroxybenzotriazole on acid in the presence of dicyclohexylcarbodiimide according to the hydroxy-tridimensionale (BOP) in accordance with the method described in Synthesis, 1976, 751-752, can be carried out in a solvent, the nature of which is selected depending on the solubility of the compounds and the type of activation of the acid function, preferably in the presence of a base, such as tertiary amine, such as triethylamine; the reaction is usually carried out at a temperature of 0 - 30oC.

In the first stage of the method according to the invention have the connection I, where Z, X' and Y' have the specified values. When in the compound of formula I" Y' represents either a radical (a), or radical (b0), in which R0represents a group CH2COOR", then the specified connection may also be a target product of formula I', where Y represents either a radical (a), or radical (b), in which R represents a group CH2COOR', where R' - C1-C4-alkyl, and Z and X' have the specified values.

When in the compound of formula I, Y' represents a group (b0), in which R0is an N-protective group or a group CH2COOR", the connection may be subject to deletion of the N-protective group to obtain compounds of the formula I', in which Y represents the group (b), where R is hydrogen, or it may be subjected to saponification or the Wallpaper group CH2COOH.

When in the compound of formula I, Y' represents a group (c0), then the specified connection is subjected to the operations of removal of the protective groups, to which is added the dehydrogenation.

Acid Y COOH, in which R0in the radicals (b0) and (c0) refers to protective acyl group such as acetyl, can be obtained by exposure acetylchloride or acetic anhydride, for example, Y COOH, in which R0= H, and in the presence of the equivalent of triethylamine or 4-dimethylaminopyridine, for example, in dichloromethane.

When the functional derivative of the acid II is a mixed anhydride, it can be obtained by exposure of alkylphosphonate on acid, in the presence of a base, usually a tertiary amine, such as triethylamine; the reaction is most often carried out in a solvent such as dichloromethane, dichloroethane or chloroform.

When you want to get indole-2-carboxamide formula I', where R is hydrogen, R0denotes the N-protective group in the radicals (b0) and (c0).

Thus, the derivative I', in which Y denotes

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can be obtained from the compounds obtained by the condensation of aminothiazole III functional proizvolbnuu for the protection of NH2groups in the condensation reactions of amino acids, such as - COOC(CH3)3; - COOCH2C6H5; -CO-CH3; N-protective group can then be removed when using classical methods of removal of the protective groups.

The same connection can also be obtained from the compounds obtained by condensation of aminothiazole III derivative of indolin-2-carboxylic acid formula

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in which R00denotes the N-protective group, such as-COOC(CH3)3,

to obtain the compounds of formula IV

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and R00can be removed from compound IV by exposure to a strong acid in an anhydrous medium such as triperoxonane acid in dichloromethane or hydrochloric acid in diethyl ether.

The thus obtained compound is then digitalout.

The reaction is carried out by exposure to indolinyl balance classic dehydrating reagents, such as 2,3,5,6-tetrachloro-1,4-benzoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDH) or cyclohexyl, in the presence of palladium in an inert high-boiling solvent such as diphenyl ether, xylene 1,2-dimethoxyethane or 2-methoxyethylamine ether at an elevated temperature, and the group, denoted by R00represents acetyl, you can also get a group R substituent Y of the desired product of formula I.

The hydrolysis of complex C1-C4-Olkiluoto ether group, R0to obtain products of formula I', where Y denotes CH2COOH, carried out either in an acidic environment, or preferably in a basic medium, for example, by exposure to inorganic bases, such as alkali metal hydroxide, in aqueous-alcoholic medium.

Aminothiazole formula 2-amino-4-/2,4,5-trimethoxyphenyl/-5-methylthiazole and 2-amino-4-/2,4,5-trimethoxyphenyl/-thiazol described in Rev. Latinoam. Quim, 1990, 21 (3-4), 102-105.

Aminothiazole formula III'

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in which X denotes a (hetero)aryl radical, selected from the group comprising 4-chloro-2,6-acid, 2,6-dimethoxy-4-were, 4-methyl-2,3,6-trimethoxyphenyl, 2,4,6-trimetoksi-5-chlorophenyl, 2,4,6-trimetoksi-3-pyridinyl, 2,4,6-trimetoksi-5-pyrimidinyl, 2,4-dimethoxy-6-methyl-3-pyridinyl, 6-chloro-2,4-dimethoxy-5-pyrimidinyl, 5-chloro-2,4-acid, 5-chloro-2-methoxy-4-were, 2,5-dimethoxy-4-methyl-phenyl, 4-trifluoromethyl-2,6-dimethoxy-phenyl, 2,4-dimethoxy-5-were, 5-ethyl-2,4-acid;

Z represents hydrogen, C1-C4-alkyl or benzyl, precord X" denotes a 3-pyridinoline radical, substituted simultaneously at positions 2 and 4, or when X is 5-pyrimidinyl radical substituted simultaneously at positions 4 and 6,

are new and form part of the invention.

Of the compounds of formula III' especially preferred is 2-amino-4-[4-chloro-2,6-acid]-thiazole;

2-amino-4-[5-chloro-2,4-acid] -thiazole; 2-amino-4-[5-chloro-2,4-acid]-5-methylthiazole; 2-amino-4-[5-chloro-2-methoxy-4-were]-thiazole; 2-amino-4-[2,6-dimethoxy-4-were] -thiazole; 2-amino-4-[2,4-dimethoxy-5-were]-5-methylthiazole.

You may receive one of the above methods, especially in Bull. Soc. Chim. (C) 1963, 2498 - 2503.

Usually the thiourea enter into interaction with alpha-halogenated ketone, and preferably alpha-chlorinated ketone, according to the following reaction scheme I

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and X' and Z have the specified value.

Ketones (Y) can be obtained, for example:

(1) by reaction Friedel -:

according to Chem. Pharm. Bull, 1991.39, 9, 2400 - 2407;

(2) by reaction with the use of organolithium compounds:

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according to European patent A-0432040.

Aminothiazole III can also be obtained in one stage, using the Hoesch reaction (according to Dubois. Orga is th benzene derivative, followed by cyclization with thiourea.

Aminothiazole III can also be obtained in one stage of aromatic ketones according to the following reaction scheme 2:

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The original aromatic ketones of the formula VII are obtained by reaction of the Friedel-derived X H. Derivatives of X H is known or obtained by known methods.

Some acid Y COOH known and even has for sale; other acids are obtained by using methods known to molecules analogues. They are all illustrated in European patent A-0432040.

So, indole-2-carboxylic acid formula

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in which R0means alkoxycarbonylmethyl group with 1-4 C-atoms, can be obtained from commercially available or obtained by classical methods according to the scheme below 3 indole-2-carboxylic acid

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in which Hal denotes a halogen atom;

Q denotes a benzyl group.

The original complex benzaouia esters scheme 3 is obtained by exposure of the appropriate acid in benzyl alcohol in the presence of one of the activators of the acid functions commonly used in peptide synthesis such as described in European patent A-to obtain in the usual way by the introduction of acid or base in a solution of the compounds of formula I'. Salt allocate according to its solubility characteristics after evaporation of the solvent or adding herstories (precipitator).

According to another aspect of the invention the subject invention are also pharmaceutical compositions containing the above compounds of formula I'.

More specifically, the compounds of formula I are the object of research linking in vitro related to CCK receptors,

The study of agonistic effects of the compounds on the secretion of amylase is implemented as follows. Pancreatic acini obtained by enzymatic digestion (collagenase) rat pancreas, subjected to starvation for 18 hours. Aliquots (485 Ám) incubated at 30oC for 30 minutes in the presence of increasing concentrations of agonist according to Jensen and others, J. Biol. Chem. 1982, 257 (10), 5554. Incubation stop by centrifugation for 15 seconds. The supernatant stored in an ice bath for measurement of amylase according to the method Ceska and others, Clin. Chim. Acta. 1969, 26, 437 (phadebas-reagent):amylase test according to Pharmacia Diagnostic. Compound dissolved in dimethyl sulfoxide, and then in the buffer for incubation.

Connection f compared with the maximum effect in the presence of CCK) about 10-9 M

The study of agonistic effect in respect of CCK compounds on food intake is as follows. Male rats (200-240 g) Sprague Dawley (Charles River, France) isolated 10 days before the experiment and every day consistently subjected to 18 hours of fasting and 6 hours of starvation and 6 hours feeding: food is available from 10 to 16 hours, water is available on request. On the day of the experiment, intraperitonal introduce products ( in the form of a suspension of 0.6% solution of methylcellulose) or excipient. After 30 minutes after treatment (10 hours) in a cage introduce a known amount of feed: measure the consumption of food after 1 hour and 3 hours.

The compounds of formula I reduce food intake and, therefore, behave as agonists of CCK receptors (J. Gibbs and others, J. Comp. Physiol. Psychol., 1973, 84, 488-495), in particular:

N-/4-/5-chloro-2,4-acid/thiazole/2-Il-/1H-indole-2 - carboxamide;

N-/4-/5-chloro-2,4-acid/-5-methylthiazole-2-yl/-1H-indole - 2-carboxamide,

N-/-4/5-chloro-2,4-acid/-5-methylthiazole-2-yl/-1-/ carboxymethyl/-indol-2-carboxamid-triptorelin,

N-/4-/5-chloro-2-methoxy-4-were/-thiazol-2-yl/-1H-indole-2 - carboxamide,

are active at a dose of 3 mg/kg, a dose at which they reduce food intake by 30 - 40%. the agonists of CCK receptors, designed to combat the diseases the treatment of which requires stimulation by complete or partial agonism receptors cholecystokin.

The compounds of formula I little toxic; their toxicity is compatible with their use as pharmaceutical compositions.

The new compounds of formula I' can be formulated into pharmaceutical compositions for administration to mammals, including humans, for the treatment of diseases involving CCK receptors.

Dosage varies depending on the treatment and causes of painful conditions, and may be, for example, 0.05 to 100 mg per day for adult oral.

Pharmaceutical compositions containing as an active start one of the above compounds. These compositions are produced in a form convenient for insertion through their digestive or parenteral.

Pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal injection of the active ingredient can be contained in a therapeutically effective dose together with classical pharmaceutical carriers. The relevant edenchrista, powders, granules or in the form of oral solutions or suspensions, forms for sublingual and oral administration forms for subcutaneous, intramuscular, intravenous, intraocular or intranasal administration and forms for rectal administration.

When preparing a solid composition in the form of tablets, the active principle is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or similar substances. Tablets may be coated with sucrose or other appropriate materials or they can be treated so that they have a prolonged or delayed activity and continuously release a predetermined amount of current beginning.

The formulation in the form of gelatin capsules with the medicine are obtained by mixing the active ingredient with a diluent and by introducing the resulting mixture into soft or hard gelatin capsules.

The formulation in the form of a syrup or elixir may contain the active principle together with sweetening substance, preferably low-calorie, methyl paraben and propyl paraben as antiseptics, or giving a taste of the agent and cotacao in a mixture with dispersing agents or wetting, or suspendresume agents, as polyvinylpyrrolidone, just as with sweetening matter or improving the taste substances.

For rectal (intestinal) introduction use candles, which are prepared with binders, melting at rectal temperature, for example, cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular injection using aqueous suspensions, isotonic saline solutions or sterile solutions which contain pharmacologically acceptable dispersant and/or wetting, such as propylene glycol or butyleneglycol.

The active principle may also be formulated as microcapsules, in some cases with one or more carriers or additives.

The active principle may also be in the form of a complex with a cyclodextrin, for example, as -, - or - cyclodextrin, 2-hydroxypropyl -- cyclodextrin or methyl -- cyclodextrin.

The composition may contain a single dose, in the amount of 0.05 - 100 mg of active beginning.

The following describes the embodiments of the invention and methods of obtaining some intermediates of the synthesis formulario to tetramethylsilane was.

In the preparation examples, the following abbreviations are used: DMH - dichloromethane; ether - diethyl ether; saafir - diisopropyl ether; CCl4- carbon tetrachloride; MeOH - methanol; EtOH is ethanol; AcOEt - ethyl acetate; DMF is dimethylformamide; THF - tetrahydrofuran; CHCl3-chloroform; AlCl3-aluminium chloride; ZnCl2- chloride of zinc; TiCl4- titanium tetrachloride; HCl is hydrochloric acid; H2SO4- sulfuric acid; TKF - triperoxonane acid; KHSO4- potassium hydrosulfate; NaOH-sodium hydrosulphate; silicon dioxide H - silica gel 6OH, manufactured in the sale of the company MER CK (Darmstadt); tBu-tertbutyl; F is the melting temperature, TKip-boiling temperature; TC - room temperature; NMR - nuclear magnetic resonance; C. - singlet; n broadened singlet; m - array.

Preparation 1. Connection X H.

A. 2,4,6-Trimethoxyaniline.

This connection receive according to the method described in J. Am. Chem. Soc. 1932, 54, 727-733.

B. 2,4-Dimethoxy-6-methylpyridin.

First obtained 1,2-dihydro-4-hydroxy-6-methyl-2-oxopyridine according to the method described in J. Heterocycl. Chem 1975, 12 (5), 963-967.

The mixture 7.51 g videolooking connections and 75 ml of phosphorus oxychloride is heated at 120

Within 36 hours at a temperature of 130 - 140oC, in a reactor under a pressure of 5 bar, heated mixture of 9.7 g videolooking connection, 7,13 g of sodium methylate in 15 ml of methanol. After cooling, add 200 ml of ether, filtered and the filtrate is evaporated in vacuum. Chromatographic on the silicon dioxide, elwira DHM. Get 4 g monoethoxylate product, which again lead to the reaction. For 20 hours at a temperature 132-140oC, in the reactor under a pressure of 5 bar, heated mixture of 4 g videolooking product with a solution of sodium methylate derived from 0.7 g of sodium and 15 ml of methanol. After cooling, add 200 ml of ether, filtered and the filtrate is evaporated at atmospheric pressure. The residue is distilled in vacuum and obtain 2.5 g of the target product. TKip= 101-103oC at 0.02 bar.

C. 1-Chloro-2,4-dimethoxybenzene

To a solution of 20 g of 4-chlororesorcinol in 200 ml ethanol add to 82.6 g of 50 weight. %-aqueous solution of cesium hydroxide in water. Evaporated in vacuo, the residue obreal cesium dissolved in 100 ml of DMF, add 40 ml under the conditions and heated at 80oC for 3 hours. The reaction mixture is evaporated in vacuo, the residue is absorbed DHM, washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate and the solvent is evaporated in vacuum. Chromatographic in dioxane silicon, elwira toluene. Distilled in vacuum and obtain 13 g of the target product. TKip=138oC at 0.02 bar.

year 2-chloro-5-methoxytoluene

To a solution of 20 g of 4-chloro-3-METHYLPHENOL in 200 ml ethanol add 42,05 g of 50 wt.%-aqueous solution of cesium hydroxide. Evaporated in vacuo, the residue is absorbed by isopropanol, again evaporated in a vacuum and this operation is repeated 3 times. The thus obtained cesium salt was dissolved in 100 ml of DMF, add 3 - ml under the conditions and heated at 80oC for 3 hours. The reaction mixture is evaporated in vacuo, the residue is absorbed DHM, washed with water, saturated sodium carbonate solution, dried over magnesium sulfate and the solvent is evaporated in vacuum. Chromatographic on the silicon dioxide, elwira toluene. Distilled in vacuum and obtain 14 g of the target product. TKip=105oC at a pressure of 0.02 bar.

D. 2.5-Dimethoxytoluene.

A mixture of 12 g methilhill for 4 days. After cooling, the reaction mixture is filtered and evaporated filter in the vacuum. The remainder absorb 150 ml of concentrated ammonia solution, stirred for 2 hours, diluted with water, extracted with DHM, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic in dioxane silicon H, elwira mixture of heptane with DHM (50:50 by volume). Obtain 12 g of the target product. NMR spectrum (200 MHz, DMCO), : 2,05 (C., 3H), 3,60 (C.,3H), 3,65 (C., 3H), 6,5 - 6,9 (m, 3H).

Preparation II. Alpha chloretone formula V.

A. 1-(2,6-Dimethoxy-4-were)-2-chloro-1-Etalon.

to 7.61 g of 3,5-Dimethoxytoluene and 6,10 g tetramethylethylenediamine dissolved, under nitrogen atmosphere, 150 ml of hexane. The solution is cooled to 0oC add to 32.8 ml of a 1.6 M solution of utility in hexane, the mixture was stirred at 10oC for 20 minutes, then at 20oC for 1 hour. To a cooled to -10oC derived lithium for 20 minutes add cooled to 0oC solution 6,13 g of N-methoxy-N-METHYLCHLOROSILANE in 50 ml of THF. The reaction mixture is left for 1 hour at a temperature of 0 to 5oC, for 1 hour at 20oC, then poured into 100 ml of water. Extracted 2 times with 300 ml of diethyl ether, the ether phase washed naydenivanov. The remainder chromatographic on the silicon dioxide, elwira mixture DHM/hexane (50: 50 by volume). Concentration of the pure fractions gives 1.6 g of the target product. So pl. = 82 - 84oC.

B. 1-(2,4,6-Trimetoksi-3-pyridinyl)-2-chloro-1-Etalon.

(according to Chem. Pharm. Bull 1986, 34, 3658, and J. Am. Chem. Soc. 1932, 54, 727)

24 g of 2,6-Dichloropyridine, 200 ml triperoxonane acid and 28 ml of 33% hydrogen peroxide is heated at 100oC for 4 hours. Cool, then add 600 ml of water and concentrated in vacuo to a volume of 50 - 100 ml Alkalinized with sodium bicarbonate, then extracted with DHM, the organic phase is decanted and dried over sodium sulfate. Filtered, concentrated in vacuo and the residue will recrystallized from ethyl acetate to obtain 18,8 g 2,6-dichloropyridine-N-oxide; so pl. = 138 - 140oC.

18,8 g videolooking connection is refluxed for 6 hours in 40 ml of phosphorus oxychloride and leave overnight at room temperature, the mixture is then concentrated in vacuo. The residue was poured into cold water, then neutralized with sodium carbonate, extracted with ether, the ether phase is decanted, dried over sodium sulfate, filtered and concentrated in is their pure fractions gives 14.6 g of 2,4,6-trichloropyridine.

A mixture of 14.6 g videolooking product and 129,7 g of sodium methylate in 400 ml of methanol is refluxed over night. Add 0.7 l of water, then successively extracted with DHM, the organic extract washed with water and dried over sodium sulfate. Concentrated in vacuo and the residue will recrystallized from pentane, getting 9.5 g of 2,4,6-trimethoxyaniline. So pl. = 47 - 49oC.

In the atmosphere of nitrogen at -40oC add 15 ml of anhydrous THF 7.5 ml of 1.6 M solution metallice in the air, 0,02 ml Diisopropylamine, and then stirred for 5 minutes at -40oC, for 10 minutes, add 1.13 g videolooking derivative of pyridine in solution in 10 mg THF. The mixture is stirred for 3 hours at 0oC. Then cooled to -70oC for 5 minutes add 0,824 g of N-methyl-N-methoxybenzamide in the form of a solution in 20 ml of THF and leave for an hour to raise the temperature up to 10oC. the Reaction mixture was poured into 300 ml of cold water, saturated sodium chloride, and extracted with ether. The organic extract was successively washed with a saturated solution of sodium chloride, decanted, dried over sodium sulfate, filtered and concentrated in vacuo. The residue x is Ricci pure product gives 0,61 g target ethanone; so pl. = 85 - 87oC.

Century 1-(2,4-Dimethoxy-5-were)-2-chloro-1-Etalon.

This connection receive according to Chem. Pharm. Bull.1991, 39, (9) 2400-2407.

Suspension of 5.24 g of AlCl3, 0.52 g ZnCl2in 40 ml of 1,2-dichloroethane is cooled to 0oC and added dropwise a solution of 5.0 g of 2,4-dimethoxytoluene in 20 ml of 1,2-dichloroethane. Then cooled to - 10oC and added dropwise a solution of 2.9 ml of chloroacetanilide in 1.5 ml 1,2-dichloroethane, maintaining the temperature of the reaction medium at from -10oC to 7oC. Leave to stand under stirring to raise the temperature to room temperature, the reaction mixture was poured into a mixture of ice / concentrated HCl, extracted with DHM, the combined organic phases are washed with water, dried over sulfate and evaporated the solvent under vacuum. The residue is treated with heptane and the precipitate is filtered off. Obtain 3.0 g of the target product. So pl. = 166 - 167oC.

G 1-(4-Trifluoromethyl-2,6-acid)-2-chloro-1-Etalon.

The solution 9,73 g 3-amino-5-methoxy-1-cryptomelane in 400 ml of 2 N. HCl cooled to 10oC for 10 minutes, add a solution of sodium 3.80 g of nitrate in 20 ml of water. Leave for 30 minutes under stirring at 10oC and add a solution of 800 ml of konzentrierte 95oC and left overnight at room temperature. Add 1000 g of ice to the reaction mixture, extracted with ether, washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated in vacuum. Gain of 9.8 g of 3-hydroxy-5-methoxy-1 - cryptomelane. So pl.= 75oC (according to J. Chem. Soc., 1951, 2013).

To a solution of 9.8 g videolooking compound in 100 ml of acetone type of 7.90 g of potassium carbonate and heated to 50oC. and Then added dropwise at this temperature and for 20 minutes, 6,74 g dimethylsulfate and refluxed for 2 hours. The reaction mixture is evaporated in vacuo, the residue is treated with 30 ml of 20% ammonia solution and 50 ml of water, extracted with ether, washed with a saturated solution of sodium chloride, dried over sulfate, sodium, and the solvent is evaporated in vacuum. Obtain 8.7 g of 3,5-dimethoxy-1-cryptomelane, after vacuum distillation. TKip.= 92 - 94oC at a pressure of 0.02 bar.

To a solution of 8.6 g videolooking compound in 100 ml of hexane added 5,09 g tetramethylethylenediamine. Cooled to -5oC and in an atmosphere of nitrogen for 15 minutes, add a 27.4 g, 1.6 M solution of utility in hexane, then leave when re is about derived cooled to -25oC solution 5,41 g N-metoki-N-METHYLCHLOROSILANE in 45 ml of THF and leave for 2 hours under stirring until the temperature rises to +5oC. Add 100 ml of water, extracted with ether, washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 3.6 g of the target product, after crystallization from hexane. So pl.= 120 - 122oC.

Chlorinated ketones of the formula V, described in table I, get one of the above ways of making and using the appropriate starting materials:

Preparation III. Aromatic ketones of the formula VII

A. 1-(5-Chloro-2,4-acid)-1-Etalon.

A mixture of 2 g of 1-chloro-2,4-dimethoxybenzene, 0.9 g of acetylchloride in 20 ml of CCl4cooled to 0oC and added dropwise a solution of 1.3 ml of TiCl4in 7 ml of CCl4. Left under stirring for 2 hours to raise the temperature to room. The reaction mixture was poured into a mixture of concentrated HCl with ice, extracted with DHM, dried over magnesium sulfate and the solvent is evaporated in vacuum. Chromatographic on silica H, elwira mixture DHM with heptane (70:30 by volume). Get 1, 19 g of the target product. So pl. - 138ois Pininfarina in 20 ml of CCl4cooled to 0oC and added dropwise a solution of 1.3 ml of TiCl4in 7 ml of CCl4. Left under stirring for 2 hours to raise the temperature to room. The reaction mixture was poured into a mixture of concentrated HCl with ice, extracted with DHM, dried over magnesium sulfate and evaporated the solvent under vacuum. Chromatographic on silica H, elwira mixture DHM (80: 20 by volume). Get to 1.14 g of the target product. So pl. 115oC.

C. 1-(5-Chloro-2-methoxy-4-were)-1-Etalon.

Suspension 2,12 g AlCl3in 20 ml of CCl4cooled to 0oC, in nitrogen atmosphere, was added dropwise a solution of 1.25 g of acetylchloride in 10 ml of CCl4. Then was added dropwise a solution of 2.5 g of 2-chloro-5-methoxytoluene in 10 ml of CCl4and left under stirring for 2 hours to raise the temperature to room. Poured into a mixture of concentrated HCl with ice, extracted with DHM, dried over magnesium sulfate and the solvent is evaporated in vacuum. Chromatographic on silica H, elwira mixture DHM with heptane (70:30 by volume). Gain of 0.68 g of the target product. So PL = 83oC.

Year 1-(5-Chloro-2-methoxy-4-were)-1-propanone.

A suspension of 2.55 g of AlCl3in 30 ml DHM cooled to 0opl.= 79oC.

D. 1-(5-Ethyl-2,4-acid)-1-propanone.

A suspension of 10 g of 4-ethyl-resorcinol in 20 ml of epirate of boron TRIFLUORIDE is cooled to +4oC and added dropwise to 11.7 g of propionic anhydride. Heated at 75oC for 6 hours and, after cooling, the reaction mixture was poured into a mixture of ice water. Leave for 2 hours under stirring, the precipitate is filtered off, washed with water, treated him with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated in vacuum. Chromatographic on the silicon dioxide, elwira with assistance. DHM, then using a mixture DHM/ethyl acetate (90:10 by volume). Get to 9.32 g of 1-(5-ethyl-2,4-dihydroxyphenyl)-1-propanone. So pl. 74 - 75oC.

Within 48 hours, refluxed suspension of 5 g videolooking connection, 30 g of potassium carbonate, 30 ml of potassium carbonate, 30 ml dimethylsulfate in 500 ml of acetone. PEFC is using 100 ml of concentrated ammonia solution. After stirring for 1 hour, add 400 ml of water, the precipitate is filtered off, washed with water, absorb it with DHM, the organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated in vacuum. Get of 5.68 g of the target product. So pl. = 64 - 65oC.

E. 1-(2,4-Acid)-3-phenyl-1-propanone.

To a suspension of 43.2 g of AlCl3, of 37.5 g of 1,3-dimethoxybenzene in 210 ml of CCl4was added dropwise a solution of 45.5 g of acid chloride of 3-phenylpropane acid in 50 ml of CCl4. Leave under stirring and at room temperature for 1 hour and the reaction medium is poured into a mixture of 400 g of ice and 150 ml of concentrated HCl. After stirring for 30 minutes, extracted with DHM, the combined organic phases are washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and the solvent is evaporated in vacuum. Get 66.5 g of the desired product in the form of oil, which is used as is.

Aromatic ketones of the formula VII are described in table II, get one of the above ways of making and using the appropriate starting materials.

Preparation IV 2-Aminothiazole formula Uluniu II, A/, product and 0,164 g of thiourea are dissolved in 50 ml of absolute ethanol. The reaction mixture is refluxed for 18 hours, then concentrated in vacuo. The residue is absorbed with 100 ml of 2 n NaOH solution, then extracted 2 times with 200 ml DHM, the organic phase is decanted, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is crystallized from ether, receiving 0.34 g of the target aminothiazole. So pl. 204 - 206oC.

B. 2-Amino-4-(2,4,6-trimetoksi-3-pyridyl)-thiazole.

A mixture of 0.55 g obtained according to preparation II, B/, ketone, and 0.21 g of thiourea in 25 ml of absolute ethanol is refluxed for 24 hours. The reaction mixture was concentrated in vacuo, the residue is treated with water and add 10% solution of sodium carbonate. Extracted with ethyl acetate, the organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is crystallized from a minimum amount of ISO-ether. Obtain 0.51 g of the target thiazole. So pl. = 191oC.

C. 2-Amino-4-(5-chloro-2,4-acid)-thiazole.

To a solution of 1.08 g obtained in preparation III, A/ compound in 20 ml of CCl4added dropwise, at room imperatorial is evaporated in vacuum. The residue is absorbed in 20 ml of ethanol, add 2 g of thiourea and refluxed for 3 hours. Evaporated in vacuo, extracted with DHM, washed with saturated sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuum. Chromatographic on the silicon dioxide, elwira mixture DHM/methanol (100:1 by volume). Get to 0.92 g of the target product. So pl. =162oC.

Year 2-Amino-4-(5-chloro-2,4-acid)-5-methylthiazole.

To a solution of 1.12 g obtained in preparation III, B), the compound in 20 ml DHM, was added dropwise, at room temperature, a solution of 0.25 ml of bromine in 5 ml DHM. The organic phase is washed with water, dried with magnesium sulfate and the solvent is evaporated in vacuum. The residue is absorbed in 20 ml of ethanol, add 1.0 g of thiourea and refluxed for 2 hours. Evaporated in vacuo, the residue is treated with saturated solution of sodium carbonate, extracted with DHM, dried over magnesium sulfate and evaporated in vacuum. The residue is treated with ether and filtered off the precipitate. Obtain 1.26 g of the target product. So pl. = 188oC.

2-Aminothiazole formula III, described in table III, shown n the II.

Indolocarbazole acid get according to European patent A-0432040.

Example 1.

Monohydrate N-/4-(2,6-dimethoxy-4-were)thiazol-2-yl/-1H-indole-2 - carboxamide-hydrochloride (Method A).

< / BR>
0.33 g videolounge, according to preparation IV, And/, Amin, 0.29 grams N-acetylindole-2-carboxylic acid, 0.7 g of BOP and 0.16 g of triethylamine dissolved in 40 ml DHM. The reaction mixture is stirred for 48 hours at room temperature, successively added 50 ml of buffer solution with pH 2, the organic phase is decanted, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is treated with 80 ml of 96oethanol, add 10 ml of 2 n NaOH solution and the reaction mixture was stirred at room temperature for 2.5 hours. The solution is neutralized with 1.8 ml of concentrated HCl. The formed precipitate was separated by filtration, washed with water and dried in vacuum at 60oC, receiving 0.45 g of the target compound. So pl. = 250-252oC.

Example 2.

N-/-4-(2,4,6-Trimetoksi-3-pyridinyl)-thiazol-2-yl/ -1H-indole-2-carboxamide (Method A)

< / BR>
Stirred for 24 hours at room temperature a solution of 0.5 g of aminothiazole received from Aut 20 ml of water, the organic phase is decanted, dried over sodium sulfate, filtered and concentrated in vacuo. The remainder chromatographic on silica gel H, elwira mixture DHM with methanol (100:1 by volume). First remove impurities in the form of the head part, then the product of the combination, the corresponding derivative, acetylated at the indole nitrogen. These fractions are concentrated in vacuo and the residue is dissolved in 50 ml of absolute ethanol. To this solution add 5 ml of 2 n NaOH solution and the reaction mixture was stirred at room temperature for 1.5 hours. Neutralized by the addition of 0.85 ml of concentrated HCl and concentrated in vacuo. The residue is treated with water, to which was added sodium carbonate, filtered and the precipitate washed successively with water, then the absolute benchmark, receiving of 0.44 g of the target compound. So pl.=285 - 287oC.

Example 3

N-/-4-(2,6-Dimethoxy-4-were)-thiazol-2-yl/-quinoline-3 - carboxamide (Method B).

< / BR>
1, 2-Amino-4-(2,6-dimethoxy-4-were)-thiazole, 0,76 g quinoline-3-carboxylic acid, of 0.65 ml of triethylamine and 2, 15 g of BOP are dissolved in 10 ml of DMF and allowed to stand, the reaction mixture for 48 hours at room temperature. Then it is poured into the buffer Rast the water, mix in 5% sodium carbonate solution, filtered, then dissolved in DHM. Washed with 5% sodium carbonate solution, then the organic phase is decanted, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is stirred in ether, filtered and dried, obtaining 1,58 g of target compound. So pl. = 245 - 246oC.

Example 4.

N-/4-(4-Chloro-2,6-acid)thiazol-2-yl/-1-(carboxymethyl) indole-2-carboxamide (the Way In).

< / BR>
0.7 g of 2-Amino-4-(2,6-dimethoxy-4-chlorophenyl)-thiazole, and 0.61 g of N-(methoxycarbonylmethyl)-indole-2-carboxylic acid, of 0.42 ml of triethylamine and 1.4 g of BOP are dissolved in 5 ml of DMF, then the reaction mixture is left to stand at room temperature for 48 hours. The mixture was poured into sulphate buffer with a pH of 2, then the precipitate is filtered off, then washed with water and dissolved in DHM. The solution was washed with 5% sodium hydrogen carbonate solution, then sulfate buffer with a pH of 2, the organic phase is decanted, dried over sodium sulfate, filtered and concentrated in vacuo. The remainder chromatographic on silica gel H. Concentration of the fractions of pure product gives 1,08 g target complex methyl ester. So the ol in the presence of 1.5 ml N. NaOH solution. The reaction mixture was stirred at room temperature for 48 hours and concentrated in vacuo. The residue is treated with water and then added dropwise concentrated HCl until pH 1. The precipitate is filtered off and dried it, getting 0.84 g of the target hydrochloride. So pl. above 300oC.

Example 5.

N-/-4-(2,6-Dimethoxy-4-were)thiazol-2-yl/-1-(carboxymethyl) indole-2-carboxamide-triptorelin (method D).

< / BR>
1.07 g of N-/-4-(2,6-Dimethoxy-4-were)-2-thiazolyl/- 1-(tert. - butoxycarbonylmethyl)indole-2-carboxamide (obtained according to European patent A-0432040) dissolved in a mixture of 2 ml of anisole and 20 ml of TFA. The reaction mixture was kept 3/4 hours at room temperature, then concentrated in vacuo. The residue is treated with ether, then the precipitate is filtered off and dried in a drying Cabinet, getting 1.13 g of the target compound. So pl.=223 - 224oC.

Example 6

N-/4-(2,3,6-Trimetoksi-4-were)-thiazol-2-yl/-1H-indole-2 - carboxamide (Method D).

< / BR>
0.16 g of 2-Amino-4-(2,3,6-trimetoksi-4-were)-thiazole are dissolved in 10 ml of DMF. Added 0.18 g of N-(tert.-butyloxycarbonyl)-indolin-2-carboxylic acid, 0.2 ml of triethylamine, 0,38 g of BOP, and the reaction mixture is stored at re what can be carried on, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in 10 ml of chloroform, then add 10 ml of TFA and the reaction mixture was stirred at room temperature for 2.5 hours. Concentrated in vacuo, adding 3 times with 20 ml of benzene. The residue is dissolved in 20 ml of dimethoxyethane, then add 0.1 ml of triethylamine and 0,112 g DDH and the reaction mixture is left to stand overnight at room temperature. Concentrated in vacuo, the residue is treated with ethyl acetate and washed sequentially with 1 n NaOH solution, the solution of KHSO4and sodium chloride solution, the organic phase is decanted, dried over sodium sulfate, filtered and concentrated in vacuo. The remainder chromatographic on silica gel, elwira with a mixture of chloroform with ethyl acetate (50:50 by volume). The fractions of pure product was concentrated in vacuo and the residue specify in pentane, receiving 0.08 g of the target product. So PL = 200oC.

Example 7.

N-/4-(5-Chloro-2,4-acid)-thiazol-2-yl/-1H-indole-2 - carboxamide (Method E).

< / BR>
A mixture of 0.9 g of the compound obtained in preparation IV, B, of 0.67 g of P-acetylindole-2-carboxylic acid, 1.5 g of BOP, and 0.46 ml of triethylamine in 4 ml of DMF was stirred at the room for filtrovat and washed with water. The residue is treated with DHM, washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuum. Chromatographic on the silicon dioxide, elwira mixture DHM/ethyl acetate (100: 1 by volume). Acetylated on the indole nitrogen derivative, which is obtained, is treated with 30 ml of ethanol, add 1 g of sodium carbonate and stirred over night at room temperature. The reaction mixture is evaporated in vacuo, the residue is treated with water, the precipitate is filtered off, washed with water and dried in a vacuum drying cupboard. Obtain 0.56 g of the target product. So PL = 293oC.

Example 8.

N-/4-(5-Chloro-2,4-acid)-5-methylthiazole-2-yl/-1H-indole-2 - carboxamide (Method E).

< / BR>
A mixture of 1.24 g of the compound obtained in preparation IV, G/, 0.88 g of N-acetylindole-2-carboxylic acid, 1,95 g BOF of 0.60 ml of triethylamine in 4 ml of DMF is stirred overnight at room temperature. The reaction mixture was poured in a buffer solution with a pH of 2, the precipitate is filtered and washed precipitate with water. The residue is treated with DHM, washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate and evaporated the e, acetylated on the indole nitrogen derivative is treated with 30 ml of ethanol, add 2 g of sodium carbonate and stirred over night at room temperature. The reaction mixture is evaporated in vacuo, the residue is treated with water, the precipitate is filtered off, washed with water, then ether and dried in a vacuum drying Cabinet. Get 0,81 g of the target product. So pl. = 249oC.

Example 9.

N-/4-(5-Chloro-2,4-acid)-5-methylthiazole-2-yl/-1- (carboxymethyl) indole-2-carboxamide-triptorelin (Method g).

< / BR>
A mixture of 1 g of the compound obtained in preparation IV,G/, 0.96 g of N-(tert. -butoxycarbonylmethyl)-indole-2-carboxylic acid, 1.6 g of BOP, of 0.49 ml of triethylamine in 6 ml of DMF is stirred overnight at room temperature. The reaction mixture was poured in a buffer solution with a pH of 2, the resulting precipitate is filtered and washed with water. The residue is treated with DHM, washed with buffer solution with pH 2, saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuum. Chromatographic on the silicon dioxide, elwira mixture DHM with methanol (100:1.5 for volume). The obtained complex tert.-butyl ether is treated with the aid of the residue is treated with water, the formed precipitate is filtered off, washed with water and dried in a vacuum drying Cabinet. Gain of 1.37 g of the desired product. So pl. = 167oC.

Example 10.

N-/-4-(2,5-Dimethoxy-4-were)thiazol-2-yl/-1-carboxymethyl) -indole-2-carboxamide (Method 3).

< / BR>
A mixture of 1.0 g of 2-amino-4-(2,5-dimethoxy-4-were)thiazole, of 1.09 g of N-(tert. -butoxycarbonylmethyl)indole-2-carboxylic acid, 2.0 g of BOP, with 0.55 ml of triethylamine in 5 ml of DMF is stirred for 48 hours at room temperature. The reaction mixture was poured in a buffer solution with a pH of 2, the resulting precipitate is filtered and washed with water. The residue is treated with DHM, washed with saturated sodium hydrogen carbonate solution, the buffer solution with pH 2, dried over magnesium sulfate and evaporated in vacuum. Chromatographic on the silicon dioxide, elwira mixture DHM/ethyl acetate (100:1.5 for volume). The obtained complex tert.-butyl ether is treated with 10 ml TFA and left under stirring for 3 hours. Evaporated in vacuo, the residue is treated 2 N. NaOH solution, washed with DHM, the aqueous phase is acidified by adding concentrated HCl, the precipitate is filtered off and dried in vacuum susielibation/-thiazol-2-yl/-1H - indole-2-carboxamide (Method E).

< / BR>
The mixture 0,609 g 2-amino-4-(4-trifluoromethyl-2,6-acid)-thiazole, 0,447 g N-acetylindole-2-carboxylic acid, of 1.062 g of BOP, 0,243 g of triethylamine in 30 ml DHM stirred for 48 hours at room temperature. Add 100 ml of water, after decanting, the organic phase is dried over sodium sulfate and evaporated in vacuum. Received, acetylated at the indole nitrogen derivative is treated with 50 ml of methanol, add 2 g of sodium carbonate and stirred over night at room temperature. Evaporated in vacuo, the residue is treated with 100 ml of water, extragere using DHM, dried over sodium sulfate and evaporated in vacuum. Gain of 0.54 g of the target product, after crystallization from DHM. So pl. above 260oC.

Example 12.

N-/4-(4-Trifluoromethyl-2,6-acid)-thiazol-2-yl/-1- (tert-butoxy-carbonylmethyl)-indole-2-carboxamide (Method)

< / BR>
The mixture 0,609 g 2-amino-4-(4-trifluoromethyl-2,6-acid)-thiazole, 0,606 g of N-(tert.-butoxycarbonylmethyl)-indole-2-carboxylic acid, of 1.062 g of BOP and 0,243 g of triethylamine in 30 ml DHM stirred for 24 hours at room temperature. Then add 50 ml of water, after decanting, the organic phase is dried over sodium sulfate and evaporated who 0,79 g of the target product, after crystallization from ether. So pl. = 214 - 216oC.

Example 13.

N-/4-(4-Trifluoromethyl-2,6-acid)-thiazol-2-yl/-1- (carboxymethyl) indole-2-carboxamide-triptorelin (How TO)

< / BR>
Cooled to 10oC 20 ml of TFA, add 0.5 g of the compound obtained in example 12, and left under stirring at 10oC for 3 hours. Evaporated in vacuo, the residue is treated with water, extracted with ethyl acetate, dried over sodium sulfate and evaporated in vacuum. Get to 0.47 g of the desired product, after crystallization from ether. So pl. = 230 - 232oC.

Acting according to the methods of operation described above, are compounds of formula I, described in table IV.

1. Derivatives polyamidine 2-amido-4-phenylthiazole formula I

< / BR>
in which Y denotes a 3-hyalinella or 2-indolering group of the formula

< / BR>
in which R denotes hydrogen, acetyl group or the group CH2COOR1and R1is hydrogen or C1- C4- alkyl;

X denotes a (hetero)aryl radical, selected from the group comprising 4-chloro-2,6-dimethoxyphenyl, 2,6-dimethoxy-4-methylphenyl, 2,4,5-trimethoxyphenyl, 4-methyl-2,3,6-trimethoxyphenyl, 2,6-dimethoxy-4-ethylphenol-2,4-dimethoxy-5-pyrimidinyl, 2,4,6-trimetoksi-5-pyrimidinyl, 5-chloro-2,4-dimethoxyphenyl, 5-chloro-2-methoxy-4-methylphenyl, 2,5-dimethoxy-4-methylphenyl, 4-trifluoromethyl-2,6-dimethoxyphenyl, 2,4-dimethoxy-5-methylphenyl, 5-ethyl-2,4-dimethoxyphenyl, 2,4-dimethoxyphenyl group;

Z represents hydrogen, C1- C4-alkyl or benzyl, provided that Z is necessarily denotes hydrogen, when X denotes a phenyl radical substituted simultaneously at positions 2 and 6, or when X is 3-pyridinoline radical substituted simultaneously at positions 2 and 4, or when X - 5-pyrimidinyl radical substituted simultaneously at positions 4 and 6;

or their pharmaceutically acceptable salt or solvate as a full or partial agonist of the receptor cholecystokinin.

2. Derivatives under item 1, corresponding to the formula I'

< / BR>
in which Y denotes a 3-hyalinella group (a) or 2-indolering group (b) formula

< / BR>
in which R denotes hydrogen, acetyl group or the group CH2COOR1and R1is hydrogen or C1- C4- alkyl;

X' denotes a (hetero)aryl radical, selected from the group comprising 4-chloro-2,6-dimethoxyphenyl, 2,6-dimethoxy-4-methylphenyl, 2,4,5-trimethoxyphenyl, 4-metamodeling, 2,4-dimethoxy-6-methyl-3-pyridinyl, 6-chloro-2,4-dimethoxy-5-pyrimidinyl, 5-chloro-2,4-dimethoxyphenyl, 5-chloro-2-methoxy-4-methylphenyl, 2,5-dimethoxy-4-methylphenyl, 4-trifluoromethyl-2,6-dimethoxyphenyl, 2,4-dimethoxy-5-methylphenyl, 5-ethyl-2,4-dimethoxyphenyl group;

Z represents hydrogen, C1- C4-alkyl or benzyl, provided that Z is necessarily hydrogen, when X' is a phenyl radical substituted simultaneously at positions 2 and 6, or when X' is 3-pyridinoline radical substituted simultaneously at positions 2 and 4, or when X' is a 5 - pyrimidinyl radical substituted simultaneously at positions 4 and 6,

or its salt, or a solvate.

3. Connection on p. 2 of the formula I', in which Y represents the group (b), where R represents hydrogen or the group CH2COOH, as well as its pharmaceutically acceptable salt or solvate.

4. Connection on p. 2 of the formula I', in which Z is hydrogen or methyl, as well as its pharmaceutically acceptable salt or solvate.

5. Connection on p. 2 of the formula I', in which Y denotes a radical (b), where R is hydrogen or the group CH2COOH, Z is hydrogen or methyl and X' - aryl radical, selected from the group consisting of 5-chloro-2,4-dimethoxyaniline, 4-chloro-2,6-dimethoxymethylsilyl group (where Z is necessarily hydrogen, when X' denotes 4-chloro-2,6-dimethoxyaniline or 2,6-dimethoxy-4-methylphenyl group), or its pharmaceutically acceptable salt, or its solvate.

6. Connection on p. 2, selected from the group comprising N-[4-(4-chloro-2,6-acid)thiazol-2-yl] -1-(carboxymethyl)indole-2-carboxamide; N-[4-(4-chloro-2,6-acid)thiazol-2-yl] -1-(carboxymethyl) indole-2-carboxamide-hydrochloride; N-[4-(5-chloro-2,4-acid)-thiazol-2-yl] -1H-indole-2-carboxamide; N-[4-(5-chloro-2,4-acid)-5-methylthiazole-2-yl] -1H-indole-2-carboxamide; N-[4-(5-chloro-2,4-acid)-5-methylthiazole-2-yl] -1-(carboxymethyl) indole-2-carboxamide; N-[4-(5-chloro-2,4-acid)-5-methylthiazole-2-yl] -1-(carboxymethyl) indole-2-carboxamide-triptorelin; N-[4-(5-chloro-2-methoxy-4-were)-thiazol-2-yl] -1H-indole-2-carboxamide; N-[4-(2,6-dimethoxy-4-were)-thiazol-2-yl] -1H-indole-2-carboxamide; N-[4-(2,6-dimethoxy-4-were)-thiazol-2-yl] -1H-indole-2-carboxamide-hydrochloride-monohydrate; N-[4-(2,4-dimethoxy-5-were)-5-methylthiazole-2-yl]-1H-indole-2-carboxamide; N-[4-(2,4,5-trimethoxyphenyl)-5-methylthiazole-2-yl]-1H-indole-2-carboxamide; its pharmaceutically acceptable salt and solvate.

7. The method of obtaining compounds of formula I' according to p. 2, characterized in that the acid of the formula >< / BR>
< / BR>
or 2-indolinyl radical (c0)

< / BR>
and R0denotes the N - protective group or a group CH2COOR", where R" is C1- C4-alkyl;

or a functional derivative of the acid of formula II is condensed with 2-aminothiazole formula III

< / BR>
in which X' and Z are specified in paragraph 2 values

in the presence of a base to obtain the compounds of formula I"

< / BR>
in which X and Z are specified in paragraph 2 values

Y' is one of the radicals of formulae (a), (b0) or (c0)

then, when the compound I" Y' denotes a radical (b0), if desired, the resulting product of formula I (b0)

< / BR>
subjected to reaction in the removal of N-protective group, or saponification or acid hydrolysis; when the compound (I" Y' denotes a radical (c0), the obtained product of formula I" c0< / BR>
< / BR>
subjected to dehydration, in some cases with prior removal of the N-protective group, the saponification or acid hydrolysis, to obtain the compounds of formula I', in which Y is a radical (b), where R is hydrogen or the group CH2COOR', where X', Z and R' are specified in paragraph 2 values, and the product of formula I' emit as is, or in the form of a solvate, or one of its salts.


Z is hydrogen, C1- C4-alkyl or benzyl, with the restriction that Z is hydrogen when X is a phenyl radical substituted simultaneously at positions 2 and 6, or when X is 3-pyridinoline radical substituted simultaneously at positions 2 and 4, or when X is 5-pyrimidinyl radical substituted simultaneously at positions 4 and 6,

as intermediate compounds for the synthesis.

9. Thiazole under item 8, selected from the group comprising 2-amino-4-(4-chloro-2,6-acid)-thiazole; 2-amino-4-(5-chloro-2,4-acid)-thiazole; 2-amino-4-(5-chloro-2,4-acid)-5-methylthiazole; 2-amino-4-(5-chloro-2-methoxy-4-were)-thiazole; 2-amino-4-(2,6-dimethoxy-4-were)-thiazole; 2-amino-4-(2,4-dimethoxy-5-were)-5-methylthiazole.

10. Pharmaceutical composition having agonistic activity is the lasting themes as the active agent contains at least one compound of General formula I' in PP.2 - 6 in a pharmaceutically effective dose.

11. The composition according to p. 10, characterized in that it is in the form of a unit dose for oral or parenteral administration.

12. The composition according to p. 10, characterized in that it contains 0.05 - 100.0 mg of the compound according to any one of paragraphs.2 - 6 in Association with at least one excipient.

 

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< / BR>
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