Heterocyclic derivatives or their salts with acids or bases

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds as substances possessing properties antagonist of factor activation of blood platelets. The inventive product-heterocyclic derivatives of f-crystals I , where A Is O or S; B Is C or N: Z1-C1-C2alkylene or phenylene, Z2-C1-C2alkylene; W is a group NR1R2where R1-H or C1-C4-alkyl, R2-H, C1-C4the alkyl group CONQ1Q2or CSNQ1Q2where Q1-Q2-N or C1-C4-alkyl; SO2Q3or COQ3where Q Q(3) C1-C4-alkyl; COOQ4where Q Q(4) C1-C4-alkyl; or R1and R2taken together with the nitrogen atom, form a saturated a heterocycle of the research, pyrrolidine, piperidine or 4-(C1-C3) -alkylpiperazine, or W-N-oxide amines NR1R2where R1and R2-C1-C3-alkyl; or W is C1-C4-alkoxy or C1-C4-dialkoxy; COOQ5where Q Q(5) C1-C5-alkyl; or W is a group CONQ1Q2pyridyl or imidazolyl; R3absent when B is a nitrogen atom, or represents a hydrogen atom, a C1-C4-and the-C4-alkoxy, hydroxy-, carboxypropyl, COOQ6where Q Q(6) C1-C4-alkyl; carboxamido, cyano, amino, atsetamino, nitro, trifluoromethyl, or Ar1-thienyl, thienyl, indolyl, naphthyl, benzyl or cyclohexyl; or Ar1and R3/taken together form the group of f-crystals II where Ar2-chinolin, indolyl or pyridyl which may be substituted C1-C3-alkyl or chlorine, or their salts with acids or bases. 8 C. p. F.-ly, 6 PL.

The invention relates to heterocyclic derivatives, method for their production and to their therapeutic application.

Known derivatives of 2-aminothiazole with the formula

in which R'2is, in particular an aromatic group, R'3represents H or alkyl group1-C4and R'4represents aminoalkyl group in which the nitrogen of the amino group can belong, in particular, heterocycle, such as pyridine, pyrrolidine, piperidine or piperazine; these compounds are agonists of the Central muscarinic receptors and have activity, stimulating cholinergic transmission in the Central nervous system [1]

Known 2-amino-4,5-diphenyloxazole, disubstituted Amin on the group the alkyl and hydroxyalkyl, having anti-inflammatory activity [2, 3]

Among the derivatives of 2-amino-4-phenyl-1,2,4-thiazolo you can specify antimalarial derivatives described in J. t. Chem. , 611 (1973), in which AMINOPHENYL replaced by dialkylaminoalkyl and thiadiazolyl, or anesthetics, described in CH-497453, which are substituted on AMINOPHENYL the alkyl and aminoalkyl.

Among the derivatives of 2-amino-4-phenyl-1,2,4-oxadiazole you can specify a local anaesthetic and vasodilators (vasodilator), described in the patent FR-2 148430, which are disubstituted on aminophenol dialkylaminoalkyl.

Compounds in accordance with the invention do not have any of these activities, however, are antagonists PHAT-acheter (factor of activated platelets); they correspond to the formula I

where a represents O or S;

In represents C or N;

Z1is alkylen1-C4or phenylene;

Z2is alkylen1-C4;

W represents NR1R2where R1is H or alkyl WITH1-C4and R2is H, alkyl WITH1-C4, NQ1Q2in which Q1and Q2predstavljaet an alkyl WITH1-C4, Q4where Q4represents alkyl WITH1-C4or benzyl, or R1and R2considered together, form a saturated a heterocycle such as morpholine, pyrrolidine, piperidine, piperazine or 4-alkyl(C1-C3)-piperazine, or W may be a W-oxide amines NR1R2or even W represents alkoxy or dialkoxy1-C4, NQ1Q2or SNQ1Q2, pyridyl, imidazolyl or Q5where Q5represents alkyl WITH1-C5;

R3absent when b is N, or represents H, alkyl WITH1-C8or halogen, when is C;

AG1represents phenyl, substituted, if necessary, one or more groups selected from among halogen, alkyl, alkoxy or toolcategory1-C4, hydroxy-group, carboxypropyl, Q6or SQ6in which Q6is alkyl WITH1-C4, carboxamido, amino, acetamidoxime, nitro, trifloromethyl, or Ar1represents an aromatic thienyl, purely, indaily a heterocycle, or even Ar1represents the, the carbon of the phenyl is linked to position 4 of the heterocycle, and where q equals 2-4, Xpidentical or different, represent H, alkyl WITH1-C3or halogen, and n equals 1-3;

AG2represents a nitrogen-containing aromatic heterocycle of pyrimidinyl, chinoline, isoquinoline, indolyl, isoindolyl or pyridyl, substituted if necessary, alkyl or alkoxygroup1-C3or halogen; and salts of these compounds with acids or bases.

Alkyl, Allenova, alkoxy, dialkoxy groups are linear or branched.

Salts with pharmaceutically acceptable acids or bases are preferred, but salt, which can afford to isolate compounds with formula I, in particular, to cleanse them, are also objects of the invention.

Prefer compounds in which a represents a carbon atom and, in particular, derivatives of thiazole, in which AG1is a phenyl ring, at least, ortho-substituted, or those in which Ar1represents phenyl without substituent in the ortho-position, and R3represents a halogen Ilie NR1R2where R1, R2are independently H or alkyl WITH1-C4or NR1R2form a rich heterocycle; finally, prefer to Z1represented an ethylene or propylene.

Among the latter compounds, a preferred group of compounds may be represented by formula II

in which R1and R2each represent a hydrogen atom or alkyl WITH1-C3or form together with the nitrogen atom to which they relate, pyrrolidinyl or piperidino, Z2represents CH2or SSN3, R3represents N, and A1represents a phenyl group bearing at least one substituent in the ortho-position, or R3represents Cl, Br or alkyl WITH1-C6and1represents phenyl, substituted, if necessary, with the substituents of the phenyl group are selected among halogen atoms and alkyl or alkoxygroup1-C4and n equals 2 or 3.

As will be seen hereinafter, compounds of particular interest are of formula III

in which R3represents H or halogen, such as Br or CL, R' performance is entrusted represent H or alkyl WITH1-C3or together with the nitrogen atom to which they are bound, form pyrrolidinyl or piperidino, and Peregrina group substituted in position 2 or 3.

Among the preferred compounds can be specified, for example, N-[N',N'-dimethyl-2-amino-ethyl] -N-[3-pyridylmethyl]-2 - amino-4-/2,4,6-triisopropylphenyl-thiazole, N-[N', N'-dimethyl-2-amino-ethyl] -N-[3-pyrid - ylmethyl] -2-amino-4-/2,4,6-trimetilfenil/ -thiazole, N-[N',N'-dimethyl-2-amino-ethyl]-N-[3-pyridylmethyl] -2-amino-4-/2,4-dichlor - enyl/-5-methyl-thiazole and oxazole and N-[N',N'-dimethyl-2-amino-ethyl]-N-[3-pyridylmethyl]-2-amino-4-/2,4,6-triisopropyl life(or bromo-) thiazole.

Methods for obtaining compounds of formula I constitute another object of the invention.

On the one hand, compounds obtained by reaction of the secondary amine with the formula IV with a heterocycle with the formula V, Deputy containing X, which is nucleofuge, such as halogen or sulfonate, in accordance with the reaction scheme (a):

in which a, b, R3, AG1, Z2, AG2, Z1W have the same meaning as in formula I, except that R3-halogen, or Ar1, Ar2W represent the corresponding groups in which the reactive functions was that X was In, the substitution is carried out in an aprotic solvent, in the General case of non-polar, such as aliphatic or aromatic hydrocarbons, preferably in the presence of a base to neutralize the acid formed; when a represents O or S, and is represented by N, prefer X is CL, and the replacement is carried out in an inert solvent, such as alcohol, aliphatic or aromatic hydrocarbon, a ketone or a chlorinated solvent such as methylene chloride.

You can also obtain compounds with formula I from compounds of formula V, in two stages, conducting a first reaction with a primary amine Ar2-Z2-NH2or W-Z1-NH2and then acting halide or sulfonate in accordance with the formula W-Z1-Y or Ar2-Z2-Y on the resulting secondary amine, preferably in the presence of a base. When a represents O, a represents a N, in connection with formula V used in the first stage, X can represent CCL3.

When connection with formula I contain a thiazole as the heterocycle can also be obtained directly aminothiazol, substituted relevant about what Econom, or as a result of the reaction of the secondary amine with alphadictionary.com in accordance with the reaction scheme (b):

NNH2+ArCOCHXR3___ in which W, R3, Z1, Z2, Ar1and Ar2have the same meaning as in formula I, except for the value of the halogen for R3or the fact that W, AG1, Ar2represent the corresponding groups in which the reactive functions are protected in the classical manner, and X represents a halogen atom, especially chlorine or bromine, preferably bromine, and the reaction scheme (s):

NH+ArCO ___ in which W, R3, Z1, Z2, Ar1and Ar2have the same meaning as in formula I, except for the value of the halogen for R3or the fact that W Ar1, Ar2represent the corresponding groups in which the reactive functions are protected in the classical manner.

In case (b) can, if necessary, to use the connection VII, protecting pre-carbonyl function in videotitles group, which will be chipped off during collabrasuite condensation; the reaction conditions are those which are commonly used in reactions of this type, and can be Soltis is in polar solvent at a temperature enclosed between the 40aboutand 100aboutC. Among the suitable solvents can be specified alcohols, such as ethanol, methanol or isopropanol, aliphatic acids such as acetic acid, nitrides, such as acetonitrile, ethers, such as dioxane or tetrahydrofuran. Preferably add a strong acid to the reaction medium to accelerate the reaction, when thiourea with formula VI does not dissolve in an acidic environment.

In case (C), as a rule, a solution of known compounds IV and VIII in an inert solvent, such as aliphatic or aromatic hydrocarbons, is maintained for several hours with stirring and at a temperature that is between room temperature, i.e. about 20aboutWith, and temperature phlegmy the selected solvent, and preferably at a temperature that is between 60 and 110aboutC.

When used in connection with formula IV-VIII contain features that could respond in the experimental conditions used to obtain the compounds of formula I, these functions previously protected; thus, when W represents NR1R2and R1and/or R2are H, can block aminophenol as Corbetta easily under the action of anhydrous acid, such as triperoxonane acid or chloromethane acid; when AG1, Ar2or W contain an acid function, the pre-receive connection with formula I, containing the appropriate function of ester of alkyl WITH1-C4that is hydrolyzed in the usual manner in the main environment, or, if necessary, in an acidic environment; when Ar1or Ar2contain the function of the primary amine, it is possible to get pre-compound with the formula I containing acetamide function, which is hydrolized in an acidic or basic environment.

However, when W represents NR1R2with R2which NQ1Q2, SNQ1Q2, SO2Q3, Q3it is possible to obtain compounds with the formula I in terms of the latter, in which R2represents N.

Connection with formula I, in which R3is a halogen atom, obtained by the action of halogen, CL2, Br2or CL, to the corresponding compound with the formula I in which R3represents H, using, in particular, the method described for thiazolo in J. Am. Chem. Soc. , 453-458 (1946).

The products of formula I are distinguished from the reaction medium and ochiltree of these products are oily liquids, and then they prefer to be isolated as a salt of joining with a mineral or organic acid salt, which sometimes hydrated or collaterals; salts obtained by the action of acid on a compound with the formula I in solution, for example, alcohol or a simple ester, and are distinguished either by deposition or by deposition, or by evaporation of the solvent; can be converted into a salt all AMINOPHENYL molecules or only some, depending on experimental conditions and used acid.

N-Oxide of aminophenol can be obtained by the action of a suitable oxidizing agent in connection with formula I, in particular, when step 2-/phenylsulfonyl/-3-phenyloxazolidine in accordance with the method described in J. Org. Chem. RV 5856 (1988).

Under these conditions, the nitrogen atoms of the heterocycle and Ar2not oxidized.

Most of the products of formulas IV-VIII are not commercial, and some are new, but they can be obtained using methods that are known in itself and which application was described for similar products.

Thus, secondary amines with the formula IV are obtained, on the basis of primary amines Ar2-Z2-NH2or W-Z2-Z2-Y or formula W-Z1-Y, where Y represents a halogen atom or a sulphonate group ZSO3-, in which Z represents alkyl WITH1-C4or phenyl, substituted, if necessary, or by condensation of a primary amine with a ketone or aldehyde in a dehydrating environment with subsequent recovery of the formed imine in the classical manner using a metal hydride or with hydrogen in the presence of a catalyst, such as Pd, according to the following reaction scheme (d):

R4NH2-R5COR6__ RHR5R6in which R4is a-Z2Ar2in the case when R5R6is a-Z1W, or R4is a-Z1W when-R5R6is a-Z2Ar2in accordance with the method described, in particular, in Methods Org. Chemie, IV /Id/ 355-363, (1981).

Ketones with the formula can be obtained by halogenation of ketones with the formula Ar1PINES2R3in the case of the known and commonly available in the trade; otherwise lucatti acid Lewis.

Alpha-brominated ketones receive, based on Ar1COCH3R3in particular, under the action of bromine in a solvent such as acetic acid, carbon tetrachloride or a simple ester, such as ethyl ether, under the action of bromide of divalent copper, using the method described in J. Org. Chem. p. 3459-3461 (1964), under the action of tribromide Quaternary ammonium compounds, as described in Bull. Chem. Soc. Japan , 1159-1160 and 2667-2668 (1987), alpha-chlorinated ketones can be obtained by the action of dichlorides Quaternary ammonium compounds, as described in Synthesis, p. 545-546 (1988).

In some cases, preference is given to obtaining alpha-brominated ketones by the reaction of the Friedel-between aromatic derivative with the formula AG1H and acid chloride acid R3-CHBr-COCl, using the method described in Methods der Org. Chemie, VII (2a), R. 110-132 (1977).

Finally, when R3represents N, then we can proceed from the carboxylic acid Ar1COCl, which is affected by diazomethane, followed by hydrolysis of the obtained diazoketone under the action of the hydrogen of the acid, by the method described, in particular, in Org. Synth. Coll. vol. , p. 119-120.

Thiourea with formula VI can be obtained through the mediation coitianta with the formula Q-N=C=S, where Q represents an acyl group capable of dissociation in an acidic environment, in particular, acetyl, benzoyl or trimethylacetyl, and preferably trimethylacetyl; itself derived Q-N= C=S is obtained by the action of acid chloride of the carboxylic acid on the metal thiocyanate in an anhydrous solvent, such as acetone or methyl ethyl ketone.

Connection with formula IV obtained when the strong acid in connection with formula IX, for example, under the action of aqueous solution of Hcl at a temperature that is between 10 and 100aboutAnd in particular, 12 n Hcl.

Thiocyanation can be obtained by the action of thiocyanate metal to the corresponding alpha-halogenated ketone in anhydrous solvent, applying the method of Chernyak, described, in particular, in Heterocyclic compounds, (1), R. 271-273 (1979).

2-Halogenate with the formula in which a is S, b is S, can be obtained by the action of anhydrous environment halogenation acid solution thiocyanation in accordance with the method described in Heterocyclic Compounds, (1), R. 273-276 (1979).

2-Halogenation with the formula in which a is Oh and b is S, can be obtained on the basis of oxazoline-2-it, in particular, under the action of Pastorelli the P CLASS="ptx2">

About ways to get oxazolinone you can refer to the overview Y. S. Rao and R. Filler in Heterocyclic Compounds, p. 660-665 (1986), I. J. Turchi, Ed. J. Willy and Sons.

It is possible, in particular, to get them as a result of cyclodehydration carbamates with formula IX in accordance with the reaction scheme (f):

ArC__NH2__ and carbamates are obtained on the basis of the alpha-hydroxylated ketones Ar1-CO-CHOH-R3.

5-Chloro-1,2,4-thiadiazole can be obtained by the action of perchloromethylmercaptan on amidin Ar1C/NH/NH2in accordance with the known method, described in particular in hem. Ber. , 182-187 (1957).

5-Chloro-1,2,4-oxadiazole can be obtained by the action of the agent chlorination on 1,2,4-oxadiazoline-5-he, in particular, the action of phosphorus oxychloride in the presence of an amine, as described in Yakugaku Zasshi, , 1061-1064 (1964) (Chem. Abs. 62, 5270 d).

Finally, 5-trichloromethyl-1,2,4-oxadiazole can be obtained by the action of trichloroacetic anhydride on amidoxime Ar1C/NOH/NH2as described in lv. Chem. Acta , 1067-1073 (1963).

Examples obtain the intermediate compounds and compounds with formula I, and their physico-chemical characteristics are given below.

The specialist will choose the method most suitable is the ability of intermediate compounds and their stability.

Connection with formula I and their salts are antagonists PHAT-ecetera. This phospholipid is a biological mediator, the chemical structure of which was determined in 1979 as a structure 1-0-hexadecyl-2-0-acetyl-sn-glycero-3 - phosphorylcholine, however, the release of which basophils during anaphylactic reactions were detected already in 1972, the mediator has a different physiological activity, among which you can specify the potentiating effect of platelet aggregation, the effect of the designer smooth muscles of the bronchi and cause inflammation effect and hypotensive activity.

You can refer to the article published in ISI Atlas of Science: Pharmacology, 1 (3), R. 187-198 (1987), which considers the physiological activity VEILS and therapeutic use of antagonists of this phospholipid, responsible for numerous pathologies, at least as a contributing factor.

There are various methods for detection of antagonistic activity VEILS.

Thus, in vitro it is possible to study the inhibition of platelet aggregation in rabbit called PHAT-achetera in accordance with the method described in Thrombosis Research , 211-226 (1986). In this experiment the majority of the compounds with formula I aracia 4x10-10M) less than 10-6M, and for many products in the order of 10-9M, whereas under the same conditions, the compound, called WEB 2086, i.e., a known antagonist described in J. Pharmacol. .. Therap. , 974-981 (1987), has CL50the value of 5x10-8M. Among the most active compounds, among which Cl50is of the order of 10-9M and which have a duration of action greater than that of WEB 2086, you can specify connection with formula II, which are explained previously.

In the same experimental conditions connection with formula I at a concentration of 10-4M are inactive with respect to aggregation caused arahidonovoy acid with a concentration of 10-4M or 5'-diphosphate with a concentration of 10-5M

Various methods have also been applied to identify animals inhibition by antagonists of the effects caused by the FOP, for example, inhibition of bronchospasm induced in Guinea pigs, which are described in Thromb. Haemostas. (I), 40-44 (1986), and inhibition of protection against lethal shock in mice, which is described in J. Pharmacol. Exp. Ther. , (2), 617-23 (1988).

As an example, you can specify that the connection with formula III, explained above, is completely inhibit bronchospasm caused and the g or oral route with a dose of 3 mg/kg; these same compounds reduced by 50% mortality of mice, if they are entered for 1 h before the injection of the IV value of 100 g/kg FAT with doses of about 0.5 mg/kg by IV and 10 mg/kg oral route. Among these compounds, N-/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/2,4,6-Tris - propylene/-thiazole completely inhibits bronchospasm induced in Guinea pigs, with a dose of 1 mg/kg by IV or 3 mg/kg by mouth for more than 96 hours

On the other hand at the dose of 5 mg/kg by mouth following compounds: N-/N', N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/2,4,6-trimethyl - phenyl/thiazole;

N/N', N'-dimethyl-2-amino-ethyl/-N-/3 - pyridylmethyl/-2-amino-4-/2,4,6-triiso - propylphenyl/-5-chloro- (or 5-bromo-thiazole; N-/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/2,4-dichlorophen - Il/-5-methylthiazole (or oxazol) protect mice from common lethal shock VEILS at the dose of 100 g/kg

Thus, on the other hand, the invention relates to pharmaceutical compositions containing as an active ingredient at least one compound with the formula I or one of its pharmaceutically acceptable salts in combination with eccipienti (indifferent substances), normal to the introduction of oral, Reineke, from nature and severity of the disease, the patient, and the route of administration; in the General case for oral route a single dose for an adult will be from 5 to 500 mg, whereas the intravenous route, it will be from 0.05 to 10 mg, these doses are comparable to the doses at which the pharmacological activity of these compounds is manifested in animals with no apparent toxic effect.

The composition of the invention are useful, in particular, in the treatment of asthma, some allergic or inflammatory conditions, cardiovascular diseases, including atherosclerosis, thrombosis, hypotension or arrhythmia, cerebral and cardiac ischemia, and various kidney disorders, including glomerulonephritis, or even as a contraceptive agent.

In the subsequent presentation first will be described the production of intermediate compounds of formulas IV-VIII. Referred to the melting temperature (TPLare instant; the boiling temperature (TKip) were in General measured during distillation under reduced pressure.

Amines with formula IV.

A) N,N-aminobutiramida N'-/3-pyridylmethyl/academin.

(R1=R2=CH/CH3/2; Z1 to the solution, containing 25 g of N,N-diisopropylethylamine in 150 ml of toluene, in the presence of molecular sieve (zeolite) 4 A.

After 1 h of incubation at room temperature, filtered zeolite and the solvent is evaporated under reduced pressure to about 30about; Remove residual liquid oil through 150 ml of anhydrous methanol and cooled the solution between 0 and 10aboutC. Then add portions 6 g of sodium borohydride and allow to return to room temperature; after several hours of stirring injected into the reaction medium 10 ml of 1 n aqueous Hcl, then add 10 n aqueous NaOH solution to pH 8 before carrying out the extraction of the final product with methylene chloride. The organic phase is dried on sodium sulfate, filtered and concentrated under reduced pressure to approximately 70aboutC. the liquid oil distilled under vacuum. Get to 30.1 g of the expected compound.

TKip=115aboutC/5 PA.

In) N,N-dimethyl-N'-/3-pyridylmethyl/-amandemen.

(R1=R2=CH3; Z1=/CH2/2; Z2=CH2; Ar2=3-pyridyl).

In an inert atmosphere was added 4 g of N,N-dimethylethanamine to a chilled solution containing 4.7 g of 3-pyridi anatoy temperature filtered zeolite and solution refrigerated between 0 and 10aboutC, add sodium borohydride. After 12 h stirring at room temperature, concentrate the reaction medium under reduced pressure and poured 10 ml of 1 n aqueous Hcl to the residue; then add a concentrated solution of KOH to a pH greater than 8, and the reaction medium is extracted with ethyl ether; the organic phase is dried and the solvent removed under reduced pressure. The liquid oil is distilled under vacuum. Gain of 5.4 g of the expected compound.

TKip=84aboutC/40 PA.

C) N,N-dimethyl-N'-/1-(3-pyridyl)-ethyl/-amandemen.

(R1=R2=CH3; Z1=/CH2/2; Z2=CHCH3; Ar2=3-pyridyl).

In a flask equipped with a Dean stark separator, heated to education phlegmy for about 5 h 30 g of 3-acetylpyridine, 28.4 g of N,N-dimethylethanamine and 20 mg of para-toluenesulfonic acid in 300 ml of anhydrous benzene. After concentration under reduced pressure of about 50aboutWith remove residual liquid oil by 300 ml of anhydrous methanol and at a temperature of less 10aboutC, add 10 g of sodium borohydride, then treated reaction medium under the conditions described in

D) N-/piperidinoethyl/-N-/1-(3-pyridyl)-ethyl/-Amin.

Z1=/CH2/2; Z2=CH-CH3; Ar2=3-pyridyl).

In a flask equipped with a Dean stark separator, heated to education phlegmy for about 3 hours 7,26 g 3-acetylpyridine, 8 g of piperidinoethyl, 0.2 g of para-toluenesulfonic acid in 100 ml of toluene. Is evaporated under vacuum of the solvent at a temperature of about 60aboutWith and remove liquid oil in 100 ml of anhydrous methanol; then at a temperature of about 5aboutWith added 2.3 g sodium borohydride in portions. After stirring overnight at room temperature, add 10 ml of acetone to destroy excess borohydride and after 15 minutes add 15 ml of 5 n aqueous solution of NaOH. After concentration under vacuum, remove residue by means of methylene chloride 3 times 50 ml of the Organic phase dried on anhydrous magnesium sulfate, filtered and concentrated under vacuum. After distillation of 11.5 g of the expected compound.

TKip=115about/42 PA.

E) N,N-/1-di(3-pyridyl)-ethyl/-Amin

(W=3-pyridyl; Z1=Z2=CHCH3; Ar2=3-pyridyl).

At a temperature of about 5aboutWith added portions of 8.8 g of cyanoborohydride operature about 20aboutC. After stirring for approximately 14 h at room temperature in a reaction medium introduced 50 g of 3-acetylpyridine, then after several hours of stirring in the reaction medium was cooled to 5aboutWith, enter 5 g cyanoborohydride sodium. Then allow to return to room temperature and after stirring for approximately 14 h, concentrated to dryness at a temperature of about 50aboutC. Then the residue is acidified under traction to a pH close to 2 by adding 12 n aqueous Hcl, filtered, and the filtrate is brought to about pH 8 in the addition of 10 n aqueous solution Paon. The aqueous phase is extracted with ethyl acetate and, after drying of the organic phase and removal of the solvent the residual liquid oil distilled under vacuum at a temperature of about 140aboutAnd pressure of 21 PA. Get so 32 g Amin. The hydrochloride, obtained by the action of Hcl on the amine in solution in 400 ml of isopropanol, melts at temperatures above 250aboutC. you Can select 2 diastereoisomer in the fractional deposition in aqueous methanol.

F) N,N-dimethyl-N'-/2-(3-pyridyl)-ethyl/-amandemen.

(R1=R2=CH3; Z1=/CH2/2; Z2=/CH2/2; Ar2=3-perederina, 16.3 g of N,N-dimethylethanamine, and 18.5 g of sodium bicarbonate and 13 g of potassium iodide in 150 ml of ethanol. The solvent is evaporated and remove the remainder by 100 ml of water before you add 10 n aqueous NaOH solution to pH 8; then the aqueous phase is extracted 3 times with 80 ml ethyl acetate. The combined organic phases are dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residual liquid oil distilled, resulting in 6.7 g of the expected product.

TKip=100-107aboutC/10 PA.

G) N-/tert-butyloxycarbonyl/-N-methyl-N'-/3-pyridylmethyl/-amandemen.

(R1=CH3; R2=tert-C4H9OCO; Z1=/CH2/2; Z2=CH2; Ar2=3-pyridyl).

With stirring to a mixture consisting of 6 g of N-methyl-N'-/3-pyridylmethyl/-academia, 95 ml of dioxane, 20 ml of water and of 1.74 g of magnesium oxide are added slowly at a temperature of about 3aboutWith 5.9 g of bicarbonate of ditertbutyl in 60 ml of dioxane. After 15 min the reaction medium is injected approximately 15 ml of 2 n sodium hydroxide solution; then the precipitate is separated and the filtrate is concentrated under reduced pressure; the residue is dissolved in about 200 ml of ethyl acetate, then dried on the AC the second liquid oil is purified by chromatography on silica with elution with ethyl ether, and then with a mixture of methylene chloride/methanol (95/5 v/v). N,N'-dicarbamate eluted first, followed by the desired product (mass of 3.9 g) to carbamate formed on the nitrogen that carries methylpyridyl group.

N) N-/3-pyridylmethyl/-N-/tert-butyloxycarbonyl/-amandemen.

(R1=H; R2=tert-C4H9OCO; Z1=/CH2/2; Z2=CH2; Ar2=3-pyridyl).

At a temperature of about 5aboutWith the introduce of 2.92 g of 3-pyridylcarboxylic in a solution containing 4,82 g N/tert-butyloxycarbonyl/-academia in 50 ml of toluene in the presence of a dehydrating agent (zeolite 4 A).

The diamine can be obtained in accordance with the method described in J. Med. Chem. , 898 (1988). After incubation for 4 hours at room temperature, the zeolite is separated and the solvent evaporated under reduced pressure. The residual liquid oil is dissolved in 30 ml of anhydrous methanol, then injected into the solution at a temperature between 0 and 5aboutWith of 0.68 g of sodium borohydride. After stirring for 2 h at room temperature and injected into the reaction medium in 10 ml of acetone, then evaporated the solvent under reduced pressure. The residue is dissolved in 50 ml of methylene chloride saturated with water with 0.5 g of KOH; then argumentami; elution is carried out with a mixture of methylene chloride and methanol (90/10 V/V).

Allocate therefore of 5.1 g of amine in the form of liquid oil.

Amines of table. 1 were obtained using one of the methods above.

THIOUREA WITH FORMULA VI

1) N-/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-thiourea.

(R1=R2=CH3; Z1=(CH2)2; Z2=CH2; Ar2=3-pyridyl).

i/-trimethylethylenediamine: slowly added to 18.7 g of trimethylacetylchloride to chilled to a temperature of about 4aboutWith the suspension containing 15.1 g of potassium thiocyanate in 150 ml of anhydrous acetone. Leave with stirring for about 3 h at the same temperature.

ii/ previous reaction medium is slowly added, maintaining the temperature below 10aboutC, 20 g of N-/dimetil2-amino-ethyl/-N-/3-pyridylmethyl/-Amin. After 1 h of incubation at room temperature the reaction medium is evaporated to dryness under reduced pressure and a temperature of about 60aboutWith and extract the residue in methylene chloride before rinse with diluted ammonia solution; the solvent is evaporated under reduced pressure and the extract obtained liquid malerne 80aboutC for 1 h, After cooling, adjusted to pH 8 by adding ice-cold solution of ammonia, then extracted 3 times with methylene chloride; the organic phase is dried on magnesium sulfate to remove solids and concentrated under reduced pressure and a temperature of about 60aboutC. the liquid oil (41 g) can be used in this form in the next stage or be purified by chromatography under normal pressure on silica (eluent:methylene chloride/methanol 8/2 v/v). The pure product crystallized in ethyl acetate.

TPL=104aboutC.

Thiourea as intermediate compounds for the synthesis of compounds were obtained using this technique; the melting temperature of some of them appear in the table. 2.

Alpha brometane with formula VII

J) /2,4,6-trimethyl-phenyl-/2-bromo/-alanon

(VII: Ar1=2,4,6-(CH3/3-C6H2; R3=H; X=Br)

Slowly introducing 52 g of bromine in 10aboutC in a solution containing 50 g of (2,4,6-trimetilfenil/-ethanone in 100 ml of acetic acid. After stirring for 1 h at this temperature and for 2 h at a temperature of about 20aboutWith the reaction medium prilisaetsa to the volume of ice water and is extracted by Atila the following drying MgSO4concentrated under reduced pressure and a temperature of about 60aboutC. Obtain 66 g of liquid oil which can be purified by distillation or crystallization in pentane at a temperature of about 20aboutC.

TPL<50C.

K) /2-trifluoromethyl-phenyl-/2-bromo/-alanon

(VII: Ar1=2-/CF3/-C6H4; R3=H; X=Br)

In an inert atmosphere introducing of 28.2 g of finely ground bromide divalent copper in a solution containing 8.5 g /2-trifluoromethyl/-phenylethanone in 25 ml ethyl acetate and 25 ml of chloroform, at a temperature of phlegmy; the reaction medium is maintained for 3 hours at a temperature of her phlegmy, then the solids are separated and the filtrate is concentrated, and then distilled under reduced pressure. Get so 10.7 g of the ketone.

TKip=80aboutWith/3 PA.

L) /2,4,6-triisopropyl/-phenyl-/2-bromo/-alanon

(VII: Ar1=2,4,6-/CH3/2CH-C6H2; R3=H; X=Br)

In an inert atmosphere at a temperature of 0aboutTo enter into a slurry containing 16.5 g of anhydrous aluminium chloride in 200 ml of 1,2-dichloroethane solution containing 25 g of 1,3,5-triisopropylbenzene in 50 ml of 1,2-dichloroethane.

After stirring for 30 min atoi temperature and after stirring for 5 h the reaction medium is poured to 2 volumes of a mixture of water and ice (50/50); after 15 minutes add 1 volume of methylene chloride and the decanted organic phase. The latter is washed in an aqueous solution of NaHCO3(6% p/v), then with water and dried on MgSO4. After removal of the solvents by distillation at a temperature of approximately 70aboutWith residual liquid oil is purified by distillation under reduced pressure. TKip=116-124aboutC/1 PA. Get to 29.8 g of the ketone, which melts at a temperature of 56-58aboutC.

M) /2,4-dimethyl-6-methoxy-phenyl-/2-bromo/-alanon

(VII: Ar1=2,4-/CH3/2-6-OCH3/-C6H2; R3=H; X=Br)

i) At a temperature of less than 10aboutTo enter 2.9 g of acetylchloride in a mixture consisting of 3.5-dimethylanisole and 4.9 g of anhydrous aluminium chloride in 50 ml of 1,2-dichloroethane. After stirring for 3-4 hours at room temperature the reaction medium is poured to 2 volumes of a mixture of water and ice. Then add the amount of methylene chloride and the organic phase is separated. The latter is dried, and then concentrated under reduced pressure and a temperature of about 60aboutC. the Residual liquid oil is purified by distillation under reduced pressure.

TKip=81aboutC/50 PA.

ii) the ketone pomeroys using CuBr2using method K.<"ptx2">

This ketone is obtained in accordance with method M based on isovalerylglycine.

TPL=110aboutC.

Intermediate gidroksilirovanii ketone melts at 109aboutC.

A) 3,5-dimethyl-4-/2-bromo-1-oxoethyl/-acetanilide.

(VII: Ar1=3,5-(CH3)2-4-/NH-COCH3/-C6H2; R3=H; X=Br).

At a temperature of about -5aboutWith slowly introduced into a solution containing 3.4 g of 3,5-dimethyl-4-acetylacetonate received in accordance with the method described in J. Org. Chem. , 496-500 (1963), in 40 ml of tetrahydrofuran, 6,24 g tribromide of phenyltrimethylammonium dissolved in 40 ml of tetrahydrofuran.

After incubation for 30 min at a temperature of about 5aboutWith add at a temperature of 20aboutWith 3 ml of water Hydrosulphite solution sodium (0.5% p/v) and 30 ml of water. The organic phase is separated, and the aqueous phase is extracted by 30 ml of ethyl ether. The solvents are evaporated from the combined organic phases; allocate so 3 g of the desired product, melting at 142aboutC.

R) 3,5-dimethyl-4-/2-bromo-1-oxoethyl/-benzonitrile.

(VII: Ar1=3,5-/CH3/2-4-/CN/-C6H2; R3=H; X=Br)

At a temperature of about what about in accordance with the method, described in J. Chem. Soc. Perkin Trans. P, R. 943-949 (1988), in 10 ml of diethyl ether and 5 ml of dioxane. Give back the mixture to room temperature and after stirring for 1 h put 15 ml of a saturated aqueous solution of ammonium chloride. The organic phase is separated and the solvent is removed under reduced pressure, resulting in a gain of 4.8 g of the desired product.

TPL=76aboutC.

Alpha brometane of the table. 3, obtained in accordance with one of the previous methods, were isolated in pure form, others were used in crude form.

ALPHA THIOCYANATION WITH FORMULA VIII

Q) /2,4,6-trimethyl-phenyl-/2-thiocyanato/-Etalon.

Maintained at a temperature of about 50aboutC for 3 h in a mixture consisting of 7 g of anhydrous potassium thiocyanate, 16 g /2,4,6-trimethyl-phenyl-/2-bromo/-ethanone and 180 ml of acetonitrile. Formed precipitate is filtered at a temperature of approximately 15aboutAnd the filtrate is concentrated under reduced pressure. Poured to the residue 250 ml of ethyl ether, separating the solid and remove the ether. The residual liquid oil is dissolved in isopropyl ether and the solution cooled to 0aboutC. the precipitate Formed is separated. Get so 13,1 g iscil/-phenyl-/2-bromo/-this - Nona, get /2,4,6-triisopropyl/-phenyl-2-thiocyanation, which melts at 86aboutC.

2-HALOGENATE FORMULA V

R) 2-bromo-4-/2,4-triisopropylphenyl/-thiazole.

Cooled to 0aboutWith a solution containing 2 g /2,4,6-triisopropyl/-phenyl-2-thiocyanation in 80 ml of acetonitrile, and saturated at the same temperature, this solution of Hydrobromic acid by ozonation. Then, the reaction medium is brought to 50aboutWith in which it is maintained for 2 h in an atmosphere saturated Hydrobromic acid, then cooled to 10aboutC, filtered precipitate appeared under a stream of nitrogen. Get so 2.2 g of bromhidrosis expected connection.

TPL=236aboutC.

Applying the same technique to /2,4,6-trimethyl-phenyl-2-thiocyanation - ONU receive bromohydrin 2-bromo-4-/2,4,6-trimetilfenil/-thiazole, which melts at 270aboutC.

Introducing into the reaction medium gaseous chloroethanol acid instead of Hydrobromic acid, receive hydrochloride 2-chloro-4-/2,4,6-trimetilfenil/-thiazole, which melts at 216aboutC.

2-HALOGENATION FORMULA V

S) 2-chloro-4-/2,4-dichlorophenyl/-5-methoxazole

i-2-hydro is propiophenone in anhydrous methanol, in an inert atmosphere, then at 0aboutTo enter 12.4 g of KOH in 60 ml of methanol. The reaction medium is left under stirring for 16 h at room temperature, then the solvent is evaporated under reduced pressure. The residue is extracted by 100 ml of water and 150 ml of methylene chloride; the organic phase is then separated, washed with water and the solvent evaporated. Poured to the residue 100 ml of 5% aqueous solution of sulfuric acid (about./about), then after 20 min add 100 ml of dichloromethane. The organic phase is separated and the solvent is removed under reduced pressure. The remainder chromatographies on silica with elution with heptane, and then with a mixture of heptane/ethyl acetate (99/1-about./vol.). Get so 7 g of the product described.

ii-4-/2,4-dichlorophenyl/-5-methyl-2-oxa - salinan.

In an inert atmosphere is injected at a temperature of about -50aboutC in a solution containing 6 g of hydroxyketone received in accordance with /i/, and 8.2 ml of dimethylaniline in 80 ml of anhydrous toluene, a solution of 3.6 ml of trichloromethylcarbonate in 20 ml of anhydrous toluene. After stirring for 1 h at this temperature, allow the reaction medium to return to ambient temperature and maintain it at this temperature is t with stirring for 2 h before removal of sediment. The organic phase is washed with water, dried and concentrated under reduced pressure to a volume of about 20 ml. Formed precipitate is highlighted, and then purified by chromatography on silica with elution with a mixture of isopropyl ether and heptane (8/2 v/v). Allocate thus 3.1 g of the desired product, which melts at 170aboutC.

iii-2-chloro-4-/2,4-dichlorophenyl/-5-METI - oxazol.

Dissolve 3 g of oxazolinone obtained in (ii), in 15 ml of phosphorus oxychloride. At 0aboutWith introducing the solution of 1.75 ml of triethylamine, the mixture is then aged for 6 hours at a temperature of her phlegmy. Then the volatile products are distilled under reduced pressure, and the residue is neutralized by adding a saturated aqueous solution of sodium bicarbonate at a temperature of about 10aboutC. the Aqueous phase is extracted 3 times with 80 ml of ethyl acetate; the combined organic phases are concentrated, resulting in a gain of 2.8 g of the expected product which melts at 78aboutC.

The same methods receive a 4-in/4-were/-5-methyloxazolidine-2, which melts at 169aboutWith, and 2-chloro-4-/4-were/-5-methoxazole, which melts at least at the 50aboutC.

5-HARTIG inert atmosphere slowly adjusted to the 100aboutWith 5 g of 2,4,6-trimethylbenzoyl and $ 2.68 g of sodium amide in 80 ml of toluene, then allow the mixture to return to room temperature and left at this temperature for about 16 hours Then injected into the reaction medium was cooled to a temperature of about 10aboutWith 10 ml ethanol, then 100 ml of water and 200 ml of ejaculate.

The organic phase is separated, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on silica with elution with methylene chloride, and then 25% (mol.about.) aqueous solution of NH4OH in a mixture with methanol (2/8.vol.). Get thus 2 g of amidine, melting at 178aboutC.

ii-5-chloro-3-/2,4,6-trimetilfenil/-1,2,4-thiadiazole.

In an inert atmosphere at a temperature of about -20aboutC in a solution containing 2 g of 2,4,6-trimethylbenzene in 16 ml of dichloromethane, enter 2.2 g of trichlorocarbanilide, then slowly at a temperature of about -10aboutWith type 2 g of NaOH dissolved in 3.2 ml of water. After one hour of incubation at a temperature of about -5aboutWith the formed precipitate is isolated, and the organic phase is separated and washed with 6 ml of water. After drying TO2CO3she concentrated under reduced pressure, resulting in="ptx2">

5-CHLOROXYLENOL WITH THE FORMULA V

U) 5-chloro-3-/2,4-dimetilfenil/-1,2,4-oxadiazol

i-2,4-dimethylbenzamide.

Incubated for 16 hours at a temperature of phlegmy 25 g of 2,4-dimethylbenzonitrile, 14.6 g of hydroxylamine hydrochloride, 29 g of potassium carbonate in 150 ml of ethanol and 35 ml of water. Then added to 7.3 g of hydroxylamine hydrochloride, then 14.5 g of potassium carbonate and continue irrigation phlegm during the 5 o'clock

Then, the reaction medium is concentrated to 70 ml in the evaporation under reduced pressure, and thereto was added 100 ml of water and 100 ml of methylene chloride. The organic phase is separated, and the aqueous phase is extracted 2 times with 100 ml of methylene chloride. The solvent is removed from 3 the combined organic solutions as a result of distillation under reduced pressure, then the residue is purified by chromatography on a column of silica with elution with a mixture of cyclohexane and ethyl acetate (95/5 by vol./about. then about 50/50./vol.). Isolate thus 17 g of solid, which after recrystallization in ethyl acetate melts at 150aboutC.

ii-3-/2,4-dimetilfenil/1,2,4-oxadi-Zolin-5-he.

In an inert atmosphere dissolved in 10.5 g of 2,4-dimethylbenzamide in 40 ml of anhydrous toluene; arr of phlegmy for 5 h, then at room temperature precipitate formed is isolated, then again dissolved in a mixture of 100 ml of water and 100 ml of ethyl acetate; after stirring and decanting, the organic phase is separated and concentrated under reduced pressure. Isolate thus 7.6 g of the expected product which melts at 170aboutC.

iii-5-chloro-3-/2,4-dimetilfenil/-1,2,4-oxadiazol.

At a temperature of about 100aboutWith incubated for 24 h 2 g of the product obtained in accordance with (ii), with 0.5 ml of pyridine, 0.5 ml of dimethylformamide and 15 ml of phosphorus oxychloride. The reaction medium after cooling prilisaetsa to 50 g of ice, and the formed aqueous phase is extracted 3 times with 50 ml of ethyl ether. The organic phases are combined, washed with water, dried and concentrated under reduced pressure. The residue is dissolved in a mixture of heptane-ethyl acetate (90/10-about./vol.), filtered on silica. After evaporation of the solvent isolate 1.3 g of the expected compound, which melts at 54aboutC.

In the following description describes embodiments of the invention; NMR spectra were recorded at 250 MHz except in opposite directions; chemical shifts are expressed in PP relative. -/2-(1-pyrrolidinyl)-ethyl-N-/1-(3-pyridyl)-ethyl/-2-amino-4-/2,4,6-trimethyl Anil

(Formula I: A= S; B=C; Ar1=2,4,6-/CH3/3-C6H2; R3=H; Ar2=3-pyridyl; Z1= /CH2/2; Z2=CH-CH3; W=1-pyrrolidinyl).

In an inert atmosphere at a temperature of approximately 70aboutWith stand 2.4 g N-/2-(1-pyrrolidinyl)-ethyl/-N-/1-(3-pyridyl)-ethyl/-thiourea, 2,04 g 1/2,4,6-trimetilfenil/-2-brometea and 0.3 ml to about 12 n aqueous Hcl in 60 ml of ethanol. Then, the reaction medium is concentrated by distillation under reduced pressure and to the residue is poured 50 ml of 1 n aqueous Hcl. After washing the aqueous phase twice with 20 ml of methylene chloride was added 4 N. aqueous solution of NaOH to pH 8. Then extracted with 3 times 50 ml of methylene chloride and, after drying, concentrated organic phase.

The residual liquid oil (3.7 g) is purified by chromatography on a column of silica with an average pressure in the elution with a mixture of ethyl acetate and methanol (50/50, then about 30/70./vol.). Get so 3,05 g of the desired product in the form of liquid oil.

NMR1N /DMSO-D6/Amin: =8,58 /m 1H/; 8,49 /m 1H/; to 7.77 /m 1H/; 7,38 /m 1H/; 6,86 /C, 2N/; 6,51 /C, 1H/; 5,40 /q, 1H/; 3,42 /m, 2N/; 2,65 /m 1H/; 2,37 /m, 5H/; 2,23 /C, 3N/; 2,03 g of liquid oil in 2 ml of anhydrous methanol, 11 ml of 2 n Hcl solution in CH3SOOS2H5. Salt is isolated after removal of the solvents under reduced pressure. After drying at 50aboutC and a pressure of 0.1 PA isolate 3.57 g monohydronitrogena of trichlorohydrin.

TPL=155aboutC.

P R I m m e R 2. N-/N,N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/2,4, 6-triisopropylphenyl/-thiazole.

(Formula I: A=S; B=C; Ar1=2,4,6-/CH(CH3)2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/2).

In an inert atmosphere at a temperature of phlegmy incubated for about 20 hours of 9.8 g of 1-/2,4,6-triisopropylphenyl/-2-brometea, 5 g N-/3-pyridylmethyl/-N-/N', N'-dimethyl-2-amino-ethyl/-thiourea in 100 ml of anhydrous ethanol. Then distilled volatile products under reduced pressure and poured to the residue 100 ml of 2 n aqueous NaOH solution; the aqueous phase is extracted 3 times with 100 ml of methylene chloride and the organic phase after washing with water and drying concentrated under reduced pressure. The residual liquid oil is dissolved in about 50 ml of a mixture of methylene chloride/methanol (9/1-about./about.) and filtered on silica. The filtrate is brought to dryness and the residue dissolved in 30 ml of acetone, schaut thus dioxalate final product.

TPL=156-158aboutC.

AMINOPHENYL exempt under the action of NaOH in aqueous solution of dioxalate. The product crystallized in petroleum ether.

TPL=84aboutC.

NMR1N /DMSO-D6/ Amin: =8,55 /c, 1H/; of 8.47 /m 1H/; 7,7 /m 1H/; 7,33 /m 1H/; 7,00 /C, 2N/; 6,51 /C, 1H/; 4,74 /C, 2N/; 3,54 /m, 2N/; 2,87 /m 1H/; 2,71 /m, 2N/; 2,48 /m, 2N/; 2,15 /s, 6N/; 1,22 /d 6N/; 1,06 /d, N/.

You can get monopolar under the action of 1.2 equivalents of fumaric acid in 10% of /p/v/ solution of the base in isopropanol.

TPL=195aboutC.

Nanomeasurement, which crystallizes with 2 molecules of water can be obtained in a mixture of ethyl ether and isopropanol (10/1 v/v).

TPL=180aboutC.

Trimulean obtained in a mixture of ethyl ether/acetone (2/7 about./vol.), melts at 115aboutC.

Trichlorohydrin, which crystallizes with 3 molecules of water can be obtained in ethyl ether.

TPL=140aboutC.

Connection with formula I, where A=S, B=S, from examples 3 through 63, which appear in the table. 4 were obtained using one of the previous methods. Characteristics of the NMR spectra of these compounds appear in the table. 6.

P R I m e R 64. N-/2-pipn3/3-C6H2; R3=H; Ar2=3-pyridyl; Z1= /CH2/2; Z2=CH2; W=piperidino).

At the 50aboutWith incubated for 48 h 2.3 g 1-/2,4,6-trimetilfenil/-2-theorientation and 2.1 g of N-piperidino-N'-/3-pyridylmethyl/-academia in 40 ml of anhydrous toluene. At room temperature, extracted by 50 ml of 1 n aqueous Hcl organic phase; after washing 2 times with 20 ml of methylene chloride aqueous phase of the latter is brought to a pH of about 8 by addition of 10 n aqueous NaOH solution, then extracted 3 times with 30 ml of methylene chloride. The organic phases are concentrated after drying and the residual liquid oil is purified by chromatography on a column of silica with elution with ethyl ether, and then with a mixture of methylene chloride/methanol (96/4, v/v).

The final product is a liquid oil, of which the oxalate under the action of 0.65 g digidratirovannogo oxalic acid 1.08 g of oil in 35 ml of acetone. Isolate thus monoidratado salt, which contains 2 molecules of acid to one molecule of the product with the formula 1 and which melts at 100aboutC.

NMR1N/DMSO-D6/ Sol: =8,53 /m, 2N/; 7,75 /m 1H/; 7,40 /m 1H/; 6,68 /C, 2N/; 6,63 /C, 1H/; 4,73 /m 2 is of IMT-N'-methyl-2-amino-ethyl/-N-/3-pyrid - ylmethyl/ -2-amino-4-/2,4,6-triisopropylphenyl/-thiazole.

(Formula I: A= S; B=S; Ar1=2,4,6-CH(CH3)2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/COOC/CH3/2).

If 65aboutWith stand within 72 h of 4.2 g of N-/t/butyloxycarbonyl-N-methyl/-N-/3-pyridylmethyl/-academia and 4.8 g of 1-/2,4,6-triisopropyl/phenyl-2-thiocyanato - Tanana in 50 ml of toluene. Then remove the solvent under reduced pressure and purify the residual liquid oil by chromatography on a column of silica with elution first with a mixture of ethyl ether and methylene chloride (50/50 v/v) and then with methylene chloride. Isolate thus a 4.53 g of the expected product in the form of liquid oil.

NMR1N/Cl3/ Amin: =8,59 /m, 2N/; 7,66 /m 1H/; 7,25 /m 1H/; 7,03 /C, 2N/; 6,27 /C, 1H/; 4,77 /c, 2N/; 3,50 /m, 4H/; 2,87 /C, 3N/; 2,9-2,74 /m, 3H/; 1.44MB /s, N/; 1,26 /d 6N/; 1,14 /d, N/.

P R I m e R 66. N-/N'-methyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/2,4,6-triisopropylphenyl Il/-thiazole.

(Formula I: A=S; B=C; Ar1=2,4,6-/CH(CH3)2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=NHCH3).

In an inert atmosphere dissolved 1.9 g of the previous compound in 20 ml of anhydrous ethylacetamide and after stirring for 2 h, cooled at a temperature of about 5aboutC before the addition of 5 n aqueous solution Paon to alkaline pH values. Then the organic phase is decanted, dried and concentrated at a temperature of approximately 70aboutC and reduced pressure. The residual liquid oil is dissolved in 60 ml of isopropanol and discolored by using 50 mg of activated charcoal, then add 50 ml of 0.5 M solution digidratirovannogo of oxalic acid in isopropanol; precipitated salt is isolated by filtration. Get so 1.5 g of oxalate containing two molecules palpitations oxalic acid.

Tpl.=130aboutC.

NMR1N /DMSO-D6/ Sol: =8,53 /m, 2N/; 7,72 /m 1H/; 7,39 /m 1H/; 7,02 /C, 2N/; 6,63 /C, 1H/; 4,75 /m, 2N/; 3,75 /t, 2N/; 3,22 /t, 2N/; 2,86 /C, 1H/; 2,71 /C, 2N/; 2,58 /C, 3N/; 1,21 /d 6N/; 1,08 /d, N/.

P R I m e R 67. N-/(N'-tert-butyloxycarbonyl)-2-amino-ethyl-N-/3-pyridylmethyl/-2-amino-4- /2,4,6-triisopropylphenyl/-thiazole.

(Formula I: A=S; B=S; Ar1=2,4,6-/CH(CH3)2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=NHCOOC/CH3/3).

This product is produced using the method of example 65 based on N-/tert-butyloxycarbonyl/-N-/3-pyridylmethyl/-ethane - diamine.

TPL /m, 2N/; 3,20 /m, 2N/; 2,86 /m 1H/; 2,70 /m, 2N/; 1,37 /s, N/; 1,21 /d 6N/; 1,05 /d, N/.

P R I m e R 68. N-/2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/2,4,6-isopropyl - phenyl/thiazole.

(Formula I: A= S; B=C; Ar1=2,4,6-CH(CH3)2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=NH2).

Connection have been derived from the compound from example 67 using the methods described in example 66.

Palpitations dioxalate melts at 187aboutC.

NMR1N /DMSO-D6/ Sol: =8,53 /m, 2N/; 8,2 /C, 2N/; 7,74 /m 1H/; 7,38 /m 1H/; 7,02 /C, 2N/; 6,62 /C, 1H/; 4,74 /C, 2N/; 3,71 /m, 2N/; 3,10 /m, 2N/; 2,89 /m 1H/; 2,71 /m, 2N/; 1,21 /d 6N/; 1,08 /d, N/.

Connection with formula I of examples 69-77, described in table. 5 where A=S and B=C, were obtained using the methods of examples 64-66; the NMR spectra of these compounds appear in the table. 6.

P R I m e R 78. N/2(N-methyl-N'-phenylamino)-ethyl/-N-/3-pyridylmethyl/-2-amino-4- /2,4,6-trimetilfenil/-thiazole.

(Formula I: A= S, B=S; Ar1=2,4,6-/CH3/3-C6H2; R3=H; Ar2=3-pyridyl; Z1= /CH2/2; Z2=CH2; W=NCH3C6H5).

At a temperature of about 60aboutWith inert the hydrate of 2-bromo-4-/2,4,6-trimetilfenil/ -thiazole in 50 ml of toluene. Then concentrate under reduced pressure and poured into 20 ml of 1 n aqueous solution Paon before extraction 3 times with 20 ml of methylene chloride. The organic phase, washed and dried, concentrated under reduced pressure and the residual liquid oil is purified by chromatography on a column of silica with elution with a mixture of methylene chloride and methanol (99/1 v/v). Isolate thus, 1.1 g of the final product in the form of liquid oil.

Trichloride, obtained by the action of Hcl in ethyl ether, crystallizes with 1.5 molecules of water; it melts at 160aboutC.

NMR1N /DMSO-D6/ Sol: =8,84 /m, 2N/; 8,45 /m 1H/; 7,97 /m 1H/; 7,15 /m, 2N/; 6,85 /m, 5H/; 6,7 /C, 1H/; 4,92 /C, 2N/; 3.75 per m, 4H/; 2,92 /C, 3N/; 2,22 /C, 3N/; 1,98 /s, 6N/.

P R I m e R 79. N/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/2,4 - dichlorophenyl/-5-methoxazole.

(Formula I: A= O;= S; Ar1=2,4-/Cl/2-C6H3; R3=H; Ar2=3-pyridyl; Z1= /CH2/2; Z2=CH2; W=N/CH3/2).

A solution containing 0.7 g of 2-chloro-4-/2,4-dichlorophenyl/-5-methoxazole and 1.4 g N/dimethyl-2-amino-ethyl/-N-/3-pyridyl - ethyl/-amine in 40 ml of anhydrous toluene, is aged for 80 hours at a temperature of about 95aboutWith in a trade is a saturated solution of sodium bicarbonate to alkaline pH values for the release of Amina. Then concentrate under reduced pressure and the residue is purified by chromatography on a column of silica with elution successively with ethyl ether, methylene chloride and a mixture of methylene chloride/methanol (98/2 c/c).

Isolate thus 0.45 g of the expected product in the form of liquid oil.

His tribological (1,5/COOH/2), obtained by the action of hydrated oxalic acid in isopropanol, crystallizes with 3 H2O.

TPL=130aboutC.

NMR1N /DMSO-D6/ Sol: =8,60 /C, 1H/; 8,53 /m 1H/; 7,78 /m, 2N/; 7,44 /m, 3H/; with 4.64 /C, 2N/; 3,7 /t, 2N/; 3,36 /t, 2N/; 2,82 /s, 6N/; 2,2 /C, 3N/.

P R I m e R 80. N/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-4-/4-were/ -5-methoxazole.

(Formula I: A= 0; B= C; Ar1=4-/CH3/-C6H4; R3=CH3; Ar2=3-pyridyl; Z1= /CH2/2; Z2=CH2; W=N/CH3/2).

This compound was obtained by using the method of example 79.

Dioxalate (2/COOH/2), crystallized from 1.5 H2Oh, melts at 180-190aboutC.

NMR1N /DMSO-D6/ base: =8,55 /m, 2N/;7,70 /m 1H/; 7,45 /m, 3H/; 7,22 /m, 2N/; 4,66 /C, 2N/; 3,76 /m, 2N/; 3,38 /m, 2N/; 2,86 /s, 6N/; 2,43 /C, 3N/; 2,32 /C, 3N/.

(Formula I: A= O; B=C; Ar1=2,4-/Cl/2-C6H3; R3=CH3; Ar2=3-pyridyl; Z1= /CH2/2; Z2=CH2;

W-N

This compound was obtained by using the method of example 79.

Oxalate crystallized from 4 H2Oh, melts at 145aboutC.

NMR1N /DMSO-D6/ Sol: =8,5 /m, 2N/; 7,8 /m, 2N/; 7,4 /m, 3H/; 4,6 /C, 2N/; 4,3 /m, 8H/; 2,2 /C, 3N/; 1,9 /m, 4H/.

P R I m e R 82. N/N',N'-dimethyl-2-amino-ethyl/-N-/2-(3-pyridyl)-ethyl/-5-amino-3-/2,4,6 - trimetilfenil/-1,2,4-thiadiazole.

(Formula I: A=S; B=N; Ar1=2,4,6-/CH3/3-C6H2; R3absent; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/2).

In an inert atmosphere at a temperature of approximately 55aboutC for 7 h stand 0.45 g of 5-chloro-3-/2,4,6-trimetilfenil/-1,2,4-telazol and 1.2 g of N,N-dimethyl-N'-/2-(3-pyridyl)-ethyl/-academia dissolved in 10 ml of ethanol, then at room temperature was added 0.5 ml of 1 n aqueous NaOH solution and 2 g of silica. Concentrate to dryness and the residue chromatographic on a column of silica with elution consistently pure dichloromethane and then a mixture of methanol (98/2 v/v). Get thus 0.52 g of the desired prolvide at 131aboutC.

NMR1N /DMSO-D6/ Sol: =8,45 /m, 2N/; 7,7 /m 1H/; 7,3 /m 1H/; 6,9 /C, 2N/; 3,9 /m, 2N/; 3,6 /m, 2N/; 3,3 /m, 2N/; 3 /m, 2N/; 2,8 /6H/; 2,27 /C, 3N/; 2,09 /m, 6N/.

Compounds of examples 83-86 were obtained by use of the method according to example 82.

P R I m e R 83. N/N',N'-dimethyl-2-amino-ethyl/-4-N-/3-pyridylmethyl/-5-amino-3-/2,4,6 - trimetilfenil/-1,2,6-thiadiazole.

(Formula I: A=S; B=N; Ar1=2,4,6-/CH3/3-C6H2; R3absent; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/2).

Salt with 1.5 molecules of oxalic acid, crystallized with 0.5 molecules of water and 0.5 molecules of acetone, melts at a temperature of about 145aboutC.

P R I m e R 84. N/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-5-amino-3 - phenyl-1,2,4 - thiadiazole.

(Formula I: A= S; B= N; Ar1=C6H3; R3absent; Ar2= 3-pyridyl; Z1= /CH2/2; Z2=CH2; W=N/CH3/2).

Dioxalate this compound melts at 173aboutC.

P R I m e R 85. N/methoxyethyl/-N-/3-pyridylmethyl/-5-amino-3-/2,4,6-timelife - Nile/-1,2,4 - thiadiazole.

(Formula I: A=S; B=N; Ar1=2,4,6-/CH3/3-C6H2; R3Usatovo connection crystallized from 1.5 H2Oh, melts at 145aboutC.

P R I m e R 86. N/N',N'-dimethyl-2-amino-ethyl/-N-/3/pyridylmethyl/-5-amino-3-/2,4 - dimetilfenil/-1,2,4-oxadiazol.

(Formula I: A=O;=N; Ar1=2,4-/CH3/2-C6H3; R3absent; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/2).

In an inert atmosphere at room temperature and incubated with stirring for 16 h with 0.5 g of 5-chloro-3-/2,4-dimetilfenil/-1,2,4-oxadiazole and 1.3 g of N,N-dimethyl-N'-/3-pyridylmethyl/-atandi - amine in 20 ml of anhydrous toluene. Remove the precipitate by filtration and added to the filtrate 10 ml of 5% (p/v) ammonia solution; the organic phase is separated and restrained 2 times with 15 ml of ethyl acetate. The combined organic phases are concentrated under reduced pressure and the residue is purified by chromatography on a column of silica with elution with a mixture of methylene chloride and methanol (98/2 v/v). Get so 0.6 g of the expected product in the form of liquid oil.

His dioxalate obtained in acetone, melts at 166aboutC.

NMR1N /DMSO-D6/ Sol: =8,62 /m 1H/; 8,53 /m 1H/; 7,7 /m, 2N/; 7,4 /m 1H/; 7,16 /m, 2N/; 4,77 /C, 2N/; 3,9 /t, 2N/; 2,82 /s, 6N/; 2,47 /C, 3N/; 2,31 /sedesol.

(Formula I: A=O; B=N; Ar1=2,4-/CH3/2-C6H3; R3is missing).

The compound obtained using the methods described in example 86.

Salt of oxalic acid, which contains 2.5 molecules of oxalic acid, melts at 148aboutC.

NMR1N /DMSO-D6/ Sol: =8,57 /l, 1H/; 7,88 /t, 1H/; 7,71 /l, 1H/; 7,49 /l, 1H/; 7,4 /m 1H/; 7,14 /m, 2N/; 4,84 /C, 2N/; 4,0 /t, 2N/; 3,48 /t, 2N/; 2,9 /s, 6N/; 2,42 /C, 3N/; 2,3 /s, 3N/.

P R I m e R 88. N/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-5-amino - 3-phenyl-1,2,4-oxadiazol.

(Formula I: A= O; B= N; Ar1=C6H5; R3absent; Ar2=3-pyridyl; Z1= /CH2/2; Z2=CH2; W=N/CH3/2).

i-N/N',N'-dimethyl-2-amino-ethyl/-5-amino-3-phenyl-1,2,4-oxadiazol.

When 35aboutWith stand for about 65 hours a mixture consisting of 1.5 g of 5-trichloromethyl-3-phenyl-1,2,4-oxadiazole, obtained as described in Helv. Chem. Acta, , 1067-1073 (1963), and 2.2 g of N,N-dimethylethanamine. The excess amine is removed by distillation under reduced pressure and poured to the residue 10 ml of saturated aqueous sodium bicarbonate solution; the aqueous phase is extracted 3 times with 10 ml ethyl acetate and the combined organic phases are concentrated to dryness is the asle. ii-N/N', N'-dimethyl-2-amino-ethyl/-N-/3-pyridyl-methyl/-5-amino-3-phenyl - 1,2,4-oxadiazol.

Stand under stirring for 16 h the mixture consisting of 1 g of the product obtained in /i/, 0,78 g of 3-chloromethylpyridine, 25 ml of methylene chloride and 20 ml of 50% (p/v) aqueous solution of NaOH.

Then the organic phase is separated and the aqueous phase restrained one volume of methylene chloride. The combined organic phases are washed with water, dried and concentrated. The remainder chromatographies on silica with elution successively with ethyl ether, methylene chloride and a mixture of methylene chloride/methanol (97/3 v/v). Get so 0.8 g of the desired product.

Dioxalate (2/COOH/2) obtained in acetone and crystallized with 0.5 N2Oh, melts at 125aboutC.

NMR1N /DMSO-D6/ Sol: =8,65 /C, 1H/; 8,56 /m 1H/; 7,9 /m, 3H/; 7,5 /m, 4H/; 4,80 /C, 2N/; 3,93 /C, 2N/; 3,42 /t, 2N/; 2,86 /s, 6N/.

P R I m e R 89. N-oxide of the compound of example 2.

(Formula I: A=S; B=C; Ar1=2,4,6-/CH(CH3)2/-2,4,6-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/O//CH3/2).

Enter 0.5 g of the compound from example 2 in 5 ml of a solution containing 0.56 g of 2-/phenylsulfonyl h at room temperature in an inert atmosphere to concentrate the reaction medium under reduced pressure and chromatographic the residue on a column of silica with elution successively with a mixture of methylene chloride/methanol (95/5, then 90/10 v/v) and methylene chloride/methanol/ NH4OH 25% (p/v) aqueous solution at a ratio of (80/15/5 v/v/v).

Get so 0.35 g of N-oxide crystallized with 2 molecules of water, which melts at 115aboutC.

NMR1N /DMSO-D6/ base: =8,56 /l, 1H/; 8,55 /m 1H/; 7,73 /m 1H/; 7,35 /m 1H/; 7,01 /C, 2N/; 6,59 /C, 1H/; 4,79 /C, 2N/; 3,97 /m, 2N/; 3,47 /m, 2N/; 3,05 /6H/; 2,87 /m 1H/; 2,7 /m, 2N/; 1,21 /d 6N/; 1,07 /d, N/.

P R I m e R 90. N/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-5 - bromo-4-/2,4,6 - triisopropylphenyl/-thiazole.

(Formula I: A=S; B=C; Ar1=2,4,6-/CH(CH3)2/3-C6H2; R3=Br; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/2).

Dissolve 2.3 g of the compound from example 2 in 100 ml of 0.05 M aqueous solution of Hydrobromic acid, injected slowly 0.8 g of bromine and bring the mixture to form phlegmy for 30 min before concentrating to dryness under reduced pressure. The residue is dissolved in a mixture of methylene chloride/methanol (95/5 v/v), filtered on silica, and then concentrated.

The residual solid is precipitated in ethanol by adding ethyl ether.

Get so 1.2 g monohydronitrogena dibr is SUP>N /DMSO-D6/ Sol: =8,84 /m, 2N/; 8,30 /m 1H/; 7,94 /m 1H/; 7,05 /C, 2N/; 4,91 /C, 2N/; 3,94 /t, 2N/; 3,47 /t, 2N/; 2,86 /s, 6N/; 2,52 /m, 3H/; 1,24 /d 6N/; 1,13 /d 6N/; 1,01 /d 6N/.

P R I m e R 91. N/N',N'-dimethyl-2-amino-ethyl/-N-/3-pyridylmethyl/-2-amino-5 - chloro-4- /2,4,6-triisopropylphenyl/-thiazole.

(Formula I: A=S; B=C; Ar1=2,4,6-/CH(CH3)2/3-C6H2; R3=Cl; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/2).

Dissolve 2.3 g of the compound from example 2 in a mixture consisting of 80 ml of water and 10 ml of 1 n aqueous HCl solution and injected into a solution of 0.36 g of gaseous chlorine. After keeping overnight at room temperature, concentrated to dryness and poured to the residue in about 20 ml of ice-cold 2 n aqueous solution of NaOH to explicitly alkaline pH values. The aqueous phase is extracted with methylene chloride; the organic phase after washing and drying the concentrated and the residue is purified by chromatography on silica with elution with a mixture of methylene chloride and methanol (98/2.vol.).

Dioxalate obtained in acetone, melts at 178aboutC.

NMR1N /DMSO-D6/ Sol: =8,54 /m, 2N/; 7,70 /m 1H/; 7,40 /m 1H/; 7,06 /C, 2N/; 4,71 /C, 2N/; 3,82 /t, 2N/; 3,30 /t, 2N/; was 2.76 /s, 6N/; 2,61 /m, 3H/; 1,24 /d 6N/; 1,13 /d 6N/; 1,04 /d 6N/.

(Formula I: A=S; In=C; Ar1=4-/COOH/-2,6-/CH3/2-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=N/CH3/2).

Heated for 3 hours at a temperature of phlegmy solution containing 50 ml of methanol and 1.6 g of compound from example 61, with a solution containing a 2.13 g of KOH in 50 ml of water, neutralized reaction medium by adding 2 n aqueous Hcl, then methanol is evaporated under reduced pressure. The aqueous phase is extracted with methylene chloride, resulting in a gain of 1.4 g of the desired compound crystallized with 0.5 N2Oh, which melts at 125aboutC.

NMR1N /DMSO-D6-D2About/ base: =8,53 /m, 2N/; 7,72 /m 1H/; 7,60 /C, 2N/; 7,35 /m 1H/; 6,60 /C, 1H/; 4,72 /C, 2N/; 3,55 /t, 2N/; 2,47 /t, 2N/; 2,15 /s, 6N/; 2,10 /s, 6N/.

P R I m e R 93. N-methyl-N-{N'-(3-pyridylmethyl)-N'-/4-(2,4,6-triisopropylphenyl)-2 - thiazolyl/-2-amino-ethyl}-ndimethylacetamide.

(Formula I: A=S; B=C; Ar1=2,4,6-/CH(CH3)2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=NCH3COCH3).

At a temperature of about 10aboutWith the solution containing 0.35 g of the compound from example 66 and 0.2 ml of triethylamine in 20 ml of dichloromethane, enter 0.06 g acetylcoa phase, from which is extracted with 0.32 g of the expected compound in the form of liquid oil.

Diphosphate obtained in isopropanol crystallized from 1.5 H2Oh, melts at 165aboutC.

NMR1N /DMSO-D6/ base: =8,5 /m, 2N/; 7,7 /m 1H/; 7,4 /m 1H/; 7 /C, 2N/; 6,55 /m 1H/; 4,73 /C, 2N/; 3,55 /m, 4H/; 3-2,65 /m, 6N/; 1,90 /C, 3N/; 1,22 /d 6N/; 1,05 /d, N/.

P R I m e R 94. N-methyl-N-{N'-/3-pyridylmethyl/-N-/4-(2,4,6-triisopropylphenyl)-2-thiazolyl /-2-amino-ethyl}-methanesulfonamide.

(Formula I: A=S; B=C; Ar1=2,4,6-/SN(CH3/2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=NCH3SO2CH3).

The compound obtained using the method according to example 93 with methanesulfonamide instead of acetylchloride.

This compound crystallized with 1/3 water molecules, melts at 120aboutC.

NMR1N /DMSO-D6/ base: =8,55 /m, 2N/; 7,72 /m 1H/; 7,30 /m 1H/; 7,02 /C, 2N/; 6,28 /C, 1H/; 4,78 /C, 2N/; 3,69 /t, 2N/; 3,40 /t, 2N/; 2,86 /C, 3N/; 2,80 /m, 3H/; was 2.76 /C, 3N/; 1,26 /d 6N/; 1,14 /d, N/.

P R I m e R 95. N-methyl-N'-methyl-N'-{N ' -/3-pyridylmethyl/-N-/4-(2,4,6-carisopro - pilfer)-2-thiazolyl/-2-amino-ethyl}-calm surroundings - Icewine.

(Formula I: A=S; B=C; Ar1=2,4,6-/CH(CH3)2/3-CSUB>).

Enter 0.08 g methylisothiocyanate in 5 ml of a solution containing 0.5 g of the compound from example 66 in dichloromethane. After stirring for 1 h at room temperature, concentrated to dryness and add to the residue 10 ml of isopropyl ether. The precipitate is isolated and precrystallization in ethyl acetate, resulting in a gain of 0.26 g of the desired compound, which melts at 160aboutC.

NMR1N/l3/ base: = 8,63 /m, 2N/; of 7.90 /C, 1H/; 7,70 /m 1H/; 7,38 /m 1H/;? 7.04 baby mortality /C, 2N/; 6,35 /C, 1H/; br4.61 /C, 2N/; 3,55 /s, 4H/; 3,26 /s, 34/; 2,90 /m 1H/; 2,70 /m, 2N/; 2,07 /C, 3N/; 1,22 /d 6N/; 1,11 /d, N/.

P R I m e R 96. N-methyl-N'-methyl-N'-{N ' -/3-pyridylmethyl/-N-/4-(2,4,6-carisopro - pilfer)- 2-thiazolyl/-2-amino-ethyl}-urea.

(Formula I: A=S; B=C; Ar1=2,4,6-/SN(CH3)2/3-C6H2; R3=H; Ar2=3-pyridyl; Z1=/CH2/2; Z2=CH2; W=NCH3CONHCH3).

This compound is obtained using the method in example 95, replacing methylisothiocyanate to methyl isocyanate. It melts at 138aboutC.

NMR1N /DMSO-D6/ base: =8,51 /m, 2N/; 7,69 /m 1H/; 7,35 /m 1H/; 7,02 /C, 2N/; 6,58 /C, 1H/; 6,48 /l, 1H/; 4,71 /C, 2N/; 3,55 /m, 2N/; 3,3 H /m, 2N/; 2,72 /m, 3H/, 2,69 /C, 3N/; 2,15 /d, 3H/; 1,18 /d, 6N/; 1,05 /d, N/.

Bring to education phlegmy for 4 h in a solution containing 0.8 g of the compound from example 55 a mixture of 5 ml ethanol and 2 ml of 12 n aqueous solution chloroethanol acid. Then remove the solvent was transferred to an alkaline environment in the result of the addition of ice-cold 2 n aqueous NaOH solution and extracted with ethyl acetate. Liquid oil obtained upon evaporation of the organic solvent, soluble in acetone, from which precipitated triaxolam of the desired product by adding a solution containing 0.3 g of oxalic acid (dihydrate). Get specified 0.6 g of product which melts at 157aboutC.

NMR1N /DMSO-D6/ Sol: =8,55 /m, 2N/; 7,73 /m 1H/; 7,41 /m 1H/; 6,51 /C, 1H/; 6,29 /C, 2N/; 4,72 /C, 2N/; 3,86 /t, 2N/; 3,3 /t, 2N/; 2,81 /s, 6N/; 1,96 /s, 6N/.

1. Heterocyclic derivatives of General formula

< / BR>
where As oxygen or sulphur;

B carbon or nitrogen;

Z1WITH1WITH4-alkylene or phenylene;

Z2WITH1WITH4-alkylen;

W group NR1R2where R1hydrogen or C1- C4 and Q2independently from each other, hydrogen or C1WITH4-alkyl; SO2Q3or COQ3where Q3WITH1-C4-alkyl, Q4where Q4< / BR>
WITH1-C4-alkyl; or R1and R2taken together with the nitrogen atom, form a saturated a heterocycle of the research, pyrrolidine, piperidine or 4-(C1WITH3)alkylpiperazine, or W N-oxide amines NR1R2where R1and R2- C1-C4-alkyl, or W1-C4-alkoxy or C1-C4-Tolkacheva, group Q5where Q5- C1-C5-alkyl, or W group NQ1Q2, pyridyl or imidazolyl;

R3absent when B is nitrogen, or represents hydrogen, C1-C8-alkyl or halogen;

Ar1phenyl which may be substituted by one or more groups selected from chlorine, WITH1-C4-alkyl, C1- C4-alkoxy, hydroxy-group, carboxypropyl, Q6where Q6- C1-C4-alkyl; carboxamido, ceanography, amino, acetaminop, nitro, trifloromethyl, or Ar1thienyl, indolyl, naphthyl, benzyl or cyclohexyl, or Ar1and R3taken together form a group

l or pyridyl, which may be substituted WITH1WITH3-alkyl or chlorine,

or salts of these derivatives with acids or bases.

2. Derivatives under item 1, where B is carbon, or their salts with acids or bases.

3. Derivatives under item 1, where B is carbon, A sulfur, or their salts with acids or bases.

4. Derivatives under item 1, where B is carbon, A is sulfur, Ar1phenyl substituted in anthopology, or their salts with acids or bases.

5. Derivatives under item 1, where B is carbon, A is sulfur, Ar1phenyl, R3WITH1-C3-alkyl, or their salts with acids or bases.

6. Derivatives PP. 1 to 5, where W1-C2-alkoxy - or dialkoxy, or their salts.

7. Derivatives PP. 1 to 5, where W is an amino group, or their salts.

8. Derivatives PP. 1 to 5, where Z1WITH2-C3-alkylen, or their salts.

9. Derivatives under item 1, selected among N-(N,N-dimethyl-2-amino-ethyl) -N-(3-pyridylmethyl)-2-amino-4-(2, 4, 6-triisopropylphenyl)-thiazole, N-(N,N-dimethyl-2-amino-ethyl)- N-(3-pyridylmethyl)-2-amino-4-(2, 4, 6-trimetilfenil)-thiazole, N-(N,N-dimethyl-2-amino-ethyl)- N-(3-pyridylmethyl)-2-amino-4-(2, 4-dichlorophenyl)-5-methylthiazole, N-(N,N-dimethyl-2-amino-ethyl)- N-(3-pyridylmethyl)-2-amino-4-(2, 4-N,N-dimethyl-2-amino-ethyl)-N-(3-pyridylmethyl)-2-amino-4-(2, 4, 6-triisopropylphenyl)- 5-bromothiazole

or their salts.

 

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