Derivatives of amides thiazolidinediones acids or their pharmaceutically acceptable salts having anti-allergic and anti-asthmatic activity and ability to reduce platelet activating factor

 

(57) Abstract:

The use of the invention as anti-allergic and protivoastmaticheskih, but also lower platelet activating factor substances. The essence of the invention: derivatives of amides thiazolidinediones acids total f-crystals, where R1or R2is hydrogen or pyridyl, unsubstituted or C1-C4-alkyl substituted; R3is hydrogen, C1-C4-alkyl, C1-C4-alkoxycarbonyl; R4is hydrogen, C1-C4alkyl; A-C2-C7-alkylen or alkylidene; Z - group;; that may have Deputy C1-C4the alkyl has carbon atom of the ring; R5and R6the same or different and each is phenyl which may be substituted with halogen or halo (C1-C4-alkyl, or unsubstituted aromatic 5 - or 6-membered heterocyclic group containing as the heteroatom nitrogen or sulfur; E is a bond or an oxygen atom, or their pharmaceutically acceptable salts. Reagent 1: acid f-crystals , where R1-R3above or its reactive derivative. Reagent 2: Amin f-crystals ZANHR4where the radicals mentioned above. Reaction conditions: with the removal of the protective groups, if necessary, and with the output of thiazolidine, specifically, new derived thiazolidinediones acids of General formula

where R1or R2represents a hydrogen atom or pyridyloxy group, unsubstituted or substituted by at least one alkyl group having from 1 to 4 carbon atoms;

R3represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, or alkoxycarbonyl group having from 2 to 5 carbon atoms;

R4represents a hydrogen atom or alkyl group having from 1 to 4 carbon atoms;

And is alkylenes and alkylidene group having 2 to 7 carbon atoms; and Z

represents a group of the formula

-NN-CH (II) (II)

-N-C-E-CH (III) (III)

-N C=C (IV) (IV)

-N CH-R5(V) (V) or a group of formula (II), (III), (IV) or (V) in which one or more ring atoms is substituted by an alkyl group having from 1 to 4 carbon atoms, and in which

R5and R6are the same or different, and each represents unsubstituted phenyl group, substituted phenyl group, which contains at least one of substituents (a) defined below, or unsubstituted aromatic heterocyclic group which has 5 or 6 ring atoms, of which audy what's groups, having from 1 to 4 carbon atoms;

E represents a direct carbon-carbon single bond or an oxygen atom, or their pharmaceutically acceptable salts, which possess anti-allergic and anti-asthmatic activity and can reduce platelet activating factor.

The number of known compounds having anti-allergic activity, and, in addition, it is known that compounds having a heterocyclic structure alkylamide, possess antiallergic activity [1,2].

PHAT (platelet activating factor) is a value which indicates the degree of activation and aggregated platelets, from which he acquired this name. In recent years, however, it was found that it can serve as a possible crucial mediator in a variety of pathological processes. In addition, this factor has a hypotensive effect and increases vascular permeability; believe that it may play a decisive role in the occurrence of shock (for example, when the shock caused by endotoxin or anaphylactic shock), and to act as a mediator of inflammatory diseases. It was also established that it plays an important role in nephritis, myocardial infarction, steeareas and immune and renal disorders.

For example, it is known that certain derivatives of thiazolidine for example, the Compound (A), the formula of which is given below

has the ability to influence PHAT - being of his antagonist, but its anti-allergic activity is very low [3] . Other compounds described in this U.S. patent are also antagonists VEILS, but their anti-allergic activity is also very small or almost non-existent.

Provides compounds of General formula I, in which is combined a strong anti-allergic and anti-asthmatic activity with strong activity against VEILS, all - in-one connection, the combination of activities, is that we realize that this was not known until the present time. In addition, the compounds of our invention have low toxicity, which makes possible their use for the treatment and prevention of diseases.

The purpose of the present invention is to provide a series of new derivatives of amide thiazolidinediones acid.

In addition, there is a more specific objective of the present invention, which consists in the creation of such compounds, which possess anti-allergic activity is gained can be obtained in various ways, well known in the synthesis of compounds of this type. For example, they can be obtained by the reaction of compounds of formula VI

COOH (in which R1, R2and R3defined above) or a reactive derivative on the basis of this compound with the compound of the formula VII

HN (in which A, Z and R4defined above). If any of the compounds contains a reactive group in one of the substituents Z, R1, R2, R3and R4it can be replaced before the reaction and after the reaction, the protective group can be removed using methods well known in the art. If necessary, the resulting compound of formula (I) can be translated into salt.

Carboxylic acid of the formula (VI) may be used as such or in the form of a reactive carboxylic acid derivative of the formula (VI). Examples of suitable reactive derivatives include: galodamadruga acid such as the acid chloride or bromohydrin; acid azide; active esters with, for example, N-oxybenzoates or N-oxysuccinimide; partial anhydrides of carboxylic acid; and mixed anhydrides with, for example ether mono(C1-C4-alkyl) carboxylic acids lots, such as monofilament or monoelectronic, the preferred mixed anhydride with monoalkylammonium.

The reaction between respectively carboxylic acid of formula (VI) and the amine of formula (VII) may preferably be carried out in the presence or absence of base, in the presence of a condensing means and in an inert solvent.

Any restriction on the nature of the condensing means, which is used in the wording is absent, provided that it can contribute to the formation of amide bond between carboxylic acid and amine, and preferred examples include - dicyclohexylcarbodiimide (DCC), diethylphosphoramidite (DEPC), carbonyldiimidazole, diphenylphosphoryl (DFA) and diethylazodicarboxylate/triphenylphosphine, more preferred dicyclohexylcarbodiimide or diethylphosphoramidite.

Similarly, there are no restrictions on the nature of the used grounds, provided that the Foundation has no harmful effect on the reagents, and preferred examples of such compounds include organic amines such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methyl-morpholine and N,N-dimethylpyridin, more preferred triethylamine astout, provided that it has no harmful effect on the reaction process or reagents, and provided that it can dissolve the reagents, at least to some extent. Examples of such solvents include: aromatic hydrocarbons, such as benzene, toluene, and xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane, and chloroform; esters such as ethyl acetate, propyl; ethers, such as diethyl ether, tetrahydrofuran and dioxane; amides, in particular amides of fatty acids, such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide; and NITRILES, such as acetonitrile. Among them, preferred ethers (particularly tetrahydrofuran), halogenated hydrocarbons (particularly methylene chloride), amides (particularly dimethylformamide) and esters (especially acetate).

The reaction can be carried out in a wide temperature range, and the exact temperature of the reaction is not critical to this invention. The reaction is conveniently carried out in the temperature range from -10aboutto +50aboutS, and more preferably, from 0about30aboutC. Time p is epine - from the reaction temperature and the nature of the reagents. However, if the reaction is carried out in the presence of the preferred conditions outlined above, the reaction can usually be sufficient from 30 minutes to 20 hours

Alternatively, the desired compound of formula (I) can be obtained by transformation of a carboxylic acid of formula (VI) in its reactive derivative, with subsequent interaction of the reactive derivative with the amine of formula (VII).

Reactive derivatives of carboxylic acids, such as galoyanized or acid anhydride can be obtained in the traditional way, for example, in the interaction of carboxylic acids of the formula (VI) with an appropriate active halogen (e.g., thionyl chloride, tierbroker, acid chloride or bromohydrin the desired carboxylic acid with the formation of a mixed anhydride, methylcarbonate, atilglukuronida, isobutylparaben, phenylcarbamates, tolylboronic) at a suitable temperature, for example, 20about100aboutWith over a suitable period of time, for example, from 1 to 20 hours, in an inert solvent (e.g. methylene chloride, benzene or tetrahydrofuran) in the presence of a base (n is the amide compound is an acid or an active ester, they can be obtained by the reaction of carboxylic acids of the formula (VI) with the appropriate connection (e.g., attestation acid, N-oxybenzoates or N-oxysuccinimide); the conditions of the reaction, the same as that used to obtain the amide bond in the interaction of carboxylic acids of the formula (VI) with an amine of formula (VII), which were listed above.

The preferred option when a reactive carboxylic acid derivative of the formula (VI) is reacted with an amine of formula (VII) in an inert solvent. Any restriction on the nature of the solvent in which the reaction is carried out, is missing, except that the solvent should not have a harmful effect on the reaction or used in the reaction reagents, and that he should dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane and chloroform; esters such as ethyl acetate; ethers, such as diethyl ether, tetrahydrofuran, and dioxane; and aromatic hydrocarbons such as menstrual and xylene. Among dissolve the

Alternatively, in some cases, the compound of formula (VII) can be used in large excess, in these cases, this connection can serve also as a solvent.

The reaction can be carried out in a wide temperature range, and the exact value of the reaction temperature is not critical to this invention. In General, we found that the reaction is conveniently carried out at temperatures from -10aboutto +50aboutWith (more preferably from 0aboutup to 25aboutC). The time of reaction may vary within wide limits and depends on many factors, but an appreciable extent on the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out in the preferred conditions outlined above, the time required for the reaction is usually from 5 minutes to 20 hours (more preferably, when the reaction is carried out from 30 min to 10 h).

In addition, if necessary, the compound of formula (I) in which R3represents tert-butoxycarbonyl group, at the beginning should interact with the acid in an inert solvent, to obtain the corresponding compound in which R3represents a hydrogen atom.

What are the real acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, and nitric acid; carboxylic acids such as acetic acid, triperoxonane acid, benzoic acid; and sulfonic acids such as methanesulfonate, benzosulfimide, a pair of toluensulfonate.

Similarly, there are no restrictions on the nature of the used solvent, provided that it has no harmful effect on the reaction process or on the reagents used in the reaction, and that he should dissolve the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol and ethanol; ethers, such as acetonitrile and water. Among these solvents, preferred ethers, and water.

The reaction can be conducted in a wide range of temperatures, and the precise value of the reaction temperature is not critical reaction. It is convenient to conduct the reaction at a temperature of from 0about50aboutWith (preferably at about room temperature). The time required for the reaction may also vary widely and depend on many factors, but an appreciable extent from the temperature reacts above, to flow normally from 1 to 20 hours

The compound obtained in the reactions described above can be isolated from the reaction mixture according to conventional methods. For example, one suitable procedures for selection includes neutralization of the reaction mixture, followed by distillation of the solvent from the neutralized mixture, or simply the distillation of the solvent from the reaction mixture, if necessary; after the reaction mixture was poured into water and then extracted with a water-insoluble organic solvent, the desired compound can then be obtained after removal of the solvent from the extract, usually under reduced pressure. The product thus obtained, if necessary, subjected to further purification by traditional methods, such as recrystallization, pereosazhdeniya or using different chromatog - raficheskih methods, mainly column chromatography or preparative thin-layer chromatography.

The original compound of formula (VI) can be known by itself or it can be easily obtained using known methods (for example, FR 2267089; Japanese Kokai Hei 2-179) or similar methods.

The original connection (VIm. Pharm. Bull. 37, 100, 1989; J. Med., 32, 583, 1989) or similar methods. Alternatively, the compound of formula (VII) in which R4represents an alkyl group containing from 1 to 4 carbon atoms, can be easily obtained by the reaction of the corresponding N - (C1-C4aliphatic acyl) connection [which can be obtained by traditional methods, for example, J. Org. Chem. 27, 4058 (1962)] or according to a similar reaction between the reactive derivative of carboxylic acid of the formula (VI), but using the derived acid forming aliphatic acyl group, and the compounds of formula (VII) with sociallyengaged in a suitable solvent (for example, a simple ether, such as diethyl ether or tetrahydrofuran) in the temperature interval from room temperature to 80aboutWith the passage of time from 30 min to 5 h

Derivatives of amides thiazolidinediones acid of the present invention have excellent protivole - ecological and anti-asthmatic activity, as well as show antagonism against VEILS and, therefore, are useful as therapeutic agents for the treatment or prevention of allergic diseases and asthma.

Compounds of this izaberete the above, and for these purposes can be created on the basis of suitable pharmaceutical preparations, as is well known to experts in this field. The compounds may be administered orally, for example in the form of tablets, capsules, granules, powders, syrups or other well-known forms, parenteral, for example, by injection, suppositories or in other ways, for example, patches, inhalation formulations or ophthalmic solutions.

These pharmaceutical preparations can be prepared using conventional methods and may contain known adjuvants normally used in this field, for example, fillers, binders, disintegrators, lubricant, stabilizers, correct - ing additives and so on, depending on the purpose of the application and release forms of the drug. The dose will be determined by the conditions, age, body weight of the patient, nature and severity of the disease, which intend to treat, but in the case of oral administration to adult patient person, usually offered total daily dose of from 10 to 1000 mg, more preferably, the daily dose is from 10 to 500 mg, it can be taken at once or may be divided into atdec compounds of the present invention is demonstrated in the following experiments. In these experiments, the compounds of this invention identify the numbers of the following examples, which illustrate their receipt.

Experiment I.

Inhibitory effect on passive cutaneous anaphylaxis in rats (PKA).

According to Mot. as I. Mota, Immunology 7, 681-699 (1964) anticavity (256 multiple PKA titer) rats protivoyuznogo albumin was obtained and diluted 4-fold with physiological saline. Male SD rats (5 weeks of age) were used as experimental animals in groups containing 4 animals. Rats were senzibilizirani by subcutaneous injection of 0.05 ml of diluted antisera in the dorsal region. After 48 h after the injection of a suspension of the test compounds in aqueous 0.5 weight/vol. % solution of tragakant oral introduced rats, which during the day were kept on starvation diet, and after 60 min them into the tail vein were injected with 5 ml/kg of body weight of physiological saline containing 0.4 wt/vol.% egg albumin and 1.0 wt/vol% Evans Blue. After 30 min after the last injection, rats were euthanized with carbon dioxide, and Evans Blue, released in the dorsal part, was determined according to the method Harada's/Harada and others, J. Phrn. Pharmac, neniam, were evaluated to determine the degree of inhibition by comparing the average number of exudate dye allocated in the control group of animals not treated with the test compounds.

The degree of inhibition was calculated by the following equation:

(I-B/A) x 100%, where a is the number exagerating dye in the control group;

In the number exagerating dye in the test group.

The results are shown in table.1.

Experiment 2.

Inhibitory action in vitro on an individual PHAT aggregation of blood platelets.

Blood samples were obtained by taking cardiac puncture in rabbits and one volume part of the sample was immediately mixed with 0.1 part of 3.8 wt./vol.% an aqueous solution of sodium citrate. The fraction of plasma, platelet-rich (TOC), obtained by centrifugation of the samples at 150 x 6 for 15 min at room temperature, and the fraction of plasma reduced platelets (CCI) received then by subsequent centrifugation at 1,000 x 6 for 15 minutes the Number of platelets in the TOP diluted to 6 x 105on l by adding the appropriate number of CCI faction. According to the method proposed is m in 6 channel aggregometer (Hemetra-ce/Hemetracer, NKB, Tokyo, Japan). An aliquot TOP (272 l) were pre-incubated with 3 l of a solution of test compound in dimethyl sulfoxide for 1 min, and then stimulated by adding x-C16:0PHAT (at final concentrations of 10-83x10-8M) at 37aboutWith under stirring (100 rpm). Changes in the passage of light was noted for 5 minutes the Solvent (dimethyl sulfoxide) were controlled simultaneously, and the inhibitory activity of the test compounds was determined by the value of the maximum aggregation. Values IR50was calculated by least-squares.

The results are shown in table.2.

Experiment 3.

Inhibitory effect on receptor binding VEILS.

Blood samples were taken from the rabbit heart. 1 volume part of each sample was immediately mixed with 1/9 part 0,077 M solution of disodium ethylenediaminetetraacetate. After the procedure similar to that described in experiment 2, there were obtained samples of deposition of blood platelets. This sample of blood platelets washed and, after re-cooling and thawing, leading to rupture of the cells, it was placed on top of two layers consisting of 0.25 M and 1.5 M solution of sukr M and 1.5 M solutions sucrose, and considered as the fraction of membrane receptor VEILS. The experiment on the binding of the receptor was then carried out according to a method similar to the method described by Hwang and others [Bac San Hwang and others: J. Biol. Chem 260, 15639-15645 (1985). Specific binding3N-VEILS was measured using Wattman filter GF/C. the Test compound was dissolved in dimethyl sulfoxide and diluted 100-fold with buffer containing 0.5% bovine serum albumin. Nine parts by volume of solution used to experiment on the binding of the receptor, mixed with one part of the solution under test compounds prepared above. The percent inhibition of specific binding was delayed relative to the concentration of the test compound, and 50% inhibitory concentration (IC50) was calculated from the linear plot that connects all pending points.

The results are presented in table.3.

The invention is illustrated by the examples which do not limit it. Getting some of the original materials used in these examples is illustrated in the following preparations.

P R I m e R 1. 3-Tert-butoxycarbonyl-4(R)-[3-(4-diphenylmethyl-1-piperazinil) - propellerblades]-2-(3-Piri is slots, 500 mg (1,61 mmole) of 1-(3-aminopropyl)-4-(diphenylmethyl)Pipa-Razin (obtained as described in preparation 16) 263 mg (1,61 mmole) of diethylphosphoramidite, 163 mg (1,61 mmole) of tri - ethylamine and 10 ml of tetrahydrofuran is stirred at room temperature overnight. After this time the reaction mixture is concentrated by evaporation under reduced pressure, diluted with water and extracted with methyl chloride. Then the solvent is removed by evaporation under reduced pressure, and the obtained residual product evaporation is subjected to separation in a chromatographic column filled with alumina using ethyl acetate as eluent, and the result is 840 mg (yield 89%) of the final compound in the form of oil. Data infrared absorption spectrum (IR spectrum) (CVG),maxcm-1: 3350, 2973, 2934, 2808, 1669, 1367, 1158. Mass spectrum, m/z (%): 601 (M+, 0,2), 407 (16), 167 (100).

P R I m m e R 2. 4(R)-[3-(4-diphenylmethyl-1-piperazinil) replicabuy] -2-(3-pyridyl)thiazolidine and its hydrochloride

0.8 g (1,36 mmole) of 3-tert-butoxycarbonyl-4(R)-[3-(4-diphenylmethyl-1-piperazinil) -propellerblades]-2-(3-pyridyl)thiazolidin (obtained as described in example 1) is dissolved in 15 ml of 10% (wt/V) aqueous hydrochloric the camping is neutralized and extracted with chloroform. The solvent is removed from the extract by evaporation under reduced pressure, and the obtained residual product is subjected to separation in chromatogra - specific column filled with silica gel, using as eluent a mixture of methylene chloride with methanol in the ratio (volume) of 20:1, and the result is 0.5 g (yield 74%) of the final compound in the form of butter.

IR absorption spectrum (l3);maxcm-1: 3000, 2900, 2800, 1665, 1520, 1450.

Mass spectrum, m/z (%): 501 (M+, 4), 167 (100), 125 (48).

Thus obtained oil is dissolved in ethyl acetate, and the resulting solution was injected 4-normal solution of hydrogen chloride in ethyl acetate. Precipitated precipitated crystals are removed by filtration, and the result is the desired hydrochloride having a melting point of 193-195aboutC (with decomposition).

P R I m e R s 3-10. Are procedures in the same manner as described in example 1 using the same carboxylic acid, with the difference that you use is determined for each sample aminoalkylation together 4-(3-aminopropyl)-1-(diphenylmethyl) piperazine used in example 1, and the result is the following connection.

This compound is obtained from 4-(2-amino-ethyl)-1-(diphenylmethyl)piperazinil (known compounds) with the release of 69%.

IR absorption spectrum (CHCl3),maxcm-1: 3375, 2970, 1685, 1510.

Mass spectrum, m/z (%): 587 (M+, 4), 265 (48), 167 (100).

P R I m e R 4. 3-tert-Butoxycarbonyl-4(R)-[4-(4-diphenylmethyl-1-piperazinil) butylcarbamoyl]-2-(3-pyridyl)thiazolidin.

This compound is obtained with a yield of 61% of 1-(4-aminobutyl)-4-(diphenylmethyl)piperazine (obtained as described in preparation 17). IR absorption spectrum (CHCl3),maxcm-1: 3350, 2940, 1685, 1530.

Mass spectrum: m/z (%): 615 (M+, 5), 421 (72), 167 (100).

P R I m e R 5. 3-tert-Butoxycarbonyl-4(R)-{2-[4-bis(4-forfinal)-methyl-1 - piperazinyl]ethylcarbamate}-2-(3-pyridyl)-TIA - solidin.

This compound is obtained with a yield of 73% of 1-(2-amino-ethyl)-4-[bis(4-forfinal)methyl]piperazine (obtained as described in preparation 18).

IR absorption spectrum (CHCl3),maxcm-1: 3340, 2975, 2937, 2814, 1698, 1505.

Mass spectrum, m/z (%): 624 (M+, 6), 393 (57), 203 (100).

P R I m e R 6. 3-tert-Butoxycarbonyl-4(R)-{3-[4-bis(4-forfinal)-methyl-1 - piperazinyl]propellerblades}-2-(3-pyridyl)- thiazolidin.

Dan is written in preparation 19).

IR absorption spectrum (CHCl3),maxcm-1: 3350, 2973, 2938, 2811, 1698, 1505.

Mass spectrum, m/z (%): 637 (M+, 3), 407 (34), 203 (100).

P R I m e R 7. 3-tert-Butoxycarbonyl-4(R)-{4-[4-bis(4-forfinal)-methyl-1 - piperazinil]butylcarbamoyl}-2-(3-pyridyl)-t - azalides.

This compound is obtained with a yield of 70% of 1-(4-aminobutyl)-4-[bis(4-forfinal)methyl]piperazine (obtained as described in preparation 20).

IR absorption spectrum (CHCl3),maxcm-1: 2970, 2930, 1685, 1505.

Mass spectrum, m/z (%): 651 (M+, 2), 421 (36), 203 (100).

P R I m e R 8. 3-tert-Butoxycarbonyl-4(R)-[3-{4-[alpha-(4-chlorophenyl)benzyl-1 - piperazinil}propellerblades]-2-(3-pyridyl)- thiazolidin.

Next, a connection is received with the output 76% of 1-(3-aminopropyl)-4-[alpha-(4-chlorophenyl)benzyl] piperazine (obtained as described in preparation 23).

IR absorption spectrum (CHCl3),maxcm-1: 3350, 2970, 2830, 1690, 1525.

Mass spectrum, m/z (%): 635 (M+, 6), 407 (71), 201 (100).

P R I m e R 9. 3-tert-Butoxycarbonyl-4(R)-[2-(4-diphenylmethylene-1-piperidyl) -ethylcarboxyl]-2-(3-pyridyl)thiazolidin.

This compound is obtained with a yield of 70% of 1-(2-amino-ethyl)-4-(diphenylmethylene)piperidine (poluchennogo the 1544.

Mass spectrum, m/z (%): 598 (M+, 34), 323 (45), 262 (100).

P R I m e R 10. 3-tert-Butoxycarbonyl-4(R)-[3-(4-diphenylmethylene-1-piperidyl) -propellerblades]-2-(3-pyridyl)thiazolidin.

This compound is obtained with a yield of 91% of 1-(3-aminopropyl)-4-(vinylethylene)piperidine (obtained as described in preparation 15).

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2980, 1690, 1560.

Mass spectrum, m/z (%): 584 (M+, 18), 365 (12), 262 (100).

P R I m e R s 11-16. The compounds obtained according to examples 3-8 are treated in the same manner as described in example 2, and the resulting compounds of examples 11-16, respectively.

P R I m e R 11. 4(R)-{2-(4-diphenylmethyl-1-piperazinil)ethylcarbamate]-2-(3-pyrid - yl)- thiazolidin.

This compound, melting at 183-185aboutWith that obtained with the yield of 58%.

IR absorption spectrum (KBR),maxcm-1: 3380, 3270, 1662, 1516.

Mass spectrum, m/z (%): 487 (M+, 19), 265 (53), 167 (100).

P R I m e R 12. 4(R)-[4-(4-diphenylmethyl-1-piperazinil)butylcarbamoyl] -2(3-Piri - DIL) thiazolidin.

This compound is obtained with a yield of 93%.

IR absorption spectrum (HCl3),maxcm-1: 3380, 3270, 2950, 1670, 1520.

This compound, melting at 162-164aboutWith that obtained with the yield of 92%.

IR absorption spectrum (KBr),maxcm-1: 3380, 3263, 2808, 1658, 1506.

Mass spectrum, m/z (%): 523 (M+, 11), 301 (28), 203 (100).

P R I m e R 14. 4(R)-{3-[4-Bis(4-tortenelemmel-1-piperazinil]-propylgallate - yl}- 2-(3-pyridyl)thiazolidine and its hydrochloride.

This compound is obtained with a yield of 92%.

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2970, 1605, 1505.

Mass spectrum, m/z (%): 537 (M+, 19), 203 (100), 125 (41).

The processing of this end connections 4-normal solution of hydrogen chloride in ethyl acetate results in the formation of the hydrochloride, melting at 185-188aboutC (with decomposition).

P R I m e R 15. 4(R)-{4-[4-Bis(-4-forfinal)methyl-1-piperazinil]-butylcarbamoyl}- 2-(3-pyridyl)thiazolidine and its hydrochloride.

This compound is obtained with a yield of 86%.

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2950, 1670, 1510.

Mass spectrum, m/z (%): 551 (M+, 3), 293 (10), 203 (100).

Treatment of this compound 4-normal solution of hydrogen chloride in ethyl acetate as described in example 2 leads to the formation of chargelevel)benzyl]-1-piperazinil}- propellerblades]-2-(3-pyridyl)thiazolidine and its hydrochloride.

This compound is obtained with a yield of 75%.

IR absorption spectrum (KBr), max, cm1: 3290, 2940, 2810, 1660, 1520.

Mass spectrum, m/z (%): 535 (M+, 6), 201 (195), 165 (100).

Treatment of this compound 4-normal solution of hydrogen chloride in ethyl acetate as described in example 2 leads to the formation of the hydrochloride of this compound, melting at 188-190aboutC (with decomposition).

P R I m e R 17. 4(R)-{3-[4-Bis(4-forfinal)methoxy-1-piperidinyl]propilkki - mail}- 2-3-pyridyl)thiazolidine and its hydrochloride

A mixture of 400 mg (1,90 mmole) of 2-(3-pyridyl)-thiazolidin-4(R)-carboxylic acid, 686 mg (1.9 mmole) of 1-(3-aminopropyl)-4-[bis(4-forfinal)methoxy]-piperidine (obtained as described in preparation 27). 392 mg (1.9 mmole) of dicyclohexylcarbodiimide, 257 mg (1.9 mmole) of 1-oxibendazole and 6 ml of dimethylformamide is stirred at room temperature overnight. At the end of this period the reaction mixture was diluted with ethyl acetate and the insoluble matter is filtered out. The filtrate is injected with 0.5 normal aqueous solution of the hydroxide of sodium, and the mixture is extracted with ethyl acetate. In an ethyl acetate extract is introduced 1-normal aqueous solution of hydrochloric acid, and the aqueous layer obtained the same is e which it is extracted with ethyl acetate. The extract is concentrated by evaporation under reduced pressure, and the obtained residual product evaporation is passed through a chromatographic column filled with alumina using a mixture of ethyl acetate with ethanol in a ratio (volume) 20:1 as eluent, and the result is 710 mg (yield 68%) of the final compound in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 3400, 3300, 2950, 1665, 1505.

Mass spectrum, m/z (%): 552 (M+, 1), 384 (12), 165 (100).

The oil obtained is dissolved in ethyl acetate and the processing of the obtained solution of 4-normal solution of hydrogen chloride in ethyl acetate as described in example 2 is obtained the hydrochloride of this compound, melting at 114-117aboutC (with decomposition).

P R I m e R s 18 and 19. Carrying out the procedure in the same manner as described in example 17, but using piperidinol - Lamin defined in each example produces the following compounds.

Get chlorhydrate of these compounds with the quantitative outputs by the procedure described in example 2.

P R I m e R 18. 4(R)-{2-[4-Bis(4-forfinal)methoxy-1-piperidyl]-ethylcarbamate}- 2-(3-Pyrimethanil)methoxy] -piperidine (obtained as described in preparation 26).

IR absorption spectrum (CHCl3),maxcm-1: 3350, 2930, 1665, 1510.

Mass spectrum, m/z (%): 538 (M+, 0,3), 316 (39), 203 (100).

Then it turns hydrochloride in the form of a hygroscopic powder, melting at 75-77aboutC.

P R I m e R 19. 4(R)-{3-[4-alpha-oxydiphenylene)-1-piperidyl]-propylgallate - yl}- 2-(3-pyridyl)thiazolidin.

Specified in the title compound is obtained with a yield of 65% of 1-(3-aminopropyl)-4-(alpha-oxydiphenylene)-piperid (obtained as described in preparation 28).

IR absorption spectrum (CHCl3),maxcm-1: 3289, 2942, 1660, 1524.

Mass spectrum, m/z (%): 516 (M+, 1), 280 (69), 28 (100).

Then it turns hydrochloride, melting at 110-113aboutC.

P R I m e R 20. 4(R)-[2-{4-[alpha-(4-chlorophenyl)benzyl]-1-piperazinil} -tilcara - mail - 2-(3-pyridyl)thiazolidin

< / BR>
A mixture of 400 mg (1,94 mmole) of 2-(3-pyridyl)-thiazolidin-4(R)-carboxylic acid, 640 mg (1,94 mmole) 1-(2-amino-ethyl)-4-[alpha-(4-chlorophenyl)-benzyl] -piperazine (obtained as described in preparation 22), 400 mg (1,94 mmole) of 1-oxibendazole and 12 ml of dimethylformamide is stirred overnight at room temperature. At the end of this time the reaction mixture is diluted ethylacetate, and an ethyl acetate layer is separated and concentrated by evaporation in a vacuum. The residual product evaporation is passed through a chromatographic column filled with alumina using ethyl acetate as eluent, and the result is 580 mg (yield 58%) of the final desired compound in the form of crystals, melting at 157-159aboutC (after recrystallization from ethanol).

Mass spectrum: m/z (%): 521 (M+, 13), 295 (51), 201 (100).

P R I m e R 21. 4(R)-{2-[4-(Diphenylmethylene)-1-piperidyl]ethylcarbamate} -2-(3 - pyridyl)thiazolidine and its hydrochloride

< / BR>
A mixture of 1.1 g (of 1.88 mmole of 3-tert-butoxycarbonyl-4(R)-[2-(4-diphenylmethylene-1-Pipa - rider)- ethylcarboxyl]-2-(3-pyridyl)thiazolidine (obtained as described in example 9), 10 ml of 4-normal solution of hydrogen chloride in dioxane and 10 ml of methylene chloride is stirred at room temperature for 3 hours after this time the reaction mixture is poured into ice water, neutralized by adding 2-normal aqueous solution of hydrate of sodium oxide and extracted with chloroform. The extract is concentrated by distillation in vacuo, and the residual product of the distillation is passed through a chromatographic column Packed with silica gel which our selves 1.0 g (quantitative yield) of the final compound in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 3250, 2982, 1677, 1265.

Mass spectrum, m/z: 484 (M+, 13), 262 (100).

The oil obtained is dissolved in ethyl acetate, and the resulting solution is introduced 4-normal solution of hydrogen chloride in ethyl acetate. Precipitated precipitated crystals are removed by filtration, and the result is a hydrochloride of a specified compound, melting at 102-105aboutC.

P R I m e R 22. 4(R)-{3-[4-(Diphenylmethylene)-1-piperidyl]propellerblades}-2-(3 - pyridyl)thiazolidine and its hydrochloride

< / BR>
Specified in the title compound is obtained with a yield of 68% by the procedure as described in example 20 and using the same carboxylic acid as used in example 20 1-(3-aminopropyl)-4-(diphenylmethylene)piperine (obtained as described in preparation 15).

IR absorption spectrum (KBr);maxcm-1: 3300, 2942, 1979, 1661.

Mass spectrum, m/z (%): 498 (M+, 14), 359 (24), 262 (100).

Hydrochloride specified connection, melting at 140-142aboutC (with decomposition) is obtained in the same manner as described in example 2.

P R I m e R 23. 4(R)-{4-[4-(Diphenylmethylene)-1-piperidyl]butylcarbamoyl} -2-(3 - pyridyl)enous is described in example 20, and using the same carboxylic acid as used in example 20 1-(4-aminobutyl)-4-(diphenylmethylene)Pipa - ridin (obtained as described in preparation 25).

IR absorption spectrum (CHCl3),maxcm-1: 3400, 3050, 2960, 1735, 1665, 1530.

Mass spectrum, m/z (%): 512 (M+, 1), 262 (100).

The hydrochloride of this compound, melting at 122-124aboutC, is obtained in the same manner as described in example 2.

P R I m e R 24. 4(R)-[5-{4-[Bis(4-forfinal)methyl]-1-piperazinil}intercambio - yl]- 2-(3-pyridinyl)thiazolidine and its hydrochloride

< / BR>
A mixture of 500 mg (2.4 mmole) of 2-(3-pyridyl)-thiazolidin-4(R)-carboxylic acid, 900 mg (2.4 mmole) of 1-(5-aminopentyl)-4-[bis(4-forfinal)methyl]piperazine (obtained as described in preparation 21), 497 mg (2.4 mmole) of dicyclohexylcarbodiimide, 326 mg (2.4 mmole) of 1-oxibendazole and 8 ml of dimethylformamide is stirred overnight at room temperature. At the end of this period the reaction mixture was diluted with ethyl acetate and the insoluble matter is filtered out.

The filtrate is introduced from 0.5 normal aqueous solution of hydrate of sodium oxide, after which the mixture is extracted with ethyl acetate. In an ethyl acetate extract is introduced 1-normal water RA is a high water solution of hydrate of sodium oxide. Then extracted with ethyl acetate. The extract is concentrated by evaporation under reduced pressure, and the obtained residual product evaporation is passed through a chromatographic column filled with silica gel using a mixture of chloroform with methanol in a ratio (volume) 20:1 as eluent, and the result is 800 mg (yield 60%) specified in the connection name in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2960, 2830, 1745, 1670, 1610, 1505.

Mass spectrum, m/z (%): 565 (M+, 0,3), 203 (100).

The oil obtained is dissolved in ethyl acetate and the resulting solution was injected 4-normal solution of hydrogen chloride in ethyl acetate, and the result is a hydrochloride of a specified compound, melting at 174-176aboutC (with decomposition).

P R I m e R 25. 4(R)-[2-{4-[Bis(4-forfinal)-alpha-oxymethyl]-1-piperidyl}- ethylcarboxyl]-2-(3-pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 42% in the implementation process in the same manner as described in example 17, by reacting 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-4-[bis(4-forfinal)-alpha-oxymethyl] piperidine (obtained as the ptx2">

Mass spectrum, m/z (%): 538 (M+, 1), 316 (100), 298 (19).

The hydrochloride of this compound, melting at 143-145aboutC, is obtained in the same manner as described in example 2.

P R I m e R 26. 4(R)-[2-{4-[Bis(4-forfinal)methylene]-1-piperidyl}ethylcarbamate - 2-(3-pyridyl)thiazolidin.

Specified in the title compound, melting at 119-121aboutWith that obtained with the yield 91% in the implementation process in the same manner as described in example 17, by reaction of 2-(3-pyridyl)-thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-4-[bis(4-forfinal)methylene]piperidin (obtained as described in preparation 56).

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2960, 1675, 1510.

Mass spectrum, m/z (%): 520 (M+, 8), 298 (100).

P R I m e R 27. 4(R)-[5-(4-Diphenylmethylene-1-piperidyl)intercalator] -2-(3 - pyridyl)thiazolidine and its hydrochloride.

This compound is obtained with a yield of 36% with the implementation of the process in such a way as described in example 17, by reaction of 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 1-(5-aminopentyl)-4-(diphenylmethylene)piperidine (obtained as described in preparation 42).

IR absorption spectrum (CHCl3),maxcm-1: 2950, 1670, 1530, 1450.

aboutC is obtained in the same manner as described in example 2.

P R I m e R 28. 4(R)-[7-(4-Diphenylmethylene-1-piperidine)heptylcarbinol] -2-(3 - pyridyl)thiazolidin.

Specified in the title compound is obtained with a yield of 46% in the same manner as described in example 17, by reaction of 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 1-(7-aminoethyl)-4-(diphenylmethylene)piperidine (obtained as described in preparation 43).

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2935, 1670, 1525.

Mass spectrum, m/z (%): 554 (M+, 0,3), 262 (100).

P R I m e R 29. 4(R)-[3-{4-[Bis-(4-forfinal)methylene]-1-piperidyl] propileno - yl]- 2-(3-pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 15% in the same manner as described in example 17, by reaction of 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 1-(3-aminopropyl)-4-[bis(4-forfinal)methylene] piperidine (obtained as described in preparation 57).

IR absorption spectrum (CHCl3),maxcm-1: 3375, 3275, 2935, 2800, 1665, 1600, 1505.

Mass spectrum, m/z (%): 534 (M+, 18), 395 (31), 298 (100).

Hydrochloride mentioned in the title compound, melting at 95-98aboutC (with decomposition) is obtained so arbao - yl}- 2-(3-pyridyl)thiazolidin.

Specified in the title compound is obtained with a yield of 16% in the implementation process in the same manner as described in example 17, by reaction of 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 4-[alpha-(2-pyridyl)benzyl]-1-(3-aminopropyl)-piperazine (obtained as described in preparation 41).

IR absorption spectrum (CHCl3),maxcm-1: 3300, 2960, 2830, 1670, 1590, 1520.

Mass spectrum, m/z (%): 502 (M+, 6), 197 (52), 169 (100).

P R I m e R 31. 4(R)-{2-[4-(alpha-4-Pyridylmethyl)]-1-piperazinil}ethylcarbamate - 2- (3-pyridyl)thiazolidin.

Specified in the title compound, melting point 130-131aboutWith, is obtained with the output 56% in the implementation process in the same manner as described in example 17, by reaction of 2-(3-pyridyl)-thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-4-[alpha-(4-pyridyl)benzyl]-PI - perazine (obtained as described in preparation 58).

IR absorption spectrum (CHCl3),maxcm-1: 3330, 3010, 2970, 2830, 1670, 1580, 1520.

Mass spectrum, m/z (%): 486 (M+, -2, 30), 266 (52), 168 (100).

P R I m e R 32. 4(R)-{2-[4-(alpha-4-Pyridylmethyl)-1-piperazinil]ethylcarbamate}- 2-(3-pyridyl)thiazolidin.

Specified in the title compound with a melting point 160-162aboutWith(3-pyridyl)-thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-4-[alpha-(4-pyridyl)benzyl]PI - perazine (obtained as described in preparation 59).

IR absorption spectrum (CHCl3),maxcm-1: 3400, 3000, 2960, 2830, 1670, 1600, 1520.

Mass spectrum, m/z (%): 486 (M+, 13), 266 (100), 168 (98).

P R I m e R 33. 4(R)-{2-[4-(alpha-2-pyridyl-4-terbisil)-1-piperazinil] ethylcarbamate}-2-(3-pyridyl)thiazolidin.

Specified in the title compound with a melting point 144-146aboutC is obtained with a yield of 71% with a procedure analogous to example 17 by reacting 2-(3-pyridyl)-thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-4-[alpha-(2-pyridyl)-4-terbisil] - piperazine (obtained as described in preparation 60).

IR absorption spectrum (CHCl3),maxcm-1: 3380, 3000, 2950, 2820, 1670, 1605, 1590, 1505.

Mass spectrum, m/z (%): 506 (M+, 10), 215 (46), 186 (100).

P R I m e R 34. 4(R)-{2-[4-(alpha-2-pyridyl-4-trifloromethyl)-1-piperazinil] - ethylcarbamate} -2-(3-pyridyl)thiazolidine and its hydrochloride. Specified in the title compound is obtained with a yield of 54% when the process is similar opis - description of example 17 by reaction of 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-4-[alpha-(2-pyridyl)-4-three - formativeness]piperazine (obtained as described in preparation 61).

IR absorption spectrum (CHCl3),aboutC (with decomposition) is obtained in the same manner as described in example 2.

P R I m e R 35 . 4(R)-{2-[4-Bis(4-forfinal)methylene-1-piperidyl]ethylcarbamate}-3 - methyl-2-(3-pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 82% in the implementation process in the same manner as described in example 17, by reaction of 3-methyl-2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-[4-bis(4-forfinal)methylene] piperidine (obtained as described in preparation 56).

IR absorption spectrum (CHCl3),maxcm-1: 3380, 3120, 3060, 2820, 1670, 1605, 1510.

Mass spectrum, m/z (%): 534 (M+, 18), 298 (100), 179 (29).

Hydrochloride mentioned in the title compound with a melting point 148-150aboutC (with decomposition) is obtained in the same manner as described in example 2.

P R I m e R 36. 4(R)-{2-[4-Bis(4-forfinal)-alpha-hydroxy-methyl-1-piperidyl] ethylcarbamate} -3-methyl-2-(3-pyridyl)thiazole-DIN and its hydrochloride. Specified in the title compound is obtained in yield of 57% in the implementation process in the same manner as described in example 17, by reaction of 3-methyl-2-(3-pyridyl)thiazolidin-4(R)-Kar-oil acid and 1-(2-amino-ethyl)-[4-bis(4-forfinal)-alpha-oxymethyl] piperidine (who 0, 2980, 2940, 1665, 1600, 1505.

Mass spectrum, m/z (%): 520 (M+, 3), 316 (100), 123 (22).

Hydrochloride mentioned in the title compound with a melting point 115-117aboutC (with decomposition) is obtained in the same manner as described in example 2.

P R I m e R 37. 4(R)-{2-[4-alpha-2-Pyridyl)benzyl-1-piperazinil]ethylcarbamate} -3-methyl-2-(3-pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 93%, with the implementation of the process in the same manner as described in example 17, by reaction of 3-methyl-2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 1-(2-amino-ethyl)-[4-(alpha-2-pyridyl)-benzyl]piperazine (obtained as described in preparation 62).

IR absorption spectrum (HCl3),maxcm-1: 3360, 2980, 2940, 1665, 1600, 1505.

Mass spectrum, m/z (%): 502 (M+, 27), 334 (73), 169 (100).

The hydrochloride of the compounds with a melting point 148-150aboutC is obtained in the same manner as described in example 2.

P R I m e R 38. 4(R)-{3-[4-alpha-2-Thienyl)benzyliden-1-piperidyl]propilkki - mail} -2-(3-pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 47% in the implementation process in the same manner as described in Prien] piperidine (obtained as described in example 63).

IR absorption spectrum (CHCl3),maxcm-1: 3300, 3000, 2930, 1665, 1520.

Mass spectrum, m/z (%): 504 (M+, 19), 268 (100), 129 (37).

The hydrochloride of the compounds with a melting point of 133-135aboutC (with decomposition) is obtained in the same manner as described in example 2.

P R I m e R 39. 4(R)-{N-[2-(4-Diphenylmethyl-1-piperazinil ethyl]-N-methylcarbamoyl}-2-(3-pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 46% in the implementation process in the same manner as described in example 17, by reaction of 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 4-diphenylmethyl-1-[2-(N-methylamino)ethyl]-Pipa - Razin (obtained as described in preparation 36).

IR absorption spectrum (CHCl3),maxcm-1: 3320, 3020, 2960, 1650, 1495.

Mass spectrum, m/z (%): 501 (M+, 4), 265 (39), 167 (100).

The hydrochloride of this compound with a melting point 185-188aboutC (with decomposition) is obtained in the same manner as described in example 2.

P R I m e R 40. 4(R)-{2-[4-Bis(4-forfinal)methylene-1-piperidyl]ethylcarbamate}- 2- [5-(2-methylpyridyl)]thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 50% with the implementation of the acid and 1-(2-amino-ethyl)-4-[bis(4-fluoro - phenyl)methylene] piperidine (obtained as described in preparation 56).

IR absorption spectrum (CHCl3),maxcm-1: 3200, 2950, 1670, 1605, 1510, 1220.

Mass spectrum, m/z (%): 534 (M+, 10), 298 (106).

The hydrochloride of the compounds with a melting point 144-146aboutC (with decomposition) is obtained in the same manner as described in example 2.

P R I m e R 41. 4(R)-{3-[4-Bis(4-forfinal)methylene-1-piperidyl]propellerblades}- 2-[5-(2-methylpyridyl)]thiazolidine and its hydrochloride.

Specified in the title compound are obtained from the output 33% in the implementation process in the same manner as described in example 17, by the reaction of 2-[5-(2-methylpyridyl)] thiazolidin-4(R)-carboxylic acid and 1-(3-aminopropyl)-4-[bis(4-fluoro - phenyl)methylene piperidine] (obtained as described in preparation 57).

IR absorption spectrum (CHCl3),maxcm-1: 3300, 2950, 1670, 1605, 1510, 1220.

Mass spectrum, m/z (%): 548 (M+, 24), 395 (40), 298 (100).

The hydrochloride of the compounds with a melting point 146-148aboutC is obtained in the same manner as described in example 2.

P R I m e R 42. 4(R)-{3-[4-Diphenylmethylene-1-piperidyl]propellerblades-2-[5-(2 - methylpyridyl)]thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 80% with the implementation of the howling acid and 1-(3-aminopropyl)-4-(diphenyl - methylene)piperidine (obtained as described in preparation 15).

IR absorption spectrum (CHCl3),maxcm-1: 3300, 2950, 1670, 1605, 1525, 1495.

Mass spectrum, m/z (%): 512 (M+, 41), 359 (53), 212 (100).

The hydrochloride of this compound with a melting point 98-101aboutC, is obtained by implementing the process in the same manner as described in example 2.

P R I m e R 43. 4(R)-[N-{3-[4-Diphenylmethylene-1-piperidyl]propyl-N-ethylcarboxyl] -2-(3-pyridyl)-thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 27% in the implementation process in the same manner as described in example 17, by reaction of 2-(3-pyridyl)thiazolidin-4(R)-carboxylic acid and 4-diphenylmethylene-1-[3-(N-ethylamino)propyl]-piperidine (obtained as described in preparation 32).

IR absorption spectrum (CHCl3),maxcm-1: 3000, 1680, 1640, 1380.

Mass spectrum, m/z (%): 526 (M+, 47), 387 (53), 262 (100).

The hydrochloride of the compounds with a melting point 92-94aboutC, is obtained in the same manner as described in example 2.

P R I m e R 44. 4(R)-[N-{2-[4-Diphenylmethylene-1-piperidyl]ethyl}-N-methylcarbamoyl - yl] -2-(3-pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 82% with the implementation of prietenilor-1-[2-(N-methylamino)ethyl]-PI - peridine (obtained as described in preparation 30).

IR absorption spectrum (CHCl3),maxcm-1: 3000, 1740, 1640, 1500, 1400.

Mass spectrum, m/z (%): 498 (M+, 8), 262 (100).

Hydrochloride specified connection with the melting temperature of 135-140aboutC is obtained in the same manner as described in example 2.

P R I m e R 45. 4(S)-{3-[4-Diphenylmethylene-1-piperidyl]-propellerblades} -2-(3 - pyridyl)thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 27% in the implementation process in the same manner as described in example 17, by reaction of 2-(3-pyridyl)thiazolidin-4(S)-carboxylic acid (obtained as described in example 29) and 1-(3-aminopropyl)-4-(diphenylmethylene)PI-peridine (obtained as described in preparation 15).

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2940, 2710, 1680.

Mass spectrum, m/z (%): 498 (M+, 34), 359 (43), 262 (100).

The hydrochloride of the compounds with a melting point 81-83aboutC is obtained in the same manner as described in example 2.

P R I m e R 46. 4(R)-[3-(4-Diphenylmethylene-1-piperidyl)propellerblades] -2-(4-PI - rider) thiazolidine and its hydrochloride.

Specified in the title compound is obtained with a yield of 15% in the implementation process the same clicks phenylmethylene)Piperi - DIN (obtained as described in preparation 15).

IR absorption spectrum (CHCl3),maxcm-1: 3050, 2935, 2567, 1665.

Mass spectrum, m/z (%): 496 (M+, -2, 50), 359 (39), 262 (100).

Hydrochloride mentioned in the title compound with a melting point of 84-85aboutC, is obtained by implementing the process in the same manner as described in example 2.

P R I m e R 47. 4(R)-[3-(4-Diphenylmethyl-1-piperidyl)propellerblades]-2-(3-Piri-DIL) thiazolidin.

Specified in the title compound with a melting point 166-168aboutC is obtained with a yield of 50% in the same manner as described in example 17, by reaction of 2-(3-pyridyl)-thiazolidin-4(R)-carboxylic acid and 1-(3-aminopropyl)-4-(WPPT - ylmethyl)piperidine (obtained as described in preparation 45).

IR absorption spectrum (HCl3),maxcm-1: 3300, 2960, 1670, 1525.

Mass spectrum, m/z (%): 500 (M+, 1), 264 (100).

Preparation 1.

4-(Diphenylmethyl)-1-(3-phthalimido-saws)piperazine.

A mixture of 500 (1.98 mmole) 4-(diphenylmethyl)piperazine, 530 mg (1.98 mmole) of N-(3-bromopropyl)phthalimide, 840 mg (7,92 mmole) of sodium carbonate, 10 mg of sodium iodide and 12 ml of isobutyl ketone is heated under reflux during the night. Then the reaction mixture is filtered, the solvent removes the static column filled with silica gel, using a mixture of ethyl acetate with hexane in a volume ratio of 1: 1 as eluent, and the result is 830 mg (yield 96%) of the desired final compound in the form of oil.

IR absorption spectrum (CHCl3), maxcm-1: 1710, 1395.

Drugs 2-14.

Using the appropriate cyclic amines, carry out the reaction in the same manner as described in preparation 1, and receive the following connections:

The drug 2.

4-(Diphenylmethyl)-1-(4-phthalimidobutyl)- piperazine.

Specified in the title compound, having a melting point 125-129aboutC is obtained with a yield of 90%.

IR absorption spectrum (CHCl3), maxcm-1: 1770, 1710, 1495, 1365.

The drug 3.

4-[Bis-(4-forfinal)methyl]-1-(2-ftli - amidoethyl)-piperazine.

Specified in the title compound, having a melting point 125-126aboutC is obtained with a yield of 77%.

IR absorption spectrum (CHCl3),maxcm-1: 1766, 1710, 1507, 1396.

The drug 4.

4-[Bis-(4-forfinal)methyl]-1-(3-ftli - amidopropyl)piperazine.

Specified in the title compound is obtained with a yield of 96%.

IR-Spa is Teal]-1-(4-ftli-mycobutin)-piperazine.

Specified in the title compound is obtained with a yield of 85%.

IR absorption spectrum (CHCl3),maxcm-1: 1770, 1710, 1505, 1395.

The drug 6.

4-[Bis(4-forfinal)methyl]-1-(5-ftli-megapenthes)-piperazine.

Specified in the title compound is obtained with a yield of 70%.

IR absorption spectrum (CHCl3),maxcm-1: 1770, 1710, 1505, 1395.

The drug 7.

4-[alpha-(4-Chlorophenyl)benzyl]-1-(2-phthalimidomethyl)-piperazine.

Specified in the title compound is obtained with a yield of 89%.

IR absorption spectrum (KBr),maxcm-1: 1770, 1710, 1396.

The drug 8.

4-[alpha-(4-Chlorophenyl)benzyl]-1-(3-nafta - imidapril)-piperidine.

Specified in the title compound is obtained with a yield of 90%.

IR absorption spectrum (CHCl3),maxcm-1: 1770, 1710, 1395.

The drug 9.

4-(Diphenylmethylene)-1-(2-phthalimido-Tyl)piperidine.

Specified in the title compound with a melting point 106-108aboutC is obtained with a yield of 79%.

IR absorption spectrum (KBr),maxcm-1: 1767, 1710, 1397.

The drug 10.

4-(Diphenylmethylene)-1-(3-phthalimido - propyl)piperidine.

IR absorption spectrum (KBr),maxcm-1: 1770, 1705, 1403.

The drug 11.

4-(Diphenylmethylene)-1-(4-phthalimido - Tyl)piperidine.

Specified in the title compound with a melting point 102-103aboutC is obtained with a yield of 91%.

IR absorption spectrum (KBr),maxcm-1: 1770, 1704, 1393.

Preparation 12.

4-[Bis(4-forfinal)methoxy]-1-(2-nafta-Limitati)-piperidine.

Specified in the title compound is obtained with a yield of 70%.

IR absorption spectrum (HCl3),maxcm-1: 1780, 1715, 1610.

Preparation 13.

4-[Bis-(4-forfinal)methoxy]-1-(3-nafta - imidapril)-piperidine.

Specified in the title compound is obtained with a yield of 95%.

IR absorption spectrum (CHCl3),maxcm-1: 1770, 1710, 1510, 1395.

Preparation 14.

4-(alpha-Hydroxy-diphenylmethyl)-1-(3-nafta - imidapril)-piperidine.

Specified in the title compound is obtained with a yield of 83%.

IR absorption spectrum (KBr),maxcm-1: 1770, 1709, 1396.

The drug is 15.

1-(3-Aminopropyl)-4-(diphenylmethylene) - piperidine

A mixture of 900 mg (of 2.06 mmole) 4-(diphenylmethylene)-1-(3-phthalimidopropyl)piperidine (what dildocam within 2 hours At the end of this period precipitated precipitated crystals are filtered out and the solvent removed from the filtrate by distillation in vacuum, and the result is 460 mg (yield 73%) mentioned in the title compound in the form of butter.

IR absorption spectrum (HCl3),maxcm-1: 2950, 2800, 1595, 1490.

Drugs 16-28.

Carried out the reaction in the same manner as described in preparation 15 when using the respective phthalimid - governmental derivatives and hydrazine hydrate, and obtained the following compounds:

Preparation 16.

1-(3-Aminopropyl)-4-(diphenylmethyl)- piperazine.

Specified in the title compound, melting at 62-63aboutWith that obtained with the yield of 22%.

IR absorption spectrum (KBr),max, cm1: 3024, 2949, 2803, 1596, 1450.

The drug is 17.

1-(4-Aminobutyl)-4-(diphenylmethyl)PI-perazin.

Specified in the title compound is obtained with a quantitative yield.

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2950, 2830, 1670, 1600, 1500.

Preparation 18.

1-(2-amino-ethyl)-4-[bis(4-forfinal)IU - til]piperazine.

Specified in the title compound is obtained with a yield of 45%.

Specified in the title compound is obtained with a yield of 71%.

IR absorption spectrum (CHCl3),maxcm-1: 3350, 2820, 1605, 1510.

The drug is 20.

1-(4-Aminobutyl)-4-[bis(4-forfinal)- methyl]piperazine.

Specified in the title compound is obtained with a quantitative yield.

IR absorption spectrum (CHCl3),maxcm-1: 3200 (broad), 2930, 2820, 1605, 1505.

Preparation 21.

1-(5-Aminopentyl)-4-[bis(4-forfinal) - methyl]piperazine.

Specified in the title compound is obtained with a yield of 93%.

IR absorption spectrum (CHCl3),maxcm-1: 3500-3100 (wide), 2940, 2830, 1640, 1605, 1505.

Preparation 22.

1-(2-amino-ethyl)-4-[alpha-(4-chlorophenyl) - benzyl]piperazine.

Specified in the title compound is obtained with a yield of 89%.

IR absorption spectrum (CHCl3),maxcm-1: 3200 (broad), 2950, 2830, 1490.

Preparation 23.

1-(3-Aminopropyl)-4-[alpha-(4-harfe - nil)benzyl]-piperazine.

Specified in the title compound is obtained with a yield of 68%.

IR absorption spectrum (CHCl3),maxcm-1: 3200, 2 is in the title compound is obtained with a yield of 42%.

IR absorption spectrum (CHCl3),maxcm-1: 3600-3160 (wide), 2950, 2820, 1650, 1595, 1495.

Preparation 25.

1-(4-Aminobutyl)-4-(diphenylmethylene)PI - peridin.

Specified in the title compound is obtained with a quantitative yield.

IR absorption spectrum (CHCl3),maxcm-1: 3400, 2970, 1610, 1515.

Preparation 27.

1-(3-Aminopropyl)-4-[bis(4-forfinal) - methoxy]-piperidine.

Specified in the title compound is obtained with a yield of 85%.

IR absorption spectrum (CHCl3),maxcm-1: 3200, 2950, 1610, 1510.

Preparation 28.

1-(3-Aminopropyl)-4-(alpha-oxylife-ylmethyl)piperidine.

Specified in the title compound, having a melting point of 102-104aboutWith that obtained with the yield of 93%.

IR absorption spectrum (KBr), maxcm-1: 3348, 3257, 2938, 2816, 1489, 1447.

Preparation 29.

2-(3-Pyridyl)thiazolidin-4(S)-carbon - Wai acid.

A solution of 1.07 g of pyridine-3-aldehyde and 1,21 g D-cysteine in 60% (V/V aqueous ethanol is heated under reflux for 4 hours the Mixture is cooled to room temperature and the resulting solid material is removed by filtration. The filtrate concentree precipitated precipitated crystals obtained 1.13 g (yield 54%) mentioned in the title compound with a melting point 138-139aboutC.

IR absorption spectrum (KBr),maxcm-1: 3260, 2920, 2400, 1720, 1200.

The drug is 30.

4-Diphenylmethylene-1-[2-(N-methylamino) ethyl]piperidine.

A solution of 1.13 g of 4-diphenylmethylene-1-(2-N-formimidoyl)piperidine (obtained as described in preparation 31) (-CANClL) in 7 ml of tetrahydrofuran is introduced dropwise into a suspension of 140 mg of lithium hydride-aluminum in 10 ml of tetrahydrofuran at room temperature in a nitrogen atmosphere, and the mixture is heated under reflux for 1 h

At the end of this period the mixture is cooled to room tempera - tours, and the mixture is introduced decahydrate sodium sulfate order to decompose excess lithium hydride-aluminum. Insoluble material is removed by filtration. The filtrate is introduced in ethyl acetate, and the mixture is washed with water and saturated aqueous sodium chloride in that order, after which it is dried over anhydrous magnesium sulfate. After evaporation of the solvent in vacuum is obtained 830 mg (yield 80%) mentioned in the title compound in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 2875, 1500, 1440, 1100.

Preparation 31.

4-Diphenylmethylene-1-(2-N-formamido - Tyl)Piperi) in 10 ml of ethylformate heated under reflux overnight. At the end of this period the mixture is cooled to room temperature and the solvent is removed by evaporation in a vacuum. The residual product evaporation is purified in a chromatography column filled with silica gel, using as eluent a mixture of chloroform with methanol in the volume ratio of 40:1, and the result is 1.13 g (quantitative yield) specified in the connection name in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 3400, 3000, 1680 1490.

The drug is 32.

4-Diphenylmethylene-1-[3-(N-ethylamino)- propyl]piperidine.

A solution of 1.14 g of 1-(3-acetamidophenyl)-4-(diphenylmethylene)piperidine (obtained as described in preparation 33) in 7 ml of tetrahydrofuran is introduced dropwise into a suspension of 140 mg of lithium hydride-aluminum in 10 ml of tetrahydrofuran at room temperature in a nitrogen atmosphere, and the mixture is heated under reflux for 4 hours By the end of this period the mixture is cooled to room temperature, and it introduces decahydrate sodium sulfate order to decompose excess lithium hydride-aluminum. Insoluble material is removed by filtration. The filtrate is introduced in ethyl acetate, and the mixture is washed with water and saturated in who I am. After evaporation of the solvent in vacuum is obtained 710 mg (yield 65%) mentioned in the title compound in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2850, 1500, 1440, 1120.

Preparation 33.

1-(3-Acetamidophenyl)-4-(diftime-tilen)piperidine.

680 mg of triethylamine are introduced into a solution of 1.0 g of 1-(3-aminopropyl)-4-(diphenylmethylene)piperidine (obtained as described in preparation 15) in 10 ml of methylene chloride at room temperature; in this solution is introduced dropwise a solution of 680 mg of acetylchloride in 2 ml of methylene chloride at -10aboutS, after which the mixture was stirred at the same temperature for 5 minutes Then introduced methylene chloride, and the mixture is then washed with water and saturated aqueous sodium chloride in that order, after which it is dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuum turns out to 1.14 g (quantitative yield) specified in the connection name in the form of butter.

IR absorption spectrum (liquid film),maxcm-1: 3350, 2815, 1650, 1537.

Preparation 34.

2-(N-Etoxycarbonyl-N-methylamino)ethyl - methanesulfonate.

1,65 g methanesulfonanilide is introduced dropwise with ARF is Lienhard while cooling with ice, and then the solution was stirred at the same temperature for 30 minutes By the end of this period the mixture was poured into a mixture of ice-water and extracted with methylene chloride. The extracts are combined and washed with water, after which they are dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuum is obtained residual product, which is purified in a chromatography column of silica gel using as eluent a mixture of ethyl acetate with hexane in a volume ratio of 2:1, and the result is 2,62 g (yield 81%) mentioned in the title compound in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 3000, 1750, 1590, 1485.

Preparation 35.

4-Diphenylmethyl-1-[2-(N-etoxycarbonyl - N-methylamino)ethyl]piperazine.

A mixture of 0.23 g of 2-(N-etoxycarbonyl-N-methylamino)ethylmethanesulfonate (obtained as described in preparation 34) and 0.26 g of 4-diphenylbutylpiperidine stirred at 80aboutWith over 5 hours At the end of this period the mixture is purified in a chromatography column of silica gel using as eluent a mixture of ethyl acetate with ethanol in a volume ratio of 20:1, and the result is 0.25 g (yield 64%) mentioned in the title SS="ptx2">

Drug 36.

4-Diphenylmethyl-1-[2-(N-methylamino)ETH - yl]piperazine.

A solution of 1.6 g of 4-diphenylmethyl-1-[2-(N-etoxycarbonyl-N-methylamino)ethyl] Pipera - zine (obtained as described in preparation 35) in 20 ml of 10% (wt/V) aqueous solution of potassium hydroxide and 20 ml of ethylene glycol is stirred at 140aboutWith over 20 hours By the end of this period the mixture is cooled to room temperature, poured into a mixture of ice-water and extracted with methylene chloride. The extracts are combined, washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuum turns out to 1.14 g (yield 88%) mentioned in the title compound in the form of butter.

IR absorption spectrum (CHCl3),maxcm-1: 2970, 2830, 1610, 1495.

Preparation 37.

2-[5-(2-Methylpyridyl)]thiazolidin-4(R)-carboxylic acid.

Specified in the title compound with a melting point 147-148aboutWith that obtained with the yield of 81% in the same manner as described in preparation 28, by reaction of 2-methyl-5-pyridinoline and L-cysteine.

IR absorption spectrum (KBr),maxcm-1: 3260, 2920, 2420, 1950, 1720, 1610.

Preparation 38.

4-[alpha-(2-Pyridyl)benzyl] -1-(2-cyano - ethyl)Pieper is ensil]piperazine and 0.1 g of 3-prempro - dinitrile in 20 ml of methylene chloride, while cooling with ice, and the mixture was stirred at room temperature for 6 hours By the end of this period the mixture was poured into a mixture of ice-water and extracted with chloroform. The extracts are combined and dried over aqueous sodium sulfate, then the solvent is removed by evaporation in a vacuum. The obtained residual product evaporation is purified in a chromatography column of silica gel using as eluent a mixture of ethyl acetate with ethanol in a ratio (volume) of 20:1, and the result is obtained 2.1 g (yield 88%) mentioned in the title compound in the form of crystals with a melting point 114-116aboutC.

IR absorption spectrum (CHCl3), maxcm-1: 2950, 2825, 2250, 1590, 1575, 1490, 1465, 1455, 1439.

Preparation 39.

4-(Diphenylmethylene)-1-(4-cyanomethyl)-piperidine.

Specified in the title compound is obtained with a yield of 50% in the same manner as described in preparation 38, through the reaction of 4-(diphenylmethylene)piperidine and 4-bromobutyronitrile.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2850, 1500, 1450.

The drug is 40.

4-(Diphenylmethylene)-1-(6-cyanogenesis)- piperidine.

Indicated in the name of the of rangecontrol.

IR absorption spectrum (CHCl3),maxcm-1: 2930, 2860, 2520, 2240, 1600, 1490.

Preparation 41.

4-[alpha-(2-pyridyl)benzyl]-1-(3-amino - propyl)piperazin.

A solution of 2.0 g of 4-[alpha-(2-pyridyl)benzyl] -1-(2-cyanoethyl)piperazine (obtained as described in preparation 38) in 30 ml of tetrahydrofuran is introduced dropwise into a suspension of 0.24 g of lithium hydride-aluminum in 30 ml of tetrahydrofuran at 5-7aboutC, and the mixture was stirred at room temperature for 30 minutes By the end of this period the excess of lithium hydride-aluminum decomposed by entering a 4% (wt/V) aqueous solution of hydrate of sodium oxide, and insoluble material removed by filtration. The filtrate is dried over anhydrous sodium sulfate and then the solvent is removed by evaporation in vacuo, and the result is 1.8 g (yield 90%) specified in the connection name in the form of butter.

IR absorption spectrum (CHCl3), maxcm-1: 3250, 2950, 2825, 1660, 1590.

Preparation 42.

1-(5-Aminopentyl)-4-(diphenylmethylene) - piperidine.

Specified in the title compound is obtained with a yield of 36% when the process is similar to the description of the preparation 41, through the reaction of 4-(diphenylmethylene)-1-(4-cyanomethyl)ª (CHCl3),maxcm-1: 3400, 2950, 1670, 1530, 1450.

Preparation 43.

1-(7-Aminoethyl)-4-(diphenylmethylene)- piperidine.

Specified in the title compound is obtained with a yield of 91% with the implementation of the process in the same manner as described in preparation 41, through the reaction of 4-(diphenylmethylene)-1-(6-cicalese)piperidine (obtained as described in preparation 40) and lithium hydride-aluminum.

IR absorption spectrum (CHCl3),maxcm-1: 3060, 2930, 2850, 2800, 1665, 1595.

Preparation 44.

4-Diphenylmethyl-1-(3-phthalimidopropyl) - piperidine.

A mixture of 1.8 g of 4-diphenylbutylpiperidine, 1.92 g of N-(3-bromopropyl)phthalimide, 3.0 g of sodium carbonate and 20 mg of sodium iodide in 70 ml of isobutyl ketone is heated under reflux for 5 hours By the end of this period the mixture is cooled to room temperature and filtered. The filtrate is concentrated by evaporation in a vacuum, and the resulting residual product is purified in a chromatography column of silica gel, using as eluent a mixture of hexane with ethyl acetate in a volume ratio of 1:1, and the result is 3.0 g (yield 95%) specified in the connection name in the form of crystals with a melting point 104-106

1-(3-Aminopropyl)-4-diphenylmethyl - peridin.

A mixture of 2.8 g of 4-diphenylmethyl-1-(3-phthalimidopropyl)piperidine (obtained as described in preparation 44) and 0.90 g of hydrazine hydrate in 100 ml of ethanol is heated under reflux for 2 hours By the end of this period the mixture is cooled to room temperature and filtered. The filtrate is concentrated by evaporation in a vacuum, and the result of 0.93 g (yield 47%) mentioned in the title compound in the form of butter.

IR absorption spectrum (CHCl3), maxcm-1: 3400, 2970, 1670, 1600, 1495, 1455.

Preparation 46.

4-[Bis(4-forfinal)-alpha-oxymethyl]-1-(2-phthalimidomethyl)piperidine.

Specified in the title compound is obtained with a yield of 78% in the implementation process in the same manner as described in preparation 1, by the reaction of N-(2-bromacil)phthalimide and 4-[bis(4-forfinal)- -hydroxy-methyl]piperidine.

IR absorption spectrum (CHCl3),maxcm-1: 2940, 2800, 1770, 1710, 1700, 1600, 1505.

Preparation 47.

4-Diphenylmethylene-1-(2-phthalimidomethyl) - piperidine.

Specified in the title compound is obtained with a yield of 88% in the implementation process in the same manner as described in preparation 1, by reaction
cm-1: 2950, 2800, 1770, 1710, 1600, 1505.

Preparation 48.

4-[Bis(4-forfinal)methylene]-1-(3-nafta-imidapril)piperidine.

Specified in the title compound is obtained with a yield of 97% in the implementation process analogous to preparation 1, by reaction of N-(3-bromopropyl)phthalimide and 4-[bis(4-forfinal)methylene]piperidine.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2800, 1775, 1715, 1605, 1505.

Preparation 49.

4-[alpha-(3-Pyridyl)benzyl]-1-(2-FTL - aminoethyl)piperazine.

Specified in the title compound is obtained with a yield of 53% in the implementation process analogous to preparation 1, by the reaction of N-(2-bromacil)phthalimide and 4-[alpha-(3-pyridyl)benzyl]piperazine.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2810, 1775, 1710, 1395.

The drug is 50.

4-[alpha-(4-Pyridyl)benzyl]-1-(2-FTL - aminoethyl)piperazine.

Specified in the title compound is obtained with a yield of 77% when carrying out the process in such a way as described in preparation 1, by the reaction of N-(2-bromacil)phthalimide and 4-[alpha-(4-pyridyl)benzyl]Pipera - zine.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2820, 1775, 1710, 1595, 1395.

the title compound is obtained with a yield of 80% with the implementation of the process in the same way, as described in preparation 1, by the reaction of N-(2-bromacil)phthalimide and 4-[alpha-(2-pyridyl)-4-terbisil]piperazine.

IR absorption spectrum (CHCl3),maxcm-1: 2900, 1625, 1595, 1575.

Preparation 52.

4-[alpha-(2-Pyridyl)-4-trifluoromethyl - benzyl]-1-(2-phthalimidomethyl) piperidine.

Specified in the title compound is obtained with a yield of 87% in the implementation process in the same manner as described in preparation 1, by the reaction of N-(2-bromacil)phthalimide and 4-[alpha-(2-pyridyl)-4-trifloromethyl] piperazine.

IR absorption spectrum (CHCl3),maxcm-1: 2960, 2830, 1775, 1715, 1595, 1330.

Preparation 53.

4-[alpha-(2-pyridyl)benzyl]-1-(2-ftli - amidoethyl)piperazine.

Specified in the title compound with a melting point 114-117aboutC is obtained with a yield of 90% in the implementation process analogous to preparation 1, by the reaction of N-(2-bromacil)phthalimide and 4-[alpha-(2-pyridyl)benzyl]piperazine.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2800, 1780, 1710, 1590, 1400.

Preparation 54.

4-[alpha-(2-thienyl)benzylidene]-1-(3-nafta - imidapril)piperidyl.

Specified in the title compound is obtained with a yield of 84% when the[alpha-(2-thienyl)benzylidene]piperidine.

IR absorption spectrum (CHCl3),maxcm-1: 3000, 2940, 2900, 2805, 1595, 1490, 1440.

The drug 55.

1-(2-amino-ethyl)-4-[bis(4-forfinal)-al - f-oxymethyl]piperidine.

Specified in the title compound is obtained with a yield of 98% in the same manner as described in preparation 15, by the reaction of 4-[bis-(4-forfinal)-alpha-oxymethyl] -1-(2 - phthalimidomethyl)piperidine (obtained as described in preparation 46) and hydrazine hydrate.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2810, 1605, 1505.

Preparation 56.

1-(2-amino-ethyl)-4-[bis(4-forfinal)-IU - tilen]piperidine.

Specified in the title compound is obtained with a yield of 97% in the implementation process in the same manner as described in preparation 25 by the reaction of 4-[bis(4-forfinal)methylene] -1-(2-phthalimidomethyl)Pipa-ridin (obtained as described in preparation 47) and hydrazine hydrate.

IR absorption spectrum (CHCl3),maxcm-1: 2950, 2810, 1605, 1505.

Preparation 57.

1-(3-Aminopropyl)-4-[bis(4-forfinal)- methylene]piperidine.

Specified in the title compound is obtained with a yield of 20% when carrying out the process in the same manner as described in preparative 15, by the reaction of 4-[bis(4-p.

IR absorption spectrum (CHCl3),maxcm-1: 3370, 3270, 3170, 2940, 1660, 1605, 1505.

Preparation 58.

1-(2-amino-ethyl)-4-[alpha-(3-pyridyl)Ben - ZIL]piperazine.

Specified in the title compound is obtained with a yield of 98% in the implementation process in the same manner as described in preparation 15, by the reaction of 4-[alpha-(3-pyridyl)benzyl] -1-(2-phthalimidomethyl)Pipera - zine (obtained as described in preparation 49), and hydrazine hydrate.

IR absorption spectrum (CHCl3),maxcm-1: 3380, 3300, 3200, 2970, 2830, 1670, 1605, 1590, 1580.

The drug is 59.

1-(2-amino-ethyl)-4-[alpha-(4-pyridyl)Ben - ZIL]piperazine.

Specified in the title compound is obtained with a quantitative yield in the implementation process in the same manner as described in preparation 15 by the reaction of 4-[alpha-(4-pyridyl)benzyl] -1-(2-phthalimido - ethyl)piperazine (obtained as described in preparation 50), and hydrazine hydrate.

IR absorption spectrum (CHCl3),maxcm-1: 3380, 3300, 3200, 2970, 2830, 1670, 1600.

The drug is 60.

1-(2-amino-ethyl)-4-[alpha-(2-pyridyl)-4 - terbisil]piperazine.

Specified in the title compound is obtained with a yield of 88% in the implementation process in the same way that frame as described in preparation 51) and hydrazine hydrate.

IR absorption spectrum (CHCl3),maxcm-1: 3380, 3300, 3200, 2970, 2830, 1610.

Preparation 61.

1-(2-amino-ethyl)-4-[alpha-(2-pyridyl)-4 - trifloromethyl]piperazin.

Specified in the title compound is obtained with a quantitative yield in the implementation process in the same manner as described in preparation 15, by the reaction of 4-[alpha-(2-pyridyl)-4-trifloromethyl] - 1-(2-phthalimidomethyl)piperazine (obtained as described in preparation 52) and hydrazine hydrate.

IR absorption spectrum (CHCl3),maxcm-1: 3380, 3300, 3200, 2960, 2830, 2016.

Preparation 62.

1-(2-amino-ethyl)-4-[alpha-(2-pyridyl)Ben - ZIL]piperazine.

Specified in the title compound is obtained with a yield of 52% in the implementation process in the same manner as described in preparation 15, by reacting 4-[alpha-(2-pyridyl)benzyl] -1-(2-phthalimidomethyl) - piperazine (obtained as described in preparation 53) and hydrazine hydrate.

IR absorption spectrum (CHCl3), maxcm-1: 3400, 3000, 2850, 1640.

Preparation 63. 1-(3-Aminopropyl)-4-[alpha-(2-thienyl)benzylidene]piperidine.

Specified in the title compound is obtained with a yield of 92% in the implementation process the same obretenova as described in preparation 54) and hydrazine hydrate.

IR absorption spectrum (CHCl3),maxcm-1: 3200, 3030, 2950, 1660, 1595.

DERIVATIVES OF AMIDES THIAZOLIDINEDIONES ACIDS OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS HAVING ANTI-ALLERGIC AND ANTI-ASTHMATIC ACTIVITY AND ABILITY TO REDUCE PLATELET ACTIVATING FACTOR.

1. Derivatives of amides thiazolidinediones acids of General formula I

< / BR>
where R1or R2is hydrogen or Peregrina group, unsubstituted or substituted with at least one C1- C4is an alkyl group;

R3is hydrogen, C1- C4is an alkyl group, or a C2- C5-alkoxycarbonyl group;

R4is hydrogen or C1- C4is an alkyl group;

A - C2- C7- Allenova and alkylidene group;

Z is a group of General formulas II - V

< / BR>
< / BR>
< / BR>
< / BR>
or a group of General formulas II - V, in which one or more ring atoms substituted C1- C4-alkyl group and in which

R5and R6the same or different, and each represents unsubstituted phenyl group, substituted phenyl group, which contains at least one of the substituents a, defined below, or an unsubstituted rotoma nitrogen or sulfur; the above substituents selected from a halogen and a halogen-C1- C4is an alkyl group;

E - the carbon-carbon single bond or oxygen,

or their pharmaceutically acceptable salts having anti-allergic, anti-asthmatic activity and ability to reduce platelet activating factor.

2. Connection on p. 1, where R2- hydrogen.

3. Connection on p. 1, where R3- hydrogen.

4. Connection on p. 1, where R4- hydrogen.

5. Connection on p. 1, where Z is 4-(diphenylmethyl)-1-piperazinil, 4-[ -(chlorophenyl)benzyl] -1-piperazinil, 4-[bis(forfinal)methyl] -1-piperazinil, 4-(diphenylmethyl)-1-piperidyl, 4-[bis(forfinal)methoxy] -1-piperidyl, 4-(diphenylmethylene)-1-piperidyl, 4-[bis(forfinal)-methylene]-1-piperidyl, 4-( a-hydroxydiphenylmethyl)-1-piperidyl or 4-[bis (forfinal)- α-hydroxymethyl] -1-piperidyl.

6. Connection on p. 1, where R1- perederina the group which is not substituted or substituted by at least one C1- C4-alkyl Deputy; R2is hydrogen; R3is hydrogen, C1- C4is an alkyl group, or a C2- C5-alkoxycarbonyl group; R4is hydrogen or C1- C4is an alkyl group; A - C2- Cnekovee or different, each represents unsubstituted phenyl group, substituted phenyl group, which contains at least one of the substituents a', defined below, or unsubstituted aromatic heterocyclic group which has 5 or 6 ring atoms, of which 1 is a heteroatom nitrogen or sulfur; the substituents (a' - C1- C4is an alkyl group, halogen or triptoreline group; E is oxygen.

7. Connection on p. 1, where R1- unsubstituted Peregrina group; R2and R3is hydrogen; R4is hydrogen or a methyl or ethyl group; A - C2- C4-Allenova or alkylidene group; Z is a group of formulas II - V, as defined in paragraph 1, where R5and R6the same or different, each represents an unsubstituted phenyl group, substituted phenyl group, which contains at least one of the substituents a, defined below, pyridyloxy or thienyl group; the above substituents a" represents a methyl group, fluorine or chlorine; E is oxygen.

8. Connection on p. 1, where R1- perederina the group which is not substituted or contains at least one C1- C4-alkyl substituent; R2is hydrogen; R3is hydrogen, C1- C4is an alkyl group; A - C2- C6-Allenova or alkylidene group; Z is a group of formulas II - V, where R5and R6the same or different, each represents an unsubstituted phenyl group or substituted phenyl group, which contains at least one of the substituents a', which represents C1- C4is an alkyl group or halogen; E is a direct carbon-carbon single bond or oxygen.

9. Connection on p. 1, where R1- unsubstituted Peregrina group; R2and R3is hydrogen; R4is hydrogen or a methyl or ethyl group; A - C2- C4-Allenova or alkylidene group; Z is a group of formulas II - V, where R5and R6the same or different, each represents an unsubstituted phenyl group or substituted phenyl group, which contains at least one of substituents (aivthat represents a methyl group, fluorine or chlorine; E is oxygen.

10. Connection on p. 1, where R1- unsubstituted Peregrina group; R2and R3is hydrogen; R4is hydrogen or a methyl or ethyl group; A - C2- C4-Allenova or alkylidene group having Z - 4-[ a -(chlorophenyl)benzyl] -1-paidi or 4- (a-hydroxydiphenylmethyl)-1-piperideine group.

11. Connection on p. 1, representing a compound selected from the group comprising { 3-[ 4-bis( 4-forfinal )methyl-1-piperazinil ] -propellerblades } -2-(3-pyridyl)thiazolidin; { 3- [4-( a-2-pyridylmethyl)-1-piperazinil ] -propellerblades} -2-(3-pyridyl)thiazolidin; [ 2-(4-diphenylmethyl-1-piperazinil)ethylcarbamate ]-2-(3-pyridyl)thiazolidin; [ 3-{ 4-[ a -(4-chlorophenyl)benzyl ]-1-piperazinil } -propellerblades ]-2-(3-pyridyl)thiazolidin; [2-{4-[ a -(4-chlorophenyl)benzyl ]-1-piperazinil}-ethylcarboxyl ]-2-(3-pyridyl)thiazolidin; {3-[ 4-bis(4-forfinal)methoxy-1-piperidyl ]-propellerblades} 2-(3-pyridyl)thiazolidin; {2-[ 4-(diphenylmethylene)-1-piperidyl ]ethylcarbamate} -2-(3-pyridyl)thiazolidin; {3- [ 4-(diphenylmethylene)-1-piperidyl ] propellerblades}-2-(3-pyridyl)thiazolidin; {4- [ 4-(diphenylmethylene)-1-piperidyl]butylcarbamoyl} -2-(3-pyridyl)thiazolidin; [3-{4-[bis(4-forfinal)methylene]-1-piperidyl} -propellerblades ] -2-(3-pyridyl)thiazolidin; { 3-[4-( a-2-thienyl)benzyliden-1-piperidyl ]-propellerblades}-2-(3-pyridyl)thiazolidin; [N-{ 3-[4-diphenylmethylene-1-piperidyl]propyl} - N - ethylcarboxyl ] -2-(3 - pyridyl ) thiazolidin; [N-{2-[4-diphenylmethylene-1 - piperidyl]ethyl}-N - methylcarbamoyl]-2-(3 - pyridyl ) thiazolidin; {2-[4-( a - hydroxydiphenylmethyl )-1 - piperidyl ] ethylcarbamate}-2-(3 - pyridyl ) - thiazolidin,



 

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FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

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SUBSTANCE: invention relates to a solid composition eliciting with an anti-ulcer activity and to a method for its preparing. Pharmaceutical composition consists of a core containing famotidine as an active component and starch, aerosil, stearic acid salt as accessory inert substances wherein a core is covered by polymeric envelope. Core comprises glucose and stearic acid as an accessory inert substance and magnesium stearate as a stearic acid salt. Polymeric envelope comprises oxypropylmethylcellulose, propylene glycol, castor oil, talc and titanium dioxide taken in the definite ratio of all components in the composition. Method for preparing pharmaceutical composition involves preparing raw, mixing therapeutically effective amount of famotidine with glucose and starch, moistening the mixture with starch paste, granulation, drying wetted granulate, repeated granulation, powdering dry granules, tableting and applying polymeric envelope containing oxypropylmethylcellulose on prepared cores with addition of titanium dioxide, propylene glycol, castor oil and talc. Invention provides enhancement of degradability, solubility and stability in storing.

EFFECT: improved method for preparing, valuable pharmaceutical properties of composition.

3 cl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: medicine, therapy, gastroenterology.

SUBSTANCE: method involves preliminary assay of the disorder type in gallbladder motor contraction and bile-excretion ways followed by prescribing thermal low-mineralized hydrocarbonate-sodium-sulfate-calcium-magnesium mineral water in the dose by 200-300 ml, 3 times per a day, 1 h before eating, tubages № 3 with mineral water, bathes and shower with mineral water every day for 10-14 days. In the hypotonic type of motor activity method involves mineral water at temperature 25-30°C, and in the hypertonic type - at temperature 38-40°C. Method provides accelerating in scars formation of ulcers and epithelization of erosions in gastroduodenal system, to prevent frequent exacerbations and to reduce activity of Chelicobacter-induced inflammation.

EFFECT: improved therapy method.

4 tbl, 2 ex

FIELD: medicine, endocrinology.

SUBSTANCE: invention relates to treatment of diabetes mellitus in mammals. Invention proposes applying inhibitors of enzyme dipeptidyl peptidase IV as an active component in manufacturing a medicinal agent, and in a method for treatment of diabetes mellitus. Invention provides enhancing the functional activity of insulin-producing cells in animal and differentiation of epithelial cells of the pancreas.

EFFECT: improved method for insulin producing and diabetes treatment.

20 cl, 5 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

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