Esters of hinoklidina, intermediate compounds for their synthesis, pharmaceutical composition and method of treatment

 

(57) Abstract:

The invention relates to derivatives of 3-genocidally esters of the formula I or their pharmaceutically acceptable acid additive salts, where X is phenyl, Y is the group - (CH2)A- CR1R2- (CH2)BS(O)Z-R3where A and B are independently 0, 1 or 2, Z is 0, 1 or 2, R1and R2independently a hydrogen atom, (C1-C4)-alkyl, R3- (C1-C4)-alkyl or phenyl. Compounds have antagonistically activity against muscarinic receptors. The invention relates to a pharmaceutical composition having antimuskarinovoe act occurs bronchodilation action, which contains the above compound or its salt in an effective amount in a mixture with a pharmaceutically acceptable carrier or diluent and to a method of bronchodilatation, according to which impose the above compound in an effective amount. Proposed intermediate ester derivatives of hinoklidina formula II, where X is phenyl, Y is the group -(CH2)A- CR1R2-(CH2)B- SR3where A, B, R1, R2and R3have the above values. The method of obtaining compounds of formula I vkluchaia with formaldehyde to obtain the compounds of formula I, where Z = 0. If desired, the compound of formula I, where Z = 0, are oxidized with the formation of compounds of formula I, where Z = 1 or 2. If desired, the compound of the formula I can be implanted into its pharmaceutically acceptable salt. 5 C. and 12 C.p. f-crystals, 6 PL. -

The invention relates to 3-hinoksalinovym esters, namely to some 3-hinokitiol 3-hydroxymethyl 2-phenyl - or thienyl - alkanoates, which are pulmonary-selective antimuskarinovoe act occurs bronchodilatory means. Thus, these compounds are particularly useful for the treatment of chronic obstructive respiratory diseases and asthma.

Under chronic obstructive respiratory diseases understand the conditions under which to varying degrees is manifested several main-advancing clinico-pathological features, namely: the inflammatory swelling of the walls of the respiratory tract, hypertrophy of the submucosal membrane glands and excessive growth of secretory epithelial cells, which leads to increased secretion difficult to remove viscous secretions, progressive strengthening irreversible bronchospasm and reduce lung function, accompanying respiratory distress, increased illness and, finally, to see the tsya diseases, associated with the weakening of the function of the lungs in which the use antimuskarinovoe act occurs bronchodilators, as it is known, helps to improve the airway. However, existing tools are not selective with respect to muscarinic sites smooth muscle of the lungs; this reduces their effectiveness as bronchodilators and can cause unwanted side effects. It is now known that in the respiratory tract there are subtypes of muscarinic receptors (see B. J. Barnes, P. Minette and J. Maclagan, TIPS, 1988, vol, p. 412); M1 receptors are present on sympathetic nerves and parasympathetic nervous nodes; M2 receptors are present on pulmonary cholinergic nerves (predushelnoye inhibiting receptors), and M3 receptors are located on smooth muscle (poslushaniye receptors). Compounds of the present invention typically have a bronchodilator effect at doses that have little effect on the tissues of other organs such as the brain, heart, gastrointestinal tract, eyes and salivary glands. Moreover, they typically exhibit selectivity towards pokusannym the M3 receptor in comparison with predushelnoye pulmonary receptors M2 and heart of Razer, the considered compounds are likely to be useful in the treatment of urinary incontinence.

In the present invention claimed compound of General formula (I):

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or its pharmaceutically acceptable salt, where X is either (a) a phenyl group optionally substituted by one or two substituents, independently selected from a halogen atom, triptorelin group, (C1-C4)alkyl groups, (C1-C4)alkoxy group, or (b) thienyl group; Y is either (a) a group of the formula (Ya).

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where

A and B are independently 0, 1 or 2, or (b) a group of formula (Vb)

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where

D and E are independently 0 or 1 and F is 0, 1 or 2, with D + E + F = 1, 2, or 3; Z is 0, 1 or 2;

R1or R2independently are a hydrogen atom or a (C1-C4)alkyl group, or R1and R2unite and form, together with the carbon atom to which they are attached, a 3 - or 6-membered carbocycle; and

R3is (C1-C4)alkyl group, cycloalkyl group or phenyl or benzyl group, optionally containing from one to three substituents independently selected from a halogen atom, triptorelin group (Com halogen" means a fluorine atom, chlorine, bromine or iodine. Alkyl and CNS group containing 3 or 4 carbon atoms, may be straight or branched chain.

X mainly is an unsubstituted phenyl group. In that case, if the group Y is represented by formula (Va), R1and R2preferable are a hydrogen atom or, if A = 1 and B = 0, R1and R2mostly independently are hydrogen atom, methyl group or ethyl group. R3preferably is a methyl group.

The compounds of formula (I) contain two asymmetric center at the positions marked 2 and 3' in the above formula (I). If R1and R2are different, the compounds have the third asymmetric center at the carbon atom to which are attached the substituents R1and R2and if Z = 1, then formed a fourth asymmetric center at the sulfur atom. All diastereomers, regardless of whether they are selected or not, are included in the scope of claims of the present invention. The preferred compounds are nevertheless 3R - genocidally esters. In addition, if the hydrocarbon fragment group Y is attached to the carbon atom in position 2, has at least dim way the preferred compounds are (2S, 3'R)-3-genocidally esters, which can be represented in the following form

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If

Z = 1, the preferred configuration of the sulfur atom is R configuration, and in this case, the fragment containing the sulfur atom can be represented in the following form

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The most preferred individual compound of the present invention is (R) -3-hinokitiol (2S, Rs)-2-hydroxymethyl-4-(methylsulfanyl)-2-phenylbutanoate.

The compounds of formula (I) in which Z is 0, can be obtained by the reaction of an ether of the formula (II) with a strong base, such as di-ISO-propylamide lithium or potassium tert-piperonyl potassium or sodium hydride, with the formation of a carbanion and the subsequent reaction of the carbanion with formaldehyde. Formaldehyde is usually injected into the reaction in a gaseous state or in the form of paraformaldehyde (in which the solution decays with the emission of formaldehyde).

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Preferred are the following methods.

One of them ether (II) interacts in a few hours with di-ISO-propylamide lithium in tetrahydrofuran at a temperature of approximately -78oC. the Reaction mixture is allowed then soobrazhayu formaldehyde, which generate, for example, by heating paraformaldehyde.

According to another method sodium hydride, an ester (II) and paraformaldehyde interact in dimethylformamide at a temperature close to the room.

Preferred are such compounds (I), in which the configuration at the carbon atom in position 3' corresponds to the configuration of R, and such compounds it is best to obtain, starting from the ester (II) having the R configuration at the carbon atom in position 3' of the formula (II). Similarly 3S hinkleyville esters can be obtained from the esters (II) having the S configuration at the carbon atom in position 3'.

Usually most convenient to proceed from 2RS form of esters (II), even if the target connection is not 2RS form and 2R or 2S. In this case, the result is a mixture of diastereomers of the compound (I), and, if necessary, they can be divided into 2R or 2S forms by conventional means such as chromatography. As mentioned earlier, while the General case, when the hydrocarbon fragment in the Deputy V contains at least two carbon atoms, are preferred (2S, 3'R) shape of the compound (I).

The compounds of formula (I) in which Z = 1 or 2, can be obtained by oxidation of the corresponding compounds, is in fact, the solution nutritiously acid in solution triperoxonane acids are added at a low temperature, such as -10oC, to the compound dissolved in triperoxonane acid, and the mixture is allowed to warm to room temperature, and upon completion of the reaction, the solvent is evaporated. The target connection get extragere it from the remainder of the solvent. If you want to get sulfonylurea derivative (Z = 2), then you can use the excess nutritiously acid, if you want to get alvinlee derivative (Z = 1), you should use a stoichiometric amount of nutriformance acid and to maintain low temperature. Usually get a mixture of Rsand Ssstereomono sulfanilimide derived, which can be divided into conventional methods such as chromatography.

Starting compound (II) are also part of the present invention. You can get them in the usual ways, such as

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The reaction is usually carried out by boiling the reactants under reflux in an organic solvent such as toluene. Compound (III) is most conveniently used in the form of RS derivative and preferably in the form of a methyl ester.

On der, the reaction with oxalyl chloride in chloroform, and the resulting halogenated derivatives enter into the reaction with 3-hinokitiol with the formation of the compounds of formula (II).

Typically the substances of the formula (III) can be prepared by the reaction of the acid of formula X-CH-COOH with the compound of the formula Y-Hal, where Hal represents a chlorine atom, bromine and iodine, in the presence of a strong base, such as di-ISO-propylamide lithium in anhydrous solvent such as tetrahydrofuran, followed by acidification and obtaining the compounds of formula X-CH(COOH)-Y. the resulting compound can be further converted into the corresponding ester of formula (III) by conventional means, for example, interaction with methanol or ethanol in the presence of sulfuric acid.

In another method of obtaining the compounds of formula (III) thiol of the formula R3- SH interacts with the acid of formula (IY)

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where

Y' is a hydrocarbon fragment group Y in the formula (I) and Hal is a chlorine atom, bromine or iodine, usually in the presence of a strong base such as sodium hydride, followed by esterification.

In that case, if Y denotes the group-CH2-S-R3the compound of formula (II) can also be obtained by reaction of compounds of formula R3-SH with the formaldehyde and base with obtaining the compounds of formula (I).

Selectivity of compounds as antagonists of muscarinic receptor is determined as follows.

Decapitate male Guinea pigs, remove the terminal ileum, trachea, bladder and right atrium and suspended in Krebs solution under a load of 1 g at a temperature of 30oC, hareruya a mixture of 95% oxygen and 5% carbon dioxide. Compression ileum, bladder and trachea register using isotonic (powszechna intestine) or isometric transducer (bladder and trachea). The frequency of contractions spontaneously pulsating double fibrillation deduce on the basis of isometric recording cuts.

Curves of the dose in relation to carbazole build when contact time is 1-5 minutes for each dose of agonist until then, until there is a maximum response. Bath and placed in it by the authorities, drain and fill with fresh Krebs solution containing the minimum dose of the test compound. Within 20 minutes give the subject compound equilibrium distributed in tissues and repeat the construction of curves depending on the dose of the agonist to the until will not be observed maximum response. Prov.constituent compounds and repeat the above process. Usually for each type of tissue carry out measurements for the three concentrations of the test compounds.

The negative logarithm of the molar concentration (pA2) test connection, which requires a doubling of the concentration of agonist to obtain the initial response, determined by the method of shilda (Arunlakshana and Schild, Brit. J. Pharmacol, 1959, VoI. 14, pp. 48-58). Using the above pharmacological method, determine the tissue selectivity with respect antagonists muscarinic receptor.

Activity against narrowing of the lumen of the bronchi caused by agonist or bronchostenosis nervous character, or in respect of sacramemto bowel or bladder in comparison with changes in heart rate determine the shot dogs, cats or Guinea pigs. Activity in oral introduction explore the in the mind of the dog, determining the effects of compounds on the functioning of the lungs, heart rate, pupil diameter and the mobility of the intestine (gut).

The affinity of compounds in relation to other cholinergic sites examined in mice after intravenous or intraperitoneal injection. So, Opredelenie shivering (utter) injected oxotremorine.

The selectivity of the compounds for pulmonary postsynaptic compared to presinapticheskimi muscarinic receptors in anastasiosandy Guinea pigs and cats can be estimated using the following methodology. Acetylcholine secreted under the influence of nerve stimulation activates postsynaptic muscarinic M3 receptors, which leads to contraction of smooth muscles of respiratory ways and, in addition, activate presinapticheskie autoreceptor that inhibit further selection of the mediator. Animal studies indicate that these pulmonary presinapticheskie muscarinic autoreceptor represent a subtype M2 (Barnes et aI., 1989). Non-selective agents such as ipratropium bromide inhibit both plots, which leads, in the case transmitted via nerve impulses, to increase the selection of a mediator, which can overcome the blockade of postsynaptic receptor. Published literature data show that bromide ipratropium may actually increase caused by the vagus nerve, bronchostenosis at anastasiosandy Guinea pigs (Fryer and Maclagan, Eur. Jou. Pharmacol., 1987, Vol. 139, pp. 187-191). Thus, the effect of the tested compounds on presinapticheskie postsynaptic muscarinic which of the responses, caused by exogenous introduction of acetylcholine.

For example, it was found that the compound of example 29 suppresses in the same range of doses of bronchostenosis at anastasiosandy Guinea pigs, caused by acetylcholine, and the vagus nerve. This result differs from the action of ipratropium bromide, which is much less active against bronchostenosis caused by the vagus nerve, than to bronchostenosis caused by the introduction of acetylcholine. Next, at doses of bromide ipratrop less than 1 µg/kg actually increases bronchostenosis, called the vagus nerve, which confirms its presinapticheskie action.

Similar results were obtained with politowaniem compound of example 29 and in the case anastasiasunny cats. Animals pre-injected with propranolol because the high sympathetic tone during anesthesia by chloralose can withstand the increased bronchostenosis, called the vagus nerve. The tests show that in addition to its high activity of the compound of example 29, in contrast to ipratropium bromide, does not interrupt control over the selection of a mediator as Guinea pigs, and cats. This confirms shown in the condition is the result of such selectivity in respect and postsynaptic, in comparison with presinapticheskimi muscarinic receptors of the compounds of the present invention to be more effective bronchodilators (bronchodilation) means in the case of respiratory diseases than bromide ipratropium.

Acid-additive salt (salt accession acids) compounds of formula (I) can be obtained in the usual way by treatment of a solution or suspension of the free base of formula (I) approximately one chemical equivalent of a pharmaceutically acceptable acid. To highlight the obtained salts usually use methods of concentration and recrystallization. Examples of suitable acids are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfamic acid, sulfonic acid, such as methanesulfonate acid, benzolsulfonat acid and similar acids.

In the treatment of the above conditions the compounds of formula (I) can be assigned to subyek formulations for inhalation. The compounds have the ability to penetrate through the gastrointestinal tract and, thus, it is possible to use compositions, providing a slow release of active substances.

In General therapeutically effective oral dose of the active compounds of formula (I) is from 0.01 to 1 mg/kg of body weight of the patient, mainly from 0.1 to 0.5 mg/kg In practice, the physician determines the actual dose that is best suited to the individual patient depending on age, weight, and responses to the drug in a particular patient. The above doses are examples for common cases, however, there may be individual cases where you will need larger or smaller doses, and they are also included in the scope of claims of the present invention.

Although the compounds of the present invention can be assigned individually, they are usually injected in a mixture with a pharmaceutical carrier selected depending on the proposed route of administration and conventional pharmaceutical practices. For example, oral appointment can be made in the form of tablets containing such excipients as starch or lactose, in the form of capsules both independently and in combination with fillers, in the form of aerosols or dry porosome the aim of the invention is a pharmaceutical composition, containing the compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

The invention also includes a compound of formula (I) or its pharmaceutically acceptable salt for use as a medicine.

The invention further includes the use of compounds of formula (I) or its pharmaceutically acceptable salt for the manufacture of a medicine for the treatment of chronic obstructive respiratory diseases or asthma.

Obtaining the compounds of the present invention is illustrated by the following examples.

Example 1.

(R)-3-Hinokitiol(R and S)-3-hydroxy-2-(methylthiomethyl)-2-phenylpropanoate.

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Sodium hydride (2 mg, 80% dispersion in oil) is added to a mixture of (R)-3-hinokitiol-2-phenylacrylate (see Method 1) (1,03) and methanethiol (2 ml of 10% weight/about solution in chloroform) in chloroform (8 ml). After 1 hour, the mixture is evaporated, the residue is dissolved in dimethylformamide (2.5 ml) and add it to the pre-mixed (within 5 minutes) of a mixture of paraformaldehyde (240 mg) and sodium hydride (1 mg, 80% dispersion in oil) in dimethylformamide (10 ml). After two hours, poured poluchaiut, and the resulting residue purified by chromatography on silica gel with a gradient elution with a mixture of chloroform and methanol (0-->10%) and ammonia (0-->1%). Collect the desired fraction and evaporated, receiving two of the above compounds as white solids undefined configuration on the carbon atom in position 2.

The diastereoisomer 1 (has a higher Rf value on thin layer of the chromatogram) (0.27 g, 40%, counting on single isomer), so pl. 143-145oC.

Elemental analysis, %:

Found: C 64,07; H 7,35; N 4,25;

Calculated for C18H25NO3S: C 64,44; H 7,51; N 4,18.

The diastereoisomer 2 (has a smaller Rf value on thin layer of the chromatogram) (0.17 g, 25%, counting on single isomer), so pl. 122 - 123oC.

Elemental analysis, %:

Found: C 64,23; H 7,39; N 4,25;

Calculated for C18H25NO3S: C 64,44; H 7,51; N 4,18.

Example 2.

(R)-3-Hinokitiol(R and S)-2-hydroxymethyl-4-(methylthio)-2-phenylbutanoate.

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Sodium hydride (320 mg, in the form of an 80% suspension in oil) is added dropwise within 1 hour to a mixture of (R)-3-hinokitiol(RS)-4-(methylthio)-2-phenylbutanoate (see Getting 2 (Method 2) (22 g) and paraformaldehyde (6.2 g) in dimethylformamide (90 ml) at room temperature. After 2 h Ave elewaut in a mixture of ethyl acetate and water, the organic layer is separated, washed with water, dried over magnesium sulfate and evaporated, and the resulting residue purified by chromatography on silica gel with a gradient elution with a mixture of chloroform and methanol (0-->10%) and ammonia (0-->1%). Collect the desired fraction and evaporated, receiving two of the above compounds as white solids with a specific configuration at the carbon atom in position 2.

The diastereoisomer 1 (R configuration) (4 g, 33%, counting on single isomer), so pl. 109-110oC.

Elemental analysis, %:

Found: C 65,60; H a 7.92; N 4,01;

Calculated for C19H27NO3S: C 65,29; H 7,79; N 4,01.

The diastereoisomer 2 (S configuration) (4.4 g, 37%, counting on single isomer), so pl. 134-135oC.

Elemental analysis, %:

Found: C 65,09; H to 7.84; N 3,94;

Calculated for C19H27NO3S: C 65,29; H 7,79; N 4,01.

Examples 3 to 9.

The following examples of compounds of General formula

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are given in table. 1, get on techniques similar to that shown in example 2, hydroxymethylpropane appropriate way of substituted (R)-3-hinkleyville ether. Individual experimental differences indicated in the table. The term "diastereomers 1 and 2 indicates their relative is < / BR>
Synthesis of starting compound see Methods 3.

Experimental differences:

The reaction is interrupted by the addition of 2N hydrochloric acid. When chromatographicaliy use a mixture of ethyl acetate/ether/diethylamine/methanol(50 : 50 : 5 : 5). Each diastereoisomer (the carbon atom in position 2) contains a 50 : 50 mix of compounds, differing in the configuration of the carbon atom in position 4.

Analytical data:

The diastereoisomer 1 - solid white with so pl. 141 - 143oC.

Elemental analysis, %:

Found: C 65,86; H 8,12; N 3,86;

Calculated for C20H29NO3S: C 66,08; H 8,04; N 3,85.

The diastereoisomer 2 - solid white with so pl. 100 - 102oC.

Elemental analysis, %:

Found: C 65,91; H 7,88; N 4,00;

Calculated for C20H29NO3S: C 66,08; H 8,04; N 3,85.

Example 4.

R-value:

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Synthesis of starting compound see Methods 5.

Experimental differences:

The reaction is interrupted by the addition of 2N hydrochloric acid. When chromatographicaliy use a mixture of ethyl acetate/ether/diethylamine/methanol(50:50:5: 5). Each diastereoisomer (the carbon atom in position 2) contains a 50: 50 mix of compounds, otlichalsya substance of white color with so pl. 157 - 159oC.

Elemental analysis, %:

Found: C 66,98; H to 8.41; N 3,92;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

The diastereoisomer 2 - solid white with so pl. 89-91oC.

Elemental analysis, %:

Found: C 66,95; H 8,01; N A 3.87;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

Example 5.

R-value:

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Synthesis of starting compound see Methods 6.

Experimental differences:

Dimethylformamide evaporated from the reaction mixture without interrupting the reaction. When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

The diastereoisomer 1 - solid white with so pl. 105-106oC.

Elemental analysis, %:

Found: C 69,76; H 7,13; N 3,26;

Calculated for C24H29NO3S: C 70,04; H 7,10; N 3,40.

The diastereoisomer 2 - solid white with so pl. 138-139oC.

Elemental analysis, %:

Found: C 69,77; H 7,13; N 3,24;

Calculated for C24H29NO3S: C 70,04; H 7,10; N 3,40.

Example 6.

R-value:

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Synthesis of starting compound see Methods 7.

Analytical data:

The diastereoisomer 1 - solid white with so pl. 114-115oC.

Elemental analysis, %:

Found: C 65,98; H 8,00; N 3,85;

Calculated for C20H29NO3S: C 66,08; H 8,04; N 3,85.

The diastereoisomer 2 - solid white with so pl. 149-141oC.

Elemental analysis, %:

Found: C, 65.22 per; H of 7.96; N 3,83;

Calculated for C20H29NO3S: C 66,08; H 8,04; N 3,85.

Example 7.

R-value:

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Synthesis of starting compound see Methods 8.

Experimental differences:

The reaction mass is poured into a mixture of water and ethyl acetate.

Analytical data:

The diastereoisomer 1 - solid white with so pl. 137-138oC.

Elemental analysis, %:

Found: C 66,57; H 8,21; N 3,63;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

The diastereoisomer 2 - solid white with so pl. 153-154oC.

Elemental analysis, %:

Found: C 66,58; H 7,81; N 3,66;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

Example 8.

R-value:

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Synthesis of starting compound see Methods 9.

Experimental differences:

Reacted substance of white color with so pl. 109-110oC.

Elemental analysis, %:

Found: C 66,13; H 8,01; N 3,88;

Calculated for C20H29NO3S: C 66,08; H 8,04; N 3,85.

The diastereoisomer 2 - solid white with so pl. 125-126oC.

Elemental analysis, %:

Found: C 65,69; H of 7.97; N 3,89;

Calculated for C20H29NO3S: C 66,08; H 8,04; N 3,85.

Example 9.

R-value:

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Synthesis of starting compound see Methods 10.

Experimental differences:

The reaction mass is poured into a mixture of water and ethyl acetate.

Analytical data:

The diastereoisomer 1 - solid white with so pl. 109-110oC.

Elemental analysis, %:

Found: C 66,49; H 8,08; N 3,54;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

The diastereoisomer 2 - solid white with so pl. 109-110oC.

Elemental analysis, %:

Found: C 66,57; H 8,09; N 3,69;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

Example 10.

(R)-3-hinokitiol (R and S)-3-hydroxymethyl-4-methyl-4-(methylthio)-2-phenylpentane.

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Di-ISO-propylamide lithium (5,7 ml of 1.5 M solution in cyclohexane) is added at -78oC to a solution of (R)-3-gioclase to slowly warm to room temperature and during this time continuously miss gaseous formaldehyde [generated by heating paraformaldehyde (1.5 g) in a stream of nitrogen]. Then add a saturated solution of ammonium chloride and the product extracted with ethyl acetate. The organic extract is dried over magnesium sulfate and evaporated under reduced pressure and the residue is purified by chromatography on silica gel, using as eluent a mixture of ethyl acetate: diethylamine: methanol(50 : 50 : 5 : 5). Collect the desired fraction and evaporated, receiving two of the above compounds as white solids, unspecified configuration at the carbon atom in position 2.

The diastereoisomer 1 (has a higher R value) to thin the chromatogram) (0.35 g, 24%, counting on single isomer), so pl. 179-180oC.

Elemental analysis, %:

Found: C 66,56; H of 8.37; N 3,49;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

The diastereoisomer 2 (has a smaller Rf value on thin layer of the chromatogram) (0.31 g, 21%, counting on single isomer), so pl. 135-137oC.

Elemental analysis, %:

Found: C 66,48; H 8,32; N 3,45;

Calculated for C21H31NO3S: C 66,80; H 8,28; N 3,71.

Example 11.

(R)-3-Hinokitiol (R and S)-3-hydroxy-2-(methylsulfonylmethyl)-2-phenylpropanoate

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Nutritiously acid (0,36 ml of 3M solution in triperoxonane acid) is added during 5oC, stirred for 1 hour and evaporated, obtaining a residue, which was poured into 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, evaporated and the residue purified by chromatography on silica gel with a gradient elution with a mixture of chloroform/methanol (0-->10%) and aqueous solution of ammonia (0-->1%). Collect the desired fraction and evaporated, obtaining the target compound, a single diastereoisomer with uncertain configuration at the carbon atom in position 2 (90 mg, 43%) as white matter with so pl. 136-137oC.

Elemental analysis, %:

Found: C 58,84; H 6,86; N 3,81;

Calculated for C18H25NO5S: C 58,66; H 6,62; N 3,65.

Example 12.

(R)-3-Hinokitiol (S)-2-hydroxymethyl-4-(methylsulphonyl)-2-phenylbutanoate.

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Nutritiously acid (0,36 ml of 3M solution in triperoxonane acid) is added at -10oC to a solution of (R)-3-hinokitiol (S)-3-hydroxy-4-(methylthio)-2-phenylbutanoate (see example 2) (0,189 g) in triperoxonane acid (2 ml). Allow the mixture to warm to room temperature, stirred for 1 hour and evaporated, poluchaetsja dried over sodium sulfate, evaporated and the residue purified by chromatography on silica gel with a gradient elution with a mixture of chloroform/methanol (0-->10%) and aqueous solution of ammonia (0-->1%). Collect the desired fraction and evaporated, obtaining the target compound (0,155 g, 74%) as white matter with so pl. 154-155oC.

Elemental analysis, %:

Found: C 59,65; H 7,19; N, TO 3.58;

Calculated for C19H27NO5S: C TO 59.82; H 7,14; N 3,67.

Examples 13 to 20.

The following examples of compounds of General formula

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in table 2, get on techniques similar to that shown in example 12, by oxidation of the corresponding sulfide. The original sulfides with uncertain configuration at the carbon atom in position 2, each time are diastereoisomers having a smaller Rf value according to thin-layer chromatography in the corresponding example. Individual experimental differences indicated in the table.

Table 2.

Example 13.

The value of the X-S-Y:

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Synthesis of starting compound, see example 3.

Experimental differences:

During extraction, instead of combining an aqueous solution of potassium carbonate/chloroform are combined aqueous ammonia/chloroform. Dissolve what about the yellow color in the form of a mixture of 50:50 diastereomers on the carbon atom in position 4.

Range PMR (300 MHz, chloroform-d): M. D., 1,0-3,4 (20H, multiplet), 4.1 and 4.5 (2H, multiplet), 4,9 (1H, multiplet), 7,2-7,3 (5H, multiplet).

Mass spectrum m/e (MH+) 396.

Example 14.

The value of the X-S-Y:

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Synthesis of starting compound, see example 10.

Experimental differences:

The extraction uses a combination of aqueous ammonia/ethyl acetate. Chromatography is not carried out, the product is purified by recrystallization from ethyl acetate.

Analytical data:

The substance of white color with so pl. 167-169oC.

Elemental analysis, %:

Found: C 61,38; H 7,35; N 3,25;

Calculated for C21H31NO5S: C 61,58; H 7,63; N 3,42.

Example 15. The value of the X-S-Y:

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Synthesis of starting compound, see example 4.

Experimental differences:

The extraction is carried out, as described in example 14. Chromatography were carried out as described for example 12 and receive two partially separated diastereoisomer on the carbon atom in position 4.

The diastereoisomer 1 (has a higher Rf value on thin layer of the chromatogram) - the substance of white color with so pl. 144-145oC.

Elemental analysis, %:

Found: C 60,99; H to 7.67; N 3,30;

Calculated for C21is a response to T. pl. 128-130oC.

Elemental analysis, %:

Found: C 61,57; H 7,15; N 3,36;

Calculated for C21H31NO5S: C 61,58; H 7,63; N 3,42.

Example 16. The value of the X-S-Y:

< / BR>
Synthesis of starting compound, see example 5.

Experimental differences:

When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

Solid white with so pl. 179-180oC.

Elemental analysis, %:

Found: C 63,67; H 6,70; N 3.04 FROM;

Calculated for C24H29NO5S1/2H2O: C 63,69; H OF 6.68; N 3,09.

Example 17. The value of the X-S-Y:

< / BR>
Synthesis of starting compound, see example 6.

Experimental differences:

When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

Solid white with so pl. 158-159oC.

Elemental analysis, %:

Found: C 57,56; H 6,88; N 3,30;

Calculated for C20H29NO5S1/5CHCl3: C 57,85; H 7,01; N 3,34.

Example 18. The value of the X - S - Y:

Synthesis of starting compound, see example 7.

< / BR>
Eksperimentalnaya ammonia (0-->1.5 percent).

Analytical data:

Solid white with so pl. 187-188oC.

Elemental analysis, %:

Found: C 59,68; H 7,34; N 3,26;

Calculated for C21H31NO5S1/8CHCl3: C 59,77; H 7,39; N 3,30.

Example 19. The value of the X - S - Y:

< / BR>
Synthesis of starting compound, see example 8.

Experimental differences:

When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

Foamy substance.

Elemental analysis, %:

Found: C 56,32; H is 6.78; N 3,16;

Calculated for C20H29NO5S1/3CHCl3: C 56,09; H 6,79; N 3,20.

Example 20. The value of the X - S - Y:

< / BR>
Synthesis of starting compound, see example 9.

Experimental differences:

When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

Solid white with so pl.: 81-83oC.

Elemental analysis, %:

Found: C 61,36; H 7,29; N 3,40;

Calculated for C21H31NO5S: C 61,59; H 7,63; N 3,42.

Example 21.

(R)-3-Hinokitiol(2RS,RsSs)-3-the thief in triperoxonane acid) is added at -5oC to a solution of diastereoisomer 2(R)-3-hinokitiol(R or S)-3-hydroxy-2-(methylthiomethyl)-2-phenylpropanoate (see example 1) (0,335 g) in triperoxonane acid (3 ml). The mixture is stirred for 1/2 hour, warmed to room temperature, stirred for 1 hour and evaporated. The residue was poured into 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, evaporated and the residue purified by chromatography on silica gel with a gradient elution with a mixture of chloroform/methanol (0-->10%) and aqueous solution of ammonia (0-->1%). Collect the desired fraction and evaporated, obtaining the target compound, a single diastereoisomer with uncertain configuration at the carbon atom in position 2 (0.14 g, 40%) as white matter with so pl. 126-127oC.

Elemental analysis, %:

Found: C 61,49; H 7,24; N 3,79;

Calculated for C18H25NO4S: C 61,51; H 7,17; N 3,99.

Examples 22 to 28.

The following examples of compounds of the General formula:

< / BR>
in table 3, receive on techniques similar to that shown in example 21, by oxidation of the corresponding sulfide. The original sulfides with uncertain configuration at the carbon atom in position 2, cardiomem example. Attempts to separate isomeric sulfoxidov not been undertaken. Individual experimental differences indicated in the table.

Table 3

Example 22. The value of the X - S - Y:

< / BR>
Synthesis of starting compound, see example 3.

Experimental differences:

The extraction uses a combination of aqueous ammonia/chloroform.

Analytical data:

A viscous yellow oil as a mixture of 50:50 diastereomers on the carbon atom in position 4.

Range PMR (300 MHz, chloroform-d): M. D., 1,0 - 3,4 (20H, multiplet), 4.0 to 4.5 (2H, multiplet), is 4.85 (1H, multiplet), and 7.1 to 7.4 (5H, multiplet).

Mass spectrum m/e (MN+) 380.

Example 23. The value of the X - S - Y:

< / BR>
Synthesis of starting compound, see example 10.

Experimental differences:

The extraction uses a combination of aqueous ammonia/ethyl acetate.

Analytical data:

Viscous clear oil.

Range PMR (300 MHz, chloroform - d): M. D., of 0.9 to 2.0 (11H, multiplet), about 2.2-2.8 (10H, multiplet), 3,1 (1H, multiplet), 4,2-4,5 (2H, multiplet), 4,8 (1H, multiplet), of 7.2 to 7.4 (5H, multiplet).

Mass spectrum m/e (MN+) 394.

Example 24. The value of the X - S - Y:

< / BR>
The synthesis of the original coodinator ammonia/ethyl acetate.

Analytical data:

Foamy substance in the form of a mixture of 50:50 diastereomers on the carbon atom in position 4.

Range PMR (300 MHz, chloroform - d): M. D., 0,4 - 3,0 (22H, multiplet), and 3.3 (1H, multiplet), 4 - 4,4 (2H, multiplet), 4,9 (1H, multiplet), 5,4 - 6,0 (1H, broad singlet), of 7.0 to 7.4 (5H, multiplet).

Mass spectrum m/e: MN+) 394.

Example 25. The value of the X - S - Y:

< / BR>
Synthesis of starting compound, see example 6.

Experimental differences:

The extraction uses a combination of a potassium carbonate/chloroform. When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

Solid white with so square 138 - 139oC.

Elemental analysis, %:

Found: C 60,14; H 7,42; N 3,49;

Calculated for C20H29NO4S. 1/5CHCl3: C 60,14; H 7,30; N 3,47.

Example 26. The value of the X - S - Y:

< / BR>
Synthesis of starting compound, see example 7.

Experimental differences:

The extraction uses a combination of a potassium carbonate/chloroform. When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analysis is/BR> Found: C 63,53; H 7,50; N 3,51;

Calculated for C21H31NO4S: C 64,09; H 7,94; N 3,56.

Example 27. The value of the X - S - Y:

< / BR>
Synthesis of starting compound, see example 8.

Experimental differences:

During extraction, use of a combination of a potassium carbonate/chloroform. When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., 1,2 - 2,8 (19H, multiplet), 3,1 (1H, multiplet), 4,0 (1H, doublet), 4,25 (1H, doublet), is 4.85 (1H, multiplet), a 7.1 to 7.5 (5H, multiplet).

Mass spectrum m/e (MH+) 380.

Example 28. The value of the X - S - Y:

Synthesis of starting compound, see example 9.

< / BR>
Experimental differences:

The extraction uses a combination of a potassium carbonate/chloroform. When chromatography as eluent a mixture of chloroform/methanol (0-->15%) and aqueous ammonia (0-->1.5 percent).

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., 1,1 - 2,9 (21H, multiplet) and 3.15 (1H, multiplet), 4,0 (1H, doublet), 4.2V (1H, doublet), is 4.85 (1H, multiplet), of 7.2 to 7.4 (5H, multiplet).

Mass specitically)-2-phenylbutanoate.

< / BR>
Nutritiously acid (4 ml of a 3M solution in triperoxonane acid) is added at a temperature in the range from -3 to 0oC to a solution of (R)-3-hinokitiol(S)-3-hydroxy-4-(methylthio)-2-phenylbutanoate (see example 2) (4,19 g) in triperoxonane acid (18 ml). Allow the mixture to warm to room temperature, stirred for 1 hour and evaporated. The residue was poured into 10% aqueous potassium carbonate solution and extracted with chloroform. The organic extract is dried over sodium sulfate, evaporated and the residue purified by chromatography on silica gel with a gradient elution with a mixture of chloroform/methanol (0-->15%) and aqueous solution of ammonia (0-->1.5 percent). Collect the desired fraction and evaporated, obtaining the target compound (4 g, 91%) as a mixture of Rsand Ssdiastereomers.

The resulting mixture was purified liquid chromatography high resolution using phase Kromas: 1 C-8 silica gel and an aqueous solution containing triperoxonane acid (1%) and acetonitrile (11%). Collecting appropriate fractions and evaporated, receiving two target compounds with the specified configuration at the sulfur atom in the form of solids white.

The diastereoisomer 1 (eluted first, the configuration of Ss) (70 mg, 28%, counting on a single UB>19H27NO4S: C 62,43; H 7,45; N 3,83.

The diastereoisomer 2 (eluted second, the configuration of Rs) (70 mg, 28%, counting on single isomer), so pl. 84 - 85oC.

Elemental analysis, %:

Found: C 62,19; H 7,45; N 3,81;

Calculated for C19H27NO4S: C 62,43; H 7,45; N 3,83.

The following methods belong to intermediate compounds used in the synthesis of the target compounds of the present invention.

Methodology 1.

(R)-3-Hinokitiol-2-phenylacrylate.

< / BR>
Chloride, oxalyl (44,2 ml) are added to a solution of 2-phenylacrylate acid (50 g) (receive, see J. Chem. Soc., 1923. Vol 123, p. 2557) and dimethylformamide (0.5 ml) in chloroform (500 ml). The resulting mixture is stirred for 1/2 hour, add dimethylformamide and the mixture is stirred for 1/2 hour, then evaporated and the residue extracted with chloroform (2 x 100 ml) and evaporated. The residue is again dissolved in chloroform (500 ml) and to the resulting solution at 10 - 15oC add (R) - 3-hinokitiol (produced by the method described in Acta. Pharm. Suec., 1979, Vol. 16, p. 281) dissolved in chloroform (500 ml). The mixture is stirred for 1/2 hour, allow to rise slowly to room temperature, poured into 25% aqueous solution crystallizability of hexane, receiving the target compound in the form of solid white (66 g, 76%) with T. pl. 83 - 85oC.

Elemental analysis, %:

Found: C 74,39; H 7,47; N THE 5.45;

Calculated for C16H19NO2: C 74,67; H 7,44; N, 5,44.

Method 2.

(R)-3-Hinokitiol (RS)-4-(methylthio)-2-phenylbutanoate.

< / BR>
Sodium hydride (0.64 g in the form of an 80% dispersion in oil) is added to a mixture of methyl-(RS)-4-(methylthio)-2-phenylbutanoate (see Methods 11) (19.1 g) and (R) - 3-hinokitiol (see getting Acta. Pharm. Suec., 1979, Vol. 16, p. 281) (12.7 g) in toluene (440 ml). The mixture is boiled for 1.5 hours, constantly fending off the distillate and from time to time by adding the required amount of fresh toluene. Cooled, extracted with 2M hydrochloric acid and the aqueous layer was washed with ethyl acetate, alkalinized with potassium carbonate and extracted with chloroform. The organic extracts are combined, dried over sodium sulfate, evaporated and the residue poured into aqueous 10% potassium carbonate solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated, obtaining the target compound (22,4 g, 82%) as a yellow oil.

Range PMR (300 MHz, chloroform - d): M. D., of 1.1 to 1.7 (6H, multiplet), 1.8 - to 2.2 (6H, multiplet), about 2.2 - 2.8 (5H, multiplet), 3,1 (1H, Medenine General formula

< / BR>
casting in table 4, get with methods similar to that shown in the Method 2 interesterification reaction between the corresponding substituted with methyl ester of phenylacetic acid and R-3-hinokitiol. Individual experimental differences are noted in the table, the separation of the diastereomers is omitted.

Table 4

Method 3.

Broadcast:

< / BR>
Synthesis of starting compound see Methods 12.

Experimental differences:

The product was then purified by chromatography on silica gel, using as eluent chloroform/methanol (0-->20%).

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., of 1.1 to 1.8 (7H, multiplet), 1,8 - 2,2 (4H, multiplet), about 2.2 - 2.8 (8H, multiplet), 3,1 (1H, multiplet), a 3.9 (1H, multiplet), 4,7 (1H, multiplet), and 7.3 (5H, multiplet).

Method 4.

Broadcast:

< / BR>
Synthesis of starting compound see Methods 13.

Analytical data:

Butter yellow color.

Range of PFP (300 MHz, chloroform - d): M. D., of 1.2 (6H, multiplet), 1,3-2,4 (10H, multiplet), 2,5-2,9 (5H, multiplet), 3,1 (1H, multiplet), and 3.8 (1H, multiplet), 4,7 (1H, multiplet), and 7.1 to 7.4 (5H, multiplet).

Method 5. Broadcast:

< / BR>
SinTe the>Range of PFP (300 MHz, chloroform - d): M. D., of 0.95 (3H, multiplet), 1,1-2,8 (18H, multiplet), and 3.2 (1H, multiplet), 4,0 (1H, multiplet), 4,8 (1H, multiplet), 6 to 7.2 to 7.4 (5H, multiplet), 4,8 (1H, multiplet), 6 to 7.2 to 7.4 (5H, multiplet).

Methodology 6. Broadcast:

< / BR>
Synthesis of starting compound see Methods 15.

Experimental differences:

The product was then purified by chromatography on silica gel, using as eluent a mixture of chloroform/methanol (0-->20%) and aqueous ammonia (0-->1%).

Analytical data:

Elemental analysis %:

Found: C 72,98; H 6,87; N 3,85;

Calculated for C23H27NO2S: C 72,40; H 7,13; N 3,67.

Methodology 7.

(R)-3-Hinokitiol(RS)-4-(ethylthio)-2-phenylbutanoate.

< / BR>
Chloride, oxalyl (0.9 ml) and chloroform (2 ml) is added at room temperature to a solution of (RS) - 4-(ethylthio)-2-phenylbutanoate acid (see Methods 16) (2.0 g) and dimethylformamide (10 μl) in chloroform (20 ml). The resulting mixture is stirred for 2 hours and evaporated, the residue is dissolved in chloroform, and to the resulting solution at 0oC add (R)-3-hinokitiol (1.27 g) in chloroform (10 ml). Allow the mixture to warm to room temperature, stirred for 3 h and washed with 10% aqueous solution of CT is inania in the form of a yellow oil (2.3 g 78%).

Elemental analysis, %:

Found: C 68,24; H of 8.06; N 4,48;

Calculated for C19H27NO2S: C 68,63; H 8,19; N 4,21.

Technique 8 - 10.

The following compounds of General formula

< / BR>
in table 5, get ways similar to that shown in Method 7 reaction of esterification between the corresponding substituted phenylacetic acid and R - 3 - hinokitiol. Individual experimental differences are noted in the table, the separation of the diastereomers conducted only in Method 8.

Table 5

Methodology 8. Acid:

< / BR>
Synthesis of starting compound see Methods 15.

Experimental differences:

The crude product is purified by chromatography on silica gel, using as eluent a mixture of chloroform/methanol (0-->10%) and aqueous ammonia (0-->1%).

Two stereoisomer share, but again unite for use in synthesis example 16.

Analytical data:

The diastereoisomer 1 (has a higher Rf value on thin layer of the chromatogram) - butter yellow color.

Range of PFP (300 MHz, chloroform - d): M. D., 1,1-3,0 (21H, multiplet), and 3.2 (1H, multiplet), a 3.9 (1H, triplet), is 4.85 (1H, multiplet), a 7.1 to 7.5 (5H, multiplet).

Diastereomer The Hz, chloroform - d): M. D., 1,1-3,0 (21H, multiplet), and 3.2 (1H, multiplet), and 3.8 (1H, triplet), is 4.85 (1H, multiplet), a 7.2 to 7.5 (5H, multiplet).

Methodology 9. Acid:

< / BR>
Synthesis of starting compound see Methods 18.

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., 1,1 - 1,9 (9H, multiplet), 2,0 (3H, singlet), of 2.0-2.2 (2H, multiplet), about 2.2-2.8 (5H, multiplet), 3,1 (1H, multiplet), 3,5 (1H, multiplet), 4,7 (1H, multiplet), of 7.0 to 7.4 (5H, multiplet).

The method 10. Acid:

< / BR>
Synthesis of starting compound see Methods 19.

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., 1,1 - 1,9 (11H, multiplet), 1,8-2,2 (5H, multiplet), 2,2-2,9 (5H, multiplet), 3,1 (1H, multiplet), 3,5 (1H, triplet), 4,8 (1H, multiplet), a 7.1 to 7.5 (5H, multiplet).

Technique 11.

Methyl (RS)-4-(methylthio)-2-phenylbutanoate.

< / BR>
At a temperature of from 0 to 5oC add di-ISO-propylamide lithium (450 ml of 1.5 M solution in cyclohexane) to a stirred solution of phenylacetic acid (40,8 g) in tetrahydrofuran (300 ml). Allow the mixture to warm to room temperature, stirred for 1.5 hours, add a solution of 2-chloroethylnitrosourea (30 ml) in tetrahydrofuran (30 ml) and added dropwise to the resulting solution a solution of concentrated sulfuric acid (50 ml) in methanol (250 ml) and boil the mixture under reflux for 1.5 hours, and then evaporated. The residue is poured into water and extracted with chloroform, the organic extracts washed with 10% aqueous potassium carbonate solution, dried over sodium sulfate and evaporated, getting the oil light brown (55 g). Part of the obtained product (33 g) is distilled, obtaining the target compound (24.5 g, 61%) as a clear liquid with so Kip. 128-135oC at 5 mm RT.article.

Range PMR (300 MHz, chloroform - d): M. D., of 2.0 (4H, multiplet), 2,2-2,5 (3H, multiplet), and 3.6 (3H, singlet), and 3.7 (1H, multiplet), and 7.1 to 7.4 (5H, multiplet).

Methods 12 - 15.

The following compounds of General formula

< / BR>
in table 6, get ways similar to that shown in Method 11 alkylation dianion formed of phenylacetic acid, the corresponding substituted chloridesulfate (R-C1). Individual experimental differences indicated in the table.

Table 6

Technique 12. Values of R - Cl:

< / BR>
Synthesis of starting compound: get method; described in I. Am. Chem. Soc., Vol. 90, p. 2075, 1968.

Experimental differences:

The intermediate formed acid cleaned, pouring the residue after evaporation in water and washing with ether. The aqueous phase is acidified with 2N solution Solent chromatography on silica gel, elwira dichloromethane. Gather the necessary fractions, evaporated and the obtained residue atrificial.

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., of 1.3 (3H, multiplet), 1,8 - 2,6 (6H, multiplet), the 3.65 (3H, singlet), a 3.9 (1H, multiplet), and 7.1 to 7.4 (5H, multiplet).

Methodology 13. The value of R - Cl:

< / BR>
Synthesis of starting compound: obtained according to the method described in I. Am. Chem. Soc., Vol. 90, p. 2075, 1968.

Experimental differences:

The intermediate formed acid cleaned, pouring the residue after evaporation in 2N hydrochloric acid and extracted with ethyl acetate, the organic extract is dried, evaporated and the residue atrificial.

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., 1,2 (3H, singlet), and 1.8 (1H, multiplet), of 1.95 (3H, singlet), 2,6 (1H, multiplet), and 3.6 (3H, singlet), a 3.9 (1H, singlet), and 7.1 to 7.4 (5H, multiplet).

Technique 14. Values of R - Cl:

< / BR>
Synthesis of starting compound receive according to the method described in I. Am. Chem. Soc., Vol. 90, p. 2075, 1968.

Experimental differences:

The intermediate formed acid cleaned, pouring the residue after evaporation in water and washing with ether. The aqueous phase is tion, evaporated and the residue is purified chromatographically on silica gel, elwira dichloromethane. Gather the necessary fractions, evaporated and the obtained residue atrificial.

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform-d): M. D., of 1.0 (3H, multiplet), 1,4 - 2,4 (8H, multiplet), the 3.65 (3H, doublet), 4,0 (1H, multiplet), 7,0 is 7.3 (5H, multiplet).

Methodology 15. The value of R - Cl:

< / BR>
Experimental differences:

The intermediate formed acid cleaned, pouring the residue after evaporation in 2N hydrochloric acid and extracted with ethyl acetate, the organic extract is dried, evaporated and the residue atrificial.

Analytical data:

Butter yellow color.

Range PMR (300 MHz, chloroform - d): M. D., of 2.1 (1H, multiplet), 2,4 (1H, multiplet), 2,9 (2H, multiplet), and 3.7 (3H, singlet), 3,85 (1H, multiplet), and 7.3 (10H, multiplet), and 7.3 (10H, multiplet).

(RS)-4-(Ethylthio)-2-phenylbutanoate acid.

< / BR>
A solution of (RS)-4-bromo-2-phenylbutanoate acid (obtained according to the method described in Farmaco (pavia) Ed. Sci., 1966, Vol. 21(5), p. 355) (2,43 g) in dimethylformamide (5 ml) is added to a stirred suspension of sodium hydride (0.33 g in the form of an 80% dispersion in oil) and sodium salt of ethanthiol (1.26 g) in di is arevut. The residue is poured into water, washed with ethyl acetate, the aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extract is dried over sodium sulfate and evaporated, obtaining the target compound (2 g, 89%) as oil.

Elemental analysis, %:

Found: C 64,07; H 7,08;

Calculated for C12H16O2S: C 64,25; H 7,19.

Technique 17.

(RS)-4-(ISO-Propylthio)-2-phenylbutanoate acid.

< / BR>
The target product in the form of oil are similar to the method described in Method 16, instead of using the sodium salt ethanol sodium salt of ISO-propertie (generated in situ from sodium hydride and ISO-propertie).

Range PMR (300 MHz, chloroform - d): M. D., of 1.25 (6H, multiplet), and 2.1 (1H, multiplet), 2,3 - 2,5 (3H, multiplet), of 2.7 - 3.0 (2H, multiplet), and 3.8 (3H, triplet), a 7.2 to 7.5 (5H, multiplet).

Technique 18.

(RS)-5-(Methylthio)-2-phenylpentane acid.

< / BR>
The target product in the form of oil are similar to the method described in Method 16, using instead of (RS)-4-bromo-phenylbutanoate acid (RS)-5-bromo-2-phenylpentane acid (produced according to the method described in Arkio., For., Kemi, 431, 1957).

Range PMR (300 MHz, chloroform-d): M. D., 1,5 (2H,="ptx2">

Method 19.

(RS)-6-(Methylthio)-2-phenylhexanoic acid.

< / BR>
The target product in the form of a yellow oil get similar to the method described in Method 16, using instead of (RS)-4-bromo-phenylbutanoate acid (RS)-6-bromo-2-phenyl-hexanoic acid (produced according to the method described in UK patent 1309375).

Range PMR (300 MHz, chloroform-d): M. D., 1,3 (2H, multiplet), 1,6 (2H, multiplet), and 1.8 (1H, multiplet), and 2.1 (4H, multiplet), a 2.45 (2H, triplet), 3,55 (1H, multiplet), 7,1 - 7,5 (5H, singlet).

1. Derivatives of 3-genocidally esters of the General formula I

< / BR>
in which X is a phenyl group;

Y is a group of General formula Va

< / BR>
where A and B independently = 0, 1, or 2,

Z = 0, 1, or 2;

R1and R2independently is hydrogen or C1- C4= an alkyl group,

R3- C1- C4= an alkyl group or phenyl group,

or their pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, in which R1and R2both hydrogen.

3. Connection on p. 1, in which A = 1, B = 0, and R1and R2independently is hydrogen, methyl or ethyl.

4. Compounds according to any one of paragraphs.1 to 3, in which R3is a methyl group.

< I A

< / BR>
6. Compounds according to any one of paragraphs.1 to 5, in which Z = 1, with R-configuration at the sulfur atom substituent Y, and structurai fragment corresponds to the formula

< / BR>
7. (R)-3-Hinokitiol(2,S,RS)-2-hydroxymethyl-4-(methylsulfinyl)- 2-phenyl of butanoate or its pharmaceutically acceptable acid additive salt.

8. Connection on p. 1 or their pharmaceutically acceptable acid salt additive, which has antagonistic activity against muscarinic receptors.

9. Pharmaceutical composition having antimuskarinovoe act occurs bronchodilation action, containing the active ingredient in a mixture with a pharmaceutically acceptable carrier or diluent, wherein the active component includes a connection on p. 1 or its pharmaceutically acceptable acid additive salt and an effective amount.

10. Ester derivatives of hinoklidina General formula II

< / BR>
in which X is a phenyl group;

Y is a group of General formula Vc

-(CH2)A-CR1R2-(CH2)B-CR3,

where A and B independently = 0, 1, or 2;

R1and R2independently is hydrogen or C1- C4-alkyl;

R3- C< the derived 3-hinokitiol ether, characterized in that use a connection on p. 1 effective for this quantity.

12. The method of obtaining derivatives of 3-genocidally esters of the General formula I

< / BR>
in which X and Y have values under item 1,

or their pharmaceutically acceptable acid additive salts, characterized in that the compound of General formula III

< / BR>
where X and Y are set to p. 10,

subjected to strong interaction with the substrate and resulting carbanion is subjected to interaction with formaldehyde to obtain the compounds of formula I, where Z = 0, followed, if desired, its oxidation to obtain the compounds of formula I in which Z = 1 or 2 and, if desired, the resulting compound of formula I is transformed into its pharmaceutically acceptable acid additive salt.

13. The method according to p. 12, characterized in that when carrying out the oxidation process is carried out using nutritiously acid.

14. The method according to p. 12 or 13, characterized in that the gain of the compounds of General formula I, where R1and R2both hydrogen.

15. The method according to p. 12 or 13, characterized in that the gain of the compounds of General formula I, where A = 1, B = 0 and R1and R2independently is hydrogen, methyl or ethyl.

/P> 17 . The method according to PP.12 to 16, characterized in that the gain of the compounds of General formula I, which have the R-configuration at position 3' and S-configuration at position 2, which correspond to the formula IA

< / BR>
18. The method according to PP. 12 to 17, characterized in that the gain of the compounds of General formula I, where Z = 1, with R-configuration at the sulfur atom in the Deputy Y, in which structurai fragment corresponds to the formula

< / BR>
19. The method according to p. 14, characterized in that the receive (R)-3-hinokitiol(2S,RS)-2-hydroxymethyl-4-(methylsulfinyl)-2 - phenylbutanoate.

 

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The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to new compounds with pharmacological activity, in particular bicyclic 1-Aza-cycloalkanes General formula

(I) where R is lower alkyl, unsubstituted or substituted furan, thiophene or imidazole; alkenyl with 3-6 carbon atoms; quinil with 3-6 carbon atoms; phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or by halogen; benzyl, unsubstituted or substituted by halogen; pyridyl; pyrimidinyl;

A, b and C independently of one another denote-CH2or a simple bond;

n is 0 or 1, mixtures of isomers, or individual isomers and their pharmacologically tolerable acid additive salts exhibiting holinoliticheskoy properties

The invention relates to new pcoralcalciumonline derived nitrogen-containing heterocyclic compounds, in particular to compounds of the formula I mentioned in the description

The invention relates to medicine, namely to otolaryngology, and can be used for the treatment of patients with sensorineural hearing loss in acute and chronic periods

The invention relates to new derivatives of 1,8-benzonitriles, method of production thereof, to compositions based on them and to intermediate compounds for the synthesis of novel derivatives

The invention relates to new derivatives of hinoklidina, pharmaceutical compositions containing such compounds and to the use of such compounds for the treatment and prevention of inflammatory disorders and disorders of the Central nervous system, as well as some other disorders

The invention relates to medicine and veterinary medicine, specifically to immunomodulatory drugs on the basis of hydrophobic derivatives of interferon inductors used in antiviral therapy

The invention relates to medicine, namely to otorhinolaryngology and can be used in the treatment of sensorineural hearing loss

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

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