4-[(2-benzothiazolyl)methylamino]-alpha-[(3,4-divergence) methyl]-1-piperazineethanol in the form of a racemic mixture or (s)- form or its pharmaceutically acceptable salt accession acid, method thereof, pharmaceutical composition exhibiting protivojinfectini effect on brain tissue

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with protivojinfectini effect on brain tissue. The inventive 4-/(2-benzothiazolyl)methylamino/- -/(3,4-divergence)methyl/-1-piperazineethanol in the form of a racemic mixture or (S)-form or its pharmaceutically acceptable salt accession acid. Describes pharmaceutical compositions based on the compounds exhibiting protivojinfectini properties on the brain tissue, the method of obtaining the specified connection. 3 S. and 4 C.p. f-crystals, 2 tab.

The invention relates to racemic mixtures and (S)-4-[(2-benzothiazolyl)methylamino]- -[(3,4-differience)methyl]-1-piperazineethanol, which can be represented by formula

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and its pharmaceutically acceptable acid additive salts (salts of acid absorption).

In U.S. Patent 4861785 described benzoxazol and benzothiazolinone having activity against anoxia. The benzothiazole compounds conforming to the invention show unexpected activity against stroke (paralysis) in comparison with structurally related compound sabeluzole.

Salt acid accession, as Alania, which are capable of forming a compound of formula (1). The latter can be easily obtained by the interaction between the main form with the appropriate acids, such as, for example, inorganic acids such as halomonadaceae acid, for example hydrochloric, Hydrobromic, etc., sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as, for example, acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, tanginoa, proportionaly, batandjieva, (Z)-2-batandjieva, (E)-2-batandjieva, 2-hydroxybutanone, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic, 7,7-dimethyl-2-oxobicyclo-[2,2,1] heptane-1-methanesulfonate, 2-[(4-were)sulfonylamino] pentagyna, etc. acids. On the contrary, the salt form can be converted to the form of the free base of the handle lye.

The term salt of the acid accession or acid additive salt, which is used here, also includes a solvate, which is able to form compounds of formula (1), s, the alcoholate, etc.

Connections matching the invention have an asymmetric carbon atom, and the absolute configuration of this asymmetric center may be indicated stereochemical descriptors R and S. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms. Hereafter, the term "enantiomerically pure" means a compound having the enantiomeric excess of at least 94% (i.e., at least 97% of one enantiomer and a maximum of 3% of the other enantiomer) to the enantiomeric excess of 100% (i.e. 100% of one enantiomer and zero else), in particular, compounds having an enantiomeric excess of 96% to 100% and especially with the enantiomeric excess of 98% to 100%

Preferred compounds according to the invention are: (S)-4-[(2-benzothiazolyl)methylamino] - -[(3,4-differience)methyl-1-piperazineethanol and his dihydrochloride salt.

The compounds of formula (1) can be usually obtained N-alkylation of the piperidine of formula (II) alkylating reagent of formula (III) by means known in the art techniques N-alkylation.

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In the formula (III) W1represents an appropriate reactive leaving or delete a group, such as, Livonians-, benzosulfimide-, 4-methylbenzenesulfonate, etc. of the deleted group. This reaction of N-alkylation may conveniently be carried out by mixing the reagents usually in a reaction inert solvent such as, for example, an aromatic solvent such as benzene, methylbenzol, xylene, etc.1-6-alkanol, for example methanol, ethanol, 1-butanol, etc., a ketone, such as 2-propane, 4-methyl-2-pentanone and so forth; ester such as ethyl acetate, mutilation etc. simple ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, etc., dipolar aprotic solvent, for example, dimethylformamide, , -dimethylacetamide, dimethylsulfoxide, pyridine, 1-methyl-2-pyrrolidinone, nitrobenzene, acetonitrile, etc., or mixtures of such solvents. The addition of an appropriate base, such as, for example, carbonate, bicarbonate, hydroxide, oxide, carboxylate, alcoholate, hydride or amide, alkali or alkaline earth metal, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methylate, sodium hydride, sodium amide, etc., or organic bases, such as, for example a tertiary amine, for example-diethylethanamine, -(1-methyl-ethyl)-2-propanamine acid, which is formed during the reaction. In some cases it may be appropriate to add iodide salt, preferably, iodide of an alkali metal, or crownether, for example 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane etc. Mixing and slightly rising temperatures may increase the rate of the reaction; in particular, the reaction can be carried out at the temperature of reflux distilled reaction mixture. Alternatively, the specified-alkylation may be carried out using known conditions of catalytic reactions, phase transfer. Somewhat elevated temperatures may be used to increase the rate of reaction.

In this and subsequent methods of obtaining the reaction products can be isolated from the environment and, if necessary, and then purified by the known methods, for example, extraction, crystallization, grinding and chromatography.

The compound of formula (1) can be also obtained by the reaction of a piperidine of formula (II) with an epoxide of formula (IV).

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This reaction can be conducted by stirring and, if desired, by heating the reactants in a reaction-inert solvent such as, for example, water, an aromatic hydrocarbon, for example benzene, methylbenzol, etc. of spec. dipolar aprotic solvent, e.g. dimethylformamide, dimethylacetamide, etc., or a mixture of such solvents.

The compounds of formula (I) can also be obtained by cyclization of a derivative of thiourea of the formula (VII), which may be formed by reaction of the amine of formula (V) with an isocyanate of the formula (VI) in an appropriate reaction-inert solvent such as, for example, alkanol, simple, ether, ketone, etc.

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In the formula (VI) and (VII) W2is, for example, hydrogen, halogen, such as chloro - and bromo-; C1-6-alkoxy or C1-6-alkylthio-. This cyclization reaction can be generally performed in the presence of a suitable oxidant, such as, for example, dihalogenide, for example chlorine or bromine. This cyclization reaction can be performed in a reaction-inert solvent such as, for example, halogenated hydrocarbons such as carbon tetrachloride, trichloromethane, dichloromethane, etc., hydrocarbons such as benzene, methylbenzol, hexane, etc., a simple ether, for example tetrahydrofuran, etc., a ketone, e.g. 2-propanone, 2-butanone, etc; alcohol, for example methanol, ethanol, 2-propanol, etc., dipolar aprotic solvent, for example-dimethylforamide, -dimethylacetamide, etc. N what can alternatively be obtained by the reaction of an appropriate reagent of formula (VIII) with benzothiazole of the formula (IX).

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In (VIII) and (IX) Q1and Q2are selected so that during the alkylation reaction formed a radical of the formula N(CH3)-. For example, when Q1is the corresponding leaving group, Q22 - is a radical of the formula NH(CH5), or when Q1is a radical NH(CH3), Q2is the corresponding leaving group. Appropriate leaving group are, for example, halogen, for example chlorine, bromine, etc., sulfonyloxy group, for example, methanesulfonate, 4-methyl-benzosulfimide and so on, the Reaction can be carried out in a reaction inert solvent such as, for example, aromatic hydrocarbons such as benzene, methylbenzol etc; simple ether, e.g. 1,4-dioxane, tetrahydrofuran, etc., halogenated hydrocarbons such as trichloromethane, carbon tetrachloride, etc; alkanol, for example methanol, ethanol, 1-butanol, etc., ketone, for example, 2-propanone, 4-methyl-2-pentanon etc. dipolar aprotic solvent, e.g. dimethylformamide, dimethylacetamide, etc., the Addition of an appropriate base, such as, for example, carbonate or bicarbonate of an alkali metal, for example sodium carbonate, sodium bicarbonate, etc., sodium hydride; or

organic osnovaniya during the reaction.

The compounds of formula (I) can be also obtained by the reaction of substituted 4-piperidine formula (X) with benzothiazoline formula (XI) using a known method recovery-alkylation.

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The reaction of (X) (XI) can usually be performed by a shift reagents in an appropriate reaction-inert solvent with an appropriate reducing agent. Preferably, the ketone of formula (X) are initially introduced into a reaction with an intermediate compound of formula (XI) with the formation of the enamine, which can usually be isolated and then purified, with subsequent restoration of the specified enamine. Appropriate solvents are, for example, water; C1-6-alkanols, for example methanol, ethanol, 2-propanol, etc., esters. for example, 1,4-dioxane, etc., halogenated hydrocarbons such as trichloromethane, etc., dipolar aprotic solvents, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc., or a mixture of such solvents. Appropriate reducing agents are, for example, metal hydrides or complex metal hydrides, such as borohydride sodium, cyanoborohydride sodium, lithium aluminum hydride, etc., the Alternative can be used as a water reducing agent. the La in order to prevent further unwanted hydrogenation of some functional groups in the reactants and the reaction products must be added to the reaction mixture effective suitable catalyst poison, such as, for example, thiophene, etc.

Enantiomerically pure forms of compounds of formula (I) can be obtained by transformation of a racemic mixture of compounds of formula (I) using the corresponding separating or release agent, such as, for example, chiral acid, such as tartaric, malic, almond acid, camphorsulfonic acid, 4,5-dihydro-I-2-benzopyran-2-carboxylic acid, etc. in a mixture of diastereomeric salts; physical separation of these mixtures, for example, selective crystallization or by chromatography, for example, liquid chromatography, etc. methods; and, finally, the translation of these separated diastereomeric salts into the corresponding enantiomers of the compounds of formula (I) by hydrolysis in an acidic or alkaline aqueous medium, optionally at elevated temperature.

Alternatively, enantiomerically pure form can easily be obtained from enantiomerically pure isomeric forms of the starting materials, provided that the latter is obtained by reaction of enantiomerically pure epoxide of formula (IV) with an intermediate compound of formula (II), as explained above. Enantiomerically pure epoxide of formula (IV) can be obtained by reaction of 3,4-differenoe with enantiomerically pure epoxide of the formula (XVII) as described below.

As a further alternative, the enantiomers can be separated using liquid chromatography using a chiral stationary phase.

The number of intermediate materials in the above methods of production are known compounds which can be obtained by known methods to obtain these or similar compounds. Ways to get some other intermediate compounds are described in more detail below.

The intermediate compound of formula (II) can be obtained by oxidative cyclization of a derivative of thiourea of the formula (XII), where P is the corresponding removable group, such as, for example, WITH1-6-allyloxycarbonyl, phenylmethanesulfonyl, phenylmethyl, etc. and W2matter described above, using the same techniques described earlier to obtain (I) from (VII) and subsequent removal of the protective group P in the thus obtained intermediate compound (XIII).

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The removal of the protective group P in (XIII) can be performed following investissement from nature P.

These intermediate compounds of formula (XII) can, in turn, be obtained by the reaction of an amine of formula (XIV) with an isocyanate of the formula (XV), as described previously, to obtain (VII) from (V) and (VI).

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The intermediate compound of formula (IV) can be obtained by the reaction of 3,4-differenoe (XVI) with an epoxide of the formula (XVII). In the formula (XVII) W1has the previously described meaning.

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This alkylation reaction may be performed, as described previously, to obtain (I) from (II) and (III).

The compound of formula (I) (racemic mixture and the (S)-form) and its pharmaceutically acceptable acid salt of accession have antidormi properties in vivo, which can be confirmed by a test called "Post-treatment photochemical model of stroke in rats", which is described in the experimental part below.

These compounds, such known compounds of U.S. Patent 4861785 (such as sabeluzole), are potential antihypoxic agents. An unexpected property of these compounds in comparison with these known compounds is that these connections are strong for use as antigenic agents in vivo, while Assemini compounds is unexpected from the point of view of the fact that the claimed compounds are slightly less strong antihypoxic agents compared with sabeluzole. Obviously, there is no simple relationship between hypoxic penetration and impact resistance activity in vivo. Therefore, the inventive compounds may be used in acute treatment of shock, whereas the known compounds are only used for chronic treatment of shock, such as when maintenance therapy. Additional advantages of the inventive compounds of the above known compounds are more long-term preservation of antihypoxic activity, the absence of the phenomenon calm and violation of coordination of movements in mice and the absence of eyelid ptosis in rats.

From the point of view of their useful pharmacological properties, the inventive compounds can be formed in the form of formulations in various pharmaceutical forms for the purposes of the assignment. To obtain pharmaceutical compositions corresponding to the invention, an effective amount of a particular compound, in the form of an acid salt attaching or base, as an active ingredient together in a close relationship with a pharmaceutically acceptable carrier, which composition may be desirable in the form of a unit dosage, suitable for use, preferably, for oral administration, rectal, skin, or parenteral injection. For example, to obtain compositions in the form of dosage forms for oral administration can be applied to any pharmaceutical environment, such as, for example, water, glycols, oils, alcohols, etc., in the case of liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents, etc., in the case of powders, pills, capsules and tablets. Due to their ease of destination tablets and capsules represent the most common form of a unit dosage for oral administration, and in both cases are commonly used solid pharmaceutical carriers. In the case of parenteral compositions, the carrier usually contains sterile water, at least in the most part, though, for example, for the purposes of solubility, may be included other ingredients, for example, can be prepared injectable solutions, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing the compounds of formula (I) may also be formed in wt is e oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of fatty acids with long chain and mixtures of these and other oils. Can also be prepared injectable suspension, which can apply the appropriate liquid carriers, suspendresume agents, etc., In compositions intended for skin purposes, the media typically contains an agent that enhance the penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minimal proportions, so that the additive had no harmful effects on the skin. These supplements can facilitate application to the skin and/or may be useful to obtain the desired compositions. These compositions can be applied in various ways, for example, transdermal, or in the form of ointment. Salt acid accession (I), due to their increased water solubility over the corresponding basic form, are more appropriate for obtaining water compositions.

Interesting compositions among groups of compositions are compositions containing cyclodextrin (CD) or ether derivative as a complex forming agent and/or a solubilizer. As a researcher who Sevodnya.

Specific derivatives of such dextrins are described in U.S. Patent 3459731, European patent A-0149197 and European patent A-0197571.

Typically, these derivatives ether or mixed esters include a -, b - and g-CD, where one or more hydroxyl groups substituted WITH1-6-alkyl, in particular the stands, ethyl or isopropyl, hydroxy-C1-6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6-alkyl, particularly carboxymethyl or carboxyethyl; C1-6-allyloxycarbonyl-C1-6-alkyl or carboxy-C1-6-alkyloxy-C1-6the alkyl, especially, carboxyphenoxypropane or carboxitherapy. Especially noteworthy when complacently and/or solubilization are b-CD, 2,6-dimethyl-b-CD and, in particular 2-hydroxypropyl-b-CD, 2-hydroxyethyl-b-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy)propyl-b-CD. In the above-mentioned derivatives of cyclodextrin C3 (degree of substitution, i.e. the average number of substituted hydroxybenzyl on glucose level), preferably in the range of 0.125 to 3, in particular from 0.2 to 2, or from 0.2 to 1.5. More preferably C3 varies from 0.2 to 0.7, in particular from 0.35 to 0.5, and most often OK in the range from 0.125 to 10, in particular from 0.3 to 3, or from 0.3 to 1.5. More preferably, the MOH varies from 0.3 to 0.8, in particular from 0.35 to 0.5, and most often about 0.4. These compositions can be easily obtained by dissolving the cyclodextrin or its ether derivative in water and adding to the compound of formula (I) solution, as well as other adjuvants and components, such as, for example, sodium chloride, potassium nitrate, glucose, mannitol, sorbitol, xylitol and buffer compounds, such as, for example, phosphates, acetates or citrates; and usually by concentrating or drying the solution by evaporation under reduced pressure or by lyophilization; and further mixing of liofilizirovannogo residue with water. The amount of cyclodextrin or its ether derivative in the final composition is typically in the range from 1 to 40%, in particular from 2.5 to 25% and more frequently from 5 to 20%

A special advantage is the conversion or formation of the above pharmaceutical compositions in the form of single doses to facilitate assignment and uniformity of dosage. Dosage unit form as used in the description and the claims refers to physically discrete units suitable for single dosing, with each unit of sod is KTA, in combination with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including uncoated or coated tablets), capsules, pills, sachets of powder, wafers, injectable solutions or suspensions, teas, decoctions, etc., and separate sets.

From the point of view antigenic properties, the compound of formula (I) (racemic mixture and the (S)-form) and its salts acid accession can be used for acute treatment of subjects suffering from conditions such as, for example, ischemic attack, stroke with hemorrhage, subarachnoid hemorrhage, or they can be used in the acute treatment of post-asphyxiating brain damage in newborns. In an additional aspect, the invention provides a method of treating subjects suffering from these conditions, and this method provides a systematic use of effective shock resistant amount of the compounds of formula (I) or pharmaceutically acceptable salts thereof accession. Experts in the field of treatment of a disease can easily determine an effective number of the results are presented below. It is generally considered that an effective protective against stroke is IMEMO 50 mg per day. It may be appropriate to assign the required dose in the form of two, three or more sub-doses at intervals of intake through the day. These sub-doses may be made in the form of a unit dosage, for example, containing from 0.1 to 100 mg, in particular from 1 to 50 mg of the active ingredient in the form of a unit dosage.

The compound of formula (I) preferably used intravenously. Compositions for intravenous administration can contain, in addition to effective shockproof amount of the compounds of formula (I), a buffer system, isotonic agent, water, cyclodextrin or its ether derivative and optional additional pharmaceutically acceptable ingredient.

The following examples are provided to illustrate but not to limit the scope of the invention.

Experimental part

A. the production of intermediate compounds

Example 1

To a stirred and cooled (ice bath) mixture of 13.0 g of 3,4-differenoe and 200 ml of dimethylformamide, was added 4.8 g of a dispersion of sodium hydride in mineral oil (50%) and, after stirring for 1 h, a solution of 22.8 g (S)-(oxiranylmethyl)-4-methylbenzenesulfonate (ether) in the same-dimethylformamide. Stirring at room temperature what ylbenzyl. The extract was washed with NaCl (razb.) and water and then dried, filtered and evaporated. The residue was converted (13.3 PA:55oC), giving 9.5 g (51,0%) (S)-[(3,4-divergence)methyl]-oxirane (intermediate compound 1).

Example 2

The mixture 117,1 g of 3,4-differenoe, 185,5 g chloromethyloxirane, 125 g of potassium carbonate and 500 ml of 2-propanone was mixed for 48 hours at a temperature of reflux distilled. The reaction mixture was evaporated, and the residue was taken in dichloromethane. Then all was sequentially rinsed with water, Paon (aq.) (twice) and water, and then dried, filtered and evaporated. The residue was converted (13.3 PA, 58o(C) giving to 90.4 g (54,0%) [(3,4-divergence)methyl]oxirane (intermediate compound 2).

C. obtain the final compounds.

Example 3

A mixture of 3.4 g of intermediate compound 2, 6,1 g-methyl -(4-piperidinyl)-2-benzothiazolesulfonamide, 100 ml of 2-propanol and 5.3 g of sodium carbonate were mixed overnight at the temperature of reflux distilled. The reaction mixture was evaporated, and the residue was distributed between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was purified on a chromatographic column (silica gel; CHCI3:CH3HE 98: 2). Eluent VC is camping, were washed with 2-propanol and 2,2-oxybisethanol and dried at 60oAnd when 80oWith the giving of 6.1 g (80,3%) of 4-(2-benzothiazolylthio)- -[(3,4-divergence)methyl] -1-piperidinecarboxylate; so pl. 211,8o(compound 1). This image was also obtained: (-)-(S)-4-[(2-benzothiazolyl)methylamino]-a-[(3,4-divergence) oxy)methyl]-1-piperazineethanol (E)-2-butenedioate (1:1); so pl. 167,8oC;

[]2D0-7,44o(conc. 1% in methanol) (compound 2).

Example 4

To a stirred mixture of 10 g of intermediate compound 1, 14.3 parts-methyl--(4-piperidinyl)-2-benzothiazoline (obtained as described in U.S. Patent 4861785); 14.2 g of sodium carbonate and 112 ml of 1-butanol was added dropwise and 11.2 ml of water. After stirring for 16 hours at a temperature of reflux distilled, the reaction mixture was diluted to 100 ml water. The organic layer was separated, dried, filtered and evaporated. The residue was dissolved in 200 ml of dichloromethane, and the solution was mixed for 2 h with 50 g of silica gel. The silica gel was filtered off and was washed with a mixture of dichloromethane and methanol (95: 5). The filtrate was evaporated, and the residual oil is crystallized from 2,2'-oxybisethane. The product was filtered off and dried at 50oWith, giving 7.5 g (38,7%) of (+)-(S)-4-[(0+of 4.38o(conc. 1% in methanol) (compound 3).

Similarly worked also ()(RS)-4-[(2-benzothiazolyl)methyl-amino] - -[(3,4-divergence)methyl] -1-piperazineethanol; so pl. 86,4o(Compound 4).

Example 5

4.0 g of compound 2 was treated with ammonia to obtain the free base. The solution was evaporated, and the residue was turned into dihydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol and 2,2'-oxybisethane and dried in vacuum at 30oWith, giving 3.0 g (81,4%) of (-)-(S)-4-[(2-benzothiazolyl)-methylamino] -a -[(3,4-dittoheads)methyl] -1-piperidinecarboxylate; so pl. 148, 7mmoC; []2D0-9,01o(conc. 1% in methanol) (compound 5).

Example 6

To a stirred solution of 6.9 g of compound 3 in 100 ml of 2-propanone was added dropwise 10 ml of 2-propanol saturated with hydrogen bromide at room temperature. The precipitate was filtered, and the filtrate was evaporated. The residue was turned into hydrobromide salt in 2-propanone. The product was filtered, washed 2,2'-oxybisethane and dried at 60oWith, giving 5.5 g (58,1%) of (-)-(S)-4-[(2-benzothiazolyl)methylamino] - -[(3,4-divergence)methyl]-1-piperazinecarboxamide; so pl. 213,7o(SOS 9,40 g of 7,7-dimethyl-2-oxabicyclo[2,2,1] heptane-1-methanesulfonic acid. The reaction mixture was heated until then, until it became homogeneous. After cooling to 20oWith all mixed together for 24 hours of Vegascasinoonline the product was filtered off, washed twice with 25 ml of ethyl acetate and dried at 50oWith, giving 7 g (77,9%) of (+)-(S)-4-[(2-benzothiazolyl)methylamino] -a -[(3,4-divergence)methyl] -1-piperazineethanol (S)-7,7-dimethyl-2-oxobicyclo [2,2,1]heptane-1-methanesulfonate (1:2); so pl. 119,5oC (compound 7).

Example 8

To a stirred solution of 4.38 g of compound 3 in 100 ml of 2-propanol was added 3.11 g of (+)-(L)-2-[(4-were)sulfonylamino]pentanedionato acid. The reaction mixture was heated until then, until it became homogeneous. After slow cooling to 20oC, the reaction mixture was stirred for 68 h at 20oC. Precipitated precipitated product was filtered off, washed with 25 ml of 2-propanol and dried in vacuum at 50oWith giving 6,87 g (93,5%) of (+)-(S)-4-[(2-benzothiazolyl)methylamino] -a-[(3; 4 divergence)methyl]-1-piperazineethanol (+)-(L)-2-[(4-were)sulfonyl]amino]pentanoate (1:1) (compound 8).

C. Pharmacological examples

Useful anti-shock properties of the compounds of formula (1) are demonstrated using the following test procedures. what 260-280 g was anesthesiologis the halothane gas in N2O/O2-mixtures. Animals were placed in a stereotactic apparatus, the scalp was into fragments to open the cranial surface, and a catheter was introduced into the lateral tail vein. Rose Bengal (30 mg/kg; 15 mg/ml in 0.9% NCI) was injected intravenously to the animals for 2 min with normal hemodynamic and blood gases. After this skull focal lit cool white light for 5 min using a fiber-optic beam with a 1-mm diameter lens. The light was focused on the area of the posterior limb of the right parietal sensorimotor of the neocortex. After 5 min after infarction induction (i.e., within 5 min after removal of light) rats were injected with intravenous (centuries) ball joints 5 or its carrier, 10% hydroxypropyl-b-cyclodextrin. Neurological tests, including the reaction space of the limbs, was conducted during the first two days after the development of a heart attack at 24-hour intervals after induction, tactile space ahead and to the side was tested by the easy contact of the edge of the table with the dorsal and lateral sides of the legs (2 tests).

Proprioceptive space forward and sideways included pushing feet against the edge of the table in order to stimulate the muscles and joints of the limbs (2 trials). Rats placed line: paw slightly pulled down and away from the edge of the platform, and, after a sudden release, were tested for the return and accommodation (1 IP.). For each of the 5 trials evaluating placement were: 0, no host; 1, incomplete and/or delayed placement; or 2 immediate, full accommodation. For each limb total score tactile/proprioceptive placing, including the test platform was a maximum of 10. In trials at each dose used 6 rats. Below are the test results for the connection 5. Table. 1 gives the average and extreme estimates placement of limbs along with the number of protected rats (score 5) in 1 and 2 postinfarction days. 50% for compound 5, which is the dose that gives protection of neurological function in 50% of rats, at 95% confidence limit was 0,16 (0,13-0,20) and 0.13 (0,08-0,20) mg/kg (intravenous) in 1 and 2 postinfarction days, respectively.

Example 10. Post-treatment photochemical model of stroke in rats. The test conditions are the same as described in example 9, except that after 60 min after intravenous injection of balls of the test animals were given inwariantny oral dose of 10 mg/kg of the test compounds.

The test results for a number of compounds according to the invention sleet average and extreme estimates placement of limbs along with the number of protected rats (score 5) in the 2nd posleinfarktnoy day after taking a dose of 1.25 mg/kg centuries + 10 mg/kg (through the mouth) of the test compounds.

C. Examples of songs

The following formulations are examples of typical pharmaceutical compositions in the form of a unit dose suitable for systemic or local destination for warm-blooded animals in accordance with the invention.

"Active ingredient" (and.and.), used throughout these examples relates to a compound of formula (I), its pharmaceutically acceptable salt, acid or accession stereochemical isomeric form.

Example 11. Injectable solutions.

a) 1.8 g methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxy-benzoate are dissolved in about 0.5 l of boiling water for injection. After cooling to approximately the 50oSince there is added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 1 g and.and. The solution is cooled to room temperature, and thereto is added water for injection, padded to 1 l volume with obtaining a solution of 1 mg and.and. on the ml Solution is sterilized by filtration (U. S. P. XVII p. 811) and poured into a sterile container.

C) the active ingredient 4 mg

Sodium chloride 3,59 mg

Sodium citrate 2 water to 5.8 mg

Citric acid 1 aq. 62 mcg

Hydroxypropyl-b-cikis sodium (1 norms)

Water up to 1 ml

The method of obtaining

18 liters of cold free from pyrogens water is sterilized by filtration. There is added with stirring 2 kg of hydroxypropyl-b-cyclodextrin (MOH=0,4), 116 g of sodium citrate (dihydrate), 1.24 g of citric acid (IH2O) and 71,8 g of sodium chloride. The solution is cooled to 25oC and the pH is brought to pH 6.9 by adding Paon (1 standards) and NCl (1 standards.). The solution is mixed to a homogeneous state and cooled to 2-8oC. 80 g of compound of formula (I) is added to a buffer solution of citric acid and stirred for 5 min at a temperature below 8oC. This solution is diluted with cold free from pyrogens water to a final volume of 20 l and sterilized by filtration in the sterile atmosphere of nitrogen. The final solution is poured into a sterile 1 ml containers.

The following recipe is prepared similarly using the appropriate quantities of the ingredients to obtain the final solution of the desired composition.

C)

Active ingredient 1 mg

Hydrochloric acid (1 normal). 6,35 mg

Hydroxypropyl - b-cyclodextrin 10 mg

Glucose, betwedn. 46 mg

Sodium hydroxide (1 standards.) to pH 4

Water up to 1 mloC. After cooling to 30-40oWith added 35 l of polyethylene glycol, and the mixture is well mixed. Then there is added a solution of 1750 g of sodium saccharin in 2.5 l of purified water and while stirring there is added 2.5 l of cocoa flavor and polyethylene glycol in an amount to obtain a total volume of 50 l, receiving the internal solution (oral) drops containing 1 mg/ml.and. The ultimate solution filled in the appropriate containers.

Example 13. The solution for the reception inside

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioate acid and then 8 g and.and. The latter solution is combined with the rest of the first solution, and thereto is added 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of sodium saccharin is dissolved in 0.5 l of water and added 2 ml of raspberry and 2 ml of gooseberry family essences. The latter solution is combined with the first, water is added to a volume of 20 l with obtaining a solution for oral administration containing 2 mg and.and. on a teaspoon (5 ml). The final solution is poured into suitable containers.

Example 14. Capsules

2 g and.and. 6 g of lauryl sodium . the received mixture is subsequently filled 1000 suitable hard gelatin capsules, each containing 2 mg and.and.

Example 15. The tablets are film-coated.

Obtain core tablets

A mixture of 10 g and. I. 500 g lactose and 200 g starch is well mixed and then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-90in a sample of 200 ml of water. Wet powder mixture is screened, dried and screened again. Then added 100 g microcrystalline cellulose (Avicel) and 15 g hydrogenated vegetable oil (Sarotex). All is well mixed and pressed into tablets to obtain 10,000 tablets each containing 1 mg and.and.

Floor

To a solution of 10 g methyl cellulose (Metozel 60 HG HG) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel 22 SDR) in 150 ml of dichloromethane. Then there is added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first, and then there is added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ukryvaetsya thus obtained mixture in the equipment for coating.

1. 4-[(2-Benzothiazolyl)methylamino]-alpha-[(3,4 - divergence)methyl]-1-piperazineethanol General formula I

< / BR>
in the form of a racemic mixture or (S)-form or its pharmaceutically acceptable salt accession acid.

2. Connection on p. 1, selected from the group consisting of (S)-4-[2-benzothiazolyl) methylamino]-alpha-[3,4-divergence)methyl]-1-piperazineethanol or dihydrochloride salt.

3. Connection under item 1 or 2, showing protivojinfectini effect on brain tissue.

4. The pharmaceutical composition exhibiting protivojinfectini effect on brain tissue containing the active substance and a pharmaceutically acceptable carrier, wherein the active substance contains a connection on p. 1 in an effective amount.

5. The composition according to p. 4, characterized in that it additionally includes a buffer system, isotonic agent and water.

6. The composition according to p. 4 or 5, characterized in that the carrier comprises a cyclodextrin or its ether derivative.

7. The method of obtaining 4-[2-benzothiazolyl)methylamino]-alpha-[(3,4-divergence)methyl] 1-piperazineethanol formula I

< / BR>
in the form of a racemic mixture or (S)-form or the pharmaceutical is t interaction with the epoxide of formula IV

< / BR>
if necessary, in obtaining the compounds of formula I in the form of a racemic mixture to turn it into a mixture of diastereoisomeric salts with a suitable disintegrating agent, such as, for example, chiral acid, and then carry out a physical Razdolie this mixture using, for example, selective crystallization or chromatographic techniques and, finally, the transformation of these separated diastereomeric salts into the corresponding enantiomers of the compounds of formula I by hydrolysis in acidic or basic medium, optionally at elevated temperature or, if necessary, turn the compound of formula I in salt form by processing pharmaceutically acceptable acid, or Vice versa, convert the salt form into the free base by treatment with alkali.

 

Same patents:

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment of diseases associated with degeneration of the tissues, and to a method of production thereof

The invention relates to new benzanilide derivatives, processes for their preparation and the pharmaceutical compositions

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to medicine, namely to neuropathology

The invention relates to new derivatives of aryl - and heteroarylboronic, to the way they are received, to contain their pharmaceutical compositions and to their use as therapeutic agents

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

The invention relates to 3,4,4-triple-substituted piperidinyl-N-alkylcarboxylic and to methods of their use as peripheral opioid antagonists

The invention relates to new esters of carboxylic acids with valuable properties, in particular the esters taylorbow acids and aminoalcohols of General formula (I)

< / BR>
where a group

< / BR>
where m and n are independent of each other represent 1 or 2,

Q group of formulae

< / BR>
Q' группаNR, where R denotes hydrogen or alkyl with 1 to 4 carbon atoms, unsubstituted or substituted with halogen or hydroxyl, or a group NRR', where R' is alkyl with 1 to 4 carbon atoms, or R and R' together form alkylene with 4 to 6 carbon atoms, and in the case of the fourth connection to the positive charge of the nitrogen atom is the equivalent of the anion (X),,

R1thienyl, phenyl, furyl, cyclopentyl and cyclohexyl, unsubstituted or substituted stands, and thienyl and phenyl may be substituted by fluorine or chlorine,

R2hydrogen, alkoxy 1 to 4 carbon atoms or alkyl with 1 to 4 carbon atoms,

Rahydrogen, fluorine, chlorine or methyl, provided that when a represents 3-tropanol, R1hydroxyl and R

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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