The way the selective extraction of one of the enantiomers of racemic mixtures

 

(57) Abstract:

Usage: in chemistry stereoisomeric chemicals, in particular in the way the selective extraction of one of the enantiomers of racemic mixtures. The inventive product (-) or(+)-5-[[1,3-(1,1-dimethylethyl)-4-hydroxyphenyl] methyl]-4-thiazolidinone. BF C18H27NO2's angle of rotation -73,6°C /S= 1.0, the Meon/ Reagent 1: racemate of compound f-ly I specified in the text description, with appropriate substituents. Reagent 2:tartrate ligand having stereochimia, get the opposite enantiomer. Reagent 3: hydrogen peroxide and alkoxysilane. Reaction conditions: preferably in the presence of water. 6 C. p. F.-ly, 1 table.

Mammals, both humans and animals, are known to be susceptible to various diseases, including inflammatory condition of the intestine. Such States are typically characterized by such unpleasant symptoms as diarrhea, colic and loss of appetite. Some of these painful conditions, especially colitis, are also characterized by the formation of ulcerations. Accordingly there is a need for safe medication that can reduce the severity of intestinal inflammation and relieve associated symptoms.

Features compound of formula (I) used for the treatment of inflammatory bowel disease in a mammal suffering from these diseases or affected them, including the application on the specified mammal an effective amount of the compounds of formula (I)

(I) in which R1and R2independently of one another represent hydrogen, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl,2-6quinil,1-C4alkyl-O--(Cis achene; R3represents hydrogen or C1-C6alkyl; R4and R5represent hydrogen or together form a bond; R6and R7represent hydrogen or together represent S, or in the case where one of R6or R7hydrogen, the other radical represents HE or SCH3; X is a group , where m is 0,1 or 2; and Q represents-CH2-, -O - or-NR8where R8represents hydrogen, C1-C6alkyl, C2-C6alkenyl,3-C8cycloalkyl, -SO2CH3or -(CH2)n-Y, where n is an integer in the range of About-3, including extreme values, and Y represents cyano, OR9, -R10, tetrazolyl, -NR11R12, -SH, -S(C1-C4alkyl) or a group of formula (A).

OCC4(A). in which R9represents hydrogen, C1-C4alkyl, or --C1-C4alkyl; R10represents a C1-C4alkyl, C1-C4alkoxy or-NH2; R11and R12independently of one another represent hydrogen, C1-C6alkyl, C2-C6alkenyl,2-C6quinil, -(CH2)don, -(CH< ) (B) in which n has the abovementioned meaning, and g is an integer in the range of 1-6, including extreme values; or R11and R12together form morpholino, piperidinyl, piperazinilnom or N-methylpiperazine ring; or pharmaceutically applicable salt. The proposed method is designed to safely and effectively reduce the severity of intestinal inflammation, as well as to relieve the unpleasant symptoms associated with inflammation. The invention also provides a process for the selective isolation, with almost pure enantiomeric form, one of the enantiomers of racemic mixtures of compounds of formula I in which X represents-S-; R4and R5represent hydrogen; and R1, R2, R3, R6, R7and Q have the meanings indicated for formula I, including:

A) reaction of racemic sulfide compound with the reagent prepared from combinations tartrate ligand, an alkoxide of titanium, hydroperoxide and optionally water, which is held up until almost all of the unwanted enantiomer sulfide substrate will not turn in his sulfoxides similar; and

B) isolation of unreacted portions of the original sulfide material, consisting in the OS is the term "C1-C6alkyl" refers to normal or branched aliphatic radicals containing 1-6 carbon atoms, including the boundary values of the interval, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentane, isopentane, n-hexane, isohexane, etc., the Term "C1-C6alkyl" includes the term "C1-C4alkyl".

The term "C1-C6alkoxy" refers to alkylene radicals containing 1-6 carbon atoms attached to the remainder of the molecule through oxygen and a represents methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexose etc.

The term "C1-C6alkoxy" includes within its definition the term "C1-C4alkoxy".

The term "C2-C6alkenyl" refers to normal and branched radicals containing 2 to 6 carbon atoms, including extreme values of the interval having the double bond. This term includes ethylene, propylene, isopropylene, 1-butene, 2-butene, 2-methyl-1-propene, 1-penten, 2-penten, 2-methyl-2-butene, etc.

The term "C2-C6quinil" refers to normal and branched radicals containing 2-6 Entin, 3-methyl-1-butyn, 1-hexyne, 2-hexyne, 3-hexyne, etc.

The compounds of formula I in which R1and R2have values other than1-C4alkyl-O--(C1-C4the alkyl), R8has a value other than2-C6alkenyl, Y has a value other than-SH or-S(C1-C4the alkyl), and R11and R12have values other than2-C6alkenyl or2-C6the quinil, are preferred for use in the treatment of inflammatory bowel disease of the present invention. In this preferred group of compounds is slightly more preferred are the compounds of formula I in which R1and R2represent1-C6alkyl, C2-C6alkenyl,1-C6alkoxy or-CH2Is-S-; where R3represents hydrogen; R4and R5represent hydrogen or together form a bond; R6and R7represent hydrogen or together S; X represents a group in which m is 0; and Q represents-0 - or-NR8where R8has the value specified for the preferred group of compounds. From this somewhat more predpochitala intestines are compounds in which R1, R2, R3, R4, R5, R6, R7, X and m have the above meanings, and Q represents NR8where R8represents hydrogen, C1-C8alkyl or -(CH2)n-Y, where n is 0 and Y is-NR11R12(R11and R12independently from each other represent hydrogen or C1-C6alkyl).

Of these preferred compounds, especially preferred substances for use in the method of the invention are those compounds in which R1and R2independently from each other, represent a1-C6alkyl, especially 1,1-dimethylethyl; R3, R4, R5, R6and R7represent hydrogen; X group in which m is 0, and Q represents NR8where R8represents hydrogen. The most preferred compounds for use in the treatment of inflammatory bowel disease, obtained in the invention is 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl] -2-thiazolidinone, 5-[[3-(1,1-dimethylethyl)-4-hydroxy-5-propylphenyl]methyl]-4-thiazolidinone and 5-[[3,5-dipropyl-4-hydroxyphenyl]methyl]-4-thiazolidinone.

Connection of the Ute a hydrogen, contain an asymmetric center at the carbon atom in position 5 of rhodanine or its derivative. Therefore, such compounds can exist as racemic mixtures or as individual stereoisomers. The method and compounds of the invention encompass both the racemate and its individual stereoisomers. The method of the invention provides a method of obtaining stereoisomers of some compounds of the invention, as well as some of the compounds used in the method of the invention.

Compounds and method of the invention also include pharmaceutically applicable salt. Such salts can be obtained by the reaction of compounds of formula I with a strong base like sodium hydroxide, or a strong acid, as chlorotoluron acid.

Compounds of the invention include the following substances: 5-[[3,5-diethenyl-4-hydroxyphenyl]methylene]-2-(3-methoxypropyl)-2 - thioxo-4-thiazolidinone;

5-[[3,5-bis-(4-pentyn)-4-hydroxyphenyl] methyl]-3-ethylamino-4 - thiazolidinone;

5-[[3-ethylthiophene-4-hydroxy-5-were]methylene]-2-thioxo-4 - thiazolidinone;

5-[[3-(2-butene)4-hydroxy-5-isopropoxyphenyl] methyl]-3-(3-diethyl - aminopropyl)-4-thiazolidinone;

5-[[3-(2-propenyl)-4-hydroxy-5-(1,1-dimethylethylene]methylene]-3 - CEC is
5-[[3,5-diacetyl-4-hydroxyphenyl]methyl]-4-thiazolidinone;

5-[[3-(3-methyl-1-butene)-4-hydroxy-5-propylphenyl] methylene] -3 - atilano-4-thiazolidinone;

5-[[3-(2-propenyl)-4-hydroxy-5-methoxyphenyl] methyl] -3-ethoxy - 4-thiazolidinone;

5-[[3,5-di-2-propenyl)-4-hydroxyphenyl] methylene]-3-(methylamino - methyl)-2-thioxo-4-thiazolidinone;

The following compounds, in addition to the above, are examples of substances suitable for use in the method of the invention. 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-(3-methoxypropyl)-2-t

5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methylene] -2-thioxo - 4-thiazolidinone; 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-thiazolidinone; 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone;

5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-2-thioxo-4 - thiazolidinone;

3-acetyl-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methylene]-4 - thiazolidinone;

5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl-3] -methyl- (1-methylethyl)amino-4-thiazolidinone;

5-[4-hydroxybenzyl]rodann;

5-(4-hydroxy-3-methoxybenzylidene)rodann;

5-[(4-hydroxy-3,5-DIPROPYLENE)methylene] -3-[2-(dimethylamino)ethyl] 4-thiazolidinone;

5-[[3,5-bis-(1-methylpropyl)-4-hydroxyphenyl] methyl] -3-methyl-4 - toxifier] methyl] -3-(methylsulphonyl) 4 thiazolidinone; 5-[[4-hydroxy-3,5-bis(1,1-dimethylethyl)phenyl] methyl] -3-(propylamino-4 - thiazolidinone;

3-amino-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2 - thioxo-4-thiazolidinone; 5-[[3,5-bis-(1-methylethyl)4-hydroxyphenyl]methyl]-3-methyl-4-thiazolidinone;

5-[(4-hydroxy-3,5-acid)methyl]-3-methyl-2-thioxo-4 - thiazolidinone;

5-[(hydroxy-3,5-acid)methylene]-3-methyl-2-thioxo-4 - thiazolidinone.

Some compounds used in the method of the invention are known substances. However, most of the compounds used in the proposed method, as well as compounds of the invention are new substances. Typically, such compounds can be synthesized.

The method and compounds of the invention encompass both the racemate and its individual stereoisomers. Typically, the stereoisomers can be obtained in accordance with methods well known from the literature. However, for compounds of formula I in which X represents-S-; R4and R5represent hydrogen; and R1, R2, R3, R6, R7and Q have the meanings specified for such formulas, individual stereoisomers can be isolated in almost pure isomeric form in accordance with pre those compounds of formula I, in which X represents a group-S-; R4and R5represent hydrogen; R1, R2, R3, R6, R7and Q have the values specified for the preferred compounds of the invention.

Racemic sulfide compound of the formula I is reacted with a reagent obtained by combining tartrate ligand, an alkoxide of titanium, hydroperoxide and, optionally, water. The alkoxides of titanium, suitable for use in the present method can serve as the titanium alkoxides of the formula T: (C1-C4alkoxy)4. Particularly preferred titanium alkoxide is an alkoxide, in which1-C4alkoxy group represents isopropoxy. Similarly, suitable tartrate ligands for use in the present method include di(C1-C4alkyl)tartratami, and especially preferred are diethyltartrate or diisopropylate. Finally, suitable hydroperoxides, which can be used in this way include cumene hydroperoxide, tert-butylhydroperoxide, etc. are Particularly preferred hydroperoxide is tert-butylhydroperoxide. This reaction is performed by mixing these reagents in IBS toluene, etc. such halogenated alkanes as methylene chloride, 1,2-dichloroethane / chloroform, etc., such esters as tetrahydrofuran, diethyl ether, etc., ketones such as acetone, etc., Particularly preferred inert solvent is methylene chloride. Typically, the amount of solvent should be sufficient to ensure that all compounds remained in solution during the reaction. However, you should avoid using excessive amounts of solvent, since the selection of the product may be undesirable losses. The amount of titanium alkoxide used in this reaction is not critical. The titanium alkoxide may be used in amounts from 0.4 to 22.0 equivalents relative to the original racemic sulfide. For the reasons explained in detail below, the titanium alkoxide is preferably used in quantities sufficient to achieve a ratio of titanium alkoxide and sulfide substrate is from 0.5:1.0 to 0.75 to 1.0 second. If the titanium alkoxide used in quantities lower than equimolar relative to the sulfide source material, if desirable, can be added molecular sieves 3Aaboutor 4Aaboutin order to avoid deactivation dittany with the amount of titanium alkoxide and also not decisive. As a rule, tartrate ligand is used in quantities sufficient to achieve a ratio tartrate ligand and the alkoxide of titanium, lying in the range from 1:1 to 5:1, preferably the ratio is 2:1. Similarly, the amount of hydroxide may range from one to two equimolar amounts relative to the titanium alkoxide. The used amount of water can vary in the range from anhydrous reaction conditions (i.e. absence of equivalents of water) to 5 equivalents of water relative to the amount present of the titanium alkoxide. When using anhydrous reaction conditions tartrate ligand should be used in a quantity sufficient to achieve a ratio tartrate ligand and titanium alkoxide corresponding to the upper value of the specified interval ratios.

Stereochemistry tartrate ligand determines the nature of the stereoisomer that will be obtained from racemic sulfide substrate. For example, if in this reaction using (+)-diisopropylate, it will be highlighted in almost pure isomeric form (-) enantiomer of the original sulphide material. Accordingly, when using (-)-diethyltartrate must be chosen so to its stereochemistry was the opposite stereochemistry of the desired isomeric form.

Racemic sulfide substrate of the proposed method is reacted with a reagent derived from the alkoxide of titanium, tartrate ligand, cumene hydroperoxide, and, optionally, of water up until almost all of the unwanted enantiomer sulfide source material doesn't turn in his sulfoxides similar. The conversion of the sulfoxide is conveniently performed at a temperature lying in the range from -50 to +50aboutC, and the preferred temperature is -20aboutC. After almost all unwanted enantiomer turned in his sulfoxides similar, the reaction being removed by rapid cooling of the mixture in accordance with well known methods.

To ensure the transformation of almost all unwanted enantiomer in sulfoxide, while minimizing the conversion of the desired enantiomer, only 50-70% of racemic sulfide substrate Dol tenderly to react with a reagent containing a titanium alkoxide. Restriction reactions 50-70% can be carried out at least in two ways. First, the hydroperoxide may be used in quantities which provide a ratio of hydroperoxide Bivalents relatively sulfide substrate under the condition track the progress of the reaction using standard analytical techniques, for example, thin-layer chromatography (TLC) or liquid chromatography high resolution (HPIC). If such equipment is installed, which turned out 50-70% of the sulfide starting material, the reaction is stopped to prevent further conversion. After termination of the reaction the unreacted portion of the sulfide substrate can be isolated from the cooled reaction with MESI using well-known to specialists. Such unreacted part will consist of the desired enantiomer in almost pure enantiomeric form.

The following examples illustrate how the selective extraction of enantiomers provided by the invention. These examples are merely illustrative and do not limit in any way the scope of the invention.

P R I m e R 1. (2)-5-[[3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methyl] -4-thiazolidinone.

In a three-neck round bottom flask with a capacity of 50 ml, containing 25 ml of methylene chloride, add 1,31 g 4Aaboutthe molecular sieves of 0.56 ml (1.88 mmol) of isopropylate titanium, of 0.79 ml (3.75 mmol) of (+)-aminobutiramida tartrate and 34 μl (1.88 mmol) of deionized water. The resulting solution is stirred for 20 min and then Denny the resulting solution was cooled to -20aboutWith and added to 0.73 ml (1.88 mmol) 2.57 M solution of tert-butylhydroperoxide in isooctane. Then the reaction solution is stirred for 6 h at -20aboutC. After 6 hours, the reaction solution was rapidly cooled, pouring it into 50 ml of a solution derived from 9,9 g of iron sulfate heptahydrate (II), and 3.3 g of citric acid and water. The resulting solution was stirred for 30 minutes and then the stirring was stopped, so that it was possible to separate the organic and aqueous layers. The aqueous layer was decantation and washed with methylene chloride. Wash methylenchloride liquid was combined with the specified organic layer and the resulting solution was washed with a saturated solution of brine and then dried over sodium sulfate. The sodium sulfate was removed by filtration and the remaining liquid is evaporated from the receipt of 1.81 g of residue. This residue was dissolved in 25 ml of methylene chloride and the resulting solution was chromatographically on a column with silica gel. In the elution 6000 ml 10-51% ethyl acetate in hexane gradient has received various fractions containing the specified target connection. These fractions were combined, and the liquid evaporated to obtain 0,19 g of target compound.

I I25-73,6

Found, With 67,50; N 8,53 N 4,48.

P R I m e R s 2, 3 and 4. (+)-5-[[3,5-Bis-(1,1-dimethylethyl)-4 - hydroxyphenyl]methyl]-4-thiazolidinone,(-)-5-[[3,5-Bis-(1,1-dimethylethyl)-4-Hydra oxiranyl] methyl]-4-thiazo - lidine-1-oxide and(+)-5-[[3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone-1 - oxide.

1. According to the manner similar to that described in example 1, the reaction between 0,89 ml (3.0 mmol) of isopropylate titanium, of 1.27 ml (6.0 mmol) of (-)-aminobutiramida tartrate, 54 μl (3.0 mmol) of deionized water, of 1.61 g (5.0 mmol) of racemic 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl] -4 - thiazolidinone and 2.4 ml (6.5 mmole) 2.57 M solution of tert-butylhydroperoxide in isooctane to obtain a residue. The residue was dissolved in 75 ml of methylene chloride and the resulting solution was chromatographically on a chromatographic column with silica gel. Carrying out elution with 6000 ml 10-50% ethyl acetate in hexane gradient, has received various fractions containing(+)-5-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxy - phenyl] methyl]-4-thiazolidinone. These fractions were combined and evaporated the liquid phase with the receipt of 0.43 g of the product. Further elution with 4000 ml of a 50% aqueous solution of isopropanol in hexane received a different faction. Faction, which Cost to obtain 0.87 g of the product. The fractions containing(+)-5-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] methyl] -4-thiazolidinone-1 - oxide, were combined and evaporated liquid to obtain 0.27 g of the product.

2. (+)-5-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] methyl] -4 - thiazolidinone.

(a)25+70,41about(1,0, Meon).

Elemental analysis for: C18H27NO2S

Calculated With 67,25; N. Of 8.47; N 4,36.

Found, With 66,95; N By 8.22; N, 4.26 Deaths.

3. (-)-5-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] methyl] -4 - thiazolidinone-1-oxide.

So pl. 182-184aboutC.

(a)25-21,84about(1,0, Meon).

Elemental analysis for C18H27NO3S

Calculated With 64,06; N. Of 8.06; N 4,15.

Found, 63,84; N. Of 8.09; N 4,12.

4. (+)-5-[[3,5-bis-(1,1-dimethylethyl)4-hydroxyphenyl] methyl]-4 - thiazolidinone-1-oxide.

So pl. 177-181aboutC.

(a)25 +163,05about(C=1.0, the Meon)

Elemental analysis for C18H27NO3S

Calculated With 64,06; N. Of 8.06; N 4,15.

Found, 63,88; N 8,12; N 4,29.

P R I m e R 5. (-)-5-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methyl] -3-methyl-4 - thiazolidinone.

According to the manner similar to that described in example 1, the reaction between 0,45 ml (1.5 mmol) of isopropylate Titanal)-hydroxyphenyl] methyl]-3-methyl-4-thiazolidinone and of 0.58 ml (1.5 mmol) of 2.75 M solution of tert-butylhydroperoxide in isooctane to obtain a residue. This residue was dissolved in 25 ml of methylene chloride and the resulting solution was chromatographically on a column of silica gel. By elution with 1000 ml of methylene chloride and then with 6000 ml of 0-10% ethyl acetate in methylenchloride the gradient, then using a 4000 ml 20-50% isopropyl alcohol in hexane gradient and then with 2000 ml of a 50% aqueous solution of isopropyl alcohol in hexane, were treated with different fractions containing the target compound. These fractions were combined and evaporated liquid to obtain 0.35 g of the target compound.

Elemental analysis for C19H29NO2S

Calculated M 68,02; N 8,71; N 4,17.

Found, C 67,95; N 8,55; N 4,18.

NMR (300 MHz, CDCl3) 1.4 singlet, N), 2,9 (singlet, 3H), 3.0 a (double doublet, 1H), 3,3 (double doublet, 1H), 3,8 (double doublet, 1H), 4,0 (doublet, 1H), 4.2V (doublet, 1H), 5,1 (singlet, 1H), 7,1 (singlet, 2H).

The invention provides a method of treating inflammatory bowel disease in mammals. This activity is demonstrated in the following test systems.

Rats Sprague-Dawley lab Charles river, Portage, M1 (a group of six animals weighing approximately 250 g) twice a day orally was administered test carlismo with 2% solution of acetic acid, the enema tip was placed 8 cm above the rim of the anus. This concentration of acetic acid provides severe inflammation of the colon, characterized by rectal bleeding, diarrhea, erosion of epithelial tissue and destruction of crypts and glands cells. After 24 h of subjects and control animals umertvlâl and distal colon length ten inches were removed and cut along the longitudinal axis. Violations of the tissues inside the remote, open part of the colon was assessed by three independent observers in the scale of assessments 0-4 (0 normal, 4 the most severe inflammation). Each group used 5-7 rats. The results of these tests are presented in the table.

The data presented in the table show that the compounds used in the method of the invention, capable of treating inflammatory diseases of the digestive tract. The term "inflammatory disease of the stomach", as used in the text of the invention, refers to any disorder of the digestive system, which is characterized by inflammation. Examples of such problems include Crohn's disease, mucous colitis, ulcerative colitis, pseudomembranous enterocolitis, not the config enteritis and colitis, idiomaticheskii diffusion ulcerative agranulosis enteritis caused by non-steroidal anti-inflammatory medication inflammation, cellular spore, etc.

The method of the invention includes the application of a mammal suffering from inflammatory bowel disease, an effective amount of one or more compounds of formula I. Such application may be therapeutically or prophylactically and is implemented using pharmaceutical compositions, which are obtained by methods well known in the pharmaceutical industry.

The compounds of formula I effective in a wide range of dosages for the treatment of inflammatory bowel disease. Thus, used in the text, the term "effective amount" refers to the interval of doses of 0.001-200 mg/kg of body weight per day. In the treatment of adults preferred is the range of 0.1 to 50 mg/kg in single or divided doses. However, it should be borne in mind that the actually used amount will be determined by the physician based on the particular circumstances, including the condition of the patient, the choice of the applicable connection, choosing the path of application, the patient's age, patient's weight, patient's response to medication and the ptx2">

Although the compounds of formula I preferably apply orally or vnutriuretrale, connections can also be used in various other ways, for example, transdermal, subcutaneous, inside the nose, intramuscularly and intravenously.

The invention also relates to pharmaceutical compositions that include at least one compound of formula I together with one or more pharmaceutically applicable thinners, eccipienti or media.

In the preparation of pharmaceutical compositions of the invention one or more compounds of the formula I is usually mixed with a carrier, or diluted by a carrier or capsulebuy in the media, which may be in the form of capsules, paper or other container. In this case, when the media acts as a diluent, it may be a solid, semi-solid, or liquid material which acts as a binder, excipient or medium for the active ingredient. For example, the composition can be in the form of tablets, pills, powders, pellets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid and in liquid medium), ointments containing, for example, up to 10 wt. active compound, soft and TV is AMI suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, Arabic gum, calcium phosphate, alginates, tragant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Such formulations can additionally include lubricating agents, wetting agents, emulsifying and suspendresume agents, protecting agents, sweetening agents or perfumes. Compositions of the invention can be formed in such a manner that a rapid, prolonged or delayed release of the active ingredient after use on the patient using techniques well known in the field. Composition, form, preferably in unit dosage form so that each dosage contains 5-500 mg, usually 25-300 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units intended for single dose when applied to humans and other mammals, each unit contains a certain amount of active material calculated the pharmaceutical diluents, eccipienti or media.

1. The WAY the SELECTIVE extraction of ONE of the ENANTIOMERS of RACEMIC MIXTURES of compounds of General formula I

< / BR>
where R1and R2, independently of one another, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C2-C6alkenyl,2-C6-quinil,1-C4-alkyl - or

where n is an integer in the range 0-3, including extreme values of the interval;

R3hydrogen or C1-C6-alkyl;

R6and R7hydrogen or together form a group S, or in the case when one of R6and R7hydrogen, the other radical is the value HE or SCH3;

Q-CH2-, -O - or-NR8where R8hydrogen, C1-C6-alkyl, C2-C6alkenyl,3-C8-cycloalkyl, SO2CH3or (CH2)n-Y, where n is an integer in the range 0-3, including both extreme values;

Y cyano, tetrazolyl-, NR11R12, SH, S (C1-C4-alkyl) or group where R9hydrogen, C1-C4-alkyl or

R10WITH1-C4-alkyl, C1-C4-alkoxy or-NH2;

R11and R12independently from each other SUB>2
)q-N(C1-C4- alkyl)2, -(CH2)qS (C1-C4-alkyl) or where n has the values specified above, and q is an integer in the range 1-6, including extreme values,

or R11and R12together form morpholinyl, piperidinyl, piperazinil or N-methylpiperazine ring,

characterized in that carry out the reaction of the racemic mixture of compounds of formula I with a reagent prepared from tartrate ligand having the stereochemistry opposite to get the desired enantiomer, titanium alkoxide, and cumene hydroperoxide, and preferably water, and then allocate the desired enantiomer from the reaction mixture.

2. The method according to p. 1, characterized in that as starting compounds are used racemic sulfide compound, where R1and R2- C1-C6-alkyl WITH2-C6alkenyl, C1-C6-alkoxy or

R3, R6and R7hydrogen

Q NR8where R8hydrogen, C1-C6-alkyl or -(CH2)n-Y, where n is 0, NR11R12where R11and R12independently from each other hydrogen or C1-C6-alkyl. 3. The method according to p. 1 or 2, is great for the PP. 1-3, characterized in that as tartrate ligand is used diisopropylate.

5. The method according to any of paragraphs. 1-4, characterized in that as cumene hydroperoxide, tert used-butylhydroperoxide.

6. The method according to p. 2, characterized in that as starting compound used racemic 5-[(3,5 bis(1,1-dimethylethyl)-4-hydroxyphenyl)methyl]-4-thiazole-idine and this compound is reacted with a reagent derived from a combination of Ti(O-isopropyl)4, (-)-aminobutiramida tartrate, tert-butylhydroperoxide and water to obtain almost pure(+)-5-[(3,5-bis)1,1-dimethylethyl )-4-hydroxyphenyl)methyl]-4-thiazolidinone.

7. The method according to p. 2, characterized in that as starting compound used racemic 5-[/3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl/methyl/-4-thiazolidinone and this compound is reacted with a reagent derived from a combination of Ti(O-isopropyl)4, (+)-diisopropylaniline, tert-butylhydroperoxide and water to obtain almost pure(-)-5-[(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl (methyl)-4-thiazolidinone.

 

Same patents:

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to dipeptide mimetic selected from glutaminyl thiazolidine or glutaminyl pyrrolodine and salts thereof as well as to using of such compounds in treatment of abnormal glucose tolerance, glucoseuria, diabetes mellitus and other disordered as well as complications associated with diabetes mellitus in mammalians.

EFFECT: new effectors of dipeptidyl peptidase IV.

18 cl, 3 tbl, 2 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to aldimines used to produce a polymer precursor, obtained via reaction of at least one sterically hindered aliphatic aldehyde A of formula with an aliphatic amine B, where all values of substitutes are given in the claim, via a condensation reaction with splitting of water, a product containing an aldimine-containing compound, and use thereof as a protected cross-linking agent for the polymer precursor and as a source of amines [H2N]m-R4-[XH]y (B).

EFFECT: obtaining polymer precursors containing isocyanate groups, which are characterised by high stability during storage.

15 cl, 51 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of moguisteine, which is an ethyl ether of (R,S)-3-[2-[(2-methoxyphenoxy)methyl]-1,3-thiazolidin-3-yl]-3-oxypropionic acid, involving a) reaction of guaiacol with 2-X-methyl-1,3-dioxolane to obtain 2-[(2-methoxyphenoxy)methyl]-1,3-dioxolane, b) reaction with cysteaminein the presence of an acid to obtain (R,S)-2-[(2- methoxyphenoxy)methyl]-1,3- thiazolidine, c) reaction with monoethylmalonic acid or a salt thereof in the presence of a condensing agent to obtain moguisteine.

EFFECT: obtaining moguisteine with high output and purity.

18 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel trans-2-decenoic acid derivative of formula (I') or a pharmaceutically acceptable salt thereof , possessing preventive or therapeutic effect for peripheral nervous system disorders, caused by anti-cancer agents, and/or neurotrophic factor-like activity and/or analgesic action, as well as to a pharmaceutical agent based thereon.

EFFECT: prevention and treatment of nervous system disorders.

14 cl, 11 tbl, 56 ex

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