An improved method of producing preparations of thiazolidinediones, new preparations of thiazolidinediones and drugs based on them

 

(57) Abstract:

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent. Medicines contain conventional additives and auxiliary substances and one of the derivatives thiazolidinedione specified above. Derivative thiazolidinedione used for getting medicines for diabetes treatment. Effect: improved method for obtaining preparations of thiazolidinediones. 3 S. and 4 C.p. f-crystals, 1 PL.

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In the application WO 94/27995 described derivative thiazolidinedione General formula

< / BR>
in which a represents a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic ring with up to 4 heteroatoms, and hetero can carry one or more nitrogen atoms, the oxygen atom,

In denotes-CH=CH-, -N=CH-,

-CH=N-, O or S,

W represents CH2Oh , CH(OH), or-CH=CH-,

X represents S, O or NR2where the remainder R2is hydrogen or C1-C6the alkyl,

Y denotes CH or N,

R denotes a naphthyl, pyridyl, furyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine,

R1denotes hydrogen or C1-C6alkyl and

n denotes 1 to 3

and describes their tautomers, enantiomers, diastereomers and physiologically acceptable salts.

Compounds of General formula I can form salts with bases, as thiazolidinediones rings they are acidic IT group. As examples of appropriate pharmaceutical salts can be called alkali metal salts such as lithium salts, sodium or potassium, salts of alkaline earth metals such as calcium salts or magnesium salts of other metals, such as aluminium salts, ammonium salts or salts with organic bases, such as, for example, diethanolamine, Ethylenediamine, Diisopropylamine and others. Especially preferred salt is sodium. The process of obtaining these salts Khujand is the first Foundation by known techniques.

The process of obtaining these compounds is carried out usually by using one of the known methods by subsequent synthesis of thiazolidindiones cyclic system through-halogenated carboxylic acids. To obtain these carboxylic acids diazotised aromatic group and a salt of the page subjected to the interaction with the ethyl ester of acrylic acid in the presence of halogenation acid and salts of copper. This way when it is used in industrial scale, where the product is obtained in quantities measurable in many kilograms, has some weaknesses related to security, with the possibility of improvement, usability and production costs for its implementation. Thus, in particular, when the conversion of aromatic amines in-halogenated carboxylic acids necessary to carry out the diazotization and work with toxic ester of acrylic acid, and this reaction does not provide a satisfactory output. In addition, application of this technology on an industrial scale is extremely problematic and even for security reasons and for environmental reasons.

According to another proposed in the present invention a method for preamplifiers>and n have the above values. However, the catalytic hydrogenation is a very expensive process operation. Especially when using these types of compounds, which in addition to contained in thiazolidinedione ring sulfur are in the molecule one atom of sulfur, it is necessary to take into account such factors as the poisoning of the catalyst gray that, firstly, leads to a significant increase in the duration of the reaction, and secondly, necessitates repeated regeneration of the catalyst.

From literature is known another method recovery compounds of General formula II, namely, that as the reductant used magnesium [see , for example, C. C. Cantello, etc. in Journ. Med. Chem. 37, 3977 (1994)].

This method avoids the inherent way catalytic hydrogenation of interferences caused by the presence contained in the molecule of sulphur, however, in the case of the above mentioned compounds of General formula II there is a partial restoration of the five-membered unsaturated heterocycle, which leads to the formation of impurities, which are difficult to remove from the desired product.

In an unexpected way was ustanovlennoy degree of purity without partial recovery of double bonds membered heterocyclic system, if as a reductant instead of magnesium to use metal aluminum, and aluminum is preferably activated by surface treatment with salts of noble metals. This method is effective primarily when working with a particularly valuable subclasses of compounds of General formula I, below General formula III.

With regard to the foregoing, an object of the present invention is a method of obtaining compounds of General formula III

< / BR>
where And denotes CH=CH or S,

W denotes OH,

X represents S, O or NR2where the remainder R2is hydrogen or C1-C6the alkyl,

Y denotes CH or N,

R denotes naphthyl, thienyl or phenyl, which optionally one or twofold substituted C1-C3the alkyl, CF3WITH1-C3alkoxygroup, F, Cl or bromine,

R1denotes hydrogen or C1-C6alkyl and

n = 1-3.

The proposed method consists in the fact that the compound of General formula IV

< / BR>
in which A, W, X, Y, R, R1and n have the above values, restore activated metallic aluminum in proton solvent. Activating the surface ALM. Particularly suitable for this purpose is a dilute solution of mercury chloride. Aluminum can be used in the form of chips, grains or powder. As proton acceptable solvents, preferably lower alcohols, especially methanol, and water. To improve the solubility can be added aprotic organic miscible with alcohols or water, solvents, or they can be used in vast number. The reaction is carried out at 0-80oC, preferably at room temperature or at slightly elevated temperatures up to 40oC.

The invention relates to new compounds of General formula I, which are not described in the application WO 94/27995 and compared to the described in this application, the compounds exhibit unexpectedly greater and more effective action in the treatment of diabetes. These include the following connections:

5- {4- [2- (5-methyl-2- (Tien-2-yl)oxazol-4-yl)ethoxy] benzo [b] thiophene-7-ylmethyl] thiazolidine-2,4-dione,

5- [4- [2- (5-methyl-2- (4-florfenicol) -4-yl)ethoxy] benzo [b] thiophene-7-ylmethyl} thiazolidine-2,4-dione,

5- {4- [2- (5-methyl-2- (4-chlorophenylacetyl) -4-yl)ethoxy] benzo [b] thiophene - 7 - ylmethyl} thiazolidine -2,4-dione,

5- {4- [2-(5-methyl-2-(4-triphenylimidazole) -4-yl)ethoxy] benzo [b] thiophene-7-ylmethyl] thiazolidine-2,4-dione,

as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.

Another object of the invention is a medicinal product, containing the above compounds as the active substance and intended for the treatment of diabetes. These medicines are manufactured and used on a regular described in WO 94/27995 method.

A new method of obtaining compounds of the formula III is illustrated in more detail by the following examples, which in no way limit it presents particular cases. The process of obtaining compounds of General formula IV is carried out according to the method specified in WO 94/27995.

Example 1. 5- [4- [2- (5-methyl-2-phenyloxazol-4-yl)ethoxy] benzo [b] thiophene-7-ylmethyl} thiazolidine-2,4-dione

a) production of activated aluminum

5 ml of a saturated solution of mercury chloride (II) in ethanol diluted with ethanol to a volume of 50 ml and within a short period of time shaken with 10 g of aluminum needles. Then the solution is decanted and needles washed twice with ethanol, once with diethyl ether and once with tetrahydrofuran.

b) the Connection specified in the header example

The solution of 2,03 g (4,3 IMO is(C) in 130 ml of tetrahydrofuran is mixed with 10 g of the needles of activated aluminum and 1 ml of water. Then for 50 min with stirring, heated to 50oAnd the solid fraction is filtered off. The filtrate is evaporated and the residue chromatographic on silica gel using a mixture of about 88.parts of toluene, about 10. parts 2-butanone and about 2.parts of glacial acetic acid.

Yield: 1.65 g (83%), tPL204-206oC.

Example 2. Similarly receive the following connections:

and) 5- {4- [2-(5-methyl-2-(Tien-2-yl)oxazol-4-yl)ethoxy]benzo[b]thiophene-7-ylmethyl}thiazolidine-2,4-dione (yield: 57%, tPL115-117o(C) receive from 5- {4- [2-(5-methyl-2-(Tien-2-yl)oxazol-4-yl)ethoxy] benzo[b] thiophene-7-iletiler} thiazolidin-2,4-dione (tPL229-234oC);

b) 5- {4- [2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]naphthas-1-ylmethyl}thiazolidine-2,4-dione (yield: 76%; tPL187-191o(C) receive from 5-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy] naphthas-1-iletiler}thiazolidin-2,4-dione (tPL252-254oC);

in) 5- { 4- [2-(5-methyl-2-(4-florfenicol)-4-yl)ethoxy]benzo[b]thiophene-7-ylmethyl} thiazolidine-2,4-dione (yield: 81%; tPL205o(C) receive from 5-{4- [2- (5-methyl-2- (4-florfenicol) -4-yl)ethoxy] benzo [b] thiophene-7-iletiler}thiazolidin-2,4-dione (tPL240PL208o(C) receive from 5- { 4- [2- (5-methyl-2- (4-chlorophenylacetyl) -4-yl)ethoxy] benzo [b] thiophene-7-iletiler}thiazolidin-2,4-dione (tPL270oC);

d) 5- { 4- [2- (5-methyl-2- (4-cryptomaterial) -4-yl)ethoxy] benzo [b] thiophene-7-ylmethyl} thiazolidine-2,4-dione (yield: 57%; tPL191o(C) receive from 5-{4- [2-(5-methyl-2-(4-cryptomaterial)-4-yl)ethoxy] benzo [b] thiophene-7-iletiler} thiazolidin-2,4-dione (tPL260oC);

e) 5- {4- [2- (5-methyl-2- (2,4-differeniation) -4-yl)ethoxy] benzo [b] thiophene-7-ylmethyl}thiazolidine-2,4-dione (yield: 78%; tPL189o(C) receive from 5-{ 4-[2-(5-methyl-2-(2,4-differeniation)-4-yl)ethoxy] benzo [b] thiophene-7-iletiler} thiazolidin-2,4-dione (amorphous powder, tPLfrom 255oC).

REPORT ON TOXICOLOGICAL STUDY

The compounds: VM 13.1258 and VM 15.2054

Toxicological profile of both compounds was estimated by pretensioning study male and female rats. In the conducted experiment, both compounds were administered to the animals forced to use a probe for 4 weeks in suspension with Na-carboxymethyl cellulose. Daily dose injection was 25 mg/kg

When the histopathological issleduya VM 13.1258, there was a significant decrease in the content of the erythrocytes, the fall in hemoglobin and a decrease in the total cell volume. In the case of the introduction of VM 15.2054 this effect was not observed. Because the application of known preparations of thiazolidinediones in pharmacochemistry associated with a number of problems related to Hematology, and therefore the lack of effect of a decline in red blood cells and hemoglobin is an important advantage of the claimed compounds in comparison with the known.

VM 15.2054 = 5- {4- [2- (5-methyl-2- (Tien-2-yl)oxazol-4-yl)ethoxy]-benzo [b] thiophene-7-ylmethyl} thiazolidine-2,4-dione (rated connection).

VM 13.1258 = 5-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy] benzo [b] thiophene-7-ylmethyl}thiazolidine-2,4-dione (known compound, WO 94/27995)

Examples of pharmaceutical compositions are shown in table.

1. The way to obtain preparations of thiazolidinediones of the formula III

< / BR>
where And denotes CH= CH or S;

W - O;

X is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl;

Y is CH or N;

R - naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3WITH1-C3alkoxygroup, F, Cl or bromine;

R1- hydrogen eleroy And, W, X, Y, R, R1and n have the above values,

recover metallic aluminum in proton solvent.

2. The method according to p. 1, characterized in that the aluminum metal is activated by surface treatment with salts of noble metals.

3. The method according to p. 1 or 2, characterized in that the activation of aluminum is carried out with a solution of chloride of mercury.

4. Preparations of thiazolidinediones selected from the group including

5-{ 4-[2-(5-methyl-2-(Tien-2-yl)oxazol-4-yl)ethoxy] benzo[b] thiophene-7-ylmethyl} thiazolidine-2,4-dione,

5-{ 4-[2-(5-methyl-2-(4-florfenicol)-4-yl)ethoxy] benzo[b] thiophene-7-ylmethyl} thiazolidine-2,4-dione,

5-{ 4-[2-(5-methyl-2-(4-chlorophenylacetyl)-4-yl)ethoxy] benzo[b] thiophene-7-ylmethyl} thiazolidine-2,4-dione,

5-{ 4-[2-(5-methyl-2-(4-cryptomaterial)-4-yl)ethoxy] benzo[b] thiophene-7-ylmethyl} thiazolidine-2,4-dione,

5-{ 4-[2-(5-methyl-2-(2,4-differeniation)-4-yl)ethoxy] benzo[b] thiophene-7-ylmethyl} thiazolidine-2,4-dione,

as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.

5. Connection on p. 4, a physiologically acceptable metal salts or salts with organic bases.

6. Connection on p. 4 TES tool possessing antidiabetic effect, containing an active substance, a common carrier and excipient, characterized in that the active substance it contains one of the compounds under item 4 or 5.

 

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