CS241531B2 - Method of mineral acids' substituted thiazolidinylesters production - Google Patents

Description

The present invention relates to a process for the preparation of novel substituted thiazolidinyl esters of mineral acids and salts thereof, which compounds have valuable pharmacological properties.

The compounds produced by the process according to the invention correspond to the general formula I ^R i%

OC — NO — CO

3 _from C ^ ONNC- _s .C. In Η OA (n in which one of R 1 and R 2 is an alkyl radical of 3 or 4 carbon atoms, unsaturated at the 2, 3 position and the other one represents the same radical or an alkyl group of not more than 7 carbon atoms,

R 3 and R 4 are each independently hydrogen or methyl and

A is a residue of formula Ib

OZz /

—P = O \

OZ3 (Ib) where

Zz represents an alkyl group having at most 7 carbon atoms and

Z 3 represents a hydrogen atom.

The invention also relates to a process for the preparation of salts of the compounds of the formula I with bases, in particular of pharmaceutically acceptable salts with bases.

The alkyl group R 1 and / or R 2 unsaturated at the 2, 3 position in the compounds of formula I contains a double or triple bond at the 2, 3 position. Examples of such groups include allyl, 1- or 2-methylallyl or 2-propynyl. The alkyl group R 1 or R ₂ and optionally the alkyl group Z ₂ preferably contain up to 4 carbon atoms. Examples of such groups are the pentyl, isopentyl, neopentyl, hexyl and heptyl groups, preferably the propyl, isopropyl, butyl and isobutyl groups, in particular the ethyl group and, primarily, the methyl group.

The base salts of those compounds of the formula I which are capable of forming salts are, for example, metal salts such as alkali metals such as sodium or potassium salts or alkaline earth metal salts such as magnesium or calcium salts, ammonium salts and salts with primary salts. , secondary or tertiary monovalent or polyvalent organic bases such as ethylamine, 2-aminoethanol, diethylamine, iminodiethanol, triethylamine, 2- (diethylamino) ethanol, nitrilotriethanol or pyridine or 1,2-ethanediamine. .

The compounds of the formula I can be present in the form of a mixture of isomers, for example mixtures of racemates (mixtures of diastereomers) or racemates, or in the form of pure isomers, for example pure racemates or optical antipodes.

The novel compounds of the formula I and their salts have valuable pharmacological properties, in particular tumor growth inhibitory activity. This efficacy can be demonstrated in animal experiments, for example by oral or parenteral administration, such as intraperitoneal or subcutaneous administration at doses between 10 and 250 mg / kg in the case of Ehrlich's carcinoma in mice [transplant: 1 X 10 ⁶ cells (ascites), intraperitoneal Ehrlich's ascitic carcinoma on (add growth inhibition poses.) (Mg / kg) tumor (%) in NMRI mice], Walker carcinosarcoma 256 in rats [transplant: 0.5 ml solid tumor suspension in Hanks' solution, subcutaneous or intramuscular administration to rats male (Wistarjj, transplantable mammary adenocarcinoma R 3230 AC in rats [transplant: 0.5 ml solids suspension in Hanks' solution, subcutaneous or intramuscular administration to female rats (Fischer)] and in particular mammary carcinoma in rats induced by 7,12- dimethylbenz [ce] anthracene [carcinoma induced by oral administration of 15 mg 7,12-dimethylbenz [ia] anthracene in 1 ml sesame o 50 day old female Sprague Dawley, and after 6 to 8 weeks, a number of tumors will develop.

For example, it was found in the case of Ehrlich's carcinoma after four intraperitoneal administration (4 hours after and then 1, 2 and 3 days post-transplant; each dose tested on 10 animals; 10 days post-transplant to determine the amount of fluid in ml). for Walker carcinosarcoma 256 after four oral or intraperitoneal administration (1, 2, 3 and 4 days post-transplant; each dose tested on 8 to 110 animals; 10 days post-transplant, tumor weight in grams) followed by tumor growth inhibition compared to in untreated control animals:

256 dose of growth inhibition (mg / kg: tumor (%))

4 X 100 Ip 51 4 X 50 Ip 31

X 250 p. 32

4 X 50 pt 21 - -

4 X 50 pt 19 - -

Legend:

the route of administration is indicated by the following abbreviations: i. p. intraperitoneal p. o. oral

In the case of mammary gland carcinoma induced by 7,12-dimethylbenz [a] anthracene, the following values of tumor growth inhibition and regression of already developed tumors were found after five-week (25 unit doses) or six-week (30 unit doses) treatment (numbers given in the following in the table indicate the average size of all tumors in all experimental animals).

compound (example #) dose (mg / kg) average tumor size (treated / untreated experimental animals) reduction of tumors (%) 2 30 X 10 pp. 2.27 / 24.82 91 30 X 25 p. 6.38 / 21.04 70 5 30 X 10 pp. 8.77 / 22.27 61 30 x 25 p. 6.07 / 22.27 72 6 30 X 10 pp. 9.03 / 22.27 59 30 X 25 p. 5.65 / 22.27 75

Legend:

method of application is indicated by the following abbreviations:

c. subcutaneous

oral

i. p. intraperitoneal

(a) the figures represent the average tumor size in all experimental animals

Compared to strong antitumor efficacy, the toxicity and side effects of the compounds of the invention are very small to moderate (single, maximum tolerated dose for intraperitoneal administration is between 500 and 1250 mg / kg, for oral administration greater than 2500 mg / kg) thus, the compounds described can be used as such or in particular in the form of pharmaceutical preparations for the treatment of neoplastic diseases of warm-blooded animals, particularly mammary carcinomas. Administration is effected enterally, particularly orally, or parenterally, with therapeutically effective doses being administered.

In particular, the invention provides a process for the preparation of those compounds of formula I wherein one of R 1 and R 2 is an allyl or 2-methylallyl group and the other one represents either or preferably a methyl group, and R 3, R 1 and A are as defined in formula (I), wherein A is preferably a radical of formula (1b) with a group as defined above, in particular a methyl group of Z ²¹ and a hydrogen atom of Z 3 and salts, in particular pharmaceutically acceptable salts thereof; corresponding alkali metal salts, such as sodium salts.

In particular, the invention provides a process for the preparation of those compounds of formula I wherein R 1 is allyl or 2-methyallyl and R 2 is one or preferably methyl, R 3 is hydrogen or especially methyl and R 1 is hydrogen, while A is in particular a radical of formula (1b), in which Z 2 is in particular a methyl group and Z 3 is a hydrogen atom, and salts, in particular pharmaceutically acceptable salts thereof.

First of all, the invention describes a process for the preparation of the compounds and salts, preferably pharmaceutically acceptable salts, such as alkali metal salts, of the corresponding salt-forming compounds, and in particular methyl-3-methyl-2 - {[5-methyl- 3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono} -4-oxo-2-thiazolidinyl hydrogen phosphate, and in particular its salts, as pharmaceutically acceptable salts, for example the corresponding alkali metal salts, such as sodium salts .

The novel compounds of formula (I) can be prepared in a manner known per se. In accordance with the invention, these compounds are prepared by compounding a compound of formula III

R, R _t ¹ 'λ - CO

WS 0-A _o

H (III) in which

R 1, R 2, R 5 and R 1 are as defined above and

A 0 represents a residue of formula IIIb

Y2 /

—P = O \

Y3 (IIIb) where

Y 2 and Y 3 are alkoxy groups of up to 7 carbon atoms, act with a nucleophilic agent selected from the group consisting of thiophenol, thiourea and sterically hindered amino compounds, in an inert solvent at a temperature of from -10 ° C to - 100 ° C; I is converted to the free compound or to another salt, and / or the compound of formula I obtained is converted to a salt, and / or the optionally obtained mixture of isomers is separated into individual isomers.

In alkoxy groups Y 2 and Y 3, the alkyl moiety is as defined for Z 2.

In the starting materials of the formula III in which Y2 and Y3 are alkoxy of up to 7 carbon atoms and in particular methoxy, this radical can advantageously be replaced by a nucleophilic substitution reaction with a hydroxy group. Such cleavage can be accomplished by treatment with a suitable nucleophilic reagent on the corresponding starting material of formula (III), which preferably comprises an etherifiable hydroxyl or especially mercapto group, or a substitutable, including quaternary, amino group. Such agents include, but are not limited to, a suitably substituted thiophenolate derivative, such as thiophenol in the presence of an inorganic or organic base such as triethylamine, or a suitable urea derivative or especially thiourea, such as thiourea itself. butylamine, and tri (lower) alkylamine, such as trimethylamine, N- (lower alkylmorpholine or thiomorpholine, for example N-methylmorpholine, or pyridine).

The above reactions are carried out in a manner known per se, in the absence, but preferably in the presence of a suitable inert solvent such as an optionally halogenated hydrocarbon such as benzene or methylene chloride, a lower alkanol such as methanol, dimethylsulfoxide or acetonitrile, or a solvent mixture, usually under mild reaction conditions. conditions, preferably at a temperature between about -10 ° C and 100 ° C, in particular at room temperature or at a slightly elevated temperature of up to about 50 ° C, if necessary in a closed vessel and / or in an inert gas atmosphere such as nitrogen atmosphere. The reaction products may be isolated in the form of the free acids or directly converted into salts, for example alkali metal salts.

The starting materials of the above formula III, wherein Y2 and Y3 are the above-defined alkoxy groups, can be obtained by reacting a compound of the formula II with a

^OC-fi FY j ^with i> C = NN ~ /

_N -CO

AND

OH in which

R1, R2, R3 and R1 are as defined above and reacted with a compound of formula V

O — Y2

X2 — P — O \

O-Y3 (V) wherein

X 2 represents a reactive, functionally altered hydroxy group.

A reactive, functionally altered hydroxy group is, for example, a hydroxy group etherified with an inorganic or organic acid, such as a hydrohalic or aryl- or alkanesulfonic acid, for example p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid. In particular, X2 represents a halogen atom such as bromine and especially chlorine. Suitable starting materials of the formula (V) are, for example, di (lower) alkyl or lower alkylene phosphorochloridates or also the corresponding phosphorobromidates.

The reaction of the compound of formula (II) with the compound of formula (V) is preferably carried out in an inert, particularly aprotic organic solvent, for example methylene chloride, acetonitrile, dimethylformamide or dimethylsulfoxide, and preferably in the presence of an acid binding agent such as an organic base such as tri (lower jalkylamine, such as ethyldiisopropylamine or triethylamine, for example pyridine or imidazole, or a lower alkali metal alkoxide such as sodium methoxide or ethoxide, or an inorganic base such as sodium hydroxide or potassium hydroxide, and a basic ion exchanger. and 100 ° C, preferably at room temperature or at a slightly elevated temperature, and the reaction may, if desired, be carried out in a closed vessel and / or in an inert gas atmosphere such as a nitrogen atmosphere.

The starting materials of the formula II are known (see, for example, DOS No. 2 405 395) or can be prepared in analogy to the known compounds.

The starting materials of the formula III can also be obtained by reacting the compound of the formula II under mild reaction conditions with, for example, an equimolar amount of phosphorus oxychloride and treating the resulting intermediate with, for example, an appropriate alkali metal alkoxide such as sodium methoxide or sodium ethoxide.

The salts of the salt-forming compounds of the formula (I) obtained by the process according to the invention (II) can be converted into the free compounds in a manner known per se, for example by treatment with an acid reagent such as an acid, or they can be converted into other salts.

Salts of the compounds of the formula I which are suitable for the preparation of salts, in particular the pharmaceutically acceptable salts of such compounds, such as those mentioned above, can be prepared in a manner known per se, for example by treatment with a suitable base such as an alkali metal hydroxide, ammonia or a salt-forming amine.

Mixtures of isomers may be separated into the individual isomers in a manner known per se; mixtures of racemates, inter alia, by physical separation methods, for example, fractional crystallization or distillation, or chromatography, inter alia, high pressure liquid chromatography, and racemates, inter alia, by preparing salts with optically active bases and separating the mixture thus obtained, for example by fractional crystallization.

The invention also encompasses embodiments of the process of the invention wherein the starting material is formed under the reaction conditions, or wherein one of the reaction components is optionally present in the form of a salt.

In carrying out the reactions according to the invention, it is expedient to use those starting materials which give rise to the above-mentioned particularly high-ranking groups of the resulting compounds and, in particular, to the formation of the preferred or specifically described products.

The substances produced by the process according to the invention can serve as pharmacologically active compounds, in particular as carcinostatically active compounds. The daily dosage of these compounds for mammals, depending on the type of disease and the active ingredient selected, on the age and condition of the patient and on the route of administration, ranges from about 2 mg to 250 milligrams, in particular from about 5 mg to 100 milligrams per patient. kilogram of body weight, within this range at. parenteral administration, for example by intramuscular or subcutaneous injection, or intravenous infusion, generally use lower doses than enteral, i.e., oral or rectal. The compounds of formula I and their pharmaceutically acceptable salts are administered orally or rectally, preferably in unit dosage forms such as tablets, dragees or capsules or suppositories, and parenterally, in particular in the form of injectable solutions, emulsions or suspensions, or infusion solutions, such as these solutions are primarily solutions of the respective salts.

Pharmaceutical preparations for enteral, for example oral or rectal, or for parenteral administration, comprise a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof having salt-forming properties, optionally together with a pharmaceutically acceptable carrier or carrier mixture, which carriers may be inorganic or organic, solid or liquid. Appropriate unit dosage forms, in particular for oral administration, for example dragees, tablets or capsules, preferably contain from about 50 to 500 mg, in particular about 100 to 400 mg, of a compound of formula I or a pharmaceutically acceptable salt of a corresponding compound of formula I capable of to form a salt, together with pharmaceutically acceptable carriers.

Suitable carriers are, in particular, fillers, such as sugars, e.g. lactose, sucrose, mannitol or sorblt, cellulose preparations and / or calcium salts of phosphoric acid, for example calcium phosphate or dibasic calcium phosphate, binders such as starch oils made from maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or optionally tablet disintegrating agents such as the aforementioned starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof such as sodium salt. The adjuvants are primarily flow control agents and glidants such as silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores may be provided with suitable coatings, optionally resistant to gastric juices. For the preparation of these coatings, inter alia, concentrated sugar solutions containing, if appropriate, acacia, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for preparing gastric juice resistant coatings, solutions suitable cellulosic preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain coloring agents or pigments, for example to identify or distinguish different doses of the active ingredients.

Other pharmaceutical preparations for oral administration are push-fit capsules of gelatin as well as soft sealed capsules of gelatin and a plasticizer, such as glycerine and sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers such as lactose, binders such as starches, and / or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

Suitable rectally administrable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rectal capsules which contain a combination of the active ingredient with a matrix. Suitable bases are, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

For parenteral administration, aqueous solutions of the active compound in water-soluble form, for example in the form of a water-soluble salt, are particularly suitable, as well as suspensions of the active compound as the corresponding oily injection suspensions using suitable lipophilic solvents or carriers such as fatty oils. , for example, sesame, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or further, aqueous injection suspensions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers.

The pharmaceutical preparations according to the invention can be prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, the pharmaceutical preparations for oral administration can be obtained by mixing the active ingredient with carriers, the resulting mixture being optionally granulated and processing the mixture or granulate, if necessary after adding suitable excipients, into tablets or dragee cores.

The invention is illustrated by the following non-limiting examples.

Example 1

To a solution of 33 g (0.10 mol) of 5-hydroxy-3-methyl-2 - {[5-methyl-3- (2-methylllyl) -4-ΟΧΟ-2-thiazolidinylidene] hydrazono} -4-thiazolidinone and 43 ml of ethyldiisopropylamine in 250 ml of methylene chloride are added dropwise with stirring dropwise 21 ml (0.2 mol) of dimethylphosphorochloridate, initially the reaction is slightly exothermic and the reaction temperature is maintained at 25 DEG C. by cooling. The mixture is shaken first with 100 ml of ice-cold 2N hydrochloric acid and then twice with 100 ml of water each time, and the methylene chloride solution is dried over magnesium sulphate and evaporated in a water pump vacuum to give dimethyl- {3-methyl-2- [ (5-Methyl-3- (2'-methylallyl) -4-oxo-2-thiazolidinylidene) hydrazone-4-oxo-5-thiazolidinyl} -phosphate melting once after recrystallization from diethyl ether at 99-103 ° C.

Example 2

To a solution of 22 g (0.05 mol) of dimethyl-3-methyl-2- [[5-methyl-3- (2-methylllyl) -4-oxo-2-thiazolidinylidene / hydrazono] -412

of oxo-5-thiazolidinyl] -phosphate and 26 ml of thiophenol in 70 ml of dioxane are added dropwise with stirring 56 ml of triethylamine, the reaction temperature rising to 40 ° C. The reaction mixture was stirred at room temperature for a further 2 hours. 400 ml of diethyl ether were added thereto, leaving a heavy oil.

The ethereal solution is decanted off, the residual oil is dissolved in 200 ml of isopropanol and treated with stirring with a sodium methoxide solution prepared from 1.15 g (0.05 mol) of sodium and 30 ml of methanol, precipitating sodium methyl- {3-Methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinyl] -idene / hydrazono] -4-oxo-5-thiazolidinyl-phosphate, which is filtered off with suction, washed with a small amount isopropanol and diethyl ether, and then dried under high vacuum at 60 ° C for 15 hours. The product melts at 146-150 ° C.

The product is a mixture of diastereomers which can be separated into both racemates, for example by high pressure liquid chromatography using a stationary phase consisting of chemically bonded Cie-phase silica (250 x 4 mm column dimensions) and a liquid phase consisting, for example, of methanol. , water and 0.01M aqueous sodium dihydrogen phosphate solution in a ratio of 40: 40: 20.

Example 3

To a suspension of 30 g (0.10 mol) of 2 - [(3-allyl-4-oxo-2-thiazolidinylidene) hydrazono] -5-hydroxy-3-methyl-4-thiazolidinone and 21.7 g (0.15 mol) of dimethylphosphorochloridate in 250 ml of methylene chloride, 16.7 ml (0.12 mol) of triethylamine are added dropwise with stirring at 5-10 ° C. The reaction is slightly exothermic and the suspended solids are dissolved, except for the triethylamine hydrochloride formed. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, then shaken first with 200 ml of ice-cold water and then with 100 ml of ice-cold, saturated sodium bicarbonate solution. The methylene chloride solution was dried (MgSO4) and evaporated under reduced pressure until crystallization started. 100 ml of diethyl ether are added to the residue, and the resulting {2 - [(3-allyl-4-oxo-2-thiazalidinylidene) hydrazonol-3-methyl-4-oxo-5-thiazolidinyl] dimethylphosphate is filtered off with suction. 148 [deg.] C.

The starting material can be prepared as follows.

and 17.1 g (0.10 mol) of 3-allyl-2,4-thiazolidinedione-2-hydrazone [colorless oil, see U.S. Pat. No. 3,699,116, Examples 8a) to d) and 8.0 g. (0.11 mol) of methyl isothiocyanate was refluxed in 70 ml of isopropanol for 2 hours, whereby 3-allyl-2,4-thiazolidinedlone-2- (4-methyl-3-thiosemylcarbazone) precipitated as a large crystal precipitate. . The reaction mixture is cooled in ice, the product is filtered off with suction and washed with a mixture of equal parts of pentane and diethyl ether. The product melts at 148-151 degrees Celsius.

b) Dissolve 11.0 g (0.12 mol) of glyoxylic acid monohydrate in 40 ml dioxane, dilute the solution with 200 ml of carbon tetrachloride and add 24.4 g (0.10 mol) with stirring.

3-allyl-2,4-thiazolidinedione-2- (4-methyl-3-thiosemicarbazone). The mixture is then heated and 120 ml of azeotrope of carbon tetrachloride and water is distilled off by means of a descending condenser while 120 ml of carbon tetrachloride are added dropwise. The reaction mixture is cooled to 20 ° C, the thick crystal suspension is diluted with 100 ml of diethyl ether, the crystals are filtered off with suction and washed with diethyl ether. The thus obtained 2 - [(3-allyl-4-ox-o-2-thiazolidinylidene) hydrazono] -5-hydroxy-3-methyl-4-thiazolidinone melts at 209 to 210 degrees Celsius.

Example 4

In an analogous manner to Example 3, 5-hydroxy-3-methyl-2-methyl- (3-allyl-5-methyl-4-oxo-2-thiazclidinylidene) hydrazono-5-methyl-3-methyl is obtained from 31.4 g (0.10 mol). -4-thiazolidinone,

21.7 g (0.15 mol) of dimethylphosphorochloridate and 16.7 ml (0.12 mol) of triethylamine in 250 ml of methylene chloride give {2 - [(3-allyl-5-methyl-4-oxo-2-thiazolidinylidene) Hydrazono] -3-methyl-4-oxo-5-thiazolidinyl dimethyl phosphate, m.p. 102-107 ° C.

The starting material was prepared as follows.

(aj 11.0 g (0.13 mol) of glyoxylic acid monohydrate is dissolved in 40 ml of dioxane, diluted with 200 ml of carbon tetrachloride and 25.8 g (0.10 mol) of 3-allyl- 5-methyl-2,4-thiazolidinedione-2- (4-methyl-3-thiosemicarbazone) [see U.S. Pat. No. 3,699,116, Examples 8a) -e). The reaction mixture is then heated and 120 ml of an azeotropic mixture of carbon tetrachloride and water are distilled off by means of a descending condenser, while 120 ml of carbon tetrachloride are added dropwise. The resulting mixture was cooled to 20 ° C, the thick crystal suspension was diluted with 100 mL of diethyl ether and 200 mL of pentane, and the crystals were filtered off with suction and washed with a 2: 1 mixture of pentane and diethyl ether. methyl-4-oxo-2-thiazolidinylidene) hydrazono] -5-hydroxy-3-methyl-4-thiazolidinone melts at 164-166 ^° C.

Example 5

To a suspension of 40.8 g (0.10 mol) of {2 - [(3-allyl-4-oxo-2-thiazolidinylidene) hydrazono] -3-methyl-4-oxo-5-thiazolidinyl) dimethylphosphate and 20.5 ml (0.20 mol) of thicphenol in 250 ml of isopropanol is added dropwise with stirring 41.4 ml (0.30 mol) of triethylamine, the reaction temperature rising to 30 ° C. The clear yellow reaction solution was stirred at 35 ° C for a further 4 hours. A solution of sodium methoxide prepared from 2.3 g (0.10 mol) of sodium and 50 ml of methanol was added dropwise at 30-35 ° C. sodium 2- [3-allyl-4-oxo-2-thiazelidinylidene] hydrazono] -3-methyl-4-oxo-5-thiazolidinyl] methylphosphate is precipitated, which is filtered off with suction and washed with isopropanol and diethyl ether. After recrystallization from isopropanol / water (4: 1) the product melts at 200-205 ° C with decomposition.

Example 6

In analogy to Example 5, 42.2 g (0.10 mol) of 2 - [(3-allyl-5-ethyl-1-oxo-β-thiazolidinylidene) hydrazono] -3-methyl-4-oxo-5 are obtained. -thiazolidinyl) -dimethylphosphate, 20.5 ml (0.20 mol) of thicphenol and 41.4 ml (0.30 mol) of triethylamine in 250 ml of isopropanol and using 23 ml of a 10% (w / v) methanolic sodium methoxide solution to convert the product to the sodium salt, obtaining sodium {2 - [(3-allyl-5-methyl-4-o-xo-2-thiazolidinyl) hydrazono-3-methyl-4-oxo-5-thiazolidinyl); - methyl phosphate melting at 190 ° C with decomposition.

Example 7

To a mixture of 2.18 g of dimethyl (3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene) hydraxone] -4-axo-5-thiazolidinylphosphate A solution of 0.4 g of tert-butylemine in 5 ml of methylene chloride was added dropwise under stirring and cooling to 4 DEG C. over 7 minutes under a nitrogen atmosphere, and the resulting clear yellow solution was allowed to rise to room temperature and the solution was stirred at room temperature. The reaction mixture was stirred at room temperature for 16 hours, then another 2 ml of t-butylamine was added and the mixture was stirred for an additional 29.5 hours. The precipitate was filtered off and washed first with methylene chloride / diethyl ether (1: 3) and then with diethyl ether to give (N-methyl-tert-butylaroonium) methyl (3-methyl-2 - [[5]). -methyl-3- (2-methylallyl) -4-oxo-2-thiazclidinylidene / hydraztono-4-oxo-5-thiazolidinyl-4-oxo The melt is melted at 216 DEG-217 DEG C. with decomposition after high-vacuum drying at room temperature. This product can, for example, be converted into the sodium salt by treatment with a methanolic sodium methoxide solution.

Example 8

A mixture of 2.2 g of dimethyl {3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene / hydrazono] -4-oxo-5-thiazolidinyl] phosphate and 0 38 g of thiourea in 2.3 ml of methanol are heated under reflux in a 70-80 ° C bath for 6 hours, changing to a solution which is allowed to stand for 16 hours. The resulting thick crystal suspension is diluted with 4-5 ml of diethyl ether, the solid material is ground, filtered and washed first with a 2: 1 mixture of diethyl ether and methanol and then with diethyl ether. The thus obtained [S-methylisothiuronium] methyl-3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazone] -4-cxo-5-thiazolidinylphosphate melts with decomposition at. 189 DEG -191 DEG C. and can be converted, for example, into a sodium salt by treatment with a methanolic sodium methoxide solution.

Example 9

To a solution of 49.4 g of sodium methyl [3-methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5- of thiazolidinylphosphate in 800 ml of deionized water, while stirring, 120 ml of 1N hydrochloric acid are added to form a thick, partially gel-like mass which is dissolved in 1500 ml of dioxane at 30-35 ° C and diluted with 2500 ml of methylene chloride. The aqueous phase is extracted twice with 200 ml of methylene chloride each time, the combined organic solutions are washed once with 400 ml of a mixture of equal parts of concentrated aqueous sodium chloride solution and water and dried over 200 g of magnesium sulfate for 5 minutes. The mixture is filtered, washed with dioxane / methylene chloride (1: 2), the filtrate is evaporated under reduced pressure at a bath temperature of 45-50 ° C to a volume of 800 ml, the resulting crystalline precipitate is filtered off and washed twice with a small amount of dioxane and then diethyl ether. methyl β-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene / hydrazono] -4-oxo-5-thiazolidinyl] -hydrogen phosphate melting at 193-191 was obtained Deň: 32 ° C.

Example 10

Suspension of 7 g of methyl (3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene / hydrazino]] - 4-oxo-5-thiazolidinyl] hydragenephosphate ( see Example 9) in 40 ml of distilled water, adjust to pH 7 with ca 4% aqueous potassium hydroxide solution while stirring, stir the slightly cloudy solution with ca 0.5 g of activated carbon and filter. 15 g, a syrup-like residue, some of which contains a solid, is dissolved in 50 ml of isopropanol and diethyl ether is added portionwise with stirring to form a viscous precipitate, to which more diethyl ether is added, the supernatant is decanted off and 40 ml of acetone is added to form a powder precipitate, diethyl ether is again added to this material, the non-filterable precipitate is rinsed into another vessel with acetone, 20 ml of isopropanol is added and the mixture Dilute with 150 ml diethyl ether to give filterable potassium methyl- {3-methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5 -thiazolidinyl] -phosphate, which is dried under reduced pressure at 60 ° C for 24 hours. The resulting product has a melting point of 167-170 ° C (decomposition from 177 ° C).

Example 11

Suspension pH of 8 g of methyl {3-methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl'-hydrogenphosphate ( Example 9] in 50 ml of distilled water is adjusted to pH 7-8 with about 4% aqueous ammonium hydroxide solution while stirring. The slightly turbid solution is clarified with activated carbon, filtered and the filtrate is evaporated to a residue of 20 g under reduced pressure. The residue is diluted with 80 ml of isopropanol and diethyl ether is added until the beginning of turbidity, and crystallization can be induced by seeding to form ammonium-methyl-1,3-methyl-2- [[5-methyl-3- (2-methylallyl)]. The 4-oxo-2-thiazolidinylidene / hydrazono] -4-oxo-5-thlazolidinyl] -phosphate was filtered off and dried under high vacuum at room temperature for 20 hours, the product melting at 195-197 ° C.

Example 1 a d 12

To a suspension of 1 g of methyl 3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-clo5-thiazolidinynyl hydrogen phosphate (see Example 9) in 10 ml of distilled water A 5% aqueous solution of 2-hydroxyethylamine was added portionwise with stirring to a pH of 7-8. The resulting solution was clarified with 0.3 g of activated carbon, filtered and evaporated to about 2 g under reduced pressure. The precipitate thus obtained is dissolved in about 20 ml of methanol, a small amount of activated carbon is added to the solution, the mixture is filtered and the clear filtrate is evaporated to a volume of about 5 ml. The desired (2-hydroxy-ethylammonium) methyl-; 3-methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -1-cxo-5 ml. -thiazolidinyl} -phosphate is crystallized by addition of diethyl ether and then filtered off, melting at 186-187 ° C C.

Example 13

Suspension of 1 g of methyl {3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazone] -4-oxo-5-thiazolidinyl] hydrogen phosphate (see Example 9) ) in 10

241331 and milliliters distilled were brought to pH 7-8 with stirring by successively adding a 5% aqueous solution of tri- (2-hydroxyethyl) amine to form a clear solution which became cloudy after about 5 minutes. The solution is evaporated to a 3 g residue under reduced pressure, diluted with 20 ml of absolute ethanol, stirred with 0.5 g of activated carbon and filtered. The clear filtrate was evaporated to a residue of about 3 g under reduced pressure, starting to crystallize [tri- (2-hydroxyethyl) ammonium] ethyl- {3-methyl-2 - [[5-methyl-3- (2-methylallyl)]. -4-oxo-2-thiazololidinylldene / hydrazone-4-oxo-5-thlazolidinyl phosphate. To the residue was added 10 mL of absolute ethanol and 10 mL portionwise of diethyl ether, the resulting salt was filtered off and dried under high vacuum at 40 ° C for 6 hours. Mp 145-146 ^° C.

Example 14

Lacquered tablets containing 300 mg of sodium methyl-3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-6-o-2-thiazolidinylidene] hydrazone-4- The ox-o-5-thiazolidinyl phosphate can be prepared as follows.

Composition for 10,000 tablets;

sodium methyl-3-methyl-2- [(5-methyl-3- (2-methylallyl)) - o10-2-thiazolidinylidene / hydrazono] -4-oxo-5-thiazolidinyl-

-phosphate 3,030.0 g cornstarch 680.0 g colloidal silicic acid 200.0 g magnesium magnesium stearate 20,0 g stearic acid 50,0 g natriumkarbonymethyiškrob 250.0 g science as required

Sodium-methyl {3-methyl-2 - [[5-methyl-3- (2-methylallyl)] -4-ox-c-2-thiazolidinylidene / hydrazino-4-oxo-5-thiazolidinyl] phosphate 50 g of corn starch and colloidal silicic acid are treated with a starch sebum prepared from 250 g of corn starch and 2.2 kg of demineralized water to a wet mass, which is sieved through a sieve of 3 mm and then dried at 30 ° C for 30 minutes. 45 ° C in a fluid bed dryer. The dry granulate is passed through a 1 mm sieve, mixed with a pre-prepared and sieved (1 mm sieve) blend of 330 g corn starch, magnesium stearate, stearic acid and sodium carboxymethyl starch, and the resulting blend is pressed into slightly domed tablets.

The moldings are coated in a 45 cm diameter auction drum over 30 minutes by uniformly spraying a solution of 20 g of pork and 40 g of hydroxypropyl methylcellulose (lower viscosity) in 110 g of methanol and 1350 g of methylene chloride while drying at 60 G.

Instead of the aforementioned active ingredient, it is also possible to use the same amount of some of the other active ingredients of the preceding examples as (2-hydroxyethyl-2-hydroxy) -inethyl- (3-methyl-2- [t -methyl-3- (2-methylallyl)]. (4-Oxo-2-t-azolidinylidene / hytirazono) -4-oxo-5-thiazolidinyl] -phosphate Example 15

300 mg of sodium methyl 3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-a-e-2-thiazolidinylidene / hydrazono] -4-oxo-5-thiazolidinyl] phosphate in each case mixtures of 60 mg of rice starch are encapsulated in hard gelatin capsules.

An equal amount of [2-hydpoxyethylammonium 1-methyl-5-methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazone] may also be used in place of the above active ingredient. -4-oxo-5-thiazolinyl; phosphate.

Example 16

The ampoules are each filled with 5 ml of a sterile 4% aqueous solution of sodium methyl-β-methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo. 5-thiazolidinyl'-phosphate, corresponding to 200 mg of the active substance, are then sealed and checked for leaks.

The same amount of (2-hydroxyethylaroonium) -methyl- (3-methyl-2- [[5-: methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene]) may also be used. (hydrazone-4-oxo-5-thiazolidinyl) -phosphate.

415 31

Claims (12)

SUBJECT VYNALEZU Process for the preparation of substituted thiazolidyl esters of mineral acids of the general formula I / 0 ° C S ‘ OC WN ~ what η ι i! N ^l 3 CX ". ^ C ^ N ~ | ý =: Cx _F, X H C-A (s) in which one of R 1 and R 2 denotes an alkyl radical having 3 or 4 carbon atoms, unsaturated in the 2-position; R 5 and R d are each independently hydrogen or methyl, and A is a residue of formula Ib Mark 2 where Y 2 and Y 0 are alkoxy groups of up to 7 carbon atoms, act with a nucleophilic agent selected from the group consisting of thtophenol, thiourea and spherically hindered amino compounds, in an inert solvent at a temperature of from -10 ° C to -100 ° C; I is converted to the free compound or to another salt, and / or the compound of formula I obtained is converted to a pharmaceutically acceptable salt, and / or the optionally obtained mixture of isomers is separated into the individual isomers. 2. The method of item 1, for the preparation of compounds of formula I according to item 1, wherein one of R1 and R2 is allyl, 1-methylallyl, 2-methylallyl or 2-propynyl and the other of these ^: the radicals also represent one of these groups or a methyl group, and R 5, R 1 and A are as defined in 1 above, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (III) is: -P = O \ OZs (Ib) Ri s OC-— N _N -what Z 5 represents an alkyl group having at most 7 carbon atoms and Z 5 represents a hydrogen atom, isomers thereof and pharmaceutically acceptable salts thereof, characterized in that nu of formula III R, i OC —NN ” ..... ‘t • ί - N - Οχ '3 li (I H) to merge- in which - CO R 1, R 1i, R 3 and R 1 have the above I know and A 0 represents the remainder of the formula i R, Yz / —P == O \ (Ul! Y3 (Illb) in which R 1, R 5, R 3 and R d are as defined above and A 0 represents a residue of formula IIIb Y2 / —P O \ Ys (Illb) where Y 2 and Y 5 are alkoxy groups of up to 7 carbon atoms, act at 0 to 100 ° C with thiophenol or a tertiary organic base, optionally converting the reaction product of formula I into a pharmaceutically acceptable base salt or liberating the corresponding free acid from the obtained salt . 3. The method of item 1, wherein R 1, R 5, R 3, R 1 and A are as defined in item 1, characterized in that thiophenol, thiourea or a spherically hindered amino compound is used as the nucleophilic agent. , such as lower trialkylamine, N- (lower jalkylmorpholine or -thiomorpholine). 4. A process according to claim 2 for the preparation of compounds of formula (I) wherein R1, R2, R5, Rd and A are as defined in item 2, characterized in that the alkoxy group Y is replaced by hydroxy by the action of ihiofence in the presence triethylamine, operating at 20 to 40 ^° C in isopropanol or dioxane as solvent. 5. A process according to claim 1 or 3, wherein the corresponding starting materials are used to form compounds of formula I wherein one of R1 and R2 is allyl or 2-methylallyl and the other is also one of the following: of these groups or a methyl group, and R 5, R d and A are as defined in point 1, and pharmaceutically acceptable salts thereof. 6. A process according to any one of Claims 2 or 4, wherein the corresponding starting materials are used to form compounds of formula (I) wherein one of R1 and R2 is allyl or 2-methylallyl and the other of it also represents any one of these groups or a methyl group, and R 3, R d and A are as defined in point 1, and pharmaceutically acceptable salts thereof. 7. The method of any one of items 1 or 2 3, characterized in that the corresponding starting materials are used to give compounds of the formula I in which one of R1 and R2 is an allyl or 2-methylallyl group and the other is also one or a methyl group , R 3 and R d are as in 1 a A represents the remainder of the above formula Ib with an alkyl group as defined above Z2 and hydrogen as defined by Z3 and pharmaceutically acceptable salts thereof. 8. The method of any one of items 1 or 4, characterized in that the corresponding starting materials are used to give compounds of formula (I) in which one of R1 and R2 is an allyl or 2-methylallyl group and the other is also one or a methyl group , R 3 and R d are as in 1 a A is a residue of the formula I, with the above-defined alkyl group Z 2 and hydrogen Z 3, and pharmaceutically acceptable salts thereof. 9. The method of any one of items 1 or 2 3, characterized in that the corresponding starting materials are used to give compounds of the formula I in which: R1 is allyl or 2-methylallyl, R2 is one of R1 or methyl, R3 represents a hydrogen atom on the methyl group, Rd represents a hydrogen atom and A is a radical of formula (Ib) with a methyl group Z 1 and hydrogen Z 1, and pharmaceutically acceptable salts thereof. Process according to either of Claims 2 or 4, characterized in that the corresponding starting materials are used to give compounds of the formula I in which: R1 is allyl or 2-methylallyl, R? represents one of the groups given by Rt or methyl, R 5 represents a hydrogen atom or a methyl group, Rd represents a hydrogen atom and A is a radical of formula (Ib) with methyl group Za and hydrogen Z3, and pharmaceutically acceptable salts thereof. . 11. A process according to any one of claims 1 or 3, wherein the corresponding starting materials are used to give methyl-3-methyl-2- [[5-methyl-3- (2-methyl-allyl)] - 4-oxo-2. thiazolidinylidene / hydrazono-4-oxo-2-thiazolidinyl hydrogenphosphate and pharmaceutically acceptable salts thereof. 12. The method of any one of 2 or 4, characterized in that the corresponding starting materials are used to give methyl {3-methyl-2- [[5-methyl-3- (2-methylsilyl) -4-oxo-2-thiazolidinylidene] -hydrazono] - 4-oxo-2-thiazolidinyl} -hydrogenphosphate and pharmaceutically acceptable salts thereof.