CS241544B2 - Method of mineral acids' substituted thiazolidinylesthers production - Google Patents

Description

The 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, n OC co

'0 ~ A

C 1 -C-N-N = C.

(I) wherein 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 of the same radical or an alkyl radical of not more than 7 carbon atoms,

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

A represents a radical of formula Ia-SO ₂ -O-χ (1a) wherein

Ζχ represents a hydrogen atom or an alkyl group of up to 7 carbon atoms.

The invention also relates to a process for the preparation of salts of the compounds of the formula I in which Ζχ represents a hydrogen atom with bases, in particular 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-piropinyl. The alkyl group R @ 1 or R @ ₂ and optionally the alkyl group Z @ 1 preferably contain up to 4 carbon atoms. Examples of such groups include 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, for example sodium or sodium salts, or salts with alkaline earth metals, such as gentian, sodium or calcium salts, and ammonium salts. and salts with primary, secondary or tertiary monovalent or polybased organic bases such as ethylamine, 2-aminoethainol, diethylamine, iminodiethanol, triethylamine, 2- (diethylamino), ethanol, nitrilotrietbanol or pyridine or 1,2-ethylenediamine. appropriate pharmaceutically acceptable, non-toxic salts.

The compounds of the formula I can be present in the form of mixtures 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 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 χ 10 ⁶ cells (• aiscites), intraperitoneal administration to mice NMRI], Walker carcino, sarcoma 256 in rats [transplant: 0.5 ml suspension of solid tumor in Hanks' solution, subcutaneous or intramuscular administration to male rats (Wistar)], transplantable mammary adenocarcinoma R 3 230 AC in rats [transplant: 0.5 ml suspension of solid tumor in Hanks' solution, subcutaneous or intramuscular administration to female rats [Fischer]] and in particular mammary gland carcinoma induced by 7,12-dimethylhenz [«] anthracene [carcinoma induced by oral administration of 15 mg 7, 12-dimethylbenz [a-] anthiracene in 1 ml sesame oil to 50-day-old female Sprague Dawley; after 6 to 8 weeks, a number of tumors develop]].

For example, it was found in Ehrlich's carcinoma after four intraperitoneal administration (4 hours after and then 1, 2 <and 3 days after transplantation; each dose was tested on 10 animals each; in case of Walker carcinosarcoma 256 after four oral or intraperitoneal administration (1, 2, 3 and 4 days post-transplant; each dose tested on 8 to 10 animals; 10 days post-transplant, tumor weight in grams] and in mammary adenocarcinoma R 3 230 AC ten-fold oral or intraperitoneal administration [five times a week for 2 weeks starting 4 hours post transplant; each dose tested on 10-15 animals; 20 days post transplant, tumor weight in grams is determined) Inhibition of tumor growth compared to that of untreated control animals:

compound Ehrlich's ascites (Example #) carcinoma

Walker's carcinoma-arcom 256 mammary gland adenocarcinoma R 3 230 AC

tumor growth inhibition dose (mg / kg) (%) dose (mg / kg) inhibition of tumor growth (%) dose (mg / kg) Inhibition of tumor growth (%) 1 4 x 50 ip 94 4 x 50 i. 84 10 x 50 p. 62 4 x 250 p. 53 10 x 250 p. 43 5 4 x 50 ip 42 4 x 50 p. 72 - -

Legend:

method of application is indicated by the following abbreviations:

i. p. intraperitoneal p. o. oral

In the case of mammary gland carcinoma induced by 7,12-d-imethylbenz [a], anthracene, the following Inhibition of tumor growth and regression of already developed tumors were found after five weeks (25 unit doses) or six weeks (30 unit doses) of treatment shown in the table below mean the average size of all tumors in all experimental animals).

compound (example #) dose (mg / kg) average tumor size (treated / untreated experimental animals a ⁾ tumor reduction (%) 1 30 x 10 pp. 1.13 / 24.73 95 30 x 25 p. 2.50 / 20.63 88 5 25 x 25 i. 6.31 / 15.97 61 25 x 100 p. 0.96 / 19.03 95

Legend:

The method of application is indicated by the following abbreviations:

c. subcutaneous

oral

ip intraperitoneal ^(a) the numbers represent the average size of all tumors in all experimental animals

Compared to the 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 ranging between 500 and 1250 mg / g, for oral administration greater than 2500 mg / kg J, so that 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, in particular mammary carcinomas. benefits.

In particular, the invention provides those compounds of formula I wherein one of R 1 and R _{2 is} an allyl or 2-methyl-allyl group and the other is either one of these groups, or preferably a methyl group, and R ₃ , R ₄ and A is as defined in formula (I), wherein A is in particular a radical of formula Ia with hydrogen in the meaning of Zj, and salts, in particular pharmaceutically acceptable bases, of those compounds in which Zj is hydrogen, e.g. as sodium salts.

The invention especially discloses compounds of general formula I in which R ₍₂ represents allyl-or- methylaUylovou group and R ₂ represents any of těchto- skupiin or preferably methyl, R ₃ is hydrogen or especially methyl, and R ₄ represents hydrogen while A is as defined in formula (I), but in particular is the abovementioned preferred moiety, and salts, especially the pharmaceutically acceptable salts of those compounds wherein Z 1 is hydrogen.

First of all, the invention describes, by way of example, the compounds and salts, preferably pharmaceutically acceptable salts, such as alkali metal salts, of the corresponding salt-forming compounds, and in particular

3-methyl-2 - {[5-methyl-3- (2-methylallyl) -4-OKo-5-thiazolidinylidene] hytirazinoyl-4-OXO-5-thiazolidinylnyl hydrogen sulphate, 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) above may be prepared in a manner known per se. In accordance with the invention, these compounds are prepared by treating a compound of formula II

OC 'W

Xí

Rj 'N-CO ^{1 1} uC ~ N ~~ N ~ C.

OH tm in which

R 1, R ₂ , R ₃ and R ₄ are as defined above, reacted with an oxygen-containing sulfur compound selected from the group consisting of sulfur trioxide or its k-omplex with pyridine or a compound of formula IV

XJ-SO ₂ -O-Rev (IV) wherein

Xj represents a reactive, functionally altered hydroxy group, in an inert solvent or solvent mixture, at a temperature between -0 and 100 ° C, whereupon the optionally obtained compound of the formula I is converted into another compound of the general formula I and / or the optionally obtained salt is converted to the free compound or another salt, and / or the compound of formula I in which Z 1 is hydrogen is converted to a salt, and / or the optionally obtained mixture of isomers is separated into individual isomers.

The reactive, functionally altered hydroxyl group in the meaning of Xj in the compounds of formula (IV) above is, for example, a hydroxy group esterified with an inorganic or organic acid, such as hydrohalic or aryl or alkanesulfonic acid, for example p-toluenesulfoic acid, methanesulfonic acid or ethanesulfonic acid.

In particular, the symbol _Xt represents a halogen atom, such as thunder and especially chlorine. Suitable starting materials of the formula (IV) are, for example, chloirsulfonic acid and its lower alkyl esters.

The reaction with sulfur trioxide is preferably carried out in an inert solvent or a mixture of solvents, wherein the sulfur trioxide-pyridine complex is used, for example, in methylene chloride or dimethylformamide or mixtures thereof with pyridine, and the sulfur trioxide is used, for example. dimethylformamide. The reaction temperatures range from about 0 ° C to 100 ° C, preferably at room temperature or at a slightly elevated temperature. When the sulfur trioxide-pyridine complex is used as the primary reaction product, the pyridinium salt of the compound of formula I is obtained, which can be converted to the corresponding acid or, preferably, directly to other salts, for example alkali metal salts. The use of sulfur trioxide gives rise to free acids, which are optionally possible directly, i.e.. without prior treatment, to be converted into salts, for example alkali metal salts.

The reaction of the compounds of the formula II with the compounds of the formula IV is preferably carried out in an inert, in particular 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 trl (lower). alkylamine, such as. ethyldlisopropylamine or triethylamine, for example pyridine or imidazole, or a lower alkali metal alkoxide, for example sodium methoxide or ethoxide, or an inorganic base, for example sodium hydroxide or potassium hydroxide, and a basic ion exchanger.

The reaction is carried out, for example, at a reaction temperature of between about 0 and 100 ° C, preferably at room temperature or at a slightly elevated temperature, and the reaction can be carried out in a closed vessel and / or an inert gas atmosphere such as a nitrogen atmosphere. .

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

The compounds of the formula I obtained by the process according to the invention can be converted into other compounds within the scope of the general formula in a manner known per se.

Thus, compounds of formula I wherein A is a radical of the aforementioned formula Ia and a. Z _t is an alkyl group as defined above, in particular methyl, can be converted to compounds of formula I wherein A is a radical of the above, of formula Ia, wherein Z 1 represents a hydrogen atom.

Conversion of the alkoxy group -OZ _} to a hydroxyl group can be accomplished preferably by a nucleophilic substitution reaction. The reaction may be carried out by treatment with a suitable nucleophilic reagent for the corresponding product of formula (I), which preferably comprises an etherifiable hydroxyl or, in particular, a mercapto group, or a substitutable, including quaternizable, 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; for example t-butylamine, further tri (lower alkylamine, such as trimethylamine, N- (lower) alkylmorpholine or thiomorpholine, for example N-methylmorpholine, or pyridine).

Cleavage .alkoxyskupiny -.OZ _t also can be accomplished by treatment with a strong inorganic base, alkali hydroxide Jato, metal such as sodium hydroxide or potassium hydroxide, preferably in the presence of an alcohol, Jaiku lower alkanol, for example ethanol, or ammonium hydroxide, or by treatment with a suitable neutral salts, in particular alkali metal or alkaline earth metal halides or thiocyanates such as sodium iodide, barium iodide. or thiocyanate, sodium aitain.

Further, it is possible in the compounds of the formula I in which A represents a radical of the formula. Ia, where Z₍ represents a hydrogen atom, to replace these hydrogen atoms by alkyl groups, for example by reacting the compound or the salt thereof an alkanol ester with a strong acid such as an appropriate alkyl halide; e.g., chloride, bromide or iodide, or an appropriate arene or alkane sulfonic acid alkyl ester, e.g. methanesulfonic acid.

The salts of the salt-forming compounds of the formula I obtained by the process according to the invention can be converted into the free compounds in a manner known per se, for example by treatment with an acidic agent, 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 alkali metal hydroxide, ammonia or salt-forming amine.

Mixtures of isomers may be separated into the individual isomers in a manner known per se; racemate mixtures by physical separation methods, for example fractional crystallization or distillation, or chromatography, inter alia by high pressure liquid chromatography, and the racemates, inter alia, by preparing salts with optically active bases and separating the thus obtained salt mixture, for example 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 lead to the formation of the above-mentioned particularly elevated groups of the resulting compounds and, in particular, to the formation of the preferred or specially described products.

The novel substances produced by the process according to the invention can be used as pharmacologically active compounds, in particular as carcinostatically active compounds. The daily dosages of these compounds used in mammals, depending on the type of disease and the active ingredient selected, on the patient's age and condition, and on the mode of administration, are from about 2 mg to 250 mg, in particular from about 5 mg to 100 mg per patient. within this range, lower doses are generally used for parenteral administration, for example by intramuscular or subcutaneous injection, or intravenous infusion, than for 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 solutions are primarily solutions of the respective salts.

Pharmaceutical preparations for enteral, for example oral or rectal, non-parenteral administration, comprise a therapeutically effective amount of a compound of Formula 1 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 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 compound of formula I capable of forming a salt, together with pharmaceutically acceptable carriers.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol sorbate, cellulose preparations and / or calcium salts of phosphoric acid, for example calcium phosphate or dibasic phosphate, as well as binding agents such as starch maize made from maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose or / and / or optionally tablet disintegrants such as the aforementioned starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof such as sodium salt.

The excipients 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 optionally acacia, talc, polyvinylipyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of gastric fluid resistant coatings, cellulose 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 glycerin or soirbit. The push-fit bands 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 ingredient in water-soluble form, for example in the form of a salt, are particularly suitable.

Water-soluble suspensions, as well as suspensions of the active ingredient, such as corresponding oily injection suspensions, using a suitable lipophilic solvent or carrier, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or longer aqueous suspensions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbiit 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, draining 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, 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 32.8 g (0.1 mol) of 5-hydroxy-3-methyl-2 - [[5-meithyl-3- (2-methylallyl) -4-aro-4-thiazolidiinylidene] hydrazomoyl-4-thiazolidinone in 700 ml of methylene chloride and 200 ml of anhydrous pyridine are added 56 g (0.35 mol) of sulfur trioxide-pyridine complex, stirred for 20 hours at 20-25 ° C, then 700 ml of water are added, the resulting mixture is stirred for a further 20 The methylene chloride solution was dried over magnesium sulfate and evaporated in a water-jet vacuum, 500 ml of diethyl ether were added to the residue, the precipitated yellow reaction product was filtered off with suction and washed first with acetone and then with diethyl ether three times. 3-Methyl-2 - [(5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl] sulfate melts at 187 ° C.

To convert to the sodium salt, 48.7 g (0.10 mol) of the above pyridinium salt is dissolved in 1100 ml of methylene chloride and 100 ml of methanol, and sodium methoxide solution prepared from 2.3 g (0.10) is added dropwise with vigorous stirring. After addition of 300 ml of ether, the salt is filtered off with suction, washed twice with methylene chloride, then once with a mixture of diethyl ether and methanol (4: 1) and finally with ether. under high vacuum at 60 ° C, the obtained {{3-methyl-2 - [(5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5- </RTI> salt melts. thiazolidinyl sulfate with decomposition at 195 degrees Celsius,

Example 1 a d 2

In analogy to Example 1, 5-hydroxy-2 - [(3-methyl-4-oxo- ^, 2-thiiazolidiinylidene) hydrazonoyl-3- (2-methylallyl) -4] was obtained from 31.4 g (0.10 mol). -thiazolidinone and 56 g (0.35 mol) of sulfur trioxide-pyridine complex prepare pyrrolidine, {2 - [(3-meithyl-4-oxo-2-thlazolidinylidene) hydrazono] -3- (2-methylallyl) -4- 161 DEG-168 DEG C. oxo-5-thiazoliidinyl] sulfate.

Also analogously to Example 1, from 47.4 g (0.10 mol) of the above pyridinium salt in 800 ml of methylene chloride and a sodium methoxide solution prepared from 2.3 g (0.10 mol) of sodium and 200 ml of methanol , yields the corresponding sodium salt melting at 216 ° C with decomposition.

Example 3

To a solution of 31.4 g (0.1 mol) of 5-hydroxy-2 - [[3-methyl-4-oxo-2-thiazolidinylidene] hydrazono] -3- (2-methyl-allyl) -4-thiazolidinone in 500 ml of methylene chloride and 100 ml of pyridine, a suspension which was previously prepared by dropwise addition of 180 ml of pyridine was added to a solution of 23.3 g (0.34 mol) of chlorosulfonic acid in 400 ml of methylene chloride under a nitrogen atmosphere of -10. The reaction mixture was stirred at 20-25 ° C for 20 hours, then 700 ml of water was added, the mixture was stirred for 20 minutes, then the two layers were separated. magnesium sulfate and evaporated in a water pump vacuum.

The thus obtained pyridinium-2 - [(3-methyl-4-nitro-2-thiazolyl-diinylidene) hydrazono] -3- (2-methyl-allyl) -4-owo-5-th, azolidinyl] -sulfate melts at 190-191 ° C.

To convert to the sodium salt, 47.3 g (0.10 mol) of the above pyridinium salt are dissolved in 600 ml of methylene chloride and 400 ml of dimethylformamide and 75 ml of a 2.95% solution of sodium methoxide in methanol are added dropwise with vigorous stirring. Addition of 1500 ml of diethyl ether precipitates the sodium salt, which is filtered off with suction and washed once with a mixture of diethyl ether and methanol (4: 1) and then with diethyl ether.

After drying under high vacuum at 60 ° C, sodium 12 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -3- (2-methylallyl) -4-oxo-5- melts. thiazolidinyl sulfate with decomposition at 216 ° C.

Example 4

In analogy to Example 3, from 60.1 g (0.20 mol) of 3-allyl-5-hydroxy-2 - ((3-methyl-4-oxo-2-thiazolidinylidene) hydrazone-4-thiazolidinone), 46 6 ml (0.70 mol) of chlorosulfonic acid and 250 ml of pyridine in 700 ml of meithyl chloride, and using 100 ml of a 3.4% meithanolic solution of sodium meth-oxide to convert to the sodium salt, yields sodium 3-allyl. -2 - [(3-methyl-4-oxo-2-thiazolldinylidene} hydrazono] -4-o-xo-5-thiazolidinyl] -sulfate melting with decomposition at 217 degrees Celsius.

Example 5

In analogy to Example 1, from 68 g (0.20 mol) of 3-allyl-2 - [(3-allyl-5-methyl-4-oxo'-2-thlazolidinylidene) hydrazono] -5-hydroxyxy Of 4-thiazolidinone, 81.6 g (0.7 mol) of chlorosulfonic acid and 300 ml of pyridine in 400 ml of methylene chloride, and using 50 ml of a 7.6% methanolic sodium methoxide solution to convert to the sodium salt yielding sodium [3-allyl-2 - [(3-allyl-5-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl N-sulfate, m.p. 190 ° C.

Example 6

Lacquered tablets containing 300 mg of sodium (3-methyl-2 - [(5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl; The sulfate can be prepared as follows.

Composition for 10 000 tablets:

sodium- (3-meithyl-2 - [(5-methyl-3- (2-methylallyl) -4-oxo-2-thiazo) 000.0 g 680.0 g 200.0 g 20.0 g 50, 0 g 250.0 g (as appropriate lidinylidene) hydrazono} -4-o-thiazolidinyl] sulphate maize starch colloidal silicic acid magnesium stearate stearic acid sodium starch-xym-ethyl starch water

A mixture of sodium {3-methyl-2 - [(5-methyl-3/2-methylallyl) -4-oxo-2-thiazolidlidinylidene] hydrazono] -4-axo-5-thiazolidinyl] sulfate, 50 grams of corn starch and The colloidal silicic acid is treated with a starch sebum prepared from 250 g of corn starch and 2.2 kg of demineralized water to form a damp mass which is passed through a 3 mm sieve and then dried at 45 ° C for 30 minutes in a whirling oven. The dry granulate is passed through a 1 mm sieve, mixed with a preformed and screened sieve (1 mm sieve) with a mixture of 330 g of corn starch, magnesium stearate, stearic acid and sodium-starch glycol starch, and the resulting mixture. a slightly domed tablet is pressed.

The moldings are coated in a draining drum of 45 cm diameter over 30 minutes by uniform spraying with a solution of 20 g of shellac and 40 g of hydroxypropylmethylcellulose (lower viscosity) in 110 g of methanol and 1350 g of methylene chloride, while simultaneously drying under air. 60 ° C.

Instead of the abovementioned active substance, the same amount of some other active substance of the preceding examples can also be used, such as sodium-3-allyl-2 - [(3-methyl-4-oxo-2-thiazolyl) vinyl] n. Hydrazono] -4-oxo-5-thiazolidinyl] sulfate.

Example 7

300 mg of sodium (3-m-ethyl-2 - [(5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene) hydrazono-4-oxo-5-thiazolidinyl) in each case; The sulfate in a mixture with 60 mg of rice starch is encapsulated in hard gelatin capsules.

Example 8

The ampoules are each filled with 5 ml of a sterile 4% aqueous solution of sodium-3-methyl-2 - [(5-methyl-3- / 2-methylthylallyl) -4-oxo-2-thiazolinyl] The azono-4-eno-5-thiazolidinyl-s-ulphate hydrate is then sealed and checked for leaks.

Claims (19)

SUBJECT OF THE INVENTION A process for the preparation of substituted thiazolidinyl esters of mineral acids of the general formula I R, R 'is saturated in p-o-lcze 2, 3 and the other of these symbols represents the same radical or an alkyl group having at most 7 carbon atoms, _{R i} and R ₄ independently represent hydrogen or- methyl group and A represents a residue of formula Ia -SO. ₇ -O-Z, CN-N = C. Ο-Λ (iaj where e which (I) Z | represents a hydrogen atom or an alkyl group having at most 7 carbon toms, and-in particular farm isoimerů -or- mixtures thereof, and salts of said ra-sho compounds in -nichž _t Z represents hydrogen, characterized in that a compound of formula One of R 1 and R ₂ is C 3 -C 4 alkyl, not found. Oc ¹ I ² N AND CO i C ^ CC NN N-N C CC ^C. OH (If) in which R _f , R ₂ , R ₃ and R ₄ are as defined above, reacted with an oxygenated sulfur compound selected from the group consisting of sulfur trioxide or a complex thereof with pyridine, or a compound of formula IV Xi-SOa-O-Zi (IV) wherein X 1 represents a reactive, functionally altered hydroxy group and Z is as hereinbefore defined, in an inert solvent or solvent mixture, at a temperature between 0 and 100 ^° C, whereupon the optionally obtained compound of formula I is converted into another compound of formula I and / or the optionally obtained salt is converted into the free compound or to another salt, and / or the compound of the formula I in which Z is hydrogen is converted into a salt, and / or the optionally obtained mixture of isomers is separated into individual isomers. 2. Method according to claim 1 for the manufacture of compounds of formula I according to claim 1, wherein one of the symbols R, and R ₂ represents allyl, 1-methylallyl, 2-miethylallylovou or 2-propinyíovou group and the other of the symbols · it also represents one of these groups or a methyl group, and R ₃ , R ₄ and A are as defined in point 1, in the form of individual isomers or mixtures thereof, and salts of those compounds in which Zt is hydrogen, characterized in that the compound of formula II according to point I, wherein R _b R ₂ , R ₃ and R ₄ are as defined above, reacted with an oxygenated sulfur compound selected from the group consisting of sulfur trioxide or a complex thereof with pyridine, or a compound of the above formula IV wherein X 1 is reactive a hydroxy group, in an inert solvent or solvent mixture, at a temperature of 0 to 100 ° C, after which the optionally obtained compound of formula I is converted to another compound of formula I and / or the optionally obtained salt is converted to a free compound or and / or converting the compound of formula I in which Z _t is hydrogen to a salt, and / or optionally obtaining a mixture of isomers resolved into individual isomers. 3. Process according to claim 1 for the preparation of compounds of formula I in which R _{(R 2, R i,} R ₄ and A are as defined in claim 1, wherein the compound of formula II is reacted with sulfur trioxide or a complex thereof with pyridine. 4. Method according to claim 1 for the preparation of compounds of formula I in which R _t, R _2, R _3, R and A are as defined in claim 1, characterized in that a compound of formula II is reacted with the compound of formula IV wherein X 1 is a reactive, functionally altered hydroxy group. 5. The method of item 2 for the preparation of compounds of formula I wherein R _{1 (} R ₂ , R ₃ , R ₄ and A are as defined in item 2), characterized in that the compound of formula II is reacted with the compound of formula (IV) above wherein X 1 is a reactive, functionally altered hydroxy group. 6. A method pcDL claim 1 for the manufacture of compounds of general formula I, ·, in which R _{1 (R 2,} R ^, _R4 and A are as defined in claim 1, ⁴ aznačující above-said compound of formula II is reacted obecnémlho is reacted with a compound of formula IV wherein X is halogen. 7. The process of Claim 2 for the manufacture of compounds obecného- formula I in which R _t, R _2, R _3, A ₄ and A are as defined in claim 2, wherein the compound of formula II is reacted with a compound of formula IV wherein X is halogen. 8. The method of claim 1, wherein the resulting compound of formula (I) is replaced by an alkoxy group of formula -OZ, wherein Z) is an alkyl group as defined above, a nucleophilic substitution reaction or a hydroxy group. 9. The method of claim 8, wherein a suitable nucleophilic reagent is used which comprises an etherizable hydroxy group of the mercapto group or a substitutable amino group, including a quaternizable amino group. 10. A method according to claim 9, characterized in that. The method according to claim 1, wherein a suitable thiophenoxide, a suitable urea or thiourea or a spherically hindered amino compound, a lower trialkylamine, N- (lower alkyl alkyl morpholine, or thiomorpholine, or pyridine) is used. 11. The process of claim 2, wherein the resulting compound of formula (I) is replaced with an alkoxy group of the formula -OZj, wherein Zj is an alkyl group as defined above, by treatment with thiophenoxide with a hydroxy group. 12. The method according to claim 1, characterized by using the corresponding starting materials, to give compounds of formula I in which one of R _t and R ₂ represents allyl or 2-meth.ylallylovou · radical and the other of these symbols it also represents one of these groups or a methyl group, and R _;! R ₄ and A are as defined in 1, and salts of those compounds wherein Z 1 is hydrogen. 13. The method according to claim 2, characterized by applying the appropriate starting materials, to give compounds of formula I in which one of R _t and R ₂ represents allyl or 2-methallyl, and the other of these radicals is also one or a methyl group, and R ₃ , R ₄ and A are as in 1, and salts of those compounds wherein Z 1 is hydrogen. 14. The method according to claim 1, characterized by using the corresponding starting materials, to give compounds of formula I in which one of the symbols R, _and R ₂ represents allyl or 2-methylallyl · radical and the other of these symbols also represents any of these groups or a methyl group, R ₃ and R /; have the same meaning as in point 1 and A represents the remainder of the above formula (Ia) with hydrogen as defined by Z _b and their salts. 15. The method according to claim 2, characterized in that using the corresponding starting materials, to give compounds of formula I wherein one of R, and R ₂ represents allyl or 2-methallyl, and the other of these symbols also represents · any of these groups or a methyl group, R ₃ and R ₄ have the same meaning as in 1a A is a radical of the above formula (Ia) with hydrogen as Z _1; and their salts. 16. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R ₁ represents an allyl or 2-methylallyl group, R ₂ represents one of the groups mentioned for R, or a methyl group, _R3 is hydrogen or methyl, R ₄ represents an atom. hydrogen and A is a radical of formula (Ia) with hydrogen in the meaning of the symbol Zj, and their salts, 17. The process of claim 2, wherein the corresponding starting materials are used to form the compounds of formula (I) wherein: R 1 is a .alpha., Or 2-meithylallyl group; R ₂ represents any of the groups mentioned under R @ _t or methyl, R ·; represents a hydrogen atom or methyloA represents a radical of formula (Ia) with hydrogen as defined by Z1, and salts thereof. 18. A process according to claim 1, wherein the corresponding starting materials are used to give {2 - [(3-methyl-4-oxo-2-thiaeolidinylidene) hydrazomo] -3- (2-methylallyl) -4- oxo-5-thiazoliidinyl'-sulfate and salts thereof. 19. A process according to claim 2, wherein the corresponding starting materials are used to give (2 - [(3-methyl-4-O'XO-2-thiazolidinylidene) hydrazono] -3- (2-methylallyl) -4 oxo-5-thiazolidinyl] sulfate and salts thereof.