DE2035406A1 - Process for the production of new azines - Google Patents

Description

Dr. F. Zunnteln ι · η. - Dr. E. * t »man
Dr.ltKo "öia" b # ro * r - Dipl.Phya.R. Holxb «u # r

Dr. F.Zumatein jun.
* P- * »■ '· nlenwflhi
S IMacfc · » 2, Bräuhaujstraß · 4 / III

Process for the production of new azines

The present invention relates to a process for the preparation of new azines, these compounds as new substances, medicinal products containing them and their Use.

Azines of the general formula I ₁

CH

^ -cft \ = nn = c ^ \ h ₂ (ι)

O = C-N {I-C = O

in which

R is an allyl or 2-methylallyl group,
have not yet become known. As has now been found, these compounds have valuable pharmacological properties. The compounds of general formula I inhibit the growth of tumors, as in animal experiments with subcutaneous and oral administration, for example on Walker's carcinoma of the rat and on dimethylbenzanthracene
induced mammary carcinoma of the rat in the absence of pannus

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education could be determined. For example, the compounds of the general formula 1 which can be prepared according to the invention, the 2,2'-azine des 3-allyl-5-methyl-2,4-thiazolidinedione and des 3-methyl-2,4-thiazolidinedione and the 2,2'-azine of 3-methyl-2,4-thiazoledinedione and 3- (2-methylallyl) -5-methyl-2,4-thiazolidinedione when administered orally through diraethylbenzanthracene induced Mammae arc inom in a total of 15 doses of 100 mg / kg each Inhibition of tumor growth of 76-99% within 3 weeks. In Walker's carcinoma, those which can be produced according to the invention are effective ™ Compounds of general formula I, in, the same order indicated as above, with subcutaneous administration of 100 mg / kg each on 4 consecutive days, an inhibition of tumor growth of 52 or 38%,

. The rats with mammary carcinoma induced by dimethylbenzanthracene, which had been treated with the compounds of general formula I according to the invention according to the above-mentioned animal experiment, were ophthalmologically controlled; In none of the animals was during long-term observation. damage to the cornea through pannus formation _s - "ct» .h * - ·. eiueftühntig-dk ^ r cornea through formation of. granulation tissue found ,, ■

Compounds of the general formula - I are prepared 'by adding a compound of the general. Formula II. Or a 'salt of a tautomeric form of a Ί

CH ₃ -CH C = NJH- ^
O = C - N_R

in which

R has the meaning given above with a reactive Ester / with respect to the hydiroxyl function of glycolic acid Formula III. . '.

HO-CH ₂ -COOH.,. ·. . .. ■; - (in)

a compound of the general formula (Ha) or a salt of a tautomeric form of such a compound

in which

R has the meaning given above, with a reactive ester with respect to the hydroxyl function of lactic acid Formula IHa,.

HO-CH-COOH (IHa)

CH ₃
in the heat. '

The salts of the thiosemicarbazones of the general formula II or Ha required for the preparation of the azines of the general formula I are prepared, for example, in situ by adding a base or a salt of a weak acid, for example sodium acetate. The reaction is, for example, in a lower alkanol, such as ethanol, propanol, isopropanol or butanol, at temperatures between 50 ° and 150 ° _t preferably at the boiling point of the solvent used, performed. Suitable reactive esters with regard to the hydroxyl function of glycolic acid or lactic acid are, for example, hydrohalic acid

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and sulfuric acid esters *, in particular arenesulfonic acid t U O b 4 U D and methanesulfenic acid esters, i.e. the corresponding 2-halogen, 2-Arensuif © nyloxy and methanesulfonyloxy acetic acids and propionic acids. As functional derivatives of these reactive esters with respect to the carboxyl function, for example, are suitable Anilides or lower alkyl esters. i.e. 2-halo, 2-arenesulfonyloxy * and 2-methanesulfonyloxy-acetanilide and-propionanilide resp. the corresponding esters.

■ You can use the thiosemicarbazones used as starting materials of the general formula II or Ha in a technically advantageous one Reaction sequences starting from 4-substituted 1-alkanoyl 3-thiosemicarbazides of the general formula IV

in which

R- the methyl, allyl or methallyl group and

R- is hydrogen or a lower alkyl group, in particular

the methyl group means to produce.

Of the compounds of the general formula IV. Are Representatives are known and others are analogous to the known compounds from the corresponding 4-substituted 3-thiosemicarbafcides by ^ heating with anhydrous formic acid or with Acetic anhydride or anhydrides of other lower ones. Alkanoic acids can be produced * By condensation of the compounds of the general Formula IV with 2-haloalkanoic acids of the general formula V,

R ₃ - CH - CO - OH _(v)

Shark

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in which

Hal means chlorine, .. bromine or iodine, and Ro is hydrogen when R of the formula IV is a methyl

group, and otherwise denotes the methyl group, with the help of sodium acetate in a lower alkanol, in particular Aethanoiy at its boiling point, substituted ones are obtained N '-Alkanoyl-2,4-thiazolidinedione-2-hydrazones of the general Formula VI

■ - ■ - ■ R ₀ - CH C = N - NH - CO - R _{0 Λ} , _τΛ

0 ■ »C - N - ^R x

in which

Ri, R ₂ and Ro have the meaning given under formula IV and formula V, respectively. Instead of 4-substituted 1-alkanoyl-3-thiosemicarbazides of the general formula IV, 1-alkanoyl-3-thiosemicarbazides can also be used and converted into the condensation products of the general formula VII obtained in this case

R "- -CH C = K-H-CO-L

^J II ^Z (VII)

0 = C

in which R ₂ and R ^ have the meaning given under formula IV or formula V, subsequently introduce the 3-substituent Rt by converting the compounds of the general formula VII into their alkali metal compounds and converting the latter with reactive esters of alcohols of the general formula VIII R ₁ - OH (VIII)

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in which

R _{1 has} the meaning given under formula IV, but only denotes a methyl group therein if IU in formula VII is hydrogen and otherwise denotes the allyl or 2-methylallyl group.

The alkali metal compounds are for example by Effect of sodium hydride, lithium or sodium amide in dimethylformamide at 0 ° to room temperature and obtained in the same Medium at room temperature or moderately elevated temperature with reactive esters of alcohols of the general formula VIII, e.g. with halides such as methyl iodide, allyl or 2-methyl allyl iodide or bromide, allyl or 2-methylallyl chloride, alkanesulfonic acid or arenesulfonic acid esters, such as the corresponding ones Methanesulfonic acid or p-toluenesulfonic acid esters, or furthermore also implemented with dimethyl sulfate. ·

The obtained by one or the other process variant Compounds of the general formula VI are used for cleavage the alkanoyl group in a lower alkanol in the presence heated by hydrogen chloride and optionally water, wherein one hydrazones of the general formula IX

0 = C ₁
in which

R and Ro have the meanings given under formula IV and V. receives. For example, you cook a starting material of the general Formula VI approx. One to 15 hours in a mixture of one

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anhydrous lower alkanol, especially ethanol, also methanol or propanol, and abs. ethereal hydrogen chloride solution, their hydrogen chloride content at least for salt formation, with the released hydrazone is sufficient tmter, reflux. Iin ':,.; The reaction medium mentioned crystallizes the desired hydrazone of the general formula IX gradually in the form of its hydrochloride and can after the reaction * cooling and optionally Adding an organic liquid that reduces the solubility of the hydrochloride in the reaction medium, such as by Per trol ether or other diethyl ether, are filtered off. Instead of of hydrogen chloride one can also use a corresponding, i.e. at least one compound of the general formula VIII used equivalent amount of conc. Use hydrochloric acid, bringing the reaction medium a corresponding water content is also given. In this case, the reaction is preferably carried out in a lower one Alkanol, e.g. ethanol, carried out at its boiling point. The resulting hydrochlorides of the hydrazones of the general formula IX are at least partially in this reaction medium dissolved and are isolated e.g. by evaporation in a vacuum. the Release of the. Hydrazones from the liydrochlbriden kanri in usual

Way, e.g. by dissolving in water, adding the calculated amount a base such as sodium carbonate or sodium hydroxide, and taking up of the hydrazone deposited as OeI in one with water. immiscible organic solvents or mixed solvents, e.g. in methylene chloride and / or petroleum ether. The hydrazones of the general formula IX are obtained finally through-reaction with an isothiocyanate of the general

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ORIGINAL INSPECTED

my formula X,

S = C = N - R ₄ (X)

in which

R, the methyl group, if R ~ of the formula IX also denotes a methyl group, or the allyl or the methallyl group, when R ^ is hydrogen, the thiosemicarbazones of the general formula II or Ha.

The implementation is preferably carried out in an opposite || Hydrazines inert organic solvents, e.g. in one

lower alkanol, such as methanol, ethanol, propanol or isopropanol, an ethereal solvent such as diethyl ether, dibutyl ether, tetrahydrofuran or dioxane, a hydrocarbon such as Benzene, toluene or hexane, or a halogenated hydrocarbon such as chloroform, at room temperature or moderately elevated temperatures up to approx. 100 ° or the boiling point of the solvent used. The reaction time depends on the reaction temperature and reactivity of the starting materials, between approx. half an hour and 24 hours.

The daily doses of azines of the general formula I suitable for the treatment of neoplasias are for mammals between 1 mg and 100 mg per kg of body weight and within this range for parenteral, especially intramuscular or subcutaneous application is generally lower than for oral application. The azines of general formula I are orally or rectally, preferably in unit dosage forms, such as tablets, coated tablets or capsules or suppositories, and parenterally as Injection solutions applied.

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Unit dose forms for oral use containing as active ingredients preferably between 107 _o and 90% of an azine of the general formula I. For the preparation of the active ingredient are mixed, for example, with solid, pulverulent carriers "such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants, magnesium or calcium stearate or polyethylene glycols, and presses the mixture into tablets or coated tablets. The latter are coated, for example, with concentrated sugar solutions, which may contain, for example, gum arabic, talc and / or titanium dioxide, or with a lacquer dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, for example to indicate different doses of active ingredient. .

Comes as unit dose forms for rectal use e.g. suppositories, which consist of a combination of an azine of general formula I exist with a neutral fat base, or also gelatin rectal capsules, which are a combination of the active ingredient or a suitable salt thereof with polyethylene glycols, into consideration.

Ampoules for parenteral, especially intramuscular, intravenous or subcutaneous administration contain a water-soluble, pharmaceutically acceptable salt of an azine of the general formula I suitable for salt formation in a concentration of preferably 0.5-10%, optionally together with suitable statifying agents and buffer substances, in aqueous solution.

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Further, ampoules come with aqueous * by means of suitable Lbsungsvermittler and / or emulsifiers dispersions prepared ⁵ ^ of any azines of the general formula I in question. r> B

Below is the production of tablets and dragees each explained by an example:

a) 250 g of active ingredient, e.g. 2,2'-azine of 3-methyl-2,4-thiazolidinedione and of 5-methyl-3- (2-methylallyl) -2,4-thiazolidinedione, are mixed with 175.80 g of lactose and 169.7Og of potato starch, the mixture is moistened with an alcoholic solution of 10 g of stearic acid and granulated through a sieve. Mix after drying one 160 g potato starch, 200 g talc, 2.50 g magnesium stearate and 32 g colloidal silicon dioxide and press the mixture 10,000 tablets each weighing 100 mg and containing 25 mg of active ingredient, if desired with partial notches for a finer adjustment of the Dosage can be provided.

b) From 250 g of active ingredient, e.g. 2,2'-azine des 3-methy1-2 / 4-thiazolidinedione and des S-allyl-S-methyl-Z 1-4 thiazolidinedione, 175.90 g Lactose and the alcoholic solution of 10 g of stearic acid are made into granules, which after drying with 56.60 g of colloidal Mixes silicon dioxide, 165 g talc, 20 g potato starch and 2.50 g magnesium stearate and presses them into lO'OOO coated tablets. These are then made with a concentrated syrup 502.28 g of crystall. Sucrose, 200 g talc, 6 g shellac, 10 g arabic Gum, 0.22 g dye and 1.5 g titanium dioxide Coated and dried. The coated tablets each weigh 140 mg and contain 25 mg of active ingredient each.

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The following example explains the inventive Preparation of the azines of the general formula I, but this should do not limit the scope of the invention. The temperatures are given in degrees Celsius.

example 1

a) 47.0g (0.1725 mol) 3- (2-methylallyl) -5-methyl-2,4-thia _r

zolidinedione-2- (4-methyl-3-thiosemicarbazone), 17.9 g (0.190 mol) Chloroacetic acid and 35.4 g (0.431 mol) of anhydrous sodium acetate are refluxed in 400 ml of n-propanol with stirring for 3 hours boiled, then the reaction mixture is mixed with 700 ml of water and allowed to cool to room temperature. That Precipitated 2,2'-azine of 3-methyl-2,4-thiazolidinedione and 3- (2-methylallyl) -5-methyl-2,4-thiazolidinedione is filtered off and washed with 300 ml of water. After a single recrystallization from methylene chloride-hexane, 40.5 g (78.17 * of theory) of pure azine with a melting point of 154 ° are obtained.

The following are produced in an analogous manner:

2,2'-Azine of 3-allyl-5-methyl-2,4-thiazolidinedione and 3-methyl-2,4-thiazolidinedione, m.p. 166-167 °, 8.6 g (55% of theory, ) starting from 13.5 g (0.052 mol) of 3-allyl-5-methyl-2,4-thiazolidinedione-2- (4-methyl-3-thiosemicarbazone), 5.4 g (0.057 mol) of chloroacetic acid and 10.7 g (0.131 moles) of anhydrous sodium acetate; 2.2 ^1- azine of 3-methyl-2,4-thiazolidinedione and 3- (2-methylallyl) -5-methyl-2,4-thiazolidinedione, melting point 154 °, 14.6 g (70% of theory). ), starting from 17.8 g (0.069 mol) of 3-methyl-2,4-thiazolidinedione-2- [4- (2-methylallyl) -3-thiosemicarbazone] 11.6 g (0.076 mol) of 2-bromo

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propionic acid and 13.9 g (0.17 mol) of anhydrous sodium acetate.

2,2'-Azine des S-Allyl-S-methyl ^^ - thiazolidinedione and des a-methyl-Z.A-thiazolidinedione, m.p. 166-167 °, 14.0 g (69% of theory), starting from 16.6 g (0.068 mol) of 3-methyl-2,4-thiazolidinedione-2- (4-allyl-3-thiosemicarbazone), 11.2 g (0.074 moles) of 2-bromopropionic acid and 13.9 g (0.17 moles) of anhydrous sodium acetate.

b) The thiosemicarbazones required as starting compounds are prepared as follows:

474.1 g (3.612 mol) 4-allyl-3-thiosemicarbazide, prepared according to G, Pulvermacher and H. Hempel, Ber. 27., 625 (1894) suspended in 3500 ml of chloroform and mixed with 442.5 g (4.334 mol) of acetic anhydride with stirring and cooling at 25-30 °. Afterward the reaction mixture is boiled for 2 hours with stirring and reflux. It is then cooled to 5 ° in an ice bath. The precipitated 1-acetyl ^ -allyl-S-thiosemicarbazide is suction filtered, washed with ether and 20 hours in a water jet vacuum dried at 70 °. The yield is 586.6 g (93.7% of theory) with a melting point of 131-132 °.

The following are produced in an analogous manner:

1-acetyl-4-methyl-3-thiosemicarbazide, m.p. 155-156 °, 119 g (81% of theory), starting from 105.2 g (1 mol) of 4-methyl-3-thiosemicarbazide and 112.3 g (1.1 moles) of acetic anhydride;

1-Acetyl-4- (2-methylallyl) -3-thiosemicarbazide, m.p. 146-148 °, 165 g (90% of theory), starting from 142.4 g (0.98 mol) 4- (2-methylallyl) 3-thiosemicarbazide and 122 g (1.17 moles) acetic anhydride.

009886 / ^ 2 2.4-5 ¹ ^ 0 0

c) 155.9 g (0.900 mol) of l-acetyl ^ -allyl-S-thiosemicarbazide, 158.4 g (1.035 mol) 2-bromopropionic acid and 184.6 g (2 * 26 mol) anhydrous sodium acetate are in 1090 ml abs, ethanol under Stir refluxed for 3 hours. Then you let cool to 20 ° and filtered off from the precipitated inorganic salts. The filtrate is concentrated in a water jet vacuum. the Any remaining smear is taken up in 500 ml of methylene chloride and mixed with 2N sodium hydroxide solution until the pH value is 8 «The mixture is shaken well, then the methylene chloride * solution separated and the aqueous phase three times with each 150 ml of methylene chloride extracted. The combined methylene chloride solutions are dried over 30 g of anhydrous magnesium sulfate. This is then filtered off and the filtrate in a water -, - jet vacuum evaporated. : 141.7 g (69.2% of theory) 3-. Are obtained; Allyl-5-methyl-2,4-thiazolidinedione-2- (2-acetylhydrazone) vom M.p. 108-110 °,

The following are produced in an analogous manner:

S-methyl ^^ - thiazolidinedione - ^ - (2-acetyl-hydrazone), stop. 202-204 °, 4.0 g (71.4% of theory) based on 4.4 g (0.030 Hol) 1-acetyl-4-methyl-3-thiosemicarbazide and 3.5 g (0.037 mol) chloroacetic acid;

5-methyl-3- (2-methylallyl) -2,4-thiazolidinedione-2- (2-acetylhydrazone), M.p. 104-107 °, 62.8 g (65.1% of theory), starting from 74 g ' (0.400 moles) 1-acetyl-4- (2-methylallyl) -3-thiosemicarbazide and 68 g (0.440 moles) 2-bromopropionic acid.

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d) 141 »7 g (0.623 mol) 3-allyl-5-methyl ~ 2,4-thiazolidinediori-2- (2-acetyl-hydrazone) are in 500 nil abs. Dissolved ethanol and while stirring at 35 ° with 285 ml of a 0.67-n. essential hydrochloric acid solution offset. The reaction mixture is then refluxed for 3 hours, and after one and a half hours a pretty good thick crystal pulp begins to precipitate. The mixture is then cooled to 5 ° using an ice bath and 500 ml of petroleum ether (Kp.40-60 °) allowed to run. The precipitated 3-allyl-5-methyl-2,4-thiazolidinedione-2 * hydrazine hydrochloride is suction filtered and washed with 200 ml of ether. The yield is 108 g (87.5% of theory) of melting point 167.5-169 °.

In an analogous way the following are obtained:

3-methyl-2,4-thiazolidinedione-2 * hydrazone hydrochloride, m.p. 260 °, 7.87 g (86.67% of theory), starting from 9V ^ g (OtOSOMoI) 3 ^ methyl-2,4-thiazolidinedione-2- (2-acetylhydrazone) r

5-methyl-3- (2-methylallyl) -2,4-thiazplidinedione-2-hydrazone hydrochloride, M.p. 160-161 °, 52.4 g (81.9% of theory), starting from 65.5 g (0.271 mol) of 5-methyl-3- (2-methylallyl) -2,4-thiazolidinedione-2- (2-acetyl-hydrazone).

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e) To release the base, 108 g (0.486 mol) of 3-allyl-5-mettiyl-2,4-thia2olidinedione-2-hydra2on * h: ydrochiorid dissolved in 300 ml of water and the solution with ice cooling and stirring Saturated potassium carbonate. The oil which separates out is dissolved in a mixture of 150 ml of methylene chloride and 150 ml of petroleum jelly (bp. 40-60 °), separated from the aqueous phase and extracted with a solution of 50 g of potassium carbonate in 150 ml of water. The organic phase is separated off and evaporated in a water jet vacuum. 88.4 g (97.5% of theory) of 3-allyl-5-methyl-2,4-thiazolidinedione-2-hydrazone are obtained as oil that crystallizes when standing, 47-48 °.

In an analogous way one obtains:

3-methyl-2,4-thiazolidinedione-2-hydrazone »m.p. 99-100 °, 4.6 g (73% of theory), starting from 7.87 g (0.043 mol) of 3-methyl-2,4-thiazolidinedione-2-hydrazone hydrochloride;

5-methyl-3- (2-n-ethylallyl) -2,4-thiazolidinedione-2-hydrazone, 43.3 g (97.5% of theory), starting from 52.4 g (0.222 mol) of 5-methyl-3 - (2-me thy 1 al Iy 1) - 2,4 <-thiazol idindione-2-hy drazon-hydrochloride.

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f) 88.4 g (0.477 mol) 3 * -allyl ~ 5-methyl-2,4-thiasolidinedione-

2-hydrazone and 38.4 g (0.524 mol) methyl isothioeyanate are in 1400 ml of methanol dissolved and refluxed for 2 hours. The methanoi is then evaporated in a water jet vacuum. The residue is divided twice from chloroform on hexane. 107.8 g of 3-AllyL-5Hroth ^ 2,4-thiazolidinedione * 2- (4- · methy1-3-thiosemicarbazone m.p. 79-82 °.

In an analogous manner the following are obtained:. ·

3-methyl-2 _f 4-thiazolidinedione-2- (4-allyl-3-thiosemic * arbazon) m.p. 166-167 °, 13.9 g (94.8 Zd.Th.), starting from 8.7 g (0.060 mol) 3-methyl-2,4-thiazolidinedione-2-hyteiäs © n and 6.5 g (0.066 mol) allyl isothiocyanate;

54ietbyl-3- (2-4i 'thylallyl) -2, A-thiazolidinedione-2- (4-siethyl-3-thiosemicarbazoia) ₉ Snip.ll5 s' -d (89 _(3% ^o ₉ ..52. "2 Th.) _F starting from 43.3 g (0.216 mol) 548 © £ & g $ .o3- (2
dindione-2-hydrazone and 17 »4 g (@ ₀ S3? tl @ l) Sfe?

3-Methyl-2 ^ -thia2olAdtadione-2- | 4-C2 »a @ fcfeyliiIIyl) -3- £ lhi © - semicarbazon), m.p. 134-135 °, 13.4 g (86.4% of theory) ο based on 8.7 g (0.060 mol) 34fethyl-2,4-thia2olidinedione-2 * hydca & on and 7.5 g (0.066 mol) (2-methyiallyl) isothiocyanate

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Claims (6)

: .. claims ,) New azines of the general formula T ₉ CHo-CH Q = NN = C GH, 0 » I-I ¹ I. "O CH ₃ in which ' R is an allyl or 2-methylallyl group. 2. The 2,2'-azine of 3-methyl-2,4-thiazolidinedione and of 3- (2-methylallyl) -5-methyl-2,4-thiazolidinedione. 3. The 2,2 'azine of 3-allyl-S-metlqrl-2 · 4-thiazolidinedione and des 3-methyl-2,4-thiazolidinedione. 4.Use of a compound of the general defined in claim 1 Formula I for the production of therapeutic preparations with tumor-inhibiting effectiveness, characterized by the content on a compound of the general formula I, in which R has the meaning given there, in combination with an inert one ■ Carrier and, if necessary, other additives. 12/6/70
HFO / mk 009886/2245