Pharmaceutically acceptable salts of substituted 6h-1,3,4 - thiadiazin-2-amines and their pharmaceutical compositions

 

(57) Abstract:

Describes the new substituted 6N-1,3,4-thiadiazin-2-amines of General formula I, where is morpholinyl, thiomorpholine, piperidinyl, pyrolidine or hexamethyleneimino fragment, or their pharmaceutically acceptable salts, their use as anaesthetics cardiovascular and hypometabolic means and containing pharmaceutical compositions. 3 S. and 3 C.p. f-crystals, 2 PL.

The invention relates to new derivatives 6N-1,3,4-thiadiazin-2-amines and their use as anaesthetics, cardiovascular and hypometabolic tools used in medicine and veterinary medicine, and containing pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Anesthesia can be in General described as a condition in which harmful effects, such as surgical procedures, are invisible to the body; this condition may be accompanied by loss of consciousness (General anesthesia), or occurs without loss of consciousness (local anesthesia). Full or General anesthetic, administered inhalation or intravenously, induces a state of deep sleep, and loss of motor activity (hypnosis), analgesia, Rel is CA. Anesthetics in General are hypometabolic activity and often act as respiratory or cardiovascular depressant. Some anesthetics can be used to intentionally create a hypotensive effect, which is very valuable for intracranial and other surgical operations. Despite the fact that a large number of chemicals with anaesthetic or cardiovascular activity, created and/or communicated to the pharmaceutical market, there is a continuing need for new tools with hypometabolic activity, which could cause sleep, reduced motor activity, to cause hypotension, a bradycardia, hypocoagulable, antiplatelet and other geometricheskie effects, such as reduced oxygen consumption and decreased body temperature, which would be valuable for use in complex surgery or in the treatment of life-threatening and/or traumatic conditions such as concussion, myocardial infarction, and who would possess high activity, long-lasting effect and excellent profiles of toxicity to the Central nervous system and cardiovascular system without side effects such as tremors, convulsions, narocin-2-amines (see reviews [1-3]). Also in the patent literature there is evidence miorelaksantnoe [4-7], sedative [8, 9], antispasmodic [1-12] and other kinds of biological activity [3]. A series of 5-aryl-substituted 1,3,4-thiadiazines specifically described in the inventions [14-20], as well as their 6-alkyl and 6-phenyl analogues [13 and 21]. The value of 6H-1,3,4-thiadiazin-2-amines as hypometabolic anesthetics and cardiovascular agents still has not been announced. Moreover, many of these substances are new and were not previously described in the literature.

Prior to the invention of the 6-R-1,3,4-thiadiazin-2-amines include:

1. H. Beyer, Z. Chem., 1969, Bd. 9, S. 361.

2. C. C.'tseva, G. P. Andronnikov is shown, V. S. Mokrushin, Chemistry of heterocycle. connect., 1991, No. 4, S. 435.

3. A. P. Novikov, N. M.Perov, O. N. Chupakhin, Chemistry of heterocycle. connect., 1991, N. 11, S. 1443.

4. W. D. Jones and F. P. Miller. US-A-4309426 (1982).

5. W. D. Jones and F. P. Miller. BE-A-884991 (1980).

6. W. D. Jones and F. P. Miller. DE-A-3042295 (1982).

7. FR-A-2493844 (1982).

8. US-A-4272532 (1981).

9. F. P. Miller and W. D. Jones. BE-A-884990 (1980).

10. W. D. Jones and F. P. Miller. DE-A-3031703 (1981).

11. Fisons PLC, Japan Kokai, Tokyo Koho JP-A-6253976.

12. W. D. Pfeiffer and E. Bulka, DD-A-220311 (1985).

13. N. Yoshida, K. Tanaka, and Y. Iizuka. Japan Kokai 7488889 (1974).

14. L. N. Racine is rnal, 26(3), 62-64 (1992).

16. N. M.Perov and other Chemistry of heterocycle. connect., N 4, 565-6 (1993).

17. E. Bulka and W. D. Pfeiffer, DD-A-288824.

18. W. D. Pfeiffer and E. Bulka, Synthesis, N 7, 485-6 (1977).

19. T. Werner et al, US-A-4,940,790 (1990).

20. A. P. Novikov, and other SU-A-1726478.

21. E. Bulka et al, DD-A-228248.

THE GENERAL FORMULA OF THE INVENTION

According to one aspect of the invention features the use of substituted 6H-1,3,4-thiadiazin-2-amine following General formula as an anaesthetic or cardiovascular drugs:

< / BR>
where is morpholinyl, thiomorpholine, piperidinyl, pyrolidine or hexamethyleneimino fragments; or pharmaceutically acceptable salts of these compounds.

In accordance with the following aspect of the invention offers new substituted 6H-1,3,4-thiadiazin-2-amines of the above formula.

According to another aspect of the invention features a pharmaceutical composition that includes one or more of the above-described derivatives of 6H-1,3,4-thiadiazin-2-amines or their pharmaceutically acceptable salts.

DESCRIPTION OF THE INVENTION

1,3,4-Thiadiazine suitable for use in this invention, substituted in position 5 thiadiazine ring ethoxalyl is soedineniya substituted in position 2 thiadiazine cycle balance cycloalkylation, mainly consisting of morpholino, thiomorpholine, piperidino, pyrolidine and hexamethyleneimino fragments.

The invention further concerns a method for obtaining the above-described 1,3,4-thiadiazine, according to which ester (mainly ethyl) -halo,--methoxymethylethoxy acid is subjected to interaction with thiosemicarbazide formula where has the values defined above.

1,3,4-Thiadiazine can be isolated and/or used in free form or transformed into additive salts with pharmaceutically acceptable mineral or organic acids. Suitable for the preparation of additive salts with acids are, for example, mineral acids such as Hydrobromic acid, hydrochloric, sulphuric or phosphoric acid; organic carboxylic acids such as acetic, lactic, maleic, fumaric, oxalic, tartaric, citric or gluconic acid; or with organic sulfonic acids, such as sulfonic acid, benzosulfimide, paratoluenesulfonyl, methansulfonate, triftoratsetata and cyclohexanesulfonic acid.

Substituted thiosemicarbazide used in napisannymi reference Houben-Weyl, Tom. E4, pages 506-515, and K. Jensen with al., Acta Chem. Scand. 22, 1-50 (1968). So, thiosemicarbazide can be obtained by the addition of the hydrazide to the isothioscyanates or by reaction of the appropriate N,N-disubstituted thiocarbamoylation with hydrazine, or the interaction of ethyldiethanolamine formula with hydrazine. In order to avoid complications associated with adverse reactions, obtaining thiosemicarbazides are mostly in aprotic solvents, such as, for example, chloroform, carbon tetrachloride, diethyl ether or dioxane.

Interaction-halo--methoxyaminomethyl with thiosemicarbazide is advisable to carry out using equimolar amounts of both reagents in a solvent or diluent which is inert with respect to these reagents. Suitable for this purpose are, in particular, lower alcohols such as methanol, ethanol, n-propanol, isopropanol, and various butanol, or ethyl acetate and mixtures of these solvents, but the advantage should be given to ethanol. The reaction is usually conducted at temperatures between 5oC and 30oC, preferably between 18oC and 20oC. depending on the reactivity of the reactants, the nature of the reaction medium and the temperature of the reaction time IU during slow cooling of the reaction mixture.

Depending on the solubility of the compounds can be administered either orally or by parenteral injection of dissolved forms. They can be used independently, for example in the form of microcapsules, in mixtures with one another or in combination with appropriate auxiliary AIDS and/or fillers.

The invention also relates to pharmaceutical compositions or preparations comprising an effective amount of at least one of the above thiadiazine connections, if required, in the form of one of the additive salts with acids and which contain at least one of these active substances in addition to pharmaceutically acceptable excipients, diluents and/or excipients. Suitable solid or liquid dosage forms include, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, elixirs, suspensions, emulsions, drops or injectable solutions and drugs with targeted delivery of the active substance in the production of commonly used excipients, such as fillers, disintegrators, binders, create the wrapper agents, razryhlitelya, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk albumin, gelatin, flour, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water and monatomic and polynuclear alcohols, such as glycerin.

The pharmaceutical preparations are preferably produced and used in the treatment in dosage forms, each of which contains as an active ingredient a certain dose of at least one thiadiazine connection and/or at least one corresponding additive salt with acid. In the case of injection solutions thiadiazin mainly used for treatment in doses of from 10 to about 600, preferably from about 20 to about 500, even more preferably from about 30 to about 400 mg/kg

Compounds suitable for use, represented by the following examples:

1. Ethyl-1-methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5 - yl)acetate, hydrobromide;

2. Ethyl-1-methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5 - yl)acetate, mesilate;

3. Ethyl-1-methoxyimino-1-(2-thiomorpholine-6H-1,3,4-thiadiazin-5 - yl)acetate, hydrobromide ;

4. Ethyl-1-methoxyimino-1-(2-Timor is t, the hydrobromide;

6. Ethyl-1-methoxyimino-1-(2-pyrrolidino-6H-1,3,4-thiadiazin-5 - yl)acetate, hydrobromide;

7. Ethyl-1-methoxyimino-1-(2-hexamethyleneimino-6H-1,3,4-thiadiazin - 5-yl)acetate, hydrobromide.

EXAMPLES

All connections obtained with yields of 60-80% of the condensation of ethyl-bromo-methoxykynuramine with the appropriate 4-substituted thiosemicarbazide flowing smoothly when heated in ethanol.

The structure of compounds proven spectral data (UV, IR,1H NMR); their purity confirmed by thin-layer chromatography and elemental analysis.

Example 1.

Ethyl-1-methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5 - yl)acetate, hydrobromide.

The cooled solution of 5 g (0.02 mole) ethyl-bromo-methoxykynuramine in 15 ml of absolute ethanol was added dropwise to a suspension of 3.2 g (0.02 mol) of morpholine thiocarbanilide acid in 30 ml of absolute ethanol at 5-7oC. the Mixture was stirred first at the above temperature for 2 hours and then at 18-20oC for 5 hours. The colorless precipitate was filtered and recrystallized twice from absolute ethanol. Yield 6.5 g (82%). So pl. 213 - 214oC. Rfor = 0.6 (eluent: butanol - acetic acid-SO-d6, , ppm: of 1.30 (3H, t, -CH3, COOC2H5); of 3.85 (8H, m, morpholino), 4,06 (2H, s, CH2S); 4,10 (3H, s, OCH3); 4,30 (2H, q, OCH2-, COOC2H5).

Example 2.

Ethyl-1-methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5 - yl)acetate, mesilate.

Methansulfonate, 0.7 g (to 0.007 mol) was added dropwise with stirring to a solution of 2 g (0,006 mol) of the compound 1 in dry benzene. A colorless precipitate obtained after 15-20 minutes stirring, was filtered and recrystallized from absolute ethanol. Yield 2.5 g (95%). So pl. 181-182oC. Rf= 0,45 (eluent: butanol - acetic acid - water 4:1:5). Found, %: C 38,2; H 5,5; N 13,6. C13H22N4O7S2. Calculated, %: C 38,1; H 5,4; N 13,7.1H NMR in DMSO-d6, , ppm: of 1.28 (3H, t, -CH3, COOC2H5); to 2.35 (3H, s, SCH3); 3,74 (8H, m, morpholino), 3,88 (2H, s, CH2S); as 4.02 (3H, s, OCH3); the 4.29 (2H, q, OCH2-, COOC2H5).

Example 3.

Ethyl-1-methoxyimino-1-(2-thiomorpholine-6H-1,3,4-thiadiazin-5 - yl)acetate, hydrobromide.

Compound 3 was obtained similarly to the synthesis of compound 1 by the reaction of ethyl-bromo-methoxykynuramine with thiomorpholine thiocarbanilide acid at 18-20oC for 6 hours. The yield was 73%. So pl. 202-203oC. Rf= 0,7 (e Calculated %: C 35,0; H 4,6; N 13,6. 1H NMR in DMSO-d6, , ppm: of 1.27 (3H, t, -CH3, COOC2H5); 2,84 (4H, m, N(CH2)2thiomorpholine); 4,06 (3H, s, OCH3); 4,10 (4H, m, S(CH2)2thiomorpholine); to 4.17 (2H, s, CH2S); 4,30 (2H, q, OCH2-, COOC2H5).

Example 4.

Ethyl-1-methoxyimino-1-(2-thiomorpholine-6H-1,3,4-thiadiazin-5-yl)acetate, mesilate.

Compound 4 was obtained analogously to the synthesis of compound 2 of 2-thiomorpholine-5-ethoxalyl-6H-1,3,4-thiadiazine and methansulfonate. Output 90%. So pl. 171-172oC. Rf= 0,59 (eluent: butanol - acetic acid - water 4:1:5). Found, %: C 36,4; H 5,4; N 13,2. C13H22N4O6S3. Calculated, %: C 36,6; H 5,2; N 13,1.1H NMR in DMSO-d6, , ppm: of 1.34 (3H, s, -CH3); of 2.33 (3H, s, SCH3); 2,9 [4H, m, N(CH2)2thiomorpholine]; 3,90 (3H, s, OCH3); 4,10 [4H, m, S(CH2)2thiomorpholine]; 4,18 (2H, s, CH2S); 4,32 (2H, q, OCH2-, COOC2H5).

Example 5.

Ethyl-1-methoxyimino-1-(2-piperidino-6H-1,3,4-thiadiazin-5 - yl)acetate, hydrobromide.

Compound 5 was obtained analogously to the synthesis of compound 1 by the interaction of ethyl-bromo-methoxykynuramine with 4,4-pentamethylenetetrazol. Yield 67%. So pl. 201-202oC. Rf= 0,35 (eluent: butanol - acetic acid is H NMR in DMSO-d6, , ppm: to 1.32 (3H, t, -CH3, COOC2H5); 1,72 (6H, t, piperidine); 3,88 (4H, m, piperidine); 4,08 (2H, s, CH2S); 4,10 (3H, s, OCH3); 4,32 (2H, q, OCH2-, COOC2H5).

Example 6.

Ethyl-1-methoxyimino-1-(2-pyrrolidino-6H-1,3,4-thiadiazin-5 - yl)acetate, hydrobromide.

Compound 6 was obtained analogously to the synthesis of compound 1 by the interaction of ethyl-bromo-methoxykynuramine with 4,4-tetraethylorthosilicate. Yield 59%. So pl. 208-209oC. Rf= 0,29 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 38,0; H 5,1; N 15,0. C12H19BrN4O3S. Calculated, %: C 38,0; H 5,0; N 14,8.1H NMR in DMSO-d6, , ppm: to 1.31 (3H, t, -CH3, COOC2H5); 1,90-2,03 (4H, m, pyrrolidine); 3,50-of 3.95 (4H, m, pyrrolidine); 4,06 (2H, s, CH2S); to 4.17 (3H, s, OCH3); 4,32 (2H, q, OCH2-, COOC2H2).

Example 7.

Ethyl-1-methoxyimino-1-(2-hexamethyleneimino-6H-1,3,4-thiadiazin - 5-yl)acetate, hydrobromide.

Compound 7 was obtained analogously to the synthesis of compound 1 by the reaction of ethyl-bromo-methoxykynuramine with 4,4-hexamethylenebiguanide. An output of 60%. So pl. 186-187oC. Rf= 0,3 (eluent: butanol - acetic acid - water 4: 1: 5). Found, %: C 41,8; H 5,2; N Is 13.5. C14H23BrN4O3S. Calculated 3,75-4,0 (4H, m, hexamethylenimine), of 4.05 (2H, s, CH2S); 4,18 (3H, s, OCH3); of 4.35 (2H, q, OCH2-, COOC2H5).

EXPERIMENTAL BIOLOGICAL PART

Hypometabolic activity of the compounds according to the invention was demonstrated as follows. In all cases the tests were performed on mice of BALB 3-4 months of age. In all experiments we used non-toxic doses of the substances under study, which ranged from 60 to 400 mg/kg In the case of water-soluble substances aqueous solutions of the test compounds were administered intraperitoneally (i.p.), while insoluble compounds were administered orally (p. O.).

To demonstrate the influence of the studied substances on body temperature and oxygen consumption in vivo experiments for each dose were used 5-6 mice.

Changes in rectal temperature (absolute values inoC) was measured by the medical elektrotermometria TREM-1 (table. 1). The rate of oxygen consumption was monitored by measuring the concentration of oxygen in a closed vessel using opto-acoustic gas analyzer MN 5130. Data on the consumption of oxygen is given in percentage relative to the initial concentration of oxygen is taken as 100% (temperature in the range of from 3 to 15oC depending on the structure of the substance, dose and method of administration. It is established that some of the tested substances cause a sharp drop in body temperature (7-8oC for 30 minutes), while others find only a modest effect (7-10oC for 3 hours), which illustrates the table. 1.

Compound 1 was dissolved in a mixture of twin-water 1:9 (the concentration of the saturated solution was 40 mg/ml) and injected intraperitoneally at the rate of 0.2 ml per 20 g mouse. Values LD16, LD50, LD84defined as 788,4; 830,5 and 881,5 mg/kg. Introducing the compound 1 caused a drop in body temperature, akineziyu, suppression of reflexes to external stimuli, depression mice.

Data on the consumption of oxygen for a period of 10-300 minutes with a 30-minute interval are presented in table. 2. It was found that compound 1 reduces the consumption of oxygen in 7-10 times during the first hour, 3-4 times over the next 2 hours and 2 times during the fourth hour relative to the initial values (table. 2).

Rectal temperature of the mice fell within 10 minutes after administration of the drug by about 3-4oC, and after 30 minutes 7-8oC for mice and about 5oC rats. Maxim the tour was 2oC. Full recovery oxygen consumption was not observed (table. 2).

Example 8.

Composition for the manufacture of tablets.

The hydrobromide ethyl-1-methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5 - yl)acetate 200 mg

Wheat starch 30 mg

Lactose - 67 mg

Magnesium stearate 3 mg

Part of the wheat starch used to prepare the granular starch paste, which together with the remainder of the wheat starch granularit, sieved and mixed with the active ingredient and magnesium stearate. The mixture is pressed into tablets weighing 300 mg each.

Similarly produce tablets, the active ingredient which are the following compounds according to the invention:

mutilateral-1 methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5 - yl)acetate,

the hydrobromide ethyl-1-methoxyimino-1-(2-thiomorpholine-6H-1,3,4 - thiadiazin-5-yl)acetate,

mesilate ethyl-1-methoxyimino-1-(2-thiomorpholine-6H-1,3,4-thiadiazin - 5-yl)acetate,

the hydrobromide ethyl-1-methoxyimino-1-(2-piperidine-6H-1,3,4 - thiadiazin-5-yl)acetate,

the hydrobromide ethyl-1-methoxyimino-1-(2-pyrrolidino-6H-1,3,4 - thiadiazin-5-yl)acetate, and

hydrobromide-1 methoxyimino-1-(2-hexamethyleneimino-6H-1,3,4 - thiadiazin-5-yl)aceta is R> where is morpholinyl, thiomorpholine, piperidinyl, pyrolidine or hexamethyleneimino fragment.

2. Pharmaceutically acceptable salts of substituted 6H-1,3,4-thiadiazin-2-amines under item 1, selected from the following range:

ethyl-1-methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-thiomorpholine-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-piperidino-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-pyrrolidino-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-hexamethyleneimino-6H-1,3,4-thiadiazin-5-yl)acetate.

3. Pharmaceutically acceptable salts of substituted 6H-1,3,4-thiadiazin-2-amines, the formula of which is given in paragraph 1, with hypometabolic and cardiovascular activity.

4. Pharmaceutically acceptable salts of substituted 6H-1,3,4-thiadiazin-2-amines under item 3, selected from the following range:

ethyl-1-methoxyimino-1-(2-morpholino-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-thiomorpholine-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-piperidino-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-pyrrolidino-6H-1,3,4-thiadiazin-5-yl)acetate,

ethyl-1-methoxyimino-1-(2-hexamethyleneimino-6H-1,3,4-tiedostoa activity comprising an effective amount of an active agent and a pharmaceutically acceptable excipient, diluent and/or other excipients, characterized in that it as the active agent contains one of the compounds of General formula I on p. 1.

6. The pharmaceutical composition according to p. 5, characterized in that it as the active agent contains one of the compounds listed in paragraph 4.

 

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1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

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