Substituted 6-r-1,3,4-thiadiazin-2-amines and their pharmaceutical composition

 

(57) Abstract:

Describes the new substituted 6-R-1,3,4-thiadiazin-2-amines of the following General formula I, where AG represents phenyl or phenyl substituted by one or more chlorine atoms, bromine, C1-C4alkoxy or C1-C4alkyl group; each of R1and R2represents, independently, a hydrogen atom or a C1-C4the alkyl residue; R3and R4independently selected from C1-C4alkyl group; and their pharmaceutically acceptable salts, their use as anaesthetics, cardiovascular and hypometabolic means and containing pharmaceutical compositions. 3 c. and 3 C.p. f-crystals, 2 PL.

The technical field

The invention relates to new derivatives of 6-R-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 guide or General anesthetic, input inhalation or intravenously, induces a state of deep sleep, and loss of motor activity (hypnosis), analgesia, muscle relaxation and provides protection against increases in blood pressure and heart rate from surgical stress. 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 induce sleep, reduce 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, by TAVIA and excellent profiles of toxicity to the Central nervous system and cardiovascular system without side effects, such as tremors, convulsions, respiratory failure and heart palpitations.

There is a significant amount of data regarding 6-R-1,3,4-thiadiazin-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]. Value 6-R-1,3,4-thiadiazin-2-amines as hypometabolic anesthetics and cardiovascular agents so far has not been recognized. 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. N. 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, N. 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-2493 844 (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. Yoshida, K. Tanaka, and Y. Iizuka. Japan Kokai 7488889 (1974).

14. L. N. Racine, O. N. Chupakhin, M. C. Sibiryak, Radiobiology, 30 (2), 162-5 (1990).

15. A. C. Belik and other Chemical and pharmaceutical journal, 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. So Werner et al, US-A-4940790 (1990).

20. A. P. Novikov, and other SU-A-172 6478.

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

Summary of the invention

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

< / BR>
where Ar is phenyl or phenyl substituted by one or more chlorine atoms, bromine, C1-C4alkoxy or C1-C4alkyl group; each of R1and R2represents, independently, a hydrogen atom or a C1-C4the alkyl residue; and R3and R4independently selected from C1-C4alkyl group; and their pharmaceutically acceptable salts.

According to further aspect of the invention offers new substituted 6-To-1,3,4-thiadiazin-2-amines of the above about the as the active agent one or more of the above substituted derivatives of 6-R-1,3,4-Taliesin-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 is unsubstituted phenyl or phenyl substituted by one or more straight or branched C1-C4alkyl, alkenylamine, alkoxy or acyloxy groups, one or more hydroxy groups or halogen atoms. In the preferred compounds of this formula, Ar represents either unsubstituted phenyl or phenyl substituted by one or more alkyl or CNS groups, chlorine atoms or bromine substitution is preferred in positions 3 or 4 aryl fragment. In addition, the compounds contain in position 2 thiadiazine cycle the remainder of the 4-amino-1-phenyl-2,3-dialkylphenol-5-or 4-(N-alkylamino)-1-phenyl-2,3-dialkyl-pyrazole-5-it, in which the phenyl part is unsubstituted phenyl or phenyl substituted C1-C4alkyl, alkenylphenol, alkoxy or acyloxy groups, one or more hydroxy groups or halogen atoms. In addition, compounds may be substituted in position 6 thiadiazine ring (R1and/or the amino group in position 2 thiadiazine ring (R2one of R1-R1)X thiosemicarbazide formula NH2-NH-CS-NR2Y, where Ar, R1and R2defined above, X is halogen, preferably, chlorine atom or bromine, and Y is 1-phenyl-2,3-dialkylphenol-5-one-4-yl, in which alkyl or dulcelina group, preferably, are straight or branched alkyl, C1-C4circuits, and in which the phenyl residue is unsubstituted phenyl or phenyl substituted C1-C4alkyl, alkenylphenol, CNS, or Allexinno groups, or one or more halogen atoms or hydroxy groups.

1,3,4-Thiadiazine can be selected 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

organic sulfonic acids, such as sulfonic acid, benzosulfimide, pair-toluensulfonyl killkenny, used as starting substances "when receiving the above-described thiadiazine known from the literature or can be obtained from arylalkenes by reaction with a suitable halogenation agents according to the method described in reference Houben-Weyl, vol. E4 (1960), pp. 171-189. Suitable compounds are, for example, bromoaniline and-bromoaniline, in which aryl can be phenyl or substituted phenyl received by halogenoalkanes appropriately substituted 1-arylalkenes elementary bromine or copper bromide (II) by the method of king and Ostrom, J. Org. Chem. 29, 3459-3461 (1964).

Substituted thiosemicarbazide, which are used as starting materials, in most cases known from the literature or can be obtained by the methods described in the Handbook Houben-Weyl, vol. 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 of Vidor or dioxane.

Reaction-haloarylation 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 carried out at temperatures between 20oC and the boiling point of this reaction medium, but often between 20oC and 70oC. depending on the reactivity of the reactants, the nature of the reaction medium and temperature, the reaction time can be from 5 minutes to 2 hours. The final products are usually crystallize in analytically pure form on slow cooling of the reaction mixture.

Depending on the solubility of the compounds can be administered either orally or via 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 farm above thiadiazine compounds, 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, disintegrating agents, lubricants additives, flavors, sweeteners or soljubilizatory. Suitable excipients are, 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 for treatment in the th 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. 2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4-thiadiazin;

2. 2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-bromophenyl)-6N-1,3,4-thiadiazin;

3. 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4-thiadiazin;

4. 2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-6-ethyl-1,3,4-thiadiazin;

5. 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-6-ethyl-1,3,4-thiadiazin;

6. 2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin;

7. 2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin;

8. 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(3-bromophenyl) -6N-1,3,4-thiadiazin;

9. 2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(3-bromophenyl)-6N-1,3,4-thiadiazin.

Examples

All soedineniyami, 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.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5 - phenyl-6N-1,3,4-thiadiazin.

Compound 1 was obtained by heating 2 g (0.01 mol) of bromoacetophenone with 2.9 g (0.01 mol) of 4-methyl-4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-thiosemicarbazide in ethanol for 20 minutes. The reaction mixture was cooled and podslushivaet diluted ammonia solution to pH 8-9. The colorless precipitate was filtered, recrystallized from 30% water-ethanol mixture and dried. Yield 2.7 g (70%). So pl. 154-156oC. Rf= 0.6 (eluent: ethanol / chloroform 1: 8). Found, %: C, 64.4; H, 5.4; N, 17.7. C21H21N5OS. Calculated, %: C, 64.4; H, 5.4; N, 17.9.1H NMR in DMSO-d6, ppm: 2.2 (3H, s, CH3); 3.2 (3H, br. s, NCH3); 3.35 (3H, br. s, NCH3); 3.7 (2H, s, CH2S); 7.4-7.9 (10H, m, two C6H5).

Example 2.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5- (4-bromophenyl)-6N-1,3,4-thiadiazin.

Compound 2 was obtained similarly to the synthesis of compound 1-bromo-4-bromoacetophenone and 4-methyl-4-(1-phenyl-2,3-dimethylpyrazol-5-on-4 and 14.6. C21H20BrN5OS. Calculated, %: C, 53.6; H, 4.3; N, 14.9.1H NMR in DMSO-d6, , ppm: 2.2 (3H, s, CH2); 3.2 (3H, br. s, NCH3); 3.35 (3H, br. s, NCH3); 3.65 (2H, s, CH2S); 7.4-8.0 (9H, m, C6H5and C6H4).

Example 3.

2-N-(1-Phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4 - thiadiazin.

Compound 3 was obtained similarly to the synthesis of compound 1 of bromoacetophenone and 4-(1-phenyl-2,3 - dimethylpyrazol-5-one-4-yl)-thiosemicarbazide. Yield 88%. So pl. 112-114oC. Rf= 0.58 (eluent: ethanol / chloroform 1:8). Found, %: C, 63.5; H, 5.2; N, 18.4. C20H19N5OS. Calculated, %: C, 63.6; H, 5.1; N, 18.5.1H NMR in DMSO-d6, , ppm: 2.2 (3H, s, CH3); 3.1 (3H, s, NCH3); 3.9 (2H, s, CH2S); 7.3-8.0 (10H, m, two C6H5).

Example 4.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)- amino-5-phenyl-6N-6-ethyl-1,3,4-thiadiazin.

Compound 4 was obtained by heating 0.5 g (0.002 mol) of bromothiophene with 0.5 g (0.002 mol) of 4-methyl-4-(1-phenyl-2,3-dimethylpyrazol-5-one-4 - yl)-thiosemicarbazide in 10 ml of ethanol for 20 minutes. The reaction mixture was cooled, podslushivaet 7% ammonia solution to pH 9 and was kept for 30 minutes. The yellowish precipitate was filtered, recrystallized from a mixture of water and isopropanol 30:70 andH25N5OS. Calculated, %: C, 64.5; H, 6.2; N, 16.3.1H NMR in DMSO-d6, d, ppm: 0.9 (3H, t, -CH3); 2.2 (3H, s, CH3); 3.05 (2H, q, -CH2-); 3.18 (3H, br. s, NCH3); 3.30 (3H, br. s, NCH3); 4.25 (1H, m, =CH); 7.2-8.1 (10H, m, two C6H5).

Example 5.

2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-6-Ethyl - 1,3,4-thiadiazin.

Compound 5 is obtained analogously to the synthesis of compound 4 from bromothiophene and 4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-thiosemicarbazide. Yield 74%. So pl. 79-80oC. Rf= 0.32 (eluent: ethanol / chloroform 1:10). Found, %: C, 63.3; H, 5.7; N, 17.6. C22H23N5OS. 0.5 H2O. Calculated, %: C, 63.8; H, 5.8; N, 17.8.1H NMR in DMSO-d6, d, ppm: 1.05 (3H, t, -CH3); 1.70 (2H, m, CH2); 2.20 (3H, s, CH3); 3.10 (3H, br. s, NCH3); 4.35 (1H, m, =CH); 7.0-8.1 (10H, m, two C6H5).

Example 6.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)- amino-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin.

Compound 6 was obtained by heating 2.4 g (0.01 mol) of 4-ethoxy--bromoacetophenone with 2.8 g (0.01 mol) of 4-methyl-4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-thiosemicarbazide in 100 ml of absolute ethanol for 20 minutes. The reaction mixture was cooled, podslushivaet 7% ammonia solution to pH 8-9. The yellowish precipitate was filtered, paracrystal roform 1: 10). Found, %: C, 63.3; H, 5.9; N, 15.8. C23H25N5O2S. Calculated, %: C, 63.4; H, 5.8; N, 16.1. 1H NMR in DMSO-d6, d, ppm: 1.34 (3H, t, -CH3); 2.2 (3H, s, CH3); 3.14 (3H, s, NCH3); 3.30 (3H, br. s, NCH3); 3.60 (2H, br. s, CH2S); 4.13 (2H, q, OCH2-); 7.45 (5H, m, C6H5).

Example 7.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino - 5-(4-chlorophenyl)-6N-1,3,4-thiadiazin.

Compound 7 was obtained analogously to the synthesis of compound 6 from 4-chloro-bromoacetophenone and 4-methyl-4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)thiosemicarbazide. Yield 77%. So pl. 178-179oC. Rf= 0.3 (eluent: ethanol / chloroform 1:10). Found, %: C, 57.7; H, 4.7; N, 15.8. C21H20ClN5OS5H2O. Calculated, %; C, 58.0; H, 4.8; N, 16.2.1H NMR in DMSO-d6, , ppm: 2.20 (3H, s, CH3); 3.15 (3H, br. s, NCH3); 3.30 (3H, br. s, NCH3); 3.65 (2H, s, CH2S); 7.3-8.0 (9H, m, C6H5and C6H4).

Example 8.

2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(3 - bromophenyl)-6N-1,3,4-thiadiazin.

Compound 8 was obtained analogously to the synthesis of compound 6 from 3-bromo-bromoacetophenone and 4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)thiosemicarbazide. Yield 76%. So pl. 69-70oC. Rf= 0.38 (eluent: ethanol / chloroform 1:10). Found, %: C, 50.6; H, 4.2; N, 14.6. C20H18BrN5OSH2<2S); 7.1-8.0 (9H, m, C6H5and C6H4).

Example 9.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino - 5-(3-bromophenyl)-6N-1,3,4-thiadiazin.

Compound 9 was obtained analogously to the synthesis of compound 6 from 3-bromo - bromoacetophenone and 4-N-methyl-(1-phenyl-2,3-dimethylpyrazol-5 - one-4-yl)thiosemicarbazide. Yield 82%. So pl. 88-90oC. Rf= 0.48 (eluent: ethanol / chloroform 1: 10). Found, %: C, 49.4; H, 4.4; N, 14.7. C21H20BrN5OS 2H2O. Calculated, %: C, 49.8; H, 4.7; N, 14.9. 1H NMR in DMSO-d6, , ppm: 2.20 (3H, s, CH3); 3.15 (3H, br. s, NCH3); 3.25 (3H, br. s, NCH3); 3.55 (2H, s, CH2S); 7.0-8.2 (N, m, C6H5and C6H4).

Eksperimentalnaya biological part

Hypometabolic activity used here compounds 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 effect which was isovalues 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% (Table. 2).

Found that when used in non-toxic doses of all compounds reduced rectal 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 administered orally at a dose of 0.16 mg/kg (1/2 LD16), and then measured rectal temperature. After 1 hour, the temperature was about 5oC lower than the original. Over the next 4 hours it decreased further, reaching 26.4oC (the total drop is 12.5oC), whereas after 24 hours temperature before recovering is the learn of smaller doses (1/4 LD16or 1/8 LD16) observed a smaller temperature drop.

When the dose of 1/2 LD16compound 1 also caused a significant drop in oxygen consumption: 76% of the initial level after 5 minutes with a maximum drop to the level of 58% in 60-90 minutes (Table. 2). The period of maximum temperature drop is accompanied by a pronounced akinesia and suppression of reflex functions, but no tremor or convulsions were observed.

Example 10.

Composition for manufacturing tablets

2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)amino-5-phenyl - 6N-1,3,4-thiadiazin 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:

2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)amino-5-(4-bromophenyl) -6N-1,3,4-thiadiazin;

2-N-(1-phenyl-2,3-dimethylpyrazole;

2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)amino-5-phenyl-6N-6-ethyl-1,3,4 - thiadiazin;

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)amino-5-(4-ethoxyphenyl) -6N-1,3,4-thiadiazin;

2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)amino-5-(4-chlorophenyl)- 6N-1,3,4-thiadiazin;

2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)amino-5-(3-bromophenyl)- 6H-1,3,4-thiadiazin and

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)amino-5-(3-bromophenyl)- 6N-1,3,4-thiadiazin.

1. Substituted 6-R-1,3,4-thiadiazin-2-amines of General formula

< / BR>
where Ar is phenyl or phenyl substituted by one or more chlorine atoms, bromine, C1- C4alkoxy or C1- C4alkyl groups;

each of R1and R2represents, independently, a hydrogen atom or a C1- C4the alkyl residue;

R3and R4independently selected from the range of C1- C4alkyl groups;

and their pharmaceutically acceptable salts.

2. Substituted 6-R-1,3,4-thiadiazin-2-amines under item 1, selected from the following range: 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-bromophenyl)-6N-1,3,4-thiadiazin; 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4-thiadiazin; 2-N-methyl-N-the-5-phenyl-6N-6-ethyl-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin; 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(3-bromophenyl)-6N-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(3-bromophenyl)-6N-1,3,4-thiadiazin, and their pharmaceutically acceptable salts.

3. Substituted 6-R-1,3,4-thiadiazin-2-amines, the formula of which is given in paragraph 1, and their pharmaceutically acceptable salts with hypometabolic and cardiovascular activity.

4. Substituted 6-R-1,3,4-thiadiazin-2-amines under item 3, selected from the following range: 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-bromophenyl)-6N-1,3,4-thiadiazin; 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-6-ethyl-1,3,4-thiadiazin; 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-6-ethyl-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin; 2-N-methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin; 2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(3-bromphen efticiency acceptable salt.

5. Pharmaceutical composition having hypometabolic and cardiovascular 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 or its pharmaceutically acceptable salt.

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, or its pharmaceutically acceptable salt.

 

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The invention relates to new heterocyclic substituted phenoxyacetamide, methods for their preparation and use as a means protivodiareynogo

The invention relates to ether compounds and their use

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.

EFFECT: improved and valuable properties of agent.

8 cl, 1 tbl, 5 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: medicine.

SUBSTANCE: claimed composition contains (i) aliskiren; (ii) amplodipin; and (iii) hydrochlorotiazid. Invention is useful in treatment of condition or disease such as hypertension, heart failure, angina pectoris, Alzheimer's disease, stroke, etc.

EFFECT: composition of prolonged therapeutic effect and synergetic action.

7 cl

FIELD: medicine; cardiology.

SUBSTANCE: individual low-calorie diet is combined with introduced diuretics amylorhid 5 mg once in the morning and hydrochlorothiazide 50 mg once in the morning and methphormine 500 mg 2 times a day.

EFFECT: effective and rapid correction of thrombocyte haemostasis disturbance associated with metabolic syndrome.

1 ex

FIELD: medicine.

SUBSTANCE: treatment includes individual hypocalorific diet, sensibly graduated static and dynamic physical activities. Also 500 mg of metformin 2 times per day, 80 mg of valsartan once per day, and 25 mg of hydrochlorthiazide in the mornings are prescribed. The treatment course takes 6 months.

EFFECT: possibility to avoid complications in hemostatic system.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns normalisation of functional activity of thrombocytes at sick of an arterial hypertonia at a metabolic syndrome (MS). For this purpose within 24 weeks carry out the complex treatment including individually picked up hypohigh-calorie diet, and also administration of atenolol in a dose of 50 mg in the morning, Hydrochlorthiazidum in a dose of 25 mg in the morning and acetate tocopherol in capsules on 0.2 g on 1 capsule 2 times a day.

EFFECT: expansion of an arsenal of methods of effective correction platelet hemostasis at sick of a metabolic syndrome; reduction thrombotic complications at the expense of an optimum combination of not medicamental therapy and specific medicinal preparations.

1 ex

FIELD: medicine.

SUBSTANCE: during 2 months the complex treatment is carried out including high calorie diet selected individually, as well as injection of 6.21 mg of Spirapril 1 time in the morning, 5 mg of Amlodipin 1 time in the morning, 12.5 mg of Hydrochlorthiazidum 1 time in the morning, 500 mg of Metforminum 2 times a day, 1 mg of Rilmenidin in the morning and 2.5 mg of Indapamid in the morning.

EFFECT: extension of effective thrombocyte hemostasis correction for patient which have metabolic syndrome, decrease in the number of thrombotic complications due to optimum combination of non medicamental therapy and particular medical products.

1 ex

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