Substituted 5r1,6r2 -1,3,4-thiadiazine-2-amines and pharmaceutical compositions comprising thereof as pharmacologically active agents eliciting anticoagulant and anti-aggregating effect

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

 

1. The technical field to which the invention relates.

This invention relates to the field of biologically active compounds. The object of the invention are substituted 5R1, 6R2-1,3,4-thiadiazin-2-amines (formula I) and containing pharmaceutical compositions which can be used in medicine as a potential pharmacologically active substances with both anticoagulant and antiplatelet effect, and allows you to treat diseases such as myocardial infarction, cerebrovascular disease, rejection of transplanted organs and tissues and can prevent the formation of thrombosis and embolism.

2. The level of technology

Medicinal regulation of hemostasis in medical practice is carried out by direct or indirect exposure to a known antithrombotic agents (antiaggregants and anticoagulants) [the State Register of drugs, 2000, vol II, 749 S. Moscow, ed. OOO "Cultural initiative"; Great Russian encyclopedia of drugs, T.I and II, M: Remedium, 2001, 354 S.].

So, anticoagulants of direct action, such as mucopolysaccharides (heparin and heparinoid), and hirudin, very quickly "on the end of the needle" effect (in vitro and in vivo), lasting no more than 5 hours. All this is due to the inhibition of a number of plasma fact the moat of blood coagulation through the formation of a complex with antithrombin III (heparin) or without (hirudin).

Anticoagulants of indirect action, such as ethyl ether di-(4-oxycodeine-3) acetic acid (neodikumarin), effective only in vivo and after the incubation period (6-12 hours). During this period in the plasma and in the liver are depleted of clotting factors (II, VII, IX, X), the synthesis of which they stop (table 1).

The duration of action of such drugs depends on the pharmacokinetics and varies within 48-72 hours.

The inhibition of platelet aggregation achieved acetylsalicylic acid; 2,6-bis-[bis-(β-oxyethyl)-amino]-4,8-di-N-piperidino-pyrimido-(5,4-(1)-pyrimidine (dipyridamole); 3,7-dimethyl-1-(5-oxohexyl)-Centinela (pentoxifylline) and other Such drugs, strictly speaking, are not combined, because the suppression of aggregation does not reduce within the specified limits of integration clotting. However, these drugs still affect the adhesion of blood platelets by reducing the level of thromboxane A2through a number of mechanisms (calcium, metabolic, anticatalytically).

Known anticoagulants - compounds of rare earth elements (La, Pr, Nd, Sm, Yb). Their effect is manifested both in vitro and in vivo. However, in medical practice, they are not found because of the high toxicity and ability to cumulation.

Thus, the disadvantage of all used medical PRA is tick antithrombotic means, they do not have the ability to inhibit platelet aggregation in combination with anticoagulant activity (table 1) and therefore can not fully meet modern requirements medicine to such drugs.

3. The invention

The objective of the invention is solved by the fact that offered substituted 5R1, 6R2-1,3,4-thiadiazin-2-amines that possess a unique combination of properties: pronounced anticoagulant activity in combination with the ability to inhibit platelet aggregation.

According to one aspect of the invention features the use of substituted 5R1, 6R2-1,3,4-thiadiazin-2-amines of General formula I as pharmacologically active substances with concomitant anticoagulant and antiplatelet action.

where R1represents phenyl which may be substituted by one or more chlorine atoms, bromine, C1-C4-alkoxy, C1-C4alkylene groups, or R1represents the residue of ethyl acetate-1-methoxyimino-;

R2represents a hydrogen atom or a C1-C4alkyl group;

R3is N-morpholinyl, N-thiomorpholine, N-piperidinyl, N-pyrrolidinyl, N-hexamethyleneimino, N-methylamino-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl), N-amino-(1-phenyl-2,3-dimethylpyrazol-5-it-4-is l) and their pharmaceutically acceptable salts as pharmacologically active substances, with anticoagulant and antiplatelet action.

According to another paragraph of the invention offers a substituted 5R1, 6R2-1,3,4-thiadiazin-2-amines of General formula

where R1represents the residue of ethyl acetate-1-methoxyimino-,

R2represents a hydrogen atom,

R3is N-morpholinyl, N-thiomorpholine, N-piperidinyl, N-pyrrolidinyl, N-hexamethylenimine.

According to another claim offers a pharmaceutically acceptable salt of substituted 5R1, 6R2-1,3,4-thiadiazin-2-amines of General formula I, where R1represents the residue of ethyl acetate-1-methoxyimino-; R2represents a hydrogen atom; R3is N-morpholinyl, N-thiomorpholine, N-piperidinyl, N-pyrrolidinyl, N-hexamethylenimine.

According to another paragraph of the invention features a pharmaceutical composition comprising an effective amount of the inventive compounds or its pharmaceutically acceptable salt as an active agent and a pharmaceutically acceptable excipient, diluent and/or other auxiliary substances.

4. Information confirming the possibility of carrying out the invention. Examples of synthesis of compounds.

5R1, 6R2-1,3,4-Thiadiazin-2-amines, proposed for use in this invention, the can is to be allocated 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 of 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, a pair of toluensulfonate, methanesulfonate, triftoratsetata and cyclohexanesulfonic acid.

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 pharmaceutical compositions or preparations, which include at least one of the above-mentioned 5R1, 6R2-1,3,4-thiadiazin-2-amines, 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 pharmaceutical forms including the Ute, for example, granules, powders, coated tablets, tablets, microcapsules, 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 dosage forms, each of which contains as an active ingredient a certain dose of at least one of the 5R1, 6R2-1,3,4-thiadiazin-2-amine and/or at least one corresponding additive salt with acid.

In the case of injection solutions of these substances are mainly used for treatment in doses from 2 to 80 mg/kg, preferably from 20 to 80 mg/kg Connection, it is acceptable to use the tion, presents the following examples:

1. 2 Thiomorpholine-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin, hydrobromide.

2. 2 Thiomorpholine-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide.

3. 2 Morpholino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin, hydrobromide.

4. 2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide.

5. 2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin.

6. 2 Morpholino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, basis.

7. 2 Morpholino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, mesilate.

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

All connections obtained with yields of 60-80% by condensation α-haloarylation or ethyl - γ-bromo-α-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 chromatography and elemental analysis.

Example 1.

2 Thiomorpholine-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin, hydrobromide (1).

Compound 1 obtained by heating 0.7 g (0.003 mol) of 4-ethoxy-α-bromoacetophenone with 0.5 g (0.003 mol) thiomorpholine thiocarbanilide acid in 15 ml of absolute ethanol in the presence of 0.3 ml of concentrated NVG for 20 minutes. The mixture was cooled with ice to obtain a yellow precipitate, which was filtered, peracre wallisville of absolute ethanol. Yield 0.8 g (70%). TPL 169-170°C. Rf=0.33 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 45.0; N, 5.2; N, 10.3. C15H20BrN3OS2. Calculated, %: 44.8; N, 5.0; N, 10.4.1H NMR in DMSO-d6that δ, ppm: 1.32 (3H, t, CH3); 2.88 [4H, m, N(CH2)2thiomorpholine];4.12 [4H,m, S(CH2)2thiomorpholine]; 4.26 (2H, q, OCH2-); 4.37 (2H, s, CH2S); and 7.5 (4H, dd,6H4).

Example 2.

2 Thiomorpholine-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide (2).

Compound 2 obtained by heating 2 g (0.01 mol) α-bromoacetophenone with 1.8 g (0.01 mol) thiomorpholine thiocarbanilide acid in 25 ml of absolute ethanol in the presence of 1.2 ml of concentrated NVG for 20 minutes. The mixture was cooled with ice to obtain a yellow precipitate, which was filtered, recrystallized from absolute ethanol and dried. The yield 2.8 g (78%). TPL 183-184°C. Rf=0.51 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 43.7; H 4.6; N, 11.7. C13H16BrN3S2. Calculated, %: 43.6; N, 4.5; N, 11.7.1H NMR in DMSO-d6that δ, ppm: 2.9 (4H, m, N(CH2)2thiomorpholine); 4.15 (4H, m, S(CH2)2thiomorpholine); 4.42 (2H, s, CH2S); 7.4-8.1 (5H,m6H5).

Example 3.

2 Morpholino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin, hydrobromide (3).

Compound 3 is obtained analogously to the synthesis of compound 2. Yield 67%. TPL 242-243°C. Rf=0.37 (eluent: butanol-Sosna acid-water 4:1:5). Found, %: 41.7; N, 4.1; N, 11.4. C13H15BrClN3OS. Calculated, %: 41.7; N, 4.0; N, 11.2.1H NMR in DMSO-d6that δ, ppm: 3.85 (8H, m, morpholino); 4.40 (2H, s, CH2S); 7.70 and 7.90 (4H, dd,6H4).

Example 4.

2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide (4).

Compound 4 obtained by heating 2 g (0.01 mol) α-bromoacetophenone with 1.6 g (0.01 mol) of morpholine thiocarbanilide acid in 20 ml of absolute ethanol for 30 minutes. The product obtained after cooling is filtered off and recrystallized twice with activated carbon. Yield 1.8 g (75%). TPL 191-192°C. Rf=0.35 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 45.7; H 4.7; N, 12.1. C13H16BrN3OS. Calculated, %: 45.6; H 4.7; N, 12.3.1H NMR in DMSO-d6that δ, ppm: 3.85 (8H, m, morpholino), 4.45 (2H, s, CH2S); 7.45-8.1 (5H, m, C6H5).

Example 5.

2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin (5).

To 3.6 g (0.01 mol) of compound 4, suspended in 40 ml of aqueous ethanol (1:1), is added dropwise 7% aqueous ammonia solution to pH 9. The precipitate is filtered off, washed with cold water and crystallized from aqueous ethanol (1:1). Yield 2.3 g (85%). TPL 117-118°C. Found, %: C 59,72; N 5,8; N 16,1. C13H15N3OS. Calculated, %: C 59,74; N 5,8; N 16,1.1H NMR in DMSO-d6that δ, ppm: 4,1 (8H, m, morpholino), 4.5 (2H, s, CH2S); 7.45-8.1 (5H, m6H5).

Example 6.

2-Mor is Olya-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, the base (6).

To a suspension of 3.2 g (0.02 mol) of morpholine thiocarbanilide acid in 70 ml of ethanol is added a solution of 2.7 g (0.02 mol) of sodium acetate in 5 ml of water, then under stirring at 18°With added dropwise a solution of 5 g (0.02 mol) γ-bromo-α-methoxykynuramine in 15 ml of ethanol for 10 minutes, the Reaction mass is aged for 10 hours. The reaction mass is evaporated, and the residue orange crystallized from absolute ethanol. Yield 4.1 g (64%), TPL 102-103°C. Found, %: C 45,8; N, 5.7; S 10,5; C12H18N4About4S. Calculated, %: C 45,9; N, 5.7; S 10,2.1H NMR in CDCl3that δ, ppm: 1.35 (3H, t, CH3, SOOS2H5); of 3.54 (2H, s, CH2S); 3.75 (8H, m, morpholino); 4,08 (3H, s, och3); 4.4 (2H, q, och2, COOC2H5).

Example 7.

2 Morpholino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, mesilate (7).

Methansulfonate, 0.7 g (0.007 mol)was added dropwise with stirring to a solution of 2 g (0.006 mol) of compound 6 in dry benzene. A colorless precipitate obtained after 15-20 minutes stirring, was filtered and recrystallized from absolute ethanol. Yield 2.5 g (95%). TPL 181-182°C. Rf=0.45 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 38.2; N, 5.5; N, 13.6. C13H22N4O7S2. Calculated, %: 38.1; H 5.4; N, 13.7.1H NMR in DMSO-d6that δ, ppm: 1.28 (3H, t, CH3, SOOS2 H5); 2.35 (3H, s, SCH3); 3.74 (8H, m, morpholino), 3.88 (2H, s, CH2S); 4.02 (3H, s, och3); 4.29 (2H, q, OCH2-, COOC2H5).

Example 8.

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

Compound 8 was obtained by heating 2 g (0.01 mol) α-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 razbavleniem ammonia solution to pH 8-9. The colorless precipitate was filtered, recrystallized from 30% water-ethanol mixture and dried. Yield 2.7 g (70%). TPL 154-156°C. 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-d6that δ, 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 (10 H, m, With two6H5).

Example 9.

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

Compound 9 was obtained analogously to the synthesis of compound 8 from α-bromo-4-bromoacetophenone and 4-methyl-4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-thiosemicarbazide. Yield 72%. TPL 169-170°C. Rf=0.5 (eluent: ethanol / chloroform 10: 1). Found, %: 53.6; H 4.3; N, 14.6. C21H20BrN5OS. Calculated, %: 53.6; H 4.3; N, 14.9.1H NMR in DMSO-d6that δ ppm: 2.2 (3H, s, CH3 ); 3.2 (3H, br. s, NCH3); 3.35 (3H, br. s, NCH3); 3.65 (2H, s, CH2S); 7.4-8.0 (M, m6H5and C6H4).

Example 10.

2-N-(1-Phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6N-1,3,4-thiadiazin (10).

Compound 10 was obtained analogously to the synthesis of compound 8 from α-bromoacetophenone and 4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-thiosemicarbazide. Yield 88%. TPL 112-114°C. Rf=0.58 (eluent: ethanol / chloroform 1:8). Found, %: 63.5; N, 5.2; N, 18.4. C20H19N5OS. Calculated, %: 63.6; N, 5.1; N, 18.5.1H NMR in DMSO-d6that δ, ppm: 2.2 (3H, s, CH3); 3.1 (3H, s, NCH3); 3.9 (2H, s, CH2S); 7.3-8.0 (10H, m, With two6H5).

Example 11.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6-ethyl-1,3,4-thiadiazin (11).

Compound 11 was obtained by heating 0.5 g (0.002 mol) α-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 and dried. Yield 0.6 g (75%). TPL 88-89°C. Rf=0.35 (eluent: ethanol / chloroform 1:10). Found, %: C 64.4; N, 6.0; N, 16.7. With23H25N5OS. Calculated, %: 64.5; N, 4.4; N, 16.3.1H NMR in DMSO-d6that δ, 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, With two6H5).

Example 12.

2-N-(1-Phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-phenyl-6-ethyl-1,3,4-thiadiazin (12).

Compound 12 is obtained analogously to the synthesis of compound (11) from α-bromothiophene and 4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-thiosemicarbazide. Yield 74%. TPL 79-80°C. Rf=0.32 (eluent: ethanol / chloroform 1:10). Found, %: 63.3; H 5.7; N, 17.6. C22H23N5OS·0.5 N2O. Calculated, %: 63.8; H 5.8; N, 17.8.1H NMR in DMSO-d6that δ, 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, With two6H5).

Example 13.

2-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin (13).

Compound 13 was obtained by heating 2.4 g (0.01 mol) of 4-ethoxy-α-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, recrystallized from a mixture of water and ethanol 80:20 and dried. Yield 3.5 g (74%). TPL 164-165°C. Rf=0.25 (eluent: ethanol / chloroform 1:10). Found, %: 63.3; H 5.9; N, 15.8. With23H25N5O2S. Calculated, %: 63.4; H 5.8; N, 16.1.1H NMR in DMSO-d6that δ, ppm: 1.34 (3H, t, -CH ); 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 14.

2-N-Methyl-N-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin (14).

Compound 14 was obtained analogously to the synthesis of compound 13 from 4-chloro-α-bromoacetophenone and 4-methyl-4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)thiosemicarbazide. Yield 77%. TPL 178-179°C. Rf=0.3 (eluent: ethanol / chloroform 1: 10). Found, %: 57.7; H 4.7; N, 15.8. C21H20CIN5OS·0.5 H2O. Calculated, %: 58.0; H 4.8; N, 16.2.1H NMR in DMSO-d6that δ, 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 (M, m6H5and C6H4).

Example 15.

2-N-(1-Phenyl-2,3-dimethylpyrazol-5-one-4-yl)-amino-5-(3-bromophenyl)-6N-1,3,4-thiadiazin (15).

Compound 15 was obtained analogously to the synthesis of compound 13 from 3-bromo-α-bromoacetophenone and 4-(1-phenyl-2,3-dimethylpyrazol-5-one-4-yl)thiosemicarbazide. Yield 76%. TPL 69-70°C. Rf=0.38 (eluent: ethanol / chloroform 1:10). Found, %: 50.6; N, 4.2; N, 14.6. C20H18BrN5OS·N2O. Calculated, %: 50.2; N, 3.9; N, 14.8.1H NMR in DMSO-d6that δ, ppm: 2.20 (3H, s, CH3); 3.10 (3H, br. s, NCH3); 3.95 (2H, S, CH2S); 7.1-8.0 (9H, m6H5H and C6H4).

Example 16.

2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin, mesilate (16). Methanol is facecloth, 0.4 g (0.004 mol)was added dropwise to a solution of 1 g (0.004 mol) of the compound 5 in 70 ml of dry ether. A colorless precipitate obtained after 20 minutes of stirring, was filtered and recrystallized from absolute ethanol. Yield 1.2 g (88%). TPL 173-174°C. Rf=0.38 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 47.0; N, 5.5; N, 11.6. With14H19N3O4S2. Calculated, %: 47.1; H 5.3; N, 11.8.1H NMR in DMSO-d6that δ, ppm: 2.30 (3H, s, SCH3); 3.82 (8H, m, morpholino), 4.29 (2H, s, CH2S); 7.4-8.0 (5H, m6H5).

Example 17.

2 Morpholino-5-(3-bromophenyl)-6N-1,3,4-thiadiazin, hydrobromide (17).

Compound 17 is obtained analogously to the synthesis of compound 1 from 3-bromo-α-bromoacetophenone and morpholide thiocarbanilide acid. Yield 70%. TPL 191-192°C. Rf=0.3 eluent: butanol-acetic acid-water 4:1:5). Found, %: 37.4; H 3.6. C13H15Br2N3OS. Calculated, %: 37.1; H 3.6.1H NMR in DMSO-d6that δ, ppm: 3.80 (8H, m, morpholino); 4.29 (2H, s, CH2S); 7.3-8.2 (4H, m6H4).

Example 18.

2 Thiomorpholine-5-(4-methoxyphenyl)-6N-1,3,4-thiadiazin, hydrobromide (18).

Compound 18 is obtained analogously to the synthesis of compound 1 of 4-methoxyphenyl-α-bromoacetophenone and thiomorpholine thiocarbanilide acid. Yield 77%. TPL 201-202°C. Rf=0.35 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 43.6; H 4.7; N, 10.9. C14H18 BrN3OS2. Calculated, %: 43.3; H 4.6; N, 10.8.1H NMR in DMSO-d6that δ, ppm: 2.88 [4H, m, N(CH2)2thiomorpholine]; 3.85 (3H, s, och3); 4.12 [4N. m, S(CH2)2thiomorpholine]; 4.32 (2H, s, CH2S); 7.5 (4H, dd,6H4).

Example 19.

2 Thiomorpholine-5-(2-chlorophenyl)-6N-1,3,4-thiadiazin, hydrobromide (19).

Compound 19 is obtained by heating 0.7 g (0.003 mol) α-bromo-2-chloracetophenone with 0.5 g (0.003 mol) thiomorpholine thiocarbanilide acid in 30 ml of absolute ethanol in the presence of 0.3 ml of concentrated HBr for 30 minutes. After cooling with ice 30 ml of dry ether was added to the reaction mixture, causing the appearance of a yellow precipitate, which was filtered, recrystallized from absolute ethanol and dried. Yield 0.85 g (71%). TPL 190-191°C. Rf=0.38 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 39.8; N, 4.2; N, 10.6. C13H15BrCIN3S2. Calculated, %: 39.7; H 3.8; N, 10.7.1H NMR in DMSO-d6that δ, ppm: 2.88 [4H, m, N(CH2)2thiomorpholine]; 4.15 [4H, m, S(CH2)2thiomorpholine]; 4.25 (2H, s, CH2S); of 7.4-7.8 (4H, dd,6H4).

Example 20.

2 Thiomorpholine-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin, hydrobromide (20).

Compound 20 was obtained by heating 2.3 g (0.01 mol) α-bromo-4-chloroacetophenone with 1.8 g (0.01 mol) thiomorpholine thiocarbanilide acid in 50 ml of absolute ethanol for 25 the minutes. The mixture was cooled with ice to obtain a yellow precipitate, which was filtered, recrystallized from absolute ethanol and dried. Yield 3.0 g (77%). TPL 201-202°C. Rf=0.50 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 40.0; N, 4.2; N, 10.6. With13H15BrCIN3S2. Calculated, %: 39.7; H 3.8; N, 10.7.1H NMR in DMSO-d6that δ, ppm: 2.88 [4H, m, N(CH2)2thiomorpholine]; 4.18 [4H, m, S(CH2)2thiomorpholine]; 4.39 (2H, s, CH2S); and 7.3 (4H, dd,6H4).

Example 21.

2 Hexamethyleneimino-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide (21).

Compound 21 is obtained analogously to the synthesis of compound 1 of the α-bromoacetophenone 4,4-hexamethylenediisocyanate. Yield 68%. TPL 203-204°C. Rf=0.42 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 50.6; H 5.6; N, 11.6. With15H20BrN3S. Calculated, %: 50.8; H 5.6; N, 11.9.1H NMR in DMSO-d6that δ, ppm: 1.4-2.2 (8H, m, (CH2)4hexamethylenimine); 3.7-4.2 [4H, m, N(CH2)2hexamethylenimine]; 4.48 (2H. s, CH2S); 7.2-8.1 (5H, m6H5).

Example 22.

2-Piperidino-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide (22).

Compound 22 is obtained analogously to the synthesis of compound 1 of the α-bromoacetophenone 4,4-pentamethylenetetrazol. Yield 68%. TPL 230-232°C. Rf=0.7 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 49.5; H 5.4; N, 12.4. C14H 18BrN3S. Calculated, %: 49.4; H 5.3; N, 12.4.1H NMR in DMSO-d6that δ, ppm: 1.5-2.2 [6N, m, (CH2)4, piperidino]; 3.5-3.8 [4H, m, N(CH2)2, piperidino]; 4.35 (2H, s, CH2S); 7.2-8.1 (5H, m6H5).

Example 23.

2-Pyrrolidino-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide (23).

Compound 23 is obtained analogously to the synthesis of compound 1 of the α-bromoacetophenone 4,4-tetramethylenedisulfotetramine. Yield 78%. So pl. 182-183°C. Rf=0.49 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 47.6; N, 4.9; N, 12.9. C13H18BrN3S. Calculated, %: 47.9; N, 5.0; N, 12.9.1H NMR in DMSO-d6that δ, ppm: 2.1 [4H, m, (CH2)2, pyrrolidino]; 3.7 [4H, m, N(CH2)2, pyrrolidino]; 4.45 (2H, s, CH2S); 7.4-8.0 (5H, m6H5).

Example 24.

2 Hexamethyleneimino-5-(4-bromophenyl)-6N-1,3,4-thiadiazin, hydrobromide (24).

Compound 24 is obtained analogously to the synthesis of compound 1 of the α-bromo-4-bromoacetophenone 4,4-hexamethylenediisocyanate. A yield of 75%. TPL 201-203°C. Rf=0.38 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 42.0; H 4.6; N, 9.4. C15H19Br2N3S. Calculated, %: 41.6; N, 4.4; N, 9.7.1H NMR in DMSO-d6that δ, ppm: 1.4-2.3 [8H, m, (CH2)4hexamethylenimine]; 3.6-4.1 [4H, m, N(CH2)2hexamethylenimine]; 4.5 (2H, s, CH2S); 7.8 (4H, dd,6H4).

Example 25.

2-Hexamethylene the but-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin, the hydrobromide (25).

Compound 25 is obtained analogously to the synthesis of compound 1 of the α-bromo-4-chloroacetophenone 4,4-hexamethylenediisocyanate. Yield 68%. TPL 199-200°C. Rf=0.30 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 46.4; N, 5.2; N, 10.6. C15H19BrCIN3S. Calculated, %: 46.3; N, 4.9; N, 10.8.1H NMR in DMSO-d6that δ, ppm: 1.4-2.3 [8H, m, (CH2)4hexamethylenimine]; 3.6-4.2 [4H, m, N(CH2)2hexamethylenimine]; 4.47 (2H, s, CH2S); 7.75 (4H, dd,6H4).

Example 26.

2 Hexamethyleneimino-5-(4-bromophenyl)-6N-1,3,4-thiadiazin, mesilate (26).

Methansulfonate, 0.4 g (0.004 mol)was added dropwise to a solution of 1.5 g (0.004 mol) of compound 24 and the reaction mixture was stirred at room temperature for 30 minutes. The colorless crystalline product was filtered and recrystallized from absolute ethanol. Yield 1.7 g (89%). TPL 201-202°C. Rf=0.26 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 42.7; N, 4.9; N, 14.1. C16H22BrN3O3S2. Calculated, %: 42.9; N, 4.9; N, 14.3.1H NMR in DMSO-d6that δ, ppm: 1.38-2.05 [8H, m, (CH2)4hexamethylenimine]; 2.35 (3H, s, SCH3)T 3.6-4.0 [4H, m, N(CH2)2hexamethylenimine]; 4.35 (2H, s, CH2S); 7.80 (4H, dd,6H4).

Example 27.

2 Morpholino-5-(2-chlorophenyl)-6N-1,3,4-thiadiazin, hydrobromide (27).

Connection 27 sex is constrained by heating 1.2 g (0.005 mol) α -bromo-2-chloracetophenone with 0.8 g (0.005 mol) of morpholine thiocarbanilide acid in 30 ml of absolute ethanol for 20 minutes. The mixture was cooled to highlight a yellow precipitate, which was filtered, recrystallized from absolute ethanol and dried. Yield 1.4 g (76%). TPL 204-205°C. Rf=0.32 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 41.6; N, 4.1; N, 11.3. C13H15BrCIN3OS. Calculated, %: 41.4; N, 4.0; N, 11.2.1H NMR in DMSO-d6that δ, ppm: 3,85 [8H, m, (CH2)2morpholino]; 4.25 (2H, s, SCH2); the 7.4-7.9 (4H, m6H4).

Example 28.

2 Thiomorpholine-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, hydrobromide (28).

Compound 28 was obtained analogously to the synthesis of compound 6 by the reaction of ethyl-γ-bromo-α-methoxykynuramine with thiomorpholine thiocarbanilide acid at 18-20°C for 6 hours. The yield was 73%. TPL 202-203°C. Rf=0.7 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 35.6; N, 4.8; N, 13.7. C12H19BrN4O3S2. Calculated, %: 35.0; H 4.6; N, 13.6.1H NMR in DMSO-d6that δ, ppm: 1.27 (3H, t, -CH3, COCC2H5); 2.84 (4H, m, N(CH2)2thiomorpholine); 4.06 (3H, s, och3); 4.10 (4H, m, S(CH2)2(thiomorpholine); 4.17 (2H, s, CH2S); 4.30 (2H, q, OCH2-SOOS2H5).

Example 29.

2-Piperidino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, hydrobromide (29).

Compound 29 was obtained analogously to the synthesis of compound 6 by the interaction of ethyl-γ-bromo-α-methoxykynuramine with 4,4-pentamethylenetetrazol. Yield 67%. TPL 201-202°C. Rf=0.35 (eluent: butanol-acetic acid-water 4:1:5). Found, %: 39.5; N, 5.7; N, 14.3. C13H21BrN4O3S. Calculated, %: 39.7; H 5.3; N, 14.3.1H NMR in DMSO-d6that δ, ppm: 1.32 (3H, t, -CH3, SOOS2H5); 1.72 (6N, m, piperidine); 3.88 (4H, m, piperidine); 4.08 (2H, s, CH2S); 4.10 (3H, s, och3); 4.32 (2H, q, OCH2-SOOS2H5).

Example 30.

2-Pyrrolidino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, hydrobromide (30).

Compound 30 was obtained analogously to the synthesis of compound 6 by the interaction of ethyl-γ-bromo-α-methoxykynuramine with 4,4-tetraethylorthosilicate. Yield 59%. TPL 208-209°C. Rf=0.29 (slutt: butanol-acetic acid-water 4:1:5). Found, %: C 38.0; N, 5.1; N, 15.0. C12H19BrN4O3S. Calculated, %: C 38.0; N, 5.0; N, 14.8.1H NMR in DMSO-d6that δ, ppm: 1.31 (3H, t, -CH3, SOOS2H5); 1.90-2.03 (4H,m, pyrrolidine); 3.50-3.95(4H, m, pyrrolidine); 4.06 (2H, s, CH2S); 4.17 (3H, s, och3); 4.32 (2H, q, OCH2-, COOC2H5).

Example 31.

2 Hexamethyleneimino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, hydrobromide (31).

Compound 31 was obtained analogously to the synthesis of compound 6 interaction is m ethyl-γ -bromo-α-methoxykynuramine with 4,4-hexamethylenebiguanide. An output of 60%. TPL 186-187°C. Rf=0.3 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 41.8; N, 5.2; N, 13.5. C14H23BrN4O3S. Calculated, %: 41.3; H 5.7; N, 13.5.1H NMR in DMSO-d6that δ, ppm: 1.30 (3H, t, -CH3, COOC2H5); 1.5-2.1 (8H, m, hexamethylenimine); 3.75-4.0 (4H, m, hexamethylenimine), 4.05 (2H, s, CH2S); 4.18 (3H, s, och3); 4.35 (2H, q, OCH2-, COOC2H5).

Example 32.

Composition for the manufacture of tablets:

2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin 20 mg,

Wheat starch,10 mg,

Lactose - 68 mg,

Magnesium stearate - 2 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 of 100 mg each.

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

2 Thiomorpholine-5-(4-ethoxyphenyl)-bn-1,3,4-thiadiazin, hydrobromide.

2 Thiomorpholine-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide.

2 Morpholino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin, hydrobromide.

2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide.

2 Morpholino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, the basis of the definition.

2 Morpholino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, mesilate.

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

Example 33.

Solutions for injection:

2 Morpholino-5-phenyl-6N-1,3,4-thiadiazin, the hydrobromide is dissolved in water or physiological solution at a ratio of 30 mg/ml (taking into account the solubility of the drug). For injection use freshly prepared solutions.

Similarly prepare solutions of the active ingredient which are the following compounds according to the invention is:

- 2-Thiomorpholine-5-(4-ethoxyphenyl)-6N-1,3,4-thiadiazin, hydrobromide.

- 2-Thiomorpholine-5-phenyl-6N-1,3,4-thiadiazin, hydrobromide.

- 2-Morpholino-5-(4-chlorophenyl)-6N-1,3,4-thiadiazin, hydrobromide.

- 2-Morpholino-5-(ethyl-1-methoxyimino)-6N-1,3,4-thiadiazin, mesilate.

5. The essential features of pharmacological activity of the claimed compounds

1. The influence of the 5R1, 6R2-1,3,4-thiadiazin-2-amine for example substances 1, 2, 3, 4, 7, 8 on the intensity of parenchymal bleeding from the liver of rats.

The characteristic of the material and the applied doses

The experiments were carried out at 180 white rats weighing 200±10 g, the animals took in the experience after the incubation period (14 days) and adaptation to the conditions of the decentralized vivarium. According to the program of the experiment, the order of doses was 20 and 80 mgkg.

Applicable model parenchymal bleeding is caused by applying the measured surface damage of the liver. Rats were narcoticyou with Nembutal at a dose of 50 mg/kg, secured in position on the back (special machine). Then the middle section with the transition in the transverse (in the epigastric region) opened the abdominal wall and had access to shares of the liver. The left lateral and right lateral lobe of the liver was taken to the operating wound and specialized scarificator was dealt 3 damage to a size of 0.4×0.1×0.3 see the Beginning of bleeding was recorded by a stopwatch, which was stopped at the moment of cessation of the hemorrhage. In the process of bleeding wounds blotted with sterile cloth every 5 seconds; the first "clean" cloth was considered evidence of complete hemostasis.

Scheme of the experiment.

According to the program recorded the bleeding time of each substance, introduced in two doses (20 and 80 mg/kg) after 1 hour and 40 minutes (100 minutes) and 3 hours 40 minutes (220 minutes) after application. Mandatory condition was combined in each group experienced (treated investigated the connection) and control (intact) animals. Thus, to study the effect of a single connection used 30 rats divided into 6 groups (5 animals each): rat 1-intact rats 2 and 4 received the substance at a dose of 20 mg/kg, rat 3, and 5 received substance at a dose of 80 mg/kg After 1 hour simulated parenchymal hemorrhage in the rat 1, after 1 hour and 40 minutes on rats 2 and 4, after 3 hours 40 minutes on rats 3 and 5 (additional 40 minutes required for complete absorption of the drug when administered orally). According to the program tested the effect of substances 1, 2, 3, 4, 7, 8 in two doses (20 and 80 mg/kg) when injected into the stomach. Two groups of animals were subjected to experience through 100, and 200 minutes after application connection. The results of the experiments are shown in table 2 and figure 1, 2, 7. Substance 4 are soluble in water, and his example was studied parenchymal bleeding from the liver of rats and intraperitoneal injection (Fig.7).

Thus, all investigated compounds exhibit anticoagulant properties. The greatest effect of substances 1 and 4, and the lowest is 7. Agent 1 has the greatest impact on the duration of capillary bleeding. The effect lasts at least 3 hours. In the range of doses (20 and 80 mg/kg) is not marked dose-dependent.

2. The influence 5R1, 6R2-1,3,4-thiadiazin-2-amine for example substances 1-4 on platelet aggregation in the experience of in vitro and in vivo (rabbits). Set a time limit of effectiveness: early action 15-60 min (depends on route of administration), the end - depending on the nature of the model - from 180 min to 24 hours (table 1). Influence of material 4 on induced aggregation trom acetow rabbits at doses of 20 and 80 mg/kg and rates of thromboelastography when administered intravenously to rabbits is shown in figure 3-6.

Thus, all investigated compounds exhibit antiplatelet activity. It is revealed that the substance 4 has maximum activity in a large range of doses (from 2 to 80 mg/kg) and all used variants of models (platelet aggregation, activation of the "internal" and "external" ways to suppress hemostasis).

3. The number of studied 5R1, 6R2-1,3,4-thiadiazin-2-amines shown the ability to effectively concentration-dependently suppress the transport of ions of CA2+different types of calcium channels in the plasma membrane, including channels transplantable tumor cells pheochromocytoma PC-12.

6. List of drawings

figure 1. Influence of substances 1-4, 7, 8 at a dose of 20 mg/kg for a duration of parenchymal bleeding from the liver of rats after intragastric administration.

figure 2. Influence of substances 1-4, 7, 8 at a dose of 80 mg/kg for a duration of parenchymal bleeding from the liver of rats after intragastric administration.

Figure 3. Influence of material 4 at a dose of 20 mg/kg induced platelet aggregation when administered intravenously to rabbits.

Figure 4. Influence of material 4 at a dose of 80 mg/kg induced platelet aggregation when administered intravenously to rabbits.

Figure 5. Influence of material 4 at a dose of 80 mg/kg at a rate of thromboelastogram "To" when administered intravenously to rabbits.

Fig 6. Influence of material 4 at a dose of 80 mg/kg is as an indicator of thromboelastogram "ME" when administered intravenously to rabbits.

7. Influence of material 4 on parenchymal bleeding from the liver of rats by intraperitoneal injection.

1. The use of substituted 5R1,6R2-1,3,4-thiadiazin-2-amines of General formula I

where R1represents phenyl which may be substituted by one or more chlorine atoms, bromine, C1-C4alkoxy, C1-C4alkyl groups, or R1is the rest of etelaat-1 methoxyimino;

R2represents a hydrogen atom or a C1-C4alkyl group;

R3is N-morpholinyl, N-thiomorpholine, N-piperidinyl, N-pyrrolidinyl, N-hexamethyleneimino, N-methylamino-(1-phenyl-2,3-dimethylpyrazol-5-he-Il) or N-amino-(1-phenyl-2,3-dimethylpyrazol-5-he-Il),

and their pharmaceutically acceptable salts as pharmacologically active substances with concomitant anticoagulant and antiplatelet action.

2. Substituted 5R1,6R2-1,3,4-thiadiazin-2-amines of General formula I

where R1is the rest of etelaat-1 methoxyimino;

R2represents a hydrogen atom;

R3is N-morpholinyl, N-timoha the Nile, N-piperidinyl, N-pyrrolidinyl, N-hexamethylenimine.

3. Pharmaceutically acceptable salts of substituted 5R1,6R2-1,3,4-thiadiazin-2-amines of General formula I, where R1, R2and R3defined in item 2.

4. Pharmaceutical composition having anticoagulant and antiplatelet effect and containing an effective amount of at least one of the compounds of General formula I according to claim 2 or pharmaceutically acceptable salt according to claim 3 as an active agent and a pharmaceutically acceptable excipient, diluent and/or other excipients.



 

Same patents:

FIELD: organic chemistry, pesticides, agriculture.

SUBSTANCE: invention relates to compounds that elicit high pesticide activity and can be used in control of pests of domestic and agricultural animals. Indicated compounds show the formula (I):

wherein R1 means halogen atom, (C1-C6)-halogenalkyl; R2 means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkylene-phenyl; X1 means nitrogen atom (N); X2 means group C(CN); X3 means oxygen atom (O); Q means CH; R3 and R4 mean independently of one another hydrogen atom (H) or in common with carbon atom with which they are bound form (C3-C7)-cycloalkyl ring; R5 means a substitute taken among group including (C1-C6)-halogenalkyl, halogen atom being if m above 1 then substitutes R5 can be similar or different; m = 1, 2 or 3; n = 0 or 1. Also, invention describes a method for their preparing and method for control of pests.

EFFECT: valuable pesticide properties of compounds.

7 cl, 3 tbl, 14 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry.

SUBSTANCE: method relates to new method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I . Claimed compound is high effective drug and is used in medicine as myorelaxant of central action. Claimed method includes condensation of N,N-dimethyldichloromethyleneammonium chloride with 5-chloro-4-amino-1,1,3-benzothiadiazole in organic solvent followed by treatment of formed alpha-chloroformamidine of formula R-N=C(Cl)N(CH3)2, wherein R is 5-chloro-2,1,3-benzothiazol-4-yl, with ethylenediamine. Formed intermediate of formula R-N=C(NH-CH2-CH2-NH2)N(CH3)2 is treated with hydrochloric acid, heated in organic solvent and 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I is isolated.

EFFECT: simplified method for preparation of target compound directly in hydrochloride form.

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

The invention relates to organic chemistry and can find application in medicine

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where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 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

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

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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