Condensed derived 1,2,4-thiadiazine, pharmaceutical composition and method for producing a medicinal product

 

(57) Abstract:

The present invention relates to condensed derivatives of 1,2,4-thiadiazine containing system thiophene and 1,2,4-thiadiazole rings. Also described pharmaceutical composition and method for producing a medicinal product on the basis of connections. The compounds possess the ability to impact on KATP-regulated potassium channels, which makes them useful in the treatment of the endocrine system, in particular they can be used to reduce hyperinsulinemia and thereby to prevent diabetes. 3 s and 5 C.p. f-crystals.

The present invention relates to condensed derivatives of 1,2,4-thiadiazine, methods for their preparation, compositions comprising these compounds, the use of these compounds as medicines and their use in the treatment of, for example, diseases of the Central nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

PROTOTYPES OF THE INVENTION

Potassium channels play an important role in physiological and pharmacological regulation of cell membrane potential. Among the different types of potassium channels have ATP-sensitive (KATP-channels detected in cells from various tissues, such as heart cells, pancreas, skeletal muscle, smooth muscle, Central neurons and cells adenogipofiza. These channels are associated with different cellular functions, such as secretion of hormones (insulin from pancreatic beta cells, growth hormone and prolactin cells adenogipofiza), dilation of blood vessels (smooth muscle cells), the potential duration of cardiac action, highlighting neurotransmitters in the Central nervous system.

Found that for the treatment of various diseases is important modulators TOATP-channels. Some sulfonylureas, which are used to treat non-insulin dependent diabetes mellitus, act by stimulating insulin secretion by inhibition of KATP-channels in pancreatic beta-cells.

Discovered that substances that open potassium channels (potassium channel openers) that include a heterogeneous group of compounds able to relax vascular smooth muscle, and therefore they can be used for the treatment of hypertension.

In addition, substances that open potassium channels, can be used as bronchodilators salavia channels, promotirovat hair growth and can be used to treat baldness.

Substances that open potassium channels, can also relax the smooth muscle of the bladder, and, therefore, they can be used to treat urinary incontinence. Substances, the opening of potassium channels, which relax smooth muscle, can be used to prevent preterm birth.

By acting on potassium channels in the Central nervous system it is possible to use these compounds for the treatment of various neurological and psychiatric diseases, such as Alzheimer's disease, epilepsy and cerebral ischemia.

It was also discovered that these compounds are useful in the treatment of benign prostatic hypertension, erectile dysfunction and contraception.

Compounds of the present invention, which inhibit insulin secretion through activation of potassium channels in beta-cells, can be used in combination with other compounds that can be used for the treatment of non-insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus. Examples of such compounds include insulin, insulin sensitizers, such as thiazolidinedione, nodoby peptide (GLP1), inhibitors-glucosidase and hepatic enzymes responsible for the biosynthesis of glucose.

Currently, it is shown that diazoxide (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide) and some derivatives of 3-(alkylamino)-4H-pyrido[4,3-e] -1,2,4-thiadiazine 1,1-dioxide inhibit insulin secretion by the activation of KATPchannels of pancreatic beta-cells (Pirotte Century and other Biochem. Pharmacol., 47, 1381-1386 (1994); (Pirotte B. and other Med. Chem., 36, 3211-3213 (1993)). It is also shown that diazoxide inhibits the attack of diabetes in BB-rats (Vlahos W. D. and others, Metabolism, 40, 39-46 (1991)). On greasy rats (obese zucker rats) have shown that diazoxide reduces insulin secretion and increases the binding of insulin receptors and, therefore, improves glucose tolerance and reduces weight gain (Alemzadeh R. and others Endocrinol., 133, 705-712, 1993). It is expected that compounds that activate KATP-channels can be used to treat diseases characterized by excessive production of insulin, and for the treatment and prevention of diabetes.

European Patent 618209 discloses a class derived peridotites with alkyl or alkylamino in position 3 thiadiazine rings. It is stated that these compounds are antagonists of AMPA receptors-gluta as agents chemotherapeutic value. Shown mainly junction 3 of aminoimidazo[4,5-e] -1,2,4-thiadiazine 1,1-dioxide and N-benzylaminopurine[4,5-e] -1,2,4-thiadiazine 1,1-dioxide.

DESCRIPTION OF THE INVENTION

The present invention relates to derivatives of condensed 1,2,4-thiadiazine and condensed 1,4-thiazine General formula I:

< / BR>
where is >NR5or >CR5R6where R5and R6independently are hydrogen; hydroxyl; C1-6-alkoxygroup or C1-6-alkyl, C3-6-cycloalkyl,2-6-alkenyl or2-6-quinil, optionally mono - or polyamidine halogen, or R5and R4together represent one of the bonds in the double bond between the atoms 2 and 3 of formula I;

D represents-S(=O)2- or independently-S(=O)- or

D-B is-S(=O)(R7)= N-,

where R7is C1-6-alkyl; or aryl or heteroaryl, optionally mono - or polyamidine halogen, hydroxyl, C1-6-alkoxygroup, arroceros, arialcategory, a nitro-group, amino group, C1-6-monoalkyl or dialkylamino, cyano, acyl or C1-6-alkoxycarbonyl;

R1is hydrogen; hydroxyl; C1-6-alkoxy is ina mono - or polyamidine halogen, and R4is hydrogen; or R4together with R5represents a single bond of a double bond between the atoms 2 and 3 of formula I; or R1together with R4represents a single bond of a double bond between the atoms 3 and 4 of formula I;

R2is hydrogen; hydroxyl; C1-6-alkoxygroup or C1-6-alkyl, C3-6-cycloalkyl,2-6-alkenyl or2-6-Alki-Neal, optionally mono - or polyamidine halogen;

R3is R8; -OR8; -C(=X)R8; -NR8R9; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroallyl, optionally mono - or polyamidine halogen, C1-6-alkoxygroup, arroceros, arialcategory, a nitro-group, amino group, C1-6-monoalkyl or dialkylamino, cyano, exography, acyl or C1-6-alkoxycarbonyl; or aryl, substituted C1-6-alkyl;

where R8is hydrogen; C3-6-cycloalkyl or (C3-6-cycloalkyl)3-6-alkyl, WITH3-6-cycloalkyl group optionally mono - or polyamidine1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup; 3-6-membered saturated cyclic system, cabezuelo mono - or polyamidine halogen, the hydroxyl or C1-6-alkoxygroup, C1-6-alkylthiophene,3-6-cycloalkyl, aryl, arroceros, arialcategory, a nitro-group, amino group, C1-6-monoalkyl or dialkylamino, cyano, exography, formyl group, acyl, carboxyla, C1-6-alkoxycarbonyl or carbamoyl;

X represents O or S;

R8is hydrogen, C1-6-alkyl; C2-6-alkenyl; C3-6-cycloalkyl, optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup; or

R8and R9together with the nitrogen atom form a 3-12-membered mono - or bicyclic system, in which one or more carbon atoms may be replaced by nitrogen, oxygen or sulfur, each of these cyclic systems optionally mono - or polyamidine halogen, C1-6-alkyl, hydroxyl, C1-6-alkoxygroup,1-6-alkoxy-C1-6-alkyl, a nitro-group, amino group, cyano, trifluoromethyl, C1-6-monoalkyl or dialkylamino, exography; or R3is

< / BR>
where n, m, p is independently 0, 1, 2, 3, and

R10is hydrogen; hydroxyl; C1-6-gidroksila or C1-6-alkoxygroup; C1-6-alkyl, C2-6-alkenyl or2-6-quinil, optionally mono - or polyamidine halogen; or

R2and R3together with the nitrogen atom form a 3-12-membered mono - or bicyclic system, in which one or more carbon atoms may be replaced by nitrogen, oxygen or sulfur, each of these cyclic systems optionally mono - or polyamidine halogen, C1-6-alkyl, hydroxyl, C1-6-alkoxygroup,1-6-alkoxy-C1-6-alkyl, a nitro-group, amino group, cyano, trifluoromethyl, C1-6-monoalkyl or dialkylamino or oxopropoxy;

Together with carbon atoms 5 and 6 of formula I is 5 - or 6-membered heterocyclic system containing one or more nitrogen atoms, oxygen or sulfur, with the heterocyclic system optionally mono - or polyamidine halogen, C1-12-alkyl, C3-6-cycloalkyl; hydroxyl, C1-6-alkoxygroup; C1-6-alkoxy-C1-6-alkyl; nitro-group, the amino group; a cyano; cyanomethyl; perhalogenated; C1-6-monoalkyl or dialkylamino; sulfamoyl group; C1-6-alkylthiophene; C1-6-alcelaphus; arylsulfonyl group; arylsulfonyl group, this aryl group is optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup; C1-6-alkoxycarbonyl; C1-6-alkoxycarbonyl-C1-6-alkyl; carbamino; carbamylation; C1-6-monoalkyl or dialkylaminoalkyl; C1-6-monoalkyl or dialkyldimethylammonium; ureidopropionic; C1-6-monoalkyl or dialkiltiakarbotsianinov; cheoreography; C1-6-monoalkyl or dialkyldithiocarbamato; C1-6-monoalkyl or dialkylaminoalkyl; carboxyla; carboxy-C1-6-alkyl; acyl; aryl, arylalkyl, arroceros, while aryl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup; (1,2,4-oxadiazol-5-yl)- or (1,2,4-oxadiazol-3-yl)-C1-6-alkyl, with oxadiazolyl group optionally substituted C1-6-alkyl or C3-6-cycloalkyl; or a 5-6-membered cycle, nitrogen-containing, optionally substituted by phenyl or C1-6-alkyl;

provided that together with carbon atoms 5 and 6 of formula I does not form a pyridine ring and that is not including the Jn 1,1-dioxide,

or their salts with pharmaceutically acceptable acid or base.

In the scope of the present invention includes all optical isomers of compounds of formula I, some of which are optically active, as well as mixtures thereof, including racemic mixtures.

The scope of the present invention also includes the tautomeric forms of the compounds of formula I.

Salts include pharmaceutically acceptable salts of joining acids, such as hydrochloric, Hydrobromic, itestosterone, phosphoric, sulfuric, triperoxonane, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, almond, benzoic, cinnamic, methansulfonate, econsultancy, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), and incorporated herein by reference, pharmaceutically acceptable metal salts, such as lithium, sodium, potassium, magnesium and the like, or salts of optionally alkylated ammonium.

Used here, the term "C1-6-alkoxygroup", by itself or in combination, refers to a linear or branched monovalent Deputy, wklug oxygen and having from 1 to 6 carbon atoms, for example methoxy-, ethoxy-, propoxy-, isopropoxy, butoxy, phenoxypropan.

Used here, the term "C1-6-allylthiourea", by itself or in combination, refers to a linear or branched monovalent Deputy, including lower alkyl group linked through an atom of bivalent sulfur, with a free valence bond from the sulfur atom and having from 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, intelligroup.

Used herein, the term "C2-6alkenyl"' refers to an unsaturated hydrocarbon chain having 2-6 carbon atoms and one double bond, such as, for example, vinyl, 1-propenyl, allyl, Isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.

Used herein, the term "C3-6-cycloalkyl" refers to a radical of a saturated cyclic hydrocarbon having the specified number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Used herein, the term "C2-6-quinil" refers to unsaturated hydrocarbons containing a triple bond such as, for example, -CLO-SSN3, -CH2CCH, -CH2CH2CCH, (CH3)CLO and the like.

Ispolzovaniya oxygen, such as, for example, -CH2-O-CH3, -CH2-O-CH2-, CH3, -CH2-O-CH-(CH3)2and like that.

The term "halogen" denotes fluorine, chlorine, bromine or iodine.

The term "perhalogenated" denotes trifluoromethyl, trichloromethyl, tribromoethyl or triacetyl.

Used here, the terms "C1-6-alkyl, C1-12-alkyl" and "C1-18-alkyl", alone or in combination, refers to a linear or branched saturated hydrocarbon chain having the specified number of carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. Used here, the term "C1-18-alkyl" includes secondary3-6-alkyl and tertiary4-6-alkyl.

Used here, the term "C1-6-monoalkylamines" refers to the amino group in which one of the hydrogen atoms substituted linear or branched saturated hydrocarbon chain having the specified number of carbon atoms, such as, for example, methylamino, ethylamino, propylamino-, n-butyl is ethylmethylamino-, neopentylene, h-hexylamino-, 2,2-dimethylpropyleneurea and the like.

Used here, the term "C1-6-dialkylamino" refers to the amino group in which two hydrogen atoms independently substituted linear or branched saturated hydrocarbon chain having the specified number of carbon atoms, such as, for example, dimethylamino-N-ethyl-N-methylamino, diethylamino, dipropylamino-, N-(n-butyl)-N-methylamino-, di(n-pentyl)amino group and the like.

Used here, the term "acyl" refers to a monovalent Deputy, which includes the C1-6is an alkyl group linked through a carbonyl group, such as, for example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.

Used here, the term "C1-6-alkoxycarbonyl" refers to a monovalent Deputy, including C1-6-alkoxy group linked through a carbonyl group, such as, for example, methoxycarbonyl, carboethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, second-butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutanoyl, n-hexoxyethanol and the like.

Used here, the term "3-12-membered mono - or bichde R2and R3or R8and R9together with the nitrogen atom form a 3-12-membered mono - or bicyclic system, in which one or more carbon atoms may be replaced by nitrogen, oxygen or sulfur, such as 1-Pirro-lidin, piperidino, morpholino, thiomorpholine, 4-methylpiperazin-1-yl, 7-azabicyclo[2.2.1]heptane-7-yl and the like.

Used here, the term "3-6-membered saturated cyclic system" refers to a monovalent Deputy, which includes monocyclic saturated system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and 3-6 members, and have a free valence on a carbon atom, such as, for example, 2-pyrrolidine, 4-piperidyl, 3-morpholinyl, 1,4-dioxane-2-yl, 5-oxazolidinyl, 4-isoxazolidine or 2-thiomorpholine.

Used here, the term "bicycloalkyl" refers to a monovalent Deputy, which includes bicyclic structure composed of 6-12 carbon atoms, such as, for example, 2-norbornyl, 7-norbornyl, 2-bicyclo[2.2.2]octyl and 9-bicyclo[3.3.1]nonanal.

Used here, the term "aryl" refers to phenyl, 1-naphthyl or 2-naphthyl.

Used here, the term "heteroaryl one or combination of the and 9-10 membered bicyclic aromatic system, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as, for example, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazin, pyrimidine, pyridazine, isothiazol, isoxazol, oxazol, oxadiazole, thiadiazole, quinoline, isoquinoline, hinzelin, cinoxacin, indole, benzimidazole, benzofuran, pteridine and purine.

Used here, the term "arylalkyl" refers to linear or branched saturated carbon chain containing from 1 to 6 carbons and substituted aromatic carbohidratos, such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like.

Used here, the term "alloctype" refers to fenoxaprop, 1-naphthyloxy or 2-naphthyloxy.

Used here, the term "arielalexisxrp" refers to C1-6alkoxygroup, substituted aromatic carbohidratos, such as benzyloxy, venetucci-, 3-phenylpropoxy-, 1 aftermatket-, 2-(1-naphthyl)ethoxypropan and the like.

Used here, the term "heteroaromatic" refers to linear or branched saturated carbon chain containing from 1 to 6 carbons and the substituted heteroaryl group, such as (2-furyl)methyl, (3-furyl)methyl, (2-t is followed by a session in the term1-6-alkylsulfonyl" refers to a monovalent Deputy, including C1-6is an alkyl group linked through sulfonyloxy group, such as, for example, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, second-butylsulfonyl ISO-butylsulfonyl, tert-butylsulfonyl, n-peterculter, 2-methylbutanoyl, 3-methylbutanoyl, n-hexylsilane, 4-methylphenylsulfonyl, neopentylene, n-hexylsilane and 2,2-dimethylpropanoyl.

Used here, the term "C1-6-monoalkylbenzenes" refers to a monovalent Deputy, including C1-6-monoalkylamines connected through sulfonyloxy group, such as, for example, methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylimidazole-were radioactive, n-butylaminoethyl, second-butylaminoethyl, ISO-butylaminoethyl, tert-butylaminoethyl, n-intramyocellular, 2-methylbutylamine, 3-methylbutylamine, n-exelonexelon, 4-methylphenylsulfonyl, neopatrimonialism, n-exelonexelon and 2,2-dimethylpropyleneurea.

Used here, the term "C1-6-dialkylaminomethyl group, such as dimethylaminomethyl, N-ethyl-N-methylaminomethyl, diethylaminosulfur, dipropylenetriamine, N-(n-butyl)-N-methylaminomethyl, di(n-pentyl)aminosulfonyl and the like.

Used here, the term "C1-6-alkylsulfonyl" refers to a monovalent Deputy, including linear or branched C1-6is an alkyl group linked through sulfinyl group (-S(=O)-), such as, for example, methylsulfinyl, ethylsulfinyl, isopropylphenyl, butylsulfonyl, pentasulfide and the like.

Used here, the term "C1-6-alkylcarboxylic" refers to the amino group in which one hydrogen atom is substituted by an acyl group, such as, for example, acetamidophenyl, isopropylcarbodiimide and the like.

Used here, the term "(3-6-cycloalkyl)C1-6-alkyl", by itself or in combination, refers to a linear or branched saturated hydrocarbon chain which has from 1 to 6 carbon atoms and is monosubstituted WITH3-6-cycloalkyl group, with cycloalkyl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup, such pushing and such.

Used here, the term "aristocrata" refers to an aryl group linked through an atom divalent sulfur and having a free valence bond from the sulfur atom, with the aryl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup, for example, phenylthio-, (4-were)thio-, (2-chlorophenyl)tighrope and the like.

Used here, the term "arylsulfonyl" refers to an aryl group linked through sulfonyloxy group (S(=O)-), aryl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup, such as phenylsulfonyl, (4-chlorophenyl)sulfinil and the like.

Used here, the term "arylsulfonyl" refers to an aryl group linked through sulfonyloxy group, this aryl group is optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup, such as phenylsulfonyl, tosyl and the like.

Used here, the term "C1-6-monoalkylamines" refers to a monovalent Deputy, which includes the C1-6-monoalkylamines, linked through a carbonyl granil, n-butylaminoethyl, second-butylaminoethyl, isobutylparaben, tert-butylaminoethyl, n-intramyocardial, 2-methylbutylamine, 3-methylbutylamine, n-mexiletineciclovir, 4-methylaminomethyl, neopentylglycol, n-mexiletineciclovir and 2,2-dimethylpropyleneurea.

Used herein, the term "C1-6-dialkylaminoalkyl" refers to a monovalent Deputy, which includes the C1-6-dialkylamino, linked through a carbonyl group, such as dimethylaminoethyl, N-ethyl-N-methylamine-bonil, diethylaminoethyl, dipropylamino, N-(n-butyl)-N-methylaminomethyl, di(n-pentyl)aminocarbonyl and the like.

Used here, the term "C1-6-monoalkanolamines" refers to the amino group in which one of the hydrogen atoms substituted C1-6-monoacylglycerols group, such as, for example, methylaminoquinoline, ethylenediamino, h-propylenecarbonate, isopropylaminocarbonyl, h-butylenediamine-, second -, butylenediamine, isobutyleneisoprene-, tert-butylaminoethyl - and 2-methylethylenediamine.

Ispoljzuemo hydrogen substituted C1-6-dialkylaminoalkyl group, such as, for example, dimethylaminocarbonylmethyl-, N-ethyl-N-methylaminoquinoline, diethylaminoethylamine, dipropylenetriamine-, N-(n-butyl)-N-methylaminoquinoline-, di(n-pentyl)aminocarbonylmethyl and the like.

Used here, the term "5 - or 6-membered heterocyclic system" refers to a monocyclic unsaturated or saturated system containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur and having 5 members, such as, for example, pyrrole, furan, thiophene, pyrrolin, dihydrofuran, dihydrothiophene, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazol, isothiazol, 1,2,3-oxadiazole, furazan, 1,2,3-triazole, 1,2,3-thiadiazole, or 2,1,3 - thiadiazole; aromatic monocyclic system, containing two or more nitrogen atoms and having 6 members, such as, for example, pyrazin, pyrimidine, pyridazine, 1,2,4-triazine, 1,2,3-triazine or tetrazine; non-aromatic monocyclic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and having 6 members, such as, for example, Piran, thiopyran, piperidine, dioxane, oxazin, isoxazine, Titian, oxacin, teasin, piperazine, thiadiazin, Dityatin the valence Deputy, which includes monocyclic unsaturated or saturated system containing one or more nitrogen atoms and having 5 or 6 members, such as, for example, pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidine, pyrazoline, piperidyl, piperazinil, pyrrolyl, 2-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholine, isothiazolin, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1,3-dioxolane and 1,4-DIOXOLANYL.

In a preferred embodiment of the present invention, the connection obshei formula I are selected from

< / BR>
where R1and R5independently are hydrogen; hydroxyl; C1-6-alkoxygroup or C1-6-alkyl, C3-6-cycloalkyl,2-6-alkenyl or2-6-quinil, optionally mono - or polyamidine halogen, and R4is hydrogen; or

R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of the formula I, and R1the same as defined above; or

R4together with R1represent one of the bonds in the double bond between the atoms 3 and 4 of formula I, and R5the same as defined above;

D represents-S(=O)2- or-S(=O)-.

In is hydrogen; C1-6-alkoxygroup or C1-6-alkyl, C3-6-cycloalkyl,2-6-alkenyl or2-6-quinil, optionally mono - or polyamidine halogen, and R4is hydrogen; or

R4together with R1represent one of the bonds in the double bond between the atoms 3 and 4 of formula I;

D represents-S(=O)(R7)=,

where R7is C1-6-alkyl; or aryl or heteroaryl, optionally mono - or polyamidine halogen, hydroxyl, C1-6-alkoxygroup, arroceros, arialcategory, a nitro-group, amino group, C1-6-monoalkyl or dialkylamino, cyano, acyl or C1-6-alkoxycarbonyl.

In another preferred embodiment of this invention the compound of General formula I are selected from

< / BR>
where R1, R5and R6independently are hydrogen; hydroxyl; C1-6-alkoxygroup or C1-6-alkyl, C3-6-cycloalkyl,2-6-alkenyl or2-6-quinil, optionally mono - or polyamidine halogen, and R4is hydrogen; or

R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of the formula I, and R1and R6the waiting atoms 3 and 4 of the formula I, and R5and R6such as defined above;

D represents-S(=O)2- or-S(=O)-.

The preferred General formula I is (Ia).

In another preferred embodiment of this invention, D represents-S(=O)2-.

In another preferred embodiment of this invention R1selected from hydrogen, C1-6-alkyl, C3-6-cycloalkyl or2-6-alkenyl. Preferably R1is hydrogen or C1-6-alkyl.

In another preferred embodiment of this invention R1together with R4represent one of the bonds in the double bond between the atoms 3 and 4 of formula I.

In another preferred embodiment of this invention R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of formula I.

In another preferred embodiment of this invention R2selected from hydrogen, hydroxyl, C1-6-alkyl, C3-6-cycloalkyl or2-6-alkenyl. Preferably R3is hydrogen or C1-6-alkyl.

In another preferred embodiment of this invention R3selected from R8, -OR8, -NR8R9or aryl, with and the scrap; (C3-6-cycloalkyl)C1-6-alkyl, and 3-6-membered system includes one, two or three nitrogen atom, oxygen or sulfur; or a linear or branched C1-18-alkyl, optionally substituted with halogen, hydroxyl, C1-6-alkoxygroup, C1-6-alkylthiophene,3-6-cycloalkyl, aryl; R9is hydrogen, C1-6-alkyl or C3-6-cycloalkyl; or R8and R9together with the nitrogen atom form a 4-6-membered cycle, predominantly 1-pyrrolidyl, piperidine or morpholinyl cycle.

In another preferred embodiment of this invention R3choose from a secondary3-6-alkyl, tertiary4-6-alkyl, C3-6-cycloalkyl or (C3-6-cycloalkyl)methyl, optionally mono - or polishmaster 1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup. R3preferably selected from isopropyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, 2,3-dimethylbutyl, 1-ethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-2,2-dimethylpropyl, 2,3,3-trimethylbutane, 2-methylbutyl, 1,5-dimethylhexane, 3-methylbutyl, 3-methylhexane, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclohexylmethyl.

In another preferred embodiment of this invention R2and R3together with the nitrogen atom form a six-membered cycle, optionally substituted at the 2 position of the C1-6is an alkyl group, preferably selected from methyl, ethyl or isopropyl. Six-membered cycle is mainly a piperidine, piperazine or thiomorpholine cycle.

In another preferred embodiment of this invention R7selected from C1-6-alkyl, phenyl or pyridyl.

In another preferred embodiment of the present invention And, together with carbon atoms 5 and 6 of formula I forms a 5-membered heterocyclic system containing one heteroatom selected from nitrogen and sulfur, a 5-membered heterocyclic system containing two heteroatoms selected from nitrogen, oxygen and sulfur, 6-membered aromatic heterocyclic system containing two or three nitrogen atom, a 6-membered nonaromatic heterocyclic system containing one or two atoms selected from nitrogen, oxygen and sulfur; however, the heterocyclic system optionally mono - or tizamidine halogen; C1-12-alkyl, C3-6-cycloalkyl; cyano, cyanomethyl; perhalogenated; sulfamoylbenzoyl, moreover, the aryl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxyl or C1-6-alkoxygroup; C1-6-alkoxycarbonyl-C1-6-alkyl; carbamylation; carboxy-C1-6-alkyl; arroceros; (1,2,4-oxadiazol-5-yl)- or (1,2,4-oxadiazol-3-yl)C1-6-alkyl, with oxadiazolyl group optionally substituted C1-6-alkyl or C3-6-cycloalkyl, or 5-6-membered nitrogen cycle, optionally substituted by phenyl or C1-6-alkyl.

Together with carbon atoms 5 and 6 preferably forms a thieno[3,2-e] -cycle or pyrrolo[3,2-e]-cycle, thiophene, imidazole, thiazole, pyrazole, isoxazol or isothiazol, pyrazino[2,3-e], pyrimido[4,5-e], pyrimido[5,4-e]-, pyridazino[4,5-e] pyridazino[4,3-e]-cycle, thiopyran, piperidine, dioxane, oxazin or Titian.

The preferred compounds of this invention are

7-cyano-3-isopropylamino-6-methyl-4H-thieno[2,3-e] -1,2,4-thiadiazine 1,1-dioxide;

7-cyano-6-methyl-3-propylamino-4H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-isobutylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(1-methylheptan)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(1-ethylphenyl)amino-4H-titlar-3-(1-etylhexyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclohexylethylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

ethyl-3-(6-chloro-1,4-dihydro-1,1-dioxolane[3,2-e]-16,2,4-thiadiazin-3-ylamino)butanoate;

3-(6-chloro-1,4-dihydro-1,1-dioxolane[3, 2-e] -16,2, 4-thiadiazin-3-ylamino)butyric acid;

6-chloro-3-(3-hydroxy-1-methylpropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

(R)-6-chloro-3-(phenylethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

(S)-3-Deut-butylamino-6-chloro-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-isopropylamino-4H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclopentylamine-4H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

6-bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

3 isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-fluoro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

3 cyclobutylamine-5,6-dimethyl-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

3 cyclopentylamine-5,6-dimethyl-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

3 isopropylamino-6,7-dimethyl-4H-thieno[2,3-e] -1,2,4-thiadiazine 1,1-dioxide;

3 cyclobutylamine-6,7-dimethyl-4H-thieno[2,3-e] -1,2,4-thiadiazine 1,1-dioxide;

3 cyclopentylamine-6,7-dimethyl-4H-thieno[2,3 is pilipino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5-chloro-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5-chloro-6-methyl-3-isopropylamino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-isopropylamino-5-methyl-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclopentylamine-5-methyl-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-fluoro-3-propylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-fluoro-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5-fluoro-3-propylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5-fluoro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

3 isopropylamino-7-methyl-4H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclobutylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(2-hydroxyethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

()-3-Exo-bicyclo[2.2.1]hept-2-ylamino-6-chloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

(R)-6-chloro-3-(2-hydroxypropyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5,6-dibromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclohexylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(furan-2-ylmethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chlorine is diazen 1,1-dioxide;

6-chloro-3-(2-methylallyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide or

6-cyano-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide.

Compounds of the present invention interact with potassium channels and, therefore, act as the starting substances or as blockers TOATP-regulated potassium channels, which makes them useful in the treatment of various diseases of the cardiovascular system, such as cerebral ischemia, hypertension, coronary heart disease, angina and coronary heart disease; pulmonary system; gastrointestinal system; cerebral nervous system and the endocrine system.

As someATP-opening substances able to deal with vasospasm in basilar and cerebral arteries, the compounds of the present invention can be used to treat vasospastic violations, such as subarachnoid hemorrhage and migraine.

Compounds of the present invention can also be used to treat diseases associated with reduced blood flow to skeletal muscle, such as Raynaud's disease and intermittent claudication.

In addition, the compounds of the present invention mobilnost muscle (detrusor muscle instability), derivative syndrome infravesical obstruction, and therefore, kidney stones, facilitating their passage through the urethra.

Compounds of the present invention can also be used to treat symptoms associated with disorders of the gastro-intestinal mobility, such as irritable bowel syndrome. In addition, the compounds can be used to prevent preterm birth and the treatment of dysmenorrhea.

Substances that open potassium channels, hyperpolarized neurons and inhibit the secretion of neurotransmitters, and it is expected that such compounds can be used for treatment of various diseases of the Central nervous system such as epilepsy, ischemia and neurodegenerative diseases, and to relieve pain.

In addition, substances that open potassium channels, promotirovat hair growth, therefore, the compounds of the present invention can be used to treat baldness.

Substances that open potassium channels, relaxes smooth muscle, therefore, the compounds of the present invention can be used to treat urinary incontinence.

In such diseases as hyperplasia of pancreatic ostrovkovaya can be used to decrease insulin secretion. With obesity often occurs hyperinsulinemia and insulin resistance. This condition may lead to the development of non-insulin dependent diabetes mellitus (NIDDM). Expect that matter, opening potassium channels, and therefore, the compounds of the present invention can be applied to reduce hyperinsulinemia and thereby to prevent diabetes and reduce obesity. When explicit NIDDM treatment of hyperinsulinemia with substances that open potassium channels, and therefore, the compounds of the present invention may be useful to restore sensitivity to glucose and normal insulin secretion.

In case of early insulin-dependent diabetes mellitus (IDDM) or pre-diabetic cases can be applied substances, opening potassium channels, and therefore, the compounds of the present invention to induce dormancy pancreatic cells that can prevent the development of autoimmune diseases.

Substances of the present invention, the opening of potassium channels, can be taken in combination with immunosuppressants or agent type nicotinamide, which will reduce autoimmune degeneration of the beta cells.

The unification of the rest of the beta cells with treatment what is another aspect of the present invention. Insulin dependent or type 1 diabetes (IDDM), and a subsequent attack IDDM (also known as 1.5, for example, patients with non-insulin-dependent type 2 diabetes (NIDDM) with autoreactivity against epitopes of beta-cells, which then causes insulin dependence) are self-reactive circulating monocytes/lymphocytes that are returned to the islets/beta cells and produce their own cytokines. Some of these cytokines (eg, interleukin-l (IL-1), factor and tumor necrosis (TNFa) and interferon (IFN) are specifically toxic relative to beta-cells, for example, through the induction of nitric oxide (NO) and other free radicals. Inhibition of this cytotoxicity, for example, through the introduction of nicotinamide (NA), its derivatives or other cytokinetic connections pre-diabetic/diabetic patients receiving treatment RNO-connection is an example of this aspect of the invention. Nicotinamide belongs to the family of b-vitamins and is a derivative of nicotinic acid in the amidation of carboxyl group. It does not affect the pharmacological properties of nicotine. NA is converted to NAD+, which acts as a coenzyme for proteins, involved in tissue respiration. Predpoll the a-cells. Animal experiments and early Nasledie experiments in humans have shown a protective role of such compounds against IDDM, and cytokine/immune-mediated destruction of beta cells.

Another aspect of this proposal concerns the application of RDF-connection, by itself or in combination with an inhibitor of cytokine/immune-mediated damage to the beta cells in transplantation, for example, islet transplantation in diabetic patients. The use of one or both of these methods of treatment can reduce the risk of rejection of transplanted islets/beta cells of the pancreas.

Compounds of the present invention, which act as blockers TOATPchannels can be used for the treatment of NIDDM.

Preferably the compounds of the present invention can be used for treatment or prevention of diseases of the endocrine system, such as hyperinsulinemia and diabetes.

Thus, another aspect of this invention concerns compounds of General formula I or its pharmaceutically acceptable salt accession acid for use as a therapeutically acceptable substances, preferably for use as terapeuticas is ome, the invention also concerns the use of the claimed compounds of formula I in the form of medicines useful for treatment of hyperinsulinemia or for the treatment or prevention of diabetes.

In another aspect, the present invention relates to methods of obtaining the above mentioned compounds. These methods include

a) reaction of compounds of formula II

< / BR>
where a, b, D, R1and R4such as defined above, and Z represents tsepliaeva group, such as alkoxygroup, allylthiourea, halogen, preferably chlorine, bromine, iodine, trimethylaminuria or methylsulphonyl,

with the compound of the formula III

< / BR>
where R2and R3defined above,

with the formation of compounds of General formula I;

b) reaction of compounds of formula IV

< / BR>
where R1represents hydrogen, and a, b, D, and X are such as defined above, or represents NH and R1The A , D and X are such as defined above,

with the compound of the formula III or a suitable salt in the presence of P2O5and high-boiling tertiary amine or a suitable salt with the formation of compounds of General formula I;

C) reaction of compounds of formula IV

< / BR>
where R1is hydrogen and a, b, D and X such as A III or a suitable salt in the presence of titanium tetrachloride and the solvent, with which it can form a complex, such as, for example, tetrahydrofuran or a mixture of toluene and anisole, with the formation of compounds of General formula I;

g) reaction of compounds of formula V

< / BR>
where R1and As such, as defined above,

with the compound of the formula IV

R3NCO,

where R3such as defined above,

with the formation of compounds of General formula I, where D is the SO2In is >NR5, R2is N, and R4and R5together form a bond;

d) reaction of compounds of formula V

< / BR>
where R1and As such, as defined above,

with the compound of the formula VII

R3NC(=O)Cl (VII),

where R3defined above,

with the formation of compounds of General formula I, where D is the SO2In is >NR5, R2is N, and R4and R5together form a bond;

e) reaction of compounds of formula V

< / BR>
where R1and As such, as defined above,

with the compound of the formula VIII

< / BR>
where Y represents NH or S,

or a suitable salt with the formation of compounds of General formula I, where D is the SO2In is >NR5, R4and R5together form a bond, and R211is R1or EtOC(=O) R1and As such, as defined above,

with the compound of the formula X

R3N=C=S (X),

where R3such as defined above,

with the formation of the adduct, which can be any of the two structures XI or XII or represent a mixture of both

< / BR>
< / BR>
any of them with the closure of the cycle, for example, when processing

with phosgene in a suitable solvent, forms a compound of General formula I, if R11is R1where D represents S(=O)2In is >NR5, R2is H and R4and R5together form a bond, and the compound of General formula XIII, if R11is EtOC(=O);

< / BR>
C) hydrolysis and subsequent decarboxylation of compounds of General formula XIII

< / BR>
with the formation of compounds of General formula I, where D is S(=O)2In is >NR5, R1and R2is H and R4and R5together form a bond, for example, by heating the parent compound in aqueous base.

Starting materials are either known compounds or compounds that can be obtained by analogy with getting known compounds or by analogy with the known is -22 (Russ.) (1976), Torliss J. G., US 3641017 (1972), Kotovskaya S. K., and others, Khim-Farm. Zh., 13, 54-57 (Russ.) (1979), Meyer R. F. , J. Heterocycl. Chem., 6, 407-408 (1969), Hattori M., Yoneda, M. and Goto, M., Bull. Chem. Soc. Jap., 46, 1890-1 (1973), Williams T. R. and D. J. Cram, J. Org. Chem., 38, 20-26 (1973), Barnes, A. C., Kennewell, P. D. And Taylor, J. B., J. Chem. Soc. Chem. Commun., 1973, 776-777, Stoss and Satzinger, Chem. Ber., 109., 2097 (1976), G. Kresze, Hatjiissaak A., Phosphorus Sulfur, 29, 41-47 (1987), Dillard R. D., Yen, T. T., P. Stark, D. E. Pavey, J. Med. Chem., 23, 717-722 (1980).

PHARMACOLOGICAL METHODS

The ability of compounds to interact with potassium channels can be defined in various ways. If you use a technique with patch-clamp patch-clamp) (Hamin O. P., Marty A., Neher E., Sakmann Century and Sigworth F. J., Plugers Arch., 391, 85-100 (1981)), you can register the ionic current through a single channel of the cell.

The activity of these compounds as substances that open potassium channels, can be measured as a relaxation of aortic rings rat in accordance with the following procedure.

Cut out a section of rat thoracic aorta between the aortic arch and the diaphragm and preparing medicines for the research in the form of rings, as described by Taylor, P. D., and others, Britt. J. Pharmacol., 111, 42-48 (1994).

After 45 minutes of equilibrium when the tension of 2 g are reducing drugs, reaching 80% of the maximum response, using an appropriate concentration of phenylephrine. When re is but small amounts, using a semi-log molar increments with an interval of 2 minutes. Relaxation is expressed as a percentage of the tension reducing (contracted tension). Connectivity is expressed as the concentration required to achieve 50% relaxation of the tissue.

Relaxation of rings of rat aorta

Example - EC50micro M

4 - 2,8

6 - 20,5

In-cell of the pancreas can be defined opening TO aATPchannels, and measuring the subsequent change in the concentration of free CA2+in the cytoplasm according to the method Arkhammar, P., and others, J. Biol. Chem., 262, 5448-5454 (1987).

Outflow86Rb+from cell line

Cell line RIN 5F are cultivated in a nutrient medium RPMI 1640 with Glutamax I, supplied with 10% serum, fetal cow (from GibcoBRL, Scotland, UK), supporting in an atmosphere of 5% CO2/95% air at 37oC. the Cells are separated with a solution of Trypsin-EDTA (GibcoBRL, Scotland, UK), resuspended in a nutrient medium, add 1 millicurie/ml86Rb+and re-seeded in plates for micrometrology (set 3596 on 96 wells, sterile, from Costar Corporation, MA, USA) at a density of 50,000 cells/cell 100 l/cell and cultured for 24 hours before use in the study.

Plates are washed 4 times with ringer buffer the aqueous or the compounds, dissolved in DMSO. After incubation with a lid for 1 hour at room temperature, transferred to 50 l of the supernatant in PicoPlates (Packard Instrument Company, CT, USA) and add 100 l MicroScint40 (Packard Instrument Company, CT, USA). The plate is considered in a TopCount (Packard Instrument Company, CT, USA) for 1 min/cell program32P.

Calculation EC50and Emaxproduced by the SlideWrite (Advanced Graphics Software, Inc., CA, USA), using the estimated graph with four parameters: y = (a-d)/(1+(x/C)b)+d, where a = activity defined at zero concentration, b = slope coefficient, C = concentration in the middle of the curve and d = activity, some at very high concentrations.

Increased Rb-outflow cells RIN 5F

Example - EC50micro M

4 - 5,5

6 - 31

The compounds of this invention is effective at a dosage in a wide range. In the main, satisfactory results are obtained with a dosage of from about 0.05 to 1000 mg, preferably from about 0.1 to 500 mg, per day. The most preferred dose is from about 1 to 100 mg per day. The exact dose will depend on the route of administration, take the form of a patient to be treated, the body weight of the subject to treatment of the patient and the preference and experience of the attending physician yedinenie to the appropriate or desired site of action, such as oral way or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, while the preferred oral route of administration.

Typical compositions include a compound of formula I or its pharmaceutically acceptable salt accession acid together with a pharmaceutically acceptable excipient, which may be a carrier or a diluent, or the connection can be diluted with a carrier, or can be enclosed inside the carrier, which may be a capsule, sachet, paper or other container. In the preparation of compositions you can use any technology to obtain pharmaceutical compositions. For example, the active compound is usually mixed with a carrier, or diluted by a carrier, or enter into the inside of the carrier, which may be an ampoule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a carrier, excipient or medium for the active connection. The active compound can be adsorbed on a granular solid container, for example, in the sachet. Some example is Noah castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, monoglycerides of fatty acids and polyvinylpyrrolidone. The preparations may also include wetting agents, emulsifiers and suspendresume agents, preservatives, sweetening agents or flavoring agents. The preparations of this invention can be designed to provide rapid, prolonged or delayed release of the active ingredient after administration to the patient, applying well-known to experts in the procedure.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salts, influencing osmotic pressure, buffers and/or tinted substances and similar materials that do not enter in harmful interaction with the active compounds.

For parenteral application, particularly suitable solvents or suspension for injection, predominantly aqueous solutions of the active compound dissolved in polyhydroxyalkane castor oil.

For oral administration are particularly suitable tablets, pills or capsules having talc and/or carbohydrate as a carrier, a binder or the like. Predpochtitel is In cases when you can use sweetened media, you can use syrup or elixir.

Usually connections are distributed in the form of standard forms, about 1-100 mg standard dosage form in a pharmaceutically acceptable carrier.

A typical tablet suitable for use in this way, can be prepared by conventional means tabletting and contains:

Active connection - 5.0 mg

Lactose (Lactosum) and 67.8 mg Ph.Eur.

Avicel- to 31.4 mg

Amberlite- 0.25 mg Ph.Eur.

EXAMPLES

Next, a method of obtaining compounds of formula I are illustrated by the following examples, which, however, are not restrictive.

EXAMPLE 1

7-Cyano-3-isopropylamino-6-methyl-4H-thieno[2,3-e] -1,2,4-thiadiazine 1,1-dioxane

a) 4-Cyano-2-hydrazinophenyl-5-methylthiophene-3-sulfonamide

Methyl-4-cyano-5-methyl-3-allfamilies-2-carboxylate (2.9 g) was obtained from methyl 3-amino-4-cyano-5-methylthiophene-2-carboxylate in analogy to known procedures, for example the work of F. Junquera and others, Eur. J. Med. Chem. , 23, 329 (1988), suspended in 10 ml of ethanol. Add hydrazinoacetate (2 ml) and the mixture is stirred for 1 hour at room temperature, and then vypivaut with water and dried, getting yellow crystals indicated in the title compound (yield 1.63 g); so pl. 186-191oC.

1H NMR (DMSO-d6), (M. D. ): to 7.25 (broad, 5H, NH/NH2), of 2.51 (s, 3H, CH3).

b) 4-Cyano-5-methyl-3-allfamilies-2-carbonylated

A solution of sodium nitrite (to 0.47 g) in 5 ml of water is added drop by drop to a stirred solution of 4-cyano-2-hydrazinophenyl-5-methylthiophene-3-sulfonamida (1.6 g) in 38 ml of 1 M hydrochloric acid at 0oC. the resulting mixture was stirred for 30 minutes at 0oC and then filtered. The residue on the filter is washed with water and dried in vacuum, obtaining 1.35 g specified in the connection header.

1H NMR (DMSO-d6), (M. D.): 7,75 (broad, 1H, NH2), a 2.75 (s, 1H, CH3).

C) 4-Cyano-2-ethoxycarbonyl-5-methylthiophene-3-sulfonamide

4-Cyano-5-methyl-3-allfamilies-2-carbonylated (1.35 g) is added in small portions over 5 minutes to 50 ml of absolute ethanol at the boiling point under reflux. The resulting solution was refluxed for 5 minutes and then evaporated. Then, the crystalline residue is triturated with 20 ml of ethyl acetate. The crystals are filtered, washed with ethyl acetate and dried, obtaining specified in sagalowsky, 2H, CH2), of 2.51 (s, 3H, CH3), a 1.25 (t, 3H, CH3).

g) N-(4-Cyano-2-ethoxycarbonyl-5-methyl-3-thienylmethyl)-N'-isopropyltoluene

A mixture of 4-cyano-2-ethoxycarbonyl-5-methylthiophene-3-sulfonamida (0.50 g), potassium carbonate (0.36 g) and isopropylethylene (300 l) in 10 ml of dry acetone is heated under 55oC for 18 hours and then evaporated to dryness. The residue is dissolved in 10 ml of water and adjusted pH to 2 by adding one drop of 1 M hydrochloric acid. The precipitate is filtered off, washed with a small amount of water and dried, obtaining 0.34 g specified in the connection header; so pl. 169-171oC.

d) Ethyl-7-cyano-3-isopropylamino-6-methyl-4H-thieno[2,3-e]-1,2,4-thiadiazin-4-carboxylate 1,1-dioxide

To a stirred solution of N-(4-cyano-2-ethoxycarbonyl-5-methyl-3-thienylmethyl)-N'-isopropyltoluene (0.3 g) and triethylamine (320 l) in 10 ml of dry THF at 0oWith add 750 liters of 20% solution of phosgene in toluene. The mixture was stirred at 0oC for 1 hour and then evaporated to dryness. The residue is triturated with 10 ml of water, filtered off, washed on the filter with water and dried, obtaining 0.24 g of crude compound indicated in the title; so pl. 116-119oC. the Product is used for the next stage without purification.

oC.

1H NMR (DMSO-d6), (M. D.): 11,35 (s, 1H, NH), 7,55 (broad d, 1H, NH), 3,98-of 3.77 (m, 1H, CH), 2,50 (s, 1H, CH3) and 1.15 (d, 6N, CH3).

EXAMPLE 2

7-Cyano-6-methyl-3-propylamino-4H-thieno[2,3-e] -1,2,4-thiadiazine 1,1-dioxide

a) N-(4-Cyano-2-ethoxycarbonyl-5-methyl-3-thienylmethyl)-N'-propylthiophene

Specified in the title compound is obtained from 4-cyano-2-ethoxycarbonyl-5-methylthiophene-3-sulfonamida and propalestinian by analogy with the synthesis described in example 1-g, so pl. 167-168oC.

b) Ethyl-7-cyano-6-methyl-3-propylamino-4H-thieno[2,3-e]-1,2,4-thiadiazin-4-carboxylate 1,1-dioxide

Specified in the title compound is obtained from N-(4-cyano-2-ethoxycarbonyl-5-methyl-3-thienylmethyl)-N'-proportionately by analogy with the procedure described in example 1-d; so pl. 175-179oC.

C) 7-Cyano-6-methyl-3-propylamino-4H-thieno[2,3-e] -1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound obtained by hydrolysis and subsequent the and by analogy with the synthesis, described in example 1-e, so pl. 293-298oC.

1H NMR (DMSO-d6), (M. D.): the 11.6 (s, 1H, NH), the 7.65 (broad, 1H, NH), 3,14 (DD, 2H, CH2), 2,58 (s, 1H, CH3), 1,65-1,4 (m, 2H, CH2), to 0.89 (t, 3H, CH3).

EXAMPLE 3

6-Chloro-3-(3-methylbutyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1 - dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-(3-methylbutyl)thiourea

Tert-piperonyl potassium (0,49 g, 4.4 mmol) are added to a solution of 5-amino-5-chlorothiophene-2-sulfonamida (5 ml) with stirring in a bath with ice. After 10 minutes, to the resulting suspension was added a drop of 3-methylbutylamine (0.31 g, 2.4 mmol) and the mixture was stirred at 0-20oWith over 3.5 hours. A large part of the solvent is evaporated at 40oWith and the residue is placed in 25 ml of water, treated with decolorizing charcoal and filtered. Acidification of the filtrate with acetic acid to pH 3-4 and filtering to give 0.21 g specified in the connection header; so pl. 114-115oC (decomposes).

1H NMR (DMSO-d6), (M. D.): 0,85 (d, 6N, HSN3), 1,40 (Quartet, 2H, CH2), 1,50 (m, 1H, CH), 3.45 points (Quartet, 2H, CH2), 6,45 (broad, 2H, NH2), of 6.65 (s, 1H, H-4), 8,30 (broad t, 1H, NH), 11,3 (Shir. c, 1H).

b) 6-Chloro-3-(3-methylbutyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

To g, 0.42 mmol) and dry triethylamine (amount of 0.118 ml, 0.85 mmol) in dry tetrahydrofuran (3 ml) under stirring at 0oC. the Mixture is stirred for 2 hours at 0oWith and evaporated to dryness. Conduct crystallization from ethyl acetate and the precipitate are filtered, washed with water and dried, obtaining 38 mg (27%) specified in the connection header; so pl. 230-231oC.

1H NMR (DMSO-d6), (M. D.): 0,90 (d, 6N, HSN3), 1,40 (Quartet, 2H, CH2), to 1.60 (m, 1H, CH), 3,20 (Quartet, 2H, CH2), 7,05 (s, 1H, H-5), 7,25 (broad s, 1H, NH), 10,95 (s, 1H, NH).

Mass spectrum: m/e 307 (M+).

EXAMPLE 4

6-Chloro-3-(1-methylheptan)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-(3-methylheptan)thiourea

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and 1-methylheptacosane by analogy with the procedure described in example 3-a; get syrup (yield 29%).

1H NMR (DMSO-d6), (M. D.): of 0.90 (t, 3H, CH3), of 1.10 (d, 3H, CH3), 1,25 (m, 8H), of 1.47 (quintet, 1H, CH), and 6.5 (broad s, 2H, NH2), of 6.65 (s, 1H, H-4), 7,95 (broad, 1H, NH), and 11.2 (broad s, 1H).

b) 6-Chloro-3-(1-methylheptan)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

Ukazanniy with the procedure described in example 3-b (71% yield); so pl. 179-181oC.

1H NMR (DMSO-d6), (M. D.): of 0.85 (t, 3H, CH3) and 1.15 (d, 3H, CH3), of 1.30 (m, 8H), of 1.45 (m, 2H, CH2in ), 3.75 (quintet, 1H, CH), 7,05 (s, 1H, H-5), 7,10 (broad s, 1H, NH), 10,65 (s, 1H, NH).

Mass spectrum: m/e 349 (M+).

EXAMPLE 5

6-Chloro-3-(1-ethylphenyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-(3-ethylphenyl)thiourea

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and 1-ethylphenethylamine by analogy with the procedure described in example 3-a; get syrup (yield 36%).

lH NMR (DMSO-d6), (M. D.): 0.8 in (2 Quartet, 6N, HSN3), 1,2 (m, 4H), 1,5 (m, 4H), 4,20 (sextet, 1H, CH), 6,55 (broad, 2H, NH2), of 6.65 (s, 1H, H-4), a 7.85 (broad d, 1H, NH), and 11.3 (broad s, 1H, NH).

b) 6-Chloro-3-(1-ethylphenyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound is obtained from N-(3-amino-5-chloro-2-thienylmethyl)-N'-(3-ethylphenyl)thiourea by analogy with the procedure described in example 3-b (yield 35%); so pl. 165-167,5oC.

1H NMR (DMSO-d6), (M. D.): 0,85 (2 Quartet, 6N, HSN3), 1,25 (m, 4H), of 3.65 (m, 1H, CH), 7,0 (broad, 1H, NH), 7,05 (s, 1H, H-5), 10,65 (W is 2-f]-1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-(3-methylbutyl)thiourea

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and 2-methylbutyl isothiocyanate by analogy with the procedure described in example 3 (yield 28%); so pl. 116,5-118oC.

1H NMR (DMSO-d6), (M. D.): 0.8 in (2 d, 6N, HSN3), 1,10 (m, 1H), 1,30 (m, 1H), 1,65 (m, 1H), 3,40 (m, 2N + HDO, CH2), 6,45 (broad, 2H, NH2), of 6.65 (s, 1H, H-4), of 8.25 (broad t, 1H, NH), and 11.3 (broad s, 1H).

b) 6-Chloro-3-(2-methylbutyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound is obtained from N-(3-amino-5-chloro-2-thienylmethyl)-N'-(3-methylbutyl)thiourea by analogy with the procedure described in example 3-b (yield 39%); so pl. 232-234oC.

1H NMR (DMSO-d6), (M. D.): 0,85 (2 d, 6N, HSN3) and 1.15 (m, 1H), 1,40 (m, 1H), 1,60 (m, 1H), 3,10 (m, 2H, CH2), 7,05 (s, 1H, H-5), 7,25 (broad, 1H, NH), 10,85 (broad s, 1H, NH).

Mass spectrum: m/e 307 (M+).

Elemental analysis

Calculated for C10H14ClN3O2S2,%: 39,02; N 4,58; N 13,65.

Found,%: C 38,98; N 4,72; N 13,40.

EXAMPLE 7

6-Chloro-3-(2-etylhexyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-tamilselvi is vanamide hydrochloride and 1-methylhexaneamine by analogy with the procedure described in example 3-a; get syrup (yield 43%).

1H NMR (DMSO-d6), (M. D.): of 0.85 (t, 3H, CH3), of 1.10 (d, 3H, CH3), 1,25 (m, 6N), a 1.45 (m, 2H), 4,25 (m, 1H, CH), 6,50 (Shir. 2H, NH2), 6,66 (c. 1H, H-4), to 7.93 (broad, 1H, NH), and 11.3 (broad s, 1H, NH).

b) 6-Chloro-3-(2-etylhexyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound is obtained from N-(3-amino-5-chloro-2-thienylmethyl)-N'-(1-etylhexyl)thiourea by analogy with the procedure described in example 3-b (yield 63%); so pl. 158-162oC.

1H NMR (DMSO-d6), (M. D.): of 0.85 (t, 3H, CH3) and 1.15 (d, 3H, CH3), 1,25 (m, 6N), a 1.45 (m, 2H), 3.45 points (m, 1H, CH), 7,05 (s, 1H, H-5), to 7.15 (broad s, 1H, NH), is 10.75 (broad s, 1H, NH).

Mass spectrum: m/e 335 (M+).

EXAMPLE 8

6-Chloro-3-(cyclopentyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-cyclopentylamine

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and cyclopentylpropionate by analogy with the procedure described in example 3 (yield 46%).

1H NMR (DMSO-d6), (M. D. ): 1,30-1,70 (m, 6N), 1,90 (m, 2H), 4,40 (sextet, 1H, CH), 6,55 (broad, 2H, NH2), of 6.65 (s, 1H, H-4), 8,15 (broad d, 1H, NH), and 11.2 (broad s, 1H, NH).

oC.

1H NMR (DMSO-d6), (M. D.): 1,40-1,70 (m, 6N, CH3), 1,90 (m, 2H), 3,95 (sextet, 1H, CH), 7,05 (s, 1H, H-5), and 7.3 (broad, 1H, NH), 10,70 (SL.s, 1H, NH).

Mass spectrum: m/e 305 (M+).

EXAMPLE 9

6-Chloro-3-(cyclohexylmethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-cyclohexylethylamine

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and cyclohexyldimethylamine by analogy with the procedure described in example 3-a; get syrup (yield 8%).

1H NMR (DMSO-d6), (M. D.): 0,95 (m, 2H), 1,25 (m, 3H), 1.70 to (m, 6N), of 3.45 (d, 2H, CH2), of 4.45 (broad, HDO+NH), of 6.65 (s, 1H, H-4).

b) 6-Chloro-3-(cyclohexylmethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound is obtained from N-(3-amino-5-chloro-2-thienylmethyl)-N'-(1-cyclohexylmethyl)thiourea by analogy with the procedure described in example 3-b (yield 68%); so pl. >200oC (decomposes).

1H NMR (DMSO-d6), (M. D.): 0,90 (m, 2H) and 1.15 (m, 3H), 1.70 to (m, 6N), was 3.05 (t, 2H, CH2), 7,05 (s, 1H, H-5), 7,25 (broad, 1H, NH), 10,95 (broad s, 1H, NH).

Mass spectrum: m/e 333 (M+).

An EXAMPLE of the Ino-5-chlortan-2-yl)sulfonyl]touraid}of butanoate

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and 3-isothiocyanatobenzene by analogy with the procedure described in example 3 (yield 93%).

1H NMR (DMSO-d6), (M. D.): of 1.18 (d, 3H, CH3), of 1.20 (t, 3H, CH3), 2,61 (m, 2H, CH2), 4,08 (Quartet, 2H, CH2), 4,58 (m, 1H, CH), 6,46 (broad s, 2H, NH2), of 6.65 (s, 1H, H-4), a 8.34 (broad d, 1H, NH), 11,35 (broad s, 1H).

b) Ethyl-3-(6-chloro-1,4-dihydro-1,1-dioxolane[3,2-e] -12,2,4-thiadiazin-3-ylamino)butanoate

Specified in the title compound is obtained from ethyl-3-{3[(3-amino-5-chlortan-2-yl)sulfonyl] touraid} butanoate by analogy with the procedure described in example 3-b, except that the product is cleaned by way of column chromatography (yield 71%); so pl. 151-155oWith (ethyl acetate).

1H NMR (DMSO-d6), (M. D.): of 1.18 (t, 3H, CH3), of 1.20 (d, 3H, CH3), to 2.57 (m, 2H, CH2), 4,07 (Quartet, 2H, CH2), 4,17 (m, 1H, CH), 7,05 (s, 1H, H-5), 7,25 (broad, 1H, NH), 10,99 (s, 1H, NH).

Mass spectrum: m/e 351/353 (M+).

Elemental analysis

Calculated for C11H14Cl1O4S20.2 ethyl acetate,%: 38,36; N 4.26 Deaths; N 11,37.

Found,%: C 38,35; N 4,18; N 11,58.

EXAMPLE 11

3-(6-Chloro-1,4-dihydro-1,UP>2
,2,4-thiadiazin-3-ylamino)butanoate (0.5 g, of 1.42 mmol) hydrolyzing to acid, stirring in 5 ml of 2 n sodium hydroxide for 2 hours at room temperature. The solution is treated with decolorizing charcoal, filtered and acidified with 4 M hydrochloric acid to pH 2. The precipitate are filtered, washed with water and dried, obtaining 294 mg (64%) specified in the connection header; so pl. 218-223oC.

1H NMR (DMSO-d6), (M. D.): 1,19 (d, 3H, CH3), 2.49 USD (m, 2H, CH2), 4,10 (m, 1H, CH), 7,06 (s, 1H, H-5), 7,25 (broad, 1H, NH), 10,99 (s, 1H, NH), 12,38 (broad s, 1H, HE).

Mass spectrum: m/e 305/307 (M-N2O)+.

Elemental analysis

Calculated for C9H10N3Cl1O4S2,%: 33,39; N 3,11; N 12,98.

Found,%: C 33,62; N 3,11; N 12,81.

EXAMPLE 12

6-Chloro-3-(3-hydroxy-1-methylpropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Toluene (5 ml) is cooled to 10oWith and add sociallyengaged (114 mg, 3 mmol), and then of 0.53 ml of tetrahydrofuran. Ethyl-3-(6-chloro-1,4-dihydro-1,1-dioxolane[3,2-e] -12,2,4-thiadiazin-3-ylamino)butanoate (352 mg, 1 mmol) are added to this cooled solution and the mixture is stirred for 2 hours at 0oC and then at room temperature is islote. The mixture is extracted with ether (3 x 30 ml) and the organic phase is washed with water, dried and evaporated to dryness. The crude product is mixed with a solid substance, which was formed in the aqueous phase, and finally cleaned by way of column chromatography on silica with a mixture of ethyl acetate/methanol (9: 1) as eluent, receiving 120 mg (39%) specified in the connection header; so pl. 199-203oC.

1H NMR (DMSO-d6), (M. D.): to 1.14 (d, 3H, CH3), of 1.65 (m, 2H, CH2), of 3.48 (m, 1H, CH2), 3,90 (m, 1H, CH), 4,60 (broad s, 1H, HE), 7,06 (s, 1H, H-5), 7,17 (broad, 1H, NH), 10,86 (s, 1H, NH).

Mass spectrum: m/e 309/311 (M+).

Elemental analysis

Calculated for C9H12N3Cl1O3S20.15 ethyl acetate, %: 35.70 Barm; N 4,12; N 13,01.

Found,%: 35.7; H 4,1; N 13,1.

EXAMPLE 13

(R)-6-Chloro-3-(1-phenylethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

a) (R)-N-(3-Amino-5-chloro-2-thienylmethyl)-N'-(1-phenylethyl)thiourea

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and D-methylbenzyl isothiocyanate by analogy with the procedure described in example 3 (yield 96%, messy product).

1H NMR (DMSO-d6), (M. D.): a 1.46 (d, 3H, CH3 1H).

b) (R)-6-Chloro-3-(1-phenylethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound is obtained from crude (R)-N-(3-amino-5-chloro-2-thienylmethyl)-N'-(1-phenylethyl)thiourea by analogy with the procedure described in example 3-b, except that the product is cleaned by way of column chromatography on silica with a mixture of dichloromethane/methanol (19:1) as eluent (yield 17%); so pl. 218-220oWith (ethyl acetate).

1H NMR (DMSO-d6), (M. D.): to 1.48 (d, 3H, CH3), equal to 4.97 (quintet, 1H, CH), 7,10 (s, 1H, H-5), of 7.2 to 7.4 (m, 5H, AGN), 7,73 (broad, 1H, NH), 10,81 (s, 1H, NH).

Mass spectrum: m/e 341/343 (M+).

Elemental analysis

Calculated for C13H12N3Cl1ABOUT2S2,%: 45,68; N 3,54; N 12,29.

Found,%: C 45,83; N 3,55; N 12,04.

EXAMPLE 14

(S)-3-Deut-Butylamino-6-chloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) and (S)-(+)-sec-butylamine (0,31 ml, 3.0 mmol) is stirred in 10 ml of absolute ethanol for 4 days at 80oWith in-stoppered flask. The cooled solution was concentrated in vacuo and the residue stirred with water (10 ml), and then adjusted pH to 2 using 4 M hydrochloric acid. The original is trevanian, washed with water and recrystallized from a mixture of ethyl acetate/methanol, and then dried overnight in vacuum at 30oWith getting 181 mg (62%) of pure compound indicated in the title; so pl. 228-230oWith (ethyl acetate).

1H NMR (DMSO-d6), (M. D.): 0,88 (t, 3H, CH3), to 1.14 (d, 3H, CH3), for 1.49 (m, 2H, CH2), 3,68 (m, 1H, CH), was 7.08 (s, 1H, H-5), 7,13 (broad, 1H, NH), of 10.73 (broad s, 1H, NH).

Mass spectrum: m/e 293/295 (M+).

Elemental analysis

Calculated for C9H12N3Cl1O2S2,%: 36,79; N 4,12; N 14,30.

Found,%: C 36,79; N 4,1; N 14,2.

EXAMPLE 15

6-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

a) N-[5-chloro-3-(isopropylaminocarbonyl)allfamilies-2-yl]ndimethylacetamide

tert-Piperonyl potassium (135 mg, 1.2 mmol) are added to a solution of N-(5-chloro-3-allfamilies-2-yl)ndimethylacetamide (255 mg, 1.0 mmol) in dry N,N-dimethylformamide (5 ml) with stirring in a bath with ice. After 5 minutes, add drop by drop isopropylethylene (0,128 ml, 1.2 mmol) and the solution stirred at 0oC for 30 minutes and then at room temperature for 3 hours. To the solution was added an additional amount of tert-butoxide potassium (135 mg, 1.2 mmol) and stirring , the residue is placed in 10 ml of water and adjusted pH to 2 using 4 M hydrochloric acid. The obtained precipitate was separated by filtration, washed with water and dried, obtaining 274 mg (77%) of crude compound specified in the header.

1H NMR (DMSO-d6), (M. D.):1,12 (d, 6N, HSN3), of 2.28 (s, 3H, PINES3), is 4.21 (m, 1H, NCH), to 7.15 (s, 1H, H-4), a 8.34 (broad d, 1H, NH), 10,26 (s, 1H, NH).

b) 6-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Phosgene (0,416 ml, 20% in toluene) are added drop by drop to a solution of N-[5-chloro-3-(isopropylaminocarbonyl)allfamilies-2-yl] ndimethylacetamide (261 mg, 0.73 mmol) and dry triethylamine (0,209 ml, 1.5 mmol) in dry tetrahydrofuran (5 ml) under stirring at 0oC. the Mixture is stirred for 1 hour at 0oWith and evaporated to dryness. The residue is triturated with 10 ml of water and the precipitate was separated by filtration, washed with water and finally will deacetylase under stirring in 2 ml of 2 n sodium hydroxide for 90 minutes at room temperature. The solution is acidified to pH 2 with 4 M hydrochloric acid and the precipitate is filtered off and perekristallizatsiya of ethyl acetate with decolorizing charcoal, receiving 44 mg (21%) of pure compound indicated in the title; so pl. 272-274oWith (ethyl acetate).

1H NMR(DMSO-d6

EXAMPLE 16

6-Chloro-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

a) N-[5-Chloro-3-(cyclopentanecarbonyl)allfamilies-2-yl]ndimethylacetamide

Specified in the title compound is obtained from N-(5-chloro-3-allfamilies-2-yl)ndimethylacetamide and cyclopentylpropionate by analogy with the procedure described in example 15-a (crude yield (93%).

1H NMR (DMSO-d6), (M. D.): 1,3-2,0 (m, 8H, (CH2)4), of 2.28 (s, 3H, CH3), 4,32 (sextet, 1H, CH), 7,16 (s, 1H, H-4), 8,48 (broad d, 1H, NH), 10,23 (broad s, 1H, NH).

b) 6-Chloro-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound is obtained from N-[5-chloro-3-(cyclopentanecarbonyl)allfamilies-2-yl] ndimethylacetamide by analogy with the procedure described in example 15-b (yield 32%); so pl. 280-282oWith (aqueous ethanol).

1H NMR (DMSO-d6), (M. D.): 1,4-2,0 (m, 8H, CH2)4), 3,96 (sextet, 1H, CH), of 7.23 (s, 1H, H-7), a 7.62 (broad, 1H, NH), 11,09 (s, 1H, NH).

Mass spectrum: m/e 305/307 (M+).

EXAMPLE 17

6-Bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Bromine (0,12 ml, 2.3 mmol) is added drop by drop to a solution of 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (280 mg, 1.0 mmol) in 10 ml oxysporium to dryness, and the residue is triturated with water, getting a solid, which is recrystallized from a mixture of ethanol/water (1: 1) to give 118 mg (39%) specified in the header, contaminated with 10% of the original substance; so pl. approximately 279oWith (aqueous ethanol).

1H NMR (DMSO-d6), (M. D.): 1,16 (d, 6N, HSN3), 3,86 (m, 1H, CH), 7,14 (s, 1H, H-5), 7,18 (broad, 1H, NH), a 10.74 (s, 1H, NH).

Mass spectrum: m/e 323/325 (M+).

EXAMPLE 18

3 Isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Powdered potassium hydroxide (128 mg, 2.28 mmol) are added to a solution of 6-chloro-3-isopropylamino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide (319 mg, to 1.14 mmol) in 25 ml of methanol and the mixture hydronaut at room temperature and atmospheric pressure for 3 days with 150 g of 10% palladium on carbon. The catalyst was removed by filtration and washed with ethanol and water. The combined filtrate acidified with 4 M hydrochloric acid and evaporated to dryness. The residue is recrystallized from a mixture of ethanol/water and finally from ethyl acetate with decolorizing charcoal, getting mentioned in the title compound, contaminated with source material that can be removed by way of column chromatography on silica gel.

1H NMR (DMSO-d6), (M. D.): 1,16 (d, 6N, /BR> 3 Isopropylamino-7-methyl-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

a) Cyanomethylene

Dry THF (200 ml) saturated with ammonia at -10oWith, then add in small portions over 20 minutes at -10oWith the solution cyanomethylphosphonate (13,9 g, obtained according Sammes, etc., J. Chem. Sc., 1971, 2151-5155) in 10 ml dry THF. After adding the raise the temperature to 0oC and the reaction mixture is filtered. Remove from the filtrate the solvent and purification of residue by way of column chromatography on silica gel with elution by ethyl acetate to give specified in the title compound in the form of beige crystals; so pl. 97-99oC.

IR (KBr) (cm-1): 3316, 3328 (N-H), 2266 (CN), 1371, 1151 (SO2).

b) 2-Amino-4-methylthiophene-3-sulfonamide

A mixture of cyanomethylene (1.0 g), 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane (0.75 g) and triethylamine (100 l) in absolute ethanol (7 ml) is heated at 45-50oWith under nitrogen for 3 hours. Then the solvent is evaporated and the residue portioned in water (30 ml) and ethyl acetate (50 ml). The aqueous phase is extracted with ethyl acetate, 4 x 50 ml combined an ethyl acetate phase is dried over sodium sulfate and evaporated. The residue is cleaned by way of column chromatography on silica gel with elwer the 1%); so pl. 142-144oC.

1H NMR (CD3OD), (M. D. ): 7,19 (s, 1H, C(5)H), 4,88 (broad, 4H, SO2NH2+H2O), 4,71 (s, 2H, NH2), is 2.41 (s, 3H, NH2).

Mass spectrum: 192(M+), 112 (M+-SO2NH2), 72(CH3-C2HS+).

C) N-(2-Amino-4-methyl-3-thienylmethyl)-N'-isopropyltoluene

A mixture of 2-amino-4-methylthiophene-3-sulfonamida (0,30 g), potassium carbonate (0.32 g) and isopropylethylene (271 l) in dry acetone (5 ml) is heated at 50-55oWith during the night. Then the solvent is evaporated and the residue dissolved in water (15 ml); adjusted pH to 2 by adding 4 M hydrochloric acid, and the mixture is stirred for 30 minutes. Saducees the crystals are filtered, washed with a small amount of water and dried, obtaining 0.24 g (yield 54%) specified in the connection header; so pl. 118-120oC.

g) 3-Isopropylamino-7-methyl-4H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide

a 20% solution of phosgene in toluene (175 l) add to the mix and chilled solution of N-(2-amino-4-methyl-3-thienylmethyl)-N'-isopropyltoluene (0,22 g) and triethylamine (313 l) in dry THF (5 ml), keep the temperature below 5oC. After stirring for 1.5 hours the mixture is evaporated and triturated with 10 ml with 5 ml of ethyl acetate and the resulting mixture cool for 10 minutes before the 0oC and then filtered. The filter residue washed with a small amount of ethyl acetate and dried, obtaining 0,087 g (yield 45%) indicated in the title compound as reddish-brown crystals; so pl. 152-154oC.

1H NMR (DMSO-d6), (M. D. ): 7,10 (broad d, 1H, NH), of 6.61 (s, 1H, N(4)H), of 6.52 (s, 1H, C(6)H), with 3.89 (m, 1H, CH2), 2,32 (s, 3H, CH3), of 1.18 (d, 6N, CH3).

EXAMPLE 20

6-Chloro-3-cyclobutylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) in cyclobutylamine (1.0 ml) is stirred for 18 hours at 90oWith in-stoppered flask. This cooled solution was concentrated in vacuo and the residue stirred with water (10 ml) at 0oWith, then bring the pH to 2 using 4 M hydrochloric acid. The product distinguish by filtration, washed with water and recrystallized from methanol/ethyl acetate, and then dried in vacuum at room temperature, getting 155 mg (53%) of pure compound indicated in the title; so pl. 315-317oC (decomposes).

1H NMR (DMSO-d6), (M. D.): 1,58-of 1.75 (m, 2H), 1,89-2,05 (m, 2H), 2,19-of 2.30 (m, 2H), 4.16 the (m, 1H), 7,06 (s, 1H), 7.62mm (broad s, 1H), 10,83 (broad s, 1H).

Mass spectrum: m/e 291/293 (M+).

0.

Found,%: C 37,18; N 3,48; N 14,19.

EXAMPLE 21

6-Chloro-3-(2-hydroxyethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (206 mg, 0.8 mmol) in ethanolamine (1.0 ml) is stirred for 18 hours at 100oWith in-stoppered flask. This cooled solution was concentrated in vacuo and the residue stirred with water (5 ml) at 0oWith, then bring the pH to 2 using 4 M hydrochloric acid. The product distinguish by filtration, washed with water and recrystallized from a mixture of ethanol/water, receiving the 135 mg (60%) of pure compound indicated in the title; so pl. 260-261oC (decomposes).

1H NMR (DMSO-d6), (M. D.): 3,26 (distorted Quartet, 2H), 3,50 (t, 2H), around 4.85 (broad s, 1H), 7,07 (s, 1H), 7,20 (broad s, 1H), up 10.9 (broad s, 1H).

Mass spectrum: m/e 281/283 (M+).

Elemental analysis

Calculated for C7H8N3CL1O3S2,%: 29,84; N 2,86; N 14,91.

Found,%: C 30,13; N 2,84; N 14,79.

EXAMPLE 22

()-3-Exo-bicyclo[2.2.1] hept-2-ylamino-6-chloro-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (206 mg, 0.8 mmol) in Exo-2-aminomorpholine (1.0 ml) is stirred for 20 the pH to 2 using 4 M hydrochloric acid. The product distinguish by filtration, washed with water and recrystallized from a mixture of ethyl acetate/methanol, getting 168 mg (60%) of pure compound indicated in the title; so pl. 323-324oC (decomposes).

1H NMR (DMSO-d6), (M. D.): 1,05-of 1.55 (m, 7H), 1,68-to 1.77 (m, 1H), 2,18-of 2.28 (m, 2H), to 7.09 (s, 1H), 7,2 (broad s, 1H), roughly 10.5 (broad s, 1H),

Mass spectrum: m/e 331/333 (M+).

Elemental analysis

Calculated for C12H14N3Cl1O2S2,%: 43,43; N 4,25; N 12,66.

Found,%: C 43,67; N 4.26 Deaths; N 12,55.

EXAMPLE 23

(R)-6-Chloro-3-(2-hydroxypropyl)amino-4H-thieno-[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (200 mg, 0.78 mmol) in the (R)-(-)-1-amino-2-propanol (1.0 ml) is stirred for 18 hours at 100oWith in-stoppered flask. This cooled solution is stirred with water (3 ml) at 0oWith, then bring the pH to 2 using 4 M hydrochloric acid. The product distinguish by filtration, washed with water and dried in vacuum at room temperature, receiving 170 mg (74%) of pure compound indicated in the title; so pl. 210-211oC.

1H NMR (DMSO-d6), (M. D.): a 1.08 (d, 3H), 3,0-3,1 (m, 1H), 3.15 and is 3.25 (m, 1H), 3.72 points-is 3.82 (m, 1H), 4,91 (broad s, 1H), to 7.09 (s, 1H), 7,14 (which is Designed for C8H10N3Cl1O3S20.5 N2O%: 31,53; N. OF 3.64; N 13,79.

Found,%: C 31,57; N To 3.58; N Of 13.58.

EXAMPLE 24

6-Bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Bromine (1,26 ml, 25 mmol) is added drop by drop to a solution of 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,3-thiadiazine 1,1-dioxide (2.3 g, 8.2 mmol) in 25 ml of acetic acid and the mixture is stirred for 24 hours at 100oWith in-stoppered flask. The cooled mixture is evaporated to dryness, and the residue, which consists of two main products, triturated with water, getting a solid, which is recrystallized from a mixture of ethyl acetate/methanol with decolorizing charcoal, receiving 538 mg (20%) specified in the connection header. Analytically pure sample can be obtained by preparative high performance liquid chromatography on a column of Source 15 RPC, using as eluent a mixture of acetonitrile/water (20:80) with 0.1 TFA (triperoxonane acid); so pl. 282-283oWith (aqueous ethanol).

1H NMR (DMSO-d6), (M. D.): 1,16 (d, 6N), 3,86 (m, 1H), 7,14 (s, 1H), 7,18 (broad, 1H), a 10.74 (s, 1H),

Mass spectrum: m/e 323/325 (M+).

Elemental analysis

Calculated for C8H10N3Br1O2S2,%: 29,64; N 3,11;2,4-thiadiazine 1,1-dioxide

The mother liquor from the crystallization of 6-bromo-3-isopropylamino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide, described above, is evaporated to dryness and the residue is cleaned chromatography in silica with a mixture of dichloromethane/methanol (95: 5) as eluent. Recrystallization from ethyl acetate to give 270 mg (8%) of pure compound indicated in the title; so pl. 250-251oC.

1H NMR (DMSO-d6), (M. D.): 1,18 (d, 6N), 3,86 (m, 1H), 7,18 (broad, 1H), 10,31 (s, 1H).

Mass spectrum: m/e 405/403/401 owner's manual (M+).

Elemental analysis

Calculated for C8H9N3VG2O2S2,%: 23,84; N 2,25; N 10,42.

Found,%: C 24,14; N 2,18; N Of 10.25.

EXAMPLE 26

6-Chloro-3-cyclohexylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-(3-cyclohexyl)thiourea

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and cyclohexylethylamine by analogy with the procedure described in example 3 (yield 78%).

1H NMR (DMSO-d6), (M. D.): 1,1-1,9 (m, 10H), 4,0 (m, 1H), 6,45 (broad s, 2H), 6,66 (s, 1H), 8,05 (broad d, 1H), and 11.2 (broad s, 1H).

b) 6-Chloro-3-cyclohexylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Specified the procedure, described in example 3-b (yield 66%); so pl. 282-284oWith (ethyl acetate/methanol).

1H NMR (DMSO-d6), (M. D.):1,1-1,9 (m, 10H), 3,55 (m, 1H), was 7.08 (s, 1H), 7,19 (broad, 1H), of 10.73 (broad s, 1H).

Mass spectrum: m/e 321/319 (M+).

Elemental analysis

Calculated for C11H14N3Cl1O2S2,%: 41,31; N TO 4.41; N 13,14.

Found,%: C 41,66; N. Of 4.45; N 12,99.

EXAMPLE 27

6-Chloro-3-(furan-2-ylmethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

a) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-(furan-2-ylmethyl)thiourea

Specified in the title compound is obtained from 3-amino-5-chlorothiophene-2-sulfonamida hydrochloride and furfurylamine by analogy with the procedure described in example 3-a (crude yield: 92%).

b) 6-Chloro-3-(furan-2-ylmethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide

Specified in the title compound is obtained from the crude N-(3-amino-5-chloro-2-thienylmethyl)-N'-(furan-2-ylmethyl)thiourea by analogy with the procedure described in example 3-b, except that the product is cleaned by way of column chromatography on silica with a mixture of dichloromethane/methanol (9:1) as eluent (yield 11%); so pl. 224-225oC.

1H NMR (DMSO-d6)entry analysis

Calculated for C10H8N3CL1O3S2,%: 37,80; N. OF 2.54; N 13,22.

Found,%: C 37,87; N. Of 2.51; N 13,10.

EXAMPLE 28

6-Cyano-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

To a solution of 6-bromo-3-isopropylamino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide (243 mg, 0.75 mmol) in dry N,N-dimethylformamide (2 ml) was added copper cyanide(I) (135 mg, 1.5 mmol) and the mixture is heated at 150oC for 2 hours under nitrogen. The dark mixture is allowed to cool to room temperature and add water. This suspension is alkalinized to a basic pH by adding 1 n sodium hydroxide, filtered and the filtrate is acidified by adding 4 M hydrochloric acid. The precipitate clean way preparative high-performance liquid chromatography on a column of Source 15 RPC, using as eluent a mixture of acetonitrile/water (20: 80) with 0.1 TFA (triperoxonane acid), get 4 mg (2%) of net connection specified in the header.

Mass spectrometry with liquid chromatography (LC-MS): m/e 271 (M+1)+.

EXAMPLE 29

6-Bromo-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

Bromine (0,12 ml, 2.3 mmol) is added drop by drop to a solution of 6-chloro-3-cyclopentylamine-4H-thieno[3,2-e] -1,2,4-thiadiazine (305 mg, ohlazhdeniya the mixture is evaporated to dryness, and the residue is triturated with water, getting a solid, which is recrystallized from ethyl acetate and ethanol, getting mentioned in the title compound (166 mg, 47%) contaminated with 33% of the original substance. Cleaning way preparative HPLC gives specified in the title compound (65 mg, 18%) contaminated with 3% of the source material. Decomposes at 287-294oC.

1H NMR (DMSO-d6), (M. D.): to 10.7 (s, 1H, NH), 7,35 (broad s, 1H, NH), 7,13 (s, 1H, H-7), 4,00 (sextet, 1H), and 1.9 (m, 2H), 1,7-1,4 (m, 6N).

EXAMPLE 30

6-Chloro-3-(2-methylallyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide

A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (128 mg, 0.5 mmol) in metalline (0.5 ml) was stirred at 90oC for 48 hours in a stoppered flask. The cooled solution was concentrated in vacuo and the residue stirred with water (3 ml), then adjusted pH to 2 using 4 M hydrochloric acid. The product distinguish by filtration and washed with getting 92 mg (64%) of pure compound indicated in the title; so pl. 224-226oC (decomposes).

1H NMR (DMSO-d6), (M. D.): 1,72 (s, 3H), of 3.75 (d, 2H), a 4.83 (s, 2H), 7,05 (s, 1H), 7,45 (broad s, 1H), and 11.0 (broad s, 1H).

1. Condensed derived 1,2,4-
6-chloro-3-isobutylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(1-methylheptan)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(1-ethylphenyl)amino-4H-thieno(3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(2-methylbutyl)amino-4H-thieno[3,2-e]-1,2,4 thiadiazine 1,1-dioxide;

6-chloro-3-(1-etylhexyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclopentylamine-4H-thieno [3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-incoherently-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

etil-(6-chloro-1,4-dihydro-1,1-dioxolane[3,2-e]-16,2,4-thiadiazin-3-ylamino)butanoate;

3-(6-chloro-1,4-dihydro-1,1-dioxolane[3,2-e] -16, 2,4-thiadiazin-3-ylamino)butyric acid;

6-chloro-3-(3-hydroxy-1-methylpropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

(R)-6-chloro-3-(1-phenylethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

(S)-3-Deut-butylamino-6-chloro-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-isopropylamino-4H-thieno [2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclopentylamine-4H-thieno [2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

6-bromo-3-isopropylamino-4H-thieno [3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

3 isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-fluoro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazin is 5,6-dimethyl-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

3 isopropylamino-6,7-dimethyl-4H-thieno [2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

3 cyclobutylamine-6,7-dimethyl-4H-thieno[2,3-e] -1,2,4-thiadiazine 1,1-dioxide;

3 cyclopentylamine-6,7-dimethyl-4H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

5-chloro-3-isopropylamino-4H-thieno [3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5-chloro-3-propylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1 dioxide;

5-chloro-3-cyclopentylamine-4H-thieno [3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5-chloro-6-methyl-3-isopropylamino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-isopropylamino-5-methyl-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclopentylamine-5-methyl-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-fluoro-3-propylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-fluoro-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

5-fluoro-3-propylamino-4H-thieno [3,2-e]-1,2,4-thiadiazine 1,1 dioxide;

5-fluoro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

3 isopropylamino-7-methyl-4H-thieno [2,3-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclobutylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(2-hydroxyethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

()-3-Exo-bicyclo-[2.2.1] hept-2-ylamino-6-chloro-4H-thieno-[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

(R)-6-chloro-3-(who Yasin 1,1-dioxide;

5,6-dibromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-cyclohexylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(furan-2-ylmethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(1-ethylpropyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine 1,1-dioxide;

6-bromo-3-cyclopentylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;

6-chloro-3-(2-methylallyl)amino-4H-thieno[3, 2-e]-1,2,4-thiadiazine 1,1-dioxide or

6-cyano-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide,

its salt with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a mixture of racemates, or any tautomeric form.

2. Pharmaceutical composition, affecting TOATP- regulated potassium channels, including a connection on p. 1 or its pharmaceutically acceptable salt with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form with one or more pharmaceutically acceptable carriers or diluents.

3. The pharmaceutical composition according to p. 2, characterized in that it is suitable for Leche Pharmaceutical composition according to p. 2 or 3 in the form of standard dosage forms for oral or parenteral administration.

5. The pharmaceutical composition under item 2 or 3, where the join is taken as the dose is in the range from 0.05 to 1000 mg per day, preferably from 0.1 to 500 mg per day, and particularly preferably from 50 to 200 mg per day.

6. Connection on p. 1 or its pharmaceutically acceptable salt with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form, affecting TOATP- regulated potassium channels.

7. Connection on p. 1 or its pharmaceutically acceptable salt with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form, affecting TOATP- regulated potassium channels, suitable for the treatment or prevention of diseases of the endocrine system, such as hyperinsulinemia and diabetes.

8. The method of obtaining a medicinal product on the basis of a connection on p. 1, characterized in that it comprises applying the compounds of formula I on p. 1 or its pharmaceutically acceptable salt in a unit dosage form Galanova of the drug.

Priority points is 43 to 45 in paragraph 1.

 

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< / BR>
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