Derivatives of condensed 1,2,4-thiadiazine and condensed 1,4-thiazine, receipt and use of

 

(57) Abstract:

Describes new derivatives of condensed 1,2,4-thiadiazine General formula I, where In represents one of the bonds in the double bond between the atoms 2 and 3 of ring of formula I, D is - S(=O)2-, R1is hydrogen, R4represents hydrogen or R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of the formula I, or R1together with R4is one of the bonds in the double bond between the atoms 3 and 4 of formula I, R2represents hydrogen, C1-6-alkyl, C3-6-cycloalkyl,2-6alkenyl, R3is R8, aryl, substituted C1-6-alkyl, where R8represents hydrogen, C3-6-cycloalkyl or (C3-6-cycloalkyl)1-6-alkyl, unbranched or branched C1-18-alkyl, optionally mono - or politeley hydroxy, C3-6- cycloalkyl, aryl, carboxy, And with 5 and 6 carbon atoms of the formula I are 5-membered heterocyclic system containing one or two nitrogen atom or one sulfur atom, and the heterocyclic system optionally mono - or polyamidine halogen, excluding the following compounds what about the salt with a pharmaceutically acceptable acid or base. The new compounds possess activity as a means of opening TO aATP-regulated potassium channels. Also describes a pharmaceutical composition having an action on KATP-regulated potassium channels, and the method of exposure TOATP-adjustable channels. 6 C. and 12 C.p. the formulas.

The technical field to which the invention relates

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

Prior art

Potassium channels play an important role in membrane potential. Among the different types of potassium channels are ATP-sensitive (KATP) channels, which are regulated by changes in intracellular concentration of adenosine triphosphate. TOATPthe channels were detected in cells from various tissues, such as heart cells, pancreatic cells, ski cellular functions, for example, the 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 activity, secretion of neurotransmitters in the Central nervous system.

It was found that the modulators TOATPchannels are of great importance in the treatment of various diseases. Some sulfonylureas, which have been used to treat non-insulin dependent diabetes mellitus, act by stimulating insulin secretion by inhibition of KATPchannels in pancreatic beta-cells,

It was found that the discoverers of potassium channels, which include a heterogeneous group of compounds able to relax vascular smooth muscle and are therefore used for the treatment of hypertension.

In addition, the discoverers of potassium channels, can be used as bronchodilators in the treatment of asthma and various other diseases.

Moreover, it was shown that the potassium channels openers stimulate hair growth, they have been used to treat baldness.

Openers potassium ka is ecene incontinence. Openers potassium channels, which relaxes smooth muscle of the uterus, can be used to prevent premature birth.

Due to the action on potassium channels in the Central nervous system, these compounds can be used for the treatment of various neurological and psychiatric diseases, such as Alzheimer's disease, epilepsy and cerebral ischemia.

Recently it was shown that diazoxide (1,1-dioxide 7-chloro-3-methyl-2H-1,2,4-benzotiadiazina) and some derivatives of 1,1-dioxide 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thia-on diazines and inhibit insulin secretion through activation of KATPchannels in pancreatic beta-cells (C. Pirotte et al., Biochem. Pharmacol., 47, 1381-1386 (1994); B. Pirotte et al., J. Med. Chem. , 36, 3211-3213 (1993)). In addition, it was shown that diazoxide slows down the onset of diabetes in BB-rats (Vlahos WD et al., Metabolism, 40, 39-46 (1991). It has been shown that in obese rats suckling diazoxide reduces insulin secretion and increases insulin binding receptors and, therefore, improves glucose tolerance and reduces the increase in the mass (Alemzadeh R. et al., Endocrinol., 133, 705-712, 1993). It is assumed that such compounds can be used to treat diseases characterized by increased production of insuline peridotites, with alkyl or alkylamino in position 3 of the ring thiadiazine. It is stated that these compounds are agonists AMPA receptor glutamate.

In J. Med. hem., 1980, 23,575-577, describes the synthesis of 4(5)-amino-formylamino-5(4)-carboxamides and their properties as a means chemotherapeutic value. In particular presents compounds 1,1-dioxide-3-aminoimidazo[4,5-e] -1,2,4-thiadiazine and 1,1-dioxide, N-benzylaminopurine[4,5-e]-1,2,4-thiadiazine.

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 represent hydrogen; hydroxy; C1-6-alkoxy, C1-6-alkyl, C3-6- cycloalkyl, C2-6alkenyl or C2-6-quinil, optionally mono - or politeley 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-S(=O)- or

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

where R7represents C1-6-alkyl, or aryl, or heteroaryl, optionally mono - or politeley Gal is, cyano, acyl or C1-6-alkoxycarbonyl;

R1represents hydrogen; hydroxy; C1-6-alkoxy or C1-6-alkyl, C3-6-cycloalkyl, C2-6alkenyl or C2-6-quinil, optionally mono - or politeley halogen, and R4represents hydrogen or R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of the formula I, or R1together with R4represent one of the bonds in the double bond between the atoms 3 and 4 of formula I;

R2represents hydrogen; hydroxy; C1-6-alkoxy or C1-6-alkyl, C3-6-cycloalkyl, C2-6alkenyl or C2-6-quinil, optionally mono - or politeley halogen;

R3is R8; -OR8; -C(=X)R8; -NR8R9; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroaromatic, optionally mono - or politeley halogen, hydroxy, C1-6-alkoxy, aryloxy, Allakaket, nitro, amino, C1-6-monoalkyl or dialkylamino, cyano, oxo, acyl or C1-6-alkoxycarbonyl, or aryl, substituted C1-6-alkyl,

where R8represents hydrogen, C3-6-cycloalkyl or (C3-6-cycloalkyl)C1-6-alkyl, and C3-6-cycloalkyl is 6-membered saturated cyclic system, containing one or more atoms of nitrogen, oxygen, or sulfur, or an unbranched or branched C1-18-alkyl, optionally mono - or politeley halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkyl, aryl, aryloxy, Allakaket, nitro, amino,1-6-monoalkyl or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C1-6-alkoxycarbonyl or carbamoyl;

X represents O or S;

R9represents hydrogen, C1-6-alkyl, C2-6alkenyl; C3-6-cycloalkyl, optionally mono - or politeley C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy, 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, and each of these cyclic systems is optionally mono - or polyamidine halogen, C1-6-alkyl, hydroxy, C1-6-alkyl, hydroxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, nitro, amino, cyano, trifluoromethyl, C1-6-monoalkyl or dialkylamino, oxo,

or R3is

< / BR>
< / BR>
where n, m, p is independently 0, 1, 2, 3 and
1-6-alkyl, halogen, hydroxy or C1-6-alkoxy, C1-6-alkyl, C2-6alkenyl or C2-6-quinil, optionally mono - or politeley 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, and each of these cyclic systems is optionally mono - or polyamidine halogen, C1-6-alkyl, hydroxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, nitro, amino, cyano, trifluoromethyl, C1-6-monoalkyl or dialkylamino, or oxo;

And with 5 and 6 carbon atoms of the formula I are 5 - or 6-membered heterocyclic system containing one or more nitrogen atoms, oxygen or sulfur, and heterocyclic system optionally mono - or polyamidine halogen; C1-12-alkyl, C3-6-cycloalkyl; hydroxy; C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl; nitro; amino; cyano; cyanomethyl; perhalogenated; C1-6-monoalkyl or dialkylamino; sulfamoyl; C1-6-alkylthio; C1-6-alkylsulfonyl, C1-6-alkylsulfanyl; C1-6-alkylcarboxylic; aryl is-alkyl, halogen, hydroxy or C1-6-alkoxy, C1-6-alkoxycarbonyl; C1-6-alkoxycarbonyl-C1-6-alkyl; carbamino; carbamylation; C1-6-monoalkyl or dialkylaminoalkyl; C1-6-monoalkyl or dialkyldimethylammonium; ureido; C1-6-monoalkyl or dialkylaminomethyl, touraid; C1-6-monoalkyl or dialkyldithiocarbamate; C1-6-monoalkyl or dialkylaminoalkyl; carboxy; carboxy-C1-6-alkyl; acyl; aryl, arylalkyl, aryloxy, and aryl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy; (1,2,3-oxadiazol-5-yl)- or (1,2,4-oxadiazol-3-yl)-C1-6-alkyl, and oxadiazolyl group optionally substituted C1-6-alkyl or C3-6-cycloalkyl, or 5-6-membered nitrogen containing ring, 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 does not include the following compounds: 1,1-dioxide, 3-amino-2,5-dihydroimidazo[4,5-e] -1,2,4-thiadiazine and 1,1-dioxide, 3-benzoylamino-2,5-dihydro-imidazo[4,5-e]-1,2,4-thiadiazine,

or their salts with pharmaceutically acceptable acid or OS is that of which is optically active, as well as mixtures thereof, including racemic mixtures.

Scope of the invention also includes all tautomeric forms of compounds of formula I.

Salts include pharmaceutically acceptable acid additive salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts such as salts of hydrochloric, Hydrobromic, idiscovered, phosphoric, sulfuric, triperoxonane, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, almond, benzoic, cinnamic, methanesulfonic, econsultancy, picric acid and the like, and include acids related to the pharmaceutical acceptable salts listed in Journal of Pharmaceutical Science, 66, 2(1977), and is introduced here as a reference, or salts of lithium, sodium, potassium, magnesium and the like.

The term "C1-6-alkoxy", as used here, separately or in combination, refers to an unbranched or branched monovalent Deputy containing C1-6is an alkyl group linked through oxygen simple ester having a free valence bond from the oxygen a simple ester group containing from 1 to 6 carbon atoms, northey here separately or in combination, refers to an unbranched or branched monovalent Deputy containing lower alkyl group linked through a divalent sulfur atom having a free valence bond from the sulfur atom and containing from 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, pentylthio.

The term "C2-6alkenyl", as used here, refers to an unsaturated hydrocarbon chain containing 2 to 6 carbon atoms and one double bond, such as vinyl, 1-propenyl, allyl, Isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.

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

The term "C2-6-quinil", as used here, refers to unsaturated hydrocarbons containing a triple bond such as, for example, and the like.

The term "C1-6-alkoxy-C1-6-alkyl", as used here, refers to a group of 2-12 carbon atoms, interrupted About, such as CH2-O-CH3CH2-O-CH2-CH3CH2-O-CH(CH3)2and things like that. the reformer, trichloromethyl, tribromoethyl or triodetic.

The terms "C1-6-alkyl, C1-12-alkyl" and "C1-18-alkyl", as used here, separately or in combination, refers to an unbranched or branched saturated hydrocarbon chain having the specified number of carbon atoms, such as methyl, ethyl, n-propyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term "C1-18-alkyl", as used here, also includes secondary C3-6-alkyl and tertiary C4-6-alkyl.

The term "C1-6-monoalkylamines", as used here, refers to the amino group where one of the hydrogen atoms substituted unbranched or branched saturated hydrocarbon chain having the specified number of carbon atoms, such as methylamino, ethylamino, propylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamine, 2-methylbutylamine, n-hexylamino, 4-methylpentylamino, no-pentylamine, n-hexylamine, 2,2-dimethylpropylene and the like.

The term "C1-6-dialkylamino", as used here, refers to the amino group, the specified number of carbon atoms, such as dimethylamino, N-ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino, di(n-pentyl)amino and the like.

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

The term "C1-6-alkoxycarbonyl", as used here, refers to a monovalent Deputy containing C1-6-alkoxygroup, linked through a carbonyl group, such as, for example, methoxycarbonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxy-carbonyl, tert-butoxycarbonyl, 3-methylbutanoyl, n-hexoxyethanol and the like.

The term "3-12-membered mono - or bicyclic system", as used here, refers to a monovalent Deputy formula-NR2R3or-NR8R9where 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-pyrrolidyl, piperidino, m is the Term "3-6-membered saturated cyclic system, used here, refers to a monovalent Deputy containing monocyclic saturated system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, with 3-6 members and having a free valence at a carbon atom, such as 2-pyrrolidyl, 4-piperidyl, 3-morpholinyl, 1,4-dioxane-2-yl, 5-oxazolidinyl, 4-isoxazolidine or 2-thiomorpholine.

The term "bicycloalkyl", as used here, refers to a monovalent Deputy containing bicyclic structure formed from 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.

The term "aryl", as used here, refers to phenyl, 1-naphthyl or 2-naphthyl.

The term "heteroaryl" used herein, alone or in combination, refers to a monovalent Deputy containing 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, for example, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazin, pyrimidine, pyridazine, isothiazol, isoxazol, oxazol, oxadiazole, thiadiazole, quinoline, isoquinoline, hin is Amy here refers to an unbranched or branched saturated carbon chain containing from 1 to 6 carbon atoms and substituted aromatic hydrocarbons, such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like.

The term "aryloxy", as used here, refers to phenoxy, 1 naphthyloxy or 2-naphthyloxy.

The term "Allakaket", as used here, refers to C1-6alkoxygroup, substituted aromatic hydrocarbons, such as benzyloxy, penetrate, 3 phenylpropoxy, 1 aftermatket, 2-(1-naphthyl)ethoxy and the like.

The term "heteroaromatic", as used here, refers to an unbranched or branched saturated carbon chain containing from 1 to 6 carbon atoms and substituted heteroaryl group, such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.

The term "C1-6-alkylsulfonyl" as used here, refers to a monovalent Deputy containing C1-6is an alkyl group linked through sulfonyloxy group, such as, for example, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfide methylbutylamine, n-hexylsilane, 4-methylphenylsulfonyl, neopentylene, n-hexylsilane and 2,2-dimethylpropanoyl.

The term "C1-6-monoalkylbenzenes", as used here, refers to a monovalent Deputy containing C1-6-monoalkylamines connected through sulfonyloxy group, such as, for example, methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, n-butylaminoethyl, second-butylaminoethyl, sibutraminesolution, tert-butylaminoethyl, n-intramyocellular, 2-methylbutylamine, 3-methylbutylamine, n-exelonexelon, 4-methylphenylsulfonyl, neopatrimonialism, n-exelonexelon and 2,2-dimethylpropyleneurea.

The term "C1-6-dialkylaminoalkyl", as used here, refers to a monovalent Deputy containing C1-6-dialkylamino connected through sulfonyloxy group, such as dimethylaminomethyl, N-ethyl-N-methylamino-sulfonyl, diethylaminosulfur, dipropylenetriamine, N-(n-butyl)-N-methylaminomethyl, di(n-pentyl)aminosulfonyl and the like.

The term "C1-6-alkylsulfonyl" as used here is the group connected through sulfinyl group (-S(=O)-), such as, for example, methylsulfinyl, ethylsulfinyl, isopropylphenyl, butyl sulfinil, pentasulfide and the like.

The term "C1-6-alkylcarboxylic", as used here, refers to the amino group where one of the hydrogen atoms is substituted by an acyl group, such as, for example, acetamido, propionamido, isopropylcarbodiimide and the like.

The term "(C3-6-cycloalkyl)C1-6-alkyl", as used here, separately or in combination, refers to an unbranched or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms and mono-substituted C3-6-cycloalkyl, and cycloalkyl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy, such as, for example, cyclopropylmethyl, (1-methylcyclopropyl)methyl, 1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

The term "aristeo" used herein, alone or in combination, refers to an aryl group linked through a divalent sulfur atom having a free valence bond from the sulfur atom, and the aryl group optionally mono - or polyamidine C1-6- the similar.

The term "arylsulfonyl", as used here, refers to an aryl group linked through sulfinyl group (-S(=O)-), and aryl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy, such as, for example, phenylsulfonyl, (4-chlorophenyl)sulfinil and the like.

The term "arylsulfonyl", as used here, refers to an aryl group linked through sulfonyloxy group, and aryl group optionally mono - or polyamidine1-6-alkyl, halogen, hydroxy or C1-6-alkoxy; such as, for example, phenylsulfonyl, tosyl and the like.

The term "C1-6-monoalkylamines", as used here, refers to a monovalent Deputy containing C1-6-monoalkylamines, linked through a carbonyl group, such as, for example, methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, n-butylaminoethyl, second-butylaminoethyl, isobutylparaben, tert-butylaminoethyl, n-intramyocardial, 2-methylbutylamine, 3-methylbutylamine, n-mexiletineciclovir, 4-methylbenzyloxycarbonyl, neopentylglycol, n-hexylamine, refers to monovalent Deputy containing C1-6-dialkylamino, linked through a carbonyl group, such as dimethylaminoethyl, N-ethyl-N-methylaminomethyl, diethylaminoethyl, dipropylamino, N-(n-butyl)-N-methylaminomethyl, di(n-pentyl)aminocarbonyl and the like.

The term "C1-6-monoalkylammonium", as used here, refers to the amino group where one of the hydrogen atoms substituted C1-6-monoacylglycerols group, for example, methylaminoquinoline, ethylenediamino, n-propylenecarbonate, isopropylaminocarbonyl, n-butylenediamine, sec-butylenediamine, isobutyleneisoprene, tert-butylaminoethyl and 2 methylethylenediamine.

The term "C1-6-dialkylaminomethyl", as used here, refers to the amino group where one of the hydrogen atoms substituted C1-6-dialkylaminoalkyl group, such as dimethylaminocarbonylmethyl, N-ethyl-N-methylaminoquinoline, diethylaminoethylamine, dipropylenetriamine, N-(n-butyl)-N-methylaminoquinoline, di(n-pentyl)aminocarbonyl and the like.

The term "5 - or 6-membered g is Birmingham, containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur and having 5 members, such as 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, an aromatic monocyclic system containing two or more nitrogen atoms and having 6 members, such as piratin, pyrimidine, pyridazine, 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 Piran, thiopyran, piperidine, dioxane, oxazin, isoxazine, Titian, oxacin, teasin, piperazine, thiadiazin, Dityatin or oxadiazon.

The term "5 - or 6-membered nitrogen-containing ring", as used here, refers to a monovalent Deputy containing monocyclic unsaturated or saturated system containing one or more nitrogen atoms and having 5 or 6 members, such as pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidine, pyrazoline, piperidyl, piperazinil, pyrrolyl 2N-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, primitivecount and 1,4-DIOXOLANYL.

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

In a preferred implementation of the invention of General formula I are selected from

< / BR>
where R1and R5independently represent hydrogen; hydroxy; C1-6-alkoxy or C1-6-alkyl, C3-6-cycloalkyl, C2-6alkenyl or C2-6-quinil, optionally mono - or politeley halogen, and R4represents hydrogen or R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of the formula I and R1such as defined above, or

R4together with R1represent one of the bonds in the double bond between the atoms 3 and 4 of the formula I and R5such as defined above,

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

In another preferred implementation of the invention of General formula I are selected from

< / BR>
where R1represents hydrogen; hydroxy; C1-6-alkoxy or C1-6-alkyl, C3-6-cycloalkyl, C2-6alkenyl or C2-6-quinil, optionally mono - or politeley halogen, and R4represents hydrogen or R7=

where R7represents C1-6-alkyl; aryl or heteroaryl, optionally mono - or politeley halogen, hydroxy, C1-6-alkoxy, aryloxy, nitro, amino, C1-6-monoalkyl or dialkylamino, cyano, acyl or C1-6-alkoxycarbonyl.

In another preferred implementation of the invention compounds of General formula I are selected from

< / BR>
where R1, R5and R6independently represent hydrogen; hydroxy; C1-6-alkoxy or C1-6-alkyl, C3-6-cycloalkyl, C2-6alkenyl or C2-6-quinil, optionally mono - or politeley halogen, and R4represents 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 R6such as defined above, or R4together with R1represent one of the bonds in the double bond between the 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 formula Ia.

In another preferred implementation D represents-S(=O)2-.

In another preferred implementation of the invention R1represents hydrogen or C1-6-alkyl.

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

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

In another preferred implementation of the invention R2selected from the group comprising hydrogen, hydroxy, C1-6-alkyl, C3-6-cycloalkyl and C2-6alkenyl. R2preferably represents hydrogen or C1-6-alkyl.

In another preferred implementation of the invention R3selected from R8, -OR8, -NR8R9or aryl, and aryl group optionally substituted C1-6-alkyl, where R8represents hydrogen, C3-6-cycloalkyl; (C3-6-cycloalkyl)C1-6-alkyl; 3-6-membered saturated cyclic system containing one, two or three nitrogen atom, oxygen or sulfur, or an unbranched or branched C1-18-alkyl, optionally substituted by halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkyl or aryl is ω nitrogen form a 4-6-membered ring, preferably 1-pyrrolidyl, piperidine or morpholine.

In another preferred implementation of the invention R3selected from the group comprising secondary C3-6-alkyl, tertiary C4-6-alkyl, C3-6-cycloalkyl or (C3-6-cycloalkyl)methyl, optionally mono - or politeley C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy. R3preferably chosen from the group comprising 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-trimethylpentyl, 2-methylbutyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 1-(cyclopropyl)ethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

In a further preferred implementation of the invention R2and R3together with the nitrogen atom form a six-membered ring, optionally substituted in 2-position C1-6is an alkyl group, preferably selected from methyl, ethyl or isopropyl. The preferred six-membered ring is a piperidine ring, piperazine, research or thiomorpholine.

In CLASS="ptx2">

In another preferred implementation of the invention And together with carbon atoms 5 and 6 of formula I form 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 heteroatoms selected from nitrogen, oxygen and sulfur, and these heterocyclic system optionally mono - or tizamidine substituents, selected from the group including halogen; C1-12-alkyl, C3-6-cycloalkyl; cyano; cyanomethyl; perhalogenated; sulfamoyl; C1-6-alkylthio; C1-6-alkylsulfonyl; C1-6-alkylsulfanyl; aaltio, arylsulfonyl, arylsulfonyl, and aryl group optionally mono - or polyamidine1-6-alkyl, halogen, hydroxy or C1-6-alkoxy, C1-6-alkoxycarbonyl-C1-6-alkyl; carbamoylmethyl; carboxy-C1-6-alkyl; aryloxy; (1,2,4-oxadiazol-5-yl)- or (1,2,4-oxadiazol-3-yl)C1-6-alkyl, and oxadiazolyl group optionally substituted C1-6-alkyl or C1-6-alkyl.

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

Preferred compounds of the invention are:

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

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

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

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

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

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

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

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

1,1-dioxide, 6-chloro-3-octylamine-4H-thieno[3,2-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-3,4-thiadiazin;

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

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

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

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

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

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

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

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

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

1,1-dioxide, 3-hexylamino-6-methyl-4H-thiazolo[4,5-e]-1,2,4-thiadiazine;

1,1-dioxide, 6-methyl-3-octylamine-4H-thiazolo[4,5-e]-1,2,4-thiadiazine;

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

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

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

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

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

1,1-dioxide, 3-isopropylamino-6-methoxy-4H-enous the-isopropylamino-4H-thiazolo[5,4-e]-1,2,4-thiadiazine;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1,1-dioxide 5,7-dichloro-3-isopropylamino-4H-thieno[3,4-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-cyclopropylamino-7-methyl-4,7-dihydropyrazolo[4,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-hexylamino-7-methyl-4,7-dihydropyrazolo[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide 7-methyl-3-octylamine-4,7-dihydropyrazolo[4,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 2,5-dihydro-3-isopropylaminomethyl[4,5-e]-1,2,4-thiadiazine;

1,1-dioxide, 2,5-dihydro-3-isopropylamino-5-methylimidazo-[4,5-e]-1,2,4-thiadiazine;

1,1-dioxide 2,7-dihydro-3-isopropylamino-7-methylimidazo-[4,5-e]-1,2,4-thiadiazine;

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

1,1-dioxide, 3-isopropylamino-5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-4H-pyrimido[4,5-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(1,2-dimethylpropyl)amino-2H-pyrazino[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(1-methylpropyl)amino-2H-pyrazino[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(2-methylpropyl)amino-2H-pyrazino[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-Buti is the oxide-3-(1,2,2-trimethylpropyl)amino-2H-pyrazino[2,3-e]-1,2,4-thiadiazine;

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

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

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

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

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

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

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

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

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

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

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

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

1,1-dioxide, 3-(1,2-dimethylpropyl)amino-2H-pyrimido[4,5-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(1-methylpropyl)amino-2H-pyrimido[4,5-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(2-methylpropyl)amino-2H-pyrimido[4,5-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-butylamino-2H-pyrimido[4,5-e]-l,2,4-thiadiazine;

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

1,1-dioxide, 3-(1,2,2-trimethylpropyl)amino-2H-pyrimido[4,5-e]-1,2,4-t is)amino-2H-pyridazino[4,5-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-(2-methylpropyl)amino-2H-pyridazino[4,5-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-butylamino-2H-pyridazino[4,5-e]-1,2,4-thiadiazine;

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

1,1-dioxide, 3-(1,2,2-trimethylpropyl)amino-2H-pyridazino[4,5-e] -1,2,4-thiadiazine.

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

Since some KATP-openers able to create antagonism to vasospasm basal or cerebral arteries, the compounds of the present invention can be used for the treatment of vasospastic disorders such as subarachnoid hemorrhage and migraine.

Openers potassium channels hyperpolarizes neurons and inhibit the secretion of transmitters, and it is anticipated that this connection can ispolnitelnih diseases, and to relieve pain.

Due to the action on potassium channels in the Central nervous system compounds of the present invention can be used for the treatment of various neurological and psychiatric diseases, such as Alzheimer's disease, epilepsy and cerebral ischemia.

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

In addition, the compounds of the invention can be used for the treatment of chronic respiratory diseases, including asthma, and for treatment of unstable bladder muscles engaged in emptying the side for syndrome infravesical obstruction, and hence for kidney stones by facilitating their passage through the ureter. Openers potassium channels also relaxes the smooth muscle of the bladder, therefore, compounds of the present invention can be used to treat urinary incontinence.

These compounds can also be used to treat conditions associated with disorders of gastrointestinal motility such as touchy it is.

In addition, the potassium channels openers stimulate hair growth, therefore, the compounds of the present invention can be used to treat baldness.

In diseases such as hyperplasia of pancreatic islets and insuloma in which hypersecretion of insulin causes severe hyperglycemia, the compounds of the present invention can be used to reduce insulin secretion. Obesity is very often hyperinsulinemia and insulin resistance. This condition can lead to the development of non-insulin-dependent diabetes (NIDDM). It is assumed that the discoverers of potassium channels and, consequently, the compounds of the present invention can be used to reduce hyperinsulinemia and thereby prevent diabetes and reduce obesity. When explicit NIDDM treatment of hyperinsulinemia openers potassium channels and, therefore, these compounds can have a positive impact on restoring glucose sensitivity and normal insulin secretion.

In the early stages of insulin-dependent diabetes mellitus (IDDM) or pre-diabetic cases openers potassium channels and, therefore, these compounds can be used for Indus.

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

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

Accordingly, in another aspect the invention relates to a compound of General formula I or its pharmaceutically acceptable acid salt additive for use as a therapeutically acceptable substances, preferably for use as therapeutically acceptable substances for the treatment of hyperinsulinemia and treatment or prevention of diabetes.

In addition, the invention relates to the use of the claimed compounds of the formula I as drugs useful for the treatment of hyperinsulinemia and treatment or prevention of diabetes.

In another aspect the present invention relates to methods of producing the above-mentioned compounds. The method is:

a) reaction of compounds of formula II

< / BR>
where a, b, D, R1and R4such as defined above, and Z represents a leaving group, such as alkoxy, alkylthio, g is>BR>
where R2and R3defined above,

for the formation of compounds of formula I using the methods described, for example, So-called. Cronon et al., J. Med.Chem., 11, 136(1968); L. Raffa et al. , Farmaco Ed. Sci., 29, 411 (1974); B. Pirotte et al., J. Med.Chem., 36, 3211 (1993).

Another method involves:

b) reaction of compounds of formula IV

< / BR>
where R1is 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 P2ABOUT5and high-boiling tertiary amine or a suitable salt using the method described by K. Jensen and G. Pedersen E. C., Chem. Scr., 20, 248-250 (1988), and Andersen L. , Nielsen, F. E. and Pedersen, E. B., Chem.Scr., 29, 45-49 (1989), for the formation of compounds of General formula I,

b) reaction of compounds of formula IV

< / BR>
where R1is hydrogen and a, b, D, and X are such as defined above, or represents NH and R1And, D and X are such as defined above,

with the compound of the formula III or a suitable salt in the presence of titanium tetrachloride and the solvent with which it can form a complex may, for example, tetrahydrofuran or a mixture of toluene and anisole according to the methods described in R. I. Fryer, J. V. Earley, G. F. Field, W General formula I,

g) reaction of compounds of formula V

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

with the compound of the formula VI

R3NCO (VI)

where R3such as defined above,

using the method described Chern J. W. et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), for the formation of compounds of General formula I, where D is the SO2In is >NR5, R2is H 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

R3NHC(=O)CI

where R3such as defined above,

using the method described Chern J. W. et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), for the formation of compounds of General formula I, where D is the SO2In is >NR5, R2is H 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 using techniques described Kotovskaya S. K. et. al., Khim.-Farm.Zh., 13, 54-57 (Russ.) (1979), and Topliss, J. G. et al., J.Org. Chem., 28, 2313 (1963), for the formation of compounds of General form is P> and R3represent H,

f) reaction in the presence of a base compound of formula IX

< / BR>
or a suitable salt,

where R11is R1or EtOC(=O),

where R1and As such, as defined above,

with the compound of the formula X

R3N=C=S (X)

where R3such as defined above,

for the formation of the adduct, which can have one of two structures XI and XII, or may be a mixture of these two structures

< / BR>
< / BR>
any of them through the circuit loop, for example, by treatment 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>
for the formation of compounds of General formula I, where D is S(=O)2In is >NR5, R1and R2represent N and R4and R5together form a bond, for example, by heating the parent compound in aqueous base.

The source materials I have local connections or by analogy with known methods, as described, for example, Huang B.-S. et al., J. Med.Chem., 23, 575-7 (1980), Ofitserov V. I. et al., Khim.Geterotsikl. Soedin., 1119-22 (Rus.)(1976), Topliss, J. G., U. S. 3641017 (1972), Kotovskaya S. K. et al., Khim.-Farmo. Zh., 13, 54-57 (Rus.) (1979), Meyer R. F., J. Heterocycl.Chem., 6, 407-408 (1969), and 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), Bames A. S., 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. When using the methods open closed (Hamill, O. P., Marty A., Nefer E., Sakman Century and Sigworth F. J., Arch. , 391, 85-100 (1981)), you can register the ionic current through a single channel of the cell.

The activity of compounds as revealers of potassium channels can also be measured by the relaxation method of the rings art rats according to the following procedure.

The area of the thoracic aorta of rats between the arch of the aorta and diaphragm dissected and prepared in the form of preparations of the rings, as described Taylor P. D. et al., Brit. J. Pharmacol., 111, 42-48 (1994).

After a 45-min period balance at a voltage of 2 g samples were reduced to a value of 80% of the maximum response using Trebjesa with intervals of 2 min cumulative added potential vasodilatory agents using half-logarithmic molar quantities. Relaxation was expressed as a percentage of the specified voltage. The activity of the compounds was expressed as the concentration required to induce a 50% relaxation of the tissue.

Relaxation of aortic rings of rats

Connection - EC50Microm

1 - 1,2

2 - 15

16 - 6,1

In pancreatic-cell opening of KATPchannels can be determined by measuring subsequent changes in the concentration of cytoplasmic free CA2+by way Arkhammer P. et al., J. Biol. Chem., 262, 5448-5454 (1987).

Leakage86Rb+from cell line

Cell line RIN 5F were cultured in medium RPMI 1640 with Glutamax I supplemented with 10% fetal calf serum (GibcoBRL, Scotland, UK) and maintained in an atmosphere of a mixture of 5% CO2/95% air at 37oC. the Cells were separated with a solution of trypsin-EDTA (GibcoBRL, Scotland, UK), resuspendable in the environment, was added 1 MCI/ml86Rb+and perseval in titration microplates (cluster with 96 holes 3596, sterile, from Costar Corporation, MA, USA) at a density of 50,000 cells/well in 100 ml/well and cultured for 24 h before use in the analysis.

The microplate was washed 4 times with ringer buffer (150 mm NaCl, 10 mm HEPES, 3.0 mm KS1, 1.0 mm CaCl2, 20 mm sucrose, pH of 7.1). Added 80 μl of buffer Range temperature with lid 50 μl of supernatant was transferred into a PicoPlates (Packard Instrument Company, CT, USA) was added to 100 μl of MicroScint 40 (Packard Instrument Company, CT, USA). The calculation of the microplates was performed in a TopCount (Packard Instrument Company, CT, USA) at a rate of 1 min/well in the program32P.

Calculation EC50and Emaxconducted by SlideWrite (software provides graphics, Inc. , CA, USA) using the calculated curve with four parameters: y= (a-d)/(1+(x/C)b)+d, where a is the activity, evaluated at zero concentration, b - factor of the slope, with concentration in the middle of the curve and d - activity, evaluated at infinite concentration. EC50= C and Emax= d when the curve turns at infinite concentration.

Inhibition of leakage Rb in cells RIN 5F

Connection - EC50Microm

1 - 2,7

16 - 5,9

Compounds according to the invention is effective in a wide range of doses. In General, satisfactory results are obtained with doses of from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg per day. A more preferred dose is from about 5 mg to about 200 mg per day. The exact dose will depend on the method of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian.

Typical compositions include a compound of formula I or its pharmaceutically acceptable acid additive salt, associated with a pharmaceutically acceptable excipient, which may be a carrier or a diluent, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, pouch, paper or other container. In the manufacture of compositions you can use conventional methods to obtain pharmaceutical compositions. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of capsules, capsule, pouch, 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 bag. Some examples of suitable carriers Jain, lactose, amylose, magnesium stearate, talc, silicic acid, monoglycerides and diglycerides of fatty acids, esters of pentaerythritol and fatty acids, hydroxymethylcellulose and polyvinylpyrrolidone. The finished formulation may also include moisturizing agents, emulsifying and suspendresume agents, preserving agents, sweeteners or corrigentov. Finished formulations of the invention can be manufactured so as to provide rapid, prolonged or delayed release of the active ingredient after administration to the patient by using methods that are well known in this field.

The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like which do not react with the active compounds with the deterioration of their quality.

For parenteral application, particularly suitable injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxyalkane castor oil.

Tablets, coated tablets or capsules with talc and/or Stateline carriers for tablets, pills or capsules include lactose, corn starch and/or potato starch. A syrup or elixir can be used in cases where you can use sweetened filling.

A typical tablet suitable for use in this way, you can get a conventional tabletting methods, it contains:

Active connection, mg - 5,0

Lactose, mg Ph.Eur. and 67.8

Avicelmg - 31,4

Amberlitmg - 1,0

Magnesium stearate, mg Ph.Eur. - 0,25

Due to the high degree of their activity, the compounds of the invention can enter an animal in need of such treatment, prevention, relief or reduction in intensity of symptoms of various diseases mentioned above, and especially diseases of the endocrine system, such as hyperinsulinemia and diabetes. Such animals include domesticated animals, such as Pets, and nadomestnih animals, such as wild animals. Preferred animal is a mammal, especially man.

The method of obtaining compounds of formula I and containing products is further illustrated by the following examples, which however shall not be construed as limiting the invention.

5-chloro-2-allfamilies-3-carboxylate

A solution of 2-(N-tert-butylcarbamoyl)-5-chlorothiophene-3-carboxylic acid (60,0 g; 0,201 mol), obtained according to the method described by B. Unterhalt and S. Moghaddam, Pharmazie, 49, 115-117 (1994), in 700 ml of absolute ethanol saturated with hydrogen chloride was heated with stirring while boiling under reflux for 17 hours, the Cooled solution is evaporated to dryness and the residue was purified by rubbing with water and dried, obtaining the 52.3 g (96%) specified in the connection header.

1H-NMR (DMSO-d6): of 1.31 (t, J=7 Hz, 3H, CH3), 4,32 (q, J=7 Hz, 2H, CH2), at 7.55 (s, 1H), to 7.77 (br.s, 2H, NH2).

b) 5-Chloro-2-allfamilies-3-carbohydrazide

Ethyl-5-chloro-2-allfamilies-3-carboxylate (50.0 g, 0.185 mol) was added in one portion to 98% hydrazinehydrate (50 ml) with stirring at room temperature. The reaction was slightly exothermic. The solution was stirred for 90 min and concentrated. The residue was led by rubbing with 250 ml of water, the mixture was acidified with concentrated hydrochloric acid to pH 2-3 and was stirred for 30 min at 0oC. the Product was isolated by filtration, washed with water and dried, obtaining 42,4 g (89%) specified in the connection header.

1H-NMR (DMSO-d6): 4, (br.s, 2H, NH2), 7,49 (s, 1H), 7,71 (br.s) in 20 ml of water was added dropwise with stirring at 0oTo a solution of 5-chloro-2-allfamilies-3-carbohydrazide (10.0 g, 39,1 mmol) in 80 ml of 1 M hydrochloric acid and the mixture was stirred for 15 minutes the Precipitate was isolated by filtration, washed with water and dried, getting to 9.93 g (96%) specified in the connection header.

1H-NMR (DMSO-d6): of 7.55 (s, 1H), 7,97 (br.s, 2H. NH2).

g) 1,1-Dioxide, 6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine

5-Chloro-2-sulfamoyl-3-enolase (7.0 g, to 26.2 mmol) was added in portions to 50 ml of boiling under reflux in dry toluene for 10 minutes and the Mixture was stirred for 5 min and cooled on an ice bath. The precipitate was isolated by filtration, washed with toluene and dried, obtaining 5,90 g (94%) specified in the connection header; so pl. 245-248oC (decomposition).

1H-NMR (DMSO-d6): 6,93 (s, 1H), 11,98 (s, 1H, NH).

d) 1,1-Dioxide, 6-chloro-3-(1,2-dimethylpropyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine

The phosphorus pentoxide (2,84 g, 20 mmol), N,N-dimethylcyclohexylamine (5 ml, 33 mmol) and hydrochloride 1,2-dimethylpropylene (2,47 g, 20 mmol) was carefully mixed in a three-neck flask, equipped with a mechanical stirrer and a fridge with a drying tube. The mixture was heated on an oil bath at 200oFrom until, until he was polol) and the mixture was stirred at 240oC for 45 minutes the Mixture was allowed to cool to approximately 100oC, was added 150 ml of water and stirring continued at room temperature for approximately 1 h Gidralizovanny the mixture was filtered and the dark precipitate was washed with water and dissolved in boiling ethanol, treated with charcoal, filtered and finally evaporated to dryness. Flash chromatography (ethyl acetate/silica gel) gave 105 mg (7%) of the net specified in the connection header; so pl. 216-218oC.

1H-NMR (DMSO-d6): 0,90 (d, 6N, CH(CH3)2), 1.08 (d, 3H, NCHCH2), 1.75 (m, 1H, CH(CH3)2), 3.65 (m, 1H, NHCH), 7.11 (br.s, 2H, 5-H + NH), 10.68 (s, 1H, NH). MS m/e: 307/309 (M+).

Alternative 1,1-dioxide, 6-chloro-3-(1,2-dimethylpropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine can be obtained by the following method ( B)

a) 1,1-Dioxide 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine

A suspension of 1,1-dioxide 6-chloro-2,3-dihydro-3-oxo-4H-thieno-[3,2-e] -1,2,4-thiadiazine (10,75 g, 0.045 mol) in phosphorus oxychloride (100 ml) was cooled in an ice bath and was added dropwise dry pyridine (7.3 ml, 0.09 mol) at such a speed that the temperature did not exceed 10oC. the Mixture then was heated at 95-100oC for 16 h and cooled to room temperature. The yellow precipitate was removed fil is within 1 h and filtered. Selected solid product was dissolved in saturated aqueous sodium bicarbonate (100 ml) and filtered to remove a small amount of insoluble material. After processing decolorizing charcoal, 4 M hydrochloric acid, the pH of the filtrate was determined 2 and the precipitate which formed was separated by filtration, washed with water and dried, obtaining of 5.55 g (48%) specified in the connection header; so pl. >240oWith (Razlog.).

b) 1,1-Dioxide, 6-chloro-3-(1,2-dimethylpropyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine

A solution of 1,1-dioxide 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine (0.3 g, 1.94 mmol) in 1,2-dimethylpropylene (5 ml) was stirred for 48 h at 100oWith in a sealed vessel. The cooled mixture was concentrated in vacuo and the residue was stirred with water (20 ml), followed by the establishment of 4 M hydrochloric acid, the pH of the mixture 2. Originally formed by resinous product was led by stirring the mixture for about 2 h at 0oC. the Precipitate was isolated by filtration, washed with water and recrystallize from a mixture of ethyl acetate/methanol, followed by drying in vacuum at 60oWith during the night, getting 0,43 g (72%) of the net specified in the connection header.

EXAMPLE 2

1,1-Clohexane (3 ml, 20 mmol) and ethylamine hydrochloride (1.63 g, 20 mmol) was carefully mixed and heated with stirring on an oil bath at 180oWith over 20 minutes To a homogeneous mass was added 1,1-dioxide, 6-chloro-2,3-dihydro-3-oxo-4H-thieno-[3,2-e] -1,2,4-thiadiazine (1.2 g, 5 mol) and the mixture was stirred at 180oC for 5 hours After cooling to approximately 100oWith added water (150 ml) and the mixture was stirred for 1 h at room temperature. Then the mixture was extracted with ethyl acetate (3 x 100 ml). The organic phase was washed with saturated aqueous sodium bicarbonate, dried and evaporated to dryness. The residue was recrystallize from a mixture of ethyl acetate/methanol, getting 282 mg (21%) of the net specified in the connection header; so pl. 271-274oC.

1H-NMR (DMSO-d6): 1.11 (t, 3H, CH3), 3.22 (m, 2H, CH2),? 7.04 baby mortality (s, 1H, 5-H), and 7.3 (br. s, 1H, NH), 11,1 (br. s, 1H, NH). MS m/e: 265/267 (M+). (C7H8N3ClO2S2) is calculated, %: C 31,64, N 3,03, N 15,81; found 31,57, N 3,12, N 15,63.

EXAMPLE 3

1,1-Dioxide, 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained by the method similar to that described in example 2, except that as the primary amine hydrochloride used isop is(d, 6N, CH(CH3)2), 3,88 (m, 1H, CH), 7.08 (s, 1H, 5-H), 7.20 (br.d, 1H, NH), 10.74 (br.s, 1H, NH). MS m/e: 279/281 (M+). (C8H10N3ClO2S2) is calculated, %: 34,35, N Of 3.60, N 15,02; found 34,37, N 3,70, N 14,95.

Alternative 1,1-dioxide, 6-chloro-3-isopropylamino-4H-thieno[3,2-e] -1,2,4-thiadiazine can be obtained by the following method (B).

a) tert-Butylamide 3-amino-5-chlorothiophene-2-sulfonic acid

A solution of 38.1 g (0.15 mol) of tert-butylamide 5-chlorothiophene-2-sulfonic acid in 300 ml of dry tetrahydrofuran was cooled to -70oWith and was added n-BuLi (190 ml, 1.6 M in hexane), keeping the temperature <-65C. After addition the mixture was allowed to warm to -20oC and stirred at this temperature for 30 minutes was Added a solution of p-toluensulfonate (34 g, to 0.17 mol) in 100 ml of dry tetrahydrofuran, maintaining the temperature at -20oWith, and the cooling bath was removed. After the mixture at room temperature was added water (100 ml). The organic phase was separated and the aqueous phase was extracted with toluene (2 x 50 ml). To the combined organic phases were added bromide hexadecyltrimethylammonium (a 7.62 g, 15 mmol) followed by the addition dropwise of a solution of sodium borohydride (6,58 g, 0,174 mol) in 20 ml of water at peremeshivanii water (100 ml). The organic phase was separated, washed with water (2 x 100 ml), dried and evaporated to dryness. The oily residue was dissolved in ethyl acetate (150 ml) and washed with 1 N. sodium hydroxide (6 x 100 ml). The organic phase was dried with sodium sulfate and evaporated, obtaining quantitative output (40.6 g) crude specified in the connection header in the form of oil, which was used without further purification in the next stage.

b) Hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida

tert-Butylamide 3-amino-5-chlorothiophene-2-sulfonic acid (40,4 g) was heated with stirring at a temperature of from 50 to 60oWith 200 ml of concentrated hydrochloric acid for 2.5 hours the Crude product was isolated from the cooled mixture by filtration, dried and purified by rubbing with 60 ml of ether, receiving 17.8 g (48%) specified in the connection header.

1H-NMR (DMSO-d6): only 6.64 (s, 1H), 6,84 (very wide., 5H).

C) N-(3-Amino-5-chloro-2-thienylmethyl)-N'-isopropyltoluene

tert-Piperonyl potassium (0,49 g, 4.4 mmol) was added to a solution of hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida (0.5 g, 2.0 mmol) in dry N,N-dimethylformamide (5 ml) with stirring on an ice bath. After 5 min to the resulting suspension was added dropwise isopropylethylene is continued at room temperature for 30 minutes The solvent is evaporated at <50With and the residue was dissolved in 25 ml of water, was treated with decolorizing charcoal and filtered. Acidification of the filtrate with acetic acid to pH 3-4 and filtering gave 0.50 g (80%) specified in the connection header; so pl. 142,0-142,5oWith (Razlog.).

1H-NMR (DMSO-d6): 1.12 (d, 6N), 4.25 (m, 1H), 6.48 in (br.s, 2H), 6.65 (s, 1H), 8.02 (d,1H), 11.2 (br.s, 1H).

g) 1,1-Dioxide, 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine

Phosgene (1,14 ml, 20% in toluene) was added dropwise to a solution of N-(3-amino-5-chloro-2-thienylmethyl)-N'-isopropyltoluene (to 0.63 g, 2.0 mmol) and dry triethylamine (of 0.56 ml, 4.0 mmol) in dry tetrahydrofuran (10 ml) with stirring at 0oC. the Mixture was stirred for 1 h at 0oWith and evaporated to dryness. The residue is triturated with water and the precipitate was isolated by filtration, washed with water and dried, obtaining 0.52 g (93%) specified in the connection header.

Alternative 1,1-dioxide, 6-chloro-3-isopropylamino-4H-thieno[3,2-e] -1,2,4-thiadiazine can be obtained by the following method ().

A solution of 1,1-dioxide 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine (1.5 g, 5.83 mmol) in Isopropylamine (10 ml) was stirred in a pressure vessel made of stainless steel, Teflon lined, with 100oestevadeordal acid to pH 2. The mixture was stirred in an ice bath for about 1 h, receiving 0,99 g (61%) indicated in the title compound as a crystalline product.

EXAMPLE 4

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

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and L--methylbenzenesulfonate by the method similar to the method described in example BV-g; so pl. 195-204oWith (ethyl acetate).

1H-NMR (DMSO-d6): 1.46 (d, 3H), 4.95 (m, 1H), 7.1 (s, 1H), 7.2-7.45 (m, 5H), 7.78 (br.s, 1H), 10.85 (s, 1H).

EXAMPLE 5

1,1-Dioxide, 3-allylamino-6-chloro-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and allylisothiocyanate by the method similar to the method described in example BV-g; so pl. 217-221oC.

1H-NMR (DMSO-d6): 3.83 (distorted t, 2H), 5.08-5.27 (m, 2H), 5.75-5.99 (m, 1H), 7.07 (s, 1 H), 7.49 (br.t, 1H), 11.1 (s, 1H).

EXAMPLE 6

1,1-Dioxide, 6-chloro-3-cyclopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and cyclopropylacetylene by the method similar to the method described in 5 (br.s, 1H).

EXAMPLE 7

1,1-Dioxide, 6-chloro-3-hexylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and n-exisitent by the method similar to the method described in example BV-g; so pl. 207-209oC.

1H-NMR (DMSO-d6): 0.87 (distorted t, 3H), 1.28 (m, 6N), 1.51 (m, 2H), 3.17 (q, 2H), 7.05 (s, 1H), 7.30 (br.s, 1H), 11.01 (s, 1H).

EXAMPLE 8

1,1-Dioxide, 6-chloro-3-tetradecanamide-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and n-tetradecylthioacetic by the method similar to the method described in example SBW-g; so pl. 157-158oC.

1H-NMR (DMSO-d6): 0.85 (distorted t, 3H), 1.25 (m, 22H), 1.50 (m, 2H), 3.19 (q, 2H), 7.05 (s, 1H), 7.26 (br.s, 1H), 10.95 (br.s, 1H).

EXAMPLE 9

1,1-Dioxide, 6-chloro-3-methylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and methylisothiocyanate by the method similar to the method described in example BV-g; so pl. >190oWith (Razlog.).

1H-NMR (DMSO-d6): 2.75 (s, 3H), 7.02 (s, 1H), 7.25 (br., 1H), 11.3 (br.s, 1H).

EXAMPLE 10

1,1-Deoxidated 3-amino-5-chlorothiophene-2-sulfonamida and benzylisothiocyanate according to the method similar to the method described in example BV-g; so pl. 223-226oC;

1H-NMR (DMSO-d6): 4.42 (d, 2H), 7.05 (s, 1H), 7.30 (m, 5H), 7.78 (br. t, 1H), 11.22 (br.s, 1H).

EXAMPLE 11

1,1-Dioxide, 6-chloro-3-octylamine-4H-thieno[3,2-e]-1,2,4-thiadiazine

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and n-attributeoriented by the method similar to the method described in example BV-g; so pl. 190oWith (Razlog).

1H-NMR (DMSO-d6): 0.85 (t, 3H), 1.28 (m, 10H), 1.50 (m, 2H), 3.18 (q, 2H), 7.03 (s, 1H), 7.25 (br.s, 1H), 10.2 (br.s, 1H).

EXAMPLE 12

1,1-Dioxide, 6-chloro-3-isobutylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and isobutylphthalate by the method similar to the method described in example BV-g; so pl. 262 to 264oC.

1H-NMR (DMSO-d6): 0.90 (d, 6N), 2.85 (m, 1H), 3.02 (t, 2H), 7.08 (s, 1H), 7.3 (br.s, 1H), 10.9 (br.s, 1H).

EXAMPLE 13

1,1-Dioxide, 6-chloro-3-(4-phenibut)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and 4-privatisationand by the method similar to the method described in example BV-g; so pl. 201-BER 14

1,1-Dioxide, 6-chloro-3-(1,5-diethylhexyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and 1.5-diethylhexylphthalate by the method similar to the method described in example BV-g; so pl. 197-199oWith (ethyl acetate).

1H-NMR (DMSO-d6): 0.85 (d, 6H), 1.12 (d, 3H), 1.1-1.6 (m, 7H), 3.77 (m, 1H), 7.07 (s, 1H), 7.12 (br.s, 1H), 10.72 (br.s, 1H).

EXAMPLE 15

1,1-Dioxide, 6-chloro-3-propylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from 1,1-dioxide 3,6-dichloro-4H-thieno[3,2-e] -1,2,4-thiadiazine and n-Propylamine by the procedure analogous to the procedure described in example BW, except that the mixture was stirred for 16 h at 60oWith; so pl. 258-261oWith (ethyl acetate).

1H-NMR (DMSO-d6): 0.89 (t, 3H), 1.52 (sext, 2H), 3.15 (q, 2H), 7.05 (s, 1H), 7.29 (br.s, 1H), 10.95 (br.s, 1H).

EXAMPLE 16

1,1-Dioxide, (R)-6-chloro-3-(2-hydroxy-1-methylethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine.

Specified in the title compound was obtained from 1,1-dioxide 3,6-dichloro-4H-thieno[3,2-e] -1,2,4-thiadiazine and (R)-(-)-2-amino-1-propanol by the method similar to the method described in example b; so pl. 203-204oWith (water).

1H-NMR (DMSO-d

Specified in the title compound was obtained from 1,1-dioxide 3,6-dichloro-4H-thieno[3,2-e] -1,2,4-thiadiazine and L-alaninol by the method similar to the method described in example b; so pl. 204-206oWith (water).

1H-NMR (DMSO-d6): 1.11 (d, 3H), 3.4 (d, 2H), 3.78 (m, 1H), 4.95 (br.s, 1H), 7.05 (br.s, 1H), 7.09 (s, 1H), 10.8 (br.s, 1H).

EXAMPLE 18

1,1-Dioxide, (R)-3-Deut-butylamino-6-chloro-4H-thieno[3,2-e] -1,2,4-thiadiazine.

Specified in the title compound was obtained from 1,1-dioxide 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine and (R)-(-)-terbutaline by the method similar to the method described in example b; so pl. 215-220oWith (water).

1H-NMR (DMSO-d6): 0.88 (t, 3H), 1.11 (d, 3H), 1.48 (m, 2H), 3.69 (m, 1H), 7.07 (s, 1H), 7.14 (br.s, lH), 10.75 (br.s,1H).

EXAMPLE 19

1,1-Dioxide, 3-butylamino-6-chloro-4H-thieno[3,2-e]-1,2,4-thiadiazine.

Specified in the title compound was obtained from hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida and n-butylaminoethyl by the method similar to the method described in example b-g; so pl. 218-219oC.

1H-NMR (DMSO-d6): 0.90 (t, 3H), 1.35 (sext, 2H), 1.50 (quint, 2H), 3.18 (q, 2H), 7.02 (s, 1H), 7.25 (br.s, 1H), 10.95 (br.s, 1H).

EXAMPLE 20

1,1-Dioxide, 3-isopropylamino-7-methyl-4,7-dihydropyrazolo[4,3-e]-1,2,4-thiadiazine.

a) 1-Methyl-what codice Bellemin and Festal, J. Heterocycl.Chem., 1984, 21, 1017, was mixed with 1 ml hydrazino-novedrate at room temperature for 3 h and then evaporated to dryness. The residue was dissolved in 5 ml of water and was extracted with 25 ml dichloromethane. The aqueous phase is evaporated, receiving of 0.85 g (90%) indicated in the title compound in the form of a slowly crystallizing oil. Rubbing with 5 ml of a mixture of 2: 1 methanol and ethyl acetate gave pure product; so pl. 172-173oC.

b) 1-Methyl-4-(azidocarbonyl)pyrazole-5-sulfonamide

A solution of sodium nitrite (0,19 g) in 5 ml of water was added dropwise to a stirred solution of 1-methyl-5-sulfamoylbenzoyl-4-carbohydrazide (0.55 g) in 8 ml of 1 M hydrochloric acid at 0oC. the resulting mixture was stirred for 15 min and then filtered. The filter cake was washed with water and dried in vacuum, obtaining 0,29 g (47%) indicated in the title compound as a crystalline solid product. The product was pure according to TLC data (ethyl acetate), was used immediately in the next stage.

C) 1-Methyl-4-(ethoxycarbonyl)pyrazole-5-sulfonamide

1-Methyl-4-(azidocarbonyl)pyrazole-5-sulfonamide (0.29 grams) was added over 5 min to 10 ml of abs. ethanol at a temperature of phlegmy. The resulting solution was boiled with the IDA yellow oil, contains a small residue of ethanol. The product was used without purification for the next stage.

g) N-(4-Ethoxycarbonyl-1-methyl-5-personality)-N'-isopropyltoluene

A mixture of 1-methyl-4-(ethoxycarbonyl)pyrazole-5-sulfonamida (0,42 g), potassium carbonate (0.34 g) and isopropylethylene (280 μl) in 10 ml dry acetone was heated at 55oC for 18 h and then evaporated to dryness. The residue was dissolved in 10 ml of water and added dropwise to 4 M hydrochloric acid was set pH to 2. The precipitate was separated by filtration, washed with a small amount of water and dried, obtaining of 0.38 g (64%) specified in the connection header, so pl. 141-144oC.

d) 1,1-Dioxide 4-etoxycarbonyl-3-isopropylamino-7-methyl-4,7-dihydropyrazolo[4,3-e]-1,2,4-thiadiazine

To a stirred solution of N-(4-ethoxycarbonylphenyl)-1-methyl-5-personality)-N'-isopropyltoluene (0,37 g) and triethylamine (0.45 ml) in 5 ml dry THF at 0oWith added 1.0 ml of 20% solution of phosgene in toluene. The mixture was stirred at 0oC for 30 min and then evaporated to dryness. The residue is triturated with 10 ml of water, filtered, washed on the filter with water and dried, obtaining 0.27 g (82%) specified in the connection header; so pl. 141-145oC.

oC.

1H-NMR (DMSO-d6): (ppm) 10.25 (s, 1H, NH), 7.42 (s, 1H, 3-H), 7.21 (br.d, 1 H, NH), 3.98-3.75 (m, 4H, CH and N-CH3) and 1.15 (d, 6N, CH3).

EXAMPLE 21

1,1-Dioxide, 3-isopropyl-6-methyl-4H-thiazolo[4,5-e]-1,2,4-thiadiazine.

Specified in the title compound can be obtained by the method similar to the method described in example 20, based on ethyl-2-methyl-5-sulfamethizole-4-carboxylate, which, in turn, obtained by the method of Tamura et al.,Chem.Pharm.Bull., 1971, 19, 119.

Example A.

1,1-Dioxide, 6-chloro-3-(cyclohexylmethyl)amino-4H-thieno[3,2-e] -1,2,4-thiadiazine.

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

tert-Piperonyl potassium was added to a solution of hydrochloride of 3-amino-5-chlorothiophene-2-sulfonamida in dry N,N-dimethyltrimethylene and the mixture was stirred for 3.5 hours at 0-20oC. the Greater part of the solvent was evaporated at 40oWith and the residue was dissolved in 25 ml of water, was treated with decolorizing charcoal and filtered. Acidification of the filtrate with acetic acid to pH 3-4 and filtering gave specified in the title compound (yield 8%) as syrup.

1H-NMR (DMSO-d6): 0.95 (m, 2H), 1.25 (m, 3H), 1.70 (m, 6H), 3.45 (d, 2H, CH2), 4.45 (br, HDO+NH), 6.65 (s, 1H, H-4).

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

The phosgene was added dropwise to a solution of N-(3-amino-5-chloro-2-thienylmethyl)-N'-cyclohexylethylamine and dry triethylamine in dry tetrahydrofuran with stirring at 0oC. the Mixture was stirred for 2 h at 0oWith and evaporated to dryness. The residue was recrystallized from ethyl acetate, the precipitate was isolated by filtration, washed with water and dried, obtaining mentioned in the title compound (yield 68%); so pl. >200oC.

1H-NMR (DMSO-d6): 0.90 (m, 2H), 1.15 (m, 3H), 1.70 (m, 6H), 3.05 (t, 2H, CH2), 7.05 (s, 1H, H-5), 7.25 (br, 1H, NH), 10.95 (br.s, 1H, NH). MS: M/e 333 (M+).

Example B.

3-(6-Chloro-1,4-dihydro-1,1-dioxolane[3,2-e] -16, 2,4-thiadiazin-3-ylamino)butane acid.

Ethyl-3-(6-chloro-1,4-dihydro-1,1-dioxolane[3,2-e] -16,2,4 at room temperature. The solution was treated with decolorizing charcoal, filtered and acidified with hydrochloric acid to pH 2. The resulting precipitate was isolated by filtration, washed with water and dried, obtaining mentioned in the title compound (yield 64%); so pl. 218-223oC.

1H-NMR (DMSO-d6): 1.19 (d, 3H, CH3), 2.49 (m, 2H, CH2), 4.1 (m, 1H, CH), 7.06 (s, 1H, H-5), 7.25 (br, 1H, NH), 10.99 (s, 1H, NH), 12.38 (br.s, 1H, OH). MS: M/e 305/307 (M-H2O)+. (C9H10ClS2) is calculated,%: 33,39, N 3,11, N 12,98; found,%: C 33,62, H 3,11, N 12,81.5

1. Derivatives of condensed 1,2,4-thiadiazine General formula 1

< / BR>
where is >NR5where R5represents hydrogen, or R5and R4together represent one of the bonds in the double bond between the atoms 2 and 3 of ring of formula 1;

D is S(=O)2-;

R1represents hydrogen;

R4represents hydrogen, or R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of the formula I, or R1together with R4is one of the bonds in the double bond between the atoms 3 and 4 of formula I;

R2represents hydrogen, C1-6-alkyl, C3-6-cycloalkyl,2-6alkenyl;

R3is R8, aryl, substituted With1-18-alkyl, optionally mono - or politeley hydroxy, C3-6-cycloalkyl, aryl, carboxy;

And with 5 and 6 carbon atoms of the formula I are 5-membered heterocyclic system containing one or two nitrogen atom or one sulfur atom, and the heterocyclic system optionally mono - or polyamidine halogen, excluding the following compounds: 1,1-dioxide, 3-aminoimidazo[4,5-e] -1,2,4-thiadiazine and 1,1-dioxide, 3-(benzoylamine)imidazo [4,5-e]-1,2,4-thiadiazine, or its salt with a pharmaceutically acceptable acid or base.

2. Connection on p. 1, where R2represents hydrogen or C1-6-alkyl.

3. Connection under item 1 or 2, where R3is R8or aryl, and aryl groups are optionally substituted C1-6-alkyl, where R8represents hydrogen, C3-6-cycloalkyl, (C3-6-cycloalkyl)1-6-alkyl, or unbranched or branched C1-18alkyl, optionally substituted by hydroxy.

4. The compound according to any one of the preceding paragraphs, where R3is secondary WITH3-6-alkyl, tertiary4-6-alkyl, C3-6-cycloalkyl or (C3-6

6. The compound according to any one of the preceding paragraphs, where a together with carbon atoms 5 and 6 of formula I form a 5-membered heterocyclic system containing two heteroatoms, selected from nitrogen and sulfur, and heterocyclic system optionally substituted with halogen.

7. The compound according to any one of paragraphs.1-6, where the General formula I is

< / BR>
where R1, R4, R5independently represent hydrogen, or R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of the formula I and R1such as defined above, or R4together with R1represent one of the bonds in the double bond between the atoms 3 and 4 of the formula I and R5the same as defined above;

D represents-S(=O)2-;

A, R2and R3such as defined above.

8. Connection on p. 7, where R1and R4represent hydrogen.

9. Connection on p. 7 or 8, where R1together with R4represent one of the bonds in the double bond between the atoms 3 and 4 of formula I.

10. The compound according to any one who CLASS="ptx2">

11. The compound according to any one of paragraphs.7-10, where D represents-S(=O)2.

12. A compound selected from the following:

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

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

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

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

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

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

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

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

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

1,1-dioxide, 6-chloro-3-(1,5-diethylhexyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine;

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

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

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

1,1-dioxide, 3-isopropylamino-7-methyl-4,7-dihydropyrazolo[4,3-e]-1,2,4-thiadiazine.

13. The compound according to any one of the preceding paragraphs, which act as a means of opening TO aATP-regulated potassium channels.

14. Pharmaceutical composition having an action on KATP-regulated potassium channels, characterized in that it contains as an active ingredient the compound according to any one of paragraphs.1-13 or its pharmaceutically acceptable salt with a pharmaceutically acceptable acid or base, associated with a pharmaceutically acceptable filler.

15. The pharmaceutical composition according to p. 14, characterized in that it can be used in the form of an oral dosage unit or parenteral dosage unit.

16. The compound according to any one of paragraphs.1-13 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 for therapeutic use through exposure to TOATP-adjustable potassium Cana is acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the manufacture of a medicinal product for impact TOATP-regulated potassium channels.

18. The method of exposure TOATP-regulated potassium channels in a subject in need thereof, which consists in the introduction of an effective amount of a compound according to any one of paragraphs.1-13 this subject.

Priority points

17.01.1996 - PP.1-3, 5-6, 8-11, 13-18;

16.01.1997 - p. 4;

basically 17.01.1996, in particular 27.08.1996 - p. 7;

17.01.1996 connection 1, 15, 19 p. 12;

27.08.1996 connection 2, 3 under item 12.

16.01.1997 connection 4-14, 16-18, 20 p. 12.

 

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< / BR>
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< / BR>
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