Derivatives of pyrido-1,2,4-thiadiazine or pyrido-1,4-thiazine, pharmaceutical composition and method manifestations inhibiting insulin secretion activity

 

(57) Abstract:

The invention relates to the field of organic chemistry. Describes derivatives of pyrido-1,2,4-thiadiazine or pyrido-1,4-thiazine General formula (I)

< / BR>
where is >NR5or >CR5R6where R5and R6independently can be C1-6-alkoxy or C1-6-alkyl; D represents-S(=O)2-; R1is hydrogen 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, R2is hydrogen; R3is R11, -NR11R12arylalkyl,where R11represents hydrogen, an unbranched or branched C1-18-alkyl, possibly mono - or politeley halogen, hydroxy, C1-6-alkoxy or aryl, and R12is hydrogen; And together with carbon atoms 5 and 6 thiazine forms a pyridine ring, selected from

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< / BR>
where R7, R8, R9independently represent hydrogen or halogen, provided that when b is NR5D is SO2and R2petsa pharmaceutical composition, possessing inhibitory insulin activity, and the manner of the manifestation of inhibiting the release of insulin activity. The technical result obtained new compounds with useful biological properties. 4 C. and 13 C.p. f-crystals, 1 table.

The invention relates to derivatives of pyrido-1,2,4-thiadiazine and pyrido-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, skeletal muscle, smooth muscle, Central neurons and cells adenogipofiza. These channels are associated with a variety of cellular functions, such as CE is a), the 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 potassium channels openers 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 channels can also choose to relax the smooth muscle of the bladder, therefore, they can be used for the treatment of h is I 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-thiadiazine inhibit insulin secretion through activation of KATPchannels in pancreatic beta-cells (C. Pirotte et al., Biochem. Pharmacol., 47, 1381-1386 (1994); C. 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 W. D. 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 insulin, and for the treatment and prevention of diabetes.

In the European patent EP 618 209 describes a class derived peridotites with Alki the receptor of glutamate.

In Acta Crystallographica, Section C, 1995, s(9), 1903-1905, describes the crystal structure of 1,1-dioxide 3-benzamido-4H-pyrido[4,3-e]-1,2,4-thiadiazine.

Description of the invention

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

< / BR>
where is >NR5or >CR5R6where R5and R6independently can be hydrogen; hydroxy; C1-6-alkoxy or C1-6-alkyl, C3-6-cycloalkyl, C2-6-alkenyl or C2-6-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-S(=O)-, or

D-B is-S(= O)(R10)=N-, where R10represents C1-6-alkyl, or aryl, or heteroaryl, optionally mono - or politeley halogen, hydroxy, C1-6-alkoxy, aryloxy, Allakaket, nitro, amino, C1-6-monoalkyl or dialkylamino, 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 polysome 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 R11; -OR11; -C(=X)R11; -NR11R12; 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 R11represents hydrogen, C3-6-cycloalkyl or (C3-6-cycloalkyl)-C1-6-alkyl, and C3-6-cycloalkyl group, optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy; 3-6-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 polyamidine halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, Cthe CSR the formyl, acyl, carboxy, C1-6-alkoxycarbonyl or carbamoyl;

X represents O or S;

R12represents hydrogen, C1-6-alkyl, C2-6alkenyl; C3-6-cycloalkyl, optionally mono - or politeley C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy, or

R11and R12together 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, oxo, or

R3is

< / BR>
where n, m and p independently is 0, 1, 2, 3 and R13represents hydrogen; hydroxy; C1-6-alkoxy, C1-6-cycloalkyl, optionally mono - or politeley C1-6-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 mo is the genus, or sulfur, 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 formula I forms a pyridine ring, selected from

< / BR>
< / BR>
where R7, R8, R9independently represent hydrogen; 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; aaltio, arylsulfonyl, arylsulfonyl, and aryl group optionally mono - or polyamidine1-6-alkyl, halogen, hydroxy or C1-6-alkoxy, C1-6-alkoxycarbonyl; C1-6-alkoxycarbonyl-C1-6-alkyl; carbamyl, carbamoylmethyl; C1-6-monoalkyl or dialkylaminoalkyl; C1-6-monoalkyl or dialkylaminoalkyl; ureido; C1-6-monoalkyl or dialkylaminomethyl, touraid; C1-6-monoalkyl - and the B>-alkyl; acyl; aryl, arylalkyl, aryloxy, and aryl group optionally mono - or polyamidine C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy; (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 C3-6-cycloalkyl, or 5-6-membered nitrogen-containing ring, optionally substituted by phenyl or C1-6-alkyl, provided that when b is NR5D is SO2and R2represents hydrogen, C1-6-alkyl or C3-6-cycloalkyl, R3cannot represent hydrogen, unsubstituted C1-6-alkyl, C3-6-cycloalkyl (C3-6-cycloalkyl)-C1-6-alkyl, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or benzoyl,

or their salts with pharmaceutically acceptable acid or base.

Within 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.

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

Salts include pharmaceutically acceptable acid additive salt farm is stevedorage, Hydrobromic, itestosterone, phosphoric, sulfuric, triperoxonane, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, almond, benzoic, cinnamic, methanesulfonic, econsultancy, picric acid and the like, including acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), and is introduced here as a reference, or a salt 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, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentox.

The term "C1-6-alkylthio" used herein, alone 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 ASS="ptx2">

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 things like that.

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

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

The term "perhalogenated" means trifluoromethyl, 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, n-propyl, isopropyl, 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, neopentylene, n-hexylamino, 2, 2 dimethylpropylene and the like.

The term "C1-6-dialkylamino", as used here, refers to the amino group in which two hydrogen atoms independently substituted unbranched or branched saturated hydrocarbon chain having 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.

Those who PU, 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, second-butoxycarbonyl, 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-NR11R12where R2and R3or R11and R12together 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, morpholino, thiomorpholine, 4-methylpiperazin-1-yl, 7-azabicyclo[2,2,1]heptane-7-yl, Trapani and the like.

The term "3-6-membered saturated cyclic system", as used here, refers to a monovalent Deputy containing monocyclic 3 to 6 members and having a free valence at a carbon atom, for example, 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, hinzelin, cinoxacin, indole, benzimidazole, benzofuran, pteridine and purine).

The term "arylalkyl", as used here, refers to an unbranched or branched saturated carbon chain containing from 1 to 6 carbon atoms and substituted aromaticheski the>

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, venetucci, 3 phenylpropoxy, 1 aftermatket, 2-(1-naphthyl)staxi 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-butylsulfonyl, second-butylsulfonyl, isobutylamine, tert-butylsulfonyl, n-peterculter, 2-methylbutanoyl, 3-methylbutanoyl, n-hexylsilane, 4-methylphenylsulfonyl, neopentylene, n-hexylsilane and 2,2-dimethylpropanoyl.

terashima 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-methylaminomethyl, diethylaminosulfur, dipropylenetriamine, N-(n-butyl)-N-methylaminomethyl, di(n-pentyl)aminosulfonyl and the like.

The term "C1-6-alkylsulfonyl", as used here, refers to a monovalent Deputy containing unbranched or branched C1-6is an alkyl group linked through sulfinyl group (-S(=O)-), such as, for example, methylsulfinyl, ethylsulfinyl, isopropylphenyl, butisol is, 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 is monosubstituted C3-6-cycloalkyl group, and cycloalkenyl 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-alkyl, halogen, hydroxy or C1-6-alkoxy, such as phenylthio, (4-were)thio, (2-chlorophenyl)thio, and the like.

The term "arylsulfonyl", as used here, refers to an aryl group linked through culpin is, is 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, stylenolabel, n-propylaminosulfonyl, isopropylaminocarbonyl, n-butylaminoethyl, second-butylaminoethyl, isobutylparaben, tert-butylaminoethyl, n-intramyocardial, 2-methylbutylamine, 3-methylbutylamine, 4-methylbenzyloxycarbonyl, neopentylglycol, n-mexiletineciclovir and 2,2-dimethylpropyleneurea.

The term "C1-6-dialkylaminoalkyl", as used here, refers to a monovalent Deputy containing C1-6-dialkylamino, linked through a carbonyl group, t-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 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, imidiatly, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholine, isothiazolin, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1,3-DIOXOLANYL 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 compounds 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 R5the same as defined above;

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

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

< / BR>
where R1represents hydrogen; hydroxy; Cbut mono - or politeley halogen, and R4represents 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)R10=,

where R10represents C1-6-alkyl; aryl or heteroaryl, optionally mono - or politeley halogen, hydroxy, C1-6-alkoxy, aryloxy, Allakaket, nitro, amino, C1-6-monoalkyl or dialkylamino, cyano, acyl or C1-6-alkoxycarbonyl.

In another preferred implementation of the invention with Obedinenie 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 poly substituted with 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)-.

Preferred on the>
-.

In another preferred implementation of the invention R1selected from the group including hydrogen, C1-6-alkyl, C3-6-cycloalkyl and C2-6alkenyl. Preferably 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.

In another preferred implementation of the invention R3selected from R11, -OR11, -NR11R12or aryl, and aryl group optionally substituted C1-6-alkyl; where R11represents 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 C12represents hydrogen, C1-6-alkyl or C3-6-cycloalkyl or R11and R12together with the nitrogen atom form a 4-6-membered ring, preferably 1-pyrrolidyl, piperidino or morpholino.

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)ethylcyclopentadienyl, cyclopentylmethyl go 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, e is a or thiomorpholine.

In another preferred implementation of the invention R10selected from C1-6-alkyl, phenyl or pyridyl.

In another preferred implementation of the invention R7, R8, R9independently represent hydrogen; 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; carbonylmethyl; 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 C3-6-cycloalkyl; acyl or 5 - to 6-membered nitrogen-containing ring, optionally substituted by phenyl or C1-6-alkyl.

The preferred compounds are:

1,1-dioxide, 3-hydrazino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-benzylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(R)-(1-phenylethylamine)-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(S)-(1-phenylethylamine is ID 7-chloro-3-(R)-(1-phenylethylamine)-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide 7-chloro-3-(S)-(1'-phenylethylamine)-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-benzylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(R)-(1-phenylethylamine)-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(S)-(1-phenylethylamine)-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-hexylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide 7-chloro-3-hexylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-octylamine-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide 7-chloro-3-octylamine-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-allylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-allylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine;

1,1-dioxide 7-chloro-3-(2-methoxy-1-methylethyl)amino-4H-pyrido[2,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-(2-methoxy-1-methylethyl)amino-4H-pyrido[4,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-(2-hydroxy-1-methylethyl)amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-benzylamino-2-methyl-2H-pyrido[4,3-e]-1,2,4-thiadiazine;

4,4-Dioxide, 2-isopropylamino-3,3-dimethoxy-3H-pyrido[2,3-b][1,4]thiazine;

1,1-dioxide, 3-methoxyimino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-amoxiline-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-cyclopropylmethoxy-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-diox the ina;

1,1-dioxide, 3-butoxyaniline-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-cyclopentyloxy-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-allylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-benzylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

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

1,1-dioxide, 3-(2-methylhydrazino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(2-acylhydrazone)-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(2-isopropylpyrazine)-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(2-methyl-2-acylhydrazone)-4H-pyrido(4,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-(2-methyl-2-isopropylpyrazine)-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

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

1,1-dioxide, 3-(1,1,1,3,3,3-hexamer-2-propyl)amino-4H-pyrido[4,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-(2-(1,1-bis(trifluoromethyl)propyl) amino-4H-pyrido-[4,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-(1-methyl-2,2-deferror)amino-4H-pyrido[4,3-e] -1,2,4-thiadiazine;

1,1-dioxide, 3-(1-methyl-2,2-decanoate)amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(2-bicyclo[2,2,2] octyl)amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(2-adamantylamine)-4H-pyrido[4,3-e]-1,2,4-thiadiazine;

1,1-dioxide, 3-(1-a is a;

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

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

1,1-dioxide, 3-(3-methylbutyl)amino-4H-pyrido[4,3-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.

Because someATP-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, it is assumed that these compounds could be used to treat various diseases of the Central nervous system, napu 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, side 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 irritable bowel syndrome. Additionally, these compounds can be used for the treatment of premature birth and dysmenorrhea.

In addition, the potassium channels openers stimulate hair growth, therefore, the compounds of this is practical islets and insulinoma, 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 to 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 to induce dormancy beta cells, which can prevent the development of autoimmune disease.

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

With endocrinol 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 also 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 imidazol-1-yl, alkoxy, alkylthio, halogen, preferably chlorine, bromine, iodine, trimethylamine or methylsulphonyl,

with the compound of the formula III

< / BR>
where R2and R3defined above,

for the formation of compounds of General formula I using the methods described, for example, b includes:

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 P2O5and high-boiling tertiary amine or a suitable salt using the method described by Jensen K. G. and Pedersen, E. B., Chem. Scr., 20, 248-250 (1988) and Andersen L., Nielsen, F. E. and E. Pedersen 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. Zally and L. H. Stembach, J. Org. Chem., 34, 1143-1145 (1969); J. B. Press et al., J. Med. Chem. 22, 725-731 (1979); G. Roma et al., Eur. J. Med. Chem. 26, 489-496 (1991), for 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 VI

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)Cl (VII)

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 represents 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 J. Topliss G et al., J. Org. Chem, 28, 2313 (1963), for the formation of compounds of General formula I, where D represents the SO2In is >NR5, R4and R5together form a bond and R2and R3represent N.

Starting materials are either known compounds or compounds that cat 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 (Russ.) (1976), Topliss, J. G., U. S. 3641017 (1972), Kotovskaya S. K. et al., Khim.-Farm. Zh., 13, 54-57 (Russ.) (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., Stark R, Pavey D. E., 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 C. and P. J. Sigworth, Plugers 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 trebuemyh with intervals of 2 min cumulative added potential vasodilatory agents using half-logarithmic molar quantities. Relaxation was expressed as the percentage of reduced voltage. The activity of the compounds was expressed as the concentration required to induce a 50% relaxation of the tissue.

In pancreatic /the cage opening TO aATPchannels 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 l/well and cultured for 24 hours before use in the analysis.

The microplate was washed 4 times with ringer buffer (150 mm NaCl, 10 mm HEPES, 3.0 mm KCl and 1.0 mm CaCl2, 20 mm sucrose, pH of 7.1). Added eighty μl of ringer buffer and 1 ál of the control or test compounds dissolved in DMSO. After encubierta the Lyali 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 program32R.

Calculation EC50and Emaxconducted using SlideWrite (software provides graphs. 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 (cm. table).

Measurement of insulin secretion from pancreatic islets incubated allocated collagenase way from fed female Wistar albino rats

Groups of 10 islets, each of which is received from the same batch of islets, pre-incubated for 30 min at 37oWith 1 ml of buffered bicarbonate solution (in mm: 115 NaCl, 5 KCl, 2,56 l2, 1 MgCl2, 24 Panso3), supplemented with 2.8 mm glucose, 0.5% (wt./about.) cialisovernight albumin (fraction V, Sigma Chemical Co), and relatively balanced mixture of O2(95%) and CO2(5%). Groups of 10 islets were then incubated at 37othe IU, the selected compound.

This technique simultaneously incubated for 6 to 8 series of 10 laboratory glasses. In each episode 8 glasses contain groups of 10 islets and 2 glasses are considered as the control cups (handled in the same way, contain physiological environment, but without Islands). To ensure homogeneous distribution of the Islands among the different series, the collected islets are placed sequentially into one of the glasses of each series. The first and last of a series of 10 cups (8 cups with Islands, 2 cups without islets in each series) incubated in the presence of 16.7 mm glucose (without added pharmacological compounds; these series are considered as control series). 4-6 other series of 10 cups incubated in an environment of 16.7 mm glucose, enriched with selected pharmacological connection (or connections, either 1 or 2 compounds tested at various concentrations). After incubation environment for incubation, remove from glass Pasteur pipette and stored at -20oC. insulin Secretion measured radioimmunoassay using insulin in rats as standard. The experiment is repeated 2-4 times, on different days (which implies Priuli in absolute values for the secretion of insulin from one to another immunoassay) led us to the expression rate of secretion relative to control values (100% = average of the absolute values of the first and last of a series of glasses in each experiment: control series). Thus, for each experimental series absolute values expressed as % of control conditions in the same experiment.

At a concentration of 50 μm in some compounds strongly inhibit insulin secretion:

connection - % residual allocated insulin

1 - 75

3 is 17.5

6 - 52,3

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, the body weight of the subject to be treated, and the preferred use of the physician or veterinarian.

The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, percutaneous, subcutaneous, intravenous, intramuscular or intranasal, preferably oral path.

Typical compositions include a compound of formula I or its pharmaceutical may be a carrier or 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 are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane castor oil, gelatin, 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, is but to make so to ensure 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 containing talc and/or carbohydrate carrier or binder or the like, particularly suitable for oral administration. Preferred carriers for tablets, coated tablets 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 accepted is 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.

EXAMPLES

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.

EXAMPLE 1

The production of intermediate products

Monohydrate 1,1-dioxide 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine

Compound I was obtained according to published methods (B. Pirotte et. al., J. Med. Chem., 1993, 36, 3211-3213).

1,1-dioxide 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine

A solution of 2-amino-5-chloropyridin-3-sulfonamida (8.0 g) and thiocarbonyldiimidazole (20.5 g) in dioxa ended, the solvents were removed under reduced pressure. The residue was dissolved in aqueous NaOH solution (4 g in 150 ml water). The solution quickly turned into a suspension of sodium salt specified in the connection header. Salt was collected by filtration and washed with a small volume of water. The salt was dissolved in water (200 ml), treated with charcoal, filtered and set the pH of the filtrate 5-6 using 1 N. Hcl. The precipitate was collected by filtration, washed with water and dried (yield 8.8 g); so pl. 330-331o(Compound II).

1,1-Dioxide, 3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine

Used the same methodology as described for compound II, based on 2-aminopyridin-3-sulfonamida (5.0 g) and thiocarbonyldiimidazole (13 g), except that the sodium salt is not precipitated after addition of NaOH. The alkaline solution was treated with charcoal, filtered and the pH of the filtrate was installed 5-6 using 1 N. Hcl. The precipitate was collected by filtration, washed with water and dried (yield 4.8 g); so pl. 312-314o(Compound III).

1,1-Dioxide, 2-methyl-3-thioxo-2,3-dihydro-4H-pyrido[4,3-e]-1,2,4-thiadiazine

A solution of N-methyl-4-aminopyridine-3-sulfonamida (de Tullio et al., Tetrahedron 1995, 3221-3234) (5.0 g) and thiocarbonyldiimidazole (7.5 g) in dioxane (30 ml) and DMF (15 ml) was heated at 90oSince t is eremetical within 30 minutes The alkaline solution was treated with charcoal, filtered and the pH of the filtrate was installed 4-5. The precipitate was collected by filtration, washed with water and dried (yield 4 g); so pl. 195-198o(Compound IV).

1,1-Dioxide, 2-methyl-3-methylsulfanyl-2H-pyrido[4,3-e]-1,2,4-thiadiazine

A solution of 1,1-dioxide, 2-methyl-3-thioxo-2,3-dihydro-4H-pyrido[4,3-e] -1,2,4-thiadiazine (1.0 g) in acetonitrile (20 ml) was added potassium carbonate (1.0 g), then methyliodide (1 ml). After incubation for 1 hour at room temperature the solvent was removed by distillation under reduced pressure. The residue was dispersible in water (50 ml) and formic acid have set the pH of the suspension 5. Insoluble material was collected by filtration, washed with water and dried (yield 0.8 g); so pl. 135-138o(Compound V).

1H-Pyrido[2,3-b][1,4]thiazin-2(3H)-tion

Tonirovanie 1H-pyrido[2,3-b] [1,4] thiazin-2(3H)-she (obtained according to Dunn and Norrie, J. Prakt. Chem. 1990, 332 (4) 444-452) pentasulfide phosphorus in toluene standard techniques (see, for example, N. Tawada et al., Chem. Pharm. Bull. 1990, 38, 1238-1245) gave specified in the header of the connection; so pl. 233-234o(Compound VI).

2 Isopropylamino-3H-pyrido[2,3-b][1,4]thiazin

1H-Pyrido[2,3-b] [1,4] thiazin-2(3H)-tion (0.5 g) was dissolved in 10 ml of Isopropylamine and left storyli in 25 ml of a mixture of ethyl acetate/methanol (4:1), was treated with charcoal and filtered through a bed of silica. The filter was suirable 210 ml of a mixture of ethyl acetate/methanol (4: 1). The filtrate is evaporated and slowly kristallizuetsya the residue is triturated with 5 ml of ethyl acetate and then 3 ml of diethyl ether. The crystals were separated by filtration and dried, obtaining specified in the header of the connection; so pl. 135-139o(Compound VII).

EXAMPLE 2

1,1-dioxide, 3-hydrazino-4H-pyrido[4,3-e]-1,2,4-thiadiazine

Monohydrate 1,1-dioxide 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine (1.0 g) was added to hydrazinehydrate (0.8 ml) and the mixture was heated at 70oC for 30 minutes After cooling, the reaction mixture was added methanol (10 ml) and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 2M NaOH (20 ml), treated with charcoal, filtered and the pH of the filtrate was determined 6-7 using 1M Hcl. Thus obtained precipitate was collected by filtration, washed with water and dried (yield 0.8 g); so pl. 290-292o(Connection 1).

EXAMPLE 3

1,1-Dioxide, 3-aralkylamines-4H-1,2,4-peridotites

A mixture of a suitable precursor (compound I, II or III) (0.5 g) and the appropriate aralkylamines (2.5 ml) was boiled under reflux for 30 to 60 minutes (until etilovym ether (100 ml). The aqueous layer was separated and treated with charcoal, then filtered. Using formic acid was established pH of the filtrate 6-7. The resulting precipitate was collected by filtration, washed with water and dried (yield 70-85%).

Thus were obtained the following compounds:

1,1-dioxide, 3-benzylamino-4H-pyrido[4,3-e] -1,2,4-thiadiazine; so pl. 198-201o(Compound 2),

1,1-dioxide, 3-(R)-(1-phenylethylamine)-4H-pyrido[4,3-e]-1,2,4-thiadiazine; so pl. 236-238o(Compound 3),

1,1-dioxide, 3-(S)-(1-phenylethylamine)-4H-pyrido[4,3-e]-1,2,4-thiadiazine; so pl. 233-235o(Compound 4),

1,1-dioxide, 3-benzylamino-7-chloro-4H-pyrido[2,3-e] -1,2,4-thiadiazine; so pl. 244-245o(Compound 5),

1,1-dioxide 7-chloro-3-(R)-(1-phenylethylamine)-4H-pyrido-[2,3-e]-1,2,4-thiadiazine; so pl. 261-262o(Compound 6),

1,1-dioxide 7-chloro-3-(S)-(1-phenylethylamine)-4H-pyrido-[2,3-e]-1,2,4-thiadiazine; so pl. 262-265o(Compound 7),

1,1-dioxide, 3-benzylamino-4H-pyrido[2,3-e] -1,2,4-thiadiazine; so pl. 232-233o(Compound 8),

1,1-dioxide, 3-(R)-(1-phenylethylamine)-4H-pyrido[2,3-e]-1,2,4-thiadiazine; so pl. 207-210o(Compound 9),

1,1-dioxide, 3-(S)-(1-phenylethylamine)-4H-pyrido[2,3-e]-1,2,4-thiadiazine; so pl. 213-214o(Compound 10).

EXAMPLE 4

1,1-Dioxide, 3-exile is and hexylamine (5.0 ml) was boiled under reflux for 3-4 hours (until until the end of the reaction; TLC) amine was distilled under reduced pressure. The residue was dissolved in 1 N. NaOH (150 ml), treated with charcoal, filtered and formic acid have established a pH of 5-6. The resulting precipitate was collected by filtration, washed with water and dried (yield of 0.38 g), so pl. 170-171oC (compound 11).

Similarly, it was obtained the following compound: 1,1-dioxide 7-chloro-3-hexylamino-4H-pyrido[2,3-e] -1,2,4-thiadiazine; so pl. 176-179oWith; 1,1-dioxide 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e] -1,2,4-thiadiazine and hexylamine (Compound 12).

EXAMPLE 5

1,1-Dioxid 3 octylamine-4H-pyrido[4,3-e]-1,2,4-thiadiazine

A mixture of the monohydrate 1,1-dioxide 3-methylsulfanyl-4H-pyrido[4,3-e] -1,2,4-thiadiazine (0.5 g), octylamine (0.5 ml) and m-chlorotoluene (3 ml) was boiled under reflux for 2-3 hours (until then, until the reaction; TLC). A large part of the solvent was removed by distillation and the residue was dispersively in a mixture of water (30 ml) and methanol (30 ml) and was supplemented with 10% (mass. /about.) NaOH in water (2 ml). The mixture was treated with charcoal, filtered and using 1 N. Hcl has set the pH of the filtrate 6. The resulting precipitate was collected by filtration, washed with water and dried (yield of 0.29 g); so pl. 176-179o(Compound 13).

Such pl. 170-175oC) of 1,1-dioxide 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e] -1,2,4-thiadiazine and octylamine (compound 14).

EXAMPLE 6

1,1-Dioxide, 3-allylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine

A mixture of the monohydrate 1,1-dioxide 3-methylsulfanyl-4H-pyrido[4,3-e] -1,2,4-thiadiazine (0.5 g) and allylamine (4 ml) was heated in a sealed pressure vessel for 4-5 h at 120oC. After cooling, the amine was removed by distillation under reduced pressure. The residue was dissolved in 0.5 n NaOH, treated with charcoal, filtered and using 1 N. Hcl has set the pH of the filtrate 6. The resulting precipitate was collected by filtration, washed with water and dried, obtaining specified in the title compound in the form of dihydrate (yield of 0.44 g); so pl. 206-208o(Compound 15).

Similarly, it was obtained the following compound: 1,1-dioxide, 3-allylamino-7-chloro-4H-pyrido[2,3-e] -1,2,4-thiadiazine (so pl. 224-227oC) of 1,1-dioxide 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e] -1,2,4-thiadiazine and allylamine (compound 16).

EXAMPLE 7

1,1-Dioxide 7-chloro-3-(2-methoxy-1-methylethyl)amino-4H-pyrido-[2,3-e] -1,2,4-thiadiazine

A mixture of 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine (0.5 g) and 2-amino-1-methoxypropane (5 ml) was boiled under reflux for 24 atively coal, was filtered and the pH of the filtrate was installed 5-6. The suspension was kept for 24 hours at +4oC. the Precipitate was collected by filtration, washed with a minimum amount of water and dried (yield 0.25 g); so pl. 150-156o(Compound 17).

EXAMPLE 8

1,1-Dioxide, 3-(2-methoxy-1-methylethyl)amino-4H-pyrido-[4,3-e] -1,2,4-thiadiazine

Used the same method, what is described above (except that the starting material was monohydrate 1,1-dioxide 3-methylsulfanyl-4H-pyrido[4,3-e] -1,2,4-thiadiazine), until the establishment of the pH of an aqueous solution of 5-6. However, in this case there was no deposition. Then the solvent was removed by distillation under reduced pressure. The residue was dispersively in a small volume of water (4 ml). Insoluble material was collected by filtration. The solid product was dispersible in acetone (30 ml). Insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in a small volume of acetone (3 ml). After a few minutes, appears fine precipitate, which was collected by filtration, washed with acetone and dried, obtaining mentioned in the title compound in the form of a monohydrate (yield 0.1 g); so pl. 174-178o(Compound 18).

EXAMPLE 9

1,1-Deok sulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine and 2-amino-1-propanol (0.75 ml) was boiled under reflux for 90 min (until completion of the reaction; TLC). After cooling, add diethyl ether (20 ml) was caused by the separation of the oil residue. After decanting the ether solution of the residue was dissolved in methanol (1 ml) and then was added diethyl ether (15 ml). The oily residue was separated again. After decanting the supernatant oily residue was dissolved in acetone (6 ml). Immediately appeared fine-grained sediment. After storage for 3 h at +4oWith the resulting precipitate was collected by filtration, washed with acetone and dried (yield 0.33 g); so pl. 213-216o(Compound 19).

EXAMPLE 10

1,1-Dioxide, 3-benzylamino-2-methyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine

A solution of 1,1-dioxide, 2-methyl-3-methylsulfanyl-4H-pyrido-[4,3-e]-1,2,4-thiadiazine (0.5 g) and benzylamine (0.5 ml) in dioxane (2.5 ml) was boiled under reflux to complete the reaction (TLC). After cooling, the addition of ether caused the precipitation specified in the connection header. The precipitate was collected by filtration, washed with ether and recrystallize from methanol-ether (yield 0.4 g); so pl. 142-146o(Compound 20).

EXAMPLE 11

4,4-Dioxide, 2-isopropylamino-3,3-dimethoxy-3H-pyrido-[2,3-b][1,4]thiazine

To a stirred solution of 2-isopropylamino-3H-pyrido-[2,3-b][1,4]thiazine (0.10 g) in 2 ml of methanol domovladenie 1 h Then add 10 ml of water and the mixture was extracted 3 times with 5 ml dichloromethane. The combined extracts were dried over sodium sulfate and the solvent was removed in vacuum. The residue was purified on a column of silica with elution with a mixture of 9:1 ethyl acetate and methanol, getting mentioned in the title compound, so pl. 123-126oC; m/e 299 (M+).

1H NMR (Dl3), (M. D.): a 7.92 (m, 1H, 6-H), 7,39-of 7.23 (m, 7-H and residual chloroform), 7,16-7,07 (m, 1H, 8-H), 5,79 (Shir. d, 1H, NH), from 4.2 to 4.0 (m, 1H, CH), 3,66 (s, 3H, CH3O), of 3.57 (s, 3H, CH3O), of 1.35-1.26 in (DV. d, 6N, (CH3)2(C) (compound 21).

1. Derivatives of pyrido-1,2,4-tadisina or pyrido-1,4-thiazine General formula I

< / BR>
where is >NR5or >CR5R6where R5and R6independently, can be C1-6-alkoxy or C1-6-alkyl;

D represents-S(= O)2-;

R1is hydrogen 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;

R3is R11, -NR11R12arylalkyl,elsamadisy halogen, hydroxy, C1-6-alkoxy or aryl; and R12represents hydrogen;

Together with carbon atoms 5 and 6 thiazine forms a pyridine ring, selected from

< / BR>
< / BR>
where R7, R8, R9independently represent hydrogen or halogen, provided that when b is NR5D is SO2and R2is hydrogen, R3cannot represent hydrogen or unsubstituted C1-6-alkyl.

2. Connection on p. 1, where R3is R11or NR11R12where R11represents hydrogen, an unbranched or branched C1-18-alkyl, possibly mono - or politeley halogen, hydroxy, C1-6-alkoxy or aryl, and R12represents hydrogen.

3. The compound according to any one of paragraphs. 1 and 2, where the General formula I is

< / BR>
where A, D, R1-R5such as defined above.

4. Connection on p. 3, where R5represents C1-6-alkyl.

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

6. The compound according to any one of paragraphs. 3-5, where R4together with R5represent one of the links mule 1 is

< / BR>
where a, D, R1-R5such as defined above.

8. Connection on p. 7, where R5and R6independently represent C1-6-alkyl.

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 of paragraphs. 7-9, where R4together with R5represent one of the bonds in the double bond between the atoms 2 and 3 of formula I.

11. A compound selected from the following: 1,1-dioxide, 3-hydrazino-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-benzylamino-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-(R)-(1-phenylethylamine)-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-(S)-(1-phenylethylamine)-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-benzylamino-7-chloro-4H-pyrido[2,3-e] -1,2,4-thiadiazine, 1,1-dioxide 7-chloro-3-(R)-(1-phenylethylamine)-4H-pyrido[2,3-e] -1,2,4-thiadiazine, 1,1-dioxide 7-chloro-3-(S)-(1'-phenylethylamine)-4H-pyrido[2,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-benzylamino-4H-pyrido[2,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-(R)-(1-phenylethylamine)-4H-pyrido[2,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-(S)-(1-phenylethylamine)-4H-pyrido[2,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-octylamine-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 1,1-dioxide 7-chloro-3-octylamine-4H-pyrido[2,3, -e] -1,2,4-tied is diazine, 1,1-dioxide 7-chloro-3-(2-methoxy-1-methylethyl)amino-4H-pyrido[2,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-(2-methoxy-1-methylethyl)amino-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-(2-hydroxy-1-methylethyl)amino-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 1,1-dioxide, 3-benzylamino-2-methyl-4H-pyrido[4,3-e] -1,2,4-thiadiazine, 4,4-dioxide, 2-isopropylamino-3,3-dimethoxy-3H-pyrido[2,3-b] [1,4] thiazine.

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

13. Pharmaceutical composition having inhibitory insulin activity and containing the connection on p. 1 or its pharmaceutically acceptable salt with a pharmaceutically acceptable acid or base, together with one or more pharmaceutically acceptable carriers or diluents.

14. The pharmaceutical composition according to p. 13, characterizing the fact that it can be used in the form of an oral dosage unit or parenteral dosage unit.

15. The compound according to any one of paragraphs. 1-12 or its pharmaceutically acceptable salt with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including the CLASS="ptx2">

16. The compound according to any one of paragraphs. 1-12 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 forms for obtaining a medicinal product with inhibitory insulin activity.

17. The manner of the manifestation of inhibiting insulin secretion activity of the subject, ordaudio, which consists in the introduction of an effective amount of a compound according to any one of paragraphs. 1-12 this subject.

Priority points:

17.01.1996 on PP. 1 and 2, 12-17;

05.03.1996 on PP. 3-17;

16.01.1997 on PP. 11 and 12.

 

Same patents:

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

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