RU2199542C2 - Derivatives of condensed 1,2,4-thiadiazine and condensed 1,4-thiazine, their synthesis and using - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, pharmacy. SUBSTANCE: invention describes novel derivatives of condensed 1,2,4-thiadiazine of the general formula (I)

given in the description where B means one of bonds in double bond between atoms 2 and 3 of ring of the formula (I); D means -S(=O)₂-; R¹ means hydrogen atom; R⁴ means hydrogen atom; or R⁴ in common with R⁵ means one of bonds in double bond between atoms 2 and 3 of the formula (I); or R¹ in common with R⁴ means one of bonds in double bond between atoms 3 and 4 of the formula (I); R² means hydrogen atom, C_1-6-alkyl, C_3-6-cycloalkyl, C_2-6-alkenyl; R³ means R⁸, aryl substituted with C_1-6-alkyl where R⁸ means hydrogen atom, C_3-6-cycloalkyl or (C_3-6-cycloalkyl)-C_1-6-alkyl, unbranched or branched C_1-18-alkyl, with optionally mono- or polysubstituted hydroxy-group, C_3-6-cycloalkyl, aryl, carboxy-group; A in common with 5 and 6 carbon atoms of the formula (I) means 5-membered heterocyclic system containing one or two nitrogen atoms or one sulfur atom being heterocyclic systems are optionally mono- or poly-substituted with halogen atom under condition of excluding the following compounds: 3-aminoimidazo-[4,5-e] -1,2,4-thiadiazine 1,1-dioxide and 3-(benzoylamino)-imidazo-[4,5-e] -1,2,4-thiadiazine 1,1-dioxide or its salt with pharmaceutically acceptable acid or base. New compounds are used as agents opening K_ATF-regulated potassium channels. Also, invention describes pharmaceutical composition eliciting effect on K_ATF-regulated potassium channels and method of effect on K_ATF-regulated channels. EFFECT: improved method of synthesis, valuable medicinal properties of compounds. 18 cl, 23 ex

Description

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

Prior art
Potassium channels play an important role in membrane potential. Among the various types of potassium channels there are ATP-sensitive (K _ATP ) channels, which are regulated by changes in the intracellular concentration of adenosine triphosphate. K _ATP channels were found in cells from various tissues, such as cardiac cells, pancreatic cells, skeletal muscle, smooth muscle, central neurons, and adenohypophysis cells. These channels are associated with various cellular functions, for example, secretion of hormones (insulin from pancreatic beta cells, growth hormone and prolactin from adenohypophysis cells), expansion of blood vessels (in smooth muscle cells), potential duration of cardiac activity, and the release of neurotransmitters in the central nervous system.

It was found that modulators of K _ATP channels are of great importance in the treatment of various diseases. Some sulfonylureas that have been used to treat non-insulin-dependent diabetes mellitus act by stimulating the release of insulin by inhibiting K _ATP channels in pancreatic beta cells,
It was found that potassium channel openers, which include a heterogeneous group of compounds, are able to relax the smooth muscles of blood vessels and are therefore used to treat hypertension.

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

 Moreover, it was shown that potassium channel openers stimulate hair growth, they were used to treat baldness.

 Potassium channel openers are also able to relax the smooth muscles of the bladder, therefore, they can be used to treat urinary incontinence. Potassium channel openers that relax the smooth muscles of the uterus can be used to prevent premature birth.

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

It has recently been shown that diazoxide (1,1-dioxide 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine) and some derivatives of 1,1-dioxides 3- (alkylamino) -4H-pyrido [4, 3rd] -1,2,4-thia-diazines inhibit insulin release by activation of K _ATP channels in pancreatic beta cells (B. Pirotte et al., Biochem. Pharmacol., 47, 1381-1386 (1994); Pirotte B. et al., J. Med. Chem., 36, 3211-3213 (1993)). In addition, diazoxide has been shown to slow the onset of diabetes in BB rats (Vlahos WD et al., Metabolism, 40, 39-46 (1991). Diazoxide has been shown to reduce insulin secretion and increase binding in obese sucker rats. insulin receptors and therefore increases glucose tolerance and reduces weight gain (Alemzadeh R. et al., Endocrinol., 133, 705-712, 1993). It is believed that such compounds can be used to treat diseases characterized by increased insulin production, and for the treatment and prevention of diabetes.

 EP 618209 describes a class of pyridothiadiazine derivatives having an alkyl or alkylamino group at position 3 of the thiadiazine ring. These compounds are claimed to be AMPA glutamate receptor agonists.

 In J. Med. Chem., 1980, 23,575-577, describes the synthesis of 4 (5) -amino-and-formylaminoimidazo-5 (4) -carboxamides and their properties as chemotherapeutic agents. In particular, the compounds 1,1-dioxide-3-aminoimidazo [4,5-e] -1,2,4-thiadiazine and 1,1-dioxide N-benzoylaminoimidazo [4,5-e] -1,2,4 -thiadiazine.

где В представляет >NR⁵ или >CR⁵R⁶, где R⁵ и R⁶ независимо представляют водород; гидрокси; C_1-6-алкокси; C_1-6-алкил, C_3-6- циклоалкил, C_2-6-алкенил или C_2-6-алкинил, необязательно моно- или полизамещенный галогеном; или R⁵ и R⁴ вместе представляют одну из связей в двойной связи между атомами 2 и 3 формулы I;
D представляет -S(=О)₂- или -S(=О)- или
D-B представляет -S(=О)(R⁷)=N-,
где R⁷ представляет C_1-6-алкил, или арил, или гетероарил, необязательно моно- или полизамещенный галогеном, гидрокси, C_1-6-алкокси, арилокси, арилалкокси, нитро, амино, C_1-6-моноалкил- или диалкиламино, циано, ацилом или C_1-6-алкоксикарбонилом;
R¹ представляет водород; гидрокси; C_1-6-алкокси или C_1-6-алкил, C_3-6-циклоалкил, C_2-6-алкенил или C_2-6-алкинил, необязательно моно- или полизамещенный галогеном, и R⁴ представляет водород или R⁴ вместе с R⁵ представляют одну из связей в двойной связи между атомами 2 и 3 формулы I или R¹ вместе с R⁴ представляют одну из связей в двойной связи между атомами 3 и 4 формулы I;
R² представляет водород; гидрокси; C_1-6-алкокси или C_1-6-алкил, C_3-6-циклоалкил, C_2-6-алкенил или C_2-6-алкинил, необязательно моно- или полизамещенный галогеном;
R³ представляет R⁸; -OR⁸; -C(=X)R⁸; -NR⁸R⁹; бициклоалкил, арил, гетероарил, арилалкил или гетероарилалкил, необязательно моно- или полизамещенный галогеном, гидрокси, C_1-6-алкокси, арилокси, арилалкокси, нитро, амино, C_1-6-моноалкил- или диалкиламино, циано, оксо, ацилом или C_1-6-алкоксикарбонилом, или арил, замещенный C_1-6-алкилом,
где R⁸ представляет водород; C_3-6-циклоалкил или (C_3-6-циклоалкил)C_1-6-алкил, причем C_3-6-циклоалкильная группа необязательно моно- или полизамещена C_1-6-алкилом, галогеном, гидрокси или C_1-6-алкокси; 3-6-членная насыщенная циклическая система, содержащая один или несколько атомов азота, кислорода или серы, или неразветвленный или разветвленный C_1-18-алкил, необязательно моно- или полизамещенный галогеном, гидрокси, C_1-6-алкокси, C_1-6-алкилтио, C_3-6-циклоалкилом, арилом, арилокси, арилалкокси, нитро, амино, C_1-6-моноалкил- или диалкиламино, циано, оксо, формилом, ацилом, карбокси, C_1-6-алкоксикарбонилом или карбамоилом;
Х представляет О или S;
R⁹ представляет водород, C_1-6-алкил, C_2-6-алкенил; C_3-6-циклоалкил, необязательно моно- или полизамещенный C_1-6-алкилом, галогеном, гидрокси или C_1-6-алкокси, или R⁸ и R⁹ вместе с атомом азота образуют 3-12-членную моно- или бициклическую систему, в которой один или несколько атомов углерода могут быть заменены на азот, кислород или серу, причем каждая из этих циклических систем является необязательно моно- или полизамещенной галогеном, C_1-6-алкилом, гидрокси, C_1-6-алкилом, гидрокси, C_1-6-алкокси, C_1-6-алкокси-C_1-6-алкилом, нитро, амино, циано, трифторметилом, C_1-6-моноалкил- или диалкиламино, оксо,
или R³ представляет

где n, m, p независимо равны 0, 1, 2, 3 и
R¹⁰ представляет водород; гидрокси; C_1-6-алкокси; C_3-6-циклоалкил, необязательно моно- или полизамещенный C_1-6-алкилом, галогеном, гидрокси- или C_1-6-алкокси; C_1-6-алкил, C_2-6-алкенил или C_2-6-алкинил, необязательно моно- или полизамещенный галогеном, или R² и R³ вместе с атомом азота образуют 3-12-членную моно- или бициклическую систему, в которой один или несколько атомов углерода могут быть заменены на азот, кислород или серу, причем каждая из этих циклических систем является необязательно моно- или полизамещенной галогеном, C_1-6-алкилом, гидрокси, C_1-6-алкокси, C_1-6-алкокси-C_1-6-алкилом, нитро, амино, циано, трифторметилом, C_1-6-моноалкил- или диалкиламино, или оксо;
А вместе с 5 и 6 атомами углерода формулы I представляют 5- или 6-членную гетероциклическую систему, содержащую один или несколько атомов азота, кислорода или серы, причем гетероциклические системы необязательно моно- или полизамещены галогеном; C_1-12-алкилом; C_3-6-циклоалкилом; гидрокси; C_1-6-алкокси; C_1-6-алкокси-C_1-6-алкилом; нитро; амино; циано; цианометилом; пергалогенметилом; C_1-6-моноалкил- или диалкиламино; сульфамоилом; C_1-6-алкилтио; C_1-6-алкилсульфонилом, C_1-6-алкилсульфинилом; C_1-6-алкилкарбониламино; арилтио, арилсульфинилом, арилсульфонилом, причем арильная группа необязательно моно- или полизамещена C_1-6-алкилом, галогеном, гидрокси или C_1-6-алкокси; C_1-6-алкоксикарбонилом; C_1-6-алкоксикарбонил-C_1-6-алкилом; карбамилом; карбамилметилом; C_1-6-моноалкил- или диалкиламинкарбонилом; C_1-6-моноалкил- или диалкиламинотиокарбонилом; уреидо; C_1-6-моноалкил- или диалкиламинокарбониламино, тиоуреидо; C_1-6-моноалкил- или диалкиламинотиокарбониламино; C_1-6-моноалкил- или диалкиламиносульфонилом; карбокси; карбокси-C_1-6-алкилом; ацилом; арилом, арилалкилом, арилокси, причем арильная группа необязательно моно- или полизамещена C_1-6-алкилом, галогеном, гидрокси или C_1-6-алкокси; (1,2,3-оксадиазол-5-ил)- или (1,2,4-оксадиазол-3-ил)-C_1-6-алкилом, причем оксадиазолильная группа необязательно замещена C_1-6-алкилом или C_3-6-циклоалкилом, или 5-6-членным азотсодержащим кольцом, необязательно замещенным фенилом или C_1-6-алкилом;
при условии, что А вместе с атомами углерода 5 и 6 формулы I не образуют кольцо пиридина и что не включены следующие соединения: 1,1-диоксид 3-амино-2,5-дигидроимидазо[4,5-е] -1,2,4-тиадиазина и 1,1-диоксид 3-бензоиламино-2,5-дигидро-имидазо[4,5-е]-1,2,4-тиадиазина,
или их солям с фармацевтически приемлемой кислотой или основанием.Description of the invention
The present invention relates to derivatives of fused 1,2,4-thiadiazine and fused 1,4-thiazine of general formula I

where B represents> NR ⁵ or> CR ⁵ R ⁶ where R ⁵ and R ⁶ independently represent hydrogen; hydroxy; C _1-6 alkoxy; C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally mono- or polysubstituted with halogen; or R ⁵ and R ⁴ together represent one of the bonds in the double bond between atoms 2 and 3 of formula I;
D represents -S (= O) ₂ - or -S (= O) - or
DB is —S (= O) (R ⁷ ) = N—,
wherein R ⁷ is C _1-6 alkyl or aryl or heteroaryl, optionally mono- or polysubstituted with halogen, hydroxy, C _1-6 alkoxy, aryloxy, arylalkoxy, nitro, amino, C _1-6 monoalkyl or dialkylamino , cyano, acyl or C _1-6 alkoxycarbonyl;
R ¹ represents hydrogen; hydroxy; C _1-6 alkoxy or C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally mono or polysubstituted with halogen, and R ⁴ is hydrogen or R ⁴ together with R ⁵ represent one of the bonds in the double bond between atoms 2 and 3 of the formula I or R ¹ together with R ⁴ represent one of the bonds in the double bond between the atoms 3 and 4 of the formula I;
R ² represents hydrogen; hydroxy; C _1-6 alkoxy or C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally mono- or polysubstituted with halogen;
R ³ represents R ⁸ ; -OR ⁸ ; -C (= X) R ⁸ ; -NR ⁸ R ⁹ ; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, optionally mono- or polysubstituted with halogen, hydroxy, C _1-6 alkoxy, aryloxy, arylalkoxy, nitro, amino, C _1-6 monoalkyl or dialkylamino, cyano, oxo, acyl C _1-6 alkoxycarbonyl, or aryl substituted with C _1-6 alkyl,
where R ⁸ represents hydrogen; C _3-6 cycloalkyl or (C _3-6 cycloalkyl) C _1-6 alkyl, wherein the C _3-6 cycloalkyl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy; A 3-6 membered saturated ring system containing one or more nitrogen, oxygen or sulfur atoms, or a straight or branched C _1-18 alkyl, optionally mono or polysubstituted with halogen, hydroxy, C _1-6 alkoxy, C _{1- 6-} alkylthio, C _3-6 cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, C _1-6 monoalkyl or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C _1-6 alkoxycarbonyl or carbamoyl;
X represents O or S;
R ⁹ represents hydrogen, C _1-6 alkyl, C _2-6 alkenyl; C _3-6 cycloalkyl optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy, or R ⁸ and R ⁹ together with the nitrogen atom form a 3-12 membered mono- or bicyclic a system in which one or more carbon atoms can be replaced by nitrogen, oxygen or sulfur, each of these cyclic systems being optionally mono- or polysubstituted with halogen, C _1-6 alkyl, hydroxy, C _1-6 alkyl, hydroxy , C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkyl, nitro, amino, cyano, trifluoromethyl, C _1-6 monoalkyl or dialkylamino, oxo,
or R ³ represents

where n, m, p are independently 0, 1, 2, 3 and
R ¹⁰ represents hydrogen; hydroxy; C _1-6 alkoxy; C _3-6 cycloalkyl optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy; C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally mono- or polysubstituted with halogen, or R ² and R ³ together with a nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more carbon atoms can be replaced by nitrogen, oxygen or sulfur, each of these cyclic systems being optionally mono- or polysubstituted with halogen, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C _{1- 6-} alkoxy-C _1-6 alkyl, nitro, amino, cyano, trifluoromethyl, C _1-6 monoalkyl or dialkylamino, or oxo;
And together with 5 and 6 carbon atoms of the formula I represent a 5- or 6-membered heterocyclic system containing one or more nitrogen, oxygen or sulfur atoms, the heterocyclic systems optionally mono- or polysubstituted with halogen; C _1-12 alkyl; C _3-6 cycloalkyl; hydroxy; C _1-6 alkoxy; C _1-6 alkoxy-C _1-6 alkyl; nitro; amino; cyano; cyanomethyl; perhalogenomethyl; C _1-6 monoalkyl or dialkylamino; sulfamoyl; C _1-6 alkylthio; C _1-6 alkylsulfonyl; C _1-6 alkylsulfinyl; C _1-6 alkylcarbonylamino; arylthio, arylsulfinyl, arylsulfonyl, wherein the aryl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy; C _1-6 alkoxycarbonyl; C _1-6 alkoxycarbonyl-C _1-6 alkyl; carbamyl; carbamylmethyl; C _1-6 monoalkyl or dialkylamine carbonyl; C _1-6 monoalkyl or dialkylaminothiocarbonyl; ureido; C _1-6 monoalkyl or dialkylaminocarbonylamino, thioureido; C _1-6 monoalkyl or dialkylaminothiocarbonylamino; C _1-6 monoalkyl or dialkylaminosulfonyl; carboxy; carboxy-C _1-6 -alkyl; acyl; aryl, arylalkyl, aryloxy, wherein the aryl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy; (1,2,3-oxadiazol-5-yl) - or (1,2,4-oxadiazol-3-yl) -C _1-6 alkyl, wherein the oxadiazolyl group is optionally substituted with C _1-6 alkyl or C _{3 -6-} cycloalkyl, or a 5-6-membered nitrogen-containing ring, optionally substituted with phenyl or C _1-6 -alkyl;
provided that A together with the carbon atoms 5 and 6 of formula I do not form a pyridine ring and that the following compounds are not included: 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 a pharmaceutically acceptable acid or base.

 All optical isomers of compounds of formula I are included within the scope of the invention, some of which are optically active, as well as mixtures thereof, including racemic mixtures thereof.

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

 Salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkyl ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malic, pyruvic, citric, tartaric acid salts. fumaric, almond, benzoic, cinnamon, methanesulfonic, ethanesulfonic, picric acid and the like, and include acids related to pharmaceutical iemlemym salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), and incorporated herein by reference, or lithium, sodium, potassium, magnesium, and the like.

The term “C _1-6 alkoxy” as used herein, alone or in combination, refers to a straight or branched monovalent substituent containing a C _1-6 alkyl group bonded through ether oxygen having a free valence bond from oxygen of the ether group and containing from 1 to 6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.

The term “C _1-6 alkylthio” as used herein, alone or in combination, refers to an unbranched or branched monovalent substituent containing a lower alkyl group bonded via a divalent sulfur atom, having a free valence bond from a sulfur atom and containing from 1 to 6 carbon atoms, for example methylthio, ethylthio, propylthio, butylthio, pentylthio.

The term “C _2-6 alkenyl” as used herein refers to an unsaturated hydrocarbon chain containing 2-6 carbon atoms and one double bond such as vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.

The term “C _3-6 -cycloalkyl” as used herein refers to a saturated cyclic hydrocarbon radical of the indicated number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

и тому подобное.The term “C _2-6 alkynyl” as used herein refers to unsaturated hydrocarbons that contain triple bonds, such as, for example,

etc.

The term “C _1-6 alkoxy-C _1-6 alkyl” as used herein refers to a group of 2-12 carbon atoms interrupted by O, such as CH ₂ —O — CH ₃ , CH ₂ —O — CH ₂ —CH ₃ , CH ₂ —O — CH (CH ₃ ) ₂ and the like.

 The term “halogen” means fluoro, chloro, bromo or iodo.

 The term “perhalogenomethyl” means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.

The terms “C _1-6 alkyl”, “C _1-12 alkyl” and “C _1-18 alkyl”, as used herein, alone or in combination, refer to a straight or branched saturated hydrocarbon chain having the indicated 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 “C _1-18 alkyl” as used herein also includes secondary C _3-6 alkyl and tertiary C _4-6 alkyl.

The term “C _1-6 -monoalkylamino” as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a straight or branched saturated hydrocarbon chain having the indicated number of carbon atoms, such as methylamino, ethylamino, propylamino, n-butylamino, sec- butylamino, isobutylamino, tert-butylamino, n-pentylamino, 2-methylbutylamino, n-hexylamino, 4-methylpentylamino, non-opentylamino, n-hexylamino, 2,2-dimethylpropylamino and the like.

The term “C _1-6 dialkylamino” as used herein refers to an amino group wherein two hydrogen atoms are substituted with a straight or branched saturated hydrocarbon chain having the indicated 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 herein refers to a monovalent substituent containing a C _1-6 alkyl group linked through a carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valery and the like.

The term “C _1-6 alkoxycarbonyl” as used herein refers to a monovalent substituent containing a C _1-6 alkoxy group linked through a carbonyl group, such as, for example, methoxycarbonyl, carbetoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec- butoxy-carbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.

The term “3-12 membered mono- or bicyclic system,” as used herein, refers to a monovalent substituent of the formula —NR ² R ³ or —NR ⁸ R ⁹ , wherein R ² and R ³ or R ⁸ and R ⁹ together with a nitrogen atom form a 3-12 membered mono- or bicyclic system in which one or more carbon atoms can be replaced with nitrogen, oxygen or sulfur, such as 1-pyrrolidyl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 7 -azabicyclo [2.2.1] heptan-7-yl, tropanil and the like.

 The term “3-6 membered saturated ring system” as used herein refers to a monovalent substituent containing a monocyclic saturated system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, having 3-6 members and having a free valency at the atom carbon, for example 2-pyrrolidyl, 4-piperidyl, 3-morpholinyl, 1,4-dioxan-2-yl, 5-oxazolidinyl, 4-isoxazolidinyl or 2-thiomorpholinyl.

 The term “bicycloalkyl” as used herein refers to a monovalent substituent containing a 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] nonanyl.

 The term “aryl,” as used herein, refers to phenyl, 1-naphthyl or 2-naphthyl.

 The term “heteroaryl” as used herein, alone or in combination, refers to a monovalent substituent containing a 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, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuin, benzofuin.

 The term “arylalkyl” as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbon atoms and substituted with an aromatic hydrocarbon such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- (1-naphthyl) ethyl and the like.

 The term “aryloxy” as used herein refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy.

The term "arylalkoxy" as used herein refers to a C _1-6 alkoxy group substituted with an aromatic hydrocarbon such as benzyloxy, phenethyloxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2- (1-naphthyl) ethoxy and the like.

 The term “heteroarylalkyl,” as used herein, refers to a straight or branched saturated carbon chain containing from 1 to 6 carbon atoms and substituted with a 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 “C _1-6 alkylsulfonyl” as used herein refers to a monovalent substituent containing a C _1-6 alkyl group linked via a sulfonyl group, such as, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl , sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, neopentylsulfonyl, n-hexylsulfonylphenylsulfonylphenylsulfonylphenylsulfonylphenylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl

The term “C _1-6 monoalkylaminosulfonyl” as used herein refers to a monovalent substituent containing a C _1-6 monoalkylamino group bonded through a sulfonyl group such as, for example, methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonylamino, n-butyl sec-butylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl, n-hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopentylamino ulphonyl, n-hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.

The term “C _1-6 dialkylaminosulfonyl” as used herein refers to a monovalent substituent containing a C _1-6 dialkylamino group bonded through a sulfonyl group such as dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, - (n-butyl) -N-methylaminosulfonyl, di (n-pentyl) aminosulfonyl and the like.

The term “C _1-6 alkylsulfonyl,” as used herein, refers to a monovalent substituent containing a straight or branched C _1-6 alkyl group linked through a sulfinyl group (-S (= O) -), such as, for example, methylsulfinyl ethylsulfinyl, isopropylsulfinyl, butyl sulfinyl, pentyl sulfinyl and the like.

The term “C _1-6 alkylcarbonylamino” as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with an acyl group such as, for example, acetamido, propionamido, isopropylcarbonylamino and the like.

The term (C _3-6 cycloalkyl) C _1-6 alkyl, as used herein, alone or in combination, refers to a straight or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms and monosubstituted with C _3-6 - cycloalkyl, wherein the cycloalkyl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy, such as, for example, cyclopropylmethyl, (1-methylcyclopropyl) methyl, 1- (cyclopropyl) ethyl, cyclopentylmethyl cyclohexylmethyl and the like.

The term “arylthio,” as used herein, alone or in combination, refers to an aryl group bonded via a divalent sulfur atom having a free valence bond from a sulfur atom, wherein the aryl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy, for example phenylthio, (4-methylphenyl) thio, (2-chlorophenyl) thio and the like.

The term “arylsulfinyl,” as used herein, refers to an aryl group bonded through a sulfinyl group (—S (= O) -), wherein the aryl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 -alkoxy, such as, for example, phenylsulfinyl, (4-chlorophenyl) sulfinyl and the like.

The term “arylsulfonyl,” as used herein, refers to an aryl group bonded through a sulfonyl group, wherein the aryl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy; such as, for example, phenylsulfonyl, tosyl and the like.

The term “C _1-6 monoalkylaminocarbonyl” as used herein refers to a monovalent substituent containing a C _1-6 monoalkylamino group bonded through a carbonyl group, such as, for example, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butyl sec-butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl, n-hexylaminocarbonyl, 4-methylpentylaminocarbonyl, neopentylaminocarbon aminocarbonyl and 2,2-dimetilpropilaminokarbonil.

The term “C _1-6 dialkylaminocarbonyl” as used herein refers to a monovalent substituent containing a C _1-6 dialkylamino group bonded through a carbonyl group, such as dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N n-butyl) -N-methylaminocarbonyl, di (n-pentyl) aminocarbonyl and the like.

The term “C _1-6 -monoalkylaminocarbonylamino” as used herein refers to an amino group where one of the hydrogen atoms is substituted with a C _1-6 -monoalkylaminocarbonyl group, for example methylaminocarbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, secopropylaminocarbonylamino-amino, butopropylaminocarbonylamino-amino, isobutylaminocarbonylamino, tert-butylaminocarbonylamino and 2-methylbutylaminocarbonylamino.

The term “C _1-6 dialkylaminocarbonylamino” as used herein refers to an amino group where one of the hydrogen atoms is substituted with a C _1-6 dialkylaminocarbonyl group such as dimethylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethylaminocarbonylamino, dipropylaminocarbonylamino n-butyl) -N-methylaminocarbonylamino, di (n-pentyl) aminocarbonylamino and the like.

 The term “5- or 6-membered heterocyclic system” as used herein refers to a monocyclic unsaturated or saturated system containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur and having 5 members, such as pyrrole, furan, thiophene , pyrroline, dihydrofuran, dihydrothiophene, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazole, isothiazole, 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 parts new, such as pyrazine, pyrimidine, pyridazine, 1,2,3-triazine or tetrazine; a non-aromatic monocyclic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and having 6 members, such as pyran, thiopyran, piperidine, dioxane, oxazine, isoxazine, dithian, oxatin, thiazine, piperazine, thiadiazine, dithiazine or oxadiazine .

 The term “5- or 6-membered nitrogen-containing ring” as used herein refers to a monovalent substituent containing a monocyclic unsaturated or saturated system containing one or more nitrogen atoms and having 5 or 6 members, for example pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolidinyl , piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, 1,3-diaziazole lanyl and 1,4-dioxolanyl.

 All optical isomers of compounds of formula I are included in the scope of the invention, some of which are optically active, as well as mixtures thereof, including racemic mixtures thereof.

где R¹ и R⁵ независимо представляют водород; гидрокси; C_1-6-алкокси или C_1-6-алкил, C_3-6-циклоалкил, C_2-6-алкенил или C_2-6-алкинил, необязательно моно- или полизамещенный галогеном, и R⁴ представляет водород или R⁴ вместе с R⁵ представляют одну из связей в двойной связи между атомами 2 и 3 формулы I и R¹, такой - как определено выше, или
R⁴ вместе с R¹ представляют одну из связей в двойной связи между атомами 3 и 4 формулы I и R⁵ - такой, как определено выше,
D представляет (-S(=O)₂- или -S(=O)-.In a preferred embodiment of the invention, the general formula of formula I is selected from

where R ¹ and R ⁵ independently represent hydrogen; hydroxy; C _1-6 alkoxy or C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally mono or polysubstituted with halogen, and R ⁴ is hydrogen or R ⁴ together with R ⁵ represent one of the bonds in the double bond between atoms 2 and 3 of the formula I and R ¹ , such as defined above, or
R ⁴ together with R ¹ represent one of the bonds in the double bond between atoms 3 and 4 of the formula I and R ⁵ - such as defined above,
D represents (-S (= O) ₂ - or -S (= O) -.

где R¹ представляет водород; гидрокси; C_1-6-алкокси или C_1-6-алкил, C_3-6-циклоалкил, C_2-6-алкенил или C_2-6-алкинил, необязательно моно- или полизамещенный галогеном, и R⁴ представляет водород или R⁴ вместе с R¹ представляют одну из связей в двойной связи между атомами 3 и 4 формулы I;
D представляет -S(=O)R⁷=
где R⁷ представляет C_1-6-алкил; арил или гетероарил, необязательно моно- или полизамещенный галогеном, гидрокси, C_1-6-алкокси, арилокси, нитро, амино, C_1-6-моноалкил- или диалкиламино, циано, ацилом или C_1-6-алкоксикарбонилом.In another preferred embodiment of the invention, the general formula of formula I is selected from

where R ¹ represents hydrogen; hydroxy; C _1-6 alkoxy or C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally mono or polysubstituted with halogen, and R ⁴ is hydrogen or R ⁴ together with R ¹ represent one of the bonds in the double bond between atoms 3 and 4 of the formula I;
D represents -S (= O) R ⁷ =
where R ⁷ represents C _1-6 -alkyl; aryl or heteroaryl, optionally mono- or polysubstituted with halogen, hydroxy, C _1-6 alkoxy, aryloxy, nitro, amino, C _1-6 monoalkyl or dialkylamino, cyano, acyl or C _1-6 alkoxycarbonyl.

где R¹, R⁵ и R⁶ независимо представляют водород; гидрокси; C_1-6-алкокси или C_1-6-алкил, C_3-6-циклоалкил, C_2-6-алкенил или C_2-6-алкинил, необязательно моно- или полизамещенный галогеном, и R⁴ представляет водород или
R⁴ вместе с R⁵ представляют одну из связей в двойной связи между атомами 2 и 3 формулы I и R¹ и R⁶ такие, как определено выше, или R⁴ вместе с R¹ представляют одну из связей в двойной связи между атомами 3 и 4 формулы I и R⁵ и R⁶ такие, как определено выше;
D представляет -S(=O)₂- или -S(=O)-.In another preferred embodiment of the invention, the compounds of general formula I are selected from

where R ¹ , R ⁵ and R ⁶ independently represent hydrogen; hydroxy; C _1-6 alkoxy or C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally mono or polysubstituted with halogen, and R ⁴ represents hydrogen or
R ⁴ together with R ⁵ represent one of the bonds in the double bond between atoms 2 and 3 of the formula I and R ¹ and R ⁶ are as defined above, or R ⁴ together with R ¹ represent one of the bonds in the double bond between the atoms 3 and 4 formulas I and R ⁵ and R ⁶ are as defined above;
D represents —S (= O) ₂ - or —S (= O) -.

 A preferred general formula I is formula Ia.

In another preferred embodiment, D is —S (═O) ₂ -.

In another preferred embodiment of the invention, R ^{1 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and C _2-6 alkenyl. Preferably, R ¹ is hydrogen or C _1-6 alkyl.

In another preferred embodiment of the invention, R ¹ together with R ⁴ represent one of the bonds in the double bond between atoms 3 and 4 of formula I.

In another preferred embodiment of the invention, R ⁴ together with R ⁵ represent one of the bonds in the double bond between atoms 2 and 3 of formula I.

In another preferred embodiment of the invention, R ^{2 is} selected from the group consisting of hydrogen, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl and C _2-6 alkenyl. R ^{2 is} preferably hydrogen or C _1-6 alkyl.

In another preferred embodiment of the invention, R ^{3 is} selected from R ⁸ , —OR ⁸ , —NR ⁸ R ⁹ or aryl, wherein the aryl group is optionally substituted with C _1-6 alkyl, where R ⁸ is hydrogen; C _3-6 cycloalkyl; (C _3-6 cycloalkyl) C _1-6 alkyl; A 3-6 membered saturated ring system containing one, two or three nitrogen, oxygen or sulfur atoms, or a straight or branched C _1-18 alkyl optionally substituted with halogen, hydroxy, C _1-6 alkoxy, C _{1- 6-} alkylthio, C _3-6 -cycloalkyl or aryl; R ⁹ represents hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, or R ⁸ and R ⁹ together with the nitrogen atom form a 4-6 membered ring, preferably 1-pyrrolidyl, piperidine or morpholino.

In yet another preferred embodiment of the invention, R ^{3 is} selected from the group consisting of secondary C _3-6 alkyl, tertiary C _4-6 alkyl, C _3-6 cycloalkyl or (C _3-6 cycloalkyl) methyl, optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy. R ^{3 is} preferably selected from the group consisting of 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-trimethylbutyl, 2-methylbutyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 1- (cyclopropyl ) ethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

In a further preferred embodiment of the invention, R ² and R ³ together with a nitrogen atom form a six-membered ring, optionally substituted at the 2-position with a C _1-6 alkyl group, preferably selected from methyl, ethyl or isopropyl. A preferred six-membered ring is a piperidine, piperazine, morpholine or thiomorpholine ring.

In another preferred embodiment of the invention, R ^{7 is} selected from C _1-6 alkyl, phenyl or pyridyl.

In another preferred embodiment of the invention, A, 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, A 6-membered aromatic heterocyclic system containing two or three nitrogen atoms, a 6-membered non-aromatic heterocyclic system containing one or two heteroatoms selected from nitrogen, oxygen and sulfur, these heterocyclic with Stem optionally mono- or disubstituted with substituents selected from the group consisting of halogen; C _1-12 alkyl; C _3-6 cycloalkyl; cyano; cyanomethyl; perhalogenomethyl; sulfamoyl; C _1-6 alkylthio; C _1-6 alkylsulfonyl; C _1-6 alkylsulfinyl; arylthio, arylsulfinyl, arylsulfonyl, wherein the aryl group is optionally mono- or polysubstituted with C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy; C _1-6 alkoxycarbonyl-C _1-6 alkyl; carbamoylmethyl; carboxy-C _1-6 -alkyl; aryloxy; (1,2,4-oxadiazol-5-yl) - or (1,2,4-oxadiazol-3-yl) C _1-6 alkyl, wherein the oxadiazolyl group is optionally substituted with C _1-6 alkyl or C _{3- 6} -cycloalkyl; acyl or a 5- or 6-membered nitrogen-containing ring, optionally substituted with phenyl or C _1-6 -alkyl.

 And preferably, together with 5 and 6 carbon atoms form a thieno [3,2-e] - or pyrrolo [3,2-e] -ring, thiophene, imidazole, thiazole, pyrazole, isoxazole or isothiazole, pyrazino [2,3-e ] -, pyrimido [4,5-e] -, pyrimido [5,4-e] -, pyridazino [4,5-e] - or pyridazino [4,5-e] ring, thiopyran, piperidine, dioxane, oxazine or dithian.

Preferred compounds of the invention are:
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;
1,1-dioxide (R) -6-chloro-3- (1-phenylethyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine;
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-tetradecylamino-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-octylamino-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-dimethylhexyl) 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;
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-sec-butylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine;
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-е] -1,2,4-thiadiazine 1,1-dioxide;
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;
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-octylamino-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-thiazolo [4,5-e] -1,2,4-thiadiazine 1,1-dioxide;
3-Isopropylamino-4H-thiazolo [5,4-e] -1,2,4-thiadiazine 1,1-dioxide
6-Bromo-3-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-Benzenesulfonyl-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-methylhexyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide;
3-Isopropylamino-4H-thieno [2,3-e] -1,2,4-thiadiazine 1,1-dioxide;
3-Isopropylamino-7-methyl-4H-thieno [2,3-e] -1,2,4-thiadiazine 1,1-dioxide;
7-cyano-3-isopropylamino-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;
1,1-dioxide 7-cyano-3-isopropylamino-4H-thieno [2,3-e] -1,2,4-thiadiazine;
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-е] -1,2,4-thiadiazine 1,1-dioxide;
3-hexylamino-7-methyl-4,7-dihydropyrazolo [4,3-е] -1,2,4-thiadiazine 1,1-dioxide;
7-methyl-3-octylamino-4,7-dihydropyrazolo [4,3-е] -1,2,4-thiadiazine 1,1-dioxide;
2,5-dihydro-3-isopropylaminoimidazo [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-Butylamino-2H-pyrazino [2,3-e] -1,2,4-thiadiazine 1,1-dioxide;
3-propylamino-2H-pyrazino [2,3-e] -1,2,4-thiadiazine 1,1-dioxide;
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-thiadiazine 1,1-dioxide;
3- (1,2-dimethylpropyl) 1,1-dioxide-2H-pyridazino [4,5-e] -1,2,4-thiadiazine;
3- (1-methylpropyl) amino-2H-pyridazino 1,1-dioxide [4,5-e] -1,2,4-thiadiazine;
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 1,1-dioxide.

 The 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 in the treatment of various diseases of the cardiovascular system, for example cerebral ischemia, hypertension, coronary heart disease, angina pectoris and coronary heart disease; pulmonary system, gastrointestinal system; central nervous system and endocrine system.

Since some K _ATP openers are capable of antagonizing vasospasm of the basal or cerebral arteries, the compounds of the present invention can be used to treat vasospastic disorders such as subarachnoid hemorrhage and migraine.

 Potassium channel openers hyperpolarize neurons and inhibit the release of transmitters, and it is believed that the present compound can be used to treat various diseases of the central nervous system, such as epilepsy, ischemia and neurodegenerative diseases, and to eliminate pain.

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

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

 In addition, the compounds of the invention can be used to treat chronic diseases of the respiratory tract, including asthma, and to treat instability of the muscles of the bladder, which empties it, side by side with the syndrome of infravesical obstruction, and, therefore, for kidney stones by facilitating their passage through the ureter. Potassium channel openers also relax the smooth muscles of the bladder, so the compounds of the present invention can be used to treat urinary incontinence.

 The present compounds can also be used to treat conditions associated with an impaired gastrointestinal motility, such as irritable bowel syndrome. Additionally, these compounds can be used to treat preterm labor and dysmenorrhea.

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

 In diseases such as pancreatic islet hyperplasia and insuloma, in which insulin hypersecretion causes severe hyperglycemia, the compounds of the present invention can be used to reduce insulin secretion. In obesity, hyperinsulinemia and insulin resistance are very common. This condition can lead to the development of non-insulin-dependent diabetes (NIDDM). It is contemplated that potassium channel openers, and therefore the compounds of the present invention, can be used to reduce hyperinsulinemia and thereby prevent diabetes and reduce obesity. With explicit NIDDM, treatment of hyperinsulinemia with potassium channel openers and therefore with these compounds can have a beneficial effect on the restoration of glucose susceptibility and normal insulin secretion.

 In cases of early stages of insulin-dependent diabetes (IDDM) or in pre-diabetic cases, potassium channel openers and therefore the present compounds can be used to induce dormancy of beta cells (basophilic cells), which can prevent the development of autoimmune disease.

Compounds of the present invention that act as blockers of K _ATP channels can be used to treat NIDDM.

 The compounds of the present invention can preferably be used for the treatment or prophylaxis 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 a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance for treating hyperinsulinemia and treating or preventing diabetes.

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

где А, В, D, R¹ и R⁴ такие, как определено выше, и Z представляет уходящую группу, такую как алкокси, алкилтио, галоген, предпочтительно хлор, бром, иод, триметиламино или метилсульфонил,
с соединением формулы III

где R² и R³ определены выше,
для образования соединения формулы I с использованием методик, описанных, например, Т. Н. 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).In another aspect, the present invention relates to methods for producing the above compounds. The method consists in:
a) the reaction of the compounds of formula II

where A, B, D, R ¹ and R ⁴ are as defined above, and Z represents a leaving group, such as alkoxy, alkylthio, halogen, preferably chlorine, bromine, iodine, trimethylamino or methylsulfonyl,
with a compound of formula III

where R ² and R ^{3 are as} defined above,
for the formation of the compounds of formula I using the techniques described, for example, T. N. 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).

где R¹ представляет водород и А, В, D и Х такие, как определено выше, или В представляет NH и R¹, A, D и Х такие, как определено выше,
с соединением формулы III или с его подходящей солью в присутствии Р₂О₅ и высококипящего третичного амина или его подходящей соли с использованием методики, описанной Jensen K.G. and Pedersen Е.В., Chem. Scr., 20, 248-250 (1988), and Andersen L. , Nielsen F.E. and Pedersen E.B., Chem.Scr., 29, 45-49 (1989), для образования соединения общей формулы I,
в) реакцию соединения формулы IV

где R¹ представляет водород и А, В, D и Х такие, как определено выше, или В представляет NH и R¹, А, D и Х такие, как определено выше,
с соединением формулы III или с его подходящей солью в присутствии тетрахлорида титана и растворителя, с которым он может образовать комплекс, возможно, например, тетрагидрофурана или смеси толуола и анизола, по методам, описанным в R.I. Fryer, J.V.Earley, G.F.Field, W.Zally and L.H.Steinbach, J.Org.Chem., 34, 1143-1145 (1969); J.В.Press et al., J.Med.Chem., 22, 725-731 (1979), or G.Roma et al., Eur.J.Med.Chem., 26, 489-496 (1991), для образования соединения общей формулы I,
г) реакцию соединения формулы V

где R¹ и А такие, как определено выше,
с соединением формулы VI
R³NCO (VI)
где R³ такой, как определено выше,
с использованием метода, описанного Chern J.W. et al., J.Heterocycl. Chem., 27, 1909-1915 (1990), для образования соединения общей формулы I, где D представляет SO₂, В представляет >NR⁵, R² представляет Н и R⁴ и R⁵ вместе образуют связь,
д) реакцию соединения формулы V

где R¹ и А такие, как определено выше,
с соединением формулы VII
R³NHC(=O)CI
где R³ такой, как определено выше,
c использованием метода, описанного Chern J.W. et al., J.Heterocycl. Chem., 27, 1909-1915 (1990), для образования соединения общей формулы I, где D представляет SO₂, В представляет >NR⁵, R² представляет Н и R⁴ и R⁵ вместе образуют связь,
е) реакцию соединения формулы V

где R¹ и А такие, как определено выше,
с соединением формулы VIII

где Y представляет NH или S,
или с его подходящей солью с использованием методик, описанных Kotovskaya S.K. et. al., Khim.-Farm.Zh., 13, 54-57 (русск.) (1979), and Topliss J. G. et al., J.Org. Chem., 28, 2313 (1963), для образования соединения общей формулы I, где D представляет SO₂, В представляет >NR⁵, R⁴ и R⁵ вместе образуют связь и R² и R³ представляют Н,
ж) реакцию в присутствии основания соединения формулы IX

или его подходящей соли,
где R¹¹ представляет R¹ или EtOC(=O),
где R¹ и А такие, как определено выше,
с соединением формулы Х
R³N=C=S (X)
где R³ такой, как определено выше,
для образования аддукта, который может иметь одну из двух структур XI и XII или может быть смесью этих двух структур

любая из которых посредством замыкания цикла, например, обработкой фосгеном в подходящем растворителе, образует соединение общей формулы I, если R¹¹ представляет R¹, где D представляет S(=O)₂, В представляет >NR⁵, R² представляет Н и R⁴ и R⁵ вместе образуют связь и соединение общей формулы ХIII, если R¹¹ представляет EtOC(=O);

з) гидролиз и последующее декарбоксилирование соединения общей формулы ХIII

для образования соединения общей формулы I, где D представляет S(=O)₂, В представляет >NR⁵, R¹ и R² представляют Н и R⁴ и R⁵ вместе образуют связь, например, нагреванием исходного соединения в водном основании.Another method involves:
b) the reaction of the compounds of formula IV

where R ¹ represents hydrogen and A, B, D and X are as defined above, or B is NH and R ¹ , A, D and X are as defined above,
with a compound of formula III or with a suitable salt thereof in the presence of P ₂ O ₅ and a high boiling tertiary amine or a suitable salt thereof using the procedure described by Jensen KG and Pedersen EV, Chem. Scr., 20, 248-250 (1988), and Andersen L., Nielsen FE and Pedersen EB, Chem. Scr., 29, 45-49 (1989), to form a compound of general formula I,
C) the reaction of the compounds of formula IV

where R ¹ represents hydrogen and A, B, D and X are as defined above, or B is NH and R ¹ , A, D and X are as defined above,
with a compound of formula III or with a suitable salt thereof in the presence of titanium tetrachloride and a solvent with which it can complex, possibly for example tetrahydrofuran or a mixture of toluene and anisole, according to the methods described in RI Fryer, JVEarley, GFField, W.Zally and LHSteinbach, J. Org. Chem., 34, 1143-1145 (1969); J. B. Press et al., J. Med. Chem., 22, 725-731 (1979), or G. Roma et al., Eur. J. Med. Chem., 26, 489-496 (1991) , for the formation of compounds of General formula I,
g) the reaction of the compounds of formula V

where R ¹ and A are as defined above,
with a compound of formula VI
R ³ NCO (VI)
where R ³ is as defined above,
using the method described by Chern JW et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), to form a compound of general formula I, where D is SO ₂ , B is> NR ⁵ , R ² is H, and R ⁴ and R ⁵ together form a bond,
d) the reaction of the compounds of formula V

where R ¹ and A are as defined above,
with the compound of formula VII
R ³ NHC (= O) CI
where R ³ is as defined above,
using the method described by Chern JW et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), to form a compound of general formula I, where D is SO ₂ , B is> NR ⁵ , R ² is H, and R ⁴ and R ⁵ together form a bond,
e) the reaction of the compounds of formula V

where R ¹ and A are as defined above,
with the compound of formula VIII

where Y represents NH or S,
or with a suitable salt thereof using the procedures described by Kotovskaya SK et. al., Khim.-Farm.Zh., 13, 54-57 (Russian) (1979), and Topliss JG et al., J. Org. Chem., 28, 2313 (1963), to form a compound of general formula I, where D is SO ₂ , B is> NR ⁵ , R ⁴ and R ⁵ together form a bond and R ² and R ³ are H,
g) reaction in the presence of a base of a compound of formula IX

or a suitable salt thereof,
where R ¹¹ represents R ¹ or EtOC (= O),
where R ¹ and A are as defined above,
with a compound of formula X
R ³ N = C = S (X)
where R ³ is as defined above,
for the formation of an adduct, which may have one of two structures XI and XII or may be a mixture of these two structures

any of which, by closing the loop, for example by treating with phosgene in a suitable solvent, forms a compound of general formula I if R ¹¹ represents R ¹ , where D represents S (= O) ₂ , B represents> NR ⁵ , R ² represents H and R ⁴ and R ⁵ together form a bond and a compound of general formula XIII, if R ¹¹ is EtOC (= O);

h) hydrolysis and subsequent decarboxylation of the compounds of General formula XIII

to form a compound of general formula I, where D is S (= O) ₂ , B is> NR ⁵ , R ¹ and R ² are H and R ⁴ and R ⁵ together form a bond, for example, by heating the starting compound in an aqueous base.

 The starting materials are either known compounds or compounds that can be obtained by analogy with the preparation of known compounds 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 RF, 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 Cram D.J., 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), Kresze G., Hatjiissaak A., Phosphorus Sulfur, 29, 41-47 (1987), Dillard RD, Yen TT , Stark P., Pavey DE, J. Med. Chem., 23, 717-722 (1980).

Arch. , 391, 85-100 (1981)), можно зарегистрировать ионный ток через отдельный канал клетки.Pharmacological methods
The ability of compounds to interact with potassium channels can be determined in various ways. When open-close techniques are used (Hamill, O.R., Marty A., Nefer E., Sakman B. and Sigworth FJ,

Arch. , 391, 85-100 (1981)), it is possible to register an ion current through a separate channel of the cell.

 The activity of compounds as potassium channel openers can also be measured by the relaxation method of rat aortic rings according to the following procedure.

 The portion of the rat thoracic aorta between the aortic arch and the diaphragm is dissected and prepared as ring preparations, as described by Taylor P.D. et al., Brit. J. Pharmacol., 111, 42-48 (1994).

 After a 45 min equilibrium period at a voltage of 2 g, the preparations were reduced to 80% of the maximum response using the required phenylephrine concentration. When the response to phenylephrine reached a plateau, potential vasodilating agents were cumulatively added to the bath in small volumes at intervals of 2 minutes using half logarithmic molar amounts. Relaxation was expressed as a percentage of the target voltage. The activity of the compound was expressed as the concentration required to induce 50% tissue relaxation.

Rat Aortic Ring Relaxation
Connection - EC ₅₀ microM
1 - 1,2
2 - 15
16 - 6.1
In pancreatic β-cell, the opening of K _ATP channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca ²⁺ according to the method of Arkhammer P. et al., J. Biol. Chem., 262, 5448-5454 (1987).

Leakage of ⁸⁶ Rb ⁺ from the β cell line
The RIN 5F cell line was cultured in RPMI 1640 medium with Glutamax I supplemented with 10% fetal calf serum (from GibcoBRL, Scotland, UK) and kept in an atmosphere of 5% CO ₂ /95% air at 37 ^° C. The cells were separated with a trypsin-solution EDTA (from GibcoBRL, Scotland, UK), resuspended in medium, 1 mCi / ml ⁸⁶ Rb ^{+ was} added and subcultured into microtiter plates (96-well cluster, 3596, sterile, from Costar Corporation, MA, USA) at a density of 50,000 cells / well in 100 ml / well and cultured 24 hours before use in the analysis.

The microplates were washed 4 times with Ringer's buffer (150 mM NaCl, 10 mM HEPES, 3.0 mM KCl, 1.0 mM CaCl ₂ , 20 mM sucrose, pH 7.1). 80 μl of Ringer's buffer and 1 μl of the control or test compound dissolved in DMSO were added. After incubation for 1 h at room temperature with a lid, 50 μl of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 μl of MicroScint 40 (Packard Instrument Company, CT, USA) was added. Microplate counting was performed at TopCount (Packard Instrument Company, CT, USA) at a speed of 1 min / well in a ³² P. program.

Calculation of EC ₅₀ and _Еmax was carried out according to SlideWrite (software of the given graphs, Inc., CA, USA) using a calculation curve with four parameters: y = (ad) / (1+ (x / s) ^b ) + d, where a is the activity estimated at zero concentration, b is the slope factor, c is the concentration in the middle of the curve, and d is the activity estimated at infinite concentration. EC ₅₀ = c and E _max = d when the curve rotates at infinite concentration.

Inhibition of Rb Flow in RIN 5F Cells
Connection - EC ₅₀ microM
1 - 2.7
16 - 5.9
The compounds of the invention are effective over 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 route of administration, the form in which it is administered, the subject to be treated, and the body weight of the subject to be treated, and the preferences and experience of the doctor or veterinarian.

 The route of administration may be any route that effectively transfers the active compound to a suitable or desired locus of action, such as an oral or parenteral route, for example, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, with the oral route being preferred.

 Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient, which may be a carrier or diluent, or diluted with a carrier or enclosed in a carrier, which may be in the form of a capsule, pouch, paper or other container. In the manufacture of compositions, conventional methods for the preparation of pharmaceutical compositions can be used. For example, the active compound will usually be mixed with a carrier, or diluted with a carrier, or enclosed in a carrier, which may be in the form of an ampoule, capsule, pouch, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a carrier, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example in a bag. Some examples of suitable carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, monoglycerides and diglycerides of fatty acids, pentaerythritol and fattyl esters of fatty acids and hydroxy fattyl ethers, hydrochloride and fatty acids, hydroxy fatty acids and fatty acids. Formulations may also include wetting agents, emulsifying and suspending agents, preservatives, sweeteners or flavoring agents. The formulations of the invention can be formulated to provide quick, sustained or delayed release of the active ingredient after administration to the patient, using methods well known in the art.

 Pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, emulsifiers, salt to influence osmotic pressure, buffers and / or coloring agents and the like, which do not react with active compounds with a deterioration in their quality.

 Injectable solutions or suspensions, especially aqueous solutions with an active compound dissolved in polyhydroxylated castor oil, are particularly suitable for parenteral use.

 Tablets, dragees, or capsules having talc and / or a carbohydrate carrier, or a binder, or the like, are particularly suitable for oral use. Preferred carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch. A syrup or elixir may be used in cases where a sweetened filler may be used.

A typical tablet suitable for use in this method can be obtained by conventional tabletting methods, it contains:
Active compound, mg - 5.0
Lactose, mg Ph.Eur. - 67.8
Avicel ^® , mg - 31.4
Amberlit ^® , mg - 1.0
Magnesium Stearate, mg Ph.Eur. - 0.25
Owing to the high degree of their activity, the compounds of the invention can be administered to an animal in need of such treatment, prophylaxis, relief or reduction of the intensity of the symptoms of various diseases mentioned above, and especially diseases of the endocrine system, such as hyperinsulinemia and diabetes. Such animals include both domestic animals, for example pets, and domestic animals, such as wild animals. A preferred animal is a mammal, especially a human.

 The method for producing compounds of formula I and preparations containing them is further illustrated by the following examples, which, however, should not be construed as limiting the invention.

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

a) Ethyl 5-chloro-2-sulfamoylthiophene-3-carboxylate
A solution of 2- (N-tert-butylsulfamoyl) -5-chlorothiophene-3-carboxylic acid (60.0 g; 0.21 mol) obtained according to the procedure 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 at the boil under reflux for 17 hours. The cooled solution was evaporated to dryness and the residue was purified by trituration with water and dried, obtaining 52.3 g (96%) of the specified connection header.

1,31 (t, J=7 Hz, 3Н, СН₃), 4,32 (q, J=7 Hz, 2H, CH₂), 7,55 (s, 1H), 7,77 (br.s, 2H, NH₂). ¹ H-NMR (DMSO-d ₆ ):

1.31 (t, J = 7 Hz, 3H, CH ₃ ), 4.32 (q, J = 7 Hz, 2H, CH ₂ ), 7.55 (s, 1H), 7.77 (br.s , 2H, NH ₂ ).

b) 5-Chloro-2-sulfamoylthiophene-3-carbohydrazide
Ethyl 5-chloro-2-sulfamoylthiophene-3-carboxylate (50.0 g, 0.185 mol) was added in one portion to 98% hydrazine hydrate (50 ml) with stirring at room temperature. The reaction was slightly exothermic. The solution was stirred for 90 minutes and concentrated. The residue was crystallized by trituration with 250 ml of water, the mixture was acidified with concentrated hydrochloric acid to pH 2-3 and stirred for 30 minutes at 0 ^° C. The product was isolated by filtration, washed with water and dried to obtain 42.4 g (89%) of the title connections.

¹ H-NMR (DMSO-d ₆ ): δ 4, (br.s, 2H, NH ₂ ), 7.49 (s, 1H), 7.71 (br.s, 2H, NH ₂ ), 9, 94 (br.s, 1H, NH).

c) 5-Chloro-2-sulfamoyl-3-tenoylazide
A solution of sodium nitrite (3.0 g, 43.4 mmol) in 20 ml of water was added dropwise with stirring at 0 ^{° C.} to a solution of 5-chloro-2-sulfamoylthiophene-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, yielding 9.93 g (96%) of the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 7.55 (s, 1H), 7.97 (br.s, 2H. NH ₂ ).

g) 1,1-dioxide 6-chloro-2,3-dihydro-3-oxo-4H-thieno [3,2-е] -1,2,4-thiadiazine
5-Chloro-2-sulfamoyl-3-tenoylazide (7.0 g, 26.2 mmol) was added portionwise to 50 ml of refluxing dry toluene over 10 minutes. The mixture was stirred for 5 minutes and cooled in an ice bath. The precipitate was isolated by filtration, washed with toluene and dried, yielding 5.90 g (94%) of the title compound; so pl. 245-248 ^o C (decomposition).

¹ H-NMR (DMSO-d ₆ ): δ 6.93 (s, 1H), 11.98 (s, 1H, NH).

d) 1,1-dioxide 6-chloro-3- (1,2-dimethylpropyl) amino-4H-thieno [3,2-е] -1,2,4-thiadiazine
Phosphorus pentoxide (2.84 g, 20 mmol), N, N-dimethylcyclohexylamine (5 ml, 33 mmol) and 1,2-dimethylpropylamine hydrochloride (2.47 g, 20 mmol) were carefully mixed in a three-necked flask equipped with a mechanical stirrer and refrigerator with a drain tube. The mixture was heated in an oil bath at 200 ^{° C.} until a homogeneous mass was obtained. Then, 6-chloro-2,3-dihydro-3-oxo-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide (1.2 g, 5 mmol) was added and the mixture stirred at 240 ^o C for 45 minutes The mixture was allowed to cool to approximately 100 ^{° C.} , 150 ml of water was added and stirring was continued at room temperature for approximately 1 hour. The hydrolyzed 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) afforded 105 mg (7%) of the pure title compound; so pl. 216-218 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 0.90 (d, 6H, CH (CH ₃ ) ₂ ), 1.08 (d, 3H, NCHCH ₂ ), 1.75 (m, 1H, CH (CH ₃ ) 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 ⁺ ).

Alternatively, 1,1-dioxide 6-chloro-3- (1,2-dimethylpropyl) amino-4H-thieno [3,2-е] -1,2,4-thiadiazine can be obtained by the following method (B)
a) 1,1-dioxide 3,6-Dichloro-4H-thieno [3,2-е] -1,2,4-thiadiazine
Suspension of 6-chloro-2,3-dihydro-3-oxo-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide (10.75 g, 0.045 mol) in oxychloride phosphorus (100 ml) was cooled in an ice bath and dry pyridine (7.3 ml, 0.09 mol) was added dropwise at such a rate that the temperature did not exceed 10 ^o C. The mixture was then heated at 95-100 ^o C for 16 h and cooled to room temperature. The yellow precipitate was removed by filtration and the filtrate was concentrated in vacuo. 200 g of ice was added to the residue, and the resulting mixture was stirred for 1 h and filtered. The isolated solid was dissolved in saturated aqueous sodium bicarbonate (100 ml) and filtered to remove a small amount of insoluble material. After treatment with decolorizing charcoal with 4 M hydrochloric acid, the pH of the filtrate was adjusted to 2 and the precipitate that formed was separated by filtration, washed with water and dried, yielding 5.55 g (48%) of the title compound; so pl. > 240 ^o C (decomp.).

b) 1,1-dioxide 6-chloro-3- (1,2-dimethylpropyl) amino-4H-thieno [3,2-е] -1,2,4-thiadiazine
Solution of 3,6-dichloro-4H-thieno [3,2-е] -1,2,4-thiadiazine 1,1-dioxide (0.3 g, 1.94 mmol) in 1,2-dimethylpropylamine (5 ml ) was stirred for 48 hours at 100 ^o C in a sealed vessel. The cooled mixture was concentrated in vacuo and the residue was stirred with water (20 ml), followed by setting the pH to mixture 2 with 4 M hydrochloric acid. The initially formed gummy product was crystallized by stirring the mixture for about 2 hours at 0 ^° C. The precipitate was isolated by filtration, washed with water and recrystallized. from ethyl acetate / methanol, followed by drying in vacuo at 60 ^{° C.} overnight to afford 0.43 g (72%) of the pure title compound.

EXAMPLE 2
6-Chloro-3-ethylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

Phosphorus pentoxide (2.84 g, 20 mmol), N, N-dimethylcyclohexylamine (3 ml, 20 mmol) and ethylamine hydrochloride (1.63 g, 20 mmol) were carefully mixed and heated with stirring in an oil bath at 180 ^o C in within 20 minutes To the 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 180 ^{° C.} for 5 hours. After cooling to approximately 100 ^{° C.,} water (150 ml) was added and the mixture was stirred for 1 hour at room temperature. The mixture was then 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 recrystallized from ethyl acetate / methanol to give 282 mg (21%) of the pure title compound; so pl. 271-274 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 1.11 (t, 3H, CH ₃ ), 3.22 (m, 2H, CH ₂ ), 7.04 (s, 1H, 5-H), 7.3 (br s, 1H, NH), 11.1 (br.s, 1H, NH). MS m / e: 265/267 (M ⁺ ). (C ₇ H ₈ N ₃ ClO ₂ S ₂ ) calculated,%: C 31.64, H 3.03, N 15.81; Found C 31.57, H 3.12, N 15.63.

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

The title compound was prepared according to a procedure similar to that described in Example 2, except that isopropylamine hydrochloride (1.91 g, 20 mmol) was used as the primary amine. Yield 150 mg (11%); so pl. 281-283 ^o C (ethyl acetate).

¹ H-NMR (DMSO-d ₆ ): δ 1.15 (d, 6H, CH (CH ₃ ) 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 ⁺ ). (C ₈ H ₁₀ N ₃ ClO ₂ S ₂ ) calculated,%: C 34.35, H 3.60, N 15.02; Found C 34.37, H 3.70, N 14.95.

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

a) 3-amino-5-chlorothiophen-2-sulfonic acid tert-butylamide
A solution of 38.1 g (0.15 mol) of 5-chlorothiophen-2-sulfonic acid tert-butylamide in 300 ml of dry tetrahydrofuran was cooled to -70 ^° C and n-BuLi (190 ml, 1.6 M in hexane) was added, maintaining the temperature <-65 ^° C. After adding the mixture, it was allowed to warm to -20 ^{° C.} and stirred at this temperature for 30 minutes. A solution of p-toluenesulfonylazide (34 g, 0.17 mol) in 100 ml of dry tetrahydrofuran was added, maintaining the temperature at -20 ^° C, and the cooling bath was removed. After the mixture reached room temperature, water (100 ml) was added. The organic phase was separated and the aqueous phase was extracted with toluene (2 x 50 ml). Hexadecyl tributylphosphonium bromide (7.62 g, 15 mmol) was added to the combined organic phases, followed by dropwise a solution of sodium borohydride (6.58 g, 0.174 mol) in 20 ml of water with stirring and cooling to room temperature. The mixture was stirred overnight at room temperature and water (100 ml) was added. 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 to give a quantitative yield (40.6 g) of the crude title compound as an oil, which was used without further purification in the next step.

b) 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride
3-amino-5-chlorothiophen-2-sulfonic acid tert-butylamide (40.4 g) was heated with stirring at a temperature of from 50 to 60 ^{° C.} in 200 ml of concentrated hydrochloric acid for 2.5 hours. The crude product was isolated from chilled the mixture was filtered, dried and purified by trituration with 60 ml of ether to obtain 17.8 g (48%) of the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 6.64 (s, 1H), 6.84 (very broad, 5H).

c) N- (3-amino-5-chloro-2-thienylsulfonyl) -N'-isopropylthiourea
Potassium tert-butoxide (0.49 g, 4.4 mmol) was added to a solution of 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride (0.5 g, 2.0 mmol) in dry N, N-dimethylformamide (5 ml) with stirring in an ice bath. After 5 minutes, isopropylisothiocyanate (0.26 ml, 2.4 mmol) was added dropwise to the resulting suspension, and the mixture was stirred for 30 minutes at 0 ^° C. The cooling bath was removed and stirring was continued at room temperature for 30 minutes. The solvent was evaporated at <50 ^° C and the residue was dissolved in 25 ml of water, treated with decolorizing charcoal and filtered. Acidification of the acetic acid filtrate to pH 3-4 and filtration gave 0.50 g (80%) of the title compound; so pl. 142.0-142.5 ^° C (decomp.).

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

d) 6-chloro-3-isopropylamino-4H-thieno 1,1-dioxide [3,2-е] -1,2,4-thiadiazine
Phosgene (1.14 ml, 20% in toluene) was added dropwise to a solution of N- (3-amino-5-chloro-2-thienylsulfonyl) -N'-isopropylthiourea (0.63 g, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry tetrahydrofuran (10 ml) with stirring at 0 ^° C. The mixture was stirred for 1 h at 0 ^{° C.} and evaporated to dryness. The residue was triturated with water and the precipitate was isolated by filtration, washed with water and dried, yielding 0.52 g (93%) of the title compound.

 Alternatively, 6-chloro-3-isopropylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide can be prepared according to the following procedure (B).

A solution of 1,1-dioxide 3,6-dichloro-4H-thieno [3,2-е] -1,2,4-thiadiazine (1.5 g, 5.83 mmol) in isopropylamine (10 ml) was stirred in a vessel high pressure stainless steel lined with Teflon at 100 ^{° C.} for 24 hours. The excess amine was evaporated and the residue was stirred in water (25 ml), followed by the addition of 4 M hydrochloric acid to pH 2. The mixture was stirred in an ice bath for about 1 h, yielding 0.99 g (61%) of 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.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and L-α-methylbenzylisothiocyanate in a manner analogous to that described in Example 3Bv-g; so pl. 195-204 ^o C (ethyl acetate).

¹ H-NMR (DMSO-d ₆ ): δ 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
3-Allylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and allylisothiocyanate in a manner analogous to that described in Example 3Bv-d; so pl. 217-221 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 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
6-Chloro-3-cyclopropylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and cyclopropylisothiocyanate in a manner analogous to that described in Example 3Bv-g; so pl. 272-273 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 0.55 (m, 2H), 0.78 (m, 2H), 2.6 (m, 1H), 7.10 (s, 1H), 7.88 (br.s, 1H), 10.95 (br.s, 1H).

EXAMPLE 7
6-Chloro-3-hexylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and n-hexylisothiocyanate in a manner analogous to that described in Example 3Bv-g; so pl. 207-209 ^o C.

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

EXAMPLE 8
6-Chloro-3-tetradecylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and n-tetradecyl isothiocyanate in a manner analogous to that described in Example CBB-g; so pl. 157-158 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 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
6-Chloro-3-methylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and methyl isothiocyanate in a manner analogous to that described in Example 3Bv-d; so pl. > 190 ^o C (decomp.).

¹ H-NMR (DMSO-d ₆ ): δ 2.75 (s, 3H), 7.02 (s, 1H), 7.25 (br., 1H), 11.3 (br.s, 1H).

EXAMPLE 10
3-Benzylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and benzylisothiocyanate in a manner analogous to that described in Example 3Bv-d; so pl. 223-226 ^o C;
¹ H-NMR (DMSO-d ₆ ): δ 4.42 (d, 2H), 7.05 (s, 1H), 7.30 (m, 5H), 7.78 (br. T, 1H), 11.22 (br.s, 1H) .

EXAMPLE 11
6-Chloro-3-octylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide
The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and n-octyl isothiocyanate in a manner analogous to that described in Example 3Bv-g; so pl. 190 ^o C (decomposition).

¹ H-NMR (DMSO-d ₆ ): δ 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
6-Chloro-3-isobutylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and isobutyl isothiocyanate in a manner analogous to that described in Example 3Bv-g; so pl. 262-264 ^o C.

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

EXAMPLE 13
6-Chloro-3- (4-phenibutyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide and 4-phenylbutylisothiocyanate hydrochloride in a manner analogous to that described in Example 3Bv-d; so pl. 201-205 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 1.55 (m, 4H), 2.6 (t, 2H), 3.2 (q, 2H), 7.04 (s, 1H), 7.1-7.4 (m, 6H), 10.94 (br.s, 1H).

EXAMPLE 14
6-Chloro-3- (1,5-dimethylhexyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and 1,5-dimethylhexylisothiocyanate in a manner analogous to that described in Example 3Bv-g; so pl. 197-199 ^o With (ethyl acetate).

¹ H-NMR (DMSO-d ₆ ): δ 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
6-Chloro-3-propylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine and n-propylamine 1,1-dioxide by a method similar to that described in Example 1Bb, except that the mixture was stirred for 16 hours at 60 ^° C; so pl. 258-261 ^o With (ethyl acetate).

¹ H-NMR (DMSO-d ₆ ): δ 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-е] -1,2,4-thiadiazine.

The title compound was prepared from 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide and (R) - (-) - 2-amino-1- propanol according to a method similar to that described in example 1Bb; so pl. 203-204 ^o C (water).

¹ H-NMR (DMSO-d ₆ ): δ 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 17
1,1-dioxide (S) -6-chloro-3- (2-hydroxy-1-methylethyl) amino-4H-thieno [3,2-е] -1,2,4-thiadiazine.

The title compound was prepared from 1,1-dioxide 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine and L-alanine according to a procedure similar to that described in Example 1Bb; so pl. 204-206 ^o C (water).

¹ H-NMR (DMSO-d ₆ ): δ 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-sec-butylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine.

The title compound was obtained from 1,1-dioxide 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine and (R) - (-) - sec-butylamine according to a procedure analogous to the procedure described in example 1Bb; so pl. 215-220 ^o With (water).

¹ H-NMR (DMSO-d ₆ ): δ 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
3-Butylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide.

The title compound was prepared from 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride and n-butylaminoisothiocyanate in a manner analogous to that described in Example 3Bb-g; so pl. 218-219 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 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
3-Isopropylamino-7-methyl-4,7-dihydropyrazolo [4,3-е] -1,2,4-thiadiazine 1,1-dioxide.

a) 1-Methyl-5-sulfamoylpyrazole-4-carbohydrazide
Ethyl 1-methyl-5-sulfamoylpyrazole-4-carboxylate (1.0 g), prepared according to the method of Bellemin and Festal, J. Heterocycl. Chem., 1984, 21, 1017, was mixed with 1 ml of hydrazinomine hydrate at room temperature for 3 hours and then evaporated to dryness. The residue was dissolved in 5 ml of water and extracted with 25 ml of dichloromethane. The aqueous phase was evaporated, yielding 0.85 g (90%) of the title compound as a slowly crystallizing oil. Trituration with 5 ml of a 2: 1 mixture of methanol and ethyl acetate gave a pure product; so pl. 172-173 ^o C.

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-sulfamoylpyrazole-4-carbohydrazide (0.55 g) in 8 ml of 1 M hydrochloric acid at 0 ^° C. The resulting mixture stirred for 15 min and then filtered. The filter cake was washed with water and dried in vacuo to give 0.29 g (47%) of the title compound as a crystalline solid. The product was pure according to TLC (ethyl acetate), it was used immediately in the next step.

c) 1-Methyl-4- (ethoxycarbonylamino) pyrazole-5-sulfonamide
1-Methyl-4- (azidocarbonyl) pyrazole-5-sulfonamide (0.29 g) was added over 5 minutes to 10 ml of abs. ethanol at reflux temperature. The resulting solution was refluxed for 15 minutes and then evaporated, yielding 0.33 g of the title compound as a yellow oil containing a small ethanol residue. The product was used without purification for the next step.

d) N- (4-Ethoxycarbonylamino-1-methyl-5-pyrazolsulfonyl) -N'-isopropylthiourea
A mixture of 1-methyl-4- (ethoxycarbonylamino) pyrazole-5-sulfonamide (0.42 g), potassium carbonate (0.34 g) and isopropylisothiocyanate (280 μl) in 10 ml of dry acetone was heated at 55 ^{° C.} for 18 hours and then evaporated to dryness. The residue was dissolved in 10 ml of water and pH 4 was added dropwise with 4 M hydrochloric acid. The precipitate was filtered off, washed with a small amount of water and dried, yielding 0.38 g (64%) of the title compound, mp. 141-144 ^o C.

d) 4-Ethoxycarbonyl-3-isopropylamino-7-methyl-4,7-dihydropyrazolo [4,3th] -1,2,4-thiadiazine 1,1-dioxide
To a stirred solution of N- (4-ethoxycarbonylamino) -1-methyl-5-pyrazolsulfonyl) -N'-isopropylthiourea (0.37 g) and triethylamine (0.45 ml) in 5 ml of dry THF at 0 ^{° C.} 0 ml of a 20% solution of phosgene in toluene. The mixture was stirred at 0 ^{° C.} for 30 minutes and then evaporated to dryness. The residue was triturated with 10 ml of water, filtered, washed on the filter with water and dried, yielding 0.27 g (82%) of the title compound; so pl. 141-145 ^o C.

e) 3-Isopropylamino-7-methyl-4,7-dihydropyrazolo [4,3-e] -1,2,4-thiadiazine 1,1-dioxide
A mixture of 7,7-dioxide 4-ethoxycarbonyl-5-isopropylamino-1-methyl-1, 4-dihydropyrazolo [4,3-е] -1,2,4-thiadiazine (0.23 g) in 2 ml of 2 M aqueous sodium hydroxide was heated under reflux for 2 hours. Then the mixture was cooled to room temperature and the pH was adjusted to 2 by adding dropwise 4 M hydrochloric acid. After stirring for 15 minutes, the precipitate was separated by filtration, washed with a small amount of water and dried, yielding 0.11 g (61%) of the title compound; so pl. 242-243 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ (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-CH ₃ ), 1.15 (d, 6H, CH ₃ ).

EXAMPLE 21
3-Isopropyl-6-methyl-4H-thiazolo [4,5-e] -1,2,4-thiadiazine 1,1-dioxide.

 The title compound can be obtained by a method similar to that described in example 20, starting from ethyl 2-methyl-5-sulfamoylthiazole-4-carboxylate, which, in turn, was obtained by the method of Tamura et al., Chem. Pharm .Bull., 1971, 19, 119.

 Example A.

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

a) N- (3-amino-5-chloro-2-thienylsulfonyl) -N'-cyclohexylmethylthiourea
Potassium tert-butoxide was added to a solution of 3-amino-5-chlorothiophen-2-sulfonamide hydrochloride in dry N, N-dimethylformamide with stirring in an ice bath. After 10 minutes, cyclohexylmethylisothiocyanate was added dropwise to the resulting suspension, and the mixture was stirred for 3.5 hours at 0-20 ^° C. Most of the solvent was evaporated at 40 ^{° C.} and the residue was dissolved in 25 ml of water, treated with decolorizing charcoal and filtered. Acidification of the filtrate with acetic acid to pH 3-4 and filtration gave the title compound (8% yield) as a syrup.

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

b) 1,1-dioxide 6-chloro-3- (cyclohexylmethyl) amino-4H-thieno [3,2-е] -1,2,4-thiadiazine
Phosgene was added dropwise to a solution of N- (3-amino-5-chloro-2-thienylsulfonyl) -N'-cyclohexylmethylthiourea and dry triethylamine in dry tetrahydrofuran with stirring at 0 ^° C. The mixture was stirred for 2 hours at 0 ^{° C.} and evaporated to dryness. The residue was recrystallized from ethyl acetate, the precipitate was isolated by filtration, washed with water and dried to obtain the title compound (yield 68%); so pl. > 200 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 0.90 (m, 2H), 1.15 (m, 3H), 1.70 (m, 6H), 3.05 (t, 2H, CH ₂ ), 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-dioxotieno [3,2-е] -1λ ⁶ , 2,4-thiadiazin-3-ylamino) butanoic acid.

Ethyl 3- (6-chloro-1,4-dihydro-1,1-dioxothieno [3,2-е] -1λ ⁶ , 2,4-thiadiazin-3-ylamino) butanate was hydrolyzed to acid by mixing with 5 ml of 2 n sodium hydroxide for 2 hours 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 to obtain the title compound (yield 64%); so pl. 218-223 ^o C.

¹ H-NMR (DMSO-d ₆ ): δ 1.19 (d, 3H, CH ₃ ), 2.49 (m, 2H, CH ₂ ), 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 (MH ₂ O) ⁺ . (C ₉ H ₁₀ ClS ₂ ) calculated,%: C 33.39, H 3.11, N 12.98; Found,%: C 33.62, H 3.11, N 12.81.5

Claims (19)

1. Derivatives of the condensed 1,2,4-thiadiazine of the general formula 1

where B represents> NR ⁵ , where R ⁵ represents hydrogen, or R ⁵ and R ⁴ together represent one of the bonds in the double bond between atoms 2 and 3 of the ring of formula 1;
D represents S (= O) ₂ -;
R ¹ represents hydrogen;
R ⁴ represents hydrogen, or R ⁴ together with R ⁵ represent one of the bonds in the double bond between atoms 2 and 3 of the formula I, or R ¹ together with R ⁴ represents one of the bonds in the double bond between the atoms 3 and 4 of the formula I;
R ² represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl;
R ³ is R ⁸ , aryl substituted with C _1-6 alkyl, where R ⁸ is hydrogen, C _3-6 cycloalkyl, or (C _3-6 cycloalkyl) C _1-6 alkyl, straight or branched C ₁ - ₁₈ -alkyl, optionally mono- or polysubstituted with hydroxy, C _3-6 -cycloalkyl, aryl, carboxy;
And together with 5 and 6 carbon atoms of the formula I, they represent a 5-membered heterocyclic system containing one or two nitrogen atoms or one sulfur atom, the heterocyclic systems optionally mono- or polysubstituted with halogen, provided that the following compounds are excluded: 1,1-dioxide 3 -aminoimidazo [4,5-e] -1,2,4-thiadiazine and 1,1- dioxide 3- (benzoylamino) imidazo [4,5-e] -1,2,4-thiadiazine, or a salt thereof with a pharmaceutically acceptable acid or base. 2. The compound according to claim 1, where R ² represents hydrogen or C _1-6 -alkyl. 3. The compound according to claim 1 or 2, where R ³ represents R ⁸ or aryl, wherein the aryl groups are optionally substituted with C _1-6 alkyl, where R ⁸ represents hydrogen, C _3-6 cycloalkyl, (C _3-6 - cycloalkyl) C _1-6 alkyl, or straight or branched C _1-18 alkyl optionally substituted with hydroxy. 4. The compound according to any one of the preceding paragraphs, wherein R ³ is secondary C _3-6 alkyl, tertiary C _4-6 alkyl, C _3-6 cycloalkyl or (C _3-6 cycloalkyl) methyl.  5. The compound according to any one of the preceding paragraphs, where A together with the carbon atoms 5 and 6 of formula I form a 5-membered heterocyclic system containing one heteroatom selected from nitrogen and sulfur, the heterocyclic system optionally mono- or disubstituted with halogen.  6. The compound according to any one of the preceding paragraphs, where A together with the carbon atoms 5 and 6 of formula I form a 5-membered heterocyclic system containing two heteroatoms selected from nitrogen and sulfur, the heterocyclic system being optionally substituted with halogen. 7. The compound according to any one of claims 1 to 6, where the General formula I represents

where R ¹ , R ⁴ , R ⁵ independently represent hydrogen, or R ⁴ together with R ⁵ represent one of the bonds in the double bond between atoms 2 and 3 of the formula I and R ¹ as defined above, or R ⁴ together with R ¹ represent one of the bonds in the double bond between atoms 3 and 4 of the formula I and R ⁵ such as defined above;
D represents —S (= O) ₂ -;
A, R ² and R ³ are as defined above. 8. The compound according to claim 7, where R ¹ and R ⁴ represent hydrogen. 9. The compound according to claim 7 or 8, where R ¹ together with R ⁴ represent one of the bonds in the double bond between atoms 3 and 4 of formula I. 10. The compound according to any one of claims 7 to 9, where R ⁴ together with R ⁵ represent one of the bonds in the double bond between atoms 2 and 3 of formula I. 11. The compound according to any one of claims 7 to 10, where D is —S (= O) ₂ . 12. A compound selected from the following:
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;
1,1-dioxide (R) -6-chloro-3- (1-phenylethyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine;
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-tetradecylamino-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-octylamino-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-dimethylhexyl) 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;
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-sec-butylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine;
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. 13. The compound according to any one of the preceding paragraphs, which act as a means of opening K _ATP- regulated potassium channels. 14. A pharmaceutical composition having an action on K _ATP- regulated potassium channels, characterized in that it as an active component contains a compound according to any one of claims 1 to 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 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 claims 1 to 13 or a pharmaceutically acceptable salt thereof 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 K _ATP- regulated potassium channels. 17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof 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 the manufacture of a medicament for influencing K _ATP- regulated potassium channels. 18. The method of exposure to K _ATP- regulated potassium channels in a subject in need of this, consisting in the introduction of an effective amount of a compound according to any one of claims 1 to 13 to this subject. Point priority
01/17/1996 - according to claims 1-3, 5-6, 8-11, 13-18;
01/16/1997 - according to claim 4;
mainly 01/17/1996, in particular 08/27/1996 - according to claim 7;
01/17/1996 - compounds 1, 15, 19 according to item 12;
08/27/1996 - connections 2, 3 according to item 12.  01/16/1997 - compounds 4-14, 16-18, 20 according to item 12.