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MXPA00000223A - Fused 1,2,4-thiadiazine derivatives, their preparation and use - Google Patents

Fused 1,2,4-thiadiazine derivatives, their preparation and use

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Publication number
MXPA00000223A
MXPA00000223A MXPA/A/2000/000223A MXPA00000223A MXPA00000223A MX PA00000223 A MXPA00000223 A MX PA00000223A MX PA00000223 A MXPA00000223 A MX PA00000223A MX PA00000223 A MXPA00000223 A MX PA00000223A
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MX
Mexico
Prior art keywords
carbon atoms
alkyl
amino
dioxide
thiadiazine
Prior art date
Application number
MXPA/A/2000/000223A
Other languages
Spanish (es)
Inventor
Flemming Elmedlund Nielsen
John Bondo Hansen
Holger Claus Hansen
Tina Moller Tagmose
John Patrick Mogensen
Original Assignee
Novo Nordisk A/S
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Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Publication of MXPA00000223A publication Critical patent/MXPA00000223A/en

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Abstract

1,2,4-Thiadiazine and 1,4-thiazine derivates represented by formula (I) wherein A, B, D, R1, R2, R3 and R4 are defined in the description, compositions thereof and methods for preparing the compounds are described. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.

Description

DERIVATIVES OF 1, 2, - I D IAZ INA FUSIONADA, ITS PREPARATION AND USE FIELD OF THE INVENTION The present invention relates to derivatives of 1, 2, 4-ti adi azine fused, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and to their use in therapy. for example, in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrine system.
BACKGROUND OF THE INVENTION Potassium channels play an important role in the physiological and pharmacological control of cell membrane potential. Among the different types of potassium channels are the ATP-sensitive channels (KATP-) that are regulated by changes in the intracellular concentration of adenosine triphosphate. The KATP channels have been found REF: 32395 in cells of various tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, central neurons and adenohypophila cells. The channels have been associated with various cellular functions, for example the secretion of hormones (insulin from pancreatic beta cells, growth hormone and prolactin from adenohypophysi cells), vasodi lation (in the cells of the smooth muscles). ), duration of cardiac action potential, and release of neurotransmitters in the central nervous system.
It has been found that modulators of KATP-channels are of importance for the treatment of various diseases. Certain sul fi cials that have been used for the treatment of insulin-dependent diabetes mellitus act by stimulating the release of insulin through "an inhibition of KAtp-channels in pancreatic beta cells.
It has been found that the openers of the Potassium channels, which comprise a heterogeneous group of compounds, are able to relax vascular smooth muscles and have therefore been used for the treatment of hypertension.
In addition, potassium channel openers can be used as bridges in the treatment of asthma and several other diseases.
In addition, potassium channel openers have been shown to promote hair growth and have been used for the treatment of hair loss. . .
The potassium channel openers are also able to relax the smooth muscle of the urinary bladder and can therefore be used for the treatment of urinary incontinence. The potassium channel openers that relax the smooth muscle of the uterus can be used to treat preterm labor. By acting on the potassium channels of the central nervous system these Compounds can be used for the treatment of various neurological and psychiatric diseases such as Alzheimer's, epilepsy and cerebral ischemia.
In addition, the compounds are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and co-susceptibility.
The compounds of the present invention that inhibit insulin secretion by activating "potassium channels of beta cells, can be used in combination with other compounds that can be used to treat diabetes mellitus noninsulin in diabetes and diabetes mellitus insul inodependien Examples of these compounds are insulin, insulin sensitizers, such as idolipin, insulin secretors, such as repaglinide, tolbutamide, gl ibenzyme, and the glucagon-like peptide (GLP1), inhibitors of α-glucosides ace and liver enzymes responsible for glucose biosynthesis.
It has recently been shown that diazoxide (1,1-dioxide 7-clors-3-me ti 1 -2H-1, 2,4-benzoyl-adi-azine) and certain derivatives of 1,1-dioxide 3 - (at which 1 amino) -4H-pyridine [4, 3 -e] -1, 2, 4-ti adi azine, inhibit insulin release by activation of KATP-channels in pancreatic beta cells (Pirotte B. et al. Bi o ch em Ph a rm ac ol, 4_7_, 1381-1386 (1994); Pirotte B. et al. Med. Ch em. , 3_6_, 3211-3213 (1993). It has also been shown that diazoxide delays the onset of diabetes in BB rats (Vlahos WD et al., Me t ab ol i sm 40, 39-46 (1991)). In obese zucker rats, diazoxide has been shown to decrease insulin secretion and increase binding to the insulin receptor and consequently to increase glucose tolerance and decrease weight gain (Alemzadeh R. et al., Endocrinol. , 705-712, 1993). It is expected that the compounds that activate the KATp-channels can be used for the treatment of diseases characterized by an overproduction of insulin and for the treatment and prevention of diabetes.
EP 618 209 describes a class of derivatives of pyridium tiadiaz ina having an alkyl or alkylamino group in the 3-position of the thiadiazine ring. These compounds are claimed as antagonists of the AMPA-glu cose receptor.
In J. Med. Chem. 1980, 23, 575-577, the synthesis of 4 (5) -amino-5 (4) carboxyamy and of the forylaminoimide zo-5 (4) carboxamide and its properties as chemo-therapeutic agents. Especially, the compounds 1,1-dioxide of 3-aminoimidazo [5-e] -1,2,4-diazine and 1,1-dioxide of N-benzoylimidamide [4, 5-e] - 1, 2, 4-t iadi az ina.
DESCRIPTION OF THE INVENTION The present invention relates to 1, 2, 4-iadiaz ina-fused derivatives and fused 1,4-thiazine, of the general formula I: ( where B represents > NR5 or > CR5R6, wherein R5 and R6 are independently hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono-sub stained or po 1 and their titre with halogen; or R5 and R4 represent with one of the bonds in a double bond between atoms 2 and 3 of formula I; D represents -S (= 0 .S (= 0) D-B represents -S (= 0) (R7) = N- wherein R7 is alkyl of 1 to 6 carbon atoms; or optionally mono- or heteroaryl heteroaryl substi tuted with halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6. carbon, cyano, acyl, or alkoxycarbonyl atoms of 1 to 6 carbon atoms; R1 is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono-sub stained or polysubstituted with halogen and R 4 is hydrogen; or R4 together with R5 represents one of the bonds in a double bond between atoms 2 and 3 of formula I; or R1 together with R4 represents one of the bonds in a double bond between atoms 3 and 4 of formula I; R is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms; alkenyl having 2 to 6 carbon atoms or alkynyl having 2 to 6 carbon atoms, optionally mono-substituted or halogen-substi tuted; R3 is R8; -OR8; -C (= X) R8; bicycloalkyl, aryl, heteroaryl, arylalkyl, or heteroaryl, which optionally mono-sub stained or substituted by halogen, hydroxy, alkoxy of 1 to 6 atoms carbon, aryloxy, arylalkoxy, nitro, amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms, cyano, oxo, acyl or alkoxycarbonyl of 1 to 6 carbon atoms; or aryl substituted with alkyl of 1 to 6 carbon atoms, wherein R is hydrogen; cycloalkyl of 3 to 6 carbon atoms or (cycloalkyl of 3 to 6 carbon atoms) to which from 1 to 6 carbon atoms, the cycloalkyl group of 3 to 6 carbon atoms is optionally mono substratum or poly subs ti tuido with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; a saturated ring system of 3 to 6 members comprising one or more nitrogen, oxygen or sulfur atoms; or straight or branched alkyl of optionally mono- or sub-branched carbon atoms subsitiated or pro-substituted with halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, aryloxy, arylalkoxy, nitro, amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms, cyano, oxo, formyl, acyl, carboxy, alkoxycarbonyl of 1 to 6 carbon atoms, or carbamoyl; X is O or S; R- is hydrogen, alkyl of 1 carbon atom; alkenyl of 2 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms optionally mono-sub stained or polysubstituted with alkyl of 1 to 6. carbon, halogen, hydroxy or alkoxy atoms of 1 to 6 carbon atoms; or R8 and R together with the nitrogen atom form a monocyclic or bicyclic system of 3 to 12 members in which one or more of the carbon atoms can be exchanged with nitrogen, oxygen or sulfur, each of these ring systems is optionally monosubstituted or substituted by halogen, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms - to 1 to 1 to 1 to 6 carbon atoms carbon, nitro, amino, cyano, tri-fluororhene, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms; oxo; R3 is wherein n, m, p are independently 0, 1, 2, 3 and R10 is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; optionally monosubstituted cycloalkyl of 3 to 6 carbon atoms or poly substituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; alkyl of 6 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; optionally mono substratum or po i i subsi tuted with halogen; or R and R together with the nitrogen atom Form a monocyclic or bicyclic system of 3 to 12 members in which one or more of the carbon atoms can be exchanged with nitrogen, oxygen or sulfur, each * of these systems of The ring is optionally mono-sub-substituted or substituted by halogen, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, nitro, amino, cyano, tri-1orornethi, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms or oxo; A together with the carbon atoms 5 and 6 of the formula I represent a 5- or 6-membered heterocyclic system containing one or more nitrogen, oxygen or sulfur atoms, the heterocyclic systems are optionally mono substratized on the sub-surface. halogen stitches; alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, nitro, amino, cyano, cyanomethyl, perhalomethyl, monoalkylamino from 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms, sulfamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms; Arylthio, arisulphyl, nickel, foni lo, the aryl group is optionally monosubstituted or po isi tuted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 atoms of carbon, alkoxycarbonyl of 1 to 6 carbon atoms; alkoxycarbonyl of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms; carbamyl; carba i lo-me t i lo; monocarbon having 1 to 6 carbon atoms or di to 1 to 1 aminocarbonyl or 1 to 6 carbon atoms; monoalkyl 1 amino tio carboni 1 or 1 to 6 carbon atoms or dialkyl 1 amino thio carboni lo of 1 to 6 carbon atoms; ureido; onoal qui 1 aminocarboni lamino of 1 to 6 carbon atoms or di to qui 1 aminocarboni 1 amino of 1 to 6 carbon atoms, thioureido; monoalkyl 1 amino tio carboni 1 or 1 to 6 carbon atoms - amino or di-alkylamino-aminocarboni-amino of 1 to 6 carbon atoms; mono to which 1 aminosul foni lo of 1 to 6 carbon atoms or dial qui 1 aminosul foni lo of 1 to 6 ato ss of carbon; carboxy; c arboxi - at 1 qui that of 1 to 6 carbon atoms; acyl; aryl, arylalkyl, aryloxy, the aryl group is optionally monosubs tu tiido or po i i subscribed with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; (1,2,4-oxadi to zo 1 - 5- i 1) - to the one of 1 to 6 carbon atoms or (1, 2, 4 -oxadi to zol-3-i 1) - to the one who from 1 to 6 carbon atoms and the oxadiazolyl group is optionally substituted with alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; or a ring containing nitrogen of 5 to 6 members, optionally substituted with phenyl or alkyl of 1 to 6 carbon atoms; with the proviso that A together with the carbon atoms 5 and 6 of formula I do not form a pyridine ring and that the following compounds 1,1-dioxide of 3-amino-1-yl [4, 5-e] -1 , 2, 4-thia-adiazine and 3- (benzoylamino) imidazo [4,5-e] -1,2-thiadiazine 1,1-dioxide are not included; or a salt thereof with a pharmaceutically acceptable acid or base.
Within its scope the invention includes all optical isomers of the compounds of formula I, some of which are optically active ingredients, and also their mixtures include racemic mixtures thereof.
The scope of the invention also includes all the technical forms of the formula I compounds.
The salts include the pharmaceutically acceptable acid addition salts, the pharmaceutically acceptable metal salts or optionally the alkylated ammonium salts, such as those of hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, t-fluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, me t ansulphonic, etansulonic, picric and the like, and includes acids related to the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977) and which are incorporated herein by reference, or the salts of lithium, sodium, potassium, magnesium and the like.
The term "C 1 -C 6 alkoxy" as used herein, alone or in combination, refers to a monovalent, straight or branched substituent, which comprises an alkyl group of 1 to 6 carbon atoms bonded to through an ether oxygen having its valence bond free from the oxygen of the ether and having from 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term "C 1 -C 6 alkylthio" as used herein, alone or in combination, refers to a straight or branched movalent substituent comprising a lower alkyl group linked through a divalent sulfur atom which it has its free valence bond, of the sulfur atom, and having 1 to 6 carbon atoms, for example, methylthio, ethylthio, propylthio, butylthio and pent i 11 io.
The term "C 2 -C 6 alkenyl" as used herein refers to a hydrocarbon chain unsaturated having 2 to 6 carbon atoms and a double bond such as, for example, vinyl, 1-propenyl, allyl, isopropene, n-butenyl, n-pentenyl and n-hexenyl.
The term "cycloalkyl of 3 to 6 carbon atoms" as used herein refers to a radical of a saturated cyclic hydrocarbon, with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexylo.
The term "C2-C6 alkynyl" as used herein refers to unsaturated hydrocarbons containing triple bonds, such as, for example, -C = CH, -C = CCH3, -CH2C = CH, - CH2CH2C = CH, -CH (CH3) C = CH, and the like.
The term "C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl" as used herein refers to a group of 2 to 12 carbon atoms interrupted by an O such as, for example, CH 2 - 0-CH3, CH2-0-CH2-CH3, CH2-0-CH (CH3) 2 and the like. " The term "halogen" means fluorine, chlorine, bromine or iodine.
The term "ethyl perhalo" means tri-fluororhexyl, tri-chloroyl-1-one, tri-hydrogen or triiodomethyl.
The terms "alkyl of 1 to 6 carbon atoms", "alkyl of 1 to 12 carbon atoms" and "alkyl of 1 to 18 carbon atoms" as used herein, alone or in combination, refer to to a chain of saturated hydrocarbons, straight or branched, having the indicated number of carbon atoms, such as for example methyl,. ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methyl isobutyl, 3-methylbutyl, 4-methyl tiyl, neopentyl, n -hexyl, 1, 2 -dime ti lpropi lo, 2, 2 -dime ti Ipr opi lo, 1, 2, 2 - tr ime ti lpropi lo and the like. The term "alkyl of 1 to 18 carbon atoms" as used herein also includes secondary alkyl of 3 to 6 carbon atoms and tertiary alkyl of 4 to 6 carbon atoms.
The term "monoalkylamino of 1 to 6 carbon atoms" as used herein refers to an amino group in which one of the hydrogen atoms is substituted with a straight or branched saturated hydrocarbon chain, having the number of carbon atoms, such as, for example, methylamino, ethylamino, propylamino, n-butylamino, sec-butylamino, i-butbutyl, tert-butylamino, n-pentylamino, .2-methyl butylamino, n-hexylamino, 4-me ti lpen ti 1 amino, neopen ti 1 amino, n-hexi 1 amino, 2, 2-dime ti lprop i lamino ysii lares.
The term "dialkylamino of 1 to 6 carbon atoms" as used herein refers to an amino group wherein the two hydrogen atoms are independently substituted with a straight or branched saturated hydrocarbon chain, having the number indicated of carbon atoms; such as dimethylamino, N- e t i 1-N-me t i 1 mino, diethylamino, dipropylamino, N- (n-butyl) -N-methylamino, di (n-pent i 1) amino and the like.
The term "acyl" as used herein refers to a monovalent substituent comprising an alkyl group of 1 to 6 carbon atoms bonded through a carbonyl group; such as, for example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, and the like.
The term "C 1 -C 6 alkoxycarbonyl" as used herein refers to a monovalent substituent comprising an alkoxy group of 1 to 6 carbon atoms bonded through a carbonyl group; such as, for example, the toxi carboni 1, carbethoxy, propox i car oni 1 or, isopropoxy-carbonyl, n-butoxycarbonyl, sec-butoxy carbonyl or, tert-butoxycarbonyl, 3- et i lbuto icarboni lo, n -hexoxi carboni 1 oys imi lares.
The term "3 to 12 membered monocyclic or bicyclic system" as used herein, refers to a monovalent substituent of the formula -NR2R3 or -NR8R9 wherein R2 and R3, or R8 and R9 together with the nitrogen atom they form a monocyclic or bicyclic system of 3 to 12 members, in which one or more of the carbon atoms can be exchanged with nitrogen, oxygen or sulfur, such as 1-pi 1-1-one, piperidino, morpholino, t iomor fo 1 ino, 4-methylpiperazin-1-yl, 7-azabicyclo [2.2.1] heptan-7-yl, tropanil and the like.
The term "3 to 6-membered saturated ring system" as used herein refers to a monovalent substituent - which comprises a saturated monocyclic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and having 3 to 6 members and having its valence free of a carbon atom, for example, 2-pi rro lidi lo, 4-piperidilo, 3 -mor f olinilo, 1, 4 -dioxan-2-i 1, 5- oxazo 1 idini lo, 4-is oxa zo 1 i dini lo, or 2-thiomorpholinyl.
The term "bi-cycloalkyl" as used herein refers to a monovalent substituent comprising a bicyclic structure made from 6 to 12 carbon atoms such as, for example, 2-norborni lo, 7 -norborni lo, 2-bicyclo [2.2.2] octyl, and 9-bicyclo [3.3.1] nonanil.
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. comprising a 5 to 6 membered monocyclic aromatic system or a 9 to 10 membered bicyclic aromatic system, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, for example, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, p rx imidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, and sochi canvas, quinazoline, quinoxaline, indole, benz imide zo 1, benzofuran, pteridine, and purine.
The term "arylalkyl" as used herein refers to a straight or branched chain of saturated carbons, of 1 to 6 carbon atoms, substituted with a carbohydride aromatic such as benzyl, phenethyl, 3-phenylpropyl, 1 -naphtimethyl, 2 - (1 -na ft i 1) e t i lo and s i i lares.
The term "aryloxy" as used herein refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy.
The term "arylalkoxy" as used herein refers to an alkoxy group of 1 to 6 carbon atoms substituted with an aromatic carbohydride, such as benzyloxy, phenetoxy, 3-phenopropoxy, 1-naphthalether. oxy, 2- (l-naphthyl) ethoxy and the like.
The term "heteroarylalkyl" as used herein refers to a straight or branched chain of saturated carbons, containing 1 to 6 carbons substituted with a heteroaryl group; such as (2-furyl) methyl, (3-fur il) and ilo, (2-ti eni 1) me t ilo, (3-t ieni 1) eti lo, (2-piri di 1) me ti 1 or, 1-methyl-1- (2-pyridyl) ethyl and the like.
The term "C 1 -C 6 alkylsulfonyl" as used herein refers to a monovalent substituent comprising an alkyl group of 1 to 6 carbon atoms bonded through a sulfonyl group such as, for example, the sulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropyl sulfoyl, n-buyl sulphonyl, sulphonic acid, sulfuryl, n-propylsulphonyl, isopropyl sulfoxide fonilo, n-pent il sulphi lo, 2-me ilbutyl sulphonyl, 3-methyl sulphonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, neopen ti 1 sulphonyl, n-hexyl 1 sulphyl and 2 , 2-dimet i lpropi 1 sulfonyl or.
The term "monoalkylaminosulfonyl of 1 to 6 carbon atoms" as used herein refers to a monovalent substituent that yields a monoalkylamino group of 1 to 6 carbon atoms bonded through a sulfonyl group, such as, for example, 1-amino-sulphonyl, ethyl-amino-sulfonyl, n-propylamino-sulphonyl, isopropyl-lamino-sulfonyl or, n-butyl-amino-sulfonyl, sec-bu-1-amino-sulphonyl, sobu t ilamino sul f oni 1 o, tert -but i lamino sul fonilo, n-pentylaminosulfonilo, 2-methylbut i laminosul fonilo, 3-methylbutilaminosulfonilo, n-hexylaminosulfonilo, 4-me ti Ipent i lamino sul fonilo, neopent i 1 amino sul f oni 1 o, n -hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.
The term "di al qui 1 aminosul fonilo of 1 to 6 carbon atoms" as used herein refers to. a monovalent substituent comprising a dialkylamine group of 1 to 6 carbon atoms bonded through a sulfonyl group, such as dimethylamino sulfonyl, N-ethyl-N-methyl-1-sulphonyl, di-ti-laminosul phylo, dipropylaminosulfonyl, N- (n-butyl) -N-ethylaminosulfonyl, di (n-pentyl) to inosulfonyl, and imides.
The term "at least 1 to 6 carbon atoms" as used herein refers to a monovalent substituent which comprises an straight or branched alkyl group of 1 to 6 carbon atoms, linked to through a sulfinyl group (-S (= 0) -); as for Examples are sulphite, sulphityl, isopropylsulfinyl, butylsulfinyl, pentyl sulphyl, and the like.
The term "C 1 -C 6 alkylcarbonyl mino" as used herein refers to an amino group in which one of the hydrogen atoms is substituted with an acyl group, such as, for example, acetamido, propionate, i soprop i 1 carboni 1 amino, and the like.
The term "(cycloalkyl of 3 to 6 carbon atoms) to 1 to 1 to 6 carbon atoms" as used herein, alone or in combination, refers to a chain of saturated hydrocarbons, straight or amylite, which has 1 to 6 carbon atoms and which is mono-substituted with a cycloalkyl group of 3 to 6 carbon atoms, the cycloalkyl group is optionally mono-sub stained or optionally substituted with alkyl from 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; such as for example cyclopropylmethyl, (1 -me t i 1 ci clopropi 1) me t i lo, 1- (cyclopropyl) ethyl, cyclopentylmethyl-, cyclohexyl, and the like. "~ The term "arylthio" as used herein, alone or in combination, refers to an aryl group linked through a divalent sulfur atom having its valence bond free from the sulfur atom, the aryl group optionally being mono sub sti tuido or po 1 i subsu tuted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; for example, phenylthio, (4-methyl-phenyl) -thio, (2-chloro-phenyl) -thio, and the like.
The term "arylsulfyl" as used herein refers to an aryl group linked through a sulfinyl group (-S (= 0) -), the aryl group is optionally mono substratum or polysubstituted. with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; such as, for example, phenylsulphyl, (4-cyano phenyl) sulphonyl, and iminoles.
The term "aryl sulphide" as used herein refers to an aryl group linked through a sulfonyl group, the aryl group is optionally mono subsi tuted or poly substituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; such as, for example, phenyl sulfonyl, tosyl, and the like.
The term "monoalkyl 1 aminocarbonyl of 1 to 6 carbon atoms" as used herein refers to a monovalent substituent comprising a monoalkylamino group of 1 to 6 carbon atoms bonded through a carbonyl group, such as, for example, aminocarbonyl, ethylaminocarbonyl, n-propyl, 1-aminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert-butyl, 1-aminocarbonyl, n-pentyl, 1-to-carbonyl, 2-methyl butyl 1-aminocarbonyl, 3-methylbutylaminocarbonyl, n-hexylaminocarbonyl, 4-methyl butyl aminocarbonyl, neopenthylamino carbonyl 1, n-hexyl and 1 aminocarbonyl and 2-2- dimethylpropylaminocarbonyl.
The term "di a 1 qui 1 mino c arboni 1 o de 1 a 6 carbon atoms" as used herein refers to a monovalent substituent that comprises a di-lyalkylamino group of 1 to 6 carbon atoms linked through a carbonyl group such as dime ti 1 aminocarbonyl or, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl,. N- (n-butyl) -N-methylaminocarbonyl, di (n-pentyl) to incarbonyl, and imi res.
The term "monoalkylaminocarbonylamino of 1 to 6 carbon atoms" as used herein refers to an amino group in which one of the hydrogen atoms is substituted with a "monoalkyl" aminocarbonyl group. from 1 to 6 carbon atoms, for example me ti 1 aminocarboni 1 amino, ethyl amino carboni lamino, n-propylamino-carboni 1 amino, isopropylaminocarbonylamino, n-butylaminocarbonylamino, sec-butylane-carbonyl, and sobu ti laminoca rboni lamino, tert- butylaminocarbonylamino, methylbutylaminocarbonylamino.
The term "di-amino-1-aminocarbon carbonylary of 1 to 6 carbon atoms" as used herein refers to an amino group in which one of the hydrogen atoms is substituted with a di-amino-carbon-1-amino group. from 1 to 6 carbon atoms, such as dimethylaminocarboni 1 amino,. N-ethyl-N-methylaminocarbonylamino, diethylaminocarbonyl-a, dipropylaminocarboni 1 amino, N- (n-butyl) -N-methylaminocarboni 1 amino, di- (n-pent i 1) aminocarbonilamino, and the like.
The term "5- or 6-membered heterocyclic system" as used herein refers to: a saturated or unsaturated monocyclic system containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur and having 5 members, per Examples are pyrrole, furan, thiophene, pyrroline, dihydro-fur ano, dihydro-thiophene, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazole, isothiazole, 1,2,3-oxadiazole, furazano, 1, 2, 3 - t r iazo 1, 1, 2, 3 - t i adi a z or 1 or 2, 1, 3- t iadi azo 1; an aromatic monocyclic system containing two or more nitrogen atoms and having 6 members, for example pyrazine, pyridine, pyridazine, 1,2,4-triazine, 1, 2, 3-1 riazine or tetrazine, a system non-aromatic monocyclic containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and having 6 members, for example pyran, thiopyran,. piperidine, dioxane, oxazine, isoxazine, dithiane, oxathine, thiazine, piperazine, thiadiazine or oxadiazine.
The term "5 or 6-membered nitrogen containing ring" as used herein refers to a monovalent substituent comprising a saturated or unsaturated monocyclic system containing one or more nitrogen atoms and having 5 or 6 members, for example, pi 1, pyrrolinyl, imida zo 1 idini lo, pyrazo 1 idini lo, pi raz o 1 ini lo, piperidyl, piper az ini lo, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl , pi rimidini 1, pyridazinyl, morpholino, ti orno r fo 1 ino, Iso thiazole i, isoxazolyl, oxazolyl, oxadi to zo 1 i lo, t i adi a zo 1 i lo, 1, 3-di oxo 1 ani 1 o, and 1, 4-dioxolanilo.
In a preferred embodiment of the invention the general formula of formula I is selected from wherein R1 and R5 are independently hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono-substituted or poly-substituted with halogen and R 4 is hydrogen; or R4 together with R5 represent one of the bonds in a double bond between atoms 2 and 3 of Formula I and R1 is as defined above; or R4 together with R1 represents one of the bonds in a double bond between atoms 3 and 4 of formula I and R5 is as defined above; D represents -S (= 0) - or -S (= 0) -, In another preferred embodiment of the invention, the general formula of formula I is selected from wherein R1 is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono substratum or po 1 i substi tuted with halogen and R 4 is hydrogen; or R4 together with R1 represents one of the bonds in a double bond between atoms 3 and 4 of the form ul to I; D represents -S (= 0) R7 = wherein R7 is alkyl of 1 to 6 carbon atoms; or aryl or heteroaryl optionally monosubstituted or substi tuted with halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms, cyano, acyl or alkoxycarbonyl of 1 to 6 carbon atoms.
In another preferred embodiment of the invention the general formula of formula I is selected from (you) wherein R1, R5 and R6 are independently hydrogen, hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono substi tuted or polysubstituted with halogen and R 4 is hydrogen; or R4 together with R5 represents one of the bonds in a double bond between atoms 2 and 3 of formula 1 and R1 and R6 are as defined above; or R4 together with R1 represent one of the bonds in a double bond between atoms 3 and 4 of formula I and R5 and R6 are as defined ant erically; D represents -S (= 0) 2- or S (= 0).
Preferably, the general formula of formula I is (la).
In another preferred embodiment of the invention D is -S (= 0) 2-.
In another preferred embodiment of the invention Ra is selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or alkenyl of 2 to 6 carbon atoms. Preferably R1 is hydrogen or alkyl of 1 to 6 carbon atoms.
In another preferred embodiment of the invention R1 together with R4 represent one of the bonds in a double bond between atoms 3 and 4 of the formula I.
In another preferred embodiment of the invention R4 together with R5 represent one of the bonds in a double bond between atoms 2 and 3 of the formula I.
In another preferred embodiment of the invention R is selected from hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or alkenyl of 2 to 6 carbon atoms. carbon. Preferably R is hydrogen or alkyl of 1 to 6 carbon atoms.
In another preferred embodiment of the invention R3 is selected from R8, -OR8, -NR8R9 or aryl, the aryl group is optionally substituted with alkyl of 1 to 6 carbon atoms; wherein R8 is hydrogen; cycloalkyl of 3 to 6 carbon atoms; (C3 -C6 cycloalkyl) alkyl of 1 to 6 carbon atoms; a 3 to 6 member saturated ring system comprising one, two or three nitrogen, oxygen or sulfur atoms; or straight or branched alkyl of 1 to 18 carbon atoms, optionally substituted by halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or aryl; R9 is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; or R8 and R9 together with the nitrogen atom form a ring of 4 to 6 members, preferably 1-pyridine or 1-pi, piperidine or morpholine.
In yet another preferred embodiment of the invention R3 is selected from secondary alkyl of 3 to 6 carbon atoms, tertiary alkyl of 4 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or (cycloalkyl of 3 to 6 carbon atoms) ) optionally monosubstituted or polysubstituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms. Preferably R3 is selected from isopropyl. 1 -me ti lpropi lo, 2-me t ilpropi lo, tert-butyl, 1, 1 -dime t ilprop i lo, 1, 2-dime ti lpropi lo, 1, 2, 2 - tr ime ti lprop i lo, 2,3-dime ti lbut i lo, 1 -e ti lpropi lo, l-etil-2-etilpropilo, 1 - eti 1-2, 2 -dimet i lpropi 1 o, 2,3,3-trime ti lbu ti It is 2-methyl, 1,5-di-ethylhexyl, 3-methyl butyl, 3-methyl, cyclopropyl, 1-methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 1- (cyclopropyl) ethylcyclobutylmethyl, cyclopentylmethyl or clohexylimethyl.
In a further preferred embodiment of the invention, R2 and R3 together with the nitrogen atom form a 6-membered ring, optionally substituted at the 2-position with an alkyl group of 1 to 6 carbon atoms, preferably selected from methyl, ethyl or isopropyl. Preferably the 6-membered ring is a ring of piperidine, piperazine, morpholine or t iomor fol ina.
In another preferred embodiment of the invention, R7 is selected from alkyl of 1 to 6 carbon atoms. carbon, phenyl or pyridyl.
In another preferred embodiment of the invention, A, together with the carbon atoms 5 and 6 of formula I, forms a 5-membered heterocyclic system containing a 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 non-aromatic 6-membered heterocyclic system containing one or two heteroatoms selected from nitrogen, oxygen and sulfur, the heterocyclic systems being optionally mono substrates disubstituted with halogen, alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyano; cyanomethyl; perha lome t i lo; sulfamoyl; alkylthio of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms; arylthio, aryl sulphiol, aryl sulphide, the aryl group is optionally monosubstituted or substituted by alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms. to 6 carbon atoms; alkoxycarbonyl having 1 to 6 carbon atoms - at least 1 to 6 carbon atoms; carbamilme t ilo; carboxy-alkyl of 1 to 6 carbon atoms; aryloxy; (1,2,4-oxadiazole-5-1) -alkyl of 1 to 6 carbon atoms or (1, 2, 4 -oxadi azo 1 - 3 -i 1) - to the one of 1 to 6 atoms of carbon, the oxadiazolyl group is optionally substituted with alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; acyl; or a ring containing nitrogen of 5 to 6 members, optionally substituted with phenyl or alkyl of 1 to 6 carbon atoms.
Preferably, A forms together with the carbon atoms 5 and 6 a thieno ring [3, 2 -e] - or pi rrol or [3, 2-e] -, thiophene, imidazole, thiazole, pyrazole, isoxazole or isothiazole, a pi pi raz ino ring [2, 3 -e] -, a pyrimido ring [4, 5-e] -, a ring pi ri ido [5, 4 -e] -, a ring pir ida z ino [, 5 - e] - or a ring pi r ida z ino [4, 3 -e] -, thiopyran, piperidine, dioxane, oxazine or di tiano.
The preferred compounds of the invention are 1, 1-7-Cyano-3-isopropylamino-6-metii-4H-thieno [2,3-e] -1,2,4-thi-adi-azine 1,1-cyano-di-oxide dioxide -6-methyl-3-propylamino-4H-ti eno [2, 3-e] -1, 2,4-thiadiazine 1,1-di-6-chloro-3-isopentylamino-4H-thieno [3] oxide , 2-e] - 1, 2, -thiadizine 1,1-6-chloro-3- (1-methylheptyl) amino-4H-thieno [3,2-e] -1,2,4-thiadizine di-oxide 1,1-di-6-chloro-3- (1-ethylpentyl) amino-4H-thieno [3, 2-e] -1, 2, -thiadizine 1,1-6-chloro-3- dioxide 2-methylbutyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-di-6-chloro-3- (2-me thylhexyl) 1-mino-4H-thieno [3, 2-e] - 1, 2, 4-thiadiazine 1,1-6-chloro-3-cyclopentyl lamino-4H- dioxide thieno [3, 2-e] -1, 2, 4-thiadiazine 1,1-dioxide, 6-chloro-3-cyclohexy, me thi-1-amino-4H-thieno [3, 2-e] -1, 2, -thiadiazine 3- (6-chloro-l, 4-dihydro-l, 1-dioxothieno [3, 2-e] -l? 6, 2, 4 - 11 adi-az-3-ylamino) but-ethyl-ano-ethyl 3- (6-Chloro-l, 4-dihydro-l, 1-dioxothieno [3,2-e] -l-6, 2,4-thiadiazin-3-ylamino) butanoic 1,1-dioxide 6- chloro-3 - (3-hydroxy-1-methyl-propyl) -amino-4H-thieno [3,2-e] -1,2,4-thiadiazine-1,1-dioxide (R) -6-chloro- 3- (1- phenylethyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide of (S) -3- s ec-But i 1 amino- 6 - chloro- 4H-thieno [3,2-e] -1,4,4-thiadiazine 1,1-dioxide 6-chloro-3-i sopr opi 1 amino- 4H-thieno [2, 3-e] - 1, 2, 4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopentylamino-4H-thieno [2, 3-e] - 1, 2,4-thiadiazma 1,1-dioxide 6-bromine - 3 - isopropyl-1-amino-4H-thieno [3,2-e] -1,2,4-thiadiazine-1,1-dioxide 3-isopropyl-1-amino-4H-ti-ene [3, 2-e] - 1, 2, 4-thiadiazine 1,1-dioxide 6- f luor o- 3-isopropy 1 amino- 4 H -thieno [3,2- e] -1,2-thiadiazine 1,1-dioxide 3 - ciclobut i 1 amino - 5, 6-dime ti 1 - 4H- thieno [3, 2-e] -1, 2, 4-thiadiazine 1,1-dioxido of 3-cyclopentylamino-5,6-dimethyl-4H-thieno [3,2-e] -l, 2, 4-thiadiazine 1,1-dioxide 3-i sopr opi 1 amino-6,7-dimethyl-1-4H-t-ene [2, 3-e] - 1, 2, 4-ti adi az ina 1,1 3-cyclobutyl 1-amino-6,7-dimetho-1,4-thieno [2,3-e] -1,2,4-thiadiazine 1,1-dioxide 3-cyclopentyl-lamino-6 dioxide , 7 -dime ti 1 - 4H- ti eno [2, 3 -e] - 1, 2, 4 - ti adi az ine 1,1-dioxide of 5-chloro-3-i sopropi 1 mino- 4H-thieno [ 3, 2-e] -1, 2-thiadiazine 1,1-chloro-3-propyl-1-amino-4-HT-ieno [3, 2-e] - 1, 2, 4-t iadi azine 5-chloro-3-cyclopentylamino-4-Ht ene [3, 2-e] -1,2,4-thi-adi-azo-1,1-dioxide-5-chloro-6-me-1,1-dioxide ti 1 - 3 - is opropi 1 amino-4H-thieno [3,2-e] -1,2-thiadiazine 1,1-dioxide 6-chloro-3-isopropyl amino-5-me thi-4H- thieno [3, 2-e] - 1, 2, 4-thiadiazine 1,1-dioxide 6-chloro-3-c iclopent i lamino- 5 • methyl-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide 6-f luoro-3-prop i lamino-4H-ti eno [3, 2-e] -1 , 2, 4-thiadiazine 1,1-dioxide-6-fluorine or -3-cyclopentyl-lamino-4H-thieno [3, 2-e] - 1, 2, 4 - tiadiaz ina - Fluorine 1,1-dioxide or 3-prop-lamino-H-thieno [3,2-e] -1,2,4-thiadiazine-5-fluoro-3-isopropyl-1-amino-1,1-dioxide - 4 H-thieno [3, 2-e] -1, 2, 4-thiadiazine 1,1-dioxide, 3-I, sopropi-1-amino-7-methyl-1, 4H-thieno [2, 3-e] - 1, 2, 4-thiadiazine 1,1-dioxide 6-chloro-3-cyclobutyl-1-amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide chloro-3- (2-hydroxy-1) amino-4H-thieno [3,2-e] -1,2, 4-thiadiazine 1,1-dioxide of (±) 3-exo-bi-cyclo [2.2. 1] hep t-2-amylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide (R) -6-chloro-3- (2-hydroxypropyl) amino-4H-thieno [3,2-e] -1,2,4-t-dihydroxy 1,1-dioxide 6-Brorno - 3 - i sopropi 1 amino - 4H - ti eno [3, 2 - e] - 1, 2, 4 - ti adi az ina 1,1 - dioxide of 5, 6 - dibromo - 3 - i sopropi 1 amino-4H-thieno [3,2-e] -1,2,4-thiadiazine-6-chloro-3-cyclohexylamino-4H-t-ene [3, 2-e] -1, 2-dioxide , 4-ti adi az ine 1,1-dioxido 6-chloro-3 - (furan-2-ylmethyl) amino-4H-thieno [3,2- e] -1,4,4-thiadiazine 1, 1- 6-chloro-3 - (1-et ilpr opi 1) amino-4H-t-ene [3, 2-e] - 1, 2, 4-ti adía z ina 1-dioxide 6-Brorno-1,1-dioxide-3-cyclopentyl-1-amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide-6-chloro-3- (2-dioxide) -me tilali 1) amino-Ht i eno [3, 2-e] - 1, 2, 4 - t iadi az ine or 6-cyano -3-isopr opyl amino-4H-thieno 1,1-dioxide [3 , 2-e] -1, 2, 4-thiadiazine The compounds of the present invention interact with the potassium channels and hence act as openers or blockers of the potassium channels regulated by the ATE, which makes them useful in the treatment of various diseases of the cardiovascular system, for example, the cerebral ischemia, hypertension, ischemic heart disease, angina pectoris and coronary heart disease; the pulmonary system; the gastrointestinal system; the central nerviso system and the "" endocrine system.
Since some KATP-openers are capable of antagonizing vasospasms in the basilar or cerebral arteries, the compounds of the present invention can be used for the treatment of vascular disorders or other conditions such as subarachnoid hemorrhage and migraine.
The compounds of the present invention can be used for the treatment of diseases associated with decreased blood flow in skeletal muscle such as Ráynauds disease and intermittent claudication.
In addition, the compounds of the invention can be used for the treatment of chronic respiratory diseases, including asthma, and for the treatment of detrusor muscle instability secondary to obstruction of the flow of the bladder and therefore for stones of the Kidneys, helping in its passage along the urethra.
The compounds of the present invention could be used for the treatment of conditions associated with disturbances in gastrointestinal mobility such as irritable bowel syndrome. Additionally these compounds can be used for the treatment of premature labor and dysmenorrhea.
The openers of the hyperpo-potassium channels undermine the neurons and inhibit the release of neurotransmitters and it is expected that these compounds can be used for the treatment of several diseases of the central nervous system, for example, epilepsy, ischemia and neurodegenerative diseases, and for pain management.
In addition, the openers of the potassium channels promote hair growth, therefore the compounds of the present invention can be used for the treatment of baldness.
The potassium channel openers also relax the smooth muscle of the urinary bladder and therefore the compounds of the present invention can be used for the treatment of urinary incontinence.
In diseases such as idiob 1 s and is insulinoma, in which an insulin hyper-struction causes severe hypoglycemia, the compounds of the present invention can be used to reduce insulin secretion. In Hypouric inemia due to obesity and insulin resistance is very common. This condition could lead to the development of non-insulin-dependent diabetes (NIDDM). It is expected that the openers of the potassium channels, and hence the compounds of the present invention, can be used to reduce hyperinsulinemia and therefore prevent diabetes and reduce obesity. In the obvious treatment of NIDDM of high insulins with potassium channel openers, and hence with the compounds herein, they may be of benefit in restoring sensitivity to glucose and normal insulin secretions.In early cases of insulin-deficient diabetes mellitus (IDDM) or in prothiabject cases, the potassium channel openers and hence the compounds herein can be used to induce rest of the pancreatic cells which can prevent the progression of the autoimmune disease.
The openers of the potassium channels of the present invention can be administered in combination with an immunosuppressant or with an agent such as the N-coamide, which will reduce the autoimmune degeneration of the beta cells.
Combining the rest of the beta cells with a protective treatment of the beta cells against that of cytokine mediated cytotoxicity / cytotoxicity of the beta cells is another aspect of this invention. Type 1 or insulin-requiring diabetes (IDDM) as well as the late-onset IDDM (also known as type 1.5, for example Type 2 that does not require insulin (NIDHR) patients with auto-reactiveness against cell epitopes. Beta, which subsequently becomes a type that requires insulin) has monocytes / 1 autoreactive, circulating inf ocs that are hosted in the cells / beta cells and release their cytokines. Some of these cytokines (for example, in ter leucine-Ib (IL-lb), tumor necrosis factor-a (TNFa) and interferon g (IFNg)) are specifically toxic to beta cells, for example, by induction of nitric oxide (NO) and other free radicals. The inhibition of this cytotoxicity, for example, by co-administering neither co-inamide (NA), a derivative thereof, or other cytokine-protecting compounds for diabetic predi abiotic patients treated with the compound PCO is an example of this aspect. Nicotinamide belongs to the family of vitamin B and is derived from nicotinic acid by inhibiting it. carboxyl group. It does not possess any of the pharmacological properties of nicotine. NA becomes NAD +, which acts as a coenzyme for proteins involved in tissue respiration. NA has been proposed as one that influences several molecular events, int cellular, putative, following the immune attack on beta cells. Experiments in animals and first experiments not blindly, in humans, have indicated a protective role of this compound against IDDM as well as in the destruction of beta cells mediated by cytokines / immune factors. Yet another aspect of this application concerns the use of a PCO compound alone or in combination with the inhibitor of beta cell damage mediated by cytokines / immune factors, in transplants, for example in islet transplantation in patients with diabetes. The use of one or both of these treatments may reduce the risk of rejection of islob / beta cells / beta cells engineered / pancreas transplanted.
The compounds of the present invention which act as blockers of KATP channels can be used for the treatment of NIDDM.
Preferably, the compounds of the present invention can be used in the treatment or prevention of diseases of the endocrine system such as hypertension and diabetes.
Accordingly, in another aspect the invention relates to a compound of the 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, preferably for the use as a therapeutically acceptable substance in the treatment of hyper insul inemia or prevention of diabetes.
In addition, the invention also relates to the use of inventive compounds of formula I as medicaments useful for the treatment of hyperinsulinemia and for the treatment or prevention of diabetes.
In still another aspect, the present invention relates to methods for preparing the aforementioned compounds. The methods include: reacting a compound of formula II where A, B, D, R1 and R4 are as previously * stated and Z is a leaving group such as alkoxy, alkylthio, halogen, preferably chlorine, bromine, iodine, rime t 1 amino, or me tyl sulphonyl with a compound of formula III: R ^ / HN RJ (III) where R 'and R; they are • as previously defined to form a compound 'of general formula I; b) reacting a compound of formula IV wherein R1 is hydrogen and A, B, D and X are as defined above, or B is NH and R1, A, D, and X are as defined above, with the compound of formula III, or a suitable salt of the same, in the presence of P205 and an amine tertiary high boiling point or a suitable salt thereof, to form a compound of the general formula I; c) reacting a compound of formula IV: wherein R1 is hydrogen and A, B, D and X are as defined above or B is NH and R1, A, D and X are as defined above, with a compound of formula III, or a suitable salt thereof, in the presence of titanium tetrachloride and a solvent with which it can form a complex, such as for example tetrahydrofuran, or a mixture of toluene and anisole, to form a compound of the general formula I; d) reacting a compound of formula V wherein R1 and A are as defined above, with a compound of formula VI R3NCO (VI) wherein R is as defined above, to form a compound of the general formula I wherein D is S02, B is > NR5, R2 is H, and R4 and R5 together form a bond; reacting a compound of formula V wherein R1 and A are as defined above, with a compound of formula VII R3NHC (= 0) CI (il) wherein R3 is as defined, to form a compound of the general formula I wherein D is S02, B is > NR5, R2 is H, and R4 and R5 together form a bond; reacting a compound of formula V wherein R1 and A are as defined above, cpon a compound of formula VIII wherein Y is NH or S, or a suitable salt thereof, to form a compound of the general formula I, wherein D is S02, B is > NR5, R2 is H, and R4 and R5 together form a bond, and R2 and R3 are H; g) reacting in the presence of a base a compound of formula IX or a suitable salt thereof, wherein R11 is R1 or EtOC (= 0), wherein R1 and A are as defined above, with a compound of formula X R? N = C = S (X) wherein R3 is as defined above, to form an adduct which can be either of the two structures XI or XII or can be a mixture of the two any of which by ring closure, for example by treatment with phosgene in a suitable solvent, forms a compound of the general formula I, if R11 is R1, where D is S (= 0) 2, B is > NR5, R2 is H, and R4 and R "together form a bond, and a compound of the general formula XIII and R11 is EtOC (= 0); (Xlll) h) hydrolyzing and subsequently decomposing a compound of the general formula XIII -to form a compound of the general formula I, where D is S (= 0) 2, B is > NR "R1 and R2 are H, and R4 and R5 together form a bond, for example, by heating the initial compound in an aqueous base.
The starting materials are either known compounds or are compounds that can be prepared by analogy to the preparation of known compounds or by analogy with known methods such as those described, for example, in Huang B.-S., et al., J. Med. Chem., 23, 575-7 (1980), Ofitserov VI et al., Khim. Geterotsikl. Soedin , 1119-22 (russ.) (1976), Topliss J. G., U.S. 3,641,017 (1972), Kotovs aya S. K. et al., Khim. -Farm. Zh. , 13, 54-57 (russ.) (1979), Meyer R. F., J. Heterocycl. Chem., 6_, 407-408 (1969) and Hattori M., Yoneda M., and Goto M., Bull. Chem. Soc. Jap. , 46, 1890-1 (1973), Williams T. R. and Cram D. J., J. Org. Chem., 38, 20-26 (1973), Barnes A.C., Kenne ell P.D. and Taylor JB, J. Chem. Soc. Chem. Commun., 1973, 776-777, Stoss and Satzinger, Chem. Ber., 109, 2097 (1976), Kresze G., Hatjiisssaak A., Phosphorus Sulfur, 29, 41-47 (1987), Dillard RD, Yen TT, Stark P., -Pavey DE, J. Med. Chem., 23, 717-722 (1980).
PHARMACOLOGICAL METHODS The ability of compounds to interact with potassium channels can be determined through several methods. When membrane pricking techniques are used (Ha ill OP, Marty A., Neher E., Sakmann B. and Sig orth FJ, Plügers Arch., 391, 85-100 (1981)), the ionic current can be recorded at through a single channel of a cell.
The activity of the compounds as potassium channel openers can also be measured co or the relaxation of a rat aorta ring, in accordance with the following procedure: A section of rat thoracic aorta is dissected between the aortic arch and the diaphragm, and assembled as ring preparations as described by Taylor P.D. et al, bri t J. Ph a rma c ol, 111, 42-48 (1994).
After an equilibrium period of 45 minutes, under a tension of 2 g, the preparations contracted to achieve 80% of the maximum response, using the required concentration of phenylephrine. When the response to phenylephrine reached a point of no affectation to the dependent variable, potential vasodilating agents were added to the bath, in a cumulative manner, in small volumes, using molar increments at 6-minute intervals. Relaxation was expressed as the percentage of tension contracted. The potency of a compound was expressed as the concentration required to produce 50% tissue relaxation.
Relation of rat aorta rings Ex empl o EC50 micro M 4 2.8 6 20.5 In pancreatic b cells the opening of KATp channels can be determined by measuring the subsequent change in free cytoplasmic Ca + 2 concentration, in accordance with the method of Arkhammar P. et al., J. Bí l. Ch em. , 2 62, 5448-5454 (1987).
Efluj or 8SRb + of a Beta cell line The RIN 5F cell line was cultured in RPMI 1640 with Glutamax I, supplemented with 10% fetal calf serum (from GibcoBRL, "Scotland, UK) and kept in an atmosphere of 5% C02 / 95% air, a 37 ° C. The cells were separated with a solution of Tr ips ina-EDTA (from GibcoBRL, Scotland, UK), they were resuspended in the medium, 1 Ci / l 86Rb + was added and they were reapplied in micro plates. tulation (grouping of 96 wells 3596, sterile, of Costar Corporation, MA, USA) at a density of 50000 cells / well in 100 μl / well, and were cultured 24 hours before use in the assay.
Plates were washed 4 times with ringer buffer (150 mM NaCl, 10 mM Hepes, 3.0 mM KCl, 1.0 mM CaCl2, 20 M Sucrose, pH 7.1). Eighty μl of Ringer buffer and 1 μl of the control or control compound dissolved in DMSO were added. After incubation at 1 hour at room temperature with a lid, 50 μl of the supernatant was transferred to PicoPlacas (Instrument Packard Company, CT, USA) and 100 μl of MicroScint 40 (Packard Instrument Company, CT, USA) was added. The plates were counted in a TopCount (Packard Instrument Company, CT, USA) for 1 minute / plate in the 32P program.
The calculation of the ECS0 and the Emax was done by SlideWrite (Advance Graphics Software, Inc., CA, USA) using a four parameter logistic curve: y = (ad) / (1 + (x / c) b) + d, where a = the activity estimated at zero concentration, b = a slope factor, c = the concentration at the center of the curve and, d = the estimated activity at infinite concentration. EC50 = c and Emax = d, when the curve continues towards infinite concentrations.
Rb Efflux Increased in 5F rin cells Example EC50 micro M 4 • 5.5 31 The compounds according to the invention are effective over a wide range of dosages. In general satisfactory results are obtained with dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day. A more preferable dosage is from about 1 mg to about 100 mg per day. The exact dosage will depend on the mode of administration, the way in which it is administered, the subject to be treated and of the body weight of the subject to be treated, and of the preference and experience of the doctor or veterinarian in charge.
The route of administration can be any route that effectively transports the active compound to the appropriate or desired site of action, such as orally or parenterally, for example, rectal, tr anside, subcutaneous, intravenous, intramuscular or intranasal, with the preferred oral route Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which can be a carrier or a diluent, or can be diluted by a carrier, or enclosed within a carrier that can be found in the form of a capsule, sachet, paper or other type of container. Conventional technique can be used to make the compositions for the preparation of pharmaceutical compositions. For example, the active compound will usually be mixed with a carrier or it will be diluted by a carrier, or it will be enclosed within a carrier that may be in the form of a vial, capsule, sachet, paper, or other type of container. When the carrier serves as a diluent it can be a solid, semi-solid, or liquid material, which acts as a vehicle, excipient, or medium for the active compound. The active compound can then be adsorbed in a solid granular container, for example, in a pouch. Examples of suitable carriers are water, saline solutions, alcohols, polyolefins, castor oil, hydroxy-ethoxy side, gelatin, lactose, and ilose, stearate. of magnesium, talc, silicic acid, monoglycerides and diglycerides of fatty acids, fatty acid esters of pentaerythritol, hi-hydroxy-t-cellulose and poly-inylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents. The formulations of the invention can be formulated in such a way as to provide a rapid, sustained or of the active ingredient after administration to the patient, employing procedures well known in the art.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, edul sifi cant, salt for influencing the osmotic pressure, buffers and / or coloring substances and the like, which do not react perj ectively with the compounds acti os For parenteral application, injectable solutions or suspensions are particularly convenient, preferably aqueous solutions with the active compound dissolved in 1-hydroxylated castor oil.
Tablets, dragees, or capsules having talc and / or a carbohydrate carrier or binder or the like, are particularly suitable for oral application. Preferred carriers for tablets, dragees, or capsules include lactose, corn starch, and / or potato starch. You can use a syrup or elixir in cases where a sweetened vehicle can be used. Generally the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier, per unit dosage.
A typical tablet, suitable for use in this method can be prepared through conventional tablet-forming techniques and contains: Active compound 5.0 mg Lactose 67.8 mg European Pharmacopoeia Avicel ™ 31.4 mg Amberlite ™ 1.0 mg Magnesium stearate 0.25 mg European Pharmacopoeia AND EMPLOYMENT The process of preparation of the compounds of formula I is further illustrated in the following examples that are not considered to be limiting, however.
EXAMPLE 1 1,1-Dioxy-3-y-sopropi-lamino-6-me t i 1-4H-thieno [2, 3-e] -1,2,4-thiadiazine 1,1-dioxide 4-Cyano-2-hydrazinocarbonyl-5-methyl-thiophene-3-sulfonamide Suspend, in 10 ml of ethanol, 4-cyano-5- e t i -3-sulfo-1-thio-phenyl-2-carboxylic acid methyl ester (2.9 g) prepared from methyl 3-amino-4-cyano-5-methyl-methyl-1-thio-phenyl-2-carboxylate, analogously to known procedures, for example, F. Junquera et al., Eur. J. Med. Chem. 23, 329 (1988). Hydrazine monohydrate (2 ml) is added and the mixture is stirred for 1 hour at room temperature and then evaporated. The oily residue (3.3 g) is triturated with 10 ml of water and the precipitating crystals are collected by filtration, washed with water and dried to give yellow crystals of the title compounds (yield 1.62 g); p.f. 186-91 ° C: H-NMR (DMSO-de), d (ppm): 7.25 (broad signal, 5H, NH / NH2), 2.51 (s, 3H, CH3). b) azide of 4-cyano-5-me t i 1 -3-sul famo il-t i or fen-2-carboni 1 or A solution of sodium nitrite (0.47 g) in 5 ml of water is added dropwise to a stirred solution of 4-cyano-2-hydr azocarboni 1 -5-me thi-thio f en- 3 - s ul fonami da (1.6 g) in 38 ml of 1 M hydrochloric acid at 0 ° C. The resulting mixture is stirred for 30 minutes at 0 ° C and then filtered. The filter cake is washed with water and dried under vacuum to give 1.35 g of the title compound; 1 H NMR (DMS0-d 6), d (ppm): 7.75 (broad signal, 1H, NH 2), 2.75 (s, 1H, CH 3) c) 4-Cyano-2-ethoxycarbonyl amino-5-methyl-1-thiophen-3-sulfonamide 4-Cyano-5-me t -yl-3-sulphi-1-thio-phenyl-2-carbonyl azide (1.35 g) is added in small portions, over 5 minutes, to 50 ml of absolute ethanol at reflux temperature. The resulting solution is subjected to reflux during minutes and then it evaporates. The residue is crystallized when it is triturated with 20 ml of ethyl acetate. The crystals are separated by filtration, rinsed with ethyl acetate and dried to give the title compound; 1 H-NMR (DMS0-d 6), d (ppm): 9.45 (s, 1 H, NH), 7.82 (broad signal, 2 H, NH 2), 4.23 (quatrain, 2 H, CH 2), 2.51 (s, 3 H, CH 3), 1.25 (t, 3H, CH3). d) N- (4-cyano-2-ethoxycarbonylamino-5-methyl-3-thienyl sulfonyl) -N'-isopropylthiourea A mixture of 4-cyano-2-ethoxycarbonylane-5-methyl-1-thio-3-sulphonamide (0.50 g), potassium carbonate (0.36 g) and isopropyl sulfonate (300 μl) in 10 ml of dry acetone is heated at 55 ° C for 18 hours and then evaporated to dryness. The residue is dissolved in 10 ml of water, and the pH is adjusted to 2 by the addition, dropwise, of 1 M hydrochloric acid. The above is separated by filtration, rinsed with a small amount of water and dried for give 0.34 g of the title compound; p.f. 169-171 ° C. e) 1,1-ci ano-3-isopropyl-1-amine-6-methyl-4H-thieno [2,3-e] -1,2-thiadiazine-4-carboxylic acid 1,1-dioxide _ a stirred solution of N- (4-cyano-2-ethoxycarbonylamino-5-methyl-3-thienylsulfonyl) -N'-isopropylthiourea (0.3 g) and triethylamine (320 μl) in 10 ml of dry THF at 0 ° C is added 750 μl of a 20% solution of phosgene in toluene. The mixture is stirred at 0 ° C for 1 hour and then evaporated to dryness. The residue is triturated with 10 ml of water, separated by filtration, rinsed on the filter with water and dried to give 0.24 g of the crude title compound; p.f. 116-119 ° C. The product is Use for the next step without purification. f) 7-cyano-3- isopropylamino-6-methyl-4H-thieno [2,3-e] -1,2,4-thiadiazine 1,1-dioxide A mixture of 7-cyano-3-isopropylamino-6-methyl-4H-thieno [2,3-e] -1,2,4-thiadiazine-ethylcarbamate 1,1-dioxide (0.15 g) and 5 ml of 1 M aqueous sodium hydroxide solution is stirred at room temperature for 1 hour.
The mixture is then filtered and the pH adjusted to 1-2 by the addition, dropwise, of 4M hydrochloric acid. After stirring for 30 minutes the precipitate is filtered off, rinsed with a small amount of water and dried to give the title compound; p.f. 235-238 ° C; X H NMR (DMSO-d 6), d (ppm): 11.35 (s, 1 H, NH), 7.55 (double amplium, 1H, NH), 3.98-3.77 (, 1H, CH), 2.50"(s, 1H, CH3), 1.15 (d, 6H, CH3).
EXAMPLE 2 7-cyano-6-me thi-1,3-propylamino-4H-threo [2,3-e] -1,2,4-thiadiazine 1,1-dioxide. a) N- (-ci ano -2-et oxy carboni lamino-5-methyl-3-thienylsulfonyl-N '• propyl thiourea The title compound is prepared from 4-cyano-2-ethoxycarbonylamino-5-methyl-thiophene-3-sulfonamide and propyl isocyanate by analogy with the synthesis described in Example 1-d; p.f. 167-168 ° C. b) 7-cyanobutyl-6-methyl-3-propyl amino-4H-thieno [2,3-e] -1,2,4-thiadiazine-4-carboxylic acid 1,1-dioxide The title compound is prepared by ring closure of the N- (4-cyano-2-ethoxycarbonylamino-5-methyl-3-thienylsulfonyl) -N'-propyl 1 tine by analogy with the synthesis described in Example 1-e; p.f. 175-179 ° C. c) 7-cyano-1,1-dioxide 6-me t i 1 -3-pr opi 1 amino-4 H -thieno [2,3-e] -1,2,4-thiadiazine The title compound is prepared by hydrolysis and that of the subsequent carboxylic acid of 1,1-dioxide of 7-cyano-6-me thi-1-3-propylamino-4H-thieno [2, 3-e] - 1, 2,4-thiadiazine-4-carboxylic acid ethyl ester, by analogy with the synthesis described in Example 1-f; p.f. 293-298 ° C; NMR tE (DMSO-d6), d (ppm): 11.6 (s, 1H, NH), 7.65 (broad signal, 1H, NH), 3.14 (dd, 2H, CH2), 2.58 (s, 1H, CH3), 1.65-1.4 (m, 2H, CH2), 0.89 (t, 3H, CH3).
EXAMPLE 3 6-Chloro-3- (3-methyl-1-butyl) -1-amino-4H-thieno [3, 2-e] -1,2,4-t-adi-azine a) N- (3-amino-5-chloro-2-thienylsulfonyl) - N '- (3-methylbutyl) thiourea Potassium tert-butoxide (0.49 g, 4-.4 mmol) is added to a solution of 3-amino-5-chloro-4-t-hydrochloride in-2-sulphonamide (0.5 g, 2.0 mmol) in N , Nd ime ti 1 dry formamide (5 ml) with application on an ice bath. After 10 minutes, the resulting suspension is added dropwise to the solution of 3-methylbutyl (0.31 g, 2.4 mmol) and the mixture is stirred for 3.5 hours at a temperature of 0 to 20 ° C. . The majority of the solvent is evaporated at 40 ° C and the residue is taken up in 25 ml of water, treated with decolorizing charcoal and filtered. Acidification of the filtrate with acetic acid to a pH of 3-4 and filtration yield 0.21 g (29%) of the title compound: m.p. 114-115 ° C with decomposition, RM? 1H (DMSO-d6): d 0.85 (d, 6H, 2 X CH3), 1.40 (quartet, 2H, CH2), 1.50 (m, 1H, CH), 3.45 (quartet, 2H, CH2), 6.45 (broad signal, 2H, CH2), 6.65 (s, 1H, H-4), 8.30 (wide triplet, 1H, NH ), 11.3 (singlet a pl io, 1H). b) 6-chloro-3- (3-methyl-1-butyl) -1-amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide Phosphine (0.242 ml, 20% in toluene) is added to a solution of • N- (3-amino-5-cl or ro-2-thienylsulfonyl) - N '- (3-methylbutyl) thiourea (0.153 g, 0.42 mmol ) and dry triethylamine (0.118 ml, 0.85 mmol) in dry tetrahydrofuran (3 ml) with stirring at 0 ° C. The mixture is stirred for 2 hours at 0 ° C, and evaporated to dryness. The crystallization is obtained in ethyl acetate, and the precipitate is isolated by filtration, washed with water and dried to yield 38 mg (37%) of the title compound. p.f. 230-231.5 ° C, NMR aH (DMSO-de): d 0.90 (d, 6H, 2 X CH3), 1.40 (quartet, 2H, CH2), 1.60 (m, 1H, CH), 3.20 (quartet, 2H, CH2), 7.05 (s, 1H, H-5), 7.25 (broad singlet, 1H, NH), 10.95 (S, 1H, NH). MS: M / e 307 (M +).
EXAMPLE 4 6-Chloro-3- (1-methyl-1-yl) -1-amino-4-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide a) N- (3-amino-5-chloro-2-thienylsulfonyl) - N-time ti Ihep ti 1) thiourea The title compound is prepared from 3-mino-5-chloro-thiofen-2-sulfonamide hydrochloride and 1-methylated thiocyanate by a procedure analogous to the procedure described in Example 3-a; Do you get a syrup (29% yield), RM? 1H (DMSO-dg): d 0.90 (triplet, 3H, CH3), 1.10 (d, 3H, CH3), 1.25 (m, 8H), 1.47 (m, 2H, CH2), 4.25 (p, 1H, CH) , 6.5 (broad singlet, 2H,? H2), 6.65 (s, 1H, H-4), 7.95 (broad signal, 1H,? H), 11.2 (broad singlet, 1H). b: 1, 1-dioxy-di-cl-gold-3 - (1-ethylheptyl) amino-4H-thieno [3, 2-e] -1, 2, thiadiazine The title compound is prepared starting from N- (3-amino-5-cl or ro-2-thienylsulfonyl) -N '- (1-methylheptyl) thiourea hydrochloride by a procedure analogous to the procedure described in Example 3-b; (yield of 71); p.f. 179-181 ° C, RM? XH (DMSO-de): d 0.85 (t, 3H, CH3), 1.15 (d, 3H, CH3), 1.30 (, 8H), 1.45 (m, 2H, CH2), 3.75 (p, 1H, CH), 7.05 (s, 1H, H-5), 7.10 (broad singlet, 1H,? H), 10.65 (s, 1H,? TT) -. MS M / e 349 (M +).
EXAMPLE 5 _ _ ~ _ 6-C-loro-3 - (e t i lpent i 1) amino-4 H -thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide _ ... __ _ _ a) N- (3-Mino-5-chloro-2-thienylsulfonyl) - N '- (1-ethylpentyl) thiourea The title compound is prepared from 3-amino-5-chloro-thio-2-sulphonamide hydrochloride and 1-ethyl ester by an analogous procedure to the procedure described in Example 3 -to; you get a syrup (36% yield), RM? XH (DMSO-de): d 0.8 (2 quartet, 6H, 2 x CH3), 1.2 (, 4H), 1.5 (m, 4H), 4.20 (sextet, 1H, CH), 6.55 (broad signal, 2H, NH2) , 6.65 (s, 1H, H-4), 7.85 (broad double, 1H, NH), 11.3 (singlet a pl io, 1H, NH). b) 1,1-dioxide, 6-cl-oro-3 - (1-e-tylpen t i 1) amino-4-H-ti-ene [3, 2-e] - 1, 2, 4-t i adi a z The title compound is prepared from N- (3-amino-5-chloro-2-thienylsulfonyl) -N '- (1 -et i lpent i 1) thiourea by a procedure analogous to the procedure described in Example 3 -b; (35% yield); p.f. 165-167.5 ° C, XH NMR (DMSO-dβ): d 0.85 (2 quartets, 6H, 2 x CH 3), 1.25 (m, 4H), 1.45 (m, 4H), 3.65 (m, 1H, CH), 7.0 (broad signal, 1H, NH), 7.05 (s, 1H, H-5), 10.65 (broad singlet, 1H, NH). MS: M / e 335 (M +).
EXAMPLE 6 6-chloro-3- (me ti lbut i 1) amino-4H-thieno [3,2-e] - 1, 2,4-t-diadiazine 1,1-dioxide a) N- (3-amino-5-chloro-2-thienylsulfonyl) - N '- (2-methylbutyl) thiourea The title compound is prepared from the 3-amino-5-chloro or f-2-sulfone hydrochloride ida and the 2-thiothione sulfonate by a procedure analogous to the procedure described in Example 3-a; (28% yield); p.f. 116.5-118 ° C, RM? XH (DMSO-d6): d 0.8 (2 d, 6H, 2 x CH3), 1.10 (m, 1H), 1.30 (m, 1H), 1.65 (, 1H), 3.40 (, 2H + HDO, CH2), 6.45 (broad signal, 2H,? H2), 6.65 (s, 1H, H-4), 8.25 (broad triplet, 1H,? H), 11.3 (broad singlet, 1H). b) 6-Cl-oro-3 - (2-met i lbu t i 1) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide The title compound is prepared from N- (3-amino-5-chloro-2-thienylsulfonyl) -N '- (2-ethylbutyl) thiourea by a procedure analogous to the procedure described in Example 3-b; (49% yield); p.f. 232-234 ° C, RM? aH (DMSO-ds): d 0.85 (2 d, 6H, 2 x CH3), 1.15 (, 1H), 1.40 (m, 1H), 1.60 (m, 1H), 3.10 (m, 2H, CH2), 7.05 (s, 1H, H-5), 7.25 (broad signal, 1H, NH), 10.85 (broad singlet, 1H, NH). MS M / e 307 (M +).
Calculated Analysis for C10H? 4ClN302S2 C 39.02 H 4.58 N 13.65, Found C 38.98 H 4.72 N 13.40 EXAMPLE 7 _ 6-chloro-3 - (1-methyl-1-ethylhexyl) -amino-4-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide a) N- (3-amino-5-chloro-2-thienylsulfonyl) - N '- (1 -me t ihexy 1) t iourea The title compound is prepared from 3-amino-5-chloro t-thio-2-sulphonamide eisotiocyan hydrochloride of 1-methylhexylo by a procedure analogous to the procedure described in Example 3-a; a syrup is obtained (43% yield), XH NMR (DMSO-ds): d 0.85 (triplet, 3H, CH3), 1.10 (d, 3H, CH3), 1.25 (, 6H), 1.45 (m, 2H), 4.25 (, 1H, CH), 6.50 (broad signal, 2H, NH2), 6.55 (s, 1H, H-4), 7.93 (broad signal, 1H, NH), 11.3 (broad singlet, 1H, NH). b) 6-chloro-3 - (1-methexyl-1-yl) dioxide to ino-4H-thieno [3, 2-e] -1, 2,4-thiadiazineThe title compound is prepared from N- (3-amino-5-chloro-2-thienylsulfonyl) -N '- (1 -met ihexyl) thiourea by a procedure analogous to the procedure described in Example 3-b; (63% yield); p.f. 158-162 ° C, 1 E NMR (DMS0-d6): d 0.85 (t, 3H, CH3), 1.15 (d, 3H, CH3), 1.25 (m, 6H), 1.45 (m, 2H), 3.75 ( , 1H, CH), 7.05 (singlet, 1H, H-5), 7.15 (broad singlet, 1H, NH), 10.75 (broad singlet, 1H, NH), MS M / e 335 (M +).
EXAMPLE 8 6-chloro-3 - (ci cl opent i 1) amino-4H-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide N- (3-amino-5-chloro-2-thienylsulfonyl) - N '-cyclopentylthiourea The title compound is prepared from 3-amino-5-chloro-thio-f-2-sulfonamide hydrochloride and cyclopentyl cyclopentyl chloride by a procedure analogous to the procedure described in Example 3-a; (46% yield); XH NMR (DMSO-d6): d 1.30-1.70 (m, ßH), 1.90 (m, 2H), 4.40 (sextet, 1H CH), 6.55 (broad signal, 2H, NH2), 6.65 (s, 1H, H -4), 8.15 (wide double, 1H, NH), 11.2 (broad singlet, 1H, NH). - b) 6-chloro-3 - (cyclopent i 1) amino-4-thieno [3,2-e] -1,4-thiadiazine 1,1-dioxide The title compound is prepared from N- (3-amino-5-chloro-2-thienylsulfonyl) -W-cyclopentyl-1-thiourea by a procedure analogous to the procedure described in Example 3-b; (57% yield); p.f. 291-292 ° C, RM? 1 E (DMSO-d6): d 1.40-1.70 (m, 6H, CH3), 1.90 (, 2H), 3.95 (sextet, 1H, CH), 7.05 (s, 1H, H-5), 7.3 (broad signal , 1H,? H), 10.70 (broad singlet, 1H,? H). MS: M / e 305 (M +).
EXAMPLE 9 6-Chloro-3- (cyclohexylimide) 1-amino-4H-t-ene [3, 2-e] - 1, 2, 4-tiadiazine-1,1-dioxide a) N- (3 -A-ino-5-chloro-2-thienylsulfonyl) - N'-cyclohexylmethylthiourea The title compound is prepared from 3-mino-5-chloro-thio-2-sulphonamide hydrochloride and cyclohexyl thiocyanate hydrochloride by a procedure analogous to the procedure described in Example 3 -to; Do you get a syrup (8% yield) RM? XH (DMSO-dβ): d 0.95 (m, 2H), 1.25 (m, 3H), 1.70 (m, 6H), 3.45 (d, 2H, CH2), 4.45 (broad signal, HDO +? H), 6.65 (s, 1H, H-4). 6-chloro-3 - (cyclohexy-1-yl) -amino-4H-thieno [3, 2-e] -1, 2-thiadiazine 1,1-dioxide The title compound is prepared from N- (3-amino-5-chloro-2-thienylsulfonyl) -N'-cyclohexylmethylthiourea hydrochloride by a procedure analogous to procedure described in Example 3-b; (68% yield); p.f. > 200 ° C with decomposition., 1 H NMR (DMSO-d 6): d 0.90 (m, 2H), 1.15 (, 3H), 1.70 (m, 6H), 3.05 (t, 2H, CH2), 7.05 (s, 1H, H-5), 7.25 (broad signal, 1H, NH), 10.95 (broad singlet, 1H, NH). MS M / e 333 (M +).
EXAMPLE 10 - 3- (6-chloro-l, 4-dihydro-l, 1-dioxothieno [3,2-e] -l? 6, 2, 4-t i adi az ind 3-i lamino) bu t anoa t o ethyl a) 3-. { 3 [(3-amino-5-chlorot i en-2 ii) sul foni 1] t i oureido} but anoa t of ethyl The title compound is prepared from 3-amino-5-c-loro-t-f-2-sulfonamide hydrochloride and ethyl 3-iso-thiocyanatobutyl hydrochloride by a procedure analogous to the procedure described in Example 3-a; (93% yield); XH NMR (DMS0-d6): d 1.18 (d, 3H, CH3), 1.20 (t, 3H, CH3), 2.61 (m, 2H, CH2), 4.08 (quartet, 2H, CH2), 4.58 (m, 1H, CH), 6.46 (broad singlet, 2H, NH2), 6.65 (s, 1H, H- 4), 8.34 (broad double, 1H, NH 11.35 (broad singlet, 1H). b) 3- (6-chloro-l, 4-dihydro-l, 1-dioxothieno [3,2-e] -l? 6, 2,4-thiadiazin-3-yl-a) ethyl) butane-ethyl ester The title compound is prepared from 3 - hydrochloride. { 3 [(3-amino-5-cyro-t-en-2-yl) sulphon-1] t-oureido} butanoat or ethyl by a procedure analogous to the procedure described in Example 3-b except that the product is purified by column chromatography (71% yield) m.p. 151-155 ° C (ethyl acetate); 1 E NMR (DMSO-d6): d 1-18 (t, 3 H, CH 3), 1.20 (d, 3 H, CH 3), 2.57 (m, 2 H, CH 2), 4.07 (quatrain, 2 H, CH 2), 4.17 ( m, 1H, CH), 7.05 (s, 1H, H-5), 7.25 (broad signal, 1H, NH), 10.99 (s, 1H, NH); MS: m / e 351/353 (M +); (C ??H14N3Cl ?O4S2-0.2 ethyl acetate) calculated C38.36 H.4.26 N 11.37, found H 4.18 N 11.58.
EXAMPLE 11 3- (6-Chloro-l, 4-dihydro-l, 1-dioxothieno [3, 2 e] -l? 6, 2,4-thiadiazin-3-ylamino) butanoic acid It hydrolyzes ethyl 3- (6-chloro-1,4-dihydro- or 1,1-dioxothieno [3, 2-e] -l- 6,6-, 2,4-thiadiazin-3-yl) buty anoate (0.5 g, 1.42 mmol) in the acid by stirring in 5 ml of 2 N sodium hydroxide, for 2 hours, at room temperature. The solution is treated with decolorizing charcoal, filtered and acidified with 4 M hydrochloric acid to pH 2. The resulting precipitate is isolated by filtration, washed with water and dried to give 294 mg (64%) of the title compound.; p.f. 218-223 ° C; XH NMR (DMSO-d6): d 1.19 (d, 3H, CH3), 2.49 , m, 2H, CH 2 I 4.10 m, 1H, CH 7.06 1H, H-5), 7.25 (broad signal, 1H, NH), 10.99 (s, 1H, NH), 12.38 (broad singlet, 1H, OH); MS m / e 305/307 (M-H20) +; (C 9H? 0N3C 1? 04 S2) calculated C 33.39 H 3.11 N 12.98, found C 33.62 H 3.11 N 12.81.
EXAMPLE 12 1, 1-dioxy-di-6-chloro-3- (3-bidroxy-1-methylpropyl) amino-4H-thieno [3, 2-e] -1, 2, ti adiaz ina Cool toluene (5 ml) to 10 ° C and add lithium aluminum hydride (114 mg, 3 mmol) followed by 0.53 ml of tetrahydrofuran. 3 - (6-lor o-1, 4-dihydro-1,1-dioxothieno [3,2-e] -l? 6,2,4-thiadizin-3-yl-1-amino) buty-anoate of ethyl (352 g, 1 mmol) to the cooled solution and the mixture is stirred for 2 hours at 0 ° C and then at room temperature overnight. The mixture is cooled on an ice bath and 10 ml of water are added dropwise, followed by 5-10 ml of 20% sulfuric acid. The mixture is extracted with ether (3 x 30 ml) and the organic phase is washed with water, dried and evaporated to dryness. The crude product is mixed with the solid formed in the aqueous phase and finally purified by column chromatography on silica, with ethyl acetate / 1: 9 (1: 1) to yield 120 mg (39%) of the composed of the title; p.f. 199-203 ° C; 1 E NMR (DMSO-d6): d 1.14 (d, 3 H, CH 3), 1.65 (, 2 H, CH 2), 3.48 (m, 2 H, CH 2), 3.90 (, 1 H, CH), 4.60 (broad singlet, 1 H , OH), 7.06 (s, 1H, H-5), 7.17 (broad signal, 1H, NH), 10.86 (s, 1H, NH); MS m / e 309/311 (M +); (C9H? 2N3C l? 03S2 • 0.15 ethyl acetate) calculated C 35.70 H 4.12 N 13.01, found C 35.7 H. 4.1 N 13.1.
EXAMPLE 13 1,1-Dioxide of (R) -6-chloro-3- (1-phenylethyl) mino ' 4H-Thieno [3, 2-e] - 1, 2, 4-thiadiazine a) (R) -N- (3-amino-5-chloro-2-thienylsulfonyl) -N '(1-phene 1 e t i 1) t i our ea The title compound is prepared from 3-amino-5-chloro t-thio-2-sulphonamide hydrochloride and Da-methylbenzene isocyanate by a procedure analogous to the procedure described in Example 3 -to; (yield of 96% impure product); NMR XH (DMS0-d6): d 1.46 (d, 3H, CH3), 5.36 (quintupl e t, 1H, CH), 6.45 (broad singlet, 2H, NH2), 6.64 (s, 1H, H-4), 7.2-7.4 (m, 5H, ArH), 8.53 (broad double, 1H, NH 11-3 (broad singlet, 1H). 1,1-dioxy-di (R) -chloro-3- (1-phenylethyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine The title compound is prepared from (R) -N- (3-Amino-5-chloro-2-thienylsulfonyl) -N '- (1-f-1-yi-1) -thiourea by a procedure analogous to the procedure described in Example 3-b except that the product is purified by column chromatography on silica with dichloromethane / methanol (19: 1), (yield 17%); p.f. 218-220 ° C (ethyl acetate); XH NMR (DMSO-de): d 1.48 (d, 3H, CH3), 4.97 (quintuplet, 1H, CH), 7.10 (s, 1H, H-5), 7.2- 7.4 (, 5H, ArH), 7.73 (broad signal, 1H, NH), . 81 (s, 1H, NH); MS: m / e 341/343 (M +); (C? 3H12N3Cl? 03S2) calculated C 45.68 H 3.54 N 12.29, found C 45.83 H 3.55 N 12.04.
EXAMPLE 14 1,1-dioxide of (S) -3-s ec-But-il-amino-6-c 1 or ro- 4 H-thieno [3, 2-e] -1, 2,4-thiadiazine A solution of 3,6-di chloro- or 4H-t-ieno [3, 2-e] - 1, 2, 4-ti adi az ine 1,17-dioxide (257 mg, 1.0 mmol) and (S) - (+) - s ec-but i 1 amine (0.31 ml, 3.0 mmol) is stirred in 10 ml of absolute ethanol for 4 days at 80 ° C in a sealed flask. The cooled solution is concentrated in vacuo and the residue is stirred with water (10 ml) followed by adjustment to pH 2 with 4 M hydrochloric acid. The gummy product initially formed is crystallized by stirring at 0 ° C. The precipitate is isolated by filtration, washed with water, and recrystallized from ethyl acetate followed by drying in vacuo.
° C overnight to give 181 mg (62%) of the pure title compound; p.f. 228-230 ° C (ethyl acetate); X H NMR (DMSO-d 6): d 0.88 (triplet 3 H, CH 3), 1.14 (d, 3 H, CH 3), 1.49 (m, 2 H, CH 2), 3.68 (, 1 H, CH), 7.08 (s, 1 H, H -5), 7.13 (broad signal, 1H, NH), 10.73 (broad singlet, 1H, NH); MS: m / e 293/295 (M +); (CsHu aCUOsYes) calculated C 36.79 H 4.12 N 14.30, found C 36.9 H 4.1 N 14.2.
EXAMPLE 15 1, 1-6-chloro-3-isopropylamino-4H-thieno [2, 3-e] -1,2,4-thiadiazine dioxide a) N- [5-Chloro-3- (isopropylthio-carbamoyl) sulf-amoylthiophen-2-yl] acetamide Tert-but potassium oxide (135 mg, 1.2 mmol) is added to a solution of N- (5-chloro-3-sul famoi 11 io fen-2 -i 1) -acetylamide (255 mg, 1.0 mmol) in N, N-d ime ti 1 dry form (5 ml) with stirring on an ice bath. After 5 minutes, isopropyl ion (0.128 ml, 1.2 mmol) is added dropwise, and the solution is stirred for 30 minutes at 0 ° C and then at room temperature for 3 hours. An additional amount of potassium t-butoxide (135 mg, 1.2 mmol) is added to the solution and stirring is continued at room temperature for 1 hour. The solvent is evaporated at a temperature < 50 ° C, and the residue is taken up in 10 ml of water and the aqueous solution is adjusted to pH 2 with 4 M hydrochloric acid. The resulting precipitate is isolated by filtration, washed with water and dried to give 274 mg (77%) of the crude title compound; XH NMR (DMSO-d6): d 1.12 (d, 6H, 2 x CH3), 2.28 (s, 3H, C0CH3), 4.21 (, 1H, NCH), 7.15 (s, 1H, H-4), B. 34 (broad doublet, 1H, NH), 10.26 (s, 1H, NH). b) 1,1-dioxide of 6-cl oro-3-isopropyl-1-amino-4H-thieno [2, 3-e] - 1, 2, 4 - 1 i adi a z Phosgene (0.416 -mi, 20% in toluene) is added dropwise to a solution of N- [5-cl oro-3- (isopropylthiocarbamoyl) sulfamoylthiophen-2-yl] acetamide (261 mg, 0.73 mmol) and triethylamine dry (0.209 ml, 1.5 mmol) in dry tetrahydrofuran (5 ml) with stirring at 0 ° C. The mixture is stirred for 1 hour at 0 ° C and evaporated to dryness. The residue is triturated with 10 ml of water and the precipitate is isolated by filtration, washed with water and finally deacetylated by stirring in 2 ml of 2 N sodium hydroxide for 90 minutes at room temperature. The solution is acidified to pH 2 with 4 M hydrochloric acid and the precipitate is separated by filtration and recrystallized from ethyl acetate with decolorizing carbon to yield 44 mg (21%) of the pure title compound; p.f. 272-274 ° C (ethyl acetate); XH NMR (DMS0-d6): d 1.16 (d, 6H, 2 x CH3), 3.85 (m, 1H, NCH), 7.23 (s, 1H, H.7), 7.48 (broad double, 1H, NH), 11.12 (s, 1H, NH); MS: m / e 279/281 (M +).
EXAMPLE 16 1, 1-6-chloro-3-cyclopentylamino-4H-thiophene [2, 3-e] -1,2,4-thiadiazine di-oxide ___ a) N- [5-chloro-3- (cyclopentylthiocar-bamoyl) sulfamoylthiophen-2-yl] acetamide The title compound is prepared from N- (5-chloro-3-sulfamoylthiophen-2-yl) acetamide and cyclopentyl iso-thiocyanate by a procedure analogous to the procedure described in Example 15a (yield of crude product: 93% ); XH NMR (DMSO-d6): d 1.3-2.0 (, 8H, (CH2) 4), 2.28 (s, 3H, CH3), 4.32 (sextet, 1H, CH), 7.16 (s, 1H, H-4) , 8.48 (broad double, 1H, NH), 10.23 (broad singlet, 1H, NH). b) 1,1-dioxide of 6-cl-oro-3-cyclopentyl-1-ami-4-thieno [2, 3-e] -1,4,4-thiadiazine __ _ The title compound is prepared from N- [5-chloro-3- (cyclopentylthiocarbamoyl) sul f a-moi 11 io fen-2-i1] acetamide by a procedure analogous to the procedure described in Example 15b (yield 32%); p.f. 280-282 ° C (aqueous ethanol); XH NMR (DMSO-d6): d 1.4-2.0 (m, 8H, CH2) 4), 3.96 (sextet, .1H, CH), 7.23 (s, 1H, H-7), 7.62 (broad signal, 1H, NH), 11.09 (s, 1H, NH); MS m / e 305-307 (M +).
EXAMPLE 17 1, 1-6-Bromo-3-isopropylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide Bromine (0.12 ml, 2.3 m or 1) is added, dropwise, to a solution of 6-chloro-3-isopropylamino-4H-thieno 1,1-dioxide [3, 2-e] - 1, 2, 4 -thiadiazine (280 mg, 1.0 mmol) in 10 ml of acetic acid and the mixture is stirred for 24 hours at 100 ° C in a sealed flask. The cooled mixture is evaporated to dryness and the residue is crushed with water to give a solid which is recrystallized from ethanol / water (1: 1) yielding 118 mg (39%) of the title compound contaminated with 10% of the starting material; p.f. about 279 ° C (aqueous ethanol); XH NMR (DMSO-de): d 1.16 (d, 6H, 2 x CH3), 3.86 (m, 1H, CH), 7.14 (s, 1H, H-5), 7.18 (broad signal, 1H, NH), 10.74 (s, 1H, NH); MS: m / e 323/325 (M +).
EXAMPLE 18 3-i-1,1-dioxide sopropi-1-amino-4H-t-ene [3, 2-e] 1, 2, 4-ti a di a zin Powdered potassium hydroxide (128 mg, 2.28 mmol) is added to a solution of 6-chloro-3-isopropylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide. (319 g, 1.14 mmol) in 25 ml of methanol and the mixture is hydrogenated at room temperature and at atmospheric pressure for three days with 150 mg of 10% palladium on carbon. The catalyst is removed by filtration and washed with ethanol and water. The combined filtrate is acidified with 4 M hydrochloric acid and evaporated to dryness. The residue is recrystallized in water / ethanol and finally ethyl acetate with decolorizing carbon to produce the title compound contaminated with starting material which is removed by column chromatography with silica gel; XH NMR (DMSO-d6): d 1.16 (d, 6H, 2 x CH3), 3.88 (m, 1H, CH), 6.95 (d, 1H, H-5), 7.03 (broad double, 1H, NH), 7.88 (d, 1H, H-6), 10.70 (broad singlet, 1H).
EXAMPLE 19 1, 1-3-isopropylamino-7-methyl-4H-thieno [2, 3-e] -1, 2, -thiadiazine dioxide a) C i anome t ans ul f onami da Dry TFH (200 mL) is saturated with ammonia at -10 ° C. Then a solution of cyanome tumunum foni lo (13.9 g, prepared according to Sammes et al, J. Chem. Soc., 1971, 2151-5155) in 10 ml of dry THF, is added in small portions. with stirring for a time of 20 minutes at -10 ° C. After the addition, the temperature is raised to 0 ° C and the reaction mixture is filtered. The 'elimination of Solvent of the filtrate and purification of the residue by column chromatography on silica gel and elution with ethyl acetate, produces the title compound as beige crystals; p.f. 97-99 ° C; IR (KBr), v (cm "x): 3316, 3328 (N-H), 2266 (C = N), 1371, 1151 (S02). b) 2 -Amino-4-methyl-thiophene-3-sulfonamide A mixture of cinnamon tansul fonami gives (1.0 g), 2, 5-dihydroxy-2, 5- dime ti 1 - 1, -dia ti an (0.75 g), and triethylamine (100 μl) in absolute ethanol (7 ml ) is heated to a temperature of 45 to 50 ° C under nitrogen for 3 hours. Then the solvent is evaporated and the residue is partitioned between water (30 ml) and ethyl acetate (50 ml). The aqueous phase is extracted with 4 x 50 ml of ethyl acetate. The combined phases of ethyl acetate are dried over sodium sulfate and evaporated. The residue is purified by column chromatography on silica gel eluted with ethyl acetate. The title compound is obtained as a yellow solid, yield of .0.65 (41%); p.f. 142-144 ° C; NMR XH (CD30D), d (ppm): 7.19 (s, 1 H, C (5) H), 4.88 (broad signal, 4 H, S02NIT2 + H20), 4.71 (s, 2 H, M2), 2.41 (s, 3 H, CH3); MS: 192 (M +). 112 (M + -S02NH2), 72 (CH3-C2HS +). c) N- (2-amino-4-methyl-3-thienylsulfonyl) -N 'isopropylthiourea A mixture of 2-amino-4-methyl-111-thio-3-sulfonamide (0.30 g), potassium carbonate (0.32 g), is heated overnight at 50-55 ° C overnight. Isopropyl ether (272 μl) in dry acetone (5 ml) under nitrogen. The solvent is then evaporated and the residue dissolved in water (15 ml); the pH is adjusted to 2 by the addition of 4 M hydrochloric acid, and the mixture is stirred for 30 minutes. The precipitated crystals are separated by filtration, rinsed with a small amount of water and dried to give 0.24 g (54% yield) of the title compound; p.f. 118-120 ° C. d) 1,1-dioxide of 3-i s opropi 1 amino-7-me t i 1 - 4 H -thieno [2, 3-e] - 1, 2,4-thiadiazine - ~ A 20% solution of phosgene in toluene (715 μl) is added to a stirred solution and cooled N- (2-amino-4-methyl-1,3-thienylsulfonyl) -N'-isopropyl thiourea (0.22 g) and triethylamine (313 μl) in dry THF \ 5 ml) and the temperature is maintained by below 5 ° C. After stirring for 1.5 hours the mixture is evaporated and triturated with 10 ml of water. The precipitate is collected by filtration and dried to give 0.14 g of the crude product. The crystals are heated to 70 ° C with 5 ml of ethyl acetate and the resulting mixture is cooled to 0 ° C for 10 minutes and then filtered. The filter cake is rinsed with a small amount of ethyl acetate and dried to give 0.087 g (yield 45%) of the title compound as tan crystals; p.f. 152-154 ° C; XH NMR (DMS0-d6): d (ppm): 7.10 (wide doublet, 1 H, Nff), 6.61 (s, 1 H, N (4) H), 6.52 (s, 1 H, C (6) f), 3.89 (m, 1 H, C H3), 1.18 (d, 6 H, C H3).
EXAMPLE 20 1, 1-6-chloro-3-cyclobutylamino-4H-thieno [3, 2-e] -1,2,4-thiadiazine dioxide A solution of 3,6-dichloro-4H-thieno [3,2-e] -1,4,4-thiadiazine 1,1-dioxide solution is stirred for 18 hours at 90 ° C in a sealed flask. 257 mg, 1.0 mmol) in the clobutum and the laminate (1.0 ml). The cooled solution is concentrated in vacuo and the residue is filtered with water (10 ml) at 0 ° C followed by adjusting to pH 2 with 4 M hydrochloric acid. The product is isolated by filtration, washed with water and recrystallized in water. tanol / ace tat or ethyl followed by drying in va at room temperature to give 155 mg (53%) of the pure title compound; p.f. 315-317 ° C with decomposition .; XH NMR (DMS0-d6): d 1.58-1.75 (m, 2H), 1.89-2.05 (, 2H), 2.19-2 -.30 (m, 2H), 4.16 (, 1H), 7.06 (s, 1H) , 7.62 (broad singlet, 1H), 10.83 (broad singlet, 1H); MS m / e 291/293 (M +); (C9H10N3C l? 02S2) calculated 37.05 H 3.45 N 14.40, found C 37.18 H 3.48 N 14.19.
EXAMPLE 21 6-Chloro-3 - (2-hydrox i e t i 1) amino-4H-thieno [3, 2-e] - 1,2,4-t i adi a zine 1,1-dioxide A solution of 3,6-di-chloro-4H-t-ieno [3, 2-e] -1,2,4-diadiaz-1,1-dioxide (206 mg, 0.8 mmol) in ethanolamine (1.0 ml) ) is stirred for 18 hours at 100 ° C in a sealed flask. The cooled solution is concentrated in vacuo and the residue is stirred with water (5 ml) at 0 ° C followed by adjustment to pH 2 with 4 M hydrochloric acid. The product is isolated by filtration, washed with water, and recrystallized from ethanol / water to give 135 mg (60%) of the pure title compound; p.f. 260-261 ° C with decomposition; XH NMR (DMSO-d6): d 3.26 (distorted quartet, 2H), 3.50 (t, 2H), 4.85 (broad singlet, 1H), 7.07 (s, 1H), 7.20 (wide singlet, 1H), 10.9 (singlet) broad 1H); MS: m / e 281/283 (M +): (C7H8N3C l? 03S2) calculated C 29.84 H 2.86 N 14.91, found C 30.13 H 2.84 N 14.79.
EXAMPLE 22 1, 1-dioxide (+) 3-exo-Bicyclo [2.2.1] ept-2-ylamino-6-chloro-4H-thieno [3, 2-e] -1, 2,4-thiadiazine It is stirred, for 20 hours, at 100 ° C, in a sealed flask, a solution of 1,1-dioxide 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine (206 mg, 0.8 mmol) in exo-2-aminonorbornane (1.0 ml). The mixture is stirred with water (10 ml) at 0 ° C followed by adjustment to pH 2 with 4 M hydrochloric acid. The product is isolated by filtration, washed with water, and recrystallized from ethyl acetate. 1 to give 168 mg (63%) of the pure title compound; p.f. 323-324 with decomposition; XH NMR (DMS0-d6): d 1.05-1.55 (m, 7H), 1.68-177 (m, 1H), 2.1-8-2.28 (m, 2H), 3.51 (m, 1H), 7.09 (s, 1H) ), 7.2 (broad singlet, 1H), ca. 10.5 (broad singlet, 1H),: MS: m / e 331/333 (M +); (C? 2H14N3Cl? 02S2) calculated C 43.43 H 4.25 N 12.66, found C 43.67 H 4.26 N 12.55.
EXAMPLE 23 1, 1-dioxyde of R) - 6-chloro-3- (2-hydroxypropyl) amino-4H-thieno [3, 2-e] -1, 2, 4-t i adia z ina A solution of 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine (200 mg, 0.78 g) is stirred for 18 hours at 100 ° C in a sealed flask. mmol) in (R) - (-) - 1-amino-2-propanol (1.0 ml). The cooled solution is stirred with water (3 ml) at 0 ° C followed by adjustment to pH 2 with 4 M hydrochloric acid. The product is isolated by filtration, washed with water, and dried in vacuo at room temperature to give 170 mg (74%) of the pure title compound; p.f. 210-211 ° C.; XH NMR (DMSO-de): d 1.08 (d, 3H), 3.0-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.72-3.82 (m, 1H), 4.91 (broad singlet, 1H) , ..7.09 (s, 1H), 7.14 (broad singlet, 1H), 10.95 (broad singlet, 1H); MS m / e 297/295 (M +); (C8H? 0N3C l? 03S2 • 0.5 H20) calculated 31.53 H 3.64 N 13.79, found C 31.57 H 3.58 N 13.58.
EXAMPLE 24 1, 1-6-Bromo-3-isopropyl amino-4H-t-ieno [3,2-e] -1,2,4-thiadiazine dioxide Bromine (1.26 ml, 25 mmol) is added dropwise to a solution of 1,1-dioxido of 6-chloro-3-isopropylamino-4H-ti eno [3, 2-e] -1, 2, 4 -thiadiazine (2.3 g, 8.2 mmol) in 25 ml of acetic acid and the mixture is stirred for 48 hours at 100 ° C in a sealed flask. The cooled mixture is evaporated to dryness and the residue consisting of two main products is triturated with water to give a solid, which is recrystallized from ethyl acetate with decolorizing carbon to yield 538 mg (20%) of the composed of the title. An analytically pure sample is obtained by preparative HPLC on a Source RCP 15 column using acetoni tri lo / water (20:80) with 0.1% TFA as eluye-nte; p.f. 282-283 ° C; X H NMR (DMSO-de): d 1.16 (d, 6H), 3.86 (m, 1H), 7.14 (s, 1H), 7.18 (broad signal, 1H), 10.74 (s, 1H); MS: m / e 323/325 (M +); (CßHioNsBrjOzSz) calculated C 29.64 H 3.11 N 12.96; found C 29.49 H 3.04 N 12.59 EXAMPLE 25 ,6-Dibromo-3-i-sopropi lamino-4H-thieno [3,2-e] -l, 2,4-thiadiazine 1,1-dioxide The mother liquor of the crystallization of the 6-bromo-3-isopropyl-1-amino-4H-thieno [3,2-e] -1,4-thiadiazine 1,1-dioxide described above is evaporated to dryness and the The residue is purified by chromatography on silica with dichloromethane / grade 1 (95: 5). Recrystallization from ethyl acetate affords 270 mg (8%) of the pure title compound; p.f. 250-251 ° C; X H NMR (DMSO-d 6): d 1.18 (d, 6H), 3.86 (m, 1H), 7.18 (broad signal, 1H), 10.31 (s, 1H); MS; m / e 405/403/401 (M +); (C8H9N3Br202S2) calculated C 23.84 H 2.25 N 10.42; found C 24.14 H 2.18 N 10.25.
EXAMPLE 26 1, 1-6-chloro-3-cyclohexylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide a) N- (3-Amino-5- cl-oro- 2-thienyl sul foni 1) -N'-cyclohexyl) thiourea The title compound is prepared from 3-amino-5-chloro-thio-phenyl-2-sulfonamide and isotiocyanate or cyclohexyl hydrochloride by a procedure analogous to the procedure described in Example 3-a (78% yield); XH NMR (DMS0-d6): d 1.1-1.9 (m, 10H), 4.0 (m, 1H), 6.45 (broad singlet, 2H), 6.66 (s, 1H), 8.05 (broad double, 1H), 11.2 (wide singlet, 1H). b) 6-chloro-3-cyclohexyl amino-4H-thieno [3,2-e] -1,4-thiadiazine 1,1-dioxide The title compound is prepared from N- (3-amino-5-chloro-2-thienylsulfonyl) -N'- (cyclohexy-1) thiourea by a procedure analogous to the procedure described in the Example 3-b (66% yield); p.f. 282-284 ° C (ethyl acetate / methanol); X H NMR (DMSO-d 6): d 1.1-1.9 (, 10H), 3.55 (m, 1H), 7.08 (s, 1H), 7. 19 (broad signal, 1H), 10.73 (broad singlet, 1H); MS; m / e 321/319 (M +); (C ??H14N3Cl ?2S2) calculated C 41.31 H 4.41 N 13.14, found C 41.66 H 4.45 N 12.99.
EXAMPLE 27 6-chloro-3- (furan-2-i Ime t i 1) 1,1-dioxide to ino- 4 H -thieno [3, 2-e] -1, 2,4-thiadiazine a) N- (3-amino-5-chloro-2-thienylsulfonyl) -N '- (cyclohexy 1) t ioure a The title compound is prepared from 3-amino-5-c-loro-t-f-2-sulphonamide and furfuryl isothiocyte hydrochloride by a procedure analogous to the procedure described in Example 3-a ( crude product: 92%). b) 1,1-6-chloro-3- (furan-2-ylmethyl) amino-4H-thieno [3, 2-e] -1,2,4-thiadiazine dioxide The title compound is prepared from N- (3-amino-5-c-loro-2-yl-en-sulfonyl) -N '- (furan-2-yl) methyl thiourea by a procedure analogous to the procedure described in Example 3-b except that the product is purified by column chromatography on silica with dichloromethane / methanol (19: 1), (11% yield); p.f. 224-225 ° C; XH NMR (DMSO-d6): d 4.41 (d, 2H), 6.33 (m, 1H), 6.41 (m, 1H), 7.05 (s, 1H), 7.62 (broad singlet, 1H), 7.75 (broad triplet, 1H), 11.2 (broad singlet, 1H); (C? 0H8N3Cl? O3S2); calculated C 37.80 H 2.54 N 13.22; found C 37.87 H 2.51 N 13.10).
EXAMPLE 28 1, 1-6-cyano-3-isopropyl amino-4-thieno [3, 2-e] -1,2,4-thiadiazine di-oxide To a solution of 6-bromo-3-isopropylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide (243 mg, 0.75 mmol) in N, N-dime ti Dry formamide (2 ml) is added copper (I) cyanide (135 mg, 1.5 mmol) and the mixture is heated at 150 ° C for 2 hours under nitrogen. The dark mixture is allowed to cool to room temperature and water is added. The suspension is made basic by the addition of 1N sodium hydroxide is filtered, and the filtrate is acidified by the addition of 4M hydrochloric acid. The resulting precipitate is purified by preparative HPLC on a Source RPC 15 column using ace t oni tri water (20:80) with 0.1% TFA as eluent to yield 4 mg (2%) of the pure title compound; LC-MS; m / e 271 ((M + l) +).
EXAMPLE 29 1, 1-6-Bromo-3-cyclopentyl-1-amino-4-thieno [3, 2-e] -1,2,4-thiadiazine dioxide Bromine (0.12 ml, 2.3 mmol) is added to a solution of 6-chloro-3-cyclopentyllamino-4H-t-ene [3, 2-e] -1,4,4-diadiazine (305 mg, 1.0 mmol) in acetic acid (10 ml) and the mixture is stirred for 21 hours at 100 ° C in a sealed flask. The cooled mixture is evaporated to dryness and the residue triturated with water to give a solid which is recrystallized from ethyl acetate and ethanol to yield the title compound (166 mg, 47%) contaminated with 33% of the starting material. Purification by preparative HPLC yields the title compound (65 mg, 18%) contaminated with 3% of the starting material. X H NMR (DMSO-d 6): d 10.7 (s, 1 H, NH); 7.35 (broad singlet, 1H, NH); 7.13 (s, 1H, H-7); 4.00 (sextet, 1H); 1.9 (m, 2H); from 1.7 to 1.4 ppm (m, 6H). Decomposition .: 287-294 ° C.
EXAMPLE 30 6-Chloro-3 - (2-methyl-1-yl-1) amino-H-t-ene [3, 2-e] -1, 2,4-thiadiazine 1,1-dioxide A solution of 1,1-dioxide of 3,6-dichloro-4H-thieno [3, 2-e.] -1, 2, 4 is stirred for 98 hours at 90 ° C in a sealed flask. thiadiazine (128 mg, 0.5 mmol) in methallylamine (0.5 ml). The cooled solution is concentrated in vacuo and the residue is stirred with water (3 ml) followed by adjustment to pH 2 with 4 M hydrochloric acid. The product is isolated by filtration and washed with water, to give 92 mg (64%). of the pure title compound; p.f. 224-226 ° C (decomposition); XH NMR (DMSO-d6): d 1.72 (s, 3H), 3.75 (d, 2H), 4.83 (s, 2H), 7.05 (s, 1H), 7.45 (broad singlet, 1H), 11.0 (broad singlet, 1 HOUR) .
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (37)

1. A compound of the general formula I characterized because B represents > NR5 or > CR5R6, wherein R5 and R6 are independently hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono-sub stained or po 1 i susbtained with halogen; or R5 and R4 together represent one of the bonds in a double bond between atoms 2 and 3 of formula I; D represents -S (= 0) 2- or -S (= O) -; or D- B repre s ent a - S (= 0) (R 7 ') \ == NM - wherein R 7 is alkyl of 1 to 6 carbon atoms; or heteroaryl optionally monosubstituted or polysubstituted with halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms. carbon, cyano, acyl, or alkoxycarbonyl of 1 to 6 carbon atoms; Rx is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono-sub stained or po 1 i subsided with halogen and R 4 is hydrogen; or R4 together with R5 represents one of the bonds in a double bond between atoms 2 and 3 of the formula I; or R1 together with R4 represents one of the bonds in a double bond between atoms 3 and 4 of formula I; R2 is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms; alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono-sub stained or po 1 isubsti tuted with halogen; R3 is R8; -OR8; -C (= X) R8; bicycloalkyl, aryl, heteroaryl, arylalkyl •• or heteroaryl to the optionally mono-sub stained or substituted by halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro , amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms, cyano, oxo, acyl or alkoxycarbonyl of 1 to 6 carbon atoms; or aryl substituted with alkyl of 1 to 6 carbon atoms; wherein R8 is hydrogen; cycloalkyl of 3 to 6 carbon atoms or (cycloalkyl of 3 to 6 carbon atoms) to the one of 1 to 6 carbon atoms, the cycloalkyl group of 3 to 6 carbon atoms is optionally mono subsi tuted or polysubstituted with alkyl of 1 to 6 atoms carbon, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; a saturated ring system of 3 to 6 members comprising one or more nitrogen, oxygen or sulfur atoms; or straight or branched alkyl of optionally mono or straight carbon atoms subsubstituted or substitued with halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, aryloxy, arylalkoxy, nitro, amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms, cyano, oxo, formyl, acyl, carboxy, alkoxycarbonyl of 1 to 6 carbon atoms, or carbamoyl; X is O or S R is hydrogen, alkyl of 1 to 6 carbon atoms; alkenyl of 2 to 6 carbon atoms; C3-C6-cycloalkyl optionally mono-substituted or substituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; or R8 and R9 together with the nitrogen atom form a monocyclic or bicyclic system of 3 to 12 members in which one or more of the carbon atoms can be exchanged with nitrogen, oxygen or sulfur, each of these ring systems is optionally monosubstituted or polysubstituted with halogen, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to -6 carbon atoms, nitro, amino, cyano, tr i fluoromet i lo, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms; oxo; or R3 is wherein n, m, p are independently 0, 1, 2, 3 and Rxo is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; optionally monosubstituted cycloalkyl of 3 to 6 carbon atoms or polysubstituted with alkyl of 1 to 6 carbon atoms carbon, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; optionally mono substratum or po I i subsumed with halogen; or R2 and R3 together with the nitrogen atom Form a monocyclic or bicyclic system of 3 to 12 members in which one or more of the carbon atoms can be exchanged with nitrogen, oxygen or sulfur, each of these ring systems it is optionally mono-sub stained or poly-substituted with halogen, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 atoms carbon, nitro, amino, cyano, tri-fluororhene, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms or oxo; A together with carbon atoms 5 and 6 of formula I represent a 5- or 6-membered heterocyclic system containing one or more nitrogen, oxygen or sulfur atoms, the systems heterocyclics are optionally monosubstituted or polyunsubstituted with halogen; alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms; C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl; nitro; Not me; cyano; cyanomethyl; perha lome t i lo; monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms; sulfamo-ilo; alkylthio of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms; to which 1 s ul finyl of 1 to 6 carbon atoms; alkylcarbonylamino of 1 to 6 carbon atoms; arylthio, arylsulfonyl, aryl sulphonyl, the aryl group is optionally unsubstituted or polysubstituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms; alkoxycarbonyl of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms; carbamyl; carba i lo-met i lo; monoalkylaminocarbonyl of 1 to 6 carbon atoms or di-alkylaminocarbonyl of 1 to 6 carbon atoms; .monoalkylaminothiocarbonyl of 1 to 6 atoms carbon or dial qui lamino thiocarboni lo of 1 to 6 carbon atoms; ureido; monoal qui 1 aminocarboni 1 amino of 1 to 6 carbon atoms or dial qui 1 aminocarboni 1 amino of 1 to 6 carbon atoms, thioureido; monoal qui 1 amino thio carboni 1 or from 1 to 6 carbon atoms-amino or dialkyl lamino thiocarboni lo-a ino of 1 to 6 carbon atoms; monoalkyl 1 aminosul foni lo of 1 to 6 carbon atoms or dial qui 1 aminosul foni lo of 1 to 6 carbon atoms; carboxy; carboxy-alkyl of 1 to 6 carbon atoms; acyl; aryl, arylalkyl, aryloxy, the aryl group is optionally monosubstituted or poly-substituted with alkyl of 1 to 6 carbon atoms, - • halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; (1,2,4-oxadiazol-5-yl) -alkyl of 1 to 6 carbon atoms or (1, 2, 4 -oxadi a zol-3-i 1) - to the 1 or 1 to 6 atoms of carbon and the oxadiazolyl group is optionally substituted with alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; or a ring containing nitrogen of 5 to 6 members, optionally substituted with phenyl or alkyl of 1 to 6 carbon atoms; with the proviso that A together with the carbon atoms 5 and 6 of formula I do not form a pyridine ring and that the following compounds 1,1-dioxide of 3-amino imide zo [4, 5 e] -1, 2, 4-ti adi az ine and 3- (benzoylamino) imidazo [4,5-e] -1,2,4-thiadiazine 1,1-dioxide are not included; or a salt thereof, with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or an automatic t-form.
2. A compound according to claim 1, characterized in that R 2 is hydrogen or alkyl of 1 to 6 carbon atoms.
3. A compound according to claim 1 or 2, characterized in that R3 is R8, -OR8, NR8R9 or aryl, the aryl groups are optionally substituted with alkyl of 1 to 6 carbon atoms; where R8 is hydrogen; cycloalkyl of 3 to 6 atoms carbon; (C3 -C6 cycloalkyl) alkyl of 1 to 6 carbon atoms; a 3 to 6 member saturated ring system comprising one, two or three nitrogen, oxygen or sulfur atoms; or straight or branched alkyl of 1 to 18 carbon atoms, optionally substituted by halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or aryl, R! is hydrogen, alkyl of 1 carbon atoms or cycloalkyl of carbon atoms or R8 and R9 together with the nitrogen atom form a ring of 4 to 6 members.
4. A compound according to any of the preceding claims, characterized in that R3 is secondary alkyl of 3 to 6 carbon atoms, tertiary alkyl of 4 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or (cycloalkyl of 3 to 6) carbon atoms) me you.
5. A compound according to any of the preceding claims, characterized in that A together with the carbon atoms 5 and 6 of formula I form a 5-membered heterocyclic system containing a heteroatom selected from nitrogen and sulfur, the heterocyclic system is optionally mono subs ti tuido or gave sus tu tuido with halogen; alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyano; cyanomethyl; perhalome t i lo; sulfamoyl; alkylthio of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms, to 1 to 1 sulfur or 1 to 6 carbon atoms; arylthio, arylsulfinyl, arylsulphonyl, the aryl group is optionally monosubstituted or polysubstituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; C 1 -C 6 alkoxycarbonyl- C 1-6 -alkyl; carbami Íme t i 1 o; carboxy -alkyl of 1 to 6 carbon atoms; aryloxy; (1, 2, 4 -oxadi azole-5-yl) - alkyl of 1 to 6 carbon atoms or (1, 2, 4-oxadiazol-3-yl) alkyl of 1 to 6 carbon atoms, the oxadiazolyl group this optionally substituted with alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; acyl or a ring containing nitrogen of 5 to 6 members, optionally substituted with phenyl or alkyl of 1 to 6 carbon atoms.
6. A compound according to any of the preceding claims, characterized in that A together with the carbon atoms 5 and 6 of the formula I forms a 5-membered heterocyclic system containing two heteroatoms selected from nitrogen, oxygen and sulfur, the system heterocyclic is optionally substituted with halogen; alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyano; cyanomethyl; perhalome t i lo; sulfamoyl; alkylthio of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms; to which 1 is from 1 to 6 carbon atoms; arylthio, aryl sulphiol, aryl sulphide, the aryl group is optionally monosubstituted or substi tuted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 atoms of carbon; alkoxycarbonyl of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms; carbamilme t ilo; carbox i -al to 1 to 6 carbon atoms; aryloxy; (1, 2, 4 -oxadi a zo 1 - 5- i 1) -alkyl of 1 to 6 carbon atoms or (1,2,4-oxadiazol-3-yl) -alkyl of 1 to 6 carbon atoms, the oxadiazolyl group is optionally substituted with alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; acyl; or a ring containing nitrogen of 5 to 6 members, optionally substituted with phenyl or alkyl of 1 to 6 carbon atoms.
7. A compound according to any of the preceding claims, characterized in that A together with the carbon atoms 5 and 6 of the formula I form a 6-membered aromatic heterocyclic system containing two or three nitrogen atoms, the heterocyclic system is optionally substituted with halogen; alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyano; cyanomethyl; perhalo et ilo; sulfamoyl; alkylthio of 1 to 6 atoms carbon; alkylsulfonyl of 1 to 6 carbon atoms; to which lsul f ini lo of 1 to 6 carbon atoms; arylthio, arylsulfinyl, arylsulfonyl, the aryl group is optionally monosubstituted or polysubstituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms; alkoxycarbonyl of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms; Iamyl carbamy; carboxy- to the one of 1 to 6 carbon atoms; aryloxy; (1, 2,4-oxadiazol-5-yl) -alkyl of 1 to 6 carbon atoms or (1,2,4-oxadiazol-3-yl) -alkyl of 1 to 6 carbon atoms, the oxadiazolyl group is optionally substituted with alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; acyl; or a ring containing nitrogen of 5 to 6 members, optionally substituted with phenyl or alkyl of 1 to 6 carbon atoms.
8. A compound according to any of the preceding claims, characterized in that A together with the atoms of carbon 5 and 6 of formula I form a non-aromatic 6-membered heterocyclic system containing one or two heteroatoms selected from nitrogen, oxygen and sulfur; the heterocyclic system is optionally substituted with halogen; alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyano; cyanomethyl; perha lome t i lo; sulfamoyl; alkylthio of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms; arylthio, arylsulfonyl, aryl sulphonyl, the aryl group is optionally monosubstituted or substituted with alkyl of 1 to 6 carbon atoms, halogen, hydroxy or • alkoxy of 1 to 6 carbon atoms; alkoxycarbonyl having 1 to 6 carbon atoms - at least 1 to 6 carbon atoms; carbami Íme t i 1 o; carboxy-alkyl of 1 to 6 carbon atoms; aryloxy; (1,2,4-oxadiazol-5-yl) -alkyl of 1 to 6 carbon atoms or (1, 2, -oxadiazol-3-yl) -alkyl of 1 to 6 carbon atoms, the oxadiazolyl group is optionally substituted with alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; acyl; or a ring that contains 5 to 6 membered nitrogen, optionally substituted with phenyl or alkyl of 1 to 6 carbon atoms.
9. A compound according to any of claims 1 to 8, characterized in that general formula I is where Rx and R5 are independently hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally monosubstituted or polysubstituted with halogen and R 4 is hydrogen; or R4 together with R5 represent one of the bonds in a double bond between atoms 2 and 3 of formula I and Rx is as defined above; or R4 together with R1 represents one of the bonds in a double bond between atoms 3 and 4 of formula I and R5 is as defined above; D represents -S (= 0) 2- or -S (- = 0) -, and A, R2 and R3 are as defined above.
10. A compound according to claim 9, characterized in that R x and R 5 independently are hydrogen or alkyl of 1 to 6 carbon atoms.
11. A compound according to claim 9 or 10, characterized in that R1 together with R4 represent one of the bonds in a double bond between atoms 3 and 4 of formula I.
12. A compound in accordance with any of claims 9 to 11, characterized in that R4 together with R5 represent one of the bonds in a double bond between atoms 2 and 3 of formula I.
13. A compound according to any of claims 9 to 12, characterized in that D is -S (= 0) 2-.
14. A compound according to any of claims 1 to 8, characterized in that general formula I is where R1 is hydrogen; hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally monosubstituted or poi substituted with halogen and R 4 is hydrogen; or R4 together with Rx represents one of the bonds in a double bond between atoms 3 and 4 of formula I; D represents -S (= 0) R7 = wherein R is alkyl of 1 to 6 carbon atoms; or aryl or heteroaryl optionally monosubstituted or pol i sub stained with halogen, hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, monoalkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon, cyano, acyl or alkoxycarbonyl atoms of 1 to 6 carbon atoms; Y A, R2 and R3 are as defined above
15. A compound according to claim 14, characterized in that Rx is hydrogen or alkyl of 1 to 6 carbon atoms.
16. A compound according to claim 14 or 15, characterized in that Rx together with R4 represent one of the bonds in a double bond between atoms 3 and 4 of the formula I.
17. A compound according to any of claims 14 to 16, characterized in that R7 is alkyl of 1 to 6 carbon atoms, phenyl o-pyridyl.
18. A compound according to any of claims 1 to 8, characterized in that general formula I is where R1, R5 and R6 are independently hydrogen, hydroxy; alkoxy of 1 to 6 carbon atoms; or alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms optionally mono-sub stained or poly i sub stained with halogen and R 4 it is hydrogen; or R4 together with R5 represent one of the bonds in a double bond between atoms 2 and 3 of formula I and Rx and R6 are as defined above; or R4 together with R1 represent one of the bonds in a double bond between atoms 3 and 4 of the formula I and R5 and R6 are as defined above; D represents -S (= 0) 2- S (= 0) - A, R and R are as defined above
19. A compound according to claim 18, characterized in that Rx, R5 and R6 are independently hydrogen or alkyl of 1 to 6 carbon atoms.
20. A compound according to claim 18 or 19, characterized in that Rx together with R4 represent one of the bonds in a double bond between atoms 3 and 4 of the formula I.
21. A compound according to any of claims 18 to 20, characterized in that R4 together with R5 represent one of the bonds in a double bond between atoms 2 and 3 of formula I.
22. A compound according to any of claims 18 to 21, characterized in that D is -S- (= 0) 2-.
23. A compound characterized in that it is selected from the following: 7-Cyano-3- i -sypropi-1-amino-6-me thi-4H-thieno [2,3-e] -l, 2,4-thiadiazine-1,1-dioxide-7-cyano-1,1-dioxide - 6-me ti 1 - 3-propi lamino-4H-thieno [2,3-e] -1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-i sopent i lamino-4H-thieno [3, 2-e] - 1, 2, 4 - t iadizine 6-Chloro-3- (1-methyl-1-ethylhexyl) -amino-4H-thieno [3,2-e] -l, 2,4-thiadizine 1,1-dioxide 6-Chloride 1,1-dioxide -3- (1-et ilpent il) amino-4H-thieno [3,2-e] -1,2,4-thiadizine 1,1-dioxido of 6-chloro-3- (2-me t ilbut il) amino-4H-thieno [3, 2-e] -1, 2, 4-thiadiazine 1,1-dioxido of 6-chloro-3- (2-methyl-1-yl) -1-amino-4 H-thieno [3, 2-e] -1, 2 , 4-thiadiazine 1,1-dioxido of 6-Chloro-3-cyclopentyllamino-Ht ieno [3, 2-e] - 1, 2, 4 - tiadiaz ina 1,1-dioxide of 6-Chloro-3 -cyclohexymethyl-4H-thieno [3,2-e] -1,2,4-thiadiazine 3- (6-chloro-l, 4-dihydro-l, 1-dioxothien [3, 2-e] - l 6, 2, 4-thiadiazin-3-ylamino) but anoat or ethyl acid 3 - (6-chloro-1,4-dihydro-1,1-dioxo-ti-ene [3, 2-e] -l 6, 2, 4-thiadiazin-3-ylamino) butanoic 1,1-dioxide of 6-c-par-3 - (3-hydroxy-1-methyl-1-propyl) amino-H-thieno [3, 2 -e] -1, 2, 4 -thiadiazin 1,1-dioxide (R) -6-chloro-3- (1-phenylethyl) amino-4H-thieno [3,2-e] - l, 2,4-thiadiazine 1,1-dioxide (S) -3-s ec-But i 1 amino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1 , 6-chloro-3-i-sopropi-1-amino-4H-thieno [2, 3-e] -1, 2,4-thiadiazine-dioxide 6-Chloro-3-cyclopentylamino-4H-thieno [2,3-e] -1,2,4-thiadiazine 1,1-dioxide 6-bromo-3-i sopropi-1-amino acid 1,1-dioxide H-Thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide 3 -i-sopropi-1-amino-4H-t-ene [3, 2-e] -1,2,4-thiadiazine 6-f luoro-3-i-sopropi-1-amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxido-3-cyclobutyl-1-amino-1,1-dioxide , 6-dime ti 1 - 4 H-thieno [3, 2-e] -1,2, 4-thiadiazine-1,1-dioxide 3-cyclopent y 1 amino-5, 6-dime ti 1 - 4H -thien [3, 2-e] -1, 2, 4-thiadiazine 1,1-dioxide of 3-i sopropil amino-6,7-dime thi-4H-thieno [2, 3-e] -1, 2,4-thiadiazine 1,1-dioxide of 3-cyclobuteralkylamino-6,7-dimetho-1,4-thieno [2, 3-e] -1,2,4-thiadiazine 1,1-dioxide 3-cyclopentyl and 1 amino-6,7-dimetyl 1-4H-thieno [2, 3-e] -1,2,4-thiadiazine 1,1-dioxide 5-chloro-3-i sopropi 1 amino - 4H-Thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide 5-chloro-3-propylamino-4 H-thieno [3, 2-e] -1, 2, 4-thiadiazine 1,1-dio 5-chloro-3-cyclopentylamino-4H-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide 5-chloro-6-me thi-3-i sopr opi 1 Not me- 4H-Thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide of 6-c-loro-3-y-sopropi-1-amino-5-me thi-4H-thieno [3, 2- e] -1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopentyl-1-amino-5-methyl-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide 6- f luoro-3-prop i 1 amino- 4 H-thieno [3,2- e] -1,2,4-thiadiazine 1,1-dioxide 6- f luoro-3- cyclopentyl-lamino-4H-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide of 5-f-1-or-3-propylamino-H-thieno [3, 2-e ] -1, 2, 4-thiadiazine 1,1-dioxide 5- f luoro-3-i sopropi 1 amino-4 H-thieno [3,2-e] -1,2,4-thiadiazine 1,1- 3-isopropyl amino-7-methyl-4H.-t-ene dio [2, 3-e] -1,2,4-ti adi az ine 1,1-dioxo-6-chloro-3-cyclobutyl-4H-dioxide dioxide -thien [3, 2-e] -1, 2, 4-thiadiazine, 1,1-dioxide, 6-chloro-3 - (2-hydroxy-1) amino-4H-tiene [3,2-e] - 1, 2,4-thiadiazine 1,1-dioxide of (±) 3-exo-bi-cyclo [2.2.1] hept-2-ylamino-6-chloro-4H-thieno [3, 2-e] -1, 2, thiadiazine 1,1-Dioxide of (R) -6-chloro-3- (2-hydroxypropyl) amino-4H-thieno. [3, 2-e] -1, 2, -thiadiazine, 1,1-dioxide, 6-bromo-3-isopropylamino-4H- thieno [3, 2-e] -1,2-thiadiazine 1,1,6-dibromo-3-isopropylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1-dioxide , 1-6-chloro-3-cyclohexylamino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-diol 6-chloro-3- (furan-2-dioxide ilmethyl) amino-4H-thieno [3,2 -e] -1,2-thiadiazine 1,1-di-6-chloro-3- (1-ethylpropyl) amino-4H-thieno [3, 2-e] ] -1, 2, 4-thiadiazine 1,1-6-bromo-3-cyclopentyl-1-amino-4H-ti-ene [3, 2-e] -1, 2-thiadiazine 1,1-dioxide dioxide 6-Chloro-3- (2-methylallyl) amino-4H-thi eno [3, 2-e] - 1, 2, 4 - 1 i adi-azine or 1,1-di-6-cyano-3-oxide - i sopropi 1 amino-4H-thieno [3, 2-e] -1, 2, -thiadiazi na
24. The compounds according to any of the preceding claims, characterized in that they act as openers of the regulated potassium channels
25. A method of preparing a compound of formula I, characterized in that it consists of a) reacting a compound of formula I. wherein A, B, D, R x and R 4 are as defined above and Z is a leaving group such as alkoxy, alkylthio, halogen, preferably chlorine, bromine, iodine, trimethoxyamino, or me tilsul fonyl with a compound of Formula III: / HN. (lll) wherein R2 and R3 are as defined above to form a compound of general formula I; reacting a compound of formula IV: wherein Rx is hydrogen and A, B, D and X are as defined above, or B is NH and Rx, A, D, and X are as defined above, with the compound of formula III, or a suitable salt thereof, in the presence of P20s and a high-boiling tertiary amine or a suitable salt thereof, to form a compound of the general formula I; c) reacting a compound of formula IV: wherein Rx is hydrogen and A, B, D and X are as defined above or B is NH and R1, A, D and X are as defined above, with a compound of the formula III, or a suitable salt thereof, in the presence of titanium tetrachloride and a solvent with which it can form a complex, such as for example tetrahydrofuran, or a mixture of toluene anisole, to form a compound of the general formula I; d) reacting a compound of formula V wherein R and A are as defined above, with a compound of formula VI R3NCO (VI) wherein R3 is as defined above, to form a compound of the general formula I wherein D is S02, B is > NR5, R2 is H, and R4 and R5 together form a bond; e) reacting a compound of formula V wherein Rx and A are as defined above, with a compound of formula VII R3NHC (= O) CI (il) wherein R3 is as defined, to form a compound of the general formula I wherein D is S02, B is > NR5, R2 is H, and R4 and Rs together form a bond; f) reacting a compound of formula V wherein Rx and A are as defined above, with a compound of formula VIII (viii) wherein Y is NH or S, or a suitable salt thereof, to form a compound of the general formula I, wherein D is S02, B is > NR5, R2 is H, and R4 and R5 together form a bond, and R2 and R3 are H; g) reacting in the presence of a base a compound of formula IX or a suitable salt thereof, wherein Rxx is Rx or EtOC (= 0), wherein Rx and A are as defined above, with a compound of formula X R3N = C = S (X wherein R3 is as defined above, to form an adduct which can be either of the two structures XI or XII or can be a mixture of the two any of which by closing the ring, for example by treatment with phosgene in a suitable solvent, forms a compound of the general formula I, if Rxx is Rx, where D is S (= 0) 2, B is > NR5, R2 is H, and R4 and R5 together form a bond, and a compound of the general formula XIII and Rxx is EtOC (= 0); h) hydrolyzing and subsequently decarboxylating a compound of the general formula XIII to form a compound of the general formula I, where D is S (= 0) 2, B is > NR5, Rx and R: are H, and R4 and R5 together form a bond, for example, by heating the initial compound in an aqueous base.
26. A pharmaceutical composition characterized in that it comprises a compound according to any of the claims 1 to 24 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 together with one or more carriers or pharmaceutically acceptable diluents.
27. A pharmaceutical composition for use in the treatment of diseases of the endocrine system, such as hyperinsulinemia and diabetes, characterized in that it comprises a compound according to any one of the claims 1 to 24 or a pharmaceutically acceptable salt thereof. same, with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
28. The pharmaceutical composition according to claim 26 or 27 characterized because it has the form of an oral dosage unit or a parenteral dosage unit.
29. A pharmaceutical composition according to claim 26 or 27, characterized in that the compound is administered as a dose in a range from about 0.05 to 1,000, preferably from about 0.1 to 500 and especially in the range of 50 to 200 mg per day.
30. A compound characterized in that it is in accordance with any one of claims 1 to 24 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.
31. A compound characterized in that it is in accordance with any of claims 1 to 24 or a salt pharmaceutically acceptable thereof with a pharmaceutically acceptable salt or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutic use in the treatment or prevention of diseases of the endocrine system, such as Hyperinsul inemi and diabetes.
32. The use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, which. they include a racemic mixture, or any tautomeric form, as a medicament.
33. The use of a compound according to any one of claims 1 to 24, for preparing a medicament.
34. The use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt of the same, 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 preparation of a medicament for the treatment or prevention of endocrine system diseases such as Hyper insul inemi and diabetes.
35. A method of treating or preventing diseases of the endocrine system, such as hyperinsulinemia and diabetes, in a subject in need thereof, characterized in that it comprises administering to the subject an effective amount of a compound- in accordance with any of the claims from 1 to 24.
36. A process for the manufacture of a medicament, particularly for use in the treatment or prevention of diseases of the endocrine system, such as hyperinsulinemia and diabetes, characterized in that it comprises carrying, a compound of the formula I in accordance with any of the claims 1 to 24 or a pharmaceutically acceptable salt thereof, to a galenic dosage form.
37. Any novel feature or combination of these characteristics, characterized because they are described in the present.
MXPA/A/2000/000223A 1997-07-16 2000-01-04 Fused 1,2,4-thiadiazine derivatives, their preparation and use MXPA00000223A (en)

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Application Number Priority Date Filing Date Title
DK0872/97 1997-07-16
DK0368/98 1998-03-17

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Publication Number Publication Date
MXPA00000223A true MXPA00000223A (en) 2001-05-07

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