CN1264384A - Fused 1,2,4-thiadiazine derivatives, their preparation method and use - Google Patents
Fused 1,2,4-thiadiazine derivatives, their preparation method and use Download PDFInfo
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- CN1264384A CN1264384A CN98807264A CN98807264A CN1264384A CN 1264384 A CN1264384 A CN 1264384A CN 98807264 A CN98807264 A CN 98807264A CN 98807264 A CN98807264 A CN 98807264A CN 1264384 A CN1264384 A CN 1264384A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
1,2,4-Thiadiazine and 1,4-thiazine derivates represented by formula (I) wherein A, B, D, R<1>, R<2>, R<3> and R<4> 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
Invention field
The present invention relates to 1,2, the 4-thiadiazine derivatives, its preparation method, contain these compound compositions, and these compounds are being treated central nervous system, cardiovascular systems, pulmonary system, the purposes in gastrointestinal system and the endocrine system disease as the purposes of medicine with them.
Background of invention
Potassium channel plays an important role in the physiology of cell membrane potential and pharmacology control.ATP sensitivity (K in dissimilar potassium channels
ATP-) passage be to regulate by the variation of adenosine triphosphate (ATP) IC.Have been found that K
ATP-passage is present in the various histocytes as the heart cell, pancreatic cell, skeletal muscle, unstriated muscle, axoneuron and adenopituicyte.These passages are relevant with panoramic cell function, for example with hormone secretion (from the Regular Insulin of pancreas beta cell, from the tethelin and the prolactin of adenopituicyte), vasorelaxation (in smooth muscle cell), heart action potential phase, release neurotransmitters is relevant in central nervous system.
Have been found that K
ATPThe conditioning agent of-passage is extremely important to treating multiple disease.Some sulfonyl urea compound has been used to treat the diabetes of non-insulin-dependent, and its mechanism is by suppressing the K on the pancreatic beta cell
ATP-passage stimulates Regular Insulin to discharge.
Have been found that potassium channel unlatching thing (compound that contains the xenogenesis group) can loosen cardiovascular unstriated muscle, therefore be used to treat hypertension.
In addition, potassium channel is opened the bronchodilator that thing can be used as treatment asthma and multiple other disease.
And potassium channel is opened thing and has been shown trichogenous ability, therefore, has been used to treat baldness.
Potassium channel is opened thing can also loosen smooth muscle of bladder, therefore can be used for the treatment of the urinary incontinence.The potassium channel unlatching thing that can loosen uterine smooth muscle can be used for treating premature labor.
By the potassium channel effect to central nervous system, these compounds can be used for treating multiple neuropathy and psychosis, as alzheimer's disease, and epilepsy and cerebral ischemia.
People find that also these compounds can be used for treating benign prostatic hyperplasia, impotence and infertile (incontraception).
Suppress the The compounds of this invention of insulin secretion by the potassium channel that activates the β cell and can unite use with other compound that is used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes.These examples for compounds have: Regular Insulin; the insulin sensitiser thing; as thiazolidinedione; insulin secretagogue; as repaglinide; tolbutamide, glyburide and glucagon class peptide (GLP1), the inhibitor of responsible glucose biological synthetic alpha-glucosidase and liver enzyme.
It is found that recently, by activating K on the pancreas beta cell
ATP-passage, diazo oxide (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1, the 1-dioxide) and some 3-(alkylamino)-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1, the 1-dioxide derivative can suppress Regular Insulin and discharge (people such as Pirotte B., " biological chemistry pharmacology " (Biochem.Pharmacol.), 47,1381-1386 (1994); People such as Pirotte B., " pharmaceutical chemistry magazine " (J.Med.Chem.), 36,3211-3213 (1993).And, diazo oxide shown the onset diabetes that can delay the BB mouse (people such as Vlahos WD, " metabolism " (Metabolism), 40,39-46 (1991)).Zucker mouse for hypertrophy, diazo oxide has shown and can reduce insulin secretion and increase the insulin receptor combination, so improve the glucose tolerance and reduce weight increase (people such as Alemzadeh R., " incretology " (Endocrinol.), 133,705-712 (1993)).People wish to activate K
ATPIt is disease and the treatment and the prevent diabetes of feature that the compound of-passage can be used for the treatment of to produce hyperinsulinism.
EP 618 209 discloses a class 3 pyrido thiadiazine derivatives that an alkyl or alkylamino are arranged on the thiadiazine ring.Its claimed these compounds that the AMPA glutamate receptor had antagonistic action.
At " pharmaceutical chemistry magazine " (J.Med.Chem.), 23, described 4 (5) among the 575-577 (1980)-amino-and methylamino-imidazoles-5 (4) methane amides and they as the character, particularly compound 3-aminooimidazole of chemotherapeutics also [4,5-e]-1,2,4-thiadiazine 1,1-dioxide and N-benzamido imidazo [4,5-e]-1,2,4-thiadiazine 1,1-dioxide.
Invention is described
The present invention relates to formula (I) and condense 1,2,4-thiadiazine and condense 1,4-thiazine derivative, or the salt that forms with pharmaceutically acceptable acid or alkali,
Wherein, B representative＞NR
5Or＞CR
5R
6, R wherein
5And R
6Each is hydrogen naturally; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl; Or R
5And R
4Represent a key in two keys between formula (I) atom 2 and 3 together; D representative-S (=O)
2-or-S (=O)-; Or D-B representative-S (=O) (R
7)=N-, wherein R
7Be C
1-6Alkyl; Or optional by halogen, hydroxyl, C
1-6Alkoxyl group, aryloxy, alkoxy aryl, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group, acyl group or C
1-6Carbalkoxy list or polysubstituted aryl or heteroaryl; R
1Be hydrogen; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl, and R
4Be hydrogen; Or R
4And R
5Represent a key in two keys between formula (I) atom 2 and 3 together; Or R
1And R
4Represent a key in two keys between the atom 3 and 4 of formula (I) together; R
2Be hydrogen; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl; R
3Be R
8-OR
8-C (=X) R
8-NR
8R
9Optional by halogen, hydroxyl, C
1-6Alkoxyl group, aryloxy, alkoxy aryl, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group, oxygen base, acyl group or C
1-6Carbalkoxy list or polysubstituted bicyclic alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Or by C
1-6The aryl that alkyl replaces;
Wherein, R
8Be hydrogen; C
3-6Cycloalkyl or (C
3-6Cycloalkyl) C
1-6Alkyl, wherein C
3-6
Cycloalkyl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted;
Contain one or more nitrogen-atoms, 3-6 person's saturated rings of Sauerstoffatom or sulphur atom; Or optional quilt
Halogen, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, aryl, fragrant oxygen
Base, alkoxy aryl, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group,
The oxygen base, formyl radical, acyl group, carboxyl, C
1-6Carbalkoxy or formamyl list or polysubstituted
Straight or branched C
1-18Alkyl;
X is O or S;
R
9Be hydrogen; C
1-6Alkyl; C
2-6Alkenyl; Optional by C
1-6Alkyl, halogen, hydroxyl or
C
1-6Alkoxyl group list or polysubstituted C
3-6Cycloalkyl; Or R
8And R
9Form 3-12 person's list or bicyclic ring system with nitrogen-atoms, wherein, one or more carbon atoms can be by nitrogen-atoms, and Sauerstoffatom or sulphur atom are replaced, and each ring system is optional by halogen, C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, nitro, amino, cyano group, trifluoromethyl, C
1-6-one alkyl-or dialkyl amido, oxygen base list or polysubstituted; Or R
3Be
Wherein, n, m, p each naturally 0,1,2,3; R
10Be hydrogen; Hydroxyl; C
1-6Alkoxyl group;
Optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted C
3-6Cycloalkanes
Base; Optional by halogen list or polysubstituted C
1-6Alkyl, C
2-6Alkenyl or C
2-6Alkynyl;
Or R
2And R
3Form 3-12 person's list or bicyclic ring system with nitrogen-atoms, wherein one or more carbon atoms can be by nitrogen-atoms, and Sauerstoffatom or sulphur atom are replaced, and each ring system is optional by halogen, C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, nitro, amino, cyano group, trifluoromethyl, C
1-6-one alkyl-or dialkyl amido, oxygen base list or polysubstituted; Carbon atom 5 and 6 representatives of A in formula (I) contain one or more nitrogen-atoms, 5 or 6 element heterocycle systems of Sauerstoffatom or sulphur atom, and this heterocyclic system is optional single or polysubstituted by following groups: halogen; C
1-12Alkyl; C
3-6Cycloalkyl; Hydroxyl; C
1-6Alkoxyl group; C
1-6Alkoxy-C
1-6Alkyl; Nitro; Amino; Cyano group; Cyano methyl; The perhalogeno methyl; C
1-6-one alkyl-or dialkyl amido; Sulfamyl; C
1-6Alkylthio; C
1-6Alkyl sulphonyl; C
1-6Alkyl sulphinyl; C
1-6Alkyl-carbonyl-amino; Arylthio, aryl sulfonyl kia, aryl sulfonyl, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; C
1-6Carbalkoxy; C
1-6Carbalkoxy C
1-6Alkyl; Formamyl; The carbamyl ylmethyl; C
1-6-one alkyl-or dialkyl amino carbonyl amino; Thioureido; C
1-6-one alkyl-or dialkyl amido thiocarbonyl-amino; C
1-6-one alkyl-or dialkyl amino sulfonyl; Carboxyl; Carboxyl C
1-6Alkyl; Acyl group; Aryl, aralkyl, aryloxy, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; (1,2,4-oxadiazole-5-yl)-or (1,2,4-oxadiazole-3-yl) C
1-6Alkyl, Qi Zhong oxadiazole base is optional by C
1-6Alkyl or C
3-6Cycloalkyl substituted; Or 5 or 6 Yuans contain azo-cycle, optional by phenyl or C
1-6Alkyl replaces; Condition is: the carbon atom 5 and 6 of A and formula (I) does not form pyridine ring, and does not comprise also [4,5-e]-1,2 of compound 3-aminooimidazole, 4-thiadiazine 1,1-dioxide and 3-(benzamido) imidazo [4,5-e]-1,2,4-thiadiazine 1,1-dioxide.
Belong to all optically active isomers that also comprise formula (I) compound in the scope of the invention, wherein some is to have optically actively, also comprises their racemic mixture.
All tautomeric forms that also comprise formula (I) compound in the scope of the invention.
Salt comprises the pharmaceutically acceptable acid additive salt, and pharmaceutically acceptable metal-salt or optional alkylated ammonium are for example with hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichoroacetic acid(TCA), oxalic acid, toxilic acid, pyruvic acid, propanedioic acid, succsinic acid, citric acid, tartrate, fumaric acid, amygdalic acid, phenylformic acid, styracin, methylsulfonic acid, the salt that ethyl sulfonic acid, picric acid etc. form, and with " pharmaceutical science magazine " (Journalof Pharmaceutical Science), 66,2 (1977) (this article all is hereby incorporated by reference) are gone up the salt that the relevant acid of listed pharmacologically acceptable salt forms, or and lithium, sodium, potassium, the salt that magnesium etc. form.
Term " C used herein
1-6Alkoxyl group ", no matter be to use separately or be used in combination, refer to the C that connects by ether oxygen
1-6The straight or branched monovalence substituting group that alkyl constitutes, said ether oxygen has its ether oxygen free valence bond; Said alkoxyl group has 1-6 carbon atom, as methoxyl group, and oxyethyl group, propoxy-, isopropoxy, butoxy, pentyloxy.
Term " C used herein
1-6Alkylthio ", no matter be to use separately or be used in combination, refer to the straight or branched monovalence substituting group that constitutes by the low alkyl group that bivalent sulfur atom connects; said sulphur atom has the free valence bond of this sulphur atom and has 1-6 carbon atom, as methylthio group, ethylmercapto group; rosickyite base, butylthio, penta sulfenyl.
Term " C used herein
2-6Alkenyl " refer to have the aliphatic unsaturated hydrocarbon of 2-6 carbon atom and two keys, vinyl for example, 1-propenyl, allyl group, pseudoallyl, n-butene base, positive pentenyl and n-hexylene base.
Term " C used herein
3-6Cycloalkyl " refer to have the saturated cyclic of some amount carbon atom, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Term " C used herein
2-6Alkynyl " refer to contain the triple-linked unsaturated hydrocarbons, for example ,-C ≡ CH ,-C ≡ CCH
3,-CH
2C ≡ CH ,-CH
2CH
2C ≡ CH ,-CH (CH
3) C ≡ CH etc.
Term " C used herein
1-6Alkoxy-C
1-6Alkyl " refer to have 2-12 carbon atom and the middle group that connects by oxygen, for example CH
2-O-CH
3, CH
2-O-CH
2-CH
3, CH
2-O-CH (CH
3)
2Deng.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " perhalogeno methyl " refers to trifluoromethyl, trichloromethyl, trisbromomethyl or three iodomethyls.
Term " C used herein
1-6Alkyl ", " C
1-12Alkyl " and " C
1-18Alkyl ", no matter be to use separately or be used in combination, refer to have the straight or branched stable hydrocarbon of specified quantity carbon atom, as methyl; ethyl, n-propyl, sec.-propyl, normal-butyl; sec-butyl, isobutyl-, the tertiary butyl, n-pentyl; 2-methyl butyl, 3-methyl butyl, 4-methyl amyl, neo-pentyl; n-hexyl, 1,2-dimethyl propyl, 2; 3-dimethyl propyl, 1,2,2-trimethylammonium propyl group etc.Used term " C
1-18Alkyl " also comprise secondary C
3-6Alkyl and uncle C
4-6Alkyl.
Term " C used herein
1-6One alkylamino " refer to that a kind of amino, one of them hydrogen atom are had the straight or branched stable hydrocarbon of the carbon atom of specified quantity to replace, as methylamino; ethylamino, propyl group amino, normal-butyl amino; sec-butyl amino, isobutylamino, tertiary butyl amino; n-pentyl amino, 2-methyl butyl amino, n-hexyl amino; 4-methyl amyl amino; neo-pentyl amino, 2,2-dimethyl propyl amino etc.
Term " C used herein
1-6Dialkyl amido " refer to a kind of amino, wherein two hydrogen atoms are had the straight or branched stable hydrocarbon of the carbon atom of specified quantity to replace separately, as dimethylamino; N-ethyl-N-methylamino, diethylamino, dipropyl amino; N-(normal-butyl)-N-methylamino, two (n-pentyl) amino etc.
Term used herein " acyl group " refers to contain the C that connects by carbonyl
1-6The monovalence substituting group of alkyl, as ethanoyl, propionyl, butyryl radicals, isobutyryl, valeryl, pentanoyl etc.
Term " C used herein
1-6Carbalkoxy " refer to contain the C that connects by carbonyl
1-6The monovalence substituting group of alkoxyl group, as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, positive butoxy carbonyl, secondary butoxy carbonyl, tertbutyloxycarbonyl, 3-methyl butoxy carbonyl, just own oxygen carbonyl etc.
Term used herein " 3-12 person's list or bicyclic ring system " refers to formula-NR
2R
3Or-NR
8R
9The monovalence substituting group of expression, wherein R
2And R
3, or R
8And R
9Form 3-12 person's list or bicyclic ring system with nitrogen-atoms, wherein one or more carbon atoms can with nitrogen-atoms, Sauerstoffatom or sulphur atom exchange, the example of this ring has: 1-pyrrolidyl, piperidino-(1-position only), morpholino, thiomorpholine generation, 4-methylpiperazine-1-base, 7-azabicyclo [2.2.1] heptan-7-base, henbane alkyl etc.
Term used herein " the saturated ring system of 3-6 person " refers to contain saturated monocyclic monovalence substituting group, this ring contains one or more nitrogen-atoms that are selected from, the heteroatoms of Sauerstoffatom or sulphur atom, and 3-6 carbon atom arranged and from the free valency of carbon atom, comprise for example 2-pyrrolidyl, the 4-piperidyl, morpholinyl, 1,4-diox-2-base, 5-oxazolidinyl, 4-isoxazole alkyl or 2-thio-morpholinyl.
Term used herein " bicyclic alkyl " refers to contain the monovalence substituting group of the twin nuclei that is made of 6-12 carbon atom, as the 2-norcamphyl, and 7-norcamphyl, 2-dicyclo [2.2.1] octyl group and 9-dicyclo [3.3.1] nonyl.
Term used herein " aryl " refers to phenyl, 1-naphthyl or 2-naphthyl.
Term used herein " heteroaryl " no matter be separately or combination, refers to the monovalence substituting group that is made of 5-6 person's monocycle aromatic nucleus or 9-10 person's Bicyclic ring, said ring contains one or more nitrogen-atoms that are selected from, the heteroatoms of Sauerstoffatom or sulphur atom, and said heteroaryl comprises, pyrroles for example, imidazoles, pyrazoles, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole isoxazole ， oxazole ， oxadiazole, thiadiazoles, quinoline, isoquinoline 99.9, quinazoline, quinoxaline, indoles, benzoglyoxaline, cumarone, pteridine and purine.
The straight or branched saturated carbon chains that term used herein " arylalkyl " refers to contain 1-6 carbon atom and replaced by an aromatic hydrocarbon, as benzyl, styroyl, 3-phenyl propyl, 1-naphthyl methyl, 2-(1-naphthyl) ethyl etc.
Term used herein " aryloxy " refers to phenoxy group, 1-naphthyloxy or 2-naphthyloxy.
Term used herein " alkoxy aryl " refers to by the C of an aromatic hydrocarbon replacement
1-6Alkoxyl group, as benzyloxy, benzene oxyethyl group, 3-phenyl propoxy-, 1-naphthyl methoxyl group, 2-(1-naphthyl) oxyethyl group etc.
The straight or branched saturated carbon chains that term used herein " heteroarylalkyl " refers to contain 1-6 carbon atom and replaced by a heteroaryl, as (2-furyl) methyl, (3-furyl) methyl, (2-thienyl) methyl, (3-thienyl) methyl, (2-pyridyl) methyl, 1-methyl isophthalic acid-(2-pyrimidyl) ethyl etc.
Term " C used herein
1-6Alkyl sulphonyl " refer to the C that connects by alkylsulfonyl
1-6The monovalence substituting group that alkyl constitutes, as methylsulfonyl, ethylsulfonyl; positive third alkylsulfonyl, different third alkylsulfonyl, positive fourth alkylsulfonyl; the Zhong Ding alkylsulfonyl, isobutyl alkylsulfonyl, tertiary butyl alkylsulfonyl; positive penta alkylsulfonyl, 2-methyl fourth alkylsulfonyl, 3-methyl fourth alkylsulfonyl; just own alkylsulfonyl; 4-methylpent alkylsulfonyl, new penta alkylsulfonyl and 2,2-dimethyl propylene alkylsulfonyl.
Term " C used herein
1-6One alkyl amino sulfonyl " refer to the C that connects by alkylsulfonyl
1-6The monovalence substituting group that one alkylamino constitutes; as the methylamino alkylsulfonyl; the ethylamino alkylsulfonyl; the n-propyl amino-sulfonyl; the sec.-propyl amino-sulfonyl; the normal-butyl amino-sulfonyl, sec-butyl amino-sulfonyl, isobutylamino alkylsulfonyl; tertiary butyl amino-sulfonyl; the n-pentyl amino-sulfonyl, 2-methyl butyl amino-sulfonyl, 3-methyl butyl amino-sulfonyl; the n-hexyl amino-sulfonyl; 4-methyl amyl amino-sulfonyl, neo-pentyl amino-sulfonyl and 2,2-dimethyl propyl amino-sulfonyl.
Term " C used herein
1-6Dialkyl amino sulfonyl " refer to the C that connects by alkylsulfonyl
1-6The monovalence substituting group that dialkyl amido constitutes, as the dimethylamino alkylsulfonyl, N-ethyl-N-methylamino alkylsulfonyl, diethylamino alkylsulfonyl, dipropyl amino-sulfonyl, N-(normal-butyl)-N methylamino alkylsulfonyl, two (n-pentyl) amino-sulfonyl etc.
Term " C used herein
1-6Alkyl sulphinyl " refer to the straight or branched C that connects by sulfinyl (S (=O)-)
1-6The monovalence substituting group that alkyl constitutes, as methylsulfinyl, ethyl sulfinyl, sec.-propyl sulfinyl, butyl sulfinyl, amyl group sulfinyl etc.
Term " C used herein
1-6Alkyl-carbonyl-amino " refer to such amino, one of them hydrogen atom is by acyl substituted, as kharophen, propionamido, sec.-propyl carbonylamino etc.
Term " (C used herein
3-6Cycloalkyl) C
1-6Alkyl ", no matter be to use separately or be used in combination, refer to contain 1-6 carbon atom and by a C
3-6The mono-substituted straight or branched saturated carbon chains of cycloalkyl, this cycloalkyl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted, the content of said term comprise, cyclopropyl methyl for example, (1-methyl cyclopropyl) methyl, 1-(cyclopropyl) ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.
Term used herein " arylthio " no matter be to use separately or be used in combination, refers to that it has the free valence bond from sulphur atom by the aryl of bivalent sulfur atom connection, and this aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted, thiophenyl for example, (4-aminomethyl phenyl) sulfenyl, (2-chloro-phenyl-) sulfenyl etc.
Term used herein " aryl sulfonyl kia " refers to the aryl that connected by sulfinyl (S (=O)-), and this aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted, phenyl sulfinyl for example, (4-chloro-phenyl-) sulfinyl etc.
Term used herein " aryl sulfonyl " refers to the aryl by the alkylsulfonyl connection, and this aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted, phenyl sulfonyl for example, tosyl group etc.
Term " C used herein
1-6One alkyl amino-carbonyl " refer to the C that connects by carbonyl
1-6The monovalence substituting group that one alkylamino constitutes, as the methylamino carbonyl, the ethylamino carbonyl, the n-propyl aminocarboxyl, sec.-propyl aminocarboxyl, normal-butyl aminocarboxyl, the sec-butyl aminocarboxyl, isobutylamino carbonyl, tertiary butyl aminocarboxyl, the n-pentyl aminocarboxyl, 2-methyl butyl aminocarboxyl, 3-methyl butyl aminocarboxyl, the n-hexyl aminocarboxyl, 4-methyl amyl aminocarboxyl, neo-pentyl aminocarboxyl and 2,2-dimethyl propyl aminocarboxyl.
Term " C used herein
1-6Dialkyl amino carbonyl " refer to the C that connects by carbonyl
1-6The monovalence substituting group that dialkyl amido constitutes, as the dimethylamino carbonyl, N-ethyl-N-methylamino carbonyl, diethylamino carbonyl, dipropyl aminocarboxyl, N-(normal-butyl)-N-methylamino carbonyl, two (n-pentyl) aminocarboxyl etc.
Term " C used herein
1-6One alkyl amino-carbonyl amino " refer to such amino, one of them hydrogen atom is by C
1-6One alkyl amino-carbonyl replaces, for example, the methylamino carbonylamino, the ethylamino carbonylamino, n-propyl amino carbonyl amino, sec.-propyl amino carbonyl amino, the normal-butyl amino carbonyl amino, sec-butyl amino carbonyl amino, isobutylamino carbonylamino, tertiary butyl amino carbonyl amino and 2-methyl butyl amino carbonyl amino.
Term " C used herein
1-6Dialkyl amino carbonyl amino " refer to such amino, one of them hydrogen atom is by C
1-6Dialkyl amino carbonyl replaces, for example, and the dimethylamino carbonylamino, N-ethyl-N-methylamino carbonylamino, diethylamino carbonylamino, dipropyl amino carbonyl amino, N-(normal-butyl)-N-methylamino carbonylamino, two (n-pentyl) amino carbonyl amino etc.
Term used herein " 5 or 6 element heterocycle " refers to contain one, two or three heteroatomic unsaturated or saturated monocycle that is selected from nitrogen, oxygen and sulphur, and 5 Yuans are encircled for example pyrroles, furans, thiophene, pyrroline, dihydrofuran, dihydro-thiophene, imidazoles, tetrahydroglyoxaline, pyrazoles, pyrazoline ， oxazole, thiazole ， isoxazole, isothiazole, 1,2,3-oxadiazole, furazan, 1,2,3-triazoles, 1,2,3-thiadiazoles or 2,1,3-thiadiazoles; Contain two or more nitrogen-atoms and be the fragrant monocycle pyrazine for example of 6 Yuans rings, pyrimidine, pyridazine, 1,2,4-triazine, 1,2,3-triazine or tetrazine; Contain and one or morely be selected from the heteroatoms of nitrogen, oxygen and sulphur and be that the non-fragrant monocycle of 6 Yuans rings is a pyrans for example, thiapyran, piperidines, diox; oxazine, different oxazine, dithiane, oxathiane (oxathine), thiazine, piperazine, thiadiazine, dithiazine Huo oxadiazine.
Term used herein " 5 or 6 Yuans contain azo-cycle " refers to by the monovalence substituting group that contains one or more nitrogen-atoms and have 5 or 6 Yuans unsaturated or saturated monocycle to constitute, pyrrolidyl for example, pyrrolinyl, imidazolidyl, pyrazolidyl, pyrazolinyl, piperidyl, piperazinyl, pyrryl, the 2H-pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, morpholino, thiomorpholine generation, isothiazolyl ， isoxazolyl oxazolyl oxadiazole base, thiadiazolyl group, 1,3-alkyl dioxin and 1, the 4-alkyl dioxin.
At a preferred version formula of of the present invention (I) is compound (Ia),
R wherein
1And R
5Each is hydrogen naturally; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl, and R
4Be hydrogen; Or R
4And R
5Represent a key in two keys between the atom 2 and 3 of formula (I) together, and R
1Definition as above; Or R
4And R
1Represent a key in two keys between the atom 3 and 4 of formula (I) together, and R
5Definition as above; And D representative-S (=O)
2-or-S (=O)-.
At another preferred version formula of (I) of the present invention is compound (Ib),
R wherein
1Be hydrogen; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl, and R
4Be hydrogen; Or R
4And R
1Represent a key in two keys between the atom 3 and 4 of formula (I) together; D representative-S (=O) R
7=, wherein, R
7Be C
1-6Alkyl; Or optional by halogen, hydroxyl, C
1-6Alkoxyl group, aryloxy, alkoxy aryl, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group, acyl group or C
1-6Carbalkoxy list or polysubstituted aryl or heteroaryl.
At another preferred version formula of (I) of the present invention is compound (Ic),
R wherein
1, R
5And R
6Each is hydrogen naturally; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl, and R
4Be hydrogen; Or R
4And R
5Represent a key in two keys between the atom 2 and 3 of formula (I) together, and R
1And R
6Definition as above; Or R
4And R
1Represent a key in two keys between the atom 3 and 4 of formula (I) together, and R
5And R
6Definition as above; D representative-S (=O)
2-or-S (=O)-.
Preferred general formula (I) is compound (Ia).
In another preferred version of the present invention D be-S (=O)
2-.
R in another preferred version of the present invention
1Be selected from hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl or C
2-6Alkenyl.Preferred R
1Be hydrogen or C
1-6Alkyl.
R in another preferred version of the present invention
1And R
4Represent a key in two keys between formula (I) atom 3 and 4 together.
R in another preferred version of the present invention
4And R
5Represent a key in two keys between formula (I) atom 2 and 3 together.
R in another preferred version of the present invention
2Be selected from hydrogen, hydroxyl, C
1-6Alkyl, C
3-6Cycloalkyl or C
2-6Alkenyl.Preferred R
2Be hydrogen or C
1-6Alkyl.
R in another preferred version of the present invention
3Be selected from R
8,-OR
8,-NR
8R
9Or aryl, this aryl is by C
1-6Alkyl replaces; Wherein, R
8Be hydrogen; C
3-6Cycloalkyl; (C
3-6Cycloalkyl) C
1-6Alkyl; Contain one, two or three nitrogen-atoms, 3-6 person's saturated rings of Sauerstoffatom or sulphur atom; Or optional by halogen, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6The straight or branched C that cycloalkyl or aryl replace
1-18Alkyl; R
9Be hydrogen, C
1-6Alkyl, or C
3-6Cycloalkyl; Or R
8And R
9Form 4-6 person's ring with nitrogen-atoms, preferred 1-pyrryl, piperidyl or morpholinyl.
R in another preferred version of the present invention
3Be selected from optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted secondary C
3-6Alkyl, uncle C
4-6Alkyl, C
3-6Cycloalkyl or (C
3-6Cycloalkyl) methyl.Preferred R
3Be selected from sec.-propyl, 1-methyl-propyl, 2-methyl-propyl, the tertiary butyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 1,2,2-trimethylammonium propyl group, 2, the 3-dimethylbutyl, 1-ethyl propyl, 1-ethyl-2-methyl-propyl, 1-ethyl-2, the 2-dimethyl propyl, 2,3,3-trimethylammonium butyl, 2-methyl butyl, 1,5-dimethyl hexyl, 3-methyl butyl, 3-methyl hexyl, cyclopropyl, 1-methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl methyl, 1-(cyclopropyl) ethyl, cyclobutylmethyl, cyclopentyl-methyl or cyclohexyl methyl.
R in another preferred version of the present invention
2And R
3Form 6 Yuans rings with nitrogen-atoms, wherein, optional by C at 2
1-6Alkyl replaces, and said alkyl is selected from methyl, ethyl or sec.-propyl.Preferred 6 Yuans rings are piperidines, piperazine, morpholine or thiomorpholine.
R in another preferred version of the present invention
7Be selected from C
1-6Alkyl, phenyl or pyridyl.
A forms one with carbon atom 5 and 6 in the formula (I) and contains heteroatomic 5 element heterocycle systems that are selected from nitrogen-atoms and sulphur atom in another preferred version of the present invention, or contain two heteroatomic 5 element heterocycle systems that are selected from nitrogen-atoms, Sauerstoffatom or sulphur atom, or contain 6 Yuans aromatic heterocycle systems of two or three nitrogen-atoms, or contain heteroatomic 6 Yuans nonaromatic heterocycles systems that one or two is selected from nitrogen-atoms, Sauerstoffatom or sulphur atom; Optional single or two replacements of these heterocyclic systems: halogen by following groups; C
1-12Alkyl; C
3-6Cycloalkyl; Cyano group; Cyano methyl; The perhalogeno methyl; Sulfamyl; C
1-6Alkylthio; C
1-6Alkyl sulphonyl; C
1-6Alkyl sulphinyl; Arylthio, aryl sulfonyl kia, aryl sulfonyl, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; C
1-6Carbalkoxy C
1-6Alkyl; The carbamyl ylmethyl; Carboxyl C
1-6Alkyl; Aryloxy; (1,2,4-oxadiazole-5-yl)-or (1,2,4-oxadiazole-3-yl) C
1-6Alkyl, Qi Zhong oxadiazole base is optional by C
1-6Alkyl or C
3-6Cycloalkyl substituted; Acyl group; Or 5 or 6 Yuans contain azo-cycle, optional by phenyl or C
1-6Alkyl replaces.
Preferred A forms thieno-[3,2-e] ring or pyrrolo-[3,2-e] ring, thiophene with carbon atom 5 and 6, imidazoles, thiazole, pyrazoles ， isoxazole or isothiazole, pyrazolo [3,2-e] ring, Mi Dingbing [4,5-e] ring, Mi Dingbing [5,4-e] ring, pyridazine also [4,5-e] ring or pyridazine also [4,3-e] ring, the sulfo-pyrans, piperidines ， diox ， oxazine or dithiane.
Preferred compound of the present invention is as follows: 7-cyano group-3-sec.-propyl amino-6-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-cyano group-6-methyl-3-propyl group amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-isopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(1-methylheptyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(1-ethyl heptyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(2-methyl butyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(1-methyl hexyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclohexyl methyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 3-(6-chloro-1,4-dihydro-1,1-dioxy thiophene also [3,2-e]-1 λ 6,2,4-thiadiazine-3-base is amino) ethyl butyrate 3-(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ 6 also, 2,4-thiadiazine-3-base is amino) butyric acid 6-chloro-3-(3-hydroxyl-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 (S)-3-sec-butyl amino-6-chloro-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-sec.-propyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopentyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-fluoro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclobutyl amino-5,6-dimethyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopentyl amino-5,6-dimethyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 3-sec.-propyl amino-6,7-dimethyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclobutyl amino-6,7-dimethyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopentyl amino-6,7-dimethyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 5-chloro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 5-chloro-3-propyl group amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 5-chloro-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 5-chloro-6-methyl-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-sec.-propyl amino-5-methyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopentyl amino-5-methyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-fluoro-3-propyl group amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-fluoro-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 5-fluoro-3-propyl group amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 5-fluoro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 3-sec.-propyl amino-7-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclobutyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(2-hydroxyethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (±)-3-table-dicyclo [2.2.1] heptan-2-base amino-6-chloro-4H-thieno-[3,2-e] 1,2,4-thiadiazine 1,1-dioxide (R)-6-fluoro-3-(2-hydroxypropyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 5,6-two bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclohexyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(furans-2-ylmethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(1-ethyl propyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-bromo-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(2-methacrylic) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide, or 6-cyano group-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide.
Therefore The compounds of this invention and potassium channel interactors are used as the unlatching thing or the blocking-up thing of the potassium channel of ATP adjusting, and then are used to treat multiple cardiovascular system diseases, as cerebral ischemia, hypertension, ischemic heart disease, stenocardia and coronary heart disease; The pulmonary system disease; The gastrointestinal system disease; Central nervous system disease; And endocrine system disease.
Because some K
ATP-opening thing can antagonism basis artery or the vasospasm of arteriae cerebri, so The compounds of this invention can be used for treating vasospasm class disease, as subarachnoid hemorrhage and migraine.
The compounds of this invention also can be used for treatment and reduces diseases associated with the skeletal muscle blood flow, as raynaud's disease and intermittent claudication.
In addition, The compounds of this invention also can be used for treating chronic tracheal disease, comprises asthma, also can treat to force flesh unstable secondary bladder to overflow to block, and therefore can discharge treatment urinary stone disease by urethra.
The compounds of this invention also can be used for treatment and the disorderly diseases associated of stomach and intestine mobility, as the pungency bowel syndrome.In addition, these compounds can also be used for the treatment of premature labor and dysmenorrhoea.
Potassium channel is opened the release that thing makes the neurone hyperpolarization and suppresses neurotransmitter, and therefore, people wish that such compound can be used in the multiple central nervous system disease of treatment, as epilepsy, and local asphyxia and neurodegenerative disease, and pain management.
In addition, potassium channel is opened thing can promote hair growth, and therefore, The compounds of this invention can be used for treating baldness.
Potassium channel is opened thing can also loosen smooth muscle of bladder, and therefore, The compounds of this invention can be used for treating the urinary incontinence.
Since insulism cause that serious hypoglycemia forms such as nesidioblastosis and insulinemia in, The compounds of this invention can be used to reduce insulin secretion.For obesity, can usually run into hyperinsulinemia and Regular Insulin resistance.This disease will cause the development of non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM).Therefore, people wish that potassium channel opens thing, especially The compounds of this invention, can be used for reducing hyperinsulinemia and then prevent diabetes and minimizing obesity.Treating among the tangible NIDDM with potassium channel unlatching thing, The compounds of this invention helps recovering the susceptibility and the normal insulin secretion of glucose.
At the early stage or pre-diabetes of insulin-dependent diabetes (IDDM), potassium channel opens thing and The compounds of this invention all can be used to make pancreatic cell to have a rest, and then can prevent the development of autoimmune disease.
Potassium channel of the present invention open thing can with the medicament Combined Preparation of immunosuppressor or niacinamide and so on, they will reduce the autoimmunization sex change of beta cell.
The present invention be on the other hand with beta cell have a rest with protect beta cell in case cytokine mediated β cell impaired/cytotoxic treatment combines.Insulin requirement-or the IDDM of l type diabetes (IDDM) and outbreak later on (be also referred to as 1.5 types, for example, diabetes B (NIIDM) patient that non-insulin needs have anti-β cell epitope from the body activity, this disease becomes the insulin requirement type subsequently) have circulation from body active unicellular/lymphocyte, make them get back on island/beta cell and discharge their cytokine.Some of them cytokine (for example, il-1 b (1L-1b), tumour necrosis factor a (TNFa) and Interferon, rabbit g (IFNg)) is poisonous especially to beta cell, for example, and by inducing of nitrogen oxide (NO) and other free residue.Suppress this cytotoxicity, for example by niacinamide (NA) Combined Preparation, the compound of its derivative or the protection of other cytokine is this example on the one hand of the present invention to the pre-diabetes/diabetic subject's effect with the PCO compounds for treating.Niacinamide belongs to vitamins B family, and is by with Carboxylamideization and from the nicotinic acid deutero-.It does not possess the pharmacological property of Nicotine.NA is transformed into NAD+, and it is as the proteinic coenzyme that relates to tissue respiration.NA has been considered to the activity (events) of molecule in the cell of the several supposition existence of meeting influence after the immunity outbreak on beta cell.Experimentation on animals and the early stage non-blind experiment of human body show that IDDM and cytokine/immune-mediated beta cell destroys provide protection to this compound to resisting.This application relate to independent use PCO compound on the other hand, or itself and cytokine/immune-mediated beta cell infringement inhibitor is united use, in transplanting, is for example carried out island (islet) to the diabetic subject and transplant.The use of these methods of treatment one or both of can reduce the danger that island/beta cell/engineering beta cell/pancreas generation is repelled of transplanting.
As K
ATPThe The compounds of this invention of-channel blocker can be used for treating NIDDM.
Preferred The compounds of this invention is used for the treatment of or prevents endocrine system disease, as hyperinsulinemia and diabetes.
Therefore, the present invention relates to general formula (I) compound or its pharmaceutically acceptable acid additive salt on the other hand, goes up acceptable material as treatment, is preferably used as acceptable material in the treatment for the treatment of hyperinsulinemia and treatment or prevent diabetes.
In addition, the invention still further relates to the purposes of formula of the present invention (I) compound as treatment hyperinsulinemia and treatment or prevent diabetes medicine.
On the other hand, the present invention relates to prepare the method for above-claimed cpd.This method comprises a) with formula (II) compound
Wherein, A, B, D, R
1And R
4Define as above, Z is a leavings group, as alkoxyl group, and alkylthio, halogen, preferred chlorine, bromine or iodine, three methylamino-s or methyl sulphonyl, with the reaction of formula (III) compound,
Wherein, R
2And R
3Definition as above forms general formula (I) compound; B) with formula (IV) compound
Wherein, R
1Be hydrogen, A, B, D and X define as above, and perhaps, B is NH, R
1, A, D and X define as above, with formula (III) compound or its suitable salt, at P
2O
5There is reaction down with high boiling point tertiary amine or its salt, forms general formula (I) compound; C) with formula (IV) compound
Wherein, R
1Be hydrogen, A, B, D and X define as above, and perhaps, B is NH, R
1, A, D and X definition as above, with formula (III) compound or its suitable salt, at titanium tetrachloride with can form the solvent of mixture with it, as tetrahydrofuran (THF), or there is reaction down in the mixture of toluene and phenylmethylether, formation general formula (I) compound; D) with the formula V compound
Wherein, R
1Define as above with A, with the reaction of formula (VI) compound,
R
3NCO (VI) wherein, R
3Define as above, forming D is SO
2, B is＞NR
5, R
2Be H, and R
4And R
5Form general formula (I) compound of a key together; E) with the formula V compound
Wherein, R
1Define as above with A, with the reaction of formula (VII) compound,
R
3NHC (=O) Cl (VII) wherein, R
3Define as above, forming D is SO
2, B is＞NR
5, R
2Be H, and R
4And R
5Form general formula (I) compound of a key together; F) with the formula V compound
Wherein, R
1Define as above with A, with formula (VIII) compound or its suitable reactant salt,
Wherein, Y is NH or S, and forming D is SO
2, B is＞NR
5, R
4And R
5Form a key together, and R
2And R
3It is general formula (I) compound of H; G) in the presence of alkali with formula (IX) compound or its suitable salt
Wherein, R
11Be R
1Or EtOC (=O), and R
1Define as above with A, with the reaction of formula (X) compound,
R
3N=C=S (X) wherein, R
3The definition as above, form a kind of adducts, it both can be structure XI and XII the two one of, also can be the mixture of the two,
Perhaps in appropriate solvent, form closed loop, if R with the light gas disposal
11Be R
1, then form D and be-S (=O)
2-, B is＞NR
5, R
2Be H, and R
4And R
5Form general formula (I) compound of a key together; If R
11Be EtOC (=O), then form general formula (XIII) compound;
H) with general formula (XIII) compound hydrolysis, decarboxylationization then, such as, in buck, heat initial compounds,
Form D and be-S (=O)
2-, B is＞NR
5, R
1And R
2Be H, and R
4And R
5Form general formula (I) compound of a key together.
Starting raw material both can be a known compound, also can be with preparation similar approach of known compound or the described currently known methods preparation of similar following document: Huang, people such as B.S., " pharmaceutical chemistry magazine " (J.Med.Chem.), 23,575-7 (1980); People such as Ofitserov V.I., Khim.Geterotsikl.Soedin., 1119-22 (Russian) (1976); Topliss J.G., U.S.3,641,017 (1972); People such as Kotovskaya S.K., Khim.-Farm.Zh., 13,54-57 (Russian) (1979); Meyer R.F., " heterocyclic chemistry magazine " (J.Heterocycl.Chem.), 6,407-408 (1969); Hattori M., Yoneda M. and Goto M., " communication of Japanese Chemical Society, " (Bull.Chem.Soc.Jap.), 46,1890-1 (1973); Williams T.R. and Cram D.J., " organic chemistry magazine ", 38,20-26 (1973); Barnes A.C., Kennewell P.D. and TaylorJ.B., " Chemical Society's magazine, chemical communication " (J.Chem.Soc.Chem.Commun.), 1973,776-777; Stoss and Satzinger, Chem.Ber., 109,2097 (1976); Kresze G. and Hatjiissaak A., " p and s " (Phosphorus Sulfur), 29,41-47 (1987); Dillard R.D., Yen T.T., Stark P. and Pavey D.E., " pharmaceutical chemistry magazine ", 23,717-722 (1980).Pharmacological method
The interaction ability of The compounds of this invention and potassium channel can be measured with several different methods.When using patch clamping technique (Hamill O.P., Marty A., Neher E., Sakmann B. and Sigworth F.J., PlugersArch., 391,85-100 (1981)), can write down ionic current by the single passage of cell.
Can measure the activity of opening the compound of thing as potassium channel according to following method by diastole mouse aortic annulus:
The aortic arch of mouse and one section thoracic aorta between the barrier film are cut down, then according to people such as TaylorP.D., " Britain's pharmacology magazine " (Brit.J.Pharmacol.), 111, the described method of 42-48 (1994), and be prepared into annular sample.
After 45 minutes, in the balance period under 2g tension force, shrink annular sample to reach 80% of peak response with the phenylephrine concentration that needs.When the phenylephrine response reaches constant, effective vasodilator is added in the little volume bathing pool cumulatively, with the incremental representation of semilog mole, the timed interval is 2 minutes.The diastole effect is represented as the per-cent of shrink tension.The effectiveness of compound is represented as impels the needed concentration of tissue 50% diastole.The diastole of mouse aortic annulus
Embodiment E C
50(mM)
4 2.8
6 20.5
K in the pancreas beta cell
ATPThe unlatching of-passage can be according to people such as Arkhammar P., " journal of biological chemistry " (J.Biol.Chem.), 262,5448-5454 (1987), described method is by measuring Free Ca in the tenuigenin
2+A series of variations of concentration are measured.Effusive from β clone
86Rb
+
RIN 5F clone is grown in the RPMI 1640 with GlutamaxI, and (derive from GibcoBRL, Scotland UK), and remains on 37 ℃ of 5% CO to replenish 10% foetal calf serum
2In the atmosphere of/95% air.(derive from GibcoBRL, Scotland UK) separately, and is suspended in the substratum this cell again, adds 1mCi/ml with Trypsin-EDTA solution
86Rb
+, then with the density of 100 μ l/ hole correspondences be 50000 cells/well with its move into titer plate (96 holes, cluster 3596, aseptic, derive from CosterCorporation, MA, USA) in, growth is 24 hours before measuring.
Titer plate woods lattice damping fluid (150mM NaCl, 10mM Hepes, 3.0mM KCl, 1.0mM CaCl
2, 20mM Sucrose, pH7.1) washing is 4 times.Add the 80 μ l woods lattice damping fluids and 1 μ l contrast or the test compound that are dissolved in DMSO.Behind incubated at room temperature 1h, a lid 50 μ l supernatant liquors are transferred to PicoPlates (Packard Instrument Company, CT, USA) in, and add 100 μ l MicroScint 40 (Packard Instrument Company, CT, USA).With this titer plate be placed on TopCount (Packard Instrument Company, CT, USA) on, use
32The P program was counted with the time in 1 minute/hole.
(CA USA) calculates EC for Advanced Graphics Software, Inc. with SlideWrite
50And E
Max, adopt four parameter logarithmic curve: y=(a-d)/(1+ (x/c)
b)+d, wherein active estimated value during the a=zero-dose; The b=slope factor; C=curve intermediary concentration; Active estimated value when reaching d=concentration infinity.When the infinite general goal of concentration is turned back, EC
50=c and E
Max=d.The Rb effluent increases in the rin 5F cell
Embodiment E C
50(mM)
4 5.5
6 31
The compounds of this invention is effective in very wide dosage range.Usually, obtain dosage about 0.05-1000mg every day of satisfactory result, preferably about 0.1-500mg/d.Most preferred dosage is about 1-100mg/d.Dosage will depend on administering mode accurately, form of administration, the object that treat and body weight thereof, doctor in charge or animal doctor's selection and experience.
Route of administration can be any approach, as long as active compound is transported to position suitable or that will act on, for example, and oral or parenteral admin, subcutaneous as rectum through skin, intravenously, intramuscular or intranasal administration, preferred oral administration.
Typical composition contains formula (I) compound or its pharmaceutically acceptable acid additive salt, and pharmaceutically acceptable vehicle, and this vehicle can be carrier or thinner, or with carrier dilution, or be encapsulated in the carrier, this carrier can be a capsule form, sachet, paper or other packing.When the preparation composition, can use the routine techniques of preparation composition.For example, active compound usually will mix with carrier, or dilutes with carrier, or is encapsulated in the carrier, and carrier can be an ampoule, capsule, sachet, paper or other packing.When carrier was used as thinner, it can be a solid, semisolid or liquid, and as the carrier of active compound, vehicle or medium.Active compound can be adsorbed on the particulate solid container, for example, be adsorbed in the sachet.Suitable carriers comprises water, salts solution, ethanol, polyoxyethylene glycol, poly-hydroxyl-oxethyl Viscotrol C, gelatin, lactose, amylose starch, Magnesium Stearate, talcum, silicic acid, lipid acid monoglyceryl ester and two glyceryl ester, pentaerythritol fatty ester, Walocel MT 20.000PV and polyvinylpyrrolidone.Can also contain wetting agent in the preparation, emulsifying agent and suspension agent, sanitas, sweeting agent or correctives.Preparation of the present invention can be formed in the formulation of or delayed release of active elements quick, lasting to energy after patient's administration with method well-known in the art.
Pharmaceutical preparation can be through sterilization, if desired, with assistant agent, emulsifying agent, the salt that influences osmotic pressure, buffer reagent and/toning agent etc. mixes, deleterious interaction can not take place with active compound in these materials.
Use for parenteral, specially suitable preparation is injection solution or suspension, preferably will have the active compound aqueous solution and be dissolved in the polyhydroxylated Viscotrol C.
Adopt talcum and/or carbohydrate to make the tablet of carrier and binding agent etc., dragee or capsule are specially adapted to oral administration.The preferred carrier of tablet, dragee or capsule is a lactose, W-Gum and/or yam starch.Syrup or elixir also can be used in the situation of using sweetened vehicle.
In a word, The compounds of this invention is dispersed in the unitary dose, and this unitary dose contains the 1-100mg dosage of having an appointment in pharmaceutically acceptable carrier.
The typical tablet that is applicable to the inventive method can be made with conventional tabletting technology, contains usually:
Ingredient m g/ sheet
Active compound 5.0mg
Lactose 67.8mg Ph.Eur.
Avicel
31.4mg
Amberlite
1.0mg
Magnesium Stearate 0.25mg Ph.Eur. embodiment
The following example is the preparation method of Ming Dynasty style (I) compound furtherly, does not limit the present invention.
Embodiment 17-cyano group-3-sec.-propyl amino-6-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide be 4-cyano group-2-diazanyl carbonyl-5-methyl-thiophene-3-sulphonamide a)
To use similar Junquera; F. wait the people; " European pharmaceutical chemistry magazine " (Eur.J.Med.Chem.); 23,329 (1988) described methods are suspended in 10ml ethanol from the 4-cyano group-5-methyl-3-sulfamyl-thiophene-2-carboxylic acid methyl esters (2.9g) of 3-amino-4-cyano group-5-methyl-thiophene-2-carboxylic acid methyl esters preparation.Add a hydrazine hydrate (2ml), and mixture was at room temperature stirred 1 hour, then evaporation.Water (10ml) grinds oily residuum (3.3g), filters the crystal of collecting precipitation, washes with water, and dry then, obtaining title compound is yellow crystals (1.62g); M.p.186-191 ℃;
1H-NMR (DMSO-d
6), δ (ppm): 7.25 (br, 5H, NH/NH
2), 2.51 (s, 3H, CH
3).B) 4-cyano group-5-methyl-3-sulfamyl-thiophene-2-carbonyl azide thing
In the 38ml 1M hydrochloric acid of 4-cyano group-2-diazanyl carbonyl-5-methyl-thiophene-3-sulphonamide (1.6g) that Sodium Nitrite (0.47g) aqueous solution (5ml) is added drop-wise to 0 ℃ of stirring.The gained mixture is continued to stir 30 minutes at 0 ℃, filter then.Filter cake washes with water, and vacuum-drying then obtains the 1.35g title compound;
1H-NMR (DMSO-d
6), δ (ppm): 7.75 (br, 1H, NH
2), 2.75 (s, 1H, CH
3).C) 4-cyano group-2-ethoxycarbonyl amino-5-methyl-thiophene-3-sulphonamide
4-cyano group-5-methyl-3-sulfamyl-thiophene-2-carbonyl azide thing (1.35g) is divided into 5 fens clock times of small quantities of usefulness to be added in the 50ml dehydrated alcohol under the reflux temperature.Gained solution was refluxed 5 minutes, then evaporation.Grind residuum with the 20ml ethyl acetate and obtain crystallization.Leach crystal, use the ethyl acetate rinsing, dry then, obtain title compound;
1H-NMR (DMSO-d
6), δ (ppm): 9.45 (s, 1H, NH), 7.82 (br, 2H, NH
2), 4.23 (q, 2H, CH
2), 2.51 (s, 3H, CH
3), 1.25 (t, 3H, CH
3).D) N-(4-cyano group-2-ethoxycarbonyl amino-5-methyl-3-thienyl sulphonyl base)-N '-sec.-propyl thiocarbamide
With 4-cyano group-2-ethoxycarbonyl amino-5-methyl-thiophene-3-sulphonamide (0.50g), the 10ml anhydrous propanone of the mixture of salt of wormwood (0.36g) and isopropyl isothiocyanate (300 μ l) is evaporated to dried 55 ℃ of heating 18 hours then.Residuum is dissolved in water (10ml), drips 1M hydrochloric acid, make pH reach 2.Leach precipitation, use the less water rinsing, dry then, obtain the 0.34g title compound; M.p.169-171 ℃.E) 7-cyano group-3-sec.-propyl amino-6-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine-4-carboxylic acid, ethyl ester 1,1-dioxide
To the toluene solution that in the 10ml anhydrous THF solution of the N-of 0 ℃ of stirring (4-cyano group-2-ethoxycarbonyl amino-5-methyl-3-thienyl sulphonyl base)-N '-sec.-propyl thiocarbamide (0.3g) and triethylamine (320 μ l), adds 750 μ l, 20% phosgene.Mixture was stirred 1 hour at 0 ℃, be evaporated to dried then.Residuum water (10ml) grinds, and leaches precipitation, and the filter cake water rinse is dry then, obtains the thick title compound of 0.24g; M.p.116-119 ℃.Need not purifying, product promptly can be used for the next step.F) 7-cyano group-3-sec.-propyl amino-6-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide
With 7-cyano group-3-sec.-propyl amino-6-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine-4-carboxylic acid, ethyl ester 1,1-dioxide (0.15g) and 1M aqueous sodium hydroxide solution (5ml) mixture at room temperature stir 1h.Filtering mixt drips 4M hydrochloric acid, makes pH reach 1-2.Stir and leach precipitation after 30 minutes, use the less water rinsing, dry then, obtain title compound; M.p.235-238 ℃;
1H-NMR (DMSO-d
6), δ (ppm): 11.35 (s, 1H, NH), 7.55 (br d, 1H, NH), 3.98-3.77 (m, 1H, CH), 2.50 (s, 1H, CH
3), 1.15 (d, 6H, CH
3).
Embodiment 27-cyano group-6-methyl-3-propyl group amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide is N-(4-cyano group-2-ethoxycarbonyl amino-5-methyl-3-thienyl sulphonyl base)-N '-propyl group thiocarbamide a)
With the described synthetic method of similar embodiment 1-d, prepare title compound from 4-cyano group-2-ethoxycarbonyl amino-5-methyl-thiophene-3-sulphonamide and propyl isothiocyanide; M.p.167-168 ℃.B) 7-cyano group-6-methyl-3-propyl group amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine-4-carboxylic acid, ethyl ester 1,1-dioxide
With the described synthetic method of similar embodiment 1-e,, prepare title compound by with N-(4-cyano group-2-ethoxycarbonyl amino-5-methyl-3-thienyl sulphonyl base)-N '-sec.-propyl thiocarbamide closed loop; M.p.175-179 ℃.C) 7-cyano group-6-methyl-3-propyl group amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide
With the described synthetic method of similar embodiment 1-f, by with 7-cyano group-3-propyl group amino-6-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine-4-carboxylic acid, ethyl ester 1, the hydrolysis of 1-dioxide, decarboxylationization then, preparation title compound; M.p.293-298 ℃; 1H-NMR (DMSO-d
6), δ (ppm): 11.6 (s, 1H, NH), 7.65 (br, 1H, NH), 3.14 (dd, 2H, CH
2), 2.58 (s, 1H, CH
3), 1.65-1.4 (m, 2H, CH
2), 0.89 (t, 3H, CH
3).
Embodiment 36-chloro-3-(3-methyl butyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(3-methyl butyl) thiocarbamide a)
(0.49g, (0.5g, anhydrous N 2.0mmol) in dinethylformamide (5ml) solution, and stir in ice bath 4.4mmol) to be added to 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride with potassium tert.-butoxide.(0.31g 2.4mmol) is added drop-wise in the gained suspension, and mixture is stirred 3.5h at 0-20 ℃ with isothiocyanic acid 3-methyl butyl ester after 10 minutes.Evaporate most of solvent at 40 ℃, then residuum is dissolved in 25ml water, handle, filter with decoloration active carbon.With acetate filtrate is acidified to pH3-4, obtains 0.21g (29%) title compound after the filtration; M.p.114-115 ℃ of decomposition;
1H-NMR (DMSO-d
6): δ 0.85 (d, 6H, 2 * CH
3), 1.40 (q, 2H, CH
2), 1.50 (m, 1H, CH
2), 3.45 (q, 2H, CH
2), 6.45 (br, 2H, NH
2), 6.65 (s, 1H, H-4), 8.30 (br t, 1H, NH), 11.3 (brs, 1H).B) 6-chloro-3-(3-methyl butyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With phosgene (0.242ml; 20% in toluene) be added drop-wise to N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(3-methyl butyl) thiocarbamide (0.153g; 0.42mmol) and anhydrous triethylamine (0.118ml, in anhydrous tetrahydro furan 0.85mmol) (3ml) solution, and 0 ℃ of stirring.With mixture evaporate to dryness behind 0 ℃ of stirring 2h.From the ethyl acetate crystallization, leach precipitation, the washing after drying obtains 38mg (27%) title compound; Mp230-231.5 ℃,
1H-NMR (DMSO-d
6): δ 0.90 (d, 6H, 2 * CH
3), 1.40 (q, 2H, CH
2), 1.60 (m, 1H, CH), 3.20 (q, 2H, CH
2), 7.05 (s, 1H, H-5), 7.25 (br s, 1H, NH), 10.95 (s, 1H, NH), MS:M/e 307 (M+).
Embodiment 46-chloro-3-(1-methylheptyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-methylheptyl) thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid 1-methylheptyl ester, obtain soup compound (productive rate 29%);
1H-NMR (DMSO-d
6): δ 0.90 (t, 3H, CH
3), 1.10 (d, 3H, CH
3), 1.25 (m, 8H), 1.47 (m, 2H, CH
2), 4.25 (p, 1H, CH), 6.5 (br s, 2H, NH
2), 6.65 (s, 1H, H-4), 7.95 (br, 1H, NH), 11.2 (br s, 1H).B) 6-chloro-3-(1-methylheptyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound (productive rate 71%) from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-methylheptyl) thiocarbamide; Mp 179-181 ℃,
1H-NMR (DMSO-d
6): δ 0.85 (d, 3H, CH
3), 1.15 (d, 3H, CH
3), 1.30 (m, 8H), 1.45 (m, 2H, CH
2), 3.75 (p, 1H, CH), 7.05 (s, 1H, H-5), 7.10 (br, s, 1H, NH), 10.65 (s, 1H, NH) .MS:M/e 349 (M+).
Embodiment 56-chloro-3-(1-ethyl pentyl group) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-ethyl pentyl group) thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid 1-ethyl pentyl group ester, obtain soup compound (productive rate 36%);
1H-NMR (DMSO-d
6): δ 0.8 (2q, 6H, 2 * CH
3), 1.2 (m, 4H), 1.5 (m, 4H), 4.20 (sextet, 1H, CH), 6.55 (br, 2H, NH
2), 6.65 (s, 1H, H-4), 7.85 (br d, 1H, NH), 11.3 (br s, 1H, NH) .b) 6-chloro-3-(1-ethyl pentyl group) amino-4H-thieno-s [3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound (productive rate 35%) from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-ethyl pentyl group) thiocarbamide; Mp 165-167.5 ℃,
1H-NMR (DMSO-d
6): δ 0.85 (2, q, 6H, 2 * CH
3), 1.25 (m, 4H), 1.45 (m, 4H), 3.65 (m, 1H, CH), 7.0 (br, 1H, NH), 7.05 (s, 1H, H-5), 10.65 (br s, 1H, NH) .MS:M/e 335 (M+).
Embodiment 66-chloro-3-(2-methyl butyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(2-methyl butyl) thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid 2-methyl butyl ester, obtain soup compound (productive rate 28%); Mp 116.5-118 ℃,
1H-NMR (DMSO-d
6): δ 0.8 (2d, 6H, 2 * CH
3), 1.10 (m, 1H), 1.30 (m, 1H), 1.65 (m, 1H), 3.40 (m, 2H+HDO, CH
2), 6.45 (br, 2H, NH
2), 6.65 (s, 1H, H-4), 8.25 (br t, 1H, NH), 11.3 (br s, 1H) .b) 6-chloro-3-(2-methyl butyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound (productive rate 49%) from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(2-methyl butyl) thiocarbamide; Mp 232-234 ℃,
1H-NMR (DMSO-d
6): δ 0.85 (2d, 6H, 2 * CH
3), 1.15 (m, 1H), 1.40 (m, 1H), 1.60 (m, 1H), 3.10 (m, 2H, CH
2), 7.05 (s, 1H, H-5), 7.25 (br, 1H, NH), 10.85 (br s, 1H, NH) .MS:M/e 307 (M+) .C
10H
14ClN
3O
2S
2The ultimate analysis calculated value: C 39.02; H 4.58; N 13.65; Measured value: C 38.98; H 4.72; N 13.40.
Embodiment 76-chloro-3-(1-methyl hexyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-methyl hexyl) thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid 1-methyl polyhexamethylene, obtain soup compound (productive rate 43%);
1H-NMR (DMSO-d
6): δ 0.85 (t, 3H, CH
3), 1.10 (d, 3H, CH
3), 1.25 (m, 6H), 1.45 (m, 2H), 4.25 (m, 1H, CH), 6.50 (br, 2H, NH
2), 6.65 (s, 1H, H-4), 7.93 (br, 1H, NH), 11.3 (br s, 1H, NH) .b) 6-chloro-3-(1-methyl hexyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound (productive rate 63%) from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-methyl hexyl) thiocarbamide; Mp 158-162 ℃,
1H-NMR (DMSO-d
6): δ 0.85 (t, 3H, CH
3), 1.15 (d, 3H, CH
3), 1.25 (m, 6H), 1.45 (m, 2H), 3.75 (m, 1H, CH), 7.05 (s, 1H, H-5), 7.15 (br s, 1H, NH), 10.75 (br s, 1H, NH) .MS:M/e 335 (M+).
Embodiment 86-chloro-3-(cyclopentyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-cyclopentyl thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound (productive rate 46%) from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid cyclopentyl ester;
1H-NMR (DMSO-d
6): δ 1.30-1.70 (m, 6H), 1.90 (m, 2H), 4.40 (sextet, 1H, CH), 6.55 (br, 2H, NH
2), 6.65 (s, 1H, H-4), 8.15 (br d, 1H, NH), 11.2 (br s, 1H, NH) .b) 6-chloro-3-(cyclopentyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound (productive rate 57%) from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-cyclopentyl thiocarbamide; Mp 291-292 ℃,
1H-NMR (DMSO-d
6): δ 1.40-1.70 (m, 6H, CH
3), 1.90 (m, 2H), 3.95 (sextet, 1H, CH), 7.05 (s, 1H, H-5), 7.3 (br, 1H, NH), 10.70 (br s, 1H, NH) .MS:M/e 305 (M+).
Embodiment 96-chloro-3-(cyclohexyl methyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-cyclohexyl methyl thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid cyclohexyl methyl ester, obtain soup compound (productive rate 8%);
1H-NMR (DMSO-d
6): δ 0.95 (m, 2H), 1.25 (m, 3H), 1.70 (m, 6H), 3.45 (d, 2H, CH
2), 4.45 (br, HDO+NH), 6.65 (s, 1H, H-4) .b) 6-chloro-3-(cyclohexyl methyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound (productive rate 68%) from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-cyclohexyl methyl thiocarbamide; M.p.＞200 ℃ decomposition;
1H-NMR (DMSO-d
6): δ 0.90 (m, 2H), 1.15 (m, 3H), 1.70 (m, 6H), 3.05 (t, 2H, CH
2), 7.05 (s, 1H, H-5), 7.25 (br, 1H, NH), 10.95 (br s, 1H, NH) .MS:M/e 333 (M+).
Embodiment 103-(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ 6,2 also, and 4-thiadiazine-3-base is amino) ethyl butyrate is 3-{3-[(3-amino-5-chlorothiophene-2-yl a)) alkylsulfonyl] thioureido } ethyl butyrate
With the described method of similar embodiment 3-a, begin to prepare title compound (productive rate 93%) from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 3-isothiocyano ethyl butyrate;
1H-NMR (DMSO-d
6): δ 1.18 (d, 3H, CH
3), 1.20 (t, 3H, CH
3), 2.61 (m, 2H, CH
2), 4.08 (q, 2H, CH
2), 4.58 (m, 1H, CH), 6.46 (br s, 2H, NH
2), 6.65 (s, 1H, H-4), 8.34 (br d, 1H, NH), 11.35 (br s, 1H) .b) 3-(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ 6,2 also, and 4-thiadiazine-3-base is amino) ethyl butyrate
With the described method of similar embodiment 3-b, from 3-{3-[(3-amino-5-chlorothiophene-2-yl) alkylsulfonyl] thioureido } ethyl butyrate begins to prepare title compound, and process column chromatography purifying (productive rate 71%); M.p.151-155 ℃ (ethyl acetate);
1H-NMR (DMSO-d
6): δ 1.18 (t, 3H, CH
3), 1.20 (d, 3H, CH
3), 2.57 (m, 2H, CH
2), 4.07 (q, 2H, CH
2), 4.17 (m, 1H, CH), 7.05 (s, 1H, H-5), 7.25 (br, 1H, NH), 10.99 (s, 1H, NH); MS:m/e 351/353 (M+) .C
11H
14N
3ClO
4S
20.2 the ultimate analysis of ethyl acetate; Calculated value: C 38.36; H 4.26; N 11.37; Measured value: C 38.35; H 4.18; N 11.58.
(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ also for embodiment 113-
6, 2,4-thiadiazine-3-base is amino) butyric acid
(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ also with 3-under the room temperature
6, 2,4-thiadiazine-3-base is amino) (0.5g 1.42mmol) stirred 2 hours in 5ml 2N sodium hydroxide ethyl butyrate, and it is hydrolyzed into acid.Solution is handled with decoloration active carbon, filter, and with the 4M hcl acidifying to pH2.Leach the gained precipitation, washing is also dry, obtains 294mg (64%) title compound; M.p.218-223 ℃,
1H-NMR (DMSO-d
6): δ 1.19 (d, 3H, CH
3), 2.49 (m, 2H, CH
2), 4.10 (m, 1H, CH), 7.06 (s, 1H, H-5), 7.25 (br, 1H, NH), 10.99 (s, 1H, NH), 12.38 (brs, 1H, OH); MS:m/e 305/307 (M-H
2O)
+C
9H
10N
3ClO
4S
2The ultimate analysis calculated value: C 33.39; H 3.11; N 12.98; Measured value: C 33.62; H 3.11; N 12.81.
Embodiment 126-chloro-3-(3-hydroxyl-1-methyl-propyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
Toluene (5ml) is cooled to 10 ℃, and (114mg is 3mmol) with the 0.53ml tetrahydrofuran (THF) successively to add lithium aluminum hydride then.(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ also with 3-
6, 2,4-thiadiazine-3-base is amino) (352mg 1mmol) is added in the gained cold soln ethyl butyrate, and mixture was stirred 2 hours at 0 ℃, then in stirred overnight at room temperature.Mixture is cooled off on ice bath, successively drip 10ml water and 5-10ml 20% sulfuric acid.(3 * 30ml) extract mixture, and organic phase washes with water, and drying also is evaporated to dried with ether.Crude product is mixed with the solid that forms at aqueous phase, and use silica gel chromatography, ethyl acetate/methanol (9: 1) wash-out obtains 120mg (39%) title compound; M.p.199-203 ℃;
1H-NMR (DMSO-d
6): δ 1.14 (d, 3H, CH
3), 1.65 (m, 2H, CH
2), 3.48 (m, 2H, CH
2), 3.90 (m, 1H, CH), 4.60 (br s, 1H, OH), 7.06 (s, 1H, H-5), 7.17 (br, 1H, NH), 10.86 (s, 1H, NH); MS:m/e 309/311 (M+); C
9H
12N
3ClO
3S
20.15 the ultimate analysis calculated value of ethyl acetate: C 35.70; H 4.12; N 13.01; Measured value: C 35.7; H 4.1; N 13.1.
Embodiment 13 (R)-6-chloro-3-(1-phenylethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide be (R)-N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-phenylethyl) thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound (productive rate 96%, not pure products) from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid D-α-Jia Jibianji ester;
1H-NMR (DMSO-d
6): δ 1.46 (d, 3H, CH
3), 5.36 (quint, 1H, CH), 6.45 (br s, 2H, NH
2), 6.64 (s, 1H, H-4), 7.2-7.4 (m, 5H, ArH), 8.53 (br d, 1H, NH), 11.3 (br s, 1H) .b) (R)-6-chloro-3-(1-phenylethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound from crude product (R)-N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(1-phenylethyl) thiocarbamide, and through silica gel chromatography, methylene chloride (19: 1) wash-out (productive rate 17%); M.p.218-220 ℃ (ethyl acetate);
1H-NMR (DMSO-d
6): δ 1.48 (d, 3H, CH
3), 4.97 (quint, 1H, CH), 7.10 (s, 1H, H-5), 7.2-7.4 (m, 5H, ArH), 7.73 (br, 1H, NH), 10.81 (s, 1H, NH); MS:m/e 341/343 (M+); C
13H
12N
3ClO
2S
2The ultimate analysis calculated value: C 45.68; H 3.54; N 12.29; Measured value: C 45.83; H 3.55; N 12.04.
Embodiment 14 (S)-3-sec-butyl amino-6-chloro-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
In the flask of a sealing with 3,6-two chloro-4H-thieno-s [3,2-e]-1,2,4-thiadiazine 1, the 1-dioxide (257mg, 1.0mmol) and (S)-(+)-(0.31ml, 10ml ethanol solution 3.0mmol) stirred 4 days at 80 ℃ sec-butylamine.With the refrigerative solution for vacuum concentration, residuum stirs with water (10ml), with 4M hydrochloric acid pH is transferred to 2 then.By make the gluey product crystallization of initial formation 0 ℃ of stirring.Leach precipitation, wash with water, and, spend the night 30 ℃ of vacuum-dryings then, obtain the pure title compound of 181mg (62%) from the ethyl acetate/methanol recrystallization; M.p.228-230 ℃ (ethyl acetate);
1H-NMR (DMSO-d
6): δ 0.88 (t, 3H, CH
3), 1.14 (d, 3H, CH
3), 1.49 (m, 2H, CH
2), 3.68 (m, 1H, CH), 7.08 (s, 1H, H-5), 7.13 (br, 1H, NH), 10.73 (br s, 1H, NH); MS:m/e 293/295 (M+); C
9H
12N
3ClO
2S
2The ultimate analysis calculated value: C 36.79 H 4.12; N 14.30; Measured value: C 36.9; H 4.1; N 14.2.
Embodiment 156-chloro-3-sec.-propyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide be N-[5-chloro-3-(iprotiazem is for formamyl) sulfamyl thiophene-2-yl a)] ethanamide
(135mg, (255mg, anhydrous N 1.0mmol) in dinethylformamide (5ml) solution, and stir in ice bath 1.2mmol) to be added to N-(5-chloro-3-sulfamyl thiophene-2-yl) ethanamide with potassium tert.-butoxide.(0.128ml 1.2mmol), and stirs 30min with solution at 0 ℃, then at stirring at room 3h to drip isopropyl isothiocyanate behind the 5min.In solution, add again potassium tert.-butoxide (135mg, 1.2mmol), and continuously stirring 1h at room temperature.＜50 ℃ of solvent evaporated, then residuum is dissolved in 10ml water, with 4M hydrochloric acid the aqueous solution is transferred to pH2.Leach precipitation, washing is also dry, obtains the crude product of 274mg (77%) title compound;
1H-NMR (DMSO-d
6): δ 1.12 (d, 6H, 2 * CH
3), 2.28 (s, 3H, COCH
3), 4.21 (m, 1H, NCH), 7.15 (s, 1H, H-4), 8.34 (br d, 1H, NH), 10.26 (s, 1H, NH) .b) 6-chloro-3-sec.-propyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide
With phosgene (0.416ml; 20% in toluene) be added drop-wise to N-[5-chloro-3-(iprotiazem is for formamyl) sulfamyl thiophene-2-yl] ethanamide (261mg; 0.73mmol) and anhydrous triethylamine (0.209ml, in anhydrous tetrahydro furan 1.5mmol) (5ml) solution, and 0 ℃ of stirring.1 hour after it be evaporated to dried 0 ℃ of stirring mixture.In 10ml water, grind residuum, leach precipitation and washing.At last, continued deacetylated in 90 minutes by at room temperature in 2ml 2N sodium hydroxide, stirring.With 4M hydrochloric acid solution is acidified to pH2, leaches precipitation, from re-crystallizing in ethyl acetate, obtain the pure title compound of 44mg (21%) with decoloration active carbon; M.p.272-274 ℃ (ethyl acetate);
1H-NMR (DMSO-d
6): δ 1.16 (d, 6H, 2 * CH
3), 3.85 (m, 1H, NCH), 7.23 (s, 1H, H-7), 7.48 (br d, 1H, NH), 11.12 (s, 1H, NH); MS:m/e 279/281 (M+).
Embodiment 166-chloro-3-cyclopentyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide be N-[5-chloro-3-(encircling penta thiocarbamoyl) sulfamyl thiophene-2-yl a)] ethanamide
With the described method of similar embodiment 15-a, begin to prepare title compound (productive rate of crude product is 93%) from N-(5-chloro-3-sulfamyl thiophene-2-yl) ethanamide and isothiocyanic acid cyclopentyl ester;
1H-NMR (DMSO-d
6): δ 1.3-2.0 (m, 8H, (CH
2)
4), 2.28 (s, 3H, CH
3), 4.32 (sext, 1H, CH), 7.16 (s, 1H, H-4), 8.48 (br d, 1H, NH), 10.23 (br s, 1H, NH) .b) 6-chloro-3-cyclopentyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 15-b, from crude product N-[5-chloro-3-(encircling penta thiocarbamoyl) sulfamyl thiophene-2-yl] ethanamide begins to prepare title compound (productive rate 32%); M.p.280-282 ℃ (aqueous ethanolic solution);
1H-NMR (DMSO-d
6): δ 1.4-2.0 (m, 8H, (CH
2) 4), 3.96 (sext, 1H, CH), 7.23 (s, 1H, H-7), 7.62 (br, 1H, NH), 11.09 (s, 1H, NH); MS:m/e 305/307 (M+).
Embodiment 176-bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
(0.12ml 2.3mmol) is added drop-wise to 6-chloro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1 with bromine, 2,4-thiadiazine 1,1-dioxide (280mg, 1.0mmol) the 10ml acetic acid solution in, and mixture stirred 24 hours at 100 ℃ in the flask of sealing.The refrigerative mixture is evaporated to dried, residuum grinds with water, obtains solid.It from ethanol/water (1: 1) recrystallization, is obtained the title compound that 118mg (39%) has 10% starting raw material; M.p. about 279 ℃ (aqueous ethanolic solutions);
1H-NMR (DMSO-d
6): δ 1.16 (d, 6H, 2 * CH
3), 3.86 (m, 1H, CH), 7.14 (s, 1H, H-5), 7.18 (br, 1H, NH), 10.74 (s, 1H, NH); MS:m/e 323/325 (M+).
Embodiment 183-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
(128mg 2.28mmol) is added to 6-chloro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1 with powdered potassium hydroxide, 2,4-thiadiazine 1,1-dioxide (319mg, 1.14mmol) the 25ml methanol solution in, and with mixture under room temperature and normal atmosphere with 150mg 10% palladium hydrocarbonize 3 days.Remove by filter catalyzer, with ethanol and water washing.The filtrate that merges is used the 4M hcl acidifying, is evaporated to dried then.Residuum is from water/ethyl alcohol recrystallization, at last with decoloration active carbon from re-crystallizing in ethyl acetate, obtain containing the title compound of starting raw material.Remove starting raw material through silica gel column chromatography;
1H-NMR (DMSO-d
6): δ 1.16 (d, 6H, 2 * CH
3), 3.88 (m, 1H, CH), 6.95 (d, 1H, H-5), 7.03 (br d, 1H, NH), 7.88 (d, 1H, H-6), 10.70 (br s, 1H).
Embodiment 193-sec.-propyl amino-7-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1, the 1-dioxide is the cyano group Toluidrin a)
Anhydrous THF (200ml) is saturated at-10 ℃ with ammonia, in-10 ℃ of stirrings, use the 20min time with cyano group methylsulfonyl chloride (13.9g then, according to people such as Sammes, " Chemical Society's magazine " (J.Chem.Soc.), 1971,2151-5155, described method preparation) 10ml anhydrous THF solution divides several small quantities of addings.After having added temperature is risen to 0 ℃, then filter reaction mixture.Remove the solvent in the filtrate, residuum is through silica gel chromatography, eluent ethyl acetate, and obtaining title compound is beige crystals; M.p.97-99 ℃; IR (KBr), v (cm
-1): 3316,3328 (N-H), 2266 (C ≡ N), 1371,1151 (SO
2) .b) 2-amino-4-methyl-thiophene-3-sulphonamide
Under the nitrogen with cyano group Toluidrin (1.0g), 2,5-dihydroxyl-2,5-dimethyl-1, absolute ethanol (7ml) mixture of 4-dithiane (0.75g) and triethylamine (100 μ l) 45-50 ℃ the heating 3h.Evaporation removes and desolvates, and residuum distributes between water (30ml) and ethyl acetate (50ml).Water is with 4 * 50ml ethyl acetate extraction.The ethyl acetate that merges is used dried over sodium sulfate mutually, then evaporation.Residuum is through silica gel chromatography, eluent ethyl acetate, and obtaining title compound is yellow solid (0.65g, productive rate 41%); M.p.142-144 ℃;
1H-NMR (CD
3OD), δ (ppm): 7.19 (s, 1H, C (5) H), 4.88 (br, 4H, SO
2NH
2+ H
2O), 4.71 (s, 2H, NH
2), 2.41 (s, 3H, CH
3); MS:192 (M
+), 112 (M
+-SO
2NH
2), 72 (CH
3-C
2HS
+).C) N-(2-amino-4-methyl-3-thienyl sulphonyl base)-N '-sec.-propyl thiocarbamide
With 2-amino-4-methyl-thiophene-3-sulphonamide (0.30g), anhydrous propanone (5ml) mixture of salt of wormwood (0.32g) and isothiocyanic acid isopropyl esters (272 μ l) is 50-55 ℃ of heated overnight under the nitrogen.Evaporation removes and desolvates, and residuum is dissolved in water (15ml).With 4M hydrochloric acid solution is transferred to pH2, and mixture is stirred 30min.Leach sedimentary crystal, use the less water rinsing, dry then, obtain 0.24g title compound (productive rate 54%); M.p.118-120 ℃.D) 3-sec.-propyl amino-7-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide
The toluene solution (715 μ l) of 20% phosgene is added in anhydrous THF (5ml) solution of stirring and N-(2-amino-4-methyl-3-thienyl sulphonyl base)-N '-sec.-propyl thiocarbamide (0.22g) that is cooling off and triethylamine (313 μ l), and maintains the temperature at below 5 ℃.Evaporating mixture behind the stirring 1.5h grinds with 10ml water then.Filter collecting precipitation, obtain the 0.14g crude product after the drying.With the gained crystal with the 5ml ethyl acetate 70 ℃ of heating.Mixture is cooled to filter behind 0 ℃ of 10min.With amount of ethyl acetate rinsing filter cake, obtaining 0.087g (productive rate 45%) title compound after the drying is the brown crystal; M.p.152-154 ℃;
1H-NMR (DMSO-d
6): δ (ppm): 7.10 (br d, 1H, NH), and 6.61 (s, 1H, N (4) H), 6.52 (s, 1H, C (6) H), 3.89 (m, 1H, CH), 2.32 (s, 3H, CH
3), 1.18 (d, 6H, CH
3).
Embodiment 206-chloro-3-cyclobutyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With 3,6-two chloro-4H-thieno-s [3,2-e]-1,2,4-thiadiazine 1, (257mg, cyclobutyl amine (1.0ml) solution 1.0mmol) stirs 18h in 90 ℃ to the 1-dioxide in the flask of sealing.To carry out vacuum concentration after the solution cooling, residuum 0 ℃ of stirring, transfers to 2 with 4M hydrochloric acid with pH with water (10ml) then.Leach product, wash with water, and from the methanol/ethyl acetate recrystallization, vacuum-drying at room temperature then obtains the pure title compound of 155mg (53%); M.p.315-317 ℃ of decomposition;
1H-NMR (DMSO-d
6): δ 1.58-1.75 (m, 2H), 1.89-2.05 (m, 2H), 2.19-2.30 (m, 2H), 4.16 (m, 1H), 7.06 (s, 1H), 7.62 (br s, 1H), 10.83 (br s, 1H); MS:m/e 291/293 (M
+); C
9H
10N
3ClO
2S
2The ultimate analysis calculated value: C 37.05; H 3.45; N 14.40; Measured value: C 37.18; H 3.48; N 14.19.
Embodiment 216-chloro-3-(2-hydroxyethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With 3,6-two chloro-4H-thieno-s [3,2-e]-1,2,4-thiadiazine 1, (206mg, thanomin 0.8mmol) (1.0ml) solution stirred 18 hours in 100 ℃ in the flask of sealing the 1-dioxide.To carry out vacuum concentration after the solution cooling, residuum 0 ℃ of stirring, transfers to 2 with 4M hydrochloric acid with pH with water (5ml) then.Leach product, wash with water, and, obtain the pure title compound of 135mg (60%) from the ethanol/water recrystallization; M.p.260-261 ℃ of decomposition;
1H-NMR (DMSO-d
6): δ 3.26 (q of distortion, 2H), 3.50 (t, 2H), 4.85 (br s, 1H), 7.07 (s, 1H), 7.20 (br s, 1H), 10.9 (br s, 1H); MS:m/e 281/283 (M
+);
C
7H
8N
3ClO
3S
2Ultimate analysis
Calculated value: C 29.84; H 2.86; N 14.91;
Measured value: C 30.13; H 2.84; N 14.79.
Embodiment 22 (±)-3-external form-dicyclo [2.2.1] heptan-2-base amino-6-chloro-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With 3,6-two chloro-4H-thieno-s [3,2-e]-1,2,4-thiadiazine 1, (206mg, amino norbornane (1.0ml) solution of table 0.8mmol)-2-stirred 20 hours in 100 ℃ in the flask of sealing the 1-dioxide.With mixture with water (10ml) 0 ℃ of stirring, with 4M hydrochloric acid pH is transferred to 2 then.Leach product, wash with water, and, obtain the pure title compound of 168mg (63%) from the ethyl acetate/methanol recrystallization; M.p.323-324 ℃ of decomposition;
1H-NMR (DMSO-d
6): δ 1.05-1.55 (m, 7H), 1.68-1.77 (m, 1H), 2.18-2.28 (m, 2H), 3.51 (m, 1H), 7.09 (s, 1H), 7.2 (br s, 1H), ca.10.5 (br s, 1H).; MS:m/e 331/333 (M
+); C
12H
14N
3ClO
2S
2The ultimate analysis calculated value: C 43.43; H 4.25; N 12.66; Measured value: C 43.67; H 4.26; N 12.55.
Embodiment 23 (R)-6-fluoro-3-(2-hydroxypropyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With 3,6-two chloro-4H-thieno-s [3,2-e]-1,2,4-thiadiazine 1, (200mg, (R)-(-) 0.78mmol)-1-amino-2-propyl alcohol (1.0ml) solution stirred 18 hours in 100 ℃ in the flask of sealing the 1-dioxide.Cooling solution, with its with water (3ml) 0 ℃ of stirring, with 4M hydrochloric acid pH is transferred to 2 then.Leach product, wash with water, and, obtain the pure title compound of 170mg (74%) in room temperature vacuum-drying; Mp 210-211 ℃,
1H-NMR (DMSO-d
6): δ 1.08 (d, 3H), 3.0-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.72-3.82 (m, 1H), 4.91 (br s, 1H), 7.09 (s, 1H), 7.14 (br s, 1H), 10.95 (br s, 1H).; MS:m/e 297/295 (M
+); C
8H
10N
3ClO
3S
20.5H
2The ultimate analysis calculated value of O: C 31.53; H 3.64; N 13.79; Measured value: C 31.57; H 3.58; N 13.58.
Embodiment 246-bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With bromine (1.26ml 25mmol) is added drop-wise to 6-chloro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1, (2.3g in 25ml acetic acid solution 8.2mmol), and stirs mixture 48 hours in 100 ℃ in sealed flask the 1-dioxide.The refrigerative mixture is evaporated to dried, residuum at this moment is made of two kinds of primary products.It is ground with water, obtain solid.With solid with decoloration active carbon from the ethyl acetate/methanol recrystallization, obtain 538mg (20%) title compound.Being prepared property HPLC on Source RPC 15 posts makes eluent with the acetonitrile/water (20: 80) that contains 0.1%TFA, obtains analytically pure sample; Mp282-283 ℃,
1H-NMR (DMSO-d
6): δ 1.16 (d, 6H), 3.86 (m, 1H), 7.14 (s, 1H), 7.18 (br, 1H), 10.74 (s, 1H); MS:m/e323/325 (M
+); C
8H
10N
3BrO
2S
2The ultimate analysis calculated value: C 29.64; H 3.11; N 12.96; Measured value: C 29.49; H 3.04; N 12.59.
Embodiment 255,6-two bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With above-mentioned 6-bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1, the mother liquid evaporation that the crystallization of 1-dioxide obtains is to doing, and residuum silica gel chromatography purifying is with methylene chloride (95: 5) wash-out.From re-crystallizing in ethyl acetate, obtain the pure title compound of 270mg (8%); Mp 250-251 ℃;
1H-NMR (DMSO-d
6): δ 1.18 (d, 6H), 3.86 (m, 1H), 7.18 (br, 1H), 10.31 (s, 1H); MS:m/e 405/403/401 (M
+); C
8H
9N
3Br
2O
2S
2The ultimate analysis calculated value: C 23.84; H 2.25; N 10.42; Measured value: C 24.14; H 2.18; N 10.25.
Embodiment 266-chloro-3-cyclohexyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(cyclohexyl) thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound (productive rate 78%) from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid cyclohexyl ester;
1H-NMR (DMSO-d
6): δ 1.1-1.9 (m, 10H), 4.0 (m, 1H), 6.45 (br s, 2H), 6.66 (s, 1H), 8.05 (br d, 1H), 11.2 (br s, 1H) .b) 6-chloro-3-cyclohexyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound (productive rate 66%) from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(cyclohexyl) thiocarbamide; M.p.282-284 ℃ (ethyl acetate/methanol);
1H-NMR (DMSO-d
6): δ 1.1-1.9 (m, 10H), 3.55 (m, 1H), 7.08 (s, 1H), 7.19 (br, 1H), 10.73 (br s, 1H); MS:m/e 321/319 (M
+); C
11H
14N
3ClO
2S
2The ultimate analysis calculated value: C 41.31; H 4.41; N 13.14; Measured value: C 41.66; H 4.45; N 12.99.
Embodiment 276-chloro-3-(furans-2-ylmethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide is N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(furans-2-ylmethyl) thiocarbamide a)
With the described method of similar embodiment 3-a, begin to prepare title compound (crude product productive rate 92%) from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isothiocyanic acid furyl ester.B) 6-chloro-3-(furans-2-ylmethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With the described method of similar embodiment 3-b, begin to prepare title compound from N-(3-amino-5-chloro-2-thienyl sulphonyl base)-N '-(furans-2-ylmethyl) thiocarbamide, through silica gel chromatography and methylene chloride (19: 1) wash-out (productive rate 11%); Mp 224-225 ℃;
1H-NMR (DMSO-d
6): δ 4.41 (d, 2H), 6.33 (m, 1H), 6.41 (m, 1H), 7.05 (s, 1H), 7.62 (br s, 1H), 7.75 (br t, 1H), 11.2 (br s, 1H); C
10H
8N
3ClO
3S
2The ultimate analysis calculated value: C 37.80; H 2.54; N 13.22; Measured value: C 37.87; H 2.51; N 13.10.
Embodiment 286-cyano group-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
At the amino 4H-thieno-of 6-bromo-3-sec.-propyl [3,2-e]-1,2,4-thiadiazine 1,1-dioxide (243mg, anhydrous N 0.75mmol), (135mg 1.5mmol), and stirs mixture 2 hours in 150 ℃ under nitrogen to add cupric cyanide (I) in dinethylformamide (2ml) solution.Treat that the gained dark mixture slowly adds water behind the cool to room temperature.Add 1N sodium hydroxide and make gained suspension be alkalescence, filter, use 4M hydrochloric acid the filtrate acidifying.Being prepared property HPLC on Source RPC 15 posts makes eluent with the acetonitrile/water (20: 80) that contains 0.1%TFA, with the gained deposition and purification; LC-MS:m/e 271 (M+1)
+
Embodiment 296-bromo-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
With bromine (0.12ml 2.3mmol) is added drop-wise to 6-chloro-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1, (305mg in 10ml acetic acid solution 1.0mmol), and stirs 21hs in 100 ℃ with mixture to the 1-dioxide in sealed flask.The refrigerative mixture is evaporated to dried, residuum grinds with water, obtains solid.Solid from ethyl acetate and ethyl alcohol recrystallization, is obtained containing the title compound (166mg, 47%) of 33% raw material.Through preparation property HPLC purifying, obtain containing the title compound of 3% raw material; M.p.287-294 ℃ of decomposition;
1H-NMR (DMSO-d
6): δ 10.7 (s, 1H, NH); 7.35 (br s, 1H, NH); 7.13 (s, 1H, H-7); 4.00 (sextet, 1H); 1.9 (m, 2H); 1.7 to 1.4ppm (m, 6H).
Embodiment 306-chloro-3-(2-methacrylic) amino-4H-thieno-[3,2-el-1,2,4-thiadiazine 1,1-dioxide
With 3,6-two chloro-4H-thieno-s [3,2-e]-1,2,4-thiadiazine 1, (128mg, methylene propyl group amine (0.5ml) solution 0.5mmol) stirred 48 hours in 90 ℃ in sealed flask the 1-dioxide.With chilled solution for vacuum concentration, residuum stirs with water (3ml), adds 4M hydrochloric acid then pH is transferred to 2.Leach product, obtain the pure title compound of 92mg (64%) after the washing; M.p.224-226 ℃ of decomposition;
1H-NMR (DMSO-d
6): δ 1.72 (s, 3H), 3.75 (d, 2H), 4.83 (s, 2H), 7.05 (s, 1H), 7.45 (br s, 1H), 11.0 (br s, 1H).
Claims (37)
1. general formula (I) compound, or the salt that forms with pharmaceutically acceptable acid or alkali, or the mixture of its all optically active isomers or optically active isomer comprise racemic mixture, or its all tautomeric forms,
Wherein, B representative＞NR
5Or＞CR
5R
6, R wherein
5And R
6Each is hydrogen naturally; Hydroxyl; C
1-
6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl; Or R
5And R
4Represent a key in two keys between the atom 2 and 3 of formula (I) together; D representative-S (=O)
2-or-S (=O)-; Or D-B representative-S (=O) (R
7)=N-, wherein, R
7Be C
1-6Alkyl; Or optional by halogen, hydroxyl, C
1-6Alkoxyl group, aryloxy, alkoxy aryl, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group, acyl group or C
1-6Carbalkoxy list or polysubstituted aryl or heteroaryl; R
1Be hydrogen; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6 alkynyls, and R
4Be hydrogen; Or R
4And R
5Represent a key in two keys between formula (I) atom 2 and 3 together; Or R
1And R
4Represent a key in two keys between the atom 3 and 4 of formula (I) together; R
2Be hydrogen; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl; R
3Be R
8-OR
8-C (=X) R
8-NR
8R
9Optional by halogen, hydroxyl, C
1-6Alkoxyl group, aryloxy, alkoxy aryl, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group, oxygen base, acyl group or C
1-6Carbalkoxy list or polysubstituted bicyclic alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Or by C
1-6The aryl that alkyl replaces;
R wherein
8Be hydrogen; C
3-6Cycloalkyl or (C
3-6Cycloalkyl) C
1-6Alkyl, wherein C
3-6
Cycloalkyl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; Contain
One or more nitrogen-atoms, 3-6 person's saturated rings of Sauerstoffatom or sulphur atom; Or optional by halogen,
Hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, aryl, aryloxy, aryl alkane
The oxygen base, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group, oxygen base, formyl
Base, acyl group, carboxyl, C
1-6Carbalkoxy or formamyl list or polysubstituted straight or branched
C
1-18Alkyl;
X is O or S;
R
9Be hydrogen; C
1-6Alkyl; C
2-6Alkenyl; Optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6
Alkoxyl group list or polysubstituted C
3-6Cycloalkyl; Or R
8And R
9Form 3-12 person's list or bicyclic ring system with nitrogen-atoms, wherein, one or more carbon atoms can be by nitrogen-atoms, and Sauerstoffatom or sulphur atom are replaced, and each ring system is optional by halogen, C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, nitro, amino, cyano group, trifluoromethyl, C
1-6-one alkyl-or dialkyl amido, oxygen base list or polysubstituted; Or R
3Be
Wherein, n, m, p each naturally 0,1,2,3; R
10Be hydrogen; Hydroxyl; C
1-6Alkoxyl group;
Optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted C
3-6Cycloalkyl;
Optional by halogen list or polysubstituted C
1-6Alkyl, C
2-6Alkenyl or C
26Alkynyl; Or R
2And R
3Form 3-12 person's list or bicyclic ring system with nitrogen-atoms, wherein one or more carbon atoms can be by nitrogen-atoms, and Sauerstoffatom or sulphur atom are replaced, and each ring system is optional by halogen, C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, nitro, amino, cyano group, trifluoromethyl, C
1-6-one alkyl-or dialkyl amido, oxygen base list or polysubstituted; A contains one or more nitrogen-atoms with carbon atom 5 in the formula (I) and 6 representatives, 5 or 6 element heterocycle systems of Sauerstoffatom or sulphur atom, and this heterocyclic system is optional single or polysubstituted by following groups: halogen; C
1-12Alkyl; C
3-6Cycloalkyl; Hydroxyl; C
1-6Alkoxyl group; C
1-6Alkoxy C
1-6Alkyl; Nitro; Amino; Cyano group; Cyano methyl; The perhalogeno methyl; C
1-6-one alkyl-or dialkyl amido; Sulfamyl; C
1-6Alkylthio; C
1-6Alkyl sulphonyl; C
1-6Alkyl sulphinyl; C
1-6Alkyl-carbonyl-amino; Arylthio, aryl sulfonyl kia, aryl sulfonyl, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; C
1-6The alcoxyl carbon back; C
1-6Carbalkoxy C
1-6Alkyl; Formamyl; The carbamyl ylmethyl; C
1-6-one alkyl-or dialkyl amino carbonyl amino; Thioureido; C
1-6-one alkyl-or dialkyl amido thiocarbonyl-amino; C
1-6-one alkyl-or dialkyl amino sulfonyl; Carboxyl; Carboxyl C
1-6Alkyl; Acyl group; Aryl, aralkyl, aryloxy, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; (1,2,4-oxadiazole-5-yl)-or (1,2,4-oxadiazole-3-yl)-C
1-6Alkyl, Qi Zhong oxadiazole base is optional by C
1-6Alkyl or C
3-6Cycloalkyl substituted; Or 5 or 6 Yuans contain azo-cycle, optional by phenyl or C
1-6Alkyl replaces;
Condition is: the carbon atom 5 and 6 of A and formula (I) does not form pyridine ring, and, do not comprise also [4,5-e]-1 of compound 3-aminooimidazole, 2,4-thiadiazine 1,1-dioxide and 3-(benzamido) imidazo [4,5-e]-1,2,4-thiadiazine 1,1-dioxide.
2. according to the compound of claim 1, R wherein
2Be hydrogen or C
1-6Alkyl.
3. according to the compound of claim 1 or 2, R wherein
3Be R
8-OR
8-NR
8R
9Or aryl, and aryl is optional by C
1-6Alkyl replaces;
Wherein, R
8Be hydrogen; C
3-6Cycloalkyl; (C
3-6Cycloalkyl) C
1-6Alkyl; Contain one,
3-6 person's saturated rings of two or three nitrogen-atoms, Sauerstoffatom or sulphur atoms; Or optional by halogen,
Hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6The straight chain that cycloalkyl or aryl replace or
Side chain C
1-18Alkyl;
R
9Be hydrogen; C
1-6Alkyl or C
3-6Cycloalkyl; Or
R
8And R
9Form 4-6 person's ring with nitrogen-atoms.
4. according to the compound of above-mentioned arbitrary claim, R wherein
3Be secondary C
3-6Alkyl, uncle C
4-6Alkyl, C
3-6Cycloalkyl or (C
3-6Cycloalkyl) methyl.
5. according to the compound of above-mentioned arbitrary claim, wherein the carbon atom 5 and 6 of A in formula (I) forms 5 element heterocycle systems that contain a nitrogen-atoms or sulphur atom, optional single or two replacements by following groups of this heterocyclic system: halogen; C
1-12Alkyl; C
3-6Cycloalkyl; Cyano group; Cyano methyl; The perhalogeno methyl; Sulfamyl; C
1-6Alkylthio; C
1-6Alkyl sulphonyl; C
1-6Alkyl sulphinyl; Arylthio, aryl sulfonyl kia, aryl sulfonyl, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; C
1-6Carbalkoxy C
1-6Alkyl; The carbamyl ylmethyl; Carboxyl C
1-6Alkyl; Aryloxy; (1,2,4-oxadiazole-5-yl)-or (1,2,4-oxadiazole-3-yl) C
1-6Alkyl, Qi Zhong oxadiazole base is optional by C
1-6Alkyl or C
3-6Cycloalkyl substituted; Acyl group; Or 5-6 person contains azo-cycle, and is optional by phenyl or C
1-6Alkyl replaces.
6. according to the compound of above-mentioned arbitrary claim, wherein the carbon atom 5 and 6 of A in formula (I) forms one and contains two heteroatomic 5 element heterocycle systems that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and this heterocyclic system is optional to be replaced by following groups: halogen; C
1-12Alkyl; C
3-6Cycloalkyl; Cyano group; Cyano methyl; The perhalogeno methyl; Sulfamyl; C
1-6Alkyl sulphonyl; C
1-6Alkyl sulphinyl; Arylthio, aryl sulfonyl kia, aryl sulfonyl, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; C
1-6Carbalkoxy C
1-6Alkyl; The carbamyl ylmethyl; Carboxyl C
1-6Alkyl; Aryloxy; (1,2,4-oxadiazole-5-yl)-or (1,2,4-oxadiazole-3-yl) C
1-6Alkyl, Qi Zhong oxadiazole base is optional by C
1-6Alkyl or C
3-6Cycloalkyl substituted; Acyl group; Or 5-6 person contains azo-cycle, and is optional by phenyl or C
1-6Alkyl replaces.
7. according to the compound of above-mentioned arbitrary claim, wherein the carbon atom 5 and 6 of A in formula (I) forms 6 Yuans aromatic heterocycle systems that contain two or three nitrogen-atoms, and this heterocyclic system is optional to be replaced by following groups: halogen; C
1-12Alkyl; C
3-6Cycloalkyl; Cyano group; Cyano methyl; The perhalogeno methyl; Sulfamyl; C
1-6Alkylthio; C
1-6Alkyl sulphonyl; C
1-6Alkyl sulphinyl; Arylthio, aryl sulfonyl kia, aryl sulfonyl, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; C
1-6Carbalkoxy C
1-6Alkyl; The carbamyl ylmethyl; Carboxyl C
1-6Alkyl; Aryloxy; (1,2,4-oxadiazole-5-yl)-or (1,2,4-oxadiazole-3-yl) C
1-6Alkyl, Qi Zhong oxadiazole base is optional by C
1-6Alkyl or C
3-6Cycloalkyl substituted; Acyl group; Or 5-6 person contains azo-cycle, and is optional by phenyl or C
1-6Alkyl replaces.
8. according to the compound of above-mentioned arbitrary claim, wherein the carbon atom 5 and 6 of A in formula (I) forms one and contains one or two heteroatomic 6 Yuans nonaromatic heterocycles system that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and this heterocyclic system is optional to be replaced by following groups: halogen; C
1-12Alkyl; C
3-6Cycloalkyl; Cyano group; Cyano methyl; The perhalogeno methyl; Sulfamyl; C
1-6Alkylthio; C
1-6Alkyl sulphonyl; C
1-6Alkyl sulphinyl; Arylthio, aryl sulfonyl kia, aryl sulfonyl, wherein aryl is optional by C
1-6Alkyl, halogen, hydroxyl or C
1-6Alkoxyl group list or polysubstituted; C
1-6Carbalkoxy-C
1-6Alkyl; The carbamyl ylmethyl; Carboxyl C
1-6Alkyl; Aryloxy; (1,2,4-oxadiazole-5-yl)-or (1,2,4-oxadiazole-3-yl) C
1-6Alkyl, Qi Zhong oxadiazole base is optional by C
1-6Alkyl or C
3-6Cycloalkyl substituted; Acyl group; Or 5-6 person contains azo-cycle, and is optional by phenyl or C
1-6Alkyl replaces.
9. according to the compound of one of claim 1-8, wherein, general formula (I) is compound (Ia),
R wherein
1And R
5Be respectively hydrogen; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl, and R
4Be hydrogen; Or R
4And R
5Represent a key in two keys between the atom 2 and 3 of formula (I) together, and R
1Definition as above; Or R
4And R
1Represent a key in two keys between the atom 3 and 4 of formula (I) together, and R
5Definition as above; D representative-S (=O)
2-or-S (=O)-; And A, R
2And R
3Definition as above.
10. according to the compound of claim 9, R wherein
1And R
5Each is hydrogen or C naturally
1-6Alkyl.
11. according to the compound of claim 9 or 10, wherein R
1And R
4Represent a key in two keys between the atom 3 and 4 of formula (I) together.
12. according to the compound of one of claim 9-11, wherein R
4And R
5Represent a key in two keys between the atom 2 and 3 of formula (I) together.
13. according to the compound of one of claim 9-12, wherein D be-S (=O)
2-.
14. according to the compound of one of claim 1-8, its formula of (I) is compound (Ib),
R wherein
1Be hydrogen; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl, and R
4Be hydrogen; Or R
4And R
1Represent a key in two keys between the atom 3 and 4 of formula (I) together; D representative-S (=O) R
7=, wherein, R
7Be C
1-6Alkyl; Or optional by halogen, hydroxyl, C
1-6Alkoxyl group, aryloxy, alkoxy aryl, nitro, amino, C
1-6-one alkyl-or dialkyl amido, cyano group, acyl group or C
1-6Carbalkoxy list or polysubstituted aryl or heteroaryl; A, R
2And R
3Definition as above.
15. according to the compound of claim 14, wherein R
1Be hydrogen or C
1-6Alkyl.
16. according to the compound of claim 14 or 15, wherein R
1And R
4Represent together formula (I) atom 3 and 4 between a key in two keys.
17. according to the compound of one of claim 14-16, wherein R
7Be C
1-6Alkyl, phenyl or pyridyl.
18. according to the compound of one of claim 1-8, its formula of (I) is compound (Ic),
R wherein
1, R
5And R
6Each is hydrogen naturally; Hydroxyl; C
1-6Alkoxyl group; Or it is optional by halogen list or polysubstituted C
1-6Alkyl, C
3-6Cycloalkyl, C
2-6Alkenyl or C
2-6Alkynyl, and R
4Be hydrogen; Or R
4And R
5Represent a key in two keys between the atom 2 and 3 of formula (I) together, and R
1And R
6Definition as above; Or R
4And R
1Represent a key in two keys between the atom 3 and 4 of formula (I) together, and R
5And R
6Definition as above; D representative-S (=O)
2-or-S (=O)-; And A, R
2And R
3Definition as above.
19. according to the compound of claim 18, wherein R
1, R
5And R
6Each is hydrogen or C naturally
1-6Alkyl.
20. according to the compound of claim 18 or 19, wherein R
1And R
4Represent together formula (I) atom 3 and 4 between a key in two keys.
21. according to the compound of one of claim 18-20, wherein R
4And R
5Represent a key in two keys between the atom 2 and 3 of formula (I) together.
22. according to the compound of one of claim 18-21, wherein D be-S (=O)
2-.
23. following compounds: 7-cyano group-3-sec.-propyl amino-6-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 7-cyano group-6-methyl-3-propyl group amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-isopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(1-methylheptyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(1-ethyl heptyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(2-methyl butyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(1-methyl hexyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-cyclohexyl methyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 3-(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ 6,2 also, and 4-thiadiazine-3-base is amino) ethyl butyrate; 3-(6-chloro-1,4-dihydro-1,1-dioxy thiophene be [3,2-e]-1 λ 6,2 also, 4-thiadiazine 1,1-dioxide-3-base is amino) butyric acid; 6-chloro-3-(3-hydroxyl-1-methyl-propyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; (R)-and 6-chloro-3-(1-phenylethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; (S)-and 3-sec-butyl amino-6-chloro-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-sec.-propyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-cyclopentyl amino-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 6-bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-fluoro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 3-cyclobutyl amino-5,6-dimethyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 3-cyclopentyl amino-5,6-dimethyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 3-sec.-propyl amino-6,7-dimethyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 3-cyclobutyl amino-6,7-dimethyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 3-cyclopentyl amino-6,7-dimethyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 5-chloro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 5-chloro-3-propyl group amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 5-chloro-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 5-chloro-6-methyl-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-sec.-propyl amino-5-methyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-cyclopentyl amino-5-methyl-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-fluoro-3-propyl group amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-fluoro-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 5-fluoro-3-propyl group amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 5-fluoro-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 3-sec.-propyl amino-7-methyl-4H-thieno-[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-cyclobutyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(2-hydroxyethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; (±)-3-table-dicyclo [2.2.1] heptan-2-base amino-6-chloro-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; (R)-and 6-fluoro-3-(2-hydroxypropyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 5,6-two bromo-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-cyclohexyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(furans-2-ylmethyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(1-ethyl propyl) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-bromo-3-cyclopentyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3-(2-methacrylic) amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide, or 6-cyano group-3-sec.-propyl amino-4H-thieno-[3,2-e]-1,2,4-thiadiazine 1,1-dioxide.
24. the compound according to above-mentioned arbitrary claim is used as K
ATPThe unlatching thing of the potassium channel of-adjusting.
25. the method for preparation formula (I) compound is characterized in that a) with formula (II) compound
Wherein, A, B, D, R
1And R
4Define as above, Z is a leavings group, as alkoxyl group, and alkylthio, halogen, preferred chlorine, bromine or iodine, three methylamino-s or methyl sulphonyl, with the reaction of formula (III) compound,
Wherein, R
2And R
3Definition as above forms general formula (I) compound; B) with formula (IV) compound
Wherein, R
1Be hydrogen, A, B, D and X define as above, and perhaps, B is NH, R
1, A, D and X define as above, with formula (III) compound or its suitable salt, at P
2O
5There is reaction down with high boiling point tertiary amine or its suitable salt, forms general formula (I) compound; C) with formula (IV) compound
Wherein, R
1Be hydrogen, A, B, D and X define as above, and perhaps, B is NH, R
1, A, as above with formula (III) compound or its suitable salt, at titanium tetrachloride with can form the solvent of mixture with it, there is reaction down in D and X definition, formation general formula (I) compound as the mixture of tetrahydrofuran (THF) or toluene and phenylmethylether; D) with the formula V compound
Wherein, R
1Define as above with A, with the reaction of formula (VI) compound,
R
3NCO (VI) wherein, R
3Define as above, forming D is SO
2, B is＞NR
5, R
2Be H, and R
4And R
5Form general formula (I) compound of a key together; E) with the formula V compound
Wherein, R
1Define as above with A, with the reaction of formula (VII) compound,
R
3NHC (=O) Cl (VII) wherein, R
3Define as above, forming D is SO
2, B is＞NR
5, R
2Be H, and R
4And R
5Form general formula (I) compound of a key together; F) with the formula V compound
Wherein, R
1Define as above with A, with formula (VIII) compound or its suitable reactant salt,
Wherein, Y is NH or S, and forming D is SO
2, B is＞NR
5, R
4And R
5Form a key together, and R
2And R
3It is general formula (I) compound of H; G) in the presence of alkali with formula (IX) compound or its suitable salt
Wherein, R
11Be R
1Or EtOC (=O), and R
1Define as above with A, with the reaction of formula (X) compound,
R
3N=C=S (X) wherein, R
3The definition as above, generate a kind of adducts, it both can be structure XI and XII the two one of, also can be the mixture of the two,
Perhaps in appropriate solvent, form closed loop, if R with the light gas disposal
11Be R
1, then form D and be-S (=O)
2-, B is＞NR
5, R
2Be H, and R
4And R
5Form general formula (I) compound of a key together; If R
11Be EtOC (=O), then form general formula (XIII) compound;
H) with general formula (XIII) compound hydrolysis, decarboxylationization then, such as in buck, heating initial compounds,
Form D and be-S (=O)
2-, B is＞NR
5, R
1And R
2Be H, and R
4And R
5Form general formula (I) compound of a key together.
26. pharmaceutical composition, contain the pharmacologically acceptable salt that the compound of one of with good grounds claim 1-24 or itself and pharmaceutically acceptable acid or alkali form, or the mixture of its optically active isomer or optically active isomer, comprise racemic mixture, or its tautomeric form, and one or more pharmaceutically acceptable carrier or thinner.
27. be used for the treatment of the pharmaceutical composition of endocrine system disease such as hyperinsulinemia and diabetes, contain the pharmacologically acceptable salt that the compound of one of with good grounds claim 1-24 or itself and pharmaceutically acceptable acid or alkali form, or the mixture of its optically active isomer or optically active isomer, comprise racemic mixture, or its tautomeric form, and one or more pharmaceutically acceptable carrier or thinner.
28., be oral dosage units or parenteral dosage unit form according to the pharmaceutical composition of claim 26 or 27.
29. according to the pharmaceutical composition of claim 26 or 27, wherein said compound is the dosage range administration with 0.05-1000mg every day, preferably about 0.1-500mg/ days, and more preferably from about 50-200mg/ days.
30. the pharmacologically acceptable salt that forms according to the compound of the treatment usefulness of one of claim 1-24 or itself and pharmaceutically acceptable acid or alkali, or the mixture of its optically active isomer or optically active isomer comprise racemic mixture, or its tautomeric form.
31. the pharmacologically acceptable salt of the compound of using for treatment or prevention endocrine system disease such as hyperinsulinemia and diabetes according to one of claim 1-24 or itself and pharmaceutically acceptable acid or alkali formation, or the mixture of its optically active isomer or optically active isomer, comprise racemic mixture, or its tautomeric form.
32. the pharmacologically acceptable salt that forms according to the compound of one of claim 1-24 or itself and pharmaceutically acceptable acid or alkali, or the mixture of its optically active isomer or optically active isomer comprise racemic mixture, or its tautomeric form are used as the purposes of medicine.
33. the purposes of compound in the preparation medicine according to one of claim 1-24.
34. the pharmacologically acceptable salt that forms according to the compound of one of claim 1-24 or itself and pharmaceutically acceptable acid or alkali, or the mixture of its optically active isomer or optically active isomer, comprise racemic mixture, or its tautomeric form is at preparation treatment or prevention endocrine system disease, as the purposes in hyperinsulinemia and the diabetes medicament.
35. the method for treatment or prevention endocrine system disease such as hyperinsulinemia and diabetes comprises to needing the patient to use the compound according to one of claim 1-24 of significant quantity.
36. method for preparing medicine, this medicine is especially for treatment or prevent endocrine system disease as hyperinsulinemia and diabetes, and this method comprises covers the human relations formulation with making according to formula (I) compound or pharmaceutically acceptable salt thereof of one of claim 1-24.
37. the combination of all new features as herein described or these features.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0872/1997 | 1997-07-16 | ||
| DK87297 | 1997-07-16 | ||
| DK0368/1998 | 1998-03-17 | ||
| DK36898 | 1998-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1264384A true CN1264384A (en) | 2000-08-23 |
Family
ID=26063863
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98807264A Pending CN1264384A (en) | 1997-07-16 | 1998-06-30 | Fused 1,2,4-thiadiazine derivatives, their preparation method and use |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1000066A1 (en) |
| JP (1) | JP2001510195A (en) |
| KR (1) | KR20010021936A (en) |
| CN (1) | CN1264384A (en) |
| AU (1) | AU757693B2 (en) |
| BR (1) | BR9810592A (en) |
| CA (1) | CA2294830A1 (en) |
| HU (1) | HUP0003999A3 (en) |
| IL (1) | IL133604A0 (en) |
| NO (1) | NO315470B1 (en) |
| PL (1) | PL338013A1 (en) |
| RU (1) | RU2215004C2 (en) |
| WO (1) | WO1999003861A1 (en) |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1368948A (en) * | 1970-11-11 | 1974-10-02 | Manuf Prod Pharma | Pyridine derivatives |
| FR2703051B1 (en) * | 1993-03-26 | 1995-04-28 | Adir | New pyridothiadiazines, processes for their preparation, and pharmaceutical compositions containing them. |
| EP0876379A1 (en) * | 1996-01-17 | 1998-11-11 | Novo Nordisk A/S | Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use |
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1998
- 1998-06-30 KR KR1020007000501A patent/KR20010021936A/en not_active Application Discontinuation
- 1998-06-30 PL PL98338013A patent/PL338013A1/en unknown
- 1998-06-30 EP EP98930653A patent/EP1000066A1/en not_active Withdrawn
- 1998-06-30 RU RU2000103491/04A patent/RU2215004C2/en not_active IP Right Cessation
- 1998-06-30 HU HU0003999A patent/HUP0003999A3/en unknown
- 1998-06-30 JP JP2000503085A patent/JP2001510195A/en active Pending
- 1998-06-30 AU AU81018/98A patent/AU757693B2/en not_active Ceased
- 1998-06-30 WO PCT/DK1998/000288 patent/WO1999003861A1/en not_active Application Discontinuation
- 1998-06-30 BR BR9810592-2A patent/BR9810592A/en not_active IP Right Cessation
- 1998-06-30 CN CN98807264A patent/CN1264384A/en active Pending
- 1998-06-30 IL IL13360498A patent/IL133604A0/en unknown
- 1998-06-30 CA CA002294830A patent/CA2294830A1/en not_active Abandoned
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2000
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| NO20000185L (en) | 2000-01-14 |
| IL133604A0 (en) | 2001-04-30 |
| AU8101898A (en) | 1999-02-10 |
| BR9810592A (en) | 2000-09-12 |
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| AU757693B2 (en) | 2003-03-06 |
| KR20010021936A (en) | 2001-03-15 |
| NO20000185D0 (en) | 2000-01-14 |
| NO315470B1 (en) | 2003-09-08 |
| WO1999003861A1 (en) | 1999-01-28 |
| EP1000066A1 (en) | 2000-05-17 |
| HUP0003999A3 (en) | 2003-03-28 |
| HUP0003999A2 (en) | 2001-08-28 |
| CA2294830A1 (en) | 1999-01-28 |
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