WO1999003861A1 - Derives de 1,2,4-thiadiazine fusionnee, leur preparation et utilisation - Google Patents

Derives de 1,2,4-thiadiazine fusionnee, leur preparation et utilisation Download PDF

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Publication number
WO1999003861A1
WO1999003861A1 PCT/DK1998/000288 DK9800288W WO9903861A1 WO 1999003861 A1 WO1999003861 A1 WO 1999003861A1 DK 9800288 W DK9800288 W DK 9800288W WO 9903861 A1 WO9903861 A1 WO 9903861A1
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alkyl
thiadiazine
dioxide
thieno
formula
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PCT/DK1998/000288
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English (en)
Inventor
Flemming Elmedlund Nielsen
John Bondo Hansen
Holger Claus Hansen
Tina Møller TAGMOSE
John Patrick Mogensen
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Novo Nordisk A/S
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Priority to EP98930653A priority Critical patent/EP1000066A1/fr
Priority to AU81018/98A priority patent/AU757693B2/en
Priority to IL13360498A priority patent/IL133604A0/xx
Priority to KR1020007000501A priority patent/KR20010021936A/ko
Priority to HU0003999A priority patent/HUP0003999A3/hu
Priority to CA002294830A priority patent/CA2294830A1/fr
Priority to JP2000503085A priority patent/JP2001510195A/ja
Priority to BR9810592-2A priority patent/BR9810592A/pt
Publication of WO1999003861A1 publication Critical patent/WO1999003861A1/fr
Priority to NO20000185A priority patent/NO315470B1/no

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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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to fused 1 ,2,4-thiadiazine derivatives, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy e.g. in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
  • Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential.
  • the K ATP -channels have been found in cells from various tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, central neurons and adenohypophysis cells.
  • the channels have been associated with diverse cellular functions for example hormone secretion (insulin from pancreatic beta- cells, growth hormone and prolactin from adenohypophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration, neurotransmitter release in the central nervous system.
  • Modulators of the K ATP -channels have been found to be of importance for the treatment of various diseases.
  • Certain sulphonylureas which have been used for the treatment of non- insulin-dependent diabetes mellitus act by stimulating insulin release through an inhibition of the K ATP -channels on pancreatic beta-cells.
  • potassium channel openers which comprise a heterogeneous group of compounds, have been found to be able to relax vascular smooth muscles and have therefore been used for the treatment of hypertension.
  • potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.
  • potassium channel openers have been shown to promote hairgrowth, and have been used for the treatment of baldness.
  • Potassium channel openers are also able to relax urinary bladder smooth muscle and therefore, can be used for the treatment of urinary incontinence. Potassium channel openers which relax smooth muscle of the uterus can be used for treatment of premature labor. By acting on potassium channels of the central nervous system these compounds can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsia and cerebral ischemia.
  • the compounds are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and in contraception.
  • Compounds of the present invention which inhibit insulin secretion by activating potassium channels of the beta-cell can be used in combination with other compounds which may be used to treat non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.
  • examples of such compounds are insulin, insulin sensitizers, such as thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide, glibenclamide and glucagon like peptide ( GLP1), inhibitors of ⁇ -glucosidases and hepatic enzymes responsible for the biosynthesis of glucose.
  • Diazoxide (7-chioro-3-methyl-2H-1 ,2,4-benzothiadiazine 1,1 -dioxide) and certain 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1 ,1-dioxide derivatives inhibit insulin release by an activation of K ATP -channels on pancreatic beta-cells (Pirotte B. et al. Biochem. Pharmacol, 4Z, 1381-1386 (1994); Pirotte B. et al., J. Med. Chem., 3 ⁇ , 3211-3213 (1993).
  • Diazoxide has furthermore been shown to delay the onset of diabetes in BB-rats ( Vlahos WD et al. Metabolism 40, 39-46 (1991)). In obese zucker rats diazoxide has been shown to decrease insulin secretion and increase insulin receptor binding and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R. et al. Endocrinol. 122, 705-712, 1993). It is expected that compounds which activate K ATP -channels can be used for treatment of diseases characterised by an overproduction of insulin and for the treatment and prevention of diabetes.
  • EP 618 209 discloses a class of pyridothiadiazine derivatives having an alkyl or an alkylamino group in position 3 of the thiadiazine ring. These compounds are claimed to be agonists at the AMPA-glutamate receptor.
  • the present invention relates to fused 1 ,2,4-thiadiazine and fused 1 ,4-thiazine derivatives of the general formula I:
  • B represents >NR 5 or >CR 5 R 6 , wherein R 5 and R 6 independently are hydrogen; hydroxy;
  • R 5 and R 4 together represent one of the bonds in a double bond between the atoms 2 and 3 of formula I;
  • R 7 is C 1-6 -alkyi; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, C 1-6 -alkoxy, aryloxy, arylalkoxy, nitro, amino, C 1-6 -monoalkyl- or dialkylamino, cyano, acyl, or C 1-6 -alkoxycarbonyl;
  • R 1 is hydrogen; hydroxy; C 1-6 -alkoxy; or C ⁇ -alkyl, C ⁇ -cycloalkyl, C 2 . 6 - alkenyl or C 2-6 - alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; or R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I; or R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I;
  • R 2 is hydrogen; hydroxy; C 1-6 -alkoxy; or C 1-6 -alkyl, C ⁇ -cycloalkyl, C 2 . 6 - alkenyl or C 2 . 6 - alkynyl optionally mono- or polysubstituted with halogen;
  • R 8 is hydrogen; Ca. 6 -cycloalkyl or (C ⁇ -cycloalky C ⁇ -alkyl, the C ⁇ -cycloalkyl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 - alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms; or straight or branched C 1-18 -alkyl optionally mono- or polysubstituted with halogen, hydroxy, C ⁇ -alkoxy, C L e-alkylthio, C ⁇ -cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, C ⁇ - monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C 1-6 -alkoxy- carbonyl, or carbamoyl; X is O or S;
  • R 9 is hydrogen; C 1-6 -alkyl; C 2 . 6 -alkenyl; C ⁇ -cycloalkyl optionally mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C ⁇ -alkoxy; or
  • R 8 and R 9 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C ⁇ -alky!, hydroxy, C ⁇ -alkoxy, Cj.e-alkoxy-C L s-alkyl, nitro, amino, cyano, trifluoromethyl, C 1-6 -monoalkyl- or dialkylamino, oxo; or R 3 is
  • n,m,p independently are 0,1 ,2,3 and R 10 is hydrogen; hydroxy; C 1-6 -alkoxy; C M - cycloalkyl optionally mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 - alkoxy; C ⁇ -alkyl, C 2 . 6 -alkenyl or C 2-6 -alkynyl optionally mono- or polysubstituted with halogen; or
  • R 2 and R 3 together with the nitrogen atom forms a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C 1-6 -alkyl, hydroxy, C 1-6 -alkoxy, C 1 . 6 -alkoxy-C 1 . 6 -alkyl, nitro, amino, cyano, trifluoromethyl, C 1-6 -monoalkyl- or dialkylamino or oxo;
  • a together with carbon atoms 5 and 6 of formula I represents a 5 or 6 membered heterocyclic system comprising one or more nitrogen-, oxygen- or sulfur atoms, the heterocyclic systems optionally being mono- or polysubstituted with halogen; C 1-12 -alkyl; C ⁇ -cycloalkyl; hydroxy; C 1-6 -alkoxy; C ⁇ -alkoxy-C L ⁇ -alkyl; nitro; amino; cyano; cyanomethyl; perhalome- thyl; C 1-6 -monoalkyl- or dialkylamino; sulfamoyl; C 1-6 -alkylthio; C 1-6 -alkylsulfonyl; C 1-6 - alkylsulfinyl; C 1-6 -alkylcarbonylamino; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysub
  • the invention includes all optical isomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixture thereof.
  • the salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methane- sulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceuti- cally acceptable salts listed in Journal of Pharmaceutical Science, 6.6, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.
  • pharmaceutically acceptable acid addition salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic
  • C ⁇ -alkoxy refers to a straight or branched monovalent substituent comprising a C ⁇ -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • C e-alkylthio refers to a straight or branched monovalent substituent comprising a lower alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio.
  • C 2 . 6 -alkenyl refers to an unsaturated hydrocarbon chain having 2-6 carbon atoms and one double bond such as e.g. vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.
  • C ⁇ -cycloalkyl refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • C 2 . 6 -alkynyl refers to unsaturated hydrocarbons which contain triple bonds, such as e.g. -CsCH, -C ⁇ CCH 3 , -CH 2 C--CH, -CH 2 CH 2 CsCH, -CH(CH 3 )C ⁇ CH, and the like.
  • the term as used herein refers to a group of 2-12 carbon atoms interrupted by an O such as e.g. CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 3 , CH 2 -O-CH(CH 3 ) 2 and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
  • C 1-6 -alkyl ⁇ C,. 12 -alkyr and u C 1-18 -alkyl
  • ⁇ C,. 12 -alkyr and u C 1-18 -alkyl refers to a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as e.g.
  • C 1-18 -alkyl as used herein also includes secondary C ⁇ -alkyl and tertiary C ⁇ -alkyl.
  • C ⁇ -monoalkyiamino refers to an amino group wherein one of the hydrogen atoms is substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as e.g. methylamino, ethylamino, propylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamino, 2-methylbutylamino, n-hexylamino, 4-methylpentylamino, neopentylamino, n-hexylamino, 2,2-dimethylpropylamino and the like.
  • C L g-dialkylamino refers to an amino group wherein the two hydrogen atoms independently are substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms; such as dimethylamino, N-ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methyiamino, di(n- pentyl)amino, and the like.
  • acyl refers to a monovalent substituent comprising a C 1-6 -alkyl group linked through a carbonyl group; such as e.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, and the like.
  • C ⁇ -alkoxycarbonyl refers to a monovalent substituent comprising a C 1-6 -alkoxy group linked through a carbonyl group; such as e.g. methoxycar- bonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
  • 3-12 membered mono- or bicyclic system refers to a monovalent substituent of formula -NR 2 R 3 or -NR 8 R 9 where R 2 and R 3 , or R 8 and R 9 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, such as 1-pyrrolidyl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 7- azabicyclo[2.2.1]heptan-7-yl, tropanyl and the like.
  • 3-6 membered saturated ring system refers to a monovalent substituent comprising a monocyclic saturated system containing one or more hetero atoms selected from nitrogen, oxygen and sulfur and having 3-6 members and having its free valence from a carbon atom, e.g. 2-pyrrolidyl, 4-piperidyl, 3-morpholinyl, 1 ,4-dioxan-2- yl, 5-oxazolidinyl, 4-isoxazolidinyl, or 2-thiomorpholinyl.
  • bicycloalkyl refers to a monovalent substituent comprising a bicyclic structure made of 6-12 carbon atoms such as e.g. 2- ⁇ orbornyl, 7-norbomyl, 2- bicyclo[2.2.2]octyl, and 9-bicyclo[3.3.1]nonanyl.
  • aryl refers to phenyl, 1-naphthyl, or 2-naphthyl.
  • heteroaryl refers to a monovalent substituent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.
  • pyrrole imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine, and purine.
  • arylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy.
  • arylalkoxy refers to a C 1-6 -alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1- naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
  • heteroarylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1- methyl-1-(2-pyrimidyl)ethyl and the like.
  • C ⁇ -alkylsulfonyl refers to a monovalent substituent comprising a d-e-alkyl group linked through a sulfonyl group such as e.g. methylsulfonyl, ethylsul- fonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso- butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, 2-methylbutylsulfonyl, 3- methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, neopentylsulfonyl, n- hexylsulfonyl, 4-methylpentyl
  • C ⁇ -monoalkylaminosulfonyl refers to a monovalent substituent comprising a C ⁇ s-monoalkylamino group linked through a sulfonyl group such as e.g.
  • methylaminosuifonyl ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, sec-butylaminosulfonyl, isobutyiaminosulfonyl, tert- butylaminosulfonyl, n-pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3- methylbutylaminosulfonyl, n-hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopenty- laminosulfonyl, n-hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.
  • C ⁇ -dialkylaminosulfonyl refers to a monovalent substituent comprising a C 1-6 -dialkylamino group linked through a sulfonyl group such as dimethylami- nosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, N- (n-butyl)-N-methylaminosulfonyl, di(n-pentyl)aminosulfonyl, and the like.
  • C ⁇ -alkylcarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with an acyl group, such as e.g. acetamido, propiona- mido, isopropylcarbonyiamino, and the like.
  • (C ⁇ -cycloalky C ⁇ -alkyl) refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubstituted with a C ⁇ -cycioalkyl group, the cycloalkyl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or such as e.g. cyclopropylme- thyl, (l-methylcyclopropyl)methyl, 1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • arylthio refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 - alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio, and the like.
  • arylsulfonyl refers to an aryl group linked through a sulfonyl group, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C ⁇ -alkoxy; such as e.g. phenylsulfonyl, tosyl, and the like.
  • C ⁇ -monoalkylaminocarbonyl refers to a monovalent substituent comprising a C ⁇ -monoalkylamino group linked through a carbonyl group such as e.g. methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butyiaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert- butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3- methylbutylamino-carbonyl, n-hexylaminocarbonyl, 4-methylpentylaminocarbonyl, neo- pentylaminocarbonyl, n-hexylaminocarbonyl and 2-2-dimethylpropylaminocarbonyl
  • C ⁇ -dialkylaminocarbonyl refers to a monovalent substituent comprising a C 1-6 -dialkylamino group linked through a carbonyl group such as dimethylami- nocarbonyl, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-(n-butyl)-N-methylaminocarbonyl, di(n-pentyl)aminocarbonyl, and the like.
  • C ⁇ -monoalkylaminocarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a C ⁇ -monoalkylaminocarbonyl group, e.g. methylaminocarbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, isopropylaminocarbonylamino, n-butylaminocarbonylamino, sec-butylaminocarbonylamino, isobutylaminocarbonylamino, tert-butylaminocarbonylamino, and 2- methylbutylaminocarbonylamino.
  • C ⁇ -dialkylaminocarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a C ⁇ -dialkylaminocarbonyl group, such as dimethylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethyla- minocarbonylamino, dipropylaminocarbonylamino, N-(n-butyl)-N- methylaminocarbonylamino, di(n-pentyl)aminocarbonylamino, and the like.
  • 5- or 6-membered heterocyclic system refers to: a monocyclic unsaturated or saturated system containing one, two or three hetero atoms selected from nitrogen, oxygen and sulfur and having 5 members, e.g. pyrrole, furan, thiophene, pyrroline, dihydrofuran, dihydrothiophene, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazole, isothiazole, 1 ,2,3-oxadiazole, furazan, 1 ,2,3-triazole, 1 ,2,3- thiadiazole or 2,1 ,3-thiadiazole; an aromatic monocyclic system containing two or more nitrogen atoms and having 6 members, e.g.
  • pyrazine pyrimidine, pyridazine, 1 ,2,4- triazine, 1 ,2,3-triazine or tetrazine; a non-aromatic monocyclic system containing one or more hetero atoms selected from nitrogen, oxygen and sulfur and having 6 members, e.g. pyran, thiopyran, piperidine, dioxane, oxazine, isoxazine, dithiane, oxathine, thiazine, piperazine, thiadiazine, dithiazine or oxadiazine.
  • 5- or 6-membered nitrogen containing ring refers to a monovalent substituent comprising a monocyclic unsaturated or saturated system containing one or more nitrogen atoms and having 5 or 6 members, e.g. pyrrolidinyl, pyrrolinyl, imida- zolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1 ,3-dioxolanyl, and 1 ,4- dioxolanyl.
  • pyrrolidinyl
  • R 1 and R 5 independently are hydrogen; hydroxy; C 1-6 -alkoxy; or C ⁇ -alkyl, C ⁇ -cycloalkyl, C 2-6 -alkenyi or C 2 . 6 -alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; or
  • R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I and R 1 is as defined above; or
  • R is hydrogen; hydroxy; C 1-6 -alkoxy; or C ⁇ -alkyl, C ⁇ -cycloalkyl, C 2 . 6 -alkenyl or C 2 . 6 - alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; or
  • R 4 together with R 1 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I;
  • R 7 is C 1-6 -alkyl; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, C 1-6 -alkoxy, aryloxy, arylalkoxy, nitro, amino, C ⁇ -monoalkyl- or dialkylamino, cyano, acyl or C ⁇ -alkoxycarbonyl.
  • R ⁇ R 5 and R s independently are hydrogen; hydroxy; C 1-6 -alkoxy; or C 1-6 -alkyl, C M - cycloalkyl, C 2 . 6 -alkenyl or C 2 . 6 -alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; or
  • R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I and R 1 and R 6 are as defined above; or
  • R 4 together with R 1 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I and R 5 and R 6 are as defined above;
  • the general formula of formula I is (la).
  • R 1 is selected from hydrogen, C 1-6 -alkyl, C 3 . 6 -cycloalkyl or C 2 . 6 -alkenyl.
  • R 1 is hydrogen or C 1-6 -alkyl.
  • R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I.
  • R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I.
  • R 2 is selected from hydrogen, hydroxy, C 1-6 -alkyl, C 3 . 6 -cycloalkyl or C 2 ⁇ -alkenyl.
  • R 2 is hydrogen or C 1-6 alkyl.
  • R 3 is selected from R 8 ,-OR 8 , -NR 8 R 9 or aryl, the aryl group optionally being substituted with C 1-6 -alkyl; wherein R 8 is hydrogen; C ⁇ 6 -cycloalkyl; (C 3 .
  • R 3 is selected from secondary C ⁇ - alkyl, tertiary C ⁇ -alkyl, C ⁇ -cycloalkyl or (C ⁇ -cycloalky methyl optionally mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy.
  • R 3 is selected from isopropyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 1 ,2,2-trimethylpropyl, 2,3-dimethylbutyl, 1-ethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-2,2- dimethylpropyl, 2,3,3-trimethylbutyl, 2-methylbutyl, 1 ,5-dimethylhexyl, 3-methylbutyl, 3- methylhexyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopro- pylmethyl, 1-(cyclopropyl)ethyl cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
  • R 2 and R 3 together with the nitrogen atom forms a six membered ring, optionally substituted in the 2-position with a C ⁇ -alkyl group, preferably selected from methyl, ethyl or isopropyl.
  • a C ⁇ -alkyl group preferably selected from methyl, ethyl or isopropyl.
  • the six membered ring is a piperidine, piperazine, morpholine or thiomorpholine ring.
  • R 7 is selected from C 1-6 -alkyl, phenyl or pyridyl.
  • A forms together with carbon atoms 5 and 6 of formula I a 5 membered heterocyclic system containing one hetero atom selected from nitrogen and sulfur, a 5 membered heterocyclic system containing two hetero atoms selected from nitrogen, oxygen and sulfur, a 6 membered aromatic heterocyclic system containing two or three nitrogen atoms, a 6 membered non-aromatic heterocyclic system containing one or two hetero atoms selected from nitrogen, oxygen and sulfur; the heterocyclic systems optionally being mono- or disubstituted with halogen; C 1-12 -alkyl; C ⁇ - cycloalkyl; cyano; cyanomethyl; perhalomethyl; suifamoyl; C 1-6 -alkylthio; C L e-alkylsulfonyl; C ⁇ -alkylsulfinyl; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally
  • A forms together with carbon atoms 5 and 6 a thieno[3,2-e]- or pyrrolo[3,2-e]- ring, thiophene, imidazole, thiazole, pyrazole, isoxazole or isothiazole, a pyrazino[2,3-e]-, a pyrimido[4,5-e]-, a pyrimido[5,4-e]-, a pyridazino[4,5-e]- or a pyridazino[4,3-e]-ring, thiopyran, piperidine, dioxane , oxazine or dithiane.
  • Preferred compounds of the invention are:
  • the compounds of the present invention interact with the potassium channels and hence act as openers or blockers of the ATP-regulated potassium channels, which make them useful in the treatment of various diseases of the cardiovascular system, e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases; the pulmonary system; the gastrointestinal system; the central nervous system and the endocrinological system.
  • the compounds of the present invention can be used for the treatment of vaso- spastic disorders such as subarachnoid haemorrhage and migraine.
  • the compounds of the present invention may also be used for the treatment of diseases associated with decreased skeletal muscle blood flow such as Raynauds disease and intermittent claudication.
  • the compounds of the invention may be used for the treatment of chronic airway diseases, including asthma, and for treatment of detrusor muscle instability secondary to bladder outflow obstruction and therefore for kidney stones by aiding their passage along the urethra.
  • the present compounds could also be used for treatment of conditions associated with disturbances in gastrointestinal mobility such as irritable bowel syndrome. Additionally these compounds can be used for the treatment of premature labour and dysmenorrhea.
  • Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and it is expected that such compounds can be used for the treatment of various diseases of the central nervous system, e.g. epilepsia, ischemia and neurodegenerative diseases, and for the management of pain.
  • potassium channel openers promote hairgrowth, therefore, the compounds of the present invention can be used for the treatment of baldness.
  • Potassium channel openers also relax urinary bladder smooth muscle, thus, the compounds of the present invention can be used for the treatment of urinary incontinence.
  • the compounds of the present invention can be used to reduce insulin secretion.
  • hyperinsulinemia and insulin resistance is very frequently encountered. This condition could lead to the development of noninsulin dependent diabetes (NIDDM).
  • NIDDM noninsulin dependent diabetes
  • potassium channel openers and hence the compounds of the present invention, can be used for reducing the hyperinsulinemia and thereby prevent diabetes and reduce obesity.
  • overt NIDDM treatment of hyperinsulinemia with potassium channel openers, and hence the present compounds can be of benefit in restoring glucose sensitivity and normal insulin secretions.
  • potassium channel openers and hence the present compounds can be used to induce pancreatic cell rest which may prevent the progression of the autoimmune disease.
  • the potassium channel openers of the present invention can be administered in combination with an immunosuppressant or with an agent like nicotinamide, which will reduce autoimmune degeneration of beta-cells.
  • Insulin requiring or Type 1 diabetes (IDDM) as well as late onset IDDM also known as type 1.5.
  • IDDM Insulin requiring or Type 1 diabetes
  • late onset IDDM also known as type 1.5.
  • NIDM non-insulin-requiring Type 2 patients with autoreactivity against beta-cell epitopes that later turns insulin requiring
  • NIDM non-insulin-requiring Type 2 patients with autoreactivity against beta-cell epitopes that later turns insulin requiring
  • cytokines e.g.
  • interleukin-1b IL-lb
  • TNFa tumour necrosis factor a
  • IFNg interferon g
  • Nicotinamide belongs to the B-vitamin family and is derived from nicotinic acid by amidation of the carboxyl group. It processes none of nicotine's pharmacological properties.
  • NA is converted into NAD+, which acts as a coenzyme for proteins involved in tissue respiration.
  • NA has been proposed to influence several of the putative intracellular molecular events following immune attack on the beta-cells. Animal experiments and early non-blinded experiments in humans have indicated a protective role of this compound against IDDM as well as in cytokine/immune mediated beta-cell destruction.
  • Yet another aspect of this application concerns the use of a PCO compound alone or in combination with the inhibitor of cytokine/immune mediated beta-cell impairment , in transplantation, e.g. islet transplantation into diabetes patients. The use of one or both of these treatments may reduce the risk of rejection of the transplanted islets/beta- cells/engineered beta-cells/pancreas.
  • the compounds of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hyperinsulinaemia and diabetes.
  • the invention relates to a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperinsulinaemia and treatment or prevention of diabetes. Furthermore, the invention also relates to the use of the inventive compounds of formula I as medicaments useful for treating hyperinsulinaemia and treating or preventing diabetes
  • the present invention relates to methods of preparing the above mentioned compounds.
  • the methods comprises:
  • A, B, D, R 1 and R 4 are as defined above and Z is a leaving group such as alkoxy, alkylthio, halogen, preferentially chloro, bromo, iodo, trimethylamino, or methylsulfonyl with a compound of formula III:
  • R 1 is hydrogen and A, B, D and X are as defined above, or B is NH and R 1 , A, D and X are as defined above, with the compound of formula III, or a suitable salt thereof in the presence of P 2 O 5 and a high boiling tertiary amine or a suitable salt thereof, to form a compound of the general formula I;
  • R 1 is hydrogen and A, B, D and X are as defined above or B is NH and R ⁇ A, D and X are as defined above, with a compound of the formula III, or a suitable salt thereof in the presence of titanium tetrachloride and a solvent with which it may form a complex, like e.g. tetrahydrofuran, or a mixture of toluene and anisole, to form a compound of the general formula I;
  • R 3 is as defined above, to form a compound of the general formula I wherein D is SO 2 , B is >NR 5 , R 2 is H, and R 4 and R 5 together form a bond;
  • R 3 is as defined, to form a compound of the general formula I wherein D is SO 2 , B is >NR 5 , R 2 is H, and R 4 and R 5 together form a bond;
  • Y is NH or S, or a suitable salt thereof, to form a compound of the general formula I, wherein D is SO 2 , B is >NR 5 , R 4 and R 5 together form a bond, and R 2 and R 3 are H;
  • the starting materials are either known compounds or compounds which may be prepared in analogy with the preparation of known compounds or in analogy with known methods as described by e.g Huang B.-S., et al., J. Med. Chem., 22, 575-7 (1980), Ofitserov V. I. et al., Khim. Geterotsikl. Soedin., 1119-22 (russ.) (1976), Topliss J. G., U.S. 3,641 ,017 (1972), Kotovskaya S. K. et al., Khim.-Farm. Zh., 13, 54-57 (russ.) (1979), Meyer R. F., J. Heterocycl.
  • the ability of the compounds to interact with potassium channels can be determined by various methods.
  • patch-clamp techniques Hamill O.P., Marty A., Neher E., Sakmann B. and Sigworth F.J., Pl ⁇ gers Arch., 221, 85-100 (1981)
  • the ionic current through a single channel of a cell can be recorded.
  • the activity of the compounds as potassium channel openers can also be measured as relaxation of rat aorta rings according to the following procedure:
  • the opening of the K ATP -channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca 2+ concentration according to the method of Arkhammar P. et al. , J. Biol. Chem., 2g2, 5448-5454 (1987).
  • the RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with 10 % fetal calf serum (from GibcoBRL, Scotland, UK) and maintained in an atmosphere of 5 % CO 2 / 95 % air at 37°C.
  • the cells were detached with a Trypsin-EDTA solution (from GibcoBRL, Scotland, UK), resuspended in medium, added 1 mCi/ml 86 Rb + and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 ⁇ l/well, and grown 24 hours before use in assay.
  • the plates were washed 4 times with Ringer buffer (150 mM NaCI, 10 M Hepes, 3.0 mM KCI, 1.0 mM CaCI 2 , 20 mM Sucrose, pH 7.1). Eighty ⁇ l Ringer buffer and 1 ⁇ l control- or test compound dissolved in DMSO was added. After incubation 1 h at room temperature with a lid, 50 ⁇ l of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 ⁇ l MicroScint40 (Packard Instrument Company, CT, USA) added. The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 32 P program.
  • Ringer buffer 150 mM NaCI, 10 M Hepes, 3.0 mM KCI, 1.0 mM CaCI 2 , 20 mM Sucrose, pH 7.1.
  • the compounds according to the invention are effective over a wide dose range. In general satisfactory results are obtained with dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day. A most preferable dosage is about 1 mg to about 100 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • Methyl 4-cyano-5-methyl-3-sulfamoyl-thiophene-2-carboxylate (2.9 g), prepared from methyl 3-amino-4-cyano-5-methyl-thiophene-2-carboxylate in analogy with known procedures, e.g. F. Junquera et al. , Eur.J. Med. Chem. 23, 329 (1988), was suspended in 10 ml of ethanol. Hydrazine monohydrate (2 ml) was added and the mixture was stirred for 1 h at room temperature and then evaporated.
  • Phosgene (0.242 ml, 20 % in toluene) was added dropwise to a solution of ⁇ /-(3-amino-5- chloro-2-thienylsulfonyl)- ⁇ /'-(3-methylbutyl)thiourea (0.153 g, 0.42 mmol) and dry triethylamine (0.118 ml, 0.85 mmol) in dry tetrahydrofuran (3 ml) with stirring at 0°C. The mixture was stirred for 2 h at 0°C, and evaporated to dryness.
  • Ethyl 3-(6-chloro-1 ,4-dihydro-1 ,1-dioxothieno[3,2-e]-1 ⁇ 6 ,2,4-thiadiazin-3- ylamino)butanoate (0.5 g. 1.42 mmol) was hydrolyzed to the acid by stirring in 5 ml of 2 N sodium hydroxide for 2 h at room temperature. The solution was treated with decolorising charcoal, filtered and acidified with 4 M hydrochloric acid to pH 2.
  • Potassium terf-butoxide (135 mg, 1.2 mmol) was added to a solution of N-(5-chloro-3- sulfamoylthiophen-2-yi)-acetamide(255 mg, 1.0 mmol) in dry ⁇ /, ⁇ -dimethylformamide (5 ml) with stirring on an ice bath. After 5 min, isopropyl isothiocyanate (0.128 ml, 1.2 mmol) was added dropwise and the solution was stirred for 30 min at 0°C and then at room temperature for 3 h. A further amount of potassium tert-butoxide (135 mg, 1.2 mmol) was added to the solution and stirring was continued at room temperature for 1 h.
  • Phosgene (0.416 ml, 20 % in toluene) was added dropwise to a solution of N-[5-chloro-3- (isopropylthiocarbamoyl)sulfamoylthiophen-2-yl]acetamide(261 mg, 0.73 mmol) and dry triethylamine (0.209 ml, 1.5 mmol) in dry tetrahydrofuran (5 ml) with stirring at 0°C. The mixture was stirred for 1 h at 0°C, and evaporated to dryness.
  • Powdered potassium hydroxide (128 mg, 2.28 mmol) was added to a solution of 6-chloro- 3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide (319 mg, 1.14 mmol) in 25 ml of methanol and the mixture was hydrogenated at room temperature and atmospheric pressure for 3 days with 150 mg of 10 % palladium on carbon. The catalyst was removed by filtration and washed with ethanol and water. The combined filtrate was acidified with 4 M hydrochloric acid and evaporated to dryness.
  • the title compound was prepared from crude N-(3-Amino-5-chloro-2-thienylsuifonyl)-N ' - (furan-2-ylmethyl)thiourea by a procedure analogous to the procedure described in example 3-b except that the product was purified by column chromatography on silica with dichloromethane/methanol (19:1), (yield 11%); mp 224-225°C; 1 H-NMR (DMSO-d 6 ): ⁇ 4.41 (d, 2H), 6.33 (m, 1 H), 6.41 (m, 1 H), 7.05 (s, 1 H), 7.62 (br s, 1 H), 7.75 (br t, 1 H), 11.2 (br s, I calc C 37.80 H 2.54 N 13.22; found C 37.87 H 2.51 N 13.10).

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Abstract

L'invention concerne des dérivés de 1,2,4-thiadiazine et de 1,4-thiazine représentés par la formule (I), dans laquelle A, B, D, R?1, R2, R3 et R4¿ sont tels que définis dans le descriptif. L'invention concerne en outre des compositions de ces dérivés et des procédés de préparation des composés. Les composés sont utiles dans le traitement de maladies du système nerveux central, l'appareil cardio-vasculaire, le système pulmonaire, l'appareil digestif et le système endocrinien.
PCT/DK1998/000288 1997-07-16 1998-06-30 Derives de 1,2,4-thiadiazine fusionnee, leur preparation et utilisation WO1999003861A1 (fr)

Priority Applications (9)

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EP98930653A EP1000066A1 (fr) 1997-07-16 1998-06-30 Derives de 1,2,4-thiadiazine fusionnee, leur preparation et utilisation
AU81018/98A AU757693B2 (en) 1997-07-16 1998-06-30 Fused 1,2,4-thiadiazine derivatives, their preparation and use
IL13360498A IL133604A0 (en) 1997-07-16 1998-06-30 Fused 1, 2, 4-thiadiazine derivatives, their preparation and use
KR1020007000501A KR20010021936A (ko) 1997-07-16 1998-06-30 융합된 1,2,4-티아디아진 유도체, 그의 제조와 사용
HU0003999A HUP0003999A3 (en) 1997-07-16 1998-06-30 Fused 1,2,4-thiadiazine derivatives, their preparation, their use and pharmaceutical compositions containing them
CA002294830A CA2294830A1 (fr) 1997-07-16 1998-06-30 Derives de 1,2,4-thiadiazine fusionnee, leur preparation et utilisation
JP2000503085A JP2001510195A (ja) 1997-07-16 1998-06-30 縮合化１，２，４−チアジアジン誘導体、その調製及び使用
BR9810592-2A BR9810592A (pt) 1997-07-16 1998-06-30 Composto, processos para preparar um composto, para tratar ou prevenir doenças do sistema endócrino e para a fabricação de um medicamento, composição farmacêutica, e, uso de um composto
NO20000185A NO315470B1 (no) 1997-07-16 2000-01-14 Kondenserte 1,2,4-tiadiazinderivater, farmasöytiske preparater som omfatterdisse forbindelsene, anvendelse av forbindelsene til fremstillingav medikamenter og fremgangsmåte for fremstilling av medikamenter

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EP1000066A1 (fr) 2000-05-17
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CN1264384A (zh) 2000-08-23
BR9810592A (pt) 2000-09-12
RU2215004C2 (ru) 2003-10-27
NO20000185D0 (no) 2000-01-14
IL133604A0 (en) 2001-04-30
HUP0003999A2 (hu) 2001-08-28
AU757693B2 (en) 2003-03-06
NO315470B1 (no) 2003-09-08
AU8101898A (en) 1999-02-10
CA2294830A1 (fr) 1999-01-28

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