Classifications

• • 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 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.
• 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.
• 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 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;
• 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.
• 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 1-18 -alkyl as used herein also includes secondary C ⁇ -alkyl and tertiary C ⁇ -alkyl.
• 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.
• 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.
• 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.
• 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 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 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.
• the general formula of formula I is (la).
• 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 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.
• 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.
• 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 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 also relax urinary bladder smooth muscle, thus, the compounds of the present invention can be used for the treatment of urinary incontinence.
• 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.
• 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.
• 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:
• 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 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 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 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 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 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.
• 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:
• 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.

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