WO2000055147A1 - Derives de 1,4-thiazine-2-carbonitrile fusionnes, leur preparation et leur utilisation - Google Patents

Derives de 1,4-thiazine-2-carbonitrile fusionnes, leur preparation et leur utilisation Download PDF

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WO2000055147A1
WO2000055147A1 PCT/DK2000/000100 DK0000100W WO0055147A1 WO 2000055147 A1 WO2000055147 A1 WO 2000055147A1 DK 0000100 W DK0000100 W DK 0000100W WO 0055147 A1 WO0055147 A1 WO 0055147A1
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formula
compound
defined above
dioxide
carbonitrile
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PCT/DK2000/000100
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Holger Claus Hansen
Tina Møller TAGMOSE
John Bondo Hansen
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Novo Nordisk A/S
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Priority to EP00909065A priority Critical patent/EP1163233A1/fr
Priority to JP2000605576A priority patent/JP2002539202A/ja
Priority to AU31475/00A priority patent/AU3147500A/en
Publication of WO2000055147A1 publication Critical patent/WO2000055147A1/fr

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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
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to fused 1 ,4-thiazine-2-carbonitrile 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 or prevention of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an antidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of diabetes, including prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), as well as insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.
  • pharmacologically active compounds e.g. an antidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of diabetes, including prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), as well as insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.
  • Suitable antidiabetics comprise short and long acting insulins, insulin analogues as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibenclam
  • metformin metformin
  • benzoic acid derivatives e.g. repaglinide
  • thiazolidin- ediones e.g. troglitazone, rosiglitazone, pioglitazone and ciglitazone
  • inhibitors of ⁇ -glucosidase e.g. acarbose and voglibose, inhibitors of hepatic enzymes responsible for the biosynthesis of glucose, e.g. glycogen phosphorylase inhibitors.
  • Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential.
  • the KATP-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 A ⁇ p-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.
  • the 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 labour.
  • these compounds 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.
  • mellitus including prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
  • IGF impaired fasting glucose
  • ITT impaired glucose tolerance
  • Examples of such compounds are short and long acting insulins, insulin analogues, insulin sentizers, insulin 5 secretagogues as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibenclamide and glipizide; biguanides, e.g. metformin; benzoic acid derivatives, e.g.
  • repaglinide e.g. troglitazone, rosiglitazone, pioglitazone and ciglitazone
  • thiazolidinediones e.g. troglitazone, rosiglitazone, pioglitazone and ciglitazone
  • inhibitors of ⁇ -glucosidase e.g. acarbose and voglibose, inhibitors of hepatic enzymes 10 responsible for the biosynthesis of glucose, e.g. glycogen phosphorylase inhibitors.
  • the compounds of the present invention can be used for the treatment of vasospastic disorders such as subarachnoid haemorrhage and migraine.
  • Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and it is expected that the present 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.
  • diazoxide (7-chloro-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 A ⁇ p-channels on pancreatic beta- cells (Pirotte B. et al. Biochem. Pharmacol, 4Z, 1381-1386 (1994); Pirotte B. et al., J. Med.
  • Diazoxide has furthermore been shown to delay the onset of diabetes in BB-rats ( Vlahos WD et al. Metabolism 40, 39-46 (1991 )).
  • 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. Endocrinoi. 133, 705-
  • the present invention relates to fused 1 ,4-thiazine-2-carbonitrile derivatives of the general formula (I)
  • n 1 or 2;
  • R 3 is hydrogen; C ⁇ - 6 -alkyl, C 2 -6-alkenyl, C 2 -6-alkynyl, C 3 . 6 -cycloalkyl or C 3 ⁇ -cycloalkyl-C ⁇ - 6 - alkyl optionally being mono- or polysubstituted with hydroxy or halogen; aryl, aryl-C ⁇ - 6 - alkyl, heteroaryl or heteroaryl-C ⁇ . 6 -alkyl, aryl or heteroaryl optionally being mono- or polysubstituted with halogen, hydroxy, trifluoromethyl, or C ⁇ . 6 -alkoxy;
  • R 4 , R s , R 6 , R 7 independently are hydrogen; halogen; hydroxy; cyano; trifluoro- methyl; trifluoromethylsulfanyl; trifluoromethoxy; Ci- ⁇ -alkoxy; C ⁇ -6-alkoxy-C ⁇ - 6 - alkyl; C ⁇ - 6 -alkylsulfanyl; C ⁇ .
  • 6 -alkylsulfonyl C - 6 -alkylsulfinyl; aryl, arylsulfanyl, arylsulfinyl, arylsulfonyl, aryioxy, the aryl group optionally being mono- or polysubstituted with halogen, hydroxy, trifluoromethyl, C ⁇ -6-alkyl or C ⁇ . 6 -alkoxy;
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form.
  • the present invention relates to compounds of the general formula (I) wherein A together with the carbon atoms a and b is
  • the present invention relates to compounds of the general formula (I) wherein R 3 is C- ⁇ - 6 -alkyl.
  • the present invention relates to compounds of the general formula (I) wherein wherein R 4 , R 5 , R 6 , R 7 independently are hydrogen; halogen or trifluoromethyl.
  • the present invention relates to compounds of the general formula (I) wherein R 5 and R 6 independently are trifluoromethyl or halogen and the remaining substituents are hydrogen.
  • n 1 or 2;
  • R 3 is C ⁇ - 6 -alkyl, C 2 -6-alkenyl, C 2 -6-alkynyl, C 3 . 6 -cycloalkyl, C 3 . 6 -cycloalkyl-C ⁇ -6-alkyl or C ⁇ - 6 - alkyl-C 3 . 6 -cycloalkyl, optionally being mono- or polysubstituted with hydroxy or halogen; aryl, aryl-C ⁇ - 6 -alkyl, heteroaryl or heteroaryl-d-6-alkyl, aryl or heteroaryl optionally being mono- or polysubstituted with halogen, hydroxy, trifluoromethyl, C ⁇ . 6 -alkyl or C ⁇ - 6 -alkoxy;
  • R 4 , R 5 , R 6 , R 7 independently are hydrogen; halogen; hydroxy; cyano; trifluoromethyl; trifluoromethylsulfanyl; trifluoromethoxy; C ⁇ . 6 -alkyl; C ⁇ . 6 -alkoxy; Ci-e-alkoxy-C-i-e- alkyl; C ⁇ - 6 -alkylsulfanyl; C ⁇ - 6 -alkylsulfonyl; C ⁇ . 6 -alkylsulfinyl; aryl;
  • 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 scope of the invention also includes all tautomeric forms of the compounds of formula I as well as metabolites or prodrugs.
  • a “metabolite” of a compound disclosed in this application is an active derivative of a compound disclosed herein which is produced when the compound is metabolized. Metabolites of compounds disclosed herein can be identified either by administration of a compound to a host and an analysis of blood samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the incubant.
  • a “prodrug” is a compound that either is converted into a compound disclosed in the application in vivo or has the same active metabolite as a compound disclosed in this application.
  • 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, maionic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methane- sulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, fifi, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • Ci- ⁇ -alkyl refers to a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1 ,2- dimethylpropyl, 2,2-dimethylpropyl, 1 ,2,2-trimethylpropyl and the like.
  • C ⁇ .6-alkoxy refers to a straight or branched monovalent substituent comprising a C ⁇ - 6 -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 ⁇ - 6 -alkoxy-C ⁇ .6-aikyl 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.
  • 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 3 - 6 -cycloalkyl refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • (C 3 - 6 -cycloalkyl)-C ⁇ -6-alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubstituted with a C 3 -6-cycloalkyl group, the cycioalkyl group optionally being mono- or polysubstituted with d- ⁇ -alkyl, halogen, hydroxy or C ⁇ . 6 -alkoxy; such as e.g. cyclopropyl- methyl, (l-methytcyclopropyl)methyl, 1 -(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexyl- methyl, and the like.
  • C ⁇ - 6 -alkylsulfanyl 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.
  • Ci-e-alkylsulfonyl refers to a monovalent substituent comprising a C ⁇ - 6 -alkyl group linked through a sulfonyl group such as e.g.
  • aryl refers to phenyl, 1 -naphthyl, or 2-naphthyl.
  • aryl-C ⁇ . 6 -alkyl 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.
  • aryioxy refers to phenoxy, 1 -naphthyloxy or 2-naphthyloxy.
  • arylsulfanyl 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 Ci- ⁇ -alkyI, halogen, hydroxy or d- ⁇ - 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 ⁇ - 6 -alkyl, halogen, hydroxy or Ci-e-alkoxy; such as e.g. phenylsulfonyl, tosyl, and the like.
  • 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.
  • heteroaryl-Ci-e-alkyl 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.
  • n is 2.
  • R 3 is C ⁇ . 6 -alkyl, preferably methyl.
  • R 4 , R 5 , R 6 , R 7 are independently hydrogen, halogen, trifluoromethyl, trifluoromethoxy or trifluoromethylsulfanyi.
  • R 4 is hydrogen and R 5 , R 6 , R 7 are independently hydrogen, halogen, trifluoromethyl, trifluoromethoxy or trifluoromethylsulfanyi.
  • R 5 and R 6 are independently trifluoromethyl or halogen, and R 4 and R 7 are hydrogen.
  • R 4 , R 6 and R 7 are hydrogen, and R is halogen, trifluoromethyl, trifluoromethoxy or trifluoromethylsulfanyi.
  • R 4 , R 5 and R 7 are hydrogen, and R 6 is halogen, trifluoromethyl, trifluoromethoxy or trifluoromethylsulfanyi.
  • 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 15 diseases; the pulmonary system; the gastrointestinal system; the central nervous system and the endocrinological system.
  • various diseases of the cardiovascular system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart 15 diseases; the pulmonary system; the gastrointestinal system; the central nervous system and the endocrinological system.
  • K A ⁇ p-channel openers therefore could be important for treatment of various diseases characterised by cellular degeneration and death, e.g.
  • Type 1 diabetes Alzheimers disease, Parkinsons disease and stroke.
  • 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 Reynauds 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.
  • NIDDM non-insulin dependent diabetes
  • Potassium channel openers, and hence the compounds of the present invention can be used for counteracting 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 secretion.
  • the compounds of the present invention can be used for the treatment of NIDDM.
  • potassium channel openers and hence the present compounds can be used to induce pancreatic beta-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.
  • NIDDM non-insulin-requiring Type 2 patients with autoreactivity against beta-cell epitopes that later turns insulin requiring
  • NIDDM non-insulin-requiring Type 2
  • interleukin-1b IL-1b
  • 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.
  • Hyperinsulinemia and insulin resistance is associated with polycystic ovary syndrome in women.
  • a K A ⁇ p-channel opener which reduce insulin secretion could be used to alleviate the symptoms of this disease (Nestler J.E. et al, J. Clin. Endocrinol. And Metabolism. (1989), fiS, 1027-1032).
  • the compounds of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hypehnsulinaemia and diabetes, including prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
  • IGF impaired fasting glucose
  • IGT impaired glucose tolerance
  • 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, NIDDM and prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
  • IGF impaired fasting glucose
  • ITT impaired glucose tolerance
  • 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, NIDDM and prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an antidiabetic or other pharmacologically active material.
  • Suitable antidiabetics comprise short and long acting insulins, insulin analogues as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibenciamide and glipizide; biguanides, e.g.
  • metformin metformin; benzoic acid derivatives, e.g. repaglinide; thiazolidinediones, e.g. troglitazone, rosiglitazone, pioglitazone and ciglitazone; glucagon like peptide 1 (GLP-1 ), GLP-1 derivatives and GLP-1 analogues; inhibitors of ⁇ -glucosidase, e.g. acarbose and vogli- bose, inhibitors of hepatic enzymes responsible for the biosynthesis of glucose, e.g. glycogen phosphorylase inhibitors.
  • benzoic acid derivatives e.g. repaglinide
  • thiazolidinediones e.g. troglitazone, rosiglitazone, pioglitazone and ciglitazone
  • the present invention relates to methods of preparing the above mentioned compounds.
  • the methods comprises:
  • A is as defined above with haioacetonitrile, e.g. iodoacetonitrile, in the presence of a base to give a compound of formula (III):
  • A is as defined above, which by acylation with a carboxylic acid anhydride of formula
  • a and R are as defined above, which in turn by oxidation with a suitable oxidizing agent, e.g. an organic or inorganic peracid or a peroxide, selectively gives either a mono- or a dioxide of formula (V):
  • a suitable oxidizing agent e.g. an organic or inorganic peracid or a peroxide
  • A is as defined above and Y is a leaving group, preferentially halogen, with a source of HS " or a HS ' synthon, e.g. sodium sulfide, hydrogensulfide, thiophosphate, thiosulfate, ethylthiolate, or thiourea, to give a compound of formula (XI):
  • A is as defined above, which by oxidation with a suitable oxidizing agent, e.g. an organic or inorganic peracid or a peroxide, selectively gives either a mono- or a dioxide of formula (XIII):
  • a suitable oxidizing agent e.g. an organic or inorganic peracid or a peroxide
  • a and R are as defined above with a suitable oxidizing agent, e.g. an organic or inorganic peracid or a peroxide, to give selectively either a mono- or a dioxide of formula (1):
  • a suitable oxidizing agent e.g. an organic or inorganic peracid or a peroxide
  • A is as defined above with a suitable oxidizing agent, e.g. an organic or inorganic peracid or a peroxide, to give selectively either a mono- or a dioxide of formula (XVIII):
  • a suitable oxidizing agent e.g. an organic or inorganic peracid or a peroxide
  • a and n are as defined above which by acylation with a carboxylic acid anhydride of formula
  • a and n are as defined above with an orthoester R -C(OR) 3 , wherein R is methyl or ethyl, and subsequently with an organic base, e.g. a tertiary amine, to give a compound of formula (I):
  • A' together with the atoms marked a and b represents a ring selected from
  • R 3 R 4 , R 5 , R 6 , R 7 and n are as defined above, to a compound of formula (I),
  • A, R and n are as defined above, by chemically modifying the substitution of the A'-ring by classical methods by modifying substituents or by introducing new substituents, e.g. by halogenation, electrophilic aromatic substitution, nucleophilic aromatic substitution, cross coupling, oxidation or reduction.
  • 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. El-Taweel et al., Arch. Pharmacol. Res., 121, 261 -264 (1990), Liso et al., Synthesis, 1233, 755 - 757, Kano et al., Heterocycles, 12, 681 - 684 (1979), C. Bieniarz and M.J. Comwell, Tetrahedron Lett, 34 (6) 939-942 (1993), Sharpe.C.J.
  • the ability of the compounds to interact with potassium channels can be determined by various methods.
  • Potassium channel modulators may be studied using the inside-out and whole-cell configurations of the patch-clamp technique (Hamill et al., Pl ⁇ gers Arch., 321, 85-100 (1981 )). This method allows the direct study of the activity of ion channels from primary 0 cells, cell lines, ceils transfected with and oocytes expressing the ion channel of interest. Whole-cell recordings contain the summed activity of all ion channels in the cell and is a reliable measure of the degree of channel activation or inhibition. Inside-out patches allow the recording of a single or a few individual ion channels thereby giving more information on the mechanism(s) of action of the drug(s) tested. 5
  • the activity of the compounds as potassium channel openers can also be measured as relaxation of rat aorta rings according to the following procedure:
  • a section of rat thoracic aorta between the aortic arch and the diaphragm was dissected 0 out and mounted as ring preparations as described by Taylor P.D. et al , Brit J. Pharma- col, HI, 42-48 (1994). After a 45 min. equilibration period under a tension of 2 g, the preparations were contracted to achieve 80% of the maximum response using the required concentration of phenylephrine. When the phenylephrine response reached a plateau, potential vasodilator/ agents were added cumulatively to the bath in small volumes using half log molar increments at 2 min intervals. Relaxation was expressed at the percentage of the contracted tension. The potency of a compound was expressed as the concentration required to evoke a 50% relaxation of the tissue.
  • the opening of the K A ⁇ p-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., 202, 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 mM Hepes, 3.0 mM KCl, 1.0 mM CaC- 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 mM Hepes, 3.0 mM KCl, 1.0 mM CaC- 2 , 20 mM Sucrose, pH 7.1 .
  • KATP-channel modulators on pancreatic beta-cells can be determined by measuring qualitative changes in membrane potential in the insulin producing cell line ⁇ - TC3 using fluorescence imaging techniques.
  • the slow fluorescent membrane potential probe DiBAC was used.
  • the cells were kept in Ca 2+ -HEPES buffer supplemented with 10 mM glucose. After 5 s of each 60 s run the compound was added. 48 wells were run in each set, taking about 1 h. The same cells were then run again, now adding 25 mM KCl after 5 s, and the depolarisation-induced increase in DiBAC fluorescence monitored for 55 s.
  • K A ⁇ p-channel modulators on pancreatic beta-cells can be determined by measuring the increase or decrease in insulin release from insulin producing beta-cell lines or isolated islets.
  • the beta cells are cultured with change of media every three-four days.
  • Cells are then seeded in 96 well microtiter dishes and cultured for three day at 38 °C, 5% CO 2 and 95% humidity.
  • the cells are washed with NN -buffer (+10mM Hepes + 0.1% BSA) for one minute and glucose (final cone. 22 mM), IBMX (final conc.O.l mM) and compounds (final cone, from 5 x 10 '5 M - 5 x 10 "8 M) added. All cells are then incubated for three hours (38 °C, 5% CO 2 and 95% humidity). Supemates are harvested into Greiner minisorb microtiter wells and frozen. Insulin is measured using elisa-techniques.
  • the compounds of the present invention show high potency in the insulin release test and high selectivity compared to the relaxation of rat aorta rings test.
  • the present invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutically acceptable carrier or diluent.
  • compositions comprising a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 h Fri.. 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or- topical applications.
  • 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, syrup, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • 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, emuisifiers, salt for influencing osmotic pressure, buffers and/or coloring sub- stances 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.
  • 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, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, topical, ophthalmic solution or an oinment, oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, abso ⁇ tion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • suiatable are 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.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • the compounds of the invention may be administered to a mammal, especially a human, in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above and especially of diseases of the endocrinological system such as hyperinsulinaemia and diabetes.
  • mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, in an effective amount.
  • the compounds according to the invention are effective over a wide dose range.
  • dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg of a compound of formula I, conveniently given from 1 to 5 times 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 compounds are dispensed in unit dosage form comprising from about 1 to about 100 mg of the compounds of formula I in or together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
  • 2-Acetylamino-5-chioro-benzenesulfonyl chloride was prepared from 2-acetylamino-5- chloro-benzenesulfonic acid pyridinium salt according to Barco et al., Synthesis 1974, 877, and was immediately reduced to the title compound by treatment with 4- methylbenzenethiol and triethylamine according to the general method described by Lee and Field, Synthesis, 1990, 391 .
  • N-(4-Chioro-2-cyanomethylsulfonylphenyl)acetamide (0.73 g) was added at room 0 temperature to 0.5 M aqueous NaOH (10 ml) to form a yellow solution. After 45 min 0.1 g of charcoal was added and the mixture was filtered through celite. The filtrate was cooled to 0 °C and 1 M HCI (7.5 ml) was added. After 30 min the precipitate was collected by filtration and dried to give 0.66 g of the title compound. Recrystallization from methanol gave pale crystals.
  • the cold mixture was diluted with dichloromethane (20 ml), extracted with saturated aqueous sodium bicarbonate (10 ml), washed with water (2 x 50 ml), dried (Na 2 SO ) and concentrated in vacuo.
  • the residue was purified by flash chromatography using ethyl acetate / heptane 1 :1 as eluent.
  • the title compound was obtained as a sirup. Yield 1.72 g (100 %).
  • the compound could be crystallised from ethyl acetate/ heptane, mp 88.5 - 89.5 °C; El SP/MS: 302 (M+).
  • N-(2-Cyanomethylsulfonyl-5-trifluoromethylphenyl)butyramide (0.41 g) in 0.5 M aqueous NaOH (5 ml) was stirred at room temperature for 2 h. The mixture was cooled to 0 °C and 1 M HCI (4 ml) was added.
  • Acetyl chloride (575 ⁇ l, 8 mmol) in THF (2 ml) and subsequently pyridine (645 ⁇ l, 8 mmol) in THF (2 ml) were added to a stirred solution of (2-amino-3,5-difiuoro- phenylsulfanyl)acetonitrile (1.53 g) in THF (20 ml) at 0 °C. The mixture was stirred at 0 °C for 15 min, then at ambient temperature for 1 h. Additional amounts of acetyl chloride (57 ⁇ l) and pyridine (65 ⁇ l) were added, and stirring was continued for 1 h.
  • N-(2-Cyanomethylsulfanyl-4,6-difluoro-phenyi)acetamide (0.25 g) was suspended in glacial acetic acid (2 ml). Hydrogen peroxide (35 %, 1 ml) was added and the mixture was stirred at 100 °C for 1 h 45 min. Then the mixture was cooled to 0 °C and water (5 ml) was added. After stirring for Vz h a white precipitate was isolated by filtration, washed with water and dried to give the title compound as white needles.
  • the title compound could be further purified by recrystaiiization from 96 % ethanol; mp 100.5 - 101.5 °C; 1 H-NMR (DMSO-de), ⁇ (ppm): 9.68 (s, 1 H, NH), 7.50 - 7.30 (m, 2H, Ar-H), 7.23 - 7.07 (m, 1 H, Ar- H), 4.26 (s, 2H, CH 2 ), 2.05 (s, 3H, CH 3 ); IR (KBr) v (cm '1 ): 3239 (NH), 2244 (C ⁇ N), 1641 and 1579 (amide).
  • N-(2-Cyanomethylsulfanyl-4-fluoro-phenyl)acetamide (0.43 g) was suspended in glacial acetic acid (2 ml). Hydrogen peroxide (35 %, 1 ml) was added and the mixture was stirred at 100 °C for 1 h. Then the mixture was cooled to 0 °C and water (15 ml) was added. After stirring for 10 min a white precipitate was isolated by filtration, washed with water and dried.
  • N-(2-Cyanomethylsulfonyl-4-fluoro-phenyl)acetamide (0.21 g) was dissolved in 0.5 M NaOH (3 ml) at room temperature. After 1 1 / 2 h the mixture was filtered. The filtrate was cooled to 0 °C and 4M HCI (0.5 ml) was added. A white precipitate was isolated by filtration, washed with water (5 ml) and dried to give the title compound as a white solid.
  • N-(2-Cyanomethylsulfanyl-5-fiuoro-phenyl)acetamide was oxidized by a procedure similar to the one described in EXAMPLE 2 d) to give the title compound as white crystals, mp 131 - 132 °C; 1 H-NMR (DMSO-d 6 ), ⁇ (ppm): 9.65 (s, 1 H, NH), 8.07 - 7.93 (m, 2H, Ar-H), 7.41 - 7.28 (m, 1 H, Ar-H), 5.32 (s, 2H, CH 2 ), 2.16 (s, 3H, CH 3 ).

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Abstract

La présente invention concerne des dérivés de 1,4-thiazine-2-carbonitrile fusionnés, des compositions les contenant et les procédés de préparation de ces composés. Ces composés sont utilisés dans le traitement de maladies du système nerveux central, du système cardiovasculaire, du système pulmonaire, du système gastro-intestinal et du système endocrinien.
PCT/DK2000/000100 1999-03-12 2000-03-10 Derives de 1,4-thiazine-2-carbonitrile fusionnes, leur preparation et leur utilisation WO2000055147A1 (fr)

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EP00909065A EP1163233A1 (fr) 1999-03-12 2000-03-10 Derives de 1,4-thiazine-2-carbonitrile fusionnes, leur preparation et leur utilisation
JP2000605576A JP2002539202A (ja) 1999-03-12 2000-03-10 融合１，４−チアジン−２−カルボニトリル誘導体、その製造および使用
AU31475/00A AU3147500A (en) 1999-03-12 2000-03-10 Fused 1,4-thiazine-2-carbonitrile derivatives, their preparation and use

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021340A1 (fr) * 2004-08-23 2006-03-02 F.Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
WO2010093243A1 (fr) * 2009-02-12 2010-08-19 Coöperatieve Mirzorg U.A., Arnhem Utilisation d'une combinaison de diazoxyde et de metformine pour le traitement de l'obésité ou des troubles liés à l'obésité
WO2013191984A1 (fr) * 2012-06-21 2013-12-27 Boehringer Ingelheim International Gmbh Thiazin-3-ones fusionnées utilisées comme inhibiteurs du kca3.1

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997026265A1 (fr) * 1996-01-17 1997-07-24 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnee et de 1,4-thiazine fusionnee, leur preparation et utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997026265A1 (fr) * 1996-01-17 1997-07-24 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnee et de 1,4-thiazine fusionnee, leur preparation et utilisation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021340A1 (fr) * 2004-08-23 2006-03-02 F.Hoffmann-La Roche Ag Composés antiviraux hétérocycliques
KR100847181B1 (ko) * 2004-08-23 2008-07-17 에프. 호프만-라 로슈 아게 이종환 항바이러스 화합물
US7479489B2 (en) 2004-08-23 2009-01-20 Roche Palo Alto Llc Heterocyclic antiviral compounds
WO2010093243A1 (fr) * 2009-02-12 2010-08-19 Coöperatieve Mirzorg U.A., Arnhem Utilisation d'une combinaison de diazoxyde et de metformine pour le traitement de l'obésité ou des troubles liés à l'obésité
WO2013191984A1 (fr) * 2012-06-21 2013-12-27 Boehringer Ingelheim International Gmbh Thiazin-3-ones fusionnées utilisées comme inhibiteurs du kca3.1
US9533999B2 (en) 2012-06-21 2017-01-03 Boehringer Ingelheim International Gmbh Fused thiazin-3-ones as KCA3.1 inhibitors

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