WO1999032467A1 - Derives de 1,2,4-benzothiadiazine, leur preparation et leur utilisation - Google Patents

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

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Publication number
WO1999032467A1
WO1999032467A1 PCT/DK1998/000546 DK9800546W WO9932467A1 WO 1999032467 A1 WO1999032467 A1 WO 1999032467A1 DK 9800546 W DK9800546 W DK 9800546W WO 9932467 A1 WO9932467 A1 WO 9932467A1
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Prior art keywords
benzothiadiazine
dioxide
chloro
compound
bromo
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PCT/DK1998/000546
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English (en)
Inventor
Pascal De Tullio
Flemming Elmelund Nielsen
John Bondo Hansen
Holger Claus Hansen
Bernard Pirotte
Stéphane Boverie
Fabian Somers
Philippe Lebrun
John Patrick Mogensen
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Novo Nordisk A/S
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Priority to AU15559/99A priority Critical patent/AU1555999A/en
Publication of WO1999032467A1 publication Critical patent/WO1999032467A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom

Definitions

  • the present invention relates to 1 ,2,4-benzothiadiazine 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.
  • 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. Furthermore, 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, epilepsy 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-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 ATP -channels on pancreatic beta-cells (Pirotte B. et al. Biochem. Pharmacol, 4Z, 1381-1386 (1994); Pirotte B. et al., J. Med. Chem., 3f>, 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)).
  • 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. 133. 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 A PA-glutamate receptor.
  • the present invention relates to 1 ,2,4-benzothiadiazine derivatives of the general formula
  • R is hydrogen; C,. 6 -alkyl, C 2-6 -alke ⁇ yl or C 2-6 -alkynyl optionally mono- or polysub- stituted with halogen, hydroxy or C 1-6 -alkoxy; or C ⁇ -cycloalkyl optionally mono- or polysubstituted with C ⁇ -alkyl, halogen, hydroxy or C ⁇ -alkoxy;
  • R 3 is C ⁇ -cycloalkyl or (C 3 . 6 -cycloalkyl)C 1-6 -alkyl the C ⁇ -cycloalkyl group optionally being mono- or polysubstituted with C ⁇ -alky!, halogen, hydroxy or C 1-6 -alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms, optionally being mono- or polysubstituted with halogen, cyano, trifluoromethyl, C,. 6 -alkyl, C 1-6 -alkoxy, C 1 .
  • n, m and p independently are 0, 1 , 2 or 3 and R 10 is hydrogen; hydroxy; C 1-6 - alkoxy; C ⁇ s-cycloalkyl optionally mono- or polysubstituted with C,. 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;
  • R 5 , R 6 , R 7 , R 8 independently are hydrogen, halogen; C 1-18 -alkyl; C ⁇ -cycloalkyl; hydroxy; C-,. 6 -alkoxy; nitro; amino; cyano; cyanomethyl; perhalomethyl; C,- 6 - monoalkyl- or dialkylamino; sulfamoyl; C ⁇ -alkylthio; C ⁇ -alkylsulfonyl; C 1-6 -alkylsulfinyl; C,.
  • 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 pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66_, 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, malonic, succin
  • C 1-6 -alkoxy refers to a straight or branched monovalent substituent comprising a C ⁇ -alky! 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 ⁇ -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 and “C 2 . 18 -alkenyl” as used herein refers to an unsaturated hydrocarbon chain having 2-6 or 2-18 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 -cycloalkyr refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopropyi, cyclobutyl, cyclopentyl, or cyclohexyl.
  • C ⁇ -alkoxy-C ⁇ -alkyl 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 refers to a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as e.g.
  • u C 1-18 -alkyr as used herein also includes secondary C ⁇ -alkyl and tertiary C 4-6 -alkyl.
  • C 1-6 -monoalkylamino 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.
  • C ⁇ -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-methylamino, 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 L e-alkoxycarbonyl refers to a monovalent substituent comprising a C ⁇ -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.
  • 3-6 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-norbornyl, 7-norbornyl, 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-naphtyimethyl, 2-(1-naphtyl)ethyl and the like.
  • aryioxy refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy.
  • arylalkoxy refers to a C ⁇ -alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1- naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
  • C... 6 -alkylsulfonyr refers to a monovalent substituent comprising a Ci-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-methylpenty
  • C L s-monoalkylaminosulfonyl refers to a monovalent substituent comprising a C L ⁇ -monoalkylamino group linked through a sulfonyl group such as e.g.
  • methylaminosulfonyl methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, sec-butylaminosulfonyl, isobutylaminosulfonyl, tert- butylaminosulfonyl, n-pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3- methylbutylaminosulfonyl, n-hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopenty- laminosulfonyl, n-hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.
  • C.. 6 -dialkylaminosulfonyr 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 1-6 -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, isopropylcarbonylamino, 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 ⁇ -cycloalkyl group, the cycloalkyl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C ⁇ -alkoxy; 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 ⁇ - 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 ⁇ -alkyl, halogen, hydroxy or C 1-6 -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, ethylaminocarbonyi, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert- butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3- methylbutylamino-carbonyl, n-hexylaminocarbonyl, 4-methylpentylaminocarbonyl, neo- pentylaminocarbonyl, n-hexylaminocarbonyl and 2-2-dimethylpropylaminocarbonyl.
  • d-g-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 1-6 -monoalkylaminocarbonyl group, e.g. methylaminocarbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, isopropylaminocarbonylamino, n-butylaminocarbonylamino, sec-butyiaminocarbonylamino, o isobutyiaminocarbonylamino, tert-butylaminocarbonylamino, and 2- methylbutylaminocarbonylamin ⁇ .
  • Ci-e-dialkylaminocarbonylamino refers to an amin ⁇ group wherein one of the hydrogen atoms is substituted with a C ⁇ -dialkylaminocarbonyl group, such as 5 dimethylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethyla- minocarbonylamino, dipropylaminocarbonylamino, N-(n-butyl)-N- methylaminocarbonylamino, di(n-pentyl)aminocarbonylamino, and the like.
  • 5- or 6-membered nitrogen, oxygen or sulfur containing ring refers to a monovalent substituent comprising a monocyclic unsaturated or saturated system containing one or more nitrogen, oxygen or sulfur atoms and having 5 or 6 members, e.g.
  • pyrrolidinyl pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidi- nyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, 5 thiadiazolyl, 1,3-dioxolanyl, and 1 ,4-dioxolanyl.
  • 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-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.
  • Compounds of the present invention which act as blockers of K ATP -channels can be used for the treatment of NIDDM.
  • 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.
  • 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 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 insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.
  • Suitable antidiabetics comprise insulin 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;and thiazolidinediones, e.g. troglitazone and ciglitazone.
  • the present invention relates to methods of preparing the above mentioned compounds.
  • the methods comprises:
  • R 3 is as defined above and X is a leaving group such as halogen or sulfate, preferentially chloro, bromo or iodo to form a compound of the general formula I wherein Z is O or S.
  • the reaction may be carried out in a suitable solvent and in the presence of a base.
  • R' and R" together as two substituents on methyl form a group R'R"CH meeting the criteria defined above for R 3 , to form a compound of the general formula I wherein Z is O and R 3 is R'R"CH.
  • R 5 , R 6 , R 7 and R 8 are as defined above and Q is a leaving group such as halogen, preferentially chloro, bromo, iodo; amino, trimethylamino, imidazol-1-yl, methylsulfanyl, methylsulfinyl or methylsulfonyl with a compound of formula VI:
  • R 3 is as defined above and Y is O or S to form a compound of the general formula I wherein Z is O or S.
  • the reaction may be carried out in a suitable solvent and in the presence of a base.
  • R 3 , R 5 , R 6 , R 7 and R 8 are as defined above with an aminating agent according to known procedures, see e.g. P.D. Kennenwell, J.B. Taylor, Chem.Soc.Rev. (1980) 477- 498 and P.D. Kennenwell, J.B. Taylor, Chem.Soc.Rev. (1975) 189-209, to form a compound of the general formula VIII
  • n 1 or 2.
  • R 5 , R 6 , R 7 and R 8 are as defined above with CS 2 in the presence of a base to give the corresponding sulfonylimino carbodithioate which in turn is treated with an alkylating agent of formula III
  • R 3 is as defined above and X is a leaving group such as halogen or sulfate, preferentially chloro, bromo or iodo to form a compound of formula X
  • R 3 , R 5 , R 6 , R 7 and R 8 are as defined above and PG is a protecting group, e.g. substituted benzyl, with chlorosulfonyl isocyanate (CI-S0 2 -NCO) and subsequent ring closure folllowed by removal of the protecting group to form a compound of formula I.
  • PG is a protecting group, e.g. substituted benzyl, with chlorosulfonyl isocyanate (CI-S0 2 -NCO) and subsequent ring closure folllowed by removal of the protecting group to form a compound of formula I.
  • 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., 23, 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 Hail O.P., Marty A., Neher E.,
  • 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., 262, 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 % C0 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 NaCl, 10 mM 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 NaCl, 10 mM 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 o 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. 5 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 0 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 0 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 active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, 5 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, 0 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 particulariy 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:
  • the compounds were obtained as described by Girard (Y. Girard et al., J. Chem. Soc. Perkin I, 1043, 1 979) using nitromethane as the solvent for the reaction of the appropriate aniline with chlorosulfonyl isocyanate.
  • the crude product was purified by dissolution in a 5 % w/v aqueous solution of sodium hydrogen carbonate (20-30 mL/g) or in a 2.5 % w/v niethanol-water 1 : 1 solution of sodium hydrogen carbonate (40-60 mL/g).
  • the resulting suspension or solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 0 with 1 2N HCI.
  • the precipitate was collected by filtration, washed with water and dried (yields: 40-60 %).
  • the solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 0 with 1 2N HCI.
  • the precipitate was collected by filtration, washed with water and dissolved in a hot 5 % w/v aqueous solution of sodium hydrogen carbonate (400-600 mL) or in a 2.5 % w/v methanol-water 1 : 1 solution of sodium hydrogen carbonate (800 mL).
  • the resulting suspension was treated with charcoal, filtered, and the filtrate was adjusted to pH 0.
  • the precipitate was collected by filtration, washed with ' water and dried (yields: 60-80%).
  • alkyl halide (1 .5 - 2.0 equiv.) was added to the solution and the mixture was heated at 70-80 °C for 4-6 h (until completion of the reaction checked by t.l.c).
  • Two compounds were usually formed: the title compound: 3-alkoxy-4H-1 ,2,4-benzothiadiazine 1 , 1 -dioxide, and the compound of N-alkylation: 2-alkyl-2,3-dihydro-3-oxo-4H-1 ,2,4- benzothiadiazine 1 , 1 -dioxide.
  • the solvent was removed by distillation under reduced pressure and the residue was suspended in distilled water (30 mL). The suspension was adjusted to pH 14 with NaOH 5% w/v in water.
  • the insoluble material was eliminated by filtration and the filtrate was treated with charcoal and filtered.
  • the filtrate was carefully adjusted to pH 10 and the resulting precipitate (essentially the compound of N-alkyiation) was collected by filtration.
  • the filtrate was adjusted to pH 1 and the resulting precipitate (the compound of O-alkylation) was collected by filtration, washed with water and dried.
  • the title compound was obtained from 7-fluoro-3-oxo-2,3-dihydro-4H- 1 ,2,4- benzothiadiazine 1 ,1 -dioxide and isopropyl iodide; mp 200-205 °C, IR (KBr): 3594, 3532, 2988, 1591 , 1543, 1499, 1317, 1287, 1260, 1 167, 1092 cm-1 .
  • the title compound was obtained from 7-methoxy-3-oxo-2,3-dihydro-4H- 1,2,4- benzothiadiazine 1,1 -dioxide and isopropyl iodide; mp 162-176 °C, IR (KBr): 3570, 3513, 3053, 2983, 1586, 1541, 1504, 1318, 1279, 1170, 1095 cm-1.
  • the title compound was obtained from 7-chloro-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and cyclopentyl bromide.
  • the compound was purified by refiuxing in ethyl acetate for 20 min. The suspension was cooled and the insoluble material was collected by filtration, washed with ethyl acetate and dried; mp >300 °C, IR (KBr): 3253, 3188, 3104, 2952, 2875, 1617, 1601, 1580, 1521, 1480,
  • the title compound was obtained from 7-fluoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and ethyl bromide; mp 205-208 °C, IR (KBr): 3603, 3536, 3078, 3056, 2980, 2946, 1634, 1609, 1564, 1527, 1494, 1287, 1268, 1233, 1197, 1156, 1134 cm-1.
  • the title compound was obtained from 7-fluoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and cyclopropylmethyl bromide; mp 218-224 °C, IR (KBr): 3237, 3073, 1552, 1521, 1487, 1303, 1260, 1224, 1193, 1150, 1130 cm-1.
  • the title compound was obtained from 7-bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and cyclopropylmethyl bromide; mp 242-244 °C, IR (KBr): 3233, 3183, 3088, 3012, 1607, 1598, 1553, 1517, 1478, 1296, 1253, 1201, 1157, 1146, 1091 cm-1.
  • the title compound was obtained from 6-fiuoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and ethyl bromide; mp 218-220 °C, IR (KBr): 3238, 3200, 3153, 3107, 3081, 1617, 1558, 1477, 1297, 1268, 1206, 1154, 1121 cm-1.
  • the title compound was obtained from 6-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and ethyl bromide; mp 233-240 °C, IR (KBr): 3230, 3180, 3099, 3068, 1605, 1595, 1557, 1471, 1297, 1197, 1160, 1138, 1096 cm-1.
  • the title compound was obtained from 6-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and isopropyl iodide; mp 249-253 °C, IR (KBr): 3251, 3082, 2967, 1606, 1553, 1466, 1300, 1198, 1157, 1136, 1090 cm-1.
  • the title compound was obtained from 6-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclopropylmethyl bromide; mp 212-217 °C, IR (KBr): 3232, 3179, 3097, 3064, 1594, 1555 > 1471, 1303, 1196, 1160, 1137, 1095 cm-1.
  • 6-Chloro-3-cyclobutylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide The title compound was obtained from 6-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclobutyl bromide; mp 251-254 °C, IR (KBr): 3224, 3173, 3064, 2984, 1606, 1552, 1463, 1300, 1196, 1157, 1121, 1088 cm-1.
  • the title compound was obtained from ⁇ -bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and ethyl bromide; mp 269-273 °C, IR (KBr): 3232, 3177, 3078, 3056, 2984, 1603, 1557, 1518, 1465, 1293, 1202, 1159, 1140, 1082 cm-1.
  • the title compound was obtained from 6-bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1 -dioxide and isopropyl iodide; mp 244-252 °C, IR (KBr): 3239, 3178, 3073, 2970, 2927, 1597, 1552, 1465, 1291, 1198, 1163, 1137, 1082 cm-1.
  • the title compound was obtained from 6,7-dichloro-3-thioxo-2,3-dihydro-4H-1 ,2,4- benzothiadiazine 1 ,1 -dioxide and isopropyl iodide; m.p.: > 300°C, IR (KBr): 3252, 3183, 3089, 1612, 1557, 1459, 1303, 1286, 1 160 cm-1 .
  • the title compound was obtained from the reaction of 7-chloro-3-isopropylsulfanyl-4H- 1 ,2,4-benzothiadiazine 1 , 1 -dioxide with bromine in alkaline medium as described above.
  • the crude compound was purified by stirring in methanol.
  • the insoluble material was collected by filtration and suspended in diethylether (two fold).
  • the insoluble compound was collected by filtration, washed with diethylether and dried; mp 257-260 °C, IR (KBr): 3148, 2977, 1 606, 1 570, 1 507, 1477, 1 326, 1 173, 1 1 10, 1060, 1028 cm-1 .

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Abstract

L'invention concerne des dérivés de 1,2,4-benzothiadiazine de la formule générale (I) dans laquelle R?3, R5, R6, R7, R8¿ et Z sont tels que définis dans la description, des compositions de ceux-ci et des procédés pour préparer les composés. Ces derniers sont utiles dans le traitement de maladies du système nerveux central, du système cardio-vasculaire, du système pulmonaire, du système gastro-intestinal et du système endocrinien.
PCT/DK1998/000546 1997-12-19 1998-12-11 Derives de 1,2,4-benzothiadiazine, leur preparation et leur utilisation WO1999032467A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102977054A (zh) * 2012-12-12 2013-03-20 中国药科大学 一类选择性α2A受体激动剂的治疗阿尔茨海默病用途
CN105999097A (zh) * 2016-07-08 2016-10-12 王恩禄 一种治疗乙肝的中药组合物

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US5378704A (en) * 1992-04-15 1995-01-03 E. R. Squibb & Sons, Inc. Non-peptidic angiotensin-II-receptor-antagonists
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US5378704A (en) * 1992-04-15 1995-01-03 E. R. Squibb & Sons, Inc. Non-peptidic angiotensin-II-receptor-antagonists
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ARZNEIM.-FORSCH./DRUG RES., Volume 31, No. 2, 1981, VON H. WOLLWEBER et al., "3-Amino-2H-1,2,4-Benzothiadiazin-1,1-Dioxi de mit Antihypertensiver und Potentieller Diabetongener Wirkung", pages 279-288. *
IL FARMACO-ED. SC., Volume 17, No. 12, 1962, E. GRANA et al., "Azione Cardiovascolare di Derivati del 1,2,4-Benzotiadiazin-1,1-Diossido", pages 974-987. *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102977054A (zh) * 2012-12-12 2013-03-20 中国药科大学 一类选择性α2A受体激动剂的治疗阿尔茨海默病用途
CN105999097A (zh) * 2016-07-08 2016-10-12 王恩禄 一种治疗乙肝的中药组合物

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