WO1999058497A1 - Guanidines et diaminonitroethenes substituees, preparation et applications - Google Patents

Guanidines et diaminonitroethenes substituees, preparation et applications Download PDF

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Publication number
WO1999058497A1
WO1999058497A1 PCT/DK1999/000251 DK9900251W WO9958497A1 WO 1999058497 A1 WO1999058497 A1 WO 1999058497A1 DK 9900251 W DK9900251 W DK 9900251W WO 9958497 A1 WO9958497 A1 WO 9958497A1
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Prior art keywords
cyano
trifluoromethyl
guanidine
dichlorophenyl
bis
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PCT/DK1999/000251
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English (en)
Inventor
John Patrick Mogensen
John Bondo Hansen
Tina Møller TAGMOSE
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Novo Nordisk A/S
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Priority to CA002331299A priority Critical patent/CA2331299A1/fr
Priority to JP2000548301A priority patent/JP2002514621A/ja
Priority to AU35957/99A priority patent/AU3595799A/en
Priority to EP99917806A priority patent/EP1077933A1/fr
Publication of WO1999058497A1 publication Critical patent/WO1999058497A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/28—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to substituted guanidines and diaminonitroethenes, 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 labor. By acting on potassium channels of the central nervous system these compounds can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsia and cerebral ischemia.
  • the compounds are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and in contraception.
  • Compounds of the present invention which inhibit insulin secretion by activating potassium channels of the beta-cell can be used in combination with other compounds which may be used to treat non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.
  • examples of such compounds are insulin, insulin sensitizers, such as thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide, glibenclamide and glucagon like peptide ( GLP1), inhibitors of ⁇ -glucosidases and hepatic enzymes responsible for the biosynthesis of glucose.
  • Diazoxide (7-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, 47, 1381-1386 (1994); Pirotte B. et al., J. Med. Chem., 36, 3211-3213 (1993).
  • Diazoxide has furthermore been shown to delay the onset of diabetes in BB-rats ( Vlahos WD et al. Metabolism 40, 39-46 (1991)). In obese zucker rats diazoxide has been shown to decrease insulin secretion and increase insulin receptor binding and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R. et al. Endocrinol. 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.
  • N-N'-substituted cyanoguanidines are claimed for the use as curing agent for epoxy resins.
  • EP-747374-A1 EP 354553 and EP 405525 derivatives of the N-cyano-N'-aryl-N"-alkyl-guanidine type have been claimed as potassium channel activators related to smooth muscles.
  • N-cyano-N'-aryl-N"-aryl-guanidines have been claimed in WO 9422807.
  • N-aryl-N'-alkyl-2-nitro-1 ,1-ethenediamines have been described in U.S Pat. 4567.188 In J.Med.Chem 35 , 2327-2340 (1992) the synthesis of N-aryl-N'-alkyl-2-nitro-1 ,1- ethenediamine and N-heteroaryl-N'-alkyl-2-nitro-1 , 1 -ethenediamine and their properties as agents for relaxation of smooth muscle are described .
  • the present invention relates to compounds of the general formula I:
  • R 1 and R 2 are independently hydrogen, trifluoromethyl or halogen
  • R 3 is trifluoromethyl, methoxy or halogen
  • R 4 is straight or branched C 1-12 -alkyl,. C 2 . 12 -alkenyl, C 2 . 12 -alkynyl or C 3 . 8 -cycloalkyl optionally substituted with C 3 . 8 -cycloalkyl, halogen, hydroxy, aryloxy, arylalkoxy, C ⁇ -alkoxy, C 1-6 - alkylthio, arylthio, C L g-alkylamino, C ⁇ -dialkylamino, heteroaryl, heteroarylalkyl or aryl, any or heteroaryl group optionally being substituted with halogen or trifluoromethyl; or
  • R 4 is Y-R 5 , Y being -O- or -N(R 6 )- ;
  • R 5 and R 6 are independently straight or branched C 1-12 -alkyl, C 2 . 12 -alkenyl, C 2 . 12 -alkynyl or C 3 _ 8 -cycloalkyl optionally substituted with C 3 .
  • R 5 and R 6 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C ⁇ -alkyl, hydroxy, C 1-6 -alkoxy, C 1 physically 6 -alkoxy-C 1 . 6 -alkyl, nitro, amino, cyano, trifluoromethyl, C ⁇ 6 -monoalkyl- or dialkylamino or oxo;
  • X is N-CN or CH-NO 2 ;
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form 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, malo- nic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, 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, malo- nic
  • C ⁇ -alkoxy refers to a straight or bran- ched monovalent substituent comprising a C ⁇ -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • C.,. 6 -alkylthio refers to a straight or bran- ched 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.
  • cycloalkyl refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclo- hexyl.
  • C 2 . 12 -alkenyl 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, isopro- penyl, n-butenyl, n-pentenyl and n-hexenyl.
  • C 2 . 12 -alkynyl refers to unsaturated hydrocarbons which contain triple bonds, such as e.g. -C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CH, -CH 2 CH 2 C ⁇ CH, -CH(CH 3 )C ⁇ CH, and the like.
  • 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 -0-CH(CH 3 ) 2 and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • perhalomethyl means trifluoromethyl, t chloromethyl, tribromomethyl or triiodo- methyl.
  • C 1-12 -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 1-18 -alkyl as used herein also includes secondary C 3-6 -alkyl and tertiary C 4 . 6 -alkyl.
  • C ⁇ -monoalkylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a straight or branched, saturated hydrocarbon chain ha- ving the indicated number of carbon atoms such as e.g.
  • C ⁇ -diaikyiamino 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.
  • 3-12 membered mono- or bicyclic system refers to a monovalent substituent of formula -NR 2 R 3 or -NR 1 R 12 where R 2 and R 3 , or R 11 and R 12 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, such as 1-pyrrolidyl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 7-azabicyclo[2.2.1]heptan-7- yl, tropanyl and the like.
  • 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, pyridazi- ne, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazo- line, quinoxaline, indole, benzimidazole, benzofuran, pteridine, and purine.
  • arylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy.
  • arylalkoxy refers to a C ⁇ -alkoxy group substituted with an aro- matic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
  • heteroarylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1-(2-pyrimidyl)ethyl and the like.
  • arylthio refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio, and the like.
  • R 3 is selected from trifluoromethyl and R 2 from hydrogen or trifluoromethyl.
  • R 2 and R 3 are selected from halogen and R 4 is branched C 1-12 -alkyl.
  • R 2 and R 3 are selected from halogen and R 4 is C 5 -alkyl, branched at the C(2), C(3) or C(4) carbon atom counted from the attachment to the nitrogen atom, in particular compounds where R 2 and R 3 both are chloro.
  • 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 pul- monary 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 diseases; the pul- monary 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 vasospastic disor- ders 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. Further, 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 non insulin dependent diabetes (NIDDM).
  • NIDDM non insulin 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.
  • the present compounds Owing to the efficiency of the present compounds to improve glucose sensitivity they are useful for the treatment and/or prevention of ailments and disorders involving elevated plasma blood glucose, such as hyperglycaemia. Furthermore, they may find use in the treatment and/or prevention of dyslipidemia, Type I diabetes, NIDDM, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance, obesity, diabetic dyslipidemia, hyperlipide- mia and hypertension.
  • 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 nicotina ide, 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 patients with autoreactivity against beta-cell epitopes that later turns insulin requiring
  • cytokines e.g.
  • interleukin-1 b IL-1b
  • TNF ⁇ tumour necrosis factor ⁇
  • IFN ⁇ interferon ⁇
  • IL-1b interleukin-1 b
  • NNF ⁇ tumour necrosis factor ⁇
  • IFN ⁇ interferon ⁇
  • 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 indi- cated 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.
  • transplantation e.g. islet transplantation into diabetes patients.
  • the use of one or both of these treatments may reduce the risk of rejection of the transplanted islets/beta-cells/engineered beta-cells/pancreas.
  • the compounds of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hyperinsulinaemia and diabetes.
  • the invention relates to a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperinsulinaemia and treatment or prevention of diabetes. Furthermore, the invention also relates to the use of the inventive compounds of formula I as medicaments useful for treating hyperinsulinaemia and treating or preventing diabetes.
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an an- tidiabetic 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; bigua- nides, e.g. metformin; benzoic acid derivatives, e.g. repaglinide;and thiazolidinediones, e.g. troglitazone and ciglitazone.
  • the compounds of the present invention may be prepared by various methods known to those skilled in the art. For example the methods for preparation of 2-nitro-1 ,1- ethenediamines by Niemers et al. U.S Pat, 4,567,188 and P.W Manley et al. J. Med. Chem. 35, 2327-2340 (1992):
  • X NCN, CHNO,
  • 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 in Kogyo Kagaku Zashi, 59,(6) 1-33 (1956) and Zh. Obshch. Khim., 35, 2055 (1965).
  • the ability of the compounds to interact with potassium channels can be determined by vari- ous methods.
  • patch-clamp techniques Hamill O.P., Marty A., Neher E., Sakmann B. and Sigworth F.J., Pl ⁇ gers Arch., 391. 85-100 (1981)
  • patch-clamp techniques Hamill O.P., Marty A., Neher E., Sakmann B. and Sigworth F.J., Pl ⁇ gers Arch., 391. 85-100 (1981)
  • the activity of the compounds as potassium channel openers can also be measured as rela- xation 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., 231, 5448-5454 (1987).
  • An opening of K ATP -channels will result in an efflux of potassium ions.
  • 86 Rb + a radioactive potassium mimic
  • the test expresses the ability of the compounds to regulate the secretion of insulin from the beta-cells.
  • 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 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 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 KCI after 5 s, and the depolarisation-induced increase in DiBAC fluorescence monitored for 55 s.
  • K ATP -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.
  • K ATP -channel modulators can be measured using the following procedure: 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.lmM) 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% C0 2 and 95% humidity).
  • the compounds according to the invention are effective over a wide dose range. In general satisfactory results are obtained with dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day. A most preferable dosage is about 1 mg to about 100 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be trea- ted, and the preference and experience of the physician or veterinarian in charge.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxy- ethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulo- se 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 delay- ed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tablet- ting techniques and contains:
  • N-Cyano-N'-(3.5-bis(thfluoromethyl)phenyl)-N"-(1-methylethyl)-guanidine N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350 mg) and iso- propylamine (1 ml) was stirred in a sealed flask for 19 h at 75 °C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2 SO 4 ) and concentrated.
  • N-(3-Trifluoromethylphenyl)-N'-cyano-O-phenylisourea (1 mmol, 290 mg) was stirred for 19 h at 80 °C in cyclopentylamine (1 ml). After concentration of the cold reaction mixture, the residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2 SO 4 ) and concentrated. The residue was purified by column chromatography
  • N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and isopropylamine (1 ml) was stirred in a sealed flask for 19 h at 75 °C. After concentration the residue was dis- solved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2 SO 4 ) and concentrated. The residue was crystallised from ethyl acetate / heptane 1 :3 to give the title compound (115 mg, 43%) as white crystals.
  • N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-phenylisourea 0.6 mmol, 200 mg
  • 3-methylbutylamine 1.31 mmol, 0.152 ml
  • triethylamine (0.66 mmol, 0.091 ml)

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Abstract

Cette invention, qui a trait à des dérivés de guanidine et de diaminonitroéthène correspondant à la formule (I), X, R?1, R2, R3 et R4¿ étant définis dans le descriptif, concerne également des compositions à base de ces substances ainsi que des procédés de préparation des composés décrits. Ces composés s'avèrent des plus utiles en matière de traitement de maladies du système nerveux central, du système cardio-vasculaire, du système pulmonaire, de l'appareil digestif et du système endocrinien.
PCT/DK1999/000251 1998-05-11 1999-05-06 Guanidines et diaminonitroethenes substituees, preparation et applications WO1999058497A1 (fr)

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CA002331299A CA2331299A1 (fr) 1998-05-11 1999-05-06 Guanidines et diaminonitroethenes substituees, preparation et applications
JP2000548301A JP2002514621A (ja) 1998-05-11 1999-05-06 置換グアニジン及びジアミノニトロエテン、それらの製造及び使用
AU35957/99A AU3595799A (en) 1998-05-11 1999-05-06 Substituted guanidines and diaminonitroethenes, their preparation and use
EP99917806A EP1077933A1 (fr) 1998-05-11 1999-05-06 Guanidines et diaminonitroethenes substituees, preparation et applications

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
JP2004506713A (ja) * 2000-08-21 2004-03-04 パシフィック　コーポレーション 新規チオウレア誘導体およびこれを含有する薬学的組成物
WO2006000607A1 (fr) * 2004-06-23 2006-01-05 Neurotec Pharma, S.L. Composes destines au traitement de l'inflammation du systeme nerveux central
US11111266B2 (en) 2016-10-18 2021-09-07 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11279730B2 (en) 2016-07-07 2022-03-22 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11407782B2 (en) 2016-05-06 2022-08-09 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11732000B2 (en) 2015-07-06 2023-08-22 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11851457B2 (en) 2016-10-18 2023-12-26 Sage Therapeutics Oxysterols and methods of use thereof
US11884697B2 (en) 2016-04-01 2024-01-30 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11905309B2 (en) 2013-03-13 2024-02-20 Sage Therapeutics, Inc. Neuroactive steroids and methods of use thereof
US11926646B2 (en) 2016-09-30 2024-03-12 Sage Therapeutics, Inc. C7 substituted oxysterols and methods of use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6268284B1 (en) 1998-10-07 2001-07-31 Tokyo Electron Limited In situ titanium aluminide deposit in high aspect ratio features

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004506713A (ja) * 2000-08-21 2004-03-04 パシフィック　コーポレーション 新規チオウレア誘導体およびこれを含有する薬学的組成物
WO2006000607A1 (fr) * 2004-06-23 2006-01-05 Neurotec Pharma, S.L. Composes destines au traitement de l'inflammation du systeme nerveux central
US11905309B2 (en) 2013-03-13 2024-02-20 Sage Therapeutics, Inc. Neuroactive steroids and methods of use thereof
US11732000B2 (en) 2015-07-06 2023-08-22 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11884697B2 (en) 2016-04-01 2024-01-30 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11407782B2 (en) 2016-05-06 2022-08-09 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11878995B2 (en) 2016-05-06 2024-01-23 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11279730B2 (en) 2016-07-07 2022-03-22 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11926646B2 (en) 2016-09-30 2024-03-12 Sage Therapeutics, Inc. C7 substituted oxysterols and methods of use thereof
US11111266B2 (en) 2016-10-18 2021-09-07 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11613556B2 (en) 2016-10-18 2023-03-28 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
US11851457B2 (en) 2016-10-18 2023-12-26 Sage Therapeutics Oxysterols and methods of use thereof

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