WO2003045955A1 - Utilisation d'activateurs selectifs d'ouverture de canaux potassiques - Google Patents

Utilisation d'activateurs selectifs d'ouverture de canaux potassiques Download PDF

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WO2003045955A1
WO2003045955A1 PCT/DK2002/000798 DK0200798W WO03045955A1 WO 2003045955 A1 WO2003045955 A1 WO 2003045955A1 DK 0200798 W DK0200798 W DK 0200798W WO 03045955 A1 WO03045955 A1 WO 03045955A1
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dioxide
thiadiazine
thieno
chloro
alkyl
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PCT/DK2002/000798
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English (en)
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Jeppe Sturis
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Novo Nordisk A/S
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Priority to AU2002365289A priority Critical patent/AU2002365289A1/en
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • the present invention relates to a use of SUR1/Kir6.2 selective potassium chan- nel openers for the preparation of a medicament for the prevention or the treatment of diabetes in women with prior Gestational Diabetes Mellitus (GDM) as well as a pharmaceutical composition for use in the treatment of diabetes in women with prior GDM.
  • GDM Gestational Diabetes Mellitus
  • Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential.
  • the different types of potassium channels are the ATP-sensitive (K A ⁇ p-) channels, which are regulated by changes in the intracellular concentration of adenosine triphosphate.
  • the K A ⁇ p-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), vasodi- lation (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 A ⁇ p-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 hyperpolarize neurons and inhibit neurotransmitter release and it is expected that PCOs can be used for the treatment of various diseases of the central nervous system, e. g. epilepsia, ischemia and neurodegenerative diseases, such as Alzheimer's disease, and for the management of pain.
  • diseases of the central nervous system e. g. epilepsia, ischemia and neurodegenerative diseases, such as Alzheimer's disease, 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 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)).
  • the present invention relates to a use of SUR1/Kir6.2 selective potassium channel openers for the preparation of a medicament for the treatment or the prevention of diabetes in women with prior GDM.
  • B represents >NR 5 or >CR 5 R 6 , wherein R 5 and R 6 independently are hydrogen; hydroxy; C 1-6 -alkoxy; or C 1-6 -alkyl, C 3 . 6 -cycloalkyl, C 2-6 -alkenyl or C 2-6 -alkynyl optionally mono- or poly substituted with halogen; or R 5 and R 4 together represent one of the bonds in a double bond between the atoms 2 and 3 of formula (I);
  • R 7 is Ci.e-alkyl; or aryl or heteroaryl optionally mono- or poly substituted with halogen, hydroxy, C ⁇ -6 -alkoxy, aryloxy, arylalkoxy, nitro, amino, C ⁇ - 6 -monoalkyl- or dialkyl- amino, cyano, acyl, or C 1-6 -alkoxycarbonyl;
  • R 1 is hydrogen; hydroxy; C 1-6 -alkoxy; or C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 - alkenyl or C 2 . 6 - alkynyl optionally mono- or poly substituted with halogen and R 4 is hydrogen; or R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula (1); or R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula (I);
  • R 2 is hydrogen; hydroxy; C 1-6 -alkoxy; or C ⁇ . 6 -alkyl, C 3 . 6 -cycloalkyl, C 2-6 - alkenyl or C 2-6 - alkynyl optionally mono- or poly substituted with halogen
  • R 8 is hydrogen; C 3 . 6 -cycloalkyl or (C 3 . 6 -cycloalkyl)C 1-6 -alkyl, the C 3-6 -cycloalkyl group optionally being mono- or poly substituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 - alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen, oxygen or sulfur atoms; or straight or branched C 1-18 -alkyl optionally mono- or poly substituted with halogen, hydroxy, C 1-6 -alkoxy, C 1-6 -alkylthio, C 3 .
  • X is O or S;
  • R 9 is hydrogen; C ⁇ -6 -alkyl; C 2 . 6 -alkenyl; C 3 . 6 -cycloalkyl optionally mono- or poly substituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; or
  • R 8 and R 9 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or poly substituted with halogen, C -6 -alkyl, hydroxy, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, nitro, amino, cyano, trifluoro- methyl, C 1-6 -monoalkyl- or dialkylamino, oxo; or o R 3 is
  • n, m, p independently are 0,1 ,2,3 and R 10 is hydrogen; hydroxy; C 1-6 -alkoxy; C 3-6 - cycloalkyl optionally mono- or poly substituted with C ⁇ . 6 -alkyl, halogen, hydroxy or C 1-6 - alkoxy; C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl optionally mono- or poly substituted with s halogen; or
  • R 2 and R 3 together with the nitrogen atom forms a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or poly substituted with halo- 0 gen, C 1-6 -alkyl, hydroxy, C 1-6 -alkoxy, C 1-6 -alkoxy-C ⁇ -6 -alkyl, nitro, amino, cyano, trifluoro- methyl, C 1-6 -monoalkyl- or dialkylamino or oxo;
  • a together with carbon atoms 5 and 6 of formula (I) represents a 5 or 6 membered hetero- cyclic system comprising one or more nitrogen-, oxygen- or sulfur atoms, the heterocyclic 5 systems optionally being mono- or poly substituted with halogen; C ⁇ . ⁇ 2 -alkyl; C 3 . 6 - cycloalkyl; hydroxy; C 1-6 -alkoxy; C 1-6 -alkoxy-C 1-6 -alkyl; nitro; amino; cyano; cyanomethyl; perhalomethyl; C 1-6 -monoalkyl- or dialkylamino; sulfamoyl; C 1-6 -alkylthio; C-
  • the present invention relates to a pharmaceutical composition for use in the treatment or prevention of diabetes in women with prior GDM, comprising a compound of the formula (I) or (la) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical iso- mers including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
  • the present invention relates to a method for treating or preventing diabetes in women with prior GDM comprising administering an effective amount of a compound of the formula (I) or (la) to said subject.
  • Figure 1 shows an oral glucose tolerance test in panel A and perfused pancreas in panel B.
  • prevention in the context of "the treatment or the prevention of diabe- tes” means that the development of diabetes in women with prior GDM can be delayed or attenuated. Women with prior GDM have an increased risk of developing diabetes but the onset of the disease can be delayed and/or the severity of the disease attenuated by administration of a compound according to the present invention.
  • halogen designates an atom selected from the group consisting of F, Cl, Br and I.
  • C ⁇ . 6 -alkyl designates a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms.
  • C ⁇ . ⁇ 8 -alkyl as used herein also includes secondary C 3-6 -alkyl and tertiary C 4-6 -alkyl.
  • C L ⁇ -alkoxy refers to a straight or branched monovalent substituent comprising a C-
  • Representatives groups include, but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.
  • C 2-6 -alkenyl refers to a straight or branched, unsatu- rated hydrocarbon chain having 2-6 carbon atoms and one double bond.
  • examples of such groups include, but are not limited to vinyl, 1-propenyl, 2-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl, n-hexenyl and the like.
  • C 2-6 -alkynyl refers to a straight or branched, unsatu- rated hydrocarbons which contain triple bonds. Examples of such groups include, but are not limited to -C ⁇ CH, -CsCCH 3 , -CH 2 C ⁇ CH, -CH 2 CH 2 C ⁇ CH, -CH(CH 3 )C ⁇ CH and the like.
  • C 1-6 -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.
  • C 3 . 6 -cycloalkyl refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons.
  • C 1-6 -alkoxy-C 1-6 -alkyl refers to a group of 2-12 carbon atoms interrupted by an O.
  • Representative examples are CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 3 , CH 2 -O-CH(CH 3 ) 2 and the like.
  • perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
  • C ⁇ -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 1-6 -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 1-6 -alkoxycarbonyl refers to a monovalent substituent comprising a C 1-6 -alkoxy group linked through a carbonyl group; such as e.g. methoxy- carbonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
  • 3-12 membered mono- or bicyclic system refers to a monovalent substituent of formula -NR 2 R 3 or -NR 8 R 9 where R 2 and R 3 , or R 8 and R 9 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, such as 1-pyrrolidyl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 7-azabi- cyclo[2.2.1]heptan-7-yl, tropanyl and the like.
  • 3-6 membered saturated ring system refers to a mono- valent 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-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy or 2- naphthyloxy.
  • arylalkoxy refers to a C 1-6 -alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1- naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
  • heteroarylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2-furyl) methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2- pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.
  • d-e-alkylsulfonyl refers to a monovalent substituent comprising a C ⁇ -6 -alkyl group linked through a sulfonyl group such as e.g. methylsulfonyl, ethylsulfonyl, 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 1-6 -monoalkylaminosulfonyl refers to a monovalent substituent comprising a C-
  • methylaminosulfonyl methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, sec-butylaminosulfonyl, iso- butylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, 2- methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl, n-hexylaminosulfonyl, 4- methylpentylaminosulfonyl, neopentylaminosulfonyl, n-hexylaminosulfonyl and 2,2- dimethylpropylaminosulfonyl.
  • C 1-6 -dialkylaminosulfonyl refers to a monovalent substituent comprising a C ⁇ -6 -dialkylamino group linked through a sulfonyl group such as dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropyl- aminosulfonyl, N-(n-butyl)-N-methylaminosulfonyl, di(n-pentyl)aminosulfonyl, and the like.
  • C ⁇ . 6 -alkylcarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with an acyl group, such as e.g. acetamido, propionamido, isopropylcarbonylamino, and the like.
  • (C ⁇ -cycloalky d-e-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 cycloalkyl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; such as e.g. cyclo- propylmethyl, (1-methylcyclopropyl) methyl, 1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclo- hexylmethyl, 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 d. 6 -alkyl, halogen, hydroxy or C 1-6 - alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl) thio, and the like.
  • arylsulfonyl refers to an aryl group linked through a sulfonyl group, the aryl group optionally being mono- or polysubstituted with d. 6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; such as e.g. phenylsulfonyl, tosyl, and the like.
  • C 1-6 -monoalkylaminocarbonyl refers to a monovalent substituent comprising a C 1-6 -monoalkylamino group linked through a carbonyl group such as e.g.
  • C L e-dialkylaminocarbonyl refers to a monovalent substituent comprising a d. 6 -dialkylamino group linked through a carbonyl group such as di- methylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl, dipro- pylaminocarbonyl, N-(n-butyl)-N-methylaminocarbonyl, di(n-pentyl)aminocarbonyl, and the like.
  • C ⁇ -monoalkylaminocarbonylamino refers to an amino group wherin one of the hydrogen atoms is substituted with a C ⁇ . 6 -monoalkylaminocarbonyl group, e.g. methylaminocarbonylamino, ethylamino-carbonylamino, n-pro- pylaminocarbonylamino, isopropylaminocarbonylamino, n-butylaminocarbonylamino, sec- butylaminocarbonylamino, isobutylaminocarbonylamino, tert-butylaminocarbonylamino, and 2-methylbutylaminocarbonylamino.
  • C 1-6 -dialkylaminocarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a C 1-6 -dialkylaminocarbonyl group, such as dimethylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, di- ethylaminocarbonylamino, dipropylaminocarbonylamino, N-(n-butyl)-N- methylaminocarbonylamino, di(n-pentyl) aminocarbonylamino, and the like.
  • 5- or 6-membered heterocyclic system refers to: a monocyclic unsaturated or saturated system containing one, two or three hetero atoms selected from nitrogen, oxygen and sulfur and having 5 members, e.g. pyrrole, furan, thiophene, pyrroline, dihydrofuran, dihydrothiophene, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazole, isothiazole, 1 ,2,3-oxadiazole, furazan, 1,2,3- triazole, 1 ,2,3-thiadiazole or 2,1,3-thiadiazole; an aromatic monocyclic system containing one or more nitrogen atoms and having 6 members, e.g.
  • pyridine pyrazine, pyrimidine, pyridazine, 1 ,2,4-triazine, 1,2,3-triazine or tetrazine
  • 5- or 6-membered nitrogen containing ring refers to a monovalent substituent comprising a monocyclic unsaturated or saturated system containing one or more nitrogen atoms and having 5 or 6 members, e.g. pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thio- morpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1 ,3-dioxolanyl and 1 ,4-dioxolanyl.
  • pyrrolidinyl
  • 4- to 12-membered bicyclic or tricyclic carbocyclic system refers to a a monovalent substituent comprising a bicyclic or a tricyclic structure made of 4-12 carbon atoms such as e.g. bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bi- cyclo [2.2.2]octane, octahydrovpentalene, bicyclo[2.2.0]hexane, adamantane, noradaman- tane or tricyclo-(4.3.1.1 (3,8))undecane.
  • treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complica- tions, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • the present invention therefore relates to a use of SUR1/Kir6.2 selective potassium channel openers for the preparation of a pharmaceutical composition for the treatment or the prevention of diabetes in women with (prior) GDM.
  • SUR1/Kir6.2 selective potassium channel openers for the preparation of a pharmaceutical composition for the treatment or the prevention of diabetes in women with (prior) GDM.
  • potassium channel agonists are compounds, which activate
  • Potassium channel agonists can readily be determined by those skilled in the art. Methods therefore has been described in e.g. WO 97/26264 , WO 97/26265, WO 99/03861 , WO 00/37474 , and recently reviewed: McClenaghan: Diabetes, Obesitas and Metabolism, 1, 137-150, (1999); Yokoshiki: Am. J. Physiol. . 274. C25-C37, (1998); Aguliar-Bryan: Endocrine Reviews, 20, 101-135, (1999).
  • B represents >NR 5 or >CR 5 R 6 , wherein R 5 and R 6 independently are hydrogen; hydroxy; C-i-e-alkoxy; or C 1-6 -alkyl, C 3 . 6 -cycloalkyl, C 2-6 -alkenyl or C 2-6 -alkynyl optionally mono- or poly substituted with halogen; or R 5 and R 4 together represent one of the bonds in a double bond between the atoms 2 and 3 of formula (I);
  • R 7 is C- ⁇ -6 -alkyl; or aryl or heteroaryl optionally mono- or poly substituted with halogen, hydroxy, d. 6 -alkoxy, aryloxy, arylalkoxy, nitro, amino, C 1-6 -monoalkyl- or dialkylamino, cyano, acyl, or C 1-6 -alkoxycarbonyl;
  • R 1 is hydrogen; hydroxy; d. 6 -alkoxy; or C 1-6 -alkyl, C 3- 6-cycloalkyl, C 2-6 - alkenyl or C 2-6 - alkynyl optionally mono- or poly substituted with halogen and R 4 is hydrogen; or R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula (I); or R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula (I);
  • R 2 is hydrogen; hydroxy; C 1-6 -alkoxy; or C ⁇ -6 -alkyl, C 3-6 -cycloalkyl, C 2-6 - alkenyl or C 2-6 - alkynyl optionally mono- or poly substituted with halogen;
  • R 8 is hydrogen; C 3-6 -cycloalkyl or (C 3 . 6 -cycloalkyl)d. 6 -alkyl, the C 3-6 -cycloalkyl group optionally being mono- or poly substituted with d.
  • 6 -alkyl halogen, hydroxy or C -6 - alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms; or straight or branched C 1-18 -alkyl optionally mono- or poly substituted with halogen, hydroxy, C 1-6 -alkoxy, C 1-6 -alkylthio, C 3-6 -cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, C 1-6 - monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C ⁇ . 6 -alkoxy- carbonyl, or carbamoyl;
  • X is O or S
  • R 9 is hydrogen; C 1-6 -alkyl; C 2-6 -alkenyl; C 3-6 -cycloalkyl optionally mono- or poly substituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; or
  • R 8 and R 9 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or poly substituted with halogen, d. 6 -alkyl, hydroxy, C ⁇ . 6 -alkoxy, d.6-alkoxy-C 1-6 -alkyl, nitro, amino, cyano, trifluoromethyl, C ⁇ . 6 -monoalkyl- or dialkylamino, oxo; or R 3 is
  • n, m, p independently are 0,1,2,3 and R 10 is hydrogen; hydroxy; C 1-6 -alkoxy; C 3 . 6 - cycloalkyl optionally mono- or poly substituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 - alkoxy; C 1-6 -alkyl, C 2-6 -alkenyl or C 2 . 6 -alkynyl optionally mono- or poly substituted with halogen; or
  • R 2 and R 3 together with the nitrogen atom forms a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or poly substituted with halogen, C ⁇ -6 -alkyl, hydroxy, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, nitro, amino, cyano, trifluoromethyl, C 1-6 -monoalkyl- or dialkylamino or oxo;
  • a together with carbon atoms 5 and 6 of formula (I) represents a 5 or 6 membered hetero- cyclic system comprising one or more nitrogen-, oxygen- or sulfur atoms, the heterocyclic systems optionally being mono- or poly substituted with halogen; C 1-12 -alkyl; C 3 . 6 - cycloalkyl; hydroxy; C 1-6 -alkoxy; d.
  • the invention includes all optical isomers of compounds of the present invention, some of which are optically active, and also their mixtures including ra- cemic mixture thereof.
  • the scope of the invention also includes all tautomeric forms of the compounds of the present invention 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, 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, succinic
  • B of formula (I) is >NR 5 and R 5 and R 4 together represent one of the bonds in a double bond between the atoms 2 and 3 of for- mula (I).
  • R 2 is hydrogen or C 1-6 -alkyl.
  • R 3 is R 8 , -OR 8 , NR 8 R 9 or aryl, the aryl groups optionally being substituted with C 1-6 -alkyl; wherein R 8 is hydrogen; C 3-6 -cycloalkyl; 6 -cycloalkyl)C 1-6 -alkyl; a 3 - 6 membered saturated ring system comprising one, two or three nitrogen-, oxygen- or sulfur atoms; or straight or branched optionally substituted with halogen, hydroxy, C ⁇ . 6 -alkoxy, d.
  • R 9 is hydrogen, C 1-6 -alkyl or C 3-6 -cycloalkyl; or R 8 and R 9 together with the nitrogen atom form a 4 - 6 membered ring.
  • R 3 is secondary C 3 . 6 -alkyl, tertiary C . 6 -alkyl, C 3-6 -cycloalkyl or (C 3-6 -cycloalkyl)methyl.
  • a together with carbon atoms 5 and 6 of formula (I) forms a 5 membered heterocyclic system containing one hetero atom selected from nitrogen and sulfur, the heterocyclic system optionally being mono- or disubstituted with halogen; C 1-12 -alkyl; C 3 .
  • a together with carbon atoms 5 and 6 of formula (I) forms a 5 membered heterocyclic system containing two hetero atoms selected from nitrogen, oxygen and sulfur, the heterocyclic system optionally being substituted with halogen; C 1-12 -alkyl; C 3 - 6 -cycloalkyl; cyano; cyanomethyl; perhalomethyl; sulfamoyl; d-e- alkylsulfonyl; C 1-6 -alkylsulfinyl; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; C 1-6 - alkoxycarbonyl-C 1-6 -alkyl; carbamylmethyl; carboxy-C 1-6 -alkyl; aryloxy; (1 ,2,4
  • a together with carbon atoms 5 and 6 of formula (I) forms a 6 membered aromatic heterocyclic system containing one, two or three nitrogen atoms, the heterocyclic system optionally being substituted with halogen; C 1- 2 - alkyl; C 3-6 -cycloalkyl; cyano; cyanomethyl; perhalomethyl; sulfamoyl; C 1-6 -alkylthio; d- ealkylsulfonyl; C 1-6 -alkylsulfinyl; arylthio, arylsulfinyl, arylsulfonyl, the aryll group optionally being mono- or polysubstituted with C 1-6 -aikyl, halogen, hydroxy or C ⁇ -6 -alkoxy; C 1-6 - alkoxycarbonyl-d.6-alkyl; carbamylmethyl; carboxy-C 1-6 -alkyl: ary
  • Examples of specific compounds of formula (I) to be used according to this invention are: 6-Chloro-3-(1 ,2-dimethylpropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 6-Chloro-3-ethylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1 ,1 -dioxide; 6- Chloro-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; (R)-6-Chloro-3- (1-phenylethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1 -dioxide; 3-Allylamino-6- chloro-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide; 6-Ch
  • Another example of a specific compound of formula (I) to be used according to this invention is 6-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide.
  • X and Y independently are hydrogen, halogen, perhalomethyl, d -6 -alkyl or C 1-6 -alkoxy;
  • R 11 , R 21 and R 31 independently are C 1-6 -alkyl, C 2 - 6 -alkenyl, C 2 - 6 -alkynyl, C 3 . 6 -cycloalkyl, carboxy, C 1-6 -alkoxycarbonyl or aryl, all of which are optionally being mono- or polysubstituted with halogen, hydroxy, oxo, or aryl; or
  • R 11 is as defined above and R 21 -C-R 31 form a C 3 . 6 -cycloalkyl group, optionally being mono- or polysubstituted with C 1-6 -alkyl, perhalomethyl, halogen, hydroxy or aryl; or
  • X is halogen and Y is hydrogen. In another embodiment of the invention, in formula (la), X is chloro.
  • R 11 , R 21 and R 31 all are d-e-alkyl.
  • R 11 is methyl.
  • R 21 -C-R 31 forms a C 3 . 6 - cycloalkyl group.
  • -CR 11 R 21 R 31 forms a tricyclic carbocyclic system.
  • specific compounds of formula (la) to be used according to this invention are: 3-tert-Butylamino-6-chloro-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 6-Chloro-3-(1 , 1 -dimethylpropylamino)-4H-thieno[3,2-e]- ,2,4-thiadiazine 1 , 1 -dioxide; 6- Chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 6- Chloro-3-(2-hydroxy-1 ,1-dimethylethylamino)-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1- dioxide; 6-Chloro-3-(2-hydroxy-1 ,1-
  • Another example of a specific compound of formula (la) to be used according to this invention is 6-Chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide.
  • the compounds of formula (I) and (la) of the present invention may be prepared by using the methods taught in e.g. WO 97/26264 , WO 97/26265, WO 99/03861 and WO 00/37474 , which are hereby incorporated by reference.
  • the compounds of the present invention may be used in combination with compounds that are used for the treatment of type 2 diabetes, obesitas or hypertension.
  • the pharmaceutical composition of the invention may comprise a compound of formula (I) or (la) 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, insulin sensitizers, insulin secretagogues as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibenclamide and glipizide; biguanides, e.g.
  • metformin metformin
  • benzoic acid derivatives e.g. repaglinide
  • thiazolidinediones e.g. rosiglitazone, pioglitazone and cigli- tazone
  • glucagon like peptide 1 GLP-1
  • GLP-1 GLP-1 derivatives
  • GLP-1 analogues GLP-1 analogues
  • inhibitors of ⁇ -glucosidase e.g. acarbose and vogli- bose
  • inhibitors of hepatic enzymes responsible for the biosynthesis of glucose e.g. gly- cogen phosphorylase inhibitors.
  • the present invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the present invention 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 th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions or suspensions.
  • compositions include a compound of the present invention 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, pen- taerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrroli- done.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • 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.
  • the route of administration may be any route, which effectively transports the ac- tive compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intramuscular or intranasal, the 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 the present invention 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, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • 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, dra- gees, 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 of the invention may be administered to a mammal, especially a human, in need of such reducing or lowering of the intake of fat food.
  • 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.
  • Pharmaceutical compositions containing a compound according to the invention may be administered one or more times per day or week, conveniently administered at mealtimes.
  • An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against consumption of fat food. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.
  • a convenient daily dosage can be in the range from 0.001-500 mg/kg/day.
  • pancreata from animals treated with 6-chloro- 3-(1 -methylcylodopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide displayed reduced hyperinsulinemia and an improved insulin secretory responsiveness to glucose when the data are expressed relative to baseline. The results are shown in Figure 1.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
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  • Public Health (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
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  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne l'utilisation d'activateurs sélectifs d'ouverture de canaux potassiques SUR1/Kir6.2 pour la préparation d'une composition pharmaceutique destinée à la prévention ou au traitement de diabètes chez les femmes souffrant déjà de diabète sucré de la grossesse, ainsi qu'une composition pharmaceutique destinée au traitement de diabètes chez les femmes souffrant déjà du diabète sucré de la grossesse.
PCT/DK2002/000798 2001-11-30 2002-11-28 Utilisation d'activateurs selectifs d'ouverture de canaux potassiques WO2003045955A1 (fr)

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WO2006091800A2 (fr) * 2005-02-24 2006-08-31 Janssen Pharmaceutica N.V. Nouveaux derives de pyridine tenant lieu d'elements d'ouverture des canaux potassiques ioniques

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005299A1 (fr) * 2002-07-04 2004-01-15 Novo Nordisk A/S Formes polymorphiques d'un derive de 4h-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxyde
WO2006091800A2 (fr) * 2005-02-24 2006-08-31 Janssen Pharmaceutica N.V. Nouveaux derives de pyridine tenant lieu d'elements d'ouverture des canaux potassiques ioniques
WO2006091800A3 (fr) * 2005-02-24 2006-10-05 Janssen Pharmaceutica Nv Nouveaux derives de pyridine tenant lieu d'elements d'ouverture des canaux potassiques ioniques
US7671065B2 (en) 2005-02-24 2010-03-02 Janssen Pharmaceutica N.V. Pyridine derivatives as potassium ion channel openers

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