WO2000014090A1 - Derives de 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine - Google Patents

Derives de 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine Download PDF

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WO2000014090A1
WO2000014090A1 PCT/DK1999/000448 DK9900448W WO0014090A1 WO 2000014090 A1 WO2000014090 A1 WO 2000014090A1 DK 9900448 W DK9900448 W DK 9900448W WO 0014090 A1 WO0014090 A1 WO 0014090A1
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substituents
optionally substituted
compound according
alkyl
pharmaceutically acceptable
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PCT/DK1999/000448
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English (en)
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Peter Madsen
Jane Marie Lundbeck
Niels Westergaard
Palle Jakobsen
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Novo Nordisk A/S
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Priority to AU51546/99A priority Critical patent/AU5154699A/en
Publication of WO2000014090A1 publication Critical patent/WO2000014090A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine derivatives, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, e.g. to their use for treatment of human and animal disorders.
  • the invention relates to modulation of the activity of molecules with glucose-6-phosphate recognition units, including glucose-6-phosphatases (G-6-Pases) in in vitro systems, microorganisms, eukaryotic cells, whole animals and human beings, especially in the treatment of diseases related to glucose metabolic pathways.
  • G-6-Pases glucose-6-phosphatases
  • Glucose is the major energy substrate in mammals and regulation of blood glucose levels within a narrow range seems to be of crucial importance to devoid serious physiological complications as seen in diabetes (DeFronzo, Bonadonna, & Ferrannini. 1992). Blood glucose homeostasis is maintained by dietary intake of carbohydrates, the uptake of glucose by peripheral tissues and the brain, and storage or release of glucose from the liver. The liver therefore seems to play a major role in the homeostatic regulation of blood glucose levels. Gluconeogenesis and glycogenolysis are the two metabolic pathways from which glucose can be produced in the liver. These pathways are under tight hormonal control. Insulin resistance and insulin deficiency have a substantial impact on glucose production in the liver (Consoli.
  • G-6-Pase Glucose-6-phosphatase catalyses the terminal step in the above mentioned pathways by converting glucose-6-phosphate (G-6- P) to glucose, and is largely situated in the liver, with some expression in the kidney after prolonged fasting.
  • the G-6-Pase is a multicomponent system comprising of the G-6-Pase catalytic enzyme with its active site located at the luminal site of the endoplasmic reticulum (microsomal fraction), a specific transporter T1 which mediates entry of G-6-P into the luminal compartment, and transporter T2 and T3 which mediates export to the cytosol of inorganic phosphate and glucose, respectively (Nordlie, Bode, & Foster. 1993; Sukalski & Nordlie. 1989). It has been shown that the rate of hydrolysis of G-6-P and the hepatic glucose output were increased under diabetic conditions (Lyall, Grant, Scott, & Burchell.
  • G-6-Pase catalytic enzyme protein ArArgaud, Zhang, Pan, Maitra, Pilkis, & Lange. 1996; Burchell & Cain. 1985. This makes G-6-Pase enzyme a potential target in control of excess glucose production seen in diabetes.
  • R1 is a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents, an unsaturated straight or branched C 2 . 8 -hydrocarbon chain optionally substituted with one or more substituents, a saturated C 3 . 8 -alicyclic hydrocarbon group optionally substituted with one or more substituents, an unsaturated C 5 . 8 -alicyclic hydrocarbon group optionally substituted with one or more substituents,
  • R2 is a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents, an unsaturated straight or branched C 2 . 8 -hydrocarbon chain optionally substituted with one or more substituents, a saturated C 3-8 -alicyclic hydrocarbon group optionally substituted with one or more substituents, an unsaturated C 5-8 -alicyclic hydrocarbon group optionally substituted with one or more substituents, aralkyl optionally substituted with one or more substituents or
  • R3 is a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents, an unsaturated straight or branched C 2 . 8 -hydrocarbon chain optionally substituted with one or more substituents, a saturated C 3 . 8 -alicyclic hydrocarbon group optionally substituted with one or more substituents, an unsaturated C 5 . 8 -alicyclic hydrocarbon group optionally substituted with one or more substituents, an aryl optionally substituted with one or more substituents, an aralkyl optionally substituted with one or more substituents or W optionally substituted with one or more substituents.
  • Q and W are independently selected from the list consisting of
  • X and Y are independently selected from the group consisting of NR4, O, S, >SO, >SO 2 ,
  • R4 is selected from the list consisting of hydrogen, a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents, an unsaturated straight or branched C 2 . 8 -hydrocarbon chain optionally substituted optionally substituted with one or more substituents, a saturated C 3 . 8 -alicyclic hydrocarbon group optionally substituted with one or more substituents, an unsaturated C 5 . 8 -alicyclic hydrocarbon group optionally substituted with one or more substituents, C 1-8 -acyl, C ⁇ -alkoxycarbonyl, or mono- or dialkylcarbamoyl,
  • R5, R6, R7 being independently selected from amino-C ⁇ -alkyl, hydroxy-C ⁇ -alkyl, hydrogen, C 1-6 -alkyl, aryl, aralkyl, aryloxy, aryloxy-C 1-6 -alkyl, benzyl, halogen, hydroxy, mercapto, cyano, nitro, carboxy, carbamoyl, CONHC M -alkyl, CON(C 1-4 alkyl) 2 , C 1-4 -acyl, C 1-4 -alkoxy , C 1-4 -alkylthio, -SOC 1-6 -alkyl, -SOzC ⁇ -alkyl, C 1-4 -alkoxycarbonyl, C 1-4 - alkanoyloxy, amino, optionally substituted mono- or di-C ⁇ -alkylamino, acylamino, -NC 1-4 - alkylCOC 1-4 -alkyl, -SO3H, -SO
  • each of the above substituents being selected from the group consisting of halogen, hydroxyl, carboxy, carboxyalkenyl, 2-carboxyethenyl, cyano, nitro, carbamoyl, C 1-8 - alkylcarbamoyl (preferably metanoyl), C 1-8 -acyl (preferably acetyl, propionyl, isopropionyl), acetamido, C ⁇ -alkoxy (preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert.butoxy), C 1-8 -alkyl, C 1-8 -alkoxycarbonyl (preferably methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl), C 1-8 -alkanoyloxy (preferably acetyloxy, propionyloxy, isopropionyloxy), C M -alkylthio (preferably methylthio, ethylthio, propylthi
  • benzyloxy hydroxyalkyl, perhaloalkoxy (preferably trifluroromethoxy), alkoxyaryl, C 1-8 -acyl, perhaloalkyl (preferably trifluoromethyl), oxo, C 1-4 - alkanoylamino-C 1-4 -alkyl, alkoxyoxoindanyl, dimethylhydrazidyl, methylendioxy, thioxothiazolyl, imidazolyl or 2-morpholin-4-ylethoxy.
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form.
  • the invention relates to compounds of general formula (I) wherein R5, R6 and R7 is hydrogen.
  • the invention relates to compounds of general formula (I), wherein R2 is COR3 wherein R3 is as defined above.
  • the invention relates to compounds of general formula (I), wherein R1 is Q optionally substituted with one or more substituents and Q is
  • the invention relates to compounds of general formula (I), wherein X is NR4 or O .preferably NR4, wherein R4 is as defined above.
  • the invention relates to compounds of general formula (I), wherein R4 is a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R4 is methyl.
  • the invention relates to compounds of general formula (I), wherein R1 is Q optionally substituted with one or more substituent and Q is
  • the invention relates to compounds of general formula (I), wherein R1 is N-methylpiperidinyl, tetrahydrofuryl or tetrahydropyranyl.
  • the invention relates to compounds of general formula (I), wherein R1 is tetrahydropyran-4-yl, tetrahydrofuran-3- yl or 1-methylpiperidin-4-yl.
  • the invention relates to compounds of general formula (I), wherein R1 is optionally substituted phenyl, thienyl preferably 2-thienyl, 3-thienyl, 4-thienyl 5- thienyl or furanyl, preferably 2-fura ny I, 3-furanyl, 4-furanyl, 5-furanyl, Benzo[1 ,3]dioxol preferably Benzo[1 ,3]dioxol-5yl, pyridyl or cyclohexyl.
  • R1 is optionally substituted phenyl, thienyl preferably 2-thienyl, 3-thienyl, 4-thienyl 5- thienyl or furanyl, preferably 2-fura ny I, 3-furanyl, 4-furanyl, 5-furanyl, Benzo[1 ,3]dioxol preferably Benzo[1 ,3]dioxol-5yl, pyridyl or
  • the invention relates to compounds of general formula (I), wherein the substituents of R1 are selected from the group consisting of halogen, perhaloalkyl, perhaloalkoxy, Cj. ⁇ -alkoxy, C ⁇ -alkyl .C ⁇ -alkylamino, C 1-8 -dialkylamino or C 2 . 5 - cycloalkylamino.
  • the invention relates to compounds of general formula (I), wherein the substituents of R1 are selected from the group consisting of chloro, fluoro trifluoromethyl, trifluoromethoxy, methoxy, methyl or dimethylamino.
  • the invention relates to compounds of general formula (I), wherein R1 is selected from the group consisting of phenyl, 4-chlorophenyl, 3-fluorophenyl, 2,4-chlorophenyl, 3,5-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethylphenyl, 4- trifluoromethoxyphenyl, 4-dimethylaminophenyl, 4-pyridyl, 2-thienyl, 5-chloro-2-thienyl, 3- chloro-2-thienyl, Benzo[1 ,3]dioxol-5yl, cyclohexyl or 4-methoxycyclohexyl.
  • R1 is selected from the group consisting of phenyl, 4-chlorophenyl, 3-fluorophenyl, 2,4-chloroph
  • the invention relates to compounds of general formula (I), wherein R3 is a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents. In another preferred embodiment the invention relates to compounds of general formula (I), wherein R3 is a saturated straight or branched C 1-4 -alkyl optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R3 is an unsaturated straight or branched C 2 . 8 -hydrocarbon chain optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R3 is an unsaturated straight or branched C 2J( -alkenyl optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R3 is a saturated C 3 . 8 -alicyclic hydrocarbon group optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R3 is a saturated cyclohexyl optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R3 is an aryl optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R3 is phenyl, alkoxyphenyl, dialkoxyphenyl, hydroxyphenyl, indanyl, imidazolyl, pyridyl, benzofuranyl, indolyl, benzimidazolyl, thienyl, furanyl, pyranyl optionally substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein R3 is W optionally substituted with one or more substituents wherein W is as defined above. In another preferred embodiment the invention relates to compounds of general formula (I), wherein W is optionally substituted with one or more substituents and W is
  • the invention relates to compounds of general formula (I), wherein X is NR4 and R4 is as defined above.
  • the invention relates to compounds of general formula (I), wherein R4 is a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents or R4 is a C 1-8 -acyl.
  • the invention relates to compounds of general formula (I), wherein R4 is methyl or methanoyl.
  • the invention relates to compounds of general formula (I), wherein the substituents being selected from the group consisting halogen, hydroxyl, C 1-4 - alkoxy, C M -alkyl, C ⁇ -alkylthio, C 1-4 -alkylsulphinyl, aryl, aryloxy, hydroxyalkyl, perhaiomethoxy, C 1-8 -acyl, perhalomethyl, oxo, C ⁇ -alkanoylamino-C ⁇ -alkyl, alkoxyoxoindanyl, dimethylhydrazidyl, methylendioxy, thioxothiazolyl, imidazol, aminoalkoxy, carboxy, carboxyalkenyl, cyano or C ⁇ -alkanoyloxy.
  • the invention relates to compounds of general formula (I), wherein the substituents being selected from the group consisting fluorine, chlorine, bromine, hydroxyl, methoxy, ethoxy, methyl, methylthio, methylsulphinyl, furanyl, thienyl, phenyl, indolyl, pyranyl, dimethoxyphenyl, methoxyphenyl, hydroxyphenyl, hydroxymethyl, trifluoromethoxy, trifluoromethyl, imidazol, methanoyl, oxo, methanoylamino-methyl, methoxyoxoindanyl, dimethylhydrazidyl, methylendioxy, thioxothiazolyl, carboxy, cyano, acetamido, nitro, acetyl, acetyloxy, dimethylamino, 2-dimethylaminoethoxy, 2-carboxyethenyl or 2-morpholin-4-
  • the invention relates to compounds of general formula (I), wherein R2 is COR3 wherein R3 is selected from the group consisting of phenyl, 3-methoxyphenyl, 4-methoxyphenyl 4-chlorophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 3,4-dimethoxyphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-trifluoromethoxyphenyl, 4-dimethylaminophenyl, 4-bromophenyl, 4-hydroxyphenyl, 4-hydroxymethylphenyl, 4-hydroxymethylphenyl,
  • the present invention relates furthermore to a salt of a compound of the general formula (I) with a pharmaceutically acceptable acid or base.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, acetic, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethanesulfonic, picric and the like, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference; pharmaceutically acceptable metal salts, such as lithium, sodium, potassium, or magnesium salts and the like; or - optionally alkylated - ammonium salts; or amine salts of the compounds of this invention, such as the sodium, potassium, C 1-B - alkylamine, di (C 1-8 -alkyl) amine, tri (C 1
  • acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • saturated aliphatic hydrocarbon chains having 1 to 8 carbon atoms examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, tert.pentyl, n-hexyl, isohexyl, octyl.
  • Example of the unsaturated aliphatic hydrocarbon chains having 2 to 8 carbon atoms include ethenyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, ethynyl, 1- propionyl, 2-propionyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl.
  • Examples of the saturated alicyclic hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Examples of unsaturated C 5 . 8 -alicyclic hydrocarbon group having 5 to 8 carbon atoms such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cyclooctenyl.
  • aryl refers to an aryl or a heteroaryl and includes phenyl, alkoxyphenyl, dialkoxyphenyl, hydroxyphenyl, biphenyl, indene, indane, fluorene, naphthyl (1 -naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), pyrrolyl (2-pyrrolyl), pyrazolyl (e.g.
  • perhalomethyl as used herein means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
  • perhaiomethoxy means trifluoromethoxy, trichloromethoxy, tribromomethoxy or triiodomethoxy.
  • C ⁇ -alkyl refers to a straight, branched or cyclic C 1-8 -hydrocarbon chain.
  • aralkyl refers to an optionally substituted aryl residue as defined above, connected to an optionally substituted C 1-6 -alkyl as defined above.
  • aralkyl residue include benzyl, 2-phenylethyl, 2-phenylethenyl, 3-(2-pyridyl)propyl, 3- phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
  • C 1-8 -alkoxy refers to a straight or branched monovalent substituent comprising a C 1-8 -alkyl group as defined above linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 8 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • Preferred compounds of the invention are:
  • the compounds of the present invention are normoglycaemic agents (i.e. compounds that are able to normalise blood glucose levels from hyper-/hypoglycemic conditions) that interact with the glucose-6-phosphatase catalytic enzyme activity, and hence make them useful in the treatment and prevention of various diseases of the endocrinological system, especially ailments related to carbohydrate metabolism and especially the glucose metabolism, e.g. hyperglycaemia, diabetes mellitus, and especially non-insulin dependent diabetes mellitus (NIDDM) including long-term complications, such as retinopathy, neuropathy, nephropathy, and micro- and macroangiopathy, and hypoglycaemia resulting from, e.g., glycogen storage disease (von Gierke's Disease all types).
  • NIDDM non-insulin dependent diabetes mellitus
  • the present compounds are useful in the prophylactic treatment of hyperlipidaemia, hypertension, liver and bile diseases, and atherosclerosis associated with diabetes.
  • the present compounds are especially useful in the treatment of diseases associated with an increased or reduced activity of the glucose-6- phosphatase complex, e. g. the G-6-Pase catalytic enzyme.
  • the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
  • a pharmaceutically acceptable acid or base or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form for therapeutical use.
  • diseases of the endocrinological system preferably hyperglycaemia or diabetes.
  • the invention also relates to the use of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament.
  • the invention also relates to the use of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, preferably hyperglycaemia or diabetes.
  • the invention also relates to the use of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of glycogen storage disease or hypoglycaemia.
  • the invention relates furthermore to a method of treating or preventing diseases of the endocrinological system, preferably hyperglycaemia or diabetes in a subject in need thereof comprising administering an effective amount of a compound of the general formula (I) to said subject.
  • the compounds of the invention can be prepared by the following methods:
  • Agents which can introduce ring closure could be chosen among Trifluoroacetic acid, Phosphoroxy chloride, Phosphorpentoxide, Sulphuric acid, Methanesulphonic acid, mixtures thereof , or other agents known in the art.
  • R1 ,R5,R6,and R7 has the meaning described above.
  • R1 ,R2,R5,R6, and R7 has the meaning defined above.
  • L being a good leaving group as halogen, sulfate, sulfonate or acyl ; when R2 is R3CO- where R3 is as defined above, L can be selected from fluorine, chlorine, bromine, iodine, 1- imidazolyl, 1 ,2,4-triazolyl, 1-benzotriazolyloxy, 1-(4-aza benzotriazolyl)oxy, pentafluorophenoxy, N-succinyloxy 3,4-dihydro-4-oxo-3-(1 ,2,3-benzotriazinyl)oxy, R3COO- , or any other leaving group known to act as a leaving group in acylation reactions.
  • a base can be either absent (i.e.
  • compound V acts as a base) or triethylamine, N-ethyl-N,N- diisopropylamine, N-methylmorpholine, 2,6-lutidine, 2,2,6,6-tetramethylpiperidine, potassium carbonate, sodium carbonate, caesium carbonate or any other base known to be useful in acylation reactions.
  • R3CO-L can be prepared by activation of the corresponding carboxylic acid in the presence or absence of the alcohol component of the activated ester, such as HOBt, HOAt, HOSu, HOPFP, using various carbodiimide reagents, such as dicyclohexyl- or diisopropylcarbodiimide, EDAC and the like, or using phosphorous based activation reagents, such as PyBOP, PyBrOP, TFFH and the like, carbonyldi-azole reagents such as carbonyldiimidazole, carbonyldi-1 ,2,4-triazole, or any other activation or coupling reagent known to those skilled in the art.
  • the activated ester such as HOBt, HOAt, HOSu, HOPFP
  • carbodiimide reagents such as dicyclohexyl- or diisopropylcarbodiimide, EDAC and the like
  • R1 ,R5,R6,R7 has the meaning defined above.
  • the reaction can conveniently be carried out by by activation of the carboxylic acid with agents such as such as HOBt, HOAt, HOSu, HOPFP, using various carbodiimide reagents, such as dicyclohexyl- or diisopropylcarbodiimide, EDAC and the like, or using phosphorous based activation reagents, such as PyBOP, PyBrOP, TFFH and the like, carbonyldi-azole reagents such as carbonyldiimidazole, carbonyldi-1 , 2,4-triazole, or any other activation or coupling reagent known to those skilled in the art.
  • agents such as such as HOBt, HOAt, HOSu, HOPFP
  • carbodiimide reagents such as dicyclohexyl- or diisopropylcarbodiimide, EDAC and the like
  • phosphorous based activation reagents such as PyBOP, PyBrOP
  • R1 ,R5,R6,R7 having the meaning defined above, A being an agent which can introduce ring closure like Trifluoroacetic acid, Phosphoroxy chloride, Phosphorpentoxide, Sulphuric acid, Methanesulphonic acid, or other acids , or anhydrides or mixtures thereof or other agents capable of introducing ring closure under water absorption known in the art.
  • the reducing agent can be chosen among Sodium Borohydride, Lithium Aluminium Hydride, Lithium triethylborohydride , Aluminium hydride and other reducing agents known in the art.
  • G-6-Pase glucose-6-phosphatase
  • Pig liver microsomes were prepared in a buffer containing 250 mM sucrose, 1 mM EDTA, 25 mM HEPES and 250 mg/l Bacitrazin (pH 7.5) essentially as described by Arion et al.,1980 (Arion, Lange, & Walls. 1980). Microsomes were kept at -80 °C until use.
  • the compounds of the invention are preferably characterized by having a glucose-6- phosphatase inhibitory activity corresponding to an IC 50 value of less than 100 ⁇ M, more preferably less than 10 ⁇ M, even more preferably less than 1 ⁇ M, still more preferably less than 100 nM.
  • the compounds according to the invention are effective over a wide dosage range. In general satisfactory results are obtained with dosages from about 0.05 to about 1000 or 5000mg, preferably from about 0.1 to about 500 mg, per day. A most preferable dosage is about 5 mg to about 200 mg per day. The exact dosage will depend upon the mode of administration, form in which the compound is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the present invention relate furthermore to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound of the general formula (I) or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
  • the dosage unit of the pharmaceutical compositions according to the invention typically contains from 0.05mg to 1000mg, preferably from 0.1 mg to 500mg, or, preferably from 5mg to 200mg per day of the active ingredient, which is, preferably, a novel 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine derivative as described herein or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof; or the active ingredient is a previously described 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine derivative or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intra urethra I, intramuscular, intrapulmonary, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more compounds exhibiting a different activity, e.g., a plasma iipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material.
  • a plasma iipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material e.g., a plasma iipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material.
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and
  • compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • Typical compositions include a compound of formula (I) or a pharmaceutically acceptable acid addition salt or metal 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.
  • conventional techniques for the preparation of pharmaceutical compositions may be used.
  • 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, sachet, paper, or other container.
  • a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • 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, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated in any galenic dosage form 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.
  • the preparation may contain a compound of formula (I) dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • 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.
  • solubilizing agents e.g. propylene glycol
  • surfactants e.g. propylene glycol
  • absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin
  • preservatives such as parabenes.
  • 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.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • the compounds of the invention may be administered to a mammal in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above and especially of diseases of the endocrinological system such as hyperinsuiinaemia and diabetes.
  • mammals include both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the mammal is a human.
  • Hydrogen oxalate It was prepared by neutralisation of solution of above base in diethyl ether with a solution of oxalic acid dihydrate in acetone. Hydrogen oxalate was contaminated with hydrogen oxalate of 2-(3-thienyl)ethylamine. A suspension of the mixture was repeatedly boiled with water and filtrated. This afforded, after drying, pure 4-(4- trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine, hydrogen oxalate 2.5 g (8 %), m.p. 190-195 °C.
  • 2-(3-Thienyl)ethanamine was prepared analogous to the method described by M. Cardellini et al. Thiophene-3-carboxaldehyde (15.0 g), nitromethane (9.79 g) and sodium methoxide ( 2 M, 71.25 ml) were mixed in methanol ( dry , 50 ml).
  • 2-(3-Thienyl)ethanamine (3 g) was treated with 4-methoxycyclohexanecarboxylic acid ( cis/trans mixture , 3.73 g) , HOBT ( 3.18 g) , and EDAC (6.78 g) in DMF (180 ml). The mixture is stirred overnight , evaporated to dryness. The resulting oil is redissolved in methylene chloride ( 100 ml) and extracted with NaOH (2 M, 100 ml). The organic phase was separated and further extracted consecutively with sat. Saline (100 ml) , HCI (0.1 M, 100 ml), NaOH (0.5 M, 100 ml) .
  • Tetrahydro-3-furoic acid (2-thiophen-3-yl-ethyl)-amide(3.35 g) ,POCI3 (4.06 ml) were reacted in toluene (150 ml) exactly as described in example 4.
  • HPLC-MS analyses were performed on a PE Sciex API 100 LC/MS System using a WatersTM 3 mm x 150 mm 3.5 ⁇ C-18 Symmetry column and positive ionspray with a flow rate at 20 ⁇ L/minute.

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Abstract

L'invention porte sur un composé de la formule générale (I) dans laquelle R1 est un C1-8-alkyl, C2-8-alcényl, C3-8-cycloalkyl, C5-8-cycloalcényl, Q ou aryl; R2 est C1-8-alkyl, C2-8-alcényl, C3-8-cycloalkyl, C5-8-cycloalcényl, aralkyl ou COR3; R3 est un C1-8-alkyl, C2-8-alcényl, C3-8-cycloalkyl, C5-8-cycloalcényl, w ou aryl; R5, R6, R7 étant sélectionnés indépendamment parmi amino-C1-6-alkyl, hydroxy-C1-6-alkyl, hydrogène, C1-6-alkyl, aryl, aralkyl, aryloxy, aryloxy-C1-6-alkyl, benzyl, halogène, hydroxy, mercapto, cyano, nitro, carboxy, carbamoyl, CONHC1-4-alkyl, CON(C1-4-alkyl)2, C1-4-acyl, C1-4-alkoxy, C1-4-alkylthio, -SOC1-6-alkyl, -SO2C1-6-alkyl, C1-4-alkoxycarbonyl, C1-4-alkanoyloxy, amino, mono- ou di-C1-6-alkylamino, acylamino éventuellement substitué, -NC1-4-alkylCOC1-4-alkyl, -SO3H, -SO2NH-C1-6-alkyl, tetrazolyl, perhalométhoxy R1, R2 and R3 sont tous éventuellement substitués par un ou plusieurs substituants. L'invention porte également sur un sel de ce composé comprenant un acide ou une base pharmaceutiquement acceptable, ou tout isomère optique, une composition pharmaceutique les contenant, et sur l'utilisation de ce composé dans la préparation de médicaments destinés au traitement des maladies du système endocrinien, de préférence, l'hyperglycémie ou les diabètes.
PCT/DK1999/000448 1998-09-02 1999-08-23 Derives de 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine WO2000014090A1 (fr)

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WO2004092156A1 (fr) * 2003-04-16 2004-10-28 F. Hoffmann-La Roche Ag Acetamides de 3-cyanothiophene substitues en tant qu'antagonistes de recepteur de glucagon
EP1549655A2 (fr) * 2002-09-12 2005-07-06 Merck & Co., Inc. Derives de thiophene bicycliques substitues, compostions contenant lesdits composes et methodes d'utilisation
EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
US7714134B2 (en) 2004-06-11 2010-05-11 4Sc Ag Compounds and use of tetrahydropyridothiophenes
US7714136B2 (en) 2005-05-25 2010-05-11 4Sc Ag Tetrahydropyridothiophenes
US7714135B2 (en) 2005-02-09 2010-05-11 4Sc Ag Tetrahydropyridothiophenes for the treatment of proliferative diseases such as cancer
US7723523B2 (en) 2004-05-28 2010-05-25 4Sc Ag Tetrahydropyridothiophenes
US7741488B2 (en) 2005-02-11 2010-06-22 4Sc Ag Tetrahydropyridothiophenes as antiproliferative agents for the treatment of cancer
US7763728B2 (en) 2005-05-25 2010-07-27 4Sc Ag Tetrahydropyridothiophenes
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
EP1743655A1 (fr) 2000-01-21 2007-01-17 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabétiques
EP1549655A2 (fr) * 2002-09-12 2005-07-06 Merck & Co., Inc. Derives de thiophene bicycliques substitues, compostions contenant lesdits composes et methodes d'utilisation
EP1549655A4 (fr) * 2002-09-12 2006-05-31 Merck & Co Inc Derives de thiophene bicycliques substitues, compostions contenant lesdits composes et methodes d'utilisation
CN100398533C (zh) * 2003-04-16 2008-07-02 霍夫曼-拉罗奇有限公司 作为胰高血糖素受体拮抗剂的取代的3-氰基噻吩乙酰胺
US7138529B2 (en) 2003-04-16 2006-11-21 Hoffmann-La Roche Inc. Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
KR100779324B1 (ko) * 2003-04-16 2007-11-28 에프. 호프만-라 로슈 아게 글루카곤 수용체 길항제로서의 치환된 3-사이아노싸이오펜아세트아마이드
WO2004092156A1 (fr) * 2003-04-16 2004-10-28 F. Hoffmann-La Roche Ag Acetamides de 3-cyanothiophene substitues en tant qu'antagonistes de recepteur de glucagon
US7803945B2 (en) 2004-05-28 2010-09-28 4Sc Ag Tetrahydropyridothiophenes
US7723523B2 (en) 2004-05-28 2010-05-25 4Sc Ag Tetrahydropyridothiophenes
US7714134B2 (en) 2004-06-11 2010-05-11 4Sc Ag Compounds and use of tetrahydropyridothiophenes
US7714135B2 (en) 2005-02-09 2010-05-11 4Sc Ag Tetrahydropyridothiophenes for the treatment of proliferative diseases such as cancer
US7741488B2 (en) 2005-02-11 2010-06-22 4Sc Ag Tetrahydropyridothiophenes as antiproliferative agents for the treatment of cancer
US7714136B2 (en) 2005-05-25 2010-05-11 4Sc Ag Tetrahydropyridothiophenes
US7763728B2 (en) 2005-05-25 2010-07-27 4Sc Ag Tetrahydropyridothiophenes
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose

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