WO1999045013A1 - Derives de 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine - Google Patents

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

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Publication number
WO1999045013A1
WO1999045013A1 PCT/DK1999/000079 DK9900079W WO9945013A1 WO 1999045013 A1 WO1999045013 A1 WO 1999045013A1 DK 9900079 W DK9900079 W DK 9900079W WO 9945013 A1 WO9945013 A1 WO 9945013A1
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optionally substituted
compound according
benzo
furanyl
thiadiazol
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PCT/DK1999/000079
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English (en)
Inventor
Niels Westergaard
Peter Madsen
Jane Marie Lundbeck
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Novo Nordisk A/S
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Priority to AU26104/99A priority Critical patent/AU2610499A/en
Publication of WO1999045013A1 publication Critical patent/WO1999045013A1/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

Definitions

  • the present invention relates to 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine derivatives, to com- positions 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, eu- karyotic cells, whole animals and human beings, especially in the treatment of diseases re- lated 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 inor- ganic 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, & 2 Lange. 1996; Burchell & Cain. 1985. This makes G-6-Pase enzyme a potential target in control of excess glucose production seen in diabetes.
  • the present invention relates to compounds of the general formula
  • a together with the double bond of formula I forms a cyclic system selected from the group consisting of benzene, thiophene, furan, pyridine, pyrimidine, pyrazine, pyridaz- ine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole or thiazole,
  • R 1 is furanyl; preferably 2-furanyl, 3-furanyl, 4-furanyl or 5-furanyl; thienyl, preferably 2- thienyl, 3-thienyl or 4-thienyl, 5-thienyl; pyrazolyl, preferably 4-pyrazolyl or 5-pyrazolyl; tetrazolyl, preferably 5-tetrazolyl; isoxazolyl, preferably 3-isoxazolyl, 4-isoxazolyl or 5- isoxazolyl; isothiazolyl , preferably 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl; 1 ,2,3- oxadiazolyl, preferably 1 ,2,3-oxadiazol-4-yl or 1 ,2,3-oxadiazol-5-yl; 1 ,2,3-thiadiazolyl, preferably 1 ,2,3-thiadiazol-4-yl or 1 ,2,3-thiadiazol-5-yl
  • R 2 is an optionally substituted C 1-6 -alkyl, optionally substituted aralkyl, or COR 3 ,
  • R 3 is an optionally substituted C,. 6 -alkyl, optionally substituted aralkyl, optionally sub- stitued aryl, or
  • W optionally substituted with one or more substituents.
  • W are independently selected from the list consisting of
  • X and Y are independently selected from the group consisting of NR 10 , O, S, >SO,
  • R 10 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,
  • R 4 and R 5 independently are hydrogen, halogen, perhalomethyl, optionally substituted C 1-6 -alkyl, hydroxy, optionally substituted C 1-6 -alkoxy, nitro, cyano, amino, optionally substituted mono- or optionally substituted di-C 1-6 -alkylamino, acylamino, C 1-6 - alkoxycarbonyl, carboxy or carbamoyl, n is 0, 1 , or 2, and m is 0, 1 , or 2,
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form.
  • 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 1-6 - alkylamine, di (C 1-6 -alkyl) amine, tri (C
  • acid addition salts are the hydrates which the present compounds are able to form.
  • the 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 sol- vent 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.
  • C L e-alkyl refers to a straight or branched, saturated or unsaturated hydrocarbon chain.
  • the C ⁇ -alky! residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyclic hydrocarbon residues.
  • aliphatic hydrocarbon residues examples include saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, tert.pentyl, n-hexyl, iso- 6 hexyl.
  • saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, tert.pentyl, n-hexyl, iso- 6 hexyl.
  • Example of the unsaturated aliphatic hydrocarbon residues include those having 2 to 6 carbon atoms such as 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.
  • alicyclic hydrocarbon residue examples include saturated ali- cyclic hydrocarbon residues having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl; and C 5 . 6 unsaturated alicyclic hydrocarbon residues having 5 to 6 carbon atoms such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl.
  • lower alkyl and “lower alkoxy” mean C 1-6 -alkyl and C- ⁇ -alkoxy, respectively.
  • aryl refers to an aryl which can be optionally substituted or a het- eroaryl which can be optionally substituted and includes phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), pyrrolyl (2-pyrrolyl), pyrazolyl (e.g.
  • 2-furanyl, 3-furanyl, 4-furanyl and 5-furanyl 2-furanyl, 3-furanyl, 4-furanyl and 5-furanyl
  • thienyl e.g. 2-thienyl, 3-thienyl, 4-thienyl and 5-thienyl
  • optionally substituted with one or more substituents 2-furanyl, 3-furanyl, 4-furanyl and 5-furanyl
  • 2-thienyl, 3-thienyl, 4-thienyl and 5-thienyl optionally substituted with one or more substituents.
  • substituents include, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, cyano, nitro, trifluoromethyl, carbamoyl, C ⁇ -acyl (e.g. acetyl, propionyl, isopropionyl), C 1-6 -alkoxy (e.g.
  • C 1-6 -alkyl as defined above, C 1-6 -alkoxycarbonyl (e.g. ones having 2 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl), C 1-6 -alkanoyloxy (e.g. ones having 2 to 6 carbon atoms such as acetyloxy, propionyloxy, isopropionyloxy), C ⁇ -alkylthio (e.g.
  • C 1-4 -alkylsulphinyl e.g. ones having 1-4 carbon atoms such as methylsulphinyl and ethylsulphinyl
  • C 1-4 - alkylsulphonyl e.g. ones having 1-4 carbonatoms such as methylsulphonyl and ethyl- sulphonyl
  • C 1-4 -alkylamino e.g.
  • aminoalkyl e.g. one having an amino containing group connected to a C 1-6 -alkyl group as defined above, such as 2-dimethylaminoethyl and 1-pyrrolidinylmethyl
  • aminoalkoxy e.g. one having an amino containing group connected via a C 1-6 -alkyl group as defined above to an oxygen atom, such as 2-dimethylaminoethoxy, 2- (4-morpholinyl)ethoxy and 1-pyrrolidinylmethoxy
  • aryl as defined above (e.g. phenyl and 4- pyridinyl), aryloxy (e.g. phenyloxy), and aralkyloxy (e.g. benzyloxy).
  • halogen as used herein means fluorine, chlorine, bromine or iodine.
  • perhalomethyl as used herein means trifluoromethyl, trichloromethyl, tribro- momethyl or triiodomethyl.
  • perhalomethoxy means trifluoromethoxy, trichloromethoxy, tri- bromomethoxy or triiodomethoxy.
  • 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-pyhdyl)propyl, 3- phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
  • C ⁇ -alkoxy refers to a straight or branched monovalent substituent comprising a C 1-6 -alkyl group linked through an ether oxy- gen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • carbamoyl refers to a carbamoyl which can be optionally substituted by one or two residues selected from the list consisting of optionally substituted C 1-6 - alkyl as defined above, optionally substituted aryl as defined above and optionally substituted aralkyl as defined above.
  • a together with the double bond of formula I forms a cyclic system selected from the group consisting of benzene, thiophene, furan, pyridine, pyrimidine, pyrazine, pyridaz- 9 ine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole or thiazole,
  • R 1 is furanyl; preferably 2-furanyl, 3-furanyl, 4-furanyl or 5-furanyl; thienyl, preferably 2- thienyl, 3-thienyl or 4-thienyl, 5-thienyl; pyrazolyl, preferably 4-pyrazolyl or 5-pyrazolyl; tetrazolyl, preferably 5-tetrazolyl; isoxazolyl, preferably 3-isoxazolyl, 4-isoxazolyl or 5- isoxazolyl; isothiazolyl , preferably 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl; 1 ,2,3- oxadiazolyl, preferably 1 ,2,3-oxadiazol-4-yl or 1 ,2,3-oxadiazol-5-yl; 1 ,2,3-thiadiazolyl, preferably 1 ,2,3-thiadiazol-4-yl or 1 ,2,3-thiadiazol-5-yl
  • R 2 is an optionally substituted C ⁇ -alkyl, optionally substituted aralkyl, or COR 3 ,
  • R 3 is an optionally substituted C 1-6 -alkyl, optionally substituted aralkyl, or optionally sub- stitued aryl,
  • R 4 and R 5 independently are hydrogen, halogen, perhalomethyl, optionally substituted C 1-6 -alkyl, hydroxy, optionally substituted C,. ⁇ -alkoxy, nitro, cyano, amino, optionally substituted mono- or optionally substituted di-C 1-6 -alkylamino, acylamino, C 1-6 - alkoxycarbonyl, carboxy or carbamoyl,
  • n 0, 1 , or 2
  • m 0, 1 , or 2
  • the invention relates to compounds of general formula (I) in which A is selected from benzene or thiophene, preferably thiophene.
  • the invention relates to compounds of general formula (I) in which R 1 is furanyl, preferably 2-furanyl, 3-furanyl, 4-furanyl or 5-furanyl, or thienyl, preferably 2- thienyl, 3-thienyl or 4-thienyl, 5-thienyl.
  • the invention relates to compounds of general formula (I), wherein each one of R ⁇ R 2 , and R 3 is substituted with one or more substituents.
  • the invention relates to compounds of general formula (I), wherein the substituents of R 1 are selected from the group consisting of hydrogen, halogen, perhalomethyl, perhalomethoxy, or C 1-6 -alkoxy.
  • the invention relates to compounds of general formula (I), wherein the substituents of R 1 are selected from the group consisting of chloro, trifluorome- thyl, methoxy, trifluoromethoxy.
  • the invention relates to compounds of general formula (I), wherein R 2 is COR 3 or (CH 2 ) q -aryl, and q is 0, 1 , 2, 3, 4, 5, or 6.
  • the invention relates to compounds of general formula (I), wherein R 2 is COR 3 .
  • the invention relates to compounds of general formula (I), wherein R 3 is optionally substituted alkyl.
  • the invention relates to compounds of general formula (I), wherein R 3 is optionally substituted cyclohexyl.
  • the invention relates to compounds of general formula (I), wherein R 3 is methoxycyclohexyl. 11 In another preferred embodiment the invention relates to compounds of general formula (I), wherein R 3 is optionally substituted aryl.
  • the invention relates to compounds of general formula (I), wherein R 3 is optionally substituted aralkyl.
  • the invention relates to compounds of general formula (I), wherein R 3 is (3-furanyl)-ethen-2-yl.
  • the invention relates to compounds of general formula (I), wherein R 3 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-trifluoromethylphenyl, dimethylamino- phenyl, 4-(2-carboxyethenyl)phenyl, 4-(2-dimethylaminoethoxy)phenyl, 4-(2-morpholin-4- ylethoxy)phenyl, 1 H-indol-5-yl, 3-chloro-4-methoxyphenyl, and 1 H-benzimidazol-5-yl.
  • R 3 is selected from the group consisting of phenyl, 3-methoxyphenyl, 4- methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphen
  • the invention relates to compounds of general formula (I), wherein R 3 is W optionally substituted with one or more substituents wherein W is as defined above.
  • 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 NR 10 , wherein R 10 is as defined above.
  • the invention relates to compounds of general formula (I), wherein R 10 is a saturated straight or branched C 1-8 -hydrocarbon chain optionally substituted with one or more substituents or R 10 is a C 1-8 -acyl. 12 In another preferred embodiment the invention relates to compounds of general formula (I), wherein R 10 is methyl or methanoyl.
  • the invention relates to compounds of general formula (I), wherein R 4 and R 5 independently is hydrogen, chloro, or methoxy.
  • the invention relates to compounds of general formula (I), wherein n is 0 or 1 and m is 0 or 1.
  • the invention relates to compounds of general formula (I), wherein n is 0 and m is 1.
  • the invention relates to compounds of general formula (la):
  • R 6 and R 8 independently are hydrogen, hydroxy, halogen, preferably chloro, bromo or fluoro, methyl, tert-butyl, phenyl, dimethylamino, methoxy, ethoxy, 2-dimethylamino- ethoxy, 2-carboxyethenyl, 2-morpholin-4-ylethoxy, perhalomethyl, preferably trifluoromethyl, perhalomethoxy, preferably trifluoromethoxy, carboxy, cyano, methylthio, methylsulfonyl, acetamido, nitro, acetyl, acetoxy, or hydroxymethyl.
  • the invention relates to compounds of general formula (la):
  • R 6 and R 8 independently are hydrogen, hydroxy, halogen, preferably chloro, bromo or fluoro, methyl, tert-butyl, phenyl, dimethylamino, methoxy, ethoxy, 2- dimethylaminoethoxy, 2-carboxyethenyl, 2-morpholin-4-ylethoxy, perhalomethyl, pref- 13 erably trifluoromethyl, perhalomethoxy, preferably trifluoromethoxy, carboxy, cyano, methylthio, methylsulfonyl, acetamido, nitro, acetyl, acetoxy, or hydroxymethyl
  • R11 is selected from the group consisting of is hydrogen, halogen, preferably chloro or C ⁇ g-alkoxy, preferably methoxy or perhalomethyl, preferably trifluoromethyl, or perhalomethoxy, preferably trifluormethoxy.
  • the invention relates to compounds of general formula (lb):
  • R 3 is as defined above and R 9 is hydrogen, halogen, preferably chloro, methoxy or perhalomethyl, preferably trifluoromethyl, or perhalomethoxy, preferably trifluormethoxy.
  • R9 (Id) wherein R 3 and R 9 are as defined above.
  • the invention relates to compounds of general formula (le): 14
  • R 7 is hydrogen, halogen, perhalomethyl, or perhalomethoxy
  • 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.
  • NIDDM non-insulin dependent diabetes mellitus
  • 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).
  • 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 invention or a pharmaceutically acceptable acid addition salt or other salt as defined above thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperglycaemia and treatment or prevention of diabetes.
  • the invention also relates to the use of the inventive compounds of the invention as medicaments useful for treating hyperglycaemia and treating or preventing diabetes.
  • the present invention relates to methods of preparing the above mentioned compounds.
  • Methods of preparing compounds of general formula I comprises:
  • R 1 , R 3 , R 4 , R 5 , n, and m are as defined above and L is a leaving group and are 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, R 3 COO where R 3 is as defined above, or any other leaving group known to act as a leaving group in acylation reactions.
  • the base can be either absent (i.e.
  • compound X acts as a base) or thethylamine, 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.
  • R 2 is optionally substituted C 1-6 alkyl or aralkyl:
  • M is a leaving group and is selected from chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p- toluenesulfonyloxy or any other group known to act as a leaving group in alkylation reactions.
  • the base can be either absent (i.e.
  • compound X acts as a base) or thethylamine, 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 alkylation reactions.
  • R ⁇ R 2 , R 4 , R 5 , n, and m are as defined above, R 11 is as defined for R 2 but one (1 ) carbon atom shorter.
  • the reducing agent can be selected from the following list: NaCNBH 3 , NaBH(OAc) 3 , diborane, BH 3 complexes (eg. with tetrahydrofuran or dimethylsulfide), metallic sodium, or H 2 /catalyst or any reductant known to be effective in the reductive alkylation re- action.
  • the compounds of the invention may be prepared by art-recognized procedures from known compounds or readily prepared intermediates.
  • the starting materials are either known compounds or compounds which may be prepared in analogy with the preparation of known compounds or in analogy with known methods as described by e.g Tupper D.E. et al., J. Heterocyclic Chem., 33, 1123-9 (1996), Stokker G.E., Tetrahedron Lett., 37, 5453-6 (1996), Nakagawa, M. et al., Chem. Pharm. Bull., 41 , 287-91 (1993), Singh H. et al., Heterocycles, 23, 107-10 (1985), Skinner W.A. et al., Can. J. Chem., 43, 2251-3 (1965). P. Kumar et al., J.
  • 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 dosage unit of the pharmaceutical compositions according to the invention typically contains from 0.05mg to 1000mg, preferably from 0.1mg 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[3,2-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 19 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[3,2-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, transder- mal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, 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 lipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material.
  • a plasma lipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material e.g., a plasma lipid 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 Practise of Pharmacy. 19 h Ed.. 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt 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.
  • 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.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, sil- 20 icic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hy- droxymethylcellulose 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 in- fluencing 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, la, lb or lc dissolved or suspended in a liquid carrier, in particular an aqueous car- rier, for aerosol application.
  • a liquid carrier in particular an aqueous car- rier
  • 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.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tablet- ting techniques and contains:
  • Active compound (as free compound or salt thereof) 5.0 mg Colloidal silicon dioxide (Aerosil) 1.5 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 hyperinsulinaemia and diabetes.
  • mammals include both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the mammal is a human.
  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule générale (I), dans laquelle A, ensemble avec la double liaison de formule (I), forme un système cyclique sélectionné dans le groupe constitué par benzène, thiophène, furane, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole ou thiazole, R2 représente un alkyle C¿1-5? éventuellement substitué, un aralkyle éventuellement substitué, ou COR?3, où R3¿ représente un alkyle C¿1-5? éventuellement substitué, un aralkyle éventuellement substitué, ou un aryle éventuellement substitué, ou un hétérocyclyle éventuellement substitué, R?1¿ représente un hétéroaryle éventuellement substitué, ou un de ses sels avec une base ou un acide pharmaceutiquement acceptable, ou tout isomère optique, une composition pharmaceutique les renfermant, et l'utilisation de ces composés pour la préparation de médicaments destinés au traitement ou à la prévention de maladies du système endocrinien, de préférence l'hyperglycémie ou le diabète.
PCT/DK1999/000079 1998-03-06 1999-02-25 Derives de 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine WO1999045013A1 (fr)

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AU26104/99A AU2610499A (en) 1998-03-06 1999-02-25 4,5,6,7-tetrahydro-thieno(3,2-c)pyridine derivatives

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DK0309/98 1998-03-06
DK30998 1998-03-06
DK34998 1998-03-12
DK0349/98 1998-03-12
DKPA199801113 1998-09-03
DKPA199801113 1998-09-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007011820A2 (fr) 2005-07-15 2007-01-25 Amr Technology, Inc. Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4174448A (en) * 1977-07-12 1979-11-13 Parcor Process for the preparation of thienopyridine derivatives
NL7807819A (nl) * 1978-06-26 1980-01-23 Smithkline Corp Gesubstitueerde 1-thienyl- en furyl-2,3,4,5-tetrahydro- -1h-3-benzazepineverbindingen met o.a. cardiovasculaire activiteit.
US5440033A (en) * 1993-11-09 1995-08-08 Schering Corporation Indolyl-, pyrrolyl- and pyrazolyl substituted benzazepines
WO1996034870A1 (fr) * 1995-05-03 1996-11-07 Synthelabo Derives d'azacycloalcanes, leur preparation et leurs applications en therapeutique
WO1998040385A1 (fr) * 1997-03-07 1998-09-17 Novo Nordisk A/S DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4174448A (en) * 1977-07-12 1979-11-13 Parcor Process for the preparation of thienopyridine derivatives
NL7807819A (nl) * 1978-06-26 1980-01-23 Smithkline Corp Gesubstitueerde 1-thienyl- en furyl-2,3,4,5-tetrahydro- -1h-3-benzazepineverbindingen met o.a. cardiovasculaire activiteit.
US5440033A (en) * 1993-11-09 1995-08-08 Schering Corporation Indolyl-, pyrrolyl- and pyrazolyl substituted benzazepines
WO1996034870A1 (fr) * 1995-05-03 1996-11-07 Synthelabo Derives d'azacycloalcanes, leur preparation et leurs applications en therapeutique
WO1998040385A1 (fr) * 1997-03-07 1998-09-17 Novo Nordisk A/S DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007011820A2 (fr) 2005-07-15 2007-01-25 Amr Technology, Inc. Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine
US7956050B2 (en) 2005-07-15 2011-06-07 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8791101B2 (en) 2005-07-15 2014-07-29 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9403776B2 (en) 2005-07-15 2016-08-02 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

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