EP0973778A1 - DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO 3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION - Google Patents

DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO 3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION

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Publication number
EP0973778A1
EP0973778A1 EP98906858A EP98906858A EP0973778A1 EP 0973778 A1 EP0973778 A1 EP 0973778A1 EP 98906858 A EP98906858 A EP 98906858A EP 98906858 A EP98906858 A EP 98906858A EP 0973778 A1 EP0973778 A1 EP 0973778A1
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EP
European Patent Office
Prior art keywords
tetrahydro
thieno
compound
pyridin
methanone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP98906858A
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German (de)
English (en)
Inventor
Peter Madsen
Jane Marie Lundbeck
Niels Westergaard
Lars Naerum
Annemarie Reinhardt Varming
Helle Demuth
Morten Heide
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Novo Nordisk AS
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Novo Nordisk AS
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Publication of EP0973778A1 publication Critical patent/EP0973778A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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 meth- ods for their preparation, 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 glu- cose-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 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, & 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 I: wherein
  • a together with the double bond of formula I forms a cyclic system selected from the group consisting of benzene, thiophene, furan, pyhdine, pyrimidine, pyrazine, pyridazine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole or thiazole,
  • R 1 is C 1-6 -alkyl, or aryl, optionally substituted with one or more substituents
  • R 2 is C ⁇ -alkyl, aralkyl, or COR 3 optionally substituted with one or more substituents
  • R 3 is C 1-6 -alkyl, aralkyl, or aryl, optionally substitued 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 ⁇ -alkoxy, nitro, cyano, amino, optionally substituted mono- or di-C 1-6 -alkylamino, acylamino, C 1-6 -alkoxycarbonyl, carboxy or carbamoyl, n is O, 1 , or 2, and m is 0, 1 , or 2, or a 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.
  • the invention includes all isomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixture thereof.
  • 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, fuma c, mandelic, benzoic, cinnamic, methanesulfonic, ethanesulfonic, picric and the like, and include the pharmaceutically ac- ceptable salts listed in Journal of Pharmaceutical Science, 6_6_, 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, ⁇ - alkylamine, di (C ⁇ -alkyl)
  • acid addition salts are the hydrates which the present compounds are able to form.
  • the acid addition salts may be obtained as the di- rect 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.
  • C 1- ⁇ -alkyl refers to a straight or branched, saturated or unsaturated hydrocarbon chain.
  • the C 1-6 -alkyl residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyclic hydrocarbon residues.
  • aliphatic hydrocarbon residues examples include saturated aliphatic hy- drocarbon 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- 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 alicyclic hydrocarbon residues having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl; and C 5 ⁇ unsaturated alicyclic hydrocarbon residues having 5 to 6 car- bon atoms such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyciopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl.
  • lower alkyl and lower alkoxy mean C 1- ⁇ -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 means an aryl residue as defined above or a C 1-6 -alkyl residue as defined above that may be unsubstituted or may have 1 or more preferably 1 to 5 substituents, which are the same as or different from one another.
  • substituents include, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, cyano, ni- tro, trifluoromethyl, carbamoyl, C 1-4 -acyl (e.g. acetyl, propionyl, isopropionyl), C 1-6 -alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert.butoxy), C 1-6 -alkyl as defined above, C ⁇ -alkoxycarbonyl (e.g.
  • C ⁇ -alkanoyloxy e.g. ones having 2 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl
  • C ⁇ -alkanoyloxy e.g. ones having 2 to 6 carbon atoms such as acetyloxy, propionyloxy, isopropionyloxy
  • C 1-4 -alkylthio e.g. ones having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio, and isopropylthio
  • C 1-4 -alkylsuiphinyl e.g.
  • C 1-4 - alkylsulphonyl e.g. ones having 1-4 carbonatoms such as methylsulphonyl and ethyl- sulphonyl
  • C ⁇ -alkylamino e.g. one having 1 to 4 carbon atoms such as methylamino, eth- ylamino, dimethylamino, and 1-pyrrolidinyl
  • aminoalkyl e.g.
  • 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-pyridyl)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 ⁇ -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • 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.
  • the invention relates to compounds of general formula (I) in which A is selected from benzene or thiophene.
  • the invention relates to compounds of general formula (I), wherein R 1 is optionally substituted phenyl.
  • 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 is 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 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 from the group consisting of chloro, trifluoromethyl, methoxy, trifluoromethoxy.
  • the invention relates to compounds of general formula (I), wherein R 1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4- trifluoromethylphenyl, and 4-trifluoromethoxyphenyl.
  • R 1 is 2,3-dihydrobenzofuran or 4-methoxyphenyl.
  • 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 3 is selected from the group consisting of phenyl, 3-methoxyphenyl, 4- methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-(2-dimethylaminoethoxy)phenyl, or 4-(2-morpholin-4-ylethoxy)phenyl.
  • the invention relates to compounds of general formula (I), wherein R 3 is selected from the group consisting of 4-methylphenyl, 3,4-dimethoxyphenyi, 4- ethoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, dimethylaminophenyl, 4-(2- carboxyethenyl)phenyl, 4-(2-dimethylaminoethoxy)phenyl, 4-(2-morpholin-4-ylethoxy)phenyi, 1 H-indol-5-yl, 3-chloro-4-methoxyphenyl, and 1 H-benzimidazol-5-yl.
  • R 3 is selected from the group consisting of 4-methylphenyl, 3,4-dimethoxyphenyi, 4- ethoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, dimethylaminophenyl, 4-(2- carboxyethenyl)phenyl, 4-(2-dimethylaminoe
  • 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 or 1.
  • R 7 is hydrogen, halogen, preferably chloro, methoxy, perhalomethoxy, preferably thfluoromethoxy, perhalomethyl, preferably trifluoromethyl, diloweralkylamino, preferably di- methylamino, or nitro
  • 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, preferably trifluoromethyl, perhalomethoxy, preferably thfluoromethoxy, carboxy, cyano, methylthio, methylsulfonyl, acetamido, nitro, acetyl, acetoxy, or hydroxy methyl.
  • the invention relates to compounds of general formula (la):
  • R 7 is halogen, perhalomethyl, or perhalomethoxy and R 6 and R 8 independently are hydrogen, methoxy, ethoxy, hydroxy, fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, dimethylamino, 2-carboxyethenyl, 2-dimethylaminoethoxy, or 2- morpholin-4-ylethoxy.
  • R 7 is preferably selected from the group consisting of chloro, methoxy and trifluoromethyl, more preferably thfluoromethoxy.
  • R 6 and R 8 are independently hydrogen, methoxy, chloro, trifluoromethyl, 2- dimethylaminoethoxy, or 2-morpholin-4-ylethoxy.
  • the invention relates to compounds of general formula (lb):
  • R 7 is as described above, and
  • R 6 is hydroxy, halogen, preferably chloro or fluoro, methyl, dimethylamino, methoxy, ethoxy, perhalomethyl, preferably trifluoromethyl, perhalomethoxy, preferably trifluoromethoxy, cyano, methylthio, acetyl, acetoxy, or hydroxymethyl.
  • R 7 is as defined above, and R 9 is 4-pyridyl, 5-hydroxypyrazin-2-yl, 5-chloro-6-hydroxypyridin-3-yl, 2-chloropyridin-3-yl, benzofuran-2-yl, benzothiophen-2-yl-, 7-methoxybenzofuran-2-yl, indolyl, preferably 1 H- indol-5-yl, benzimidazol, preferably 1 H-benzimidazol-5-yl or thienyl, preferably 5- chlorothiophen-2-yl.
  • R 7 is as defined above and R 9 is indolyl, preferably 1 H-indol-5-yl or benzimidazol, preferably 1 H-benzimidazol-5-yl.
  • R 9 is preferably benzothiophen-2-yl, indolyl, preferably 1 H- indol-5-yl, or benzimidazol, preferably 1 H-benzimidazol-5-yl.
  • the invention relates to compounds of general formula (Id):
  • R 7 is as defined above, and R 10 is optionally substituted aralkyl as defined above, preferably 2-(4-methoxyphenyl)-ethenyl, 2-(3-methoxyphenyl)-ethenyl, 2-(4-chlorophenyl)- ethenyl, 2-(4-fluorophenyl)-ethenyl, 2-(4-thfluoromethylphenyl)-ethenyl, 2-(4-methoxy- phenyl)-ethyl, 2-(4-chlorophenyl)-ethyl, 4-chlorobenzyl, 4-methoxy benzyl, 2-(2-furyl)-ethenyl, 2-(4,5-dimethyl-2-furyl)-ethenyl, 2-(5-methyl-2-furyl)-ethenyl, 2-(3-furyl)-ethenyl, 2-(2-thienyl)- ethenyl
  • R 7 is as defined above, and R 10 is 4-methoxyphenyl-2-ethenyl.
  • R 7 is preferably as defined above and R 10 is optionally sub- stituted aralkyl as defined above, preferably 2-(4-methoxyphenyl)-ethenyl, 2-(2-furyl)-ethenyl, 2-(5-methyl-2-furyl)-ethenyl, 2-(3-furyl)-ethenyi, or 2-(3-thienyl)-ethenyl.
  • the invention relates to compounds of general formula (le):
  • R 11 is pyridyl, preferably 4-pyridyl
  • 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, preferably trifluoromethyl, perhalo- methoxy, preferably trifluoromethoxy, carboxy, cyano, methylthio, methylsulfonyl, acetamido, nitro, acetyl, acetoxy, or hydroxy methyl.
  • R 10 is optionally substituted aralkyl as defined above, preferably 2-(4- methoxyphenyl)-ethenyl, 2-(3-methoxyphenyl)-ethenyl, 2-(4-chlorophenyl)-ethenyl, 2-(4- fluorophenyl)-ethenyl, 2-(4-thfluoromethylphenyl)-ethenyl, 2-(4-methoxyphenyl)-ethyl, 2-(4- chlorophenyl)-ethyl, 4-chlorobenzyl, 4-methoxybenzyl, 2-(2-furyi)-ethenyl, 2-(4,5-dimethyl-2- furyl)-ethenyl, 2-(5-methyl-2-furyl)-ethenyl, 2-(3-furyl)-ethenyl, 2-(2-thienyl)-ethenyl, or 2-(3- thienyl)-e
  • R 12 is aryl or aralkyl
  • 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, preferably trifluoromethyl, perhalomethoxy, preferably trifluoromethoxy, carboxy, cyano, methylthio, methylsulfonyl, acetamido, nitro, acetyl, acetoxy, or hydroxy methyl.
  • R 12 is aryl, preferably 4-trifluoromethoxyphenyl, or aralkyl, preferably benzyl, and
  • R 13 is aralkyl as defined above, preferably 2-(4-methoxyphenyl)-ethenyl, 2-(3- methoxyphenyl)-ethenyl, 2-(4-chlorophenyl)-ethenyl, 2-(4-fluorophenyl)-ethenyl, 2-(4- trifluoromethylphenyl)-ethenyl, 2-(4-methoxyphenyl)-ethyl, 2-(4-chlorophenyl)-ethyl, 4- chlorobenzyl, 4-methoxybenzyl, 2-(2-furyl)-ethenyl, 2-(4,5-dimethyl-2-furyl)-ethenyl, 2-(5- methyl-2-furyl)-ethenyl, 2-(3-furyl)-ethenyl, 2-(2-thienyl)-ethenyl, or 2-(3-thienyl)-ethenyl
  • 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, la, lb, Ic 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 therapeuti- cally 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 formula I, la, lb, and Ic 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 ⁇ 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 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.
  • 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 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 alkylation reactions.
  • R 1 , R 2 , R 4 , R 5 , n, and m are as defined above, R 1 is as defined for R 2 but one (1 ) carbon atom shorter.
  • the reducing agent can be selected from the following list: NaCNBH 3 ,
  • the compounds of formulae I, la, lb, and Ic may be prepared by art-recognized procedures from known compounds or readily preparable 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/I Bacitrazin (pH 7.5) essentially as described by Arion et al.,1980 (Arion, Lange, & Walls. 1980). Microsomes were kept at -80 °C until use.
  • IC 50 is the concentration of a compound that produces 50% inhibition.
  • 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 0.1 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[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 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 pre- ferred.
  • 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 pre- pared 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, 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, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hy- droxymethylcellulose and poiyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or giyceryl 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, emulsifi- ers, 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, la, lb or Ic 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:
  • 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.
  • Methyl 4-hydroxybenzoate (10 g, 66 mmoles) was dissolved in N,N-dimethylformamide (200 mL).
  • Potassium carbonate (45 g, 0.33 moles) and 2-chloro-N,N-dimethylethylamine hydro- chloride (14.2 g, 99 mmoles) were added and the resulting mixture was stirred vigorously at room temperature for 7 days.
  • More 2-chloro-N,N-dimethylethylamine hydrochloride (3 g, 20 mmoles) was added and stirring at room temperature was continued for 2 days.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, one corresponding to T R 44-50 min and one corre- sponding to T R 62-72 min. Fractions from the two runs corresponding to T R 44-50 min were separately pooled and evaporated to yield 12.1 mg of the title compound.
  • the column was eluted isocratically with a 1 :1 mixture of n-heptane and 2-propanol at a flow rate of 10 mUmin and fractions collected corresponding to 1 min/fraction.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, one corresponding to T R 27-32 min and one corresponding to T R 62-74 min. Fractions corresponding to T R 27-32 min were pooled and evaporated to yield 7.1 mg of the title compound.
  • the column was 20*250 mm ODS 10 ⁇ m (YMC) eluted with a gradient of acetonitrile (solvent B) and de-ionised water added 0.05% TFA (solvent A), 45%B to 100% B over 30 minutes. Fractions corresponding to T R 12 - 14 minutes were pooled to yield 8.3 mg of the title compound.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, one corresponding to T R 28-32 mininutes and one correspond- ing to T R 51-58 minutes. Fractions corresponding T R 28-32 minutes were pooled and evaporated to yield 1.8 mg of the title compound.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, one corresponding to T R 40-43 minutes and one corresponding to T R 55-59 minutes. Fractions corresponding to T R 40-43 minutes were pooled and evaporated to yield 4.0 mg of the title compound.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, one corresponding to T R 20-25 minutes and one corresponding to T R 27-33 minutes. Fractions corresponding to T R 20-25 minutes were pooled and evaporated to yield 8.4 mg of the title compound.
  • the column was eluted isocratically with a 70:30:0.1 mixture of heptane, 2-propanol and diethylamine at a flow rate of 6 ml/min and fractions col- lected corresponding to 1 minute/fraction.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, one corresponding to T R 40-47 minutes and one corresponding to T R 50-59 minutes. Fractions corresponding to T R 40-47 minutes were pooled and evaporated to yield 4.1 mg of the title compound.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, one corresponding to T R 24-30 minutes and one corresponding to T R 41-47 minutes. Fractions corresponding to T R 24-30 minutes were pooled and evaporated to yield 2.5 mg of the title compound.
  • the compounds of this invention can also be prepared by parallel syntheses, for example by a method essentially as described above, e.g. as described in example 3.
  • the 1- hydroxybenzotriazole or another hydroxy azole known to be effective as alcohol component in active ester mediated amide coupling reactions can either be present in the reaction or it can be omitted depending on the substitution on the carboxylic acid part. This will be recognised by those skilled in the art.
  • Phenethylamine (0.59 g, 4.9 mmol), 4-trifluoromethoxybenzoic acid (1.0 g, 4.9 mmol) and N- (3-dimethylaminopropyl)-N-ethylcarbodimide, HCI (1.39 g, 7.3 mmol) were mixed in N,N- dimethylformamide (50 mL) at room temperature and the reaction mixture was stirred for 16 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL).
  • the column was eluted isocratically with a mixture of n-heptane and 2-propanol (1 :1) at a flow rate of 10 ml/min and fractions were collected corresponding to 1 min/fraction.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, corresponding to T R 24-29 minutes and T R 42-50 minutes, respectively. Fractions corresponding to T R 24-29 minutes were pooled and evaporated to yield 8.8 mg of the title compound.
  • the eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, corresponding to T R 16-19 minutes and T R 27-35 minutes, respectively. Fractions corresponding to T R 16-19 minutes were pooled and evaporated to yield 7.2 mg of the title compound.

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Abstract

Les dérivés de 4,5,6,7-tétrahydro-thiéno[3,2-c]pyridine modulent l'activité de molécules à l'aide d'unités de reconnaissance glucose-6-phosphate, notamment des glucose-6-phosphatases dans des systèmes in vitro, des micro-organismes, des cellules eucaryotes, des animaux entiers et des humains, et sont utiles dans le traitement de maladies associées aux voies métaboliques du glucose.
EP98906858A 1997-03-07 1998-03-06 DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO 3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION Withdrawn EP0973778A1 (fr)

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DK24997 1997-03-07
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DK136597 1997-11-27
PCT/DK1998/000083 WO1998040385A1 (fr) 1997-03-07 1998-03-06 DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION

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Families Citing this family (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045013A1 (fr) * 1998-03-06 1999-09-10 Novo Nordisk A/S Derives de 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine
US6090797A (en) * 1998-09-02 2000-07-18 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno(2,3-C)pyridine derivatives
WO2000014090A1 (fr) * 1998-09-02 2000-03-16 Novo Nordisk A/S Derives de 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine
US8080380B2 (en) 1999-05-21 2011-12-20 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US8481268B2 (en) 1999-05-21 2013-07-09 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
DE60124861T2 (de) 2000-01-21 2007-05-10 Novartis Ag Zusammensetzungen bestehend aus dipeptidylpeptidase-iv inhibitoren und antidiabetica
UA74826C2 (en) 2000-05-17 2006-02-15 Ortho Mcneil Pharm Inc ?-carboline derivatives as phosphodiesterase inhibitors
ATE307133T1 (de) 2001-07-13 2005-11-15 Pharmacia & Upjohn Co Llc Hexahydroazepino(4,5-g)indole und -indoline als 5-ht-rezeptor-liganden
US6953787B2 (en) 2002-04-12 2005-10-11 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
GB0224557D0 (en) * 2002-10-22 2002-11-27 Glaxo Group Ltd Novel compounds
US7265128B2 (en) * 2003-01-17 2007-09-04 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7138529B2 (en) * 2003-04-16 2006-11-21 Hoffmann-La Roche Inc. Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
PL2332921T3 (pl) 2003-06-17 2016-08-31 Arena Pharm Inc Chlorowodorek 8-chloro-1-metylo-2,3,4,5-tetrahydro-1H-3-benzazepiny
EP2332920A3 (fr) 2003-06-17 2011-12-21 Arena Pharmaceuticals, Inc. Procédés de préparation de 3-benzazepines
CA2531064C (fr) * 2003-07-15 2012-05-22 Dainippon Sumitomo Pharma Co., Ltd. Nouveau derive d'heteroaryle
BRPI0414541B8 (pt) 2003-09-17 2021-05-25 Janssen Pharmaceutica Nv compostos heterocíclicos fundidos tendo atividade de modulação de receptor de serotonina, método de preparação de compostos intermediários
CN101084193B (zh) 2004-12-21 2011-12-07 艾尼纳制药公司 (r)-8-氯-1-甲基-2,3,4,5-四氢-1h-3-苯并氮杂卓盐酸盐的晶型
ME01541B (me) 2005-04-13 2014-04-20 Astex Therapeutics Ltd DERIVATI HIDROKSIBENZAMIDA l NJIHOVA PRIMJENA KAO INHIBITORA HSP90
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
PE20080145A1 (es) 2006-03-21 2008-02-11 Janssen Pharmaceutica Nv Tetrahidro-pirimidoazepinas como moduladores de trpv1
JP5199997B2 (ja) 2006-04-03 2013-05-15 アリーナ ファーマシューティカルズ， インコーポレイテッド ８−クロロ−１−メチル−２，３，４，５−テトラヒドロ−１ｈ−３−ベンズアゼピンおよびこれに関連する中間体を調製するためのプロセス
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
JP5410285B2 (ja) 2006-10-12 2014-02-05 アステックス、セラピューティックス、リミテッド 医薬化合物
GB0620259D0 (en) 2006-10-12 2006-11-22 Astex Therapeutics Ltd Pharmaceutical compounds
JP5518478B2 (ja) 2006-10-12 2014-06-11 アステックス、セラピューティックス、リミテッド 医薬化合物
EP2073807A1 (fr) 2006-10-12 2009-07-01 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008044029A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
ES2522587T3 (es) 2006-12-05 2014-11-17 Arena Pharmaceuticals, Inc. Procesos para preparar (R)-8-cloro-1-metil-2,3,4,5-tetrahidro-1H-3-benzacepina e intermedios de la misma
PE20091102A1 (es) 2007-12-17 2009-07-25 Janssen Pharmaceutica Nv Moduladores imidazolo-, oxazolo-, y tiazolopirimidina del trpv1
US8822727B2 (en) 2008-03-04 2014-09-02 Arena Pharmaceuticals, Inc. Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
GB0806527D0 (en) 2008-04-11 2008-05-14 Astex Therapeutics Ltd Pharmaceutical compounds
WO2010148207A2 (fr) 2009-06-18 2010-12-23 Arena Pharmaceuticals, Inc. Procédés pour la préparation d'agonistes du récepteur 5-ht2c
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
CN102834393B (zh) 2010-02-03 2015-07-22 武田药品工业株式会社 细胞凋亡信号调节激酶1抑制剂
KR20130112848A (ko) 2010-06-02 2013-10-14 아레나 파마슈티칼스, 인크. 5-ｈｔ2ｃ 수용체 아고니스트의 제조 방법
CN101863900B (zh) * 2010-06-29 2012-07-25 天津药物研究院 一氧化氮供体型噻吩并吡啶衍生物、其制备方法和用途
EP2611449A1 (fr) 2010-09-01 2013-07-10 Arena Pharmaceuticals, Inc. Administration de lorcasérine à des individus présentant une insuffisance rénale
JP6272695B2 (ja) 2010-09-01 2018-01-31 エーザイ・アール・アンド・ディー・マネジメント株式会社 体重管理のために有用な５−ｈｔ２ｃアゴニストの改変放出剤形
WO2012030938A1 (fr) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Sels de lorcasérine dotés d'acides optiquement actifs
CN103189360A (zh) 2010-09-01 2013-07-03 艾尼纳制药公司 5-ht2c激动剂的非吸湿性盐
US9242994B2 (en) 2012-03-23 2016-01-26 Memorial Sloan-Kettering Cancer Center Treatment of pancreatic and related cancers with 5-acyl-6,7-dihydrothieno[3,2-c]pyridines
UY34436A (es) 2012-10-09 2014-07-31 Arena Pharm Inc Metodo de control del peso
SG11201606080SA (en) 2014-02-03 2016-08-30 Vitae Pharmaceuticals Inc Dihydropyrrolopyridine inhibitors of ror-gamma
PT3207043T (pt) 2014-10-14 2019-03-25 Vitae Pharmaceuticals Llc Inibidores de di-hidropirrolopiridina de ror-gama
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
ES2856931T3 (es) 2015-08-05 2021-09-28 Vitae Pharmaceuticals Llc Moduladores de ROR-gamma
EP3377482B1 (fr) 2015-11-20 2021-05-12 Vitae Pharmaceuticals, LLC Modulateurs de ror-gamma
TWI757266B (zh) 2016-01-29 2022-03-11 美商維它藥物有限責任公司 ＲＯＲ－γ調節劑
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US20200062776A1 (en) * 2016-06-16 2020-02-27 Memorial Sloan-Kettering Cancer Center Hedgehog acyltransferase inhibitors and uses thereof
AR112461A1 (es) 2017-07-24 2019-10-30 Vitae Pharmaceuticals Inc PROCESOS PARA LA PRODUCCIÓN DE SALES Y FORMAS CRISTALINAS DE INHIBIDORES DE RORg
WO2019018975A1 (fr) 2017-07-24 2019-01-31 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror gamma
AR113826A1 (es) 2017-11-02 2020-06-17 Aicuris Gmbh & Co Kg Indol-2-carboxamidas sustituidas con amino-tiazol activas contra el virus de la hepatitis b (vhb)
WO2020191151A1 (fr) * 2019-03-19 2020-09-24 Oncovalent Therapeutics Inc. Composés inhibiteurs de sumo et leurs utilisations
WO2023137297A2 (fr) * 2022-01-11 2023-07-20 Suvalent Therapeutics, Inc. Inhibiteurs de 5,6-dihydro-4h-thieno[2,3-c]pyrrole sumo et leurs utilisations
CN114507155A (zh) * 2022-02-16 2022-05-17 浙江欣禾生物股份有限公司 一种间三氟甲基苯乙酮肟的制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD210278A5 (de) * 1982-03-05 1984-06-06 Boehringer Ingelheim Kg Verfahren zur herstellung neuer basisch substituierter 4-phenyl-4,5,6,7-tetrahydro-thieno-(2,3-c)pyridine
DE3412947A1 (de) * 1984-04-06 1985-10-17 Bayer Ag, 5090 Leverkusen Tetrahydothienopyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
GB8429087D0 (en) * 1984-11-16 1984-12-27 Scras Thienopyridine derivatives
FR2595356B1 (fr) * 1986-03-05 1991-05-24 Pasteur Strasbourg Universite Derives des nitro ou aminobenzyltetrahydroisoquinoleines, procedes d'obtention, compositions pharmaceutiques les contenant, proprietes pharmacologiques et applications
FR2733750B1 (fr) * 1995-05-03 1997-06-13 Synthelabo Derives de l'acide gamma-oxo-alpha-(phenylmethyl)-5,6- dihydro-4h-thieno(3,4-c)pyrrole-5-butanoique, leur preparation et leur application en therapeutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9840385A1 *

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WO1998040385A1 (fr) 1998-09-17
JP2001514631A (ja) 2001-09-11
AU6290998A (en) 1998-09-29

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