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

Info

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
Authority
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.)
Withdrawn
Application number
EP98906858A
Other languages
German (de)
English (en)
Inventor
Peter Madsen
Jane Marie Lundbeck
Niels Westergaard
Lars Naerum
Annemarie Reinhardt Varming
Helle Demuth
Morten Heide
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP0973778A1 publication Critical patent/EP0973778A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DK24997 1997-03-07
DK24997 1997-03-07
DK136597 1997-11-27
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

Publications (1)

Publication Number Publication Date
EP0973778A1 true EP0973778A1 (fr) 2000-01-26

Family

ID=26063610

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98906858A Withdrawn EP0973778A1 (fr) 1997-03-07 1998-03-06 DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO 3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION

Country Status (4)

Country Link
EP (1) EP0973778A1 (fr)
JP (1) JP2001514631A (fr)
AU (1) AU6290998A (fr)
WO (1) WO1998040385A1 (fr)

Families Citing this family (59)

* 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
AU5154699A (en) * 1998-09-02 2000-03-27 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno(2,3-c)pyridine derivatives
US8481268B2 (en) 1999-05-21 2013-07-09 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US8080380B2 (en) 1999-05-21 2011-12-20 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
ES2433476T3 (es) 2000-01-21 2013-12-11 Novartis Ag Combinaciones que contienen inhibidores de la dipeptidilpeptidasa-IV y agentes 5 antidiabéticos
UA74826C2 (en) 2000-05-17 2006-02-15 Ortho Mcneil Pharm Inc ?-carboline derivatives as phosphodiesterase inhibitors
WO2003006466A1 (fr) 2001-07-13 2003-01-23 Pharmacia & Upjohn Company Hexahydroazepino (4, 5-g) indoles et indolines, ligands du recepteur 5-ht
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
EP2189448B1 (fr) 2003-06-17 2014-01-29 Arena Pharmaceuticals, Inc. Procédés de séparation de racemates de 3-Benzazepines
CN101792417A (zh) 2003-06-17 2010-08-04 艾尼纳制药公司 用于治疗5ht2c受体相关疾病的苯并氮杂卓衍生物
ATE556051T1 (de) 2003-07-15 2012-05-15 Dainippon Sumitomo Pharma Co Neues heteroarylderivat
ATE420881T1 (de) 2003-09-17 2009-01-15 Janssen Pharmaceutica Nv Kondensierte heterocyclische verbindungen als modulatoren des serotoninrezeptors
KR101281919B1 (ko) 2004-12-21 2013-07-03 아레나 파마슈티칼스, 인크. (ｒ)-8-클로로-1-메틸-2,3,4,5-테트라히드로-1ｈ-3-벤즈아제핀 히드로클로라이드의 결정질 형태
JP5154406B2 (ja) * 2005-04-13 2013-02-27 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
PL1931350T5 (pl) 2005-09-14 2021-11-15 Takeda Pharmaceutical Company Limited Podanie inhibitorów dipeptydylo-peptydazy
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
EP2001852A2 (fr) 2006-04-03 2008-12-17 Arena Pharmaceuticals, Inc. Procédés de préparation de 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine et produits intermédiaires associés
GB0620259D0 (en) 2006-10-12 2006-11-22 Astex Therapeutics Ltd Pharmaceutical compounds
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
EP2081891A2 (fr) 2006-10-12 2009-07-29 Astex Therapeutics Limited COMPOSES PHARMACEUTIQUES AYANT UNE ACTIVITE INHIBITRICE OU MODULATRICE HSP90& xA;
JP5721949B2 (ja) 2006-10-12 2015-05-20 アステックス、セラピューティックス、リミテッドＡｓｔｅｘ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ 複合薬剤
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
EP2073804B1 (fr) 2006-10-12 2017-09-13 Astex Therapeutics Limited Composes amides d'acide benzoique substitues par un groupe hydroxyle pour son utilisation dans le traitement de la douleur
CA2670285A1 (fr) 2006-12-05 2008-06-12 Arena Pharmaceuticals, Inc. Procedes de preparation de (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine et intermediaires de celle-ci
TW200942549A (en) 2007-12-17 2009-10-16 Janssen Pharmaceutica Nv Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1
JP5491421B2 (ja) 2008-03-04 2014-05-14 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 ５−ｈｔ２ｃアゴニストである（ｒ）−８−クロロ−１−メチル−２，３，４，５−テトラヒドロ−１ｈ−３−ベンゾアゼピンに関連する中間体の調製のためのプロセス
GB0806527D0 (en) 2008-04-11 2008-05-14 Astex Therapeutics Ltd Pharmaceutical compounds
CN102648170A (zh) 2009-06-18 2012-08-22 艾尼纳制药公司 制备5-ht2c受体激动剂的方法
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
PT2531501E (pt) 2010-02-03 2014-02-17 Takeda Pharmaceutical Inibidores da cinase de regulação do sinal de apoptose 1
US9045431B2 (en) 2010-06-02 2015-06-02 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
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
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
EP2939677A1 (fr) 2010-09-01 2015-11-04 Arena Pharmaceuticals, Inc. Administration de lorcasérine à des individus avec une insuffisance rénale
WO2012030938A1 (fr) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Sels de lorcasérine dotés d'acides optiquement actifs
ES2704455T3 (es) 2010-09-01 2019-03-18 Arena Pharm Inc Formas farmacéuticas de liberación modificada de agonistas de 5-HT2C útiles para la gestión del peso
CN104364257B (zh) * 2012-03-23 2017-03-01 纪念斯隆-凯特琳癌症中心 5‑酰基‑6,7‑二氢噻吩并[3,2‑c]吡啶类化合物对胰腺及相关癌症的治疗作用
AU2012392187B2 (en) 2012-10-09 2018-07-12 Arena Pharmaceuticals, Inc. Method of weight management
PE20161372A1 (es) 2014-02-03 2017-01-08 Vitae Pharmaceuticals Inc Inhibidores de dihidropirrolopiridina de ror-gamma
UA118989C2 (uk) 2014-10-14 2019-04-10 Вітае Фармасьютікалс, Інк. Дигідропіролопіридинові інгібітори ror-гамма
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
EP3331876B1 (fr) 2015-08-05 2020-10-07 Vitae Pharmaceuticals, LLC Modulateurs de ror-gamma
MA53943A (fr) 2015-11-20 2021-08-25 Vitae Pharmaceuticals Llc Modulateurs de ror-gamma
TW202220968A (zh) 2016-01-29 2022-06-01 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
EP3471723A4 (fr) * 2016-06-16 2020-03-04 Memorial Sloan Kettering Cancer Center Inhibiteurs d'acyltransférase hedgehog et utilisations de ces derniers
CN111225914B (zh) 2017-07-24 2022-10-11 生命医药有限责任公司 RORγ的抑制剂
WO2019018975A1 (fr) 2017-07-24 2019-01-31 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror gamma
EP3704127A1 (fr) 2017-11-02 2020-09-09 AiCuris GmbH & Co. KG Nouveaux indole-2-carboxamides à substitution amino-thiazole hautement actifs agissant contre le virus de l'hépatite b (vhb)
PL3870578T3 (pl) 2018-10-22 2024-03-04 C4X Discovery Limited Związki terapeutyczne
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 *

Also Published As

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

Similar Documents

Publication Publication Date Title
EP0973778A1 (fr) DERIVES DE 4,5,6,7-TETRAHYDRO-THIENO 3,2-c]PYRIDINE, LEUR PREPARATION ET LEUR UTILISATION
US6177443B1 (en) 4,5,6,7-tetrahydro-thieno[3, 2-C]pyridine derivatives, their preparation and use
US11945794B2 (en) Nuclear transport modulators and uses thereof
EP1355889B1 (fr) Derives de triazole diamine substitues inhibiteurs de kinases
TWI313264B (en) Triamide-substituted heterobicyclic compounds
JP5570435B2 (ja) アミド−チオフェン化合物およびその使用
BR112012007828B1 (pt) compostos inibidores da xantina oxidase, processo para preparar os compostos, e, composição farmacêutica para a inibição da xantina oxidase
CN110072850A (zh) 3-磺酰基-5-氨基吡啶-2,4-二醇apj激动剂
JP2008501628A (ja) インドール誘導体およびがんの治療用途
JP2002523448A (ja) ｐ３８−αキナーゼのインヒビター
CN105722835B (zh) 3-芳基-5-取代的-异喹啉-1-酮化合物及它们的疗法应用
CN102741250A (zh) 作为pde10a酶抑制剂的杂芳族苯基咪唑衍生物
US20080234280A1 (en) Use of Mc4 Receptor Agonist Compounds
WO1999040062A1 (fr) Derives d'hydrazone
SA95160203B1 (ar) مشتقات بيرولوكربازول كيميائية علاجية Chemotheraqeutic Pyrrolocarbazole Derivatives
WO2000014090A1 (fr) Derives de 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine
US4258047A (en) Pyrazole derivatives, pharmaceutical formulations thereof
US6090797A (en) 4,5,6,7-tetrahydro-thieno(2,3-C)pyridine derivatives
JP2001354658A (ja) ヒドロキシホルムアミジン化合物及びその塩並びにそれらを含む医薬
CN105658645A (zh) 作为mpge-1抑制剂的哌啶基苯并咪唑衍生物
WO1999045013A1 (fr) Derives de 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine
JPH08508509A (ja) フェニルピロール誘導体および抗精神病薬としてのそれらの使用
JPH08504802A (ja) スクアレンシンターゼ阻害剤としてのキヌクリジン誘導体
JP2000128785A (ja) うっ血性心不全を治療する方法
EP1712550A2 (fr) Dérivés de triazole diamine substitués comme inhibiteurs de kinases

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19991007

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 19991007;LT PAYMENT 19991007;LV PAYMENT 19991007;MK PAYMENT 19991007;RO PAYMENT 19991007;SI PAYMENT 19991007

17Q First examination report despatched

Effective date: 20020430

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020911

RTI1 Title (correction)

Free format text: 4,5,6,7-TETRAHYDRO-THIENO 3,2-C PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE