WO1998040385A1 - 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE - Google Patents

4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE Download PDF

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WO1998040385A1
WO1998040385A1 PCT/DK1998/000083 DK9800083W WO9840385A1 WO 1998040385 A1 WO1998040385 A1 WO 1998040385A1 DK 9800083 W DK9800083 W DK 9800083W WO 9840385 A1 WO9840385 A1 WO 9840385A1
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Prior art keywords
tetrahydro
thieno
compound
pyridin
methanone
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PCT/DK1998/000083
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French (fr)
Inventor
Peter Madsen
Jane Marie Lundbeck
Niels Westergaard
Lars Naerum
Annemarie Reinhardt Varming
Helle Demuth
Morten Heide
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Novo Nordisk A/S
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Priority to AU62909/98A priority Critical patent/AU6290998A/en
Priority to JP53909998A priority patent/JP2001514631A/en
Priority to EP98906858A priority patent/EP0973778A1/en
Publication of WO1998040385A1 publication Critical patent/WO1998040385A1/en

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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.

Abstract

4,5,6,7-tetrahydro-thieno[3,2-c]pyridine derivative modulate the activity of molecules with glucose-6-phosphate recognition units, including glucose-6-phosphatases (G-6-Pases) in in vitro systems, microorganisms, eukaryotic cells, whole animals and human beings, and are useful in the treatment of diseases related to glucose metabolic pathways.

Description

4.5.6.7-Tetrahvdro-thieno[3.2-c]pyridine Derivatives, their Preparation and Use
Field of the invention
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.
Background of the invention
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. 1992; DeFronzo, Bonadonna, & Ferrannini. 1992; Clore, Stillman, Stevens, Blackard, Levy, & Richmond. 1996). Glucose-6-phosphatase (G-6-Pase) 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. 1992; DeFronzo, Bonadonna, & Ferrannini. 1992). The increased activity could mainly be accounted for by increased G-6-Pase catalytic enzyme protein (Argaud, 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.
Bibliography
Argaud, D., Zhang, Q., Pan, W., Maitra, S., Pilkis, S.J., & Lange, A. (1996). Regulation of rat liver glucose-6-phosphatase gene expression in different nutritional and hormonal states. Diabetes, 45:1563-1571. Arion, J.M., Lange, A.J., & Walls, H.E. (1980). Microsomal membrane integrity and the inter- actions of phlorizin with the glucose-6-phosphatase system. J Biol Chem, 255:10387-10395. Burchell, A., & Cain, D.I. (1985). Rat hepatic microsomal glucose-6-phosphatase protein levels are increased in streptozotocin-induced diabetes. Diabetologia, 28: (852). 856 Clore, J.N., Stillman, J.S., Stevens, W., Blackard, W.G., Levy, J., & Richmond, V.A. (1996). Chronic hyperinsulinemia supresses glucose-6-phosphatase mRNA. Diabetes, 44 (suppl 7J.-253A
Consoli, A. (1992). Role of liver in pathophysiology of NIDDM. Diabetes Care, 15:430-441. DeFronzo, R.A., Bonadonna, R.C., & Ferrannini, E. (1992). Pathogenesis of NIDDM: A Balanced overview. Diabetes Care, 75:318-368. Lyall, H., Grant, A., Scott, H.M., & Burchell, A. (1992). Regulation of the hepatic microsomal glucose-6-phosphatase enzyme. Biochem Soc Trans, 20, 271 S (abstract).
Nordlie, R.C., Bode, A.M., & Foster, J.D. (1993). Recent advances in hepatic glucose 6- phosphatase regulation and function. Proc Soc Exp Biol Med, 203:274-285. Sukalski, K.A., & Nordlie, R.C. (1989). Glucose-6-phosphatase: Two concepts of membrane function relationship. In A. Meister (Ed.), Advances in Enzymology and realted areas of mo- lecular biology, (pp. 93-117). New York: John Wiley and Sons.
Description of the invention
The present invention relates to compounds of the general formula I:
Figure imgf000005_0001
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,
R1 is C1-6-alkyl, or aryl, optionally substituted with one or more substituents, R2 is C^-alkyl, aralkyl, or COR3 optionally substituted with one or more substituents, R3 is C1-6-alkyl, aralkyl, or aryl, optionally substitued with one or more substituents,
R4 and R5 independently are hydrogen, halogen, perhalomethyl, optionally substituted C1-6-alkyl, hydroxy, optionally substituted C^-alkoxy, nitro, cyano, amino, optionally substituted mono- or di-C1-6-alkylamino, acylamino, C1-6-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.
Within its scope 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 scope of the invention also includes all tautomeric forms of the compounds of formula I.
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) amine, tri (C^-alkyl) amine and the four (4) corresponding omega- hydroxy analogues (e.g. methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, di(hydroxyethyl)amine, and the like; Also intended as pharmaceutically acceptable 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. In the alternative, 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.
The term "C1-β-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated or unsaturated hydrocarbon chain. The C1-6-alkyl residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyclic hydrocarbon residues. Examples of the aliphatic hydrocarbon residues 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 includ 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. Examples of the alicyclic hydrocarbon residue include saturated alicyclic hydrocarbon residues having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl; and C5^ 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.
The terms "lower alkyl" and "lower alkoxy" mean C1-β-alkyl and C^-alkoxy, respectively. The term "aryl" as used herein 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. 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl), imidazolyl (1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), thazolyl (1 ,2,3-triazol-1-yl, 1 ,2,3-triazol-2- yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6- isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3- benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro- benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3- dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro- benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro- benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7- indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6- benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2- benzoxazolyl), benzothiazolyl (1 -benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5- benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3- carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H- dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H- dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H- dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H- dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H- dibenz[b,f]azepine-5-yl), furanyl (e.g. 2-furanyl, 3-furanyl, 4-furanyl and 5-furanyl), thienyl (e.g. 2-thienyl, 3-thienyl, 4-thienyl and 5-thienyl) optionally substituted with one or more substituents. The term "optionally substituted" as used herein means an aryl residue as defined above or a C1-6-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. Examples of these substituents include, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, cyano, ni- tro, trifluoromethyl, carbamoyl, C1-4-acyl (e.g. acetyl, propionyl, isopropionyl), C1-6-alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert.butoxy), C1-6-alkyl as defined above, C^-alkoxycarbonyl (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), C1-4-alkylthio (e.g. ones having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio, and isopropylthio), C1-4-alkylsuiphinyl (e.g. ones having 1-4 carbon atoms such as methylsulphinyl and ethylsulphinyl), C1-4- 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. one having an amino containing group connected to a C1-6-alkyl group as defined above, such as 2-dimethylaminoethyl and 1-pyrrolidinylmethyl), aminoalkoxy (e.g. one having an amino containing group connected via a C1-6-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).
The term "halogen" as used herein means fluorine, chlorine, bromine or iodine.
The term "perhalomethyl" as used herein means trifluoromethyl, trichloromethyl, tribro- momethyl or triiodomethyl.
The term "perhalomethoxy" as used herein means trifluoromethoxy, trichloromethoxy, tri- bromomethoxy or triiodomethoxy.
The term "aralkyl" as used herein refers to an optionally substituted aryl residue as defined above, connected to an optionally substituted C1-6-alkyl as defined above. Examples of the aralkyl residue include benzyl, 2-phenylethyl, 2-phenylethenyl, 3-(2-pyridyl)propyl, 3- phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like. The term "C^-alkoxy" as used herein, alone or in combination, 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.
The term "carbamoyl" as used herein refers to a carbamoyl which can be optionally substituted by one or two residues selected from the list consisting of optionally substituted C1-6- alkyl as defined above, optionally substituted aryl as defined above and optionally substituted aralkyl as defined above.
In a preferred embodiment the invention relates to compounds of general formula (I) in which A is selected from benzene or thiophene.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein R1 is optionally substituted phenyl.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein each one of R\ R2, and R3 is substituted with one or more substituents.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein the substituents of R1 is halogen, perhalomethyl, perhalomethoxy, or C1-6-alkoxy.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein the substituents of R1 are selected from the group consisting of hydrogen, halogen, perhalomethyl, perhalomethoxy, or C1-6-alkoxy.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein the substituents of R1 are selected from from the group consisting of chloro, trifluoromethyl, methoxy, trifluoromethoxy.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein R1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4- trifluoromethylphenyl, and 4-trifluoromethoxyphenyl. In another preferred embodiment the invention relates to compounds of general formula (I), wherein R1 is 2,3-dihydrobenzofuran or 4-methoxyphenyl.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein R2 is COR3 or (CH2)q-aryl, and q is 0, 1 , 2, 3, 4, 5, or 6.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein R3 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.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein R3 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.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein R4 and R5 independently is hydrogen, chloro, or methoxy.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein n is 0 or 1 and m is 0 or 1.
In another preferred embodiment the invention relates to compounds of general formula (I), wherein n is 0 and m is or 1.
In a another preferred embodiment the invention relates to compounds of general formula (la):
Figure imgf000010_0001
wherein R7 is hydrogen, halogen, preferably chloro, methoxy, perhalomethoxy, preferably thfluoromethoxy, perhalomethyl, preferably trifluoromethyl, diloweralkylamino, preferably di- methylamino, or nitro, and R6 and R8 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.
In another preferred embodiment the invention relates to compounds of general formula (la):
Figure imgf000011_0001
wherein R7 is halogen, perhalomethyl, or perhalomethoxy and R6 and R8 independently are hydrogen, methoxy, ethoxy, hydroxy, fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, dimethylamino, 2-carboxyethenyl, 2-dimethylaminoethoxy, or 2- morpholin-4-ylethoxy.
R7 is preferably selected from the group consisting of chloro, methoxy and trifluoromethyl, more preferably thfluoromethoxy.
Preferably, R6 and R8 are independently hydrogen, methoxy, chloro, trifluoromethyl, 2- dimethylaminoethoxy, or 2-morpholin-4-ylethoxy.
In another preferred embodiment the invention relates to compounds of general formula (lb):
Figure imgf000011_0002
wherein R7 is as described above, and
R6 is hydroxy, halogen, preferably chloro or fluoro, methyl, dimethylamino, methoxy, ethoxy, perhalomethyl, preferably trifluoromethyl, perhalomethoxy, preferably trifluoromethoxy, cyano, methylthio, acetyl, acetoxy, or hydroxymethyl.
In another preferred embodiment the invention relates to compounds of general formula (Ic):
wherein R7 is as defined above, and R9 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.
In another preferred embodiment the invention relates to compounds of general formula (Ic):
Figure imgf000012_0002
wherein R7 is as defined above and R9 is indolyl, preferably 1 H-indol-5-yl or benzimidazol, preferably 1 H-benzimidazol-5-yl.
In the compounds of formula (Ic) R9 is preferably benzothiophen-2-yl, indolyl, preferably 1 H- indol-5-yl, or benzimidazol, preferably 1 H-benzimidazol-5-yl. In another preferred embodiment the invention relates to compounds of general formula (Id):
Figure imgf000013_0001
wherein R7 is as defined above, and R10 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, or 2-(3-thienyl)-ethenyl.
In another preferred embodiment the invention relates to compounds of general formula (Id):
Figure imgf000013_0002
wherein R7 is as defined above, and R10 is 4-methoxyphenyl-2-ethenyl.
In the compounds of formula (Id) R7 is preferably as defined above and R10 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.
In another preferred embodiment the invention relates to compounds of general formula (le):
Figure imgf000013_0003
wherein R11 is pyridyl, preferably 4-pyridyl, and
R6 and R8 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.
In another preferred embodiment the invention relates to compounds of general formula (If):
Figure imgf000014_0001
wherein R10 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)-ethenyl, and R11 is pyridyl, preferably 4-pyridyl.
In another preferred embodiment the invention relates to compounds of general formula (Ig):
Figure imgf000014_0002
wherein R12 is aryl or aralkyl, and
R6 and R8 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.
In another preferred embodiment the invention relates to compounds of general formula (Ih):
Figure imgf000015_0001
wherein R12 is aryl, preferably 4-trifluoromethoxyphenyl, or aralkyl, preferably benzyl, and
R13 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 most preferred compounds of the invention are:
(+)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 1),
(-)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 2),
(+)-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- trifiuoromethylphenyl)-methanone, (compound No. 3), (-)-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(4- trifluoromethylphenyl)-methanone, (compound No. 4),
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 5),
(+)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 6),
(-)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 7),
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3)2-c]pyhdin-5-yl]-(3-methoxyphenyl)- methanone, (compound No. 8), (+)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(3- methoxyphenyl)-methanone, (compound No. 9),
(-)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(3- methoxyphenyl)-methanone, (compound No. 10),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-phenyl-methanone,
(compound No. 11),
(+)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-phenyl-methanone, (compound No. 12),
(-)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-phenyl-methanone,
(compound No. 13),
(4-(2-Dimethylaminoethoxy)phenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 14), (+)-(4-(2-Dimethylaminoethoxy)phenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 15),
(-)-(4-(2-Dimethylaminoethoxy)phenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 16),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-(2-[2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 17),
(+)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-(2-[2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 18),
(-).[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-(2-[2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 19), [4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(4- dimethylaminophenyl)-methanone, (compound No 20),
3-{4-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]phenyl}acrylic acid, (compound No 21 ),
(4-Chlorophenyl)-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-methanone, both the racemate, the two pure enantiomers, and mixtures thereof (compound No 22),
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 24),
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 25), [4-(2-Dimethylaminoethoxy)-phenyl]-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 26),
[4-(2-Dimethylaminoethoxy)-phenyl]-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 27),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 28),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 29),
[4-(4-Thfluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 30),
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 31),
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 32), [4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(1 H-indol-5-yl)-methanone,
(compound No. 33),
(1 H-lndol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]- methanone, (compound No. 34),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-fluorophenyl)-methanone, (compound No. 35),
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yI]-(4-fluorophenyl)- methanone, (compound No. 36),
4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2- dimethylaminoethoxy)phenyl]-methanone, (compound No. 37), [4-(2-Dimethylaminoethoxy)phenyl]-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 38),
[7-Chloro-1-(2,3-dihydrobenzofuran-7-yl)-8-methoxy-1 ,2,4,5-tetrahydrobenzo[d]azepin-3-yl]-
[4-(2-dimethylaminoethoxy)-phenyl]-methanone, (compound No. 39),
[4-(3,4-Dimethoxyphenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-6-yl]-[4-(2- dimethylaminoethoxy)-phenyl]-methanone, (compound No. 40),
(3,4-Dimethoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-
5-yl]methanone, (compound No. 41 ),
(3-Chloro-4-methoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, (compound No. 42), (4-Ethoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone, (compound No. 43),
(4-Methylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone, (compound No. 44),
3-(4-Methoxyphenyl)-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl]propenone, (compound No. 45),
(1 H-Benzimidazol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-
5-yl]methanone, (compound No. 46),
(4-Methoxyphenyl)-[4-(4-thfluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(4- methoxyphenyl)-methanone
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methylsulfanylphenyl)-methanone 4-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]benzoic acid methyl ester
(4-Hydroxymethylphenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-
5-yl]methanone
(4-Acetoxyphenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
(4-Cyanophenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
1-{4-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5- carbonyl]phenyl}ethanone 3-Furan-2-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
3-(5-Methylfuran-2-yl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Benzo[b]thiophen-2-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-y I] methanone
3-Furan-3-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
3-Thiophen-3-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone 3-Thiophen-2-yl-1-[4-(4-thfluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methylsulfanylphenyl)methanone
4-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]benzonitrile 3-Furan-3-yl-1-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]propenone (4-Methoxyphenyl)-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5- yljmethanone
(4-Fluorophenyl)-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
(4-Chlorophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
(4-Methylsulfanylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone (4-Dimethylaminophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyhdin-5-yl]methanone
(4-Hydroxymethylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
3-Furan-3-yl-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
4-(4-Chlorophenyl)-5-(4-methoxybenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochlo- ride
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- hydroxyphenyl)methanone 1-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-2-(4- methoxyphenyl)ethanone
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(3- dimethylaminophenyl)methanone
N-{4-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]- phenyl}acetamide
[4-(4-ChIorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methanesulfonylphenyl)methanone
2-(4-Chlorophenyl)-1-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljethanone 2-(4-Methoxyphenyl)-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-
5-yl]-ethanone
(3-Dimethylaminophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]-methanone N-{4-[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]- phenylj-acetamide
(4-Methanesulfonylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]-methanone 2-(4-Chlorophenyl)-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]-ethanone
Biphenyl-4-yl-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
(3,4-Dichlorophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
(4-tert-Butylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5- yljmethanone
Pyridin-4-yl-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5- yljmethanone (5-Hydroxypyrazin-2-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-
5-y I] methanone
(5-Chloro-6-hydroxypyhdin-3-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
3-(4,5-Dimethylfuran-2-yl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]propenone
(1-Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-(4-methoxyphenyl)methanone
(1-Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-(4-chlorophenyl)methanone
(1H-Benzoimidazol-5-yl)-(1-benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)methanone
1 -(1 -Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-3-furan-3-ylpropenone 1 -(1 -Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-3-(4-methoxyphenyl)propenone
1 -(1 -Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-3-(4-methoxyphenyl)propan-1 -one
1 -(1 -Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-2-(4-methoxyphenyl)ethanone
(5-Chlorothiophen-2-yl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)methanone
(5-Chlorothiophen-2-yl)-[4-(4-dimethylaminophenyl)4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl)-methanone
(5-Chlorothiophen-2-yl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl)methanone (4-Hydroxymethylphenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)methanone [4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-(4- hydroxymethylphenyl)-methanone
[4-(4-Nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-(4-hydroxymethylphenyl)- methanone (4-Chlorophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)methanone
(4-Chlorophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
(4-Chlorophenyl)-[4-(4-dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl)- methanone
(4-ChIorophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone (4-Methoxyphenyl)-[4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
(4-Methoxyphenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone
[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl]-(4-methoxyphenyl)- methanone
3-(4-Methoxyphenyl)-1-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-propenone
(5-Chlorothiophen-2-yl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
3-(4-Methoxyphenyl)-1-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone
1-[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-3-(4- methoxyphenyl)-propenone
3-(4-Methoxyphenyl)-1-(4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)- propenone
(4-Dimethylaminophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
(4-Dimethylaminophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)- methanone
(4-Dimethylaminophenyl)-[4-(4-dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-
5-yl]-methanone
(4-Dimethylaminophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone (1 H-Benzoimidazol-5-yl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
(1H-Benzoimidazol-5-yl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
(1H-Benzoimidazol-5-yl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone
(4-Fluorophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone (4-Fluorophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone [4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-fluorophenyl)- methanone
(4-Fluorophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-methanone (4-Bromophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl)-methanone
(4-Bromophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
(4-Bromophenyl)-[4-(4-dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone
(4-Bromophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone 3-Furan-3-yl-1 -(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone
3-(3-Furan-3-yl)-1-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone
1-[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-5-yl)-3-(3-furan-3-yl)- propenone
3-(3-Furan-3-yl)-1-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone [4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-hydroxyphenyl)- methanone, less polar enantiomer,
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-hydroxyphenyl)- methanone, more polar enantiomer,
(1 H-Benzoimidazol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, less polar enantiomer,
(1H-Benzoimidazol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, more polar enantiomer,
(5-Chlorothiophen-2-yl)-[1-(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]- methanone (4-Chlorophenyl)-[1-(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]-methanone
(4-Methoxyphenyl)-[1-(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]- methanone
3-(4-Methoxyphenyl)-1 -[1 -(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2- yljpropenone 3-Furan-3-yl-1 -[1 -(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]propenone
(4-Trifluoromethoxyphenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyhdin-5-yl]methanone
(7-Methoxybenzofuran-2-yl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone Benzofuran-2-yl-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
3-(4-Fluorophenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- propenone 3-(4-Trifluoromethylphenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]propenone
3-(3-Methoxyphenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
3-(4-Chlorophenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
3-(4-Methoxyphenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]propan-1-one
3-(4-Chlorophenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]propan-1-one
and salts thereof with a pharmaceutically acceptable acid or base.
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). Moreover, 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.
Accordingly, in another aspect 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.
Furthermore, 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.
In yet another aspect, the present invention relates to methods of preparing the above mentioned compounds. Methods of preparing compounds of general formula I comprises:
Method A:
When R2 is COR3:
Reacting a compound of formula X with a compound of formula Y to form compounds of general formula lb:
Figure imgf000024_0001
X Y lb
wherein R\ R3, R4, R5, 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, R3COO where R3 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.
Method B: When R2 is optionally substituted C1-6 alkyl or aralkyl:
a) Reacting a compound of formula X with a compound of formula Z in an alkylation reaction to form compounds of general formula I:
Figure imgf000025_0001
X
wherein R\ R2, R4, R5, n, and m are as defined above, 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.
Method C :
Reacting a compound of formula X with an aldehyde of formula Zz in a reductive alkylation reaction to form compounds of general formula I:
Figure imgf000025_0002
X Zz
wherein R1, R2, R4, R5, n, and m are as defined above, R 1 is as defined for R2 but one (1 ) carbon atom shorter. The reducing agent can be selected from the following list: NaCNBH3,
NaBH(OAc)3, diborane, BH3 complexes (eg. with tetrahydrofuran or dimethylsulfide), metallic sodium, or H2/catalyst or any reductant known to be effective in the reductive alkylation reaction.
Or 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. Heterocyclic Chem., 19, 677-9 (1982), L. K. Lukanov et al., Synthesis, 1987, 204-6, A. L. Stanley & S. P. Stanforth, J. Heterocyclic Chem., 31, 1399-1400 (1994), A. K. Bose et al., J. Org. Chem., 56, 6968-70 (1991), K. Kementani et al., Heterocycles, 3, 311-41 (1975), E. Domonguez et al., Tetrahedron, 43, 1943-8 (1987), J. B. Bremner et al., Aust. J. Chem., 41 , 1815-26 (1988), M. J. O'Donnel et al., Tetrahedron. Lett., 23, 4259-62 (1982).
Pharmacological methods
The ability of compounds to inhibit glucose-6-phosphatase (G-6-Pase) catalytic enzyme activity from pig liver microsomes was tested in the following way:
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.
Prior to measurement microsomes were treated with Triton X-100 (0.04%) ("disrupted microsomes"). G-6-Pase activity were assayed for 6 min at 30°C in a total volume of 325 μL con- taining 0.5 mM glucose-6-phosphate, 30 mM MES (pH 6.5), test compound and disrupted microsomes (0.05 mg). The reaction was terminated by addition of 100 μL Sigma phosphorus reagent (cat no 360-3C). This mixture was allowed to stand for 2 min, where the absor- bance (A) was measured at 340 nm. All values were corrected for blank. The inhibitory effect was expressed as percent of control value, i.e. IC50 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 IC50 value of less than 100 μM, more preferably less than 10 μM, even more preferably less than 1 μM, 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.
Optionally, 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.
Pharmaceutical 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. 19th Ed.. 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt or metal salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, 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. 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. Some examples of 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. Similarly, 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.
For administration, preferably nasal administration, 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. 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. For parenteral application, particularly suitable are 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:
Core: Active compound (as free compound or salt thereof) 5.0 mg
Colloidal silicon dioxide (Aerosil) 1.5 mg
Cellulose, microcryst. (Avicel) 70 mg
Modified cellulose gum (Ac-Di-Sol) 7.5 mg
Magnesium stearate Ad.
Coating:
HPMC approx. 9 mg
*Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
Due to their high degree of activity, 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. Such mammals include both domestic animals, e.g. household pets, and non-domestic animals such as wildlife. Preferably the mammal is a human. EXAMPLES
The process for preparing compounds of formula I, la, lb, and/or Ic and preparations containing them is further illustrated in the following examples which, however, are not to be construed as limiting.
EXAMPLE 1 Preparation of
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 5)
Figure imgf000030_0001
4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.35 mmol) was dissolved in dichloromethane (0.5 mL) and triethylamine (0.5 mL) was added. To this solution p-anisoyl chloride (60 mg, 0.35 mmol) dissolved in dichloromethane (0.5 ml) was added in one portion. The mixture was filtered and evaporated to afford 148 mg (100%) of the title compound.
MS (electrospray): m/z 418 (M+1 )
HR-MS: Calculated for C22H18F3NO2S: 417.1010, Found: 417.0999.
EXAMPLE 2:
Preparation of
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(3-methoxyphenyl)- methanone, (compound No. 8)
Figure imgf000031_0001
4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.35 mmol) was dissolved in dichloromethane (1 mL) and diisopropylethylamine (0.5 mL) was added. To this solution m-anisoyl chloride (50 μL, 0.35 mmol) was added. The mixture was shaken overnight and evaporated to afford the title compound.
MS (electrospray): m/z 418 (M+1 )
HR-MS: Calculated for C22H18F3NO2S: 417.1010, Found: 417.1020.
EXAMPLE 3: Preparation of
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-phenyl-methanone, (compound No 11)
Figure imgf000031_0002
Benzoic acid (46 mg, 0.38 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 mmol) were dissolved in a mixture of dichloromethane (1 mL) and N,N-dimethylformamide (0.5 mL). N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol) was added and the mixture was shaken 0.5 hour at room temperature. 4-(4-ChIorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.38 mmol) dissolved in dichloromethane (0.5 ml) was added and the mixture was shaken at 1000 rpm for 3 hours. Water (1 mL) was added and the mixture was shaken at 1000 rpm overnight at room temperature. The organic phase was evaporated to give 129 mg (97%) of the title compound as an oil.
MS (electrospray): m/z 354 (M+1)
HR-MS: Calculated for C20H16CINOS: 353.0641 , Found: 353.0646.
EXAMPLE 4: Preparation of
(4-(2-Dimethylaminoethoxy)phenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No 14)
Figure imgf000032_0001
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 reaction mixture was poured into water (600 mL) and extraction with ethyl acetate (2 x 200 mL), washing of the combined organic phases with water (200 mL), drying over MgS04 and evaporation afforded 11.9 g (81%) of methyl 4-(2-dimethylaminoethoxy)benzoate as an oil.
The above benzoate (11.9 g, 53 mmoles) was dissolved in 5 N hydrochloric acid and the mixture was heated at reflux temperature for 2 days. Cooling, filtration and washing with water afforded 8.63 g (66%) of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride as crystals. The above benzoic acid (93 mg, 0.38 mmoles) was suspended in N,N-dimethylformamide (1 mL). 1-Hydroxybenzotriazole (55 mg, 0.42 mmoles), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (79 mg, 0.42 mmoles), and triethylamine (106 μL, 0.76 mmoles) were added and the resulting mixture was shaken at 1000 rpm for 1.5 hour. 4-(4- Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (108 mg, 0.38 mmoles) were added and the resulting mixture was shaken at 1000 rpm for 3 hours. Water (2 mL) and ethyl acetate (1 mL) were added and the resulting mixture was shaken at 1000 rpm for 15 minutes. The organic phase was evaporated to afford 144 mg (80%) of the title compound as an oil.
MS (eiectrospray): m/z 475.0 (M+1 )
HR-MS: Calculated for C25H25F3N2O2S: 474.1588, Found: 474.1580.
EXAMPLE 5:
Preparation of
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morphoiin-4- ylethoxy)phenyl]-methanone, (compound No 17)
Figure imgf000033_0001
Methyl 4-hydroxybenzoate (10 g, 66 mmoles) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (45 g, 0.33 moles) and 4-(2-chloroethyl)morpholine hydrochloride (18.3 g, 99 mmoles) were added and the resulting mixture was stirred vigorously at room temperature for 5 days. The reaction mixture was poured into water (500 mL) and extraction with ethyl acetate (2 x 250 mL), washing of the combined organic phases with water (200 mL), drying over MgSO4 and evaporation afforded 16.8 g (96%) of methyl 4-(2-morpholin-4- ylethoxy)benzoate as an oil. The above benzoate (16.8 g, 63 mmoles) was dissolved in 5 N hydrochloric acid and the mixture was heated at reflux temperature for 16 hours. Cooling, filtration and washing with water afforded 15.6 g (86%) of 4-(2-morpholin-4-ylethoxy)benzoic acid hydrochloride as crystals.
The above benzoic acid (111 mg, 0.38 mmoles) was suspended in N,N-dimethylformamide (1 mL). 1-Hydroxybenzotriazole (55 mg, 0.42 mmoles), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (79 mg, 0.42 mmoles), and triethylamine (106 μL, 0.76 mmoles) were added and the resulting mixture was shaken at 1000 rpm for 1.5 hour. 4-(4- Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.38 mmoles) was added and the resulting mixture was shaken at 1000 rpm for 3 hours. Water (2 mL) and ethyl acetate (1 mL) were added and the resulting mixture was shaken at 1000 rpm for 15 minutes. The organic phase was evaporated to afford 122 mg (66%) of the title compound as an oil.
MS (electrospray): m/z 483.0 (M+1 )
HR-MS: Calculated for C26H27CIN2O3S: 482.1431 , Found: 482.1430.
EXAMPLE 6:
Preparation of
(+)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No 1)
Figure imgf000034_0001
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone (30 mg) was dissolved in a 1 :1 mixture of n-heptane and 2-propanol (5 mL) and fractionated by HPLC (2 runs) using a 21.1 x 250 mm (R.R)-Whelk-O column (Regis). The column was eluted isocratically with a 1 :1 mixture of n-heptane and 2-propanol at a flow rate of 12 mlJmin and fractions collected corresponding to 0.8 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 TR 44-50 min and one corre- sponding to TR 62-72 min. Fractions from the two runs corresponding to TR 44-50 min were separately pooled and evaporated to yield 12.1 mg of the title compound.
100% ee (Determined by HPLC using a 4.6 x 250 mm (f?,R)-Whelk-O column eluted with a 1 :1 mixture of n-heptane and 2-propanol, the flow rate was 1 ml/min, eluting sample was monitored spectroscopically at 225 and 245 nm, TR 15.5 min).
EXAMPLE 7:
Preparation of (-)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No 2)
Figure imgf000035_0001
Fractions from the two runs of example 6 corresponding to TR 62-72 min were separately pooled and evaporated to yield 12.5 mg of the title compound
98% ee (Conditions as described in example 6, TR 20.8 min).
Optical rotation, using a Perkin Elmer Polarimeter (Model 241 ): [α]20 D= - 170.0 (c=0.25, ethyl acetate).
EXAMPLE 8: Preparation of
(+)-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- trifluoromethylphenyl)-methanone, (compound No 3)
Figure imgf000036_0001
[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-trifluoromethylphenyl)- methanone (17 mg) was dissolved in a 1 :2:2 mixture of ethyl acetate, n-heptane and 2- propanol (2.5 mL) and fractionated by HPLC using a 21.1 x 250 mm (R.R)-Whelk-O column (Regis). 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 TR 27-32 min and one corresponding to TR 62-74 min. Fractions corresponding to TR 27-32 min were pooled and evaporated to yield 7.1 mg of the title compound.
100% ee (Determined by HPLC using a 4.6 x 250 mm ( R)-Whelk-O column eluted with a 1 :1 mixture of n-heptane and 2-propanol, the flow rate was 1 mL/min, eluting sample was monitored spectroscopically at 225 and 245 nm, TR9.2 min)
Optical rotation, using a Perkin Elmer Polarimeter (Model 241), [α]20 D= + 175.4 (c=0.142, ethyl acetate).
EXAMPLE 9:
Preparation of
(-)-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- trifluoromethylphenyl)-methanone, (compound No 4)
Figure imgf000037_0001
Fractions from the two runs of example 8 corresponding to TR 62-74 min were separately pooled and evaporated to yield 6.8 mg of the title compound.
>99.5% ee (Conditions as described in example 8, TR 17.0 min).
[α]20 D= - 170.6 (c=0.136, ethyl acetate).
EXAMPLE 10:
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- dimethylaminophenyl)-methanone, (compound No 20)
Figure imgf000037_0002
4-Dimethylaminobenzoic acid (0.20 g, 1.2 mmol) was dissolved in N,N-dimethylformamide (3 ml) and 1-hydroxybenzotriazole (0.20 g, 1.5 mmol) was added. To the resulting mixture N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.28 g, 1.5 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 4-(4-Trifluoromethylphenyl)- 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.41 g, 1.5 mmol) followed by diisopropylethylamine (0.42 ml, 2.4 mmol) were added and the mixture was stirred at room temperature for 16 hours, water (2 ml) was added and the mixture was extracted with ethyl acetate (2 x 5 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (4 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound.
MS (electrospray): m/z 431 (M+1 ) HPLC (Method B): Rt = 29 min.
EXAMPLE 11 :
3-{4-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]phenyl}acrylic acid, (compound No 21 )
Figure imgf000038_0001
(E)-4-(2-tert-Butoxycarbonylvinyl)benzoic acid (0.36 g, 1.4 mmol) was dissolved in N,N- dimethylformamide (50 ml) and 1-hydroxybenzoetriazole (0.20 g, 1.4 mmol) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.28 g, 1.4 mmol) were added and the mixture was stirred at room temperature for 20 minutes. 4-(4-Chlorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine (0.30 g, 1.2 mmol) and N-ethyl-N,N-diisopropylamine (420 μl, 2.4 mmol) were added to the mixture and stirring at room temperature was continued for 16 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with saturated sodium chloride (80 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by coloumn chromatography over silica gel (60 ml) eluting with a mixture of ethyl acetate and heptane (1 :2). This afforded 0.56 g (97%) of 3-{4-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]- pyridine-5-carbonyl]phenyl}acrylic acid tert butyl ester as an oil.
1H-NMR (300 MHz, DMSO-d6): δ = 1.50 (9H, s), 2.8-3.1 (2H, m), 3.25 (1 H, m), 3.65 (1 H, m), 6.58 11 H, d), 6.78 (1 H, bs), 6.87 (1 H, d), 7.3-7.45 (7H, m), 7.60 (1 H, d), 7.77 (2H, d). The above tert-butyl ester (0.30 g, 0.62 mmol) was dissolved in dichloromethane (3 ml) and the mixture was cooled to 0 °C. At 0 °C trifluoroacetic acid (3 ml) was added and the mixture was stirred at 0 °C for 30 minutes. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml), concentrated in vacuo dissolved again in methanol (5 ml) and concentrated in vacuo. 10.6 mg of the residue was dissolved in 750 μl methanol and purified by preparative HPLC using a Gilson binary gradient HPLC system equipped with 305 / 306 master/slave pumps, 117 UV detector and fraction collector. The eluting sample was detected at 210 and 225 nm. Flow rate was 15 ml/minute. The column was 20*250 mm ODS 10 μm (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 TR 12 - 14 minutes were pooled to yield 8.3 mg of the title compound.
MS: m/z 424 (M+1 ).
EXAMPLE 12:
(4-Chlorophenyl)-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-methanone, (compound No 22), less polar enantiomer
Figure imgf000039_0001
(4-Chlorophenyl)-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-methanone (4.1 mg) was dissolved in a 1 :2:4 mixture of ethyl acetate, heptane and 2-propanol (3.5 ml) and fractionated by HPLC using a 21.1 x 250 mm (R.R)-Whelk-O column (Regis). The column was eluted isocratically with a 1 :1 mixture of heptane and 2-propanol at a flow rate of 10 ml/min 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 TR 28-32 mininutes and one correspond- ing to TR 51-58 minutes. Fractions corresponding TR 28-32 minutes were pooled and evaporated to yield 1.8 mg of the title compound.
100% ee (Determined by HPLC using a 4.6 x 250 mm (R,R)-Whelk-O column eluted with n- heptane:2-propanol (1 :1), the flow rate was 1 ml/min, eluting sample was monitored spectroscopically at 225 nm, TR9.9 min)
EXAMPLE 13:
(4-Chlorophenyl)-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-methanone, (compound No 23), more polar enantiomer
Figure imgf000040_0001
Fractions from example 12 corresponding to TR 51-58 minutes were pooled and evaporated to yield 2.6 mg of the title compound.
99.5% ee (Conditions as described in example 12, TR 15.5 min).
EXAMPLE 14:
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 24), less polar enantiomer
Figure imgf000041_0001
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone (11.2 mg) was dissolved in a 1 :1 mixture of heptane and 2-propanol (2 ml) and fractionated by HPLC using a 21.1 x 250 mm (R.R)-Whelk-O column (Regis). The column was eluted isocratically with a 1 :1 mixture of heptane and 2-propanol at a flow rate of 10 ml/min and fractions collected 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 TR 40-43 minutes and one corresponding to TR 55-59 minutes. Fractions corresponding to TR 40-43 minutes were pooled and evaporated to yield 4.0 mg of the title compound.
>99% ee (Determined by HPLC using a 4.6 x 250 mm (R,R)-Whelk-O column eluted with a 1 :1 mixture of heptane and 2-propanol, the flow rate was 1 ml/min, eluting sample was monitored spectroscopically at 225 and 245 nm, TR 12.6 min).
EXAMPLE 15:
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 25), more polar enantiomer
Figure imgf000041_0002
Fractions from example 14 corresponding to TR 55-59 minutes were pooled and evaporated to yield 4.0 mg of the title compound.
99% ee (Conditions as described in example 14, TR 16.4 min).
EXAMPLE 16:
[4-(2-Dimethylaminoethoxy)-phenyl]-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 26), less polar enantiomer
Figure imgf000042_0001
[4-(2-Dimethylaminoethoxy)-phenyl]-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone (ca. 20 mg) was dissolved in a 1 :1 mixture of heptane and 2-propanol (1 ml) and fractionated by HPLC using a 20 x 250 mm Chiralcel OD column. The column was eluted isocratically with a 7:3:0.01 mixture of heptane, 2-propanol and di- ethylamine at a flow rate of 6 ml/min 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 TR 20-25 minutes and one corresponding to TR 27-33 minutes. Fractions corresponding to TR 20-25 minutes were pooled and evaporated to yield 8.4 mg of the title compound.
>99.9% ee (Determined by HPLC using a 4.6 x 250 mm Chiralcel OD column eluted with a 70:30:0.07 mixture of heptane, 2-propanol and diethylamine, the flow rate was 0.4 ml/min, eluting sample was monitored spectroscopically at 225 and 245 nm, TR 15.4 min).
EXAMPLE 17: [4-(2-Dimethylaminoethoxy)-phenyl]-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 27), more polar enantiomer
Figure imgf000043_0001
Fractions from example 16 corresponding to TR 27-33 minutes were pooled and evaporated to yield 8.9 mg of the title compound.
>99% ee (Conditions as described in example 16, TR 20.1 min).
EXAMPLE 18:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 28), less polar enantiomer
Figure imgf000043_0002
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morpholin-4- ylethoxy)phenyl]-methanone (ca. 10 mg) was dissolved in 3 ml a 15:15:1 :0.2 mixture of heptane, 2-propanol, ethyl acetate and diethylamine (3 ml) and fractionated by HPLC using a 20 x 250 mm Chiralcel OD column. 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 TR 40-47 minutes and one corresponding to TR 50-59 minutes. Fractions corresponding to TR 40-47 minutes were pooled and evaporated to yield 4.1 mg of the title compound.
>99.9% ee (Determined by HPLC using a 4.6 x 250 mm Chiralcel OD column eluted with a 70:30:0.07 mixture of heptane, 2-propanol and diethylamine, the flow rate was 0.4 ml/min, eluting sample was monitored spectroscopically at 225 nm, TR22.9 min).
EXAMPLE 19:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 29), more polar enantiomer
Figure imgf000044_0001
Fractions from example 18 corresponding to TR 50-59 minutes were pooled and evaporated to yield 4.0 mg of the title compound.
98% ee (Conditions as described in example 18, TR 28.5 min).
EXAMPLE 20:
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 30), less polar enantiomer
Figure imgf000045_0001
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxy- phenyl)-methanone (10 mg) was dissolved in 2-propanol (0.5 ml) and fractionated by HPLC using a 21.1 x 250 mm (R.R)-Whelk-O column (Regis). The column was eluted isocratically with a 1 :1 mixture of heptane and 2-propanol at a flow rate of 10 ml/min and fractions collected 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 TR 24-30 minutes and one corresponding to TR 41-47 minutes. Fractions corresponding to TR 24-30 minutes were pooled and evaporated to yield 2.5 mg of the title compound.
>99.8% ee (Determined by HPLC using a 4.6 x 250 mm (R,R)-Whelk-O column eluted with a 1 :1 mixture of n-heptane and 2-propanol, the flow rate was 1 ml/minute, eluting sample was monitored spectroscopically at 225 and 254 nm, TR 12.0 min)
EXAMPLE 21 :
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyi)-methanone, (compound No. 31 ), more polar enantiomer
Figure imgf000045_0002
Fractions from example 20 corresponding to TR 41-47 minutes were pooled and evaporated to yield 2.3 mg of the title compound.
99.1% ee (Conditions as described in example 20, TR 15.8 min).
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.
A general procedure for parallel preparation of compounds of the invention is given in example 22:
EXAMPLE 22:
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 32)
Figure imgf000046_0001
A solution of 4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N,N- dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) was added to a solution of 4- methoxybenzoic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol). To this solution 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) was added. The mixture was shaken overnight at room temperature at 1000 rpm, added saturated NaCI (2 ml), and extracted with ethyl acetate (2 x 1 ml). The combined organic extracts were evaporated to afford the title compound.
MS (electrospray): m/z 434 (M+1 ) HPLC (Method B): Rt = 33.2 min.
EXAMPLE 23:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(1 H-indol-5-yl)-methanone, (compound No. 33)
Figure imgf000047_0001
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of indole-5-carboxylic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 393 (M+1 )
HPLC (Method B): Rt = 30.7 min.
EXAMPLE 24:
(1H-lndol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone, (compound No. 34)
Figure imgf000048_0001
Similarly as described in example 22 using a solution of 4-(4-Trifluoromethoxyphenyl)- 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of indole-5-carboxylic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 443 (M+1 ) HPLC (Method B): Rt = 31.5 min.
EXAMPLE 25:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-fluorophenyl)-methanone, (compound No. 35)
Figure imgf000048_0002
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-fluorobenzoic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z 372 (M+1 )
HPLC (Method B): Rt = 32.6 min.
EXAMPLE 26:
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-fluorophenyl)- methanone, (compound No. 36)
Figure imgf000049_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-fluorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 422 (M+1 ) HPLC (Method B): Rt = 32.2 min.
EXAMPLE 27:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2- dimethylaminoethoxy)phenyl]-methanone, (compound No. 37)
Figure imgf000050_0001
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N- dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 μl), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 441 (M+1 )
HPLC (Method B): R, = 23.4 min.
EXAMPLE 28:
[4-(2-Dimethylaminoethoxy)phenyl]-[4-(4-trifiuoromethoxyphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 38)
Figure imgf000050_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethyl- formamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 μl), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 491 (M+1 ) HPLC (Method B): R, = 24.9 min.
EXAMPLE 29:
[7-Chloro-1-(2,3-dihydrobenzofuran-7-yl)-8-methoxy-1 ,2,4,5-tetrahydrobenzo[d]azepin-3-yl]- [4-(2-dimethylaminoethoxy)-phenyl]-methanone, (compound No. 39)
Figure imgf000051_0001
Similarly as described in example 22 using a solution of 7-chloro-1-(2,3-dihydrobenzofuran- 7-yl)-8-methoxy-1 ,2,4,5-tetrahydrobenzo[d]azepine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 μl), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in di- chloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 521 (M+1 )
HPLC (Method B): Rt = 22.9 min.
EXAMPLE 30:
[4-(3,4-Dimethoxyphenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-6-yl]-[4-(2- dimethylaminoethoxy)-phenyl]-methanone, (compound No. 40)
Figure imgf000052_0001
Similarly as described in example 22 using a solution of 4-(3,4-Dimethoxyphenyl)-4,5,6,7- tetrahydro-thieno[2,3-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N- dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 μl), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 467 (M+1 )
HPLC (Method B): Rt = 18.1 min.
EXAMPLE 31:
(3,4-Dimethoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl]methanone, (compound No. 41)
Figure imgf000052_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3,4-dimethoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 464 (M+1 ) HPLC (Method B): Rt = 32.1 min
EXAMPLE 32:
(3-Chloro-4-methoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, (compound No. 42)
Figure imgf000053_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-chloro-4-methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 468 (M+1 )
HPLC (Method B): R, = 34.4 min
EXAMPLE 33:
(4-Ethoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]methanone, (compound No. 43)
Figure imgf000054_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-ethoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 448 (M+1)
HPLC (Method B): Rt = 35.1 min
EXAMPLE 34:
(4-Methylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yijmethanone, (compound No. 44)
Figure imgf000054_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlo- ride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z 418 (M+1 )
HPLC (Method B): R, = 35.2 min
EXAMPLE 35:
3-(4-Methoxyphenyl)-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl]propenone, (compound No. 45)
Figure imgf000055_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxy-phenyl)- 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxycinnamic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 460 (M+1 ) HPLC (Method B): Rt = 35.0 min
EXAMPLE 36:
(1H-Benzimidazol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl]methanone, (compound No. 46)
Figure imgf000056_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of benzimidazole-5-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z 444 (M+1 )
HPLC (Method B): Rt = 23.1 min
EXAMPLE 37:
(4-Methoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone
Figure imgf000056_0002
4-Methoxybenzoic acid (0.64 g, 4.2 mmol) was dissolved in N.N-dimethylformamide (25 ml) and 1-hydroxybenzotriazole (0.71 g, 5 mmol) was added followed by N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol). The resulting mixture was stirred at room temperature for 30 minutes. 4-(4-Trifluoromethoxyphenyl)- 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.5 g, 5 mmol) followed by N,N- diisopropylethylamine (1.4 ml, 8.4 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (10 ml) was added and the mixture was extracted with diethyl ether (3 x 20 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluting with a mixture of ethyl acetate and heptane (1 :2). The pure fractions were pooled and concentrated in vacuo. The residue was crystallised from a mixture of methyl tert-butyl ether and heptane to afford 2.13 g (98%) of the title compound.
M.p. 68 - 70 °C.
Calculated for C22H18F3NO3S.0.25H2O: C, 60.34%; H, 4.26%; N, 3.20%. Found: C, 60.35%; H, 4.38%; N, 3.07%; C, 60.34%; H, 4.33%; N, 3.09%.
EXAMPLE 38:
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone
Figure imgf000057_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxy-3-nitrobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/e: 479 (M+1 )
HPLC (method B): R, = 32.5 min.
EXAMPLE 39:
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methylsulfanylphenyl)-methanone
Figure imgf000058_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methylsulfanylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 434 (M+1) HPLC (method B): R, = 33.5 min.
EXAMPLE 40:
4-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]benzoic acid methyl ester
Figure imgf000059_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of mono methyl terephthalic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 446 (M+1 )
HPLC (method B): Rt = 31.9 min.
EXAMPLE 41 :
(4-Hydroxymethylphenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl] methanone
Figure imgf000059_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-hydroxymethylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hy- drochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z: 418 (M+1 )
HPLC (method B): Rt = 27.2 min.
EXAMPLE 42:
(4-Acetoxyphenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000060_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-acetoxybenzoic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 446 (M+1 ) HPLC (method B): Rt = 30.7 min.
EXAMPLE 43:
(4-Cyanophenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000061_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-cyanobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 413 (M+1 )
HPLC (method B): Rt = 30.6 min.
EXAMPLE 44:
1 -{4-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5- carbonyl]phenyl}ethanone
Figure imgf000061_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-acetylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z: 430 (M+1 )
HPLC (method B): R, = 30.5 min.
EXAMPLE 45:
3-Furan-2-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000062_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethyiphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-(furan-2-yl)acryiic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 404 (M+1) HPLC (method B): Rt = 32.2 min.
EXAMPLE 46:
3-(5-Methylfuran-2-yl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000063_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-(5-methylfuran-2-yl)acrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 418 (M+1)
HPLC (method B): Rt = 33.7 min.
EXAMPLE 47:
Benzo[b]thiophen-2-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl] methanone
Figure imgf000063_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of benzo[b]thiophen-2-yl-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z: 444 (M+1)
HPLC (method B): Rt = 35.1 min.
EXAMPLE 48:
3-Furan-3-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000064_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-furan-3-ylacrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 404 (M+1) HPLC (method B): R, = 31.4 min.
EXAMPLE 49:
3-Thiophen-3-yl-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000065_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-thiophen-3-ylacrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 420 (M+1)
HPLC (method B): Rt = 32.8 min.
EXAMPLE 50:
3-Thiophen-2-yl-1 -[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000065_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-thiophen-3-ylacrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hy- drochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z: 420 (M+1 )
HPLC (method B): Rt = 33.3 min.
EXAMPLE 51:
[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methylsulfanylphenyl)methanone
Figure imgf000066_0001
Similarly as described in example 22 using a solution of 4-(4-methoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methylsulfanylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 396 (M+1) HPLC (method B): R, = 29.5 min.
EXAMPLE 52:
4-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]benzonitrile
Figure imgf000067_0001
Similarly as described in example 22 using a solution of 4-(4-methoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-cyanobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 375 (M+1)
HPLC (method B): Rt = 26.2 min.
EXAMPLE 53:
3-Furan-3-yl-1 -[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]propenone
Figure imgf000067_0002
Similarly as described in example 22 using a solution of 4-(4-methoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-(furan-3-yl)acryiic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z: 366 (M+1 )
HPLC (method B): R, = 26.9 min.
EXAMPLE 54:
(4-Methoxyphenyl)-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000068_0001
Similarly as described in example 22 using a solution of 4-(4-methoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 380 (M+1)
HPLC (method B): R, = 27.6 min.
EXAMPLE 55:
(4-Fluorophenyl)-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000068_0002
Similarly as described in example 22 using a solution of 4-(4-methoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-fluorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 368 (M+1) HPLC (method B): R, = 27.7 min.
EXAMPLE 56:
(4-Chlorophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000069_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 438 (M+1)
HPLC (method B): Rt = 32.8 min.
EXAMPLE 57: (4-Methylsulfanylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
Figure imgf000070_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methylsulfanylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 450 (M+1 ) HPLC (method B): R, = 32.6 min.
EXAMPLE 58:
(4-Dimethylaminophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
Figure imgf000070_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-dimethylaminobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hy- drochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 447 (M+1)
HPLC (method B): R, = 27.1 min.
EXAMPLE 59:
(4-Hydroxymethylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
Figure imgf000071_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-hydroxymethylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 434 (M+1 ) HPLC (method B): Rt = 26.6 min.
EXAMPLE 60: 3-Furan-3-yl-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000072_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-(3-furan-3-yl)acrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 420 (M+1)
HPLC (method B): Rt = 30.4 min.
EXAMPLE 61 :
4-(4-Chlorophenyl)-5-(4-methoxybenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride
Figure imgf000072_0002
4-(4-Chlorophenyl)- 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.10 g, 0.38 mmol) was dis- solved in N.N-dimethylformamide (0.5 ml) and triethylamine (110 μl, 0.76 mmol) and 4- methoxybenzyl chloride (51 μl, 0.38 mmol) were added and the resulting mixture was shaken at 1000 rpm for 3 days. Water (2 ml) was added and the mixture was extracted with ethyl acetate (2 x 1 ml). The combined organic extracts were concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of ethyl acetate and heptane (1 :4) to afford the free base. This was dissolved in diethyl ether and 1N HCI in diethyl ether was added drop wise to complete precipitation to afford 52 mg (34%) of the title compound.
HPLC-MS: R, = 9.57 min. m/z = 370 (M+1 ).
EXAMPLE 62:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- hydroxyphenyl)methanone
Figure imgf000073_0001
4-Hydroxybenzoic acid (1.3 g, 9.6 mmol) was dissolved in N.N-dimethylformamide (25 ml) and 1-hydroxybenzotriazole (1.3 g, 9.6 mmol) was added followed by N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.8 g, 9.6 mmol), 4-(4- chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (2.0 g, 8 mmol) and N,N- diisopropylethylamine (2.5 ml, 16 mmol). The resulting mixture was stirred at room temperature for 16 hours. Water (200 ml) was added and the mixture was extracted with diethyl ether (3 x 100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (150 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluting with a mixture of ethyl acetate and heptane (1 :1). The pure fractions were pooled and concentrated in vacuo to afford 3.14 g (100%) of the title compound. M.p. 202 - 207 °C.
Calculated for C20H16CINO2S: C, 64.95%; H, 4.36%; N, 3.79%. Found: C, 64.54%; H, 4.74%; N, 4.29%; C, 64.63%; H, 4.76%; N, 4.28%.
HPLC-MS: Rt = 14.18 min. m/z: 370 (M+1 )
EXAMPLE 63:
1-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-2-(4- methoxyphenyl)ethanone
Figure imgf000074_0001
Similarly as described in example 22 using a solution of 4-(4-chlorophenyi)-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxyphenylacetic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 398 (M+1) HPLC (method B): R, = 32.2 min.
EXAMPLE 64:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(3- dimethylaminophenyl)methanone
Figure imgf000075_0001
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-dimethylaminobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 397 (M+1)
HPLC (method B): Rt = 25.9 min.
EXAMPLE 65:
N-{4-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]- phenyl}acetamide
Figure imgf000075_0002
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-acetamidobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z: 411 (M+1 )
HPLC (method B): Rt = 27.2 min.
EXAMPLE 66:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methanesuIfonylphenyl)methanone
Figure imgf000076_0001
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methanesulfonylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 432 (M+1 ) HPLC (method B): R, = 28.1 min.
EXAMPLE 67:
2-(4-Chlorophenyl)-1-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljethanone
Figure imgf000077_0001
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorophenylacetic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 402 (M+1)
HPLC (method B): Rt = 34.5 min.
EXAMPLE 68:
2-(4-Methoxyphenyl)-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl]-ethanone
Figure imgf000077_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorophenylacetic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlo- ride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. MS (electrospray): m/z: 448 (M+1)
HPLC (method B): Rt = 32.9 min.
EXAMPLE 69:
(3-Dimethylaminophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]-methanone
Figure imgf000078_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-dimethylaminobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 447 (M+1 )
HPLC (method B): Rt = 27.2 min.
EXAMPLE 70:
N-{4-[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]- phenyl}-acetamide
Figure imgf000079_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-acetamidobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 461 (M+1 )
HPLC (method B): Rt = 28.2 min.
EXAMPLE 71 :
(4-Methanesulfonylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]-methanone
Figure imgf000079_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methanesulfonylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 482 (M+1) HPLC (method B): Rt = 29.1 min.
EXAMPLE 72:
2-(4-Chlorophenyl)-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]-ethanone
Figure imgf000080_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorophenyiacetic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 452 (M+1 )
HPLC (method B): Rt = 34.9 min.
EXAMPLE 73:
Biphenyl-4-yl-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000081_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-biphenylcarboxyiic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 480 (M+1 )
HPLC (method B): Rt = 36.7 min.
EXAMPLE 74:
(3,4-Dichlorophenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl] methanone
Figure imgf000081_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3,4-dichlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 472 (M+1 ) HPLC (method B): R, = 36.2 min.
EXAMPLE 75:
(4-tert-Butylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000082_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-tert-butylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 460 (M+1)
HPLC (method B): Rt = 37.0 min.
EXAMPLE 76:
Pyridin-4-yl-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000083_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of pyridine-4-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 405 (M+1 )
HPLC (method B): R, = 23.9 min.
EXAMPLE 77:
(5-Hydroxypyrazin-2-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl]methanone
Figure imgf000083_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 5-hydroxypyrazine-2-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 422 (M+1 ) HPLC (method B): R, = 26.0 min.
EXAMPLE 78:
(5-Chloro-6-hydroxypyridin-3-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
Figure imgf000084_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 2-hydroxy-3-chloropyridine-5-carboxyiic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 455 (M+1 )
HPLC (method B): Rt = 26.8 min.
EXAMPLE 79:
3-(4,5-Dimethylfuran-2-yl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]propenone
Figure imgf000085_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-(4,5-dimethylfuran-2-yl)acryiic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
MS (electrospray): m/z: 432 (M+1) HPLC (method B): R, = 35.2 min.
EXAMPLE 80:
(1-Benzyi-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-(4-methoxyphenyl)methanone
Figure imgf000085_0002
Similarly as described in example 22 using a solution of 1 -benzyl-1 ,2,3,4-tetrahydro- isoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. HPLC-MS: Rt = 15.0 min. m/z: 358 (M+1 )
EXAMPLE 81:
(1-Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-(4-chlorophenyl)methanone
Figure imgf000086_0001
Similarly as described in example 22 using a solution of 1 -benzyl-1 ,2,3,4-tetrahydro- isoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- chlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.1 min. m/z: 362 (M+1)
EXAMPLE 82:
(1 H-Benzoimidazol-5-yl)-(1 -benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)methanone
Figure imgf000086_0002
Similarly as described in example 22 using a solution of 1 -benzyl-1 , 2,3,4-tetrahydro- isoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of benzimi- dazole-5-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in di- chloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 9.55 min. m/z: 368 (M+1 )
EXAMPLE 83:
1-(1 -Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-3-furan-3-ylpropenone
Figure imgf000087_0001
Similarly as described in example 22 using a solution of 1 -benzyl-1 ,2,3,4-tetrahydro- isoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-(3- furan-3-yl)acrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 14.7 min. m/z: 344 (M+1)
EXAMPLE 84:
1 -(1 -Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-3-(4-methoxyphenyl)propenone
Figure imgf000088_0001
Similarly as described in example 22 using a solution of 1 -benzyl-1 ,2,3,4-tetrahydro- isoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxycinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.7 min. m/z: 384 (M+1 )
EXAMPLE 85:
1-(1 -Benzyl-1 ,2,3,4-tetrahydro-isoquinolin-2-yl)-3-(4-methoxyphenyl)propan-1 -one
Figure imgf000088_0002
Similarly as described in example 22 using a solution of 1 -benzyl-1 , 2,3,4-tetrahydro- isoquinoline in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxyhydrocinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.7 min. m/z: 386 (M+1 )
EXAMPLE 86: 1-(1 -Benzyl-1 , 2,3,4-tetrahydro-isoquinolin-2-yl)-2-(4-methoxyphenyl)ethanone
Figure imgf000089_0001
Similarly as described in example 22 using a solution of 1 -benzyl-1 ,2,3,4-tetrahydro- isoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxyphenylacetic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.2 min. m/z: 372 (M+1 )
Preparation of 4-(4-nitro-phenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine trifluoroacetate:
Figure imgf000089_0002
2-(2-Thienyl)-ethylamine (5 g, 39.4 mmol), 4-nitrobenzaldehyde and triethylamine (10 ml) were dissolved in ethanol (100 ml). The reaction mixture was stirred at room temperature for 48 hours. The solid formed was filtered and dried to afford 7.75 g (76%) (4- nitrobenzylidene)-(2-thiophen-2-yl-ethyl)-amine.
M.p.: 83.9-84.4 °C. The above (4-nitrobenzylidene)-(2-thiophen-2-yl-ethyl)-amine (1 g, 3.8 mmol) was added trifluoroacetic acid (100 ml) at once (strongly exothermic reaction). The reaction mixture was stirred at room temperature for 72 hours, then evaporated in vacuo. Crystallisation from a mixture of diethyl ether and dichloromethane afforded 1.2 g (85%) of the title compound.
M.p.: 128-129.5 °C.
Preparation of dimethyl-[4-(4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-4-yl)-phenyl]-amine:
Figure imgf000090_0001
2-(2-Thienyl)-ethylamine (5 g, 39.4 mmol), 4-dimethylaminobenzaldehyde (5.9 g, 94 mmol) triethylamine (6 ml) and ethanol (150ml) were mixed at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concen- trated to 75 ml by evaporation in vacuo and the solid formed was filtered and dried to afford 6.82 g (67%) dimethyl-{4-[(2-thiophen-2-yl-ethylimino)-methyl]-phenyl}-amine.
M.p.: 76.8-77 °C.
The above dimethyl-{4-[(2-thiophen-2-yl-ethylimino)-methyl]-phenyl}-amine (1 g, 3.9 mmol) was added TFA (20 mL) at once (strongly exothermic reaction). The reaction mixture was stirred at room temperature for 72 hours, then evaporated in vacuo. The crude oil was suspended in dichloromethane (75 ml) and extracted with 1 N hydrochloric acid (50 ml). The aqueous phase was added 2 N sodium hydroxide to pH=10, then extracted with di- chloromethane (3x125 ml). The organic phase was dried with MgSO4, filtered, evaporated in vacuo to afford 0.96 g (95%) of the title compound.
M.p.: 95-98 °C.
Preparation of 4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine:
Figure imgf000091_0001
2-(2-Thienyl)-ethylamine (2 g, 15.7 mmol) and benzaldehyde (1.67 g, 15.7 mmol) were dis- solved in toluene (50 ml) and the reaction mixture was heated at reflux until 20 ml of toluene and water was distilled of in a Dean Stark trap. The remaining mixture was evaporated in vacuo to give the crude imine (3.44 g). The crude imine was added trifluoroacetic acid (50 ml) at once (strongly exothermic reaction). The reaction mixture was stirred at room temperature for 72 hours, then evaporated in vacuo. The crude oil was dissolved in di- chloromethane (50 ml) and washed with 2 N sodium hydroxide (30 ml). The aqueous phase was extracted with dichloromethane (3x30ml). The combined organic phases were dried with MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (19:1 ). This afforded 0.823 g (24%) of the title compound.
M.p.: 79.8-80.7 °C
Preparation of 4-(pyridin-4-yl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine, NNC 60-0372.
Figure imgf000091_0002
2-(2-Thienyl)-ethylamine (2 g, 15.7 mmol) 4-pyridylaldehyde (1.68 g, 15.7 mmol), triethylamine (1 ml) and ethanol (15 ml) were mixed and the reaction mixture was stirred at room temperature for 15 hours, then evaporated in vacuo. The crude oil was added trifluoroacetic acid (75 m) at once (strongly exothermic reaction). The reaction mixture was stirred at room temperature for 0.5 hour, then evaporated in vacuo. The residue was dissolved in dichloromethane (150 ml) and washed with 2 N sodium hydroxide (100 ml). The aqueous phase was extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried with MgSO4, filtered and evaporated in vacuo to give an oil (3.21 g) which was crystallised from a mixture of dichloromethane and hexane to afford 2.4 g (71%) of the title compound.
M.p.: 81.8-83.8 °C.
Preparation of 1-(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydro-isoquinoline:
Figure imgf000092_0001
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 combined organic phases were dried (MgSO4), filtered and evaporated in vacuo giving 1.5 g crude product which was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (9:1). This afforded 0.67 g (45%) of N- phenethyl-4-trifluoromethoxybenzamide.
M.p.: 143.2-143.9 °C.
The above N-phenethyl-4-trifluoromethoxybenzamide (0.67 g, 2.2 mmol) was added to a mixture of phosphorous pentoxide (0.92 g, 6.5 mmol) and phosphorous oxychloride (1.03 g, 6.7 mmol) in xylene (50 mL). The reaction mixture was stirred at 140 °C for 16 hours. After cooling, water (50 mL) was added and the mixture was basified with 1 N NaOH. The aqueous phase was extracted with xylene (3 x 50 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo giving 0.96 g crude product which was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (9:1). This afforded 0.40 g (62%) of 1-(4-Trifluoromethoxy-phenyl)-3,4-dihydro-isoquinoline as an oil. The above 1-(4-trifluoromethoxyphenyl)-3,4-dihydro-isoquinoline (0.40 g, 1.4 mmol) was dissolved in methanol (20 mL) and sodium borohydride (0.08 g, 2.1 mmol) was added slowly. The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was evapo- rated in vacuo, redissolved in 1 N NaOH (20 mL) and extracted with dichloromethane (50 mL). The organic phase was dried (MgSO4), filtered and evaporated in vacuo. The remaining oil (0.35 g) was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (9:1). This afforded 0.56 g (56%) of the title compound.
M.p.: 56.6- 57.1 °C.
EXAMPLE 87:
(5-Chlorothiophen-2-yl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)methanone
Figure imgf000093_0001
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 5- chlorothiophene-2-carboxylic acid acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 9.27 min. m/z: 361 (M+1 )
EXAMPLE 88:
(5-Chlorothiophen-2-yl)-[4-(4-dimethylaminophenyl)4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl)-methanone
Figure imgf000094_0001
Similarly as described in example 22 using a solution of 4-dimethylaminophenyl)4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 5-chlorothiophene-2-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 10.70 min. m/z: 403 (M+1 )
EXAMPLE 89:
(5-Chlorothiophen-2-yl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl)methanone
Figure imgf000094_0002
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 5- chlorothiophene-2-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.18 min. m/z: 405 (M+1 )
EXAMPLE 90:
(4-Hydroxymethylphenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)methanone
Figure imgf000095_0001
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- hydroxymethylbenzoic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 12.33 min. m/z: 350 (M+1 )
EXAMPLE 91 :
[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-(4- hydroxymethylphenyl)-methanone
Figure imgf000096_0001
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-hydroxymethylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 8.07 min. m/z: 393 (M+1 )
EXAMPLE 92:
[4-(4-Nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-(4-hydroxymethylphenyl)- methanone
Figure imgf000096_0002
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- hydroxymethylbenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. HPLC-MS: Rt = 12.44 min. m/z: 395 (M+1 )
EXAMPLE 93:
(4-Chlorophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)methanone
Figure imgf000097_0001
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- chlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in di- chloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.90 min. m/z: 355 (M+1 )
EXAMPLE 94:
(4-Chlorophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000097_0002
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- chlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 9.18 min. m/z: 355 (M+1)
EXAMPLE 95:
(4-Chlorophenyl)-[4-(4-dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)- methanone
Figure imgf000098_0001
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 10.43 min. m/z: 397 (M+1 )
EXAMPLE 96:
(4-Chlorophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000099_0001
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- chlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 15.81 min. m/z: 399 (M+1 )
EXAMPLE 97:
(4-Methoxyphenyl)-[4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000099_0002
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 14.83 min. m/z: 350 (M+1 ) EXAMPLE 98:
(4-Methoxyphenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000100_0001
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 8.50 min. m/z: 351 (M+1 )
EXAMPLE 99:
[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone
Figure imgf000100_0002
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 9.55 min. m/z: 393 (M+1 )
EXAMPLE 100:
[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone
Figure imgf000101_0001
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 14.80 min. m/z: 395 (M+1)
EXAMPLE 101 :
3-(4-Methoxyphenyl)-1-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-propenone
Figure imgf000102_0001
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxycinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.45 min. m/z: 376 (M+1 )
EXAMPLE 102:
(5-Chlorothiophen-2-yl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000102_0002
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 5- chlorothiophene-2-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 16.42 min. m/z: 360 (M+1 ) EXAMPLE 103:
3-(4-Methoxyphenyl)-1-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone
Figure imgf000103_0001
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxycinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 mi of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 9.42 min. m/z: 377 (M+1 )
EXAMPLE 104:
1-[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-3-(4- methoxyphenyi)-propenone
Figure imgf000103_0002
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxycinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 10.32 min. m/z: 418 (M+1 )
EXAMPLE 105:
3-(4-Methoxyphenyl)-1-(4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)- propenone
Figure imgf000104_0001
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- methoxycinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in di- chloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.47 min. m/z: 421 (M+1 )
EXAMPLE 106:
(4-Dimethylaminophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000105_0001
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- dimethylaminobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 11.83 min. m/z: 363 (M+1 )
EXAMPLE 107:
(4-Dimethylaminophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)- methanone
Figure imgf000105_0002
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- dimethylaminobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound. HPLC-MS: Rt = 7.5 min. m/z: 364 (M+1 )
EXAMPLE 108:
(4-Dimethylaminophenyl)-[4-(4-dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin- 5-yl]-methanone
Figure imgf000106_0001
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-dimethylaminobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 8.15 min. m/z: 406 (M+1 )
EXAMPLE 109:
(4-Dimethylaminophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone
Figure imgf000107_0001
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- dimethylaminobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 12.68 min. m/z: 408 (M+1)
EXAMPLE 110:
(1 H-Benzoimidazol-5-yl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000107_0002
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of benzimidazole-5-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 9.27 min. m/z: 360 (M+1 ) EXAMPLE 111 :
(1 H-Benzoimidazol-5-yl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000108_0001
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of benzimidazole-5-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 7.17 min. m/z: 403 (M+1 )
EXAMPLE 112:
(1 H-Benzoimidazol-5-yl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone
Figure imgf000108_0002
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of benzimidazole-5-carboxylic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 9.50 min. m/z: 405 (M+1 )
EXAMPLE 113:
(4-Fluorophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000109_0001
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- fluorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.07 min. m/z: 339 (M+1 )
EXAMPLE 114:
(4-Fluorophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000110_0001
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- fluorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 8.62 min. m/z: 339 (M+1 )
EXAMPLE 115:
[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-fluorophenyl)- methanone
Figure imgf000110_0002
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-fluorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 9.68 min. m/z: 381 (M+1 ) EXAMPLE 116:
(4-Fluorophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-methanone
Figure imgf000111_0001
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- fluorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 14.95 min. m/z: 383 (M+1)
EXAMPLE 117:
(4-Bromophenyl)-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000111_0002
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- bromobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.07 min. m/z: 398 + 400 (M+1 )
EXAMPLE 118:
(4-Bromophenyl)-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000112_0001
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- bromobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 9.30 min. m/z: 399 + 401 (M+1 )
EXAMPLE 119:
(4-Bromophenyl)-[4-(4-dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone
Figure imgf000113_0001
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-bromobenzoic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 10.72 min. m/z: 441 + 443 (M+1 )
EXAMPLE 120:
(4-Bromophenyl)-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-methanone
Figure imgf000113_0002
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4- bromobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 15.84 min. m/z: 442 + 444 (M+1 ) EXAMPLE 121 :
3-Furan-3-yl-1-(4-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone
Figure imgf000114_0001
Similarly as described in example 22 using a solution of 4-phenyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3- furan-3-ylacrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 14.77 min. m/z: 336 (M+1 )
EXAMPLE 122:
3-(3-Furan-3-yl)-1-(4-pyridin-4-yl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone
Figure imgf000114_0002
Similarly as described in example 22 using a solution of 4-pyridin-4-yl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3- furan-3-ylacrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 8.58 min. m/z: 337 (M+1 )
EXAMPLE 123:
1-[4-(4-Dimethylaminophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-3-(3-furan-3-yl)- propenone
Figure imgf000115_0001
Similarly as described in example 22 using a solution of 4-(4-dimethylaminophenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-furan-3-ylacrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 9.38 min. m/z: 379 (M+1 )
EXAMPLE 124:
3-(3-Furan-3-yl)-1-[4-(4-nitrophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl)-propenone
Figure imgf000116_0001
Similarly as described in example 22 using a solution of 4-(4-nitrophenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3- furan-3-ylacrylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 14.57 min. m/z: 381 (M+1 )
EXAMPLE 125:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-hydroxyphenyl)- methanone, less polar enantiomer,
Figure imgf000116_0002
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-hydroxyphenyl)- methanone (21 mg) was dissolved in a 1 :1 :1 mixture of ethyl acetate, 2-propanol and n- heptane (3 ml) and fractionated by HPLC using a 21.1 x 250 mm (R.R)-Whelk-O column (Regis). 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 TR 24-29 minutes and TR 42-50 minutes, respectively. Fractions corresponding to TR 24-29 minutes were pooled and evaporated to yield 8.8 mg of the title compound.
100% ee (Determined by HPLC using a 4.6 x 250 mm (R,R)-Whelk-O column eluted with n- heptane:2-propanol (1 :1), the flow rate was 1 ml/min, eluting sample was monitored spectroscopically at 225 and 280 nm, TR 8.9 min).
EXAMPLE 126:
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-hydroxyphenyl)- methanone, more polar enantiomer,
Figure imgf000117_0001
Fractions from example 125 corresponding to TR 42-50 minutes were pooled and evaporated to yield 9.1 mg of the title compound.
99.4 % ee (Conditions as described in example 125, TR 12.5 min).
EXAMPLE 127:
(1 H-Benzoimidazol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, less polar enantiomer,
Figure imgf000117_0002
(1 H-Benzoimidazol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5>6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone (15 mg) was dissolved in a 1 :1 mixture of n-heptane:2-propanol (2 ml) and fractionated by HPLC using a 20 x 250 mm Chiralpak AS column. The column was eluted isocratically with a mixture of n-heptane, ethanol and diethylamine (70:30:0.1 ) at a flow rate of 6 ml/min 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, corresponding to TR 16-19 minutes and TR 27-35 minutes, respectively. Fractions corresponding to TR 16-19 minutes were pooled and evaporated to yield 7.2 mg of the title compound.
100% ee (Determined by HPLC using a 4.6 x 250 mm Chiralpak AS column eluted with a mixture of n-heptane, ethanol and diethylamine (70:30:0.07), the flow rate was 0.6 ml/min, eluting sample was monitored spectroscopically at 225 and 245 nm, TR 8.4 min).
EXAMPLE 128:
(1 H-Benzoimidazol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, more polar enantiomer,
Figure imgf000118_0001
Fractions from example 127 corresponding to TR 27-35 minutes were pooled and evaporated to yield 8.0 mg of the title compound.
>99% ee (Conditions as described in example 127, TR 14.7 min). EXAMPLE 129:
(5-Chlorothiophen-2-yI)-[1-(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]- methanone
Figure imgf000119_0001
Similarly as described in example 22 using a solution of 1-(4-trifluoromethoxyphenyl)-1 ,2,3,4- tetrahydroisoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 5-chlorothiophene-2-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlo- ride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 17.75 min. m/z: 438 (M+1 )
EXAMPLE 130:
(4-Chlorophenyl)-[1-(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]-methanone
Figure imgf000119_0002
Similarly as described in example 22 using a solution of 1-(4-trifluoromethoxyphenyl)-1 ,2,3,4- tetrahydroisoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorobenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 17.42 min. m/z: 432 (M+1 )
EXAMPLE 131 :
(4-Methoxyphenyl)-[1-(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]- methanone
Figure imgf000120_0001
Similarly as described in example 22 using a solution of 1-(4-trifluoromethoxyphenyl)-1 , 2,3,4- tetrahydroisoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.42 min. m/z: 428 (M+1 )
EXAMPLE 132:
3-(4-Methoxyphenyl)-1 -[1 -(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2- yljpropenone
Figure imgf000121_0001
Similarly as described in example 22 using a solution of 1-(4-trifluoromethoxyphenyl)-1 , 2,3,4- tetrahydroisoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxycinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 17.02 min. m/z: 454 (M+1)
EXAMPLE 133:
3-Furan-3-yl-1 -[1 -(4-trifluoromethoxyphenyl)-1 ,2,3,4-tetrahydroisoquinolin-2-yl]propenone
Figure imgf000121_0002
Similarly as described in example 22 using a solution of 1-(4-trifluoromethoxyphenyl)-1 ,2,3,4- tetrahydroisoquinoline in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-furan-3-ylacrylic acid in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.12 min. m/z: 414 (M+1) EXAMPLE 134:
(4-Trifluoromethoxyphenyl)-[4-(4-trifIuoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
Figure imgf000122_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-trifluoromethoxybenzoic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 17.01 min. m/z: 472 (M+1)
EXAMPLE 135:
(7-Methoxybenzofuran-2-yl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone
Figure imgf000122_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 7-methoxybenzofuran-2-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.98 min. m/z: 458 (M+1 )
EXAMPLE 136:
Benzofuran-2-yl-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone
Figure imgf000123_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of benzofuran-2-carboxylic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N,-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 17.01 min. m/z: 428 (M+1)
EXAMPLE 137:
3-(4-Fluorophenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- propenone
Figure imgf000124_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-fluorocinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.58 min. m/z: 432 (M+1 )
EXAMPLE 138:
3-(4-Trifluoromethylphenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]propenone
Figure imgf000124_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-trifluoromethylcinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 17.38 min. m/z: 482 (M+1) EXAMPLE 139:
3-(3-Methoxyphenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000125_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 3-methoxycinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 16.54 min. m/z: 444 (M+1 )
EXAMPLE 140:
3-(4-Chlorophenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljpropenone
Figure imgf000125_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorocinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 17.41 min. m/z: 448 (M+1 )
EXAMPLE 141:
3-(4-Methoxyphenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]propan-1-one
Figure imgf000126_0001
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-methoxyhydrocinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: R, = 16.41 min. m/z: 446 (M+1 )
EXAMPLE 142:
3-(4-Chlorophenyl)-1-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]propan-1-one
Figure imgf000126_0002
Similarly as described in example 22 using a solution of 4-(4-trifluoromethylphenyl)-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a solution of 4-chlorohydrocinnamic acid in N.N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol) and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
HPLC-MS: Rt = 17.38 min. m/z: 450 (M+1 )
General:
The HPLC-MS analyses were performed on a PE Sciex API 100 LC/MS System using a WatersTM 3 mm x 150 mm 3.5 μ C-18 Symmetry column and positive ionspray with a flow rate at 20 μL/minute. The column was eluted with a linear gradient of 5-90% A, 85-0% B and 10% C in 15 minutes at a flow rate of 1 ml/min (solvent A = acetonitrile, solvent B = water and solvent C = 0.1% trifluoroacetic acid in water).
The given HPLC (method B) refers to the following system:
The used HPLC-system was comprised of a Merck Hitachi L-4000 UV Detector (detection at 254 nm), a Merck Hitachi L-6200A Intelligent Pump, a Merck Hitachi AS-2000A Autosam- pler, and a 4 mm * 250 mm 5 μ Licrosorp RP-18 column. The compounds were eluted using a gradient of 20% to 80% acetonitrile/0.1% trifluoroacetic acid/water during 30 minutes at 1 ml/minute, followed by a gradient of 80% to 100% acetonitrile/0.1% trifluoroacetic acid/water during 5 minutes at 1 ml/minute then with 100% acetonitrile/0.1% trifluoroacetic acid during 1 minute at 1 ml/minute and 4 minutes at 2 ml/minute.

Claims

1. A compound of the general formula I
Figure imgf000128_0001
wherein
A together with the double bond of formula I forms a cyclic system selected from the group consisting of benzene, thiophene, furan, pyridine, pyrimidine, pyrazine, pyridaz- ine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole or thiazole,
R1 is an optionally substituted C^-alkyl, or optionally substituted aryl, R2 is an optionally substituted C^-alkyl, optionally substituted aralkyl, or COR3, R3 is an optionally substituted C^-alkyl, optionally substituted aralkyl, or optionally sub- stitued aryl,
R4 and R5 independently are hydrogen, halogen, perhalomethyl, optionally substituted C1-6-alkyl, hydroxy, optionally substituted C1-6-alkoxy, nitro, cyano, amino, optionally substituted mono- or optionally substituted di-C1-6-alkylamino, acylamino, C1-6- alkoxycarbonyl, carboxy or carbamoyl,
n is 0, 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.
2. A compound according to claim 1 , wherein A is selected from benzene or thiophene.
3. A compound according to any one of claims 1 and 2, wherein R1 is optionally substituted phenyl.
4. A compound according to any one of the preceding claims, wherein each one of R\ R2, and R3 is substituted with one or more substituents.
5. A compound according to claim 3 or 4, wherein the substituents of R1 is halogen, perhalomethyl, perhalomethoxy, or C1-6-alkoxy.
6. A compound according to claim 3 or 4, wherein the substituents of R1 are selected from the group consisting of hydrogen, halogen, perhalomethyl, perhalomethoxy, or C^- alkoxy.
7. A compound according to claim 5 or 6, wherein the substituents of R1 are selected from from the group consisting of chloro, trifluoromethyl, methoxy, trifluoromethoxy.
8. A compound according to claim 3, wherein R1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, and 4-trifluoromethoxyphenyl.
9. A compound according to any one of claims 1 to 3, wherein R1 is 2,3-dihydrobenzofuran or 4-methoxyphenyl.
10. A compound according to any one of the preceding claims wherein R2 is COR3 or (CH2)q-aryl, and q is 0, 1 , 2, 3, 4, 5, or 6.
1 1. A compound according to claim 10, wherein R3 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.
12. A compound according to claim 10, wherein R3 is selected from the group consisting of 4-methylphenyl, 3,4-dimethoxyphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4- trifluoromethylphenyl, dimethylaminophenyl, 4-(2-carboxyethenyl)phenyl, 4-(2- dimethylaminoethoxy)phenyl, 4-(2-morpholin-4-ylethoxy)phenyl, 1H-indol-5-yl, 3-chloro- 4-methoxyphenyl, and 1 H-benzimidazol-5-yl.
13. A compound according to any one of the preceding claims, wherein R4 and R5 independently is hydrogen, chloro, or methoxy.
14. A compound according to any one of the preceding claims, wherein n is 0 or 1 and m is 0 or 1.
15. A compound according to any one of the preceding claims, wherein n is 0 and m is or 1.
16. A compound according to claim 1 and having the general formula la:
Figure imgf000130_0001
wherein R7 is hydrogen, halogen, preferably chloro, methoxy, perhalomethoxy, preferably trifluoromethoxy, perhalomethyl, preferably trifluoromethyl, diloweralkylamino, pref- erably dimethylamino, or nitro, and R6 and R8 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.
17. A compound according to claim 1 and having the general formula (la):
Figure imgf000130_0002
wherein R7 is halogen, perhalomethyl, or perhalomethoxy and R6 and R8 independently are hydrogen, methoxy, ethoxy, hydroxy, fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, dimethylamino, 2-carboxyethenyl, 2- dimethylaminoethoxy, or 2-morpholin-4-ylethoxy.
18. A compound according to claim 16, wherein R7 is selected from the group consisting of chloro, methoxy and trifluoromethyl.
19. A compound according to claim 16 or 17 wherein R7 is trifluoromethoxy.
20. A compound according to any one of claims 17, 18 and 19, wherein R6 and R8 independently are hydrogen, methoxy, chloro, trifluoromethyl, 2-dimethylaminoethoxy, or 2- morpholin-4-ylethoxy.
21. A compound according to claim 1 and having the general formula (lb):
Figure imgf000131_0001
wherein R7 is as described above, and
R6 is hydroxy, halogen, preferably chloro or fluoro, methyl, dimethylamino, methoxy, ethoxy, perhalomethyl, preferably trifluoromethyl, perhalomethoxy, preferably trifluoromethoxy, cyano, methylthio, acetyl, acetoxy, or hydroxy methyl.
22. A compound according to claim 1 and having the general formula (Ic):
Figure imgf000131_0002
wherein R7 is as defined above, and
R9 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.
23. A compound according to claim 1 and having the general formula (Ic):
Figure imgf000132_0001
wherein R7 is as defined above and R9 is indolyl, preferably 1 H-indol-5-yl or benzimidazol, preferably 1 H-benzimidazol-5-yl.
24. A compound according to claim 22 wherein R7 is as defined above and R9 is benzothio- phen-2-yl, indolyl, preferably 1H-indol-5-yl, or benzimidazol, preferably 1 H-benzimidazol- 5-yl.
25. A compound according to claim 1 and having the general formula (Id):
Figure imgf000132_0002
wherein R7 is as defined above, and R10 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-trifluoromethylphenyl)-ethenyl, 2-
(4-methoxyphenyl)-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, or 2-(3-thienyl)-ethenyl.
26. A compound according to claim 1 and having the general formula (Id):
Figure imgf000132_0003
wherein R7 is as defined above, and R10 is 4-methoxyphenyl-2-ethenyl.
27. A compound according to claim 25 wherein R7 is as defined above and R10 is optionally substituted aralkyl as defined above, preferably 2-(4-methoxyphenyl)-ethenyl, 2-(2- furyl)-ethenyl, 2-(5-methyl-2-furyl)-ethenyl, 2-(3-furyl)-ethenyl, or 2-(3-thienyl)-ethenyl.
28. A compound according to claim 1 and having the formula (le):
Figure imgf000133_0001
wherein R11 is pyridyl, preferably 4-pyridyl, and
R6 and R8 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, meth- ylsulfonyl, acetamido, nitro, acetyl, acetoxy, or hydroxymethyl.
29. A compound according to claim 1 and having the formula (If):
Figure imgf000133_0002
wherein R10 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-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)-ethenyi, and
R11 is pyridyl, preferably 4-pyridyl.
30. A compound according to claim 1 and having the formula (Ig):
Figure imgf000134_0001
wherein R12 is aryl or aralkyl, and
R6 and R8 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 hydroxymethyl.
31. A compound according to claim 1 and having the formula (Ih):
Figure imgf000134_0002
wherein R12 is aryl, preferably 4-trifluoromethoxyphenyl, or aralkyl, preferably benzyl, and
R13 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.
32. A compound according to claim 1 , selected from the group consisting of
(+)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 1 ), (-)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 2),
(+)-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- trifluoromethylpheny -methanone, (compound No. 3), (-)-[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- trifluoromethylphenyl)-methanone, (compound No. 4),
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 5),
(+)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 6),
(-)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 7),
[4-(4-Trifiuoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(3- methoxyphenyl)-methanone, (compound No. 8), (+)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-cjpyridin-5-yl]-(3- methoxyphenyl)-methanone, (compound No. 9),
(-)-[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(3- methoxyphenyl)-methanone, (compound No. 10),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-phenyl-methanone, (compound No. 11),
(+)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-phenyl-methanone,
(compound No. 12),
(-)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-phenyl-methanone,
(compound No. 13), (4-(2-Dimethylaminoethoxy)phenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 14),
(+)-(4-(2-Dimethylaminoethoxy)phenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 15),
(-)-(4-(2-Dimethylaminoethoxy)phenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 16),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-(2-[2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 17),
(+)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-(2-[2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 18), (-)-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-(2-[2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 19),
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- dimethylaminophenyl)-methanone, (compound No 20), 3-{4-[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]phenyl}- acrylic acid, (compound No 21),
(4-ChlorophenylH4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-cjpyridin-5-yl]- methanone, both the racemate, the two pure enantiomers, and mixtures thereof
(compound No 22), [4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 24),
[4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 25),
[4-(2-Dimethylaminoethoxy)-phenyl]-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 26),
[4-(2-Dimethylaminoethoxy)-phenyl]-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 27),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 28), [4-(4-Chlorophenyl)-4,5)6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2-morpholin-4- ylethoxy)phenyl]-methanone, (compound No. 29),
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 30),
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 31),
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- methoxyphenyl)-methanone, (compound No. 32),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(1 H-indol-5-yl)- methanone, (compound No.33), (1H-lndol-5-yl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone, (compound No.34),
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-fluorophenyl)- methanone, (compound No. 35),
[4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- fluorophenyl)-methanone, (compound No. 36),
4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-[4-(2- dimethylaminoethoxy)phenyl]-methanone, (compound No. 37),
[4-(2-Dimethylaminoethoxy)phenyl]-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]-methanone, (compound No. 38),
[7-Chloro-1-(2,3-dihydrobenzofuran-7-yl)-8-methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-
3-yl]-[4-(2-dimethylaminoethoxy)-phenyl]-methanone, (compound No. 39),
[4-(3,4-Dimethoxyphenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-6-yl]-[4-(2- dimethylaminoethoxy)-phenyl]-methanone, (compound No. 40), (3,4-Dimethoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]methanone, (compound No. 41),
(3-Chloro-4-methoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, (compound No. 42),
(4-Ethoxyphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone, (compound No. 43),
(4-Methylphenyl)-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yljmethanone, (compound No. 44),
3-(4-Methoxyphenyl)-1-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-5-yl]propenone, (compound No. 45), (1H-Benzimidazol-5-ylH4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-5-yl]methanone, (compound No. 46), or a salt thereof with a pharmaceutically acceptable acid or base.
33. A salt of a compound according to the preceding claim with a pharmaceutically accept- able base.
34. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 - 33, or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical iso- mers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
35. A pharmaceutical composition for use in the treatment of diseases of the endocrinologi- cal system such as hyperglycaemia and diabetes comprising, as an active ingredient, a compound according to any of the claims 1 - 33 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 together with one or more pharmaceutically acceptable carriers or diluents.
36. The pharmaceutical composition according to claim 34 or 35 in the form of an oral dosage unit or a parenteral dosage unit.
37. A pharmaceutical composition according to claim 34 or 35 wherein said ingredient is present in a unit dose in a range from about 0.05 to 1000, preferably from about 0.1 to
500 and especially in the range from 5 to 200 mg.
38. A compound according to any of the claims 1 - 33 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
39. A compound according to any of the claims 1 - 33 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or prevention of diseases of the endocrinological system, preferably hyperglycaemia or diabetes.
40. A compound according to any of the claims 1 - 33 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, characterized by having a glucose-6-phosphatase inhibitory activity corresponding to an IC50 value of less than 100 ╬╝M, preferably less than 10 ╬╝M, more preferably less than 1 ╬╝M, still more preferably less than 100 nM.
41. The use of a compound according to any of the claims 1 - 33 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament.
42. The use of a compound according to any of the claims 1 - 33 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, preferably hyperglycaemia or diabetes.
43. The use of a compound according to any of the claims 1 - 33 or a pharmaceutically ac- ceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of glycogen storage disease or hypoglycaemia.
44. The use of a compound selected from the group consisting of
[4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4-methoxyphenyl)- methanone, (compound No. 47),
(4-Chlorophenyl)-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone, (compound No. 48), (4-Chlorophenyl)-[4-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5- yl]-methanone, (compound No. 49),
(2-Chlorophenyl)-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone, (compound No.50),
(4-Chlorophenyl)-[4-(methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]- methanone, (compound No.51),
[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(4- trifluoromethylphenyl)-methanone, (compound No. 52),
(2-Chloropyridin-3-yl)-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyrin-5-yl]- methanone, (compound No. 53), [4-(4-Chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(2-thienyl)-methanone,
(compound No. 54),
[4-(4-Methoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl]-(2-thienyl)-methanone,
(compound No. 55),
(4-Chlorophenyl)-(4-propyl-4,5,6,7-tetrahydro-thieno[3,2-cjpyridin-5-yl)-methanone, (compound No. 56).
or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament.
45. The use of a compound selected from the group of compounds of the preceding claim for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system.
46. The use of a compound selected from the group of compounds of claim 44 for the preparation of a medicament for the prevention or treatment of hyperglycaemia or diabetes, preferably NIDDM.
47. A method for the treatment of ailments in a subject in need thereof comprising administering an effective amount of a compound according to any one of claims 1-33, and 44, or of a composition according to any one of the preceding composition claims, to said subject.
48. A method of treating or preventing diseases of the endocrinological system, preferably hyperglycaemia or diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any one of the preceding compound claims to said subject.
49. A method of treating or preventing hyperglycaemia or hypoglycaemia in a subject in need thereof comprising administering an effective normoglycaemic amount of a pharmaceutically acceptable salt of a compound according to any one of the preceding compound claims, or of a composition according to any one of the preceding composition claims, to said subject.
50. A process for the manufacture of a medicament, particular to be used in the treatment or prevention of diseases of the endocrinological system, such as, hyperglycaemia, diabetes, hypoglycaemia, and glycogen storage disease, which process comprises bringing a compound according to any of the claims 1-33, and 44 or a pharmaceutically accept- able 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, into a galenic dosage form.
51. Any novel feature or combination of features as described herein.
PCT/DK1998/000083 1997-03-07 1998-03-06 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE WO1998040385A1 (en)

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JP53909998A JP2001514631A (en) 1997-03-07 1998-03-06 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine derivatives, their production and use
EP98906858A EP0973778A1 (en) 1997-03-07 1998-03-06 4,5,6,7-TETRAHYDRO-THIENO 3,2-c]PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE

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Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045013A1 (en) * 1998-03-06 1999-09-10 Novo Nordisk A/S 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES
WO2000014090A1 (en) * 1998-09-02 2000-03-16 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine derivatives
US6090797A (en) * 1998-09-02 2000-07-18 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno(2,3-C)pyridine derivatives
WO2004092156A1 (en) * 2003-04-16 2004-10-28 F. Hoffmann-La Roche Ag Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
US6864253B2 (en) 2000-05-17 2005-03-08 Orth-Mcneil Pharmaceutical, Inc. Benzo[4,5]thieno[2,3-c]pyridine and Benzo[4,5]furo[2,3-c]pyridine Derivatives Useful as Inhibitors of Phosphodiesterase
US6953787B2 (en) 2002-04-12 2005-10-11 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
JP2006505623A (en) * 2002-10-22 2006-02-16 グラクソ　グループ　リミテッド Bicyclic benzamide compounds as histamine H3 receptor ligands useful in the treatment of neurological diseases
US7022694B2 (en) 2001-07-13 2006-04-04 Pharmacia & Upjohn Company Indoles and indolines having 5-HT activity
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US7402680B2 (en) 2003-09-17 2008-07-22 Janssen Pharmaceutica, N.V. Fused heterocyclic compounds
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US7704993B2 (en) 2003-06-17 2010-04-27 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
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WO2011097079A1 (en) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
US8080380B2 (en) 1999-05-21 2011-12-20 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US8168624B2 (en) 2004-12-21 2012-05-01 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
US8168782B2 (en) 2006-04-03 2012-05-01 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8277807B2 (en) 2006-10-12 2012-10-02 Astex Therapeutics Limited Pharmaceutical combinations
US8299241B2 (en) 2006-12-05 2012-10-30 Arena Pharmaceuticals, Inc. Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof
US8367657B2 (en) 2003-06-17 2013-02-05 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US8383619B2 (en) 2008-04-11 2013-02-26 Astex Therapeutics Limited Pharmaceutical compounds
US8481268B2 (en) 1999-05-21 2013-07-09 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US8637527B2 (en) 2007-12-17 2014-01-28 Janssen Pharmaceutica Nv Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1
US8653084B2 (en) 2006-10-12 2014-02-18 Astex Therapeutics Ltd. Hydrobenzamide derivatives as inhibitors of Hsp90
US8673895B2 (en) 2006-03-21 2014-03-18 Janssen Pharmaceutica Nv Tetrahydro-pyrimidoazepines as modulators of TRPV1
US8779132B2 (en) 2006-10-12 2014-07-15 Astex Therapeutics Limited Pharmaceutical compounds
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
US8883790B2 (en) 2006-10-12 2014-11-11 Astex Therapeutics Limited Pharmaceutical combinations
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
US8952197B2 (en) 2009-06-18 2015-02-10 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
US8999970B2 (en) 2010-09-01 2015-04-07 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
US9045431B2 (en) 2010-06-02 2015-06-02 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
US9169213B2 (en) 2012-10-09 2015-10-27 Arena Pharmaceuticals, Inc. Method of weight management
US9248133B2 (en) 2010-09-01 2016-02-02 Arena Pharmaceuticals, Inc. Salts of lorcaserin with optically active acids
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9365521B2 (en) 2010-09-01 2016-06-14 Arena Pharmaceuticals, Inc. Non-hygroscopic salts of 5-HT2C agonists
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9597320B2 (en) 2012-03-23 2017-03-21 Memorial Sloan-Kettering Cancer Center Treatment of pancreatic and related cancers with 5-acyl-6,7-Dihydrothieno[3,2-C]pyridines
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9730912B2 (en) 2006-10-12 2017-08-15 Astex Therapeutics Limited Pharmaceutical compounds
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
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US10226471B2 (en) 2010-09-01 2019-03-12 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonists useful for weight management
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US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
WO2020191151A1 (en) * 2019-03-19 2020-09-24 Oncovalent Therapeutics Inc. Sumo inhibitor compounds and uses thereof
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
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US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004206812A1 (en) * 2003-01-17 2004-08-05 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7425642B2 (en) 2003-07-15 2008-09-16 Dainippon Sumitomo Pharma Co. ,Ltd. Heteroaryl derivative

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0088250A2 (en) * 1982-03-05 1983-09-14 Boehringer Ingelheim Kg Basic substituted 4-phenyl-4,5,6,7-tetrahydrothieno(2,3-c) pyridines, process for their preparation and pharmaceutical compositions containing them
EP0157324A2 (en) * 1984-04-06 1985-10-09 Bayer Ag Tetrahydrothienopyridines, process for their preparation and their pharmaceutical application
US4681888A (en) * 1984-11-16 1987-07-21 Societe De Conseils De Recherches Et D'applications Scientifiques Thienopyridine derivatives and anti-thrombotic compositions containing the same
WO1987005295A1 (en) * 1986-03-05 1987-09-11 Universite Louis Pasteur Derivatives of (nitro-2 or amino-2 benzyl)-2 tetrahydro-1,2,3,4 isoquinoleines, as well as methods for obtaining them and pharmaceutical compositions containing them
WO1996034870A1 (en) * 1995-05-03 1996-11-07 Synthelabo Azacycloalcane derivatives, preparation thereof and their applications in therapy

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0088250A2 (en) * 1982-03-05 1983-09-14 Boehringer Ingelheim Kg Basic substituted 4-phenyl-4,5,6,7-tetrahydrothieno(2,3-c) pyridines, process for their preparation and pharmaceutical compositions containing them
EP0157324A2 (en) * 1984-04-06 1985-10-09 Bayer Ag Tetrahydrothienopyridines, process for their preparation and their pharmaceutical application
US4681888A (en) * 1984-11-16 1987-07-21 Societe De Conseils De Recherches Et D'applications Scientifiques Thienopyridine derivatives and anti-thrombotic compositions containing the same
WO1987005295A1 (en) * 1986-03-05 1987-09-11 Universite Louis Pasteur Derivatives of (nitro-2 or amino-2 benzyl)-2 tetrahydro-1,2,3,4 isoquinoleines, as well as methods for obtaining them and pharmaceutical compositions containing them
WO1996034870A1 (en) * 1995-05-03 1996-11-07 Synthelabo Azacycloalcane derivatives, preparation thereof and their applications in therapy

Cited By (102)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045013A1 (en) * 1998-03-06 1999-09-10 Novo Nordisk A/S 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES
WO2000014090A1 (en) * 1998-09-02 2000-03-16 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine derivatives
US6090797A (en) * 1998-09-02 2000-07-18 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno(2,3-C)pyridine derivatives
US8883424B2 (en) 1999-05-21 2014-11-11 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
US9289766B2 (en) 1999-05-21 2016-03-22 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
EP1741446A2 (en) 2000-01-21 2007-01-10 Novartis AG Combinations comprising dipeptidylpeptidase-IV inhibitors and antidiabetic agents
EP1743655A1 (en) 2000-01-21 2007-01-17 Novartis AG Combinations comprising dipeptidylpeptidase-IV inhibitors and antidiabetic agents
US6864253B2 (en) 2000-05-17 2005-03-08 Orth-Mcneil Pharmaceutical, Inc. Benzo[4,5]thieno[2,3-c]pyridine and Benzo[4,5]furo[2,3-c]pyridine Derivatives Useful as Inhibitors of Phosphodiesterase
US7022694B2 (en) 2001-07-13 2006-04-04 Pharmacia & Upjohn Company Indoles and indolines having 5-HT activity
US6953787B2 (en) 2002-04-12 2005-10-11 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8546379B2 (en) 2002-04-12 2013-10-01 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8575149B2 (en) 2002-04-12 2013-11-05 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8846906B2 (en) 2002-04-12 2014-09-30 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US7514422B2 (en) 2002-04-12 2009-04-07 Arena Pharmaceuticals, Inc. 5HT2c receptor modulators
US8993750B2 (en) 2002-04-12 2015-03-31 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8273734B1 (en) 2002-04-12 2012-09-25 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US8207158B2 (en) 2002-04-12 2012-06-26 Arena Pharmaceuticals, Inc. 5HT2c receptor modulators
US7977329B2 (en) 2002-04-12 2011-07-12 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US7446103B2 (en) 2002-10-22 2008-11-04 Glaxo Group Limited Bicyclic benzamide compound as histamine H3 receptor ligand useful in the treatment of neurological diseases
JP2006505623A (en) * 2002-10-22 2006-02-16 グラクソ　グループ　リミテッド Bicyclic benzamide compounds as histamine H3 receptor ligands useful in the treatment of neurological diseases
KR100779324B1 (en) * 2003-04-16 2007-11-28 에프. 호프만-라 로슈 아게 Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
WO2004092156A1 (en) * 2003-04-16 2004-10-28 F. Hoffmann-La Roche Ag Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
US7138529B2 (en) 2003-04-16 2006-11-21 Hoffmann-La Roche Inc. Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
CN100398533C (en) * 2003-04-16 2008-07-02 霍夫曼-拉罗奇有限公司 Substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
US8404675B2 (en) 2003-06-17 2013-03-26 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5HT2C receptor associated diseases
US8946207B2 (en) 2003-06-17 2015-02-03 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US7704993B2 (en) 2003-06-17 2010-04-27 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases
US9102627B2 (en) 2003-06-17 2015-08-11 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US8367657B2 (en) 2003-06-17 2013-02-05 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US7579470B2 (en) 2003-09-17 2009-08-25 Janssen Pharmaceutica Nv Fused heterocyclic compounds
US7897771B2 (en) 2003-09-17 2011-03-01 Janssen Pharmaceutica Nv Fused heterocyclic compounds
US7402680B2 (en) 2003-09-17 2008-07-22 Janssen Pharmaceutica, N.V. Fused heterocyclic compounds
US8980881B2 (en) 2004-12-21 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
US8168624B2 (en) 2004-12-21 2012-05-01 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
US8697686B2 (en) 2004-12-21 2014-04-15 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-thtrahydro-1H-3-benzazepine hydrochloride
US8530469B2 (en) 2005-04-13 2013-09-10 Astex Therapeutics Ltd. Therapeutic combinations of hydroxybenzamide derivatives as inhibitors of HSP90
US8101648B2 (en) 2005-04-13 2012-01-24 Astex Therapeutics, Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US9914719B2 (en) 2005-04-13 2018-03-13 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US8816087B2 (en) 2005-04-13 2014-08-26 Astex Therapeutics Limited Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
WO2007033266A2 (en) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors for treating diabetis
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
US8106057B2 (en) 2006-03-01 2012-01-31 Astex Therapeutics, Ltd. Dihydroxyphenyl isoindolylmethanones
US9738649B2 (en) 2006-03-21 2017-08-22 Janssen Pharmaceutica N.V. Tetrahydro-pyrimidoazepines as modulators of TRPV1
US9422293B2 (en) 2006-03-21 2016-08-23 Janssen Pharmaceutica Nv Tetrahydro-pyrimidoazepines as modulators of TRPV1
US8673895B2 (en) 2006-03-21 2014-03-18 Janssen Pharmaceutica Nv Tetrahydro-pyrimidoazepines as modulators of TRPV1
US8802845B2 (en) 2006-04-03 2014-08-12 Arena Phamaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8501935B2 (en) 2006-04-03 2013-08-06 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8168782B2 (en) 2006-04-03 2012-05-01 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US9428439B2 (en) 2006-10-12 2016-08-30 Astex Therapeutics Ltd. Hydrobenzamide derivatives as inhibitors of Hsp90
US9730912B2 (en) 2006-10-12 2017-08-15 Astex Therapeutics Limited Pharmaceutical compounds
US8883790B2 (en) 2006-10-12 2014-11-11 Astex Therapeutics Limited Pharmaceutical combinations
US8653084B2 (en) 2006-10-12 2014-02-18 Astex Therapeutics Ltd. Hydrobenzamide derivatives as inhibitors of Hsp90
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
US8277807B2 (en) 2006-10-12 2012-10-02 Astex Therapeutics Limited Pharmaceutical combinations
US8779132B2 (en) 2006-10-12 2014-07-15 Astex Therapeutics Limited Pharmaceutical compounds
US8299241B2 (en) 2006-12-05 2012-10-30 Arena Pharmaceuticals, Inc. Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof
US8637527B2 (en) 2007-12-17 2014-01-28 Janssen Pharmaceutica Nv Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1
US9440978B2 (en) 2007-12-17 2016-09-13 Janssen Pharmaceutica Nv Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of 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
US8383619B2 (en) 2008-04-11 2013-02-26 Astex Therapeutics Limited Pharmaceutical compounds
US8664218B2 (en) 2008-04-11 2014-03-04 Astex Therapeutics Ltd. Pharmaceutical compounds
US8952197B2 (en) 2009-06-18 2015-02-10 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
WO2011041293A1 (en) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Pyrazolo [1, 5-a] pyrimidine derivatives as apoptosis signal-regulating kinase 1 inhibitors
WO2011097079A1 (en) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
US9045431B2 (en) 2010-06-02 2015-06-02 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-HT2C receptor agonists
CN101863900A (en) * 2010-06-29 2010-10-20 天津药物研究院 Novel nitric oxide donating thienopyridine derivative and preparation method and application thereof
CN101863900B (en) * 2010-06-29 2012-07-25 天津药物研究院 Novel nitric oxide donating thienopyridine derivative and preparation method and application thereof
US9365521B2 (en) 2010-09-01 2016-06-14 Arena Pharmaceuticals, Inc. Non-hygroscopic salts of 5-HT2C agonists
US9248133B2 (en) 2010-09-01 2016-02-02 Arena Pharmaceuticals, Inc. Salts of lorcaserin with optically active acids
US10226471B2 (en) 2010-09-01 2019-03-12 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonists useful for weight management
US8999970B2 (en) 2010-09-01 2015-04-07 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
US9770455B2 (en) 2010-09-01 2017-09-26 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
US10463676B2 (en) 2010-09-01 2019-11-05 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonists useful for weight management
US9597320B2 (en) 2012-03-23 2017-03-21 Memorial Sloan-Kettering Cancer Center Treatment of pancreatic and related cancers with 5-acyl-6,7-Dihydrothieno[3,2-C]pyridines
US9943507B2 (en) 2012-03-23 2018-04-17 Memorial Sloan-Kettering Cancer Center Treatment of pancreatic and related cancers with 5-acyl-6,7-dihydrothieno[3,2-c]pyridines
US9169213B2 (en) 2012-10-09 2015-10-27 Arena Pharmaceuticals, Inc. Method of weight management
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017218874A1 (en) * 2016-06-16 2017-12-21 Memorial Sloan-Kettering Cancer Center Hedgehog acyltransferase inhibitors and uses thereof
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
WO2019086141A1 (en) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Novel, highly active amino-thiazole substituted indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2020191151A1 (en) * 2019-03-19 2020-09-24 Oncovalent Therapeutics Inc. Sumo inhibitor compounds and uses thereof
WO2023137297A3 (en) * 2022-01-11 2023-08-24 Suvalent Therapeutics, Inc. 5,6-dihydro-4h-thieno[2,3-c]pyrrole sumo inhibitors and uses thereof
CN114507155A (en) * 2022-02-16 2022-05-17 浙江欣禾生物股份有限公司 Preparation method of m-trifluoromethyl acetophenone oxime

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