WO1999040062A1 - Derives d'hydrazone - Google Patents

Derives d'hydrazone Download PDF

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Publication number
WO1999040062A1
WO1999040062A1 PCT/DK1999/000053 DK9900053W WO9940062A1 WO 1999040062 A1 WO1999040062 A1 WO 1999040062A1 DK 9900053 W DK9900053 W DK 9900053W WO 9940062 A1 WO9940062 A1 WO 9940062A1
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Prior art keywords
hydrazine
phenyl
ylidene
diphenyl
benzylidene
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PCT/DK1999/000053
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English (en)
Inventor
Palle Jacobsen
Peter Madsen
Niels Westergaard
Original Assignee
Novo Nordisk A/S
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Priority to AU26102/99A priority Critical patent/AU2610299A/en
Publication of WO1999040062A1 publication Critical patent/WO1999040062A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/80—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/84—Hydrazones having doubly-bound carbon atoms of hydrazone groups being part of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/88—Hydrazones having also the other nitrogen atom doubly-bound to a carbon atom, e.g. azines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to Hydrazone-derivatives, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, e.g. to their use for treatment of human and animal disorders.
  • the invention relates to modulation of the activity of molecules with glucose-6-phosphate recognition units, including glucose-6- phosphatases (G-6-Pases) in in vitro systems, microorganisms, eukaryotic cells, whole animals and human beings, especially in the treatment of diseases related to glucose metabolic pathways.
  • G-6-Pases glucose-6- phosphatases
  • Glucose is the major energy substrate in mammals and regulation of blood glucose levels within a narrow range seems to be of crucial importance to avoid serious physiological com- plications 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 & Nord- lie. 1989). It has been shown that the rate of hydrolysis of G-6-P and the hepatic glucose output were increased under diabetic conditions (Lyall, Grant, Scott, & Burchell.
  • G-6-Pase catalytic enzyme protein ArArgaud, Zhang, Pan, Maitra, Pilkis, & 2 Lange. 1996; Burchell & Cain. 1985. This makes G-6-Pase enzyme a potential target in control of excess glucose production seen in diabetes.
  • the present invention relates to compounds of the general formula I or II:
  • aryl optionally substituted with halogen, perhalomethyl, C ⁇ -alkyl, hydroxy, acyl, C,- 6 -alkoxy, nitro, cyano, amino, mono- or di-C ⁇ -alkylamino, acylamino, C 1-6 -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, oxo, sulfonamide , or N-mono or di -substituted sulfonamide or heteroaryl selected from the group thiophene, furan, pyridine, pyrimidine, pyrazine, pyridaz- ine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole quinazolin, fluorene, xanthene, triazol, quinoline, isoquinoline, isoindane, benzhydryl, acridine, and
  • R1 and R2 may together form a cyclic structure being mono or polycylic, carbocyclic or het- erocyclic, optionally substituted with halogen, perhalomethyl, C ⁇ -alky!, hydroxy, C ⁇ -alkoxy, nitro, cyano, amino, mono- or di-C ⁇ -alkylamino, acylamino, C ⁇ -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, oxo, sulfonamide, or N-mono or di -substituted sulfonamide;
  • R3 and R4 independently are
  • aryl optionally substituted with halogen, perhalomethyl, C,. 6 -alkyl, hydroxy, acyl, C ⁇ -alkoxy, nitro, cyano, amino, mono- or di-C ⁇ -alkylamino, acylamino, C ⁇ -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, oxo, sulfonamide , or N-mono or di -substituted sulfonamide, or heteroaryl selected from the group thiophene, furan, pyridine, pyrimidine, pyrazine, pyridaz- ine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole quinazolin, fluorene, xanthene, triazol, quinoline, isoquinoline, isoindane, benzhydryl, acridine, and thi
  • R3 and R4 may together form a ring system selected from the group consisting of quinazolin, fluorene, xanthene, quinoline, isoquinoline, isoindane, benzhydryl, acridine, carbazol, triazole, phenazine, phenothiazine, phenoxazine, tetrahydroquinoline, and tetrahydroisoqui- noline; optionally substituted with halogen, perhalomethyl, C,- 6 -alkyl, hydroxy, acyl, C ⁇ - alkoxy, nitro, cyano, amino, mono- or di-C ⁇ -alkylamino, acylamino, C ⁇ -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, oxo, sulfonamide , or N-mono or di -substituted sulfonamide;
  • R1 and R2 has the meaning described above and n is 0,1 or 2. m is 0,1 or 2.
  • R5 and R6 are independently hydrogen, halogen, perhalomethyl, C 1-6 -alkyl, hydroxy, acyl, C,. 6 -alkoxy, nitro, cyano, amino, mono- or di-C ⁇ -alkylamino, acylamino, C 1 . 6 -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, oxo, sulfonamide , or N-mono or di -substituted sulfonamide,
  • the invention relates to compounds of general formula (la) wherein n and m is 1 and R5 and R6 is hydrogen.
  • the invention relates to compounds of general formula (lb)
  • R1 , R5, and R6 has the meaning described above.
  • R1 has the meaning described above.
  • the invention relates to compounds of general formula (lc)
  • R5 and R6 has the meaning described above and R1 is selected from
  • R7, R8, R9, R10 and R11 are selected from the group hydrogen, halogen, perhalomethyl, C,. 6 -alkyl, hydroxy, acyl, C,- 6 -alkoxy, nitro, cyano, amino, mono- or di-C ⁇ -alkylamino, acylamino, C L ⁇ -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, oxo, sulfonamide , or N-mono or di -substituted sulfonamide,
  • the invention relates to compounds of general formula (lc) r ⁇ X R7
  • R5 and R6 independently are H, -OCH 3 , or perhalomethyl
  • R7 and R8 independently are H , -OCH 3 , OH, -NH-CO-CH 3 , -CO-OH, -CO-OCH 3 or halogen.
  • R7 is as defined above, more preferred R7 is selected from H , -OCH 3 , OH, -NH-CO-CH 3 , CO-OH, -CO-OCH 3 or halogen.
  • the invention relates to compounds of general formula (I) wherein R1 is
  • R9 and R9 is H, -NO 2 , or C ⁇ -alkyl and R5 and R6 independently are H, OCH 3 or perhalomethyl.
  • R9 and R9 is H, -NO 2 , or C ⁇ -alkyl and R5 and R6 independently are H, OCH 3 or perhalomethyl.
  • the invention relates to compounds of general formula (I) wherein R1 is
  • R10 is Hydrogen, halogen, C ⁇ -alky or C ⁇ -alkoxy and R5 and R6 independently are H, OCH 3 or perhalomethyl.
  • the invention relates to compounds of general formula (I) wherein R1 is
  • R11 is Hydrogen, halogen, C ⁇ -alky or C ⁇ -alkoxy and R5 and R6 independently are H, OCH 3 or perhalomethyl.
  • the invention relates to compounds of general formula wherein R1 and R2 together form a cyclic structure selected from the group consisting of indane, tetrahydronaphtalene, tetrahydroquinoline, quinazolin, fluorene, xanthene, triazol, quinoline, isoquinoline, isoindane, benzhydryl, acridine and xanthene, optionally substituted with halogen, perhalomethyl, C 1- ⁇ -alkyl, hydroxy, C ⁇ -alkoxy, nitro, cyano, amino, mono- or 10 di-C ⁇ -alkylamino, acylamino, C ⁇ -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, oxo, sulfonamide, or N-mono or di -substituted sulfonamide.
  • the invention relates to compounds of general formula wherein R1 and R2 together form a ring : 6-methoxy-1 ,2,3,4-tetrahydronaphtalene-1-ylidene.
  • the invention relates to compounds of general formula wherein R3 and R4 together form a ring system selected from the group consisting of acridine, carbazol, quinazolin, fluorene, xanthene, triazol, quinoline, isoquinoline, isoindane, benzhydryl, acridine, phenazine, phenothiazine, phenoxazine, tetrahydroquinoline, and tetrahydroisoquinoline.
  • R1 and R2 independently are H, C1-8 alkyl, C3-8-cycloalkyl,C1-6 arylalkyi, aryl or het- eroaryi selected from the group thiophene, furan, pyridine, pyrimidine, pyrazine, pyridaz- ine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole quinazolin, fluorene, xanthene, triazol, quinoline, isoquinoline, isoindane, benzhydryl, acridine, and thiazole, optionally substituted with halogen, perhalomethyl, optionally substituted C ⁇ -alkyl, hydroxy, optionally substituted C ⁇ -alkoxy, nitro, cyano, amino, optionally substituted mono- or di-C,- 6 -alkylamino, acylamino, C ⁇ -alkoxycarbony
  • R1 and R2 may together form a cyclic structure being mono or polycylic, carbocyclic or heterocyclic, optionally substituted with halogen, perhalomethyl, optionally substituted C,.- 6 -alkyl, hydroxy, optionally substituted C,. 6 -alkoxy, nitro, cyano, amino, optionally substi- tuted mono- or di-C ⁇ -alkylamino, acylamino, C ⁇ -alkoxycarbonyl, carboxy or carbamoyl, trifluoromethoxy, sulfonamide, or N-mono or di -substituted sulfonamide; 11 R3 and R4 independently are H, C ⁇ -alkyl, C 3 .
  • R3 and R4 may together form a ring system selected from the group consisting of quina- zolin, fluorene, xanthene, quinoline, isoquinoline, isoindane, benzhydryl, acridine, carba- zol, triazole, phenazine, phenothiazine, phenoxazine, tetrahydroquinoline, and tetrahy- droisoquinoline; optionally substituted with halogen, perhalomethyl, optionally substituted C,.
  • R1 , R2, R3, and R4 have the meaning described above,
  • Preferred compounds of the invention are: 12
  • the present invention relates furthermore to a salt of a compound of the general formula (I) or (II) with a pharmaceutically acceptable acid or base.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts, such as hydrochloric, 15 hydrobromic, hydroiodic, phosphoric, sulfuric, acetic, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethanesulfonic, picric and the like salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, ⁇ 6, 2 (1977) and incorporated herein by reference; pharmaceutically acceptable metal salts, such as lithium, sodium, potassium, or magnesium salts and equivalents; or - optionally alkylated - ammonium salts; or amine salts of the compounds of this invention, such as the sodium, potassium, C 1-6 - alkylamine, di (C ⁇ -alkyl) amine, tri (C
  • acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • C ⁇ -alky refers to a straight or branched, saturated or unsaturated hydrocarbon chain.
  • the C ⁇ -alkyl residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyciic hydrocarbon residues.
  • Examples of the aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec. butyl, tert.
  • Example of the unsaturated aliphatic hydrocarbon residues included 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,
  • alicyciic hydrocarbon residue examples include saturated all- cyclic hydrocarbon residues having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl; and C 5 - 6 unsaturated alicyciic hydrocarbon residues having 5 to 6 carbon atoms such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl. 16
  • aryl refers to an aryl or a heteroaryl and includes phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2- anthracenyl, 3-anthracenyl), pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3-triazol-1-yl, 1 ,2,3-triazol-2- yl 1 ,2,3-triazol-4-yl, 1 ,2,4-thazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl), thiazolyl
  • the invention also relates to partly or fully saturated analogues of the ring systems mentioned above 17
  • substituents include, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, cyano, nitro, trifluoromethyl, carbamoyl, C ⁇ -acyl (e.g. acetyl, propionyl, isopropionyl), C ⁇ -alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert.butoxy), C ⁇ -alky!
  • C,- 6 -alkoxycarbonyl e.g. ones having 2 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl
  • Ci- ⁇ -alkanoyloxy e.g. ones having 2 to 6 carbon atoms such as acetyloxy, propionyloxy, isopropionyloxy
  • C,. 4 -alkylthio e.g. ones having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio, and isopropylthio
  • C ⁇ -alkylamino e.g.
  • aminoalkyi e.g. one having an amino containing group connected to a C ⁇ -alkyl group as defined above, such as 2- dimethylaminoethyl and 1-pyrrolidinylmethyl
  • aminoalkoxy e.g. one having an amino con- taining group connected via a C ⁇ -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, trichioromethyl, tribromomethyl or triiodomethyl.
  • perhalomethoxy means trifluoromethoxy, trichloromethoxy, tribromomethoxy or triiodomethoxy.
  • arylalkyi refers to an aryl residue as defined above, connected to an C ⁇ -alkyl as defined above.
  • arylalkyi residue include benzyl, 2- phenylethyl, 2-phenylethenyl, 3-(2-pyridyl)propyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like.
  • Ci-e-alkoxy refers to a straight or branched monovalent substituent comprising a Ci- ⁇ -alkyI group linked through an ether 18 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 substi- tuted by one or two residues selected from the list consisting of optionally substituted C ⁇ - alkyl as defined above, optionally substituted aryl as defined above and optionally substituted aralkyl as defined above.
  • the compounds of the present invention are normoglycaemic agents (i.e. compounds that are able to normalize blood glucose levels from hyper-/hypoglycemic conditions) that interact with the glucose-6-phosphatase catalytic enzyme activity, and hence make them useful in the treatment and prevention of various diseases of the endocrinological system, especially ailments related to carbohydrate metabolism and especially the glucose metabolism, e.g. hyperglycaemia, diabetes mellitus, and especially non-insulin dependent diabetes mellitus (NIDDM) including long-term complications, such as retinopathy, neuropathy, nephropathy, and micro- and macroangiopathy, and hypoglycaemia resulting from, e.g., glycogen storage disease (von Gierke's Disease all types).
  • NIDDM non-insulin dependent diabetes mellitus
  • the present compounds are useful in the prophylactic treatment of hyperlipidaemia, hypertension, liver and bile diseases, and atherosclerosis associated with diabetes.
  • the present compounds are especially useful in the treatment of diseases associated with an increased or reduced activity of the glucose-6- phosphatase complex, e. g. the G-6-Pase catalytic enzyme.
  • the invention relates to a compound of the general formula (I) or (II) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
  • a pharmaceutically acceptable acid or base or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
  • a pharmaceutically acceptable acid or base or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form for therapeutical use.
  • diseases of the endocrinological system preferably hyperglycaemia or diabetes.
  • the invention also relates to a compound selected from N-(4-Dimethylamino-phenyl)-3-(phenylacetyl-hydrazono)-butyramide 3-[(4-Methoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one 3-[(Furan-3-ylmethylene)-amino]-2-phenyl-3H-quinazolin-4-one 3-[(4-Dimethylamino-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one 2-(4-Bromo-phenyl)-3-[(3,4-dihydroxy-benzylidene)-amino]-3-H-quinazolin-4-one 19
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form for therapeutical use, preferably for treatment or prevention of diseases of the endocrinological system, preferably hyperglycaemia or diabetes.
  • the invention also relates to the use of a compound of the general formula (I) or (II) 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, NIDDM or diabetes.
  • the invention also relates to the use of a compound of the general formula (I) or (II) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of glycogen storage disease or hypoglycaemia.
  • the invention also relates to the use of a compound selected from
  • N-Fluoren-9-ylidene-N'-furan-2-ylmethylene-hydrazine N-Fluoren-9-ylidene-N'-[2-(1 ,3,3-trimethyl-1 ,3-dihydro-indol-2-ylidene)-ethylidene]-hydrazine
  • N,N-Dibenzyl-N'-furan-2-ylmethylenehydrazine N,N-Dibenzyl-N'-(4-hydroxybenzylidene)hydrazine 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, NIDDM or diabetes or glycogenstorage disease or hypoglycaemia.
  • diseases of the endocrinological system preferably hyperglycaemia, NIDDM or diabetes or glycogenstorage disease or hypoglycaemia.
  • the invention relates furthermore to a method for the treatment of ailments in a subject in need thereof comprising administering an effective amount of a compound of formula I or II to said subject.
  • diseases of the endocrinological system preferably hypergly- caemia or diabetes.
  • the invention relates furthermore to a method for the treatment of ailments in a subject in need thereof comprising administering an effective amount of a compound selected from N-(4-Dimethylamino-phenyl)-3-(phenylacetyl-hydrazono)-butyramide 3-[(4-Methoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one 3-[(Furan-3-ylmethylene)-amino]-2-phenyl-3H-quinazolin-4-one 3-[(4-Dimethylamino-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one 2-(4-Bromo-phenyl)-3-[(3,4-dihydroxy-benzylidene)-amino]-3-H-quinazolin-4-one 4-(Carbazol-9-yliminomethyl)-phenol 22
  • N,N-Dibenzyl-N'-furan-2-ylmethylenehydrazine N,N-Dibenzyl-N'-(4-hydroxybenzylidene)hydrazine to said subject.
  • diseases of the endocrinological system preferably hypergly- caemia or diabetes.
  • Examples of compounds of the invention include the compounds prepared according to the examples herein, and any salt thereof with a pharmaceutically acceptable acid or base, including any salts thereof as defined herein.
  • the invention relates to the use of any 23 enantiomeric form or mixture of enantiomers of any one of said compounds including any salt thereof with a pharmaceutically acceptable acid or base, as defined herein, as well as the use of the novel compounds of the formulae I, II, la, lb, and lc and as defined in the compound claims herein, for the preparation of a medicament, especially for the preparation of a medicament for the treatment and/or prevention of hyperglycaemia or diabetes mellitus, preferably NIDDM.
  • the invention relates to a compound of the general formula I, II, la, lb, lc or a pharmaceutically acceptable acid addition salt or other salt as defined above thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperglycaemia and treatment or prevention of diabetes.
  • the invention also relates to the use of the novel compounds of formula I, II, la, lb, and lc as medicaments for the treatment of diseases, and said compounds are useful for treating hyperglycaemia and treating or preventing diabetes .
  • the present invention relates to methods of preparing the above mentioned compounds.
  • Methods for preparing compounds of general formula I are described in the literature e.g.: Bull. Soc. Chim. France.1948, 979 -989. - Liebig 572, (1951 ), 121-144 - Bull. Soc. Chim. France 1937 , 481 - 499. And references therein. We developed a modification of the known method for use in parallel synthesis.
  • the acidity of the reaction medium can be adjusted by means of a mineral acid like hydrochloric acid or sulfuric acid or a carboxylic acid, such as acetic acid, methanoic acid or any other suitable lower-chain car- boxylic acid.
  • a mineral acid like hydrochloric acid or sulfuric acid or a carboxylic acid, such as acetic acid, methanoic acid or any other suitable lower-chain car- boxylic acid.
  • the method of the invention is however by no means restricted to the use of those acids, also buffers and other organic acids may be used.
  • Preferred solvents for the reaction are alcohols, such as isopropanol, ethanol, butanol, or solvents, such as DMF, or mixtures thereof.
  • Preparation of a structure of the general formula (II) is performed by reaction of a molecule of the general formula (IV) with equimolar amounts of a molecule of the general formula (V) at a pH between 5 and 6. 25
  • the acidity of the reaction medium can be adjusted by means of a mineral acid like hydrochloric acid or sulfuric acid or a carboxylic acid, such as acetic acid, methanoic acid or any other suitable lower-chain carboxylic acid.
  • a mineral acid like hydrochloric acid or sulfuric acid or a carboxylic acid, such as acetic acid, methanoic acid or any other suitable lower-chain carboxylic acid.
  • the method of the invention is however by no means restricted to the use of those acids, also buffers and other organic acids may be used.
  • Preferred solvents for the reaction are alcohols like isopropyl alcohol, ethanol, butanol or solvents like DMF, or mixtures thereof.
  • the compounds of formulae I, II, la, lb, and lc 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.
  • the invention relates to the use of commercially available Hydrazone- derivatives, including salts thereof with farmaceutically acceptable acids or bases and any optical isomer, racemic mixtures and tautomeric forms thereof, from companies like SPECS, SALOR, Maybridge , Buttpark, and Bionet for the preparation of a medicament.
  • Hydrazone- derivatives including salts thereof with farmaceutically acceptable acids or bases and any optical isomer, racemic mixtures and tautomeric forms thereof, from companies like SPECS, SALOR, Maybridge , Buttpark, and Bionet for the preparation of a medicament.
  • Such compounds are useful in the preparation of a medicament for the treatment of diseases of the endocrinological system, such as diabetes, preferably NIDDM, and hyperglycaemia.
  • G-6-Pase glucose-6-phosphatase catalytic enzyme ac ⁇ tivity 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/l Bacitrazin (pH 7.5) essentially as described by Arion et al.,1980 (Arion, Lange, & Walls. 1980). Microsomes were kept at -80 °C until use. 27
  • the compound 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, preferably less than 10 ⁇ M, more preferably less than 1 ⁇ M, still more preferably less than 100nM.
  • the compounds according to the invention are effective over a wide dosage range. In general satisfactory results are obtained with dosages from about 0.05 to about 1000 or 5000mg, preferably from about 0.1 to about 500 mg, per day. A most preferable dosage is about 5 mg to about 200 mg per day. The exact dosage will depend upon the mode of administration, form in which the compound is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the present invention relate furthermore to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound of the general formula (l)or (II) or a pharmaceutical 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 together with one or more pharmaceutically acceptable carriers or diluents.
  • the present invention relate furthermore to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound selected from
  • N,N-Dibenzyl-N'-benzylidenehydrazine N,N-Dibenzyl-N'-furan-2-ylmethylenehydrazine N,N-Dibenzyl-N'-(4-hydroxybenzylidene)hydrazine or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any 29 tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
  • the dosage unit of the pharmaceutical compositions according to the invention typically contains from 0.05mg to 1000mg, preferably from 0.1 mg to 500mg, or, preferably from 5mg to 200mg per day of the active ingredient, which is, preferably, a novel hydrazone 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 hydrazone derivative or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intrapulmonary, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more compounds exhibiting a different activity, e.g., a plasma lipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material.
  • a plasma lipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material e.g., a plasma lipid lowering compounds, sulphonylurea like compounds, or other oral agents useful in the treatment of diabetes, or other pharmacologically active material.
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and
  • compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt or metal salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • conventional techniques for the preparation of pharmaceutical compositions may be used.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, 30 capsule, sachet, paper, or other container.
  • a carrier which may be in the form of a ampoule, 30 capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monogiycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated in any galenic dosage form so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • the preparation may contain a compound of formula I, II, la, lb or lc dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • 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.
  • 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, com 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 tabletting 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.
  • N,N-Dibenzylhydrazine (5.0 g, 24 mmol) was dissolved in DMF (20 ml) and 4- chlorobenzaldehyde (3.3 g, 24 mmol) was added followed by triethyl orthoformiate (10 ml).
  • N,N-Dibenzylhydrazine (5.0 g, 24 mmol) was dissolved in DMF (20 ml) and 5-ethylfurfural (2.9 g, 24 mmol) was added followed by triethyl orthoformiate (10 ml). The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuo to afford 6.99 g (93%) of the title compound.
  • N,N-Dibenzylhydrazine (3.0 g, 14 mmol) was dissolved in DMF (30 ml) and 4- pyridinecarboxaldehyde (1.5 g, 14 mmol) was added followed by triethyl orthoformiate (15 ml). The resulting mixture was stirred at room temperature for 16 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic extracts were washed with brine (100 ml), dried (MgS0 4 ) and evaporated in vacuo to afford 4.42 g (100%) of the title compound.
  • N,N-Dibenzylhydrazine (5.0 g, 24 mmol) was dissolved in DMF (20 ml) and 4- methoxybenzaldehyde (3.2 g, 24 mmol) was added followed by triethyl orthoformiate (10 ml). The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1 :4). This afforded 6.16 g (79%) of the title compound.
  • the compounds of this invention can also be prepared in a parallel setup as illustrated in the following:
  • HPLC-MS analyses were performed on a PE Sciex API 100 LC/MS System using a WatersTM 3 mm x 150 mm 3.5 ⁇ C-18 Symmetry column and positive ionspray with a flow rate at 20 ⁇ L/minute.
  • LC/MS method B refers to the following system:
  • the instrument control and data acquisition is done by the Sciex Sample control software running on a Macintosh PowerPC 7200 computer.
  • the HPLC pump is connected to four eluent reservoirs containing:
  • samples contain approximately 500 ⁇ g/mL of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentration.)
  • an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof.
  • the analysis is performed at room temperature by injecting 20 ⁇ Lof the sample solution on the column which is eluted with a gradient of acetonitrile in either 0.05% TFA or 0.002 M ammonium acetate. Depending on the analysis method varying elution conditions are used.
  • the eluate from the column is passed through a flow splitting T-connector which passes approximately 20 ⁇ l/min (1/50) through approx. 1 m. 75 ⁇ fused silica capillary to the API interface of API 100 spectrometer. 46
  • the remaining 1.48 mlJmin (49/50) is passed through the UV detector and to the ELS detector.
  • the detection data are acquired concurrently from mass spectrometer, UV detector and ELS detector.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés d'hydrazone de formule (I) ou (II), leurs sels, leurs hydrates et leurs isomères optiques. L'invention concerne en outre les compositions renfermant les composés, l'utilisation de ces composés comme médicaments et leur utilisation thérapeutique, plus particulièrement dans le traitement de maladies liées aux voies métaboliques du glucose.
PCT/DK1999/000053 1998-02-05 1999-02-03 Derives d'hydrazone WO1999040062A1 (fr)

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DK0159/98 1998-02-05
DK15998 1998-02-05
US7400198P 1998-02-09 1998-02-09
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Cited By (15)

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JP2004504401A (ja) * 2000-07-20 2004-02-12 ビーエーエスエフ　アクチェンゲゼルシャフト 配位子、錯体、及びこれらをオレフィンの重合に使用する方法
EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
CN100394307C (zh) * 2003-05-30 2008-06-11 三星电子株式会社 吖嗪基电荷转移材料
EP2107908A2 (fr) * 2007-02-02 2009-10-14 Redpoint Bio Corporation Utilisation d'un inhibiteur de trpm5 pour réguler une sécrétion d'insuline et de glp-1
AU2006311826B2 (en) * 2005-11-03 2010-11-11 Redpoint Bio Corporation Hydrazone derivatives and uses thereof
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose
US7998986B2 (en) 2001-12-21 2011-08-16 Exelixis Patent Company Llc Modulators of LXR
US8013001B2 (en) 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR
JP2012046453A (ja) * 2010-08-27 2012-03-08 Stelic Institute Of Regenerative Medicine 慢性炎症性疾患治療剤
CZ303748B6 (cs) * 2011-10-11 2013-04-17 Vysoká skola chemicko - technologická v Praze Ftalazin-1-ylhydrazony a jejich pouzití k lécbe nádorových onemocnení
CN104610152A (zh) * 2015-02-13 2015-05-13 佛山市赛维斯医药科技有限公司 一类环丙基酰肼类gpr119激动剂、制备方法及其用途
CN106146342A (zh) * 2015-04-17 2016-11-23 香港科技大学深圳研究院 芴基水杨醛联肼类衍生物及其制备方法和应用
CN115433108A (zh) * 2022-09-01 2022-12-06 河南师范大学 一种合成含三氟甲基的手性腙类化合物的方法

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EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
EP1743655A1 (fr) 2000-01-21 2007-01-17 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabétiques
JP2004504401A (ja) * 2000-07-20 2004-02-12 ビーエーエスエフ　アクチェンゲゼルシャフト 配位子、錯体、及びこれらをオレフィンの重合に使用する方法
US8013001B2 (en) 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR
US7998986B2 (en) 2001-12-21 2011-08-16 Exelixis Patent Company Llc Modulators of LXR
CN100394307C (zh) * 2003-05-30 2008-06-11 三星电子株式会社 吖嗪基电荷转移材料
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
AU2006311826C1 (en) * 2005-11-03 2011-06-16 Redpoint Bio Corporation Hydrazone derivatives and uses thereof
AU2006311826B2 (en) * 2005-11-03 2010-11-11 Redpoint Bio Corporation Hydrazone derivatives and uses thereof
EP2107908A4 (fr) * 2007-02-02 2011-07-20 Redpoint Bio Corp Utilisation d'un inhibiteur de trpm5 pour réguler une sécrétion d'insuline et de glp-1
JP2010518008A (ja) * 2007-02-02 2010-05-27 レッドポイント バイオ コーポレイション インスリンおよびｇｌｐ−１の放出を調節するｔｒｐｍ５阻害物質
EP2107908A2 (fr) * 2007-02-02 2009-10-14 Redpoint Bio Corporation Utilisation d'un inhibiteur de trpm5 pour réguler une sécrétion d'insuline et de glp-1
US8193168B2 (en) * 2007-02-02 2012-06-05 Redpoint Bio Corporation Use of a TRPM5 inhibitor to regulate insulin and GLP-1 release
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose
JP2012046453A (ja) * 2010-08-27 2012-03-08 Stelic Institute Of Regenerative Medicine 慢性炎症性疾患治療剤
CZ303748B6 (cs) * 2011-10-11 2013-04-17 Vysoká skola chemicko - technologická v Praze Ftalazin-1-ylhydrazony a jejich pouzití k lécbe nádorových onemocnení
CN104610152A (zh) * 2015-02-13 2015-05-13 佛山市赛维斯医药科技有限公司 一类环丙基酰肼类gpr119激动剂、制备方法及其用途
CN106146342A (zh) * 2015-04-17 2016-11-23 香港科技大学深圳研究院 芴基水杨醛联肼类衍生物及其制备方法和应用
CN106146342B (zh) * 2015-04-17 2019-02-12 香港科技大学深圳研究院 芴基水杨醛联肼类衍生物及其制备方法和应用
CN115433108A (zh) * 2022-09-01 2022-12-06 河南师范大学 一种合成含三氟甲基的手性腙类化合物的方法

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