WO2015024448A1 - Composés de cycle benzopipéridine et de cycle benzomorpholine, procédé de préparation et applications médicales de ces composés - Google Patents

Composés de cycle benzopipéridine et de cycle benzomorpholine, procédé de préparation et applications médicales de ces composés Download PDF

Info

Publication number
WO2015024448A1
WO2015024448A1 PCT/CN2014/083806 CN2014083806W WO2015024448A1 WO 2015024448 A1 WO2015024448 A1 WO 2015024448A1 CN 2014083806 W CN2014083806 W CN 2014083806W WO 2015024448 A1 WO2015024448 A1 WO 2015024448A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
propoxy
fluoro
benzo
methyl
Prior art date
Application number
PCT/CN2014/083806
Other languages
English (en)
Chinese (zh)
Inventor
欧阳孔德
刘振刚
蔡艳
Original Assignee
上海润诺生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海润诺生物科技有限公司 filed Critical 上海润诺生物科技有限公司
Publication of WO2015024448A1 publication Critical patent/WO2015024448A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • 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
    • C07D409/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel benzopiperidine ring and a benzomorpholine ring derivative, and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, and a process for the preparation thereof.
  • the present invention also relates to the benzopiperidinyl ring and a benzomorpholine ring derivative, and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, in the preparation of a therapeutic agent, particularly a GPR40 agonist, and in the preparation of a diabetic treatment Use in medicines for diseases such as metabolic disorders. Background technique
  • type II diabetes accounts for more than 90% of the entire diabetes population, and its main manifestations are insulin resistance (target organ sensitivity to insulin) and insufficient insulin secretion.
  • hypoglycemic substances such as metformin, which reduce the decomposition of hepatic glycogen
  • promote insulin secretion such as hydrazide, DPP-4 inhibitor and GLP-1 analogue, etc.
  • Insulin secretion of ⁇ -cells ⁇ -glucosidase inhibitors inhibit the production of glucose in the intestine
  • Peroxisome proliferator-activated receptor ⁇ ( ⁇ ⁇ ) activators improve the body's sensitivity to insulin.
  • these drugs have certain side effects such as hypoglycemia, weight gain, gastrointestinal side effects, drug tolerance, and the like.
  • GPR40 i.e., free fatty acid receptor 1, FFAR1
  • the endogenous ligand of GPR40 is a long-chain free fatty acid, mainly a 12-18 carbon saturated fatty acid and an 18-22 carbon unsaturated fatty acid such as oleic acid, linoleic acid and the like.
  • GPR40 is a Gq protein coupled receptor, activation may cause the elevation of intracellular IP 3, IP 3 to activate the release of intracellular calcium stores sensitive, causing increased intracellular Ca 2+ concentration, followed by calcium-dependent insulin produced secretion. At the same time, GPR40 activation affects the calcium channel on the cell membrane and promotes the influx of extracellular Ca 2+ .
  • GSIS glucose-stimulated insulin secretion
  • GPR40 promotes insulin secretion with glucose dependence: ie at low concentrations In glucose, GPR40 has little effect on insulin secretion, so it does not cause blood glucose concentration to continue to decrease. At high concentrations, it promotes insulin secretion and can effectively lower blood glucose concentration. Therefore, GPR40 agonists can prevent the risk of hypoglycemia while treating type II diabetes.
  • GPR40 agonists can be used to treat type II diabetes and related indications such as obesity, metabolic syndrome, atherosclerosis, and hyperlipidemia. Therefore, the discovery and modification of GPR40-targeted agonists is of great value for scientific research and clinical applications.
  • GPR40 agonists include WO200508666K WO200800193K WO2010045258, WO201207269K WO2012011125, WO2012004269, WO2011161030, US2011313008, US2011312995, US2012004234 and US2012035196, and the like.
  • the object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof Form, and its medicinal
  • A is independently selected from -CH 2 - or -0-;
  • R 1 is independently selected from hydroxy or C 1 -C 8 alkoxy, preferably C 1 -C 6 alkoxy, more preferably C 1 -C 3 alkoxy, such as methoxy, ethoxy and/or propoxy;
  • R 2 is independently selected from a hydrogen atom or a halogen, preferably a fluorine atom
  • R 3 is independently selected from a hydrogen atom, a halogen, preferably chlorine and/or fluorine, or a C1-C8 fluorenyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as a methyl group, an ethyl group and/or a propyl group;
  • R 4 and R 5 are each independently selected from a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably
  • a C1-C3 alkyl group such as methyl, ethyl and/or propyl
  • R 6 is independently selected from a hydrogen atom, a halogen, preferably fluorine and/or chlorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
  • R 7 is independently selected from a hydrogen atom, -OR 8 ;
  • R 8 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; C 3 -C 8 cycloalkyl, preferably C 3 -C 6 cycloalkyl, more preferably C3-C4 cycloalkyl, e.g.
  • cyclopropyl and / or cyclobutyl containing -S0 2 - or C3-C8 heterocyclic group, preferably -S0 2 - group of C3-C6 heterocyclyl More preferably, a C4 and/or C5 heterocyclic group containing -S0 2 -, wherein the C1-C8 alkyl group or the C3-C8 cycloalkyl group is optionally a C1-C8 alkoxy group, preferably a C1-C6 alkoxy group , more preferably C1-C3 alkoxy group such as methoxy, ethoxy and / or propoxy; containing -S0 2 - C3-C8 heterocyclic group, preferably containing -S0 2 - the C3-C6 heterocyclyl a group, more preferably a C4 and/or C5 heterocyclic group containing -S0 2 -; or a -S0 2 R 9 substituent;
  • R 9 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; or C 3 -C 8 cycloalkyl, preferably C 3 - C6 cycloalkyl, more preferably C3-C4 cycloalkyl, such as cyclopropyl and/or cyclobutyl.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non-pair Isomers, mixtures thereof, and their pharmaceutically acceptable
  • Y is independently selected from C1-C8 alkylene, preferably C1-C6 alkylene, more preferably C3-C5 alkylene, such as propylene, butylene and/or pentylene; or C3-C8 hypocycloal a group, preferably a C3-C6 cycloalkylene group, more preferably a C3-C4 cycloalkylene group, such as a cyclopropylene group and/or a cyclobutylene group;
  • A is independently selected from -CH 2 - or -0-;
  • R 1 is independently selected from hydroxy or C 1 -C 8 alkoxy, preferably C 1 -C 6 alkoxy, more preferably C 1 -C 3 alkoxy, such as methoxy, ethoxy and/or propoxy;
  • R 2 is independently selected from a hydrogen atom or a halogen, preferably a fluorine atom
  • R 3 is independently selected from a hydrogen atom, a halogen, preferably chlorine and/or fluorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
  • R 4 and R 5 are each independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl;
  • R 6 is independently selected from a hydrogen atom, a halogen, preferably fluorine and/or chlorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
  • R 9 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; or C 3 -C 8 cycloalkyl, preferably C 3 - C6 cycloalkyl, more preferably C3-C4 cycloalkyl, such as cyclopropyl and/or cyclobutyl.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same, for use in the preparation of a GPR40 agonist.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, the use of a prodrug thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating a disease of diabetes and metabolic syndrome, wherein said diabetes is II Type 2 diabetes.
  • the invention also relates to a method for treating diseases of diabetes and metabolic syndrome, the method
  • the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof. And a mixture thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, which is a medicament for the treatment of diseases of diabetes and metabolic syndrome a form, a mixture of diastereomers, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein said diabetes is preferably type II diabetes.
  • Another aspect of the invention relates to a method of modulating insulin comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen, a topical A steroid, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
  • a compound of formula (I) or a tautomer thereof a mesogen, a topical A steroid, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof as a medicament for regulating insulin Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof.
  • Alkyl means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n
  • Alkylene means a group formed by the elimination of two hydrogen atoms by a saturated aliphatic hydrocarbon, including linear and branched groups of 1 to 20 carbon atoms.
  • alkylene groups include methylene, ethylene, isopropylidene, butylene, pentylene, hexylene, 1,2-ethylidene, 1,3-propylene, and the like.
  • the alkylene group can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, it can be a 3, 4, 5, or 6-membered ring.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Cycloalkylene means a radical formed by the elimination of two hydrogen atoms from a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon.
  • monocyclic cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexylene, cyclooctylene, 1,2-cyclopropylene , 1,3-cyclopentylene, 1,4-cyclohexylene, and the like.
  • Alkoxy means -0-(alkyl) and -0-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0)m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of - ⁇ - ⁇ -,-0-S- or -SS-, and the remaining ring atoms are carbon.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxamorpholinyl, homopiperazinyl and the like.
  • Haldroxy means an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can be unstable when they do not pay an amino group having a free hydrazine in combination with a saturated carbon atom. of.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity. Method for synthesizing the compound of the present invention
  • the compound of the formula (Ix) can be prepared as shown in the scheme 1, the nitro group, the hydroxy-substituted phenyl compound la and the alkyl acrylate lb are reacted in the presence of a catalyst to obtain a C-c reaction.
  • the phenyl-substituted phenyl compound Ic, the propylene-substituted phenyl compound Ic is reacted with a reducing agent in the presence of a catalyst to obtain a compound Id, and the compound Id and the bromoacetophenone Ie are cyclized in a solvent under basic conditions.
  • the intermediate Ic can be directly reacted with bromoacetophenone Ie to obtain a compound oxime, and the compound Ii undergoes a Miyaura reaction under a catalyst condition to obtain a compound Ij, and the compound Ij is reacted with a reducing agent in a solvent to obtain a compound Ik, a compound Ik and a benzene.
  • the thiol II is subjected to a Suzuki coupling reaction in a solution catalyzed by a catalyst to obtain an ester of the compound (Ix) of the formula, and the obtained product is optionally subjected to one-step hydrolysis to give the corresponding acid or salt.
  • the compound of the formula (Iy) can be prepared as shown in Scheme 2, and the quinoline compound Ila and the alkyl acrylate lb are Heck-reacted in the presence of a catalyst to obtain a propylene-substituted quinoline compound lib, which is in a solvent. Reaction with a reducing agent to obtain compound IIc, compound lie is reacted with an oxidizing agent in a solvent to obtain compound lid, compound lid is reacted with a reagent of 13 ⁇ 4 to obtain compound lie, and compound lie and borate compound Ilf are subjected to Suzuki coupling in solution under catalyst catalysis.
  • reaction gives compound IIg, and the compound Ilg is reacted with trifluoromethanesulfonic anhydride under basic conditions to obtain compound IIh, compound Ilh and borate compound Ih.
  • Suzuki coupling reaction occurs in solution under catalyst catalysis to obtain compound IIi.
  • Compound Ili is reacted with a reducing agent in a solvent to obtain an ester of the compound (Iy) of the formula, and the obtained product is optionally hydrolyzed to obtain a compound (Iy).
  • the acid or salt is optionally hydrolyzed to obtain a compound (Iy).
  • the intermediate lie and the boronic acid ester compound Ilj can be subjected to a Suzuki coupling reaction in a catalyst to obtain a compound IIi, and the compound Ili is reacted with a reducing agent in a solvent to obtain an ester of the compound (Iy) of the formula.
  • the obtained product is optionally hydrolyzed in one step to give an acid or a salt in the compound (Iy).
  • Acids which provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, hydrochloric acid, methanesulfonic acid, tetrabutylammonium chloride.
  • Bases which provide basic conditions include organic bases and inorganic bases including, but not limited to, triethylamine, 4-dimethylaminopyridine, imidazole, indole, indole-diisopropylethylamine, n-butyl Lithium, potassium t-butoxide, tetrabutylammonium bromide, preferably triethylamine; said inorganic bases including but not limited to sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate It is preferably potassium carbonate or cesium carbonate.
  • Catalysts include, but are not limited to, tetra-triphenylphosphine palladium, triphenylphosphine, palladium dichloride, palladium acetate, 1,1,-bis(dibenzylphosphine) dichlorodipentadium iron palladium, tris(dibenzylidene) Acetone) dipalladium, palladium/carbon or Raney nickel.
  • Oxidizing agents include, but are not limited to, tetraoxide, phosphorus oxychloride.
  • Halogenating agents include, but are not limited to, bromine water or phosphine; phosphorus oxychloride is preferred.
  • Reducing agents include, but are not limited to, sodium borohydride, lithium borohydride, borane, zinc powder, iron powder or hydrogen.
  • Solvents used include, but are not limited to: acetic acid, methanol, ethanol, acetone, tert-butanol, diethyl ether, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, toluene, 1,4-dioxane, water or hydrazine, hydrazine- dimethylformamide.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or spectral (MS).
  • NMR nuclear magnetic resonance
  • MS spectral
  • the NMR was measured by Bruker AVANCE-400 or Varian Oxford-300 NMR, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol. (CD 3 OD), the internal standard is tetramethylsilane (TMS), and the chemical shift is given in units of 10 - 6 (ppm).
  • the MS was measured using an Agilent SQD (ESI) spectrometer (manufacturer: Agilent, model: 6110) or Shimadzu SQD (ESI) spectrometer (manufacturer: Shimadzu, model: 2020).
  • ESI Agilent SQD
  • ESI Shimadzu SQD
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 ⁇ , column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm, 5 ⁇ column;).
  • the thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5mm. silicone board.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Beijing Coupling Companies such as chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen gas ball of about 1 L volume.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using Beijing Jiawei Kechuang Technology Co., Ltd. GCD-500G high purity hydrogen gas generator and BLT-2000 medium pressure hydrogenation instrument.
  • the hydrogenation reaction is usually carried out by vacuuming, charging with hydrogen, and repeating the reaction three times.
  • the microwave reaction was carried out using a CEM Discover-SP type microwave reactor.
  • reaction temperature is room temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, volume ratio of solvent The adjustment is made according to the polarity of the compound.
  • the system of the eluent for column chromatography and the system for the developer of the thin layer chromatography using the purified compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, Triethylamine is adjusted with an acidic or alkaline reagent or the like.
  • a 250 mL dry single-mouth bottle was weighed into a quinoline compound la (500 mg, 2.2 mmol, prepared by the known method "WO2008051805", added with dichloromethane (50 mL), and cooled to 0 in an ice water bath. C, then m-chloroperoxybenzoic acid (751 mg, 4.4 mmol) was added portionwise. After stirring for 1 hour at 0 ° C, the mixture was allowed to naturally warm to room temperature and stirring was continued, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with aqueous sodium sulphate and extracted with dichloromethane (100 mL ⁇ 3).
  • 2 ',6'-dimethylbiphenyl-3-phenol le (1.2 g, 6 mmol) was weighed into a 100 mL dry single-mouth bottle, and dichloromethane (20 mL) and diisopropylethylamine (1.5 g, 12mmol). Trifluoromethane anhydride (2.5 g, 9 mmol) was then slowly added while cooling in an ice water bath, which was naturally returned to room temperature and stirring was continued, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with saturated sodium bicarbonate (15 mL).
  • 2',6'-dimethylbiphenyl-3-yltrifluoromethanesulfonate is weighed into a 100 mL dry three-necked bottle.
  • reaction system was replaced with a nitrogen atmosphere, hydrazine, ⁇ '-dimethylformamide (6 mL) was added, and then the reaction was stirred at 100 ° C, and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, the reaction system was diluted with 100 mL of water, and extracted with ethyl acetate (15 mL ⁇ 3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent.
  • reaction system was replaced with a nitrogen atmosphere, toluene (10 mL), ethanol (5 mL) and water (2.5 mL) were added, and then the reaction was stirred at 80 ° C, and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, the reaction system was diluted with 30 mL of water, and extracted with ethyl acetate (40 mL ⁇ 3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent.
  • EtOAc EtOAc
  • EtOAc HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Example 1 The synthesis of lg in Example 1 was carried out using the compound 6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate (240 mg, 0.53 mmol). The method was synthesized to give the title product 4,4,5,5-tetramethyl-2-(6'-methyl-4'-(3-methylsulfonyl)propoxy)biphenyl-3-yl-1 , 3,2-dioxaborane 6d (141 mg, colorless oily liquid), yield: 62%.
  • 2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate utilizes 2',6'-dimethyl-4 '-(3-(Methanesulfonyl)propoxy)biphenyl-3-phenol 8a (0.5 g 1.5 mmol) was used as a starting material, and the title compound 2',6'-dimethyl -4'-(3-(Methanesulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate 8b (0.7 g, pale yellow oil), yield: 90%. The product was used in the next reaction without purification.
  • 6-bromo-7-fluoroquinoline 8d (3.4 g, 15 mmol, prepared by the known method "WO2008051808"), palladium acetate (363 mg, 1.5 mmol), tri-o-tolylphosphine (912 mg, 3 mmol).
  • the system was replaced with a nitrogen atmosphere, and hydrazine, ⁇ '-dimethylbenzamide (40 mL), ethyl acrylate (3.9 g, 45 mmol) and triethylamine (4.5 g, 45 mmol).
  • the reaction was then stirred at 100 ° C and the reaction was monitored by TLC until the reaction was complete.
  • Methyl (7-fluoroquinolin-6-yl) acrylate 8e (2.3 g, 10 mmol), sodium hydrogencarbonate (2.7 g, 31.9 mmol), and methanol (56 mL) were weighed in a 250 mL single-necked flask. Oxone (12.2 g, 20 mmol), water (22 mL;) was then added with stirring. The system was replaced by a nitrogen atmosphere at 50. The reaction was stirred at C for 24 hours.
  • the system was replaced with a nitrogen atmosphere, dioxane (10 mL) and water (2 mL), then at 85 C.
  • the reaction was stirred, and the reaction was monitored by TLC until the reaction mixture was completed.
  • the mixture was cooled to room temperature.
  • the mixture was diluted with water (20 mL), ethyl acetate (30 mL ⁇ 3), and the organic phase was combined and washed with brine, dried over anhydrous sodium sulfate
  • the desiccant was de-dissolved under reduced pressure, and the residue was purified mjjjjjjjjjj Propyloxy)biphenyl-3-yl)-7-fluoroquinolin-6-yl)methyl acrylate 8h (300 mg, pale yellow oil), yield 56%.
  • 2-Bromo-1-(3-bromophenyl)ethanone 17a (1.53 g, 5.5 mmol, prepared by the known method "Patent WO2013041468”), 3-(3-hydroxy-4-nitrobenzene Methyl acrylate 16c (1.13 g, 5.5 mmol), tetrabutylammonium fluoride (1.59 g, 6.1 mmol) and cesium carbonate (1.99 g, 6.1 mmol) were dissolved in hydrazine, hydrazine, dimethylformamide ( In 30 mL), stir at room temperature until the reaction was completed. After quenching with water, it was extracted with ethyl acetate (20 mL > ⁇ 5).
  • Methyl 3-(5-(2-(3-bromophenyl)-2-oxoethoxy)-2-fluoro-4-nitrophenyl)acrylate 19c (600 mg, 1.4 mmol) in a dry three-neck flask ), dipinocol borate (427 mg, 1.68 mmol), hydrazine, hydrazine-bis(diphenylphosphino)ferrocene palladium dichloride (102 mg, 0.14 mmol) and potassium acetate (412 mg, 4.2 mmol)
  • a mixed solution of 1,4-dioxane (10 mL) was heated to 95 ° C under a nitrogen atmosphere and stirred overnight.
  • Methyl 3-(4-amino-2-fluoro-5-hydroxyphenyl)acrylate Methyl-methyl-3-(2-fluoro-5-hydroxy-4-nitrophenyl) acrylate 19b (700 mg, 2.90 mmol) was dissolved in methanol (10 mL) and Pd/C (70 mg). The reaction system was replaced with a hydrogen balloon to a hydrogen atmosphere (1 atm), and stirred at room temperature overnight. Filtration and concentration of the filtrate gave the title product-methyl 3-(2-fluoro-5-hydroxy-4-aminophenyl) acrylate 20a (500 mg, brown liquid), yield: 57%.
  • the examples 26-28 were synthesized using the appropriate reactants in accordance with the steps of Example 20.
  • the following are the example numbers, structures and characterization data:
  • Test Example 1 Activation efficacy of the compound of the present invention on HEK293/hGPR40 cells The following method was used to test the activation efficacy of the present compound on human GPR40.
  • HEK293/hGPR40 cells were seeded in 384-well cell culture plates (HEK293 cell line stably expressing human GPR40 constructed by lipofection, HEK293/hGPR40 cells for short (HEK293 cells purchased from ATCC, catalog number CRL-1573; human)
  • the source GPR40 ⁇ pellet was extracted from pancreatic cancer cell line BXPC-3 cells, and the density was 8000 cells/well. The cells were cultured overnight at 37 ° C under 5% C0 2 . On the day of the experiment, the culture solution was discarded, and 4 was added per well.
  • Example 23 B Example 24 B Example 25 B Example 26 A Example 27 A Example 28 A
  • a ⁇ 100 nM; B 100 to 500nM; C > 500 nM
  • the compounds of the present invention have significant activation potency against human GPR40.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de cycle benzopipéridine et de cycle benzomorpholine, un procédé de préparation et des applications médicales de ceux-ci. Spécifiquement, l'invention concerne, comme présenté dans la formule (I), de nouveaux dérivés de cycle benzopipéridine et de cycle benzomorpholine, leurs sels pharmaceutiques ou des compositions médicales les contenant, et un procédé de préparation correspondant. L'invention concerne en outre l'application des dérivés de cycle benzopipéridine et de cycle benzomorpholine, de leurs sels pharmaceutiques ou de compositions médicales les contenant dans la préparation d'agents thérapeutiques, en particulier, d'un agoniste de GPR40, et dans la préparation de médicaments permettant de traiter des maladies telles que le diabète et des maladies métaboliques. Les substituants de la formule (I) ont la même définition que dans la description.
PCT/CN2014/083806 2013-08-19 2014-08-06 Composés de cycle benzopipéridine et de cycle benzomorpholine, procédé de préparation et applications médicales de ces composés WO2015024448A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310362120.1 2013-08-19
CN201310362120.1A CN104418801B (zh) 2013-08-19 2013-08-19 苯并哌啶环与苯并吗啉环类化合物、其制法及医药应用

Publications (1)

Publication Number Publication Date
WO2015024448A1 true WO2015024448A1 (fr) 2015-02-26

Family

ID=52483057

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/083806 WO2015024448A1 (fr) 2013-08-19 2014-08-06 Composés de cycle benzopipéridine et de cycle benzomorpholine, procédé de préparation et applications médicales de ces composés

Country Status (2)

Country Link
CN (1) CN104418801B (fr)
WO (1) WO2015024448A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017172505A1 (fr) * 2016-03-29 2017-10-05 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11225471B2 (en) 2017-11-16 2022-01-18 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114163426B (zh) * 2020-09-10 2024-03-19 上海爱博医药科技有限公司 苯并含氧杂环类化合物及其医药应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080971A1 (fr) * 2003-03-11 2004-09-23 Bristol-Myers Squibb Company Derives de tetrahydroquinoline utiles en tant qu'inhibiteurs de serine protease
CN1946666A (zh) * 2004-02-27 2007-04-11 埃姆艮股份有限公司 用于治疗代谢性疾病的化合物、药物组合物和方法
WO2012101068A1 (fr) * 2011-01-26 2012-08-02 F. Hoffmann-La Roche Ag Dérivés inédits de la tétrahydroquinoline

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103030646B (zh) * 2011-09-29 2016-08-24 上海恒瑞医药有限公司 苯并二氧六环类衍生物、其制备方法及其在医药上的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080971A1 (fr) * 2003-03-11 2004-09-23 Bristol-Myers Squibb Company Derives de tetrahydroquinoline utiles en tant qu'inhibiteurs de serine protease
CN1946666A (zh) * 2004-02-27 2007-04-11 埃姆艮股份有限公司 用于治疗代谢性疾病的化合物、药物组合物和方法
WO2012101068A1 (fr) * 2011-01-26 2012-08-02 F. Hoffmann-La Roche Ag Dérivés inédits de la tétrahydroquinoline

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190071412A1 (en) * 2016-03-29 2019-03-07 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US10676458B2 (en) 2016-03-29 2020-06-09 Merch Sharp & Dohne Corp. Rahway Antidiabetic bicyclic compounds
WO2017172505A1 (fr) * 2016-03-29 2017-10-05 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US11225471B2 (en) 2017-11-16 2022-01-18 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

Also Published As

Publication number Publication date
CN104418801B (zh) 2016-10-05
CN104418801A (zh) 2015-03-18

Similar Documents

Publication Publication Date Title
WO2015024448A1 (fr) Composés de cycle benzopipéridine et de cycle benzomorpholine, procédé de préparation et applications médicales de ces composés
CN107573332B (zh) 芳香乙炔或芳香乙烯类化合物、其中间体、制备方法、药物组合物及应用
CN111138301B (zh) 联苯类化合物、其中间体、制备方法、药物组合物及应用
TWI330639B (en) Oxazole compound and pharmaceutical composition
KR102007633B1 (ko) 신규 페닐 프로피온 산 유도체 및 이의 용도
KR102301152B1 (ko) 핵 수용체의 효능제인 아이속사졸 유도체 및 이의 용도
JP2020097526A (ja) 複素環化合物
JP6579549B2 (ja) Ｈｉｖ複製阻害作用を有する３環性複素環誘導体
CZ283993A3 (en) Phenoxy- and phenoxyalkyl piperidines as antiviral active substances
WO2020192650A1 (fr) Procédé de préparation de composé amide et son application dans le domaine de la médecine
KR101592280B1 (ko) Ｃｅｔｐ 억제제로서의 바이아릴 또는 헤테로사이클릭 바이아릴 치환 사이클로헥센 유도체 화합물
KR102603436B1 (ko) 방향족 화합물, 약학적 조성물 및 그 용도
JP2008308496A (ja) 医薬
JP2022510736A (ja) 大環状化合物とその使用
TWI817191B (zh) 新穎聯芳基衍生物及其作為針對二醯基甘油醯基轉移酶２之抑制劑之用途
CN107428682B (zh) 酰胺类衍生物、其制备方法及其在医药上的用途
CN115466243A (zh) 用于tead抑制剂的杂环化合物
JP2015536987A (ja) ジアシルグリセロールアシルトランスフェラーゼ阻害剤としての新規化合物
WO2021228215A1 (fr) COMPOSÉ BIARYLE CAPABLE DE SERVIR DE RÉGULATEUR DE RORγ
CN114195776A (zh) 新型fxr小分子激动剂制备及其用途
RU2798235C9 (ru) Макроциклическое соединение и его применение
WO2008098396A2 (fr) Nouveaux hypocholestérolémiants
CN114456123A (zh) Fxr调节剂及其制备方法和用途
WO2022174796A1 (fr) Composé de pyrimidine utile en tant qu'inhibiteur de wee-1
CN114401935A (zh) 离子通道拮抗剂/阻断剂及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14837462

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14837462

Country of ref document: EP

Kind code of ref document: A1