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WO2016107544A1 - Composé intermédiaire pour la préparation d'un composé pyrrole amide et son procédé de préparation et d'utilisation - Google Patents

Composé intermédiaire pour la préparation d'un composé pyrrole amide et son procédé de préparation et d'utilisation Download PDF

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WO2016107544A1
WO2016107544A1 PCT/CN2015/099387 CN2015099387W WO2016107544A1 WO 2016107544 A1 WO2016107544 A1 WO 2016107544A1 CN 2015099387 W CN2015099387 W CN 2015099387W WO 2016107544 A1 WO2016107544 A1 WO 2016107544A1
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group
compound
solvent
tert
butyryl
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PCT/CN2015/099387
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Chinese (zh)
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李进
李雪明
窦登峰
万金桥
高剑
穆云
李才奎
潘飞
钟国庆
胡晓
刘绍军
吕鹏
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成都先导药物开发有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to an intermediate compound for preparing a pyrrolamide compound and a preparation method and application thereof.
  • Inactivation of genes that control cell growth in the body is a hallmark of tumorigenesis.
  • the epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modification of other components in the chromatin high-level structure. These modifications alter the chromatin configuration, leading to changes in gene transcriptional regulation, and dysregulation of gene transcription. Cell proliferation is abnormal, resulting in tumor production.
  • the more important acetylation site is H3. Lys 9 and Lys 14 , and Lys 5 , Lys 8 , Lys 12 and Lys 16 on H4.
  • the acetylation of HAT causes the amino group of the N-terminal lysine of the histone to be acetylated, and the positive charge on the amino group is eliminated.
  • the negative charge carried by the DNA molecule itself facilitates the unfolding of the DNA conformation, and the structure of the nucleosome becomes slack. Conducive to the contact of transcription factors and co-transcriptional activators with DNA molecules, histone acetylation can activate the transcriptional expression of specific genes.
  • histone deacetylation is not conducive to the expression of specific genes (eg, Rb, p21, p27).
  • the acetylation and deacetylation of histones becomes a switch for specific gene expression (Thiagalingam S, Cheng KH, Lee HJ, et al. Histone deacetylases: unique players in shaping the epigenetic histone code [J]. Ann NY Acad Sci, 2003, 983:84-100).
  • Histone acetylation is regulated by a pair of functionally antagonistic protease histone acetyltransferases (HATs) and histone deacetylases (HDACs). In normal cells, this pair of enzymes is in a state of dynamic equilibrium. In general, increased levels of histone acetylation are associated with increased transcriptional activity, while low levels of acetylation are associated with inhibition of gene expression (Forsberg EC, Bresnick EH. Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world [ J]. Bioessays, 2001, 23(9): 820-830).
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • HDAC histone deacetylase inhibitors
  • HDAC inhibitors inhibit HDAC enzyme activity by inhibiting HDAC, blocking gene expression inhibition due to HDAC recruitment dysfunction, and altering chromatin structure by altering the degree of histone acetylation, thereby regulating genes Expression for the treatment of cancer. It treats the growth arrest, differentiation or apoptosis of tumor cells
  • HDAC inhibitors are tumor-specific and have cytotoxic effects on both proliferating and resting variant cells, whereas normal cells are more than 10 times more tolerant and do not cause normal cell growth arrest and apoptosis.
  • the clinical dose of HDAC inhibitors is much lower than the maximum tolerated dose of the human body, and the toxicity to the body is low.
  • the development and utilization of HDAC inhibitors has become a new hot spot in cancer therapy.
  • HDAC inhibitors that have been researched and developed can be divided into five categories: (1) hydroxamic acid compounds, functional groups are hydroxamic acid, and representatives are TSA, SAHA (Curtin ML, Garland RB, Heyman HR, et A1.Succinimide hydroxamic acids as potent inhibitors of histone deacetylase [J]. Bioorg Med Chem Lett, 2002, 12(20): 2919-2923), LAQ824 (Atadja P, Hsu M, Kwon P, et a1.
  • Chinese Patent No. WO 103420917 A discloses a benzamide compound having a fused ring structure, as shown in Formula A, for histone deacetylase inhibitory activity and in treating malignant tumors and diseases related to differentiation and proliferation.
  • Chinese Patent CN 103288728 A discloses a naphthylcarboxamide derivative, as shown in Formula B, which is effective for treating some diseases caused by abnormality of protein kinase regulation;
  • Chinese Patent CN 103539695 A discloses a substituted diphenyl ether.
  • a histone deacetylase inhibitor as shown in Formula C
  • Chinese Patent CN 103467359 A discloses a cinnamamide-containing histone deacetylase inhibitor containing hydrazine, as shown in Formula D
  • Chinese Patent CN 102659630 A discloses a hydroxamic acid compound as shown in Formula E.
  • Chinese patent CN 102786458 A discloses a pyrrolecarboxamide derivative, as shown in Formula F, for use as an anti-malignant drug, particularly for the preparation of a medicament for the treatment of breast cancer, lung cancer and gastric cancer.
  • R 1 , R 2 , R 3 , R 4 are: a C1-C6 straight or branched alkyl group, a C3-C6 cycloalkyl group;
  • R 5 and R 6 are simultaneously or respectively: hydrogen, C1-C6 alkyl; hydroxy, halogen, C1-C4 alkoxy, nitrate-substituted C1-C6 alkyl.
  • the SAHA developed by Merck is a listed histone deacetylase inhibitor, which is limited to the treatment of cutaneous T-cell lymphoma, and is not effective for many other cancers.
  • Other HDAC inhibitors developed have certain problems in anticancer activity, toxic side effects, and subtype selectivity. Therefore, the development of a novel compound having histone deacetylase inhibitory activity has important social and economic significance.
  • the invention provides an intermediate compound for preparing a pyrrolamide compound, as shown in formula I:
  • R 1 , R 2 , R 3 , R 4 are respectively or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, sulfonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , C 1 ⁇ C 6 aminoalkyl of, C 2 ⁇ C 6 amide group is, C 2 ⁇ C 6 aminoacyl, the heterocyclic group of C 3 ⁇ C 6, heterocycloalkenyl of C 3 ⁇ C 6, Phenoxy, phenyl or substituted phenyl.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 2 -C 6 ammonia
  • R 6 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 2 -C 6 ammonia
  • R 7 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 1 -C 6 amino Alkyl group, C 2 -C 6 aminoacyl group, C 3 -C 6 heterocyclic group, C 3 -C 6 heterocycloalkenyl group, phenoxy group, phenyl group, substituted phenyl group, piperazinyl group or substituted group Piperazinyl;
  • R 8 and R 9 are each independently or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 2 -C 6 amide group, C 2 -C 6 aminoacyl group, C 3 -C 6 heterocyclic group, C 3 -C 6 heterocycloalkenyl group, phenoxy group, phenyl group, substituted phenyl group , piperazinyl or substituted piperazinyl.
  • R 1 , R 2 , and R 3 are respectively or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, pentyl, hexane, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentanoxy, Hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutylalkyl, aminopentyl, aminohexane, carboxamide, acetylamino, n-propionyl, isopropylamide, positive Butyramide, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetyl,
  • R 5 is selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pen
  • R 6 is selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pen
  • n 1 or 2;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, Aminoethyl, aminopropyl, aminobutylalkyl, aminopentyl, aminohexane, carboxamido, acetylamino, n-propionylamino, isopropylamide, n-butyryl, isobutyryl, Tert-butylamide, pentanoamide, hexane amide, methyl, acetyl, n
  • R 8 and R 9 are respectively or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , pentyl, hexane, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentaneoxy, hexaneoxy Base, aminomethyl, aminoethyl, aminopropyl, aminobutylalkyl, aminopentyl, aminohexane, carboxamide, acetylamino, n-propionyl, isopropylamide, n-butyryl , isobutyryl amide, tert-butyryl amide, pentane amide, hexane amide, carbamoyl,
  • the invention also provides a preparation method of the intermediate compound represented by the above formula I, and the synthetic route thereof is:
  • Boc represents tert-butoxycarbonyl
  • TFA represents trifluoroacetic acid
  • Fmoc-Cl represents fluorenylmethoxycarbonyl chloride
  • HATU 2-(7-azobenzotriazole)-N,N,N',N' - tetramethylurea hexafluorophosphate
  • DIEA stands for N,N-diisopropylethylamine
  • the molar ratio of the compound IM-4 to lithium hydroxide is 1:1 to 10; the mass ratio of the compound IM-4 to the mixed solvent is 1:7 to 20 g/ml; in the mixed solvent, the ether The volume ratio of solvent to water is 1 to 2:1;
  • N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid of step a is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, and trifluoroacetic acid is added at 20 ° C. After stirring at ⁇ 30°C for 2h ⁇ 12h, the reaction liquid is obtained; the reaction liquid is concentrated to obtain a yellow oil, which is compound IM-3;
  • the mass to volume ratio of the N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid to a halocarbon solvent is 1:5-20 g/ml; the mass ratio of the N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid to trifluoroacetic acid: 1:2 ⁇ 10g / ml;
  • the molar ratio of the compound IM-3, sodium carbonate and hydrazine oxychloride is 1:1 to 5: 0.9 to 1.5; the mass ratio of the compound IM-3 to the mixed solvent is 1:10 to 25 g/ml; The volume ratio of the ether solvent to water in the mixed solvent is 1 to 2:1;
  • the molar ratio of methyl urea hexafluorophosphate to N,N-diisopropylethylamine is 1:1 to 2:1 to 2:2 to 4; the mass volume of the compound IM-2 and the halogen hydrocarbon solvent The ratio is 1:9-20g/ml;
  • the compound IM-1 of the step d, the piperidine and the nitrogen-containing solvent are stirred at 25 ° C to 30 ° C for 4 h to 6 h, diluted with water, extracted with an ester solvent, and the organic phase is combined, and the organic phase is dried and filtered. Concentrated to obtain the compound IM;
  • the mass-to-volume ratio of the compound IM-1 to piperidine is 1:1 to 4 g/ml; and the mass-to-volume ratio of the compound IM-1 to the nitrogen-containing solvent is 1:5 to 20 g/ml.
  • the molar ratio of the compound IM-4 to lithium hydroxide is 1:4.5 to 5; the mass ratio of the compound IM-4 to the mixed solvent is 1:10 to 12 g/ml; in the mixed solvent, the ether The volume ratio of solvent to water is 2:1;
  • N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid of step a is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h. After that, the reaction liquid is obtained; the reaction liquid is concentrated to obtain a yellow oil, which is the compound IM-3;
  • the molar ratio of the compound IM-3, sodium carbonate and decyloxycarbonyl chloride is 1:3:1; the compound IM-3 is mixed with The mass to volume ratio of the solvent is 1:20g / ml; in the mixed solvent, the volume ratio of the ether solvent to water is 5:3;
  • the compound IM-2, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(7-azobenzotriazole)-N,N,N',N'-four The molar ratio of methyl urea hexafluorophosphate to N,N-diisopropylethylamine is 1:1.1:1.2:3; the mass to volume ratio of the compound IM-2 to the halocarbon solvent is 1:9 ⁇ 10g/ml;
  • the mass-to-volume ratio of the compound IM-1 to piperidine was 1:2 g/ml; the mass-to-volume ratio of the compound IM-1 to the nitrogen-containing solvent was 1:10 g/ml.
  • the ether solvent is any one or more of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and dibutyl ether;
  • the halogen hydrocarbon solvent is dichloromethane. Any one or more of ethyl chloride, dichloroethane, chloroform, and carbon tetrachloride;
  • the ester solvent is any one or more of ethyl acetate and ethyl formate;
  • the nitrogen-containing solvent is any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and pyridine.
  • the invention also provides another preparation method of the intermediate compound represented by the above formula I, the synthetic route thereof is:
  • R 5 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 2 -C 6 ammonia
  • R 6 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 2 -C 6 ammonia
  • R 7 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 1 -C 6 amino Alkyl group, C 2 -C 6 aminoacyl group, C 3 -C 6 heterocyclic group, C 3 -C 6 heterocycloalkenyl group, phenoxy group, phenyl group, substituted phenyl group, piperazinyl group or substituted group Piperazinyl;
  • R 8 and R 9 are each independently or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 2 -C 6 amide group, C 2 -C 6 aminoacyl group, C 3 -C 6 heterocyclic group, C 3 -C 6 heterocycloalkenyl group, phenoxy group, phenyl group, substituted phenyl group , piperazinyl or substituted piperazinyl;
  • R 10 is selected from halogen
  • R 5 is selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pen
  • R 6 is selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, carboxamide, Acetylamino, n-propionamido, isopropylamide, n-butyryl, isobutyryl, t-butyryl, pentane amide, hexane amide, carbamoyl, acetylyl, n-alanyl , isopropylamino, n-butyryl, isobutyryl, tert-butyryl, pen
  • n 1 or 2;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentylene, hexyl Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, Aminoethyl, aminopropyl, aminobutylalkyl, aminopentyl, aminohexane, carboxamido, acetylamino, n-propionylamino, isopropylamide, n-butyryl, isobutyryl, Tert-butylamide, pentanoamide, hexane amide, methyl, acetyl, n
  • R 8 and R 9 are respectively or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , pentyl, hexane, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentaneoxy, hexaneoxy Base, aminomethyl, aminoethyl, aminopropyl, aminobutylalkyl, aminopentyl, aminohexane, carboxamide, acetylamino, n-propionyl, isopropylamide, n-butyryl , isobutyryl amide, tert-butyryl amide, pentane amide, hexane amide, carbamoyl,
  • R 10 is selected from the group consisting of fluorine, chlorine, bromine or iodine.
  • the halogen hydrocarbon solvent is any one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform, and carbon tetrachloride.
  • the invention also provides a method for preparing a pyrrole amide compound by using the intermediate compound of the formula I, the synthetic route of which is:
  • R 5 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 2 -C 6 ammonia
  • R 6 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 2 -C 6 ammonia
  • R 7 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 amide, C 1 -C 6 amino Alkyl group, C 2 -C 6 aminoacyl group, C 3 -C 6 heterocyclic group, C 3 -C 6 heterocycloalkenyl group, phenoxy group, phenyl group, substituted phenyl group, piperazinyl group or substituted group Piperazinyl;
  • R 8 and R 9 are each independently or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 2 -C 6 amide group, C 2 -C 6 aminoacyl group, C 3 -C 6 heterocyclic group, C 3 -C 6 heterocycloalkenyl group, phenoxy group, phenyl group, substituted phenyl group , piperazinyl or substituted piperazinyl;
  • the intermediate compound TM-1 (a) or TM-1 (b) or TM-1 (c) is prepared according to any one of claims 8 to 12;
  • the compound TM-1 (a) of the step i is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C to 30 ° C for 1 h to 12 h, and then the solvent is removed.
  • the crude product is purified by preparative high performance liquid chromatography to obtain the compound TM (a); the mass ratio of the compound TM-1 (a) to the halocarbon solvent is 1:50-100 g/ml; the compound The mass to volume ratio of TM-1 (a) to trifluoroacetic acid is 1:10 to 50 g/ml;
  • the compound TM-1 (b) of the step i is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C to 30 ° C for 1 h to 12 h, and then the solvent is removed to obtain a crude product;
  • the crude product is purified by preparative high performance liquid chromatography to obtain a compound TM (b); the mass ratio of the compound TM-1 (b) to the halocarbon solvent is 1:50 to 100 g/ml; the compound TM- The mass to volume ratio of 1(b) to trifluoroacetic acid is 1:10 to 50 g/ml;
  • the compound TM-1 (c) of the step i is dissolved in a halogen hydrocarbon solvent at 0 ° C to 5 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C to 30 ° C for 1 h to 12 h, and then the solvent is removed to obtain a crude product;
  • the crude product is purified by preparative high performance liquid chromatography to obtain the compound TM (c); the mass ratio of the compound TM-1 (c) to the halocarbon solvent is 1:50 to 100 g/ml; the compound TM- The mass to volume ratio of 1(c) to trifluoroacetic acid is 1:10 to 50 g/ml.
  • the compound TM-1 (a) of the step i is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h, then the solvent is removed to obtain a crude product; Purification by chromatography to obtain the compound TM (a); the mass ratio of the compound TM-1 (a) to the halocarbon solvent is 1:60-65 g/ml; the compound TM-1(a) and three The mass to volume ratio of fluoroacetic acid is 1:25 g/ml;
  • the compound TM-1 (b) of the step i is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h, and then the solvent is removed to obtain a crude product; the crude product is purified by preparative high performance liquid chromatography. , obtaining a compound TM (b); the mass ratio of the compound TM-1 (b) to the halocarbon solvent is 1:60 to 65 g / ml; the compound The mass to volume ratio of TM-1(b) to trifluoroacetic acid is 1:25 g/ml;
  • the compound TM-1 (c) of the step i is dissolved in a halogen hydrocarbon solvent at 0 ° C, trifluoroacetic acid is added, and the reaction is stirred at 25 ° C for 2 h, then the solvent is removed to obtain a crude product; the crude product is purified by preparative high performance liquid chromatography.
  • the mass ratio of the compound TM-1(c) to the halocarbon solvent is 1:60 to 65 g/ml; the compound TM-1(c) and trifluoroacetic acid
  • the mass to volume ratio is 1:25 g/ml.
  • the halogen hydrocarbon solvent is any one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform, and carbon tetrachloride.
  • the preparation of the pyrrole amide compound by using the compound of the formula I of the invention has the advantages of short process route, simple operation, high production efficiency, low energy consumption, safety and environmental protection, and the oleamide compound having good deacetylase inhibitory activity can be conveniently obtained.
  • Histone deacetylase plays an important role in gene transcription and regulation, signal transduction, growth and development, differentiation and apoptosis, metabolic diseases and tumors. If the histone deacetylase activity is abnormal, it will trigger a series of abnormalities in histone deacetylase activity. These include cell proliferative diseases, autoimmune diseases, inflammation, neurodegenerative diseases, viral diseases (for example, a review of diseases applicable to HDAC6 inhibitors in World Patent WO2011011186).
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (Ca to b) alkyl group indicates any alkyl group having "a" to "b” carbon atoms.
  • (C1-4) alkyl refers to an alkyl group containing from 1 to 4 carbon atoms.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • the invention includes isotopically labeled compounds, which are the same as the compounds listed herein, but wherein one or more of the atoms are replaced by another atom, the atomic
  • the atomic mass or mass number is different from the atomic mass or mass number that is common in nature.
  • Isotopes which may be introduced into the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S.
  • the key intermediates and compounds in the present invention are isolated and purified in a manner common to separation and purification methods in organic chemistry and examples of such methods include filtration, extraction, drying, spin drying, and various types of chromatography. Alternatively, the intermediate can be subjected to the next reaction without purification.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • Boc represents a tert-butoxycarbonyl group
  • TFA represents trifluoroacetic acid
  • Fmoc-Cl represents an anthraceneoxycarbonyl chloride
  • HATU represents 2-(7-azobenzotriazole)-N,N,N',N. '-Tetramethylurea hexafluorophosphate
  • DIEA stands for N,N-diisopropylethylamine
  • DCM stands for dichloromethane.
  • the starting material: 4'-((dimethylamino)methyl))-[1,1'-biphenyl]-4-sulfonyl chloride can be obtained by purchasing a commercially available product, or can be obtained by the following production method:
  • Bromobenzene (1.5 g, 10 mmol) was dissolved in 50 mL of dioxane and 10 mL of water, then sodium carbonate (2.1 g, 20 mmol,) and 4-(N,N-dimethylaminomethyl)benzeneboronic acid were added.
  • Dimethyl butanediol ester hydrochloride (2.6 g, 10 mmol, manufacturer: Belling Technology Co., Ltd.), followed by [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 500mg).
  • the solution was replaced three times with nitrogen and heated to 80 ° C for 6 hours. After completion of the reaction, the reaction mixture was evaporated in vacuo tolulululululu
  • the crude product was purified by column chromatography eluting elut elut elut elut eluting
  • N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (7 g, 36 mmol) was dissolved in 70 mL of dichloromethane, then 30 mL of trifluoroacetic acid was added dropwise and stirred. The mixture was slowly stirred to 25 ° C and the reaction was stirred for 2 h to obtain a reaction mixture. The reaction mixture was concentrated to give a yellow oil, 2,5-dihydro-1H-pyrrole-3-carboxylic acid (4.0 g, 99% yield) .
  • N-Methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (11.0 g, 32.8 mmol) was dissolved in 100 mL of dichloromethane, and then O-(tetrahydro-2H-pyran- 2-yl)hydroxylamine (4.2 g, 36 mmol), HATU (15 g, 39.4 mmol), DIEA (12.8 g, 98.4 mmol; manufacturer: Belling Technology Co., Ltd.), stirring at 25 ° C overnight to obtain a reaction solution; The reaction mixture was diluted with water (50 mL), EtOAc (EtOAc) N-methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (12 g, 48% yield).
  • N-Methoxycarbonyl-2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (10 g, 23 mmol) was dissolved in 100 mL of DMF then 20 mL of piperidine The reaction was stirred at 25 ° C for 4 hours, then diluted with 800 mL of water, extracted with ethyl acetate, and the organic phase was combined. The organic phase was dried, filtered and concentrated to give a white solid 2,5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo)-carboxamide (4.5 g, 92% yield).
  • Examples 1 to 26 show that the preparation of the pyrrole amide compound by the compound of the formula I of the present invention has a short process route, simple operation, high production efficiency, low energy consumption, safety and environmental protection, and the amide compound can be conveniently obtained.
  • the HDA inhibitory activity of the compounds of the invention is tested in a substrate deacetylation assay.
  • HDAC 6 removes the acetyl group on the substrate, allowing the substrate to activate, being able to act on the subsequently added chromogenic solution and releasing the fluorophore, the magnitude of which reflects the activity of HDAC 6.
  • the IC50 detection method for this enzyme is disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative Disease Friedreich's Ataxia: A New Synthetic Route.
  • the total reaction system (100 ⁇ L/well) contained 0.35 ng/ ⁇ L of HDAC 6, 20 ⁇ M substrate and various concentrations of compound.
  • HDAC 3 removes the acetyl group on the substrate, activates the substrate, acts on the chromogenic solution and releases the fluorophore, and the size of the fluorescent signal reflects the activity of HDAC 3.
  • the IC50 detection method for this enzyme is disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative Disease Friedreich's Ataxia: A New Synthetic Route.
  • the inhibition of the compound was determined from the obtained data and plotted against the compound concentration to obtain a concentration response curve, and the IC50 value was fitted according to a four-parameter model.
  • HDAC6 Activity HDAC3
  • HDAC6 Activity HDAC3
  • HDAC6 Activity HDAC3 1 ++ + 15 +++ + 2 +++ + 16 +++ + 3 ++ ++ 17 +++ + 4 +++ ++ 18 ++ + 5 +++ + 19 +++ + 6 +++ ++ 20 ++ +
  • test results indicate that the pyrrolamide compounds 1 to 26 prepared by using the compound of the formula I of the present invention have good deacetylase inhibitory activity and have the potential to prevent and/or treat diseases caused by abnormal histone deacetylase activity.
  • Test Example 2 Cell assay - Cell growth inhibition assay
  • HepG2 cell line, Hep3B cell line, HuH7 cell line and Li7 cell line were purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; DMEM high-sugar medium and MEM medium were purchased from Hyclone; fetal bovine serum was purchased from Gibco; trypsin was purchased From Invitrogen Shanghai; CCK-8 kit was purchased from Biyuntian Biotechnology Research Institute (beyotime); other cell culture dishes and other consumables were purchased from Corning China.
  • HepG2 cells, Hep3B cells, Huh7 cells and Li7 cells in the logarithmic growth phase were digested with trypsin, and the cell suspension was counted as a uniform cell suspension.
  • the cell density was adjusted to 1500 cells/well in a medium containing 10% serum, and re-inoculated into 96 cells.
  • a culture volume of 200 ⁇ L was cultured at 37 ° C in a 5% CO 2 incubator; the culture was carried out for 24 hours and used for the experiment.
  • the cells cultured for 24 hours were taken out from the incubator, and the culture medium in the well plate was aspirated, and 200 ⁇ L of a compound solution prepared in a medium containing 10% fetal bovine serum was added to each well, and each concentration was 5 parallel, and DMSO was set as a negative.
  • Control, CCK-8 detection was carried out by culturing at 37 ° C, 5% CO 2 culture for 72 hours.
  • the cells cultured for 72 hours were taken out from the incubator, the culture medium in the well plate was aspirated, 120 ⁇ L of LCCK-8 working solution was added to each well, and 120 ⁇ L of LCCK-8 working solution was added to the cell-free well plate as a blank control at 37 ° C. 5% CO2
  • the incubator was incubated for 1 hour (this process needs to be protected from light).
  • Tx absorbance measured by CCK-8 after 72 hours of compound action
  • the test results show that the pyrrolamide compounds 1-26 prepared by using the compound of the formula I of the present invention have good inhibitory activities on different liver cancer cells (HepG2, Huh-7, Li-7, Hep3B), and have clinical application prospects.
  • the method for preparing a pyrrole amide compound by using the compound of the formula I of the invention has the advantages of short process, simple operation, high production efficiency, low energy consumption, safety and environmental protection, and convenient obtaining of a deacetylase inhibiting activity.

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

Abstract

Composé intermédiaire représenté par la formule (I) pour la préparation d'un composé pyrrole amide. Le composé pyrrole amide a une bonne activité inhibitrice de l'histone désacétylase. La définition spécifique des groupes dans la formule (I) se trouve dans la description.
PCT/CN2015/099387 2014-12-29 2015-12-29 Composé intermédiaire pour la préparation d'un composé pyrrole amide et son procédé de préparation et d'utilisation WO2016107544A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP3241823A4 (fr) * 2014-12-29 2018-06-20 Hitgen Ltd. Composé pyrrole-amide, procédé de préparation de ce dernier, et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010014054A1 (fr) * 2008-07-28 2010-02-04 The Regents Of The University Of California Inhibiteurs de prényltransférases de protéine
CN102786458A (zh) * 2012-06-04 2012-11-21 天津渤海职业技术学院 吡咯甲酰胺衍生物、其制备方法和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060035884A1 (en) * 2004-05-20 2006-02-16 Elan Pharmaceuticals, Inc. N-cyclic sulfonamido inhibitors of gamma secretase
CN103420917B (zh) * 2012-05-18 2015-08-19 国药一心制药有限公司 含稠环结构的苯甲酰胺类化合物及其作为抗肿瘤药物应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010014054A1 (fr) * 2008-07-28 2010-02-04 The Regents Of The University Of California Inhibiteurs de prényltransférases de protéine
CN102786458A (zh) * 2012-06-04 2012-11-21 天津渤海职业技术学院 吡咯甲酰胺衍生物、其制备方法和用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3241823A4 (fr) * 2014-12-29 2018-06-20 Hitgen Ltd. Composé pyrrole-amide, procédé de préparation de ce dernier, et son utilisation

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