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WO2019029295A1 - Inhibiteur double cible pour hdac et vegfr suivant la structure du pazopanib, son procédé de préparation et son application - Google Patents

Inhibiteur double cible pour hdac et vegfr suivant la structure du pazopanib, son procédé de préparation et son application Download PDF

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WO2019029295A1
WO2019029295A1 PCT/CN2018/093968 CN2018093968W WO2019029295A1 WO 2019029295 A1 WO2019029295 A1 WO 2019029295A1 CN 2018093968 W CN2018093968 W CN 2018093968W WO 2019029295 A1 WO2019029295 A1 WO 2019029295A1
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amino
methyl
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张颖杰
徐文方
臧杰
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Shandong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a HDAC and VEGFR dual target inhibitor based on pazopanib structure and a preparation method and application thereof.
  • Pazopanib is a multi-target receptor tyrosine kinase inhibitor that binds to three subtypes of the vascular endothelial growth factor receptor VEGFR (VEGFR-1, VEGFR-2, VEGFR-3) and its associated receptors.
  • VEGFR-1, VEGFR-2, VEGFR-3 vascular endothelial growth factor receptor
  • VEGFR-3 vascular endothelial growth factor receptor
  • the tyrosine kinases (PDGFR ⁇ , c-Kit, FGF-R1, c-fms) all showed good inhibitory activity (IC 50 : 10, 30, 47, 84, 74, 140, 146 nM) (Harris, pHilip A.etc) .Journal of Medicinal Chemistry 2008, 51, 4632).
  • Pazopanib was approved by the US Food and Drug Administration in October 2009 for the treatment of advanced renal cell carcinoma in patients with previous chemotherapy experience (Bukowski.etc., Nature Reviews Drug Discovery, 2010, 9, 17) In April 2012, it was approved by the FDA for the treatment of advanced soft tissue sarcoma (Wilky, Breelyn A.etc., Current opinion in oncology, 2013, 25, 373). However, in recent years, pazopanib has had a low response rate and drug resistance in clinical application (Gotink K J.etc., Cellular Oncology, 2015, 38, 119). The combination of drugs and the development of multi-target drugs is A strategy to enhance tumor sensitivity to drugs and reduce tumor resistance.
  • Histone deacetylase HDACs are a group of enzymes that regulate histone acetylation levels in vivo. Histone acetylation levels have an important influence on chromatin structure and transcriptional regulation of genes. HDACs mutations and abnormal expression are usually associated with tumors. It is closely related. HDACs inhibitors have been shown to have anti-tumor effects, and five small molecule HDAC inhibitors have been approved for use in the treatment of a variety of hematomas (Li X.etc., Current Drug Targets, 2014, 15, 622). With the clarification of the relationship between HDAC and VEGF/VEGFR signaling pathways, the combination of pazopanib and HDAC inhibitors has attracted the interest of researchers.
  • pazopanib and HDAC inhibitors showed additive or synergistic anti-tumor effects in vitro and in vivo in soft tissue sarcomas, and the combination can reverse the pazopanib-resistant tumor strain. Resistance (Tavallai S.etc., Cancer Biology & Therapy, 2014, 15, 578).
  • HDAC inhibitor AR-42 and pazopanib showed a killing effect on dalafini/tmetinib-resistant melanoma in vitro and in vivo, synergistically and activating multiple signals Path related (Booth L.etc., Oncotarget, 2017, 8, 16367).
  • Multi-target drugs refer to single drug molecules that act on multiple targets at the same time. Multi-target drugs not only have the advantages of combination therapy, but also overcome some shortcomings of the combination drug. The multi-target drug pharmacokinetics is simple, avoids drug-drug interaction, is safer, improves patient compliance, and becomes a hot trend in current anti-tumor drug design. At present, HDAC and VEGFR dual target inhibitors based on pazopanib structure have not been reported in the prior art.
  • the present invention provides HDAC and VEGFR dual target inhibitors based on pazopanib structure, and the present invention also provides a preparation method and use of the above compounds.
  • the present invention comprises a pazopanib structure-based HDAC/VEGFR dual-target inhibitor, a pharmaceutically acceptable salt, solvate or prodrug thereof having the structure represented by the following formula I, II or III:
  • n 0 to 9;
  • n 0 to 7;
  • the present invention comprises a preparation method of HDAC and VEGFR dual target inhibitor based on pazopanib structure, which is one of the following methods:
  • the benzene rings of 4a, 5a, 6a, and 6d are para-substituted, and the benzene rings of 4b, 5b, 6b, and 6e are meta-substituted.
  • Reagents and conditions in the above reaction formula (a) 2, 4-dichloropyrimidine, sodium hydrogencarbonate, absolute ethanol, reflux, 4 h; (b) cesium carbonate, methyl iodide, N, N-dimethylformamide , room temperature, 2 h; (c) isopropanol, concentrated hydrochloric acid, reflux, 4 h; (d) O-benzotriazole-N, N, N', N'-tetramethyl urea tetrafluoroboric acid, triethyl Amine, o-phenylenediamine, N,N-dimethylformamide, 0 ° C - room temperature, overnight; (e) anhydrous methanol, thionyl chloride, reflux, overnight; (f) hydroxylamine hydrochloride, potassium hydroxide, Anhydrous methanol, room temperature, 2 h.
  • the different substituted anilines are: p-aminobenzoic acid, m-aminobenzoic acid or 5-amino-2-methylbenzoic acid.
  • the benzene rings of 4a, 7a, 8a, 9a, 10a are para-substituted, and the benzene rings of 4b, 7b, 8b, 9b, 10b are meta-substituted.
  • Reagents and conditions in the above reaction formula (a) N, O-dimethylhydroxylamine hydrochloride, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethyl Amine, N,N-dimethylformamide, room temperature, overnight; (b) lithium aluminum hydride, tetrahydrofuran, -20 ° C, 4 h; (c) triethyl phosphonoacetate, sodium hydride, tetrahydrofuran, 0 ° C - Room temperature, overnight; (d) Hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2 h.
  • intermediate 4 and amino chain alkyl ester of different chain lengths are subjected to amide condensation reaction to obtain intermediate 11 and intermediate 11 is subjected to aminolysis of ester to obtain final product 13; 11 is hydrolyzed to intermediate 12 under basic conditions of sodium hydroxide, and intermediate 12 is reacted with o-phenylenediamine by amide to give the final product 14.
  • 4a, 11a-11g, 12a-12g, 13a-13g, 14a-14g of the benzene ring are para-substituted, 4b, 11h, 13h of the benzene ring is a meta-substitution, and n is 1-7.
  • Reagents and conditions in the above reaction formula (a) amino chain alkyl ester of different chain length, O-benzotriazole-N, N, N', N'-tetramethyl urea tetrafluoroboric acid, triethyl Amine, N,N-dimethylformamide, room temperature, overnight; (b) Hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2 h; (c) 3M NaOH, methanol, room temperature, 2 h; Phenylenediamine, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine, N,N-dimethylformamide, room temperature, overnight.
  • amino chain alkyl esters of different chain lengths are: glycine methyl ester, methyl 3-aminopropionate, methyl 4-aminobutyrate, methyl 5-aminopentanoate, methyl 6-aminocaproate, Methyl 7-aminoheptanoate or methyl 8-aminooctanoate.
  • the intermediate 12a1g was added to 100 mL of anhydrous N,N-dimethylformamide, and under ice bath, O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoro was added. After 0.89 g of boric acid and 0.45 g of triethylamine, after activation for 30 min, 0.29 g of o-phenylenediamine was added, and the reaction was carried out at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, and N,N-dimethylformamide was removed by washing with water.
  • n 1 to 7.
  • Reagents and conditions in the above reaction (a) different chain length methyl bromide, potassium carbonate, acetone, reflux, overnight; (b) Pd / C, methanol, hydrogen, room temperature, overnight; (c) isopropanol Concentrated hydrochloric acid, refluxed, overnight; (d) Hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2 h.
  • methyl bromides are: methyl 2-bromoacetate, methyl 3-bromopropionate, methyl 4-bromobutyrate, methyl 5-bromopentanoate, 6-bromohexanoic acid Methyl ester, methyl 7-bromoheptanoate or methyl 8-bromooctanoate.
  • the intermediate 16f 1.00g was added to 50mL of methanol, 10% Pd / C 0.1g was added, hydrogen was introduced under normal pressure stirring, and the reaction was carried out at room temperature overnight, filtered, and the filter residue was washed with methanol, and the filtrate and washing liquid were combined and steamed under reduced pressure. In addition to the solvent, 0.79 g of product 17f was obtained as a light brown solid.
  • n 1 to 7.
  • Reagents and conditions for the above reaction (a) p-nitroaniline, isopropanol, concentrated hydrochloric acid, reflux, overnight; (b) Pd / C, methanol, hydrogen, room temperature, overnight; (c) different chain length of alkane Monomethyl acid, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine, N'N-dimethylformamide, room temperature, overnight; d) Hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2 h.
  • the monomethyl adipates of different chain lengths are: monomethyl malonate, monomethyl succinate, monomethyl glutarate, monomethyl adipate, monomethyl pimelate, Monomethyl malonate or monomethyl sebacate.
  • n 1 to 7.
  • Reagents and conditions for the reaction (a) methyl amino alkanoate of different chain length, potassium carbonate, N,N-dimethylformamide, 50 ° C, overnight; (b) Pd / C, hydrogen, methanol, overnight; (c) Concentrated hydrochloric acid, isopropanol, reflux, overnight; (d) Hydroxylamine hydrochloride, potassium hydroxide, anhydrous methanol, room temperature, 2 h.
  • methyl chain amino alkanoates of different chain lengths are: glycine methyl ester, methyl 3-aminopropionate, methyl 4-aminobutyrate, methyl 5-aminopentanoate, methyl 6-aminocaproate, Methyl 7-aminoheptanoate or methyl 8-aminooctanoate.
  • the intermediate 25e was suspended in 70 mL of methanol, and 10% Pd/C 0.1 g was added thereto. Hydrogen was introduced under normal pressure and stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure and the residue was evaporated. Crystallization gave 0.71 g of product 26e as a brown solid.
  • the structural formula of the target compound is as follows:
  • ACHN cells are human renal cell adenocarcinoma cells
  • AGS cells are human gastric adenocarcinoma cells
  • HEL cells are human red leukocyte leukemia cells
  • HeLa cells are human cervical cancer cells
  • HT-1080 cells are human fibrosarcoma cells
  • HT-29 cells are human colon cancer cells, K562.
  • the cells are human chronic myeloid leukemia cells
  • KG1 cells are human acute myeloid leukemia cells
  • MDA-MB-231 is human breast cancer cells
  • MOLT-4 is human acute lymphoblastic leukemia cells
  • PC-3 cells are human prostate cancer cells and HUVEC cells.
  • the present invention also provides the use of a pazopanib-based HDAC and VEGFR dual target inhibitor compound for the preparation of a medicament for preventing or treating a tumor-associated disease.
  • the tumor-related diseases include various types of hematomas and various types of solid tumors.
  • the various types of hematoma include: various types of leukemia, myeloprolifeenoma.
  • leukemia such as severe acute lymphocytic leukemia, acute myeloid leukemia, acute megakaryoblastic leukemia and the like.
  • Myelodysplastic tumors include chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis, and other unclassified bone marrow Hyperplastic tumor.
  • the solid tumor includes: various forms of nasopharyngeal carcinoma, renal cell carcinoma, soft tissue sarcoma, papillary thyroid carcinoma, thymoma, liver cancer, breast cancer, melanoma, prostate cancer, retinoblastoma and the like.
  • a pharmaceutical composition for preventing or treating a tumor-associated disease comprising the pazopanib structure-based HDAC and VEGFR dual target inhibitor of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically A carrier or excipient can be accepted.
  • Figure 1 shows the results of Western Blot experiments of compounds 6d and 13f after HeLa cells treatment for 4 h;
  • FIG. 1 shows that compounds 6d and 13f inhibit the lumen formation of HUVECs
  • Figure 3 shows that the compounds 6d and 13f inhibit the angiogenesis of the rat thoracic aorta
  • Figure 4 is a photo of a nude mouse tumor
  • Example 1 Synthesis of compound 6a-6c, taking 6a as an example.
  • KOH 28.0 g and hydroxylamine hydrochloride 23.53 g were dissolved in 70 mL and 120 mL of anhydrous methanol, respectively, to obtain a solution A and a solution B. Under ice bath, solution A was added dropwise to solution B, and after stirring for 2 hours, the precipitate was filtered off, and the obtained filtrate was a methanol solution of potassium hydroxyamine. 0.50 g of compound 9a was dissolved in 30 mL of potassium hydroxyamine solution, stirred at room temperature for 2 h, then concentrated under reduced pressure to remove most solvent, and the residue was adjusted to pH 5-6 with 1M HCl to precipitate a white solid, which was filtered and dried to give 0.29 g.
  • KOH 28.0 g and hydroxylamine hydrochloride 23.53 g were dissolved in 70 mL and 120 mL of anhydrous methanol, respectively, to obtain a solution A and a solution B. Under ice bath, solution A was added dropwise to solution B, and after stirring for 2 hours, the precipitate was filtered off, and the obtained filtrate was a methanol solution of potassium hydroxyamine.
  • Compound 11a (0.50 g, 1.09 mmol) was dissolved in 30 mL of potassium hydroxyamine solution, stirred at room temperature for 2 h, then concentrated under reduced pressure to remove most solvent. The residue was adjusted to pH 5-6 with 1M HCl.
  • the intermediate 16f 1.00g was added to 50mL of methanol, 10% Pd / C 0.1g was added, hydrogen was introduced under normal pressure stirring, and the reaction was carried out at room temperature overnight, filtered, and the filter residue was washed with methanol, and the filtrate and washing liquid were combined and steamed under reduced pressure. From the solvent, 0.79 g of product 17f was obtained as a light brown solid, yield: 88%; ESI-MS m/z: 251.4 [M+H] +
  • Example 7 Synthesis of compound 23a-23g, taking compound 23f as an example
  • the intermediate 20 1.00g was suspended in 70mL of methanol, 10% Pd / C 0.1g was added, hydrogen was introduced under normal pressure stirring, and the reaction was carried out at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure and the residue was crystallised from ethyl acetate. 0.78 g of product 21 was obtained as a light brown solid, yield: 84%; ESI-MS m/z: 360.4 [M+H] + .
  • Example 8 Synthesis of compound 28a-28g, taking compound 28e as an example
  • the intermediate 25e was suspended in 70 mL of methanol, and 10% of Pd/C 0.1 g was added thereto. Hydrogen was introduced under normal pressure and stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure and the residue was crystallised from ethyl acetate. 0.71 g of product 26e was obtained as a brown solid, yield: 80%; ESI-MS m/z: 237.4 [M+H] + .
  • Example 9 In vitro HDAC inhibitory activity test of a compound
  • HeLa nuclear extract mainly containing HDAC1 and HDAC2
  • HDAC1 and HDAC2 the HDAC enzyme source
  • Representative compounds 10a and 13f of hydroxamic acid are similar to the positive control drug SAHA, and both are broad-spectrum HDAC inhibitors, but compound 13f has better inhibitory activity against HDAC6 than SAHA.
  • Representative compounds of o-phenylenediamines 6d and 14g are similar to the positive control drug MS275, and are all Class I selective HDAC inhibitors.
  • the percent inhibition of VEGFR-2 by all target compounds at a concentration of 0.2 ⁇ M was first determined, and the IC 50 values of in vitro anti-VEGFR-2 of four representative compounds (10a, 13f, 6d, 14g) were further determined.
  • Example 12 Western blotting of representative compounds
  • Compound 6d can significantly increase the level of acetylated histone H4 (Ac-HH4) at 1 ⁇ M, and its activity is equivalent to that of MS275, but compound 6d can not increase the level of acetylated tubulin (Ac-tubulin), indicating that compound 6d is A Class I HDAC selective inhibitor.
  • Compound 13f significantly increased the level of acetylated tubulin (Ac-tubulin) at 100 nM, and its activity was better than that of TubA and SAHA; 13f also increased the level of acetylated histone H4 (Ac-HH4), indicating that compound 13f is a broad spectrum. HDAC inhibitor.
  • Example 13 In vitro anti-tumor cell proliferation activity of representative compounds
  • MS275 is comparable to anti-tumor cell proliferation activity.
  • Example 14 Representative Compound Inhibits Vascular Cavity Experiment of Human Umbilical Vein Endothelial Cells

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Abstract

L'invention concerne un inhibiteur double cible pour HDAC et VEGFR suivant la structure du pazopanib, son procédé de préparation et son application. Ledit composé adopte la structure de la formule I, II ou III. La présente invention concerne également un procédé de préparation de ce type de composé et son application dans la préparation ou la prévention de maladies oncologiques.
PCT/CN2018/093968 2017-08-10 2018-07-02 Inhibiteur double cible pour hdac et vegfr suivant la structure du pazopanib, son procédé de préparation et son application Ceased WO2019029295A1 (fr)

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CN201710677980.2A CN107619407B (zh) 2017-08-10 2017-08-10 基于帕唑帕尼结构的hdac和vegfr双靶点抑制剂及其制备方法和应用
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CN116987066B (zh) * 2023-06-20 2025-07-25 四川大学 一种嘧啶类化合物及其制备方法和应用
CN117024355B (zh) * 2023-07-20 2025-11-07 天津市肿瘤医院（天津医科大学肿瘤医院） 一种肿瘤细胞抑制剂及其制备方法和应用
CN119306700A (zh) * 2024-08-28 2025-01-14 山东大学 Dnmt1-hdac双靶点抑制剂及其制备方法和应用

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WO2005105094A2 (fr) * 2004-04-16 2005-11-10 Smithkline Beecham Corporation Methode de traitement du cancer
US20100291025A1 (en) * 2009-04-13 2010-11-18 Auspex Pharmaceuticals, Inc. Indazole inhibitors of tyrosine kinase
CN102060848A (zh) * 2010-12-09 2011-05-18 天津药物研究院 芳香胺取代的嘧啶衍生物的制备及用途
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