WO2015139656A1 - Composé pour le traitement de tumeurs et son utilisation - Google Patents

Composé pour le traitement de tumeurs et son utilisation Download PDF

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Publication number
WO2015139656A1
WO2015139656A1 PCT/CN2015/074698 CN2015074698W WO2015139656A1 WO 2015139656 A1 WO2015139656 A1 WO 2015139656A1 CN 2015074698 W CN2015074698 W CN 2015074698W WO 2015139656 A1 WO2015139656 A1 WO 2015139656A1
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WO
WIPO (PCT)
Prior art keywords
compound
cancer
formula
deuterated
compound according
Prior art date
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PCT/CN2015/074698
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English (en)
Chinese (zh)
Inventor
樊磊
胥珂馨
龚瑜
陈元伟
Original Assignee
成都海创药业有限公司
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Publication of WO2015139656A1 publication Critical patent/WO2015139656A1/fr

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Classifications

    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to a compound for treating a tumor and uses thereof.
  • PARP Poly ADP-ribose polymerase
  • PARP inhibitors are not only sensitizers for chemoradiotherapy, but also Breast cancers with BRCA1 and BRCA2 mutations can be used alone to selectively kill cancer cells with defective DNA repair.
  • Veliparib is a new type of benzimidazole compound with high selective inhibition of PARP.
  • the in vitro and in vivo experiments show that this product has a significant inhibitory effect on PARP activity. Significant effects have been achieved in the treatment of metastatic breast cancer, colon cancer, metastatic melanoma and brain tumors.
  • the research on Veliparib is mainly focused on itself, such as preparation process research (for example, Lu Tianxiang, etc., synthesis process improvement of PARP inhibitor veliparib, Chinese Journal of Medicinal Chemistry, 2013, 23(6), 476-479) and Clinical drug research (for example, WO2013173428A1; Kim A.
  • Veliparib analogues there is still a lack of research into the study of Veliparib analogues. Therefore, based on the structure of Veliparib, it is particularly important to develop a new drug that can effectively treat cancer.
  • the present invention provides a compound shown below or a pharmaceutically acceptable salt thereof:
  • R 1 - R 10 are each independently selected from H, hydrazine, C 1 -C 4 alkyl, partially deuterated or fully deuterated C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.
  • R 1 to R 10 are each independently selected from the group consisting of H, hydrazine, C 1 -C 4 alkyl, partially deuterated or fully deuterated C 1 -C 4 alkyl.
  • the C 1 -C 4 alkyl group is selected from the group consisting of methyl and ethyl.
  • At least one of R 1 to R 10 is an anthracene or a deuterated alkyl group.
  • At least one of R 1 to R 3 is hydrazine.
  • R 4 is a methyl group or a deuterated methyl group.
  • At least one of R 5 to R 8 is hydrazine.
  • At least one of R 9 and R 10 is hydrazine.
  • R 1 , R 2 and R 3 are all ⁇ , or all of H, or any two are ⁇ and the other is H;
  • R 4 is a methyl group or a deuterated methyl group
  • R 5 , R 6 , R, 7 and R 8 are all ⁇ or all of H;
  • R 9 and R 10 are all ⁇ or all H.
  • the compound is one of the following compounds:
  • the present invention also provides a process for the preparation of the above compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • the present invention also provides another method of preparing the above compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • R 1 to R 10 is an anthracene or a deuterated alkyl group.
  • HATU is a condensing agent
  • DIPEA is a base
  • N,N-dimethylformamide is used as a solvent, and a condensation reaction is carried out at room temperature
  • the compound of the formula IV, the compound of the formula V The molar ratio of HATU to DIPEA is 1:1.2:1.5:(2-4);
  • R 1 to R 10 is an anthracene or a deuterated alkyl group.
  • the ratio of the compound of the formula IV to N,N-dimethylformamide is 1: (1.38-1.74) mmol/mL.
  • the reaction temperature of the step (2) is 110 ° C, and the reaction time is 1 hour.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of an anticancer drug.
  • the drug is a PARP inhibitor drug.
  • the medicament is a medicament for treating primary breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, gastric cancer, blood cancer, melanoma, solid tumor or intracranial tumor.
  • the medicament is a medicament for treating metastatic breast cancer, colon cancer, melanoma or intracranial tumor.
  • the medicament is a medicament for treating triple-negative breast cancer.
  • the present invention also provides a pharmaceutical composition which is a preparation comprising an effective amount of the above compound or a pharmaceutically acceptable salt thereof.
  • HOAc acetic acid
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (CAS148893-10-1)
  • DIPEA N,N-diisopropylethylamine
  • TEMPO 2,2,6,6-tetramethylpiperidine oxide
  • Boc t-Butyloxy carbonyl tert-butyloxycarbonyl
  • 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” are the acid and/or basic salts of the compounds or their stereoisomers with inorganic and/or organic acids and bases, as well as zwitterionic salts (internal salts). Also included are 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 a compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium.
  • 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.
  • test results show that the compound provided by the invention exhibits excellent pharmacokinetic properties, high drug peak concentration, high drug absorption, long elimination half-life, and is significantly superior to Veliparib, which can improve the efficacy of clinical use and reduce drug administration. Frequency; in addition, it also has good inhibition of PARP kinase use.
  • the compound prepared by the present invention or a pharmaceutically acceptable salt thereof can be used as a PARP inhibitor and has certain antitumor activity, especially for triple negative, primary or metastatic breast cancer, colon cancer, uterine cancer, Pancreatic cancer, lung cancer, gastric cancer, blood cancer, melanoma, solid tumor or intracranial tumor have good therapeutic activity and provide a new choice for clinical use.
  • the raw materials used in the present invention are as follows:
  • the crude product was dissolved in 10 mL of tetrahydrofuran, 6M hydrochloric acid was added, and stirred at room temperature until the end of the reaction. Ethyl acetate was added, washed with 10% of Na 2 CO 3 and the separated organic phase was concentrated under reduced pressure. The crude product was separated and purified by a column to obtain deuterated veliparib.
  • D3300, D3302, D0302, D0300, D3342, D2300, D2302, D2342, D4000, D4002, D4300, D4302, D4342, D5000, D5002, D5300, D5302, D5342 by using the corresponding deuterated starting materials or intermediates according to the compounds of this example
  • the preparation method of D3000 was synthesized, and the results were as follows:
  • SD rats Male, weighing 180-220 g.
  • Each test compound was administered by intragastric administration of 5 mg/kg, and the compounds were all prepared in 5% DMSO/5% Tween 80/90% 0.5% CMC-Na in a volume of 10 mL/kg. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h 3 rats at each time point, 0.2 mL of venous blood was taken from the posterior venous plexus of the rat at the above set time point, and EDTA was placed.
  • the compound of the present invention has a higher peak concentration, higher drug absorption, and longer elimination half-life than Veliparib, which can improve the clinical efficacy and reduce the frequency of administration.
  • Test Example 2 In vitro activity test (PARP kinase test)
  • the enzyme activity assay was carried out in a buffer solution containing 50 mM Tris (pH 8.0), 1 mM DTT, and 4 mM MgCl 2 .
  • the PARP reaction contained 1.5 ⁇ M [3H]-NAD+ (1.6 ⁇ Ci/mmol), 200 nM biotin histone H1, 200 nM slDNA, and 1 nM PARP-1 or 4 nM PARP-2 enzyme.
  • SPA detection was performed on a 96-well plate to which 100 ⁇ L of the reaction solution was added. 50 ⁇ L of a 2 ⁇ NAD + substrate mixture was added to 50 ⁇ L of a 2 ⁇ enzyme solution mixture containing PARP and DNA, and the reaction was started.
  • the reaction was stopped by the addition of 150 ⁇ L of 1.5 mM benzamide. 170 ⁇ L of the reaction stop solution was transferred to a streptavidin-coated flash coating, incubated for 1 hour, and counted using a microplate scintillation counter. Ki data was determined from the inhibition rate curves of the test compounds at various concentrations.
  • the compound of the present invention has a good inhibitory ability against PARP kinase, wherein compound D3000 is superior to the control drug Veliparib, and has an inhibitory activity of nearly 40%.
  • the compound provided by the invention has high drug peak concentration, high drug absorption and long elimination half-life, and can improve the clinical efficacy and reduce the frequency of administration.
  • a compound prepared by the present invention or A pharmaceutically acceptable salt, which can act as a PARP inhibitor has certain antitumor activity, especially for triple negative, primary or metastatic breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, blood cancer, Melanoma, solid tumor or intracranial tumor has good therapeutic activity and provides a new choice for clinical use.

Abstract

La présente invention concerne un composé servant au traitement de tumeurs et son utilisation, et concerne également un composé tel que représenté dans la formule I ou son sel pharmaceutiquement acceptable. Le composé de l'invention présente une concentration de pic de médicament élevée, une absorption de médicament élevée et une demi-vie d'élimination longue, et peut améliorer l'efficacité du médicament dans une utilisation clinique et réduire la fréquence des doses. Le composé ou son sel pharmaceutiquement acceptable préparé par la présente invention peut agir en tant que médicament inhibiteur de la PARP, présente une certaine activité anti-tumorale, et présente en particulier une bonne activité thérapeutique sur le cancer du sein triple négatif, primaire ou métastatique, le cancer du côlon, le cancer de l'utérus, le cancer du pancréas, le cancer du poumon, le cancer de l'estomac, la leucémie, les mélanomes, les tumeurs solides ou les tumeurs intracrâniennes et propose un nouveau choix de médicament clinique.
PCT/CN2015/074698 2014-03-21 2015-03-20 Composé pour le traitement de tumeurs et son utilisation WO2015139656A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410109653 2014-03-21
CN201410109653.3 2014-03-21

Publications (1)

Publication Number Publication Date
WO2015139656A1 true WO2015139656A1 (fr) 2015-09-24

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CN (1) CN104926793B (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017020869A1 (fr) * 2015-08-06 2017-02-09 苏州晶云药物科技有限公司 Forme cristalline b de 2-[(2r)-2-méthyl-2-pyrrolidinyl]-1h-benzimidazole-7-carboxamide, procédé de préparation et utilisation
US10556887B2 (en) 2017-10-24 2020-02-11 Apotex Inc. Processes for the preparation of Veliparib and intermediates thereof

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106995436A (zh) * 2016-01-25 2017-08-01 重庆医药工业研究院有限责任公司 一种维利帕尼晶型a及其制备方法
CN107200704A (zh) * 2016-03-18 2017-09-26 罗欣生物科技（上海）有限公司 一种维利帕尼的中间体晶体及其制备方法
CN108368059B (zh) * 2016-04-18 2022-02-01 深圳市塔吉瑞生物医药有限公司 一种取代的酞嗪酮化合物及其药物组合物
CN107586315B (zh) * 2016-07-08 2020-03-31 成都海创药业有限公司 一种嵌合分子
CN111471039B (zh) * 2020-05-20 2023-07-25 上海腾卓药业有限责任公司 维利帕尼的制备方法
CN115925617A (zh) * 2022-08-25 2023-04-07 中山大学·深圳 一种氘代钌配合物及其制备方法和在光催化抗肿瘤中的应用
CN116375601B (zh) * 2023-06-05 2023-08-04 成都泰莱康科技有限公司 一种抗黑色素瘤化合物及其制备方法和应用

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CN101155797A (zh) * 2005-04-11 2008-04-02 艾博特公司 在2-位上被一个季碳原子取代的1h-苯并咪唑-4-甲酰胺化合物是有效的parp抑制剂
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WO2014037340A1 (fr) * 2012-09-05 2014-03-13 Bayer Cropscience Ag Utilisation de 2-amidobenzimidazoles, de 2-amidobenzoxazoles et de 2-amidobenzothiazoles substitués ou de leurs sels comme principes actifs contre le stress abiotique des plantes

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PENNING, T.D. ET AL.: "Discovery of the Poly (ADP-ribose) Polymerase (PARP) Inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT 888", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 2, 22 December 2008 (2008-12-22), pages 514 - 523, XP055225513, ISSN: 0022-2623 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017020869A1 (fr) * 2015-08-06 2017-02-09 苏州晶云药物科技有限公司 Forme cristalline b de 2-[(2r)-2-méthyl-2-pyrrolidinyl]-1h-benzimidazole-7-carboxamide, procédé de préparation et utilisation
US10556887B2 (en) 2017-10-24 2020-02-11 Apotex Inc. Processes for the preparation of Veliparib and intermediates thereof

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CN104926793B (zh) 2017-05-24
CN104926793A (zh) 2015-09-23

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