WO2017128036A1 - Inhibiteur de parp-1 à base de quinazolinone et son procédé de préparation, composition pharmaceutique et utilisation associées - Google Patents

Inhibiteur de parp-1 à base de quinazolinone et son procédé de préparation, composition pharmaceutique et utilisation associées Download PDF

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WO2017128036A1
WO2017128036A1 PCT/CN2016/072135 CN2016072135W WO2017128036A1 WO 2017128036 A1 WO2017128036 A1 WO 2017128036A1 CN 2016072135 W CN2016072135 W CN 2016072135W WO 2017128036 A1 WO2017128036 A1 WO 2017128036A1
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group
substituted
methyl
unsubstituted
straight
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PCT/CN2016/072135
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Chinese (zh)
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徐柏玲
陈晓光
姚海平
季鸣
金晶
周洁
王珂
赵大龙
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中国医学科学院药物研究所
北京科莱博医药开发有限责任公司
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Priority to PCT/CN2016/072135 priority Critical patent/WO2017128036A1/fr
Priority to CN201680080100.7A priority patent/CN110088098B/zh
Publication of WO2017128036A1 publication Critical patent/WO2017128036A1/fr

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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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • C07D403/10—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 carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel class of quinazoline-2,4-dione PARP-1 inhibitors, physiologically acceptable salts, and processes for their preparation, pharmaceutical compositions containing said compounds, and said compounds as The drug, in particular, is used as an antitumor drug or as a tumor drug sensitizer in combination with an antitumor drug.
  • PARP Poly(ADP-Ribose) polymerase
  • PARP-1 is one of the important functional proteins in the DNA damage repair pathway, and inhibiting the activity of PARP-1 is one of the potentially promising pathways for the creation of anti-tumor drugs (AméJC et al., Bioessays, 2004, 26, 882-893).
  • chemotherapeutic drugs aim to kill tumor cells by damaging DNA. Tumor cells also initiate repair pathways against different chemotherapeutic drugs, and fight against chemotherapeutic drugs to produce drug resistance.
  • the activation of PARP-1 is one of the important repair pathways. Therefore, inhibition of PARP-1 enzyme activity can resist drug resistance of tumor cells and increase the sensitivity of chemotherapy drugs. Therefore, the combination of PARP-1 inhibitors and cytotoxic chemotherapeutic drugs is a potential tumor treatment strategy and one of the most important reasons for the initial attention of PARP-1 inhibitors (Ellisen LW et al., Cancer Cell, 2011, 19, 165). -167; Tentori L et al., Pharmacol Res, 2005, 52, 25-33).
  • BRCA1 and BRCA2 play an important role in the process of homologous recombination to repair double-strand break DNA.
  • PARP inhibitors can block single-strand break DNA damage repair, and BRCA deficiency causes double-strand break DNA damage repair function. This ultimately leads to tumor cell apoptosis (Drew Y et al., Drug Resist Updat, 2009, 12, 153-156).
  • This mechanism makes BRCA-deficient tumors more sensitive to PARP1 inhibitors. It is based on the above-mentioned "Synthetic lethality" strategy that can be improved
  • the selectivity of PARP-1 inhibitor antitumor drugs to tumor cells reduces the side effects of drugs. (Farmer H et al., Nature, 2005, 434, 917-921; Bryant HE et al., Nature, 2005, 434, 913-917).
  • ABT-888 developed by Abbott is in Phase II/III clinical stage in the treatment of various tumors
  • AG-014699 developed by Pfizer is currently in Phase II/III clinical stage in the treatment of breast cancer and ovarian cancer
  • Merck The company's MK-4827 is currently in Phase I/III clinical trials for the treatment of solid tumors (Anwar M, Aslam HM, Anwar S. PARP inhibitors.
  • Lupo B Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: Old and new paradigms revisited.
  • AZD2281 (Olaparib), developed by AstraZeneca, was launched in December 2014 and became the first anti-tumor drug to be marketed as a PARP-1 inhibitor.
  • This patent design synthesizes a new structure of quinazolinedione-based PARP-1 inhibitors, and some compounds have certain selectivity for PARP-1, which can become highly active and low-toxic anti-tumor drugs, or anti-tumor drugs.
  • Agent This patent aims to find new anti-tumor drugs with anti-tumor activity and improved pharmacokinetic properties or sensitizers for anti-tumor drugs.
  • the technical problem solved by the present invention is to provide a quinazoline-2,4(1H,3H)-dione derivative represented by Formula I, and a stereoisomer and a physiologically acceptable salt thereof, a preparation method thereof, and a medicament Compositions, and their use in the preparation of PARP-1 inhibitors and their potential drugs, in the preparation of anti-tumor drugs or anti-tumor drug sensitizers.
  • the present invention provides the following technical solutions:
  • a first aspect of the present invention provides a quinazolinedione derivative as shown in Formula I, and a stereoisomer or a physiologically acceptable salt thereof:
  • A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , R b 4 , Ra 8 , Rb 5 is independently selected from the group consisting of H, methyl, and ethy
  • stereoisomers resulting from the substitution of A, B, C, D include the (R)-configuration and the (S)-configuration, preferably the (R)-configuration;
  • R A is selected from the group consisting of the following atoms or groups or structural fragments:
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently preferably selected from the group consisting of H, F, Cl, Br and CN.
  • the A, D are independently preferably from H, B, C independently from H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2 ; further, A Preferably, B and D are independently selected from H, C, and are preferably H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2 .
  • Preferred compounds of the invention and stereoisomers or physiologically acceptable salts thereof according to the general formula I of the invention include, but are not limited to, the compounds of the formula (IA):
  • At least one of A, B, C, and D is not hydrogen.
  • A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , R b 4 , Ra 8 Rb 5 is independently selected from the group consisting of H, methyl, and ethyl.
  • stereoisomers resulting from the substitution of A, B, C, D include the (R)-configuration and the (S)-configuration, preferably the (R)-configuration;
  • R A is selected from the group consisting of the following atoms or groups or structural fragments:
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently preferably selected from H, F, Cl, Br and CN.
  • the A, D are independently preferably from H, B, C independently from H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2 ; further, A Preferably, B and D are independently selected from H, C, and are preferably H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2 .
  • Preferred compounds of the invention, and stereoisomers or physiologically acceptable salts thereof, according to the general formula IA of the present invention include, but are not limited to, the compounds of the formula IA-1:
  • At least one of A', B', C', D' is not hydrogen
  • A', B', C', D' are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropene a methyl, substituted C1-3 straight or branched alkyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , wherein said Ra 1 , Ra 2 , Ra 3 and Rb 1 are independently selected from the group consisting of H, methyl, and ethyl.
  • stereoisomers resulting from the substitution of A', B', C', D' include the (R)-configuration and the (S)-configuration, preferably the (R)-configuration;
  • R' A is selected from the group consisting of the following atoms or groups or structural fragments:
  • the propyl group, the propylene propylene group, and the cyclobutyl group; the oxyheterocycloalkyl group and the nitrogen heterocycloalkyl group of the 3-8 membered ring may have one hetero atom or may contain a plurality of hetero atoms at the same time.
  • R' 1 , R' 2 , R' 3 and R' 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • R' 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , CH 2 ORx 9 , CH 2 NRx 10 Ry 6 , C1-C3 linear or branched alkyl, halogen-substituted C1-C3 straight or branched alkyl, C2-4 straight or branched Alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein said Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry 2 , Rx 6 , Ry 3 , Rx
  • R '1, R' 2, R '3, R' 4, R '5 are independently preferably selected from H, F, Cl, Br, CN.
  • the A', D' are independently preferably from H, B', C', independently from H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2
  • A', B', D' are independently preferably selected from H, C', preferably from H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2 .
  • Preferred compounds of the invention and stereoisomers or physiologically acceptable salts thereof according to the general formula I of the invention include, but are not limited to, the compounds of the formula IB:
  • R B is selected from the group consisting of the following atoms or groups or structural fragments:
  • a substituted or unsubstituted C1-6 straight or branched alkyl group a substituted or unsubstituted C2-6 straight or branched alkenyl group, a substituted or unsubstituted C2-6 straight or branched alkynyl group
  • the substituent is selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, an oxetanyl group, a cyclopentyl group, wherein Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently preferably selected from the group consisting of H, F, Cl, Br and CN.
  • Preferred compounds of the invention, and stereoisomers or physiologically acceptable salts thereof, according to the general formula I of the invention include, but are not limited to, the compounds of the formula IC:
  • At least one of A, B, C, and D is not hydrogen.
  • A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , R b 4 , Ra 8 Rb 5 is independently selected from the group consisting of H, methyl, and ethyl.
  • stereoisomers resulting from the substitution of A, B, C, D include the (R)-configuration and the (S)-configuration, preferably the (R)-configuration;
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently preferably selected from H, F, Cl, Br and CN.
  • the A, D are independently preferably from H, B, C independently from H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2 ; further, A Preferably, B and D are independently selected from H, C, and are preferably H, methyl, ethyl, propyl, CH 2 CF 3 , CHF 2 .
  • Preferred compounds of the invention and stereoisomers or physiologically acceptable salts thereof according to the general formula I of the invention include, but are not limited to, the compounds of the formula ID:
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently preferably selected from H, F, Cl, Br and CN.
  • preferred compounds include, but are not limited to:
  • a second aspect of the present invention provides a method for preparing the compound of the first aspect, which comprises the following steps: R 1 -R 4 substituted different quinazolinedione and 3-containing R 5 substituted
  • the methoxycarbonyl bromide undergoes a selective alkylation reaction under the action of HMDS, and after hydrolysis, contains different 3-((2,4-dioxo-3,4-) substituted by R 1 -R 5
  • Dihydroquinazoline-1(2H)-yl)methyl)benzoic acid is then condensed with piperazine or piperidine derivatives to give a partial 1-benzylquinazolinedione PARP-1 inhibitor, this part
  • the compound can be further deprotected, alkylated, acylated, oxidized to obtain another part of the 1-benzylquinazolinedione derivative, and some of the compounds are subjected to 3-((2,4-dioxo-3).
  • Reagents and reaction conditions (a) urea, 140 ° C, 6 h; (b) i) lithium hexamethyldisilazide (HMDS), concentrated sulfuric acid, toluene, reflux, 2 h, ii) substituted 5-(bromo Methyl 2-fluorobenzoate, 145 ° C, 3 h, iii) methanol, hexanes, 70 ° C, 30 min; (c) LiOH, MeOH, H 2 O, THF, 55 ° C, 2 h; (d) 2 -(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBT), diisopropyl Ethylamine (DIEA), DMF (N,N-dimethylformamide), overnight (overnight);
  • HMDS lithium hexamethyldisilazide
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, B, C, D, and X described above are the same as those of the compound of the first aspect of the invention.
  • the compounds of formula I may exist in solvated or unsolvated forms, and crystallization from different solvents may result in different solvates.
  • the pharmaceutically acceptable salts of the formula I include salts of different acids, such as the salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, Tannin, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.
  • the pharmaceutically acceptable salts of formula I also include various alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and organics which provide physiologically acceptable cations. Salts of bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All of these salts within the scope of the invention can be prepared by conventional methods.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable Common carrier.
  • the composition includes at least one compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, an injection, a sustained release preparation, a controlled release preparation, or various microparticle delivery systems.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • auxiliary materials used for the manufacture of tablets, capsules and coating agents are conventional auxiliaries such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils. Such as corn oil, peanut oil, olive oil and so on.
  • auxiliaries such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like may also be present in the formulations containing the compounds of the invention.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low-
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidants of the formulations used to prepare the tablets of the present invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizing agent or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulating agent may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 1 to 500 mg/kg body weight, preferably from 10 to 400 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • a fourth aspect of the present invention provides the use of the compound of the first aspect of the present invention, and a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the preparation of a PARP-1 inhibitor, in the preparation of prophylaxis and/or treatment
  • a medicament for a disease associated with PARP-1 the use thereof in the preparation of an antitumor drug
  • a medicament for the preparation of a tumor associated with a tumor wherein the tumor is selected from the group consisting of melanoma, gastric cancer, lung cancer, and breast.
  • Cancer kidney cancer, liver cancer, oral epithelial cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, glioma.
  • This patent application quinazolinone PARP1 inhibitor has a very strong inhibitory activity, and the PARP1 inhibitory activity reaches a level of 10 -8 to 10 -10 M.
  • Some of the compounds of this patent have certain selectivity for PARP1 compared to PARP2 inhibitory activity. Represented by Examples 10, 35 and 36, it has a very strong antitumor activity in a variety of tumor animal models, and its inhibitory effect on tumors is stronger than that of clinical candidate drugs ABT-888 or AZD-2281, or tumor inhibitory activity. It is equivalent to the clinical candidate drug ABT-888 or AZD-2281.
  • the compound can penetrate the blood-brain barrier and thus can be used for the treatment of brain tumors, and pharmacodynamic experiments show that the compound is effective against temozolomide-resistant brain tumors.
  • Another characteristic of the compound is that the compound has less toxicity and is less effective in reducing the platelet and leukocytes through the nude mouse body weight test and blood system index test; and the pharmacokinetic study shows that the drug concentration in the tumor tissue is high. Further reduce the toxic side effects of the compound.
  • the compounds of the present patent application are potentially highly active, low toxicity anti-tumor drugs.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS). NMR was measured using Varian mercury 300 or Varian mercury 400, solvent for measurement was CDCl3, DMSO-d6, acetone- d6, CD 3 OD, internal standard TMS, chemical shifts are given in ppm as a unit. Mp is the melting point given in ° C and the temperature is not corrected. Silica gel column chromatography generally uses 200 to 300 mesh silica gel as a carrier.
  • NBS N-bromosuccinimide
  • DMAP 4-dimethylaminopyridine
  • AIBN azobisisobutyronitrile
  • Boc tert-butoxycarbonyl
  • HMDS lithium hexamethyldisilazide
  • HBTU O-benzotriazole-tetramethylurea hexafluorophosphate
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • TFA trifluoroacetic acid
  • Anthranilic acid (5g, 36.46mmol) and urea (50g, 83.25mmol) were added to the reaction flask, and the temperature was raised to 150 ° C. After 7 h, the temperature was lowered to 100 ° C, a small amount of water was poured, and the mixture was filtered under reduced pressure. Wash with a small amount of water and methanol, dissolve the filter cake with 1 L of hot sodium hydroxide solution, adjust the pH to 3 with concentrated hydrochloric acid at 0 ° C, vacuum filter under reduced pressure, and wash the filter cake with a small amount of water. 4.5 g of a white solid were obtained in a yield of 76.1%.
  • Methyl 2-fluoro-5methylbenzoate 100 mg, 0.60 mmol
  • NBS 112 mg, 0.63 mmol
  • AIBN 60 mg, 0.36 mmol
  • CCl 4 5 mL
  • N-Boc piperazine (2 g, 10.74 mmol) was added to the reaction flask under ice-cooling with N 2 , and dissolved by adding about 100 mL of DCM, and added dropwise to TEA (1.81 mL, 13.02 mmol), followed by dropwise addition of trifluoroethyl
  • TEA 1.81 mL, 13.02 mmol
  • trifluoroethyl trifluoroethyl
  • the anhydride (1.81 mL, 13.02 mmol) was allowed to react to room temperature overnight, washed with water and silica gel column chromatography.
  • 2,6-Dimethylpiperazine was dissolved in about 20 mL of anhydrous DCM, and an anhydrous DCM solution of Boc anhydride was added dropwise at 0 ° C. The reaction was continued at 0 ° C for 1 h, washed with water, concentrated, and then purified by silica gel column chromatography. Oil, yield 74.8%.
  • the reaction mixture was diluted with DCM (15 mL), and the organic phase was saturated with sodium bicarbonate (10 mL ⁇ 2), saturated ammonium chloride (10 mL ⁇ 2), saturated salt Washed with water (10 mL ⁇ 2), dried over anhydrous magnesium sulfate, EtOAc (EtOAc: EtOAc EtOAc The alkane was recrystallized to give a white solid, 40 mg, yield 62.5%, mp 128-130 °.
  • N-Boc-4 oxopiperidine was added to the reaction flask, and about 5 mL of a 2.08 M HCl solution in dioxane was added, and the mixture was stirred for 5 hr.
  • reaction solution was poured into 100 mL of water and extracted with 100 mL of DCM, and the organic layer was sequentially diluted with 1M HCl (100 mL). Washed with NaCl (100 mL) and water (100 mL).
  • NAD + (5 pmol) prepared in 35 ⁇ l assay buffer, 10 ⁇ l purification buffer, 5 ⁇ l Sheared DNA (1 ⁇ g/ml), plus Add 30 ⁇ l of NAD + (5 pmol), 10 ⁇ l of PARP1 (0.005 Units), 5 ⁇ l of Sheared DNA (1 ⁇ g/ml), 30 ⁇ l of NAD + (5 pmol), 5 ⁇ l of ABT-888, and 10 ⁇ l of PARP1.
  • NAD + 5 pmol
  • assay buffer 10 ⁇ l purification buffer
  • 5 ⁇ l Sheared DNA 1 ⁇ g/ml
  • 10 ⁇ l of PARP2 (0.005 Units)
  • 5 ⁇ l of Sheared DNA 1 ⁇ g/ml
  • 30 ⁇ l of NAD + 5 pmol
  • 5 ⁇ l of AZD-2281 dilution 10 ⁇ l of PARP2 to the positive control wells.
  • PARP inhibitors and BRCA 1/BRCA 2 mutations can cause tumor cell death (especially breast cancer and ovarian cancer) if they act on tumor cells at the same time, and do not affect normal cells.
  • PARP inhibitors are lethal by this synthesis. The principle exerts its anti-tumor effect.
  • the study also found that PARP inhibitors have similar synergistic effects with other gene deletions.
  • Example 10 In BRCA-deficient tumor cells, the proliferation of these cells was effectively inhibited, and IC 50 is shown in Table 2. Example 10 was also effective in inhibiting cell proliferation in some other gene-deficient triple-negative breast cancer cells (Table 3).
  • Example 10 Significant sensitization of temozolomide (TMZ), topotecan (TPT), cisplatin (CisP), doxorubicin (ADM) in MX-1 breast cancer cells (Fig. 1). In other tumor cells, Example 10 also had a good sensitizing effect on temozolomide (Fig. 2).
  • Example 10 overcomes temozolomide resistance and potentiates the effect of temozolomide (Figure 3).
  • Example 35 A significant sensitizing effect on temozolomide (TMZ), topotecan (TPT), cisplatin (CisP), doxorubicin (ADM) in MX-1 breast cancer cells (Fig. 4). In brain tumor cells, Example 35 also had a good sensitizing effect on temozolomide (Fig. 5). In temozolomide-resistant glioma cells, Example 35 overcomes temozolomide resistance and potentiates the effect of temozolomide ( Figure 5).
  • TTZ temozolomide
  • TPT topotecan
  • CisP cisplatin
  • ADM doxorubicin
  • Example 36 has significant sensitizing effects on temozolomide (TMZ), topotecan (TPT), and doxorubicin (ADM) in MX-1 breast cancer cells (Fig. 6). In brain tumor cells, Example 36 also had a good sensitizing effect on temozolomide (Fig. 7). In temozolomide-resistant glioma cells, Example 36 overcomes temozolomide resistance and potentiates the effect of temozolomide ( Figure 7).
  • TTZ temozolomide
  • TPT topotecan
  • ADM doxorubicin
  • Example 10 The antitumor activity of the compound prepared in Example 10 was evaluated using the MX-1 nude mouse xenograft experiment. The method was as follows: 72 female Balb/c nude mice were injected subcutaneously into MX-1 transplanted tumor tissue homogenate to prepare a transplanted tumor model. Six days after modeling, the transplanted tumor volume was 100-300 mm 3 , and the control group and TMZ were randomly grouped.
  • Temozolomide 50 mg/kg
  • ABT-888 25 mg/kg
  • TMZ+ABT-888 25 mg/kg
  • Example 10 25 mg/kg
  • TMZ+ Example 10 (12.5 mg/kg) and TMZ+ examples 10 (25 mg/kg) group.
  • TMZ was administered continuously for 5 days once a day, ABT-888, and Example 10 for 8 consecutive days, once daily.
  • the body weight of the mice was weighed and the tumor volume was measured. The observation was continued after the end of the administration, and the body weight of the mice and the tumor volume were measured.
  • Example 10 During the course of the experiment, the nude mice of Example 10 alone showed no significant decrease in body weight (weight or increase in body weight), and no other adverse reactions occurred (Fig. 9). In Example 10, the number of neutrophils (A), white blood cells (B), and platelets (C) was comparable to that of the unadministered group (Fig. 10). It can be seen that Example 10 has good safety.
  • mice Using MX-1 nude mice xenograft experiments, 42 female Balb/c nude mice were injected subcutaneously into MX-1 transplanted tumor tissue homogenate to prepare a transplanted tumor model. Six days after model establishment, the transplanted tumor volume was 100-300 mm 3 and randomized. Grouped control group, CisPt (cisplatin, 6 mg/kg), Olaparib (25 mg/kg), CisPt+Olaparib (25 mg/kg), Example 10 (25 mg/kg), CisPt+ Example 10 (12.5 mg/kg) And CisPt + Example 10 (25 mg/kg) group. CisPt was administered once a week for Olaparib, Example 10 for 8 consecutive days, once daily.
  • CisPt CisPt was administered once a week for Olaparib, Example 10 for 8 consecutive days, once daily.
  • Example 10 had a sensitizing effect on cisplatin (Fig. 11, Table 5).
  • TMZ Temozolomide
  • Example 10 25 mg/kg
  • TMZ + Example 10 12.5 mg/kg
  • TMZ + Example 10 25 mg/kg
  • Taxol 24 mg/kg
  • TMZ was administered continuously for 5 days, once a day, in Example 10 for 22 days, and in the Example 10 combination group for 14 days, once daily, Taxol was administered every 3 days for 3 times.
  • Example 10 alone has a certain anti-tumor effect on MCF-7 (Fig. 12, Table 6).
  • U251/TMZ nude mice xenografts were used in temozolomide-resistant U251/TMZ nude mice.
  • 54 female Balb/c nude mice were transplanted with U251/TMZ tumors.
  • the transplanted tumor volume was 100-300 mm 3 , TMZ (temozolomide, 50 mg/kg and 75 mg/kg), AZD-2281 (50 mg/kg), TMZ+AZD-2281 (25 mg/kg), TMZ+AZD-2281 (50 mg/kg), Example 10 (50 mg) /kg), TMZ + Example 10 (25 mg/kg) and TMZ + Example 10 (50 mg/kg) groups.
  • TMZ was administered continuously for 5 days once a day, AZD-2281, and Example 10 for 7 days, once daily.
  • the body weight of the mice was weighed and the tumor volume was measured. The observation was continued after the end of the administration, and the body weight of the mice and the tumor volume were measured.
  • the results show that Example 10 has a good sensitizing effect on temozolomide and overcomes the resistance of temozolomide (Fig. 13, Table 7).
  • Examples 35 and 36 were evaluated using the MX-1 nude mouse xenograft experiments.
  • the method is as follows: human breast cancer MX-1 tumor cells are collected under aseptic conditions, and the cell density is adjusted to 1 ⁇ 10 7 cells/ml with sterile physiological saline, 0.2 ml is inoculated into the back of the nude mice, and the tumor grows to a diameter. 1 cm in size, taken out under aseptic conditions, homogenized and evenly inoculated into the back of the nude mice. After the tumor was grown to 100-300 mm3 after 7 days, the animals were randomly divided into groups to start administration (denoted as day 0).
  • temozolomide was continuously administered for 5 days, and the test compound was administered continuously for 6 days in the combined administration group, and the test compound single drug group was continuously administered for 10 days.
  • the body weight was weighed three times a week and the length and width of the tumor were measured with a vernier caliper.
  • the nude control group and each single drug group (except the TMZ group) were sacrificed and sacrificed on the 10th day after administration, and the combined administration group and the TMZ group were administered for 17 days.
  • the nude mice were dislocated and sacrificed, the tumor tissues were dissected, weighed and photographed. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • the experiment was divided into blank control group, TMZ group (50 mg/kg), positive drug Olaparib group (25 mg/kg), Example 35 (25 mg/kg), Example 36 (25 mg/kg), and combined administration of Olaparib (25 mg/kg).
  • +TMZ (50 mg/kg) group Example 35 (12.5 mg/kg) + TMZ (50 mg/kg) group, Example 35 (25 mg/kg) + TMZ (50 mg/kg) group, Example 36 (12.5) Mg/kg) + TMZ (50 mg/kg) group, Example 36 (25 mg/kg) + TMZ (50 mg/kg) group.
  • the combined administration group TMZ was continuously administered for 5 days, and each inhibitor was administered for 6 days, and each group had a remarkable tumor suppressing effect (Fig. 14, Fig. 15). Since the TMZ group had a good anti-tumor effect, the persistence of the sensitization effect of each PARP inhibitor on TMZ was continuously observed after stopping the treatment in each group. Tumor growth curves showed that the sensitization effect of TMZ in Examples 35 and 36 lasted until day 14 (day 9 after TMZ withdrawal), and its sensitization effect was superior to Olaparib (Day 12). Animals were treated on day 17, and the combination of Example 35 and Example 36 had a significant antitumor effect compared to the TMZ group (Fig. 14, Fig. 15), which was superior to the Olaparib coadministration group.
  • Example 35 and Example 36 against human glioma U87MG/Luc was evaluated on a nude mouse orthotopic brain tumor model.
  • METHODS Human glioma tumor cells U87MG/Luc were collected under sterile conditions, and the cell density was adjusted to 2 ⁇ 10 8 cells/ml with sterile saline and placed on ice. After intraperitoneal injection of 50 mg/kg sodium pentobarbital in nude mice, the prone position of the animal was fixed in a mouse brain stereotaxic apparatus.
  • the scalpel cut the scalp of the nude mouse sagitally, and the incision was cleaned by 3% H 2 O 2 to expose the skull. 2mm behind the anterior iliac crest, 1.5mm on the right side, and drilled in the dental drill.
  • the No. 26 microsyringe was injected with 5 ⁇ l of U87-MG tumor solution (about 1 ⁇ 10 6 cells, the needle depth was 3 mm, the needle was withdrawn 0.5 mm, and the injection time was about 5 min). After the needle was stopped for 5 minutes, the needle was slowly pulled and the incision was disinfected. Intraperitoneal injection of 50,000 units of penicillin to fight infection.
  • the in vivo imaging test was performed 4 days after the operation to confirm the tumor formation, and the drug was administered in groups.
  • Oral administration temozolomide was continuously administered for 5 days, and the test compound was administered continuously for 5 days in the combined administration group, and the test compound single drug group was continuously administered for 5 days.
  • Tumor size was determined by small animal nuclear magnetic imaging MRI. The experiment was divided into blank control group, TMZ group (30 mg/kg), TMZ group (50 mg/kg), Example 35 (50 mg/kg), and Example 35 (25 mg/kg) + TMZ (50 mg/kg) group.
  • Example 35 (50 mg/kg) + TMZ (50 mg/kg) group, Example 36 (50 mg/kg), Example 36 (25 mg/kg) + TMZ (50 mg/kg) group, Example 36 (50 mg/kg) +TMZ (50 mg/kg) group.
  • the combined administration group TMZ was administered continuously for 5 days, and each inhibitor was administered continuously for 5 days.
  • Example 10 13 mg/mL DMSO
  • AZD-2281 mother liquor 25 mg/mL DMSO
  • acetonitrile 25 mg/mL DMSO
  • 50 ⁇ L of blank plasma was added to 50 ⁇ L of internal standard (propranolol, 10 ⁇ g/mL) and 50 ⁇ L of different concentrations of Example 10 or AZD-2281 working solution, and then centrifuged (14000 rpm ⁇ 5 min) twice, and the supernatant was taken for 10 ⁇ L.
  • internal standard propranolol, 10 ⁇ g/mL
  • AZD-2281 working solution 50 ⁇ L of different concentrations of Example 10 or AZD-2281 working solution
  • Example 10 A 0.2 mg/mL solution was formulated with a mixed solvent (5% DMSO, 45% PEG, and 50% physiological saline) for intravenous administration.
  • the formulation of the AZD-2281 oral and intravenous drug was the same as in Example 10.
  • Rats were orally administered with blood from the orbital venous plexus at 5, 15, 30, 1, 2, 4, 6, 8, 12, 24 h after oral administration of Example 10 or AZD-2281 (20 mg/kg); Or 2, 5, 15, 30, 1, 1.5, 2, 4, 6, 8, 12 h after AZD-2281 (1 mg/mL), blood was taken from the orbital venous plexus, and 50 ⁇ L of plasma was separated and stored frozen.
  • Plasma pharmacokinetic parameters were calculated using WinNonlin software.
  • Example 10 The plasma pharmacokinetic profile of Example 10 was evaluated and compared to AZD-2281 as shown in Table 9.
  • Rats were orally administered with Example 10 (20 mg/kg).
  • the Cmax of the PEG group was significantly higher than that of the CMC group (362.7 ng/mL vs 6.7 ng/mL), and the AUC was about 4 times that of the CMC group.
  • the bioavailability of the oral administration Example 10 (20 mg/kg) CMC group and PEG group in rats was 1.2% and 4.5%, respectively.
  • Rats were orally administered with AZD-2281 (20 mg/kg), and the Cmax and AUC of the PEG group were approximately twice that of the CMC group.
  • the bioavailability of the oral AZD-2281 (20 mg/kg) CMC group and the PEG group in rats was 3.9% and 9.0%, respectively.
  • Example 10 The mother liquor of Example 10 (DMSO preparation, 13 mg/mL) was diluted with acetonitrile to a concentration of 1, 2.5, 10, 50, 100, 250, 500, 1000 ng/mL working solution.
  • 50 ⁇ L of blank plasma was added to 50 ⁇ L of internal standard (propranolol, 10 ⁇ g/mL) and 50 ⁇ L of working solution of Example 10 in different concentrations. After mixing, centrifuge (14000 rpm ⁇ 5 min) twice, and take 10 ⁇ L of the supernatant for LC/MS/ MS analysis.
  • the solution is for oral and intravenous administration.
  • Example 10 a Beagle dogs were orally administered with blood from the orbital venous plexus at 5, 15, 30, 1, 2, 4, 6, 8, 24 hours after oral administration of Example 10 (20 mg/5 mL/kg). After one week of washing, the lower extremity was intravenously injected with Example 10 ( Blood was taken from the upper extremity vein at 2, 5, 15, 30, 1, 1.5, 2, 4, 8, 12, 24 h after 0.4 mg / 2 mL / kg), and 50 ⁇ L of plasma was separated and stored frozen.
  • Plasma pharmacokinetic parameters were calculated using WinNonlin software.
  • Example 10 The dog peaked at 15-30 min after oral administration of Example 10 (20 mg/kg), and the mean plasma drug peak concentration was 3367.01 ng/mL, and t 1/2 was 2.65 h.
  • the bioavailability of Oral Administration Example 10 was 18.8%, which was higher than that of rats (4.5%).
  • the tumor-bearing (MX-1) nude mice were given a single dose of 25 mg/kg in Example 10, and the tissue distribution was as shown in Table 11.
  • the concentration of Example 10 in the tumor tissue was higher, about 60% of the plasma drug concentration.
  • the compound can Can have better security and better PD / PK correlation.
  • Example 35 The mother liquor of Example 35 and Example 36 (DMSO, 10 mg/mL) was diluted with acetonitrile to a concentration of 2.5, 5, 10, 25, 50, 100, 250, 500, 1000 ng/mL working solution.
  • Rats were divided into two groups of three. Fasted for 12 hours before administration and free to drink water.
  • the test used a continuous blood sampling method. Rats were orally administered with blood from the orbital venous plexus at 5, 15, 30, 1, 2, 4, 6, 8, 12, 24 h after oral administration of Example 35 and Example 36 (20 mg/kg, Tween 10 ⁇ L + CMC). 70 ⁇ L of plasma was frozen.
  • 70 ⁇ L of plasma sample was added with 70 ⁇ L of acetonitrile and 70 ⁇ L of internal standard. After mixing, it was centrifuged twice (14,000 rpm ⁇ 5 min), and 5 ⁇ L of the supernatant was taken for LC/MS/MS analysis.
  • Rats were divided into two groups of three. Fasted for 12 hours before administration and free to drink water. Rats were orally administered with blood and brain tissue at 5, 30, and 15 minutes after oral administration of Example 35 and Example 36 (20 mg/kg, Tween 10 ⁇ L). After washing the tissue with physiological saline, the filter paper was used to absorb water and weighed. A 25% tissue homogenate was prepared by adding physiological saline. 70 ⁇ L of tissue homogenate was taken, 70 ⁇ L of acetonitrile and 70 ⁇ L of internal standard were added, mixed and centrifuged (14,000 rpm ⁇ 5 min) twice, and 5 ⁇ L of the supernatant was taken for LC/MS/MS analysis.
  • Plasma pharmacokinetic parameters were calculated using WinNonlin software.
  • Example 35 and Example 36 The mother liquid (DMSO, 3 mg/mL) of Example 35 and Example 36 was diluted with acetonitrile to a mixed working solution having a concentration of 5, 10, 50, 200, 500, 1000, 1500, 2000 ng/mL.
  • 60 ⁇ L of blank plasma was added to 60 ⁇ L of internal standard (propranolol, 1 ⁇ g/mL) and 60 ⁇ L of mixed test compound in different concentrations. After mixing, centrifuge (14000 rpm ⁇ 5 min) twice, and take 3 ⁇ L of supernatant. LC/MS/MS analysis.
  • Example 35 Three of the Beagle dogs were orally administered to Example 35 for one week after oral administration of Example 36.
  • the dog was orally administered with blood from the upper extremity at 5, 15, 30, 1, 2, 4, 6, 8, 12, 24 h after oral administration of Example 35 or Example 36 (20 mg/5 mL/kg).
  • 60 ⁇ L of plasma was separated and frozen for 15 min.
  • -4h plasma samples were diluted with 15 ⁇ L of 45 ⁇ L of blank plasma and frozen.
  • Plasma pharmacokinetic parameters were calculated using a non-compartmental model.
  • Example 35 and Example 36 After oral administration of Example 35 and Example 36 (20 mg/mL), the dogs peaked at 0.7 h and 2.7 h, respectively, with C max of 6438 ng/mL and 4927 ng/mL, respectively, and t 1/2 was 3.8 h and 3.4 h, respectively. (0-t) were 4.7 h and 4.4 h, respectively, and AUC (0-t) was 34248 h*ng/mL and 320665*ng/mL, respectively.
  • Example 10 The acute toxicity of the single dose oral and intraperitoneal administration of Example 10 was evaluated in Kunming mice. Mice were given a single oral dose of 5 g/kg and an intraperitoneal injection of 500 mg/kg, respectively, and 8 days after the administration, clinical signs and mortality of all animals were observed, and body weights were recorded at designated intervals. The mice were dissected after sacrifice and the organs were observed.
  • mice did not die after oral administration of 5 g/kg for 1, 2, 4, 12, and 24 hours. After 4 and 8 days of administration, the mice showed no abnormal signs and no decrease in body weight. The animals were sacrificed and the organs were observed and observed. No abnormalities were observed.
  • mice did not die after intraperitoneal injection of 500 m/kg for 1, 2, 4, 12, and 24 hours. After 4 and 8 days of administration, the mice showed no abnormal signs and no decrease in body weight. The animals were sacrificed and the organs were observed. No abnormalities were found, and no residual compounds were found in the abdominal cavity.
  • Example 10 did not induce mutations in Salmonella either directly or through metabolic activation when the concentration of Example 10 reached a maximum dissolved concentration of 500 ⁇ g/plate.
  • Example 35 The acute toxicity of a single oral dose of Example 35 was evaluated in Kunming mice. Mice were administered a single dose of each of the different doses of Example 35, observed for 10 days after administration, clinical signs and mortality of all animals were observed, and body weights were recorded at designated intervals. The mice were dissected after sacrifice and the organs were observed.
  • the LD 50 of Example 35 ranged from 3.5 to 5 g/kg.
  • Example 36 The acute toxicity of the single dose oral administration of Example 36 was evaluated in Kunming mice.
  • the mice were administered a single dose of different doses of Example 36, and 10 days after the administration, clinical signs and mortality of all animals were observed, and body weights were recorded at designated intervals.
  • the mice were dissected after sacrifice and the organs were observed.
  • the LD 50 of Example 36 ranges from 1 to 3 g/kg.

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Abstract

La présente invention concerne une nouvelle classe d'inhibiteurs de PARP-1 à base de quinazoline-2,4(1H,3H)-dicétone, et leur procédé de préparation et une composition pharmaceutique et une utilisation associées. En particulier, la présente invention concerne un dérivé de quinazoline-2,4(1H,3H)-dicétone tel que représenté par la formule générale I et un stéréoisomère de celui-ci, des sels pharmaceutiquement acceptables de celui-ci, et son procédé de préparation, une composition comprenant un ou plusieurs de ces composés, et une utilisation de ces composés dans la préparation de médicaments pour la prévention et/ou le traitement de tumeurs.
PCT/CN2016/072135 2016-01-26 2016-01-26 Inhibiteur de parp-1 à base de quinazolinone et son procédé de préparation, composition pharmaceutique et utilisation associées WO2017128036A1 (fr)

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PCT/CN2016/072135 WO2017128036A1 (fr) 2016-01-26 2016-01-26 Inhibiteur de parp-1 à base de quinazolinone et son procédé de préparation, composition pharmaceutique et utilisation associées
CN201680080100.7A CN110088098B (zh) 2016-01-26 2016-01-26 喹唑啉酮类parp-1抑制剂及其制备方法、药物组合物和用途

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CN113929674A (zh) * 2021-11-22 2022-01-14 中国药科大学 含1,4-二氢喹唑啉结构的化合物及其制备方法与应用
CN117871740A (zh) * 2024-03-11 2024-04-12 炉霍雪域俄色有限责任公司 俄色果原浆液相色谱品质检测方法

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CN113288892A (zh) * 2020-02-24 2021-08-24 甫康（上海）健康科技有限责任公司 聚adp核糖聚合酶抑制剂在抗冠状病毒中的应用
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CN117871740B (zh) * 2024-03-11 2024-05-10 炉霍雪域俄色有限责任公司 俄色果原浆液相色谱品质检测方法

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