CN110194762B - Phthalazinone derivatives, preparation method and application thereof - Google Patents

Phthalazinone derivatives, preparation method and application thereof Download PDF

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CN110194762B
CN110194762B CN201810162895.7A CN201810162895A CN110194762B CN 110194762 B CN110194762 B CN 110194762B CN 201810162895 A CN201810162895 A CN 201810162895A CN 110194762 B CN110194762 B CN 110194762B
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CN110194762A (en
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谭村
张小飞
杨春皓
缪泽鸿
宋姗姗
宦霞娟
陈奕
丁健
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Shanghai Institute of Materia Medica of CAS
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    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to phthalazinone derivatives shown as a general formula (I), geometric isomers or pharmaceutically acceptable salts thereof, a preparation method and application in preparation of medicines for preventing or treating diseases related to poly (adenosine diphosphate ribose) polymerase resistance.

Description

Phthalazinone derivatives, preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to phthalazinone derivatives, geometric isomers thereof, pharmaceutically acceptable salts thereof, a preparation method thereof and application thereof in preparing medicaments for preventing or treating diseases related to drug resistance of poly (adenosine diphosphate ribose) polymerase (PARP), such as malignant tumors.
Background
Poly (ADP) -ribosepolymerase (PARP) is a family of enzymes found in the nucleus of most eukaryotic cells. Since the first discovery by Chambon et al in 1963, a total of 17 PARP family members have been discovered so far [ riffleljl, et al, natrevdrug discovery 2012; 11:923-936], wherein 7 PARP enzymes including PARP-1 and PARP-2 were characterized and confirmed. The PARP family is a multifunctional protein post-translational modification enzyme, although the function research on the subtype thereof is continuously expanding, because PARP-1/2 is the most abundant ribozyme in the PARP family, and more than 90 percent of DNA damage depends on PARP-1 repair; among PARP-1 deficient cells, PARP-2 is responsible for DNA damage repair.
Bryant 2005 (Nature 2005; 434: 913-; 434: 917-.
Currently, there is already Olapari from AstraZeneca
Figure BDA0001583549100000011
(2014) Lukapari by Clovis Oncology
Figure BDA0001583549100000012
Nilaparide tosylate (2016. RTM.) from Moshadong
Figure BDA0001583549100000013
Drugs targeting PARP (2017) are successfully marketed in sequence, and meanwhile, many projects targeting PARP are developed in various stages of clinical research.
With the successful marketing of PARP inhibitors, tumor cell lines resistant to the existing inhibitors have emerged clinically. Tumor resistance is a great problem limiting the curative effect of the current cancer chemotherapy drugs; many cancer patients have significant efficacy in the early stages of chemotherapy, but as treatment time increases, the resistance of cancer cells increases, eventually leading to treatment failure. Researches on the drug resistance of PARP inhibitors and tumor cells have been reported, and Norquist et al [ JClin Oncol,2011,29(22):3008-3015] found in clinical researches that 2 of 6 BRCA gene mutation ovarian cancer patients who are resistant to carboplatin and treated by Olaparib show drug resistance; liu et al [ Mol cancer Res,2009,7(10):1686-1692] studies showed that HCT116 colorectal cancer cells treated with temozolomide in combination with ABT-888 also exhibited drug resistance; researchers have also found that continuous administration of the potent PARP-1 inhibitor KU0058948 to CAPAN1 pancreatic cancer cells with mutations in the BRCA2 gene can cause cancer cell resistance, and that CAPAN1 cells that are resistant to cisplatin also develop resistance to the PARP-1 inhibitor AG 14361; in a mouse breast cancer model with BRCA gene mutation and an inactivated cancer suppressor gene p53, Olaparib treatment is given, the growth of breast cancer can be obviously inhibited at the beginning, however, after long-term administration of treatment, the tumor inhibition effect of Olaparib is gradually weakened [ TrendsPharmacolSci,2012,33(1):42-48 ]; sakai et al [ cancer Res,2009,69(16):6381-6386] found that the ovarian cancer cell strain PEO4 with BRCA2 gene mutation is resistant to PARP-1 inhibitor AG 14361; the mechanism of tumor cell resistance to PARP inhibitors varies depending on the type and stage of cancer and the method of treatment [ NatMed,2013,19(11):1381-1388 ].
With the progress of basic research related to the drug resistance of PARP inhibitors, researchers have proposed many strategies to address the problem of PARP inhibition of drug-resistant tumors. The main of these strategies is the use of PARP inhibitors in combination with other therapeutic approaches. Such as: PARP inhibitors are used in combination with the cytotoxic drugs Temozolomide (Temozolomide), Taxanes, Platinum salts (Platinum salts) and Gemcitabine (Gemcitabine), etc.; PARP inhibitors are used in combination with other targeted inhibitors such as EGFR inhibitors, PI3K inhibitors, HDAC inhibitors, IGF-1R inhibitors, VEGFR inhibitors, HSP90 inhibitors, CHK1/2 inhibitors, and the like; PARP inhibitors in combination with immunotherapy and the like [ Critical Reviews in Oncology/Hematology 108(2016) 73-85 ].
However, there is still a need to develop drugs that can solve the problem of PARP inhibitor resistance.
Disclosure of Invention
The invention provides phthalazinone derivatives shown as a general formula I, geometric isomers and pharmaceutically acceptable salts thereof on one hand,
Figure BDA0001583549100000021
wherein:
r is selected from H, C1-C6Alkyl (e.g. methyl or ethyl), C2-C6Alkenyl radical, C2-C6An alkynyl group; preferably H or methyl;
n is an integer of 1-6; for example 2 to 5, preferably 4;
het is selected from substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C6-C12Aryl or substituted or unsubstituted 5-12 membered heteroaryl; the substituted substituent is selected from halogen, nitryl, amino, cyano, hydroxyl and C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, hydroxy C1-C6Alkyl radical, C1-C6Alkylamino, di-C1-C6Alkylamino radical, C1-C6Alkylsulfonamide group, C1-C6Amide group, C1-C6Acyloxy, C1-C6Alkoxycarbonyl, C1-C6An alkylcarbonyl group,Boric acid group, C1-C6Alkyl sulfone group, C1-C6Alkyl sulfoxide group, C1-C6Alkylmercapto, 3-8 membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-8 membered heterocyclyl (e.g., glycidylalkyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), C6-C10One or more of aryl (e.g., phenyl, naphthyl) and 5-10 membered heteroaryl (e.g., furyl, pyrrolyl, oxazolyl, imidazolyl, pyridyl, pyridazinyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl).
In a preferred embodiment of the present invention, the phthalazinone derivative compound includes a phthalazinone derivative represented by formula ii:
Figure BDA0001583549100000031
wherein Het is as defined above.
Preferably, Het in the above general formulae I and II is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted five-membered and six-membered heteroaryl; further preferably selected from the group consisting of substituted or unsubstituted thienyl, substituted or unsubstituted indolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, and substituted or unsubstituted pyrazinyl.
The substituents substituted in the Het definition are preferably selected from halogen, nitro, amino, cyano, hydroxy, C1-C4Alkyl radical, C1-C6Alkoxy, halogen-substituted C1-C4Alkyl, morpholinyl, piperidinyl, pyrrolidinyl, C1-C4One or more of alkylamino groups; or,
Figure BDA0001583549100000032
wherein X is selected from O, N, S;
Y1and Y2Each independently selected from N or C, but not both.
In a preferred embodiment of the invention, said Het is selected from pyridyl, chloropyridyl, indolyl, pyrrolyl, thiazolyl, pyrimidinyl, aminotrifluoromethylpyridyl, azaindolyl, dimethylisoxazolyl, piperidinylpyridyl, morpholinylpyridyl, pyrrolidinopyridyl, diethylaminopyridyl, ethylaminopyridyl, methylaminopyridyl, naphthyl, aminopyridinyl, benzofuranyl; more preferably 4-pyridyl, 2-chloro-5-pyridyl, 3-indolyl, 2-pyrrolyl, 4-thiazolyl, 5-pyrimidyl, 2-amino-6- (trifluoromethyl) -5-pyridyl, 7-azaindolyl, 3, 5-dimethyl-4-isoxazolyl, 2-piperidyl-5-pyridyl, 2-morpholinyl-5-pyridyl, 2-pyrrolidine-5-pyridyl, 2-diethylamino-5-pyridyl, 2-ethylamino-5-pyridyl, 2-methylamino-5-pyridyl, 1-naphthyl, 6-azaindolyl, 2-pyridyl, 5-pyridyl, 2-pyridyl, etc, 2-amino-5-pyridyl, 3-benzofuranyl and 3-pyridyl.
In another preferred embodiment of the present invention, the phthalazinone derivative is selected from the following compounds:
Figure BDA0001583549100000041
Figure BDA0001583549100000051
“C1-C6alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms in the chain, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like.
“C1-C6Alkylamino "refers to an amino group substituted with a straight or branched alkyl group having 1 to 6 carbon atoms in one chain, and includes, without limitation, methylamino, ethylamino, propylamino, isopropylamino, butylamino, and the like.
' di C1-C6Alkylamino "means an amino group substituted on N by two identical or different straight or branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms, for example, N-dimethylamino, N-diethylamino, N-di-N-propylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-butyl-N-methylamino.
“C1-C6The alkylsulfonamide group "means a straight or branched alkylsulfonamide group having 1 to 6 carbon atoms in the alkyl moiety, for example, a methylsulfonamide group, an ethylsulfonamide group, an n-propylsulfonamide group, an isopropylsulfonamide group, an n-butylsulfonamide group, an isobutylsulfonamide group or a tert-butylsulfonamide group.
“C1-C6The amide group "means a straight or branched alkyl amide group having 1 to 6 carbon atoms in the alkyl moiety, for example, a methyl amide group, an ethyl amide group, an n-propyl amide group, an isopropyl amide group, an n-butyl amide group, an isobutyl amide group or a tert-butyl amide group.
“C1-C6Acyloxy "refers to straight or branched chain alkanoyloxy having 1 to 6 carbon atoms in the alkyl moiety, for example, methacryloyloxy, ethylacetoxy, n-propylacyloxy, isopropylacyloxy, n-butylacyloxy, isobutylacyloxy or tert-butylacyloxy.
“C1-C6Alkylcarbonyl "refers to straight or branched chain alkylcarbonyl having 1 to 6 carbon atoms in the alkyl moiety, for example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl or tert-butylcarbonyl.
“C1-C6Alkoxy "refers to straight or branched chain O-alkyl groups containing from 1 to 6 carbon atoms in the alkyl moiety, for example,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
“C1-C6By alkylmercapto "is meant a straight or branched chain S-alkyl group containing from 1 to 6 carbon atoms in the alkyl moiety, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio.
"Borate" means-B (OH)2。
“C1-C6The alkyl sulfone group "means a straight-chain or branched alkyl sulfone group having 1 to 6 carbon atoms in the alkyl moiety, for example, a methyl sulfone group, an ethyl sulfone group, an n-propyl sulfone group, an isopropyl sulfone group, an n-butyl sulfone group, an isobutyl sulfone group or a tert-butyl sulfone group.
“C1-C6The alkyl sulfoxide group "means a linear or branched alkyl sulfoxide group having 1 to 6 carbon atoms in the alkyl moiety, for example, a methyl sulfoxide group, an ethyl sulfoxide group, an n-propyl sulfoxide group, an isopropyl sulfoxide group, an n-butyl sulfoxide group, an isobutyl sulfoxide group or a tert-butyl sulfoxide group.
“C2-C6Alkenyl "refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms containing at least one unsaturated carbon-carbon double bond in the chain, including without limitation ethenyl, propenyl, isopropenyl.
“C2-C6Alkynyl "means a straight or branched chain alkynyl group of 2 to 6 carbon atoms containing at least one unsaturated carbon-carbon triple bond in the chain, including, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl.
"3-8 membered cycloalkyl" refers to a group containing one or more saturated and/or partially saturated rings, all ring-forming atoms being carbon atoms, which includes from 3 to 8 carbon atoms; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptatrienyl, cyclooctyl, indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
"3-8 membered heterocyclyl" means a heterocyclic group containing one or more saturated and/or partially saturated rings, including 3 to 8 ring atoms, wherein one or more ring atoms is selected from nitrogen, oxygen, or a heteroatom of s (o) m (wherein m is an integer from 0 to 2), the remaining ring atoms being carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
"halogen" refers to fluorine, chlorine, bromine and iodine.
“C6-C12Aryl "refers to an aromatic ring group containing 6 to 12 ring atoms, but no hetero atom in the ring atoms, preferably a 6-to 10-membered aryl group (i.e., an aryl group having 6 to 10 carbon atoms), such as phenyl or naphthyl.
"5-12 membered heteroaryl" refers to an aromatic cyclic group containing 5-12 ring atoms and 1-4 heteroatoms in the ring atoms as ring members. The heteroatoms may be selected from nitrogen, oxygen or sulfur. The heteroaryl group may be a monocyclic heteroaryl group having 5 to 7 ring atoms, or a bicyclic heteroaryl group having 7 to 12 ring atoms. The bicyclic heteroaryl group may have one ring as long as it is a heteroaromatic ring, and the other ring may be aromatic or non-aromatic, and may or may not contain a heteroatom. In addition, the bicyclic heteroaryl may be a fused ring structure, a spiro ring structure, or two heterocycles may be directly connected. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, furanyl, thienyl, isoxazolyl, indolyl, and the like.
In a second aspect, the present invention provides a method for preparing the phthalazinone derivatives of the present invention, the method comprising the step of subjecting compound III to condensation reaction with acid IV to obtain a compound represented by general formula I, as shown in the following reaction formula:
Figure BDA0001583549100000071
wherein R, n and Het are as defined above.
The condensation reaction can be carried out in the presence of a base, a condensing agent and a solvent, wherein the solvent is one or a mixture of more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, tetrahydrofuran or 1, 4-dioxane, and is preferably N, N-dimethylformamide; the base can be one or more of triethylamine, N-Diisopropylethylamine (DIEA), triethylene diamine, 1, 8-diazabicycloundeca-7-ene (DBU), potassium carbonate, sodium carbonate or sodium bicarbonate, preferably triethylamine; the condensing agent is one or a mixture of more of O- (benzotriazole-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HBOt) or 1-hydroxy-7-azobenzotriazol (HOAt), and the HBTU is preferred.
The temperature of the condensation reaction can be 0-100 ℃, and room temperature is preferred, wherein the room temperature is 20-30 ℃;
in a preferred embodiment, the compound of formula IV is prepared by a process comprising: subjecting compound V and compound VI to a Wittig reaction to obtain compound VIII, and then subjecting the compound VIII and the compound VI to a hydrolysis reaction to obtain compound IV,
Figure BDA0001583549100000081
wherein,
R1is methyl or ethyl;
het and R are as defined above.
The wittig reaction can be carried out in an organic solvent and is carried out at the temperature of about 60-120 ℃. The hydrolysis reaction may be carried out in the presence of a basic solution.
The organic solvent can be one or a mixture of more selected from toluene, xylene, THF and dioxane;
the alkali solution may be one aqueous solution selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
In a preferred embodiment, the compound of formula III is prepared by a process comprising the steps of: carrying out condensation reaction on a compound shown as a general formula IX and alcohol amine VIII to obtain a compound X; carrying out esterification reaction on the compound X and methylsulfonyl chloride to obtain a compound XI; the compound XI is subjected to substitution reaction in the presence of phthalimide salt, and then is subjected to hydrazinolysis to obtain a compound III, which is shown in the following formula,
Figure BDA0001583549100000082
wherein n is as defined in formula I.
The condensation reaction may be carried out in the presence of a base, a condensation agent and a solvent.
The esterification reaction may be carried out in the presence of a base and a solvent.
The base in the condensation reaction and the esterification reaction is respectively and independently selected from one or more of triethylamine, N-Diisopropylethylamine (DIEA), triethylene diamine, 1, 8-diazabicycloundece-7-ene (DBU), potassium carbonate, sodium carbonate or sodium bicarbonate, and is preferably triethylamine.
The condensing agent is one or a mixture of more of O- (benzotriazole-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HBOt) or 1-hydroxy-7-azobenzotriazol (HOAt), and the HBTU is preferred.
The solvent in the condensation reaction and the esterification reaction is respectively and independently selected from one or a mixture of more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, tetrahydrofuran or 1, 4-dioxane, and is preferably N, N-dimethylformamide.
The temperature of the condensation reaction is 0-100 ℃, and the room temperature is preferably selected, wherein the room temperature is 20-30 ℃;
the phthalimide salt is selected from phthalimide potassium salt or phthalimide sodium salt, and is preferably phthalimide potassium salt.
In a third aspect, the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of one or more selected from the group consisting of the phthalazinone derivatives, geometric isomers thereof, and pharmaceutically acceptable salts thereof as an active ingredient, and a pharmaceutically acceptable carrier.
The phthalazinone derivatives represented by the general formula I, geometric isomers and pharmaceutically acceptable salts thereof can be used as cell poly adenosine diphosphate ribose polymerase (PARP) drug-resistance related inhibitors; can be used for preparing medicines for preventing and/or treating diseases related to the drug resistance of poly (adenosine diphosphate ribose) polymerase (PARP); can be used for preparing medicaments for preventing and/or treating cancers; can also be used for preparing medicaments for preventing and/or treating ischemic diseases; or used for preparing medicines for treating neurodegenerative diseases.
By "therapeutically effective amount" is meant: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Generally, a unit dose of a pharmaceutical composition may contain 1-2000mg of active ingredient, more preferably, 10-200mg of active ingredient. Preferably, the "unit dose" is, for example, a tablet, or a capsule.
The term "pharmaceutically acceptable salt" refers to a salt with an inorganic acid such as phosphoric acid, sulfuric acid, or hydrochloric acid, or an organic acid such as acetic acid, tartaric acid, citric acid, or malic acid, or an acidic amino acid such as aspartic acid or glutamic acid, or a salt with an inorganic base after forming an ester or amide with the above acid, such as sodium, potassium, calcium, aluminum salt, and ammonium salt.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soya oil, sesame oil, peanut oil, olive oil, sesame oil, peanut oil, sesame oil, peanut oil, corn oil, sesame oil, peanut oil, sesame oil, peanut oil, corn oil, sesame oil, corn oilOlive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier
Figure BDA0001583549100000091
Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
The solid dosage forms may also be prepared using coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other therapeutic agents, such as chemotherapeutic agents.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
In a fourth aspect, the invention also provides the use of the phthalazinone derivatives represented by the general formula I, their geometric isomers and pharmaceutically acceptable salts in the preparation of medicaments for preventing or treating diseases associated with poly (adenosine diphosphate ribose) polymerase (PARP) drug resistance.
The diseases related to the drug resistance of poly (adenosine diphosphate ribose) polymerase (PARP) comprise: cancer, various ischemic diseases and neurodegenerative diseases, etc.
The cancer includes, but is not limited to, solid and non-solid tumors, such as breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer, gastric cancer, lung cancer, glioma, recurrent blood cancer, ewing's sarcoma, pancreatic cancer, endometrial cancer, and the like.
The ischemic diseases include, but are not limited to, ischemic cerebrovascular diseases, coronary heart diseases, ischemic spinal cord diseases, mesenteric vascular ischemic diseases, ischemic retinopathy, ischemic enteritis, etc.
The neurodegenerative disease includes but is not limited to Parkinson's disease, Alzheimer's disease, muscular dystrophy and the like.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
In all of the embodiments described herein, the first,1HNMR were recorded by a nuclear magnetic resonance apparatus of the Varian Mercury-300 or Varian Mercury-400 type, chemical shifts being expressed in δ (ppm); mass spectra were recorded on a Finnigan/MAT-95(EI) and Finnigan LCQ/DECAad Micromass Ultra Q-TOF (ESI) type mass spectrometer; the separation of the compound selects 200-300 mesh silica gel of Qingdao ocean chemical industry.
In the invention, the Chinese name table of the reagent represented by the chemical formula or English letter abbreviation is as follows:
EtOH is ethanol; DCM dichloromethane; MeOH is methanol; NaOH is sodium hydroxide; DMF is N, N-dimethylformamide; THF is tetrahydrofuran; et (Et)3N is triethylamine; MsCl is methanesulfonyl chloride and DBU is 1, 8-diazabicycloundec-7-ene.
Preparation of intermediates
A) Preparation method of key intermediate compound III-1
Route 2
Figure BDA0001583549100000111
Step 1 preparation of Compound X-1
Compound IX-1(5.96g,20.0mmol) and compound 4(3.14g,20.0mmol) were added to a three-necked reaction flask containing anhydrous DMF (100mL) under nitrogen, followed by HBTU (8.3g,22.0mmol) and triethylamine (4.0g,40.0mmol) at 25 ℃ until the main starting compound 1 was substantially disappeared. The reaction was then poured into ice water (800mL), the combined system was extracted with DCM (200mL × 3), the DCM phase was washed with saturated sodium chloride solution, dried and concentrated to give the crude product. The crude product was flash chromatographed (200-300 mesh silica gel with DCM: MeOH: 100: 1-40: 1, v/v mobile phase) to afford compound X-17.4g, 83% yield.1H-NMR(300Hz,DMSO-d6)δ:12.58(s,1H),8.251(d,J＝7.5Hz,1H),7.96(d,J＝7.5Hz,1H),7.86(m,2H),7.40(brs,1H),7.28(d,J＝6.6Hz,1H),7.20(t,1H),4.45(brs,1H),4.34(s,3H),3.38(q,2H),2.93(m,1H),2.70(m,1H),1.73(d,1H),1.40(m,4H)；MS(ESI)：438.2m/z[M+H]+。
Step 2: preparation of Compound XI-1
Compound X-1(7.0g,16.0mmol) was dissolved in DCM (100mL) and Et was added3N (3.2g,32.0mmol) and cooling the reaction to about 0 deg.C, a solution of MsCl (1.9g,16.8mmol) in DCM (10.0mL) was slowly added dropwise, the temperature was controlled below 50 deg.C until the starting material completely disappeared by stirring at room temperature. And then adding a saturated citric acid solution for washing, then washing with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, drying and concentrating to obtain a crude product. The crude product was flash chromatographed (200-300 mesh silica gel with DCM: MeOH: 800: 1-40: 1, v/v mobile phase) to give compound XI-17.2g, 87.8% yield.
1H-NMR(400Hz,DMSO-d6)δ:12.59(s,1H),8.24(d,J＝8Hz,1H),7.94(d,J＝8Hz,1H),7.92～7.88(m,2H),7.39(brs,1H),7.27(d,J＝6.4Hz,1H),7.19(t,1H),4.43(d,J＝12.8Hz,1H),4.31(s,1H),3.62(t,2H),3.31(s,3H),3.05～3.10(q,2H),2.93(t,1H),2.69～2.72(m,1H),1.65～1.72(m,3H),1.45(brs,2H),1.32～1.38(q,2H),1.14～1.17(t,4H),0.94～1.04(m,1H).MS(ESI)：m/z 516.2[M+H]+。
And step 3: preparation of Compound III-1
Compound XI-1(6.28g,12.2mmol) and phthalimide potassium salt (2.7g,14.6mmol) were dissolved in anhydrous DMF (50.0mL) at room temperature, then the reaction was heated to an internal temperature of 90 ℃ to react until the main starting material was reacted completely, and cooled to room temperature. The reaction was poured into ice water (200mL) and stirred, DCM (50mL × 3) was added for extraction, the DCM phase was washed with saturated sodium chloride solution, dried and concentrated to give the crude product. The crude product was flash chromatographed (200-300 mesh silica gel with DCM: MeOH: 80: 1-20: 1, v/v mobile phase) to afford 2.8g of intermediate in 40% yield.
The intermediate (2.6g,4.6mmol) obtained in the above step and 80% hydrazine hydrate (0.6mL,23.0mmol) were added to 95% ethanol (50.0mL), and then the reaction system was warmed to reflux state until the main raw material was completely disappeared, a white solid was filtered to obtain a filtrate, and the filtrate was concentrated to obtain a crude product. The crude product is flash chromatographed (200-300 mesh silica gel with DCM: MeOH: 20: 1-10: 1, v/v mobile phase) to give compound III-10.9g, 45% yield.1H-NMR(300Hz,DMSO-d6)δ:8.26(d,J＝7.8Hz,1H),8.02～8.05(m,1H),7.690(d,J＝7.8Hz,1H),7.77～7.90(m,2H),7.39～7.43(q,1H),7.42(d,J＝6.6Hz,1H),7.21(t,1H),4.44(d,J＝15.3Hz,1H),4.32(s,1H),3.19～3.27(m,1H),2.92(t,1H),2.60～2.73(m,2H),1.70～1.76(m,,1H),1.39～1.43(m,4H),1.17～1.27(m,5H),0.83～1.01(m,2H).MS(ESI)m/z:437.0[M+H]+。
B) The compounds VII-1 to VII-22 can be obtained by direct purchase or by the following scheme (scheme 3)
Route 3
Figure BDA0001583549100000131
Wherein as described in Table 1, is prepared by
Figure BDA0001583549100000132
Middle query, compounds VII-1 to VII-22 except three compounds vii-8, vii-15 and vii-17 without CAS number [ remarks: TABLE 1 CAS numbers for only non-single isomers ] the present invention provides a scheme for the preparation of intermediates VII-8, VII-15 and VII-17, other intermediates being commercially available or prepared by methods referred to for VII-8.
TABLE 1 substituted acrylic Compounds VII-1 to VII-22
Figure BDA0001583549100000133
Figure BDA0001583549100000141
Figure BDA0001583549100000151
Process for the preparation of intermediates VII-8, VII-15 and VII-17
1) Preparation of Compound VII-8:
n- (5-formyl-4- (trifluoromethyl) pyridin-2-yl) pivaloamide (548mg,2.0mmol) and methoxycarbonylmethylenetriphenylphosphine (734.8mg,2.2mmol) were added to toluene (20.0mL) at 100 ℃ to react until the aldehyde was completely disappeared, the toluene was concentrated to remove, silica gel was added, and the mixture was stirred with petroleum ether: the column was filtered through ethyl acetate 15:1 to 8:1 to give 630mg of methyl 3- (6-pivaloylamino-4- (trifluoromethyl) pyridin-3-yl) acrylate as a white solid.1H-NMR(300Hz,CDCl3)δ:8.64(s,1H),8.61(s,1H),8.21(s,1H),7.90(d,J＝15.9Hz,1H),6.43(d,J＝15.9Hz,1H),3.83(s,3H)；ESI(m/z):331.0[M+1]+
Methyl 3- (6-pivaloylamino-4- (trifluoromethyl) pyridin-3-yl) acrylate (344mg,1.0mmoL) was dissolved in 95% ethanol (50mL) and sodium hydroxide (400mg,10.0mmoL) was added and the reaction was allowed to proceed under reflux until hydrolysis of the starting material was complete. Concentrating to remove ethanol, adding water, adjusting pH to about 5 with dilute hydrochloric acid, precipitating to obtain a large amount of solid, filtering to obtain solid, and drying to obtain 230mg of compound VII-8.1H-NMR(300Hz,CDCl3)δ:8.64(s,1H),8.61(s,1H),8.21(s,1H),7.90(d,J＝15.9Hz,1H),6.43(d,J＝15.9Hz,1H)；ESI(m/z):233.0[M+1]+。
2) Preparation of Compound VII-15
6- (ethylamino) nicotinaldehyde (225mg,1.5mmol) and methoxycarbonylmethylenetriphenylphosphine (551mg,1.65mmol) were added to toluene (20.0mL) at 100 ℃ to react until the aldehyde completely disappeared, the toluene was concentrated off, silica gel was added, and the mixture was stirred with petroleum ether: ethyl acetate 15: 1-8: 1, v/v, and column chromatography gave 240mg of methyl 3- (6- (ethylamino) pyridin-3-yl) acrylate as a white solid.1H-NMR(300Hz,CDCl3)δ:8.19(d,J＝2.4Hz,1H),7.64(d,J＝2.4Hz,0.5H),7.61(s,1H),7.55(s,0.5H),6.38(d,J＝8.7Hz,1H),6.21(d,J＝15.9Hz,1H),3.78(s,3H),3.36(q,2H),1.27(t,3H)；ESI(m/z):207.1[M+1]+。
Adding reaction residue of methyl 3- (6- (ethylamino) pyridin-3-yl) acrylate (206mg,1.0mmol) into 95% ethanol (10mL), adding sodium hydroxide (400mg,10mmol) under reflux to react until the reaction of the raw materials is complete, concentrating to remove ethanol, adding water, adjusting pH to about 5 with dilute hydrochloric acid, precipitating a large amount of solid, filtering to obtain a solid, and drying to obtain 110mg of compound VII-15.1H-NMR(300Hz,CDCl3)δ:8.19(d,J＝2.4Hz,1H),7.64(d,J＝2.4Hz,0.5H),7.61(s,1H),7.55(s,0.5H),6.38(d,J＝8.7Hz,1H),6.21(d,J＝15.9Hz,1H),3.36(q,2H),1.27(t,3H)；ESI(m/z):193.1[M+1]+。
3) Preparation of Compound VII-17
6-chloronicotinaldehyde (560mg,4.0mmol) and ethyl 2- (triphenylphosphine ylidene) propionate (1.33g,4.4mmol) were added to toluene (20.0mL) and reacted at 100 ℃ until the aldehyde completely disappeared, the toluene was concentrated off, silica gel was added, and the mixture was stirred with petroleum ether: ethyl acetate 15: 1-8: 1, v/v, and the column was passed to give 896mg of methyl 3- (6-chloropyridin-3-yl) acrylate as a white solid.1H-NMR(300Hz,DMSO-d6)δ:8.52(d,J＝2.7Hz,1H),8.00(dd,J＝0.6Hz,8.1Hz),7.59(d,J＝6.9Hz,1H),7.58(s,1H),4.18～4.25(q,2H),2.04(d,J＝1.5Hz,3H),1.27(t,3H)；ESI(m/z):212.1[M+1]+。
Adding reaction residue of 3- (6-chloropyridin-3-yl) methyl acrylate (422mg,2.0mmol) into 95% ethanol (20mL), adding sodium hydroxide (800mg,20mmol) under reflux for reaction until the raw materials react completely, concentrating to remove ethanol, adding water, adjusting pH to about 5 with dilute hydrochloric acid, precipitating a large amount of solid, filtering to obtain a solid, and drying to obtain 315mg of compound VII-17.
1H-NMR(300Hz,DMSO-d6)δ:12.76(s,1H),8.52(d,J＝2.7Hz,1H),7.98(dd,J＝8.4Hz,2.7Hz,1H),7.57～7.60(m,2H),2.02(d,J＝1.2Hz,3H)；ESI(m/z):198.1[M+1]+。
Preparation example
Preparation method and data analysis of compounds I-1 to I-22
Figure BDA0001583549100000171
Compound III-1(1.5mmol,1eq) and the corresponding compound IV (1.65mmol,1.1eq) were dissolved in DMF (10mL) and stirred, followed by the addition of HBTU (1.8mmol,1.2eq) and triethylamine (2.25mmol,1.5eq) and reaction at room temperature until compound III-1 was completely reacted. The reaction was poured into ice water and extracted with DCM to give an organic phase. The DCM phase was washed with brine, dried over anhydrous sodium sulfate, and passed through silica gel (200-300 mesh) column to obtain the corresponding compounds, the specific data are shown in table 2 below.
Table 2: mass and nuclear magnetic data of Compounds I-1 to I-22
Figure BDA0001583549100000172
Figure BDA0001583549100000181
Figure BDA0001583549100000191
Figure BDA0001583549100000201
Figure BDA0001583549100000211
Test example
Activity test experiment of Compounds I-1 to I-22
Methods and sources for primary reagent production
The culture medium for various tumor cells is derived from Gibco, CCK-8 is derived from Dongnan chemical, nicotinamide adenine dinucleotide NAD+Purchased from sigma, DNA purchased from Shanghai biosynthesis, Histone purchased from Yuanshigen, Anti-PAR Polycolonal Antibody (rabbit) purchased from Trevigen, Goat Anti-rabbitlgG-HRP purchased from Jackson, 96 well plate purchased from corning, Tris (hydroxymethyl) aminomethane (Tris-HCL) and Tween purchased from national pharmaceutical group reagents, magnesium chloride (MgCl)2) Bovine Serum Albumin (BSA), and o-phenylenediamine (OPD) were purchased from bioengineering (shanghai) gmbh, and the positive control compound olaparib (AZD2281) was purchased from LC lab.
Test example 1
Experiment on PARP molecule level inhibition and cell proliferation inhibition
The experimental method comprises the following steps: Enzyme-Linked immunosorbent assay (ELISA) (reference: Decker, P.; Miranda, E.A.; de Murcia, G.and Muller, S.A. and improved nonosonic test to screen a large series of new inhibitors of poly (ADP-ribose) polymerase activity for therapeutic applications, Clin. cancer Res.1999,5, 9-. The principle is that the substrate histone is coated on an adsorptive 96-well plate, and PARP1 recombinase and substrate NAD are added+The PARP1 enzyme activity can be reflected by the fact that PARP1 is enzymatically reacted by activated DNA to produce a product PAR (poly-adenosine-diphosphate ribose) by histone, then an antibody against PAR (anti-PAR) is added, and the strength of the product PAR on the histone coated on a 96-well plate is detected.
For detailed procedures of the experiment and preparation of reagents used, such as reaction buffers and buffers, reference is made to TREVIGENHTF instructions for the homologous poly (adenosine diphosphate-nucleic acid) polymerase inhibition kit.
The experimental operation steps are as follows:
1. histone (3 ng/well) was immobilized on absorbent 96-well plates in phosphate buffer (150mM NaCl, 7.7mM Na phosphate disodium dodecahydrate2HPO4·12H2O, 2.3mM sodium dihydrogen phosphate dihydrate NaH2PO4·2H2O, pH8.0), 100 mu L/hole, shaking overnight at 37 ℃;
2. washing with phosphate buffer containing 0.2 wt.% Tween-20 for three times, and oven drying;
3. dissolving the compound to be tested in dimethyl sulfoxide, and then diluting with phosphate buffer to the inhibitor of the concentration required by the experiment; then nicotinamide adenine dinucleotide (PARP1 enzyme system plus 0.8. mu.M/well) (PARP2 enzyme system plus 26. mu.M/well), DNA (100 ng/well), PARP1/2 enzyme (10 ng/well) (reaction buffer 50mM Tris, 2mM MgCl2pH8.0 dilution), adding inhibitor with a certain dilution concentration of 10 μ L into each well, setting each concentration for 2 times, reacting in 100 μ L/well (supplemented with reaction buffer solution), shaking table reacting at 37 deg.C for 1.5 hr, and setting blank, positive and negative controls;
4. washing with 0.2 wt.% Tween-20 in phosphate buffer for three times, adding anti-PAR polyclonal antibody (1: 6000, diluted with 5mg/mL bovine serum albumin in 0.2% Tween-20 in phosphate buffer), 100. mu.L/well, and incubating at 37 ℃ for 1.5 hours in a shaker;
5. washing with phosphate buffer containing 0.2 wt.% Tween-20 for three times, and performing shaking reaction on goat anti-rabbit antibody (1: 2000 diluted with 5mg/mL bovine serum albumin in phosphate buffer containing 0.2 wt.% Tween-20) labeled with horseradish peroxidase at 100 μ L/well at 37 deg.C for 1 hr;
6. washed three times with phosphate buffer containing 0.2 wt.% tween-20, 2mg/mL o-phenylenediamine (i.e., OPD, formulated with 5mM citric acid in sodium citrate buffer, 15mM sodium citrate) was added 0.1% of 30% H2O2100 mu L/hole, reacting for 5-15 minutes;
7. with 50. mu.L of 2M H2SO4Termination is inverseOD was measured at 490 nm.
The experimental observation indexes are as follows:
OD was measured at 490nm wavelength using a microplate reader (VERSAmax).
And (3) judging and explaining the experimental results:
inhibition rate ═ 100% (control OD value-administration OD value-blank OD value)/(control OD value-blank OD value) ×
The compounds were set up for 6 concentration gradients and IC calculated50。
The experimental results are as follows: compounds were evaluated for inhibition of PARP1/2 using olaparib (AZD2281) as a positive control, and the results are shown in table 3 using a 10-fold dilution of 1 μ M with 6 concentration gradients on PARP1 and PARP2 enzymes.
TABLE 3 inhibition of PARP molecular level and inhibition of cell proliferation by Compounds I-1 to I-22
Figure BDA0001583549100000231
Test example 2
Experiment of inhibition effect of partial compounds on MDA-MB-436 parent and drug-resistant cell proliferation
The experimental method comprises the following steps: the proliferation inhibition effect and the proliferation inhibition degree of the compound are compared by using a Cell proliferation toxicity detection Kit (CCK-8) method for BRCA 1-deficient human breast cancer MDA-MB-436 parent cells and Olaparib (AZD2281) drug-resistant cells.
The experimental operation steps are as follows:
1. cells in logarithmic growth phase were seeded at 180. mu.L/well in 96-well culture plates and cultured at 37 ℃ for 18 hours until the cells adhered.
2. 20 μ L of drug at a dilution concentration was added to each well in triplicate for each concentration. And setting physiological saline solvent control and cell-free zero setting holes with corresponding concentrations, and making cell-free zero setting holes with corresponding drug concentrations if the drugs are colored.
3. Tumor cells were incubated at 37 ℃ with 5% CO2Cultured for 7 days under the condition.
4. Adding 10 mu L of CCK-8 solution per well, and continuing culturing for 3-5 hours (controlling the OD value to be about 1.0).
5. And measuring an OD450 value by using a microplate reader.
The experimental observation indexes are as follows: OD was measured at a wavelength of 450nm using a microplate reader (VERSAmax).
And (3) judging and explaining the experimental results:
calculating the inhibition rate of the tested substance on the growth of cancer cells, half inhibition IC according to the following formula50The values were calculated using the Logit method.
Inhibition rate (control OD value-administration OD value)/control OD value × 100%
The compounds were set up for 6 concentration gradients and IC calculated50。
The experimental results are as follows: and (3) evaluating the proliferation inhibition of partial compounds on MDA-MB-436 parent and AZD2281 drug-resistant strain pair cells by taking AZD2281 as a positive control, and performing 5-fold dilution on 50 mu M in an experiment to act on the cells with 6 concentration gradients for 7 days. Computing IC50The results are shown in Table 4.
TABLE 4 proliferation inhibition of a subset of compounds on MDA-MB-436 parent and AZD2281 drug-resistant strains on cells
Figure BDA0001583549100000241
As can be seen from Table 4, the proliferation inhibition of MDA-MB-436/AZD2281 resistant cells by most compounds was better than that of AZD 2281.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (14)

1. A phthalazinone derivative shown as a general formula I and pharmaceutically acceptable salts thereof,
Figure FDA0003155948430000011
wherein,
r is selected from H and C1-C6An alkyl group;
n is an integer of 1-6;
het is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted five-membered and six-membered heteroaryl, wherein the heteroaryl contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur in a ring atom; the substituted substituent is selected from halogen, nitryl, amino, cyano, hydroxyl and C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, hydroxy C1-C6Alkyl radical, C1-C6Alkylamino, di-C1-C6One or more of an alkylamino group and a 3-8 membered heterocyclyl group, wherein one or more ring atoms of the heterocyclyl group are selected from heteroatoms of nitrogen, oxygen and sulfur.
2. The phthalazinone derivatives of formula I and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein,
r is selected from H, methyl and ethyl;
n is an integer of 2 to 5.
3. The phthalazinone derivative of formula I and a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the phthalazinone derivative of formula I is a phthalazinone derivative of formula II,
Figure FDA0003155948430000012
het is as defined in claim 1.
4. The phthalazinone derivative of formula I as claimed in any one of claims 1 to 3, wherein,
the substituted substituent is selected from halogen, nitryl, amino, cyano, hydroxyl and C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, hydroxy C1-C6Alkyl radical, C1-C6Alkylamino, di-C1-C6One or more of alkylamino, pyrrolidinyl, piperidinyl, and morpholinyl.
5. The phthalazinone derivative of formula I as claimed in any one of claims 1 to 3, wherein,
het is substituted or unsubstituted indolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl or
Figure FDA0003155948430000021
Wherein X is selected from O, N or S;
Y1and Y2Each independently selected from N or C, both not simultaneously N,
the substituted substituent is selected from halogen, nitryl, amino, cyano, hydroxyl and C1-C4Alkyl radical, C1-C6Alkoxy, halogen-substituted C1-C4Alkyl, morpholinyl, piperidinyl, pyrrolidinyl and C1-C4One or more of alkylamino groups.
6. The phthalazinone derivative of formula I as claimed in any one of claims 1 to 3, wherein,
het is selected from pyridyl, chloropyridyl, indolyl, pyrrolyl, thiazolyl, pyrimidinyl, aminotrifluoromethylpyridyl, azaindolyl, dimethylisoxazolyl, piperidinyl pyridyl, morpholinyl pyridyl, pyrrolidino pyridyl, diethylamino pyridyl, ethylamino pyridyl, methylaminopyridyl, naphthyl, aminopyridyl, benzofuranyl.
7. The phthalazinone derivative of formula I as claimed in any one of claims 1 to 3, wherein,
het is selected from 4-pyridyl, 2-chloro-5-pyridyl, 3-indolyl, 2-pyrrolyl, 4-thiazolyl, 5-pyrimidinyl, 2-amino-6- (trifluoromethyl) -5-pyridyl, 7-azaindolyl, 3, 5-dimethyl-4-isoxazolyl, 2-piperidinyl-5-pyridyl, 2-morpholinyl-5-pyridyl, 2-pyrrolidin-5-pyridyl, 2-diethylamino-5-pyridyl, 2-ethylamino-5-pyridyl, 2-methylamino-5-pyridyl, 1-naphthyl, 6-azaindolyl, 2-pyridyl, 5-pyridyl, 2-pyridyl, etc, 2-amino-5-pyridyl, 3-benzofuranyl and 3-pyridyl.
8. The phthalazinone derivative of formula i and pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the phthalazinone derivative of formula i is selected from the group consisting of:
Figure FDA0003155948430000022
Figure FDA0003155948430000031
Figure FDA0003155948430000041
9. a process for preparing the phthalazinone derivative of claim 1, the process comprising the step of condensing compound III with acid IV to produce a compound of formula I:
Figure FDA0003155948430000042
wherein R, n and Het are as defined in claim 1.
10. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the phthalazinone derivatives and pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 8 as an active ingredient, and a pharmaceutically acceptable carrier.
11. Use of the phthalazinone derivative according to any one of claims 1-8 and pharmaceutically acceptable salts thereof or the pharmaceutical composition according to claim 10 for preparing a medicament for preventing or treating diseases related to poly (adenosine diphosphate ribose) polymerase resistance.
12. The use of claim 11, wherein the disease associated with poly (adenosine diphosphate ribose) polymerase resistance comprises: cancer, ischemic diseases and neurodegenerative diseases.
13. The use of claim 12, wherein the cancer comprises solid and non-solid tumors, and the ischemic disease comprises ischemic cerebrovascular disease, coronary heart disease, spinal cord ischemic disease, mesenteric vascular ischemic disease, ischemic retinopathy and ischemic enteritis; the neurodegenerative disease comprises Parkinson's disease, Alzheimer's disease and muscular dystrophy.
14. The use according to claim 12, wherein the cancer is selected from breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer, gastric cancer, lung cancer, glioma, recurrent hematological cancer, ewing's sarcoma, pancreatic cancer, endometrial cancer.
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