CN102731416A - 1-(aryl methyl)-quinazoline-2,4-dione as PARP inhibitor and its application - Google Patents

1-(aryl methyl)-quinazoline-2,4-dione as PARP inhibitor and its application Download PDF

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CN102731416A
CN102731416A CN2011100824756A CN201110082475A CN102731416A CN 102731416 A CN102731416 A CN 102731416A CN 2011100824756 A CN2011100824756 A CN 2011100824756A CN 201110082475 A CN201110082475 A CN 201110082475A CN 102731416 A CN102731416 A CN 102731416A
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quinazoline
carbonyl
diketone
cancer
benzyl
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董海军
蔡遂雄
田野
许庆兵
吴利珍
刘丽军
江洋珍
鲍庆立
王国相
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NANJING THERAPEUTICS Inc
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NANJING THERAPEUTICS Inc
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Priority to CN2011100824756A priority Critical patent/CN102731416A/en
Priority to TW101111039A priority patent/TWI527800B/en
Priority to CN201280001822.0A priority patent/CN103097361B/en
Priority to PL12765230T priority patent/PL2709990T3/en
Priority to JP2014501428A priority patent/JP6270713B2/en
Priority to EP12765230.3A priority patent/EP2709990B1/en
Priority to HUE12765230A priority patent/HUE046121T2/en
Priority to PT12765230T priority patent/PT2709990T/en
Priority to AU2012237776A priority patent/AU2012237776B2/en
Priority to CN201410398758.5A priority patent/CN104230827B/en
Priority to DK12765230.3T priority patent/DK2709990T3/en
Priority to RS20190877A priority patent/RS59091B1/en
Priority to CA2831015A priority patent/CA2831015C/en
Priority to ES12765230T priority patent/ES2736299T3/en
Priority to US14/006,722 priority patent/US9290460B2/en
Priority to SG2013071543A priority patent/SG193599A1/en
Priority to TR2019/10675T priority patent/TR201910675T4/en
Priority to PCT/CN2012/073362 priority patent/WO2012130166A1/en
Priority to SI201231630T priority patent/SI2709990T1/en
Publication of CN102731416A publication Critical patent/CN102731416A/en
Priority to US15/042,366 priority patent/US9926304B2/en
Priority to US15/935,694 priority patent/US10316027B2/en
Priority to US16/415,803 priority patent/US11358955B2/en
Priority to HRP20191273TT priority patent/HRP20191273T1/en
Priority to CY20191100769T priority patent/CY1121847T1/en
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Abstract

The invention provides novel 1-(aryl methyl)-quinazoline-2, 4-dione as shown in the formula I, wherein Ar and R1-R6 are defined. The compound in the formula I is a PARP inhibitor. Therefore, the compound provided by the invention can be used to treat diseases (such as cancer) caused by abnormal PARP activity.

Description

1-(arylmethyl)-quinazoline-2, the 4-diketone is as PARP suppressor factor and application thereof
Technical field
The invention belongs to the pharmaceutical chemistry field.The present invention be more particularly directed to 1-(arylmethyl)-quinazoline-2, the 4-diketone, and as treating the application of going up effective poly (ADP-ribose) polysaccharase (PARP) suppressor factor and cancer therapy drug.
Background technology
(poly (ADP-ribose) polymerase, PARP) catalysis is added poly (ADP-ribose) by NAD+ to poly (ADP-ribose) polysaccharase on the target protein molecule, is the important component part of corresponding DNA injury repairing DNA process.This process is most important to keeping DNA and chromosomal complete sum to stablize, and is the important leverage that guarantees the cells of mamma animals survival.Intracellular most ADP-ribose polymerization vigor is to be formed by PARP-1 catalysis, though PARP-2 also has this function with other hypotypes.The mouse that knocks out PARP-1 does not possess single stranded DNA injury repairing function (Krishnakumar and Kraus, 2010, Molecular Cell 39:8).Simultaneously; The BRCA1 or the BRCA2 absence type cancer cells of disappearance dna homology recombination function contain the platinum-based chemotherapy medicine to comprising under the condition that suppresses ADP-ribose polymerization vigor; Dna methylation class anticancer chemotherapeutic agent and DNA topoisomerase enzyme inhibitor class etc. cause the anticancer chemotherapeutic agent of dna damage, or radiotherapy is especially responsive.Clinical the second stage of testing data shows that it is effectively that PARP-1 suppressor factor olaparib (AZD2281) is used to treat advanced breast cancer, has proved feasibility (Andrew Tutt et al., 2009, the J.Clin.Oncol 27:18s of this thinking; Andrew Tutt et al., 2010Lancet 376:235; R.A.Dent et al., 2010J.Clin.Oncol.28:15s).These a series of science and clinical test results show that the PARP-1 suppressor factor can be used as cancer therapy drug and treat multiple cancer effectively.Treat cancer mainly based on two kinds of mechanism with the PARP-1 suppressor factor.One of which because the cancer cell dna replication dna that increases fast is higher than the normal cell of slow growth far away, can cause the medicine of dna damage to cause death to cancer cells selectively.But because the existence of DNA repair enzyme, the property of medicine of this type medicine can not be given full play to.Therefore the PARP-1 suppressor factor is used in combination with dna damage based chemotherapy cancer therapy drug commonly used because it has greatly amplified dna damage kind anti-cancer drugs thing to the inhibition that DNA repairs, such as TM (temozolamide) thus property of medicine generation synergistic effect.Its two, DNA is repaired defective cancer cells, such as the cancer cells such as triple negative breast cancer of BRCA1 or BRCA2 disappearance, the PARP-1 suppressor factor can directly kill these cells independently as cancer therapy drug.Approximately the mammary cancer of 10-15% all has the hereditary factor of family history according to statistics.The mammary cancer that wherein causes owing to BRCA1 or BRCA2-transgenation accounts for the 15-20% of all HBCs again.PARP-1 participates in DNA and repairs, and the reparation that is suppressed DNA by the PARP-1 suppressor factor can be used for treating effectively selectively the cancer that heredity DNA rectification of defects is arranged that comprises triple negative breast cancer.The PARP-1 suppressor factor also possibly be used to treat other necrocytosis property diseases in addition, for example central nervous system disease such as apoplexy and nerve degenerative diseases etc. (Akinori Iwashita et al., 2004J.Pharmacol.Exp.Thera.310:425).
The active available PARP-1 enzymatic determination of PARP-1 suppressor factor.Simultaneously, for example MMS is to the cytotoxicity of cancer cells because the PARP-1 suppressor factor can increase dna damage based chemotherapy cancer therapy drug, and the also available dna damage kind anti-cancer drugs of the activity of PARP-1 suppressor factor is measured the cytotoxicity experiment mtt assay of cancer cells.
But known many cancer therapy drug cancer cell specific induction of apoptosis.Apoptosis Mechanism comprises that the activation of a series of proteolytic ferments makes cell get into reversible and irreversible apoptotic state.Relating to the topmost histone lytic enzyme of apoptosis is Caspases.Caspases is not usually there to be active proenzyme state to be present in the cell.Caspases is halfcystine-aspartic acid proteolytic ferment.Their common ground is the peptide bond behind the hydrolysis asparagicacid residue specifically.Caspase-3 wherein ,-6 and the-7th, crucial caspases, they can cut the protein substrate in the various kinds of cell, cause apoptosis.Intracellular caspase activity can adopt fluorescently-labeled substrate to measure.Because the PARP-1 suppressor factor can increase the for example cell death inducing effect of MMS of dna damage based chemotherapy cancer therapy drug, the also available dna damage based chemotherapy of the activity of PARP-1 suppressor factor cancer therapy drug inductive caspase vigor in cancer cells is tested and is measured.
The open 8-hydroxyl quinazoline-2 of JP2007137818, the 4-derovatives is as the PARP suppressor factor.X=(CH wherein 2) nN=1-4; Y=H, NR1R2,1,2,3,4-tetrahydro isoquinolyl, octahydro isoquinolyl, pyridyl, benzyl etc.
Figure BDA0000053539850000021
WO2006003148 discloses preparation quinazoline-2, and the 4-derovatives is as the PARP suppressor factor.Wherein X and Y are N or CH independently; L 1Be a key or alkyl; L 2Be a tendon, CO, alkyl, CO-alkyl etc.; R 1Be H or OH; Z is H, can substituted aryl or heteroaryl.
Figure BDA0000053539850000031
Summary of the invention
Like structural formula I, shown in formula II and the formula III, the invention provides novel 1-(arylmethyl)-quinazoline-2, the 4-diketone is as the PARP suppressor factor.
The present invention also provides the formula I that comprises a significant quantity, and the medicinal compsns of formula II or formula III compound is used for treating cancer.
In one embodiment, said medicinal compsns also can contain one or more pharmaceutically acceptable carrier or thinner.
In one embodiment, said medicinal compsns also can contain the pharmacologically acceptable salt of at least a known cancer therapy drug or said cancer therapy drug.
The present invention also relates to structural formula I, the preparation method of the compounds of formula II and formula III.
Embodiment
Suc as formula I, shown in formula II and the formula III, the present invention finds novel 1-(arylmethyl)-quinazoline-2, and the 4-diketone can be used as PARP suppressor factor efficiently.
Specifically, can be used for compound of the present invention is formula I compound or pharmaceutically acceptable salt thereof or prodrug: Wherein, Ar is can substituted aryl or can substituted heteroaryl; R 1-R 6Independent be hydrogen, halogen, can substituted amino, can substituted alkoxyl group, can substituted C 1-10Alkyl, alkylhalide group, thiazolinyl, alkynyl, hydroxyalkyl, amido alkyl, carboxyalkyl, nitro, cyanic acid, carboxamido-group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base or can substituted alkylthio; R wherein 4It or not hydroxyl.
Ar is can randomly substituted phenyl or pyridyl in the preferred formula I compound.More preferred Ar is a phenyl.R in the preferred formula I compound 5And R 6All be hydrogen.
Preferred compound of the present invention wherein one group be expressed as formula II compound or pharmaceutically acceptable salt thereof or prodrug:
Figure BDA0000053539850000041
Wherein, R 1-R 4Independent be hydrogen, halogen, can substituted amino, can substituted alkoxyl group, can substituted C 1-10Alkyl, alkylhalide group, thiazolinyl, alkynyl, hydroxyalkyl, amido alkyl, carboxyalkyl, nitro, cyanic acid, carboxamido-group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base or can substituted alkylthio; R wherein 4It or not hydroxyl.R 7-R 11Independent be hydrogen, halogen, can substituted amino, alkoxyl group, C 1-10Alkyl; Alkylhalide group; Aryl; Carbocylic radical; Heterocyclic radical; Heteroaryl; Alkenyl; Alkynyl; Arylalkyl; Aromatic yl alkenyl; Aromatic yl polysulfide yl; Heteroarylalkyl; The heteroaryl alkenyl; The heteroaryl alkynyl; The carbocyclic ring alkyl; Heterocyclylalkyl; Hydroxyalkyl; The hydroxy alkoxy base; The amido alkyl; The amido alkoxyl group; Carboxyalkyl; The carboxyl alkoxyl group; Nitro; Cyanic acid; Carboxamido-group; Aminocarboxyl; Hydroxyl; Sulfydryl; Acyloxy; Azido-; Carboxyl; The oxyamide base; Alkyl sulphonyl; The amido alkylsulfonyl; Two substituted alkyl amido alkylsulfonyls; Alkyl sulphinyl; Alkylthio; Or substituted carbonyl.R in one group of preferred formula II compound 7Be hydrogen.Another is organized in the preferred formula II compound, R 8It is substituted carbonyl.
Preferred compound of the present invention wherein one group be expressed as formula III compound or pharmaceutically acceptable salt thereof or prodrug:
Figure BDA0000053539850000042
Wherein, R 1-R 4Independent be hydrogen, halogen, can substituted amino, can substituted alkoxyl group, can substituted C 1-10Alkyl, alkylhalide group, thiazolinyl, alkynyl, hydroxyalkyl, amido alkyl, carboxyalkyl, nitro, cyanic acid, carboxamido-group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base or can substituted alkylthio; R wherein 4It or not hydroxyl.R 7, R 9-R 11Independent be hydrogen, halogen, can substituted amino, alkoxyl group, C 1-10Alkyl; Alkylhalide group; Aryl; Carbocylic radical; Heterocyclic radical; Heteroaryl; Alkenyl; Alkynyl; Arylalkyl; Aromatic yl alkenyl; Aromatic yl polysulfide yl; Heteroarylalkyl; The heteroaryl alkenyl; The heteroaryl alkynyl; The carbocyclic ring alkyl; Heterocyclylalkyl; Hydroxyalkyl; The hydroxy alkoxy base; The amido alkyl; The amido alkoxyl group; Carboxyalkyl; The carboxyl alkoxyl group; Nitro; Cyanic acid; Carboxamido-group; Aminocarboxyl; Hydroxyl; Sulfydryl; Acyloxy; Azido-; Carboxyl; The oxyamide base; Alkyl sulphonyl; The amido alkylsulfonyl; Two substituted alkyl amido alkylsulfonyls; Alkyl sulphinyl; Alkane sulphur or substituted carbonyl.R 12For can substituted amino, alkoxyl group, C 1-10Alkyl, alkylhalide group, aryl, carbocylic radical, heterocyclic radical, heteroaryl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroaryl alkenyl, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, amido alkyl, amido alkoxyl group, carboxyalkyl, carboxyalkyl, carboxamido-group, sulfydryl, oxyamide base, alkyl sulphonyl or amido alkylsulfonyl.R in one group of preferred formula III compound 7Be hydrogen.Another is organized in the preferred formula III compound, R 12Be can substituted amino.Another is organized in the preferred formula III compound, R 12Being can substituted aryl, can substituted carbocylic radical, can substituted heterocyclic radical or can substituted heteroaryl.Formula I, the preferred compound embodiment of formula II and formula III includes but not limited to: 1-(3-methoxycarbonyl benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-cyclohexyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-([1,2,4] triazolo [4,3-b] pyridazine-6 base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-ethyl piperazidine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(4-chlorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(4-bromobenzene formyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(tetrahydrochysene-2H-pyrans-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-cyclopropyl carbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-ethyl sulphonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-methyl carbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(3-(4-(pyrazine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(4-fluoro-3-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(4-fluoro-3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; 1-(4-fluoro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone; Or its pharmacologically acceptable salt or prodrug.
" alkyl " used herein is meant alkyl itself or the straight or branched group up to ten carbon atoms.Useful alkyl comprises straight or branched C 1-10Alkyl, preferred straight or branched C 1-6Alkyl, more preferably C 1-3Alkyl.Typical C 1-10Alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec.-butyl, the tertiary butyl, 3-amyl group, hexyl and octyl group.
" thiazolinyl " used herein is meant that straight or branched contains 2-10 carbon atom, wherein is the group that contains two keys between two carbon atoms in the chain at least.Preferred thiazolinyl is the thiazolinyl that contains 2-4 carbon atom.Typical alkenyl comprises vinyl, 1-propenyl, 2-methyl isophthalic acid-propenyl, 1-butylene base and crotyl.
" alkynyl " used herein is meant that straight or branched contains 2-10 carbon atom, wherein is the group that contains one three key between two carbon atoms in the chain at least.Preferred alkynyl is the alkynyl that contains 2-4 carbon atom.Typical alkynyl comprises ethynyl, 1-proyl, 1-methyl-2-propynyl, 2-propynyl, ethyl acetylene base and 2-butyne base.
Useful alkoxyl group comprises by the substituted oxygen base of alkyl, for example by above-mentioned C 1-10The oxygen base of alkyl section is preferably by above-mentioned C 1-6It (is C that alkyl replaces 1-6Alkoxyl group), C more preferably 1-3Alkoxyl group.
Useful alkylthio comprises by any above-mentioned C 1-10Alkyl (preferably, C 1-6Alkyl, more preferably, C 1-3Alkyl) substituted sulfenyl, the alkyl in the alkylthio can be substituted.The sulfoxide and the sulfone that also comprise this type alkylthio simultaneously.
Useful amino comprises-NH 2,-NHR 15With-NR 15R 16, R wherein 15And R 16Be C 1- 10Alkyl or C 3-C 8Naphthenic base, perhaps R 15And R 16Form with N and to encircle for example piperidines, perhaps R 15And R 16Form with N and with other group and to encircle for example piperazine.Said alkyl can be substituted with ring.
Among this paper; When being substituted; Alkyl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, naphthenic base, carbocyclic ring and heterocycle can be selected from the substituting group replacement of following group by one or more (for example 1,2,3 or 4): halogen, hydroxyl, carboxyl, amino, amido, nitro, cyanic acid, C 1-6Amido, C 1-6Acyloxy, C 1-6Alkoxyl group, aryloxy, alkylthio, C 6-C 10Aryl, C 4-C 7Naphthenic base, C 2-C 6Alkenyl, C 6-C 10Aryl (C 2-C 6) alkenyl, C 6-C 10Aryl (C 2-C 6) alkynyl, saturated and undersaturated heterocyclic radical or heteroaryl.In preferred enforcement, alkoxyl group can be selected from the substituting group replacement of following group by one or more (for example 1～4 or 1～3 is not waited): halogen, morpholinyl, ammonia comprise alkylamine and dialkylamine and carboxyl ester.
Among this paper, when being substituted, aryl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroaryl and heteroarylalkyl can be selected from the substituting group replacement of following group by one or more (for example 1,2,3 or 4): halogen, methylene-dioxy, C 1-C 6Haloalkyl, C 6-C 10Aryl, C 4-C 7Naphthenic base, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 6-C 10Aryl (C 1-C 6) alkyl, C 6-C 10Aryl (C 2-C 6) alkenyl, C 6-C 10Aryl (C 2-C 6) alkynyl, C 1-C 6Hydroxyalkyl, nitro, amino, amido, urea groups, cyanic acid, C 1-C 6Acyl group amido, hydroxyl, sulfydryl, C 1-C 6Acyloxy, aminocarboxyl, azido-, C 1-C 6Alkoxyl group, carboxyl, two (C 1-C 10) amido, alkyl sulphonyl, aryl sulfonyl, dialkyl amino alkylsulfonyl or alkyl sulphinyl.
" aryl " used herein is meant aryl itself or as the part of other group, refers to contain monocycle, dicyclo or the three cyclophane family groups of 6 to 14 carbon atoms.
Useful aryl comprises C 6-14Aryl, C more preferably 6-10Aryl.Typical C 6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthryl, indenyl, biphenyl, biphenylene group and a fluorenyl group.
Here indication " carbocyclic ring " comprises the carbon ring group of naphthenic base and fractional saturation.Useful naphthenic base is C 3-8Naphthenic base.Typical naphthenic base comprises ring third class, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
Useful carbon ring group saturated or fractional saturation is top described naphthenic base and cycloalkenyl group, for example cyclopentenyl, cycloheptenyl and cyclooctene base.
Useful halogen or halogen group comprise fluorine, chlorine, bromine and iodine.
" arylalkyl " used herein comprises by arbitrary above-mentioned C 6-14The substituted C of aryl 1-10Alkyl.The preferred aryl groups alkyl is benzyl, styroyl or menaphthyl.
" aryl alkenyl " used herein comprises by arbitrary above-mentioned C 6-14The substituted C of aryl 2-10Thiazolinyl.
" aromatic yl polysulfide yl " used herein comprises by arbitrary above-mentioned C 6-14The substituted C of aryl 2-10Alkynyl.
" aryloxy " used herein comprises by arbitrary above-mentioned C 6-14The substituted oxygen base of aryl, its aryl can be substituted.Useful aryloxy comprises phenoxy and 4-methylphenoxy.
" alkoxy aryl " used herein comprises by the substituted C of arbitrary above-mentioned aryl 1-10Alkoxyl group, its aryl can be substituted.Useful alkoxy aryl comprises benzyloxy and phenyl ethoxy.
Useful haloalkyl comprises by one or more fluorine, chlorine, the substituted C of bromine or iodine atom 1-10Alkyl, for example methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 1,1-two fluoro ethyls, chloromethyl, chlorine methyl fluoride and trichloromethyl.
Useful acyl group amido (carboxamido-group) is to be connected any on the amido nitrogen C1-6Acyl group (alkyloyl), for example acetamido, chloracetyl amido, propionamido-, amide-based small, valeryl amido and hexanoyl amido, and the substituted C of aryl 1-6Acyl group amido, for example benzoylamino.
Useful acyloxy is to be connected oxygen (any C O-) 1-6Acyl group (alkyloyl), for example methanoyl, acetoxyl group, propionyloxy, butyryl acyloxy, penta acyloxy and hexylyloxy.
Heterocycle used herein is meant 3-7 person's monocycle of saturated or fractional saturation; Or 7-10 person's bicyclic system; It is chosen 1-4 heteroatoms wantonly by carbon atom with from O, N, S and forms; Wherein heteroatoms nitrogen and sulphur can be by any oxidations, and nitrogen also can be quaternary ammoniated arbitrarily, and comprise that any above-mentioned heterocycle quilt that defines in the bicyclic system merges with phenyl ring.If the compound that produces is stable, on heterocyclic carbon atom or the nitrogen-atoms substituting group can be arranged so.
Useful saturated or fractional saturation heterocyclic group comprises tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl, imidazolidyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, quinuclidinyl, morpholinyl, different chromanyl, chromanyl, pyrazolidyl and pyrazolinyl.
" hetero-aromatic ring " used herein be meant and contain 5-14 annular atoms, and have 6, and 10 or 14 πDian Zis are shared on member ring systems.And contained annular atoms be carbon atom and from oxygen, nitrogen, sulphur optional 1-3 heteroatoms.
Useful heteroaryl comprises thienyl, benzo [b] thienyl, benzo [2; 3-b] thienyl, thianthrenyl, furyl, pyranyl, different benzopyranyl, chromenyl, xanthyl, thiophene dislike base (phenoxanthiinyl), pyrryl, imidazolyl, pyrazolyl, pyridyl, include, but are not limited to phenodiazine (mixing) phenyl, phenanthroline base, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazan base, Phenazoxine base, 1 between 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indyl, pseudoindoyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, acridyl, naphthalene embedding; 4-dihydro-quinoxaline-2; 3-diketone, the amino Isocoumarin >97 of 7-, pyrido [1; 2-a] pyrimidin-4-one, five members of tetrahydro-[c] pyrazole-3-yl, imidazoles [1; 5-a] pyrimidyl, 1,2-benzisoxa oxazole-3-base, benzimidazolyl-, 2-oxindole base, thiadiazole base and 2-oxo benzimidazolyl-.When heteroaryl contained nitrogen-atoms in ring, such nitrogen-atoms can be the N-oxide form, for example pyridyl N-oxide compound, pyrazinyl N-oxide compound and pyrimidyl N-oxide compound.
" heteroaryloxy " used herein comprises by the substituted oxygen base of arbitrary above-mentioned heteroaryl wherein on the heteroaryl substituting group can being arranged.Useful heteroaryloxy comprises pyridyloxy, pyrazine oxygen base, pyrroles's oxygen base, pyrazoles oxygen base, imidazoles oxygen base and thiophenyl oxygen base.
" heteroaryl alkoxyl group " used herein is meant by the substituted C of arbitrary above-mentioned heteroaryl 1-10Alkoxyl group wherein can have substituting group on the heteroaryl.
Some The compounds of this invention possibly comprise that optically active isomer exists as steric isomer.The present invention includes the racemic mixture of all steric isomers and such steric isomer, and the independent enantiomorph that can separate according to the well-known method of those skilled in the art.
The example of pharmacologically acceptable salt comprises inorganic and organic acid salt, for example hydrochloride, hydrobromate, vitriol, Citrate trianion, lactic acid salt, tartrate, PHENRAMINE MALEATE, fumarate, mandelate and oxalate; And with alkali inorganic and organic alkali salt of forming of sodium hydroxyl, three (hydroxymethyl) amido methane (TRIS, amine trihydroxybutane) and N-NMG for example.
The embodiment of the prodrug of The compounds of this invention comprise the compound that contains carboxylic acid simple ester (for example according to means known in the art through with C 1-4Alcohol condensation and the ester that obtains); Contain the compound of hydroxyl ester (for example according to means known in the art through with C 1-4Carboxylic acid, C 3-6Diacid or its acid anhydrides be succinyl oxide and fumaric acid anhydride condensation and the ester that obtains for example); Contain amino compound imines (for example according to means known in the art through with C 1-4Aldehydes or ketones condensation and the imines that obtains); The carbamate that contains amino compound, for example those esters of people (J.Med.Chem.42:3657-3667 (1999)) descriptions such as people (J.Med.Chem.42:3623-3628 (1999)) such as Leu and Greenwald; Ethylidene ether or the ketone acetal (for example according to means known in the art those acetals) that contain the compound of alcohol through obtaining with chloromethyl methyl ether or chloromethyl ethyl ether condensation.
The compounds of this invention can use method known to those skilled in the art or novel method of the present invention to make.Specifically, have formula I, the The compounds of this invention of formula II or formula III can make shown in the reaction embodiment in the reaction scheme 1.Quinazoline-2, (1H, 3H) diketone and hexamethyldisilazane (HMDS) back flow reaction in the toluene and the vitriol oil gets intermediate product 2 to 4-, 4-two (trimethylsiloxy group) quinazoline.2,4-two (trimethylsiloxy group) quinazoline and 3-bromomethyl-benzoic acid methyl ester react in dioxane and methyl alcohol at DMF then, get product 1-(3-methoxycarbonyl benzyl) quinazoline-2,4-(1H, 3H) diketone.1-(3-methoxycarbonyl benzyl) quinazoline-2, and 4-(1H, 3H) diketone is at sodium hydroxide, and back flow reaction hydrolysis in water and the methyl alcohol gets product 1-(3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone.1-(3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone with replace for example 1-(pyridine-2-yl) piperazine of ammonia; Condensing agent HATU and DIPEA react in DMF; Get title product 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone.Reaction scheme 1
Figure BDA0000053539850000101
Similarly, The compounds of this invention can make shown in the reaction embodiment in the reaction scheme 2.2,4-two (trimethylsiloxy group) quinazoline and 3-brooethyl-6-fluorophenyl carbamate react in dioxane and methyl alcohol at DMF then, get product 1-(4-fluoro-3-methoxycarbonyl benzyl) quinazoline-2,4-(1H, 3H) diketone.1-(4-fluoro-3-methoxycarbonyl benzyl) quinazoline-2, and 4-(1H, 3H) diketone is at sodium hydroxide, and back flow reaction hydrolysis in water and the methyl alcohol gets product 1-(4-fluoro-3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone.1-(4-fluoro-3-formic acid benzyl) quinazoline-2; 4-(1H; 3H) diketone (0.2mmol) with replace for example 1-cyclopentylcarbonyl piperazine of ammonia, condensing agent HATU and DIPEA react in DMF, must title product 1-(4-fluoro-3-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2; 4-(1H, 3H) diketone.Reaction scheme 2
Figure BDA0000053539850000111
An importance of the present invention is to have found formula I, and the compound of formula II and formula III is the PARP suppressor factor.Therefore, these compounds can be used for treating the multiple clinical disease that causes because PARP is unusually active, for example cancer.
The present invention also comprises the formula I that uses significant quantity to animal, the treat-ment of formula II or formula III compound or pharmaceutically acceptable salt thereof or prodrug.Wherein said treat-ment is used to treat the various illnesss that cause because PARP is active unusual (be the disease of PARP mediation, further, the disease of PARP-1 mediation), for example cancer.Such diseases include, but are not limited to cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer , Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, delay, chronic pull cell leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, stomach cancer , colon cancer, malignant pancreatic islet tumors, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head or neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, neuroblastoma , rhabdomyosarcoma, Kaposi's sarcoma, urinary and reproductive system cancer disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytopenic histiocytosis, adrenal cortical carcinoma, skin cancer and prostate cancer.The present invention also comprises and is used to treat PARP (for example PARP-1) active unusual and other necrocytosis property diseases of causing, for example central nervous system disease such as apoplexy and nerve degenerative diseases.
When the embodiment of the present invention treat-ment, use the pharmaceutical prepn of significant quantity for the patient that one or more these symptoms are arranged.Said pharmaceutical prepn contains the formula I of effective treatment concentration, and formula II or formula III compound are formulated into the form that is used for oral, intravenous injection, part or topical administration, are used to treat cancer and other diseases.Dosage is to improve or eliminate the dose of one or more illnesss effectively.For the treatment of specified disease, significant quantity is the dose that is enough to improve or alleviates with some mode the symptom relevant with disease.Such dose can be used as single dose and uses, perhaps can be according to the administration of efficacious therapy scheme.Dosage is also permitted cure diseases, but administration is normally in order to improve the symptom of disease.Generally need repetitively administered to realize required doing well,improving.
The present invention also relates to formula I of the present invention, formula II or formula III compound are used for treating or prevent the purposes by the medicine of the active unusual and disease that causes of PARP in preparation.The disease that said PARP activity causes unusually comprises cancer.In the preferred embodiment, said disease is selected from cancer.In preferred embodiment, said disease is selected from liver cancer, colorectal carcinoma, lung cancer and mammary cancer.In other preferred embodiment, said medicine also can contain other known anticarcinogen, includes but not limited to various known anticarcinogen as herein described.
A kind of medicinal compsns is provided in another embodiment, has wherein contained the formula I of PARP suppressor factor, formula II or formula III compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
Another embodiment of the invention relates to the medicinal compsns that can treat cancer effectively; The formula I that wherein comprises the PARP suppressor factor; Formula II or formula III compound, or its pharmacologically acceptable salt or prodrug, shared with the pharmacologically acceptable salt associating of at least a known cancer therapy drug or cancer therapy drug.The known anticancer drugs that can be used for the anti-cancer combination treatment includes but not limited to dna damage based chemotherapy cancer therapy drug; Comprising alkylating agent for example busulfan, melphalan; TV, endoxan, ifosfamide; TM, bendamustine, cis-platinum, ametycin, bleomycin and carboplatin; Topoisomerase I formulation example such as NSC 94600, irinotecan and hycamtin; The topoisomerase II suppressor factor is Zorubicin for example, pidorubicin, and NSC-208734, mitoxantrone, elliptinium and inscription holder pool are general; For example 5-azepine born of the same parents are general for the RNA/DNA metabolic antagonist, gemcitabine, 5-fluorine urine crows to suck with first atmosphere butterfly chants; The DNA metabolic antagonist is 5-fluoro-2 '-uracil deoxyriboside, fludarabine for example, nelarabine, ara-C, the cry of certain animals of sulphur bird throat, pralatrexate, pemetrexed, hydroxyurea and thioguanine; Antimitotic agent is NSC-757., vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol for example, ipsapirone, cabazitaxel and docetaxel; Antibody is campath for example, Panitumumab, Ofatumumab, Avastin, Trastuzumab and Rituxan; SU11752 for example imatinib, ZD1939, erlotinib, lapatinibditosylate, sorafenib, Sutent, nilotinib, Dasatinib, handkerchief azoles handkerchief Buddhist nun, special cancer accommodates SDZ-RAD; Hdac inhibitor is Vorinostat and romidepsin for example.Other known anticancer drugs that can be used for anticancer combined therapy comprise tamoxifen, letrozole, fulvestrant, mitoguazone, Sostatin, vitamin A acid, arsenic, Zoledronic acid, Velcade, Sa Li polyamines and Revlimid.
When the method for embodiment of the present invention, The compounds of this invention can be used as single medicinal compsns administration with at least a known cancer therapy drug.In addition, The compounds of this invention also can with at least a known anticarcinogen separate administration.An embodiment, the similar administration simultaneously of The compounds of this invention and at least a known anticarcinogen, promptly all medicines are used simultaneously or are used successively, as long as compound reaches treatment concentration simultaneously in blood.In the another one embodiment, compound of the present invention and the dosage administration separately of at least a known anticarcinogen basis are as long as compound reaches treatment concentration in blood.
Another embodiment of the invention is a kind of biological coupling thing of being made up of said compound that can effectively suppress tumour.This biological coupling thing that can suppress tumour is by said compound and the antibody that medical functions is arranged, like Trastuzumab or Rituxan, or growth hormone; Like DGF or NGF; Or cytohormone, like interleukin II or 4, or arbitrarily can with the molecular composition of cell surface bonded.This antibody and other molecular energies are delivered to its target spot to said compound, make it to become effective cancer therapy drug.This biological coupling thing also can improve the antibody that medical functions is arranged, like the anticancer effect of Trastuzumab or Rituxan.
Another embodiment of the present invention relates to a kind of medicinal compsns that can effectively suppress tumour, comprises the formula I of PARP suppressor factor, formula II or formula III compound, but or its medication salt or prodrug, with the radiotherapy combination therapy.At this embodiment, The compounds of this invention can be in identical time or different time administration with radiotherapy.
Another embodiment of the present invention relates to a kind of medicinal compsns of treating behind the cancer operation of effectively being used for, and comprises the formula I of PARP suppressor factor, formula II or formula III, but or its medication salt or prodrug.The invention still further relates to and use ocal resection, then with this mammiferous treatment for cancer method of medicinal compsns treatment of the present invention.
Medicinal compsns of the present invention comprises that the amount of all The compounds of this invention can realize the medicine preparation of its re-set target effectively.Though everyone demand has nothing in common with each other, those skilled in the art can confirm the optimal dose of each part in the medicine preparation.Generally speaking, said compound, but or its medication salt, to mammal oral administration every day, dose is according to about 0.0025 to 50 milligram/kg body weight.But preferably the per kilogram oral administration is about 0.01 to 10 milligram.If also use a known cancer therapy drug, its dosage should be realized its its intended purposes effectively.The optimal dose of these known cancer therapy drugs is well-known to those skilled in the art.
The unit oral dosage can comprise about 0.01 to 50 milligram, preferably about 0.1 to 10 milligram The compounds of this invention.Unitary dose can give one or many, and be one or more pieces every day, and every contains and has an appointment 0.1 to 50 milligram, eligibly about 0.25 to 10 milligram The compounds of this invention or its solvolyte.
In the external application preparation, the concentration of The compounds of this invention can be about 0.01 to 100 milligram of every gram carrier.
The compounds of this invention can be used as undressed medicine administration.The compounds of this invention also can be used as a part of administration of a suitable pharmaceutical preparation that contains pharmaceutically suitable carrier (comprising auxiliary material, auxiliary agent).These pharmaceutically acceptable carrier help being processed into pharmaceutically useful pharmaceutical prepn to compound.Preferred drug substances, particularly those oral and preferred administering mode types, like tablet, lozenge and capsule, and be suitable for injecting or oral solution, comprise about 0.01% to 99%, preferably from about 0.25% to 75% reactive compound and auxiliary material.
Scope of the present invention also comprises the nontoxicity pharmacologically acceptable salt of The compounds of this invention.Acid salt forms by mixing nontoxicity pharmaceutically acceptable acid solution and compound solution of the present invention.Said acid is hydrochloric acid for example, fumaric acid, toxilic acid, succsinic acid, acetate, Hydrocerol A, tartrate, carbonic acid, phosphoric acid, oxalic acid etc.Base addition salt forms by mixing a pharmaceutically acceptable alkaline solution of nontoxicity and compound solution of the present invention.Said alkali is sodium hydroxide for example, Pottasium Hydroxide, hydrogen choline, yellow soda ash, Tris, N-methyl-glycamine etc.
Pharmaceutical preparation of the present invention can give any mammal, as long as they can obtain the result of treatment of The compounds of this invention.Of paramount importance in these Mammalss is the mankind and veterinary animal, though that the present invention does not plan is so limited.
Pharmaceutical prepn of the present invention can be through any administration to reach its intended purposes.For example, can pass through outside the intestines, subcutaneous, vein, muscle, in the abdominal cavity, transdermal, the oral cavity, in the sheath, encephalic, nasal cavity or external application administration.As an alternative or concurrently, can the administered through oral administration.The dosage of medicine will be according to patient's age, health and body weight, and the kind of concurrent treatment, the frequency of treatment, and required treatment benefit decides.
Pharmaceutical prepn of the present invention can be made in a known manner.For example,, granulate system ingot, dissolving, or freezing dry process manufacturing by traditional mixing.When making oral prepns, can combine solid adjuvant material and active compound, the selectivity grinding mixture.After adding appropriate amount of addition agent if desired or in case of necessity, the processing granular mixture obtains tablet or lozenge core.
Proper supplementary material is filler particularly, for example carbohydrate such as lactose or sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose preparation or calcium phosphate, for example tricalcium phosphate or secondary calcium phosphate; And sticker, for example starch paste comprises W-Gum, wheat starch, Starch rice, yam starch, gelatin, tragacanth, methylcellulose gum, Vltra tears, Xylo-Mucine, or Vinylpyrrolidone polymer.If desired, can increase disintegrating agent, such as starch above-mentioned, and CMS; Cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt are like sodium-alginate. and auxiliary is flowing regulator and lubricant particularly; For example, silica, talcum; Stearates, like the magnesium calcium stearate, Triple Pressed Stearic Acid or polyoxyethylene glycol.If desired, can examine core to lozenge the suitable dressing that can resist gastric juice is provided.For this reason, can use concentrated saccharide solution.This solution can contain Sudan Gum-arabic, talcum, Vinylpyrrolidone polymer, polyoxyethylene glycol and/or titanium oxide, lacquer solution and appropriate organic solvent or solvent mixture.In order to prepare the dressing of resistant to gastric juice, can use suitable cellulose solution, for example FM phthalic acid or Vltra tears phthalic acid.Can add dyestuff or pigment to the dressing of tablet or lozenge nuclear core.For example, be used to discern or in order to characterize the combination of activeconstituents dosage.
The pharmaceutical prepn of other taking orally comprises the compression joint type capsule that gelatin is processed, and the sealing soft capsule of processing with softening agent such as gelatin and glycerine or sorbyl alcohols.This compression joint type capsule can contain the active compound of particle form, and with filler lactose for example, sticker is starch for example, and lubricant is talcum powder or Magnesium Stearate for example, and stablizer mixes.At soft capsule, active compound preferably is dissolved or suspended in suitable liquid for example in grease or the whiteruss, wherein can add stablizer.
The preparation that is appropriate to the intestines external administration comprises the aqueous solution of reactive compound, like the solution and the alkaline solution of water soluble salt.In addition, can use the oily injection suspensions of suitable active compound.Suitable lipophilic solvent or carrier comprise for example sesame oil of grease, and Acrawax is OE for example, triglyceride level or PEG 400, cremophor, or Schardinger dextrins.Water injection suspension liquid can contain the material that increases the suspension-s viscosity, Xylo-Mucine for example, sorbyl alcohol, or VISOSE.Also can contain suspension stabilizer.
External preparation of the present invention can be processed finish through preferred suitable carriers, creme, emulsion agent, ointment etc.Suitable carriers comprises plant or MO, white mineral oil (paraffinum molle alba), and chain fatty or grease, animal tallow and high molecular alcohol are (greater than C 12).Preferred carrier is that activeconstituents can be dissolved in those carriers wherein.Also can comprise emulsifying agent, stabilizing agent, NMF and antioxidant, and if necessary, give the reagent of color or fragrance.In addition, these external preparations can comprise the transdermal penetration toughener.The example of this toughener can be referring to U.S. Patent number 3,989, and 816 and 4,444,762.
Creme is preferably used MO, the preparation of the mixture of self-emulsifying beeswax and water, be dissolved in minor amount of oil for example the activeconstituents of Prunus amygdalus oil mix.A typical creme example comprises about 40 parts of water, 20 parts of beeswaxs, 40 parts of MO and 1 portion of Prunus amygdalus oil.
Ointment can be prepared like this, will contain the for example Prunus amygdalus oil and the warm soft wax mixing of vegetables oil of activeconstituents, makes this mixture cooling then.A typical ointment example comprises the Prunus amygdalus oil of about 30% weight and the paraffinum molle alba of 70% weight.
The application also relates to formula I of the present invention, II or the III compound purposes in the compsn (for example medicinal compsns) of active (the especially activity of the PARP-1) usefulness of preparation inhibition PARP.
The following example is to illustrate, rather than limits method and formulation of the present invention.Suitable modification and improvement that other will become apparent to those skilled in the art that and in clinical treatment, can run into usually to various conditions and parameter, all within the spirit and scope of the present invention.The general explanation of embodiment agents useful for same all is commercial qualities.Solvent is all according to the dry purifying of standard method.Analytical data of mass spectrum is measured (platform II, Agilent 6110) with single level Four bar mass spectrograph of electron spray(ES).The hydrogen spectrum is measured by Br ü cker AMX300 million nuclear magnetic resonance spectrometers under 300 ° of K of temperature.It is unit from low beginning with ppm as interior mark (0.00ppm) that chemical shift is recorded as with TMS, and coupling constant J value is unit with the hertz.Embodiment 11-(3-methoxycarbonyl benzyl) quinazoline-2,4-(1H, 3H) diketone is quinazoline-2,4-(1H, 3H) diketone (1.0g, 6.2mmol), hexamethyldisilazane (HMDS; 2.5g, 15.4mmol) join in two mouthfuls of bottles of 100mL with toluene 50mL, stir adding vitriol oil 0.06g down, back flow reaction 8h.Toluene and excessive HMDS are removed in underpressure distillation, get intermediate product 2,4-two (trimethylsiloxy group) quinazoline.
In 50mL single port bottle, add intermediate product 2 successively, (2.1g 9.2mmol) and DMF (1mL), is warming up to 115-130 ℃ of reaction 3h for 4-two (trimethylsiloxy group) quinazoline, 3-bromomethyl-benzoic acid methyl ester.Add dioxane (6mL) and methyl alcohol (10mL) after being cooled to 100 ℃, backflow 0.5h.After being cooled to room temperature, filter.Filter cake is water (20mL) and methyl alcohol (10mL) washing respectively, and oven dry gets white solid 1-(3-methoxycarbonyl benzyl) quinazoline-2,4-(1H, 3H) diketone (1.6g, 83.7%). 1H NMR (DMSO-d 6): 11.76 (s, 1H), 8.00 (dd, J=7.8,1.2Hz, 1H), 7.89 (s, 1H), 7.83 (d, J=7.8Hz, 1H), 7.65-7.43 (m, 3H), 7.23 (m, 2H), 5.36 (s, 2H), 3.80 (s, 3H) .MS:m/z311 [M+H] +. embodiment 21-(3-formic acid benzyl) quinazoline-2, and 4-(1H, 3H) diketone adds 1-(3-methoxycarbonyl benzyl) quinazoline-2 in the 250mL there-necked flask; 4-(1H, 3H) diketone (1.6g, 5.2mmol), sodium hydroxide (0.31g; 7.7mmol), water (40mL) and methyl alcohol (40mL), back flow reaction 3h.After reaction finished, methyl alcohol was removed in underpressure distillation, had a large amount of solids to separate out with 3N hydrochloric acid adjust pH to 2-3.Filter, filter cake water and methanol wash, dry white solid 1-(3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone (1.2g, 78%yield). 1H NMR (300M, DMSO-d 6): 13.09 (sb, 1H), 11.77 (s, 1H), 8.01 (d, J=6.6Hz, 1H), 7.82 (m, 2H), 7.63 (m, 1H), 7.53 (d, J=7.8Hz, 1H), 7.44 (t, J=7.8Hz, 1H), 7.24 (m, 2H), 5.36 (s, 2H) .MS:m/z 297 [M+H] +. embodiment 31-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, and 4-(1H, 3H) diketone adds compound 1-(3-formic acid benzyl) quinazoline-2 in the 50mL two-mouth bottle; 4-(1H, 3H) diketone (0.2mmol), 1-(pyridine-2-yl) piperazine (0.2mmol), 2-(7-azepine-1H-benzotriazole-1-yl)-1,1; 3, and 3-tetramethyl-urea phosphofluoric acid ester (HATU, 0.26mmol), N; The N-diisopropylethylamine (DIPEA, 0.4mmol) and DMF (5mL), stirring at room 3h.Add entry 50mL, extract with methylene dichloride (50mL x 2).Organic layer is used saturated brine (50mL x 2) washing again with 1N HCl (50mL x 2) washing, anhydrous sodium sulfate drying, and concentrating under reduced pressure gets crude product.Through column chromatography (ETHYLE ACETATE) title product 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone be white solid (7.7mg, 8.6%yield). 1H NMR (DMSO-d 6): 11.69 (s, 1H), 8.09 (d, J=3.3Hz, 1H), 7.99 (d, J=6.3Hz; 1H), 7.64 (t, J=6.9Hz, 1H), 7.53 (t, J=7.8Hz; 1H), 7.40-7.21 (m, 6H), 6.77 (d, J=8.7Hz, 1H); 6.64 (m, 1H), 5.34 (s, 2H), 3.40-3.20 (m, 8H) .MS:m/z 442.3 [M+H] +. the compound method that following compound application class is similar to described embodiment 3 makes, and starting raw material is 1-(3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone and pairing substituted-piperazinyl or piperidines.Embodiment 41-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.71 (s, 1H), 8.36 (d, J=4.8Hz, 2H), 8.01 (d, J=6.9Hz, 1H), 7.64 (t, J=6.9Hz, 1H), 7.42-7.24 (m, 6H), 6.65 (t, J=4.8Hz, 1H), 5.35 (s, 2H), 3.40-3.20 (m, 8H) .MS:m/z 443.3 [M+H] +. embodiment 51-(3-(4-cyclohexyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.74 (s, 1H), 8.00 (d, J=7.8Hz, 1H), 7.62 (t, J=7.5Hz, 1H); 7.38 (m, 2H), 7.26-7.20 (m, 4H), 5.33 (s, 2H), 3.40-3.20 (m; 4H), 2.19 (m, 4H), 1.96-1.70 (m, 5H), 1.14 (m, 6H) .MS:m/z 447.3 [M+H] +. embodiment 61-(3-(4-([1,2,4] triazolo [4,3-b] pyridazine-6 base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.73 (s, 1H), 9.24 (s, 1H), 8.12 (d, J=10.2Hz, 1H), 8.02 (d, J=7.8Hz, 1H), 7.66 (t, J=6.9Hz, 1H), 7.42-7.24 (m, 7H), 5.36 (s, 2H), 3.40-3.20 (m, 8H) .MS:m/z 483.3 [M+H] +. embodiment 71-(3-(4-ethyl piperazidine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.72 (s, 1H), 8.01 (d, J=7.8Hz, 1H), 7.62 (t, J=8.1Hz, 1H), 7.38 (m, 2H), 7.24 (m, 4H), 5.34 (s, 2H), 3.40-3.20 (m, 4H), 2.31 (m, 5H), 0.97 (t, J=7.2Hz, 3H) .MS:m/z 393.2 [M+H] +. embodiment 81-(3-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.71 (s, 1H), 7.97 (d, J=8.1Hz, 1H), 7.59 (s, 1H), 7.50-7.25 (m, 9H), 7.18 (s, 2H), 5.34 (s, 2H), 3.40-3.20 (m, 8H) .MS:m/z 469.3 [M+H] +. embodiment 91-(3-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.71 (s, 1H), 7.99 (d, J=7.8Hz, 1H), 7.60-7.19 (m, 11H), 5.34 (s, 2H), 3.60-3.20 (m, 8H) .MS:m/z 487.3 [M+H] +. embodiment 101-(3-(4-(4-chlorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.73 (s, 1H), 7.97 (m, 1H), 7.52-7.19 (m, 11H), 5.33 (s, 2H), 3.75-3.15 (m, 8H) .MS:m/z 503.2,505.2 [M+H] +. embodiment 111-(3-(4-(4-bromobenzene formyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.74 (s, 1H), 7.97 (m, 2H), 7.67 (m, 2H), 7.40-7.15 (m, 8H), 5.35 (s, 2H), 3.40-3.20 (m, 8H) .MS:m/z 547.2,549.2 [M+2H] +. embodiment 121-(3-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.73 (s, 1H), 7.99 (d, J=7.2Hz, 1H), 7.59 (m; 1H), 7.40-7.29 (m, 6H), 7.20 (d, J=8.7Hz, 2H); 6.97 (d, J=8.7Hz, 2H), 5.33 (s, 2H), 3.77 (s; 3H), 3.56-3.15 (m, 8H) .MS:m/z 499.3 [M+1]. embodiment 131-(3-(4-(tetrahydrochysene-2H-pyrans-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.74 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.75-7.60 (m; 1H), 7.41 (m, 2H), 7.32-7.23 (m, 4H), 5.36 (s; 2H), 3.83 (m, 2H), 3.75-3.10 (m, 10H), 2.84 (m; 1H), 1.52 (m, 4H) .MS:m/z 477.3 [M+1]. embodiment 141-(3-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.71 (s, 1H), 8.01 (d, J=6.9Hz, 1H), 7.63 (m; 1H), and 7.41-7.39 (m, 2H), 7.30-7.21 (m, 4H); 5.34 (s, 2H), 3.70-3.10 (m, 8H), 2.92 (m; 1H), 1.80-1.40 (m, 8H) .MS:m/z 461.3 [M+1]. embodiment 151-(3-(4-cyclopropyl carbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.71 (s, 1H), 8.01 (d, J=6.6Hz, 1H), 7.63 (t, J=7.2Hz, 1H), 7.41-7.21 (m, 6H), 5.34 (s, 2H), 3.80-3.15 (m, 9H), 0.72-0.69 (m, 4H) .MS:m/z 433.2 [M+H] +. embodiment 161-(3-(4-ethyl sulphonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.74 (s, 1H), 8.01 (d, J=7.8Hz, 1H), 7.70-7.55 (m; 1H), 7.41 (m, 2H), 7.31-7.19 (m, 4H), 5.35 (s; 2H), and 3.75-3.11 (m, 6H), 3.10-2.90 (m, 4H); 1.20 (t, J=7.4Hz, 3H) .MS:m/z 457.2 [M+1]. embodiment 171-(3-(4-methyl carbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (DMSO-d 6): 11.71 (s, 1H), 8.01 (d, J=6.6Hz, 1H), 7.63 (t, J=7.2Hz, 1H), 7.41 (m, 2H), 7.30-7.21 (m, 4H), 5.34 (s, 2H), 3.70-3.10 (m, 8H), 1.93 (s, 3H) .MS:m/z 407.2 [M+H] +. embodiment 181-(3-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (300M, DMSO-d 6): 11.75 (s, 1H), 7.98 (d, J=6.6Hz, 1H), 7.61 (t, J=7.2Hz, 1H), 7.41-7.17 (m, 11H), 5.37 (s, 2H), 3.32 (m, 2H), 3.05 (m, 1H), 2.73 (m, 2H), 1.97-1.51 (m, 4H) .MS:m/z 407.2 [M+H] +. embodiment 191-(3-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (300M, DMSO-d 6): 11.75 (s, 1H), 8.03 (d, J=6.6Hz, 1H), 7.67 (t, J=7.2Hz; 1H), 7.43 (m, 2H), 7.34-7.21 (m, 6H), 6.92 (d, J=8.1Hz; 2H), 6.81 (t, J=7.2Hz, 1H), 5.37 (s, 2H); 3.71 (m, 2H), 3.16 (m, 4H), 2.96 (m, 2H) .MS:m/z 441.3 [M+H] +. embodiment 201-(3-(4-(pyrazine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (300M, DMSO-d 6): 11.75 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 8.02 (d, J=7.8Hz, 1H), 7.88 (s, 1H), 7.67 (t, J=7.2Hz, 1H), 7.44-7.24 (m, 6H), 5.37 (s, 2H), 3.80-3.25 (m, 8H) .MS:m/z 443.3 [M+H] +. embodiment 211-(4-fluorine 3-methoxycarbonyl benzyl) quinazoline-2, (1H, 3H) the diketone compound method is similar to embodiment 1 to 4-.White solid.MS:m/z 329.1 [M+H] +. embodiment 221-(4-fluoro-3-formic acid benzyl) quinazoline-2, (1H, 3H) the diketone compound method is similar to embodiment 2 to 4-.White solid.MS:m/z315.3 [M+H] +. the compound method that following compound application class is similar to described embodiment 3 makes, and starting raw material is 1-(4-fluoro-3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone and pairing substituted-piperazinyl.Embodiment 231-(4-fluoro-3-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (300M, DMSO-d 6): 11.73 (s, 1H), 8.00 (d, J=6.9Hz, 1H), 7.64 (t, J=7.8Hz, 1H), 7.43-7.21 (m, 5H), 5.30 (s, 2H), 3.56-2.97 (m, 8H), 2.86 (m, 1H), 1.80-1.40 (m, 8H) .MS:m/z 479.3 [M+H] +. embodiment 241-(4-fluoro-3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (300M, DMSO-d 6): 11.74 (s, 1H), 8.12 (d, J=3.3Hz, 1H), 8.02 (d, J=6.6Hz, 1H); 7.67 (m, 1H), 7.56 (m, 1H), 7.41 (m, 2H), 7.32-7.24 (m, 3H); 6.82 (d, J=8.4Hz, 1H), 6.67 (m, 1H), 5.32 (s, 2H); 3.71 (m, 2H), 3.57 (m, 2H), 3.37 (m.2H), 3.25 (m, 2H) .MS:m/z 460.3 [M+H] +. embodiment 251-(4-fluoro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone white solid. 1H NMR (300M, DMSO-d 6): 11.72 (s, 1H), 8.37 (d, J=4.8Hz, 2H), 8.00 (d, J=7.8Hz; 1H), 7.65 (t, J=6.8Hz, 1H), 7.30 (m, 2H), 7.25 (m; 3H), 6.66 (t, J=4.8Hz, 1H), 5.31 (s, 2H); 3.79 (m, 2H), 3.67-3.60 (m, 4H), 3.21 (m, 2H) .MS:m/z 461.3 [M+H] +. embodiment 26 uses MTT cancer cells toxicity test and measures 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2; 4-(1H; 3H) diketone and its resemblance are used MTT cancer cells toxicity test to the synergistic enhancing effect of the inhibition cell enlargement effect of methyl methylsulfonate (MMS); Human colon cancer cell SW620 is used to measure the PARP suppressor factor to dna damage kind anti-cancer drugs thing, for example the synergistic enhancing effect of the inhibition cell enlargement effect of methyl methylsulfonate (MMS).RPMI 1640 (Gibco) substratum contains 10%FBS (Hyclone) and is used to culturing cell.Tested first day, and with in cell seeding to the 96 porocyte culture plate, placed 5%CO with 4000 cells/well 2The inherent 37 ℃ of overnight cultures of incubator.Removed cell culture fluid in second day, every hole adds the fresh culture that 180 μ l contain MMS 1.5 μ g/ml.Add 20 μ l then and contain the positive compound (AZD2281 and ABT-888) or the testing compound of 10 times of concentration.Positive compound and testing compound carry out the continuous series dilution by 1: 3 and 1: 10 usefulness DMSO.The diluent of ten times of concentration is mixed with by 10 μ l DMSO diluents and 90 μ l fresh cultures and forms.The ultimate density of DMSO is 1% in the nutrient solution.Cell is put back to 5%CO then 2Incubator is cultivated 5 days (120 hours) for inherent 37 ℃.Taking out 96 porocyte culture plates afterwards adds 20 μ l MTT (concentration) and hatched 4 hours at 37 ℃ in every hole.Remove nutrient solution, in every hole, add 100 μ l DMSO, shake well 10 minutes.96 orifice plates are put into ELIASA, and 520/690nm carries out reading.Data analysis is carried out with Prism 5 softwares of GraphPad company.Data draw IC by with the compound concentration of logarithmetics the difference of 520/690nm reading being mapped and carried out the curve equation model with equation 50Value, Y (absorption value)=minimal absorption value+(obtained the maximum absorption-minimal absorption value)/(1+10^ (the logarithmetics compound concentration-LogIC50)).The IC that calculates 50Value is meant the synergistic enhancing effect of specific compound to the inhibition cell enlargement effect of methyl methylsulfonate (MMS), is summarised in the form 1.Form 1. compounds are to the IC of the synergistic enhancing effect of the inhibition cell enlargement effect of MMS 50Value.
Embodiment MTT synergistic enhancing effect IC 50(nM)
1 ＞10000
2 ＞10000
3 90
4 12
5 5356
6 7026
7 5269
8 112
9 500
10 439
11 618
12 533
13 727
14 102
15 666
16 7259
17 ＞10000
18 ＞10000
23 8.2
24 26
25 9.8
AZD2281 28
ABT-888 2642
Therefore; Through measuring 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2; 4-(1H, 3H) diketone (embodiment 3) and its resemblance are to dna damage kind anti-cancer drugs thing, and for example the inhibition cell enlargement effect of methyl methylsulfonate (MMS) has good synergistic enhancing effect.Embodiment 27 uses Caspase-3 enzymic activity measuring 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2; 4-(1H; 3H) diketone and its resemblance are used to measure the PARP-1 suppressor factor to dna damage kind anti-cancer drugs thing to the synergistic enhancing effect people source breast cancer cell T47D of the cell death inducing effect of methyl methylsulfonate (MMS), for example the synergistic enhancing effect of the cell death inducing effect of methyl methylsulfonate (MMS).The vigor of Caspase-3 is used as detects apoptotic index.DMEM/F12 (Hyclone) substratum contains 0.2U/mL Regular Insulin (Genview) and 10%FBS (Hyclone) is used to cultivate the T47D cell.Test previous day, with in cell seeding to the 96 porocyte culture plate, place 37 ℃ at 5%CO with 20000 cells/well 2The incubator overnight cultures.Remove nutrient solution next day, every hole adds the fresh culture that 180 μ l contain 100nM MMS (Sigma) respectively.Add 20 μ l then and contain the positive compound (AZD2281 and ABT-888) or the testing compound of 10 times of concentration.Positive compound and testing compound carry out the continuous series dilution by 1: 3 and 1: 10 usefulness DMSO.The diluent of ten times of concentration is mixed with by 10 μ l DMSO diluents and 90 μ l fresh cultures and forms.Behind the 24h, culture plate in the centrifugal 5min of 1000g, is removed supernatant, every hole adds 50 μ l cell pyrolysis liquids (Lysis Buffer:10mM Tris, pH7.5,0.1M NaCl, 1mM EDTA, 0.01%Triton X-100) at 4 ℃ of level vibration 30min.Then behind 4 ℃ of centrifugal 10min of 1000g; Draw respectively 20 μ l supernatants to the corresponding 384 hole blackboards from every hole; Every subsequently hole adds 20 μ l and contains 20 μ M caspase-3 fluorogenic substrate ((Ac-DEVD) 2-R110; AnaSpec Cat #60304-5) damping fluid (20mM PIPES, pH7.4,4mMEDTA and 0.2%CHAPS).Hatch 3h in 37 ℃ behind the concussion mixing, in ex:496nm, fluorescence intensity under the em:520nm (Varioskan Flash, Thermo Fisher Scientific).Compound inductive caspase-3 activity is expressed with relative intensity of fluorescence (RFU).Data analysis is carried out with Prism 5 softwares of GraphPad company.Data draw the EC50 value, Y (fluorescent value)=minimum fluorescence reading+(maximum fluorescence reading-minimum fluorescence reading)/(1+10^ (LogEC50-logarithmetics compound concentration)) by with the compound concentration of logarithmetics Caspase vigor index fluorescent value being mapped and carried out the curve equation model with equation.EC 50Value with S shape dose response curve equation model measure (GraphPad Software, Inc).Compound is to the EC of the synergistic enhancing effect of the cell death inducing effect of methyl methylsulfonate (MMS) 50Value is summarised in the form 2.Form 2. compounds are to the EC of the synergistic enhancing effect of the cell death inducing effect of MMS 50Value
Embodiment Caspase synergistic enhancing effect EC 50(nM)
1 ＞10,000
2 ＞10,000
3 56
4 12
5 450
6 2518
7 2655
8 120
9 426
10 400
11 214
12 318
13 6601
14 39
15 803
16 9206
17 5018
18 ＞10000
19 ＞10000
20 139
23 4.0
24 20
25 3.9
AZD2281 24
ABT-888 3494
Therefore; Through measuring 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2; 4-(1H, 3H) diketone (embodiment 3) and its resemblance are to dna damage kind anti-cancer drugs thing, and for example the cell death inducing effect of methyl methylsulfonate (MMS) has good synergistic enhancing effect.Wherein embodiment 23 and 25 specific activity positive compound AZD2281 are strong about 5 times.Embodiment 28 Using P ARP-1 enzymic activity measuring 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2; 4-(1H; 3H) diketone and its resemblance are to adopt 96 hole chemical luminescence reagent kit (4676-096-K of Trevigen company to the retarding effect PARP-1 enzymic activity of PARP-1 enzymic activity; Trevigen, Inc.Gaithersburg, MD 20877USA) test.In simple terms, 96 hole chemical luminescence reagent kits of Trevigen company adopt histone to measure PARP-1 catalytic biotin labeled gathering (ADP-ribose) polymerization above that as carrier, monitor with chemiluminescence method then.Positive compound (AZD2281) and testing compound carry out the continuous series dilution by 1: 10 usefulness 1X damping fluid.In the hole that is attached with histone accordingly, add positive compound or the testing compound that 10 μ l contain 5 times of concentration, the PARP enzyme total amount of 15 μ l is every hole 0.5 unit and 25 μ l reaction solutions.Cultivating incubated at room 60 minutes.The washings that adds 0.1%Triton X-100 with 200 μ l PBS afterwards washes twice and 200 μ l PBS wash twice.Gently knock on the paper handkerchief remove unnecessary liquid after every hole add the Strep-HRP solution of 50 μ l.Room temperature was cultivated 60 minutes.The washings that adds 0.1%Triton X-100 with 200 μ lPBS more afterwards washes twice and 200 μ l PBS wash twice, on paper handkerchief, gently knocks and removes unnecessary liquid.With equal-volume mixing PeroxyGlow TMBehind solution A and the B, every hole adds to be put into Varioskan Flash ELIASA (Thermo Fisher Scientific) behind the 100 μ l and carries out chemiluminescence readings at once.Data analysis is carried out with Prism 5 softwares of GraphPad company.Data draw IC by with the compound concentration of logarithmetics chemiluminescence readings being mapped and carried out the curve equation model with equation 50Value, Y (values of chemiluminescence)=minimum value+(obtained the maximum absorption-minimal absorption value)/(1+10^ (the logarithmetics compound concentration-LogIC50)).Compound is to the EC of the retarding effect of PARP-1 enzymic activity 50Value is summarised in the form 3.Form 3. compounds are to the IC of the retarding effect of PARP-1 enzymic activity 50Value
Embodiment IC 50(nM)
3 4.2
4 0.96
8 5.3
14 2.3
AZD2281 2.2
Therefore,through measuring 1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, (1H, 3H) diketone (embodiment 3) has the good restraining effect with its resemblance to the PARP-1 enzymic activity to 4-.Though described the present invention fully, it will be appreciated by those skilled in the art that and under the situation that does not influence the scope of the invention or its any embodiment, extensively and in condition, preparation and other parameter area of being equal to carry out identical enforcement.All patents, patented claim and the publication that this paper quoted all introduced this paper for your guidance in full.

Claims (15)

1. the compound of formula I, or its pharmacologically acceptable salt or prodrug:
Figure FDA0000053539840000011
Wherein, Ar is can substituted aryl or can substituted heteroaryl;
R 1-R 6Independent be hydrogen, halogen, can substituted amino, can substituted alkoxyl group, can substituted C 1-10Alkyl, alkylhalide group, thiazolinyl, alkynyl, hydroxyalkyl, amido alkyl, carboxyalkyl, nitro, cyanic acid, carboxamido-group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base or can substituted alkylthio; R wherein 4It or not hydroxyl.
2. the compound of claim 1, wherein R 5And R 6Be hydrogen, Ar is can substituted phenyl or pyridyl.
3. the compound of formula II, or its pharmacologically acceptable salt or prodrug:
Figure FDA0000053539840000012
Wherein, R 1-R 4Independent be hydrogen, halogen, can substituted amino, can substituted alkoxyl group, can substituted C 1-10Alkyl, alkylhalide group, thiazolinyl, alkynyl, hydroxyalkyl, amido alkyl, carboxyalkyl, nitro, cyanic acid, carboxamido-group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base or can substituted alkylthio; R wherein 4It or not hydroxyl;
R 7-R 11Independent be hydrogen, halogen, can substituted amino, alkoxyl group, C 1-10Alkyl; Alkylhalide group; Aryl; Carbocylic radical; Heterocyclic radical; Heteroaryl; Alkenyl; Alkynyl; Arylalkyl; Aromatic yl alkenyl; Aromatic yl polysulfide yl; Heteroarylalkyl; The heteroaryl alkenyl; The heteroaryl alkynyl; The carbocyclic ring alkyl; Heterocyclylalkyl; Hydroxyalkyl; The hydroxy alkoxy base; The amido alkyl; The amido alkoxyl group; Carboxyalkyl; The carboxyl alkoxyl group; Nitro; Cyanic acid; Carboxamido-group; Aminocarboxyl; Hydroxyl; Sulfydryl; Acyloxy; Azido-; Carboxyl; The oxyamide base; Alkyl sulphonyl; The amido alkylsulfonyl; Two substituted alkyl amido alkylsulfonyls; Alkyl sulphinyl; Alkylthio; Or substituted carbonyl.
4. the compound of claim 3, wherein R 8Be substituted carbonyl.
5. the compound of formula III, or its pharmacologically acceptable salt or prodrug:
Figure FDA0000053539840000021
Wherein, R 1-R 4Independent be hydrogen, halogen, can substituted amino, can substituted alkoxyl group, can substituted C 1-10Alkyl, alkylhalide group, thiazolinyl, alkynyl, hydroxyalkyl, amido alkyl, carboxyalkyl, nitro, cyanic acid, carboxamido-group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base or can substituted alkylthio; R wherein 4It or not hydroxyl;
R 7, R 9-R 11Independent be hydrogen, halogen, can substituted amino, alkoxyl group, C 1-10Alkyl; Alkylhalide group; Aryl; Carbocylic radical; Heterocyclic radical; Heteroaryl; Alkenyl; Alkynyl; Arylalkyl; Aromatic yl alkenyl; Aromatic yl polysulfide yl; Heteroarylalkyl; The heteroaryl alkenyl; The heteroaryl alkynyl; The carbocyclic ring alkyl; Heterocyclylalkyl; Hydroxyalkyl; The hydroxy alkoxy base; The amido alkyl; The amido alkoxyl group; Carboxyalkyl; The carboxyl alkoxyl group; Nitro; Cyanic acid; Carboxamido-group; Aminocarboxyl; Hydroxyl; Sulfydryl; Acyloxy; Azido-; Carboxyl; The oxyamide base; Alkyl sulphonyl; The amido alkylsulfonyl; Two substituted alkyl amido alkylsulfonyls; Alkyl sulphinyl; Alkylthio; Or substituted carbonyl;
R 12For can substituted amino, alkoxyl group, C 1-10Alkyl, alkylhalide group, aryl, carbocylic radical, heterocyclic radical, heteroaryl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroaryl alkenyl, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, amido alkyl, amido alkoxyl group, carboxyalkyl, carboxyalkyl, carboxamido-group, sulfydryl, oxyamide base, alkyl sulphonyl or amido alkylsulfonyl.
6. the compound of claim 5, wherein R 12Be can substituted amino, can substituted aryl, can substituted carbocylic radical, can substituted heterocyclic radical or can substituted heteroaryl.
7. the compound of claim 1,3 and 5, wherein said compound is selected from:
1-(3-methoxycarbonyl benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-formic acid benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-cyclohexyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-([1,2,4] triazolo [4,3-b] pyridazine-6 base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-ethyl piperazidine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(4-chlorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(4-bromobenzene formyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(tetrahydrochysene-2H-pyrans-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-cyclopropyl carbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-ethyl sulphonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-methyl carbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(3-(4-(pyrazine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(4-fluoro-3-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(4-fluoro-3-(4-(pyridine-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
1-(4-fluoro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4-(1H, 3H) diketone;
Or its pharmacologically acceptable salt or prodrug.
8. the purposes of each described compound in the medicine of the disease of preparation treatment PARP mediation in the claim 1～7.
According to claim 8, wherein said disease is cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, delay, chronic pull cell leukemia, primary brain cancer, malignant melanoma small cell lung cancer, stomach cancer, colon cancer, malignant pancreatic islet tumors, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head or neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, urinary and reproductive system cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera , idiopathic thrombocythemia, adrenal cortical carcinoma, skin cancer or prostate cancer.
10. the purposes of claim 9, wherein said medicine also comprises at least a known cancer therapy drug, or the pharmacologically acceptable salt of said cancer therapy drug.
11. the purposes of claim 10, wherein said cancer therapy drug is selected from down group: busulfan, melphalan, TV, endoxan, ifosfamide; TM, bendamustine, cis-platinum, ametycin, bleomycin, carboplatin, NSC 94600, irinotecan, hycamtin; Zorubicin, pidorubicin, NSC-208734, mitoxantrone; Elliptinium, inscription holder pool is general, and 5-azepine born of the same parents are general, gemcitabine, 5-fluorine urine are crowed and suck, the cry of certain animals of first atmosphere butterfly; 5-fluoro-2 '-uracil deoxyriboside, fludarabine, nelarabine, ara-C, the cry of certain animals of sulphur bird throat, pralatrexate, pemetrexed, hydroxyurea, thioguanine; NSC-757., vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol, ipsapirone, cabazitaxel, docetaxel, campath; Panitumumab, Ofatumumab, Avastin, Trastuzumab, Rituxan, imatinib, ZD1939, erlotinib, lapatinibditosylate, sorafenib, Sutent, nilotinib, Dasatinib, handkerchief azoles handkerchief Buddhist nun, special cancer are fitted; SDZ-RAD, Vorinostat, romidepsin, tamoxifen; Letrozole, fulvestrant, mitoguazone, Sostatin, vitamin A acid, arsenic, Zoledronic acid, Velcade, Sa Li polyamines or Revlimid.
12. the purposes of claim 9, wherein said medicine and radiotherapy coupling.
13. a medicinal compsns comprises each described compound and pharmaceutically acceptable carrier in the claim 1～7.
14. the medicinal compsns of claim 13, wherein said compsn also contain at least a known cancer therapy drug, or the pharmacologically acceptable salt of said cancer therapy drug.
15. the medicinal compsns of claim 14, wherein, said compsn also contains at least a cancer therapy drug that is selected from down group: busulfan, melphalan, TV, endoxan; Ifosfamide, TM, bendamustine, cis-platinum, ametycin, bleomycin, carboplatin, NSC 94600, irinotecan and hycamtin; Zorubicin, pidorubicin, NSC-208734, mitoxantrone; Elliptinium, inscription holder pool is general, and 5-azepine born of the same parents are general, gemcitabine, 5-fluorine urine are crowed and suck, the cry of certain animals of first atmosphere butterfly; 5-fluoro-2 '-uracil deoxyriboside, fludarabine, nelarabine, ara-C, the cry of certain animals of sulphur bird throat, pralatrexate, pemetrexed, hydroxyurea, thioguanine; NSC-757., vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol, ipsapirone, cabazitaxel, docetaxel, campath; Panitumumab, Ofatumumab, Avastin, Trastuzumab, Rituxan, imatinib, ZD1939, erlotinib, lapatinibditosylate, sorafenib, Sutent, nilotinib, Dasatinib, handkerchief azoles handkerchief Buddhist nun, special cancer are fitted; SDZ-RAD, Vorinostat, romidepsin, tamoxifen; Letrozole, fulvestrant, mitoguazone, Sostatin, vitamin A acid, arsenic, Zoledronic acid, Velcade, Sa Li polyamines or Revlimid.
CN2011100824756A 2011-04-01 2011-04-01 1-(aryl methyl)-quinazoline-2,4-dione as PARP inhibitor and its application Pending CN102731416A (en)

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CN2011100824756A CN102731416A (en) 2011-04-01 2011-04-01 1-(aryl methyl)-quinazoline-2,4-dione as PARP inhibitor and its application
TW101111039A TWI527800B (en) 2011-04-01 2012-03-29 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof
RS20190877A RS59091B1 (en) 2011-04-01 2012-03-31 1-((3-((1-piperazinyl)carbonyl)phenyl)methyl)-2,4(1h,3h)-quinazolinedione derivatives as parp inhibitors for treating cancer
ES12765230T ES2736299T3 (en) 2011-04-01 2012-03-31 Derivatives of 1¿ ((3¿ ((1¿piperazinyl) carbonyl) phenyl) methyl) ¿2,4 (1H, 3H) ¿quinazolinadione as inhibitors of PARP to treat cancer
JP2014501428A JP6270713B2 (en) 2011-04-01 2012-03-31 1- (Allylmethyl) quinazoline-2,4 (1H, 3H) -dione as a PARP inhibitor and uses thereof
EP12765230.3A EP2709990B1 (en) 2011-04-01 2012-03-31 1-((3-((1-Piperazinyl)carbonyl)phenyl)methyl)-2,4(1H,3H)-quinazolinedione derivatives as PARP inhibitors for treating cancer
HUE12765230A HUE046121T2 (en) 2011-04-01 2012-03-31 1-((3-((1-Piperazinyl)carbonyl)phenyl)methyl)-2,4(1H,3H)-quinazolinedione derivatives as PARP inhibitors for treating cancer
PT12765230T PT2709990T (en) 2011-04-01 2012-03-31 1-((3-((1-piperazinyl)carbonyl)phenyl)methyl)-2,4(1h,3h)-quinazolinedione derivatives as parp inhibitors for treating cancer
AU2012237776A AU2012237776B2 (en) 2011-04-01 2012-03-31 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP inhibitors and the use thereof
CN201410398758.5A CN104230827B (en) 2011-04-01 2012-03-31 1-(aryl methyl) quinazoline-2,4 (1H, 3H)-diketone is as PARP inhibitor and application thereof
DK12765230.3T DK2709990T3 (en) 2011-04-01 2012-03-31 1 - ((3 - ((1-Piperazinyl) carbonyl) phenyl) methyl) -2,4 (1H, 3H) -quinazoline dione derivatives as PARP inhibitors for the treatment of cancer
CN201280001822.0A CN103097361B (en) 2011-04-01 2012-03-31 1-(aryl methyl)-quinazoline-2,4-dione as parp inhibitor and its application
CA2831015A CA2831015C (en) 2011-04-01 2012-03-31 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof
PL12765230T PL2709990T3 (en) 2011-04-01 2012-03-31 1-((3-((1-Piperazinyl)carbonyl)phenyl)methyl)-2,4(1H,3H)-quinazolinedione derivatives as PARP inhibitors for treating cancer
US14/006,722 US9290460B2 (en) 2011-04-01 2012-03-31 1-(Arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP inhibitors and the use thereof
SG2013071543A SG193599A1 (en) 2011-04-01 2012-03-31 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof
TR2019/10675T TR201910675T4 (en) 2011-04-01 2012-03-31 1 - ((3 - ((1-piperazinyl) carbonyl) phenyl) methyl) -2,4 (1H, 3H) -quinazolinedione derivatives as PARP inhibitors for treating cancer.
PCT/CN2012/073362 WO2012130166A1 (en) 2011-04-01 2012-03-31 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof
SI201231630T SI2709990T1 (en) 2011-04-01 2012-03-31 1-((3-((1-Piperazinyl)carbonyl)phenyl)methyl)-2,4(1H,3H)-quinazolinedione derivatives as PARP inhibitors for treating cancer
US15/042,366 US9926304B2 (en) 2011-04-01 2016-02-12 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP inhibitors and the use thereof
US15/935,694 US10316027B2 (en) 2011-04-01 2018-03-26 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP inhibitors and the use thereof
US16/415,803 US11358955B2 (en) 2011-04-01 2019-05-17 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP inhibitors and the use thereof
HRP20191273TT HRP20191273T1 (en) 2011-04-01 2019-07-16 1-((3-((1-piperazinyl)carbonyl)phenyl)methyl)-2,4(1h,3h)-quinazolinedione derivatives as parp inhibitors for treating cancer
CY20191100769T CY1121847T1 (en) 2011-04-01 2019-07-18 1-((3-((1-PIPERAZINYL)CARBONYL)PHENYL)METHYL)-2,4(1H,3H)-QUINAZOLINODIONE DERIVATIVES AS PARP INHIBITORS FOR THE TREATMENT OF CANCER

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WO2017128036A1 (en) * 2016-01-26 2017-08-03 中国医学科学院药物研究所 Quinazolinone parp-1 inhibitor and preparation method, pharmaceutical composition and use thereof
CN107405349A (en) * 2015-04-03 2017-11-28 上海瑛派药业有限公司 PARP inhibitor solid pharmaceutical dosage formulation and its application
US10597399B2 (en) 2015-11-23 2020-03-24 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Substituted triazolopiperazine PARP inhibitor, preparation method therefor and use thereof
CN114206864A (en) * 2019-05-14 2022-03-18 苏州四体康宸医药科技有限公司 Quinazoline-2, 4-dione derivatives as PARP inhibitors

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CN107405349A (en) * 2015-04-03 2017-11-28 上海瑛派药业有限公司 PARP inhibitor solid pharmaceutical dosage formulation and its application
CN107405349B (en) * 2015-04-03 2021-03-02 上海瑛派药业有限公司 Solid pharmaceutical dosage form of PARP inhibitor and application thereof
US10597399B2 (en) 2015-11-23 2020-03-24 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Substituted triazolopiperazine PARP inhibitor, preparation method therefor and use thereof
WO2017128036A1 (en) * 2016-01-26 2017-08-03 中国医学科学院药物研究所 Quinazolinone parp-1 inhibitor and preparation method, pharmaceutical composition and use thereof
CN110088098A (en) * 2016-01-26 2019-08-02 中国医学科学院药物研究所 Quinazolinones PARP-1 inhibitor and preparation method thereof, pharmaceutical composition and purposes
CN110088098B (en) * 2016-01-26 2022-04-15 中国医学科学院药物研究所 Quinazolinone PARP-1 inhibitor and preparation method, pharmaceutical composition and application thereof
CN114206864A (en) * 2019-05-14 2022-03-18 苏州四体康宸医药科技有限公司 Quinazoline-2, 4-dione derivatives as PARP inhibitors
CN114206864B (en) * 2019-05-14 2024-05-24 苏州四体康宸医药科技有限公司 Quinazoline-2, 4-dione derivatives as PARP inhibitors

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