CN102898377B - One class phthalazinone derivatives and uses thereof - Google Patents
One class phthalazinone derivatives and uses thereof Download PDFInfo
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- CN102898377B CN102898377B CN201210032055.1A CN201210032055A CN102898377B CN 102898377 B CN102898377 B CN 102898377B CN 201210032055 A CN201210032055 A CN 201210032055A CN 102898377 B CN102898377 B CN 102898377B
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- 0 *C1N(CCNC2)C2=**1 Chemical compound *C1N(CCNC2)C2=**1 0.000 description 1
- WAMQNKAILXDXNE-UKTHLTGXSA-N CC(c1ccccc1/C(/Cl)=N\N)Cl Chemical compound CC(c1ccccc1/C(/Cl)=N\N)Cl WAMQNKAILXDXNE-UKTHLTGXSA-N 0.000 description 1
- BUMQMCDLYZAZNA-UHFFFAOYSA-N CCC(NNC)=O Chemical compound CCC(NNC)=O BUMQMCDLYZAZNA-UHFFFAOYSA-N 0.000 description 1
- XFDUHJPVQKIXHO-UHFFFAOYSA-N Nc1cccc(C(O)=O)c1 Chemical compound Nc1cccc(C(O)=O)c1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides compound and isomer, pharmacy acceptable salt, solvate, chemoprotectant form and the prodrug of a class phthalazone; They as PARP inhibitor application and comprise the pharmaceutical composition of compound of this kind of phthalazone; Wherein A, R
1, X has shown definition.Described medicine is used for the treatment of: vascular disease; Neurotoxicity; Or the disease of the improvement by suppressing PARP active; Or be used as cancer therapy auxiliary or for strengthen radiation or chemotherapeutic to the therapeutic action of tumour cell, described cancer refers to mammary cancer, ovarian cancer, colorectal carcinoma, melanoma, lung cancer, gastrointestinal stromal tumor, the cancer of the brain, cervical cancer, carcinoma of the pancreas, prostate cancer, cancer of the stomach, chronic marrow sample hypercytosis, liver cancer, lymphoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumor, advanced malignance, glioblastoma multiforme.
Description
Technical field
The present invention relates to a class phthalazinone derivatives and the pharmaceutical composition comprising this analog derivative, relate generally to 2，3-benzodiazine ketone derivatives and the purposes as medicine thereof.Specifically, the present invention relates to these compounds for suppressing the purposes of the activity of poly-(ADP-ribose) polysaccharase (also referred to as poly-(ADP-ribose) synthase and poly-ADP-ribosyltransferase, so-called PARP).
Background technology
Mammiferous enzyme PARP (multi-domain proteins of a kind of 113kDa) is identified by it and take part in the intracellular signaling (D'Amours etc., Biochem.J.342:249-268 (1999)) of DNA damage fast in conjunction with the ability of DNA single chain or double-strand break.
Poly adenosine diphosphate (ADP) (ADP-ribose) ribose synthetic enzyme family comprises about 18 kinds of protein now, and be divided into 3 types, I type is mainly present in nucleus, comprises PARP-1, PARP-2, PARP-3 etc.; II type is mainly present in organoid, comprises V-PARP etc.; III type is main relevant with the telomere of cell, comprises Tankyrase1, Tankyrase2.PARP-1 is as the Major Members of PARP family, and its research is many also comparative maturities.All these protein show a certain amount of homology in its catalyst structure domain, but on its cell function different (Ame etc., Biochem., 26 (8), 882-893 (2004).In family, PARP-1 (member found the earliest) and PARP-2 is the enzyme stimulating its catalytic activity solely by there is DNA break found at present, and this makes them be very unique in this family.And PARP-1 is that in PARP family, structure is the most typical, also be most study, its molecular weight is 114KDa, be that substrate is at receptor protein (comprising self) upper synthesis polyadenylic acid bisphosphate ribose (PRA) (Sakamoto-HOjoET with ADP, BalajeeAS.TargetingPoly (ADP) ribosePolynlerase I (PARP-I) andPARP-I interactingProteinsforcancertreatment [J] .AnticancerAgentsMedChem, 2008,8 (4): 402-16).
PARP-1 mainly contains 3 structural domains: 1, N-end DNA land; This structural domain comprises two zinc fingerses and a nucleic acid positioning sequence.Wherein, zinc fingers can combine with the DNA of damage, thus causes self activating.2, self-modification structure territory; This structural domain is positioned at the center of PARP-1 albumen, ribosylating with self and relevant with other protein-interactings.3, C-holds catalyst structure domain; This structural domain can NAD
+be converted into ADP ribose, and make it extend, branch forms ADP-polymkeric substance.Various chemical factors comprises radiation, ischemia/reperfusion injury, temperature etc. cause cytoactive oxygen/nitrogen level to increase, free radical increases, finally cause the damage of DNA, the DNA of damage can activate PARP-1 enzyme with the N-terminal domains identification of PARP-1, activates PARP-1 and mainly plays following several function: 1, poly-adenosine diphosphate (ADP) ribosylation [poly (ADP-ribosylation), pADPr] acts on; Hold catalyst structure domain by C, PARP-1 can catalyzing N AD
+for nicotinamide and ADP ribose, and can chain or branch-like be become to be covalently bound on receptor protein by catalysis ADP ribose.By this ribosylating process, PARP-1 can change the molecular configuration of its downstream albumen, changes its biological function.But this ribosylating process is to consume based on cellular energy, the PARP-1 that appropriate DNA damage causes activates the effect serving and repair and cell is replied; And a large amount of DNA damages makes PARP excessive activation, cellular NAD can be caused by this ribosylating effect
+dead with ATP energy exhaustion.2, direct protein-protein interaction; A lot of research display, there is direct protein-protein interaction between PARP-1 albumen and many nuclear receptors, they form dimer or polymer together, jointly play biological function.
PARP-1 participates in DNA damage reparation and transcriptional regulatory, and be considered to cell survival and dead important regulatory factor, also participate in the regulation and control (Peralta-LealA of some transcription factors in tumour generation and inflammatory reaction, Rodriguez-VargasJM, Aguilar-QuesadaR, etal.PARPinhibitors:newPartnersinthetherapyofcancerandin flammatorydiseases [J] .FreeRadieBiolMed, 2009,47 (l): 13-26).Oneself discovery PARP-1 of people high expression level in the malignant tumour of the multiple mankind so far, as malignant lymphoma (TomodaT, KurashigeT, MorikiT, etal.EnhaneedexpressionofPo1y (ADP-ribose) synthetasegeneinmalignantlylnPhoma [J] .AmJHematol, 1991, 37 (4): 223-7), mammary cancer (HuJJ, RoushGC, DubinN, etal.Poly (ADP-ribose) Polymeraseinhumanbreascancer:acase-controlanalysis [J] .pharmacogeneties, 1997, 7 (4): 309-16.), ewing's sarcoma (PrasadSC, ThravesPJ, BhatiaKGetal.EnhancedPoly (adenosinediphosphateribose) PolymeraseactivityandgeneexpressioninEwing, ssarcomacells [J] .CanceRes, 1990, 50 (l): 38-43.), hepatocellular carcinoma (ShiobaraM, MiyazakiM, ItoH, etal.EnhancedPolyadenosinediphosphate-ribosylationincirr hoticliverandcarcinomatissuesinpatientswithhepatocellula rcarcinoma [J] .JGastroenterolHePatol, 2001, 16 (3): 338-44.) etc., and have report (MasutaniM, NozakiT, SasakiH, etal.Poly (ADP-ribose) Polylllerase-lgeneinhumantumorcelllines:Itsexpressionand strueturalalteration [J] .ProceedingsoftheJapanAeademy, SeriesB, 2004, 80 (2): 114-8.) high expression level that also there is PARP-1 in human osteosarcoma cell system is presented at.
Because PARP-1 participates in DNA damage reparation, independent application PARP-1 activity inhibitor or the death (BryantHE of cell can be promoted with DNA damage drug combination, HelledayT.Poly (ADP-ribose) Polymeraseinhibitorsaspotentialchemotherapeutieagents [J] .BioehemSoeTrans, 2004,32 (Pt6): 959-61.).Large quantifier elimination has confirmed the tissue injury that Drug inhibition or gene knockout PARP-1 can not only avoid oxidative stress relative disease to cause, prognosis (the Aguilar-QuesadaR of tumour patient can also be improved, Munoz-GamezJA, Martin-OlivaD, etal.ModulationoftranscriptionbyPARP-l:consequencesincar cinogenesisandinflammation [J] .CurrMedChem, 2007,14 (11): 1179-87.).And in lung cancer, colorectal carcinoma, in the kinds of tumors such as cervical cancer, PARP-1 inhibitor effectively can strengthen the susceptibility (NoelQ of cell to chemicotherapy, GodonC, FernetM, etal.RadiosensitizationbythePoly (ADP-ribosePolymeraseinhibitor4-amino-l, 8-naphthalimideisspecificoftheSphaseofthecellcycleandinv olvesarrestofDNAsynthesis [J] .MolCaneerTher, 2006, 5 (3): 564-74. etc.), independent application PARP-1 inhibitor also has lethal effect to the tumour (mainly mammary cancer) that DNA loses rectification of defects, bibliographical information (BryantHE, SchultzN, ThomasHD, etal.sPecifickillingofBRCA2-deficientumourswithinhibitor sofPoIy (ADP-ribose) polylmerase [J] .Nature, 2005, 434 (7035) 913-7. etc.) PARP-1 inhibitor has significant restraining effect to the mammary cancer that BRCA-1 and BRCA-2 suddenlys change.Document there was reported the relation of PARP-1 inhibitor and vasculogenesis in addition, the propagation of the Human umbilical vein endothelial cells having at least five kinds of PARP inhibitor that vascular endothelial growth factor (VEGF) can be suppressed in vitro to induce at present, migration and vascularization (RajeshM, MukhopadhyayP, BatkaiS, etal.PharmacologicalinhibitionofPoly (ADP-ribose) Polymeraseinhibitsangiogenesis [J] .BiochemBioPhysResCommun, 2006,350 (2): 352-7 etc.].
Existing it is known that: PARP participates in a series of function relevant with DNA, comprise gene amplification, cell fission, differentiation, apoptosis, DNA base excision repair, and affect telomere length and chromosome stability (d ' people such as AddadiFagagna, 1999, NatureGen., 23 (1): 76-80).
The study mechanism of the reparation of PARP-1 regulating DNA and other process is confirmed that it is for the importance (Althaus forming poly-(ADP-ribose) chain in nucleus, and Richter F.R., C., " ADP ribosylation of protein: zymetology and biological importance " Springer-Verlag, Berlin1987).The PARP-1 of the activation be combined with DNA utilizes NAD
+at the upper synthesis of a series of nucleus target point protein (comprising topoisomerase, histone and PARP itself) poly-(ADP-sugar), comprise topoisomerase, histone enzyme and the PARP (people such as Rhun itself, Biochem.Biophys.Res.Commun., 245:1-10 (1998)).
Poly-(ADP-ribosyl) is changed also relevant with vicious transformation.Such as, higher in the active fibroblastic core transformed at isolated SV40-of PARP-1, and leukemia cell and colon cancer cell show higher enzymic activity (people such as Miwa, Arch.Biochem.Biophys.181:313-321 (1977) than corresponding normal white cell and colon mucosa; Burzio etc., Proc.Soc.Exp.Bioi.Med.149:933-938 (1975); And Hirai etc., CancerRes.43:3441-3446 (1983)).
Further, many low-molecular-weight PARP inhibitor change the function affect in DNA repairs for illustrating poly-(ADP-ribosyl).In the cell with alkylating reagent process, the suppression of PARP be result in remarkable increase (people such as Durkacz, 1980, Nature283:593-596 of DNA splitting of chain and necrocytosis; BergenN.A., 1985, RadiationResearch, 101:4-14).
Confirmed afterwards, this inhibitor can strengthen effect (people such as Ben-Hur, 1984, BritishJournalofCancer, 49 (Suppl.VI): the 34-42 of radiation response by suppressing the reparation of potential lethal damage; The people such as Schlicker, 1999, Int.J.Radiat.Bioi., 75:91-100).It is reported, PARP inhibitor to the hypoxic tumor cells of radiation sensitization effectively (US5,032,617.US5,215,738 and US5,041,653).
In addition, the animal that PARP rejects ((PARP-/-) reveals genomic instability ((people such as Wang, 1995, GenesDev., 9:509-520 to alkylating reagent and radiometer; The people such as MenissierdeMurcia, 1997, Proc.Natl.Acad.Sci.USA, 94:7303-7307).Also demonstrate that effect (people such as Cantoni, 1989, Biochim.Biophys.Acta, 1014:1-7 of PARP in some vascular disease, septic shock, ischemic injury and neurotoxicity; The people such as Szabo, 1997, J.Clin.lnvest., 100:723-735).
Confirm through the research of PARP inhibitor, causing can be main inducing (people such as Cosi, 1994, J.Neurosci.Res., 39:38-46 that these diseases occur at the oxyradical DNA damage of the DNA splitting of chain identified by PARP subsequently; The people such as Said, 1996, Proc.Natl.Acad.Sci.U.S.A., 93:4688-4692).Recently, confirmed that PARP plays an important role in the morbidity of hemorrhagic shock (people such as Liaudet, 2000, Proc.Natl.Acad.Sci.U.S.A., 97 (3): 10203-10208).
Nearest data show that PARP-1 and PARP-2 all has overlapping and nonredundant function in the maintenance of Genome stability, and this makes them all become interesting target spot.(M é nissier-deMurcia etc., EMBO.J., 22 (9), 2255-2263 (2003)).
Phthalazone analog derivative is used for PARP-1 inhibitor, and prior art WO2004080976 discloses a kind of structure and is
pARP-1 inhibitor;
WO2006021801 discloses a kind of structure
pARP-1 inhibitor;
US2008/0161280A1 discloses a kind of structure
poly-(ADP-ribose) AG14361.
Summary of the invention
A first aspect of the present invention relates to a class phthalazinone derivatives, and its structure is as shown in logical formula I, and its isomer, salt, solvate or hydrate, chemoprotectant form and prodrug.
Wherein X is CH
2, NH, O, S;
N is 0,1,2,3,4;
A is
But when A is
time, X is not CH
2;
Y is selected from CH or N;
represent singly-bound or double bond, when
when representing singly-bound, Z is selected from NH or CH
2; When
when representing double bond, Z is selected from N or CH;
R
1for H, halogen, amino, nitro, cyano group, hydroxyl, carboxyl, C
1-12alkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino;
R
2for H, hydroxyl, amino, C
1-12alkyl, C
3-10cycloalkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclic radical, wherein said C
1-12alkyl, C
1-12alkoxyl group, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclyl is further by hydroxyl, amino, C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, CONR
5r
6replace;
R
3for H, hydroxyl, halogen, amino, nitro, cyano group, carbonyl, C
1-12alkyl, C
3-10cycloalkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclic radical ,-OP (O) (OH)
2, wherein said C
1-12alkyl, C
1-12alkoxyl group, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclyl is further by hydroxyl, amino, C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, CONR
5r
6replace;
R
4for H, hydroxyl, halogen, amino, carbonyl, C
1-12alkyl, C
3-10cycloalkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclic radical, wherein said C
1-12alkyl, C
1-12alkoxyl group, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclyl is further by hydroxyl, amino, C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, CONR
5r
6replace;
R
5and R
6be H, C independently
1-12alkyl;
Wherein preferably R
1for H, halogen, amino, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group; More preferably R
1for H, Cl, Br, F, C
1-6alkyl, C
1-6alkoxyl group;
Preferably R
2for C
1-10alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, C
6-12aryl, C
3-7heteroaryl, C
3-7heterocyclic radical; More preferably R
2for C
1-8alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, phenyl, naphthyl, pyrryl, pyridyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl;
Preferably R
3for C
1-10alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, C
6-12aryl, C
3-7heteroaryl, C
3-7heterocyclic radical ,-OP (O) (OH)
2; More preferably R
3for C
1-8alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, phenyl, naphthyl, pyrryl, pyridyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl;
Preferably R
4for C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, C
6-12aryl, C
3-7heteroaryl, C
3-7heterocyclic radical; More preferably R
4for C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, phenyl, naphthyl, pyrryl, pyridyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl;
Preferably R
5and R
6be H, C independently
1-6alkyl; More preferably R
5and R
6be H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl independently.
When A is selected from
as general formula (I a) shown in:
X is NH, O, S;
N is 0,1,2,3,4;
R
1for H, halogen, amino, nitro, cyano group, hydroxyl, carboxyl, C
1-12alkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino; Preferably R
1for H, halogen, amino, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group; More preferably R
1for H, Cl, Br, F, C
1-6alkyl, C
1-6alkoxyl group;
R
2for H, hydroxyl, amino, C
1-12alkyl, C
3-10cycloalkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclic radical, piperidines, wherein said C
1-12alkyl, C
1-12alkoxyl group, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclyl is further by hydroxyl, amino, C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, CONR
5r
6replace;
Preferably R
2for C
1-10alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, C
6-12aryl, C
3-7heteroaryl, C
3-7heterocyclic radical;
More preferably R
2for C
1-8alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, phenyl, naphthyl, pyrryl, pyridyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl;
R
5and R
6be H, C independently
1-12alkyl; Preferably R
5and R
6be H, C independently
1-6alkyl; More preferably R
5and R
6be H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl independently.
When A is selected from
as general formula (I b) shown in:
X is NH, O, S;
N is 0,1,2,3,4;
R
1for H, halogen, amino, nitro, cyano group, hydroxyl, carboxyl, C
1-12alkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino; Preferably R
1for H, halogen, amino, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group; More preferably R
1for H, Cl, Br, F, C
1-6alkyl, C
1-6alkoxyl group;
R
4for H, hydroxyl, halogen, amino, carbonyl, C
1-12alkyl, C
3-10cycloalkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclic radical, wherein said C
1-12alkyl, C
1-12alkoxyl group, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclyl is further by hydroxyl, amino, C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, CONR
5r
6replace;
Preferably R
4for C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, C
6-12aryl, C
3-7heteroaryl, C
3-7heterocyclic radical;
More preferably R
4for C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, phenyl, naphthyl, pyrryl, pyridyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl;
R
5and R
6be H, C independently
1-12alkyl; Preferably R
5and R
6be H, C independently
1-6alkyl; More preferably R
5and R
6be H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl independently.
When A is selected from
as general formula (I c) shown in:
X is CH
2, O, S, NH;
Y is selected from CH or N;
represent singly-bound or double bond, when
when representing singly-bound, Z is selected from NH or CH
2; When
when representing double bond, Z is selected from N or CH;
N is 0,1,2,3,4;
R
1for H, halogen, amino, nitro, cyano group, hydroxyl, carboxyl, C
1-12alkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino; Preferably R
1for H, halogen, amino, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group; More preferably R
1for H, Cl, Br, F, C
1-6alkyl, C
1-6alkoxyl group;
R
3for H, hydroxyl, halogen, amino, nitro, cyano group, carbonyl, C
1-12alkyl, C
3-10cycloalkyl, C
1-12alkoxyl group, halo C
1-12alkyl, halo C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclic radical ,-OP (O) (OH)
2, wherein said C
1-12alkyl, C
1-12alkoxyl group, C
6-14aryl, C
3-10heteroaryl, C
3-10heterocyclyl is further by hydroxyl, amino, C
1-12alkoxyl group, list (C
1-12alkyl) amino, two (C
1-12alkyl) amino, CONR
5r
6replace;
Preferably R
3for H, hydroxyl, amino, C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, C
6-12aryl, C
3-7heteroaryl, C
3-7heterocyclic radical;
More preferably R
3for H, hydroxyl, amino, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group, list (C
1-6alkyl) amino, two (C
1-6alkyl) amino, phenyl, naphthyl, pyrryl, pyridyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl;
R
5and R
6be H, C independently
1-12alkyl; Preferably R
5and R
6be H, C independently
1-6alkyl; More preferably R
5and R
6be H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl independently.
The term " alkyl " used as a part for group or group in this article or " alkoxyl group " mean that this group is straight or branched, preferred C
1-12alkyl, more preferably C
1-6alkyl.The example of suitable alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl.The example of suitable alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy and tert.-butoxy, pentyloxy, hexyloxy.
The cycloalkyl mentioned herein is preferably C
3-10cycloalkyl, more preferably C
3-6cycloalkyl, can typical example as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The haloalkyl mentioned herein is preferably halo C
1-6alkyl, can typical example as trifluoromethyl, trifluoroethyl, difluoromethyl.
The halogenated alkoxy mentioned herein is preferably halo C
1-6alkoxyl group, can typical example as trifluoromethoxy, trifluoro ethoxy, difluoro-methoxy.
Term used herein " halogen " refers to fluorine, chlorine, bromine and iodine.Preferred halogen is fluorine.
The term " aryl " used as a part for group or group herein refers to the univalent perssad obtained from an annular atoms removing hydrogen atom of aromatics, and described compound contains a ring or two or more ring; One is had at least to be aromatic ring in wherein said ring.Suitable Examples of aryl groups comprises phenyl and naphthyl.
The term " heteroaryl " used as a part for group or group herein refers to the heteroatomic 3-10 unit heteroaromatic ring system being selected from N, O and S containing 1-4, preferred 3-7 unit heteroaromatic ring system.The specific examples of these groups comprises pyrryl, furyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl group, triazinyl, tetrazyl, indyl, benzothienyl, benzimidazolyl-and quinolyl.
The term " heterocyclic radical " used as a part for group or group herein refers to the univalent perssad obtained from an annular atoms removing hydrogen atom of the heterogeneous ring compound of non-aromatic, described compound contains a ring or two (such as the rings of volution, condensed ring, bridge joint) and containing heteroatoms, has at least one to be heterocycle in wherein said ring.The specific examples of these groups comprises tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl, imidazolidyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, quinuclidinyl, morpholinyl, isochroman base, chromanyl, pyrazolidyl, pyrazolinyl.
The pharmacy acceptable salt of indication of the present invention is the salt that formula (I) is formed with any acid, and pharmaceutically acceptable is sour as phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, propanedioic acid, amygdalic acid, succsinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, oxalic acid, tartrate, tosic acid, methanesulfonic, camphorsulfonic acid.
Compound of the present invention or its pharmacy acceptable salt, is characterized in that described pharmacy acceptable salt comprises the acceptable phosphoric acid ester of compound of Formula I, such as an alkali metal salt, alkaline earth salt.Described salt is preferably the organic phosphate disodium salt of the compounds of this invention.
The isomer of indication of the present invention refers to that one or more stereoisomer forms exist, and comprises various three-dimensional enantiomer, diastereomer, tautomer and geometrical isomer.The present invention includes Formula (I), its steric isomer and pharmaceutically acceptable salt thereof.Compound of the present invention may occur with the active form of the mixture of steric isomer, single stereoisomers or tool.
For tautomer: it comprises following tautomeric form:
Term " solvate " is in this article in a conventional sense for representing the mixture of solute (such as the salt of compound, compound) and solvent.If solvent is water, so solvate can be called as hydrate aptly, such as monohydrate, dihydrate, trihydrate etc.
Term " chemoprotectant form " refers to that wherein one or more reactive functional groups are protected with the compound avoiding occurring undesirable chemical reaction under defined terms (such as, pH, temperature, irradiation, solvent etc.) in this article in a conventional sense.In practice, well-known chemical process can be adopted reversibly to make those otherwise the functional group reacted is not reacted under prescribed conditions.In chemoprotectant form, one or more reactive functional groups is protected or blocking group (also referred to as masked or shelter group or be blocked or blocking group).By protective reaction functional group, can carry out relating to the reaction of other not protected reactive functional groups and not affect protected group; Blocking group usually can be removed in a subsequent step and substantially not affect the remainder of molecule.
Such as, hydroxyl can protectedly be ether (-OR) or ester (-OC (=O) R), and such as protection is: tertbutyl ether; Benzyl, diphenyl-methyl (diphenyl methyl) or trityl (trityl group) ether; TMS or t-butyldimethylsilyi ether; Or ethanoyl ester (-OC (=O) CH
3,-OAc).
Such as, aldehydes or ketones group can be distinguished protected is acetal (R-CH (OR)
2) or ketal (R
2c (OR)
2), wherein carbonyl (> C=O) is converted into diether (> C (OR) by reacting with such as primary alconol
2).Water excessive is in a large number used can easily to regenerate aldehydes or ketones group by hydrolytic action in the presence of acid.
Such as, amine groups can protectedly be such as acid amides (-NRCO-R) or urethane (-NRCO-OR), is such as protectedly: methyl nitrosourea (-NHCO-CH
3); Benzyloxy-amide (-NHCO-OCH
2c
6h
5,-NH-Cbz); Tert.-butoxy acid amides (-NHCO-OC (CH
3)
3,-NH-Boc), 2-xenyl-2-propoxy-acid amides (-NHCO-OC (CH
3)
2c
6h
4c
6h
5-NH-Bpoc), 9-fluorenyl methoxy acid amides (-NH-Fmoc), 6-nitro black false hellebore oxygen base acid amides (-NH-Nvoc), 2-trimethylsilylethoxy acid amides (-NH-Teoc), 2,2,2-tri-chloroethoxy base acid amides (-NH-Troc), allyloxy acid amides (-NH-Alloc), (2-benzenesulfonyl) oxyethyl group acid amides (-NH-Psec); Or under appropriate circumstances (such as, cyclic amine), protected is Nitrous Oxide (nitroxide) atomic group (> N-O).
Such as, hydroxy-acid group can protectedly be ester, is such as protectedly: C
1-7alkyl ester (such as methyl ester, tertiary butyl ester); C
1-7haloalkyl ester (such as C
1-7tri haloalkyl ester); Three C
1-7alkyl tin groups, alkyl silane groups-C
1-7alkyl ester; Or C
5-20aryl-C
1-7alkyl ester (such as benzyl ester, nitrobenzyl ester); Or acid amides, such as methyl nitrosourea.
Such as, sulfydryl can protectedly be thioether (-SR), is such as protectedly: benzyl thioether; Acetylamino methyl ether (-S-CH
2nHC (=O) CH
3).
Term used herein " prodrug " relates to when by the compound of active compound needed for producing time metabolism (such as in vivo).Usually, prodrug is non-activity, or activity is lower than active compound, but can provide favourable process, use or metabolisming property.
Such as, some prodrugs are esters (ester unstable in acceptable metabolism on such as physiology) of active compound.Between metabilic stage, ester group (-C (=O) OR) is cleaved, produces active medicine.This kind of ester can be formed by esterification; the esterification of such as, any hydroxy-acid group (-C (=O) OH) in parent compound, in a suitable manner, protects other reactive group any be present in parent compound in advance; if needed, then carry out protection.
And some prodrugs are by enzyme activation thus generate active compound or generate the compound (such as in ADEPT, GDEPT, LIDEPT etc.) of active compound after further chemical reaction.Such as, prodrug can be sugar derivatives or other glucosides conjugates, or can be amino acid ester derivative.
A second aspect of the present invention relates to the pharmaceutical composition comprising the compound shown in logical formula I and pharmaceutically acceptable carrier or thinner.
A third aspect of the present invention relates to the purposes of the compound shown in logical formula I in the method for the treatment of the mankind or animal body.
Present invention also offers and be used for the treatment of or the method for prevention of various diseases model and effective composition, these diseases comprise: the disease that vascular disease, septic shock, ischemic injury, neurotoxicity, hemorrhagic shock, virus infection maybe can be alleviated by suppressing PARP active.
Another aspect of the present invention provides compound that the present invention defines and is used as cancer therapy additives or for strengthening ionizing rays or chemotherapeutics to the purposes in the medicine of the result for the treatment of of tumour cell in preparation.
The invention provides following particular compound:
4-(3-(4-pyridinecarboxylic piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(3-(4-(2-propyl group valeryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(3-(4-(ring is formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-one
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluoroanilino) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-pyridinecarboxylic piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-furans-3-formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-one
4-(3-(4-propionyl piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-Valerylpiperazin-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-is acyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(morpholine-4-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenylamino) phthalazines-1 (2H)-one
4-(4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-base amido) benzoyl) piperazine-1-base)-N-methyl-4-oxo butyramide
4-(the fluoro-3-of 4-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(3-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(3-(4-furans-2-formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(3-(4-(ring is formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluorophenoxy) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-furans-3-formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-5-of 2,3,6-tri-(morpholine-4-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-Valerylpiperazin-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-is acyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-5-of 2,3,6-tri-(4-Valerylpiperazin-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(the fluoro-5-of 2,3,6-tri-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(the fluoro-5-of 2,3,6-tri-(4-is acyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-(4-methoxyl group-2-(2-methoxy ethyl) butyryl radicals) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(3-(the positive dodecanoyl piperazine of 4--1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one
4-(3-(4-(2-butyl caproyl) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-5-of 2-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
4-(3-(4-(2-ethylbutanoyl base) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one
4-(4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-base oxygen base) benzoyl) piperazine-1-base)-N-methyl-4-oxo butyramide 4-(the fluoro-3-of 4-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one
4-(3-(4-(2,2-diethyl butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(4-(3-hydroxypropanoyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one
4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-N, N-dipropyl-1-methane amide
4-(the fluoro-3-of 4-(5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(3-sec.-propyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one
4-(5-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-2-fluorophenyl oxygen base) phthalazines-1 (2H)-one
4-(3-(4-Acetylpiperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one
N-ethyl-4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-1-methane amide
4-(the fluoro-3-of 4-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(3-cyclopropyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(3-hydroxyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(5,6,7,8-tetrahydro-imidazo is [1,2-a] pyrazine-7-carbonyl also) benzyl) phthalazines-1 (2H)-one
4-(the fluoro-3-of 4-(5,6,7,8-tetrahydro-imidazo is [1,5-a] pyrazine-7-carbonyl also) benzyl) phthalazines-1 (2H)-one
Embodiment:
The present invention can adopt two lines to synthesize, synthesis when route 1 is NH for X, synthesis when route 2 is O or S for X, and route 3 is CH for X
2time synthesis.
Route 1:
1), tert-butoxycarbonyl-piperazine, triethylamine, an amido phenylformic acid are dissolved in N; in dinethylformamide, add benzotriazole-N, N; N'; N'-tetramethyl-urea phosphofluoric acid ester, stirring at room temperature, after reaction terminates; the cancellation that adds water is reacted and is separated out solid product; filter, dry, obtain 4-(3-amido benzoyl) piperazine-1-t-butyl formate.
2), under ice bath (0 DEG C), in the ethanolic soln of triethylamine, trifluoroacetic acid is added; add step gained 4-(3-amido benzoyl) piperazine-1-t-butyl formate and 1; 4-dichloro phthalazines; be heated to backflow, after reaction terminates, add ethyl acetate; and wash; organic phase is dry, concentrated, obtains 4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-t-butyl formate.
3), 4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-t-butyl formate is dissolved in the mixture of ethanol, water, concentrated hydrochloric acid; stirring at room temperature; reaction terminates rear concentrated except except desolventizing, obtains 3-(4-chlorine phthalazines-1-amido) phenylpiperazine-1-methyl ketone.
4), 3-(4-chlorine phthalazines-1-amido) phenylpiperazine-1-methyl ketone is added N; in dinethylformamide, add triethylamine, the carboxylic acid of replacement, benzotriazole-N, N; N'; N'-tetramethyl-urea phosphofluoric acid ester stirring at room temperature, after reaction terminates, add water cancellation; extraction into ethyl acetate; drying, concentrated, obtain 4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-substituent methyl ketone.4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-substituent methyl ketone (0.01mol) is dissolved in acetic acid; add sodium-acetate; be heated to backflow; after reaction terminates; add water cancellation; extraction into ethyl acetate, recrystallization, obtains 4-(3-(4-substituted formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one [i.e. formula (I a) compound].
Or by the morpholino of morpholine or replacement for tert-butoxycarbonyl-piperazine, adopt step 1.1,1.2,1.5, namely obtain formula (I compound b).
Or will
replace tert-butoxycarbonyl-piperazine, adopt step 1.1,1.2,1.5, namely obtain formula (I
c) compound.
[reaction formula]
Route 2:
1), the carboxylic acid of tert-butoxycarbonyl-piperazine, triethylamine, replacement is dissolved in DMF, adds benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, stirring at room temperature, after reaction terminates, filter, dry, concentrated, obtain the 4-substituted formyl piperazine-1-formyl tert-butyl ester.
2), the 4-substituted formyl piperazine-1-formyl tert-butyl ester is dissolved in the mixture of ethanol, water, concentrated hydrochloric acid, stirring at room temperature, reaction terminates rear concentrated, obtains 1-(piperazine-1-) substituent methyl ketone.
3), 1-(piperazine-1-) substituent methyl ketone is added N; in dinethylformamide; add triethylamine, m-Salicylic acid, benzotriazole-N, N, N'; N'-tetramethyl-urea phosphofluoric acid ester stirring at room temperature; after reaction terminates, extraction into ethyl acetate, dry; concentrated, obtain 1-(4-(3-hydroxy benzoyl) piperazine-1-) substituent methyl ketone.
4), 1-(4-(3-hydroxy benzoyl) piperazine-1-) substituent methyl ketone is dissolved in DMF, adds K
2cO
3with Isosorbide-5-Nitrae-dichloro phthalazines, be heated to backflow, after reaction terminates, extraction into ethyl acetate, dry, concentrated, obtain 1-(4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) piperazine-1-) substituent methyl ketone.
5), 1-(4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) piperazine-1-) substituent methyl ketone is dissolved in acetic acid; add sodium-acetate; be heated to backflow; after reaction terminates; extraction into ethyl acetate; recrystallization, obtains 4-(3-(4-substituted formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one.
Or by the morpholino of morpholine or replacement for 1-(piperazine-1-) substituent methyl ketone, adopt step 2.3,2.4,2.5, namely obtain formula (I compound b).
Or will
replace 1-(piperazine-1-) substituent methyl ketone, adopt step 2.3,2.4,2.5, namely obtain formula (I
c) compound.
[reaction formula]
When X is S, use
replace in aforesaid method
Route 3:
Will
the fluoro-5-of diisopropyl ethyl amine, 2-((4-oxygen-3,4-dihydro phthalazines-1-base) methyl) phenylformic acid is dissolved in DMF, add benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, stirring at room temperature, after reaction terminates, add water cancellation, filter, dry, concentrated, post is separated, and namely obtains X and is selected from CH
2formula (I
c) compound.
[reaction formula]
Specific embodiment:
The preparation (001) of embodiment 1:4-(3-(4-pyridinecarboxylic piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
By tert-butoxycarbonyl-piperazine (4.28g; 0.023mol), triethylamine (6.98g; 0.069mol), an amido phenylformic acid (7.01g; 0.023mol) be dissolved in N; in dinethylformamide (100ml); add benzotriazole-N, N, N'; N'-tetramethyl-urea phosphofluoric acid ester (8.72g; 0.023mol), stirring at room temperature, after reaction terminates; the cancellation that adds water is reacted and is separated out solid product; filter, dry, obtain 4-(3-amido benzoyl) piperazine-1-t-butyl formate.
In ethanol (50ml) solution of triethylamine (0.3ml), trifluoroacetic acid (0.25ml) is added under ice bath (0 DEG C), step gained 4-(3-amido benzoyl) piperazine-1-t-butyl formate (1.65g is added after 15min, 0.0054mol) He 1, 4-dichloro phthalazines (1.07g, 0.0054mol), be heated to backflow, after reaction terminates (about 30min), add ethyl acetate (100ml), washing (3*50ml), organic phase is dry through anhydrous Na 2SO4, concentrated, obtain 4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-t-butyl formate.
By 4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-t-butyl formate (2.10g; 0.0045mol) be dissolved in the mixture 60ml (V:V:V=1:1:1) of ethanol, water, concentrated hydrochloric acid; stirring at room temperature; reaction terminates rear concentrated except except desolventizing, obtains 3-(4-chlorine phthalazines-1-amido) phenylpiperazine-1-methyl ketone.
By 3-(4-chlorine phthalazines-1-amido) phenylpiperazine-1-methyl ketone (6.98g; 0.019mol) add N; in dinethylformamide; add triethylamine (5.87g; 0.058mol), the carboxylic acid (0.019mol), the benzotriazole-N that replace; N; N', N'-tetramethyl-urea phosphofluoric acid ester (7.21g, 0.019mol) stirring at room temperature; after reaction terminates; add water cancellation, extraction into ethyl acetate, dry; concentrated, obtain 4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-substituent methyl ketone.
4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-substituent methyl ketone (0.01mol) is dissolved in acetic acid (50ml); add sodium-acetate (2.10g; 0.025mol); be heated to backflow; after reaction terminates, add water cancellation, extraction into ethyl acetate; recrystallization, obtains 4-(3-(4-pyridinecarboxylic piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one.Fusing point >220 DEG C.
ESI-MSm/z:455.4 (m+H)
+, calculated value: 455.2.
Embodiment 2:4-(the preparation (003) of 3-(4-(2-propyl group valeryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
Preparation method's reference example 1: obtain target compound, fusing point 204-205 DEG C.
ESI-MSm/z:475.7 (m+H)
+, calculated value: 475.3.
The preparation (007) of embodiment 3:4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
Preparation method's reference example 1, fusing point >230 DEG C.
ESI-MSm/z:415.9 (m-H)
-, calculated value: 416.2.
The preparation (008) of embodiment 4:4-(3-(4-(ring is formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-one
Preparation method's reference embodiment 1, fusing point 187-189 DEG C.
ESI-MSm/z:460.2 (m+H)
+, calculated value: 460.2.
The preparation (010) of embodiment 5:4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluoroanilino) phthalazines-1 (2H)-one
Preparation method's reference example 1, fusing point 189-191 DEG C.
ESI-MSm/z:436.4 (m+H)
+, calculated value: 436.2.
The preparation (012) of embodiment 6:4-(the fluoro-3-of 4-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
Preparation method's reference example 1, fusing point 197-199 DEG C.
ESI-MSm/z:494.4m/z (m+H)
+, calculated value: 494.2.
The preparation (013) of embodiment 7:4-(the fluoro-3-of 4-(4-pyridinecarboxylic piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one
Preparation method's reference embodiment 1, fusing point >220 DEG C.
ESI-MSm/z:473.4 (m+H)
+, calculated value: 473.2.
Embodiment 8:4-(the fluoro-3-of 4-(4-furans-3-formyl radical) piperazine-1-carbonyl) anilino) preparation (015) of phthalazines-1 (2H)-one
Preparation method's reference embodiment 1, fusing point 190-192 DEG C.
ESI-MSm/z:460.1 (m-H)
-, calculated value: 460.2.
The preparation (017) of embodiment 9:4-(3-(4-propionyl piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-one
Preparation method's reference embodiment 1, fusing point 170-172 DEG C.
ESI-MSm/z:404.0 (m-H)
-, calculated value: 404.2.
Embodiment 10:4-(the fluoro-3-of 4-(4-Valerylpiperazin-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one (022)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:452.3 (m+H)
+, calculated value: 452.2.
Embodiment 11:4-(the fluoro-3-of 4-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-one (025)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:508.1 (472.1) (m+Cl)
-; Calculated value: 508.
Embodiment 12:4-(the fluoro-3-of 4-(4-is acyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one (026)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:466.3 (m+H)
+, calculated value: 466.2.
Embodiment 13:4-(the fluoro-3-of 4-(morpholine-4-carbonyl) phenyl amido) phthalazines-1 (2H)-one (028)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:369.2 (m+H)
+, calculated value: 369.1.
Embodiment 14:4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one (029)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:463.2 (m+H)
+, calculated value: 463.2.
Embodiment 15:4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenylamino) phthalazines-1 (2H)-one (030)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:481.3 (m+H)
+; Calculated value: 481.2.
Embodiment 16:4-(4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-base amido) benzoyl) piperazine-1-base)-N-methyl-4-oxo butyramide (032)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:479.4 [M-H]
-; Calculated value: 479.2.
Embodiment 17:4-(the fluoro-3-of 4-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one (034)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:467.2 [M+H]
+; Calculated value: 467.3.
Embodiment 18:4-(the fluoro-3-of 4-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-one (035)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:453.2 [M+H]
+; Calculated value: 453.2.
The preparation (002) of embodiment 19:4-(3-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
The carboxylic acid (0.023mol) of tert-butoxycarbonyl-piperazine (4.28g, 0.023mol), triethylamine (6.98g, 0.069mol), replacement is dissolved in N, in dinethylformamide (100ml), add benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (8.72g, 0.023mol), stirring at room temperature, after reaction terminates, add water cancellation, filter, drying, concentrated, obtain the 4-substituted formyl piperazine-1-formyl tert-butyl ester.
By the 4-substituted formyl piperazine-1-formyl tert-butyl ester (2.10g, 0.0045mol) be dissolved in the mixture 60ml (V:V:V=1:1:1) of ethanol, water, concentrated hydrochloric acid, stirring at room temperature, reaction terminates rear concentrated, obtains 1-(piperazine-1-) substituent methyl ketone.
1-(piperazine-1-) substituent methyl ketone (0.019mol) is added N; in dinethylformamide (80ml); add triethylamine (5.87g; 0.058mol), m-Salicylic acid (2.62g; 0.019mol), benzotriazole-N; N; N', N'-tetramethyl-urea phosphofluoric acid ester (7.21g, 0.019mol) stirring at room temperature; after reaction terminates; add water cancellation, extraction into ethyl acetate, dry; concentrated, obtain 1-(4-(3-hydroxy benzoyl) piperazine-1-) substituent methyl ketone.
1-(4-(3-hydroxy benzoyl) piperazine-1-) substituent methyl ketone (0.01mol) is dissolved in DMF (100ml), adds K2CO
3(3.45g; 0.025mol) He 1; 4-dichloro phthalazines (4.98g; 0.025mol), be heated to backflow, after reaction terminates; extraction into ethyl acetate; drying, concentrated, obtain 1-(4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) piperazine-1-) substituent methyl ketone.
1-(4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) piperazine-1-) substituent methyl ketone (0.004mol) is dissolved in acetic acid (40ml); add sodium-acetate (0.012mol); be heated to backflow; after reaction terminates; add water cancellation; extraction into ethyl acetate, recrystallization, obtains 4-(3-(4-substituted formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one.Fusing point 121-123 DEG C.
ESI-MSm/z:421.1 (m+H)
+, calculated value: 421.2.
The preparation (005) of embodiment 20:4-(3-(4-furans-2-formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
Preparation method's reference embodiment 19, fusing point 200-201 DEG C.
ESI-MSm/z:443.1 (m-H)
-, calculated value: 443.1.
The preparation (006) of embodiment 21:4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
Preparation method's reference embodiment 19, fusing point 190-192 DEG C.
ESI-MSm/z:417.1 (m-H)
-, calculated value: 417.2.
The preparation (009) of embodiment 22:4-(3-(4-(ring is formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
Preparation method's reference embodiment 19, fusing point 174-176 DEG C.
ESI-MSm/z:459.2 (m-H)
-, calculated value: 459.2.
The preparation (011) of embodiment 23:4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluorophenoxy) phthalazines-1 (2H)-one
Preparation method's reference embodiment 19, fusing point 191-193 DEG C.
ESI-MSm/z:437.1 (m+H)
+, calculated value: 437.2.
The preparation (014) of embodiment 24:4-(the fluoro-3-of 4-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one
Preparation method's reference embodiment 19, fusing point 167-168 DEG C.
ESI-MSm/z:(m+H)
+439.2, calculated value: 439.2.
Embodiment 25:4-(the fluoro-3-of 4-(4-furans-3-formyl radical) piperazine-1-carbonyl) phenoxy group) preparation (016) of phthalazines-1 (2H)-one
Preparation method's reference embodiment 19, fusing point 167-169 DEG C.
ESI-MSm/z:463.2 (m+H)
+, calculated value: 463.1.
Embodiment 26:4-(the fluoro-3-of 4-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one (018)
Preparation method is with reference to embodiment 19.
ESI-MSm/z:495.3 (m+H)
+, calculated value: 495.2.
Embodiment 27:4-(the fluoro-5-of 2,3,6-tri-(morpholine-4-carbonyl) phenoxy group) phthalazines-1 (2H)-one (019)
Preparation method is with reference to embodiment 19.
ESI-MSm/z:406.3 (m+H)
+, calculated value: 406.1.
Embodiment 28:4-(the fluoro-3-of 4-(4-Valerylpiperazin-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one (020)
Preparation method is with reference to embodiment 19.
ESI-MSm/z:453.3 (m+H)
+, calculated value: 453.2.
Embodiment 29:4-(the fluoro-3-of 4-(4-is acyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one (023)
Preparation method is with reference to embodiment 19.
ESI-MSm/z:467.3 (m+H)
+, calculated value: 467.2.
Embodiment 30:4-(the fluoro-5-of 2,3,6-tri-(4-Valerylpiperazin-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one (027)
Preparation method is with reference to embodiment 19.
ESI-MSm/z:(m+H)
+489.3, calculated value: 489.2.
Embodiment 31:4-(the fluoro-5-of 2,3,6-tri-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one (031)
Preparation method is with reference to embodiment 19.
ESI-MSm/z:531.2 (m+H)
+, calculated value: 531.2.
Embodiment 32:4-(the fluoro-5-of 2,3,6-tri-(4-is acyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one (033)
Preparation method is with reference to embodiment 19.
ESI-MSm/z:503.1 (m+H)
+, calculated value: 503.2.
Embodiment 33:4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one (036)
Preparation method is with embodiment 19.
ESI-MSm/z:482.3 (m+H)
+, calculated value 482.2.
Embodiment 34:4-(the fluoro-3-of 4-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one (040)
Preparation method is with embodiment 19.
ESI-MSm/z:475.1 (m+H)
+, calculated value 475.2.
Embodiment 35:4-(the fluoro-3-of 4-(4-(4-methoxyl group-2-(2-methoxy ethyl) butyryl radicals) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one (041)
Preparation method is with embodiment 19.
ESI-MSm/z:527.2 (m+H)
+, calculated value 527.2.
Embodiment 36:4-(3-(the positive dodecanoyl piperazine of 4--1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one (042)
Preparation method is with embodiment 19.
ESI-MSm/z:551.4 (m+H)
+, calculated value 551.2.
Embodiment 37:4-(3-(4-(2-butyl caproyl) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one (043)
Preparation method is with embodiment 19.
ESI-MSm/z:523.1 (m+H)
+, calculated value 523.2
Embodiment 38:4-(the fluoro-5-of 2-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-one (045)
Preparation method is with embodiment 19.
ESI-MSm/z:495.3 (m+H)
+, calculated value 495.2
Embodiment 39:4-(3-(4-(2-ethylbutanoyl base) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one (047)
Preparation method is with embodiment 19.
ESI-MSm/z:467.3 (m+H)
+, calculated value 467.2
Embodiment 40:4-(4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-base oxygen base) benzoyl) piperazine-1-base)-N-methyl-4-oxo butyramide (051)
Preparation method is with embodiment 19.
ESI-MSm/z:482.3 (m+H)
+, calculated value 482.2
Embodiment 41:4-(the fluoro-3-of 4-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one (052)
Preparation method is with embodiment 19.
ESI-MSm/z:468.2 (m+H)
+, calculated value 468.2
Embodiment 42:4-(the fluoro-3-of 4-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one (053)
Preparation method is with embodiment 19.
ESI-MSm/z:454.2 (m+H)
+, calculated value 454.2.
Embodiment 43:4-(3-(4-(2,2-diethyl butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one (054)
Preparation method is with embodiment 19.
ESI-MSm/z:495.3 (m+H)
+, calculated value 495.
Embodiment 44:4-(the fluoro-3-of 4-(4-(3-hydroxypropanoyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one (056)
Preparation method is with embodiment 19.
ESI-MSm/z:441.4 (m+H)
+, calculated value 441.2.
Embodiment 45:4-(the fluoro-3-of 4-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one (057)
Preparation method is with embodiment 1.
ESI-MSm/z:471.0 (m-H)
-, calculated value 471.2.
Embodiment 46:4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-N, N-dipropyl-1-methane amide (058)
Preparation method is with embodiment 19.
ESI-MSm/z:496.2 (m+H)
+, calculated value 496.2
Embodiment 47:4-(the fluoro-3-of 4-(5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one (059)
By 5, 6, 7, 8-tetrahydrochysene-[1, 2, 4] triazolo [4, 3-a] piperidine hydrochlorate, diisopropyl ethyl amine, the fluoro-5-of 2-((4-oxygen-3, 4-dihydro phthalazines-1-base) methyl) phenylformic acid is dissolved in N, in dinethylformamide, add benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, stirring at room temperature, after reaction terminates, add water cancellation, filter, dry, concentrated, obtain white solid product, i.e. 4-(the fluoro-3-(5 of 4-, 6, 7, 8-tetrahydrochysene-[1, 2, 4] triazolo [4, 3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one.
ESI-MSm/z:405.2 (m+H)
+, calculated value 405.2
Embodiment 48:4-(the fluoro-3-of 4-(3-sec.-propyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one (060)
Preparation method is with embodiment 47.
ESI-MSm/z:447.2 (m+H)
+calculated value 447.2
Embodiment 49:4-(5-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-2-fluorophenyl oxygen base) phthalazines-1 (2H)-one (062)
Preparation method is with embodiment 19.
ESI-MSm/z:437.1 (m+H)
+, calculated value 437.1
Embodiment 50:4-(3-(4-Acetylpiperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-one (063)
Preparation method is with embodiment 19.
ESI-MSm/z:411.2 (m+H)
+, calculated value 411.1
Embodiment 51:N-ethyl-4-(the fluoro-5-of 2-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-1-methane amide (064)
Preparation method is with embodiment 19.
ESI-MSm/z:440.2 (m+H)
+, calculated value 440.2
Embodiment 52:4-(the fluoro-3-of 4-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one (065)
Preparation method is with embodiment 47.
ESI-MSm/z:419.2 (m+H)
+, calculated value 419.2
Embodiment 53:4-(the fluoro-3-of 4-(3-cyclopropyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one (066)
Preparation method is with embodiment 47.
ESI-MSm/z:445.2 (m+H)
+, calculated value 445.2
Embodiment 54:4-(the fluoro-3-of 4-(3-hydroxyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-one (067)
Preparation method is with embodiment 47.
ESI-MSm/z:421.2 (m+H)
+, calculated value 421.1
Embodiment 55:4-(the fluoro-3-of 4-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-one (071)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:420.2 (m+H)
+, calculated value: 420.1.
Embodiment 56:4-(the fluoro-3-of 4-(5,6,7,8-tetrahydro-imidazo is [1,2-a] pyrazine-7-carbonyl also) benzyl) phthalazines-1 (2H)-one (072)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:404.2 (m+H)
+, calculated value: 404.4.
Embodiment 57:4-(the fluoro-3-of 4-(5,6,7,8-tetrahydro-imidazo is [1,5-a] pyrazine-7-carbonyl also) benzyl) phthalazines-1 (2H)-one (073)
Preparation method is with reference to embodiment 1.
ESI-MSm/z:404.2 (m+H)
+, calculated value: 404.4.
Embodiment 58: suppress poly ADP mono-ribose polymerase active
The enzyme process evaluation of PARP-1 inhibitor.
Material: PARP-1 enzyme (high purity human recombination protein, Trevigen), activated dna (Sigma) .6 (5H)-Fei steep ketone (PND) (Sigma), NAD
+(Sigma), PARP tests damping fluid (20mMTris, 2mMMgCl
2, pH8.0), methyl phenyl ketone (alcohol the is solvent) .2MKOH of 20%, 88% formic acid.
Adopt ELISA method to set up the molecular screening model of PARP inhibitor, substrate Histone (source leaf is biological, Shanghai, the China) bag of PARP1 enzyme, by 96 orifice plates (Corning, Lowell, the U.S.), is added NAD
+(Sigma, LouisMO, the U.S.), DNA (the raw work in Shanghai, Shanghai, China), add compound, positive control AZD2281 (LClaboratories, Woburn respectively, the U.S.) and PARP1 recombinase make it react, generate product P AR (polyadenylic acid ribose) be combined with substrate Histone.Then, add anti-PAR (anti-PAR) antibody (Santacruz, CA, the U.S.) and Goatanti-rabbitlgG-HRP (Santacruz, CA, the U.S.) detect the intensity of the PAR on the Histone of institute's bag quilt on 96 orifice plates, by O-PhenylenediamineDihydrochloride (the raw work in Shanghai, Shanghai, China) colour developing, H
2sO
4stop, under 490nm wavelength, survey OD value by microplate reader (VERSAmax, MolecularDevice, SunnyvaleCA, the U.S.).Analyte is calculated to the inhibiting rate of PARP1 enzyme reaction by (control group OD value-administration group OD value-blank group OD value)/(control group OD value-blank group OD value) × 100%; IC
50value VERSAmax microplate reader carries the inhibiting rate curve calculation of software according to 4 parameter method matchings.
The Preliminary activation test result of PARP-1 enzyme level part of compounds sees the following form:
| Sample# | X | (R 1) n | R 4 | IC 50(nM) |
| 028 | NH | F | H | 34.03 |
"-" represents unsubstituted
Claims (13)
1. lead to compound or its pharmacy acceptable salt of formula I,
Wherein X is CH
2, NH or O;
N is 1;
A is
Y is selected from CH and N;
represent double bond, Z is selected from N and CH;
R
1for halogen;
R
3for H, hydroxyl, C
1-12alkyl, C
3-10cycloalkyl or halo C
1-12alkyl;
Condition is described compound is not following compound:
4-[[the fluoro-3-of 4-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo [4,3-α] pyrazine-7-carbonyl]-phenyl] methyl]-2H-phthalazines-1-ketone;
4-[[3-(3,4-dihydro-1H-pyrrolo-[1,2-α] pyrazine-2-carbonyl) the fluoro-phenyl of-4-] methyl]-2H-phthalazines-1-ketone;
4-[[3-(6,8-dihydro-5H-imidazo [1,2-α] pyrazine-7-carbonyl) the fluoro-phenyl of-4-] methyl]-2H-phthalazines-1-ketone;
4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,5-α] pyrazine-7-carbonyl] phenyl] methyl]-2H-phthalazines-1-ketone;
4-[[3-(6,8-dihydro-5H-[1,2,4] triazolo [4,3-α] pyrazine-7-carbonyl) the fluoro-phenyl of-4-] methyl]-2H-phthalazines-1-ketone;
4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo [4,3-α] pyrazine-7-carbonyl] the fluoro-phenyl of-4-] methyl]-2H-phthalazines-1-ketone; With
4-[[the fluoro-3-of 4-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4] triazolo [4,3-α] pyrazine-7-carbonyl] phenyl] methyl]-2H-phthalazines-1-ketone.
2. the compound of logical formula I according to claim 1 or its pharmacy acceptable salt, wherein R
1for Cl, Br or F.
3. the compound of logical formula I according to claim 1 or its pharmacy acceptable salt, wherein R
3for H, hydroxyl, C
1-6alkyl, C
3-8cycloalkyl or halo C
1-6alkyl.
4. the compound of logical formula I according to claim 3 or its pharmacy acceptable salt, wherein R
3for H, hydroxyl, C
1-6alkyl, C
3-6cycloalkyl or halo C
1-6alkyl.
5. compound according to claim 1 or its pharmacy acceptable salt, wherein said compound is following compound:
4-(the fluoro-3-of 4-(3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-one;
4-(the fluoro-3-of 4-(3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-one;
4-(the fluoro-3-of 4-(3-sec.-propyl-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-one;
4-(the fluoro-3-of 4-(3-methyl-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-one;
4-(the fluoro-3-of 4-(3-cyclopropyl-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-one;
4-(the fluoro-3-of 4-(3-hydroxyl-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-one;
4-(the fluoro-3-of 4-(3-methyl-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-one;
4-(the fluoro-3-of 4-(6,8-dihydro-5H-imidazo [1,5-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-one.
6. the compound according to any one of claim 1 to 5 or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is the salt formed with following acid: phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, propanedioic acid, amygdalic acid, succsinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, oxalic acid, tartrate, tosic acid, methanesulfonic or camphorsulfonic acid, or as the R in general formula I
3for during hydroxyl being also an alkali metal salt of phosphoric acid ester or the alkaline earth salt of compound of Formula I.
7. prepare a method for compound described in any one of claim 1 to 6 or its pharmacy acceptable salt, described method comprises:
1) when X is NH, with amido phenylformic acid between replacing and
for raw material, obtain formula (I c) compound according to the following formula
2) when X is O, with the carboxylic acid replaced and
for raw material, obtain (I c) compound according to the following formula
3) when X is CH
2time, with
for raw material, obtain (I c) compound according to the following formula
Optionally, by described method 1), 2) or 3) product that obtains and corresponding acid-respons prepare its pharmacy acceptable salt;
Wherein Y, Z, R
1, R
3, n has definition as described in any one of claim 1-6.
8. a pharmaceutical composition, comprises general formula (I) compound described in any one of claim 1-6 or its pharmacy acceptable salt.
9. general formula (I) compound according to any one of claim 1-6 or its pharmacy acceptable salt or pharmaceutical composition according to claim 8 suppress the purposes of the medicine of PARP activity in preparation.
10. purposes according to claim 9, wherein said medicine be used as cancer therapy auxiliary or for strengthen radiation or chemotherapeutic to the therapeutic action of tumour cell.
11. purposes according to claim 10, wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, melanoma, lung cancer, gastrointestinal stromal tumor, the cancer of the brain, cervical cancer, carcinoma of the pancreas, prostate cancer, cancer of the stomach, chronic marrow sample hypercytosis, liver cancer, lymphoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumor.
12. purposes according to claim 10, wherein said cancer is advanced malignance.
13. purposes according to claim 10, wherein said cancer is glioblastoma multiforme.
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