CN102898377A - Novel phthalazinone derivatives and uses thereof - Google Patents
Novel phthalazinone derivatives and uses thereof Download PDFInfo
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- CN102898377A CN102898377A CN2012100320551A CN201210032055A CN102898377A CN 102898377 A CN102898377 A CN 102898377A CN 2012100320551 A CN2012100320551 A CN 2012100320551A CN 201210032055 A CN201210032055 A CN 201210032055A CN 102898377 A CN102898377 A CN 102898377A
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Abstract
The present invention provides novel phthalazinone compounds and isomer thereof, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs; which can be used as PARP inhibitor and pharmaceutical compositions containing the novel phthalazinone compounds; wherein A, R1 and X are defined as shown. The medicine is used for the treatment of: vascular diseases, neurotoxicity, or diseases improved through the inhibition of PARP activity; or used as adjuvants for the treatment of cancers, or used for enhancing the therapeutic effect of radiation or chemotherapeutic agents on tumor cells, wherein the cancers includes breast cancer, ovarian cancer, colon cancer, melanoma, lung cancer, gastrointestinal stromal tumor, brain cancer, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic myeloid leukocytes hypercytosis, liver canser, lymphoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumors, advanced solid tumors, and glioblastoma.
Description
Technical field
The present invention relates to the novel phthalazinone derivatives of a class and comprise the pharmaceutical composition of this analog derivative, relate generally to the 2，3-benzodiazine ketone derivatives and as the purposes of medicine.Specifically, the present invention relates to the purposes that these compounds are used for the activity of poly-(ADP-ribose) polysaccharase (being also referred to as poly-(ADP-ribose) synthase and poly-ADP-ribosyltransferase, so-called PARP) of inhibition.
Background technology
Mammiferous enzyme PARP (the Multidomain protein of a kind of 113kDa) is by its identification and the signal conduction (D'Amours etc., Biochem. J. 342:249-268(1999) that has participated in fast dna damage 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, is divided into 3 types, and the I type mainly is present in the nucleus, comprises PARP-1, PARP-2, PARP-3 etc.; The II type mainly is present in the organoid, comprises V-PARP etc.; The 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, the member that PARP-1(finds the earliest) and PARP-2 be only enzyme that stimulates its catalytic activity by dna break occurs of finding at present, this is so that they are very unique in this family.And PARP-1 is that structure is the most typical in the PARP family, it also is most study, its molecular weight is 114KDa, synthesize polyadenylic acid bisphosphate ribose (PRA) (Sakamoto-HOjo E T take ADP as substrate at receptor protein (comprising self), Balajee A S.Targeting Poly (ADP) ribose Polynlerase I (PARP-I) andPARP-I interacting Proteins for cancer treatment[J] .Anticancer Agents Med Chem, 2008,8 (4): 402-16).
PARP-1 mainly contains 3 structural domains: 1, the terminal DNA of N-land; This structural domain comprises two zinc fingerses and a nucleic acid positioning sequence.Wherein, zinc fingers can with the DNA combination of damage, thereby cause self activating.2, self-modification structure territory; This structural domain is positioned at the center of PARP-1 albumen, with self ribose and relevant with other protein-interactings.3, C-end catalyst structure domain; This structural domain can be NAD
+Be converted into ADP ribose, and make its prolongation, branch forms the ADP-polymkeric substance.Various chemical factors comprise radiation, ischemia/reperfusion injury, temperature etc. cause cytoactive oxygen/nitrogen level to increase, free radical increases, finally cause the damage of DNA, thereby the DNA of damage can activate the PARP-1 enzyme with the N-end structure territory identification of PARP-1, activates PARP-1 and mainly brings into play following several function: 1, poly-adenosine diphosphate (ADP) ribosylation [poly (ADP-ribosylation), pADPr] effect; By C end catalyst structure domain, PARP-1 can catalyzing N AD
+Be nicotinamide and ADP ribose, and can become chain or branch-like to be covalently bound on the receptor protein by catalysis ADP ribose.By this ribose process, PARP-1 can change the molecular configuration of its downstream albumen, changes its biological function.But this ribose process is to consume cellular energy as the basis, and the PARP-1 that an amount of dna damage causes activates the effect that cell is replied of repairing of having played; And a large amount of dna damages makes the excessive activation of PARP, can cause cellular NAD by this nuclear saccharification
+With the ATP energy exhaustion and death.2, direct protein-protein interaction; Studies show that much exist direct protein-protein interaction between PARP-1 albumen and the many nuclear receptors, they form dimer or polymer together, jointly bring into 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 regulation and control (the Peralta-Leal A of some transcription factors in tumour generation and the inflammatory reaction, Rodriguez-Vargas J M, Aguilar-Quesada R, et al.PARP inhibitors:new Partners in the therapy of cancer and inflammatory diseases[J] .Free Radie Biol Med, 2009,47 (l): 13-26).So far people oneself find PARP-1 high expression level in the multiple mankind's malignant tumour, such as malignant lymphoma (TomodaT, KurashigeT, MorikiT, et al.Enhaneed expression of Po1y (ADP-ribose) synthetase gene in malignant lylnPhoma[J] .Am J Hematol, 1991,37 (4): 223-7), mammary cancer (.HuJJ, RoushGC, Dubin N, et al.Poly (ADP-ribose) Polymerase in human breas cancer:acase-control analysis[J] .pharmacogeneties, 1997,7 (4): 309-16.), ewing's sarcoma (Prasad S C, Thraves P J, Bhatia K G et al.Enhanced Poly (adenosine diphosphate ribose) Polymerase activity and gene expression in Ewing, s sarcoma cells[J] .Cance Res, 1990,50 (l): 38-43.), hepatocellular carcinoma (Shiobara M, Miyazaki M, Ito H, et al.Enhanced Polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma[J] .J Gastroenterol HePatol, 2001,16 (3): 338-44.) etc., and report (Masutani M arranged, Nozaki T, Sasaki H, et al.Poly (ADP-ribose) Polylllerase-l gene in human tumor cell lines:Its expression and struetural alteration[J] .Proceedings of the Japan Aeademy, Series B, 2004,80 (2): 114-8.) be presented at the high expression level that also has PARP-1 in the human osteosarcoma cell system.
Because PARP-1 participates in the dna damage reparation, use separately the PARP-1 activity inhibitor or can promote death (the Bryant H E of cell with the dna damage drug combination, Helleday T.Poly (ADP-ribose) Polymerase inhibitors as potential chemotherapeutie agents[J] .Bioehem Soe Trans, 2004,32 (Pt6): 959-61.).A large amount of research has confirmed the tissue injury that medicine suppresses or gene knockout PARP-1 can not only avoid the oxidative stress relative disease to cause, can also improve prognosis (the Aguilar-Quesada R of tumour patient, Munoz-Gamez J A, Martin-Oliva D, et al.Modulation of transcription by PARP-l:consequences in carcinogenesis and inflammation[J] .Curr Med Chem, 2007,14 (11): 1179-87.).And in lung cancer, colorectal carcinoma, in the kinds of tumors such as cervical cancer, the PARP-1 inhibitor can effectively strengthen cell to susceptibility (the Noel Q of chemicotherapy, Godon C, Fernet M, et al.Radiosensitization by the Poly (ADP-ribose Polymerase inhibitor 4-amino-l, 8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis[J] .Mol Caneer Ther, 2006,5 (3): 564-74. etc.), use separately the PARP-1 inhibitor tumour (mainly being mammary cancer) that DNA loses rectification of defects is also had lethal effect, bibliographical information (Bryant H E, Schultz N, Thomas H D, et al.sPecific killing of BRCA2-deficient umours with inhibitors of PoIy (ADP-ribose) polylmerase[J] .Nature, 2005,434 (7035) 913-7. etc.) the PARP-1 inhibitor has significant restraining effect to the mammary cancer of BRCA-1 and BRCA-2 sudden change.Document has also been reported the relation of PARP-1 inhibitor and vasculogenesis in addition, have at present five kinds of PARP inhibitor at least in the external propagation that can suppress the Human umbilical vein endothelial cells that vascular endothelial growth factor (VEGF) induces, migration and vascularization (Rajesh M, Mukhopadhyay P, Batkai S, et al.Pharmacological inhibition of Poly (ADP-ribose) Polymerase inhibits angiogenesis[J] .Biochem BioPhys Res Commun, 2006,350 (2): 352-7 etc.].
Now be known that: PARP participates in a series of functions relevant with DNA, comprise gene amplification, cell fission, differentiation, apoptosis, DNA base excision reparation, and affect telomere length and the chromosome stability (people such as d'Adda di Fagagna, 1999, NatureGen., 23 (1): 76-80).
Mechanism to the reparation of PARP-1 regulating DNA and other process studies confirm that it is for the importance (Althaus that forms poly-(ADP-ribose) chain in nucleus, F. R. and Richter, C., " ADP ribosylation of protein: zymetology and biological importance " Springer-Verlag, Berlin 1987).The PARP-1 of the activation of being combined with DNA utilizes NAD
+At a series of nucleus target point proteins (comprising topoisomerase, histone and PARP itself) synthetic poly-(ADP-sugar), comprise topoisomerase, histone enzyme and the PARP itself (people such as Rhun, Biochem. Biophys. Res. Commun., 245:1-10(1998)).
Poly-(AD P-ribosyl) changed also relevant with vicious transformation.For example, the PARP-1 activity is higher in fibroblastic nuclear that isolated SV40-transforms, and leukemia cell and colon cancer cell show higher enzymic activity people such as (, Arch. Biochem. Biophys. 181:313-321(1977) Miwa than corresponding normal white corpuscle and mucous membrane of colon layer; Burzio etc., Proc. Soc.Exp. Bioi. Med. 149:933-938(1975); And Hirai etc., Cancer Res. 43:3441-3446(1983)).
And many low-molecular-weight PARP inhibitor have been used for illustrating poly-(ADP-ribosyl) and have changed the function affect of repairing at DNA.In the cell of processing with alkylating reagent, the inhibition of PARP has been caused remarkable increase (people such as Durkacz, 1980, the Nature 283:593-596 of DNA splitting of chain and necrocytosis; Bergen N. A., 1985, Radiation Research, 101:4-14).
Confirm that afterwards this inhibitor can strengthen by the reparation that suppresses potential mortality damage effect (people such as Ben-Hur, 1984, British Journal of Cancer, 49 (Suppl.VI): the 34-42 of radiation response; The people such as Schlicker, 1999, Int. J. Radiat. Bioi., 75:91-100).It is reported that the PARP inhibitor is to the hypoxic tumor cells effective (US 5,032,617. US 5,215,738 and US 5,041,653) of radiation sensitization.
In addition, the animal that PARP rejects ((PARP-/-) is revealed genomic instability ((people such as Wang, 1995, Genes Dev., 9:509-520 to alkylating reagent and radiometer; The people such as Menissier deMurcia, 1997, Proc. Natl. Acad. Sci. USA, 94:7303-7307).Effect (people such as Cantoni, 1989, Biochim. Biophys. Acta, the 1014:1-7 of PARP in some vascular disease, septic shock, ischemic injury and neurotoxicity, have also been confirmed; The people such as Szabo, 1997, J. Clin. lnvest., 100:723-735).
Studies confirm that through the PARP inhibitor, cause it to be main inducing that these diseases occur (people such as Cosi, 1994, J. Neurosci. Res., 39:38-46 at the oxyradical dna damage of the DNA splitting of chain of being identified by PARP subsequently; The people such as Said, 1996, Proc. Natl. Acad. Sci. U. S. A., 93:4688-4692).Recently, PARP in the morbidity of hemorrhagic shock, play an important role (people such as Liaudet, 2000, Proc. Natl. Acad.Sci. U. S. A., 97 (3): 10203-10208) have been confirmed.
Nearest data show that PARP-1 and PARP-2 all have overlapping and nonredundant function aspect the maintenance of genome stability, and this is so that they all become interesting target spot.(M é nissier-de Murcia etc., EMBO.J., 22 (9), 2255-2263 (2003)).
The phthalazone analog derivative is used for the PARP-1 inhibitor, and prior art WO2004080976 discloses a kind of structure and has been
WO2006021801 discloses a kind of structure
US2008/0161280A1 discloses a kind of structure
Summary of the invention
A first aspect of the present invention relates to the novel phthalazinone derivatives of a class, its structure shown in logical formula I, with and 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
Or
Or
But when A is
Or
The time, X is not CH
2
Y is selected from CH or N;
R
1Be 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
2Be 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
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R
3Be 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) is (OH)
2, wherein said C
1-12Alkyl, C
1-12Alkoxyl group, C
6-14Aryl, C
3-10Heteroaryl, C
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R
4Be 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
3-10Heterocyclic radical is optional 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;
R preferably wherein
1Be H, halogen, amino, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group; R more preferably
1Be H, Cl, Br, F, C
1-6Alkyl, C
1-6Alkoxyl group;
R preferably
2Be 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; R more preferably
2Be 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 preferably
3Be 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) is (OH)
2R more preferably
3Be 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 preferably
4Be 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; R more preferably
4Be 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 preferably
5And R
6Be H, C independently
1-6Alkyl; R more preferably
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
1Be 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 preferably
1Be H, halogen, amino, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group; R more preferably
1Be H, Cl, Br, F, C
1-6Alkyl, C
1-6Alkoxyl group;
R
2Be 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
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R preferably
2Be 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;
R more preferably
2Be 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; R preferably
5And R
6Be H, C independently
1-6Alkyl; R more preferably
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
, shown in general formula (I b):
X is NH, O, S;
N is 0,1,2,3,4;
R
1Be 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 preferably
1Be H, halogen, amino, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group; R more preferably
1Be H, Cl, Br, F, C
1-6Alkyl, C
1-6Alkoxyl group;
R
4Be 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
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R preferably
4Be 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;
R more preferably
4Be 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; R preferably
5And R
6Be H, C independently
1-6Alkyl; R more preferably
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
, shown in general formula (I c):
（Ⅰc）
X is CH
2, O, S, NH;
Y is selected from CH or N;
N is 0,1,2,3,4;
R
1Be 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 preferably
1Be H, halogen, amino, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group; R more preferably
1Be H, Cl, Br, F, C
1-6Alkyl, C
1-6Alkoxyl group;
R
3Be 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) is (OH)
2, wherein said C
1-12Alkyl, C
1-12Alkoxyl group, C
6-14Aryl, C
3-10Heteroaryl, C
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R preferably
3Be 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;
R more preferably
3Be 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; R preferably
5And R
6Be H, C independently
1-6Alkyl; R more preferably
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 " or " alkoxyl group " that use as the part of group or group in this article 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 of mentioning herein is preferably C
3-10Cycloalkyl, more preferably C
3-6Cycloalkyl can typical example such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The haloalkyl of mentioning herein is preferably halo C
1-6Alkyl can typical example such as trifluoromethyl, trifluoroethyl, difluoromethyl.
The halogenated alkoxy of mentioning herein is preferably halo C
1-6Alkoxyl group can typical example such as trifluoromethoxy, trifluoro ethoxy, difluoro-methoxy.
Term used herein " halogen " refers to fluorine, chlorine, bromine and iodine.Preferred halogen is fluorine.
The term " aryl " that uses as the part of group or group herein refers to remove a resulting univalent perssad of hydrogen atom from the annular atoms of aromatics, and described compound contains a ring or two or more ring; Having one in the wherein said ring at least is aromatic ring.Suitable aryl example comprises phenyl and naphthyl.
The term " heteroaryl " that uses as the part of group or group herein refers to contain 1-4 the first heteroaromatic ring system of heteroatomic 3-10 that is selected from N, O and S, the first heteroaromatic ring system of preferred 3-7.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 " that uses as the part of group or group herein refers to remove a resulting univalent perssad of hydrogen atom from the annular atoms of the heterogeneous ring compound of non-aromatic, described compound contains a ring or two (for example rings of volution, condensed ring, bridge joint) and contain heteroatoms, has at least one to be heterocycle in the 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 formula (I) and the formed salt of any acid, and pharmaceutically acceptable is sour such 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, for example 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 comprise various three-dimensional enantiomers, diastereomer, tautomer and geometrical isomer.The present invention includes compound formula (I), its steric isomer and acceptable salt pharmaceutically thereof.Compound of the present invention may be with mixture, the single stereoisomers of steric isomer or the form appearance with opticity.
Take tautomer as example: it comprises following tautomeric form:
Term " solvate " is used for the mixture of expression solute (for example salt of compound, compound) and solvent in this article at conventional meaning.If solvent is water, solvate can be called as hydrate, such as monohydrate, dihydrate, trihydrate etc. aptly so.
Term " chemoprotectant form " refers to that at conventional meaning wherein one or more reactive functional groups are protected to avoid at the lower compound that undesirable chemical reaction occurs of defined terms (for example, pH, temperature, irradiation, solvent etc.) in this article.In practice, can adopt well-known chemical process reversibly to make those otherwise the functional group that reacts is not reacted under prescribed condition.In chemoprotectant form, one or more reactive functional groups are protected or blocking group (be also referred to as masked or shelter group or be blocked or blocking group).By protective reaction functional group, can relate to other not protected reactive functional groups reaction and do not affect protected group; Blocking group usually can be removed in step subsequently and basically not affect the remainder of molecule.
For example, hydroxyl can protectedly be that (OR) or ester (OC (=O) R), for example protection is ether: tertbutyl ether; Benzyl, diphenyl-methyl (diphenyl methyl) or trityl (trityl group) ether; TMS or tertiary butyl dimethylsilyl ether; Or ethanoyl ester (OC (=O) CH
3,-OAc).
For example, the aldehydes or ketones group can be distinguished the protected acetal (R-CH (OR) that is
2) or ketal (R
2C (OR)
2), wherein carbonyl (＞C=O) by being converted into diether (＞C (OR) with the reaction of primary alconol for example
2).In the presence of acid, use a large amount of excessive water by the hydrolytic action aldehydes or ketones group of can easily regenerating.
For example, amine groups can be protected for for example acid amides (NRCO-R) or urethane (NRCO-OR), for example protectedly be: methyl nitrosourea (NHCO-CH
3); Benzyloxy acid amides (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), (NH-Fmoc), (NH-Nvoc), 2-trimethyl silane base oxethyl acid amides (NH-Teoc), 2 for 6-nitro black false hellebore oxygen base acid amides for 9-fluorenyl methoxy acid amides, 2,2-, three chloroethoxy acid amides (NH-Troc), the allyloxy acid amides (NH-Alloc), (2-benzenesulfonyl) the oxyethyl group acid amides (NH-Psec); Perhaps in situation about being fit to (for example, cyclic amine), protected be Nitrous Oxide (nitroxide) atomic group (＞N-O).
For example, hydroxy-acid group can protectedly be ester, for example protectedly is: C
1-7Alkyl ester (for example methyl ester, tertiary butyl ester); C
1-7Haloalkyl ester (C for example
1-7The tri haloalkyl ester); Three C
1-7Alkyl tin groups, alkyl silane groups-C
1-7Alkyl ester; Or C
5-20Aryl-C
1-7Alkyl ester (for example benzyl ester, nitrobenzyl ester); Or acid amides, for example methyl nitrosourea.
For example, sulfydryl can protectedly be that thioether (SR), for example protectedly is: the benzyl thioether; Acetylamino methyl ether (S-CH
2NHC (=O) CH
3).
Term used herein " prodrug " relates to when the compound that is produced required active compound by metabolism when (for example in vivo).Usually, prodrug is non-activity, and perhaps activity is lower than active compound, but can provide favourable processing, use or metabolisming property.
For example, some prodrugs are esters (for example on the physiology in the acceptable metabolism unsettled ester) of active compound.Between metabilic stage, ester group (C (=O) OR) is cleaved, produces active medicine.This class ester can form by esterification; the for example esterification of any hydroxy-acid group in the parent compound (C (=O) OH), in suitable situation, in advance protection is present in any other reactive group in the parent compound; if necessary, then go protection.
And, thereby some prodrugs are generated active compound by enzyme activation or generate the compound (such as in ADEPT, GDEPT, LIDEPT etc.) of active compound after further chemical reactions.For example, prodrug can be sugar derivatives or other glucosides conjugates, perhaps can be amino acid ester derivative.
A second aspect of the present invention relates to and comprises the compound shown in the logical formula I and the pharmaceutical composition of pharmaceutically acceptable carrier or thinner.
A third aspect of the present invention relates to the purposes of compound in the method for the treatment mankind or animal body shown in the logical formula I.
The present invention also provides and has been used for the treatment of or the method for prevention of various diseases model and effective composition, and these diseases comprise: vascular disease, septic shock, ischemic injury, neurotoxicity, hemorrhagic shock, virus infection maybe can be by suppressing the active disease that alleviate of PARP.
Another aspect of the present invention provides the defined compound of the present invention preparing as the cancer therapy additives or for strengthening ionizing rays or the chemotherapeutics purposes to the medicine of the result for the treatment of of tumour cell.
The invention provides following particular compound:
4-(3-(4-pyridine formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(2-propyl group valeryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(encircling formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluoroanilino) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-pyridine formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-furans-3-formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-ketone
4-(3-(4-propionyl piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-pentanoyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-is acyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(morpholine-4-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenylamino) phthalazines-1 (2H)-ketone
4-(4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-base amido) benzoyl) piperazine-1-yl)-N-methyl-4-oxo butyramide
4-(4-fluoro-3-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-furans-2-formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(encircling formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluorophenoxy) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-furans-3-formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(morpholine-4-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-pentanoyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-is acyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(4-pentanoyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(4-is acyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(4-methoxyl group-2-(2-methoxy ethyl) butyryl radicals) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(the positive dodecanoyl piperazine of 4--1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(3-(4-(2-butyl caproyl) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(2-fluoro-5-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(2-ethyl butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-base oxygen base) benzoyl) piperazine-1-yl)-N-methyl-4-oxo butyramide
4-(4-fluoro-3-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(3-(4-(2,2-diethyl butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(3-hydroxyl propionyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-N, N-dipropyl-1-methane amide
4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-sec.-propyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(5-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-2-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(3-(4-ethanoyl piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
N-ethyl-4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-1-methane amide
4-(4-fluoro-3-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-cyclopropyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-hydroxyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-imidazo [1,5-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
Embodiment:
The present invention can adopt two lines synthetic, and synthesizing when route 1 is NH for X, synthesizing when route 2 is O or S for X, it is CH that route 3 is used for X
2The time synthetic.
Route 1:
1), tert-butoxycarbonyl-piperazine, triethylamine, an amido phenylformic acid are dissolved in N; in the dinethylformamide, add benzotriazole-N, N; N'; N'-tetramethyl-urea phosphofluoric acid ester, stirring at room is after reaction finishes; add go out reaction and separate out solid product of shrend; filter, drying gets 4-(3-amido benzoyl) piperazine-1-t-butyl formate.
2), under ice bath (0 ℃), in the ethanolic soln of triethylamine, add trifluoroacetic acid; step gained 4-(3-amido benzoyl) piperazine-1-t-butyl formate and 1 in the adding; 4-dichloro phthalazines; be heated to backflow, after reaction finishes, add ethyl acetate; and washing; organic phase is dry, and is concentrated, gets 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; concentrated except desolventizing after reaction finishes, get 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 the dinethylformamide, add triethylamine, the carboxylic acid of replacement, benzotriazole-N, N; N'; N'-tetramethyl-urea phosphofluoric acid ester stirring at room, reaction adds shrend and goes out after finishing; ethyl acetate extraction; drying, concentrated, get 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 finishes; adding shrend goes out; ethyl acetate extraction, recrystallization gets 4-(3-(4-substituted formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone [be formula (I is compound a)].
Or with the morpholino of morpholine or replacement for tert-butoxycarbonyl-piperazine, adopt step 1.1,1.2,1.5, namely obtain the compound of formula (I 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 with tert-butoxycarbonyl-piperazine, triethylamine, replacement is dissolved in the DMF adding benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, stirring at room is after reaction finishes, filter, drying, concentrated, get 4-substituted formyl piperazine-1-formyl tert-butyl ester.
2), 4-substituted formyl piperazine-1-formyl tert-butyl ester is dissolved in the mixture of ethanol, water, concentrated hydrochloric acid, stirring at room, concentrated after reaction finishes, get 1-(the substituent methyl ketone of piperazine-1-).
3), (piperazine-1-) substituent methyl ketone adds N with 1-; in the dinethylformamide; add triethylamine, m-Salicylic acid, benzotriazole-N, N, N'; N'-tetramethyl-urea phosphofluoric acid ester stirring at room; after reaction finishes, ethyl acetate extraction, drying; concentrated, get 1-(the substituent methyl ketone of 4-(3-hydroxy benzoyl) piperazine-1-).
4), (piperazine-1-) substituent methyl ketone is dissolved in the DMF 4-(3-hydroxy benzoyl), adds K with 1-
2CO
3And Isosorbide-5-Nitrae-dichloro phthalazines, be heated to backflow, after reaction finishes, ethyl acetate extraction, drying, concentrated, get 1-(the substituent methyl ketone of 4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) piperazine-1-).
5), (piperazine-1-) substituent methyl ketone is dissolved in acetic acid to 4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) with 1-; add sodium-acetate; be heated to backflow; after reaction finishes; ethyl acetate extraction; recrystallization gets 4-(3-(4-substituted formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone.
Or (the substituent methyl ketone of piperazine-1-) adopts step 2.3,2.4,2.5, namely obtains the compound of formula (I b) for 1-with the morpholino of morpholine or replacement.
Or will
(the substituent methyl ketone of piperazine-1-) adopts step 2.3,2.4,2.5, namely obtains formula (I to replace 1-
C) compound.
[reaction formula]
When X is S, use
Replace in the aforesaid method
Route 3:
Will
, diisopropyl ethyl amine, 2-fluoro-5-((4-oxygen-3,4-dihydro phthalazines-1-yl) methyl) phenylformic acid be dissolved in the DMF, add benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, stirring at room is after reaction finishes, adding shrend goes out, filter, drying, concentrated, post separates, 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-pyridine formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
With tert-butoxycarbonyl-piperazine (4.28g, 0.023mol), triethylamine (6.98g, 0.069mol), an amido phenylformic acid (7.01g; 0.023mol) be dissolved in the DMF (100ml), add benzotriazole-N; N, N', N'-tetramethyl-urea phosphofluoric acid ester (8.72g; 0.023mol), stirring at room is after reaction finishes; add go out reaction and separate out solid product of shrend; filter, drying gets 4-(3-amido benzoyl) piperazine-1-t-butyl formate.
Under ice bath (0 ℃), in ethanol (50ml) solution of triethylamine (0.3ml), add trifluoroacetic acid (0.25ml); add upper step gained 4-(3-amido benzoyl) piperazine-1-t-butyl formate (1.65g behind the 15min; 0.0054mol) and 1; 4-dichloro phthalazines (1.07g; 0.0054mol); be heated to backflow; after reaction finishes (about 30min); add ethyl acetate (100ml); washing (3*50ml); organic phase is dry through anhydrous Na 2SO4, and is concentrated, gets 4-(3-(4-chlorine phthalazines-1-amido) benzoyl) piperazine-1-t-butyl formate.
With 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; concentrated except desolventizing after reaction finishes, get 3-(4-chlorine phthalazines-1-amido) phenylpiperazine-1-methyl ketone.
With 3-(4-chlorine phthalazines-1-amido) phenylpiperazine-1-methyl ketone (6.98g; 0.019mol) adding N; in the 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; after reaction finishes; add shrend and go out, ethyl acetate extraction, drying; concentrated, get 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; reaction adds shrend and goes out, ethyl acetate extraction after finishing; recrystallization gets 4-(3-(4-pyridine formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone.Fusing point〉220 ℃.
ESI-MS m/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)-ketone
Preparation method's reference example 1: get target compound, fusing point 204-205 ℃.
ESI-MS m/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)-ketone
Preparation method's reference example 1, fusing point〉230 ℃.
ESI-MS m/z: 415.9 (m-H)
- ,Calculated value: 416.2.
The preparation (008) of embodiment 4:4-(3-(4-(encircling formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-ketone
The preparation method is with reference to embodiment 1, fusing point 187-189 ℃.
ESI-MS m/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)-ketone
Preparation method's reference example 1, fusing point 189-191 ℃.
ESI-MS m/z: 436.4 (m+H)
+, calculated value: 436.2.
The preparation (012) of embodiment 6:4-(4-fluoro-3-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
Preparation method's reference example 1, fusing point 197-199 ℃.
ESI-MS m/z: 494.4 m/z (m+H)
+, calculated value: 494.2.
The preparation (013) of embodiment 7:4-(4-fluoro-3-(4-pyridine formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
The preparation method is with reference to embodiment 1, fusing point〉220 ℃.
ESI-MS m/z: 473.4 (m+H)
+, calculated value: 473.2.
Embodiment 8:4-(4-fluoro-3-(4-furans-3-formyl radical) piperazine-1-carbonyl) anilino) preparation (015) of phthalazines-1 (2H)-ketone
The preparation method is with reference to embodiment 1, fusing point 190-192 ℃.
ESI-MS m/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)-ketone
The preparation method is with reference to embodiment 1, fusing point 170-172 ℃.
ESI-MS m/z: 404.0 (m-H)
-, calculated value: 404.2.
Embodiment 10:4-(4-fluoro-3-(4-pentanoyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone (022)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 452.3 (m+H)
+, calculated value: 452.2.
Embodiment 11:4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone (025)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 508.1(472.1) (m+Cl)
-Calculated value: 508.
Embodiment 12:4-(4-fluoro-3-(4-is acyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone (026)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 466.3 (m+H)
+, calculated value: 466.2.
Embodiment 13:4-(4-fluoro-3-(morpholine-4-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone (028)
The preparation method is with reference to embodiment 1.
ESI-MS m/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)-ketone (029)
The preparation method is with reference to embodiment 1.
ESI-MS m/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)-ketone (030)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 481.3 (m+H)
+Calculated value: 481.2.
Embodiment 16:4-(4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-base amido) benzoyl) piperazine-1-yl)-N-methyl-4-oxo butyramide (032)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 479.4[M-H]
-Calculated value: 479.2.
Embodiment 17:4-(4-fluoro-3-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone (034)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 467.2 [M+H]
+Calculated value: 467.3.
Embodiment 18:4-(4-fluoro-3-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone (035)
The preparation method is with reference to embodiment 1.
ESI-MS m/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)-ketone
The carboxylic acid (0.023mol) of tert-butoxycarbonyl-piperazine (4.28g, 0.023mol), triethylamine (6.98g, 0.069mol), replacement is dissolved in N, in the dinethylformamide (100ml), add benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (8.72g, 0.023mol), stirring at room, reaction adds shrend and goes out after finishing, filter, drying, concentrated, get 4-substituted formyl piperazine-1-formyl tert-butyl ester.
4-substituted formyl piperazine-1-formyl tert-butyl ester (2.10g, 0.0045mol) is dissolved in the mixture 60ml (V:V:V=1:1:1) of ethanol, water, concentrated hydrochloric acid, stirring at room, concentrated after reaction finishes, get 1-(the substituent methyl ketone of piperazine-1-).
(piperazine-1-) substituent methyl ketone (0.019mol) adds N with 1-; in the 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; after reaction finishes; add shrend and go out, ethyl acetate extraction, drying; concentrated, get 1-(the substituent methyl ketone of 4-(3-hydroxy benzoyl) piperazine-1-).
(4-(3-hydroxy benzoyl) piperazine-1-) substituent methyl ketone (0.01mol) is dissolved in N with 1-; in the dinethylformamide (100ml), add K2CO3 (3.45g, 0.025mol) and 1; 4-dichloro phthalazines (4.98g; 0.025mol), be heated to backflow, after reaction finishes; ethyl acetate extraction; drying, concentrated, get 1-(the substituent methyl ketone of 4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) piperazine-1-).
(piperazine-1-) substituent methyl ketone (0.004mol) is dissolved in acetic acid (40ml) to 4-(3-(4-chlorine phthalazines-1-hydroxyl) benzoyl) with 1-; add sodium-acetate (0.012mol); be heated to backflow; after reaction finishes; adding shrend goes out; ethyl acetate extraction, recrystallization gets 4-(3-(4-substituted formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone.Fusing point 121-123 ℃.
ESI-MS m/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)-ketone
The preparation method is with reference to embodiment 19, fusing point 200-201 ℃.
ESI-MS m/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)-ketone
The preparation method is with reference to embodiment 19, fusing point 190-192 ℃.
ESI-MS m/z:417.1 (m-H)
-, calculated value: 417.2.
The preparation (009) of embodiment 22:4-(3-(4-(encircling formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
The preparation method is with reference to embodiment 19, fusing point 174-176 ℃.
ESI-MS m/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)-ketone
The preparation method is with reference to embodiment 19, fusing point 191-193 ℃.
ESI-MS m/z:437.1 (m+H)
+, calculated value: 437.2.
The preparation (014) of embodiment 24:4-(4-fluoro-3-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
The preparation method is with reference to embodiment 19, fusing point 167-168 ℃.
ESI-MS m/z:(m+H)
+439.2, calculated value: 439.2.
Embodiment 25:4-(4-fluoro-3-(4-furans-3-formyl radical) piperazine-1-carbonyl) phenoxy group) preparation (016) of phthalazines-1 (2H)-ketone
The preparation method is with reference to embodiment 19, fusing point 167-169 ℃.
ESI-MS m/z:463.2 (m+H)
+, calculated value: 463.1.
Embodiment 26:4-(4-fluoro-3-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone (018)
The preparation method is with reference to embodiment 19.
ESI-MS m/z:495.3 (m+H)
+, calculated value: 495.2.
Embodiment 27:4-(2,3,6-, three fluoro-5-(morpholine-4-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone (019)
The preparation method is with reference to embodiment 19.
ESI-MS m/z:406.3 (m+H)
+, calculated value: 406.1.
Embodiment 28:4-(4-fluoro-3-(4-pentanoyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone (020)
The preparation method is with reference to embodiment 19.
ESI-MS m/z:453.3 (m+H)
+, calculated value: 453.2.
Embodiment 29:4-(4-fluoro-3-(4-is acyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone (023)
The preparation method is with reference to embodiment 19.
ESI-MS m/z:467.3 (m+H)
+, calculated value: 467.2.
Embodiment 30:4-(2,3,6-, three fluoro-5-(4-pentanoyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone (027)
The preparation method is with reference to embodiment 19.
ESI-MS m/z:(m+H)
+489.3, calculated value: 489.2.
Embodiment 31:4-(2,3,6-, three fluoro-5-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone (031)
The preparation method is with reference to embodiment 19.
ESI-MS m/z:531.2 (m+H)
+, calculated value: 531.2.
Embodiment 32:4-(2,3,6-, three fluoro-5-(4-is acyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone (033)
The preparation method is with reference to embodiment 19.
ESI-MS m/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)-ketone (036)
The preparation method is with embodiment 19.
ESI-MS m/z:482.3 (m+H)
+, calculated value 482.2.
Embodiment 34:4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone (040)
The preparation method is with embodiment 19.
ESI-MS m/z:475.1 (m+H)
+, calculated value 475.2.
Embodiment 35:4-(4-fluoro-3-(4-(4-methoxyl group-2-(2-methoxy ethyl) butyryl radicals) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone (041)
The preparation method is with embodiment 19.
ESI-MS m/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)-ketone (042)
The preparation method is with embodiment 19.
ESI-MS m/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)-ketone (043)
The preparation method is with embodiment 19.
ESI-MS m/z:523.1 (m+H)
+, calculated value 523.2
Embodiment 38:4-(2-fluoro-5-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone (045)
The preparation method is with embodiment 19.
ESI-MS m/z:495.3 (m+H)
+, calculated value 495.2
Embodiment 39:4-(3-(4-(2-ethyl butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone (047)
The preparation method is with embodiment 19.
ESI-MS m/z:467.3 (m+H)
+, calculated value 467.2
Embodiment 40:4-(4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-base oxygen base) benzoyl) piperazine-1-yl)-N-methyl-4-oxo butyramide (051)
The preparation method is with embodiment 19.
ESI-MS m/z:482.3 (m+H)
+, calculated value 482.2
Embodiment 41:4-(4-fluoro-3-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone (052)
The preparation method is with embodiment 19.
ESI-MS m/z:468.2 (m+H)
+, calculated value 468.2
Embodiment 42:4-(4-fluoro-3-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone (053)
The preparation method is with embodiment 19.
ESI-MS m/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)-ketone (054)
The preparation method is with embodiment 19.
ESI-MS m/z:495.3 (m+H)
+, calculated value 495.
Embodiment 44:4-(4-fluoro-3-(4-(3-hydroxyl propionyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone (056)
The preparation method is with embodiment 19.
ESI-MS m/z:441.4 (m+H)
+, calculated value 441.2.
Embodiment 45:4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (057)
The preparation method is with embodiment 1.
ESI-MS m/z:471.0 (m-H)
-, calculated value 471.2.
Embodiment 46:4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-N, N-dipropyl-1-methane amide (058)
The preparation method is with embodiment 19.
ESI-MS m/z:496.2 (m+H)
+, calculated value 496.2
Embodiment 47:4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (059)
With 5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidine hydrochlorate, diisopropyl ethyl amine, 2-fluoro-5-((4-oxygen-3,4-dihydro phthalazines-1-yl) methyl) phenylformic acid be dissolved in the DMF, add benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, stirring at room is after reaction finishes, add shrend and go out, filter drying, concentrated, get the white solid product, i.e. 4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone.
ESI-MS m/z:405.2 (m+H)
+, calculated value 405.2
Embodiment 48:4-(4-fluoro-3-(3-sec.-propyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (060)
The preparation method is with embodiment 47.
ESI-MS m/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)-ketone (062)
The preparation method is with embodiment 19.
ESI-MS m/z:437.1 (m+H)
+, calculated value 437.1
Embodiment 50:4-(3-(4-ethanoyl piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone (063)
The preparation method is with embodiment 19.
ESI-MS m/z:411.2 (m+H)
+, calculated value 411.1
Embodiment 51:N-ethyl-4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-1-methane amide (064)
The preparation method is with embodiment 19.
ESI-MS m/z:440.2 (m+H)
+, calculated value 440.2
Embodiment 52:4-(4-fluoro-3-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (065)
The preparation method is with embodiment 47.
ESI-MS m/z:419.2 (m+H)
+, calculated value 419.2
Embodiment 53:4-(4-fluoro-3-(3-cyclopropyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (066)
The preparation method is with embodiment 47.
ESI-MS m/z:445.2 (m+H)
+, calculated value 445.2
Embodiment 54:4-(4-fluoro-3-(3-hydroxyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (067)
The preparation method is with embodiment 47.
ESI-MS m/z:421.2 (m+H)
+, calculated value 421.1
Embodiment 55:4-(4-fluoro-3-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone (071)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 420.2 (m+H)
+, calculated value: 420.1.
Embodiment 56:4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (072)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 404.2 (m+H)
+, calculated value: 404.4.
Embodiment 57:4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-imidazo [1,5-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone (073)
The preparation method is with reference to embodiment 1.
ESI-MS m/z: 404.2 (m+H)
+, calculated value: 404.4.
Embodiment 58: it is active to suppress poly ADP one ribose polymerase
The enzyme process evaluation of PARP-1 inhibitor.
Material: the PARP-1 enzyme (the high purity human recombination protein, Trevigen), activated dna (Sigma). the steep ketone of 6 (5H)-Fei (PND) (Sigma), NAD
+(Sigma), PARP test damping fluid (20mM Tris, 2mM MgCl
2, pH8.0), 20% methyl phenyl ketone (alcohol is solvent). 2 M KOH, 88% formic acid.
Adopt the ELISA method to set up the molecular screening model of PARP inhibitor, the substrate Histone(source leaf of PARP1 enzyme is biological, Shanghai, China) coated 96 orifice plates (Corning, Lowell, the U.S.), add NAD
+(Sigma, Louis MO, the U.S.), the worker is given birth in DNA(Shanghai, Shanghai, China), add respectively compound, positive control AZD2281(LC laboratories, Woburn, the U.S.) and the PARP1 recombinase make its reaction, generate product P AR(polyadenylic acid ribose) be combined with substrate Histone.Then, add anti-PAR(anti-PAR) antibody (Santa cruz, CA, the U.S.) and Goat anti-rabbit lgG-HRP(Santa cruz, CA, the U.S.) detect the intensity of the PAR on the Histone that is coated with on 96 orifice plates, give birth to the worker with O-Phenylenediamine Dihydrochloride(Shanghai, Shanghai, China) colour developing, H
2SO
4Stop, under 490 nm wavelength, survey the OD value with microplate reader (VERSAmax, Molecular Device, Sunnyvale CA, the U.S.).Calculate analyte 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 carries software according to the inhibiting rate curve calculation of 4 parameter method matches with the VERSAmax microplate reader.
The preliminary active testing that the PARP-1 enzyme suppresses part of compounds the results are shown in following table:
| Sample # | X | (R 1) n | R 2 | R 3 | IC 50 (nM) |
| AZD2281 | CH 2 | F |
 |
— | 24 |
| 012 | NH | F |
 |
— | 5 |
| 018 | O | F |
 |
— | 1 |
| 041 | O | F |
 |
— | 9 |
| 042 | O | F |
 |
— | 8 |
| 047 | O | F | — | 12 | |
| 058 | O | F |
 |
— | 10 |
| 064 | O | F |
 |
— | 7 |
| Sample # | X | (R 1) n | R 4 | IC 50 (nM) |
| 028 | NH | F | H | 34.03 |
| Sample # | X | Y | Z | (R 1) n | R 3 | IC50 (nM) |
| 025 | NH | N | N | F | CF 3 | 27 |
| 040 | O | N | N | F | CF 3 | 5 |
| 057 | CH 2 | N | N | F | CF 3 | 3 |
| 059 | CH 2 | N | N | F | H | 5 |
| 060 | CH 2 | N | N | F |
 |
3 |
| 065 | CH 2 | N | N | F | -CH 3 | 3 |
| 066 | CH 2 | N | N | F |
 |
2 |
| 067 | CH 2 | N | N | F |
 |
3 |
| 071 | NH | N | N | F | -CH 3 | 6 |
| 072 | CH 2 | N | C | F | — | 5 |
| 073 | CH 2 | C | N | F | — | 5 |
"
-" the expression unsubstituted
Claims (10)
1. the compound or its isomer, pharmacy acceptable salt, solvate, chemoprotectant form and the prodrug that lead to formula I,
（Ⅰ）
Wherein X is CH
2, NH, O, S;
N is 0,1,2,3,4;
A is
Or
Or
But when A is
Or
The time, X is not CH
2
Y is selected from CH or N;
R
1Be 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
2Be 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
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R
3Be 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) is (OH)
2, wherein said C
1-12Alkyl, C
1-12Alkoxyl group, C
6-14Aryl, C
3-10Heteroaryl, C
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R
4Be 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
3-10Heterocyclic radical is optional 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.
2. the compound of logical formula I according to claim 1 or its isomer, pharmacy acceptable salt, solvate, chemoprotectant form and prodrug,
Wherein working as A is
, as general formula (I a) shown in:
X is NH, O, S;
N is 0,1,2,3,4;
R
1Be 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 preferably
1Be H, halogen, amino, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group; R more preferably
1Be H, Cl, Br, F, C
1-6Alkyl, C
1-6Alkoxyl group;
R
2Be 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
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R preferably
2Be 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;
R more preferably
2Be 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; R preferably
5And R
6Be H, C independently
1-6Alkyl; R more preferably
5And R
6Be H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl independently.
3. the compound of logical formula I according to claim 1 or its isomer, pharmacy acceptable salt, solvate, chemoprotectant form and prodrug,
Wherein working as A is
, shown in general formula (I b):
X is NH, O, S;
N is 0,1,2,3,4;
R
1Be 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 preferably
1Be H, halogen, amino, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group; R more preferably
1Be H, Cl, Br, F, C
1-6Alkyl, C
1-6Alkoxyl group;
R
4Be 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
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R preferably
4Be 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;
R more preferably
4Be 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; R preferably
5And R
6Be H, C independently
1-6Alkyl; R more preferably
5And R
6Be H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl independently.
4. the compound of logical formula I according to claim 1 or its isomer, pharmacy acceptable salt, solvate, chemoprotectant form and prodrug,
Wherein working as A is
, shown in general formula (I c):
X is CH
2, O, S, NH;
Y is selected from CH or N;
N is 0,1,2,3,4;
R
1Be 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 preferably
1Be H, halogen, amino, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group; R more preferably
1Be H, Cl, Br, F, C
1-6Alkyl, C
1-6Alkoxyl group;
R
3Be 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) is (OH)
2, wherein said C
1-12Alkyl, C
1-12Alkoxyl group, C
6-14Aryl, C
3-10Heteroaryl, C
3-10Heterocyclic radical is optional further by hydroxyl, amino, C
1-12Alkoxyl group, list (C
1-12Alkyl) amino, two (C
1-12Alkyl) amino, CONR
5R
6Replace;
R preferably
3Be 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 ,-OP (O) is (OH)
2
R more preferably
3Be 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; R preferably
5And R
6Be H, C independently
1-6Alkyl; R more preferably
5And R
6Be H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl independently.
5. compound according to claim 1 or its isomer, pharmacy acceptable salt, solvate, chemoprotectant form and prodrug are particularly preferably following compound:
4-(3-(4-pyridine formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(2-propyl group valeryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(encircling formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluoroanilino) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-pyridine formyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-furans-3-formyl radical) piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-ketone
4-(3-(4-propionyl piperazine-1-carbonyl) anilino) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-pentanoyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-is acyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(morpholine-4-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenylamino) phthalazines-1 (2H)-ketone
4-(4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-base amido) benzoyl) piperazine-1-yl)-N-methyl-4-oxo butyramide
4-(4-fluoro-3-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(3-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-furans-2-formyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(encircling formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-4-fluorophenoxy) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-isobutyryl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-furans-3-formyl radical) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(morpholine-4-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-pentanoyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-is acyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(4-pentanoyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(2,3,6-, three fluoro-5-(4-is acyl piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(4-(dimethylin) butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(4-methoxyl group-2-(2-methoxy ethyl) butyryl radicals) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(the positive dodecanoyl piperazine of 4--1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(3-(4-(2-butyl caproyl) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(2-fluoro-5-(4-(2-propyl group pentanoyl) piperazine-1-carbonyl) phenoxy group) phthalazines-1 (2H)-ketone
4-(3-(4-(2-ethyl butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-base oxygen base) benzoyl) piperazine-1-yl)-N-methyl-4-oxo butyramide
4-(4-fluoro-3-(4-(4-methyl amido) butyryl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(3-methyl amido) propionyl piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(3-(4-(2,2-diethyl butyryl radicals) piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(4-(3-hydroxyl propionyl) piperazine-1-carbonyl) phenyl oxygen base) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-N, N-dipropyl-1-methane amide
4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-sec.-propyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(5-(4-(cyclopropane carbonyl) piperazine-1-carbonyl)-2-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
4-(3-(4-ethanoyl piperazine-1-carbonyl)-4-fluorophenyl oxygen base) phthalazines-1 (2H)-ketone
N-ethyl-4-(2-fluoro-5-(4-oxo-3,4-dihydro phthalazines-1-oxygen base) benzoyl) piperazine-1-methane amide
4-(4-fluoro-3-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-cyclopropyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-hydroxyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] piperidines-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine-7-carbonyl) phenyl amido) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone
4-(4-fluoro-3-(5,6,7,8-tetrahydrochysene-imidazo [1,5-a] pyrazine-7-carbonyl) benzyl) phthalazines-1 (2H)-ketone.
6. according to claim 1 to 5 each described compound or its pharmacy acceptable salts, wherein said pharmacy acceptable salt is the salt that forms 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, camphorsulfonic acid or its analogue, or be an alkali metal salt, the alkaline earth salt of the phosphoric acid ester of compound of Formula I.
7. method for preparing each described compound of claim 1 to 6 or its pharmacy acceptable salt, described method comprises:
1) when X is NH, take amido phenylformic acid between replacing and tert-butoxycarbonyl-piperazine as raw material, (I is compound a) to obtain formula according to following formula
Wherein the morpholino with morpholine or replacement replaces tert-butoxycarbonyl-piperazine, adopts step 1.1,1.2,1.5, namely obtains the compound of formula (I b);
Will
Replace tert-butoxycarbonyl-piperazine, adopt step 1.1,1.2,1.5, namely obtain formula (I
C) compound;
2) when X is O, take the carboxylic acid that replaces and tert-butoxycarbonyl-piperazine as raw material, obtain according to following formula that (I is compound a)
Wherein (the substituent methyl ketone of piperazine-1-) adopts step 2.3,2.4,2.5, namely obtains the compound of formula (I b) for 1-with the morpholino of morpholine or replacement;
Will
(the substituent methyl ketone of piperazine-1-) adopts step 2.3,2.4,2.5, namely obtains formula (I to replace 1-
C) compound;
When X is S, use
Replace in the aforesaid method
3) when X be CH
2The time, with
Be raw material, obtain (I c) compound according to following formula
[reaction formula]
Randomly, with described method 1), 2) or 3) product and the corresponding acid-respons that obtain prepare its pharmacy acceptable salt;
R wherein
1, R
2, R
3, R
4Has the definition described in each such as claim 1-6.
8. a pharmaceutical composition comprises claim 1-6 each described general formula (I) compound or its pharmacy acceptable salt.
9. according to claim 1-6 or each described compound of 8 or pharmaceutical composition suppress the purposes of the medicine of PARP activity in preparation.
10. according to claim 9 purposes, described medicine is used as the auxiliary of cancer therapy or for strengthening the therapeutic action to tumour cell of radiation or chemotherapeutic, preferably 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.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014019468A1 (en) * | 2012-08-01 | 2014-02-06 | 中国科学院上海药物研究所 | Piperazinotrizole compound, preparation method therefor, and use thereof in drug preparation |
| CN104003940A (en) * | 2014-06-16 | 2014-08-27 | 华东理工大学 | 2,4-difluoro-5-( phthalazone-1-methyl)-benzoyl piperazine compound and application thereof |
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| CN105646497A (en) * | 2016-02-01 | 2016-06-08 | 南京格亚医药科技有限公司 | Pyrrolo-triazinone derivatives |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1568187A (en) * | 2001-08-15 | 2005-01-19 | Icos股份有限公司 | 2H-2,3-dinitrogen phenodiazine-1-ketone and using method thereof |
| CN1905864A (en) * | 2003-12-01 | 2007-01-31 | 库多斯药物有限公司 | DNA damage repair inhibitors for treatment of cancer |
| CN102372716A (en) * | 2010-08-09 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazone derivative, its preparation method and application in medicine thereof |
| CN103130723A (en) * | 2011-11-30 | 2013-06-05 | 成都地奥制药集团有限公司 | Poly (aenosine diphosphate glucose pyrophospheralase (ADP)-ribose) polymerase inhibitor |
-
2012
- 2012-02-14 CN CN201210032055.1A patent/CN102898377B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1568187A (en) * | 2001-08-15 | 2005-01-19 | Icos股份有限公司 | 2H-2,3-dinitrogen phenodiazine-1-ketone and using method thereof |
| CN1905864A (en) * | 2003-12-01 | 2007-01-31 | 库多斯药物有限公司 | DNA damage repair inhibitors for treatment of cancer |
| CN102372716A (en) * | 2010-08-09 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazone derivative, its preparation method and application in medicine thereof |
| CN103130723A (en) * | 2011-11-30 | 2013-06-05 | 成都地奥制药集团有限公司 | Poly (aenosine diphosphate glucose pyrophospheralase (ADP)-ribose) polymerase inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| KEITH A. MENEAR ET AL.: "4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1", 《J. MED. CHEM.》 * |
| XIAO-LING COCKCROFT: "Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (33)
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| WO2014019468A1 (en) * | 2012-08-01 | 2014-02-06 | 中国科学院上海药物研究所 | Piperazinotrizole compound, preparation method therefor, and use thereof in drug preparation |
| CN104003940A (en) * | 2014-06-16 | 2014-08-27 | 华东理工大学 | 2,4-difluoro-5-( phthalazone-1-methyl)-benzoyl piperazine compound and application thereof |
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