CN1788000B - 酞嗪酮衍生物 - Google Patents
酞嗪酮衍生物 Download PDFInfo
- Publication number
- CN1788000B CN1788000B CN2004800128781A CN200480012878A CN1788000B CN 1788000 B CN1788000 B CN 1788000B CN 2004800128781 A CN2004800128781 A CN 2004800128781A CN 200480012878 A CN200480012878 A CN 200480012878A CN 1788000 B CN1788000 B CN 1788000B
- Authority
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- China
- Prior art keywords
- compound
- alkyl
- aryl
- heterocyclic radical
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical class C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 226
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 100
- 125000003118 aryl group Chemical group 0.000 claims abstract description 36
- 150000002148 esters Chemical class 0.000 claims abstract description 28
- 125000003368 amide group Chemical group 0.000 claims abstract description 22
- 125000002252 acyl group Chemical group 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 210000004027 cell Anatomy 0.000 claims description 70
- 238000002360 preparation method Methods 0.000 claims description 54
- 150000003254 radicals Chemical class 0.000 claims description 44
- 125000004429 atom Chemical group 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 37
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 29
- 101150008921 Brca2 gene Proteins 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 108020004414 DNA Proteins 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 25
- 101150072950 BRCA1 gene Proteins 0.000 claims description 20
- 102000052609 BRCA2 Human genes 0.000 claims description 18
- 108700020462 BRCA2 Proteins 0.000 claims description 18
- 230000002950 deficient Effects 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 102000036365 BRCA1 Human genes 0.000 claims description 14
- 108700020463 BRCA1 Proteins 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 239000004215 Carbon black (E152) Substances 0.000 claims description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 230000001419 dependent effect Effects 0.000 claims description 12
- 229930195733 hydrocarbon Natural products 0.000 claims description 12
- 150000003568 thioethers Chemical class 0.000 claims description 12
- 230000008859 change Effects 0.000 claims description 11
- 230000005865 ionizing radiation Effects 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 230000000973 chemotherapeutic effect Effects 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000004185 ester group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 150000003462 sulfoxides Chemical class 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 230000008439 repair process Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 210000004881 tumor cell Anatomy 0.000 claims description 4
- 208000032456 Hemorrhagic Shock Diseases 0.000 claims description 3
- 206010029350 Neurotoxicity Diseases 0.000 claims description 3
- 206010040070 Septic Shock Diseases 0.000 claims description 3
- 206010049771 Shock haemorrhagic Diseases 0.000 claims description 3
- 206010044221 Toxic encephalopathy Diseases 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 208000037906 ischaemic injury Diseases 0.000 claims description 3
- 230000007135 neurotoxicity Effects 0.000 claims description 3
- 231100000228 neurotoxicity Toxicity 0.000 claims description 3
- 238000011275 oncology therapy Methods 0.000 claims description 3
- 230000036303 septic shock Effects 0.000 claims description 3
- 208000019553 vascular disease Diseases 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 3
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 230000037361 pathway Effects 0.000 claims 2
- 230000007812 deficiency Effects 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 9
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- 239000000243 solution Substances 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 230000000694 effects Effects 0.000 description 32
- 238000000034 method Methods 0.000 description 31
- 239000002904 solvent Substances 0.000 description 31
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 28
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 26
- 239000000203 mixture Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 239000003513 alkali Substances 0.000 description 19
- 229910052760 oxygen Inorganic materials 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000001301 oxygen Substances 0.000 description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
- 238000009835 boiling Methods 0.000 description 15
- 230000005782 double-strand break Effects 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 230000006801 homologous recombination Effects 0.000 description 13
- 238000002744 homologous recombination Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 12
- 229940002612 prodrug Drugs 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
- 239000012661 PARP inhibitor Substances 0.000 description 10
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical group 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000005864 Sulphur Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 6
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- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 5
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- 238000010168 coupling process Methods 0.000 description 5
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
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- 150000003233 pyrroles Chemical class 0.000 description 5
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- 238000002560 therapeutic procedure Methods 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
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- 125000000129 anionic group Chemical group 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
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- 125000001072 heteroaryl group Chemical group 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
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- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 3
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- 125000000468 ketone group Chemical group 0.000 description 3
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- 230000004060 metabolic process Effects 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
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Abstract
Description
本发明涉及酞嗪酮衍生物和它们作为药物的用途。确切而言,本发明涉及这些化合物抑制聚(ADP-核糖)聚合酶活性的用途,该酶也称聚(ADP-核糖)合成酶和聚ADP-核糖基转移酶,普遍被称为PARP。
哺乳动物酶PARP(一种113kDa的多结构域蛋白质)通过其识别和迅速结合DNA单链或双链断裂的能力而在DNA损伤的信号传输中有牵连(D′Amours等,Biochem.J.,342,249-268(1999))。
若干观察结果已经得出结论,PARP参予多种DNA-相关功能,包括基因扩增、细胞分裂、分化、细胞程序死亡、DNA碱基切除修复,以及影响端粒长度和染色体稳定性(d′Adda di Fagagna等,Nature Gen.,23(1),76-80(1999))。
对PARP调控DNA修复和其他过程的机理研究已经确认它在细胞核内聚(ADP-核糖)链生成中的重要性(Althaus,E.R.和Richter,C.,“ADP-Ribosylation of Proteins:Enzymology and Biological Significance”,Springer-Verlag,Berlin(1987))。与DNA结合的活化的PARP利用NAD在多种核靶蛋白质上合成聚(ADP-核糖),包括拓扑异构酶、组蛋白和PARP本身(Rhun等,Biochem.Biophys.Res.Commun.,245,1-10(1998))。
聚(ADP-核糖基)化作用也与恶性转化有关。例如,PARP活性在所分离的SV40-转化的成纤维细胞的核中更高,而白血病细胞和结肠癌细胞都显示比相当的正常白细胞和结肠粘膜更高的酶活性(Miwa等,Arch.Biochem.Biophys.,181,313-321(1977);Burzio等,Proc.Soc.Exp.Bioi.Med.,149,933-938(1975);以及Hirai等,Cancer Res.,43,3441-3446(1983))。
PARP的大量低分子量抑制剂已经用于阐明聚(ADP-核糖基)化作用在DNA修复中的功能角色。在经烷基化剂处理的细胞中,PARP的抑制引起DNA-链断裂和细胞杀死的显著增加(Durkacz等,Nature,283,593-596(1980);Berger,N.A.,Radiation Research,101,4-14(1985))。
随后,这类抑制剂已经显示通过抑制潜在致命性损伤的修复而增强放射响应的效果(Ben-Hur等,British Journal of Cancer,49(增刊VI),34-42(1984);Schlicker等,Int.J.Radiat.Bioi.,75,91-100(1999))。PARP抑制剂已据报道在放射敏感的低氧肿瘤细胞中有效(US 5,032,617;US 5,215,738and US 5,041,653)。
此外,PARP剔除(PARP-/-)的动物表现响应于烷基化剂和γ-照射的基因组不稳定性(Wang等,Genes Dev.,9,509-520(1995);Menissier deMurcia等,Proc.Natl.Acad.Sci.USA,94,7303-7307(1997))。
PARP的角色已经在某些血管疾病、脓毒性休克、缺血损伤和神经毒性中得到证明(Cantoni等,Biochim.Biophys.Acta,1014,1-7(1989);Szabo等,J.Clin.Invest.,100,723-735(1997))。引起随后被PARP识别的DNA链断裂的氧自由基DNA损伤是对这类疾病状态的主要贡献因素,如PARP抑制剂研究所示(Cosi等,J.Neurosci.Res.,39,38-46(1994);Said等,Proc.Natl.Acad.Sci.U.S.A.,93,4688-4692(1996))。最近,PARP已被证明在出血性休克的发病中扮演角色(Liaudet等,Proc.Natl.Acad.Sci.U.S.A.,97(3),10203-10208(2000))。
也已证明,哺乳动物细胞的高效逆病毒感染受到PARP活性抑制的阻滞。重组逆病毒载体感染的这类抑制作用发生在多种不同的细胞类型中(Gaken等,J.Virology,70(6),3992-4000(1996))。PARP抑制剂因而已被开发用在抗病毒疗法和癌症治疗中(WO 91/18591)。
而且,PARP抑制据推测可延缓人成纤维细胞老化特征的出现(Rattan和Clark,Biochem.Biophys.Res.Comme 201(2),665-672(1994))。这可能涉及PARP在控制端粒功能中所扮演的角色(d′Addadi Fagagna等,Mature Gen.,23(1),76-80(1999))。
有些本发明人以前已经描述过(WO 02/36576)一类1(2H)-酞嗪酮化合物,它们充当PARP抑制剂。这些化合物具有下列通式:
其中A和B一起代表可选被取代的稠合芳族环,其中Rc由-L-RL所代表。大量实例是下式:
其中R代表一个或多个可选的取代基。
本发明人现已发现,其中R具有某些属性的化合物表现出惊人水平的PARP活性抑制作用,和/或强化放射疗法和多种各种化学疗法对肿瘤细胞的作用。
因此,本发明的第一方面提供式(I)化合物:
及其异构体、盐、溶剂合物、化学保护形式和前体药物,其中:
A和B一起代表可选被取代的稠合芳族环;
X可以是NRX或CRXRY;
如果X=NRX,则n是1或2,如果X=CRXRY,则n是1;
RX选自H、可选被取代的C1-20烃基、C5-20芳基、C3-20杂环基、酰氨基、硫代酰氨基、酯、酰基和磺酰基;
RY选自H、羟基、氨基;
或者RX和RY可以一起构成螺-C3-7环烃基或杂环基;
RC1和RC2都是氢,或者当X是CRXRY时,RC1、RC2、RX和RY与它们所连接的碳原子一起可以构成可选被取代的稠合芳族环;且
R1选自H和卤素。
因此,如果X是CRXRY,则n是1,该化合物是式(Ia):
如果X是NRX,且n是1,则该化合物是式(Ib):
如果X是NRX,且n是2,则该化合物是式(Ic):
本发明的第二方面提供药物组合物,包含第一方面化合物和药学上可接受的载体或稀释剂。
本发明的第三方面提供用在人或动物体治疗方法中的第一方面化合物。
本发明的第四方面提供如本发明第一方面所定义的化合物在制备用于抑制PARP活性的药物中的用途。
本发明的其他方面提供如本发明第一方面所定义的化合物在药物制备中的用途,该药物用于治疗:血管疾病;脓毒性休克;缺血损伤;神经毒性;出血性休克;病毒感染;或者因PARP活性抑制而改善的疾病。
本发明的另一方面提供如本发明第一方面所定义的化合物在药物制备中的用途,该药物用作癌症疗法的辅助手段或者用于强化电离放射或化学治疗剂对肿瘤细胞的治疗。
本发明的其他方面提供因PARP抑制而改善的疾病的治疗,包括对需要治疗的对象给予治疗有效量的如第一方面所定义的化合物,优选药物组合物的形式,和癌症的治疗,包括对需要治疗的对象给予同时或先后与电离放射或化学治疗剂组合的治疗有效量的如第一方面所定义的化合物、优选药物组合物的形式。
在本发明的其他方面中,化合物可以用于制备用于治疗癌症的药物,该癌症是同源重组(HR)依赖性DNA DSB修复活性缺陷的,或者用于治疗癌症患者,该癌症是HR依赖性DNA DSB修复活性缺陷的,包括对所述患者给予治疗有效量的化合物。
HR依赖性DNA DSB修复途径经由同源机理修复DNA的双链断裂(DSB),以重新生成连续的DNA螺旋(K.K.Khanna和S.P.Jackson,Nat.Genet.27(3):247-254(2001))。HR依赖性DNA DSB修复途径的组分包括但不限于ATM(NM_000051)、RAD51(NM_002875)、RAD51L1(NM_002877)、RAD51C(NM_002876)、RAD51L3(NM_002878)、DMC1(NM_007068)、XRCC2(NM_005431)、XRCC3(NM_005432)、RAD52(NM_002879)、RAD54L(NM_003579)、RAD54B(NM_012415)、BRCA1(NM_007295)、BRCA2(NM_000059)、RAD50(NM_005732)、MRE11A(NM_005590)和NBS1(NM_002485)。其他牵涉在HR依赖性DNA DSB修复途径中的蛋白质包括调节因子,例如EMSY(Hughes-Davies等,Cell,115,523-535页)。HR组分也描述在Wood等,Science,291,1284-1289(2001)中。
HR依赖性DNA DSB修复缺陷的癌症可以包含或者由一种或多种这样的癌细胞组成,它们相对于正常的细胞而言通过该途径修复DNA DSB的能力减低或者取消,即HR依赖性DNA DSB修复途径的活性可能在一种或多种癌细胞中被减低或者取消。
HR依赖性DNA DSB修复途径的一种或多种组分的活性可能在患有HR依赖性DNA DSB修复缺陷癌症的个体的一种或多种癌细胞中被消除。HR依赖性DNA DSB修复途径的组分在本领域中被充分表征(例如参见Wood等,Science,291,1284-1289(2001)),包括上文所列举的组分。
在有些优选的实施方式中,癌细胞可能具有BRCA1和/或BRCA2缺陷的表型,即BRCA1和/或BRCA2活性在该癌细胞中被减低或消除。具有这种表型的癌细胞可能是BRCA1和/或BRCA2缺陷的,即BRCA1和/或BRCA2的表达和/或活性可能在该癌细胞中被减低或消除,例如借助编码性核酸的突变或多态性,或者借助编码调节因子的基因的扩增、突变或多态性,例如编码BRCA2调节因子的EMSY基因(Hughes-Davies等,Cell,115,523-535)。
BRCA1和BRCA2是已知的肿瘤抑制剂,它们的野生型等位基因经常在杂合载体肿瘤中丧失(Jasin M.,Oncogene,21(58),8981-93(2002);Tutt等,Trends Mol Med.,8(12),571-6(2002))。BRCA1和/或BRCA2突变与乳腺癌的关联在本领域中已被充分认识(Radice,P.J.,Exp Clin Cancer Res.,21(增刊3),9-12(2002))。编码BRCA2结合因子的EMSY基因的扩增已知也与乳腺癌和卵巢癌有关。
BRCA1和/或BRCA2中突变的载体也处于卵巢、前列腺和胰腺癌症的升高风险中。
在有些优选的实施方式中,个体就BRCA1和/或BRCA2或其调节剂的一种或多种变异如突变和多态性而言是杂合的。BRCA1和BRCA2变异的检测是本领域熟知的,例如描述在EP 699754;EP 705903;Neuhausen,S.L.和Ostrander,E.A.,Genet.Test,1,75-83(1992);Chappnis,P.O.和Foulkes,W.D.,Cancer Treat Res,107,29-59(2002);Janatova M.等,Neoplasm,50(4),246-50(2003);Jancarkova,N.,Ceska Gynekol.,6(1),11-6(2003)中。BRCA2结合因子EMSY扩增的测定描述在Hughes-Davies等,Cell,115,523-535中。
与癌症有关的突变和多态性可以通过检测变异核酸序列的存在而在核酸水平上检测,或者通过检测变异(也就是突变或等位基因变异)多肽的存在而在蛋白质水平上检测。
定义
术语“芳族环”在本文中于常规意义上用于表示环状芳族结构,也就是具有离域π-电子轨道的环状结构。
与主核稠合即由-A-B-所构成的芳族环可以携带其他稠合芳族环(例如导致萘基或蒽基)。芳族环可以仅包含碳原子,或者可以包含碳原子和一个或多个杂原子,包括但不限于氮、氧和硫原子。芳族环优选地具有五或六个环原子。
芳族环可以可选地被取代。如果取代基本身包含芳基,则该芳基不被视为它所连接的芳基的一部分。例如,联苯在本文被视为被苯基取代的苯基(包含单一芳族环的芳基)。类似地,苄基苯基被视为被苄基取代的苯基(包含单一芳族环的芳基)。
在一组优选的实施方式中,芳族基团包含单一的芳族环,它具有五或六个环原子,这些环原子选自碳、氮、氧和硫,该环是可选被取代的。这些基团的实例包括但不限于苯、吡嗪、吡咯、噻唑、异噁唑和噁唑。2-吡喃酮也可以被视为芳族环,但是较为不优选。
如果芳族环具有六个原子,则优选地至少四个或者甚至五个或全部环原子是碳。其余环原子选自氮、氧和硫,氮和氧是优选的。适合的基团包括具有下列杂原子的环:没有杂原子(苯);一个氮环原子(吡啶);两个氮环原子(吡嗪、嘧啶和哒嗪);一个氧环原子(吡喃酮);一个氧和一个氮环原子(噁嗪)。
如果芳族环具有五个环原子,则优选地至少三个环原子是碳。其余环原子选自氮、氧和硫。适合的环包括具有下列杂原子的环:一个氮环原子(吡咯);两个氮环原子(咪唑、吡唑);一个氧环原子(呋喃);一个硫环原子(噻吩);一个氮和一个硫环原子(异噻唑、噻唑);一个氮和一个氧环原子(异噁唑或噁唑)。
芳族环可以在任意可用的环位置上携带一个或多个取代基。这些取代基选自卤素、硝基、羟基、醚、巯基、硫醚、氨基、C1-7烃基、C3-20杂环基和C5-20芳基。芳族环也可以携带一个或多个一起构成一个环的取代基。确切而言,它们可以是式-(CH2)m-或-O-(CH2)p-O-,其中m是2、3、4或5,p是1、2或3。
烃基:本文所用的术语“烃基”涉及从具有1至20个碳原子(另有指定除外)的烃化合物的碳原子上除去氢原子所得到的一价部分,它可以是脂族的或脂环族的,并且可以是饱和的或不饱和的(例如部分不饱和的、完全不饱和的)。因而,术语“烃基”包括小类链烯基、炔基、环烷基、环烯基、环炔基等,见下文的讨论。
就烃基而言,前缀(例如C1-4、C1-7、C1-20、C2-7、C3-7等)表示碳原子数或者碳原子数的范围。例如,本文所用的术语“C1-4烃基”涉及具有1至4个碳原子的烃基。烃基的实例包括C1-4烃基(低级烃基)、C1-7烃基和C1-20烃基。注意第一前缀可以根据其他限制而变化,例如,就不饱和的烃基而言,第一前缀必须至少是2;就环状烃基而言,第一前缀必须至少是3;等等。
(未取代的)饱和烃基的实例包括但不限于甲基(C1)、乙基(C2)、丙基(C3)、丁基(C4)、戊基(C5)、己基(C6)、庚基(C7)、辛基(C8)、壬基(C9)、癸基(C10)、十一基(C11)、十二基(C12)、十三基(C13)、十四基(C14)、十五基(C15)和二十基(C20)。
(未取代的)饱和直链烃基的实例包括但不限于甲基(C1)、乙基(C2)、正丙基(C3)、正丁基(C4)、正戊基(戊基)(C5)、正己基(C6)和正庚基(C7)。
(未取代的)饱和支链烃基的实例包括异丙基(C3)、异丁基(C4)、仲丁基(C4)、叔丁基(C4)、异戊基(C5)和新戊基(C5)。
链烯基:本文所用的术语“链烯基”涉及具有一条或多条碳-碳双键的烃基。链烯基的实例包括C2-4链烯基、C2-7链烯基、C2-20链烯基。
(未取代的)不饱和链烯基的实例包括但不限于乙烯基(-CH=CH2)、1-丙烯基(-CH=CH-CH3)、2-丙烯基(烯丙基,-CH-CH=CH2)、异丙烯基(1-甲基乙烯基,-C(CH3)=CH2)、丁烯基(C4)、戊烯基(C5)和己烯基(C6)。
炔基:本文所用的术语“炔基”涉及具有一条或多条碳-碳叁键的烃基。炔基的实例包括C2-4炔基、C2-7炔基、C2-20炔基。
(未取代的)不饱和炔基的实例包括但不限于乙炔基(-C≡CH)和2-丙炔基(炔丙基,-CH2-C≡CH)。
环烃基:本文所用的术语“环烃基”涉及也是环状基团的烃基;也就是从碳环化合物碳环的脂环族环原子上除去氢原子所得到的一价部分,该碳环可以是饱和的或不饱和的(例如部分不饱和的、完全不饱和的),该部分具有3至20个碳原子(另有指定除外),包括3至20个环原子。因而,术语“环烃基”包括小类环烯基和环炔基。优选地,每个环具有3至7个环原子。环烃基的实例包括C3-20环烃基、C3-15环烃基、C3-10环烃基、C3-7环烃基。
环烃基的实例包括但不限于从下列化合物衍生的那些:
饱和的单环烃化合物:环丙烷(C3)、环丁烷(C4)、环戊烷(C5)、环己烷(C6)、环庚烷(C7)、甲基环丙烷(C4)、二甲基环丙烷(C5)、甲基环丁烷(C5)、二甲基环丁烷(C6)、甲基环戊烷(C6)、二甲基环戊烷(C7)、甲基环己烷(C7)、二甲基环己烷(C8)、薄荷烷(C10);
不饱和的单环烃化合物:环丙烯(C3)、环丁烯(C4)、环戊烯(C5)、环己烯(C6)、甲基环丙烯(C4)、二甲基环丙烯(C5)、甲基环丁烯(C5)、二甲基环丁烯(C6)、甲基环戊烯(C6)、二甲基环戊烯(C7)、甲基环己烯(C7)、二甲基环己烯(C8);
饱和的多环烃化合物:苧烷(C10)、蒈烷(C10)、蒎烷(C10)、莰烷(C10)、降蒈烷(C7)、降蒎烷(C7)、降冰片烷(C7)、金刚烷(C10)、萘烷(十氢萘)(C10);
不饱和的多环烃化合物:莰烯(C10)、苧烯(C10)、蒎烯(C10);
具有芳族环的多环烃化合物:茚(C9)、二氢化茚(例如2,3-二氢-1H-茚)(C9)、四氢萘(1,2,3,4-四氢萘)(C10)、苊(C12)、芴(C13)、phenalene(C13)、醋菲(C15)、醋蒽(C16)、胆蒽(C20)。
杂环基:本文所用的术语“杂环基”涉及从杂环化合物的环原子上除去氢原子所得到的一价部分,该部分具有3至20个环原子(另有指定除外),其中1至10个是环杂原子。优选地,每个环具有3至7个环原子,其中1至4个是环杂原子。
在这方面,前缀(例如C3-20、C3-7、C5-6等)表示环原子数或者环原子数的范围,无论碳原子还是杂原子。例如,本文所用的术语“C5-6杂环基”涉及具有5或6个环原子的杂环基。杂环基的实例包括C3-20杂环基、C5-20杂环基、C3-15杂环基、C5-15杂环基、C3-12杂环基、C5-12杂环基、C3-10杂环基、C5-10杂环基、C3-7杂环基、C5-7杂环基和C5-6杂环基。
单环杂环基的实例包括但不限于从下列化合物衍生的那些:
N1:氮杂环丙烷(C3)、氮杂环丁烷(C4)、吡咯烷(四氢吡咯)(C5)、吡咯啉(例如3-吡咯啉、2,5-二氢吡咯)(C5)、2H-吡咯或3H-吡咯(异吡咯、异吖唑)(C5)、哌啶(C6)、二氢吡啶(C6)、四氢吡啶(C6)、氮杂(C7);
S1:硫杂环丙烷(C3)、硫杂环丁烷(C4)、硫杂环戊烷(四氢噻吩)(C5)、硫杂环己烷(四氢噻喃)(C6)、硫杂环庚烷(C7);
O2:二氧杂环戊烷(C5)、二噁烷(C6)和二氧杂环庚烷(C7);
O3:三噁烷(C6);
N2:咪唑烷(C5)、吡唑烷(二唑烷)(C5)、咪唑啉(C5)、吡唑啉(二氢吡唑)(C5)、哌嗪(C6);
N1O1:四氢噁唑(C5)、二氢噁唑(C5)、四氢异噁唑(C5)、二氢异噁唑(C5)、吗啉(C6)、四氢噁嗪(C6)、二氢噁嗪(C6)、噁嗪(C6);
N1S1:噻唑啉(C5)、噻唑烷(C5)、硫代吗啉(C6);
N2O1:噁二嗪(C6);
O1S1:氧硫杂环戊烯(C5)和氧硫杂环己烷(噻噁烷)(C6);和
N1O1S1:噁噻嗪(C6)。
取代的(非芳族)单环杂环基的实例包括从环状形式的糖类衍生的那些,例如呋喃糖类(C5),例如阿拉伯呋喃糖、呋喃来苏糖、呋喃核糖和呋喃木糖,和吡喃糖类(C6),例如别吡喃糖(allopyranose)、阿卓吡喃糖、吡喃葡萄糖、吡喃甘露糖、吡喃古洛糖、吡喃艾杜糖、吡喃半乳糖和吡喃塔罗糖。
螺-C3-7环烃基或杂环基:本文所用的术语“螺-C3-7环烃基或杂环基”表示这样一种C3-7环烃基或C3-7杂环基环,与另一个环通过二环共用的单一原子连接。
C5-20芳基:本文所用的术语“C5-20芳基”涉及从C5-20芳族化合物的芳族环原子上除去氢原子所得到的一价部分,所述化合物具有一个环或者两个或多个环(例如稠合),并且具有5至20个环原子,其中至少一个所述环是芳族环。优选地,每个环具有5至7个环原子。
环原子可以都是碳原子,正如“碳芳基”,在这种情况下,该基团可以适宜地被称为“C5-20碳芳基”。
不具有环杂原子的C5-20芳基(也就是C5-20碳芳基)的实例包括但不限于从苯(即苯基)(C6)、萘(C10)、蒽(C14)、菲(C14)和芘(C16)衍生的那些。
作为替代选择,环原子可以包括一个或多个杂原子,包括但不限于氧、氮和硫,如“杂芳基”。在这种情况下,该基团可以适宜地被称为“C5-20杂芳基”,其中“C5-20”表示环原子,无论碳原子或杂原子。优选地,每个环具有5至7个环原子,其中0至4个是环杂原子。
C5-20杂芳基的实例包括但不限于从下列化合物衍生的C5杂芳基:呋喃(氧杂环戊二烯)、噻吩(硫杂环戊二烯)、吡咯(吖唑)、咪唑(1,3-二唑)、吡唑(1,2-二唑)、三唑、噁唑、异噁唑、噻唑、异噻唑、噁二唑、四唑和噁三唑;和从下列化合物衍生的C6杂芳基:异噁嗪、吡啶(吖嗪)、哒嗪(1,2-二嗪)、嘧啶(1,3-二嗪,例如胞嘧啶、胸腺嘧啶、尿嘧啶)、吡嗪(1,4-二嗪)和三嗪。
杂芳基可以经由碳或杂环原子键合。
包含稠合环的C5-20杂芳基的实例包括但不限于C9杂芳基,衍生自苯并呋喃、异苯并呋喃、苯并噻吩、吲哚、异吲哚;C10杂芳基,衍生自喹啉、异喹啉、苯并二嗪、吡啶并吡啶;C14杂芳基,衍生自吖啶和呫吨。
上述烃基、杂环基和芳基无论单独还是作为另一取代基的一部分,本身可以可选地被一个或多个基团取代,取代基选自它们自身和下文列举的另外取代基。
卤素:-F、-Cl、-Br和-I。
羟基:-OH。
醚:-OR,其中R是醚取代基,例如C1-7烃基(也被称为C1-7烃氧基)、C3-20杂环基(也被称为C3-20杂环氧基)或C5-20芳基(也被称为C5-20芳氧基),优选C1-7烃基。
硝基:-NO2。
氰基(腈、甲腈):-CN。
酰基(酮基):-C(=O)R,其中R是酰基取代基,例如C1-7烃基(也被称为C1-7烃基酰基或C1-7烃酰基)、C3-20杂环基(也被称为C3-20杂环基酰基)或C5-20芳基(也被称为C5-20芳基酰基),优选C1-7烃基。酰基的实例包括但不限于-C(=O)CH3(乙酰基)、-C(=O)CH2CH3(丙酰基)、-C(=O)C(CH3)3(丁酰基)和-C(=O)Ph(苯甲酰基、苯酮)。
羧基(羧酸):-COOH。
酯(羧酸酯、羧酸的酯、氧羰基):-C(=O)OR,其中R是酯取代基,例如C1-7烃基、C3-20杂环基或C5-20芳基,优选C1-7烃基。酯基的实例包括但不限于-C(=O)OCH3、-C(=O)OCH2CH3、-C(=O)OC(CH3)3和-C(=O)OPh。
酰氨基(氨基甲酰基、氨甲酰基、氨基羰基、甲酰胺):-C(=O)NR1R2,其中R1和R2独立地是氨基取代基,如关于氨基所定义的。酰氨基的实例包括但不限于-C(=O)NH2、-C(=O)NHCH3、-C(=O)N(CH3)2、-C(=O)NHCH2CH3和-C(=O)N(CH2CH3)2,以及这样的酰氨基,其中R1和R2与它们所附着的氮原子一起构成杂环结构,例如哌啶子基羰基、吗啉代羰基、硫代吗啉代羰基和哌嗪基羰基。
氨基:-NR1R2,其中R1和R2独立地是氨基取代基,例如氢、C1-7烃基(也被称为C1-7烃基氨基或二-C1-7烃基氨基)、C3-20杂环基或C5-20芳基,优选H或C1-7烃基,或者在“环状”氨基的情况下,R1和R2与它们所附着的氮原子一起构成具有4至8个环原子的杂环。氨基的实例包括但不限于-NH2、-NHCH3、-NHC(CH3)2、-N(CH3)2、-N(CH2CH3)2和-NHPh。环状氨基的实例包括但不限于氮杂环丙烷基、氮杂环丁烃基、吡咯烃基、哌啶子基、哌嗪基、全氢二氮杂基、吗啉代基和硫吗啉代基。环状氨基可以在它们的环上被本文所定义的任意取代基取代,例如羧基、羧酸酯和酰氨基。
酰基酰氨基(酰基氨基):-NR1C(=O)R2,其中R1是酰胺取代基,例如氢、C1-7烃基、C3-20杂环基或C5-20芳基,优选H或C1-7烃基,最优选H,R2是酰基取代基,例如C1-7烃基、C3-20杂环基或C5-20芳基,优选C1-7烃基。酰基酰胺基团的实例包括但不限于-NHC(=O)CH3、-NHC(=O)CH2CH3和-NHC(=O)Ph。R1和R2可以一起构成环状结构,例如琥珀酰亚氨基、马来酰亚氨基和邻苯二酰亚氨基:
琥珀酰亚氨基 马来酰亚氨基 邻苯二酰亚氨基
脲基:-N(R1)CONR2R3,其中R2和R3独立地是氨基取代基,如关于氨基所定义的,R1是脲基取代基,例如氢、C1-7烃基、C3-20杂环基或C5-20芳基,优选氢或C1-7烃基。脲基的实例包括但不限于-NHCONH2、-NHCONHMe、-NHCONHEt、-NHCONMe2、-NHCONEt2、-NMeCONH2、NMeCONHMe、-NMeCONHEt、-NMeCONMe2、-NMeCONEt2和-NHCONHPh。
酰氧基(反酯):-OC(=O)R,其中R是酰氧基取代基,例如C1-7烃基、C3-20杂环基或C5-20芳基,优选C1-7烃基。酰氧基的实例包括但不限于-OC(=O)CH3(乙酰氧基)、-OC(=O)CH2CH3、-OC(=O)C(CH3)3、-OC(=O)Ph、-OC(=O)C6H4F和-OC(=O)CH2Ph。
巯基:-SH。
硫醚(硫化物):-SR,其中R是硫醚取代基,例如C1-7烃基(也被称为C1-7烃硫基)、C3-20杂环基或C5-20芳基,优选C1-7烃基。C1-7烃硫基的实例包括但不限于-SCH3和-SCH2CH3。
亚砜(亚磺酰基):-S(=O)R,其中R是亚砜取代基,例如C1-7烃基、C3-20杂环基或C5-20芳基,优选C1-7烃基。亚砜基团的实例包括但不限于-S(=O)CH3和-S(=O)CH2CH3。
磺酰基(砜):-S(=O)2R,其中R是砜取代基,例如C1-7烃基、C3-20杂环基或C5-20芳基,优选C1-7烃基。砜基团的实例包括但不限于-S(=O)2CH3(甲磺酰基、甲磺酰)、-S(=O)2CF3、-S(=O)2CH2CH3和4-甲基苯磺酰基(甲苯磺酰基)。
硫代酰氨基(硫代氨甲酰基):-C(=S)NR1R2,其中R1和R2独立地是氨基取代基,如关于氨基所定义的。酰氨基的实例包括但不限于-C(=S)NH2、-C(=S)NHCH3、-C(=S)N(CH3)2和-C(=S)NHCH2CH3。
磺酰氨基:-NR1S(=O)2R,其中R1是氨基取代基,如关于氨基所定义的,R是磺酰氨基取代基,例如C1-7烃基、C3-20杂环基或C5-20芳基,优选C1-7烃基。磺酰氨基的实例包括但不限于-NHS(=O)2CH3、-NHS(=O)2Ph和-N(CH3)S(=O)2C6H5。
如上所述,构成以上所列取代基的基团、例如C1-7烃基、C3-20杂环基和C5-20芳基,本身可以被取代。因而,上述定义涵盖被取代的取代基。
附图简要说明
图1显示暴露于本发明化合物(4)的细胞的克隆发生存活曲线。
图1A显示连续暴露于化合物4的Brca1野生型(11CO:■)、杂合(Cre6:▲)和缺陷(Cre10:●)的ES细胞。误差棒代表均值的标准误差。
图1B显示连续暴露于化合物4的Brca2野生型(D3:■)、杂合(Cre6:▲)和缺陷(Cre24:)的ES细胞。误差棒代表均值的标准误差。
进一步的优选
下列优选能够应用于本发明的每一方面,只要适用的话。
本发明中,由-A-B-代表的稠合芳族环优选地仅由碳环原子构成,因而可以是苯、萘,更优选苯。如上所述,这些环可以被取代,但是在有些实施方式中优选地是未取代的。
如果由-A-B-代表的稠合芳族环携带取代基,则它优选连接的原子本身连接于中心环羰基间位。因而,如果稠合芳族环是苯环,优选的取代位置如下式中的*所示:
它通常被称为酞嗪酮部分的5-位。
R1优选地选自H、Cl和F,更优选F。
优选地,RC1和RC2都是氢。
当n是2时,X是NRX。在这些实施方式中,RX优选地选自下列基团:H;可选被取代的C1-20烃基;可选被取代的C5-20芳基;可选被取代的酯基,其中酯取代基优选地是C1-20烃基;可选被取代的酰基;可选被取代的酰氨基;可选被取代的硫代酰氨基;和可选被取代的磺酰基。RX更优选地选自下列基团:H;可选被取代的C1-20烃基;可选被取代的C5-20芳基;和可选被取代的酯基,其中酯取代基优选地是C1-20烃基。
当n是1时,X可以是NRX或CRXCRY。
在其中X是NRX的实施方式中,RX优选地选自下列基团:H;可选被取代的C1-20烃基;可选被取代的C5-20芳基;可选被取代的酰基;可选被取代的磺酰基;可选被取代的酰氨基;和可选被取代的硫代酰氨基。
在其中X是CRXRY的实施方式中,RY优选地是H。RX优选地选自下列基团:H;可选被取代的C1-20烃基;可选被取代的C5-20芳基;可选被取代的C3-20杂环基;可选被取代的酰基,其中酰基取代基优选地选自C5-20芳基和C3-20杂环基(例如哌嗪基);可选被取代的酰氨基,其中氨基优选地选自H和C1-20烃基,或者与氮原子一起构成C5-20杂环基团;和可选被取代的酯基,其中酯取代基优选地选自C1-20烃基。
特别优选的化合物包括:1、2、3、4、10、21、74、97、152、153、163、167、169、173、185、232、233、250、251、252、260和263。
上述优选酌情可以彼此组合在一起。
包括其他形式
上文包括这些取代基的熟知的离子、盐、溶剂合物和被保护形式。例如,对羧酸(-COOH)的称谓还包括阴离子(羧酸根)形式(-COO-)、其盐或溶剂合物以及常规被保护形式。类似地,对氨基的称谓包括质子化形式(-N+HR1R2)、氨基的盐或溶剂合物,例如盐酸盐,以及氨基的常规被保护形式。类似地,对羟基的称谓还包括阴离子形式(-O-)、其盐或溶剂合物以及羟基的常规被保护形式。
异构体、盐、溶剂合物和被保护形式
某些化合物可以存在一种或多种特定的几何、旋光、对映、非对映、差向异构、立体异构、互变异构、构象或端基异构型,包括但不限于顺式(cis)-与反式(trans)-型;E-与Z-型;c-、t-与r-型;内-与外-型;R-、S-与内消旋-型;D-与L-型;d-与l-型;(+)与(-)型;酮基-、烯醇-与烯醇化物-型;顺(syn)-与反(anti)-型;顺错-与反错-型;α-与β-型;轴向与平伏型;船-、椅-、扭曲-、信封-与半椅-型;及其组合,以下统称为“异构体”(或“异构型”)。
如果化合物是结晶形式,则它可以存在多种不同的多晶型。
注意,除了下文关于互变异构型的讨论,特别要从本文所用的术语“异构体”中排除在外的是结构(或构造)异构体(也就是在原子之间的连接而非仅仅是原子的空间位置有差别的异构体)。例如,对甲氧基-OCH3的称谓不被解释为对其结构异构体、即羟甲基-CH2OH的称谓。类似地,对邻-氯苯基的称谓不被解释为对其结构异构体、即间-氯苯基的称谓。不过,对一类结构的称谓也可以包括属于这种类别的结构异构型(例如,C1-7烃基包括正丙基和异丙基;丁基包括正-、异-、仲-与叔-丁基;甲氧基苯基包括邻-、间-与对-甲氧基苯基)。
上述排除不涉及互变异构型,例如酮-、烯醇-和烯醇化物-形式,例如下列互变异构对:酮/烯醇、亚胺/烯胺、酰胺/亚氨基醇、脒/脒、亚硝基/肟、硫酮/烯硫醇、N-亚硝基/羟基偶氮和硝基/酸式硝基。
与本发明特别相关的是下述互变异构对:
注意:在术语“异构体”中特别包括具有一个或多个同位素取代的化合物。例如,H可以是任意同位素形式,包括1H、2H(D)和3H(T);C可以是任意同位素形式,包括12C、13C和14C;O可以是任意同位素形式,包括16O和18O;等等。
除非另有指定,对特定化合物的称谓包括全部这样的异构型,包括其(完全或部分)外消旋和其他混合物。制备(例如不对称合成)和分离(例如分步结晶和色谱手段)这类异构型的方法是本领域已知的,或者以已知方式调整本文所教导的方法或已知方法而容易获得。
除非另有指定,对特定化合物的称谓也包括其离子、盐、溶剂合物和被保护的形式,如下文所讨论,以及它的不同多晶型。
可能适宜或者需要制备、纯化和/或处理相应的活性化合物的盐,例如药学上可接受的盐。药学上可接受的盐的实例讨论于Berge等,“药学可接受的盐”,J.Pharm.Sci.,66,1-19(1977)。
例如,如果化合物是阴离子的或者具有可以是阴离子的官能团(例如,-COOH可以是-COO-),则可以与适合的阳离子生成盐。适合的无机阳离子的实例包括但不限于碱金属离子如Na+和K+,碱土金属阳离子如Ca2+和Mg2+,和其他阳离子如Al3+。适合的有机阳离子的实例包括但不限于铵离子(即NH4 +)和取代的铵离子(例如NH3R+、NH2R2+、NHR3+、NR4 +)。某些适合的取代的铵离子的实例是从下列衍生的那些:乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺和氨丁三醇,以及氨基酸如赖氨酸和精氨酸。常见季铵离子的实例是N(CH3)4 +。
如果化合物是阳离子性的或者具有可以是阳离子的官能团(例如-NH2可以是-NH3 +),则可以与适合的阴离子生成盐。适合的无机阴离子的实例包括但不限于从下列无机酸衍生的那些:盐酸、氢溴酸、氢碘酸、硫酸、亚硫酸、硝酸、亚硝酸、磷酸和亚磷酸。适合的有机阴离子的实例包括但不限于从下列有机酸衍生的那些:乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、棕榈酸、乳酸、苹果酸、扑酸、酒石酸、柠檬酸、葡糖酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、天冬氨酸、苯甲酸、肉桂酸、丙酮酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙磺酸、乙二磺酸、草酸、羟乙磺酸、戊酸和葡糖酸。适合的聚合阴离子的实例包括但不限于从下列聚合酸衍生的那些:鞣酸、羧甲基纤维素。
可能适宜或者需要制备、纯化和/或处理相应的活性化合物的溶剂合物。术语“溶剂合物”在本文中在常规意义上用于表示溶质(例如活性化合物、活性化合物的盐)与溶剂的配合物。如果溶剂是水,则溶剂合物适宜被称为水合物,例如一水合物、二水合物、三水合物等。
可能适宜或者需要制备、纯化和/或处理活性化合物的化学保护形式。在本文中使用的术语“化学保护形式”涉及这样的化合物,其中一个或多个反应性官能团被保护免于发生不需要的化学反应,也就是说为被保护的或保护基团(也称被掩蔽或掩蔽基团或者被封闭或封闭基团)的形式。通过保护反应性官能团,可以进行牵涉其他未保护的反应性官能团的反应,而不影响被保护的基团;通常在随后的步骤中可以除去保护基团,而不实质性影响分子的其余部分。例如参见Protective Groups in Organic Synthesis(T.Green和P.Wuts;第3版;John Wiley and Sons,1999)。
例如,羟基可以被保护为醚(-OR)或酯(-OC(=O)R),例如叔丁基醚;苄基、二苯甲基(二苯基甲基)或三苯甲基(三苯基甲基)醚;三甲代甲硅烷基或叔丁基二甲基甲硅烷基醚;或乙酰基酯(-OC(=O)CH3,-OAc)。
例如,醛或酮基团可以分别被保护为醛缩醇或酮缩醇,其中羰基(>C=O)借助与例如伯醇的反应转化为二醚(>C(OR)2)。在酸的存在下使用大为过量的水,借助水解作用容易再生出醛或酮基团。
例如,胺基团可以被保护为例如酰胺或氨甲酸乙酯,例如甲酰胺(-NHCO-CH3);苄氧基酰胺(-NHCO-OCH2C6H5,-NH-Cbz);叔丁氧基酰胺(-NHCO-OC(CH3)3,-NH-Boc);2-联苯-2-丙氧基酰胺(-NHCO-OC(CH3)2C6H4C6H5,-NH-Bpoc);9-芴基甲氧基酰胺(-NH-Fmoc);6-硝基藜芦氧基酰胺(-NH-Nvoc);2-三甲代甲硅烷基乙氧基酰胺(-NH-Teoc);2,2,2-三氯乙氧基酰胺(-NH-Troc);烯丙氧基酰胺(-NH-Alloc);(2-苯磺酰基)乙氧基酰胺(-NH-Psec);或者在适合的情况下,为N-氧化物(>NO·)。
例如,羧酸基团可以被保护为酯,例如C1-7烃基酯(例如甲基酯、叔丁基酯);C1-7卤代烃基酯(例如C1-7三卤烃基酯);三C1-7烃基甲硅烷基-C1-7烃基酯;C5-20芳基-C1-7烃基酯(例如苄基酯、硝基苄基酯);或酰胺,例如甲基酰胺。
例如,巯基可以被保护为硫醚(-SR),例如苄基硫醚;乙酰氨基甲基醚(-S-CH2NHC(=O)CH3)。
可能适宜或需要制备、纯化和/或处理活性化合物的前体药物形式。本文所用的术语“前体药物”涉及这样一种化合物,它在被代谢时(例如体内),产生所需的活性化合物。通常,前体药物是无活性的,或者活性低于活性化合物,但是可以提供有利的处理、给药或代谢性质。
例如,有些前体药物是活性化合物的酯(例如生理学上可接受的、代谢上不稳定的酯)。在代谢期间,酯基(-C(=O)OR)被裂解,产生活性药物。这类酯可以这样生成,例如借助母体化合物中的任意羧酸基团(-C(=O)OH)的酯化作用,酌情预先保护存在于母体化合物中的任意其他反应性基团,如果需要的话继之以去保护。这类代谢上不稳定的酯的实例包括这些,其中R是C1-20烃基(例如-Me、-Et);C1-7氨基烃基(例如氨乙基、2-(N,N-二乙氨基)乙基、2-(4-吗啉代)乙基);和酰氧基-C1-7烃基(例如酰氧基甲基、酰氧基乙基,例如新戊酰氧基甲基、乙酰氧基甲基、1-乙酰氧基乙基、1-(1-甲氧基-1-甲基)乙基-碳酰氧基乙基、1-(苯甲酰氧基)乙基、异丙氧基-碳酰氧基甲基、1-异丙氧基-碳酰氧基乙基、环己基-碳酰氧基甲基、1-环己基-碳酰氧基乙基、环己氧基-碳酰氧基甲基、1-环己氧基-碳酰氧基乙基、(4-四氢吡喃氧基)碳酰氧基甲基、1-(4-四氢吡喃氧基)碳酰氧基乙基、(4-四氢吡喃基)碳酰氧基甲基和1-(4-四氢吡喃基)碳酰氧基乙基)。
进一步适合的前体药物形式包括膦酸酯和羟乙酸盐。确切而言,羟基(-OH)可以这样被制成膦酸酯前体药物:先与氯代二苄基亚磷酸酯(盐)反应,继之以氢化,生成膦酸酯基-O-P(=O)(OH)2。这样一种基团可以在代谢期间被磷酸酶清除,得到具有羟基的活性药物。
而且,有些前体药物被酶活化,得到活性化合物或者在进一步化学反应之后得到活性化合物的化合物。例如,前体药物可以是糖衍生物或其他糖苷缀合物,或者可以是氨基酸酯衍生物。
字首缩略词
为方便起见,很多化学部分用熟知的缩写代表,包括但不限于甲基(Me)、乙基(Et)、正丙基(nPr)、异丙基(iPr)、正丁基(nBu)、叔丁基(tBu)、正己基(nHex)、环己基(cHex)、苯基(Ph)、联苯(biPh)、苄基(Bn)、萘基(naph)、甲氧基(MeO)、乙氧基(EtO)、苯甲酰基(Bz)和乙酰基(Ac)。
为方便起见,很多化合物用熟知的缩写代表,包括但不限于甲醇(MeOH)、乙醇(EtOH)、异丙醇(i-PrOH)、甲乙酮(MEK)、乙醚或二乙醚(Et2O)、乙酸(AcOH)、二氯甲烷(亚甲基氯,DCM)、三氟乙酸(TFA)、二甲基甲酰胺(DMF)、四氢呋喃(THF)和二甲基亚砜(DMSO)。
合成
在下文给出的合成途径中,为方便起见,A-B稠合环被显示为稠合苯环。使用适当的替代原料、利用类似于下文所述的方法可以合成其中A-B环不是苯的化合物。
本发明化合物可以这样合成:使式1化合物:
其中R1如前文所定义,与式2化合物反应:
其中n、RC1、RC2和X如前文所定义,反应这样进行:在偶联试剂系统存在下,例如2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐或(二甲氨基丙基)乙基碳二亚胺盐酸盐/羟基苯并三唑,在碱如二异丙基乙胺存在下,在溶剂例如二甲基乙酰胺或二氯甲烷中,在0℃至所用溶剂沸点的温度范围内。
作为替代选择,本发明化合物可以这样合成:利用熟知的方法将式1化合物转化为活化品种,例如酰氯或者活化的酯,例如N-羟基琥珀酰亚胺酯,再使该活化品种与式2化合物反应。
式1化合物可以这样合成:使式3化合物:
式3
其中R1如前文所定义,或式4化合物:
其中R1如前文所定义,或者式3化合物与式4化合物的混合物与肼源例如水合肼反应,反应这样进行:可选地在碱例如三乙胺存在下,可选地在溶剂例如工业用甲醇化酒精存在下,在0℃至所用溶剂沸点的温度范围内。
式3或式4化合物或者其混合物可以这样合成,使式5化合物:
其中R1如前文所定义,与能够水解腈部分的试剂例如氢氧化钠反应,反应这样进行:在溶剂例如水存在下,在0℃至所用溶剂沸点的温度范围内。
式5化合物可以这样合成:使式6化合物:
式6
其中R1如前文所定义,与式7化合物反应:
式7
反应这样进行:在碱例如甲醇钠存在下,在溶剂例如甲醇中,可选地在水清除剂例如丙酸乙酯存在下,在0℃至所用溶剂沸点的温度范围内。
式1化合物也可以这样合成:使式8化合物:
其中R1如前文所定义,与能够水解腈部分的试剂例如氢氧化钠反应,反应这样进行:在溶剂例如水存在下,在0℃至所用溶剂沸点的温度范围内,继之以使所得中间体与肼源例如水合肼反应,反应在0℃至所用溶剂沸点的温度范围内进行。
式8化合物可以这样合成:使式9化合物:
式9
其中Ra是C1-4烃基,与式6化合物反应,反应这样进行:在碱例如三乙胺或六甲基二硅氮化锂存在下,在溶剂例如四氢呋喃存在下,在-80℃至所用溶剂沸点的温度范围内。
式9化合物可以借助类似于WO 02/26576所述的方法合成。
式1化合物也可以借助类似于上述的方法合成,其中全部式中的腈部分被其他能够生成羧酸的部分代替,例如酯或酰胺部分。
式2化合物是商业上可得到的或者可以借助化学文献所报道的方法合成。
本发明化合物,其中X是CRXRY,其中RX或RY之一是酰氨基部分,因此可以由式10所代表:
式10
其中n、RC1、RC2、R1和RX如前文所定义,RN1和RN2各自选自H、可选被取代的C1-20烃基、C5-20芳基、C3-20杂环基,或者可以一起构成可选被取代的C3-7环烃基或杂环基,该化合物可以这样合成:使式11化合物:
式11
其中n、RC1、RC2、R1和RX如前文所定义,与式HNRN1RN2化合物反应,其中RN1和RN2如前文所定义,反应这样进行:在偶联试剂系统的存在下,例如2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐或(二甲氨基丙基)乙基碳二亚胺盐酸盐/羟基苯并三唑,在碱例如二异丙基乙胺存在下,在溶剂例如二甲基乙酰胺或二氯甲烷中,在0℃至所用溶剂沸点的温度范围内。
作为替代选择,式10化合物可以这样合成:利用熟知的方法将式11化合物转化为活化品种,例如酰氯或者活化的酯,例如N-羟基琥珀酰亚胺酯,再使该活化品种与式HNRN1RN2化合物反应。
式11化合物可以这样合成:使式11化合物的被保护形式去保护,例如式12化合物:
其中n、RC1、RC2、R1和RX如前文所定义,R01是C1-4烃基,去保护利用熟知的方法,例如碱催化的水解,反应这样进行:在氢氧化物源例如钠或锂的氢氧化物存在下,在溶剂例如水和/或四氢呋喃存在下,在0℃至所用溶剂沸点的温度范围内。
式12化合物可以借助前述方法从式1化合物合成。
式HNRN1RN2化合物是商业上可得到的或者可以借助化学文献所报道的方法合成。
本发明化合物,其中X是NH,因此可以由式13所代表:
其中n、RC1、RC2和R1如前文所定义,该化合物可以这样合成,使式13化合物的被保护形式去保护,例如式14化合物:
式14
其中n、RC1、RC2和R1如前文所定义,去保护利用熟知的方法,例如酸催化的裂解,反应这样进行:在酸例如三氟乙酸或盐酸存在下,在溶剂例如二氯甲烷或乙醇和/或水存在下,在0℃至所用溶剂沸点的温度范围内。
式14化合物可以借助前述方法从式1化合物合成。
本发明化合物,其中X是NRX,其中RX是酰基部分,因此可以由式15化合物所代表:
其中n、RC1、RC2和R1如前文所定义,RC3选自可选被取代的C1-20烃基、C5-20芳基和C3-20杂环基,该化合物可以这样合成:使式13化合物与式RC3COX化合物反应,其中RC3如前文所定义,X是适合的离去基团,例如卤素如氯,反应这样进行:可选地在碱例如吡啶、三乙胺或二异丙基乙胺存在下,可选地在溶剂例如二氯甲烷存在下,在0℃至所用溶剂沸点的温度范围内。
式RC3COX化合物是商业上可得到的或者可以借助化学文献所报道的方法合成。
式15化合物也可以这样合成:使式13化合物与式RC3CO2H化合物反应,其中RC3如前文所定义,反应这样进行:在偶联试剂系统存在下,例如2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐或(二甲氨基丙基)乙基碳二亚胺盐酸盐/羟基苯并三唑,在碱例如二异丙基乙胺存在下,在溶剂例如二甲基乙酰胺或二氯甲烷中,在0℃至所用溶剂沸点的温度范围内。
式RC3CO2H化合物是商业上可得到的或者可以借助化学文献所报道的方法合成。
本发明化合物,其中X是NRX,其中RX是酰氨基或硫代酰氨基部分,因此可以由式16化合物所代表:
其中n、RC1、RC2和R1如前文所定义,Y是O或S,RN3选自可选被取代的C1-20烃基、C5-20芳基和C3-20杂环基,该化合物可以这样合成:使式13化合物与式RN3NCY化合物反应,其中Y和RN3如前文所定义,反应这样进行:在溶剂例如二氯甲烷存在下,在0℃至所用溶剂沸点的温度范围内。
式RN3NCY化合物是商业上可得到的或者可以借助化学文献所报道的方法合成。
本发明化合物,其中X是NRX,其中RX是磺酰基部分,因此可以由式17化合物所代表:
其中n、RC1、RC2和R1如前文所定义,RS1选自可选被取代的C1-20烃基、C5-20芳基和C3-20杂环基,该化合物可以这样合成:使式13化合物与式RS1SO2Cl化合物反应,其中RS1如前文所定义,反应这样进行:可选地在碱例如吡啶、三乙胺或二异丙基乙胺存在下,在溶剂例如二氯甲烷存在下,在0℃至所用溶剂沸点的温度范围内。
式RS1SO2Cl化合物是商业上可得到的或者可以借助化学文献所报道的方法合成。
本发明化合物,其中X是NRX,其中RX选自可选被取代的C1-20烃基或C3-20杂环基,因此可以由式18化合物所代表:
其中n、RC1、RC2和R1如前文所定义,RC4和RC5各自选自H、可选被取代的C1-20烃基、C5-20芳基、C3-20杂环基,或者可以一起构成可选被取代的C3-7环烃基或杂环基,该化合物可以这样合成:使式13化合物与式RC4CORC5化合物反应,其中RC4和RC5如前文所定义,反应这样进行:在还原剂例如氰基硼氢化钠或三乙酰氧基硼氢化钠存在下,在溶剂例如甲醇存在下,可选地在酸催化剂例如乙酸存在下,在0℃至所用溶剂沸点的温度范围内。
式RC4CORC5化合物是商业上可得到的或者可以借助化学文献所报道的方法合成。
用途
本发明提供活性化合物,具体而言在抑制PARP的活性中有活性。
本文所用的术语“活性”涉及能够抑制PARP活性的化合物,具体包括具有内在活性的化合物(药物)以及这类化合物的前体药物,这些前体药物本身可能表现很少或没有内在活性。
在下文实施例中描述了一种可以适宜用于评估由特定化合物所提供的PARP抑制作用的测定法。
本发明进一步提供抑制细胞中PARP活性的方法,包括使所述细胞与有效量的活性化合物、优选药学上可接受的组合物形式接触。这样一种方法可以在体外或体内实施。
例如,可以使细胞样品体外生长,使活性化合物与所述细胞接触,观察该化合物对这些细胞的效应。作为“效应”的实例,可以测定在某一时间实现的DNA修复的量。若发现活性化合物对细胞发挥影响,则这可以用作化合物在治疗携带相同细胞型细胞的患者的方法中的功效的预后或诊断标志。
就治疗病症而言,本文所用的术语“治疗”一般涉及治疗和疗法,无论是人类还是动物(例如在兽医应用中),其中达到一定的所需治疗作用,例如病症进展的抑制,包括进展速率的降低、进展速率的终止、病症的改善和病症的治愈。也包括作为预防性措施的治疗(即预防)。
本文所用的术语“辅助手段”涉及活性化合物与已知治疗手段的联合应用。这类手段包括用于治疗不同癌症类型的药物细胞毒性方案和/或电离放射。确切而言,活性化合物已知可强化大量癌症化学疗法的治疗作用,这包括用于治疗癌症的拓扑异构酶类毒物(例如托泊替康、伊立替康、鲁比替康(rubitecan))、大多数已知的烃基化剂(例如DTIC、替莫唑胺(temozolamide))和铂类药物(例如卡铂、顺铂)。
活性化合物也可以用作抑制PARP的细胞培养添加剂,例如为了使细胞敏感于已知化学治疗剂或体外电离放射治疗。
活性化合物也可以用作体外测定法的一部分,例如为了测定候选宿主是否可能从有关化合物治疗中受益。
给药
活性化合物或包含活性化合物的药物组合物可以借助任意适宜的给药途径对对象给药,无论系统性/外周性还是在所需作用部位,包括但不限于口服(例如摄食);局部(包括例如透皮、鼻内、眼、口腔和舌下);肺(例如吸入或吹入疗法,例如使用气雾剂,例如通过口或鼻);直肠;阴道;肠胃外,例如注射,包括皮下、皮内、肌内、静脉内、动脉内、心脏内、鞘内、脊柱内、囊内、囊下、眼眶内、腹膜内、气管内、表皮下、关节内、蛛网膜下和胸骨内;药库的植入,例如皮下或肌内。
所述对象可以是真核生物、动物、脊椎动物、哺乳动物、啮齿动物(例如豚鼠、仓鼠、大鼠、小鼠)、鼠科动物(例如小鼠)、犬科动物(例如狗)、猫科动物(例如猫)、马科动物(例如马)、灵长目动物、类人猿(例如猴子或猿)、猿猴(例如狨、狒狒)、猿(例如大猩猩、黑猩猩、猩猩、长臂猿)或人类。
制剂
尽管活性化合物有可能单独给药,不过优选作为药物组合物(例如制剂)呈递,该组合物包含至少一种如上所定义的活性化合物以及一种或多种药学上可接受的载体、助剂、赋形剂、稀释剂、填充剂、缓冲剂、稳定剂、防腐剂、润滑剂或本领域技术人员熟知的其他材料和可选的其他治疗剂或预防剂。
因而,本发明进一步提供如上所定义的药物组合物和制备药物组合物的方法,包括混合至少一种如上所定义的活性化合物以及一种或多种药学上可接受的载体、赋形剂、缓冲剂、助剂、稳定剂或其他材料,如本文所述。
本文所用的术语“药学上可接受的”涉及这样的化合物、材料、组合物和/或剂型,它们在合理的医药判定范围内适用于与对象(例如人)的组织接触,而没有过分的毒性、刺激性、变态反应或者其他问题或并发症,与合理的利益/风险比相称。每种载体、赋形剂等在与制剂其他成分相容的意义上也必须是“可接受的”。
适合的载体、稀释剂、赋形剂等可以参见标准的药学著作。例如参见“药物添加剂手册”,第2版(M.Ash和I.Ash编辑),001(SynapseInformation Resources,Inc.,Endicott,纽约,USA)、“Remington药学科学”。第20版,Lippincott,Williams & Wilkins出版,2000和“药物赋形剂手册”,第2版,1994。
制剂可以适宜地呈递在单元剂型中,可以借助药学领域熟知的任意方法制备。这类方法包括使活性化合物与构成一种或多种附属成分的载体相结合的步骤。一般而言,制剂这样制备:均匀和紧密地使活性化合物与液体载体或微细粉碎的固体载体或者两种载体相结合,然后如果必要的话使产物成形。
制剂可以是液体、溶液、悬液、乳剂、酏剂、糖浆剂、片剂、锭剂、颗粒剂、粉剂、胶囊剂、扁囊剂、丸剂、安瓿剂、栓剂、阴道栓、软膏剂、凝胶剂、糊剂、霜剂、喷雾剂、烟雾剂、泡沫剂、洗剂、油剂、大丸剂、干药糖剂或气雾剂的形式。
适合于口服给药(例如摄入)的制剂可以呈递为离散的单元,例如胶囊剂、扁囊剂或片剂,每一单元含有预定量的活性化合物;粉剂或颗粒剂;在水性或非水性液体中的溶液或悬液;水包油型液体乳剂或油包水型液体乳剂;大丸剂;干药糖剂;或者糊剂。
片剂可以借助常规手段制备,例如压制或模制,可选地还有一种或多种附属成分。压制片可以这样制备:在适合的机械中压制活性化合物的自由流动形式,例如粉末或颗粒,可选地混合有一种或多种粘合剂(例如聚维酮、明胶、阿拉伯胶、山梨糖醇、黄蓍胶、羟丙基甲基纤维素)、填充剂或稀释剂(例如乳糖、微晶纤维素、磷酸氢钙)、润滑剂(例如硬脂酸镁、滑石、二氧化硅)、崩解剂(例如羟乙酸淀粉钠、交联聚维酮、交联羧甲基纤维素钠)、表面活性剂或分散剂或湿润剂(例如月桂基硫酸钠)和防腐剂(例如对-羟基苯甲酸甲酯、对-羟基苯甲酸丙酯、山梨酸)。模制片可以这样制备:在适合的机械中模制用惰性液体稀释剂湿润了的粉状化合物的混合物。片剂可以可选地被包衣或刻划,并且经过配制可以提供其中的活性化合物的缓释或控释,例如使用不同比例的羟丙基甲基纤维素,以提供所需的释放特性。片剂可以可选地带有肠溶衣,以提供在肠道部分而非胃中的释放。
适合于局部给药(例如透皮、鼻内、眼、口腔和舌下)的制剂可以被配制成软膏剂、霜剂、悬液、洗剂、粉剂、溶液、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。作为替代选择,制剂可以包含药贴或敷料,例如浸渍有活性化合物和可选的一种或多种赋形剂或稀释剂的绷带或粘附性硬膏剂。
适合于口内局部给药的制剂包括锭剂(lozenge),其在经过矫味的基质中包含活性化合物,通常为蔗糖和阿拉伯胶或黄蓍胶;锭剂(pastille),在惰性基质例如明胶和甘油或者蔗糖和阿拉伯胶中包含活性化合物;和漱口剂,在适合的液体载体中包含活性化合物。
适合于对眼睛局部给药的制剂也包括滴眼剂,其中活性化合物溶解或悬浮在适合的载体中,尤其是用于活性化合物的水性溶剂。
其中载体是固体的适合于鼻给药的制剂包括粗粉,粒径例如在约20至约500微米的范围内,采取鼻吸的方式给药,也就是说通过鼻腔从紧邻鼻放置的粉剂容器中迅速吸入。其中载体是液体的、用于以例如鼻喷雾剂、滴鼻剂或通过雾化器以气雾剂给药的适合制剂包括活性化合物的水溶液或油溶液。
适合于吸入给药的制剂包括从加压包装中以气雾剂呈递的那些,采用适合的抛射剂,例如二氯二氟甲烷、三氯氟代甲烷、二氯四氟乙烷、二氧化碳或其他适合的气体。
适合于经由皮肤局部给药的制剂包括软膏剂、霜剂和乳剂。当配制在软膏剂中时,活性化合物可以可选地与石蜡类或水混溶性软膏基质一起使用。作为替代选择,可以利用水包油型霜剂基质将活性化合物配制在霜剂中。如果需要的话,霜剂基质的水相可以包括例如至少约30%w/w多元醇,即具有两个或多个羟基的醇,例如丙二醇、丁烷-1,3-二醇、甘露糖醇、山梨糖醇、甘油和聚乙二醇及其混合物。局部制剂可合乎需要地包括增强活性化合物穿过皮肤或其他病患区域的吸收或渗透的化合物。这类皮肤渗透增强剂的实例包括二甲基亚砜和有关的类似物。
当配制成局部乳剂时,油相可以可选地仅包含乳化剂,或者它可以包含至少一种乳化剂与脂肪或油或者脂肪和油的混合物。优选地,包括亲水性乳化剂以及充当稳定剂的亲脂性乳化剂。还优选同时包括油和脂肪。总体而言,乳化剂以及或者没有稳定剂一起构成所谓的乳化性蜡,该蜡与油和/或脂肪一起构成所谓的乳化性软膏基质,后者构成霜剂的油性分散相。
适合的乳化剂和乳剂稳定剂包括吐温60、司盘80、鲸蜡硬脂醇、肉豆蔻醇、甘油单硬脂酸酯和月桂基硫酸钠。适合于制剂的油或脂肪的选择基于实现所需的美容性质,因为活性化合物在大多数可能用在药物乳剂的油中的溶解度可能非常低。因而,霜剂应当优选是非油腻、非掉色和可洗涤的产品,具有适合的粘稠度,以避免从管或其他容器中漏出。可以使用直链或支链一元或二元烃基酯,例如异己二酸二酯、硬脂酸异鲸蜡基酯、椰子脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、棕榈酸2-乙基己基酯或已知称为Crodamol CAP的支链酯的掺合物,后三者是优选的酯。它们可以单独或联合使用,这依赖于所需的性质。作为替代选择,可以使用高熔点脂质,例如白软石蜡和/或液体石蜡或其他矿物油。
适合于直肠给药的制剂可以呈递为栓剂,含有适合的基质,例如包含可可脂或水杨酸酯。
适合于阴道给药的制剂可以呈递为阴道栓、棉塞、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂,除了活性化合物以外还含有本领域已知的适当的载体。
适合于肠胃外给药(例如注射,包括皮肤、皮下、肌内、静脉内和皮内)的制剂包括水性与非水性的等渗、无热原、无菌注射溶液,它可以含有抗氧化剂、缓冲剂、防腐剂、稳定剂、制菌剂和赋予制剂与受药者血液等渗的溶质;水性与非水性无菌悬液,它可以包括悬浮剂和增稠剂;和脂质体或其他微粒系统,它们被设计成使化合物靶向于血液组分或者一种或多种器官。适合用在这类制剂中的等渗载体的实例包括氯化钠注射液、林格氏溶液或乳酸化林格氏注射液。通常,活性化合物在溶液中的浓度是约1ng/ml至约10μg/ml,例如约10ng/ml至约1μg/ml。制剂可存放于单剂或多剂密封容器中,例如安瓿和小瓶,并且可以贮存在冷冻干燥(冻干)条件下,仅需在使用前不久加入无菌液体载体例如注射用水即可。从无菌粉剂、颗粒剂和片剂可以制备临时注射溶液和悬液。制剂可以是脂质体或其他微粒系统的形式,它们被设计成使活性化合物靶向于血液组分或者一种或多种器官。
剂量
可以理解的是,活性化合物和包含活性化合物的组合物的适当剂量可以因患者而异。确定最佳剂量一般将牵涉本发明治疗的治疗益处水平与任何风险或有害副作用之间的平衡。所选择的剂量水平将依赖于多种因素,包括但不限于特定化合物的活性、给药途径、给药时间、化合物的排泄速率、治疗的持续时间、联合使用的其他药物、化合物和/或材料,以及患者的年龄、性别、体重、条件、一般健康状况与既往病史。化合物的量和给药途径最终将取决于医师,不过一般而言,剂量所实现的在作用部位的局部浓度将实现所需效果,而不导致实质性伤害或有害副作用。
体内给药可以在一剂中实现,连续地或间歇地(例如按适当间隔以分开的剂量)遍及治疗过程。确定最有效的给药手段和剂量的方法是本领域技术人员所熟知的,将因疗法所用制剂、治疗目的、所治疗的靶细胞和所治疗的对象而异。单次或多次给药可以以主治医师选择剂量水平和方式进行。
一般而言,活性化合物的适合剂量在约100μg至约250mg每千克对象体重每天的范围内。若活性化合物是一种盐、酯、前体药物等,则基于母体化合物计算给药量,因此所用的实际重量会成比例地增加。
合成数据
一般实验方法
制备型HPLC
样品用Waters质量-定向式纯化系统纯化,采用Waters 600LC泵、Waters Xterra C18柱(5μm,19mm×50mm)和Micromass ZQ质谱计,按阳离子电喷雾电离模式操作。流动相A(含0.1%甲酸的水)和B(含0.1%甲酸的乙腈)按梯度使用:5%B至100%历经7分钟,保持3分钟,流速20ml/min。
分析型HPLC-MS
分析型HPLC用Spectra System P4000泵和Jones Genesis C18柱(4μm,50mm×4.6mm)进行。流动相A(含0.1%甲酸的水)和B(乙腈)按梯度使用:5%B达1分钟,5分钟后升至98%B,保持3分钟,流速2ml/min。用TSP UV 6000LP检测器在254nm下检测,PDA范围210-600mm。质谱计是Finnigan LCQ,按阳离子电喷雾模式操作。
NMR
1H NMR和13C NMR利用Bruker DPX 300光谱计分别在300MHz和75MHz下记录。化学位移按百万分之份数(ppm)、相对于内标四甲基硅烷的δ报告。除非另有规定,全部样品均溶解于DMSO-d6中。
关键中间体的合成
a.3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A)
将27%甲醇钠的甲醇溶液(400g,2mol)与甲醇(150ml)的混合物在环境温度与30℃之间历经15分钟滴加到搅拌着的2-苯并[c]呋喃-2-酮(67g,0.5mol)、3-甲酰基苄腈(65.5g,0.5mol)与丙酸乙酯(250ml)的混合物中,将混合物在环境温度下搅拌40分钟,在回流温度下搅拌1小时,然后冷却至环境温度。过滤收集所得红色固体,用乙酸乙酯洗涤(2×50ml),溶于水(1800ml)。向该溶液加入乙酸(60ml)酸化,过滤收集所得红色固体,用水洗涤(2×200ml),在真空中干燥,得到3-(1,3-二氧代二氢化茚-2-基)苄腈(83.2g),为暗红色固体,m.pt.179-182℃,m/z(M+H)+248,无需进一步纯化即可使用。
将3-(1,3-二氧代二氢化茚-2-基)苄腈(74.18g,0.3mol)分批加入到氢氧化钠(36g,0.9mol)的水(580ml)溶液中,将所得暗红色悬液在回流温度下搅拌5小时,然后冷却至环境温度,用乙酸乙酯洗涤(3×300ml)。向水溶液滴加浓盐酸(110ml)酸化,将混合物在环境温度下搅拌1小时,然后过滤收集所得固体,用水洗涤(2×200ml),在真空中干燥,得到3-(1,3-二氧代二氢化茚-2-基)苯甲酸(M+H)+267与2-[2-(3-羧基苯基)乙酰基]苯甲酸(M+H)+285的1∶1混合物(69.32g),无需进一步纯化即可使用。
将前步所得混合物(52.8g)加入到三乙胺(37.55g,0.372mol)的工业用甲醇化酒精(500ml)溶液,将所得浑浊溶液通过过滤助剂垫过滤,得到澄清溶液。在环境温度下一次性加入一水合肼(9.3g,0.186mol),将搅拌着的混合物在回流下加热1小时,然后在真空中浓缩至大约250ml,加入到乙酸钠(41g,0.5mol)的水(500ml)溶液中。向混合物滴加浓盐酸至pH7,然后在环境温度下搅拌3小时。过滤收集所得固体,用水(50ml)洗涤,在真空中干燥,得到白色固体(15.62g)。合并滤液和洗液,加入盐酸酸化至pH6,然后将混合物在环境温度下搅拌3小时。过滤收集所得固体,用水(50ml)洗涤,在真空中干燥,得到第二批灰白色固体(17.57g)。合并来自第二批的滤液和洗液,重新调节至pH6,如上处理,得到第三批淡橙色固体(6.66g)。合并三批,得到基本上纯的3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A),(M+H)+281,δH4.4(2H,s),7.2-7.4(1H,m),7.5-7.6(1H,m),7.7-8.0(5H,m),8.1-8.2(1H,m),12.6(1H,s)。
b.2-氟-5-(4-氧代-3,4-二氢-酞嗪-1-基甲基)苯甲酸(B)
在0℃下,将亚磷酸二甲酯(22.0g,0.2mol)滴加到甲醇钠(43.0g)的甲醇(100ml)溶液中。然后向反应混合物分批加入2-羧基苯甲醛(21.0g,0.1mol)的甲醇(40ml)浆液,同时温度保持低于5℃。使所得淡黄色溶液历经1小时升温至20℃。向反应滴加甲磺酸(21.2g,0.22mol),在真空中蒸发所得白色悬液。将白色残余物用水猝灭,萃取到氯仿中(3×100ml)。合并有机萃取液,用水洗涤(2×100ml),经MgSO4干燥,在真空中蒸发,得到(3-氧代-1,3-二氢-异苯并呋喃-1-基)膦酸二甲基酯,为白色固体(32.0g,95%,95%纯度)。然后无需进一步纯化即可用于下一阶段。
向(3-氧代-1,3-二氢-异苯并呋喃-1-基)膦酸二甲基酯(35.0g,0.14mol)的四氢呋喃(200ml)溶液与2-氟-5-甲酰基苄腈(20.9g,0.14mol)的四氢呋喃(130ml)溶液的混合物历经25分钟滴加三乙胺(14ml,0.14mol),同时温度保持低于15℃。使反应混合物历经1小时缓慢升温至20℃,在真空中浓缩。将白色残余物悬浮在水(250ml)中达30分钟,过滤,用水、己烷和乙醚洗涤,干燥,得到2-氟-5-(3-氧代-3H-异苯并呋喃-1-亚基甲基)苄腈,为E与Z异构体的50∶50混合物(37.2g,96%),m/z[M+1]+266(98%纯度)。
向2-氟-5-(3-氧代-3H-异苯并呋喃-1-亚基甲基)苄腈的水悬液(200ml)加入氢氧化钠(26.1g)的水(50ml)溶液,将反应混合物在氮下加热至90℃达30分钟。将反应混合物部分冷却至70℃,加入水合肼(100ml),在70℃下搅拌18小时。将反应冷却至室温,用2M HCl酸化至pH4。将混合物搅拌10分钟,过滤。将所得固体用水、己烷、乙醚、乙酸乙酯洗涤,干燥,得到2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸,为淡粉红色粉末(30.0g,77%)。m/z[M+1]+299(96%纯度),δH4.4(2H,s),7.2-7.3(1H,m),7.5-7.6(1H,m),7.8-8.0(4H,m),8.2-8.3(1H,m),12.6(1H,s)。
c.1-[3-(4-氧代-3,4-二氢-酞嗪-1-基甲基)苯甲酰基]哌啶-4-甲酸(C)
将3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A)(7.0g,0.25mol)、4-哌啶甲酸乙酯(5ml,0.32mol)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HBTU)(12.3g,0.32mol)和N,N-二异丙基乙胺(10.0ml,0.55mol)加入到二甲基乙酰胺(40ml)中,搅拌18小时。向反应混合物加入水(100ml),产物萃取到二氯甲烷中(4×50ml)。合并有机层,用水洗涤(3×100ml),经MgSO4干燥,过滤,在真空中蒸发,得到油。向该油的四氢呋喃(100ml)溶液加入10%氢氧化钠水溶液(20ml),将反应搅拌18小时。浓缩反应,用乙酸乙酯洗涤(2×30ml),用2M HCl酸化至pH2。将水层用二氯甲烷萃取(2×100ml),萃取液然后经MgSO4干燥,过滤,蒸发,得到1-[3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酰基]哌啶-4-甲酸(C),为黄色固体(7.0g,65%),m/z[M+1]+392(96%纯度),δH1.3-1.8(5H,m),2.8-3.1(4H,m),4.4(2H,s),7.2-7.3(1H,m),7.3-7.4(1H,m),7.7-8.0(5H,m),8.2-8.3(1H,m),12.6(1H,s)。
d.1-[2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酰基]哌啶-4-甲酸(D)
将2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(B)(3.1g,0.14mol)、4-哌啶甲酸乙酯(1.7ml,0.11mol)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HBTU)(5.1g,0.13mol)和N,N-二异丙基乙胺(10.0ml,0.55mol)加入到二甲基乙酰胺(15ml)中,搅拌18小时。向反应混合物加入水(100ml),产物萃取到二氯甲烷中(4×50ml)。合并有机层,过滤,用水洗涤(3×100ml),经MgSO4干燥,过滤,在真空中蒸发,得到橙色的油。该油经过快速色谱纯化(乙酸乙酯),得到1-[2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酰基]哌啶-4-甲酸,为甲基酯(1.5g,33%,96%纯度)。向甲基酯的四氢呋喃∶水(2∶1,40ml)溶液加入氢氧化钠(0.3g,0.075mol),将反应搅拌18小时。浓缩反应,用乙酸乙酯洗涤(2×20ml),用2M HCl酸化至pH2。将水层用二氯甲烷萃取(2×20ml),合并萃取液,经MgSO4干燥,蒸发,得到1-[3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酰基]哌啶-4-甲酸(D),为黄色固体(0.6g,65%),m/z[M+1]+392(96%纯度)。
实施例1-关键化合物的合成
a.4-[3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(1)的合成
将3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A)(5.0g,0.17mol)、1-哌嗪甲酸叔丁酯(3.9g,0.21mol)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HBTU)(8.6g,0.22mol)和N,N-二异丙基乙胺(6.7ml,0.38mol)加入到二甲基乙酰胺(40ml)中,搅拌18小时。加入水(100ml),将反应混合物加热至100℃达1小时。将悬液冷却至室温,过滤,干燥,得到白色固体。将固体溶于6M HCl与乙醇的溶液(2∶1,50ml),搅拌1小时。浓缩反应,用氨碱化至pH9,产物萃取到二氯甲烷中(2×50ml)。合并有机层,用水洗涤(2×50ml),经MgSO4干燥,在真空中蒸发,得到4-[3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(1),为黄色结晶性固体(4.0g,77%);m/z[M+1]+349(97%纯度),δH2.6-3.8(8H,m),4.4(2H,s),7.2-7.5(4H,m),7.7-8.0(3H,m),8.2-8.3(1H,m),12.6(1H,s)。
b.4-[4-氟-3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(2)的合成
使用2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(B),按照上文(a)所述方法进行合成,得到4-[4-氟-3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(2),为白色结晶性固体(4.8g,76%);m/z[M+1]+367(97%纯度),δH2.6-3.8(8H,m),4.4(2H,s),7.2-7.5(3H,m),7.7-8.0(3H,m),8.2-8.3(1H,m),12.6(1H,s)。
c.4-[3-([1,4]二氮杂环庚烷-1-羰基)苄基]-2H-酞嗪-1-酮(3)的合成
使用3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A)和1-高哌嗪(homopiperazine)甲酸叔丁酯,按照上文(a)所述方法进行合成,得到4-[3-([1,4]二氮杂环庚烷-1-羰基)苄基]-2H-酞嗪-1-酮(3),为灰色结晶性固体(5.3g,97%);m/z[M+1]+363(97%纯度);δH2.6-3.8(10H,m),4.4(2H,s),7.2-7.5(4H,m),7.7-8.0(3H,m),8.2-8.3(1H,m),12.6(1H,s)。
d.4-[3-([1,4]二氮杂环庚烷-1-羰基)-4-氟苄基]-2H-酞嗪-1-酮(4)的合成
使用2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(B)和1-高哌嗪甲酸叔丁酯,按照上文(a)所述方法进行合成,得到4-[3-([1,4]二氮杂环庚烷-1-羰基)苄基]-2H-酞嗪-1-酮(4),为黄色结晶性固体(5.3g,68%);m/z[M+1]+381(97%纯度);δH2.6-3.8(10H,m),4.4(2H,s),7.2-7.5(3H,m),7.7-8.0(3H,m),8.2-8.3(1H,m),12.6(1H,s)。
实施例2
a.4-{3-[4-(6-氯苯并噻唑-2-基)-1,4-二氮杂环庚烷-1-基羰基]苄基}-1(2H)-酞嗪酮
在环境温度下,将2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(150mg,0.47mmol)、二异丙基乙胺(102mg,0.8mmol)和6-氯-2-(1,4-二氮杂环庚烷-1-基)-1,3-苯并噻唑(115mg,0.43mmol)先后加入到搅拌着的3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A)(100mg,0.36mmol)的无水二甲基乙酰胺(1ml)溶液中,将混合物在环境温度下搅拌1小时,在环境温度下放置16小时,然后滴加到搅拌着的冷水(10ml)中。30分钟后,过滤收集所得固体,用水(2×1ml)和己烷(1ml)洗涤,在真空中干燥,利用制备型HPLC纯化,得到所需化合物(5)(166mg),为灰色固体;HPLC纯度90%;HPLC保留时间4.21分钟;m/z(M+H)+530。
b.按照类似于上文(a)所述的方式合成下列化合物,但是使用适当的替代胺原料。
注1:13不需要经由制备级HPLC纯化-反应产物是基本上纯的。
实施例3
a.4-{3-[4-(4-氟苯基)哌嗪-1-基羰基]苄基}-1(2H)-酞嗪酮(22)
在环境温度下,将2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(150mg,0.47mmol)、二异丙基乙胺(102mg,0.8mmol)和1-(4-氟苯基)哌嗪(65mg,0.47mmol)先后加入到搅拌着的3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A)(100mg,0.36mmol)的无水二甲基乙酰胺(1ml)溶液中,将混合物在环境温度下搅拌4小时,在环境温度下放置16小时,然后滴加到搅拌着的冷水(10ml)中。30分钟后,过滤收集所得固体,用水(2×1ml)和己烷(1ml)洗涤,在真空中干燥,利用制备型HPLC纯化,得到4-{3-[4-(4-氟苯基)哌嗪-1-基羰基]苄基}-1(2H)-酞嗪酮(22)(76mg),为膏状固体;m/z(M+H)+443;HPLC纯度90%;HPLC保留时间4.00分钟。
b.按照类似于上文(a)所述的方式合成下列化合物,但是使用适当的替代胺原料。
注2:36不需要经由制备级HPLC纯化-反应产物是基本上纯的。
实施例4
将1-[3-(4-氧代-3,4-二氢-酞嗪-1-基甲基)-苯甲酰基]-哌啶-4-甲酸(C)(0.24mmol)加入到适当的胺(0.2mmol)的二甲基乙酰胺(2ml)溶液中。然后加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(0.3mmol)和Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例5
将1-[2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酰基]-哌啶-4-甲酸(D)(0.24mmol)加入到适当的胺(0.2mmol)的二甲基乙酰胺(2ml)溶液中。然后加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(0.3mmol)和Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例6
将适当的磺酰氯(0.24mmol)加入到4-[3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(1)(0.2mmol)的二氯甲烷(2ml)溶液中。然后加入Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例7
将适当的磺酰氯(0.24mmol)加入到4-[3-([1,4]二氮杂环庚烷-1-羰基)苄基]-2H-酞嗪-1-酮(3)(0.2mmol)的二氯甲烷(2ml)溶液中。然后加入Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例8
将适当的酰氯(0.24mmol)加入到4-[3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(1)(0.2mmol)的二氯甲烷(2ml)溶液中。然后加入Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。所合成的化合物列在下面。
实施例9
将适当的酰氯(0.24mmol)加入到4-[4-氟-3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(2)(0.2mmol)的二氯甲烷(2ml)溶液中。然后加入Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例10
将适当的酰氯(0.24mmol)加入到4-[3-([1,4]二氮杂环庚烷-1-羰基)苄基]-2H-酞嗪-1-酮(3)(0.2mmol)的二氯甲烷(2ml)溶液中。然后加入Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例11
将适当的酰氯(0.24mmol)加入到4-[3-([1,4]二氮杂环庚烷-1-羰基)-4-氟苄基]-2H-酞嗪-1-酮(4)(0.2mmol)的二氯甲烷(2ml)溶液中。然后加入Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例12
将适当的异氰酸酯(0.24mmol)加入到4-[3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(1)(0.2mmol)的二氯甲烷(2ml)溶液中。将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例13
将适当的异硫氰酸酯(0.24mmol)加入到4-[3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(1)(0.2mmol)的二氯甲烷(2ml)溶液中。将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例14
将3-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(A)(0.24mmol)加入到适当的胺(0.2mmol)的二甲基乙酰胺(2ml)溶液中。然后加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(0.3mmol)和Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
化合物 | R | LC RT (分钟) | M+1 | LC纯度 (%) |
231 | *-CH<sub>3</sub> | 2.72 | 378 | 90 |
实施例15
将2-氟-5-(4-氧代-3,4-二氢酞嗪-1-基甲基)苯甲酸(B)(0.24mmol)加入到适当的胺(0.2mmol)的二甲基乙酰胺(2ml)溶液中。然后加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(0.3mmol)和Hunigs碱(0.4mmol),将反应在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例16
将适当的醛(0.2mmol)和4-[3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(1)(0.24mmol)溶于二氯甲烷(2ml)。然后加入三乙酰氧基硼氢化钠(0.28mmol)和冰乙酸(6.0mmol),在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例17
将适当的醛(0.2mmol)和4-[4-氟-3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮(2)(0.24mmol)溶于二氯甲烷(2ml)。然后加入三乙酰氧基硼氢化钠(0.28mmol)和冰乙酸(6.0mmol),在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例18
将适当的醛(0.2mmol)和4-[3-([1,4]二氮杂环庚烷-1-羰基)苄基]-2H-酞嗪-1-酮(3)(0.24mmol)溶于二氯甲烷(2ml)。然后加入三乙酰氧基硼氢化钠(0.28mmol)和冰乙酸(6.0mmol),在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例19
将适当的醛(0.2mmol)和4-[3-([1,4]二氮杂环庚烷-1-羰基)-4-氟苄基]-2H-酞嗪-1-酮(4)(0.24mmol)溶于二氯甲烷(2ml)。然后加入三乙酰氧基硼氢化钠(0.28mmol)和冰乙酸(6.0mmol),在室温下搅拌16小时。反应混合物然后经过制备型HPLC纯化。
所合成的化合物列在下面。
实施例20
为了评估化合物的抑制作用,利用下列测定法测定IC50值。
将从Hela细胞核提取物中分离的哺乳动物PARP用Z-缓冲液(25mMHepes(Sigma);12.5mM MgCl2(Sigma);50mM KCl(Sigma);1mM DTT(Sigma);10%甘油(Sigma);0.001%NP-40(Sigma);pH7.4)在96孔FlashPlates(商标)(NEN,UK)中孵育,加入不同浓度的所述抑制剂。全部化合物均稀释在DMSO中,最终测定浓度在10与0.01μM之间,DMSO的最终浓度为1%每孔。每孔的总测定体积为40μl。
在30℃下培育10分钟后,加入10μl反应混合物引发反应,反应混合物中含有NAD(5μM)、3H-NAD和30mer双链DNA-寡聚物。指定阳性和阴性反应孔与化合物孔(未知)一起处理,以计算酶活性%。然后将平板摇动2分钟,在30℃下孵育45分钟。
在孵育之后,向每孔加入50μl 30%乙酸猝灭反应。然后将平板在室温下摇动1小时。
将平板转移至TopCount NXT(商标)(Packard,UK)供闪烁计数。所记录的数值是每孔计数30秒后得到的每分钟的计数(cpm)。
然后利用下列方程计算每种化合物的酶活性%:
计算IC50值(抑制50%酶活性的浓度),其是在不同浓度范围内测定的,通常从10μM至0.001μM。这类IC50值用作对比值,以鉴别增加的化合物效力。
全部所测试的化合物都具有小于0.1μM的IC50。
下列化合物具有小于0.01μM的IC50:2,3,4,59,10,13,14,15,16,17,18,19,20,21,25,27,28,29,31,33,34,35,37,40,41,44,46,47,48,49,51,53,73,74,75,76,77,78,79,80,83,84,85,97,98,99,101,103,105,106,107,111,112,113,114,117,118,119,120,121,122,130,131,132,133,138,139,140,143,149,153,155,156,157,159,160,161,175,176,177,178,179,181,182,186,188,190,191,195,197,198,200,201,202,203,205,206,207,208,209,210,211,212,213,214,216,217,218,219,221,222,223,225,226,227,228,229,232,237,240,243,245,246,256。
下列化合物以及上述那些具有小于0.02μM的IC50:1,6,7,8,11,12,22,23,24,26,32,36,38,39,42,43,45,50,54,55,56,58,59,81,82,86,87,88,89,90,91,92,93,94,95,96,100,104,108,109,110,115,116,123,126,127,128,134,135,137,141,145,146,147,150,151,152,154,158,162,163,174,180,185,187,189,192,193,194,196,199,204,215,220,224,230,233,234,235,239,241,242,244,250,251,258,259和261。
计算化合物的强化系数(PF50),为对照细胞生长的IC50除以+PARP抑制剂的细胞生长的IC50之比。对照和化合物处理细胞的生长抑制曲线是在烷基化剂甲磺酸甲酯(MMS)的存在下生成。使用0.2微摩尔固定浓度的供试化合物。MMS的浓度跨越从0至10μg/ml的范围。
利用磺基罗丹明B(SRB)测定法评估细胞生长(Skehan,P.等,(1990),“用于抗癌药物筛选的新的比色细胞毒性测定法”,J.Natl.Cancer Inst.82,1107-1112.)。将2,000个HeLa细胞接种到平底96孔微量滴定平板的每孔中,体积为100μl,在37℃下孵育6小时。将细胞用单独的培养基或者含有最终浓度为0.5、1或5μM的PARP抑制剂的培养基培养。使细胞另外生长1小时,然后向未处理细胞或PARP抑制剂处理细胞加入一定浓度范围的MMS(通常为0、1、2、3、5、7和10μg/ml)。使用用单独PARP抑制剂处理过的细胞来评估PARP抑制剂的生长抑制作用。
将细胞静置另外16小时,然后更换培养基,使细胞在37℃下生长另外72小时。然后除去培养基,用100μl冰冷的10%(w/v)三氯乙酸固定细胞。将平板在4℃下孵育20分钟,然后用水洗涤四次。然后将每孔细胞用100μl 0.4%(w/v)的SRB 1%乙酸溶液染色20分钟,然后用1%乙酸洗涤四次。然后将平板在室温下干燥2小时。向每孔加入100μl 10mM Tris碱,使来自染色细胞的染剂增溶。轻轻摇动平板,在室温下静置30分钟,然后在Microquant微量滴定平板读数器上测量564nm下的光密度。
全部所测试的化合物在200nM下均具有至少2.0的PF50。
实施例21
材料和方法
PARP的小分子抑制剂
将化合物(4)溶于DMSO,浓度10mM,贮存在-20℃暗处。
细胞系
VC8细胞和小鼠Brca2 BAC-补充的衍生物如M.Kraakman-van derZwet等,Mol Cell Biol 22,669-79(2002)所述。Brca2功能缺陷的ES细胞以前已有描述(Tutt等,EMBO Rep 3,255-60(2002))。Brca1缺陷的ES细胞的构建将另有描述但以前已有验证(Foray等,Embo J,22,2860-71(2003))。
克隆发生测定法
就细胞对PARP抑制剂(化合物4)的敏感性测量而言,将呈指数生长的细胞培养物用胰蛋白酶处理,按不同密度接种在6孔平板中的丝裂霉素C灭活的小鼠胚胎成纤维细胞上,18小时后酌情用供试化合物处理。就连续暴露而言,每4天向细胞重新供应新鲜的培养基和抑制剂。10-14天后,将细胞用PBS洗涤,固定在甲醇中,用结晶紫染色。计数含有大于约50个细胞的集落。实验至少进行三次,一式三份。
结果
BRCA1和BRCA2缺陷细胞的活力减低
使用化合物4探查Brca1或Brca2缺陷的细胞对PARP活性抑制的敏感性。克隆发生测定法显示:Brca1和Brca2缺陷的细胞系相比较其他等基因细胞而言对化合物4都是极其敏感的(图1A、1B)。化合物4的SF50(50%细胞存活的剂量)就Brca1缺陷的细胞而言为1.5×10-8M,就匹配的野生型细胞而言为7×10-6M(图1A)。这代表了Brca1突变细胞的敏感性增强,为野生型细胞的467倍。
化合物4的SF50就Brca2缺陷的细胞而言为1.2×10-8M,就匹配的野生型细胞而言为1.8×10-5M(图1B)。这代表了Brca2突变细胞的敏感性增强,为野生型细胞的1,500倍。
与Brca2-补充的衍生物(VC8-BAC)相比,用Brca2缺陷的中国仓鼠卵巢细胞(VC8)获得相似的结果(图2)。化合物4的SF50就Brca2缺陷的VC8细胞系而言为5×10-8M,就匹配的对照VC8-BAC而言为3×10-5M(图2)。这代表了Brca2突变细胞的敏感性增强,为野生型细胞的600倍。
Claims (28)
1.式(I)化合物或其盐:
其中:
A和B一起代表稠合苯环,其任选被选自卤素、硝基、羟基、醚、巯基、硫醚、氨基、C1-7烃基、C3-20杂环基和C5-20芳基的取代基取代;
X是NRX或CRXRY;
如果X=NRX,则n是1或2,如果X=CRXRY,则n是1;
RX选自H和C1-20烃基、C5-20芳基、C3-20杂环基、酰氨基、硫代酰氨基、酯、酰基和磺酰基,其中C1-20烃基、C5-20芳基、C3-20杂环基任选被取代,所述任选的取代基选自C1-20烃基、C5-20芳基、C3-20杂环基、卤素、羟基、醚、硝基、氰基、酰基、羧基、酯、酰氨基、酰基酰氨基、脲基、酰氧基、巯基、硫醚、亚砜、磺酰基、硫代酰氨基和磺酰氨基;
RY选自H、羟基、氨基;
或者RX和RY一起构成螺-C3-7环烃基或C3-20杂环基;
RC1和RC2都是氢,或者当X是CRXRY时,RC1、RC2、RX和RY与它们所连接的碳原子一起构成任选被取代的稠合芳族环,其中所述任选的取代基选自C1-7烃基、C5-20芳基、C3-20杂环基、羟基、醚、巯基、硫醚、氨基和-O-(CH2)p-O-,p=1、2或3;且
R1选自H和卤素;
其中所述醚为-OR,R是醚取代基,所述取代基为C1-7烃基,C3-20杂环基或C5-20芳基;
其中所述硫醚为-SR,R是硫醚取代基,所述取代基为C1-7烃基、C3-20杂环基或C5-20芳基;
其中酰氨基为-C(=O)NR1R2,R1和R2独立地是氨基取代基,为氢、C1-7烃基、C3-20杂环基或C5-20芳基,或者R1和R2与它们所附着的氮原子一起构成杂环结构;
其中酰基为-C(=O)R,R是酰基取代基,所述取代基为C1-7烃基、C3-20杂环基或C5-20芳基;
其中酯为-C(=O)OR,R是酯取代基,所述取代基为C1-7烃基、C3-20杂环基或C5-20芳基;
其中硫代酰氨基为-C(=S)NR1R2,R1和R2独立地是氨基取代基,所述取代基为氢、C1-7烃基、C3-20杂环基或C5-20芳基,或者在“环状”氨基的情况下,R1和R2与它们所附着的氮原子一起构成具有4-8个环原子的杂环。
2.根据权利要求1的化合物,其中R1选自H、Cl和F。
3.根据权利要求1的化合物,其中RC1和RC2都是氢。
4.根据权利要求2的化合物,其中RC1和RC2都是氢。
5.根据权利要求1至4任意一项的化合物,其中n是2,X是NRX,RX选自H、任选被取代的C1-20烃基、任选被取代的C5-20芳基、酯基、酰基、酰氨基、硫代酰氨基和磺酰基,其中所述任选的取代基选自C1-20烃基、C5-20芳基、C3-20杂环基、卤素、羟基、醚、硝基、氰基、酰基、羧基、酯、酰氨基、酰基酰氨基、脲基、酰氧基、巯基、硫醚、亚砜、磺酰基、硫代酰氨基和磺酰氨基。
6.根据权利要求1至4任意一项的化合物,其中n是1,X是NRX,RX选自H、任选被取代的C1-20烃基、任选被取代的C5-20芳基、酰基、磺酰基、酰氨基和硫代酰氨基,其中所述任选的取代基选自C1-20烃基、C5-20芳基、C3-20杂环基、卤素、羟基、醚、硝基、氰基、酰基、羧基、酯、酰氨基、酰基酰氨基、脲基、酰氧基、巯基、硫醚、亚砜、磺酰基、硫代酰氨基和磺酰氨基。
7.根据权利要求1至4任意一项的化合物,其中n是1,X是CRXRY,RY是H,RX选自H、任选被取代的C1-20烃基、任选被取代的C5-20芳基、任选被取代的C3-20杂环基、酰基、酰氨基和酯基,其中所述任选的取代基选自C1-20烃基、C5-20芳基、C3-20杂环基、卤素、羟基、醚、硝基、氰基、酰基、羧基、酯、酰氨基、酰基酰氨基、脲基、酰氧基、巯基、硫醚、亚砜、磺酰基、硫代酰氨基和磺酰氨基。
9.药物组合物,包含根据权利要求1至8任意一项的化合物和药学上可接受的载体或稀释剂。
10.根据权利要求1至8任意一项的化合物在制备用于抑制PARP活性的药物中的用途。
11.根据权利要求1至8任意一项的化合物在制备药物中的用途,该药物用于治疗因PARP活性抑制而改善的疾病。
12.根据权利要求11的用途,其中所制备的药物用于治疗因PARP活性抑制而改善的以下疾病:血管疾病;脓毒性休克;缺血损伤;神经毒性;出血性休克;病毒感染。
13.根据权利要求1至8任意一项的化合物在制备药物中的用途,该药物用作癌症疗法的辅助手段或者用于强化电离放射或化学治疗剂对肿瘤细胞的治疗。
14.根据权利要求1至8任意一项的化合物在制备药物中的用途,该药物用于治疗个体的癌症,其中所述癌症是HR依赖性DNA DSB修复途径缺陷的。
15.根据权利要求14的用途,其中所述癌症包含一种或多种通过HR修复DNA DSB的能力相对于正常细胞而言减低或取消的癌细胞。
16.根据权利要求15的用途,其中所述癌细胞具有BRCA1或BRCA2缺陷的表型。
17.根据权利要求16的用途,其中所述癌细胞是BRCA1或BRCA2缺陷的。
18.根据权利要求14至17任意一项的用途,其中所述个体就编码HR依赖性DNA DSB修复途径组分的基因的突变而言是杂合的。
19.根据权利要求18的用途,其中所述个体就BRCA1和/或BRCA2突变而言是杂合的。
20.根据权利要求14至17任意一项的用途,其中所述癌症是乳腺癌、卵巢癌、胰腺癌或前列腺癌。
21.根据权利要求18的用途,其中所述癌症是乳腺癌、卵巢癌、胰腺癌或前列腺癌。
22.根据权利要求19的用途,其中所述癌症是乳腺癌、卵巢癌、胰腺癌或前列腺癌。
23.根据权利要求14至17任意一项的用途,其中所述治疗进一步包括给予电离放射或化学治疗剂。
24.根据权利要求18的用途,其中所述治疗进一步包括给予电离放射或化学治疗剂。
25.根据权利要求19的用途,其中所述治疗进一步包括给予电离放射或化学治疗剂。
26.根据权利要求20的用途,其中所述治疗进一步包括给予电离放射或化学治疗剂。
27.根据权利要求21的用途,其中所述治疗进一步包括给予电离放射或化学治疗剂。
28.根据权利要求22的用途,其中所述治疗进一步包括给予电离放射或化学治疗剂。
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US11135218B2 (en) | 2011-07-22 | 2021-10-05 | Pacylex Pharmaceuticals Inc. | Synthetic lethality and the treatment of cancer |
US11788145B2 (en) | 2015-07-17 | 2023-10-17 | Pacylex Pharmaceuticals Inc. | Epigeneiic silencing of NMT2 |
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WO2002036576A1 (en) * | 2000-10-30 | 2002-05-10 | Kudos Pharmaceuticals Limited | Phthalazinone derivatives |
WO2002090334A1 (en) * | 2001-05-08 | 2002-11-14 | Kudos Pharmaceuticals Limited | Isoquinolinone derivatives as parp inhibitors |
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CN102485721A (zh) * | 2010-12-03 | 2012-06-06 | 苏州科瑞戈医药科技有限公司 | 取代的2,3-二氮杂萘酮化合物及其用途 |
WO2012072033A1 (zh) * | 2010-12-03 | 2012-06-07 | 苏州科瑞戈医药科技有限公司 | 取代的2,3-二氮杂萘酮化合物及其用途 |
CN102485721B (zh) * | 2010-12-03 | 2015-12-09 | 曹亚 | 取代的2,3-二氮杂萘酮化合物及其用途 |
US11135218B2 (en) | 2011-07-22 | 2021-10-05 | Pacylex Pharmaceuticals Inc. | Synthetic lethality and the treatment of cancer |
US11788145B2 (en) | 2015-07-17 | 2023-10-17 | Pacylex Pharmaceuticals Inc. | Epigeneiic silencing of NMT2 |
Also Published As
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US20170226124A1 (en) | 2017-08-10 |
US8912187B2 (en) | 2014-12-16 |
US7981889B2 (en) | 2011-07-19 |
US20140378442A1 (en) | 2014-12-25 |
US20160000781A1 (en) | 2016-01-07 |
SI1633724T1 (sl) | 2011-09-30 |
LU92680I2 (fr) | 2015-11-02 |
US20200000802A1 (en) | 2020-01-02 |
GB0305681D0 (en) | 2003-04-16 |
CN1788000A (zh) | 2006-06-14 |
PT1633724E (pt) | 2011-07-13 |
ATE508118T1 (de) | 2011-05-15 |
US11160803B2 (en) | 2021-11-02 |
US20080200469A1 (en) | 2008-08-21 |
US10449192B2 (en) | 2019-10-22 |
US20120010204A1 (en) | 2012-01-12 |
US20180185363A1 (en) | 2018-07-05 |
ZA200507097B (en) | 2006-06-28 |
DK1633724T3 (da) | 2011-08-15 |
ES2364140T3 (es) | 2011-08-25 |
US9169235B2 (en) | 2015-10-27 |
TWI336694B (en) | 2011-02-01 |
US9566276B2 (en) | 2017-02-14 |
TW200505871A (en) | 2005-02-16 |
DE602004032537D1 (de) | 2011-06-16 |
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