CN1738788A - 作为***剂的取代的苯基萘 - Google Patents
作为***剂的取代的苯基萘 Download PDFInfo
- Publication number
- CN1738788A CN1738788A CNA028247361A CN02824736A CN1738788A CN 1738788 A CN1738788 A CN 1738788A CN A028247361 A CNA028247361 A CN A028247361A CN 02824736 A CN02824736 A CN 02824736A CN 1738788 A CN1738788 A CN 1738788A
- Authority
- CN
- China
- Prior art keywords
- naphthol
- hydroxyphenyl
- compound
- chloro
- mmol
- 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.)
- Pending
Links
- 239000000262 estrogen Substances 0.000 title description 31
- IYDMICQAKLQHLA-UHFFFAOYSA-N 1-phenylnaphthalene Chemical class C1=CC=CC=C1C1=CC=CC2=CC=CC=C12 IYDMICQAKLQHLA-UHFFFAOYSA-N 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims description 292
- 238000000034 method Methods 0.000 claims description 143
- 229910052799 carbon Inorganic materials 0.000 claims description 45
- -1 3 - (3 - fluoro-4 - hydroxyphenyl) -7 - hydroxy-1 - naphthyl Chemical group 0.000 claims description 41
- 241000124008 Mammalia Species 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 230000005764 inhibitory process Effects 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 206010003246 arthritis Diseases 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 230000006378 damage Effects 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000000324 neuroprotective effect Effects 0.000 claims description 5
- 229930192474 thiophene Natural products 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 150000002632 lipids Chemical class 0.000 claims description 4
- 208000008423 pleurisy Diseases 0.000 claims description 4
- IPBYYNRPJBGKET-UHFFFAOYSA-N 1-bromo-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(Br)=C(O)C=C2)C2=C1 IPBYYNRPJBGKET-UHFFFAOYSA-N 0.000 claims description 3
- NLFWTSXMRSTIKQ-UHFFFAOYSA-N 2-chloro-4-naphthalen-2-ylphenol Chemical compound C1=C(Cl)C(O)=CC=C1C1=CC=C(C=CC=C2)C2=C1 NLFWTSXMRSTIKQ-UHFFFAOYSA-N 0.000 claims description 3
- JZAALJHRGIVUQB-UHFFFAOYSA-N 2-fluoro-4-naphthalen-2-ylphenol Chemical compound C1=C(F)C(O)=CC=C1C1=CC=C(C=CC=C2)C2=C1 JZAALJHRGIVUQB-UHFFFAOYSA-N 0.000 claims description 3
- QZUOTBJDFQFRGT-UHFFFAOYSA-N 2-hydroxy-6-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(C#N)=C(O)C=C2)C2=C1 QZUOTBJDFQFRGT-UHFFFAOYSA-N 0.000 claims description 3
- VLJUOFGVEJAFFK-UHFFFAOYSA-N 6-(2,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC(F)=C(O)C=C1F VLJUOFGVEJAFFK-UHFFFAOYSA-N 0.000 claims description 3
- AUZLISXBMGKYGA-UHFFFAOYSA-N 6-(2,6-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=C(F)C=C(O)C=C1F AUZLISXBMGKYGA-UHFFFAOYSA-N 0.000 claims description 3
- FNSIACDWDZGUHN-UHFFFAOYSA-N 6-(2-chloro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound ClC1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 FNSIACDWDZGUHN-UHFFFAOYSA-N 0.000 claims description 3
- MAFQDFZNSVYFEW-UHFFFAOYSA-N 6-(2-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound FC1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 MAFQDFZNSVYFEW-UHFFFAOYSA-N 0.000 claims description 3
- DZGRIHNLLUZLTL-UHFFFAOYSA-N 6-(3,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC(F)=C(O)C(F)=C1 DZGRIHNLLUZLTL-UHFFFAOYSA-N 0.000 claims description 3
- MBESMLNJQCOTRU-UHFFFAOYSA-N 6-(4-hydroxyphenyl)naphthalen-1-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(O)=CC=C2)C2=C1 MBESMLNJQCOTRU-UHFFFAOYSA-N 0.000 claims description 3
- AOWCVRXIHIHAPN-UHFFFAOYSA-N 7-hydroxy-3-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC(C#N)=C(C=C(O)C=C2)C2=C1 AOWCVRXIHIHAPN-UHFFFAOYSA-N 0.000 claims description 3
- XSODNSMEBNRYBI-UHFFFAOYSA-N 8-bromo-7-hydroxy-3-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC(C#N)=C(C(Br)=C(O)C=C2)C2=C1 XSODNSMEBNRYBI-UHFFFAOYSA-N 0.000 claims description 3
- DGVWRZXKKCDNLS-UHFFFAOYSA-N 8-chloro-3-(3-fluoro-4-hydroxyphenyl)-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(F)C(O)=CC=C1C1=CC(C#N)=C(C(Cl)=C(O)C=C2)C2=C1 DGVWRZXKKCDNLS-UHFFFAOYSA-N 0.000 claims description 3
- ZOCBCFXUQAYMNS-UHFFFAOYSA-N 8-chloro-7-hydroxy-3-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC(C#N)=C(C(Cl)=C(O)C=C2)C2=C1 ZOCBCFXUQAYMNS-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 206010046851 Uveitis Diseases 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005466 alkylenyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 3
- LKNGKJDCKVVOLK-UHFFFAOYSA-N 1,5-dichloro-8-fluoro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1Cl LKNGKJDCKVVOLK-UHFFFAOYSA-N 0.000 claims description 2
- YTFVBUBYMJJWQZ-UHFFFAOYSA-N 1,8-dichloro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(Cl)=C(C(Cl)=C(O)C=C2)C2=C1 YTFVBUBYMJJWQZ-UHFFFAOYSA-N 0.000 claims description 2
- DZNMJDCCSRLHNP-UHFFFAOYSA-N 1-chloro-6-(2,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(O)=CC(F)=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 DZNMJDCCSRLHNP-UHFFFAOYSA-N 0.000 claims description 2
- LIGCNYLVJJWYIY-UHFFFAOYSA-N 1-chloro-6-(2,6-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound FC1=CC(O)=CC(F)=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 LIGCNYLVJJWYIY-UHFFFAOYSA-N 0.000 claims description 2
- LSVPDXDJCFTDSL-UHFFFAOYSA-N 1-chloro-6-(2-chloro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound ClC1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 LSVPDXDJCFTDSL-UHFFFAOYSA-N 0.000 claims description 2
- XIWROJLPONIAKV-UHFFFAOYSA-N 1-chloro-6-(2-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound FC1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 XIWROJLPONIAKV-UHFFFAOYSA-N 0.000 claims description 2
- AHELSLCUIPWEII-UHFFFAOYSA-N 1-chloro-6-(3,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=C(Cl)C(O)=CC=C2C=C1C1=CC(F)=C(O)C(F)=C1 AHELSLCUIPWEII-UHFFFAOYSA-N 0.000 claims description 2
- FWRUMAVROMTQMY-UHFFFAOYSA-N 1-chloro-6-(3-chloro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(Cl)C(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 FWRUMAVROMTQMY-UHFFFAOYSA-N 0.000 claims description 2
- HZPYQCSGTTZVLW-UHFFFAOYSA-N 1-chloro-6-(3-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 HZPYQCSGTTZVLW-UHFFFAOYSA-N 0.000 claims description 2
- GGWIHGXEDCXOIL-UHFFFAOYSA-N 1-chloro-6-(4-hydroxy-2-methylphenyl)naphthalen-2-ol Chemical compound CC1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 GGWIHGXEDCXOIL-UHFFFAOYSA-N 0.000 claims description 2
- YHEHVRSGKUYDON-UHFFFAOYSA-N 1-chloro-6-(4-hydroxyphenyl)-2-naphthol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 YHEHVRSGKUYDON-UHFFFAOYSA-N 0.000 claims description 2
- IPEUQNVORWKWRB-UHFFFAOYSA-N 1-chloro-6-phenylnaphthalen-2-ol Chemical compound C1=CC2=C(Cl)C(O)=CC=C2C=C1C1=CC=CC=C1 IPEUQNVORWKWRB-UHFFFAOYSA-N 0.000 claims description 2
- DXLDXLIYYQFLKD-UHFFFAOYSA-N 1-chloro-8-fluoro-6-(3-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(O)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1 DXLDXLIYYQFLKD-UHFFFAOYSA-N 0.000 claims description 2
- OYUGBGZDLCAQEA-UHFFFAOYSA-N 1-chloro-8-fluoro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1 OYUGBGZDLCAQEA-UHFFFAOYSA-N 0.000 claims description 2
- VQATUPWMFYRKSD-UHFFFAOYSA-N 1-fluoro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(F)=C(O)C=C2)C2=C1 VQATUPWMFYRKSD-UHFFFAOYSA-N 0.000 claims description 2
- NTESIIXLFNAOOM-UHFFFAOYSA-N 3-(3,5-difluoro-4-hydroxyphenyl)-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(C#N)C2=CC(O)=CC=C2C=C1C1=CC(F)=C(O)C(F)=C1 NTESIIXLFNAOOM-UHFFFAOYSA-N 0.000 claims description 2
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- MYVOVZDBAWARDP-UHFFFAOYSA-N 6-(4-hydroxyphenyl)-1-nitronaphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(=C(O)C=C2)[N+]([O-])=O)C2=C1 MYVOVZDBAWARDP-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明提供了一种式(I)***受体调节剂或其药学可接受的盐,具有结构(I),其中R1,R2,R3,R4,R5,R6,R7,R8,R9和R10如说明书所定义。
Description
发明背景
本发明涉及取代的苯基萘,其用作***剂。
已经有文献充分证明了***在哺乳动物组织中的多向性效应,现在认为***会影响许多器官***[Mendelsohn and Karas,NewEngland Journal of Medicine 340:1801-1811(1999),Epperson等人,Psychosomatic Medicine 61:676-697(1999),Crandall,Journal ofWomens Health & Gender Based Medicine 8:1155-1166(1999),Monkand Brodaty,Dementia & Geriatric Cognitive Disorders 11:1-10(2000),Hurn and Macrae,Journal of Cerebral Blood Flow &Metabolism 20:631-652(2000),Calvin,Maturitas 34:195-210(2000),Finking等人,Zeitschrift fur Kardiologie 89:442-453(2000),Brincat,Maturitas 35:107-117(2000),Al-Azzawi,Postgraduate MedicalJournal 77:292-304(2001)]。***可能以若干方式影响组织,其作用机理的最大特征在于它们与***受体相互作用,该受体导致在基因转录中的变化。***受体是配体-触发的转录因子,属于核激素受体总科。该族的其它成员包括***受体、雄激素受体、糖皮质激素受体和盐皮质激素受体。当结合到配体上时,这些受体二聚然后可激活基因转录,即,通过直接与DNA上的特定序列(通常称为应答码)结合,或通过与其它转录因子(诸如AP1)相互作用,后者然后直接结合特定的DNA序列[Moggs and Orphanides,EMBO Reports 2:775-781(2001),Hall等人,Journal of Biological Chemistry 276:36869-36872(2001),McDonnell,Principles Of Molecular Regulation.p351-361(2000)]。一类″共同调节(coregulatory)″蛋白质还可以与配体结合的受体相互作用,进一步调节其转录活性[McKenna等人,EndocrineReviews 20:321-344(1999)]。还已经表明,***受体可以配体-依赖型和独立型两种方式抑制NFκB-调节的转录作用[Quaedackers等人,Endocrinology 142:1156-1166(2001),Bhat等人,Journal of SteroidBiochemistry & Molecular Biology 67:233-240(1998),Pelzer等人,Biochemical & Biophysical Research Communications 286:1153-7(2001)]。
***受体还可以被磷酸化作用激活。这种磷酸化作用通过诸如EGF的生长因子调节,并导致在没有配体存在的情况下基因转录的改变[Moggs and Orphanides,EMBO Reports 2:775-781(2001),Hall等人,Journal of Biological Chemistry 276:36869-36872(2001)]。
***影响细胞的次要特征方式是通过所谓的膜受体。这种受体的存在是有争议的,但是已经充分证明了***可引起来自细胞的非常快速的非基因组应答。负责转换这种效应的分子单元还没有最后被分离,但是有证据建议其至少与***受体的中心形式有关[Levin,Journal of Applied Physiology 91:1860-1867(2001),Levin,Trends in Endocrinology & Metabolism 10:374-377(1999)]。
迄今为止已经发现了两种***受体。第一种***受体是在约15年前克隆的,目前被称为ERα[Green等人,Nature 320:134-9(1986)]。相比之下,第二种***受体形式在最近发现,被称为ERβ[Kuiper等人,Proceedings of the National Academy of Sciences of the United Statesof America 93:5925-5930(1996)]。早期对ERβ的研究集中在确定其对于各种配体的亲合性,实际上发现了其与ERα的一些差别。ERβ的组织分布已经很好地在啮齿动物体内被标记,其与ERα不一致。组织,诸如小鼠和大鼠的子宫,主要表达了ERα,而小鼠和大鼠的肺主要表达ERβ[Couse等人,Endocrinology 138:4613-4621(1997),Kuiper等人,Endocrinology 138:863-870(1997)]。甚至在相同的器官内,可划分出ERα和ERβ的分布。例如,在小鼠的卵巢中,ERβ在卵泡细胞中被高度表达,ERα只限于膜和基质细胞[Sar and Welsch,Endocrinology 140:963-971(1999),Fitzpatrick等人,Endocrinology 140:2581-2591(1999)]。但是,有的实例中,受体是被共同表达的,体外试验证明ERα和ERβ可形成杂二聚物[Cowley等人,Journal of Biological Chemistry 272:19858-19862(1997)]。
已经公开了大量化合物,它们模拟或阻断17β-***的活性。具有大致和17β-***一样的生物效应的化合物,最有效的内源***,被称为“***受体拮抗剂”。那些在与17β-***联合使用时阻断其效应的化合物被称作“***受体拮抗剂”。事实上,在***受体激动剂和***受体拮抗剂活性之间存在一种连续统一体,实际上一些化合物在一些组织中相当于***受体激动剂,在其它组织中相当于***受体拮抗剂。这些具有混合活性的化合物被称作选择性的***受体调节剂(SERMS),它们是有用的治疗剂(例如EVISTA)[McDonnell,Journal of the Society for GynecologicInvestigation 7:S10-S15(2000),Goldstein等人,Human ReproductionUpdate 6:212-224(2000)]。为什么相同的化合物可具有特定的细胞效应,其确切的原因尚未阐明,但是已经暗示是受体构造的差别和/或共同调节(coregulatory)蛋白质的环境的差别。
已经了解了一段时间,当结合配体时,***受体采用不同的构造。但是,仅在最近显示了这些变化的结果和细微差别。ERα和ERβ的三维结构通过与各种配体的共同析晶得到,并清楚地显示了在***受体拮抗剂的存在下螺旋12的复位,所述的***受体拮抗剂空间阻碍了受体-共同调节蛋白质相互作用需要的蛋白质序列[Pike等人,Embo 18:4608-4618(1999),Shiau等人,Cell 95:927-937(1998)]。另外,噬菌体显示技术已经用于确定在不同的配体存在下与***受体相互作用的肽[Paige等人,Proceedings of the National Academy ofSciences of the United States of America 96:3999-4004(1999)]。例如,确定了一种肽,其在与完全的***受体激动剂17β-***和二乙基己烯雌酚结合时不同。一种不同的肽显示了在与ERα和ERβ结合的氯美酚的区别。这些数据指出,各个配体可能以唯一的方式和不可预测的构造连接到受体上,后者似乎具有不同的生物活性。
如上所述,***影响了生物过程的防护性覆盖物。另外,在已描述了有性别差异(例如疾病频率、对刺激的应答等)的情况下,解释说明可能涉及到男性和女性之间***水平的差别。
发明概述
本发明提供了具有下述结构的式I***化合物或其药学可接受的盐,
其中
R1、R2、R3和R4分别独立地选自氢、羟基、1-6个碳原子的烷基、1-6个碳原子的烷氧基或卤素;
R5、R6、R7、R8、R9和R10分别独立地是氢、1-6个碳原子的烷基、2-7个碳原子的烯基、2-7个碳原子的炔基、卤素、1-6个碳原子的烷氧基、-CN、-CHO、苯基或具有1-4个选自O、N或S的杂原子的5或6-元杂环;其中R5、R6、R7、R8、R9或R10的烷基或烯基部分可任选被羟基、-CN、卤素、三氟烷基、三氟烷氧基、-NO2或苯基取代;其中R5、R6、R7、R8、R9或R10的苯基部分可任选被一、二或三取代,取代基选自1-6个碳原子的烷基、2-7个碳原子的烯基、卤素、羟基、1-6个碳原子的烷氧基、-CN、-NO2、氨基、1-6个碳原子烷基氨基、每个烷基具有1-6个碳原子的二烷基氨基、巯基、1-6个碳原子的烷硫基、1-6个碳原子的烷基亚磺酰基、1-6个碳原子的烷基磺酰基、2-7个碳原子的烷氧羰基、2-7个碳原子的烷基羰基或苯甲酰基;
前提是R1、R2、R3、R4、R7、R8、R9或R10中的至少一个是羟基。
当本发明的化合物含有碱性片段时,可药用盐可由有机酸和无机酸形成,例如乙酸、丙酸、乳酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、邻苯二甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、甲磺酸、萘磺酸、苯磺酸、甲苯磺酸、樟脑磺酸和类似的已知的可接受的酸。当本发明的化合物含有酸性片段时,盐可由有机碱和无机碱形成,如碱金属盐(例如钠、锂或钾)、碱土金属盐、铵盐、含1-6的碳原子的烷基铵盐或每个烷基具1-6个碳原子的二烷基铵盐,以及每个烷基含有1-6个碳原子的三烷基铵基盐。
术语烷基和烯基包括支链和直链的片断,例如分别具有1-6个和2-7个碳原子。实例包括甲基、乙基、丙基、丁基、异丙基、仲丁基、叔丁基、乙烯基、烯丙基、1-甲基乙烯基等。当烷基或烯基片断是取代的时,它们可通常被一、二、三或多取代。卤素取代的例子包括1-溴乙烯基、1-氟乙烯基、1,2-二氟乙烯基、2,2-二氟乙烯基、1,2,2-三氟乙烯基、1,2-二溴乙烷、1、2-二氟乙烷、1-氟-2-溴基乙烷、CF2CF3、CF2CF2CF3等。术语卤素包括溴、氯、氟和碘。
优选的5-6元杂环包括呋喃、噻吩、吡咯、异吡咯、吡唑、咪唑、***、二硫杂环戊二烯、氧杂硫杂环戊二烯(oxathiole)、异噁唑、噁唑、噻唑、异噻唑、噁二唑、呋咱、噁***、二噁唑、噁噻唑(oxathiazole)、四唑、吡喃、吡啶、哒嗪、嘧啶、吡嗪、三嗪、噁秦、噁噻嗪(oxathiazine)或噁二嗪(oxadiazine)。更优选杂环是呋喃、噻吩或吡啶。
正如根据本发明使用的,术语″提供″就提供被发明所包括的化合物或物质而言,是指将这类化合物或物质直接给药,或使用前体药物、衍生物或同型物,其在体内能够形成有效量的所述化合物或物质。
对于本发明的化合物,优选具有下列结构的式I化合物或其药学可接受的盐:
其中
R1和R2分别独立地选自氢、羟基、1-6个碳原子的烷基、2-7个碳原子的烯基和2-7个碳原子的炔基、1-6个碳原子的烷氧基或卤素;
R5、R6、R7、R8和R9分别独立是氢、1-6个碳原子的烷基、2-7个碳原子的烯基、2-7个碳原子的炔基、卤素、1-6个碳原子的烷氧基、-CN、-CHO、三氟甲基、7-12个碳原子的苯基烷基、苯基或具有1-4个选自O、N或S的杂原子的5或6-元杂环;其中R5、R6、R7、R8、R9或R10的烷基或烯基部分可任选被羟基、-CN、卤素、三氟烷基、三氟烷氧基、-NO2或苯基取代;其中R5、R6、R7、R8、R9或R10的苯基部分可任选被一、二或三取代,取代基选自1-6个碳原子的烷基、2-7个碳原子的烯基、卤素、羟基、1-6个碳原子的烷氧基、-CN、-NO2、氨基、1-6个碳原子的烷基氨基、每个烷基具有1-6个碳原子的二烷基氨基、巯基、1-6个碳原子的烷硫基、1-6个碳原子的烷基亚磺酰基、1-6个碳原子的烷基磺酰基、2-7个碳原子的烷氧羰基、2-7个碳原子的烷基羰基或苯甲酰基;
前提是R5或R9中的至少一个不是氢,
或其药学上可接受的盐。
更优选具有下式结构的式I化合物或其药学可接受的盐,
特别优选具有1-4个选自O、N或S的杂原子的5或6-元杂环是呋喃、噻吩或吡啶。尤其优选R5、R6、R7、R8和R9分别独立地是氢、卤素、-CN或2-7个碳原子的炔基。
R1和R2的实例彼此独立地选自氢和氟。
例如,R5、R6、R7、R8和R9可分别独立地是氢、卤素、-CN或2-7个碳原子的炔基。
R5可以是例如选自氢、氟或氰基。
R9可选自氢、氟或氰基。
R6、R7和R8可以彼此独立地是氢。
特别优选具有1-4个选自O、N或S的杂原子的5或6-元杂环是例如呋喃、噻吩或吡啶。
包括上述结构(I)的本发明化合物的实例:
8-氟-6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-8-氟-6-(3-氟-4-羟基苯基)-2-萘酚;
3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈;
3-(3,5-二氟-4-羟基苯基)-7-羟基-1-萘甲腈;
6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,6-二氟-4-羟基苯基)-2-萘酚;
6-(2,5-二氟-4-羟基苯基)-2-萘酚;
6-(3,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3,5-二氟-4-羟基苯基)-2-萘酚;
6-(2,6-二氟-4-羟基苯基)-2-萘酚;或
8-氯-3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈;
7-(4-羟基苯基)-2-萘酚;
7-(3-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-萘酚;
6-苯基-2-萘酚;
6-(3-羟基苯基)-2-萘酚;
6-(3-氯苯基)-2-萘酚;
2-氟-4-(2-萘基)酚;
6-(3-氯-4-羟基酚(phenol))-2-萘酚;
1-氯-6-苯基-2-萘酚;
1-溴-6-(4-羟基苯基)-2-萘酚;
1-氯-6-(4-羟基苯基)-2-萘酚;
1-氟-6-(4-羟基苯基)-2-萘酚;
2-羟基-6-(4-羟基苯基)-1-萘甲腈;
6-(4-羟基苯基)-1-苯基-2-萘酚;
6-(4-羟基苯基)-1-甲基-2-萘酚;
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-硝基-2-萘酚;
1-氯-6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲氧苯基)-2-萘酚;
6-(2-氯-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氯-4-羟基苯基)-2-萘酚;
6-(2-氟-4-羟基苯基)-2-萘酚;
8-氟-6-(4-羟基苯基)-2-萘酚;
1-氯-8-氟-6-(4-羟基苯基)-2-萘酚;
8-氯-6-(4-羟基苯基)-2-萘酚;
1,5-二氯-8-氟-6-(4-羟基苯基)-2-萘酚;
2-氯-4-(2-萘基)苯酚;
3-溴-8-氯-6-(4-羟基苯基)-2-萘酚;
1,8-二氯-6-(4-羟基苯基)-2-萘酚;
3-溴-1,8-二氯-6-(4-羟基苯基)-2-萘酚;
7-羟基-3-(4-羟基苯基)-1-萘甲腈;
8-氯-3-(4-羟基苯基)-7-羟基-1-萘甲腈;
8-溴-7-羟基-3-(4-羟基苯基)-1-萘甲腈;或
其药学可接受的盐。
此外,提供了用于制备包括上述结构(I)的本发明化合物的方法。根据本发明提供了一种用于制备包括上述结构(I)的上述定义的萘基化合物的方法,其包括下述之一:
a)将下式化合物脱烷基或脱芳烷基
其中,R1-R10定义如上,条件是R1、R2、R3、R4、R7、R8、R9或R10中的至少一个是烷氧基或芳烷氧基,得到相应的式I化合物,其中R1、R2、R3、R4、R7、R8、R9或R10中的至少一个是羟基;{例如,下式化合物脱烷基或脱芳烷基,
其中,R和R′中的至少一个式烷基(例如1-6个碳的烷基)或芳烷基(例如7-12个碳的芳烷基),得到相应的式(I)化合物};
或
b)卤式I化合物
其中R10是羟基;{诸如下式化合物:
得到相应的1-卤代萘酚};
或
c)将式I的碱性化合物转化为其盐或反之亦然。
在任何在此描述的反应中,任何反应基团或位置可在反应前被保护,并在反应后将保护基除去。
在制备本发明化合物中使用的反应物可以是从市场购买的或可通过文献中所述的标准方法制备。
在下述路线1-15中描述了本发明一些代表性实例的制备。
路线2
路线3
路线4
路线5
路线7
路线9
路线11
路线12
路线13
路线15
可容易地获得标准药理学试验方法用以确定给定的试验化合物的活性。下面简略地概述若干代表性试验过程,并且可包括本发明典型化合物的数据。全部试验,除了放射性配体结合试验外,可用于测定化合物的***受体激动剂或拮抗剂活性。通常,***受体激动剂活性通过将所述化合物和参考***(例如17β-***、17α-乙炔基、17β-***、雌甾酮、二乙基己烯雌酚等)比较进行。***受体拮抗剂活性的测定通常是通过共同处理试验化合物和参考***并与单独使用参考***得到的结果比较进行。在美国专利4418068和5998402中也提供了用于SERMs的标准药理学试验方法,所述的文献引用在此作为参考。
对于ERα和ERβ的结合亲合性的评价
在常规放射性配体结合试验中,评价本发明代表实施例相对于17β-***对ERα和ERβ受体的亲和力。该试验方法提供了确定对ERα和ERβ受体相对结合亲合性的方法。使用的方法简述如下。
制备用于结合选择性表征的受体萃取物。配体结合区域,在此方便地定义为DNA结合区域的所有下游序列,通过PCR得到,使用了全长cDNA作为模板和引物,引物包含用于亚克隆的适合的限制位点,同时含有用于表达的适合的阅读框。这些模板包含人ERα的氨基酸M250-V595[Green等人,Nature 320:134-9(1986)]和人ERβ的M214-Q530[Ogawa,etal.,Biochemical & Biophysical Research Communications 243:122-6(1998)]。人ERβ被克隆到pET15b(Novagen,Madison WI),其作为Nco1-BamH1片段具有一个C-末端Flag标记物。人ERα被克隆为人ERβ,不同的是加入一个N-末端加了一个His标记物。使用的所有结构的序列通过两个链的全序列确定。
BL21(DE3)细胞用来表达人蛋白质。通常使用10ml过夜培养物接种含有100μg/ml氨苄青霉素的LB介质的1L培养物。在37℃培养过夜后,将IPTG加入得到1mM的最终浓度,培养在25℃进行2小时。离心(1500Xg)收集细胞,洗涤颗粒并将其再悬浮在100ml的50mM Tris-Cl(pH7.4)、150mM NaCl中。将细胞两次通过在12000psi的弗氏压碎器进行细胞溶解。通过在4℃在12,000Xg离心30分钟将溶胞产物澄清,并在-70℃存储。
评价萃取物对特定[3H]-***的结合。杜尔贝科磷酸盐缓冲盐水(Gibco,1x最后浓度)补充了1mM乙二胺四乙酸,将其用作本试验的缓冲剂。为了优化在分析中使用的受体的量,将[3H]-17β-***(NewEngland Nuclear;最终浓度=2纳米)±0.6μM二乙基己烯雌酚和100μL的各种稀释度的大肠杆菌溶菌产物加入到高结合掩蔽的微量滴定板的各个穴中(EG & G Wallac)。最终的分析体积是120μl,DMSO的浓度≤1%。在室温培养5-18小时后,吸出未结合的物质,用约300μl的分析缓冲剂冲洗三次滴定板。洗涤后,将135μl的闪烁鸡尾酒试剂(OptiphaseSupermix,EG & G Wallac)加入到各穴中,将板密封并振动至少5分钟,将闪烁剂与残留的洗涤缓冲剂混合。通过液体闪烁计数评价结合放射性(EG & G Wallac Microbeta Plus)。
在确定提供最大特异性结合的各受体制品的稀释度后,用各种稀释度的受体制品评价未标记17β-***的IC50,以此进一步优化分析。为各个受体制品选择最后的工作稀释度,在该稀释度下,未标记的17β-***的IC50是2-4纳米。
配体结合竞争试验方法。先将测试化合物溶解在二甲亚砜中,在结合分析中二甲亚砜的最终浓度为≤1%。每个测试化合物在8种稀释度下用作[3H]-17β-***的未标记竞争剂。通常,一系列稀释度的化合物会同时在人ERα和ERβ上进行测试。结果用测量DPM对测试化合物浓度的曲线图表示。为了拟合剂量-反应曲线,设置了基于转化的权重数据的四参数逻辑模型,IC50被定义为[3H]-***结合降低50%的化合物浓度。
对于本发明的典型实施例,对ERα和ERβ的结合亲合性(以IC50测定)列于表(1)。
表1:本发明典型化合物的ER结合亲合性 | ||
实施例 | ER-βIC50(nM) | ER-αIC50(nM) |
1a | 0.054 | 0.280 |
1b | 0.570 | 3.140 |
1c | 0.527 | 3.405 |
1d | 0.006 | 0.022 |
1e | 0.0175 | 0.180 |
1f | 0.245 | 0.638 |
1g | 0.374 | 1.345 |
1h | 0.030 | 0.230 |
1i | 0.519 | 1.360 |
1j | 0.242 | 2.120 |
1k | 0.006 | 0.092 |
1l | 0.011 | 0.107 |
1m | 0.468 | 1.785 |
1n | 1.360 | 3.070 |
1o | 0.0127 | 0.266 |
1p | 0.0025 | 0.091 |
1q | 0.114 | 0.884 |
1r | 0.007 | 0.077 |
1s | 0.081 | 1.402 |
1t | 0.657 | 1.720 |
1u | 0.017 | 0.282 |
1v | 0.004 | 0.143 |
1w | 0.032 | 0.356 |
1x | 0.206 | 0.802 |
1y | 0.013 | 0.140 |
1z | 0.0095 | 0.039 |
1aa | 0.027 | 0.074 |
1ab | 0.001 | 0.006 |
1ac | 0.0032 | 0.0032 |
1ad | 0.0020 | 0.024 |
表1:本发明典型化合物的ER结合亲合性 | ||
1ae | 0.0027 | 0.018 |
1af | 0.002 | 0.008 |
1ag | 0.0012 | 0.058 |
1ah | 0.011 | 0.131 |
1ai | 0.0025 | 0.038 |
1aj | 0.0016 | 0.022 |
1ak | 0.0015 | 0.021 |
1al | 0.0011 | 0.040 |
1am | 0.0025 | 0.125 |
1an | 0.0035 | 0.029 |
1ao | 0.0016 | 0.012 |
1ap | 0.002 | 0.029 |
1aq | 0.002 | 0.017 |
1ar | 0.004 | 0.052 |
1as | 0.0085 | 0.043 |
1at | 0.010 | 0.160 |
1au | 0.0023 | 0.105 |
1av | 0.0028 | 0.208 |
1aw | 0.006 | 0.109 |
1ax | 0.011 | 0.299 |
1ay | 0.0084 | 0.092 |
1az | 0.058 | 0.548 |
1ba | 0.011 | 0.519 |
1bb | 0.0095 | 0.095 |
在上述标准药理学试验方法中得到的结果证明本发明的化合物结合***受体的两个亚型。对于ERβ,IC50通常较低,这表明这些化合物优选是ERβ的选择性配体,但是仍然认为其对ERα具有活性。本发明的化合物向显示出基于或至少是部分基于其受体亲和性选择性特征的许多活性。因为本发明化合物结合ERβ的亲合性高于结合ERα的亲合性,其将用于通过ERβ可调节的疾病的治疗或抑制。另外,因为各个受体配体配合物是唯一的,因此其与各种共同调节蛋白质的相互作用是唯一的,根据细胞组织,本发明化合物将显示不同的且不可预知的活性。例如,在一些细胞型中,一种化合物可起***受体激动剂的作用,同时在其它组织中,其为***受体拮抗剂。具有这种活性的化合物有时被称为SERM(选择性的***受体调节剂)。但是,与许多***不同,许多SERM不会导致子宫湿重的增加。这些化合物在子宫中是抗***的,并且可完全对抗本在子宫组织中***受体激动剂的营养效应。但是,这些化合物在骨骼、心血管和中枢神经***中起***受体激动剂的作用。由于这些化合物的这种组织选择性,其可用于治疗和抑制哺乳动物与***缺乏(在某些组织中,如骨骼或心血管)或***过量(在子宫或乳腺中)有关的疾病病症或综合征。另外,本发明的化合物还具有这样的可能性,其在一种受体类型中相当于***受体激动剂,同时在其它类型上相当于***受体拮抗剂。例如,已经证明了化合物可通过ERβ对抗17β-***的作用,同时其显示出与ERα的***受体激动剂活性[Sun等人,Endocrinology 140:800-804(1999)]。在这系列化合物中,这种ERSAA(***受体选择性激动剂拮抗剂)活性提供了药理学上明确的***活性。
金属硫蛋白-II mRNA的调节
如Harris所述,***通过ERβ而不是ERα作用,可向上调节金属硫蛋白II mRNA在Saos-2细胞中的水平[Endocrinology 142:645-652(2001)]。该试验方法得到的结果可与下述测试方法(ERE指示剂试验法)得到的结果结合,得到本发明化合物选择性的概况(也可参见WO00/37681)。本发明典型化合物的数据列于表(2)。
表2:在Saos-2细胞中金属硫蛋白-IImRNA的调节 | |
实施例1e | 17.0 |
实施例1l | 5.5 |
实施例1o | 5.7 |
实施例1p | 6.0 |
实施例1s | 4.9 |
使用ERE-指示剂试验法在MCF-7乳腺癌细胞中对测试化合物的评 价。在DMSO中制备试验化合物的原液(通常0.1M),然后用DMSO稀释10-100倍,制成1或10mM的工作溶液。二甲亚砜原液储藏在4℃(0.1M)或-20℃(<0.1M)。将MCF-7细胞用生长培养基[D-MEM/F-12介质,包括10%(vv)加热灭活的胎牛血清,1%(v/v)青霉素-链霉素和2mMglutaMax-1]每周两次继代移种。将细胞保存在有开口的烧瓶内,放置在37℃、5%CO2/95%湿度的有氧培养箱中。在处理前一天,将细胞和生长培养基以25,000细胞/穴的量植入96穴板然后在37℃培养过夜。
以50μl/穴的量用在实验介质[无酚红D-MEM/F-12介质,包括10%(v/v)加热灭活的脱碳(charcoal-stripped)胎牛血清、1%(v/v)青霉素-链霉素,2mM的glutaMax-1、1mM丙酮酸钠]中1∶10稀释的腺病毒5-ERE-tk-荧光素酶在37℃感染细胞2小时。然后用150μl的实验介质洗涤穴一次。最后,细胞在37℃用150μl/穴的载体(≤0.1%v/v二甲亚砜)或用实验介质≥1000倍稀释的化合物处理24小时,每次平行处理8个穴。
用一剂1μM单独的被测化合物(***受体激动剂模式)或与0.1nM17β-***结合的被测化合物(EC80:***受体拮抗剂模式)完成测试化合物的最初筛选。各个96穴板还包括载体对照组(0.1%v/v二甲亚砜)和***受体激动剂对照组(0.1或1nM17β-***)。剂量-反应实验以***受体激动剂和/或***受体拮抗剂模式进行,活性化合物的记录从10-14增加到10-5M。由这些剂量-反应曲线,可分别得到EC50和IC50值。在各个试验组的最后一个穴,包括5μl的3×10-5M ICI-182,780(10-6M最终浓度)作为***受体拮抗剂对照物。
处理后,在振荡器上用25μl/穴的1X细胞培养溶胞反应物(PromegaCorporation)溶解细胞15分钟。细胞溶菌产物(20μl)被转移到96穴光度计板上,在MicroLumat LB 96P光度计(EG & G Berthold)中测定荧光素酶活性,使用100μl/穴的荧光素酶基底(Promega Corporation)。在注射基底前,对每个穴进行1秒钟背景测量。在注射基底后,延迟1秒钟对荧光素酶活性进行10秒钟测试。数据从光度计传输到Macintosh个人计算机上,用JMP软件(SAS Institute)分析;该程序从每个穴的荧光素酶测量值中扣掉了背景读数,然后确定各次处理的平均和标准偏差。
荧光素酶数据转化为对数,用Huber M-估算器对***转换测量进行下加权。JMP软件用来对单程ANOVA进行转换和加权数据分析(Dunnett′s试验)。在***受体激动剂模式中,所述化合物处理可与载体对照组的结果比较,或在***受体拮抗剂模式中,与正的***受体激动剂对照结果(0.1nM17β-***)比较。对于最初的一剂实验,如果化合物处理结果与合适的对照显著不同(p<0.05),那么结果报告为相对于17β-***对照组的百分比[即,((化合物-载体对照)/(17β-***对照-载体对照))×100]。JMP软件此外用于从非线性的剂量-反应曲线确定EC50和/或IC50值。
子宫营养活性的评价
试验化合物的子宫营养活性可根据下面的标准药理学试验法测定。
过程1:从Taconic得到性发育未全的(18日龄)Sprague-Dawley大鼠,提供无限制的酪蛋白基饮食(Purina Mills 5K96C)和水。在19、20和21天,给大鼠皮下给药17α-乙炔基-17β-***(0.06μg/鼠/天)、测试化合物或载体(50%DMSO/50% Dulbecco′s PBS)。为了评价***受体拮抗剂,化合物与17α-乙炔基-17β-***(0.06μg/鼠/天)共同给药。每组有6只大鼠,在最后一次注射约24小时后,通过CO2窒息和气胸施行安乐死。摘除子宫,在清理了结合的脂肪并挤出任何内部液体之后,将子宫称重。也可将组织样品急冻用于基因表达分析(例如,补体因子3mRNA)。从本发明典型化合物得到的结果列于表(3)。
表3:在大鼠子宫营养试验法中所选择化合物的评价 | |
化合物 | 平均子宫重量(mg)±SEM |
载体 | 21.4±1.6 |
17α-乙炔基-17β-***(0.06μg/大鼠/天) | 85.5±3.1 |
实施例1av(2mg/大鼠/天) | 23.3±1.3 |
实施例1 1av(2mg/大鼠/天)+17α-乙炔基-17β-***(0.06μg/大鼠/天) | 81.9±4.2 |
过程2:从Taconic得到性发育未全的(18日龄)129 SvE小鼠,提供无限制的酪蛋白基饮食(Purina Mills 5K96C)和水。在22、23、24和25天对小鼠在皮下给予化合物或载体(玉米油)。每组有6只小鼠,在最后一次注射约6小时后,通过CO2窒息和气胸施行安乐死。摘除子宫,在清理了结合的脂肪并挤出任何内部液体之后,将子宫称重。以下结果(表(4))得自本发明典型的化合物。
表4:在小鼠子宫营养试验法中所选择化合物的评价 | |
化合物 | 平均子宫重量(mg)±SEM |
载体 | 10.3±0.8 |
17β-***(50mg/kg/天) | 45.3±1.9 |
实施例1av(50mg/kg/天) | 12.6±0.8 |
骨质疏松症和脂类调节(心脏保护)的评价
切除卵巢或进行了假手术的雌性Sprague-Dawley大鼠在手术后1天从Taconic Farms得到(重量范围240-275克)。将其以每笼3或4只大鼠按照12/12(明/暗)时间表在室中饲养,提供无限制的食物(Purina 5K96C大鼠食物)和水。在到达后1天开始为所有的研究进行处理,大鼠每周给药7天,进行6周。年龄相匹配的、做了假手术的大鼠组不接受任何处理,其用作每个研究的无损伤、***充足的对照组。
全部试验化合物在载体50%二甲亚砜(JT Baker,Phillipsburg,NJ)/1x Dulbecco′s磷酸盐生理盐水(GibcoBRL,Grand Island,NY)中制备成规定的浓度,从使处理体积是0.1ml/100克体重。17β-***溶于玉米油(20μg/ml)并皮下注射,0.1ml/大鼠。以三周为间隔根据组平均体重测量值调节全部剂量,皮下给药。
开始处理5周之后且在研究终止前1周,对每只大鼠进行骨骼矿物密度(BMD)评价。用XCT-960M(pQCT;Stratec Medizintechnik,Pforzheim,德国)评价被麻醉大鼠近端胫节的总密度和小梁密度。测量是进行如下:在扫描前15分钟,通过腹腔内注射45毫克/公斤***、8.5毫克/公斤甲苯噻嗪和1.5毫克/公斤乙酰丙嗪麻醉每只大鼠。
将右后肢通过直径25mm的聚碳酸酯管,用胶带绑在丙烯酸框上,踝关节在90度角,膝关节在180度角。聚碳酸酯管被固定在滑台上,使其垂直于pQCT的窗孔。调节平台,从而使股骨的远端和胫节的近端处于扫描场中。双向探测观察持续10mm长度,谱线分辨度0.2mm。在探测视察显示在监视器上之后,固定胫节近端。从该点开始pqct扫描3.4毫米到末梢。pqct扫描为1mm厚度,具有voxel(三维的像素)尺寸0.140mm,从该部分的开始到结束由145个投影组成。
在完成pQCT扫描后,影像显示在监视器上。勾画了包括胫节但不包括腓骨的研究区域的轮廓。用迭代算法从数学上除去软组织。剩下的骨骼的密度(总密度)以mg/cm3报告。骨骼外面的55%按照同心螺线从数学上被剥离。剩下的骨骼密度(小梁密度)以mg/cm3报告。
BMD评价1周后,通过CO2窒息和气胸将大鼠安乐死,收集血液进行胆甾醇测定。另外,摘除子宫,在整理结合的脂肪并挤出任何腔内液体之后将子宫称重。总胆固醇通过Boehringer-Mannheim Hitachi911临床的分析仪用胆甾醇/HP试剂盒测定。用单向方差分析和Dunnet′s试验比较统计数字。
抗氧化活性评价
从屠宰场得到猪的主动脉,清洗,送到冷却的PBS,采集主动脉内皮细胞。为了采集所述细胞,结扎主动脉的脉间脉管,并将主动脉的一端夹住。将新鲜的、无菌的过滤的0.2%胶原酶(Sigma型I)置于血管中,并随后将血管的另一端夹住,形成一个封闭***。该主动脉在37℃培养15-20分钟,随后收集胶原酶溶液并在2000Xg离心5分钟。各颗粒悬浮在7ml的内皮细胞培养介质中,所述介质由补充了脱碳FBS(5%)的无酚红DMEM/Ham′s F12介质、NuSerum(5%)、L-谷氨酸盐(4mM)、青霉素-链霉素(1000μg/ml,100μg/ml)和庆大霉素(75μg/ml)组成,将颗粒接种在100mm平皿中,在37℃在5%二氧化碳中培养。在20分钟后,细胞用PBS清洗,加入新鲜的介质,在24小时时再将此重复1次。约1周后细胞融合。内皮细胞通常每周加料两次,当融合时,胰蛋白酶化,并以在1∶7比例接种。在所述化合物存在下进行12.5μg/mLLDL的细胞介导的氧化,在37℃评价4小时(5μM)。结果可表示为氧化过程的抑制百分比,其通过用于分析游离醛的TBARS(丙二酰硫脲反应性物质)方法测定[Yagi,Biochemical Medicine 15:212-6(1976)]。
孕酮受体mRNA调节标准药理学试验法
该试验法可用于评价本发明化合物的***活性或抗***活性[Shμghrue等人,Endocrinology 138:5476-5484(1997)]。本发明典型化合物的数据列于表(5)。
表5.本发明典型化合物调节大鼠脑视前区孕酮mRNA的作用 | |
化合物 | ***受体mRNA(arbitrary units;mean±stdev) |
载体 | 55.4±9.4 |
17β-***(30μg/kg) | 557.1±80.6 |
实施例1av(10mg/kg) | 33.7±20.6 |
大鼠热潮红试验法
化合物在热潮红方面的作用可在标准药理学试验法中评价,所述方法测量被测化合物减弱尾部表皮温度增加的能力,所述的尾部表皮温度增加发生在咖啡上瘾的大鼠用纳洛酮急性脱离药物的情况下[Merchenthaler等人,Maturitas 30:307-16(1998)]。通过与对照***共同给药,该方法还可以用来测定***受体拮抗剂活性。
在分离的大鼠主动脉环中血管收缩功能的评价
Sprague-Dawley大鼠(240-260克)被分成4组:
1.正常的未切除卵巢的(无损伤的);
2.切除卵巢(ovex)用载体处理的;
3.切除卵巢用17β-***处理的(1毫克/公斤/天)
4.切除卵巢的动物用试验化合物(各种剂量)处理的。
在处理之前约3周将动物切除卵巢。每只动物接受17-β***硫酸盐(1毫克/公斤/天)或试验化合物,其悬浮在有1%吐温80的蒸馏去离子水中,通过胃强饲法施用。载体处理的动物接受适量在药物处理组所用的载体。
动物通过二氧化碳吸入和放血被处死。将胸主动脉迅速摘除,放入37℃的生理溶液中,所述生理溶液有以下组成(mM):NaCl(54.7)、KCl(5.0)、NaHCO3(25.0)、MgCl2 2H2O(2.5)、D-葡萄糖(11.8)和CaCl2(0.2),用CO2-O2充气,95%/5%,最终pH为7.4。将advantitia从外表面除去,血管被切成2-3mm宽的环。将环悬浮在10ml组织浴中,一端连接到池底,另一端连接测力传感器。将1克的静止张力施加到环上。将环平衡1小时,获取并分析信号。
在平衡后,将环暴露在浓度增加的苯肾上腺素(10-8至10-4M)下,记录张力。然后用新鲜的缓冲液冲洗三次浴。在冲洗后,将200mML-NAME加入组织浴中,并平衡30分钟。然后重复苯肾上腺素浓度反应曲线。
评价心脏保护活性
从Taconic Farms获得脱脂蛋白E-缺乏的C57/B1J(apo E KO)小鼠。全部动物操作严格按照IACUC指南进行。切除卵巢的雌性apo E KO小鼠,4-7周龄,在履带板-箱笼中饲养,允许自由进食和饮水。动物被随机按重量分成组(n=12-15小鼠/组)。用精确剂量方法在饮食中给动物施用测试化合物或***(17β-***硫酸盐,1毫克/公斤/天),其中每周测定消耗的饮食的量,据此基于动物的体重调节剂量。使用的饮食是西式饮食(57U5),由Purina制备,含0.50%胆甾醇、20%猪油和25IU/KG维生素E。使用这种模式给动物用药/喂食12周。用西式饮食饲喂对照动物,不喂给化合物。在研究阶段末,将动物处死,得到血浆样品。就地灌注心脏,首先用盐水灌注,然后用中性缓冲剂10%甲醛液灌注。
为了测定血浆脂质和脂蛋白,分别用Boehringer Mannheim和Wako Biochemicals制造的市售试剂盒以酶促法确定总胆固醇和三酸甘油酯,然后用Boehringer Mannheim Hitachii 911分析仪分析。用FPLC尺寸精馏进行血浆脂蛋白的分离和定量评价。简而言之,过滤50-100ml的血清,将其注入Superose 12和Superose 6串连的柱中,以恒流速用1mM钠EDTA和0.15M NaCl洗脱。用Waters Millennium软件对表示VLDL、LDL和HDL的各个曲线的面积积分,通过用每个相应的色谱峰的相对百分比面积乘以总胆甾醇值确定各脂蛋白百分率。
为了定量评价主动脉的动脉粥样硬化,将主动脉小心分离并在处理前放入***固定剂中48-72小时。用油红O染色剂确定动脉粥样硬化损害。血管被略略脱色,然后用装有Sony 3CCD摄影体系的NikonSMU800显微镜成像,同时使用IMAQ Configuration Utility(NationalInstrument)作为影像俘获软件。用常规阈值实用软件包(ColemanTechnologies)沿着主动脉弓上面确定损害。在血管上用程序的阈函数进行自动操作损害评价,具体地说,在包含在主动脉弓内的区域上测试,所述的主动脉弓从头臂干的近边到左侧锁骨下动脉的远边。主动脉动脉粥样硬化数据可表示为在该定义的腔区域中确实牵连损害的百分比。
认识力增强的评价
使切除卵巢的大鼠(n=50)熟悉8-支路径向支路迷宫,连续5天每天10分钟。在熟习和测试前使动物失水。将100μl等分量的水置于各支路的末端作为补充。通过让动物能够达到有诱饵的支路,实现支路迷宫中得以成功完成轮班任务。在喝水后,动物离开支路重新进入中央室,在其中,动物现在可进入早先探访过的支路,或进入新的支路。当动物选择进入新的支路时,记录正确应答。各个动物每天可尝试5次,持续3天。在最后得到尝试后,将动物分成以下4组:
1.阴性对照:每天注入10%二甲亚砜/芝麻油载体一次,进行6天(1ml/kg,SC)
2.阳性对照:注入17β-苯甲酸***2天并在第二次注射(17β-苯甲酸***,10μg/0.1ml/大鼠)后4天测试
3.***:每天注入17β-***6天(20μg/kg,SC)
4.测试化合物:每天注入,进行6天(改变剂量)
在最后一天学习后开始所有的注射。在检验工作记忆前2小时对1、3和4组进行最后一次注射。
对工作记忆的检验采用15、30和60秒延迟的一种对样品的延迟的非对比作业(DNMS)。该工作是添加工作的变化,其中大鼠被置于中央场地中,并允许其如前所述进入一个支路中。一旦该大鼠沿着第一个支路移动到一半时,就打开第二个支路,并再次要求该大鼠选择该支路。当其已经沿着第二个支路通过一半时,将两个门均关闭,开始延时。一旦延时期满,将开始的两个门和第三个新的门同时打开。当该动物沿着第三个新的支路通过一半时,记录正确应答。当该动物沿着第一个或第二个支路移动过半时,记录不正确应答。在三个延时间隔时间,每只动物在每个时间进行5次尝试,每个受试者总共进行15次尝试。
对胸膜炎影响的评价
根据Cuzzocrea方法评价对大鼠的实验引起的胸膜炎症状的减轻能力[Endocrinology 141:1455-63(2000)]。
评价对谷氨酸盐引起细胞毒性的防护性能(神经保护)
本发明化合物的神经保护活性可在用谷氨酸盐诱导的体外标准药理学试验方法中评价[Zaulyanov等人,Cellular & MolecularNeurobiology 19:705-18(1999);Prokai等人,Journal of MedicinalChemistry 44:110-4(2001)]。
在乳腺末端芽体试验中的评价
乳腺管的完全导管延伸和分枝需要***,随后在***的影响下发展成小叶蜂窝状末端芽体。在该试验法中,本发明所选择的化合物的激乳腺活性根据下述标准药理学试验方法评价。将28日龄的Sprague-Dawley大鼠(Taconic Farms,Germantown,NY)切除卵巢,然后休息9天。将动物饲养在12小时明/暗周期的环境中,并饲喂酪蛋白基的Purina Laboratory啮齿动物膳食5K96(Purina,Richmond,IN),允许自由饮水。然后给大鼠皮下注射6天载体(50%二甲亚砜(JT Baker,Phillipsburg,NJ)/50%1x Dulbecco′s磷酸盐缓冲盐水(GibcoBRL,Grand Island,NY)、17β-***(0.1毫克/公斤)或试验化合物(20毫克/公斤)。在最后三天,给大鼠皮下注射***(30毫克/公斤)。在第七天,将大鼠处死,切除***脂垫。对该脂垫分析酪蛋白激酶IImRNA,其作为末端芽体增殖的标示物。酪蛋白激酶II mRNA用实时RT-PCR分析。
简要地说,根据制备说明,按照Trizol(GibcoBRL,Grand Island,NY)分离RNA,使用无DNA的试剂盒(Ambion)用DNA酶I处理样品,用Taqman Gold方法(PE Applied Biosystems)通过实时RT-PCR测定酪蛋白激酶II mRNA水平。以酪蛋白激酶II特定引物对(5′引物,CACACGGATGGCGCATACT;3′引物,CTCGGGATGCACCATGAAG)和定制的探针(TAMRA-CGGCACTGGTTTCCCTCACATGCT-FAM)一式三次分析总共50ng RNA。酪蛋白激酶II mRNA水平被校正到18s核糖体RNA,其包括在使用引物和PE Applied Biosystems提供的探针的各个样品反应中。得到下述本发明典型的化合物的结果(表(6))。
表6:化合物在大鼠激乳腺分析中的评价 | |
化合物 | 酪蛋白激酶IImRNA/18S rRNA(mean±SEM) |
载体 | 2.66±0.13 |
***(30mg/kg)+17β-***(0.1mg/kg) | 39.0±5.4 |
***(30mg/kg)+实施例1av(20mg/kg) | 1.06±0.17 |
在HLA大鼠标准药理学试验中对炎症性肠病的评价
本发明的化合物可在模拟人炎症性肠病的HLA大鼠标准药理学试验中进行评价。以下简述所用的方法和得到的结果。从Taconic得到雄性HLA-B27大鼠(8-10周龄),给其提供无限制的食物(PMI Lab膳食5001)和水。在46天中,每天给大鼠口服载体(2%吐温-80/0.5%甲基纤维素)或实施例1av(10mg/公斤)。每天观察粪便特性,并根据以下标度分级:腹泻=3;软便=2;正常便=1。在研究结束时,收集血清并在-70℃储存。准备一段结肠用于组织分析,另一段用于对髓过氧物酶活性进行分析。得到下述结果(表(7)),表明在实施例1av给药21天内粪便的特征正常化。
表7:口服载体或实施例1av 46天处理的HLA大鼠的粪便记录。报道的数值是开始给药26天每组的平均值。 | ||
天 | 载体 | 实施例1av |
1 | 2.75 | 2.75 |
2 | 3 | 2.5 |
3 | 3 | 2.25 |
4 | 3 | 2.5 |
5 | 3 | 2.25 |
6 | 3 | 2.5 |
7 | 3 | 2.5 |
8 | 3 | 2 |
9 | 3 | 2 |
10 | 3 | 1.5 |
11 | 3 | 1.5 |
12 | 3 | 1.5 |
13 | 3 | 1.75 |
14 | 3 | 1.75 |
15 | 3 | 1.5 |
16 | 3 | 1.5 |
17 | 3 | 1.25 |
18 | 3 | 1.25 |
19 | 3 | 1.25 |
20 | 3 | 1.25 |
21 | 3 | 1.25 |
22 | 3 | 1 |
23 | 3 | 1 |
24 | 3 | 1 |
25 | 3 | 1 |
3=腹泻;2=软便;1=正常便 |
为了进行组织分析,将结肠组织浸于10%中性缓冲的***中。将各段结肠样品分成四份样品进行评价。将***固定的组织在Tissue Tek vacuum infiltration处理***(Miles,Inc;West Haven,Connecticut)中处理进行石蜡包埋。将样品切成5μm的薄片,然后用苏木紫和曙红(H & E)着色,在Boμghton-Smith后用修正的标度进行组织的盲评价。在完成记录后,将样品明确,列表显示数据并用复合平均对比通过ANOVA线性模型进行分析。评价结肠组织薄片,用于指示多种疾病并得到相关数据。如表(8)所示,实施例1av在降低组织损伤的若干测量值方面有效。
表8:在口服载体或实施例1av46天后,HLA-B27大鼠模型的患病组织记录 | |||||
组别 | 溃疡(0-2) | 炎症(0-3) | 深度损伤(0-2) | 纤维化(0-2) | 总分 |
载体 | 1.19±0.69 | 2.38±0.32 | 1.0±0.54 | 0.94±0.75 | 5.50±2.1 |
实施例1av | 0.44±0.43 | 1.13±0.43* | 0.38±0.43 | 0.07±0.13* | 2.00±1.14* |
*信号<载体 |
在两个关节炎模型中的评价
佐剂引起关节炎的Lewis大鼠的分析。根据标准研究室操作方法饲养60只雌性12周龄Lewis大鼠。它们得到无限制的标准食物和水饲喂。各只动物通过标记项目组和动物数量的笼卡区分。每只大鼠的编号用持久性墨水标记在尾部。在研究前至少10-21天将其麻醉并用标准无菌外科术切除卵巢。
用弗氏完全佐剂(Freund′s Adjuvant-Complete)(Sigma ImmunoChemicals,St.Louis,MO)引起关节炎,每毫升含1毫克热灭活并干燥的结核分枝杆菌、0.85ml矿物油和0.15ml一油酸二缩甘露醇酯Lot No.084H8800。
下面是两个试验的实例。抑制试验方法:给30只大鼠在尾基真皮注射0.1ml的弗氏完全佐剂。将动物随机分组,每组6只。每天,各组接受载体(50%二甲亚砜(JT Baker,Phillipsburg,NJ)/1x Dulbecco′s磷酸盐生理盐水(GibcoBRL,Grand Island,NY))或试验化合物(皮下给药)。所有大鼠在第1天开始处理。实施例1av的数据列于表(9)。
治疗试验方法:给30只大鼠在尾基真皮注射0.1ml的弗氏完全佐剂。将动物随机分为四组,每组包括六只大鼠。每天,各组接受载体(50%二甲亚砜(JT Baker,Phillipsburg,NJ)/1x Dulbecco′s磷酸盐生理盐水(GibcoBRL,Grand Island,NY))或试验化合物(皮下给药)。在注射助剂后的第8天开始处理所有大鼠。实施例1av的数据列于表(10)、(11)和(12)。
用Abacus Concepts Super ANOVA(Abacus Concepts,Inc.,Berkeley,CA)进行统计分析。对所有感兴趣的参数在各组之间用邓肯新多程的后期测试(Duncan′s new multiple range post hoc testing)进行方差分析。全部数据以平均标准偏差(SD)表示,如果p<0.05,则认为差异显著。
每日监视关节炎的严重程度,折合成以下病情指数:后爪发红,后爪肿大,关节触痛以及运动和姿势。0至3的整数标度被用来量化红斑的级别(0=正常爪,1=轻微发红,2=中度发红,3=严重发红)和膨胀的级别(0=正常爪,1=轻微肿大,2=中度肿大,3=后爪严重肿大)。每天最多记录12次。
在研究结束时,将大鼠用CO2处死,从尸体上除去四肢,并在10%缓冲的***中固定,将跗关节脱钙,埋蜡。组织切片用苏木精和曙红或Saffranin O-坚牢绿着色。
将载玻片编号,从而检查员对试验组盲检。如下所述,对来自跗关节的滑膜组织在滑膜增生、炎性细胞浸润和血管翳形成方面进行评价[Poole and Coombs,International Archives of Allergy & AppliedImmunology 54:97-113(1977)]。
类型 | 分级 |
1.滑膜衬里细胞 | |
a.无变化 | 0 |
b.细胞扩大,稍微变厚 | 1 |
c.细胞扩大,数量增加,中等变厚。无绒毛存在 | 2 |
d.细胞扩大,变厚。存在绒毛 | 3 |
2.纤维组织形成 | |
a.无变化 | 0 |
b.在衬细胞下存在纤维增生 | 1 |
c.小面积的蜂窝组织被纤维组织代替 | 2 |
d.纤维组织代替蜂窝组织 | 3 |
3.炎性细胞 | |
a.偶而见到,散布在整个选择的区域 | 0 |
b.存在少量细胞,位于衬细胞层中或恰好在衬细胞层下和/或在血管周围 | 1 |
c.可存在细胞的小病灶聚集 | 2 |
d.大量细胞存在于包膜并在衬细胞层内或衬细胞层下。常见到大的病灶。 | 3 |
4.血管翳 | |
a.未检出 | 0 |
b.可检出 | 1 |
另外,如下所述,用Mankin′s组织分级***评价关节软骨和骨骼[Mankin等人,Journal of Bone & Joint Surgery-American Volume 53:523-37(1971)]。
类型 | 分级 |
1.结构 | |
a.正常 | 0 |
b.表面不规则 | 1 |
c.血管翳和表面不规则 | 2 |
d.劈开过渡带 | 3 |
e.劈开放射带 | 4 |
f.劈开钙化带 | 5 |
g.完全解体 | 6 |
2.细胞 | |
a.正常 | 0 |
b.弥漫性细胞增殖 | 1 |
c.克隆化 | 2 |
d.细胞过少 | 3 |
3.番红精-O着色 | |
a.正常 | 0 |
b.稍微降低 | 1 |
c.少量降低 | 2 |
d.严重降低 | 3 |
e.无染色指示 | 4 |
4.潮标完整性 | |
a.无损伤 | 0 |
b.被血管交错 | 1 |
表9:Lewis大鼠关节炎症的评价:抑制方法
天 | 载体 | 实施例1av |
1 | 0.00 | 0.00 |
2 | 0.00 | 0.00 |
3 | 4.50 | 2.66 |
4 | 5.50 | 1.83 |
5 | 9.33 | 2.66 |
6 | 10.50 | 2.16 |
7 | 10.60 | 2.00 |
8 | 11.00 | 1.66 |
9 | 11.50 | 2.00 |
10 | 11.33 | 2.00 |
11 | 10.83 | 1.66 |
12 | 10.83 | 1.66 |
13 | 11.00 | 2.16 |
14 | 11.00 | 2.00 |
15 | 11.00 | 2.00 |
16 | 11.00 | 1.00 |
17 | 10.50 | 1.33 |
表10:Lewis大鼠关节炎症的评价:治疗方法
天 | 载体 | 实施例lav |
1 | 10.83 | 11.33 |
2 | 11.00 | 10.83 |
3 | 10.83 | 9.33 |
4 | 11.33 | 8.00 |
5 | 11.50 | 5.83 |
6 | 11.50 | 3.33 |
7 | 11.50 | 3.00 |
8 | 11.50 | 2.50 |
9 | 11.00 | 2.50 |
10 | 11.00 | 2.50 |
11 | 10.66 | 2.50 |
12 | 10.66 | 2.50 |
13 | 10.50 | 2.50 |
14 | 9.83 | 2.50 |
15 | 8.10 | 2.00 |
16 | 7.35 | 1.33 |
17 | 6.50 | 1.00 |
表11:Lewis大鼠跗关节滑膜炎的组织学得分(平均值±SD):治疗方案
组 | 滑膜结构(0-3) | 纤维增生(0-3) | 炎性细胞(0-3) | 血管翳(0-1) | 总滑膜炎得分(0-10) |
载体 | 2.58±0.38 | 1.75±0.42 | 2.92±0.20 | 1.00±0.89 | 8.25±1.57 |
实施例1av10mg/kg | 1.58±0.38* | 0.75±0.42* | 1.25±0.42* | 0.33±0.61* | 3.83±0.93* |
*信号<载体
表12:Lewis大鼠跗关节中软骨变化的组织学损伤(Mankin得分)(平均值±SD):治疗方法
组 | 软骨结构(0-6) | 软骨细胞(0-3) | Saffranin-O坚牢绿完整性(0-4) | 潮标着色(0-1) | 总Mankin得分(0-14) |
载体 | 2.83±0.26 | 2.58±0.38 | 2.50±0.32 | 0 | 7.92±0.74 |
实施例1av10mg/kg | 1.83±0.68* | 0.75±0.42* | 1.25±0.52* | 0 | 3.83±1.21* |
*信号<载体
在关节炎HLA-B27大鼠模型中评价。本发明的化合物可在模拟人关节炎的HLA-B27大鼠标准药理学试验中进行评价。以下简述所用的方法和得到的结果。从Taconic得到雄性HLA-B27大鼠,给其提供无限制的食物(PMI Lab膳食5001)和水。如上述佐剂引起的关节炎Lewis大鼠模型所述,评价关节损伤和组织结构。大鼠(8-10周龄)每天一次口服给予载体(2%吐温80/0.5%甲基纤维素)或实施例1av(10mg/公斤),进行46天。每组有4只大鼠,在处死前2小时给最后一剂。如表(13)所示,通过用实施例1av处理,减轻了关节炎症。此外,还减轻了滑膜炎和Mankin得分(表(14)),但是统计上没有不同于那些用载体处理的大鼠。
表13:用实施例1av口服处理46天的HLA大鼠关节炎症的评价
天 | 载体 | 实施例1av(10mg/kg) |
29 | 2.5 | 0.5 |
30 | 6 | 0.5 |
31 | 5 | 0.5 |
32 | 6.75 | 1 |
33 | 8 | 1.75 |
34 | 8 | 1.5 |
35 | 8 | 1 |
36 | 6 | 1.75 |
37 | 7.5 | 1.75 |
38 | 6.5 | 1.5 |
39 | 7.5 | 0.75 |
40 | 7.5 | 0.75 |
41 | 6.5 | 0.5 |
42 | 6.5 | 1.5 |
43 | 6 | 1.25 |
44 | 6.75 | 1.75 |
45 | 5.5 | 1.25 |
46 | 6 | 0.75 |
表14:用实施例1av口服处理46天的HLA大鼠关节组织学的评价
化合物 | 滑膜炎得分(平均值±SD) | Mankin得分(平均值±SD) |
载体 | 7.6±3.1 | 6.5±1.2 |
实施例lav(10mg/kg) | 5.0±2.5 | 4.5±1.8 |
在体内致癌模型中的评价
本发明化合物治疗和抑制各种恶性肿癌或hyperprolific病症的能力可在从文献容易得到的标准药理学试验法中评价,具体包括下面两个方法。
乳腺癌。从Charles River实验室(Wilmington,MA)获得切除卵巢的无胸腺nu/nu(裸)小鼠。在肿瘤细胞注入前一天,给动物植入缓释颗粒,所述颗粒含有0.36-1.7mg17β-***(60或90天释放,InnovativeResearch of America,Sarasota,FL)或安慰剂。用10-计量精度套针将颗粒皮下引入肩胛内区域。随后,在小鼠***组织中皮下注入1×107MCF-7细胞或1×107BG-1细胞。细胞与等体积的matrigel(一种基膜基料制品)以促进肿瘤的形成。试验化合物可通过在肿瘤细胞移植后一天给药(抑制方案)或者通过在肿瘤达到某个尺寸后给药(处理方案)进行评价。每天在含有1%吐温-80的生理盐水载体中将化合物经腹膜内给药或经口给药。每3天或7天评价肿瘤尺寸。
结肠癌。在Smirnoff试验法中可评价治疗或抑制结肠癌的能力[Oncology Research 11:255-64(1999)]。
在两种体内试验中评价神经保护
蒙古沙鼠中暂时脑局部缺血。用下述试验方法测定试验化合物在防止或治疗由于缺氧/再灌注造成的脑损伤的作用。
雌性蒙古沙鼠(60-80克;Charles River实验室,Kingston,NY)在Wyeth-Ayerst动物养护研究室(AAALAC认证)饲养,采用12小时光照,12-小时黑暗的光周期,可自由饮用自来水和摄取低***酪蛋白膳食(Purina;Richmond,IN)。适应环境后(3-5天),将沙鼠用异氟烷(2-3%与O2的混合物)麻醉,切除卵巢(第0天)。从接下来的早晨开始(第1天),沙鼠每天用载体(10%EtOH/玉米油)、17β-***(1毫克/公斤,sc)或者实验化合物皮下处理。在第6天,用异氟烷麻醉沙鼠(n=4-5/组),用中线颈切割暴露共用的颈动脉干道,将两个动脉同时用无创微脑动脉瘤夹阻断5分钟。在阻断后,移动钳使得大脑再灌注,用创钳关闭颈部切口。在促进稳定缺血性伤害的大脑局部缺血手术前,所有的动物被禁食过夜。在第12天,将沙鼠暴露在致死量的CO2下,将脑在干冰中冷冻并储存在-80℃。评述用于这些研究的动物记录,并通过在Wyeth-AyerstResearch的Radnor/Collegeville Animal Care和Use Committee(RACUC/CACUC)审定。
通过原位杂交分析neurogranin mRNA评价神经元保护程度。简而言之,在涂有明胶的载玻片上聚积20μm冠状cryostat区,干燥并在-80℃储存。在处理的时候,将干贮的载玻片箱升温至室温,将载玻片在4%低聚甲醛中再固定,用乙酸酐处理,然后用氯仿和乙醇脱脂脱水。然后,将被测定的处理后切片的载玻片与200μl(6×106DPM/载玻片)用于Neurogranin(35S-UTP-标记的NG-241;基质99-340)的一种反义核糖探针(riboprobe)或感应(对照物)riboprobe在50%甲酰胺中杂交。杂交混合,然后在55℃,在增湿载玻片室中不加盖片地培养过夜。在接着的早晨,将载玻片收集在搁架上,浸于2x SSC(0.3M NaCl,0.03M柠檬酸钠;pH7.0)/10mM DTT,用核糖核酸酶A处理(20μg/ml),然后在67℃在0.1x SSC中洗涤(2X 30分钟),除去非特异性标记。脱水后,将载玻片与BioMax(BMR-1;Kodak)X线胶片对置过夜。
neurogranin杂交信号水平用来定量评价在损伤后CA1区域神经元损失的程度,以及用于评价17β-***和试验化合物的效果。neurogranin mRNA被选择用于这些研究是因为其在包括海马神经元的CA1中被高度表达,但是在神经胶质和该脑区的其它细胞类型中不存在。因此,neurogranin mRNA存在量的测定值表示了存活的神经元。neurogranin杂交信号的相对光密度测量值用基于计算机图象分析***(C-Imaging Inc.,Pittsburgh,PA)的感光胶片放射自显影图获得。每只动物6个切片的结果(40μm间隔)进行平均,然后进行统计评价。数值报道为平均值±SEM。单向方差分析用来检验neurogranin mRNA水平的差异,在得到的切片中,所有无差异的描述表示为p>0.05。
小鼠大脑中动脉封闭。根据Dubal所述的测试方法可评价神经保护[见,Dubal等人,Proceedings of the National Academy of Sciences of theUnited States of America 98:1952-1957(2001),Dubal等人,Journal ofNeuroscience 19:6385-6393(1999)]。
***抑制标准药理学试验法
该试验法用于确定试验化合物是否可抑制或改变***时间。其还可以用来确定******的数目[Lundeen等人,J Steroid Biochem MolBiol 78:137-143(2001)]。
基于在该标准药理学试验中得到的结果,本发明的化合物是***受体调节剂,用于治疗或抑制的状况、病症或疾病状况至少部分是由于***缺乏或过量引起的,或者是通过使用***剂可治疗或抑制的。本发明的化合物特别用于治疗绝经前、绝经或绝经后的患者,其体内产生的内源***水平大大地减少。绝经期通常定义为最后的天然经期,特征在于卵巢功能的终止,导致了血流中循环***的显著的减少。在这里使用的绝经期同时包括***生成的减少,这可能是由于外科的、化学的或由疾病导致的,这些因素使得卵巢功能过早降低或终止。
本发明的化合物还用于抑制或治疗其它***丧失现象,包括热潮红、***的或外阴萎缩、萎缩性***炎、***干燥、瘙瘁、***疼痛、排尿困难、尿频、尿失禁、***。其它的生殖道用途包括治疗或抑制功能性***。该化合物还用于治疗或抑制子宫内膜异位。
本发明的化合物还在脑部有活性,因此可用于抑制或治疗阿尔茨海默氏病、认知下降、***低下、老年性痴呆、神经变性病症、忧郁症、焦虑、失眠、精神***症和不育。本发明的化合物还适用于治疗或抑制良性的或恶性的异常组织长生,包括肾小球硬化症、***肥大、子宫平滑肌瘤、乳腺癌、硬皮病、纤维瘤病、子宫内膜癌、***、子宫内膜息肉、良性***疾病、子宫内膜异位、卵巢癌、黑瘤、***癌、结肠癌、CNS癌(如神经胶质瘤或astioblastomia)。
本发明的化合物具有心脏保护作用,是抗氧化剂,并且适用于降低胆甾醇、三酸甘油酯、Lp(a)和LDL水平;抑制或治疗血胆甾醇过多、血脂质过多、心血管疾病、动脉粥样硬化、外周血管疾病、再狭窄和血管痉挛,抑制由于细胞间隙导致的、向免疫调节的血管损伤发展的血管壁破坏。
本发明的化合物还适用于治疗与炎症或自身免疫疾病有关的病症,包括炎性肠病(克罗恩氏病、溃疡性结肠炎、不确定的(indeterminate)结肠炎)、关节炎(类风湿性关节炎、脊柱关节炎、骨关节炎)、胸膜炎、局部缺血/再灌注损伤(例如中风、移植排斥反应、心肌梗死等)、哮喘、巨细胞动脉炎、***炎、间质性膀胱炎、眼色素层炎、牛皮癣、多发性硬化、***性红斑狼疮和脓血症。
本发明的化合物还可用于治疗或抑制眼部病症,包括白内障、眼色素层炎和黄斑衰退,并可用于治疗皮肤病症,如老化、脱发和痤疮。
本发明的化合物还可用于治疗或抑制代谢失调,诸如II型糖尿病、脂类代谢失调、食欲失调(例如神经性厌食症和食欲过盛)。
本发明的化合物还用于治疗或抑制出血病症,如遗传性出血性毛细血管扩张症、功能性***以及对抗出血性休克。
本发明的化合物可用于闭经是有利的疾病状态,如白血病、子宫内膜烧蚀、慢性肾病或肝病或凝血疾病或病症。本发明的化合物可用作避孕药,特别是与孕酮结合使用。
当给药用于治疗或抑制特定的疾病状态或病症时,应认为有效剂量可根据所使用的特定化合物、给药模式、条件和疾病严重程度、要治疗的状况以及各种与被治疗个体有关的物理因素变化。可给出的本发明化合物的有效口服给药量是约0.1毫克/天至约1,000毫克/天。优选给药量是约10毫克/天至约600毫克/天,更优选约50毫克/天至约600毫克/天,以单剂给药或分两或多剂给药。设计的日剂量预计随给药途径变化。
这种剂量可以任何适用于将活性化合物引入患者血流的方式给药,包括口服、通过植入给药、非肠道给药(包括静脉内、腹膜内和皮下注射)、直肠给药、鼻内给药、局部给药,眼部给药(使用滴眼剂)、***给药和经皮肤给药。
含有本发明活性化合物的口服配方可包括任何通常所用的口服形式,包括片剂,胶囊,口腔用药剂形式、锭剂、糖锭和口服液体、悬浮液或溶液。胶囊可包括活性化合物和惰性填料和/或稀释剂的混合物,所述的稀释剂是诸如药学可接受的淀粉(例如玉米、马铃薯或木薯淀粉)、糖、人造甜味剂、粉末纤维素(如结晶纤维素和微晶纤维素)、面粉、明胶、树胶等。有用的片剂配方可以通过常规的压片、湿法造粒或干法造粒方法制备,使用药学可接受的稀释剂、粘合剂、润滑剂、崩解剂、表面改性剂(包括表面活性剂)、悬浮或稳定剂,非限制性地包括硬脂酸镁、硬脂酸、滑石、月桂基硫酸钠、微晶纤维素、羧甲基纤维素钙、聚乙烯吡咯烷酮、明胶、藻酸、金合欢胶、黄原胶、柠檬酸钠、复合硅酸盐、碳酸钙、甘氨酸、糊精、蔗糖,山梨醇、磷酸氢钙、硫酸钙、乳糖、高岭土、甘露糖醇、氯化钠、滑石、干淀粉和糖粉。首选的表面改性剂包括非离子和阴离子表面改性剂。表面改性剂的典型实例非限制性地包括泊洛沙姆188、氯化苯甲烃铵、硬脂酸钙、鲸蜡硬脂醇、cetomacrogol乳化蜡、脱水山梨糖醇酯、胶态二氧化硅、磷酸盐、十二烷基磺酸钠、镁铝硅酸盐和三乙醇胺。在此,口服配方可使用标准的延迟或定时释放的配方以改变活性化合物的吸收。口服配方还可构成活性成分在水中或果汁中给药的形式,如果需要,包括合适的增溶剂或乳化剂。
有时可能希望化合物直接以气雾剂的形式给药。
本发明的化合物还可不经肠道给药或在腹膜内给药。这些活性化合物作为游离碱或药学上可接受的盐的溶液或悬浮液可通过在水中适当地与表面活性剂(诸如羟基-丙基纤维素)混合制备。分散液还可在甘油、液体聚乙二醇和其在油中的混合物中制备。在普通的储存和使用条件下,这些制品含有抑制微生物生长的防腐剂。
适用于注射使用的药物形式包括无菌水溶液或分散液以及用于临时配制无菌可注射溶液或分散液的无菌粉末。在所有情况下,所述的形式必须是无菌的,并且必须是液体,从而具有容易注射的特性。其必须在生产和储存条件下稳定,并且必须防腐,以阻止诸如细菌和真菌的微生物的污染。载体可以是溶剂或分散介质,包括例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)或其适合的混合物,以及植物油。
出于公开的目的,认为透皮给药包括全部通过身体表面和身体通道内层(包括上皮组织和粘膜组织)的给药。这种给药可用所述化合物或其药学可接受盐以洗液、霜剂、泡沫剂、贴片、悬浮液、溶液和栓剂形式(直肠用和***用)进行。
透皮给药可以通过使用透皮贴剂实现,所述贴剂包括活性化合物和对活性化合物呈惰性的载体,对皮肤无毒,能够传递药剂,通过皮肤全身吸收进入血流。载体可采用多种形式,诸如霜剂或软膏、糊剂、凝胶剂和封闭装置。霜剂和软膏可以是粘性液体或水包油或油包水形式的半固体乳液。糊剂也是适合的,其由吸附粉末组成,所述粉末分散在含有活性成分的石油产品或亲水性石油产品中。各种封闭装置可用来将活性成分释放到血流中,诸如用半透膜覆盖在盛有含或不含载体的活性成分的容器上,或覆盖在含有活性成分的基料上。其它封闭装置是在文献中已知的。
栓剂配方可由常规材料制造,包括可可脂,添加或不添加蜡以改变栓剂的熔点,还可使用甘油。也可同时使用水溶性的栓剂基质,如各种分子量的聚乙二醇。
本发明典型实施例的的制备描述如下。
路线1中化合物的合成
中间体2
三氟甲磺酸(7-甲氧基-2-萘基)酯
向7-甲氧基-2-萘酚(4.75克,27.27毫摩尔)和吡啶(3.5毫升,44毫摩尔)在200毫升二氯甲烷的0℃溶液中加入三氟甲磺酸酐(10.0克,35毫摩尔)。将溶液缓慢温热至室温并搅拌过夜。将溶液冷却到0℃并与冰水一起搅拌,分解过量的酸酐。加入饱和碳酸氢钠溶液将混合物稍微碱化。分离得到的各层,水层用二氯甲烷(2×250毫升)萃取。将合并的有机层用水洗涤,用硫酸镁干燥,过滤,蒸发溶剂,得到红色的油,将其用二氧化硅色谱法(5%乙酸乙酯-己烷)提纯,得到8.08克(97%)标题化合物,为纯净无色的油。
1H NMR(DMSO-d6)δ3.92(3H,s),7.30(1H,dd,J=2.58Hz,J=8.93Hz),7.42(1H,dd,J=2.59Hz,J=8.93Hz),7.52(1H,d,J=2.38Hz),7.96(1H,d,J=9.12Hz),8.00(1H,d,J=2.38Hz),8.06(1H,d,J=8.73Hz);MS(EI)m/z306(M-)+.
对C12H9F3O4S的分析
计算值:C:47.06 H:2.96
实验值:C:46.62 H:2.84
中间体3
2-甲氧基-7-(4-甲氧苯基)萘
方法A
三氟甲磺酸(7-甲氧基-2-萘基)酯(3.15克,10.3毫摩尔)、4-甲氧基-苯基硼酸(2.2克,14毫摩尔)、碳酸钠(10毫升的2N水溶液)、四(三苯基膦)钯(0.59克,0.05毫摩尔)和100毫升乙二醇二甲醚的混合物加热回流8小时。冷却混合物至室温并倾入100毫升的1N NaOH中。混合物用乙酸乙酯(3×250毫升)萃取,用盐水(2×100毫升)洗涤,用硫酸镁干燥,过滤,蒸发溶剂,用二氧化硅色谱法(5%-10%乙酸乙酯-己烷)提纯,得到2.17克(79%)标题化合物,为白色固体:
mp 154℃;1H NMR(CDCl3):δ3.87(3H,s),3.94(3H,s),7.02(2H,d,J=8.72Hz),7.13(1H,dd,J=2.54Hz,J=9.09Hz),7.18(1H,d,J=2.55Hz),7.56(1H,dd,J=1.82Hz,J=8.36Hz),7.65(2H,d,J=8.72Hz),7.74(1H,d,J=9.09Hz),7.81(1H,d,J=8.36Hz),7.89(1H,d,J=1.09Hz);MS(EI)m/z264(M-).
对C18H16 2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.78 H:6.17
中间体4
2-甲氧基-7-(3-甲氧苯基)萘
根据上述方法A,通过三氟甲磺酸7-甲氧基-2-萘基酯(2.20克,7.18毫摩尔)与3-甲氧基苯基硼酸(1.20克,7.90毫摩尔)反应制备标题化合物,得到白色固体:
mp 58-59℃;1H NMR(CDCl3):δ3.89(3H,s),3.93(3H,s),6.91-6.94(1H,m),7.15(1H,dd,J=2.42Hz,J=8.83Hz),7.191H,d,J=2.27Hz),7.23-7.25(1H,m),7.28-7.31(1H,m),7.37-7.42(1H,m),7.59(1H,dd,J=1.56Hz,J=8.46Hz),7.75(1H,d,J=8.84Hz),7.83(1H,d,J=8.45Hz),7.94(s1H,s);MS(ESI)m/z265(M+H)-.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.61 H:5.99
中间体5
2-甲氧基-7-苯基萘根据上述方法A,通过三氟甲磺酸7-甲氧基-2-萘基酯(3.01克,9.83毫摩尔)与苯基硼酸(1.4克,12毫摩尔)反应制备标题化合物,得到1.95g(85%)白色固体:
mp 62-64℃;1H NMR(CDCl3)δ3.95(3H,s),7.15(1H,dd,J=2.56Hz,J=8.79Hz),7.20(1H,d,J=2.56Hz),7.36-7.39(1H,m),7.46-7.50(2H,m),7.60(1H,dd,J=1.83Hz,J=8.42Hz),7.70-7.73(2H,m),7.76(1H,d,J=8.79Hz),7.84(1H,d,J=8.42Hz),7.94(1H,d,J=1.46Hz);MS(EI)m/z 234(M-)+.
对C17H14O·0.1H2O的分析:
计算值:C:86.48 H:6.06
实验值:C:86.29 H:6.04
实施例1a
7-(4-羟基苯基)-2-萘酚
方法B
2-甲氧基-7-(4-甲氧基-苯基)萘(1.02克,3.86毫摩尔)在190℃加入到盐酸吡啶鎓(10g)中。溶液在190℃搅拌3小时,然后冷却至室温,与200毫升的1N HCl一起搅拌。过滤得到的悬浮液,溶于乙酸乙酯(500毫升)。合并的有机层用水(200毫升)洗涤,用硫酸镁干燥,过滤,在真空下除去溶剂,产品用二氧化硅色谱法(40%乙酸乙酯-己烷)提纯,得到0.36克(39%)白色固体:
mp 210℃;1HNMR(DMSO-d6):δ6.89(2H,d,J=8.58Hz),7.05(1H,dd,J=2.42Hz,J=8.77Hz),7.17(1H,d,J=2.24Hz),7.52(1H,dd,J=1.68Hz,J=8.40Hz),7.61(2H,d,J=8.58Hz),7.74(1H,d,J=8.58Hz),7.79(1H,d,J=8.58Hz),7.86(1H,d,J=1.12Hz),9.60(1H,bs),9.72(1H,bs);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:81.23 H:5.09
实施例1b
7-(3-羟基苯基)-2-萘酚
根据方法B,通过2-甲氧基-7-(3-甲氧苯基)-萘(0.52克,1.97毫摩尔)与盐酸吡啶鎓(8克)在190℃反应,得到0.13克(28%)白色固体:
mp 163-165℃;1H NMR(DMSO-d6):δ6.78-6.80(1H,m),7.08(1H,dd,J=2.56Hz,J=8.54Hz),7.13-7.14(1H,m),7.17-7.20(2H,m),7.27-7.30(1H,m),7.51(1H,dd,J=2.14Hz,J=8.54Hz),7.70(1H,d,J=8.97Hz),7.83(1H,d,J=8.54Hz),7.90(1H,d,J=1.28Hz),9.55(1H,s),9.78(1H,s);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:80.96 H:5.07
实施例1c
7-苯基-2-萘酚
根据方法B,通过2-甲氧基-7-苯基萘(0.53克,2.26毫摩尔)与盐酸吡啶鎓(10克)在190℃反应,得到0.36克(72%)白色固体:
mp 142-143℃;1H NMR(DMSO-d6):δ7.10(1H,dd,J=2.75Hz,J=8.70Hz),7.23(1H ,d,J=2.29Hz),7.37-7.40(1H,m),7.48-7.51(2H,m),7.58(1H,dd,J=1.83Hz,8.70Hz),7.78-7.90(3H,m),7.86(1H,d,J=8.24Hz),7.99(1H,d,J=0.92Hz)9.81(1H,s);MS(ESI)m/z 219(M-H)-.
对C16H12O·0.1H2O的分析:
计算值:C:86.66 H:5.47
实验值:C:86.72 H:5.62
路线2中化合物的合成
中间体6
6-(三氟甲烷磺酸盐)-1-四氢萘酮
在500毫升烧瓶中,6-羟基-1-四氢萘酮(4.8克,29.6毫摩尔)与二甲苯共沸,溶于无水CH2Cl2(220毫升)。然后将溶液冷却到0℃,加入无水吡啶(3.35毫升,41.4毫摩尔),再加入三氟甲磺酸酐(10.0克,35.5毫摩尔)。在0℃0.5小时后,反应用饱和碳酸氢钠淬灭,并用水洗涤。将有机层通过硅塞,浓缩得到8.39克(96%)产物,为浅黄色油:
1H NMR(300MHz,DMSO-d6)δ2.07(2H,m),2.65(2H,t,J=6.5Hz),3.03(2H,t,J=6.0Hz),7.47(1H,dd,J=8.7Hz,2.3Hz),7.57(1H,d,J=1.9Hz),8.03(1H,d,J=8.7Hz).
中间体7
6-(4-羟基苯基)-1-四氢萘酮
4-{[叔丁基(二甲基)甲硅烷基]氧基}苯基硼酸。在500毫升烧瓶中加入(4-溴代苯氧基)-叔丁基二甲基硅烷(15.0克,52.2毫摩尔)和无水THF(125毫升)。将混合物冷却至-78℃,用注射器缓慢加入正丁基锂(25毫升在己烷中2.5M的溶液,62.7毫摩尔)。在搅拌0.5小时后,加入三异丙基硼酸酯(60毫升,261毫摩尔),溶液在-78摄氏搅拌1.5小时,然后温热至室温。然后加入冰冷的2N HCl(150毫升),搅拌混合物10分钟。然后用乙酸乙酯(3x)萃取混合物,用硫酸钠干燥,减压浓缩至大约50毫升。将己烷加入到浓缩物中诱导结晶(3批),然后通过过滤收集,在真空下干燥,得到12.36克(89%)黄白色固体:
1H NMR(300MHz,DMSO-d6)δ0.19(6H,s),0.95(9H,s),6.80(2H,d,J=8.1Hz),7.67(2H,d,J=8.1Hz).
在500毫升烧瓶中加入6-(三氟甲烷磺酸盐)-1-四氢萘酮(5.0克,17.0毫摩尔)、4-{[叔丁基(二甲基)甲硅烷基]氧基}苯基硼酸(5.45克,20.4毫摩尔,如上制备)、碳酸钠(4.56克,2N水溶液,42.5毫摩尔)和在DME(200毫升)中的四(三苯基膦)钯(0)(0.98克,0.85毫摩尔),回流12小时。将反应冷却,用乙酸乙酯(3x)萃取,浓缩得到固体。固体用己烷洗涤,在真空下干燥,得到3.68克产物(92%)棕色固体。
mp 208-210℃;1HNMR(300MHz,DMSO-d6)δ2.06(2H,m),2.60(2H,t,J=6.5Hz),2.99(2H,t,J=5.9Hz),6.87(2H,d,J=8.6Hz),7.57(4H,m),7.86(1H,d,J=8.7Hz),9.74(1H,s);MSm/z237(M-H+);
对C16H14O2:的分析:
计算值:C:80.65 H:5.92
实验值:C:79.04 H:5.60
实施例1d
6-(4-羟基苯基)-1-萘酚
向25毫升烧瓶中加入6-(4-羟基苯基)-1-四氢萘酮(500毫克,2.12毫摩尔)、披钯碳(510毫克)和对异丙基苯甲烷(15毫升)。混合物加热回流24小时,冷却,用硅藻土过滤,用1M NaOH(2×25毫升)萃取。然后酸化水层,用***(3x)萃取,通过硅塞。减压浓缩,得到260毫克(53%)产品,为棕色固体:
mp高于200℃(dec.);1H NMR(300MHz,DMSO-d6)δ6.82(1H,d,J=7.5Hz),6.87(2H,d,J=8.1Hz),7.29(1H,t,J=7.5Hz),7.38(1H,d,J=7.5Hz),7.63(2H,d,J=8.2Hz),7.70(1H,d,J=8.5Hz),7.99(1H,s)8.14(1H,d,J=8.5Hz),9.59(1H,s),10.09(1H,s);MS m/z 235(M-H+).
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:81.22 H:5.30
路线3中化合物的合成
中间体10
2-甲氧基-7-(4-甲氧苯基)萘
向2-溴-6-甲氧基萘(23.79克,100.3毫摩尔)和四(三苯基膦)钯(5.8克,5毫摩尔)的混合物中加入4-甲氧基苯基溴化镁在THF中的溶液(400毫升的0.5N溶液,200毫摩尔)。搅拌的溶液加热回流3小时,冷却到室温,然后在200毫升的1N HCl中搅拌。混合物用二氯甲烷萃取,通过短的硅塞和二氯甲烷一起过滤。除去溶剂得到粗黄色固体,将其进一步用二氧化硅色谱法提纯(20-50%乙酸乙酯-己烷),得到25.68克(97%)标题化合物白色固体:mp190℃;1H NMR(CDCl3):δ3.86(3H,s),3.93(3H,s),7.01(2H,d,J=8.57Hz),7.14-7.18(2H,m),7.63(2H,d,J=8.50Hz),7.67(1H,dd,J=1.68Hz,J=8.73Hz),7.76-7.80(2H,m),7.91(1H,d,J=0.94Hz);MS(ESI)m/z 265(M+H)+.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:82.04 H:6.17
中间体11
2-(4-甲氧苯基)萘
通过2-溴萘(3.04克,14.7毫摩尔)和4-甲氧基苯基溴化镁根据制备中间体10所用的方法反应制备标题化合物,得到2.89克(89%)白色固体:
mp 114℃;1H NMR(CDCl3):δ3.86(3H,s),7.01(2H,d,J=9.06Hz),7.43-7.50(2H,m),7.65(2H,d,J=8.73Hz),7.71(1H,dd,J=1.84Hz,J=8.56Hz),7.83-7.89(3H,m),7.98(1H,d,J=0.67Hz);MS(EI)m/z234(M-)+.
对C17H14O的分析:
计算值:C:87.15 H:6.02
实验值:C:86.75 H:6.14
中间体12
2-甲氧基-6-苯基萘
通过2-溴-6-甲氧基萘(1.97克,8.31毫摩尔)和苯基溴化镁根据制备中间体10所用的方法反应制备标题化合物,得到1.59克(82%)白色固体:
mp 122-126℃;1HNMR(CDCl3):δ3.94(3H,s),7.16-7.18(2H,m),7.34-7.37(1H,m),7.46-7.49(2H,m),7.69-7.72(2H,m),7.78-7.82(2H,m),7.97(1H,s);MS(EI)m/z 234.2(M-)+.
对C17H14O的分析:
计算值:C:87.15 H:6.02
实验值:C:86.79 H:6.14
中间体13
2-甲氧基-6-(3-甲氧苯基)萘
通过6-甲氧基-2-溴萘(3.09克,13.0毫摩尔)和3-甲氧基苯基硼酸(2.18克,14.3毫摩尔)根据方法A反应制备标题化合物,得到1.18克(34%)白色固体:
mp 80℃;1H NMR(CDCl3):δ3.88(3H,s),3.92(3H,s),6.90(1H,dd,J=2.17Hz,J=7.76Hz),7.14-7.18(2H,m),7.22-7.24(1H,m),7.28(1H,d,J=7.45Hz),7.36-7.39,(1H,m),7.70(1H,dd,J=1.86Hz,J=8.70Hz),7.77-7.80(2H,m),7.96(1H,d,J=1.24Hz);MS(ESI)m/z265(M+H)+.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.61 H:6.47
实施例1i
6-(3-氯苯基)-2-萘酚
6-溴-2-萘酚(1.78克,8.0毫摩尔)、2-氯苯基硼酸(1.5克,9.6毫摩尔)、碳酸钠(2.11g的2N水溶液,20.0毫摩尔)和四(三苯基膦)钯(0)(550毫克,0.48毫摩尔)在DME中(95毫升)的混合物根据方法A反应。柱色谱(30%乙酸乙酯-己烷)得到520毫克(26%)的产品,为黄褐色固体:
mp 116-118℃;1H NMR(300MHz,DMSO-d6)δ7.13(2H,m),7.42(1H,td,J=7.9Hz,0.9Hz),7.51(1H,t,J=7.6Hz),7.80(5H,m),8.16(1H,s),9.88(1H,s);MS m/z 253/255(Cl pattern)(M-H+);
对C16H11ClO的分析:
计算值:C:75.45 H:4.35
实验值:C:75.20 H:4.34
实施例1e
6-(4-羟基苯基)-2-萘酚
根据方法B,将2-甲氧基-6-(4-甲氧苯基)萘(5.61g,21.2毫摩尔)在190℃加入盐酸吡啶鎓(30克)中,得到4.88克(98%)白色固体:
mp>220(大于200℃失色);1H NMR(DMSO-d6):δ6.87(2H,d,J=8.54Hz),7.08(1H,dd,J=2.34Hz,J=8.76Hz),7.11(1H,d,J=2.14Hz),7.58(2H,d,J=8.54Hz),7.65(1H,dd,J=1.92Hz,J=8.76Hz),7.71(1H,d,J=8.54Hz),7.79(1H,d,J=8.97Hz),7.95(1H,s),9.56(1H,bs),9.70(1H,bs);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:81.05 H:5.18
实施例1f
4-(2-萘基)酚
根据方法B,在190℃,通过2-(4-甲氧苯基)-萘(1.01克,4.31毫摩尔)和10g盐酸吡啶鎓反应制备标题化合物,得到0.84克(89%)白色固体:
mp 148℃;1H NMR(DMSO-d6):δ6.92(2H,d,J=8.71Hz),7.46-7.53(2H,m),7.66(2H,d,J=8.71Hz),7.79(1H,dd,J=1.78Hz,J=8.51Hz),7.90(1H,d,J=8.31Hz),7.95(2H,d,J=8.31Hz),8.11(1H,d,J=1.19Hz),9.65(1H,s);MS(ESI)m/z219(M-H)-.
对C16H12O2的分析:
计算值:C:87.25 H:5.49
实验值:C:87.31 H:5.86
实施例1g
6-苯基-2-萘酚
根据方法B,在190℃通过2-甲氧基-6-苯基萘(0.54克,2.30毫摩尔)和盐酸吡啶鎓(10g)反应制备标题化合物,得到0.32克(63%),为浅粉色固体:
mp 169-170℃;1H NMR(DMSO-d6):δ7.12(1H,dd,J=2.56Hz,J=8.54Hz),7.16(1H,d,J=2.56Hz),7.35-7.38(1H,m),7.47-7.50(2H,m),7.73(1H,dd,J=1.71Hz,J=8.54Hz),7.76-7.79(3H,m),7.85(1H,d,J=8.54Hz),8.08(1H,d,J=1.28Hz),9.82(1H,s);MS(ESI)m/z 219(M-H)-.
对C16H12O的分析:
计算值:C:87.25 H:5.49
实验值:C:87.05 H:5.55
实施例1h
6-(3-羟基苯基)-2-萘酚
根据方法B,在190℃,通过2-甲氧基-6-(3-甲氧苯基)-萘(0.51克,1.90毫摩尔)和盐酸吡啶鎓(6克)反应制备标题化合物,得到0.21克(47%)的米色固体:
mp 192-194℃;1H NMR(DMSO-d6):δ6.75-6.78(1H,m),7.10-7.14(3H,m),7.16-7.18(1H,m),7.65(1H,dd,J=1.79Hz,J=8.57Hz),7.75(1H,d,J=8.77Hz),7.84(1H,d,J=8.77Hz),8.01(1H,d,J=1.59Hz),9.51(1H,s),9.78,(1H,s);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:80.94 H:5.09
路线4中化合物的合成
中间体14
1-溴-2-甲氧基-6-(4-甲氧苯基)萘
向2-甲氧基-6-(4-甲氧苯基)萘(9.68克,36.6毫摩尔)和冰醋酸(150毫升)的混合物中缓慢加入溴(5.85g,36.6毫摩尔)在冰醋酸(20毫升)中的溶液。混合物搅拌1小时,得到的悬浮液倾入水(200毫升)中,过滤收集固体产物。固体首先与水一起研磨,然后和乙酸乙酯一起研磨,得到11.25克(90%)标题化合物白色固体:
mp 172-174℃;1H NMR(CDC13):δ3.88(3H,s),4.05(3H,s),7.04(2H,d,J=8.56Hz),7.30(1H,d,J=9.01Hz),7.67(2H,d,J=8.65Hz),7.81(1H,dd,J=1.61Hz,J=8.84Hz),7.87(1H,d,J=9.04Hz),7.94(1H,d,J=1.47Hz),8.27(1H,d,J=8.92Hz);MS(EI)m/z 343(M)+.
对C18H15BrO2的分析:
计算值:C:62.99 H:4.41
实验值:C:62.66 H:4.57
中间体15
1-氯-2-甲氧基-6-(4-甲氧苯基)萘
方法C
2-甲氧基-6-(4-甲氧苯基)萘(0.51克,1.93毫摩尔)和NCS(0.28克,2.13毫摩尔)在乙腈(20毫升)中的悬浮液加热回流3小时。得到的溶液冷却到室温,过滤收集得到的固体,用乙腈冲洗,得到0.41g(72%)标题化合物,为白色固体:
mp 158-164℃;1H NMR(CDCl3):δ3.87(3H,s),4.05(3H,s),7.03(2H,d,J=8.62Hz),7.32(1H,d,J=9.02Hz),7.65(2H,d,J=8.55Hz),7.82(2H,d,J=9.01Hz),7.95(1H,d,J=1.36Hz),8.27(1H,d,J=8.81Hz);MS(EI)m/z 298(M-)+.
对C18H15ClO2的分析:
计算值:C:72.36 H:5.06
实验值:C:72.06 H:4.89
实施例1o
1-溴-6-(4-羟基苯基)-2-萘酚
在0℃向6-(4-羟基苯基)-2-萘酚(4.02克,17.0毫摩尔)在乙腈(150毫升)中的溶液中加入NBS(3.03克,17.0毫摩尔)。反应在0℃搅拌3小时,然后倾入水(200毫升)中,用乙酸乙酯(3×300毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,用二氧化硅柱色谱(20%乙酸乙酯-己烷)提纯,得到5.33克(100%)标题化合物,为黄褐色固体。进一步用逆向高压液相色谱法提纯标题化合物,得到白色固体:
mp 208-210℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.47Hz),7.28(1H,d,J=8.80Hz),7.63(2H,d,J=8.50Hz),7.85(2H,d,J=8.84Hz),8.02-8.06(2H,m),9.60(1H,s),10.54(1H,s);MS(ESI)m/z 313/315(M-H)-.
对C16H11BrO2的分析:
计算值:C:60.98 H:3.52
实验值:C:60.63 H:3.46
实施例1p
1-氯-6-(4-羟基苯基)-2-萘酚
根据方法B,在190℃,通过1-氯-2-甲氧基-6-(4-甲氧苯基)-萘(0.32克,1.07毫摩尔)和盐酸吡啶鎓(7g)反应制备标题化合物,得到0.12克(41%)的米色固体:
mp 222-224℃(dec.);1H NMR(DMSO-d6):δ6.88(2H,d,J=8.46Hz),7.29(1H,d,J=8.88Hz),7.63(2H,d,J=8.50Hz),7.81-7.88(2H,m),8.02-8.08(2H,m),9.59(1H,s),10.43(1H,s);MS(ESI)m/z 269/271(M-H)-.
对C16H11ClO2:的分析:
计算值:C:70.99 H:4.10
实验值:C:70.59 H:4.12
实施例1q
6-(4-羟基苯基)-1-甲氧基-2-萘酚
1-溴-6-(4-羟基苯基)-2-萘酚(0.41克,1.30毫摩尔)、CuBr(0.19克,0.13毫摩尔)、甲醇钠(3毫升4.4N在甲醇中的溶液)和DMF(6毫升)的混合物加热回流3小时。将反应混合物冷却至室温,倾入HCl(50毫升的1N水溶液),用乙酸乙酯(3×100毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,脱去溶剂,用二氧化硅柱色谱提纯(40%乙酸乙酯-己烷),得到0.31克(89%)标题化合物白色固体:
mp 204-206℃;1H NMR(DMSO-d6):δ6.88(2H,d,J=8.47Hz),7.19(1H,d,J=8.81Hz),7.57-7.60(3H,m),7.71(1H,dd,J=1.41Hz,J=8.78Hz),7.94-7.98(2H,m),9.54(2H,s);MS m/z(M-H)-=265;
对C17H14O3的分析:
计算值:C:76.68 H:5.30
实验值:C:76.46 H:5.13
路线5中化合物的合成
中间体16
2-甲氧基-6-(4-甲氧苯基)-1-氟萘
在-78℃向2-甲氧基-6-(4-甲氧苯基)-1-溴萘(1.28克,3.72毫摩尔)在THF(25毫升)中的溶液中缓慢加入正丁基锂(1.9毫升2.5N的在己烷中的溶液)得到的溶液在-78℃搅拌30分钟,加入N-氟苯磺酰亚胺(1.40克,4.5毫摩尔)在THF(10毫升)中的溶液。在-78℃再过2小时后,反应升温至室温,倾入水中,用乙酸乙酯(2×250毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,用二氧化硅色谱法(5%THF-己烷)提纯,得到0.66克(63%)的白色固体:
mp 150-155℃;1H NMR(CDCl3):δ3.88(3H,s),4.04(3H,s),7.02(2H,d,J=8.69Hz),7.28-7.34(1H,m),7.62-7.67(3H,m),7.74(1H,dd,J=1.60Hz,J=8.79Hz),7.93(1H,s),8.09(1H,d,J=8.77Hz).
对C18H15O2F的分析:
计算值:C:76.58 H:5.36
实验值:C:75.78 H:5.95
中间体17
2-甲氧基-6-(4-甲氧苯基)-1-萘甲腈
1-溴-2-甲氧基-6-(4-甲氧苯基)萘(0.76克,2.21克)、CuCN(0.24克,2.66毫摩尔)和DMF(10毫升)的混合物在120℃搅拌4小时。反应混合物冷却至室温,用乙酸乙酯制浆,通过二氧化硅过滤,蒸发溶剂,用二氧化硅柱色谱(20%乙酸乙酯-己烷)提纯,得到0.19g(30%)标题化合物,为浅黄固体:
1H NMR(CDCl3):δ3.88(3H,s),4.09(3H,s),7.03(2H,d,J=8.73Hz),7.29(1H,d,J=9.12Hz),7.63(2H,d,J=8.73Hz),7.88(1H,dd,J=1.98Hz,J=8.73Hz),7.97(1H,d,J=1.98Hz),8.09(1H,d,J=9.12Hz),8.14(1H,d,J=8.73Hz).
对C19H15O2N的分析:
计算值:C:78.87 H:5.23 N:4.84
实验值:C:79.06 H:7.27 N:2.91
中间体18
2-甲氧基-6-(4-甲氧苯基)-1-苯基萘
向2-甲氧基-6-(4-甲氧苯基)-1-溴萘(0.80克,2.33毫摩尔)和四(三苯基膦)钯(0.13克,0.12毫摩尔)在THF(10毫升)中的混合物中加入苯基溴化镁(2.2毫升3N在***中的溶液)。反应混合物在回流下搅拌过夜,冷却至室温,倾入1N盐酸中(100毫升),用乙酸乙酯(3×200毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸镁干燥,过滤,蒸发溶剂,通过二氧化硅柱色谱(10%乙酸乙酯-己烷)提纯,得到0.42克(53%)灰色固体:
mp 157-160℃;1HNMR(CDCl3):δ3.85(3H,s),3.87(3H,s),7.01(2H,d,J=8.64Hz).7.38-7.46(4H,m),7.49-7.57(4H,m),7.64(2H,d,J=8.64Hz),7.92(1H,d,J=9.05Hz),7.97(1H,s);MS(ESI)m/z 341(M+H)+.
对C24H20O2·0.5H2O的分析:
计算值:C:82.50 H:6.06
实验值:C:82.60 H:5.66
中间体19
2-甲氧基-6-(4-甲氧苯基)-1-甲基萘
向2-甲氧基-6-(4-甲氧苯基)-1-溴萘在THF(25毫升)中的溶液中在0℃缓慢加入正丁基锂(2ml,2.5N)和TMEDA(0.60克,5.13毫摩尔,新从KOH蒸馏得到)。在0℃30分钟后,加入碘代甲烷(7.3克,51.3毫摩尔,通过碱性三氧化二铝),搅拌溶液使其升温至室温过夜。将反应物倾入水(100毫升)中,用乙酸乙酯(3×200毫升)萃取。合并的有机层用水洗涤,用硫酸镁干燥,过滤,蒸发溶剂,通过二氧化硅柱色谱(5%THF-己烷)提纯,得到0.63克(88%)白色固体:
mp 136-138℃;1H NMR(CDCl3):δ3.87(3H,s),3.96(3H,s),7.02(2H,d,J=8.74Hz),7.29(1H,d,J=9.01Hz),7.60-7.80(4H,m),7.95(1H,d,J=1.76Hz),8.00(1H,d,J=8.86Hz);MS(ESI)m/z279(M+H)+.
对C19H18O2·0.3H2O的分析:
计算值:C:80.43 H:6.61
实验值:C:80.20 H:6.33
实施例1r
1-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过2-甲氧基-6-(4-甲氧苯基)-1-氟萘(0.250克,0.886毫摩尔)与三溴化硼(2.7毫升1N溶液,2.7毫摩尔)反应制备标题化合物,得到0.13克(15%)白色固体:
mp219-224℃;1H NMR(DMSO-d6):δ(6.89(2H,d,J=8.49Hz),7.22-7.28(1H,m),7.61(2H,d,J=8.53Hz),7.65(1H,d,J=9.12Hz),7.79(1H,d,J=8.77Hz),7.92(1H,d,J=8.73Hz),8.05(1H,s),9.63(1H,bs),10.00(1H,bs);MS(ESI)m/z253(M-H)-.
对C16H11FO2:的分析:
计算值:C:75.58 H:4.36
实验值:C:75.13 H:4.40
实施例1s
2-羟基-6-(4-羟基苯基)-1-萘甲腈
根据方法D,通过2-甲氧基-6-(4-甲氧苯基)-萘甲腈(0.115g,0.397毫摩尔)与盐酸吡啶鎓(4g)在190℃反应,得到0.025g(24%)棕褐色固体:
mp>220℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.37Hz),7.28(1H,d,J=9.07Hz),7.63(2H,d,J=8.42Hz),7.88-7.98(2H,m),8.12-8.16(2H,m),9.63(1H,s),11.65(1H,bs);MS(ESI)m/z260(M-H)-
对C17H11NO2·0.4H2O的分析:
计算值:C:76.05 H:4.43 N:5.22
实验值:C:76.09 H:4.25 N:4.83.
实施例1t
6-(4-羟基苯基)-1-苯基-2-萘酚
方法D
向2-甲氧基-6-(4-甲氧苯基)-1-苯基萘(0.36克,1.06毫摩尔)在CH2Cl2(25毫升)中的混合物中在0℃缓慢加入三溴化硼(3.2毫升,1N在CH2Cl2中的溶液)。将混合物温热至室温并搅拌过夜。将得到的溶液倾入水(100毫升)中,用乙酸乙酯(3×150毫升)萃取。合并的有机层用饱和碳酸氢钠溶液洗涤,用硫酸镁干燥,蒸发溶剂,通过二氧化硅柱色谱(25%乙酸乙酯-己烷)提纯,然后用制备逆相HPLC法提纯,在真空下在105℃干燥,得到0.14克(42%)标题化合物,为白色固体:
mp 142-146℃;1H NMR(DMSO-d6):δ6.86(2H,d,J=8.50Hz),7.26-7.42(5H,m),7.48-7.61(5H,m),7.84(1H,d,J=8.96Hz),8.02(1H,d,J=1.46Hz),9.52(2H,s);MS(ESI)m/z 311(M-H)-.
对C22H16O2·0.1H2O的分析:
计算值:C:84.11 H:5.20
实验值:C:83.90 H:5.15
实施例1u
6-(4-羟甲基)-1-甲基-2-萘酚
根据方法D,通过2-甲氧基-6-(4-甲氧苯基)-1-甲基萘(0.35克,1.26毫摩尔)与三溴化硼(3.8毫升1N溶液,3.8毫摩尔)反应制备标题化合物,得到0.15克(48%)白色固体:
mp>170℃(dec.);1H NMR(DMSO-d6):δ2.42(3H,s),6.87(2H,k d,J=8.33Hz),7.15(1H,d,J=8.81Hz),7.59(2H,d,J=8.35Hz),7.65(1H,d,J=8.93Hz),7.71(1H,dd,J=1.24Hz,J=8.90Hz),7.88(1H,d,J=8.87Hz),7.95(1H,s),9.49(1H,s),9.52(1H,s);MS(ESI)249 m/z(M-H)-.
对C17H14O2的分析:
计算值:C:81.58 H:5.64
实验值:C:81.15 H:5.58
路线6中化合物的合成
中间体27
叔丁基[(6-溴-2-萘基)氧基]二甲基甲硅烷
方法E
向6-溴-2-萘酚(13.68克,61.33毫摩尔)和TBDMS-Cl(11.09克,73.6毫摩尔)在DMF(50毫升)中的溶液中加入咪唑(10.2克,150毫摩尔)。将溶液搅拌3小时,与碳酸氢钠溶液(250毫升)混合,用50%乙酸乙酯-己烷(3×250毫升)萃取。合并的有机层用水洗涤,用硫酸镁干燥,过滤,然后蒸发溶剂,得到棕褐色的油,其在真空下干燥,得到19.92g(97%)标题化合物,为白色固体:
1H NMR(CDCl3):δ0.24(6H,s),1.01(9H,s),7.08(1H,dd,J=2.26Hz,J=8.81Hz),7.14(1H,d,J=2.15Hz),7.46(1H,dd,J=1.80Hz,J=8.77Hz),7.54(1H,d,J=8.77Hz),7.61(1H,d,J=8.81Hz),7.90(1H,s);MS(EI)m/z 336/338(M-)+.
对C16H21BrO1Si·0.25H2O的分析:
计算值:C:56.97 H:6.27
实验值:C:56.81 H:6.43
中间体22
叔丁基(4-溴-2,6-二氟-苯氧基)二甲基甲硅烷
根据方法E,通过4-溴-2,6-二氟-酚(10.54克,50.4毫摩尔)与TBDMS-Cl(9.88克,150.7毫摩尔)反应制备标题化合物,得到14.61克(90%)的一种清澈无色的油:
1H NMR(CDCl3)δ0.17(6H,s),0.99(9H,s),7.02(H,d.J=7.13Hz).
中间体28
叔丁基[(2-(6-萘基硼酸)氧基]二甲基甲硅烷
方法F
向叔丁基[(6-溴-2-萘基)氧基]二甲基甲硅烷(19.18克,56.9毫摩尔)在THF(200毫升)中的溶液中在-78℃缓慢加入正丁基锂(25毫升,2.5N在己烷中的溶液)。搅拌溶液30分钟,然后加入三异丙基硼酸酯(53.5克,285毫摩尔)。在-78℃搅拌溶液1小时,然后升温至室温过夜。然后冷却溶液至0℃,与盐酸(200毫升1N溶液)一起搅拌10分钟。混合物用乙酸乙酯(3×250毫升)萃取。合并的有机层浓缩到25毫升体积。用己烷引导结晶,过滤收集固体产物,在真空下干燥,得到13.5克(79%)标题化合物,为米色固体:
1H NMR(DMSO-d6):δ0.25(6H,s),0.99(9H,s),7.10(1H,dd,J=2.56Hz.J=8.97Hz),7.26(1H,d,J=2.56Hz),7.73(1H,d,J=8.54Hz),7.82(1H,dd,J=1.07Hz,J=8.33Hz),7.83(1H,d,J=8.97Hz),8.30(1H,s);MS(ESI)m/z 303(M+H)+.
对C16H23BO3Si的分析:
计算值:C:63.58 H:7.67
实验值:C:46.97 H:6.78
中间体29
3-氟-4-甲氧基苯基硼酸
根据方法F,通过4-溴-2-氟茴香醚(10克,0.049摩尔)与正丁基锂(23.4毫升,2.5M在己烷中的溶液,0.059摩尔)反应,然后与三异丙基硼酸酯(45.2毫升,36.9g,0.196摩尔)反应制备标题化合物,得到7.1克(85.2%)白色固体:
MS(ESI)m/z 169(M-H)-:1H NMR(DMSO-d6):δ3.84(3H,s),7.10-7.16(1H,m),7.51-7.60(2H,m).
中间体30
3,5-二氟-4-叔丁基二甲基甲硅烷氧基硼酸
根据方法F,叔丁基(4-溴-2,6-二氟-苯氧基)二甲基甲硅烷(12.98克,40.19毫摩尔)与正丁基锂(27.6毫升,1.6N溶液,44.2毫摩尔)反应,然后与三异丙基硼酸酯(37.8克,200毫摩尔)反应制备标题化合物,得到4.38克(38%)白色固体:
1H NMR(DMSO-d6):δ0.25(6H,s),1.06(9H,s),7.54(2H,d,J=7.93Hz).
中间体31
4-甲氧基-2-甲基苯基硼酸
根据方法F,通过4-溴-3-甲基茴香醚(10克,0.050摩尔)与正丁基锂(24毫升2.5M在己烷中的溶液,0.055摩尔)反应,然后与三异丙基硼酸酯(57.7毫升,47.02g,0.25摩尔)反应制备标题化合物,得到5.7克(69%)白色固体:MS(ESI)m/z 313(2M-H2O-H)-.
中间体33
2-(3-氟-4-甲氧苯基)萘
根据方法A,通过2-溴萘(0.31克,1.50毫摩尔)与3-氟-4-甲氧基苯基硼酸(0.31克,1.80毫摩尔)反应制备标题化合物,得到0.30克(79%)白色固体:
mp 108-110℃;1H NMR(CDCl3):δ(3.96,3H,s),7.04-7.10(1H,m),7.43-7.52(4H,m),7.68(1H,dd,J=1.81Hz,J=8.57Hz),7.84-7.92(3H,m),7.97(1H,d,J=1.05Hz).
对C17H13FO的分析:
计算值:C:80.93 H:5.19
实验值:C:81.01 H:4.78
实施例1ay
6-(3,5-二氟-4-羟基苯基)-2-萘酚
根据方法A,通过6-溴-2-萘酚(0.165克,0.74毫摩尔)与3,5-二氟-4-叔丁基二甲基甲硅烷氧基硼酸(0.25克,0.87毫摩尔)反应制备标题化合物,得到0.14克(70%)棕褐色固体该原料进一步通过制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 216-220℃;1H NMR(DMSO-d6):δ7.09-7.13(2h,m),7.50(2H,d,J=10.00Hz),7.73(2H,s),7.78(1H,d,J=8.58Hz),8.10(1H,s),9.83(1H,s),10.2891H,s);MS(ESI)m/z 271(M-H)-.
对C16H10F2O2·0.25H2O的分析:
计算值:C:69.44 H:3.82
实验值:C:69.70 H:3.63
中间体34
6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-溴-2-萘酚(3.2克,18.8毫摩尔)与3-氟-4-甲氧基苯基硼酸(3.5g,15.7毫摩尔)反应制备标题化合物,得到3.3克(78%)白色固体:
mp 174-176℃;1H NMR(DMDO-d6):δ3.89(3H,s),7.11(1H,dd,J=8.79Hz,J=1.95Hz),7.13(1H,s),7.26(1H,J=8.79Hz),7.57(1H,d,J=8.79Hz),7.66(1H,dd,J=13.18Hz,J=1.95Hz),7.71(1H,dd,J=8.79Hz,J=1.46Hz),7.75(1H,d,J=8.79Hz),7.82(1H,d,J=8.79Hz),8.07(1H,s),9.81(1H,s);MS(ESI)m/z 267(M-H)-.
对C17H13FO2的分析:
计算值:C:76.11 H:4.88
实验值:C:76.03 H:4.78
中间体35
6-(4-甲氧基-2-甲基苯基)-2-萘酚
根据方法A,通过6-溴-2-萘酚(1.8克,5.4毫摩尔)与4-甲氧基-3-甲基苯基硼酸(1.74g,7.0毫摩尔)反应制备标题化合物,得到1.56克(73%)微黄的固体:
mp 124-126℃;1H NMR(DMDO-d6):δ2.25(3H,s),3.78(3H,s),6.85(1H,dd,J=8.35Hz,J=2.56Hz),6.90(1H,d,J=2.37Hz),7.09(1H,dd,J=8.75Hz,J=2.25Hz),7.13(1H,s),7.20(1H,d,J=8.33Hz),7.35(1H,dd,J=8.39Hz,J=1.37Hz),7.67(1H,s),7.70(1H,d,J=8.53Hz),7.78(1H,d,J=8.78Hz),9.74(1H,s);MS(ESI)m/z 263(M-H)-.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.43 H:6.01
实施例1j
2-氟-4-(2-萘基)酚
根据方法D,通过2-(3-氟-4-甲氧苯基)-萘(0.22克,0.87毫摩尔)与三溴化硼(1.75毫升1N溶液,1.75毫摩尔)反应制备标题化合物,得到0.13克(63%)白色固体:
mp 110-112℃;1H NMR(DMSO-d6):δ7.05-7.11(1H,m),7.47-7.54(3H,m),7.65(1H,dd,J=2.20Hz,J=12.92Hz),7.82(1H,dd,J=1.80Hz,J=8.62),7.90-7.98(3H,m),8.17(1H,bs),10.07(1H,bs);MS(ESI)m/z 237(M-H)-.
对C16H11FO:的分析:
计算值:C:80.66 H:4.65
实验值:C:80.31 H:4.29
实施例1k
6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过6-(3-氟-4-甲氧苯基)-2-萘酚(600毫克,2.24毫摩尔)与三溴化硼(6.27毫升1.0M在CH2Cl2中的溶液,6.27毫摩尔)制备标题化合物,得到385毫克(68%)微黄固体:
mp 216-219℃;1H NMR(DMDO-d6):δ7.03-7.13(3H,m),7.43(1H,dd,J=8.37Hz,J=1.77Hz),7.58(1H,dd,J=12.92Hz,J=2.13Hz),7.68(1H,dd,J=8.68Hz,J=1.61Hz),7.74(1H,d,J=8.68Hz),8.03(1H,s),9.79(1H,s),9.98(1H,s);MS(ESI)m/z 253(M-H)-.
对C16H11FO2·0.13H2O的分析:
计算值:C:74.89 H:4.42
实验值:C:74.86 H:4.33
路线7中化合物的合成
中间体36
1-氯-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-(3-氟-4-甲氧基苯基)-2-萘酚(1克,3.73毫摩尔)和NCS(748毫克,5.60毫摩尔)在THF(35毫升)中反应制备标题化合物,得到780毫克(69%)棕色固体:
mp 137-139℃;1H NMR(DMDO-d6):δ3.89(3H,s),7.26-7.33(2H,m),7.61(1H,d,J=8.63Hz),7.71(1H,dd,J=13.08Hz,J=2.16Hz),7.84(1H,d,J=8.93Hz),7.92(1H,dd,J=8.92Hz,J=1.80Hz),8.06(1H,d,J=8.86Hz),8.19(1H,d,J=1.55Hz),10.52(1H,s);MS(ESI)m/z301/303(M-H)-.
对C16H11ClO的分析:
计算值:C:67.45 H:4.00
实验值:C:67.35 H:3.78
中间体37
1-氯-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-(4-甲氧基-2-甲基苯基)-2-萘酚(800毫克,3.03毫摩尔)和NCS(485毫克,3.61毫摩尔)在THF(35毫升)中反应制备标题化合物,得到640毫克(71%)黄色固体:
1H NMR(DMDO-d6):δ2.26(3H,s),3.79(3H,s),6.86(1H,dd,J=8.36Hz,J=2.63Hz),6.91(1H,d,J=2.51Hz),7.22(1H,d,J=8.34Hz),7.31(1H,d,J=8.89Hz),7.56(1H,dd,J=8.71Hz,J=1.71Hz),7.79-7.83(2H m),8.04(1H,J=8.91Hz),10.46(1H,s);13C NMR(DMDO-d6):δ20.54,55.07,111.48,112.21,115.71,118.73,121.94,127.92,128.15,128.35,129.34,130.12.130.87,133.26,136.14,136.36,150.99,158.49;MS(ESI)m/z 297/299(M-H)-.
对C18H15ClO2的分析:
计算值:C:72.36 H:5.06
实验值:C:72.02 H:5.03
实施例1v
1-氯-6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-6-(3-氟-4-甲氧基苯基)-2-萘酚(420毫克,1.39毫摩尔)与三溴化硼(3.9毫升1.0M在CH2Cl2中的溶液,3.89毫摩尔)反应制备标题化合物,得到330毫克(82%)微黄固体:
mp 195-198℃;1H NMR(DMDO-d6):δ7.08(1H,t,J=8.86Hz),7.32(1H,d,J=8.89Hz),7.47(1H,dd,J=8.42Hz,J=1.52Hz),7.63(1H,dd,J=12.88Hz,J=1.98Hz),7.83(1H,d,J=8.95Hz),7.88(1H,dd,J=8.93Hz,J=1.61Hz),8.05(1H,d,8.86Hz),8.15(1H,d,J=1.25Hz),10.05(1H,s),10.50(1H,s);MS(ESI)m/z 287/289(M-H)-.
对C16H10ClFO2的分析:
计算值:C:66.56 H:3.49
实验值:C:66.37 H:3.65
实施例1y
1-氯-6-(4-羟基-2-甲基苯基)-2-萘酚
根据方法D,通过1-氯-6-(4-甲氧基-2-甲基苯基)-2-萘酚(400毫克,1.41毫摩尔)与三溴化硼(4.0毫升1.0M在CH2Cl2中的溶液,4.0毫摩尔)反应制备标题化合物,得到310毫克(77%)微黄固体:
mp 216-218℃;1H NMR(DMDO-d6):δ2.20(1H,s),6.68(1H,dd,J=8.19Hz,J=2.42Hz),6.72(1H,d,J=2.13Hz),7.10(1H,d,J=8.16Hz),7.29(1H,d,J=8.89Hz),7.29(1H,d,J=8.89Hz),7.53(1H,dd,J=8.78Hz,J=1.62Hz),7.76(1H,d,J=1.38Hz),7.80(1H,d,J=8.94Hz),8.02(1H,d,J=8.72Hz),9.4(1H,s),10.43(1H,s);13NMR(DMDO-d6):δ20.47,112.20,112.99,117.00,118.66,121.85,127.83,128.09,128.38,129.47,130.00,130.88,131.65,136.09,136.51,150.88,156.62;MS(ESI)m/z 283/285(M-H)-.
对C18H15ClO2的分析:
计算值:C:71.71 H:4.60
实验值:C:71.30 H:4.66
路线8中化合物的合成
中间体38
6-甲氧基-2-萘基硼酸
在500毫升烧瓶中加入2-溴-6-甲氧基萘(8.02克,33.8毫摩尔)、无水THF(125毫升)和一些1,10-菲咯啉结晶作为指示剂。将混合物冷却至-78℃,用注射器缓慢加入仲丁基锂(56毫升在己烷中1.3N的溶液,72.8毫摩尔)。在搅拌0.5小时后,加入三异丙基硼酸酯(47毫升,203.7毫摩尔),溶液在-78℃搅拌1小时,然后温热至室温。然后加入冰冷的2N盐酸(100毫升),混合物搅拌5分钟后,再加入2N盐酸(100毫升),再搅拌5分钟。然后将混合物用乙酸乙酯(3x)萃取,用硫酸镁干燥,浓缩到接近干燥。将己烷加入到浓缩液中,诱导结晶,然后过滤收集结晶,在真空下干燥,得到7.01克(约100%)浅橙色粉末。
1H NMR(500MHz,DMSO-d6)δ3.88(3H,s),7.15(1H,dd,J=8.9Hz,2.7Hz),7.29(1H,d,J=2.5Hz),7.75(1H,d,J=8.3Hz),7.83(2H,appt),8.30(1H,s);MS(EI)m/z 202.17(M+).
中间体39
2-氯-4-(6-甲氧基-2-萘基)酚
4-溴-2-氯酚(730毫克,3.5毫摩尔)、(6-甲氧基-2-萘基)硼酸(780毫克,3.85毫摩尔)、碳酸钠(930毫克的2N水溶液,8.8毫摩尔)和四(三苯基膦)钯(0)(203毫克,0.18毫摩尔)在DME(45毫升)中的混合物回流12小时。然后将反应冷却,用乙酸乙酯(3x)萃取,用硫酸钠干燥然后浓缩。柱色谱(30% EtOAc/己烷)得到360毫克(30%)的产物,为白色固体。
mp 129-130℃;1H NMR(300MHz,DMSO-d6)δ3.88(3H,s),7.08(1H,d,J=8.2Hz),7.17(1H,dd,J=8.6Hz,2.1Hz),7.34(1H,d,J=2.1Hz),7.59(1H,dd,J=8.6Hz,2.1Hz),7.75(2H,m),7.87(1H,d,J=8.8Hz),7.88(1H,d,J=8.6),8.09(1H,s),10.34(1H,s);MS m/z 283/285(Cl pattem)(M-H+);
对C17H13ClO2:的分析:
计算值:C:71.71 H:4.60
实验值:C:71.68 H:4.72
中间体40
3-氯-4-(6-甲氧基-2-萘基)酚
根据方法A,4-溴-3-氯酚(3.8克,18.3毫摩尔)和I12372-104(4.81g,23.8毫摩尔)反应制备标题化合物,得到5.09克(98%)白色固体:
mp 139-142℃;1H NMR(DMSO-d6):δ3.89(3H,s),6.87(1H,dd,J=8.39Hz,J=2.45Hz),6.98(1H,J=2.40Hz),7.19(1H,dd,J=8.98Hz,J=2.46Hz),7.32(1H,d,J=8.39Hz),7.35(1H,d,J=2.38Hz),7.50(1H,dd,J=8.47Hz,J=1.73Hz),7.83-7.88(3H,m),10.04(1H,s):MS(ESI)m/z 283/285(M-H)-.
对C16H11ClO:的分析:
计算值:C:71.71 H:4.60
实验值:C:71.50 H:4.62
中间体41
2,6-二氟-4-(6-甲氧基-2-萘基)酚
根据方法A,4-溴-2,6-二氟苯酚(3.5克,16.8毫摩尔)和中间体38(4.2克,20.2毫摩尔)反应制备标题化合物,得到1.1克(23%)白色固体:
mp 188-190℃;1H NMR(DMSO-d6):δ3.89(3H,s),7.19(1H,dd,J=8.92Hz,J=2.52Hz),7.34(1H,J=2.41Hz),7.48-7.59(2H,m),7.80(1H,dd,J=8.61Hz,J=1.76Hz),7.88(1H,d,J=8.65Hz),8.17(1H,d,J=1.25Hz),10.31(1H,s);MS(ESI)m/z 285(M-H)-.
对C17H12F2O2:的分析:
计算值:C:71.32 H:4.23
实验值:C:71.10 H:4.17
中间体42
4-甲基苯磺酸(4-(6-羟基-2-萘基)-3-甲氧苯基)酯4-甲基苯磺酸(4-溴-3-甲氧苯基)酯
4-溴-间苯二酚(4.92克,26.0毫摩尔)、对甲苯磺酰氯(5.95克,31.2毫摩尔)、碳酸钾(23克,167毫摩尔)和丙酮(300毫升)的混合物回流16小时。加入碘代甲烷(9.89克,70毫摩尔),混合物再回流12小时。将混合物冷却至室温,加入***(200毫升),过滤悬浮液。将滤液脱除溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到6.49克(70%)标题化合物,为白色固体。
1H NMR(CDCl3):δ2.45(3H,s),3.78(3H,s),6.40(1H,dd,J=2.45Hz,J=8.60Hz),6.59(1H,d,J=2.48Hz),7.33(2H,d,J=8.30Hz),7.40(1H,d,J=8.69Hz),7.71(2H,d,J=8.23Hz);MS(ESI)m/z 355/357(M-H)-
对C14H13BrO4S的分析:
计算值:C:47.07 H:3.67
实验值:C:47.14 H:3.57
根据方法A,通过4-甲基苯磺酸(4-溴-3-甲氧苯基)酯(3.07克,8.60毫摩尔)和叔丁基[(2-(6-萘基硼酸)氧基]二甲基甲硅烷(2.86克,9.46毫摩尔)反应制备标题化合物,得到2.15克(53%)橙色固体:
1H NMR(CDCl3):δ2.44(3H,s),3.65(3H,s),6.69(1H,dd,J=2.10Hz,J=8.29Hz),6.74(1H,d,J=2.10Hz),7.06-7.11(2H,m),7.36(1H,d,J=8.27Hz),7.4569(1H,dd,J=1.32Hz,J=8.57Hz),7.51(1H,d,J=8.28Hz),7.67(1H,d,J=8.61Hz),7.77(1H,d,J=8.80Hz),7.80-7.85(3H,m),9.78(1H,s);MS(ESI)m/z 419(M-H)-.
对C24H20O5S·0.25H2O的分析:
计算值:C:67.82 H:4.86
实验值:C:67.75 H:4.56
实施例1aa
6-(4-羟甲基-2-甲氧苯基)-2-萘酚
4-甲苯磺酸(4-(6-羟基-2-萘基)-3-甲氧苯基)酯(1.74克,4.05毫摩尔)、氢氧化钾(5克)、水(85毫升)和乙醇(85毫升)的溶液在90℃搅拌2小时。将反应冷却至室温,浓缩至50%体积,用乙酸中和,用乙酸乙酯(3×200毫升)萃取。合并的有机层用盐水洗涤,用硫酸镁干燥,过滤,蒸发溶剂,通过二氧化硅柱色谱(25%乙酸乙酯-己烷)提纯,得到1.01克(94%)标题化合物,为棕褐色固体。样品进一步用制备逆相HPLC提纯,得到棕褐色固体:
mp 152-154℃;1H NMR(DMSO-d6):δ3.72(3H,s),6.46(1H,dd,J=1.52Hz,J=8.20Hz),6.52(1H,d,J=1.77Hz),7.04-7.09(2H,m),7.16(1H,d,J=8.23Hz),7.47(1H,d,J=8.50Hz),7.63(1H,d,J=8.57Hz),7.72-7.75(2H,m),9.56(1H,bs),9.68(1H,bs);MS(ESI)m/z 265(M-H)-.
对C17H14O3的分析:
计算值:C:76.68 H:5.30
实验值:C:76.68 H:5.30
实施例1l
6-(3-氯-4-羟基酚)-2-萘酚
2-氯-4-(6-甲氧基-2-萘基)酚(192毫克,0.71毫摩尔)和盐酸吡啶(3克,26毫摩尔)的混合物加热至200℃1小时,同时搅拌。将混合物冷却后,加入水溶解固体,水层用***(3x)萃取。合并***层,用硫酸钠干燥,通过二氧化硅填料。减压蒸发得到180毫克(98%)棕褐色固体产品。
mp 176-177℃;1H NMR(300MHz,DMSO-d6)δ7.09(3H,m),7.57(1H,dd,J=7.6Hz,1.5Hz),7.70(3H,m),7.82(1H,d,J=8.6Hz),8.02(1H,s),9.77(1H,s),10.28(1H,s);MS m/z 269/271(Clpattern)(M-H+);
对C16H11ClO2的分析:
计算值:C:70.99 H:4.10
实验值:C:70.64 H:4.16
实施例1ab
6-(2-氯-4-羟基苯基)-2-萘酚
根据方法D,通过3-氯-4-(6-甲氧基-2-萘基)酚(2.4g,8.43毫摩尔)和三溴化硼(21.9毫升,1.0M在CH2Cl2中的溶液,21.9毫摩尔)反应制备标题化合物,得到2.1克(92%)微黄固体:mp 209-210℃;1H NMR(DMDO-d6):δ6.86(1H,dd,J=8.42Hz,J=2.45Hz),6.97(1H,d,2.41Hz),7.11(1H,dd,J=8.78Hz,J=2.35Hz),7.16(1H,d,J=2.15Hz),7.30(1H,d,J=8.40Hz),7.42(1H,dd,J=8.51Hz,J=1.71Hz),7.71(1H,d,J=8.59Hz),7.76(1H,s),7.80(1H,d,J=8.82Hz),9.82(1H,s),10.01(1H,s);13C NMR(DMDO-d6):δ108.45,114.79,116.21,118.90,125.53,127.43,127.77,127.92,129.56,130.70,131.73,132.34,133.18,133.52,155.56,157.46;MS(ESI)m/z269/271(M-H)-.
对C16H11ClO2的分析:
计算值:C:70.99 H:4.10
实验值:C:70.68 H:4.09
实施例1w
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚
根据方法A,通过6-(3-氯-4-羟基苯基)-2-萘酚(500毫克,1.85毫摩尔)和NCS(346毫克,2.59毫摩尔)在THF(37毫升)中反应制备标题化合物,得到380毫克(68%)微黄固体:
mp 174-175℃;1HNMR(DMDO-d6):δ7.09(1H,d,8.47Hz),7.31(1H,d,J=8.89Hz),7.60(1H,dd,J=8.20Hz,J=2.26Hz),7.78(1H,d,J=2.22Hz),7.84(1H,d,J=8.99Hz),7.88(1H,dd,J=9.00Hz,J=1.80Hz),8.05(1H,d,J=8.86Hz),8.14(1H,d,J=1.60Hz),10.37(1H,s),10.49(1H,s);MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2的分析:
计算值:C:62.98 H:3.30
实验值:C:62.65 H:3.21
实施例1ac
1-氯-6-(2-氯-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2-氯-4-羟基苯基)-2-萘酚(500毫克,1.85毫摩尔)和NCS(321毫克,2.40毫摩尔)在THF(40毫升)中反应制备标题化合物,得到435毫克(77%)微黄固体:
mp 224-226℃;1HNMR(DMDO-d6):δ6.86(1H,dd,J=8.42Hz,J=2.41Hz),6.96(1H,d,J=2.44Hz),7.30(1H,d,J=3.19Hz),7.33(1H,d,J=2.65Hz),7.62(1H,dd,J=8.81Hz,J=1.71Hz),7.83(1H,d,J=8.93Hz),7.86(1H,d,J=1.54Hz),8.04(1H,J=8.76Hz),10.04(1H,s),10.51(1H,s);13C NMR(DMDO-d6):δ112.24,114.84,116.26,118.79,121.84,128.16,128.24,128.35,129.27,130.03,130.40,131.73,132.38,133.98,151.24,157.70;MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2的分析:
计算值:C:62.98 H:3.30
实验值:C:62.69 H:3.36
实施例1ba
1-氯-6-(3,5-二氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(3,5-二氟-4-羟基苯基)-2-萘酚(300毫克,1.10毫摩尔)和NCS(155毫克,1.16毫摩尔)在THF(30毫升)中反应制备标题化合物,得到264毫克(78%)灰色固体:
mp 209-210℃;1H NMR(DMSO-d6):δ7.32(1H,d,J=8.89Hz),7.50-7.61(2H,m),7.83(1H,d,J=8.96Hz),7.92(1H,dd.J=8.94Hz,J=1.59Hz),8.05(1H,d,J=8.88Hz),8.22(1H,d,J=1.19Hz),10.36(1H,s),10.54(1H,s);MS(ESI)m/z 305/307(M-H)-.
对C16H9ClF2O2的分析:
计算值:C:62.66 H:2.96
实验值:C:62.58 H:3.09
路线9中化合物的合成
中间体43
6-溴-1-氯萘-2-酚
根据方法C,通过6-溴-2-萘酚(3克,13.4毫摩尔)和NCS(2.47克,18.5毫摩尔)在THF(50毫升)中反应制备标题化合物,得到2.2g(64%)黄色固体:
1H NMR(DMDO-d6):δ7.34(1H,d,J=8.87Hz),7.69(1H,dd,J=1.75Hz,J=6.09Hz),7.79(1H,d,J=8.96Hz),7.96(1H,d,J=9.03Hz),8.17(1H,d,J=1.75Hz),10.68(1H,s);MS(ESI)m/z 255/257/259(M-H)-.
实施例1m
1-氯-6-苯基-2-萘酚
根据方法A,通过6-溴-1-氯-萘-2-酚(300毫克,1.17毫摩尔)和苯基硼酸(170.7毫克,1.40毫摩尔)反应制备标题化合物,得到240毫克(81%)白色固体:
mp 135-137℃;1H NMR(DMDO-d6):δ7.33(1H,d,J=8.85Hz),7.39(1H,td,J=7.25Hz,J=0.75Hz),7.51(2H,t,J=7.59Hz),7.80(2H,d,J=7.63Hz),7.88(1H,d,J=8.96Hz),7.93(1H,dd,J=8.85Hz,J=1.19.Hz),8.10(1H,d,J=8.84Hz),8.20(1H,s),10.53(1H,s);MS(ESI)m/z253/255(M-H)-.
对C16H11ClO的分析:
计算值:C:75.45 H:4.35
实验值:C:75.16 H:4.17
中间体44
6-溴-1-硝基-2-萘酚
将4-硝基-4-甲基-2,3,5,6-四溴-2,5-环己二烯-1-酮(2.53克,4.95毫摩尔,纯度:82.6%)加入到在40毫升无水***中的6-溴-2-萘酚(1克,4.5毫摩尔)中。反应在室温进行1.5小时。过滤固体得到2,3,5,6-四溴-4-甲基苯酚(144毫克)。然后在真空下蒸发溶液。将粗混合物溶于乙酸乙酯并用水洗涤。用无水硫酸钠干燥有机层,在真空下除去溶剂。通过用乙酸乙酯-己烷重结晶粗产物得到2,3,5,6-四溴-4-甲基苯酚(1.2克)。母液浓缩到Florosil上,在二氧化硅柱(15%-20%乙酸乙酯-己烷)上提纯,得到0.731克(61%)标题化合物,为黄色固体:
mp 111-113℃;1H NMR(DMDO-d6):δ7.39(1H,d,J=9.07Hz),7.54(1H,d,J=9.05Hz),7.75(1H,dd,J=9.05Hz,J=1.70Hz),8.03(1H,d,J=9.14Hz),8.29(1H,d,J=1.84Hz),11.65(1H,s);MS(ESI)m/z 266/268(M-H)-;IR 1350cm-1,1490cm-1.
对C10H6BrNO3·0.18H2O的分析:
计算值:C:44.27 H:2.36 N:5.16
实验值:C:44.24 H:2.14 N:4.76.
中间体45
6-[4-(叔丁基-二甲基甲硅烷氧基)-苯基]-1-硝基-2-萘酚
根据方法A,通过6-溴-1-硝基-2-萘酚(560毫克,2.1毫摩尔)和4-叔丁基-二甲基甲硅烷氧基硼酸(688毫克,2.73毫摩尔)反应制备标题化合物,得到347毫克(42%)微黄固体:
1H NMR(DMDO-d6):δ0.23(6H,s),0.98(9H,s),6.99(2H,d,J=8.47Hz),7.35(1H,d,J=9.05Hz),7.64(1H,d,J=8.86Hz),7.70(2H,d,J=8.51Hz),7.94(1H,dd,J=6.62Hz,J=1.25Hz),8.08(1H,d,J=9.16Hz),8.22(1H,s),11.45(1H,s);MS(ESI)m/z 394(M-H)-.
实施例1x
6-(4-羟基苯基)-1-硝基-2-萘酚
向6-[4-(叔丁基-二甲基甲硅烷氧基)-苯基]-1-硝基-2-萘酚(302毫克,0.764毫摩尔)在THF(12毫升)中的溶液中加入TBAF(0.92毫升,0.917毫摩尔,1.0M在THF中的溶液)。溶液在室温搅拌10分钟,倾入水中。混合物用乙酸乙酯萃取。合并的有机层用盐水洗涤,用无水硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱上提纯(20%-40%乙酸乙酯-己烷),得到130毫克(61%)橙色固体。分析样品进一步用乙酸乙酯-己烷重结晶提纯,得到标题化合物,为橙色固体:
mp 199-201℃;1H NMR(DMDO-d6):δ6.89(2H,d,J=8.51Hz),7.33(1H,d,J=9.05Hz),7.62(1H,d,J=8.94Hz),7.63(2H,d,8.48Hz),7.91(1H,dd,J=8.87Hz,J=1.59Hz),8.06(1H,d,9.18Hz),8.17(1H,d,J=1.31Hz),9.64(1H,s),11.40(1H,s);MS(ESI)m/z 280(M-H)-.
对C16H11NO4的分析:
计算值:C:68.32 H:3.94 N:4.98
实验值:C:67.91 H:4.06 N:4.60
路线10中化合物的合成
中间体52
2-(2,5-二氟-4-甲氧苯基)-6-甲氧基萘
根据方法A,通过4-溴-2,5-二氟苯甲醚(4.06克,18.3毫摩尔)和中间体38(4.81克,23.8毫摩尔)反应制备标题化合物,得到5.18克(94.2%)白色固体:
mp 153-155℃;1H NMR(DMSO-d6):δ3.90(3H,s),3.91(3H,s),7.20(1H,dd,J=8.94Hz,J=2.50Hz),7.28(1H,dd,J=12.38Hz,J=7.47Hz),7.36(1H,d,J=2.42Hz),7.56(1H,dd,J=12.17Hz,J=7.53Hz),7.62-7.66(1H,m),7.89(2H,d,J=8.67Hz),8.02(1H,s);MS(ESI)m/z 301(M-H)+;HRMS:C18H14F2O2的计算值,300.0962;实验值(Cl(ISOBUTANE)),300.0953
对C18H14F2O2的分析:
计算值:C:71.99 H:4.70
实验值:C:73.00 H:4.62
中间体53
2-(2,6-二氟-4-甲氧苯基)-6-甲氧基萘
根据方法A,通过4-溴-3,5-二氟苯甲醚(4.06克,18.3毫摩尔)和中间体38(4.43克,22.0毫摩尔)反应制备标题化合物,得到3.4克(62%)白色固体:
mp 130-132℃;1H NMR(acetone-d6):δ3.91(3H,s),3.94(3H,s),6.72-6.80(2H,m),7.20(1H,dd,J=8.97Hz,J=2.54Hz),7.35(1H,d,J=2.48Hz),7.48-7.52(1H,m),7.85-7.90(3H,m);MS(ESI)m/z 301(M-H)+.
对C18H14F2O2的分析:
计算值:C:71.99 H:4.70
实验值:C:71.67 H:4.81
中间体50
三氟-甲磺酸(2-氟-4-甲氧基-苯基)酯
2-氟-4-甲氧基-苯酚
4-溴-2-氟苯酚(8克,41.9毫摩尔)、CuBr(6.0克,41.9毫摩尔)、甲醇钠(95.8毫升4.4M在甲醇中的溶液)和DMF(200毫升)的混合物在150℃加热4小时。反应混合物冷却到室温,倾入HCl(419毫升,2N水溶液)中,通过硅藻土过滤,然后用乙酸乙酯萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,蒸发溶剂,用二氧化硅柱色谱(5%-15%乙酸乙酯-己烷)提纯,得到5.63克(95%)标题化合物,为微黄色油:
1H NMR(DMDO-d6):δ3.67(3H,s),6.55(1H,m),6.78(1H,dd,J=12.97Hz,J=2.95Hz),6.85(1H,dd,J=10.14Hz,J=8.87Hz),9.24(1H,s)3.67(3H,s)
根据方法B,通过2-氟-4-甲氧基-苯酚(2.8克,19.7毫摩尔)与三氟甲磺酸酐(4.31毫升,7.23克,25.6毫摩尔)反应制备标题化合物,得到3.86克(68%)澄清的黄色油。
1H NMR(DMSO-d6):δ3.82(3H,s),6.89-6.94(1H,m),7.24(1H,dd,J=12.49Hz,J=2.98Hz),7.61(1H,t,J=9.09Hz).
中间体54
2-(2-氟-4-甲氧苯基)-6-甲氧基萘
根据方法A,通过三氟甲磺酸(2-氟-4-甲氧基-苯基)酯(3.86克,14.0毫摩尔)和中间体38(2.97克,14.8毫摩尔)反应制备标题化合物,得到2.27克(58%)的白色固体:
mp 104-106℃;1H NMR(DMSO-d6):δ3.83(3H,s),3.89(3H,s),6.92(1H,dd,J=8.46Hz,J=2.64Hz),6.98(1H,dd,J=12.92,J=2.48Hz),7.19(1H,dd,J=8.94Hz,J=2.46Hz),7.35(1H,J=2.38Hz),7.53-7.63(2H,m),7.90(2H,d,J=8.72Hz),7.97(1H,s);MS(ESI)m/z 283(M+H+).
对C18H15FO2的分析:
计算值:C:76.58 H:5.36
实验值:C:76.30 H:5.23
实施例1ar
2-氯-4-(2-萘基)苯酚
根据方法A,4-溴-2-氯苯酚(1.45克,6.98毫摩尔)、2-萘硼酸(1.0克,5.81毫摩尔)、碳酸钠(1.54克2N水溶液,14.53毫摩尔)和四(三苯基膦)钯(0)(340毫克,0.3毫摩尔)在DME(70毫升)中的混合物回流6小时。然后将反应冷却,用乙酸乙酯(3x)萃取,用硫酸钠干燥,然后浓缩。柱色谱(30%乙酸乙酯-己烷)得到610毫克(34%)白色固体产品。分析样品通过制备逆相HPLC(CH3CN/H2O,0.1%TFA)制备。
mp 99.5-100.0℃;1H NMR(300MHz,DMSO-d6)δ7.10(1H,d,J=8.4Hz),7.52(2H,m),7.63(1H,dd,J=8.5Hz,2.0Hz),7.81(2H,m),7.95(3H,m),8.17(1H,s),10.40(1H,s);MS m/z 253/255(Cl pattern)(M-H+);
对C16H11ClO.的分析:
计算值:C:75.45 H:4.35
实验值:C:75.24 H:4.34
实施例1z
6-(4-羟基-2-甲基苯基)-2-萘酚
根据方法D,通过6-(4-甲氧基-2-甲基苯基)-2-萘酚(420毫克,1.59毫摩尔)和三溴化硼(4.53毫升1.0M在CH2Cl2中的溶液,4.53毫摩尔)反应制备标题化合物,得到400毫克(定量得到)微黄固体:
mp 191-193℃;1H NMR(DMDO-d6):δ6.68(1H,dd,J=8.41Hz,J=2.21Hz),6.72(1H,d,J=2.21Hz),7.07-7.11(2H,m),7.14(1H,d,J=2.21Hz),7.33(1H,dd,J=8.41Hz,J=2.21Hz),7.64(1H,d,J=0.885Hz),7.68(1H,d,J=8.41Hz),7.77(1H,d,J=9.29Hz),9.33(1H,s),9.69(1H,s);13C NMR(DMDO-d6):δ108.34,112.82,116.84,118.68,125.47,127.13,127.56,128.02,129.26,130.71,132.26,133.02,135.63,135.90,155.11,156.31;MS(ESI)m/z 249(M-H)-.
对C17H14O2的分析:
计算值:C:81.58 H:5.64
实验值:C:81.36 H:5.53
实施例1ad
6-(2-氟-4-羟基苯基)-2-萘酚
根据方法D,通过2-(2-氟-4-甲氧苯基)-6-甲氧基-萘(1.12克,3.97毫摩尔)和三溴化硼(23.8毫升1.0M在CH2Cl2中的溶液,23.8毫摩尔)制备标题化合物,得到0.92克(91%)白色固体:mp208-209℃;1H NMR(DMSO-d6):δ6.66-6.75(2H,m),7.08-7.13(2H,m),7.41(1H,dd,J=9.37Hz,J=8.57Hz),7.49-7.53(1H,m),7.72(1H,d,J=8.64Hz),7.80(1H,d,J=8.76Hz),7.86(1H,s),9.79(1H,s),10.01(1H,s);MS(ESI)m/z 255(M+H)+,MS(ESI)m/z 253(M-H)-.
对C16H11FO2·0.15H2O的分析:
计算值:C:74.79 H:4.43
实验值:C:74.79 H:4.23
实施例1ae
6-(2,5-二氟-4-羟基苯基)-2-萘酚
根据方法D,通过2-(2,5-二氟-4-甲氧苯基)-6-甲氧基萘(1.5克,5.0毫摩尔)和三溴化硼(25毫升,1.0M在CH2Cl2中的溶液,25毫摩尔)制备标题化合物,得到1.28克(94%)的微黄固体:
mp 217-219℃;1H NMR(DMSO-d6):δ6.90(1H,dd,J=11.87Hz,J=7.51Hz),7.10-7.15(2H,m),7.45(1H,dd,J=11.87,J=7.61Hz),7.53-7.55(1H,m),7.74(1H,d,J=8.65Hz),7.92(1H,s),9.85(1H,s),10.50(1H,s);MS(ESI)m/z 271(M-H)-.
对C16H10F2O2的分析:
计算值:C:70.59 H:3.70
实验值:C:70.35 H:3.65
实施例1af
6-(2,6-二氟-4-羟基苯基)-2-萘酚
根据方法D,通过2-(2,6-二氟-4-甲氧苯基)-6-甲氧基萘(1.5克,5.0毫摩尔)和三溴化硼(25毫升1.0M在CH2Cl2中的溶液,25毫摩尔)反应制备标题化合物,得到1.35克(99%)的微黄固体:
mp>240℃;1H NMR(DMSO-d6):δ6.55-6.63(2H,m),7.11(1H,dd,J=8.76Hz,J=2.34Hz),7.15(1h,d,J=2.05Hz),7.36(1H,dd,J=8.58Hz,J=1.34Hz),7.39(1H,d,J=8.83Hz),7.79(1H,s),7.80(1H,d,J=8.74Hz),9.85(1H,s),10.48(1H,s);MS(ESI)m/z 271(M-H)-;MS(ESI)m/z 543(2M-H)-.
对C16H10F2O2的分析:
计算值:C:70.59 H:3.70
实验值:C:70.19 H:3.58
实施例1ag
1-氯-6-(2-氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2-氟-4-羟基苯基)-2-萘酚(300毫克,1.18毫摩尔)和NCS(191毫克,1.43毫摩尔)在THF(30毫升)中反应制备标题化合物,得到170毫克(50%)微黄固体:
mp 179-180℃;1HNMR(DMSO-d6):δ6.73(1H,dd,J=12.69Hz,J=2.44Hz),6.75(1H,dd,J=8.30Hz,J=2.44Hz),7.31(1H,d,J=8.79Hz),7.45(1H,t,J=9.28Hz),7.70-7.72(1H,m),7.83(1H,d,J=8.79Hz),7.97(1H,s),8.06(1H,d,J=7.79Hz),10.06(1H,s),10.48(1H,s);MS(ESI)m/z 287/289(M-H)-.
对C16H10ClFO2的分析:
计算值:C:66.56 H:3.49
实验值:C:66.45 H:3.52
实施例1ah
1-氯-6-(2,5-二氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2,5-二氟-4-羟基苯基)-2-萘酚(500毫克,1.84毫摩尔)和NCS(295毫克,2.21毫摩尔)在THF(37毫升)中反应制备标题化合物,得到370毫克(66%)微黄固体:
mp 203-204℃;1HNMR(DMSO-d6):δ6.90(1H,dd,J=11.90Hz,J=7.50Hz),7.32(1H,d,J=8.88Hz),7.49(1H,dd,J=11.87Hz,J=7.60Hz),7.72-7.76(1H,m),7.84(1H,d,J=8.97Hz),8.03(1H,s),8.06(1H,d,8.87Hz),10.58(2H,s);MS(ESI)m/z 305/307(M-H)-;HRMS C16H9ClF2O2的计算值306.02591,观察值305.01863(M-H)-.
对C16H9ClF2O2·0.4H2O的分析:
计算值:C:61.22 H:3.15
实验值:C:61.29 H:3.17
实施例1ai
1-氯-6-(2,6-二氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2,6-二氟-4-羟基苯基)-2-萘酚(510毫克,1.86毫摩尔)和NCS(301毫克,2.25毫摩尔)在THF(30毫升)中反应制备标化合物,得到440毫克(77%)的微黄固体:
mp 213-214℃;1H NMR(丙酮-d6):δ6.71-6.78(2H,m),7.47(1H,d,J=8.85Hz),7.76(1H,dd,J=8.12Hz,J=1.52Hz),7.97(1H,d,J=8.90Hz),8.04(1H,s),8.29(1H,d,J=8.80Hz),9.26(1H,s),9.60(1H,s);MS(ESI)m/z 305/307(M-H)-;HRMS:C16H9ClF2O2的计算值,306.0259;实验值(ESI-),306.01991
对C16H9ClF2O2·0.25H2O的分析:
计算值:C:61.75 H:3.08
实验值:C:61.75 H:2.90
路线11中化合物的合成
中间体56
N-(7-羟基萘基)乙酰胺
向8-氨基2-萘酚(149.1克,0.937摩尔)在甲醇(1L)中的溶液中加入乙酸酐(93毫升,0.984摩尔)。反应回流90分钟,然后冷却至室温。除去溶剂,残余物通过硅塞与乙酸乙酯一起过滤。除去溶剂,得到175.8克(93%)标题化合物,为暗紫色固体。分析样品进一步通过逆相制备HPLC提纯,得到粉红色固体:
mp 161-162℃;1H NMR(DMSO-d6):δ2.15(3H,s),7.09(1H,dd,J=1.95Hz,J=8.79Hz),7.20-7.26(2H,m),7.49(1H,d,J=7.31Hz),7.63(1H,d,J=8.11Hz),7.77(1H,d,J=8.81Hz),9.76(1H,s),9.79(1H,s);MS(ESI)m/z 202(M+H)+.
对C12H11NO2.的分析:
计算值:C:71.63H:5.51 N:6.96
实验值:C:71.21H:5.45 N:6.89
中间体57
N-(7-甲氧基萘基)乙酰胺
向N-(7-羟基萘基)乙酰胺(175.4克,0.872摩尔)、碳酸钾(301克,2.18摩尔)和丙酮(1L)的混合物中加入碘代甲烷(270毫升,4.36摩尔)。反应混合物回流6小时,冷却至室温,除去溶剂。残余物与二氧化硅和乙酸乙酯一起过滤,与乙酸乙酯一起研磨,得到161.6克(86%)灰色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 154-155℃;1H NMR(DMSO-d6):δ2.19(3H,s),3.90(3H,s),7.19(1H,dd,J=2.39Hz,J=8.94Hz),7.29-7.34(2H,m),7.39(1H,d,J=1.86Hz),7.75-7.68(2H,m),7.87(1H,d,J=8.96Hz),9.82(1H,s);MS(ESI)m/z 216(M+H)+.
对C13H13NO2的分析:
计算值:C:72.54 H:6.09 N:6.51
实验值:C:72.24 H:6.43 N:6.52.
中间体58
7-甲氧基萘胺
N-(7-甲氧基萘基)乙酰胺(160.6克,0.747摩尔)和HCl(1.51,1N溶液)的混合物回流5小时。冷却的反应物用固体碳酸氢纳中和,然后用二氯甲烷萃取直至UV澄清。合并的有机层通过二氧化硅过滤,蒸发溶剂,得到的89.5克(69%)棕色固体。分析样品通过制备HPLC制备,得到标题化合物白色固体:
mp 134-136℃;1HNMR(CDCl3):δ3.94(3H,s),4.01(2H,bs),6.80(1H,d,J=7.26Hz),7.05(1H,d,J=2.20Hz),7.12-7.19(2H,m),7.28(1H,d,J=8.17Hz),7.71(1H,d,J=8.93Hz);MS(ESI)m/z 174(M+H)+
对C11H11NO·CF3CO2H的分析:
计算值:C:54.55 H:3.87 N:4.89
实验值:C:54.39 H:4.28 N:4.78.
中间体59
1-氟-7-甲氧基萘
向冷却到10℃的7-甲氧基萘胺(10.94克,63.24毫摩尔)、HCl(15.8毫升,12N溶液,190毫摩尔)和水(50毫升)的混合物中用10分钟加入亚硝酸钠(4.58克,66.40毫摩尔)水中(25毫升)的溶液。将溶液搅拌30分钟,然后与氟硼酸(100毫升)合并。得到的绿色固体通过过滤收集,先用水洗涤,然后用乙醇洗涤,再用***洗涤,得到黄固体[15.48克(90%)不典型的重氮氟硼酸盐中间体]。该黄色固体与二甲苯(250毫升)合并,回流1小时。除去溶剂,残余物在乙酸乙酯和碳酸氢钠溶液之间分配。有机层用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅上提纯(己烷),得到标题化合物,为浅黄色液体。
1H NMR(CDCl3):δ3.94(3H,s),7.10-7.28(3H,m),7.34(1H,d,J=2.50Hz),7.55(1H,d,J=8.12Hz),7.75(1H,dd,J=1.69Hz,J=9.00Hz);MS(EI)m/z 176(M)+.
对C11H9FO的分析:
计算值:C:74.99 H:5.15
实验值:C:74.84 H:5.14
中间体60
8-氯-2-甲氧基萘
将CuCl2(4.6克,24.6毫摩尔)和亚硝酸叔丁酯(4.46克,43.3毫摩尔)加入到0℃的乙腈(125毫升)中。向该混合物中缓慢地加入7-甲氧基萘胺(4.99克,28.8毫摩尔)在乙腈(25毫升)中的溶液。反应温热至室温,与HCl(400毫升,2N溶液)一起搅拌,用乙酸乙酯(3×200毫升)萃取。合并的有机层用2N的HCl洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(己烷)上提纯,得到2.27克(41%)的橙色液体。分析样品进一步用逆相制备HPLC提纯,得到标题化合物黄固体:
mp 32-34℃;1H NMR(CDCl3):δ3.98(3H,s),7.20(1H,dd,J=2.52Hz,J=8.96Hz),7.22-7.27(1H,m),7.52(1H,d,J=2.47Hz),7.55(1h,d,J=7.47Hz),7.69(1H,d,J=8.15Hz),7.75(1H,d,J=8.95Hz);MS m/z191/193(M-H)-.
对C11H9ClO的分析:
计算值:C:68.58 H:4.71
实验值:C:68.35 H:4.85
中间体61
1-溴-7-甲氧基萘
向CuBr2(15.7克,70.3毫摩尔)和TBN(9.05克,87.9毫摩尔)在乙腈(250毫升)中的0℃的溶液中缓慢加入2-甲氧基萘胺(10.14克,58.6毫摩尔)在乙腈(60毫升)中的溶液。深色的溶液在0℃搅拌2.5小时,在二氧化硅上浓缩,用二氧化硅柱提纯,得到4.03克(29%)白色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 54-58℃;1H NMR(CDCl3):δ3.97(3H,s),7.15-7.21(2H,m),7.50(1H,d,J=2.42Hz),7.71-7.76(3H,m);MS(EI)m/z 236(M-)+.
对C11H9BrO的分析:
计算值:C:55.72 H:3.83
实验值:C:55.58 H:3.60
中间体62
7-甲氧基-1-萘甲腈
1-溴-7-甲氧基萘(3.26克,13.8毫摩尔)、Zn(CN)2(2.26克,19.2毫摩尔)和四(三苯基膦)钯(1.6克,1.4毫摩尔)在DMF(50毫升)中的混合物在120℃搅拌15小时。冷却的反应混合物倾入200毫升1N的氯化铵溶液中,然后用乙酸乙酯(3×350毫升)萃取。合并的有机层用盐水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到1.28克(51%)标题化合物,为白色固体:
mp 62-66℃;1H NMR(DMSO-d6):δ4.00(3H,s),7.25(1H,dd,J=2.48Hz,J=8.96Hz),7.36-7.47(1H,m),7.47(1H,d,J=2.39Hz),7.81(1H,d,J=9.00Hz),7.88(1H,dd,J=0.81Hz,J=7.23Hz),8.00(1H,d,J=8.21Hz);MS(EI)m/z 183(M-)+;
对C12H9NO:的分析:
计算值:C:78.67 H:4.95 N:7.65
实验值:C:78.83 H:4.60 N:6.80.
中间体64
7-甲氧基-3,4-二氢萘-1-甲腈
向7-甲氧基-1-四氢萘酮(39.65克,0.23摩尔)、碘化锌(1.73克,5.4毫摩尔)和苯(100毫升)的混合物中加入三甲基甲硅烷基氰(25.0克.0.25摩尔)。混合物在室温搅拌过夜。加入吡啶(350毫升),然后滴加磷酰氯(100毫升),同时稍微升高温度。混合物加热回流并保持6小时。TLC显示所需产物的mid-Rf点。混合物在室温搅拌过夜。将混合物小心地倾倒在冰/盐酸(约1.5升的10%HCl)上。总体积是2升。用乙酸乙酯(3×500毫升)萃取该混合物,合并有机物,用水洗涤(2×500毫升),然后用盐水(500毫升)洗涤。用硫酸镁干燥乙酸乙酯并蒸发,得到的液体静置时固化。该粗固体悬浮在在己烷中,过滤得到31.3克(74%)黄褐色固体。将一些这种物质用硅胶色谱法(10%乙酸乙酯-己烷)提纯,得到固体:
mp 47-49℃;1H NMR(DMSO-d6):δ2.44-2.50(2H,m),2.72(2H,t,J=8.4Hz),6.81(1H,d,J=2.6Hz),6.90(1H,dd,J=2.9Hz,J=8.2Hz),7.17-7.19(2H,m);MS m/z 168([M-H]-);
对C12H11NO的分析:
计算值:C:77.81 H:5.99 N:7.56
实验值:C:77.71 H:5.69 N:7.50
中间体62
7-甲氧基-1-氰基萘
向7-甲氧基-3,4-二氢萘-1-甲腈(9.95克,53.1毫摩尔)在对异丙基甲苯(100毫升)中的混合物中加入10%Pd/C(5克),搅拌反应混合物并加热到150℃过夜。冷却混合物,通过过滤助剂过滤除去催化剂。对异丙基甲苯用真空泵在转叶上除去,得到的液体静置时固化。将该固体悬浮在己烷中,过滤并干燥,得到白色固体(4.3克,44%)。将一部分用过硅胶(10%乙酸乙酯-己烷)提纯,得到白色固体:mp77-78℃;1H NMR(DMSO-d6):δ3.97(3H,s),7.36(1H,s),7.39(1H,d,J=2.5Hz),7.52(1H,t,J=7.4Hz),8.04-8.13(2H,m),8.24(1H,d,J=8.2Hz).
对C12H9NO的分析:
计算值:C:78.67 H:4.95 N:7.51
实验值:C:78.47 H:4.73 N:7.51
路线12中化合物的合成
中间体65
8-氟-2-萘酚
根据方法D,通过1-氟-7-甲氧基萘(7.99克,45.34毫摩尔)和三溴化硼(68毫升,1N溶液,68毫摩尔)反应制备标题化合物,得到3.99克(54%)的红色固体。分析样品通过制备逆相HPLC制备,得到白色固体:
mp 89-92℃;1H NMR(DMSO-d6):δ7.16(1H,dd,J=2.42Hz,J=8.90Hz),7.21-7.25(3H,m),7.62-7.65(1H,m),7.85(1H,dd,J=1.72Hz,J=8.87Hz),10.08(1H,s);MS(ESI)m/z 161(M-H)-.
对C10H7FO的分析:
计算值:C:74.07 H:4.35
实验值:C:73.90 H:4.30
中间体66
8-氯-2-萘酚
根据方法D,通过8-氯-2-甲氧基萘(10.25克,53.4毫摩尔)和三溴化硼(67毫升,1N溶液,67毫摩尔)反应制备标题化合物,得到8.76克(92%)黄色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 95-100℃;1H NMR(DMSO-d6):δ7.18(1H,dd,J=2.37Hz,J=8.85Hz),7.23-7.28(1H,m),7.41(1H,d,J=2.28Hz),7.59(1H,d,J=7.37Hz),7.81(1H,d,J=8.15Hz),7.87(1H,d,J=8.86Hz),10.17(1H,s);MS m/z 177/179(M-H)-.
对C10H7ClO的分析:
计算值:C:67.24 H:3.95
实验值:C:66.99 H:4.06
中间体67
7-羟基-1-萘甲腈
根据方法D,通过7-甲氧基-1-萘甲腈(1.19克,6.50毫摩尔)和盐酸吡啶鎓(9克)反应制备标题化合物,得到0.88克(80%)白色固体:
mp 184-188℃;1H NMR(DMSO-d6):δ7.25(1H,dd,J=2.30Hz,J=8.88Hz),7.38(1H,d,J=2.20Hz),7.39-7.44(1H,m),7.98(1H,d,J=8.91Hz),8.04(1H,d,J=7.14Hz),8.17(1H,d,J=8.19Hz),10.48(1H,s);MS(ESI)m/z 170([M+H]+);MS(ESI)m/z 168(M-H)-.
对C11H7NO的分析:
计算值:C:78.09 H:4.17 N:8.28
实验值:C:77.99 H:3.99 N:8.47.
中间体68
6-溴-8-氟-2-萘酚
向8-氟-2-萘酚(3.24克,20.0毫摩尔)在冰醋酸(30毫升)中的溶液中缓慢加入溴(7.35克,46.0毫摩尔)在冰醋酸(30毫升)中的溶液。溶液在100℃搅拌1小时。冷却反应至室温,倾入水(50毫升)中,然后用乙酸乙酯(3×150毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(2.5%乙酸乙酯-己烷)上提纯,得到3.96克(12.4毫摩尔,62%)中间体1,6-二溴-8-氟-2-萘酚,黄色固体。将该固体与SnCl2(7.0克,31毫摩尔)、冰醋酸(35毫升)和HCl(35毫升,12N)合并,加热到100℃1小时。将得到的溶液冷却至室温,倾入水(100毫升)中,然后用乙酸乙酯(3×200毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅上(2.5%乙酸乙酯-己烷)提纯,得到1.97克(41%)标题化合物,为白色固体:
mp 124-126℃;1H NMR(DMSO-d6):δ7.20(1H,s),7.23(1H,d,J=2.39Hz),7.48(1H,dd,J=1.78Hz,J=10.52Hz),7.84-7.88(1H,m),7.94(1H,d,J=0.79Hz),10.28(1H,s);MS(ESI)m/z 239/241(M-H)-.
对C10H6BrFO的分析:
计算值:C:49.83 H:2.51
实验值:C:49.86 H:2.46
中间体69
3,6-二溴-8-氯-2-萘酚
向8-氯-2-萘酚(4.92克,27.6毫摩尔)在冰醋酸(40毫升)中的溶液中缓慢加入溴(9.7克,60.7毫摩尔)在冰醋酸(40毫升)中的溶液。溶液在100℃搅拌1小时,冷却至室温,倾入水(250毫升)中,用乙酸乙酯萃取。合并的有机层用碳酸氢钠洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅柱(20%乙酸乙酯-己烷)上提纯,得到4.61克(50%)黄色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 156-158℃;1H NMR(DMSO-d6):δ7.57(1H,s),7.82(1H,d,J=1.89Hz),8.11(1H,d,J=1.69Hz),8.31(1H,s),11.30(1H,bs);MS(ESI)m/z 333/335/337(M-H)-.
对C10H5Br2ClO的分析:
计算值:C:35.70 H:1.50
实验值:C:35.74 H:1.44
中间体70
3-溴-7-羟基-1-萘甲腈
向7-羟基-1-萘甲腈(26.03克,154.0毫摩尔)和冰醋酸(400毫升)的混合物中加入溴(51.8克,323毫摩尔)。混合物在100℃搅拌6小时。加入HCl(400毫升,12N溶液)和SnCl2(69克,308毫摩尔),混合物在100℃搅拌1小时。得到的溶液冷却至室温,倾入水(1升)中。得到的黄色沉淀通过过滤收集,在真空下干燥,与乙酸乙酯一起研磨,得到14.68克(38%)标题化合物,为黄白色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 222-224℃;1H NMR(DMSO-d6):δ7.28-7.35(2H,m),7.97(1H,d,J=8.73Hz),8.26(1H,s),8.47(1H,s),10.65(1H,s);MS(ESI)m/z246/247(M-H)-.
对C11H6BrNO的分析:
计算值:C:53.26 H:2.44 N:5.65
实验值:C:52.81 H:2.70 N:4.82.
中间体71
叔丁基[(3,6-二溴-8-氯-2-萘基)氧基]二甲基甲硅烷
根据方法F,通过3,6-二溴-8-氯-2-萘酚(3.00克,8.92毫摩尔)和TBDMS-Cl(1.75克,150.7毫摩尔)反应制备标题化合物,得到3.36克(84%)白色固体:
mp 58-64℃;1H NMR(CDCl3):δ0.34(6H,s),1.08(9H,s),7.57(1H,s),7.62(1H,d,J=1.72Hz),7.75(1H,d,J=1.24Hz),7.97(1H,s);MS(ESI)m/z 333/335/337(M-H)-.
对C16H19Br2ClOSi的分析:
计算值:C:42.64 H:4.25
实验值:C:42.73 H:4.08
中间体72
8-氟-6-(4-甲氧苯基)-2-萘酚
根据方法A,通过6-溴-8-氟-2-萘酚(0.39克,1.62毫摩尔)和4-甲氧苯基硼酸(0.34克,2.27毫摩尔)反应制备标题化合物,得到0.35克(81%)白色固体:
mp 150-151℃;1H NMR(DMSO-d6):δ3.81(3H,s),7.05(2H,d,J=8.75Hz),7.16-7.20(2H,m),7.57(1H,dd,J=1.21Hz,J=12.76Hz),7.74(214,d,J=8.74Hz),7.89-7.92(2H,m),10.10(1H,s);MS(ESI)m/z 269(M-H)+.
对C17H13FO2·0.1H2O的分析:
计算值:C:75.60 H:4.93
实验值:C:75.30 H:4.57
中间体73
8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-溴-8-氟-2-萘酚(0.66克,2.73毫摩尔)和3-氟-4-甲氧苯基硼酸(0.56克,3.3毫摩尔)反应制备标题化合物,得到0.67克(85%)白色固体:
mp 138-140℃;1HNMR(DMSO-d6):δ3.90(3H,s),7.17-7.30(3H,m),7.60-7.65(2H,m),7.71(1H,dd,,J=2.19Hz),,J=13.14Hz),7.90(1H,d,,J=8.37Hz),7.99(1H,bs),10.15(1H,bs);MS(ES)m/z 285(M-H)-.
对C17H12F2O2的分析:
计算值:C:71.32 H:4.23
实验值:C:71.09 H:4.15
中间体74
叔丁基[(3-溴-8-氯-(4-甲氧苯基)-2-萘基)氧基]二甲基甲硅烷
叔丁基[(3,6-二溴-8-氯-2-萘基)氧基]二甲基甲硅烷(1.95克,4.32毫摩尔)、4-甲氧基苯基溴化镁(13.8毫升的0.5N溶液,6.9毫摩尔)和四(三苯基膦)钯(0.25克,0.21毫摩尔)在THF(10毫升)中的溶液回流搅拌8小时。反应用水(100毫升)淬灭,用乙酸乙酯(3×150毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(5%乙酸乙酯-己烷)上提纯,得到1.42克(69%)标题化合物,为白色固体:
1H NMR(CDCl3):δ0.36(6H,s),1.10(9H,s),3.87(3H,s),7.01(2H,d,J=8.78Hz),7.33(1H,d,J=1.36Hz),7.58(2H,d,J=8.75Hz),7.73(1H,s),7.78(1H,d,J=1.62Hz),8.10(1H,s).
中间体75
7-羟基-3-(4-甲氧苯基)-1-萘甲腈
根据方法A,通过3-溴-7-羟基-1-萘甲腈(0.249克,1.00毫摩尔)与4-甲氧基苯基硼酸(0.21克,1.4毫摩尔)反应制备标题化合物,得到0.19克(69%)浅黄色固体:
mp 226℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.07(2H,d,J=8.82Hz),7.26(1H,dd,J=2.32Hz,J=8.90Hz),7.37(1H,d,J=2.27Hz),7.80(2H,d,J=8.80Hz),8.02(1H,d,J=8.96Hz),8.37(1H,d,J=1.85Hz),8.44(1H,d,J=1.43Hz),10.48(1H,bs);MS(ESI)m/z 274(M-H)-.
对C18H13NO2·0.1H2O的分析:
计算值:C:78.02 H:4.80 N:5.05
实验值:C:77.73 H:4.65 N:4.92.
中间体76
3-(3-氟-4-甲氧苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-7-羟基-1-萘甲腈(0.208克,0.839毫摩尔)与3-氟-4-甲氧基苯基硼酸(0.18克,1.1毫摩尔)反应制备标题化合物,得到0.16克(65%)浅黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物白色固体:
mp 214-216℃;1H NMR(DMSO-d6):δ3.90(3H,s),7.23-7.32(2H,m),7.37(1H,d,J=2.24Hz),7.65-7.70(1H,m),7.79(1H,dd,J=2.22Hz,J=13.10Hz),8.03(1H,d,J=8.96Hz),8.41(1H,d,J=1.86Hz),8.50(1H,d,J=1.43Hz),10.55(1H,s);MS(ESI)m/z 292(M-H)-.
对C18H12FNO2·0.1H2O的分析:
计算值:C:73.26 H:4.17 N:4.75
实验值:C:72.91 H:4.01 N:4.60.
中间体77
3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚
方法I
向叔丁基[(3-溴-8-氯-(4-甲氧苯基)-2-萘基)-氧基]二甲基甲硅烷(0.50克,1.06毫摩尔)在THF(20毫升)中的溶液中加入TBAF(5毫升1N在THF中的溶液,55毫摩尔)。溶液在室温搅拌1小时,蒸发溶剂,置于水中(50毫升),用乙酸乙酯(3×150毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到0.34克(88%)白色色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 138-139℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,J=8.76Hz),7.5891H,s),7.73(2H,d,J=8.73Hz),7.94(1H,d,J=1.56Hz),8.07(H,bs),8.34(1H,s),11.05(1H,s);MS(ESI)m/z 361/363/365(M-H)-.
对C17H12BrClO2·0.6H2O的分析:
计算值:C:54.53 H:3.55
实验值:C:54.30 H:3.11
实施例1az
3-(3,5-二氟-4-羟基苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-7-羟基-1-萘甲腈(0.124克,0.50毫摩尔)和2,5-二氟-4-叔丁基二甲基甲硅烷氧基苯基硼酸(0.17克,0.59毫摩尔)反应制备标题化合物,得到0.090克(61%)黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为浅黄色固体:
mp 300-304℃(d);1H NMR(DMSO-d6):δ7.2791H,dd,J=2.26Hz,J=8.88Hz),7.36(1H,d,J=2.12Hz),7.63-7.66(2H,m),8.00(1H,d,J=8.95Hz),8.43(1H,d,J=1.77Hz),8.52(1H,s),10.44(1H,s),10.54(1H,s);MS(ESI)m/z 296(M-H)-.
对C17H9F2NO2·0.3H2O的分析:
计算值:C:67.46 H:3.20 N:4.63
实验值:C:67.18 H:2.89 N:4.55.
实施例1aj
8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过8-氟-6-(4-甲氧苯基)-2-萘酚(0.10克,0.37毫摩尔)和三溴化硼(0.56毫升的1N溶液,0.56毫摩尔)反应制备标题化合物,得到0.10克(定量地)白色固体:
mp 236-238℃;1H NMR(DMSO-d6):δ6.87(2H,d,J=8.57Hz),7.14-7.18(2H,m),7.52(1H,dd,J=1.18Hz,J=12.78Hz),7.61(2H,d,J=8.59Hz,7.86-7.89(2H,m),9.61(1H,bs),10.05(1H,bs);MS(ESI)m/z 253(M-H)-.
对C16H11FO2·0.1H2O的分析:
计算值:C:75.06 H:4.41
实验值:C:75.01 H:4.11
实施例1ak
8-氟-6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚(0.10克,0.35毫摩尔)和三溴化硼(0.7毫升的1N溶液,0.7毫摩尔)反应制备标题化合物,得到0.020克(21%)白色固体:
mp 218-220℃d;1H NMR(DMSO-d6):δ7.01-7.07(1H,m),7.16-7.19(2H,m),7.46(1H,dd,,J=1.74Hz,,J=8.40Hz),7.56-7.65(2H,m),7.88(1H,d,,J=8.31Hz),7.93(1H,bs),10.04(1H,s),10.11(1H,s);MS(ESI)m/z 271(M-H)-.
对C16H10F2O2·0.25H2O的分析
计算值:C:69.44 H:3.82
实验值:C:69.13 H:3.45
实施例1au
7-羟基-3-(4-羟基苯基)-1-萘甲腈
根据方法B,通过7-羟基-3-(4-甲氧苯基)-1-萘甲腈(0.14克,0.51毫摩尔)和盐酸吡啶鎓(3克)反应制备标题化合物,得到0.10克(75%)白色固体:
mp 254-257℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.53Hz),7.25(1H,dd,J=2.15Hz,J=8.88Hz),7.36(1H,d,J=1.86Hz),7.67(2H,d,J=8.55Hz),8.00(1H,d,J=8.94Hz),8.31-8.38(2H,m),9.70(1H,bs),10.44(1H,bs);MS(ESI)m/z 260(M-H)-.
对C17H11NO2·0.25H2O的分析
计算值:C:76.83 H:4.36 N:5.27
实验值:C:76.85 H:4.31 N:5.10.
实施例1av
3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈
根据方法B,通过7-羟基-3-(3-氟-4-甲氧苯基)-1-萘甲腈(0.12克,0.41毫摩尔)和盐酸吡啶鎓(3克)反应制备标题化合物,得到0.085克(74%)白色固体:
mp 265-269℃;1H NMR(DMSO-d6):δ7.04-7.09(1H,m),7.26(1H,dd,J=2.31Hz,J=8.88Hz),7.36(1H,d,J=2.19Hz),6.52(1H,d,J=2.19Hz),6.52(1H,dd,J=1.76Hz,J=8.40Hz),6.71(1H,dd,J=2.22Hz,J=12.88Hz),8.01(1H,d,J=8.97Hz),8.37(1H,d,J=1.83Hz),8.45(1H,d,J=1.41Hz),10.33(2H,bs);MS(ESI)m/z278(M-H)-.
对C17H10FNO2.的分析:
计算值:C:73.11 H:3.61 N:5.02
实验值:C:72.75 H:3.45 N:4.82.
路线13中化合物的合成
中间体78和中间体79
1-氯-6-甲氧基-2-萘酚和1,5-二氯-6-甲氧基-2-萘酚
根据方法A,6-甲氧基-2-萘酚(5.43克,31.17毫摩尔)、NCS(4.58克,34.3毫摩尔)和乙腈(150毫升)的混合物在室温搅拌过夜。除去溶剂,得到的棕色固体残留物溶于乙酸乙酯(500毫升)中,用水洗涤,用硫酸钠干燥,蒸发溶剂,在二氧化硅柱(20%乙酸乙酯-己烷)上提纯,得到白色固体。该固体进一步用逆相制备HPLC提纯,得到3.91克(60%)中间体78,为白色固体:
mp 104-105℃;1H NMR(DMSO-d6):δ3.85(3H,s),7.22-7.26(2H,m),7.31(1H,d,J=2.42Hz),7.68(1H,d,J=8.91Hz),7.93(1H,d,J=9.17Hz);MS(ESI)m/z207/209(M-H)-.
对C11H9ClO2的分析:
计算值:C:63.32 H:4.35
实验值:C:63.21 H:4.50
HPLC分离进一步得到0.83克(3.43毫摩尔)的中间体79,为白色固体:
mp 152-158℃;1H NMR(DMSO-d6):δ3.97(3H,s),7.41(1H,d,J=9.22Hz),7.63(1H,d,J=9.17Hz),7.97(1H,d,J=9.23Hz),8.04(1H,d,J=9.34Hz),10.51(1H,s);MS(ESI)m/z 241/243(M-H)-.
对C11HXCl2O2的分析:
计算值:C:54.35 H:3.32
实验值:C:54.13 H:3.21
中间体80
三氟甲磺酸(1-氯-6-甲氧基-2-萘基)酯
根据中间体6,通过1-氯-6-甲氧基-2-萘酚(0.70克,3.36毫摩尔)和三氟甲磺酸酐(1.23克,4.4毫摩尔)反应制备标题化合物,得到1.02克(89%)白色固体:
mp 60-61℃;1HNMR(CDCl3):δ3.95(3H,s),7.17(1H,d,J=2.48Hz),7.35(1H,dd,J=2.50Hz,J=9.30Hz),7.39(1H,d,J=9.06Hz),7.71(1H,d,J=9.11Hz),8.21(1H,d,J=9.28Hz);MS(EI)m/z 340/342(M-)+.
对C12H8ClF3O4S的分析
计算值:C:42.30 H:2.37
实验值:C:42.20 H:2.37
中间体81
三氟甲磺酸(1,5-二氯6-甲氧基-2-萘基)酯
根据中间体6,通过1,5-二氯-6-甲氧基-2-萘酚(0.27克,1.11毫摩尔)和三氟甲磺酸酐(0.41克,1.44毫摩尔)反应制备标题化合物,得到0.37克(89%)白色固体:
mp 73-78℃;1H NMR(CDCl3):64.08(3H,s),7.48-7.52(2H,m),8.24-8.30(2H,m);MS(EI)m/z 374/376/378(M-)+.
对C12H7Cl2F3O4S的分析:
计算值:C:38.42 H:1.88
实验值:C:38.65 H:1.90
中间体82
1-氯-2-甲氧基-2-(4-甲氧苯基)萘
根据方法A,通过三氟甲磺酸(1-氯-6-甲氧基-2-萘基)酯(0.95克,2.79毫摩尔)和4-甲氧苯基硼酸(0.59克,3.9毫摩尔)反应制备标题化合物,得到0.71克(85%)白色固体:mp126-128℃;1H NMR(CDCl3):δ3.88(3H,s),3.95(3H,s),7.01(2H,d,J=8.60Hz),7.16(1H,d,J=2.49Hz),7.27(1H,dd,J=1.97Hz,J=8.99Hz),7.41(1H,d,J=8.45Hz),7.46(2H,d,J=8.61Hz),7.68(1H,d,J=8.48Hz),8.28(1H,d,J=9.27Hz);MS(ESI)m/z 299/301(M+H)+.
对C18H15ClO2·0.25H2O的分析
计算值:C:71.29 H:5.15
实验值:C:70.84 H:4.80
中间体83
1,5-二氯-2-甲氧基-6-(4-甲氧苯基)萘
根据方法A,通过三氟甲磺酸(1,5-二氯-6-甲氧基-2-萘基)酯(0.32克,0.85毫摩尔)和4-甲氧苯基硼酸(0.18克,1.2毫摩尔)反应制备标题化合物,得到0.27克(95%)白色固体:
mp 146-149℃;1H NMR(CDCl3):δ3.88(3H,s),4.07(3H,s),7.02(2H,d,J=8.73Hz),7.41(1H,d,J=9.52Hz),7.46(2H,d,J=8.83Hz),7.53(1H,d,J=8.73Hz),8.19(1H,d,J=8.73Hz),8.36(1H,d,J=9.12Hz);
对C18H14Cl2O2的分析:
计算值:C:64.88 H:4.23
实验值:C:64.63 H:4.28
实施例1ao
5-氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-6-甲氧基-2-(4-甲氧基苯基)萘(0.65克,2.18毫摩尔)和三溴化硼(6.5毫升的1N溶液)反应制备标题化合物,得到0.44克(75%)白色固体:
mp>220℃;1H NMR(DMSO-d6):δ6.86(2H,d,J=8.33Hz),7.23-7.28(2H,m),7.30(2H,d,J=8.32Hz),7.37(1H,d,J=8.51Hz),7.72(1H,d,J=8.55Hz),8.13(1H,d,J=9.07Hz);MS(ESI)m/z 269/271(M-H)-.
对C16H11ClO2·0.1H2O的分析
计算值:C:70.52 H:4.14
实验值:C:70.52 H:4.05
实施例1ap
1,5-二氯6-(4-羟基苯基)-2-萘酚
根据方法D,通过1,5-二氯-2-甲氧基-6-(4-甲氧苯基)萘(0.15克,0.45毫摩尔)和三溴化硼(1.4毫升的1N溶液)反应制备标题化合物,得到0.10克(73%)白色固体:
mp 204-206℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.47Hz),7.33(2H,d,J=8.45Hz),7.46(1H,d,J=9.26Hz),7.56(1H,d,J=8.80Hz),8.06(1H,d,J=8.81Hz),8.17(1H,d,J=9.28Hz),9.68(1H,bs),10.84(1H,bs);MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2的分析
计算值:C:62.98 H:3.30
实验值:C:62.78 H:3.28
路线14中化合物的合成
中间体84
8-氯-6-(4-甲氧苯基)-2-萘酚
向3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚(0.254克,0.698毫摩尔)在THF(25毫升)中的-78℃的溶液中缓慢加入叔丁基锂(1.65毫升的1.7N溶液,2.8毫摩尔)。得到的溶液在-78℃搅拌20分钟,加入2.5毫升水,混合物缓慢温热至室温同时进行搅拌。反应物倾入50毫升的水中,用乙酸乙酯(3×100毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到0.15克(88%)黄色固体。分析样品进一步用逆相制备HPLC制备,得到标题化合物,为浅黄色固体:
mp 116-118℃;1H NMR(DMSO-d6):δ3.81(3H,s),7.05(2H,d,J=8.75Hz),7.19(1H,dd,J=2.34Hz,J=8.84Hz),7.40(1H,d,J=2.25Hz),7.74(2H,d,J=8.73Hz),7.89(1H,d,J=1.65Hz),7.92(1H,d,J=8.93Hz),8.07(1H,s),10.19(1H,s);MS(ESI)m/z 283/285(M-H)-.
对C17H13ClO2·0.1H2O的分析:
计算值:C:71.26 H 4.64
实验值:C:71.18 H:4.43 N
中间体85
1-氟-8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法C,通过8-氟-6-(3-氟-4-甲氧基-苯基)-2-萘酚(0.30克,1.05毫摩尔)和NCS(0.17克,1.26毫摩尔)反应制备标题化合物,得到0.21克(62%)浅橙色固体:
mp 126-128℃;1H NMR(DMSO-d6):δ3.90(3H,s),7.25-7.31(1H,m),7.35(1H,d,,J=8.91Hz),7.64-7.67(1H,m),7.70-7.78(2H,m),7.87(1H,dd,,J=1.58Hz,,J=9.04Hz),10.68(1H,s);MS(ESI)m/z 319/321(M-H)-.
对C17H11ClF2O2的分析:
计算值:C:63.66 H:3.46
实验值:C:63.23 H:3.39
中间体86
1-氯-8-氟-6-(4-甲氧苯基)-2-萘酚
根据方法C,8-氟-6-(4-甲氧苯基)-2-萘酚(0.17克,0.63毫摩尔)和NCS(0.10克,0.76毫摩尔)在THF(20毫升)中的溶液在氮气下在室温搅拌过夜。将溶液浓缩到硅酸铝担体(Florosil)上,在二氧化硅柱上提纯(20%乙酸乙酯-己烷),得到0.16克(84%)标题化合物,为黄色固体。分析样品进一步通过制备逆相HPLC制备,得到浅黄色固体:
mp 120-124℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,,J=8.80Hz),7.34(1H,d,J=8.91Hz),7.67(1H,dd,J=1.69Hz,,J=15.48Hz),7.78(2H,d,J=8.78Hz),8.01(1H,d,J=1.54Hz),10.62(1H,s);MS(ESI)m/z 301/303(M-H)-.
对C17H12ClFO2的分析
计算值:C:67.45 H:4.00
实验值:C:67.23 H:3.65
中间体87
1,5-二氯-8-氟-6-(4-甲氧苯基)-2-萘酚
根据方法C,通过8-氟-6-(4-甲氧苯基)-2-萘酚(0.24克,0.90毫摩尔)和NCS(0.22克,1.6毫摩尔)在乙腈(20毫升)中反应制备标题化合物,得到0.22克(73%)黄色固体:
1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,J=8.69Hz),7.39(1H,d,J=14.34Hz),7.47(2H,d,J=8.68Hz),7.53(1H,d,J=9.36Hz),8.22(1H,dd,J=1.65Hz,J=9.32Hz),11.01(1H,s);MS(ESI)m/z 335/337(M-H)-.
中间体88
3-溴-1,8-二氯-6-(4-甲氧苯基)-2-萘酚
根据方法C,通过3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚(0.69克,1.90毫摩尔)和NCS(0.31克,2.3毫摩尔)在THF(25毫升)中反应制备标题化合物,得到0.61克(81%)黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 176-178℃(dec.);1H NMR(DMSO-d6):δ3.82(3H,s),7.08(2H,d,J=8.77Hz),7.77(2H,d,J=8.75Hz),8.00(1H,d,J=1.84Hz),8.19(1H,d,J=1.84Hz),8.39(1H,s),10.53(1H,bs);MS(ESI)m/z 395/397/399(M-H)-.
对C17H11BrCl2O2的分析
计算值:C:51.29 H:2.79
实验值:C:51.37 H:2.62
中间体89
8-溴-7-羟基-3-(4-甲氧苯基)-1-萘甲腈
根据方法C,通过7-羟基-3-(4-甲氧苯基)-1-萘甲腈(0.160克,0.58毫摩尔)和NBS(0.12克,0.70毫摩尔)在THF(10毫升)中反应制备标题化合物,得到0.080克(39%)黄色固体:
mp 145-146℃;1HNMR(DMSO-d6):δ3.83(3H,s),7.08(2H,d,J=8.79Hz),7.42(1H,d,J=8.79Hz),7.84(2H,d,J=8.79Hz),8.04(1H,d,J=8.79Hz),8.42(1H,d,J=1.95Hz),8.53(1H,d,J=1.95Hz),11.21(1H,s);MS(ESI)m/z 354/356(M+H+;MS(ESI)m/z352/354(M-H)-.
对C18H12BrNO2·0.25H2O的分析
计算值:C:60.27 H:3.51 N:3.90
实验值:C:60.27 H:3.51 N:3.46.
中间体90
1,8-二氯-6-(4-甲氧苯基)-2-萘酚
根据制备中间体84的方法,通过3-溴-1,8-二氯-6-(4-甲氧苯基)-2-萘酚(0.30克,0.754毫摩尔)和叔丁基锂(1.75毫升的1.7N溶液,3.0毫摩尔)反应并用水淬灭,制备标题化合物,得到0.19克(79%)的黄色固体。分析样品进一步用逆相制备HPLC制备,得到标题化合物,为浅黄色固体:
mp 132-134℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,J=8.77Hz),7.37(1H,d,J=8.90Hz),7.77(2H,d,J=8.75Hz),7.89-7.93(2H,m),8.15(1H,d,J=1.85Hz),10.68(1H,s);MS(ESI)m/z 317/319/321(M-H)-.
对C17H12Cl2O2的分析
计算值:C:63.97 H:3.79
实验值:C:63.57 H:3.65
实施例1al
1-氯-8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-8-氟-6-(4-甲氧基-苯基)-2-萘酚(0.14克,0.46毫摩尔)和三溴化硼(0.69毫升的1N溶液,0.69毫摩尔)反应制备标题化合物,得到0.050克(38%)白色固体:
mp 174-176℃;1H NMR(DMSO-d6):δ6.88(2H,d,J=8.62Hz),7.33(1H,d,J=8.92Hz),7.60-7.67(3H,m),7.86(1H,dd,,J=1.43Hz,J=9.02Hz),7.95(1H,d,J=1.37Hz),9.68(1H,s),10.59(1H,s);MS(ESI)m/z 287/289(M-H)-.
对C16H10ClFO2·0.25H2O的分析
计算值:C:65.54 H:3.61
实验值:C:65.52 H:3.19
实施例1am
1-氯-8-氟-6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚(0.13克,0.41毫摩尔)和三溴化硼(0.8毫升的1N溶液,0.8毫摩尔)反应制备标题化合物,得到0.070克(56%)白色固体:
mp 198-200℃;1H NMR(DMSO-d6):δ7.03-7.09(1H,m)7.34(1H,d,J=8.92Hz),7.49-7.52(1H,m),7.68(2H,d,,J=15.0Hz),7.85-7.88(1H,m),8.02(1H,d,J=0.70Hz),10.13(1H,s),10.66(1H,s);MS(ESI)m/z 305/307(M-H)-.
对C16H9ClF2O2的分析
计算值:C:62.66 H:2.96
实验值:C:62.27 H:2.90
实施例1an
8-氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过8-氯-6-(4-甲氧苯基)-2-萘酚(0.10克,0.35毫摩尔)和三溴化硼(0.9毫升的1N溶液,0.9毫摩尔)反应制备标题化合物,得到0.080克(85%)的产品,将其进一步用逆相制备HPLC提纯,得到标题化合物,为白色固体:
mp 204-206℃;1H NMR(DMSO-d6):δ6.87(2H,d,J=8.61Hz),7.17(1H,dd,J=2.34Hz,J=8.83Hz),7.38(1H,d,J=2.26Hz),7.62(2H,d,J=8.59Hz),7.85(1H,d,J=1.64Hz),7.90(1H,d,J=8.92Hz),8.01(1H,bs),9.62(1H,s),10.14(1H,s);MS(ESI)m/z269/(M-H)-.
对C16H11ClO2·0.25H2O的分析
计算值:C:70.99 H:4.10
实验值:C:69.95 H:3.89
实施例1aq
1,5-二氯-8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1,5-二氯-8-氟-6-(4-甲氧苯基)-2-萘酚(0.15克,0.445毫摩尔)和三溴化硼(0.67毫升的1N溶液,0.67毫摩尔)反应制备标题化合物,得到0.12克(83%)浅黄色固体。
mp 206-216℃;1H NMR(DMSO-d6):δ6.88(2H,d,J=8.55Hz),7.34-7.39(3H,m),7.51(1H,d,J=9.34Hz),8.21(1H,dd,J=1.66Hz,J=9.34Hz),9.74(1H,bs),10.99(1H,bs);MS(ESI)m/z 321/323/326(M-H)-.
对C16H9Cl2FO2·0.1H2O的分析
计算值:C:59.13 H:2.85
实验值:C:58.88 H:2.85
实施例1ar
3-溴-8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚(0.24克,0.66毫摩尔)和三溴化硼(1.6毫升的1N溶液,1.6毫摩尔)反应制备标题化合物,得到0.14克(61%)黄色油。产品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 188-190℃;1H NMR(DMSO-d6):δ6.88(1H,d,J=8.60Hz),7.57(1H,s),7.71(2H,d,J=8.61Hz),7.89(1H,d,J=1.60Hz),8.02(1H,s),8.31(1H,s),9.67(1H,s),11.01(1H,s);MS(ESI)m/z 347/349/351(M-H)-.
对C16H10BrClO2的分析:
计算值:C:54.97 H:2.88
实验值:C:54.68 H:2.82
实施例1as
1,8-二氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1,8-二氯-6-(4-甲氧苯基)-2-萘酚(0.12克,0.38毫摩尔)和三溴化硼(0.75毫升的1N溶液,0.75毫摩尔)反应制备标题化合物,得到0.10(86%)产物,将其进一步用逆相制备HPLC提纯,得到标题化合物,为白色固体:
mp 172-174℃(dec.);1H NMR(DMSO-d6):δ6.89(2H,d,J=8.54Hz),7.36(1H,d,J=8.90Hz),7.65(2H,d,J=8.56Hz),7.88-7.91(2H,m),8.10(1H,d,J=1.63Hz),9.69(1H,s),10.64(1H,s);MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2·0.25H2O的分析
计算值:C:62.98 H:3.30
实验值:C:61.80 H:3.08
实施例1at
3-溴-1,8-二氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过3-溴-1,8-二氯-6-(4-甲氧苯基)-2-萘酚(0.18克,0.45毫摩尔)和三溴化硼(0.9毫升的1N溶液,0.9毫摩尔)反应制备标题化合物,得到0.12克(69%)浅棕色固体。产品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 184-188℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.59Hz),7.65(2H,d,J=8.61Hz),7.95(1H,d,J=1.78Hz),8.13(1H,d,J=1.75Hz),8.37(1H,s),9.74(1H,s),10.50(1H,s);MS(ESI)m/z 381/383/385(M-H)-.
对C16H9BrCl2O2·0.25H2O的分析
计算值:C:50.04 H:2.36
实验值:C:49.10 H:2.14
实施例1bb
8-溴-7-羟基-3-(4-羟基苯基)-1-萘甲腈
根据方法D,通过8-溴-7-羟基-3-(4-甲氧苯基)-1-萘甲腈(0.13克,0.37毫摩尔)和三溴化硼(1.1毫升的1N溶液,1.1毫摩尔)反应制备标题化合物,得到0.050克(40%)米色固体:
mp 204-208℃(d);1H NMR(DMSO-d6):δ6.90(2H,d,J=8.30Hz),7.41(1H,d,J=8.79Hz),7.72(2H,d,J=8.79Hz),8.02(1H,d,J=9.23Hz),8.37(1H,d,J=1.95Hz),8.47(1H,d,J=2.44Hz),9.72(1H,s),11.16(1H,s);MS(ESI)m/z 338/340(M-H).
对C17H10BrNO2的分析
计算值:C:60.02 H:2.96 N:4.12
实验值:C:59.84 H:3.18 N:3.83.
路线15中化合物的合成
中间体91
3-溴-8-氯-7-羟基-1-萘甲腈
向在压力管中的8-氯-7-羟基-1-萘甲腈(0.127克,0.63毫摩尔)和冰醋酸(1毫升)的混合物中加入溴(0.24克,1.5毫摩尔)在冰醋酸(2毫升)中的溶液。将管密封,混合物在100℃搅拌过夜。冷却反应,倾入水(50毫升)中,然后用乙酸乙酯(3×100毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅柱上提纯(20%乙酸乙酯-己烷),得到0.10克(56%)标题化合物,为黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 148-150℃;1H NMR(DMSO-d6):δ7.47(1H,d,J=8.98Hz),7.95(1H,d,J=9.02Hz),8.32(1H,d,J=2.08Hz),8.55(1H,d,J=2.08Hz),11.33(1H,s);MS(ESI)m/z280/282/284(M-H)-.
对C11H5BrClNO·0.25H2O的分析:
计算值:C:46.03 H:1.93 N:4.88
实验值:C:45.92 H:1.75 N:4.78.
中间体91
3-溴-8-氯-7-羟基-1-萘甲腈
根据方法C,通过3-溴-7-羟基-1-萘甲腈(0.32克,1.28毫摩尔)和NCS(0.24克,1.8毫摩尔)在THF(25毫升)中在45℃反应3小时制备标题化合物,得到0.30克(83%)黄色固体。分析样品通过制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 148-150℃;1H NMR(DMSO-d6):δ7.47(1H,d,J=8.98Hz),7.95(1H,d,J=9.02Hz),8.32(1H,d,J=2.08Hz),8.55(1H,d,J=2.08Hz),11.33(1H,s);MS(ESI)m/z 280/282/284(M-H)-
对C11H5BrClNO·0.25H2O的分析:
计算值:C:46.03 H:1.93 N:4.88
实验值:C:45.92 H:1.75 N:4.78.
中间体92
8-氯-3-(3-氟-4-甲氧苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-8-氯-7-羟基-1-萘甲腈(0.20克,0.71毫摩尔)与3-氟-4-甲氧基苯基硼酸(0.17克,1.0毫摩尔)反应制备标题化合物,得到0.14(60%)黄色固体:
mp 198-200℃;1H NMR(DMSO-d6):δ3.91(3H,s),7.27-7.33(1H,m),7.45(1H,d,J=8.93Hz),7.71-7.74(1H,m),7.85(1H,dd,J=2.23Hz,J=13.09Hz),8.00(1H,d,J=9.08Hz),8.48(1H,d,J=1.97Hz),8.57(1H,d,J=1.95Hz),11.18(1H,s);MS(ESI)m/z 326/328(M-H)-.
对C18H11ClFNO2的分析
计算值:C:65.97 H:3.38 N:4.27
实验值:C:65.76 H:3.36 N:4.11.
实施例1aw
8-氯-3-(4-羟基苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-8-氯-7-羟基-1-萘甲腈(0.10克,0.37毫摩尔)与4-叔丁基二甲基甲硅烷氧基苯基硼酸(0.13克,0.52毫摩尔)反应制备标题化合物,得到0.036克(33%)白色固体:
mp 254-256℃;1H NMR(DMSO-d6):δ6.90(2H,d,J=8.64Hz),7.43(1H,d,J=8.95Hz),7.72(2H,d,J=8.64Hz),7.99(1H,d,J=8.97Hz),8.38(1H,d,J=1.95Hz),8.47(1H,d,J=1.92Hz),9.73(1H,s),11.08(1H,s);MS(ESI)m/ z294/296(M-H)-.
对C17H10ClNO2的分析
计算值:C:69.05 :H3.41 N:4.74
实验值:C:69.01 H:3.63 N:4.31.
实施例1ax
8-氯-3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈
根据方法D,通过8-氯-3-(3-氟-4-甲氧苯基)-7-羟基-1-萘甲腈(0.042克,0.13毫摩尔)和盐酸吡啶鎓(1.8克)反应制备标题化合物,得到0.033克(78%)黄褐色固体。该物质进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 246-252℃;1H NMR(DMSO-d6):δ7.04-7.10(1H,m),7.4491H,d,J=8.94Hz),7.56(1H,dd,J=1.66Hz,J=8.37Hz),7.76(1H,dd,J=2.20Hz,J=12.88Hz),7.99(1H,d,J=9.09Hz),8.43(1H,d,J=1.98Hz),8.52(1H,d,J=1.94Hz),10.19(1H,bs),11.05(1H,bs);MS(ESI)m/z 312/314(M-H)-.
对C17H9ClFNO2·0.25H2O的分析:
计算值:C:64.16 H:3.01 N:4.40
实验值:C:63.75 H:2.84 N:4.20.
Claims (31)
1.具有下述结构的化合物或其药学可接受的盐,
其中
R1、R2、R3和R4分别独立地选自氢、羟基、1-6个碳原子的烷基、1-6个碳原子的烷氧基或卤素;
R5、R6、R7、R8、R9和R10分别独立地是氢、1-6个碳原子的烷基、2-7个碳原子的烯基、2-7个碳原子的炔基、卤素、1-6个碳原子的烷氧基、-CN、-CHO、苯基或具有1-4个选自O、N或S的杂原子的5或6-元杂环;其中R5、R6、R7、R8、R9或R10的烷基或烯基部分可任选被羟基、-CN、卤素、三氟烷基、三氟烷氧基、-NO2或苯基取代;其中R5、R6、R7、R8、R9或R10的苯基部分可任选被一、二或三取代,取代基选自1-6个碳原子的烷基、2-7个碳原子的烯基、卤素、羟基、1-6个碳原子的烷氧基、-CN、-NO2、氨基、1-6个碳原子烷基氨基、每个烷基具有1-6个碳原子的二烷基氨基、巯基、1-6个碳原子的烷硫基、1-6个碳原子的烷基亚磺酰基、1-6个碳原子的烷基磺酰基、2-7个碳原子的烷氧羰基、2-7个碳原子的烷基羰基或苯甲酰基;
前提是R1、R2、R3、R6、R7、R8、R9或R10中的至少一个是羟基。
3.根据权利要求1或权利要求2的化合物,其中R1和R2彼此独立地选自氢和氟。
4.根据权利要求1-3任一项的化合物,其中R5、R6、R7、R9和R9分别独立地是氢、卤素、-CN或2-7个碳原子的炔基。
5.根据权利要求1-4任一项的化合物,其中R5选自氢、氟或氰基。
6.根据权利要求1-5任一项的化合物,其中R9选自氢、氟或氰基。
7.根据权利要求1-6任一项的化合物,其中R6、R7和R8是氢。
8.根据权利要求1-7任一项的化合物,其中具有1-4个选自O、N或S的杂原子的5或6-元杂环是呋喃、噻吩或吡啶。
9.根据权利要求1的化合物,其为8-氟-6-(3-氟-4-羟基苯基)-2-萘酚或其药学可接受的盐。
10.根据权利要求1的化合物,其为1-氯-8-氟-6-(3-氟-4-羟基苯基)-2-萘酚或其药学可接受的盐。
11.根据权利要求1的化合物,其为3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈或其药学可接受的盐。
12.根据权利要求1的化合物,其为3-(3,5-二氟-4-羟基苯基)-7-羟基-1-萘甲腈或其药学可接受的盐。
13.萘酚化合物,其为下述化合物之一:
6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,6-二氟-4-羟基苯基)-2-萘酚;
6-(2,5-二氟-4-羟基苯基)-2-萘酚;
6-(3,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3,5-二氟-4-羟基苯基)-2-萘酚;
6-(2,6-二氟-4-羟基苯基)-2-萘酚;或
8-氯-3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈;
或其药学可接受的盐。
14.化合物,其为下述之一:
7-(4-羟基苯基)-2-萘酚;
7-(3-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-萘酚;
6-苯基-2-萘酚;
6-(3-羟基苯基)-2-萘酚;
6-(3-氯苯基)-2-萘酚;
2-氟-4-(2-萘基)苯酚;
6-(3-氯-4-羟基酚)-2-萘酚;
1-氯-6-苯基-2-萘酚;
1-溴-6-(4-羟基苯基)-2-萘酚;
1-氯-6-(4-羟基苯基)-2-萘酚;
1-氟-6-(4-羟基苯基)-2-萘酚;
2-羟基-6-(4-羟基苯基)-1-萘甲腈;
6-(4-羟基苯基)-1-苯基-2-萘酚;
6-(4-羟基苯基)-1-甲基-2-萘酚;
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-硝基2-萘酚;
1-氯-6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲氧苯基)-2-萘酚;
6-(2-氯-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氯-4-羟基苯基)-2-萘酚;
6-(2-氟-4-羟基苯基)-2-萘酚;
8-氟-6-(4-羟基苯基)-2-萘酚;
1-氯-8-氟-6-(4-羟基苯基)-2-萘酚;
8-氯-6-(4-羟基苯基)-2-萘酚;
1,5-二氯-8-氟-6-(4-羟基苯基)-2-萘酚;
2-氯-4-(2-萘基)苯酚;
3-溴-8-氯-6-(4-羟基苯基)-2-萘酚;
1,8-二氯-6-(4-羟基苯基)-2-萘酚;
3-溴-1,8-二氯-6-(4-羟基苯基)-2-萘酚;
7-羟基-3-(4-羟基苯基)-1-萘甲腈;
8-氯-3-(4-羟基苯基)-7-羟基-1-萘甲腈;
8-溴-7-羟基-3-(4-羟基苯基)-1-萘甲腈
或其药学可接受的盐。
15.治疗或抑制哺乳动物***炎或间质性膀胱炎的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
16.一种为需要的哺乳动物治疗或抑制炎症性肠病、克罗恩氏病、溃疡性直肠炎或结肠炎的方法,包括给所述的哺乳动物提供有效量的权利要求1-14任一项的化合物或其药学可接受的盐。
17.一种给需要的哺乳动物治疗或抑制***肥大、子宫平滑肌瘤、乳腺癌、子宫内膜癌、***、子宫内膜息肉、良性***疾病、子宫内膜异位、卵巢癌、黑瘤、***(prostrate)癌、结肠癌,神经胶质瘤或astioblastomia的方法,其包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
18.一种方法,用于给需要的哺乳动物降低胆甾醇、三酸甘油酯、Lp(a)或LDL水平;抑制或治疗高胆固醇血症;血脂质过多;心血管疾病;动脉粥样硬化;高血压;外周血管疾病;再狭窄或血管痉挛;或抑制血管壁由于细胞间隙导致免疫调节性血管损伤产生的损坏,该方法包括给所述哺乳动物提供有效量的权利要求1-14任一项的化合物或其药学可接受的盐。
19.一种方法,给需要的哺乳动物提供认识增强或神经保护;或治疗或抑制老年性痴呆、阿尔茨海默氏病、认知下降、中风、焦虑或神经变性疾病,该方法包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
20.治疗或抑制哺乳动物自由基诱发性疾病的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
21.一种给需要的哺乳动物治疗或抑制***或外阴萎缩;萎缩性***炎;***干燥症;瘙痒;***疼痛;排尿困难;尿频;尿失禁;***的方法,其包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
22.一种给需要的哺乳动物治疗或抑制血管收缩症状的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
23.一种给需要的哺乳动物抑制妊娠的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
24.一种给需要的哺乳动物治疗或抑制关节炎的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
25.根据权利要求24的方法,其中所述的关节炎是类风湿性关节炎、骨关节炎或脊柱关节炎。
26.一种方法,用于给需要的哺乳动物治疗或抑制关节膨胀或侵蚀;或治疗或抑制在关节内窥过程或外科手术过程中伴随的关节损坏的方法,其包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
27.一种治疗或抑制哺乳动物牛皮癣或皮肤炎的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
28.一种方法,用于需要的哺乳动物治疗或抑制局部缺血、再灌注损伤、哮喘、胸膜炎、多发性硬化、全身性红斑狼疮、眼色素层炎、脓血症、出血性休克、黄斑变性或II型糖尿病,其包括给所述哺乳动物提供有效量的权利要求1-14任一项的化合物或其药学可接受的盐。
29.一种给需要的哺乳动物治疗或抑制子宫内膜异位的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
30.一种药物组合物,其包括权利要求1-14任一项的化合物或其药学可接受的盐和药物载体。
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US34116401P | 2001-12-13 | 2001-12-13 | |
US60/341,164 | 2001-12-13 |
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US (2) | US6914074B2 (zh) |
EP (1) | EP1453782A2 (zh) |
JP (1) | JP4566561B2 (zh) |
KR (1) | KR20040071197A (zh) |
CN (1) | CN1738788A (zh) |
AR (1) | AR038019A1 (zh) |
AU (2) | AU2002361659A1 (zh) |
BR (1) | BR0215042A (zh) |
CA (1) | CA2470109C (zh) |
HU (1) | HUP0501025A2 (zh) |
IL (1) | IL161740A0 (zh) |
MX (1) | MXPA04005629A (zh) |
NO (1) | NO20042955L (zh) |
PL (1) | PL374300A1 (zh) |
RU (2) | RU2314283C2 (zh) |
TW (1) | TWI306450B (zh) |
WO (1) | WO2003051805A2 (zh) |
ZA (1) | ZA200405512B (zh) |
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- 2002-12-12 EP EP02797299A patent/EP1453782A2/en not_active Withdrawn
- 2002-12-12 PL PL02374300A patent/PL374300A1/xx unknown
- 2002-12-12 CN CNA028247361A patent/CN1738788A/zh active Pending
- 2002-12-12 KR KR10-2004-7009120A patent/KR20040071197A/ko not_active Application Discontinuation
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102675056A (zh) * | 2012-05-24 | 2012-09-19 | 盛世泰科生物医药技术(苏州)有限公司 | 一种6-溴-8-氟-2-萘酚的制备方法 |
CN103193601A (zh) * | 2013-04-11 | 2013-07-10 | 山东大学 | 2-苯基萘衍生物及其在制备抗肿瘤药物中的应用 |
CN107474038A (zh) * | 2017-07-17 | 2017-12-15 | 苏州楚凯药业有限公司 | 一类靶向***受体荧光探针及其制备和使用方法 |
CN107474038B (zh) * | 2017-07-17 | 2020-10-09 | 苏州楚凯药业有限公司 | 一类靶向***受体荧光探针及其制备和使用方法 |
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HUP0501025A2 (en) | 2006-03-28 |
AU2002361659A1 (en) | 2003-06-30 |
IL161740A0 (en) | 2005-11-20 |
EP1453782A2 (en) | 2004-09-08 |
TW200300668A (en) | 2003-06-16 |
WO2003051805A2 (en) | 2003-06-26 |
JP2005538924A (ja) | 2005-12-22 |
RU2004121227A (ru) | 2006-01-10 |
RU2007128958A (ru) | 2009-02-10 |
BR0215042A (pt) | 2006-06-06 |
US6914074B2 (en) | 2005-07-05 |
ZA200405512B (en) | 2007-02-28 |
CA2470109C (en) | 2010-12-21 |
MXPA04005629A (es) | 2004-12-06 |
WO2003051805A3 (en) | 2003-09-04 |
US20030181519A1 (en) | 2003-09-25 |
PL374300A1 (en) | 2005-10-03 |
CA2470109A1 (en) | 2003-06-26 |
US7067524B2 (en) | 2006-06-27 |
AR038019A1 (es) | 2004-12-22 |
JP4566561B2 (ja) | 2010-10-20 |
US20040225123A1 (en) | 2004-11-11 |
RU2314283C2 (ru) | 2008-01-10 |
TWI306450B (en) | 2009-02-21 |
KR20040071197A (ko) | 2004-08-11 |
NO20042955L (no) | 2004-07-12 |
AU2009222567A1 (en) | 2009-10-22 |
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