CN1201392A - 五环化合物、中间体、制备过程、组合物和方法 - Google Patents
五环化合物、中间体、制备过程、组合物和方法 Download PDFInfo
- Publication number
- CN1201392A CN1201392A CN96198083A CN96198083A CN1201392A CN 1201392 A CN1201392 A CN 1201392A CN 96198083 A CN96198083 A CN 96198083A CN 96198083 A CN96198083 A CN 96198083A CN 1201392 A CN1201392 A CN 1201392A
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- Prior art keywords
- chemical compound
- alkyl
- piperidino
- phenyl
- formula
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 249
- 238000002360 preparation method Methods 0.000 title claims abstract description 123
- 238000000034 method Methods 0.000 title claims abstract description 109
- 239000000203 mixture Substances 0.000 title abstract description 109
- 239000000543 intermediate Substances 0.000 title description 3
- -1 2-oxo-1-piperidinyl Chemical group 0.000 claims abstract description 72
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 92
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- 238000011282 treatment Methods 0.000 claims description 49
- 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 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 150000005053 phenanthridines Chemical class 0.000 claims description 6
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- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 abstract 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 129
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- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 16
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 16
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- 239000000908 ammonium hydroxide Substances 0.000 description 14
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Abstract
本发明涉及式(Ⅰ)和(Ⅱ)化合物或其药学上可接受的盐,其中X为-O-,-S-或-NR5-;Y为-O-,-S-,-CH2-,-CH2CH2-,-CH=CH-或-NR5-;B为-CH2-或-CO-;R1、R2和R3各自独立为-H,-OH,-O(C1-C4烷基),-OCOC6H5,-OCO(C1-C6烷基),-OSO2(C4-C6烷基),-OSO2CF3,Cl或F;n为1或2;W为CH2或C=O;R4为1-哌啶基,2-氧代-1-哌啶基,1-吡咯烷基,甲基-1-吡咯烷基,二甲基-1-吡咯烷基,2-氧代-1-吡咯烷基,4-吗啉代,二甲基氨基,二乙基氨基或1-六亚甲基亚氨基;R5为C1-C3烷基,-COC6H5,-CO(C1-C6烷基),-C(O)OC6H5,-C(O)O(C1-C6烷基),-SO2(C1-C6烷基),-SO2C6H5或-SO2CF3。本发明也提供中间体化合物;用于制备式(Ⅰ)和(Ⅱ)化合物的方法;和利用式(Ⅰ)和(Ⅱ)化合物的药学方法和制剂。
Description
本发明涉及药物化学和有机化学领域,并提供用于治疗与经绝后综合征有关的各种疾病和子宫肌瘤、子宫内膜异位和主动脉平滑肌细胞增生的新的五环化合物。本发明还涉及中间体化合物和用于制备本发明的药理活性化合物和药用组合物的方法。
“经绝后综合征”是用来描述经常影响已经进入或完成称为绝经的生理变态的妇女的各种病理症状的术语。尽管许多病理症状打算使用该术语,经绝后综合征的三个主要结果为医学上长期关注的重大问题:骨质疏松、心血管作用例如血脂过多和雌激素依赖性癌症,特别是乳腺癌和子宫癌。
骨质疏松为一系列由各种病因引起的疾病,然而,它们的特征为每单位体积骨质的净丢失。这种骨质的丢失和产生骨折的结果是骨骼不能提供充分的身体结构支撑作用。最常见的骨质疏松类型之一为与绝经有关的骨质疏松。大部分妇女在停止月经后的3-6年内在骨的小梁腔中丢失骨质的约20%-约60%。这种迅速的丢失一般与骨吸收和形成的增加有关。然而,吸收周期更占优势,其结果为骨质的净丢失。骨质疏松为经绝后妇女的常见和严重的疾病。
据估计仅在美国有2千5百万妇女受这种疾病的折磨。骨质疏松的结果可以造成个人的伤害并且也由于其为慢性病和需要广泛及长期的对该疾病后遗症的治疗(医院治疗和家庭护理)而引起大的经济损失。对于老年患者尤其如此。此外,尽管一般认为骨质疏松不是一种威胁生命的疾病,然而在老年妇女中20%-30%的死亡率与髋骨折有关。这种死亡率的大部分直接与经绝后骨质疏松有关。
由于经绝后骨质疏松的影响在骨中最易受损的组织是骨小梁。该组织往往称为海绵状或网状骨质,尤其集中在靠近骨端(靠近关节)和在脊柱的脊椎中。所述骨小梁的组织特征在于其内部彼此连接的小的类骨质结构以及更坚硬和密度更大的皮质组织构成骨的外表面和中心骨干。这种内部连接的网状骨小梁产生对于外层皮质结构的外侧的支撑作用并对于其整个结构的生物机械强度是至关重要的。在经绝后骨质疏松中,主要是骨小梁的净吸收和丢失,它导致骨缺乏和骨折。根据在经绝后妇女中骨小梁的丢失,最常见的骨折是那些高度依赖骨小梁支撑的骨头例如脊椎、承重骨的颈部如股骨和前臂就毫不奇怪了。髋骨折、科利斯骨折和椎骨粉碎性骨折是经绝后骨质疏松的标志。
目前,唯一被广泛接受的治疗经绝后骨质疏松的方法是雌激素替补疗法。尽管治疗一般是成功的,依从该治疗的患者很少,这主要是因为雌激素治疗经常产生不良的副作用。
在整个绝经前的时间,大部分的妇女与相同年龄段的男性相比心血管疾病的发病率较低。然而在绝经后,妇女患心血管疾病的比率逐渐上升达到与男性相同的比率。这种保护作用的丧失与雌激素的丢失有关,特别是与雌激素调节血脂水平能力的丧失有关。雌激素调节血脂能力的机理还不完全清楚,然而,目前已有证据表明雌激素可以调节(upregulate)肝中的低密度脂质(LDL)受体,除去过量的胆固醇。此外,雌激素对于胆固醇的生物合成具有一定的作用并对于心血管的健康具有其它有益的作用。
文献中已经报道接受雌激素替补疗法的经绝后妇女的血脂水平已恢复到绝经前的浓度。从而,雌激素似乎是这类疾病的合理的治疗方法。然而,雌激素替补疗法的副作用为大多数妇女所不能接受,因而限制了该治疗方法的使用。这类疾病的理想疗法为这样一种制剂,它能像雌激素一样调节血脂水平,然而避免其副作用和与雌激素治疗有关的风险。
第三种与经绝后综合征有关的病症为雌激素依赖性乳腺癌和稍微少见一些的其它器官(尤其子宫)的雌激素依赖性癌症。尽管这类肿瘤并不仅限于经绝后妇女,然而这类肿瘤在老年、经绝后人群中更为流行。目前这类癌症的化疗主要依赖使用抗雌激素化合物例如像他莫西芬。尽管这类混合的兴奋剂-拮抗剂对于治疗这类癌症具有有益的作用,在急性危及生命的情况下,所述雌激素的副作用是可以忍受的,然而,它们并不理想。例如这类制剂由于其雌激素(兴奋剂)的性质具有对子宫中的某些癌细胞群的刺激作用,然而在某些情况下,它们可以产生抗生殖作用(contraproductive)。用于治疗这类癌症的更好的疗法为对可生殖的组织具有可忽略不计的或无雌激素兴奋性质的抗雌激素化合物的制剂。
作为对于明显需要能减轻尤其经绝后综合征症状的新的药用制剂的响应,本发明提供新的五环化合物、其药用组合物及使用这类化合物治疗经绝后综合征和其它与雌激素有关的病理学症状例如以下所述病症的方法。
子宫纤维化(子宫肌瘤)为一个古老的并一直存在的临床难题,它具有以下名称,包括:子宫肌瘤、子宫肥大、子宫lieomyomata、子宫肌层肥大、子宫纤维变性和子宫炎。本质上,子宫纤维化指的是纤维化的组织不适当地沉淀到子宫壁上的疾病状态。
该病症为妇女痛经和不育症的起因。该病症的准确起因知之甚少,然而有证据显示它是纤维样组织对于雌激素的不适当的应答。通过每日给予雌激素3个月,在兔中已经产生了该病症。通过每日给予雌激素4个月,在豚鼠中已经产生了该病症。此外,在大鼠中雌激素引起类似的肥大。
子宫纤维化的最常见治疗方法为既花费高有时又易引起并发症例如造成腹膜粘连和感染的外科手术方法。在一些患者中,初期的手术仅是临时性治疗,肌瘤可再生长。在进行子宫切除术的情况下,有效地终止所述纤维瘤,然而也终止了患者的生育功能。也可以给予释放激素拮抗剂的促性腺激素,然而其作用受这一事实的影响,即它们可以导致骨质疏松。因而,需要治疗子宫纤维化的新方法,而本发明的方法正好满足了这一需要。
子宫内膜异位是严重痛经的病症,它伴随着剧痛、出血到子宫内膜质或腹膜腔中并经常导致不育症。该病症的起因似乎是异位的子宫内膜的生长,它们是对正常的激素控制的不适当的响应并位于不适当的组织中。由于子宫内膜生长的位置不适当,该组织似乎诱发导致巨噬细胞浸润的局部炎症样应答和导致疼痛反应的一系列问题发生。该疾病的确切病因还不十分清楚,通过激素疗法的治疗为互异的、难以定义的和以许多不需要的及或许危险的副作用为特征。
对于这类疾病的治疗方法之一是使用低剂量的雌激素通过对中枢促性腺激素释放的负反馈作用和随后卵巢产生雌激素抑制子宫内膜的生长;然而,有时需要连续使用雌激素以便控制其症状。这种雌激素的使用方法经常导致不良的副作用,甚至有患子宫内膜癌的危险。
另一种治疗方法包括连续给予孕激素,它诱导经闭及通过抑制卵巢雌激素的生成可以引起子宫内膜生长的消退。长期使用孕激素治疗经常伴随孕激素的使人不愉快的CNS(中枢神经系统)的副作用,并由于抑制了卵巢功能往往导致不育症。
第三种治疗方法包括给予弱的雄激素,它们有效地控制子宫内膜异位;然而,它们诱导严重的男性化作用。用于子宫内膜异位的这几种治疗方法随着连续治疗也可以引起温和程度的骨丢失。从而,需要治疗子宫内膜异位的新方法。
主动脉平滑肌细胞增生在例如动脉粥样硬化和再狭窄疾病中起着重要的作用。在经皮经管腔的冠状血管成形术(PTCA)后的血管再狭窄已经显示其特征为早期和晚期的组织反应。早期出现在PTCA后几小时至几天内,它归因于伴有某些血管痉挛的再狭窄,而后期似乎由主动脉平滑肌细胞过量的增生和迁移所支配。通过这类肌细胞和巨噬细胞增加的细胞能动性和移生对该疾病的发病机理具有显著的贡献。主动脉血管平滑肌细胞的过量增生和迁移可以是在PTCA、atherectomy、激光血管成形术和动脉分流术移植手术后冠状动脉再闭塞的主要机理。见“Intimal Proliferation of Smooth Muscle Cells as anExplanation for Recurrent Coronary Artery Stenosis after PercutaneousTransluminal Coronary Angioplasty”Austin et al.,Joutnal of theAmerican College of Cardiology,8:369-375(1985年8月)。
血管再狭窄仍然是通过经皮经管腔的冠状血管成形术(PTCA)、atherectomy、激光血管成形术和动脉分流术移植手术阻塞动脉的外科手术后的一个主要的长期的并发症。在接受PTCA的患者中约35%在手术后3-6个月内出现血管重新闭塞。目前用于治疗血管再狭窄的对策包括通过例如移植片固定物(stents)装置的机械介入或药物疗法包括肝素、低分子量肝素、香豆素、阿司匹林、鱼油、钙拮抗剂、甾醇和前列环素。这些对策不能控制再闭塞的比率并对于治疗和预防血管再狭窄无效。见“Prevention of Restenosis after Percutaneous TransluminalCoronary Angioplasty:The Search for a‘Magic Bullet’”,Hermans er al.,American Heart Journal,122:171-187(1991年7月)。
在再狭窄的致病机理中,由于血液和损伤的动脉血管壁中的细胞成分产生的生长因子(它们在血管再狭窄过程中调解平滑肌细胞的增生)的结果,出现过量的细胞增生和迁移。
可以抑制主动脉平滑肌细胞增生和/或迁移的制剂用于治疗和预防血管再狭窄。本发明提供作为主动脉平滑肌细胞增生抑制剂并从而作为血管再狭窄抑制剂的化合物用途。
转化生长因子-β(TGF-β)为肽生长因子,它指的是一般类型的肽,经常称为异构形式(isoforms),指的是该类型的成员具有氨基酸同系性和/或具有类似的生理作用。TGF-β‘s尤其TGF-β1、β2和β3特别与涉及组织修复的过程和涉及异常修复过程的疾病有关[见Sporn andRoberts“The Transforming Growth Factor-β‘s”,Peptide Growth Factorsand their Receptors I,419-472(Berlin:Springer Verlag,1990)]。
诱导产生TGF-β‘s尤其TGF-β3的制剂用于促进组织修复和治疗涉及异常组织修复的疾病。其用途包括(但不限于)创伤愈合、减小瘢痕(见Ferguson,“Wound Healing,Scarring,TGF-β Antagonists,andIsoforms”,Abst.NIH TGF-β Symposium,Bethesda MD,3 May 1994)和由化疗和放疗诱导的溃疡性粘膜炎(见Sonis and Haley,“Preventionof Chemotherapy-Induced Ulcerative Mucositis by Transforming GrowthFactor-β3”,Abst.NIH TGF-β Symposium,Bethesda MD,3 May 1994)。本发明提供作为组织修复过程的促进剂和作为涉及异常组织修复的疾病的治疗剂的化合物的用途。
X为-O-,-S-或-NR5-;
Y为-O-,-S-,-CH2-,-CH2CH2-,-CH=CH-或-NR5-;
R1、R2和R3各自独立为-H,-OH,-O(C1-C4烷基),-OCOC6H5,-OCO(C1-C6烷基),-OSO2(C4-C6烷基),-OSO2CF3,Cl或F;
n为1或2;
W为CH2或C=O;
R4为1-哌啶基,2-氧代-1-哌啶基,1-吡咯烷基,甲基-1-吡咯烷基,二甲基-1-吡咯烷基,2-氧代-1-吡咯烷基,4-吗啉代,二甲基氨基,二乙基氨基或1-六亚甲基亚氨基;
R5为C1-C3烷基,-COC6H5,-CO(C1-C6烷基),-C(O)OC6H5,-C(O)O(C1-C6烷基),-SO2(C1-C6烷基),-SO2C6H5或-SO2CF3。
B为-CH2-或-CO-;
Y、R1、R2、R3、R4、n和W如上所定义。
本发明也提供用于制备本发明的药用活性化合物的式III和式VI中间体化合物,其结构如下:其中
R1a、R2a和R3a各自独立为-H,-O(C1-C4烷基),-Cl,-F或适当保护的羟基;
Z为-OH,-OC6H5,-O(C1-C4烷基)或4-羟基苯基;
X和Y如上所定义;其中
R1a、R2a和R3a和Y如上所定义。
本发明还涉及含有式I或式II化合物的药用组合物,可选含有雌激素或孕激素,并涉及这类化合物单独或与雌激素或孕激素混合用于减轻经绝后综合征的症状尤其骨质疏松、与心血管有关的病理症状和雌激素依赖性癌症的用途。在此所用术语“雌激素”包括具有雌激素活性的甾族化合物例如像17b-雌二醇、雌酮、共轭雌激素(Premarin)、马雌激素、17a-乙炔基雌二醇等。在此所用术语“孕激素”包括具有促孕活性的化合物例如像黄体酮、异炔诺酮、nongestrel、乙酸孕甾酮、炔诺酮等。
本发明的化合物也用于抑制妇女子宫肌瘤和子宫内膜异位及人主动脉平滑肌细胞增生,特别是血管再狭窄。
R1a、R2a和R3a各自独立为-H,-O(C1-C4烷基),-Cl,-F或适当保护的羟基;
X和Y如上所定义;
G为-OH或-O(CH2)nWR4
其中
n、W和R4如上所定义;该方法包括:
R1a、R2a、R3a、X和Y如上所定义;
Za为-OH,-OC6H5,-O(C1-C4烷基);其中
Ga为-OSi(CH3)3,即适当保护的羟基,它可以在R1a、R2a和R3a或-O(CH2)nWR4存在下选择性去保护其中
n、W、R4如上所定义;
b)当Ga为-OSi(CH3)3或其它适当保护的基团时,可选除去该保护基团,此后使产生的-OH与Q-(CH2)nW-R4反应,其中Q为溴基、氯基或羟基;和
c)可选使得自步骤a)或b)的反应产物成盐。
X为-O-,-S-或-NR5-;
Y为-O-,-S-,-CH2-,-CH2CH2-,-CH=CH-或-NR5-;
R1、R2和R3各自独立为-H,-OH,-O(C1-C4烷基),-OCOC6H5,-OCO(C1-C6烷基),-OSO2(C4-C6烷基),-OSO2CF3,Cl或F;
n为1或2;
W为CH2或C=O;
R4为1-哌啶基,2-氧代-1-哌啶基,1-吡咯烷基,甲基-1-吡咯烷基,二甲基-1-吡咯烷基,2-氧代-1-吡咯烷基,4-吗啉代,二甲基氨基,二乙基氨基或1-六亚甲基亚氨基;
R5为C1-C3烷基,-COC6H5,-CO(C1-C6烷基),-C(O)OC6H5,-C(O)O(C1-C6烷基),-SO2(C1-C6烷基),-SO2C6H5或-SO2CF3。
用在在此所述的化合物描述中的一般性术语具有其通用的含义。例如,“C1-C6烷基”指的是具有1-6个碳原子的直链或支链的脂肪族链,包括甲基、乙基、丙基、异丙基、丁基、正丁基、戊基、异戊基、己基、异己基等。
用于制备本发明化合物的一条路线的原料为具有下式V的化合物:其中
R1a、R2a和R3a各自独立为-H,-O(C1-C4烷基),-F,-Cl或适当保护的羟基;
X和Y如上所定义;
R1a、R2a和R3a如上所定义;
X’为-O-,-S-或-NH-。优选R1a和R2a为甲氧基或适当保护的羟基,R3a为-H和X’为-O-。
一般将容易得到的,具有下式的硫代-3-吲哚酚:其中R2a如上所定义,与具有下式的苯甲醛反应:其中,Xb为-OH,-SH或-NH2,R1a和R2a如上所定义。所述反应一般在弱碱例如三乙胺和质子(protic)溶剂例如乙醇存在下,并在室温或室温以下进行。然后,通过现有技术中已知的各种方法,最优选经过与2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)的反应,使上述缩合的产物脱氢产生式V化合物。
如需要的话,可以通过与三氯化铝和乙硫醇的反应使式V化合物(其中R1b、R2b和/或R3b为甲氧基)去保护并在此阶段用可替换的酚保护基团重新保护。优选在温和的条件下可以除去的保护基团例如叔丁基二甲硅烷基。
通过市场上可买到的拟雌内酯的标准保护过程得到式Vc可选择的原料其中
R1c和R2c为适当保护的羟基。优选在温和的条件下可以除去的保护基团例如叔丁基二甲硅烷基。
通过如Organic Reactions[7:1(1953)]中所述的von Pechman反应制备式Vd原料:其中
R1a、R2a和R3a如上所定义;
X”为-O-或-S-;和
Y”为-CH2-,-CH2-CH2-或-CH=CH-。
一般使具有下式的易得到的四氢萘酮或2,3-二氢-1-茚酮:其中R2a如上所定义,Yd为-CH2-或-CH2-CH2-;在缩合剂例如三氯氧化磷、五氧化二磷、硫酸、三氯化铝等的影响下,与具有下式的适当取代的苯酚或苯硫酚缩合:其中
R1a’为-OH,-H,-O(C1-C4烷基),-F,-Cl或适当保护的羟基;
R3a如上所定义;和
Xd为-OH或-SH,优选R1a’为-OH,R3a为-H,Xd为OH,Yd为CH2CH2,及R2a为甲氧基,所述反应在在甲苯或苯中,于80-110℃,利用三氯氧化磷作为缩合剂进行。
如果所述von Pechman产物含有酚的部分,在该阶段可以将其保护或可选如果R2d为甲氧基,可以使其经过如同上述的去烷基化/重新保护的反应程序。如果需要,然后,通过与DDQ或其它脱氢剂反应可选引入双键。
基本按照Heterocycles[35:1425(1993)]、美国专利号5073553(1991年,12月17日授权)和Indian Journal of Chemistry[24B:556(1989)]中所述方法制备另外的具有式Ve的原料:其中
Xe和Ye各自独立为-O-,-S-,-NH-或-NR5;
R1a、R2a、R3a和R5如上所定义。
基本按照Indian Journal of Chemistry[14B:132(1976)]和Journal ofthe Chemical Society,Perkin Trans.I,1747(1974)中所述的方法制备具有下式的其它原料:其中
R1a、R2a和R3a如上所定义;
Xf为-NH-或-NR5-;和
Yf为-CH2-,-CH2-CH2-或-CH=CH。如果需要双键(Yf为-CH=CH-),可以以上文所述方法,通过使用DDQ得到所需双键。
R1a、R2a、R3a、X和Y如上所定义。一般而言,该还原反应在低于0℃,优选在-50℃--100℃之间进行。然后,可以将式IIIb化合物立即或在分开的步骤中,通过与醇或酚R6OH并可选酸性化合物或脱水剂例如硫酸镁反应可以转化成为具有下式IIIc的化合物:其中
R6为-C1-C4烷基或-C6H5或
R1a、R2a、R3a、X和Y如上所定义;优选以分开的步骤,在CH2Cl2或氯苯中,在室温和回流温度之间进行所述转化。优选R1a和R2a为适当保护的羟基,R3a为H,X为-O-,Y为-O-或-S-,及R6为-C6H5。
可选择将式V化合物(其中X为-NH-)在氮气中酰化,然后通过在酸性化合物例如盐酸和醇溶剂中与NaBH4或类似的还原剂反应,直接转化成式IIIc化合物。在IIIc的该实例中,优选R1a和R2a为甲氧基,R3a为H,X为-N(COC6H5)-或-N(COC(CH3)4)-,Y为-O-,及R6优选为-C2H5。
在下一步骤中,在溶剂例如甲苯、THF、乙醚、二氯甲烷或其混合物中,于室温或室温以下,使式IIIb或IIIc化合物与具有下式的酰基Grignard试剂反应:
其中
Ga为-OSi(CH3)3,即适当保护的羟基,它可以在R1a和R2a或
-(CH2)nWR4存在下选择性去保护;
其中
n、W、R4如上所定义。
所述反应可选在Lewis酸例如三氟化硼合乙醚、四氯化锡、四氯化钛
等的存在下促进反应。
当式IVa的Ga为-O(CH2)nWR4时,该Grignard反应提供式Ib化
R1a、R2a和R3a各自独立为-H,-O(C1-C4烷基),-Cl,-F或适当保护的羟基;
X、Y、n、W和R4如上所定义;如下文所述,该化合物可选去保护和衍生化,以提供所需的式I化合物。
可选当式IVa的Ga为-OSi(CH3)3或另外适当保护的羟基时,在原样保留R1a、R2a和R3a的条件下,在该阶段使所述保护基断裂,提供式Ic化合物:其中
R1a、R2a、R1a、X和Y如上所定义。该反应条件取决于所述保护基的性质并对于本领域的技术人员是众所周知的[见:例如Greeneand Wuts,Protective Groups in Oganic Synthesis,2nd ed.,(1991)]。在优选的实例中(其中R1a和R2a为叔丁基二甲硅氧基或甲氧基,R3a为H和Ga为-OSi(CH3)4),该反应可以通过于室温或室温以下,在助溶剂例如THF或乙醚的存在下,短暂地受到碳酸钾甲醇淤浆的作用而完成。
通过利用在图式I中所示的合成路线之一,可以将式Ic化合物转变成式Ib化合物。在图式I中,R1a、R2a、R3a、R4、W、X、Y和n如上所定义。
例如,式Ic化合物可以与下式化合物反应提供式Ib化合物,
R4-W-(CH2)n-Q其中,R4、W和n如上所定义,Q为溴基或优选氯基部分。通过在过量的碳酸钾细粉的存在下,使用等当量至稍微过量的所述Q-(CH2)-R3反应物进行所述反应,一般可以完成烷基化过程。
更优选的方法包括式Ic化合物与下式化合物在三苯基磷、偶氮二羧酸二乙酯(DEAD)和适当的溶剂存在下,产生式Ib化合物的反应,
R4-W-(CH2)n-OH其中,R4、W和n如上所定义。该过程在现有技术中称为Mitsunobu偶合。优选在各2-5个当量的三苯基磷和DEAD的存在下,在惰性溶剂例如甲苯中,于室温下,使2-4个当量的1-(2-羟乙基)吡咯烷与式Ic化合物反应。在该温度下,所述反应只需要约30分钟至约3小时,然而,所述反应条件的变化将影响完成该反应所需要的时间。当然,该反应步骤的进程可以通过标准的层析技术来监测。
在另一条合成路线中,使式Ic化合物与过量的下式烷基化剂在碱溶液中反应,
J-W-(CH2)n-J’其中,J和J’各自为相同或不同的离去基团。
合适的离去基团包括:例如磺酸酯如甲磺酸酯、4-溴磺酸酯、甲苯磺酸酯、乙磺酸酯、异丙磺酸酯、4-甲氧基苯磺酸酯、4-硝基苯磺酸酯、2-氯苯磺酸酯等;卤素如溴、氯、碘等和其它有关的基团。优选的烷基化试剂为1,2-二溴乙烷,每当量的作用物,至少2当量,优选2当量以上的1,2-二溴乙烷。
用于该烷基化反应的优选的碱溶液包括在惰性溶剂例如甲乙酮(MEK)或DMF中的碳酸钾。在该溶液中,式IIId化合物的苯甲酰基部分的4-羟基以酚盐离子的形式存在,它替代了所述烷基化剂的离去基团之一。
所述反应最好在当使含有反应物和反应剂的碱溶液达回流状态下进行,并完成反应。当使用MEK作为优选的溶剂时,反应时间约需要6-约20小时。
式Id化合物可选地通过具有下式的醇与式Ic化合物的反应,经过Mitsunobu偶合过程制备
J-W-(CH2)n-OH其中J选自上述离去基团。优选的醇为2-溴乙醇。
然后,使来自该步骤的反应产物即式Id化合物与1-哌啶、1-吡咯烷、甲基-1-吡咯烷、二甲基-1-吡咯烷、4-吗啉、二甲基胺、二乙基胺或1-六亚甲基亚胺反应,使用标准技术形成式Ib化合物。优选使哌啶盐酸盐与式Ib化合物在惰性溶剂例如无水DMF中反应,并在约60℃-约110℃范围内加热。当使所述混合物加热到约90℃的优选温度下时,所述反应只需要约30分钟至约1小时。然而,反应条件的变化将影响该反应进行完毕所需要的时间。当然,使用标准层析技术可以监测所述反应步骤的进程。
如果需要提供式I的药用活性化合物,可以通过本技术领域的一个普通技术人员所熟知的方法,进行式Ia化合物的端基保护羟基的脱烷基化/去保护过程。用于去掉叔丁基二甲硅醚(R1a和R2a的优选实例)的优选方法包括将其在合适的溶剂例如THF中与可溶性来源的氟化物例如氟化四-正丁基铵在室温下搅拌。
上述过程提供式I化合物的新的、药用活性化合物,其中R1、R2和R3各自为氢、羟基、C1-C4烷氧基、氯或氟。优选的式Ia化合物为其中R1和R2各自为甲氧基或R1和R2各自为羟基,R3为氢,R4为哌啶基或吡咯烷基,X为-O-,Y为-S-,W为-CH2-,及n为1的化合物。这些优选的化合物以及其它的式Ia化合物可以用作药物或可以进一步衍生化以提供也用于实施本发明的方法的其它式I化合物。
也可以使用自式V化合物制备式I或Ia化合物的可选择的“一罐(one-pot)”法。该路线包括:
1)使用氢化二异丁基铝或类似的还原剂,在THF中,于低于-60℃下还原式V化合物。
2)用等摩尔的质子溶剂例如甲醇或异丙醇抑制过量的还原剂。
4)反应混合物的标准提取处理和浓缩。
5)可选择用强酸例如盐酸处理残留物的THF溶液达24小时,然后用碱处理。有时候,所述“一罐”法可以提供式Ia产物,如上所述可以将其去保护。另外,所述最终的酸处理可以产生伴随的去保护作用并导致直接制备式I化合物。来自该反应的优选的式I化合物是与优选的上述式I化合物相同的化合物,并可以根据在此所述方法用作药用活性剂或可以衍生化提供也可以用于本发明方法(下文)的其它新的式I化合物。
B为-CH2-或-CO-;
Y、R1、R2、R3、R4、n和W如上所定义。
在制备式II化合物中的一个重要的中间体是式VI化合物:其中
R1a、R2a、R3a和Y如上所定义。在图式II中介绍了其中Y是-CH2CH2-的VI、VIa的优选实例的合成。
从而,其中R2a如上所定义的易得到的四氢萘酮VIIa与一个当量的4-氨基酚缩合,优选无溶剂,在使所述混合物熔融的温度(一般约180℃)下,在氮气流下进行。在反应的过程中,可以加入4-氨基酚以替补经升华损失的原料。所生成的式VIIIa亚胺在冷却过程中固化,并可选择进行重结晶。
作为其甲硅烷基衍生物VIIIa’的VIIIa的羟基的保护在标准条件下进行,通过使用具有下式的芳酰卤的酰基化反应将所述亚胺转变成式IXa的烯酰胺(enamide)其中R1a和R2a如上所定义,所述反应一般在弱碱例如三乙胺存在下,在惰性溶剂例如二氯甲烷中,在室温至回流温度下进行。
然后,将式IXa化合物在石英浸渍阱(quartz immmersion well)中,使用Hanovia汞灯,在溶剂例如醚或苯中光解4小时至一周时间,提供式VIa’化合物。所述过程基本上与Journal of the Chemical Society,Perkin Transactions I,[762(1975)]中所介绍的方法相同。
然后,在标准条件下,式VIa’化合物脱甲硅烷基提供式VIa化合物。就所列的合适的反应条件而言,例如见Greene and Wuts,ProtectiveGroups in Organic Synthesis[2nd ed.,p.80,161(1991)]。优选的式VI化合物为其中R1a和R2a各自独立为氢或甲氧基,R3a为氢的化合物。最优选其中R1a和R2a为甲氧基的化合物。
通过以上所述用于将式Ic化合物转变成式Ib化合物的方法,将式VI化合物转变成式IIb化合物:其中
R1a、R2a、R3a、R4、Y、n和W如上所定义。例如,优选的方法为式VI化合物与1-(2-羟乙基)吡咯烷或1-(2-羟乙基)哌啶的Mitsunobu偶合。
R1a、R2a、R3a、R4、Y、n和W如上所定义。用于完成该还原的一个方法包括使式IIa化合物与氢化锂铝在惰性溶剂例如THF中反应。如果所述反应在室温下进行,可以分离出中间体产物,在用硼氢化钠在乙酸中的进一步还原过程中,将其转变成式IIc化合物。可选择,如果所述反应在回流温度下进行,可以将所需要的式IIc化合物直接分离出来。可选将式IIc化合物脱烷基化/去保护以提供式II化合物。
在其中Y为-CH2CH2-的优选的情况下,即式IIa为:其中
R1a、R2a、R3a、R4、n和W如上所定义。该脱氢化过程可以使用本领域各种已知的方法,最优选通过与2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)的反应来完成。
可选择地,最好在式VIa’化合物合成的初期进行所述脱氢化过程,以提供式VIb化合物:然后,通过类似于将VIa转变成IIa的方法,将式VIb化合物转变成式IIe化合物。
R1a、R2a、R3a、R4、n和W如上所定义。然后可选将式IIe化合物去保护/脱烷基化以提供式II化合物。
总起来说,具有其不同定义的取代基的式IIa-e化合物和/或如同上述其去保护的产物作为本发明的式II化合物的代表。
例如,当式IIe化合物的R1a、R2a和/或R3a为C1-C4烷基羟基保护基时,通过标准脱烷基化技术可以除去这类基团以制备式IIe的特别优选的化合物。在式II化合物的最优选的实例中,R1和R2各自独立为-H,-OH或甲氧基,Y为-CH=CH-,B为-CH2-,n为1,W为-CH2-,及R4为1-哌啶基或1-吡咯烷基。
一个可选择的方法包括通过用甲氧基代替式I或式II化合物的R1、R2和/或R3羟基,形成式I或式II的优选化合物。用众所周知的方法[例如参见Greene and Wuts,Protective Groups in Organic Synthesis,2nd ed.,p.(1991)]完成这种转变。特别优选的方法包括单或双酚化合物与过量重氮甲烷的反应。
使用众所周知的方法(例如参见美国专利4358593),用式-O-CO-(C1-C6烷基)或-O-SO2-(C4-C6烷基)部分代替新形成的式I或式II化合物的R1、R2和/或R3羟基来制备式I或II的其它优选化合物。
例如,当需要-O-CO-(C1-C6烷基)时,使式I的二羟基化合物与试剂如酰氯、溴化物、氰化物或叠氮化物反应或与合适的酸酐或混合酸酐反应。所述反应容易在碱性溶剂例如吡啶、二甲基吡啶、喹啉或异喹啉中进行或在叔胺溶剂例如三乙胺、三丁胺、甲基哌啶等中进行。所述反应也可以在惰性溶剂例如乙酸乙酯、二甲甲酰胺、二甲亚砜、二氧六环、二甲氧基乙烷、乙腈、丙酮、甲乙酮等中进行,其中已经加入至少一当量的酸清除剂(以下介绍的除外)例如叔铵。如需要,可以使用酰化催化剂例如4-二甲氨基吡啶或4-吡咯烷代吡啶(pyrrolidinopyirdine)[例如参见Haslam,et al.,Tetrahedron,36:2409-2433(1980)]。
提供式I或式II化合物的上述末端R1、R2和R3基团的酰化反应在约-25℃-约100℃范围内的适度温度下进行,多数是在惰性气体例如氮气中。然而,室温一般适合于所述反应进行。
这类羟基的酰化过程可以通过合适的羧酸在惰性有机溶剂中或加热下的酸催化反应进行。使用酸性催化剂例如硫酸、多磷酸、甲磺酸等。
上述式I或式II化合物的R1、R2和/或R3基团也可以通过形成合适酸的活性酯被提供,例如与已知的试剂例如二环己基碳二亚胺、酰基咪唑、硝基酚、五氯苯酚、N-羟基琥珀酰亚胺和1-羟基苯并三唑形成的酯[例如参见Bull.Chem.Soc.Japan,38:1979(1965),and Chem.Ber.,788 and 2024(1970)]。
上述提供-O-CO-(C1-C6烷基)部分的每一种技术在以上讨论的溶剂中进行。这些技术在其反应的过程中不产生酸性产物,自然不需要在反应混合物中使用酸性清除剂。
当需要其中式I化合物的R1、R2和/或R3基团被转变成式-O-SO2-(C4-C6烷基)或-O-SO2-CF3基团的式I或式II化合物时,使式I二羟基化合物与例如磺酸酐或磺酸的适当的衍生物例如磺酰氯、磺酰溴或磺酰铵盐反应[如King and Monoir所述,J.Am.Chem.Soc.,97:2566-2567(1975)]或与试剂例如N-苯基三氟甲磺酰亚胺反应[如Hendrickson and Bergeron所述,Tetrahedron Letters,4607(1973)]。所述二羟基化合物也可以与合适的磺酸酐、混合磺酸酐或磺酰亚胺反应。这类反应在例如以上所讨论与酰卤等的反应条件下进行。
在式I或式II化合物的R1、R2和/或R3基团已经被转变成-O-SO2-CF3的情况下,可以进一步将该衍生物转变成其中-O-SO2-CF3基团已经用氢替换的式I或式II化合物。从而,在下文实施例7中所述的条件下或如Ritter所述[Synthesis,735(1993)]还原式I或式II三氟甲磺酸酯。
尽管式I或式II化合物的游离碱形式可以用在本发明的方法中,制备和使用药学上可接受的盐的形式有时更有利。从而,用在本发明方法中的化合物主要形成与各种有机和无机酸的药学上可接受的酸加成盐,并包括经常用于药物化学中的生理上可接受的盐。这类盐也是本发明的一部分。用于形成这类盐的典型的无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可以使用由有机酸例如脂肪族一和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链二烷酸、芳族酸、脂肪族和芳族磺酸衍生的盐。从而,这类药学上可接受的盐包括乙酸盐、苯乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、邻-乙酰氧基苯甲酸盐、萘-2-苯甲酸盐、溴化物、异丁酸盐、苯基丁酸盐、b-羟基丁酸盐、丁炔-1,4-二酸盐、己炔-1,4-二酸盐、癸酸盐、辛酸盐、氯化物、桂皮酸盐、柠檬酸盐、甲酸盐、延胡索酸盐、乙醇酸盐、庚酸盐、马尿酸盐、乳酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、丙二酸盐、扁桃酸盐、mesylate、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二甲酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯基丙酸盐、水杨酸盐、癸二酸盐、琥珀酸盐、辛二酸盐、硫酸盐、硫酸氢盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磺酸盐、苯磺酸盐、对-溴苯磺酸盐、氯苯磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、甲磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、对-甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等。优选盐是盐酸盐。
所述药学上可接受的加成盐一般是通过式I或式II化合物与等摩尔或过量的酸的反应形成的。一般将反应物在共有的溶剂例如乙醚或乙酸乙酯中混合。所述盐一般在约1小时至10天的时间内自溶液中析出沉淀,并经过滤可以分离或通过常规方法除去溶剂。
所述药学上可接受的盐与其衍生前的化合物相比一般具有增强的溶解性,从而一般更容易配成液体或乳剂。
以下提供的实施例进一步介绍本发明化合物的制备。不打算将本发明限制在任何下列实施例的范围内。
下列实施例的NMR数据为使用GE 300 MHz NMR仪测定的,除非另外注明,使用无水丙酮-d6作为溶剂。
制备1a
将1N盐酸水溶液(200ml)加入含有2-二甲氨基-6-甲氧基苯并-[b]-噻吩(参照U.S.5420349)(20.00g,96.5 mmol)的四氢呋喃(200ml)溶液中,将所形成的混合物加热到回流达3小时。将所述混合物冷却,使其分层,用二氯甲烷(300ml)提取其水层。用水(250ml)洗涤合并后的有机层,干燥(硫酸镁),过滤并浓缩产生粗品,经3A-乙醇重结晶并室温下真空干燥产生目的化合物(13.89g,77.0mmol,80%):
mp 80-82℃;IR(KBr)1713,1605,1485,1287,1015,865,813 cm-1;1H NMR(DMSO-d6)δ7.22(d,1H,J=8.4Hz),7.11(s,1H),6.78(d,1H,J=8.4 Hz),4.06(s,2H),3.71(s,3H);13C NMR(DMSO-d6)δ203.5,159.0,136.9,125.6,124.6,112.3,108.4,55.3,46.2.计算值(Anal.Calcd.)C9H8O2S:C,59.98;H,4.47;S,17.78。实测值(Found):C,60.19;H,4.57;S,18.03。
制备1b
6a,11a-二氢-3,9-二甲氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-酮
于室温下,将4-甲氧基水杨醛(17.5 g,115 mmol),然后三乙胺(567mg,784ml,5.6mmol)加入搅拌下的6-甲氧基硫茚-2-酮(见Docket B-9459)(20g,111mmol)在乙醇(100ml)和二氯甲烷(50ml)混合物的溶液中。30分钟后,固体开始析出并继续搅拌过夜。然后,用冷却的己烷(1L)稀释所述混合物,并过滤产生28.7g(82%)灰白色固体状的目的产物,纯度经1H-NMR分析。经甲苯重结晶得到淡黄色结晶状的分析样品:
mp 157-165d℃:1H-NMR(300MHz,CDCl3)d 7.33(d,J=8.6 Hz,1H),7.31(d,J=8.1 Hz,1H),6.75(d,J=2.4 Hz,1H),6.70(m,2H),6.60(d,J=2.5Hz,1H),5.22(d,J=7.2 Hz,1H),4.33(d,J=7.2 Hz,1H),3.79(s,3H),3.76(s,3H);IR(CHCl3)1759 cm-1;MS(FD)m/e314(M+);Anal.calc′d.for C17H14O4S:C,64.95;H,4.50.Found:C,65.01;H,4.58.
制备23,9-二甲氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-酮
将制备2的产物(4.5g,14.3mmol)和2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)(3.4g,15mmol)在二氯乙烷(100ml)中的混合物短暂加热到80℃,导致形成沉淀。热过滤该混合物,用二氯甲烷漂洗其沉淀,并真空浓缩其母液。将残留物溶于热的二氯甲烷中,过滤除去剩余的对苯二酚并再浓缩。将其产物经甲苯重结晶,提供3.94 g(88%)白色针晶状的目的化合物,mp.220-221℃:1H-NMR(丙酮-d6/DMSO-d6)d 8.41(d,J=8.9 Hz,1H),7.82(d,J=8.7 Hz,1H),7.74(d,J=2.3 Hz,1H),7.20(dd,J=8.9,2.4 Hz,1H),7.09(d,J=2.4 Hz,1H),7.03(dd,J=8.6,2.4 Hz,1H),3.94(s,3H),3.91(s,3H);IR(KBr)1717cm-1;MS(FD+)m/e 312(M+);Anal.calc′d.for C17H12O4S:C,65.37;H,3.88.Found:C,65.51;H,3.90.
制备3
将乙硫醇(11.9g,13.4ml,192mmol),然后三氯化铝(38.4g,288mmol)分批加入制备2的产物(12g,38.4mmol)在二氯甲烷(220ml)的机械搅拌的淤浆中。将该反应混合物于室温下搅拌5小时,然后冷却到0℃并用四氢呋喃(THF)(250ml),然后饱和碳酸氢钠(250ml)小心地抑制该反应。用THF(1L)稀释该混合物,使其分层并用THF (200ml)洗涤其水层。将合并的有机层干燥(硫酸钠)并浓缩产生11.1g(102%)黄色固体状的粗品二酚,它可以直接使用而不需要进一步纯化。
将该粗品在二氯甲烷(220ml)中形成淤浆,并用三乙胺(20.2g,28ml,200mmol)和氯化叔丁基二甲基硅烷(20.3g,134.4mmol)处理。将该混合物在室温下搅拌5小时,在此期间,将其缓慢搅拌均匀。在用己烷(600ml)稀释后,用盐水(600ml)洗涤该混合物并用己烷(300ml)提取其水层。干燥合并的有机层(硫酸钠),浓缩并经己烷重结晶其残留物提供18.0g(91%)蓬松白色固体状的目的产物,mp 142-144℃:
1H-NMR(300 MHz,CDCl3)d 8.50(d,J=8.7 Hz,1H),7.58(d,J=8.5 Hz,1H),7.32(d,J=2.1 Hz,1H),7.05(dd,J=8.7,2.1 Hz,1H),6.92(d,J=2.2 Hz,1H),6.84(dd,J=8.4,2.2 Hz,1H),1.01(s,9H),1.00(s,9H),0.27(s,6H),0.25(s,6H);13C-NMR(75 MHz,DMSO-d6)d158.4,157.0,154.6,152.7,149.6,138.5,130.5,125.2,124.6,120.0,117.6,116.3,112.7,111.3,108.0,25.6,25.6,18.2,18.2,-4.4,-4.4;IR(CHCl3)1717cm-1;MS(FD)m/e 512(M+);Anal.calc′d.for C27H36O4SSi2:C,63.24;H,7.08.Found:C,63.45;H,7.36.
制备4
3,9-双[(叔丁基二甲硅烷基)氧基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-醇
将制备3产物(2.0g,3.9mmol)在甲苯(200ml)中的溶液冷却到-92℃并以维持内温在-89℃以下的速度,滴加氢化二异丁基铝的1.0M甲苯溶液(11.3ml,11.3mmol)。将该混合物搅拌约3小时,同时其温度逐渐升到-77℃,然后用甲醇(5ml)和10%柠檬酸水溶液(50ml)抑制反应。用二氯甲烷(200ml)稀释后,用饱和酒石酸钾钠(100ml)洗涤该混合物,并用二氯甲烷(2×200ml)提取其水层,用盐水(300ml)洗涤合并的有机层,再用二氯甲烷(100ml)提取该盐水。将其有机层干燥(硫酸钠),浓缩并使其残留物经层析纯化(硅胶,1-15%乙酸乙酯/己烷)产生360mg(18%)的起始物,1.21g(60%,基于回收的起始物质为74%)的白色结晶固体状的目的化合物(分析样品经己烷/乙酸乙酯重结晶,mp162-164℃):1H NMR(300 MHz)d 7.70(d,J=9.0 Hz,1H),7.46(d,J=2.1 Hz,1H),7.29(d,J=8.1 Hz,1H),7.00(dd,J=8.5,1.8 Hz,1H),6.85(br s,1H),6.6(m,2H),6.39(br s,1H),1.01(s,9H),1.00(s,9H),0.25(s,6H),0.25(s,6H);13C NMR(125 MHz)d 156.9,153.3,151.7,139.9,131.9,124.5,123.9,121.7,118.8,113.7,113.1,112.7,108.7,90.7,25.1,25.1,17.9,-5.2,-5.2;IR(CHCl3)3540cm-1;MS(FD+)m/e 514(M+);Anal.calc′d.for C27H38O4SSi2:C,62.98;H,7.45.Found:C,63.25;H,7.68,和260mg(13%,基于回收的起始物为16%)的无定形固体状的以下二醇化合物:
1H NMR(300 MHz,CDCl3)d 7.73(d,J=8.7 Hz,1H),7.29(d,J=2.0 Hz,1H),7.16(d,J=8.2 Hz.1H),6.98(dd,J=8.7,2.0 Hz,1H),6.5(m,3H),6.30(br s,1H),4.71(s,2H),1.01(s,9H),1.00(s,9H),0.22(s,6H),0.19(s,6H);IR(CHCl3)3600,3510 cm-1;MS(FD+)m/e 516(M+);Anal.calc′d.for C27H40O4SSi2:C,62.73;H,7.82.Found:C,62.49;H,7.83.
制备5
3,9-双[(叔丁基二甲硅烷基)氧基]-6-苯氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
将无水硫酸镁(4.5g)加入制备4的产物(4.52g,8.78mmol)和苯酚(4.13g,43.9mmol)在二氯甲烷(100ml)的溶液中,并于室温下搅拌生成物淤浆4小时。将其混合物过滤和浓缩,将其残留物溶于氯苯中并于约70℃再次真空浓缩。然后将其残留物溶于二氯甲烷(300ml)中,用饱和碳酸钠(3×300ml)和水(3×200ml)洗涤,干燥(硫酸钠)并浓缩产生5.16g(99%)的无定形固体状的目的化合物,它可以直接使用不需要进一步纯化: 1H NMR(300 MHz)d 7.67(d,J=8.7 Hz,1H),7.50(d,J=2.1 Hz,1H),7.4-7.5(m,4H),7.23(d,J=8.41H),7.08(t,J=7.2 Hz,1H),6.99(dd,J=8.7,2.1 Hz,1H),6.67(dd,J=8.4,2.3 Hz,1H),6.62(d,J=2.3 Hz,1H),0.99(s,9H),0.96(s,9H),0.24(s,6H),0.21(s,6H);13C NMR(125 MHz)d 156.9,153.3,151.7,139.9,131.9,124.5,123.9,121.7,118.8,113.7,113.1,112.7,108.7,90.7,25.1,25.1,17.9,-5.2,-5.2;MS(FD+)m/e 590(M+); Anal.calc′d.for C33H42O4SSi2:C,67.06;H,7.18.Found:C,66.78;H,6.96.
制备6
于0℃下,将4-[2-(1-哌啶基)乙氧基]苯基溴化镁(在碘的THF溶液的催化下,由相应的溴代苯和镁屑制备,27ml,13.5mmol)的0.5MTHF溶液加入制备5的产物(4.0g,6.7mmol)在甲苯(100ml)的溶液中。使该混合物温热到室温并搅拌1.5小时。在用水(300ml)抑制反应后,用乙酸乙酯(2×300ml)提取该混合物,干燥其有机层(硫酸钠)并浓缩。使其残留物经层析纯化(硅胶,3∶1己烷∶乙酸乙酯,0.1%氢氧化铵)产生3.85g(82%)的无色、树胶固体状的目的化合物:
1H NMR(300 MHz)d 7.45(s,1H),7.2-7.3(m,4H),6.8-6.9(m,3H),6.68(s,1H),6.51(d,J=8.1 Hz,1H),6.36(s,1H),4.01(t,J=6.0 Hz,2H),2.62(t,J=6.0 Hz,2H),2.41(m,4H),1.4-1.6(m,4H),1.3-1.4(m,2H),0.99(s,9H),0.96(s,9H),0.22(s,6H),0.20(s,6H);13C NMR(125 MHz)d 160.3,157.9,154.0,153.5,141.0,132.8,132.6,130.1,129.8,126.1,124.8,122.7,119.4,115.3,114.5,114.2,114.0,109.4,78.2,66.9,58.5,55.6,26.8,26.0,26.0,25.0,18.7,-4.3,-4.3;MS(FD)m/e 702(M+);Anal.calc′d.for C40H55NO4SSi2:C,68.43;H,7.90;N,2.00.Found:C,68.58;H,8.00;N,2.26.
实施例1
3,9-二羟基-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
将氟化四-正丁基铵(TBAF)的1.0M THF溶液(27.4ml,27.4mmol)加入制备6的产物(3.85g,5.5mmol)在THF(150ml)的溶液中。于室温下搅拌该溶液2小时,然后用乙酸乙酯(300ml)稀释并用饱和氯化铵(300ml)洗涤。用乙酸乙酯(150 ml)洗涤其含水层,并用饱和碳酸氢钠(300ml)洗涤合并的有机层,干燥(硫酸钠)并浓缩。使其残留物经层析纯化(硅胶,1∶1己烷∶乙酸乙酯,10%甲醇,0.1%氢氧化铵)产生2.35g(90%)的红色泡沫状的目的产物。经甲醇结晶产生灰白色的粉末,mp242-245d℃:
1H NMR(300 MHz)d 8.58(br s,2H),7.35(d,J=2.1 Hz,1H),7.26(d,J=8.6 Hz,2H),7.17(d,J=8.2 Hz,1H),7.16(d,J=8.6 Hz,1H),6.84(d,J=8.5 Hz,2H),6.80(m,J=2.2 Hz,1H),6.63(s,1H),6.46(dd,J=8.2,2.2 Hz,1H),6.35(d,J=2.3 Hz,1H),4.02(t,J=6.0 Hz,2H),2.63(t,J=6.0 Hz,2H),2.42(m,4H),1.4-1.6(m,4H),1.3-1.4(m,2H);13C NMR(125 MHz,二甲甲酰胺-d7)d 160.2,159.9,156.4,153.2,140.8,132.8,130.9,129.6,125.3,124.6,122.5,115.2,115.1,112.2,109.6,108.8,108.7,104.5,77.6,66.6,58.3,55.3,26.5,24.8;HRMS(FAB+)m/e calc′d.for C28H28NO4S474.1739(MH+),found 474.1726;Anal.calc′d.forC28H27NO4S·0.8H2O:C,68.90;H,5.92;N,2.87.Found:C,68.88;H,5.76;N,2.86.
实施例2
3,9-二甲氧基-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃于室温下,用重氮甲烷在乙醚/乙醇(约16mmol)中的溶液处理实施例1产物(300mg,0.633mmol)在甲醇(75ml)中的溶液。搅拌该混合物直到气体释放停止,鼓泡通入氮气10分钟以便除去过量的重氮甲烷,浓缩该混合物。使其残留物经径向层析纯化(1∶1己烷∶乙酸乙酯,2%甲醇,在氨气下)提供118mg(37%)白色结晶状的目的化合物,mp134-36℃:
1H NMR(300 MHz)d 7.51(d,J=2.2 Hz,1H),7.2-7.4(m,J=8.6 Hz,4H),6.86(m,3H),6.70(s,1H),6.55(dd,J=8.4,2.3 Hz,1H),6.41(d,J=2.4 Hz,1H),4.01(t,J=6.0Hz,2H),3.83(s,3H),3.74(s,3H),2.62(t,J=6.0 Hz,2H),2.40(m,4H),1.4-1.6(m,4H),1.3-1.4(m,2H);13C NMR(125 MHz,CDCl3)d 160.8,159.2,157.1,152.6,140.3,131.6,131.3,130.5,129.1,124.3,124.0,121.7,114.6,114.0,112.8,107.6,105.7,102.3,77.9,65.8,57.8,55.5,55.2,54.9,25.9,24.1;MS(FD+)m/e 501(M+);Anal.calc′d.forC30H31NO4S:C,71.83;H,6.23;N,2.79.Found:C,71.53;H,6.20;N,2.84.
实施例3
于室温下,用10分钟,经注射器将将三乙胺(0.18ml,1.27mmol),然后苯甲酰氯(0.15ml,1.27mmol)加入实施例1的产物(200mg,0.42mmol)在二氯甲烷(25ml)的溶液中。搅拌该反应混合物16小时,然后用饱和碳酸氢钠(25ml),然后水(25ml)洗涤。干燥其有机层(硫酸钠)并浓缩,使其残留物经径向层析纯化(硅胶,12∶12∶1乙酸乙酯∶己烷∶甲醇,在氨气下)提供200mg(69%)黄褐色固体状的目的化合物:1HNMR(300 MHz,DMSO-d6)d 8.1-8.2(m,5H),7.5-7.8(m,8H),7.2-7.3(m,3H),6.9-7.0(m,5H),4.00(t,J=5.5 Hz,2H),2.60(t,J=4.8 Hz,2H),2.38(m,4H),1.4-1.5(m,4H),1.3-1.4(m,2H);HRMS(FAB+)m/e calc′d.for C42H36NO6S 682.2263(MH+),found 682.2286.
实施例4
根据实施例2的方法,使实施例1的产物(200mg,0.42mmol)与三乙胺(0.18ml,1.27mmol)和新戊酰氯(0.16ml,1.27mmol)在二氯甲烷(25ml)溶液中反应,提供190mg(70%)白色泡沫状的目的化合物:
1H NMR(300 MHz,CDCl3)d 7.58(d,J=1.7 Hz,1H),7.35(d,J=8.1 Hz,1H),7.26(d,J=9.6 Hz,2H),7.14(d,J=8.7 Hz,1H),6.93(dd,J=8.8,2.1 Hz,1H),6.83 (d,J=8.6 Hz,2H),6.70(dd,J=4.3,2.1 Hz,1H),6.63(s,2H),4.13(t,J=5.4 Hz,2H),2.83(m,2H),2.58(m,4H),1.66(m,4H),1.46(m,2H),1.37(s,9H),1.33(s,9H);MS(FD+)m/e 641(M+);HRMS(FAB+)m/ecalc′d.for C38H44NO6S 642.2889(MH+),found 642.2848;Anal.calc′d.for C38H43NO6S:C,71.11;H,6.75;N,2.18.Found:C,71.86;H,6.49;N,2.09.
实施例5
根据实施例2的方法,使实施例1的产物(200mg,0.42mmol)与三乙胺(0.18ml,1.27mmol)及正丁基磺酰氯(0.17ml,1.27mmol)在二氯甲烷(25ml)中反应,提供120mg(40%)澄清的棕色树胶状目的化合物:
1H NMR(300 MHz,CDCl3)d 7.77(s,1H),7.38(d,J=8.5 Hz,1H),7.29(d,J=9.5 Hz,2H),7.11(s,2H),6.8-6.9(m,4H),6.63(s,1H),4.08(t,J=5.4 Hz,2H),3.2-3.2(m,4H),2.77(t,J=5.4 Hz,2H),2.51(m,4H),1.9-2.0(m,4H)1.4-1.6(m,10H),0.9-1.0(m,6H);HRMS(FAB+)m/e calc′d.forC38H44NO8S3 714.2229(MH+),found 714.2206.
实施例6
3,9-双(三氟甲磺酰氧基)-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
于室温下,将三乙胺(0.64g,0.69ml,6.36mmol),然后N-苯基三氟甲磺酰亚胺(0.83g,2.33mmol)加入含有二甲甲酰胺(2ml)的实施例1的产物(500mg,1.06mmol)在THF(25ml)的溶液中。搅拌该反应混合物12小时,温热到60℃,加入另外的N-苯基三氟甲磺酰亚胺(0.30g,0.85mmol)。30分钟后,将该反应混合物冷却到室温,并浓缩,通过径向层析(硅胶,1∶1己烷∶乙酸乙酯,1%甲醇在氨气下)纯化其残留物提供780mg(100%)白色泡沫状的目的化合物:
1H NMR(300 MHz,methanol-d4)d 7.63(d,J=8.8 Hz,1H),7.56(d,J=2.5 Hz,1H),7.13(dd,J=8.8,2.7Hz,1H),7.03(d,J=8.8 Hz,2H),6.80(d,J=8.9 Hz,2H),6.49(d,J=2.5 Hz,1H),6.39(d,J=8.7 Hz,1H),6.05(dd,J=8.7,2.6 Hz,1H),4.00(t,J=5.5 Hz,2H),2.67(m,2H),2.45(m,4H),1.4-1.6(m,4H),1.3-1.4(m,2H);13C NMR(125MHz)d 159.8,152.8,150.2,146.9,140.4,136.6,130.5,129.2,127.3,125.3,123.4,119.2,118.9,116.3,114.7,114.6,110.4,77.7,66.0,57.6,54.7,25.8,24.0;MS(FD)m/e737(M+);Anal.calc′d for C30H25F6NO8S3:C,48.84;H,3.42;N,1.90.Found:C,49.05;H,3.71;N,1.72.
实施例7
6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
于室温下,将实施例6的产物(780mg,1.06mmol)、乙酸钯(II)(42mg,0.19mmol)、1,2-双(二苯基)膦基丙烷(149mg,0.36mmol)、甲酸(0.6ml)和三乙胺(3.0ml)在无水二甲甲酰胺(40ml)中的溶液搅拌4天。在浓缩后,使其残留物经层析纯化(硅胶,1∶1己烷∶乙酸乙酯,2-10%甲醇,0.1%氢氧化铵)。浓缩含有各组分的产物,在二氯甲烷(100ml)和饱和碳酸氢钠(100ml)之间分配,用二氯甲烷(50ml)提取其水层。干燥合并的有机提取物(硫酸钠),浓缩并经层析纯化其残留物(硅胶,1∶1己烷∶乙酸乙酯,2-10%甲醇,0.1%氢氧化铵)产生267mg(57%)油状的目的化合物,经醚/己烷研磨产生白色、结晶固体,mp 107℃:1H NMR(300 MHz,CDCl3)d 7.86(d,J=7.4 Hz,1H),7.40(m,1H),7.1-7.3(m,6H),6.97(t,J=7.3 Hz,1H),6.89 (d,J=8.1Hz,1H),6.84(d,J=8.6 Hz,2H),6.66(s,1H),4.07(t,J=6.1 Hz,2H),2.75(t,J=6.1 Hz,2H),2.49(m,4H),1.5-1.7(m,4H),1.4-1.5(m,2H);13C NMR(125 MHz,CDCl3)d 159.1,151.6,139.3,137.1,133.0,131.5,129.8,129.1,126.8,124.6,124.4,123.7,122.6,121.5,121.5,119.3,116.9,114.6,77.6,65.7,57.7,54.9,25.8,24.0;MS(FD+)m/e 441(M+);Anal.calc′d for C28H27NO2S:C,76.15;H,6.17;N,3.17.Found:C,75.93;H,6.44;N,3.01.
制备7
3,9-双[(叔丁基二甲硅烷)氧基]-6-[4-羟苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
于0℃下,将4-(三甲硅烷氧基)苯基溴化镁(在THF溶液中碘的催化下,由相应的溴代苯和镁屑制备,25.4ml,10.16mmol)的0.4M的THF溶液加入制备5的产物(3.0g,5.08mmol)在甲苯(150ml)的溶液中。使该混合物温热到室温并搅拌1.5小时。用乙醚(250ml)稀释后,再用饱和氯化铵(250ml)抑制所述混合物,干燥其有机层(硫酸钠)并浓缩。使残留物在甲醇(100ml)中形成淤浆,再加入乙醚直至混合物变得均匀。使溶液冷却至0℃,用无水碳酸钾(3g)处理15分钟。经乙醚(250ml)稀释后,将混合物通过硅藻土过滤,并用饱和氯化铵溶液洗涤,另外再用乙醚(100ml)提取水层。将合并的有机层干燥(硫酸钠)并浓缩。使残留物经层析纯化(硅胶,10∶1己烷∶乙酸乙酯),经己烷重结晶产生2.6g(87%)淡粉红色固体状的目的化合物,mp 174-175℃:
1H NMR(300 MHz)d 8.49(s,1H),7.44(d,J=2.2 Hz,1H),7.3-7.4(m,4H),6.83(dd,J=8.7,2.2 Hz,1H),6.76(d,J=8.5 Hz,2H),6.65(s,1H),6.50(dd,J=8.2,2.3 Hz,1H),6.36(d,J=2.3 Hz,1H),0.98(s,9H),0.95(s,9H),0.21(s,6H),0.20(s,6H);13CNMR(125 MHz)d 158.7,157.8,153.9,153.5,140.9,132.7,131.6,131.1,129.9,126.1,124.7,122.7,119.3,116.1,114.4,114.0,113.9,109.3,78.3,26.0,25.9,18.7,-4.3;IR(CHCl3)3590,3310 cm-1;MS(FD+)m/e 590(M+);Anal.cald′d.for C33H42O4SSi2:C,67.07;H,7.16.Found:C,66.79;H,7.05.
制备8
3,9-双[(叔丁基二甲硅烷)氧基]-6-[4-[2-(1-吡咯烷基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
于室温下,用偶氮二羧酸二乙酯(DEAD)(470mg,425ml,2.7mmol)处理制备7的产物(400mg,0.68mmol)、三苯基磷(708mg,2.7mmol)和1-(2-羟乙基)吡咯烷(390mg,396ml,3.39mmol)的甲苯溶液,并搅拌2小时。然后,用醚(100ml)稀释该混合物,用饱和氯化铵(100ml)洗涤,用另外的醚(50ml)洗涤其含水层。干燥合并的有机层(硫酸钠),浓缩,并用己烷沉淀残留的氧化三苯基磷。浓缩其己烷母液,并使其残留物经层析纯化(硅胶,1∶1己烷∶乙酸乙酯,3-5%甲醇,0.1%氢氧化铵)产生359mg(77%)无色油状的目的化合物: 1H NMR(300 MHz)d 7.45(d,J=2.1 Hz,1H),7.28(d,J=8.6 Hz,2H),7.22(m,2H),6.85(d,8.6 Hz,2H),6.83(dd,J=8.6,2.3 Hz,1H),6.68(s,1H),6.50(dd,J=8.3,2.2 Hz,1H),6.36(d,2.2 Hz,1H),4.03(t,J=6.0 Hz,2H),2.77(t,J=6.0 Hz,2H),2.50(m,4H),1.67(m,4H),0.98(s,9H),0.95(s,9H),0.21(s,6H),0.20(s,6H);13C NMR(125 MHz)d160.1,157.8,153.9,153.4,140.9,132.7,132.5,131.1,129.8,125.9,124.7,122.6,119.3,115.1,114.4,114.1,113.9,109.4,78.1,67.7,55.2,54.9,26.0,25.9,24.0,18.6,-4.3;MS(FD+)m/e 687(M+);Anal.calc′d.for C39H53NO4SSi2:C,68.06;H,7.78;N,2.04.Found:C,67.94;H,7.61;N,2.21.
实施例8
3,9-二羟基-6-[4-[2-(1-吡咯烷基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
通过实施例1所述过程,使制备8的产物(331mg,0.48mmol)与在THF中的1.0M TBAF(2.4mmol)反应,在径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,30%甲醇,在氨气下)后,产生200mg(91%)白色固体状的目的化合物,mp 237-240d℃:1H NMR(300 MHz,
二甲甲酰胺-d7)d 10.05(br,2H),7.45(d,J=2.0 Hz,1H),7.30(d,J=8.4 Hz,2H),7.23(d,J=8.6 Hz,1H),7.19(d,J=8.2 Hz,1H),6.91(d,J=8.7 Hz,2H),6.86(dd,J=8.9,2.2 Hz,1H),6.74(s,1H),6.51(dd,J=8.2,2.1 Hz,1H),6.40(d,J=2.1 Hz,1H),4.14(t,J=5.6 Hz,2H),2.96(t,J=5.5 Hz,2H),2.6-2.8(m,4H),1.6-1.8(m,4H);13C NMR(125 MHz,二甲甲酰胺-d7)d 160.2,159.6,156.4,153.2,140.8,133.0,130.8,129.6,125.2,124.6,122.4,115.3,115.1,112.2,109.7,108.8,104.5,77.6,66.8,54.8,54.7,23.8;IR(KBr)3286 cm-1;HRMS(FAB+)m/e calc′d.forC27H26NO4S 460.1583(MH+),found 460.1572;Anal.calc′d.forC27H25NO4S·0.5H2O:C,69.20;H,5.60;N,2.99.Found:C,69.13;H,5.31;N,2.58.
制备9
通过制备8中所述的方法,使制备7的产物(450mg,0.76mmol)、三苯基磷(799mg,3.1mmol)和N,N-二甲基乙醇胺(340mg,383ml,3.81mmol)与偶氮二羧酸二乙酯(DEAD)(531mg,480ml,3.1mmol)在甲苯(30ml)中反应。层析纯化(硅胶,1∶1己烷∶乙酸乙酯,3%甲醇,0.1%氢氧化铵)提供357mg(71%)白色泡沫状的目的化合物:
1H NMR(300 MHz)d 7.45(d,J=2.1 Hz,1H),7.27(d,J=8.6 Hz,2H),7.24(m,2H),6.83(m,3H),6.67(s,1H),6.50(dd,J=8.2,2.2 Hz,1H),6.36(d,2.2 Hz,1H),4.00(t,J=5.9 Hz,2H),2.60(t,J=5.9 Hz,2H),2.20(s,6H),0.98(s,9H),0.95(s,9H),0.21(s,6H),0.20(s,6H);13C NMR(125 MHz)d 160.1,157.8,153.9,153.4,141.0,132.7,132.6,131.2,129.8,126.0,124.7,122.7,119.4,115.2,114.4,114.1,113.9,109.4,78.1,67.0,58.7,46.0,26.0,25.9,18.6,-4.3;MS(FD+)m/e 661.5(M+);Anal.calc′d.for C37H51NO4SSi2:C,67.11;H,7.78;N,2.12.Found:C,67.38;H,7.52;N,2.09.
实施例9
通过实施例1所述过程,使制备9的产物(328mg,0.50mmol)与在THF中的1.0M TBAF(2.5mmol)反应,在径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,30%甲醇,在氨气下)后,产生212mg(99%)的目的化合物,它经四氯化碳/丙酮结晶为粉红色固体,mp 130-140d℃:
1H NMR(300 MHz)d 7.34(d,J=2.1Hz,1H),7.25(d,J=8.6 Hz,2H),7.15(m,2H),6.9-7.0(m,3H),6.62(s,1H),6.45(dd,J=8.3,2.3 Hz,1H),6.34(d,J=2.2 Hz,1H),4.01(t,J=5.8 Hz,2H),2.64(t,J=5.8 Hz,2H),2.30(s,6H);13C NMR(125 MHz)d 160.0,159.8,156.0,153.5,141.1,133.0,131.4,130.2,129.8,125.3,124.8,122.6,115.3,115.2,112.7,109.7,109.0,104.8,78.0,66.6,58.6,45.8;IR(KBr)3300 cm-1;HRMS(FAB+)m/e calc′d.forC25H24NO4S 434.1426(MH+),found 434.1440;Anal.calc′d.forC25H23NO4S·0.4CCl4:C,61.62;H,4.69;N,2.83.Found:C,60.93;H,4.73;N,2.95.
制备10
3,9-双[(叔丁基二甲硅烷)氧基]-6-[4-[2-(2-氧代-1-吡咯烷基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
通过制备8中所述的方法,使制备7的产物(450mg,0.76mmol)、三苯基磷(799mg,3.1mmol)和1-(2-羟乙基)-2-吡咯烷酮(pyrrolidinone)(492mg,431ml,3.81mmol)与偶氮二羧酸二乙酯(DEAD)(531mg,480ml,3.1mmol)在甲苯(30ml)中反应。层析纯化(硅胶,1∶1己烷∶乙酸乙酯)提供368mg(69%)白色泡沫状的目的化合物:
1H NMR(300 MHz)d 7.45(d,J=2.1 Hz,1H),7.28(d,J=8.7 Hz,2H),7.23(d,J=8.2 Hz,1H),7.22(d,J=8.6 Hz,1H),6.88(m,3H),6.69(s,1H),6.51(dd,J=8.5,2.5 Hz,1H),6.36(d,2.3 Hz,1H),4.05(t,J=5.4 Hz,2H),3.54(t,J=5.4 Hz,2H),3.46(t,J=7.0 Hz,2H),2.15(t,J=8.0 Hz,2H),1.91(m,2H),0.98(s,9H),0.95(s,9H),0.21(s,6H),0.20(s,6H);13C NMR(125 MHz)d 175.0,160.1,158.1,154.2,153.6,141.2,133.2,133.0,131.4,130.1,126.2,125.0,122.9,119.6,115.5,114.6,114.4,114.2,109.6,78.3,67.0,48.7,42.7,31.2,26.2,26.2,18.9,-4.1;IR(CHCl3)1673cm-1;HRMS(FAB+)m/e calc′d.forC39H51NO5SSi2 701.3027(M+),found 701.3039.
实施例10
3,9-二羟基-6-[4-[2-(2-氧代-1-吡咯烷基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
通过实施例1所述过程,使制备10的产物(331mg,0.47mmol)与在THF中的1.0M TBAF(2.4mmol)反应,在径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,20%甲醇,在氨气下)并经丙酮重结晶后,产生161mg(72%)红色固体状的目的化合物,mp 150-160d℃:1H NMR(300 MHz,甲醇-d4)d 7.21(m,3H),7.11(d,J=8.3Hz,1H),7.02(d,J=8.7 Hz,1H),6.80(d,J=8.6 Hz,2H),6.71(dd,J=8.6,2.2 Hz,1H),6.51(s,1H),6.37(dd,J=8.2,2.3 Hz,1H),6.25(d,J=2.3 Hz,1H),4.04(t,J=5.2Hz,2H),3.57(t,J=5.2 Hz,2H),3.48(t,J=7.1 Hz,2H),2.28(t,J=8.1 Hz,2H),1.91(五重峰J=7.5 Hz,2H);13CNMR(125 MHz,甲醇-d4)d 178.0,160.2,160.0,156.2,153.9,141.7,133.7,131.9,130.9,130.3,125.6,125.0,122.7,115.6,115.4,113.4,109.8,109.0,104.9,78.6,66.6,43.4,31.8,30.7,18.9;IR(CHCl3)1680 cm-1;MS(FD+)m/e 474(MH+);Anal.calc′d.for C27H23NO5S·(CH3)2CO:C,67.77;H,5.51;N,2.64.Found:C,67.92;H,5.56;N,2.59.
实施例10a
通过实施例1所述过程,使制备11的产物(458mg,0.66mmol)与在THF中的1.0M TBAF(3.3mmol)反应,在径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,10-20%甲醇,在氨气下)并经丙酮/醚结晶后,产生296mg(72%)红色固体状的目的化合物,mp 118-123d℃:
1H NMR(300 MHz)δ7.35(d,J=2.1 Hz,1H),7.26(d,J=8.6 Hz,2H),7.16 (d,J=8.1 Hz,1H),7.13(d,J=8.5Hz,1H),6.81(m,3H),6.62(s,1H),6.45(dd,J=8.3,2.3Hz,1H),6.35(d,J=2.2 Hz,1H),3.98(t,J=6.2 Hz,2H),2.78(t,J=6.2 Hz,2H),2.56(q,J=7.1 Hz,4H),0.97(t,J=7.1 Hz,6H);13C NMR(75 MHz)δ160.2,159.7,155.9,153.5,141.1,132.9,131.5,130.2,129.9,125.4,124.8,122.7,115.2,112.8,109.6,108.9,104.8,78.1,67.5,52.6,48.3,12.4;IR(KBr)3311 cm-1;MS(FD+)m/e 462(MH+);Anal.calc′d.for C27H27NO4S:C,70.04;H,6.13;N,3.04.Found:C,70.26;H,5.90;N,3.03.
实施例10b
3,9-二羟基-6-[4-[2-(1-吗啉基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
通过实施例1所述过程,使制备12的产物(521mg,0.74mmol)与在THF中的1.0M TBAF(3.7mmol)反应,在径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,15%甲醇,在氨气下)并经丙酮/醚结晶后,产生286mg(81%)红色固体状的目的化合物,mp 147-153d℃:
1H NMR(300 MHz)δ7.35(d,J=2.1 Hz,1H),7.25(d,J=8.6 Hz,2H),7.16(d,J=8.3 Hz,1H),7.14(d,J=8.6Hz,1H),6.81(m,3H),6.62(s,1H),6.46(dd,J=8.2,2.2Hz,1H),6.35(d,J=2.2 Hz,1H),4.04(t,J=5.7 Hz,2H),3.56(t,J=4.7 Hz,4H),2.68(t,J=5.7 Hz,2H),2.47(t,J=4.3 Hz,4H);13C NMR(75 MHz)δ160.0,159.7,155.9,153.5,141.1,132.9,131.4,129.8,129.7,125.4,124.8,122.6,115.2,112.8,109.6,108.9,104.7,78.0,67.2,66.5,58.1,54.7;IR(KBr)3471 cm-1;MS(FD+)m/e 475(MH+);Anal.calc′d.for C27H25NO5S·0.25H2O:C,67.54;H,5.36;N,2.92.Found:C,67.58;H,5.51;N,2.57.
于室温下,将三乙胺(2.0ml,14.8mmol),然后水杨醛(32ml,300mmol)加入6-甲氧基硫茚-2-酮(52.6g,290mmol)在乙醇(260ml)和二氯甲烷(130ml)混合物的搅拌的溶液中。1小时后,固体开始析出沉淀并继续搅拌3.5小时。然后,用冷的己烷稀释该混合物,过滤产生68.3g(83%)的粉末白色固体状的目的产物,纯度经1H-NMR分析:
1H NMR(300 MHz,CDCl3)δ7.45(d,J=7.5 Hz,1H),7.33(m,2H),7.17(m,1H),7.07(d,J=8.1 Hz,1H),6.77(d,J=2.4 Hz,1H),6.69(dd,J=2.4,8.5 Hz,1H),5.25(d,J=7.4 Hz,1H),4.37(d,J=7.3 Hz,1H),3.77(s,3H);13CNMR(75 MHz,CDCl3)δ166.4,160.7,150.8,141.4,130.1,129.0,127.7,127.0,124.9,119.5,117.2,111.2,108.3,55.5,50.6,49.6;IR(CHCl3)1766cm-1;MS(FD)m/e 284(M+);Anal.calc′d.for C16H12O3S:C,67.59;H,4.26.Found:C,67.77;H,4.24.
制备12b
9-甲氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-酮
将制备12a的产物(14.0g,49mmol)和2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)(11.6g,51mmol)在二氯乙烷(350ml)中的混合物迅速加热到回流,导致沉淀的形成。将该混合物热过滤,用二氯甲烷漂洗其沉淀,并真空浓缩其母液。然后,用丙酮漂洗该粗品几次并真空干燥提供12.6g(91%)白色蓬松固体状的目的产物:
1H NMR(300 MHz,CDCl3)δ8.55(d,J=8.9 Hz,1H),7.70(dd,J=1.2,8.0 Hz,1H),7.4-7.6(m,2H),7.33(m,2H),7.13(dd,J=2.3,8.9 Hz,1H),3.91(s,3H);IR(CHCl3)1722cm-1;MS(FD)m/e 282(M+);Anal.calc′dfor C16H10O3S:C,68.07;H,3.57.Found:C,67.80;H,3.53.
制备12c
9-(叔丁基二甲硅烷)氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-酮
将乙硫醇(5.9ml,80mmol),然后三氯化铝(15.8g,120mmol)分批加入制备12b的产物(9.0g,32mmol)在二氯甲烷(235ml)的机械搅拌的淤浆中。将该反应混合物于室温下搅拌1小时,然后冷却到0℃并用四氢呋喃(THF),然后饱和碳酸氢钠小心地抑制该反应。用THF稀释该混合物,使其分层并用THF洗涤其水层数次。将合并的有机层干燥(硫酸钠)并浓缩产生7.4g(86%)灰白色略带粉红色的固体状的粗品酚,它可以直接使用而不需要进一步纯化。
将该粗品在二氯甲烷(200ml)中形成淤浆,并用三乙胺(19.1ml,140mmol)和氯化叔丁基二甲基硅烷(10.4g,69mmol)处理。将该混合物在室温下搅拌过夜,在此期间,将其变得均匀。用己烷稀释后,用盐水洗涤该混合物两次。干燥其有机层(硫酸钠),浓缩并经己烷重结晶其残留物提供9.8g(80%)蓬松白色固体状的目的化合物:
1H NMR(300 MHz,CDCl3)δ8.55(d,J=8.5 Hz,1H),7.72(d,J=8.7 Hz,1H),7.4-7.6(m,2H),7.34(m,2H),7.08(dd,J=2.2,8.8 Hz,1H),1.02(s,9H),0.26(s,6H);IR(CHCl3)1717cm-1;MS(FD)m/e 382(M+);Anal.calc′d for C21H22O3SSi:C,65.93;H,5.80.Found:C,66.23;H,5.84.
制备12d
9-(叔丁基二甲硅烷)氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-醇
使来自制备12c中产物(3.5g,9.1mmol)在甲苯(490ml)中的溶液冷却到-78℃并以维持其内温低于-70℃下的速度,滴加氢化二异丁基铝(11.0ml,11mmol)的1.0M甲苯溶液处理。将该混合物搅拌约4小时,然后用甲醇(14ml)、10%柠檬酸水溶液(140ml)和水(315ml)抑制反应。用二氯甲烷(560ml)提取其水层三次。干燥其有机层(硫酸钠),浓缩并使其残留物经层析纯化(硅胶,2%的乙酸乙酯的己烷溶液至20%的乙酸乙酯的己烷溶液梯度洗脱)产生1.7g(49%)白色结晶固体状的目的化合物:
1H NMR(300 MHz)δ7.77(d,J=8.6 Hz,1H),7.50(d,J=2.1 Hz,1H),7.42(m,1H),7.28(m,1H),7.05(m,2H),6.89(m,1H),6.46(m,1H),1.02(s,9H),0.26(s,6H);IR(CHCl3)2959,2932,2861,1612,1598cm-1;MS(FD)m/e 384 (M+);Anal.calc′d forC21H24O3SSi:C,65.59;H,6.29.Found:C,65.51;H,6.32.
制备12e9-(叔丁基二甲硅烷)氧基-6-苯氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
将制备12d的产物(1.5g,3.9mmol)和苯酚(2.7g,29mmol)溶解在氯代苯(50ml)中,并在回流下搅拌该混合物3.5小时。将该混合物浓缩并将残留物再溶解在氯代苯中,于约70℃再真空浓缩。然后,将其残留物溶于乙醚中,用饱和碳酸钠、水和盐水洗涤三次。干燥其有机层(硫酸钠)并浓缩产生1.7g(93%)蓬松白色固体状的目的化合物,可以直接使用不需要进一步纯化:其1H NMR(300 MHz)与其结构一致。
实施例10c
于0℃下,将溴化4-[2-(1-哌啶基)乙氧基]苯基镁(由相应的溴代苯和镁屑在THF中的碘的催化下制备,45.3ml,9.1mmol)的0.2M THF溶液加入制备12e的产物(1.7g,3.6mmol)在甲苯(50ml)的溶液中。使该混合物温热到室温并搅拌14小时。在用水抑制该反应后,用二氯甲烷提取该混合物三次,并干燥其有机层(硫酸钠)并浓缩。使其残留物经层析纯化(硅胶,己烷-4∶1己烷∶乙酸乙酯)产生2.6g(126%)部分纯化的甲硅烷基化物。
将氟化四正丁基铵(TBAF)(5.0ml,5.0mmol)的1.0M THF溶液加入部分纯化的产物(2.6g,3.6mmol)在THF(40ml)的溶液中。于室温下,搅拌该溶液10分钟,然后用乙酸乙酯稀释,用饱和碳酸氢钠和盐水洗涤5次。干燥其有机层(硫酸钠)并浓缩。使残留物经层析纯化(硅胶,1∶1己烷∶乙酸乙酯,0-10%甲醇,0.1%氢氧化铵)产生0.93g(56%)的白色蓬松固体状的目的化合物:1HNMR(300 MHz)δ6.7-7.4(m,12H),4.02(t,J=6.0 Hz,2H),2.63(t,J=6.0 Hz,2H),2.41(m,4H),1.49(m,4H),1.37(m,2H);IR(KBr)2934,1609 cm-1;MS(FD)m/e 457 (M+);HRMS(FAB) m/e calc′d for C28H28NO3S(MH+):458.1790.Found:458.1798;Anal.calc′d for C28H27NO3S·0.5H2O:C,72.08;H,6.05;N,3.00.Found:C,71.97;H,6.04;N,3.06.
制备12f
3-(叔丁基二甲硅烷)氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-酮
将乙硫醇(1.4ml,18.0mmol),然后三氯化铝(1.6g,12mmol)分批加入3-甲氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-酮[Journal ofOrganic Chemistry,40:3169(1975)](1.0g,3.6mmol)在二氯甲烷(30ml)的机械搅拌的淤浆中。将该反应混合物于室温下搅拌1.5小时,然后冷却到0℃并用四氢呋喃(THF),然后饱和碳酸氢钠小心地抑制该反应。用THF稀释该混合物,使其分层并用THF洗涤其水层数次。将合并的有机层干燥(硫酸钠)并浓缩产生粗品酚,它可以直接使用而不需要进一步纯化。
将该粗品在二氯甲烷(30ml)中形成淤浆,并用三乙胺(2.5ml,18mmol)和氯化叔丁基二甲基硅烷(1.3g,9.0mmol)处理。将该混合物在室温下搅拌过夜,在此期间,将其变得均匀。用己烷稀释后,用盐水洗涤该混合物两次。干燥其有机层(硫酸钠),浓缩并使其残留物经层析纯化(硅胶,己烷-4∶1己烷∶乙酸乙酯)提供0.95g(69%)蓬松白色固体状的目的化合物:
1H NMR(300 MHz,丙酮-d6)δ8.57(d,J=7.8 Hz,1H),8.10(d,J=8.0 Hz,1H),7.81(d,J=8.2 Hz,1H),7.5-7.7(m,2H),6.99(m,2H),1.03(s,9H),0.33(s,6H);IR(CHCl3)1716 cm-1;MS(FD)m/e 382(M+);Anal.calc′d for C21H22O3SSi:C,65.93;H,5.80.Found:C,66.11;H,5.83.
制备12g
3-(叔丁基二甲硅烷)氧基-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃-6-醇
使来自制备12f中产物(5.0g,13mmol)在甲苯(700ml)中的溶液冷却到-78℃并以维持其内温低于-70℃下的速度,滴加氢化二异丁基铝(15.7ml,15.7mmol)的1.0M甲苯溶液处理。将该混合物搅拌约4小时,然后用甲醇(20ml)、10%柠檬酸水溶液(200ml)和水(450ml)抑制反应。用二氯甲烷(800ml)提取其水层三次。干燥其有机层(硫酸钠),浓缩并使其残留物经层析纯化(硅胶,2%的乙酸乙酯的己烷溶液至20%的乙酸乙酯的己烷溶液梯度洗脱)产生1.7g(45%)白色蓬松固体状的目的化合物:1H NMR(300 MHz)δ7.96(d,J=7.7 Hz,1H),7.83(d,J=6.7 Hz,1H),7.3-7.8(m,3H),6.91(m,1H),6.62(m,2H),1.00(s,9H),0.26(s,6H);IR(CHCl3)2958,2932,2861,1616,1594 cm-1;MS(FD)m/e 384(M+);Anal.calc′d for C21H24O3SSi:C,65.59;H,6.29.Found:C,65.31;H,6.18.
制备12h
将制备12g的产物(0.09g,0.24mmol)和苯酚(0.25g,2.6mmol)溶解在氯代苯(10ml)中,并在100℃下搅拌该混合物3小时。将该混合物浓缩并将残留物再溶解在氯代苯中,于约70℃再真空浓缩。然后,将其残留物溶于乙醚中,用饱和碳酸钠、水和盐水洗涤五次。干燥其有机层(硫酸钠)并浓缩产生0.11g(100%)蓬松白色固体状的目的化合物,可以直接使用不需要进-步纯化:其1H NMR(300MHz)与其结构一致。
实施例10d
于0℃下,将溴化4-[2-(1-哌啶基)乙氧基]苯基镁(由相应的溴代苯和镁屑在THF中的碘的催化下制备,7.6ml,1.5mmol)的0.2M THF溶液加入制备12h的产物(0.28g,0.61mmol)在甲苯(20ml)的溶液中。使该混合物温热到室温并搅拌1小时。在用水抑制该反应后,用二氯甲烷提取该混合物六次,干燥其有机层(硫酸钠)并浓缩。使其残留物经层析纯化(硅胶,4∶1-1∶1己烷∶乙酸乙酯)产生0.41g(119%)部分纯化的甲硅烷基化物。
将氟化四正丁基铵(TBAF)(0.67ml,0.67mmol)的1.0M THF溶液加入部分纯化的产物(0.41g,0.72mmol)在THF(10ml)的溶液中。于室温下,搅拌该溶液10分钟,然后用乙酸乙酯稀释,用饱和碳酸氢钠和盐水洗涤3次。干燥其有机层(硫酸钠)并浓缩。使残留物在二氯甲烷中研磨,过滤其沉淀,并用二氯甲烷漂洗,产生0.23g(82%)的白色粉末固体状的目的化合物。使该固体在甲醇中形成淤浆,并滴加三氟乙酸直到所有物质进入溶液中,滤去不溶物,真空浓缩其母液产生0.28g(80%)蓬松橙色固体状的TFA盐:1H NMR(300 MHz)δ7.95(m,1H),7.38(m,1H),7.2-7.3(m,5H),6.90(d,J=8.6 Hz,2H),6.76(s,1H),6.51(dd,J=2.2,8.2 Hz,1H),6.38(d,J=2.3 Hz,1H),4.44(t,J=4.9 Hz,2H),3.5-3.7(m,4H),3.0-3.2(m,2H),1.7-2.0(m,5H),1.4-1.7(m,1H);IR(CHCl3)3271,3022,3009,1670,1610cm-1;MS(FD)m/e 457(M+);HRMS(FAB)m/e calc′d for C28H28NO3S(MH+):458.1790.Found:458.1781;Anal.calc′d for C28H2NO3S·CF3COOH·1.2H2O:C,60.69;H,5.12;N,2.36.Found:C,60.62;H,4.82;N,2.40.
制备18a
将制备10的产物(7.0g,13.8mmol)和2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)(3.3g,14.5mmol)在二氯乙烷(100ml)中的混合物在回流下加热过夜,导致沉淀的形成。将该混合物热过滤,用二氯甲烷漂洗其沉淀,并真空浓缩其母液。然后,使其残留物在己烷∶醚和水之间分配,并干燥有机层(硫酸镁),浓缩,经己烷重结晶提供5.5g(79%)黄褐色固体状的目的产物,mp 154-156℃: 1H-NMR(300 MHz,CDCl3)δ9.69(d,J=9.4 Hz),8.80(s,2H),8.01(d,J=9.5 Hz),7.34(dd,J=9.3,2.5 Hz,1H),7.28(d,J=5.4 Hz,1H),6.90(m,2H),1.05(s,9H),1.03(s,9H),0.29(s,12H);IR(CHCL3)1711,1622,1604cm-1;MS(FD)m/e506(M+);Anal.calc′d.for C29H38O4Si2:C,68.72 ;H,7.57.Found:C,68.93;H,7.36.
制备18b
2,8-双[(叔丁基二甲硅烷)氧基]-5H-苯并[b]萘并[2,1-d]吡喃-5-醇
通过制备4中所述的过程,使制备18a的产物(5.0g,9.9mmol)与1.0M的氢化二异丁基铝的甲苯溶液(11.9ml,11.9mmol)反应,经己烷∶醚重结晶后产生4.14g(82%)白色固体状的目的化合物,mp 188-190℃:1H NMR(300 MHz,CDCl3)δ7.98(d,J=9.1 Hz,1H),7.86(d,J=8.8Hz,1H),7.79(d,J=8.6 Hz,1H),7.75(d,J=8.2 Hz,1H),7.23(d,J=2.3 Hz,1H),7.18(dd,J=9.0,2.4 Hz,1H),7.06(d,J=7.4 Hz,1H),6.67(m 2H),3.24(d,J=7.7 Hz,1H),1.04(s,9H),1.02(s,9H),0.27(s,6H),0.27(s,6H);IR(CHCl3)3574 cm-1;MS(FD)m/e 508(M+);Anal.calc′d.forC29H40O4Si2:C,68.44;H,7.94.Found:C,68.63;H,8.11.
制备18c
通过制备5中所述的过程,使制备18b的产物(3.5g,6.88mmol)与苯酚(3.2g,34.3mmol)反应产生3.82g(95%)无定形白色固体状的目的化合物,可以直接使用而不需要进一步纯化:
1H NMR(300 MHz)δ7.9-8.1(m,4H),7.61(s,1H),7.3-7.5(m,3H),7.2-7.3(m,3H),7.11(t,J=7.3 Hz,1H),6.74(dd,J=8.5,2.3 Hz,1H),6.62(d,J=2.4 Hz,1H),1.03(s,9H),0.99(s,9H),0.29(s,6H),0.24(s,6H);13C NMR(75 MHz)δ 157.9,157.6,154.3,151.8,135.1,130.4,130.1,126.4,125.8,125.1,124.9,123.9,123.6,123.1,121.1,118.5,116.7,116.2,115.7,110.0,94.8,26.0,25.9,18.8,18.7,-4.3,-4.4;MS(FD)m/e 584(M+).
制备18d
2,8-双[(叔丁基二甲硅烷)氧基]-5-[4-[2-(1-哌啶基)乙氧基]苯基]-5H-苯并[b]萘并[2,1-d]吡喃
通过制备6中所述的过程,使制备18c的产物(3.5g,6.0mmol)与溴化4-[2-(1-哌啶基)乙氧基]苯基镁的0.2M THF溶液反应,层析纯化后(硅胶,3∶2己烷∶乙酸乙酯,0.1%氢氧化铵)提供3.5g(84%)的无色树脂固体状的目的化合物:1H NMR(300 MHz)δ7.97(d,J=8.8 Hz,1H),7.89(d,J=8.7 Hz,1H),7.76(d,J=8.3 Hz,2H),7.35(d,J=2.4 Hz,1H),7.10(m,3H),7.02(s,1H),6.73(d,J=8.7 Hz,2H),6.53(dd,J=8.3,2.4 Hz,1H),6.37(d,J=2.2 Hz,1H),3.95(t,J=6.0 Hz,2H),2.58(t,J=6.0 Hz,2H),2.38(m,4H),1.4-1.5(m,4H),1.3-1.4(m,2H),1.00(s,9H),0.94(s,9H),0.25(s,6H),0.19(s,6H);13C NMR(75 MHz)δ 159.8,157.6,154.1,154.0,135.0,132.2,130.1,128.6,127.3,126.3,126.2,125.6,124.7,123.4,121.6,118.0,116.5,115.0,114.5,110.3,76.0,66.8,58.5,55.6,26.8,26.0,26.0,25.0,18.7,18.7,-4.2,-4.3;MS(FD)m/e 696(M+);Anal.calc′d.forC42H57NO4Si2:C,72.46;H,8.27;N,2.01.Found:C,72.53;H,8.49;N,2.08.
实施例11b
通过实施例1中所述的过程,使制备18d的产物(3.4g,4.9mmol)与在THF中的1.0M的TBAF(24.4mmol)反应,在层析纯化(硅胶,1∶1己烷∶乙酸乙酯,10%甲醇,0.1%氢氧化铵)和用醚研磨后,提供2.2g(96%)白色固体状的目的化合物,mp 158-161℃:1H NMR(300 MHz)δ7.89(d,J=8.7 Hz,1H),7.77(d,J=8.7 Hz,1H),7.68(m,2H),7.23(d,J=2.4 Hz,1H),7.09(m,3H),6.97(s,1H),6.71(d,J=8.7 Hz,2H),6.49(dd,J=8.3,2.4 Hz,1H),6.36(d,J=2.3 Hz,1H),3.95(t,J=6.0 Hz,2H),2.60(t,J=6.0 Hz,2H),2.40(m,4H),1.4-1.5(m,4H),1.3-1.4(m,2H);13C NMR(75 MHz)δ159.5,159.5,155.8,153.9,135.0,132.4,130.1,128.0,126.7,125.6,125.4,125.3,124.7,121.4,119.9,116.1,114.8,111.0,110.1,105.5,75.8,66.1,58.3,55.3,26.3,24.7;IR(KBr)2934cm-1;MS(FD)m/e 468(MH+);Anal.calc′d.for C30H29NO4·H2O:C,74.19;H,6.45;N,2.88.Found:C,74.13;H,6.45;N,2.88.
制备22a
2,8-二甲氧基-5-[4-[(叔丁基二甲硅烷)氧基]苯基]-6H-苯并[c]菲啶-6-酮
将制备22的产物(100mg,0.19mmol)和2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)(47mg,0.21mmol)在二氯乙烷(10ml)中的混合物在回流下加热2小时,导致形成沉淀。将该混合物冷却到室温,过滤并用二氯甲烷(70ml)稀释该滤液,用1N氢氧化钠(2×70ml)洗涤,干燥(硫酸钠)并浓缩提供98mg(98%)的白色结晶固体状的目的化合物,mp 211-213℃:1H NMR(300 MHz,CDCl3)δ8.21(d,J=9.0 Hz,1H),8.16(d,J=8.9 Hz,1H),7.95(d,J=2.8 Hz,1H),7.60(d,J=8.8 Hz,1H),7.37(dd,J=9.0,2.8 Hz,1H),7.25(d,J=9.7 Hz,1H),7.21(d,J=8.7 Hz,2H),7.08(d,J=2.7 Hz,1H),6.93(d,J=8.7 Hz,2H),6.66(dd,J=9.7,2.8 Hz,1H),3.94(s,3H),3.87(s,3H),1.02(s,9H),0.25(s,6H);13C NMR(75 MHz,CDCl3)6 163.1,159.2,156.9,154.9,137.3,136.3,133.8,129.8,128.3,127.4,126.4,123.9,123.7,122.9,120.7,120.5,119.5,116.5,115.7,109.1,106.9,55.5,55.1,25.7,18.3,-4.2;IR(CHCl3)1646,1619cm-1;MS(FD)m/e 511(M+);Anal.calc′d.forC31H33NO4Si:C,72.75;H,6.51;N,2.74.Found:C,72.57;H,6.50;N,2.83.
制备23a
2,8-二甲氧基-5-(4-羟基苯基)-6H-苯并[c]菲啶-6-酮
将制备22a的产物(6.8g,13.3mmol)溶解在1∶1乙腈∶二氯甲烷(200ml)中,并用氟化氢-吡啶(80ml)处理1小时。用盐水(500ml)稀释该混合物,并用THF(3×300ml)提取。用饱和的碳酸氢钠中和合并的有机层,并用THF(2×500ml)洗涤所形成的含水层。然后,合并所有的含水层,并用THF(500ml)洗涤,干燥合并的有机层(硫酸钠),浓缩,用丙酮洗涤其固体残留物,提供5.27g(100%)灰白色粉末状的目的化合物,mp 310d℃: 1H NMR(300 MHz,DMSO-d6)δ9.79(bs,1H),8.52(d,J=9.0 Hz,1H),8.42(d,J=9.0Hz,1H),7.72(m,2H),7.47(dd,J=8.7,2.3 Hz,1H),7.31(d,2.1 Hz,1H),7.21(d,J=9.6 Hz,1H),7.07(d,J=8.4Hz,2H),6.82(d,J=8.3 Hz,2H),6.68(dd,J=9.3,2.6 Hz,1H),3.87(s,3H),3.79(s,3H);MS(FD)m/e 397(M+).
实施例12a
2,8-羟基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-11,12-二氢-6H-苯并[c]菲啶-6-酮
通过实施例14所述过程,使实施例12的产物(310mg,0.61mmol)与乙硫醇(189mg,3.1mmol)和三氯化铝(611mg,4.6mmol)反应,在径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,10-20%甲醇,在氨气下)后,提供237mg(81%)黄色泡沫状的目的化合物,用醚研磨析出结晶,mp166-174d℃:1H NMR(300 MHz,甲醇-d4)δ7.80(d,J=8.9 Hz,1H),7.73(d,J=2.6 Hz,1H),7.30(dd,J=8.9,2.7 Hz,1H),7.19(d,J=8.8 Hz,2H),6.97(d,J=8.9 Hz,2H),6.66(d,J=2.5 Hz,1H),6.56(d,J=8.7 Hz,1H),6.21(dd,J=8.7,2.6 Hz,1H),4.16(t,J=5.6 Hz,2H),2.86(s,4H),2.81(t,J=5.6 Hz,2H),2.59(m,4H),1.6-1.7(m,4H),1.4-1.6(m,2H);IR(CHCl3)3673,1637,1602 cm-1;MS(FD)m/e 482(M+);Anal.calc′d.for C30H30N2O4·H2O:C,71.96;H,6.46;N,5.60.Found:C,71.68;H,6.63;N,5.46.
实施例12b
2,8-二甲氧基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-11,12-二氢-6H-苯并[c]菲啶
用氢化锂铝(129mg,3.4mmol)处理实施例12的产物(350mg,0.69mmol)在THF(25ml)中的溶液,导致适度放热。使该混合物恢复到室温,并搅拌2小时,然后,迅速加热到回流状态,冷却,并用乙酸乙酯(50ml),然后饱和氯化铵(50ml)抑制反应。用乙酸乙酯(2×50ml)提取其含水层,干燥合并的有机层(硫酸钠),浓缩并经径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,5%甲醇,在氨气下)提供248mg(64%)黄色泡沫状的目的化合物:1H NMR(300MHz,CDCl3)δ7.28(d,J=8.5 Hz,1H),7.05(d,J=8.5 Hz,1H),6.79(m,3H),6.72(d,J=2.6 Hz,1H),6.65(d,9.0 Hz,2H),6.58(d,J=2.6 Hz,1H),6.52(dd,J=8.6,2.6 Hz,1H),4.65(s,2H),3.94(t,J=6.1 Hz,2H),3.74(s,3H),3.74(s,3H),2.96(dd,J=8.3,5.6,2H),2.81(dd,J=8.3,5.9 Hz,2H),2.66(t,J=6.1 Hz,2H),2.43(m,4H),1.5-1.6(m,4H),1.3-1.5(m,2H);13C NMR(75 MHz,CDCl3)δ158.5,158.3,153.3,141.7,138.4,134.6,132.3,126.6,126.2,125.3,122.9,121.7,120.5,114.9,113.4,112.3,111.2,111.0,65.8,57.8,55.6,55.2,55.1,54.8,29.0,25.7,24.0,22.2;IR(CHCl3)1610,1506cm-1;MS(FD)m/e 496(M+);Anal.calc′d.for C32H36N2O3:C,77.37;H,7.32;N,5.64.Found:C,77.25;H,7.12;N,5.75.
实施例12c
2,8-二甲氧基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-6H-苯并[c]菲啶-6-酮
通过实施例12中所述的方法,使制备23a的产物(4.8g 12.1mmol)、三苯基磷(6.3g,24.2mmol)和1-(2-羟乙基)哌啶(3.9g,30.3mmol)与重氮二羧酸二乙酯(DEAD)(4.2g,24.2mmol)反应,经层析纯化(硅胶,1∶1己烷∶乙酸乙酯,5-20%甲醇,0.1%氢氧化铵)和经乙酸乙酯重结晶后提供5.14g(84%)白色蓬松固体状的目的化合物,mp176℃:
|1H NMR(300 MHz,CDCl3)δ8.25(d,J=9.1 Hz,1H),8.21(d,J=8.8 Hz,1H),7.96(d,J=2.8 Hz,1H),7.64(d,J=8.8 Hz,1H),7.40(dd,J=9.0,2.8 Hz,1H),7.31(d,J=9.7 Hz,1H),7.26(d,J=8.8 Hz,2H),7.10(d,J=2.7 Hz,1H),6.99(d,J=8.9 Hz,2H),6.70(dd,J=9.6,2.7 Hz,1H),4.16(t,J=6.0 Hz,2H),3.95(s,3H),3.88(s,3H),2.81(t,J=6.0 hz,2H),2.53(m,4H),1.5-1.7(m,4H),1.4-1.5(m,2H);13C NMR(75 MHz,CDCl3)δ163.2,159.2,157.9,156.9,136.3,135.7,133.7,129.7,128.3,127.3,126.4,123.9,123.7,122.8,120.5,119.4,116.6,115.7,115.1,109.1,106.9,66.2,57.8,55.5,55.1,55.0,25.9,24.1;IR(CHCl3)1647,1619cm-1;MS(FD)m/e 508(M+);Anal.calc′d.for C32H32N2O4:C,75.56;H,6.35;N,5.51.Found:C,75.58;H,6.28;N,5.77.
实施例12d
2,8-羟基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-6H-苯并[c]菲啶-6-酮
通过实施例14所述过程,使制备12a的产物(500mg,0.98mmol)与乙硫醇(304mg,4.9mmol)和三氯化铝(987mg,7.4mmol)反应,在经层析纯化(硅胶,1∶1己烷∶乙酸乙酯,10-30%甲醇,0.1%氢氧化铵)和经甲醇结晶后,提供397mg(84%)白色粉末状的目的化合物。分析样品经甲醇/氯仿重结晶,mp 227-232d℃:1H NMR(300MHz,DMSO-d6)δ10.15(bs,1H),9.82(bs,1H),8.43(d,J=8.9 Hz,1H),8.34(d,J=9.2 Hz,1H),7.69(s,1H),7.63(d,J=9.0 Hz,1H),7.34(d,J=8.9 Hz,1H),7.0-7.3(m,6H),6.58(d,J=9.6 Hz,1H),4.13(t,J=5.6 Hz,2H),2.69(t,J=5.5 Hz,2H),2.46(m,4H),1.3-1.6(m,6H);13C NMR(75MHz,DMF-d7/丙酮-d6/CDCl3)δ162.2,158.4,157.3,155.9,137.4,137.2,133.9,130.8,127.6,127.5,126.9,125.0,124.0,123.1,121.1,119.0,117.3,115.7,115.5,112.8,110.6,63.4,55.8,53.6,23.2,22.1;IR(KBr)3303,1643,1602 cm-1;MS(FD)m/e 480(M+);Anal.calc′d.forC30H28N2O4·0.5H2O:C,73.59;H,5.98;N,5.72.Found:C,73.72;H,5.88;N,5.71.
实施例13
2,8-二甲氧基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-6H-苯并[c]菲啶
用氢化锂铝(1.43g,37.5mmol)处理实施例12a的产物(3.82g,7.51mmol)在THF(250ml)中的溶液,导致适度放热。在该放热过程停止后,使该混合物加热到回流状态过夜,冷却到室温,并用乙酸乙酯(200ml),然后1N氢氧化钠(200ml)小心地抑制反应。使其分层并用乙酸乙酯(2×200ml)提取其水层,用盐水(200ml)洗涤合并的有机层,干燥(硫酸钠)并浓缩。使残留物经己烷∶乙酸乙酯重结晶,提供3.24g(87%)灰白色固体状的目的化合物,mp 136-137℃:
1H NMR(300 MHz,CDCl3)δ7.91(d,J=8.6 Hz,1H),7.74(d,J=8.8 Hz,2H),7.61(d,J=8.6 Hz,1H),7.12(d,J=2.5 Hz,1H),6.95(dd,J=9.2,2.6,1H),6.91(dd,J=8.5,2.6 Hz,1H),6.6-6.8(m,5H),4.75(s,2H),3.95(t,J=6.1Hz,2H),3.90(s,3H),3.79(s,3H),2.68(t,J=6.1 Hz,2H),2.44(m,4H),1.5-1.7(m,4H),1.4-1.5(m,2H);13C NMR(75 NHz,CDCl3)δ159.1,157.3,153.4,143.5,137.9,135.0,134.1,126.5,125.6,124.9,124.2,123.8,123.7,122.4,121.7,118.1,114.9,113.8,111.2,106.4,65.8,57.8,55.8,55.2,54.8,25.7,24.0;IR(CHCl3)1506cm-1;MS(FD)m/e 494(M+);Anal.calc′d.for C32H34N2O3:C,77.70;H,6.94;N,5.66.Found:C,77.54;H,6.99;N,5.63.
制备11
3,9-双[(叔丁基二甲硅烷)氧基]-6-[4-(2-二乙氨基乙氧基)苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃
通过制备8中所述的方法,使制备7的产物(500mg,0.85mmol)、三苯基磷(892mg,3.4mmol)和N,N-二乙基乙醇胺(496mg,438ml,4.23mmol)与偶氮二羧酸二乙酯(DEAD)(592mg,535ml,3.4mmol)在甲苯(35ml)中反应。层析纯化(硅胶,3∶1己烷∶乙酸乙酯,0.1%氢氧化铵)提供540mg(92%)的无色油状的目的化合物:
1H NMR(300 MHz)d 7.46(d,J=2.5 Hz,1H),7.3-7.4(m,4H),6.86(m,3H),6.69(s,1H),6.51(dd,J=8.3,2.3 Hz,1H),6.37(d,2.2 Hz,1H),3.98(t,J=6.3 Hz,2H),2.77(t,J=6.3 Hz,2H),2.54(q,J=7.1 Hz,4H),0.99(s,9H),0.97(t,J=7.0 Hz,6H),0.96(s,9H),0.22(s,6H),0.21(s,6H);13C NMR(125 MHz)d 160.0,157.5,153.7,153.3,140.8,132.6,132.3,131.1,129.7,125.7,124.6,122.5,119.2,115.0,114.2,113.9,113.7,109.3,78.1,67.2,52.3,48.1,26.0,26.0,18.6,12.5,-4.3;MS(FD+)m/e 689(M+);
制备12
通过制备8中所述的方法,使制备7的产物(500mg,0.85mmo1)、三苯基磷(892mg,3.4mmol)和1-(2-羟乙基)吗啉(555mg,512ml,4.23mmol)与偶氮二羧酸二乙酯(DEAD)(592mg,535ml,3.4mmol)在甲苯(35ml)中反应。层析纯化(硅胶,3∶1己烷∶乙酸乙酯,0.1%氢氧化铵)提供569mg(95%)的粉红色泡沫状的目的化合物:
1H NMR(300 MHz)d 7.46(d,J=2.1Hz,1H),7.2-7.3(m,4H),6.86(m,3H),6.70(s,1H),6.51(dd,J=8.2,2.3 Hz,1H),6.37(d,2.7 Hz,1H),4.04(t,J=5.8 Hz,2H),3.57(t,J=4.5 Hz,2H),2.69(t,J=5.7 Hz,2H),2.47(m,4H),0.99(s,9H),0.96(s,9H),0.22(s,6H),0.21(s,6H);13C NMR(125 MHz)d 159.8,157.6,153.7,153.2,140.8,132.5,132.5,131.1,129.7,125.8,124.6,122.5,119.2,115.1,114.2,114.0,113.8,109.3,78.2,67.0,66.2,57.9,54.6,26.0,25.9,18.6,-4.3;MS(FD+)m/e 703(M+);
制备13
3,9-双[(叔丁基二甲硅烷)氧基]6-H-苯并呋喃并[3,2-c][1]苯并吡喃-6-酮
使拟雌内酯(10g,37.3mmol)在二氯甲烷(600ml)中形成淤浆,冷却到0℃,并用三乙胺(24.9g,34.3ml,246mmol)和氯化叔丁基二甲基硅烷(24.7g,164mmol)处理。将该混合物温热到室温并搅拌过夜,在此期间,使其缓慢变均匀。用醚(800ml)稀释后,用盐水(800ml)洗涤该混合物并用醚(500ml)提取其水层。干燥合并的有机层(硫酸钠),浓缩,使其残留物经己烷重结晶提供14.2g(77%)白色粉末状的目的化合物,mp 118-119℃:
1H-NMR(300 MHz,CDCl3)d 7.90(d,J=8.5 Hz,1H),7.82(d,J=8.5 Hz,1H),7.10(d,J=2.0 Hz,1H),6.97(m,2H),6.90(dd,J=8.5,2.0 Hz,1H),1.03(s,9H),1.02(s,9H),0.28(s,6H),0.25(s,6H);IR(CHCl3)1733 cm-1;MS(FD+)m/e 496(M+);Anal.calc′d.for C27H36O5Si2:C,65.27;H,7.32.Found:C,65.57;H,7.26.
制备14
通过制备4中所述的方法,使制备13的产物(5.0g,10.0mmol)与氢化二异丁基铝(12.0ml,12.0mmol)的1.0M甲苯溶液在甲苯(450ml)中反应。经己烷重结晶产生1.26g以所述醛的互变异构体混合物形式的目的化合物。层析纯化(硅胶,2-15%乙酸乙酯/己烷)其母液提供1.37g的起始化合物(约67%纯度),重结晶后,对于总产量为1.85g(37%)的互变异构混合物而言,得到580mg的目的化合物: 1H NMR(300 MHz)d 10.15(s,0.5H),9.2(br s,0.5H),7.99(d,J=8.4 Hz,1H),7.56(d,J=8.4 Hz,1H),7.50(m,0.5H),7.09(d,J=2.0 Hz,1H),6.96(m,1H),6.6-6.7(m,2H),6.55(m,0.5H),1.01(s,9H),1.00(s,9H),0.27(s,6H),0.25(s,6H);IR(CHCl3)3550,1663cm-1;MS(FD)m/e 499(MH+);Anal.calc′d.for C27H38O5Si2:C,65.02;H,7.69.Found:C,65.32;H,7.76.
制备15
通过制备5中所述的方法,使制备14的产物(464mg,0.93mmol)与苯酚(1.05g,11.2mmol)在含有无水硫酸镁(1.0g)的氯代苯(25ml)中反应,产生467mg(87%)以不稳定的粉色泡沫存在的粗品目的化合物,它可以直接使用而不用纯化:1H NMR(300 Mhz)d 7.1-7.7(m,8H),6.6-6.9(m,3H),1.01(s,9H),1.00(s,9H),0.28(s,6H),0.25(s,6H)。
制备16
3,9-双[(叔丁基二甲硅烷)氧基]-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-苯并呋喃并[3,2-c][1]苯并吡喃
通过制备6中所述的方法,使制备15的产物(467mg,0.81mmol)与溴化4-[2-(1-哌啶基)乙氧基]苯基镁(2.6ml,1.62mmol)的0.5M的THF溶液在甲苯(15ml)中反应。径向层析(硅胶,2∶1己烷∶乙酸乙酯,1%甲醇,在氨气下)提供500mg(90%)的无色树胶固体状的目的化合物: 1H NMR(300 MHz)d 7.39(m,3H),7.04(d,J=2.0 Hz,1H),6.92(d,J=8.6 Hz,2H),6.78(d,J=8.4 Hz,1H),6.68(d,J=8.1Hz,1H),6.68(s,1H),6.53(dd,J=8.2,2.2 Hz,1H),6.38(d,J=2.6 Hz,1H),4.05(t,J=5.9 Hz,2H),2.64(t,J=6.1 Hz,2H),2.42(m,4H),1.4-1.6(m,4H),1.3-1.4(m,2H),0.96(s,9H),0.95(s,9H),0.20(s,6H),0.19(s,6H);13CNMR(125 MHz)d 160.3,158.0,156.8,155.5,154.0,148.2,132.7,129.8,121.6,121.1,119.8,117.3,115.3,113.8,110.6,109.8,109.1,103.8,79.0,66.9,58.5,55.6,26.8,26.0,26.0,25.0,18.7,-4.3,-4.3;MS(FD)m/e 686(M+);Anal.calc′d.for C40H55NO5Si2:C,70.03;H,8.08 ;N,2.04.Found:C,70.28;H,8.14;N,2.08.
实施例11
通过实施例1中所述的过程,使制备16的产物(520mg,0.76mmol)与在THF中的1.0M TBAF(4.5mmol)反应,在径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,10%甲醇,在氨气下)后,产生292mg(72%)鲜红色泡沫状的目的化合物,它经四氯化碳结晶:
1H NMR(300 MHz,二甲甲酰胺-d7)d 10.00(br s,1H),9.83(br s,1H),7.3-7.5(m,3H),7.10(s,1H),6.98(d,J=8.5 Hz,2H),6.7-6.9(m,3H),6.54(dd,J=8.1,1.8 Hz,1H),6.42(s,1H),4.10(t,J=5.8 Hz,2H),2.67(m,2H),2.44(m,4H),1.4-1.6(m,4H),1.3-1.4(m,2H);13C NMR(125 MHz,二甲甲酰胺-d7)d 160.2,159.9,156.8,156.4,155.1,147.2,133.0,129.5,121.4,119.5,118.9,115.1,112.9,109.2,108.9,108.3,104.3,98.7,78.5,66.5,58.2,55.3,26.4,24.6;IR(KBr)3220 cm-1;HRMS(FAB+)m/e calc′d.for C28H28NO5 458.1967(MH+),found 458.1974;Anal.calc′d.for C28H27NO4S.0.25CCl4:C,68.40;H,5.49;N,2.82.Found:C,68.58;H,5.81;N,2.94.
制备17
2-甲氧基-8-羟基-11,12-二氢-5H-苯并[b]萘并[2,1-d]吡喃-5-酮
于室温搅拌下,将三氯氧化磷(12.0g,7.3ml,18.3mmol)滴加到1-甲氧甲酰基-6-甲氧基-2-四氢萘酮(见Colvin,Martin,and Shroot,Chemistry and Industry,2130(1966))(18.0g,76.8mmol)和间苯二酚(8.9g,80.7mmol)在甲苯(450ml)的溶液中,将该混合物加热到80℃达12小时。在冷却到室温后,将该混合物倒入水(500ml)中并过滤,用醚漂洗其沉淀。分出滤液层,用乙酸乙酯(3×500ml)提取其含水层,干燥合并的有机层(硫酸钠)并浓缩。用甲醇使其残留物重结晶,提供16.0g黄色固体状的目的化合物,mp 244-249d℃: 1HNMR(300 MHz,DMSO-d6)d 10.55(br s,1H),8.24(d,J=8.6Hz,1H),7.75(d,J=8.7 Hz,1H),6.6-7.0(m,4H),3.76(s,3H),2.8-3.0(m,4H);13C NMR(125 MHz,DMSO-d6)d 170.3,160.3,158.3,158.1,153.3,147.7,137.5,127.4,125.8,122.5,114.5,112.6,112.4,110.9,101.4,54.6,26.3,22.7;IR(KBr)3250,1676,1618cm-1;MS(FD+)m/e 294(M+);Anal.calc′d.for C18H14O4:C,73.45;H,4.80.Found:C,73.15;H,4.86.
通过制备3中所述过程,使制备17的产物(4.17g,14.2mmol)与乙硫醇(3.53g,3.95ml,56.8mmol)和三氯化铝(9.0g,67.5mmol)在二氯甲烷(100ml)中反应。使其粗品进一步与三乙胺(8.6g,11.9ml,85.2mmol)和氯化叔丁基二甲基硅烷(8.6g,56.8mmol)在二氯甲烷(100ml)中反应,在经己烷重结晶后,提供黄色固体状的目的化合物,mp 145-147℃: 1H NMR(300 MHz,CDCl3)d 8.37(d,J=8.6 Hz,1H),7.58(d,J=9.3 Hz,1H),6.83(s,1H),6.81(m,2H),6.72(d,J=2.4 Hz,1H),2.8-3.0(m,4H),1.00(s,18H),0.27(s,6H),0.24(s,6H);13C NMR(125 MHz,CDCl3)d 159.8,158.6,155.4,153.9,147.1,137.7,128.6,125.0,123.9,119.0,118.1,117.5,117.3,113.8,107.5,27.4,25.7,25.6,23.9,18.3,18.2,-4.3,-4.4;IR(CHCl3)1708,1612cm-1;MS(FD)m/e 508(M+).
制备19
6-甲氧基-1-[(4-羟基)苯基]亚氨基-1,2,3,4-四氢萘
在氮气流下,将6-甲氧基四氢萘酮(25g,142mmol)和4-羟基苯胺(16.3g,149mmol)加热到180℃述2小时。冷却到室温后,使其固体部分经甲苯/甲醇重结晶:
1H NMR(300 MHz)d 8.15(d,J=9.7 Hz,1H),6.5-7.9(m,6H),3.80(s,3H),2.84(t,J=7.3 Hz,2H),2.51(t,J=6.8 Hz,2H),1.85(m,2H).
制备20
6-甲氧基-1-[(4-羟基)苯基]亚氨基-1,2,3,4-四氢萘
将制备19的产物(36g,134.7mmol)溶解在1∶1二氯甲烷∶THF(300ml)中,并用三乙胺(28.6g,39.4ml,283mmol)和氯化叔丁基二甲硅烷(30.5g,202mmol)处理。搅拌其混合物过夜,加入另外部分的三乙胺(6.8g,9.4ml,67mmol)和氯化叔丁基二甲硅烷(10.2g,67mmol),以便促进反应完成。5小时后,用醚(500ml)稀释该混合物,过滤,浓缩,并用己烷/醚洗涤其残留物。过滤其提取物,浓缩,并用快速层析纯化其残留物(硅胶,18∶1-10∶l己烷∶乙酸乙酯)产生21.0g(41%)淡黄色泡沫状的目的化合物:1H NMR(300 MHz,CDCl3)d 8.32(d,J=9.7 Hz,1H),6.86(m,3H),6.73(m,3H),3.92(t,J=5.8 Hz,2H),2.57(t,J=6.8Hz,2H),1.96(m,2H),1.05(s,9H),0.26(s,6H).
制备21
6-甲氧基-1-[N-[[4-(叔丁基二甲硅烷)氧基]苯基]-N-(2,5-二甲氧苯甲酰基)]氨基-3,4-四氢萘
将制备20的产物(10.2g,26.8mmol)溶解在二氯甲烷(100ml)中,冷却到0℃,并用三乙胺(3.8g,5.2ml,37.5mmol),然后2,5-二甲氧基苯甲酰氯(6.72g,33.5mmol)在二氯甲烷(25ml)中的溶液处理。将该混合物加热到回流状态过夜,然后用另外的三乙胺(1.4g,1.9ml,13.4mmol)和酰氯(2.7g,13.4mmol)处理,并再继续加热12小时。真空浓缩后,将其残留物溶于醚(250ml)中,用盐水(250ml)洗涤,干燥(硫酸钠)并浓缩。通过层析纯化其残留物(硅胶,9∶1-4∶1己烷∶乙酸乙酯)提供10.3g白色泡沫状的目的化合物: 1HNMR(300 MHz,CDCl3)d 6.4-7.6(br m,11H),5.83(br s,1H),3.4-3.8(br m,9H),1.9-3.0(br m,4H),0.95(2 br s,9H),0.14(2 brs,6H);IR(CHCl3)1651,1607,1507cm-1;MS(FD)m/e 545(M+);Anal.calc′d for C32H39NO5Si:C,70.43;H,7.20;N,2.57.Found:c,70.53;H,7.26;N,2.76.
制备22
2,8-二甲氧基-5-[4-[(叔丁基二甲硅烷)氧基]苯基]-11,12-二氢-6H-苯并[c]菲啶-6-酮
将制备21的产物(2.73g,5mmol)在苯(250ml)中的溶液经冷冻/抽气/融化三循环脱气,和在氮气下的石英浸渍肼中用450瓦的内部汞灯辐照。22小时后,将该混合物浓缩,并使残留物经层析纯化(硅胶,20∶1甲苯∶醚)提供675 mg(26%)黄色泡沫状的目的化合物。经己烷/醚结晶得到淡黄色结晶状的分析样品,mp 194-95℃:
1H NMR(300 MHz,CDCl3)7.94(d,2.8 Hz,1H),7.73(d,8.9 Hz,1H),7.32(dd,J=8.9,2.8 Hz,1H),7.17(d,J=8.7 Hz,2H),6.84(d,J=8.7 Hz,2H),6.76(d,J=2.6 Hz,1H),6.67,(d,J=8.8 Hz,1H),6.35(dd,J=8.8,2.7 Hz,1H),3.94(s,3H),3.75(s,3H),2.90(s,4H),0.99(s,9H),0.21(s,6H);13C NMR(125 MHz,CDCl3)d 162.6,158.3,157.7,154.4,139.7,134.3,133.6,129.9,129.8,128.1,126.2,123.7,123.2,122.6,119.8,114.9,112.7,110.4,108.6,55.3,54.8,29.3,25.5,23.5,18.1,-4.4;IR(CHCl3)1640,1615,1507cm-1;MS(FD+)m/e 513(M+);Anal.calc′d for C31H35NO4Si:C,72.48;H,6.87;N,2.73.Found:C,72.66;H,6.95;N,2.86.
制备23
2,8-二甲氧基-5-(4-羟基苯基)-11,12-二氢-6H-苯并[c]菲啶-6-酮
将制备22的产物(790mg,1.5mmol)溶解在3∶2乙腈∶二氯甲烷(50ml)中并分两次(间隔1小时)用氟化氢-吡啶(10ml)处理。再搅拌1小时后,将该混合物用THF(100ml)稀释,过滤,用甲醇和醚洗涤。用THF(200ml)稀释,并用盐水(200ml)和饱和碳酸氢钠(200ml)洗涤滤液。用THF(100ml)提取合并的含水层,并干燥合并的有机层(硫酸钠),浓缩提供340mg(57%)的黄色粉末,mp 250-275d℃,它可以不经纯化直接使用: 1H NMR(300MHz,二甲甲酰胺-d7)d 9.80(br s,1H),7.91(d,J=9.7 Hz,1H),7.81(d,J=1.9Hz,1H),7.44(dd,J=9.7,1.9 Hz,1H),7.20(d,J=8.7 Hz,2H),6.8-7.0(m,4H),6.47(dd,J=8.7,1.9 Hz,1H),3.94(s,3H),3.74(s,3H),2.89(m,4H);MS(FD+)m/e 399(M+).
实施例12
将偶氮二羧酸二乙酯(DEAD)(296mg,268ml,1.7mmol)加入制备23的产物(340mg,0.85mmol)、三苯基磷(446mg,1.7mmol)和1-(2-羟乙基)哌啶(275mg,282ml,2.1mmol)在THF(20ml)的溶液中,并于室温下搅拌该混合物过夜。真空浓缩后,层析纯化(硅胶,1∶1己烷∶乙酸乙酯,5-20%甲醇,0.1%氢氧化铵)提供338mg(66%)黄色泡沫状的目的化合物: 1H NMR(300 MHz)d 7.82(m,2H),7.35(dd,J=9.7,2.9 Hz,1H),7.23(d,J=9.7 Hz,2H),6.91(d,J=9.7 Hz,2H),6.82(m,1H),6.70(d,J=9.7Hz,1H),6.38(dd,J=9.7,1.9 Hz,1H),4.12(t,J=5.8 Hz,2H),3.90(s,3H),3.70(s,3H),2.86(m,6H),2.65(m,4H),1.5-1.7(m,4H),1.4-1.5(m,2H).
实施例13
2,8-二甲氧基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-6H-苯并[c]菲啶
用DDQ(352mg,1.55mmol)处理实施例12的产物(753mg,1.47mmol)在二氯乙烷(20ml)中的溶液,并加热到80℃。几小时后,将该混合物冷却到室温,用二氯甲烷(100ml)稀释,用饱和碳酸钠洗涤,干燥有机层(硫酸钠)并浓缩。使其残留物经层析纯化(硅胶,1∶1己烷∶乙酸乙酯,15%甲醇)得到330mg(44%)的黄色固体。
将以上得到的固体(309mg,0.61mmol)溶解在THF(25ml)中,并用氢化锂铝(LAH)(115mg,3.05mmol)于室温下处理。10分钟后,用乙酸乙酯(50ml)抑制过量的LAH,用饱和氯化铵(25ml)洗涤该混合物。用乙酸乙酯(25ml)洗涤其含水层,用盐水(2ml)洗涤合并的有机层,干燥(硫酸钠),浓缩,并使其经径向层析纯化(硅胶,1∶1己烷∶乙酸乙酯,5%甲醇,在氨气下)。然后,使其产物溶解在冰乙酸(10ml)中并用硼氢化钠(69mg,1.82mmol)处理。1小时后,用饱和碳酸氢钠使该混合物骤冷,并在二氯甲烷和饱和碳酸氢钠之间分配。干燥有机层(硫酸钠),浓缩,并不经进一步纯化直接使用其残留物:1H NMR(300MHz)d 7.99(d,J=8.6 Hz,1H),7.82(d,J=8.6 Hz,1H),7.74(d,J=9.4 Hz,1H),7.71(d,J=8.4 Hz,1H),7.28(d,J=2.3 Hz,1H),6.92(m,2H),6.81(d,J=2.3 Hz,1H),6.69(d,J=9.2 Hz,2H),6.63(d,J=9.1,2H),3.89(t,J=6.2Hz,2H),3.87(s,3H),3.75(s,3H),2.57(t,J=6.1 Hz,2H),2.39(m,4H),1.4-1.5(m,4H),1.3-1.4(m,2H).
实施例14
2,8-二羟基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-6H-苯并[c]菲啶
用乙硫醇(200mg,220ml,3.2mmol)和三氯化铝(320mg,2.4mmol)处理实施例13的产物(195mg,0.39mmol)在二氯甲烷(25ml)中的溶液。于室温下搅拌4小时后,小心地用THF(25ml)和饱和碳酸氢钠(25ml)使其混合物骤冷。使其分层,用THF(25ml)提取该含水层,并干燥合并的有机层(硫酸钠),浓缩。经径向层析(硅胶,1∶1己烷∶乙酸乙酯,10-20%甲醇,在氨气下)纯化其残留物提供110mg(60%)黄褐色泡沫状的目的化合物。经甲醇结晶的分析样品为淡红色固体:1H NMR(300 MHz,二甲甲酰胺-d7)d 9.92(br s,1H),9.74(br s,1H),7.99(d,J=8.8 Hz,1H),7.78(d,J=8.5 Hz,1H),7.69(d,J=9.0 Hz,1H),7.63(d,J=8.7 Hz,1H),7.23(d,J=2.0 Hz,1H),6.98(dd,J=9.0,2.1 Hz,1H),6.84(dd,J=8.4,2.1 Hz,1H),6.73(m,5H),3.92(t,J=5.9 Hz,2H),2.57(t,J=5.9 Hz,2H),2.38(m,4H),1.4-1.5(m,4H),1.3-1.4(m,2H);IR(KBr)3560,3490cm-1;MS(FD+)m/e 466(M+);Anal.calc′d.for C30H30N2O3·0.5H2O:C,75.75;H,6.58;N,5.89.Found:C,75.82;H,6.76;N,5.95.
实施例15
8-二羟基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-5H-苯并[b]萘并[2,1-d]吡喃
在说明所述方法的实施例中,使用经绝后模型以确定不同治疗方法对于循环血液脂质的作用效果。
由Charles River Laboratories(Protage,MI)获得七十五天龄的雌性Sprague Dawley大鼠(体重在200-225g范围内)。使所述动物或者两侧卵巢切除(OVX)或者在Charles River Laboratories接受Sham手术,一周后起运。到达后,将它们以每笼3或4只一组饲养在悬挂的金属笼内,并容许任意觅食(钙含量约为0.5%)和饮水达一周时间。维持室温在22.2℃±1.7℃,最低相对湿度为40%。室内的光照周期为12小时明,12小时暗。
剂量制度组织收集。一周适应期(即OVX后两周)后,开始每日给予试验化合物。除非另外指明外,以在1%羧甲基纤维素中的悬浮液或溶解在20%的环糊精中的形式口服给予17a-乙炔基雌二醇或试验化合物。动物每日定量给药共4天。依照方案给药后,称量动物并用氯胺酮∶甲苯噻嗪(2∶1,V∶V)混合物麻醉动物通过心脏穿刺收集血样。然后,通过采用二氧化碳窒息处死动物,通过中线切口取出子宫,测定湿的子宫的重量。
胆固醇的分析。使血样在室温下凝聚2小时,以3000rpm离心10分钟后得到血清。使用Boehringer Mannheim Diagnostics高效胆固醇测定仪测定血清胆固醇。简言之,将胆固醇氧化成胆甾-4-烯-3-酮和过氧化氢。然后,使过氧化氢与苯酚和4-氨基安替比林在过氧化物酶存在下反应,产生对醌亚胺染料,在500nm经分光光度法测定其示数。然后,对照标准曲线计算胆固醇的浓度。整个测定过程使用BiomekAutomated Workstation自动进行。
子宫嗜酸性细胞过氧化物酶(EPO)测定。将子宫于4℃下保存直到进行酶分析。将子宫在含有0.005%Triton X-100的50倍体积的50mM Tris缓冲液(pH约8.0)中匀化。加入在Tris缓冲液中的0.01%过氧化氢和10mM邻苯二胺(最终浓度)后,在450nm监测吸光度增加达1分钟。在所述子宫中嗜酸性细胞的存在表明化合物的雌激素活性。在反应曲线的开始的线性部分后测定15秒钟间隔期的最大速率。
化合物来源:17α-乙炔基雌二醇由Sigma Chemical Co.,St.Louis,MO获得。
式I和II化合物对于血清胆固醇的影响及兴奋剂/非兴奋剂活性的确定
以下表1中所示的数据表明在卵巢切除大鼠、用17α-乙炔基雌二醇(EE2;可得到的雌激素的口服形式)处理的大鼠和用本发明的某些化合物处理的大鼠中的比较结果。尽管当以0.1mg/kg天口服给予EE2时引起血清胆固醇的降低,然而,它对于子宫也具有刺激作用,因此EE2子宫的重量明显重于卵巢切除的试验动物的子宫重量。这种子宫对于雌激素的应答在本领域中被充分认识。
与卵巢切除的对照动物相比不仅本发明的化合物一般降低血清胆固醇,而且使用大多数的试验化合物可以使子宫重量增加幅度最小至略有降低。与本领域内已知的雌激素化合物相比,降低血清胆固醇,而对子宫重量无不利影响的益处是难得的和所需要的。
如以下数据所示,通过估价嗜酸性细胞浸润子宫的不利的反应也可以评价雌激素作用。尽管雌二醇引起显著的、预料到的在嗜酸性细胞浸润的增加,本发明的化合物不引起任何在卵巢切除大鼠的间质层中可观察到的嗜酸性细胞数量的增加。
表1
剂量 子宫重量 子宫EPO 血清胆固醇
化合物 mg/kg (% 增加 vs.OVX) (V.max) (% 降低 vs.OVX)EE2 0.1 86.3 116.4 81.4
实施例1 0.1 25.3 7.8 72.8
1.0 9.2 3.0 51.0
10.0 5.9 2.1 54.6
实施例3 0.1 32.5 4.2 51.5
1.0 7.4 3.0 50.8
实施例4 0.1 10 3.3 62.6
1.0 15.3 3.3 48.2
实施例5 0.1 -5.1 4.5 -9
1.0 18.6 4.8 61.3
实施例6 0.1 23 4.2 -2.5
1.0 6.4 1.8 9.9
10.0 50.0 3.6 -11.4
实施例7 0.1 28.9 4.8 39.8
1.0 31.2 6.6 65.5
10.0 14.7 3.6 54.0
实施例8 0.01 10.2 2.1 50.5
0.1 27.4 4.8 38.5
1.0 27.2 4.8 68.0
实施例9 0.1 77.8 52.2 40.1
109.1 83.1 54.7
94.6 75.0 65.2
实施例11 0.1 -8.8 2.7 17.4
1.0 3 4.2 30.9
10.0 -12.6 4.2 36.3
实施例14 0.01 -0.6 2.7 24.8
0.1 60.0 5.4 59.5
1.0 49.1 36.0 60.7
除了本发明化合物的上述益处(特别是当与雌二醇比较时)之外,以上数据清楚地显示式I和II化合物不是雌激素的模仿物。此外,对于任何治疗而言,没有观察到有害的毒性作用(生存性)。骨质疏松试验方法
按照下文中的通用制备方法,每日治疗大鼠达35天(每个治疗组6只大鼠),在第36天通过二氧化碳窒息处死动物。这35天的时间期限足以使骨质密度有最大的降低(按照在此所述的方法测定)。在处死动物时,取出子宫,剔除无关的组织,在测定湿重前,排除液体含量以便确证雌激素缺乏与完全卵巢切除有关。对于卵巢切除而言,子宫重量一般降低约75%。然后,将子宫置于10%的中性福尔马林缓冲液中,以便于其后的组织学分析。
切除右股骨并在远侧的干骺端通过图像分析程序(NIH图像)产生digitilized X-射线和分析。也通过定量计算的X-射线断层照相术扫描来自这些动物的胫骨近端面。
按照上述过程,将在20%羟丙基b-环糊精中的本发明化合物和乙炔基雌二醇(EE2)口服给予试验动物。在下表2和表3中所示的股骨远侧干骺端的数据为式I化合物治疗与完整的和卵巢切除的试验动物比较的结果。以相对于卵巢切除的保护百分数来表示试验结果。
表2化合物/治疗 剂量/kg 股骨远侧干骺端X-射线图像分析的Gray分数
EE2 0.1mg 62.4*
实施例1 0.01mg 14.2*
0.1mg 49.8*
1.0mg 51.7*
10.0mg 48.2*
*P<=0.5对于原始数据的两个尾部的学生t检验。
总之,卵巢切除的试验动物与完整的,溶媒治疗的对照动物相比股骨密度显著降低。口服给予乙炔基雌二醇(EE2)可以防止这种骨质丢失,然而,采用这种治疗方法对子宫刺激的风险总是存在。
本发明的化合物也可以以一般的、剂量依赖方式防止骨质的丢失。因此,本发明的化合物可以用于治疗经绝后综合征,尤其骨质疏松。MCF-7增生测定
MCF-7乳腺癌细胞(ATCCHTB 22)保持在补充10%的牛胚胎血清(FBS)(V/V)、L-谷氨酰胺(2mM)、丙酮酸钠(1mM)、HEPES{(N-[2-羟乙基]哌嗪-N’-[2-乙磺酸]10mM}、非必需氨基酸和牛胰岛素(1μg/ml)(维持培养基)的MEM(最低必需培养基,无酚红,Sigma,St.Louis,MO)中。在测定前10天,将MCF-7细胞转变成补充10%葡聚糖涂层炭剥离的牛胚胎血清(DCC-FBS)测定培养基的维持培养基代替10%的FBS,以便排除内储存的类固醇。使用细胞分离培养基(补充10mMHEPES和2mM EDTA的不含Ca++/Mg++的HBSS(无酚红)),由保养瓶中转移MCF-7细胞。用测定培养基洗涤细胞两次,调节到80000细胞/ml。将约100ml(8000细胞)加入平底微量细胞培养穴中(Costar 3596)并于37℃,在5%二氧化碳润湿的培养箱中孵化48小时,以使细胞在转移后粘连和平衡。在测定培养基中制备药物的连续稀释液或作为稀释剂对照的DMSO,将50ml调成一式三份微量细胞培养物,然后每份加入50ml测定培养基以使最终体积为200ml。于37℃,在5%二氧化碳润湿的培养箱中再孵化48小时后,用氚化胸苷(1μCi/穴)给微量细胞培养物加脉冲达4小时。通过于-70℃冷冻24小时终止培养,然后融化并使用Skatron半自动细胞收获器收获微量细胞培养物。使用Wallac BetaPlaceb计数器,经液相闪烁给样品计数。下表3中的结果显示本发明的某些化合物的IC50。
表3
化合物(实施例参照) IC50 nM
1 0.2
2 100
3 3.0
4 5.0
5 1000
6 500
11 0.7
14 1对DMBA诱导的乳房癌的抑制
在雌性Sprague-Dawley大鼠(购自Harlan Industries,Indianapolis,Indiana)中产生雌激素依赖性的乳房癌。在约55天龄,使所述大鼠口服接受单独剂量的20mg 7,12-二甲基苯并[a]蒽(DMBA)。在给予DMBA 6周后,每隔一周触摸乳腺以检查肿瘤的出现。每当出现一个或多个肿瘤时,用公制测径器测定每个肿瘤的最大和最小直径,记录测定结果,而且选择该动物用于试验。努力在治疗组和对照组间均匀地分配不同大小的肿瘤,以致平均大小的肿瘤在试验组间被等量地分配。每个对照组和试验组各包括5-9只动物。
式I化合物或者通过在2%的阿拉伯胶中腹膜内注射或者口服。口服给予的化合物溶于或悬浮于0.2ml的玉米油中。每种治疗(包括阿拉伯胶和玉米油对照治疗)每日给予每只试验动物一次。在开始肿瘤测量和选择试验动物后,每周利用上述方法测定肿瘤的大小。动物的治疗和测量持续3-5周,此时测定肿瘤的最终面积。对于每个化合物和对照治疗而言,测定平均肿瘤面积的变化。子宫纤维变性的试验过程试验1
给予3-20名具有子宫纤维变性的妇女本发明的化合物。给予的化合物的量为0.1-1000mg/天,给药期为3个月。
在给药期间观察这些妇女对于子宫纤维变性的作用,直到停止给药后3个月。试验2
除了给药期为6个月外,所用过程与试验1相同。试验3
除了给药期为1年外,所用过程与试验1相同。A.在豚鼠中诱发子宫肌瘤。
长期使用雌激素刺激以便在性成熟的雌性豚鼠中诱发平滑肌瘤。每周给动物注射3-5次的雌二醇达2-4个月或直到出现肿瘤。每日给予包括本发明的化合物或溶媒的治疗达3-16周,然后处死动物,收获子宫,并分析肿瘤的消退。B.在裸鼠中移植人子宫肌瘤组织。
将来自人的平滑肌瘤的组织移植到性成熟、切除卵巢的雌性裸鼠的腹腔和/或子宫肌层中。提供外原的雌激素以便诱发移植组织的生长。在某些情况下,将收获的肿瘤细胞在移植前在体外培养。每日通过胃管提供包括本发明化合物或溶媒的治疗达3-16周,并取出植入体,测定其生长或消退。在处死时,收获子宫以便评价该器官的状态。试验5A.收获来自人子宫肌瘤的组织并在体外保存作为主要的不能转变的培养基。使手术样品通过无菌的筛网或可选剔除周围组织以便产生单独的细胞悬浮液。将细胞保持在含有10%血清和抗生素的培养基中。测定存在和不存在雌激素条件下的生长速度。测定细胞产生补体成分C3的能力和它们对生长因子和生长激素的应答。在体外评价培养物用孕激素、GnRH、本发明的化合物和溶媒治疗后的增生应答。每周评价类固醇激素受体的水平以便确定是否在体外保持重要的细胞特征。使用来自5-25名患者的组织。
至少上述试验之一中的活性表明本发明的化合物在治疗子宫肌瘤方面有效。子宫内膜异位试验过程
在试验1和2中,可以检验给予本发明的化合物14天和21天对于移植的子宫内膜组织生长的作用。试验1
使用12-30只成年CD族雌性大鼠作为试验动物。将其分成相同数量的3组。监测所有动物的动情期。在动情前期,对每只雌性动物进行手术。已将每组中的雌性动物的左侧子宫角取出,切成小的方块,并将该小方块松散地缝合在靠近肠系膜血流的不同部位。此外,已将在组2中的雌性动物的卵巢取出。
在手术后,使组1和2的动物接受腹膜内注射水达14天,而组3的动物在相同期间接受腹膜内注射每公斤体重为1.0mg的本发明的化合物。在治疗14天后,处死每只雌性动物,取出子宫内膜植入体、肾上腺、保留的子宫和卵巢(当可用时)并制备用于组织学检验。称量该卵巢和肾上腺。试验2
使用12-30只成年CD族雌性大鼠作为试验动物。将其分成相同数量的2组。监测所有动物的动情期。在动情前期,对每只雌性动物进行手术。已将每组中的雌性动物的左侧子宫角取出,切成小的方块,并将该小方块松散地缝合在靠近肠系膜血流的不同部位。
手术后约50天,指定组1的动物接受腹膜内注射水达21天,而组2的动物在相同期间接受腹膜内注射每公斤体重为1.0mg的本发明的化合物。在治疗21天后,处死每只雌性动物,取出子宫内膜植入体、肾上腺并称重。测定所述植入体作为生长的指征。监测动情期。试验3A.手术诱发的子宫内膜异位
使用子宫内膜组织的自动图(autographs)在大鼠和/或兔子中诱发子宫内膜异位。使生殖成熟期的雌性动物经受两侧子宫切除术,并提供外原性雌激素,从而产生特别和恒定的激素水平。将自身的子宫内膜组织移植入5-150只动物的腹膜。并提供雌激素以便诱发移植组织的生长。通过每日胃管提供包括本发明的化合物的治疗达3-16周,取出植入体,并测定生长或消退。在处死时,收获所述完整的子宫角以便评价子宫内膜的状态。B.在裸鼠中移植人子宫内膜组织。
将来自人子宫内膜损伤的组织移植入性成熟、切除卵巢的雌性裸鼠的腹膜中。供给外原性雌激素以便诱发移植组织的生长。在某些情况下,在移植以前,体外培养收获的子宫内膜细胞。通过每日胃管提供包括本发明的化合物的治疗达3-16周,取出植入体,并测定生长或消退。在处死时,收获所述子宫以便评价完整子宫内膜的状态。试验4A.收获来自人子宫内膜损伤的组织并在体外保存作为主要的不能转变的培养物。使手术样品通过无菌的筛网或可选剔除周围组织以便产生单独的细胞悬浮液。将细胞保持在含有10%血清和抗生素的培养基中。测定存在和不存在雌激素条件下的生长速度。测定细胞产生的补体成分C3的能力和它们对生长因子和生长激素的应答。在体外评价培养物用孕激素、GnRH、本发明的化合物和溶媒治疗后其增生应答。每周评价类固醇激素受体的水平以便确定是否在体外保持重要的细胞特征。使用来自5-25名患者的组织。
以上任何测试中的活性表明本发明的化合物可用于治疗子宫内膜异位。抑制主动脉平滑肌细胞增生/再狭窄的试验过程
本发明的化合物具有抑制主动脉平滑肌细胞增生的能力。这可以通过使用培养的来自兔主动脉的平滑肌细胞来证明,通过测定DNA的合成来测定增生。通过如Ross所述的移植方法得到细胞[J.of CellBio.50:172(1971)]。将细胞平铺在96穴的微量滴定板上达5天。该培养物融合和生长受阻。然后,将该细胞转移到含有0.5-2%的贫血小板血浆、2mM的L-谷氨酰胺、100U/ml青霉素、100mg/ml的链霉素、1mC/ml 3H-胸苷、20ng/ml来自血小板的生长因子和各种浓度的本发明化合物的Dulbecco’s Modified Eagle’s Medium(DMEM)中。制备在二甲亚砜中的所述化合物的原料溶液,然后在上述测定培养基中稀释到适当的浓度(0.01-30mM)。然后,将细胞于37℃下,在5%二氧化碳/95%空气中孵化24小时。在24小时后,将所述细胞在甲醇中固定。然后通过Bonin等人所述的闪烁计数器[Exp.Cell Res.181:475-482(1989)]测定掺入DNA中的3H-胸苷。
通过测定主动脉平滑肌细胞对于指数增长细胞的作用进一步证实本发明的化合物对于主动脉平滑肌细胞增生的抑制作用。将来自兔主动脉的平滑肌细胞种在含有10%的牛胚胎血清、2mM的L-谷氨酰胺、100U/ml青霉素、100mg/ml的链霉素的DMEM中的12穴组织培养平板中。24小时后,束缚所述细胞并用含有10%血清、2mM的L-谷氨酰胺、100U/ml青霉素、100mg/ml的链霉素和所需浓度的所述化合物的DMEM替换所述培养基。使细胞生长4天。用胰蛋白酶处理细胞,并使用ZM-Coulter计数器计数测定每份培养物中的细胞数量。
以上试验中的活性表明本发明的化合物治疗再狭窄有效。
本发明也提供减轻妇女经绝后综合征的方法,它包括使用式I化合物的上述方法,还包括给予该妇女有效量的雌激素或孕激素。这些治疗特别用于治疗骨质疏松症和降低血清胆固醇,因为该患者接受每一种药用制剂的益处,同时本发明的化合物将抑制雌激素和孕激素的不合需要的副作用。在下文的任何经绝后试验中这类联合治疗的活性表明该联合治疗可以用于减轻妇女经绝后综合征的症状。
雌激素和孕激素的不同形式可以从市场上买到。雌激素基的制剂包括例如乙炔基雌激素(0.01-0.03mg/天)、乙炔雌二醇甲酯(0.05-0.15mg/天)和共轭的雌激素例如Premarin(Wyeth-Ayerst;0.3-2.5mg/天)。孕激素基制剂包括例如甲羟孕酮例如Provera(Upjohn;2.5-10mg/天)、羟炔诺酮(1.0-10.0mg/天)和炔诺酮(0.5-2.0mg/天)。优选雌激素基化合物为Premarin,羟炔诺酮和炔诺酮为优选的孕激素基制剂。
给予每种雌激素基和孕激素基的制剂的方法与本领域中已知的方法一致。对于本发明的大部分方法而言,连续给予式I和II化合物,每日1-3次。然而,周期性治疗可以特别用于治疗子宫内膜异位或可以在该疾病的疼痛发作期紧急使用。在再狭窄的情况下,可以将治疗局限于在医学治疗例如血管成形术后短的(1-6个月)的间隔内。
在此所用的术语“有效量”指的是能够减轻在此所述的各种病理状态的症状的本发明化合物的量。当然,根据本发明给予的化合物的特定剂量由与该病例有关的具体情况所决定,包括:例如所用的药物、给药途径、患者的状况和治疗的病理状态。典型的日剂量将包含非毒性剂量水平的约5mg-约600mg/天的本发明的化合物。优选的日剂量一般为约15mg-约80mg/天。
本发明的化合物可以通过不同途径给药,包括口服、直肠、经皮、皮下、静脉、肌内和鼻内。在给药前,优选将这些化合物配成制剂,这将由主治医生来选择。从而,本发明的另一个方面为含有有效量的式I或II化合物或其药学上可接受的盐的组合物,可选含有有效量的雌激素或孕激素和药学上可接受的载体、稀释剂或赋形剂。
在这类制剂中总的活性成分占所述制剂的0.1%-99.9%(重量)。所谓“药学上可接受的”指的是所述载体、稀释剂、赋形剂和盐必须与该制剂的其它成分相容,并且对于其接受者无害。
通过本领域内已知的方法,使用熟知的和易得的成分可以制备本发明的药用制剂。例如,可以将式I或II化合物包括或不包括雌激素或孕激素化合物与一般的赋形剂、稀释剂、或载体一起配制,并形成片剂、胶囊、悬浮液、粉末剂等。适用于这类制剂的赋形剂、稀释剂和载体的实例包括下列成分:填料和增量剂例如淀粉、蔗糖、甘露醇和硅酸衍生物;粘合剂例如羧甲基纤维素和其它的纤维素的衍生物,藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂例如甘油;崩解剂例如碳酸钙和碳酸氢钠;用于延缓溶解的试剂例如石蜡;吸收促进剂例如季铵化合物;表面活性剂例如十六烷醇、甘油单硬脂酸酯;吸附载体例如高岭土和皂土;及润滑剂例如滑石粉、硬脂酸钙和镁和固体聚乙二醇。
也可以将所述化合物配制成便于口服的酏剂或溶液剂或配制成适合胃肠外给药的溶液剂,例如通过肌肉、皮下或静脉途径。此外,所述化合物非常适合配制成缓释剂型等。所述制剂可以如此构成,以致它们只在或优选在特定的生理位置释放活性成分,可能在较长的时间内释放。例如,可以由聚合物或蜡制备包衣层、膜和保护层(matrices)。
一般将式I和II化合物单独或与本发明的药用试剂一起以方便的制剂形式给药。下列制剂实例仅为了说明,不准备限制本发明的范围。
制剂
在下列制剂中,“活性成分”指的是式I或II化合物或其盐或溶剂合物。
制剂1:明胶胶囊
硬明胶胶囊使用如下成分制备:
成分 | 用量(mg/胶囊) |
活性成分 | 0.1-1000 |
淀粉,NF | 0-650 |
淀粉可流动粉末 | 0-650 |
硅氧烷流体350厘沲 | 0-15 |
根据所提供的合理的演变可以改变上述制剂。
使用下列成分制备片剂:
制剂2:片剂
共混所述成分并压制成片剂。
成分 | 用量(mg/片) |
活性成分 | 2.5-1000 |
纤维素,微晶 | 200-650 |
二氧化硅,锻制 | 10-650 |
硬脂酸 | 5-15 |
可选按照下列配方制备各含有2.5-1000mg活性成分的片剂:
制剂3:片剂
成分 | 用量(mg/片) |
活性成分 | 25-1000 |
淀粉 | 45 |
纤维素,微晶 | 35 |
聚乙烯吡咯烷酮(为10%水溶液) | 4 |
羧甲基纤维素钠 | 4.5 |
硬脂酸镁 | 0.5 |
滑石粉 | 1 |
使活性成分、淀粉和纤维素通过45目美国筛并充分混合。将聚乙烯吡咯烷酮溶液与形成的粉末混合,然后使其通过14目美国筛。将所形成的颗粒在50-60℃下干燥,并通过18目美国筛。然后,将预先通过60目美国筛的羧甲基淀粉钠、硬脂酸镁和滑石粉加入所述颗粒中,混合后,在压片机上压制成片。
按如下配方制备每5ml剂量各含有0.1-1000mg药物的的悬浮液:
制剂4:悬浮液
成分 | 用量(mg/5ml) |
活性成分 | 0.1-1000mg |
羧甲基纤维素钠 | 50mg |
糖浆 | 1.25mg |
苯甲酸溶液 | 0.10ml |
香料 | q.v. |
着色剂 | q.v. |
纯化水加到 | 5ml |
使所述药物通过45目美国筛,并与羧甲基纤维素钠和糖浆混合形成均匀的糊剂。用部分水稀释苯甲酸溶液、香料和着色剂,并加入所述糊剂中并搅拌。然后加入足量的水产生所需的体积。
制备含有下列成分的气溶胶溶液:
制剂5:气溶胶
成分 | 用量(%重量) |
活性成分 | 0.25 |
乙醇 | 25.75 |
抛射剂22(氯代二氟甲烷) | 70.00 |
将所述活性成分与乙醇混合,并将该混合物加入部分抛射剂22中,冷却到30℃并转移到填充装置中。然后,将所需量供入不锈钢容器中,并用剩下的抛射剂稀释。然后将阀装置安装到该容器上。
按下列配方制备栓剂:
制剂6:栓剂
成分 | 用量(mg/栓剂) |
活性成分 | 250 |
饱和脂肪酸甘油酯 | 2000 |
使活性成分通过60目美国筛并悬浮在用最低的所需热量预先融化的饱和脂肪酸甘油酯中。然后,将该混合物倒入标称2g容量的栓剂模中并使其冷却。
按照下列配方制备静脉注射剂:
制剂7:静脉注射液
成分 | 用量 |
活性成分 | 50mg |
等渗盐水 | 1000ml |
将上述成分的溶液以每分钟约1毫升的速度静脉给予患者。
制剂8:组合胶囊I
成分 | 用量(mg/胶囊) |
活性成分 | 50 |
Premarin | 1 |
Avicel pH 101 | 50 |
淀粉1500 | 117.50 |
硅油 | 2 |
吐温80 | 0.50 |
Cab-O-Sil | 0.25 |
制剂9:组合胶囊II
成分 | 用量(mg/胶囊) |
活性成分 | 50 |
异炔诺酮 | 5 |
Avicel pH 101 | 82.50 |
淀粉1500 | 90 |
硅油 | 2 |
吐温80 | 0.50 |
制剂10:组合片
成分 | 用量(mg/胶囊) |
活性成分 | 50 |
Premarin | 1 |
玉米淀粉NF | 50 |
Povidone,K29-32 | 6 |
Avicel pH 101 | 41.50 |
Avicel pH 102 | 136.50 |
Crospovidone XL10 | 2.50 |
硬脂酸镁 | 0.50 |
Cab-O-Sil | 0.50 |
本发明的化合物可以含有一个或多个不对称中心(assymetriccenters),从而可以以异构体的混合物或以单独的异构体存在。无论是混合物还是单独的异构体均可以用于本发明中。
Claims (13)
1.式I或II化合物或其药学上可接受的盐:其中
X为-O-,-S-或-NR5-;
Y为-O-,-S-,-CH2-,-CH2CH2-,-CH=CH-或-NR5-;
B为-CH2-或-CO-;
R1、R2和R3各自独立为-H,-OH,-O(C1-C4烷基),-OCOC6H5,-OCO(C1-C6烷基),-OSO2(C4-C6烷基),-OSO2CF3,Cl或F;
n为1或2;
W为CH2或C=O;
R4为1-哌啶基,2-氧代-1-哌啶基,1-吡咯烷基,甲基-1-吡咯烷基,二甲基-1-吡咯烷基,2-氧代-1-吡咯烷基,4-吗啉代,二甲基氨基,二乙基氨基或1-六亚甲基亚氨基;
R5为C1-C3烷基,-COC6H5,-CO(C1-C6烷基),-C(O)OC6H5,-C(O)O(C1-C6烷基),-SO2(C1-C6烷基),-SO2C6H5或-SO2CF3。
2.根据权利要求1的式I化合物,其中X为-O-和Y为-S-。
3.根据权利要求1的式II化合物,其中Y为-CH=CH-。
4.根据权利要求1-3中任一项的化合物,其中-O-(CH2)n-W-R4为2-(1-哌啶基)乙氧基。
5.根据权利要求1的化合物,它选自下列化合物:3,9-二羟基-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-二甲氧基-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-双(苯甲酰氧基)-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-双(新戊酰氧基)-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-双(1-丁基磺酰氧基)-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-双(三氟甲磺酰氧基)-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-二羟基-6-[4-[2-(1-吡咯烷基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-二羟基-6-[4-(2-二甲氨基乙氧基)苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-二羟基-6-[4-[2-(2-氧代-1-吡咯烷基)乙氧基]苯基]-6-H-[1]苯并噻吩并[3,2-c][1]苯并吡喃;3,9-二羟基-6-[4-[2-(1-哌啶基)乙氧基]苯基]-6-H-苯并呋喃并[3,2-c][1]苯并吡喃;2,8-二甲氧基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-11,12-二氢-6H-苯并[c]菲啶-6-酮;2,8-二甲氧基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-6H-苯并[c]菲啶;2,8-二羟基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-6H-苯并[c]菲啶;和2,8-二羟基-5-[4-[2-(1-哌啶基)乙氧基]苯基]-5H-苯并[b]萘并[2,1-d]吡喃。
X为-O-,-S-或-NR5-;
Y为-O-,-S-,-CH2-,-CH2CH2-,-CH=CH-或-NR5-;
R1、R2和R3各自独立为-H,-OH,-O(C1-C4烷基),-OCOC6H5,-OCO(C1-C6烷基),-OSO2(C4-C6烷基),-OSO2CF3,Cl或F;
n为1或2;
W为CH2或C=O;
R4为1-哌啶基,2-氧代-1-哌啶基,1-吡咯烷基,甲基-1-吡咯烷基,二甲基-1-吡咯烷基,2-氧代-1-吡咯烷基,4-吗啉代,二甲基氨基,二乙基氨基或1-六亚甲基亚氨基;
R5为C1-C3烷基,-COC6H5,-CO(C1-C6烷基),-C(O)OC6H5,-C(O)O(C1-C6烷基),-SO2(C1-C6烷基),-SO2C6H5或-SO2CF3;该方法包括:
R1a、R2a、R3a各自独立为-H,-O(C1-C4烷基),-Cl,-F或保护的-OH;
X和Y如上所定义;
和Za为-OH,-OC6H5或-O(C1-C4烷基);与具有下式的Grignard试剂反应:其中
(4)可选使前述步骤产物成盐。
7.制备具有下式化合物或其药学上可接受的盐的方法:其中
B为-CH2-或-CO-;
Y为-O-,-S-,-CH2-,-CH2CH2-,-CH=CH-或-NR5-;
R1、R2和R3各自独立为-H,-OH,-O(C1-C4烷基),-OCOC6H5,-OCO(C1-C6烷基),-OSO2(C4-C6烷基),-OSO2CF3,Cl或F;
n为1或2;
W为CH2或C=O;
R4为1-哌啶基,2-氧代-1-哌啶基,1-吡咯烷基,甲基-1-吡咯烷基,二甲基-1-吡咯烷基,2-氧代-1-吡咯烷基,4-吗啉代,二甲基氨基,二乙基氨基或1-六亚甲基亚氨基;
R5为C1-C3烷基,-COC6H5,-CO(C1-C6烷基),-C(O)OC6H5,-C(O)O(C1-C6烷基),-SO2(C1-C6烷基),-SO2C6H5或-SO2CF3;该方法包括:
(1)使具有下式的化合物烷基化:其中
Y如上所定义,和
R1a、R2a、R3a各自独立为-H,-O(C1-C4烷基),-Cl,-F或保护的-OH;
(2)可选还原其羰基;
(3)可选使前述步骤的产物脱氢,其中Y为-CH2-CH2-;
(4)使步骤(1)、(2)或(3)中任一步骤的产物中R1a、R2a、R3a上的任何羟基保护基脱去;和
(5)可选使前述步骤的产物成盐。
8.具有下式的化合物:其中
X为-O-,-S-或-NR5-;
Y为-O-,-S-,-CH2-,-CH2CH2-,-CH=CH-或-NR5-;
R1a、R2a、R3a各自独立为-H,-O(C1-C4烷基),Cl,F或保护的-OH;和
Z为-OH,-OC6H5,-O(C1-C4烷基)或4-羟基苯基。
10.含有根据权利要求1的化合物以及药学上可接受的载体、稀释剂或赋形剂的药用组合物。
11.用于抑制骨丢失或骨吸收的方法,它包括给予所需患者有效量的权利要求1的化合物。
12.根据权利要求12的方法,其中所述骨丢失或骨吸收是由于绝经或子宫切除所造成的。
13.降低血清胆固醇水平的方法,它包括给予所需患者有效量的权利要求1的化合物。
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AU (1) | AU705454B2 (zh) |
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CN109678878A (zh) * | 2019-02-27 | 2019-04-26 | 陕西科技大学 | 一种苯并噻吩并香豆素类化合物及其合成方法 |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
JPH11510479A (ja) * | 1995-06-07 | 1999-09-14 | ネオルックス コーポレイション | タモキシフェン類似体による心臓血管疾病の予防及び治療 |
WO2000037083A1 (en) * | 1998-12-18 | 2000-06-29 | Schering Corporation | Oral antiestrogen pharmaceutical composition |
US7105679B2 (en) | 2001-12-19 | 2006-09-12 | Kanojia Ramesh M | Heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators |
US7329654B2 (en) | 2001-12-19 | 2008-02-12 | Janssen Pharmaceutica N.V. | Heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators |
US7271264B2 (en) | 2002-07-24 | 2007-09-18 | Eli Lilly And Company | Pentacyclic oxepines and derivatives thereof, compositions and methods |
JP2005538091A (ja) | 2002-07-24 | 2005-12-15 | イーライ・リリー・アンド・カンパニー | ジヒドロ−ベンゾ[b,e]オキセピンに基づく選択的エストロゲン受容体調節物質、組成物および方法 |
JP3887588B2 (ja) * | 2002-08-30 | 2007-02-28 | 株式会社リガク | X線回折による応力測定法 |
US7119206B2 (en) | 2002-09-25 | 2006-10-10 | Eli Lilly And Company | Derivative of dihydro-dibenzo (a) anthracenes and their use as selective estrogen receptor modulators |
US6894061B2 (en) | 2002-12-04 | 2005-05-17 | Wyeth | Substituted dihydrophenanthridinesulfonamides |
US7074779B2 (en) * | 2003-07-02 | 2006-07-11 | Ortho-Mcneil Pharmaceutical, Inc. | Estrieno[3,2-b]/[3,4-c]pyrrole derivatives useful as modulators of the estrogen receptors |
KR100849559B1 (ko) * | 2004-01-22 | 2008-07-31 | 일라이 릴리 앤드 캄파니 | 혈관운동 증상의 치료를 위한 선택적 에스트로겐 수용체조절제 |
CN1910167B (zh) * | 2004-01-22 | 2011-08-10 | 伊莱利利公司 | 用于治疗血管舒缩症状的选择性雌激素受体调节剂 |
WO2005073244A1 (en) * | 2004-01-22 | 2005-08-11 | Eli Lilly And Company | Selective estrogen receptor modulators |
BR112012032189B1 (pt) | 2010-06-16 | 2020-11-03 | Endorecherche, Inc | usos de um agonista ou antagonista de lhrh em associação com um modulador de receptor de estrogênio seletivo e com um precursor de esteróide sexual para a preparação de uma medicamento para o tratamento ou prevenção de doenças relacionadas com estrogênio e kits |
KR102021162B1 (ko) * | 2011-11-01 | 2019-09-11 | 메르크 파텐트 게엠베하 | 유기 전계발광 소자 |
US8829993B2 (en) | 2012-10-30 | 2014-09-09 | Eta Devices, Inc. | Linearization circuits and methods for multilevel power amplifier systems |
Family Cites Families (10)
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US2884427A (en) * | 1958-01-22 | 1959-04-28 | Oliver H Emerson | Synthesis of coumestrol and its esters |
US2987398A (en) * | 1958-05-12 | 1961-06-06 | Emanuel M Bickoff | Coumestrol ethers and use thereof |
US3912740A (en) * | 1974-02-28 | 1975-10-14 | Us Health | Method for the preparation of oxygenated benzo{8 c{9 phenanthridine compounds |
US4230862A (en) * | 1975-10-28 | 1980-10-28 | Eli Lilly And Company | Antifertility compounds |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4659671A (en) * | 1983-07-01 | 1987-04-21 | Massachusetts Institute Of Technology | Enzymatic separation of racemic mixtures of hydroxy compounds |
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US5147880A (en) * | 1991-07-22 | 1992-09-15 | Eli Lilly And Company | Benzo[a]fluorene compounds |
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US5336687A (en) * | 1993-08-04 | 1994-08-09 | American Home Products Corporation | Inhibition of bone loss by 4-aryloxy-5-hydroxy-2(5H)-furanones |
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