CN1278250A - 玻连蛋白受体拮抗剂 - Google Patents
玻连蛋白受体拮抗剂 Download PDFInfo
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- CN1278250A CN1278250A CN98810811A CN98810811A CN1278250A CN 1278250 A CN1278250 A CN 1278250A CN 98810811 A CN98810811 A CN 98810811A CN 98810811 A CN98810811 A CN 98810811A CN 1278250 A CN1278250 A CN 1278250A
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- dibenzo
- dihydro
- suberene
- compound
- amino
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- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- AEOKOTHPXHJDTN-UHFFFAOYSA-N tert-butyl n-[6-(1-hydroxyethyl)pyridin-2-yl]-n-methylcarbamate Chemical compound CC(O)C1=CC=CC(N(C)C(=O)OC(C)(C)C)=N1 AEOKOTHPXHJDTN-UHFFFAOYSA-N 0.000 description 1
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/12—Nitrogen atoms not forming part of a nitro radical
- C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
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- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/14—[b,f]-condensed
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
公开作为玻连蛋白受体拮抗剂并且于治疗骨质疏松症的式(Ⅰ)化合物或其药学上可接受的盐,其中:A是CH2或O;R1是H、卤素或C1-6烷基;R2是H、C1-6烷基或CH2NR″R″;X是O或CH2;Y是(a)、(b)、(c)、(d)、(e)、(f)或(g);G是NR″、S或O;R′是H、C1-6烷基、OC1-6烷基、SC1-6烷基、NR″R″或卤素;R″各自独立为H或C1-6烷基;以及s是0、1或2。
Description
发明领域
本发明涉及药学活性化合物,其能抑制玻连蛋白受体并可用于治疗炎症、癌症和心血管疾病,如动脉粥样硬化和再狭窄,以及其中骨吸收是病因的疾病,如骨质疏松症。
发明背景
整联蛋白是细胞粘着受体的超家族,细胞粘着受体是表达在各种细胞上的跨膜糖蛋白。这些细胞表面粘着受体包括gpIIb/IIIa(血纤蛋白原受体)和αVβ3(玻连蛋白受体)。血纤蛋白原受体gpIIb/IIIa表达在血小板表面,并介导血小板聚集及在流血伤口处形成止血凝块。Philips等,Blood.,1988,71,831。玻连蛋白受体αVβ3表达在许多细胞上,包括内皮细胞、平滑肌细胞、破骨细胞和肿瘤细胞,因此其具有多种功能。表达在破骨细胞膜上的该αVβ3受体介导破骨细胞对骨基质的粘着,其是骨吸收过程中的关键步骤。Ross等,J.Biol.Chem.,1987,262,7703。以过量骨吸收为特征的疾病是骨质疏松症。表达在人体主动脉平滑肌细胞上的该αVβ3受体介导向新内膜的迁移,该过程导致经皮冠状血管成形术后的再狭窄。Brown等,CardiovascularRes.,1994,28,1815。另外,Brooks等。Cell,1994,79,1157已表明αVβ3拮抗剂能促进肿瘤退化,包括形成血管的编程性细胞死亡。因此,阻断玻连蛋白受体的药物可用于治疗疾病,如骨质疏松症、再狭窄和癌症。
现在知道该玻连蛋白受体是指三种不同的整联蛋白,用αVβ1、αVβ3和αVβ5表示。Horton等,Int.J.Exp.Pathol.,1990,71,741。αVβ1结合纤连蛋白和玻连蛋白。αVβ3结合多种配体,包括血纤蛋白、血纤蛋白原、层粘连蛋白、血小板反应蛋白、玻连蛋白、vonWillebrand氏因子、骨桥蛋白和骨涎蛋白I。αVβ5结合玻连蛋白。已表明该玻连蛋白受体αVβ5涉及各种细胞类型的细胞粘连,包括微血管内皮细胞,(Davis等,J.Cell.Biol.,1993,51,206),其对血管发生的作用已被证实。Brooks等,Science,1994,264,569。整联蛋白表达在人体损伤颗粒形成组织的血管上,但不在正常皮肤上。
已知玻连蛋白与含有三肽Arg-Gly-Asp(或RGD)基序的骨基质蛋白质结合。因此,Horton等,Exp.Cell Res.1991,195,368中公开含RGD的肽和抗玻连蛋白受体抗体(23C6)抑制齿质再吸收和破骨细胞引起的细胞扩散。另外,Sato等,在J.Cell Biol.1990,111,1713中公开echistatin,一种含有RGD序列的蛇毒液肽,是一种组织培养中有效的骨再吸收抑制剂,并抑制破骨细胞向骨的附着。
现已发现某些化合物是αVβ3和αVβ5受体的有效抑制剂。更详细地讲,已发现这些化合物是抑制玻连蛋白受体比抑制血纤蛋白原受体更有效的抑制剂。
发明概述
本发明包括如下所述的式(I)化合物,其具有抑制玻连蛋白受体的药理活性,并可用于治疗炎症、癌症和心血管疾病,如动脉粥样硬化和再狭窄,以及其中骨吸收是病因的疾病,如骨质疏松症。
本发明还包括药用组合物,其包含根据式(I)的化合物以及药学上可接受的载体。
本发明还包括治疗由玻连蛋白受体介导的疾病的方法。更详细地讲,本发明化合物用于治疗动脉粥样硬化、再狭窄、炎症、癌症和其中骨吸收是病因的疾病,如骨质疏松症。
详细说明
本发明包括新的化合物,其是抑制玻连蛋白受体比抑制血纤蛋白原受体更有效的抑制剂。该新的化合物包含一个二苯并环庚烯母核,其中含有氮原子的取代基在该二苯并环庚烯的芳族六元环之一上,含有酸性部分的脂族取代基在该二苯并环庚烯的七元环上。认为该二苯并环庚烯环系取向于在该六元和七元环上的取代基侧链,因此它们可与玻连蛋白受体顺利地相互作用。优选通过最短分子间路径的约12-14个***的共价键存在于该二苯并环庚烯的七元环的脂族取代基上的酸性基团和该二苯并环庚烯的芳族六元环之一上的含有氮原子的取代基的氮原子之间。
本发明包括式(I)化合物或其药学上可接受的盐:其中:
A是CH2或O;
R1是H、卤素或C1-6烷基;
R2是H、C1-6烷基或CH2NR″R″;
X是O或CH2;
G是NR″、S或O;
R′是H、C1-6烷基、OC1-6烷基、SC1-6烷基、NR″R″或卤素;
R″各自独立为H或C1-6烷基;以及
s是0、1或2。
本发明还包括药学上可接受的本发明化合物的加成盐和复合物。在其中本发明化合物可具有一个或多个手性中心的情况下,除非详细说明,本发明包括每一个独特的可通过常用技术合成或拆分的非外消旋化合物。在其中化合物具有不饱和碳-碳双键情况下,顺式(Z)和反式(E)式异构体都包括在本发明范围之内。在其中化合物存在互变异构形式情况下,如酮-烯醇互变异构体,如:和
,无论以平衡状态存在或通过用适当的取代基R′锁定一种形式存在,每种互变异构体都包括在本发明之内。
式(I)化合物抑制玻连蛋白和其它含有RGD的肽与玻连蛋白受体的结合。对在破骨细胞上的玻连蛋白受体的抑制作用抑制破骨的骨吸收,可用于治疗其中病理学上与骨吸收有关的疾病,如骨质疏松症和骨关节炎。
另一方面,本发明提供刺激骨形成的方法,其包括给予可引起骨钙蛋白释放增加的化合物。增加的骨产生对其中缺乏矿化骨质或需要骨质重建的疾病明显有益,如骨折愈合及骨折的预防。导致骨结构损失的疾病和代谢紊乱也能从这些治疗中获益。例如,甲状旁腺功能亢进、Paget氏病、恶性高血钙、骨转移引起的溶骨损害、由固定术或性激素缺乏引起的骨损失、Behcet氏病、骨软化症、骨肥厚和骨硬化症均可得益于给予本发明化合物。
另外,由于本发明化合物抑制多种不同类型细胞上的玻连蛋白受体,所以该化合物可用于治疗炎症,如类风湿性关节炎和牛皮癣,以及心血管疾病,如动脉粥样硬化和再狭窄。本发明的式(I)化合物可用于治疗或预防其它疾病,包括,但不限于血栓栓塞疾病、哮喘、过敏反应、成人呼吸窘迫综合症、移植物抗宿主疾病、器官移植排斥、败血性休克、湿疹、接触性皮炎、肠炎和其它自身免疫疾病。本发明化合物还可用于伤口的愈合。
本发明化合物还可用于治疗,包括预防血管生成疾病。此处所用术语血管生成疾病包括涉及异常新血管形成的病症。新血管生长的原因或归咎于与疾病有关的病理因素,抑制血管生成能降低该疾病的有害影响。这种疾病目标的实例是糖尿病性视网膜病。由于需要新血管生长支持有害组织的生长,抑制血管形成能降低向该组织提供血液,因此能降低以血液供应需要为基础的组织质量。实例包括肿瘤生长,其中为使肿瘤生长并使形成的固体肿瘤转移持续需要新血管形成。因此,本发明化合物可抑制肿瘤组织血管生成,所以抑制了肿瘤的转移和肿瘤的生长。
因此,根据本发明的方法,用本发明的化合物抑制血管生成可缓解该疾病的症状,在某些情况下可以治愈该疾病。
本发明化合物的另一治疗目标是以新血管形成为特征的眼部疾病。这些眼部疾病包括角膜新血管疾病,如角膜移植、疱疹性角膜炎、梅毒性角膜炎、翼状胬肉和与使用接触性镜片有关的新血管角膜翳。其它的眼部疾病还包括与年龄有关的黄斑变性、假定的眼组织胞浆菌病、未熟儿视网膜病和新血管性青光眼。
本发明还提供抑制肿瘤生长的方法,其包括逐步给予或以物理组合物的形式给予式(I)化合物和抗肿瘤剂,如托泊替堪和顺铂。
对于式(I)化合物而言:
以下是本发明新化合物的代表或其药学上可接受的盐。(±)-10,11-二氢-3-[2-(6-氨基吡啶-2-基)-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[4-(吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(3,4,5,6-四氢嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[2-[2-(乙氨基)噻唑-4-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-6-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-[4-(2-丙氧基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-[4-(二甲氨基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-[4-(乙硫基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-氯吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-2-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-氨基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-二苯并[b,f]氧杂庚英(oxepine)-10-乙酸;(±)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-二苯并[b,f]氧杂庚英-10-乙酸;和(S)-10,11-二氢-3-[3-(2-氨基吡啶-4-基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸。
在其中本发明化合物可具有一个或多个手性中心的情况下,除非特别说明,本发明包括每一个独特的可通过常用技术合成和拆分的非外消旋化合物。根据本发明,优选式(I)化合物的(S)构型。
在其中化合物具有不饱和碳-碳双键的情况下,顺式(Z)和反式(E)异构体都包括在本发明范围之内。在任何情况下的任何取代基的意义,都是独立的意义,或者在任何其它情况下,任何其它取代基的意义。
本发明还包括本发明化合物的前药。前药被认为是在体内释放出式(I)活性母体药物的任何以共价键结合的载体。因此,本发明另一方面是新的式(II)前药或其药学上可接受的盐,其也是制备式(I)化合物的中间体:其中:A是CH2或O;R1是H、卤素或C1-6烷基;R2是H、C1-6烷基或CH2NR″R″;X是O或CH2;Y是 或G是NR″、S或O;R′是H、C1-6烷基、OC1-6烷基、SC1-6烷基、NR″R″或卤素;R″各自独立为H或C1-6烷基;以及s是0、1或2。本发明另一方面是新的式(III)中间体或其药学上可接受的盐:其中:
A是CH2或O;
R1是H、卤素或C1-6烷基;
R2是H、C1-6烷基或CH2NR″R″;
X是O或CH2;
R′是H、C1-6烷基、OC1-6烷基、SC1-6烷基、NR″R″或卤素;以及
R″各自独立为H或C1-6烷基。
此处采用肽和化学领域中所用的一般缩写和符号说明本发明的化合物。一般而言,氨基酸缩写遵循Eur.J.Biochem.,158,9(1984)中所述的IUPAC-IUB联合委员会生化命名原则。
此处所用C1-4烷基是指任选取代的1-4个碳原子的烷基,包括甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。C1-6烷基还包括戊基、正戊基、异戊基、新戊基和己基以及其简单的脂族异构体。C0-4烷基和C0-6烷基还表示不必有烷基存在(如:存在共价键)。
任何C1-4烷基或C1-6烷基可任选由RX取代,RX可在能产生稳定结构并可通过常用合成技术得到的任何的碳原子上。适当的RX基团包括C1-4烷基、OR″、SR″、C1-4烷基磺酰基、C1-4烷基sulfoxyl、-CN、N(R″)2、CH2N(R″)2、-NO2、-CF3、-CO2R″、-CON(R″)2、-COR″、NR″C(O)R″、F、Cl、Br、I或CF3S(O)r-,其中r是0、1或2。
卤素或卤代指F、Cl、Br和I。
此处所用Ar或芳基指苯基或萘基、或由1-3个如以上所定义的烷基,特别是C1-4烷基、C1-4烷氧基、C1-4烷硫基、CF3、NH2、OH、F、Cl、Br或I的取代基取代的苯基或萘基。
此处将某些基团缩写。t-Bu指叔丁基,Boc指叔丁氧基羰基,Fmoc指芴基甲氧基羰基,Ph指苯基,Cbz指苯甲氧基羰基,Bn指苯甲基,Me指甲基,Et指乙基,Ac指乙酰基,Alk指C1-4烷基,Nph指1-或2-萘基以及cHex指环己基。Tet指5-四唑基。
某些试剂此处使用缩写。DCC指二环己基碳化二亚胺,DMAP指二甲氨基吡啶,DIEA指二异丙基乙胺,EDC指1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐。HOBt指1-羟基苯并***,THF指四氢呋喃,DIEA指二异丙基乙胺,DEAD指偶氮二甲酸二乙酯,PPh3指三苯膦,DIAD指偶氮二甲酸二异丙酯,DME指二甲氧基乙烷,DMF指二甲基甲酰胺,NBS指N-溴代琥珀酰亚胺,Pd/C指钯碳催化剂,PPA指多磷酸,DPPA指二苯基磷酰基叠氮化物,BOP指苯并***-1-基氧基-三(二甲氨基)磷鎓六氟磷酸盐,HF指氢氟酸,TEA指三乙胺,TFA指三氟乙酸,PCC指氯铬酸吡啶鎓。
其中R1、R2、Y和A按式(I)中定义,可带有任何被保护的活性官能团,L1是OH或卤素;然后除去任何保护基而制备,并任选形成药学上可接受的盐。
其中R1、R2、R′、R″和A按式(I)中定义,可带有任何被保护的活性官能团;然后除去任何保护基而制备,并任选形成药学上可接受的盐。
式(IV)化合物与式(VI)化合物之间的反应适于在非质子化溶剂中,在偶氮二甲酸二乙酯和三苯膦存在下进行。
另外,某些式(I)化合物可通过使式(IV)化合物与式(VII)化合物反应:
其中R1、R2、R″和A按式(I)中定义,可带有任何被保护的活性官能团;然后除去任何保护基而制备,并任选形成药学上可接受的盐。
式(IV)化合物与式(VII)化合物之间的反应适于在非质子溶剂中,在偶氮二甲酸二乙酯和三苯膦存在下进行。
式(I)化合物可按Bondinell等(PCT公布号WO 97/01540(国际申请号PCT/US96/11108),1997年,1月,16日公开)所述的方法制备,所有公开内容结合到本发明中作为参考。
另外,式(I)化合物可通过与以下详述的方案中所述的类似方法制备。
方案Ia)10%Pd/C,HOAc;b)SOCl2,甲苯;c)AlCl3,CH2Cl2
方案I详尽说明用于制备式(I)化合物的中间体的制法。
方案IIa)LiN(TMS)2,溴代乙酸乙酯;b)Jones试剂,OsO4;c)H2,10%Pd/C,HOAC;d)C2O2Cl2,DMF;e)AlCl3,CH2Cl2,RT;f)H2,10%Pd/C,HOAC
方案II也详尽说明用于制备式(I)化合物的中间体的制法。
方案IIIa)EtOAc/LiHMDS,THF;b)H2,10%Pd/C,浓HCl,AcOH;c)EtSH,AlCl3,CH2Cl2;d)2-[(3-羟基-1-丙基)氨基]-4-硝基吡啶-N-氧化物,DEAD,(Ph)3P;e)NaOEt,EtOH;f)环庚烯,10%Pd/C,EtOH;g)1.0N NaOH,EtOH;h)HCl。
方案III详尽说明制备式(I)化合物的方法。在醛醇缩合-型反应中的III-1(即方案I-3化合物)与乙酸乙酯的烯醇化物反应得到III-2,该烯醇化物可通过将乙酸乙酯暴露于适当的氨化物碱(如二异丙基氨化锂(LDA)或双(三甲基甲硅烷基)氨化锂(LiHMDS)中产生。虽然经常使用在各种添加剂(如HMPA或TMEDA)存在下的THF,但THF是醛醇缩合反应的常用试剂。通过在矿酸如HCl存在下,在适当的溶剂如乙酸中,在适当的催化剂如钯碳(Pd/C)作用下氢解完成III-2到III-3(即方案II-6化合物)的还原反应。或者,可用Orfanopoulos和Smonou(Synth.Commun.1988,833)的通法,在醚合三氟化硼存在下,通过将III-2用三乙基硅烷处理完成该还原反应。通过在惰性溶剂如CH2Cl2中与BBr3反应,或者通过在惰性溶剂优选CH2Cl2中与乙硫醇和AlCl3反应完成III-3到III-4的脱甲醚反应。其它除去甲醚的有用方法见Greene,“Protective Groups in Organic Synthesis″(John Wileyand Sons出版)中所述。在Mitsunobu-型偶合反应(Organic Reactions1992,42,335-656;Synthesis 1981,1-28)中,使方案3的化合物4(III-4)与2-[(3-羟基-1-丙基)氨基]-4-硝基吡啶-N-氧化物反应得到III-5。该反应通过在偶氮二甲酸二乙酯和三苯膦之间形成的复合物介导,并在非质子溶剂如THF、CH2Cl2或DMF中进行。使化合物III-5与适当醇的碱金属盐反应得到III-6。适当的碱金属包括锂、钠、钾和铯,用于置换反应的醇一般用作该溶剂。对本领域技术人员来讲,形成醇的碱金属盐的方法是熟悉的。将III-6的吡啶-N-氧化物部分还原成对应的吡啶III-7可在转移氢解条件下,用钯催化剂,优选活性炭负载钯,在惰性溶剂如甲醇、乙醇或2-丙醇中进行。在该类型反应中,用作氢转移剂的一般为环己烯、1,4-环己二烯、甲酸和甲酸盐,如甲酸钾或甲酸铵。可用碱的水性溶液,如LiOH的THF水溶液或NaOH的甲醇或乙醇水溶液,将III-7的乙酯水解,并用适当的酸如TFA或HCl酸化该中间体羧酸盐生成羧酸III-8。或者,如需要可以分离该中间体羧酸,或者可通过本领域技术人员熟悉的方法制备该游离羧酸的羧酸盐。
方案IV(a)NaH,2-[N-(3-甲磺酰氧基-1-丙基)-N-(叔丁氧羰基)氨基]吡啶-N-氧化物,DMSO;(b)TFA,CH2Cl2;(c)见方案III。
方案IV说明另一种制备式(I)化合物的方法。在极性、非质子溶剂中,通常为THF、DMF、DMSO或其混合物中,使化合物IV-1与碱,优选碱金属氢化物如氢化钠或氢化钾,反应得到对应的碱金属的酚盐。另外,可用碱金属氨化物如LDA,或六甲基二硅氮烷的锂、钠或钾盐进行脱质子化反应。该酚盐的中间体一般不经分离,但在原位与适当的亲电试剂,如2-[N-(3-甲磺酰氧基-1-丙基)-N-(叔丁氧羰基)氨基]吡啶-N-氧化物,反应生成偶合产物IV-2。在酸性条件下,如4M HCl的1,4-二氧六环液或TFA的CH2Cl2液,除去IV-2中的叔丁氧基羰基保护基得到IV-3。对本领域技术人员来讲,除去该叔丁氧基羰基保护基的条件是熟悉的,某些有用的方法在标准参考书如Greene,“Protective Groups in Organic Synthesis”中说明。接着按方案III说明的方法,将IV-3转化成IV-4。
方案V(a)PhOH,Cu,K2CO3;(b)硫,吗啉;(c)KOH,H2O,i-PrOH;(d)SOCl2,苯;(e)AlCl3,CH2Cl2;(f)EtOAc,LiN(TMS)2,TMEDA,THF;(g)Et3SiH,BF3·OEt2,CH2Cl2;(h)H2,Pd/C,EtOH;(i)BBr3,CH2Cl2。
在铜金属和适当碱如K2CO3存在下,使商业提供的2-氟-4-甲氧基苯乙酮与醇如苯酚反应得到二芳基醚V-2。根据Harris(J.Med.Chem.1982,25,855)的通法,用硫和适当的伯或仲胺(优选吗啉)处理,在典型的Willgerodt-Kindler反应中将V-2转化为V-3。通过在醇的水溶液中,如MeOH、EtOH或i-PrOH的水溶液,与碱金属的氢氧化物(KOH适当)反应,将以上得到的硫代酰胺水解得到对应的羧酸V-4。根据本领域技术人员熟悉的条件,通过与SOCl2或草酰氯反应,将羧酸V-4转化成对应的酰氯。在惰性溶剂中,如CH2Cl2或CS2中,将该酰氯用适当的Friedel-Crafts催化剂,如AlCl3或SnCl4,处理得到环酮V-5。另外,可在酸性条件下,如具有多磷酸条件下,将酸V-4直接转化为酮V-5。在醛醇缩合-型反应中的V-5与乙酸乙酯的烯醇化物的反应得到V-6,该烯醇化物可通过将乙酸乙酯暴露于适当的氨化物碱(如二异丙基氨化锂(LDA)或双(三甲基甲硅烷基)氨化锂(LiHMDS)中产生。虽然经常使用在各种添加剂(如HMPA或TMEDA)存在下的THF,但THF是醛醇缩合反应的常用试剂。可用Orphanopoulos和Smonu(Synth.Commun.1988,833)的通法,在醚合三氟化硼存在下,通过用三乙基硅烷处理V-6完成V-6还原成V-7的反应。可通过在适当的溶剂如MeOH或EtOH中,用适当的催化剂如钯碳(Pd/C)作用下氢化,将该醇消除反应中生成的任何烯副产物还原。另外,可在矿酸如HCl存在下,通过氢解完成V-6还原成V-7的反应。一般地说,该反应用Pd/C催化,并最适于在乙酸中进行。通过在惰性溶剂如CH2Cl2中与BBr3反应,或者通过在惰性溶剂优选CH2Cl2中与乙硫醇和AlCl3反应完成V-7到V-8的脱甲醚反应。其它除去甲醚的有用方法见Greene,“Protective Groups in OrganicSynthesis"(John Wiley and Sons出版)中所述。按方案III中所提的方法,再将V-8转化为式(I)化合物。
可用标准方法,在适当的溶剂中,用该母体化合物与过量的酸,如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、乙酸、三氟乙酸、马来酸、琥珀酸或甲磺酸,制备该化合物的酸加成盐。某些化合物形成可接受的内盐或两性离子。阳离子盐可通过将该母体化合物用过量的含有适当阳离子的碱试剂,如氢氧化物、碳酸盐或醇盐,或者用适当的有机胺处理制备。阳离子如Li+、Na+、K+、Ca++、Mg++和NH4 +是存在于药学上可接受的盐中的阳离子的具体实例。
本发明还提供药用组合物,其包含根据式(I)的化合物和药学上可接受的载体。因此,式(I)化合物可用于制备药物。可将按以上所述制备的式(I)化合物的药用组合物配制成供非肠道给药的溶液或冷冻干燥的粉末。在使用之前,通过加入适当的稀释剂或其它药学上可接受的载体,将粉末复制成溶液。液体制剂可以是缓冲、等渗、水溶液。适当稀释剂的实例为生理等渗盐水溶液、标准5%葡萄糖水溶液或者乙酸胺或乙酸钠的缓冲溶液。这些制剂特别适用于非肠道给药,但也可用于口服给药或装于计量剂量吸入器或喷雾器中供吹入给药。其可加入赋形剂,如聚乙烯吡咯烷酮、明胶、羟基纤维素、***胶、聚乙二醇、甘露糖醇、氯化钠或柠檬酸钠。
另外,可将这些化合物包胶囊、压片或制成乳剂或糖浆剂供口服给药。可加入药学上可接受的固体或液体载体以增强或稳定该组合物,或以便于制备组合物。固体载体包括淀粉、乳糖、硫酸钙二水合物、石膏粉、硬脂酸镁或硬脂酸、滑石粉、果胶、***树胶、琼脂或明胶。液体载体包括糖浆、花生油、橄榄油、盐水和水。载体可包括缓释物质如单硬脂酸甘油酯或二硬脂酸甘油酯,可单独或与蜡类合用。固体载体的量可变化,优选在每剂量单位约20mg-约1g。药物制剂可按常用的药物技术制备,包括研磨、混合、制粒和必要时制成片剂形式时的压片;或制成硬明胶胶囊的研磨、混合和填充。当用液体载体时,制剂为糖浆剂、酏剂、乳剂或者水或非水混悬剂形式。可将此液体制剂直接口服或填充于软明胶胶囊中给药。
供直肠给药时,可将本发明化合物与赋形剂结合,如可可脂、甘油、明胶或聚乙二醇,并模制成栓剂。
本发明所述的化合物为玻连蛋白受体的拮抗剂,并可用于治疗其中基本病理与玻连蛋白受体相互作用的配体或细胞引起的疾病。例如,该化合物可用于治疗其中骨基质损失引起的疾病。因此,这些化合物可用于治疗骨质疏松症、甲状旁腺功能亢进、Paget氏病、恶性高血钙、骨转移引起的溶骨损害、由固定术或性激素缺乏引起的骨损失。还认为本发明化合物具有抗肿瘤、抗血管生成、抗炎和抗转移剂作用,并可用于治疗动脉粥样硬化和再狭窄。
可以以药物浓度足以抑制骨吸收或其它症状形式,将该化合物口服或非肠道给予患者。可根据患者的状况,将含有本发明化合物的药用组合物以约0.1-约50mg/kg口服剂量给予患者。优选口服剂量为约0.5-约20mg/kg。对于急性治疗,优选非肠道给药。虽然也可用肌内大剂量注射,但最有效的是该肽的5%葡萄糖水溶液或生理盐水溶液的静脉输液或具有合适赋形剂的类似制剂。一般而言,非肠道给药剂量约为0.01-约100mg/kg;优选在0.1-20mg/kg之间。可将该化合物每日给予1-4次,以达到每日总剂量约0.4-约400mg/kg/日的水平。通过比较该药物的血液水平与需要具有治疗效果的浓度,本领域常规的技术人员很容易确定给予该化合物的准确水平和给予方法。
本发明还提供治疗骨质疏松症或抑制骨损失的方法,其包括逐步给予或以物理组合物形式给予式(I)化合物和其它骨吸收抑制剂,例如二膦酸盐类(如阿仑膦酸盐(allendronate))、激素替代疗法、抗***或降钙素。另外,本发明提供用本发明化合物和合成代谢剂,如骨成型素蛋白、异丙黄酮(iproflavone),用于抑制骨损失和/或增加骨质。
另外,本发明还提供治疗抑制肿瘤生长的方法,其包括逐步给予或以物理组合物的形式给予式(I)化合物和抗肿瘤剂。喜树碱类似物类化合物,如托泊替堪、伊立替康和9-氨基喜树碱,以及铂配位络合物,如顺铂、奥马铂和四铂,都是熟知的抗肿瘤剂。在美国专利Nos.5,004,758、4,604,463、4,473,692、4,545,880、4,342,776、4,513,138、4,399,276、欧洲专利申请公布号0418099和0088642,Wani等,J.Med.Chem.,1986,29,2358,Wani等,J.Med.Chem.,1980,23,554,Wani等,J.Med.Chem.,1987,30,1774和Nitta等,Proc.14th International Congr.Chemotherapy.,1985,Anticancer Section I,28中说明喜树碱类似物类的化合物,在此将每篇的所有公开内容结合到本发明中作为参考。铂配位络合物,顺铂由Bristol Myers-SquibbCorporation以商品名Platinol提供。顺铂有用的制剂在美国专利号5,562,925和4,310,515中说明,在此将每篇的所有公开内容结合到本发明中作为参考。
在其中包括逐步给予或以物理组合物的形式给予式(I)化合物和抗肿瘤剂抑制肿瘤生长的方法中,用慢速静脉输注给予铂配位化合物,如顺铂。优选的载体为葡萄糖/含甘露醇的盐水。铂配位化合物的给药安排可依据每个疗程每平方米体表面积约1-约500mg(mg/m2)为依据。输注铂配位化合物可每周给予1-2次,该周次治疗可重复几次。使用非肠道给予喜树碱类似物类化合物,该治疗过程一般为连续约五日每日每体表面积约0.1-300.0mg(mg/m2)。最优选使用托泊替堪的治疗过程为连续约五日每日每体表面积约1.0-约2.0mg(mg/m2)。优选在约7日至约28日间隔内,该治疗过程至少重复一次。
可将药用组合物配制成式(I)化合物与抗肿瘤剂在相同包装内的剂型,但优选在不同包装内。当两种药物都是液体形式时,可将其装在输注/注射***内以供同时给药或按先后给药。
为方便同时或不同时给予式(I)化合物和抗肿瘤剂,制备试剂盒,包括单包装,如盒、纸盒或其它容器,单个瓶、袋、管瓶或其它容器,其每个具有有效量的供非肠道给药的如上所述的式(I)化合物以及有效量的供非肠道给药的如上所述的抗肿瘤剂。这些试剂盒可包括,如这些药物的独立包装或同一包装形式,任选作为冷冻干燥的塞状物以及含用于再复制溶液的容器形式。这类改变形式包括在单一容器的两室中的可在使用前混合的供复制的溶液和冷冻干燥的塞状物。这类安排可将抗肿瘤剂和本发明的化合物在两个容器内独立包装,或一起冷冻干燥成粉末并在同一容器内提供。
当两种试剂均为溶液形式时,可将它们配成用于同步给药的输液/注射***或配成相继给药形式。例如,式(I)化合物可以是静脉注射形式或通过插管与在另一个输液袋中的抗肿瘤剂串连的输液袋形式。使用这一***,患者可先接受式(I)化合物的起始大剂量注射或输注,然后输注抗肿瘤剂。
可用几种生物测定方法的一种测试该化合物,以确定具有一定的药理活性所需要的化合物浓度。玻连蛋白结合的抑制固态[3H]-SK&F-107260对αVβ3的结合:将缓冲液T(含2mM CaCl2和1%辛基葡萄糖甙)中的人体胎盘或人体血小板αVβ3(0.1-0.3mg/mL)用含有1mM CaCl2、1mM MnCl2、1mM MgCl2(缓冲液A)和0.05%NaN3的缓冲液T稀释,然后以每孔0.1mL立即加入到96-孔ELISA平板(Corning,New York,NY)中。每孔加入0.1-0.2μg的αVβ3。在4℃下,将该平板温育过夜。实验时,将每孔用缓冲液A洗涤一次,然后室温下,在相同缓冲液中与0.1ml 3.5%牛血清清蛋白温育。温育后,将每孔完全抽出,用0.2ml缓冲液A洗涤两次。
将化合物溶于100%DMSO中制备2mM储备液,将其用结合缓冲液(15mM Tris-HCl(pH7.4)、100mM NaCl、1mM CaCl2、1mMMnCl2、1mM MgCl2)稀释得到最终化合物的浓度为100μM。然后将该溶液稀释至所需的最终化合物的浓度。将各种浓度的未标记拮抗剂(0.001-100μM)一式三份加入到各孔中,然后加入5.0nM的[3H]-SK&F-107260(65-86Ci/mmol)。
室温下将该平板温育1小时。温育后,将每孔完全抽出,以孔至孔的方式,用0.2mL冰冷的缓冲液A洗涤一次。将该受体用0.1ml的1%SDS增溶,在Beckman LS液体闪烁计数器上,加入3mL ReadySafe,通过液体闪烁计数测定40%效力的结合的[3H]-SK&F-107260。在2μM SK&F-107260存在下测定未特异性结合的[3H]-SK&F-107260,非特异结合一般少于总放射性配体输入的1%。通过从LUNDON-2程序改进的适用于常规的非线性最小二乘方曲线测定IC50值(即抑制50%[3H]-SK&F-107260结合的该拮抗剂的浓度)。根据方程:Ki=IC50/(1+L/Kd)计算Ki(拮抗剂的解离常数),其中L和Kd分别是[3H]-SK&F-107260的浓度和解离常数。
本发明化合物抑制玻连蛋白与SK&F 107260结合的浓度范围约为2.5-0.001μmol。
还可按本领域评价对骨形成抑制的标准测定方法,如在EP 528587中公开的凹窝(pit)形成实验法,其中可用人体破骨细胞代替大鼠的破骨细胞,以及由Wronski等,Cells and Materials 1991,Sup.1,69-74所述的切除卵巢的大鼠模型,来对本发明化合物进行体外和体内骨吸收测试。血管平滑肌细胞迁移测定
使用大鼠或人体的主动脉平滑肌细胞。通过使用8um孔的聚碳酸酯膜(Costar),在Transwell细胞培养箱中检测该细胞的迁移。将该滤膜的下表面用玻连蛋白涂层。将细胞在补充有0.2%牛血清清蛋白的DMEM中混悬至浓度为2.5-5.0×106细胞/mL,然后在20℃下,用不同浓度的受试化合物预处理20分钟。用溶剂作为对照。在该培养箱的上部分放入0.2mL该细胞悬浮液。下部分包含0.6mL补充有0.2%牛血清清蛋白的DMEM。在37℃下,在95%空气/5%CO2中温育24小时。温育后,将该滤膜上表面未迁移的细胞轻轻刮去。然后将该滤膜在甲醇中固定,用10%吉姆萨染液染色。通过a)计量已迁移到该滤膜下表面的细胞数量或通过b)用10%乙酸提取染色的细胞,然后在600nM处测定吸收度来测定迁移。甲状腺甲状旁腺切除的大鼠模型
每个实验组包括5-6只成年雄性Sprague-Dawley大鼠(体重250-400g)。在使用前7天切除大鼠的甲状腺甲状旁腺(由卖主TaconicFarms完成)。所有大鼠每3天接受代替剂量的甲状腺素。收到大鼠,通过尾静脉穿刺取血到肝素化管中后,立即测定全血中的循环离子化钙的水平。如果该离子化的Ca水平(用Ciba-Coming型634钙pH分析仪测定)<1.2mM/L,该大鼠可用。将每只大鼠装配埋藏静脉和动脉导管以分别用于传递实验物质和血液样本。然后给大鼠喂养无钙杂食和去离子水。测定基线Ca水平,然后用外注射泵通过连续向静脉导管静脉输注,给予每只大鼠对照溶媒或人体甲状旁腺激素1-34肽(hPTH1-34,剂量为1.25μg/kg/h的盐水/0.1%牛血清清蛋白液,Bachem,Ca)或hPTH1-34与实验物质的混合物。在输注的6-8小时期间,每两小时间隔测定每只鼠的血钙响应。人体破骨细胞吸收和粘附测定
用源于破骨细胞瘤组织的正常人体破骨细胞进行并标准化凹窝吸收和粘附测定。测定1通过使用激光聚焦显微镜测定破骨细胞凹窝体积来进行。测定2按高通量筛选进行,其中胺原片段(吸收中释放的)通过竞争性ELISA测定。测定1(使用激光聚焦显微镜)
将等份源于人体破骨细胞瘤细胞的悬浮液从液氮储备下取出,迅速温热至37℃,通过离心(在4℃下,1000rpm 5分钟),在RPMI-1640培养基中洗涤1次。
将该培养基吸出并用鼠的抗-HLA-DR抗体代替,然后在RPMI-1640培养基中以1∶3稀释。将该悬浮液在冰中温育30分钟并不断混合。· 将该细胞用冷的RPMI-1640培养基洗涤2次,然后离心(在4℃下,1000rpm 5分钟),再将该细胞转移至无菌的15ml离心管中。在改进的Neubauer计数室中计量单核细胞的数目。· 将包被有山羊抗小鼠IgG(Dynal,GreatNeck,NY)的足量磁珠(5/单核细胞)从其储存瓶中取出,再置于5ml新鲜的培养基中(该步用于洗掉毒性的叠氮化物防腐剂)。通过在磁体上固定磁珠除去培养基,再用新鲜的培养基代替。· 将该磁珠与细胞混合,再在冰上将该悬浮液温育30分钟。不断混合该悬浮液。· 将包被有磁珠的细胞在磁体上固定,再将剩余的细胞(富含破骨细胞部分)倾倒于无菌的50ml离心管中。· 将新鲜的培养基加入到包被有磁珠的细胞中以移去任何所截留的破骨细胞。将该洗涤过程重复10次。弃去包被有磁珠的细胞。· 用荧光素二乙酸酯标记活的细胞,将存活的破骨细胞在计数室中计数。用大孔一次性的塑料巴氏吸管将样品加入到该计数室中。· 通过离心将破骨细胞沉淀,在补充有10%胎牛血清和1.7g/L碳酸氢钠的EMEM培养基中,将密度调节至适当值(该破骨细胞的数目随肿瘤而变化)。· 将3ml等份该细胞悬浮液(每个化合物处理)倾倒于15ml离心管中。将该细胞通过离心沉淀。· 向每个管中,加入3ml适当化合物处理(在EMEM培养基中稀释至50μM)。还包括适当的溶媒对照、阳性对照(将抗-玻连蛋白受体鼠的单克隆抗体[87MEM1]稀释至100μg/ml)和同型对照(IgG2a稀释至100μg/ml)。在37℃下,将该样品温育30分钟。· 将0.5ml等份该细胞接种于48-孔平板中的无菌的齿质切片上,在37℃下温育2小时。将每份处理样本筛选四次。· 将该切片用温热的PBS交替洗涤6次(六孔平板中,10ml/孔),然后置于含有该化合物处理或对照样品的新培养基中。在37℃下,将该样品温育48小时。耐受酒石酸的酸性磷酸酶(TRAP)方法(对破骨细胞谱系的细胞选择性染色)· 将含有附着破骨细胞的骨切片在磷酸盐缓冲盐水中洗涤,然后在2%戊二醛(在0.2M二甲砷酸钠中)固定5分钟。· 然后在水中洗涤,再在37℃下,在TRAP缓冲液中(溶于N,N-二甲基甲酰胺的0.5mg/ml萘酚AS-BI磷酸盐,并与含有10mM酒石酸钠的0.25M柠檬酸缓冲液(pH4.5)混合)温育4分钟。· 在冷水中洗涤后,将该切片在冷的含有1mg/ml固红石榴红的乙酸盐缓冲液(0.1M,pH6.2)中浸渍,在4℃下温育4分钟。· 吸去过量的缓冲液,水洗后,将该切片在空气中干燥。· 通过明视野显微镜计量该TRAP阳性破骨细胞(砖红/***沉淀)数目,然后通过超声从该齿质表面除去。· 用Nikon/Lasertec ILM21W聚焦显微镜测定凹窝体积。测定2(用ELISA读出)
按测定1开始的9步中所述富集并制备供筛选化合物的人体破骨细胞。为清楚起见,将这些步骤重复如下。· 将等份源于人体破骨细胞瘤细胞的悬浮液从液氮储备中取出,迅速温热至37℃,通过离心(在4℃下,1000rpm 5分钟),在RPMI-1640培养基中洗涤1次。· 将该培养基吸出并用鼠的抗-HLA-DR抗体代替,然后在RPMI-1640培养基中以1∶3稀释。将该悬浮液在冰上温育30分钟并不断混合。· 将该细胞用冷RPMI-1640培养基洗涤2次,然后离心(在4℃下,1000rpm 5分钟),再将该细胞转移至无菌的15ml离心管中。在改进的Neubauer计数室中计量单核细胞的数目。· 将包被有山羊抗小鼠IgG(Dynal,Great Neck,NY)的足量磁珠(5/单核细胞)从其储存瓶中取出,再置于5ml新鲜的培养基中(该步用于洗掉毒性的叠氮化物防腐剂)。通过在磁体上固定磁珠除去培养基,再用新鲜的培养基代替。· 将该磁珠与细胞混合,再在冰上将该悬浮液温育30分钟。不断混合该悬浮液。· 将包被有磁珠的细胞在磁体上固定,再将剩余的细胞(富含破骨细胞部分)倾倒于无菌的50ml离心管中。· 将新鲜的培养基加入到包被有磁珠的细胞中以移去任何所截留的破骨细胞。将该洗涤过程重复10次。弃去包被有磁珠的细胞。· 用荧光素二乙酸酯标记活的细胞,将存活的破骨细胞在计数室中计数。用大孔一次性的塑料巴氏吸管将样品加入到该计数室中。· 通过离心将破骨细胞沉淀,在补充有10%胎牛血清和1.7g/L碳酸氢钠的EMEM培养基中,将密度调节至适当值(该破骨细胞的数目随肿瘤而变化)。
与以上测定1中所述的方法相反,按下列所述,以4剂量筛选化合物而获得IC50值。· 在37℃下,将破骨细胞制备物与受试化合物(4剂量)或对照预温育30分钟。· 然后将该细胞接种于48-孔组织培养平板中的牛皮质骨的切片上,在37℃下再温育2小时。· 将该骨的切片用温热的磷酸盐缓冲盐水(PBS)交替洗涤6次以除去非粘附的细胞,然后再加入到含有新化合物或对照的48孔平板的孔中。· 然后在37℃下,将该组织培养平板温育48小时。· 将各孔的上清液吸至各管中,并在竞争性ELISA中筛选,ELISA可检测在吸收过程中释放的I型胶原蛋白的c-端肽。ELISA可由商业提供(Osteometer,Denmark),其含有能专一性与8-氨基酸序列(Glu-Lys-Ala-His-Asp-Gly-Gly-Arg)反应的兔抗体,该氨基酸序列存在于I型胶原蛋白的a1-链的羧基-终端的端肽上。其结果用相对于溶媒对照的吸收抑制的%表示。人体破骨细胞粘附测定
按以上测定的初始9步中所述富集并制备供筛选化合物的人体破骨细胞。为清楚起见,将这些步骤重复如下。· 将等份源于人体破骨细胞瘤细胞的悬浮液从液氮储备中取出,迅速温热至37℃,通过离心(在4℃下,1000rpm 5分钟),在RPMI-1640培养基中洗涤1次。· 将该培养基吸出并用鼠的抗-HLA-DR抗体代替,然后在RPMI-1640培养基中以1∶3稀释。将该悬浮液在冰上温育30分钟并不断混合。· 将该细胞用冷RPMI-1640培养基洗涤2次,然后离心(在4℃下,1000rpm 5分钟),再将该细胞转移至无菌的15ml离心管中。在改进的Neubauer计数室中计量单核细胞的数目。· 将包被有山羊抗小鼠IgG(Dynal,GreatNeck,NY)的足量磁珠(5/单核细胞)从其储存瓶中取出,再置于5ml新鲜的培养基中(该步用于洗掉毒性的叠氮化物防腐剂)。通过在磁体上固定磁珠除去培养基,再用新鲜的培养基代替。· 将该磁珠与细胞混合,再在冰上将该悬浮液温育30分钟。不断混合该悬浮液。· 将包被有磁珠的细胞在磁体上固定,再将剩余的细胞(富含破骨细胞部分)倾倒于无菌的50ml离心管中。· 将新鲜的培养基加入到包被有磁珠的细胞中以移去任何所截留的破骨细胞。将该洗涤过程重复10次。弃去包被有磁珠的细胞。· 用荧光素二乙酸酯标记活的细胞,将存活的破骨细胞在计数室中计数。用大孔一次性的塑料巴氏吸管将样品加入到该计数室中。· 通过离心将破骨细胞沉淀,在补充有10%胎牛血清和1.7g/L碳酸氢钠的EMEM培养基中,将密度调节至适当值(该破骨细胞的数目随肿瘤而变化)。· 在37℃下,将源于破骨细胞瘤的破骨细胞与化合物(4剂量)或对照预温育30分钟。· 然后将该细胞接种于包被有骨桥蛋白的载玻片上(人或鼠的骨桥蛋白,2.5μg/ml),在37℃下温育2小时。· 在磷酸盐缓冲盐水中,通过剧烈冲洗该载玻片以移去未粘附的细胞,将载玻片上遗留的细胞在丙酮中固定。· 将破骨细胞进行耐受酒石酸的酸性磷酸酶(TRAP)染色,即该表型细胞(见步骤15-17)的选择性标记,通过光学显微镜计数。结果用相对于溶媒对照的粘附抑制的%表示。细胞粘附测定细胞和细胞培养基
从ATCC(目录号CRL 1573)获得的人体胚肾细胞(HEK293细胞)。在含有Earl氏盐、10%胎牛血清、1%谷氨酰胺和1%青霉素-链霉素的Earl氏基本必需培养基(EMEM)中培养细胞。构建物与转染
将αV亚基的3.2kb EcoRI-KpnI片段和β3亚基的2.4kb XbaI-XhoI片段***到pCDN载体的EcoRI-EcoRV克隆位置(Aiyar等,1994),该载体含有CMV启动子和通过平端连接的G418选择性标记物。为稳定表达,用基因脉冲发生器(Gene Pulser)(Hensley等,1994)将80×106HEK 293细胞与αV+β3构建物(每亚基20μg DNA)电转化,然后接种于100mm平板中(5×105细胞/平板)。48小时后,将该生长培养基用450μg/mL遗传霉素(G418硫酸盐,GIBCO-BRL,Bethesda,MD)补充。将该细胞保存在选择性培养基中直至集落长大可用于测试。转染细胞的免疫细胞化学分析
为确定HEK 293转染子是否表达玻连蛋白受体,通过离心将该细胞固定在玻璃显微镜载玻片上,室温下在丙酮中固定2分钟,空气干燥。可用标准间接免疫荧光法测定与23C6的专一活性,对该αVβ3复合物单克隆抗体专一性。细胞粘附研究
在4℃下,用0.1mL人体玻连蛋白(RPMI培养基中0.2μg/mL)将Coming 96-孔ELISA平板预包被。实验时,将该平板用RPMI培养基冲洗一次,然后在室温下在RPMI培养基中,用3.5%BSA封闭1小时。将转染的293细胞再混悬于RPMI培养基中,在密度0.5×106细胞/mL下,该培养基补充了20mM Hepes,pH7.4和0.1%BSA。在各种αVβ3拮抗剂存在或不存在下,在每个孔中加入0.1mL细胞混悬液,在37℃下温育1小时。温育后,加入0.025mL 10%甲醛溶液,pH7.4,室温下将该细胞固定10分钟。将平板用0.2mL RPMI培养基洗涤三次,室温下将该粘附细胞用0.1mL 0.5%甲苯胺蓝染色20分钟。用去离子水充分洗涤以除去过量的染料。通过加入0.1mL含有50mM HCl的50%乙醇洗脱结合入细胞的甲苯胺蓝。用微量滴定板读出器(Titertek Multiskan MC,Sterling,VA),在光密度600nm下定量细胞粘附性。固态αVβ5结合测定
从人体胎盘中纯化玻连蛋白受体αVβ5。将受体制备物用50mMTris-HCl,pH7.5、100mM NaCl、1mM CaCl2、1mM MnCl2、1mMMgCl2(缓冲液A)稀释,然后以每孔0.1mL立即加入到96-孔ELISA平板中。每孔加入0.1-0.2μg的αVβ3。在4℃下,将该平板温育过夜。在实验时,将各孔用缓冲液A洗涤一次,室温下,在相同缓冲液中与0.1ml 3.5%牛血清清蛋白温育。温育后,将各孔完全抽出,用0.2ml缓冲液A洗涤两次。
在[3H]-SK&F-107260竞争性测定中,将各种浓度未标记的拮抗剂(0.001-100μm)加入到各孔中,然后加入5.0nM的[3H]-SK&F-107260。室温下将该平板温育1小时。温育后,将各孔完全抽出,以孔至孔的方式,用0.2m1冰冷缓冲液A洗涤一次。将该受体用0.1ml的1%SDS增溶,在Beckman LS6800液体闪烁计数器上,加入3mLReady Safe,通过液体闪烁计数测定40%效力的结合的[3H]-SK&F-107260。在2μM SK&F-107260存在下,测定未特异性结合的[3H]-SK&F-107260,非特异结合一般少于总放射性配体输入的0.1%。通过从LUNDON-2程序改进的适用于常规的非线性最小二乘方曲线测定IC50值(即抑制50%[3H]-SK&F-107260结合的该拮抗剂的浓度)。根据Cheng和Prusoff方程:Ki=IC50/(1+L/Kd)计算Ki(拮抗剂的解离常数),其中L和Kd分别是[3H]-SK&F-107260的浓度和解离常数。
RGD-介导GPIIb-IIIa结合的抑制GPIIb-IIIa的纯化
将十单位过时的、洗过的人体血小板(从Red Cross获得)在4℃的3%辛基葡萄糖甙、20mM Tris-HCl,pH7.4、140mM NaCl、2mMCaCl2中轻轻搅拌2小时溶解。将该溶解产物在100,000g下离心1小时。将得到的上清液加入预先用20mM Tris-HCl,pH7.4、100mMNaCl、2mM CaCl2、1%辛基葡萄糖甙(缓冲液A)平衡的5mL晶状体凝集素琼脂糖凝胶4B柱(E.Y.Labs)上。2小时温育后,将该柱用50mL冷缓冲液A洗涤。将保留的凝集素GPIIb-IIIa用含有10%葡萄糖的缓冲液A洗脱。所有过程在4℃下进行。通过SDS聚丙烯酰胺凝胶电泳显示获得的GPIIb-IIIa纯度>95%。脂质体中GPIIb-IIIa的渗入
通氮气流下,将磷脂酰丝氨酸(70%)和磷脂酰胆碱(30%)的混合物(Avanti Po1ar Lipids)干燥于玻璃管的壁上。将纯化的GPIIb-IIIa稀释至最终浓度0.5mg/mL,再与磷脂以蛋白质∶磷脂比率1∶3(w∶w)混合。将该混合物再混悬,用水浴超声机超声5分钟。然后用12,000-14,000分子量截断透析管向1000倍过量的50mM Tris-HCl,pH7.4、100mM NaCl、2mM CaCl2(替换2次)中将该混合物透析过夜。将含有GPIIb-IIIa的脂质体在12,000g下离心15分钟,在透析缓冲液中再混悬,最终蛋白质浓度大约1mg/mL。将该脂质体存放于-70℃下,备用。与GPIIb-IIIa竞争性结合
通过使用[3H]-SK&F-107260作为RGD-型配体的间接竞争性结合方法进行结合血纤蛋白原受体(GPIIb-IIIa)测定。在96-孔滤板装置(Millipore Corporation,Bedford,MA)中,使用0.22μm亲水性durapore薄膜进行该结合实验。在室温下,用0.2mL 10μg/mL聚赖氨酸(SigmaChemical Co.,St.Louis,MO.)将该孔预涂1小时以阻断非特异性结合。将各种浓度的非标记苯并氮杂以一式四份加入到这些孔中。将[3H]-SK&F-107260以最终浓度4.5nM加入到每个孔中,然后加入1μg含有纯化的血小板GPIIb-IIIa的脂质体。室温下,将该混合物温育1小时。用Millipore过滤支管,通过过滤从未结合的当中将GPIIb-IIIa结合的[3H]-SK&F-107260分离出,然后用冰冷却的缓冲液洗涤(2次,每次0.2mL)。在1.5mL Ready Solve(BeckmanInstruments,Fullerton,CA)中,在Beckman液体闪烁计数器(LS6800型)上算出40%效力的遗留在滤器上的结合的放射活性。在2μM未标记的SK&F-107260存在下测定非特异结合,非特异结合一般少于加入样品的总放射活性的0.14%。所有数据点是四份测定的平均值。
通过适用于方法的非线性最小二乘方曲线分析竞争性结合数据。该方法提供该拮抗剂的IC50值(即抑制平衡中50%[3H]-SK&F-107260特异性结合的该拮抗剂的浓度)。该IC50与基于Cheng和Prusoff方程:Ki=IC50/(1+L/Kd)的该拮抗剂的平衡解离常数(Ki)有关,其中L是该竞争结合测定中所用的[3H]-SK&F-107260的浓度(4.5nM),Kd是按Scatchard分析确定的4.5nM的[3H]-SK&F-107260的解离常数。
本发明优选的化合物对玻连蛋白受体的亲和力相对于血纤蛋白原受体大于10∶1。多数优选的化合物具有大于100∶1的活性比率。
可用几种可移植性小鼠肿瘤模型测定式(I)化合物本身或与抗肿瘤剂联合的效力。这些模型的详细内容见美国专利号5,004,758和5,633,016。
以下实施例不以任何方式限定本发明的范围,但用于说明如何实现和使用本发明的化合物。对本领域那些技术人员来讲,许多其它的实施方案是显而易见的。
实施例
总则
质子核磁共振(1H NMR)光谱在250或400MHz下测定。以内标四甲基硅烷起向低物以每百万分之份数记录化学位移(δ)。NMR数据的缩写如下:s=单峰,d=双重峰,t=三重峰,q=四重峰,m=多重峰,dd=两个双重峰,dt=两个三重峰,app=表观,br=宽。J表示以赫兹测定的NMR偶合常数。CDCl3是氘代氯仿,DMSO-d6是六氘代二甲亚砜,CD3OD是四氘代甲醇。红外(IR)光谱以透射方式记录,谱带位置以波数的倒数(cm-1)记录。用电子喷雾(ES)或FAB离子化技术测定质谱。元素分析可由内部的或由Quantitative Technologies Inc.,Whitehouse,NJ测定。熔点用Thomas-Hoover熔点仪测定,熔点未经校正。所有温度均为摄氏温度。用Analtech硅胶GF和E.Merck硅胶60F-254薄层板进行薄层层析。快速和重力层析均用E.Merck Kieselgel60(230-400目)硅胶进行。分析和制备HPLC用Rainin或Beckman色谱仪进行,ODS指十八烷基甲硅烷衍生化的硅胶色谱固定相。5μApex-ODS指具有5μ公称粒度的十八烷基甲硅烷衍生化的硅胶色谱固定相,由Jones Chromatography,Littleton,Colorado制造。YMCODS-AQ是ODS色谱固定相,其为日本Kyoto YMC Co.Ltd.注册的商标。PRP-1是聚合(苯乙烯-二乙烯苯)色谱固定相,其为HamiltonCo.,Reno,Nevada注册的商标。Celite是由酸洗的硅藻土组成的助滤剂,其为Manville Corb.,Denver,Colorado注册的商标。
(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯、(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯和(±)-10,11-二氢-3-(三氟甲磺酰氧基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯根据WO 9701540-A1制备。2-[2-(4-甲氧基苄氨基)吡啶-6-基]乙醇根据WO 95/32710制备。6-甲氧基-1-(2,3-二氢茚酮)根据House和Hudson(J.Org.Chem.1970,35,647)的方法制备。
制备1制备2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物a)2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物
将2-氯吡啶-N-氧化物盐酸盐(16.6g,0.1mol)、3-氨基-1-丙醇(15.3mL,0.2mol)、NaHCO3(42g,0.5mol)和叔戊醇(100mL)的混合物加热回流。21小时后,将该反应物冷却,用CH2Cl2(300mL)稀释,抽滤除去不溶物质。浓缩滤液,用甲苯再浓缩得到黄色油状物。硅胶层析(20%MeOH/CHCl3)得到标题化合物(15.62g,93%),为黄色固体:TLC(20%MeOH/CHCl3)Rf0.48;1H NMR(250,CDCl3)δ8.07(dd,J=6.6,1.2Hz,1H),7.34(brt,1H),7.10-7.30(m,1H),6.64(dd,J=8.5,1.4Hz,1H),6.40-6.60(m,1H),4.49(brs,1H),3.65-3.90(m,2H),3.35-3.60(m,2H),1.75-2.00(m,2 H);MS(ES)m/e 169(M+H)+.
制备2制备2-[(3-羟基-1-丙基)氨基]-4-硝基吡啶-N-氧化物a)2-氯-4-硝基吡啶-N-氧化物
在0℃下,将浓H2SO4(30mL)和发烟HNO3(54mL)的溶液滴加到2-氯吡啶-N-氧化物盐酸盐(15.2g,91.56mmol)的浓H2SO4(30mL)溶液中。在90℃下,将该反应混合液加热1小时,然后冷却至室温,倒入冰(500g)中。将该反应混合液在RT下保持过夜,然后用冰浴冷却,慢慢加入50%NaOH得到沉淀。收集沉淀,干燥得到标题化合物(5.88g,37%),为浅黄色固体:1H NMR(400MHz,CDCl3)δ8.42-8.37(m,2H),8.06-8.04(m,1H)。b)2-[(3-羟基-1-丙基)氨基]-4-硝基吡啶-N-氧化物
按照制备1的方法,用2-氯-4-硝基吡啶-N-氧化物代替2-氯吡啶-N-氧化物盐酸盐,硅胶层析(1∶9 MeOH/CH2Cl2)后得到标题化合物,为黄色粉末。从MeOH/CH2Cl2/Et2O中重结晶得到该标题化合物:MS(ES)214.1(M+H)+。
制备3制备2-[(3-羟基-1-丙基)氨基]-4-甲基吡啶-N-氧化物a)2-氯-4-甲基吡啶
在0℃下,将亚硝酸钠(13.88g,200mmol)慢慢加入到2-氨基-4-甲基吡啶(15.0g,139mmol)的浓HCl(200mL)溶液中。将该反应混合液温热至室温,搅拌16小时,然后倒入冰(500g)中。用浓NH4OH将pH调至8.0,将该混合液用***(3×300mL)提取。将合并的醚层顺次用H2O(2×200mL)和盐水(200mL)洗涤。干燥(MgSO4),浓缩得到标题化合物(10.3g,58%),为暗黄色油状物:MS(ES)m/e 127.8(M+H)+。b)2-氯-4-甲基吡啶-N-氧化物盐酸盐
将2-氯-4-甲基吡啶(10.0g,78.3mmol)和34%过乙酸(76.05g,91.0mmol)的冰AcOH(10mL)混合液加热至70℃3小时。将该反应混合液冷却,加入浓HCl(35mL),将该混合液在旋转蒸发器上浓缩。用正丁醇重结晶,然后用***研磨得到标题化合物(7.16g,51%),为白色固体:MS(ES)m/e 143.9(M+H)+。c)2-[(3-羟基-1-丙基)氨基]-4-甲基吡啶-N-氧化物
将2-氯-4-甲基吡啶-N-氧化物盐酸盐(7.16g,39mmol)、3-氨基丙醇(6.01g,80mmol)和NaHCO3(16.8g,200mmol)的叔戊醇(50mL)混合液加热回流19小时。将该反应混合液用CH2Cl2(200mL)稀释,过滤,将该滤液在旋转蒸发器上浓缩。从CH2Cl2/Et2O中重结晶得到标题化合物(5.41g,75%),为黄色固体:TLC(15%MeOH/CH2Cl2)Rf0.44;1HNMR(400,CDCl3)δ7.92(d,J=6.7,1H),7.28(brt,1H),6.43(s,1H),6.33(dd,J=6.6,2.1Hz,1H),3.73(t,J=5.7Hz,2H),3.47(q,H=6.3Hz,2H),2.29(s,3H),1.82-1.88(m,2H),MS(ES)m/e 183(M+H)+。
制备4制备6-(甲氨基)-2-吡啶乙醇a)2-(叔丁氧基羰基氨基)-6-甲基吡啶
在50℃下,将2-氨基-6-甲基吡啶(21.63g,200mmol)和二碳酸二叔丁酯(52.38g,240mmol)的CH2Cl2(200mL)溶液在旋转蒸发器上浓缩,将得到的残留物用旋转蒸发器在50℃下真空旋转。21.5小时后,将该反应液用己烷(400mL)稀释,通过硅胶(己烷,然后20%EtOAc/己烷)过滤。浓缩得到标题化合物(41.84g,定量),为亮黄色油状物,放置逐渐固化:1H NMR(250MHz,CDCl3)δ7.71(d,J=8.3Hz,1H),7.40-7.65(m,2H),6.80(d,J=7.5Hz,1H),2.43(s,3H),1.50(s,9H);MS(ES)m/e 153(M+H-C4H8)+。b)2-[(叔丁氧基羰基)甲氨基]-6-甲基吡啶
用数分钟将NaH(60%在矿油中,3.60g,90mmol)分次加入到15℃下(冷水浴)的2-(叔丁氧基羰基氨基)-6-甲基吡啶(15.62g,75mmol)和碘甲烷(9.3mL,150mmol)的无水DMSO(75mL)溶液中。内温升至35℃。当停止放出气体后,移去冷水浴,在RT下搅拌该反应物。0.5小时后,将该暗黄色混合液倒入冰/水(300mL)中,用Et2O(3×300mL)提取。将合并的有机层顺次用H2O(2×75mL)和盐水(75mL)洗涤。干燥(MgSO4),浓缩得到黄色油状物,经硅胶层析(7%EtOAc/己烷)。得到标题化合物(13.01g,78%),为淡黄色油状物:1H NMR(250MHz,CDCl3)δ7.51(appt,1H),7.37(d,J=8.2Hz,1H),6.86(d,J=7.2Hz,1H),3.38(s,3H),2.49(s,3H),1.51(s,9H);MS(ES)m/e 223(M+H)+。c)6-[(叔丁氧基羰基)甲氨基]-2-吡啶基乙酸乙酯
在0℃、通氩气下,用二异丙基胺(19.5mL,139.14mmol)和2.5M正丁基锂的己烷液(46.4mL,115.95mmol)的干燥THF(350mL)溶液制备LDA。将该溶液冷却至-78℃,用10分钟滴加2-[(叔丁氧基羰基)甲氨基]-6-甲基吡啶(10.31g,46.38mmol)的干燥THF(46mL)溶液。再用干燥THF(2mL)转移。在-78℃下,将该橙色溶液搅拌15分钟,然后快速加入碳酸二乙酯(6.2mL,51.02mmol)。在-78℃下,将该红色溶液搅拌15分钟,然后用半饱和的NH4Cl(175mL)猝灭。将该混合液温至+5℃,用EtOAc(175mL)提取,然后用CH2Cl2(2×100mL)提取。将合并的有机液用盐水(100mL)洗涤,干燥(MgSO4),浓缩。将该混浊、黄色油状物经硅胶层析(15%EtOAc/己烷)得到标题化合物(10.72g,79%),为亮黄色油状物:1H NMR(250MHz,CDCl3)δ7.51-7.63(m,2H),6.91-7.03(m,1H),4.19(q,J=7.1Hz,2H),3.77(s,2H),3.38(s,3H),1.27(t,J=7.1Hz,3H),1.51(s,9H),MS(ES)m/e295(M+H)+。d)6-(甲氨基)-2-吡啶基乙酸乙酯
将6-[(叔丁氧基羰基)甲氨基]-2-吡啶基乙酸乙酯(10.72g,36.42mmol)的干燥二氧六环(91mL)溶液冷却至溶剂部分结晶点,加入4MHCl/二氧六环(91mL,364.2mmol)。将该溶液温热至RT,搅拌17小时,然后浓缩。将得到的亮黄色固体用CH2Cl2/甲苯制成淤浆并浓缩得到标题化合物(8.48g,定量),为亮黄色粉末:1H NMR(250MHz,CD3OD)δ7.84(dd,J=9.0,7.2Hz,1H),6.96(d,J=9.0Hz,1H),6.78(d,J=7.2 Hz,1H),4.22(q,J=7.1Hz,2H),3.93(s,2H),3.05(s,3H),1.27(t,J=7.1Hz,3H),MS(ES)m/e 195(M+H)+。e)6-(甲氨基)-2-吡啶基乙醇
在0℃、通氩气下,将1.0M LiAlH4的THF溶液(95mL,95mmol)滴加到机械搅拌下的2-(甲氨基)-6-吡啶基乙酸乙酯(7.34g,31.82mmol)的干燥THF(64mL)混悬液中。慢慢加入直至停止放出气体,然后将余下的溶液快速加入。再需要5-7分钟。将该反应液温热至RT,搅拌45分钟,然后加热回流。10分钟后,将该反应液冷却至0℃,通过顺次滴加H2O(3.6mL)、15%NaOH(3.6mL)和H2O(10.8mL)处理。将该混合液在0℃下搅拌15分钟,再在RT下搅拌15分钟,然后通过布氏漏斗过滤。将滤饼用足量的THF洗涤,浓缩滤液。将残留物用甲苯再浓缩,然后经硅胶层析(5%MeOH的1∶1 EtOAc/CHCl3液)得到标题化合物(3.23g,67%),为黄色油状物,其固化为蜡状固体:1HNMR(250MHz,CDCl3)δ7.36(dd,J=8.3,7.3Hz,1H),6.42(d,J=7.3Hz,1H),6.26(d,J=8.3Hz,1H),4.93-5.28(m,1H),4.38-4.60(m,1H),3.96(t,J=5.4Hz,2H),2.90(d,J=5.2Hz,3H),2.84(t,J=5.4Hz,2H);MS(ES)m/e 153(M+H)+。
制备5制备2-(乙氨基)-4-噻唑乙醇a)2-乙酰氨基-4-噻唑乙酸乙酯
将2-氨基-4-噻唑乙酸乙酯(3.72g,20mmol)加入到乙酸(4mL)和乙酸酐(4mL)中,将得到的悬浮溶液加热回流3小时。浓缩,经硅胶快速层析(5%MeOH/CH2Cl2)得到标题化合物(4.1g,91%),为白色固体:MS(ES)m/e 229(M+H)+。b)2-(乙氨基)-4-噻唑乙醇
向搅拌的1.0M LiAlH4的THF溶液(179mL,179mmol)中滴加2-乙酰氨基-4-噻唑乙酸乙酯(4.4g,17.9mmol)的THF(50mL)溶液。加完后,将反应混合液加热回流3小时,然后通过顺次加入H2O(0.7mL)、10%NaOH(0.7mL)和H2O(2.1mL)处理。将得到的混合液通过celite过滤,浓缩滤液。经硅胶快速层析(5%MeOH/CH2Cl2)纯化得到标题化合物(1.6g,53%),为琥珀色油状物:MS(ES)m/e 173(M+H)+。
制备6制备6-氨基-2-吡啶基乙醇a)6-氨基-2-吡啶基乙醇
将根据WO 95/32710的方法制备的2-[2-(4-甲氧基苄氨基)吡啶-6-基]乙醇(0.95g,3.7mmol)的6N HCl溶液加热到60℃。16小时后,将该反应物真空浓缩,用干燥KOH使残留物呈碱性。将得到的混合液用MeOH提取,将该MeOH提取液干燥(MgSO4),浓缩。经硅胶快速层析(5%MeOH/CH2Cl2)得到标题化合物(0.2g,40%),为浅黄色油状物:MS(ES)m/e 139(M+H)+。
制备7制备3-(4-硝基苄氧基羰基)氨基-1-丙醇a)3-(4-硝基苄氧基羰基)氨基-1-丙醇
向室温下、通氩气的氯甲酸4-硝基苄酯(5g,23mmol)和三乙胺(6.4mL,46mmol)的THF(25mL)混悬液中加入3-氨基-1-丙醇(1.9mL,26mmol)。将得到的混合液搅拌72小时,然后浓缩。残留物经硅胶层析(0.5-2%MeOH/CH2Cl2)得到标题化合物(2g,34%),为浅黄色油状物:MS(ES)m/e 255.3(M+H)+。
制备8制备1-[(3-羟基-1-丙基)氨基]异喹啉-N-氧化物a)1-氯异喹啉-N-氧化物
根据文献(Brown,E.V.,J.Amer.Chem.Soc.1957,79,3565-3566)中所述的通法,应用亚硝酸钾和浓HCl将1-氨基异喹啉-N-氧化物盐酸盐(Deady,L.W.Synthetic Communications 1977,509-514)转化为1-氯异喹啉-N-氧化物。所制备的标题化合物为亮棕色固体:MS(ES)m/e179.9(M+H)+。b)1-[(3-羟基-1-丙基)氨基]异喹啉-N-氧化物
根据制备1(a)中的方法,用1-氯异喹啉-N-氧化物代替2-氯吡啶-N-氧化物盐酸盐,所制备的标题化合物为琥珀色固体:MS(ES)m/e219.1(M+H)+。
制备9制备2-[N-(3-甲磺酰氧基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物a)2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物
将2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物(8.0g,47.6mmol)的叔丁醇(80mL)溶液用二碳酸二叔丁基酯(11.4g,55.3mmol)处理。18小时后,将该溶液浓缩,将残留物用己烷研磨。将得到的固体真空干燥得到标题化合物(12.5g,98%),为灰白色固体:MS(ES)m/e 269.3(M+H)+。b)2-[N-(3-甲磺酰氧基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物
0℃下,将甲磺酰氯(0.17mL,2.20mmol)滴加到2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物(0.50g,1.86mmol)和吡啶(0.23mL,2.84mmol)的CHCl3(5mL,用K2CO3干燥)溶液中。通过TLC检测反应完成后,将该反应液用CHCl3稀释,用冰水洗涤,干燥(Na2SO4),浓缩。硅胶层析(10%MeOH/CHCl3)得到标题化合物(0.41g,64%),为无色油状物:1H NMR(250MHz,CDCl3)δ8.25(dd,J=6.0,1.9Hz,1H),7.25(m,4H),4.35(t,J=6.2Hz,2H),3.75(t,J=6.6Hz,2H),3.00(s,3H),2.00(m,2H),1.40(s,9H)。从色谱提纯中也可回收未变化的2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物(0.18g,36%)。
制备10制备(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)6-甲氧基-1-苯基茚
室温、通氩气下,将3.0M溴化苯基镁的Et2O溶液(680mL,2.04mol)搅拌下用Et2O(700mL)稀释,用1小时滴加6-甲氧基-1-(2,3-二氢茚酮)(277g,1.71mol)的THF(1400mL)溶液。室温下,将该反应混合物搅拌2小时,然后搅拌下倒入饱和的NH4Cl(2.8L)中。加入H2O(1.4L),分离有机层。将水层用Et2O(2×1L)提取,再将合并的有机提取液浓缩得到粗品6-甲氧基-1-苯基-1-茚满醇(445g),为棕色油状物。将该油状物溶于甲苯(2.5L)中,加入对甲苯磺酸单水合物(12.3g,0.065mol)。用带有冷凝器的Dean-Stark分水器将该溶液搅拌并加热回流16小时。2小时后收集到的H2O最少,一共28mL。将该溶液冷却,顺次用5%Na2CO3(1L)和H2O(2×1L)提取。将有机层浓缩得到暗棕色油状物(400g)。将该油状物真空蒸馏得到标题化合物(298.2g,79%),为黄色油状物:bp 152-190℃/2.0 Torr;TLC(10%EtOAc/己烷)Rf0.75。b)2-苯甲酰基-4-甲氧基苯乙酸
将丙酮(4.2L)冷却至10℃,用1.5小时一起加入6-甲氧基-1-苯基茚(271g,1.22mol)的丙酮(1.8L)溶液和Jones试剂(1.8L,从CrO3(470g,4.70mol)、H2O(1L)和浓H2SO4(405mL)制备)。分两次向得到的混合液中加入4%OsO4水溶液(153mL),一次在加料开始时,第二次在加料中间时,期间保持反应温度低于15℃。加完后,将该反应混合液温热至22℃,并搅拌1.5小时,期间温和放热升高温度至28℃。然后将该反应混合液冷却至20℃以下,加入异丙醇(1L),最初滴加,并在最初放热消失后快速加入。期间搅拌变得困难。加入异丙醇中,温度达到32℃。加入H2O(2L),将该混合液转移至分液漏斗中。再加入H2O以溶解沉淀的亚铬酸,将该混合液用CH2Cl2(2L)提取。分离有机层(上层),将水相用CH2Cl2(2×1L)提取。将合并的CH2Cl2提取液顺次用H2O(2L)和饱和盐水(2L)洗涤,然后浓缩得到湿润的灰色固体(416g)。将其用丙酮和EtOAc的混合物研磨,过滤,干燥得到标题化合物(225.4g,71%),为灰白色固体:mp 158-159℃。c)2-苄基-4-甲氧基苯乙酸
将2-苯甲酰基-4-甲氧基苯乙酸(215.5g,0.80mol)分成两等份,将每份溶于2.5L压力瓶中的冰AcOH(1.5L)中。向每份中加入5%Pd/C(10g,0.0048mol),室温、通氢气下,在Parr装置上将每份混合物振摇。2.5小时后,将该混合物过滤除去催化剂,用EtOAc洗涤滤饼。将合并的滤液浓缩得到标题化合物(215g,定量),为深黄色油状物,放置结晶:1H NMR(250MHz,CDCl3)δ7.05-7.35(m,6H),6.77(dd,J=8.3,2.7Hz,1H),6.71(d,J=2.7Hz,1H),4.00(s,2H),3.76(s,3H),3.54(s,2H)。d)10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮
室温、通氩气下,将2-苄基-4-甲氧基苯乙酸(215g,为含有204.6g(0.80mol)纯品的粗产物)的CH2Cl2(1L)的溶液搅拌,再加入DMF(1mL),然后加入草酰氯(400mL,4.59mol)。用1小时加入草酰氯,最初滴加以控制剧烈放出气体。室温下将该溶液搅拌16小时,然后浓缩得到粗酰氯(207.7g,0.756mol,95%),为黄色液体。将该液体溶于CH2Cl2中使总体积至500mL,室温、通氩气下,搅拌下用1小时将该溶液和AlCl3(100.8g,0.756mol)同时加入到CH2Cl2(3.7L)中。加完后,温度为28℃。室温下将该反应混合液搅拌16小时,期间固体沉淀。用30分钟,最初滴加加入H2O(1L)。然后分离该混合液,将有机相顺次用H2O(1L)和5%NaHCO3水溶液(1L)洗涤。然后将CH2Cl2溶液浓缩得到黄色固体(175.3g)。用EtOAc/己烷重结晶得到标题化合物(128g,71%):mp107-109℃。e)(±)-10,11-二氢-10-羟基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
-70℃、通氩气下,将1.0M双(三甲基甲硅烷基)氨化锂的己烷(1282mL,1.282mol)加入到THF(4.0L)中,然后用20分钟滴加EtOAc(146mL,1.49mol)。将该反应混合液搅拌15分钟,然后用20分钟加入N,N,N′,N′-四甲基乙二胺(378mL,2.5mol)。将该反应混合液搅拌10分钟,然后用40分钟滴加10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮(119.2g,0.50mo1)的无水THF(1.26L)溶液。加入这些物料期间,温度保持低于-65℃。于-65至-70℃将该反应混合物搅拌20分钟,然后剧烈搅拌下倒入NH4Cl(6.2L)饱和水溶液中。分离有机层,将水层用EtOAc(2×1L)提取。将合并的有机提取液用H2O(2×1L)洗涤,然后浓缩得到浅棕色油状物(175g)。薄层层析(20%EtOAc/己烷)显示主成分(所要求产物)Rf0.5,次成分(回收的酮)Rf0.7。该粗产物经硅胶层析(2kg,10%EtOAc/己烷)得到标题化合物(101g,61%),为黄色油状物:1H NMR(250MHz,CDCl3)δ7.63(d,J=7.7Hz,1H),7.00-7.30(m,4H),6.80(d,J=2.6Hz,1H),6.69(dd,J=8.2,2.6Hz,1H),3.95-4.35(m,2H),4.07(s,2H),3.76(s,3H),3.68(s,1H),3.64(d,J=14.2Hz,1H),3.35(d,J=14.2Hz,1H),2.79(d,J=16.0Hz,1H),2.66(d,J=16.0Hz,1H),1.22(t,J=7.2Hz,3H)。f)(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(±)-10,11-二氢-10-羟基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(101g,0.31mol)溶于冰醋酸(1.8L)中,加入12N HCl(28.5mL,0.34mol)。将该混合液置于含有5%Pd/C(20g,0.0094mol)的2.5L压力瓶中,35℃、通氢气下,在装备套层加热器的Parr装置上将得到的混合液振摇。18小时后,将该反应液冷却至室温,过滤除去催化剂。滤液浓缩得到浅黄色油状物(85.1g)。经硅胶层析(2kg,用5%-10%EtOAc/己烷逐步梯度洗脱)得到标题化合物(69.1g,72%),为油状物:1H NMR(250MHz,CDCl3)δ7.05-7.22(m,4H),7.01(d,J=8.2Hz,1H),6.76(d,J=2.7Hz,1H),6.67(dd,J=8.2,2.7Hz,1H),4.30(d,J=15.0Hz,1H),4.11-4.25(m,2H),3.85(d,J=15.0Hz,1H),3.70-3.90(m,1H),3.77(s,3H),3.31(dd,J=15.0,4.1Hz,1H),2.93(dd,J=15.0,9.2Hz,1H),2.64(dd,J=15.6,5.0Hz,1H),2.52(dd,J=15.6,9.3Hz,1H),1.27(t,J=7.1Hz,3H)。g)(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气、搅拌下,将(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(8.5g,0.027mol)的CH2Cl2(150mL)溶液冷却至-10℃。加入乙硫醇(10.7mL,0.144mol),然后用15分钟分两次加入AlCl3(20.6g,0.154mol)。加完后,放热使温度升至0℃,然后用水浴使温度升至25℃。在25℃-30℃下,将该反应混合液搅拌2.25小时,然后倒入冰-水中。分离有机层,加入甲醇(100mL),将该混合液用CH2Cl2(2×50mL)提取。将合并的CH2Cl2提取液用H2O(250mL)洗涤,然后浓缩得到粘性油状物(8.6g)。将其溶于Et2O(150mL)中,蒸发***,加入己烷代替。先分离出所要求的为油状物的苯酚,室温搅拌下结晶。收集两次得到的固体,得到标题化合物(7.1g,89%):mp110-112℃。
制备11HPLC分离(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯的对映体a)(R)-(+)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯和(S)-(-)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
用以下条件将(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯拆分为对映体:Daicel Chiralcel OJ柱(21.2×250mm),流动相为20%乙醇的己烷液,流速为15mL/min,在254nm处uv检测,注射量为140mg;(S)-(-)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯的tR=10.4min;(R)-(+)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯的tR=13.1min。
制备12制备(±)-10,11-二氢-7-氟-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)1-(3-氟苯基)-6-甲氧基-1-茚满醇
根据制备10(a)的方法,但用3-氟苯基溴化镁代替苯基溴化镁,得到标题化合物,为琥珀色油状物:MS(ES)m/e 276.0(M+H)+。b)1-(3-氟苯基)-6-甲氧基茚
根据制备10(a)的方法,但用1-(3-氟苯基)-6-甲氧基-1-茚满醇代替6-甲氧基-1-苯基-1-茚满醇,硅胶层析(4%EtOAc/己烷)后,得到标题化合物,为无色油状物:MS(ES)m/e 241.1(M+H)+。c)2-(3-氟苯甲酰基)-4-甲氧基苯乙酸
根据制备10(b)的方法,但用2-(3-氟苯基)-6-甲氧基茚代替6-甲氧基-1-苯基茚,得到标题化合物,为白色固体:MS(ES)m/e 289.2(M+H)+。d)2-(3-氟苯甲基)-4-甲氧基苯乙酸
根据制备10(c)的方法,但用2-(3-氟苯甲酰基)-4-甲氧基苯乙酸代替2-苯甲酰基-4-甲氧基苯乙酸,得到标题化合物,为无色油状物:MS(ES-)m/e 273.2(M-H)-。e)10,11-二氢-7-氟-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮
根据制备10(d)的方法,但用2-(3-氟苯甲基)-4-甲氧基苯乙酸代替2-苯甲基-4-甲氧基苯乙酸,得到标题化合物,为白色固体:Mp129-130℃;MS(ES)m/e 279.2(M+Na)+。f)(±)-10,11-二氢-7-氟-10-羟基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据制备10(e)的方法,但用10,11-二氢-7-氟-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮代替10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮,硅胶层析(8%EtOAc/己烷)后,得到标题化合物:MS(ES)m/e362.2(M+NH4)+。g)(±)-10,11-二氢-7-氟-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据制备10(f)的方法,但用(±)-10,11-二氢-7-氟-10-羟基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(±)-10,11-二氢-10-羟基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,硅胶层析(10%EtOAc/己烷)后,得到标题化合物,为无色油状物:MS(ES)m/e 329.2(M+H)+h)(±)-10,11-二氢-7-氟-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据制备10(g)的方法,但用(±)-10,11-二氢-7-氟-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,硅胶层析(1%MeOH/CH2Cl2)后,得到标题化合物,为白色固体:MS(ES)m/e315.0(M+H)+,332.0(M+NH4)+。
制备13制备(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
RT、通氩气下,向(±)-10,11-二氢-7-氟-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.4g,1.33mmol)的含有2M二甲胺的MeOH(1.0mL)液的95%乙醇溶液中加入37%甲醛水溶液(0.5mL)。20小时后,将该反应液加热回流5小时,然后在旋转蒸发器上浓缩。将残留物在H2O和Et2O之间分配,分层。将水层用Et2O提取,将合并的有机层用盐水洗涤,干燥(MgSO4),旋转蒸发浓缩得到标题化合物(330mg,67%),为无色油状物:1H NMR(400MHz,CDCl3)δ7.20(m,1H),6.88(m,2H),6.67(s,2H),4.25(d,J=15.1Hz,1H),4.18(q,2H),3.78(m,1H),3.74(d,J=15.1Hz,1H),3.55(s,2H),3.20(dd,1H),2.80(dd,1H),2.60(dd,1H),2.53(dd,1H),2.29(s,6H),1.27(t,3H);MS(ES)m/e 372.3(M+H)+。
制备14制备(±)-10,11-二氢-3-羟基-2-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)(±)-10,11-二氢-2-甲酰基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
RT、通氩气下,将POCl3(17mL)滴加到(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(1.0g,3mmol)的干燥DMF(40mL)溶液中,将该暗色溶液加热至90℃48小时。将该反应液在旋转蒸发器上浓缩,再将残留物在H2O和EtOAc之间分配。分离有机层,干燥(MgSO4),旋转蒸发浓缩。将残留物用二甲苯再浓缩(除去任何残留的DMF),然后经硅胶层析(7%EtOAc的己烷液)得到标题化合物(230mg,21%),为无色油状物:MS(ES)m/e 339.3(M+H)+。b)(±)-10,11-二氢-3-甲氧基-2-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
RT、通氢气(60psi)下,将(±)-10,11-二氢-2-甲酰基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(220mg,0.65mmol)、10%Pd/C(90mg)、冰醋酸(15mL)和浓HCl(2mL)的混合液振摇。20小时后,将该混合液通过celite过滤,浓缩该滤液得到标题化合物(200mg,95%),为无色油状物:MS(ES)m/e 325.2(M+H)+。c)(±)-10,11-二氢-3-羟基-2-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
向冰浴冷却的干燥CH2Cl2(30mL)中加入二乙基硫(0.38mL,3.3mmol),再加入AlCl3(438mg,3.3mmol)。向该溶液中滴加(±)-10,11-二氢-3-甲氧基-2-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(200mg,0.6mmol)的干燥CH2Cl2(6mL)液,RT下将得到的混合液搅拌2小时。用1.0N HCl(10mL)猝灭该反应,分层。将有机层干燥(MgSO4),旋转蒸发浓缩得到标题化合物(100mg,56%),为无色油状物:MS(ES)m/e 311.2(M+H)+。
制备15制备(±)-10,11-二氢-3-羟基-6-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)6-甲氧基-1-(2-甲基苯基)-1-茚满醇
根据制备10(a)的方法,但用2-甲基苯基溴化镁代替苯基溴化镁,得到标题化合物,为油状物:MS(ES)m/e 277.0(M+Na)+。b)6-甲氧基-1-(2-甲基苯基)茚
根据制备10(a)的方法,但用6-甲氧基-1-(2-甲基苯基)-1-茚满醇代替6-甲氧基-1-苯基-1-茚满醇,硅胶层析(3%EtOAc/己烷)后,得到标题化合物,为无色油状物:MS(ES)m/e 237.2(M+H)+。c)4-甲氧基-2-(2-甲基苯甲酰基)苯乙酸
根据制备10(b)的方法,但用6-甲氧基-1-(2-甲基苯基)茚代替6-甲氧基-1-苯基茚,得到标题化合物,为粘性油状物:MS(ES)m/e 285.3(M+NH4)+。d)4-甲氧基-2-(2-甲基苯甲基)苯乙酸
根据制备10(c)的方法,但用4-甲氧基-2-(2-甲基苯甲酰基)苯乙酸代替2-苯甲酰基-4-甲氧基苯乙酸,得到标题化合物,为粘性油状物:MS(ES)m/e 288.2(M+NH4)+。e)10,11-二氢-3-甲氧基-6-甲基-5H-二苯并[a,d]环庚烯-10-酮
根据制备10(d)的方法,但用4-甲氧基-2-(2-甲基苯甲基)苯乙酸代替2-苯甲基-4-甲氧基苯乙酸,硅胶层析(6%EtOAc/己烷)后,得到标题化合物,为白色固体:MS(ES)m/e 253.0(M+H)+。f)(±)-10,11-二氢-10-羟基-3-甲氧基-6-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据制备10(e)的方法,但用10,11-二氢-3-甲氧基-6-甲基-5H-二苯并[a,d]环庚烯-10-酮代替10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮,硅胶层析(8%EtOAc/己烷)后,得到标题化合物:MS(ES)m/e358.2(M+NH4)+。g)(±)-10,11-二氢-3-甲氧基-6-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据制备10(f)的方法,但用(±)-10,11-二氢-10-羟基-3-甲氧基-6-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(±)-10,11-二氢-10-羟基-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,硅胶层析(5%EtOAc/己烷)后,得到标题化合物,为无色油状物:MS(ES)m/e 325.3(M+H)+。h)(±)-10,11-二氢-3-羟基-6-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据制备10(g)的方法,但用(±)-10,11-二氢-3-甲氧基-6-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,经用MeOH研磨后,得到标题化合物,为白色固体:MS(ES)m/e 311.2(M+H)+。
制备16制备(±)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)(±)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
RT、通氩气下,将2-[(3-羟基-1-丙基)氨基]-4-硝基吡啶-N-氧化物(0.85g,4mmol)和偶氮二甲酸二乙酯(0.63mL,4mmol)的干燥DMF(10mL)溶液滴加到(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.59g,2mmol)和三苯膦(1.10g,4.2mmol)的干燥DMF(10mL)溶液中。23小时后,将反应液浓缩,残留物用二甲苯(2x)再浓缩。硅胶层析(梯度:1∶1 EtOH/己烷,然后EtOAc,然后5%MeOH的1∶1EtOAc/CHCl3液)得到粗品标题化合物。从1∶1 EtOH/己烷部分中可回收未变化的(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸酯。将粗品标题化合物再层析(3%MeOH的1∶1 EtOAc/CHCl3液)得到纯标题化合物(0.72g,73%),为黄色泡沫状物:TLC(10%MeOH的1∶1 EtOAc/CHCl3液)Rf0.59;1H NMR(250MHz,CDCl3)δ8.19(d,J=7.1Hz,1H),7.46(d,J=2.9Hz,1H),7.35(dd,J=7.1,2.9Hz,1H),7.00-7.30(m,5H),7.00(d,J=8.2Hz,1H),6.81(d,J=2.6Hz,1H),6.70(dd,J=8.2,2.6Hz,1H),4.29(d,J=15.1Hz,1H),4.18(q,J=7.1Hz,2H),4.08(t,J=5.5Hz,2H),3.86(d,J=15.1Hz,1H),3.72-3.90(m,1H),3.59(q,J=6.3Hz,2H),3.30(dd,J=15.0,4.2Hz,1H),2.93(dd,J=15.0,9.3Hz,1H),2.64(dd,J=15.6,5.1Hz,1H),2.51(dd,J=15.6,9.3Hz,1H),2.10-2.30(m,2H),1.27(t,J=7.1Hz,3H);MS(ES)m/e 492(M+H)+。
制备17制备(S)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)(S)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据制备16的方法,但用(S)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,制备标题化合物:MS(ES)m/e 492(M+H)+。
制备18制备10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮a)2-苄基-4-甲氧基苯乙酸
通氩气下,将2-苯甲酰基-4-甲氧基苯乙酸(13.0g,0.048mol)(根据J.Med.Chem.1981,24,998的方法制备)的冰醋酸(600mL)溶液用4.3g 10%Pd/C处理,在50psi下氢化17小时。将该混合液通过celite过滤,浓缩滤液,用甲苯和二氯甲烷再浓缩得到14.2g标题化合物:1H NMR(400MHz,CDCl3)δ3.52(s,2H),3.75(s,3H),4.0(s,3H),6.7(m,2H),7.15(m,6H)。b)10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-酮
将2-苄基-4-甲氧基苯乙酸(14.2g,0.055m)的苯(120mL)和氯化亚矾(28mL)溶液回流1小时,浓缩。将该酰氯溶于干燥的二氯甲烷(40mL)中,通氩气下,将该溶液滴加到AlCl3(14.7g,0.11mol)的二氯甲烷(600mL)溶液中。室温、通氩气下,将该反应物搅拌2.5小时,然后用冰-水(200mL)猝灭。分层,将有机相顺次用10%NaOH、水、和稀HCl洗涤。将得到的溶液用***(200mL)稀释,用MgSO4干燥,浓缩。将该固体残留物用***/己烷(1∶1)研磨,过滤收集得到9.35g标题化合物:Mp105-106℃;1H NMR(400MHz,CDCl3)δ3.72(s,3H),4.1(s,2H),4.2(s,2H),6.7(d,1H),6.82(s,1H),7.30(m,4H),8.1(d,1H)。
制备19制备(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯a)(±)-3-(3-甲氧基苯基)茚乙酸乙酯
向0℃下的3-(3-甲氧基苯基)茚(4g,18mmol)(根据J.Med.Chem.1981,24,998的方法制备)的THF(15mL)冷的溶液中,用5分钟滴加LiN(TMS)2(20mL,1M的THF液)。在-78℃下,用30分钟将得到的溶液滴加到溴代乙酸乙酯(3.34g,20mmol)的THF(15mL)溶液中。2.5小时后,将该混合液用饱和氯化铵溶液猝灭,分层。将得到的有机层用MgSO4干燥,浓缩得到粗产物,经柱层析(SiO2/2-4%EtOAc/己烷)纯化得到标题化合物(1.1g):1H NMR(400MHz,CDCl3)δ1.30(t,3H),2.50(m,1H),2.85(m,1H),3.85(s,3H),4.0(m,1H),4.20(q,2H),6.6(s,1H),6.9(m,1H),7.2(s,1H),7.35(m,6H)。b)(±)-3-[(3-甲氧基苯甲酰基)]苯基琥珀酸乙酯
将(±)-3-(3-甲氧基苯基)茚乙酸乙酯(1.1g,3.6mmol)的丙酮(30mL)溶液用4%四氧化锇水溶液(0.5mL)处理,然后滴加根据文献方法(J.Org.Chem.1993,58,4745)制备的1.2M Jones试剂(5mL,6mmol)。室温下搅拌过夜后,将该深色反应混合液用异丙醇(2.5mL)猝灭,再加入亚硫酸氢钠(0.9g)和水(30mL)。将该深色产物用乙酸乙酯提取,用盐水洗涤,经MgSO4干燥,浓缩得到固体残留物。用1∶1***/己烷研磨得到0.76g标题化合物:1H NMR(400MHz,CDCl3)δ1.18(t,3H),2.90(m,1H),3.3(m,1H),3.92(s,3H),4.1(q,2H),4.4(m,1H),4.4(d,1H),7.25(m,2H),7.5(m,6H)。c)(±)-3-[(3-甲氧基苯甲基)]苯基琥珀酸乙酯
将(±)-3-[(3-甲氧基苯甲酰基)]苯基琥珀酸乙酯(0.76g,2.1mmol)和10%Pd/C(0.6g)的冰醋酸(35mL)混合溶液在50psi下氢化17小时。将该混合液用celite过滤,将滤饼用乙酸洗涤。浓缩滤液,用甲苯和二氯甲烷再浓缩得到0.65g标题化合物:1H NMR(400MHz,CDCl3)δ1.20(t,3H),2.20(m,1H),3.0(m,1H),3.74(s,3H),4.1(q,2H),4.18(q,2H),4.4(d,1H),6.2(m,2H),7.22(m,6H)。d)(±)-10,11-二氢-3-甲氧基-11-氧代-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
向磁力搅拌下的(±)-3-[(3-甲氧基苯甲基)]苯基琥珀酸乙酯(0.65g,1.9mmol)的干燥二氯甲烷(10mL)溶液中加入DMF(0.2mL)和草酰氯(0.2mL,2.28mmol)。1.5小时后,将该溶液滴加到AlCl3(0.6g,4.5mmol)的干燥二氯甲烷(15mL)混悬液中。2小时后,用冰水猝灭该混合液,分层,将水层用二氯甲烷提取。将合并的有机层用MgSO4干燥,浓缩。残留物经柱层析(SiO2/2-4%EtOAc/己烷)纯化得到标题化合物(0.3g):1H NMR(400MHz,CDCl3)δ1.28(t,3H),2.88(m,1H),3.55(m,1H),3.84(s,3H),3.88(d,1H),4.18(q,2H),4.85(d,1H),4.95(m,1H),5.8(m,2H),7.22(m,4H),8.1(s,1H)。e)(±)-10,11-二氢-3-甲氧基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(±)-10,11-二氢-3-甲氧基-11-氧代-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.3g,0.93mmol)和10%Pd/C(0.3g)的冰醋酸(25mL)混合液在50psi下氢化18小时。将该混合液用celite过滤,用乙酸洗涤。浓缩滤液,用甲苯和二氯甲烷再浓缩得到0.25g标题化合物:1H NMR(400MHz,CDCl3)δ1.28(t,3H),2.60(m,2H),2.90(m,1H),3.30(m,1H),3.80(s,3H),3.85(d,1H),4.18(q,2H),4.30(d,1H),6.70(m,2H),7.0(d,1H),7.22(m,4H)。
制备20制备(±)-10,11-二氢-3-羟基-二苯并[b,f]氧杂庚英-10-乙酸乙酯a)4-甲氧基-2-苯氧基苯乙酮
根据Harris,T.W.等的方法(J.Med.Chem.1982,25(7),855-858),使2-氟-4-甲氧基苯乙酮(1.00g,5.95mmol)与苯酚反应得到标题化合物(1.27g),为油状物:1H NMR(300MHz,CDCl3)δ7.90(d,J=8.8Hz,1H),7.35(m,2H),7.20(m,1H),7.05(m,2H),6.70(dd,J=2.4,8.8Hz,1H),6.35(d,J=2.4Hz,1H),3.75(s,3H),2.61(s,3H)。b)2-(4-甲氧基-2-苯氧基苯基)-1-吗啉-4-基乙-1-硫酮
根据Harris,T.W.等的方法(J.Med.Chem.1982,25(7),855-858),使4-甲氧基-2-苯氧基苯乙酮(1.69g,6.98mmol)、硫(0.36g,11.2mmol)和吗啉(0.98mL,11.2mmol)反应得到标题化合物(1.24g),为白色固体:MS(ES)m/e 344.0(M+H)+c)2-(4-甲氧基-2-苯氧基苯基)乙酸
向2-(4-甲氧基-2-苯氧基苯基)-1-吗啉-4-基乙-1-硫酮(0.35g,1.02mmol)的i-PrOH(15mL)和H2O(15mL)溶液中加入KOH(0.57g,10.2mmol)。将该反应物加热回流18小时,然后冷却至室温,用H2O稀释,用Et2O洗涤。用浓HCl将该水层酸化至pH≈4,用CHCl3提取。将合并的提取液经MgSO4干燥,浓缩得到标题化合物(0.22g),为白色固体。可不经进一步纯化使用:MS(ES)m/e 259.0(M+H)+。d)3-甲氧基二苯并[b,f]氧杂庚英-10-酮
将2-(4-甲氧基-2-苯氧基苯基)乙酸(594mg,2.3mmol)的亚硫酰氯(10mL)溶液加热回流30分钟,然后浓缩至干,将残留物用甲苯再浓缩。将得到的残留物溶于干燥的CH2Cl2(3mL)中,RT、通氩气下,将该溶液滴加到装有AlCl3(673mg,5.06mmol)的干燥CH2Cl2(4mL)混悬液的火焰干燥的烧瓶中。搅拌2.5小时后,将该混合液用CH2Cl2(10mL)稀释,顺次用1.0N NaOH和盐水洗涤。干燥(MgSO4),浓缩,经硅胶快速层析(5%EtOAc/己烷)得到标题化合物(264mg,48%),为淡黄色油状物:1H NMR(300MHz,CDCl3)δ3.80(s,3H),4.02(s,2H),6.74-8.08(m,7H)。e)(±)-10,11-二氢-10-羟基-3-甲氧基二苯并[b,f]氧杂庚英-10-乙酸乙酯
在-78℃、通氩气下,将无水EtOAc(0.94mL,9.6mmol)滴加到装有双(三甲基甲硅烷基)氨化锂(1.0M的THF液,7mL,7mmol)的干燥THF(7mL)溶液的火焰干燥的烧瓶中。0.5小时后,加入TMEDA(2.4mL,16mmol)。再过5分钟后,用3分钟滴加3-甲氧基二苯并[b,f]氧杂庚英-10-酮(760mg,3.2mmol)的THF(2ml)溶液。再用干燥THF(0.4mL)转移。在-78℃至-40℃下,将该反应液搅拌1小时,然后用饱和NH4Cl(10mL)猝灭。将该混合液温至室温,用EtOAc提取。干燥(MgSO4),浓缩,经硅胶快速层析(10%EtOAc/己烷)得到标题化合物,为澄清油状物:1H NMR(300MHz,CDCl3)δ1.14-1.20(t,3H),1.21-1.30(m,1H),2.62-2.68(dd,1H),2.94-3.02(dd,1H),3.24-3.30(dd,1H),3.40-3.46(dd,1H),3.40-3.46(dd,1H),3.78(s,3H),4.08-4.18(m,2H),6.60-7.26(m,6H),7.64-7.68(dd,1H)。f)(±)-10,11-二氢-3-甲氧基二苯并[b,f]氧杂庚英-10-乙酸乙酯
在0℃、通氩气下,将醚合三氟化硼(0.48mL,3.9mmol)加入到(±)-10,11-二氢-10-羟基-3-甲氧基二苯并[b,f]氧杂庚英-10-乙酸乙酯(690mg,1.95mmol)和三乙基硅烷(0.62mL,3.9mmol)的干燥CH2Cl2溶液中。20分钟后,将该反应液用5%NaHCO3猝灭,将该混合液用CH2Cl2提取。干燥(MgSO4),浓缩得黄色油状物。将其溶于无水乙醇(20mL)中,加入10%Pd/C(413mg,0.39mmol)。在Parr氢化装置中,将该混合液在50psi下氢化3小时。通过celite过滤除去催化剂,将滤液浓缩得到标题化合物(523mg,86%),为澄清油状物:1HNMR(300MHz,CDCl3)δ7.18-6.58(m,7H),4.18-4.08(m,2H),3.80(s,3H),3.80-3.74(m,1H),3.40-3.30(dd,1H),2.98-2.84(dd,1H),2.74-2.62(dd,1H),2.60-2.52(m,1H),1.32-1.20(t,3H)。g)(±)-10,11-二氢-3-羟基二苯并[b,f]氧杂庚英-10-乙酸乙酯
在0℃、通氩气下,将(±)-10,11-二氢-3-甲氧基二苯并[b,f]氧杂庚英-10-乙酸乙酯(523mg,1.68mmol)的CH2Cl2(6.8mL)溶液滴加到BBr3的CH2Cl2的***液(1.0M,6.7mL,6.7mmol)中。将该反应液搅拌20分钟然后小心加入CH3OH(7mL)。将该混合液浓缩,残留物经硅胶快速层析(15-20%EtOAc/己烷)得到标题化合物(407mg,89%),为浅黄色油状物:MS(ES)m/e 299(M+H)+。
制备21制备2-[(3-溴代-1-丙基)氨基]-4-甲基吡啶-N-氧化物氢溴酸盐a)2-[(3-溴代-1-丙基)氨基]-4-甲基吡啶-N-氧化物氢溴酸盐
在0℃下,用15-20分钟将SOBr2(5.0mL,64.5mmol)的CH2Cl2(20mL)溶液滴加到2-[(3-羟基-1-丙基)氨基]-4-甲基吡啶-N-氧化物(10.0g,54.87mmol)的CH2Cl2(100mL)溶液中。将该反应液温热至室温,搅拌2小时,然后慢慢加入Et2O(200mL)。从胶状沉淀中倾去溶剂,将该沉淀再用CH2Cl2/Et2O洗涤(数次)。将得到的黄棕色残留物在冰箱中放置过夜固化。收集该固体,用Et2O洗涤得到标题化合物(15.07g),为黄色固体。通过浓缩合并的有机层又得到标题化合物(2.05g),为白色针状物。标题化合物的总收率为17.89g(96%):MS(ES)m/e 245和247(M+H)+。
以下化合物说明从如以上制备中所述的中间体化合物来制备本发明生物活性化合物的方法。
实施例1制备(±)-10,11-二氢-3-[4-(吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸a)4-(2-四氢吡喃基氧基)-1-三丁基甲锡烷基-1-丁炔
用2分钟将正丁基锂的己烷溶液(1.6M,18.8mL,30mmol)连续加入到通氩气0℃下的2-(3-丁炔氧基)四氢-2H-吡喃(4.7mL,30mmol)的干燥THF(60mL)溶液中。0.5小时后,一次全部加入氯化三丁基锡(8.1mL,30mmol);将该反应物温至室温。3小时后,将该反应物用己烷(300mL)稀释,顺次用H2O(2×60mL)、10%KF(2×30mL)和饱和盐水(60mL)洗涤。干燥(Na2SO4),浓缩,用硅胶层析(3%EtOAc/己烷)得到标题化合物(3.58g,27%),为几乎无色油状物:TLC(5%EtOAc/己烷)Rf0.37;1H NMR(400MHz,CDCl3)δ4.66(窄t,1H),3.75-3.96(m,2H),3.49-3.62(m,2H),2.56(app t,2H),1.76-1.91(m,1H),1.65-1.78(m,1H),1.42-1.65(m,10H),1.22-1.41(m,6H),0.82-1.08(m,15H)。b)(±)-10,11-二氢-3-[4-(2-四氢吡喃基氧基)-1-丁炔-1-基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,将(±)-10,11-二氢-3-(三氟甲磺酰氧基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(1.34g,3.13mmol)、4-(2-四氢吡喃基氧基)-1-三丁基甲锡烷基-1-丁炔(1.66g,3.76mmol)、LiCl(398mg,9.39mmol)、双(三苯膦)二氯化钯(110mg,0.094mmol)和无水二氧六环(31mL)的混合物加热回流。1.5小时后,将反应物浓缩除去大部分二氧六环,将残留物溶于Et2O(100mL)中。加入10%KF(50mL),将该混合液充分搅拌0.5小时。除去水层,将Et2O层通过celite和MgSO4混合物过滤。将滤液浓缩,残留物经硅胶层析(10%EtOAc/己烷)得到标题化合物(1.12g,83%),为浅黄色油状物:TLC(20%EtOAc/己烷)Rf0.40;1H NMR(400MHz,CDCl3)δ7.21-7.30(m,1H),7.06-7.20(m,5H),7.00(d,J=7.8Hz,1H),4.69(t,J=3.6Hz,1H),4.31(d,J=15.2Hz,1H),4.11-4.23(m,2H),3.76-3.97(m,4H),3.59-3.68(m,1H),3.48-3.57(m,1H),3.34(dd,J=15.2,4.1Hz,1H),2.97(dd,J=15.2,9.5Hz,1H),2.70(t,J=7.3Hz,2H),2.65(dd,J=15.7,4.8Hz,1H),2.51(dd,J=15.7,9.5Hz,1H),1.78-1.92(m,1H),1.68-1.78(m,1H),1.44-1.68(m,4H),1.27(t,J=7.1Hz,3H);MS(ES)m/e 455(M+Na)+。c)(±)-10,11-二氢-3-[4-(2-四氢吡喃基氧基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
室温、通氢气(50psi)下,在Parr装置中,将(±)-10,11-二氢-3-[4-(2-四氢吡喃基氧基)-1-丁炔-1-基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(1.2g,2.77mmol)、10%Pd/C(0.3g,0.28mmol)和EtOAc(28mL)的混合物振摇。3小时后,将该反应液通过celite过滤,浓缩滤液。硅胶层析(10%EtOAc/己烷)得到标题化合物(1.06g,88%),为无色油状物:TLC(20%EtOAc/己烷)Rf0.51;1H NMR(400MHz,CDCl3)δ7.05-7.20(m,4H),6.92-7.03(m,3H),4.53-4.60(m,1H),4.34(d,J=15.1Hz,1H),4.12-4.26(m,2H),3.80-3.90(m,3H),3.71-3.80(m,1H),3.44-3.53(m,1H),3.35-3.44(m,1H),3.33(dd,J=15.1,4.1Hz,1H),2.95(dd,J=15.1,9.4Hz,1H),2.65(dd,J=15.5,4.9Hz,1H),2.49-2.61(m,3H),1.77-1.90(m,1H),1.45-1.77(m,9H),1.27(t,J=7.1Hz,3H);MS(ES)m/e 459(M+Na)+。d)(±)-10,11-二氢-3-(4-羟基-1-丁基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
室温下,将(±)-10,11-二氢-3-[4-(2-四氢吡喃基氧基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(456.0mg,1.04mmol)和对甲苯磺酸单水合物(60mg,0.31mmol)的无水EtOH(10mL)溶液搅拌。2小时后,将该反应液用5%NaHCO3(1mL)猝灭,浓缩除去EtOH。将残留物用H2O(2mL)稀释,用CH2Cl2提取。干燥(MgSO4),浓缩,硅胶层析(1∶1 EtOAc/己烷)得到标题化合物(342.4mg,93%),为无色油状物:TLC(1∶1 EtOAc/己烷)Rf0.49;1H NMR(250MHz,CDCl3)δ6.85-7.25(m,7H),4.34(d,J=15.1Hz,1H),4.08-4.30(m,2H),3.75-3.95(m,2H),3.53-3.72(m,2H),3.33(dd,J=15.1,4.1Hz,1H),2.95(dd,J=15.1,9.4Hz,1H),2.40-2.75(m,4H),1.45-1.80(m,4H),1.27(t,J=7.1Hz,3H);MS(ES)m/e 353(M+H)+。e)(±)-10,11-二氢-3-[4-(N-苯邻二酰亚氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
室温、通氩气下,将偶氮二甲酸二乙酯(0.2mL,1.26mmol)滴加入(±)-10,11-二氢-3-(4-羟基-1-丁基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.37g,1.05mmol)、三苯膦(0.33g,1.26mmol)和苯邻二甲酰亚胺(0.19g,1.26mmol)的无水THF(10mL)溶液中。23小时后,将该反应液在旋转蒸发器上浓缩。硅胶层析(30%EtOAc/己烷)得到标题化合物(0.35g,70%),为无色油状物:MS(ES)m/e 504.3(M+Na)+。f)(±)-10,11-二氢-3-(4-氨基-1-丁基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
室温下,将肼单水合物(0.11g,2.18mmol)加入到(±)-10,11-二氢-3-[4-(N-苯邻二酰亚氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.35g,0.73mmol)的无水EtOH(10mL)和甲苯(2mL)溶液中。于RT下,将该反应液搅拌17小时,然后过滤,将滤饼用甲苯洗涤。在旋转蒸发器上浓缩得到标题化合物(0.23g,90%),为无色固体:MS(ES)m/e 352.3(M+H)+。g)(±)-10,11-二氢-3-[4-(1-氧代吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将2-氯吡啶-N-氧化物盐酸盐(0.31g,1.88mmol)、(±)-10,11-二氢-3-(4-氨基-1-丁基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.22g,0.63mmol)和NaHCO3(0.26g,3.13mmol)的叔戊醇(6mL)溶液加热回流21小时。将该反应混合液用CH2Cl2(100mL)稀释,过滤,将滤液用旋转蒸发器浓缩。硅胶层析(1∶9∶5 MeOH/CH2Cl2/EtOAc)得到标题化合物(82mg,30%),为黄色油状物:MS(ES)m/e 445.2(M+H)+。h)(±)-10,11-二氢-3-[4-(吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,将(±)-10,11-二氢-3-[4-(1-氧代吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.07g,0.16mmol)、10%Pd/C(0.08g,0.075mmol)、环己烯(0.16mL,1.6mmol)和异丙醇(4mL)混合液加热回流14小时,然后通过celite过滤除去催化剂。将滤饼用异丙醇和MeOH洗涤,将滤液用旋转蒸发器浓缩得到标题化合物(0.046g,69%),为澄清油状物:MS(ES)m/e 429.3(M+H)+。i)(±)-10,11-二氢-3-[4-(吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
于RT下,将(±)-10,11-二氢-3-[4-(吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(46mg,0.11mmol)和1.0N LiOH(0.66mL,0.66mmol)的THF(3mL)和H2O(3mL)混合溶液搅拌。24小时后,将该反应混合液用旋转蒸发器浓缩,残留物用H2O(5mL)稀释。将该溶液冰浴冷却,慢慢加入1.0N AcOH得到白色沉淀。在C-18YMC上层析(含0.1TFA的45%CH3CN/H2O)得到标题化合物(13mg,21%),为白色固体:MS(ES)m/e 401.3(M+H)+。C26H28N2O2·0.75H2O·1.5CF3CO2H分析计算值:C,59.54;H,5.31;N,4.72。实测值:C,59.69;H,5.31;N,4.72。
实施例2制备(±)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-3-[3-(4-乙氧基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(±)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.67g,1.36mmol)、1.0M NaOEt的乙醇液(6.8mL,6.8mmol)和无水乙醇(6.8mL)混合,用预先设置为70℃的油浴加热该混合物。加热10分钟得到暗色溶液,然后移去油浴,在无外部加热下,将该溶液再搅拌5-7分钟。将得到的溶液在冰中冷却,然后用冰醋酸(0.47mL,8.2mmol)猝灭该反应。将该混合液浓缩,再将残留物在CH2Cl2(10mL)和半饱和NH4Cl(10mL)之间分配。分层,将水层用CH2Cl2(2×10mL)提取。将合并的有机层干燥(MgSO4),浓缩,残留物用甲苯再浓缩得到红-橙色油状物。硅胶层析(5%MeOH/CHCl3)得到标题化合物(601.1mg,90%),为黄色油状物:TLC(5%MeOH/CHCl3)Rf0.36;1H NMR(250MHz,CDCl3)δ7.95(d,J=7.1Hz,1H),6.88-7.30(m,6H),6.77(d,J=2.6Hz,1H),6.67(dd,J=8.2,2.6Hz,1H),5.95-6.20(m,2H),4.28(d,J=15.0Hz,1H),4.18(q,J=7.2Hz,2H),4.04(t,J=5.6Hz,2H),3.65-4.00(m,4H),3.46(q,J=6.5Hz,2 H),3.30(dd,J=15.0,4.2Hz,1H),2.93(dd,J=15.0,9.2Hz,1H),2.65(dd,J=15.6,5.0Hz,1H),2.52(dd,J=15.6,9.4Hz,1H),1.95-2.25(m,2H),1.10-1.45(m,6H);MS(ES)m/e 491(M+H)+。b)(±)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,将(±)-10,11-二氢-3-[3-(4-乙氧基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(601.1mg,1.23mmol)、环己烯(1.2mL,12.3mmol)、10%Pd/C(130mg,0.012mmol)和无水乙醇(12.3mL)的混合物加热回流。23.5小时后,将该反应液通过celite热过滤,将滤饼用乙醇洗涤。浓缩滤液,将残留物用甲苯再浓缩。硅胶层析(5%MeOH的1∶1 EtOAc/CHCl3液)得到标题化合物(528.1mg,90%),为亮黄色油状物:TLC(10%MeOH的EtOAc/CHCl3液)Rf0.67;1H NMR(400MHz,CDCl3)δ7.89(d,J=5.8Hz,1H),7.05-7.18(m,4H),6.99(d,J=8.2Hz,1H),6.77(d,J=2.6Hz,1H),6.66(dd,J=8.2,2.6Hz,1H),6.17(dd,J=5.8,2.1Hz,1H),5.86(d,J=2.1Hz,1H),4.73(brt,1H),4.28(d,J=14.9Hz,1H),4.11-4.25(m,2H),4.04(t,J=5.9Hz,2H),3.98(q,J=7.0Hz,2H),3.83(d,J=14.9Hz,1H),3.76-3.85(m,1H),3.43(q,J=6.4Hz,2H),3.30(dd,J=15.0,4.1Hz,1H),2.93(dd,J=15.0,9.2Hz,1H),2.64(dd,J=15.6,4.8Hz,1H),2.52(dd,J=15.6,9.5Hz,1H),2.01-2.11(m,2H),1.37(t,J=7.0Hz,3H),1.27(t,J=7.0Hz,3H);MS(ES)m/e 475(M+H)+。c)(±)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
室温下,将1.0N NaOH(1.7mL,1.7mmol)滴加入(±)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(528.1mg,1.11mmol)的无水乙醇(11mL)溶液中,将该溶液用预先设置为45℃的油浴加热。20小时后,将该反应物浓缩,再将残留物用H2O浓缩。将得到的残留物溶于H2O(10mL)中,过滤。用1.0N HCl将该pH调至7,将该混合液充分搅拌使最初形成的胶状沉淀转化成固体。用玻璃棒和刮匙研磨促进该转化过程。将得到的混合溶液的pH再调至7,收集该固体,用足量的H2O洗涤。将该滤液浓缩,将残留物溶于有少量1.0N NaOH的H2O中。将pH调至7得到少量二次产物。将产物合并,真空干燥(40-50℃)得到标题化合物(453.7mg,82%),为灰白色固体:HPLC(Hamilton PRP-1,含0.1%TFA的45%CH3CN/H2O液)k′=1.32;1H NMR(400MHz,DMSO-d6)δ7.78(d,J=6.6Hz,1H),7.35-7.65(m,1H),7.02-7.22(m,4H),6.97(d,J=8.3Hz,1H),6.82(d,J=2.4Hz,1H),6.68(dd,J=8.3,2.4Hz,1H),6.29(dd,1H),6.15(窄d,1H),4.20(d,J=14.6Hz,1H),3.93-4.12(m,4H),3.89(d,J=14.6Hz,1H),3.60-3.71(m,1H),3.30-3.50(m,2H),3.20(dd,J=15.1,4.1Hz,1H),2.83(dd,J=15.1,10.1Hz,1H),2.60(dd,J=16.0,5.3Hz,1H),2.48(dd,J=16.0,8.9Hz,1H,部分被残留的溶剂信号遮蔽),1.90-2.05(m,2H),1.30(t,J=6.9Hz,3H);MS(ES)m/e 447(M+H)+。C27H30N2O4·1.5HCl分析计算值:C,64.70;H,6.33;N,5.59。实测值:C,64.53;H,6.14;N,5.31。
实施例3制备(±)-10,11-二氢-3-[2-[2-(乙氨基)噻唑-4-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-101乙酸a)(±)-10,11-二氢-3-[2-[2-(乙氨基)噻唑-4-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
室温下,用5分钟将2-(乙氨基)-4-噻唑乙醇(0.33g,1.9mmol)和偶氮二甲酸二乙酯(0.30mL,1.9mmol)的无水DMF(5mL)溶液滴加入(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(296.4mg,1mmol)和三苯膦(525mg,2mmol)的无水DMF(5mL)溶液中。滴加过程中,将该反应物用RT水浴冷却。16小时后,将该反应液浓缩,将残留物用二甲苯(2x)再浓缩。硅胶层析(20%EtOAc/己烷)得到标题化合物(145.0mg,32%),为黄色油状物:TLC(1∶1 EtOAc/己烷)Rf0.60;1H NMR(250MHz,CDCl3)δ7.00-7.30(m,4H),6.98(d,J=8.2Hz,1H),6.77(d,J=2.6Hz,1H),6.68(dd,J=8.2,2.6Hz,1H),6.21(s,1H),5.00-5.25(m,1H),4.04-4.38(m,5H),3.81(d,J=15.1Hz,1H),3.70-3.90(m,1H),3.13-3.40(m,3H),2.99(t,J=6.7Hz,2H),2.92(dd,J=14.9,9.3Hz,1H),2.64(dd,J=15.6,5.0Hz,1H),2.51(dd,J=15.6,9.3Hz,1H),1.27(t,J=7.2Hz,3H);MS(ES)m/e 451(M+H)+。b)(±)-10,11-二氢-3-[2-[2-(乙氨基)噻唑-4-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
将1.0N LiOH(0.32mL,0.32mmol)滴加入0℃下的(±)-10,11-二氢-3-[2-[2-(乙氨基)噻唑-4-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(145.0mg,0.32mmol)的THF(2.4mL)和H2O(0.48mL)溶液中。在0℃下,将得到的粉橙色两相混合液搅拌10分钟,期间颜色渐变为橙黄色,然后温热至室温。1.5小时后,再加入少量水(5滴),然后将该反应物搅拌42小时,再冷却至0℃,用TFA(0.025mL)中和。旋转蒸发除去THF,将得到的油状残留物用0.1%TFA/CH3CN稀释得到均相溶液。ODS层析(梯度:含0.1%TFA的40%CH3CN/H2O液,然后含0.1%TFA的45%CH3CN/H2O液)得到含标题化合物的部分。合并该部分,旋转蒸发除去CH3CN。在0℃下,将得到的含水混合液碱化得到均相溶液。用1.0N HCl小心酸化至pH4-5得到固体沉淀,收集沉淀,用足量H2O洗涤,干燥得到标题化合物(80.9mg,51%),为灰白色固体:HPLC(Hamilton PRP-1,含0.1%TFA的45%CH3CN/H2O液)k′=0.89;1H NMR(400MHz,CD3OD)δ7.02-7.18(m,4H),7.00(d,J=8.3Hz,1H),6.79(d,J=2.6Hz,1H),6.68(dd,J=8.3,2.6Hz,1H),6.45(s,1H),4.26(d,J=14.9Hz,1H),4.20(t,J=6.4Hz,2H),3.87(d,J=14.9Hz,1H),3.68-3.80(m,1H),3.34(q,J=7.3Hz,2H,部分被残留的溶剂信号遮蔽),3.30(dd,1H,被残留的溶剂信号遮蔽),2.99(t,J=6.4Hz,2H),2.92(dd,J=15.0,9.4Hz,1H),2.62(dd,J=15.9,5.0Hz,1H),2.47(dd,J=15.9,9.3Hz,1H),1.27(t,J=7.3Hz,3H);MS(ES)m/e 423(M+H)+。C24H26N2O3S·0.67CF3CO2H分析计算值:C,61.03;H,5.39;N,5.62。实测值:C,61.21;H,5.36;N,5.60。
实施例4制备(S)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,向搅拌的(S)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(35g,118mmol)的干燥THF(1.1L)和干燥DMF(600mL)溶液中加入2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物(29.4g,175mmol)和三苯膦(45.9g,175mmol)。待所有的固体完全溶解后(约1小时),将该反应物用冰浴冷却至0℃,用注射器加入偶氮二甲酸二异丙酯(36.4mL,95%,175mmol)。将该反应物慢慢温热至室温,搅拌18小时。浓缩,经硅胶快速层析(95∶5 CHCl3/MeOH),然后再经硅胶快速层析(80∶20∶5 CHCl3/EtOAc/EtOH)第二次纯化得到标题化合物(37.66g,71%),为浅黄色固体泡沫状物:1H NMR(400MHz,DMSO-d6)δ8.08(dd,J=6.3,1.1Hz,1H),7.29(t,1H),7.19-7.06(m,5H),6.97(d,J=8.3Hz,1H),6.84(d,J=2.5,1H),6.79(dd,J=8.5,1.6Hz,1H),6.69(dd,J=8.3,2.6Hz,1H),6.57(m,1H),4.17(d,J=14.7Hz,1H),4.13-4.07(m,2H),4.00(t,2H),3.91(d,J=14.7Hz,1H),3.66(m,1H),3.39(t,2H),3.19(dd,J=15.1,4.5Hz,1H),2.85(dd,J=15.1,10.0Hz,1H),2.65(dd,J=15.8,5.4Hz,1H),1.99(m,2H),1.18(t,3H);MS(ES)m/e 447.3(M+H)+。b)(S)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
向搅拌的(S)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(37.66g,84mmol)的异丙醇(700mL)溶液中加入10%活性炭负载的钯(18g,16.9mmol,通氩气下预先小心在异丙醇中润湿)和环己烯(85mL,839mmol)。然后在通氩气下,再设置为90℃的油浴中加热该反应物至回流。6小时后,再加入10%活性炭负载的钯(18g,84mmol,通氩气下预先小心在异丙醇中润湿)和环己烯(85mL,839mmol)。再过18小时后,将该反应液通过celite热过滤,将滤饼用1∶1 MeOH/CHCl3(600mL)洗涤。真空浓缩滤液,残留物经硅胶快速层析(95∶5 CHCl3/MeOH)纯化得到标题化合物(29.2g,81%),为浅黄色油状物:1HNMR(400MHz,DMSO-d6)δ7.94(dd,J=5.4,1.9Hz,1H),7.35-7.31(m,1H),7.18(d,J=7.2,1H),7.14-7.06(m,3H),6.97(d,J=8.3Hz,1H),6.83(d,J=2.6,1H),6.68(dd,J=8.3,2.6Hz,1H),6.54(t,1H),6.44(m,2H),4.17(d,J=14.6Hz,1H),4.13-4.02(m,2H),4.00(t,2H),3.91(d,J=14.7Hz,1H),3.66(m,1H),3.35(m,2H),3.19(dd,J=15.1,4.4Hz,1H),2.86(dd,J=15.1,10.1Hz,1H),2.65(dd,J=15.8,5.4Hz,1H),2.55(dd,J=15.8,8.7Hz,1H),1.93(m,2H),1.18(t,3H);MS(ES)m/e 431.4(M+H)+。c)(S)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
向搅拌的(S)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(29.20g,68mmol)的二氧六环(350mL)溶液中加入1.0N NaOH水溶液(110mL,110mmol)。在50℃下的油浴中将该混浊的反应液搅拌24小时,然后将得到的均相溶液用1.0NHCl水溶液(110mL,110mmol)中和。旋转蒸发将该溶液浓缩近干而沉淀出产物。倾出上清液,减压干燥余下的胶状固体,然后再溶于1∶1甲醇/CHCl3中。然后旋转蒸发再浓缩该澄清溶液,真空彻底干燥。将余下的固体用少量水研磨,过滤,真空干燥得到标题化合物(26.85g,94%),为灰白色粉末:HPLC(Hamilton PRP-1,含0.1%TFA的35%CH3CN/H2O液)k′=2.88;1H NMR(400MHz,DMSO-d6)δ7.94(dd,J=4.7,1.6Hz,1H),7.38(m,1H),7.18(d,J=7.3,1H),7.14(d,J=3.9Hz,2H),7.08(m,1H),6.97(d,J=8.4Hz,1H),6.83(d,J=8.6Hz,1H),6.78(brs,1H),6.68(dd,J=8.3,2.6Hz,1H),6.50(d,J=8.3Hz,1H),6.47(dd,1H),4.20(d,J=14.6Hz,1H),4.00(t,2H),3.88(d,J=14.6Hz,1H),3.67(m,1H),3.37(m,1H),3.20(dd,J=15.2,4.4Hz,1H),2.83(dd,J=15.2,10.1Hz,1H),2.60(dd,J=15.9,5.3Hz,1H),2.50(dd,1H),1.95(m,2H);MS(ES)m/e 403.3(M+H)+。C25H26N2O3·H2O分析计算值:C,71.41;H,6.71;N,6.66。实测值:C,71.21;H,6.53;N,6.54。
实施例5制备(±)-10,11-二氢-3-[2-(6-氨基吡啶-2-基)-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-3-[2-(6-氨基吡啶-2-基)-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
室温下,将6-氨基-2-吡啶基乙醇(0.23g,1.68mmol)和偶氮二甲酸二乙酯(0.26mL,1.68mmol)的无水DMF(5mL)溶液滴加入(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯和三苯膦(0.48g,1.82mmol)的无水DMF(5mL)溶液中。1小时后,将该反应液浓缩,残留物经硅胶快速层析(1∶1 EtOAc/己烷)纯化得到标题化合物(0.030g):MS(ES)m/e 417(M+H)+b)(±)-10,11-二氢-3-[2-(6-氨基吡啶-2-基)-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
室温下,将(±)-10,11-二氢-3-[2-(6-氨基吡啶-2-基)-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.030g,0.072mmol)和1.0N NaOH(0.14mL,0.14mmol)的MeOH(2mL)溶液搅拌过夜,然后浓缩。将残留物溶于水中,用1.0N HCl调节溶液pH至7。浓缩,经C-18键合洗脱柱层析(10∶9∶1 CH3CN/H2O/TFA)得到标题化合物(0.013g):MS(ES)m/e 389(M+H)+
实施例6制备(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(R)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
室温、通氩气下,用10分钟将2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物(0.70g,4mmol)和偶氮二甲酸二乙酯(0.65mL,4mmol)的无水DMF(20mL)溶液滴加到(R)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.45g,2mmol)和三苯膦(1.2g,4mmol)的无水DMF(8mL)溶液中。23.5小时后,旋转蒸发浓缩该反应液,残留物用二甲苯再浓缩而除去残留的DMF。硅胶层析(1-4%CH3OH/CH2Cl2)得到标题化合物(0.50g,74%),为黄色油状物:MS(ES)m/e 447(M+H)+。b)(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(R)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.5g,1mmol)、10%Pd/C(0.25g,0.2mmol)、环己烯(2mL,20mmol)和异丙醇(10mL)混合液加热回流18小时,然后通过celite过滤除去催化剂。硅胶层析(0.5-2%CH3OH/CH2Cl2)得到标题化合物(0.4g,83%),为亮黄色油状物:MS(ES)m/e 431(M+H)+。c)(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
将(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.4g,93mmol)和1.0N NaOH(1.1mL,1.1mmol)的无水EtOH(10mL)混合液在设置为50℃下的油浴中温热。18小时后,将该反应液旋转蒸发浓缩,将残留物溶于H2O中。将该水溶液用3N HCl调节至pH4,收集固体沉淀,用H2O洗涤。在40℃下高真空干燥该物质得到标题化合物(0.36g,96%),为近无色固体:[α]D+50.8°(c=0.12,CH3OH);MS(ES)m/e 403(M+H)+。C25H26N2O3·0.5H2O分析计算值:C,72.97;H,6.61;N,6.80。实测值:C,73.09;H,6.38;N,6.58。
实施例7制备(S)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(a)中的方法,但用6-(甲氨基)-2-吡啶基乙醇代替2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物并用(S)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,经硅胶层析(0.2-2%MeOH/CH2Cl2)得到标题化合物,为无色油状物:MS(ES)m/e 431.2(M+H)+。b)(S)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
将(S)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(80mg,0.18mmol)溶于THF(4mL)中,加入LiOH·H2O(35mg,0.84mmol)的H2O(4mL)溶液。RT下,将该溶液搅拌72小时,然后用***(10mL)稀释。倾去上清液,将该固体混溶于H2O中。用3N HCl小心酸化至pH4得到标题化合物,为白色固体:MS(ES)403(M+H)+。C25H26N2O3·0.75H2O分析计算值:C,72.18;H,6.66;N,6.73。实测值:C,72.44;H,6.52;N,6.71。
实施例8制备(±)-10,11-二氢-3-[3-(3,4,5,6-氢嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-3-[3-(4-硝基苄氧基羰基)氨基-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(a)中的方法,但用3-(4-硝基苄氧基羰基氨基)-1-丙醇代替2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物并用(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物,为琥珀色油状物:MS(ES)533.3(M+H)+。b)(±)-10,11-二氢-3-(3-氨基-1-丙氧基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
在H2(48psi)下,将(±)-10,11-二氢-3-[3-(4-硝基苄氧基羰基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(1.6g,3mmol)、10%Pd/C(0.8g,1mmol)和乙醇(50mL)混合液振摇3小时,然后通过celite过滤除去催化剂。将滤液浓缩得到标题化合物(1.2g,100%),为黄色油状物:MS(ES)348.2(M+H)+c)(±)-10,11-二氢-3-[3-(嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,将(±)-10,11-二氢-3-(3-氨基-1-丙氧基)-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.4g,1mmol)、碳酸氢钠(0.5g,6mmol)、2-溴代嘧啶(0.34g,2mmol)和乙醇(10mL)混合液加热回流18小时。然后将该溶液倾析,浓缩。残留物经硅胶层析(0.2-2%MeOH/CH2Cl2)纯化得到标题化合物(0.17g,34%),为浅黄色油状物:MS(ES)432.3(M+H)+。d)(±)-10,11-二氢-3-[3-(3,4,5,6-四氢嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
在H2(48psi)下,将(±)-10,11-二氢-3-[3-(嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.17g,0.38mmol)、10%Pd/C(0.085g,0.08mmol)、4M HCl的二氧六环(0.1mL,0.4mmol)和乙醇(5mL)混合液振摇6小时,然后通过celite过滤除去催化剂。将滤液浓缩得到标题化合物(0.19g),为黄色油状物:MS(ES)436.3(M+H)+。e)(±)-10,11-二氢-3-[3-(3,4,5,6-四氢嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
室温下,将(±)-10,11-二氢-3-[3-(3,4,5,6-四氢嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.17g,0.36mmol)、LiOH·H2O(0.042g,1mmol)、THF(3mL)和H2O(10mL)的溶液搅拌20小时,然后浓缩。将残留物溶于水中,用3N HCl将该溶液酸化至pH4。将得到的溶液在冰箱中放置过夜,从固体中倾去上清液。真空干燥该固体得到标题化合物(0.145g,91%),为褐色固体:MS(ES)408.3(M+H)+。C24H29N3O3·1.3HCl分析计算值:C,63.37;H,6.71;N,9.23。实测值:C,63.67;H,6.84;N,9.46。
实施例9制备(±)-10,11-二氢-3-[3-(异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-3-[3-(1-氧代异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(a)中的方法,但用1-[(3-羟基-1-丙基)氨基]-异喹啉-N-氧化物代替2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物并用(±)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,制备标题化合物,为浅黄色油状物:MS(ES)m/e 497.2(M+H)+。b)(±)-10,11-二氢-3-[3-(异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(b)中的方法,但用(±)-10,11-二氢-3-[3-(1-氧代异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,制备标题化合物,为澄清油状物:MS(ES)m/e481.3(M+H)+。c)(±)-10,11-二氢-3-[3-(异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例6(c)中的方法,但用(±)-10,11-二氢-3-[3-(异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,制备标题化合物,为琥珀色固体:MS(ES)m/e 453.2(M+H)+。C29H28N2O3·1.3TFA·0.25H2O分析计算值:C,62.71;H,4.96;N,4.63。实测值:C,62.45;H,4.92;N,4.41。
实施例10制备(±)-10,11-二氢-3-[3-[4-(乙硫基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-3-[3-[4-(乙硫基)-1-氧代吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(±)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(300mg,0.61mmol)和硫代乙醇钠(145mg,1.22mmol)的DMF(5mL)溶液加热至70℃3小时。旋转蒸发除去溶剂,残留物经硅胶层析(2-6%CH3OH/CH2Cl2)纯化得到标题化合物(90mg),为橙黄色油状物:MS(ES)m/e 507.3(M+H)+。b)(±)-10,11-二氢-3-[3-[4-(乙硫基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(±)-10,11-二氢-3-[3-[4-(乙硫基)-1-氧代吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(60mg,0.119mmol)、Fe粉(70mg)和冰醋酸(2mL)混合液加热至100℃1.5小时。将混合液冷却至RT,用H2O和EtOAc稀释,用固体Na2CO3将pH调节至7-8。分层,将水层用EtOAc提取。将合并的有机层用H2O洗涤,干燥(MgSO4),浓缩得到标题化合物(60mg),为黄色油状物:MS(ES)m/e 491.3(M+H)+。c)(±)-10,11-二氢-3-[3-[4-(乙硫基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例6(c)中的方法,但用(±)-10,11-二氢-3-[3-[4-(乙硫基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,制备标题化合物,为黄色:1H NMR(400MHz,DMSO-d6)δ7.77-7.76(d,1H),7.17-7.15(d,1H),7.13-7.12(d,2H),7.08-7.07(m,1H),6.96-6.94(d,1H),6.81-6.80(s,1H),6.68-6.67(d,1H),6.52(s,1H),6.35-6.33(d,2H),6.30(s,1H),4.20-4.16(d,1H),3.99-3.96(t,2H),3.89-3.85(d,1H),3.65-3.63(m,1H),3.36-3.32(m,2H),3.22-3.15(m,1H),2.96-2.90(m,2H),2.85-2.78(m,1H),2.62-2.56(m,2H),1.94-1.90(m,2H),1.26-1.22(t,3H);MS(ES)m/e 463.4(M+H)+。
实施例11制备(±)-10,11-二氢-2-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-2-甲基-3-[3-[N-(叔丁氧基羰基)-N-(1-氧代吡啶-2-基)氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,将NaH(60%分散在矿油中,0.14g,0.37mmol)加入到(±)-10,11-二氢-3-羟基-2-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(100mg,0.32mmol)的DMSO(2mL)溶液中,于RT下,将该反应物搅拌0.5小时。然后滴加2-[N-(3-甲磺酰氧基-1-丙基)-N-(叔丁氧羰基)氨基]吡啶-N-氧化物(160mg,0.4mmol)的DMSO(1mL)溶液。于RT、通氩气下,将该反应物搅拌18小时,然后用水(20mL)猝灭该反应,用EtOAc提取。干燥(MgSO4),浓缩,经硅胶层析(1%MeOH/CH2Cl2)得到标题化合物(85mg,42%),为无色油状物:MS(ES)m/e 561.3(M+H)+。b)(±)-10,11-二氢-2-甲基-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将TFA(0.16g,1.4mmol)滴加到(±)-10,11-二氢-2-甲基-3-[3-[N-(叔丁氧基羰基)-N-(1-氧代吡啶-2-基)氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(80mg,0.14mmol)的干燥CH2Cl2(3mL)溶液中。将该反应物搅拌5小时,然后旋转蒸发浓缩得到标题化合物(60mg,43%),为无色油状物:MS(ES)m/e 461.1(M+H)+。c)(±)-10,11-二氢-2-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(b)中的方法,但用(±)-10,11-二氢-2-甲基-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,制备标题化合物,为灰白色固体:MS(ES)m/e417.3(M+H)+。d)(±)-10,11-二氢-2-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例6(c)中的方法,但用(±)-10,11-二氢-2-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物,为灰白色固体:1HNMR(400MHz,CDCl3)δ7.75(d,1H),7.65(t,1H),7.15(m,3H),7.05(m,1H),6.83(s,1H),6.7(d,1H),6.65(m,1H),6.60(s,1H),4.25(d,J=15.1Hz,1H),4.05(t,2H),3.80(m,1H),3.75(d,J=15.1Hz,1H),3.50(t,2H),3.25(dd,1H),2.85(dd,1H),2.68(dd,1H),2.60(dd,1H),2.15(t,2H),2.10(s,3H);MS(ES)m/e 417.3(M+H)+。
实施例12制备(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(a)中的方法,但用(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,经硅胶层析(梯度:1∶1EtOH∶己烷,然后EtOH,然后20%MeOH/CH2Cl2,然后30%MeOH/CH2Cl2)得到标题化合物:MS(ES)m/e 522.3(M+H)+。b)(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(b)中的方法,但用(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,硅胶层析(10%MeOH/CH2Cl2)后得到标题化合物:MS(ES)m/e 506.2(M+H)+。c)(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例6(c)中的方法进行皂化反应,但用(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯。将该反应物用冰醋酸酸化,将粗产物经XAD-2树脂层析脱盐得到标题化合物,为白色固体:MS(ES)m/e 478.3(M+H)+。C30H36FN3O5·1.25H2O分析计算值:C,64.32;H,6.92;N,7.50 。实测值:C,63.87;H,6.47;N,7.96。
实施例13制备(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[3-(4-甲基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
于RT、通氩气下,用10分钟将2-[(3-羟基-1-丙基)氨基]-4-甲基吡啶-N-氧化物(1.72g,9.45mmol)和偶氮二甲酸二乙酯(1.49mL,9.45mmol)的无水DMF(50mL)溶液滴加到(S)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(1.4g,4.72mmol)和三苯膦(2.60g,9.92mmol)的无水DMF(50mL)溶液中。19小时后,将该反应液旋转蒸发浓缩,将残留物用二甲苯再浓缩除去残留的DMF。硅胶层析(梯度:30%EtOAc/己烷(0.5L),然后EtOAc(1L),然后5%MeOH/CHCl3)得到标题化合物(1.31g,60%),为黄色油状物:MS(ES)m/e 461.3(M+H)+。b)(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,将(S)-10,11-二氢-3-[3-(4-甲基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.86g,1.87mmol)、10%Pd/C(0.86g,0.81mmol)、环己烯(1.89mL,18.7mmol)和异丙醇(20mL)混合液加热回流19小时,然后通过celite过滤除去催化剂。硅胶层析(1∶9∶10 MeOH/CH2Cl2/EtOAc)得到标题化合物(0.65g,78%),为澄清油状物:MS(ES)m/e 445.2(M+H)+。c)(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
将(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(2.08g,4.69mmol)和1.0N NaOH(7.0mL,7.0mmol)的无水EtOH(45mL)混合液用设置为45℃的油浴加热。18小时后,将该反应液旋转蒸发浓缩,用1.0N HCl将pH调节至7。收集固体沉淀,用H2O洗涤。干燥过夜得到标题化合物(1.61g,82%),为近无色固体:MS(ES)m/e 417.4(M+H)+。C26H28N2O3·1.0H2O分析计算值:C,71.87;H,6.96;N,6.45。实测值:C,71.63;H,6.96;N,6.30。
实施例14制备(S)-10,11-二氢-3-[3-[4-(2-丙氧基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[3-[4-(2-丙氧基)-1-氧代吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸异丙酯
将(S)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.2g,0.4mmol)和异丙醇钠(0.067g,0.8mmol)的异丙醇(5mL)混合液在80℃下加热3.5小时,然后再加入异丙醇钠(0.05g,0.6mmol),于RT下,将该反应物搅拌过夜。浓缩,硅胶层析(梯度:5%-15%MeOH/CH2Cl2)得到标题化合物(0.106g,52%),为亮棕色油状物:MS(ES)519.3(M+H)+。b)(S)-10,11-二氢-3-[3-[4-(2-丙氧基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸异丙酯
根据实施例13(b)中的方法,但用(S)-10,11-二氢-3-[3-[4-(2-丙氧基)-1-氧代吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸异丙酯代替(S)-10,11-二氢-3-[3-(4-甲基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,硅胶层析(5%MeOH/CH2Cl2)后得到标题化合物,为微黄色油状物:MS(ES)503.4(M+H)+。c)(S)-10,11-二氢-3-[3-[4-(2-丙氧基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例13(c)中的方法,但用(S)-10,11-二氢-3-[3-[4-(2-丙氧基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸异丙酯代替(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物,为白色粉末:MS(ES)461.3(M+H)+。C28H32N2O4·0.96HCl分析计算值:C,67.86;H,6.70;N,5.65。实测值:C,68.26;H,6.86;N,5.25。
实施例15制备(S)-10,11-二氢-3-[3-(4-氯吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[3-(4-氯-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(S)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.47g,0.96mmol)的乙酰氯(7mL,98mmol)溶液加热回流1小时。将该反应混合液倒入冰(50g)中,用饱和NaHCO3(注意:剧烈冒泡!)将pH调至8.0。将该混合液用CH2Cl2(2×100mL)提取,将合并的有机层顺次用H2O(50mL)和盐水(50mL)洗涤。干燥(MgSO4),浓缩得到标题化合物:MS(ES)481.2(M+H)+。b)(S)-10,11-二氢-3-[3-(4-氯吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(S)-10,11-二氢-3-[3-(4-氯-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.13g,0.27mmol)和2.0M PCl3的CH2Cl2(8mL,16mmol)的混合液加热回流22小时。将该反应混合液冷却,倒入冰(200g)中,用40%NaOH将pH调至12。用CH2Cl2(2×100mL)提取,干燥(MgSO4),浓缩,硅胶层析(4%MeOH/CH2Cl2)得到标题化合物(93mg,74%),为亮黄色油状物:MS(ES)465.3(M+H)+。c)(S)-10,11-二氢-3-[3-(4-氯吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例13(c)中的方法,但用(S)-10,11-二氢-3-[3-(4-氯吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物,为灰白色粉末:MS(ES)437.2(M+H)+。C25H25N2O3·1.0HCl分析计算值:C,63.43;H,5.54;N,5.92。实测值:C,63.11;H,5.82;N,5.62。
实施例16制备(S)-10,11-二氢-3-[3-[4-(二甲氨基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[3-(4-氯-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(±)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.47g,0.96mmol)的乙酰氯(7mL,98mmol)溶液加热回流1小时。将该反应混合液倒入冰(50g)中,用饱和NaHCO3将pH调至8.0(注意:剧烈冒泡!)。将该混合液用CH2Cl2(2×100mL)提取,将合并的有机层顺次用H2O(50mL)和盐水(50mL)洗涤。干燥(MgSO4),浓缩得到粗品标题化合物,不经进一步纯化直接进行下一步反应:MS(ES)481.3(M+H)+。b)(S)-10,11-二氢-3-[3-[4-(二甲氨基)-1-氧代吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
将(S)-10,11-二氢-3-[3-(4-氯-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(0.96mmol)和2.0M二甲胺的MeOH溶液(3mL,6mmol)的混合液加热回流16小时。浓缩,硅胶层析(7%MeOH/CH2Cl2)得到标题化合物(0.049g,10%),为亮棕色粉末:MS(ES)490.3(M+H)+。也从层析纯化中回收未变化的(S)-10,11-二氢-3-[3-(4-氯-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯。c)(S)-10,11-二氢-3-[3-[4-(二甲氨基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例13(b)中的方法,但用(S)-10,11-二氢-3-[3-[4-(二甲氨基)-1-氧代吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(S)-10,11-二氢-3-[3-(4-甲基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,硅胶层析(8%MeOH/CH2Cl2)后得到标题化合物,为白色粉末:MS(ES)474.3(M+H)+。d)(S)-10,11-二氢-3-[3-[4-(二甲氨基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例13(c)中的方法,但用(S)-10,11-二氢-3-[3-[4-(二甲氨基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物,为白色粉末:MS(ES)446.2(M+H)+。C27H31N3O3·0.5H2O·10HCl分析计算值:C,66.04;H,6.77;N,8.56。实测值:C,65.96;H,6.60;N,8.26。
实施例17制备(S)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[3-(4-乙氧基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例2(a)中的方法,但用(S)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(496.9mg,1.01mmol)代替(±)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,并在置换反应中使用0.53M NaOEt(4.0mL,2.12mmol)和无水乙醇(10mL),制备标题化合物(456.2mg,92%):MS(ES)m/e 491(M+H)+。b)(S)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例2(b)中的方法,但用(S)-10,11-二氢-3-[3-(4-乙氧基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(456.2mg,0.93mmol)代替(±)-10,11-二氢-3-[3-(4-乙氧基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,制备标题化合物(475.2mg,定量):MS(ES)m/e 475(M+H)+。c)(S)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
将1.0N NaOH(2.0mL,2.0mmol)加入到(S)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(475.2mg,1.0mmol)的无水乙醇(10mL)溶液中,用油浴将该溶液加热至50℃。20小时后,将该反应液浓缩,冰浴将该残留物水溶液冷却至0℃。搅拌下慢慢加入1.0N HCl水溶液(2.0mL,2.0mmol)。不透明固体残留物沉淀,用烧结玻璃漏斗收集。在真空干燥器内干燥过夜得到标题化合物(452.6mg,83%):MS(ES)m/e 447(M+H)+。C27H30N2O4·0.20H2O·1.75HCl分析计算值:C,63.10;H,6.30;N,5.45。实测值:C,63.10;H,5.98;N,5.38。
实施例18制备(±)-10,11-二氢-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-7-氟-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(a)中的方法,但用(±)-10,11-二氢-7-氟-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,经硅胶层析(梯度:1∶1 EtOAc/己烷,然后EtOAc,然后4%MeOH/CH2Cl2)后得到标题化合物,为无色油状物:MS(ES)m/e465.3(M+H)+。b)(±)-10,11-二氢-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(b)中的方法,但用(±)-10,11-二氢-7-氟-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物:MS(ES)m/e 449.2(M+H)+。c)(±)-10,11-二氢-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例6(c)中的方法,但用(±)-10,11-二氢-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物:MS(ES)m/e 421.1(M+H)+。C25H25FN2O3·0.5H2O分析计算值:C,69.99;H,6.10;N,6.52。实测值:C,69.86;H,5.90;N,6.35。
实施例19制备(±)-10,11-二氢-6-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(±)-10,11-二氢-6-甲基-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(a)中的方法,但用(±)-10,11-二氢-3-羟基-6-甲基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,经硅胶层析(梯度:1∶1 EtOAc/己烷,然后EtOAc,然后4%MeOH/CH2Cl2)得到标题化合物,为无色油状物:MS(ES)m/e461.3(M+H)+。b)(±)-10,11-二氢-6-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
根据实施例6(b)中的方法,但用(±)-10,11-二氢-6-甲基-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,经硅胶层析(1%MeOH/CH2Cl2)得到标题化合物:MS(ES)m/e 445.3(M+H)+。c)(±)-10,11-二氢-6-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
根据实施例6(c)中的方法,但用(±)-10,11-二氢-6-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯代替(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯,得到标题化合物,为白色固体:MS(ES)m/e 417.3(M+H)+。C26H28N2O3·1.25H2O分析计算值:C,71.13;H,7.02;N,6.38。实测值:C,71.33;H,6.67;N,6.01。
实施例20制备(S)-10,11-二氢-3-[3-(4-氨基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)(S)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
在0℃、通氩气下,将偶氮二甲酸二异丙酯(1.7mL,8mmol)的THF(10mL)溶液滴加到(S)-10,11-二氢-3-羟基-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(426.5mg,1.5mmol)、2-[(3-羟基-1-丙基)氨基]-4-硝基吡啶-N-氧化物(1.7g,8mmol)和三苯膦(2.5g,8mmol)的无水DMF(20mL)溶液中。在0℃下将该黄色溶液保持10分钟,然后温热至室温。23小时后,将该反应液浓缩。硅胶层析(梯度:30-100%EtOAc/己烷)得到标题化合物(2.7g,81%),为橙色泡沫状物:MS(ES)m/e 491.8(M+H)+。b)(S)-10,11-二氢-3-[3-(4-氨基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
通氩气下,将(S)-10,11-二氢-3-[3-(4-硝基-1-氧代吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(2.7g,6mmol)、环己烯(6mL,60mmol)、10%Pd/C(1.2g,1.10mmol)和异丙醇(30mL)混合液加热回流20.5小时,然后通过celite热过滤。将滤饼用热EtOAc洗涤,将合并的滤液浓缩。残留物经硅胶层析(5%MeOH/CHCl3)得到标题化合物(2.4g,98%),为无色泡沫状物:MS(ES)m/e 445.9(M+H)+。c)(S)-10,11-二氢-3-[3-(4-氨基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
于RT下,将(S)-10,11-二氢-3-[3-(4-氨基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯(2.4g,5mmol)、LiOH H2O(0.3g,7mmol)、THF(30mL)和H2O(10mL)混合液搅拌48小时,然后浓缩。将残留物用H2O稀释,用Et2O提取。弃去Et2O层。真空微微加热下搅拌水层除去残留的有机溶剂,然后过滤。在RT下,将得到的水溶液搅拌,期间用1.0N HCl慢慢及小心地将pH调节至5.5-6.0。将该混合液搅拌0.5小时,然后抽滤收集固体,用足量的H2O洗涤。在60℃下真空干燥得到标题化合物(1.0g,42%),为玻璃状固体:MS(ES)m/e 417.7(M+H)+。C25H27N3O3·1.4HCl分析计算值(468.554):C,64.08;H,6.11;N,8.97。实测值:C,64.16;H,6.20;N,8.71。
实施例21制备(±)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]二苯并[b,f]氧杂庚英-10-乙酸a)(±)-10,11-二氢-3-[3-(4-甲基-1-氧代吡啶-2-基氨基)-1-丙氧基]二苯并[b,f]氧杂庚英-10-乙酸乙酯
RT、通氩气下,将(±)-10,11-二氢-3-羟基二苯并[b,f]氧杂庚英-10-乙酸乙酯(257mg,0.86mmol)、2-[(3-溴-1-丙基)氨基]-4-甲基吡啶-N-氧化物氢溴酸盐(308mg,0.94mmol)、NaOH片(110mg,2.75mmol)和CH3CN(4mL)混合液搅拌过夜。过滤该混合液,固体用CH3CN洗涤。将该滤液浓缩,残留物经硅胶快速层析(1-2.5%CH3OH/CH2Cl2)得到标题化合物(190mg,48%)为白色泡沫:MS(ES)m/e 462.6(M+H)+。b)(±)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-二苯并[b,f]氧杂庚英-10-乙酸乙酯
将(±)-10,11-二氢-3-[3-(4-甲基-1-氧代吡啶-2-基氨基)-1-丙氧基]二苯并[b,f]氧杂庚英-10-乙酸乙酯(183mg,0.4mmol)、10%Pd/C(85mg,0.08mmol)、环己烯(810mg,8mmol)和异丙醇(4mL)混合液加热回流过夜。通过celite过滤除去催化剂,将滤饼用***洗涤,浓缩滤液得到标题化合物(122mg,68%),为橙清油状物:MS(ES)m/e446.9(M+H)+。c)(±)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-二苯并[b,f]氧杂庚英-10-乙酸
将(±)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-二苯并[b,f]氧杂庚英-10-乙酸乙酯(119mg,0.27mmol)和0.991 NNaOH(0.545mL,0.54mmol)的无水EtOH(2mL)混合液在设置为45℃的油浴中加热。20小时后,将该反应液旋转蒸发浓缩,将残留物溶于H2O(1.5mL)中。将该溶液过滤除去不溶物质,将滤液通过滴加1.0N HCl(0.54mL,0.54mmol)小心中和。收集沉淀,高真空下干燥得到标题化合物(68mg,58%),为白色固体:MS(ES)m/e 418.9(M+H)+。C25H26N2O4·0.45HCl分析计算值:C,69.05;H,6.13;N,6.44。实测值:C,69.25;H,6.27;N,6.16。
实施例22制备(±)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-二苯并[b,f]氧杂庚英-10-乙酸a)(±)-10,11-二氢-3-[2-[6-(N-叔丁氧基羰基)-N-甲氨基]吡啶-2-基]-1-乙氧基]二苯并[b,f]氧杂庚英-10-乙酸乙酯
于RT、通氩气下,用10分钟将6-[N-(叔丁氧基羰基)-N-甲氨基]-2-吡啶基乙醇(397mg,1.58mmol)和偶氮二甲酸二异丙酯(0.31mL,1.58mmol)的无水CH2Cl2(8mL)溶液滴加到(±)-10,11-二氢-3-羟基二苯并[b,f]氧杂庚英-10-乙酸乙酯(186mg,0.63mmol)和三苯膦(413mg,1.58mmol)的无水CH2Cl2(3.2mL)溶液中。22小时后,将该反应液旋转蒸发浓缩,残留物经硅胶快速层析(2-13%EtOAc/己烷)得到标题化合物(146mg,44%),为澄清油状物:MS(ES)m/e 533.0(M+H)+b)(±)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-二苯并[b,f]氧杂庚英-10-乙酸乙酯
将4N HCl的二氧六环液(1.3mL,5.2mmol)滴加到(±)-10,11-二氢-3-[2-[6-(N-叔丁氧基羰基)-N-甲氨基]吡啶-2-基]-1-乙氧基]-二苯并[b,f]氧杂庚英-10-乙酸乙酯(140mg,0.26mmol)的CH2Cl2(1.3mL)溶液中。12小时后,将该混合液浓缩,残留物用***研磨得到标题化合物,为白色固体:MS(ES)m/e 432.9(M+H)+。c)(±)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-二苯并[b,f]氧杂庚英-10-乙酸
将(±)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-二苯并[b,f]氧杂庚英-10-乙酸乙酯(0.26mmol)和0.991N NaOH(0.525mL,0.52mmol)的无水EtOH(2mL)混合液在设置为50℃的油浴中加热。20小时后,将该反应液旋转蒸发浓缩,将残留物溶于H2O(1.5mL)中。将该溶液过滤除去不溶物质,将滤液通过滴加1.0N HCl小心中和。收集沉淀,高真空干燥得到标题化合物(72mg,两步30%),为灰白色固体:MS(ES)m/e 405.0(M+H)+。C24H24N2O4·1.25HCl·0.25H2O分析计算值:C,63.42;H,5.71;N,6.16。实测值:C,63.35;H,5.9;N,6.16。
实施例23制备(S)-10,11-二氢-3-[3-(2-氨基吡啶-4-基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸a)3-(2-氨基吡啶-4-基)丙-1-醇
用45分钟将根据WO94/14776制备的3-(2-氨基吡啶-4-基)丙酸盐酸盐(0.73g,3.60mmol)的THF(10mL)混悬液加入到0℃下的氢化铝锂(12mL,12mmol,1M的THF液)中。移去冰浴,RT下将该反应物搅拌4.5小时。将该反应物冷却至0℃,用甲苯(22mL)稀释,顺次加入H2O(0.86mL)和NaF(1.54g)猝灭。在0℃下将得到的混悬液搅拌45分钟。将该反应混合液过滤,沉淀用另外的10%MeOH的CHCl3液洗涤。将合并的滤液减压浓缩。快速层析(10%MeOH/CHCl3,硅胶)得到0.25g所要求的物质,为澄清油状物:MS(ES+)m/z 152.7[M+H]+。b)(S)-10,11-二氢-3-[3-(2-氨基吡啶-4-基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸乙酯
0℃下,将实施例1(a)(0.23g,1.51mmol)和偶氮二甲酸二异丙酯(0.29mL,1.50mmol)的CH2Cl2(7.5mL)溶液滴加到三苯膦(0.39g,1.50mmol)和2-[(10S)-3-羟基-10,11-二氢-5H-二苯并[a,d]环庚烯-10-基]乙酸乙酯(0.30g,1.00mmol)的CH2Cl2(5mL)溶液中。移去冰浴,将该反应液升至室温。18小时后,减压除去溶剂。快速层析(50%EtOAc/己烷至100%EtOAc,硅胶)得到0.32g含有所要求产物的物质。快速层析(75-90%EtOAc/己烷,硅胶)二次纯化得到0.23g所要求的物质:MS(ES+)m/z 430.9[M+H]+。c)(S)-10,11-二氢-3-[3-(2-氨基吡啶-4-基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸
将实施例1(b)化合物(0.22g,0.50mmol)溶于1N NaOH(0.77mL,0.77mmol)、EtOH(3mL)和THF(3mL)中。在50℃将该反应物加热18小时后,减压除去溶剂。将残留物溶于H2O(4mL)中,过滤。将该滤液用30%TFA的H2O溶液酸化,收集得到的沉淀。制备HPLC(Hamilton PRP-1,3%CH3CN/H2O-0.1%TFA)得到10mg所要求的物质,为吸湿性固体:MS(ES+)m/z 402.6[M+H]+
实施例24非肠道单位剂型组合物
按如下制备含有20mg实施例1化合物的作为无菌干燥粉末的制剂:将20mg该化合物溶于15mL蒸馏水中。在无菌条件下,将该溶液过滤到25mL多剂量安瓿中,冷冻干燥。将该粉末通过加入20mL 5%的葡萄糖水溶液(D5W)复制成静脉内或肌内注射剂。因此由注射体积确定该剂量。其后的稀释液可通过加入计量体积的该剂量单位至另一体积的供注射D5W中制成,或可将计量的剂量加入到另一分散该药物的装置中,如供IV滴注或其它注射-输注***的瓶或袋中。
实施例25口服剂型单位组合物
口服胶囊可通过将50mg实施例1化合物与75mg乳糖和5mg硬脂酸镁混合及研磨制备。筛选得到的粉末,然后填充于硬明胶胶囊中。
实施例26口服剂型单位组合物
口服片剂可通过将20mg蔗糖、150mg硫酸钙二水合物和50mg实施例1化合物与10%明胶溶液混合及制粒来制备。将该湿颗粒过筛,干燥,与10mg淀粉、5mg滑石粉和3mg硬脂酸混合;然后压制成片。
以上所述完全公开如何制备和使用本发明。但是,本发明不限于以上所述的特定实施例,但包括以下权利要求书范围内其所有的改变。此处引用的各种参考杂志、专利和其它出版物包括该技术的条件,如完全呈现一样结合到本专利中作为参考。
Claims (38)
2.根据权利要求1的化合物,其中Y是:其中R′是H、C1-4烷基、OC1-4烷基、SC1-4烷基、NR″R″或Cl,R″各自独立为H或C1-4烷基。
3.根据权利要求1的化合物,其中Y是:其中R″各自是H或C1-4烷基。
4.根据权利要求1的化合物,其中Y是:其中R″各自独立是H或C1-4烷基,s是1。
6.根据权利要求1的化合物,其中Y是:其中R″是H或C1-4烷基。
7.根据权利要求1的化合物或其药学上可接受的盐:(±)-10,11-二氢-3-[2-(6-氨基吡啶-2-基)-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[4-(吡啶-2-基氨基)-1-丁基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(R)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(3,4,5,6-四氢嘧啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[2-[2-(乙氨基)噻唑-4-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(异喹啉-1-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-乙氧基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-6-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-2-(二甲氨基)甲基-7-氟-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-[4-(2-丙氧基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-[4-(二甲氨基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-[4-(乙硫基)吡啶-2-基氨基]-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-氯吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-2-甲基-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(S)-10,11-二氢-3-[3-(4-氨基吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸;(±)-10,11-二氢-3-[3-(4-甲基吡啶-2-基氨基)-1-丙氧基]-二苯并[b,f]氧杂庚英-10-乙酸;(±)-10,11-二氢-3-[2-[6-(甲氨基)吡啶-2-基]-1-乙氧基]-二苯并[b,f]氧杂庚英-10-乙酸;或(S)-10,11-二氢-3-[3-(2-氨基吡啶-4-基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸。
8.药用组合物,其包含根据权利要求1的化合物和药学上可接受的载体。
9.药用组合物,其包含根据权利要求1的化合物、抗肿瘤剂和药学上可接受的载体。
10.根据权利要求9的药用组合物,其中该抗肿瘤剂是托泊替堪。
11.根据权利要求9的药用组合物,其中该抗肿瘤剂是顺铂。
12.治疗其中显示αVβ3受体拮抗作用的疾病状态的方法,包括给予需要其的受治疗者根据权利要求1的化合物。
13.治疗其中显示αVβ5受体拮抗作用的疾病状态的方法,包括给予需要其的受治疗者根据权利要求1的化合物。
14.治疗骨质疏松症的方法,包括给予需要其的受治疗者根据权利要求1的化合物。
15.抑制血管发生的方法,包括给予需要其的受治疗者根据权利要求1的化合物。
16.抑制肿瘤生长或肿瘤转移的方法,包括给予需要其的受治疗者根据权利要求1的化合物。
17.治疗动脉粥样硬化或再狭窄的方法,包括给予需要其的受治疗者根据权利要求1的化合物。
18.治疗炎症的方法,包括给予需要其的受治疗者根据权利要求1的化合物。
19.抑制肿瘤生长的方法,包括逐步给予或以物理组合物的方式给予根据权利要求1的化合物和抗肿瘤剂。
20.根据权利要求19的方法,其中该抗肿瘤剂是托泊替堪。
21.根据权利要求19的方法,其中该抗肿瘤剂是顺铂。
24.制备权利要求1中所定义的式(I)化合物的方法,该方法包括使式(IV)化合物与式(V)化合物反应:Y-(CH2)2-3-L1(V)
其中R1、R2、Y和A定义同式(I),可带有任何被保护的活性官能团,L1是OH或卤素;
然后除去任何保护基,并可任选形成药学上可接受的盐。
26.制备权利要求1中所定义的式(I)化合物的方法,该方法包括使式(IV)化合物与式(VII)化合物反应:
其中R1、R2、R″和A定义同式(I),可带有任何被保护的活性官能团;
然后除去任何保护基,并可任选形成药学上可接受的盐。
27.用作药物的根据权利要求1-7中任一项的化合物。
28.应用权利要求1中所定义的式(I)化合物制备用于治疗其中显示αVβ3受体拮抗作用的疾病的药物。
29.应用权利要求1中所定义的式(I)化合物制备用于治疗其中显示αVβ5受体拮抗作用的疾病的药物。
30.应用权利要求1中所定义的式(I)化合物制备用于治疗骨质疏松症的药物。
31.应用权利要求1中所定义的式(I)化合物制备用于抑制血管发生的药物。
32.应用权利要求1中所定义的式(I)化合物制备用于抑制肿瘤生长或肿瘤转移的药物。
33.应用权利要求1中所定义的式(I)化合物制备用于治疗动脉粥样硬化或再狭窄的药物。
34.应用权利要求1中所定义的式(I)化合物制备用于治疗炎症的药物。
35.应用权利要求1中所定义的式(I)化合物和抗肿瘤剂制备用于以物理组合物方式或逐步给药方式来抑制肿瘤生长的药物。
36.根据权利要求35的应用,其中该抗肿瘤剂是托泊替堪。
37.根据权利要求35的应用,其中该抗肿瘤剂是顺铂。
38.应用权利要求1中所定义的式(I)化合物和骨吸收抑制剂制备用于以物理组合物方式或逐步给药方式来治疗骨质疏松症的药物。
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WO2000046215A1 (en) | 1999-02-03 | 2000-08-10 | Merck & Co., Inc. | Benzazepine derivatives as alpha-v integrin receptor antagonists |
DE19936780A1 (de) | 1999-08-09 | 2001-02-15 | Basf Ag | Neue Antagonisten von Integrinrezeptoren |
US6881736B1 (en) | 1999-09-07 | 2005-04-19 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
EG24179A (en) * | 1999-09-07 | 2008-09-28 | Smithkline Beecham Corp | Vitronectin receptor antagonists |
US6514964B1 (en) | 1999-09-27 | 2003-02-04 | Amgen Inc. | Fused cycloheptane and fused azacycloheptane compounds and their methods of use |
FR2806082B1 (fr) * | 2000-03-07 | 2002-05-17 | Adir | Nouveaux composes bicycliques antagonistes des recepteurs de la vitronectine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
EP1289959A1 (en) | 2000-06-15 | 2003-03-12 | Pharmacia Corporation | Dihydrostilbene alkanoic acid derivatives useful as vitronectin antagonists |
JP2004513953A (ja) * | 2000-10-24 | 2004-05-13 | メルク エンド カムパニー インコーポレーテッド | ジベンズオキサゼピンαVインテグリン受容体アンタゴニスト |
CN1247258C (zh) | 2001-04-24 | 2006-03-29 | 默克专利有限公司 | 使用抗血管生成剂和TNFα的联合疗法 |
GB0215867D0 (en) * | 2002-07-09 | 2002-08-14 | Glaxosmithkline Spa | Novel method and compounds |
US20040224986A1 (en) | 2002-08-16 | 2004-11-11 | Bart De Corte | Piperidinyl targeting compounds that selectively bind integrins |
UA87854C2 (en) | 2004-06-07 | 2009-08-25 | Мерк Энд Ко., Инк. | N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators |
EP1973569B1 (en) | 2006-01-18 | 2013-05-22 | Merck Patent GmbH | Specific therapy using integrin ligands for treating cancer |
US20100069302A1 (en) | 2007-07-18 | 2010-03-18 | Stefan Krueger | Specific therapy and medicament using integrin ligands for treating cancer |
JP2012528079A (ja) | 2009-05-25 | 2012-11-12 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | 癌を治療するためのインテグリンリガンドの連続投与 |
KR20160147007A (ko) | 2014-05-30 | 2016-12-21 | 화이자 인코포레이티드 | 선택적인 안드로겐 수용체 조절제로서의 카보니트릴 유도체 |
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US3335148A (en) * | 1966-02-17 | 1967-08-08 | Lilly Co Eli | 9(3-pyridyl)derivative of fluorene, 9-fluorenol, xanthene, 9-xanthenol and the corresponding nonphytotoxic acid addition salts thereof |
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DZ2609A1 (fr) | 2003-03-01 |
ID24162A (id) | 2000-07-13 |
AU9397298A (en) | 1999-04-12 |
CO5011087A1 (es) | 2001-02-28 |
AR015446A1 (es) | 2001-05-02 |
PE122699A1 (es) | 2000-02-12 |
OA11341A (en) | 2003-12-10 |
WO1999015508A1 (en) | 1999-04-01 |
KR20010024141A (ko) | 2001-03-26 |
TW513303B (en) | 2002-12-11 |
PL339381A1 (en) | 2000-12-18 |
BR9812340A (pt) | 2001-12-18 |
HUP0003641A3 (en) | 2002-10-28 |
BG104314A (en) | 2001-01-31 |
NO20001407L (no) | 2000-03-17 |
EA200000336A1 (ru) | 2000-10-30 |
HUP0003641A2 (en) | 2001-03-28 |
CA2303487A1 (en) | 1999-04-01 |
NO20001407D0 (no) | 2000-03-17 |
AU738433B2 (en) | 2001-09-20 |
IL135028A0 (en) | 2001-05-20 |
SK4082000A3 (en) | 2000-09-12 |
NZ503389A (en) | 2002-03-28 |
EP1025090A1 (en) | 2000-08-09 |
MA26547A1 (fr) | 2004-12-20 |
EP1025090A4 (en) | 2000-11-08 |
JP2001517658A (ja) | 2001-10-09 |
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TR200000721T2 (tr) | 2000-11-21 |
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