CN105026394B - 用于治疗癌症和免疫性和自身免疫性疾病的细胞凋亡诱导剂 - Google Patents
用于治疗癌症和免疫性和自身免疫性疾病的细胞凋亡诱导剂 Download PDFInfo
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- CN105026394B CN105026394B CN201480015341.4A CN201480015341A CN105026394B CN 105026394 B CN105026394 B CN 105026394B CN 201480015341 A CN201480015341 A CN 201480015341A CN 105026394 B CN105026394 B CN 105026394B
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- A61K31/33—Heterocyclic compounds
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Landscapes
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本文公开的是抑制抗细胞凋亡Bcl‑2蛋白活性的化合物,包含该化合物的组合物和使用该化合物治疗疾病的方法。
Description
发明领域
本发明涉及抑制Bcl-2抗细胞凋亡蛋白活性的化合物,包含该化合物的组合物,和使用该化合物治疗疾病的方法。
发明背景
Bcl-2蛋白家族为有核细胞中的线粒体依赖性细胞凋亡的关键调节剂并包括抗细胞凋亡(Bcl-xL, Bcl-2, Bcl-w, A1, Mcl-1)和促细胞凋亡(Bak, Bax, Bid, Bim, Bad,Bik, Bmf, Noxa, Puma)成员。一般而言,Bcl-2蛋白的表达与很多生理功能相关,包括体内细胞凋亡的抑制,在一些情况下导致被Bcl-2抑制影响的细胞增殖。因此,Bcl-2蛋白的抑制可能降低细胞增殖,导致与癌症的治疗和预防相关的改善效果。
抗细胞凋亡Bcl-2蛋白与很多疾病有关。Bcl-2蛋白可以参与膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病(lymphoblastic leukemia)、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病(myelogenous leukemia)、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌或脾脏癌等。另外,Bcl-2可能参与免疫性和自身免疫性疾病和关节炎。Bcl-2蛋白的过度表达与在各种癌症和免疫系统障碍中对化疗、临床结果、疾病发展、全部预后或其组合的耐受性相关。
在治疗领域中存在对抑制抗细胞凋亡Bcl-2蛋白活性的化合物的持续需要。
发明概述
本发明的一种实施方案涉及化合物和其治疗上可接受的盐、前药、代谢物、或前药的盐,其可用作抗细胞凋亡Bcl-2蛋白的抗体。该化合物包括:
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2R)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5s,8s)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5r,8r)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-羟基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂螺[4.5]癸-8-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2S)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[4-(羟基甲基)四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[3-(羟基甲基)氧杂环丁烷-3-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(3-羟基-3-甲基丁基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(3-羟基三环[3.3.1.13,7]癸-1-基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧杂二环[3.1.0]己-6-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-羟基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰基]氨磺酰基}-2-硝基苯基)氨基]甲基}四氢-2H-吡喃-4-甲酸甲酯;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[2-(四氢-2H-吡喃-4-基)肼基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-噻喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(氧杂环丁烷-3-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-羟基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4,4-二氟-1-羟基环己基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲氧基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3,3-二氟环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺酰基]哌啶-4-基}甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[1-(甲基磺酰基)哌啶-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1-氧化四氢-2H-噻喃-4-基)甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氢呋喃-3-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-甲基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(反式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(顺式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(1,1-二氧化四氢-2H-噻喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-氰基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
N-[(4-{[(1-乙酰基哌啶-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-乙基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂环庚烷-6-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-环丙基苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和
4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基环己-1-烯-1-基}甲基)哌嗪-1-基]-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺。
另一种实施方案涉及用于治疗膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病(lymphoblasticleukemia)、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病(myelogenous leukemia)、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾脏癌的组合物,所述组合物包含赋形剂和治疗有效量的本发明化合物。
另一种实施方案涉及治疗需要治疗的对象中的膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾脏癌的方法,所述方法包括给予所述对象治疗有效量的本发明化合物。
另一种实施方案涉及治疗需要治疗的对象中的膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾脏癌的方法,所述方法包括给予所述对象治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
另一实施方案涉及用于治疗全身性红斑狼疮、狼疮性肾炎、或舍格伦综合症的组合物,所述组合物包含赋形剂和治疗有效量的本发明化合物。
另一实施方案涉及治疗需要治疗的对象中全身性红斑狼疮、狼疮性肾炎、或舍格伦综合症的方法,所述方法包括给予所述对象治疗有效量的本发明化合物。
另一实施方案涉及治疗需要治疗的对象中全身性红斑狼疮、狼疮性肾炎、或舍格伦综合症的方法,所述方法包括给予所述对象治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
发明详述
除非本文另有定义,与本发明结合使用的科学和技术术语应当具有本领域那些普通技术人员通常理解的含义。所述术语的含义和范围应当清晰,但是,如果有任何潜在歧义,本文所提供的定义优先于任何词典或外部的定义。在本申请中,除非另外说明,“或”的使用是指“和/或”。此外,术语“包括(including)”以及其它形式例如“包括(includes)”和“包括(included)”的使用,是非限制性的。关于本专利申请(包括权利要求书)中的词语“包含(comprise)”或“包含(comprises)”或“包含(comprising)”的使用,申请人指出,除非上下文另外要求,这些词语基于它们被解释为包含在内而非排它性的基础和清楚的理解而使用,并且申请人打算在解释本专利申请(包括下列权利要求)这些词语中的每个时作如此解释。关于本发明或本文任何其它式中的任何取代基或化合物中出现一次以上的变量,其在每次出现时的定义独立于其在每次其它出现时的定义。取代基的组合是允许的,只要这样的组合产生稳定的化合物。稳定的化合物是其可以以有用的纯度从反应混合物中分离出的化合物。
术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”是指缓解或消除疾病和/或其伴随症状的方法。
术语“预防(prevent)”、“预防(preventing)”和“预防(prevention)”是指预防疾病和/或其伴随症状发作或阻止对象患病的方法。如本文所用,“预防(prevent)”、“预防(preventing)”和“预防(prevention)”还包括延缓疾病和/或其伴随症状的发作和降低对象患病的风险。
术语“治疗有效量”是指给予化合物的量,其足以预防所要治疗的病症或障碍的一种或多种症状的发展或在一定程度上减轻所要治疗的病症或障碍的一种或多种症状。
术语“调节”是指化合物提高或降低Bcl-2蛋白的功能或活性的能力。
本文中使用的术语“组合物”旨在包括含有特定量的特定成分的产品,以及由特定量的特定成分的组合直接或间接地形成的任何产品。“药学上可接受的”意味着载体、稀释剂或赋形剂必须与制剂中的其它成分相容,并且对其接受者无害。
术语“对象”在本文中定义为包括动物,例如哺乳动物,包括但不限于灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、和小鼠等。在合适的实施方案中,对象是人。
化合物
本发明的一种实施方案涉及化合物和其治疗上可接受的盐、前药、代谢物、或前药的盐,其可用作抗细胞凋亡Bcl-2蛋白的抑制剂。
一种实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2R)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5s,8s)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5r,8r)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-羟基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂螺[4.5]癸-8-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2S)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[4-(羟基甲基)四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[3-(羟基甲基)氧杂环丁烷-3-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(3-羟基-3-甲基丁基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(3-羟基三环[3.3.1.13,7]癸-1-基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧杂二环[3.1.0]己-6-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-羟基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰基]氨磺酰基}-2-硝基苯基)氨基]甲基}四氢-2H-吡喃-4-甲酸甲酯;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[2-(四氢-2H-吡喃-4-基)肼基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-噻喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(氧杂环丁烷-3-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-羟基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4,4-二氟-1-羟基环己基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲氧基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3,3-二氟环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺酰基]哌啶-4-基}甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[1-(甲基磺酰基)哌啶-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1-氧化四氢-2H-噻喃-4-基)甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氢呋喃-3-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-甲基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(反式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(顺式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(1,1-二氧化四氢-2H-噻喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-氰基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及N-[(4-{[(1-乙酰基哌啶-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-乙基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂环庚烷-6-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(4-环丙基苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-(4-{[2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
另一实施方案涉及4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基环己-1-烯-1-基}甲基)哌嗪-1-基]-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和其治疗上可接受的盐、前药、代谢物、或前药的盐。
本发明的化合物可以包括几何异构体。本发明的化合物可以含有E或Z构型的碳-碳双键或碳-氮双键,其中如同Cahn-Ingold-Prelog优先规则所确定,术语“E”代表较高阶的取代基在碳-碳或碳-氮双键的对侧,术语“Z”代表较高阶的取代基在碳-碳或碳-氮双键的同侧。本发明的化合物还可以以“E”和“Z”异构体的混合物形式存在。环烷基或杂环烷基周围的取代基有时指定为顺式或反式构型。此外,本发明考虑获自金刚烷环系周围的取代基处理的各种异构体和其混合物。金刚烷环系内的单环周围的两个取代基称为Z或E相对构型。例如,参见C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760。
本发明的化合物可以含有不对称取代的R或S构型的碳原子,其中术语“R”和“S”由IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, PureAppl. Chem. (1976) 45, 13-10中所定义。具有不对称取代碳原子的、具有相等数量R和S构型的化合物在那些碳原子处是外消旋形式。具有一种构型相比另一构型过量的原子被指定为以更多量存在的构型,优选过量大约85%-90%,更优选过量大约95%-99%,更加优选过量大于大约99%。因此,本发明包括外消旋混合物、相对和绝对立体异构体、和相对和绝对立体异构体的混合物。
本发明化合物可以选择性Bcl-2抑制剂化合物的前药形式存在。前药为设计成缓解一些识别的、不期望的物理或生物性质的活性药物的衍生物。物理性质通常为溶解度(过多或不足够的脂质或水性溶解度)或相关稳定性,而问题生物性质包括过快代谢或差生物利用度,其本身可能涉及物理化学性质。前药通过如下制备: a) 活性药物的酯、半酯、碳酸酯、硝酸酯、酰胺、异羟肟酸、氨基甲酸盐、酰亚胺、曼尼希碱、磷酸盐、磷酸酯、和烯胺的形成, b) 用偶氮、糖苷、肽和醚官能团官能化药物, c) 药物的缩醛胺、半缩醛胺、聚合物、盐、复合物、磷酰胺、缩醛、半缩醛、和缩酮形式的使用。例如,参见Andrejus Korolkovas`s,"Essentials of Medicinal Chemistry", John Wiley-Interscience Publications,John Wiley and Sons, New York (1988), 第97-118页, 其整体并入本文中作为参考。
同位素富集或标记的化合物
本发明的化合物可以存在同位素标记或富集的形式,其包含一个或多个原子,该原子的原子量或质量数不同于自然界中最丰富发现的该原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。原子例如氢、碳、磷、硫、氟、氯和碘的同位素包括但不局限于:2H、3H、13C、14C、15N、18O、32P、35S、18F、36C1、和125I。包含这些和/或其它原子的其它同位素的化合物在本发明范围之内。
在另一种实施方案中, 同位素-标记的化合物包含氘(2H)、氚 (3H) 或14C同位素。同位素标记的本发明化合物可以利用本领域普通技术人员熟知的一般方法来制备。这种同位素标记的化合物通过实施本文所公开实施例和方案中公开的操作方法、通过用容易获得的同位素标记的试剂替代非标记的试剂可以方便地制得。在某些情况下,可用同位素标记的试剂处理化合物,以将普通原子交换成其同位素,例如,通过诸如D2SO4/D2O等氘酸的作用可实现氢向氘的交换。除了上述内容以外,相关的操作方法和中间体公开在例如:Lizondo,J等人, Drugs Fut, 21(11), 1116 (1996);Brickner, S J等人, J Med Chem, 39(3),673 (1996);Mallesham, B等人, Org Lett, 5(7), 963 (2003);PCT公开WO1997010223、WO2005099353、WO1995007271、WO2006008754;US专利号7538189;7534814;7531685;7528131;7521421;7514068;7511013;和US专利申请公开号20090137457;20090131485;20090131363;20090118238;20090111840;20090105338;20090105307;20090105147;20090093422;20090088416;和20090082471,所述方法在此引入,作为参考。
本发明同位素标记的化合物可以在结合测定中用作确定Bcl-2抑制剂有效性的标准。在药学研究中已经使用含有同位素的化合物,以通过评价非同位素标记的母体化合物的作用机理和代谢途径来研究化合物的体内代谢归宿(Blake等人 J. Pharm.Sci. 64, 3,367-391 (1975))。在安全、有效的治疗药物的设计中,这样的代谢研究是重要的,这是为了证明施用给对象的体内活性的化合物,或者从母体化合物产生的代谢产物是否是有毒或致癌的 (Foster等人, Advances in Drug Research Vol. 14,第2-36页, Academic press,London, 1985;Kato等人, J. Labelled Comp. Radiopharmaceut., 36(10):927-932(1995);Kushner等人, Can. J. Physiol.Pharmacol, 77, 79-88 (1999)。
此外,含有非放射性同位素的药物,例如被称为“重药”的氘代药物,可用于治疗与Bcl-xL活性相关的疾病和病症。将上文化合物中存在的同位素的量增加至其天然丰度以上,被称为富集。富集的量的实例包括从约0.5、1、2、3、4、5、6、7、8、9、10、12、16、21、25、29、33、37、42、46、50、54、58、63、67、71、75、79、84、88、92、96至约100 mol%。已实现用重同位素代替高达约15%的普通原子,并在哺乳动物(包括啮齿类和犬类)中维持几天至几周的时间,且观察到最小的的不良作用(Czajka D M和Finkel A J, Ann. N.Y. Acad. Sci. 196084: 770;Thomson J F, Ann. New York Acad. Sci 1960 84: 736;Czakja D M等人, Am.J. Physiol. 1961 201:357)。在人体液中,用氘急性替代高达15%-23%,已发现不会导致毒性(Blagojevic N等人,"Dosimetry & Treatment Planning for Neutron CaptureTherapy", Zamenhof R, Solares G 和Harling O Eds. 1994. Advanced MedicalPublishing, Madison Wis. pp.125-134;Diabetes Metab. 23: 251 (1997))。
稳定同位素标记的药物可以改变其理化性质,例如pKa和脂溶性。如果同位素取代影响到参与配体-受体相互作用的区域,那么这些效果和变化可以影响药物分子的药效响应。尽管稳定的同位素标记的分子在一些物理性质上会不同于未标记的分子,但化学性质和生物学性质是相同的,仅有一点重要的例外:由于重同位素的质量增加,涉及重同位素和另一原子的任何键比轻同位素和该原子之间的相同键更强。因此,在代谢或酶转化位点处引入同位素会减慢所述反应,相对于非同位素化合物潜在地改变药物动力学特性或效果。
药物组合物、组合疗法和给药
另一实施方案涉及包含本发明化合物和赋形剂的药物组合物。
又另一实施方案涉及治疗疾病的组合物,在此期间表达抗细胞凋亡Bcl-2蛋白,所述组合物包含赋形剂和治疗有效量的本发明化合物。
又另一种实施方案涉及用于治疗膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌或脾脏癌的组合物,所述组合物包含赋形剂和治疗有效量的本发明化合物。
又另一实施方案涉及治疗疾病的组合物,在此期间表达抗细胞凋亡Bcl-2蛋白,所述组合物包含赋形剂和治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
又另一种实施方案涉及用于治疗膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾脏癌的组合物,所述组合物包含赋形剂和治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
又另一实施方案涉及用于治疗全身性红斑狼疮、狼疮性肾炎、或舍格伦综合症的组合物,所述组合物包含赋形剂和治疗有效量的本发明化合物。
又另一实施方案涉及用于治疗全身性红斑狼疮、狼疮性肾炎、或舍格伦综合症的组合物,所述组合物包含赋形剂和治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
通过体外或体内代谢过程产生的本发明化合物的代谢物也可以具有治疗与抗细胞凋亡Bcl-2蛋白有关的疾病的实用性。
可以通过体外或体内代谢形成本发明化合物的某些前体化合物也可具有治疗与抗细胞凋亡Bcl-2蛋白表达有关的疾病的效用。
本发明化合物可以存在酸加成盐、碱加成盐或两性离子。化合物的盐是在所述化合物分离期间或纯化后制成的。化合物的酸加成盐是衍生自化合物与酸反应的那些盐。例如,本发明考虑包括化合物的乙酸盐、己二酸盐、藻酸盐、碳酸氢盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、甲酸盐、富马酸盐、甘油磷酸盐、谷氨酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳糖酸盐、乳酸盐、马来酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、果胶酯酸盐(pectinate)、过硫酸盐、磷酸盐、苦味酸盐、丙酸盐、丁二酸盐、酒石酸盐、硫氰酸盐、三氯乙酸盐、三氟乙酸盐、对-甲苯磺酸盐、和十一酸盐。化合物的碱加成盐是衍生自所述化合物与阳离子诸如锂、钠、钾、钙和镁的氢氧化物、碳酸盐或碳酸氢盐反应的那些盐。
本发明化合物可例如经颊(bucally)、眼用、口服、经渗透(osmotically)、胃肠外(肌内、腹膜内、胸骨内、静脉内、皮下)、经直肠、局部、透皮或经阴道给药。
本发明的化合物的治疗有效量取决于所治疗的接受者、要治疗的病症及其严重程度、含有化合物的组合物、给药时间、给药途径、治疗持续时间、化合物效能、其廓清率和是否共同给予另一种药物。用于制备以单剂量或以分开剂量每日给对象施用的组合物的本发明化合物的量是大约0.001至大约1000 mg/kg,或大约0.01至大约500 mg/kg,或大约0.1至大约300 mg/kg。单剂量组合物含有这些数量或组合的其约数量。
可以调节剂量方案以提供最佳期望响应(例如治疗或预防响应)。例如,可以给予单次大剂量(bolus),可以经时间给予几次分开的剂量或按照治疗位置障碍表示的成比例地降低或升高剂量。特别有利的是为了容易给药和剂量均匀而配制剂量单元形式的肠胃外组合物。本文中使用的剂量单元形式是指适合作为单一剂量用于待治疗的哺乳动物对象的物理离散单元;含有计算以产生需要的治疗效果的预定量的活性化合物与需要的药物载体一起的每个单元。通过并直接根据如下执行本发明的剂量单元形式的说明书(a)活性化合物的独特特征和待实现的特定治疗或预防效果,和(b)配混用于治疗个体的敏感性的此类活性化合物的领域中固有的限制。
本发明化合物可以与或不与赋形剂一同给药。赋形剂包括,例如包封材料或添加剂诸如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、膨胀剂、填充剂、调味剂、保湿剂、润滑剂、香料、防腐剂、抛射剂、释放剂、杀菌剂、甜味剂、增溶剂、润湿剂及其混合物。所述赋形剂可以为药学上可接受的赋形剂。
用于制备包含本发明化合物的口服给药的固体剂型的组合物的赋形剂包括,例如琼脂、海藻酸、氢氧化铝、苯甲醇、苯甲酸苄酯、1,3-丁二醇、卡波姆、蓖麻油、纤维素、醋酸纤维素、可可脂、玉米淀粉、玉米油、棉籽油、交联聚维酮、甘油二酯、乙醇、乙基纤维素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明胶、胚芽油、葡萄糖、甘油、落花生油(groundnut oil)、羟丙甲基纤维素、异丙醇、等渗生理盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、单甘油酯、橄榄油、花生油(peanut oil)、磷酸钾盐、土豆淀粉、聚维酮、丙二醇、林格溶液、红花油、芝麻油、羧甲基纤维素钠、磷酸钠盐、十二烷基硫酸钠、山梨醇钠、大豆油、硬脂酸、富马酸硬脂酯、蔗糖、表面活性剂、滑石、西黄蓍胶、四氢糠醇、甘油三酯、水、及其混合物。用于制备包含本发明化合物的眼用或口服给药的液体剂型的组合物的赋形剂包括,例如1,3-丁二醇、蓖麻油、玉米油、棉籽油、乙醇、脱水山梨糖醇脂肪酸酯、胚芽油、落花生油、甘油、异丙醇、橄榄油、聚乙二醇、丙二醇、芝麻油、水及、其混合物。用于制备包含本发明化合物的渗透给药的组合物的赋形剂包括,例如氯氟烃、乙醇、水及其混合物。用于制备包含本发明化合物的胃肠外给药的组合物的赋形剂包括,例如1,3-丁二醇、蓖麻油、玉米油、棉籽油、右旋糖、胚芽油、落花生油、脂质体、油酸、橄榄油、花生油、林格溶液、红花油、芝麻油、大豆油、U.S.P.或等渗氯化钠溶液、水及其混合物。用于制备包含本发明化合物的经直肠或经阴道给药的组合物的赋形剂包括,例如可可脂、聚乙二醇、蜡及其混合物。
预期本发明化合物在与烷化剂、血管生成抑制剂、抗体、抗代谢剂、抗有丝分裂药、抗增殖药、抗病毒药、极光(aurora)激酶抑制剂、其它细胞凋亡启动子(例如,Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体通路激活剂、Bcr-Abl激酶抑制剂、BiTE(双特异性T细胞接合器(Engager))抗体、抗体药物缀合物(conjugates)、生物反应调节剂、细胞周期蛋白依赖性激酶抑制剂、细胞周期抑制剂、环氧合酶-2抑制剂、DVD类、白血病病毒癌基因同源物(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白脱乙酰基酶(HDAC)抑制剂、激素疗法、免疫剂(immunological)、细胞凋亡蛋白抑制剂(IAPs)的抑制剂、嵌入抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、雷帕霉素的哺乳动物标靶抑制剂(mammalian target of rapamycin inhibitors)、微小RNA(microRNA's)、丝裂原活化的细胞外信号调节激酶抑制剂、多价结合蛋白、非甾体抗炎药(NSAISs)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂、铂化疗剂、Polo样激酶(Plk)抑制剂、磷酸肌醇-3激酶(PI3K)抑制剂、蛋白体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类视黄素(retinoids)/类维生素D(deltoids)植物生物碱、小分子抑制性核糖核酸(siRNAs)、拓扑异构酶抑制剂、和泛素连接酶抑制剂等一起使用时及与一种或多种这些药剂组合使用时是有用的。
BiTE抗体是双特异性抗体,其通过同时结合两种细胞,引导T细胞攻击癌细胞。然后T细胞攻击目标癌细胞。BiTE抗体的实例包括阿德木单抗(Micromet MT201)、和兰妥莫单抗(Micromet MT103)等。不受限于理论,T细胞引发目标癌细胞凋亡的一个机理是通过溶细胞性颗粒组分的胞吐作用,所述溶细胞性颗粒组分包括穿孔蛋白和粒酶B。In thisregard, Bcl-2 has been shown to attenuate the induction of apoptosis by bothperforin and granzyme B. These data suggest that inhibition of Bcl-2 couldenhance the cytotoxic effects elicited by T-cells when targeted to cancercells (V.R. Sutton, D.L. Vaux and J.A. Trapani, J. of Immunology 1997, 158(12), 5783)。
SiRNAs是具有内源性RNA碱基的或经化学修饰核苷酸的分子。这些修饰没有消除细胞活性,而是赋予增加的稳定性和/或增加的细胞效能。化学修饰的实例包括磷硫酰基,2'-脱氧核苷酸、含有2'-OCH3-的核糖核苷酸、2'-F-核糖核苷酸、2'-甲氧基乙基核糖核苷酸,及其组合等。siRNA可以有不同的长度(如10-200bps)和结构(如发夹、单/双链、凸起、缺口/间隙、错配),并在细胞内加工以提供活性基因沉默。双链siRNA(dsRNA)在每条链(平端)或不对称端(悬突)上可具有相同的核苷酸数目。1-2个核苷酸的悬突可以出现在正义链和/或反义链上,以及出现在约定链的5'-端和/或3'-段。例如,靶向Mcl-1的siRNA已经在多肿瘤细胞系中显示出能够增强ABT-263(即N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-((三氟甲基)磺酰基)苯磺酰胺)或BT-737 (即N-(4-(4-((4'-氯(1,1'-联苯)-2-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(二甲基氨基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-硝基苯磺酰胺)的活性(Tse 等人,Cancer Research 2008,68(9),3421,和其中的参考文献)。
多价结合蛋白是包含两个或更多个抗原结合位点的结合蛋白。多价结合蛋白被设计为具有三个或更多个的抗原结合位点,且是通常不为天然存在的抗体。术语“多特异性结合蛋白”表示能够结合两个或更多个相关或不相关标靶的结合蛋白。双重可变域(DVD)结合蛋白是四价或更高价的结合蛋白,结合蛋白包含两个或更多个的抗原结合位点。这样的DVD可以为单特异性的(即,能够结合一个抗原)或多特异性 (即,能够结合两个或更多个的抗原)。包含两条重链DVD多肽和两条轻链DVD多肽的DVD结合蛋白称为DVD Ig。每一半DVD Ig包含一条重链DVD多肽、一条轻链DVD多肽、以及两个抗原结合位点。每个结合位点包含一个重链可变域和一个轻链可变域,每个抗原结合位点共有6个CDR涉及抗原结合。
烷化剂包括六甲蜜胺、AMD-473、AP-5280、阿帕齐醌(apaziquone)、苯达莫司汀、溴他利星(brostallicin)、白消安、卡波醌、卡莫司汀(BCNU)、苯丁酸氮芥、CLORETAZINE® (拉罗莫司汀,VNP 40101M)、环磷酰胺、氨烯咪胺、雌莫司汀、福莫司汀、葡磷酰胺、异环磷酰胺、KW-2170、洛莫司汀 (CCNU)、马磷酰胺、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、氮芥N-氧化物、雷莫司汀、替莫唑胺、塞替派、TREANDA® (苯达莫司汀)、曲奥舒凡、曲磷胺(rofosfamide)等。
血管生成抑制剂包括内皮特异性受体酪氨酸激酶(Tie-2)抑制剂、表皮生长因子受体(EGFR)抑制剂、胰岛素生长因子-2受体(IGFR-2)抑制剂、基质金属蛋白酶-2(MMP-2)抑制剂、基质金属蛋白酶-9(MMP-9)抑制剂、血小板衍生生长因子受体(PDGFR)抑制剂、凝血栓蛋白类似物、血管内皮生长因子受体酪氨酸激酶(VEGFR)抑制剂等。
抗代谢药包括ALIMTA® (培美曲塞二钠、LY231514、MTA)、5-阿扎胞苷、XELODA®(卡培他滨)、卡莫氟、LEUSTAT® (克拉屈滨)、氯法拉滨、阿糖胞苷、阿糖胞苷十八烷基磷酸盐、胞嘧啶阿拉伯糖苷(cytosine arabinoside)、地西他滨、去铁胺、去氧氟尿苷、依氟鸟氨酸、 EICAR (5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺)、依诺他滨、乙炔胞嘧啶核苷、氟达拉滨、单独或与甲酰四氢叶酸组合的5-氟尿嘧啶、 GEMZAR®(吉西他滨)、羟基脲、ALKERAN®(美法仑)、巯嘌呤、6-巯嘌呤核苷、甲氨喋呤、霉酚酸、奈拉滨、诺拉曲塞、十八烷基磷酸盐(ocfosfate)、培利曲索(pelitrexol)、喷司他丁、雷替曲塞、利巴韦林、三安平(triapine)、三甲曲沙、S-1、噻唑呋林、替加氟、TS-1、阿糖腺苷、和UFT等。
抗病毒剂包括利托那韦、和羟氯喹等。
极光激酶抑制剂包括ABT-348、AZD-1152、MLN-8054、VX-680、极光A-特异性激酶抑制剂、极光B-特异性激酶抑制剂和全极光(pan-Aurora)激酶抑制剂等。
Bc1-2蛋白抑制剂包括AT-101 ((-)棉酚)、GENASENSE®(G3139或奥利默森(oblimersen) (Bcl-2靶向反义寡核苷酸))、IPI-194、IPI-565、N-(4-(4-((4'-氯(1,1'-联苯)-2-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(二甲基氨基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-硝基苯磺酰胺) (ABT-737)、N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-((三氟甲基)磺酰基)苯磺酰胺(ABT-263)、4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(ABT-199)、GX-070(奥巴拉西(obatoclax))等。
Bcr-Abl激酶抑制剂包括DASATINIB® (BMS-354825)、和GLEEVEC®(伊马替尼)等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、夫拉平度(flavopyridol)、GPC-286199、MCS-5A、PD0332991、PHA-690509、塞利昔布(seliciclib)(CYC-202、R-罗斯维汀(R-roscovitine))、和ZK-304709、dinaciclib等。
COX-2抑制剂包括ABT-963、ARCOXIA® (艾托考昔)、BEXTRA® (伐地考昔)、BMS347070、CELEBREX® (塞来考昔)、COX-189 (芦米考昔(lumiracoxib))、CT-3、DERAMAXX®(地拉考昔)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基苯基-1H-吡咯)、MK-663 (艾托考昔)、NS-398、帕瑞考昔、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VIOXX® (罗非昔布)等。
EGFR抑制剂包括ABX-EGF、抗EGFR免疫脂质体、EGF疫苗、EMD-7200、ERBITUX® (西妥昔单抗)、HR3、IgA抗体、IRESSA® (吉非替尼)、TARCEVA® (厄洛替尼或OSI-774)、TP-38、EGFR融合蛋白、TYKERB® (拉帕替尼)等。
ErbB2受体抑制剂包括CP-724-714、CI-1033 (卡奈替尼)、HERCEPTIN® (曲妥珠单抗)、TYKERB®(拉帕替尼)、OMNITARG® (2C4、帕妥珠单抗(petuzumab))、TAK-165、GW-572016(洛那法尼(ionafarnib))、GW-282974、EKB-569、PI-166、dHER2 (HER2疫苗)、APC-8024(HER-2 疫苗)、抗HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三功能性双特异性抗体、mAB AR-209、和mAB 2B-1等。
组蛋白脱乙酰基酶抑制剂包括缩酚酸肽、LAQ-824、MS-275、曲柏辛(trapoxin)、辛二酰苯胺异羟肟酸(SAHA)、TSA、和丙戊酸等。
HSP-90抑制剂包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格尔德霉素、IPI-504、KOS-953、MYCOGRAB® (人类重组HSP-90抗体)、NCS-683664、PU24FCl、PU-3、根赤壳菌素、SNX-2112、STA-9090 VER49009等。
细胞凋亡蛋白抑制剂的抑制剂包括HGS1029、GDC-0145、GDC-0152、LCL-161、LBW-242等。
抗体药物缀合物包括抗CD22-MC-MMAF、抗CD22-MC-MMAE、抗CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19Am SGN-35、SGN-75、曲妥单抗、emtansine等。
死亡受体通路激活剂包括TRAIL、靶向TRAIL或死亡受体(例如DR4和DR5)的抗体或其它药物,诸如阿扑单抗(Apomab)、可那木单抗(conatumumab)、ETR2-ST01、GDC0145(来沙木单抗)、HGS-1029、LBY-135、PRO-1762和曲妥珠单抗。
驱动蛋白抑制剂包括Eg5抑制剂,诸如AZD4877、ARRY-520;CENPE抑制剂,诸如GSK923295A等。
JAK-2抑制剂包括CEP-701 (来他替尼(lesaurtinib))、XL019和INCB018424等。
MEK抑制剂包括ARRY-142886、ARRY-438162 PD-325901、和PD-98059等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素、坦西莫司、ATP竞争性TORC1/TORC2抑制剂(包括PI-103、PP242、PP30、Torin 1)等。
非甾体抗炎药包括AMIGESIC®(双水杨酯)、DOLOBID®(二氟尼柳)、MOTRIN® (布洛芬)、ORUDIS® (酮洛芬)、RELAFEN® (萘丁美酮)、FELDENE® (吡罗昔康)、布洛芬乳膏、ALEVE® (萘普生)和NAPROSYN® (萘普生)、VOLTAREN® (双氯酚酸)、INDOCIN® (吲哚美辛)、CLINORIL® (舒林酸)、TOLECTIN® (托美汀)、LODINE® (依托度酸)、TORADOL® (酮咯酸)、DAYPRO®(奥沙普秦)等。
PDGFR抑制剂包括C-451、CP-673、CP-868596等。
铂化疗剂包括顺铂、ELOXATIN®(奥沙利铂) 依他铂、洛铂、奈达铂、PARAPLATIN®(卡铂)、沙铂、吡铂等。
Polo样激酶抑制剂包括BI-2536等。
磷酸肌醇-3激酶(PI3K)抑制剂包括渥曼青霉素、LY294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765等。
凝血栓蛋白类似物包括ABT-510、ABT-567、ABT-898、TSP-1等。
VEGFR抑制剂包括AVASTIN®(贝伐单抗)、ABT-869、AEE-788、ANGIOZYMETM(一种抑制血管生成的核酶(Ribozyme Pharmaceuticals (Boulder, Colo.)和Chiron,(Emeryville, CA))、阿昔替尼(AG-13736)、AZD-2171、CP-547,632、IM-862、MACUGEN (哌加他尼(pegaptamib))、NEXAVAR®(索拉非尼、BAY43-9006)、帕唑帕尼(GW-786034)、瓦他拉尼(PTK-787、ZK-222584)、SUTENT®(舒尼替尼、SU-11248)、VEGF捕获剂、ZACTIMATM (凡德他尼、ZD-6474)等。
抗生素包括嵌入抗菌素阿柔比星、放线菌素D、氨柔比星、安那霉素(annamycin)、阿霉素、BLENOXANE®(博来霉素)、柔红霉素、CAELYX®或MYOCET®(多柔比星脂质体)、依沙芦星、表柔比星(epirbucin)、加柔比星(glarbuicin)、ZAVEDOS®(伊达比星)、丝裂霉素C、奈莫柔比星、新制癌菌素、培洛霉素、吡柔比星、蝴蝶霉素、司替拉姆(stimalamer)、链佐星、VALSTAR®(戊柔比星)、净司他丁等。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、贝克咔啉(becatecarin)、贝洛替康、BN-80915、CAMPTOSAR® (盐酸伊立替康)、喜树碱、CARDIOXANE®(右旋丙亚胺)、二氟替康、艾特咔啉(edotecarin)、ELLENCE®或PHARMORUBICIN®(表柔比星)、依托泊苷、依沙替康、10-羟基喜树碱、吉马替康(gimatecan)、勒托替康、米托蒽醌、奥拉热星(orathecin)、吡柔比星(pirarbucin)、匹杉琼(pixantrone)、鲁比替康、索布佐生、SN-38、他氟泊苷、拓扑替康等。
抗体包括AVASTIN®(贝伐单抗)、CD40特异性抗体、chTNT-1/B、地舒单抗(denosumab)、ERBITUX®(西妥昔单抗)、HUMAX-CD4® (札木单抗)、IGF1R特异性抗体、林妥珠单抗、PANOREX® (依决洛单抗)、RENCAREX® (WX G250)、RITUXAN® (利昔妥单抗)、替西木单抗(ticilimumab)、曲妥珠单抗(trastuzimab)、I型和II型CD20抗体等。
激素疗法包括ARIMIDEX®(阿那曲唑)、AROMASIN®(依西美坦)、阿佐昔芬、CASODEX®(比卡鲁胺)、CETROTIDE®(西曲瑞克)、地加瑞克(degarelix)、地洛瑞林、DESOPAN® (曲洛司坦)、地塞米松、DROGENIL®(氟他胺)、EVISTA® (雷洛昔芬)、AFEMATM (法屈唑)、FARESTON®(托瑞米芬)、FASLODEX® (氟维司群)、FEMARA®(来曲唑)、福美坦、糖皮质激素类、HECTOROL®(度骨化醇)、RENAGEL® (碳酸司维拉姆)、拉索昔芬、醋酸亮丙瑞林、MEGACE®(甲地孕酮(megesterol))、MIFEPREX® (米非司酮)、NILANDRONTM(尼鲁米特)、NOLVADEX®(枸橼酸他莫昔芬)、PLENAXISTM(阿巴瑞克)、泼尼松、PROPECIA®(非那雄胺)、利洛司坦(rilostane)、SUPREFACT® (布舍瑞林)、TRELSTAR®(促黄体激素释放激素(LHRH))、VANTAS®(组胺瑞林植入物)、VETORYL® (曲洛司坦或莫达司坦(modrastane))、ZOLADEX®(福司瑞林(fosrelin)、戈舍瑞林)等。
类维生素D和类视黄素包括西奥骨化醇 (EB1089、CB1093)、来沙骨化醇(KH1060)、芬维A铵、PANRETIN® (阿利维A酸(aliretinoin))、ATRAGEN® (维甲酸脂质体)、TARGRETIN®(贝沙罗汀)、和LGD-1550等。
PARP抑制剂包括ABT-888 (维利帕尼(veliparib))、奥拉帕尼、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231等。
植物生物碱包括但不限于长春新碱、长春碱、长春地辛、和长春瑞滨等。
蛋白酶体抑制剂包括VELCADE®(硼替佐米)、MG132、NPI-0052、PR-171、卡非佐米等。
免疫剂的实例包括干扰素和其它免疫增强剂。干扰素包括干扰素 α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a、ACTIMMUNE® (干扰素γ-1b)或干扰素γ-n1、及其组合等。其它药物包括ALFAFERONE® ,(IFN-α)、BAM-002 (氧化谷胱甘肽)、BEROMUN® (他索纳明)、BEXXAR® (托西莫单抗)、CAMPATH® (阿仑珠单抗)、CTLA4 (细胞毒性淋巴细胞抗原4)、氨烯咪胺、地尼白介素、依帕珠单抗、GRANOCYTE® (来格司亭)、香菇多糖、白细胞α干扰素、咪喹莫特、MDX-010 (抗CTLA-4)、黑色素瘤疫苗、米妥莫单抗、莫拉司亭、MYLOTARGTM (吉妥珠单抗奥佐米星)、NEUPOGEN®(非格司亭)、OncoVAC-CL、OVAREX® (奥戈伏单抗)、帕妥莫单抗(pemtumomab)(Y-muHMFG1)、PROVENGE®(西普鲁塞T(sipuleucel-T))、沙格司亭(sargaramostim)、裂裥多糖、替西白介素、THERACYS® (卡介苗)、乌苯美司、VIRULIZIN®(免疫治疗剂,Lorus Pharmaceuticals)、Z-100 (丸山的特异性物质(SSM))、WF-10 (四氯十氧化物(TCDO))、PROLEUKIN® (阿地白介素)、ZADAXIN® (胸腺法新)、ZENAPAX®(达利珠单抗(daclizumab))、ZEVALIN® (90Y替伊莫单抗)等。
生物反应调节剂是指调节活的有机体的防御机制或组织细胞的生物反应,诸如存活、生长或分化,以引导其具有抗肿瘤活性的药物,包括云芝多糖(krestin)、香菇多糖、西佐喃(sizofuran)、溶链菌制剂PF-3512676(CpG-8954)、乌苯美司等。
嘧啶类似物包括阿糖胞苷(ara C或阿拉伯糖苷C)、胞嘧啶阿拉伯糖苷、去氧氟尿苷、FLUDARA®(氟达拉滨)、5-FU (5-氟尿嘧啶)、氟尿苷、GEMZAR® (吉西他滨)、TOMUDEX®(雷替曲塞(ratitrexed))、TROXATYLTM (三乙酰尿苷曲沙他滨)等。
嘌呤类似物包括LANVIS®(硫鸟嘌呤)和PURI-NETHOL®(巯嘌呤)。
抗有丝分裂剂包括巴他布林、埃博霉素D (KOS-862)、N-(2-((4-羟基苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、伊沙匹隆 (BMS 247550)、紫杉醇、TAXOTERE® (多西他赛)、PNU100940(109881)、帕妥匹隆(patupilone)、XRP-9881 (拉洛他赛(larotaxel))、长春氟宁、ZK-EPO (合成埃博霉素)等。
泛素连接酶抑制剂包括MDM2抑制剂(诸如努特林(nutlins))、NEDD8抑制剂(诸如MLN4924)等。
本发明化合物还可用作增强放射疗法效果的放射增敏剂。放射疗法的实例包括外线束放射疗法、远程放射疗法、近距离放射疗法和密封型、非密封型放射源放射疗法等。
此外,本发明化合物可与其它化疗剂组合,所述化疗剂例如ABRAXANETM(ABI-007)、ABT-100 (法尼基转移酶抑制剂)、ADVEXIN® (Ad5CMV-p53疫苗)、ALTOCOR®或MEVACOR® (洛伐他汀)、AMPLIGEN® (聚(poly)I:聚C12U,合成RNA)、APTOSYN® (依昔舒林)、AREDIA® (帕米磷酸)、阿加来必(arglabin)、L-天冬酰胺酶、阿他美坦 (1-甲基-3,17-二酮-雄甾-1,4-二烯)、AVAGE® (他扎罗汀)、AVE-8062(康普瑞汀(combreastatin)衍生物)、BEC2 (米妥莫单抗)、恶病质素(cachectin)或恶病质(cachexin)(肿瘤坏死因子-α)、康维辛(疫苗)、CEAVAC® (癌症疫苗)、CELEUK® (西莫白介素)、CEPLENE® (组胺二盐酸盐)、CERVARIX® (人乳头瘤病毒疫苗)、CHOP® (C: CYTOXAN® (环磷酰胺);H: ADRIAMYCIN® (羟基多柔比星);O: 长春新碱(ONCOVIN®);P: 泼尼松)、CYPATTM (醋酸环丙孕酮)、康普瑞汀A4P、DAB(389)EGF (经由His-Ala联结子与人表皮生长因子融合的白喉毒素的催化和转运域)或TransMID-107RTM (白喉毒素)、达卡巴嗪、更生霉素、5,6-二甲基氧杂蒽酮-4-乙酸(DMXAA)、恩尿嘧啶、EVIZONTM (乳酸角鲨胺)、DIMERICINE® (T4N5脂质体洗剂)、迪斯德莫来(discodermolide)、DX-8951f (甲磺酸依沙替康)、恩扎妥林(enzastaurin)、EPO906 (埃博霉素B)(epithilone B)、GARDASIL® (四价人乳头瘤病毒 (6、11、16、18型)重组疫苗)、GASTRIMMUNE®、GENASENSE®、GMK (神经节苷脂结合疫苗)、GVAX® (前列腺癌疫苗)、卤夫酮、组氨瑞林、羟基脲、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR (贝辛白介素)、IL-13-假单胞菌外毒素、干扰素α、干扰素γ、JUNOVANTM或MEPACTTM (米伐木肽)、洛那法尼(lonafarnib)、5,10-亚甲基四氢叶酸、米替福新(十六烷基磷酸胆碱)、NEOVASTAT®(AE-941)、NEUTREXIN® (葡萄糖醛酸三甲曲沙)、NIPENT® (喷司他丁)、ONCONASE® (核糖核酸酶)、ONCOPHAGE® (黑色素瘤疫苗治疗剂)、ONCOVAX® (IL-2疫苗)、ORATHECINTM (鲁比替康)、OSIDEM® (基于抗体的细胞药物)、OVAREX® MAb (鼠类单克隆抗体)、紫杉醇、PANDIMEXTM (来源于人参的包含20(S)原人参二醇(aPPD)和20(S)原人参三醇(aPPT)的糖苷配基皂苷)、帕尼单抗、PANVAC®-VF (研究中的癌症疫苗)、培门冬酶、PEG干扰素A、苯妥帝尔(phenoxodiol)、丙卡巴肼、瑞马司他、REMOVAB® (卡妥索单抗)、REVLIMID® (来那度胺)、RSR13 (乙法昔罗)、SOMATULINE® LA (兰瑞肽)、SORIATANE® (阿维A)、星形孢菌素 (链霉菌属星状孢子)、塔拉司他(talabostat)(PT100)、TARGRETIN® (贝沙罗汀)、TAXOPREXIN®(DHA-紫杉醇)、TELCYTA® (坎磷酰胺(canfosfamide)、TLK286)、特米利芬(temilifene)、TEMODAR® (替莫唑胺)、替米利芬、沙立度胺、THERATOPE® (STn-KLH)、诺拉屈西二氢氯组胺(thymitaq)(2-氨基-3,4-二氢-6-甲基-4-氧代-5-(4-吡啶基硫基)喹唑啉二盐酸盐)、TNFERADETM (腺病毒载体: 含有肿瘤坏死因子α基因的DNA载体)、TRACLEER®或ZAVESCA®(波生坦)、维甲酸(维生素A酸)、粉防己碱、TRISENOX® (三氧化二砷)、VIRULIZIN®、乌克兰抗癌药(ukrain)(来自白屈菜(greater celandine)植物生物碱的衍生物)、维他欣(vitaxin)(抗αvβ3 抗体)、XCYTRIN® (莫特沙芬钆)、XINLAYTM (阿曲生坦)、XYOTAXTM (聚谷氨酸紫杉醇)、YONDELIS® (曲贝替定)、ZD-6126、ZINECARD® (右雷佐生)、ZOMETA® (唑来膦酸(zolendronic acid))、和佐柔比星等。
很多蛋白已经参与一般自身免疫和炎症反应。因此,可以合并本发明的选择性Bcl-2抑制剂和能够改变参与一般自身免疫和炎症反应的其他蛋白功能的化合物。与自身免疫和炎性反应相关的蛋白的实例包括C5, CCL1 (I-309), CCL11 (eotaxin), CCL13(mcp-4), CCL15 (MIP-1d), CCL16 (HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19,CCL2 (mcp-1), CCL20 (MIP-3a), CCL21 (MIP-2), CCL23 (MPIF-1), CCL24 (MPIF-2 /eotaxin-2), CCL25 (TECK), CCL26, CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES),CCL7 (mcp-3), CCL8 (mcp-2), CXCL1, CXCL10 (IP-10), CXCL11 (I-TAC / IP-9),CXCL12 (SDF1), CXCL13, CXCL14, CXCL2, CXCL3, CXCL5 (ENA-78 / LIX), CXCL6(GCP-2), CXCL9, IL13, IL8, CCL13 (mcp-4), CCR1, CCR2, CCR3, CCR4, CCR5, CCR6,CCR7, CCR8, CCR9, CX3CR1, IL8RA, XCR1 (CCXCR1), IFNA2, IL10, IL13, IL17C,IL1A, IL1B, IL1F10, IL1F5, IL1F6, IL1F7, IL1F8, IL1F9, IL22, IL5, IL8, IL9,LTA, LTB, MIF, SCYE1 (内皮单核细胞激活的细胞因子), SPP1, TNF, TNFSF5, IFNA2,ABCF1, BCL6, C3, C4A, CEBPB, CRP, ICEBERG, IL1R1, IL1RN, IL8RB, LTB4R,TOLLIP, FADD, IRAK-M, IRAK1, IRAK2, IRAK4, MYD88, NCK2, TNFAIP3, TRADD,TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, ACVR1, ACVR1B, ACVR2, ACVR2B,ACVRL1, CD28, CD3E, CD3G, CD3Z, CD69, CD80, CD86, CNR1, CTLA4, CYSLTR1,FCER1A, FCER2, FCGR3A, GPR44, HAVCR2, OPRD1, P2RX7, TLR2, TLR3, TLR4, TLR5,TLR6, TLR7, TLR8, TLR9, TLR10, BLR1, CCL1, CCL2, CCL3, CCL4, CCL5, CCL7,CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22,CCL23, CCL24, CCL25, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9,CX3CL1, CX3CR1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11, CXCL12,CXCL13, CXCR4, GPR2, SCYE1, SDF2, XCL1, XCL2, XCR1, AMH, AMHR2, BMPR1A,BMPR1B, BMPR2, C19orf10 (IL27w), CER1, CSF1, CSF2, CSF3, DKFZp451J0118, FGF2,GFI1, IFNA1, IFNB1, IFNG, IGF1, IL1A, IL1B, IL1R1, IL1R2, IL2, IL2RA, IL2RB,IL2RG, IL3, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL8, IL8RA, IL8RB,IL9, IL9R, IL10, IL10RA, IL10RB, IL11, IL11RA, IL12A, IL12B, IL12RB1,IL12RB2, IL13, IL13RA1, IL13RA2, IL15, IL15RA, IL16, IL17, IL17R, IL18,IL18R1, IL19, IL20, KITLG, LEP, LTA, LTB, LTB4R, LTB4R2, LTBR, MIF, NPPB,PDGFB, TBX21, TDGF1, TGFA, TGFB1, TGFB1I1, TGFB2, TGFB3, TGFBI, TGFBR1,TGFBR2, TGFBR3, TH1L, TNF, TNFRSF1A, TNFRSF1B, TNFRSF7, TNFRSF8, TNFRSF9,TNFRSF11A, TNFRSF21, TNFSF4, TNFSF5, TNFSF6, TNFSF11, VEGF, ZFPM2, RNF110(ZNF144), FGF家族, PLGF, DLL4, NPR-1, Fcγ受体IIB调节剂, 抗类浆细胞调节剂, 免疫复合物清除改性剂例如RNase或DNase, 原癌基因抑制剂例如,但不限于c-kit和b-raf,1型纤维母细胞生长因子受体调节剂, 二氢乳清酸脱氢酶调节剂, 雌激素受体调节剂,DNA引导的DNA聚合酶抑制剂, CD85γ调节剂, 和后生改性剂。
用于治疗自身免疫和炎症疾病的组合可以包括本发明化合物和非甾族抗炎药,也称为NSAIDS,其包括药物例如布洛芬。其他组合可以包括皮脂类固醇包括脱氢波尼松;类固醇使用的熟知副作用可以通过逐渐减少与本发明组合治疗对象时需要的类固醇剂量降低或甚至消除。
可以与治疗狼疮的本发明的选择性Bcl-2抑制剂组合使用的治疗剂的非限制性实例包括以下:一种或多种细胞因子抑制性抗炎药(CSAID);其他人类细胞因子或生长因子的抗体或拮抗剂,例如, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17A, IL-17F, IL-18, IL-21,IL-22, IL-23, IL-25, IL-33, 干扰素(例如, α, β, γ等), Tweak, BAFF/BLyS,April, 趋化因子。本发明化合物也可以与抗体结合至细胞表面分子例如CD2, CD3, CD4,CD8, CD16, CD19, CD20, CD22, CD25, CD28, CD30, CD32, CD40, CD45, CD47, CD52,CD54, CD64, CD69, CD72, CD79, CD80 (B7.1), CD86 (B7.2), CD90, CD100, CD200,CTLA, ICOS-1, B7RP, BR3, TACI, BCMA, 或它们的配体包括CD154 (gp39或CD40L)。
本发明化合物也可以与其他试剂组合,所述其他试剂例如环磷酰胺、6-MP、咪唑硫嘌呤、柳氮磺胺吡啶、美沙拉嗪、奥沙拉嗪、氯喹、青霉胺、硫代苹果酸金(aurothiomalate)(肌内和口服)、咪唑硫嘌呤、秋水仙素、皮质类固醇(口服、吸入和局部注射)、选择性糖皮质激素受体调节剂(SGRMs)、Oβ-2 肾上腺素能受体激动剂(柳丁氨醇、特布他林、沙美特罗)、黄嘌呤(茶碱、氨茶碱)、色甘酸盐、奈多罗米、酮替芬、异丙托胺和氧托溴铵、环孢菌素、FK506、来氟米特、皮质类固醇例如脱氢波尼松、磷酸二酯酶抑制剂、腺苷激动剂、抗血栓形成试剂、补足抑制剂、肾上腺素试剂、通过前炎性细胞活素干扰信号传导的试剂例如TNF-α或IL-1 (例如, IRAK, NIK, IKK , p38或MAP激酶抑制剂)、IL-1β转化酶抑制剂、JAK抑制剂、BTK抑制剂、SYK抑制剂、PKC家族抑制剂、TNF-α转化酶(TACE)抑制剂、T-细胞信号传导抑制剂例如激酶抑制剂、金属蛋白酶抑制剂、柳氮磺胺吡啶、6-巯基嘌呤、血管紧张素转化酶抑制剂、可溶性细胞因子受体和其衍生物(例如, 可溶性p55或p75 TNF受体和衍生物p75TNFRIgG (EnbrelTM和p55TNFRIgG (Lenercept))、sIL-1RI, sIL-1RII, sIL-6R)、抗炎细胞因子(例如,IL-4, IL-6, IL-10, IL-11, IL12, IL-13, IL-17, IL-18, IL-33 和TGFβ)、叶酸、硫酸羟化氯喹、依那西普、英夫利昔、甲基强的松龙、美洛昔康、乙酸甲基强的龙、硫代苹果酸金钠、阿司匹林、曲安奈德、萘磺酸丙氧芬/扑热息痛、叶酸盐、双氯芬酸钠、盐酸氧可酮、氢可酮酒石酸氢盐/扑热息痛、双氯芬酸钠/米索前列醇、芬太尼、阿那白滞素、人类重组体、盐酸曲马多、氰钴维生素/fa/吡哆醇、对乙酰氨基酚、阿仑膦酸钠、氢化波尼松、硫酸吗啡、盐酸利多卡因、葡萄糖胺sulf/软骨素、盐酸阿米替林、磺胺嘧啶、sulfadiazine, 盐酸奥洛他定、米索前列醇、奥美拉唑、IL-1 TRAP、MRA、CTLA4-IG、IL-18BP、抗-IL-18、抗-IL15、BIRB-796、SCIO-469、VX-702、AMG-548、VX-740、罗氟司特、IC-485、CDC-801、Mesopram。组合可以另外包含来氟米特、环孢霉素和S1P激动剂。
可以与本发明化合物组合的用于SLE (狼疮)和狼疮性肾炎的治疗剂的实例包括如下:NSAIDs,例如双氯芬酸、萘普生、布洛芬、吡罗昔康、消炎痛;COX2 抑制剂,例如塞来昔布、罗非考昔、伐地考昔;抗-疟疾药,例如羟化氯喹;类固醇,例如强的松、氢化波尼松、budenoside、地塞米松;细胞毒素,例如咪唑硫嘌呤、环磷酰胺、霉酚酸酯、甲氨蝶呤;PDE4抑制剂或嘌呤合成抑制剂,例如Cellcept,并入本发明方法中的结合蛋白,也可以与如下试剂组合,例如柳氮磺胺吡啶、5-氨基水杨酸、奥沙拉嗪、硫唑嘌呤和干扰前炎性细胞因子例如IL-1的合成、产生或作用的试剂,例如,半胱天冬酶抑制剂例如IL-1β转化酶抑制剂和IL-1ra。本发明还可以与T细胞信号传导抑制剂,例如酪氨酸激酶抑制剂;或靶向T细胞激活分子的分子,例如CTLA-4-IgG或抗-B7家族抗体例如B7RP、抗-PD-1家族抗体一起使用。本发明,可以与IL-11或抗细胞因子抗体,例如fonotolizumab (抗-IFNg抗体)、抗-干扰素α、或抗受体受体抗体,例如抗-IL-6受体抗体(包括gp130)和针对B-细胞表面分子的抗体组合。本发明还可以与HMGB1的抑制剂,HDGF一起使用。本发明还可以与toll 样受体1, 2, 3, 4,7, 和9的抑制剂一起使用。本发明还可以与树突细胞制造剂BDCA-1, 2和3、DEC205、CD11c、Bst2 (PDCA-1)、Langerin、和SiglecH的抑制剂一起使用。本发明还可以与促进调节性T细胞功能的试剂一起使用。本发明还可以与LJP 394 (abetimus)、抑制补足的试剂,例如抗-C5、抗-C5a,消耗或去活B-细胞,例如利妥昔单抗(抗-CD20抗体)、lymphostat-B (抗-BlyS抗体)、抗-CD22、TNF 拮抗剂,例如抗-TNF抗体、阿达木单抗(PCT公开No. WO 97/29131;HUMIRA)、CA2 (REMICADE)、CDP 571、TNFR-Ig构件块、(p75TNFRIgG (ENBREL)和p55TNFRIgG(Lenercept))和其他bcl-2家族成员例如Bcl-xL、Mcl-1、A-1等的抑制剂一起使用。
可以与本发明的选择性Bcl-2抑制剂组合的用于治疗舍格伦综合症的治疗剂的实例包括但不限于人造泪液、环孢霉素、西维美林、匹鲁卡品、NSAID、皮质类固醇、免疫抑制剂、疾病改性的抗风湿药(DMARD)例如甲氨蝶呤、和羟化氯喹。
治疗方法
本发明的一个实施方案涉及治疗哺乳动物中癌症的方法,包括对其给予治疗上可接受的量的本发明化合物。
又另一实施方案涉及治疗哺乳动物中自身免疫疾病的方法,包括对其给予治疗上可接受的量的本发明化合物。
又另一实施方案涉及治疗对象疾病的方法,在此期间表达抗细胞凋亡Bcl-2蛋白,所述方法包括向该对象给予治疗有效量的本发明化合物。
又另一种实施方案涉及治疗个体中膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌或脾脏癌的方法,所述方法包括给予所述对象治疗有效量的本发明化合物。
又另一实施方案涉及治疗对象中疾病的方法,在此期间表达抗细胞凋亡Bcl-2蛋白,所述方法包括向该对象给予治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
又另一种实施方案涉及治疗膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾脏癌的方法,所述方法包括给予所述对象治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
又另一实施方案涉及治疗对象中全身性红斑狼疮、狼疮性肾炎、或舍格伦综合症的方法,所述方法包括向该对象给予治疗有效量的本发明化合物。
又另一实施方案涉及治疗对象中全身性红斑狼疮、狼疮性肾炎、和舍格伦综合症的方法,所述方法包括向该对象给予治疗有效量的本发明化合物和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂。
预期由于本发明化合物结合至Bcl-2,它们还会用作与对Bcl-2具有紧密结构同源性的抗细胞凋亡蛋白,例如抗细胞凋亡Bcl-XL、Bcl-w、Mcl-1和Bfl-1/A1蛋白的结合剂。
在共同拥有的PCT/US2004/036770(公开为WO 2005/049593)中、在PCT/US2004/037911(公开为WO 2005/049594)中、和在PCT/US01/29432(公开为WO02/24636)中记载膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌或脾脏癌等中的Bcl-2蛋白的参与。
在Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90;Blood 2000, 95(4), 1283-92;和New England Journal of Medicine 2004, 351(14), 1409-1418中记载免疫和自身免疫疾病中的Bcl-2蛋白的参与。在共同拥有的PCT/US2008/083478(公开为WO 2009/064938)中公开了关节炎中Bcl-2蛋白的参与。在共同拥有的PCT/US2011/061769(公开为WO 2012/071374)中记载治疗全身性红斑狼疮、狼疮性肾炎、和舍格伦综合症的方法中的Bcl-2蛋白的参与。在共同拥有的美国专利申请序列号No. 11/941,196中公开了骨髓移植排斥中Bcl-2蛋白的参与。
Bc1-2蛋白的过度表达与在免疫系统的多种癌症和障碍中的耐化疗性、临床结果、疾病进展、总预后(overall prognosis)或其组合有关。癌症包括但不限于血液学和实体肿瘤类型诸如听神经瘤、急性白血病、急性成淋巴细胞性白血病、急性骨髓性白血病(单核细胞性、成髓细胞性、腺癌、血管肉瘤、星细胞瘤、髓单核细胞性和前骨髓性)、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌(包括雌激素-受体阳性乳腺癌)、支气管原癌(bronchogenic carcinoma)、伯基特氏(Burkitt's)淋巴瘤、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性骨髓性(粒细胞性)白血病、慢性髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、异常增生性变化(发育异常和组织变形)、胚胎性癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食道癌、雌激素-受体阳性乳腺癌、原发性血小板增多症、尤因瘤、纤维肉瘤、胃癌、生殖细胞睾丸癌、妊娠滋养细胞病、胶质母细胞瘤、头和颈部癌、重链病、成血管细胞瘤、肝细胞瘤、肝细胞癌、激素非敏感性前列腺癌、平滑肌肉瘤、脂肉瘤、肺癌(包括小细胞肺癌和非小细胞肺癌)、淋巴管内皮-肉瘤、淋巴管肉瘤、成淋巴细胞性白血病、淋巴瘤(淋巴瘤、包括弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、霍杰金淋巴瘤和非霍杰金淋巴瘤)、膀胱、乳房、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增生性病症、T细胞或B细胞源的淋巴恶性肿瘤、白血病、髓样癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、少突胶质细胞瘤、口腔癌、骨原性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、外围T细胞淋巴瘤、松果体瘤、真性红细胞增多症、前列腺癌(包括激素非敏感性(难治性)前列腺癌)、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、睾丸癌(包括生殖细胞睾丸癌)、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸瘤、子宫癌、和维尔姆斯瘤(Wilms' tumor)等。
还期望的是本发明化合物可抑制表达源自儿科癌症或赘生物的Bc1-2蛋白的细胞生长,所述儿科癌症或赘生物包括胚胎性横纹肌肉瘤、儿科急性成淋巴细胞性白血病、儿科急性髓性白血病、儿科腺泡状横纹肌肉瘤、儿科间变性室管膜瘤、儿科间变性大细胞淋巴瘤、儿科间变性成神经管细胞瘤、中枢神经系统的儿科非典型性畸胎样/横纹肌样瘤、儿科双表型急性白血病、儿科伯基特氏淋巴瘤、尤因族瘤的儿科癌如原始神经外胚层瘤(rumors)、儿科弥漫性间变性维尔姆斯瘤、儿科良好组织型维尔姆斯瘤、儿科胶质母细胞瘤、儿科成神经管细胞瘤、儿科成神经细胞瘤、儿科成神经细胞瘤源的髓细胞组织增生、儿科前B细胞癌(如白血病)、儿科骨肉瘤(psteosarcoma)、儿科杆状肾瘤、儿科横纹肌肉瘤、和儿科T细胞癌如淋巴瘤和皮肤癌等。
自身免疫病症包括获得性免疫缺陷病综合征(AIDS)、自身免疫淋巴组织增生综合征、溶血性贫血、炎性疾病、和血小板减少症、与器官移植有关的急性或慢性免疫性疾病、艾迪生氏(Addison's)病、变态反应性疾病、脱发、局限性脱发、动脉粥样病/动脉硬化、动脉粥样硬化、关节炎(包括骨关节炎、青少年慢性关节炎、脓毒性关节炎、莱姆关节炎、牛皮癣关节炎和反应性关节炎)、自身免疫大疱病、无β脂蛋白血症(abetalipoprotemia)、获得性免疫缺陷相关的疾病、与器官移植有关的急性免疫性疾病、获得性手足发绀、急性和慢性寄生或传染过程、急性胰腺炎、急性肾衰竭、急性风湿热、急性横贯性脊髓炎、腺癌、心房(aerial)异位搏动、成年(急性)呼吸窘迫综合征、AIDS痴呆复合征、酒精性肝硬变、酒精引起的肝损伤、酒精引起的肝炎、变应性结膜炎、变应性接触性皮炎、变应性鼻炎、变应性和哮喘、同种异体移植排斥、α-l-抗胰蛋白酶缺乏症、阿尔茨海默氏病、肌萎缩性侧索硬化、贫血、心绞痛、强直性脊椎炎相关的肺病、前角细胞退化、抗体介导的细胞毒性、抗磷脂综合征、抗受体超敏性反应、主动脉和周围动脉动脉瘤、主动脉剥离、动脉高血压、动脉硬化、动静脉瘘、关节病、虚弱、哮喘、共济失调、特应性变态反应、心房颤动(持续性或阵发性)、心房扑动、房室传导阻滞、萎缩性自身免疫甲状腺机能减退、自身免疫性溶血性贫血、自身免疫肝炎、I型自身免疫肝炎(传统的自身免疫或狼疮样肝炎)、自身免疫介导的低血糖、自身免疫嗜中性白血球减少症、自身免疫血小板减少(thrombocytopaenia)、自身免疫性甲状腺病、B细胞淋巴瘤、骨移植排斥、骨髓移植(BMT)排斥、闭塞性细支气管炎、束支阻滞、烧伤、恶病质、心律不齐、心脏眩晕综合征、心脏肿瘤、心肌病、心肺转流术炎症响应、软骨移植排斥、小脑皮质退化、小脑病症、紊乱性或多源性房性心动过速、化疗相关的病症、衣原体病、胆汁淤滞(choleosatatis)、慢性酒精中毒、慢性活动型肝炎、慢性疲劳综合征、与器官移植有关的慢性免疫性疾病、慢性嗜酸细胞性肺炎、慢性炎性病变、慢性皮肤粘膜念珠菌病、慢性阻塞性肺病(COPD)、慢性水杨酸盐中毒、常见变异的免疫缺陷(常见变异型低丙种球蛋白血症)、结膜炎、结缔组织病相关的间质性肺病、接触性皮炎、库姆斯(Coombs)阳性溶血性贫血、肺原性心脏病、克罗伊茨费尔特-雅各布氏(Creutzfeldt-Jakob)病、隐源性自身免疫肝炎、隐源性纤维性肺泡炎、培养阴性脓毒症、囊性纤维化、细胞因子治疗相关病症、克罗恩病、拳击员痴呆、脱髓鞘疾病、登革热出血热、皮炎、硬皮病、皮肤病症、皮肌炎/多肌炎相关的肺病、糖尿病(diabetes)、糖尿病性动脉硬化病、糖尿病(diabetes mellitus)、弥漫性Lewy体病、扩张性心肌病、扩张充血性心肌病、盘状红斑狼疮、基底神经节的病症、弥漫性血管内凝血、中年唐氏综合征、药物引起的间质性肺病、药物引起的肝炎、由阻断CNS多巴胺受体的药物引起的药物引起的运动障碍、药物过敏性、湿疹、脑脊髓炎、心内膜炎、内分泌病、肠病性滑膜炎、会厌炎、埃-巴二氏(Epstein-Barr)病毒感染、红斑性肢痛病、锥体束外和小脑障碍、家族性噬血细胞(hematophagocytic)淋巴组织细胞增生症、胎儿胸腺移植排斥、弗里德赖希氏共济失调、功能性周围动脉病症、雌性不育、纤维化、纤维化肺病、真菌性脓毒症、气性坏疽、胃溃疡、巨细胞动脉炎、肾小球性肾炎、血管球性肾炎(glomerulonephritides)、古德帕斯彻氏综合征、甲状腺肿自身免疫甲状腺机能减退(桥本氏病)、痛风性关节炎、任何器官或组织的移植排斥、移植物抗宿主疾病、革兰氏阴性脓毒症、革兰氏阳性脓毒症、由于胞内生物体造成的肉芽肿、B组链球菌(GBS)感染、格雷夫斯病(Grave's disease)、含铁血黄素沉着相关的肺病、毛细胞白血病、毛细胞白血病、哈-斯二氏 (Hallervorden-Spatz)病、桥本氏甲状腺炎、花粉热、心脏移植排斥、血色素沉着、造血恶性肿瘤(白血病和淋巴瘤)、溶血性贫血、溶血性尿毒症综合征/血栓性血小板减少性紫癜、出血、亨-舒氏紫癜(Henoch-Schoenlein purpurea)、甲型肝炎、乙型肝炎、丙型肝炎、HIV感染/HIV神经病、何杰金氏病、甲状旁腺机能减退、亨廷顿氏舞蹈病、运动机能亢进性运动障碍、过敏性反应、过敏性肺炎、甲状腺机能亢进、运动功能减退性运动障碍、下丘脑-垂体-肾上腺轴评估、特发性艾迪生氏病、特发性白细胞减少症、特发性肺纤维化、特发性血小板减少(thrombocytopaenia)、特异质肝病、婴儿脊髓性肌萎缩、传染病、主动脉炎症、炎症性肠病、过敏性肠病、胰岛素依赖型糖尿病、间质性肺炎、虹膜睫状体炎/葡萄膜炎/视神经炎、缺血-再灌注损伤、缺血性中风、青少年恶性贫血、青少年类风湿性关节炎、青少年脊髓性肌萎缩、卡波西肉瘤、川畸氏病、肾移植排斥、军团杆菌(legionella)、利什曼病、麻风病、皮质脊髓系统的损伤、线性IgA病、脂肪水肿(lipidema)、肝移植排斥、莱姆病、淋巴水肿、淋巴细胞浸润性肺病、疟疾、特发性或NOS雄性不孕症(male infertility idiopathic orNOS)、恶性组织细胞增多症、恶性黑色素瘤、脑膜炎、脑膜炎球菌血症、肾显微血管炎、偏头痛、线粒体多系统病症、混合结缔组织病、混合结缔组织病相关的肺病、单克隆丙种球蛋白病、多发性骨髓瘤、多系统退化(Mencel Dejerine-Thomas Shi-Drager和Machado-Joseph)、肌痛性脑炎/非皇家疾病(Royal Free Disease)、重症肌无力、肾显微血管炎、鸟胞内分枝杆菌、结核分枝杆菌、脊髓发育不良(myelodyplastic)综合征、心肌梗塞、心肌缺血性病症、鼻咽癌、初生儿慢性肺病、肾炎、肾变病、肾病综合征、神经变性疾病、I型神经原性肌肉萎缩、中性粒细胞减少性发烧、非酒精性脂肪性肝炎、腹主动脉及其分支的闭塞、闭塞性动脉病症、器官移植排斥、睾丸炎/附睾炎(epidydimitis)、睾丸炎/输精管复通术、器官巨大症、骨关节病、骨质疏松症、卵巢衰竭、胰脏移植排斥、寄生虫病、甲状旁腺移植排斥、帕金森氏病、盆腔炎性疾病、寻常天疱疮、落叶状天疱疮、类天疱疮、常年性鼻炎、心包疾病、周围性动脉粥样硬化(atherlosclerotic)病、周围性血管病症、腹膜炎、恶性贫血、晶状体源性葡萄膜炎、卡氏肺囊虫病肺、肺炎、POEMS综合征(多神经病、器官巨大症、内分泌病、单克隆丙种球蛋白病、和皮肤变化综合征)、灌注后综合征、泵送后综合征、MI心切开术后综合征、感染后间质性肺病、卵巢早衰、原发性胆汁性肝硬变、原发性硬化性肝炎、原发性粘液水肿、原发性肺动脉高压、原发性硬化性胆管炎、原发性血管炎、进行性核上麻痹、牛皮癣、1型牛皮癣、2型牛皮癣、牛皮癣关节病、结缔组织病继发性肺性高血压、结节性多发性动脉炎的肺部表现、炎症后间质性肺病、放射性肺纤维化、放射治疗、雷诺氏现象和疾病、雷诺氏病(Raynoud's disease)、雷夫叙姆病(Refsum's disease)、规则性窄QRS心动过速、莱特尔氏病(Reiter's disease)、NOS肾病、肾血管高血压、再灌注损伤、限制性心肌病、类风湿性关节炎相关的间质性肺病、类风湿性脊椎炎、肉样瘤病、施密特氏综合征、硬皮病、老年性舞蹈病、路易体类型的老年性痴呆、脓毒症综合征、脓毒性休克、血清反应阴性关节病、休克、镰刀状红细胞贫血病、干燥综合征(Sjögren's disease)相关的肺病、干燥综合征、同种移植皮排异反应、皮肤变化综合征、小肠移植排斥、精液自体免疫、多发性硬化(所有亚型)、脊髓性共济失调、脊髓小脑变性、脊椎关节病(spondyloarthopathy)、散发性I型多腺缺乏、散发性II型多腺缺乏、斯蒂尔病(Still's disease)、链球菌性肌炎、中风、小脑的结构损害、亚急性硬化性全脑炎、交感性眼炎、晕厥、心血管系统的梅毒、全身过敏、全身炎性反应综合征、全身发病型青年类风湿性关节炎、系统性红斑狼疮、系统性红斑狼疮-相关的肺病、系统性硬化、系统性硬化-相关的间质性肺病、T细胞或FAB ALL、高安氏病(Takayasu'sdisease) /动脉炎、毛细血管扩张、Th2型和Th1型介导的疾病、血栓闭塞性脉管炎、血小板减少、甲状腺炎、毒性、中毒性休克综合征、移植、外伤/出血、2型自身免疫肝炎(抗-LKM抗体肝炎)、伴有黑棘皮病的B型胰岛素抵抗、III型过敏性反应、IV型过敏性、溃疡性结肠炎(colitic)关节病、溃疡性结肠炎、不稳定心绞痛、尿毒症、尿脓毒病、风疹、葡萄膜炎、心脏瓣膜病、静脉曲张、血管炎、血管炎弥散性肺病、静脉疾病、静脉血栓形成、心室纤维性颤动、白癫风急性肝病、病毒和真菌感染、病毒性脑炎(vital encephalitis)/无菌性脑膜炎、病毒(vital)相关的噬血细胞(hemaphagocytic)综合征、韦格纳肉芽肿病、韦-科二氏(Wernicke-Korsakoff)综合征、威尔逊氏病、任何器官或组织的异种移植排斥、耶尔森氏菌和沙门氏菌-相关的关节病等。
实施例
实验
以下缩写具有所指出的含义。ADDP是指1,1'-(偶氮二羰基)二哌啶;AD-mix-β是指(DHQD)2PHAL、K3Fe(CN)6、K2CO3、和K2SO4的混合物;9-BBN是指9-硼杂双环(3.3.1)壬烷;Boc是指叔丁氧羰基;(DHQD)2PHAL是指氢化奎尼定1,4-酞嗪二基二乙醚;DBU是指1,8-二氮杂二环[5.4.0]十一碳-7-烯;DIBAL是指二异丁基氢化铝;DIEA是指二异丙基乙胺;DMAP是指N,N-二甲基氨基吡啶;DMF是指N,N-二甲基甲酰胺;dmpe是指1,2-双(二甲基膦基)乙烷;DMSO是指二甲基亚砜;dppb是指1,4-双(二苯基膦基)-丁烷;dppe是指1,2-双(二苯基膦基)乙烷;dppf是指1,1'-双(二苯基膦基)二茂铁;dppm是指1,1-双(二苯基膦基)甲烷;EDAC·HCl是指1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐;Fmoc是指芴基甲氧基羰基;HATU是指O-(7-氮杂苯并三唑-1-基)-N,N'N'N'-四甲基脲鎓六氟磷酸盐;HMPA是指六甲基磷酰胺;IPA是指异丙醇;MP-BH3是指大孔的三乙铵甲基聚苯乙烯氰基硼氢化物;TEA是指三乙胺;TFA是指三氟乙酸;THF是指四氢呋喃;NCS是指N-氯代琥珀酰亚胺;NMM是指N-甲基吗啉;NMP是指N-甲基吡咯烷;PPh3是指三苯基膦。
本发明化合物可以通过合成化学方法制备,其实例在本文中示出。在共同拥有的美国专利申请序列号No. 12/951344中公开了本发明的程序和概念方面的最可用和容易理解的描述的示例性方案。应理解,可以改变方法中的步骤顺序,试剂、溶剂和反应条件可以替代所具体提及的试剂、溶剂和反应条件,且根据需要可以将易变部分进行保护和脱保护。
对于本领域那些技术人员容易明显的是在不脱离本发明范围或本文中公开的实施方案的情况下,本文中所述的本发明化合物的其他合适的改变和改动是明显的并可以使用合适的等同物制备。现在已经详细描述了本发明,其通过参考以下实施例更清楚地理解,实施例仅出于实例目的被包括而非意在限制本发明。
出现以下实施例以提供据信是本发明的程序和概念方面的最有用的并容易理解的描述。使用ACD/ChemSketch Build 59026 (03 September 2012), Advanced ChemistryDevelopment Inc., Toronto, Ontario), 或ChemDraw® Ver. 9.0.7 (CambridgeSoft,Cambridge, MA)命名各示例性化合物和中间体。
实施例 1
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2R)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 1A
4,4-二甲基-2-(三氟甲基磺酰基氧基)环己-1-烯甲酸甲酯
在0℃下向己烷洗涤的NaH (17 g)在二氯甲烷 (700 mL)中的悬浮液中逐滴添加5,5-二甲基-2-甲氧基羰基环己酮 (38.5 g)。在搅拌30分钟之后,将该混合物冷却至–78℃并添加三氟甲磺酸酐 (40 mL)。将该反应混合物温热至室温并搅拌24小时。用盐水洗涤有机层,干燥 (Na2SO4),过滤,并浓缩以提供标题化合物。
实施例 1B
2-(4-氯苯基)-4,4-二甲基环己-1-烯甲酸甲酯
将2:1 二甲氧基乙烷 /甲醇(600 mL)中的实施例 1A (62.15g), 4-氯苯基硼酸(32.24 g), CsF (64 g)和四(三苯基膦)钯(0) (2g)加热至70℃持续24小时。浓缩该混合物。添加乙醚 (4x 200 mL) 并过滤混合物。将合并的乙醚溶液浓缩以提供标题化合物。
实施例 1C
(2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲醇
通过注射器向LiBH4 (13g), 实施例 1B (53.8 g) 和乙醚 (400 mL)的混合物中缓慢添加甲醇 (25 mL)。在室温下搅拌该混合物24小时。在冰冷却下采用1N HCl水溶液淬灭该反应。用水稀释该混合物并用乙醚 (3x 100 mL)萃取。干燥 (Na2SO4)萃取物,过滤,并浓缩。在硅胶上采用0-30% 乙酸乙酯/己烷层析法处理粗产物。
实施例 1D
4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-甲酸叔丁酯
在0℃下通过注射器添加甲磺酰氯(7.5 mL)至CH2Cl2 (500 mL)中的实施例 1C(29.3 g)和三乙胺 (30 mL)中,并搅拌该混合物1分钟。添加N-叔丁氧基羰基哌嗪 (25 g)并在室温下搅拌该混合物24小时。用盐水洗涤悬浮液,干燥(Na2SO4),过滤,并浓缩。在硅胶上采用10-20% 乙酸乙酯/己烷层析法处理粗产物。
实施例 1E
1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪
将实施例 1D (1 g) 在二氯甲烷 (10 mL), 三氟乙酸 (10 mL), 和三乙基硅烷(1 mL)中搅拌1小时。浓缩该混合物,溶解于二氯甲烷 (100 mL)和饱和Na2CO3水溶液(20mL)的混合物中并搅拌10分钟。分离各层,并经Na2SO4干燥有机层,过滤,并浓缩以提供标题化合物。
实施例 1F
5-溴-1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶
向5-溴-1H-吡咯并[2,3-b]吡啶(15.4 g)在四氢呋喃 (250 mL)中的混合物中添加1M 六甲基二硅烷基氨基锂/四氢呋喃 (86 mL),并在10分钟之后,添加TIPS-Cl (三异丙基氯硅烷 ) (18.2 mL)。在室温下搅拌该混合物24小时。用乙醚稀释该反应,并用水洗涤所得溶液两次。干燥该萃取物(Na2SO4),过滤,并浓缩。在硅胶上采用10% 乙酸乙酯/己烷层析法处理粗产物。
实施例 1G
1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-醇
在-78℃下向实施例 1F(24.3 g)在四氢呋喃 (500 mL)中的混合物中添加2.5MBuLi/己烷 (30.3 mL)。在2分钟之后,添加硼酸三甲酯 (11.5 mL),使该混合物经1小时温热至室温。将该反应倾倒入水中,用乙酸乙酯萃取三次,并用盐水洗涤合并的萃取物并浓缩。在0℃下将粗产物溶解于四氢呋喃 (200 mL)中,添加1M NaOH水溶液 (69 mL) ,然后添加30% H2O2水溶液 (8.43 mL),并将该溶液搅拌1小时。添加Na2S2O3 (10 g),用浓HCl和固体NaH2PO4将pH 调节成4-5。用乙酸乙酯萃取该溶液两次,并用盐水洗涤合并的萃取物,干燥(Na2SO4),过滤,并浓缩。在硅胶上采用5-25%乙酸乙酯/己烷层析法处理粗产物。
实施例 1H
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-氟苯甲酸甲酯
在115℃下将实施例 1G(8.5 g), 2,4-二氟苯甲酸甲酯 (7.05 g), 和K3PO4(9.32 g)在二甘醇二甲醚 (40 mL)中的混合物搅拌24小时。冷却该反应,用乙醚(600 mL)稀释,并用水和盐水洗涤两次,并浓缩。在硅胶上采用2-50%乙酸乙酯/己烷层析法处理粗产物。
实施例 1I
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸甲酯
在135℃下将实施例 1H(1.55 g), 实施例 1E (2.42 g), 和HK2PO4 (1.42 g)在二甲亚砜 (20 mL)中的混合物搅拌24小时。冷却该反应,并用乙醚 (400 mL)稀释,用1MNaOH水溶液和盐水洗涤三次, 并浓缩。在硅胶上采用10-50%乙酸乙酯/己烷层析法处理粗产物。
实施例 1J
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸
在50℃下搅拌二氧杂环己烷 (10 mL)和1M NaOH水溶液 (6 mL)中的实施例 1I(200 mg) 24小时。冷却该反应,添加至NaH2PO4溶液,并用乙酸乙酯萃取三次。用盐水洗涤合并的萃取物,并浓缩以提供标题化合物。
实施例 1K
4-甲基苯磺酸(S)-(1,4-二氧杂环己烷-2-基)甲酯
向2-氯乙醇 (9.1 mL)/甲苯(17 mL)中添加Et2O•BF3 (0.30 mL),并将温水浴用于温热该混合物至38℃。逐滴添加S-(+)-表氯醇(3.4 mL),保持温度< 45℃。在约35℃下搅拌该反应20分钟,冷却至15℃,并逐滴添加20% NaOH (21 mL),保持温度< 18℃。然后,使该反应温热至室温持续1小时,添加水 (10 mL),分离各层,用甲苯萃取水层,用水洗涤合并的甲苯层,浓缩有机层成油。将NaOH (20% (wt) 水溶液, 50 g)加热至90℃,然后添加上述油,并将该混合物加热1小时,并冷却至室温。然后,添加二氯甲烷 (12 mL),然后添加对甲苯磺酰基氯 (8.0 g)。在室温下搅拌两相反应过夜。添加水 (10 mL),并用二氯甲烷 (10 mL)萃取水层两次。用1/1 水/盐水洗涤合并的二氯甲烷层并经Na2SO4干燥。在过滤和浓缩之后,在硅胶上采用65/35 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 1L
(R)-2-(叠氮基甲基)-1,4-二氧杂环己烷
将实施例 1K (2.5 g)溶解于N,N-二甲基甲酰胺 (12 mL)中,然后添加叠氮化钠(1.0 g),并在80 ℃下加热该反应3小时。然后,冷却该反应并用水稀释并用乙酸乙酯萃取。用盐水洗涤有机层并用乙酸乙酯萃取合并的水层。经Na2SO4干燥合并的有机层。在过滤和浓缩之后,在硅胶上采用3/1 庚烷/乙酸乙酯层析法粗物质以提供标题化合物。
实施例 1M
(R)-(1,4-二氧杂环己烷-2-基)甲胺
将实施例 1L (916 mg)溶解于四氢呋喃 (20 mL) 和水(5 mL)中。然后添加三甲基膦 (6.4 mL, 1.0M 在四氢呋喃中)并在室温下搅拌该反应混合物90分钟。然后,添加2NLiOH水溶液 (6 mL),用乙酸乙酯萃取。用盐水洗涤有机层两次,然后经Na2SO4干燥。在过滤和浓缩之后,将产物用于下一步骤而不进行纯化。
实施例 1N
(R)-4-((1,4-二氧杂环己烷-2-基)甲基氨基)-3-硝基苯磺酰胺
将实施例 1M (160 mg)溶解于四氢呋喃 (3 mL)中,然后添加4-氟-3-硝基苯磺酰胺 (164 mg),随后添加N-乙基-N-异丙基丙-2-胺 (0.25 mL),并在45℃下加热该混合物过夜。然后,浓缩该反应混合物并添加甲醇 (3 mL)并搅拌该混合物过夜。过滤掉固体,用更多的甲醇洗涤滤饼以提供标题化合物。
实施例 1O
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2R)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
将实施例 1N (170 mg), 实施例 1J (340 mg), 1-乙基-3-[3-(二甲基氨基)丙基]-碳二亚胺 盐酸盐(150 mg), 和4-二甲基氨基吡啶 (130 mg) 在CH2Cl2 (5 mL) 中搅拌过夜。然后,添加N1,N1-二甲基乙烷-1,2-二胺 (0.19 mL),并将该混合物搅拌90分钟。添加二氯甲烷 (15 mL),用在水中的10% 乙酸:0.75% NaCl(2 x 12 mL)洗涤反应混合物。用二氯甲烷反萃取合并的水层,并用盐水洗涤合并的有机物,经Na2SO4干燥。在过滤和浓缩之后,在硅胶上用3/7 二氯甲烷/乙酸乙酯层析法处理粗物质。在硅胶上采用1.5-2.5%CH3OH/二氯甲烷层析法处理该物质。用CH3CN研磨该物质以提供标题化合物。
实施例 2
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 2A
(S)-3-硝基-4-((1-(四氢-2H-吡喃-4-基)乙基)氨基)苯磺酰胺
通过在实施例 1N中用(S)-1-(四氢-2H-吡喃-4-基)乙胺代替实施例 1M制备标题化合物。
实施例 2B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 2A替代实施例 1N制备标题化合物。
实施例 3
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 3A
(R)-3-硝基-4-((1-(四氢-2H-吡喃-4-基)乙基)氨基)苯磺酰胺
通过在实施例 1N 中用(R)-1-(四氢-2H-吡喃-4-基)乙胺替代实施例 1M制备标题化合物。
实施例 3B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氢-2H-吡喃-4-基)乙基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 3A替代实施例 1N制备标题化合物。
实施例 4
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5s,8s)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 4A
1-氧杂螺[4.5]癸烷-8-甲腈
在0℃下逐滴添加叔丁醇钾 (1.68 g)至1-氧杂螺[4.5]癸-8-酮(0.96 g)和TosMIC试剂(甲苯磺酰基甲基异腈, 1.46 g)在1,2-二甲氧基乙烷 (30 mL)和乙醇(0.5mL)中的混合物中。将该反应混合物温热至室温并搅拌4小时,然后加热至40℃持续24小时。冷却该反应混合物,用乙醚(600 mL)稀释,用水和盐水洗涤两次,并浓缩。在硅胶上用1-20%乙酸乙酯/己烷层析法处理粗产物以提供标题化合物。
实施例 4B
1-氧杂螺[4.5]癸烷-8-基甲基胺
在0℃ 下将LiAlH4 (9.1 mL, 1M在四氢呋喃中)添加至实施例 4A(0.96 g)/四氢呋喃 (30 mL)。使该反应混合物温热至室温并搅拌1小时。用另外的2 mL 水和10 mL 1MNaOH水溶液淬灭该反应混合物,并搅拌该混合物1小时。用乙醚 (100 mL)稀释该反应混合物,过滤,并浓缩以提供标题化合物。
实施例 4C
4-(((5s,8s)-1-氧杂螺[4.5]癸-8-基甲基)氨基)-3-硝基苯磺酰胺
在50℃下将4-氟-3-硝基苯磺酰胺 (650 mg), 实施例 4B(500 mg) and 三乙胺(0.41 mL)在四氢呋喃 (12 mL)中加热2小时。浓缩该反应混合物。在硅胶上用50% 乙酸乙酯/己烷层析法处理粗产物以提供标题化合物。
实施例 4D
4-(((5r,8r)-1-氧杂螺[4.5]癸-8-基甲基)氨基)-3-硝基苯磺酰胺
还从实施例 4C分离标题化合物作为较后洗脱的级分。
实施例 4E
N-((4-(((5s,8s)-1-氧杂螺[4.5]癸-8-基甲基)氨基)-3-硝基苯基)磺酰基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)甲基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)苯甲酰胺
通过在实施例 1O中用实施例 4C替代实施例 1N制备标题化合物。
实施例 5
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5r,8r)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 4D替代实施例 1N制备标题化合物。
实施例 6
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-羟基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 6A
4-(((4-羟基四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用4-(氨基甲基)四氢-2H-吡喃-4-醇替代实施例 1M制备标题化合物。
实施例 6B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-羟基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 6A替代实施例 1N制备标题化合物。
实施例 7
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂螺[4.5]癸-8-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 7A
1,4-二氧杂螺[4.5]癸烷-8-甲腈
通过在实施例 4A 中用1,4-二氧杂螺[4.5]癸-8-酮替代1-氧杂螺[4.5]癸-8-酮制备标题化合物。
实施例 7B
1,4-二氧杂螺[4.5]癸-8-基甲胺
通过在实施例 4B中用实施例 7A替代实施例 4A制备标题化合物。
实施例 7C
4-((1,4-二氧杂螺[4.5]癸-8-基甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 7B替代实施例 1M制备标题化合物。
实施例 7D
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂螺[4.5]癸-8-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 7C替代实施例 1N制备标题化合物。
实施例 8
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 8A
4-吗啉代-3-硝基苯磺酰胺
通过在实施例 1N中用吗啉替代实施例 1M制备标题化合物。
实施例 8B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 8A替代实施例 1N制备标题化合物。
实施例 9
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2S)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 9A
甲磺酸(R)-(1,4-二氧杂环己烷-2-基)甲酯
通过在实施例 1K 中用R-(-)-表氯醇替代S-(+)-表氯醇制备标题化合物。
实施例 9B
(S)-2-(叠氮基甲基)-1,4-二氧杂环己烷
通过在实施例 1L中用实施例 9A替代实施例 1K制备标题化合物。
实施例 9C
(S)-(1,4-二氧杂环己烷-2-基)甲胺
将实施例 9B (400 mg)溶解于四氢呋喃 (15 mL)中,冷却至0℃,并添加氢化锂铝(2.0 mL, 2.0M在四氢呋喃中)。在0℃ 下搅拌该反应混合物50分钟,然后在室温下再搅拌75分钟。将该反应混合物冷却至0℃,然后小心添加水(0.16 mL),然后添加20% NaOH水溶液(0.16 mL), 和另外的水(0.48 mL)。将该混合物搅拌15分钟,添加MgSO4并添加乙醚(20mL)。搅拌该混合物15分钟, 通过硅藻土过滤,用乙醚冲洗。滤液的浓缩提供标题化合物,其用于下一步骤而不进行另外的纯化。
实施例 9D
(S)-4-((1,4-二氧杂环己烷-2-基)甲基氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 9C替代实施例 1M制备标题化合物。
实施例 9E
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2S)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 9D替代实施例 1N制备标题化合物。
实施例 10
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[4-(羟基甲基)四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 10A
4-(((4-(羟基甲基)四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用(4-(氨基甲基)四氢-2H-吡喃-4-基)甲醇替代实施例 1M制备标题化合物。
实施例 10B
4-(((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
将实施例 10A (648 mg)溶解于N,N-二甲基甲酰胺 (9 mL)中,并添加三氟甲磺酸叔丁基二甲基甲硅烷基酯(546 mg)。在室温下搅拌该溶液16小时,并在真空下除去溶剂。通过快速柱层析法在硅胶上使用50-70% 乙酸乙酯/庚烷纯化粗物质。
实施例 10C
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)苯甲酰胺
通过在实施例 1O中用实施例 10B替代实施例 1N制备标题化合物。
实施例 10D
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[4-(羟基甲基)四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
将实施例 10C (488 mg)溶解于四氢呋喃 (3 mL)中。添加四丁基氟化铵 (1M 在四氢呋喃中, 1.45 mL),并在室温下搅拌该溶液30分钟。用碳酸氢钠的饱和水溶液淬灭该反应混合物并用乙酸乙酯稀释。分离各相,用盐水洗涤有机层,然后在无水硫酸钠上干燥。在过滤和浓缩之后,在硅胶上使用乙酸乙酯,提高至5-10% 甲醇/二氯甲烷通过快速柱层析法纯化粗物质。
实施例 11
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[3-(羟基甲基)氧杂环丁烷-3-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 11A
4-(((3-(羟基甲基)氧杂环丁烷-3-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用(3-(氨基甲基)氧杂环丁烷-3-基)甲醇替代实施例 1M制备标题化合物。
实施例 11B
4-(((3-(((叔丁基二甲基甲硅烷基)氧基)甲基)氧杂环丁烷-3-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 10B中用实施例 11A替代实施例 10A制备标题化合物。
实施例 11C
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((3-(((叔丁基二甲基甲硅烷基)氧基)甲基)氧杂环丁烷-3-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯]-2-基)甲基)哌嗪-1-基)苯甲酰胺
通过在实施例 1O中用实施例 11B替代实施例 1N制备标题化合物。
实施例 11D
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[3-(羟基甲基)氧杂环丁烷-3-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 10D中用实施例 11C替代实施例 10C制备标题化合物。
实施例 12
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(3-羟基-3-甲基丁基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 12A
4-((3-羟基-3-甲基丁基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用4-氨基-2-甲基丁-2-醇替代实施例 1M制备标题化合物。
实施例 12B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(3-羟基-3-甲基丁基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 12A替代实施例 1N制备标题化合物。
实施例 13
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(3-羟基三环[3.3.1.13,7]癸-1-基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 13A
4-((3-羟基金刚烷-1-基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用3-氨基金刚烷-1-醇替代实施例 1M制备标题化合物。
实施例 13B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[3-羟基三环[3.3.1.13,7]癸-1-基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 13A替代实施例 1N制备标题化合物。
实施例 14
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧杂二环[3.1.0]己-6-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 14A
(1R,5S,6r)-3-氧杂二环[3.1.0]己烷-6-甲酸叔丁酯
经4小时添加叠氮基乙酸叔丁酯 (135 g, 15% 在甲苯中)至2,5-二氢呋喃 (100g) 和乙酸铑 (II) 二聚物 (0.95 g)/二氯甲烷 (250 mL),并搅拌该反应混合物24小时。浓缩该反应混合物并在硅胶上采用1-15% 乙酸乙酯/己烷层析法处理粗产物以分别提供产物和其2:1比率的非对映异构体。
实施例 14B
(1R,5S,6r)-3-氧杂二环[3.1.0]己烷-6-甲酸
将实施例 14A (4 g)在二氯甲烷 (20 mL)和TFA (20 mL)中搅拌2小时,并浓缩。将粗物质溶解于二氯甲烷 (200 mL)和饱和Na2CO3溶液(20 mL)中。搅拌该反应混合物10分钟,并分离有机层并经Na2SO4干燥。在过滤之后,浓缩该混合物以提供标题化合物。
实施例 14C
(1R,5S,6r)-3-氧杂二环[3.1.0]己烷-6-甲酰胺
将草酰氯(2.05 mL)添加至实施例 14B (4 g)/二氯甲烷 (40 mL)并搅拌该反应混合物24小时, 并浓缩。将粗物质溶解于二氯甲烷 (30 mL),并添加饱和NH4OH溶液(3mL),并搅拌该反应混合物30分钟。添加二氯甲烷 (30 mL)和饱和Na2CO3溶液 (20 mL),分离有机层,经Na2SO4干燥,过滤,并浓缩以提供标题化合物。
实施例 14D
3-硝基-4-{[(1R,5S,6s)-3-氧杂二环[3.1.0]己-6-基甲基]氨基}苯磺酰胺
将硼烷-四氢呋喃 络合物 (2. 5 mL, 1M 在四氢呋喃中)添加至实施例 14C(160 mg)/四氢呋喃 (2 mL),并在50℃下搅拌该反应混合物24小时。通过缓慢添加1M HCl水溶液淬灭该反应混合物,用二氯甲烷 (20 mL)稀释,并添加最低浓缩的NaOH溶液以碱化该溶液。向该混合物中添加4-氟-3-硝基苯磺酰胺 (277 mg) 和三乙胺 (2 mL),搅拌该反应混合物1小时。浓缩该反应混合物并在硅胶上采用10-100% 乙酸乙酯/己烷层析法处理粗产物以提供标题化合物。
实施例 14E
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧杂二环[3.1.0]己-6-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O下用实施例 14D处理实施例 1N制备标题化合物。
实施例 15
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-羟基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 15A
4-(((3-羟基氧杂环丁烷-3-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用3-(氨基甲基)氧杂环丁烷-3-醇替代实施例 1M制备标题化合物。
实施例 15B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-羟基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 15A替代实施例 1N制备标题化合物。
实施例 16
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 16A
4-(吗啉代氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用吗啉-4-胺替代实施例 1M制备标题化合物。
实施例 16B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-(吗啉-4-基氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 16A替代实施例 1N制备标题化合物。
实施例 17
4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰基]氨磺酰基}-2-硝基苯基)氨基]甲基}四氢-2H-吡喃-4-甲酸甲酯
实施例 17A
4-(((2-硝基-4-氨磺酰基苯基)氨基)甲基)四氢-2H-吡喃-4-甲酸甲酯
通过在实施例 1N中用4-(氨基甲基)四氢-2H-吡喃-4-甲酸甲酯替代实施例 1M制备标题化合物。
实施例 17B
4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰基]氨磺酰基}-2-硝基苯基)氨基]甲基}四氢-2H-吡喃-4-甲酸甲酯
通过在实施例 1O中用实施例 17A替代实施例 1N制备标题化合物。
实施例 18
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[2-(四氢-2H-吡喃-4-基)肼基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 18A
4-肼基-3-硝基苯磺酰胺
通过在实施例 1N中用肼一水合物替代实施例 1M制备标题化合物。
实施例 18B
3-硝基-4-(2-(四氢-2H-吡喃-4-基)肼基)苯磺酰胺
将实施例 18A (250 mg)溶解于二氯甲烷 (10 mL)和1-甲基吡咯烷酮(5 mL)中,然后添加二氢-2H-吡喃-4(3H)-酮 (119 mg),并在室温下搅拌该溶液20分钟。添加三乙酰氧基硼氢化钠(479 mg),在室温下搅拌该混合物16小时。用乙酸乙酯稀释该混合物,用饱和碳酸氢钠水溶液洗涤,用水洗涤两次,用盐水洗涤,并在无水硫酸钠上干燥。在过滤和浓缩之后,从乙酸乙酯重结晶粗物质。用乙醚洗涤固体物质,在真空下干燥以提供标题化合物。
实施例 18C
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[2-(四氢-2H-吡喃-4-基)肼基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 18B替代实施例 1N制备标题化合物。
实施例 19
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 19A
氧杂环庚烷-4-酮
在-25℃下通过注射器向二氢-2H-吡喃-4(3H)-酮 (8.5 g)和三氟化硼乙醚络合物 (15 mL)在二氯甲烷 (400 mL)中的搅拌溶液中缓慢添加 (三甲基甲硅烷基)叠氮甲烷(60 mL, 120 mmol, 2.0 M 在己烷中)。在-25℃下搅拌该反应混合物2.5小时。用水(300mL)稀释该反应混合物并用二氯甲烷 (300 mL)萃取。分离有机层,用10:1 饱和 NH4Cl水溶液: 饱和NH4OH水溶液洗涤,用盐水洗涤,经硫酸镁干燥,过滤,并在真空下浓缩。通过硅胶层析法纯化所得粗产物以提供标题化合物。
实施例 19B
氧杂环庚烷-4-甲腈
通过在实施例 4A中用实施例 19A替代1-氧杂螺[4.5]癸-8-酮制备标题化合物。
实施例 19C
氧杂环庚烷-4-基甲胺
通过在实施例 4B中用实施例 19B替代实施例 4A制备标题化合物。
实施例 19D
(R)-3-硝基-4-(氧杂环庚烷-4-基甲基氨基)苯磺酰胺
通过在实施例 1N中用实施例 19C替代实施例 1M制备标题化合物。使用改性Berger Instruments PrepSFCTM系统分离对映异构体。采用用于样品注射的Gilson 232自动取样器和在大气压下定制用于级分收集的Cavro MiniPrepTM吸量器整合手动版本的Berger系统(Olson, J.;Pan, J.;Hochlowski, J.;Searle, P.;Blanchard, D. JALA2002, 7, 69-74)。定制设计的收集鞋能够收集到18 x 150 mm管中,甲醇洗涤系统能够洗涤级分之间的鞋以最大化回收并避免级分的交叉污染。使用用于自动取样器和级分收集器对照的SFC ProNToTM软件(版本 1.5.305.15)和AbbVie开发的Visual Basic应用控制该系统。出口压力为100 bar,炉温为35 ºC,流动相流速为40 mL/min。使用的柱为ChiralpakIA, 21 x 250 mm, 5 微米。流动相为35% CH3OH (含有0.3% 二乙胺)/65 % 超临界CO2。注射样品作为1.9 mL CH3OH:DMSO 1:1中的溶液。使用用于自动取样器的定制软件和级分取样器对照的SFC ProNToTM 软件 (版本 1.5.305.15)和定制软件控制制备型SFC系统。基于UV信号阈值收集级分,通过使用正模式的ESI离子化将在线Thermo MSQ质谱仪用于分子量鉴定。使用Navigator 4.0 软件和AbbVie开发的Visual Basic界面获取质谱数据以与SFC控制软件交流。
实施例 19E
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 19D替代实施例 1N制备标题化合物。
实施例 20
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 20A
(S)-3-硝基-4-((氧杂环庚烷-4-基甲基)氨基)苯磺酰胺
如实施例 19D中所述获得标题化合物。
实施例 20B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧杂环庚烷-4-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 20A替代实施例 1N制备标题化合物。
实施例 21
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 21A
4-(((4-甲基四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
添加三乙酰氧基硼氢化钠(3513 mg)至三氟甲基乙酸 (30 mL)中。添加4-氨基-3-硝基苯磺酰胺 (800 mg)并在室温下搅拌该溶液10分钟。逐滴添加溶解于二氯甲烷 (10mL)中的4-甲基四氢-2H-吡喃-4-甲醛 (991 mg)。在添加之后,在室温下搅拌该混合物16小时。倾倒该混合物在冰冷碳酸氢钠饱和溶液上并用乙酸乙酯萃取。用水和盐水洗涤有机层并在无水硫酸钠上干燥。在过滤和浓缩之后,通过从乙酸乙酯重结晶纯化粗物质。
实施例 21B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 21A替代实施例 1N制备标题化合物。
实施例 22
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-噻喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 22A
3-硝基-4-(((四氢-2H-噻喃-4-基)甲基)氨基)苯磺酰胺
通过在实施例 1N 中用(四氢-2H-噻喃-4-基)甲胺盐酸盐替代实施例 1M制备标题化合物。
实施例 22B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-噻喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 22A替代实施例 1N标题化合物。
实施例 23
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(氧杂环丁烷-3-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 23A
3-硝基-4-((氧杂环丁烷-3-基甲基)氨基)苯磺酰胺
通过在实施例 1N中用氧杂环丁烷-3-基甲胺替代实施例 1M制备标题化合物。
实施例 23B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(氧杂环丁烷-3-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 23A替代实施例 1N制备标题化合物。
实施例 24
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 24A
(R)-((2-(烯丙基氧基)丙氧基)甲基)苯
将(R)-1-(苄基氧基)丙-2-醇 (5 g)和烯丙基溴(3.5 mL)溶解于四氢呋喃 (45mL)中。将该混合物冷却至5℃,经10分钟分四份添加95% NaH (1.1 g)。使该混合物达到室温并在干燥管下搅拌过夜。用水稀释该反应并用乙醚萃取。用盐水洗涤有机层并用乙醚反萃取合并的水层。经Na2SO4干燥合并的有机层。过滤和滤液的浓缩提供标题化合物,其在下一步骤中使用而不经进一步纯化。
实施例 24B
2-(((R)-1-(苄基氧基)丙-2-基氧基)甲基)环氧乙烷
将实施例 24A (6.2 g)溶解于二氯甲烷 (200 mL)中,冷却至0℃,添加间氯过氧苯甲酸 (13.5 g)。冷搅拌该反应混合物1小时,然后在室温下搅拌过夜。添加Na2SO3水溶液(10%, 100 mL),搅拌该混合物5分钟,分离各层。用饱和NaHCO3 (2 x 150 mL)并用盐水洗涤有机层。在经Na2SO4干燥之后,过滤并浓缩,将粗物质溶解于乙醚中,用10% Na2S2O3洗涤,用饱和NaHCO3和盐水洗涤3次。在经Na2SO4干燥之后,过滤和浓缩提供粗油。在硅胶上采用85/15 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 24C
(S)-2-(((R)-1-(苄基氧基)丙-2-基氧基)甲基)环氧乙烷
添加R,R-(salen)Co(II) 络合物 (56 mg)至净实施例 24B (4.0 g),然后添加四氢呋喃 (180 µL),然后添加乙酸(20.7 µL)。将该混合物冷却至0℃,添加水(180 µL),并在敞开25 mL烧瓶中使该反应达到室温过夜。然后在硅胶上使用85/15 庚烷/乙酸乙酯直接层析法处理该反应以提供标题化合物。
实施例 24D
(R)-2-((S)-环氧乙烷-2-基甲氧基)丙-1-醇
将实施例 24C (2.3 g)溶解于乙酸乙酯 (65 mL)中,添加碳载Pd(OH)2(20% Pd干重/总50%水, 100 mg),并在氢气球下搅拌该反应混合物2小时。在通过硅藻土过滤和浓缩之后,重新运行未完成的反应,这次使用四氢呋喃代替乙酸乙酯。在硅胶上采用35/65 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 24E
((2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲醇
将实施例 24D (800 mg)溶解于二氯甲烷 (45 mL)中,添加(1S)-(+)-樟脑磺酸(415 mg),并在室温下搅拌该反应混合物过夜。添加饱和NaHCO3,分离各层,并采用二氯甲烷 (3 x 50 mL)萃取水层。经Na2SO4干燥合并的有机层。在过滤和浓缩之后,在硅胶上采用35/65 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 24F
甲磺酸((2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲酯
将实施例 24E (400 mg)和三乙胺 (0.58 mL)溶解于二氯甲烷 (12 mL)中。将该反应混合物冷却至0℃,并逐滴添加甲烷磺酰氯 (0.28 mL)。在室温下搅拌该反应混合物1小时。添加饱和NaHCO3 (10 mL),用二氯甲烷 (3 x 7 mL)萃取水层。经Na2SO4干燥合并的有机层。过滤和滤液的浓缩提供标题化合物,其用于下一步骤而不经进一步纯化。
实施例 24G
(2R,5R)-2-(叠氮基甲基)-5-甲基-1,4-二氧杂环己烷
通过在实施例 1L中用实施例 24F替代实施例 1K制备标题化合物。
实施例 24H
((2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲胺
通过在实施例 9C中用实施例 24G替代实施例 9B制备标题化合物。
实施例 24I
4-(((2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲基氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 24H替代实施例 1M制备标题化合物。
实施例 24J
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 24I替代实施例 1N制备标题化合物。1H NMR(400MHz, 二甲亚砜-d6) δ ppm 11.65 (s, 1H), 8.57 (d, 1H), 8.55 (t, 1H), 8.03(d, 1H), 7.83 (dd, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.02 (d,2H), 6.67 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.86, 3.78, 3.70, 3.67 (allm, 5H), 3.54, 3.49 (both m, 3H), 3.08 (br m, 4H), 2.76 (br s, 2H), 2.20 (brm, 4H), 2.13 (br m, 2H), 1.94 (br m, 2H), 1.37 (t, 2H), 1.09 (d, 3H), 0.92(s, 6 H)。
实施例 25
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-羟基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 25A
1,4-二氧杂环庚烷-6-酮
向乙烷-1,2-二醇 (12.9 g)和2-重氮乙酸乙酯(47.5 g)在二氯甲烷 (400 mL)中的冷却(0℃)溶液中逐滴添加BF3Et2O (0.3 mL)。在添加之后观察到气体逸出。使温度升高至室温并搅拌该混合物24小时。然后在真空下浓缩该混合物并在接下来的反应中直接使用残余物而不经进一步纯化。向2,2'-(乙烷-1,2-二基双 (氧基))二乙酸二乙酯 (52.75 g)在DMF中的溶液中添加叔丁氧基锂(36 g)。在90℃下搅拌该混合物过夜。经10% HCl水溶液(200 mL)倾倒该混合物并用乙酸乙酯萃取三次。用水和盐水洗涤合并的萃取物三次,并经Na2SO4干燥。干燥和浓缩提供粗产物,其用于下一反应而不经进一步纯化。将6-氧代-1,4-二氧杂环庚烷-5-甲酸乙酯 (16.2 g)在10% HCl水溶液 (100 mL)中的混合物在回流下搅拌4小时。冷却该混合物,用乙醚萃取三次。用盐水洗涤合并的萃取物,经Na2SO4干燥。在过滤之后,浓缩提供标题化合物。
实施例 25B
6-(硝基甲基)-1,4-二氧杂环庚烷-6-醇
向乙醇钠(14 g, 21%w)在乙醇(20 mL)中的溶液中添加实施例 25A (3.2 g)和硝基甲烷 (3.75 g)的溶液。将该反应混合物搅拌4小时。将该反应混合物倾倒入NH4Cl水溶液(200 mL)中。用乙酸乙酯萃取水层三次。合并有机层并用MgSO4干燥。在过滤和浓缩之后,在具有600 g 柱的Analogix System 上采用0-40% 乙酸乙酯/己烷洗脱纯化粗物质以提供标题化合物。
实施例 25C
6-(氨基甲基)-1,4-二氧杂环庚烷-6-醇
向实施例 25B (1.2 g)在乙醇(60 mL)中的溶液中添加Pd/C(10%, 120 mg)。在氢气球下搅拌该混合物过夜。过滤并浓缩该混合物以提供粗产物,其直接用于下一反应而不经进一步纯化。
实施例 25D
4-(((6-羟基-1,4-二氧杂环庚烷-6-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 25C替代实施例 1M制备标题化合物。
实施例 25E
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-羟基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 25D替代实施例 1N制备标题化合物。
实施例 26
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4,4-二氟-1-羟基环己基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 26A
4-(((4,4-二氟-1-羟基环己基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用1-(氨基甲基)-4,4-二氟环己醇替代实施例 1M制备标题化合物。
实施例 26B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4,4-二氟-1-羟基环己基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 26A替代实施例 1N制备标题化合物。
实施例 27
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲氧基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 27A
4-(((4-甲氧基四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用(4-甲氧基四氢-2H-吡喃-4-基)甲胺替代实施例 1M制备标题化合物。
实施例 27B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-甲氧基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 27A替代实施例 1N制备标题化合物。
实施例 28
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3,3-二氟环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 28A
4-(((3,3-二氟环丁基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用(3,3-二氟环丁基)甲胺盐酸盐替代实施例 1M制备标题化合物。
实施例 28B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3,3-二氟环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 28A替代实施例 1N制备标题化合物。
实施例 29
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺酰基]哌啶-4-基}甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 29A
3-硝基-4-(((1-((三氟甲基)磺酰基)哌啶-4-基)甲基)氨基)苯磺酰胺
通过在实施例 1N 中用(1-((三氟甲基)磺酰基)哌啶-4-基)甲胺替代实施例 1M制备标题化合物。
实施例 29B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺酰基]哌啶-4-基}甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 29A替代实施例 1N制备标题化合物。
实施例 30
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[1-(甲基磺酰基)哌啶-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 30A
4-(((1-(甲基磺酰基)哌啶-4-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用(1-(甲基磺酰基)哌啶-4-基)甲胺替代实施例 1M制备标题化合物。
实施例 30B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[1-(甲基磺酰基)哌啶-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 30A替代实施例 1N制备标题化合物。
实施例 31
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 31A
(2R,6S)-2,6-二甲基四氢-4H-吡喃-4-酮
将2,6-二甲基-4H-吡喃-4-酮 (14 g)和四氢呋喃 (140 mL)添加至10% Pd/C, 干(2.8 g) 250 mL SS 耐压瓶中,并在50 psi下搅拌该混合物2小时。通过尼龙膜过滤该混合物并浓缩。在硅胶上采用5-50% 乙酸乙酯/己烷层析法处理粗产物以提供标题化合物。
实施例 31B
外消旋-(2R,6S)-2,6-二甲基四氢-2H-吡喃-4-甲腈
通过在实施例 4A中用实施例 31A替代1-氧杂螺[4.5]癸-8-酮制备标题化合物。
实施例 31C
4-({[(2R,4r,6S)-2,6-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯磺酰胺
将LiAlH4 (14.4 mL, 1M在四氢呋喃中)添加至实施例 31B (2 g)/四氢呋喃 (40mL)中并搅拌该混合物1小时。通过添加饱和酒石酸钠钾溶液(5 mL)淬灭该反应混合物,并搅拌该混合物30分钟。从盐滗析掉溶液并浓缩。将粗物质溶解于四氢呋喃 (50 mL),并添加三乙胺 (2.0 mL)和4-氟-3-硝基苯磺酰胺 (3.16 g)。搅拌该反应混合物1小时。用乙酸乙酯 (200 mL)稀释该反应混合物,用NaH2PO4溶液和盐水洗涤两次,并浓缩。在硅胶上采用10-50% 乙酸乙酯/己烷层析法处理粗产物以分别提供标题化合物和其非对映异构体。
实施例 31D
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 31C替代实施例 1N制备标题化合物。
实施例 32
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(1-氧化四氢-2H-噻喃-4-基)甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
将实施例 22B (450 mg)溶解于二氯甲烷 (8 mL)中,并添加3-氯过氧苯甲酸(76%, 88 mg)。在室温下搅拌该反应混合物3天。通过在硅胶上使用10-20% 甲醇/二氯甲烷通过快速柱层析法纯化粗物质。
实施例 33
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 33A
(S)-4-(((2,2-二甲基四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
在实施例 1N中用外消旋(2,2-二甲基四氢-2H-吡喃-4-基)甲胺盐酸盐替代实施例 1M制备标题化合物,并如实施例 19D所述进行手性纯化。
实施例 33B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 33A替代实施例 1N制备标题化合物。
实施例 34
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 34A
(R)-4-(((2,2-二甲基四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
还如实施例 33A中所述制备标题化合物。
实施例 34B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 34A替代实施例 1N制备标题化合物。
实施例 35
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 35A
(R)-1-(叔丁基二苯基甲硅烷基氧基)丙-2-醇
将(R)-丙-1,2-二醇 (5 g) 和咪唑 (4.5 g)溶解于二氯甲烷 (200 mL)中。将该混合物冷却至0℃,并逐滴添加叔丁基氯二苯基硅烷(18.1 g)在二氯甲烷 (50 mL)中的溶液。在干燥管下将该反应混合物保持在0℃下过夜。通过硅藻土过滤该反应混合物并浓缩。在硅胶上采用9/1 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 35B
(R)-(2-(苄基氧基)丙氧基)(叔丁基)二苯基硅烷
在150℃下在N2下加热实施例 35A (16.8 g), 苄基溴 (9.5 mL), N-乙基-N-异丙基丙-2-胺 (15.0 mL), 和碘化钠(0.82 g) 3天。将该反应冷却至室温并在乙酸乙酯和1M KHSO4之间分配。用盐水洗涤有机层,经Na2SO4干燥。在过滤和浓缩之后,在硅胶上采用98.5/1.5 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 35C
(R)-2-(苄基氧基)丙-1-醇
将实施例 35B (5.6 g)溶解于四氢呋喃 (50 mL)中,并添加四丁基氟化铵 (15mL, 1.0M 在95/5 四氢呋喃/H2O中),搅拌该反应过夜。浓缩该反应混合物并在硅胶上采用3/1 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 35D
(R)-((1-(烯丙基氧基)丙-2-基氧基)甲基)苯
通过在实施例 24A中用实施例 35C替代(R)-1-(苄基氧基)丙-2-醇制备标题化合物。
实施例 35E
2-(((R)-2-(苄基氧基)丙氧基)甲基)环氧乙烷
通过在实施例 24B中用实施例 35D替代实施例 24A制备标题化合物。
实施例 35F
(R)-2-(((R)-2-(苄基氧基)丙氧基)甲基)环氧乙烷
通过在实施例 24C中用实施例 35E替代实施例 24B和用S,S-(salen)Co(II)络合物(CAS# 188264-84-8)替代R,R-(salen)Co(II)络合物制备标题化合物。
实施例 35G
(R)-1-((R)-环氧乙烷-2-基甲氧基)丙-2-醇
将实施例 35F (780 mg)溶解于四氢呋喃 (20 mL)中,并添加碳载Pd(OH)2 (20%Pd 干重/总50%水, 80 mg)。在氢气球下搅拌该反应混合物3小时。通过硅藻土过滤和浓缩提供标题化合物,其用于下一步骤而不经纯化。
实施例 35H
((2S,6R)-6-甲基-1,4-二氧杂环己烷-2-基)甲醇
通过在实施例 24E中用实施例 35G替代实施例 24D制备标题化合物。
实施例 35I
甲磺酸((2R,6R)-6-甲基-1,4-二氧杂环己烷-2-基)甲酯
通过在实施例 24F中用实施例 35H替代实施例 24E制备标题化合物。
实施例 35J
(2S,6R)-2-(叠氮基甲基)-6-甲基-1,4-二氧杂环己烷
通过在实施例 1L中用实施例 35I替代实施例 1K制备标题化合物。
实施例 35K
((2S,6R)-6-甲基-1,4-二氧杂环己烷-2-基)甲胺
通过在实施例 9C中用实施例 35J替代实施例 9B制备标题化合物。
实施例 35L
4-(((2S,6R)-6-甲基-1,4-二氧杂环己烷-2-基)甲基氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 35J替代实施例 1M制备标题化合物。
实施例 35M
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 35L替代实施例 1N制备标题化合物。
实施例 36
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氢呋喃-3-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 36A
(S)-(四氢呋喃-3-基)甲醇
将(R)-四氢呋喃-3-甲酸 (0.50 g)/四氢呋喃 (7.5 mL)冷却至0℃,并逐滴添加硼烷四氢呋喃络合物 (14 mL 1.0M 在四氢呋喃中),保持温度< 6℃。使该反应混合物在氮气下在室温下搅拌45分钟。将该反应混合物冷却至0℃并小心添加5N NaOH (2.3 mL)。使该反应混合物搅拌几分钟,添加水和乙醚。用盐水洗涤分离的有机层并用乙醚反萃取合并的水层。经Na2SO4干燥合并的有机层,过滤,并浓缩。在硅胶上采用3/7 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 36B
甲磺酸(R)-(四氢呋喃-3-基)甲酯
通过在实施例 24F中用实施例 36A替代实施例 24E制备标题化合物。
实施例 36C
(S)-3-(叠氮基甲基)四氢呋喃
通过在实施例 1L中用实施例 36B替代实施例 1K制备标题化合物。
实施例 36D
(S)-(四氢呋喃-3-基)甲胺
通过在实施例 9C中用实施例 36C替代实施例 9B制备标题化合物。
实施例 36E
(S)-3-硝基-4-((四氢呋喃-3-基)甲基氨基)苯磺酰胺
通过在实施例 1N中用实施例 36D替代实施例 1M制备标题化合物。
实施例 36F
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氢呋喃-3-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 36E替代实施例 1N制备标题化合物。
实施例 37
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 37A
2-(烯丙基氧基)乙酸甲酯
经10-15分钟逐滴添加乙醇酸甲酯 (25 g)至NaH (7.7 g, 95%)在DMF (280 mL)中的0℃悬浮液中。然后经10-15分钟逐滴添加乙醇酸甲酯(25 g)。使该反应温热至室温,搅拌1小时,并冷却至0℃。经10-15分钟逐滴添加烯丙基溴 (36.7 g),并在室温下搅拌该反应1小时。将该反应混合物倾倒入饱和NH4Cl水溶液 (700 mL)中并用乙酸乙酯 (3 x 350 mL)萃取。用盐水洗涤合并的有机层并经Na2SO4干燥。在过滤和浓缩之后,使用Vigeraux头和vac= 3.4 mmHg蒸馏粗产物以与DMF的混合物的形式获得标题化合物。将其溶解于乙醚 (10mL)中,用水 (2 x 10 mL)和盐水洗涤,然后经MgSO4干燥。过滤和浓缩提供标题化合物。
实施例 37B
1-(烯丙基氧基)-2-甲基丙-2-醇
将实施例 37A (12 g)溶解于四氢呋喃 (200 mL)中并冷却至0℃。逐滴添加CH3MgCl (100 mL, 3.0 M在四氢呋喃中)。在N2下冷搅拌该反应混合物3.5小时。缓慢添加饱和NH4Cl (60 mL),然后添加水和乙醚。用盐水洗涤有机层并经Na2SO4干燥。过滤和滤液的浓缩提供标题化合物,其用于下一步骤而不经进一步纯化。
实施例 37C
((1-(烯丙基氧基)-2-甲基丙-2-基氧基)甲基)苯
通过在实施例 35B中用实施例 37B替代实施例 35A制备标题化合物。
实施例 37D
2-((2-(苄基氧基)-2-甲基丙氧基)甲基)环氧乙烷
通过在实施例 24B中用实施例 37C替代实施例 24A制备标题化合物。
实施例 37E
(R)- 2-((2-(苄基氧基)-2-甲基丙氧基)甲基)环氧乙烷
通过在实施例 24C中用实施例 37D替代实施例 24B和用S,S-(salen)Co(II)络合物 (CAS# 188264-84-8)替代R,R-(salen)Co(II) 络合物制备标题化合物。
实施例 37F
(R)-2-甲基-1-(环氧乙烷-2-基甲氧基)丙-2-醇
通过在实施例 35G中用实施例 37E替代实施例 35F制备标题化合物。
实施例 37G
(S)-(6,6-二甲基-1,4-二氧杂环己烷-2-基)甲醇
通过在实施例 24E中用实施例 37F替代实施例 24D制备标题化合物。
实施例 37H
甲磺酸(R)-(6,6-二甲基-1,4-二氧杂环己烷-2-基)甲酯
通过在实施例 24F中用实施例 37G替代实施例 24E制备标题化合物。
实施例 37I
(S)-6-(叠氮基甲基)-2,2-二甲基-1,4-二氧杂环己烷
通过在实施例 1L中用实施例 37H替代实施例 1K制备标题化合物。
实施例 37J
(S)-(6,6-二甲基-1,4-二氧杂环己烷-2-基)甲胺
通过在实施例 9C中用实施例 37I替代实施例 9B制备标题化合物。
实施例 37K
(S)-4-((6,6-二甲基-1,4-二氧杂环己烷-2-基)甲基氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 37J替代实施例 1M制备标题化合物。
实施例 37L
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 37K替代实施例 1N制备标题化合物。
实施例 38
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-甲基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 38A
4-(((3-甲基氧杂环丁烷-3-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用(3-甲基氧杂环丁烷-3-基)甲胺替代实施例 1M制备标题化合物。
实施例 38B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-甲基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 38A替代实施例 1N制备标题化合物。
实施例 39
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 39A
6-((二苄基氨基)甲基)-1,4-二氧杂环庚烷-6-醇
向实施例 25C (1.8 g)在二氯甲烷 (30 mL)中的溶液中添加苯甲醛 (3.82 g)和乙酸 (0.5 mL),然后添加树脂上的氰基硼氢化钠 (2.4 mmol/g, 4.5 g)。搅拌该混合物过夜。然后过滤该混合物并在真空下浓缩滤液。在硅胶柱上装载残余物并用30% 乙酸乙酯/己烷洗脱以提供标题化合物。
实施例 39B
N,N-二苄基-1-(6-氟-1,4-二氧杂环庚烷-6-基)甲胺
向实施例 39A (256 mg)在二氯甲烷 (33 mL)中的溶液中添加双(2-甲氧基乙基)氨基三氟化硫 (2 mL, 1M 在四氢呋喃中的溶液)。搅拌该混合物过夜。然后将该混合物倾倒入冰水中并用二氯甲烷 (50 mL)萃取三次。用NaHCO3水溶液、水和盐水洗涤合并的有机萃取物,并经Na2SO4干燥。在过滤和浓缩之后,通过柱层析法使用20% 乙酸乙酯/庚烷纯化粗物质以提供标题化合物。
实施例 39C
(6-氟-1,4-二氧杂环庚烷-6-基)甲胺
向实施例 39B (200 mg)在甲醇 (20 mL)中的溶液中添加Raney Ni (30 mg)。在30 psi氢气下将该混合物搅拌过夜。过滤和浓缩提供标题化合物。
实施例 39D
4-(((6-氟-1,4-二氧杂环庚烷-6-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 39C替代实施例 1M制备标题化合物。
实施例 39E
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 39D替代实施例 1N制备标题化合物。
实施例 40
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 40A
N,N-二苄基-1-(6-甲氧基-1,4-二氧杂环庚烷-6-基)甲胺
向实施例 39A (300 mg)在四氢呋喃 (3 mL)和HMPA (六甲基磷酰胺, 3 mL)中的溶液中添加NaH (200 mg, 60% 在矿物油中)。将该混合物搅拌30分钟,然后添加CH3I (0.6g)。然后在50℃ 下搅拌该混合物过夜。经NH4Cl水溶液纯化该混合物并用乙酸乙酯 (100mL)萃取三次。用水和盐水洗涤合并的有机萃取物三次,并经Na2SO4干燥。在过滤和浓缩之后,溶剂的蒸发提供粗产物,其装载在硅胶柱上并用20% 乙酸乙酯/己烷洗脱以提供标题化合物。
实施例 40B
(6-甲氧基-1,4-二氧杂环庚烷-6-基)甲胺
向实施例 40A (200 mg) 在甲醇 (20 mL)中的溶液中添加Raney Ni (50 mg)。在30 psi 氢气下搅拌该混合物过夜。在过滤之后,溶剂的真空蒸发提供标题化合物。
实施例 40C
4-(((6-甲氧基-1,4-二氧杂环庚烷-6-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 40B替代实施例 1M制备标题化合物。
实施例 40D
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧杂环庚烷-6-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 40C替代实施例 1N制备标题化合物。
实施例 41
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(反式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 41A
反式-3-(羟基甲基)环丁烷甲腈
将儿茶酚硼烷(7.1 mL)添加至3-亚甲基环丁烷甲腈 (5.6 g)/四氢呋喃 (25 mL)并搅拌该混合物24小时。通过缓慢添加乙醇(25 mL)淬灭该反应混合物,并将该混合物倾倒入乙醇 (75 mL)和四氢呋喃 (100 mL)中。经1小时向其中缓慢添加2M NaOH水溶液 (150mL)和30% H2O2水溶液 (150 mL)。再搅拌该混合物3小时,并用乙酸乙酯 (500 mL)稀释。分离各层并用1M NaOH水溶液和盐水洗涤有机层两次,并浓缩。在硅胶上采用5-100% 乙酸乙酯/己烷层析法处理粗产物以分别提供标题化合物和其顺式-非对映异构体。
实施例 41B
甲磺酸反式-3-氰基环丁基)甲酯
在-20℃下添加甲磺酰氯 (1.0 mL)至二氯甲烷 (50 mL)中的实施例 41A (1.35g) 和二异丙基乙胺 (2.33 mL)。搅拌该混合物1小时。将该反应混合物倾倒入二氯甲烷(200 mL)中并用水和盐水洗涤两次,并浓缩。在硅胶上采用10-100% 乙酸乙酯/己烷层析法处理粗产物以分别提供标题化合物。
实施例 41C
4-(((反式-3-氰基环丁基)甲基)氨基)-3-硝基苯磺酰胺
将叠氮化钠(1.1 g)添加至N,N-二甲基甲酰胺 (15 mL)中的实施例 41B (5.6 g)中并搅拌该混合物24小时。将该反应混合物倾倒入水 (75 mL)中并用乙醚 (100 mL)萃取两次。合并有机层并浓缩至10 mL。添加四氢呋喃 (25 mL),并向所得混合物中添加三苯基膦 (2.2 g) 和水(0.3 mL),并搅拌该反应24小时。添加硫酸钠(5 g)和4-氟-3-硝基苯磺酰胺 (1.86 g),并在40℃下搅拌该反应2小时。用乙酸乙酯 (300 mL)稀释该混合物。分离各层并用盐水洗涤有机层,并浓缩。在硅胶上用50% 乙酸乙酯/己烷层析法处理粗产物以提供标题化合物。
实施例 41D
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(反式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 41C替代实施例 1N制备标题化合物。
实施例 42
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(顺式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 42A
顺式-3-(羟基甲基)环己烷甲腈
还从实施例 41A中分离标题化合物。
实施例 42B
甲磺酸顺式-3-氰基环丁基)甲酯
通过在实施例 41B中用实施例 42A替代实施例 41A制备标题化合物。
实施例 42C
4-(((顺式-3-氰基环丁基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 41C中用实施例 42B替代实施例 41B制备标题化合物。
实施例 42D
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(顺式-3-氰基环丁基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 42C替代实施例 1N制备标题化合物。
实施例 43
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(1,1-二氧化四氢-2H-噻喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 43A
4-(((1,1-二氧化四氢-2H-噻喃-4-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N 中用4-(氨基甲基)四氢-2H-噻喃 1,1-二氧化物盐酸盐替代实施例 1M制备标题化合物。
实施例 43B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(1,1-二氧化四氢-2H-噻喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 43A替代实施例 1N制备标题化合物。
实施例 44
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 44A
(R)-2-(((R)-1-(苄基氧基)丙-2-基氧基)甲基)环氧乙烷
通过在实施例 24C 中用S,S-(salen)Co(II) 络合物 (CAS# 188264-84-8)替代R,R-(salen)Co(II) 络合物 (CAS# 176763-62-5)制备标题化合物。
实施例 44B
(R)-2-((R)-环氧乙烷-2-基甲氧基)丙-1-醇
通过在实施例 35G中用实施例 44A替代实施例 35F制备标题化合物。
实施例 44C
((2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲醇
通过在实施例 24E中用实施例 44B替代实施例 24D制备标题化合物。
实施例 44D
甲磺酸((2R,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲酯
通过在实施例 24F中用实施例 44C替代实施例 24E制备标题化合物。
实施例 44E
(2S,5R)-2-(叠氮基甲基)-5-甲基-1,4-二氧杂环己烷
通过在实施例 1L用实施例 44D替代实施例 1K制备标题化合物。
实施例 44F
((2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲胺
通过在实施例 9C中用实施例 44E替代实施例 9B制备标题化合物。
实施例 44G
4-(((2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基)甲基氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 44F替代实施例 1M制备标题化合物。
实施例 44H
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 44G替代实施例 1N制备标题化合物。
实施例 45
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 45A
(S)-((2-(烯丙基氧基)丙氧基)甲基)苯
通过在实施例 24A 中用(S)-1-(苄基氧基)丙-2-醇替代 (R)-1-(苄基氧基)丙-2-醇制备标题化合物。
实施例 45B
(S)-2-((R)-环氧乙烷-2-基甲氧基)丙-1-醇
通过在实施例 24B中用实施例 45A替代实施例 24A制备标题化合物。
实施例 45C
(R)-2-(((S)-1-(苄基氧基)丙-2-基氧基)甲基)环氧乙烷
通过在实施例 24C 中用S,S-(salen)Co(II)络合物 (CAS# 188264-84-8)替代R,R-(salen)Co(II)络合物(CAS# 176763-62-5)和用实施例 45B替代实施例 24B 制备标题化合物。
实施例 45D
(S)-2-((S)-环氧乙烷-2-基甲氧基)丙-1-醇
通过在实施例 35G中用实施例 45C替代实施例 35F制备标题化合物。
实施例 45E
((2S,5S)-5-甲基-1,4-二氧杂环己烷-2-基)甲醇
通过在实施例 24E中用实施例 45D替代实施例 24D制备标题化合物。
实施例 45F
甲磺酸((2R,5S)-5-甲基-1,4-二氧杂环己烷-2-基)甲酯
通过在实施例 24F中用实施例 45E替代实施例 24E制备标题化合物。
实施例 45G
(2S,5S)-2-(叠氮基甲基)-5-甲基-1,4-二氧杂环己烷
通过在实施例 1L中用实施例 45F替代实施例 1K制备标题化合物。
实施例 45H
((2S,5S)-5-甲基-1,4-二氧杂环己烷-2-基)甲胺
通过在实施例 9C中用实施例 45G替代实施例 9B制备标题化合物。
实施例 45I
4-(((2S,5S)-5-甲基-1,4-二氧杂环己烷-2-基)甲基氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 45H替代实施例 1M制备标题化合物。
实施例 45J
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 45I替代实施例 1N制备标题化合物。1H NMR(400MHz, 二甲亚砜-d6) δ 11.67 (s, 1H), 8.57 (d, 1H), 8.55 (t, 1H), 8.03 (d,1H), 7.83 (dd, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.11 (d, 1H), 7.03 (d, 2H),6.68 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.84, 3.78, 3.70, 3.66 (all m,5H), 3.54, 3.49 (both m, 3H), 3.08 (br m, 4H), 2.76 (br s, 2H), 2.20 (br m,4H), 2.14 (br m, 2H), 1.95 (br m, 2H), 1.38 (t, 2H), 1.09 (d, 3H), 0.92 (s, 6H)。
实施例 46
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-氰基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 46A
(4-氨基甲酰基-四氢-吡喃-4-基甲基)-氨基甲酸叔丁酯
将4-(氨基甲基)四氢-2H-吡喃-4-甲酰胺 (1000 mg)在乙腈 (30 mL)和1-甲基吡咯烷酮 (10 mL)中搅拌。添加N,N-二甲基吡啶-4-胺 (77 mg),然后添加二碳酸二叔丁酯(1.45 g)。在室温下搅拌该混合物1小时,然后通过在减压下蒸发除去溶剂的乙腈部分。将该混合物添加至乙酸乙酯并用水洗涤三次。然后,用盐水洗涤混合物并在无水硫酸钠上干燥。在过滤之后,除去溶剂,并使用物质而不经进一步纯化。
实施例 46B
(4-氰基-四氢-吡喃-4-基甲基)-氨基甲酸叔丁酯
将实施例 46A (1.63 g)溶解于四氢呋喃 (60 mL)中,并添加1-甲氧基-N-三乙基铵磺酰基-亚胺代甲酸盐(methanimidate) (1.58 g)。在室温下搅拌该混合物16小时。在真空下除去溶剂并将物质溶解于乙酸乙酯中。用水洗涤溶液三次,用盐水洗涤,并在无水硫酸钠上干燥。在过滤之后,除去溶剂,使用物质而不经进一步纯化。
实施例 46C
4-(氨基甲基)四氢-2H-吡喃-4-甲腈 三氟乙酸盐
将实施例 46B (610 mg)溶解于二氯甲烷 (20 mL)中。添加2,2,2-三氟乙酸(1.95 mL),并在室温下搅拌该混合物4小时。在真空下除去溶剂,将粗物质溶解于二氯甲烷,并再次在真空下除去溶剂。然后采用乙醚研磨该物质,并在真空下干燥。
实施例 46D
4-[(4-氰基-四氢-吡喃-4-基甲基)-氨基]-3-硝基-苯磺酰胺
通过在实施例 1N中用实施例 46C替代实施例 1M制备标题化合物。
实施例 46E
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-氰基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 46D替代实施例 1N制备标题化合物。
实施例 47
N-[(4-{[(1-乙酰基哌啶-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 47A
(1-乙酰基-哌啶-4-基甲基)-氨基甲酸叔丁酯
将(哌啶-4-基甲基)氨基甲酸叔丁酯 (600 mg)溶解于二氯甲烷 (20 mL)中。添加三乙胺 (1.17 mL),并添加乙酸酐(0.26 mL)。在室温下混合该溶液16小时,并在真空下除去溶剂。使用物质而不经进一步纯化。
实施例 47B
1-(4-(氨基甲基)哌啶-1-基)乙酮 三氟乙酸盐
将实施例 47A (718 mg)溶解于二氯甲烷 (20 mL)中。添加2,2,2-三氟乙酸(4.32 mL),并在室温下搅拌该溶液4小时。在真空下除去溶剂,将物质溶解于二氯甲烷中,并在真空下再次除去溶剂。然后用乙醚研磨物质,并在真空下干燥。
实施例 47C
4-[(1-乙酰基-哌啶-4-基甲基)-氨基]-3-硝基-苯磺酰胺
通过在实施例 1N中用实施例 47B替代实施例 1M制备标题化合物。
实施例 47D
N-[(4-{[(1-乙酰基哌啶-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 47C替代实施例 1N制备标题化合物。
实施例 48
4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 48A
2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯甲酸甲酯
通过在实施例 1B 中用2-氟-4-氯苯基 硼酸替代4-氯苯基 硼酸制备标题化合物。
实施例 48B
(2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲醇
通过在实施例 1C中用实施例 48A替代实施例 1B制备标题化合物。
实施例 48C
2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯甲醛
将实施例 48B (500 mg)溶解于二氯甲烷 (19 mL)中,添加Dess-Martin高碘烷(950 mg),并在室温下搅拌该反应2小时。然后浓缩该反应,粗物质在乙醚和2M Na2CO3水溶液之间分配用盐水洗涤有机层,经Na2SO4干燥,过滤,并浓缩。在硅胶上采用9/1 庚烷/乙酸乙酯层析法处理粗物质以提供标题化合物。
实施例 48D
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(哌嗪-1-基)苯甲酸甲酯
将实施例 1H (20.5 g)和哌嗪 (37.0 g)在二甲亚砜 (200 mL)中的混合物加热至110℃持续24小时,并使该混合物冷却至室温。将该混合物倾倒入水(1 L)中并采用二氯甲烷萃取三次。用水洗涤合并的萃取物两次,用盐水洗涤,过滤,并浓缩以提供标题化合物。
实施例 48E
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸甲酯
向实施例 48C (450 mg)和实施例 48D (600 mg)在二氯甲烷 (6 mL)中的溶液中添加三乙酰氧基氢化钠 (540 mg)。搅拌该混合物过夜。用乙酸乙酯 (200 mL)稀释该混合物并用饱和NaHCO3水溶液、水和盐水洗涤。在经Na2SO4干燥之后,过滤粗物质,并在硅胶上采用1/1 庚烷/乙酸乙酯层析法处理以提供标题化合物。
实施例 48F
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸
通过在实施例 1J中用实施例 48E替代实施例 1I制备标题化合物。
实施例 48G
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(哌嗪-1-基)苯甲酸甲酯
通过在实施例 1N 中用(四氢-2H-吡喃-4-基)甲胺替代实施例 1M制备标题化合物。
实施例 48H
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺
通过在实施例 1O中用实施例 48F替代实施例 1J和用实施例 48G替代实施例 1N制备标题化合物。
实施例 49
4-(4-{[2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 49A
2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯甲酸甲酯
通过在实施例 1B 中用3-氟-4-氯苯基 硼酸替代4-氯苯基硼酸制备标题化合物。
实施例 49B
(2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯基)甲醇
通过在实施例 1C中用实施例 49A替代实施例 1B制备标题化合物。
实施例 49C
2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯甲醛
通过在实施例 48C中用实施例 49B替代实施例 48B制备标题化合物。
实施例 49D
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸甲酯
通过在实施例 48E用实施例 49C替代实施例 48C制备标题化合物。
实施例 49E
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸
通过在实施例 1J中用实施例 49D替代实施例 1I制备标题化合物。
实施例 49F
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-3-氟苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺
通过在实施例 1O中用实施例 49E替代实施例 1J 和用实施例 48G替代实施例1N制备标题化合物。
实施例 50
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-乙基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 50A
4-[(4-乙基-四氢-吡喃-4-基甲基)-氨基]-3-硝基-苯磺酰胺
通过在实施例 1N 中用(4-乙基四氢-2H-吡喃-4-基)甲胺替代实施例 1M制备标题化合物。
实施例 50B
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-乙基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 50A替代实施例 1N制备标题化合物。
实施例 51
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂环庚烷-6-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 51A
2-(1,4-二氧杂环庚烷-6-叉基)乙酸叔丁酯
经20分钟按份向2-(二乙氧基磷酰基)乙酸叔丁酯 (16.9 g)在THF (250 mL)中的冷却(0℃)溶液中添加氢化钠 (60% 在矿物油中, 2.7 g),并再搅拌该混合物10分钟。添加实施例 25A (6.5 g)/THF (10 mL),并将该反应混合物搅拌1小时,同时使温度升高到室温。然后将该混合物倾倒入水(200 mL)中并用乙醚 (2x 300 mL)萃取。用水和盐水洗涤合并的乙醚萃取物,经Na2SO4干燥,过滤,并浓缩。在硅胶上使用10% 乙酸乙酯/庚烷层析提供标题化合物。
实施例 51B
2-(1,4-二氧杂环庚烷-6-基)乙酸叔丁酯
在250 mL SS耐压瓶中将实施例 51A (8.4 g)和THF (100 mL)添加至5% Pd/C(湿JM#9, 1.6 g)并在30 psi下搅拌该混合物30分钟。通过尼龙膜过滤该混合物并浓缩。
实施例 51C
2-(1,4-二氧杂环庚烷-6-基)乙酸
将实施例 51B (8.4 g)在二氯甲烷 (100 mL) / TFA (100 mL)中搅拌1小时,浓缩该混合物以提供标题化合物。
实施例 51D
((1,4-二氧杂环庚烷-6-基)甲基)氨基甲酸苄酯
在90℃下将实施例 51C (3.88 g), 二苯基磷酰基叠氮化物 (6.67 g), 苄醇(5.04 mL), 和三乙胺 (3.4 mL)在甲苯(50 mL)中的溶液搅拌48小时。冷却该混合物并倾倒入水 (100 mL)中并用乙醚 (2x 200 mL)萃取。用水和盐水洗涤合并的萃取物,经Na2SO4干燥,过滤,并浓缩。在硅胶上使用5-20% 乙酸乙酯/庚烷层析提供标题化合物。
实施例 51E
(1,4-二氧杂环庚烷-6-基)甲胺
在250 mL SS耐压瓶中将实施例 51D (4 g)和乙醇(60 mL)添加至20% Pd(OH)2/C(湿, 0.4 g)并在30 psi和50 ℃下搅拌该反应混合物30分钟。通过尼龙膜过滤该混合物并浓缩以提供标题化合物。
实施例 51F
4-(((1,4-二氧杂环庚烷-6-基)甲基)氨基)-3-硝基苯磺酰胺
通过在实施例 1N中用实施例 51E替代实施例 1M制备标题化合物。
实施例 51G
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂环庚烷-6-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 51F替代实施例 1N制备标题化合物。
实施例 52
4-(4-{[2-(4-环丙基苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 52A
2-(4-环丙基苯基)-4,4-二甲基环己-1-烯甲酸甲酯
通过在实施例 1B 中用4-环丙基苯基 硼酸替代4-氯苯基硼酸制备标题化合物。
实施例 52B
(2-(4-环丙基苯基)-4,4-二甲基环己-1-烯基)甲醇
通过在实施例 1C中用实施例 52A替代实施例 1B制备标题化合物。
实施例 52C
2-(4-环丙基苯基)-4,4-二甲基环己-1-烯甲醛
通过在实施例 48C中用实施例 52B替代实施例 48B制备标题化合物。
实施例 52D
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-环丙基苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸甲酯
通过在实施例 48E中用实施例 52C替代实施例 48C制备标题化合物。
实施例 52E
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-环丙基苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸
通过在实施例 1J中用实施例 52D替代实施例 1I 制备标题化合物。
实施例 52F
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-环丙基苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺
通过在实施例 1O中用实施例 52E替代实施例 1J和用实施例 48G替代实施例 1N制备标题化合物。
实施例 53
4-(4-{[2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 53A
2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯甲酸甲酯
通过在实施例 1B 中用3,4-二氯苯基 硼酸替代4-氯苯基 硼酸制备标题化合物。
实施例 53B
(2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯基)甲醇
通过在实施例 1C中用实施例 53A替代实施例 1B制备标题化合物。
实施例 53C
2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯甲醛
通过在实施例 48C中用实施例 53B替代实施例 48B制备标题化合物。
实施例 53D
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸甲酯
通过在实施例 48E中用实施例 53C替代实施例 48C制备标题化合物。
实施例 53E
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酸
通过在实施例 1J中用实施例 53D替代实施例 1I 制备标题化合物。
实施例 53F
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(3,4-二氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-基)-N-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基)苯甲酰胺
通过在实施例 1O中用实施例 53E替代实施例 1J 和用实施例 48G替代实施例1N制备标题化合物。
实施例 54
4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基环己-1-烯-1-基}甲基)哌嗪-1-基]-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
实施例 54A
2-(4-二氟甲基-苯基)-4,4-二甲基-环己-1-烯甲酸甲酯
通过在实施例 1B 中用(4-(二氟甲基)苯基)硼酸替代4-氯苯基 硼酸制备标题化合物。
实施例 54B
[2-(4-二氟甲基-苯基)-4,4-二甲基-环己-1-烯基]-甲醇
通过在实施例 1C中用实施例 54A替代实施例 1B制备标题化合物。
实施例 54C
2-(4-二氟甲基-苯基)-4,4-二甲基-环己-1-烯甲醛
通过在实施例 48C中用实施例 54B替代实施例 48B制备标题化合物。
实施例 54D
4-{4-[2-(4-二氟甲基-苯基)-4,4-二甲基-环己-1-烯基甲基]-哌嗪-1-基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酸甲酯
通过在实施例 48E中用实施例 54C替代实施例 48C制备标题化合物。
实施例 54E
4-{4-[2-(4-二氟甲基-苯基)-4,4-二甲基-环己-1-烯基甲基]-哌嗪-1-基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酸
通过在实施例 1J中用实施例 54D替代实施例 1I制备标题化合物。
实施例 54F
4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基环己-1-烯-1-基}甲基)哌嗪-1-基]-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
通过在实施例 1O中用实施例 54E替代实施例 1J和用实施例 48G替代实施例 1N制备标题化合物。
Bcl-2结合数据
采用时间分辨荧光共振能量转移(TR-FRET)测定,确定了本发明化合物作为抗细胞凋亡的Bc1-2蛋白的结合剂和抑制剂的效用。Tb-抗GST抗体购自Inbitrogen(目录号:PV4216)。
探针合成
除非另有说明,使用了从供应商获得的所有试剂。肽合成试剂,包括二异丙基乙胺(DIEA)、二氯甲烷(DCM)、N-甲基吡咯烷酮(NMP)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HBTU)、N-羟基苯并三唑 (HOBt)和哌啶,从Applied Biosystems,Inc.(ABI),Foster City,CA或American Bioanalytical,Natick,MA获得。预负载的9-芴基甲氧羰基(Fmoc)氨基酸柱体(Fmoc-Ala-OH、Fmoc-Cys(Trt)-OH、Fmoc-Asp(tBu)-OH、Fmoc-Glu(tBu)-OH、Fmoc-Phe-OH、Fmoc-Gly-OH、Fmoc-His(Trt)-OH、Fmoc-Ile-OH、Fmoc-Leu-OH、Fmoc-Lys(Boc)-OH、Fmoc-Met-OH、Fmoc-Asn(Trt)-OH、Fmoc-Pro-OH、Fmor-Gln(Trt)-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Val-OH、Fmoc-Trp(Boc)-OH、Fmoc-Tyr(tBu)-OH)从ABI或Anaspec,San Jose,CA获得。肽合成树脂(Fmoc-Rink酰胺MBHA树脂)和Fmoc-Lys(Mtt)-OH从Novabiochem,San Diego,CA获得。单一异构体6-羧基荧光素琥珀酰亚胺酯(6-FAM-NHS)从Anaspec获得。三氟乙酸(TFA)从Oakwood Products,WestColumbia,SC获得。苯甲硫醚、苯酚、三异丙基硅烷(TIS)、3,6-二氧杂-1,8-辛二硫醇(DODT)和异丙醇从Aldrich Chemical Co.,Milwaukee,WI获得。基质辅助的激光解吸电离质谱(MALDI-MS)记录在Applied Biosystems Voyager DE-PRO MS)上。电喷射质谱(ESI-MS)以正离子和负离子两种的模式记录在Finnigan SSQ7000 (Finnigan Corp.,San Jose,CA)上。
固相肽合成(SPPS)的一般操作方法
在ABI433肽合成仪上,使用最多250 μmol的预负载王氏树脂(Wang resin)/容器,利用250 μmol规模的Fastmoc™偶联循环合成了肽。将含有1mmol标准Fmoc-氨基酸的预负载柱体(除了荧光团的连接位置之外,其中1mmol Fmoc-Lys(Mtt)-OH置于柱体)与传导性反馈监测一起使用。在标准偶联条件下于柱体中用1mmol醋酸完成了N末端乙酰化。
从赖氨酸除去4-甲基三苯甲基(Mtt)
来自合成仪的树脂用DCM洗涤三次并保持湿润。150 mL 95:4:1的二氯甲烷:三异丙基硅烷:三氟乙酸经30分钟流过树脂床。混合物变为深黄色,随后褪为浅黄色。100 mLDMF经15分钟流过该床。然后将树脂用DMF洗涤三次并过滤。茚三酮测试显示伯胺的强信号。
用6-羧基荧光素-NHS(6-FAM-NHS)标记树脂
将树脂用含2当量的6-FAM-NHS的1% DIEA/DMF处理并在环境温度搅拌或振荡过夜。完成时,排干树脂,用DMF洗涤三次,用(1×DCM和1×甲醇)洗涤三次,干燥,得到茚三酮测试呈阴性的橙色树脂。
用于将结合树脂的肽裂解与脱保护的一般操作方法
在环境温度,在由80%TFA、5%水、5%苯甲硫醚、5%苯酚、2.5%TIS、和2.5%EDT组成的裂解混合液(1mL/0.1g树脂)中震荡3小时,将肽从树脂上裂解下来。过滤除去树脂并用TFA清洗两次。从滤液中蒸发除去TFA,产品用乙醚(10mL/0.1g树脂)沉淀,通过离心回收,用乙醚(10mL/0.1g树脂)洗涤两次并干燥,得到粗肽。
用于纯化肽的一般操作方法
粗肽在运行Unipoint®分析软件(Gilson, Inc., Middleton, WI)的Gilson制备型HPLC系统上,在含有两个填充100Å孔径的Delta-Pak™ C18 15μm颗粒的25×100mm区段的径向压缩柱上,进行了纯化并用下文列出的梯度法之一洗脱。每次注射一至两毫升的粗肽溶液(10mg/mL,于90%DMSO/水中)进行纯化。将来自每次运行的含有产物的峰收集并冻干。所有制备性运行均用缓冲液A:0.1% TFA-水和缓冲液B:乙腈为洗脱液以20mL/min的速度运行。
用于分析型HPLC的一般操作方法
分析型HPLC在运行HPLC 3D ChemStation软件版本A.03.04(Hewlett-Packard.Palo Alto, CA)的具有二极管阵列检测器和Hewlett-Packard 1046A荧光检测器的Hewlett-Packard 1200系列系统上,在充填120Å孔径的ODS-AQ 5 μm颗粒的4.6×250mmYMC柱上进行,并在起始条件下预平衡7分钟后用下文列出的梯度方法之一洗脱。洗脱液为缓冲液A:0.1% TFA-水和缓冲液B:乙腈。所有梯度的流速均为1mL/min。
F-Bak: 肽探针乙酰基-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO: 2)INR-NH2
使用一般的肽合成操作方法扩展Fmoc-Rink酰胺MBHA树脂,得到经保护的结合树脂的肽(1.020g)。如上文所述,除去Mtt基团,用6-FAM-NHS标记,裂解并脱保护,得到橙色固态的粗产物(0.37g)。通过RP-HPLC纯化该产物。通过分析型RP-HPLC测试了跨主峰的级分,分离出纯净的级分并冻干,其主峰提供了黄色固态的标题化合物(0.0802g);MALDI-MS m/z= 2137.1 [(M+H)+]。
肽探针F-Bak:乙酰基-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO: 2)INR-NH2 的可替换的合成
在Applied Biosystems 433A自动肽合成仪中,在0.25mmol Fmoc-Rink酰胺MBHA树脂(Novabiochem)上,使用预负载的1mmol氨基酸柱体(除了荧光素(6-FAM)-标记的赖氨酸以外,其中将1 mmol Fmoc-Lys(4-甲基三苯甲基)称量至柱体中),运行Fastmoc™偶合循环,组装保护的肽。将1 mmol醋酸放入柱体中并按上文所述进行偶联以并入N末端乙酰基。用95:4:1的DCM:TIS:TFA(v/v/v)溶液经15分钟流过树脂,随后用二甲基甲酰胺流过淬灭,实现了选择性除去4-甲基三苯甲基基团。将单一异构体6-羧基荧光素-NHS在含1%DIEA的DMF中与赖氨酸侧链反应,并用茚三酮测试确定反应完成。将肽从树脂上裂解下来,并用80:5:5:5:2.5:2.5的TFA/水/苯酚/苯甲硫醚/三异丙基硅烷: 3,6-二氧杂-1,8-辛二硫醇 (v/v/v/v/v/v)处理以将侧链脱保护,通过二乙醚沉淀回收粗肽。粗肽用反相高效液相色谱法纯化,并用分析型反相高效液相色谱法和基质辅助的激光解吸质谱确定其纯度与身份(m/z= 2137.1 ((M+H)+)。
时间分辨荧光共振能量转移(TR-FRET)测定
以50μM(2×初始浓度;10%DMSO)开始,用二甲亚砜(DMSO)连续稀释代表性化合物,并将10μL转移至384孔板中。然后以表1中列出的终浓度将10μL蛋白/探针/抗体混合物添加入各孔中。随后将样品在振荡器上混合一分钟,并在室温孵育额外的3小时。对于每项测定,在每个测定板上包括探针/抗体和蛋白/探针/抗体分别作为阴性和阳性对照。在Envision(Perkin Elmer)上用340/35nm激发滤光片和520/525(F-Bak肽)和495/510nm(Tb标记的抗组氨酸抗体)发射滤光片,测量了荧光。下表2中示出解离常数(Ki)并用王氏方程式(WangZ.-X., An Exact Mathematical Expression For Describing Competitive Binding OfTwo Different Ligands To A Protein Molecule. FEBS Lett. 1995, 360:111-4)确定。
表1. 用于TR-FRET测定的蛋白、探针和抗体
蛋白 | 探针 | 蛋白 (nM) | 探针 (nM) | 抗体 | 抗体 (nM) |
GST-Bcl-2 | F-Bak肽探针乙酰基-(SEQ ID NO: 1 GQVGRQLAIIGDK(6-FAM) SEQ ID NO: 2 INR-酰胺) | 1 | 100 | Tb-抗-GST | 1 |
6-FAM = 6- 羧基荧光素.;Tb =铽;GST = 谷胱甘肽S-转移酶。
然后,在振动器上混合所述样品1分钟并在室温下再孵育3小时。对于每个测定,在每个测定上包含探针/抗体和蛋白/探针/抗体分别作为阴性和阳性对照。在Envision(Perkin Elmer)上使用340/35 nm激发滤光片和520/525 (F-Bak肽)和495/510 nm (Tb-标记的抗组氨酸抗体)发射滤光片测量荧光。
使用王氏方程式(Wang Zx,. An Exact Mathematical Expression ForDescribing Competitive Binding Of Two Different Ligands To A ProteinMolecule. FEBS Lett. 1995, 360:111-4)测定化合物的抑制常数(Ki)。在化合物的Ki表示为“<” (小于)某一数值的情况下,其意在表示结合亲和力值(例如,对于Bcl-2)低于使用的测定的检测限。本发明化合物的恒定常数(Ki)示于表2中。
表2. TR-FRET Bcl-2 结合 K
i
(nM)
nd = 无数据。
所述抑制常数(Ki)为酶-抑制剂复合物或蛋白/小分子复合物的离解常数,其中所述小分子抑制一种蛋白结合至另一蛋白或肽。因此,大Ki值表示低亲和力,小Ki值表示高亲和力。表2示出Bak BH3肽探针对Bcl-2蛋白的抑制的抑制常数,并表示根据本发明的化合物具有针对抗细胞凋亡Bcl-2蛋白的高亲和力。因此,预期所述化合物具有治疗疾病的用途,在此期间表达抗细胞凋亡Bcl-2蛋白。
生物数据
RS4;11 细胞活力分析
急性成淋巴细胞性白血病(ALL)细胞系RS4;11用作原代人类细胞系以评价Bcl-2选择性试剂在体外的细胞活性和它们在体内的效果。通过BH3性能分析,分类固有细胞凋亡通路中的阻断的线粒体测定,之前的研究已经示出RS4;11细胞高度依赖于BCL-2用于存活并对Bcl-2家族成员抑制剂ABT-737敏感(Blood, 2008, Vol. 111, 2300-2309)。在RS4;11中Bcl-2复合至促细胞凋亡BH3蛋白Bim的普遍性表明这些细胞通过抗细胞凋亡蛋白Bcl-2的拮抗“倾向于”或更易于细胞死亡,这些细胞取决于抗细胞凋亡蛋白Bcl-2用于存活。
在补充了2 mM L-谷氨酰胺、10% FBS、1 mM丙酮酸钠、2 mM HEPES、1% 盘尼西林/链霉素(Invitrogen)、4.5 g/L葡萄糖并保持在37 C下含有5% CO2的RPMI-1640中培养RS4;11细胞。为了测试体外化合物细胞活性,在10%人类血清存在下在含有5% CO2的润湿室中在96-孔微量滴定板中以每孔50,000个细胞处理细胞48小时。根据制造商建议书使用CellTiter Glo (Promega)评价细胞毒性EC50值。相比于未处理的对照细胞,在处理之后以活细胞百分比的形式测定EC50值。
表3. RS4;11 EC
50
值 (μM)
表3示出使用本发明化合物以功能性抑制细胞环境中抗细胞凋亡Bcl-2蛋白。通过BH3性能分析,分类固有细胞凋亡通路中的阻断的线粒体测定,急性成淋巴细胞性白血病(ALL)细胞系RS4;11已经示出高度依赖于BCL-2用于存活并对Bcl-2家族成员抑制剂ABT-737敏感(Blood, 2008, Vol. 111, 2300-2309)。化合物杀死RS4;11细胞的能力为化合物抑制抗细胞凋亡Bcl-2蛋白功能的能力的直接测量。本发明化合物对于杀死RS4;11非常有效,如由低EC50值证实的。
已知在本领域中蛋白的Bcl-2家族的某些成员的抑制可能诱导剂量限制的血小板减少。认为严重限制用于自身免疫适应症的一些非选择性Bcl-2抑制剂的治疗使用的剂量限制的血小板减少是由于Bcl-xL的抑制(参见Mason, K.D等人, Programmed anuclear cell death delimits platelet life span. Cell, 2007. 128(6): 第1173-86页。
进行实验来评价Bcl-2选择性/ Bcl-xL少量化合物(sparing compounds)对免疫细胞和血小板的效果,如在C57Bl/6小鼠中评价的。采用化合物处理小鼠四天(30 mg/kg的剂量,通过每天腹膜内注射给予),并在第一和最后给药之后采用Cell Dyn血液学分析器测量细胞数24小时。在最后给药之后通过使用1、6、10和24小时的时间点计算化合物的暴露(在曲线下的面积)。该实验的结果在表4中示例。
表4.采用1和4剂量的Bcl-2选择性抑制剂 (30 mg/kg)处理的C57BL/6小鼠中的淋
巴细胞降低
nd = 无淋巴细胞降低。
这些数据与体外选择性特征一致并强调分别地Bcl-2对淋巴细胞和Bcl-xL对血小板存活的必要作用。该药效动力学研究示例这些化合物作为选择性Bcl-2抑制剂有效降低淋巴细胞的能力,而没有与非选择性Bcl-2抑制剂相关的副作用。
Claims (18)
1.选自如下的化合物:
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2R)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5R,8R)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-羟基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂螺[4.5]癸-8-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2S)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[4-(羟基甲基)四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-羟基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-氰基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;和
4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基环己-1-烯-1-基}甲基)哌嗪-1-基]-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺;
或其治疗上可接受的盐。
2.治疗有效量的权利要求1的化合物或其治疗上可接受的盐在制备药物中的用途,所述药物用于治疗需要治疗的对象中的膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾脏癌。
3.权利要求2所述的用途,其中所述药物包含赋形剂和治疗有效量的权利要求1的化合物或其治疗上可接受的盐。
4.治疗有效量的权利要求1的化合物或其治疗上可接受的盐和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂在制备药物中的用途,所述药物用于治疗需要治疗的对象中的膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源的淋巴恶性肿瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌、小细胞肺癌或脾脏癌。
5.治疗有效量的权利要求1的化合物或其治疗上可接受的盐在制备药物中的用途,所述药物用于治疗需要治疗的对象中的全身性红斑狼疮、狼疮性肾炎或舍格伦综合症。
6.权利要求5的用途,其中所述药物包含赋形剂和治疗有效量的权利要求1的化合物或其治疗上可接受的盐。
7.治疗有效量的权利要求1的化合物或其治疗上可接受的盐和治疗有效量的一种另外的治疗剂或多于一种另外的治疗剂在制备药物中的用途,所述药物用于治疗需要治疗的对象中的全身性红斑狼疮、狼疮性肾炎或舍格伦综合症。
8.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二氧杂环己烷-2-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
9.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2R)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
10.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(3-硝基-4-{[(5R,8R)-1-氧杂螺[4.5]癸-8-基甲基]氨基}苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
11.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-羟基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
12.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({4-[(1,4-二氧杂螺[4.5]癸-8-基甲基)氨基]-3-硝基苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
13.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(2S)-1,4-二氧杂环己烷-2-基甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
14.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-{[4-({[4-(羟基甲基)四氢-2H-吡喃-4-基]甲基}氨基)-3-硝基苯基]磺酰基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
15.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(3-羟基氧杂环丁烷-3-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
16.化合物4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-[(4-{[(4-氰基四氢-2H-吡喃-4-基)甲基]氨基}-3-硝基苯基)磺酰基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
17.化合物4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
18.化合物4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基环己-1-烯-1-基}甲基)哌嗪-1-基]-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其治疗上可接受的盐。
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