CN102947283A - 用于治疗癌症和免疫以及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以及自身免疫性疾病的细胞凋亡诱导剂 Download PDFInfo
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- CN102947283A CN102947283A CN2011800159154A CN201180015915A CN102947283A CN 102947283 A CN102947283 A CN 102947283A CN 2011800159154 A CN2011800159154 A CN 2011800159154A CN 201180015915 A CN201180015915 A CN 201180015915A CN 102947283 A CN102947283 A CN 102947283A
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- amino
- phenyl
- alkylsulfonyl
- benzamide
- piperazine
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- 210000003932 urinary bladder Anatomy 0.000 description 1
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- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
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- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000002498 viral encephalitis Diseases 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
- 229940055725 xarelto Drugs 0.000 description 1
- ZPUHVPYXSITYDI-HEUWMMRCSA-N xyotax Chemical compound OC(=O)[C@@H](N)CCC(O)=O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 ZPUHVPYXSITYDI-HEUWMMRCSA-N 0.000 description 1
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Abstract
本发明公开了抑制抗细胞凋亡Bcl-2蛋白的活性的化合物,包含该化合物的组合物以及治疗在疾病期间表达抗细胞凋亡Bcl-2蛋白的疾病的方法。
Description
发明领域
本发明涉及抑制Bcl-2抗细胞凋亡蛋白的活性的化合物,含该化合物的组合物以及治疗在疾病期间表达抗细胞凋亡Bcl-2蛋白的疾病的方法。
发明背景
抗细胞凋亡Bcl-2蛋白与许多疾病有关。因此在治疗领域中存在着对抑制抗细胞凋亡Bcl-2蛋白活性的化合物的需要。
Bcl-2蛋白的过表达与在各种癌症和免疫系统的病症中的耐化疗性、临床结果、疾病进程、总预后(overall prognosis)或其组合有关。
Bcl-2蛋白参与膀胱癌、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、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、髓细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌、脾癌等中的描述见共同拥有的以WO 2005/049593公开的PCT US2004/36770和以WO 2005/024636公开的PCT US 2004/37911中。
Bcl-2蛋白参与免疫和自身免疫性疾病的描述见以下文献:CurrentAllergy and Asthma Reports 2003,3,378-384;British Journal ofHaematology 2000,110(3),584-90;Blood 2000,95(4),1283-92;和NewEngland Journal ofMedicine 2004,351(14),1409-1418。Bcl-2蛋白参与关节炎的公开见共同拥有的美国临时专利申请60/988,479。Bcl-2蛋白参与骨髓移植排斥的公开见共同拥有的美国专利申请11/941,196中。
发明概述
本发明的一个实施方案涉及化合物或其治疗可接受的盐、前药、代谢物或其前药的盐,其可用作抗细胞凋亡Bcl-2蛋白的抑制剂,所述化合物选自
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-[(3-硝基-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯基)磺酰基]苯甲酰胺;
4-(4-{乙酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-(4-{苯甲酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-3′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(苯基乙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
4-{6-[金刚烷-1-基甲基]-2,6-二氮杂双环[3.2.1]辛-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-[(三氟甲基)磺酰基]苯基)磺酰基]-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-硝基苯基}磺酰基]苯甲酰胺;
4-{(1S,4S)-5-[金刚烷-1-基甲基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-(4-{[3-溴-5-甲基金刚烷-1-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{[3,5-二甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酰胺;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-{[4-(1-甲基-2-氧代-3-氮杂双环[3.1.1]庚-3-基)苯基]磺酰基}苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-八氢-1H-4,7-亚甲基茚-5-基氨基]苄基}哌嗪-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚-2-基]氨基}苄基)哌嗪-1-基]苯甲酰胺;
4-[4-(2-{[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-基]氨基}苄基)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;
4-(4-{[(1R,5R)-2-(4-氯苯基)-6,6-二甲基双环[3.1.1]庚-2-烯-3-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{4-[(2-{[金刚烷-2-基甲基]氨基}-5,5-二甲基环己基)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;
4-{4-[(5,5-二甲基-2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}环己基)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;
4-{4-[2-(3-氮杂双环[3.2.2]壬-3-基)-5-硝基苄基]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;
4-(4-{2-[2,3,3a,4,7,7a-六氢-1H-4,7-亚甲基茚-5-基]苄基}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;
1-[金刚烷-1-基]-4-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺;
4-(4-{2-[2-(金刚烷-1-基)-6-甲基咪唑并[1,2-a]吡啶-8-基]苄基}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;
N-(金刚烷-2-基)-6-甲基-8-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}咪唑并[1,2-a]吡啶-2-甲酰胺;
4-(4-{2-[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-烯-2-基]苄基}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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5,5,6-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺;
N-环辛基-5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-2-糠酰胺;
N-苄基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
4-[4-(2-{[(1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-基]氨基}苄基)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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苄基)哌嗪-1-基]苯甲酰胺;
4-(4-{2-[3-氮杂双环[3.2.2]壬-3-基]苄基}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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[三环[4.3.1.13,8]十一碳-4-烯-4-基]苄基}哌嗪-1-基)苯甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-苯基双环[2.2.1]庚-2-烯-1-甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]双环[2.2.1]庚-2-烯-1-甲酰胺;
N-(金刚烷-1-基甲基)-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
N-环丙基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酸;
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苄基)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;
4-{4-[金刚烷-1-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{4-[金刚烷-2-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{5-[金刚烷-1-基羰基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{1S,5S)-3-[金刚烷-1-基羰基]-3,6-二氮杂双环[3.2.0]庚-6-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-(4-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
6-{3-[金刚烷-1-基]-4-羟苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺;
4-(4-{2-[金刚烷-1-基]-2-氧代乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{[金刚烷-2-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{2-[金刚烷-1-基]乙氧基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N3-[金刚烷-1-基乙酰基]-N3-苄基-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-β-丙氨酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]哌嗪-1-基}苯甲酰胺;
4-{4-[金刚烷-1-基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[3,5-二甲基金刚烷-1-基]哌嗪-1-基}苯甲酰胺;
[(3aS,5aR,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[1,3]二氧杂环戊烯并[4,5-b4′,5′-d]吡喃-3a-基]甲基;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1R,4S)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺;
4-(4-{2-[金刚烷-1-基]乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-({(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}甲基)联苯-4-甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苯亚甲基}哌啶-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苄基}哌嗪-1-基)苯甲酰胺;
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苄基)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;
5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-(2-苯基-1,3-苯并噁唑-5-基)-2-糠酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(三苯基乙烯基)苄基]哌嗪-1-基}苯甲酰胺;
4-{4-[2-(5-甲基-5,6-二氢菲啶-6-基)苄基]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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基]哌嗪-1-基}苯甲酰胺;
4-(4-{2-[2-(2,6-二甲氧基苯甲酰基)-3-噻吩基]苯亚甲基}哌啶-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;
1-[金刚烷-1-基]-4-{2-[(1-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌啶-4-亚基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基(3-苯基丙酰基)氨基]苄基}哌嗪-1-基)苯甲酰胺;
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苯亚甲基)哌啶-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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺;
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苯亚甲基)哌啶-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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苯亚甲基}哌啶-1-基)苯甲酰胺;
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-氧代-4H-色烯-6-基)苯甲酰胺;
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(1-辛基-1H-吡唑-4-基)苯甲酰胺;
4-[5-(4-{[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]氨基甲酰基}苯基)-1,3-苯并噻唑-2-基]丁酸;
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-[(1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛-3-基]苯甲酰胺;
6-{3-[金刚烷-1-基]-4-甲氧基苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺;
4-{4-[金刚烷-1-基乙酰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{[金刚烷-1-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N-{1-[4-({[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}氨基甲酰基)苯基]哌啶-4-基}金刚烷-1-甲酰胺;
4-[金刚烷-2-基氨基]-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;和
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氧基}苯甲酰胺。
另一个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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的组合物,所述组合物包括赋形剂和治疗有效量的本发明的化合物。
另一个实施方案涉及在患者中治疗膀胱癌、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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的方法,所述方法包括将治疗有效量的本发明的化合物施用于患者。
另一个实施方案涉及在患者中治疗膀胱癌、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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的方法,所述方法包括将治疗有效量的本发明的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施用于患者。
发明详述
本文中的变量部分由标识符(大写字母与数字和/或字母上标)表示并且可以被特别地具体化。
应当理解的是对于全部部分及其组合而言,保持适当的原子价,具有多于一个原子的一价部分是从左到右画出的并且通过它们的左端连接,以及二价部分也是从左到右画出的。
还应当理解的是本文中的变量部分的特定的实施方案可以是与具有相同标识符的另一特定的实施方案相同的或不同的。
如本文中使用的术语″烯基″,是指含2-10个碳和含至少一个碳-碳双键的直或支链烃链。术语″Cx-Cy烷基″是指含至少一个碳-碳双键、包含x至y个碳原子的直或支链烃链。术语“C2-C4烯基”是指包含2-4个碳原子的烯基。烯基的代表性例子包括但不限于丁-2,3-二烯基、乙烯基、2-丙烯基、2-甲基-2-丙烯基、3-丁烯基、4-戊烯基、5-己烯基、2-庚烯基、2-甲基-1-庚烯基和3-癸烯基。
术语″亚烯基(alkenylene)″是指衍生自2-4个碳原子的直或支链烃并且含至少一个碳-碳双键的二价基团。术语″Cx-Cy亚烷基″是指衍生自含至少一个碳-碳双键和包含x至y个碳原子的直或支链烃链的二价基团。亚烯基(alkenylene)的代表性例子包括但不限于-CH=CH-和-CH2CH=CH-。
如本文中使用的术语“烷基”是指含1-10个碳原子的直或支链的饱和烃链。术语″Cx-Cy烷基″是指包含x至y个碳原子的直或支链的链状饱和烃。例如,″C2-C10烷基″是指包含2-10个碳原子的直或支链的链状饱和烃。烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基和正癸基。
术语″亚烷基″是指衍生自1-10个碳原子,例如,1-4个碳原子的直或支链的饱和烃链的二价基团。术语″Cx-Cy亚烷基″是指衍生自包含x至y个碳原子的直或支链的饱和烃的二价基团。例如″C2-C6亚烷基″是指包含2-6个碳原子的直或支链的饱和烃。亚烷基的例子包括但不限于-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-和-CH2CH(CH3)CH2-。
如本文中使用的术语“炔基”是指包含2-10个碳原子和包含至少一个碳-碳三键的直或支链烃基团。术语″Cx-Cy炔基″是指包含x至y个碳原子的直或支链烃基团。炔基的代表性例子包括但不限于乙炔基、1-丙炔基、2-丙炔基、3-丁炔基、2-戊炔基和1-丁炔基。
如本文中使用的术语″亚炔基″是指衍生自包含2-10个碳原子和包含至少一个碳-碳三键的直或支链烃基团的二价基团。
如本文中使用的术语″芳基″是指苯基。
如本文中使用的术语″环状部分″是指苯、苯基、亚苯基、环烷烃、环烷基、亚环烷基、环烯烃、环烯基、亚环烯基、环炔、环炔基、亚环炔基、杂芳烃、杂芳基、杂环烷烃、杂环烷基、杂环烯烃、杂环烯基和螺烷基。
如本文中使用的术语″亚环烷基″或环烷基″或″环烷烃″是指单环或桥连烃环系。单环环烷基是包含3-8个碳原子、零个杂原子和零个双键的碳环环系。单环环系的例子包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。单环环可以包含一或两个亚烷基桥,每个包括一个、两个或三个碳原子,每个连接两个非相邻的所述环系的碳原子。这种桥连的环烷基环系的非限制性例子包括双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷、双环[4.2.1]壬烷、三环[3.3.1.03,7]壬烷(八氢-2,5-桥亚甲基并环戊二烯(methanopentalene)或降金刚烷(noradamantane))和三环[3.3.1.13,7]癸烷(金刚烷)。单环和桥连环烷基可以通过所述环系中所含的任何可取代的原子连接到母体分子部分。
如本文中使用的术语″亚环烯基″或″环烯基″或″环烯烃″是指单环或桥连烃环系。单环环烯基具有4、5、6、7或8个碳原子和零个杂原子。四元环系具有一个双键,五或六元环系具有一或两个双键,和七或八元环系具有1、2或3个双键。单环环烯基基团的代表性例子包括但不限于环丁烯基、环戊烯基、环己烯基、环庚烯基和环辛烯基。单环环烯基环可以包含一或两个亚烷基桥,每个包括一个、两个或三个碳原子,每个连接两个非相邻的所述环系的碳原子。双环环烯基的代表性例子包括但不限于4,5,6,7-四氢-3aH-茚、八氢萘基和1,6-二氢-并环戊二烯。单环和双环环烯基可以通过所述环系中所含的任何可取代的原子连接到母体分子部分。
如本文中使用的术语″环炔″或″环炔基″或″亚环炔基″是指单环或桥连烃环系。单环环炔基具有8或更多个的碳原子,零个杂原子和一个或多个三键。单环环炔基环可以包含一或两个亚烷基桥,每个包括一个、两个或三个碳原子,每个连接两个非相邻的所述环系的碳原子。单环和桥连环炔基可以通过所述环系中所含的任何可取代的原子连接到母体分子部分。
如本文中使用的术语″杂芳烃″或″杂芳基″或″亚杂芳基″是指具有至少一个碳原子和一个或多于一个独立选择的氮、氧或硫原子的五元或六元芳族环。本发明的杂芳烃通过环中任何相邻的原子连接,条件是保持了适当的原子价。杂芳基的代表性例子包括但不限于呋喃基(包括,但不限于此,呋喃-2-基)、咪唑基(包括,但不限于此,1H-咪唑-1-基)、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡啶基(例如吡啶-4-基,吡啶-2-基,吡啶-3-基)、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基(包括,但不限于此,噻吩-2-基,噻吩-3-基)、三唑基和三嗪基。
如本文中使用的术语″杂环烷烃″或″杂环烷基″或″亚杂环烷基″是指含至少一个独立地选自O、N和S的杂原子和零个双键的单环或桥连三-、四-、五-、六-、七-或八元环。单环和桥连杂环烷烃通过所述环中所含的任何可取代的碳原子或任何可取代的氮原子连接到母体分子部分。杂环环中的氮和硫杂原子可以任选地被氧化和氮原子可以任选地被季铵化(quarternized)。杂环烷烃基团的代表性例子包括但不限于杂环烷烃基团的代表性例子包括但不限于吗啉基、四氢吡喃基、吡咯烷基、哌啶基、二氧杂环戊烷基、四氢呋喃基、硫代吗啉基、二氧杂环己烷基、四氢噻吩基、四氢噻喃基、氧杂环丁基、哌嗪基、咪唑烷基、氮杂环丁烷、氮杂环庚烷基(azepanyl)、氮杂环丙烷基(aziridinyl)、二氮杂环庚烷基(diazepanyl)、二硫杂环戊烷基、二硫杂环己烷基、异噁唑烷基、异噻唑烷基、噁二唑烷基、噁唑烷基、吡唑烷基、四氢噻吩基、噻二唑烷基、噻唑烷基、硫代吗啉基、三硫杂环己烷基和三硫杂环己烷基。
如本文中使用的术语″杂环烯烃″或″杂环烯基″或″亚杂环烯基″是指含至少一个独立地选自O、N和S的杂原子和一个或多个双键的单环或桥连三-、四-、五-、六-、七-或八元环。单环和桥连杂环烯烃通过所述环中所含的任何可取代的碳原子或任何可取代的氮原子连接到母体分子部分。杂环环中的氮和硫杂原子可以任选地被氧化和氮原子可以任选地被季铵化(quarternized)。杂环烯烃基团的代表性例子包括但不限于四氢氧杂环辛三烯基(tetrahydrooxocinyl)、1,4,5,6-四氢哒嗪基、1,2,3,6-四氢吡啶基、二氢吡喃基、咪唑啉基、异噻唑啉基、噁二唑啉基、异噁唑啉基、噁唑啉基、吡喃基、吡唑啉基、吡咯啉基、噻二唑啉基、噻唑啉基和噻喃基。
如本文中使用的术语″亚苯基″是指通过从苯基除去氢原子形成的二价基团。
如本文中使用的术语″螺烷基″是指其两端连接到相同碳原子的亚烷基,并且例证为C2-螺烷基、C3-螺烷基、C4-螺烷基、C5-螺烷基、C6-螺烷基、C7-螺烷基、C8-螺烷基、C9-螺烷基等。
如本文中使用的术语″螺杂烷基″是指螺杂烷基具有一或两个被独立选择的O、C(O)、CNOH、CNOCH3、S、S(O)、SO2或NH替换的CH2部分和一或两个未被替换的或被N替换的CH部分的螺烷基。
如本文中使用的术语″螺杂烯基″是指具有一或两个被独立选择的O、C(O)、CNOH、CNOCH3、S、S(O)、SO2或NH替换的CH2部分和一或两个未被替换的或被N替换的CH部分的螺烯基以及是指具有一或两个未被替换的或被独立选择的O、C(O)、CNOH、CNOCH3、S、S(O)、SO2或NH替换的CH2部分和一或两个被N替换的CH部分的螺烯基。
如本文中使用的术语″螺环″是指在同一碳原子上的两个取代基,其与它们所连接的碳原子一起形成环烷烃、杂环烷烃、环烯烃或杂环烯烃环。
如本文中使用的术语″C2-C5-螺烷基″是指C2-螺烷基、C3-螺烷基、C4-螺烷基和C5-螺烷基。
如本文中使用的术语″C2-螺烷基″是指亚乙-1,2-基,其两端替代同一CH2部分的氢原子。
如本文中使用的术语″C3-螺烷基″是指亚丙-1,3-基,其两端替代同一CH2部分的氢原子。
如本文中使用的术语″C4-螺烷基″是指亚丁-1,4-基,其两端替代同一CH2部分的氢原子。
如本文中使用的术语″C5-螺烷基″是指亚戊-1,5-基,其两端替代同一CH2部分的氢原子。
如本文中使用的术语″C6-螺烷基″是指亚己-1,6-基,其两端替代同一CH2部分的氢原子。
如本文中使用的术语″NH保护基″是指在合成过程期间保护NH基团免于不希望的反应的取代基。NH保护基的例子包括但不限于三氯乙氧基羰基、三溴乙氧基羰基、苄氧基羰基、对硝基苄基羰基、邻溴苄氧基羰基、氯乙酰基、二氯乙酰基、三氯乙酰基、三氟乙酰基、苯乙酰、甲酰基、乙酰基、苯甲酰基、叔戊氧基羰基、叔丁氧羰基、对甲氧基苄氧基羰基、3,4-二甲氧基苄氧基羰基、4-(苯偶氮基)苄氧基羰基、2-糠基-氧基羰基、二苯基甲氧基羰基、1,1-二甲基丙氧基-羰基、异丙氧羰基、邻苯二甲酰、琥珀酰、丙氨酰、亮氨酰、1-金刚烷氧基羰基、8-喹啉基氧基羰基、苄基、二苯甲基、三苯甲基、2-硝基苯基硫基、甲基磺酰、对甲苯磺酰、N,N-二甲基氨基亚甲基、苯亚甲基、2-羟基苯亚甲基、2-羟基-5-氯苯亚甲基、2-羟基-1-萘基-亚甲基、3-羟基-4-吡啶基亚甲基、环亚己基、2-乙氧基羰基环亚己基、2-乙氧基羰基环亚戊基、2-乙酰基环亚己基、3,3-二甲基-5-氧基环亚己基、二苯基磷酰、二苄基磷酰基、5-甲基-2-氧代-2H-1,3-间二氧杂环戊烯-4-基-甲基、三甲基甲硅烷基、三乙基甲硅烷基和三苯甲硅烷基。
如本文中使用的术语″C(O)OH保护基″是指在合成过程期间保护C(O)OH基团免于不希望的反应的取代基。C(O)OH保护基的例子包括但不限于甲基、乙基、正丙基、异丙基、1,1-二甲丙基、正丁基、叔丁基、苯基、萘基、苄基、二苯甲基、三苯甲基、对硝基苄基、对甲氧基苄基、双(对甲氧苯基)甲基、乙酰基甲基、苯甲酰基甲基、对硝基苯甲酰基甲基、对溴苯甲酰基甲基、对甲基磺酰苯甲酰基甲基、2-四氢吡喃基2-四氢呋喃基、2,2,2-三氯-乙基、2-(三甲基甲硅烷基)乙基、乙酰氧基甲基、丙酰氧基甲基、新戊酰氧基甲基、酞酰亚氨甲基、琥珀酰亚氨基甲基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基、苄氧基甲基、甲基硫基甲基、2-甲基硫基乙基、苯基硫基甲基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、二苯甲基甲硅烷基和叔丁基甲氧苯基甲硅烷基。
如本文中使用的术语″OH或SH保护基″是指在合成过程期间保护OH或SH基团免于不希望的反应的取代基。OH或SH保护基的例子包括但不限于苄氧基羰基、4-硝基苄氧基羰基、4-溴苄氧基羰基、4-甲氧基苄氧基羰基、3,4-二甲氧基苄氧基羰基、甲氧基羰基、乙氧基羰基、叔丁氧羰基、1,1-二甲基丙氧羰基、异丙氧羰基、异丁氧基羰基、二苯基甲氧基羰基、2,2,2-三氯乙氧基羰基、2,2,2-三溴乙氧基羰基、2-(三甲基甲硅烷基)乙氧基羰基、2-(苯磺酰)乙氧基羰基、2-(三苯基磷鎓基(triphenylphosphonio))乙氧基羰基、2-糠基氧基羰基、1-金刚烷氧基羰基、乙烯氧基羰基、烯丙氧基羰基、S-苄基硫代羰基、4-乙氧基-1-萘氧基羰基、8-喹啉基氧基羰基、乙酰基、甲酰基、氯乙酰基、二氯乙酰基、三氯乙酰基、三氟乙酰基、甲氧基乙酰基、苯氧基乙酰基、新戊酰、苯甲酰基、甲基、叔丁基、2,2,2-三氯乙基、2-三甲基甲硅烷基乙基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、苄基(苯基甲基)、对甲氧基苄基、3,4-二甲氧基苄基、二苯甲基、三苯甲基、四氢呋喃基、四氢吡喃基、四氢噻喃基、甲氧基甲基、甲基硫基甲基、苄氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯-乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基、1-乙氧基乙基、甲基磺酰、对甲苯磺酰、三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、二苯甲基甲硅烷基和叔丁基甲氧苯基甲硅烷基。
对于有机合成中的保护基的综述,参见Greene,T.W.;Wuts,P.G.M.Protective Groups in Organic Synthesis,第4版,Wiley-Interscience:NewYork,2006。
化合物
几何异构体可以存在于本发明的化合物中。本发明的化合物可以包含处于E或Z构型中的碳-碳双键或碳-氮双键,其中术语″E″代表高阶取代基在碳-碳或碳-氮双键的对侧上和术语″Z″代表高阶取代基在碳-碳或碳-氮双键的同侧上,如根据Cahn-Ingold-Prelog优先规则确定的。本发明的化合物也可以以″E″和″Z″异构体的混合物的形式存在。围绕环烷基或杂环烷基的取代基被指定为顺式或反式构型。
本发明的化合物可以包含在R或S构型中的被不对称取代的碳原子,其中术语″R″和″S″是如以下文献中定义的:IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem.(1976)45,13-10。具有等量R和S构型的被不对称取代的碳原子的化合物在那些碳原子处是外消旋的。相对于另一种构型具有过量的一种构型的原子被指定为以较高量存在的构型,优选地过量约85%-90%,更优选地过量约95%-99%,仍更优选地过量大于约99%。因此,本发明包括外消旋混合物,相对和绝对立体异构体,以及相对和绝对立体异构体的混合物。
包含NH,C(O)OH,OH或SH部分的本发明的化合物可以具有连接到其的形成前药的部分。形成前药的部分是通过代谢过程除去的并且在体内释放具有游离的羟基、氨基或羧酸的化合物。前药可用于调节化合物的药物动力学性能,如溶解度和/或疏水性,在胃肠道中的吸收率,生物利用率,组织穿透率和清除比率。
同位素富集或标记化合物
本发明的化合物可以以含一种或多种具有不同于自然界中最丰富地存在的原子质量或质量数的原子质量或质量数的原子的同位素-标记的或-富集的形式存在。同位素可以是放射性的或非放射性的同位素。原子如氢、碳、磷、硫、氟、氯、和碘的同位素包括但不限于2H、3H、13C、14C、15N、18O、32P、35S、18F、36Cl、和125I。含这些和/或其它原子的其它同位素的化合物在本发明的范围内。
在另一实施方案中,同位素-标记的化合物包含氘(2H)、氚(3H)或14C同位素。本发明的同位素-标记的化合物可以通过本领域技术人员众所周知的一般方法来制备。这种同位素-标记的化合物可以便利地通过用容易获得的同位素-标记的试剂代替非标记的试剂进行本文中公开的实施例和方案中所公开的程序来制备。在一些情况下,化合物可以用同位素-标记的试剂处理从而用其同位素交换常态原子,例如通过含氘酸如D2SO4/D2O的作用,可以用氘交换氢。除上述外,例如,在以下文献中公开了相关的过程和中间体:Lizondo,J等,Drugs Fut,21(11),1116(1996);Brickner,S J等,J Med Chem,39(3),673(1996);Mallesham,B等,Org Lett,5(7),963(2003);PCT公开WO1997010223、WO2005099353、WO1995007271、WO2006008754;US专利7538189;7534814;7531685;7528131;7521421;7514068;7511013;和US专利申请公开20090137457;20090131485;20090131363;20090118238;20090111840;20090105338;20090105307;20090105147;20090093422;20090088416;和20090082471,所述方法在此通过援引并入。
本发明的同位素-标记的化合物可以用作标准物以便在结合分析中确定Bcl-2抑制剂的效果。包含同位素的化合物已经用于药学研究以便通过评估非同位素-标记的母体化合物的作用和代谢途径的机理来研究化合物的体内代谢历程(Blake等J.Pharm.Sci.64,3,367-391(1975))。在设计安全、有效的治疗药物方面,这种代谢研究是重要的,因为体内活性化合物被施用于患者或者因为由母体化合物产生的代谢物证明是有毒的或致癌的(Foster等,Advances in Drug Research Vol.14,pp.2-36,Academic press,London,1985;Kato 等,J.LabelledComp.Radiopharmaceut.,36(10):927-932(1995);Kushner等,Can.JPhysiol.Pharmacol.,77,79-88(1999)。
此外,包含非放射性的同位素的药物,如氘化药物,被称为“重药”,可以用于治疗与Bcl-2活性相关的疾病和状况。将化合物中存在的同位素的量提高到高于它的自然丰度被称为富集。富集的量的例子包括从约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100mol%。用重同位素替换多达约15%的常态原子已经在包括啮齿动物和狗在内的哺乳动物中被实施并且保持达数天至数周的时间,而观察到极小的副作用(Czajka D M和Finkel A J,Ann.N.Y.Acad.Sci.196084:770;Thomson J F,Ann.New York Acad.Sci 196084:736;Czakja D M等,Am.J.Physiol.1961201:357)。用氘急性替换人体液中的高达15%-23%发现没有引起毒性(Blagojevic N等.在″Dosimetry&Treatment Planning forNeutron Capture Therapy″,Zamenhof R,Solares G和Harling O Eds.1994.Advanced Medical Publishing,Madison Wis.pp.125-134;Diabetes Metab.23:251(1997))。
药物的稳定同位素标记可以改变其理化性质如pKa和脂质溶解性。如果同位素替换影响了配体-受体相互作用中所涉及的区域,这些作用和改变可影响药物分子的药效响应。虽然稳定同位素标记的分子的物理性能中的一些不同于未标记的分子的那些,但是化学和生物性质是相同的,一个重要的例外是:由于重同位素的提高的质量,任何涉及重同位素和另一原子的键将强于轻同位素和该原子之间的相同的键。因此,在代谢或酶促转化位置处引入同位素将使得所述反应变慢,这相对于非同位素化合物而言,可能地改变药动性能或效力。
酰胺、酯和前药
前药是设计用于改善一些识别出的、不希望的物理或生物性质的活性药物的衍生物。物理性质通常是溶解度(过高或不足的脂质或水溶解性)或稳定性相关的,而有问题的生物性质包括太快的代谢或差的生物利用率,这本身可能与物理化学性质有关。
前药通常是通过下述方式制备的:a)形成活性药物的酯、半酯、碳酸酯、硝酸酯、酰胺、异羟肟酸、氨基甲酸酯、亚胺、曼尼希碱、硫酸盐、磷酸酯和烯胺,b)用偶氮、糖苷、肽和醚官能团官能化药物,c)使用药物的缩醛胺、半缩醛胺、聚合物、盐、络合物、磷酰胺、缩醛、半缩醛和缩酮形式。例如,参见Andrejus Korolkovas`s,″Essentials ofMedicinal Chemistry″,John Wiley-Interscience Publications,John Wileyand Sons,New York(1988),pp.97-118,其在此处被完整地援引并入。
酯可以通过本领域技术人员已知的一般方法由含羟基或者羧基的式(I)的底物来制备。这些化合物的典型的反应是通过另一原子代替杂原子之一的取代,例如:
方案1
酰胺可以由含氨基或羧基的式(I)的底物以类似的方式制备。酯还可以与胺或氨反应而形成酰胺。
方案2
由式(I)的化合物制备酰胺的另一方法是一起加热羧酸和胺。
方案3
在以上方案2和3中,R和R′独立地是式(I)的底物、烷基或氢。
本发明的一个实施方案涉及化合物或其治疗可接受的盐、前药、代谢物或其前药的盐,其可用作抗细胞凋亡Bcl-2蛋白的抑制剂,所述化合物选自
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-[(3-硝基-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯基)磺酰基]苯甲酰胺;
4-(4-{乙酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-(4-{苯甲酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-3′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(苯基乙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
4-{6-[金刚烷-1-基甲基]-2,6-二氮杂双环[3.2.1]辛-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-[(三氟甲基)磺酰基]苯基)磺酰基]-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-硝基苯基}磺酰基]苯甲酰胺;
4-{(1S,4S)-5-[金刚烷-1-基甲基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-(4-{[3-溴-5-甲基金刚烷-1-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{[3,5-二甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酰胺;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-{[4-(1-甲基-2-氧代-3-氮杂双环[3.1.1]庚-3-基)苯基]磺酰基}苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-八氢-1H-4,7-亚甲基茚-5-基氨基]苄基}哌嗪-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚-2-基]氨基}苄基)哌嗪-1-基]苯甲酰胺;
4-[4-(2-{[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-基]氨基}苄基)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;
4-(4-{[(1R,5R)-2-(4-氯苯基)-6,6-二甲基双环[3.1.1]庚-2-烯-3-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{4-[(2-{[金刚烷-2-基甲基]氨基}-5,5-二甲基环己基)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;
4-{4-[(5,5-二甲基-2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}环己基)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;
4-{4-[2-(3-氮杂双环[3.2.2]壬-3-基)-5-硝基苄基]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;
4-(4-{2-[2,3,3a,4,7,7a-六氢-1H-4,7-亚甲基茚-5-基]苄基}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;
1-[金刚烷-1-基]-4-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺;
4-(4-{2-[2-(金刚烷-1-基)-6-甲基咪唑并[1,2-a]吡啶-8-基]苄基}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;
N-(金刚烷-2-基)-6-甲基-8-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}咪唑并[1,2-a]吡啶-2-甲酰胺;
4-(4-{2-[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-烯-2-基]苄基}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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5,5,6-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺;
N-环辛基-5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-2-糠酰胺;
N-苄基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
4-[4-(2-{[(1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-基]氨基}苄基)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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苄基)哌嗪-1-基]苯甲酰胺;
4-(4-{2-[3-氮杂双环[3.2.2]壬-3-基]苄基}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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[三环[4.3.1.13,8]十一碳-4-烯-4-基]苄基}哌嗪-1-基)苯甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-苯基双环[2.2.1]庚-2-烯-1-甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]双环[2.2.1]庚-2-烯-1-甲酰胺;
N-(金刚烷-1-基甲基)-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
N-环丙基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酸;
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苄基)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;
4-{4-[金刚烷-1-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{4-[金刚烷-2-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{5-[金刚烷-1-基羰基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{1S,5S)-3-[金刚烷-1-基羰基]-3,6-二氮杂双环[3.2.0]庚-6-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-(4-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
6-{3-[金刚烷-1-基]-4-羟苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺;
4-(4-{2-[金刚烷-1-基]-2-氧代乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{[金刚烷-2-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{2-[金刚烷-1-基]乙氧基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N3-[金刚烷-1-基乙酰基]-N3-苄基-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-β-丙氨酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]哌嗪-1-基}苯甲酰胺;
4-{4-[金刚烷-1-基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[3,5-二甲基金刚烷-1-基]哌嗪-1-基}苯甲酰胺;
[(3aS,5aR,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[1,3]二氧杂环戊烯并[4,5-b4′,5′-d]吡喃-3a-基]甲基;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1R,4S)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺;
4-(4-{2-[金刚烷-1-基]乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-({(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}甲基)联苯-4-甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苯亚甲基}哌啶-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苄基}哌嗪-1-基)苯甲酰胺;
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苄基)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;
5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-(2-苯基-1,3-苯并噁唑-5-基)-2-糠酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(三苯基乙烯基)苄基]哌嗪-1-基}苯甲酰胺;
4-{4-[2-(5-甲基-5,6-二氢菲啶-6-基)苄基]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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基]哌嗪-1-基}苯甲酰胺;
4-(4-{2-[2-(2,6-二甲氧基苯甲酰基)-3-噻吩基]苯亚甲基}哌啶-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;
1-[金刚烷-1-基]-4-{2-[(1-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌啶-4-亚基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基(3-苯基丙酰基)氨基]苄基}哌嗪-1-基)苯甲酰胺;
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苯亚甲基)哌啶-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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺;
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苯亚甲基)哌啶-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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苯亚甲基}哌啶-1-基)苯甲酰胺;
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-氧代-4H-色烯-6-基)苯甲酰胺;
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(1-辛基-1H-吡唑-4-基)苯甲酰胺;
4-[5-(4-{[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]氨基甲酰基}苯基)-1,3-苯并噻唑-2-基]丁酸;
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-[(1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛-3-基]苯甲酰胺;
6-{3-[金刚烷-1-基]-4-甲氧基苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺;
4-{4-[金刚烷-1-基乙酰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{[金刚烷-1-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N-{1-[4-({[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}氨基甲酰基)苯基]哌啶-4-基}金刚烷-1-甲酰胺;
4-[金刚烷-2-基氨基]-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;和
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氧基}苯甲酰胺。
药物组合物、组合疗法、治疗方法和给药
另一个实施方案包括药物组合物,其包括本发明的化合物和赋形剂。
又一个实施方案包括在哺乳动物中治疗癌症的方法,其包括施用其治疗可接受量的本发明的化合物。
又一个实施方案包括在哺乳动物中治疗自身免疫性疾病的方法,其包括施用其治疗可接受量的本发明的化合物。
又一个实施方案涉及用于治疗在疾病期间表达抗细胞凋亡Bcl-2蛋白的疾病的组合物,所述组合物包括赋形剂和治疗有效量的本发明的化合物。
又一个实施方案涉及在患者中治疗在疾病期间表达抗细胞凋亡Bcl-2蛋白的疾病的方法,所述方法包括施用患者治疗有效量的本发明的化合物。
又一个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、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、髓细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌或脾癌的组合物,所述组合物包括赋形剂和治疗有效量的本发明的化合物。
又一个实施方案涉及在患者中治疗膀胱癌、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、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、髓细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌或脾癌的方法,所述方法包括施用患者治疗有效量的本发明的化合物。
又一个实施方案涉及用于治疗在疾病期间表达抗细胞凋亡Bcl-2蛋白的疾病的组合物,所述组合物包括赋形剂和治疗有效量的本发明的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。
又一个实施方案涉及在患者中治疗在疾病期间表达抗细胞凋亡Bcl-2蛋白的疾病的方法,所述方法包括施用患者治疗有效量的本发明的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。
又一个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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的组合物,所述组合物包括赋形剂和治疗有效量的本发明的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。
又一个实施方案涉及在患者中治疗膀胱癌、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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的方法,所述方法包括将治疗有效量的本发明的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施用于患者。
通过体外或体内代谢过程产生的本发明的化合物的代谢物也可具有用于治疗与抗细胞凋亡Bcl-2蛋白有关的疾病的效用。
某些前体化合物,其可以体外或体内代谢而形成具有本发明的化合物,也可具有用于治疗与抗细胞凋亡Bcl-2蛋白的表达有关的疾病的效用。
本发明的化合物可以以酸加成盐、碱加成盐或两性离子的形式存在。在化合物的分离期间或纯化后,制备化合物的盐。化合物的酸加成盐是源自化合物与酸的反应的那些。例如,化合物和其前药的乙酸盐、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(camphorate)、樟脑磺酸盐(camphorsufonate)、二葡糖酸盐(digluconate)、甲酸盐、富马酸盐、甘油磷酸盐、谷氨酸盐、半硫酸盐(hemisulfate)、庚酸盐(heptanoate)、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳糖酸盐(lactobionate)、乳酸盐、马来酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐(naphthylenesulfonate)、烟酸盐、草酸盐、扑酸盐、果胶酯酸盐、过硫酸盐、磷酸盐、苦味酸盐、丙酸盐、琥珀酸盐、酒石酸酯、硫氰酸盐、三氯乙酸(盐)、三氟乙酸(盐)、对甲苯磺酸盐和十一烷酸盐被预期是被本发明包含的。化合物的碱加成盐是衍生自化合物与阳离子如锂、钠、钾、钙和镁的氢氧化物,碳酸盐或碳酸氢盐的反应的那些。
本发明的化合物可以例如含服(bucally)、经眼(ophthalmically)、口服、渗透、肠道外(几内、腹膜内、胸骨内(intrasternally)、静脉内、皮下)、直肠、局部、经皮或阴道施用。
治疗有效量的本发明的化合物取决于治疗的受体,被治疗的病症和其严重程度,包含该化合物的组合物,给药时间/次数,给药途径,治疗的持续时间,化合物效力,其清除率(rate of clearance)和是否共同施用另外的药物。用于制备待以单次剂量(single dose)或以分次剂量(divideddose)每日施用患者的组合物的本发明的本发明化合物的量是约0.03至约200mg/kg体重。单次剂量组合物包含这些量或其约数的组合。
在有或者没有赋形剂的情况下可以施用本发明的化合物。赋形剂包括,例如,封装材料或添加剂如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、涂层剂、着色剂、稀释剂、崩解剂、乳化剂、填充剂、填料、矫臭剂、保湿剂、润滑剂、芳香剂、防腐剂、推进剂、脱模剂、杀菌剂、甜味剂、增溶剂、润湿剂及其混合物。
用于制备待以固体剂型口服施用的包含本发明的化合物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、乙酸纤维素、可可脂、玉米淀粉、玉米油、棉子油、交联的聚乙烯吡咯烷酮、甘油二酯、乙醇、乙基纤维素、月桂酸乙酯(ethyl laureate)、油酸乙酯、脂肪酸酯、明胶、胚芽油、葡萄糖、甘油、花生油(groundnut oil)、羟丙基甲基纤维素、异丙醇、等渗盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、甘油单酯、橄榄油、花生油(peanut oil)、磷酸钾盐、马铃薯淀粉、聚乙烯吡咯烷酮、丙二醇、林格溶液、红花油、芝麻油、羧甲基纤维素钠、磷酸钠盐、月桂基硫酸钠、山梨醇钠、大豆油、硬脂酸、富马酸十八烷基酯、蔗糖、表面活性剂、滑石、黄蓍胶、四氢糠醇、甘油三酯、水及其混合物。用于制备待以液体剂型经眼(ophthalmically)或口服给药的包含本发明的化合物的组合物的赋形剂包括,例如,1,3-丁二醇、蓖麻油、玉米油、棉子油、乙醇、脱水山梨糖醇的脂肪酸酯、胚芽油、花生油(groundnut oil)、甘油、异丙醇、橄榄油、聚乙二醇、丙二醇、芝麻油、水及其混合物。用于制备待渗透给药的包含本发明的化合物的组合物的赋形剂包括,例如,氯氟烃、乙醇、水及其混合物。用于制备待肠道外给药的包含本发明的化合物的组合物的赋形剂包括,例如,1,3-丁二醇、蓖麻油、玉米油、棉子油、葡萄糖、胚芽油、花生油(groundnut oil)、脂质体、油酸、橄榄油、花生油(peanut oil)、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。用于制备待直肠或阴道给药的包含本发明的化合物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。
化合物,当与烷基化剂,血管生成抑制剂、抗体、抗代谢剂、抗有丝分裂剂、抗增殖剂、抗病毒剂、极光激酶抑制剂、其它细胞凋亡启动子(例如,Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体途径的活化剂、Bcr-Abl激酶抑制剂、BiTE(双特异性T细胞接合器(Bi-Specific T cell engager))抗体、抗体药物缀合物、生物响应改性剂、依赖于细胞周期蛋白的蛋白激酶抑制剂、细胞周期抑制剂、环加氧酶-2抑制剂、DVDs、白血病病毒癌基因同系物(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白去乙酰酶(HDAC)抑制剂、激素疗法、免疫制剂(immunologicals)、细胞凋亡蛋白质的抑制剂的抑制剂(IAPs)、插入抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、雷帕霉素抑制剂的哺乳动物目标、microRNA′s、促细胞分裂剂-活化的胞外信号调节激酶抑制剂、多价结合蛋白、非类固醇抗炎药物(NSAIDs)、聚ADP(腺苷二磷酸)-核糖聚合酶(PARP)抑制剂、铂化疗药物、polo样激酶(Plk)抑制剂、磷酸肌醇-3激酶(PI3K)抑制剂、蛋白酶体(proteosome)抑制剂、嘌呤同型物、嘧啶同型物、受体酪氨酸激酶抑制剂、etinoids/deltoids植物生物碱、小抑制性核醣核酸(siRNAs)、拓扑异构酶抑制剂、泛素(ubiqutin)连接酶抑制剂等一起,以及与这些药剂中的一个或多个组合使用时,被预计是有用的。
BiTE抗体是双特异性抗体,其通过同时地结合两种细胞而引导T细胞来攻击癌细胞。T细胞然后攻击目标癌细胞。BiTE抗体的例子包括adecatumumab(Micromet MT201)、blinatumomab(Micromet MT103)等。在不受限于理论的情况下,T细胞引起目标癌细胞的细胞凋亡的机理之一是通过细胞溶解颗粒组分(其包括穿孔素和颗粒酶B)的胞吐作用。在这方面,Bcl-2已经显示出减弱由于穿孔素和粒酶B两者造成的细胞凋亡的诱导。这些数据表明抑制Bcl-2可以提高当靶向于癌细胞时由T细胞引起的细胞毒素效果(V.R.Sutton,D.L.Vaux和J.A.Trapani,J.of Immunology1997,158(12),5783)。
siRNAs是具有内源性RNA碱基或化学修饰的核苷酸的分子。修饰没有消除细胞活性,而是赋予提高的稳定性和/或提高的细胞效力。化学修饰的例子包括磷硫酰基团、2′-脱氧核苷酸、含2′-OCH3-的核糖核苷酸、′-F-核糖核苷酸、2′-甲氧基乙基核糖核苷酸、其组合等。siRNA可以具有不同长度(例如10-200bps)和结构(例如发夹、单/双链、凸出、切口/缺口、错配)并且在细胞中被加工而提供活性基因沉默。双链siRNA(dsRNA)可以在每条链(平端)或非对称末端(悬突)上具有相同数目的核苷酸。1-2核苷酸的悬突可以存在于有义链和/或反义链上,以及存在于给定链的5′-和/或3′末端上。例如,siRNAs靶向Mcl-1已经显示出在多肿瘤细胞系中提高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-((苯基硫基)甲基)丙基)氨基)-3-((三氟甲基)磺酰基)苯磺酰胺)或ABT-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-((苯基硫基)甲基)丙基)氨基)-3-硝基苯磺酰胺)的活性(Tse等,Cancer Research 2008,68(9),3421和其中的参考文献)。
多价结合蛋白是含两个或更多个抗原结合部位的结合蛋白。多价结合蛋白被设计而具有三个或更多个抗原结合部位并且一般地不是天然存在的抗体。术语″多特异性结合蛋白″是指能结合两个或更多个相关或不相关靶体的结合蛋白。双可变域(DVD/Dual variable domain)结合蛋白是四价或多价结合蛋白结合蛋白,其含两个或更多个抗原结合部位。这样的DVDs可以是单特异性的(即,能结合一个抗原)或多特异性的(即,能结合两个或更多个抗原)。含两个重链DVD多肽和两个轻链DVD多肽的DVD结合蛋白被称为DVD Ig′s。DVD Ig的每一半包含重链DVD多肽、轻链DVD多肽和两个抗原结合部位。每个结合部位包含重链可变域和轻链可变域,具有总共6个抗原结合中涉及的CDRs/每抗原结合部位。多特异性的DVDs包括DVD结合蛋白、其结合DLL4和VEGF、或C-met和EFGR或ErbB3和EGFR。
烷基化剂包括六甲蜜胺、AMD-473、AP-5280、apaziquone、苯达莫司汀(bendamustine)、brostallicin、白消安、卡波醌、卡莫司汀(BCNU)、苯丁酸氮芥、(laromustine、VNP 40101M)、环磷酰胺、氨烯咪胺(decarbazine)、雌莫司汀、福莫司汀、葡磷酰胺(glufosfamide)、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、(苯达莫司汀(bendamustine))、曲奥舒凡、rofosfamide等等。
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、凝血栓蛋白同型物、血管内皮细胞生长因子受体酪氨酸激酶(VEGFR)抑制剂等等。抗代谢剂包括(培美曲塞二钠、LY231514、MTA)、5-阿扎胞苷、(卡培他滨)、卡莫氟、(克拉屈滨)、clofarabine、阿糖胞苷、阿糖胞苷ocfosfate、阿糖胞苷、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(ribofuranosylimidazole)-4-甲酰胺)、依诺他滨、ethnylcytidine、氟达拉滨、单独或与亚叶酸结合的5-氟尿嘧啶、(吉西他滨)、羟基脲、(美法仑)、巯嘌呤、6-巯基嘌呤核糖核苷、甲氨蝶呤、麦考酚酸、奈拉滨、诺拉曲塞、ocfosfate、pelitrexol、喷司他丁、雷替曲塞、利巴韦林、triapine、三甲曲沙、S-1、噻唑呋林、替加氟、TS-1、阿糖腺苷、UFT等等。
抗病毒剂包括利托那韦、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泛极光激酶抑制剂等。
Bcl-2蛋白抑制剂包括AT-101((-)棉酚)、(G3139或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-((苯基硫基)甲基)丙基)氨基)-3-((三氟甲基)磺酰基)苯磺酰胺(ABT-263)、GX-070(obatoclax)等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、flavopyridol、GPC-286199、MCS-5A、PD0332991、PHA-690509、seliciclib(CYC-202、R-roscovitine)、ZK-304709等。
COX-2抑制剂包括ABT-963、(艾托考昔)、(伐地考昔(valdecoxib))、BMS347070、(塞来考昔)、COX-189(lumiracoxib)、CT-3、(地拉考昔)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰苯基-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、(罗非昔布(rofecoxib))等。
EGFR抑制剂包括ABX-EGF、抗EGFR免疫脂质体、EGF-疫苗、EMD-7200、(西妥昔单抗(cetuximab))、HR3、IgA抗体、(吉非替尼(gefitinib))、(埃洛替尼(erlotinib)或OSI-774)、TP-38、EGFR融合蛋白、(拉帕替尼(lapatinib))等。
ErbB2受体抑制剂包括CP-724-714、CI-1033(canertinib)、(曲妥单抗)、(拉帕替尼(lapatinib))、(2C4、petuzumab)、TAK-165、GW-572016(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 HER2三功能双特异性抗体、mAB AR-209、mAB 2B-1等。
组蛋白去乙酰酶抑制剂包括缩酚酸肽、LAQ-824、MS-275、trapoxin、辛二酰苯胺异羟肟酸(suberoylanilide hydroxamic acid)(SAHA)、TSA、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、(HSP-90的人重组体抗体)、NCS-683664、PU24FCl、PU-3、根赤壳菌素、SNX-2112、STA-9090VER49009等。
细胞凋亡蛋白质的抑制剂的抑制剂包括HGS 1029、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-19AmSGN-35、SGN-75等。
死亡受体途径的活化剂包括TRAIL、靶向TRAIL或死亡受体(例如DR4和DR5)的抗体或其它药剂如Apomab、conatumumab、ETR2-ST01、GDC0145、(lexatumumab)、HGS-1029、LBY-135、PRO-1762和曲妥单抗。
驱动蛋白抑制剂包括Eg5抑制剂如AZD4877,ARRY-520;CENPE抑制剂如GSK923295A等。
JAK-2抑制剂包括CEP-701(lesaurtinib)、XL019和INCB018424等。
MEK抑制剂包括ARRY-142886、ARRY-438162PD-325901、PD-98059等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素(rapamycin)、temsirolimus、ATP-竞争性TORC1/TORC2抑制剂、包括PI-103、PP242、PP30、Torin 1等。
非类固醇抗炎药物包括(双水杨酯)、(二氟尼柳)、(布洛芬)、(酮洛芬(ketoprofen))、(萘丁美酮)、(吡罗昔康)、布洛芬乳膏、(萘普生)和(萘普生)、(双氯芬酸)、(吲哚美辛)、(舒林酸)、(托美丁)、(依托度酸)、(酮咯酸)、(奥沙普秦)等。
PDGFR抑制剂包括C-451、CP-673、CP-868596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。
凝血栓蛋白同型物包括ABT-510、ABT-567、ABT-898、TSP-1等。VEGFR抑制剂包括(贝伐单抗)、ABT-869、AEE-788、ANGIOZYMETM(抑制血管生成的核糖酶(RibozymePharmaceuticals(Boulder,CO.)和Chiron,(Emeryville,CA))、axitinib(AG-13736)、AZD-2171、CP-547,632、IM-862、MACUGEN(pegaptamib)、(索拉非尼(sorafenib)、BAY43-9006)、pazopanib(GW-786034)、瓦他拉尼(vatalanib)(PTK-787、ZK-222584)、(舒尼替尼(Sunitinib)、SU-11248)、VEGF阱、ZACTIMATM(vandetanib、ZD-6474)、GA101、ofatumumab、ABT-806(mAb-806)、ErbB3特异性抗体、BSG2特异性抗体、DLL4特异性抗体和C-met特异性抗体等。
抗生素包括插入抗生素阿柔比星、放线菌素D、氨柔比星、annamycin、多柔比星、(争光霉素)、柔红霉素、或(多柔比星脂质体)、依沙芦星、epirbucin、glarbuicin、(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、rebeccamycin、stimalamer、链佐星、(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、amonafide、amsacrine、becatecarin、belotecan、BN-80915、(伊立替康盐酸盐)、喜树碱、(右旋丙亚胺)、diflomotecan、edotecarin、或(表柔比星)、依托泊苷、依沙替康、10-羟喜树碱、gimatecan、勒托替康、米托蒽醌、orathecin、pirarbucin、pixantrone、卢比替康、索布佐生、SN-38、tafluposide、托泊替康等。
抗体包括(贝伐单抗)、CD40-特异性抗体、chTNT-1/B、denosumab、(西妥昔单抗(cetuximab))、(zanolimumab)、IGF1R-特异性抗体、林妥珠单抗、(依决洛单抗)、(WX G250)、(利妥昔单抗)、ticilimumab、trastuzimab、I和II型CD20抗体等。
激素疗法包括(阿纳托(司)唑)、(依西美坦)、阿佐昔芬、(比卡鲁胺)、(西曲瑞克)、degarelix、地洛瑞林、(曲洛司坦)、地塞米松(dexamethasone)、(氟他胺)、(雷洛昔芬)、AFEMATM(法倔唑)、(托瑞米芬)、(氟维司群)、(来曲唑)、福美坦、糖皮质激素、(度骨化醇)、(司维拉姆碳酸盐)、拉索昔芬、亮丙瑞林(leuprolide)乙酸盐、(megesterol)、(米非司酮)、NILANDRONTM(尼鲁米特)、(枸橼酸它莫西芬)、PLENAXISTM(阿巴瑞克)、泼尼松、(非那雄胺)、rilostane、(布舍瑞林)、(促黄体素释放激素(LHRH))、(Histrelin移植物)、(曲洛司坦或modrastane)、(fosrelin、戈舍瑞林)等。
Deltoids和retinoids(维甲酸类)包括西奥骨化醇(EBl089、CB1093)、lexacalcitrol(KH1060)、芬维A胺、(aliretinoin)、(脂质体维A酸)、(贝沙罗汀)、LGD-1550等。
PARP抑制剂包括ABT-888(veliparib)、olaparib、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、长春瑞滨等。
免疫制剂的例子包括干扰素和其它提高免疫性的试剂。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、(干扰素γ-1b)或干扰素γ-n1、其组合等。其他的药剂包括(IFN-α)、BAM-002(氧化谷胱甘肽)、(他索纳明)、(托西莫单抗)、(阿仑单抗(alemtuzumab))、CTLA4(细胞毒素淋巴细胞抗原4)、氨烯咪胺、地尼白介素、依帕珠单抗、(来格司亭)、蘑菇多糖、白血球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(吉姆单抗奥佐米星)、(非格司亭)、OncoVAC-CL、(oregovomab)、pemtumomab(Y-muHMFG1)、(sipuleucel-T)、sargaramostim、sizofilan、替西白介素、(卡介苗)、乌苯美司、(immunotherapeutic、LorusPharmaceuticals)、Z-100(Maruyama 的特异性物质(SSM))、WF-10(Tetrachlorodecaoxide(TCDO))、(阿地白介素)、(胸腺法新)、(西利珠单抗)、(90Y-替伊莫单抗)等。
生物响应改性剂是这样的药剂,其改变生物机体的防卫机制或生物响应,如组织细胞的存活,生长或分化以便引导它们来具有抗肿瘤活性并且包括云芝糖肽、蘑菇多糖、西佐喃、溶链菌PF-3512676(CpG-8954)、乌苯美司等。
嘧啶同型物包括阿糖胞苷(ara C或阿糖胞苷C)、阿糖胞苷、去氧氟尿苷、(氟达拉滨)、5-FU(5-氟尿嘧啶)、氮尿苷、(吉西他滨)、(ratitrexed)、TROXATYLTM(三乙酰尿核甙曲沙他滨)等。
抗有丝分裂剂包括batabulin、epothilone D(KOS-862)、N-(2-((4-羟苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、ixabepilone(BMS 247550)、紫杉醇、(多西他赛)、PNU100940(109881)、patupilone、XRP-9881(larotaxel)、长春氟宁、ZK-EPO(合成epothilone)等。
泛素连接酶抑制剂包括MDM2抑制剂,如nutlins,NEDD8抑制剂如MLN4924等。
本发明的化合物还可用作提高放射疗法效力的放射致敏剂。放射疗法的例子包括外束放射疗法、远距疗法、近距疗法和密封、非密封源放射疗法等。
另外,本发明的化合物可以与其它化疗剂相结合,如ABRAXANETM(ABI-007)、ABT-100(法尼基转移酶抑制剂)、(Ad5CMV-p53疫苗)、或(洛伐他汀)、(poly I:poly C12U、一种合成RNA)、(依昔舒林)、(帕米膦酸)、arglabin、L-天冬酰胺酶、阿他美坦(1-甲基-3,17-二酮-雄(甾)烷-1,4-二烯)、(他扎罗汀)、AVE-8062(combreastatin衍生物)BEC2(米妥莫单抗)、恶液质因子或cachexin(肿瘤坏死因子)、canvaxin(疫苗)、(癌疫苗)、(西莫白介素)、(二盐酸组胺)、(人乳头瘤病毒疫苗)、(C:(环磷酰胺);H:(hydroxydoxorubicin);O:长春新碱P:泼尼松)、CYPATTM(醋酸环丙氯地孕酮)、combrestatinA4P、DAB(389)EGF(通过至人表皮生长因子的His-Ala连接体融合的白喉毒素的催化和易位域)或TransMID-107RTM(白喉毒素)、达卡巴嗪、放线菌素D、5,6-二甲基呫吨酮-4-乙酸(DMXAA)、恩尿嘧啶、EVIZONTM(角鲨胺乳酸盐)、(T4N5脂质体洗剂)、discodermolide、DX-8951f(依沙替康甲磺酸盐)、enzastaurin、EPO906(epithilone B)、(四价人乳头瘤病毒(6、11、16、18型)重组疫苗)、GMK(神经节糖苷缀合物疫苗)、(前列腺癌疫苗)、常山酮(halofuginone)、histerelin、羟基脲、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR(cintredekin besudotox)、IL-13-假单胞菌外毒素、干扰素-α、干扰素-γ、JUNOVANTM或MEPACTTM(mifamurtide)、lonafarnib、5,10-亚甲基四氢叶酸酯(methylenetetrahydrofolate)、米替福新(十六烷基磷酸胆碱)、(AE-941)、(三甲曲沙葡糖醛酸盐)、(pento statm)、(一种核糖核酸酶)、(黑色素瘤疫苗治疗)、(IL-2疫苗)、ORATHECINTM(卢比替康)、(抗体型细胞药物)、MAb(鼠科单克隆抗体)、紫杉醇、PANDIMEXTM(来自人参的糖苷配基皂草苷、含20(S)原人参萜二醇(aPPD)和20(S)原人参萜三醇(aPPT))、panitumumab、-VF(试验癌疫苗)、培门冬酶、PEG干扰素A、phenoxodiol、丙卡巴肼、rebimastat、(catumaxomab)、(lenalidomide)、RSR 13(efaproxiral)、LA(兰瑞肽)、(阿维A)、十字孢碱(链霉菌属星状孢子)、talabostat(PT100)、(贝沙罗汀)、(DHA-paclitaxel)、(canfosfamide、TLK286)、temilifene、(替莫唑胺)、替米利芬、沙利度胺、(STn-KLH)、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(adenovector:含肿瘤坏死因子-α的基因的DNA载体)、或(波生坦),维A酸(Retin-A)、粉防己碱、(三氧化二砷)、ukrain(来自白屈菜植物的生物碱的衍生物)、vitaxin(抗-alphavbeta3抗体)、(莫特沙芬钆)、XINLAYTM(阿曲生坦)、XYOTAXTM(紫杉醇poliglumex)、(trabectedin)、ZD-6126、(dexrazoxane)、(zolendronic酸)、佐柔比星等。
生物活性的测定
用Bcl-xL作为代表性的例子,在96孔微量滴定板中进行Bcl-2家族蛋白的抑制的测试。在DMSO中将本发明的化合物稀释至10M-10pM之间的浓度并加入板的每个孔中。将总计每孔125L的测试缓冲液(20mM磷酸盐缓冲液(pH7.4)、1mMEDTA、50mM NaCl、0.05%普鲁兰尼克F-68(pluronic F-68))、6nM BCL-XL蛋白(根据Science 1997,275,983-986中所述的方法制备)、1nM荧光素标记的BAD肽(购自Synpep,CA)和本发明的化合物的DMSO溶液的混合物振摇2分钟并放置在LJL分析仪(LJL BioSystems,CA)中。用阴性对照(DMSO、15nM BAD肽、测试缓冲液)和阳性对照(DMSO、15nMBAD肽,30nM BCL-XL、测试缓冲液)来确定检测范围。在室温下用连续的荧光灯(激发485nm,发射530nm)测定极化。通过Microsoft Excel从mP值直接计算Ki值。
在96孔微量滴定板中进行Bcl-2的抑制的测试。在DMSO中将本发明的化合物稀释至10M-10pM之间的浓度并加入板的每个孔中。将总计每孔125L的测试缓冲液(20mM磷酸盐缓冲液(pH7.4)、1mMEDTA、0.05%PF-68)、10nM Bcl-2蛋白(根据PNAS 2001,98,3012-3017中所述的方法制备)、1nM荧光素标记的BAD肽(内部制备)和本发明的化合物的DMSO溶液的混合物振摇2分钟并放置在LJL分析仪(LJL Bio Systems,CA)中。在室温下用连续的荧光灯(激发485nm,发射530nm)测定极化。用MicrosoftExcel计算Ki值。
在以下表1中显示了根据本发明的化合物的抑制常数(Ki)。其中化合物的Ki表示为″>″(大于)某一数值,意图是指结合亲合力值大于所用的分析的检测极限。其中化合物的Ki表示为″<″(小于)某一数值,意图是指结合亲合力值小于所用的分析的检测极限。
表1.FPA Bcl-2结合Ki(μM)
抑制常数(Ki)是酶-抑制剂复合物或蛋白/小分子复合物的解离常数,其中小分子抑制一种蛋白与另一蛋白的结合。所以大Ki值表明低结合亲合力,小Ki值表明高结合亲合力。
该抑制数据表明了具有式(I)的化合物作为抗细胞凋亡Bcl-2蛋白的抑制剂的效用。
据预计,因为本发明的化合物结合到Bcl-2,它们还将具有作为具有与Bcl-2密切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蛋白的结合剂的效用。
Bcl-2蛋白参与膀胱癌、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、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、髓细胞性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌、慢性淋巴细胞性白血病、骨髓瘤、前列腺癌脾癌等中的描述见共同拥有的以WO 2005/049593公开的PCT US 2004/36770和以WO2005/024636公开的PCT US 2004/37911中。
Bcl-2蛋白参与免疫和自身免疫性疾病的描述见以下文献:CurrentAllergy and Asthma Reports 2003,3,378-384;British Journal ofHaematology 2000,110(3),584-90;Blood 2000,95(4),1283-92;和NewEngland Journal of Medicine 2004,351(14),1409-1418。
Bcl-2蛋白参与关节炎的公开见共同拥有的美国临时专利申请60/988,479。
Bcl-2蛋白参与骨髓移植排斥的公开见共同拥有的美国专利申请11/941,196中。
Bcl-2蛋白的过表达与在各种癌症和免疫系统的病症中的耐化疗性、临床结果、疾病进程、总预后(overall prognosis)或其组合有关。癌症包括但不限于血液和实体肿瘤类型如听神经瘤、急性白血病、急性淋巴母细胞性白血病、急性骨髓性白血病(单核细胞白血病、成髓细胞白血病、腺癌、血管肉瘤、星形细胞瘤、髓性单核细胞白血病和前髓细胞性白血病)、急性T细胞白血病、皮肤基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌(包括雌激素-受体阳性乳腺癌)、支气管癌、伯基特氏肿瘤、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、慢性髓细胞性(粒细胞性)白血病、慢性粒性白血病、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、特发性血小板增多症、尤因瘤、纤维肉瘤、胃癌、生殖细胞睾丸癌、妊娠性滋养层细胞病、恶性胶质瘤、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、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超增生性病症、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、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、髓细胞性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、寡枝神经胶质细胞瘤、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、瓦凯氏病、前列腺癌(包括激素非敏感性(难治疗的)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、维尔姆斯肿瘤等。
还期望的是,本发明的化合物将抑制表达源自小儿癌或瘤(包括胚胎性横纹肌肉瘤、小儿急性淋巴母细胞性白血病、小儿急性骨髓性白血病、小儿腺泡状横纹肌肉瘤、小儿退行发育性室管膜瘤、小儿退行发育性大细胞淋巴瘤、小儿退行发育性成神经管细胞瘤、中枢神经系统的小儿非典型性畸胎/杆状瘤、小儿双表型(biphenotypic)急性白血病、小儿伯基特氏淋巴瘤、尤因族瘤的小儿癌如原发性神经外胚层瘤(neuroectodermalrumors)、小儿扩散退行发育性维尔姆斯瘤、小儿良好组织型维尔姆斯瘤、小儿恶性胶质瘤、小儿成神经管细胞瘤、小儿成神经细胞瘤、小儿成神经细胞瘤源的髓细胞组织增生、小儿前B细胞癌(如白血病)、小儿骨肉瘤(psteosarcoma)、小儿杆状肾瘤、小儿横纹肌肉瘤、和小儿T细胞癌如淋巴瘤和皮肤癌等等)的Bcl-2蛋白的细胞的生长。
自身免疫病症包括获得性免疫缺损病综合征(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、与器官移植有关的急性或慢性免疫性疾病、艾迪生氏病、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)、获得性免疫缺损相关的疾病、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)呼吸困难综合征、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、阿尔茨海默氏病、肌萎缩性侧索硬化、贫血、心绞痛、强直性脊柱炎相关的肺病、前角细胞退化、抗体介导的细胞毒性、抗磷脂综合征、抗受体过敏性反应、主动脉和周围动脉动脉瘤、主动脉壁夹层形成、高动脉压、动脉硬化、动静脉瘘、关节病、虚弱、哮喘、共济失调、特异反应性过敏、心房颤动(持续性或突发性)、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)、自家免疫性甲状腺病、B细胞淋巴瘤、移植骨排斥、骨髓移植(BMT)排斥、闭塞性细支气管炎、束支阻滞、烧伤、恶病质、心脏心律不齐、心脏顿抑综合征、心脏肿瘤、心肌病、凡肺分流术炎症响应、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、胆汁淤滞(choleosatatis)、慢性醇中毒、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、结肠直肠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、Coombs阳性溶血性贫血、肺原性心脏病、克罗伊茨费尔特-雅各布氏病、隐发性自身免疫肝炎、隐发性纤维性肺泡炎、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、皮炎硬皮病、皮肤状况、皮肌炎/多肌炎相关的肺病、糖尿病、糖尿病性动脉硬化病、糖尿病、扩散性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多巴胺的药物引起的药物引起的运动病症、受体、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-巴二氏病毒感染、红斑性肢痛病、锥体束外和小脑病症、家族性噬血细胞淋巴组织细胞增生症(familial hematophagocyticlymphohistiocytosis)、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、母畜不孕、纤维化、纤维化肺病、真菌性脓毒症、气性坏疽、胃溃疡、颞动脉炎、肾小球性肾炎、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瘤、B组链球菌(GBS)感染、格雷夫症、含铁血黄素沉着病相关的肺病、毛细胞白血病、毛细胞白血病、Hallerrorden-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/溶解血栓性血小板减少性紫癜、出血、Henoch-Schoenlein紫癜(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、高动力性运动障碍、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、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、青年类风湿性关节炎、青少年脊髓性肌萎缩、卡波济病、川畸(氏)病、肾移植排斥、legionella、利什曼病、麻风病、皮质脊髓系统的损伤、线性IgA病、脂血(症)(lipidema)、肝移植排斥、莱姆(氏)病、lymphederma、淋巴细胞渗透性肺病、疟疾、男性不孕症特发性或NOS、恶性组织细胞增多症、恶性黑色素瘤、脑膜炎、脑膜炎血症、肾的显微血管炎、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、单株丙种球蛋白病、多发性骨髓瘤、多系统退化((MencelDejerine-Thomas Shi-Drager和Machado-Joseph)、肌痛性脑炎/Royal FreeDisease、重症肌无力、肾的显微血管炎、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、神经原性I肌肉萎缩、中性粒细胞减少性发烧、非酒精性脂肪性肝炎、腹主动脉和它的分支的闭塞、闭塞性动脉病症、器官移植排斥、睾丸炎/附睾炎(epidydimitis)、睾丸炎/输精管切除术输精管切除、器官巨大症、骨关节病、骨质疏松、卵巢衰竭、胰脏移植排斥、侵染性病害、甲状旁腺移植排斥、帕金森氏病、盆腔炎、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、晶状体溶解性葡萄膜炎、卡氏肺囊虫病、肺炎、POEMS综合征(多神经病、器官巨大症、内分泌病、单株丙种球蛋白病、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、夏科氏肝硬变、原发性硬化引起性肝炎、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、进行性核上性眼肌麻痹、牛皮癣、I型牛皮癣、II型牛皮癣、牛皮癣关节病、继发性至结缔组织病的肺性高血压症、结节性动脉周围炎的肺表现、炎症后间质性肺病、放射后肺纤维化、放射治疗、雷诺氏现象和病、Raynoud病、雷夫叙姆病、规则性窄QRS心动过速、莱特尔氏病、肾病NOS、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、结节病、施密特氏综合征、硬皮病、老年性舞蹈病、Lewy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、镰刀形红细胞贫血病、干燥综合征相关的肺病、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(全部亚型)、脊髓性共济失调、脊髓小脑退化、脊椎关节病、脊椎关节病(spondyloarthopathy)、散发性、I型多腺缺乏散发性、II型多腺缺乏、斯提耳病、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、全身炎症响应综合征、全身发作性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、Takayasu病/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、II型自身免疫肝炎(抗-LKM抗体肝炎)、具有黑棘皮病的B型胰岛素耐受、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、瓣膜性心脏病、曲张静脉、血管炎、血管炎扩散性肺病、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、Wernicke-Korsakoff综合征、血铜蓝蛋白缺乏病、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。
方案和实验
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-硼杂二环(3.3.1)壬烷;Boc是指叔丁氧羰基;(DHQD)2PHAL是指氢化奎尼定1,4-酞嗪二基乙醚;DBU是指1,8-二氮杂双环[5.4.0]十一碳-7-烯;DIBAL是指氢化二异丁基铝;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是指三苯膦。
本发明的化合物可以通过合成化学方法来制备,其例子显示在本文中。本发明的方法和概念性方面的最有用和最容易理解的描述的示例性方案见共同拥有的美国专利申请序列号12/631,367和12/631,404中。应该理解的是方法中的步骤的顺序可以改变,试剂、溶剂和反应条件可以替换特别提及的那些,并且根据需要可以保护和去保护不稳定部分。
呈现以下实施例以便提供据信是本发明的程序和概念方面的最有用的且易于理解的描述的内容。使用ACD/ChemSketch版本12.01(2009年5月13日,Advanced Chemistry Development Inc.,Toronto,Ontario),或版本9.0.5(CambridgeSoft,Cambridge,MA)来命名所举例的化合物和中间体。
实施例1
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-[(3-硝基-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯基)磺酰基]苯甲酰胺
实施例1A
4-(4-((4′-氯联苯-2-基)甲基)哌嗪-1-基)苯甲酸
用Bruncko等,J.Med.Chem.2007,50,641-662所述的方法制备实施例1A。
实施例1B
N-(4-氯-3-硝基苯基磺酰基)-4-(4-((4′-氯联苯-2-基)甲基)哌嗪-1-基)苯甲酰胺
将实施例1A(10g)、4-氯-3-硝基苯磺酰胺(5.82g)、1-乙基-3-[3-(二甲基氨基)丙基]-碳二亚胺盐酸盐(9.42g)和4-二甲基氨基吡啶(3.00g)混合在二氯甲烷(98ml)中。混合物在室温搅拌过夜,用二氯甲烷稀释并倒至水中。用水彻底洗涤有机层,并用1M HCl水溶液和5%NaHCO3水溶液洗涤。然后用水和盐水再次洗涤有机层。将有机层在MgSO4上干燥,过滤,并将滤液在真空下浓缩。将粗物质通过快速色谱纯化,用2%甲醇/二氯甲烷至10%甲醇/二氯甲烷进行梯度洗脱。1H NMR(500MHz,二甲亚砜-d6)δ12.08(br s,1H),8.64(d,1H),8.37(d,1H),7.94(dd,1H),7.75(m,3H),7.54(m,4H),7.40(m,2H),7.35(d,2H),6.93(d,2H),4.39(br s,1H),4.02(m,1H),3.91(br s,2H),3.28(br s,2H),3.08(br s,3H),2.89(br s,2H),2.73(m,1H),2.40(m,1H),2.09(m,1H),1.97(m,1H),1.87(m,1H),1.64(m,1H),1.24(s,3H),1.12(d,3H),1.08(s,3H)。
实施例1C
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-[(3-硝基-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯基)磺酰基]苯甲酰胺
将实施例1B(40mg)和(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺(19.60mg)混合在二氧杂环己烷(1ml)中。加入三乙胺(0.027ml)。将混合物加热至90℃过夜,真空下浓缩,并通过用250x 21.20mm、5μ的C18柱的制备HPLC纯化,用20-100%CH3CN在0.1%三氟乙酸水溶液中的混合物进行梯度洗脱,获得产物,为三氟乙酸盐。1H NMR(500MHz,二甲亚砜-d6)δ12.08(br s,1H),8.64(d,1H),8.37(d,1H),7.94(dd,1H),7.75(m,3H),7.54(m,4H),7.40(m,2H),7.35(d,2H),6.93(d,2H),4.39(br s,1H),4.02(m,1H),3.91(br s,2H),3.28(br s,2H),3.08(br s,3H),2.89(br s,2H),2.73(m,1H),2.40(m,1H),2.09(m,1H),1.97(m,1H),1.87(m,1H),1.64(m,1H),1.24(s,3H),1.12(d,3H),1.08(s,3H)。
实施例2
4-(4-{乙酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例2A
4-{4-[乙酰基((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基]-氨基]-哌啶-1-基}-苯甲酸乙酯
将实施例45C(50mg)溶解在二氯甲烷(2mL)中。加入三乙胺(0.022mL,16mg),随后加入乙酰氯(0.010mL,11mg)。在室温下混合溶液16小时,然后用30%乙酸乙酯/己烷在硅胶上用快速柱色谱法纯化以获得标题化合物。
实施例2B
4-{4-[乙酰基-((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基]-氨基]-哌啶-1-基}-苯甲酸
将实施例2A(55mg)溶解在四氢呋喃(0.6mL)、甲醇(0.2mL)和水(0.2mL)中,并用氢氧化锂一水合物(22mg)处理。将该溶液在室温下搅拌16小时。用1M盐酸将该溶液酸化,用乙酸乙酯萃取,用无水硫酸钠干燥,过滤并浓缩以获得标题化合物。
实施例2C
4-氟-3-硝基-苯磺酰胺
2-氟硝基苯(141g,1.0mol)和氯磺酸(300mL)在60℃加热10小时。反应混合物冷却至室温后,小心地倒入4升的Erlenmeyer烧瓶中的冰(约1kg),通过冰-盐水浴有效冷却。用乙醚(4L)和盐水(2L)萃取混合物。将获得的溶液冷却至-40℃。然后在剧烈搅拌下加入浓的氢氧化铵(300mL),控制加入速率从而使反应混合物保持低于-10℃(内部温度)。必要时,将干冰块加入反应混合物中以降低温度。完成加入后,立即分离获得的混合物,用乙酸乙酯(2L)萃取水相。用4M盐酸水溶液(300mL)和盐水(100mL)洗涤合并的有机相,在无水硫酸镁上干燥,过滤并浓缩。从乙酸乙酯/己烷混合物中将获得的固体重结晶。浓缩来自重结晶的母液,并以相同的方式重结晶,合并获得的固体,获得标题化合物。
实施例2D
4-(环己基甲基-氨基)-3-硝基-苯磺酰胺
将四氢呋喃(15mL)中的环己基甲胺(6.0mL,5.22g)和二异丙基乙胺(8.0mL,5.92g)的溶液逐滴加入四氢呋喃(35mL)中的实施例2C(7.70g)的溶液。加入后,加入四氢呋喃(20mL),并在室温将该反应搅拌16小时。将溶液加入水中,用乙酸乙酯和二氯甲烷(体积1∶1)的溶液萃取。在无水硫酸钠上干燥该溶液,过滤,通过结晶减少滤液体积以分离标题化合物。
实施例2E
4-(4-{乙酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例1B中用实施例2B替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ8.50(br s,1H),8.40(m,1H),7.88(dd,1H),7.73(d,1H),7.71(d,1H),7.06(dd,1H),6.86(d,1H),6.81(d,1H),4.16(m,1H),3.96-3.77(m,2H),3.25(t,4H),3.18-3.06(m,2H),2.77(m,4H),2.48-2.23(m,2H),2.14-1.95(m,8H),1.86(m,2H),1.77-1.60(m,11H),1.25-1.14(m,8H),1.07-1.00(m,4H),0.95-0.86(m,2H)。
实施例3
4-(4-{苯甲酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例3A
4-{4-[苯甲酰基((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基]-氨基]-哌啶-1-基}-苯甲酸乙酯
通过在实施例2A中用苯甲酰氯替代乙酰氯而制备标题化合物。
实施例3B
4-{4-[苯甲酰基-((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基]-氨基]-哌啶-1-基}-苯甲酸
通过在实施例2B中用实施例3A替代实施例2A而制备标题化合物。
实施例3C
4-(4-{苯甲酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例1B中用实施例3B替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.98(br s,1H),8.51(br s,1H),8.42(br s,1H),7.89(dd,1H),7.43(d,2H),7.42(m,3H),7.29(d,2H),7.08(d,1H),6.85(d,2H),4.03-3.75(m,3H),3.24(t,4H),2.86(m,2H),2.37(m,2H),2.11(m,2H),1.97-1.82(m,2H),1.78-1.55(m,10H),1.23-0.91(m,11H),0.79(d,2H),0.45(s,1H)。
实施例4
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-3′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺
实施例4A
3′-溴联苯-4-甲酸甲酯
将二氧杂环己烷(40mL)中的4-(甲氧基羰基)苯基硼酸(1.55g,8.63mmol)、1-溴-3-碘苯(2.22g,7.84mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)(0.29g,0.392mmol)和CsF(2.38g,15.7mmol)在80℃搅拌8小时。冷却反应,倒入乙酸乙酯中,用水和盐水洗涤两次,浓缩合并的有机层。用2-20%乙酸乙酯在己烷中的混合物在硅胶上色谱分离残余物以获得标题化合物。
实施例4B
3′-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基]联苯-4-甲酸甲酯
将二甘醇二甲醚(5mL)中的实施例4A(146mg,0.50mmol)、(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺(92mg,0.60mmol)、三(二亚苄基丙酮)二钯(0)(23mg,0.025mmol)、四氟硼酸三叔丁基鏻(11.7mg,0.04mmol)和K3PO4(160mg,0.75mmol)在100℃搅拌24小时。冷却反应并用5%乙酸乙酯在己烷中的混合物在硅胶上色谱分离以获得标题化合物。
实施例4C
3′-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)联苯-4-甲酸
如实施例2B中所述用实施例4B替代实施例2A制备标题化合物。
实施例4D
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-3′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺
如实施例1B中所述用实施例4C替代实施例1A并用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)11.90(s,1H),8.65(m,2H),7.97(d,1H),7.93(d,2H),7.68(d,2H),7.28(d,1H),7.17(t,1H),6.88(s,1H),6.82(d,1H),6.66(d,1H),5.70(m,1H),3.65(m,1H),2.55(m,2H),2.34(m,4H),1.72(m,6H),1.52(m,1H),0.99-1.49(m,16H)。
实施例5
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(苯基乙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
实施例5A
4-{4-[苯基乙酰基((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基)-氨基]-哌啶-1-基}-苯甲酸乙酯
通过在实施例2A中用苯乙酰氯替代乙酰氯而制备标题化合物。
实施例5B
4-{4-[苯基乙酰基-((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基]-氨基]-哌啶-1-基}-苯甲酸
通过在实施例2B中用实施例5A替代实施例2A而制备标题化合物。
实施例5C
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(苯基乙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
通过在实施例1B中用实施例5B替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.98(br s,1H),8.63(m,2H),7.93(dt,1H),7.73(d,1H),7.71(d,1H),7.33-7.19(m,6H),6.91(d,2H),4.10(m,1H),3.95(m,2H),3.78(d,1H),3.29(t,4H),3.00-2.60(m,4H),2.34(m,1H),2.17(m,1H),2.05(m,1H),1.90(m,1H),1.80-1.53(m,9H),1.23-1.17(m,8H),0.99(m,2H),0.92-0.86(m,6H)。
实施例6
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺
实施例6A
4′-溴联苯-4-甲酸甲酯
如实施例4A中所述用1-溴-4-碘苯替代1-溴-3-碘苯而制备标题化合物。
实施例6B
4′-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基]联苯-4-甲酸甲酯
如实施例4B中所述用实施例6A替代实施例4A而制备标题化合物。
实施例6C
4′-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)联苯-4-甲酸
如实施例2B中所述用实施例6B替代实施例2A而制备标题化合物。
实施例6D
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺
如实施例1B中所述用实施例6C替代实施例1A并用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.90(s,1H),8.66(m,2H),7.97(d,1H),7.87(d,2H),7.66(d,2H),7.51(d,2H),7.26(d,2H),7.18(m,1H),6.79(d,2H),5.95(m,1H),3.65(m,1H),2.60(m,2H),2.33(m,2H),1.94(m,2H),1.72(m,6H),1.23(s,3H),1.19(m,4H),0.93-1.15(m,11H)。
实施例7
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺
实施例7A
4′-((3-苯基丙基)((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)氨基)联苯-4-甲酸
在1,2-二氯乙烷(5mL)中搅拌实施例6C(100mg,0.286mmol)、3-苯基丙醛(101mg,0.715mmol)和三乙酰氧基硼氢化钠(182mg,0.858mmol)24小时。用二氯甲烷和乙醚研制该混合物以获得标题化合物。
实施例7B
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺
如实施例1B中所述用实施例7A替代实施例1A并用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。
实施例8
4-{6-[金刚烷-1-基甲基]-2,6-二氮杂双环[3.2.1]辛-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例8A
2-(4-乙氧基羰基)苯基)-2,6-二氮杂双环[3.2.1]辛烷-6-甲酸苄酯
将2,6-二氮杂双环[3.2.1]辛烷-6-甲酸苄酯(300mg)溶解于二甲亚砜(3mL)中,然后加入4-氟苯甲酸乙酯(172mg)和碳酸钾(206mg)。将反应在130℃加热过夜。冷却后,用水稀释反应物并用乙酸乙酯萃取。用盐水洗涤有机层并在硫酸钠上干燥。过滤并浓缩滤液后,用7/3己烷/乙酸乙酯在硅胶上用柱色谱法纯化获得的粗物质以获得标题化合物。
实施例8B
4-(2,6-二氮杂双环[3.2.1]辛烷-2-基)苯甲酸乙酯
将实施例8A(82mg)溶解在甲醇(6mL)中,然后加入10%披钯碳(palladium on carbon)(13mg),反应在氢气囊(hydrogen balloon)下搅拌3小时。然后将反应物通过硅藻土过滤并浓缩滤液,得到用于下一步骤的不必纯化的粗产物。
实施例8C
4-{6-[金刚烷-1-基羰基]-2,6-二氮杂双环[3.2.1]辛-2-基}苯甲酸乙酯
将实施例8B(45mg)、金刚烷-1-甲酸(31mg)溶解于二氯甲烷(1mL)中,然后加入1-乙基-3-[3-(二甲基氨基)丙基]-碳二亚胺盐酸盐(38mg)和4-二甲基氨基吡啶(7mg),反应在室温搅拌过夜。然后用乙酸乙酯稀释反应物,用1M H3PO4洗涤两次,用饱和NaHCO3洗涤两次,用盐水洗涤一次。在硫酸钠上干燥有机层。过滤并浓缩后,得到标题化合物,不必进一步纯化。
实施例8D
4-{6-[金刚烷-1-基甲基]-2,6-二氮杂双环[3.2.1]辛-2-基}苯甲酸乙酯
将实施例8C(70mg)溶解于四氢呋喃(2mL)中,然后加入硼烷在四氢呋喃中的1.0M溶液(0.25mL),反应在70℃加热1小时。冷却至室温后,加入乙醇中的2.5M HCl(2mL),反应在70℃加热1小时。冷却并浓缩后,将残余物再次溶解在乙醇中的2.5M HCl,在70℃加热一小时。然后将反应冷却至室温,在乙酸乙酯和2M Na2CO3水溶液之间分配。用盐水洗涤有机层并在硫酸钠上干燥。过滤并浓缩后,得到获得的产物,不必进一步纯化。
实施例8E
4-{6-[金刚烷-1-基甲基]-2,6-二氮杂双环[3.2.1]辛-2-基}苯甲酸
将实施例8D(68mg)溶解在四氢呋喃(1mL)和甲醇(1mL)中。然后加入1N氢氧化锂水溶液(0.32mL),将混合物在65℃加热过夜。然后冷却并浓缩反应物,加入水,用2N HCl水溶液调节pH至1。用氯仿/甲醇萃取该反应混合物,将有机层在硫酸钠上干燥并过滤后,浓缩滤液以得到作为盐酸盐的标题化合物。
实施例8F
4-{6-[金刚烷-1-基甲基]-2,6-二氮杂双环[3.2.1]辛-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
将实施例8E(32mg)、实施例2D(30mg)、1-乙基-3-[3-(二甲基氨基)丙基]-碳二亚胺盐酸盐(32mg)和4-二甲基氨基吡啶(20mg)在二氯甲烷(1.5mL)中搅拌24小时。通过用250x50mm、10μ的C18柱的制备HPLC纯化产物,用20-100%CH3CN在0.1%三氟乙酸水溶液中的混合物进行梯度洗脱,获得产物,为三氟乙酸盐。1H NMR(300MHz,二甲亚砜-d6)δ12.05(br s,1H),8.79(br s,1H),8.63(m,2H),7.93(dd,1H),7.78(d,2H),7.26(d,1H),6.90(m,2H),4.90(br m,1H),4.15(br m,1H),3.90(br m,1H),3.76(br m,1H),3.26(m,4H),3.12(s,2H),2.08(br m,2H),1.99(br m,5H),1.60(m,18H),1.18(m,3H),1.00(m,2H)。
实施例9
N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-[(三氟甲基)磺酰基]苯基)磺酰基]-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
实施例9A
4-((R)-3-吗啉-4-基-1-苯磺酰基甲基-丙基氨基)-3-三氟甲烷磺酰基-苯磺酰胺
如Park,Cheol-Min;等J.Med.Chem 2008,51,6902-6915所述制备标题化合物。
实施例9B
4-{4-[(3-苯基-丙酰基)-((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基)-氨基]-哌啶-1-基}-苯甲酸乙酯
通过在实施例2A中用3-苯基丙酰氯替代乙酰氯而制备标题化合物。
实施例9C
4-{4-[(3-苯基-丙酰基)-((1S,2S,3S,5R)-2,6,6-三甲基-双环[3.1.1]庚-3-基)-氨基]-哌啶-1-基}-苯甲酸
通过在实施例2B中用实施例9B替代实施例2A而制备标题化合物。
实施例9D
N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-[(三氟甲基)磺酰基]苯基)磺酰基]-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
通过在实施例1B中用实施例9C替代实施例1A以及用实施例9A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ8.10(dd,1H),7.94(dt,1H),7.72(d,2H),7.39-7.13(m,10H),6.97-6.78(m,4H),4.20(m,1H),4.04(m,1H),3.88(m,2H),3.51(br s,4H),2.92-2.63(m,7H),2.45-2.03(m,8H),1.95(m,2H),1.85-1.54(m,4H),1.41(m,2H),1.24-1.15(m,8H),1.01-0.90(m,6H)。
实施例10
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-硝基苯基}磺酰基]苯甲酰胺
实施例10A
4-(哌嗪-1-基)苯甲酸乙酯
用Bruncko,M.,等,J.Med.Chem.,2007 50,641所述的方法制备标题化合物。
实施例10B
4-{4-[(金刚烷-1-基羰基]哌嗪-1-基}苯甲酸乙酯
通过在实施例8C中用实施例10A替代实施例8B而制备标题化合物。
实施例10C
4-{4-[(金刚烷-1-基甲基]哌嗪-1-基}苯甲酸乙酯
通过在实施例8D中用实施例10B替代实施例8C而制备标题化合物。
实施例10D
4-{4-[金刚烷-1-基甲基)哌嗪-1-基}苯甲酸
通过在实施例8E中用实施例10C替代实施例8D而制备标题化合物。
实施例10E
(R)-4-(4-吗啉代-1-(苯硫基)丁烷-2-基氨基)-3-硝基苯磺酰胺
用Wendt,M.,等,J.Med.Chem.,2006,49,1165所述的方法制备标题化合物。
实施例10F
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-硝基苯基}磺酰基]苯甲酰胺
通过在实施例8F中用实施例10D替代实施例8E以及用实施例10E替代实施例2D而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ9.82(v br s,1H),9.02(v br s,1H),8.57(d,1H),8.30(d,2H),7.87(dd,1H),7.80(d,2H),7.23(m,2H),7.16(m,4H),7.01(d,2H),4.20(m,2H),3.90(br m,2H),3.60,3.40,3.20,3.00(所有br m,总共18H),2.18(m,2H)1.99(br s,3H),1.62(br m,10H)。
实施例11
4-{(1S,4S)-5-[金刚烷-1-基甲基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例11A
(1S,4S)-5-[4-(乙氧基羰基)苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯
通过在实施例8A中用(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯替代2,6-二氮杂双环[3.2.1]辛烷-6-甲酸苄酯而制备标题化合物。
实施例11B
4-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基]苯甲酸乙酯
将实施例11A(280mg)溶解于二氧杂环己烷中的4NHCl(6mL)中并在室温搅拌1小时。然后将反应物在乙酸乙酯和饱和NaHCO3之间分配。用盐水洗涤有机层并在硫酸钠上干燥。过滤并浓缩后,得到获得的产物,不必纯化。
实施例11C
4-{(1S,4S)-5-[金刚烷-1-基羰基]-2,5-二氮杂双环[2.2.1]庚-2-基}苯甲酸乙酯
通过在实施例8C中用实施例11B替代实施例8B而制备标题化合物。
实施例11D
4-{(1S,4S)-5-[金刚烷-1-基甲基]-2,5-二氮杂双环[2.2.1]庚-2-基}苯甲酸乙酯
通过在实施例8D中用实施例11C替代实施例8C而制备标题化合物。
实施例11E
4-{(1S,4S)-5-[金刚烷-1-基甲基]-2,5-二氮杂双环[2.2.1]庚-2-基}苯甲酸
通过在实施例8E中用实施例11D替代实施例8D而制备标题化合物。
实施例11F
4-{(1S,4S)-5-[金刚烷-1-基甲基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例8F中用实施例11E替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.05(br s,1H),8.63(m,2H),8.20(br s,1H),7.93(dd,1H),7.78(d,2H),7.26(d,1H),6.70(m,2H),4.78(br s,1H),4.44(br s,1H),3.70(m,2H),3.38(m,2H),3.30(t,2H),3.12(s,2H),2.38(m,1H),2.20(m,1H),1.99(br m,3H),1.60(m,18H),1.18(m,3H),1.00(m,2H)。
实施例12
4-(4-{[3-溴-5-甲基金刚烷-1-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例12A
4-(4-{[3-溴-5-甲基金刚烷-1-基]羰基}哌嗪-1-基)苯甲酸乙酯
通过在实施例8C中用实施例10A替代实施例8B以及用3-甲基-5-溴-金刚烷-1-甲酸替代金刚烷-1-甲酸而制备标题化合物。
实施例12B
4-(4-{[3-溴-5-甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酸乙酯
通过在实施例8D中用实施例12A替代实施例8C而制备标题化合物。
实施例12C
4-(4-{[3-溴-5-甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酸
通过在实施例8E中用实施例12B替代实施例8D而制备标题化合物。
实施例12D
4-(4-{[3-溴-5-甲基金刚烷-1-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例8F中用实施例12C替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.05(v br s,1H),8.97(v br s,1H),8.63(m,2H),7.93(dd,1H),7.80(d,2H),7.25(d,1H),7.00(d,2H),3.90(br m,1H),3.60,3.40,3.20,3.00(所有br m,总共10H),2.21(s,5H)2.02(m,2H),1.70(m,7H),1.40(m,5H),1.20(m,4H),1.00(m,2H),0.86(s,3H)。
实施例13
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{[3,5-二甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酰胺
实施例13A
4-(4-{[3,5-二甲基金刚烷-1-基]羰基}哌嗪-1-基)苯甲酸乙酯
通过在实施例8C中用实施例10A替代实施例8B以及用3,5-二甲基-金刚烷-1-甲酸替代金刚烷-1-甲酸而制备标题化合物。
实施例13B
4-(4-{[3,5-二甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酸乙酯
通过在实施例8D中用实施例13A替代实施例8C而制备标题化合物。
实施例13C
4-(4-{[3,5-二甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酸
通过在实施例8E中用实施例13B替代实施例8D而制备标题化合物。
实施例13D
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{[3,5-二甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酰胺
通过在实施例8F中用实施例13C替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.05(v br s,1H),8.97(v br s,1H),8.63(m,2H),7.93(dd,1H),7.80(d,2H),7.25(d,1H),7.00(d,2H),3.90(br m,1H),3.55(br m,1H),3.30(m,8H),2.99(br s,2H),2.08(br m,1H),1.70(m,7H),1.45(s,2H),1.20(m,12H),1.00(m,2H),0.82(s,6H)。
实施例14
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-{[4-(1-甲基-2-氧代-3-氮杂双环[3.1.1]庚-3-基)苯基]磺酰基}苯甲酰胺
根据用于实施例EXAMPLE 1B的步骤用4-(1-甲基-2-氧代-3-氮杂双环[3.1.1]庚烷-3-基)苯磺酰胺替代4-氯-3-硝基苯磺酰胺而制备实施例14。1H NMR(300MHz,二甲亚砜-d6)δppm 1.45(s,3H),1.56(dd,1H),1.92-1.98(m,1H),2.63(dd,1H),2.69-2.75(m,1H),2.79-2.99(m,2H),3.01-3.21(m,4H),3.30-3.35(m,4H),3.78-4.01(m,1H),4.39(s,2H),6.88-6.95(m,2H),7.29-7.36(m,1H),7.38-7.44(m,2H),7.47-7.58(m,6H),7.72-7.79(m,3H),7.99-8.06(m,2H),9.45-9.59(m,1H)。
实施例15
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺
实施例15A
4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酸乙酯
将实施例62A(100mg)、(1S,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基硼酸(44.6mg)、三(二亚苄基丙酮)二钯(0)(11mg)、四氟硼酸三叔丁基鏻(4mg)和CsF(113mg)溶解于无水四氢呋喃(2mL)中。将该反应混合物在室温下搅拌过夜。浓缩反应混合物并用0-15%乙酸乙酯/己烷的快速色谱法纯化粗物质以获得标题化合物。
实施例15B
4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例15A替代实施例2A而制备标题化合物。
实施例15C
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺
通过在实施例1B中用实施例15B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.12(m,1H),8.66(m,2H),7.94(dd,1H),7.79(d,2H),7.64(m,1H),7.41(m,2H),7.30(d,1H),7.20(m,1H),6.99(d,2H),6.01(d,1H),4.28(m,2H),3.85(m,2H),3.28(m,12H),1.92(m,2H),1.62(m,3H),1.24(m,5H),0.94(s,3H),0.83(d,6H)。
实施例16
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-八氢-1H-4,7-亚甲基茚-5-基氨基]苄基}哌嗪-1-基)苯甲酰胺
实施例16A
4-(4-(2-硝基苄基)哌嗪-1-基)苯甲酸乙酯
将4-(哌嗪-1-基)苯甲酸乙酯(1.5g)、1-(溴甲基)-2-硝基苯(1.383g)和碳酸钠(2.036g)在室温悬浮在无水N,N-二甲基甲酰胺(20mL)中4小时。用乙酸乙酯稀释反应混合物,用水和盐水洗涤并浓缩。用10-40%乙酸乙酯/己烷通过快速色谱纯化法纯化残余物以获得标题化合物。
实施例16B
4-(4-(2-氨基苄基)哌嗪-1-基)苯甲酸乙酯
将实施例16A(1.5g)和5%Pd/C(0.3g)悬浮在无水乙醇(75mL)中。将该反应混合物在1个大气氢下搅拌2小时。过滤混合物并浓缩滤液以获得产物。
实施例16C
4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基氨基]苄基}哌嗪-1-基)苯甲酸乙酯
通过在实施例40A中用三环[5.2.1.02,6]癸-8-酮替代2-甲酰基苯硼酸以及实施例16B替代实施例23C而制备标题化合物。
实施例16D
4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基氨基]苄基}哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例16C替代实施例2A而制备标题化合物。
实施例16E
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基氨基]苄基}哌嗪-1-基)苯甲酰胺
通过在实施例1B中用实施例16D替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.09(bs,1H),8.66(m,2H),7.94(dd,1H),7.79(d,2H),7.30(d,1H),7.22(t,2H),7.01(m,2H),6.72(d,1H),6.65(m,1H),4.26(m,2H),3.85(dd,2H),3.66(m,2H),3.28(m,10H),2.26-1.61(m,14H),1.40-0.92(m,8H)。
实施例17
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚-2-基]氨基}苄基)哌嗪-1-基]苯甲酰胺
实施例17A
4-(4-(2-((1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚烷-2-基氨基)苄基)哌嗪-1-基)苯甲酸乙酯
通过在实施例40A中用(1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚烷-2-酮替代2-甲酰基苯硼酸以及用实施例16B替代实施例23C而制备标题化合物。
实施例17B
4-(4-(2-((1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚烷-2-基氨基)苄基)哌嗪-1-基)苯甲酸乙酯
通过在实施例2B中用实施例17A替代实施例2A而制备标题化合物。
实施例17C
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚-2-基]氨基}苄基)哌嗪-1-基]苯甲酰胺
通过在实施例1B中用实施例17B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.06(bs,1H),8.64(m,2H),7.94(m,1H),7.79(d,2H),7.30(d,1H),7.20(m,2H),7.00(d,2H),6.65(m,2H),3.83(m,2H),3.61(m,2H),3.30(m,14H),2.05(s,1H),1.86(m,3H),1.61(m,4H),1.45(m,1H),1.28(m,3H),0.99(s,3H),0.86(s,3H),0.77(d,3H)。
实施例18
4-[4-(2-{[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-基]氨基}苄基)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
实施例18A
4-(4-(2-((1R,5S)-6,6-三甲基双环[3.1.1]庚烷-2-基氨基)苄基)哌嗪-1-基)苯甲酸乙酯
通过在实施例40A中用(1R,5S)-6,6-三甲基双环[3.1.1]庚烷-2-酮替代2-甲酰基苯硼酸以及用实施例16B替代实施例23C而制备标题化合物。
实施例18B
4-(4-(2-((1R,5S)-6,6-三甲基双环[3.1.1]庚烷-2-基氨基)苄基)哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例18A替代实施例2A而制备标题化合物。
实施例18C
4-[4-(2-{[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-基]氨基}苄基)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1B中用实施例18B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.09(s,1H),8.66(m,2H),7.94(dd,1H),7.79(d,2H),7.30(d,1H),7.19(m,2H),6.99(d,2H),6.59(m,2H),3.85(m,4H),3.29(m,14H),2.33(m,2H),2.17(m,1H),1.82(m,7H),1.27(dd,2H),1.18(s,3H),1.09(s,3H),1.03(d,1H)。
实施例19
4-(4-{[(1R,5R)-2-(4-氯苯基)-6,6-二甲基双环[3.1.1]庚-2-烯-3-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例19A
(1R,5R)-6,6-二甲基-3-亚甲基-双环[3.1.1]庚烷-2-酮
将(1R,5S)-6,6-二甲基双环[3.1.1]庚烷-2-酮(0.938mL,920mg)加入四氢呋喃(50mL)中,用异丙醇/干冰浴将混合物冷却至-78℃。加入双(三甲基甲硅烷基)氨基锂(在四氢呋喃中1M,7.99mL),在-78℃将该溶液搅拌15分钟。将该溶液在水/冰浴中温热至0℃,将混合物搅拌45分钟。加入多聚甲醛(2000mg)。将溶液在0℃搅拌15分钟,温热至室温,额外搅拌4小时。用饱和氯化铵水溶液淬灭反应物,用乙醚萃取,用盐水洗涤,在无水硫酸钠上干燥,过滤,浓缩,并用5%乙酸乙酯/己烷通过快速柱色谱法在硅胶上纯化。
实施例19B
4-[4-((1R,5R)-6,6-二甲基-2-氧代-双环[3.1.1]庚-3-基甲基)-哌嗪-1-基]-苯甲酸乙酯
将实施例19A(417mg)和4-(哌嗪-1-基)苯甲酸乙酯(520mg)加入乙腈(6mL)中。加入三氟甲磺酸铋(III)(113mg),将混合物在50℃加热5.5小时。冷却混合物,用5%甲醇/二氯甲烷通过快速柱色谱法纯化。
实施例19C
4-{4-[(1R,5R)-2-(4-氯-苯基)-2-羟基-6,6-二甲基-双环[3.1.1]庚-3-基甲基]-哌嗪-1-基}-苯甲酸乙酯
将实施例19B(452mg)溶解在四氢呋喃(10mL)中,并用氯仿/干冰浴将混合物冷却至-60℃。逐滴加入(4-氯苯基)溴化镁(在四氢呋喃中1M,2.35mL)。完成加入后,用四氯化碳/干冰浴将混合物迅速温热至-25℃并搅拌4小时。用饱和氯化铵水溶液淬灭反应物,用乙酸乙酯萃取,在无水硫酸钠上干燥,并用20%乙酸乙酯/己烷通过快速柱色谱法在硅胶上纯化。
实施例19D
4-{4-[(1R,5R)-2-(4-氯-苯基)-6,6-二甲基-双环[3.1.1]庚-2-烯-3-基甲基]-哌嗪-1-基}-苯甲酸乙酯
将实施例19C(363mg)溶解在四氢呋喃(6mL)中,加入Burgess试剂((甲氧基羰基氨磺酰基)三乙基铵氢氧化物,内盐,209mg)。将该溶液在室温下搅拌16小时,然后用20%乙酸乙酯/己烷在硅胶上通过快速柱色谱法纯化。
实施例19E
4-{4-[(1R,5R)-2-(4-氯-苯基)-6,6-二甲基-双环[3.1.1]庚-2-烯-3-基甲基]-哌嗪-1-基}-苯甲酸
通过在实施例2B中用实施例19D替代实施例2A而制备标题化合物。
实施例19F
4-(4-{[(1R,5R)-2-(4-氯苯基)-6,6-二甲基双环[3.1.1]庚-2-烯-3-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例1B中用实施例19E替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ8.56(m,1H),8.48(m,1H),7.90(dd,1H),7.76(d,2H),7.48(d,1H),7.40(d,1H),7.14(d,1H),6.91(d,2H),6.88(d,1H),6.42(d,1H),4.14(dd,1H),3.26(m,8H),2.71(br s,2H),1.95(m,2H),1.77-1.53(m,8H),1.33-1.11(m,6H),1.07(s,3H),0.97(s,3H),0.86(m,2H)。
实施例20
4-{4-[(2-{[金刚烷-2-基甲基]氨基}-5,5-二甲基环己基)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
实施例20A
4-[4-({2-[(金刚烷-2-基甲基)氨基]-5,5-二甲基环己基}甲基)哌嗪-1-基]苯甲酸乙酯
将(2-金刚烷基甲基)胺盐酸盐(195mg)、4-(4-((5,5-二甲基-2-氧代环己基)甲基)哌嗪-1-基)苯甲酸乙酯(200mg)和乙酸钠(44mg)悬浮于无水二氯乙烷中。将该反应混合物在室温搅拌20分钟,随后加入三乙酰氧基硼氢化钠(228mg)。将该反应混合物在室温下搅拌过夜。用饱和NaHCO3水溶液淬灭反应物。用乙酸乙酯萃取反应混合物,用水和盐水洗涤。在Na2SO4上干燥有机相,过滤并浓缩。用0-5%甲醇/二氯甲烷通过快速色谱纯化法纯化残余物以获得标题化合物。
实施例20B
4-[4-({2-[(金刚烷-2-基甲基)氨基]-5,5-二甲基环己基}甲基)哌嗪-1-基]苯甲酸
通过在实施例2B中用实施例20A替代实施例2A而制备标题化合物。
实施例20C
4-{4-[(2-{[金刚烷-2-基甲基]氨基}-5,5-二甲基环己基)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1B中用实施例20B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.05(s,1H),8.65(m,2H),7.94(dd,1H),7.78(d,2H),7.30(d,1H),6.99(d,2H),3.83(m,2H),3.26(m,8H),2.98(m,4H),2.72(m,4H),2.27(m,2H),1.64(m,22H),1.25(m,5H),0.93(d,6H)。
实施例21
4-{4-[(5,5-二甲基-2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}环己基)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
实施例21A
4-(4-((5,5-二甲基-2-((1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)环己基)甲基)哌嗪-1-基)苯甲酸乙酯
通过在实施例20B中用(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺替代(2-金刚烷基甲基)胺盐酸盐而制备标题化合物。
实施例21B
4-(4-((5,5-二甲基-2-((1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)环己基)甲基)哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例21A替代实施例2A而制备标题化合物。
实施例21C
4-{4-[(5,5-二甲基-2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}环己基)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1B中用实施例21B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.07(m,1H),8.65(m,2H),7.94(dd,1H),7.77(m,2H),7.30(d,1H),6.98(d,2H),3.84(dd,2H),3.29(m,10H),2.79(m,6H),2.30(m,4H),1.78(m,11H),1.28(m,3H),1.16(m,8H),0.95(m,9H)。
实施例22
4-{4-[2-(3-氮杂双环[3.2.2]壬-3-基)-5-硝基苄基]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
实施例22A
4-(4-(甲氧基羰基)苯基)哌嗪-1-甲酸叔丁酯
如实施例45A中所述用哌嗪-1-甲酸叔丁酯替代1,4-二氧杂-8-氮杂螺[4.5]癸烷而制备标题化合物。
实施例22B
4-(4-(叔丁氧基羰基)哌嗪-1-基]苯甲酸
如实施例2B中所述用实施例22A替代实施例2A而制备标题化合物。
实施例22C
4-(4-(4-(环己基甲基氨基)-3-硝基苯基磺酰基氨基甲酰基)苯基)哌嗪-1-甲酸叔丁酯
如实施例1B中所述用实施例22B替代实施例1A并用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。
实施例22D
N-(4-(环己基甲基氨基)-3-硝基苯基磺酰基)-4-(哌嗪-1-基)苯甲酰胺三氟乙酸盐
将二氯甲烷中实施例22C(0.85g,1.4mmol)(10mL)、三氟乙酸(10mL)和三乙基硅烷(1ml)的溶液搅拌24小时。浓缩该混合物以获得标题化合物。
实施例22E
4-{4-[2-(3-氮杂双环[3.2.2]壬-3-基)-5-硝基苄基]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
将实施例22D(50mg,0.081mmol)、2-((1s,5s)-3-氮杂双环[3.2.2]壬烷-3-基)-5-硝基苯甲醛(27mg,0.097mmol)和聚合物支持的氰基硼氢化钠(41mg,0.097mmol)在四氢呋喃(1mL)和乙酸(0.33mL)中搅拌24小时。在先没有1%三乙胺、然后在有1%三乙胺的情况下用10%甲醇/乙酸乙酯,在硅胶上色谱分离粗混合物以获得标题化合物。MS(ELSD)m/e 762(M+H)+。
实施例23
4-(4-{2-[2,3,3a,4,7,7a-六氢-1H-4,7-亚甲基茚-5-基]苄基}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
实施例23A
3-硝基-4-[(四氢-吡喃-4-基甲基)-氨基]苯磺酰胺
通过在实施例2D中用4-氨基甲基四氢吡喃替代环己基甲基胺而制备标题化合物。
实施例23B
4-(4-{3-硝基-4-[(四氢-吡喃-4-基甲基)-氨基]-苯磺酰基氨基羰基}-苯基)-哌嗪-1-甲酸叔丁酯
通过在实施例1B中用4-(4-羰基-苯基)-哌嗪-1-甲酸叔丁酯替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。
实施例23C
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(哌嗪-1-基)苯甲酰胺
将实施例23B(3.813g)加入二氯甲烷(50mL)中。加入三乙基硅烷(5.5mL,4.004g),随后加入三氟乙酸(6mL,8.880g)。将该溶液在室温搅拌5小时。加入庚烷,在减压下除去溶剂,其后加入甲苯,在减压下再次除去溶剂以分离作为单三氟乙酸盐的标题化合物。
实施例23D
2,3,3a,4,7,7a-六氢-1H-4,7-亚甲基茚-5-基三氟甲烷磺酸盐
将三环[5.2.1.02,6]癸-8-酮(300mg)加入四氢呋喃(10mL)中。加入双(三甲基甲硅烷基)氨基钠(在四氢呋喃中1M,2.40mL),将该溶液在室温搅拌10分钟。用异丙醇/干冰浴将溶液冷却至-78℃,加入1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(857mg)。将该溶液温热至室温并搅拌16小时。浓缩反应混合物,用己烷(20mL)稀释,过滤并再次浓缩。用0-10%乙酸乙酯/己烷的梯度在硅胶上通过快速柱色谱法纯化残余物。
实施例23E
2-(2,3,3a,4,7,7a-六氢-1H-4,7-亚甲基-茚-5-基)-苯甲醛
将实施例23D(941mg)、2-甲酰基苯基硼酸(600mg)、磷酸三钾(1416mg)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)(244mg)加入已脱气并用氮气冲洗3次的四氢呋喃(15mL)中。将该溶液加热至60℃并搅拌16小时。浓缩溶液并用10%乙酸乙酯/己烷在硅胶上通过快速柱色谱法纯化。
实施例23F
4-(4-{2-[2,3,3a,4,7,7a-六氢-1H-4,7-亚甲基茚-5-基]苄基}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
将实施例23C(60mg)和实施例23E(26mg)加入四氢呋喃(1mL)和乙酸(0.33mL)中。加入氰基硼氢化钠(在树脂上2.38mmol/g,45mg),并将该反应在室温搅拌16小时。用5%甲醇/二氯甲烷在硅胶上通过快速柱色谱法纯化溶液以分离作为单乙酸盐的标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.94(br s,1H),8.63(t,1H),8.62(d,1H),7.93(dd,1H),7.73(d,2H),7.42(d,1H),7.28-7.20(m,4H),6.92(d,2H),6.25(d,1H),3.85(dd,4H),3.60-3.41(m,6H),3.37-3.26(m,8H),3.22(br s,2H),2.75(br s,2H),2.64(br s,2H),2.13(m,4H),1.95-1.76(m,6H),1.91(s,3H),1.64-1.50(m,6H),1.32-1.19(m,3H),1.03(m,2H)。
实施例24
1-[金刚烷-1-基]-4-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺
实施例24A
1-[金刚烷-1-基]-4-(2-甲酰基苯基)-N,N-二苯基-1H-吡唑-3-甲酰胺
将1-金刚烷-1-基-4-溴-1H-吡唑-3-甲酸联苯胺(47mg)、2-甲酰基苯硼酸(18mg)、碳酸钠(32mg)和四(三苯基膦)钯(0)(7mg)混合在二甲氧基乙烷/乙醇/水12/3/4(1mL)中并在CEM Discover微波反应器中在180℃加热5分钟。冷却反应,用水稀释并用乙酸乙酯萃取。用盐水洗涤有机层并在硫酸钠上干燥。过滤并浓缩后,用己烷/乙酸乙酯4/1在硅胶上通过柱色谱法纯化。
实施例24B
1-[金刚烷-1-基]-4-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺
通过在实施例40A中用实施例24A替代2-甲酰基苯硼酸而制备标题化合物,除了通过用250x 50mm、10μ的C18柱的制备HPLC纯化产物,用20-100%CH3CN在0.1%三氟乙酸水溶液中的混合物进行梯度洗脱,获得产物,为三氟乙酸盐。1H NMR(300MHz,二甲亚砜-d6)δ9.70(br s,1H),8.70(t,1H),8.66(d,1H),7.96(dd,1H),7.89(br s,1H),7.80(d,2H),7.63(br s,1H),7.50(br s,2H),7.32(m,6H),7.19(m,6H),6.98(d,2H),4.15(br s,1H)3.80(m,4H),3.40,(m,4H),3.25(m,4H),2.97(br s,1H),2.00,1.80,1.60(所有m,总共18H),1.24(m,4H)。
实施例25
4-(4-{2-[2-(金刚烷-1-基)-6-甲基咪唑并[1,2-a]吡啶-8-基]苄基}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
1H NMR(400MHz,二甲亚砜-d6)δppm 12.05(s,1H),8.55-8.74(m,3H),8.07(s,1H),7.93(dd,1H),7.73(d,2H),7.55-7.71(m,4H),7.48(d,1H),7.29(d,1H),6.86(d,2H),3.81-3.89(m,4H),3.31-3.38(m,2H),3.22-3.30(m,2H),2.42(s,3H),2.03(s,3H),1.91(d,8H),1.56-1.77(m,10H),1.20-1.32(m,3H).MS(ESI)m/e 856(M-H)-。
实施例26
N-(金刚烷-2-基)-6-甲基-8-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}咪唑并[1,2-a]吡啶-2-甲酰胺
1H NMR(400MHz,二甲亚砜-d6)δppm 12.10(s,1H),8.75(s,1H),8.62-8.69(m,2H),8.57(s,1H),7.88-7.98(m,2H),7.81(d,J=8.9Hz,2H),7.67-7.73(m,1H),7.60-7.67(m,2H),7.46-7.52(m,1H),7.26-7.33(m,2H),6.97(d,J=9.2Hz,2H),4.25(s,2H),3.80-3.91(m,4H),3.35(t,J=6.4Hz,3H),3.16-3.31(m,6H),2.40(s,3H),1.85-2.02(m,3H),1.82(s,2H),1.76(s,1H),1.54-1.71(m,8H),1.45(d,J=12.6Hz,2H),1.19-1.33(m,2H).MS(ESI)m/e 856(M-H)-。
实施例27
4-(4-{2-[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-烯-2-基]苄基}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
实施例27A
6,6-二甲基双环[3.1.1]庚-2-烯-2-基三氟甲烷磺酸盐
通过在实施例23D中用(1R)-(+)-诺蒎酮替代三环[5.2.1.02,6]癸-8-酮而制备标题化合物。
实施例27B
2-(6,6-二甲基-双环[3.1.1]庚-2-烯-2-基)-苯甲醛
通过在实施例23E中用实施例27A替代实施例23D而制备标题化合物。
实施例27C
4-(4-{2-[6,6-二甲基双环[3.1.1]庚-2-烯-2-基]苄基}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23F中用实施例27B替代实施例23E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.94(br s,1H),8.63(t,1H),8.62(d,1H),7.93(dd,1H),7.74(d,2H),7.47-7.35(m,2H),7.24(m,2H),7.03(m,1H),6.92(d,2H),5.55(1H),3.85(dd,2H),3.63-3.41(m,2H),3.37-3.23(m,8H),2.41(m,2H),2.37-2.29(m,4H),2.15(m,2H),1.91(s,3H),1.62(d,2H),1.40(d,1H),1.30(s,3H),1.26(m,4H),0.98(s,3H)。
实施例28
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5,5,6-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺
实施例28A
5,5,6-三甲基双环[2.2.1]庚-2-烯-2-基三氟甲烷磺酸盐
通过在实施例23D中用5,5,6-三甲基双环[2.2.1]庚烷-2-酮替代三环[5.2.1.02,6]癸-8-酮而制备标题化合物。
实施例28B
2-(5,5,6-三甲基-双环[2.2.1]庚-2-烯-2-基)-苯甲醛
通过在实施例23E中用实施例28A替代实施例23D而制备标题化合物。
实施例28C
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5,5,6-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺
通过在实施例23F中用实施例28B替代实施例23E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.93(br s,1H),8.60(m,2H),7.93(d,1H),7.74(d,2H),7.44(m,1H),7.27-7.17(m,4H),6.90(d,2H),6.20(br s,1H),3.85(dd,2H),3.56(m,2H),3.36-3.23(m,8H),2.62(br s,2H),2.42(br s,2H),1.91(br s,3H),1.82(d,2H),1.62(dd,2H),1.52(d,1H),1.28(m,5H),1.04-1.00(m,6H),0.90(s,3H)。
实施例29
N-环辛基-5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-2-糠酰胺
1H NMR(400MHz,二甲亚砜-d6)δppm 12.10(s,1H),9.21(s,1H),8.63-8.72(m,2H),8.29(d,1H),7.90-7.99(m,2H),7.81(d,1H),7.55-7.63(m,2H),7.50(t,1H),7.43(d,1H),7.30(d,1H),7.22(d,1H),7.05(d,2H),4.64(s,2H),3.93-4.17(m,3H),3.81-3.90(m,2H),3.77(s,2H),3.33-3.38(m,4H),3.22-3.30(m,4H),1.92(s,1H),1.43-1.79(m,14H),1.18-1.39(m,3H).MS(ESI)m/e 811(M-H)-。
实施例30
N-苄基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺
1H NMR(400MHz,二甲亚砜-d6)δppm 12.11(s,1H),10.06(s,1H),8.85(s,1H),8.60-8.69(m,2H),7.93(dd,J=9.1,2.0Hz,1H),7.79(d,J=8.9Hz,1H),7.37-7.51(m,3H),7.28(d,J=9.5Hz,1H),7.18-7.25(m,1H),7.01-7.12(m,3H),6.97(d,J=9.2Hz,2H),6.85(d,J=6.8Hz,2H),6.12(d,J=2.8Hz,1H),4.79(d,J=10.1Hz,1H),4.14-4.30(m,2H),4.07(dd,J=14.9,6.0Hz,2H),3.77-3.87(m,2H),3.30-3.36(m,2H),3.18-3.29(m,4H),3.14(s,2H),2.83-2.98(m,2H),2.74(d,J=11.7Hz,1H),2.61(t,J=3.2Hz,1H),2.07-2.19(m,1H),1.82-1.97(m,1H),1.70-1.80(m,1H),1.54-1.69(m,2H),1.18-1.37(m,4H),1.10(s,3H),0.92(s,3H).MS(ESI)m/e 845(M-H)-。
实施例31
4-[4-(2-{[(1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-基]氨基}苄基)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
实施例31A
4-(4-(2-((1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛烷-8-基氨基)苄基)哌嗪-1-基)苯甲酸乙酯
通过在实施例40A中用(1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛烷-3-酮替代2-甲酰基苯硼酸以及用实施例16B替代实施例23C而制备标题化合物。
实施例31B
4-(4-(2-((1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛烷-8-基氨基)苄基)哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例31A替代实施例2A而制备标题化合物。
实施例31C
4-[4-(2-{[(1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-基]氨基}苄基)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1B中用实施例31B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ9.42(s,1H),8.64(m,2H),7.93(dd,1H),7.76(m,2H),7.28(d,1H),7.17(m,1H),6.96(m,3H),6.63(s,1H),3.84(m,5H),3.26(m,15H),2.67(d,3H),2.29(m,8H),1.90(m,2H),1.59(m,2H),1.24(m,2H)。
实施例32
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苄基)哌嗪-1-基]苯甲酰胺
实施例32A
2-((1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氧基)苄腈
将2-氟苯腈(100mg)、(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺(380mg)、三乙胺(1.5mL)溶解于无水二甲亚砜(5ml)中并在130℃加热过夜。将反应混合物冷却至室温,并用乙酸乙酯稀释。用水和盐水洗涤有机相,在Na2SO4上干燥,过滤并浓缩。用0-5%甲醇/二氯甲烷通过快速色谱纯化法纯化残余物以获得标题化合物。
实施例32B
2-((1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氧基)苯甲醛
将实施例32A(80mg)溶解在无水二氯甲烷(5mL)中。在0℃冷却溶液,加入在二氯甲烷溶液中的1M二异丁基氢化铝(0.7mL)。将该反应混合物在室温搅拌3小时。用甲醇和5%L-酒石酸水溶液淬灭反应物。用乙酸乙酯萃取溶液,在Na2SO4上干燥,过滤并浓缩。用0-30%乙酸乙酯/己烷通过快速色谱纯化法纯化残余物以获得标题化合物。
实施例32C
4-(4-(2-((1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)苄基)哌嗪-1-基)苯甲酸乙酯
通过在实施例40A中用实施例32B替代2-甲酰基苯基硼酸以及用4-(哌嗪-1-基)苯甲酸乙酯替代实施例23C而制备标题化合物。
实施例32D
4-(4-(2-((1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)苄基)哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例32C替代实施例2A而制备标题化合物。
实施例32E
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苄基)哌嗪-1-基]苯甲酰胺
通过在实施例1B中用实施例32D替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.10(s,1H),8.65(m,2H),7.93(dd,1H),7.78(d,2H),7.26(m,3H),7.00(d,2H),6.73(d,1H),6.64(t,1H),4.26(m,1H),3.83(dd,2H),3.65(m,2H),3.25(m,14H),2.63(m,1H),2.32(d,1H),2.13(m,1H),1.88(m,3H),1.60(m,2H),1.48(m,1H),1.26(m,5H),1.07(m,6H)。
实施例33
4-(4-{2-[3-氮杂双环[3.2.2]壬-3-基]苄基}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
实施例33A
2-(3-氮杂双环[3.2.2]壬-3-基)苯甲醛
通过在实施例32A中用2-氟苯甲醛替代2-氟苄腈以及用(1s,5s)-3-氮杂双环[3.2.2]壬烷替代(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺而制备标题化合物。
实施例33B
4-(4-(2-(3-氮杂双环[3.2.2]壬-3-基)苄基)哌嗪-1-基)苯甲酸乙酯
通过在实施例40A中用实施例33A替代2-甲酰基苯基硼酸以及用4-(哌嗪-1-基)苯甲酸乙酯替代实施例23C而制备标题化合物。
实施例33C
4-(4-(2-(3-氮杂双环[3.2.2]壬-3-基)苄基)哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例33B替代实施例2A而制备标题化合物。
实施例33D
4-(4-{2-[3-氮杂双环[3.2.2]壬-3-基]苄基}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1B中用实施例33C替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.07(m,1H),8.65(m,2H),7.93(dd,1H),7.79(d,2H),7.56(d,1H),7.44(d,2H),7.26(m,2H),7.00(d,2H),4.48(s,2H),4.01(s,2H),3.83(dd,2H),3.28(m,10H),2.98(d,4H),1.90(m,7H),1.62(m,6H),1.25(m,2H)。
实施例34
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[三环[4.3.1.13,8]十一碳-4-烯-4-基]苄基}哌嗪-1-基)苯甲酰胺
实施例34A
三环[4.3.1.13,8]十一碳-4-烯-4-基三氟甲烷磺酸盐
通过在实施例23D中用三环[4.3.1.13,8]十一碳-4-酮替代三环[5.2.1.02,6]癸-8-酮而制备标题化合物。
实施例34B
2-三环[4.3.1.13,8]十一碳-4-烯-4-基-苯甲醛
通过在实施例23E中用实施例34A替代实施例23D而制备标题化合物。
实施例34C
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[三环[4.3.1.13,8]十一碳-4-烯-4-基]苄基}哌嗪-1-基)苯甲酰胺
通过在实施例23F中用实施例34B替代实施例23E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.97(br s,1H),8.65(t,1H),8.62(d,1H),7.93(dd,1H),7.74(d,2H),7.41(m,1H),7.28-7.21(m,3H),7.08(m,1H),6.92(d,2H),5.52(m,1H),3.84(dd,2H),3.54(m,2H),3.37-3.24(m,8H),2.57-2.44(m,2H),2.29-2.09(m,4H),1.94-1.84(m,2H),1.91(s,3H),1.62(d,2H),1.36-1.18(m,4H),0.88(s,9H)。
实施例35
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-苯基双环[2.2.1]庚-2-烯-1-甲酰胺
1H NMR(500MHz,二甲亚砜-d6)δppm 12.14(s,1H),9.63(s,1H),9.35(s,1H),8.68(t,1H),8.65(d,1H),7.94(dd,1H),7.80(d,2H),7.53-7.60(m,1H),7.33-7.41(m,2H),7.30(d,1H),7.20-7.27(m,3H),7.07(t,1H),7.01(d,2H),6.18(d,1H),4.77(s,1H),4.38(d,1H),4.07(s,2H),3.85(dd,3H),3.32-3.37(m,4H),3.22-3.30(m,4H),3.07-3.20(m,2H),2.71-2.84(m,1H),2.65(t,1H),2.12-2.25(m,1H),1.85-1.96(m,1H),1.74-1.82(m,1H),1.56-1.66(m,2H),1.20-1.34(m,4H),1.17(s,3H),1.00-1.05(m,3H).MS(ESI)m/e 831(M-H)-。
实施例36
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]双环[2.2.1]庚-2-烯-1-甲酰胺
1H NMR(500MHz,二甲亚砜-d6)δppm 12.11(s,1H),10.24(s,1H),8.57-8.73(m,2H),8.00(d,1H),7.94(dd,J=9.2,2.1Hz,1H),7.80(d,2H),7.50(dd,1H),7.33-7.43(m,2H),7.30(d,1H),7.20(dd,1H),7.01(d,2H),6.14(d,1H),4.87(d,1H),4.21-4.29(m,1H),4.06-4.20(m,4H),3.84(dd,4H),3.51-3.59(m,2H),3.35(t,2H),3.21-3.31(m,4H),3.01-3.20(m,2H),2.94(d,1H),2.63(t,1H),2.53-2.61(m,1H),2.20-2.29(m,1H),2.08-2.19(m,2H),1.80(t,2H),1.58-1.73(m,4H),1.51-1.59(m,1H),1.20-1.33(m,6H),1.17(s,3H),1.10-1.15(m,4H),0.94(s,3H),0.86(s,3H),0.47(d,3H).MS(ESI)m/e 891(M-H)-。
实施例37
N-(金刚烷-1-基甲基)-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺
1H NMR(500MHz,二甲亚砜-d6)δppm 12.14(s,1H),10.53(s,1H),8.68(t,1H),8.64(d,1H),8.17(s,1H),7.94(dd,1H),7.82(t,1H),7.47(d,1H),7.40(t,1H),7.36(t,1H),7.30(d,1H),7.23(d,1H),6.13(d,1H),4.88(d,1H),4.11-4.22(m,3H),3.84(dd,2H),3.56(d,1H),3.22-3.29(m,4H),3.14-3.22(m,2H),2.88-3.03(m,2H),2.80(dd,1H),2.62-2.68(m,1H),2.53-2.63(m,1H),2.08-2.18(m,1H),1.84-1.96(m,1H),1.68(s,4H),1.62(d,2H),1.48(d,3H),1.34(d,3H),1.20-1.30(m,4H),1.10-1.19(m,6H),1.00-1.07(m,3H),0.97(s,3H).MS(ESI)m/e 903(M-H)-。
实施例38
N-环丙基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺
1H NMR(500MHz,二甲亚砜-d6)δppm 12.15(s,1H),10.14(s,1H),8.68(t,1H),8.64(d,1H),8.04(s,1H),7.94(dd,1H),7.80(d,2H),7.53(dd,1H),7.35-7.43(m,2H),7.30(d,1H),7.12-7.17(m,1H),6.99-7.05(m,2H),6.10(d,1H),4.82(d,1H),4.27(d,1H),4.13(t,2H),3.85(dd,2H),3.35(t,2H),3.16-3.30(m,6H),3.09(s,2H),2.60(t,1H),2.52-2.58(m,1H),2.43-2.49(m,1H),2.03-2.14(m,1H),1.85-1.97(m,1H),1.62(d,3H),1.17-1.32(m,3H),1.14(s,3H),0.91(s,3H),0.45-0.58(m,2H),0.37-0.45(m,1H),0.11-0.19(m,1H).MS(ESI)m/e 795(M-H)-。
实施例39
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酸
1H NMR(500MHz,二甲亚砜-d6)δppm 11.96(s,1H),8.57-8.66(m,2H),7.92(dd,1H),7.73(d,2H),7.46-7.51(m,1H),7.40-7.46(m,1H),7.26(d,1H),7.11-7.22(m,4H),7.06(d,2H),7.00(dd,1H),6.91(d,2H),6.26(d,1H),6.16(d,1H),5.10(s,1H),4.59(s,1H),3.83(dd,2H),3.65-3.73(m,1H),3.38-3.52(m,3H),3.23(s,2H),2.50-2.56(m,4H),2.26-2.42(m,2H),1.98-2.07(m,2H),1.90(s,3H),1.46-1.66(m,4H),1.19-1.31(m,4H),1.14(s,3H),1.11(s,3H),1.01-1.10(m,2H),0.93(s,6H).MS(ESI)m/e 757(M-H)-。
实施例40
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苄基)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
实施例40A
2-((4-(4-(3-硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯基磺酰基氨基甲酰基)苯基)哌嗪-1-基)甲基)苯基硼酸
将实施例23C(151mg)和2-甲酰基苯硼酸(54mg)在四氢呋喃(3.5mL)和乙酸(1.1mL)的混合物中混合。加入氰基硼氢化钠树脂(2.38mmol/g树脂,45mg),并将该反应在室温搅拌过夜。用NaHCO3水溶液淬灭反应混合物并用二氯甲烷萃取。用水和用盐水彻底洗涤有机层,在MgSO4上干燥,过滤并在真空下浓缩。然后用乙醚研制粗物质以获得标题化合物。
实施例40B
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苄基)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
硝基-4-((四氢-2H-吡喃-4-基)甲基氨基)苯磺酰基)-2-苯氧基苯甲酰胺
将实施例40A(45mg)、8-((5-溴噻吩-2-基)甲基)-8-氮杂双环[3.2.1]辛烷盐酸盐(27mg)、双(三苯基膦)二氯化钯(II)(5mg)和氢氧化锂(7mg)混合在微波瓶中的二甲氧基乙烷(1.6mL)、甲醇(0.5mL)和水(0.7mL)的混合物中。将反应混合物在CEM Discover微波反应器中在150℃加热15分钟。通过用250x21.20mm、5μ的C18柱的制备HPLC纯化粗物质,用20-100%CH3CN在0.1%三氟乙酸水溶液中的混合物进行梯度洗脱。1H NMR(300MHz,二甲亚砜-d6)δ11.79(br s,1H),8.51(d,1H),8.41(t,1H),7.90(dd,1H),7.73(m,4H),7.60(d,2H),7.41(m,2H),7.35(m,1H),6.81(m,2H),3.83(dd,2H),3.65(s,2H),3.51(s,2H),3.17(m,4H),3.08(m,4H),2.45(m,6H),1.92(m,2H),1.62(m,4H),1.54(m,3H),1.38(m,6H)。
实施例41
4-{4-[金刚烷-1-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例41A
3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯磺酰胺
通过在实施例2D中用四氢-2H-吡喃-4-胺替代环己基甲基胺而制备标题化合物。
实施例41B
4-{4-[金刚烷-1-基羰基)哌嗪-1-基}苯甲酸
通过在实施例8E中用实施例10B替代实施例8D而制备标题化合物。
实施例41C
4-{4-[金刚烷-1-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例8F中用实施例41A替代实施例2D以及用实施例41B替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.05(br s,1H),8.64(d,1H),8.30(d,1H),7.95(dd,1H),7.56(d,2H),7.38(d,1H),6.95(d,2H),3.94(m,1H),3.76(m,2H),3.70(m,4H),3.45(m,2H),3.29(m,4H),1.90(m,11H),1.65(m,8H)。
实施例42
4-{4-[金刚烷-2-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例42A
4-{4-[(金刚烷-2-基羰基]哌嗪-1-基}苯甲酸乙酯
通过在实施例8F中用实施例10A替代实施例8B以及用金刚烷-2-甲酸替代金刚烷-1-甲酸而制备标题化合物。
实施例42B
4-{4-[金刚烷-2-基羰基)哌嗪-1-基}苯甲酸
通过在实施例8E中用实施例42A替代实施例8D而制备标题化合物。
实施例42C
4-{4-[金刚烷-2-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例8F中用实施例41A替代实施例2D以及用实施例42B替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.05(br s,1H),8.64(d,1H),8.30(d,1H),7.95(dd,1H),7.56(d,2H),7.38(d,1H),6.95(d,2H),3.94(m,1H),3.76(m,2H),3.70(m,4H),3.45(m,2H),3.29(m,4H),2.86(s,1H),2.22(s,1H),2.18(s,1H),1.90(m,5H),1.78(m,5H),1.65(m,4H),1.50(m,2H)。
实施例43
4-{5-[金刚烷-1-基羰基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例43A
4-{5-[金刚烷-1-基羰基]-2,5-二氮杂双环[2.2.1]庚-2-基}苯甲酸
通过在实施例8E中用实施例11C替代实施例8D而制备标题化合物。
实施例43B
4-{5-[金刚烷-1-基羰基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例8F中用实施例41A替代实施例2D以及用实施例43A替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.94(br s,1H),8.64(d,1H),8.30(d,1H),7.95(dd,1H),7.76(d,2H),7.38(d,1H),6.62(d,2H),5.03(v br s,1H),4.63(s,1H),3.87(m,3H),3.61(br s,1H),3.48(m,2H),3.30(m,2H),3.04(d,1H),1.90(m,8H),1.80(m,5H),1.60(m,8H)。
实施例44
4-{1S,5S)-3-[金刚烷-1-基羰基]-3,6-二氮杂双环[3.2.0]庚-6-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例44A
(1S,5S)-6-(4-乙氧基羰基)苯基)-3,6-二氮杂双环[3.2.0]庚烷-3-甲酸苄酯
通过在实施例8A中用(1S,5S)-3,6-二氮杂双环[3.2.0]庚烷-3-甲酸苄酯4-甲基苯磺酸盐替代2,6-二氮杂双环[3.2.1]辛烷-6-甲酸苄酯而制备标题化合物。
实施例44B
4-((1R,5S)-3,6-二氮杂双环[3.2.0]庚烷-6-基)苯甲酸乙酯
通过在实施例8B中用实施例44A替代实施例8A而制备标题化合物。
实施例44C
4-[(1S,5S)-3-(金刚烷-1-基羰基)-3,6-二氮杂双环[3.2.0]庚-6-基]苯甲酸乙酯
通过在实施例8C中用实施例44B替代实施例8B而制备标题化合物。
实施例44D
4-[(1S,5S)-3-(金刚烷-1-基羰基)-3,6-二氮杂双环[3.2.0]庚-6-基]苯甲酸
通过在实施例8E中用实施例44C替代实施例8D而制备标题化合物。
实施例44E
4-{(1S,5S)-3-[(1s,3R,5S)-金刚烷-1-基羰基]-3,6-二氮杂双环[3.2.0]庚-6-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例8F中用实施例41A替代实施例2D以及用实施例44D替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.94(br s,1H),8.64(d,1H),8.30(d,1H),7.95(dd,1H),7.56(d,2H),7.38(d,1H),4.71(t,1H),4.29(d,1H),4.20(d,1H),3.97(m,2H)3.86(m,2H),3.48(m,3H),3.21(m,2H),3.11(m,1H),1.85(m,6H),1.76(m,6H),1.60(m,7H)。
实施例45
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-(4-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
实施例45A
4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)苯甲酸乙酯
将-4-氟苯甲酸乙酯(11.65g,69.3mmol)、1,4-二氧杂-8-氮杂螺[4.5]癸烷(9.92g,69.3mmol)和三乙胺(9.66mL,69.3mmol)在N,N-二甲基乙酰胺(80mL)中在80℃搅拌24小时。冷却反应,倒入乙酸乙酯中,用3x水和盐水洗涤并浓缩以获得标题化合物。
实施例45B
4-(4-氧代哌嗪-1-基)苯甲酸乙酯
将实施例45A(20g,68mmol)在二氧杂环己烷(200mL)、乙酸(70mL)和水(150mL)的混合物中在90℃搅拌24小时。浓缩反应混合物并在乙酸乙酯和水之间分配。用盐水洗涤有机层并浓缩。用20%乙酸乙酯/己烷在硅胶上色谱分离残余物以获得标题化合物。
实施例45C
4-(4-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)环己基)苯甲酸乙酯
在Dean-Stark分水器(Dean-Stark trap)下将实施例45B(2.72g,11mmol)和(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺(1.69g,11mmol)在甲苯(50mL)中回流24小时。冷却获得的混合物,加入乙醇(50mL),随后分批加入NaBH4(2.0g)。将混合物搅拌30分钟并加入水。用乙醚萃取该溶液三次,用水和盐水洗涤合并的萃取物并浓缩。用乙酸乙酯在硅胶上色谱分离残余物以获得标题化合物。
实施例45D
4-(4-((3-苯基丙基)((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)氨基)环己基)苯甲酸乙酯
如实施例7A中所述用实施例45C替代实施例6C而制备标题化合物。
实施例45E
4-(4-((3-苯基丙基)((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)氨基)环己基)苯甲酸
如实施例2B中所述用实施例45D替代实施例2A而制备标题化合物。
实施例45F
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-(4-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
如实施例1B中所述用实施例45E替代实施例1A并用实施例41A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.90(s,1H),8.54(s,1H),8.14(d,1H),7.89(d,1H),7.71(d,2H),7.10-7.30(m,6H),6.84(d,2H),3.87(m,4H),3.47(t,2H),3.07(m,2H),2.75(m,2H),2.52(m,2H),2.19(m,2H),1.78-1.99(m,6H),1.53-1.75(m,7H),1.27(m,2H),1.17(m,2H),1.15(s,3H),1.00(m,2H),0.94(s,3H),0.76(d,2H)。
实施例46
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
实施例46A
4-(4-(3-苯基-N-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)丙酰氨基)环己基)苯甲酸乙酯
将3-苯基丙酰氯(0.082mL,0.55mmol)加入实施例45C(192mg,0.5mmol)、三乙胺(0.077mL,0.55mmol)和4-二甲基氨基吡啶(6mg,0.05mmol)在四氢呋喃(5mL)中的溶液中,搅拌反应物24小时。用20-50%乙酸乙酯/己烷在硅胶上色谱分离残余物以获得标题化合物。
实施例46B
4-(4-(3-苯基-N-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)丙酰氨基)环己基)苯甲酸
如实施例2B中所述用实施例46A替代实施例2A而制备标题化合物。
实施例46C
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺
如实施例1B中所述用实施例46B替代实施例1B并用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.90(s,1H),8.61(m,2H),7.92(d,1H),7.72(d,2H),7.20(m,5H),6.90(m,2H),4.07(m,4H),3.93(m,2H),3.18(m,4H),2.65-2.95(m,6H),2.08(m,2H),1.91(m,2H),1.78-1.99(m,6H),1.55-1.76(m,11H),1.22(s,3H),1.17(m,2H),1.01(s,3H),0.99(d,2H),0.90(d,2H)。
实施例47
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例8F中用实施例10D替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.05(br s,1H),8.82(br s,1H),8.62(m,2H),7.96(dd,1H),7.78(d,2H),7.26(d,1H),7.00(d,2H),3.86(br s,1H),3.55(br s,2H),3.30(m,8H),2.96(br s,1H),1.99(s,3H),1.60(m,18H),1.18(m,3H),1.00(m,2H)。
实施例48
6-{3-[金刚烷-1-基]-4-羟苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺
通过在实施例1B中用6-[3-(1-金刚烷基)-4-羟苯基]-2-萘甲酸替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.57(br s,1H),9.52(s,1H),8.68(d,1H),8.61(m,1H),8.54(s,1H),8.27-8.21(m,1H),8.14(s,1H),8.07(d,1H),8.02-7.95(m,3H),7.56-7.47(m,2H),7.25(d,1H),6.91(d,1H),2.16(br s,6H),2.07(br s,4H),1.76-1.65(m,12H),1.25-1.13(m,4H),1.01(t,2H)。
实施例49
4-(4-{2-[金刚烷-1-基]-2-氧代乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例49A
4-(4-{2-[金刚烷-1-基]-2-氧代乙基}哌嗪-1-基)苯甲酸乙酯
将4-(哌嗪-1-基)苯甲酸乙酯(100mg)、1-金刚烷基溴甲基酮(110mg)和碳酸钠(46mg)悬浮在无水乙腈(20mL)中。将该反应混合物在室温下搅拌过夜。用饱和NaHCO3水溶液淬灭反应物并用乙酸乙酯萃取。用水、盐水洗涤有机相,在Na2SO4上干燥,过滤并浓缩以获得标题化合物。
实施例49B
4-(4-{2-[金刚烷-1-基]-2-氧代乙基}哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例49A替代实施例2A而制备标题化合物。
实施例49C
4-(4-{2-[金刚烷-1-基]-2-氧代乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例1B中用实施例49B替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.16(m,1H),8.65(m,2H),7.94(dd,1H),7.81(d,2H),7.26(d,1H),7.02(d,2H),4.58(s,2H),4.01(s,2H),3.29(m,10H),1.71(m,18H),1.17(m,3H),1.00(m,2H)。
实施例50
4-{[金刚烷-2-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例50A
4-[(金刚烷-1-基甲基)-氨基]-苯甲酸乙酯
将4-氟苯甲酸乙酯(336mg)、(2-金刚烷基甲基)胺盐酸盐(504mg)和碳酸钠(636mg)混合在二甲亚砜(5mL)中。将反应物加热至130℃过夜。用乙酸乙酯稀释反应混合物,倒至水中,用水和用盐水彻底洗涤有机层。将合并的有机层在MgSO4上干燥,过滤,并在真空下浓缩。将粗物质通过快速色谱纯化,用9/1己烷/乙醚洗脱。
实施例50B
4-[(金刚烷-1-基甲基)-氨基]-苯甲酸
将实施例50A(365mg)溶解在四氢呋喃(6mL)、甲醇(2mL)和水(2mL)中。将反应物加热至60℃过夜。然后用1M HCl水溶液酸化溶液。通过过滤收集产物并在真空下干燥。
实施例50C
4-{[金刚烷-2-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例1B中用实施例50B替代实施例1A以及用实施例41A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ11.80(s,1H),8.64(d,1H),8.29(d,1H),7.94(dd,1H),7.62(d,2H),7.38(d,1H),6.57(m,3H),3.94(m,1H),3.87(m,2H),3.47(m,2H),3.17(t,2H),1.91(m,6H),1.81(m,5H),1.65(m,6H),1.50(d,2H)。
实施例51
4-{2-[金刚烷-1-基]乙氧基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例51A
4-(2-金刚烷-1-基-乙氧基)-苯甲酸乙酯
将4-羟基苯甲酸乙酯(83mg)和1-金刚烷乙醇(90mg)混合在四氢呋喃(2毫升)中。加入聚合物支持的三苯基膦(250mg of 3mmol/g)和偶氮二羧酸二-叔丁酯(173mg)。将该反应物在室温下搅拌过夜。通过硅藻土过滤除去树脂。将滤液在真空下浓缩,并用95/5己烷/乙醚研磨残余物以获得标题化合物。
实施例51B
4-(2-金刚烷-1-基-乙氧基)-苯甲酸
通过在实施例50B中用实施例51A替代实施例50A而制备标题化合物。
实施例51C
4-{2-[金刚烷-1-基]乙氧基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例1B中用实施例51B替代实施例1A以及用实施例41A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ12.25(s,1H),8.65(d,1H),8.30(d,1H),7.95(dd,1H),7.83(d,2H),7.40(d,1H),7.00(d,2H),4.09(t,2H),3.95(m,1H),3.87(m,2H),3.47(m,2H),1.92(m,5H),1.64(m,8H),1.54(d,6H),1.52(t,2H)。
实施例52
N3-[金刚烷-1-基乙酰基]-N3-苄基-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-β-丙氨酰胺
实施例52A
3-[(2-金刚烷-1-基-乙酰基)苄基-氨基]-丙酸乙酯
通过在实施例1B中用1-金刚烷乙酸替代实施例1A以及用3-(苄基氨基)丙酸乙酯替代4-氯-3-硝基苯磺酰胺而制备标题化合物。
实施例52B
3-[(2-金刚烷-1-基-乙酰基)苄基-氨基]-丙酸
通过在实施例2B中用实施例52A替代实施例2A而制备标题化合物。
实施例52C
N3-[金刚烷-1-基乙酰基]-N3-苄基-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-β-丙氨酰胺
通过在实施例1B中用实施例52B替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.12(br s,1H),8.66(t,1H),8.56(d,1H),7.86(m,1H),7.37-7.21(m,4H),7.09(t,2H),4.45(s,1H),4.34(s,1H),3.39(t,1H),2.47(t,1H),1.97(s,2H),1.86(m,3H),1.78-1.52(m,18H),1.24(s,1H),1.22-1.12(m,6H),0.98(m,2H)。
实施例53
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]哌嗪-1-基}苯甲酰胺
实施例53A
4-(双(2-羟乙基)氨基)苯甲酸乙酯
用Soloway,A.H.,Nyilas,E.,J.Org.Chem.26,1091(1961)所述的方法制备标题化合物。
实施例53B
4-(双(2-(甲基磺酰氧基)乙基)氨基)苯甲酸乙酯
将实施例53A(506mg)溶解在二氯甲烷(10mL)中,并将混合物冷却至-14°(丙酮-冰浴)。加入三乙胺(0.83mL),随后逐滴加入甲磺酰氯(0.46mL),保持温度低于2℃。除去丙酮-冰浴,并在氮气下在室温继续反应3.5小时。将反应物在饱和NaHCO3水溶液和乙醚之间分配。用1MH3PO4两次洗涤有机层,在有机层中形成晶体。过滤混合物并用乙醚洗涤固体材料并干燥以获得产物。
实施例53C
4-(4-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)哌嗪-1-基)苯甲酸乙酯
将实施例53B(409mg)溶解于乙腈(10mL)中,然后加入(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺(0.17mL)、碳酸钾(375mg)和溴化锂(183mg)。在回流下将反应物加热过夜。用水稀释反应物并用乙酸乙酯萃取。用盐水洗涤有机层并在硫酸钠上干燥。过滤混合物,用85/15己烷/乙酸乙酯在硅胶上通过柱色谱法纯化粗物质。
实施例53D
4-(4-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)哌嗪-1-基)苯甲酸
通过在实施例8E中用实施例53C替代实施例8D而制备标题化合物。
实施例53E
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]哌嗪-1-基}苯甲酰胺
通过在实施例8F中用实施例53D替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.15(br s,1H),9.40(br s,1H),8.62(m,2H),7.96(dd,1H),7.80(d,2H),7.26(d,1H),7.03(d,2H),4.14(br s,2H),3.72(br m,2H),3.28(t,2H),3.17(br m,4H),2.30(m,3H),2.00(m,2H),1.83(m,1H),1.70(m,6H),1.20(m,8H),1.07(m,4H),0.95(s,3H)。
实施例54
4-{4-[金刚烷-1-基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例54A
4-[4-(金刚烷-1-基)哌嗪-1-基]苯甲酸乙酯
通过在实施例53C中用金刚烷-1-胺盐酸盐替代(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺而制备标题化合物。
实施例54B
4-[4-(金刚烷-1-基)哌嗪-1-基]苯甲酸
通过在实施例8E中用实施例54A替代实施例8D而制备标题化合物。
实施例54C
4-{4-[金刚烷-1-基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例8F中用实施例54B替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.10(br s,1H),9.18(br s,1H),8.62(m,2H),7.96(dd,1H),7.80(d,2H),7.24(d,1H),7.03(d,2H),4.09(br d,2H),3.65(br m,2H),3.28(t,2H),3.10(br m,4H),2.20(s,3H),1.95(s,6H),1.70(m,12H),1.18(m,3H),1.00(m,2H)。
实施例55
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[3,5-二甲基金刚烷-1-基]哌嗪-1-基}苯甲酰胺
实施例55A
4-[4-(3,5-二甲基金刚烷-1-基)哌嗪-1-基]苯甲酸乙酯
通过在实施例53C中用3,5-二甲基金刚烷-1-胺盐酸盐替代(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺而制备标题化合物。
实施例55B
4-[4-(3,5-二甲基金刚烷-1-基)哌嗪-1-基]苯甲酸
通过在实施例8E中用实施例55A替代实施例8D而制备标题化合物。
实施例55C
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[3,5-二甲基金刚烷-1-基]哌嗪-1-基}苯甲酰胺
通过在实施例8F中用实施例55B替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.10(v br s,1H),9.18(v br s,1H),8.62(m,2H),7.96(dd,1H),7.80(d,2H),7.24(d,1H),7.03(d,2H),4.07(br s,2H),3.62(br s,2H),3.28(t,2H),3.10(br m,4H),2.25(m,1H),1,70(m,12H),1.35(s,3H),1.18(m,6H),1.00(m,2H),0.89(s,6H)。
实施例56
[(3aS,5aR,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[1,3]二氧杂环戊烯并[4,5-b:4′,5′-d]吡喃-3a-基]甲基(4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}苯甲酰基)氨基磺酸盐
通过在实施例1B中用((3aS,5aR,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[1,3]二氧杂环戊烯并[4,5-b:4′,5′-d]吡喃-3a-基)甲基氨基磺酸盐替代4-氯-3硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ7.81(d,2H),7.75(m,1H),7.55(m,4H),7.41(d,2H),7.35(m,1H),6.96(d,2H),4.54(dd,1H),4.35(br s,1H),4.31(d,1H),4.22(t,2H),4.14(d,1H),3.91(br s,2H),3.72(m,2H),3.60(m,3H),3.11(br s,2H),2.91(br s,2H),1.45(s,3H),1.35(s,3H),1.14(d,6H)。
实施例57
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1R,4S)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺
如实施例1B中所述用((1R,4S)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲磺酰胺替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.95(s,1H),7.80(d,2H),7.48(m,5H),7.38(m,2H),7.27(d,1H),6.93(d,2H),3.77(d,1H),3.42(m,3H),3.24(m,4H),2.40(m,4H),2.30(m,1H),2.03(m,1H),1.92(m,2H),1.55(m,1H),1.40(m,1H),1.02(s,3H),0.88(s,3H)。
实施例58
4-(4-{2-[金刚烷-1-基]乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
实施例58A
4-[4-(金刚烷-1-基乙酰基)哌嗪-1-基]苯甲酸乙酯
通过在实施例8C中用实施例10A替代实施例8B以及用1-金刚烷基乙酸替代金刚烷-1-甲酸而制备标题化合物。
实施例58B
4-{4-[2-(金刚烷-1-基)乙基]哌嗪-1-基}苯甲酸乙酯
通过在实施例8D中用实施例58A替代实施例8C而制备标题化合物。
实施例58C
4-{4-[2-(金刚烷-1-基)乙基]哌嗪-1-基}苯甲酸
通过在实施例8E中用实施例58B替代实施例8D而制备标题化合物。
实施例58D
4-(4-{2-[金刚烷-1-基]乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺
通过在实施例8F中用实施例58C替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.10(v br s,1H),9.44(v br s,1H),8.62(m,2H),7.96(dd,1H),7.80(d,2H),7.26(d,1H),7.02(d,2H),4.07(br s,2H),3.60(br s,2H),3.29(t,2H),3.10(m,6H),1.95(s,3H),1.65(m,12H),1.45(m,8H),1.18(m,3H),1.00(m,2H)。
实施例59
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺
如实施例1B中所述用((1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲磺酰胺替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.95(s,1H),7.80(d,2H),7.48(m,5H),7.38(m,2H),7.27(d,1H),6.91(d,2H),3.75(d,1H),3.40(m,3H),3.25(m,4H),2.40(m,4H),2.30(m,1H),2.03(m,1H),1.91(m,2H),1.50(m,1H),1.38(m,1H),1.02(s,3H),0.80(s,3H)。
实施例60
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-({(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}甲基)联苯-4-甲酰胺
实施例60A
4′-甲酰基联苯-4-甲酸甲酯
如实施例4A中所述用4-碘苯甲醛替代1-溴-3-碘苯而制备标题化合物。
实施例60B
4′-(((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)甲基)联苯-4-甲酸甲酯
如实施例7A中所述用(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺替代实施例6C以及用实施例60A替代苯丙醛而制备标题化合物。
实施例60C
4′-((3-苯基-N-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)丙酰氨基)甲基)联苯-4-甲酸甲酯
如实施例46A中所述用实施例60B替代实施例45C而制备标题化合物。
实施例60D
4′-((3-苯基-N-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)丙酰氨基)甲基)联苯-4-甲酸
如实施例2B中所述用实施例60C替代实施例2A而制备标题化合物。
实施例60E
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-({(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}甲基)联苯-4-甲酰胺
如实施例1B中所述用实施例60D替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.90(s,1H),8.63(d,1H),8.59(m,1H),7.94(m,3H),7.73(d,2H),7.68(d,1H),7.62(d,1H),7.05-7.26(m,7H),4.61(m,1H),4.36(m,1H),2.88(m,3H),2.30(m,3H),1.66(m,10H),1.20(m,2H),1.19(s,3H),1.17(s,3H),0.87-1.06(m,10H)。
实施例61
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苯亚甲基}哌啶-1-基)苯甲酰胺
实施例61A
4-(4-氧代哌啶-1-基)苯甲酸甲酯
用Bruncko等,J.Med.Chem.2007,50,641-662所述的方法制备本实施例。
实施例61B
4-(4-(2-溴苯亚甲基)哌啶-1-基)苯甲酸甲酯
将含有氢化钠(0.332g)的二甲亚砜(22.88mL)加热至70℃1小时,将混合物冷却至室温并以数部分加入(2-溴苄基)三苯基溴化鏻(3.40g)。将该反应混合物在室温搅拌1小时。然后加入实施例61A(1.8g)在二甲亚砜(5.20mL)中的溶液,整个周末在70℃加热反应物。用1M HCl水溶液酸化反应混合物并用乙醚萃取。用水和用盐水彻底洗涤有机层,在MgSO4上干燥,过滤并在真空下浓缩。将粗物质通过快速色谱纯化,用100%己烷-20%乙酸乙酯/己烷洗脱。
实施例61C
4-(4-(2-((1R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基)苯亚甲基)哌啶-1-基)苯甲酸
通过在实施例40B中用(1S)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基硼酸替代实施例40A以及用实施例61B替代8-((5-溴噻吩-2-基)甲基)-8-氮杂双环[3.2.1]辛烷盐酸盐而制备标题化合物。
实施例61D
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苯亚甲基}哌啶-1-基)苯甲酰胺
通过在实施例1B中用实施例61C替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ11.97(s,1H),8.64(m,2H),7.93(dd,1H),7.74(d,2H),7.30(d,1H),7.21(m,2H),7.14(m,1H),6.95(d,2H),6.36(s,1H),5.87(d,1H),3.84(m,2H),3.48(m,2H),3.40,3.32,3.24(所有m,总共6H),2.40(t,1H),2.34(m,4H),1.90(m,2H),1.61(m,3H),1.27(m,3H),1.06(m,1H),0.94(s,3H),0.83(s,3H),0.79(s,3H)。
实施例62
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苄基}哌嗪-1-基)苯甲酰胺
实施例62A
4-(4-(2-溴苄基)哌嗪-1-基)苯甲酸乙酯
用Bruncko等,J.Med.Chem.2007,50,641-662所述的方法制备本实施例。
实施例62B
4-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基)哌嗪-1-基)苯甲酸乙酯
将三(二亚苄基丙酮)二钯(0)(0.284g)和三环己基膦(0.417g)在二氧杂环己烷(75mL)中的溶液在室温搅拌30分钟。加入实施例62A(5g)、4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-双(1,3,2-二氧硼杂环戊烷)(3.46g)和乙酸钾(1.825g),并将反应物加热至85℃36小时。用乙酸乙酯稀释反应混合物,用水和用盐水彻底洗涤。将合并的有机层在MgSO4上干燥,过滤,并在真空下浓缩。用己烷并用己烷/乙醚(2∶1)洗涤粗固体以获得标题化合物。
实施例62C
4-(4-(2-(5-(4-苯基噻唑-2-基)噻吩-2-基)苄基)哌嗪-1-基)苯甲酸
通过在实施例40B中用实施例62B替代实施例40A以及用2-(5-溴噻吩-2-基)-4-苯基噻唑替代8-((5-溴噻吩-2-基)甲基)-8-氮杂双环[3.2.1]辛烷盐酸盐而制备标题化合物。
实施例62D
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苄基}哌嗪-1-基)苯甲酰胺
通过在实施例1B中用实施例62C替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.79(s,1H),8.64(s,1H),8.59(s,1H),8.06(br s,1H),7.99(d,1H),7.83(d,2H),7.60(d,2H),7.50(m,3H),7.36(d,1H),7.11(m,3H),7.01(m,4H),6.97(d,1H),3.71(m,2H),3.60(m,4H),3.45(m,4H),3.02(m,2H),2.60(m,4H),1.83(m,1H),1.56(m,4H)。
实施例63
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苄基)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
1H NMR(400MHz,二甲亚砜-d6)δppm 12.04(s,1H),8.66(t,1H),8.63(d,1H),7.93(dd,1H),7.75(d,3H),7.63(d,1H),7.57(s,3H),7.29(d,1H),7.20-7.26(m,2H),6.95(d,2H),4.56(s,1H),3.78-3.89(m,2H),3.31-3.37(m,6H),3.26(dd,4H),2.97-3.18(m,2H),2.04(s,3H),1.93(s,3H),1.93(s,3H),1.57-1.80(m,10H),1.21-1.40(m,5H).MS(ESI)m/e891(M-H)-。
实施例64
5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-(2-苯基-1,3-苯并噁唑-5-基)-2-糠酰胺
1H NMR(400MHz,二甲亚砜-d6)δppm 12.09(s,1H),10.46(s,1H),9.27(s,1H),8.59-8.70(m,2H),8.29(d,1H),8.22(dd,2H),8.02(d,1H),7.94(dd,1H),7.75-7.84(m,3H),7.59-7.73(m,7H),7.50-7.57(m,1H),7.34(s,1H),7.29(d,1H),7.05(d,2H),4.71(s,1H),4.14(s,1H),3.72-3.90(m,3H),3.20-3.32(m,4H),1.83-1.97(m,1H),1.61(d,2H),1.16-1.33(m,3H).MS(ESI)m/e 894(M-H)-。
实施例65
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(三苯基乙烯基)苄基]哌嗪-1-基}苯甲酰胺
实施例65A
4-(4-(2-(1,2,2-三苯基乙烯基)苄基)哌嗪-1-基]苯甲酸
通过在实施例40B中用实施例62B替代实施例40A以及用溴三苯亚乙烯替代8-((5-溴噻吩-2-基)甲基)-8-氮杂双环[3.2.1]辛烷盐酸盐而制备标题化合物。
实施例65B
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(三苯基乙烯基)苄基]哌嗪-1-基}苯甲酰胺
通过在实施例1B中用实施例65A替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ11.97(s,1H),8.63(s,1H),8.07(br s,1H),7.99(d,1H),7.60(d,2H),7.42(m,6H),7.30(m,4H),7.26(m,6H),7.07(m,2H),6.99(m,4H),3.82(br s,2H),3.60(m,4H),3.45(m,4H),3.02(m,2H),2.62(m,4H),1.83(m,1H),1.56(m,4H)。
实施例66
4-{4-[2-(5-甲基-5,6-二氢菲啶-6-基)苄基]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23F中用2-(5-甲基-5,6-二氢-菲啶-6-基)-苯甲醛替代实施例23E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.03(br s,1H),8.57(d,1H),8.53(t,1H),7.92(dd,1H),7.90(d,2H),7.83(dd,1H),7.76(d,2H),7.41(d,1H),7.28-6.99(m,6H),6.92(d,2H),6.77(td,1H),6.59(dd,1H),6.13(s,1H),3.91(d,1H),3.85(dd,2H),3.65(d,1H),3.30-3.23(m,2H),2.78(s,3H),2.70-2.53(m,5H),1.91(s,3H),1.90(m,1H),1.62(dd,2H),1.38-1.20(m,6H),0.86(m,2H)。
实施例67
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基]哌嗪-1-基}苯甲酰胺
通过在实施例23F中用(2-甲酰基苯基)硼酸频哪醇酯替代实施例23E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.94(br s,1H),8.60(d,1H),7.94-7.89(m,1H),7.75(d,2H),7.62(m,1H),7.50-7.21(m,4H),7.25(d,1H),6.92(d,2H),3.84(dd,2H),3.36-3.32(m,8H),2.51(br s,2H),1.91(s,3H),1.62(dt,2H),1.30(br s,9H),1.26(dd,2H),1.16(s,6H),1.07(s,2H)。
实施例68
4-(4-{2-[2-(2,6-二甲氧基苯甲酰基)-3-噻吩基]苯亚甲基}哌啶-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
实施例68A
4-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯亚甲基)哌嗪-1-基)苯甲酸甲酯
将实施例61B(259mg)、双(频哪醇)二硼(bis(pinacolato)diboron)(206mg)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷(22mg)和乙酸钾(159mg)混合在二甲亚砜(2.7mL)中。将反应混合物在90℃加热36小时。用乙酸乙酯稀释反应混合物,用水和用盐水彻底洗涤,在MgSO4上干燥,过滤并在真空下浓缩。用己烷并用己烷/乙醚(2∶1)洗涤粗固体以获得标题化合物。
实施例68B
4-(4-(2-(2-(2,6-二甲氧基苯甲酰基)噻吩-3-基)苯亚甲基)哌啶-1-基)苯甲酸乙酯
将实施例68A(0.043g)、(3-溴噻吩-2-基)(2,6-二甲氧基苯基)甲酮(0.03114g)、四(三苯基膦)钯(0)(11.00mg)和氟化铯(0.043g)混合在1,2-二甲氧基乙烷(0.333m1)和乙醇(0.143ml)中。将反应物在90℃加热2小时。用乙酸乙酯稀释反应混合物,倒入水中,用水和用盐水彻底洗涤。将合并的有机层在MgSO4上干燥,过滤,并在真空下浓缩。将粗物质通过快速色谱纯化,用1%甲醇/二氯甲烷至5%甲醇/二氯甲烷进行梯度洗脱。
实施例68C
4-(4-(2-(2-(2,6-二甲氧基苯甲酰基)噻吩-3-基)苯亚甲基)哌啶-1-基)苯甲酸
通过在实施例50B中用实施例68B替代实施例50A而制备标题化合物。
实施例68D
4-(4-{2-[2-(2,6-二甲氧基苯甲酰基)-3-噻吩基]苯亚甲基}哌啶-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1B中用实施例68C替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ11.95(s,1H),8.63(m,2H),7.93(dd,1H),7.87(d,1H),7.72(d,2H),7.27(d,1H),7.20(s,1H),7.09(m,3H),6.93(m,4H),6.40(d,2H),5.99(s,1H),3.83(dd,2H),3.60(s,6H),3.26(m,6H),2.31(m,2H),2.22(m,2H),1.90(br s,1H),1.60(m,2H),1.26(m,4H)。
实施例69
1-[金刚烷-1-基]-4-{2-[(1-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌啶-4-亚基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺
实施例69A
4-{4-[2-(1-金刚烷-1-基-3-二苯基氨基甲酰基-1H-吡唑-4-基)-苯亚甲基]-哌啶-1-基}-苯甲酸乙酯
通过在实施例68B中用1-金刚烷-1-基-4-溴-1H-吡唑-3-甲酸二苯胺替代(3-溴噻吩-2-基)(2,6-二甲氧基苯基)甲酮而制备标题化合物。
实施例69B
4-{4-[2-(1-金刚烷-1-基-3-二苯基氨基甲酰基-1H-吡唑-4-基)-苯亚甲基]-哌啶-1-基}-苯甲酸
通过在实施例50B中用实施例69A替代实施例50A而制备标题化合物。
实施例69C
1-[金刚烷-1-基]-4-{2-[(1-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌啶-4-亚基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺
通过在实施例1B中用实施例69B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ11.95(s,1H),8.64(m,2H),7.93(dd,1H),7.43(d,2H),7.52(s,1H),7.26(m,4H),7.19(m,4H),7.13(m,3H),6.91(m,6H),5.58(s,1H),3.83(dd,2H),3.47(t,2H),3.25(m,6H),2.23(m,4H),2.07(m,3H),1.89(m,6H),1.62(m,8H),1.26(m,3H)。
实施例70
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基(3-苯基丙酰基)氨基]苄基}哌嗪-1-基)苯甲酰胺
实施例70A
4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基(3-苯基丙酰基)氨基]苄基}哌嗪-1-基)苯甲酸乙酯
将实施例16C(60mg)、3-苯基丙酰氯(22mg)和二异丙基乙胺(0.05mL)溶解在无水二氯甲烷(3mL)中。将该反应混合物在室温下搅拌过夜。用饱和NaHCO3水溶液淬灭反应物并用乙酸乙酯萃取。用水和盐水洗涤有机相,在Na2SO4上干燥,过滤并浓缩。用0-5%甲醇/二氯甲烷通过快速色谱纯化法纯化残余物以获得标题化合物。
实施例70B
4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基(3-苯基丙酰基)氨基]苄基}哌嗪-1-基)苯甲酸
通过在实施例2B中用实施例70A替代实施例2A而制备标题化合物。
实施例70
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基(3-苯基丙酰基)氨基]苄基}哌嗪-1-基)苯甲酰胺
通过在实施例1B中用实施例70B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(400MHz,二甲亚砜-d6)δ12.03(m,1H),8.64(m,2H),7.93(dd,1H),7.76(d,2H),7.58(s,1H),7.39(m,2H),7.28(d,1H),7.18(m,3H),7.00(m,5H),4.32(m,1H),3.83(m,2H),3.26(m,8H),2.81(m,6H),2.19(m,2H),1.90(m,4H),1.67(m,7H),1.22(m,11H)。
实施例71
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苯亚甲基)哌啶-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
实施例71A
4-(4-(2-(5-(8-氮杂双环[3.2.1]辛烷-8-基甲基)噻吩-2-基)苯亚甲基)哌啶-1-基)苯甲酸乙酯
通过在实施例68B中用8-((5-溴噻吩-2-基)甲基)-8-氮杂双环[3.2.1]辛烷盐酸盐替代(3-溴噻吩-2-基)(2,6-二甲氧基苯基)甲酮而制备标题化合物。
实施例71B
4-(4-(2-(5-(8-氮杂双环[3.2.1]辛烷-8-基甲基)噻吩-2-基)苯亚甲基)哌啶-1-基)苯甲酸
通过在实施例50B中用实施例71A替代实施例50A而制备标题化合物。
实施例71C
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苯亚甲基)哌啶-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1B中用实施例71B替代实施例1A以及用实施例23A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.54(s,1H),9.36(br s,1H),8.48(d,1H),7.76(dd,1H),7.53(m,3H),7.34(m,3H),7.00(m,1H),6.84(d,2H),6.81(dd,1H),6.44(d,1H),6.37(br s,1H),4.36(d,2H),3.82(m,3H),3.36(m,2H),3.26(m,4H),3.18(m,2H),2.36(m,3H),2.23(m,4H),1.90(m,3H),1.81(m,2H),1.62(m,5H),1.40(m,3H)。
实施例72
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺
实施例72A
4-(4-(4-溴苯亚甲基)哌啶-1-基)苯甲酸乙酯
通过在实施例61B中用(4-溴苄基)三苯基溴化膦替代(2-溴苄基)三苯基溴化膦而制备标题化合物。
实施例72B
4-(4-(4-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)苯亚甲基)哌啶-1-基)苯甲酸乙酯
将实施例72A(40mg)、(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-胺(100μl)、2,2′-双(二苯基膦基)-1,1′-联萘(9.2mg,)、乙酸钯(II)(2.4mg)和叔丁醇钠(14mg)加入甲苯(0.2mL)中,反应物用氮气净化并在100℃加热过夜。冷却反应,然后用水稀释并用乙酸乙酯萃取。用盐水洗涤有机层并在硫酸钠上干燥。过滤并浓缩后,用94/6己烷/乙酸乙酯在硅胶上通过柱色谱法纯化粗物质。
实施例72C
4-(4-(4-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)苯亚甲基)哌啶-1-基)苯甲酸
通过在实施例8E中用实施例72B替代实施例8D而制备标题化合物。
实施例72D
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺
通过在实施例8F中用实施例72C替代实施例8E以及用实施例23A替代实施例2D而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.97(br s,1H),8.65(t,1H),8.63(d,1H),7.95(dd,1H),7.76(d,2H),7.28(d,1H),7.06(br s,2H),6.95(d,2H),6.90(v br s,2H),6.26(s,1H),3.85(m,2H),3.50(m,5H),3.33(t,2H),3.25(m,2H),2.38(m,3H),2.00(m,1H),1.94(m,2H),1.80(m,1H),1.60(m,3H),1.25(m,5H),1.21(s,3H),1.09(d,1H),1.00(s,6H)。
实施例73
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺
实施例73A
4-(4-(3-溴苯亚甲基)哌啶-1-基)苯甲酸乙酯
通过在实施例61B中用(3-溴苄基)三苯基溴化膦替代(2-溴苄基)三苯基溴化膦而制备标题化合物。
实施例73B
4-(4-(3-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)苯亚甲基)哌啶-1-基)苯甲酸乙酯
通过在实施例72B中用实施例73A替代实施例72A而制备标题化合物。
实施例73C
4-(4-(3-((1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氨基)苯亚甲基)哌啶-1-基)苯甲酸
通过在实施例8E中用实施例73B替代实施例8D而制备标题化合物。
实施例73D
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺
通过在实施例8F中用实施例73C替代实施例8E以及用实施例23A替代实施例2D而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.00(br s,1H),8.68(t,1H),8.63(d,1H),7.95(dd,1H),7.76(d,2H),7.30(d,1H),7.18(v br s,2H),6.96(d,2H),6.75(v br s,2H),6.26(s,1H),3.85(m,2H),3.50(m,5H),3.37(t,2H),3.25(m,2H),2.40(m,2H),2.37(m,1H),2.00(m,1H),1.94(m,2H),1.80(m,1H),1.60(m,3H),1.25(m,5H),1.20(s,3H),1.12(d,1H),1.00(s,6H)。
实施例74
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苯亚甲基)哌啶-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
1H NMR(400MHz,二甲亚砜-d6)δppm 11.96(s,1H),8.59-8.72(m,2H),7.93(dd,1H),7.72(d,2H),7.64(dd,1H),7.54(d,1H),7.22-7.40(m,4H),7.16(s,1H),6.94(d,2H),6.43(s,1H),3.83(dd,2H),3.53-3.62(m,2H),3.37-3.43(m,4H),3.19-3.29(m,2H),2.40-2.46(m,2H),2.28-2.36(m,2H),1.97(s,2H),1.83-1.93(m,5H),1.55-1.70(m,6H),1.18-1.31(m,2H).MS(ESI)m/e 888(M-H)-。
实施例75
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苯亚甲基)哌啶-1-基)苯甲酰胺
1H NMR(400MHz,二甲亚砜-d6)δppm 11.97(s,1H),8.58-8.71(m,2H),8.08(s,1H),7.89-7.98(m,3H),7.88-7.98(m,3H),7.74(d,2H),7.63-7.71(m,2H),7.24-7.46(m,8H),6.97(d,2H),6.47(s,1H),3.83(dd,2H),3.57-3.67(m,2H),3.38-3.46(m,2H),3.33-3.37(m,2H),3.19-3.29(m,4H),2.40-2.48(m,2H),2.29-2.37(m,2H),1.82-1.98(m,1H),1.61(d,2H),1.16-1.32(m,2H).MS(ESI)m/e 830(M-H)-。
实施例76
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-氧代-4H-色烯-6-基)苯甲酰胺
实施例76A
4-(4-氧代-4H-色烯-6-基)苯甲酸
如实施例4A中所述用4-羧基苯硼酸替代4-(甲氧基羰基)苯基硼酸以及用6-溴-4H-色烯-4-酮替代1-溴-3-碘苯而制备标题化合物。
实施例76B
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-氧代-4H-色烯-6-基)苯甲酰胺
如实施例1B中所述用实施例76A替代实施例1A以及用4-[(金刚烷-1-基甲基)氨基]-3-硝基苯磺酰胺替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.95(s,1H),8.52(d,1H),8.40(t,1H),8.33(d,1H),8.25(d,1H),8.15(d,1H),8.00(d,2H),7.89(d,1H),7.73(m,2H),7.16(d,1H),6.40(d,1H),4.03(m,1H),3.13(d,2H),1.99(m,3H),1.65(m,3H),1.58(s,6H)。
实施例77
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(1-辛基-1H-吡唑-4-基)苯甲酰胺
实施例77A
4-碘代-1-辛基-1H-吡唑
将4-碘代-1H-吡唑(1.25g,6.44mmol)加入NaH(在矿物油中60%,271mg,6.77mmol)在N,N-二甲基甲酰胺(20mL)中的浆,搅拌反应物30分钟。然后加入1-辛基溴化物(1.22mL,7.08mmol),搅拌反应物24小时。将混合物倒入水(200mL)中,用乙醚将获得的溶液萃取三次。用水和盐水将合并的乙醚萃取物洗涤三次,在Na2SO4上干燥,过滤并浓缩以获得标题化合物。
实施例77B
4-(1-辛基-1H-吡唑-4-基)苯甲酸
如实施例4A中所述用4-羧基苯硼酸替代4-(甲氧基羰基)苯硼酸以及实施例77A替代1-溴-3-碘苯而制备标题化合物。
实施例77C
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(1-辛基-1H-吡唑-4-基)苯甲酰胺
如实施例1B中所述用实施例77B替代实施例1A以及用4-[(金刚烷-1-基甲基)氨基]-3-硝基苯磺酰胺替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.95(s,1H),8.55(d,1H),8.43(t,1H),8.23(s,1H),7.90(m,3H),7.55(d,2H),7.19(d,1H),4.03(m,1H),3.14(d,2H),1.97(m,3H),1.78(t,2H),1.65(m,5H),1.58(s,6H),1.23(br s,10H),0.84(t,3H)。
实施例78
4-[5-(4-{[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]氨基甲酰基}苯基)-1,3-苯并噻唑-2-基]丁酸
实施例78A
4-[(金刚烷-1-基甲基)-氨基]-3-硝基-苯磺酰胺
通过在实施例2D中用1-金刚烷甲胺替代环己基甲胺而制备标题化合物。
实施例78B
4-(5-溴-苯并噻唑-2-基)-丁酸甲酯
将5-溴-2-甲基苯并噻唑(1000mg)溶解在四氢呋喃(25mL)中,用异丙醇/干冰浴将混合物冷却至-78℃。加入二异丙基氨基锂(在环己烷中1.5M,4.40mL),并将该溶液在-78℃搅拌30分钟。加入3-溴丙酸甲酯(1.20mL,1836mg)并将该溶液在-78℃下搅拌2小时。用1M盐酸水溶液淬灭反应物,用乙酸乙酯萃取,用盐水洗涤,在无水硫酸钠上干燥,过滤,浓缩,并用5%乙酸乙酯/己烷在硅胶上通过快速柱色谱法纯化。
实施例78C
4-[2-(3-乙氧羰基-丙基)-苯并噻唑-5-基]-苯甲酸
实施例78B(275mg)、4-羧基苯硼酸(160mg)、碳酸钠(2M水溶液,1.1mL)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷加合物(65mg)加入已脱气并用氮气冲洗3次的二甲基甲酰胺(1.5mL)、乙醇(1.5mL)和水(0.5mL)中。将该溶液加热至90℃并搅拌16小时。冷却溶液,加入水中,用乙酸乙酯萃取,用盐水洗涤,在无水硫酸钠上干燥,过滤,浓缩,并用5%甲醇/乙酸乙酯在硅胶上通过快速柱色谱法纯化并通过与乙醇溶剂转酯以获得乙酯产物。
实施例78D
4-[5-(4-{4-[(金刚烷-1-基甲基)-氨基]-3-硝基-苯基磺酰基氨基羰基}-苯基)-苯并噻唑-2-基]-丁酸乙酯
通过在实施例1B中用实施例78C替代实施例1A以及用实施例78A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。
实施例78E
4-[5-(4-{[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]氨基甲酰基}苯基)-1,3-苯并噻唑-2-基]丁酸
通过在实施例2B中用实施例78D替代实施例2A而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.52(br s,1H),12.13(br s,1H),8.68(d,1H),8.59(t,1H),8.31(d,1H),8.17(d,1H),8.00-7.91(m,5H),7.78(dd,1H),7.38(d,1H),3.22-3.13(m,4H),2.39(t,2H),2.05(m,2H),1.97(br s,4H),2.66(m,4H),1.58(br s,6H),0.86(m,1H)。
实施例79
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-[(1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛-3-基]苯甲酰胺
实施例79A
4-((1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛烷-3-基)苯甲酸乙酯
通过在实施例8A中用(1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛烷替代2,6-二氮杂双环[3.2.1]辛烷-6-甲酸苄酯而制备标题化合物。
实施例79B
4-((1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛烷-3-基)苯甲酸
通过在实施例8E中用实施例79A替代实施例8D而制备标题化合物。
实施例79C
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-[(1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛-3-基]苯甲酰胺
通过在实施例8F中用实施例41A替代实施例2D以及用实施例79B替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ11.99(br s,1H),8.63(d,1H),8.28(d,1H),7.95(dd,1H),7.74(d,2H),7.39(d,1H),6.80(d,2H),3.95(m,1H),3.88(m,2H),3.47(m,2H),3.40(d,1H),3.22(d,1H),3.18(d,1H),2.84(d,1H),1.90(m,4H),1.62(m,4H),1.40(m,1H),0.92(s,3H),0.90(s,6H)。
实施例80
6-{3-[金刚烷-1-基]-4-甲氧基苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺
通过在实施例1B中用6-(3-金刚烷-1-基-4-甲氧基-4-苯基)-萘-2-甲酸替代实施例1A以及用实施例2D替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.57(br s,1H),8.70(d,1H),8.65(t,1H),8.57(s,1H),8.21(s,1H),8.10(d,1H),8.06(d,1H),8.00(dd,1H),7.88(m,2H),7.66(dd,1H),7.58(d,1H),7.28(d,1H),7.13(d,1H),3.87(s,3H),2.63(br s,6H),2.07(br s,4H),1.78-1.62(m,12H),1.26-1.15(m,4H),1.01(t,2H)。
实施例81
4-{4-[金刚烷-1-基乙酰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例81A
4-[4-(金刚烷-1-基乙酰基)哌嗪-1-基]苯甲酸
通过在实施例8E中用实施例58A替代实施例8D而制备标题化合物。
实施例81B
4-{4-[金刚烷-1-基乙酰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例8F中用实施例41A替代实施例2D以及用实施例81A替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.05(br s,1H),8.64(d,1H),8.30(d,1H),7.95(dd,1H),7.76(d,2H),7.40(d,1H),6.95(d,2H),3.94(m,1H),3.87(m,2H),3.60(m,4H),3.45(m,2H),3.29(m,4H),2.15(s,2H),1.90(m,5H),1.60(m,14H)。
实施例82
4-{[金刚烷-1-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例82A
4-{[金刚烷-1-基甲基]氨基}苯甲酸乙酯
通过在实施例50A中用1-金刚烷甲胺替代(2-金刚烷基甲基)胺盐酸盐而制备标题化合物。
实施例82B
4-{[金刚烷-1-基甲基]氨基}苯甲酸
通过在实施例50B中用实施例82A替代实施例50A而制备标题化合物。
实施例82C
4-{[金刚烷-1-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例1B中用实施例82B替代实施例1A以及用实施例41A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。
实施例83
N-{1-[4-({[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}氨基甲酰基)苯基]哌啶-4-基}金刚烷-1-甲酰胺
实施例83A
4-(4-(叔丁氧羰基氨基)哌啶-1-基)苯甲酸乙酯
通过在实施例8A中用哌啶-4-基氨基甲酸叔丁酯替代2,6-二氮杂双环[3.2.1]辛烷-6-甲酸苄酯而制备标题化合物。
实施例83B
4-(4-氨基哌啶-1-基)苯甲酸乙酯
通过在实施例11B中用实施例83A替代实施例11A而制备标题化合物。
实施例83C
4-{4-[(金刚烷-1-基羰基)氨基]哌啶-1-基}苯甲酸乙酯
通过在实施例8C中用实施例83B替代实施例8B而制备标题化合物。
实施例83D
4-{4-[(金刚烷-1-基羰基)氨基)哌啶-1-基}苯甲酸
通过在实施例8E中用实施例83C替代实施例8D而制备标题化合物。
实施例83E
N-{1-[4-({[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}氨基甲酰基)苯基]哌啶-4-基}金刚烷-1-甲酰胺
通过在实施例8F中用实施例41A替代实施例2D以及用实施例83D替代实施例8E而制备标题化合物。1H NMR(300MHz,二甲亚砜-d6)δ12.00(br s,1H),8.64(d,1H),8.30(d,1H),7.95(dd,1H),7.76(d,2H),7.39(d,1H),7.10(d,1H),6.92(d,2H),3.90(m,6H),3.45(m,2H),2.92(m,2H),1.90(br s,6H),1.70(m,15H),1.45(m,2H)。
实施例84
4-[金刚烷-2-基氨基]-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
实施例84A
4-[金刚烷-2-基氨基]苯甲酸乙酯
通过在实施例50A中用2-金刚烷胺盐酸盐替代(2-金刚烷基甲基)胺盐酸盐而制备标题化合物。
实施例84B
4-[金刚烷-2-基氨基]苯甲酸
通过在实施例50B中用实施例84A替代实施例50A而制备标题化合物。
实施例84C
4-[金刚烷-2-基氨基]-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺
通过在实施例1B中用实施例84B替代实施例1A以及用实施例41A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ11.82(s,1H),8.63(d,1H),8.29(d,1H),7.94(dd,1H),7.61(d,2H),7.38(d,1H),6.64(d,2H),3.95(m,1H),3.88(m,2H),3.36(m,1H),3.47(m,2H),2.01(m,2H),1.92(m,4H),1.83(m,6H),1.70(m,4H),1.50(m,2H)。
实施例85
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氧基}苯甲酰胺
实施例85A
4-((1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氧基)苯甲酸乙酯
将4-碘苯甲酸乙酯(276mg)、(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-醇(154mg)、1,10-菲咯啉(36mg)、碘化铜(19mg)和碳酸铯(652mg)混合在甲苯(0.5mL)中。将反应物加热至120℃超过36小时。将反应混合物从热源移开,放置冷却,用乙酸乙酯稀释并倒入水中。用水和盐水彻底洗涤有机相,在MgSO4上干燥,过滤并在真空下浓缩。将粗物质通过快速色谱纯化,用95/5己烷/乙醚洗脱。
实施例85B
4-((1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚烷-3-基氧基)苯甲酸
通过在实施例50B中用实施例85A替代实施例50A而制备标题化合物。
实施例85C
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氧基}苯甲酰胺
通过在实施例1B中用实施例85B替代实施例1A以及用实施例41A替代4-氯-3-硝基苯磺酰胺而制备标题化合物。1H NMR(500MHz,二甲亚砜-d6)δ12.26(br s,1H),8.66(d,1H),8.30(d,1H),7.95(dd,1H),7.82(d,2H),7.40(d,1H),7.03(d,2H),4.67(m,1H),3.96(m,1H),3.88(m,2H),3.47(m,3H),2.65(m,1H),2.36(m,1H),2.25(m,1H),1.93(m,3H),1.85(m,1H),1.64(m,3H),1.23(s,3H),1.10(d,3H),0.99(s,3H)。
Claims (4)
1.选自如下的化合物:
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-[(3-硝基-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯基)磺酰基]苯甲酰胺;
4-(4-{乙酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-(4-{苯甲酰基[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-3′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(苯基乙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}联苯-4-甲酰胺;
4-{6-[金刚烷-1-基甲基]-2,6-二氮杂双环[3.2.1]辛-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-[(三氟甲基)磺酰基]苯基)磺酰基]-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-[(4-{[(2R)-4-(吗啉-4-基)-1-(苯硫基)丁烷-2-基]氨基}-3-硝基苯基}磺酰基]苯甲酰胺;
4-{(1S,4S)-5-[金刚烷-1-基甲基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-(4-{[(1R,5R)-3-溴-5-甲基金刚烷-1-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{[3,5-二甲基金刚烷-1-基]甲基}哌嗪-1-基)苯甲酰胺;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-{[4-(1-甲基-2-氧代-3-氮杂双环[3.1.1]庚-3-基)苯基]磺酰基}苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-八氢-1H-4,7-亚甲基茚-5-基氨基]苄基}哌嗪-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,4R,6S)-5,5,6-三甲基双环[2.2.1]庚-2-基]氨基}苄基)哌嗪-1-基]苯甲酰胺;
4-[4-(2-{[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-基]氨基}苄基)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;
4-(4-{[(1R,5R)-2-(4-氯苯基)-6,6-二甲基双环[3.1.1]庚-2-烯-3-基]甲基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{4-[(2-{[金刚烷-2-基甲基]氨基}-5,5-二甲基环己基)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;
4-{4-[(5,5-二甲基-2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}环己基)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;
4-{4-[2-(3-氮杂双环[3.2.2]壬-3-基)-5-硝基苄基]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;
4-(4-{2-[2,3,3a,4,7,7a-六氢-1H-4,7-亚甲基茚-5-基]苄基}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;
1-[金刚烷-1-基]-4-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺;
4-(4-{2-[2-(金刚烷-1-基)-6-甲基咪唑并[1,2-a]吡啶-8-基]苄基}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;
N-(金刚烷-2-基)-6-甲基-8-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}咪唑并[1,2-a]吡啶-2-甲酰胺;
4-(4-{2-[(1R,5S)-6,6-二甲基双环[3.1.1]庚-2-烯-2-基]苄基}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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5,5,6-三甲基双环[2.2.1]庚-2-烯-2-基]苄基}哌嗪-1-基)苯甲酰胺;
N-环辛基-5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-2-糠酰胺;
N-苄基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
4-[4-(2-{[(1R,5S)-8-甲基-8-氮杂双环[3.2.1]辛-3-基]氨基}苄基)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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(2-{[(1R,2S,3S,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苄基)哌嗪-1-基]苯甲酰胺;
4-(4-{2-[3-氮杂双环[3.2.2]壬-3-基]苄基}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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[三环[4.3.1.13,8]十一碳-4-烯-4-基]苄基}哌嗪-1-基)苯甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-苯基双环[2.2.1]庚-2-烯-1-甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]双环[2.2.1]庚-2-烯-1-甲酰胺;
N-(金刚烷-1-基甲基)-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
N-环丙基-7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酰胺;
7,7-二甲基-2-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}双环[2.2.1]庚-2-烯-1-甲酸;
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苄基)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;
4-{4-[金刚烷-1-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{4-[金刚烷-2-基羰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{5-[金刚烷-1-基羰基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{1S,5S)-3-[金刚烷-1-基羰基]-3,6-二氮杂双环[3.2.0]庚-6-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-(4-{(3-苯基丙基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-(4-{(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}哌啶-1-基)苯甲酰胺;
4-{4-[金刚烷-1-基甲基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
6-{3-[金刚烷-1-基]-4-羟苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺;
4-(4-{2-[金刚烷-1-基]-2-氧代乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{[金刚烷-2-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{2-[金刚烷-1-基]乙氧基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N3-[金刚烷-1-基乙酰基]-N3-苄基-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-β-丙氨酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]哌嗪-1-基}苯甲酰胺;
4-{4-[金刚烷-1-基]哌嗪-1-基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4-{4-[3,5-二甲基金刚烷-1-基]哌嗪-1-基}苯甲酰胺;
[(3aS,5aR,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[1,3]二氧杂环戊烯并[4,5-b4′,5′-d]吡喃-3a-基]甲基;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1R,4S)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺;
4-(4-{2-[金刚烷-1-基]乙基}哌嗪-1-基)-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)苯甲酰胺;
4-{4-[(4′-氯联苯-2-基)甲基]哌嗪-1-基}-N-({[(1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基]甲基}磺酰基)苯甲酰胺;
N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-4′-({(3-苯基丙酰基)[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}甲基)联苯-4-甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[(1R,4R)-1,7,7-三甲基双环[2.2.1]庚-2-烯-2-基]苯亚甲基}哌啶-1-基)苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苄基}哌嗪-1-基)苯甲酰胺;
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苄基)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;
5-{2-[(4-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌嗪-1-基)甲基]苯基}-N-(2-苯基-1,3-苯并噁唑-5-基)-2-糠酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(三苯基乙烯基)苄基]哌嗪-1-基}苯甲酰胺;
4-{4-[2-(5-甲基-5,6-二氢菲啶-6-基)苄基]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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-{4-[2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄基]哌嗪-1-基}苯甲酰胺;
4-(4-{2-[2-(2,6-二甲氧基苯甲酰基)-3-噻吩基]苯亚甲基}哌啶-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;
1-[金刚烷-1-基]-4-{2-[(1-{4-[({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)氨基甲酰基]苯基}哌啶-4-亚基)甲基]苯基}-N,N-二苯基-1H-吡唑-3-甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[八氢-1H-4,7-亚甲基茚-5-基(3-苯基丙酰基)氨基]苄基}哌嗪-1-基)苯甲酰胺;
4-[4-(2-{5-[8-氮杂双环[3.2.1]辛-8-基甲基]-2-噻吩基}苯亚甲基)哌啶-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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(4-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-[4-(3-{[(1S,2S,3S,5R)-2,6,6-三甲基双环[3.1.1]庚-3-基]氨基}苯亚甲基)哌啶-1-基]苯甲酰胺;
4-[4-(2-{5-[4-(金刚烷-1-基)-1,3-噻唑-2-基]-2-噻吩基}苯亚甲基)哌啶-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;
N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-4-(4-{2-[5-(4-苯基-1,3-噻唑-2-基)-2-噻吩基]苯亚甲基}哌啶-1-基)苯甲酰胺;
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(4-氧代-4H-色烯-6-基)苯甲酰胺;
N-[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]-4-(1-辛基-1H-吡唑-4-基)苯甲酰胺;
4-[5-(4-{[(4-{[金刚烷-1-基甲基]氨基}-3-硝基苯基)磺酰基]氨基甲酰基}苯基)-1,3-苯并噻唑-2-基]丁酸;
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-[(1R,5S)-1,8,8-三甲基-3-氮杂双环[3.2.1]辛-3-基]苯甲酰胺;
6-{3-[金刚烷-1-基]-4-甲氧基苯基}-N-({4-[(环己基甲基)氨基]-3-硝基苯基}磺酰基)-2-萘甲酰胺;
4-{4-[金刚烷-1-基乙酰基]哌嗪-1-基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
4-{[金刚烷-1-基甲基]氨基}-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N-{1-[4-({[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}氨基甲酰基)苯基]哌啶-4-基}金刚烷-1-甲酰胺;
4-[金刚烷-2-基氨基]-N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}苯甲酰胺;
N-{[3-硝基-4-(四氢-2H-吡喃-4-基氨基)苯基]磺酰基}-4-{[(1R,2R,3R,5S)-2,6,6-三甲基双环[3.1.1]庚-3-基]氧基}苯甲酰胺;
及其治疗可接受的盐、前药、前药的盐和代谢物。
2.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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的组合物,所述组合物包括赋形剂和治疗有效量的权利要求1的化合物。
3.在患者中治疗膀胱癌、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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的方法,所述方法包括将治疗有效量的权利要求1的化合物施用于患者。
4.在患者中治疗膀胱癌、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、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、髓细胞性白血病、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、小细胞肺癌或脾癌的方法,所述方法包括将治疗有效量的权利要求1的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施用于患者。
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WO2019210828A1 (en) * | 2018-04-29 | 2019-11-07 | Beigene, Ltd. | Bcl-2 INHIBITORS |
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CN114835704A (zh) * | 2021-02-01 | 2022-08-02 | 苏州亚盛药业有限公司 | 作为bcl-2抑制剂的磺酰基苯甲酰胺衍生物 |
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