CN109071473B - 抗病毒化合物 - Google Patents
抗病毒化合物 Download PDFInfo
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- CN109071473B CN109071473B CN201780022404.2A CN201780022404A CN109071473B CN 109071473 B CN109071473 B CN 109071473B CN 201780022404 A CN201780022404 A CN 201780022404A CN 109071473 B CN109071473 B CN 109071473B
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- alkyl
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- herpes
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- IAOSTOFAWBONAJ-UHFFFAOYSA-N tert-butyl N-[[2-[[2-[4-(2,5-difluorophenyl)phenyl]acetyl]-methylamino]-4-methyl-1,3-thiazol-5-yl]-methyl-lambda4-sulfanylidene]carbamate Chemical compound CN(C(=O)Cc1ccc(cc1)-c1cc(F)ccc1F)c1nc(C)c(s1)S(C)=NC(=O)OC(C)(C)C IAOSTOFAWBONAJ-UHFFFAOYSA-N 0.000 description 1
- WCSPUXJALUVVHD-UHFFFAOYSA-N tert-butyl N-[[2-[[2-[4-(2,5-difluorophenyl)phenyl]acetyl]-methylamino]-4-methyl-1,3-thiazol-5-yl]-methyl-oxo-lambda6-sulfanylidene]carbamate Chemical compound CN(C(=O)CC1=CC=C(C=C1)C1=C(F)C=CC(F)=C1)C1=NC(C)=C(S1)S(C)(=O)=NC(=O)OC(C)(C)C WCSPUXJALUVVHD-UHFFFAOYSA-N 0.000 description 1
- ISHLCKAQWKBMAU-UHFFFAOYSA-N tert-butyl n-diazocarbamate Chemical compound CC(C)(C)OC(=O)N=[N+]=[N-] ISHLCKAQWKBMAU-UHFFFAOYSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000020364 urothelial hyperplasia Diseases 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
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Abstract
本发明涉及式(I)的新型化合物
Description
发明内容
本发明涉及一种新型化合物、其制备方法及其作为药物特别是抗病毒药物的用途。
介绍
自古以来,病毒感染的流行性疾病一直困扰着人类,它导致皮肤粘膜感染,如唇疱疹和生殖器疱疹。疾病症状常常干扰日常活动,有时候HSV感染会导致危及生命(脑炎)或视力受损疾病(角膜炎),特别是在新生儿、老年人和免疫功能低下的患者群体如器官移植患者、癌症患者或患有遗传性免疫缺陷综合症或疾病的患者。α疱疹病毒感染后以潜伏形式在宿主的神经细胞中持续存活,周期性地重新激活并且经常导致患者的巨大的心理社会痛苦。目前无法治愈。
到目前为止,具有特定或非特异性作用模式的疫苗、白细胞介素、干扰素、治疗性蛋白质、抗体、免疫调节剂和小分子药物都缺乏功效或所需的安全性来替代核苷类药物阿昔洛韦、伐昔洛韦和泛昔洛韦作为第一选择治疗方法。
已知的噻唑基酰胺是目前发展中最有效的药物。与核苷类药物相比,这些抗病毒药物通过新的作用机制起作用并且在动物模型中显示出低的体外抗性率和优异的功效,然而,其发展受到了脱靶碳酸酐酶活性和不平常的药代动力学特征的阻碍。
本专利申请公开了缺乏(或至少显著降低)碳酸酐酶活性、显示改善的溶解度和适合用作药物的药代动力学特征的新型抗病毒化合物。
现有技术
根据出版物C.Ziegler et al.,J.Org.Chem.25,1960,1454-1455,2-氨基噻唑-5-磺酰胺是已知的。此外,德国公开文件2101640描述了具有除草作用的N-噻唑-2-基-酰胺和-脲。
WO97/24343涉及具有抗疱疹病毒特性的苯基噻唑衍生物。
WO99/42455也涉及具有抗疱疹病毒特性的苯基噻唑衍生物。
WO99/47507涉及具有抗疱疹病毒特性的1,3,4-噻二唑衍生物。
WO0147904(A1)和对应的US2004/0006076涉及具有抗疱疹病毒特性的噻唑基酰胺。
WO2003/000259涉及噻唑基酰胺的局部施用。
WO2004060860(A2)涉及一种抑制疱疹病毒复制的方法。
WO0220014(A1)涉及解旋酶-引发酶的非竞争性抑制剂。
WO0212211(A1)涉及反噻唑基酰胺衍生物。
WO0053591(A1)涉及噻唑基脲衍生物及其作为抗病毒剂的用途。
WO03000260(A1)涉及噻唑基酰胺及其作为抗病毒药物的用途。
WO0196874(A1)和EP1319185(A1)涉及一种识别具有抗疱疹活性的化合物的方法。
WO2004015416涉及识别具有抗微生物作用的药物的方法。
WO03007946涉及仲1,3-噻唑-5-基磺酰胺衍生物及其作为抗病毒药物的用途。
WO0076966涉及吲哚基酰胺衍生物。
DE19959958涉及用作抗病毒药物,特别是用作抗单纯疱疹感染的新型2-脲基-噻唑-5-磺酸酰胺衍生物。
DE10210319涉及用于治疗人和动物的病毒感染,尤其是单纯疱疹或人巨细胞病毒感染的新型噻唑-5-磺酰胺衍生物。
DE10129717涉及一种含有核苷化合物和5-磺酰基-2-苯基乙酰氨基-噻唑衍生物的组合制剂,其可用作有效抵抗疱疹病毒,尤其是单纯疱疹病毒的抗病毒药物,。
DE10129716涉及一种可用作有效抵抗疱疹病毒,特别是单纯疱疹的抗病毒药物的组合制剂,其含有乙酰水杨酸和5-磺酰基-2-苯基乙酰氨基-噻唑衍生物。
DE10044358涉及用作抗病毒药物,特别是用于控制单纯疱疹感染的新型噻唑-5-磺酰胺衍生物。
DE10044328涉及用作抗病毒药物,特别是用于控制单纯疱疹感染的新型噻唑-5-磺酰胺衍生物。
DE10039265涉及用作抗病毒药物,特别是用于治疗或预防单纯疱疹病毒感染的新型2-酰氨基-5-氨基磺酰基-1,3-噻唑衍生物。
HRP20140352涉及N-[5-氨基磺酰基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙酰胺甲磺酸盐一水合物。
WO2006103011和EP1865921涉及一种N-[5-(氨基磺酰基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙酰胺的药物制剂。
WO2005075435涉及ATP结合盒转运蛋白调节剂的化合物,其可用于治疗i.a囊胞性纤维症和阿尔茨海默病。
总之,所引用的现有技术均未涵盖氨基磺酰亚胺基、甲基磺酰亚胺基、甲基亚磺酰基、甲基硫烷基、甲基-5-亚磺酰基、氰基氨磺酰基、N-氰基-S-甲基-磺酰亚胺基、5-二氨基磷酰基、膦酰胺酸或膦酸、噻唑基乙酰胺系衍生物。因此,本发明是新的,并且新型化合物在提高的溶解度下不显示或至少显著降低脱靶碳酸酐酶活性。所选化合物的优化的药代动力学特征在适于人类临床发展的经治疗的哺乳动物和用作药物中造成了意义深远的抗病毒活性。
具体实施方式
本发明涉及通式(I)的噻唑基酰胺衍生物:
对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂化物、制剂及其药学上可接受的盐,
其中,
X选自
R1选自氢、卤素、C1-6-烷基、卤代-C1-6-烷基、C3-6-环烷基、卤代-C3-6-环烷基、-O-C1-6-烷基、-O-卤代-C1-6-烷基和-NH-C1-6-烷基;
R2选自H、-CN、-NO2、C1-10-烷基、C2-10-烯基、C2-10-炔基、C0-10-亚烃基(alkylene)-C3-10-环烷基、C0-10-亚烃基-C3-10-杂环烷基、C0-10-亚烃基-(5-至10-元杂芳基)、C0-10-亚烃基-(6-至10-元芳基)、C0-10-亚烃基-(6-至10-元杂芳基)、C0-10-亚烃基-OR11、C0-10-亚烃基-CO2R11、C0-10-亚烃基-C(=O)NR11R12、C0-10-亚烃基-C(=S)NR11R12、C0-10-亚烃基-C(=O)NR11SO2R13、C0-10-亚烃基-C(=S)NR11SO2R11、C0-10-亚烃基-C(=O)R11、C0-10-亚烃基-C(=S)R11、C0-10-亚烃基-SR11、C0-10-亚烃基-SOxR13、C0-10-亚烃基-SO3R11、C0-10-亚烃基-SO2NR11R12、C0-10-亚烃基-NR11C(=O)R11、C0-10-亚烃基-NR11C(=S)R11、C0-10-亚烃基-NR11SO2R13、C0-10-亚烃基-NR11C(=O)NR11R12、C0-10-亚烃基-NR11C(=S)NR11R12、C0-10-亚烃基-NR11SO2NR11R12、C0-10-亚烃基-NR11R12,其中,烷基、烯基、炔基、亚烃基、环烷基、杂环烷基、芳基和杂芳基是未取代的或被1至7个独立地选自由氧代、CN、-NO2、OR11、O-C2-6-亚烃基-OR11、C1-6-烷基,卤代-C1-6-烷基、卤素、CO2R11、C(=O)NR11R12、C(=O)NR11SO2R11、C(=O)R11、SR11、SOxR11、SO3R11、P(=O)(OR11)2、SO2NR11R12、NR11C(=O)R11、NR11SO2R13、NR11C(=O)NR11R12、NR11SO2NR11R12、C3-10-环烷基、O-C3-10-环烷基、C3-10-杂环烷基、O-C3-10-杂环烷基和NR11R12组成的组的取代基取代;
R3选自H、C1-6-烷基、卤代-C1-6-烷基、-O-C1-6-烷基、-O-卤代-C1-6-烷基、C3-6-环烷基和C3-6-杂环烷基,其中烷基、环烷基和杂环烷基任选地被1-5个独立地选自卤素、-CN、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H的取代基取代;
或R2和R3与它们所连接的氮一起形成含有碳原子并任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中所述环是未取代的或被1至4个独立地选自由卤素、-CN、-NO2、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H组成的组的取代基取代;
R4选自H、C1-6-烷基、C1-6-酰基、C2-6-烯基、C3-8-环烷基和C3-8-杂环烷基,其中,烷基、酰基、烯基、环烷基和杂环烷基任选地被1至5个独立地选自卤素、-CN、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基的取代基取代;
R5和R6以及R5'和R6'独立地选自H、卤素、C1-6-烷基、NH2、NHC1-6-烷基、N(C1-6-烷基)2、C0-6-亚烃基-C(=O)NH2;
或当R5和R6以及R5'和R6'与它们所连接的碳一起时,形成含有碳原子且任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中,所述环是未取代的或被1至4个独立地选自由卤素、-CN、-NO2、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H组成的组的取代基取代;
或当R5和R5'以及R6和R6'与它们所连接的两个相邻碳一起时,独立地形成含有碳原子并任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中所述环是未取代的或被1至4个独立地选自由卤素、-CN、-NO2、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H组成的组的取代基取代;
R7选自6元芳基和5-或6-元杂芳基,其中,芳基和杂芳基任选地被1-4个独立地选自卤素、-CN、-NO2、OH、C1-6-烷基、O-C1-6-烷基、C3-6-环烷基、O-C3-6-环烷基、C3-6-杂环烷基、O-C3-6-杂环烷基、SOy-C1-6-烷基、CO2H、C(=O)O-C1-6-烷基、6-至10-元芳基、5-或10-元杂芳基、O-(6-至10-元芳基)和O-(5-或10-元杂芳基)的取代基取代,其中
烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-5个独立地选自卤素、-CN、-NO2、OH、R13、OR13、CO2R11、NR11R12、C(=O)R11、C(=S)R11、C(=O)NR11R12、NR11C(=O)NR11R12、NR11C(=O)OR13、OC(=O)NR11R12、C(=S)NR11R12、NR11C(=S)NR11R12、NR11C(=S)OR13、OC(=S)NR11R12;SOy-C1-6-烷基、SOy-卤代-C1-6-烷基、SR11、SOxR13、SO3R11、SO2NR11R12、NR11SO2R13、NR11SO2NR11R12的取代基取代;
R8选自H、-CN、-NO2、C1-10-烷基、C2-10-烯基、C2-10-炔基、C0-10-亚烃基-C3-10-环烷基、C0-10-亚烃基-C3-10-杂环烷基、C0-10-亚烃基-(5-至10-元杂芳基)、C0-10-亚烃基-(6-至10-元芳基)、C0-10-亚烃基-(6-至10-元杂芳基)、C0-10-亚烃基-OR11、C0-10-亚烃基-CO2R11、C0-10-亚烃基-C(=O)NR11R12、C0-10-亚烃基-C(=S)NR11R12、C0-10-亚烃基-C(=O)NR11SO2R13、C0-10-亚烃基-C(=S)NR11SO2R11、C0-10-亚烃基-C(=O)R11、C0-10-亚烃基-C(=S)R11、C0-10-亚烃基-SR11、C0-10-亚烃基-SOx-R13、C0-10-亚烃基-SO3R11、C0-10-亚烃基-SO2NR11R12、C0-10-亚烃基-NR11C(=O)R11、C0-10-亚烃基-NR11C(=S)R11、C0-10-亚烃基-NR11SO2R11、C0-10-亚烃基-NR11C(=O)NR11R12、C0-10-亚烃基-NR11C(=S)NR11R12、C0-10-亚烃基-NR11-SO2-NR11R12、C0-10-亚烃基-NR11R12,其中,烷基、烯基、炔基、亚烃基、环烷基、杂环烷基、芳基和杂芳基是未取代的或被1至7个独立地选自由氧代、CN、-NO2、OR11、O-C2-6-亚烃基-OR11、C1-6-烷基,卤代-C1-6-烷基、卤素、CO2R11、CONR11R12、CONR11SO2R11、COR11、SOxR11、SO3H、PO(OH)2、SO2NR11R12、NR11COR11、NR11SO2R11、NR11-CO-NR11R12、NR11-SO2-NR11R12、C3-10-环烷基、O-C3-10-环烷基、C3-10-杂环烷基、O-C3-10-杂环烷基和NR11R12组成的组的取代基取代;
R9选自C1-10-烷基、C2-10-烯基、C2-10-炔基、C0-10-亚烃基-C3-10-环烷基、C0-10-亚烃基-C3-10-杂环烷基、C0-10-亚烃基-(5-至10-元杂芳基)、C0-10-亚烃基-(6-至10-元芳基)、C0-10-亚烃基-(6-至10-元杂芳基)、C0-10-亚烃基-OR11、C0-10-亚烃基-CO2R11、C0-10-亚烃基-C(=O)NR11R12、C0-10-亚烃基-C(=S)NR11R12、C0-10-亚烃基-C(=O)NR11SO2R13、C0-10-亚烃基-C(=S)NR11SO2R11、C0-10-亚烃基-C(=O)R11、C0-10-亚烃基-C(=S)R11、C0-10-亚烃基-SR11、C0-10-亚烃基-SOxR13、C0-10-亚烃基-SO3R11、C0-10-亚烃基-SO2NR11R12、C0-10-亚烃基-NR11C(=O)R11、C0-10-亚烃基-NR11C(=S)R11、C0-10-亚烃基-NR11SO2R13、C0-10-亚烃基-NR11C(=O)NR11R12、C0-10-亚烃基-NR11C(=S)NR11R12、C0-10-亚烃基-NR11SO2NR11R12、C0-10-亚烃基-NR11R12,其中,烷基、烯基、炔基、亚烃基、环烷基、杂环烷基、芳基和杂芳基是未取代的或被1至7个独立地选自由氧代、CN、-NO2、OR11、O-C2-6-亚烃基-OR11、C1-6-烷基,卤代-C1-6-烷基、卤素、CO2R11、C(=O)NR11R12、C(=O)NR11SO2R11、C(=O)R11、SR11、SOxR11、SO3R11、P(=O)(OR11)2、SO2NR11R12、NR11C(=O)R11、NR11SO2R13、NR11C(=O)NR11R12、NR11SO2NR11R12、C3-10-环烷基、O-C3-10-环烷基、C3-10-杂环烷基、O-C3-10-杂环烷基和NR11R12组成的组的取代基取代;
R10选自-CN、OH和-NO2;
R11独立地选自H、C1-6-烷基、C0-6-亚烃基-C3-10-环烷基和C0-6-亚烃基-C3-10-杂环烷基,其中烷基、亚烃基、环烷基和杂环烷基是未取代的或被1至6个独立地选自由卤素、-CN、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、NH2、NH(C1-3-烷基)、N(C1-3-烷基)2、C3-6-杂环烷基、C3-6-环烷基、SO2-NHC1-3-烷基、SO2-N(C1-3-烷基)2和SO2-C1-3-烷基组成的组的取代基取代,其中环烷基和杂环烷基是未取代的或被1-3个独立地选自由F、OH、氧代、CH3、CHF2和CF3组成的组的取代基取代;
R12独立地选自H、C1-6-烷基、卤代-C1-6-烷基和C3-6-环烷基;
或当R11和R12与它们所连接的氮一起时,形成含有碳原子并任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中该环是未取代的或被1至4个独立地选自由卤素、-CN、-NO2、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H组成的组的取代基取代;
R13独立地选自C1-6-烷基、C0-6-亚烃基-C3-10-环烷基和C0-6-亚烃基-C3-10-杂环烷基,其中烷基、亚烃基、环烷基和杂环烷基是未取代的或被1至6个独立地选自由卤素、-CN、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、NH2、NH(C1-3-烷基)、N(C1-3-烷基)2、C3-6-杂环烷基、C3-6-环烷基、SO2-NHC1-3-烷基、SO2-N(C1-3-烷基)2和SO2-C1-3-烷基组成的组的取代基取代,其中环烷基和杂环烷基是未取代的或被1-3个独立地选自由F、OH、氧代、CH3、CHF2和CF3组成的组的取代基取代;
n选自0和1;
x独立地选自1和2;
y独立地选自0、1和2;
并且,其中,R1任选地与选自R2、R3、R8、R9、R10或R12的一个残基连接形成一个5至8元杂环,其任选地被1至4个独立地选自由卤素、-CN、-NO2、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H组成的组的取代基取代。
在本发明的上下文中,“C1-10-烷基”是指具有1至10个碳原子的饱和烷基链,其可以是直链或支链。其实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、庚基、辛基、壬基和癸基。优选的是“C1-6-烷基”,更优选的是“C1-4-烷基”,最优选的是“C1-3-烷基”。
术语“卤代-C1-10-烷基”或“卤代-C1-6-烷基”分别表示烷基链中的一个或多个氢原子被卤素取代,如下所定义。其优选的实例是形成-CF3基团。
“C2-10-烯基”是指含有至少一个碳碳双键的具有1至10个碳原子的烷烃链,其可以是直链或支链的。其实例包括乙烯基、丙烯基、癸烯基、2-亚甲基己基和(2E,4E)-己-2,4-二烯基。优选的是“C2-6-烯基”。
“C2-10-炔基”是指含有至少一个碳碳三键的具有1至10个碳原子的烷烃链,其可以是直链或支链的。其实例包括乙炔基、丙炔基和癸基。优选的是“C2-6-炔基”。
“C0-10-亚烃基”是指各基团是二价的并且将所连着的残基与分子的其余部分连接起来。此外,在本发明的上下文中,“C0-亚烃基”是指代表键。优选的是“C0-6-亚烃基”。
C3-10-环烷基基团或C3-10-碳环是指包含3至10个碳原子的饱和或部分不饱和的单-、双-、螺-或多环环系。实例包括环丙基、环丁基、环戊基、环己基、环己烯基、双环[2.2.2]辛基、双环[2.2.1]庚基、金刚烷基和五环[4.2.0.02,5.03.8.04.7]辛基。优选的是C3-6-环烷基基团。更优选的是环丙基基团。
C3-10-杂环烷基是指饱和或部分不饱和的3至10元碳单-、双-、螺-或多环环系,其中1、2或3个碳原子分别被1、2或3个杂原子取代,其中杂原子独立地选自N、O、S、SO和SO2。其实例包括环氧基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基四氢吡喃基、1,4-二恶烷基、吗啉基、4-奎宁环基、1,4-二氢吡啶基和3,6-二氢-2H-噻喃基。C3-10-杂环烷基基团可以通过碳或氮原子连接。优选的是C3-6-杂环烷基。
含有最多5个杂原子的5至10元单环或双环杂芳环系统(在本申请中也称为杂芳基)是指单环杂芳环,例如吡咯基、咪唑基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、吡唑基、恶唑基、异恶唑基、三唑基、恶二唑基和噻二唑基。优选的是5-至6-元单环杂芳环。它还指双环系统,其中杂原子可以存在于包括桥头原子的一个或两个环中。其实例包括喹啉基、异喹啉基、喹喔啉基、苯并咪唑基、苯并异恶唑基、苯并二恶烷基、苯并呋喃基、苯并恶唑基、吲哚基、吲嗪基和吡唑并[1,5-a]嘧啶基。杂芳基系统的氮或硫原子也可任选地氧化成相应的N-氧化物,S-氧化物或S,S-二氧化物。如果没有另外说明,杂芳基系统可以通过碳或氮原子连接。N-连接杂环的实例是
6-至10-元的单环或双环芳环系统(在本申请中也称为芳基)是指芳族碳环,例如苯基或萘基。优选的是5-至6-元芳环(芳基),例如特别是苯基。
术语“N-氧化物”表示化合物,其中杂芳族系统(优选吡啶基)中的氮被氧化。这些化合物可以通过使本发明化合物(例如吡啶基)与H2O2或过酸在惰性溶剂中反应以已知方式获得。
卤素选自氟、氯、溴和碘,优选氟和氯。
此外,本发明化合物部分地受制于互变异构现象。例如,如果环中含有氮原子的杂芳基邻近氮原子的碳原子被羟基取代,则可能出现以下互变异构:
C3-10-环烷基或C3-10-杂环烷基可以是直链或螺环连接的,例如,当环己烷被杂环烷基氧杂环丁烷取代时,以下结构是可能的:
本领域技术人员将理解,当供选择的取代基的列表包括由于其化合价需要或其他原因而不能用于替代特定基团时,本领域技术人员理解的该列表是指仅包括列表中适合替换特定基团的列表。
用于本发明的化合物可以是药学上可接受的盐或溶剂化物的形式。术语“药学上可接受的盐”是指由药学上可接受的无毒碱或酸制备的盐,包括无机碱或酸和有机碱或酸。在本发明的化合物含有一个或多个酸性或碱性基团的情况下,本发明还包括其相应的药学上或毒理学上可接受的盐,特别是其药学上可利用的盐。因此,根据本发明,可以使用含有酸性基团的本发明化合物,例如碱金属盐、碱土金属盐或铵盐。这些盐的更精确的实例包括钠盐、钾盐、钙盐、镁盐或氨或有机胺(例如乙胺、乙醇胺、三乙醇胺或氨基酸)盐。含有一个或多个碱性基团(即可被质子化基团)的本发明化合物,可以根据本发明以其与无机或有机酸的加成盐的形式使用。适合的酸的实例包括氯化氢、溴化氢、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡萄糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其他酸。如果本发明的化合物在分子中同时含有酸性和碱性基团,则除了所提及的盐形式外,本发明还包括内盐或甜菜碱(两性离子)。各种盐可以分别通过本领域技术人员已知的常规方法获得,例如,通过将它们与有机或无机酸或碱在溶剂或分散剂中接触,或通过与其它盐的阴离子交换或阳离子交换。本发明还包括本发明化合物的所有盐,由于其低生理相容性,它们不直接适用于药物,但可用作例如化学反应的中间体或用于药学上可接受盐的制备。
取决于取代模式,本发明的化合物可以以立体异构形式存在,其表现为影像和镜像(对映异构体),或者不表现为影像和镜像(非对映异构体)。本发明涉及对映异构体或非对映异构体及其各自的混合物。与非对映异构体一样,外消旋形式可以以已知方式分离成立体异构的均匀组分。
本发明的范围包括那些一旦进入体内仅转化为式(I)和(II)的实际活性化合物的化合物(所谓的前药)。
本发明特别涉及以下实施方式:
特别优选地,本发明实施方式涉及如上定义的式(I)或如下定义的式(II)的化合物,其中
X选自由
和/或选自由
并且其中,R1、R2、R3、R4、R5、R6、R5’、R6’、R7、R8、R9、R10、R11、R12、R13、n、x和y具有如所述任一实施方式所描述的定义。
更优选地,本发明的实施方式涉及如上定义的式(I)或如下定义的式(II)的化合物,其中
X选自由
并且其中,R1、R2、R3、R4、R5、R6、R5’、R6’、R7、R8、R9、R10、R11、R12、R13、n、x和y具有如所述任一实施方式所描述的定义。
进一步特别优选的实施方式涉及如上定义的式(I)化合物,其中
R4选自C1-6-烷基、C1-6-酰基、C3-8-环烷基和C3-8-杂环烷基,其中烷基、酰基、烯基、环烷基和杂环烷基任选地被1-5个独立地选自卤素、-CN、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基的取代基取代;
R5和R6以及R5'和R6'独立地选自H和C1-3-烷基;
或当R5和R6以及R5'和R6'与它们所连接的碳一起时,独立地形成含有碳原子且任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中,所述环是未取代的或被1至4个独立地选自由卤素、OH、氧代、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3组成的组的取代基取代;
或当R5和R6以及R5'和R6'与它们所连接的两个相邻碳一起时,独立地形成含有碳原子且任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中,所述环是未取代的或被1至4个独立地选自由卤素、OH、氧代、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3组成的组的取代基取代;
R7选自6元芳基和5-或6-元杂芳基,其中芳基和杂芳基任选地被1-3个选自卤素、OH、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3的取代基取代并被6-元芳基和5-或6-元杂芳基取代,其中芳基和杂芳基任选地被1-5个独立地选自卤素、-CN、-NO2、OH、R13、OR13、CO2R11、NR11R12、C(=O)R11、C(=S)R11、C(=O)NR11R12、NR11C(=O)NR11R12、NR11C(=O)OR13、OC(=O)NR11R12、C(=S)NR11R12、NR11C(=S)NR11R12、NR11C(=S)OR13、OC(=S)NR11R12、SOy-C1-6-烷基、SOy-卤代-C1-6-烷基、SR11、SOxR13、SO3R11、SO2NR11R12、NR11SO2R13、NR11SO2NR11R12的取代基取代;
并且其中剩余的取代基具有如本文任一实施方式所描述的定义。
在进一步与上述或下述任一实施方式结合的优选的实施方式中,R4选自C1-6-烷基、C1-6-酰基、C3-8-环烷基和C3-8-杂环烷基,其中烷基、酰基、烯基、环烷基和杂环烷基任选地被1-5个独立地选自卤素、-CN、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基的取代基取代。
在与上述或下述任一实施方式结合的更优选的实施方式中,R4选自C1-3-烷基和卤代-C1-3-烷基。
在与上述或下述任一实施方式结合的更优选的实施方式中,R4选自Me(-CH3)。
在与上述或下述任一实施方式结合的另一个可选择的优选实施方式中,R5和R6以及R5'和R6'独立地选自H、卤素、C1-6-烷基、NH2、NHC1-6-烷基、N(C1-6-烷基)2、C0-6-亚烃基-C(=O)NH2;
或当R5和R6以及R5'和R6'与它们所连接的碳一起时,独立地形成含有碳原子且任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中,所述环是未取代的或被1至4个独立地选自卤素、-CN、-NO2、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H的取代基取代;
或R5和R6以及R5'和R6'当与它们所连接的两个相邻碳一起时,独立地形成含有碳原子且任选地含有1或2个选自O、S或N的杂原子的3-至8-元环,其中,所述环是未取代的或被1至4个独立地选自卤素、-CN、-NO2、OH、氧代、C1-3-烷基、卤代-C1-3-烷基、O-C1-3-烷基、O-卤代-C1-3-烷基、SO2-C1-3-烷基、CO2H的取代基取代。
在与上述或下述任一实施方式结合的更优选的实施方式中,R5和R6以及R5'和R6'独立地选自H、C1-3-烷基和卤代-C1-3-烷基。
在与上述或下述任一实施方式结合的更优选的实施方式中,R5和R6以及R5'和R6'是氢。
在与上述或下述任一实施方式结合的另一个可选择的优选实施方式中,R7选自6-元芳基和5-或6-元杂芳基,其中芳基和杂芳基任选地被1-4个独立地选自卤素、-CN、-NO2、OH、C1-6-烷基、O-C1-6-烷基、C3-6-环烷基、O-C3-6-环烷基、C3-6-杂环烷基、O-C3-6-杂环烷基、SOy-C1-6-烷基、CO2H、C(=O)O-C1-6-烷基、6-至10-元芳基、5-或10-元杂芳基、O-(6-至10-元芳基)和O-(5-或10-元杂芳基)的取代基取代,其中烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-5个独立地选自卤素、-CN、-NO2、OH、R13、OR13、CO2R11、NR11R12、C(=O)R11、C(=S)R11、C(=O)NR11R12、NR11C(=O)NR11R12、NR11C(=O)OR13、OC(=O)NR11R12、C(=S)NR11R12、NR11C(=S)NR11R12、NR11C(=S)OR13、OC(=S)NR11R12、SOy-C1-6-烷基、SOy-卤代-C1-6-烷基、SR11、SOxR13、SO3R11、SO2NR11R12、NR11SO2R13、NR11SO2NR11R12的取代基取代。
在与上述或下述任一实施方式结合的更优选的实施方式中,R7选自6-元芳基和5-或6-元杂芳基,其中芳基和杂芳基任选地被1-3个独立地选自卤素、OH、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3的取代基取代和被6-元芳基和5-或6-元杂芳基取代,其中芳基和杂芳基任选地被1-5个独立地选自卤素、-CN、-NO2、OH、R13、OR13、CO2R11、NR11R12、C(=O)R11、C(=S)R11、C(=O)NR11R12、NR11C(=O)NR11R12、NR11C(=O)OR13、OC(=O)NR11R12、C(=S)NR11R12、NR11C(=S)NR11R12、NR11C(=S)OR13、OC(=S)NR11R12、SOy-C1-6-烷基、SOy-卤代-C1-6-烷基、SR11、SOxR13、SO3R11、SO2NR11R12、NR11SO2R13、NR11SO2NR11R12的取代基取代。
在与上述或下述任一实施方式结合的甚至更优选的实施方式中,R7选自6-元芳基和5-或6-元杂芳基,其中芳基和杂芳基任选地被1-3个独立地选自卤素、OH、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3的取代基取代和被6-元芳基和5-或6-元杂芳基取代,其中芳基和杂芳基任选地被1-5个独立地选自卤素、OH、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3的取代基取代。
特别优选的是如上述任一实施方式中所定义的式(I)化合物,其中R7是苯基,任选地被1-4个取代基(Rx)取代,其独立地具有本文任一实施方式中对R7的可能取代基所定义的含义,并且其由式(II)表示
在与上述或下述任一实施方式结合的甚至更优选的实施方式中,R7选自苯基,其任选地被1-3个独立地选自F、Cl、OH、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3的取代基取代和被6-元芳基和5-或6-元杂芳基取代,其中芳基和杂芳基任选地被1-5个独立地选自F、Cl、OH、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2、OCF3的取代基取代。
在与上述或下述任一实施方式结合的甚至更优选的实施方式中,R7选自由
在与上述或下述任一实施方式结合的另一个可选择的优选实施方式中,式(I)中的基团
优选自
优选的本发明化合物也由下式(IIa)、(IIb)和(IIc)表示:
其中剩余的取代基具有如本文任一实施方式中所述的含义,并且其中Rx定义1至4个取代基(Rx),其独立地具有本文任一实施方式中对R7的可能取代基所定义的含义,优选地,1至4个取代基Rx独立地选自H、F、Cl、OH、Me(-CH3)、OMe(-O-CH3)、CHF2、CF3、OCHF2和OCF3。
在与上述或下述任一实施方式结合的另一个可选择的优选实施方式中,式(I)或式(II)中的
R1独立地选自C1-3-烷基、卤代-C1-3-烷基和环丙基,更优选地,R1是Me(-CH3)。
R1独立地选自H、卤素、C1-6-烷基、卤代-C1-6-烷基、C3-6-环烷基、卤代-C3-6-环烷基、-O-C1-6-烷基、-O-卤代-C1-6-烷基和-NH-C1-6-烷基。
在与上述或下述任一实施方式结合的另一个可选择的优选实施方式中,R2和R3独立地选自H、C1-3-烷基、卤代-C1-3-烷基、-O-C1-3-烷基、-O-氟-C1-3-烷基、C3-6-环烷基和C3-6-杂环烷基,其中烷基、环烷基和杂环烷基任选地被1至5个独立地选自F、Cl、OH、氧代、Me(-CH3)、CHF2和CF3的取代基取代;或R2和R3当与它们所连接的氮一起时,形成含有碳原子且任选地含有1个选自O、S或N的杂原子的5-至6-元环,其中,所述环是未取代的或被1至4个独立地选自由F、Cl、OH、氧代、Me(-CH3)、CHF2和CF3组成的组的取代基取代;
R8选自H、-CN、-NO2、OH、C1-3-烷基、O-C1-3-烷基、氟-C1-3-烷基和O-氟-C1-3-烷基,
R9选自C1-3-烷基、叔丁基、氟-C1-3-烷基、环丙基、氟-C1-3-烷基-环丙基、-C3-10-杂环烷基;
R10选自-CN、OH和-NO2;和
R12独立地选自H、Me(-CH3)和Et(-CH2-CH3)。
此外,在任何上述或下述的实施方式中,可以单独地或与任何彼此组合的取代基具有以下含义:
R2和R3可以独立地选自H、Me-(CH3)、Et(-CH2-CH3)、-CH2CH2OH和-CH2CH2F。
R2和R3可以是H。
R8可选自H、-CN、-NO2、OH、C1-3-烷基、O-C1-3-烷基、氟-C1-3-烷基和O-氟-C1-3-烷基。
R8可选自H、-CN、-NO2、OH、Me(-CH3)、Et(-CH2-CH3)、OMe(-O-CH3)和OEt(-O-CH2-CH3)。
R8可选自H和CN。
R9可选自C1-3-烷基、氟-C1-3-烷基、环丙基和-C3-10-杂环烷基。
R9可选自Me(-CH3)、Et(-CH2-CH3)、CHF2、CF3、环丙基和氧杂环丁烷。
R9可以是Me(-CH3)或环丙基。
R9可以是Me(-CH3)。
R10可选自-CN、OH和-NO2。
R10可以是-CN。
R12可以独立地选自H、Me(-CH3)和Et(-CH2-CH3);
在与上述或下述任一实施方式结合的另一个可选择的优选实施方式中,本发明的式(I)或式(II)中的基团
优选地,所述基团选自
在与上述或下述任一实施方式结合的另一个可选择的优选实施方式中,n选自0和1,优选地,n为0。
本发明特别优选的化合物由下式表示:
下列化合物是优选的:
下列化合物是更优选的:
下列化合物是最优选的:
本发明的另一方面涉及任一上述实施方式的化合物作为药物的用途。
特别地,本发明涉及所述化合物在治疗或预防与病毒感染相关的疾病或病症中的用途。
更具体地,本发明涉及所述化合物在治疗或预防疾病或病症中的用途,其与由疱疹病毒,例如特别是单纯疱疹病毒引起的病毒感染有关。
本发明的另一方面涉及所述化合物在治疗或预防由病毒引起的神经变性疾病,例如特别是阿尔茨海默病中的用途。
本发明的另一方面涉及所述化合物,用于治疗和预防疱疹感染,特别是单纯疱疹感染,所述疱疹感染的患者是具有唇疱疹、生殖器疱疹和疱疹相关性角膜炎、阿尔茨海默病、脑炎、肺炎、肝炎的患者;免疫系统受到抑制的患者,如艾滋病患者、癌症患者、患有遗传性免疫缺陷的患者、移植患者;新生儿和婴儿;疱疹阳性患者,特别是单纯疱疹阳性患者,用于抑制复发(抑制治疗);患者,特别是疱疹阳性患者,特别是单纯疱疹阳性患者,其对核苷类抗病毒治疗有抗性,如阿昔洛韦、喷昔洛韦、泛昔洛韦、更昔洛韦、伐昔洛韦。
本发明的另一方面涉及所述化合物,其特征在于,在Vero细胞上的体外活性选择性测定HSV-1中的IC50值(HSV-1/Vero),如在本发明的一个实施例中所描述的,优选地IC50低于100μM,更优选地IC50低于10μM,非常特别优选地IC50低于1μM。
本发明的另一方面涉及所述化合物,其特征在于,体内动物模型中的ED50值,如本发明实施例中所描述的,优选地,对于HSV-1,ED50小于10mg/kg,更优选地,对于HSV-1,ED50小于5mg/kg,非常特别优选地,对于HSV-1,ED50小于2mg/kg。
本发明的另一方面涉及所述化合物,其特征在于不显示或减少碳酸酐酶抑制,例如特别抑制碳酸酐酶I和/或碳酸酐酶II。在本发明的意义上的没有或减少碳酸酐酶抑制由IC50值(抑制浓度)定义,其根据R.Iyer et al.J.Biomol.Screen.2006,11:782在碳酸酐酶II活性测定和/或根据A.R.Katritzky et al.J.Med.Chem.1987,30:2058在碳酸酐酶I活性测定定义,IC50>2.0μM,优选>3.0μM,更优选>5.0μM。更优选地,在本发明的意义上的没有或减少的碳酸酐酶抑制通过人碳酸酐酶II活性测定的IC50值(抑制浓度)定义,如在本发明实施例中详细描述的,IC50>2.0μM,优选>3.0μM,更优选>5.0μM。
本发明的化合物被认为可以用于预防和治疗人类以及动物中的各种病症和疾病。
因此,本发明还涉及本文所述的化合物在药物制备中的用途。
此外,本发明涉及一种治疗与病毒感染相关的疾病或病症(例如与由疱疹病毒,例如特别是由单纯疱疹病毒引起的病毒感染相关的疾病或病症)的方法以及治疗由病毒引起的神经变性疾病,例如特别是阿尔茨海默病的方法,所述方法包括向有需要的人或动物施用有效量的化合物或包含本文所述化合物的组合物。
在实际应用中,根据常规药物配制技术,本发明中使用的化合物可以作为紧密混合物中的活性成分与药物载体组合。根据给药所需的制剂形式,例如口服或注射用药物(包括静脉注射),载体可以采取多种形式。在制备用于口服剂型的组合物时,可以使用任何常用的药物介质,例如,当制备例如悬浮液、酏剂和溶液的口服液体制剂的情况下,可以使用水、乙二醇、油、乙醇、调味剂、防腐剂、着色剂等;当制备例如粉末、硬和软胶囊以及片剂的口服固体制剂的情况下,可以使用淀粉、糖、微晶纤维素、稀释剂、制粒剂、润滑剂、粘合剂、崩解剂等载体,并且固体口服制剂优于液体制剂。
由于易于给药,片剂和胶囊代表最有利的口服剂量单位形式,在这种情况下显然使用固体药物载体。如果需要,可以通过标准水性或非水性技术包衣片剂。此类组合物和制剂应含有至少0.1%的活性化合物。当然,这些组合物中活性化合物的百分比可以变化,并且可以合宜地为单位重量的约2%至约60%。在这种治疗上有用的组合物中,活性化合物的量是这样的,如此可以获得有效剂量。活性化合物也可以鼻内给药,例如,液滴或喷雾剂或滴眼剂。
片剂、丸剂、胶囊等也可含有粘合剂,如黄芪胶、阿拉伯树胶、玉米淀粉或明胶;赋形剂,如磷酸二钙;崩解剂,如玉米淀粉、马铃薯淀粉、海藻酸;润滑剂如硬脂酸镁;和甜味剂,如蔗糖、乳糖或糖精。当剂量单位形式是胶囊时,除了上述类型的材料之外,它还可以含有液体载体如脂肪油。
各种其他材料可以作为包衣存在或改变剂量单位的物理形式。例如,片剂可以用虫胶、糖或两者包衣。除活性成分外,糖浆或酏剂可含有作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调味剂如樱桃或橙子调味剂。
用于本发明的化合物也可以注射给药。这些活性化合物的溶液或悬浮液可以在水中适当地与表面活性剂如羟丙基纤维素混合来制备。分散剂也可以在油中在甘油、液体聚乙二醇及其混合物中制备。在常规的储存和使用条件下,这些制剂均含有防腐剂以防止微生物的生长。
适于注射使用的药物形式包括无菌水溶液或分散液和用于临时制备无菌可注射溶液或分散液的无菌粉末。在所有情况下,该形式必须是无菌的并且必须是流动的以达到易于注射的程度。它必须在制造和储存条件下稳定,并且必须防止微生物如细菌和真菌的污染。载体可以是溶剂或含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、合适的混合物和植物油的分散介质。
可以采用任何合适的给药途径为哺乳动物,尤其是人提供有效剂量的本发明化合物。例如,可以使用口服、直肠、局部、注射(包括静脉)、眼、肺、鼻等途径。剂型包括片剂、锭剂、分散剂、悬浮液、溶液、胶囊、乳膏、软膏、气溶胶等。优选本发明化合物口服给药或作为滴眼剂给药,更优选本发明化合物口服给药。
所用活性成分的有效剂量可根据所用的具体化合物、给药方式、所治疗的病症和所治疗病症的严重程度而变化。本领域技术人员可以容易地确定这种剂量。
本发明化合物还可以与其他活性成分组合存在,特别是与一种或多种在治疗本文所述的任何疾病或疾病中表现出有利效果的活性成分组合。非常特别地,本发明化合物与至少一种其他活性物质组合存在于组合物中,所述活性物质可有效治疗与病毒感染相关的疾病或病症(抗病毒活性化合物),优选由疱疹病毒,例如特别是由单纯疱疹病毒引起的与病毒感染相关的疾病或病症,因此涉及所谓的联合治疗。至少一种有效治疗与病毒感染相关的疾病或病症的其它活性物质(抗病毒活性化合物)优选地选自核苷类药物,例如阿昔洛韦、伐昔洛韦、喷昔洛韦、更昔洛韦、泛昔洛韦和三氟尿苷,以及膦甲酸钠和西多福韦等化合物。
因此,本发明进一步涉及一种药物组合物,其包含一种或多种如本文所述的化合物和至少一种药学上可接受的载体和/或赋形剂和/或至少一种其他活性物质,所述活性物质可有效治疗与病毒感染相关的疾病或病症(抗病毒活性化合物)。
实验部分
本发明化合物可通过本领域已知的组合方法制备,包括下面方案I至III中所述的方法。
酸结构单元R7(CR5'R6')nCR5R6COOH的合成可根据WO2001/47904中所描述的制备,并与合适的噻唑结构单元偶联。为了组装二烷基膦酸酯Ia,可以用Mn(OAc)3·2H2O和二烷基亚磷酸酯处理5-未取代的噻唑(X=H)。如方案I所示,二烷基膦酸酯Ia可以用例如TMSBr皂化来得到膦酸Ib。膦酰胺的制备可以通过用草酰氯处理膦酸1b,然后用适量的氨(R2和R3=H)、伯胺和仲胺来处理。色谱分离后,目标化合物Ic和Id可以分离。合适的取代的磺酰胺(X=SO2NR2R10)的引入可以通过用卤化物-R10(例如溴化氰)烷基化已知的伯磺酰胺(X=SO2NH2)或使已知的磺酰氯中间体(X=SO2Cl)与适当的胺(例如NH2OH、NH2Cl)反应来获得。
方案I
酸结构单元R7(CR5'R6')nCR5R6COOH与5-磺酸取代的噻唑偶联可得到中间体IIa(方案II),其可用草酰氯处理而转化为磺酰氯IIa。该中间体与NHR2R3和三苯基膦反应得到目标化合物IIc,其最终可在例如NH2R8的存在下用叔丁基亚氯酸盐氧化来提供目标化合物IId。Y.Chen et al.(RSC Advances 2015,5,4171)描述了使用易得的磺酰胺,通过与不同胺在原位形成的磺酰亚胺基氯的亲核取代来形成衍生物IId的替代途径。衍生物IId的其他途径在Angew.Chem.Int.Ed.2013,52,9399和ChemMedChem 2013,8,1067中也有描述。
方案II
酸结构单元R7(CR5'R6')nCR5R6COOH与5-烷硫基取代的噻唑的偶联可以得到中间体IIIa(方案III),其可以被氧化成烷基亚磺酰基衍生物IIIb。此外,用叠氮基衍生物N3R8和FeCl2氧化中间体IIIa可以提供亚磺酰亚胺基衍生物IIIc,其可以进一步被例如NaIO4/RuCl3氧化以得到磺酰亚胺基衍生物IIId。在R8代表氰基残基的情况下,可以使用如S.J.Park et al.(ChemMedChem 2013,8,217)所述的替代途径(H2NCN,PhI(OAc)2,然后是mCPBA)。
方案III
在所有情况下,R2、R3或R8可以作为保护基团并且可以用类似于在例如Greene'sProtective Groupsin Organic Synthesis(ISBN:978-1-118-05748-3)所描述的进行脱保护。
在反应方案中,剩余的取代基可具有本发明所定义的含义。
缩略语
HPMC 羟丙基甲基纤维素
DMF 二甲基甲酰胺
DCM 二氯甲烷
THF 四氢呋喃
PE 石油醚
DMSO 二甲基亚砜
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶-3氧化物六氟磷酸
rt 室温
TFA 三氟乙酸
TMS 三甲基硅基
EDC·HCl 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐
TBDMSCl 叔丁基二甲基甲硅烷基氯
实验部分
实施例1:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-(5-(N-(4-甲氧基苄基)氨基亚磺酰基)-4-甲基噻唑-2-基)-N-甲基乙酰胺
(2-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-N-(5-(N-(4-methoxybenzyl)sulfinamoyl)-4-methylthiazol-2-yl)-N-methylacetamide)
步骤1:4-甲基-2-甲氨基-噻唑-5-磺酸(P1a)
在冰冷却条件下,将甲基-(4-甲基-噻唑-2-基)-胺(3.84g,30mmol)加入到氯磺酸(6.0mL,90mmol)中。将混合液搅拌过夜,倒入冰中,用6N NaOH中和并蒸发至干。将残余物用热EtOH萃取,将得到的萃取物浓缩至干,得到中间体P1a(2.73g,44%)。
步骤2:2-(2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰氨基)-4-甲基噻唑-5-磺酸(P1b)
将含有磺酸P1a(2.73g,13mmol)和N-甲基吗啉(3.3mL,30mmol)的DMF(5mL)溶液冷却至0℃,并且加入2-(2',5'-二氟-[1,1'-联苯]-4-基)乙酸(2.48g,10mmol;WO2003/000259)、EDC·HCl(2.11g,11mmol)和HOBt(1.49g,11mmol)的DMF(7mL)冰冷溶液。混合液达到室温,搅拌过夜并倒入Et2O中。离心沉淀物并用Et2O洗涤后,用少量THF稀释并冷却过夜。将沉淀物P1b离心并无需进一步纯化即可使用。
步骤3:2-(2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰氨基)-4-甲基噻唑-5-磺酰氯(P1c)
将含有磺酸P1b(374mg,854μmol)的无水THF(5mL)悬浮液在加入分子筛搅拌1h,然后除去分子筛并将溶液冷却至-20℃。然后加入草酰氯(220μL,2.56mmol)和2滴DMF。将混合物在室温下搅拌2h,然后加入另外的草酰氯(220μL,2.56mmol)和1滴DMF。将混合物在60℃下搅拌2h,浓缩溶解在EtOAc中并用1M的KH2PO4溶液和盐水洗涤,经Na2SO4干燥并蒸发,得到中间体P1c(167mg,43%)。
步骤4:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-(5-(N-(4-甲氧基苄基)氨基亚磺酰基)-4-甲基噻唑-2-基)-N-甲基乙酰胺(1)
将含有磺酰氯P1c(167mg,366μmol)的DCM(2.5mL)溶液冷却至-20℃,然后加入NEt3(102μL,732μmol)以及PPh3(86mg,329μmol)和对甲氧基苄胺(72μL,549μmol)的DCM(0.8mL)冷却溶液。将混合液在0℃下搅拌15min并在室温下搅拌1h,然后用PE(40mL)稀释。将沉淀物溶于DCM(2mL)中并再次从Et2O(25mL)中沉淀。将上清液浓缩至干,剩余物无需进一步纯化即可使用。MS实测值:542.3[M+H]+。
实施例2:2-[4-(2,5-二氟苯基)苯基]-N-[5-[[(4-甲氧基苄基)氨基]亚胺酰磺酰基]-4-甲基-噻唑-2-基]-N-甲基-乙酰胺
(2-[4-(2,5-Difluorophenyl)phenyl]-N-[5-[[(4-methoxybenzyl)amino]sulfonimidoyl]-4-methyl-thiazol-2-yl]-N-methyl-acetamide)
将含有化合物1(约90μmol)的无水THF(1.5mL)溶液冷却至-20℃。然后加入叔丁基亚氯酸盐的无水THF(100μL)溶液,并将溶液在0℃下搅拌30min,用NH3(0.5M在THF中;810μL,405μmol)淬灭,在0℃搅拌1h并从PE(30ml)中沉淀出来。粗产物2无需进一步纯化即可用于下一步骤。
实施例3:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-氨基亚胺酰磺酰基噻唑-2-基)乙酰胺
(2-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-sulfamimidoylthiazol-2-yl)acetamide)
向对甲氧基苄基亚胺酰磺酰胺2(约40μmol)的MeCN(0.5mL)溶液中加入硝酸铈(IV)铵(110mg,200μmol)的水(100μL)溶液,并将溶液在室温搅拌10min。分离有机层,再次用MeCN萃取水层。将合并的有机层用水稀释至MeCN/H2O=7:1的混合液,并通过HPLC纯化得到目标分子3。1H-NMR(CDCl3+CD3OD,300MHz)δ:7.58-7.54(m,3H),7.37(d,2H),7.17-7.06(m,3H),4.17(s,2H),3.79(s,3H),2.63(s,3H)。MS实测值:437[M+H]+。
或者,实施例3可以如下制备:
步骤1:N-(5-(N-(叔丁基二甲基甲硅)氨基磺酰基)-4-甲基噻唑-2-基)-2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰胺(3a)
向2-(2',5'-二氟-[1,1'-联苯基]-4-基)-N-甲基-N-(4-甲基-5-氨基磺酰基噻唑-2-基)乙酰胺(250mg,572μmol;如WO2001/47904中所描述的制备)的DMF(3mL)溶液中加入NaH(1.14mmol,46mg;在矿物油中60%的悬浮液),并将混合液在室温下搅拌1h。加入TEA(2.86mmol,399μL)后,将混合液冷却至-20℃,并添加TBDMSCl(2.86mmol,429mg)的无水THF(1mL)冷却(-20℃)溶液,在室温下继续搅拌60h。将混合液倒入水中并用EtOAc萃取两次。将合并的有机相用水洗涤两次,用饱和的NaHCO3洗涤两次,用盐水洗涤一次,用Na2SO4干燥,过滤并浓缩至干。粗中间体3a无需进一步纯化即可用于下一步骤。
步骤2:2-(2',5'-二氟-联苯-4-基)-N-[5-亚胺酰磺酰基-4-甲基-噻唑-2-基]-N-甲基乙酰胺(2-(2',5'-Difluoro-biphenyl-4-yl)-N-[5-sulfinimidamido-4-methyl-thiazole-2-yl]-N-methyl acetamide)(实施例3)
向中间体3a(约286μmol)的DCM(3mL)溶液中加入TEA(1.43mmol,200μL),将混合液冷却至-20℃。然后加入三苯基二氯化磷(572μmol,191mg)的DCM(600μL)冷却(-20℃)溶液。在室温下继续搅拌2.5h,并在冰冻条件下将混合液倒入25%NH3(aq)和THF(1:2,v/v,30mL)的混合物液中。将有机相分离并用EtOAc稀释。用EtOAc萃取水相,合并有机相,用水洗涤,用1MKHSO4洗涤一次,用盐水洗涤一次,用Na2SO4干燥,过滤并浓缩至干。将粗产物溶解在DCM(1mL)中并用PE沉淀。将获得的沉淀物溶解在DCM(1mL)中并用Et2O沉淀以获得目标分子3(79mg,在两个步骤后为50%)。
实施例3-1:N-甲基-N-(4-甲基-5-亚胺酰氨基磺酰基噻唑-2-基)-2-(4-(吡啶-2-基)苯基)乙酰胺(N-Methyl-N-(4-methyl-5-sulfamimidoylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide)
实施例3-1按照合成实施例3的方案使用(4-吡啶-2-基-苯基)乙酸进行制备。1H-NMR(CDCl3+CD3OD,300MHz)δ:8.68-8.67(s,1H),8.06-8.04(s,1H),7.95-7.93(m,3H),7.67-7.46(m,4H),4.24(s,2H),3.83(s,3H),2.65(s,3H)。MS实测值:402[M+H]+、2015[M+2H]2+。
实施例4:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-(甲基亚磺酰基)噻唑-2-基)乙酰胺
步骤1:N,4-二甲基-5-(甲硫基)噻唑-2-胺(P4a)
在冰冷却下,向5-溴-N,4-二甲基噻唑-2-胺(2.06g,9.95mmol)的MeOH(20mL)溶液中缓慢加入NaSMe(1.74g,24.9mmol)的MeOH(15ml)溶液。将混合物加热至60℃并搅拌2h,蒸发并悬浮在MeCN中。离心后,分离上清液并蒸发。将获得的固体用Et2O浆化并离心,得到中间体P4a。
其他化合物可通过使用NaS-Z制备,其中Z属于C1-3-烷基、叔丁基、氟-C1-3-烷基、环丙基、氟-C1-3-烷基-环丙基、-C3-10-杂环基团。
步骤2:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-(甲硫基)噻唑-2-基)乙酰胺(P4b)
将胺P4a(994mg;5.71mmol)和DIPEA(1.89mL,11.4mmol)的DMF(3mL)溶液冷却至-20℃,然后加入2-(2',5'-二氟-[1,1'-联苯]-4-基)乙酸(1.56g,6.28mmol;WO 2003/000259)和HATU(2.39g,6.28mmol)的DMF(5mL)冷却溶液,在室温下搅拌混合液过夜,倒入水中并用EtOAc(2x)萃取。将合并的有机层用盐水(2x)和饱和NaHCO3溶液洗涤,用Na2SO4干燥,蒸发并通过柱色谱(PE/DCM=1:0至1:1)纯化,得到中间体P4b(625mg,27%)。
步骤3:2-(2',5'-氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-(甲基亚磺酰基)噻唑-2-基)乙酰胺(4)
将中间体P4b(1.4g,3.46mmol)的MeOH(35mL)溶液冷却至0℃,然后加入过氧单硫酸钾(1.09g,1.77mmol)的水(18mL)溶液,将溶液在0℃下搅拌20min,用饱和Na2S2O3溶液淬灭并用EtOAc(2x)萃取。将合并的有机层用水(2x)和盐水洗涤,用Na2SO4干燥,蒸发并通过柱色谱(PE/DCM/MeOH=1:0:0至1:1:0至0:19:1)纯化至得到目标化合物4(419mg,29%)。1H-NMR(CDCl3,250MHz)δ:7.57-7.53(m,2H),7.37(d,2H),7.17-6.98(m,3H),4.09(s,2H),3.75(s,3H),2.96(s,3H),2.51(s,3H)。MS实测值:421.3[M+H]+、841.5[2M+H]+。
实施例5:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-(S-甲基-N-((1,1-二甲基乙氧基)羰基)亚胺酰亚磺酰基)噻唑-2-基)乙酰胺)
(2-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methyl-N-((1,1-dimethylethoxy)carbonyl)sulfinimidoyl)thiazol-2-yl)acetamide)
将化合物P4b(197mg,390μmol)和叠氮基甲酸叔丁酯(277mg,1.95mmol)的无水、脱气的DCM(1.5mL)溶液在氩气下冷却至-20℃。然后加入无水FeCl2(49mg,390μmol),使溶液达到室温并搅拌4h,用水稀释并用EtOAc(2x)萃取。将合并的有机层用水和盐水洗涤,用Na2SO4干燥并蒸发,得到目标化合物5。MS实测值:520.4[M+H]+。
实施例6:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-(S-甲基-N-((1,1-二甲基乙氧基)羰基)亚胺酰磺酰基)噻唑-2-基)乙酰胺
(2-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methyl-N-((1,1-dimethylethoxy)carbonyl)sulfonimidoyl)thiazol-2-yl)acetamide)
向化合物5(100mg,193μmol)的THF(10mL)溶液中加入NaIO4(206mg,963μmol)的水(3mL)溶液和氯化钌(III)水合物的水(330μL)溶液。5min后,将混合液用水和EtOAc稀释,并用EtOAc(3x)萃取。将合并的有机层用水和盐水洗涤,用Na2SO4干燥,蒸发并通过HPLC纯化,得到目标化合物6。
实施例7:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-(S-甲基亚胺酰磺酰基)噻唑-2-基)乙酰胺
(2-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide)
在-20℃下向化合物6的DCM溶液中加入50%TFA溶液并将混合液在室温下搅拌1h,蒸发并从叔丁醇/H2O(4:1)中冻干,得到目标化合物7。1H-NMR(CDCl3,400MHz)δ:7.56-7.53(m,2H),7.36(d,2H),7.18-6.95(m,3H),4.08(s,2H),3.75(s,3H),2.95(s,3H),2.51(s,3H)。MS实测值:436.3[M+H]+。
实施例7a:N-[5-(环丙基亚胺酰磺酰基)-4-甲基-噻唑-2-基]-2-[4-(2,5-二氟苯基)苯基]-N-甲基-乙酰胺
(N-[5-(cyclopropylsulfonimidoyl)-4-methyl-thiazol-2-yl]-2-[4-(2,5-difluorophenyl)phenyl]-N-methyl-acetamide)
采用类似的方法使用NaS-Z可以制备实施例化合物7a,其中Z是环丙基:
实施例7b:N-[5-(环丙基亚胺酰磺酰基)-4-甲基-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙酰胺
(N-[5-(Cyclopropylsulfonimidoyl)-4-methyl-thiazol-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide)
实施例7b可以使用适当的结构单元与实施例7a所述类似地的方法制备。
实施例8:(2-(2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰氨基)-4-甲基噻唑-5-基)膦酸二甲酯
(Dimethyl(2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methylacetamido)-4-methylthiazol-5-yl)phosphonate)
步骤1:2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基噻唑-2-基)乙酰胺(P8a)
将2-(2',5'-二氟-[1,1'-联苯基]-4-基)乙酸(648mg,2.61mmol;WO 2003/000259)、EDC·HCl(510mg,2.61)和HOBt(320mg,2.37mmol)的DMF(1.6mL)溶液冷却至0℃,然后加入含有N,4-二甲基噻唑-2-胺(304mg,2.37mmol)和N-甲基吗啉(235μL,2.61mmol)的DMF(1.6mL)冷却溶液。待混合液达到室温后搅拌过夜,倒入水中并用EtOAc(3x)萃取。将合并的有机层用饱和NaHCO3溶液和盐水洗涤,经Na2SO4干燥并蒸发,得到中间体P8a(677mg,72%)。
步骤2:(2-(2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰氨基)-4-甲基噻唑-5-基)膦酸二甲酯(8)
向中间体P8a(670mg,1.85mmol)的冰醋酸(25mL)溶液中加入Mn(OAc)3·2H2O(1.49g,5.55mmol),将混合液加热至80℃。然后加入亚磷酸二甲酯(327μL,2.78mmol)。1.5h后,加入另外的Mn(OAc)3·2H2O(0.75g)和亚磷酸二甲酯(218μL)。1.5h后,将混合液冷却,倒入水中并用EtOAc(2x)萃取。将合并的有机层用水、饱和NaHCO3溶液(2x)和盐水洗涤,用Na2SO4干燥,蒸发并通过柱色谱(DCM/MeOH=1:0至25:1)纯化,得到目标化合物8(539mg)。MS实测值:467.4[M+H]+,933.6[2M+H]+。
实施例9:(2-(2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰氨基)-4-甲基噻唑-5-基)膦酸
将酯8(539mg)溶解在MeCN中并冷却至-20℃,然后加入TMSBr(1.5mL)并将混合液在室温下搅拌过夜。加入另外的TMSBr(1.5mL)并将混合液在45℃下搅拌2h,倒入冰冷的EtOH中,蒸发并连续与EtOH、叔丁醇和Et2O共蒸发。从叔丁醇中冷冻干燥,得到粗目标化合物9(620mg)。1H-NMR(D2O/THF-d8/CD3OD,250MHz)δ:7.53-7.49(m,2H),7.36(d,2H),7.22-7.00(m,3H),4.11(s,2H),3.70(s,3H),2.47(d,3H)。MS实测值:439.2[M+H]+、877.4[2M+H]+。
实施例10和实施例11:P-(2-(2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰氨基)-4-甲基噻唑-5-基)膦酰胺酸(10)和N-(5-(二氨基磷酰基)-4-甲基噻唑-2-基)-2-(2',5'-二氟-[1,1'-联苯]-4-基)-N甲基乙酰胺
将化合物9(240mg,548μmol)的无水THF(8mL)溶液冷却至0℃,然后加入草酰氯(71μL,822μmol)和一滴DMF,在0℃下搅拌30min,然后在室温下搅拌2h。然后加入另外的草酰氯(71μL,822μmol)和两滴DMF,蒸发并与THF共蒸发两次。将剩余的固体溶解在THF中,冷却至-20℃并用12%NH3溶液淬灭。20min后,加入EtOAc。将有机相用6N HCl中和,并用EtOAc(2x)萃取。将合并的有机层用水和盐水洗涤,用Na2SO4干燥,蒸发并通过HPLC(H2O/ACN+0.1%TFA=1:0至0:1)纯化,得到目标化合物10的混合物(17%UV)和目标化合物11(82%UV)。单酰胺10的MS实测值:437.4[M+H]+、873.5[2M+H]+;二酰胺11的MS实测值:438.4[M+H]+、875.3[2M+H]+。
实施例12:N-(5-(N-氰基氨磺酰基)-4-甲基噻唑-2-基)-2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基乙酰胺
2-(2',5'-二氟-[1,1'-联苯]-4-基)-N-甲基-N-(4-甲基-5-氨磺酰基噻唑-2-基)乙酰胺(200mg,458μmo;如WO2001/47904中所述的方法制备)的无水DMF(2mL)溶液与NaH(916μmol,37mg 60%的矿物油悬浮液)在室温下搅拌1h。加入TEA(4.6mmol,641μL),并冷却至-20℃。在冰浴冷却下,逐滴加入含有溴化氰(2.3mmol,242mg)的无水DMF(2mL)溶液,将混合液缓慢升温至室温并搅拌16h。将混合液倒入水中并用EtOAc萃取两次。将合并的有机相用1M KHSO4、饱和NaHCO3、水、盐水洗涤,用Na2SO4干燥,过滤并蒸发。将产物溶于THF(2mL)中,用Et2O(约20mL)沉淀,通过HPLC纯化,得到目标分子12(38mg,18%)。MS实测值:463.2[M+H]+、925.4[2M+H]+。
实施例13:N-[5-(N-氰基-S-甲基-亚胺酰亚磺酰基)-4-甲基-噻唑-2-基]-2-[4-(2,5-二氟苯基)苯基]-N-甲基-乙酰胺
(N-[5-(N-Cyano-S-methyl-sulfinimidoyl)-4-methyl-thiazol-2-yl]-2-[4-(2,5-difluorophenyl)phenyl]-N-methyl-acetamide)
将中间体P4b(250mg,619μmol)和氨腈(21.24mmol,52mg)溶解在MeCN(3mL)中并冷却至-20℃。加入PhI(OAc)2(219mg,681μmol)的MeCN(5mL)冷却(-20℃)溶液。将溶液缓慢升温至室温并在室温下搅拌2h。将产物用Et2O(约30mL)沉淀并在-20℃下放置过夜。离心收集沉淀物并用Et2O洗涤。沉淀物含有约85%纯度的产物。将沉淀物悬浮在MeCN(0.5mL)中并通过两次离心收集以获得目标产物13(98mg,35%)。1H-NMR(CDCl3+CD3OD,300MHz)δ:7.56(m,2H)、7.40(m,2H)、7.16-7.04(m,3H)、4.17(s,2H)、3.82-3.81(m,3H)、3.21(m,3H)、2.59-2.58(m,3H)。MS实测值:445.3[M+H]+、889.4[2M+H]+。
实施例14:N-[5-(N-氰基-S-甲基-亚胺酰磺酰基)-4-甲基-噻唑-2-基]-2-[4-(2,5-二氟苯基)苯基]-N-甲基-乙酰胺
(N-[5-(N-Cyano-S-methyl-sulfonimidoyl)-4-methyl-thiazol-2-yl]-2-[4-(2,5-difluorophenyl)phenyl]-N-methyl-acetamide)
将实施例13(18mg,40μmol)溶解在THF(1.5mL)中。在室温下加入NaIO4(48mg,224μmol)的H2O(800μL)溶液和含有RuCl3·H2O(5.4mg,26μmol)的H2O(300μl)溶液,并剧烈搅拌混合液。5min后,再加入1ml THF,溶解在800μl H2O中的48mg NaIO4和溶解在300μl H2O中的5.4mg RuCl3 x H2O。15min后停止反应(通过倒入水/EtOAc)。用EE萃取产物2次,用水(2x)、饱和NaCl洗涤有机相,用Na2SO4干燥,过滤并浓缩至干。产物通过制备型RP-HPLC纯化。化合物14的产量为12mg(26μmol;65%)。1H-NMR(CDCl3,300MHz)δ:7.57-7.54(d,2H)、7.37(m,2H)、7.14-7.01(m,3H)、4.11(s,2H)、3.77(m,3H)、3.40(m,3H)、2.66(m,3H)。MS实测值:461.2[M+H]+、921.4[2M+H]+。
生物分析
本发明的通式(I)和式(II)化合物表现出了不可预见的令人惊讶的作用谱。它们不仅表现出抗病毒作用,尤其是针对疱疹病毒科的代表,特别是针对单纯疱疹病毒(HSV),还具有改善的溶解性和降低的碳酸酐酶活性。这些化合物特征导致改善的药代动力学特征并因此在体内产生强烈的抗病毒活性。因此,它们适用于治疗和预防由病毒尤其是疱疹病毒引起的病症,特别是由单纯疱疹病毒引起的病症。
本发明的通式(I)和式(II)的化合物表现出了不可预见的令人惊讶的降低的碳酸酐酶活性。
因此,所述化合物不显示或至少降低脱靶活性,特别是没有或减少由碳酸酐酶活性引起的副作用,例如尿路上皮增生或利尿药物学活性(G.Durand-Cavagna etal.Fund.Appl.Toxicol.1992,18:137)。
增加的溶解度改善了化合物的配方,改善了ADME特性,尤其是用于静脉注射应用的配方。
根据C.A.Lipinski et al.Adv.Drug Del.Rev.1997,46:3,在Eurofins,Cerep,Panlabs上测定水溶性(PBS,pH7.4)。
体外活性
病毒和细胞:
HSV(HSV-1Walki、HSV-1F、HSV-2MS、HSV临床分离株和HSV抗性株)在Vero细胞(ATCC CCL-81)上用如下条件培养:细胞在37℃和5%CO2下,在含有M199培养基(5%胎牛血清、2mM谷氨酰胺、100IU/mL青霉素、100μg/mL链霉素)的细胞培养瓶中生长。细胞每周分裂两次(1:4)。对于感染实验,去除培养基,用Hank’s溶液洗涤细胞,用0.05%胰蛋白酶、0.02%EDTA分离,并在上述条件下以4×105细胞/mL的密度孵育24h。去除培养基,在每175cm2表面加入2ml体积m.o.i<0.05的病毒溶液。将感染的细胞在37℃、5%CO2下孵育1h,然后将培养基补充至每175cm2瓶里有50mL的体积。感染后3天,培养物显示出明显的细胞病变效应。通过两次冷冻(-80℃)和解冻(37℃)感染的培养物释放病毒。通过离心(300g,10min,4℃)除去细胞碎片,并将上清液等分于-80℃冷冻。
使用噬菌斑测定法测定病毒滴度。为此,将Vero细胞以每孔4×105个细胞的密度接种于24孔板中,孵育24h(37℃,5%CO2)后用在100μL培养液(病毒储液的稀释液(10-2至10-12)中感染。感染1h后,去除培养基,用1mL覆盖培养基(0.5%甲基纤维素、0.22%碳酸氢钠、2mM谷氨酰胺、100IU/mL青霉素、100μg/mL链霉素、含有Earl's盐的MEM-Eagle培养基中的5%胎牛血清)覆盖细胞,并在细胞培养箱在(37℃,5%CO2)下孵育3天。然后用4%福尔马林固定细胞1h,用水洗涤,用Giemsa染色30min,然后洗涤并干燥。使用斑块观察器确定病毒滴度。用于实验的储液的滴度为1×105/mL至1×108/mL。
使用专利(DE10235967和WO2004/015416)和随后公布的活性选择性测定(G.Kleymann et al.J.Biomol.Screen.2004;9:578)在96孔或384孔微量滴定板中,使用神经元、淋巴和上皮来源的各种细胞系,例如Vero(非洲绿猴肾细胞)、MEF(小鼠胚胎成纤维细胞)、HELF(人胚胎成纤维细胞)、NT2(人神经细胞系)或Jurkat(人淋巴T细胞系)来测定抗病毒作用。用于评价本发明(公开的化合物)抗病毒活性的上述专利和出版物的相关实验细节描述如下。
与参考化合物阿昔洛韦钠(ZoviraxTM)(一种临床批准的抗疱疹化疗药物)相比较,确定了这些物质对细胞病变效应扩散的影响。
在微量滴定板(例如96孔平底细胞培养板)上,以终浓度为250至0.5μM检测化合物(溶于DMSO中的50mM储液),或检测2至4次重复(每板4至2种物质),或者在强效抗病毒化合物的情况下,250至0.5nM。还检查了化合物的毒性和细胞抑制作用或沉淀。用合适的培养基(100μL)在微量滴定板上适当稀释化合物(1:2)后,细胞悬浮液(50μL,每孔1×104个细胞)添加到每个孔中,所述细胞为例如M199培养基(含5%胎牛血清、2mM谷氨酰胺和任选地100IU/ml青霉素和100μg/ml链霉素的199培养基)中的Vero细胞,或EMEM培养基(含10%胎牛血清、2mM谷氨酰胺和任选地100IU/mL青霉素和100μg/mL链霉素的Eagle’s最低必需培养基)中的MEF或HELF细胞、或DMEM培养基(含10%胎牛血清(4.5mg/L葡萄糖加吡哆醇)、2mM谷氨酰胺、1mM丙酮酸钠、非必需氨基酸和100IU/mL青霉素和100μg/mL链霉素)中的NT2-和Jurkat细胞,并且使相关孔中的细胞感染适当量的病毒(对于Vero、HELF和MEF细胞,HSV-1或HSV-2的m.o.i(感染复数)为0.0025,对于NT2和Jurkat细胞,m.o.i为0.1。)然后将板在37℃下的细胞CO2培养箱(5%CO2)中温育数天。此后,细胞集团,例如,无病毒基质对照中的Vero细胞,从25个感染中心开始,被疱疹病毒(100%CPE)的致细胞病变效应(CPE)完全破坏或裂解。首先用显微镜视觉上评价板,然后用荧光染料分析。为此,吸出MTP的所有孔的细胞上清液,并用250μLPBS(磷酸盐缓冲盐水)洗涤溶液填充孔。然后吸出PBS并用200μL荧光染料溶液(荧光素二乙酸酯,10μg/mL在PBS中)填充所有孔。在30至90min的温育时间后,在荧光检测器中以485nm的激发波长和538nm的发射波长读取测试板。这里,IC50是相对于未感染细胞对照(100%值)的半最大荧光强度。IC50值[%]((化合物处理的感染细胞减去未处理的病毒感染细胞)除以(细胞对照或Zovirax处理的感染细胞减去未处理的感染细胞)×100)也可以参考合适的活性化合物对照(参见测定描述:在合适浓度的抗病毒化合物例如Zovirax20μM的存在下感染细胞)。该活性化合物对照相对于未感染的细胞对照达到约85-100%的荧光强度。一些化合物的结果总结在下表1中:
表1
优选本发明的抗病毒化合物,其在上述活性选择性测定中的IC50(HSV-1/Vero)优选低于100μM,更优选低于10μM,非常特别优选低于1μM。
因此,本发明的化合物对于治疗和预防由病毒,特别是疱疹病毒,非常特别是单纯疱疹病毒引起的疾病是有用的活性化合物。
令人惊讶地发现,如本文所述的制备方法的中间体化合物在要求保护的适应症中也显示出良好的活性和适用性。因此,本发明进一步涉及如本文所述(本身)的中间体化合物以及具有各自良好活性和适用性的那些中间体的相应的医学用途。
可提到的适应症范围的示例是:
1)治疗和预防具有唇疱疹、生殖器疱疹和疱疹相关性角膜炎、阿尔茨海默病、脑炎、肺炎、肝炎等患者的疱疹感染,特别是单纯疱疹感染。。
2)治疗和预防免疫系统受抑制患者(例如AIDS患者、癌症患者、具有遗传免疫缺陷的患者、移植患者)的疱疹感染,特别是单纯疱疹感染。
3)治疗和预防新生儿和婴儿的疱疹感染,特别是单纯疱疹感染
4)治疗和预防疱疹感染,特别是单纯疱疹感染,并在疱疹阳性患者,特别是单纯疱疹阳性患者中用于抑制复发(抑制治疗)。
5)治疗和预防疱疹感染,特别是单纯疱疹感染,并在疱疹阳性患者,特别是单纯疱疹阳性患者,其对核苷酸抗病毒治疗如阿昔洛韦、喷昔洛韦、泛昔洛韦、更昔洛韦、伐昔洛韦等有抗性。
碳酸酐酶活性
碳酸酐酶II活性及其各自的抑制实验根据R.Iyer etal.J.Biomol.Screen.2006,11:782进行,或者碳酸酐酶I活性,基于人类原始材料根据A.R.Katritzky et al.J.Med.Chem.1987,30:2058进行。
使用pH指示剂方法测定室温下碳酸酐酶活性的方案描述如下:
将1μL抑制剂(在DMSO中的50mM储液)稀释至最终测试浓度,其范围为100μM至1nM(或对照中的1μL水),并用0.5至2EU人碳水化合物I(180U/mg)的400μL水和200μL酚红指示剂溶液(20mg/L)中孵育2min。酶促单元(EU)定义为使非催化速率加倍的量。通过添加100μL0.5M碳酸氢盐缓冲液(0.3M Na2CO3;0.2M NaHCO3)并随后通过注射器(0.7×30mm;22G×1.25)将CO2以10mL gas/min的速率充入待测溶液来引发水合反应。颜色变化(pH 7.2)的时间用微时计或秒表确定。
抑制百分比的计算方法如下:
(没有酶的变色时间–有酶和抑制剂的变色时间)/
(没有酶的变色时间–有酶的变色时间)。
IC50值(抑制浓度)反映了抑制剂的摩尔量,其将测试系统中的EU活性降低了50%。
在测试系统中,对于实施例3,检测到了无或减少的碳酸酐酶抑制,但与该发现相反,实施例87(WO2001/047904)显示在1-3μM(IC50)范围内的碳水化合物酶抑制。
结果如下表2所示:
表2
水溶性(PBS,pH 7.4)
根据Lipinski,C.A.et al.(1997),Adv.Drug Del.Rev.,46:3-26,进行水溶性的测量。文献中的相关信息如下所述。
化合物(在DMSO中的10mM储液)的水溶解度(μM,摇瓶,24h温育,RT)通过比较含有有机溶剂(甲醇/水,60/40,v/v)的校准标准品(200μM)中主峰的峰面积(HPLC-UV/VIS)与在缓冲液样品(PBS,pH7.4)中相应峰的峰面积来确定。另外,色谱纯度(%)定义为相对于校准标准品的HPLC色谱图中的总综合峰峰面积的主峰峰面积。
在水溶性测试系统中,与实施例87(WO2001/047904)相比,实施例3检测到了显著增加的溶解度(至少一个数量级)。
结果如下表3所示:
表3
体内活性
药代动力学
实施例3的药代动力学参数在雄性小鼠C57BL/6J中以5mg/kg(异源血浆中5%DMSO,2.5ml/kg)的静脉(i.v.)剂量和10mg/kg(DMSO/0.5%HPMC(5:95),5ml/kg)的口服剂量(p.o.)测定。给药10mg/kg p.o.后的最大血浆浓度达到13.9μM(cmax)1h(tmax)。口服剂量为10mg/kg时终端半衰期为~3.5h,各自的生物利用度为94%。在给药10mg/kg的口服剂量6h后,检测到处理小鼠的脑中的明显浓度(2-3μM,1000ng化合物/g脑)。
动物模型
根据专利WO2001/047904或随后的出版物(U.A.K.Betz etal.Antimicrob.Agents Chemother.2002;46:1766或G.Kleymann et al.Nat.Med.2002;8:392)进行动物实验。用于评价本发明(公开的化合物)体内(动物模型)的抗病毒活性的上述专利和出版物的相关实验细节如下描述。
动物:
从商业育种者获得的6周龄雌性小鼠BALB/ABom株。
感染:
在密封的玻璃容器中用Et2O麻醉动物。使用移液管将50μL稀释的病毒储液(感染剂量5×104PFU(噬斑形成单位))引入麻醉动物的鼻中。在90%至100%的动物中,这种感染剂量在平均5至8天后引起明显的呼吸和中枢神经症状普遍感染导致死亡。
治疗和评估:
感染后6h,动物用0.1-150mg/kg体重的剂量进行为期5天治疗,每天3次,上午7点、下午2点和下午7点(tid)或每天2次,上午7点和下午7点(bid)或每天一次,下午1点(od),。将化合物预先溶解在DMSO中,并重悬于0.5%HPMC(羟丙基甲基纤维素)的水或PBS(DMSO/0.5%HPMC(最大5:95,理想的是1.5%DMSO,0.5%HPMC的水或PBS))中。在最后一次给药后,进一步监测动物并确定死亡时间。
对实施例3的化合物的存活曲线进行了比较,例如HSV-1的ED50小于10mg/kg,ED50指50%受感染的动物在该剂量下存活。
新型活性化合物可以以已知的方式转化成常规制剂,例如片剂、囊片、糖衣片剂、丸剂、颗粒剂、气溶胶剂,糖浆剂、药学上合适的载体和溶剂。这里,治疗活性化合物在每种情况下应以总混合物重量的约0.1-90%的浓度存在,即以足以达到所示剂量范围的量存在。
例如,如果有可能,可以使用乳化剂和(或)分散剂,例如,如果使用的稀释剂是水,则通过在适当情况下使用有机溶剂作为辅助溶剂,将活性化合物与溶剂和(或)赋形剂进行延伸来制备制剂。
给药以常规方式进行,优选口服、注射或局部给药,特别是舌或静脉内给药。
在注射给药的情况下,可以使用合适的液体载体材料的活性化合物溶液。
一般而言,已证实在静脉给药中施用剂量约0.001至20mg/kg,优选约0.01至10mg/kg体重以达到有效结果,并且在口服给药的情况下,剂量约为0.01至30mg/kg体重,优选0.1至20mg/kg体重,是有利的。
尽管如此,如果合适,可能有必要偏离所述量,即取决于体重或给药途径的类型、个体对药物的反应、其制剂的方式和时间或给药发生的间隔。因此,在某些情况下,低于上述最小量进行给药可能是足够的,而在其他情况下,必须超过所述的上限。在施用相对大量的情况下,建议在一天中将其分成几次单独给药。
如果合适,将根据本发明的化合物与其他活性物质结合,特别是与抗病毒活性化合物结合可能是有用的,即所谓的组合疗法。
Claims (22)
8.根据权利要求1-7任一项所述的化合物在制备用于治疗或预防由疱疹病毒引起的病毒感染相关的疾病或病症的药物中的用途。
9.根据权利要求8所述的用途,其中疾病或病症与由单纯疱疹病毒引起的病毒感染有关。
10.根据权利要求8所述的用途,其用于制备用于治疗或预防疱疹感染的药物。
11.根据权利要求10所述的用途,其中所述疱疹感染的患者显示为唇疱疹、生殖器疱疹或疱疹相关性角膜炎。
12.根据权利要求10所述的用途,其中所述疱疹感染的患者是单纯疱疹阳性患者。
13.根据权利要求10所述的用途,其中所述疱疹感染的患者为患有阿尔茨海默病、脑炎、肺炎、肝炎的患者。
14.根据权利要求10所述的用途,其中所述疱疹感染的患者为免疫系统受到抑制的患者。
15.根据权利要求10所述的用途,其中所述疱疹感染的患者为艾滋病患者、癌症患者。
16.根据权利要求10所述的用途,其中所述疱疹感染的患者为患有遗传性免疫缺陷的患者。
17.根据权利要求10所述的用途,其中所述疱疹感染的患者为移植患者。
18.根据权利要求10所述的用途,其中所述疱疹感染的患者为新生儿。
19.根据权利要求10所述的用途,其中所述疱疹感染的患者为婴儿。
20.根据权利要求10所述的用途,其中所述疱疹感染的患者为抑制复发的疱疹阳性患者。
21.根据权利要求10所述的用途,其中所述疱疹感染的患者为对核苷类抗病毒治疗有抗性的患者,所述对核苷类抗病毒治疗包括阿昔洛韦、喷昔洛韦、泛昔洛韦、更昔洛韦、伐昔洛韦。
22.一种药物组合物,其包含一种或多种根据权利要求中1-7任一项所述的化合物和至少一种药学上可接受的载体和/或赋形剂和/或至少一种其他抗病毒活性物质,所述抗病毒活性物质选自阿昔洛韦、伐昔洛韦、喷昔洛韦、更昔洛韦、泛昔洛韦、三氟尿苷、膦甲酸钠和西多福韦。
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WO2005075435A1 (en) * | 2004-01-30 | 2005-08-18 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
CN103269593A (zh) * | 2010-11-01 | 2013-08-28 | 罗马克实验室有限公司 | 烷基亚磺酰基取代的噻唑化物化合物 |
CN103842359A (zh) * | 2011-09-26 | 2014-06-04 | 艾库里斯有限责任两合公司 | N-[5-(氨基磺酰基)-4-甲基-1,3-噻唑-2-基]-n-甲基-2-[4-(2-吡啶基)苯基]乙酰胺甲磺酸盐一水合物 |
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