CN117756742A - 苯并噻唑类化合物或其盐、其制备方法及应用 - Google Patents
苯并噻唑类化合物或其盐、其制备方法及应用 Download PDFInfo
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- CN117756742A CN117756742A CN202311770836.5A CN202311770836A CN117756742A CN 117756742 A CN117756742 A CN 117756742A CN 202311770836 A CN202311770836 A CN 202311770836A CN 117756742 A CN117756742 A CN 117756742A
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- Prior art keywords
- thiazol
- benzo
- hydroxyheptanamide
- phenoxy
- compound
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- 238000002360 preparation method Methods 0.000 title claims abstract description 81
- -1 Benzothiazole compound Chemical class 0.000 title claims abstract description 71
- IOJUPLGTWVMSFF-UHFFFAOYSA-N cyclobenzothiazole Natural products C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 150000003839 salts Chemical class 0.000 title claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 30
- 239000001257 hydrogen Substances 0.000 claims abstract description 30
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 21
- 150000002367 halogens Chemical class 0.000 claims abstract description 21
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 18
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 13
- 208000010061 Autosomal Dominant Polycystic Kidney Diseases 0.000 claims abstract description 11
- 208000022185 autosomal dominant polycystic kidney disease Diseases 0.000 claims abstract description 11
- 102100022537 Histone deacetylase 6 Human genes 0.000 claims abstract description 10
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 claims abstract description 10
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 230000002062 proliferating effect Effects 0.000 claims abstract description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000005605 benzo group Chemical group 0.000 claims description 69
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 66
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 23
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
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- 229960001171 acetohydroxamic acid Drugs 0.000 claims description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 6
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
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- 206010006187 Breast cancer Diseases 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
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- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
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- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
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- 239000003937 drug carrier Substances 0.000 claims description 2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- QLMPWDWLVIWORW-UHFFFAOYSA-N n-hydroxyheptanamide Chemical compound CCCCCCC(=O)NO QLMPWDWLVIWORW-UHFFFAOYSA-N 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
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Abstract
本发明公开了一类苯并噻唑类化合物或其盐、其制备方法及应用。所述苯并噻唑类化合物具有式(I)所示结构,其中R1、R2至少独立地选自氢、卤素、氰基、硝基、C1‑6烷基、C1‑6烷氧基、C3‑8环烷基、芳基、杂芳基或杂环基,n为1~7。所述苯并噻唑类化合物或其药学上可接受的盐可用于制备治疗增殖性疾病等的药物。尤其是,所述苯并噻唑类化合物可靶向HDAC6治疗常染色体显性多囊肾病(ADPKD),对MDCK细胞有很好的抑制作用,且在给药剂量为1mg/kg时,对ADPKD小鼠的抑制活性与Tolvaptan与相当,为常染色体显性多囊肾病的治疗和预防提供了新的路径。
Description
技术领域
本发明具体涉及一类苯并噻唑类化合物或其盐、其制备方法及制药用途,属于医药化合物技术领域。
背景技术
组蛋白脱乙酰酶(HDACs)催化从组蛋白氨基末端的赖氨酸残基中去除乙酰基,导致染色质浓缩和转录抑制。已在人类中鉴定出18种HDACs,根据它们与酵母HDACs的同源性、亚细胞定位和酶活性,将它们分为四类。I类HDACs(1、2、3和8)与酵母RPD3蛋白同源,通常可在细胞核中检测到,并在各种人类细胞系和组织中普遍表达。II类HDACs(4、5、6、7、9和10)与酵母Hda1蛋白具有同源性,可以在细胞核和细胞质之间穿梭。IIb类HDACs,HDAC6和10存在于细胞质中并包含两个脱乙酰酶结构域。HDAC6具有独特的底物特异性,具有对细胞骨架蛋白α-微管蛋白具有特异性的α-微管蛋白脱乙酰酶(TDAC)结构域。III类HDACs(SIRT1、2、3、4、5、6和7)是酵母蛋白Sir2的同系物,需要NAD+才能发挥调节基因表达的活性,以响应细胞氧化还原状态的变化。SIRT1已被证明与p53相互作用并使p53去乙酰化,从而抑制p53介导的转录活性。HDAC11是IV类HDACs的唯一成员。它与I类和II类酶的催化核心区域具有序列相似性,但没有足够强的同一性来归入任何一类。
研究表明,HDACs拮抗剂在治疗多发性骨髓瘤,急性髓性白血病,弥漫性大B细胞淋巴瘤,阿尔茨海默病,乳腺肿瘤,非霍奇金淋巴瘤,结直肠肿瘤,皮肤T细胞淋巴瘤,胶质母细胞瘤,艾滋病毒感染,炎症性疾病,胰腺肿瘤,外周T细胞淋巴瘤以及常染色体显性多囊肾病中有积极作用。伏立诺他(vorinostat)、罗米地辛(romidepsin)、贝利司他(belinostat)、帕比司他(panobinostat)等为美国FDA批准上市,用于临床治疗外周T细胞淋巴瘤、皮肤T细胞淋巴瘤和多发性骨髓瘤;西达本胺(tucidinostat/chidamide)由我国NMPA批准上市,用于外周T细胞淋巴瘤和乳腺癌。以上这些HDACs抑制剂的开发已成为治疗上述疾病药物研发的热点方向。这类化合物具有拮抗组蛋白去乙酰化酶受体的活性,并因此可应用于治疗上述疾病。
目前上市的HDACs抑制剂大多数都是非选择性抑制剂,具有副作用大、不良反应多等缺陷。研究表明,HDAC6被敲除的小鼠能够存活并且HDAC6选择性抑制剂能够应用于ADPKD疾病治疗。目前临床上唯一被FDA(美国食品药品监督管理局)认证的ADPKD有效治疗药物是托伐普坦,但是在临床试验中,托伐普坦减缓患者肾功能下降的同时,部分患者血清肝转氨酶上升至正常水平三倍以上,这表明托伐普坦的使用会引起肝损伤。因此需要开发新的HDAC6选择性抑制剂,研发出治疗效果更好、毒副作用更小的药物来缓解疾病的发生。
发明内容
本发明的目的之一是提供一类苯并噻唑类化合物或其盐,其能作为有效的HDAC6激酶抑制剂,治疗与HDAC6激酶介导的增殖相关疾病,具有应答率高、副作用小、不良反应少等特点,满足临床用药的需求,从而克服现有技术的缺陷。
本发明的目的之二是提供所述苯并噻唑类化合物或其药学上可接受的盐在制备用于预防和/或治疗增殖性疾病的药物中的应用。
本发明的目的之三是提供所述苯并噻唑类化合物或其盐的制备方法。
为实现上述发明目的,本发明采用了如下技术方案:
本发明的第一个方面提供了一类苯并噻唑类化合物或其盐,所述苯并噻唑类化合物具有式(I)所示结构,
其中R1、R2至少独立地选自氢、卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C3-8环烷基、芳基、杂芳基和杂环基中的任一者,n为1~7中的任一整数。
其中,若定义式(I)中苯并噻唑基团为A单元,与苯并噻唑基团连接的苯环基团为B单元,与B单元通过醚键连接的基团为C单元,则B单元中R2连接在苯环的2、3或6位,C单元是连接在B单元中苯环的4位或者5位。
在一个实施例中,R1选自氢、卤素、C1-6烷基或C1-6烷氧基,R2选自氢、卤素、C1-6烷基或C1-6烷氧基。
较为优选的,R1选自氢、卤素、C1-6烷基或C1-6烷氧基,R2选自氢、卤素、甲氧基、乙氧基或甲基。
更为优选的,R1为氢,R2选自氢、卤素、甲氧基、乙氧基或甲基中的任一者。
较为优选的,R1为氢,R2选自氢、卤素、甲氧基、乙氧基或甲基中的任一者。
较为优选的,所述R1为氢,R2选自氢、卤素、甲氧基、乙氧基或甲基中的任一者。
其中,所述卤素优选为氟或氯。
较为优选的,R1为卤素,R2选自氢或甲氧基。
更为优选的,R1为氟或氯,R2选自氢或甲氧基。
较为优选的,R1为C1-6烷基,R2选自氢或甲氧基。
更为优选的,R1为甲基,R2选自氢或甲氧基。
较为优选的,R1为C1-6烷氧基,R2选自氢或甲氧基。
更为优选的,R1为甲氧基,R2选自氢或甲氧基。
在一个实施例中,所述苯并噻唑类化合物包括2-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基乙酰胺、6-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基己酰胺、7-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、8-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基辛酰胺、7-(4-(苯并[d]噻唑-2-基)-2-氟苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-甲基苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-氯苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-乙氧基苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-3-氯苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-3-氟苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2,6-二甲氧基苯氧基)-N-羟基庚酰胺、2-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基乙酰胺、4-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基丁酰胺、5-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基戊酰胺、6-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基己酰胺、7-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、8-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基辛酰胺、7-(3-(苯并[d]噻唑-2-基)-2-氯苯氧基)-N-羟基庚酰胺、7-(5-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、N-羟基-7-(2-甲氧基-5-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(5-(6-氯苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、7-(5-(6-氟苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、N-羟基-7-(2-甲氧基-5-(6-甲基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(5-(5-氯苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、N-羟基-7-(4-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(4-(6-氟苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、7-(4-(6-氯苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、N-羟基-7-(4-(6-甲基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(4-(5-氯苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、8-(5-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基辛酰胺以及7-(3-(苯并[d]噻唑-2-基)-2-氟苯氧基)-N-羟基庚酰胺中的任一者,但不限于次。
在一个实施例中,所述苯并噻唑类化合物的盐包括--盐酸盐、对甲苯磺酸盐、硫酸盐、琥珀酸盐、马来酸盐、富马酸盐、醋酸盐、磷酸盐、构橼酸盐、甲磺酸盐、钠盐中的任一者。
本发明的第二个方面提供了一类苯并噻唑类化合物的制备方法,其包括:
S1、以式(II)所示化合物为起始原料,与式(IV)所示化合物在第一反应体系中反应形成式(V)所示的第一中间体,所述第一反应体系包含连亚二硫酸钠、乙醇和水。其中,式(II)所示化合物、式(IV)所示化合物及连亚二硫酸钠的当量比可以为1~2∶1~2∶2~4,优选为1∶1∶2左右。反应的温度可以为50~100℃,优选为80℃左右。乙醇和水主要用作溶剂,乙醇和水的体积比可以为5∶1~2左右,优选为8∶3左右。
S2、使所述第一中间体(1eq)在第二反应体系中反应,得到式(VI)所示的第二中间体,所述第二反应体系包含三溴化硼和二氯甲烷。其中,所述第一中间体与三溴化硼的当量比可以为1∶3~8左右,优选为1∶6左右。二氯甲烷主要用作溶剂。所述的反应可以先在0℃左右进行0.5h左右,之后在常温下进行6~12h左右。
S3、使所述第二中间体和式(VII)所示的溴代烷基酯类化合物在第三反应体系中反应,得到式(VIII)所示的第三中间体,所述第三反应体系包括碳酸钾、碘化钾以及N,N-二甲基甲酰胺或乙腈。其中,所述第二中间体、式(VII)所示的溴代烷基酯类化合物、碳酸钾和碘化钾的当量比可以为1~2∶1~2∶2~4∶0.1~0.5,优选为1∶1.5∶2∶0.1左右。N,N-二甲基甲酰胺或乙腈主要用作溶剂。所述反应的温度可以为50~100℃,优选为80℃左右,时间可以为8~12h左右。
S4、使所述第三中间体在第四反应体系中反应,制得式(I)所示的苯并噻唑类化合物,所述第四反应体系包括羟胺的甲醇溶液。其中,所述第三中间体与羟胺的当量比可以为1∶3~3∶1。所述反应的温度可以为常温,时间可以为1-2h左右。
其中R1、R2至少独立地选自氢、卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C3-8环烷基、芳基、杂芳基和杂环基中的任-者,n为1~7中的任-整数,n1的取值为1、3、4、5、6或7,n2的取值为0或1。
本发明的第三个方面提供了一种药物组合物,其包括:
治疗有效量的所述苯并噻唑类化合物或其药学上可接受的盐;
以及,一种或多种药学上可接受的载体。
本发明的第四个方面提供了所述苯并噻唑类化合物或其药学上可接受的盐或者所述药物组合物在制备HDAC6激酶抑制剂中的用途。
本发明的第五个方面提供了所述苯并噻唑类化合物或其药学上可接受的盐或者所述药物组合物在制备用于预防和/或治疗增殖性疾病的药物中的用途。
在一个实施例中,所述增殖性疾病包括急性髓性白血病、慢性髓性白血病、甲状腺癌、胃癌、胃肠基质肿瘤、结肠直肠癌、前列腺癌、乳腺癌、卵巢癌、胰腺癌、肺癌、非小细胞肺癌、淋巴瘤、肾癌、常染色体显性多囊肾病和骨髓瘤中的任一种,且不限于此。
本发明的第六个方面提供了所述苯并噻唑类化合物或其药学上可接受的盐或者所述药物组合物在制备用于预防和/或治疗常染色体显性多囊肾病的靶向药物中的用途。
本发明提供的一类苯并噻唑类化合物或其药学上可接受的盐在用作HDAC6激酶抑制剂时,对MDCK细胞和组织胚胎肾实验有很好的抑制作用,且在给药剂量为1mg/kg时,对ADPKD小鼠的抑制活性与Tolvaptan与相当,为常染色体显性多囊肾病的治疗和预防提供了一类新型先导化合物。
具体实施方式
下面结合实施例对本发明作进一步详细说明。
通过下列的合成方案和实施例来进一步说明具体实施方案,其不应当认为是任何方式的限制。用于生成数据的实验程序将在下文中详细探讨。对于这里所有的制剂、多个剂量可按照本领域公知技术按比例配比。
本发明如下实施例中的苯并噻唑类化合物1-32的制备方法包括:
先以不同取代的2-氨基苯硫醇起始原料,与不同取代的甲氧基苯甲醛在连亚二硫酸钠、乙醇和水的体系反应,得到第一中间体;
之后,以所述第一中间体在三溴化硼和二氯甲烷的体系中反应,得到第二中间体;
然后,使所述第二中间体和不同碳链长度的溴代烷基酯类化合物在碳酸钾、碘化钾和N,N-二甲基甲酰胺或乙腈体系中反应,得到第三中间体;
最后,使所述第三中间体与羟胺的甲醇溶液反应,制得所述苯并噻唑类化合物。
所述制备方法的具体反应原理如下所示:
实施例1
2-(4-(苯并[d]噻唑-2-基)苯氧基)N-羟基乙酰胺(化合物1)的制备方法包括如下步骤:
步骤1:4-(苯并[d]噻唑-2-基)苯酚(第二中间体)的制备方法包括:
将2-氨基苯硫醇(2.0g,15.98mmol)溶于乙醇(16ml)中,加入4-羟基苯甲醛(1.95g,15.98mmol)搅拌,然后将连二亚硫酸钠(5.56g,31.95mmol)加入水(6ml)中,迅速加入上述混合物中,80℃搅拌8小时。减压蒸干溶剂,加入1M盐酸至酸性搅拌30分钟,抽滤,滤饼先用水洗三次,最后PE洗一次,得黄色固体第二中间体(3.56g,收率:98%)。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.06-7.92(m,2H),7.92-7.85(m,2H),7.50-7.32(m,2H),6.93-6.84(m,2H).MS(ESI)calculated for C13H10NOS+[M+H]+228.0;Found:227.9。
步骤2:乙基2-(4-(苯并[d]噻唑-2-基)苯氧基)乙酸酯(第三中间体)的制备方法包括:
将第二中间体(0.5g,2.2mmol)溶于乙腈(20ml)中,加入碳酸钾(0.61g,4.4mmol)和催化量的碘化钾搅拌,最后加入2-溴乙酸乙酯(0.55g,3.3mmol),80℃搅拌8小时。减压蒸干溶剂,加水(100ml)稀释,以乙酸乙酯(50ml)萃取三次,合并有机相,减压蒸干溶剂。固体残留物经硅胶柱层析纯化(洗脱剂∶PE/EA=10∶1),得淡黄色第三中间体(0.6g,收率:87%)。1H NMR(400MHz,CDCl3)δ8.07-7.99(m,3H),7.87(d,J=7.9,1.0Hz,1H),7.46(t,J=8.3,7.2,1.3Hz,1H),7.35(t,J=8.1,7.2,1.2Hz,1H),7.03-6.97(m,2H),4.69(s,2H),4.28(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).MS(ESI)calculated for C17H16NO3S+[M+H]+314.1;Found:314.0。
步骤3:2-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基乙酰胺(化合物1)的制备方法包括:
将第三中间体(0.15g,0.48mmol)溶于二氯甲烷(2ml)中,加入羟胺的甲醇溶液(6ml,6.6g氢氧化钾溶于20ml甲醇,冰浴下缓慢加入4.67g盐酸羟胺20ml的甲醇溶液中制得),室温搅拌1小时。减压蒸干溶剂,加入甲醇20ml,加入1M盐酸调PH=7-8,搅拌10分钟,抽滤,滤饼先用水洗三次,最后PE洗一次,得白色固体状的化合物1(134mg,收率:93.1%)。1HNMR(400MHz,DMSO-d6)δ10.93(s,1H),9.02(s,1H),8.07(d,J=8.1Hz,1H),8.03-7.96(m,3H),7.48(t,J=7.7Hz,1H),7.39(t,J=7.6Hz,1H),7.13-7.07(m,2H),4.56(s,2H).MS(ESI)calculated for C15H13N2O3S+[M+H]+301.1;Found:300.9。
实施例2
6-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基己酰胺(化合物2)的制备方法包括:
将实施例1的步骤2中的2-溴乙酸乙酯替换成6-溴己酸甲酯,其余所需原料,试剂及制备方法同实施例1,最终获得白色固体状的化合物2。1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.67(s,1H),8.06(d,J=7.9,1.2Hz,1H),8.01-7.93(m,3H),7.47(t,J=8.3,7.2,1.3Hz,1H),7.38(t,J=8.2,7.2,1.2Hz,1H),7.09-6.97(m,2H),4.00(t,J=6.5Hz,2H),1.95(t,J=7.3Hz,2H),1.69(p,J=6.6Hz,2H),1.52(p,J=7.3Hz,2H),1.36(p,J=9.7,5.9Hz,2H).MS(ESI)calculated for C19H21N2O3S+[M+H]+357.1;Found:357.0。
实施例3
7-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺(化合物3)的制备方法包括:
将实施例1步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1,得白色固体状的化合物3。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),8.07(d,1H),8.01-7.93(m,3H),7.48(t,J=8.3,7.2,1.3Hz,1H),7.38(t,J=8.2,7.2,1.2Hz,1H),7.12-6.98(m,2H),4.01(t,J=6.5Hz,2H),1.92(t,J=7.3Hz,2H),1.69(p,J=6.7Hz,2H),1.48(p,J=7.4Hz,2H),1.38(p,J=7.1Hz,2H),1.26(p,J=7.6,3.4Hz,2H).HRMS(ESI)calculated for C20H23N2O3S+[M+H]+371.1;Found:371.0。
实施例4
8-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基辛酰胺(化合物4)的制备方法包括:
将实施例1步骤2中的2-溴乙酸乙酯替换成8-溴辛酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤5,得白色固体状的化合物4。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),8.06(d,J=6.9Hz,1H),8.00-7.93(m,3H),7.52-7.43(m,1H),7.42-7.33(m,1H),7.05(d,J=8.9Hz,2H),4.00(t,J=6.5Hz,2H),1.91(t,J=7.4Hz,2H),1.76-1.61(m,2H),1.51-1.41(m,2H),1.41-1.32(m,2H),1.32-1.17(m,4H).MS(ESI)calculated forC21H24N2NaO3S+[M+Na]+407.1;Found:406.7。
实施例5
7-(4-(苯并[d]噻唑-2-基)-2-氟苯氧基)-N-羟基庚酰胺(化合物5)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-氟-4-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物5。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.64(s,1H),8.08(d,J=8.0Hz,1H),7.98(d,J=7.1Hz,1H),7.89-7.82(m,1H),7.79(d,J=8.6Hz,1H),7.49(t,J=8.3Hz,1H),7.40(t,J=8.2Hz,1H),7.27(t,J=8.6Hz,1H),4.08(t,J=6.5Hz,2H),1.92(t,J=7.4Hz,2H),1.75-1.66(m,2H),1.53-1.42(m,2H),1.43-1.32(m,2H),1.32-1.22(m,2H).MS(ESI)calculated for C20H21FN2KO3S+[M+K]+:427.1;found:426.6.
实施例6
7-(4-(苯并[d]噻唑-2-基)-2-甲基苯氧基)-N-羟基庚酰胺(化合物6)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成4-羟基-3-甲基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物6。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),8.05(d,J=8.1Hz,1H),7.95(d,J=7.0Hz,1H),7.86-7.80(m,2H),7.51-7.43(m,1H),7.41-7.33(m,1H),7.02(d,J=8.4Hz,1H),4.00(t,J=6.4Hz,2H),2.20(s,3H),1.93(t,J=7.4Hz,2H),1.75-1.66(m,2H),1.53-1.44(m,2H),1.44-1.35(m,2H),1.33-1.22(m,2H).MS(ESI)calculated for C21H25N2O3S+[M+H]+385.2;Found:384.7。
实施例7
7-(4-(苯并[d]噻唑-2-基)-2-氯苯氧基)-N-羟基庚酰胺(化合物7)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-氯-4-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物7。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.64(s,1H),8.08(d,J=6.8Hz,1H),8.06(d,J=2.3Hz,1H),7.98(d,J=7.1Hz,1H),7.93(d,J=8.6,2.2Hz,1H),7.49(t,J=8.3,7.2,1.3Hz,1H),7.40(t,J=8.3,7.2,1.2Hz,1H),7.25(d,J=8.7Hz,1H),4.09(t,J=6.4Hz,2H),1.93(t,J=7.3Hz,2H),1.76-1.66(m,2H),1.53-1.45(m,2H),1.44-1.35(m,2H),1.33-1.23(m,2H).MS(ESI)calculated for C20H21ClN2NaO3S+[M+Na]+427.1;Found:426.6。
实施例8
7-(4-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺(化合物8)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成4-羟基-3-甲氧基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物8。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),8.05(d,J=8.4Hz,1H),7.98(d,J=7.6Hz,1H),7.60(d,J=2.1Hz,1H),7.55(d,J=8.4Hz,1H),7.48(t,J=7.0Hz,1H),7.42-7.35(m,1H),7.06(d,J=8.4Hz,1H),3.99(t,J=6.5Hz,2H),3.85(s,3H),1.92(t,J=7.3Hz,2H),1.74-1.65(m,2H),1.53-1.43(m,2H),1.42-1.32(m,2H),1.32-1.23(m,2H).MS(ESI)calculated for C21H24N2NaO4S+[M+Na]+423.1;Found:422.7。
实施例9
7-(4-(苯并[d]噻唑-2-基)-2-乙氧基苯氧基)-N-羟基庚酰胺(化合物9)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-乙氧基-4-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物9。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.64(s,1H),8.05(d,J=7.9Hz,1H),7.97(d,J=7.6Hz,1H),7.59(s,1H),7.54(d,J=8.3Hz,1H),7.48(t,J=7.7Hz,1H),7.38(t,J=7.6Hz,1H),7.07(d,J=8.5Hz,1H),4.10(q,J=6.9Hz,2H),3.99(t,J=6.6Hz,2H),1.92(t,J=7.4Hz,2H),1.75-1.65(m,2H),1.53-1.43(m,2H),1.42-1.24(m,7H).MS(m/z)(ESI):calcdfor C22H26N2NaO4S+[M+Na]+:437.2;found:422.7.
实施例10
7-(4-(苯并[d]噻唑-2-基)-3-氯苯氧基)-N-羟基庚酰胺(化合物10)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成2-氯-4-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物10。1H NMR(400MHz,DMSO-d6)δ10.36(s,lH),8.64(s,1H),8.21-8.08(m,2H),8.03(d,J=7.7Hz,1H),7.56-7.48(m,1H),7.44(t,J=7.6Hz,1H),7.19(d,J=2.5Hz,1H),7.11-7.04(m,1H),4.03(t,J=6.5Hz,2H),1.93(t,J=7.4Hz,2H),1.74-1.62(m,2H),1.54-1.31(m,4H),1.31-1.20(m,2H).MS(ESI)calculated for C20H21ClN2KO3S+[M+K]+:443.1;found:442.6.
实施例11
7-(4-(苯并[d]噻唑-2-基)-3-氟苯氧基)-N-羟基庚酰胺(化合物11)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成2-氟-4-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物11。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.65(s,1H),8.22(t,J=8.9Hz,1H),8.13-7.97(m,2H),7.54-7.35(m,2H),7.08-6.90(m,2H),4.02(t,J=6.5Hz,2H),1.92(t,J=7.4Hz,2H),1.74-1.63(m,2H),1.54-1.43(m,2H),1.42-1.31(m,2H),1.31-1.21(m,2H).MS(ESI)calculated for C20H21FN2NaO3S+[M+Na]+:411.1;found:411.7.
实施例12
7-(4-(苯并[d]噻唑-2-基)-2,6-二甲氧基苯氧基)-N-羟基庚酰胺(化合物12)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成4-羟基-3,5-二甲氧基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物12。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.62(s,1H),8.09(d,J=7.2Hz,1H),8.02(d,J=7.7Hz,1H),7.53-7.48(m,1H),7.46-7.39(m,1H),7.29(s,2H),3.92-3.84(m,8H),1.92(t,J=7.4Hz,2H),1.65-1.56(m,2H),1.53-1.43(m,2H),1.43-1.33(m,2H),1.30-1.19(m,2H).MS(ESI)calculated for C22H26N2NaO5S+[M+Na]+:453.1;found:452.7.
实施例13
2-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基乙酰胺(化合物13)的制备方法包括:
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将实施例1步骤1中的4-羟基苯甲醛替换成3-羟基苯甲醛,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物13。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.99(s,1H),8.13(d,J=8.0Hz,1H),8.04(d,J=8.1Hz,1H),7.69-7.62(m,2H),7.56-7.41(m,3H),7.15(d,J=8.3Hz,1H),4.58(s,2H).MS(ESI)calculated forC15H13N2O3S+[M+H]+:301.1;found:301.0.
实施例14
4-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基丁酰胺(化合物14)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成4-溴丁酸甲酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物14。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.72(s,1H),8.11(d,J=8.0Hz,1H),8.04(d,J=7.1Hz,1H),7.60(d,J=7.9Hz,1H),7.57(s,1H),7.52(t,J=7.0Hz,1H),7.47-7.41(m,2H),7.11(d,J=10.7Hz,1H),4.04(t,J=6.3Hz,2H),2.14(t,J=7.4Hz,2H),1.95(p,J=6.8Hz,2H).MS(ESI)calculated for C17H17N2O3S+[M+H]+:329.1;found:329.0.
实施例15
5-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基戊酰胺(化合物15)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成5-溴戊酸甲酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物15。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.69(s,1H),8.11(d,J=7.4Hz,1H),8.04(d,J=7.6Hz,1H),7.60(d,J=8.3Hz,1H),7.57(s,1H),7.52(t,1H),7.47-7.41(m,2H),7.11(d,J=9.9Hz,1H),4.05(t,J=6.0Hz,2H),2.01(t,J=7.0Hz,2H),1.76-1.61(m,4H).MS(ESI)calculated for C18H19N2O3S+[M+H]+:343.1;found:343.0.
实施例16
6-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基己酰胺(化合物16)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成6-溴己酸甲酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物16。1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.68(s,1H),8.10(d,J=6.7Hz,1H),8.03(d,J=7.7Hz,1H),7.59(d,J=7.8Hz,1H),7.56(s,1H),7.51(t,1H),7.46-7.41(m,2H),7.10(d,J=8.3Hz,1H),4.02(t,J=6.4Hz,2H),1.95(t,J=7.3Hz,2H),1.70(p,J=7.0Hz,2H),1.53(p,J=7.4Hz,2H),1.39(p,J=8.6Hz,2H).MS(ESI)calculated forC19H21N2O3S+[M+H]+:357.1;found:356.9.
实施例17
7-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺(化合物17)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物17。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),8.10(d,J=8.0Hz,1H),8.03(d,J=8.1Hz,1H),7.59(d,J=7.8Hz,1H),7.56(s,1H),7.51(t,1H),7.43(t,J=7.7Hz,2H),7.10(d,J=8.3Hz,1H),4.02(t,J=6.4Hz,2H),1.93(t,J=7.3Hz,2H),1.70(p,J=7.3Hz,2H),1.49(p,2H),1.40(p,J=7.8Hz,2H),1.28(p,J=8.0,7.5Hz,2H).MS(ESI)calculated for C20H22N2NaO3S+[M+Na]+:393.1;found:392.8.
实施例18
8-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基辛酰胺(化合物18)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成8-溴辛酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物18。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.63(s,1H),8.17-7.97(m,2H),7.65-7.48(m,3H),7.48-7.36(m,2H),7.10(d,J=8.3,2.5Hz,1H),4.03(t,J=6.5Hz,2H),1.91(t,J=7.4Hz,2H),1.76-1.65(m,2H),1.53-1.42(m,2H),1.42-1.34(m,2H),1.34-1.18(m,4H).MS(ESI)calculated for C21H25N2O3S+[M+H]+:385.2;found:384.7.
实施例19
7-(3-(苯并[d]噻唑-2-基)-2-氯苯氧基)-N-羟基庚酰胺(化合物19)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成2-氯-3-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物19。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.66(s,1H),8.19-8.04(m,2H),7.68(d,J=7.9,1.4Hz,1H),7.55(t,J=8.2,7.7,1.4Hz,1H),7.51-7.40(m,2H),7.30(d,J=8.3,1.5Hz,1H),4.09(t,J=6.4Hz,2H),1.93(t,J=7.4Hz,2H),1.79-1.67(m,2H),1.54-1.36(m,4H),1.34-1.22(m,2H).MS(ESI)calculated for C20H21ClN2NaO3S+[M+Na]+:427.1;found:426.6.
实施例20
7-(5-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺(化合物20)的制备方法包括:
将实施例1步骤1中的4-羟基苯甲醛替换成3-羟基-4-甲氧基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物20。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),8.08-7.90(m,2H),7.61-7.53(m,2H),7.48(t,J=8.3,7.2,1.3Hz,1H),7.38(t,J=8.2,7.2,1.2Hz,1H),7.07(d,J=8.4Hz,1H),4.02(t,J=6.5Hz,2H),3.81(s,3H),1.93(t,J=7.4Hz,2H),1.76-1.66(m,2H),1.54-1.44(m,2H),1.44-1.35(m,2H),1.33-1.23(m,2H).MS(ESI)calculated for C21H24N2NaO4S+[M+Na]+:423.1;found:423.0.
实施例21
N-羟基-7-(2-甲氧基-5-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酰胺(化合物21)的制备方法包括:
步骤1:2-氨基-5-甲氧基苯硫醇的制备方法包括:
将6-甲氧基苯并[d]噻唑-2-胺(2.0g,11.11mmol)溶于水(20ml)中,加入氢氧化钾(6.23g,110.1mmol)搅拌,120℃搅拌18小时。加入1M盐酸至大量固体析出,抽滤,滤饼先用水洗三次,最后PE洗一次,得固体化合物(1.1g,收率:64%)。
步骤2:2-甲氧基-5-(6-甲氧基苯并[d]噻唑-2-基)苯酚(第二中间体)的制备方法包括:
将2-氨基-5-甲氧基苯硫醇(0.5g,3.22mmol)溶于乙醇(8ml)中,加入3-羟基-4-甲氧基苯甲醛(0.49g,3.22mmol)搅拌,然后将连二亚硫酸钠(1.2g,6.44mmol)加入水(3ml)中,迅速加入上述混合物中,80℃搅拌8小时。减压蒸干溶剂,加入1M盐酸至酸性搅拌30分钟,抽滤,滤饼先用水洗三次,最后PE洗一次,得黄色固体第二中间体(0.85g,收率:91.4%)。
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),7.87-7.80(m,1H),7.63(d,J=2.5Hz,1H),7.47-7.36(m,2H),7.09-6.99(m,2H),3.80(s,6H).MS(ESI)calculated for C15H14NO3S+[M+H]+:288.1;found:287.9.
步骤3:乙基7-(2-甲氧基-5-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酸酯(第三中间体)的制备方法包括:
将第二中间体(0.5g,1.74mmol)溶于DMF(20ml)中,加入碳酸钾(0.48g,3.5mmol)和催化量的碘化钾搅拌,最后加入7-溴庚酸乙酯(0.62g,2.6mmol),80℃搅拌8小时。减压蒸干溶剂,加水(100ml)稀释,以乙酸乙酯(50ml)萃取三次,合并有机相,减压蒸干溶剂。固体残留物经硅胶柱层析纯化(洗脱剂∶PE/EA=10∶1),得淡黄色第三中间体(0.7g,收率:90.9%)。
1H NMR(400MHz,CDCl3)δ7.92(d,J=8.9,0.8Hz,1H),7.65(s,1H),7.53(d,J=8.4,2.1,0.8Hz,1H),7.35-7.32(m,1H),7.07(d,J=9.0,2.6,0.8Hz,1H),6.93(d,J=8.5,0.8Hz,1H),4.18-4.09(m,4H),3.94(s,3H),3.89(s,3H),2.32(t,2H),1.95-1.87(m,2H),1.73-1.64(m,2H),1.57-1.49(m,2H),1.46-1.38(m,2H),1.26(t,J=7.1,0.8Hz,3H).MS(ESI)calculated for MS(m/z)(ESI):calcd for C24H30NO5S+[M+H]+:444.2;found:444.1.
步骤4:N-羟基-7-(2-甲氧基-5-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酰胺(化合物21)的制备方法包括:
将第三中间体(0.15g,0.34mmol)溶于二氯甲烷(2ml)中,加入羟胺的甲醇溶液(6ml,6.6g氢氧化钾溶于20ml甲醇,冰浴下缓慢加入4.67g盐酸羟胺20ml的甲醇溶液中制得),室温搅拌1小时。减压蒸干溶剂,加入甲醇20ml,加入1M盐酸调PH=7-8,搅拌10分钟,抽滤,滤饼先用水洗三次,最后PE洗一次,得白色固体状的化合物21(140mg,收率:96.0%)。
1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.66(s,1H),7.86(d,J=8.9Hz,1H),7.63(d,J=2.6Hz,1H),7.57-7.45(m,2H),7.10-7.00(m,2H),4.01(t,J=6.5Hz,2H),3.80(s,6H),1.92(t,J=7.3Hz,2H),1.76-1.66(m,2H),1.53-1.44(m,2H),1.44-1.35(m,2H),1.33-1.24(m,2H).MS(ESI)calculated for C22H27N2O5S+[M+H]+:431.2;found:431.0.
实施例22
7-(5-(6-氯苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺(化合物22)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成6-氯苯并[d]噻唑-2-胺,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物22。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.63(s,1H),8.23(d,J=2.1Hz,1H),7.97(d,J=8.7Hz,1H),7.61-7.47(m,3H),7.09(d,J=9.0Hz,1H),4.02(t,J=6.5Hz,2H),3.82(s,3H),1.92(t,J=7.3Hz,2H),1.77-1.64(m,2H),1.53-1.44(m,2H),1.43-1.35(m,2H),1.32-1.24(m,2H).MS(ESI)calculated for C21H24ClN2O4S+[M+H]+:435.1;found:435.0.
实施例23
7-(5-(6-氟苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺(化合物23)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成6-氟苯并[d]噻唑-2-胺,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物23。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.65(s,1H),8.04-7.95(m,2H),7.60-7.51(m,2H),7.35(t,J=9.3Hz,1H),7.09(d,J=8.3Hz,1H),4.03(t,J=6.5Hz,2H),3.82(s,3H),1.92(t,J=7.5Hz,2H),1.77-1.65(m,2H),1.54-1.45(m,2H),1.43-1.34(m,2H),1.33-1.24(m,2H).MS(ESI)calculated for C21H24FN2O4S+[M+H]+:419.1;found:419.0.
实施例24
N-羟基-7-(2-甲氧基-5-(6-甲基苯并[d]噻唑-2-基)苯氧基)庚酰胺(化合物24)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成6-甲基苯并[d]噻唑-2-胺,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物24。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),7.87-7.80(m,2H),7.57-7.49(m,2H),7.28(d,J=8.4,1.7Hz,1H),7.06(d,J=8.4Hz,1H),4.01(t,J=6.5Hz,2H),3.81(s,3H),2.40(s,3H),1.93(t,J=7.4Hz,2H),1.77-1.65(m,2H),1.53-1.45(m,2H),1.44-1.34(m,2H),1.34-1.23(m,2H).MS(ESI)calculated for C22H27N2O4S+[M+H]+:415.2;found:415.1.
实施例25
7-(5-(5-氯苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺(化合物25)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成5-氯苯并[d]噻唑-2-胺,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物25。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),8.14-8.02(m,2H),7.63-7.54(m,2H),7.44(d,J=8.6,2.2,0.8Hz,1H),7.10(d,J=8.3Hz,1H),4.02(t,J=6.2Hz,2H),3.83(s,3H),1.93(t,J=7.3Hz,2H),1.77-1.66(m,2H),1.53-1.44(m,2H),1.43-1.34(m,2H),1.33-1.25(m,2H).MS(ESI)calculated for C21H23ClN2KO4S+[M+K]+:473.1;found:472.8.
实施例26
N-羟基-7-(4-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酰胺(化合物26)的制备方法包括:
将实施例21步骤2中的3-羟基-4-甲氧基苯甲醛替换成4-羟基苯甲醛,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物26。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.92(s,1H),8.20-8.03(m,3H),7.87(s,1H),7.33-7.21(m,3H),4.22(t,J=6.8Hz,2H),4.03(s,3H),2.15(t,J=7.4Hz,2H),1.91(s,2H),1.77-1.65(m,2H),1.65-1.55(m,2H),1.55-1.44(m,2H).MS(ESI)calculated for C21H25N2O4S+[M+H]+:401.2;found:401.0.
实施例27
7-(4-(6-氟苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺(化合物27)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成6-氟苯并[d]噻唑-2-胺,步骤2中的3-羟基-4-甲氧基苯甲醛替换成4-羟基苯甲醛,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物27。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.86(s,1H),8.29-8.08(m,4H),7.56(t,J=9.1,2.7Hz,1H),7.41-7.19(m,2H),4.23(t,J=6.5Hz,2H),2.14(t,J=7.3Hz,2H),1.97-1.86(m,2H),1.74-1.66(m,2H),1.64-1.55(m,2H),1.54-1.44(m,2H).MS(ESI)calculated for C20H22FN2O3S+[M+H]+:389.1;found:389.0.
实施例28
7-(4-(6-氯苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺(化合物28)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成6-氯苯并[d]噻唑-2-胺,步骤2中的3-羟基-4-甲氧基苯甲醛替换成4-羟基苯甲醛,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物28。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),8.23(d,J=2.2Hz,1H),8.01-7.89(m,3H),7.50(d,J=8.7,2.2Hz,1H),7.15-6.97(m,2H),4.01(t,J=6.5Hz,2H),1.92(t,J=7.4Hz,2H),1.74-1.61(m,2H),1.55-1.43(m,2H),1.42-1.32(m,2H),1.31-1.22(m,2H).MS(ESI)calculated for C20H22ClN2O3S+[M+H]+:405.1;found:405.0.
实施例29
N-羟基-7-(4-(6-甲基苯并[d]噻唑-2-基)苯氧基)庚酰胺(化合物29)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成6-甲基苯并[d]噻唑-2-胺,步骤2中的3-羟基-4-甲氧基苯甲醛替换成4-羟基苯甲醛,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物29。1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.67(s,1H),7.99-7.75(m,4H),7.29(d,J=8.5Hz,1H),7.15-6.97(m,2H),4.00(t,J=6.5Hz,2H),2.40(s,3H),1.92(t,J=7.3Hz,2H),1.74-1.64(m,2H),1.54-1.43(m,2H),1.42-1.31(m,2H),1.31-1.22(m,2H).MS(ESI)calculated for C21H25N2O3S+[M+H]+:385.2;found:385.0.
实施例30
7-(4-(5-氯苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺(化合物30)的制备方法包括:
将实施例21步骤1中的6-甲氧基苯并[d]噻唑-2-胺替换成5-氯苯并[d]噻唑-2-胺,步骤2中的3-羟基-4-甲氧基苯甲醛替换成4-羟基苯甲醛,其余所需原料,试剂及制备方法同实施例21步骤1-4,得白色固体状的化合物30。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.65(s,1H),8.14-7.94(m,4H),7.43(d,1H),7.11-7.02(m,2H),4.01(t,J=6.5Hz,2H),1.92(t,J=7.4Hz,2H),1.76-1.62(m,2H),1.55-1.43(m,2H),1.42-1.31(m,2H),1.31-1.20(m,2H).MS(ESI)calculated for C20H22ClN2O3S+[M+H]+:405.1;found:405.0.
实施例31
8-(5-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基辛酰胺(化合物31)的制备方法包括:
实施例1步骤1中的4-羟基苯甲醛替换成3-羟基-4-甲氧基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成8-溴辛酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物31。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.65(s,1H),8.14-7.91(m,2H),7.62-7.54(m,2H),7.48(t,J=8.2,7.2,1.3Hz,1H),7.38(t,J=8.3,7.1,1.2Hz,1H),7.08(d,J=8.3Hz,1H),4.02(t,J=6.5Hz,2H),3.81(s,3H),1.92(t,J=14.0,6.7Hz,2H),1.78-1.63(m,2H),1.51-1.35(m,4H),1.33-1.19(m,4H).HRMS(ESI)calculated forC22H27N2O4S+[M+H]+:415.2;found:415.0.
实施例32
7-(3-(苯并[d]噻唑-2-基)-2-氟苯氧基)-N-羟基庚酰胺(化合物32)的制备方法包括:
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将实施例1步骤1中的4-羟基苯甲醛替换成2-氟-3-羟基苯甲醛,并把步骤2中的2-溴乙酸乙酯替换成7-溴庚酸乙酯,其余所需原料,试剂及制备方法同实施例1步骤1-3,得白色固体状的化合物32。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.89(s,1H),8.35(d,1H),8.27(d,J=8.2,3.5Hz,1H),8.09-7.95(m,1H),7.78-7.59(m,2H),7.56-7.42(m,2H),4.25(t,J=4.7,3.2Hz,2H),2.11(t,J=7.4,3.4Hz,2H),1.96-1.84(m,2H),1.76-1.63(m,2H),1.62-1.53(m,2H),1.52-1.38(m,2H).MS(ESI)calculated for C20H22FN2O3S+[M+H]+:389.1;found:389.0.
实施例33
体外HDAC抑制活性
在添加10%胎牛血清的MEM培养基中培养Hela细胞,在37℃、5%CO2气氛中培养。使用缓冲液(50mM Tris-HCl pH 7.4,150mM NaCl,1%Triton x-100)裂解细胞。将Hela细胞提取物在37℃条件下酶促反应30分钟。50μL反应混合物中含有25mM Tris,pH 8.0,1 mMMgCl2,0.1mg/ml BSA,137mM NaCl,2.7mM KCl,Hela提取物和酶底物(20μM Ac-leu-gly-lys(Ac)-AMC)。将前述实施例化合物1-32、SAHA分别用10%的DMSO稀释,在50μL的前述反应混合物中分别加入5μL的稀释液,使所有反应混合体系中的DMSO最终浓度均为1%。测定是通过测定酶反应后溶液中荧光产物的量来完成的。酶促反应结束后,每孔加入0.4mg/mlTrypsin 50μL,室温下再孵育15分钟。然后在Spectra Max M5微滴板阅读器上以350-360nm的激发波长和450-460nm的发射波长分析荧光。采用Prism GraphPad软件,采用归一化剂量-反应拟合的非线性回归计算IC50值。表1结果表明,化合物3和20对HDACs激酶表现出优于SAHA的抑制活性。“++++”表示IC50值小于10nM或抑制率80-100%,“+++”表示IC50值10-100nM或抑制率60-80%,“++”表示IC50值100-1000nM或抑制率40-60%,“+”表示IC50值大于1000nM或抑制率小于40%。
表1化合物1-32对HDACs激酶抑制试验
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实施例34
选定化合物的HDAC同工酶抑制活性
所有酶促反应均在37℃条件下进行30分钟。50μl反应混合物中含有25mM Tris,pH8.0,1mM MgCl2,0.1mg/ml BSA,137mM NaCl,2.7mM KCl,HDAC和酶底物。将前述化合物1-32、SAHA分别用10%的二甲基亚砜稀释,并将5μl的稀释物加入50μl的反应中,使所有反应中二甲基亚砜的最终浓度为1%。测定是通过测定酶反应后溶液中荧光产物的量来完成的。然后在Spectra Max M5微滴板阅读器上以350-360nm的激发波长和450-460nm的发射波长分析荧光。采用Prism GraphPad软件,采用归一化剂量-反应拟合的非线性回归计算IC50值。“++++”表示IC50值小于10nM或抑制率80-100%,“+++”表示IC50值10-100nM或抑制率60-80%,“++”表示IC50值100-1000nM或抑制率40-60%,“+”表示IC50值大于1000nM或抑制率小于40%。
表2化合物的HDAC同工酶抑制活性
表2结果表明化合物3和20都对于HDAC6有一定的选择性。
实施例35 PKD囊泡实验
利用MDCK细胞在AC酶激动剂forskolin的作用下形成类似PKD疾病中的囊泡,模拟疾病的发生发展并给予受试化合物(优选化合物20),观察受试化合物对其影响。
1、细胞培养
将MDCK细胞培养在37℃,5%CO2情况下,培养基采用DMEM F12培养基(康美可购买),额外加入10%胎牛血清和1%双抗。待细胞培养三天后,生长面积约在80-90%间便开始下一步实验。
2、按照下述配方配制基质胶(单孔)
3、消化细胞加入24孔板
在重新冷却基质胶的期间,消化MDCK细胞并计数。
PH调节完成后加入细胞吹匀,用1mL枪头吸取400μL配置好的液体,加入24孔板,要点如下:
1.吸取的液体应靠下吸取,避免吸取太多气泡。
2.加入24孔板时,应固定枪头位置,不可移动。最后枪尖的液体不可完全吹出。
3.全部加完后可顺时针轻度晃匀胶使其均匀分布。
配置好基质胶后将孔板放置培养箱内稳定90min,之后每孔加入1.5mL含10μMForsklin和相应浓度药物的细胞培养基,分空白对照组,AMPK激动剂(1μM)组,AMPK激动剂(10μM)组。培育10天,每12h换液一次,并在4,6,8,10天拍照。选定拍照区域并追踪特定囊泡。
在第10天对比囊泡直径以评估受试化合物的作用效果。实验结果见表9。
表9 PKD囊泡实验
囊泡实验结果显示,与对照组相比,该类化合物可明显抑制PKD疾病中的囊泡的发展。
实施例36组织胚胎肾实验
取13.5天的胚胎鼠肾脏置于transwell中,在8-Br-cAMP的刺激下形成类似PKD疾病中的囊泡,模拟疾病的发生发展并给予受试化合物(优选化合物20),观察受试化合物对其影响。
1、胚胎肾的培养
将胚胎肾培养在37℃,5%CO2情况下,培养基采用DMEM F12培养基(康美可购买),
额外加入8-Br-cAMP、胰岛素、转铁蛋白、亚硒酸钠和双抗。并加入相应浓度的药物,分对照组。培育6天,每12h换液一次,并在2,4,6天拍照。
在第6天对比囊泡面积以评估受试化合物的作用效果。实验结果见表10。
表10组织胚胎肾实验
组织胚胎肾实验结果显示,与对照组相比,该类化合物可明显抑制PKD疾病中的囊泡的发展。
实施例37 PKD小鼠实验
本实验利用PKD1基因敲除小鼠进行优选化合物20的体内药效评价。
具体操作:
1.小鼠标号和基因鉴定:小鼠出生3天后,采用剪脚趾方法进行标记,并放入提前标记ep管,剪下脚趾煮沸后,pcr后用琼脂糖电泳进行基因鉴定。
2.制备相应药剂:用电子天平精密称取相应重量药物,乘放在全新ep管中。后用移液枪加入相应量hpmc以配制所需浓度药剂。(以1mg/kg化合物20为例,称取1mg化合物20,加入500uL hpmc后,先涡旋30s(混悬大部分药物),后超声15-20分钟以粉碎大块药物,再涡旋30s。)
3.小鼠给药:小鼠出生后第6或5天开始给药(小鼠体重过小则第6天给药,其余第5天给药),固定给药时间(例:上午9点)。用食指和拇指捏起目标小鼠(背部),称取重量后,用微量进样器吸取相应量药剂,从小鼠背部隆起(拇指食指中间)中间插入进样器,进行皮下注射。
4.小鼠组织提取:小鼠给药七天后处死后精密称取重量,剖腹,摘取左肾后精密称重,并将肾脏置于水平线正中进行拍照,完成后置编号ep管于冰上暂存。后摘取右肾,相同条件称重、拍照,存编号ep管于多聚甲醛中保存。摘取肝脏ep管于冰上暂存。操作完成后将肝脏和左肾保存于-80度冰箱。
5.数据处理:计算左右肾总重,肾脏比重等。实验结果见表11。
表11 PKD小鼠实验
动物实验结果显示,与对照组相比,在延缓PKD病程的发生发展上,该类化合物表现出比Tolvaptan相当的抑制活性,即该类化合物对PKD具有较好的治疗作用。
尽管已参考说明性实施例描述了本发明,但所属领域的技术人员将理解,在不背离本发明的精神及范围的情况下可做出各种其它改变、省略及/或添加且可用实质等效物替代所述实施例的元件。另外,可在不背离本发明的范围的情况下做出许多修改以使特定情形或材料适应本发明的教示。因此,本文并不打算将本发明限制于用于执行本发明的所揭示特定实施例,而是打算使本发明将包含归属于所附权利要求书的范围内的所有实施例。
Claims (10)
1.一类苯并噻唑类化合物或其盐,其特征在于,所述苯并噻唑类化合物具有式(I)所示结构,
其中R1、R2至少独立地选自氢、卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C3-8环烷基、芳基、杂芳基和杂环基中的任一者,n为1~7中的任一整数。
2.根据权利要求1所述的苯并噻唑类化合物或其盐,其特征在于:R1选自氢、卤素、C1-6烷基或C1-6烷氧基,R2选自氢、卤素、C1-6烷基或C1-6烷氧基;
优选的,R1选自氢、卤素、C1-6烷基或C1-6烷氧基,R2选自氢、卤素、甲氧基、乙氧基或甲基;
更优选的,R1为氢,R2选自氢、卤素、甲氧基、乙氧基或甲基;
更优选的,R1为卤素,R2选自氢或甲氧基;更优选的,所述卤素为氟或氯;
更优选的,R1为C1-6烷基,R2选自氢或甲氧基,R1进一步优选为甲基;
更优选的,R1为C1-6烷氧基,R2选自氢或甲氧基,R1进一步优选为甲氧基。
3.根据权利要求1所述的苯并噻唑类化合物或其盐,其特征在于:所述苯并噻唑类化合物包括2-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基乙酰胺、6-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基己酰胺、7-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、8-(4-(苯并[d]噻唑-2-基)苯氧基)-N-羟基辛酰胺、7-(4-(苯并[d]噻唑-2-基)-2-氟苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-甲基苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-氯苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2-乙氧基苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-3-氯苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-3-氟苯氧基)-N-羟基庚酰胺、7-(4-(苯并[d]噻唑-2-基)-2,6-二甲氧基苯氧基)-N-羟基庚酰胺、2-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基乙酰胺、4-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基丁酰胺、5-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基戊酰胺、6-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基己酰胺、7-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、8-(3-(苯并[d]噻唑-2-基)苯氧基)-N-羟基辛酰胺、7-(3-(苯并[d]噻唑-2-基)-2-氯苯氧基)-N-羟基庚酰胺、7-(5-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、N-羟基-7-(2-甲氧基-5-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(5-(6-氯苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、7-(5-(6-氟苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、N-羟基-7-(2-甲氧基-5-(6-甲基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(5-(5-氯苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基庚酰胺、N-羟基-7-(4-(6-甲氧基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(4-(6-氟苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、7-(4-(6-氯苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、N-羟基-7-(4-(6-甲基苯并[d]噻唑-2-基)苯氧基)庚酰胺、7-(4-(5-氯苯并[d]噻唑-2-基)苯氧基)-N-羟基庚酰胺、8-(5-(苯并[d]噻唑-2-基)-2-甲氧基苯氧基)-N-羟基辛酰胺以及7-(3-(苯并[d]噻唑-2-基)-2-氟苯氧基)-N-羟基庚酰胺中的任一者。
4.根据权利要求1-3中任一项所述的苯并噻唑类化合物或其盐,其特征在于:所述苯并噻唑类化合物的盐包括--盐酸盐、对甲苯磺酸盐、硫酸盐、琥珀酸盐、马来酸盐、富马酸盐、醋酸盐、磷酸盐、构橼酸盐、甲磺酸盐、钠盐中的任一者。
5.一类苯并噻唑类化合物的制备方法,其特征在于,包括:
S1、以式(II)所示化合物为起始原料,与式(IV)所示化合物在第一反应体系中80℃反应形成式(V)所示的第一中间体,所述第一反应体系包含连亚二硫酸钠、乙醇和水;
S2、使所述第一中间体在第二反应体系中反应,得到式(VI)所示的第二中间体,所述第二反应体系包含三溴化硼和二氯甲烷;
S3、使所述第二中间体和式(VII)所示的溴代烷基酯类化合物在第三反应体系中反应,得到式(VIII)所示的第三中间体,所述第三反应体系包括碳酸钾、碘化钾以及N,N-二甲基甲酰胺或乙腈;
S4、使所述第三中间体在第四反应体系中反应,制得式(I)所示的苯并噻唑类化合物,所述第四反应体系包括羟胺的甲醇溶液;
其中R1、R2至少独立地选自氢、卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C3-8环烷基、芳基、杂芳基和杂环基中的任一者,n为1~7中的任一整数,n1的取值为1、3、4、5、6或7,n2的取值为0或1。
6.一种药物组合物,其特征在于,包括:
治疗有效量的权利要求1-4中任一项所述的苯并噻唑类化合物或其药学上可接受的盐;
以及,一种或多种药学上可接受的载体。
7.权利要求1-4中任一项所述的苯并噻唑类化合物或其药学上可接受的盐或者权利要求6所述的药物组合物在制备HDAC6激酶抑制剂中的用途。
8.权利要求1-4中任一项所述的苯并噻唑类化合物或其药学上可接受的盐或者权利要求6所述的药物组合物在制备用于预防和/或治疗增殖性疾病的药物中的用途。
9.根据权利要求8所述的用途,其特征在于:所述增殖性疾病包括急性髓性白血病、慢性髓性白血病、甲状腺癌、胃癌、胃肠基质肿瘤、结肠直肠癌、前列腺癌、乳腺癌、卵巢癌、胰腺癌、肺癌、非小细胞肺癌、淋巴瘤、肾癌、常染色体显性多囊肾病和骨髓瘤中的任一种。
10.权利要求1-4中任一项所述的苯并噻唑类化合物或其药学上可接受的盐或者权利要求6所述的药物组合物在制备用于预防和/或治疗常染色体显性多囊肾病的靶向药物中的用途。
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