CN114907354A - 一种磺酰胺类多环化合物及其制备方法与用途 - Google Patents
一种磺酰胺类多环化合物及其制备方法与用途 Download PDFInfo
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- CN114907354A CN114907354A CN202210050545.8A CN202210050545A CN114907354A CN 114907354 A CN114907354 A CN 114907354A CN 202210050545 A CN202210050545 A CN 202210050545A CN 114907354 A CN114907354 A CN 114907354A
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- alkyl
- sulfonamide
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- alkoxy
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- -1 Sulfonamide polycyclic compound Chemical class 0.000 title claims abstract description 48
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims description 7
- 239000003814 drug Substances 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 108010024121 Janus Kinases Proteins 0.000 claims description 10
- 102000015617 Janus Kinases Human genes 0.000 claims description 10
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 150000001204 N-oxides Chemical class 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
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- 208000025721 COVID-19 Diseases 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 230000000155 isotopic effect Effects 0.000 claims description 5
- 201000004384 Alopecia Diseases 0.000 claims description 4
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- 125000000304 alkynyl group Chemical group 0.000 claims description 4
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- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000006692 (C2-C8) heterocyclyl group Chemical group 0.000 claims description 3
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
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- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 2
- 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 2
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- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 2
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- 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 30
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 9
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- 125000004432 carbon atom Chemical group C* 0.000 description 7
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- 238000010438 heat treatment Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
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- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明公开了一种磺酰胺类多环化合物及其制备方法与用途,该类化合物具有较低的细胞毒性,在体内具有较低的毒性,对生物体生理影响小;体内可以快速起效,并且有更长的作用时间,获得了意想不到的治疗效果;本发明的化合物具有较强的透过皮肤能力。因此,本发明的磺酰胺类多环化合物具有开发为药物的巨大潜力。
Description
技术领域
本发明属于医药技术领域,具体涉及一系列磺酰胺类多环化合物制备方法与在治疗和/或预防JAK介导的相关疾病,以及在抗病毒领域的用途。
背景技术
JAK(Janus-Activated Kinase)通过细胞因子和生长因子与其受体的结合在信号转导中发挥重要作用。JAK家族有四个成员:JAK1、JAK2、JAK3和酪氨酸激酶2(TYK2),其中的JAK1、JAK2、与TYK2存在于细胞中,而JAK3仅存在于骨髓与淋巴系统。目前,已有多款JAK激酶抑制剂获得批准上市,如芦可替尼、巴瑞替尼等。巴瑞替尼是由礼来公司(Eli Lilly andCompany)和因赛特(Incyte)制药公司研制的JAK激酶抑制剂,用于治疗类风湿关节炎(Rheumatic Arthritis,RA),于2017年2月欧洲批准上市,2018年6月美国批准上市。2020年11月19日,礼来制药与因赛特医疗共同宣布,美国食品药品监督管理局(FDA)批准礼来制药巴瑞替尼的EUA(紧急使用授权),与瑞德西韦联用后用于对新型冠状病毒肺炎(COVID-19)患者的治疗,说明巴瑞替尼在抗病毒方面亦有卓越的效果。但是,巴瑞替尼也有着明显缺陷如容易引起动脉血栓、体内清除率低、对免疫系统有损伤等,巴瑞替尼的疗效与安全性还有待于进一步评估。最近越来越多的JAK抑制剂在临床暴露出感染、结核、肿瘤、肝损伤、贫血、中性粒细胞减少症、淋巴细胞减少症、心血管疾病、胃肠道穿孔、高脂血症等严重的副作用问题。此外,也可能引起肝炎病毒被重新激活,或出现肝功能障碍。
目前,JAK抑制剂发展与挑战并存,安全性成为打此种局面的关键。因此,制备出具有更优异活性的磺酰胺类多环化合物作为JAK抑制剂,改善其在生物体内的药效作用,同时提高药物的安全性具有重要意义。
发明内容
本发明一方面提供了磺酰胺类多环化合物的制备方法及其使用方法,该类化合物具有较低的细胞毒性,在体内具有治疗JAK介导的相关疾病的效果。
本发明另一方面是提供的化合物具有较强的皮肤穿透能力,皮肤吸收较好,适合开发为局部用药。本发明提供的化合物对生物体的生理指标具有较小的影响,具有开发为药物的巨大潜力。
本发明一方面提供一种如下通式(I)所示的磺酰胺类多环化合物或其水合物、溶剂化物、N-氧化物、多晶型物、同位素衍生物、药学上可接受的盐:
式(I)中,R1选自C1-C8的烷基、C1-C8的烷氧基、C2-C8的烯基、C2-C8的炔基、C3-C8的碳环基、C2-C8的杂环基;上述的烷基、烷氧基、烯基、炔基、碳环基、杂环基任选地被一个或多个下列基团取代:氢、氰基、卤素、羟基、羧基、氨基、乙酰基;
R2代表氰基、氟、C1-C8的烷基、C2-C8的烯基、或氰基取代的C1-C8的烷基;
n选自0、1、2、或3;
T-选自、F-、Cl-、Br-、I-、CH3COO-、NO2 -、NO3 -、HSO4 -、BF4 -、PF6 -、柠檬酸根、枸橼酸根、苹果酸根、甲磺酸根、对甲苯磺酸根、酒石酸根;
Ra、Rb各自独立地选自一个或多个基团A取代的C1-C8的烷基、C1-C8的烷氧基、或Ra、Rb采用合理的方式相连成环;
Rc选自C1-C8的烷基、C1-C8的烷氧基;
R4选自下列基团:C1-C8的烷基、C1-C8的烷氧基、C3-C8的碳环基、C2-C8的杂环基;
X为O、NR5;
当Q为-(C=O)-时,R3不为-COOR4;
Rd、Re各自独立地选自氢、C1-C8的烷基、C1-C8的烷氧基、或Rd、Re采用合理的方式相连成环;
R5为氢、或C1-C8的烷基;
所述的基团A选自:氢、氨基、羟基、氰基、羧基、硝基、卤素、三氟甲基、乙酰基、C1-C8的烷基、C1-C8的烷氧基、C2-C8的杂环基、C1-C6烷胺基。
进一步地,所述磺酰胺类多环化合物,如式(II)所示:
式(II)中取代基的定义如式(I)所定义的。
进一步地,所述磺酰胺类多环化合物,如式(III)所示:
式(III)中取代基的定义如式(I)所定义的。
进一步地,所述磺酰胺类多环化合物包括其无机酸盐、有机酸盐。
除本文另有特殊说明,本发明使用的专业术语均为本领域技术人员普遍了解的基本含义。
本发明实施方案中描述的多个特征可以单独地提供或者以任何合适的子组合提供。
在本申请的实施方案中,所述的杂原子指的是氮(N)、氧(O)、硫(S)原子。
在本申请的实施方案中,所述的C1-C8的烷基是指含有1~8个碳原子直链或支链化的饱和脂肪烃基,所述的C1-C8的烷基实例包括但不限于乙基、丙基、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、异庚基、正辛基等。
在本申请的实施方案中,所述的C1-C8的烷氧基是指含有1~8个碳原子的烃基在任意合理的位置插入氧原子的基团,所述的C1-C8的烷氧基实例包括但不限于乙氧基、异丙氧基、异丁氧基、叔丁氧基、新戊基、2-乙基己氧基等。
在本申请的实施方案中,所述的C1-C6烷胺基是指含有1~6个碳原子的烃基在任意合理的位置插入-NH-或者-NH2基团的基团,所述的C1-C6烷胺基的实例包括但不限于甲氨基、乙胺基、丙氨基、异丙胺基、二乙胺基、二正丙氨基、二异丙氨基等。
在本申请的实施方案中,所述的C2-C8的烯基是指由2~8个碳原子组成的含有至少一个不饱和碳碳双键的脂肪烃基,包括直链、支链或环状烯烃,也包括具有烯烃基取代基的烃基和烃基取代的烯烃基,其中烯基可以碳链或碳环中间,也可以在末端,所述的C2-C8的烯基的实例包括但不限于乙烯基、丙烯基、烯丙基、丁烯基、2-甲基-2戊烯基、环己烯基、1-甲基-1-环己烯基等。
在本申请的实施方案中,所述的C2-C8炔基是指由2~8个碳原子组成的含有至少一个不饱和碳碳三键的脂肪烃基,包括直链、支链或环状炔烃,也包括环炔烃基取代的烃基和烃基取代的环炔烃基,其中炔基可以位于碳链或碳环中间,也可以位于末端。所述C2-C8炔基的实例包括但不限于乙炔基、2-丁炔基、1-丁炔-4-基、5-甲基-1-已炔基、3-环戊基-1-丙炔基等。
在本申请的实施方案中,所述的C3-C8碳环基是指由3~8个碳原子组成的饱和或不饱和脂肪烃基,包括直链、支链或环状烃基,所述的C3-C8碳环基的实例包括但不限于环丙基、环丁基、环戊基、环己基、乙基环己基、环戊烯基等。
在本申请的实施方案中,所述的C2-C8杂环基是指含有2~8个碳原子与1~4个杂原子(选自N、O或S)组成的由1~3个环构成的饱和或不饱和环基。所述的C2-C8杂环基包括但不限于:环氧乙烷基、环氧丙烷基、吖丙啶基、哌啶基、哌嗪基、高哌嗪基、吡咯烷基、吡唑烷基、咪唑啉基、吗啉基、1,2-二氢吡啶-2-氨基等。
在本申请的实施方案中,所述的卤素为氟、氯、溴或碘。
在本申请的实施方案中,所述的药学上可接受的盐,包括但不限于无机酸盐,例如盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、或硼酸盐等;有机酸盐,例如甲磺酸盐、乙磺酸盐、苯磺酸盐、苯甲磺酸盐、枸橼酸盐、柠檬酸盐、苹果酸盐或乙酸盐等。
在一些实施方案中,所述的磺酰胺类多环化合物,具有如下结构:
一种药物组合物,其包括有效量的所述的磺酰胺类多环化合物或其水合物、溶剂化物、N-氧化物、多晶型物、同位素衍生物、药学上可接受的盐与药学上可接受的辅料制备成的制剂。
进一步地,所述的磺酰胺类多环化合物或其水合物、溶剂化物、N-氧化物、多晶型物、同位素衍生物、药学上可接受的盐,或所述的药物组合物在制备用于预防/治疗JAK(Janus Kinase)介导的相关疾病以及在抗RNA(Ribonucleic Acid)病毒领域药物中的用途。
进一步地,所述的用途,所述的JAK介导的相关疾病包括关节炎、炎症性肠病、皮肤病、局部脱发、斑秃、骨髓纤维化、秃发性毛囊炎、白癜风、急性呼吸综合征、癌症。
进一步地,所述的用途,所述的抗RNA病毒的用途包括与其他抗病毒药物如瑞德西韦、利巴韦林、氯喹联用治疗新冠肺炎(Corona Virus Disease 2019,COVID-19)。
进一步地,所述的药物组合物,所述的药学上可接受的辅料包括填充剂、粘合剂、稀释剂、润滑剂、防腐剂、掩味剂或助溶剂的一种或者几种的组合。
进一步地,所述的药物组合物,所述的药学上可接受的辅料做成的制剂剂型为片剂、胶囊、散剂、颗粒剂、丸剂、混悬剂、软膏、硬膏、巴布膏、贴片、贴剂、膜剂、或吸入制剂。
具体实施方式
为使本申请的目的、技术方案和优点更加清楚明白,下文中将对本发明的实施例进行详细说明。需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互任意组合。
以下实施例可以使本领域技术人员更全面地理解本发明,但不以任何方式限制本发明,所有化合物的结构均经MS或1H NMR确定。
实施例一:化合物DSC4101的合成
化合物3的合成:
将氰甲基磷酸二乙酯(186.00g,1.05mol)加入至3.0L四氢呋喃中,氮气保护下降温至-5.0℃,向其中缓慢加入叔丁醇钾(129.04g,1.15mol),保持内温≤0℃,移入室温搅拌反应1.0h,降温至0℃,向其中缓慢滴加1-Boc-3-氮杂环丁酮(171.19g,1.0mol)的四氢呋喃溶液0.6L,滴加过程中保持内温≤10.0℃,滴加完毕后移入室温反应12.0h,TLC监测反应完毕,向其中加入1.0L水,减压浓缩得棕色混合物,加入2.5L水,搅拌均匀后乙酸乙酯萃取(3.0L×2),合并的有机相用饱和食盐水洗涤(3.0L×1),无水硫酸干燥,浓缩,所得固体用1.5L四氢呋喃/水(4:1,V/V)重结晶,固体于45℃下鼓风干燥12.0h得中间体3精制品149.56g。收率:77%。[M+H]+=195.23。
化合物5的合成:
氮气保护下将化合物4(153.57g,1.0mol)加入至DMF中(0.6L),冷却至0℃,向其中缓慢加入氯甲酸苄酯(179.12g,1.05mol)与三乙胺(121.43g,1.2mol),控制内温≤5.0℃,加入完毕后室温反应3.0h,冷却至0℃,向其中缓慢加入冰水2.0L,大量固体析出,搅拌析晶1.0h,过滤,滤饼水洗(50mL×2),滤饼用DMF/水重结晶得产物5,45℃鼓风干燥12.0h得212.90g中间体5。收率:74%。纯度:97.3%。[M+H]+=288.37。
化合物6的合成:
向中间体5(143.85g,0.5mol)加入3.0L四氢呋喃,上述反应体系中加入丙烯醛(47.66g,0.85mol)和80%水合肼(59.45g,0.95mol),加热至回流,期间持续鼓入氧气,回流反应12.0h后停止反应,降温至室温,减压浓缩出去有机溶剂,向其中加入1.5L冰水,DCM萃取(2.0L×2),有机相饱和食盐水洗涤(2.0L×2),无水硫酸钠干燥,减压浓缩得固体,DMF/水重结晶纯化,所得固体45℃下鼓风干燥12.0h得111.76g中间体6。收率:70%。[M+H]+=320.40。
化合物7的合成:
将中间体6(95.80g,0.30mol)加入至1.2L乙腈中,加入中间体3(64.10g,0.33mol)与1,8-二氮杂二环十一碳-7-烯(54.81g,0.36mol),加热至60℃反应2.0h,减压浓缩,加入0.5L(0.1M)盐酸酸化,乙酸乙酯萃取(1.6L×3),饱和食盐水洗涤(2.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化,45℃下鼓风干燥12.0h得中间体7精制品120.13g。收率:78%。纯度:98.7%。[M+H]+=514.25。1H NMR(300MHz,CDCl3)δ:8.88(s,1H),8.43(s,1H),8.39(s,1H),7.45(d,J=6.1Hz,2H),7.40-7.37(m,4H),6.75(d,J=6.0Hz,1H),4.61(d,J=8.0Hz,2H),4.29(d,J=8.0Hz,2H),3.92(s,2H),3.70(s,2H),1.51(s,9H)。
化合物8的合成:
将中间体7(102.71g,0.20mol)加入至1.2L乙腈中,加入120mL三氟乙酸(TFA),加热至60℃反应2.0h,降温至室温,减压浓缩后向其中加入1.0L碳酸氢钠溶液(0.5M),乙酸乙酯萃取(1.2L×2),饱和食盐水洗涤(1.2L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化,45℃下鼓风干燥12.0h得中间体8精制品57.88g。收率:70%。纯度:98.0%。[M+H]+=414.34。1H NMR(300MHz,CDCl3)δ:8.85(s,1H),8.41(s,1H),8.37(s,1H),7.43(d,J=6.2Hz,2H),7.37-7.35(m,4H),6.70(d,J=6.1Hz,1H),4.57(d,J=8.1Hz,2H),4.26(d,J=8.1Hz,2H),3.88(s,2H),3.67(s,2H)。
化合物9的合成:
氮气保护下将中间体8(41.34g,0.1mol)加入至0.6L二氯甲烷中,冷却至0℃,向其中缓慢加入乙基磺酰氯(15.43g,0.12mol)与三乙胺(15.18g,0.15mol),控制内温≤5.0℃,加入完毕后室温反应5.0h,水洗(0.4L×1),饱和食盐水洗涤(0.4L×1),无水硫酸钠干燥后浓缩得固体,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得中间体9精制品35.39g。收率:70%。纯度:98.2%。[M+H]+=506.35。1H NMR(300MHz,CDCl3)δ:8.84(s,1H),8.40(s,1H),8.35(s,1H),7.41(d,J=6.5Hz,2H),7.36-7.33(m,4H),6.68(d,J=6.2Hz,1H),4.56(d,J=8.4Hz,2H),4.26(d,J=8.5Hz,2H),3.86(s,2H),3.65(s,2H),3.50-3.48(m,2H),1.30(t,J=10.4Hz,3H)。
化合物10的合成:
将中间体9(25.28g,0.05mol),加入0.5L甲醇中,加入钯碳(1.26g,5w/w%),氢气氛围下加热回流2.0h,冷却至室温,过滤,滤饼用甲醇淋洗(0.05L×2),滤液浓缩,乙腈重结晶得固体,45℃下鼓风干燥12.0h得中间体10精制品13.93g。收率:75%。纯度:98.4%。[M+H]+=372.29。1H NMR(300MHz,CDCl3)δ:8.87(s,1H),8.43(s,1H),8.39(s,1H),7.45(d,J=6.3Hz,1H),6.69(d,J=6.2Hz,1H),4.59(d,J=8.2Hz,2H),4.27(d,J=8.2Hz,2H),3.70(s,2H),3.52-3.49(m,2H),1.32(t,J=10.6Hz,3H)。
化合物11的合成:
氮气保护下将中间体10(7.43g,0.02mol)加入至150mL二氯甲烷中,冷却至0℃,向其中缓慢加入NaH(1.20g,0.03mol),搅拌反应30min后向其中缓慢加入乙酸氯甲酯(3.25g,0.03mol)与三乙胺(4.05g,0.04mol),控制内温≤5.0℃,加入完毕后室温反应3.0h,水洗(100mL×1),饱和食盐水洗涤(100mL×1),无水硫酸钠干燥后浓缩得中间体11粗品8.80g,直接用于下一步反应。
化合物12的合成:
将上述中间体11粗品8.50g加入至100mL甲醇中,加入氢氧化钠(0.2g,5.0mmol),加热至60℃反应2.0h,TLC监测反应完毕,停止反应,浓缩得棕色固体,加入100mL水,二氯甲烷萃取(100mL×2),饱和食盐水洗涤(100mL×1),无水硫酸钠干燥后浓缩得固体,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得中间体12精制品4.98g。收率:62%。纯度:98.2%。[M+H]+=402.15。1H NMR(300MHz,CDCl3)δ:8.85(s,1H),8.41(s,1H),8.38(s,1H),7.44(d,J=6.2Hz,1H),6.67(d,J=6.2Hz,1H),5.50(s,2H),4.57(d,J=8.0Hz,2H),4.26(d,J=8.0Hz,2H),3.70(s,2H),3.50-3.48(m,2H),1.30(t,J=10.1Hz,3H)。
化合物DSC4101的合成:
方法一:氮气保护下,将化合物12(0.40g,1.0mmol)溶解入15mL二氯甲烷中,向其中缓慢加入三乙胺(0.15g,1.5mmol),降温至0℃,体系中加入氯甲酸异丙酯(0.15g,1.2mmol),室温反应2.0h,加入10mL碳酸氢钠溶液(0.5M)洗涤,饱和食盐水洗涤(10mL×1),无水硫酸钠干燥,浓缩,柱层析分离得0.22g产物DSC4101。收率45%。纯度:98.2%。
方法二:氮气保护下,将化合物10(0.37g,1.0mmol)溶解入25mL二氯甲烷中,降温至0℃,体系中加入三乙胺(0.15g,1.5mmol)与氯甲基碳酸异丙酯(0.18g,1.2mmol),室温反应12.0h,加入10mL水洗涤,饱和食盐水洗涤(10mL×1),无水硫酸钠干燥,浓缩,柱层析分离得0.29g产物DSC4101。收率59%。纯度:98.4%。[M+H]+=488.18。1H NMR(300MHz,CDCl3)δ:8.86(s,1H),8.43(s,1H),8.39(s,1H),7.45(d,J=6.2Hz,1H),6.90(d,J=6.2Hz,1H),6.26(s,2H),5.16-5.14(m,1H),4.59(d,J=8.1Hz,2H),4.26(d,J=8.1Hz,2H),3.71(s,2H),3.51-3.49(m,2H),1.31(t,J=10.0Hz,3H),1.27-1.25(m,6H)。
实施例二:化合物DSC4102的合成
化合物13的合成:
氮气保护下将中间体10(3.71g,10.0mmol)加入50mL二氯甲烷中,冷却至0℃,向其中缓慢加入对硝基苯基氯甲酸酯(2.41g,12.0mmol)与三乙胺(1.52g,15.0mmol),控制内温≤5.0℃,加入完毕后室温反应3.0h,水洗(30mL×2),饱和食盐水洗涤(30mL×1),无水硫酸钠干燥后浓缩得固体,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得中间体13精制品1.87g。收率:33%。纯度:95.0%。[M+H]+=567.21。
化合物DSC4102的合成:
氮气保护下将中间体13(0.57g,1.0mmol)加入10mL四氢呋喃中,冷却至0℃,向其中缓慢加入乙二醇(0.06g,1.0mmol)与三乙胺(0.10g,1.0mmol),控制内温≤5.0℃,加入完毕后室温反应72.0h,过滤,滤液浓缩后柱层析分离,45℃下鼓风干燥12.0h得DSC4102精制品0.16g。收率:32%。纯度:96.0%。[M+H]+=490.15。1H NMR(300MHz,CDCl3)δ:8.91(s,1H),8.46(s,1H),8.40(s,1H),7.48(d,J=6.4Hz,1H),6.72(d,J=6.2Hz,1H),6.25(s,2H),4.60(d,J=8.0Hz,2H),4.40-4.38(m,2H),4.29(d,J=8.0Hz,2H),3.75(s,2H),3.55-3.53(m,2H),3.58-3.56(m,2H),1.35(t,J=10.0Hz,3H)。
实施例三:化合物DSC4104的合成
化合物14的合成:
氮气保护下将中间体8(41.34g,0.1mol)加入至0.6L二氯甲烷中,冷却至0℃,向其中缓慢加入正戊基磺酰氯(20.48g,0.12mol)与三乙胺(15.18g,0.15mol),控制内温≤5.0℃,加入完毕后室温反应3.0h,水洗(0.4L×1),饱和食盐水洗涤(0.4L×1),无水硫酸钠干燥后浓缩得固体,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得中间体14精制品41.62g。收率:76%。纯度:97.2%。[M+H]+=548.20。
化合物15的合成:
将中间体14(27.38g,0.05mol),加入0.6L甲醇中,加入钯碳(1.37g,5w/w%),氢气氛围下加热回流2.0h,冷却至室温,过滤,滤饼用甲醇淋洗(0.05L×2),滤液浓缩,乙腈重结晶得固体,45℃下鼓风干燥12.0h得中间体15精制品15.71g。收率:76%。纯度:97.3%。[M+H]+=414.15。
化合物DSC4104的合成:
氮气保护下将中间体15(12.41g,0.03mol)加入至200mL二氯甲烷中,冷却至0℃,向其中缓慢加入NaH(1.60g,0.04mol),搅拌反应30min后向其中缓慢加入氯甲基碳酸异丙酯(4.58g,0.03mol),控制内温≤5.0℃,加入完毕后室温反应12.0h,水洗(120mL×1),饱和食盐水洗涤(120mL×1),无水硫酸钠干燥后浓缩得中间体粗品,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得DSC4104精制品9.53g。收率:60%。纯度:98.6%。[M+H]+=530.21。1HNMR(300MHz,CDCl3)δ:8.84(s,1H),8.39(s,1H),8.37(s,1H),7.43(d,J=6.1Hz,1H),6.66(d,J=6.1Hz,1H),6.20(s,2H),5.09-5.07(m,1H),4.55(d,J=8.2Hz,2H),4.26(d,J=8.2Hz,2H),3.68(s,2H),3.19-3.17(m,2H),1.62-1.60(m,2H),1.32-1.28(m,10H),0.91(t,J=10.0Hz,3H)。
实施例四:化合物DSC4107的合成
化合物17的合成:
将氟甲基磷酸二乙酯(178.63g,1.05mol)加入至3.0L四氢呋喃中,氮气保护下降温至-5.0℃,向其中缓慢加入叔丁醇钾(129.04g,1.15mol),保持内温≤0℃,移入室温搅拌反应1.0h,降温至0℃,向其中缓慢滴加1-Boc-3-氮杂环丁酮(171.20g,1.0mol)的四氢呋喃溶液0.6L,滴加过程中保持内温≤10.0℃,滴加完毕后移入室温反应12.0h,TLC监测反应完毕,向其中加入1.0L水,减压浓缩得棕色混合物,加入2.5L水,搅拌均匀后乙酸乙酯萃取(3.0L×2),合并的有机相用饱和食盐水洗涤(3.0L×1),无水硫酸干燥,浓缩,所得固体用1.5L四氢呋喃/水(4:1,V/V)重结晶,固体于45℃下鼓风干燥12.0h得中间体17精制品140.41g。收率:75%。纯度:96.5%。[M+H]+=188.10。
化合物18的合成:
将中间体6(95.80g,0.30mol)加入至1.2L乙腈中,加入中间体17(61.78g,0.33mol)与1,8-二氮杂二环十一碳-7-烯(54.81g,0.36mol),加热至60℃反应2.0h,减压浓缩,加入0.5L(0.1M)盐酸酸化,乙酸乙酯萃取(1.6L×2),饱和食盐水洗涤(2.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化,45℃下鼓风干燥12.0h得中间体18精制品109.41g。收率:72%。纯度:97.0%。[M+H]+=507.22。
化合物19的合成:
将中间体18(101.31g,0.20mol)加入至1.2L乙腈中,加入100mL三氟乙酸(TFA),加热至60℃反应2.0h,降温至室温,减压浓缩后向其中加入1.0L碳酸氢钠溶液(0.5M),乙酸乙酯萃取(1.2L×2),饱和食盐水洗涤(1.2L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化,45℃下鼓风干燥12.0h得中间体19精制品56.09g。收率:69%。纯度:97.9%。[M+H]+=407.16。
化合物20的合成:
氮气保护下将中间体19(40.64g,0.1mol)加入至0.6L二氯甲烷中,冷却至0℃,向其中缓慢加入乙基磺酰氯(15.43g,0.12mol)与三乙胺(15.18g,0.15mol),控制内温≤5.0℃,加入完毕后室温反应5.0h,水洗(0.4L×1),饱和食盐水洗涤(0.4L×1),无水硫酸钠干燥后浓缩得固体,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得中间体20精制品34.90g。收率:70%。纯度:96.6%。[M+H]+=499.14。
化合物21的合成:
将中间体20(24.93g,0.05mol),加入0.5L甲醇中,加入钯碳(1.26g,5w/w%),氢气氛围下加热回流2.0h,冷却至室温,过滤,滤饼用甲醇淋洗(0.05L×2),滤液浓缩,乙腈重结晶得固体,45℃下鼓风干燥12.0h得中间体21精制品12.94g。收率:71%。纯度:97.4%。[M+H]+=365.11。
化合物DSC4107的合成:
氮气保护下将中间体21(0.36g,1.0mmol)加入至30mL二氯甲烷中,冷却至0℃,向其中缓慢加入NaH(0.06g,1.5mmol),搅拌反应30min后向其中缓慢加入氯甲基碳酸异丙酯(0.18g,1.2mmol),控制内温≤5.0℃,加入完毕后室温反应12.0h,水洗(15mL×1),饱和食盐水洗涤(15mL×1),无水硫酸钠干燥后浓缩得粗品,柱层析分离得DSC4107精制品0.22g。收率:45%。纯度:98.7%。[M+H]+=481.16。1H NMR(300MHz,CDCl3)δ:8.84(s,1H),8.42(s,1H),8.39(s,1H),7.44(d,J=6.3Hz,1H),6.89(d,J=6.3Hz,1H),6.24(s,2H),5.14-5.12(m,1H),4.57(d,J=8.2Hz,2H),4.25(d,J=8.2Hz,2H),3.70-3.67(m,2H),3.49-3.47(m,2H),1.29(t,J=10.1Hz,3H),1.26-1.24(m,6H)。
实施例五:化合物DSC4110的合成
DSC4110的合成:
氮气保护下将中间体13(0.57g,1.0mmol)加入10mL四氢呋喃中,冷却至0℃,向其中缓慢加入二乙胺盐酸盐(0.11g,1.0mmol)与三乙胺(0.20g,2.0mmol),控制内温≤5.0℃,加入完毕后室温反应72.0h,过滤,滤液浓缩后柱层析分离得DSC4110精制品0.54g。收率:54%。纯度:98.1%。[M+H]+=501.20。1HNMR(300MHz,CDCl3)δ:8.84(s,1H),8.39(s,1H),8.37(s,1H),7.40(d,J=6.0Hz,1H),6.64(d,J=6.0Hz,1H),6.18(s,2H),4.55(d,J=8.0Hz,2H),4.23(d,J=8.0Hz,2H),3.68(s,2H),3.49-3.47(m,2H),3.07-3.05(m,4H),1.30(t,J=10.2Hz,3H),1.17-1.15(m,6H)。
实施例六:化合物DSC4113的合成
化合物DSC4113的合成:
氮气保护下将中间体12(0.80g,2.0mmol)加入至50mL二氯甲烷中,冷却至0℃,向其中缓慢加入NaH(0.12g,3.0mmol),室温下搅拌反应30min,冷却至0℃,向其中加入氯甲基碳酸异丙酯(0.46g,3.0mmol),室温搅拌反应12.0h,水洗(30mL×1),饱和食盐水洗涤(30mL×1),无水硫酸钠干燥后浓缩得固体,柱层析分离得DSC4113精制品0.75g。收率:72%。纯度:98.6%。[M+H]+=518.17。1H NMR(300MHz,CDCl3)δ:8.86(s,1H),8.43(s,1H),8.39(s,1H),7.44(d,J=6.4Hz,1H),6.67(d,J=6.4Hz,1H),6.29-6.27(m,1H),5.86(s,2H),4.58(d,J=8.0Hz,2H),4.25(d,J=8.0Hz,2H),3.83(s,3H),3.71(s,2H),3.50-3.48(m,2H),1.60(d,J=10.5Hz,3H),1.33(t,J=10.4Hz,3H)。
实施例七:化合物DSC4132的合成
化合物DSC4132的合成:
氮气保护下将中间体13(0.57g,1.0mmol)加入10mL四氢呋喃中,冷却至0℃,向其中缓慢加入二乙胺基乙醇(0.12g,1.0mmol)与三乙胺(0.10g,1.0mmol),控制内温≤5.0℃,加入完毕后室温反应72.0h,过滤,滤液浓缩后柱层析分离得DSC4132精制品0.11g。收率:21%。纯度:98.0%。[M+H]+=545.04。1H NMR(300MHz,CDCl3)δ:8.88(s,1H),8.45(s,1H),8.41(s,1H),7.47(d,J=6.0Hz,1H),6.70(d,J=6.0Hz,1H),6.28(s,2H),4.60(d,J=8.1Hz,2H),4.48-4.46(m,2H),4.29(d,J=8.1Hz,2H),3.71(s,2H),3.53-3.51(m,2H),3.01-2.99(m,2H),2.82-2.80(m,4H),1.34(t,J=10.5Hz,3H),1.17-1.15(m,6H)。
实施例八:化合物DSC4135的合成
氮气保护下将化合物DSC4132(0.54g,1.0mmol)加入10mL丙酮中,冷却至0℃,向其中缓慢加入溴乙烷(0.11g,1.0mmol),控制内温≤5.0℃,加入完毕后室温反应72.0h,过滤,滤液浓缩后柱层析分离得DSC4135精制品0.12g。收率:18%。纯度:96.7%。[M+H]+=653.20。1H NMR(300MHz,CDCl3)δ:8.84(s,1H),8.43(s,1H),8.37(s,1H),7.44(d,J=6.4Hz,1H),6.67(d,J=6.4Hz,1H),6.24(s,2H),4.55(d,J=8.3Hz,2H),4.32-4.30(m,2H),4.25(d,J=8.2Hz,2H),3.67(s,2H),3.52-3.50(m,2H),2.67-2.65(m,2H),2.38-2.36(m,6H),1.31(t,J=10.1Hz,3H),1.00-0.97(m,9H)。
实施例九:化合物DSC4137的合成
化合物DSC4137的合成:
氮气保护下将中间体12(0.80g,2.0mmol)加入至50mL二氯甲烷中,冷却至0℃,向其中缓慢加入NaH(0.12g,3.0mmol),室温下搅拌反应30min,冷却至0℃,向其中加入1-氯乙基甲基碳酸酯(0.42g,3.0mmol),室温搅拌反应12.0h,水洗(30mL×1),饱和食盐水洗涤(30mL×1),无水硫酸钠干燥后浓缩得固体,柱层析分离得DSC4137精制品0.25g。收率:25%。纯度:98.3%。[M+H]+=504.14。1H NMR(300MHz,CDCl3)δ:8.85(s,1H),8.41(s,1H),8.38(s,1H),7.41(d,J=6.2Hz,1H),6.66(d,J=6.2Hz,1H),6.20(s,2H),5.80(s,2H),5.05-5.03(m,1H),4.56(d,J=8.1Hz,2H),4.24(d,J=8.1Hz,2H),3.69(s,2H),3.50-3.47(m,2H),1.31(t,J=10.1Hz,3H),1.27-1.25(m,6H)。
按照与上述实施例同样的方法,使用市售化合物或由市售化合物适当合成的中间体化合物,或通过合理的上保护基、脱保护基的手段合成了下列实施例化合物。
实施例十:磺酰胺类多环化合物的细胞毒性
以5×104个/mL的浓度将MDCK细胞(狗肾细胞)悬浮液接种到孔板中,培养箱中孵育24h(37℃,CO2),将化合物配制成0.05M的母液,分别使用DMEM培养基(含双抗)稀释后加入相应板孔中,每个化合物置三个复孔,控制最终浓度为:15.0μM,继续孵育72h,保持上述条件避光条件下加入20.0μL的MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)溶液,保持上述条件继续孵育3.0h后每孔加入100μL的DMSO溶剂,混匀后测定在490nm波长下吸光度值,计算细胞存活率=(给药组OD/正常组OD)×100%。采用SPSS 20软件计算最终结果,如下表1:
表1:化合物细胞毒性测定
化合物 | 存活率(%) | 化合物 | 存活率(%) | 化合物 | 存活率(%) | 化合物 | 存活率(%) |
DSC4101 | 67.1 | DSC4111 | 73.2 | DSC4121 | 55.2 | DSC4131 | 61.1 |
DSC4102 | 72.3 | DSC4112 | 57.5 | DSC4122 | 64.4 | DSC4132 | 74.2 |
DSC4103 | 64.7 | DSC4113 | 57.5 | DSC4123 | 62.5 | DSC4133 | 60.4 |
DSC4104 | 61.4 | DSC4114 | 59.7 | DSC4124 | 62.0 | DSC4134 | 67.5 |
DSC4105 | 55.8 | DSC4115 | 61.3 | DSC4125 | 55.1 | DSC4135 | 67.2 |
DSC4106 | 60.7 | DSC4116 | 65.0 | DSC4126 | 56.9 | DSC4136 | 62.9 |
DSC4107 | 60.3 | DSC4117 | 66.4 | DSC4127 | 59.8 | DSC4137 | 59.5 |
DSC4108 | 59.1 | DSC4118 | 60.3 | DSC4128 | 67.0 | DSC4138 | 61.2 |
DSC4109 | 55.7 | DSC4119 | 71.0 | DSC4129 | 54.2 | DSC4139 | 59.8 |
DSC4110 | 56.9 | DSC4120 | 64.7 | DSC4130 | 60.0 |
实验结果表明,磺酰胺类多环化合物表现出了较低的细胞毒性,尤其是化合物DSC4102、DSC4111、DSC4132对MDCK细胞毒性最低,细胞存活率在70%以上,提示化合物在体内具有更很高的安全性。
实施例十一:化合物DSC4102、DSC4111、DSC4132抗炎活性测试
取10周龄、体重24-26g的小鼠为实验动物,分为5组,每组10只,分别灌胃给药0.5%羟丙基甲基纤维素(空白对照组)、巴瑞替尼、DSC4102、DSC4111、DSC4132(称取定量目标化合物溶于0.5%羟丙基甲基纤维素的水溶液中),小鼠灌胃体积为10mL/kg,剂量为5.0μmol/kg。给药30min分钟后足底皮下注射40mg/kg的角叉菜胶(Sigma,C1013)造模。在造模前后的不同时间点(1.0小时、2.0小时、4.0小时、8.0小时)通过足趾肿胀仪测定足体积。数据处理:足肿胀率=(给药后的测量足体积-起始测量足体积)/基础足体积×100%。实验结果如下表2:
表2:化合物体内抗炎活性测试
数据结果表明,仅给与灌胃给药0.5%羟丙基甲基纤维素,对小鼠的炎症反应没有影响,说明造模成功。灌胃给药DSC4102、DSC4111、DSC4132后大鼠的足肿胀率明显降低,1小时后就有明显的效果,起效较快,且明显优于巴瑞替尼,说明化合物DSC4102、DSC4111、DSC4132在大鼠体内有较好的抗急性炎症的效果。同时预示合成的化合物DSC4102、DSC4111、DSC4132在大鼠体内比巴瑞替尼有较快的吸收,更快到达病变部位。
实施例十二:化合物DSC4102、DSC4111、DSC4132在体内毒性
取10周龄、体重22.0±2.0g的小鼠为实验动物100只,雌雄各半,适应性饲养1周,随即分为4组:巴瑞替尼组、DSC4102组、DSC4111组、DSC4132组,每组25只。根据小鼠的体重,通过相应剂量计算,灌胃给药,每天给药一次,每四天一个给药周期,连续实验20天,每组小鼠给相应药物的剂量信息如下表3所示:
表3:化合物巴瑞替尼组、DSC4102、DSC4111、DSC4132体内给药剂量
给药天数 | 第1-4天 | 第5-8天 | 第9-12天 | 第13-16天 | 第17-20天 |
剂量(μmol/kg/天) | 125.0 | 250.0 | 500.0 | 1000.0 | 2000.0 |
灌胃给药,各组小鼠自由饮食、饮水。实验期间记录小鼠的一般生活状况,在实验的第5、10、15、20天按照如下表4打分标准对各个小鼠的一般生活状况进行打分:
表4:小鼠一般形态打分标准
并且在实验的第5、10、15、20天称量各个小鼠的体重,并且记录各组小鼠出现第一只死亡的天数与总的死亡只数。
实验结果:
实验周期内第5、10、15、20天的各组小鼠得分通过加权平均值计算获得,统计结果如下表5所示:
表5:小鼠一般情况打分计算结果
数据表明,从实验的第10天开始各组小鼠均表现出了轻微中毒现象,第15天开始各组小鼠均表现出明显的中毒现象,第20天开始各组小鼠中毒现象严重。相对于巴瑞替尼组,本发明的化合物DSC4102、DSC4111、DSC4132通过灌胃给药在体内表现出了比巴瑞替尼巴瑞替尼更低的毒性,尤其是在大剂量给药后的第20天,小鼠的一般情况明显优于巴瑞替尼。
实验周期内第5、10、15、20天的各组小鼠体重通过加权平均值计算获得(死亡的小鼠不再计入体重统计),统计结果如下表6所示:
表6:实验周期内小鼠体重变化
数据表明,化合物巴瑞替尼、DSC4102、DSC4111、DSC4132在低剂量状态下对小鼠的生长没有明显的影响,且有小幅度增长。在较高剂量且长期给药后对小鼠的生长有影响,并且在第20天的时候DSC4102组、DSC4111组、DSC4132组比巴瑞替尼组的体重明显较高,再一次印证说明本发明的化合物DSC4102、DSC4111、DSC4132比巴瑞替尼具有更低的毒性,对小鼠的生长影响更小。
记录各组小鼠出现第一只死亡的天数与第20天后总的死亡只数如下表7所示:
表7:实验周期内小鼠死亡情汇总表
组别 | 出现第一只死亡的天数 | 第20天总死亡只数 | 致死率(%) |
巴瑞替尼组 | 第14天 | 12只 | 48 |
DSC4102组 | 第16天 | 9只 | 36 |
DSC4111组 | 第17天 | 7只 | 28 |
DSC4132组 | 第17天 | 8只 | 32 |
体内实验数据表明,DSC4102、DSC4111、DSC4132在体内致死率明显低于巴瑞替尼,说明蓄积的毒性比巴瑞替尼低。预示化合物在体内具有更高的安全性。
实施例十三:DCS4132在小型猪皮肤透皮吸收实验
小型猪6只,体重在10.0±1.0kg,分为两组:巴瑞替尼组、DSC4132组,实验前一天禁食,将小猪固定,选取背部区域合适位置剃毛,清洁完毕后在20×20cm2的区域涂抹相应化合物的溶液1.0mL(0.04%)于对应的皮肤中,涂抹均匀后用纱布包住相应部位,继续固定动物5分钟,被涂抹皮肤部分将药液吸收完毕,在第0h、1h、2h、4h、8h、24h取样。
取样方法:将小猪麻醉,揭开纱布,采集皮肤样品,然后用生物敷料填充伤口止血。所得皮肤样品去除多余的脂肪组织,PBS清洗3次,滤纸吸干水分,去除角质层,称重,放置-80℃冰箱备用。
样品处理:解冻后的皮肤,将皮肤剪碎,加入2~8℃的甲醇水溶液(20V/g),采用机械匀浆,2分钟后离心(10000r/分钟),取上清液200μL,加入200μL甲醇水溶液稀释后检测。
采用HPLC测试样品中相应化合物的含量,设置对应化合物的标准曲线,并通过面积归一法计算最终的小猪皮肤中的化合物含量,计算结果如下表8:
表8:化合物巴瑞替尼、DSC4132小猪皮肤组织透皮情况
数据表明,化合物DSC4132可以比巴瑞替尼穿透皮肤穿透能力,透皮能力大约为巴瑞替尼的2倍,预示化合物可以治疗局部皮肤炎症。
本申请描述了多个实施例,但是该描述是示例性的,而不是限制性的,并且对于本领域的普通技术人员来说显而易见的是,在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。
Claims (11)
1.一种如下通式(I)所示的磺酰胺类多环化合物或其水合物、溶剂化物、N-氧化物、多晶型物、同位素衍生物、药学上可接受的盐:
式(I)中,R1选自C1-C8的烷基、C1-C8的烷氧基、C2-C8的烯基、C2-C8的炔基、C3-C8的碳环基、C2-C8的杂环基;上述的烷基、烷氧基、烯基、炔基、碳环基、杂环基任选地被一个或多个下列基团取代:氢、氰基、卤素、羟基、羧基、氨基、乙酰基;
R2代表氰基、氟、C1-C8的烷基、C2-C8的烯基、或氰基取代的C1-C8的烷基;
n选自0、1、2、或3;
T-选自、F-、Cl-、Br-、I-、CH3COO-、NO2 -、NO3 -、HSO4 -、BF4 -、PF6 -、柠檬酸根、枸橼酸根、苹果酸根、甲磺酸根、对甲苯磺酸根、酒石酸根;
Ra、Rb各自独立地选自一个或多个基团A取代的C1-C8的烷基、C1-C8的烷氧基、或Ra、Rb采用合理的方式相连成环;
Rc选自C1-C8的烷基、C1-C8的烷氧基;
R4选自下列基团:C1-C8的烷基、C1-C8的烷氧基、C3-C8的碳环基、C2-C8的杂环基;
X为O、NR5;
当Q为-(C=O)-时,R3不为-COOR4;
Rd、Re各自独立地选自氢、C1-C8的烷基、C1-C8的烷氧基、或Rd、Re采用合理的方式相连成环;
R5为氢、或C1-C8的烷基;
所述的基团A选自:氢、氨基、羟基、氰基、羧基、硝基、卤素、三氟甲基、乙酰基、C1-C8的烷基、C1-C8的烷氧基、C2-C8的杂环基、C1-C6烷胺基。
4.如权利要求1所述磺酰胺类多环化合物包括其无机酸盐、有机酸盐。
6.一种药物组合物,其包括有效量的如权利要求1~5中任意一项所述的磺酰胺类多环化合物或其水合物、溶剂化物、N-氧化物、多晶型物、同位素衍生物、药学上可接受的盐与药学上可接受的辅料制备成的制剂。
7.权利要求1~5中任意一项所述的磺酰胺类多环化合物或其水合物、溶剂化物、N-氧化物、多晶型物、同位素衍生物、药学上可接受的盐,或权利要求6所述的药物组合物在制备用于预防/治疗JAK(Janus Kinase)介导的相关疾病以及在抗RNA(Ribonucleic Acid)病毒领域药物中的用途。
8.权利要求7所述的用途,所述的JAK介导的相关疾病包括关节炎、炎症性肠病、皮肤病、局部脱发、斑秃、骨髓纤维化、秃发性毛囊炎、白癜风、急性呼吸综合征、癌症。
9.权利要求7所述的用途,所述的抗RNA病毒的用途包括与其他抗病毒药物如瑞德西韦、利巴韦林、氯喹联用治疗新冠肺炎(Corona Virus Disease 2019,COVID-19)。
10.权利要求6所述的药物组合物,所述的药学上可接受的辅料包括填充剂、粘合剂、稀释剂、润滑剂、防腐剂、掩味剂或助溶剂的一种或者几种的组合。
11.根据权利要求6或权利要求10所述的药物组合物,所述的药学上可接受的辅料做成的制剂剂型为片剂、胶囊、散剂、颗粒剂、丸剂、混悬剂、软膏、硬膏、巴布膏、贴片、贴剂、膜剂、或吸入制剂。
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