CN114621229A - 治疗或预防猫传染性腹膜炎的化合物或组合物 - Google Patents
治疗或预防猫传染性腹膜炎的化合物或组合物 Download PDFInfo
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- CN114621229A CN114621229A CN202011447281.7A CN202011447281A CN114621229A CN 114621229 A CN114621229 A CN 114621229A CN 202011447281 A CN202011447281 A CN 202011447281A CN 114621229 A CN114621229 A CN 114621229A
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- infectious peritonitis
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
Description
技术领域
本发明涉及药物技术领域,特别涉及治疗或预防猫传染性腹膜炎的化合物或组合物。
背景技术
猫传染性腹膜炎是一种猫的慢性型的、进行性的、致死性的传染病,猫传染性腹膜炎在临床上常见于两种形式,一种是以腹膜炎、大量腹水为特征的渗出型,也就是湿型传染性腹膜炎;一种是全身没有出现明显的症状变化,但是眼部出现明显的纤维蛋白血块、视网膜出血等葡萄膜炎为特征的干性猫传染性腹膜炎。目前对于猫传染性腹膜炎的治疗主要采用以下几种疗法,第一、抑制免疫及抗炎治疗作用,高剂量类固醇、细胞毒性药物;第二、预防二次细菌感染,广谱抗生素、抗病毒药物;第三、支持治疗,强制进食(以食道或胃管),输液以矫正脱水,胸腔穿刺术以舒缓呼吸症状。猫传染性腹膜炎死亡率高达95%以上,尽管存在上述疗法,但上述方法都不能降低FIP的高死亡率,仅能短暂延缓疾病进程。
发明内容
基于此,有必要提供一种治疗或预防猫传染性腹膜炎的化合物或组合物。
一种化合物,具有通式(I)所示结构:
其中,n为8~20的整数;
X为-O-、-CR3R4-或-NH-;
R1选自:-CH3或-COOR5;
R3、R4和R5各自独立的选自:H或C1-6烷基。
上述化合物的制备方法,包括以下步骤:
将式(I-1)所示化合物和式(I-2)所示化合物进行反应,制得式(I)所示化合物。
一种组合物,包括第一组分和第二组分,所述第一组分为至少一种如上所述的化合物,所述第二组分为至少一种如通式(II)所示的化合物;
m为1~20的整数;
X为-O-、-CR3R4-或-NH-;
R2选自:-CH3或-COOR5;
R3、R4和R5各自独立的选自:H或C1-6烷基。
上述化合物或上述组合物在制备治疗或预防猫传染性腹膜炎中的药物中的应用。
上述化合物或上述组合物在制备治疗或预防猫杯状病毒所导致的疾病中的药物中的应用。
上述化合物或上述组合物在制备治疗或预防犬瘟病毒感染所导致的疾病中的药物中的应用。
有益效果
上述化合物具有优异的抗猫传染性腹膜炎病毒作用。进一步地,包含上述通式(I)所示结构化合物和通式(II)所示结构化合物的组合物,组分之间具有明显的协同作用,不仅具有优于传统抗猫传染性腹膜炎病毒化合物(如GS441524)活性,在耐药性猫传染性腹膜炎实验中,也显示出明显抑制作用,说明本发明的组合物具有用于治疗耐药性猫传染性腹膜炎的潜能。
此外,经研究显示上述化合物及包含上述化合物的组合物还具有较优的抗猫杯状病毒作用,可以用于猫口炎的治疗。
附图说明
图1为治疗期间两组临床监控受试猫体温(T℃)变化图;
图2为治疗期间两组临床监控受试猫球蛋白(GLOB)变化图;
图3为治疗期间两组临床监控受试猫白球比(ALB/GLOB)变化图
具体实施方式
为了便于理解本发明,下面将对本发明进行更全面的描述,并给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
“烷基”是指饱和脂肪族烃基,包括直链和支链基团。C1-6烷基是指含有1至6个碳原子的烷基。非限定性实施例包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基。C1-4烷基是指含有1至4个碳原子的烷基。在一实施例中,C1-4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代。
本发明的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式存在,即包括溶剂化和非溶剂化形式。
本发明中,某可取代位点可被一个或多个取代基取代,且当该可取代位点存在多个取代基时,多个取代基可以彼此相同或不同。
本发明中,药物除含有一种或多种本文所述化合物或组合物外,还可以包含生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分。例如生理学/可药用的载体和赋形剂。其中,赋形剂,可以为一种或多种缓冲剂、稳定剂、抗粘剂、表面活性剂、润湿剂、润滑剂、乳化剂、粘合剂、悬浮剂、崩解剂、填充剂、吸附剂、涂料(肠的或缓释的)防腐剂、抗氧化剂,不透明的剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其它已知的添加剂。
“药学上可接受的盐”即“可药用的盐”,是指医药上可接受的化合物的有机或无机盐。
当化合物是酸性或包括足够酸性生物电子等排体时,适当的“可药用的盐”指从医药上可接受的包括无机碱和有机碱的无毒碱中制备的盐。该盐衍生自含有铝、铵、钙、铜、铁、铁、锂、镁、锰盐、锰、钾、钠、辛等的无机碱。特定的实施方式包括铵、钙、镁、钾和钠盐。盐衍生自医药上可接受的有机无毒碱,该有机无毒碱包括一级、二级和三级胺的盐、包括自然存在的取代胺的取代胺、环胺和碱性离子交换树脂,如精氨酸、甜菜碱、咖啡因、胆碱、N,N.sup.1-二苄基乙二胺、乙二胺、2-二乙氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基六氢吡啶、还原葡糖胺、氨基葡萄糖、组氨酸、海巴明、异丙胺、赖氨酸、葡甲胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙基胺、三甲胺、三丙胺、氨丁三醇等等。
当化合物是碱性的或包括足够碱性生物电子等排体时,盐可以从医药上可接受的无毒酸中制备,包括无机和有机酸。这样的酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、苦杏仁酸,甲基磺酸、粘液酸、硝酸、双羟萘酸、泛酸、磷酸、硫酸、琥珀酸、酒石酸、对甲苯磺酸等等。特定的实施方式包括柠檬酸、氢溴酸、盐酸、磷酸、硫酸、马来酸、酒石酸。其它示例性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐,硫酸盐,磷酸盐、酸性磷酸盐、异烟酸、乳酸、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、富马酸盐、马来酸盐、龙胆酸盐、葡萄糖酸盐,葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲基磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(例如,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。
另外,包含化合物的药物制剂可以为片剂、胶囊剂、口服液体剂、丸剂、颗粒剂、散剂、软膏剂、贴剂、栓剂、口含片、滴眼剂、眼膏剂、眼膏剂、滴耳剂、喷剂、气雾剂、吸入剂、注射剂等。
术语“治疗有效量”是指有效化合物或药物试剂的用量,改善、治愈或治疗疾病或病症的一种或多种症状的必要的最小量。
另外,本发明所述的化合物和组合物可单独给药,也可以与其他药剂联合施用。对于与一种以上的活性剂的联合治疗,当该活性剂在分开的剂量制剂中时,该活性剂可以分开施用或联合施用。另外,一种药剂的施用可在另一种药剂施用之前、同时或之后进行。当与其他药剂联合施用时,第二药剂的“有效量”将视所用药物的类型而定。
施用途径
本发明的一种或多种化合物通过适合于受治疗的生物体(如猫)的任何途径施用。合适的途径包括口服、直肠、鼻、肺、局部(包括口腔和舌下)、和胃肠外(包括皮下、肌内)等。
本发明的化合物或药物组合物也可以包含在试剂盒中。
详细解释
本发明一实施例提供了一种化合物,具有通式(I)所示结构:
其中,n为8、9、10、11、12、13、14、15、16、17、18、19或20;
X为-O-、-CR3R4-或-NH-;
R1选自:-CH3或-COOR5;
R3、R4和R5各自独立的选自:H或C1-6烷基。
进一步地,n为8、9、10、11、12、13或14。
进一步地,R1选自-COOR5;更进一步地,R5选自:H或C1-4烷基;更进一步地,R5选自甲基、乙基、丙基或异丙基;更进一步地,R5选自甲基。
进一步地,X为-O-、-CH2-或-NH-;更进一步地,X为-CH2-。
进一步地,选自化合物B:
本发明一实施例还提供了上述化合物的制备方法,包括以下步骤:
将式(I-1)所示化合物和式(I-2)所示化合物进行反应,制得式(I)所示化合物。其中,可以采用现有的方法使式(I-1)所示化合物和式(I-2)所示化合物进行缩合反应,在此不进行特别限定,应理解为均在本发明的保护范围内。
进一步地,在进行缩合反应前,先采用保护基将呋喃环上两个邻位羟基进行保护,待与式(I-2)所示化合物反应完成后,再脱出保护基;更进一步地,包括以下步骤:
S101:将式(I-1)所示化合物和式(I-3)所示化合物进行反应,制得式(I-4)所示化合物;
Ra、Rb、Rc和Rd各自独立地为C1-6烷基;进一步地,Ra、Rb、Rc和Rd各自独立地为甲基或乙基。
进一步地,步骤S101包括以下步骤:将式(I-1)所示化合物和式(I-3)所示化合物溶于有机溶剂中(优选为丙酮),加入浓硫酸,反应完全后,分离制得式(I-4)所示化合物。
进一步地,步骤S101中,式(I-1)所示化合物和式(I-3)所示化合物的摩尔比为1:(3-8);更进一步地,式(I-1)所示化合物和式(I-3)所示化合物的摩尔比为1:(4.5-5.5);进一步地,步骤S101中,式(I-1)所示化合物和浓硫酸的的摩尔比为1:(1.1-2);更进一步地,步骤S101中,式(I-1)所示化合物和浓硫酸的的摩尔比为1:(1.2-1.4)。
S102:式(I-4)所示化合物和式(I-2)所示化合物进行反应,制得式(I-5)所示化合物;
进一步地,步骤S102中包括以下步骤:将式(I-4)所示化合物、式(I-2)所示化合物、碱(优选为DMAP)和1-乙基-3(3-二甲基丙胺)碳二亚胺溶于有机溶剂中(优选为二氯甲烷),进行反应,反应完全后分离,制得式(I-5)所示化合物。
进一步地,步骤S102中,式(I-4)所示化合物和式(I-2)所示化合物摩尔比为1:(1.1-1.5)。
S103:脱除式(I-5)所示化合物的保护基,制得式(I)所示化合物。
进一步地,步骤S103包括以下步骤:将式(I-5)所示化合物加入甲酸水溶液中,进行反应,反应完全后,分离制得式(I)所示化合物。更进一步地,步骤S103中甲酸和水的体积比为(0.8-1.2):1。
本发明一实施例提供了另一种化合物,具有通式(II)所示结构:
m为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20;
X为-O-、-CR3R4-或-NH-;
R2选自:-CH3或-COOR5;
R3、R4和R5各自独立的选自:H或C1-6烷基。
进一步地,m为6、7、8、9、10、11或12;进一步地,R2选自:-CH3;R3、R4和R5定义如上所述。
进一步地,上述化合物选自化合物A:
本发明还提供了一种组合物,包括第一组分和第二组分。其中,第一组分包括至少一种通式(I)所示结构化合物,第二组分包括至少一种通式(II)所示结构化合物;通式(I)所示结构化合物和通式(II)所示结构化合物如上所述,在此不再进行赘述。
目前GS441524被报道可以用于猫传染性腹膜炎的治疗(Niels C Pedersen,Michel Perron,et al.Efficacy and safety of the nucleoside analog GS-441524fortreatment of cats with naturally occurring feline infectiousperitonitis.Journal of Feline Medicine and Surgery 2019),但26只病猫中复发的病例高达8只,可见单独使用GS441524容易使猫传染性腹膜炎病毒产生耐药性,具有较高的复发率。而通过将通式(I)所示结构化合物和通式(II)所示结构化合物组合,形成组合物,实验结果显示组分之间具有明显的协同作用,不仅具有优于GS441524的抗病毒活性,在耐药性猫传染性腹膜炎实验中,显示出明显抑制作用。说明本发明的组合物具有用于治疗耐药性猫传染性腹膜炎的潜能。
进一步地,第一组分和第二组分的摩尔比为1:9-9:1;更进一步地,第一组分和第二组分的摩尔比为1:4-4:1;更进一步地,第一组分和第二组分的摩尔比为1:3-3:1;更进一步地,第一组分和第二组分的摩尔比为1:1、1:2、1:3、1:4、1:5、5:1、4:1、3:1或2:1。
进一步地,组合物中第一组分的质量百分含量为0.01%-99.99%;更进一步地,第一组分的质量百分含量为20%-80%;进一步地,第一组分的质量百分含量为30%-70%。
本发明还提供了上述化合物或上述组合物在制备治疗或预防猫传染性腹膜炎中的应用。
本发明还提供了上述化合物或上述组合物在制备治疗或预防猫杯状病毒所导致的疾病中的应用。进一步地,预防猫杯状病毒所导致的疾病为猫口炎。
本发明还提供了上述化合物或上述组合物在制备治疗或预防犬瘟病毒感染所导致的疾病中的药物中的应用;进一步地,犬瘟病毒感染所导致的疾病为犬瘟热。
本发明还提供了上述化合物或上述组合物在制备治疗或预防口炎中的应用。进一步地,口炎为猫口炎。
本发明还提供了一种治疗或预防猫传染性腹膜炎、或猫杯状病毒所导致的疾病或犬瘟病毒感染所导致的疾病的方法,包括给待治疗对象施加有效量的上述化合物或上述组合物。
可理解的,当施加上述组合物时,可以先施加第一组分或第二组分,然后再施加另一组分,也可以将第一组分和第二组分混合后再施加,应理解为均在本发明的保护范围内。且当分开施加第一组分和第二组分时,优选在施加的前一种组分代谢完毕前需要施加另一组分。
下面列举具体实施例来对本发明进行说明。
实施例1
化合物2制备
在化合物1(4.50g,15.4mmol)和2,2-二甲氧基丙烷(8.05g,77.2mmol,9.47mL)加入到丙酮(180mL)中,20~30℃下滴加浓硫酸H2SO4(2.03g,20.2mmol,1.10mL),混合物在20~30℃搅拌反应60分钟。薄层层析色谱(EA:MeOH=20:1)监测反应完全。反应液加入到100mL饱和NaHCO3溶液中,用乙酸乙酯(100mL*2)萃取,减压浓缩.浓缩液用PE:EA=1:1柱层析分离得到化合物2(4.50g,13.6mmol,87.9%yield)。HNMR:(400MHz,DMSO-d6)δ7.81-8.08(m,3H),6.85-6.95(m,2H),5.37(d,J=6.63Hz,1H),5.03(t,J=5.69Hz,1H),4.90(dd,J=3.13,6.63Hz,1H),4.32(dt,J=3.19,5.16Hz,1H),3.45-3.61(m,2H),1.64(s,3H),1.29-1.42(m,3H)。
化合物3的合成
将化合物2(4.40g,13.3mmol),和十二酸单甲酯(3.57g,14.6mmol),4-二甲氨基吡啶(DMAP)(4.06g,33.2mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(5.09g,26.6mmol)加入到20.0mL二氯甲烷(DCM)中,20~30℃搅拌反应60分钟.薄层层析色谱(PE:EA =1:2)监测到反应完全,反应液减压浓缩后柱层析分离(PE:EA=4:1)得到化合物3(5.60g,10.0mmol,75.6%yield)。HNMR:(400MHz,DMSO-d6)δ7.95(s,3H),6.90(d,J=4.52Hz,1H),6.80(d,J=4.52Hz,1H),5.40(d,J=6.27Hz,1H),4.94(dd,J=2.76,6.27Hz,1H),4.52-4.61(m,1H),4.17-4.26(m,1H),4.04-4.13(m,1H),3.57(s,3H),2.02-2.31(m,4H),1.58-1.69(m,3H),1.44-1.54(m,2H),1.37(s,5H),1.10-1.23(m,12H)。
化合物B的合成
将化合物3(5.60g,10.0mmol)加入到甲酸(60.0mL)和水(60.0mL)的混合溶液中,40~50℃搅拌反应3小时。LCMS监测反应完全.反应液用乙酸乙酯萃取浓缩后采用制备液相分离纯化产物。制备液相条件如下(制备柱:Pheno menex luna C18 250*80mm*10μm;流动相:[水(0.225%甲酸)-乙腈];B%:40%-65%,20min).所得产物B(2.90g,5.58mmol,55.6%yield,99.6%purity)为白色固体。HNMR:(400MHz,DMSO-d6)δ7.92(s,3H),6.91(d,J=4.52Hz,1H),6.79(d,J=4.52Hz,1H),6.31(d,J=6.02Hz,1H),5.37(d,J=6.02Hz,1H),4.68(t,J=5.40Hz,1H),4.31(dd,J=2.45,11.73Hz,1H),4.11-4.25(m,2H),3.89-3.96(m,1H),3.57(s,3H),2.27(t,J=7.40Hz,4H),1.41-1.55(m,4H),1.16-1.23(m,12H)。
化合物5的制备
在氮气下,将在圆底烧瓶中的化合物4(0.50g,0.83mmol)在无水二氯甲烷(5mL)中的溶液用冰浴冷却至0℃,并且用吡啶(0.14mL,1.66mmol)和DMAP(10mg,0.083mmol)处理,然后逐滴添加氯甲酸庚酯(0.165mL,0.914mmol)。将混合物温热至室温并搅拌2小时。在反应完成后,将该反应混合物用二氯甲烷(25mL)稀释,并用5%水性盐酸(25mL)和水性碳酸氢钠(25mL)洗涤。将有机层经Na2SO4干燥并通过旋转蒸发进行浓缩。
化合物A的制备
将如上制备的全部粗品用甲酸(10mL)在室温下搅拌12小时。通过旋转蒸发去除溶剂,并且使用甲醇和二氯甲烷通过快速柱色谱法将粗产物进行纯化以产生呈无色固体的化合物A。
GS441524的制备
参见(Niels C Pedersen,Michel Perron,et al.Efficacy and safety of thenucleoside analog GS-441524for treatment of cats with naturally occurringfeline infectious peritonitis.Journal of Feline Medicine and Surgery 2019)。
实施例2
抗病毒活性测定
测定方法:猫传染性腹膜炎病毒细胞的保护测定使用猫肾(CRFK)细胞和FIPV-79-1146(猫传腹病毒)。通俗的讲就是混合病毒和细胞,并在测试化合物的存在下温育7天。预滴定病毒,使对照孔出现由于病毒复制引起的85%至95%的细胞凋亡。由于测试化合物可以抑制病毒复制,所以有受试化合物存在的条件下可以观察到抗病毒效果。每个测定板包含细胞对照孔(仅细胞)、病毒对照孔(细胞和病毒)、化合物毒性对照孔(仅细胞和化合物)、化合物比色对照孔(仅化合物)以及实验孔(化合物、细胞和病毒)。通过MTS(MTS(3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑鎓)细胞增殖试剂盒测定细胞的EC50(50%细胞存活的浓度)以及细胞毒性CC50(导致50%细胞死亡的浓度)。
细胞制备:
猫肾(CRFK)细胞(美国典型培养物保藏中心(ATCC)商购)在补充有10%胎牛血清(FBS)的DMEM培养基(2.0mM L-谷氨酰胺、100单位/ml青霉素和100μg/ml链霉素)中生长。使用标准细胞培养物技术以1:10的分流比一周两次地继代培养该细胞。使用血球计数仪和台盼蓝排除法进行总细胞数和生存力百分数测定。对于测定中使用的细胞,细胞生存力必须大于95%。在测定前一天以1x104个细胞/孔的浓度在96孔组织培养板中接种细胞。
病毒制备:
用于测定的病毒是猫传腹病毒FIPV-79-1146(美国典型培养物保藏中心(ATCC)商购)在CRFK细胞中生长,产生病毒并作为储备病毒池。每次测定,从-70℃条件下移除病毒的预滴定等分部分,并在生物安全柜中将其解冻到室温。然后将病毒悬浮并稀释到组织培养基中,使得加入到每个孔的病毒的量是被确定为产生感染后4-5天在85%到95%的细胞杀死之间的量。
细胞染色:
在感染5天后,用MTS细胞增殖试剂盒染色测定细胞存活率并量化化合物毒性。通过由定量分析代谢活性细胞的线粒体酶代谢MTS产生的可溶性甲臜产物,测得细胞存活率和化合物的细胞毒性。每个孔加入20-25μL的MTS试剂,然后在37℃、5%CO2条件下温育微量滴定板4-6小时,然后测定细胞存活率。在490/650nm下按分光光度法SpectraMax Plus板读数器对该板读数。
受试化合物:
受试物分如下种:化合物A,化合物B,化合物A和B混合物(摩尔比2:1、1:1、3:1和1:2的组合物),和阳性化合物GS-441524.
数据分析:
使用计算机计算化合物对病毒抑制的EC50和细胞毒性CC50。下表1为测试化合物的活性结果。(a:小于0.2μM,b:0.2~0.3μM,c:0.3~0.5μM,d:大于0.5μM,e:大于10μM)
表1
由表1可以看到,上述化合物A和化合物B的组合物比单一化合物A和B和阳性对照化合物GS-441524具有更加显著的抑制效果。说明本发明提供的组合物具有优异的抗猫传染性腹膜炎病毒作用。
实施例3
选取10只患有猫传染性腹膜炎的猫,所有的猫都经过GS-441524治疗后再次复发,并且在继续使用GS-441524治疗中,但每只猫只要停止注射GS-441524,就会发烧并且症状加重,药物的治疗可以维持一个不发烧,症状不再严重的状态,这个情况下的10只猫体内的猫传染性腹膜炎病毒已经对GS-441524产生了耐药性。将10只猫随机分成2组,每组5只,第一组继续给与GS-441524(8mg/kg)治疗,第二组给与A/B=2/1的药物组合物(20mg/kg)治疗,给药疗程为50天,观察治疗完后10天是否能够完全缓解,不再复发,由此评定对耐药性猫传染性腹膜炎的治疗效果。监测指标有体温,球蛋白和白球比。其中,图1为治疗期间两组临床监控受试猫体温(T℃)变化图;图2为治疗期间两组临床监控受试猫球蛋白(GLOB)变化图;图3为治疗期间两组临床监控受试猫白球比(ALB/GLOB)变化图。
测试结果及结论:
从图1可以看出,两组试验猫在使用两种试验药物期间(0~50天),体温均处于正常范围(37.7~39.2℃),未出现明显变化,说明两种治疗方案都能对耐药性猫传染性腹膜炎病毒起到抑制作用。在停止治疗之后的10天后,可以看到GS-441524组的平均体温显著上升到39.6℃,而联合用药组体温依然在正常范围,说明GS-441524一经停药后,病毒便失去了抑制,在10天内陆续复发,而联合用药组对复发耐药性猫传染性腹膜炎起到了完全缓解,没有复发,具有良好的疗效。
从图2可以看出,试验猫在使用GS-441524期间,球蛋白一直处于略高于正常值(27~52),并且在停止治疗10天后,上升到60以上,炎症明显,同时根据图3的结果,白球比在治疗期间偏低并且在停止给药后迅速走低,提示治疗只起到暂时缓解作用,停药后迅速反弹。联合给药组的球蛋白则随着给药的进行,球蛋白逐步降低至正常水平,且在停药后十天内保持正常,白球比也逐步升高,并在停药后维持到正常水平,提示联合给药组没有复发,疾病得到了完全缓解。
抗猫杯状病毒(FCV-Kaos)活性检测:
F81细胞(猫肾细胞,购于ATCC)的复苏:
1)预先打开恒温水浴锅,设定温度为38℃;
2)从液氮中取出细胞冻存管,放入水浴锅中2~3min,细胞液完全融化即可;
3)将细胞冻存管离心1000r/min,离心10min;
4)在生物安全柜内将细胞冻存管上层液体弃去,注意不要吸到细胞;
5)沿冻存管管壁加入1mL 10%DMEM培养基,轻轻加入,清洗后将液体弃去,注意不要吹起细胞;
6)向冻存管内加入1mL 10%DMEM培养基,轻轻混匀;
7)将液体加入到T25细胞瓶中,补加5~6mL 10%DMEM培养基,混匀后放入37℃,5%CO2恒温培养箱中培养,每天观察细胞状态。
F81细胞的传代培养:
1)用含8%新生牛血清的DMEM培养基在37℃,5%CO2恒温培养箱中培养F81细胞;
2)待细胞长至单层时,将细胞瓶原培养液倾去,用巴氏管吸取2~3mL无血清DMEM加到细胞瓶内洗三次,倒掉培养液;
3)加入2~3mL 0.05%胰酶进行消化;
4)置于37℃,5%CO2恒温培养箱中1min,至消化好为止;
5)向培养瓶内加入适量体积的8%DMEM培养基,轻轻吹匀;
6)将细胞瓶内液体平均分到两个新的细胞培养瓶中,各补液至5~6mL体积;
7)将细胞瓶放入37℃,5%CO2恒温培养箱中培养,每隔一段时间观察细胞状态。
病毒感染力的滴定(TCID50的测定):
将猫FCV-Kaos病毒(商购于ATCC美国典型培养物保藏中心)用维持液做10倍比系列稀释不同浓度,纵向重复3孔,依次接种于已长成单层的宿主细胞的96孔板中,同时设细胞对照。37℃、5%CO2病毒培养箱中培养,倒置显微镜下逐日观察,连续观察96小时,加1%中性红50μL置37℃染色1h,弃染液,用洗液将多余染料充分洗涤,加脱色液100μL,室温脱色10min,用酶标仪在540nm波长测定OD值。根据Reed-Muench公式计算病毒液的半数感染浓度(TCID50):
细胞存活率=(各组OD值-空白对照OD值)/(正常细胞OD值-空白对照OD值);
细胞病变率=1-细胞存活率;
细胞比距=(高于50%病变率-50%)/(-高于50%病变率-低于50%病变率);
TCID50=Antilg(高于50%CPE百分率病毒稀释度+比距);
FCV-Kaos病毒在F81细胞的TCID50
测定结果见表2:
表2 96小时病毒TCID50测定
化合物抗病毒实验方法
将化合物供试样品用细胞维持液从原浓度开始分别作二倍比系列稀释共10个稀释度,设3个复孔,依次每孔加入50μL横向接种于已长成单层的F81猫肾细胞的96板孔中,每孔再加入100倍TCID50的猫杯状病毒FCV-Kaos 50μL,同时设病毒对照组、细胞对照组及药物毒性组,并设3个复孔。37℃、5%CO2培养箱中培养,逐日观察细胞病变,待病毒对照出现90%以上的病变时,加1%中性红染色,并用酶标仪在540nm波长测定OD值。应用Reed-Muench方法计算药物半数有效浓度(EC50):
EC50=[Antilog(高于50%CPE百分率病毒稀释度的值-比距)]×C
(注:C为第一孔的药物终浓度)
测定结果见表3:
表3 化合物抗病毒活性试验结果
序号 | 受试物 | EC<sub>50</sub>(μM) |
1 | A:B=2:1 | a |
2 | A:B=1:1 | b |
3 | A:B=3:1 | a |
4 | A:B=1:2 | b |
5 | B | b |
6 | A | c |
(a:小于5μM,b:5~10μM,c:10~20μM,)
由表2可以看到,上述化合物A和化合物B的组合物比单一化合物A和B对猫杯状病毒具有更加显著的抑制效果。说明本发明提供的组合物可用于抗猫杯状病毒作用,用于猫口炎的治疗。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
2.根据权利要求1所述的化合物,其特征在于,n为8、9、10、11、12、13或14;和/或
R3和R4为H;和/或
R5为甲基、乙基、丙基或异丙基。
8.根据权利要求6或7所述的组合物,其特征在于,所述第一组分和所述第二组分的摩尔比为1:9-9:1,优选为1:1、1:2、1:3、1:4、1:5、5:1、4:1、3:1或2:1。
9.权利要求1-3任一项所述的化合物或权利要求6-8任一项所述的组合物在制备治疗或预防猫传染性腹膜炎、猫杯状病毒所导致的疾病或犬瘟病毒感染所导致的疾病的药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述猫杯状病毒所导致的疾病为猫口炎;所述犬瘟病毒感染所导致的疾病为犬瘟热。
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