CN101374845A - 新化合物及其应用 - Google Patents
新化合物及其应用 Download PDFInfo
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- CN101374845A CN101374845A CNA2007800028861A CN200780002886A CN101374845A CN 101374845 A CN101374845 A CN 101374845A CN A2007800028861 A CNA2007800028861 A CN A2007800028861A CN 200780002886 A CN200780002886 A CN 200780002886A CN 101374845 A CN101374845 A CN 101374845A
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- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 5
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
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- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
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- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- 206010035664 Pneumonia Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
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- YKYBDMRQIWIRBA-UHFFFAOYSA-N 2-(2,3-dimethyl-6H-indol-6-yl)-N,N-dimethylethanamine Chemical class CC1=NC2=CC(C=CC2=C1C)CCN(C)C YKYBDMRQIWIRBA-UHFFFAOYSA-N 0.000 description 1
- LJHHJFAUMZLYRE-UHFFFAOYSA-N 2-(2,3-dimethylindolo[3,2-b]quinoxalin-6-yl)ethyl-dimethylazanium;chloride Chemical compound Cl.CC1=C(C)C=C2N=C3N(CCN(C)C)C4=CC=CC=C4C3=NC2=C1 LJHHJFAUMZLYRE-UHFFFAOYSA-N 0.000 description 1
- OIVUHPTVQVCONM-UHFFFAOYSA-N 6-bromo-4-methyl-1h-indazole Chemical compound CC1=CC(Br)=CC2=C1C=NN2 OIVUHPTVQVCONM-UHFFFAOYSA-N 0.000 description 1
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- 206010061598 Immunodeficiency Diseases 0.000 description 1
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
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- 206010038910 Retinitis Diseases 0.000 description 1
- CWHJIJJSDGEHNS-MYLFLSLOSA-N Senegenin Chemical compound C1[C@H](O)[C@H](O)[C@@](C)(C(O)=O)[C@@H]2CC[C@@]3(C)C(CC[C@]4(CCC(C[C@H]44)(C)C)C(O)=O)=C4[C@@H](CCl)C[C@@H]3[C@]21C CWHJIJJSDGEHNS-MYLFLSLOSA-N 0.000 description 1
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- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
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- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
式(I)的化合物,其中R1选自H、F、Cl、Br、CF3、C1-C6烷氧基和OH,R2选自H和C1-C6烷基;n是1-12,m是0或1,Y选自CH2、NR3、(NR3R4)+X”、O和S;R3和R4独立选自H和C1-C4烷基;而X”选自药学可接受的阴离子。一种制备该化合物的方法,其作为药物的应用,和治疗的方法。
Description
发明技术领域
本发明涉及新的吲哚并喹喔啉衍生物,它们的制备方法以及它们的药物应用。尤其是,本发明涉及新的吲哚并喹喔啉衍生物及其在治疗病毒感染上的应用。
发明背景技术
众所周知,病毒是人和动物的许多疾病,有时是威胁生命的疾病的病因。例如,疱疹病毒如1型单纯疱疹(HSV-1),2型单纯疱疹(HSV-2),巨细胞病毒(CMV),EB病毒(EBV),水痘带状疱疹病毒(VZV)和6型人疱疹病毒(HHV6)与许多常见病毒疾病是相关的。
人CMV(HCMV)感染是终生的痛苦其可造成发病和死亡。与HCMV相关的病理包括小头畸形,肝脾肿大(heptosplenomegaly),黄疸,脑炎,新生儿或宫内胎儿的感染,和免疫低下宿主的感染。
由于几个原因,越来越多的人有感染HCMV的风险,目前估计在美国有80%的成人感染了HCMV。特别易感的人群是那些免疫系统减弱的人,如AIDS患者,感染HCMV可能导致视网膜炎,胃炎和肺炎。而且,HCMV诱发的肺炎或肝炎也是频发且严重的骨髓移植并发症。
欧洲专利EP 0 238 459涉及了取代吲哚并喹喔啉,其通式如下
其中R1代表了氢或一个或几个,优选1-4个,相似的或不同的在1-4和/或7-10位上的取代基,其选自卤素,优选Br,具有不多于4个碳原子的低级烃基/烷氧基,三氟甲基,三氯甲基;X是-(CH2)n-R2基团,其中R2代表含氮碱性残基如NH2、NHR4或NR5R6,其中R4、R5和R6独立地是低级烷基或环烷基且n是1-4的整数,R3代表氢、具有不多于4个碳原子的低级烷基/环烷基,和该化合物与酸和卤素加成的药学可接受加成产品,优选与碘,一氯化碘,或一溴化碘加成。
但是,显然对于具有抗病毒功效的新药仍存在迫切的需求,尤其是针对疱疹病毒如HCMV,而本发明的目的在于提供能满足这种需求的化合物。
发明概述
在本发明的第一方面提供了一种具有式(I)的化合物:
其中
R1选自H、F、Cl、Br、CF3、C1-C6烷氧基和OH;
R2选自H和C1-C6烃基;
n是1-12;
m是0或1;和
Y选自CH2、NR3、(NR3R4)+X-、O和S;
R3和R4独立选自H和C1-C4烃基;和
X-选自药学可接受的阴离子。
根据另一方面,提供了制备具有式(I)的化合物的方法,是通过将式(II)的化合物
与式(III)的化合物在溶剂或溶剂混合物中反应,
L(CH2)n(Y)m(CH2)nL(III)
其中
R1、R2、Y、m和n如上文式(I)中所定义;和
L是离去基团。
在本发明的另一方面提供了包括具有式(I)的化合物和至少一种药学可接受赋形剂的药物组合物。
根据本发明的一个方面,该药物组合物是一种适于治疗病毒感染的抗病毒组合物。
本发明的其它方面以及它们的实施方式如权利要求所定义。
发明具体实施方式
在本发明的一个实施方式中,式(I)中的R1选自H、F、Cl、Br、CF3、OCH3和OH。
而且,在本发明的一个实施方式中,式(I)中的R2选自H和C1-C4烷基,例如H和C1-C3烷基,如H和CH3。
式(I)中的平衡离子X-可以是任何适宜的药学可接受阴离子,如Cl-,Br-,甲烷磺酸盐,甲苯磺酸盐,乙酸盐,柠檬酸盐和马来酸盐。
式(I)中的指数n可选自1-12之间的任意值,如2-10,或4-10,例如4-8;或1-6,例如1-3。
用于制备本发明化合物的式(II)的化合物本身可按照EP 0 238 459以及美国专利4,990,510的一般教导来制备,这些专利都引入本文作为参考。
式(III)的化合物,即L(CH2)n(Y)m(CH2)nL,可通过本领域技术人员公知的方法合成,或从化学供应商处购买。
式(III)中的离去基团L可适当地选自如Cl、Br、甲烷磺酰基和甲苯磺酰基,尽管本领域技术人员知道还可考虑其它离去基团。
所用的溶剂体系应该是一种在所选的反应条件下反应物在其中是可溶的并且应该是如有利于反应生成所需的产品。作为一个例子,可选择一种或几种极性的非质子或质子溶剂,如乙腈、THF、甲醇、乙醇、异丙醇、醋酸乙酯以及醋酸甲酯。本领域技术人员熟知如何选择这类溶剂体系以及适宜的反应条件。
本发明化合物用作抗病毒剂,因而在本发明的一个方面提供了一种含有式(I)的化合物和至少一种药学可接受赋形剂的抗病毒药物组合物。
在本发明的一个实施方式中,药物组合物用于病毒的治疗,病毒选自疱疹病毒,如1型单纯疱疹(HSV-1),2型单纯疱疹(HSV-2),巨细胞病毒(CMV),EB病毒(EBV),水痘带状疱疹病毒(VZV)和6型人类疱疹病毒(HHV6)。
在本发明的一个实施方式中,病毒是人类巨细胞病毒。
药学可接受赋形剂可以是例如,介质,佐剂,载体或稀释剂,如本领域技术人员所公知的和Remington在The Science and Practice of Pharmacy,第21版,Mack Printing Company,Easton,Pennsylvania(2005)所描述的。而且,考虑到除式(I)的化合物之外本发明药物组合物还可包括其它治疗活性物质,如其它抗病毒剂。
本发明药物组合物可经肠胃外或口服给药并可用于需要这种治疗的脊椎动物的局部或全身抗病毒治疗,如鸟,或哺乳动物如人类,或动物如家畜或农畜。考虑到在多药治疗中可将本发明药物组合物与其它相容药物,如其它抗病毒药物一起给药。
下文通过实施例进一步阐述了本发明,但实施例不应被解释为限制由权利要求所定义的本发明范围。应该注意双环体系中每个的编号方式与欧洲专利EP0 238 459的取代吲哚并喹喔啉的通式的是一样的,如上文所示。
实施例
本发明化合物的制备
利用来自于DMSO-d6(1H:δ=2.50ppm;13C:δ=39.5)的信号作为内标,在Bruker DPX300(300MHz)光谱仪上记录室温下DMSO-d6溶液中的NMR光谱。δ值单位为ppm。溶剂是分析纯的,按供应商提供的来使用。
实施例1
烯烃二聚物的合成
一般步骤(10mmol规模)
将B-220(式II,R1=H,R2=CH3,或其衍生物)、二卤代烷和乙腈加热15小时(在回流下或在70℃)。通过过滤分离形成的固体,用乙腈洗涤并干燥。
1a)R1=H,R2=CH3,n=3,m=0,X-=Br-
产量:70%;1H-NMR δ:8.34(d,1H),7.94(m,2H),7.77(m,2H),7.43(t,1H),4.93(br.s,2H),3.86(br.s,2H),3.54(br.s,2H),3.27(s,6H),2.39(s,6H),1.77(br.s,2H),1.28(br.s,2H)。
1b)R1=H,R2=CH3,n=5,m=0,X-=Br-
产量:49%;1H-NMR δ:8.35(d,1H),8.00(s,1H),7.92(d,1H),7.80(m,2H),7.45(t,1H),4.91(t,2H),3.85(t,2H),3.49(m,2H),3.24(s,6H),2.48(s,3H),2.45(s,3H),1.69(m,2H),1.17(s,6H)。
1c)R1=9-Br,R2=CH3,n=3,m=0,X-=Br-
产量:73%;1H-NMR δ:8.39(s,1H),8.08-7.81(m,3H),7.73(s,1H),5.16(br.s,2H),3.69(br.s,2H),3.43(br.s,2H),3.25(s,6H),2.39(s,3H),2.37(s,3H),1.88(br.s,2H),1.32(br.s,2H)。
1d)R1=9-Cl,R2=H,n=3,m=0,X-=Br-
13C-NMRDMSO-d6 δ:21.6(t),25.2(t),35.3(t),50.8(q),59.0(t),63.3(t),112.6(d),120.4(s),121.6(d),126.1(s),126.8(d),127.5(d),129.3(d),129.8(d),131.1(d),138.6(s),139.0(s),139.8(s),142.0(s),144.9(s)。
1e)R1=H,R2=H,n=1,m=1,Y=CH2,X-=Br-
13C-NMRDMSO-d6 δ:17.0(t),35.0(t),50.9(q),59.9(t),60.5(t),110.8(d),119.0(s),121.7(d),122.4(d),126.5(d),127.5(d),129.2(d)*,131.5(d),138.9(s),139.5(s),139.7(s)143.5(s),144.7(S)。
*两个碳原子一个信号
1f)R1=H,R2=H,n=3,m=0,X-=Br-
13C-NMRDMSO-d6 δ:21.7(t),25.4(t),35.0(t),50.8(q),59.2(t),63.2(t),110.7(d),119.1(s),121.8(d),122.5(d),126.6(d),127.4(d),129.2(d),129.3(d),131.6(d),139.0(s),139.6(s),139.8(s),143.6(s),144.8(s)。
实施例2
醚二聚物的合成
一般步骤(10mmol规模)
将B-220(或其衍生物)、二卤代烷和乙腈在回流下加热20小时。通过过滤分离形成的固体,用乙腈洗涤并干燥。
2a)R1=H,R2=CH3,n=2,Y=O,m=1,X-=Br-
产量:58%;1H-NMR δ:8.22(d,1H),7.84(s,1H),7.72(m,2H),7.59(s,1H),7.47(d,1H),7.38(t,1H),7.08(d,1H),4.85(t,2H),4.09(br.s,2H),3.93(m,4H),3.29(s,6H),2.35(s,3H),2.26(s,3H),2.24(s,3H)。
2b)R1=9-Br,R2=CH3,n=2,Y=O,m=1,X-=Br-
产量:91%;1H-NMR δ:8.02(d,1H),7.77-7.66(m,3H),7.49(s,1H),7.45(d,2H),7.07(d,2H),4.78(t,2H),4.11(br.s,2H),3.95-3.90(m,4H),3.27(s,6H),2.31(s,3H),2.26(s,3H),2.18(s,3H)。
生物学试验
下文描述了利用本发明化合物即实施例1的化合物1a实施针对人类巨细胞病毒的抗病毒活性试验。称作B-220的参照化合物是欧洲专利EP 0 238 459所公开的2,3-二甲基-6-(N,N-二甲氨基乙基)-6H-吲哚并(2,3-b)喹喔啉。
对病毒感染的抑制效应的试验
为评价靶向结构病毒蛋白是否与靶向病毒转录物一样有效,建立了改进的噬菌斑试验,其中将新抗病毒剂之一与公认的可抑制HCMV转录[GCV(Cymevene,Roche)和PFA(Foscavir,AstraZeneca)]或感染[IVIg(IVIG CP,BiotestPharma),一种抗体]的抗病毒剂进行比较。
在0dpi(感染后的天数)的实验中同时添加抗病毒剂和TB40/E,其指示了药剂很好地抑制感染。通过比较处理孔内被感染细胞的数量与阳性对照的数量,并计算所测药剂实现的感染抑制率从而获得该实验的结果。以HCMV的AD-169株和临床分离菌株分别重复该实验,获得基本相同的结果。
表1中显示了所测物质的抑制效果,以感染抑制率%表示。这些数据来自于由感染人类肺成纤维细胞的HCMV AD169株和TB 40的噬菌斑试验。
试验的结果表明了本发明化合物具有极好的病毒感染抑制效果。
HCMV装配(assembly)和排出(egress)的抑制试验
用抗病毒剂B-220和如表2所示的其它参照物质以及本发明化合物1a处理被感染的人类肺成纤维细胞(HL细胞)以评价本发明化合物对HCMV感染、装配和排出的效果。
这些实验中在感染后的第3或5天(dpi)添加抗病毒剂并保留在培养物中至7dpi。之后将上清液和破碎的细胞转移至新的细胞培养物中过夜随后为IE表达而进行染色。结果表明了物质极好地阻止病毒的装配和排出。更具体而言,在3dpi大部分病毒壳体在核内被装配而在5dpi它们主要在细胞质中获得它们的外壳且一些已经开始它们的第二次包膜。
在表2中显示了通过改进的噬菌斑试验测定的抗病毒物质的抑制效果。几种物质在由IE染色测定的IE表达上显示出100%的抑制且通过电子显微镜观测大部分被处理细胞的核内未观察到壳体结构。被称为1a的本发明化合物表现出堪比更昔洛韦所获得的结果的极好结果。
作用机制
本发明化合物的作用机制不希望受任何理论的限制,应该注意的是受测的本发明化合物1a显示出非常明显的IE表达抑制。另外,电子显微镜数据表明了病毒装配的减弱。事实上,用于识别和量化稳定的HCMV中间体微粒的图像分析技术表明了壳蛋白与病毒壳体结合的减弱。这些数据共同表明了本发明化合物用于抗病毒治疗中的高潜力。另外,通过使用与至少一种其它抗病毒活性剂组合的本发明化合物,如在多药物治疗中,可预期有协同效应并减弱或避免了获得耐药性的风险。
毒性
通过碘化丙啶染色被感染细胞培养物和未感染的人类肺成纤维细胞的细胞培养物的试验,本发明化合物未显示出任何毒性。10倍于实验所用的化合物1a浓度在0-7dpi的时间段未显示出毒性。在病毒实验中所用的化合物浓度是μM水平。当浓度在100μM以上B-220表现出细胞毒性。
材料和方法
细胞培养
实验中所用的人类肺成纤维细胞,HL细胞(MRC-5)在添加了10%胎牛血清(FCS)和1%青霉素和链霉素(PeSt)的含Earle′s和L谷氨酰胺(来自于GIBCO)的MEM溶液中于37℃和5%CO2下温育。
在实验开始时HL细胞被保留在175cm2的Falcon细胞培养瓶。当将它们转移至48孔多孔板(Becton Dickinson)以进行感染并用抗病毒剂温育时,利用胰蛋白酶和EDTA将细胞从细胞培养瓶释放。
在上述的相同条件下温育细胞直至达到50%的融合并被使用至第26代。
以HCMV感染细胞
以感染复数(MOI)为0.02,用HCMV,病毒株TB 40/E[G.Jahn教授友情提供的内皮适宜的临床分离菌株(UR1 814)]和病毒株AD-169分别感染HL细胞,并在上述相同的培养液中于37℃和5% CO2下温育直至感染后的第3或5天(dpi)。一些细胞(在第0天的实验)同时接触抗病毒剂(参见如下)。阴性对照是保持未感染的。
细胞与抑制剂和抗病毒剂的接触
改变了现有的培养液(在感染后的第3或5天实验中),添加了新的培养液,其含有不同浓度的抑制剂和抗病毒剂。然而在第0天实验的感染并保持温育直至感染后的第1天前这是同时进行的。在加入细胞之前将含IVIg的培养液与病毒冰浴培养1小时。
改进的噬菌斑试验
在感染后的第3或5天实验中MRC-5细胞的上清液被转移至未感染细胞以评估分泌病毒的数量。在剩余细胞中加入新培养液并通过在IKA-Vibrax-VXR上以300次/分钟摇晃多孔板10分钟与玻璃球一起破碎细胞。之后将细胞碎片转移至未感染细胞以便能够评价有感染性的细胞内病毒颗粒的数量。
以病毒颗粒感染新细胞大约1小时之后改变培养液,并洗去细胞碎片。
在第0天的实验中细胞在感染后的第1天立即被固定(按照以下解释的程序)。
如上,分别处理阳性对照(未处理的被感染细胞)和阴性对照(未处理的未感染细胞)。
细胞的免疫荧光染色
在之后的一天,用3%多聚甲醛(PFA)在室温(RT)下将新HL细胞(在感染后第3和5天实验中的)固定15分钟。为使细胞可渗透,在室温下以刚好覆盖整个表面数量的DAKO在RT下进行20分钟的背景封闭之后,利用含0.3%TritonX的磷酸缓冲液(PBS)在RT下温育15分钟。之后将所有多孔板与稀释至1:100的直接针对早期抗原(IEA,Antigene)的初级抗体(小鼠)在8℃下温育45分钟。随后将细胞与稀释至1:100的次级抗体兔抗鼠FITC(Dako Cytomation)在8℃下温育45分钟并同时以DAPI(Sigma)染色,稀释至1:250的DAPI是一种可对细胞核染色的化学物质。
如上,分别处理两种细胞株的阳性对照和阴性对照。
免疫荧光显微镜分析
利用Nikon Eclipse TE2000-U对细胞进行荧光显微镜分析。通过肉眼对孔的两个不同部分的表达IEA的细胞数量进行计数并与相同部分的细胞总数(由DAPI指示的)进行比较。利用这些值评估每孔中被感染细胞的百分比并从中计算由不同物质所实现的抑制数。因为不可能对孔内的细胞总数进行手工计数,就选择计算孔的两个部分内被感染细胞的百分比并将其应用于整个孔的方法。
Claims (17)
2.如权利要求1所述的化合物,其中R1选自H、F、Cl、Br、CF3、OCH3和OH。
3.如权利要求1或2所述的化合物,其中R2选自H和CH3。
4.如权利要求1-3任意一项所述的化合物,其中X-选自Cl-、Br-、甲烷磺酸盐、甲苯磺酸盐、乙酸盐、柠檬酸盐和马来酸盐。
5.如权利要求1-4任意一项所述的化合物,其中m是0。
6.如权利要求1-4任意一项所述的化合物,其中m是1。
7.如权利要求6所述的化合物,其中Y是O。
8.如权利要求1-7任意一项所述的化合物,其中n是4-10。
9.如权利要求1-7任意一项所述的化合物,其中n是1-3。
11.如权利要求10所述的方法,其中离去基团选自Cl、Br、甲烷磺酰基和甲苯磺酰基。
12.用作药物的如权利要求1-9任意一项所述的化合物。
13.含有权利要求1-9任意一项所述化合物和药学可接受赋形剂的药物组合物。
14.如权利要求13所述的药物组合物,用作抗病毒药物。
15.如权利要求14所述的药物组合物,用作抗疱疹病毒药物。
16.如权利要求15所述的药物组合物,其中疱疹病毒是人巨细胞病毒。
17.一种通过给药权利要求13-16任意一项所述的药物组合物治疗需要这种治疗的脊椎动物的方法。
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SE0600134A SE529777C2 (sv) | 2006-01-23 | 2006-01-23 | Nya föreningar och användning därav |
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