CN101035531A - 卤代苯甲酰胺衍生物 - Google Patents
卤代苯甲酰胺衍生物 Download PDFInfo
- Publication number
- CN101035531A CN101035531A CNA2005800338784A CN200580033878A CN101035531A CN 101035531 A CN101035531 A CN 101035531A CN A2005800338784 A CNA2005800338784 A CN A2005800338784A CN 200580033878 A CN200580033878 A CN 200580033878A CN 101035531 A CN101035531 A CN 101035531A
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- alkyl
- benzoylamide
- thiazolyl
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 40
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- -1 acetoxyl group Chemical group 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
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- ZNEBVPDLAHSKDD-UHFFFAOYSA-N n-(5-bromo-1,3-thiazol-2-yl)-2-hydroxy-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NC=2SC(Br)=CN=2)=C1O ZNEBVPDLAHSKDD-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- WHGTVAMUESZWTG-UHFFFAOYSA-N [2-[(5-bromo-1,3-thiazol-2-yl)carbamoyl]-6-methoxyphenyl] acetate Chemical compound COC1=CC=CC(C(=O)NC=2SC(Br)=CN=2)=C1OC(C)=O WHGTVAMUESZWTG-UHFFFAOYSA-N 0.000 claims description 4
- KGBAMMWIEHYQGE-UHFFFAOYSA-N [2-[(5-chloro-1,3-thiazol-2-yl)carbamoyl]-6-methylphenyl] acetate Chemical compound CC(=O)OC1=C(C)C=CC=C1C(=O)NC1=NC=C(Cl)S1 KGBAMMWIEHYQGE-UHFFFAOYSA-N 0.000 claims description 4
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- BURCGGKAXWPXOX-UHFFFAOYSA-N [2-[(5-bromo-1,3-thiazol-2-yl)carbamoyl]-5-methylphenyl] acetate Chemical compound CC(=O)OC1=CC(C)=CC=C1C(=O)NC1=NC=C(Br)S1 BURCGGKAXWPXOX-UHFFFAOYSA-N 0.000 claims description 2
- DXSXMMYSTLIFRS-UHFFFAOYSA-N [2-[(5-bromo-1,3-thiazol-2-yl)carbamoyl]phenyl] acetate Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C(Br)S1 DXSXMMYSTLIFRS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及一种卤代苯甲酰胺衍生物，其特征在于对病毒病原较高的特异性以及对有益的胃肠微生物区系较低的破坏性，根据通式(III)：其中R1为卤素原子，R2－R6独立地为氢，羟基，C1－C4烷基，－C1－C4烷氧基，酰氧基，硝基，卤素，－C(O)R7，其中R7为－C1－C4烷基，或芳香基，包括这些化合物的盐和水合物。
Description
发明领域
本发明涉及卤代苯甲酰胺衍生物，尤其是以对病毒病原较高的特异性以及对有益的肠胃微生物区系较低的破坏性为特征的苯甲酰胺衍生物。
发明背景
已知2-乙酰基氧基-N-(5-硝基-2-噻唑基)苯甲酰胺(通式(I)的化合物，也被称作硝基噻唑，硝唑尼特或NTZ)被用于寄生虫感染，细菌感染，真菌感染，腹泻和其他肠道疾病的治疗和预防(美国专利号3,950,351，4,315,018和5,578,621)，包括吸虫的处理(美国专利号5,856,348)。NTZ的制备方法公开于美国专利3,950,351中。改进的用于递送NTZ的药物组合物公开于美国专利6,117,894和5,968,961中。
据推测，NTZ在厌氧菌和原虫中的作用方式基于硝基还原酶对硝基基团的还原，且，尤其是依赖于丙酮酸铁氧化还原蛋白氧化还原酶(PFOR)的电子转移反应，该反应是厌氧能量代谢所必需的。目前NTZ对蠕虫可能的作用方式还未知，然而，厌氧电子传递的酶被认为是潜在的靶点，其中，5-硝基基团涉及该作用机理。
已知通式(II)的化合物显示抗病毒活性，并且用于治疗人类由病毒所引起的疾病，如由人巨细胞病毒，水痘-带状疱疹，Epstein Barr病毒，HSV-I和HSV-II所引起的那些疾病，其中，R1-5中的一个是-OH，R1-5中其余的是H(美国专利号5,886,013和6,020,353)。
这些化合物在起效时不只对病毒病原有选择性。也有描述说，它们对寄生虫，细菌和真菌具有很好的功效。在实践中，常常伴随着问题。具体地说，在人类和很多动物的胃肠道中含有有益的、主要由厌氧菌构成的微生物区系群。口服例如通式(II)所示的那些广谱化合物杀死胃肠细菌区系，可能引起包括腹泻的二级并发症，需进一步进行治疗。
因此，需要对更具病毒病原选择性的治疗用化合物。最优选地，这些化合物应具有抗病毒活性，但基本上缺少抗细菌和抗寄生虫活性，至少达到这样的程度，即在口服时避免对有益的胃肠微生物区系的有害作用。
本发明可以达成这个需求、以至超过这个需求，正如本领域的普通技术人员在阅读了以下公开内容和实施例之后，这些都将变得清楚。
发明概述
本发明涉及抗病毒的苯甲酰胺衍生物，所述的苯甲酰胺衍生物对病毒病原更具选择性，并由此导致在口服时对有益的胃肠微生物区系的降低的有害作用。
在第一方面，令人惊奇的是本发明是用卤素原子替换硝基取代基来完成的，而至今硝基取代基仍被认为是NTZ活性的关键。该取代可以发生在任何已知的在治疗上有效的2-苯甲酰氨基-5硝基-噻唑(thizaole)(其中苯环上可以有各种取代)上。不寻常的是，新型的卤代化合物保留了它们的抗病毒特性，但在口服时对细菌性胃肠微生物区系缺乏活性。
这些已知的2-苯甲酰氨基-5硝基-噻唑是本发明化合物的类似物，不同点只在于按照本发明的化合物中硝基基团被除去且被卤素原子替换了，这些已知的2-苯甲酰氨基-5硝基-噻唑的实例在以上提及的美国专利、特别是美国专利号5,886,013中已被详尽地阐明，这些公开被并入本文作为参考。
本发明进一步提供了如通式(III)的(5-卤代-2-噻唑基)苯甲酰胺化合物：
其中
R1是卤素原子，优选F，Cl，Br，或I，更优选Br或Cl，最优选为Br，且
R2-R6独立地是氢，羟基，C1-C4烷基，-C1-C4烷氧基，酰氧基(优选乙酰氧基或丙酰氧基)，硝基，卤素，-C(O)R7，其中R7为-C1-C4的烷基，或芳香基(优选未取代或取代的苯基或苄基)，包括这些化合物的盐及水合物。
优选地，R2-R6中的一个是羟基。
优选地，R2-R6中的至少一个不是氢，且更优选地，R2-R6中的至少两个不是氢。
两个相邻的R2-R6可以共同形成苄基环。
优选地，R2-R6包含不超过一个的酰氧基和不超过一个的卤素。
本发明进一步提供如通式(IV)的抗病毒化合物：
其中R1是卤素原子，R8是-C(O)R10，其中R10是-C1-C4烷基，且R9是-C1-C4烷基或-C1-C4烷氧基，包括这些化合物的盐和水合物。
本发明进一步提供包括通式(III)或(IV)的化合物和药学上可接受的载体的药物组合物。
最后，本发明提供治疗或预防动物或人类受试者中病毒感染的方法，所述的方法包括给予所述受试者至少一个剂量的药物组合物，所述的药物组合物包括有效量的如通式(III)或(IV)的抗病毒化合物和药学上可接受的载体。
详细说明
本发明的化合物包含如通式(III)的那些化合物：
其中
R1是卤素原子，优选是F，Cl，Br或I，更优选Br或Cl，最优选Br，且
R2-R6独立地是氢，羟基，C1-C4烷基，-C1-C4烷氧基，酰氧基(优选为乙酰氧基或丙酰氧基)，硝基，卤素，-C(O)R7，其R7为-C1-C4烷基，或芳香基(优选苯基或苄基，苯基或苄基可以被进一步取代)，包括这些化合物的盐及水合物。
优选地，R2-R6中的一个羟基。
优选地，R2-R6中的至少一个不是氢，且更优选地，R2-R6中的至少两个不是氢。
两个相邻的R2-R6可以共同形成一个苄基环。
优选地，R2-R6包含不超过一个的酰氧基以及不超过一个的卤素。本发明的化合物由以下非限制性的列表来说明：
通式(III)中优选的化合物实例包括：
2-乙酰基氧基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4803)；
2-羟基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4819)；
2-乙酰基氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4820)；
2-乙酰基氧基-5-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4821)；以及
2-乙酰基氧基-5-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4822)。
还发现在苯环邻位有羟基取代的化合物具有好的功效。因此，从以上所述的化合物中，下列化合物是优选的：RM-4819，RM-4826，RM-4827，RM-4831，RM-4832，RM-4833，RM-4834，RM-4835，RM-4836，RM-4838，RM-4839，RM-4840。
依据本发明的化合物优选包括通式(IV)的那些化合物：
其中：
R1是卤素，优选F，Cl，Br或I，更优选Br或Cl，最优选Br，
R8是-C(O)R10，其中R10是-C1-C4烷基。R10包括甲基，乙基，丙基和丁基，包括它们的异构体。甲基是优选的，由此，所述苯甲酰胺的取代基是乙酰基氧基(acetolyloxy)，且
R9是-C1-C4烷基或-C1-C4烷氧基。甲基或甲氧基是优选的。甲基是最优选的。
通式(IV)中化合物的实例包括：
2-乙酰基氧基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4803)；
2-乙酰基氧基-3-甲基-N-(5-氯-2-噻唑基)苯甲酰胺(RM4804)；以及
2-乙酰基氧基-3-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4806)。
本发明的组合物可以被配制成固体或液体剂型，或被配制成糊剂或软膏剂，并且可以任选地包含其他活性成分。
本发明的药物组合物包括药学上可接受的载体，所述的载体不受特别的限制，并且包括本领域的普通技术人员已知的范围广泛的载体，且包括湿润剂和分散剂(美国专利5,578,621)，淀粉衍生物(美国专利5,578,621)，赋型剂及诸如此类。片剂的实施方案可以任选地包括构成肠溶衣的物质的包衣，例如，在胃分泌物中基本上不溶而在肠液中基本上可溶的包衣。
包括通式(III)或(IV)的化合物的药物组合物优选地被配制用于口服，且任选地以液体的形式，例如在水或油或其他液体中的乳剂或溶液或混悬剂，所述的油例如花生油。非水相胶束溶液的配制可依据美国专利5,169,846中公开的方法来进行。可选择的是可以制成片剂，例如通过以下步骤来进行：湿式制粒；干燥；和压制。膜包衣一般用有机溶剂来进行。
本文中所用的术语“选择性抗病毒”是指，在用于预防或治疗由病毒引起的疾病的有效剂量下，其活性是抗病毒作用比抗细菌、抗真菌、或抗寄生虫作用强，并且，受试者的胃肠区系未被破坏到使用广谱抗生素所预计的程度。
本发明化合物优选的抗病毒治疗或预防的剂量可以取决于受试者的体重，并可以由本领域的普通技术人员参考以下实施例来确定，而无需过度的实验研究，实施例的提出是为了阐述明白而不是要起限制作用。
实施例1：病毒实验
方法
非肝病病毒
细胞培养与治疗。将HEp-2喉癌细胞，猴肾细胞37RC，MA104和VERO细胞，狗Madin-Darby肾脏(canine Madin-Darby kidney)(MDCK)及乳腺癌细胞(A72)于37℃、5％CO2气氛、RPMI培养基(Gibco-Invitrogen，Carsbad，CA)中生长，补充10％胎牛血清(FCS)，2mM谷氨酰胺及抗生素。将溶解于DMSO储存液(50mg/m1)中的化合物于培养基中稀释，并在1小时吸附期后立即加入受感染的细胞中。在实验期间化合物是保持在培养基中的。对照实验也使用等量的DMSO稀释液。每种化合物在每个浓度下测试两次，每次实验也重复进行两次。
病毒感染与滴定。使用以下病毒：流感A型：波多黎各株(PR8)；副粘病毒(副流感病毒)：仙台病毒(SV)；弹状病毒：水泡性口炎病毒(VSV)；轮状病毒：猴轮状病毒SA-11(SA-11)；1型单纯疱疹病毒：F1株(HSV-1)；冠状病毒：犬冠状病毒S-378株(CCoV)。37℃下，在感染复数(m.o.i.)为5HAU(血细胞凝集单位)/105细胞时，用流感A型病毒(MDCK细胞)或副粘病毒SV(37RC细胞)感染汇合成片细胞单层1小时。可选择的是于37℃下，用HSV-1(HEp-2细胞)，VSV(MA104细胞)，CCoV(A72细胞)或轮状病毒SA-11(MA104细胞)感染汇合成片细胞单层1小时，其中HSV-1，VSV和CCoV的m.o.i.为5PFU(噬斑形成单位)/105细胞，SA-11为1PFU/105细胞。吸附期后，移去病毒接种体，用磷酸缓冲盐溶液(PBS)冲洗细胞单层三次。将细胞在37℃下保存于含2％FCS的适当培养基中，培养基中有要被检测的化合物或对照稀释液。感染后(p.i.)24小时用血凝素滴定法(WSN，PR8，SV和SA-11)或50％CPE分析法(VSV，HSV-1和CCoV)确定病毒产率，所述的病毒产率的确定参照标准程序(Amici，C.，Belardo，G.，Rossi，A.& Santoro，M.G.1型单纯疱疹病毒激活IκB激酶，抗疱疹疗法的新靶点。J.Biol.Chem.276，28759-28766(2001)以及Bernasconi，D.，Amici，C.，La Frazia，S.，Ianaro，A.&Santoro，M.G.IκB激酶是引起由流感A型病毒诱发的气道上皮细胞炎性cytochine产生的关键因子。J.Biol.Chem.280，24127-24134(2005))。
细胞毒性。细胞活性由3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四唑溴化物(MTT)与MTT甲臜(formazan)转换试验来测定(Sigma-Aldrich，St Louis，MO)。在MTT试验中，通过加入100μl含有10％Triton X-100的酸性异丙醇从细胞中提取还原型MTT(甲臜)，甲臜的吸光度由ELISA酶标仪在两个不同波长下测定(540和690nm)。
乙型肝炎病毒
抗-乙肝病毒(HBV)的分析及细胞毒性的评估通过在慢性产生HBV的人肝胚细胞瘤细胞系2.2.15中的9天试验来进行，如前所述(Korba，B.E.& Gerin，J.L.使用标准化的细胞培养物试验评估核酸类似物对乙肝病毒复制的活性。Antivir.Res.19，55-70(1992))。
丙型肝炎病毒
抗-丙肝病毒(HCV)的分析及细胞毒性的评估通过在包含HCV复制子的人肝胚细胞瘤细胞系AVA5中的3天试验来进行(Okuse，C.，Rinaudo，J.A.，Farrar，K.，Wells，F.&Korba，B.E.，通过干扰素结合疗法体外加强针对丙肝病毒的抗病毒活性。Antivir.Res.65，23-34(2005))，正如前面所说过的那样(Blight，K.J.，Kolykhalov，A.A.& Rice，C.M.，细胞培养物中HCV RNA复制的有效引发。Science 290，1972-1974(2000))。
病毒检测结果
表1.在细胞培养物中RM-4803与RM-4819对病毒的活性。
| 病毒 | EC50(μM)/SI | ||
| RM4819 | RM4803 | 细胞培养物 | |
| 轮状病毒：猴轮状病毒SA-11流感A型：PR8株副粘病毒：仙台病毒冠状病毒：犬冠状病毒S-378株弹状病毒：水泡口炎病毒1型单纯疱疹病毒：F1株 | 0.3/＞5009.6/＞171.3/＞1254.9/＞331.6/＞1000.6/＞250 | 0.06/＞25002.8/＞501.1/＞1254.2/132.8/＞505.6/3 | MA104MDCK37RCA72MA104HEp-2 |
EC50＝观察到病毒DNA或RNA 2-倍阻抑时的药物浓度(相对于在未处理培养物中的平均水平)。CC50＝相对于在未处理培养物中的平均水平，观察到还原型MTT 2-倍阻抑时的药物浓度。SI(选择性指数)＝CC50/EC50。
表2.在细胞培养物中其他化合物对副粘病毒：仙台病毒的活性。
| 化合物 | 副粘病毒：仙台病毒 | |
| EC50(μM) | SI | |
| RM-4820RM-4821RM-4822 | 0.340.360.36 | 35＞507 |
EC50＝观察到病毒RNA 2-倍阻抑时的药物浓度(相对于在未处理培养物中的平均水平)。
CC50＝相对于在未处理培养物中的平均水平，观察到还原型MTT 2-倍阻抑时的药物浓度。
SI(选择性指数)＝CC50/EC50。
表3.在2.2.15细胞培养物中化合物对HBV复制的活性。
| 化合物 | 细胞外毒粒DNA | 细胞内HBV R.I. | CC50(μM) | 选择性指数 | |||
| EC50(μM) | EC90(μM) | EC50(μM) | EC90(μM) | 毒粒 | R.I. | ||
| 拉米夫定RM4803RM4819 | 0.058±0.0066.3±0.73.5±0.5 | 0.164±0.01515±1.19.0±0.8 | 0.172±0.02012±1.57.6±0.9 | 0.660±0.06850±5.522±2.6 | 2229±76＞1000§＞1000§ | 12959＞67＞111 | 3377＞20＞46 |
所示数值(±标准偏差[S.D.])，采用取自所有经处理的培养物的组合的数据由线性回归分析来计算。S.D.由线性回归分析(QuattroProTM)生成的回归标准误差来计算。EC50，EC90＝观察到HBV DNA分别为2-倍或10-倍阻抑时的药物浓度(相对于在未处理培养物中的平均水平)。CC50＝相对于在未处理培养物中的平均水平，观察到中性红染料吸收2-倍阻抑时的药物浓度。由于在本试验系统中HBV水平的至少3-倍阻抑通常是获得统计显著性所要求的，因此用EC90的值计算选择性指数[S.I.]。HBV R.I.＝细胞内HBV DNA复制中间体。
§达到最高指示浓度时未观察到显著的细胞毒作用。
表4.在AVA5细胞培养物中化合物对丙型肝炎病毒复制的活性。
| 化合物 | CC50(μM) | EC50(μM) | EC90(μM) | 选择性指数 |
| ∝-干扰素利巴韦林 | ＞10,000*§61±2.9 | 2.2±0.2*94±10 | 8.5±0.6*＞100§ | ＞4,5450.6 |
| RM4803RM4819 | 282±21164±18 | 37±2.78.9±0.7 | 98±9.379±8.2 | 7.618 |
所示数值(±标准偏差[S.D.])，采用取自所有经处理培养物的组合的数据由线性回归分析来计算。S.D.由线性回归分析(QuattroProTM)生成的回归标准误差来计算。EC50，EC90＝观察到HCV RNA分别为2-倍阻抑或10-倍阻抑时的药物浓度(相对于在未处理培养物中的平均水平)。CC50＝相对于在未处理培养物中的平均水平，观察到中性红染料吸收2-倍阻抑时的药物浓度。选择性指数＝CC50/EC50。
*干扰素的值被表示为“IU/ml”。
§达到最高指示浓度时未观察到显著的细胞毒作用或抗病毒作用。
实施例2：厌氧菌检测
方法。新近的临床厌氧菌分离物(从2000年至今)包括40种脆弱类杆菌(B.fragilis)组，26种普里沃菌/卟啉菌属(Prevotella/Porphyromonas)，28种梭杆菌门，16种厌氧格兰氏阳性球菌，14种厌氧格兰氏阳性非芽孢形成杆菌及18种梭菌。采用利用富集布氏杆菌血琼脂和1×105cfu/点的接种物的CLSI琼脂稀释MIC法。将培养板置于35℃下的厌氧手套箱中培养48小时。
结果。MIC50/MIC90值(μg/ml)如下：
| 药物 | 脆弱类杆菌组(40) | 普里沃菌/卟啉菌属(26) | 梭杆菌门(28) | 格兰氏阳性球菌(16) | 格兰氏阳性杆菌(14) | 梭菌(18) | 全部(142) |
| 硝唑尼特 | 2/4 | 4/8 | 1/4 | 0.5/2 | 16/＞32 | 0.5/4 | 2/4 |
| Tizoxanide | 2/4 | 2/16 | 0.5/2 | 0.5/1 | 8/＞32 | 0.25/2 | 2/4 |
| RM 4803 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 |
| RM 4819 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 | ＞32/＞32 |
| 阿莫西林-克拉维酸 | 1/4 | 0.06/0.5 | 0.5/4 | 0.125/0.5 | 0.25/1.0 | 0.125/1.0 | 0.5/2.0 |
| 克林霉素 | 2/＞32 | ≤0.015/≤0.015 | 0.06/0.125 | 0.125/0.5 | 0.125/4 | 1/＞32 | 0.125/8.0 |
| 甲硝唑 | 1/2 | 0.5/2 | 0.25/0.25 | 0.5/1.0 | ＞16/＞16 | 0.25/2 | 1.0/2.0 |
结果显示，除了包括乳酸菌(实际上大部分是微需氧菌)的格兰氏阳性厌氧杆菌外，硝唑尼特和tizoxanide对所有厌氧菌群都是有效的。与此对照，RM 4803与RM 4819没有显著活性。
实施例3抗病毒活性
如表5所示，本发明中通式(IV)中的化合物显示了有效的抗病毒活性。
利用分别对OH-I Hela和Madin Darby狗肾脏(MDCK)的细胞单层的多循环CPE抑制试验，通过显微和分光光度计法测定了2-乙酰基氧基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4803)，2-乙酰基氧基-3-甲基-N-(5-氯-2-噻唑基)苯甲酰胺(RM4804)及2-乙酰基氧基-3-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4806)对39型人类鼻病毒(HRV-39)及H3N2流感病毒，A型，的EC50(μg/mL)值。吡罗达韦(Pirodavir)和奥斯他韦(Oseltamivir)被包括在其中作为阳性对照。
表5.在细胞单层中RM-4803，RM-4804及RM-4806对病毒的活性。
| 化合物 | 39型人类鼻病毒OH-Hela2％McCoys+Hepes缓冲液显微分光光度计 | 流感A型病毒MDCK0％EMEM+Hepes+胰蛋白酶显微分光光度计 | ||
| R1＝溴R4＝甲基R3＝甲基(RM 4803) | 0.06 | 0.03 | 0.45 | 0.18 |
| R1＝氯R4＝甲基R3＝甲基(RM 4804) | 0.57 | 0.32 | 0.93 | 0.57 |
| R1＝溴R4＝甲基R3＝甲氧基(RM 4806) | 5.0 | 4.0 | 0.46 | 0.57 |
| 吡罗达韦 | 0.007 | 0.004 | NA | NA |
| 奥斯他韦 | NA | NA | 0.13-0.17 | 0.08-0.36 |
实施例4-选择性抗病毒活性
通过常规手段针对阴道滴虫(Trichomis vaginalis)，蓝氏贾第鞭毛虫(Giardia Intestinalis)及布氏锥虫(Trypanosoma brucei)检测上面标出的如通式(IV)的化合物。2-乙酰基氧基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4803)，2-乙酰基氧基-3-甲基-N-(5-氯-2-噻唑基)苯甲酰胺(RM4804)及2-乙酰基氧基-3-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4806)中的每一个在浓度至少为50μg/mL时都没有显现出对阴道滴虫，蓝氏贾第鞭毛虫及布氏锥虫的抗寄生虫活性。
因此，已经证明，根据本发明可以提供总体上以选择性的抗病毒活性为特征的新型化合物。
作为附加优点，已经发现上述卤代苯甲酰胺化合物对细胞内原虫是有效的，所说的细胞内原虫包括隐孢子虫属(Cryptosporidium spp.)，新孢虫属(Neospora spp.)及Sarcocystisneurona(RM-4820，RM-4821及RM-4822)。
关于以上描述，应该意识到，对本领域技术人员而言，本发明的配制和方法被认为是清楚和明显的，说明书中描述的所有等同关系应被本发明所包括。
因此，以上所述被认为仅仅是本发明原理的说明。另外，本发明不应受限制于所显示和所描述的精确结构和操作方法，因为对于本领域技术人员而言，将容易发生大量的改进和改变，因此，所有适当的改进和等同物可以被复归，落入本发明的范围。
本文中已经引用了某些参考文献、专利及其他出版物，每一件所述的出版物的教导和范围都以整体被并入本文作为参考。
Claims (21)
1.一种如通式(III)的化合物：
其中
R1是卤素原子，且
R2-R6独立地是氢，羟基，C1-C4烷基，-C1-C4烷氧基，酰氧基，硝基，卤素，-C(O)R7，其中R7是-C1-C4烷基，或芳香基，包括这些化合物的盐和水合物。
2.如权利要求1的化合物，其中R2-R6中的至少一个不是氢。
3.如权利要求1的化合物，其中R2-R6中的至少一个是羟基。
4.如权利要求3的化合物，其中所述的至少一个的羟基在邻位。
5.如权利要求3的化合物，其中R2-R6中其余的是氢。
6.如权利要求1的化合物，其中R2-R6中的至少两个不是氢。
7.如权利要求1的化合物，其中R2-R6中的一个是羟基，R2-R6中其余的独立地是氢，C1-C4烷基，-C1-C4烷氧基，酰氧基(优选乙酰氧基或丙酰氧基)，硝基，卤素，-C(O)R7，其中R7是-C1-C4烷基，或芳香基，包括这些化合物的盐和水合物。
8.如权利要求1的化合物，其中R2-R6中的一个是羟基，R2-R6中的至少一个是C1-C4烷基，-C1-C4烷氧基，酰氧基，硝基，卤素，-C(O)R7，其中R7为-C1-C4烷基，或芳香基，包括这些化合物的盐和水合物。
9.如权利要求1的化合物，其中所述酰氧基是乙酰氧基或丙酰氧基，且其中所述芳香基是苯基或苄基，该苯基或苄基可以被进一步取代。
10.如权利要求1的化合物，其中R1是Br或Cl。
11.如权利要求1的化合物，其中R2-R6包含不超过一个的酰氧基和不超过一个的卤素。
12.如权利要求1的化合物，其中两个相邻的R2-R6形成苄基环。
13.如权利要求1的化合物，其中R2-R6中的一个是羟基，R2-R6中其余的独立地是氢，C1-C4烷基，-C1-C4烷氧基，酰氧基，或-C(O)R7，其中R7是-C1-C4烷基，包括这些化合物的盐和水合物。
14.如权利要求1的化合物，所述的化合物选自由以下化合物组成的组：
2-乙酰基氧基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4803)；
2-羟基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4819)；
2-乙酰基氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4820)；
2-乙酰基氧基-5-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4821)；以及
2-乙酰基氧基-5-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4822)。
15.如通式(IV)所示的化合物：
其中
R1是卤素，
R8是-C(O)R10，其中R10是-C1-C4烷基，且
R9是-C1-C4烷基或-C1-C4烷氧基。
16.如权利要求14的化合物，其中R1是Cl或Br。
17.如权利要求14的化合物，其中R8是-C(O)R10，其中R10是甲基，乙基，丙基或丁基，包括它们的异构体。
18.如权利要求14的化合物，其中R9是甲基或甲氧基。
19.如权利要求14的化合物，所述的化合物选自由以下化合物组成的组：
2-乙酰基氧基-3-甲基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4803)；
2-乙酰基氧基-3-甲基-N-(5-氯-2-噻唑基)苯甲酰胺(RM4804)；以及
2-乙酰基氧基-3-甲氧基-N-(5-溴-2-噻唑基)苯甲酰胺(RM4806)。
20.一种药物组合物，所述的药物组合物包括作为活性剂的如通式(III)的化合物：
其中
R1是卤素原子，且
R2-R6独立地是氢，羟基，C1-C4烷基，-C1-C4烷氧基，酰氧基，硝基，卤素，-C(O)R7，其中R7是-C1-C4烷基，或芳香基，包括这些化合物的盐和水合物。
21.一种治疗病毒感染的方法，包括给予需要治疗的受试者有效量的药物组合物，所述的药物组合物包括作为活性剂的如通式(III)的化合物：
其中
R1是卤素原子，且
R2-R6独立地是氢，羟基，C1-C4烷基，-C1-C4烷氧基，酰氧基，硝基，卤素，-C(O)R7，其中R7是-C1-C4烷基，或芳香基，包括这些化合物的盐和水合物。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335171A (zh) * | 2010-07-27 | 2012-02-01 | 中国农业科学院上海兽医研究所 | 一类n-(2-噻唑)苯甲酰胺衍生物的应用 |
| CN115197164A (zh) * | 2021-04-12 | 2022-10-18 | 杜心赟 | 新型噻唑类化合物及其制备方法和用途 |
| WO2022218239A1 (zh) * | 2021-04-12 | 2022-10-20 | 杜心赟 | 新型噻唑类化合物及其制备方法和用途 |
| CN115197164B (zh) * | 2021-04-12 | 2025-04-01 | 杜心赟 | 新型噻唑类化合物及其制备方法和用途 |
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