CN101450914B - 苯甲酸衍生物 - Google Patents
苯甲酸衍生物 Download PDFInfo
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- CN101450914B CN101450914B CN2008101768821A CN200810176882A CN101450914B CN 101450914 B CN101450914 B CN 101450914B CN 2008101768821 A CN2008101768821 A CN 2008101768821A CN 200810176882 A CN200810176882 A CN 200810176882A CN 101450914 B CN101450914 B CN 101450914B
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Classifications
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- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于医药技术领域，具体涉及通式(I)所示的新的苯甲酸衍生物、其药学上可接受的盐或其立体异构体：其中R1、R2、R3、R4、R5、R6和Ar如说明书中所定义；本发明还涉及这些化合物的制备方法，含有这些化合物的药物组合物，以及这些化合物在制备治疗和/或预防感染性疾病的药物中的应用。
Description
1、技术领域
本发明属于医药技术领域，具体涉及新的苯甲酸衍生物、其药学上可接受的盐或其立体异构体，这些化合物的制备方法，含有这些化合物的药物组合物，以及这些化合物在用于制备治疗和/或预防感染性疾病的药物中的应用。
2、背景技术
随着分子生物学技术的发展、基因组学、生物信息学、结构生物学和组合化学技术在药物发现和设计方面得到了广泛的应用和发展。在过去的几年中，30多种病原微生物的全基因组测序工作已经完成，还有一些接近完成。这使许多抗菌药物筛选的靶点得以确定和深入研究，为抗菌药物的设计和筛选提供了重要的信息。
脂肪酸是细胞生物膜等的重要组成部分，故在生物体内脂肪酸的合成是必须的。根据参与脂肪酸生物合成(FAS)酶的不同，可以将脂肪酸合成途径分为两类，即存在于哺乳动物体内的I型脂肪酸合成途径和存在于细菌和植物中的II型脂肪酸合成途径。在I型脂肪酸合成途径中，参与合成反应的酶是由一条多肽链构成的，这条链包括了合成脂肪酸所需的所有催化活性中心；而在II型脂肪酸合成途径中，每一步反应都有一个单独的酶催化，而且这些酶在不同种属的细菌中具有高度的专一性。正是因为II型FAS酶在细菌中的广泛存在以及在活性位点组织结构上的差异，使得催化该途径的酶成为较理想的靶点，进行抗菌药物的筛选。近年来，世界各国的药物学家们对脂肪酸合成酶抑制剂进行了大量的研究，一些抑制剂表现出强的抗菌作用。
3、发明内容
鉴于上述的临床问题，本发明人经过大量的研究，发现了新的具有良好的抗感染活性的一类化合物。本发明的技术方案如下：
本发明提供了通式(I)所示的化合物、其药学上可接受的盐或其立体异构体：
其中，
Ar代表被1～5个R7取代或未被取代的苯基，其中，R7选自：
(1)卤素，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，或
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基；
R1和R2相同或不同，各自独立地为氢原子、C1-6烷基、3-8元环状基团，或R1和R2与所连接的碳原子相连接形成3-8元环状基团；
R3和R5相同或不同，各自独立地为氢原子或C1-6烷基；
R4为氢原子或羧基保护基；
R6为氢原子、卤素原子、羟基、氨基、羧基、三氟甲基、C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、羟基-C1-6烷基、氨基-C1-6烷基或羧基-C1-6烷基。
优选的化合物为：
其中，
Ar代表被1～5个R7取代或未被取代的苯基，其中，R7选自：
(1)氟原子，
(2)氯原子，
(3)直链或支链的被1～5个氟原子或氯原子取代或未被取代的C1-4烷基，或
(4)直链或支链的被1～5个氟原子或氯原子取代或未被取代的C1-4烷氧基；
R1和R2相同或不同，各自独立地为氢原子、C1-4烷基、3-8元饱和环状基团，或R1和R2与所连接的碳原子相连接形成3-8元饱和环状基团；
R3和R5相同或不同，各自独立地为氢原子或C1-4烷基；
R4为氢原子或羧基保护基；
R6为氢原子、氟原子、氯原子、羟基、氨基、羧基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4烷基磺酰基、羟基C1-4烷基、氨基C1-4烷基或羧基C1-4烷基。
优选的化合物为：
其中，
Ar代表被1～3个R7取代或未被取代的苯基，其中，R7选自：
(1)氟原子，
(2)氯原子，
(3)直链或支链的被1～3个氟原子或氯原子取代或未被取代的C1-4烷基，或
(4)直链或支链的被1～3个氟原子或氯原子取代或未被取代的C1-4烷氧基；
R1和R2相同或不同，各自独立地为氢原子、C1-4烷基、4-6元饱和环状基团，或R1和R2与所连接的碳原子相连接形成4-6元饱和环状基团；
R3和R5相同或不同，各自独立地为氢原子或C1-4烷基；
R4为氢原子或羧基保护基；
R6为氢原子、氟原子、氯原子、羟基、氨基、羧基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4烷基磺酰基、羟基C1-4烷基、氨基C1-4烷基或羧基C1-4烷基。
优选的化合物为：
其中，
Ar代表被1～3个R7取代或未被取代的苯基，其中，R7选自：
(1)氟原子，
(2)氯原子，
(3)被1～3个氟原子或氯原子取代或未被取代的甲基、乙基、异丙基或叔丁基，或
(4)被1～3个氟原子或氯原子取代或未被取代的甲氧基或乙氧基；
R1和R2相同或不同，各自独立地为氢原子、甲基、乙基、叔丁基或4-6元饱和环状基团，或R1和R2与所连接的碳原子相连接形成4-6元饱和环状基团；
R3和R5相同或不同，各自独立地为氢原子、甲基、乙基、异丙基或叔丁基；
R4为氢原子或羧基保护基；
R6为氢原子、氟原子、羟基、氨基、三氟甲基、甲基、乙基、甲氧基、乙氧基、甲基磺酰基、乙基磺酰基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
优选的化合物为：
其中，
Ar代表被1～2个R7取代或未被取代的苯基，其中，R7选自：
(1)氟原子，或
(2)被1～2个氟原子取代或未被取代的甲基或乙基；
R1和R2相同或不同，各自独立地为氢原子、甲基、乙基或4-6元饱和环状基团，或R1和R2与所连接的碳原子相连接形成4-6元饱和环状基团；
R3和R5相同或不同，各自独立地为氢原子、甲基、乙基或异丙基；
R4为氢原子或羧基保护基；
R6为氢原子、氟原子、羟基、氨基、三氟甲基、甲基、乙基、甲氧基、乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
优选的化合物为：
其中，
Ar代表被1～2个R7取代或未被取代的苯基，其中，R7选自氟原子、三氟甲基或二氟甲基；
R1和R2相同或不同，各自独立地为氢原子、甲基、4-6元饱和环状基团，或R1和R2与所连接的碳原子相连接形成4-6元饱和环状基团；
R3和R5相同或不同，各自独立地为氢原子、甲基或乙基；
R4为氢原子或羧基保护基；
R6为氢原子、氟原子、羟基、三氟甲基、甲氧基或乙氧基。
优选的化合物为：
其中，
Ar代表苯基；
R1和R2相同或不同，各自独立地为氢原子、甲基、环戊烷基、环己烷基，或R1和R2与所连接的碳原子相连接形成环戊烷基或环己烷基；
R3和R5为氢原子；
R4为氢原子；
R6为氢原子、羟基或三氟甲基。
本发明所述的“卤素”包括氟原子、氯原子、溴原子、碘原子。
本发明所述的“C1-6烷基”包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等。
本发明所述的“C1-6烷氧基”包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等。
本发明所述的“氨基C1-6烷基”包括氨基甲基、氨基乙基、氨基丙基、氨基异丙基、氨基丁基、氨基异丁基、氨基叔丁基、氨基戊基、氨基己基。
本发明所述的“羟基C1-6烷基”包括羟基甲基、羟基乙基、羟基1-甲乙基、羟基丙基、羟基丁基、羟基戊基、羟基己基等。
本发明所述的“羧基C1-6烷基”包括羧基甲基、羧基乙基、羧基1-甲乙基、羧基丙基、羧基丁基、羧基戊基、羧基己基等。
本发明所述的“C1-6烷基磺酰基”包括甲基磺酰基、乙基磺酰基、丙基磺酰基等。
本发明所述的“3-8元环状基团”包括环丙烷基、环丁烷基、氮杂环丁烷基、呋喃基、吡咯基、吡咯烷基、噻唑基、环戊烷基、环己烷基、吡啶基、环庚烷基、环辛烷基等。
本发明所述“羧基保护基”指常规用于取代羧酸酸性质子的保护基团。此基团的实例包括：
甲基、甲氧基甲基、甲硫甲基、四氢吡喃基、四氢呋喃基、甲氧乙基甲基、烯丙基、苄氧甲基、苯甲酰甲基、对溴苯甲酰甲基、α-甲基苯甲酰甲基、对甲氧基苯甲酰甲基、二酰基甲基、N-邻苯二甲酰亚胺基甲基、乙基、2，2，2-三氯乙基、2-卤代乙基、ω-氯代烷基、2-(三甲基甲硅烷基)乙基、2-甲硫基乙基、2-(对硝基苯硫基)乙基、2-(对甲苯硫基)乙基、1-甲基-1-苯乙基、叔丁基、环戊基、环己基、二(邻硝基苯基)甲基、9-芴基甲基、2-(9，10-二氧代)芴基甲基、5-二苯硫基、苄基、2，4，6-三甲基苄基、对溴苄基、邻硝基苄基、对硝基苄基、对甲氧基苄基、胡椒基、4-吡啶甲基、三甲基甲硅烷基、三乙基甲硅烷基、叔丁基二甲基甲硅烷基、异丙基二甲基甲硅烷基、二苯基甲基、苯基二甲基甲硅烷基、S-叔丁基、S-苯基、S-2-吡啶基、N-羟基哌啶基、N-琥珀酰亚胺基、N-邻苯二甲酰亚胺基、N-苯并三唑基、O-酰基肟、2，4-二硝基苯硫基、2-烷基-1，3-噁唑啉、4-烷基-5-氧代-1，3-噁唑烷、5-烷基-4-氧代-1，3-二噁烷、三乙基锡烷基、三正丁基锡烷基；N，N’-二异丙基酰肼等。
最优选的化合物如下：
化学名称：2，4-二羟基-3-[(4-甲基-4-环己基-5-氧代-5-苯基)戊酰胺基]苯甲酸，简称化合物1，结构式如下：
化学名称：2，4-二羟基-3-[(4-环己基-5-氧代-5-苯基)戊酰胺基]苯甲酸，简称化合物2，结构式如下：
化学名称：2，4-二羟基-3-[3-(苯甲酰环己烷-1-基)丙酰胺基]苯甲酸，简称化合物3，结构式如下：
本发明还提供了上述化合物的制备方法，但不仅限于以下方法，反应方程式如下：
反应步骤：
步骤1 化合物1的制备
于反应瓶中，投入原料1，丙酮溶解，剧烈搅拌下加入无水K2CO3，后滴加氯甲醚。缓慢升温加热回流反应，TLC检测反应终点.减压下蒸除大部分丙酮后，加入四氢呋喃溶解剩余物，加入Pd/C，搅拌反应，反应毕，过滤，滤液中加入水，然后用乙酸乙酯萃取，合并有机相，经水、饱和食盐水溶液洗涤后用无水MgSO4干燥。蒸除乙酸乙酯，所得残余物经硅胶柱层析分离纯化，得化合物1。
步骤2 化合物2的制备
于反应瓶中加入化合物1，二氯甲烷，三乙胺，搅拌溶解后降温，然后缓慢滴加含(Boc)2O的二氯甲烷溶液。滴毕。保温搅拌反应，反应液中加入水，分出水层，有机层分别用5％的碳酸氢钠溶液、饱和氯化钠溶液洗涤，无水硫酸镁干燥，减压蒸除溶剂。剩余物用乙酸乙酯：甲醇的混合液重结晶，得化合物2。
步骤3 化合物3的制备
加入化合物2，四氢呋喃，搅拌下缓慢滴正丁基锂的环己烷溶液，滴毕，保温搅拌反应，然后再缓慢加入原料2和四氢呋喃，保温搅拌反应。反应毕，小心加入水，稍搅拌后缓慢升至室温。减压蒸除有机溶剂，剩余物用乙酸乙酯萃取，合并有机层，分别用HCl溶液、碳酸氢钠溶液、饱和氯化钠溶液洗涤，无水硫酸镁干燥，减压蒸除溶剂。剩余物用乙酸乙酯：石油醚的混合液重结晶，得化合物3。
步骤4 化合物4的制备
于反应瓶中加入原料3，甲苯，然后加入叔丁醇钾，搅拌溶解后，降温，缓慢加入原料4，搅拌反应后升温，搅拌反应毕，加入水，分出有机层。有机层减压回收一半溶剂，转入反应瓶中，升温，缓慢滴加浓硫酸，搅拌反应后加入水，于室温下用浓氨水调pH，分出有机层，
水层用甲苯萃取，合并有机层，水洗，干燥，回收溶剂，得化合物4。
步骤5 化合物5的制备
于干燥的反应瓶中，加入化合物4，DMF，氯仿，然后加入O-(苯并三氮唑-1-基)-N，N，N′，N′-四甲基脲四氟硼酸酯(TBTU)，升温至回流搅拌反应。缓慢分批加入化合物3，加料完毕，保温搅拌反应。反应毕，加入水，分出水层，有机层减压浓缩，剩余物用乙醇溶解，滴加氢氧化锂水溶液，回流反应减压浓缩至干。剩余物用无水乙醇提取，将提取液移入反应瓶中，再加入HCl-MeOH，搅拌回流后加入冰水，析晶，即得化合物5。
以上反应方程式中的R1、R2、R3、R4、R5、R6和Ar代表的基团如前文所定义，即通式(I)所述的本发明化合物。
本发明的化合物可以包含一个或多个不对称的碳原子，并且可以以外消旋和旋光形式存在。所有这些化合物及其对应的异构体均包括在本发明的范围之内。
本发明所述的药学上可接受的盐为常规的盐，包括由无机酸衍生的盐，包括盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、硝酸盐、硫酸氢盐、酸式磷酸盐等；由有机酸衍生的盐，包括乳酸盐、水杨酸盐、柠檬酸盐、酸式柠檬酸盐、富马酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、延胡索酸盐、葡萄糖酸盐、葡萄糖二酸盐、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、棕榈酸盐等等；这些酸加成盐可以根据任何通用方法制备。另外，化合物(I)也可以与碱形成无毒盐，包括由金属衍生的盐、铵盐、由有机碱衍生的季铵盐和氨基酸盐。优选的金属盐的实例有由碱金属衍生的盐，例如与锂离子(Li+)、钠离子(Na+)、钾离子(K+)等形成的盐；和由碱土金属衍生的盐，例如与钙离子(Ca2+)、镁离子(Mg2+)等形成的盐，由其它金属阳离子衍生的盐，如与铁离子(Fe2+或Fe3+)、铝离子(Al3+)或锌离子(Zn2+)离子等形成的盐也包括在本发明的范围内；由有机碱衍生的季铵盐，如与葡甲胺、氨基葡萄糖、三甲基胺、三乙基胺、四甲基铵，四乙基铵、苯甲基三甲基铵或苯基三乙基铵等形成的盐；由胺衍生的盐，如与吡啶、吗啉、甲基吡啶、N-甲基哌啶、N-乙基哌啶、二环己基胺、普鲁卡因、二苄基胺、N，N’-二苄基-1，2-亚乙基二胺、烷基胺或二烷基胺形成的盐；由氨基酸盐，如与精氨酸、天冬氨酸、谷氨酸或赖氨酸等形成的盐。尽管所述盐给予患者例如哺乳动物时必须是药学上可接受的，但是实践中常常需要首先从反应混合物中分离出本发明化合物的药学上不可接受的盐，然后用碱性或酸性试剂处理后者简单地将其转化为游离碱性或酸性化合物，接着将后一游离碱或酸转化为药学上可接受的酸或碱加成盐。
本发明进一步要求保护包括上面所述的化合物、其药学上可接受的盐或其立体异构体与一种或多种药用载体和/或稀释剂的药物组合物，其中含有式(I)所示的化合物、其药学上
可接受的盐或其立体异构体有效量作为必要的活性成分，例如药物组合物中可以含有本发明化合物0.01g～10g(按式(I)所示化合物计)作为必需的活性组分，可以为0.01g、0.025g、0.05g、0.075g、0.1g、0.125g、0.25g、0.3g、0.5g、0.75g、1g、1.25g、1.5g、1.75g、2g、2.5g、3g、4g、5g、6g、7g、8g、9g、10g等。本领域普通技术人员可以理解的是：此药物剂量还依赖于哺乳动物的年龄，状况以及欲预防或/和治疗疾病的种类。
本发明所述的化合物、其药学上可接受的盐或其立体异构体与一种或多种药用载体和/或稀释剂的药物组合物，为临床上或药学上可接受的任一剂型，优选为口服制剂、注射剂或外用制剂。
用于肠胃外给药时，可制成注射剂。注射剂系指药物制成的供注入体内的溶液、乳液或混悬液及供临用前配制或稀释成溶液或混悬液的粉末或浓溶液的无菌制剂，注射剂可分为注射液、注射用无菌粉末与注射用浓溶液。注射液系指药物制成的供注射入体内用的无菌溶液型注射液、乳液型注射液或混悬型注射液，可用于肌内注射、静脉注射、静脉滴注等；其规格有1mL、2mL、5mL、10mL、20mL、50mL、100mL、200mL、250mL、500mL等，其中供静脉滴注用的大体积(一般不小于100mL)注射液也称静脉输液。注射用无菌粉末系指药物制成的供临用前用适宜的无菌溶液配制成澄清溶液或均匀混悬液的无菌粉末或无菌块状物，可用适宜的注射用溶剂配制后注射，也可用静脉输液配制后静脉滴注；无菌粉末用溶媒结晶法、喷雾干燥法或冷冻干燥法等制得。注射用浓溶液系指药物制成的供临用前稀释供静脉滴注用的无菌浓溶液。
制成注射剂时，可采用现有制药领域中的常规方法生产，可选用水性溶剂或非水性溶剂。最常用的水性溶剂为注射用水，也可用0.9％氯化钠溶液或其他适宜的水溶液；常用的非水性溶剂为植物油，主要为供注射用大豆油，其他还有乙醇、丙二醇、聚乙二醇等的水溶液。配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂，如渗透压调节剂、pH值调节剂、增溶剂、填充剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。常用的渗透压调节剂包括氯化钠、葡萄糖、氯化钾、氯化镁、氯化钙、山梨醇等，优选氯化钠或葡萄糖；常用的pH值调节剂包括醋酸-醋酸钠、乳酸、枸橼酸-枸橼酸钠、碳酸氢钠-碳酸钠等；常用的增溶剂包括聚山梨酯80、丙二醇、卵磷脂、聚氧乙烯蓖麻油等；常用的填充剂包括乳糖、甘露醇、山梨醇、右旋糖酐等；常用的抗氧剂有亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠等；常用抑菌剂为苯酚、甲酚、三氯叔丁醇等。注射剂常用容器有玻璃安瓿、玻璃瓶、塑料安瓿、塑料瓶等。
用于口服时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。片剂系指药物与适宜的辅料混匀压制而成的圆片状或异形片状的固体制剂，以口服普通片为主，另有含片、舌下片、口腔贴片、
咀嚼片、分散片、可溶片、泡腾片、缓释片、控释片与肠溶片等。胶囊剂系指药物或加有辅料充填于空心胶囊或密封于软质囊材中的固体制剂，依据其溶解与释放特性，可分为硬胶囊(通称为胶囊)、软胶囊(胶丸)、缓释胶囊、控释胶囊和肠溶胶囊等。丸剂系指药物与适宜的辅料均匀混合，以适当方法制成的球状或类球状固体制剂，包括滴丸、糖丸、小丸等。颗粒剂系指药物与适宜的辅料制成具有一定粒度的干燥颗粒状制剂，可分为可溶颗粒(通称为颗粒)、混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒和控释颗粒等。口服溶液剂系指药物溶解于适宜溶剂中制成供口服的澄清液体制剂。口服混悬剂系指难溶性固体药物，分散在液体介质中，制成供口服的混悬液体制剂，也包括干混悬剂或浓混悬液。糖浆剂系指含有药物的浓蔗糖水溶液。
制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。常用填充剂包括淀粉、糖粉、磷酸钙、硫酸钙二水物、糊精、微晶纤维素、乳糖、预胶化淀粉、甘露醇等；常用粘合剂包括羧甲基纤维素钠、PVP-K30、羟丙基纤维素、淀粉浆、甲基纤维素、乙基纤维素、羟丙甲纤维素、胶化淀粉等；常用崩解剂包括干淀粉、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素等；常用润滑剂包括硬脂酸镁、滑石粉、十二烷基硫酸钠、微粉硅胶等。
本发明药物组合物还可以制成软膏剂、乳膏剂、凝胶剂、散剂、橡胶膏剂、巴布膏剂、贴剂等外用固体、半固体制剂；洗剂、搽剂、涂膜剂等外用液体制剂。软膏剂系指药物与油脂性或水溶性基质混合制成均匀的半固体外用制剂。乳膏剂系指药物溶解或分散于乳液型基质中形成均匀的半固体外用制剂。凝胶剂系指药物与能形成凝胶的辅料制成均一、混悬或乳液型的稠厚液体或半固体制剂。散剂系指药物或与适宜的辅料经粉碎、均匀混合制成的干燥粉末状制剂，分为口服散剂和局部用散剂。橡胶膏剂是指药材提取物或化学药物与橡胶等基质混匀后，涂布于背衬材料上制成的贴膏剂。巴布膏剂是指药材提取物、药材或化学药物与亲水性基质混匀后，涂布于背衬材料上制成的贴膏剂。贴剂系指可粘贴在皮肤上，药物可产生全身性或局部作用的一种薄片状制剂；该制剂有背衬层、有(或无)控释膜的药物贮库、黏合剂层及临用前需除去的保护层；可用于完整皮肤表面，也可用于有疾患或不完整的皮肤表面。洗剂系指含药物的溶液、乳液、混悬液，供清洗或涂抹无破损皮肤用的制剂。搽剂系指药物用乙醇、油或适宜的溶剂制成的溶液、乳液或混悬液，供无破损皮肤揉擦用的液体制剂。涂剂系指含药物的水性或油性溶液、乳液、混悬液，供临用前用纱布或棉花蘸取或涂于皮肤或口腔与喉部黏膜的液体制剂。涂膜剂系指药物溶解于含成膜材料有机溶剂中，涂搽患处后形成薄膜的外用液体制剂。
本发明药物组合物制成外用固体、半固体制剂时，软膏剂常用的油脂性基质有：凡士林、
石蜡、液状石蜡、硅油、蜂蜡、硬脂酸等；水溶性基质有聚乙二醇；乳剂型基质常用的有钠皂、三乙醇胺皂类、脂肪醇硫酸(酯)钠类、聚山犁酯、羊毛脂、单甘油酯、脂肪醇等；必要时可加入保湿剂、防腐剂、抗氧剂或透皮促进剂。凝胶剂的水溶性基质一般有水、甘油或丙二醇与纤维素衍生物、卡波姆和海藻酸盐、西黄蓍胶、明胶、淀粉等构成；油性凝胶基质有液状石蜡与聚氧乙烯或脂肪油与胶体硅或铝皂、锌皂构成；必要时可加入保湿剂、防腐剂、抗氧剂或透皮促进剂。橡胶膏剂常用基质有橡胶、热可塑性橡胶、松香、松香衍生物、凡士林、羊毛脂和氧化锌等。巴布膏剂常用的基质有聚丙烯酸钠、羧甲基纤维素钠、明胶、甘油和微粉硅胶等。贴剂常用基质有乙烯—醋酸乙烯共聚物、硅橡胶和聚乙二醇等。贴膏剂(橡胶膏剂、巴布膏剂、贴剂)常用的背衬材料有棉布、无纺布、纸等；常用的盖衬材料有防粘纸、塑料薄膜、铝箔—聚乙烯复合膜、硬脂纱布等。外用液体制剂如洗剂、搽剂、涂膜剂，常用的溶剂有水、乙醇、甘油、植物油、液状石蜡等；常用的成膜材料有聚乙烯醇、聚乙烯吡咯烷酮、丙烯酸树脂类等；增塑剂有甘油、丙二醇、邻苯二甲酸二丁酯等；必要时可加适宜的对皮肤或粘膜无刺激的附加剂。
本发明要求进一步保护本发明新的苯甲酸衍生物在用于制备治疗和/或预防感染性疾病药物中的应用，其中本发明新的苯甲酸衍生物对很宽范围的有机体都具有良好的活性，其中这些有机体包括革兰阴性有机体如大肠杆菌、肺炎克雷伯菌、沙门氏菌、希拉肠球菌、鲍曼不动杆菌、卡他莫拉菌、流感嗜血杆菌、铜绿假单胞菌等，以及革兰阳性有机体如金黄色葡萄球菌、肺炎链球菌、粪肠球菌和屎肠球菌等。
本发明的新的苯甲酸衍生物与最接近的现有技术相比，具有以下优点：
(1)本发明化合物具有优良的抗菌活性并且显示低毒性，能被安全的用于治疗和/或预防各种哺乳动物(包括人类)由敏感菌所引起的各种疾病；
(2)本发明化合物抗菌谱广，抗菌活性高，对革兰阳性和阴性、需氧和厌氧菌以及医院临床病原菌均有较好的抗菌活性；
(3)本发明化合物与其它抗生素无交叉耐药性；
(4)本发明化合物具有较长抗生素后效应，抗菌作用持久；
(5)本发明化合物具有良好的药代动力学性质，用药方便；
(6)本发明化合物制备工艺简单，药品纯度高、收率高、质量稳定，易于进行大规模工业生产。
以下通过体外抗菌实验进一步阐述本发明的新的苯甲酸衍生物的有益效果，本发明其它新的苯甲酸衍生物与试验中所列举的本发明新的苯甲酸衍生物具有相同的有益效果，但不应将此理解为本发明新的苯甲酸衍生物仅具有下列有益效果。
实验例 本发明化合物的体外抗菌活性
供试菌种：以下均为临床分离菌株，购于公众机构。(1)革兰阳性菌：金黄色葡萄球菌；(2)革兰阴性菌：大肠埃希菌。
供试品：本发明化合物1-3，自制；对照药：头孢曲松，市购。
实验方法：琼脂稀释法，参考《药理试验方法学》P1659-1660，人民卫生出版社，主编：徐叔云等，版次：1982年8月第1版2002年1月第3版第5次印刷。
实验结果和结论：
表1 本发明化合物对临床分离菌的抗菌活性
由上表实验结果可见，本发明化合物对临床分离菌有很高的抗菌活性，对供试菌株的活性显著优于头孢曲松。
4、具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。以下实施例10-14中各剂型的辅料可以用药学上可接受的辅料替换，或者减少、增加。
实施例1 2，6-双(甲氧甲氧基)-苯胺的制备
于反应瓶中，投入2-硝基-1，3-苯二酚9.3g(60mmol)，丙酮100mL溶解，剧烈搅拌下加入无水K2CO3 15.0g(108mmol)，10min后滴加氯甲醚9mL(120mmol)。缓慢升温加热回流反应，TLC检测反应终点.减压下蒸除大部分丙酮后，加入四氢呋喃60mL溶解剩余物，加入Pd/C 1g，于1Mpa氢压下40℃搅拌反应1h，反应毕，过滤，滤液中加入水100mL，然后用乙酸乙酯100mL×3萃取，合并有机相，经水、饱和食盐水溶液洗涤后用无水MgSO4干燥。蒸除乙酸乙酯，所得残余物经硅胶柱层析分离纯化(V(石油醚)：V(乙酸乙酯)＝4：1)，得淡黄色油状物10.8g，产率84.8％。
实施例2 2，6-双(甲氧甲氧基)-1-(叔丁氧羰基)苯胺的制备
于反应瓶中加入2，6-双(甲氧甲氧基)-苯胺10.7g(50mmol)，二氯甲烷120mL，三乙胺8mL，搅拌溶解后降温至0℃，然后缓慢滴加含(Boc)2O 14.2g(65mmol)的二氯甲烷溶液20mL。滴
毕。保温搅拌反应4h，反应液中加入水60mL，分出水层，有机层分别用5％的碳酸氢钠溶液、饱和氯化钠溶液洗涤，无水硫酸镁干燥，减压蒸除溶剂。剩余物用乙酸乙酯：甲醇的混合液重结晶，得2，6-双(甲氧甲氧基)-1-(叔丁氧羰基)苯胺14.6g，收率：93.1％。
实施例3 2，4-双(甲氧甲氧基)-3-氨基-苯甲酸甲酯的制备
于-78℃、氮气保护下加入2，6-双(甲氧甲氧基)-1-(叔丁氧羰基)苯胺12.45g(40mmol)，四氢呋喃150mL，搅拌下缓慢滴加2.5mol/L的正丁基锂的环己烷溶液22mL，滴毕，保温搅拌反应0.5h，然后再缓慢加入氯甲酸甲酯4.7g(50mmol)和四氢呋喃20mL，保温搅拌反应2h。反应毕，小心加入水50mL，稍搅拌后缓慢升至室温。减压蒸除有机溶剂，剩余物用乙酸乙酯50mL×3萃取，合并有机层，分别用1N的HCl溶液、5％的碳酸氢钠溶液、饱和氯化钠溶液各20mL洗涤，无水硫酸镁干燥，减压蒸除溶剂。剩余物用乙酸乙酯：石油醚的混合液重结晶，得2，4-双(甲氧甲氧基)-3-氨基-苯甲酸甲酯9.2g，收率：84.5％。
实施例4 4-环己基-4-甲基-5-氧代-5-苄基戊酸的制备
于反应瓶中加入2-环己基-1-苯基-丙基-1-酮21.6g(100mmol)，甲苯200mL，然后加入叔丁醇钾11.8g(105mmol)，搅拌溶解后，降温至10℃左右，缓慢加入丙烯氰6.4g(120mmol)，搅拌反应0.5h。升温至60℃，搅拌反应6h。反应毕，加入水100mL，分出有机层。有机层减压回收一半溶剂，转入反应瓶中，升高温度至80℃以上，缓慢滴加浓硫酸20mL，搅拌反应1h。加入水100mL，于室温下用浓氨水调pH5～5.5，分出有机层，水层用甲苯萃取，合并有机层，水洗，干燥，回收溶剂，得结晶15.9g，收率：55.3％。
实施例5 4-环己基-5-氧代-5-苄基戊酸的制备
该化合物的制备方法参考实施例4，投2-环己基-1-苯基乙基酮20.2g(100mmol)，叔丁醇钾12.3g(110mmol)，丙烯氰6.4g(120mmol)。得3-(1-氧代-2-甲基-1，2，3，4-四氢化萘-2-基)丙酸16.2g，收率：58.9％。
实施例6 3-(1-苯甲酰环己烷)丙酸的制备
该化合物的制备方法参考实施例4，投环己基(苯基)甲酮18.8g(100mmol)，叔丁醇钾12.3g(110mmol)，丙烯氰6.4g(120mmol)。得3-(1-氧代-2-甲基-1，2，3，4-四氢化萘-2-基)丙酸13.1g，收率：50.4％。
实施例7 2，4-二羟基-3-[(4-甲基-4-环己基-5-氧代-5-苯基)戊酰胺基]苯甲酸(本发明化合物1)制备
于干燥的反应瓶中，加入4-环己基-4-甲基-5-氧代-5-苄基戊酸5.8g(20mmol)，DMF 10mL，氯仿50mL，然后加入O-(苯并三氮唑-1-基)-N，N，N′，N′-四甲基脲四氟硼酸酯(TBTU)7.7g(24mmol)，升温至回流搅拌反应50min。缓慢分批加入2，4-双(甲氧甲氧基)-3-氨基-苯甲酸甲
酯5.4g(20mmol)，加料完毕，保温搅拌反应2h。反应毕，加入水100mL，分出水层，有机层减压浓缩，剩余物用乙醇溶解，滴加氢氧化锂2g的水溶液10mL，回流反应0.5h，反应液减压浓缩至干。剩余物用无水乙醇提取40mL×4次，合并提取液，移入反应瓶中，再加入10％HCl-MeOH 20mL，搅拌回流20min，加入冰水100mL，析出白色固体4.1g，收率：47.1％。分子式：C25H29NO6
分子量：439.5
元素分析：实测值：C，68.15％；H，6.94％；N，3.02％
计算指：C，68.32％；H，6.65％；N，3.19％
1H NMR(300MHz，DMSO-d6)：δ11.78(br，1H)，10.13(s，1H)，8.97(s，1H)，7.71～7.68(m，2H)，7.56～7.46(m，4H)，6.42(d，J＝8.7Hz，1H)，2.28～1.09(m，18H)
质谱(m/e)：440(M+1)
实施例8 2，4-二羟基-3-[(4-环己基-5-氧代-5-苯基)戊酰胺基]苯甲酸(本发明化合物2)制备
该化合物的制备方法参考实施例7，投4-环己基-5-氧代-5-苄基戊酸5.5g(20mmol)，2，4-双(甲氧甲氧基)-3-氨基-苯甲酸甲酯5.4g(20mmol)。得2，4-羟基-3-[(4-环己基-5-氧代-5-苯基)戊酰胺基]苯甲酸4.1g，收率：48.7％。
分子式：C24H27NO6
分子量：425.47
元素分析：理论值：C，67.54％；H，6.72％；N，3.13％
计算值：C，67.75％；H，6.40％；N，3.29％
1H NMR(300MHz，DMSO-d6)：δ11.77(br，1H)，10.153(s，1H)，8.87(s，1H)，7.99～7.97(m，2H)，7.64～7.48(m，5H)，6.40(d，J＝8.7Hz，1H)，1.659～1.535(m，6H)，1.063～0.910(m，10H)
质谱(m/e)：426(M+1)
实施例9 2，4-二羟基-3-[3-(苯甲酰环己烷-1-基)丙酰胺基]苯甲酸(本发明化合物3)制备
该化合物的制备方法参考实施例7，投3-(1-苯甲酰环己烷)丙酸5.2g(20mmol)，2，4-双(甲氧甲氧基)-3-氨基-苯甲酸甲酯5.4g(20mmol)。得2，4-羟基-3-[3-(苯甲酰环己烷-1-基)丙酰胺基]苯甲酸3.8g，收率：45.6％。
分子式：C23H25NO6
分子量：411.45
元素分析：理论值：C，67.29％；H，6.35％；N，3.18％
计算值：C，67.14％；H，6.12％；N，3.40％
1H NMR(300MHz，CD3OD)：δ7.76～7.68(m，3H)，7.55～7.49(m，3H)，6.47(d，J＝8.7Hz，1H)，2.52～2.46(m，2H)，2.37～2.28(m，4H)，1.59～1.46(m，5H)，1.35～1.29(m，3H)
质谱(m/e)：412(M+1)
通过以上制备方法，还制备了下列化合物：
化合物4：2-甲氧基-4-羟基-6-三氟甲基-3-[4-乙基-4-环戊基-5-氧代-5-(4-三氟甲基苯基)戊酰胺基]苯甲酸
分子式：C28H29F6NO6 分子量：589.52 质谱(m/e)：590(M+1)
化合物5：2-乙氧基-4-羟基-3-[3-(4-二氟甲基苯甲酰环戊烷-1-基)丙酰胺基]苯甲酸
分子式：C25H27F2NO6 分子量：475.48 质谱(m/e)：476(M+1)
化合物6：2，4-二羟基-3-[4-甲基-4-环己基-5-氧代-5-(3-甲基苯基)戊酰胺基]苯甲酸
分子式：C26H31NO6 分子量：453.53 质谱(m/e)：454(M+1)
化合物7：2，4-二羟基-3-[4-甲基-4-环己基-5-氧代-5-[3-(2，2-二氟乙基苯基)]戊酰胺基]苯甲酸
分子式：C27H31F2NO6 分子量：503.53 质谱(m/e)：504(M+1)
化合物8：4-羟基-3-[4-叔丁基-4-环己基-5-氧代-5-(4-氯苯基)戊酰胺基]苯甲酸
分子式：C28H34ClNO5 分子量：500.03 质谱(m/e)：501(M+1)
化合物9：2-羟基-4-乙氧基-3-[(4-环己基-5-氧代-5-苯基)戊酰胺基]苯甲酸
分子式：C26H31NO6 分子量：453.53 质谱(m/e)：454(M+1)
化合物10：2，4-二羟基-3-[4-环己基-5-氧代-5-(3-甲氧基苯基)戊酰胺基]苯甲酸
分子式：C25H29NO7 分子量：455.50 质谱(m/e)：456(M+1)
化合物11：2-羟基-4-甲氧基-3-[3-(苯甲酰环己烷-1-基)丙酰胺基]苯甲酸
分子式：C24H27NO6 分子量：425.87 质谱(m/e)：426(M+1)
化合物12：2，4-二羟基-5-羟甲基-3-[3-(苯甲酰环己烷-1-基)丙酰胺基]苯甲酸
分子式：C24H27NO7 分子量：441.47 质谱(m/e)：442(M+1)
化合物13：2，4-二羟基-3-[3-[(4-二氟甲氧基)苯甲酰环己烷-1-基]丙酰胺基]苯甲酸
分子式：C24H25F2NO7 分子量：477.45 质谱(m/e)：478(M+1)
实施例10 本发明化合物无菌粉针的制备
1、处方：
处方1：
处方2：
处方3：
处方4：
2、制备工艺：将制备所用的抗生素玻璃瓶、胶塞等进行无菌处理；按处方称取原料，将无菌粉末置于分装机中分装，随时检测装量；加塞，压盖，成品全检，包装入库。
实施例11 本发明化合物水针剂的制备
1、处方：
处方1：
处方2：
2、制备工艺：将原料和辅料用注射用水溶解配液，经活性炭吸附处理后过滤、定容、精虑、半成品检验、灌封、灭菌、检漏、灯检、包装制成成品。
实施例12 本发明化合物片剂的制备
1、处方：
处方1：
处方2：
2、制备工艺：将原料、辅料分别过100目筛，备用；按照处方量称取原料和辅料；将原料、微晶纤维素、预胶化淀粉，混合均匀，加入水适量，搅拌均匀，制成适宜软材；过20目筛制颗粒；颗粒在60℃的条件下烘干；干燥好的颗粒加入硬脂酸镁和羧甲淀粉钠，过18目筛整粒，混合均匀；取样，半成品化验；按照化验确定的片重压片；成品全检，包装入库。
实施例13 本发明化合物乳膏的制备
1、处方：
2、制备工艺：将原料、单甘酯、十八醇、豆蔻酸异丙酯，加热熔融，混合均匀，作为油相，布洛波尔、甘油、平平加-O、水，加热混合，搅拌均匀，70℃保温，油相75℃保温，将油相慢慢加入水相中，不断搅拌，加完后，停止保温，保持搅拌状态，降温到40℃，停止搅拌，降温到室温，得乳膏，铝箔管分装成成品。
实施例14 本发明化合物冻千粉针的制备
1、处方：
处方1
处方2
2、制备工艺：将原料与辅料加约60％注射用水溶解，调节适宜pH值，补加注射用水至全量，加入配液量0.03％针用活性炭吸附20分钟，过滤脱炭，精滤，半成品化验，灌装，冻干、压塞轧盖。冻干步骤为：-40℃预冻5小时，以平均每小时1.5℃进行升温，升温至2℃进行低温真空干燥，快速升温到35℃高温真空干燥，真空度控制在0.1mm汞柱以下。
Claims (5)
1.通式(I)所示的化合物或其药学上可接受的盐：
其中，
Ar代表被1～5个R7取代或未被取代的苯基，其中，R7选自：
(1)卤素，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基；
R1和R2相同或不同，各自独立地为氢原子、C1-6烷基、环戊烷基、环己烷基、环庚烷基，或R1和R2与所连接的碳原子相连接形成环戊烷基、环己烷基、环庚烷基；
R3和R5相同或不同，各自独立地为氢原子或C1-6烷基；
R4为氢原子；
R6为氢原子、卤素原子、羟基、氨基、三氟甲基或C1-6烷基。
2.如权利要求1所述的化合物或其药学上可接受的盐：
其中，
Ar代表苯基；
R1和R2相同或不同，各自独立地为氢原子、甲基、环戊烷基、环己烷基，或R1和R2与所连接的碳原子相连接形成环戊烷基或环己烷基；
R3和R5为氢原子；
R4为氢原子；
R6为氢原子、羟基或三氟甲基。
3.如权利要求2所述的化合物或其药学上可接受的盐，所述化合物选自：
4.包括权利要求1～3任一权利要求所述的化合物或其药学上可接受的盐与一种或多种药用载体和/或稀释剂的药物组合物，为药学上可接受的任一剂型。
5.如权利要求1～3任一权利要求所述的化合物或其药学上可接受的盐在用于制备治疗和/或预防感染性疾病药物中的应用。
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