CN1231665A - 抗菌用的氮杂双环氨甲酰氧基mutili n衍生物 - Google Patents

抗菌用的氮杂双环氨甲酰氧基mutili n衍生物 Download PDF

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CN1231665A
CN1231665A CN97198347A CN97198347A CN1231665A CN 1231665 A CN1231665 A CN 1231665A CN 97198347 A CN97198347 A CN 97198347A CN 97198347 A CN97198347 A CN 97198347A CN 1231665 A CN1231665 A CN 1231665A
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compound
formula
azabicyclo
group
aza
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CN97198347A
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A·K·塔克勒
E·亨特
A·内勒
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GBGB9616305.0A external-priority patent/GB9616305D0/en
Priority claimed from PCT/EP1996/005874 external-priority patent/WO1997025309A1/en
Priority claimed from GBGB9712963.9A external-priority patent/GB9712963D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of CN1231665A publication Critical patent/CN1231665A/zh
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    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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Abstract

式(3)的化合物和其药学上可接受的盐和衍生物用于预防和治疗微生物感染,其中R1为乙烯基或乙基,而R2为基团R3、R4CH2－或R5R6C=CH－,其中每个R3和R4均为氮杂双环系统或R5和R6与它们所连接的碳原子一起形成氮杂双环系统。

Description

抗菌用的氮杂双环氨甲酰氧基MUTILIN衍生物
本发明涉及新化合物，制备这些化合物的方法、含有这些化合物的药用组合物和它们在医学治疗，尤其是抗菌治疗中的用途。
截短侧耳素(Pleuromutilin)(式(1)化合物)为一种具有抗支原体活性和适度抗菌活性的天然存在的抗生素。已表明用R-X-CH2CO2-基团取代14位的乙二醇酸酯可以改进其抗微生物活性，其中R为脂族或芳族部分，X为O、S或NR’(H Egger和H Reinshagen,J Antibiotics,1976,29,923)。硫粘菌素(式(2)化合物)，用作兽医抗生素，为该类型的衍生物(G Hogenauerin Antibiotics,Vol,V,part 1,ed.F E Hahn,Springer-Verlag,1979,p.344)。
在本申请中，使用普遍用于所述文献(G Hogenauer,loc.cit.)中的非常规的编码系统。
我们发现含有14-O-氨甲酰基的某些新的截短侧耳素类似物也改进了抗微生物活性。
因此，从广义上说，本发明提供mutilin的14-O-氨甲酰基衍生物或19,20-二氢mutilin，其中所述氨甲酰基的氮原子被一个具有氮杂双环部分的基团酰基化。
更准确地说，本发明提供具有下面通式(3)的化合物：
Figure A9719834700051
其中：R1为乙烯基或乙基，和R2为基团R3、R4CH2-或R5R6C=CH-，其中每个R3和R4均为氮杂双环系统或R5和R6与它们所连接的碳原子一起形成氮杂双环系统。
所述氮杂双环系统为桥键连接的或稠合的非芳环系统，该系统通过桥头或非桥头环碳原子连接且含有一个作为唯一杂环原子的桥头氮原子。该环系统在每个环上含有5-10个环原子并在碳原子上被至多3个取代基任选取代。适合的取代基包括烷基、烷氧基、链烯基和链烯氧基，其中每一个均可由桥头或非桥头碳原子携带。此外，所述桥头氮原子可被氧取代而形成N-氧化物，或被烷基取代形成季铵阳离子。相反离子可以是卤离子，如氯离子或溴离子，优选氯离子。
所述氮杂双环系统可以由例如式(1)表示：
Figure A9719834700052
其中R7代表如上提出的一个或多个任选的取代基，每个a、b和c为0-4，如此任何一个环具有5-10个环原子。所述氮杂双环系统还可含有一个或多个双键。
具体的氮杂双环基团包括氮杂双环[2.2.2]辛基、氮杂双环[2.2.1]庚基、氮杂双环[3.2.1]辛基、氮杂双环[4.4.0]癸基、喹宁环基、氮杂双环[3.2.1]辛烯基和氮杂双环[3.3.1]壬-5-基。
本文涉及的烷基和链烯基包括含有多至6个碳原子的直链和支链基团且任选被选自下列的一个或多个基团取代：芳基、杂环基、(C1-6)烷氧基、(C1-6)烷硫基、芳基(C1-6)烷氧基、芳基(C1-6)烷硫基、氨基、一-或二-(C1-6)烷基氨基、环烷基、环烯基、羧基及其酯、羟基和卤素。
本文涉及的环烷基和环烯基包括具有3至8个环碳原子的基团且可如上文对烷基和链烯基所述被任选取代。
术语“芳基”用于本文时意指每环适宜含有4-7个，优选5或6个环原子的单环和稠环，这些环中的每一个可以是未取代的或例如由多至3个取代基取代。稠环系统可包括脂族环且只需包括一个芳环。
适合的芳基包括苯基和萘基如1-萘基或2-萘基。
任何适合的芳基，包括苯基和萘基，可以任选由多至5个，优选多至3个取代基取代。适合的取代基包括卤素、(C1-6)烷基、芳基、芳基(C1-6)烷基、(C1-6)烷氧基、(C1-6)烷氧基(C1-6)烷基、卤代(C1-6)烷基、芳基(C1-6)烷氧基、羟基、硝基、氰基、叠氮基、氨基、一-和二-N-(C1-6)烷基氨基、酰氨基、芳基羰基氨基、酰氧基、羧基、羧酸盐、羧酸酯、氨甲酰基、一-和二-N-(C1-6)烷基氨甲酰基、(C1-6)烷氧基羰基、芳氧基羰基、脲基、胍基、磺酰基氨基、氨基磺酰基、(C1-6)烷硫基、(C1-6)烷基亚磺酰基、(C1-6)烷基磺酰基、杂环基和杂环(C1-6)烷基。此外，两个邻近的环碳原子可以通过(C3-5)亚烷基链连接而形成碳环。
除非另外限定，术语“杂环基”和“杂环的”用于本文时适宜包括芳族和非芳族的，单和稠合的环，这些环中的每一个适合含有至多4个杂原子，每个杂原子选自氧、氮和硫，这些环可以是未取代的或例如由多至3个取代基取代。每个杂环适宜具有4-7个，优选5或6个环原子。稠合的杂环系统可包括碳环且只需包括一个杂环。
对于杂环基的取代基优选自卤素、(C1-6)烷基、芳基(C1-6)烷基、(C1-6)烷氧基、(C1-6)烷氧基(C1-6)烷基、卤代(C1-6)烷基、羟基、氨基、一-和二-N-(C1-6)烷基氨基、酰氨基、羧基、羧酸盐、羧酸酯、氨甲酰基、一-和二-N-(C1-6)烷基羰基、芳氧基羰基、(C1-6)烷氧基羰基(C1-6)烷基、芳基、氧代基、脲基、胍基、磺酰基氨基、氨基磺酰基、(C1-6)烷硫基、(C1-6)烷基亚磺酰基、(C1-6)烷基磺酰基、杂环基和杂环(C1-6)烷基。
在另一方面，本发明提供制备本发明化合物的方法，该方法包括使式(4)化合物(其中X为氢或羟基保护基团，如酰基)或式(5)化合物，
Figure A9719834700071
与式R3CONCO、R4CH2CONCO或R5R6C=CHCONCO的酰基异氰酸酯反应。
制备酰基异氰酸酯的方法在文献中有描述。例如，在惰性溶剂如苯、甲苯、氯仿、二氯甲烷或1,2-二氯乙烷中，通过使酰氯(R3COCl、R4CH2COCl或R5R6C=CHCOCl)与氰酸银(如Murdock和Angier在J.Org.Chem.,1962,27,3317中所述)、三-正-丁基锡异氰酸盐(如Akteries和Jochims,Chem.Ber.,1986,119,83所述)或三甲基硅烷基异氰酸酯(如Sheludyakov等，J.Gen.Chem.USSR,1977,2061-2067所述)反应，或者使伯酰胺(R3CONH2、R4CH2CONH2或R5R6C=CHCONH2)或其N,N-双(三甲基硅烷基)衍生物与草酰氯或光气在惰性溶剂中反应(如Speziale和Smith,J.Org.Chem.,1962,27,3742；Kozyukov等，ZhObshch Khim,1983,53,2155)可以制备所述酰基异氰酸酯。
我们发现，所述酰基异氰酸酯的形成和反应可以用一种方法方便地进行。该方法一般包括在氰酸银和叔胺碱(如三乙胺、二异丙基乙胺、吡啶)，通常为三乙胺存在下，使(4)或(5)与酰氯(为氮杂双环部分的酸加成盐，通常为盐酸盐)在惰性溶剂(如氯仿、二氯甲烷、1,2-二氯乙烷)中反应。
更具体地说，在一个方面，本发明提供制备式(3)化合物的方法，该方法包括在氰酸银和碱如三乙胺存在下，使式(4)化合物与式R3COCl、R4CH2COCl或R5R6C=CHCOCl化合物反应，其中R3-R6中的每一个均受到保护(适宜时)，其后按照任何所需的顺序进行以下的一个或多个步骤：·使基团X去保护生成在11位的羟基，·使保护的基团R3-R6去保护，·使基团R3-R6中的一个转化为基团R3-R6中的另一个，和·使12位的乙烯基氢化形成乙基。
尽管有可能通过在已知化合物mutilin(在式(4)中X=H)中的14-羟基的反应制备式(3)化合物，但在实践中需要使用其中11位羟基受保护的中间体。
作为式(4)的适合的化合物包括11-O-酰基mutilin衍生物，如mutilin 11-乙酸酯(在式(4)中X=Ac)(A J Birch,C W Holzapfel,R WRichards,Tetrahedron(Suppl.),1966,8,PartⅡ,359)或mutilin 11-二氯乙酸酯或mutilin 11-三氟乙酸酯。在形成14-O-氨基甲酰基衍生物后，通过选择性水解(如使用在甲醇中的氢氧化钠)可以除去11-O-酰基基团。
在另一方面，本发明提供制备式(3)化合物的方法，该方法包括在氰酸银和碱如三乙胺存在下，使式(5)化合物与式R3COCl,R4CH2COCl或R5R6C=CHCOCl化合物反应，其中R3-R6中的每一个均受到保护(适宜时)，其后按照任何所需的顺序进行以下的一个或多个步骤：·用酸处理该产物获得式(3)化合物，·使保护的基团R3-R6去保护，·使基团R3-R6中的一个转化为基团R3-R6中的另一个，和·使12位的乙烯基氢化形成乙基。
式(5)为(3R)-3-去氧代(deoxo)-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(H Bemer,G Schulz和H Schneider,Tetrahedron,1980,36,1807)。在形成14-氨基甲酸酯后，通过在二噁烷中用浓盐酸或Lukas试剂(用氯化锌饱和的浓盐酸)处理可以使该中间体转化为(3)。
在溶剂如乙酸乙酯、乙醇、二噁烷或四氢呋喃中，通过在氨基甲酰化之前或之后，经钯催化剂(如10％钯炭)氢化使乙烯基R1还原来制备式(4)或(5)化合物的19,20-二氢类似物(其中R1为Et的式(3)化合物)。
适合的羟基、羧基和氨基保护基团为本领域内众所周知的那些基团，在常规条件下这些基团可以除去且不破坏所述分子的其余结构。有关可以保护羟基、羧基和氨基的途径以及裂解生成的被保护的衍生物的方法，在例如“Protective Groups in Organic Chemistry”(T.W.Greene和P.G.M.Wuts,Wiley-Interscience,NeW York,2nd edition,1991)中提供了充分的讨论。特别适合的羟基保护基团包括如三有机甲硅烷基例如三烷基甲硅烷基，有机羰基和有机氧代羰基，例如，乙酰基、烯丙氧基羰基、4-甲氧基苄氧基羰基和4-硝基苄氧基羰基。特别适合的羧基保护基团包括烷基和芳基，例如甲基、乙基和苯基。特别适合的氨基保护基团包括烷氧基羰基、4-甲氧基苄氧基羰基和4-硝基苄氧基羰基。
在使用式(4)中间体(如X=乙酰基)的情况下，在基团X被去保护的同时，可方便地除去对碱不稳定的保护基团。在使用式(5)中间体的情况下，在式(5)化合物转化为式(3)化合物的同时，可方便地除去对酸不稳定的保护基团。
本发明化合物中的氮杂双环系统可以含有手性中心，因而式(3)化合物可以包括非对映异构体的混合物或单一非对映异构体。通过分离该非对映异构体的混合物(可使用外消旋的氮杂双环原料合成)或通过用旋光纯的氮杂双环原料合成可以制备式(3)化合物的单一非对映异构体。
本发明的化合物可以为结晶或非结晶形式，以及(如果为晶体)可以任选为水合物或溶剂化物。当一些本发明的化合物从有机溶剂中结晶或重结晶时，结晶的溶剂可以存在于该结晶产物中。此类溶剂化物包括在本发明范围内。类似地，本发明的一些化合物可从含水溶剂中结晶或重结晶。在这样的情况下，水合作用的水可以存在于结晶产物中。化学计量的水合物以及含有可变量水(通过某些方法如冷冻干燥可以产生)的化合物也包括在本发明范围内。
根据本发明的化合物适合以基本纯的形式，例如至少50％纯度，适宜至少60％纯度，较有利至少75％纯度，优选至少85％纯度，更优选至少95％纯度，特别以至少98/％纯度的形式提供，所有的百分比均以重量/重量计算。根据本发明的化合物的不纯的或较不纯的形式可以例如用来制备适合药用的某些化合物或相关化合物(例如相应的衍生物)的较纯的形式。
本发明也包括本发明化合物的药学上可接受的盐和衍生物。当取代基中的一个携带酸性或碱性基团时，有可能形成盐。用常规方法经盐交换可以制备盐。
所述氮杂双环部分的酸加成盐可以是药学上可接受的或非-药学上可接受的盐。在后一情况下，这些盐可以用于分离和纯化式(3)化合物或其中间体，并被随后转化为药学上可接受的盐或游离碱。药学上可接受的酸加成盐包括Berge,Bighley和Monkhouse在J.Pharm.Sci.,1977,66,1-19中所述的那些盐。适合的盐包括盐酸盐、马来酸盐和甲磺酸盐，尤其是盐酸盐。
应该理解，当式(3)化合物含有游离的羧基部分时，所述式(3)化合物能形成两性离子。
本发明化合物和它们的药学上可接受的盐或衍生物具有抗微生物活性并被用于治疗动物，尤其是哺乳动物(包括人)，特别是人和家畜(包括农畜)中的微生物感染。本发明化合物可以用于治疗由例如革兰氏阳性菌和革兰氏阴性菌以及支原体属，包括例如，金黄色葡萄球菌、表皮葡萄球菌、肠球菌、白色酿脓链球菌、无乳链球菌、肺炎双球菌、嗜血杆菌属的菌种、奈瑟氏菌属的菌种、军团菌属的菌种、衣原体属的菌种、粘膜炎莫拉氏菌、肺炎支原体和鸡败血支原体引起的感染。
本发明提供含有式(3)化合物或其药学上可接受的盐或衍生物与药学上可接受的载体或赋形剂混合的组合物。
本发明也提供在动物，尤其是在人类和家畜中治疗微生物感染的方法，该方法包括给予需要此治疗的患者式(3)化合物或其药学上可接受的盐或衍生物，或根据本发明的组合物。
本发明还提供本发明化合物或其药学上可接受的盐或衍生物在制备用于治疗微生物感染的药物组合物中的用途。
根据本发明的化合物和组合物可以以类似于其它抗生素的方法配制以便能以任何方便的给药形式用于人类或兽医学领域中。
根据本发明的化合物和组合物可以配制成以任何途径，例如口服、局部或胃肠外给药的形式。例如，可以将组合物制成片剂、胶囊、粉末、颗粒、锭剂、霜剂、糖浆剂或液体制剂，例如溶液或悬浮液，所述液体制剂可以配制成口服使用或通过注射或输注的胃肠外给药的无菌形式。
用于口服给药的片剂和胶囊可以为单位剂量形式，并可含有常规的赋形剂，包括例如粘合剂如糖浆、阿拉伯胶、明胶、山梨醇、黄蓍胶或聚乙烯吡咯烷酮，填充剂如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨醇或甘氨酸，片成形润滑剂如硬脂酸镁、滑石粉、聚乙二醇或二氧化硅，崩解剂如马铃薯淀粉，及药学上可接受的润湿剂如十二烷基硫酸钠。根据通常药学实践熟知的方法可以对片剂进行包衣。
口服液体制剂可以为例如含水或含油悬浮液、溶液、乳剂、糖浆或酏剂的形式，或可作为在使用前用水或其它适合的溶媒复制的干燥产品形式。此类液体制剂可以含有常规的添加剂，包括例如悬浮剂如山梨醇、甲基纤维素、葡萄糖糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂如卵磷脂、一油酸脱水山梨醇酯或阿拉伯胶，无水溶媒(可以包括食用油)如杏仁油、油性酯(例如甘油)、丙二醇或乙醇，防腐剂如对-羟基苯甲酸甲酯或丙酯或山梨酸，及(如果需要)常用的调味剂和着色剂。
用于局部给药的本发明组合物可以为例如软膏剂、霜剂、洗剂、眼膏剂、滴眼剂、滴耳剂、滴鼻剂、鼻用喷雾剂、浸渗敷料及气溶胶的形式，且可含有适合的常规添加剂包括，例如防腐剂、帮助药物渗透的溶剂，及软膏剂和霜剂中的润肤剂。此类局部制剂还可以含有可相容的常规载体如霜剂或软膏剂的基质，以及用于洗剂的乙醇或油醇。这类载体的含量可占所述制剂的约1％-约98％(重量)，更常见为所述制剂的高达约80％(重量)。
根据本发明的组合物也可以配制成栓剂，其可包括常规的栓剂基质，例如可可油或其它甘油酯。
用于胃肠外给药的本发明组合物可以方便地为液体单位剂量形式，它可以用所述化合物和无菌溶媒(优选水)来制备。所述化合物(取决于使用的溶媒和浓度)可以悬浮于或溶解于溶媒中。在制备溶液时，所述化合物可以溶解于供注射的水中并在灌装合适的小瓶或安瓿之前过滤-除菌，然后密封。有利的是，常用的添加剂包括，例如局部麻醉剂、防腐剂和缓冲剂可以溶解于溶媒中。为提高该溶液的稳定性，所述组合物可以在灌装到小瓶中后进行冷冻并真空除去水分。然后将得到的冻干粉末密封于小瓶中，同时供应一瓶附带的注射用水以便在用前复制成液体。胃肠外的悬浮液也可用类似的方法制备，但所述化合物需悬浮于溶媒中，而不是溶解于溶媒中，且不能通过过滤的方法实现除菌。作为另一种替代方法，可以在悬浮于无菌溶媒前使其暴露于环氧乙烷对该化合物进行灭菌处理。有利的是，为使所述化合物分布均匀，此类悬浮液中包括表面活性剂和湿润剂较为有利。
根据本发明的化合物或组合物适合以抗微生物的有效量给予患者。
根据本发明的组合物可以适合含有0.1％(重量)-，优选10％-60％(重量)的本发明化合物(基于组合物的总重量)，这取决于给药的方法。
根据本发明的化合物可以适合以1.0-50mg/kg(体重)的日剂量给予患者。对于成人(体重约70kg)，可以每日给予50-3000mg，例如约1500mg的本发明化合物。适合地，成人的每日剂量为5-20mg/kg。然而，根据通常的临床实践可以采用稍高或稍低的剂量。
当根据本发明的组合物以单位剂量形式存在时，每个单位剂量适合含有25-1000mg，优选50-500mg的本发明化合物。
下列实施例说明本发明。
截短侧耳素类似物的命名注释
在实施例中，化合物(a)在IUPAC系统中具有系统名(1S,2R,3S,4S,6R,7R,8R,14R)-3,6-二羟基-2,4,7,14-四甲基-4-乙烯基-三环[5.4.3.01,8]十四烷-9-酮，该化合物采用俗名mutilin并具有H Berner,G Schulz和H Schneider在Tetrahedron,1981,37,915-919中所述编码系统。
Figure A9719834700131
同样地，化合物(b)具有系统名(1R,2R,4S,6R,7R,8S,9R,14R)-6-羟基-9-甲氧基-2,4,7,14-四甲基-4-乙烯基-三环[5.4.3.01,8]十四烷-3-酮，该化合物被称作(3R)-3-去氧代(deoxo)-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin；而化合物(c)具有系统名(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸(1S,2R,3S,4S,6R,7R,8R,14R)-3-羟基-2,4,7,14-四甲基-9--氧代-4-乙烯基-三环[5.4.3.01,8]十四-6-基酯，该化合物被称作(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸mutilin14-酯。
Figure A9719834700141
实施例1．(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸mutilin14-酯
步骤1．(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯
用PCT/EP96/05874实施例87步骤3中所述方法，将奎宁环-4-甲酸盐酸盐(Helvetica Chimica Acta,1974,57,2332)(230mg)和(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(330mg)转化为标题化合物，得到白色泡沫物(160mg)；1H NMR(CDCl3)尤其1.90(6H,dd,J8,7.4Hz),3.10(6H,dd,J8,7.4Hz),3.21(3H,s),5.00(1H,d,J17.5Hz),5.27(1H,d,J10.7Hz),5.77(1H,d,J10Hz),6.68(1H,dd,J17.5,10.7Hz),7.85(1H，宽s)；MS(ES)m/z515(MH+)。
步骤2．(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸mutilin 14-酯
用PCT/EP96/05874实施例87步骤4中所述方法，将(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯(140mg)转化为标题化合物，得到白色固体物(86mg)；1H NMR(CDCl3)尤其0.73(3H,d,J6.7Hz),0.87(3H,d,J7Hz),1.17(3H,s),1.49(3H,s),1.68(6H,dd,J8,7.3Hz),2.93(6H,dd,J8,7.3Hz),3.34(1H,dd,J10,6.6HZ),5.22(1H,d,J17.3Hz),5.36(1H,d,J11Hz),5.76(1H,d,J8.5Hz),6.54(1H,dd,J17.3,11Hz)；MS(ES)m/z501(MH+)。
实施例2．(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸mutilin14-酯盐酸盐
将(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸mutilin14-酯(71mg)溶于乙酸乙酯(5ml)/1,4-二噁烷(2ml)中并加入在二噁烷(0.2ml)中的4MHCl。通过减压蒸发溶剂使该溶液浓缩为约1ml，加入甲苯(5ml)得到白色沉淀。过滤收集沉淀，用甲苯(2ml)洗涤，真空干燥产生白色固体的标题化合物(79mg)；1H NMR(D2O)尤其0.69(3H,d,J6Hz),0.92(3H,d,J6.8Hz),1.15(3H,s),1.39(3H,s),2.16(6H,dd,J8.2,7.5Hz),3.42(6H,dd,J8.2,7.5Hz),3.58(1H,d,J6Hz),5.20(1H,d,J17.5Hz),5.28(1H,d,J11.1Hz),5.68(1H,d,J8.1Hz),6.36(1H,dd,J17.5,11.1Hz)。
实施例3．(1-氮杂-双环[2.2.1]庚烷-4-羰基)-氨基甲酸mutilin 14-酯
步骤1．(1-氮杂-双环[2.2.1]庚烷-4-羰基)-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin 14-酯
用PCT/EP96/05874实施例87步骤3中所述方法，将1-氮杂-双环[2.2.1]庚烷-4-甲酸盐酸盐(Chemical Abstracts,1989,110,95016)(700mg)和(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(1g)转化为标题化合物，得到白色固体物(330mg)；1H NMR(CDCl3)尤其2.05(4H,m),2.72(4H,m),3.08(2H,m),3.22(3H,s)3.44(1H,m),5.02(1H,d,J17.5Hz),5.30(1H,d,J11.6Hz),5.80(1H,d,J9.9Hz),6.69(1H,dd,J17.5,11.6Hz),7.48(1H,s)；MS(ES)m/z501(MH+)。
步骤2．(1-氮杂-双环[2.2.1]庚烷-4-羰基)-氨基甲酸mutilin14-酯
用PCT/EP96/05874实施例87步骤4中所述方法，将(1-氮杂-双环[2.2.1]庚烷-4-羰基)-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯(300mg)转化为标题化合物，得到白色固体物(250mg)；1H NMR(CDCl3)尤其2.28(4H,m),3.06(2H,m),3.37(1H，宽s),5.24(1H,dd,J17.3,1.4Hz),5.38(1H,dd,J11,1.4HZ),5.78(1H,d,J8.5Hz),6.64(1H,dd,J17.3,11Hz),7.38(1H,s)；MS(EI)m/z486(M+)；实测值：486.3085,C28H42N2O5计算值：486.3094。
实施例4．{(3S,4R)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin14-酯
步骤1．{(3S,4R)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯
使(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(490mg,1.46mmol)与(3S,4R)-1-氮杂-双环[2.2.1]庚烷-3-甲酰氯(280mg,1.46mmol)和氰酸银(550mg,3.67mmol)在干燥的二氯甲烷(20ml)中混合。加入三乙胺(0.20ml,1.46mmol)，在漫射光和氩气下，于室温下搅拌该反应物16小时。使混合物通过Kieselguhr过滤并用饱和碳酸氢钠水溶液(x2)和盐水洗涤滤液。干燥(硫酸镁)后，经硅胶层析纯化，用在二氯甲烷中的4％(9∶1甲醇∶氨(35％))洗脱得到标题化合物(276mg,38％)；nmax(CH2Cl2)3383,2981,1780,1749,1698,1460和1374cm-1；MS(EI)m/z500(M+)；实测值：500.3248,C29H44N2O5计算值：500.3250。
步骤2．{(3S,4R)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin14-酯
用浓盐酸(3ml)处理在二噁烷(2ml)中的步骤1的产物(260mg,0.52mmol),于室温下搅拌该反应物30分钟。用水稀释该溶液并用二氯甲烷(x2)洗涤。用饱和的碳酸氢钠水溶液碱化水相并将产物提取到二氯甲烷中。干燥(硫酸镁)有机相并浓缩产生标题化合物(187mg,74％)；nmax(CH2Cl2)3386,2962,1782,1735,1699和1467cm-1；1H NMR(d6-DMSO)0.63(3H,d,J6.6Hz),0.81(3H,d,J7.0Hz),1.05-3.12(29H,m)包括：1.09(3H,s)和1.42(3H,s),4.52(1H,d,J6.0Hz，交换)，5.03-5.12(2H,m),5.51(1H,d,J7.8Hz),6.21(1H,dd,J17.7,11.1Hz),10.40(1H,bs)；MS(CI)m/z487(MH+).
实施例5．{(3S,4R)-1-氮杂-双环[2.2.1]庚烷-4-羰基}-氨基甲酸14-脱氧-19,20-二氢-mutilin 14-酯
使在1∶1乙醇∶四氢呋喃(10ml)中的{(3S,4R)-1-氮杂-双环[2.2.1]庚烷-4-羰基}-氨基甲酸mutilin14-酯(95mg,0.20mmol)溶液经10％钯炭(90mg)氢化12小时。通过硅藻土过滤该溶液，真空蒸发溶剂得到标题化合物(85mg,87％)；nmax(KBr)3421,2957,1772,1733,1702和1464cm-1；1H NMR(d6-DMSO)尤其0.68(3H,d,J7.1Hz),0.82(3H,d,J6.8Hz),4.46(1H,d,J5.9Hz),5.46(1H,d,J7.6HZ),10.53(1H,bs)；MS(EI)m/z488(M+)。实测值：M+,488.3256,C28H44N2O5计算值：488.3250。
实施例6．(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸14-脱氧-19,20-二氢-mutilin14-酯
使在2∶1四氢呋喃∶乙醇(30ml)中的(1-氮杂-双环[2.2.2]辛烷-4-羰基)-氨基甲酸mutilin14-酯(100mg,0.20mmol)溶液经10％钯炭(10mg)氢化1小时。通过硅藻土过滤该溶液,真空蒸发溶剂得到白色固体的标题化合物(90mg,90％)；nmax(CH2Cl2)2960,1782,1733,1716和1479cm-1；1H NMR(CDCl3)尤其0.69(3H,d,J6.6Hz),3.42(1H,d,J5.9Hz),5.61(1H,d,J8.2Hz),7.37(1H,bs)；MS(EI)m/z502(M+)。实测值：M+,502.3411,C29H46N2O5计算值：502.3407。
实施例7．(1-氮杂-双环[2.2.2]辛烷-3-羰基)-氨基甲酸mutilin14-酯
步骤1．(1-氮杂-双环[2.2.2]辛烷-3-羰基)-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯
用PCT/EP96/05874实施例161中所述方法，将奎宁环-3-甲酸转化为其酰氯盐酸盐。然后通过PCT/EP96/05874实施例161中概述的方法，使该酰氯与(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(1.002g)反应，经硅胶柱层析后得到标题化合物，为白色泡沫状物(1.116g)；MS(ES)m/z515(MH+)。
步骤2．(1-氮杂-双环[2.2.2]辛烷-3-羰基)-氨基甲酸mutilin14-酯
将在1,4-二噁烷(12ml)中的得自步骤1的产物(1.13g)与浓盐酸(5ml)一起于室温下搅拌7小时。然后用乙酸乙酯稀释该溶液，用饱和碳酸氢钠溶液中和。用饱和氯化钠溶液洗涤该有机溶液，干燥(硫酸镁)并蒸发产生粗品。经硅胶层析纯化后，用在二氯甲烷中的0-20％9∶1甲醇/35％氨溶液梯度洗脱，分离标题化合物，为白色固体(0.340g)。使该固体(两种非对映异构体的混合物)溶于热乙酸乙酯中，过滤收集生成的白色固体得到标题化合物的一种纯净非对映异构体(0.140g)；1HNMR(CDCl3)尤其0.75(3H,d,J6.5Hz),0.90(3H,d,J7.0Hz),1.20(3H,s),1.40(3H,s),2.70-3.10(5H,m),3.20-3.42(3H,m),5.15-5.40(2H,ddd),5.70(1H,d,J8.3Hz),6.50(1H,dd,J10.95,17.4Hz)和7.40(1H,s)；MS(ES)m/z501(MH+)。母液主要含有标题化合物的另一种非对映异构体(0.200g)；1H NMR(CDCl3)尤其0.75(3H,d,J6.5Hz),0.90(3H,d,J7.0Hz),1.20(3H,s),1.41(3H,s),2.12-2.4(3H,m),2.70-3.10(5H,m),3.24-3.42(3H,m),5.15-5.45(2H,m),5.69(1H,d,J8.3Hz),6.50(1H,dd,J11.0,17.35Hz)和7.40(1H,s)；MS(ES)m/z501(MH+)。
实施例8．{(3S,4R)-1-氮杂-双环[2.2.1]庚烷-3-羰基)-氨基甲酸mutilin14-酯盐酸盐
用在乙醚中的1M HCl(4.2ml,4.20mmol)处理在丙酮(100ml)中的{(3S,4R)-1-氮杂-双环[2.2.1]庚烷-3-羰基)-氨基甲酸mutilin14-酯(1.0g,2.06mmol)溶液。于室温下搅拌该溶液1小时，然后真空浓缩。用乙醚研磨其残留物得到标题化合物，为白色固体(1.02g,95％)；nmax(KBr)3421,2924,1772,1734,1704和1465cm-1；1H NMR(D2O)尤其0.62(3H,d,J6.0Hz),0.90(3H,d,J6.9Hz),5.22(2H,dd,J16.7,11.1Hz),5.61(1H,d,J8.1Hz),6.35(1H,dd,J17.5,11.1Hz)。
实施例9．(1-氮杂-双环[3.2.1]辛烷-5-羰基)-氨基甲酸mutilin14-酯
步骤1．(1-氮杂-双环[3.2.1]辛烷-5-羰基)-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯
将三乙胺(0.58ml,4.2mmol)加入外消旋的1-氮杂-双环[3.2.1]辛烷-5-酰氯盐酸盐(4mmol)、(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(668mg,2mmol)和氰酸银(600mg)的二氯甲烷(25ml)的搅拌下的混合物中。于室温下搅拌该混合物过夜，过滤并蒸发滤液至干。粗产物经硅胶层析纯化，用35％氨溶液∶甲醇∶二氯甲烷1∶9∶90洗脱，产生标题化合物，为白色固体(480mg),Rf0.1；1H NMR(CDCl3)尤其7.4(1H,br,s),5.79(1H,d,J10),3.21(3H,s),2.75-3.0(6H,m)；MS(+ve离子电子喷射)m/z515(30％,MNH4+),m/z556(100％,M+H+MeCN+)。
步骤2．(1-氮杂-双环[3.2.1]辛烷-5-羰基)-氨基甲酸mutilin14-酯
使步骤1的产物(480mg,0.93mmol)溶解于二噁烷(2.5ml)中，在冰浴冷却下缓慢加入浓盐酸(2.5ml)。于室温下搅拌该澄清的溶液4小时，然后用水稀释该溶液，加入碳酸钠使之碱化。用乙酸乙酯提取该混合物并用盐水洗涤。干燥(硫酸镁)并蒸发得到粗产物，经硅胶层析纯化，用35％氨溶液∶甲醇∶二氯甲烷1∶9∶90洗脱，产生标题化合物的两种非对映异构体，为白色固体(274mg,58％)；Rf0.08；n max(CHCl3)2962,1772,1736m,1628cm-1；1H NMR(CDCl3)尤其7.58(1H,br,s),6.51(1H,dd,J17,11),5.75(1H,d,J8.4),5.34(1H,dd,J11,1.25),5.19(1H,d,J17,1.25),3.36(1H,br),3.08-3.2(1H,m),2.7-3.05(5H,m)；MS(+ve离子电子喷射)m/z501(100％,MH+),MS(-ve离子电子喷射)m/z499(100％,M-H-)。
实施例10．(1-氮杂-双环[2.2.2]辛烷-2-羰基)-氨基甲酸mutilin14-酯
步骤1．(1-氮杂-双环[2.2.2]辛烷-2-羰基)-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯
将三乙胺(0.2ml,1.5mmol)加入外消旋的1-氮杂-双环[2.2.2]辛烷-2-酰氯盐酸盐(约3mmol)、(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(501mg,1.5mmol)和氰酸银(225mg)的二氯甲烷(10ml)的搅拌下的混合物中。于室温下搅拌该混合物过夜，过滤并用二氯甲烷稀释滤液，用碳酸氢钠水溶液和盐水洗涤。干燥(硫酸镁)并蒸发得到粗产物，经硅胶层析纯化，用乙酸乙酯∶正-己烷1∶1洗脱，获得标题化合物，为无色树胶状物(220mg),Rf0.12。
步骤2．(1-氮杂-双环[2.2.2]辛烷-2-羰基)-氨基甲酸mutilin14-酯
使步骤1的产物(200mg)溶解于二噁烷(2ml)中,在冰浴冷却下缓慢加入浓盐酸(2ml)。于室温下搅拌该澄清的溶液3小时，然后用水稀释该溶液，加入碳酸氢钠使之碱化。用乙酸乙酯提取该混合物并用盐水洗涤。干燥(硫酸镁)并蒸发得到粗产物，经硅胶层析纯化，用5％甲醇的氯仿液洗脱，产生标题化合物的两种非对映异构体，为白色泡沫物(135mg,69％)；Rf0.08；n max(CHCl3)3309,2946,1780,1735m,1713cm-1；MS(+ve离子电子喷射)m/z501(22％,MH+),MS(-ve离子电子喷射)m/z499(100％,M-H-)。
实施例11
{(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin 14-酯
步骤1．{(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯
使(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-甲酸乙酯(2.0g,I.F.Cottrell,D.Hands,D.J.Kennedy,K.J.Paul,S.H.B.Wright和K.Hoogsteen,J.Chem.Soc.Perkin Trans.1,1991,1091-1097)溶于浓盐酸中，在回流下加热5小时。冷却后，减压蒸发该溶液，残留物从甲苯(x3)中再蒸发。经五氧化二磷干燥，用冷的乙酸乙酯/甲醇研磨得到(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-甲酸的盐酸盐(1.2g)。
用PCT/EP96/05874实施例161步骤1中所述方法，将(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-甲酸的盐酸盐(890mg)和(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(1.67g)转化为标题化合物，得到无色固体物(1.28g,51％)；1H NMR(CDCl3)尤其0.86(3H,d,J7.0Hz),1.01(3H,d,J6.3Hz),1.21(3H,s),1.24(3H,s),3.23(3H,s),5.05(1H,d,J17.5Hz),5.34(1H,d,J10.7HZ),5.76(1H,d,J10.0Hz),6.62(1H,dd,J17.5,10.7Hz),7.75-7.85(1H,br，交换)；MS(电子喷射)m/z501(MH+)。
步骤2．{(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin14-酯
用浓盐酸(5ml)处理在二噁烷(5ml)中的步骤1的产物(501mg)，于室温下搅拌该反应物3小时。用水稀释该溶液并用乙酸乙酯洗涤。用饱和的碳酸氢钠水溶液碱化其水相并将产物提取到氯仿中。用水和饱和氯化钠溶液洗涤有机相，干燥(硫酸镁)并浓缩。残留物经硅胶层析纯化，用氯仿/甲醇/35％氨水溶液(20∶1∶0.1)洗脱得到标题化合物，为无色固体(380mg,78％)：[α]D 20-8.00(c.0.5；EtOH)；nmax(CH2Cl2)3386,2962,1782,1735,1699和1467cm-1；1H NMR(CDCl3)尤其0.76(3H,d,J6.5Hz),0.90(3H,d,J6.8Hz),1.20(3H,s),1.45(3H,s),5.24(1H,dd,J17.3Hz),5.38(1H,d,J11.0Hz),5.73(1H,d,J8.5Hz),6.49(1H,dd,J17.3,11.0Hz),7.70-7.90(1H,br交换)；MS(电子喷射)m/z487(MH+)。
实施例12
{(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin 14-酯盐酸盐
用在乙醚(0.8ml)中的1M氯化氢处理{(3R,4S)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin 14-酯(200mg)的丙酮(15ml)溶液。于室温下搅拌该溶液1小时。收集生成的固体，用乙醚洗涤，干燥得到标题化合物，为无色固体(200mg,93％):[α]D 20-17.40(c.0.5；EtOH)；δ(D2O)尤其0.62(3H,d,J5.8Hz),0.85(3H,d,J7.0Hz),1.08(3H,s),1.32(3H,s),5.13(1H,d,J17.5Hz),5.20(1H,d,J11.0Hz),5.56(1H,d,J8.0Hz),6.30(1H,dd,J17.5和11.0Hz)；MS(电子喷射)m/z487(MH+-HCl,100％)。
实施例13
{(3R,4R)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin14-酯盐酸盐
在氩气下，搅拌(3R,4R)-1-氮杂-双环[2.2.1]庚烷-3-甲酸盐酸盐(1.91g，粗品，含有氯化钠，根据G.A.Showell,R.Baker,J.Dayies,R.Hargreaves,S.B.Freedman,K.Hoogsteen,S.Patel和R.J.Snow,J.Med.Chem.(1992),35,911-916中所述制备)在二氯甲烷(25ml)中的悬浮液并用DMF(2滴)和草酰氯(1.56ml)处理。3小时后，蒸发该溶液，加入苯(20ml)，再蒸发，加入干燥的二氯甲烷(25ml)。在氩气下搅拌该悬浮液并用(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(1.64g，根据H.Berner,G.Schulz和H.Schneider,Tetrahedron,(1980),36,1807中所述方法制备)、氰酸银(925mg)和三乙胺(0.86ml)处理。14小时后，加入饱和的碳酸氢钠水溶液(25ml)并剧烈搅拌。通过硅藻土过滤该混合物，分离各层，干燥和蒸发有机层。残留物经硅胶层析纯化，用二氯甲烷/甲醇/35％氢氧化铵水溶液(19∶1∶0.1)洗脱，获得{(3R,4R)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-酯(0.88g)：vmax(CHCl3)3393,1781,1752,1697,1466cm-1；MS(+ve离子电子喷射)m/z501(MH+,100％)。
将该物质悬浮于二噁烷(12ml)中，搅拌，冰冷却，用浓盐酸(8ml)处理。5分钟后，移去冷浴，使该溶液放置4小时。加入乙酸乙酯(30ml)和水(30ml)，接着分次加入固体碳酸氢钠直至碱性。分离各层，干燥和蒸发有机层。使残留物溶于乙酸乙酯(20ml)中，用在乙醚(3.5ml)中的1M HCl溶液处理，蒸发溶剂，用乙醚研磨残留物。过滤得到标题化合物，为白色固体(660mg)：[α]D 20+2.80(c.0.5；EtOH)；vmax(CHCl3)3548,3432,2429(宽峰)，2361(宽峰)，1724,1581cm-1；δ(DMSO)尤其0.65(3H,d,J6.3Hz),0.82(3H,d,J6.8Hz),2.41(1H,s),4.58(1H，宽峰s,D2O交换消失)，5.0-5.2(2H,m),5.49(1H,d,J7.5Hz),6.23(1H,dd,J11和17.5Hz),10.68(1H,s,D2O交换消失)，10.78(1H,s,D2O交换消失)；MS(+ve离子电子喷射)m/z487(MH+-HCl,100％)。
按类似于实施例13的方法制备下列化合物：
实施例14
{(3S,4S)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin14-酯盐酸盐
根据G.A.Showell,R.Baker,J.Davies,R.Hargreaves,S.B.Freedman,K.Hoogsteen,S.Patel和R.J.Snow,J.Med.Chem.(1992),35,911-916中所述制备(3S,4S)-1-氮杂-双环[2.2.1]庚烷-3-甲酸盐酸盐。使游离碱{(3S,4S)-1-氮杂-双环[2.2.1]庚烷-3-羰基}-氨基甲酸mutilin14-酯经在转化为盐酸盐之前硅胶层析纯化，用二氯甲烷/甲醇/35％氢氧化铵水溶液(19∶1∶0.1)洗脱，获得标题化合物，为白色固体：[α]D 20+110(c.0.5；EtOH)；vmax(CDCl3)3695,3387,2426(宽峰)，2360(宽峰)，1736,1711,1602cm-1；δ(DMSO)尤其0.64(3H,d,J6.3Hz),0.81(3H,d,J6.8Hz),2.40(1H,s),4.57(1H,d,J 5.8Hz)，D2O交换消失)，5.0-5.2(2H,m),5.49(1H,d,J7.8HZ),6.20(1H,dd,J8.6和17.5HZ),10.68(1H,s,D2O交换消失)，10.78(1H,s,D2O交换消失)；MS(氨化学电离)m/z487(MH+-HCl,100％)。
实施例15
(1-氮杂-双环[4.4.0]癸烷-4-羰基)-氨基甲酸mutilin14-酯盐酸盐(平展的异构体)
由1-氮杂-双环[4.4.0]癸烷-4-甲酸盐酸盐的平展异构体(P.A.Wyman等，Bioorg.and Med.Chem.(1996),4 255-261)制备标题化合物，分离后为白色固体(总收率35％)：δ(DMSO)尤其0.63(3H,d,J6.3HZ),0.82(3H,d,J6.3HZ),4.55(1H,d,J5.8Hz D2O交换消失)，5.03-5.13(2H,m),5.50(1H,d,J7.8Hz),6.21(1H,dd,J11.3和17.7Hz),10.1(1H,宽峰s,D2O交换消失)，10.52(1H,s,D2O交换消失)；MS(+ve离子电子喷射)m/z529(MH+,100％)。
实施例16
(1-氮杂-双环[4.4.0]癸烷-4-羰基)-氨基甲酸mutilin14-酯盐酸盐(轴向异构体)
由1-氮杂-双环[4.4.0]癸烷-4-甲酸盐酸盐的轴向异构体(P.A.Wyman等，Bioorg and Med.Chem.(1996),4,255-261)制备标题化合物，分离后为白色固体(总收率6％)：δ(DMSO)尤其0.63(3H,d,J6.3Hz),0.82(3H,d,J6.4Hz),3.43(1H,t D2O交换后为d,J5.3Hz),4.54(1H,d,J6Hz,D2O交换消失)，5.03-5.15(2H,m),5.50(1H,d,J8Hz),6.21(1H,dd,J11.3和17.7HZ),10.12(1H，宽峰s,D2O交换消失)，10.52(1H,s,D2O交换消失)；MS(+ve离子电子喷射)m/z529(MH+,100％)。
实施例17
{(1-氮杂-双环[4.4.0]癸烷-4-基)-乙酰基}-氨基甲酸mutilin14-酯
用8M盐酸使1-氮杂-双环[4.4.0]癸-4-基-乙酸乙酯的平展异构体(美国专利3692791)水解(室温下1小时)。用生成的(1-氮杂-双环[4.4.0]癸-4-基)-乙酸盐酸盐平展异构体制备标题化合物，为固体(总收率21％)：δ(CDCl3)尤其5.17(1H,d,J17.5Hz),5.31(1H,d,J12.5Hz),5.63(1H,d,J7.5Hz),6.41(1H,dd,J17.5和12.5Hz),7.27(1H,s)；MS(+ve离子电子喷射)m/z543(MH+,100％)。
实施例18
(1-氮杂-双环[3.2.1]辛-3-烯-3-羰基)-氨基甲酸mutilin14-酯
由1-氮杂-双环[3.2.1]辛-3-烯-3-甲酸盐酸盐(S.M.Bromidge等，Bioorg and Med.Chem.Letters(1994),4,1185-1190)制备标题化合物，得到白色固体(总收率12％)：δ(CDCl3)尤其0.76(3H,d,J7.5Hz),0.88(3H,d,J5HZ),3.95(1H,d,J17.5Hz),5.21(1H,dd,J17.5Hz,2Hz),5.36(1H,dd,J10Hz,2Hz),5.78(1H,d,J7.5Hz),6.52(1H,dd,J17.5Hz,10HZ),6.91(1H,d,7.5Hz),7.41(1H,s)；MS(+ve离子电子喷射)m/z499(MH+,100％)。
实施例19
(1-氮杂-双环[3.3.1]壬烷-5-羰基)-氨基甲酸mutilin14-酯
由1-氮杂-双环[3.3.1]壬烷-5甲酸(美国专利573216,1992年7月)制备标题化合物，为固体(总收率19％)：δ(CDCl3)尤其3.27(1H,d),5.12(1H,dd),5.27(1H,dd),5.68(1H,d),6.46(1H,dd)；MS(+ve离子电子喷射)m/z515(MH+)。
实施例20
{(1-氮杂-双环[2.2.2]辛-3-亚基)-乙酰基}-氨基甲酸mutilin14-酯
用8M盐酸使3-乙氧基羰基亚甲基-1-氮杂双环[2.2.2]辛烷(E,Z混合物；L.N.Yakhontov,L.I.Mastafanova,M.V.Rubstov,Zh.Obshch.Khim.(1963),33,3211-3214)水解(室温下2天，接着回流1小时)。用生成的(1-氮杂-双环[2.2.2]辛-3-亚基)-乙酸(E,Z混合物)制备标题化合物，为固体(总收率17％，由单一的双键异构体组成)：δ(CDCl3)尤其5.24(1H,d,J17.4Hz),5.39(1H,d,J11.0Hz),5.71(1H,d,J8.4Hz),6.52(1H,dd,J17.4和11.0Hz),6.68(1H,t,J2.5Hz)；7.40(1H,s)；MS(+ve离子电子喷射)m/z513(MH+,100％)。
实施例21
{(1-氮杂-双环[2.2.2]辛-3-基)-乙酰基}-氨基甲酸mutilin14-酯
通过在8M盐酸中回流5小时水解(1-氮杂-双环[2.2.2]辛-3-基)-乙酸乙酯(欧洲专利363085,1988年10月)。用生成的(1-氮杂-双环[2.2.2]辛-3-基)-乙酸盐酸盐制备标题化合物，为固体(总收率9％)：δ(CDCl3)尤其3.32(1H,d),5.0-5.4(2H,m),5.61(1H,d),6.40(1H,dd)。
参考实施例
PCT/EP96/05874的实施例87Mutilin14-[N-(1-乙基-哌啶-4-酰基)]-氨基甲酸酯
步骤1.1-乙基-异哌啶甲酸乙酯(isonipecotate)
用乙基碘(6.86g)和碳酸钾粉末(10g)处理在乙醇(35ml)中的异哌啶甲酸乙酯(6.28g)。搅拌该混合物并在回流下加热20小时。使该混合物冷却至室温，过滤除去固体，用乙醇(2×10ml)洗涤。通过减压蒸发从滤液中除去乙醇，使生成的残留物在氯仿(100ml)和水(50ml)间分配。分离有机层，用饱和氯化钠溶液洗涤，干燥(硫酸钠)。通过减压蒸发除去溶剂得到标题化合物，为黄色油状物(6.62g)；MS(EI)m/z185(M+)。
步骤2.1-乙基-异哌啶甲酸盐酸盐
将1-乙基-异哌啶甲酸乙酯(5.5g)溶于水(22ml)/浓盐酸(39ml)中，回流下加热该溶液4小时。通过减压蒸发除去溶剂。使残留物溶于水(30ml)中，通过减压蒸发除去水分。残留物用甲苯(50ml)研磨，通过减压蒸发除去甲苯得到一种固体，真空干燥该固体18小时。如此获得标题化合物，为白色粉末(5.4g)；MS(EI)m/z157(M+)。
步骤3．(3R)-3-去氧代-11-脱氧-3-甲氧基-1-氧代-4-表-mutilin14-[N-(1-乙基-哌啶-4-酰基)]-氨基甲酸酯
将1-乙基-异哌啶甲酸盐酸盐(0.95)悬浮于亚硫酰氯(8ml)中，搅拌该混合物并在回流下加热3小时产生澄清的黄色溶液。通过减压蒸发除去亚硫酰氯，使生成的残留物悬浮于甲苯(5ml)中，通过减压蒸发除去甲苯产生白色固体的1-乙基-异哌啶甲酰氯盐酸盐。将该酰氯悬浮于干燥二氯甲烷(20ml)中，加入氰酸银(1.5g)。搅拌该混合物并在回流下加热1小时。冷却该混合物至室温，加入(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin(1g)和三乙胺(0.5g)。于室温下搅拌该混合物16小时。用乙酸乙酯(50ml)稀释该混合物，过滤除去固体。用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤滤液。干燥(硫酸钠)该溶液，通过减压蒸发除去溶剂得到黄色树胶状物。使该树胶状物经硅胶层析纯化，用1∶3乙酸乙酯/氯仿和1∶9∶90氨溶液(35％)/甲醇/二氯甲烷洗脱，产生标题化合物，为无色树胶状物(134mg)；1H NMR(CDCl3)尤其2.88(2H,q,J 6.5Hz),3.08(3H,m),3.22(3H,s),3.42(1H,m),5.04(1H,d,J17.5Hz),5.33(1H,d,J10.7Hz),5.74(1H,d,J9.9Hz),6.63(1H,dd,J17.5,10.7Hz),7.47(1H,s)。
步骤4．Mutilin14-[N-(1-乙基-哌啶-4-酰基)]-氨基甲酸酯
用浓盐酸(0.7ml)处理在1,4-二噁烷(0.7ml)中的(3R)-3-去氧代-11-脱氧-3-甲氧基-11-氧代-4-表-mutilin14-[N-(1-乙基-哌啶-4-酰基)]-氨基甲酸酯(110mg)并使该溶液保持于室温2.5小。用水(10ml)稀释该溶液，用二氯甲烷(10ml)洗涤。通过小心加入固体碳酸钾碱化水相，用氯仿(3×10ml)提取生成的混合物(pH10)。干燥(硫酸钠)有机提取物，通过减压蒸发除去溶剂得到标题化合物，为白色固体(80mg)；1H NMR(CDCl3)尤其1.12(3H,t,J7.1Hz),2.48(2H,q,J7.1HZ),2.97(3H,m),3.37(1H,dd,J10.3,6.6HZ),5.24(1H,d,J17.5HZ),5.37(1H,d,J11Hz),5.70(1H,d,J8.4Hz),6.50(1H,dd,J17.5 11Hz),7.35(1H,s)；MS(EI)m/z502(M+)。
PCT/EP96/05874的实施例161。Mutilin14-[N-(N-甲基-3-哌啶甲酰基)氨基甲酸酯]
步骤1．(3R)-3-脱氧-11-脱氧-3-甲氧基-11-氧代-4-环-mutilin14-[N-(N-甲基-3-哌啶甲酰基)氨基甲酸酯]
使(±)N-甲基-3-哌啶甲酸乙酯(5.0g)溶于5M盐酸(100ml)中并于室温下搅拌16小时。然后减压蒸发溶液，使残留物从甲苯(x2)中再蒸发。研磨得到(±)-N-甲基-3-哌啶甲酸的盐酸盐，为白色固体(3.91g)。
使(±)-N-甲基-3-哌啶甲酸的盐酸盐(1.0g)悬浮于二氯甲烷(25ml)中，与草酰氯(0.58ml)和DMF(1滴)一起于室温下搅拌2小时。然后蒸发溶剂得到N-甲基-3-哌啶甲酰氯的盐酸盐，为淡黄色固体。
使以上的酰氯(0.596g)悬浮于干燥二氯甲烷中，与(3R)-3-去氧代-1l-脱氧-3-甲氧基-11-氧代-4-表-mutilin(0.334g)、氰酸银(0.450g)和三乙胺(0.276ml)一起于室温下搅拌4小时。然后通过硅藻土过滤该悬浮液，用乙酸乙酯稀释，用水和饱和氯化钠溶液洗涤。干燥(硫酸镁)有机溶液，过滤和蒸发得到粗产物。经硅胶柱层析纯化，用在二氯甲烷中的0-5％9∶1甲醇/35％氨溶液梯度洗脱，产生标题化合物，为非对映的混合物(无色油状，0.290g)；1HNMR(CDCl3)0.85和0.88(2xd，均3H,J6.9Hz),1.00(3H,d,J6.4Hz),1.05-1.85(m),1.20(3H,s),1.25(3H,s),1.9-2.40(6H,m),2.32(3H,2xs),2.48(1H,m),2.69(1H，宽res.),2.80-2.98(3H，宽q),3.22(3H,s),3.40-3.53(1H,m),4.98(1H,d,J17.6Hz),5.29(1H,d,J10.7Hz),5.62-5.72(1H,2xd,J9.9Hz)和6.78-6.91(1H,m)；MS(EI)m/z503。
步骤2．Mutilin14-[N-(N-甲基-3-哌啶甲酰基)氨基甲酸酯]
于室温下，将在1,4-二噁烷(3.0ml)中的来自步骤1的产物(0.250g)与浓盐酸(2.0ml)一起搅拌4小时。然后用乙酸乙酯稀释该溶液，用饱和碳酸氢钠溶液中和。用饱和氯化钠溶液洗涤有机溶液，经硫酸镁干燥并蒸发得到粗品产物。经硅胶层析纯化，用0-5％9∶1甲醇/35％氨液的二氯甲烷溶液递度洗脱，分离出为非对映的混合物的标题化合物，为白色泡沫状物(0.205g)；1H NMR(CDCl3)0.78(3H,2xd,J6.7Hz),0.89(3H,d,J7.0Hz),1.19(3H,s),1.35-2.40(m),1.47(3H,s),2.30(3H,3xs),2.63-2.90(2H，宽峰res),3.35(1H，宽峰res),5.22(1H,d,J17.4Hz),5.39(1H,dd,J1.4,11.0Hz),5.60-5.72(1H,2xd,J8.5Hz)和6.63(1H,dd,J11.0,17.4Hz)；MS(EI)m/z488。

Claims (9)

1．式(3)的化合物或其药学上可接受的盐或衍生物：其中：R1为乙烯基或乙基，和R2为基团R3、R4CH2-或R5R6C=CH-，其中每个R3和R4均为氮杂双环系统或R5和R6与它们所连接的碳原子一起形成氮杂双环系统。
2．权利要求1的化合物，其中每个氮杂双环系统选自氮杂双环[2.2.2]辛基、氮杂双环[2.2.1]庚基、氮杂双环[3.2.1]辛基、氮杂双环[4.4.0]癸基、喹宁环基、氮杂双环[3.2.1]辛烯基和氮杂双环[3.3.1]壬-5-基。
3．权利要求1或2的化合物，基本如以上任何一个实施例中所述。
4．制备上述权利要求中任一项的化合物的方法，该方法包括使式(4)化合物，其中X为氢或羟基保护基团，或式(5)化合物，与式R3CONCO、R4CH2CONCO或R5R6C=CHCONCO的酰基异氰酸酯反应。
5．权利要求4的方法，该方法包括在氰酸银和碱的存在下，使式(4)化合物与式R3COCl,R4CH2COCl或R5R6C=CHCOCl的化合物反应，其中R3-R6中的每一个适宜时均受到保护，其后按照任何所需的顺序进行以下的一个或多个步骤：·使基团X去保护产生11位的羟基，·使保护基团R3-R6去保护，·使R3-R6中的一个基团转化为R3-R6中的另一个基团，和·使12位的乙烯基氢化形成乙基。
6．权利要求4的方法，该方法包括在氰酸银和碱存在下，使式(5)化合物与式R3COCl,R4CH2COCl或R5R6C=CHCOCl的化合物反应，其中R3-R6中的每一个适宜时均受到保护，其后按照任何所需的顺序进行以下的一个或多个步骤：·用酸处理该产物获得式(3)化合物，·使保护基团R3-R6去保护，·使R3-R6中的一个基团转化为R3-R6中的另一个基团，和·使12位的乙烯基氢化形成乙基。
7．含有权利要求1、2或3的化合物与药学上可接受的载体或赋形剂的药用组合物。
8．治疗动物，尤其是人类和家畜中微生物感染的方法，该方法包括给予需要此治疗的患者抗微生物有效量的权利要求1、2或3的化合物或权利要求7的组合物。
9．权利要求1、2或3的化合物在制备用于治疗微生物感染的药物组合物中的用途。
CN97198347A 1996-08-02 1997-07-29 抗菌用的氮杂双环氨甲酰氧基mutili n衍生物 Pending CN1231665A (zh)

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