CN1115145C - 药理活性β－氨基酸的可耐受性的改进 - Google Patents
药理活性β－氨基酸的可耐受性的改进 Download PDFInfo
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- CN1115145C CN1115145C CN96108880A CN96108880A CN1115145C CN 1115145 C CN1115145 C CN 1115145C CN 96108880 A CN96108880 A CN 96108880A CN 96108880 A CN96108880 A CN 96108880A CN 1115145 C CN1115145 C CN 1115145C
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- amino acids
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- pentamethylene
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Abstract
本发明涉及α-氨基酸和/或其衍生物和环戊烷-β-氨基酸和/或其衍生物的混合物、上述的α-氨基酸和环戊烷-β-氨基酸的二肽和上述的混合物和二肽的混合物；与纯的环戊烷-β-氨基酸相比较，它们在温血动物中具有改善的可耐受性。
Description
由EP-A-571870、DOS4302155、JP02174753 A2和J.Antibiot.(1991)，44(5)，546-9中得知环戊烷-β-氨基酸和环戊烯-β-氨基酸。这样的β-氨基酸具有抗微生物、特别是抗霉菌作用。然而它们有副作用。
现已令人惊异地发现：α-氨基酸和/或其衍生物与环戊烷-β-氨基酸和/或其衍生物的混合物、来自上述α-氨基酸和上述环戊烷-β-氨基酸的二肽和上述混合物与上述二肽的混合物没有不合需要的副作用或者副作用较小，因此在温血动物中的可耐受性得到改善。
因此，本发明涉及包含一种或多种α-氨基酸和/或其衍生物和一种或多种环戊烷-β-氨基酸和/或其衍生物的混合物。术语“衍生物”包括衍生自相应的氨基酸并具有类似的作用的那些化合物，特别是相应的盐。
适宜于本发明混合物的α-氨基酸优选通式(Ia)α-氨基酸
式中R3代表具有3-8个碳原子的环烷基，或代表具有6-10个碳原子的芳基或氢或代表具有至多8个碳原子的直链或支链烷基，其中所述烷基可任选地被氰基、甲硫基、羟基、巯基、胍基或者式-NR7R8或R9-OC-基团取代，式中R7和R8相互独立地代表氢、具有至多8个碳原子的直链或支链烷
基或苯基， 和R9代表羟基、苄氧基、具有至多6个碳原子的烷氧基或上述的基团
-NR7R8，或者所述烷基可任选地被具有3-8个碳原子的环烷基或具有6-10个碳原的芳基取代，所述环烷基或芳基又被羟基、卤素、硝基、具有至多8个碳原子的烷氧基或基团-NR7R8取代，式中R7和R8的定义同上，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表羟基、具有6-10个碳原子的芳氧基、具有至多6个碳原子的烷氧基或基团-NR7R8，式中R7和R8的定义同上。
特别适宜的α-氨基酸是通式(Ia)α-氨基酸：式中R3代表具有至多6个碳原子的直链或支链烷基，该烷基可任选地被羟基或苯基取代，所述苯基又可被羟基取代，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表羟基。
更适宜的α-氨基酸是通式(Ia)α-氨基酸：
式中R3代表甲基，或代表式-CH(CH3)CH2CH3基团，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表羟基。
可提及的这样的α-氨基酸的实例是：(S)-异亮氨酸，(S)-丙氨酸和(S)-脯氨酸。
适宜于本发明混合物的环戊烷β-氨基酸优选通式(Ib)环戊烷β-氨基酸式中R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，或代表具有至多8个碳原子的直链或支链烷基或苯基，和Y代表氢、具有至多8个碳原子的直链或支链烷基或芳基。
特别适宜的环戊烷β-氨基酸是通式(Ib)环戊烷β-氨基酸：式中R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，或代表具有至多6个碳原子的直链或支链烷基或苯基和Y代表氢。
更适宜的环戊烷β-氨基酸是通式(Ib)环戊烷β-氨基酸：
式中R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，和Y代表氢。
可提及的这样的环戊烷-β-氨基酸的实例是：2-氨基-4-亚甲基环戊烷-1-羧酸和1，2-顺-氨基环戊烷-1-羧酸。
优选的本发明混合物包含通式(Ia)α-氨基酸和通式(Ib)环戊烷-β-氨基酸，所述通式(Ia)如下：
式中R3代表具有3-8个碳原子的环烷基，或代表具有6-10个碳原子的芳基或氢，或代表具有至多8个碳原子的直链或支链烷基，其中所述烷基可任选地被氰基、甲硫基、羟基、巯基、胍基或者式-NR7R8或R9-OC-基团取代，式中R7和R8相互独立地代表氢、具有至多8个碳原子的直链或支链烷
基或苯基，和R9代表羟基、苄氧基、具有至多6个碳原子的烷氧基或上述的基
团-NR7R8，或者所述烷基可任选地被具有3-8个碳原子的环烷基或具有6-10个碳原子的芳基取代，所述环烷基或芳基又被羟基、卤素、硝基、具有至多8个碳原子的烷氧基或基团-NR7R8取代，式中R7和R8的定义同上，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表羟基、具有6-10个碳原子的芳氧基、具有至多6个碳原子的烷氧基或基团-NR7R8，式中R7和R8的定义同上；所述通式(Ib)如下：式中R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，或代表具有至多8个碳原子的直链或支链烷基或苯基，和Y代表氢、具有至多8个碳原子的直链或支链烷基或芳基。
特别优选的本发明混合物包含通式(Ia)α-氨基酸和通式(Ib)环戊烷-β-氨基酸，所述通式(Ia)如下：
式中R3代表具有至多6个碳原子的直链或支链烷基，该烷基可任选地被羟基或苯基取代，所述苯基又可被羟基取代，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表羟基；所述通式(Ib)如下：式中R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，或代表具有至多6个碳原子的直链或支链烷基或苯基，和Y代表氢。
更优选的混合物包含通式(Ia)α-氨基酸和通式(Ib)环戊烷-β-氨基酸，所述通式(Ia)如下：
式中R3代表甲基，或代表式-CH(CH3)CH2CH3基团，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表羟基；所述通式(Ib)如下：式中R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，和Y代表氢。
可提及的这样的本发明混合物的实例是：(S)-异亮氨酸与2-氨基-4-亚甲基环戊烷-1-羧酸的混合物，(S)-丙氨酸与2-氨基-4-亚甲基环戊烷-1-羧酸的混合物或(S)-脯氨酸与1，2-顺-氨基环戊烷-1-羧酸的混合物。
在混合物的情况下，α-氨基酸和/或其衍生物与环戊烷-β-氨基酸和/或其衍生物的摩尔混合比在1∶99至99∶1范围内，优选在1∶10至10∶1范围内，特别优选在1∶5至5∶1范围内，更优选在1∶3至3∶1范围内。
本发明混合物通常通过将优选的细粉状各组分混合来获得。
本发明还涉及含有α-氨基酸或其衍生物和环戊烷-β-氨基酸或其衍生物的二肽。
适宜于本发明二肽的α-氨基酸优选在上面描述本发明混合物时所述的通式(Ia)α-氨基酸，其中在式(Ia)中的X代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分。
适宜于本发明二肽的环戊烷-β-氨基酸优选在上面描述本发明混合物时所述的通式(Ib)环戊烷-β-氨基酸，其中在式(Ib)中的Y代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分。
本发明涉及含有通式(Ia)α-氨基酸和通式(Ib)环戊烷-β-氨基酸的优选的二肽，所述通式(Ia)如下：
式中R3代表具有3-8个碳原子的环烷基，或代表具有6-10个碳原子的芳基或氢，或代表具有至多8个碳原子的直链或支链烷基，其中所述烷基可任选地被氰基、甲硫基、羟基、巯基、胍基或者式-NR7R8或R9-OC-基团取代，式中R7和R8相互独立地代表氢、具有至多8个碳原子的直链或支链烷
基或苯基，和R9代表羟基、苄氧基、具有至多6个碳原子的烷氧基或上述的基团
-NR7R8，或者所述烷基可任选地被具有3-8个碳原子的环烷基或具有6-10个碳原子的芳基取代，所述环烷基或芳基又被羟基、卤素、硝基、具有至多8个碳原子的烷氧基或基团-NR7R8取代，式中R7和R8的定义同上，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分；所述通式(Ib)如下：式中R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，或代表具有至多8个碳原子的直链或支链烷基或苯基，和Y代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分。
特别优选的二肽含有取代基如下定义的通式(Ia)α-氨基酸和通式(Ib)环戊烷-β-氨基酸；在所述通式(Ia)中R3代表具有至多6个碳原子的直链或支链烷基，该烷基可任选地被羟基或苯基取代，所述苯基又可被羟基取代，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分；在所述通式(Ib)中：R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，或代表具有至多6个碳原子的直链或支链烷基或苯基，和Y代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分。
更优选的二肽含有取代基如下定义的通式(Ia)α-氨基酸和通式(Ib)环戊烷-β-氨基酸；在所述通式(Ia)式中：R3代表甲基，或代表式-CH(CH3)CH2CH3基团，R4和R5代表氢，或者R3和R4一起形成式-(CH2)3-基团，R5代表氢，和X代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分；在所述通式(Ib)中：R1和R2代表氢，或者R1和R2一起形成式＝CH2基团，R6代表氢，和Y代表所述α-氨基酸与所述环戊烷-β-氨基酸结合的共价键部分。
下列二肽是特别优选的：1，2-顺-2-(S)-异亮氨酰基氨基-4-亚甲基环戊烷-1-羧酸和1，2-顺-2-(S)-丙氨酰基氨基-4-亚甲基环戊烷-1-羧酸。
本发明混合物和二肽可以包含基本纯的立体异构体或立体异构体的混合物。
上面所述的α-氨基酸、环戊烷-β-氨基酸和二肽还可以以其盐的形式存在。这里一般可以提及与有机或无机碱或酸形成的盐和内盐。
可使用的酸最好包括氢卤酸例如氢氯酸和氢溴酸，特别优选氢氯酸，此外还包括磷酸，硝酸，硫酸，单和双官能羧酸和羟基羧酸，例如乙酸、马来酸、丙二酸、草酸、葡糖酸、琥珀酸、富马酸、酒石酸、柠檬酸、水杨酸、山梨酸和乳酸，和磺酸，例如对甲苯磺酸盐、1，5-萘二磺酸或樟脑磺酸。
生理上可接受的盐还可以是具有游离羧基的本发明化合物的金属盐或铵盐。特别优选的盐是例如钠盐、钾盐、镁盐或钙盐，还有衍生自氨或有机胺的铵盐，所述有机胺有例如乙胺、二或三乙胺、二或三乙醇胺、二环己胺、二甲氨基乙醇、精氨酸、赖氨酸、乙二胺或苯乙胺。
本发明混合物和二肽可以立体异构形式例如以镜像(对映体)或非镜像(非对映体)形式存在，或者可以非对映体混合物或者纯的顺式或反式异构体形式存在。本发明既涉及对映体、外消旋体和非对映体混合物，也涉及纯的异构体。外消旋体象非对映体一样，可用已知方法分离成立体异构单一的成分。分离成立体异构单一的化合物这一操作可利用非对映的酯和酰胺来进行，或在光活性相上进行。还可以利用非对映盐的结晶。
在本发明中，由基团(R5R4-N-CHR3-CO-)定义的氨基酸基团是L-氨基酸。
本发明还涉及本发明二肽的制备方法。
这些二肽可用包括下述步骤的方法来制备：首先使通式(II)化合物通过与通式(III)保护的氨基酸在溶剂中并在碱存在下反应，而将其转化成通式(IV)化合物，所述通式(II)、(III)和(IV)如下：式中R1和R2的定义同上，式中R3和R4的定义同上，R10代表氨基保护基团，和R11代表在肽化学中常规的活性保护基团，优选羟基琥珀酰亚胺酯基团，或者R10和R11一起代表基团 
式中R1、R2、R3、R4和R10的定义同上；和，最后，将氨基保护基团(R10)裂解，若合适，将立体异构体分离，而且，在酯(在式(Ib)中R6≠H)的情况下，将该酸用常规方法与相应的醇反应。
若合适，将二肽用常规方法转化成盐。
按照本发明的方法可用下面的反应式举例说明：
在本发明中的氨基保护基团(R10)是在肽化学中所用的常规的氨基保护基团。
所述氨基保护基团最好包括苄氧基羰基，3，4-二甲氧基苄氧基羰基，3，5-二甲氧基苄氧基羰基，2，4-二甲氧基苄氧基羰基，4-甲氧基苄氧基羰基，4-硝基苄氧基羰基，2-硝基苄氧基羰基，2-硝基-4，5-二甲氧基苄氧基羰基，甲氧基羰基，乙氧基羰基，叔丁氧基羰基，烯丙氧基羰基，乙烯氧基羰基，3，4，5-三甲氧基苄氧基羰基，邻苯二甲酰基，2，2，2-三氯乙氧基羰基，2，2，2-三氯叔丁氧基羰基，氧基羰基，4-硝基苯氧基羰基，芴基-9-甲氧基羰基(Fmoc)，甲酰基，乙酰基，丙酰基，新戊酰基，2-氯乙酰基，2-溴乙酰基，2，2，2-三氟乙酰基，2，2，2-三氯乙酰基，苯甲酰基，苄基，4-氯苯甲酰基，4-溴苯甲酰基，4-硝基苯甲酰基，苯二酰亚氨基，异戊酰基或苄氧基亚甲基，4-硝基苄基，2，4-二硝基苄基，4-硝基苯基或2-硝基苯基亚磺酰基。Fmoc基团是特别优选的。适宜的活性羧基基团(R11)一般是与下述物质的加合物：碳化二亚胺，例如N，N’-二乙基、N，N’-二异丙基或N，N’-二环己基碳化二亚胺，N-(3-二甲氨基异丙基)-N’-乙基碳化二亚胺盐酸盐或N-环己基-N’-(2-吗啉代乙基)碳化二亚胺metho-对甲苯磺酸盐，或羰基化合物，例如碳酰二咪唑，或1，2-噁唑鎓化合物，例如2-乙基-5-苯基-1，2-噁唑鎓-3-磺酸盐或2-叔丁基-5-甲基异噁唑鎓高氯酸盐，或酰氨基化合物，例如2-乙氧基-1-乙氧基羰基-1，2-二氢喹啉，或丙烷膦酸酐，或氯甲酸异丁酯，或六氟磷酸苯并三唑基氧基-三(二甲氨基)鏻，1-羟基苯并三唑或羟基琥珀酰亚胺酯。此外，α-氨基酸成分还可以以Leuch酐(式(III)中的R10和R11一起代表基团
).
优选羟基琥珀酰亚胺酯。
适宜的溶剂是在反应条件下不变化的常规有机溶剂，最好包括醚类，例如乙醚、二氧六环、四氢呋喃、乙二醇二甲醚或二甲氧基乙烷，或烃类，例如苯、甲苯、二甲苯、己烷或环己烷，或石油馏份，或二甲基甲酰胺。也可以使用所述溶剂的混合物。四氢呋喃、乙醚和二甲氧基乙烷是优选的。还可以使用水或上述溶剂与水的混合物。
此外，例如还可以使用碱金属碳酸盐，例如碳酸钠或碳酸钾，或者碳酸氢钠或碳酸氢钾，或有机碱，例如三烷基胺类例如三乙胺、乙基二异丙基胺、N-乙基吗啉、N-甲基哌啶或N-甲基吗啉。N-甲基吗啉是优选的。
助剂和碱的用量为每摩尔通式(III)化合物1.0-3.0mol，优选1.0-1.2mol。
反应一般在常压下在0℃至100℃、最好是0℃至30℃的温度范围内进行。
反应可在常压或者加压或减压(例如0.5-5巴)下进行，最好是在常压下进行。
氨基保护基团一般用本身已知的方法在酸性或碱性条件下将其裂解掉，或者通过催化氢化例如用Pd/C在有机溶剂例如醚类如四氢呋喃或二氧六环或醇类如甲醇、乙醇或丙醇中还原将其裂解掉。
所述氢化反应一般在0℃至80℃的温度范围内进行，最好是在0℃至40℃的温度范围内进行。
所述氢化反应一般在2-8巴、最好是3-5巴的加压下进行。
碱例如哌啶、吗啉、二环己胺、对二甲氨基吡啶、二异丙基乙基胺或哌嗪适宜于裂解氨基保护基团(R10＝Fmoc)。哌啶是优选的。
助剂和碱的用量为每摩尔通式(IV)化合物1.0-3.0mol，优选1.0-1.2mol。
反应一般在常压下在0℃至100℃、最好是0℃至30℃的温度范围内进行。
反应可在常压或者加压或减压(例如0.5-5巴)下进行，最好是在常压下进行。
通式(II)化合物是已知的。
通式(III)化合物在某些情况下是已知的，或者可用常规方法来制备。
上述制备方法仅用于举例说明。X和Y一起代表共价键部分的本发明通式(Ia)和(Ib)化合物的制备不限于这些方法，该制备可以以相同的方式使用这些方法的任何的变更形式。
本发明的出发点是澄清下列机理：
所述通式(II)环戊烷-β-氨基酸由利用氨基酸转运体的各种各样的酵母富集。β-氨基酸的转运可被脂肪族氨基酸、特别是L-异亮氨酸、L-亮氨酸、L-丙氨酸、L-蛋氨酸和L-缬氨酸抑制。β-氨基酸抑制蛋白质生物合成。该抑制作用可被脂肪族氨基酸、特别是L-异亮氨酸或L-丙氨酸之一所拮抗。同时给与以混合物形式和/或共价键部分结合的二肽形式的β-氨基酸和所述具有拮抗作用的天然存在的氨基酸，能降低对温血动物的副作用，同时在体内保持抗霉菌作用。
因此，本发明化合物或混合物显示出意想不到的、有价值的药理作用谱。
按照本发明的通式(Ia)和(Ib)化合物或混合物及其酸加成盐在体内具有抗微生物、特别是强力的抗霉菌作用。同时，由于其毒性较低，因此它们具有较好的可耐受性。它们具有广谱抗霉菌作用，能抗皮真菌例如须发癣菌和犬小孢子菌，酵母菌例如白色念珠菌、Candidaglabrata和絮状表皮癣菌以及霉菌例如黑曲霉和烟曲霉。所列的微生物仅用于举例说明，按照本发明的通式(Ia)和(Ib)化合物或混合物及其酸加成盐所能杀灭的病菌不限于这些。因此，它们适于治疗皮真菌和系统性霉菌病。体内活性试验
用系统性小鼠念珠菌病作为体内抗霉菌作用的试验模型：通过给每只动物由尾静脉注射3×105CFU的白色念珠菌使体重为20g的雄性CFW1小鼠感染。
所有未治疗的对照动物在感染(p.i.)后一星期内均死于泛化念珠菌病，并伴随肾脏中肉芽肿形成。为试验活性，将溶于浓度为0.2％的葡萄糖琼脂水溶液中的制剂通过胃管经口给与感染的动物，每天两次。
日剂量为2×25mg/kg体重(BW)和2×50mg/kg体重，治疗持续时间为5天。
每天记录治疗动物的存活率直至p.i.后第10天。在此时，未治疗的动物中无一存活。
就所述制剂而言，在每种情况下，每个剂量使用10只动物和对照组。
结果见表A。
表A：
| 实施例序号 | 剂量[mg/kg，2×每日] | 给药方式 | 动物存活数 |
| 对照 | 0/10 | ||
| 2 | 25 | p.o. | 6/10 |
| 2 | 50 | p.o. | 10/10 |
或者，体内活性还可以用Wistar大鼠进行试验。这就需要较低的日剂量(基于mg/kg BW)，以达到相似的治疗效果。在这种情况下，试验如下进行：
将出生8星期且体重为200g的特种无抗原雄性Wistar大鼠通过侧尾静脉用在0.5ml PBS中的5×106CFU的白色念珠菌感染。这导致在8天之内的死亡率为100％。注射后一天，动物眼睛的近中角部位已经出血；除肾脏外，其它组织器官例如脑、心、肝、脾、视网膜和肺均受到感染。自感染的当天，在每种情况下按1ml葡萄糖(5％)-琼脂(0.2％)溶液经口给与所述物质，每天两次，持续5天。
本发明二肽或混合物较佳的可耐受性按下述方法进行试验：
用相应的物质每天饲喂Wistar大鼠，并记录重量曲线。给与β-氨基酸本身或等摩尔量的相应的混合物或含有α-氨基酸的二肽。处理5天后，大鼠仍然保持原来的体重，或者在给与本发明二肽或混合物的情况下，体重略有增加，而用β-氨基酸处理的动物体重减轻大约5-10％。
本发明还涉及用于治疗疾病、特别是真菌病的含有本发明混合物和/或二肽的药物和无毒、惰性的药用赋形剂与助剂。
若合适，所述活性化合物(一种或多种)还可以是在一种或多种上述的赋形剂中的微囊化形式。
可提及的优选的药用制剂有片剂，包衣片剂，胶囊剂，丸剂，颗粒剂，栓剂，溶液剂，混悬剂和乳剂，糊剂，软膏剂，凝胶剂，乳膏剂，洗剂，粉剂和喷雾剂。
治疗活性化合物或混合物在上述药用制剂中存在的浓度应为该混合物总重量的大约0.1-99.5％(重量)，优选大约0.5-95％(重量)。
除按照本发明的化合物外，上述药用制剂还可以含有其它的药用活性化合物。
所述活性化合物或药物可经口和胃肠外途径使用。
业已证明，为获得期望的效果，一般在人用和兽用药方面，每24小时使用本发明的化合物(一种或多种)的总量大约为0.5-500mg/kg体重有利，优选5-100mg/kg体重，若合适，以若干单剂量形式使用。单剂量最好含约1-80、特别是3-30mg/kg体重本发明的化合物(一种或多种)。
按照本发明的药物通常为用于在治疗疾病中同时、分开或交错使用的组合物制剂。
用于同时使用的组合物制剂是本发明混合物的各组分以物理混合物形式存在的产品，尤其包括片剂、包衣片剂、胶囊剂、丸剂、栓剂和安瓿剂。还可以设想用这样的混合物作为溶液、混悬液或乳液。本发明混合物的单独组分一方面包括α-氨基酸和/或其衍生物(以下称α-氨基酸组分)，另一方面包括环戊烷-β-氨基酸和/或其衍生物(以下称β-氨基酸组分)。
用于分开使用的组合物制剂是本发明混合物的各组分以在空间上彼此分离的形式存在的产品。能满足这种要求的的片剂、包衣片剂、胶囊剂、丸剂和栓剂特别适于此目的。
还可以设想用于交错使用的组合物制剂。这种制剂允许间隔一定的时间给与本发明混合物的各组分。在交错使用这样的组合物制剂的情况下，设想相对于β-氨基组分的使用，以特殊的方式使用α-氨基酸组分。α-氨基酸组分可以与β-氨基酸组分相同的使用方式来使用，或者以另一种常规的使用方式来使用，例如β-氨基酸组分可静脉给与，而α-氨基酸组分可经口或静脉给与。
在交错使用的情况下，还可以按上述的根据时间使用β-氨基酸组分的关系使用部分剂量的α-氨基酸组分，并将剩余剂量的α-氨基酸在给与该β-氨基酸组分后的一定的时间内一次或分多次给与。
起始化合物 实施例I(-)-1，2-顺-2-((N-(9-芴基甲氧基羰基)-(S)-异亮氨酰基)氨基-4-亚甲基环戊烷-1-羧酸
将(N-(9-芴基甲氧基羰基)-(S)-异亮氨酸羟基琥珀酰亚胺酯(89.2g，0.198mol)在600ml二甲氧基乙烷中的溶液于室温滴加至(-)-1，2-顺-2-氨基-4-亚甲基环戊烷-1-羧酸(35.1g，0.198mol)和碳酸氢钠(33.36g，0.397mol)在480ml水中的溶液中。将混合物于室温搅拌过夜。然后将反应混合物用稀盐酸酸化至pH2，并用乙醚萃取几次。将合并的有机相用硫酸钠干燥并真空浓缩。产物在乙醚/石油醚中结晶析出。产量：70g(收率74％)熔点：207℃[α]D 20＝-24.1(c＝1.15，在氯仿中)1H-NMR(250MHz，CDCl3)：δ＝0.88(cm，6H)；0.98-1.15，1.40-1.51，1.52-1.80(3m，3H)；2.40-2.84(M，4H)；3.12(cm，1H)；4.10-4.48(m，4H)；4.61(cm，1H)；4.90(cm，2H)；5.84(d，1H)；7.20-7.80(3m，9H).C28H32N2O5(476.6)实施例II1，2-顺-2-((N-(9-芴基甲氧基羰基)-(S)-丙氨酰基)氨基-4-亚甲基环戊烷-1-羧酸
按类似于实施例I的方法，由(-)-1，2-顺-2-氨基-4-亚甲基环戊烷-1-羧酸(2.27g，16.1mmol)、(N-(9-芴基甲氧基羰基)-(S)-丙氨酸羟基琥珀酰亚胺酯(7.0g，17.2mmol)和碳酸氢钠(1.49g，17.7mmol)制得标题化合物。将粗产物用柱层析纯化(甲苯/乙醇，9∶1)。产量：5.7g(收率81％)1H-NMR(500MHz，CD3OD)：δ＝1.30(d，3H)，2.43-2.79(m，4H)，3.10(cm，1H)，4.12，4.21，4.34，4.50(4cm，5H)，4.91(br.s.，2H)，7.30，7.39，7.66，7.79(4cm，8H).C25H26N2O5(434.5)制备实施例 实施例1(+)-1，2-顺-2-(S)-异亮氨酰基氨基-4-亚甲基环戊烷-1-羧酸
将得自实施例1的化合物(24.0g，0.050mol)在哌啶(200ml)中的溶液于室温搅拌1小时。当反应结束时，真空蒸除哌啶。将残余物溶于水中。用乙醚萃取几次后，将水相真空浓缩，加入甲苯。产物由异丙醇/乙醚中结晶析出。产量：8.5g(收率76％)熔点：198℃[α]D 20＝+23.9(c＝1.08，在水中)1H-NMR(250MHz，D2O)：δ＝0.70-0.88(m，6H)；0.91-1.18，1.19-1.43，1.53-1.72(3m，3H)；2.23-2.67(m，4H)；2.88(cm，1H)；3.28(d，1H)；4.30(cm，1H)；4.85(cm，2H).C13H22N2O3(254.3)实施例2(+)-1，2-顺-2-(S)-丙氨酰基氨基-4-亚甲基环戊烷-1-羧酸
按类似于实施例1的方法，由实施例II化合物(5.7g，13.1mmol)制得标题化合物。将粗产物用硅胶柱层析纯化(二氯甲烷/甲醇，1∶1)，并用甲醇/异丙醇/丙酮结晶。产量：0.7g(收率25％)熔点：218℃[α]D 20＝+5.4(c＝0.64，在甲醇中)1H-NMR(500MHz，D2O)：δ＝1.49(d，3H)，2.45(cm，1H)，2.55-2.75(m，3H)，3.04(cm，1H)，4.01(q，1H)，4.49(cm，1H)，5.00(br，d，2H)C10H16N2O3(212.3)实施例3(1R，2S)-2-氨基-4-亚甲基环戊烷-1-羧酸×(S)-异亮氨酸
将(-)-(1R，2S)-2-氨基-4-亚甲基环戊烷-1-羧酸(25.0g，177mmol)和(S)-异亮氨酸(23.2g，177mmol)溶于沸腾的水(250ml)和乙醇(100ml)中。将溶液放冷至室温，并于60℃真空蒸除溶剂。产量：48.2g(收率100％)熔点：230℃(分解)1H-NMR(D2O)：δ＝0.95(t，3H)，1.00(d，3H)，1.18-1.35，1.40-1.56(2m，2H)，1.99(cm，1H)，2.52-2.67，2.73-2.88(2m，4H)；3.09(cm，1H)，3.69(d，1H)，3.88(cm，1H)，5.09(cm，2H).C13H24N2O4(272.3)实施例4
将(-)-(1R，2S)-2-氨基-4-亚甲基环戊烷-1-羧酸(14.1g，100mmol)和(S)-异亮氨酸(26.2g，200mmol)研成细粉，然后以粉末形式混合。实施例5
按类似于实施例4的方法制备(-)-(1R，2S)-2-氨基-4-亚甲基环戊烷-1-羧酸(14.1g，100mmol)和(S)-异亮氨酸(65.5g，500mmol)的混合物。
Claims (4)
1.一种包含α-氨基酸和环戊烷-β-氨基酸，或其盐，以及一种可药用载体的抗菌混合物，所述α-氨基酸和环戊烷-β-氨基酸选自(S)-异亮氨酸与2-氨基-4-亚甲基环戊烷-1-羧酸，(S)-丙氨酸与2-氨基-4-亚甲基环戊烷-1-羧酸和(S)-脯氨酸与1，2-顺-氨基环戊烷-1-羧酸。
2.按照权利要求1的混合物，其中所述α-氨基酸和环戊烷-β-氨基酸分别是(S)-异亮氨酸和2-氨基-4-亚甲基环戊烷-1-羧酸。
3.按照权利要求1或2的混合物在制备用于治疗患者微生物感染的药物中的用途。
4.按照权利要求3的用途，其中所述的微生物感染是真菌病。
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| US8394813B2 (en) | 2000-11-14 | 2013-03-12 | Shire Llc | Active agent delivery systems and methods for protecting and administering active agents |
| US20060014697A1 (en) | 2001-08-22 | 2006-01-19 | Travis Mickle | Pharmaceutical compositions for prevention of overdose or abuse |
| US7169752B2 (en) | 2003-09-30 | 2007-01-30 | New River Pharmaceuticals Inc. | Compounds and compositions for prevention of overdose of oxycodone |
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| DE4302155A1 (de) * | 1993-01-27 | 1994-07-28 | Bayer Ag | Verwendung von Cyclopentan- und -penten-beta-Aminosäuren |
| US5631291A (en) * | 1992-05-29 | 1997-05-20 | Bayer Aktiengesellschaft | Cyclopentane- and -pentene-β-amino acids |
| GB9216441D0 (en) * | 1992-08-03 | 1992-09-16 | Ici Plc | Fungicidal process |
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