CN1361790A - 胺修饰的假单孢菌素化合物 - Google Patents
胺修饰的假单孢菌素化合物 Download PDFInfo
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- CN1361790A CN1361790A CN00810326A CN00810326A CN1361790A CN 1361790 A CN1361790 A CN 1361790A CN 00810326 A CN00810326 A CN 00810326A CN 00810326 A CN00810326 A CN 00810326A CN 1361790 A CN1361790 A CN 1361790A
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- alkyl
- hydrogen
- pseudomycin
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- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
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Abstract
本发明描述了结构(I)所代表的胺修饰的假单孢菌素化合物,其中R1是酰基键合基团。所述胺修饰的假单孢菌素衍生物可用作抗真菌剂或用于设计抗真菌剂。
Description
发明领域
本发明涉及假单孢菌素(pseudomycin)化合物,特别是胺修饰的假单孢菌素化合物。
发明背景
假单孢菌素是从丁香假单胞菌(Pseudomonas syringae,与植物有关的细菌)的液体培养物中分离出的天然产物,并且已表明有抗真菌活性(参见Harrison,L.等人,“假单孢菌素,一族得自丁香假单胞菌的具有广谱抗真菌活性的新肽”J.Gen.Microbiology,137(12),2857-65(1991)以及美国专利5,576,298和5,837,685)。与以前描述过的得自丁香假单胞菌的抗霉菌剂(例如丁香霉素、丁香毒素和丁香抑制素)不同,假单孢菌素A-C含有羟基天冬氨酸、天冬氨酸、丝氨酸、脱氢氨基丁酸、赖氨酸和二氨基丁酸。
假单胞菌素A、A’、B、B’、C、C’的肽部分相应于具有末端羧基的L-Ser-D-Dab-L-Asp-L-Lys-L-Dab-L-aThr-Z-Dhb-L-Asp(3-OH)-L-Thr(4-Cl),该羧基在N-末端Ser的OH上将大环闭合。类似物的区别在于N-酰基侧链,即假单孢菌素A被3,4-二羟基十四烷酰基N-酰化,假单孢菌素A’被3,4-二羟基十五烷酰基N-酰化,假单孢菌素B被3-羟基十四烷酰基N-酰化,假单孢菌素B’被3-羟基十二烷酰基N-酰化,假单孢菌素C被3,4-二羟基十六烷酰基N-酰化,假单孢菌素C’被3-羟基十六烷酰基N-酰化(参见Ballio,A.,等人,“得自丁香假单胞菌的生物活性脂缩肽:假单孢菌素,”FEBS Letters,355(1),96-100,(1994)和Coiro,V.M.,等人,“使用得自NMR数据的几何位距和分子动力学通过计算机模拟确定的丁香假单胞菌MSU16H植物毒性脂缩肽假单孢菌素A的溶液构象,”Eur.J.Biochem.,257(2),449-456(1998))。
已知假单孢菌素具有一些不利的生物作用。例如,当静脉内施用假单孢菌素时,已观察到了其破坏静脉的内皮、破坏组织、炎症、和对宿主组织的局部毒性。因为假单孢菌素具有得以证实的抗真菌活性和相当多未研究的化学特性,所以需要研究这类化合物以找到可用作具有较少不利副作用的抗真菌剂的其它潜在化合物。
发明概述
Ra和Ra′独立地为氢或甲基,或者Ra或Ra′为烷基氨基、与Rb或Rb′一起形成6-元环烷基环、6-元芳环或双键,或者与Rc一起形成6-元芳环;
Rb和Rb′独立地为氢、卤素、或甲基,或者Rb或Rb′是氨基、烷基氨基、α-乙酰乙酸酯、甲氧基、或羟基;
Rc是氢、羟基、C1-C4烷氧基、羟基(C1-C4)烷氧基,或者与Re一起形成6-元芳环或C5-C6环烷基环;
Re是氢,或者与Rf一起形成6-元芳环、C5-C14烷氧基取代的6-元芳环、或C5-C14烷基取代的6-元芳环,且
Rg是氢、或C1-C13烷基,且
Rh是C1-C15烷基、C4-C15烷氧基、(C1-C10烷基)苯基、-(CH2)n-芳基、-(CH2)n-(C5-C6环烷基),其中n=1或2;或者R是其中
Ri是氢、卤素、或C5-C8烷氧基,且
Rj是C5-C14烷氧基或C5-C14烷基,且p=0、1或2;R是其中
Rk是C5-C14烷氧基;或者R是-(CH2)-NRm-(C13-C18烷基),其中Rm是H、-CH3或-C(O)CH3;R1独立地为氢、甲酰基、酰基烷基(例如-C(O)CH3、-C(O)CH2CH3、-C(O)CH(CH3)2、和-C(O)C(CH3)3)、酰基烷基氨基(例如-C(O)CH(NH2)CH3)、酰基氮杂烷基(例如-C(O)NHCH3和-C(O)NHCH(CH3)2)、酰氧基烯烃(例如-C(O)OCH2CH=CH2)、酰氧基芳基(例如-C(O)OC6H5)、或酰基亚甲基氨基甲酸酯(例如下示化合物1(a))
R1a是C1-C10烷基、C1-C10烯基、苄基、或芳基,且R1b是氢或甲基,条件是:至少有一个R1不是氢;R2和R3独立地为-OR2a、或-N(R2b)(R2c),其中
R2a和R2b独立地为氢、C1-C10烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等)、C3-C6环烷基(例如环丙基、环丁基、环戊基、环戊基亚甲基、甲基环戊基、环己基等)、羟基(C1-C10)烷基、烷氧基(C1-C10)烷基(例如甲氧基乙基)、或C2-C10烯基、氨基(C1-C10)烷基、一-或二烷基氨基(C1-C10)烷基、芳基(C1-C10)烷基(例如苄基)、杂芳基(C1-C10)烷基(例如3-吡啶基甲基、4-吡啶基甲基)、或环杂烷基(C1-C10)烷基(例如N-四氢-1,4-噁嗪基乙基和N-哌嗪基乙基),或者
R2b是氨基酸烷基酯的羧酸烷基酯残基(例如-CH2CO2CH3、-CH(CO2CH3)CH(CH3)2、-CH(CO2CH3)CH(苯基)、-CH(CO2CH3)CH2OH、-CH(CO2CH3)CH2(对羟基苯基)、-CH(CO2CH3)CH2SH、-CH(CO2CH3)CH2(CH2)3NH2、-CH(CO2CH3)CH2(4-或5-咪唑)、-CH(CO2CH3)CH2CO2CH3、-CH(CO2CH3)CH2CO2NH2等),且
R2c是氢或C1-C6烷基。
在另一个本发明实施方案中,提供了药物制剂,其中包含上述假单孢菌素化合物和可药用载体。
在另一个本发明实施方案中,提供了在动物中治疗抗真菌感染的方法,包括给所述动物施用上述假单孢菌素化合物。
定义
除非另有说明,本文所用术语“烷基”是指含有1-30个碳原子的通式CnH2n+1烃基。烷基可以是直链烷基(例如甲基、乙基、丙基、丁基等)、支链烷基(例如异丙基、异丁基、叔丁基、新戊基等)、环状烷基(例如环丙基、环丁基、环戊基、甲基环戊基、环己基等)、或多环烷基(例如二环[2.2.1]庚烷、螺[2.2]戊烷等)。这些烷基可以被取代或未取代。类似地,烷氧基、烷酰基或烷酸酯的烷基部分具有与上述相同的定义。
术语“烯基”是指含有至少一个碳碳双键的无环烃。烯基可以呈直链、支链、环状、或多环。烯基可以被取代或未取代。烯氧基、烯酰基或烯酸酯的烯基部分具有与上述相同的定义。
术语“芳基”是指具有单环(例如苯基)或稠合环系(例如萘、蒽、菲等)的芳族基团。芳基可以被取代或未取代。
在有机化学领域内,特别是在有机生物化学领域内,众所周知有效取代的化合物是可耐受或甚至有用的。在本发明中,例如,术语烷基包括作为标准烷基的取代基例如甲基、乙基、丙基、己基、异辛基、十二烷基、十八烷基等。术语“基团”特定涉及并包括烷基上的本领域常用取代基,例如羟基、卤素、烷氧基、羰基、酮基、酯、氨基甲酸酯等,并包括未取代的烷基。然而,本领域技术人员通常知道,应当选择取代基以不给化合物的药理特征带来不利影响或者不有害地干扰药物的应用。对于任意上文定义的基团,合适的取代基包括烷基、烯基、炔基、芳基、卤素、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、一-和二烷基氨基、季铵盐、氨基烷氧基、羟基烷基氨基、氨基烷硫基、氨基甲酰基、羰基、羧基、羟乙酰基、甘氨酰基、肼基、脒基、和它们的组合。
术语“动物”是指人、宠物(例如狗、猫和马)、食物供应动物(例如牛、猪、绵羊和家禽)、动物园动物、海洋动物、鸟类以及其它类似种属动物。
发明详述
本申请人已经发现,通过修饰连接在假单孢菌素天然产物或半合成衍生物中的赖氨酸或2,4-二氨基丁酸肽单元上的侧链氨基,可提供体外实验表明可有效地抗白色念珠菌(C.albican)、新型隐球酵母(C.neoformans)和/或烟曲霉(A.fumigatus)新化合物。使用含有合适的离去基团的酰化剂将氨基修饰,这样可与假单孢菌素侧链的氨基形成酰胺、氨基甲酸酯、脲或酰亚胺键接。合适的离去基团是本领域技术人员众所周知的,并包括基团例如对硝基苯氧基和N-氧基琥珀酰亚胺。
可使用本领域技术人员众所周知的常规化学方法合成酰胺链接。合适的酰化剂包括用于制备其中R1=酰基烷基的假单孢菌素化合物所需的羧酸衍生物或者其中R1=酰基烷基胺的假单孢菌素化合物的氨基酸。酰化剂一般是通过用离去基团(例如N-氧基琥珀酰亚胺)替代羧酸的-OH而形成的。当使用氨基酸酰化剂时,在缩合之前使用本领域技术人员已知的任何常规氨基保护基(例如苄氧基羰基、对硝基苄氧基羰基、对溴苄氧基羰基、对甲氧基苄氧基羰基、对甲氧基苯基偶氮基苄氧基羰基、对苯基偶氮基苄氧基羰基、叔丁氧基羰基或环戊氧基羰基)将氨基保护。形成酰胺键后,使用标准氢化方法(例如在氢气氛下使用Pd/C)除去氨基保护基。参见下文中更详细地描述由氨基酸形成假单孢菌素酰胺衍生物的实施例。
如上所述,假单孢菌素是从丁香假单胞菌分离出的天然产物,并且其特征在于,它是含有被内酯键闭合的环肽部分,并包含特殊氨基酸例如4-氯苏氨酸(ClThr)、3-羟基天冬氨酸(HOAsp)、2,3-去氢-2-氨基丁酸(Dhb)、和2,4-二氨基丁酸(Dab)的脂缩肽。生长不同丁香假单胞菌的菌株以制备不同假单孢菌素类似物(A、A’、B、B’、C、和C’)的方法描述在Hilton等人于2000年4月14日提交的名称为“由丁香假单胞菌制备假单孢菌素”的第PCT/US00/08728号PCT专利申请、Kulanthaivel等人于2000年4月14日提交的名称为“假单孢菌素天然产物”的第PCT/US00/08727号PCT专利申请、以及美国专利5,576,298和5,837,685中,这4篇专利文献都引入本发明以作参考。
产生一种或多种假单孢菌素的分离出的丁香假单胞菌菌株是本领域内已知的。下述文献中描述了野生型菌株MSU 174和通过转座子诱变生成的该菌株的突变型MSU 16H:美国专利5,576,298和5,837,685;Harrison,等人,“假单孢菌素,一族得自丁香假单胞菌的具有广谱抗真菌活性的新肽”J.Gen.Microbiology,137,2857-2865(1991);和Lamb等人,“转座子诱变和荧光假单胞菌标记:抗真菌生成是控制Dutchelm疾病所必需的,”Proc.Natl.Acad.Sci.USA,84,6447-6451(1987)。
适于制备一种或多种假单孢菌素的丁香假单胞菌菌株可从环境来源包括植物(例如大麦作物、柑橘作物、和丁香植物)以及来源例如土壤、水、空气和灰尘中分离得到。优选的菌株是从植物分离的。从环境来源中分离的丁香假单胞菌菌株可称为野生型。本文所用的“野生型”是指天然存在于标准丁香假单胞菌群体中的显性遗传型(例如天然发现并且不是由实验室操作制得的丁香假单胞菌菌株或分离物)。象大多数生物体一样,所用的假单孢菌素制备培养物(丁香假单胞菌菌株例如MSU 174、MSU 16H、MSU 206、25-B1、7H9-1)的特征可发生变异。因此,可通过本领域已知方法获得这些菌株的后代(例如重组物、突变体和变种)。
丁香假单胞菌MSU 16H可以以保藏号ATCC 67028从AmericanType Culture Collection,Parklawn Drive,Rockville,MD,USA公众获得。丁香假单胞菌菌株25-B1、7H9-1、和67 H1是在2000年3月23日由American Type Culture Collection保藏的,并且指定了下述保藏号:
25-B1 保藏号PTA-1622
7H9-1 保藏号PTA-1623
67 H1 保藏号PTA-1621
丁香假单胞菌的突变体菌株也适于制备一种或多种假单孢菌素。本文所用的“突变体”是指在菌株表型中的突然可遗传的变化,这种变化可以是自发的,或者是通过已知的诱变剂例如放射(例如紫外放射或X-射线)、化学诱变剂(例如甲磺酸乙酯(EMS)、二环氧辛烷、N-甲基-N-硝基-N’-亚硝基鸟嘌呤(NTG)、和亚硝酸)、位点特异性诱变和转座子介导的诱变引起的。制备假单孢菌素的丁香假单胞菌突变体可通过用一定量能有效地产生下述突变体的诱变剂处理细菌而制得:即能过度地产生一种或多种假单孢菌素、相对于其它假单孢菌素过量产生一种假单孢菌素(例如假单孢菌素B)、或在有利的生长条件下产生一种或多种假单孢菌素。虽然所用的诱变剂的类型和量可以改变,但是优选的方法是将NTG系列稀释至1-100μg/ml的水平。优选的突变体是能过度产生假单孢菌素B、并在基本培养基中生长的突变体。
可选择环境分离物、突变体菌株、和其它所需的丁香假单胞菌菌株以获得所需的生长习性、生长培养基营养来源、碳来源、生长条件、氨基酸需求等的特征。优选地,选择制备假单孢菌素的丁香假单胞菌菌株以使其能在基本培养基例如N21培养基中生长和/或能产生水平大于约10μg/ml的一种或多种假单孢菌素。优选的菌株表现出这样的特征:当在包含3种或3种以下的氨基酸和任选的脂质、马铃薯产品或其组合的培养基中生长时,能产生一种或多种假单孢菌素。
重组菌株可通过使用本领域已知的方法转化丁香假单胞菌菌株而制得。通过使用重组DNA技术,可将丁香假单胞菌菌株转化以表达出除了这些菌株产生的抗生素以外的多种不同基因产物。例如,可修饰菌株以引入多个内源性假单孢菌素生物合成基因的拷贝,来获得更高的假单孢菌素产率。
为了从野生型丁香假单胞菌或丁香假单胞菌的突变体菌株中产生一种或多种假单孢菌素,在搅拌下将生物体在包含有效量的3种或3种以下氨基酸,优选谷氨酸、甘氨酸、组氨酸、或其组合的含水营养培养基中培养。或者,将甘氨酸与一种或多种马铃薯产品和脂质混合。在能有效地使丁香假单胞菌生长并且生成所需假单孢菌素的条件下进行培养。有效条件包括约22℃-约27℃的温度、和约36小时-约96小时的培养时间。在丁香假单胞菌的培养期间控制培养基中氧的浓度对于生成假单孢菌素是有利的。优选地,将氧水平保持在约5-50%饱和、更优选约30%饱和。用空气、纯氧、或包含氧的气体混合物吹扫可控制培养基中氧的浓度。
在丁香假单胞菌的培养期间控制培养基的pH也是有利的。假单孢菌素在碱性pH下不稳定,并且如果培养基的pH在大于约6的水平保持约12小时,则可发生显著的降解。优选将培养基的pH维持在6-4。当在分批培养物中生长时,丁香假单胞菌可产生一种或多种假单孢菌素。然而,分批补入或半连续补入葡萄糖和任选补入酸或碱(例如氢氧化铵)以控制pH能提高产量。通过使用其中自动补入葡萄糖和氢氧化铵的连续培养方法可进一步提高假单孢菌素产量。
选择丁香假单胞菌可影响所生成的假单孢菌素的量和分布。例如,菌株MSU 16H和67 H1分别主要生成假单孢菌素A,但是也生成假单孢菌素B和C,三者的比例通常为4∶2∶1。通常情况下,菌株67 H1生成的假单孢菌素的水平比菌株MSU 16H生成的水平高约3-5倍。与菌株MSU 16H和67 H1相比,菌株25-B1生成更多的假单孢菌素B和更少的假单孢菌素C。菌株7H9-1的与众不同之处在于,其主要生成假单孢菌素B,并且假单孢菌素B的产量大于其它菌株。例如,该菌株生成的假单孢菌素B的量可比假单孢菌素A或C大至少10倍。
或者,可由N-酰基半合成化合物形成本发明胺修饰的假单孢菌素化合物。半合成假单孢菌素化合物可通过交换L-丝氨酸单元上的N-酰基来合成。各种N-酰基衍生物的实例描述在Belvo,等人于同一日期提交的名称为“假单孢菌素N-酰基侧链类似物”的第___号PCT专利申请中,该专利申请引入本发明以作参考。通常使用4个合成步骤来从天然假单孢菌素化合物制备半合成化合物:(1)选择性地保护氨基;(2)用化学或酶法将N-酰基侧链脱酰;(3)用不同侧链再酰化;和(4)将氨基脱保护。
可使用本领域技术人员已知的保护氨基的标准方法将在2、4和5位上的侧链氨基保护。所用的氨基保护基的特定种类不是至关重要的,只要是在随后于中间体分子的其它位点上进行反应的条件下其保持稳定,并且可在适当位点选择性地除去、同时又不断裂包括其它氨基保护基在内的分子的其余部分即可。合适的氨基保护基包括苄氧基羰基、对硝基苄氧基羰基、对溴苄氧基羰基、对甲氧基苄氧基羰基、对甲氧基苯基偶氮基苄氧基羰基、对苯基偶氮基苄氧基羰基、叔丁氧基羰基、环戊氧基羰基、和邻苯二甲酰亚氨基。优选的氨基保护基是叔丁氧基羰基(t-Boc)、烯丙氧基羰基、邻苯二甲酰亚氨基、和苄氧基羰基(Cbz或CBZ)。合适的保护基的其它实例描述在T.W.Greene,“有机合成中的保护基(Protective Groups in OrganicSynthesis),”John Wiley and Sons,New York,N.Y.,(2nd ed.,1991),第7章中。
具有γ或δ羟基化侧链的N-酰基(例如3,4-二羟基十四烷酸酯)的脱酰可通过在含水溶剂中用酸处理氨基保护的假单孢菌素化合物来实现。合适的酸包括乙酸和三氟乙酸。优选的酸是三氟乙酸。如果使用三氟乙酸,该反应可在室温或接近室温的温度下完成。然而,当使用乙酸时,该反应通常在约40℃进行。合适的含水溶剂系统包括乙腈、水、及其混合物。有机溶剂能促进该反应;然而,加入有机溶剂可导致生成其它副产物。
在侧链上没有δ或γ羟基的假单孢菌素化合物(例如假单孢菌素B和C’)可用酶方法脱酰。合适的脱酰酶包括多粘菌素酰基转移酶(164-16081 Fatty Acylase(粗产物)或161-16091 Fatty Acylase(纯),得自Wako Pure Chemical Industries,Ltd.)、或ECB脱酰酶。酶法脱酰可使用本领域技术人员众所周知的标准脱酰方法来完成。例如,使用多粘菌素酰基转移酶的一般方法可参见Yasuda,N.,等人,Agric.Biol.Chem.,53,3245(1989)和Kimura,Y.,等人,Agric.Biol.Chem.,53,497(1989)。
在羰基活化剂存在下,使用所需酰基的相应酸将脱酰产物(也称为假单孢菌素核)再酰化。“羰基活化基团”是指能促进在该羰基上进行的亲核加成反应的取代基。合适的活化取代基是对羰基有净吸电子作用的基团。这样的基团包括但不限于烷氧基、芳氧基、含氮芳香杂环、或氨基(例如羟苯并三唑、咪唑基、硝基苯氧基、五氯苯氧基、N-羟琥珀酰亚胺、N,N’-二环己基异脲-O-基、和N-氧基-N-甲氧基氨基);乙酸酯;甲酸酯;磺酸酯(例如甲磺酸酯、乙磺酸酯、苯磺酸酯、和对甲苯磺酸酯);卤化物(例如氯化物、溴化物、和碘化物)。
在酰化方法中可使用多种不同的酸。合适的酸包括含有一个或多个侧链的芳基、烷基、氨基(包括伯胺、仲胺和叔胺)、羟基、烷氧基、和酰氨基的脂族酸;在脂族链内含有氮或氧的脂族酸;被烷基、羟基、烷氧基和/或烷基氨基取代的芳族酸;和被烷基、羟基、烷氧基和/或烷基氨基取代的杂芳族酸。
或者,可使用固相合成,其中是使用羟基苯并三唑-树脂(HOBt-树脂)作为酰化反应的偶联剂。
一旦氨基被去酰化和再酰化(上述),即可以通过在氢化催化剂(例如10%Pd/C)存在下氢化来除去氨基保护基(在2、4和5位)。当氨基保护基是烯丙氧基羰基时,该保护基可通过使用氢化三丁基锡和二氯化三苯基膦钯来除去。该特定保护/脱保护方案的优点在于降低了假单孢菌素结构的Z-Dhb单元的乙烯基被氢化的可能性。
然后如下所述进行N-酰基半合成化合物的胺修饰:将至少一个连接在N-酰基修饰的半合成假单孢菌素化合物的赖氨酸或2,4-二氨基丁酸肽单元上的侧链氨基酰化以形成所需的酰胺、脲、氨基甲酸酯或酰亚胺键。
可通过将假单孢菌素环的天冬氨酸和/或羟基天冬氨酸单元的侧链羧酸基团酰胺化或酯化来进一步修饰该胺修饰的假单孢菌素化合物。各种酸修饰的衍生物的实例描述在Chen等人于同一日期提交的名称为“假单孢菌素酰胺&酯类似物”的第___号PCT专利申请中,该专利申请引入本发明以作参考。酸修饰的衍生物可这样形成:将任意上述胺修饰的假单孢菌素化合物与适当醇或胺缩合以分别生成酯和酰胺。
可使用本领域技术人员众所周知的标准酯化方法形成酯基。在酸性条件下酯化一般包括在质子酸(例如HCl、TFA、对甲苯磺酸等)存在下将假单孢菌素化合物溶于或悬浮在适当醇中。在碱性条件下,一般是在弱碱(例如碳酸氢钠和碳酸钾)存在下将假单孢菌素化合物与适当的烷基卤反应。
酰氨基的形成可使用本领域技术人员众所周知的标准酰胺化方法来实现。然而,要选择偶联剂来选择性地修饰酸基团。例如,使用苯并三唑-1-基氧基三吡咯烷基鏻六氟磷酸盐(PyBOP)作为偶联剂使得能够同时分离出纯的在残基8的单酰胺和(在有些情况下)纯的二酰胺。然而,使用邻苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓四氟硼酸盐(TBTU)作为偶联剂有利于形成在残基3的单酰胺。
可分离出假单孢菌素酰胺衍生物,并以其自身的形式或其可药用盐或溶剂化物的形式使用。术语“可药用盐”是指用无机酸和有机酸形成的无毒酸加成盐。合适的盐衍生物包括卤化物、硫氰酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、芳基磺酸盐、烷基磺酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、链烷酸盐、环烷基链烷酸盐、芳基链烷酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、乳酸盐、马来酸盐、烟酸盐、草酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、新戊酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、三氟乙酸盐等。
术语“溶剂化物”是指包含一个或多个溶质分子(即胺修饰的假单孢菌素化合物)和一个或多个可药用溶剂分子例如水、乙醇等分子的聚集体。当溶剂是水时,该聚集体称为水合物。溶剂化物一般是通过在加热条件下将化合物溶于适当溶剂中,并缓慢地冷却以生成无定形或结晶溶剂化物形式。
可通过本领域技术人员已知的任何不同方法检测、测定、分离和/或纯化各种假单孢菌素化合物、半合成假单孢菌素衍生物和混合物。例如,肉汤或分离物或纯化的组合物中假单孢菌素或胺修饰的假单孢菌素活性水平可通过抗真菌例如假丝酵母属的抗真菌作用来确定,并且可通过高效液相色谱法分离和纯化。
一般是将活性组分(即本发明假单孢菌素化合物)配制成药物剂型以提供易于控制的药物剂量和给患者、医师或兽医提供雅致且易于使用的产品。制剂可含有0.1%-99.9%重量的活性组分、更通常约10%-约30%重量的活性组分。
本文所用的术语“单位剂量”或“剂量单位”是指含有经计算能产生所需疗效的预定量活性组分的物理不连续单位。当剂量单位经口服或非胃肠道途径施用时,其一般以片剂、胶囊、丸剂、粉末小包、局部施用的组合物、栓剂、糯米纸囊剂、在安瓿或多剂量容器中的测定量单位等形式提供。或者,剂量单位可以以干燥或液体气雾剂的形式施用,这样的气雾剂可吸入或喷雾给药。
给药剂量可根据动物的身体状况、动物症状的严重程度、施用药物的方法以及动物种类而变。对于给定动物,具体剂量通常由负责医生或兽医决定。
合适的载体、稀释剂和赋形剂是本领域技术人员众所周知的,并且包括材料例如碳水化合物、蜡、水溶性和/或可膨胀的聚合物、亲水或疏水性物质、明胶、油、溶剂、水等。所用的特定载体、稀释剂或赋形剂将取决于施用活性组分的手段和目的。制剂还可以包含润湿剂、润滑剂、表面活性剂、缓冲剂、增强剂、增量剂、稳定剂、乳化剂、悬浮剂、防腐剂、甜料、香料、矫味剂和它们的组合。
可使用不同方法施用药物组合物。合适的方法包括局部施用(例如膏剂或喷雾剂)、口服、注射和吸入。特定治疗方法将取决于所治疗的感染类型。
在非胃肠道静脉内施用中,通常是将制剂稀释或重新配制(如果是冷冻干燥的话)并且如果需要的话在给药前进一步稀释。对于冷冻干燥产品的重新配制规程的实例是将10ml注射用水(WFI)加到小瓶中,并轻微搅拌以溶解。重新配制时间一般少于1分钟。然后在给药前将所得溶液在输注溶液例如5%葡萄糖水溶液(D5W)中进一步稀释。
假单胞菌素化合物已显示具有抗真菌活性,例如包括抑制以下的传染性真菌的生长:假丝酵母属各种(即白色念珠菌(C.albicans)、近平滑假丝酵母(C.parapsilosis)、克鲁丝氏假丝酵母(C.krusei)、光滑假丝酵母(C.glabrata)、热带假丝酵母(C.tropicalis)或葡萄牙假丝酵母(C.lusitania));球拟酵母属各种(即光滑球拟酵母(T.glabrata));曲霉属各种(即烟曲霉(A.fumigatus));组织胞浆菌属各种(即荚膜组织胞浆菌(H.capsulatum));隐球酵母属各种(即新型隐球酵母(C.neoformans));芽生菌属各种(即皮炎芽生菌(B.dermatitidis));镰孢属各种;发癣菌属各种、Pseudallescheria boydii、粗球孢子菌、申克氏孢子丝菌等。
因此,本发明化合物和制剂可用于制备用于抗全身真菌感染或真菌皮肤感染的药物。所以本发明提供了用于抑制真菌活性的方法,包括将本发明胺修饰的假单孢菌素化合物与真菌接触。优选的方法包括抑制白色念珠菌或烟曲霉的活性。术语“接触”包括本发明化合物与真菌的结合或接合或表面的接触或相互接触。该术语不意味着对本发明方法进一步限制,例如通过抑制机理限制。所述方法定义为包括通过本发明化合物的作用或其固有的抗真菌特性抑制真菌活性。
本发明还提供了治疗真菌感染的方法,包括给需要这种治疗的宿主动物施用有效量的本发明药物制剂。优选的方法包括治疗白色念珠菌或烟曲霉感染。术语“有效量”是指能抑制真菌活性的活性化合物的量。给药剂量将随诸如感染的性质和严重程度、宿主的年龄和一般健康状况、宿主对抗真菌剂的耐受性和宿主种类这样的因素而变。特定给药方案同样可根据这些因素而变。药物可以以单次日剂量或者在一天期间多次剂量的方式施用。给药治疗可持续约2-3天到约2-3周或更长。日剂量(以单剂量或均分剂量施用)一般含有约0.01mg/kg-100mg/kg体重活性化合物的剂量水平。优选的日剂量一般为约0.1mg/kg-60mg/kg、更优选为约2.5mg/kg-40mg/kg。宿主可以是任何动物,包括人、宠物(例如狗、猫和马)、食物供应动物(例如牛、猪、羊和家禽)、动物园动物、海洋动物、鸟类以及其它类似种属动物。
实施例
在整个实施例中使用下述缩写以代表各物质:
ACN-乙腈
TFA-三氟乙酸
DMF-二甲基甲酰胺
EDCI-1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺盐酸盐
BOC=叔丁氧基羰基,(CH3)3C-O-C(O)-
CBZ=苄氧基羰基,C6H5CH2-O-C(O)-
PyBOP=苯并三唑-1-基氧基三吡咯烷基鏻六氟磷酸盐
TBTU=邻苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓四氟硼酸盐
DIEA=N,N-二异丙基乙基胺
使用下述结构II来描述在实施例1-7中观测的产物。抗真菌活性的检测和定量测定:
通过使用标准琼脂稀释测试或圆盘扩散测试获得化合物的最小抑制浓度(MIC)来在体外测定抗真菌活性。在抗真菌活性测试中使用的典型真菌是白色念珠菌。当测试样本(50μl)对接种到琼脂板上的白色念珠菌的抑制引起10-12mm直径区域带时认为有显著抗真菌活性。尾静脉毒性:
在第0、24、48和72小时,用0.1ml测试化合物(20mg/kg)经由侧尾静脉静脉内(IV)给药来治疗小鼠。每组包括2只小鼠。将化合物配制在0.5%葡萄糖和无菌注射用水中。首次治疗后监测小鼠7天,并密切观察包括红斑、肿胀、变色、坏死、尾损失在内的刺激征状以及表明毒性的其它副作用征状。
在该实验中使用的小鼠是远系繁殖的,雄性ICR小鼠的平均体重为18-20g(得自Harlan Sprangue Dawley,Indianapolis,IN)。
制备化合物2a-1:
化合物2a-1是使用在Admiak,R.W.,等人,Tetrahedron Lett.,No.22,1935-1936(1997)中描述的方法制备的。
在每一下述实施例中,使用特定假单孢菌素化合物作为原料;然而,本领域技术人员应当认识到,使用相同方法,用具有不同N-酰基的假单孢菌素化合物作为原料可合成其它N-酰基衍生物。
实施例1
实施例1举例说明了假单孢菌素B的酰基烷基胺衍生物(n=10,R2和R3=-OH)的形成。合成化合物1-1:
R1′、R1″和R1=-C(O)CH2NH2
1-1
向50ml圆底烧瓶中加入10ml无水DMF、假单孢菌素B(250.6mg,0.181mmol)和酰化剂1a-1(343.0mg,1.12mmol)。将该反应在室温下搅拌24小时。然后在真空下除去溶剂,用ACN处理残余物,并通过制备HPLC纯化,冷冻干燥后获得了172.5mg三取代的保护的胺。将134.4mg三取代的保护的胺溶于10ml MeOH/1.5ml冰醋酸溶液中。使用129.6mg 10%Pd/C标准氢化20分钟,通过过滤除去催化剂,并通过制备HPLC纯化,冷冻干燥后,获得了74.8mg化合物1-1。MS(离子喷雾)C57H97ClN15O22(M+H)+的计算值为1378.65,实测值为1378.9。
实施例2
实施例2举例说明了假单孢菌素B的酰氧基芳基衍生物(n=10,R2和R3=-OH)的合成。合成化合物2-1:
除了用化合物2a-1作为酰化剂外,使用与实施例1所述相同的方法合成化合物2-1。
或者,可如下所述合成化合物2-1:在0-4℃,将氯甲酸苯酯(389mg,2.48mmol)加到HOBT(37.5mg,2.48mmol)和DIEA(322.8mg,399ml,2.48mmol)的溶液中。将该混合物用100ml DMF稀释,并加入假单孢菌素B(1.0g,0.83mmol)。将该混合物搅拌过夜。然后在真空下除去溶剂,并通过HPLC纯化残余物,获得了430mg(产率为33%)化合物2-1。
实施例3
除了用乙酸酐作为酰化剂外,使用与实施例1所述相同的方法合成化合物3-1。合成化合物3-2:
除了用三甲基乙酸酐作为酰化剂外,使用与实施例1所述相同的方法合成化合物3-2。
实施例4
除了用异氰酸甲酯作为酰化剂外,使用与实施例1所述相同的方法合成化合物4-1。
实施例5
除了用甲酸4-硝基苯基酯作为酰化剂外,使用与实施例1所述相同的方法合成化合物5-1。
实施例6
实施例6举例说明了假单孢菌素B的酰氧基烯基衍生物(n=10,R2和R3=-OH)的合成。
除了用二碳酸二烯丙基酯(diallylpyrocarbonate)作为酰化剂外,使用与实施例1所述相同的方法合成化合物6-1。产率为77%
Claims (6)
Ra和Ra′独立地为氢或甲基,或者Ra或Ra′为烷基氨基、与Rb或Rb′一起形成6-元环烷基环、6-元芳环或双键,或者与Rc一起形成6-元芳环;
Rb和Rb′独立地为氢、卤素、或甲基,或者Rb或Rb′是氨基、烷基氨基、α-乙酰乙酸酯、甲氧基、或羟基;
Rc是氢、羟基、C1-C4烷氧基、羟基(C1-C4)烷氧基,或者与Re一起形成6-元芳环或C5-C6环烷基环;
Re是氢,或者与Rf一起形成6-元芳环、C5-C14烷氧基取代的6-元芳环、或C5-C14烷基取代的6-元芳环,且
Rg是氢、或C1-C13烷基,且
Rh是C1-C15烷基、C4-C15烷氧基、(C1-C10烷基)苯基、-(CH2)n-芳基、或-(CH2)n-(C5-C6环烷基),其中n=1或2;或者R是其中
Ri是氢、卤素、或C5-C8烷氧基,且
Rk是C5-C14烷氧基;或者R是-(CH2)-NRm-(C13-C18烷基),其中Rm是H、-CH3或-C(O)CH3;R1独立地为氢、甲酰基、酰基烷基、酰基烷基胺、酰基氮杂烷基、酰氧基烯烃、酰氧基芳基、或酰基亚甲基氨基甲酸酯,条件是:至少有一个R1不是氢;R2和R3独立地为-OR2a、或-N(R2b)(R2c),其中
R2a和R2b独立地为氢、C1-C10烷基、C3-C6环烷基、羟基(C1-C10)烷基、烷氧基烷基、或C2-C10烯基、氨基(C1-C10)烷基、一-或二烷基氨基(C1-C10)烷基、芳基(C1-C10)烷基、杂芳基(C1-C10)烷基、环杂烷基(C1-C10)烷基,或者
R2b是氨基酸烷基酯的羧酸烷基酯残基,且
R2c是氢或C1-C6烷基。
2.权利要求1的胺修饰的假单孢菌素化合物,其中所述酰基亚甲基氨基甲酸酯由结构1(a)代表其中R1a是C1-C10烷基、C1-C10烯基、苄基、或芳基,且R1b是氢或甲基。
3.权利要求1的胺修饰的假单孢菌素化合物,其中所述氨基酸烷基酯的羧酸烷基酯残基由-CH2CO2CH3、-CH(CO2CH3)CH(CH3)2、-CH(CO2CH3)CH(苯基)、-CH(CO2CH3)CH2OH、-CH(CO2CH3)CH2(对羟基苯基)、-CH(CO2CH3)CH2SH、-CH(CO2CH3)CH2(CH2)3NH2、-CH(CO2CH3)CH2(4-咪唑)、-CH(CO2CH3)CH2(5-咪唑)、-CH(CO2CH3)CH2CO2CH3、或-CH(CO2CH3)CH2CO2NH2代表。
4.前述权利要求任一项的化合物在制备用于抗全身真菌感染或真菌皮肤感染的药物中的应用。
5.一种药物制剂,它包含权利要求1的胺修饰的假单孢菌素化合物和可药用载体。
6.治疗动物中抗真菌感染的方法,该方法包括给所述动物施用权利要求1的胺修饰的假单孢菌素化合物。
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