CN106187793A - 5‑氨基酮戊酸及其衍生物的盐化合物和应用 - Google Patents
5‑氨基酮戊酸及其衍生物的盐化合物和应用 Download PDFInfo
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- CN106187793A CN106187793A CN201610568868.0A CN201610568868A CN106187793A CN 106187793 A CN106187793 A CN 106187793A CN 201610568868 A CN201610568868 A CN 201610568868A CN 106187793 A CN106187793 A CN 106187793A
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Abstract
本发明涉及5‑氨基酮戊酸及其衍生物与乙酸衍生物所生成的盐化合物,其合成方法,制剂制备和应用。本发明所述的乙酸衍生物具有治疗多种皮肤病和美容的用途,与5‑氨基酮戊酸及其衍生物生成盐用于光动力学疗法,有协同或增效作用,改善理化性质,降低皮肤刺激性。本发明所述的盐化合物可应用于光动力学治疗,诊断和美容。
Description
技术领域:
本发明涉及5-氨基酮戊酸及其衍生物的盐化合物的制备和应用,属于药物制备技术领域。
背景技术
光动力学治疗法(PDT,又称光化学治疗法)是利用光激活光敏性生物分子或光敏剂,产生治疗作用的医学技术。被光激活的光敏性分子或光敏剂可产生活性氧,造成对致病细胞或组织的破坏,达到治疗的目的。光动力学疗法是日益重要的新兴疗法,用途广泛,包括用于治疗和诊断多种癌症和皮肤疾病,还能用于美容等。它的特点为局部性,安全性,高效性和多样性,光动力学疗法将在医疗领域占有不可或缺的重要地位。
在光动力学治疗中,5-氨基酮戊酸(5-ALA)和它的酯类衍生物,如甲酯和己酯,是应用最广泛的光敏剂或光敏剂前体。人体大部份细胞都能吸收5-氨基酮戊酸和它的酯类衍生物,并通过体内血红素生物合成途径将其转变为具有强光敏性的原卟啉IX(PpIX)。癌细胞,癌前病变细胞,及病变细胞组织积累PpIX的浓度比正常细胞高,在氧的存在下,光照或光活化使PpIX激发到高能量的激发态,产生单线态氧和氧自由基,造成对病灶细胞或组织的损伤,导致病变细胞组织的凋亡和坏死。
作为在光动力学疗法中应用最广泛的光敏药物,5-氨基酮戊酸,其甲酯和己酯己应用于临床诊断和治疗癌症,癌前病变和非肿瘤性疾病。例如5-氨基酮戊酸用于治疗日光性角化症和尖锐湿疣,其甲酯在临床上用于治疗日光性角化症和浅表性基底细胞癌等。5-氨基酮戊酸己酯用于膀胱癌手术辅助治疗以及对膀胱癌和宫颈癌检测诊断(Jichlinski等,J Urol,2003,170:226-229)。此外,5-氨基酮戊酸和其甲酯在治疗中度和重度痤疮的临床试验中,已取得了令人满意的疗效。5-氨基酮戊酸和其酯已在临床试验中用于肠镜和胃镜的检测诊断,与常规方法合用能显著提高检测诊断效果。临床和临床前研究还发现,5-氨基酮戊酸和其酯的光动力学疗法具有治疗多种皮肤病的活性,包括治疗细菌(Fotinos等,Antimicrob Agents Chemother,2008,52:1366-1373)和真菌感染(Calzavara-Pinton等,Photochem Photobiol,2012,88:512-522),抗炎症(如光化性唇炎,硬皮病),治疗与病毒和癌症相关的皮肤病。同时还发现,5-氨基酮戊酸类药物可用于美容(Jeffry等,ArchDermatol,2005,141:1247-1252)。
光动力学治疗的疗效取决于光敏剂和光源对病灶组织的渗透能力,而光敏剂渗透活性尤为关键。因此,改进5-氨基酮戊酸类药物对病灶组织的渗透性能进一步提高这类药物的临床疗效和应用范围(Donnelly等,Photochem Photobiol,2014,90:641-647)。
三氯乙酸(TCA)是小分子有机酸,具有极好的皮肤渗透性和化学侵蚀活性,被广泛地应用于治疗多种皮肤病和皮肤美容。三氯乙酸对皮肤有多种作用,可凝固表皮蛋白,破坏和消除受损的皮肤细胞;刺激皮肤表层细胞分裂,促进新细胞的生成,使天然皮肤色素均匀分布;它还具有抗菌和抗炎活性。在临床上的三氯乙酸化学去皮(又称化学剥离)疗法,就是利用其极好的皮肤渗透腐蚀活性。三氯乙酸的皮肤渗透活性和渗透深度,与其浓度相关,不同浓度的三氯乙酸用于治疗不同的皮肤病症。低浓度的三氯乙酸(10-20%)用于浅皮或表皮的去皮治疗,三氯乙酸可渗透和影响到表皮和真皮-表皮的交界处,用于治疗轻度皮肤光老化,黄褐斑,粉刺性痤疮和炎症后红斑。中度渗透的去皮治疗法使用浓度为20-50%的三氯乙酸,三氯乙酸可从真皮渗透进入真皮乳头层,中度渗透用于治疗中度皮肤光老化,日光性角化症和轻度痤疮疤痕(Di Nuzzo等,Photodermatol Photoimmunol Photomed,2015,31:233-238)。高浓度的三氯乙酸(50%或更高)可渗透到真皮网状层,用于治疗外部尖锐湿疣(Yanofsky等,Expert Rev Dermatol,2013,8:321-332)和痤疮疤痕(Abdel等,DermatolSurg,2015,41:1398-404;Agarwal等,Dermatol Surg,2015,41:597-604)。
5-氨基酮戊酸光动力学疗法和三氯乙酸去皮疗法都已广泛用于多种相同的皮肤疾病的治疗,而且常显示出不同的治疗效果。例如,在治疗痤疮时,5-氨基酮戊酸光动力学疗法对丘疹脓疱型痤疮(炎症性)的疗效显著,而对粉刺性痤疮(非炎症性)的治疗效果却不佳(Wan等,Clin Cosm Invest Dermat,2014,7:145-163)。与之相反,三氯乙酸对粉刺性痤疮(非炎症性)的疗效良好,而对丘疹脓疱痤疮(炎症性)的疗效不显著(Meguid等,DermatolSurg,2015,41:1398-1404)。这种差异可从两种疗法的不同机制得到很好的解释。光动疗法能够选择性地破坏皮脂腺体。而三氯乙酸能减少角质细胞的凝聚和堵塞。因此,如将这两种不同机制的疗法有机地结合在一起,取长补短,相互协同,增强疗效,这对治疗多种常见性皮肤病如痤疮和尖锐湿疣等的临床意义和价值是显而易见的。
5-氨基酮戊酸是内源性活性分子,在体外不稳定,临床上均以其盐酸盐的形式来使用。例如,Levulan®(20% 5-氨基酮戊酸盐酸盐,DUSA Pharmaceuticals,Wilmington,美国)用于治疗光化性角化症;艾拉(20% 5-氨基酮戊酸盐酸盐,上海复旦张江生物)用于治疗外部尖锐湿疣;Metvix®(16% 5-氨基酮戊酸甲酯盐酸盐,PhotoCure ASA,Oslo,挪威)用于治疗浅表型基底细胞癌,鱗状细胞癌和光化性角化症;Hexvix®(5-氨基酮戊酸己酯盐酸盐,PhotoCure ASA,Oslo,挪威)用于膀胱癌的检测;Gliolan®(5-氨基酮戊酸盐酸盐,Medac GmbH,Wedel,德国)用于脑外科手术中对恶性脑胶质瘤组织的诊断。亦有临床报道应用5-氨基酮戊酸及其酯的盐酸盐治疗宫颈上皮内瘤样增生,痤疮,鲜红斑病,红斑狼疮,肠镜和胃镜的检测等。
5-氨基酮戊酸盐酸盐有诸多缺陷:对皮肤组织渗透性较差,影响疗效(Szeimies等,Photochem Phorobiol,1994,59:73-76);光照时产生较强的疼痛感;对皮肤有刺激性;盐酸盐有吸湿性,不利于生产和储存;其制剂产品不够稳定,故制剂多需临时配制使用(Gadmar等,J Photochem Photobiol B:Biol,2002,67:187-193)。
因此,有必要开发新的5-氨基酮戊酸类衍生物以克服上述缺陷。新的5-氨基酮戊酸类衍生物,不仅要提高其皮肤渗透活性,同时也需要降低用药引起的疼痛和刺激(Grapengiesse等,Clin Exp Dermatol,2002,27:493-497),优化其物理化学性质如吸湿性和稳定性等。我们的方法是以成盐的形式将三氯乙酸或其衍生物引入到5-氨基酮戊酸及其衍生物(例如酯)的药物中,成为该光敏剂或光敏剂前体药物的一部分。与盐酸盐相比,5-氨基酮戊酸及其衍生物的三氯乙酸盐可减少对皮肤的刺激;三氯乙酸制备的盐具有易于结晶的特性,可使5-氨基酮酸及其衍生物的三氯乙酸盐易于结晶纯化和制备,不易吸潮,有利于质量控制,贮存和提高稳定性。三氯乙酸良好的皮肤渗透性,有利于提高5-氨基酮戊酸及其衍生物的渗透性,产生协同治疗作用,增强临床疗效。
发明内容:
本发明的目的是提供一种对皮肤组织渗透性好,有协同治疗作用,可用于光动力学治疗,诊断和美容,对皮肤无刺激性,利于生产和储存,其制剂产品稳定的5-氨基酮戊酸和其衍生物的盐化合物。
本发明的另一目的是提供5-氨基酮戊酸和其衍生物的盐化合物在治疗身体内表面或外表面癌症,癌前病症,非癌症或异常症状的光动力学疗法的药物或治疗剂中的应用;在制备光动力学疗法的诊断剂中的应用;在制备光动力学疗法的美容剂中的应用。
本发明是这样实现的:5-氨基酮戊酸和其酯类衍生物与乙酸衍生物构成盐化合物,这类乙酸衍生物可以和5-氨基酮戊酸衍生物有协同的治疗作用,例如,三氯乙酸具有治疗皮肤病和美容的作用。除此之外,本发明所述的盐化合物对皮肤刺激性及吸潮性低于其相对应的临床上使用的盐酸盐类化合物。新盐化合物能被细胞吸收并经卟啉生物合成的途径转变成强光敏剂PpIX,可用于光动力学治疗,诊断和美容。
本发明所述的盐化合物由碱基化合物与乙酸衍生物制成,其结构如通式(1)和(2)所示:
NH2CH2COCH2CH2COOR·X-COOH 或 NH3 +CH2COCH2CH2COOR·X-COO- (1)
NH2CH2COCH2CH2CONR1R2·X-COOH 或 NH3 +CH2COCH2CH2CONR1R2·X-COO- (2)
其中R可选自氢,有取代或没有取代的烷基、环烷基、芳基;X分别代表R3YCH、R3(Y)2C或(Y)3C,其中Y选自Cl,Br,I或F;R3可选自氢、有取代或没有取代的烷基、环烷基、或芳基;R1和R2可以相同或不同,可独立或分别选自氢、有取代或没有取代的烷基、环烷基、或芳基。
R、R1和R2可独立或分别选自氢,含有1至20个碳原子的有取代或没有取代的直链烷基、支链烷基、或环烷基;优选为1至10个碳原子(如1至8个碳原子),特别优选的是甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、叔丁基、异戊基、异己基、环丙基、环丁基、环戊基或环己基。其中,R、R1、R2可分别任选有一个或多个相同的或不同的,亲水性或非亲水性取代基。亲水性取代基可选自羟基、硫醇、羧基、氨基甲酰、酯基、氨基、烷胺基、酰胺。非亲水性基团可选自卤素、硝基、氰基和芳基。所述芳基可含有一个或多个取代基,取代基选自一个或多个卤素、羟基、硫醇、氨基、烷氨基、羰基、酯、酰胺、烷基、卤代烷基、烷氧基(如C1-5烷氧基),羟烷基(如C1-5羟烷基)、硝基或氰基。
通式1和2中所述酸X-COOH是乙酸衍生物,其中X代表R3YCH、R3(Y)2C或(Y)3C,Y选自Cl、Br、I或F;R3可选自氢,含有1至20个碳原子的有取代或没有取代的直链烷基、支链烷基、或环烷基;优选为1至10个碳原子(如1至8个碳原子),特别优选的是甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、叔丁基、异戊基、异己基、环丙基、环丁基、环戊基或环己基。其中,R3可以任选地有一个或多个相同的或不同的,亲水性或非亲水性取代基。亲水性取代基选自羟基、硫醇、羧基、氨基甲酰、酯基、氨基、烷氨基、酰胺。非亲水性取代基选自卤素、硝基、氰基和芳基。所述芳基可含有一个或多个取代基,取代基可选自一个或多个卤素、羟基、硫醇、氨基、烷氨基、羰基、酯、酰胺、烷基、卤代烷基、烷氧基(如C1-5烷氧基),羟烷基(例如C1-5羟烷基)、硝基或氰基。
所使用的术语“卤素”,指的是氟、氯、溴或碘。术语“烷基”,除非另有说明,指的是饱和烃或不饱和烃,其目的是覆盖任何长链或短链,直链或支链的烃基。术语“亲水性取代基”表示能够形成氢键的取代基。术语“非亲水性取代基”表示可能或不能够形成氢键的取代基。术语“芳基”指5到7元芳香族含0-4杂原子,杂原子选自氮、氧或硫。
以下是本发明所述5-氨基酮戊酸和其衍生物的新盐化合物中优选的乙酸衍生物:
2-氯乙酸,
2,2,2-三氯乙酸,
以下是本发明优选的新盐化合物:
5-氨基酮戊酸 2-氯乙酸盐,
5-氨基酮戊酸 2,2,2-三氯乙酸盐,
5-氨基酮戊酸甲酯 2-氯乙酸盐,
5-氨基酮戊酸甲酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸乙酯 2-氯乙酸盐,
5-氨基酮戊酸乙酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸丙酯 2-氯乙酸盐,
5-氨基酮戊酸丙酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸丁酯 2-氯乙酸盐,
5-氨基酮戊酸丁酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸戊酯 2-氯乙酸盐,
5-氨基酮戊酸戊酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸己酯 2-氯乙酸盐,
5-氨基酮戊酸己酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸苄酯 2-氯乙酸盐,
5-氨基酮戊酸苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸2-甲基苄酯 2-氯乙酸盐,
5-氨基酮戊酸2-甲基苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-甲基苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-甲基苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-氯苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-氯苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-硝基苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-硝基苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-异丙基苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-异丙基苄酯 2,2,2-三氯乙酸盐,
根据可釆用的起始原料,本发明提供了5-氨基酮戊酸及其酯衍生物的新盐化合物的制备方法。一种方法是以 Cl-NH3 +CH2COCH2CH2COOR 或 Cl-NH3 +CH2COCH2CH2CONR1R2 盐酸盐(或其他盐,如磷酸盐)为起始物,其中R、R1和R2如权利要求1和2所述,先用碱中和,然后加入一种本发明所述的酸而得到目的盐化合物。另一种方法是以带氨基保护基的NH2CH2COCH2CH2COOR 或NH2CH2COCH2CH2CONR1R2 为起始原料,其中R、R1和R2如权利要求1和2所述,在一种本发明所述酸的存在下,除去保护基即得目的化合物,此方法为一步合成法。所用氨基保护基包括但不限于叔丁氧羰基(Boc),苄基(Bn)或苄氧羰基(Cbz)。Boc保护基可在酸性条件下除去,Bn或Cbz保护基可催用化氢解除去,所用的催化剂包括钯或铂类催化剂,亦可釆用Rany镍或其它已报道的催化剂或方法。
另一种制备方法是离子交换树脂法,可使用酸性或碱性离子交换树脂,优选的树脂是碱性离子交换树脂。如使用Amberlyst 26(OH)柱层析方法,5-氨基酮戊酸酯或其衍生物盐酸盐(或磷酸盐)的Cl一离子被0H一离子交换,得到的流出液与一种本发明所述的酸混合而得到相应的盐化合物。另外,亦可将适量的Amberlyst 26(OH)树脂和5-氨基酮戊酸酯或其衍生物的盐酸盐(或磷酸盐)在溶剂中搅拌,滤除树脂后,将滤液和一种本发明所釆用的酸混合,得到目的盐化合物。离子交换树脂法釆用的树脂均有市场供应。
在上述的制备过程中,釆用本领域熟知的操作方法,反应可在-20到100oC条件下进行,可根据所用溶剂和反应完成程度,优化反应条件。反应溶剂可以是本领域熟知的一种或混合溶剂,包括但不限于甲醇,乙醇,丙醇,异丙醇,丁醇,异丁醇,叔丁醇,丙酮,乙醚,乙酸乙酯,乙腈,四氢呋喃,二氯甲烷,石油醚,正己烷,环己烷,N,N-二甲酰胺和水等。本发明所述的5-氨基酮戊酸及其衍生物(例如酯)的盐化合物可用上述的一种或混合溶剂进行重结晶纯化。
本发明所述的盐化合物可被细胞吸收,并转化成具有高光敏活性的原卟啉IX,显示这些新盐化合物可用于光动力学治疗,诊断和美容。本发明所述盐化合物可直接应用,或优选地制成药物制剂或药物组合物使用。由此,本发明的另一个方面是关于药物组合或药物制剂及美容制剂的制备,其中含有该发明所述的一个盐化合物以及至少一个药学上可接受的或美容上可接受的辅料,添加剂,溶解介质,载体或赋形剂,还可任选地加入一个或多个其它治疗剂,或增效剂等。
本发明所述的化合物可用于身体的内部表面和外部表面的患病处或美容部位,施以有效剂量以提高给药部位细胞内PpIX的生成和聚集,然后用适当的光源照射治疗部位或暴露治疗部位于日光,诱发产生光动力学反应,引起患病细胞组织的凋亡和坏死,达到治疗目的。
本发明提供的盐化合物与对应的用在临床的盐酸盐相比,有诸多优点。本发明所述的盐化合物比对应盐酸盐的吸湿性低,由此可以降低因含水量高引起的不稳定性和分解,有利于生产中的质量控制和储存。另外,本发明公布的盐化合物对皮肤的刺激比其相对应的盐酸盐小。当给药部位是皮肤敏感处时,如尿道和宫颈,降低药物刺激性十分重要,特别是在需要多次给药的情况下,可使病人完成治疗。在细胞荧光的测试中,本发明所述的盐化合物引发PpIX生成的活性与其相对应的盐酸盐相当。更重要的是,本发明提供的盐化合物组成中的三氯乙酸本身具有治疗皮肤病和美容的多种生物活性,及极好的皮肤渗透性,可与5-氨基酮戊酸及其酯衍生物协同地损坏治疗部位的患病细胞和组织,同时还可提高5-氨基酮戊酸及其酯衍生物的皮肤渗透能力,增强疗效。
本发明提供的5-氨基酮戊酸及其酯衍生物的盐化合物或药物制剂可外用,口服和注射。外用是指施药于身体外表面和内表面。优选的使用方法是用于治疗身体外表面和内表面疾病和失调的光动力学疗法,治疗癌症(如非黑色素瘤皮肤癌),癌前病变和非肿瘤性疾病。这些疾病和失调包括但不限于基底细胞癌,宫颈上皮内瘤变、光化性角化病、脂溢性角化病、鳞状细胞癌、Bowen病、外阴佩吉特病、痤疮、银屑病、鲜红斑痣、红斑狼疮、尖锐湿疣、难治性掌跖疣、皮肤T细胞淋巴瘤;细菌感染(如革兰氏阴性株大肠杆菌,铜绿假单胞菌,革兰氏阳性菌耐甲氧西林金黄色葡萄球菌),真菌感染(如白色念珠菌,T癣菌),与炎症疾病和病毒感染相关的疾病(如病毒疣、疱疹等)。本发明公布的盐化合物及其药物制剂也可用于各种肿瘤的光动力学检测诊断或治疗诊断,包括但不限于治疗诊断检测膀胱癌,肠癌,胃癌,肺癌,脑癌,肝癌,胰腺癌,宫颈癌,前列腺癌,卵巢癌,乳腺癌,皮肤癌,口腔癌,鼻癌,咽喉癌和囊肿等。病变和失调的细胞组织积累PpIX的浓度比正常细胞高,可通过荧光強度的检测进行病症诊断。
这里所描述的身体的内表面和外表面是皮肤,所有上皮和黏膜表面。包括但不限于皮肤和结膜,口腔,鼻腔,鼻窦,气管、支气管的内壁;咽喉、食道、胃、肠、直肠、胆管和肛门管的内壁;输尿管、膀胱和尿道的内膜,阴道、子宫颈和子宫的内壁等。
本发明公布的盐化合物和药物制剂亦可用于光动力学美容,包括但不限于治疗痤疮、弥漫性或斑点色素沉着、酒渣鼻、皮脂腺增生、嫩肤、光老化、皱纹、扩大的毛孔和皮肤纹理、太阳照射引起的皮肤粗糙、触觉粗糙、灰黄和晦暗皮肤、疤痕等。
本发明所述的盐化合物可与至少一种药学上或美容上可接受的药物辅料,添加剂,载体或赋形剂制得药物制剂或美容剂,其形式可以是药物制剂中任何常规形式的制剂,适合于皮肤和身体的内表面给药,全身给药或口服。口服,皮下或静脉注射药物的形式包括片剂,胶囊,悬浮液和溶液等。优选的剂型是外用(皮肤和身体的内表面),可以是水剂,油剂,贴剂,透皮吸收剂,霜剂,粉剂,滴剂,喷雾剂,软膏,油膏,阴道栓剂,栓剂,纳米制剂。所用载体和赋形剂包括但不限于水或油基、增稠剂、胶凝剂、水凝胶、乳化剂,纳米乳化剂、增溶剂、分散剂、稳定剂、悬浮剂、色剂或推进剂、防腐剂、润滑剂、增渗剂、以及pH调节剂等。这些剂型和制剂的制备方法及技术都是本领域所熟知的。所需辅料,添加剂,赋型剂或载体均可从市场购得,其使用方法和技术也是本领域所熟知的,并且出版在文献中(例如,Hoepfner等,Fiedler Encyclopedia of Excipients for Pharmaceuticals,Cosmeticsand Related Areas,Edition Cantor,Munich,2002)。
本发明所述的盐化合物可以制成片剂、胶囊、悬浮液或溶液用于口服或注射(如皮下、肌肉、腹腔或静脉注射),在此所述的剂型中含有一个本发明所述的盐化合物和一个或多个载体或稀释剂。载体和稀释剂包括但不限于水,乙醇,甘油,山梨糖醇,玉米淀粉,乳糖,蔗糖,微晶纤维素,硬脂酸镁,聚乙烯吡咯烷酮、柠檬酸、酒石酸、丙二醇,硬脂醇,聚乙二醇,羧甲基纤维素,脂肪物质,生理盐水或缓冲溶液。以上所述制剂可釆用本专业人员熟知的或已发表的方法制得。
在药物组合或药物制剂中,本发明所述的新盐化合物的重量含量可在0.01-95%(w/w或w/v)范围,优选的含量为0.1-50%,例如0.1-30%。有效使用剂量可受多种因素影响,如年龄,体重,所治疗的疾病,不同的用途(治疗,诊断或美容)等,有效使用剂量范围可在每天0.001-5克,优选的剂量为每天0.01-2克。
本发明所述的盐化合物或药物组合或药物制剂在用药后,用特定波长的光照射用药部位,使PpIX激发到高能量激发态,产生单线态氧和氧自由基,造成病变细胞组织的凋亡和坏死。光照射的操作可按本领域熟知的技术方法进行实施,所需光的波长和强度是本领域熟知的。光源选自灯,激光,发光二极管灯或日光(Rubel等,British J Dermat,2014,171:1164-1171),不易达到的部位可使用光导纤维。处理部位的用药时间为0.01-12小时,优选为0.5-4小时。所选用的光源波长在300-1200纳米范围,优选波长范围在380-800纳米。照射的剂量可在5-150焦耳/cm2范围,优选剂量为20-120焦耳/cm2。在光动力学诊断中,首先用白光(例如600-750纳米)观测,然后用蓝光(如380-440纳米)照射检测荧光强度,诊断出病变部位。
本发明所述的盐化合物及其药物制剂可以与任何己在文献中发表的其它光敏剂合用(如Photofrin,竹红菌素等),以提高药效;与任何己在文献中发表的螯合剂合用(如CDTA,EDTA等),用以螯合亚铁离子,阻断从PpIX到血红素的转变,提高PpIX的聚集和吸收;以及与己在文献中发表的任何表面渗透剂合用(如DMSO,表面活性剂或非表面活性剂脂肪酸,胆盐等),以提高本发明所述盐的渗透吸收。本发明所述的盐化合物亦可与其它治疗皮肤病症的药物合并使用(如三氯乙酸,抗生素等)。
本发明提供应用试剂盒供光动力学治疗,诊断或美容使用,包括单瓶包装:含有有效剂量的任何一个本发明所述盐化合物或药物制剂。亦可是双瓶包装:A瓶含有有效剂量的任何一个本发明提供的盐化合物或其药物制剂;B瓶含有溶解介质(如水,缓冲液,软膏,油膏,乳霜,凝胶等常规使用的溶解介质),或一个或多个载体或赋形剂、螯合剂、表面渗透剂,治疗剂,或其他光敏剂等。
本发明的另一方面涉及通过检测体液和组织样本的荧光強度进行疾病的检测和诊断,即在避光的条件下,将本发明的盐化合物与体液或组织样本混合和孵化,然后用适当的光照射混合物(如蓝光380-440纳米),病变细胞可引起荧光強度增加。所述的体液和组织包括但不限于唾液、尿液、血液、粪便、精液、眼泪、脊髓液和活检标本等。
本发明还涉及用于协助外科医生切除肿瘤组织的体内检测和诊断方法,即在肿瘤手术前口服或手术过程中局部施予本发明提供的盐化合物或药物制剂,因为肿瘤细胞产生的PpIX比正常细胞产生的多,当用蓝光照射时(如380-440纳米),可以根据荧光強度的差别直观地鉴别和区分肿瘤组织和正常组织,更准确地切除肿瘤组织。
具体实施方式:
以下实施例是非限制地对本发明的说明,任何修改变换均在本发明的保护范围内。
缩写:
5-ALA:5-氨基酮戊酸,
Bn:苄基,
Boc:叔丁氧羰基,
Cbz:苄氧羰基,
CDTA:1,2-环己二胺四乙酸,
DMSO:二甲基亚砜,
EDTA:乙二胺四乙酸,
HCl:盐酸,
PBS:磷酸缓冲生理盐水,
PDT:光动力学疗法,
PpIX:原卟啉IX,
TCA:三氯乙酸,
NMR:核磁共振,
ppm:百万分率,
mM:毫摩尔。
实施例 1:
5-氨基酮戊酸三氯乙酸盐:将5-N-Cbz-氨基酮戊酸(2.7克,10毫摩尔)溶解于甲醇(35毫升)中,加入钯碳(10%,0.5克)和三氯乙酸(1.6克,10毫摩尔)。搅拌下常压氢化24小时。反应液过滤,减压旋转蒸发至干,得到5-氨基酮戊酸三氯乙酸盐白色固体(2.7克,92%)。1HNMR(D2O,360MHz)δppm:2.65(t,j=6Hz,2H),2.85(t,j=6Hz,2H),4.03(s,2H)。
实施例2:
5-氨基酮戊酸甲酯三氯乙酸盐:将5-氨基酮戊酸甲酯盐酸盐(1.8克,10毫摩尔)加至乙酸乙酯(50毫升)和水(20毫升)的混合液中,加入碳酸氢钠(1.7克,20毫摩尔)后振摇。分出有机相,水相用乙酸乙酯萃取(30毫升x2),合并萃取液并用无水硫酸钠干燥,过滤除去硫酸钠,向滤液中加入三氯乙酸(1.6克,10毫摩尔),减压旋转蒸发,得到白色固体5-氨基酮戊酸甲酯三氯乙酸盐(1.7克,55%)。1H NMR(D2O,360MHz)δppm:2.62(t,j=6Hz,2H),2.82(t,j=6Hz,2H),3.60(s,3H),4.03(s,2H)。
实施例3:
5-氨基酮戊酸乙酯三氯乙酸盐:将5-N-Boc-氨基酮戊酸乙酯(2.6克,10毫摩尔)溶解在四氢呋喃(20毫升)中,加入三氯乙酸(1.6克,10毫摩尔)。搅拌下60oC反应2小时,减压旋转蒸发,得到固体5-氨基酮戊酸乙酯三氯乙酸盐(2.5克,78%)。1H NMR(D2O,360MHz)δppm:1.23(t,j=7Hz,3H),2.64(t,j=6Hz,2H),2.83(t,j=6Hz,2H),4.03(m,4H)。
实施例4:
5-氨基酮戊酸己酯三氯乙酸盐:将5-氨基酮戊酸己酯盐酸盐(2.5克,10毫摩尔)溶于50%乙醇水溶液(10毫升)中,该溶液通过5克Amberlyst 26(OH)的填充柱,用50%乙醇水溶液(20毫升)洗涤,流出液加至三氯乙酸(1.6克,10毫摩尔)的乙醇溶液(5毫升)中。减压旋转蒸发,得到白色固体5-氨基酮戊酸己酯三氯乙酸盐(2.1克,56%)。1H NMR(D2O,360MHz)δppm:0.77(t,j=6Hz,3H),1.21(br,6H),1.53(m,2H),2.62(t,j=6Hz,2H),2.83(t,j=6Hz,2H),4.03(m,4H)。
本发明所述的下列盐化合物可用实施例1-4方法制备:
5-氨基酮戊酸 2-氯乙酸盐,
5-氨基酮戊酸甲酯 2-氯乙酸盐,
5-氨基酮戊酸乙酯 2-氯乙酸盐,
5-氨基酮戊酸丙酯 2-氯乙酸盐,
5-氨基酮戊酸丙酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸丁酯 2-氯乙酸盐,
5-氨基酮戊酸丁酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸戊酯 2-氯乙酸盐,
5-氨基酮戊酸戊酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸己酯 2-氯乙酸盐。
本发明所述的下列盐化合物可优选使用实施例2-4方法制备:
5-氨基酮戊酸苄酯 2-氯乙酸盐,
5-氨基酮戊酸苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸2-甲基苄酯 2-氯乙酸盐,
5-氨基酮戊酸2-甲基苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-甲基苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-甲基苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-氯苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-氯苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-硝基苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-硝基苄酯 2,2,2-三氯乙酸盐,
5-氨基酮戊酸4-异丙基苄酯 2-氯乙酸盐,
5-氨基酮戊酸4-异丙基苄酯 2,2,2-三氯乙酸盐。
实施例5:
吸湿性测定:用样品重量和外观的变化测定了本发明所述的盐化合物的吸湿和潮解能力,并与其相对应的盐酸盐做了比较。将测定盐化合物(0.2-0.4克)放置在湿度为70-85%的密闭容器中,室温24小时后,观察重量和外观的变化。5-氨基酮戊酸,甲酯和己酯的盐酸盐和5-氨基酮戊酸三氯乙酸盐均有吸湿现象,重量增加25-50%,且潮解成液态。而5-氨基酮戊酸甲酯三氯乙酸盐重量增加<5%,5-氨基酮戊酸己酯三氯乙酸盐的重量保持不变,甲酯和己酯的三氯乙酸盐的固体外观未发生変化。结果表明,三氯乙酸盐吸潮性低,有利于生产中的质量控制,亦可在长期储存中减小因吸湿而造成的分解。
实施例 6:
皮肤刺激实验:釆用对舌头表面的刺激测定了本发明所述新盐化合物对皮肤的刺激,并与其相对应的盐酸盐进行了比较。将3毫克样品放置受试者舌头表面,3到5分钟之后记录受试者的感受,测试结果列于表1中。结果表明,5-氨基酮戊酸(或酯)的三氯乙酸盐引起的对皮肤的刺激显著低于其相对应的盐酸盐。
表 1. 皮肤刺激实验(A:无刺激,B:有刺激,C:较强刺激,D:强刺激)
实施例 7:
诱导细胞生成PpIX的活性测定:使用人肺癌A549细胞(ATCC,Rockville,MD,USA)测定了荧光生成和強度,将本发明所述三氯乙酸盐诱导原卟啉IX生成的活性与对应的盐酸盐进行了比较。化合物的测定浓度(表2):5-氨基酮戊酸盐酸盐,5-氨基酮戊酸甲酯盐酸盐,5-氨基酮戊酸三氯乙酸盐和5-氨基酮戊酸甲酯三氯乙酸盐为10毫摩尔;5-氨基酮戊酸己酯盐酸盐和5-氨基酮戊酸己酯三氯乙酸盐为0.5毫摩尔或1毫摩尔。待测化合物用无菌生理盐水制成原料液,测试前以碳酸钠调pH到7-7.5,用新鮮培养液稀释至所需测试浓度。用含10%胎小牛血清的F12培养液(Gibco)将A549细胞配成单个细胞悬液,以5×104/ml接种到48或96孔培养板,将培养板放入培养箱,在37oC和5%CO2的潮湿环境中培养24小时,至细胞汇集率60-70%。测试前用PBS洗细胞两次,加入含有测试化合物的新鮮培养液,每个测定3个复孔,以锡箔纸包裹避光培养。分別在4,8和24小时检测生成PpIX的水平。除去培养液,用PBS洗细胞两次,测定PpIX生成含量(CytoFluor Series 4000,Multi-Well Plate Reader,PerSeptive Biosystems,Framingham,MA,USA),激发光源为360±40纳米,检测光源为620±40纳米。
结果显示(表2),5-氨基酮戊酸三氯乙酸盐,其甲酯三氯乙酸盐和己酯三氯乙酸盐均具有与其相对应的盐酸盐相似的诱导细胞生成PpIX的活性。此外,当己酯的三氯乙酸盐和其盐酸盐的测定浓度提高至2-5mM时,两种盐的活性相似,且比5-氨基酮戊酸和其甲酯的盐(三氯乙酸盐和盐酸盐)的活性高70-100倍。
表 2. A549细胞测定PpIX的生成:
*诱导PpIX生成的相对活性
实施例8:
溶液制剂1:将5-氨基酮戊酸己酯三氯乙酸盐(250毫克)溶解在0.9%的氯化钠溶液(5毫升)中,制得含量为5%的5-氨基酮戊酸己酯三氯乙酸盐生理盐水制剂。可以根据不同的治疗要求(如治疗检测诊断膀胱癌,肠癌,胃癌),使用不同的缓冲液如磷酸缓冲生理盐水(PBS),制得类似的溶液制剂。
实施例 9:
溶液制剂2:将5-氨基酮戊酸己酯三氯乙酸盐(250毫克)溶解在含三氯乙酸(0.1克)的0.9%的氯化钠水溶液(5毫升)中,制得含2%三氯乙酸和5%5-氨基酮戊酸己酯三氯乙酸盐的生理盐水溶液制剂。可使用不同的缓冲液如磷酸缓冲生理盐水(PBS),制得类似的溶液制剂。
实施例 10:
凝胶制剂1:将羟乙基纤维素凝胶(4.37g,1-2%,MW 725,000或250,000)加到5-氨基酮戊酸三氯乙酸盐(630毫克)中,混合均匀,得到透明凝胶,5-氨基酮戊酸三氯乙酸盐的含量为126毫克/克。
实施例 11:
凝胶制剂2:将羟乙基纤维素凝胶(4.37g,1-2%,MW 725,000或250,000)加到三氯乙酸(50毫克)和5-氨基酮戊酸三氯乙酸盐(630毫克)的混合物中,混合均匀,制得含1%三氯乙酸和125毫克/克5-氨基酮戊酸三氯乙酸盐的透明凝胶。
实施例 12:
乳霜制剂1:将5-氨基酮戊酸甲酯三氯乙酸盐(1.5克)与默克软膏(8.5克,UnguentumMerck)完全混合,得到含量为150毫克/克的5-氨基酮戊酸甲酯三氯乙酸盐乳霜制剂。
实施例 13:
乳霜制剂2:将5-氨基酮戊酸甲酯三氯乙酸盐(1.5克)和三氯乙酸(0.3克)的混合物与默克软膏(8.2克,Unguentum Merck)完全混合,得到含有3%三氯乙酸和150毫克/克5-氨基酮戊酸甲酯三氯乙酸盐的乳霜制剂。
Claims (13)
1.5-氨基酮戊酸及其酯衍生物的盐化合物,其特征在于由碱基化合物与乙酸衍生物制成,其结构如通式(1)和(2)所示:
NH2CH2COCH2CH2COOR·X-COOH 或 NH3 +CH2COCH2CH2COOR·X-COO- (1)
NH2CH2COCH2CH2CONR1R2·X-COOH 或 NH3 +CH2COCH2CH2CONR1R2·X-COO- (2)
其中,R可选自氢,有取代基或没有取代基的烷基、环烷基、芳基;X分别代表R3YCH、R3(Y)2C或(Y)3C,其中Y选自Cl,Br,I或F;R3可选自氢、有取代或没有取代的烷基、环烷基、或芳基;R1和R2可以相同或不同,可独立或分别选自氢、有取代或没有取代的烷基、环烷基、或芳基。
2.根据权利要求1所述的盐化合物,其特征在于R、R1、R2可独立或分别选自氢,或含有1至20个碳原子的有取代或没有取代的直链烷基、支链烷基、或环烷基;优选为1至10个碳原子或1至8个碳原子,特别优选的是甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、叔丁基、异戊基、异己基、环丙基、环丁基、环戊基或环己基;R、R1、R2可以分别任选有一个或多个相同的或不同的亲水性或非亲水性取代基,亲水性取代基选自羟基、硫醇、羧基、氨基甲酰、酯基、氨基、烷氨基、酰胺,非亲水性取代基选自卤素、硝基、氰基和芳基,所述芳基可含有一个或多个取代基,取代基选自卤素、羟基、硫醇、氨基、烷氨基、羰基、酯、酰胺、烷基、卤代烷基、烷氧基、羟烷基、硝基或氰基。
3.根据权利要求1所述的盐化合物,其特征在于所述酸X-COOH是乙酸衍生物,其中X代表R3YCH、R3(Y)2C或(Y)3C,Y选自Cl、Br、I或F;R3可选自氢,含有1至20个碳原子的有取代或没有取代的直链烷基、支链烷基、或环烷基;优选为1至10个碳原子或1至8个碳原子,特别优选的是甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、叔丁基、异戊基、异己基、环丙基、环丁基、环戊基或环己基,R3可以任选地有一个或多个相同的或不同的亲水性或非亲水性取代基,亲水性取代基选自羟基、硫醇、羧基、氨基甲酰、酯基、氨基、烷氨基、羟烷基、酰胺,非亲水性取代基选自卤素、硝基、氰基和芳基,所述芳基可含有一个或多个取代基,取代基可选自一个或多个卤素、羟基、硫醇、氨基、烷氨基、羰基、酯基、酰胺、烷基、卤代烷基、烷氧基、羟烷基、硝基或氰基。
4.根据权利要求1所述的盐化合物,其特征在于与乙酸衍生物生成盐的碱基化合物可选自5-氨基酮戊酸,5-氨基酮戊酸甲酯或5-氨基酮戊酸己酯。
5.根据权利要求4所述的盐化合物,其特征在于乙酸衍生物可选自一氯乙酸或三氯乙酸。
6.根据权利要求1至5,其特征在于所述的盐化合物可通过盐的转换制得,方法为用碱中和组成为 Cl-NH3 +CH2COCH2CH2COOR 或 Cl-NH3 +CH2COCH2CH2CONR1R2 盐酸盐化合物或磷酸盐化合物,其中R、R1和R2如权利要求1和2所述,然后与权利要求1或3中任意一项所述的酸反应成盐。
7.根据权利要求1至5,其特征在于所述盐化合物可由带有氨基保护基的NH2CH2COCH2CH2COOR 或NH2CH2COCH2CH2CONR1R2 制得,其中R、R1、R2如权利要求1和2所述,方法为除去氨基保护基,与权利要求1或3中任意一项所述的酸反应成盐。
8.根据权利要求1至5,其特征在于,所述的盐化合物可通过碱性树脂离子交换法制得,方法为用碱性离子交换树脂处理组成为 Cl-NH3 +CH2COCH2CH2COOR 或 Cl-NH3 +CH2COCH2CH2CONR1R2 盐酸盐或磷酸盐,其中R、R1、R2如权利要求1和2所述,然后与权利要求1或3中任意一项所述的酸反应成盐。
9.一种药物组合物或药物制剂,其特征在于包括权利要求1至5中任意一项所述的盐化合物,以及至少一种可药用或化妆用的辅料,添加剂,溶解介质,载体或赋形剂。
10.试剂盒,其特征在于单瓶包装试剂盒含有效剂量的权利要求1至5中任意一项所述的盐化合物或权利要求9中所述的药物组合物或药物制剂,亦可是双瓶包装试剂盒:A瓶含有效剂量的权利要求1至5中任意一项所述的盐化合物或权利要求9所述的药物组合物或制剂,B瓶含有溶解介质,或一个或多个辅料、添加剂、螯合剂、表面渗透剂,光敏剂或治疗剂。
11.权利要求1至5中任意一项所述的盐化合物或权利要求9中所述的药物组合物在制备治疗身体内表面或外表面癌症,癌前病症,非癌症或异常症状的光动力学疗法的药物或治疗剂中的应用。
12.权利要求1至5中任意一项所述的盐化合物或权利要求9中所述的药物组合物在制备光动力学疗法的诊断剂中的应用。
13.权利要求1至5中任意一项所述的盐化合物或权利要求9中所述的药物组合物在制备光动力学疗法的美容剂中的应用。
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EP3408254A2 (en) | 2018-12-05 |
JP6832358B2 (ja) | 2021-02-24 |
US10653653B2 (en) | 2020-05-19 |
US20190022044A1 (en) | 2019-01-24 |
WO2017132178A2 (en) | 2017-08-03 |
TWI736577B (zh) | 2021-08-21 |
TW201731811A (zh) | 2017-09-16 |
JP2019517990A (ja) | 2019-06-27 |
EP3408254B1 (en) | 2020-11-04 |
CN112010772A (zh) | 2020-12-01 |
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