CN1096197A - 含不饱和脂肪酸酯类的组合物 - Google Patents
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Abstract
脂肪酸胆固醇酯,其中的脂肪酸选自必需脂肪酸
或选自十八碳四烯酸或columbinic acids。这些脂肪
酸胆固醇酯可用于治疗疾病,尤其是治疗癌症和心血
管疾病。
Description
本发明涉及含不饱和脂肪酸酯类的组合物。
特殊类型的脂肪酸对于保持健康的组织和治疗各种疾病是相当重要的。一些脂肪酸本身是重要的;一些则因为它们可生成特殊的代谢物例如前列腺素或其他氧化衍生物;另一些两方面原因都有。这其中包括不能由机体生成的必需脂肪酸(EFAs),因此它们构成必需营养品。由于以上两方面原因而特别重要的EFAs中包括γ-亚麻酸(GLA)、二高-γ-亚麻酸(DGLA)和二十碳五烯酸(EPA)。DGLA是细胞膜的重要成分,也是前列腺素E1(PGE1)的前体;PGE1有许多合乎需要的作用,包括作为抗血栓形成剂、抗炎剂、血管舒张剂、免疫调节剂和降胆固醇剂。GLA是DGLA的直接前体,在体内能迅速转化为DGLA。EPA也是细胞膜的成分并且是PGE3的前体,PGE3具有与PGE1类似的作用。另一个作为细胞膜的成分具有特殊意义的脂肪酸是二十二碳六烯酸(DHA)。
EFAs的主要系列在体内的转化途径如下所示:
表1
n-6 n-3
18:2△-9,12 18:3△-9,12,15
(亚油酸) | (α-亚麻酸)
|
△-6去饱和酶
↓
18:3△-6,9,12 18:4△-6,9,12,15
(γ-亚麻酸) (stearidonic acid)
|
链延长
↓
20:3△-8,11,14 20:4△-8,11,14,17
(二高-γ-亚麻酸)
|
△-5去饱和酶
↓
20:4△-5,8,11,14 20:5△-5,8,11,14,17
(花生四烯酸) (二十碳五烯酸)
|
链延长
↓
22:4△-7,10,13,16 22:5△-7,10,13,16,19
(肾上腺酸)
|
△-4去饱和酶
↓
22:5△-4,7,10,13,16 22:6△-4,7,10,13,16,19
(二十二碳六烯酸)
以上转化途径在人体内正常情况下是不可逆的,而且,n-3系和n-6系脂肪酸也不能相互转化。
天然存在的该类脂肪酸均具全顺式构型,其系统名称是按照相应的十八酸、二十酸或二十二酸的衍生物来命名的,例如:△-9,12-十八碳二烯酸或△-4,7,10,13,16,19-二十二碳六烯酸,而相应的数字命名,如18∶2 n-6或22∶6 n-3是很简便的。也可使用词首字母,例如:EPA代表22∶5 n-3酸 eicosapentaenoic acid(二十碳五烯酸)]或DHA代表22∶6 n-3酸[docosahexaenoic acid(二十二碳六烯酸)],但是,当存在同样链长度和同样不饱和度的n-3和n-6酸时,如两个22∶5酸,该法就不适用。正如所示,俗名大约常用于n-6系列。在n-3系列中,只有18∶3 n-3常用其俗名:α-亚麻酸,尽管stearidonic acid名称开始用来代表18∶4 n-3酸,二十碳五烯酸和二十二碳六烯酸也使用本身名称。亚麻酸的α异构体的鉴定早于γ-亚麻酸,在文献中,特别是早期文献中统称为亚麻酸的是α-酸。
脂肪酸的胆固醇酯的价值以前一直没有被认识,这是因为存在这样的观点:即胆固醇是有害的,它可能会促成冠脉和周围动脉疾病。许多人已忘记胆固醇是身体的必需成分;而且为细胞膜的正常组成所必需。胆固醇酯形成在血液内循环的LDL(低密度脂蛋白)颗粒的主要部分。LDL颗粒被吸收入其表面具有LDL特异性受体(称作LDL受体)的细胞中。许多类型的细胞中都有LDL受体存在,但在许多癌细胞上存在大量的该受体。众所周知,LDL受体也被发现在与动脉有关的细胞上。所以,该脂肪酸的胆固醇酯是将这些脂肪酸送入具有LDL受体的细胞中的有效方式。它们也是将脂肪酸送入癌细胞和动脉粥样硬化组织的极为有效的方式。
通常,脂肪酸对某些不同疾病均有治疗价值。正如在此处及本发明者的其他专利中所讨论的,这些脂肪酸在治疗癌症方面是有价值的。脂肪酸,尤其γ-亚麻酸、二高-γ-亚麻酸、花生四烯酸、二十碳五烯酸和二十二碳六烯酸对心血管系统具合乎需要的作用且在治疗冠脉和周围动脉疾病方面有价值。在糖尿病患者身上可以有限度地产生同样的脂肪酸,所以,它们在治疗糖尿病的并发症如神经病、视网膜病和心血管疾病方面有价值。这些脂肪酸中的一些,尤其是γ-亚麻酸、二高-γ-亚麻酸和二十碳五烯酸具有抗炎的作用,因而能用于那些炎症是其重要症状的疾病如类风湿性关节炎、骨关节炎、湿疹、肠炎、牛皮癣和各种自身免疫疾病。这些脂肪酸在脑功能方面也是极为重要的,并在控制严重的大脑和精神疾病如精神分裂症、酒精中毒和痴呆症包括阿耳茨海默氏病和多梗塞性痴呆(multi-infarct dementia)方面是有价值的。但是,脂肪酸的这些可能用途是其已知用途的一部分,且本发明并不意味着只适于用该脂肪酸治疗这些具体的疾病。本文重要性在于提供通过以胆固醇形式服用这些脂肪酸来释放它们以治疗上述任何疾病和其他任何疾病的方法。
在上文中的胆固醇酯的价值还有更广泛和更新的内容。我们已发现:该胆固醇酯比脂肪酸本身或其盐或甘油三酯或其他形式都更稳定和更抗氧化。这点可通过加到供经常局部使用的乳膏和软膏中的脂肪酸的性能来很好地加以说明。过去我们制备过各种供局部使用的EFAs制剂,且使用过游离脂肪酸、其盐和甘油三酯。除非用有效抗氧剂保护,这类乳膏或软膏的脂肪酸成分会被迅速氧化。相反,配制的含胆甾烯基盐的乳膏和软膏则完全不同。例如,我们配制了含5%和10%胆固醇γ-亚麻酸酯的乳膏,不加任何抗氧剂以评估其性能。与通常出现的结果相反,即使将这些乳膏放在敞口的容器内,持继和新鲜氧气接触,结果几个月时间它们仍保持纯白色。这表明:EFAs的胆固醇酯特别抗氧化。据我们所知,该结论以前从未报导过,它为制备本专利说明书中所列的所有类型的EFAs胆固醇酯制剂提供了明确的理由。在药物制剂或其他用于护肤、化妆品或治疗皮肤病的制剂中使用胆固醇酯有特别的理由。当将这些局部用制剂薄薄地涂在皮肤表面时,它们就暴露于高浓度的氧气下,所以,此时EFAs的稳定形式则特别重要。
由上述得知,本发明包括几个方面内容。
第一,至今为止,n-6和n-3必需脂肪酸、十八碳四烯酸和columbinic acid的胆固醇酯均为新化合物。
第二,以上酯类,无论是否为新化合物,它们在药用、皮肤用和营养性组合物中的迄今未提到的和有价值的用途。
第三,该酯类在制备用于治疗上述疾病的药物方面的用途和相应的治疗疾病方法,所述疾病是一类需要将脂肪酸转运到细胞内间隙中的病症,尤其是癌症和动脉粥样硬化症(与LDL受体结合并通过该途径进入细胞是使脂肪酸进入细胞内的一般合乎需要的方法)或其它病症,在治疗这些病症中需要稳定、不易被氧化的脂肪酸,这些病很显然是那些需要使用局部用组合物的疾病,但是,脂肪酸的稳定性具普遍的重要性,且它们的不需和专门抗氧剂一起使用的特性是很有价值的。
第四,本发明不限于以上已提出的脂肪酸和已提出的目的。第五,本发明涉及脂肪酸和胆固醇酯在制备能抗空气氧化的不饱和脂肪酸尤其高不饱和脂肪酸组合物中的用途;涉及使这样的脂肪酸能抗空气氧化的方法,其中所述脂肪酸用胆固醇酯化了。
胆固醇酯为特定的分子,它们含一分子被一分子所需的脂肪酸酯化的胆固醇。它们可以通过胆固醇与有关的脂肪酸反应制得,在反应混合物中所需脂肪酸的含量宜为20%以上,以40%以上为佳,70%以上更好,90%以上最好。该脂肪酸可采用为本领域技术人员所公知的方法制备,既可由化学合成也可以从天然资源中提取、纯化来制备。酯化方法为本领域技术人员所公知。
以下给出制备脂肪酸的胆固醇酯的方法实例。首先,通过纯的脂肪酸和亚硫酰氯反应制备该脂肪酸的氯化物。然后,通过将脂肪酸氯化物与胆固醇在二氯甲烷和吡啶存在下混合制备脂肪酸胆固醇酯。反应产物为脂肪酸胆固醇酯和盐酸。另一个制备方法是将胆固醇和对甲基苯磺酸的水合物在甲苯中混合,并与相应的脂肪酸一起加热回流。该反应生成的水与甲苯形成共沸混合物,将该混合物分出去,残留的甲苯真空除去。然后将棕色油状残留物经干柱层析纯化。先用正已烷洗脱,除去走在前边的杂质,再用5%的乙醚洗脱,除去溶剂后,得所需酯产物。该类特定脂肪酸的酯是略带黄色的粘稠油状物。其他制备方法可为本领域的技术人员所使用。
按同样方法也可以制备其他不饱和脂肪酸的胆固醇酯。十八碳四烯酸(18∶4 n-3;9顺式,11反式,13反式,15顺式)是一种特别有意义的酸,因为它有强抗癌作用。Columbinic acid(18∶3 n-6;6、9顺式,13反式)也是一种重要的酸,它能履行必需脂肪酸的膜相关作用而不被转化为二十烷类(eicosanoids)。
下面是具体的实施例,包括合成下列胆固醇酯(1):
按下列方法可以合成相应于n-6和n-3必需脂肪酸、十八碳四烯酸和columbinic acid的类型(1)化合物,式中R为R2C=0,R2为链烷基:(a)通过使胆固醇(类型(2)化合物,R1=H)与类型(3)的脂肪酸(式中,R的定义同上,X=H)在催化量的适宜无机酸如对甲基苯磺酸存在下并在可与水成共沸物的惰性溶剂即甲苯、二甲苯中于100-180℃反应。
(b)通过使胆固醇(类型(2)化合物,R1=H)与类型(3)的脂肪酸(式中,R的定义同上,X=H)在缩合剂如二环已基碳二亚胺和强非亲核性碱如4-二甲氨基吡啶存在下并在适宜的惰性溶剂如二氯甲烷中于10-40℃反应。
(c)通过使胆固醇(类型(2)化合物,R1=H)与类型(3)的脂肪酸氯化物或溴化物(式中,R的定义同上,X=Cl或Br)在适宜的碱如吡啶存在下并在惰性溶剂如二氯甲烷中于0-50℃反应。
(d)通过使胆固醇醋酸酯(类型(2)化合物,R1=CH3CO)与类型(3)的脂肪酸的低级醇酯(式中,R的定义同上,X=X1=0(CH2)nCH3(n=0-2))在催化量的MX1类型的醇盐(式中,X1的定义同上,M是碱金属如钠或钾)存在下并在减压条件下于80-120℃反应。
优选的化合物是类型(1)的化合物,包括:
1A)R=(z,z,z)十八碳-6,9,12-三烯酰基C45H74O2
1B)R=(z,z,z,)二十碳-5,8,11,14-四烯酰基C47H76O2
1C)R=(z,z,z,z,z)二十碳-5,8,11,14,17-五烯酰基C47H74O2
1D)R=(z,z,z,z,z,z)-二十二碳-4,7,10,13,16,19-六烯酰基C49H76O2
类型(2)和类型(3)的起始化合物很容易买到,它们的定义如下:
2A)R1=H
2B)R1=CH3CO
3AH)R=(z,z,z)十八碳-6,9,12-三烯酰基,X=H
3ACl)R=(z,z,z)十八碳-6,9,12-三烯酰基,X=Cl
3BMe)R=(z,z,z,z)二十碳-5,8,11,14-四烯酰基,X=Me
3CMe)R=(z,z,z,z,z)二十碳-5,8,11,14,17-五烯酰基,X=Me
3DH)R=(z,z,z,z,z,z)二十二碳-4,7,10,13,16,19-六烯酰基,X=H
实施例1
(z,z,z)十八碳-6,9,12-三烯酸胆固醇酯(1A)的制备:将556份(z,z,z)十八碳-6,9,12-三烯酸(3AH)、773份的胆固醇(2A)和20份对甲基苯磺酸-水合物的甲苯(2500份)溶液在氮气下搅拌回流加热,装置上安有迪安-斯达克接头(Dean and Stark head)以便除去生成的水。约5小时后,停止生成水,将该混合物冷却。真空除去溶剂,将残留棕色油溶于正己烷(2000份)中,用水洗所得溶液并干燥(硫酸钠)。将该溶液用中压柱层析纯化(柱:6000份 Matrex二氧化硅,孔径60A,粒径35-70μm,溶剂:正己烷)。收集所需流分,真空除去溶剂,得到浅黄色非可蒸馏(non-distillable)油(z,z,z)十八碳-6,9,12-三烯酸胆固醇酯。
实施例2
(z,z,z)十八碳-6,9,12-三烯酸胆固醇酯(1A)的制备:将335份胆固醇(2A)和70份无水吡啶溶在1500份二氯甲烷中。将该溶液冷却到5-10℃,在氮气下搅拌的同时,用30分钟滴加257份(z,z,z)十八碳-6,9,12-三烯酰氯(3ACl)。将该混合物在室温下搅拌20小时。真空除去溶剂后,加入正己烷(1000份),用2M盐酸水溶液(300份)和水(3×300份)萃取该混合物。将有机层干燥(硫酸钠),并在真空下除去溶剂,得到棕色油。将该油用干柱层析纯化(柱:1000份Matrex二氧化硅,孔径60A,粒径35-70μm,溶剂:正己烷)。收集所需部分,真空除去溶剂,得到(z,z,z)十八碳-6,9,12-三烯酸胆固醇酯(1A),为淡黄色非可蒸馏油。
实施例3
(z,z,z,z,z)二十碳-5,8,11,14,17-五烯酸胆固醇酯(1C)的制备:将330份胆固醇醋酸酯(2B)、270份(z,z,z,z,z)二十碳-5,8,11,14,17-五烯酸甲酯(3CMe)和5份乙醇钠的混合物在真空下加热(110℃/0.01mmHg)搅拌4小时。冷却后,将残留物用中压柱层析纯化(柱:10000份的Matrex二氧化硅,孔径60A,粒径35-70μm,溶剂:含1%乙醚的己烷溶液)。收集所需流分,经真空蒸发,得(z,z,z,z,z)二十碳-5,8,11,14,17-五烯酸胆固醇酯(1C),为无色非可蒸馏油。
用等当量的(z,z,z,z)二十碳-5,8,11,14-四烯酸甲酯(3BMe)代替(z,z,z,z,z)二十碳-5,8,11,14,17-五烯酸甲酯,可得到(z,z,z,z)二十碳-5,8,11,14-四烯酸胆固醇酯(1B),为无色非可蒸馏油。
实施例4
(z,z,z,z,z,z)-4,7,10,13,16,19-六烯酸胆固醇酯(1D)的制备:在氮气下,向118份胆固醇(2A)、69份二环已基碳二亚胺和41份4-二甲氨基吡啶的二氯甲烷(2000份)溶液中加入100份(z,z,z,z,z,z)二十二碳-4,7,10,13,16,19-六烯酸(3DH)。将该混合物在室温下搅拌2小时,然后过滤,除去沉淀的二环已基脲。滤液在室温下真空蒸发,使残留物经干柱层析纯化(柱:10000份Matrex二氧化硅,孔径60A,粒径35-70μm,溶剂:9∶1正己烷∶乙醚)。收集所需部分,真空蒸发,得到(z,z,z,z,z,z)二十二碳-4,7,10,13,16,19-六烯酸胆固醇酯(1D),为无色非可蒸馏油。
用法
该胆固醇酯可经口服、局部、非肠道(皮下、肌内、静脉内)、肠内、直肠内、阴道内或通过其他适宜的途径给药。它们可以被制成片剂、硬或软胶囊、锭剂、乳剂、肠内或不经肠的制剂、泡沫剂、软膏、乳膏、洗剂、栓剂、阴道药栓或其他任何为本领域技术人员所公知的适宜剂型。它们可以被制成药用制剂,或制成有特别医疗和保健目的的食品,也可制成护肤用品。以总脂肪酸计,用在这些不同制剂中的胆固醇酯可含高于20重量%的所需的特定脂肪酸酯,多于40%较好,多于70%更好,最理想的是高于90%。根据供口服或非肠道或局部给药的剂量可以适当地配制制剂,以便每日释放1mg-100g胆固醇酯,以100mg-20g较好,以500mg-10g为最好。当配制供局部用药或肠内或非肠道内给药制剂或食物时,配方中胆固醇酯的含量可为终制剂的0.01-60重量%,0.1-30重量%较好,1-10重量%最好。
该制剂可用于保持健康或治疗任何可能与脂肪酸有关的疾病,尤其是治疗癌症,癌细胞常具有大量的LDL受体,所以,可能与大量的脂肪酸结合,该酸来自所给药物中的胆固醇酯。
通过下列制剂实施例进一步举例说明本发明。
制剂实施例
1.含100mg、250mg、500mg或750mgγ-亚麻酸胆固醇酯的软明胶胶囊。
2.含100mg、200mg、500mg或750mgγ-亚麻酸胆固醇酯的硬明胶胶囊。
3.含0.1-50重量%γ-亚麻酸胆固醇酯的锭剂或其他口服剂型,包括餐后甜食(whips)、泡沫状物(foams)、巧克力或肠内的或肠道外的食品。
4.含0.1-50重量%的γ-亚麻酸胆固醇酯的局部护肤或药用制剂如:乳膏、软膏或洗剂或其他制剂。
5.含100mg、250mg、500mg或750mg的γ-亚麻酸胆固醇酯的片剂。
6.γ-亚麻酸胆固醇酯的含量为0.1-20重量%的供肠内和肠道外给药的乳剂。
7-12.除含DGLA-胆固醇酯外处方同1-6的制剂。
13-18.除含EPA-胆固醇酯外,处方同1-6的制剂。
19-24.除含二十二碳六烯酸、十八碳四烯酸或Columbinic acid外,处方同1-6的制剂。
25-30.除含花生四烯酸、肾上腺酸或stearidonic acid外,处方同1-6的制剂。
31-36.除含亚油酸或α-亚麻酸外,处方同1-6的制剂。
37-72.如1-36的制剂,其中所需胆固醇酯占制剂当中所有胆固醇酯的比例一般为20%以上,40%以上较好,70%以上更好,90%以上最好。
Claims (8)
1、用于药用、护肤或营养组合物中的胆固醇和选自n-3和n-6必需脂肪酸中的脂肪酸、十八碳四烯酸及columbinic acid所成的酯。
2、如权利要求1所述的用于制备药用、护肤或营养组合物的酯在下述疾病状态方面的用途:需要促进转运脂肪酸进入细胞内间隙或需要不易氧化的稳定形式的脂肪酸。
3、按权利要求2的酯的用途,其中疾病是癌症或动脉粥样硬化症。
4、按权利要求2的酯的用途,其中疾病是糖尿病的并发症如:神经病、视网膜和心血管疾病;炎症是其重要症状的疾病如类风湿性关节炎,骨关节炎、湿疹、肠炎、牛皮癣和各种自身免疫疾病;大脑和精神疾病如精神分裂症、酒精中毒和痴呆症包括阿耳茨海默氏病和多梗塞痴呆。
5、权利要求2至4中任一权项的用途,其中所用胆固醇酯制剂中所需特定脂肪酸酯的含量为总脂肪酸重量的20%以上,为40%以上较好,70%以上更好,90%以上最好。
6、按权利要求2至4中任一权项的用途,其中胆固醇酯配制要求为:每日释放1mg-100g特定酯,每日释放特定酯100mg-20g更好,以500mg-10g为最好。
7、按权利要求2至4中任一权项的用途,其中,制剂中特定胆固醇酯占成品制剂重量的0.01-60%,以0.1-30%为佳,1-10%更好。
8、迄今为止,n-6和n-3必需脂肪酸、十八碳四烯酸和columbinicacid的胆固醇酯均为新化合物。
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GB939300125A GB9300125D0 (en) | 1993-01-06 | 1993-01-06 | Compositions containing esters of unsaturated fatty acids |
GB9300125.3 | 1993-01-06 |
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1993
- 1993-01-06 GB GB939300125A patent/GB9300125D0/en active Pending
- 1993-12-23 NZ NZ250583A patent/NZ250583A/xx unknown
- 1993-12-29 DK DK93310599T patent/DK0606012T3/da active
- 1993-12-29 DE DE69319710T patent/DE69319710T2/de not_active Expired - Fee Related
- 1993-12-29 ES ES93310599T patent/ES2119871T3/es not_active Expired - Lifetime
- 1993-12-29 EP EP93310599A patent/EP0606012B1/en not_active Expired - Lifetime
- 1993-12-29 AT AT93310599T patent/ATE168267T1/de not_active IP Right Cessation
- 1993-12-30 AU AU52763/93A patent/AU673555B2/en not_active Ceased
-
1994
- 1994-01-04 MY MYPI94000009A patent/MY110765A/en unknown
- 1994-01-04 ZA ZA9425A patent/ZA9425B/xx unknown
- 1994-01-05 RU RU94000061A patent/RU2142468C1/ru active
- 1994-01-05 CA CA002112824A patent/CA2112824A1/en not_active Abandoned
- 1994-01-05 NO NO940035A patent/NO940035D0/no unknown
- 1994-01-06 KR KR1019940000159A patent/KR940018088A/ko not_active Application Discontinuation
- 1994-01-06 US US08/178,553 patent/US5604216A/en not_active Expired - Fee Related
- 1994-01-06 JP JP6000338A patent/JPH06234644A/ja active Pending
- 1994-01-06 CN CN94100242A patent/CN1096197A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
DE69319710D1 (de) | 1998-08-20 |
EP0606012B1 (en) | 1998-07-15 |
MY110765A (en) | 1999-03-31 |
ES2119871T3 (es) | 1998-10-16 |
KR940018088A (ko) | 1994-08-16 |
DK0606012T3 (da) | 1999-04-19 |
RU2142468C1 (ru) | 1999-12-10 |
US5604216A (en) | 1997-02-18 |
GB9300125D0 (en) | 1993-03-03 |
AU673555B2 (en) | 1996-11-14 |
CA2112824A1 (en) | 1994-07-07 |
AU5276393A (en) | 1994-07-14 |
EP0606012A1 (en) | 1994-07-13 |
ZA9425B (en) | 1994-08-19 |
NO940035L (zh) | 1994-07-07 |
DE69319710T2 (de) | 1999-03-11 |
NZ250583A (en) | 1997-08-22 |
ATE168267T1 (de) | 1998-08-15 |
JPH06234644A (ja) | 1994-08-23 |
NO940035D0 (no) | 1994-01-05 |
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SE01 | Entry into force of request for substantive examination | ||
C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |