Total synthesis method for making an indole structure derivative product class, of the triptamine type, in particular, melatonin or N-acetyl-5-methoxytriptamine type, having a high purity degree and easily soluble, for therapeutic use against acquired immuno-deficiency syndromes
申请人:I.F.L.O. S.a.s. di Giorgio e Aldo Laguzzi
公开号:EP0330625A2
公开(公告)日:1989-08-30
The present invention relates to :
1) a method for the total synthesis of an indole structure derivative product class,of the triptamine type, in particular of the melatonine or N-Acetyl-5-Methoxy-triptamine type;
2) the use of melatonine or N-acetyl-5-methoxytriptamine as a drug with doses from 2 mg to 20 mg per day,in an oral,intramuscolar or endovenous way;
3) the use of melatonine or N-acetyl-5-methoxytriptamine, in combination with an azidothymidine treating process, in order to improve the curative effects.
The subject total synthesis process consists of combining potassium phthalamide and di-bromopropane in order to obtain 3-bromopropylphthalamide;adding, in the presence of ethanol dissolved sodium,acetacetic esther in order to obtain ethyl-2-acetyl-5-phthalimido-penta noate ;adding diazo-p-anisidine so as to obtain 2-carboxyethyl-3-(2-phthalimidoethyl)-5-methoxy-indole.
The main feature of the invention is that to the 2-carboxyethyl-3-(2-phthalimidoethyl)-5-methoxy-indole there are added NaOH 2N and 20% H₂SO₄ in order to obtain raw 5-methoxytriptamine;which is purified by means of hexamethyldisilazane,with the formation of the related mono and bi-derivative therefrom there is obtained the starting product which is purified by means of aqueous methanol.
The subject method,in particular,is specifically designed for provided high purity melatonine,or N-acetyl-5-methoxytriptamine,with a great yield,which is water soluble and may be used for therapeutic purposes.
The thus obtained melatonine,has such a purity that it can be used,in suitable packages,both in tumoral phrophilaxy and tumoral terapy,as well as against the acquired immuno-deficiency syndromes,o so called AIDS.
本发明涉及:
1) 三色胺类吲哚结构衍生物产品,特别是褪黑素或N-乙酰基-5-甲氧基-triptamine类吲哚结构衍生物产品的全合成方法;
2) 使用褪黑素或 N-乙酰基-5-甲氧基-triptamine 作为药物,每天剂量从 2 毫克到 20 毫克不等,口服、肌注或静脉注射;
3) 将褪黑素或 N-乙酰-5-甲氧基雷公藤多甙与叠氮胸苷治疗过程结合使用,以提高疗效。
本发明的总合成工艺包括:将邻苯二甲酰胺钾和二溴丙烷混合,得到 3-溴丙基邻苯二甲酰胺;在乙醇溶解钠的存在下,加入乙酸乙酯,得到 2-乙酰基-5-酞酰亚胺基五壬酸乙酯;加入重氮对甲氧基苯胺,得到 2-羧乙基-3-(2-酞酰亚胺基乙基)-5-甲氧基吲哚。
本发明的主要特点是,在 2-羧乙基-3-(2-酞酰亚胺基乙基)-5-甲氧基-吲哚中加入 2N NaOH 和 20% H₂SO₄ 以得到 5-甲氧基三尖杉胺原料;该原料通过六甲基二硅氮烷纯化,形成相关的单衍生物和双衍生物,从而得到起始产物,该起始产物通过甲醇水溶液纯化。
该方法特别设计用于提供高纯度的褪黑素或 N-乙酰基-5-甲氧基三尖杉酯胺,产量高,可溶于水,可用于治疗目的。
由此获得的褪黑素纯度极高,可以在适当的包装中用于肿瘤治疗和肿瘤治疗,也可用于防治获得性免疫缺陷综合症(即所谓的艾滋病)。