公开(公告)号：EP2324824A3

公开(公告)日：2011-06-15

申请号：EP10191670.8

申请日：2010-11-18

申请人： Instytut Medycyny Doswiadczalnej I Klinicznej ,  Uniwersytet Warszawski ,  Instytut Farmakologii PAN

发明人： Pokorski, Mieczyslaw ,  Rekawek,, Agnieszka ,  Zajac,, Dominika ,  Czarnocki,, Zbigniew ,  Przegalinski,, Edmund ,  Konieczny,, Jolanta ,  Roszkowski, Piotr

IPC分类号： A61K31/165 ,  A61P25/00 ,  A61P25/16

CPC分类号： A61K31/165

摘要： The subject of the present invention is the medical application of N-oleoyl-dopamine and 3'-O-methyl-N-oleoyl-dopamine for the production of a medication for treatment or prophylaxis of disturbances or states due to deficiency of dopamine, preferably chosen from the group covering oxygen deficiencies (hypoxia) in anesthetized and awake mammals, breathing with atmospheric oxygen (normoxia), for the respiratory responses to hypoxia in mammals, lack of dopamine binding to the membrane system in the mammalian brain, disturbances in metabolic pathways of dopamine metabolism, states of dopamine deficiencies provoked by morbid or genetic factors as well as under condition connected to the physiological process of aging of the organism, through the systemic introduction of the compound to the mammalian organism.
The subject of the present invention is also the method of production of 3'-O-methyl-N-oleoyl-dopamine in vitro which consists of, according to the present invention, a reaction of 3-O-methyl-dopamine hydrochloride with oleic acid in the presence of, preferably, BOP
(Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), DCC ( N , N '-dicyclohexylcarbodiimide), DMAP (4-Dimethylaminopyridine) and THF (tetrahydrofuran), CH 2 Cl 2 (dichloromethane), CHCl 3 (chloroform), toluene, diethyl ether. The reaction mixture is cooled to temperature of 0-10°C, a solution of trietanolamine is added under continuous stirring and
3'-O-methyl-N-oleoyl-dopamine is precipitated and purified by a known method.
A variant of the method of production of 3'-O-methyl-N-oleoyl-dopamie consists of, according to the present invention, a reaction of methylation of N-oleoyl-dopamine by the catechol-O-methyltransferase (COMT) in the presence of
S-adenosyl-L-methionine (SAM) and magnesium ions in phosphate buffered saline (PBS) solution buffered to pH of 7.0-8.0 at temperature of 25-45°C, followed by the precipitation and purification of 3'-O-methyl-N-oleoyl-dopamine by a known method.

公开(公告)号：EP2324824A2

公开(公告)日：2011-05-25

申请号：EP10191670.8

申请日：2010-11-18

申请人： Instytut Medycyny Doswiadczalnej I Klinicznej ,  Uniwersytet Warszawski ,  Instytut Farmakologii PAN

发明人： Pokorski, Mieczyslaw ,  Rekawek,, Agnieszka ,  Zajac,, Dominika ,  Czarnocki,, Zbigniew ,  Przegalinski,, Edmund ,  Konieczny,, Jolanta ,  Roszkowski, Piotr

IPC分类号： A61K31/165 ,  A61P25/00 ,  A61P25/16

CPC分类号： A61K31/165

摘要： The subject of the present invention is the medical application of N-oleoyl-dopamine and 3'-O-methyl-N-oleoyl-dopamine for the production of a medication for treatment or prophylaxis of disturbances or states due to deficiency of dopamine, preferably chosen from the group covering oxygen deficiencies (hypoxia) in anesthetized and awake mammals, breathing with atmospheric oxygen (normoxia), for the respiratory responses to hypoxia in mammals, lack of dopamine binding to the membrane system in the mammalian brain, disturbances in metabolic pathways of dopamine metabolism, states of dopamine deficiencies provoked by morbid or genetic factors as well as under condition connected to the physiological process of aging of the organism, through the systemic introduction of the compound to the mammalian organism.
The subject of the present invention is also the method of production of 3'-O-methyl-N-oleoyl-dopamine in vitro which consists of, according to the present invention, a reaction of 3-O-methyl-dopamine hydrochloride with oleic acid in the presence of, preferably, BOP
(Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), DCC ( N , N '-dicyclohexylcarbodiimide), DMAP (4-Dimethylaminopyridine) and THF (tetrahydrofuran), CH 2 Cl 2 (dichloromethane), CHCl 3 (chloroform), toluene, diethyl ether. The reaction mixture is cooled to temperature of 0-10°C, a solution of trietanolamine is added under continuous stirring and
3'-O-methyl-N-oleoyl-dopamine is precipitated and purified by a known method.
A variant of the method of production of 3'-O-methyl-N-oleoyl-dopamie consists of, according to the present invention, a reaction of methylation of N-oleoyl-dopamine by the catechol-O-methyltransferase (COMT) in the presence of
S-adenosyl-L-methionine (SAM) and magnesium ions in phosphate buffered saline (PBS) solution buffered to pH of 7.0-8.0 at temperature of 25-45°C, followed by the precipitation and purification of 3'-O-methyl-N-oleoyl-dopamine by a known method.

摘要翻译： 本发明的主题是N-油酰多巴胺和3'-O-甲基-N-油酰多巴胺在制备用于治疗或预防由于多巴胺缺乏引起的干扰或状态的药物中的医学应用，优选地 选自麻醉和清醒的哺乳动物中的氧缺乏（缺氧），呼吸大气氧（常氧）），哺乳动物的呼吸反应低氧，缺乏多巴胺结合哺乳动物脑中的膜系统，代谢途径紊乱 通过将化合物全面引入哺乳动物生物体中，多巴胺代谢的状态由病态或遗传因素引起的多巴胺缺乏状态以及与生物衰老生理过程相关的条件下发生。 本发明的主题还是体外制备3'-O-甲基-N-油酰多巴胺的方法，其由根据本发明的3-O-甲基多巴胺盐酸盐与油酸的反应 （苯并三唑-1-基 - 氧 - 三 - （二甲氨基）鏻六氟磷酸盐），DCC（N，N'-二环己基碳二亚胺），DMAP（4-二甲氨基吡啶）和THF（四氢呋喃）存在下， CH 2 Cl 2（二氯甲烷），CHCl 3（氯仿），甲苯，乙醚。 将反应混合物冷却至0-10℃，在连续搅拌下加入三乙醇胺溶液，通过已知方法将3'-O-甲基-N-油酰 - 多巴胺沉淀和纯化。 根据本发明的制备3'-O-甲基-N-油酰基 - 多巴胺的方法的变体由邻苯二酚-O-甲基转移酶（COMT）在N-甲基-N-甲基 - 多巴胺中的甲基化反应 在磷酸盐缓冲盐水（PBS）溶液中存在S-腺苷-L-甲硫氨酸（SAM）和镁离子，pH为7.0-8.0，温度为25-45℃，然后沉淀和纯化3'- O-甲基-N-油酰基多巴胺。