公开(公告)号：WO2006055511A3

公开(公告)日：2006-10-05

申请号：PCT/US2005041252

申请日：2005-11-16

Applicant: BIOMARIN PHARM INC ,  JUNGLES STEVEN ,  HENDERSON MARK ,  SLUZKY VICTORIA ,  BAFFI ROBERT

Inventor： JUNGLES STEVEN ,  HENDERSON MARK ,  SLUZKY VICTORIA ,  BAFFI ROBERT

IPC: A61K9/20 ,  A61K31/505 ,  A61P3/00

CPC classification number: A61K31/505 ,  A61K9/2018

Abstract: The present invention is directed to a stable solid formulations of tetrahydrobiopterin, processes for producing them, and treatment methods using such formulations.

Abstract translation: 本发明涉及四氢生物喋呤的稳定固体制剂，其制备方法和使用这些制剂的治疗方法。

公开(公告)号：WO2009088979A1

公开(公告)日：2009-07-16

申请号：PCT/US2009/000030

申请日：2009-01-06

Applicant: BIOMARIN PHARMACEUTICAL INC. ,  HENDERSON, Mark ,  JUNGLES, Steven ,  ROIDL, Gabriele ,  BAFFI, Robert ,  INDOLESE, Adriano ,  MÜLLER, Christian ,  SCHMIDT, Philipp ,  KAISER, Stefan

Inventor： HENDERSON, Mark ,  JUNGLES, Steven ,  ROIDL, Gabriele ,  BAFFI, Robert ,  INDOLESE, Adriano ,  MÜLLER, Christian ,  SCHMIDT, Philipp ,  KAISER, Stefan

IPC: C07D487/04

CPC classification number: C07D487/04

Abstract: The present disclosure provides a method that efficiently produces ( 6R )- tetrahydrobiopterin in high yield and purity. The method includes the step of hydrolyzing diacetylbiopterin to biopterin under basic conditions in a biphasic mixture comprising an organic phase and an aqueous phase. After substantially complete hydrolysis of diacetylbiopterin, the aqueous phase containing biopterin can be separated from the organic phase containing most of the organic impurities, which avoids the time-consuming step of isolating biopterin as a solid. The aqueous solution containing biopterin is stereoselectively hydrogenated to ( 6R )-tetrahydrobiopterin under basic conditions and high hydrogen pressure in the presence of a metal catalyst ( e.g. , a platinum catalyst). To improve the purification of an acid addition salt of ( 6R )-tetrahydrobiopterin ( e.g. , ( 6R )-tetrahydrobiopterin dihydrochloride), any residual salts ( e.g. , sodium salts) in the aqueous solution after the hydrogenation reaction can be removed by contacting the aqueous solution with an ion ( e.g. , cation) exchange resin or column. Alternatively, removal of residual salts from the aqueous solution can be omitted if an organic amine ( e.g. , diethylamine or triethylamine) rather than an inorganic base is used in the hydrolysis and/or hydrogenation reactions

Abstract translation: 本公开提供了以高产率和纯度有效生产（6R） - 四氢生物喋呤的方法。 该方法包括在碱性条件下在包含有机相和水相的两相混合物中将二乙酰生物蝶呤水解成生物蝶呤的步骤。 在二乙酰生物蝶呤基本上完全水解后，含有生物蝶呤的水相可以从含有大部分有机杂质的有机相中分离出来，这避免了将生物蝶呤分离成固体的耗时的步骤。 含有生物蝶呤的水溶液在碱性条件下，在金属催化剂（例如铂催化剂）存在下，氢压高，立体选择氢化成（6R） - 四氢生物喋呤。 为了改进（6R） - 四氢生物蝶呤（例如（6R） - 四氢生物喋呤二盐酸盐）的酸加成盐的纯化，氢化反应后的水溶液中的任何残留盐（例如钠盐）可以通过使水溶液 溶液与离子（如阳离子）交换树脂或色谱柱。 或者，如果在水解和/或氢化反应中使用有机胺（例如二乙胺或三乙胺）而不是无机碱，则可以从水溶液中除去残留的盐

公开(公告)号：WO2006055511A2

公开(公告)日：2006-05-26

申请号：PCT/US2005/041252

申请日：2005-11-16

Applicant: BIOMARIN PHARMACEUTICAL INC. ,  JUNGLES, Steven ,  HENDERSON, Mark ,  SLUZKY, Victoria ,  BAFFI, Robert

Inventor： JUNGLES, Steven ,  HENDERSON, Mark ,  SLUZKY, Victoria ,  BAFFI, Robert

IPC: A61K9/20 ,  A61K31/505 ,  A61P3/00

CPC classification number: A61K31/505 ,  A61K9/2018

Abstract: The present invention is directed to a stable solid formulations of tetrahydrobiopterin, processes for producing them, and treatment methods using such formulations.

Abstract translation: 本发明涉及四氢生物喋呤的稳定固体制剂，其生产方法和使用这些制剂的治疗方法。