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    POLYMORPHIC FORMS OF OLOPATADINE HYDROCHLORIDE AND METHODS FOR PRODUCING OLOPATADINE AND SALTS THEREOF
    2.
    发明申请
    POLYMORPHIC FORMS OF OLOPATADINE HYDROCHLORIDE AND METHODS FOR PRODUCING OLOPATADINE AND SALTS THEREOF 审中-公开
    奥伐他汀氢氯化物的多晶型及其制备方法及其制备方法

    公开(公告)号：WO2007110761A8

    公开(公告)日：2007-12-27

    申请号：PCT/IB2007000793

    申请日：2007-03-23

    Applicant: UNIV ZUERICH ,  AZAD PHARMACEUTICAL INGREDIENT

    Inventor： BADER THOMAS ,  BICHSEL HANS-ULRICH ,  GILOMEN BRUNO ,  MEYER-WILMES IMELDA ,  SUNDERMEIER MARK

    IPC: C07D313/12 ,  A61K31/335 ,  A61P37/00 ,  C07F9/54

    CPC classification number: C07F9/5325 ,  C07D313/12 ,  C07F9/5352 ,  C07F9/5442

    Abstract: The invention concerns a process for preparing olopatadine or a salt thereof, comprising:. (a) reacting 11-oxo-6,11-dihydroxydibenz[b,e]oxepin-2-acetic acid, a Wittig reagent selected from the group consisting of 3-dimethylamino-propyltriphenylphosphonium halides and salts thereof, and a suitable base, under Wittig reaction conditions, to provide a reaction mixture containing olopatadine; (b) adding an amount of water sufficient to protonate residual ylide present in the reaction mixture to provide a hydrolyzed reaction mixture; (c) adjusting, if necessary, the pH of the hydrolyzed reaction mixture, or aqueous phase thereof, to a pH of about pH 12 or higher to convert excess 3-dimethylamino- propyltriphenylphosphonium halide, or salt thereof, into 3-dimethylamino- propyldiphenylphosphine oxide; (d) extracting the solution of step (c) with a suitable solvent to provide a solution containing a diastereomeric mixture of olopatadine and (E)-11 -[3-dimethylaminopropylidene]- 6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid and having a substantially reduced amount of 3- dimethylamino-propyldiphenylphosphine oxide; (e) adjusting the pH of the solution obtained in step (d) to a pH between pH 4 and pH 5 to provide acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]- 6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid; (f) extracting the acid-addition salts of olopatadine and (E)-11-[3- dimethylaminopropylidene]-6,l l-dihydrodibenz[b,e]oxepin-2-acetic with a water-miscible solvent selected from the group consisting of (i) n-butanol; and (ii) mixtures of methyl-THF and a C1-C4 alcohol; provided that if the selected solvent is a mixture of methyl-THF and a Cl - C4 alcohol, then the solution is evaporated and the residue is taken up in n-butanol/water; (g) concentrating by azeotropic distillation the n-butanol/water solvent containing the acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]-6,11- dihydrodibenz[b,e]oxepin-2-acetic acid; and (h) fractionnally crystallizing the acid-addition salt of olopatadine.

    Abstract translation: 本发明涉及一种制备奥洛他定或其盐的方法，包括： （a）使11-氧代-6,11-二羟基二苯并[b，e]氧杂七环素-2-乙酸，选自3-二甲基氨基 - 丙基三苯基鏻卤化物及其盐的Wittig试剂和合适的碱， 维蒂希反应条件，提供含奥洛他定的反应混合物; （b）加入一定量的足以使存在于反应混合物中的残留叶立德质子化的水以提供水解的反应混合物; （c）如果需要，将水解的反应混合物或其水相的pH调节至约pH 12或更高的pH以将过量的3-二甲基氨基 - 丙基三苯基鏻卤化物或其盐转化为3-二甲基氨基 - 丙基二苯基膦 氧化物; （d）用合适的溶剂提取步骤（c）的溶液，以提供含有奥洛他定与（E）-11- [3-二甲氨基亚丙基] -6,11-二氢二苯并[b，e]氧杂七环素的非对映体混合物的溶液 -2-乙酸，并且具有显着减少量的3-二甲基氨基 - 丙基二苯基氧化膦; （e）将步骤（d）中获得的溶液的pH调节至pH4和pH5之间的pH，以提供奥洛他定和（E）-11- [3-二甲基氨基亚丙基] -6,1,1-三氟乙酸的酸加成盐， 二氢二苯并[b，e]氧杂七环素-2-乙酸; （f）用选自下组的水混溶性溶剂萃取奥洛他定和（E）-11- [3-二甲基氨基亚丙基] -6,11-二氢二苯并[b，e]氧杂七环素-2-乙酸的酸加成盐 由（i）正丁醇组成; 和（ii）甲基-THF和C1-C4醇的混合物; 条件是如果所选择的溶剂是甲基-THF和C1-C4醇的混合物，则将溶液蒸发并将残余物溶于正丁醇/水中; （g）通过共沸蒸馏浓缩含有奥洛他定和（E）-11- [3-二甲基氨基亚丙基] -6,11-二氢二苯并[b，e]氧杂七环素-2-乙酸的酸加成盐的正丁醇/水溶剂 酸; 和（h）将奥洛他定的酸加成盐分级结晶。

    POLYMORPHIC AND PSEUDOPOLYMORPHIC FORMS OF TRANDOLAPRILAT, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR PRODUCTION AND USE
    3.
    发明申请
    POLYMORPHIC AND PSEUDOPOLYMORPHIC FORMS OF TRANDOLAPRILAT, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR PRODUCTION AND USE 审中-公开
    三萜皂甙，药物组合物的多晶型和假多晶型以及生产和使用方法

    公开(公告)号：WO2007113680A3

    公开(公告)日：2007-12-06

    申请号：PCT/IB2007001027

    申请日：2007-04-04

    Applicant: AZAD PHARMACEUTICAL INGREDIENT ,  UNIV ZUERICH

    Inventor： BADER THOMAS

    IPC: C07D209/42 ,  A61K31/404 ,  A61P9/12

    CPC classification number: C07D209/42

    Abstract: The present invention provides novel polymorphic and pseudopolymorphic forms of Trandolaprilat, including crystalline Trandolaprilat Form A, crystalline Trandolaprilat Form B, crystalline Trandolaprilat Form C, crystalline Trandolaprilat Form D, crystalline Trandolaprilat Form E, and mixtures thereof. The invention also provides novel methods for producing Trandolaprilat, pharmaceutically acceptable salts of Trandolaprilat, and polymorphic and pseudopolymorphic forms of Trandolaprilat, pharmaceutical compositions including one or more novel Trandolaprilat compounds and methods for treating high blood pressure and/or cardiac insufficiency using one or more novel Trandolaprilat compounds.

    Abstract translation: 本发明提供了新的多晶型和假多晶型，包括结晶型Trandolaprilat A型，结晶型Trandolaprilat B型，结晶型Trandolaprilat C型，结晶型Trandolaprilat D型，结晶型Trandolaprilat型E及其混合物。 本发明还提供了用于生产Trandolaprilat，Trandolaprilat的药学上可接受的盐以及Trandolaprilat的多晶型和假多晶型形式的新颖方法，包含一种或多种新Trandolaprilat化合物的药物组合物以及使用一种或多种新型药物治疗高血压和/或心功能不全的方法 Trandolaprilat化合物。

    POLYMORPHIC FORMS OF OLOPATADINE HYDROCHLORIDE AND METHODS FOR PRODUCING OLOPATADINE AND SALTS THEREOF
    4.
    发明申请
    POLYMORPHIC FORMS OF OLOPATADINE HYDROCHLORIDE AND METHODS FOR PRODUCING OLOPATADINE AND SALTS THEREOF 审中-公开
    盐酸奥洛他定的多晶型物及其制备奥洛他定及其盐的方法

    公开(公告)号：WO2007110761A2

    公开(公告)日：2007-10-04

    申请号：PCT/IB2007000793

    申请日：2007-03-23

    Applicant: AZAD PHARMACEUTICAL INGREDIENT ,  BADER THOMAS ,  BICHSEL HANS-ULRICH ,  GILOMEN BRUNO ,  MEYER-WILMES IMELDA ,  SUNDERMEIER MARK

    Inventor： BADER THOMAS ,  BICHSEL HANS-ULRICH ,  GILOMEN BRUNO ,  MEYER-WILMES IMELDA ,  SUNDERMEIER MARK

    IPC: C07D313/12 ,  A61K31/335 ,  A61P37/00 ,  C07F9/54

    CPC classification number: C07F9/5325 ,  C07D313/12 ,  C07F9/5352 ,  C07F9/5442

    Abstract: The invention concerns a process for preparing olopatadine or a salt thereof, comprising:. (a) reacting 11-oxo-6,11-dihydroxydibenz[b,e]oxepin-2-acetic acid, a Wittig reagent selected from the group consisting of 3-dimethylamino-propyltriphenylphosphonium halides and salts thereof, and a suitable base, under Wittig reaction conditions, to provide a reaction mixture containing olopatadine; (b) adding an amount of water sufficient to protonate residual ylide present in the reaction mixture to provide a hydrolyzed reaction mixture; (c) adjusting, if necessary, the pH of the hydrolyzed reaction mixture, or aqueous phase thereof, to a pH of about pH 12 or higher to convert excess 3-dimethylamino- propyltriphenylphosphonium halide, or salt thereof, into 3-dimethylamino- propyldiphenylphosphine oxide; (d) extracting the solution of step (c) with a suitable solvent to provide a solution containing a diastereomeric mixture of olopatadine and (E)-11 -[3-dimethylaminopropylidene]- 6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid and having a substantially reduced amount of 3- dimethylamino-propyldiphenylphosphine oxide; (e) adjusting the pH of the solution obtained in step (d) to a pH between pH 4 and pH 5 to provide acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]- 6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid; (f) extracting the acid-addition salts of olopatadine and (E)-11-[3- dimethylaminopropylidene]-6,l l-dihydrodibenz[b,e]oxepin-2-acetic with a water-miscible solvent selected from the group consisting of (i) n-butanol; and (ii) mixtures of methyl-THF and a C1-C4 alcohol; provided that if the selected solvent is a mixture of methyl-THF and a Cl - C4 alcohol, then the solution is evaporated and the residue is taken up in n-butanol/water; (g) concentrating by azeotropic distillation the n-butanol/water solvent containing the acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]-6,11- dihydrodibenz[b,e]oxepin-2-acetic acid; and (h) fractionnally crystallizing the acid-addition salt of olopatadine.

    Abstract translation: 本发明涉及一种制备奥洛他定或其盐的方法，包括： （a）使11-氧代-6,11-二羟基二苯并[b，e]氧杂-2-乙酸，选自3-二甲基氨基丙基三苯基鏻卤化物及其盐的Wittig试剂与合适的碱 维蒂希反应条件下，提供含有奥洛他定的反应混合物; （b）加入足以使存在于反应混合物中的残留叶立德质子化的水以提供水解的反应混合物; （c）如果需要，将水解的反应混合物或其水相的pH调节至约pH12或更高的pH以将过量的3-二甲基氨基丙基三苯基卤化鏻或其盐转化为3-二甲基氨基 - 丙基二苯基膦 氧化物; （d）用合适的溶剂萃取步骤（c）的溶液以提供含有奥洛他定和（E）-11- [3-二甲基氨基亚丙基] -6,11-二氢二苯并[b，e]氧杂庚英的非对映异构体混合物 -2-乙酸并且具有显着减少量的3-二甲氨基 - 丙基二苯基氧化膦; （e）将步骤（d）中获得的溶液的pH调节至pH 4和pH 5之间的pH，以提供奥洛他定的酸加成盐和（E）-11- [3-二甲基氨基亚丙基] -6,11- 二氢二苯并[b，e]氧杂-2-乙酸; （f）用选自以下的水混溶性溶剂萃取奥洛他定和（E）-11- [3-二甲基氨基亚丙基] -6,11-二氢二苯并[b，e]氧杂-2-乙酸的酸加成盐 由（i）正丁醇; 和（ii）甲基-THF和C 1 -C 4醇的混合物; 条件是如果所选溶剂是甲基-THF和C 1 -C 4醇的混合物，则将溶液蒸发并将残余物溶于正丁醇/水中; （g）通过共沸蒸馏浓缩含有奥洛他定和（E）-11- [3-二甲基氨基亚丙基] -6,11-二氢二苯并[b，e]氧杂-2-乙酸的酸加成盐的正丁醇/水溶剂 酸; 和（h）分次结晶奥洛他定的酸加成盐。

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