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    Method of preparing optically pure precursors of paroxetine
    1.
    发明授权
    Method of preparing optically pure precursors of paroxetine 失效
    制备帕罗西汀光学纯的前体的方法

    公开(公告)号：US5258517A

    公开(公告)日：1993-11-02

    申请号：US926254

    申请日：1992-08-06

    申请人： Charles M. Zepp ,  Yun Gao ,  Donald L. Heefner

    发明人： Charles M. Zepp ,  Yun Gao ,  Donald L. Heefner

    IPC分类号： C07D211/22 ,  C07D211/88 ,  C12P41/00

    CPC分类号： C07D211/88 ,  C07D211/22 ,  C12P41/005

    摘要： A biocatalytic method of preparing optically pure precursors of paroxetine and a method of preparing paroxetine therefrom are disclosed. A racemic trans ester precursor compound of paroxetine is first prepared. The racemic trans ester precursor compound comprises a mixture of (3S,4R) and (3R,4S) enantiomers. The (3R,4S) enantiomer is hydrolyzed biocatalytically to the corresponding (3R,4S)-trans carboxylic acid or alternatively, the (3S,4R) enantiomer is biocatalytically hydrolyzed the to (3S,4R)-trans carboxylic acid in a reaction catalyzed by a isolated enzyme or a microorganism. In the first instance, the unhydrolyzed (3S,4R) enantiomer is separated from the (3R,4S)-trans carboxylic acid, whereas in the second instance the (3S,4R)-trans carboxylic acid is separated from the unhydrolyzed (3R,4S) enantiomer. The (3S,4R) enantiomer obtained following the selective hydrolysis is reduced to form a (-)-trans-(3S,4R) primary alcohol precursor of paroxetine. Paroxetine is then formed from the (-)-trans-(3S,4R) primary alcohol precursor.

    摘要翻译： 公开了制备帕罗西汀光学纯的前体的生物催化方法及其制备帕罗西汀的方法。 首先制备帕罗西汀的外消旋转酯前体化合物。 外消旋反式酯前体化合物包含（3S，4R）和（3R，4S）对映异构体的混合物。 将（3R，4S）对映异构体生物催化水解生成至相应的（3R，4S） - 羧酸，或者（3S，4R）对映异构体在反应催化下生物催化水解成（3S，4R） - 反式羧酸 通过分离的酶或微生物。 在第一种情况下，从（3R，4R） - 反式羧酸分离出未水解的（3S，4R）对映异构体，而在第二种情况下，将（3S，4R） - 反式羧酸与未水解的（3R， 4S）对映异构体。 在选择性水解后获得的（3S，4R）对映异构体被还原形成帕罗西汀的（ - ） - 反 - （3S，4R）伯醇前体。 然后由（ - ） - 反 - （3S，4R）伯醇前体形成帕罗西汀。

    Method for inactivating non-enveloped viruses using a viricide-potentiating agent with a photoactivatible virucide
    2.
    发明授权
    Method for inactivating non-enveloped viruses using a viricide-potentiating agent with a photoactivatible virucide 失效
    使用杀病毒剂增强剂与光活化型病毒杀灭剂灭活非包膜病毒的方法

    公开(公告)号：US5663043A

    公开(公告)日：1997-09-02

    申请号：US368780

    申请日：1995-01-04

    申请人： Charles M. Zepp ,  Donald L. Heefner

    发明人： Charles M. Zepp ,  Donald L. Heefner

    IPC分类号： A61L2/00 ,  C12N7/06 ,  A01N1/02

    CPC分类号： C12N7/00 ,  A61L2/0011 ,  A61L2/0088 ,  C12N2710/10363 ,  C12N2750/14363 ,  C12N2770/32463 ,  C12N2770/32663

    摘要： Method for inactivating non-enveloped viruses using a viricide-potentiating agent. In a preferred embodiment, the method may be used to inactivate non-enveloped viruses present within a sample of whole blood or a blood product and comprises (a) adding to the blood sample a photoactivatable viricide, such as a psoralen, hypericin, methylene blue, toluidine blue or the like, which, when activated, is effective in inactivating enveloped viruses; (b) adding to the blood sample a viricide-potentiating chemical agent that increases the sensitivity of non-enveloped viruses to the activated viricide; and (c) activating the photoactivatable viricide. Preferably, the viricide-potentiating chemical agent includes a first moiety which possesses an affinity for a component of the non-enveloped virus and a second moiety which includes a lipid tail, the first and second moieties being structurally interrelated so that, when the first moiety becomes associated with a component of the non-enveloped virus, the second moiety penetrates or at least partially surrounds the viral capsid of the non-enveloped virus. Examples of the chemical agent include cationic lipopolyamines, such as dioctadecylamidoglycylspermine.

    摘要翻译： 使用杀病毒剂增效剂灭活非包膜病毒的方法。 在优选的实施方案中，该方法可用于灭活全血或血液制品样品中存在的非包膜病毒，并且包括（a）向血液样品中加入可光活化的杀戮剂，例如补骨脂素，金丝桃素，亚甲基蓝 甲苯胺蓝等，其在活化时有效灭活包膜病毒; （b）向血液样品中加入增加非包膜病毒对活化杀戮剂的敏感性的杀病剂增效化学试剂; 和（c）活化可光活化杀戮剂。 优选地，杀病毒剂增强化学试剂包括对非包膜病毒的组分具有亲和力的第一部分和包含脂质尾部的第二部分，第一和第二部分在结构上相互关联，使得当第一部分 变得与非包膜病毒的组分相关联，第二部分渗透或至少部分地包围非包膜病毒的病毒衣壳。 化学试剂的实例包括阳离子脂多胺，如双十八烷基酰氨基甘氨酰精胺。

    Optical resolution of alkyl 1,4-benzodioxan-2-carboxylates using esterase from serratia marcescens
    3.
    发明授权
    Optical resolution of alkyl 1,4-benzodioxan-2-carboxylates using esterase from serratia marcescens 失效
    使用来自粘质沙雷氏菌的酯酶对1,4-苯并二恶烷-2-羧酸烷基酯进行光学拆分

    公开(公告)号：US5529929A

    公开(公告)日：1996-06-25

    申请号：US477381

    申请日：1995-06-07

    申请人： Richard F. Rossi, Jr. ,  Charles M. Zepp ,  Donald L. Heefner

    发明人： Richard F. Rossi, Jr. ,  Charles M. Zepp ,  Donald L. Heefner

    IPC分类号： C12P17/06 ,  C12P41/00

    CPC分类号： C12P17/06 ,  C12P41/005 ,  Y10S435/881

    摘要： A process for resolving racemic alkyl 1,4-benzodioxan-2-carboxylates useful as intermediates in the synthesis of optically pure pharmaceutical compounds such as (S)-doxazosin is disclosed. The process utilizes a microbial enzyme derived from Serratia marcescens to catalyze the enantioselective hydrolysis of the alkyl (S)-1,4-benzodioxan-2-carboxylate enantiomer of the racemic mixture to its corresponding carboxylic acid at a faster rate than the R-enantiomer. An enantiomerically pure S-configured carboxylic acid is thereby formed for subsequent pharmaceutical synthesis. The nonhydrolyzed alkyl (R)-1,4-benzodioxan-2-carboxylate enantiomer can also be isolated and racemized, and the enzymatic hydrolysis reaction repeated.

    摘要翻译： 公开了用于合成光学纯药物化合物如（S） - 恶唑嗪的中间体的外消旋烷基1,4-苯并二恶烷-2-羧酸酯的方法。 该方法利用来自粘质沙雷氏菌的微生物酶催化外消旋混合物的（S）-1,4-苯并二恶烷-2-羧酸烷基酯对映异构体对映选择性水解速率比R对映异构体 。 由此形成对映异构体纯的S-构型的羧酸用于随后的药物合成。 还可以分离非水解的（R）-1,4-苯并二恶烷-2-羧酸烷基酯对映异构体并进行外消旋化，并重复酶水解反应。

    Optical resolution of alkyl chroman-2-carboxylates
    6.
    发明授权
    Optical resolution of alkyl chroman-2-carboxylates 失效
    烷基色满-2-羧酸酯的光学拆分

    公开(公告)号：US5658796A

    公开(公告)日：1997-08-19

    申请号：US475007

    申请日：1995-06-07

    申请人： Richard F. Rossi, Jr. ,  Charles M. Zepp ,  Donald L. Heefner

    发明人： Richard F. Rossi, Jr. ,  Charles M. Zepp ,  Donald L. Heefner

    IPC分类号： C07D311/66 ,  C12P41/00

    CPC分类号： C07D311/66 ,  C12P41/004 ,  Y10S435/881

    摘要： Described herein is a process for resolving a racemic (C>3) alkyl (R, S) chroman-2-carboxylate compound useful as intermediates in the synthesis of optically pure pharmaceutical compounds is disclosed. The process utilizes a microbial enzyme derived from Serratia marcescens to catalyze the enantioselective hydrolysis of the (C>3) alkyl (S)-chroman-2-carboxylate enantiomer of the racemic mixture to its corresponding carboxylic acid at a faster rate than the R-enantiomer. An enantiomerically pure S-configured carboxylic acid is thereby formed which can undergo acidic esterification to provide an optically pure (C>3) alkyl (S)-chroman-2-carboxylate intermediate for subsequent pharmaceutical synthesis. The nonhydrolyzed (C>3) alkyl (R)-chroman-2-carboxylate enantiomer can also be isolated to provide an optically pure pharmaceutical precursor.

    摘要翻译： 本文描述了一种拆分用作光学纯药物化合物合成中的中间体的外消旋（C 3）烷基（R 3，S）色满-2-羧酸酯化合物的方法。 该方法利用来自粘质沙雷氏菌的微生物酶催化外消旋混合物的（C 3）烷基（S） - 苯并二氢吡喃-2-羧酸酯对映异构体对映体选择性水解速率比R- 对映体。 由此形成对映异构体纯的S-构型的羧酸，其可进行酸性酯化以提供用于随后的药物合成的光学纯的（C 3）烷基（S） - 苯并二氢吡喃-2-羧酸酯中间体。 也可以分离非水解（C 3）烷基（R） - 苯并二氢吡喃-2-羧酸酯对映异构体以提供光学纯的药物前体。

    In vitro method for predicting the evolutionary response of HIV protease to a drug targeted thereagainst
    7.
    发明授权
    In vitro method for predicting the evolutionary response of HIV protease to a drug targeted thereagainst 失效

    公开(公告)号：US6063562A

    公开(公告)日：2000-05-16

    申请号：US420003

    申请日：1995-04-10

    申请人： Laurence M. Melnick ,  Donald L. Heefner

    发明人： Laurence M. Melnick ,  Donald L. Heefner

    IPC分类号： C12N15/09 ,  C12N9/50 ,  C12N15/10 ,  C12Q1/37 ,  C12Q1/68 ,  C12Q1/70

    CPC分类号： C12N9/506 ,  C12N15/1048 ,  C12Q1/37 ,  C12Q1/6811 ,  G01N2333/16 ,  G01N2333/8142 ,  Y10S435/974 ,  Y10S435/975

    摘要： An in vitro method for predicting the identity of distinct, first-generation, drug-resistant, biologically-active, HIV protease mutants that may emerge in vivo in response to a drug targeted thereagainst. In a preferred embodiment, the in vitro method comprises the steps of (a) preparing, in the presence of the drug, a comprehensive library of all first-generation mutants of the protease differing therefrom by at least one and preferably no more than three amino acid substitutions, each of the protease mutants being generated as part of a polyprotein with the HIV reverse transcriptase protein; (b) isolating, in vitro, first-generation, drug-resistant, biologically-active, mutant proteases from said library by assaying for biological activity of the reverse transcriptase protein; and (c) identifying the distinct, first-generation, biologically-active, mutant proteases so isolated. The present invention also relates to an in vitro method for evaluating the efficacy of a drug against a biologically-active mutant or wild-type form of HIV protease, said method comprising the steps of (a) providing a mutant polyprotein, said mutant polyprotein including a biologically-inactive mutant form of the protease linked to HIV reverse transcriptase by one or more sites cleavable by the biologically-active or wild-type form of the protease; (b) adding the drug to the mutant polyprotein; (c) then, adding the biologically-active or wild-type form of the protease to the mutant polyprotein; and (d) then, assaying for the presence of biological activity for reverse transcriptase, whereby the presence of reverse transcriptase activity indicates that the drug is not efficacious against the biologically-active mutant or wild-type form of the protease tested. The present invention further relates to a kit for evaluating the efficacy of a drug against a biologically-active mutant or wild-type form of HIV protease.

    In vitro method for predicting the evolutionary response of a protein to a drug targeted thereagainst
    8.
    发明授权
    In vitro method for predicting the evolutionary response of a protein to a drug targeted thereagainst 失效
    用于预测蛋白质对其靶向药物的进化反应的体外方法

    公开(公告)号：US5766842A

    公开(公告)日：1998-06-16

    申请号：US706178

    申请日：1996-08-30

    申请人： Laurence M. Melnick ,  Donald L. Heefner

    发明人： Laurence M. Melnick ,  Donald L. Heefner

    IPC分类号： C12N9/50 ,  C12N15/10 ,  C12Q1/37 ,  C12Q1/68 ,  C12N15/48 ,  C12Q1/70

    CPC分类号： C12N15/1072 ,  C12N15/1048 ,  C12N9/506 ,  C12Q1/37 ,  C12Q1/6811 ,  G01N2333/16 ,  G01N2333/8142

    摘要： A method for identifying, in vitro, distinct, drug-resistant, biologically-active mutants of a protein that may emerge in vivo in response to a drug targeted against the protein is disclosed. The method involves preparing, by heterologous expression of a library of nucleotide sequences, a complete library of mutant proteins accessible in a single generation. The mutant proteins from the library that are drug resistant are identified. When all the first generation mutants have been identified in the above manner, a combination of drugs can be identified that will block the development of resistance. The same technique allows evaluation of the ultimate clinical efficacy of a drug targeted against the protein by comparing the number of resistant first generation mutants. A preferred protein is an HIV protease.

    摘要翻译： 公开了一种用于鉴定体内可鉴定的针对蛋白质靶向药物可能在体内出现的蛋白质的体外，不同的耐药性，生物活性突变体的方法。 该方法包括通过异源表达核苷酸序列文库来制备在单代中可获得的突变蛋白的完整文库。 鉴定出抗药性的文库突变蛋白。 当所有第一代突变体都以上述方式鉴定时，可以鉴定出将阻止抗性发展的药物组合。 相同的技术允许通过比较抗性第一代突变体的数量来评估靶向蛋白质的药物的最终临床疗效。 优选的蛋白质是HIV蛋白酶。