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    Stereoisomers of p-hydroxy-milnacipran, and methods of use thereof
    1.
    发明授权
    Stereoisomers of p-hydroxy-milnacipran, and methods of use thereof 有权
    对羟基米那普兰的立体异构体及其使用方法

    公开(公告)号：US07038085B2

    公开(公告)日：2006-05-02

    申请号：US10691465

    申请日：2003-10-22

    申请人： Roman V. Rariy ,  Michael Heffernan ,  Stephen L. Buchwald ,  Timothy M. Swager

    发明人： Roman V. Rariy ,  Michael Heffernan ,  Stephen L. Buchwald ,  Timothy M. Swager

    IPC分类号： C07C233/05 ,  A61K31/165

    CPC分类号： C07C237/24 ,  C07B2200/07 ,  C07C2601/02

    摘要： The present invention relates generally to the enantiomers of para-hydroxy-milnacipran or congeners thereof. Biological assays revealed that racemic para-hydroxy-milnacipran is approximately equipotent in inhibiting serotonin and norepinephrine uptake (IC50=28.6 nM for norepinephrine, IC50=21.7 nM for serotonin). Interestingly, (+)-para-hydroxy-milnacipran is a more potent inhibitor of norepinephrine uptake than serotonin uptake (IC50=10.3 nM for norepinephrine, IC50=22 nM for serotonin). In contrast, (−)-para-hydroxy-milnacipran is a more potent inhibitor of serotonin uptake compared to norepinephrin uptake (IC50=88.5 nM for norepinephrine, IC50=40.3 nM for serotonin). The invention also relates to salts and prodrug forms of the aforementioned compounds. In certain embodiments, the compounds of the present invention and a pharmaceutically acceptable excipient are combined to prepare a formulation for administration to a patient. Finally, the present invention relates to methods of treating mammals suffering from various afflictions, e.g., depression, chronic pain, or fibromyalgia, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention.

    摘要翻译： 本发明一般涉及对羟基 - 米那普兰或其同系物的对映异构体。 生物测定显示外消旋的对羟基 - 米那普仑在抑制5-羟色胺和去甲肾上腺素摄取方面几乎是等量的（对于5-羟色胺，对于去甲肾上腺素为IC 50 N = 28.7nM，对于5-羟色胺为131.7nM） 。 有趣的是，（+） - 对羟基 - 米那普仑是去甲肾上腺素摄取的更有效的抑制剂，而不是5-羟色胺摄取（去甲肾上腺素（IC 50）= 22nM 用于5-羟色胺）。 相比之下，与去甲肾上腺素摄取相比，（ - ） - 对羟基 - 米那普仑是一种更有效的5-羟色胺摄取抑制剂，对于去甲肾上腺素，IC 50 <= 50> = 对于5-羟色胺为40.3nM）。 本发明还涉及上述化合物的盐和前药形式。 在某些实施方案中，将本发明的化合物和药学上可接受的赋形剂混合以制备用于给予患者的制剂。 最后，本发明涉及治疗患有各种痛苦，例如抑郁症，慢性疼痛或纤维肌痛的哺乳动物的方法，包括向有需要的哺乳动物施用治疗有效量的本发明化合物。

    Abuse-deterrent pharmaceutical compositions of opiods and other drugs
    2.
    发明授权
    Abuse-deterrent pharmaceutical compositions of opiods and other drugs 有权
    阿片类药物和其他药物的滥用药物组合物

    公开(公告)号：US07399488B2

    公开(公告)日：2008-07-15

    申请号：US10614866

    申请日：2003-07-07

    申请人： Jane Hirsh ,  Alexander M. Kibanov ,  Timothy M. Swager ,  Stephen L. Buchwald ,  Whe Yong Lo ,  Alison B. Fleming ,  Roman V. Rariy

    发明人： Jane Hirsh ,  Alexander M. Kibanov ,  Timothy M. Swager ,  Stephen L. Buchwald ,  Whe Yong Lo ,  Alison B. Fleming ,  Roman V. Rariy

    IPC分类号： A61K9/14 ,  A61K9/50

    CPC分类号： A61K31/485 ,  A61K9/145 ,  A61K9/1617 ,  A61K9/1682 ,  A61K9/1694 ,  A61K9/4858 ,  A61K9/50 ,  A61K9/5052 ,  A61K9/5084 ,  A61K31/20 ,  A61K47/12

    摘要： An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administration of drugs, especially drugs such as opiods. In the preferred embodiment, a drug is modified to increase its lipophilicity. In preferred embodiments the modified drug is homogeneously dispersed within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles or drug particles are coated with one or more coating layers, where at least one coating is water insoluble and preferably organic solvent insoluble, but enzymatically degradable by enzymes present in the human gastrointestinal tract. The abuse-deterrent composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chopping with a blade or crushing) and the resulting material is placed in water, snorted, or swallowed. However, when administered as directed, the drug is slowly released from the composition as the composition is broken down or dissolved gradually within the GI tract by a combination of enzymatic degradation, surfactant action of bile acids, and mechanical erosion.

    摘要翻译： 已经开发了一种滥用威慑药物组合物，以减少药物不当管理的可能性，特别是诸如阿片类药物。 在优选的实施方案中，修饰药物以增加其亲油性。 在优选实施方案中，改性药物均匀地分散在由缓慢溶解或不溶于水的材料组成的微粒内。 在一些实施方案中，含有微粒或药物颗粒的药物涂覆有一个或多个涂层，其中至少一个涂层是水不溶性的，优选有机溶剂不溶，但是通过存在于人胃肠道中的酶可酶促降解。 即使制剂的物理完整性受到损害（例如通过用刀片切碎或破碎）并且将所得材料置于水中，嗅到或吞咽，滥用威慑组合物也会延缓释放药物。 然而，当按照指导给药时，由于组合物通过酶降解，胆汁酸的表面活性作用和机械侵蚀的组合被分解或逐渐溶解在胃肠道内，药物从组合物中缓慢释放。

    Abuse-Deterrent Pharmaceutical Compositions of Opiods and Other Drugs
    3.
    发明申请
    Abuse-Deterrent Pharmaceutical Compositions of Opiods and Other Drugs 有权
    鸦片和其他药物的滥用威慑药物组合物

    公开(公告)号：US20130045960A1

    公开(公告)日：2013-02-21

    申请号：US13551455

    申请日：2012-07-17

    申请人： Jane Hirsh ,  Alexander M. Klibanov ,  Timothy M. Swager ,  Stephen L. Buchwald ,  Whe Yong Lo ,  Alison Fleming ,  Roman V. Rariy

    发明人： Jane Hirsh ,  Alexander M. Klibanov ,  Timothy M. Swager ,  Stephen L. Buchwald ,  Whe Yong Lo ,  Alison Fleming ,  Roman V. Rariy

    IPC分类号： A61K31/555 ,  A61K31/485 ,  C07D489/08 ,  A61P25/36 ,  C07F3/06

    CPC分类号： A61K31/485 ,  A61K9/145 ,  A61K9/1617 ,  A61K9/1682 ,  A61K9/1694 ,  A61K9/4858 ,  A61K9/50 ,  A61K9/5052 ,  A61K9/5084 ,  A61K31/20 ,  A61K47/12

    摘要： An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administration of drugs, especially drugs such as opiods. In the preferred embodiment, a drug is modified to increase its lipophilicity. In preferred embodiments the modified drug is homogeneously dispersed within microparticles composed of a material that is either slowly soluble or not soluble in water. The abuse-deterrent composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chopping with a blade or crushing) and the resulting material is placed in water, snorted, or swallowed. However, when administered as directed, the drug is slowly released from the composition as the composition is broken down or dissolved gradually within the GI tract by a combination of enzymatic degradation, surfactant action of bile acids, and mechanical erosion.

    摘要翻译： 已经开发了一种滥用威慑药物组合物，以减少药物不当管理的可能性，特别是诸如阿片类药物。 在优选的实施方案中，修饰药物以增加其亲油性。 在优选实施方案中，改性药物均匀地分散在由缓慢溶解或不溶于水的材料组成的微粒内。 即使制剂的物理完整性受到损害（例如通过用刀片切碎或破碎）并且将所得材料置于水中，嗅到或吞咽，滥用威慑组合物也会延缓释放药物。 然而，当按照指导施用时，通过酶降解，胆汁酸的表面活性作用和机械侵蚀的组合，组合物被分解或逐渐溶解在胃肠道内，药物从组合物中缓慢释放。

    Methods for the synthesis of milnacipran and congeners thereof
    4.
    发明授权
    Methods for the synthesis of milnacipran and congeners thereof 有权
    合成米那普仑及其同系物的方法

    公开(公告)号：US07309799B2

    公开(公告)日：2007-12-18

    申请号：US11097466

    申请日：2005-04-01

    申请人： Stephen L. Buchwald ,  Timothy M. Swager ,  Roman V. Rariy

    发明人： Stephen L. Buchwald ,  Timothy M. Swager ,  Roman V. Rariy

    IPC分类号： C07C211/00 ,  C07C231/00

    CPC分类号： C07D209/48 ,  C07D307/00

    摘要： One aspect of the present invention relates to methods for synthesizing milnacipran or congeners thereof. Another aspect of the present invention relates to asymmetric methods for synthesizing enantiomerically enriched milnacipran or congeners thereof. The present invention also relates to methods for synthesizing intermediates useful in the non-asymmetric or asymmetric methods for synthesizing enantiomerically enriched milnacipran or congeners thereof.

    摘要翻译： 本发明的一个方面涉及合成米那普仑或其同系物的方法。 本发明的另一方面涉及用于合成对映体富集的米那普仑或其同系物的不对称方法。 本发明还涉及用于合成对映体富集的米那普仑或其同系物的非对称或非对称方法中的中间体的方法。

    Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds
    7.
    发明授权
    Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds 有权
    铜催化形成碳 - 杂原子和碳 - 碳键

    公开(公告)号：US07323608B2

    公开(公告)日：2008-01-29

    申请号：US11090951

    申请日：2005-03-24

    申请人： Stephen L. Buchwald ,  Artis Klapars ,  Fuk Y. Kwong ,  Eric R. Streiter ,  Jacopo Zanon

    发明人： Stephen L. Buchwald ,  Artis Klapars ,  Fuk Y. Kwong ,  Eric R. Streiter ,  Jacopo Zanon

    IPC分类号： C07C17/20

    CPC分类号： C07D213/70 ,  C07B39/00 ,  C07C17/208 ,  C07C45/63 ,  C07C51/363 ,  C07C67/307 ,  C07C201/12 ,  C07C231/12 ,  C07C233/15 ,  C07C253/14 ,  C07C253/30 ,  C07C255/53 ,  C07C303/40 ,  C07C319/14 ,  C07D209/08 ,  C07D213/38 ,  C07D213/73 ,  C07D215/18 ,  C07D215/54 ,  C07D231/14 ,  C07D271/107 ,  C07D333/62 ,  C07D333/68 ,  C07C25/18 ,  C07C21/17 ,  C07C25/02 ,  C07C49/807 ,  C07C57/60 ,  C07C69/65 ,  C07C323/62 ,  C07C323/37 ,  C07C323/32 ,  C07C323/22 ,  C07C323/20 ,  C07C323/12 ,  C07C323/09 ,  C07C321/28 ,  C07C311/16 ,  C07C255/35 ,  C07C255/50 ,  C07C255/52 ,  C07C255/54 ,  C07C255/57 ,  C07C255/58 ,  C07C205/12

    摘要： One aspect of the present invention relates to copper-catalyzed carbon-heteroatom and carbon-carbon bond-forming methods. In certain embodiments, the present invention relates to copper-catalyzed methods of forming a carbon-sulfur bond between the sulfur atom of a thiol moiety and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. In other embodiments, the present invention relates to copper(II)-catalyzed methods of forming a carbon-nitrogen bond between the nitrogen atom of an amide and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. In certain embodiments, the present invention relates to copper-catalyzed methods of forming a carbon-carbon bond between the carbon atom of cyanide ion and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. In another embodiment, the present invention relates to a copper-catalyzed method of transforming an aryl, heteroaryl, or vinyl chloride or bromide into the corresponding aryl, heteroaryl, or vinyl iodide. Yet another embodiment of the present invention relates to a tandem method, which may be practiced in a single reaction vessel, wherein the first step of the method involves the copper-catalyzed formation of an aryl, heteroaryl, or vinyl iodide from the corresponding aryl, heteroaryl, or vinyl chloride or bromide; and the second step of the method involves the copper-catalyzed formation of an aryl, heteroaryl, or vinyl nitrile, amide or sulfide from the aryl, heteroaryl, or vinyl iodide formed in the first step.

    摘要翻译： 本发明的一个方面涉及铜催化的碳 - 杂原子和碳 - 碳键形成方法。 在某些实施方案中，本发明涉及在硫醇部分的硫原子和芳基，杂芳基或乙烯基卤化物或磺酸酯的活性炭之间形成碳 - 硫键的铜催化方法。 在其它实施方案中，本发明涉及在酰胺的氮原子和芳基，杂芳基或卤化乙烯或磺酸盐的活性炭之间形成碳 - 氮键的铜（II）催化方法。 在某些实施方案中，本发明涉及在氰化物离子的碳原子和芳基，杂芳基或乙烯基卤化物或磺酸盐的活性炭之间形成碳 - 碳键的铜催化方法。 在另一个实施方案中，本发明涉及将芳基，杂芳基或氯乙烯或溴化物转化为相应的芳基，杂芳基或碘乙烯的铜催化方法。 本发明的另一个实施方案涉及可以在单个反应容器中实施的串联方法，其中该方法的第一步涉及从相应的芳基铜催化形成芳基，杂芳基或乙烯基碘， 杂芳基或氯乙烯或溴化物; 并且该方法的第二步涉及在第一步中形成的芳基，杂芳基或乙烯基腈，酰胺或硫化物从芳基，杂芳基或乙烯基碘形成铜催化的形成。

    Protecting groups useful in the synthesis of polysaccharides, natural products, and combinatorial libraries
    8.
    发明授权
    Protecting groups useful in the synthesis of polysaccharides, natural products, and combinatorial libraries 失效

    公开(公告)号：US07102023B2

    公开(公告)日：2006-09-05

    申请号：US10774070

    申请日：2004-02-06

    申请人： Stephen L. Buchwald ,  Obadiah J. Plante ,  Peter H. Seeberger

    发明人： Stephen L. Buchwald ,  Obadiah J. Plante ,  Peter H. Seeberger

    IPC分类号： C07C309/06 ,  C07C317/04

    CPC分类号： C07H15/18 ,  C07H15/203 ,  Y02P20/55

    摘要： One aspect of the present invention relates to optionally substituted halogenated benzyl halides and the like. These compounds are useful as halogenated benzyl ether-based protecting groups for a variety of functional groups. Another aspect of the present invention relates to use of said protecting groups in an orthogonal protecting group strategy for the synthesis of complex molecules that comprise a number of suitable functional groups. Another aspect of the present invention relates to saccharides bearing various arrays of protecting groups of the present invention. Another aspect of the present invention relates to a method of synthesizing an oligosaccharide or glycoconjugate, comprising the steps of: using a saccharide bearing at least one protecting group of the present invention to glycosylate a second molecule to give a product comprising said saccharide; and removing a protecting group of the present invention from said product.