公开(公告)号：US20190337911A1

公开(公告)日：2019-11-07

申请号：US16509392

申请日：2019-07-11

Applicant: The Regents of the University of California ,  The Scripps Research Institute

Inventor： Palmer TAYLOR ,  Zoran RADIC ,  Barry K. SHARPLESS ,  Valery FOKIN ,  Rakesh SIT

IPC: C07D295/13 ,  C07D451/14 ,  C07D223/06 ,  C07D209/56 ,  C07D221/22 ,  C07D471/08 ,  C07D451/02 ,  C07D223/04 ,  C07D487/08

Abstract: In alternative embodiments, the invention provides nucleophilic hydroxyimino-acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino-acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.

公开(公告)号：US20180244653A1

公开(公告)日：2018-08-30

申请号：US15558986

申请日：2016-03-24

Applicant: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA ,  THE SCRIPPS RESEARCH INSTITUTE ,  MAHIDOL UNIVERSITY

Inventor： Palmer TAYLOR ,  John YAMAUCHI ,  Todd T. TALLEY ,  Kuntarat ARUNRUNGVICHIAN ,  Opa VAJRAGUPTA ,  Valery FOKIN

IPC: C07D403/04 ,  A61K31/439 ,  A61K31/454 ,  A61K31/5377 ,  C07D451/14 ,  A61K31/46 ,  A61K31/496 ,  C07D401/14 ,  A61K31/4192 ,  A61K31/55

CPC classification number: C07D403/04 ,  A61K31/4192 ,  A61K31/439 ,  A61K31/454 ,  A61K31/46 ,  A61K31/496 ,  A61K31/5377 ,  A61K31/55 ,  C07D249/06 ,  C07D401/14 ,  C07D405/04 ,  C07D451/04 ,  C07D451/14 ,  C07D453/02 ,  C07D473/34

Abstract: In alternative embodiments, provided are selective agonists having a high affinity for the alpha7 nicotinic acetylcholine receptor (α7 nAChR), assays for selectivity of nicotinic receptor subtype and ligand-gated ion channel subtype based on receptor occupation and response, behavioral assessments for reversing cognitive impairment after scopolamine treatment, enhancing memory retention over time, pharmaceutical compositions and formulations and devices comprising them, and methods for making and using them, including characterizing and efficiently assaying them for receptor subtype selectivity. In alternative embodiments, provided are substituted anti 1,2,3-triazoles compounds with high affinity, and selective binding, for the alpha7 nicotine acetylcholine receptor (α7 nAChR), as exemplified by 5-(1-(2-(Piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1H-indole (“IND1”), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole (“IND8”) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (“QND8”). In alternative embodiments, provided are products of manufacture such as pumps, devices, syringes and the like comprising a compound, pharmaceutical composition or formulation as provided herein.

公开(公告)号：US20140066632A1

公开(公告)日：2014-03-06

申请号：US14078106

申请日：2013-11-12

Applicant: The Scripps Research Institute

Inventor： K. Barry SHARPLESS ,  Valery FOKIN ,  Vsevold A. ROSTOVTSEV ,  Luke GREEN ,  Fahmi HIMO

IPC: C07D249/04

CPC classification number: C07D249/04 ,  B01J31/1805 ,  B01J2231/327 ,  B01J2531/16 ,  B01J2531/96 ,  C07D249/06 ,  C07D403/06

Abstract: A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting an organic azide and a terminal alkyne with a source of reactive Cu(I) ion in human blood plasma to form by cycloaddition a 1,4-disubstituted 1,2,3-triazole. The source of reactive Cu(I) ion can be, for example, a Cu(I) salt, Cu(II) ion in the presence of a reducing agent, or copper metal.

Abstract translation: 使用铜催化的点击化学连接方法结合叠氮化物和末端炔烃以提供1,4-二取代的1,2,3-三唑三唑。 该方法包括使有机叠氮化物和末端炔与人血浆中的反应性Cu（I）离子源接触以通过环加成1,4-二取代的1,2,3-三唑接触。 反应性Cu（I）离子的来源可以是例如在还原剂存在下的Cu（I）盐，Cu（II）离子或铜金属。

公开(公告)号：US20150031895A1

公开(公告)日：2015-01-29

申请号：US14508552

申请日：2014-10-07

Applicant: THE SCRIPPS RESEARCH INSTITUTE

Inventor： K. Barry SHARPLESS ,  Valery FOKIN ,  Vsevold A. ROSTOVTSEV ,  Luke GREEN ,  Fahmi HIMO

IPC: C07D249/04

CPC classification number: C07D249/04 ,  B01J31/1805 ,  B01J2231/327 ,  B01J2531/16 ,  B01J2531/96 ,  C07D249/06 ,  C07D403/06

Abstract: A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting an organic azide and a terminal alkyne with a source of reactive Cu(I) ion in human blood plasma to form by cycloaddition a 1,4-disubstituted 1,2,3-triazole. The source of reactive Cu(I) ion can be, for example, a Cu(I) salt, Cu(II) ion in the presence of a reducing agent, or copper metal.

Abstract translation: 使用铜催化的点击化学连接方法结合叠氮化物和末端炔烃以提供1,4-二取代的1,2,3-三唑三唑。 该方法包括使有机叠氮化物和末端炔与人血浆中的反应性Cu（I）离子源接触以通过环加成1,4-二取代的1,2,3-三唑接触。 反应性Cu（I）离子的来源可以是例如在还原剂存在下的Cu（I）盐，Cu（II）离子或铜金属。

公开(公告)号：US20190119237A1

公开(公告)日：2019-04-25

申请号：US16029267

申请日：2018-07-06

Applicant: The Regents of the University of California ,  The Scripps Research Institute

Inventor： Palmer TAYLOR ,  Zoran RADIC ,  Barry K. SHARPLESS ,  Valery FOKIN ,  Rakesh SIT

IPC: C07D295/13 ,  C07D451/14 ,  C07D223/06 ,  C07D209/56 ,  C07D221/22 ,  C07D471/08 ,  C07D451/02 ,  C07D223/04 ,  C07D487/08

Abstract: In alternative embodiments, the invention provides nucleophilic hydroxyimino-acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino-acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.

公开(公告)号：US20160256438A1

公开(公告)日：2016-09-08

申请号：US15028669

申请日：2014-10-15

Applicant: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA ,  THE SCRIPPS RESEARCH INSTITUTE

Inventor： Palmer TAYLOR ,  Zoran RADIC ,  Valery FOKIN

IPC: A61K31/4164 ,  A61K45/06 ,  A61K38/46 ,  A61K31/4439

CPC classification number: A61K31/4164 ,  A61K31/4439 ,  A61K31/5377 ,  A61K38/465 ,  A61K45/06 ,  C12Y301/01008

Abstract: Provided are N-alkyl imidazole 2-aldoximes, including cationic imidazolium and uncharged tertiary imidazole aldoximes, and compositions and methods for making and using them, including methods for reactivating human butyrylcholinesterase (hBChE) or acetylcholinesterase (hAChE) inhibited by organophosphate (OP). By administration of a composition of the invention, the inactive or conjugated hBChE-OP or hAChE-OP is reactivated and the catalytic cycle of turnover and inactivation of the OP is completed; and in alternative embodiments, secondary mechanisms of reversible protection of hBChE and hAChE from irreversible inactivation by OPs and reactivation of tissue AChE also contribute to overall efficacy.

Abstract translation: 提供的是N-烷基咪唑2-肟，包括阳离子咪唑和不带电的叔咪唑肟，以及其制备和使用它们的组合物和方法，包括用有机磷酸酯（OP）抑制的人丁酰胆碱酯酶（hBChE）或乙酰胆碱酯酶（hAChE）的再活化方法。 通过施用本发明的组合物，使活化或缀合的hBChE-OP或hAChE-OP重新活化，完成OP的转换和灭活的催化循环; 并且在替代实施方案中，可逆保护hBChE和hAChE免受OPs的不可逆失活和组织AChE再活化的次要机制也有助于整体疗效。

公开(公告)号：US20160214946A1

公开(公告)日：2016-07-28

申请号：US15085568

申请日：2016-03-30

Applicant: The Scripps Research Institute

Inventor： K. Barry SHARPLESS ,  Valery FOKIN ,  Vsevold A. ROSTOVTSEV ,  Luke GREEN ,  Fahmi HIMO

IPC: C07D249/04

CPC classification number: C07D249/04 ,  B01J31/1805 ,  B01J2231/327 ,  B01J2531/16 ,  B01J2531/96 ,  C07D249/06 ,  C07D403/06

Abstract: A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting a solution of an organic azide and a terminal alkyne with a source of catalytic Ru ion to form a 1,4-disubstituted 1,2,3-triazole.

Abstract translation: 使用铜催化的点击化学连接方法结合叠氮化物和末端炔烃以提供1,4-二取代的1,2,3-三唑三唑。 该方法包括将有机叠氮化物和末端炔烃的溶液与催化Ru离子源接触以形成1,4-二取代的1,2,3-三唑。

公开(公告)号：US20150361060A1

公开(公告)日：2015-12-17

申请号：US14766272

申请日：2014-02-15

Applicant: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA ,  THE SCRIPPS RESEARCH INSTITUTE

Inventor： Palmer TAYLOR ,  Zoran RADIC ,  Barry K. SHARPLESS ,  Valery FOKIN ,  Rakesh SIT

IPC: C07D295/13 ,  C07D223/06 ,  C07D451/02 ,  C07D487/08 ,  C07D471/08 ,  C07D451/14

CPC classification number: C07D295/13 ,  C07D209/56 ,  C07D221/22 ,  C07D223/04 ,  C07D223/06 ,  C07D451/02 ,  C07D451/14 ,  C07D471/08 ,  C07D487/08

Abstract: In alternative embodiments, the invention provides nucleophilic hydroxyimino-acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino-acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.

Abstract translation: 在替代实施方案中，本发明提供了穿过血脑屏障（BBB）以催化中枢神经系统（CNS）中有机磷酸酯（OP）抑制的人乙酰胆碱酯酶（hAChE）的水解的亲核羟基亚氨基 - 乙酰胺基烷基胺解毒剂。 本发明的羟基亚氨基 - 乙酰氨基烷基胺被设计成适合于AChE活性中心峡谷尺寸，以合理的亲和力结合，并与峡谷中的共轭磷酸根原子反应。 本发明的羟基亚氨基 - 乙酰氨基烷基胺还被设计成具有控制两种连接的hAChE再激活步骤的亲和性和反应性的电离状态。 在替代实施例中，本发明提供泵，装置，皮下输注装置，连续皮下输注装置，输液笔，针，储存器，安瓿，小瓶，注射器，药筒，一次性笔或喷射注射器，预充式笔或 注射器或药筒，药筒或一次性笔或喷射注射器，包括本发明化合物的两室或多室泵，注射器，药筒或笔或喷射器。

公开(公告)号：US20150232432A1

公开(公告)日：2015-08-20

申请号：US14705527

申请日：2015-05-06

Applicant: The Scripps Research Institute

Inventor： K. Barry SHARPLESS ,  Valery FOKIN ,  Vsevold A. ROSTOVTSEV ,  Luke GREEN ,  Fahmi HIMO

IPC: C07D249/04

CPC classification number: C07D249/04 ,  B01J31/1805 ,  B01J2231/327 ,  B01J2531/16 ,  B01J2531/96 ,  C07D249/06 ,  C07D403/06

Abstract: A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting a solution of an organic azide and a terminal alkyne with a source of catalytic Cu(I) ion to form a 1,4-disubstituted 1,2,3-triazole, wherein the source of Cu(I) ion comprises Cu(II) and a metal capable of reducing Cu(II) to Cu(I). In some embodiments, the metal capable of reducing Cu(II) to Cu(I) is selected from the group consisting of Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.

Abstract translation: 使用铜催化的点击化学连接方法结合叠氮化物和末端炔烃以提供1,4-二取代的1,2,3-三唑三唑。 该方法包括将有机叠氮化物和末端炔烃的溶液与催化性Cu（I）离子源接触以形成1,4-二取代的1,2,3-三唑，其中Cu（I）离子源包括 Cu（II）和能够将Cu（II）还原为Cu（I）的金属。 在一些实施方案中，能够将Cu（II）还原为Cu（I）的金属选自Al，Be，Co，Cr，Fe，Mg，Mn，Ni和Zn。