公开(公告)号：US20140057910A1

公开(公告)日：2014-02-27

申请号：US13402521

申请日：2012-02-22

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy X.H. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy X.H. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter

IPC分类号： A61K31/5377 ,  A61K31/4168 ,  C07D405/06 ,  A61K31/4178 ,  C07D401/04 ,  A61K45/06 ,  A61K31/454 ,  C07D409/06 ,  C07D401/06 ,  C07D295/15 ,  A61K31/4184 ,  C07D233/88 ,  A61K31/4439

CPC分类号： C07D233/88 ,  A61K31/4168 ,  A61K31/4178 ,  A61K31/4184 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/4725 ,  A61K31/5377 ,  A61K31/655 ,  A61K45/06 ,  C07D233/46 ,  C07D233/70 ,  C07D235/02 ,  C07D239/22 ,  C07D239/70 ,  C07D271/07 ,  C07D273/00 ,  C07D295/15 ,  C07D401/04 ,  C07D401/06 ,  C07D401/08 ,  C07D401/10 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D403/06 ,  C07D403/08 ,  C07D403/10 ,  C07D403/12 ,  C07D405/06 ,  C07D405/10 ,  C07D405/14 ,  C07D407/06 ,  C07D409/04 ,  C07D409/06 ,  C07D409/10 ,  C07D409/14 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06 ,  Y02A50/411

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W is a bond, —C(═S)—, —S(O)—, —S(O)2—, —C(═O)—, —O—, —C(R6)(R7)—, —N(R5)— or —C(═N(R5))—; X is —O—, —N(R5)— or —C(R6)(R7)—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O)2—, —C(═O)— or —C(═NR5)—; U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —P(O)(OR15)—, —C(═NR5)—, —(C(R6)(R7))b— or —N(R5)—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, U is not —S(O)—, —S(O)2—, —O—, or —N(R5)—; provided that when X is —N(R5)— and W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, then U is not a bond; and R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic antagonist.

摘要翻译： 公开了式I化合物或其立体异构体，互变异构体或其药学上可接受的盐或溶剂化物，其中W为键，-C（= S） - ， - S（O） - ， - S（O） -C（= O） - ， - O - ， - C（R6）（R7） - ， - N（R5） - 或-C（= N（R5） X是-O - ， - N（R 5） - 或-C（R 6）（R 7） - ; 条件是当X是-O-时，U不是-O-，-S（O） - ， - S（O）2 - ， - C（= O） - 或-C（= NR5） - ; U是一个键，-S（O） - ， - S（O）2 - ， - C（O） - ， - O - ， - O（OR） （C（R6）（R7））b-或-N（R5） - ; 其中b为1或2; 条件是当W是-S（O） - ， - S（O）2 - ， - O-或-N（R 5） - 时，U不是-S（O） - ， - S（O） -O-或-N（R 5） - ; 条件是当X为-N（R5） - 且W为-S（O） - ， - S（O）2 - ， - O-或-N（R5） - 时，则U不为键; 并且R1，R2，R3，R4，R5，R6和R7如说明书中所定义; 以及包含式I化合物的药物组合物。还公开了抑制天冬氨酰蛋白酶的方法，特别是治疗心血管疾病，认知和神经变性疾病的方法以及抑制人类免疫缺陷病毒，plasmepins，组织蛋白酶D 和原生动物酶。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱拮抗剂组合来治疗认知或神经变性疾病的方法。

公开(公告)号：US20130004518A1

公开(公告)日：2013-01-03

申请号：US13610162

申请日：2012-09-11

申请人： Jared N. Cumming ,  Ulrich Iserloh ,  Andrew Stamford ,  Corey Strickland ,  Johannes H. Voight ,  Yusheng Wu ,  Ying Huang ,  Yan Xia ,  Samuel Chackalamannil ,  Tao Guo ,  Douglas W. Hobbs ,  Thuy X.H. Le ,  Jeffrey F. Lowrie ,  Kurt W. Saionz ,  Suresh D. Babu

发明人： Jared N. Cumming ,  Ulrich Iserloh ,  Andrew Stamford ,  Corey Strickland ,  Johannes H. Voight ,  Yusheng Wu ,  Ying Huang ,  Yan Xia ,  Samuel Chackalamannil ,  Tao Guo ,  Douglas W. Hobbs ,  Thuy X.H. Le ,  Jeffrey F. Lowrie ,  Kurt W. Saionz ,  Suresh D. Babu

IPC分类号： C07D207/09 ,  C07F9/572 ,  A61K31/675 ,  C07D217/18 ,  A61K31/472 ,  C07F9/62 ,  C07D207/12 ,  A61K31/4025 ,  C07D401/14 ,  A61K31/4439 ,  C07D205/04 ,  A61K31/397 ,  C07D211/26 ,  A61K31/4458 ,  C07D211/46 ,  A61K31/445 ,  C07D413/12 ,  A61K31/5377 ,  C07D401/12 ,  A61K31/454 ,  C07D401/04 ,  A61K31/451 ,  A61K31/4545 ,  C07D241/08 ,  A61K31/495 ,  C07D403/12 ,  A61K31/496 ,  C07D241/24 ,  C07D413/06 ,  C07D243/08 ,  A61K31/551 ,  A61K39/395 ,  A61K31/5415 ,  A61K31/505 ,  A61P25/00 ,  A61P25/28 ,  A61P29/00 ,  A61K31/40

CPC分类号： C07D243/08 ,  C07D205/04 ,  C07D207/08 ,  C07D207/09 ,  C07D207/12 ,  C07D207/26 ,  C07D209/52 ,  C07D211/26 ,  C07D211/46 ,  C07D217/18 ,  C07D233/32 ,  C07D241/04 ,  C07D241/08 ,  C07D401/06 ,  C07D401/10 ,  C07D401/12 ,  C07D403/12 ,  C07D403/14 ,  C07D409/06 ,  C07D409/12 ,  C07D413/06

摘要： Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, whereinR1 is R is —C(O)—N(R27)(R28) or and the remaining variables are as defined in the specification.Also disclosed are pharmaceutical compositions comprising the compounds of formula I.Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease.Also disclosed are pharmaceutical compositions and methods of treating cognitive or neurodegenerative diseases comprising the compounds of formula I in combination with a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor or an anti-amyloid antibody.

摘要翻译： 公开了下式的化合物或其药学上可接受的盐或溶剂化物，其中R1是R是-C（O）-N（R27）（R28），或其余的变量如说明书中所定义。 还公开了包含式I化合物的药物组合物。还公开了治疗认知或神经变性疾病如阿尔茨海默病的方法。 还公开了治疗认知或神经变性疾病的药物组合物和方法，其包含式I化合物与除式I以外的分泌抑制剂抑制剂，HMG-CoA还原酶抑制剂，γ-分泌酶抑制剂，非 - 甾族抗炎药，N-甲基-D-天冬氨酸受体拮抗剂，胆碱酯酶抑制剂或抗淀粉样蛋白抗体。

公开(公告)号：US07973067B2

公开(公告)日：2011-07-05

申请号：US12331787

申请日：2008-12-10

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy X. H. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachel C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy X. H. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachel C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse

IPC分类号： A01N43/50 ,  A61K31/415 ,  C07D233/00

CPC分类号： C07D233/46 ,  C07D233/70 ,  C07D233/88 ,  C07D239/22 ,  C07D239/70 ,  C07D271/07 ,  C07D273/00 ,  C07D401/04 ,  C07D401/08 ,  C07D401/10 ,  C07D401/12 ,  C07D403/04 ,  C07D403/06 ,  C07D403/08 ,  C07D403/10 ,  C07D403/12 ,  C07D405/10 ,  C07D409/04 ,  C07D409/10 ,  C07D409/14 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W is a bond, —C(═S)—, —S(O)—, —S(O)2—, —C(═O)—, —O—, —C(R6)(R7)—, —N(R5)— or —C(═N(R5))—; X is —O—, —N(R5)— or —C(R6)(R7)—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O)2—, —C(═O)— or —C(═NR5)—; U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —P(O)(OR15)—, —C(═NR5)—, —(C(R6)(R7))b— or —N(R5)—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, U is not —S(O)—, —S(O)2—, —O—, or —N(R5)—; provided that when X is —N(R5)— and W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, then U is not a bond; and R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

公开(公告)号：US07662816B2

公开(公告)日：2010-02-16

申请号：US10910987

申请日：2004-08-04

申请人： Jared N. Cumming ,  Ulrich Iserloh ,  Andrew Stamford ,  Corey Strickland ,  Johannes H. Voigt ,  Yusheng Wu ,  Ying Huang ,  Yan Xia ,  Samuel Chackalamannil ,  Tao Guo ,  Douglas W. Hobbs ,  Thuy X. H. Le ,  Jeffrey F. Lowrie ,  Kurt W. Saionz ,  Suresh D. Babu

发明人： Jared N. Cumming ,  Ulrich Iserloh ,  Andrew Stamford ,  Corey Strickland ,  Johannes H. Voigt ,  Yusheng Wu ,  Ying Huang ,  Yan Xia ,  Samuel Chackalamannil ,  Tao Guo ,  Douglas W. Hobbs ,  Thuy X. H. Le ,  Jeffrey F. Lowrie ,  Kurt W. Saionz ,  Suresh D. Babu

IPC分类号： A61K31/496 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D409/12 ,  C07D211/34 ,  C07D207/16 ,  C07D207/26 ,  C07D243/08 ,  C07D413/12

CPC分类号： C07D243/08 ,  C07D205/04 ,  C07D207/08 ,  C07D207/09 ,  C07D207/12 ,  C07D207/26 ,  C07D209/52 ,  C07D211/26 ,  C07D211/46 ,  C07D217/18 ,  C07D233/32 ,  C07D241/04 ,  C07D241/08 ,  C07D401/06 ,  C07D401/10 ,  C07D401/12 ,  C07D403/12 ,  C07D403/14 ,  C07D409/06 ,  C07D409/12 ,  C07D413/06

摘要： Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is R is —C(O)—N(R27)(R28) or and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I.Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease.Also disclosed are pharmaceutical compositions and methods of treating cognitive or neurodegenerative diseases comprising the compounds of formula I in combination with a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor or an anti-amyloid antibody.

摘要翻译： 公开了下式的化合物或其药学上可接受的盐或溶剂化物，其中R1是R是-C（O）-N（R27）（R28），或其余的变量如说明书中所定义。 还公开了包含式I化合物的药物组合物。还公开了治疗认知或神经变性疾病如阿尔茨海默病的方法。 还公开了治疗认知或神经变性疾病的药物组合物和方法，其包含式I化合物与除式I以外的β-分泌酶抑制剂，HMG-CoA还原酶抑制剂，γ-分泌酶抑制剂， 甾族抗炎剂，N-甲基-D-天冬氨酸受体拮抗剂，胆碱酯酶抑制剂或抗淀粉样蛋白抗体。

公开(公告)号：US07598250B2

公开(公告)日：2009-10-06

申请号：US10911030

申请日：2004-08-04

申请人： Jared N. Cumming ,  Ying Huang ,  Guoqing Li ,  Ulrich Iserloh ,  Andrew Stamford ,  Corey Strickland ,  Johannes H. Voigt ,  Yusheng Wu ,  Jianping Pan ,  Tao Guo ,  Douglas W. Hobbs ,  Thuy X. H. Le ,  Jeffrey F. Lowrie

发明人： Jared N. Cumming ,  Ying Huang ,  Guoqing Li ,  Ulrich Iserloh ,  Andrew Stamford ,  Corey Strickland ,  Johannes H. Voigt ,  Yusheng Wu ,  Jianping Pan ,  Tao Guo ,  Douglas W. Hobbs ,  Thuy X. H. Le ,  Jeffrey F. Lowrie

IPC分类号： A61K31/506 ,  A61K31/496 ,  C07D403/12 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D417/14

CPC分类号： C04B35/632 ,  C07D207/277 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D403/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/12 ,  C07D413/14 ,  C07D417/14

摘要： Disclosed are novel compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is X is —O—, —C(R14)2— or —N(R)—; Z is —C(R14)2— or —N(R)—; t is 0, 1, 2 or 3; each R and R2 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl or alkynyl; each R14 is H, alkyl, alkenyl, alkynyl, halo, —CN, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, —OR35, —N(R24)(R25) or —SR35; R41 is alkyl, cycloalkyl, —SO2(alkyl), —C(O)-alkyl, —C(O)-cycloalkyl or -alkyl-NH—C(O)CH3; and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating cognitive or neurodegenerative diseases with compounds of formula I.Also disclosed are pharmaceutical compositions and methods of treatment comprising compounds of formula I in combination with other agents useful in treating cognitive or neurodegenerative diseases.

摘要翻译： 公开了下式的新化合物或其药学上可接受的盐或溶剂合物，其中R 1是X是-O - ， - C（R 14）2 - 或-N（R） - ; Z是-C（R 14）2 - 或-N（R） - ; t为0,1,2或3; 每个R和R 2独立地为H，烷基，环烷基，环烷基烷基，芳基，杂芳基，杂环烷基，芳基烷基，杂芳基烷基，杂环烷基烷基，烯基或炔基; 每个R 14是H，烷基，烯基，炔基，卤素，-CN，卤代烷基，环烷基，环烷基烷基，芳基，杂芳基，杂环烷基，芳基烷基，杂芳基烷基，杂环烷基烷基，-OR 35，-N（R 24）（R 25）或-SR 35; R41是烷基，环烷基，-SO2（烷基），-C（O） - 烷基，-C（O） - 环烷基或 - 烷基-NH-C（O）CH3; 其余变量如本说明书中所定义。 还公开了包含式I化合物的药物组合物和用式I化合物治疗认知障碍或神经变性疾病的方法。还公开了药物组合物和治疗方法，其包含式I化合物与用于治疗认知或神经变性的其它药剂 疾病

公开(公告)号：US07138264B1

公开(公告)日：2006-11-21

申请号：US10444257

申请日：2003-05-21

申请人： Brian M. Beyer ,  Richard N. Ingram ,  Peter Orth ,  Corey Strickland

发明人： Brian M. Beyer ,  Richard N. Ingram ,  Peter Orth ,  Corey Strickland

IPC分类号： C12N9/64 ,  C12N5/10 ,  C12Q1/37 ,  A01N37/18 ,  A61K38/00

CPC分类号： C12N9/6489 ,  C07K2299/00

摘要： The present invention discloses a modified tumor necrosis factor-alpha converting enzyme (TACE) catalytic domain, that unlike the native TACE catalytic domain, is stable at high protein concentrations. The present invention further discloses methods for generating crystals of the modified TACE protein in protein-ligand complexes with a number of inhibitors. In addition, the present invention discloses methods of using the proteins, crystals and/or three-dimensional structures obtained to identify compounds that can modulate the enzymatic activity of TACE.

摘要翻译： 本发明公开了一种修饰的肿瘤坏死因子-α转化酶（TACE）催化结构域，其与天然TACE催化结构域不同，在高蛋白浓度下是稳定的。 本发明还公开了用多种抑制剂在蛋白质 - 配体复合物中产生修饰的TACE蛋白的晶体的方法。 此外，本发明公开了使用获得的蛋白质，晶体和/或三维结构来鉴定可调节TACE的酶活性的化合物的方法。

公开(公告)号：US20060111370A1

公开(公告)日：2006-05-25

申请号：US11149027

申请日：2005-06-09

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Johannes Voigt ,  Corey Strickland ,  Elizabeth Smith ,  Andrew Stamford ,  William Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy Le ,  Kurt Saionz ,  Suresh Babu ,  Rachael Hunter ,  Michelle Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Johannes Voigt ,  Corey Strickland ,  Elizabeth Smith ,  Andrew Stamford ,  William Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy Le ,  Kurt Saionz ,  Suresh Babu ,  Rachael Hunter ,  Michelle Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse

IPC分类号： A61K31/519 ,  A61K31/497 ,  A61K31/513 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/4245 ,  C07D413/02 ,  C07D403/02

CPC分类号： C07D233/46 ,  C07D233/70 ,  C07D233/88 ,  C07D239/22 ,  C07D239/70 ,  C07D271/07 ,  C07D273/00 ,  C07D401/04 ,  C07D401/08 ,  C07D401/10 ,  C07D401/12 ,  C07D403/04 ,  C07D403/06 ,  C07D403/08 ,  C07D403/10 ,  C07D403/12 ,  C07D405/10 ,  C07D409/04 ,  C07D409/10 ,  C07D409/14 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W is a bond, —C(═S)—, —S(O)—, —S(O)2—, —C(═O)—, —O—, —C(R6)(R7)—, —N(R5)— or —C(═N(R5))—; X is —O—, —N(R5)— or —C(R6)(R7)—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O)2—, —C(═O)— or —C(═NR5)—; U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —P(O)(OR15)—, —C(═NR5)—, —(C(R6)(R7))b— or —N(R5)—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, U is not —S(O)—, —S(O)2—, —O—, or —N(R5)—; provided that when X is —N(R5)— and W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, then U is not a bond; and R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

公开(公告)号：US06535820B1

公开(公告)日：2003-03-18

申请号：US09383364

申请日：1999-08-26

申请人： Corey Strickland ,  Patricia C. Weber

发明人： Corey Strickland ,  Patricia C. Weber

IPC分类号： G01N3348

CPC分类号： C12Y205/01029 ,  C07F9/113 ,  C07F9/3826 ,  C07K2299/00 ,  C12N9/1085

摘要： The present invention relates to crystalline compositions comprising farnesyl protein transferase-like polypeptides in complex with substrates and inhibitors. Also disclosed are crystallization conditions for these compositions and their use for structural determination of FPT:FPP/FPP analog: peptide/inhibitor complexes.

摘要翻译： 本发明涉及包含与底物和抑制剂复合的法呢基蛋白转移酶样多肽的结晶组合物。 还公开了这些组合物的结晶条件及其用于FPT：FPP / FPP类似物：肽/抑制剂复合物的结构测定的用途。

公开(公告)号：US06362188B1

公开(公告)日：2002-03-26

申请号：US09465523

申请日：1999-12-16

申请人： Timothy Guzi ,  Dinanath F. Rane ,  Alan K. Mallams ,  Alan B. Cooper ,  Ronald J. Doll ,  Viyyoor M. Girijavallabhan ,  Arthur G. Taveras ,  Corey Strickland ,  Joseph M. Kelly ,  Jianping Chao

发明人： Timothy Guzi ,  Dinanath F. Rane ,  Alan K. Mallams ,  Alan B. Cooper ,  Ronald J. Doll ,  Viyyoor M. Girijavallabhan ,  Arthur G. Taveras ,  Corey Strickland ,  Joseph M. Kelly ,  Jianping Chao

IPC分类号： A61K31496

CPC分类号： C07D231/12 ,  C07D233/56 ,  C07D249/08 ,  C07D401/04 ,  C07D401/14

摘要： Disclosed are compounds of the formula: wherein R8 represents a cyclic moiety to which is bound an imodazolylalkyl group; R9 represents a carbamate, urea, amide or sulfonamide group; and the remaining substituents are as defined herein. Also disclosed is a method of treating cancer and a method of inhibiting farnesyl protein transferase using the disclosed compounds.

摘要翻译： 公开了下式的化合物：其中R8表示结合有异唑基烷基的环状部分; R9表示氨基甲酸酯，脲，酰胺或磺酰胺基团; 并且其余的取代基如本文所定义。 还公开了使用所公开的化合物治疗癌症的方法和抑制法呢基蛋白转移酶的方法。

公开(公告)号：US20180237524A1

公开(公告)日：2018-08-23

申请号：US15553254

申请日：2016-02-22

申请人： Paul REICHERT ,  Winifred W. PROSISE ,  Giovanna SCAPIN ,  Xiaoyu YANG ,  Ramesh KASHI ,  Corey STRICKLAND ,  Merck Sharp & Dohme Corp.

发明人： Paul Reichert ,  Winifred W. Prosise ,  Giovanna Scapin ,  Xiaoyu Yang ,  Ramesh Kashi ,  Corey Strickland

IPC分类号： C07K16/28 ,  C07K16/00

摘要： Crystals of pembrolizumab and structurally similar anti-PD-1 monoclonal antibodies are provided, as well as methods of producing such crystals, and uses of compositions comprising such antibody crystals, e.g. in treatment of cancers. The present invention satisfies these needs and more by providing pembrolizumab crystals and a method producing pembrolizumab crystals. One embodiment of the method of the invention produces crystals suitable for X-ray diffraction, and the inventors herein used such crystals to solve the three-dimensional structure of pembrolizumab to 2.3 A resolution.