公开(公告)号：WO2008147547A1

公开(公告)日：2008-12-04

申请号：PCT/US2008/006644

申请日：2008-05-23

Applicant: AMGEN INC. ,  ZHONG, Wenge ,  HITCHCOCK, Stephen ,  PATEL, Vinod F. ,  CROGHAN, Michael ,  DINEEN, Thomas ,  HARRIED, Scott ,  HORNE, Daniel ,  JUDD, Ted ,  KALLER, Matthew ,  KREIMAN, Charles ,  LOPEZ, Patricia ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  WEISS, Matthew ,  XUE, Qiufen ,  YANG, Bryant

Inventor： ZHONG, Wenge ,  HITCHCOCK, Stephen ,  PATEL, Vinod F. ,  CROGHAN, Michael ,  DINEEN, Thomas ,  HARRIED, Scott ,  HORNE, Daniel ,  JUDD, Ted ,  KALLER, Matthew ,  KREIMAN, Charles ,  LOPEZ, Patricia ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  WEISS, Matthew ,  XUE, Qiufen ,  YANG, Bryant

IPC: C07D221/06 ,  C07D311/96 ,  C07D471/10 ,  C07D491/10 ,  C07D493/10 ,  C07D495/10 ,  A61P25/28 ,  A61K31/438

CPC classification number: C07D221/06 ,  C07D311/96 ,  C07D471/10 ,  C07D491/10 ,  C07D493/10 ,  C07D495/10

Abstract: The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and related conditions. In one embodiment, the compounds have a general Formula I or Formula II wherein RIa, RIb, RIc, B, R3, R4, R5 and W of Formula I, and RIa, RIb, RIc, R2, R2a, R3, R4, R5, R6, Al, A2, A3, A4, W, X, Z, m and n of Formula II are defined herein.

Abstract translation: 本发明包括可用于调节β-分泌酶酶活性和用于治疗β-分泌酶介导的疾病（包括阿尔茨海默病（AD））和相关病症的新一类化合物。 在一个实施方案中，化合物具有通式I或式II，其中式I的RIa，RIb，RIc，B，R3，R4，R5和W以及RIa，RIb，RIc，R2，R2a，R3，R4，R5 ，式II的R6，A1，A2，A3，A4，W，X，Z，m和n定义。

公开(公告)号：WO2012177896A1

公开(公告)日：2012-12-27

申请号：PCT/US2012/043569

申请日：2012-06-21

Applicant: AMGEN INC. ,  BROWN, James ,  CHEN, Jian J. ,  GORE, Vijay Keshav ,  HARRIED, Scott ,  HORNE, Daniel B. ,  KALLER, Matthew R. ,  LIU, Qingyian ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas T. ,  NISHIMURA, Nobuko ,  ZHONG, Wenge

Inventor： BROWN, James ,  CHEN, Jian J. ,  GORE, Vijay Keshav ,  HARRIED, Scott ,  HORNE, Daniel B. ,  KALLER, Matthew R. ,  LIU, Qingyian ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas T. ,  NISHIMURA, Nobuko ,  ZHONG, Wenge

IPC: C07D213/40 ,  C07D401/12 ,  C07D401/14 ,  C07D405/12 ,  C07D409/12 ,  C07D413/12 ,  A61K31/44 ,  A61P25/00

CPC classification number: C07D213/53 ,  C07C275/30 ,  C07D213/40 ,  C07D213/75 ,  C07D401/12 ,  C07D401/14 ,  C07D405/12 ,  C07D409/12 ,  C07D413/12

Abstract: Compounds of Formula (I) are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula (I) have the above structure, where the definitions of the variables are provided herein.

Abstract translation: 式（I）的化合物可用作TRPM8的拮抗剂。 这样的化合物可用于治疗多种TRPM8介导的病症和病症，并且可用于制备用于治疗这些病症和病症的药物和药物组合物。 这种疾病的实例包括但不限于偏头痛和神经性疼痛。 式（I）化合物具有上述结构，其中本文提供变量的定义。

公开(公告)号：WO2008147544A1

公开(公告)日：2008-12-04

申请号：PCT/US2008/006634

申请日：2008-05-23

Applicant: AMGEN INC. ,  ZHONG, Wenge ,  HITCHCOCK, Stephen ,  PATEL, Vinod F. ,  CROGHAN, Michael ,  DINEEN, Thomas ,  HORNE, Daniel ,  KALLER, Matthew ,  KREIMAN, Charles ,  LOPEZ, Patricia ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  PENNINGTON, Lewis ,  XUE, Qiufen ,  YANG, Bryant

Inventor： ZHONG, Wenge ,  HITCHCOCK, Stephen ,  PATEL, Vinod F. ,  CROGHAN, Michael ,  DINEEN, Thomas ,  HORNE, Daniel ,  KALLER, Matthew ,  KREIMAN, Charles ,  LOPEZ, Patricia ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  PENNINGTON, Lewis ,  XUE, Qiufen ,  YANG, Bryant

IPC: C07D221/06 ,  C07D311/96 ,  C07D471/10 ,  C07D491/10 ,  C07D493/10 ,  C07D495/10 ,  A61P25/28 ,  A61K31/438

CPC classification number: C07D491/107 ,  C07D221/06 ,  C07D311/96 ,  C07D471/10 ,  C07D491/10 ,  C07D493/10 ,  C07D495/10

Abstract: The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and related conditions. In one embodiment, the compounds have a general Formula I wherein R1a, R1b, R1c, B, W, R3, R4 and R5 are defined herein. In another embodiment, the invention provides compounds of general Formula II wherein A1, A2, A3, A4, R1a, R1b, R1c, R2, R4, R5, W, X and Z are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease (AD), cognitive deficits and impairment, schizophrenia and other similar central nervous system conditions. The invention also comprises further embodiments of Formula II, intermediates and processes useful for the preparation of compounds of Formulas I and II.

Abstract translation: 本发明包括可用于调节β-分泌酶酶活性和用于治疗β-分泌酶介导的疾病（包括阿尔茨海默病（AD））和相关病症的新一类化合物。 在一个实施方案中，化合物具有通式I，其中R 1a，R 1b，R 1c，B，W，R 3，R 4和R 5在本文中定义。 在另一个实施方案中，本发明提供通式II的化合物，其中A1，A2，A3，A4，R1a，R1b，R1c，R2，R4，R5，W，X和Z如本文所定义。 本发明还包括这些化合物在药物组合物中用于治疗，预防或治疗与β-分泌酶蛋白活性相关的病症和病症的用途。 这些病症包括例如阿尔茨海默病（AD），认知缺陷和损害，精神分裂症和其他类似的中枢神经系统病症。 本发明还包括式II的其它实施方案，可用于制备式I和II化合物的中间体和方法。

公开(公告)号：WO2012177893A3

公开(公告)日：2013-06-13

申请号：PCT/US2012043566

申请日：2012-06-21

Applicant: AMGEN INC ,  BISWAS KAUSTAV ,  BROWN JAMES ,  CHEN JIAN J ,  GORE VIJAY KESHAV ,  HARRIED SCOTT ,  HORNE DANIEL B ,  KALLER MATTHEW R ,  LIU QINGYIAN ,  MA VU VAN ,  MONENSCHEIN HOLGER ,  NGUYEN THOMAS T ,  YUAN CHESTER CHENGUANG ,  ZHONG WENGE ,  ST JEAN DAVID J JR

Inventor： BISWAS KAUSTAV ,  BROWN JAMES ,  CHEN JIAN J ,  GORE VIJAY KESHAV ,  HARRIED SCOTT ,  HORNE DANIEL B ,  KALLER MATTHEW R ,  LIU QINGYIAN ,  MA VU VAN ,  MONENSCHEIN HOLGER ,  NGUYEN THOMAS T ,  YUAN CHESTER CHENGUANG ,  ZHONG WENGE ,  ST JEAN DAVID J JR

IPC: C07D213/40 ,  A61K31/45 ,  A61P29/00 ,  C07D213/61 ,  C07D213/81 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/12 ,  C07D405/14 ,  C07D409/12 ,  C07D413/12 ,  C07D417/12 ,  C07D471/04 ,  C07D487/04

CPC classification number: C07D213/82 ,  C07D213/40 ,  C07D213/61 ,  C07D213/81 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/12 ,  C07D405/14 ,  C07D409/12 ,  C07D413/12 ,  C07D417/12 ,  C07D471/04 ,  C07D487/04 ,  C07D498/04

Abstract: Compounds of Formula I are useful as antagonists of transient receptor potential melastatin 8 (TRPM8). They are useful in treating disorders and conditions such as migraines and neuropathic pain. Compounds of Formula I have the following structure: where in particular X1 and X 2 may be C or N, and R1 is a ring.

Abstract translation: 式I的化合物可用作瞬时受体潜力melastatin 8（TRPM8）的拮抗剂。 它们可用于治疗疾病和病症如偏头痛和神经性疼痛。 式I的化合物具有以下结构：其中特别地，X 1和X 2可以是C或N，并且R 1是环。

公开(公告)号：WO2012177893A2

公开(公告)日：2012-12-27

申请号：PCT/US2012/043566

申请日：2012-06-21

Applicant: AMGEN INC. ,  BISWAS, Kaustav ,  BROWN, James ,  CHEN, Jian, J. ,  GORE, Vijay, Keshav ,  HARRIED, Scott ,  HORNE, Daniel, B. ,  KALLER, Matthew, R. ,  LIU, Qingyian ,  MA, Vu, Van ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas, T. ,  YUAN, Chester, Chenguang ,  ZHONG, Wenge ,  ST. JEAN, David, J., Jr.

Inventor： BISWAS, Kaustav ,  BROWN, James ,  CHEN, Jian, J. ,  GORE, Vijay, Keshav ,  HARRIED, Scott ,  HORNE, Daniel, B. ,  KALLER, Matthew, R. ,  LIU, Qingyian ,  MA, Vu, Van ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas, T. ,  YUAN, Chester, Chenguang ,  ZHONG, Wenge ,  ST. JEAN, David, J., Jr.

IPC: C07D213/40

CPC classification number: C07D213/82 ,  C07D213/40 ,  C07D213/61 ,  C07D213/81 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/12 ,  C07D405/14 ,  C07D409/12 ,  C07D413/12 ,  C07D417/12 ,  C07D471/04 ,  C07D487/04 ,  C07D498/04

Abstract: Compounds of Formula (I) are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula (I) have a structure where the definitions of the variables are provided herein.

Abstract translation: 式（I）的化合物可用作TRPM8的拮抗剂。 这些化合物可用于治疗多种TRPM8介导的病症和病症，并且可用于制备用于治疗这种病症和病症的药物和药物组合物。 这些疾病的实例包括但不限于偏头痛和神经性疼痛。 式（I）的化合物具有这里提供变量的定义的结构。

公开(公告)号：WO2011143495A1

公开(公告)日：2011-11-17

申请号：PCT/US2011/036342

申请日：2011-05-12

Applicant: AMGEN INC. ,  ALLEN, Jennifer ,  HORNE, Daniel B. ,  HU, Essa ,  KALLER, Matthew R. ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas T. ,  REICHELT, Andreas ,  RZASA, Robert M.

Inventor： ALLEN, Jennifer ,  HORNE, Daniel B. ,  HU, Essa ,  KALLER, Matthew R. ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas T. ,  REICHELT, Andreas ,  RZASA, Robert M.

IPC: C07D401/14 ,  C07D403/14 ,  C07D405/14 ,  C07D417/14 ,  C07D471/04 ,  C07D471/08 ,  C07D487/10 ,  A61K31/4709 ,  A61K31/454 ,  A61K31/4535 ,  A61P25/18

CPC classification number: C07D491/107 ,  C07D401/04 ,  C07D401/06 ,  C07D401/14 ,  C07D403/04 ,  C07D403/14 ,  C07D405/04 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D471/08 ,  C07D487/04 ,  C07D487/10

Abstract: Heteroaryloxyheterocyclyl compounds, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, Huntington's Disease, bipolar disorder, obsessive-compulsive disorder, and the like.

Abstract translation: 杂环氧基杂环基化合物和含有它们的组合物，以及这些化合物的制备方法。 本文还提供治疗通过抑制PDE10可治疗的疾病或疾病的方法，例如肥胖症，非胰岛素依赖性糖尿病，精神分裂症，亨廷顿舞蹈病，双相情感障碍，强迫症等。

公开(公告)号：WO2007061670A1

公开(公告)日：2007-05-31

申请号：PCT/US2006/044058

申请日：2006-11-13

Applicant: AMGEN INC. ,  ZHONG, Wenge ,  HITCHCOCK, Stephen ,  ALBRECHT, Brian K ,  BARTBERGER, Michael ,  BROWN, James ,  BROWN, Ryan ,  CHAFFEE, Stuart C. ,  CHENG, Yuan ,  CROGHAN, Michael ,  GRACEFFA, Russell ,  HARRIED, Scott ,  HICKMAN, Dean ,  HORNE, Daniel ,  HUNGATE, Randall ,  JUDD, Ted ,  KALLER, Matthew ,  KREIMAN, Charles ,  LA, Daniel ,  LOPEZ, Patricia ,  MASSE, Craig E. ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  NIXEY, Thomas ,  PATEL, Vinod F. ,  PENNINGTON, Lewis ,  WEISS, Matthew ,  XUE, Qiufen ,  YANG, Bryant

Inventor： ZHONG, Wenge ,  HITCHCOCK, Stephen ,  ALBRECHT, Brian K ,  BARTBERGER, Michael ,  BROWN, James ,  BROWN, Ryan ,  CHAFFEE, Stuart C. ,  CHENG, Yuan ,  CROGHAN, Michael ,  GRACEFFA, Russell ,  HARRIED, Scott ,  HICKMAN, Dean ,  HORNE, Daniel ,  HUNGATE, Randall ,  JUDD, Ted ,  KALLER, Matthew ,  KREIMAN, Charles ,  LA, Daniel ,  LOPEZ, Patricia ,  MASSE, Craig E. ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  NIXEY, Thomas ,  PATEL, Vinod F. ,  PENNINGTON, Lewis ,  WEISS, Matthew ,  XUE, Qiufen ,  YANG, Bryant

IPC: C07D405/12 ,  C07D413/12 ,  A61K31/44 ,  A61P25/28

CPC classification number: C07D405/12 ,  C07D311/68 ,  C07D413/12 ,  C07D491/052

Abstract: The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and related conditions. In one embodiment, the compounds have a general Formula (I); wherein A, B, W, R 3 , R 4 , R 5 , i and j are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula (I), methods of use for these compounds, including treatment of AD and related diseases, by administering the compound(s) of Formula (I), or compositions including them, to a subject. The invention also comprises further embodiments of Formulas (II) and (III), intermediates and processes useful for the preparation of compounds of the invention.

Abstract translation: 本发明包括可用于调节β-分泌酶酶活性和用于治疗β-分泌酶介导的疾病（包括阿尔茨海默病（AD））和相关病症的新一类化合物。 在一个实施方案中，化合物具有通式（I）; 其中A，B，W，R 3，R 4，R 5，i和j在本文中定义。 本发明还包括药物组合物，其包括一种或多种式（I）化合物，这些化合物的使用方法，包括治疗AD和相关疾病，通过施用式（I）化合物或其组合物，包括它们， 到一个主题。 本发明还包括式（II）和（III）的其它实施方案，可用于制备本发明化合物的中间体和方法。

公开(公告)号：WO2009073203A1

公开(公告)日：2009-06-11

申请号：PCT/US2008/013375

申请日：2008-12-04

Applicant: AMGEN INC. ,  NORMAN, Mark H. ,  BO, Yunxin Y. ,  GORE, Vijay Keshav ,  HORNE, Daniel ,  KALLER, Matthew ,  MA, Vu Van ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  NISHIMURA, Nobuko ,  TAMAYO, Nuria

Inventor： NORMAN, Mark H. ,  BO, Yunxin Y. ,  GORE, Vijay Keshav ,  HORNE, Daniel ,  KALLER, Matthew ,  MA, Vu Van ,  MONENSCHEIN, Holger ,  NGUYEN, Thomas ,  NISHIMURA, Nobuko ,  TAMAYO, Nuria

IPC: C07D217/04 ,  C07D217/06 ,  C07D217/22 ,  C07D401/04 ,  C07D401/06 ,  C07D401/10 ,  C07D401/12 ,  C07D405/06 ,  C07D405/12 ,  C07D413/06 ,  C07D417/06 ,  A61K31/472 ,  A61P29/00

CPC classification number: C07D217/04 ,  C07D217/06 ,  C07D217/22 ,  C07D401/04 ,  C07D401/06 ,  C07D401/10 ,  C07D401/12 ,  C07D405/06 ,  C07D405/12 ,  C07D413/06 ,  C07D417/06

Abstract: Tetrahydroisoquinoline compounds of formula (I), and compositions containing them, for the treatment of acute, inflammatory and neurophatic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neurophatic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintened pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

Abstract translation: 式（I）的四氢异喹啉化合物和含有它们的组合物，用于治疗急性，炎性和神经性疼痛，牙痛，一般头痛，偏头痛，丛集性头痛，混合血管和非血管综合征，紧张性头痛，一般炎症， 关节炎，风湿性疾病，骨关节炎，炎症性肠病，炎症性眼病，炎性或不稳定性膀胱病，牛皮癣，皮肤炎症成分投诉，慢性炎性病症，炎性疼痛及相关的痛觉过敏和异常性疼痛，神经性疼痛及相关的痛觉过敏和异常性疼痛，糖尿病 神经病痛，咳嗽痛，交感神经痛，交感综合征，哮喘，上皮组织损伤或功能障碍，单纯疱疹，呼吸系统内脏运动紊乱，泌尿生殖道，胃肠道或血管区，伤口，烧伤，过敏性皮肤反应，瘙痒，白癜风， 胃肠道消化 胃溃疡，十二指肠溃疡，腹泻，坏死因子诱发的胃损伤，毛发生长，血管舒缩或过敏性鼻炎，支气管疾病或膀胱疾病。