公开(公告)号：US20090005575A1

公开(公告)日：2009-01-01

申请号：US12069422

申请日：2008-02-08

申请人： Martin Quibell ,  Yikang Wang ,  James Nally ,  John Paul Watts ,  Virendar Kumar Agrawal ,  Michael Standen

发明人： Martin Quibell ,  Yikang Wang ,  James Nally ,  John Paul Watts ,  Virendar Kumar Agrawal ,  Michael Standen

IPC分类号： C07D487/04

CPC分类号： C07D487/04 ,  Y02P20/55

摘要： The present invention relates to a process for preparing a compound of formula I, wherein R1 is Pg1 or P1′; P1′ is CO-hydrocarbyl; P2 is CH2, O or N-Pg2; and Pg1 and Pg2 are each independently nitrogen protecting groups; (i) reacting a compound of formula II with a dioxirane to form an epoxide of formula III; where X is selected from CN, CH2N3, CH2NH-Pg2, ONH-Pg2, NHNH-Pg2, N(Pg2)NH-Pg2; (ii) converting a compound of formula III to a compound of formula I

摘要翻译： 本发明涉及制备式Ⅰ化合物的方法，其中R1是Pg1或P1'; P1'是CO-烃基; P2是CH2，O或N-Pg2; Pg1和Pg2各自独立地为氮保护基; （i）使式II化合物与二环氧环酮反应以形成式III的环氧化物; 其中X选自CN，CH 2 N 3，CH 2 NH-Pg2，ONH-Pg2，NHNH-Pg2，N（Pg2）NH-Pg2; （ii）将式III化合物转化为式I化合物

公开(公告)号：US20090192322A1

公开(公告)日：2009-07-30

申请号：US12319562

申请日：2009-01-08

申请人： Martin Quibell ,  James Nally ,  Lee Patient ,  Yikang Wang ,  Claudio Dagostin ,  John Paul Watts

发明人： Martin Quibell ,  James Nally ,  Lee Patient ,  Yikang Wang ,  Claudio Dagostin ,  John Paul Watts

IPC分类号： C07D491/048 ,  C07D307/28

CPC分类号： C07D493/04 ,  C07D307/28 ,  C07D491/04

摘要： The present invention relates to a process for preparing a compound of formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, said process comprising the steps of: (A) (i) treating a compound of formula (IVa), where R48 is alkyl or tosyl, with an oxidising agent to form a compound of formula (Va); and (ii) converting said compound of formula (Va) to a compound of formula (Ia) or (Ic); or (B) (i) treating a compound of formula (IVb), where R48 is alkyl or tosyl, with an oxidising agent to form a compound of formula (Vb); and (ii) converting said compound of formula (Vb) to a compound of formula (Ib) or (Id).

摘要翻译： 本发明涉及制备式（Ia），（Ib），（Ic）或（Id）化合物或其药学上可接受的盐，水合物，溶剂化物，复合物或前药的方法，所述方法包括以下步骤： （A）（i）（i）用氧化剂处理其中R48为烷基或甲苯磺酰基的式（Ⅳa）化合物，形成式（Ⅴa）化合物; 和（ii）将所述式（Va）化合物转化为式（Ia）或（Ic）化合物; 或（B）（i）用氧化剂处理其中R48为烷基或甲苯磺酰基的式（Ⅳb）化合物以形成式（Ⅴb）化合物; 和（ii）将式（Vb）化合物转化为式（Ib）或（Id）化合物。

公开(公告)号：US08039641B2

公开(公告)日：2011-10-18

申请号：US12319562

申请日：2009-01-08

申请人： Martin Quibell ,  James Nally ,  Lee Patient ,  Yikang Wang ,  Claudio Dagostin ,  John Paul Watts

发明人： Martin Quibell ,  James Nally ,  Lee Patient ,  Yikang Wang ,  Claudio Dagostin ,  John Paul Watts

IPC分类号： C07D491/02

CPC分类号： C07D493/04 ,  C07D307/28 ,  C07D491/04

摘要： The present invention relates to a process for preparing a compound of formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, said process comprising the steps of: (A) (i) treating a compound of formula (IVa), where R48 is alkyl or tosyl, with an oxidizing agent to form a compound of formula (Va); and (ii) converting said compound of formula (Va) to a compound of formula (Ia) or (Ic); or (B) (i) treating a compound of formula (IVb), where R48 is alkyl or tosyl, with an oxidizing agent to form a compound of formula (Vb); and (ii) converting said compound of formula (Vb) to a compound of formula (Ib) or (Id).

摘要翻译： 本发明涉及制备式（Ia），（Ib），（Ic）或（Id）化合物或其药学上可接受的盐，水合物，溶剂化物，复合物或前药的方法，所述方法包括以下步骤： （A）（i）（i）用氧化剂处理其中R48为烷基或甲苯磺酰基的式（Ⅳa）化合物以形成式（Ⅴa）化合物; 和（ii）将所述式（Va）化合物转化为式（Ia）或（Ic）化合物; 或（B）（i）用氧化剂处理其中R48为烷基或甲苯磺酰基的式（Ⅳb）化合物以形成式（Ⅴb）化合物; 和（ii）将式（Vb）化合物转化为式（Ib）或（Id）化合物。

公开(公告)号：US20090131502A1

公开(公告)日：2009-05-21

申请号：US12072414

申请日：2008-02-25

申请人： Martin Quibell ,  John Paul Watts ,  Yikang Wang ,  Lee Patient ,  Jonathan R. Heal

发明人： Martin Quibell ,  John Paul Watts ,  Yikang Wang ,  Lee Patient ,  Jonathan R. Heal

IPC分类号： A61K31/407 ,  A61P19/00 ,  A61P33/06 ,  A61P35/00 ,  G01N33/53 ,  C07D487/04 ,  C07D491/04

CPC分类号： C07D491/048 ,  C07D487/04 ,  C07D498/04

摘要： The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease and diseases involving matrix or cartilate degradation.

摘要翻译： 本发明涉及式（I）化合物及其药学上可接受的盐。 本发明还涉及包含式（I）化合物的药物组合物，以及这些化合物在治疗选自骨质疏松症，佩吉特氏病，恰加斯病，疟疾，牙龈疾病，高钙血症，代谢性骨病和涉及 基质或软骨退化。

公开(公告)号：US07799791B2

公开(公告)日：2010-09-21

申请号：US12319555

申请日：2009-01-08

申请人： Martin Quibell ,  John Paul Watts

发明人： Martin Quibell ,  John Paul Watts

IPC分类号： A61K31/427 ,  C07D491/04 ,  A61P19/10

CPC分类号： C07D491/04

摘要： A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein: one of R1 and R2 is H, and the other is selected from OR6, SR6, NR6R7, N3, Me, Et, CF3, SOR8 and SO2R8; or R1 and R2 are both H; one of R3 and R4 is H, and the other is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl; or R3 and R4 are joined together with the adjacent backbone carbon atom to form a spiro-C5-C6 cycloalkyl group; R6 and R7 are each independently selected from H, C1-8-alkyl and C3-8-cycloalkyl; or R6 and R7 are linked to form a cyclic group together with the nitrogen to which they are attached; R8 is C1-8-alkyl or C3-8-cycloalkyl; R9 is a para-substituted 6-membered monocyclic aryl or heteroaryl ring which includes up to five heteroatoms. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

摘要翻译： 式（I）化合物或其药学上可接受的盐，水合物，复合物或前药，其中：R 1和R 2之一为H，另一个选自OR 6，SR 6，NR 6 R 7，N 3，Me，Et ，CF3，SOR8和SO2R8; 或R 1和R 2均为H; R3和R4之一是H，另一个选自叔丁基甲基，异丙基甲基，仲丁基，叔丁基，环戊基和环己基; 或者R 3和R 4与相邻的主链碳原子连接在一起形成螺C5-C6环烷基; R 6和R 7各自独立地选自H，C 1-8 - 烷基和C 3-8 - 环烷基; 或R 6和R 7与它们所连接的氮一起形成环状基团; R 8是C 1-8 - 烷基或C 3-8 - 环烷基; R9是包含至多5个杂原子的对位取代的6元单环芳基或杂芳基环。 本发明还涉及包含式（I）化合物的药物组合物，以及这些化合物在治疗选自骨质疏松症，佩吉特氏病，恰加斯病，疟疾，牙龈疾病，高钙血症，代谢性骨病，涉及 基质或软骨降解，以及骨癌症如骨转移和相关的疼痛。

公开(公告)号：US20100216811A1

公开(公告)日：2010-08-26

申请号：US12773524

申请日：2010-05-04

申请人： Martin Quibell ,  John Paul Watts

发明人： Martin Quibell ,  John Paul Watts

IPC分类号： A61K31/497 ,  C12N5/02 ,  A61K31/454 ,  A61P35/00 ,  A61P19/08 ,  A61P19/10

CPC分类号： C07D491/02

摘要： The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: R3 is tert-butylmethyl, sec-butyl or tert-butyl; X is CH or N; and R4 is optionally substituted C1-8 alkyl or optionally substituted C3-8 cycloalkyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

摘要翻译： 本发明涉及式（I）化合物及其药学上可接受的盐，其中：R3是叔丁基甲基，仲丁基或叔丁基; X是CH或N; 且R 4为任选取代的C 1-8烷基或任选取代的C 3-8环烷基。 本发明还涉及包含式（I）化合物的药物组合物，以及这些化合物在治疗选自骨质疏松症，佩吉特氏病，恰加斯病，疟疾，牙龈疾病，高钙血症，代谢性骨病，涉及 基质或软骨降解，以及骨癌症如骨转移和相关的疼痛。

公开(公告)号：US20090186831A1

公开(公告)日：2009-07-23

申请号：US12319555

申请日：2009-01-08

申请人： Martin Quibell ,  John Paul Watts

发明人： Martin Quibell ,  John Paul Watts

IPC分类号： A61K38/05 ,  C07D493/04 ,  C12N9/99 ,  C12Q1/37 ,  G01N33/573 ,  A61P19/02

CPC分类号： C07D491/04

摘要： A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein: one of R1 and R2 is H, and the other is selected from OR6, SR6, NR6R7, N3, Me, Et, CF3, SOR8 and SO2R8; or R1 and R2 are both H; one of R3 and R4 is H, and the other is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl; or R3 and R4 are joined together with the adjacent backbone carbon atom to form a spiro-C5-C6 cycloalkyl group; R6 and R7 are each independently selected from H, C1-8-alkyl and C3-8-cycloalkyl; or R6 and R7 are linked to form a cyclic group together with the nitrogen to which they are attached; R8 is C1-8-alkyl or C3-8-cycloalkyl; R9 is a para-substituted 6-membered monocyclic aryl or heteroaryl ring which includes up to five heteroatoms. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

摘要翻译： 式（I）化合物或其药学上可接受的盐，水合物，复合物或前药，其中：R 1和R 2之一为H，另一个选自OR 6，SR 6，NR 6 R 7，N 3，Me，Et ，CF3，SOR8和SO2R8; 或R 1和R 2均为H; R3和R4之一是H，另一个选自叔丁基甲基，异丙基甲基，仲丁基，叔丁基，环戊基和环己基; 或者R 3和R 4与相邻的主链碳原子连接在一起形成螺C5-C6环烷基; R 6和R 7各自独立地选自H，C 1-8 - 烷基和C 3-8 - 环烷基; 或R 6和R 7与它们所连接的氮一起形成环状基团; R 8是C 1-8 - 烷基或C 3-8 - 环烷基; R9是包含至多5个杂原子的对位取代的6元单环芳基或杂芳基环。 本发明还涉及包含式（I）化合物的药物组合物，以及这些化合物在治疗选自骨质疏松症，佩吉特氏病，恰加斯病，疟疾，牙龈疾病，高钙血症，代谢性骨病，涉及 基质或软骨降解，以及骨癌症如骨转移和相关的疼痛。

公开(公告)号：US08877927B2

公开(公告)日：2014-11-04

申请号：US12319549

申请日：2009-01-08

申请人： Martin Quibell ,  John Paul Watts

发明人： Martin Quibell ,  John Paul Watts

IPC分类号： A61K31/496 ,  C07D491/044 ,  A61K31/454 ,  A61P19/00 ,  G01N33/53 ,  A61P29/00 ,  C07D491/04

CPC分类号： C07D491/04

摘要： The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof (I), wherein: one of R1 and R2 is H, and the other is selected from F and Cl, or R1 and R2 are both F; R3 is selected from cyclopentyl and cyclohexyl; R4 is an optionally substituted 5- or 6-membered monocyclic or an 8- to 10-membered bicyclic aryl or heteroaryl ring which includes up to four heteroatoms. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

摘要翻译： 本发明涉及式（I）化合物及其药学上可接受的盐，式（I）化合物或其药学上可接受的盐，水合物，复合物或前体药物（I），其中：R1和 R2为H，另一个选自F和Cl，或R1和R2均为F; R3选自环戊基和环己基; R 4是任选取代的5或6元单环或8至10元双环芳基或杂芳环，其包含至多四个杂原子。 本发明还涉及包含式（I）化合物的药物组合物，以及这些化合物在治疗选自骨质疏松症，佩吉特氏病，恰加斯病，疟疾，牙龈疾病，高钙血症，代谢性骨病，涉及 基质或软骨降解，以及骨癌症如骨转移和相关的疼痛。

公开(公告)号：US07846935B2

公开(公告)日：2010-12-07

申请号：US12319556

申请日：2009-01-08

申请人： Martin Quibell ,  John Paul Watts

发明人： Martin Quibell ,  John Paul Watts

IPC分类号： A61K31/496 ,  A61K31/454 ,  C07D491/08 ,  C12Q1/37

CPC分类号： C07D491/04

摘要： The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X is CH or N; and R4 is optionally substituted C3-8 alkyl or optionally substituted C3-8 cycloalkyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

摘要翻译： 本发明涉及式（I）化合物及其药学上可接受的盐，其中：X是CH或N; 并且R 4是任选取代的C 3-8烷基或任选取代的C 3-8环烷基。 本发明还涉及包含式（I）化合物的药物组合物，以及这些化合物在治疗选自骨质疏松症，佩吉特氏病，恰加斯病，疟疾，牙龈疾病，高钙血症，代谢性骨病，涉及 基质或软骨降解，以及骨癌症如骨转移和相关的疼痛。

公开(公告)号：US08501744B2

公开(公告)日：2013-08-06

申请号：US12823558

申请日：2010-06-25

申请人： Martin Quibell ,  John Paul Watts

发明人： Martin Quibell ,  John Paul Watts

IPC分类号： A61K31/497 ,  A61K31/40 ,  A61K31/34 ,  A01N43/38 ,  A01N43/08 ,  C07D307/93 ,  C07D307/00 ,  C07D307/02

CPC分类号： A61K31/496 ,  C07D491/048 ,  Y02A50/411

摘要： A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein one of R1 and R2 is H, and the other is selected from C1-8-alkyl, C3-6-cycloalkyl and C1-8-alkyl-C5-10-aryl; R3 is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl; R9 is selected from the following: wherein: R4 is selected from C1-8-alkyl and C3-8-cycloalkyl; G is selected from: CH, CMe and N; E is selected from: O, S, SO2, NH, NMe and N-oxide (N→O); J and R are independently selected from: CH, N and N-oxide (N→O); and R41 is selected from amino, methylamino, dimethylamino, isopropylamino, isopropyl(methyl)amino, cyclopropylamino, cyclopropyl(methyl)amino, cyclopentylamino, morpholino, piperidin-1-yl, piperidin-1-ylmethyl, morpholinomethyl, 4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl, 1-morpholinoethyl, 1-(dimethylamino)ethyl, 1-(methylamino)ethyl, 4-fluoro-1-methylpyrrolidin-2-yl, 4,4-difluoropiperidin-1-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, pyridin-3-ylamino, pyridin-2-ylamino, 1-methylpyrrolidin-3-yl, methyl, isopropyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of various diseases.

摘要翻译： 式（I）化合物或其药学上可接受的盐，水合物，复合物或前药，其中R 1和R 2之一为H，另一个选自C 1-8 - 烷基，C 3-6 - 环烷基和 C 1-8 - 烷基-C 5-10 - 芳基; R 3选自叔丁基甲基，异丙基甲基，仲丁基，叔丁基，环戊基，环己基和1-甲基环戊基; R 9选自如下：其中：R 4选自C 1-8 - 烷基和C 3-8 - 环烷基; G选自：CH，CMe和N; E选自：O，S，SO 2，NH，NMe和N-氧化物（N-> O）; J和R独立地选自：CH，N和N-氧化物（N-> O）; （甲基）氨基，环丙基氨基，环丙基（甲基）氨基，环戊基氨基，吗啉代，哌啶-1-基，哌啶-1-基甲基，吗啉代甲基，4-甲基哌嗪-1-基 （2-甲氧基乙基）哌嗪-1-基，1-吗啉代乙基，1-（二甲基氨基）乙基，1-（甲基氨基）乙基，4-氟-1-甲基吡咯烷-2-基， 二氟哌啶-1-基，哌啶-4-基，1-甲基哌啶-4-基，吡啶-3-基氨基，吡啶-2-基氨基，1-甲基吡咯烷-3-基，甲基，异丙基。 本发明还涉及包含式（I）化合物的药物组合物，以及这些化合物在治疗各种疾病中的用途。