公开(公告)号：WO2013016499A1

公开(公告)日：2013-01-31

申请号：PCT/US2012/048270

申请日：2012-07-26

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  JURKAUSKAS, Valdas ,  RUGGIERO, Piero, L. ,  ROEPER, Stefanie ,  WILLCOX, David ,  WALDO, Michael ,  GUERETTE, Dahrika, Milfred Yap ,  KLINE, Billie, J. ,  LUONG, Hoa, Q.

Inventor： JURKAUSKAS, Valdas ,  RUGGIERO, Piero, L. ,  ROEPER, Stefanie ,  WILLCOX, David ,  WALDO, Michael ,  GUERETTE, Dahrika, Milfred Yap ,  KLINE, Billie, J. ,  LUONG, Hoa, Q.

IPC: C07D333/40 ,  A61K31/381 ,  A61P31/14

CPC classification number: C07D333/40 ,  A61K9/1623 ,  A61K9/2018 ,  A61K9/2054 ,  A61K9/4858

Abstract: A method of preparing Compound (1): or a pharmaceutically acceptable salt thereof includes: a) reacting Compound (A) with 3,3- dimetylbut-l-yne in the presence of one or more palladium catalysts selected from the group consisting of Pd(PPh3)4 and Pd(PPh3)2Cl2, and one or more copper catalysts selected from the group consisting of Cul, CuBr, and CuCl, to generate Compound (B); b) treating Compound (B) with an acid to generate Compound (C): c) reducing the cyclohexanone of Compound (C) to cyclohexanol to generate Compound (D); and d) reacting Compound (D) with a base to generate Compound (1), wherein Compounds (A), (B), (C), and (D) are each as depicted herein.

Abstract translation: 制备化合物（1）的方法或其药学上可接受的盐包括：a）在一种或多种钯催化剂的存在下，使化合物（A）与3,3-二甲基丁-1-炔反应，所述钯催化剂选自Pd （PPh 3）4和Pd（PPh 3）2 Cl 2和一种或多种选自Cul，CuBr和CuCl的铜催化剂，以产生化合物（B）; b）用酸处理化合物（B）以产生化合物（C）：c）将化合物（C）的环己酮还原成环己醇以产生化合物（D）; 和d）使化合物（D）与碱反应以产生化合物（1），其中化合物（A），（B），（C）和（D）各自如本文所述。

公开(公告)号：WO2010093889A3

公开(公告)日：2010-10-28

申请号：PCT/US2010024053

申请日：2010-02-12

Applicant: VERTEX PHARMA ,  HURREY MICHAEL ,  ALARGOV DIMITAR ,  JOHNSTON STEVEN C ,  ROEPER STEFANIE ,  SNOONIAN JOHN R ,  COWANS BRETT A ,  VLAHOVA PETINKA ,  EBERLIN ALEXANDER ,  EDDLESTON MARK ,  FRAMPTON CHRIS

Inventor： HURREY MICHAEL ,  ALARGOV DIMITAR ,  JOHNSTON STEVEN C ,  ROEPER STEFANIE ,  SNOONIAN JOHN R ,  COWANS BRETT A ,  VLAHOVA PETINKA ,  EBERLIN ALEXANDER ,  EDDLESTON MARK ,  FRAMPTON CHRIS

IPC: C07D213/82 ,  A61K31/4418

CPC classification number: C07D213/82

Abstract: This invention relates to solid forms of 2-(2, 4-difluorophenyl)-6-(l- (2,6-difluorophenyl)ureido)nicotinamide and pharmaceutical compositions thereof, and methods and uses therewith.

Abstract translation: 本发明涉及2-（2,4-二氟苯基）-6-（1-（2,6-二氟苯基）脲基）烟酰胺及其药物组合物的固体形式及其方法和用途。

公开(公告)号：WO2009038683A2

公开(公告)日：2009-03-26

申请号：PCT/US2008/010728

申请日：2008-09-15

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  DEMATTEI, John ,  FENG, Yushi ,  HARRISON, Cristian ,  LOOKER, Adam ,  MUDUNURI, Praveen ,  ROEPER, Stefanie ,  ZHANG, Yuegang

Inventor： DEMATTEI, John ,  FENG, Yushi ,  HARRISON, Cristian ,  LOOKER, Adam ,  MUDUNURI, Praveen ,  ROEPER, Stefanie ,  ZHANG, Yuegang

IPC: A61K31/47 ,  C07D215/233 ,  A61P3/00 ,  A61P35/00 ,  A61P25/28 ,  A61P27/02 ,  A61P3/10

CPC classification number: C07D215/56 ,  A61K31/47 ,  A61K45/06 ,  C07D215/233

Abstract: Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide are described herein, including crystalline forms thereof.

Abstract translation: 本文描述了固体形式的N- [2,4-双（1,1-二甲基乙基）-5-羟基苯基] -1,4-二氢-4-氧代喹啉-3-甲酰胺，包括其结晶形式。

公开(公告)号：WO2013016490A1

公开(公告)日：2013-01-31

申请号：PCT/US2012/048258

申请日：2012-07-26

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  LUISI, Brian ,  WILLCOX, David ,  ROEPER, Stefanie ,  HU, Kan-Nian ,  LUONG, Hoa, Q.

Inventor： LUISI, Brian ,  WILLCOX, David ,  ROEPER, Stefanie ,  HU, Kan-Nian ,  LUONG, Hoa, Q.

IPC: C07D333/40 ,  A61K31/381 ,  A61P31/14

CPC classification number: C07D333/40 ,  A61K9/0019 ,  A61K9/1652 ,  A61K9/2054 ,  A61K9/2077 ,  A61K9/4858 ,  A61K9/4866 ,  A61K31/381 ,  A61K47/40 ,  C07D333/38

Abstract: Polymorph Forms M, H, P, X, and ZA of Compound (1) represented by the following structural formula: are described. A method of preparing polymorph Form M of Compound (1) includes stirring a mixture of Compound (1) and a solvent system that includes isopropanol, ethyl acetate, n -butyl acetate, methyl acetate, acetone, 2-butanone (methylethylketone (MEK)), or heptane, or a combination thereof at a temperature in a range of 10 °C to 47 °C to form From M of Compound (1). A method of preparing polymorph Form H of Compound (1) includes stirring a solution of Compound (1) at a temperature in a range of 48 °C to 70 °C to form Form H of Compound (1). A method of preparing polymorph Form P of Compound (1) includes stirring a mixture of Compound (1) and a solvent system that includes a solvent selected from the group consisting of dichloromethane and tetrahydrofuran (THF), and a mixture thereof at room temperature to form Form P of Compound (1). A method of preparing polymorph Form X of Compound (1) includes removing ethyl acetate from ethylacetate solvate G of Compound (1). A method of preparing polymorph Form ZA of Compound (1) includes removing n -butyl acetate from n-butyl acetate solvate A of Compound (1).

Abstract translation: 描述了由以下结构式表示的化合物（1）的多晶型：M，H，P，X和ZA。 制备化合物（1）的多晶型物M的方法包括搅拌化合物（1）和包括异丙醇，乙酸乙酯，乙酸正丁酯，乙酸甲酯，丙酮，2-丁酮（甲基乙基酮（MEK））的溶剂体系的混合物， ）或庚烷或其组合，在10℃至47℃的温度范围内，以形成化合物（1）的M。 制备化合物（1）的多晶型物H的方法包括在48℃至70℃的温度范围内搅拌化合物（1）的溶液以形成化合物（1）的H型。 制备化合物（1）的多晶型P的方法包括：将化合物（1）和包含选自二氯甲烷和四氢呋喃（THF）的溶剂的溶剂体系的混合物及其混合物在室温下搅拌至 形成化合物（1）的形式P. 制备化合物（1）的多晶型物X的方法包括从化合物（1）的乙酸乙酯溶剂化物G中除去乙酸乙酯。 制备化合物（1）的多晶型ZA的方法包括从化合物（1）的乙酸正丁酯溶剂化物A中除去乙酸正丁酯。

公开(公告)号：WO2013016491A1

公开(公告)日：2013-01-31

申请号：PCT/US2012/048260

申请日：2012-07-26

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  LUISI, Brian ,  ROEPER, Stefanie ,  WILLCOX, David ,  WANG, Hongren ,  MUDUNURI, Praveen ,  LUONG, Hoa, Q.

Inventor： LUISI, Brian ,  ROEPER, Stefanie ,  WILLCOX, David ,  WANG, Hongren ,  MUDUNURI, Praveen ,  LUONG, Hoa, Q.

IPC: C07D333/40 ,  A61K31/381 ,  A61P31/14

CPC classification number: C07D333/40 ,  A61K9/0019 ,  A61K9/1652 ,  A61K9/2054 ,  A61K9/2077 ,  A61K9/4858 ,  A61K9/4866 ,  A61K31/381 ,  A61K47/40 ,  C07D333/38

Abstract: A solvate of Compound (1) is selected from the group consisting of: Compound 1⋅ H 2 0, Compound 1⋅ethanoHsopropanol, Compound 1⋅acetone, Compound 1⋅ethylacetate, Compound 1⋅isopropylacetate, Compound l⋅ethylacetate⋅2-methyl THF, Compound 1⋅ethanol, Compound 1⋅n-butylacetate; Compound 1 ⋅heptane; Compound 1⋅2-butanone; and Compound l»methylacetate, wherein Compound 1 is represented by the following structural formula (I): and wherein the Compound 1⋅H 2 0 are in a molar ratio of 1 : 0.5 to 1 :3 (Compound 1: H 2 0). A method of preparing such a solvate of Compound (1) includes stirring a mixture of Compound (1) and a solvent desired for the formation of the solvate of Compound (1).

Abstract translation: 化合物（1）的溶剂合物选自：化合物1·H 2 O，化合物1·乙醇异丙醇，化合物1·丙酮，化合物1·乙酸乙酯，化合物1·乙酸异丙酯，化合物1·乙酸乙酯·2-甲基THF， 化合物1·乙醇，化合物1·乙酸正丁酯; 化合物1·庚烷; 化合物1·2-丁酮; 和化合物I»乙酸甲酯，其中化合物1由以下结构式（I）表示：其中化合物1·H 2 O的摩尔比为1:0.5至1:3（化合物1：H 2 O）。 制备化合物（1）的这种溶剂化物的方法包括搅拌化合物（1）和化合物（1）的溶剂合物形成所需溶剂的混合物。

公开(公告)号：WO2010093890A2

公开(公告)日：2010-08-19

申请号：PCT/US2010/024054

申请日：2010-02-12

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  ROEPER, Stefanie ,  LOOKER, Adam, R. ,  MARTINOT, Theodore, A. ,  NEUBERT-LANGILLE, Bobbianna ,  RYAN, Michael, P. ,  SNOONIAN, John, R.

Inventor： ROEPER, Stefanie ,  LOOKER, Adam, R. ,  MARTINOT, Theodore, A. ,  NEUBERT-LANGILLE, Bobbianna ,  RYAN, Michael, P. ,  SNOONIAN, John, R.

IPC: C07D213/80 ,  C07D213/803 ,  A61K31/4418 ,  A61P37/06 ,  A61P29/00

CPC classification number: C07D213/80 ,  C07D213/803

Abstract: The present invention relates to processes for the preparation of compounds useful as inhibitors of p38 kinase. The processes of the present invention are amenable for large scale preparation and produce stable phenyl-6-(l-(phenyl)ureido)nicotinamides in high purity and yields.

Abstract translation: 本发明涉及制备可用作p38激酶抑制剂的化合物的方法。 本发明的方法适用于大规模制备，并以高纯度产生稳定的苯基-6-（1-（苯基）脲基）烟酰胺。

公开(公告)号：WO2010093889A2

公开(公告)日：2010-08-19

申请号：PCT/US2010/024053

申请日：2010-02-12

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  HURREY, Michael ,  ALARGOV, Dimitar ,  JOHNSTON, Steven, C. ,  ROEPER, Stefanie ,  SNOONIAN, John, R. ,  COWANS, Brett, A. ,  VLAHOVA, Petinka ,  EBERLIN, Alexander ,  EDDLESTON, Mark ,  FRAMPTON, Chris

Inventor： HURREY, Michael ,  ALARGOV, Dimitar ,  JOHNSTON, Steven, C. ,  ROEPER, Stefanie ,  SNOONIAN, John, R. ,  COWANS, Brett, A. ,  VLAHOVA, Petinka ,  EBERLIN, Alexander ,  EDDLESTON, Mark ,  FRAMPTON, Chris

IPC: C07D213/82 ,  A61K31/4418

CPC classification number: C07D213/82

Abstract: This invention relates to solid forms of 2-(2, 4-difluorophenyl)-6-(l- (2,6-difluorophenyl)ureido)nicotinamide and pharmaceutical compositions thereof, and methods and uses therewith.

Abstract translation: 本发明涉及2-（2,4-二氟苯基）-6-（1-（2,6-二氟苯基）脲基）烟酰胺的固体形式及其药物组合物，及其方法和用途

公开(公告)号：WO2011149878A1

公开(公告)日：2011-12-01

申请号：PCT/US2011/037659

申请日：2011-05-24

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  LAUFFER, David, J. ,  LI, Pan ,  ROEPER, Stefanie ,  IBRAHIM, Shereen ,  KULDIPKUMAR, Anuj, K. ,  SHI, Yi ,  MILLER, David, B., Jr.

Inventor： LAUFFER, David, J. ,  LI, Pan ,  ROEPER, Stefanie ,  IBRAHIM, Shereen ,  KULDIPKUMAR, Anuj, K. ,  SHI, Yi ,  MILLER, David, B., Jr.

IPC: C07D513/04 ,  A61K31/4709 ,  A61P35/00

CPC classification number: C07D513/04

Abstract: The present invention relates to anhydrous and hydrated forms of Compound 1, which are useful in the inhibition of c-Met protein kinase. The invention also provides pharmaceutically acceptable compositions comprising compounds of formula I and methods of using the compositions in the treatment of proliferative disorders.

Abstract translation: 本发明涉及化合物1的无水和水合形式，其可用于抑制c-Met蛋白激酶。 本发明还提供包含式I化合物的药学上可接受的组合物和使用该组合物治疗增殖性疾病的方法。

公开(公告)号：WO2011050215A1

公开(公告)日：2011-04-28

申请号：PCT/US2010/053628

申请日：2010-10-21

Applicant: VERTEX PHARMACEUTICALS INCORPORATED ,  AMBHAIKAR, Narendra, Bhalchandra ,  HUGHES, Robert ,  HURLEY, Dennis, James ,  LEE, Elaine, Chungmin ,  LITTLER, Benjamin ,  NUMA, Mehdi ,  ROEPER, Stefanie ,  SHETH, Urvi

Inventor： AMBHAIKAR, Narendra, Bhalchandra ,  HUGHES, Robert ,  HURLEY, Dennis, James ,  LEE, Elaine, Chungmin ,  LITTLER, Benjamin ,  NUMA, Mehdi ,  ROEPER, Stefanie ,  SHETH, Urvi

IPC: C07D215/56 ,  C07D487/08

CPC classification number: C07D487/08 ,  C07D215/56

Abstract: The present invention relates to processes for preparing solid state forms of N-(4-(7-azabicyclo[2.2. 1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, including Compound 1 Form A, Compound 1 Form A- HCl, Compound 1 Form B, and Compound 1 Form B-HCl, any combination of these forms, pharmaceutical compositions thereof, and methods of treatment therewith.

Abstract translation: 本发明涉及制备固体形式的N-（4-（7-氮杂双环[2.2.1]庚-7-基）-2-（三氟甲基）苯基）-4-氧代-5-（三氟甲基） -1,4-二氢喹啉-3-甲酰胺，包括化合物1形式A，化合物1形式A- HCl，化合物1形式B和化合物1形式B-HCl，这些形式的任何组合，其药物组合物，以及 治疗。

公开(公告)号：WO2010093890A3

公开(公告)日：2010-12-16

申请号：PCT/US2010024054

申请日：2010-02-12

Applicant: VERTEX PHARMA ,  ROEPER STEFANIE ,  LOOKER ADAM R ,  MARTINOT THEODORE A ,  NEUBERT-LANGILLE BOBBIANNA ,  RYAN MICHAEL P ,  SNOONIAN JOHN R

Inventor： ROEPER STEFANIE ,  LOOKER ADAM R ,  MARTINOT THEODORE A ,  NEUBERT-LANGILLE BOBBIANNA ,  RYAN MICHAEL P ,  SNOONIAN JOHN R

IPC: C07D213/80 ,  A61K31/4418 ,  A61P29/00 ,  A61P37/06 ,  C07D213/803

CPC classification number: C07D213/80 ,  C07D213/803

Abstract: The present invention relates to processes for the preparation of compounds useful as inhibitors of p38 kinase. The processes of the present invention are amenable for large scale preparation and produce stable phenyl-6-(1-(phenyl)ureido)nicotinamides in high purity and yields.

Abstract translation: 本发明涉及制备可用作p38激酶抑制剂的化合物的方法。 本发明的方法适用于大规模制备，并以高纯度产生稳定的苯基-6-（1-（苯基）脲基）烟酰胺。