公开(公告)号：US07022841B2

公开(公告)日：2006-04-04

申请号：US10485134

申请日：2002-09-20

申请人： Raymond Cvetovich ,  Robert Wenslow ,  John M. Williams ,  Daniel Sidler ,  Louis Crocker ,  Hsien-Hsin Tung ,  Brian K. Johnson ,  Joseph Kukura, II ,  Ulf Dolling

发明人： Raymond Cvetovich ,  Robert Wenslow ,  John M. Williams ,  Daniel Sidler ,  Louis Crocker ,  Hsien-Hsin Tung ,  Brian K. Johnson ,  Joseph Kukura, II ,  Ulf Dolling

IPC分类号： C07D477/20

CPC分类号： C07D477/20 ,  C07D477/02

摘要： The present invention relates to a process for reducing the levels of organic solvents to pharmaceutically acceptable levels in thermally unstable crystalline carbapenem solids represented by formula I: or a salt thereof, wherein R1 and R2, are the same or different, and are selected from H, alkyl, aryl, and heteroaryl, comprising washing a carbapenem solid containing organic solvent with an organic solvent containing water; and using vacuum and/or inert gas (hydrated or dry) at low temperature to produce a compound of formula I containing pharmaceutically acceptable levels of organic solvents, wherein the water content of the crystalline carbapenem solid, correcting for organic solvents, is maintained at about 13% to about 25% during the process.

摘要翻译： 本发明涉及一种将由式I表示的热不稳定结晶碳青霉烯固体中的有机溶剂水平降低到可药用水平的方法：或其盐，其中R 1和R 2 包括相同或不同的选自H，烷基，芳基和杂芳基，包括用含水的有机溶剂洗涤含有有机溶剂的碳青霉烯固体; 并在低温下使用真空和/或惰性气体（水合或干燥）以产生含有药学上可接受水平的有机溶剂的式I化合物，其中将有机溶剂校正的结晶碳青霉烯固体的水含量保持在约 13％至25％。

公开(公告)号：US6096742A

公开(公告)日：2000-08-01

申请号：US212511

申请日：1998-12-15

申请人： Louis Crocker ,  James McCauley

发明人： Louis Crocker ,  James McCauley

IPC分类号： C07D20060101 ,  C07D413/06 ,  A61K31/53

CPC分类号： C07D413/06

摘要： This invention is concerned with a novel polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis. The instant polymorphic form has advantages over the other known forms of 2-(R)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

公开(公告)号：US06583142B2

公开(公告)日：2003-06-24

申请号：US10219386

申请日：2002-08-12

申请人： Louis Crocker ,  James McCauley

发明人： Louis Crocker ,  James McCauley

IPC分类号： A61K3153

CPC分类号： C07D413/06

摘要： This invention is concerned with a novel polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis. The instant polymorphic form has advantages over the other known forms of 2-(R)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

摘要翻译： 本发明涉及新化合物2-（R） - （1-（R） - （3,5-双（三氟甲基） - 苯基） - 乙氧基）-3-（S） - （4- 氟代）苯基-4-（3-（5-氧代-1H，4H-1,2,4-三唑并）甲基吗啉，其是用于治疗或预防中枢神经系统疾病，炎症性疾病的速激肽受体拮抗剂， 本发明的多晶型物质具有优于其它已知形式的2-（R） - （1-（R） - （3,5-双（三氟 - 甲基） - 苯基）乙氧基） -3-（S） - （4-氟）苯基-4-（3-（5-氧代-1H，4H-1,2,4-三唑并）甲基吗啉）的热力学稳定性和药物制剂中的适用性。

公开(公告)号：US06432953B1

公开(公告)日：2002-08-13

申请号：US09850370

申请日：2001-05-07

申请人： Louis Crocker ,  James McCauley

发明人： Louis Crocker ,  James McCauley

IPC分类号： A61K3153

摘要： This invention is concerned with a novel polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis. The instant polymorphic form has advantages over the other known forms of 2-(R)-(1-(R)-(3,1-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

公开(公告)号：US06432952B1

公开(公告)日：2002-08-13

申请号：US09697405

申请日：2000-10-26

申请人： Louis Crocker ,  Dongwei Cai ,  Jiang Wang

发明人： Louis Crocker ,  Dongwei Cai ,  Jiang Wang

IPC分类号： A61K315377

CPC分类号： C07D413/06 ,  C07C17/12 ,  C07C45/004 ,  C07C25/13 ,  C07C49/80

摘要： This invention is concerned with a novel polymorphic forms of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)4-( 5-(dimethyl-amino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine hydrochloride which is a tachykinin receptor antagonist useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis. The instant polymorphic forms have advantages over the other known forms of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)4-( 5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine hydrochloride in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

摘要翻译： 本发明涉及化合物2-（R） - （1-（R） - （3,5-双（三氟甲基）苯基）乙氧基）-4-（5-（二甲基 - 氨基）甲基 - 1,2,3-三唑-4-基）甲基-3-（S） - （4-氟苯基）吗啉盐酸盐，其是用于治疗或预防中枢神经系统疾病，炎症性疾病的速激肽受体拮抗剂， 疼痛或偏头痛，哮喘和呕吐。 本发明的多晶型物质具有优于其它已知形式的2-（R） - （1-（R） - （3,5-双（三氟甲基）苯基）乙氧基）4-（5-（二甲基氨基）甲基-1 （S） - （4-氟苯基）吗啉盐酸盐在热力学稳定性和适用于药物制剂中的适用性。

公开(公告)号：US06229010B1

公开(公告)日：2001-05-08

申请号：US09458168

申请日：1999-12-09

申请人： Louis Crocker ,  James McCauley

发明人： Louis Crocker ,  James McCauley

IPC分类号： C07D41300

CPC分类号： C07D413/06

摘要： This invention is concerned with a novel polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis. The instant polymorphic form has advantages over the other known forms of 2-(R)-(1-(R)-(3,,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

摘要翻译： 本发明涉及新化合物2-（R） - （1-（R） - （3,5-双（三氟甲基） - 苯基） - 乙氧基）-3-（S） - （4- 氟代）苯基-4-（3-（5-氧代-1H，4H-1,2,4-三唑并）甲基吗啉，其是用于治疗或预防中枢神经系统疾病，炎症性疾病的速激肽受体拮抗剂， 本发明的多晶型物质具有优于其它已知形式的2-（R） - （1-（R） - （3，5-双（三氟 - 甲基） - 苯基）乙氧基 ）-3-（S） - （4-氟）苯基-4-（3-（5-氧代-1H，4H-1,2,4-三唑并）甲基吗啉）在热力学稳定性和药物制剂中的适用性 。

公开(公告)号：US20060009641A1

公开(公告)日：2006-01-12

申请号：US11217931

申请日：2005-09-01

申请人： Louis Crocker ,  Joseph Kukura ,  Andrew Thompson ,  Christine Stelmach ,  Steven Young

发明人： Louis Crocker ,  Joseph Kukura ,  Andrew Thompson ,  Christine Stelmach ,  Steven Young

IPC分类号： C07D265/18

CPC分类号： C07D265/18

摘要： The instant invention describes a method for crystallizing (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one from a solvent and anti-solvent solvent system and producing the crystalline product. The desired final crystal form, Form I, can be produced when using methanol or ethanol. Form II is isolated from 2-propanol and can be converted to the desired crystal form at low drying temperatures, such as between about a temperature of 40° C. and 50° C.