公开(公告)号：US20080004336A1

公开(公告)日：2008-01-03

申请号：US11765481

申请日：2007-06-20

申请人： Jack Gougoutas ,  Hildegard Lobinger ,  Srividya Ramakrishnan ,  Prashant Deshpande ,  Jeffrey Bien ,  Chiajen Lai ,  Chenchi Wang ,  Peter Riebel ,  John Grosso ,  Alexandra Nirschl ,  Janak Singh ,  John DiMarco

发明人： Jack Gougoutas ,  Hildegard Lobinger ,  Srividya Ramakrishnan ,  Prashant Deshpande ,  Jeffrey Bien ,  Chiajen Lai ,  Chenchi Wang ,  Peter Riebel ,  John Grosso ,  Alexandra Nirschl ,  Janak Singh ,  John DiMarco

IPC分类号： C07D309/10 ,  A61K31/351 ,  A61P3/00 ,  A61P3/10

CPC分类号： C07H15/207 ,  A61K31/7034 ,  A61K45/06 ,  A61P3/10 ,  C07H7/04

摘要： The present invention relates to physical crystal structures of a compound of the formula I: wherein R1, R2, R2a, R3 and R4 are as defined herein, especially pharmaceutical compositions containing structures of compound I or II, processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.

摘要翻译： 本发明涉及式I化合物的物理结晶结构：其中R 1，R 2，R 2a，R SUP， > 3和R 4如本文所定义的，特别是含有化合物I或II结构的药物组合物，其制备方法，用于制备其的中间体，以及治疗疾病如 使用这种结构的糖尿病。

公开(公告)号：US20070238866A1

公开(公告)日：2007-10-11

申请号：US11764839

申请日：2007-06-19

申请人： Prashant Deshpande ,  Bruce Ellsworth ,  Janak Singh ,  Theodor Denzel ,  Chiajen Lai ,  Gerard Crispino ,  Michael Randazzo ,  Jack Gougoutas

发明人： Prashant Deshpande ,  Bruce Ellsworth ,  Janak Singh ,  Theodor Denzel ,  Chiajen Lai ,  Gerard Crispino ,  Michael Randazzo ,  Jack Gougoutas

IPC分类号： C07H15/20 ,  A61K31/70

CPC分类号： C07H23/00 ,  C07H5/04 ,  C07H5/06 ,  C07H7/00 ,  C07H15/207

摘要： Method for the production of C-aryl glucoside SGLT2 inhibitors useful for the treatment of diabetes and related diseases. and intermediates thereof. The C-aryl glucosides may be complexed with amino acid complex forming reagents.

摘要翻译： 生产用于治疗糖尿病和相关疾病的C-芳基葡萄糖苷SGLT2抑制剂的方法。 及其中间体。 C-芳基葡糖苷可以与形成氨基酸复合物的试剂络合。

公开(公告)号：US20060128726A1

公开(公告)日：2006-06-15

申请号：US11283651

申请日：2005-11-21

申请人： Xuebao Wang ,  Chiajen Lai ,  Nachimuthu Soundararajan ,  Nina Nguyen ,  Weiming Ying ,  Lori Burton ,  Rajesh Gandhi ,  Krishnaswamy Raghavan ,  Ronald West ,  Yuji Zhou ,  Lin Yan ,  Xiaotian Yin ,  John DiMarco ,  Jack Gougoutas

发明人： Xuebao Wang ,  Chiajen Lai ,  Nachimuthu Soundararajan ,  Nina Nguyen ,  Weiming Ying ,  Lori Burton ,  Rajesh Gandhi ,  Krishnaswamy Raghavan ,  Ronald West ,  Yuji Zhou ,  Lin Yan ,  Xiaotian Yin ,  John DiMarco ,  Jack Gougoutas

IPC分类号： A61K31/519 ,  C07D487/04

CPC分类号： C07D487/04

摘要： A process is provided for preparing novel crystalline forms, namely selectively and consistently preparing the H2-1 dihydrate crystalline form, the H2-2 dihydrate crystalline form, the N-3 anhydrate crystalline form and the MTBE solvate crystalline form of the IKur compound (2S)-1-[[(7R)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazolo[1,5]pyrimidine-6-yl]carbonyl]-2-(4-fluorophenyl)pyrrolidine. The process includes preparation of the H2-1 and H2-2 forms which are used in preparing the N-3 anhydrate form which is particularly stable and has suitable flow properties and desired particle size. Novel H2-1 dihydrate and H2-2 dihydrate forms, the N-3 anhydrate form and the MTBE solvate form of the above IKur compound, pharmaceutical compositions containing such novel forms and a method for preventing or treating arrhythmias including atrial fibrillation and IKur related conditions employing such novel forms are also provided.

摘要翻译： 提供了一种制备新型结晶形式的方法，即选择性和一致地制备H 2 - II二水合物结晶形式，H2-2二水合物结晶形式，N-3无水物结晶形式和IKEA化合物（2S ）-1 - [[（7R）-7-（3,4-二氯苯基）-4,7-二氢-5-甲基吡唑并[1,5]嘧啶-6-基]羰基] -2-（4-氟苯基） 吡咯烷。 该方法包括制备用于制备N-3无水物形式的H2-1和H2-2形式，其特别稳定并具有合适的流动性能和所需的粒度。 新型H2-1二水合物和H2-2二水合物形成上述IKur化合物的N-3无水物形式和MTBE溶剂化物形式，含有这种新型形式的药物组合物和用于预防或治疗包括心房颤动和IKur相关病症的心律失常的方法 也提供了这种新颖的形式。

公开(公告)号：US20070060599A1

公开(公告)日：2007-03-15

申请号：US11222597

申请日：2005-09-09

申请人： John DiMarco ,  Jack Gougoutas

发明人： John DiMarco ,  Jack Gougoutas

IPC分类号： A61K31/522 ,  C07D473/04

CPC分类号： C07D473/18

摘要： The present invention relates to crystalline forms containing [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one represented by formula I; processes for the production thereof; pharmaceutical compositions thereof; methods for preparing the pharmaceutical composition; and the use of these crystalline forms in the treatment of hepatitis B viral infections.

摘要翻译： 本发明涉及含有[1S-（1α，3α，4beta）] - 2-氨基-1,9-二氢-9- [4-羟基-3-（羟甲基）-2-亚甲基环戊基] 由式I表示的嘌呤-6-酮; 生产过程; 其药物组合物; 制备药物组合物的方法; 以及这些结晶形式在治疗乙型肝炎病毒感染中的应用。

公开(公告)号：US20060135474A1

公开(公告)日：2006-06-22

申请号：US10805724

申请日：2004-03-22

申请人： Daniel Benigni ,  Jack Gougoutas ,  John DiMarco

发明人： Daniel Benigni ,  Jack Gougoutas ,  John DiMarco

IPC分类号： C08B30/18 ,  A61K31/724

CPC分类号： C07D493/04 ,  C12N1/20 ,  C12N1/38 ,  C12P17/181 ,  C12R1/01

摘要： The present invention relates to improved methods for the production, isolation and purification of epothilone B. These methods include, for example, a fermentation process for the production of epothilone B, isolation via adsorption onto a resin, and subsequent purification.

摘要翻译： 本发明涉及埃坡霉素B的生产，分离和纯化的改进方法。这些方法包括例如用于生产埃坡霉素B的发酵方法，通过吸附到树脂上进行分离和随后的纯化。

公开(公告)号：US20060063815A1

公开(公告)日：2006-03-23

申请号：US11271456

申请日：2005-11-10

申请人： John DiMarco ,  Jack Gougoutas ,  Imre Vitez ,  Martha Davidovich ,  Michael Galella ,  Timothy Malloy ,  Zhenrong Guo ,  Denis Favreau

发明人： John DiMarco ,  Jack Gougoutas ,  Imre Vitez ,  Martha Davidovich ,  Michael Galella ,  Timothy Malloy ,  Zhenrong Guo ,  Denis Favreau

IPC分类号： A61K31/427

CPC分类号： C07D491/04 ,  C07D417/06

摘要： There are provided in accordance with the present invention two crystalline polymorphs, designated Form A and Form B, respectively, as well as mixtures thereof, of an epothilone analog represented by the formula Also provided are methods of forming the novel polymorphs, therapeutic methods utilizing them and pharmaceutical dosage forms containing them.

摘要翻译： 根据本发明，提供分别由式（I）和式（B）表示的两个结晶多晶型物及其混合物，其由式

公开(公告)号：US20060014741A1

公开(公告)日：2006-01-19

申请号：US11149525

申请日：2005-06-10

申请人： John DiMarco ,  Jack Gougoutas ,  Bharat Patel

发明人： John DiMarco ,  Jack Gougoutas ,  Bharat Patel

IPC分类号： A61K31/5377 ,  C07D487/04

CPC分类号： C07D487/04

摘要： The present invention provides a process for preparing pyrrolotriazine compounds of formula (I) or a pharmaceutically acceptable salt thereof. Also provided are crystalline forms of the pyrrolotriazine compound [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2, 1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester and pharmaceutical compositions comprising at least one crystalline form, as well of methods of using the crystalline forms in the treatment of a proliferative disease, and methods for obtaining such crystalline forms. The compounds of formula (I), including [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester, are useful for inhibiting tyrosine kinase activity of growth factor receptors such as HER1, HER2 and HER4 thereby making them useful as antiproliferative agents for the treatment of cancer and other diseases.

摘要翻译： 本发明提供了制备式（I）的吡咯并三嗪化合物或其药学上可接受的盐的方法。 还提供了吡咯并三嗪化合物[4 - [[1-（3-氟苯基）甲基] -1H-吲唑-5-基氨基] -5-甲基 - 吡咯并[2,1-f] [1,2， 4]三嗪-6-基] - 氨基甲酸，（3S）-3-吗啉基甲酯和包含至少一种结晶形式的药物组合物，以及使用结晶形式治疗增殖性疾病的方法，以及用于 获得这样的结晶形式。 式（I）化合物包括[4 - [[1-（3-氟苯基）甲基] -1H-吲唑-5-基氨基] -5-甲基 - 吡咯并[2,1-f] 4]三嗪-6-基] - 氨基甲酸，（3S）-3-吗啉基甲基酯可用于抑制生长因子受体如HER1，HER2和HER4的酪氨酸激酶活性，从而使其可用作抗增殖剂，用于治疗 癌症等疾病。

公开(公告)号：US20050256202A1

公开(公告)日：2005-11-17

申请号：US11119558

申请日：2005-05-02

申请人： Soojin Kim ,  Bruce Lotz ,  Mary Malley ,  Jack Gougoutas ,  Martha Davidovich ,  Sushil Srivastava

发明人： Soojin Kim ,  Bruce Lotz ,  Mary Malley ,  Jack Gougoutas ,  Martha Davidovich ,  Sushil Srivastava

IPC分类号： A61K31/16 ,  C07C231/02 ,  C07C243/26 ,  C07D213/42

CPC分类号： C07D213/42

摘要： A process is provided for preparing the HIV protease inhibitor atazanavir bisulfate wherein a solution of atazanavir free base is reacted with concentrated sulfuric acid in an amount to react with less than about 15% by weight of the free base, seeds of Form A crystals of atazanavir bisulfate are added to the reaction mixture, and as crystals of the bisulfate form, additional concentrated sulfuric acid is added in multiple stages at increasing rates according to a cubic equation, to effect formation of Form A crystals of atazanavir bisulfate. A process is also provided for preparing atazanavir bisulfate as Pattern C material. A novel form of atazanavir bisulfate is also provided which is Form E3 which is a highly crystalline triethanolate solvate of the bisulfate salt from ethanol.

摘要翻译： 提供了一种制备HIV蛋白酶抑制剂阿扎那韦硫酸氢盐的方法，其中阿扎那韦游离碱的溶液与浓硫酸反应的量与小于约15重量％的游离碱反应，阿扎那韦的A型晶体种子 将硫酸氢盐加入到反应混合物中，并且以硫酸氢盐形式的结晶，按照立方式以增加的速率以多个阶段多次加入另外的浓硫酸，以实现阿扎那韦硫酸氢盐的形式A晶体的形成。 还提供了制备作为图案C材料的阿扎那韦硫酸氢盐的方法。 还提供了一种新型形式的阿扎那韦硫酸氢盐，其为E3型，其是来自乙醇的硫酸氢盐的高度结晶的三乙醇盐溶剂合物。

公开(公告)号：US20060142319A1

公开(公告)日：2006-06-29

申请号：US11301433

申请日：2005-12-13

申请人： Bang-Chi Chen ,  Albert Delmonte ,  T.G. Dhar ,  Michael Galella ,  Margaret Gleeson ,  Jack Gougoutas ,  Douglas McLeod ,  Huiping Zhang

发明人： Bang-Chi Chen ,  Albert Delmonte ,  T.G. Dhar ,  Michael Galella ,  Margaret Gleeson ,  Jack Gougoutas ,  Douglas McLeod ,  Huiping Zhang

IPC分类号： A61K31/4747 ,  C07D487/10

CPC分类号： C07D487/10

摘要： The invention provides crystalline forms of 6-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic acid, its pharmaceutically acceptable salts, or solvates, thereof Further, a process is provided for preparing substituted spiro-hydantoin compounds of the formula I wherein Z is N or CR4b; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A1, A2, G, and Q are linkers; and R2, R4a, R4c, and R16 are defined in the specification. The process includes the reaction of N-substituted glycine compound and methylene precursor compound with an alkene compound. The substituted spiro-hydantoin compounds of formulae I and II are useful in the treatment of immune and/or inflammatory diseases.

摘要翻译： 本发明提供6 - [（5S，9R）-9-（4-氰基苯基）-3-（3,5-二氯苯基）-1-甲基-2,4-二氧代-1,3,7-三氮杂螺[ [4.4]非7-基]烟酸，其药学上可接受的盐或溶剂化物。此外，提供了制备式I的取代的螺 - 乙内酰脲化合物的方法，其中Z是N或CR 4b， SUB>; K和L独立地为O或S; Ar是任选取代的芳基或杂芳基; A 1，A 2，G和Q是连接体; 和R 2，R 4a，R 4c和R 16在本说明书中定义。 该方法包括N-取代的甘氨酸化合物和亚甲基前体化合物与烯烃化合物的反应。 式I和II的取代的螺 - 乙内酰脲化合物可用于治疗免疫和/或炎性疾病。

公开(公告)号：US20060074099A1

公开(公告)日：2006-04-06

申请号：US11238427

申请日：2005-09-29

申请人： Albert DelMonte ,  T. Dhar ,  Yu Fan ,  Jack Gougoutas ,  Mary Malley ,  Douglas McLeod ,  Robert Waltermire ,  Chenkou Wei

发明人： Albert DelMonte ,  T. Dhar ,  Yu Fan ,  Jack Gougoutas ,  Mary Malley ,  Douglas McLeod ,  Robert Waltermire ,  Chenkou Wei

IPC分类号： A61K31/4747 ,  A61K31/4188 ,  C07D487/10

CPC分类号： C07D487/10

摘要： A process is provided for preparing spiro-hydantoin compounds of the formula II wherein Z is N or CR4b; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A2 is a linker, G′ is a linker; Q is a linker; and R2, R4a, R4c, and Rh are defined in the specification. The process optionally includes the enantiomeric separation of intermediates to allow preparation of enantiomers of the spiro-hydantoin compounds of formula II. Substituted spiro-hydantoin compounds may be prepared from the spiro-hydantoin compounds of formula II. The spiro-hydantoin compound of formula II and the substituted spiro-hydantoin compounds are useful in the treatment of immune or inflammatory diseases. Also, provided are products made by the instant inventive process and crystalline forms (prepared by any process) of the substituted spiro-hydantoin compound, 5-[(5S, 9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof, as well as methods of use thereof. Crystalline forms of certain intermediates are provided.

摘要翻译： 提供了制备式II的螺 - 乙内酰脲化合物的方法，其中Z是N或CR 4b; K和L独立地为O或S; Ar是任选取代的芳基或杂芳基; A 2是连接体，G'是连接体; Q是一个连接符; 和R 2，R 4a，R 4c和R h H在本说明书中定义。 该方法任选地包括中间体的对映异构体分离，以允许制备式II的螺 - 乙内酰脲化合物的对映异构体。 取代的螺 - 乙内酰脲化合物可以由式II的螺 - 乙内酰脲化合物制备。 式II的螺 - 乙内酰脲化合物和取代的螺 - 乙内酰脲化合物可用于治疗免疫或炎性疾病。 此外，提供的是本发明方法制备的产物和取代的螺 - 乙内酰脲化合物的5 - [（5S，9R）-9-（4-氰基苯基）-3-（3， 5-二氯苯基）-1-甲基-2,4-二氧代-1,3,7-三氮杂螺[4.4]壬-7-基甲基] - 噻吩-3-甲酸，包括其溶剂合物及其盐，以及 使用它。 提供某些中间体的结晶形式。