公开(公告)号：WO0222626A8

公开(公告)日：2002-10-24

申请号：PCT/US0128401

申请日：2001-09-12

Applicant: SQUIBB BRISTOL MYERS CO ,  VENIT JOHN J ,  DALI MANDAR V ,  DALI MANISHA M ,  HUANG YANDE ,  DAHLHEIM CHARLES E ,  TEJWANI RAVINDRA W

Inventor： VENIT JOHN J ,  DALI MANDAR V ,  DALI MANISHA M ,  HUANG YANDE ,  DAHLHEIM CHARLES E ,  TEJWANI RAVINDRA W

IPC: A61P35/00 ,  C07C211/14 ,  C07C215/10 ,  C07C215/12 ,  C07C229/08 ,  C07C229/26 ,  C07C279/14 ,  C07D233/54 ,  C07D233/61 ,  C07F9/12 ,  A61K31/66 ,  C07D209/20

CPC classification number: C07D233/64 ,  C07C211/14 ,  C07C215/10 ,  C07C215/12 ,  C07C229/08 ,  C07C229/26 ,  C07C279/14 ,  C07F9/12

Abstract: Provided herein are novel and useful combretastatin A-4 prodrug salts that increase the solubility of combretastatin A-4, readily regenerate combretastatin A-4 in vivo under normal physiological conditions, and which produce physiologically tolerable products as a result of the regeneration of combretastatin A-4.

Abstract translation: 本文提供了新的和有用的考布他汀A-4前药盐，其增加了考布他汀A-4的溶解度，在正常生理条件下容易地在体内再生考布他汀A-4，并且由于考布他汀A的再生而产生生理上可耐受的产物 -4。

公开(公告)号：WO0228809A3

公开(公告)日：2002-06-27

申请号：PCT/US0129783

申请日：2001-09-24

Applicant: SQUIBB BRISTOL MYERS CO ,  VENIT JOHN J ,  MADDING GARY D ,  ROSSO VICTOR W ,  OKUNIEWICZ FRANCIS J ,  DISCORDIA ROBERT P ,  KIAU SUSANNE ,  KOTNIS ATUL S ,  RANDAZZO MICHAEL E ,  HENNINGS DAVID D ,  ZHU JINGYANG ,  CHEN JASON G

Inventor： VENIT JOHN J ,  MADDING GARY D ,  ROSSO VICTOR W ,  OKUNIEWICZ FRANCIS J ,  DISCORDIA ROBERT P ,  KIAU SUSANNE ,  KOTNIS ATUL S ,  RANDAZZO MICHAEL E ,  HENNINGS DAVID D ,  ZHU JINGYANG ,  CHEN JASON G

IPC: C07B57/00 ,  C07C51/41 ,  C07C51/43 ,  C07C51/487 ,  C07C57/58 ,  C07C213/08 ,  C07C213/10 ,  C07C327/32 ,  C07D233/74 ,  C07D233/78 ,  C07K1/06 ,  C07K5/062 ,  C07K5/06

CPC classification number: C07D233/78 ,  C07C51/412 ,  C07C51/43 ,  C07C213/08 ,  C07C213/10 ,  C07D233/74 ,  C07C57/58

Abstract: Provided is a dynamic resolution method of enriching a desired isomer of an alpha-substituted carboxylic acid relative to an undesired isomer, the method comprising: (a) in a solvent, contacting the alpha-substituted carboxylic acid, wherein the alpha substitution is with a leaving group and wherein the alpha carbon is chiral, with a homochiral amine to form a salt that is partially insoluble under selected reaction conditions, wherein the homochiral amine is selected so that the solubility of the amine salt of the undesired alpha-substituted carboxylic acid is greater than that of the amine salt of the desired alpha-substituted carboxylic acid under the selected reaction conditions; (b) reacting under the selected reaction conditions the salt with a nucleophile, wherein the reacting is effective in producing a net increase in the less soluble amine salt of the alpha-substituted carboxylic acid, and wherein the selected conditions are selected to (i) promote nucleophilic substitution of the nucleophile and the leaving group or (ii) to produce the increase in the less soluble amine salt in the absence of a strong base; and (c) maintaining the reaction for a period of time effective to increase the amount of the desired alpha-substituted carboxylic acid isomer.

Abstract translation: 提供了相对于不需要的异构体富集α-取代的羧酸的期望的异构体的动态拆分方法，所述方法包括：（a）在溶剂中，使α-取代的羧酸接触，其中α取代是与 离去基团，并且其中α碳是手性的，与同手性胺形成在选择的反应条件下部分不溶的盐，其中选择纯手性胺以使不需要的α-取代的羧酸的胺盐的溶解度为 在选定的反应条件下大于所需的α-取代羧酸的胺盐; （b）在选择的反应条件下使所述盐与亲核试剂反应，其中所述反应有效地产生所述α-取代羧酸的难溶性胺盐的净增加，并且其中所选条件选自（i） 促进亲核试剂和离去基团的亲核取代或（ii）在不存在强碱的情况下产生难溶性胺盐的增加; 和（c）将反应维持一段有效的时间以增加所需的α-取代的羧酸异构体的量。

公开(公告)号：WO0003981A8

公开(公告)日：2001-06-28

申请号：PCT/US9914957

申请日：1999-07-01

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： GODFREY JOLLIE D JR ,  KRONENTHAL DAVID R ,  SCHWINDEN MARK D ,  SRIVASTAVA SUSHIL K ,  RAMIG KEITH ,  VENIT JOHN J ,  JASS PAUL A ,  RACHA SAIBABA ,  DILLON JOHN L JR ,  SOUNDARARAJAN NACHIMUTHU ,  POWERS GERALD L ,  KOTNIS ATUL S

IPC: A61K31/554 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07C229/22 ,  C07D317/30 ,  C07D513/04 ,  C07D317/26 ,  C07D317/28

CPC classification number: C07C229/22 ,  C07D317/30

Abstract: The invention relates to the synthesis of 2-amino-6, 6-dimethoxy hexanoic acid, methyl ester and novel dioxalane intermediates thereof, from the reaction of glycinamide of formula I with dioxolane of formula II.

Abstract translation: 本发明涉及由式I的甘氨酰胺与式II的二氧戊环的反应合成2-氨基-6,6-二甲氧基己酸，甲酯和新的二氧杂环戊烷中间体。

公开(公告)号：WO0003981A2

公开(公告)日：2000-01-27

申请号：PCT/US9914957

申请日：1999-07-01

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： GODFREY JOLLIE D JR ,  KRONENTHAL DAVID R ,  SCHWINDEN MARK D ,  SRIVASTAVA SUSHIL K ,  RAMIG KEITH ,  VENIT JOHN J ,  JASS PAUL A ,  RACHA SAIBABA ,  DILLON JOHN L JR ,  SOUNDARARAJAN NACHIMUTHU ,  POWERS GERALD L ,  KOTNIS ATUL S

IPC: A61K31/554 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07C229/22 ,  C07D317/30 ,  C07D513/04 ,  C07D

CPC classification number: C07C229/22 ,  C07D317/30

Abstract: The invention relates to the synthesis of 2-amino-6, 6-dimethoxy hexanoic acid, methyl ester and novel dioxalane intermediates thereof, from the reaction of glycinamide of formula I with dioxolane of formula II.

Abstract translation: 本发明涉及由式I的甘氨酰胺与式II的二氧戊环反应合成2-氨基-6,6-二甲氧基己酸，甲酯和其新二氧杂环戊烷中间体。

公开(公告)号：EP1497637A4

公开(公告)日：2006-02-08

申请号：EP03728381

申请日：2003-04-10

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： ROSSO VICTOR W ,  YOUNG GLEN ,  NOLFO JOSEPH ,  VITEZ IMRE M ,  VENIT JOHN J

IPC: G01N23/20 ,  B01L3/00 ,  G01N1/28

CPC classification number: G01N1/4077 ,  B01L3/50255 ,  B01L2200/026 ,  B01L2300/0829 ,  B01L2400/049 ,  G01N23/20 ,  G01N23/20025

Abstract: Multiple samples are prepared in slurry form and deposited through a funnel plate by a multiprobe liquid handler into an array of inserts situated in openings (16) in a housing (B). Each insert (A) has a recess (18) that extends through the insert body (10) and a filter disc (12) situated in the recess to support the sample. The filter is held in place by an annular part (14) which defines a channel providing access to the filter through the lower portion (26) of the recess. A pressure differential is created across each of the filters by attaching a vacuum manifold to the bottom of the housing to simultaneously remove the liquid from each of the samples, leaving the samples in powder form. The housing is then placed in the X-ray diffractometer for sequential analysis of each of the samples, while the samples are situated in the inserts.

Abstract translation: 以浆液形式制备多个样品并通过漏斗板通过多探头液体处理器将其沉积到位于壳体（B）中的开口（16）中的插入物阵列中。 每个插入件（A）具有延伸穿过插入件主体（10）的凹槽（18）和位于凹槽中以支撑样本的过滤盘（12）。 过滤器通过环形部分（14）保持在适当的位置，环形部分（14）限定通过凹部的下部（26）提供通向过滤器的通道的通道。 通过将真空歧管连接到外壳的底部以在每个过滤器上产生压力差，以同时从每个样品中除去液体，使样品保持粉末形式。 然后将外壳放置在X射线衍射仪中，用于对每个样品进行连续分析，而样品位于插入物中。

公开(公告)号：EP1097236A4

公开(公告)日：2006-10-04

申请号：EP99933744

申请日：1999-07-07

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： DONOVAN MARY JO ,  GOLDBERG STEVEN ,  HANSON RONALD L ,  JASS PAUL A ,  LI WEN-SEN ,  PATEL RAMESH N ,  RAMIG KEITH ,  SZARKA LASZLO J ,  VENIT JOHN J

IPC: C12N15/09 ,  C12N1/19 ,  C12N9/06 ,  C12P7/62 ,  C12P13/00 ,  C12P17/04 ,  C12P17/06 ,  C12P41/00 ,  C12R1/01 ,  C12R1/84 ,  C12P13/04 ,  C07C59/185 ,  C07C229/24 ,  C12N1/16 ,  C12N1/20 ,  C12N9/02 ,  C12N15/00 ,  C12N15/70 ,  C12N15/81 ,  C12R1/19

CPC classification number: C12N9/0018 ,  C12P7/62 ,  C12P41/002 ,  C12P41/006

公开(公告)号：EP1109928A4

公开(公告)日：2004-10-13

申请号：EP99945367

申请日：1999-08-31

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： PATEL RAMESH N ,  BANERJEE AMIT ,  NANDURI VENKATA B ,  GOLDBERG STEVEN L ,  JOHNSTON ROBERT M ,  TULLY THOMAS P ,  SZARKA LASZLO J ,  SWAMINATHAN SHANKAR ,  VENIT JOHN J ,  MONIOT JEROME L ,  WINTER WILLIAM J ,  ANDERSON NEAL G ,  LUST DAVID A ,  CRISPINO GERARD ,  SRIVASTAVA SUSHIL

IPC: C12N15/09 ,  A61K38/00 ,  C07D513/04 ,  C07K5/062 ,  C07K5/078 ,  C07K14/81 ,  C12N1/20 ,  C12N1/21 ,  C12N9/06 ,  C12N9/10 ,  C12P17/18 ,  C12R1/01 ,  C12R1/38 ,  C12R1/465 ,  C07K5/06 ,  C12N15/52 ,  C12P21/02

CPC classification number: C07K5/06139 ,  A61K38/00 ,  C07K14/8103 ,  C12N9/1096

公开(公告)号：EP1235792A4

公开(公告)日：2003-06-25

申请号：EP99974268

申请日：1999-07-29

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： MONIOT JEROME L ,  RAMIG KEITH ,  JASS PAUL A ,  DILLON JOHN L JR ,  RACHA SAIBABA ,  SHRIVASTAVA SUSHIL K ,  WINTER WILLIAM J ,  VENIT JOHN J ,  SWAMINATHAN SHANKAR ,  SIMPSON JAMES ,  CHEN CHIEN-KUANG ,  PACK SHAWN K ,  SCHWINDEN MARK D

IPC: C07D513/04 ,  C07B53/00 ,  C07B61/00 ,  C07C229/04 ,  C07C229/22 ,  C07C261/00 ,  C07C319/22 ,  C07C323/59 ,  C07D281/02

CPC classification number: Y02P20/55

Abstract: N-protected-L-homocysteine disulfide of the formula (I) or an activated form thereof is reacted with (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester to give the disulfide intermediate of the formula (II). The disulfide intermediate of formula (II) is reacted to cleave the disulfide bond and the resulting monomer is subjected to an acid catalyzed cyclization reaction to give the N-protected lactam of the formula (III). Removal of the N-protecting group gives [4S-(4 alpha ,7 alpha ,10a beta ]-4-aminooctahydro-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid, methyl ester which along with its salt is useful as an intermediate in the preparation of the dual inhibitor [4S- [4 alpha (R*),7 alpha ,10a beta ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido-[2,1-b][1,3]thiazepine-7-carboxylic acid.

公开(公告)号：EP1121351A4

公开(公告)日：2003-05-02

申请号：EP99932163

申请日：1999-07-01

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： GODFREY JOLLIE D JR ,  KRONENTHAL DAVID R ,  SCHWINDEN MARK D ,  SRIVASTAVA SUSHIL K ,  RAMIG KEITH ,  VENIT JOHN J ,  JASS PAUL A ,  RACHA SAIBABA ,  DILLON JOHN L JR ,  SOUNDARARAJAN NACHIMUTHU ,  POWERS GERALD L ,  KOTNIS ATUL S

IPC: A61K31/554 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07C229/22 ,  C07D317/30 ,  C07D513/04 ,  C07D317/26 ,  C07D317/28

CPC classification number: C07C229/22 ,  C07D317/30

Abstract: The invention relates to the synthesis of 2-amino-6, 6-dimethoxy hexanoic acid, methyl ester and novel dioxalane intermediates thereof, from the reaction of glycinamide of formula I with dioxolane of formula II.

Abstract translation: 本发明涉及由式I的甘氨酰胺与式II的二氧戊环反应合成2-氨基-6,6-二甲氧基己酸，甲酯和其新二氧杂环戊烷中间体。

公开(公告)号：SK287117B6

公开(公告)日：2009-12-07

申请号：SK6722002

申请日：2001-09-12

Applicant: SQUIBB BRISTOL MYERS CO

Inventor： VENIT JOHN J ,  DALI MANDAR V ,  DALI MANISHA M ,  HUANG YANDE ,  DAHLHEIM CHARLES E ,  TEJWANI RAVINDRA W

IPC: C07F9/00 ,  A61K31/00 ,  A61P35/00 ,  C07C211/00 ,  C07C211/14 ,  C07C215/00 ,  C07C215/10 ,  C07C215/12 ,  C07C229/00 ,  C07C229/08 ,  C07C229/26 ,  C07C279/00 ,  C07C279/14 ,  C07D209/00 ,  C07D233/00 ,  C07D233/54 ,  C07D233/61 ,  C07F9/12

Abstract: The present invention relates to combretastatin A-4 phosphate prodrug mono- and di-organic optionally substituted aliphatic amine salts, mono- and di-amino acid salts, and mono- and di-amino acid ester salts, which salts have greater solubility than native combretastatin A-4, and rapidly regenerate combretastatin A-4 under physiological conditions. The use of these compounds in the manufacture of a medicament for modulating tumor growth or metastasis in an animal, a pharmaceutical composition comprising these compounds and a process for preparing them are also described.