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1. 发明授权

US5914411A Alternate method for acylating 10-deacetylbaccatin III selectively at the C-10 position 失效
标题翻译：在C-10位置选择性地酰化10-脱乙酰基浆果赤霉素III的替代方法
公开(公告)号：US5914411A
公开(公告)日：1999-06-22
申请号：US10285
申请日：1998-01-21
申请人： Nicholas J. Sisti , Jan Zygmunt , Herbert R. Brinkman , Madhavi C. Chander , Xian Liang , James D. McChesney
发明人： Nicholas J. Sisti , Jan Zygmunt , Herbert R. Brinkman , Madhavi C. Chander , Xian Liang , James D. McChesney
IPC分类号： A61K31/337 , A61P35/00 , C07D305/14
CPC分类号： C07D305/14
摘要： A method of acylating 10-deacetylbaccatin III at the C-10 position over the C-7 hydroxy position thereof to produce baccatin IIII is accomplished first by dissolving 10-deacetylbaccatin III in an acceptable ether solvent therefor, such as tetrahydrofuran. A lithium salt, preferably lithium chloride, is added. A trialkylamine base or pyridine is next added, followed by the addition of an acylating agent, such as acetyl chloride. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent. The result is baccatin III in solution. This solution may then be diluted with ethyl acetate to form an organic phase and an aqueous phase, with the organic phase being washed and thereafter reduced. Recrystallization and column chromatography may be employed to purify the baccatin III.
摘要翻译：首先通过将10-脱乙酰基浆果赤霉素III溶解在其可接受的醚溶剂如四氢呋喃中来完成在其C-7羟基上的C-10位上酰化10-脱乙酰基浆果赤霉素Ⅲ以产生浆果赤霉素IIII的方法。加入锂盐，优选氯化锂。然后加入三烷基胺碱或吡啶，然后加入酰化剂如乙酰氯。所得溶液可以例如用氯化铵淬灭，以消除过量的酰化剂。结果是溶液中的浆果赤霉素III。然后可以用乙酸乙酯稀释该溶液以形成有机相和水相，同时洗涤有机相，然后还原。可以使用重结晶和柱色谱来纯化浆果赤霉素III。

2. 发明授权

US6066749A Method for conversion of C-2'-O-protected-10-hydroxy taxol to c-2'-O-protected taxol:useful intermediates in paclitaxel synthesis 失效
标题翻译：将C-2'-O-保护的10-羟基紫杉醇转化为c-2'-O保护的紫杉醇的方法：紫杉醇合成中的有用中间体
公开(公告)号：US6066749A
公开(公告)日：2000-05-23
申请号：US71261
申请日：1998-05-01
申请人： Nicholas J. Sisti , Herbert R. Brinkman , James D. McChesney , Madhavi C. Chander , Xian Liang , Jan Zygmunt
发明人： Nicholas J. Sisti , Herbert R. Brinkman , James D. McChesney , Madhavi C. Chander , Xian Liang , Jan Zygmunt
IPC分类号： C07D305/14
CPC分类号： C07D305/14
摘要： A method of acylating C-2' O-protected-10-hydroxy taxol selectively at the C-10 hydroxyl position over the C-7 hydroxy position thereof to produce C-2' O-protected taxol is accomplished first by dissolving C-2' O-protected-10-hydroxy taxol in an acceptable ether solvent therefor, such as tetrahydrofuran, to form a first solution at a first temperature. The first solution is then cooled to a second temperature, and a lithium base, preferably n-butyl lithium, is added to form an intermediate compound having a lithium alkoxide at the C-10 position thereof. An acylating agent, such as acetyl chloride, is then added. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent and the lithium base. The result is a solution containing C-2' O-protected taxol. This solution may then be washed, concentrated and purified. The present invention is also directed to C-10 lithium alkoxide intermediate compounds for the production of paclitaxel.
摘要翻译：首先通过将C-2'O-保护的10-羟基紫杉醇溶解在C-10羟基的C- 在其可接受的醚溶剂如四氢呋喃中的O-保护的10-羟基紫杉醇在第一温度下形成第一溶液。然后将第一溶液冷却至第二温度，并加入锂碱，优选正丁基锂以形成其C-10位上具有锂醇盐的中间体化合物。然后加入酰化剂，如乙酰氯。所得溶液可以例如用氯化铵淬灭，以消除过量的酰化剂和锂碱。其结果是含有C-2'O保护的紫杉醇的溶液。然后可以将该溶液洗涤，浓缩并纯化。本发明还涉及用于生产紫杉醇的C-10锂盐中间体化合物。

3. 发明授权

US6048990A Method for selective acylation of C-2'-O-protected-10-hydroxy-taxol at the C-10 position 失效
标题翻译：在C-10位置选择性酰化C-2'-O-保护的10-羟基 - 紫杉醇的方法
公开(公告)号：US6048990A
公开(公告)日：2000-04-11
申请号：US71258
申请日：1998-05-01
申请人： Xian Liang , Jan Zygmunt , Nicholas J. Sisti , Madhavi C. Chander , Herbert R. Brinkman , James D. McChesney
发明人： Xian Liang , Jan Zygmunt , Nicholas J. Sisti , Madhavi C. Chander , Herbert R. Brinkman , James D. McChesney
IPC分类号： C07D305/14
CPC分类号： C07D305/14
摘要： A method of acylating C-2' O-protected-10-hydroxy taxol selectively at the C-10 hydroxyl position over the C-7 hydroxy position thereof to produce C-2' O-protected taxol is accomplished first by dissolving C-2' O-protected-10-hydroxy taxol in an acceptable ether solvent therefor, such as tetrahydrofuran. A lithium salt, preferably lithium chloride, is added. A trialkylamine base or pyridine is next added, followed by the addition of an acylating agent, such as acetyl chloride. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent. This solution may then be diluted with ethyl acetate to form an organic phase and an aqueous phase, with the organic phase being washed and thereafter reduced. Recrystallization and column chromatography may be employed to purify the C-2' O-protected taxol.
摘要翻译：首先通过将C-2'O-保护的10-羟基紫杉醇溶解在C-10羟基的C- 'O-保护的10-羟基紫杉醇在其可接受的醚溶剂中，例如四氢呋喃。加入锂盐，优选氯化锂。然后加入三烷基胺碱或吡啶，然后加入酰化剂如乙酰氯。所得溶液可以例如用氯化铵淬灭，以消除过量的酰化剂。然后可以用乙酸乙酯稀释该溶液以形成有机相和水相，同时洗涤有机相，然后还原。可以使用重结晶和柱色谱来纯化C-2'O保护的紫杉醇。

4. 发明授权

US06448417B1 Methods and useful intermediates for paclitaxel synthesis from C-7, C-10 di-cbz 10-deacetylbaccatin III 失效
标题翻译：从C-7，C-10 di-cbz 10-脱乙酰基浆果赤霉素III合成紫杉醇的方法和有用的中间体
公开(公告)号：US06448417B1
公开(公告)日：2002-09-10
申请号：US09674404
申请日：2001-01-11
申请人： Nicholas J. Sisti , Herbert R. Brinkman , James D. McChesney , Medhavi C. Chander , Xian Liang , Jan Zygmunt
发明人： Nicholas J. Sisti , Herbert R. Brinkman , James D. McChesney , Medhavi C. Chander , Xian Liang , Jan Zygmunt
IPC分类号： C07D30514
CPC分类号： C07D305/14 , Y02P20/55
摘要： The present invention relates to a method of producing paclitaxel or a paclitaxel analog comprising the esterification of C-7, C-10 di-CBZ 10-deacetylbaccatin III with an N-carbamate protected, C-2-protected 3-phenyl isoserine side chain. The C-7, C-10 carbobenzyloxy groups are then replaced with hydrogen and an acyl group is substituted at the C-3′ nitrogen. The resulting compound is acylated at the C-10 hydroxyl position, and deprotected at the C-2′ position by replacing the hydroxyl protecting group with hydrogen to produce paclitaxel or a paclitaxel analog. The present invention also relates to alternative methods of acylating a 10-hydroxy paclitaxel analog. The first method comprises dissolving a 10-hydroxy paclitaxel analog in an acceptable ether solvent therefor to form a first solution at a first temperature. The first solution is then cooled to a second temperature, and an alkali base is added to form an intermediate compound having a metal alkoxide at the C-10 position thereof, after which an acylating ageht is then added. The second method comprises dissolving a 10-hydroxy paclitaxel analog in an acceptable ether solvent therefor. An alkali salt is added, and a trialkyl amine base or pyridine is next added, followed by the addition of an acylating agent. The present invention is additionally directed to a C-10 metal alkoxide chemical intermediate for use in producing paclitaxel or paclitaxel analogs.
摘要翻译：本发明涉及一种制备紫杉醇或紫杉醇类似物的方法，其包括将C-7，C-10二-CZZ 10-脱乙酰基浆果赤霉素III与N-氨基甲酸酯保护的C-2-保护的3-苯基异丝氨酸侧链酯化。然后用氢代替C-7，C-10苄氧羰基，酰基在C-3'氮取代。所得化合物在C-10羟基位置被酰化，并通过用氢代替羟基保护基而在C-2'位上去保护以产生紫杉醇或紫杉醇类似物。本发明还涉及酰化10-羟基紫杉醇类似物的替代方法。第一种方法包括将10-羟基紫杉醇类似物溶解在可接受的醚溶剂中以在第一温度下形成第一溶液。然后将第一溶液冷却至第二温度，加入碱碱以形成其C-10位具有金属醇盐的中间体化合物，之后加入酰化时间。第二种方法包括将10-羟基紫杉醇类似物溶解在可接受的醚溶剂中。加入碱金属盐，然后加入三烷基胺碱或吡啶，然后加入酰化剂。本发明另外涉及用于生产紫杉醇或紫杉醇类似物的C-10金属醇盐化学中间体。

5. 发明授权

US6143902A C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof 失效
标题翻译： C-2羟基保护-N-酰基（2R，3S）-3-苯基异丝氨酸N-酰亚胺活化酯及其制备方法
公开(公告)号：US6143902A
公开(公告)日：2000-11-07
申请号：US336962
申请日：1999-06-21
申请人： Jan Zygmunt , James D. McChesney , Madhavi C. Chander
发明人： Jan Zygmunt , James D. McChesney , Madhavi C. Chander
IPC分类号： C07D207/40 , C07D207/404 , C07D207/44 , C07D207/448 , C07D209/48 , C07D209/52 , C07D209/76 , C07D305/14 , C07D207/444 , C07D209/34 , C07D209/56
CPC分类号： C07D207/404 , C07D207/448 , C07D209/48 , C07D209/52 , C07D209/76 , C07D305/14 , Y02P20/55
摘要： A chemic compound having the formula: ##STR1## wherein P.sub.1 is a hydroxyl protecting group, R.sub.1 is an alkyl group, an olefinic group, an aromatic group, Ph, PhCH.sub.2, an O-alkyl group, an O-olefinic group, an O-aromatic group, O--Ph, or O--CH.sub.2 Ph, and wherein Z is an N-imido group. In particular, P.sub.1 may be selected from the group consisting of benzyl, benzyloxymethyl and benzoyl, and Z may be a heterocyclic N-imido group, preferably having 5 to 7 atoms in the ring and alternatively substituted with at least one electron withdrawing group, preferably selected from the group consisting of a chloro group, a fluoro group and a nitro group. In particular, it is contemplated that Z may be succinimido, phthalimido, 5-norbornene-2,3-dicarboxyimido, maleimido and substituted derivatives thereof.
摘要翻译：具有下式的化学化合物：其中P1是羟基保护基，R1是烷基，烯基，芳基，Ph，PhCH2，O-烷基，O-烯烃基，O-芳族基，O-Ph或O-CH 2 Ph，其中Z为N-亚氨基。特别地，P1可以选自苄基，苄氧基甲基和苯甲酰基，Z可以是杂环N-酰亚胺基，优选在环中具有5至7个原子，或者替代地被至少一个吸电子基团取代选自氯基，氟基和硝基。特别地，预期Z可以是琥珀酰亚胺基，邻苯二甲酰亚氨基，5-降冰片烯-2,3-二羧酰亚氨基，马来酰亚胺及其取代的衍生物。

6. 发明授权

US6136999A C-2 hydroxyl protected-n-acyl (2R,3S)-3-phenylisoserine substituted phenyl activated esters and method for production thereof 失效
标题翻译： C 2羟基保护的正己酰基（2R，3S）-3-苯基异丝氨酸取代的苯基活性酯及其制备方法
公开(公告)号：US6136999A
公开(公告)日：2000-10-24
申请号：US336961
申请日：1999-06-21
申请人： Madhavi C. Chander , James D. McChesney , Jan Zygmunt
发明人： Madhavi C. Chander , James D. McChesney , Jan Zygmunt
IPC分类号： C07C233/47 , C07C233/51 , C07C233/87 , C07C271/22 , C07C229/08 , C07D305/14
CPC分类号： C07C233/87 , C07C233/47 , C07C233/51 , C07C271/22 , Y02P20/55
摘要： A chemical compound having the formula: ##STR1## wherein P.sub.1 is a hydroxyl protecting group, R.sub.1 may be H or electron withdrawing group, R.sub.2 may be H or electron withdrawing group, R.sub.3 may be H or electron withdrawing group, R.sub.4 may be H or electron withdrawing group, R.sub.5 may be H or electron withdrawing group, R.sub.6 may be an alkyl group, an olefinic group, an aromatic group, Ph, PhCH.sub.2, an O-alkyl group, an O-olefinic group, an O-aromatic group, O--Ph, or O--CH.sub.2 Ph.
摘要翻译：具有下式的化合物：其中P1是羟基保护基，R 1可以是H或吸电子基团，R 2可以是H或吸电子基团，R 3可以是H或吸电子基团，R 4可以是H或吸电子基团 R 5可以是H或吸电子基团，R6可以是烷基，烯基，芳基，Ph，PhCH2，O-烷基，O-烯烃基，O-芳族基，O-Ph ，或O-CH 2 Ph。

7. 发明授权

US06825166B2 Molecular conjugates for use in treatment of cancer 失效
标题翻译：用于治疗癌症的分子共轭物
公开(公告)号：US06825166B2
公开(公告)日：2004-11-30
申请号：US10107543
申请日：2002-03-25
申请人： James D. McChesney , Madhavi C. Chander , Teruna J. Siahaan , Christine R. Xu , Sterling K. Ainsworth
发明人： James D. McChesney , Madhavi C. Chander , Teruna J. Siahaan , Christine R. Xu , Sterling K. Ainsworth
IPC分类号： A61K31337
CPC分类号： C07K14/79 , A61K31/337 , A61K31/352 , A61K31/407 , A61K31/56 , A61K31/704 , A61K38/00 , A61K47/644 , C07D305/14 , C07D311/82 , C07H15/252 , C07J9/00
摘要： A molecular conjugate is provided having the formula: wherein n is the conjugation number, P is a moiety of a carrier molecule such as a protein, R1 is a moiety of a biologically active molecule or its analogs, derivatives, salts or secondary amines, Z is —O— or —NH—, and Y is a straight or branched alkyl having 1 to 20 carbons optionally substituted with one or more phenyl, a cycloalkyl optionally substituted with one or more alkyl or phenyl, or an aromatic group optionally substituted with one or more alkyl, electron-withdrawing or electron-donating groups. Compounds and methods useful in producing such molecular conjugates are also provided, as well as methods of concentrating biologically active molecules in selected target cells of a patient that comprise administering to the patient a selected dose of such molecular conjugates.
摘要翻译：提供了具有下式的分子结合物：其中n是共轭数，P是载体分子如蛋白质的部分，R1是生物活性分子或其类似物，衍生物，盐或仲胺的部分，Z 是-O-或-NH-，Y是具有1至20个碳的直链或支链烷基，任选被一个或多个苯基取代，任选被一个或多个烷基或苯基取代的环烷基或任选被一个或更多的烷基，吸电子基团或给电子基团。还提供了可用于制备这种分子缀合物的化合物和方法，以及将生物活性分子浓缩到患者的选定靶细胞中的方法，其包括向患者施用选定剂量的这种分子缀合物。

8. 发明授权

US06495705B2 Efficient process for the production of 10-DAB III by selective hydrazinolysis of various taxanes 失效
标题翻译：通过各种紫杉烷的选择性肼解，生产10-DAB III的有效方法
公开(公告)号：US06495705B2
公开(公告)日：2002-12-17
申请号：US09899831
申请日：2001-07-05
申请人： Madhavi C. Chander , James D. McChesney
发明人： Madhavi C. Chander , James D. McChesney
IPC分类号： C07D30514
CPC分类号： C07D305/14
摘要： The present invention describes a process for producing 10-deacetyl baccatin III from a solution containing a solvent reactive with hydrazine hydrate and a spectrum of taxanes. The solution is contacted with hydrazine hydrate thereby converting some taxanes therein into 10-deacetyl baccatin III. The process can target taxanes having an ester functionality on at least one of the C-10 and C-13 positions. The hydrazine hydrate cleaves the ester functionality of the taxane solute, The process may be used to produce 10-deacetyl baccatin III from a biomass extract by contacting the biomass extract with a mixture of a solvent and a hydrazine hydrate. The solvent may have a functional group that is cleaved by hydrazine. Acetate solvents are contemplated.
摘要翻译：本发明描述了从含有与水合肼反应的溶剂和紫杉烷类的溶液的溶液中制备10-脱乙酰浆果赤霉素III的方法。将溶液与水合肼接触，由此将其中的一些紫杉烷转化为10-脱乙酰浆果赤霉素III。该方法可以靶向在C-10和C-13位置中的至少一个上具有酯官能团的紫杉烷。水合肼切割紫杉烷溶质的酯官能团。该方法可用于通过使生物质提取物与溶剂和水合肼的混合物接触从生物质提取物中产生10-脱乙酰浆果赤霉素III。溶剂可以具有被肼切割的官能团。预期醋酸溶剂。

9. 发明授权

US06281368B1 Simple and efficient hydrazinolysis of C-10 and C-13 ester functionalities of taxanes to obtain 10-DAB III 失效
标题翻译：紫杉烷的C-10和C-13酯官能团简单有效的肼解，得到10-DAB III
公开(公告)号：US06281368B1
公开(公告)日：2001-08-28
申请号：US09527007
申请日：2000-03-16
申请人： James D. McChesney , Madhavi C. Chander , Douglas L. Rodenburg
发明人： James D. McChesney , Madhavi C. Chander , Douglas L. Rodenburg
IPC分类号： C07D30514
CPC分类号： C07D305/14
摘要： A process for producing 10-deacetyl baccatin III from an acidic solution containing a spectrum of taxanes, comprising contacting the acidic solution containing the spectrum of taxanes with a hydrazine hydrate, thereby to convert into 10-deacetyl baccatin III some taxanes in said solution that are not 10-deacetyl baccatin III.
摘要翻译：一种从含有紫杉烷类光谱的酸性溶液中生产10-脱乙酰浆果赤霉素III的方法，包括使含有紫杉烷类光谱的酸性溶液与水合肼接触，从而将所述溶液中的一些紫杉烷转化为10-脱乙酰浆果赤霉素III 不是10-脱乙酰浆果赤霉素III。

10. 发明授权

US07153946B2 Molecular conjugates for use in treatment of cancer 失效
标题翻译：用于治疗癌症的分子共轭物
公开(公告)号：US07153946B2
公开(公告)日：2006-12-26
申请号：US10996848
申请日：2004-11-24
申请人： James D. McChesney , Madhavi C. Chander , Teruna J. Siahaan , Christine R. Xu , Sterling K. Ainsworth
发明人： James D. McChesney , Madhavi C. Chander , Teruna J. Siahaan , Christine R. Xu , Sterling K. Ainsworth
IPC分类号： C07D227/10 , C07D305/14 , C07D311/78 , C07D491/12 , C07H15/24 , C07J9/00
CPC分类号： C07K14/79 , A61K31/337 , A61K31/352 , A61K31/407 , A61K31/56 , A61K31/704 , A61K38/00 , A61K47/644 , C07D305/14 , C07D311/82 , C07H15/252 , C07J9/00
摘要： A molecular conjugate is provided having the formula: wherein R1 is a de-hydroxyl or de-amino moiety respectively of a hydroxyl-bearing or amino-bearing biologically active molecule or an analog or derivative thereof, and Z is —O— or —NH—, respectively, Y is a straight or branched alkyl having 1 to 20 carbons that may be optionally substituted with one or more phenyl, a cycloalkyl optionally substituted with one or more alkyl or phenyl, or an aromatic group optionally substituted with one or more alkyl groups, electron-withdrawing groups, or electron-donating groups; and R2 is —CH═CH(W), —CH(OH)CH(OH)W, or —C(O)H, where W can be H, a straight or branched alkyl having 1 to 20 carbons that may be optionally substituted with one or more phenyl, a cycloalkyl optionally substituted with one or more alkyl or phenyl, or an aromatic group optionally substituted with one or more alkyl groups, electron-withdrawing groups, or electron-donating groups.
摘要翻译：提供具有下式的分子结合物：其中R 1分别是含羟基或含氨基的生物活性分子或其类似物或衍生物的脱羟基或脱氨基部分，以及 Z分别是-O-或-NH-，Y是具有1至20个碳的直链或支链烷基，其可任选被一个或多个苯基任选取代，任选被一个或多个烷基或苯基取代的环烷基或芳族任选被一个或多个烷基取代的基团，吸电子基团或给电子基团; 和R 2是-CH-CH（W），-CH（OH）CH（OH）W或-C（O）H，其中W可以是H，直链或支链烷基，其具有可以任选被一个或多个苯基取代的1至20个碳，任选被一个或多个烷基或苯基取代的环烷基，或任选被一个或多个烷基取代的芳族基团，吸电子基团或给电子基团。

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