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51. 发明授权

US5298625A Process for the preparation of 4-phosphinyl-3-keto-carboxylate and 4-phosphonyl-3-keto-carboxylate intermediates useful in the preparation of phosphorus containing HMG-CoA reductase inhibitors 失效
标题翻译：用于制备含磷HMG-CoA还原酶抑制剂的4-氧膦基-3-酮羧酸酯和4-膦酰基-3-酮羧酸酯中间体的方法
公开(公告)号：US5298625A
公开(公告)日：1994-03-29
申请号：US987514
申请日：1992-12-07
申请人： John K. Thottathil , Wen S. Li
发明人： John K. Thottathil , Wen S. Li
IPC分类号： C07F9/30 , C07F9/32 , C07F9/572 , C07F7/02 , C07F9/02
CPC分类号： C07F9/5728 , C07F9/301 , C07F9/3211 , C07F9/3294
摘要： A process for the preparation of compounds of formula ##STR1## or salt thereof where R.sub.1 is --X--Z and X is --C.tbd.C--,R.sub.2 and R.sub.2 ' are independently hydrogen, alkyl or trialkylsilyl;R.sub.3 is hydrogen or alkyl; andZ is a hydrophobic anchor;which includes reacting a compound of formula ##STR2## where R.sub.4 is alkyl, cycloalkyl or aryl; and R.sub.5 is trialkylsilyl or triarylsilyl with a compound of formula ##STR3## where Y is a halogen, to form a compound of formula ##STR4## and hydrolyzing the compound of formula IV to obtain the compounds of formula I. Compounds of formula I or salt thereof where R.sub.1 is --OR.sub.2 ' may be prepared by reacting a compound of formula III with a compound of formulaP(OR.sub.2).sub.3 XII.
摘要翻译：制备式I的化合物或其盐的方法，其中R 1是-X-Z，X是-C 3 -C（O）C，R 2和R 2'独立地是氢，烷基或三烷基甲硅烷基; R3是氢或烷基; Z是疏水锚; 其包括使式（II）化合物与其中R 4为烷基，环烷基或芳基的化合物反应; 并且R 5是具有式III的化合物的三烷基甲硅烷基或三芳基甲硅烷基，其中Y是卤素，以形成式IV的化合物并水解式IV的化合物以获得式I的化合物。式I化合物或其盐，其中R 1是-OR 2'可以通过使式III化合物与式P（OR 2）3 XII的化合物反应来制备。

52. 发明授权

US4900860A Process for preparing phosphonyloxyacyl amino acids 失效
标题翻译：膦酰氧基酰基氨基酸的制备方法
公开(公告)号：US4900860A
公开(公告)日：1990-02-13
申请号：US358240
申请日：1989-05-30
申请人： John K. Thottathil
发明人： John K. Thottathil
IPC分类号： C07F9/40 , C07F9/572 , C07F9/576 , C07F9/6561 , C07F9/6571
CPC分类号： C07F9/657181 , C07F9/4075 , C07F9/5728 , C07F9/5765 , C07F9/6561
摘要： A process is provided for preparing phosphonyloxyacylamino acids and derivatives thereof having the structure ##STR1## wherein X is ##STR2## which includes the steps of treating a phosphonic acid dichloride of the structure ##STR3## with an .alpha.-hydroxy acid of the structure ##STR4## in the presence of base such as triethylamine at reduced temperatures to form the cyclic mixed anhydride of the structure ##STR5## (which is a new intermediate) and reacting the cyclic mixed anhydride with an amino acid or ester of the structureHX in the presence of base such as triethylamine produces the ACE inhibitor compound ##STR6## In an alternative process, the cyclic anhydride is quenched with water to form the diacid ##STR7## which is treated with a condensing agent such as dicyclohexyl carbodiimide (DCC), 1,1-carbonyldiimidazole (CDI) or thionyl chloride followed by quenching with the amino acidHXproduces the above ACE inhibitor compound.In another variation of the process of the invention, the above cyclic anhydride is treated with an alcohol of the structureR.sub.3 OHto form the phosphonic acid diester ##STR8## which may be coupled with the amino acid or esterHXto form the ACE inhibitor ##STR9##
摘要翻译：提供了一种制备具有结构的膦酰氧基酰氨基酸及其衍生物的方法，其中X是图像+ TR图像，其包括以下步骤：将α结构的膦酸二氯化物用α - 羟基酸在碱例如三乙胺存在下，在降低的温度下反应，形成结构“IMAGE”（其是新的中间体）的环状混合酸酐，并使环状混合酐与氨基酸或在碱例如三乙胺存在下，结构HX的酯产生ACE抑制剂化合物在替代方法中，环状酸酐用水淬灭以形成二酸，其用缩合剂如二环己基碳二亚胺（DCC），1,1-羰基二咪唑（CDI）或亚硫酰氯，然后用氨基酸HX淬灭产生上述ACE抑制剂化合物。在本发明方法的另一个变化方案中，将上述环状酸酐用结构为R 3 OH的醇处理以形成可与氨基酸或酯HX偶联以形成ACE抑制剂的图像的膦酸二酯 >

53. 发明授权

US4873356A Method for preparing phosphinic acids used in preparing ace inhibitors and intermediates produced thereby 失效
标题翻译：制备用于制备ace抑制剂的次膦酸的方法及其制备的中间体
公开(公告)号：US4873356A
公开(公告)日：1989-10-10
申请号：US102694
申请日：1987-09-30
申请人： Edward W. Petrillo, Jr. , Donald S. Karanewsky , John K. Thottathil , James E. Heikes , John A. Grosso
发明人： Edward W. Petrillo, Jr. , Donald S. Karanewsky , John K. Thottathil , James E. Heikes , John A. Grosso
IPC分类号： A61K31/66 , A61P9/12 , A61P43/00 , B01J23/44 , C07B61/00 , C07F9/32 , C12N9/99
CPC分类号： C07F9/3264 , C07F9/3211
摘要： A method is provided for preparing phosphinic acid compounds, which are useful in preparing certain angiotensin converting enzyme inhibitors, which have the formula ##STR1## wherein R.sub.1 is lower alkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl;R.sub.2 is hydrogen, lower alkyl or arylalkyl;X is hydrogen, lower alkyl or phenyl;Y is hydrogen, lower alkyl, phenyl or alkoxy, or together X and Y are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH--, or ##STR2## and n is 0 or 1including salts thereof and stereoisomers thereof, which method includes the steps of reacting a phosphinic acid ester of the structure ##STR3## wherein R.sub.3 is a group removable by hydrogenolysis such as benzyl or substituted benzyl, with a halo ester of the structure ##STR4## in the presence of an organic base to form a phosphinic acid ester of the structure ##STR5## hydrogenating the above ester to form a diastereomic mixture of a phosphinic acid of the structure ##STR6## recrystallizing to recover the preferred racemic mixture and resolving same employing a resolving agent, preferably L-cinchonidine, to form the corresponding resolved salt which may be acidified to the corresponding acid. In addition, novel intermediates which are acids and salts as described above are also provided.
摘要翻译：提供了一种制备次膦酸化合物的方法，其可用于制备具有下式的其中R 1为低级烷基，芳基，芳烷基，环烷基或环烷基烷基的一些血管紧张素转换酶抑制剂; R2是氢，低级烷基或芳基烷基; X是氢，低级烷基或苯基; Y是氢，低级烷基，苯基或烷氧基，或者一起X和Y是 - （CH 2）2 - ， - （CH 2）3 - ， - CH = CH-或，n是0或1，包括其盐该方法包括以下步骤：使结构式“其中R3是通过氢解可除去的基团如苄基或取代的苄基”的结构式的次膦酸酯与结构“IMAGE”的卤代酯在存在下形成下述结构的次膦酸酯的有机碱，氢化上述酯以形成结构为重结晶的次膦酸的非对映体混合物，以回收优选的外消旋混合物，并使用拆分剂拆分，优选形成相应的分解盐，其可以酸化成相应的酸。此外，还提供了如上所述的酸和盐的新型中间体。

54. 发明授权

US4851514A Process for preparing a compound useful in preparing ace inhibitors and intermediate produced thereby 失效
标题翻译：制备可用于制备ace抑制剂的化合物及其制备的中间体的方法
公开(公告)号：US4851514A
公开(公告)日：1989-07-25
申请号：US92360
申请日：1987-09-02
申请人： John K. Thottathil
发明人： John K. Thottathil
IPC分类号： C07D207/16 , C07D207/22 , C07D207/26 , C07D207/277
CPC分类号： C07D207/277 , C07D207/16 , C07D207/22 , Y02P20/55
摘要： A compound (for preparing an ACE inhibitor), namely, triphenyl cerium and a process for preparing same by reacting cerium trichloride (CeCl.sub.3) with phenyllithium, are provided.
摘要翻译：提供化合物（用于制备ACE抑制剂），即三苯基铈及其制备方法，其中三氯化铈（CeCl 3）与苯基锂反应。

55. 发明授权

US4687865A Process for preparing 7-oxabicycloheptane amino-alcohol intermediates useful in making thromboxane A2 receptor antagonists 失效
标题翻译：制备可用于制备血栓素A2受体拮抗剂的7-氧杂双环庚烷氨基醇中间体的方法
公开(公告)号：US4687865A
公开(公告)日：1987-08-18
申请号：US870564
申请日：1986-06-04
申请人： John K. Thottathil
发明人： John K. Thottathil
IPC分类号： A61K31/34 , A61K31/557 , A61P7/02 , A61P11/08 , C07D493/08 , C07D307/00
CPC分类号： C07D493/08
摘要： A process is provided for preparing a 7-oxabicycloheptane amino alcohol intermediate of the general structure ##STR1## (wherein the above structures represents (D) or (L) isomers) which is useful in preparing thromboxane A.sub.2 receptor antagonists. This intermediate is prepared by reacting mesoanhydride with an aryl amine ##STR2## wherein R is alkyl, CH.sub.2 OH, CO.sub.2 H or CO.sub.2 alkyl, to form the acid ##STR3## which is reduced by treatment with lithium aluminum hydride or diisobutylaluminum hydride or Red-Al to form the alcohol ##STR4## wherein R.sup.1 is CH.sub.2 OH when R is CO.sub.2 H, CO.sub.2 alkyl or CH.sub.2 OH, and R.sup.1 is alkyl when R is alkyl; where in the above alcohol R.sup.1 is CH.sub.2 OH, such alcohol compound is treated with an alkyl chloroformate in the presence of base such as an alkali metal alkoxide to form the alcohol ##STR5## which undergoes cleavage by treatment with alkali metal, ammonia and acid to form the amino alcohol intermediate.Where in the above alcohol R.sup.1 is alkyl, that is ##STR6## such alcohol may be hydrogenated to form the aminoalcohol intermediate. All of the above 7-oxabicycloheptane compounds are novel and also form part of the present invention.

56. 发明授权

US4501901A Method for making substituted prolines 失效
标题翻译：取代脯氨酸的方法
公开(公告)号：US4501901A
公开(公告)日：1985-02-26
申请号：US533705
申请日：1983-09-19
申请人： John K. Thottathil , Jerome L. Moniot , David Floyd , Steven Brandt
发明人： John K. Thottathil , Jerome L. Moniot , David Floyd , Steven Brandt
IPC分类号： C07D207/16 , C07D207/12
CPC分类号： C07D207/16 , Y02P20/55
摘要： A method is provided for making substituted prolines of the structure ##STR1## wherein X is lower alkyl or aryl, R is H, lower alkyl or an alkali metal and Z is an N-protecting group, which method includes the step of reacting a compound of the structure ##STR2## wherein Z and R are as defined above and Q is Br. tosyloxy or mesylate, with an organic copper lithium compound of the structureXYCuLiwherein X is as defined above and Y is lower alkyl, aryl or CN.Where X is phenyl, the corresponding 4-cyclohexyl compound may be produced by conventional hydrogenation techniques.The compounds produced are useful as intermediates in the preparation of phosphinic acid derivatives useful in the treatment of hypertension.
摘要翻译：提供了制备取代的prol结构的方法，其中X是低级烷基或芳基，R是H，低级烷基或碱金属，Z是N-保护基，该方法包括使化合物的结构其中Z和R如上所定义，Q是Br。与具有XYCuLi结构的有机铜锂化合物，其中X如上所定义，Y是低级烷基，芳基或CN。当X是苯基时，相应的4-环己基化合物可以通过常规氢化技术制备。所制备的化合物可用作制备用于治疗高血压的次膦酸衍生物的中间体。

57. 发明授权

US10449190B2 Alpha-hydroxy carboxylic acid and derivatives and other GRAS-based prodrugs of opioids and uses thereof 有权
公开(公告)号：US10449190B2
公开(公告)日：2019-10-22
申请号：US15472758
申请日：2017-03-29
申请人： John K. Thottathil
发明人： John K. Thottathil
IPC分类号： A61K31/485 , C07D489/02 , C07D489/12
摘要： The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to opioids in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

58. 发明申请

US20170275293A9 Novel Alpha-Hydroxy Carboxylic Acid and Derivatives and Other GRAS Based Prodrugs of Oxycodone and Uses thereof 有权
公开(公告)号：US20170275293A9
公开(公告)日：2017-09-28
申请号：US14953392
申请日：2015-11-29
申请人： John K. Thottathil
发明人： John K. Thottathil
IPC分类号： C07D489/08
CPC分类号： C07D489/08
摘要： The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to the opioid oxycodone, in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

59. 发明申请

US20170152266A1 Novel Alpha-Hydroxy Carboxylic Acid and Derivatives and Other GRAS Based Prodrugs of Oxycodone and Uses thereof 有权
公开(公告)号：US20170152266A1
公开(公告)日：2017-06-01
申请号：US14953392
申请日：2015-11-29
申请人： John K. Thottathil
发明人： John K. Thottathil
IPC分类号： C07D489/08
CPC分类号： C07D489/08
摘要： The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to the opioid oxycodone, in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

60. 发明申请

US20170151228A1 Novel Alpha-Hydroxy Carboxylic Acid and Derivatives and Other GRAS-Based Prodrugs of Oxymorphone and Uses Thereof 有权
公开(公告)号：US20170151228A1
公开(公告)日：2017-06-01
申请号：US14956143
申请日：2015-12-01
申请人： John K. Thottathil
发明人： John K. Thottathil
IPC分类号： A61K31/485 , A61K9/00 , A61K47/48
CPC分类号： A61K31/485 , A61K9/0053 , A61K47/542 , A61K47/543
摘要： The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to the opioid oxymorphone, in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

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