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公开(公告)号：US08754197B2
公开(公告)日：2014-06-17
申请号：US13680434
申请日：2012-11-19
IPC分类号： C07C245/08
CPC分类号： C07C245/08
摘要： Methods are disclosed for preparing compounds of Formula I: where R1, R3, and R4 are independently hydrogen or C1 to C4 alkyl, and R2 is: where R5 is selected from the group consisting of hydrogen and C1 to C4 alkyl, or where R6, R7 and R8 are independently hydrogen or C1 to C4 alkyl; or the esters or pharmacologically acceptable salts thereof. The compounds and or their metabolites can be used to treat or prevent various diseases, particularly inflammatory conditions of the GI tract.
摘要翻译： 公开了制备式I化合物的方法：其中R 1，R 3和R 4独立地为氢或C 1至C 4烷基，R 2为：其中R 5选自氢和C 1至C 4烷基，或其中R 6， R7和R8独立地是氢或C1-C4烷基; 或其酯或药理学上可接受的盐。 化合物及其代谢物可用于治疗或预防各种疾病，特别是胃肠道的炎性病症。
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公开(公告)号：US08329958B2
公开(公告)日：2012-12-11
申请号：US11174938
申请日：2005-07-05
摘要： A simple chain-extending approach was established for the scale-up of the monoprotected monodisperse PEG diol materials. Reactions of THP-(OCH2CH2)n—OMs (n=4, 8, 12) with a large excess of commercially available H—(OCH2CH2)n—OH (n=1-4) under basic conditions led to THP-(OCH2CH2)n—OH (n=5-15). Similarly, Me-(OCH2CH2)n—OH (n=4-11, 13) were prepared from Me-(OCH2CH2)n—OMs (n=3, 7, 11). For the chain elongation steps, 40-80% yields were achieved through extraction purification. PEG oligomer libraries I and II were generated in 50-95% overall yields by alkylation or acylation of THP-(OCH2CH2)n—OH (n=1-15) followed by deprotection. Alkylation of Me-(OCH2CH2)n—OH (n=1-11, 13) with X—(CH2)m—CO2R (X=Br or OMs) and subsequent hydrolysis led to PEG oligomer library III in 30-60% overall yields. Combinatorial purification techniques were adapted to the larger-scale library synthesis. A total of 498 compounds, each with a weight of 2-5 g and a minimum purity of 90%, were synthesized.
摘要翻译： 建立了一种简单的扩链方法，用于单保护单分散PEG二醇材料的放大。 在碱性条件下，THP-（OCH2CH2）n-OMs（n = 4,8,12）与大量过量的市售H-（OCH2CH2）n-OH（n = 1-4）的反应导致THP-（OCH2CH2 ）n-OH（n = 5-15）。 类似地，Me-（OCH 2 CH 2）n-OM（n = 3,7,11）制备Me-（OCH 2 CH 2）n -OH（n = 4-11,13）。 对于链延伸步骤，通过萃取纯化获得40-80％的产率。 通过THP-（OCH2CH2）n-OH（n = 1-15）的烷基化或酰化，然后脱保护，产生PEG低聚物文库I和II以50-95％的总收率产生。 Me-（OCH2CH2）n-OH（n = 1-11,13）与X-（CH2）m-CO2R（X = Br或OMs）的烷基化，随后的水解导致PEG低聚物文库III的总体含量在30-60％ 产量。 组合纯化技术适应较大规模的文库合成。 共合成498种化合物，每种化合物的重量为2-5g，最低纯度为90％。
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公开(公告)号：US20110201792A1
公开(公告)日：2011-08-18
申请号：US13094135
申请日：2011-04-26
IPC分类号： C07C245/08
CPC分类号： C07C245/08
摘要： Methods are disclosed for preparing compounds of Formula I: where R1, R3, and R4 are independently hydrogen or C1 to C4 alkyl, and R2 is: where R5 is selected from the group consisting of hydrogen and C1 to C4 alkyl, or where R6, R7 and R8 are independently hydrogen or C1 to C4 alkyl; or the esters or pharmacologically acceptable salts thereof. The methods can involve converting a suitably functionalized aniline compound to a diazonium salt (which aniline compound can be first formed by reduction of a nitrobenzene) and coupling the diazonium salt with a suitably functionalized benzene compound. The suitably functionalized aniline compound either includes a primary alcohol or aldehyde group, which is then oxidized to a carboxylic acid group, or includes a nitrile or amide group, which is hydrolyzed to a carboxylic acid group. The methods can also involve the direct coupling (via reduction of nitro groups to form an azo linkage) of suitably functionalized nitrobenzenes. The compounds and or their metabolites can be used to treat or prevent various diseases, particularly inflammatory conditions of the GI tract.
摘要翻译： 公开了制备式I化合物的方法：其中R 1，R 3和R 4独立地为氢或C 1至C 4烷基，R 2为：其中R 5选自氢和C 1至C 4烷基，或其中R 6， R7和R8独立地是氢或C1-C4烷基; 或其酯或药理学上可接受的盐。 该方法可以包括将适当官能化的苯胺化合物转化为重氮盐（可以首先通过还原硝基苯形成苯胺化合物）并将重氮盐与适当官能化的苯化合物偶联。 适当官能化的苯胺化合物包括伯醇或醛基，然后将其氧化成羧酸基团，或包括被水解成羧酸基团的腈或酰胺基团。 所述方法还可以涉及适当官能化的硝基苯的直接偶联（通过还原硝基以形成偶氮键）。 化合物及其代谢物可用于治疗或预防各种疾病，特别是胃肠道的炎性病症。
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公开(公告)号：US20130096286A1
公开(公告)日：2013-04-18
申请号：US13680434
申请日：2012-11-19
IPC分类号： C07C245/08
CPC分类号： C07C245/08
摘要： Methods are disclosed for preparing compounds of Formula I: where R1, R3, and R4 are independently hydrogen or C1 to C4 alkyl, and R2 is: where R5 is selected from the group consisting of hydrogen and C1 to C4 alkyl, or where R6, R7 and R8 are independently hydrogen or C1 to C4 alkyl; or the esters or pharmacologically acceptable salts thereof. The compounds and or their metabolites can be used to treat or prevent various diseases, particularly inflammatory conditions of the GI tract.
摘要翻译： 的方法公开了制备式I的化合物：其中R1，R3，和R4独立地是氢或C1-C4烷基，且R 2是：其中R 5选自氢和C1至C4烷基，或其中R 6的组中选择， R7和R8独立地是氢或C1-C4烷基; 或其酯或药理学上可接受的盐。 的化合物和或它们的代谢物可用于治疗或预防各种疾病，胃肠道的特别炎性病症。
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公开(公告)号：US08314214B2
公开(公告)日：2012-11-20
申请号：US13094135
申请日：2011-04-26
IPC分类号： C07C245/08 , C09B37/00 , C09B41/00
CPC分类号： C07C245/08
摘要： Methods are disclosed for preparing compounds of Formula I: where R1, R3, and R4 are independently hydrogen or C1 to C4 alkyl, and R2 is: where R5 is selected from the group consisting of hydrogen and C1 to C4 alkyl, or where R6, R7 and R8 are independently hydrogen or C1 to C4 alkyl; or the esters or pharmacologically acceptable salts thereof. The methods can involve converting a suitably functionalized aniline compound to a diazonium salt (which aniline compound can be first formed by reduction of a nitrobenzene) and coupling the diazonium salt with a suitably functionalized benzene compound. The suitably functionalized aniline compound either includes a primary alcohol or aldehyde group, which is then oxidized to a carboxylic acid group, or includes a nitrile or amide group, which is hydrolyzed to a carboxylic acid group. The methods can also involve the direct coupling (via reduction of nitro groups to form an azo linkage) of suitably functionalized nitrobenzenes. The compounds and or their metabolites can be used to treat or prevent various diseases, particularly inflammatory conditions of the GI tract.
摘要翻译： 公开了制备式I化合物的方法：其中R 1，R 3和R 4独立地为氢或C 1至C 4烷基，R 2为：其中R 5选自氢和C 1至C 4烷基，或其中R 6， R7和R8独立地是氢或C1-C4烷基; 或其酯或药理学上可接受的盐。 该方法可以包括将适当官能化的苯胺化合物转化为重氮盐（可以首先通过还原硝基苯形成苯胺化合物）并将重氮盐与适当官能化的苯化合物偶联。 适当官能化的苯胺化合物包括伯醇或醛基，然后将其氧化成羧酸基团，或包括被水解成羧酸基团的腈或酰胺基团。 所述方法还可以涉及适当官能化的硝基苯的直接偶联（通过还原硝基以形成偶氮键）。 化合物及其代谢物可用于治疗或预防各种疾病，特别是胃肠道的炎性病症。
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公开(公告)号：US07932366B2
公开(公告)日：2011-04-26
申请号：US11631582
申请日：2005-07-07
IPC分类号： C07C245/08
CPC分类号： C07C245/08
摘要： Methods are disclosed for preparing compounds of Formula I: where R1, R3, and R4 are independently hydrogen or C1 to C4 alkyl, and R2 is: where R5 is selected from the group consisting of hydrogen and C1 to C4 alkyl, or where R6, R7 and R8 are independently hydrogen or C1 to C4 alkyl; or the esters or pharmacologically acceptable salts thereof. The methods can involve converting a suitably functionalized aniline compound to a diazonium salt (which aniline compound can be first formed by reduction of a nitrobenzene) and coupling the diazonium salt with a suitably functionalized benzene compound. The suitably functionalized aniline compound either includes a primary alcohol or aldehyde group, which is then oxidized to a carboxylic acid group, or includes a nitrile or amide group, which is hydrolyzed to a carboxylic acid group. The methods can also involve the direct coupling (via reduction of nitro groups to form an azo linkage) of suitably functionalized nitrobenzenes. The compounds and or their metabolites can be used to treat or prevent various diseases, particularly inflammatory conditions of the GI tract.
摘要翻译： 公开了制备式I化合物的方法：其中R 1，R 3和R 4独立地为氢或C 1至C 4烷基，R 2为：其中R 5选自氢和C 1至C 4烷基，或其中R 6， R7和R8独立地是氢或C1-C4烷基; 或其酯或药理学上可接受的盐。 该方法可以包括将适当官能化的苯胺化合物转化为重氮盐（可以首先通过还原硝基苯形成苯胺化合物）并将重氮盐与适当官能化的苯化合物偶联。 适当官能化的苯胺化合物包括伯醇或醛基，然后将其氧化成羧酸基团，或包括被水解成羧酸基团的腈或酰胺基团。 所述方法还可以涉及适当官能化的硝基苯的直接偶联（通过还原硝基以形成偶氮键）。 化合物及其代谢物可用于治疗或预防各种疾病，特别是胃肠道的炎性病症。
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7.发明授权Fatty acid formulations and oral delivery of proteins and peptides, and uses thereof 有权脂肪酸制剂和蛋白质和肽的口服递送及其用途公开(公告)号：US08563685B2
公开(公告)日：2013-10-22
申请号：US12581953
申请日：2009-10-20
申请人： Balasingam Radhakrishnan , Diti Aggarwal , Michelle Ferro , Kenneth D. James , Navdeep B. Malkar , Mark A. Miller , Leo Pavliv , Karen Polowy , Monica Puskas , Nnochiri N. Ekwuribe
发明人： Balasingam Radhakrishnan , Diti Aggarwal , Michelle Ferro , Kenneth D. James , Navdeep B. Malkar , Mark A. Miller , Leo Pavliv , Karen Polowy , Monica Puskas , Nnochiri N. Ekwuribe
IPC分类号： C07K14/62
CPC分类号： C07K14/62 , A61K9/0095 , A61K9/2013 , A61K9/2018 , A61K33/30 , A61K38/00 , A61K38/28 , A61K45/06 , A61K47/60 , A61K47/69 , A61K2300/00
摘要： Fatty acid compositions for administration of of pharmaceutical agents, such as proteins and peptides, protein and peptide conjugates, and/or cation-polypeptide conjugate complexes. In particular, the invention provides a solid pharmaceutical composition formulated for oral administration by ingestion, having from about 0.1 to about 75% w/w fatty acid component, where the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, C10, C11, or C12 fatty acids and/or salts of such fatty acids; and a therapeutic agent. Further, the invention provides a liquid pharmaceutical composition formulated for oral administration by ingestion, comprising: from about 0.1 to about 10% w/v fatty acid component, where the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, C10, C11, or C12 fatty acids and/or salts of such fatty acids; and a therapeutic agent.
摘要翻译： 用于施用药剂例如蛋白质和肽，蛋白质和肽缀合物和/或阳离子 - 多肽缀合物复合物的脂肪酸组合物。 特别地，本发明提供了一种配制成通过摄取口服给药的固体药物组合物，其具有约0.1至约75％w / w脂肪酸组分，其中脂肪酸组分包含饱和或不饱和C4，C5，C6，C7，C8 ，C9，C10，C11或C12脂肪酸和/或这些脂肪酸的盐; 和治疗剂。 此外，本发明提供配制成通过摄取口服给药的液体药物组合物，其包含：约0.1至约10％w / v脂肪酸组分，其中脂肪酸组分包含饱和或不饱和C4，C5，C6，C7，C8 ，C9，C10，C11或C12脂肪酸和/或这些脂肪酸的盐; 和治疗剂。
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8.发明申请ARYL CARBAMATE OLIGOMERS FOR HYDROLYZABLE PRODRUGS AND PRODRUGS COMPRISING SAME 有权用于可水解产品的ARYL碳酸酯低聚物和包含其的原料公开(公告)号：US20100081782A1
公开(公告)日：2010-04-01
申请号：US12622645
申请日：2009-11-20
CPC分类号： C07C235/48 , C07C41/16 , C07C41/26 , C07C43/23 , C07C45/673 , C07C45/71 , C07C47/575 , C07C49/84 , C07C271/22 , C07C271/28 , C07K7/02 , C07K7/06 , C07C43/2055
摘要： The present invention provides a compound having a formula: where R1 is selected from the group consisting of alkyl, CH2(OC2H4)OCH3, and —(OC2H4)OCH3; n is 0-4; Olig is an oligomer having a formula: -L-O-PAGR.R2]q where L is a optional linker moiety selected from the group consisting of —CH2O—, —CH2OX—, —OX—, —C(O)—, —C(O)X, —NH—, —NHC(O)—, —XNHC(O)—, —NHC(O)X—, —C(O)NH—, —C(O)NHX—, and where X is alky1-6 or is not present, Y is N or O or is not present, and R3 is alkyl1-6; PAG is a linear or branched polyalkylene glycol moiety; R2 is an alkyl1-22 capping moiety if X is present or alkyl2-22 if X is not present; and q is a number from 1 to the maximum number of branches on PAG; and m is 1-5.
摘要翻译： 本发明提供具有下式的化合物：其中R 1选自烷基，CH 2（OC 2 H 4）OCH 3和 - （OC 2 H 4）OCH 3; n为0-4; Olig是具有下式的低聚物：-LO-PAGR.R2] q其中L是选自-CH 2 O-，-CH 2 OX - ， - O - ， - C（O） - ， - C （O）X，-NH-，-NHC（O） - ， - N-NH（O） - ， - NHC（O）X - ， - C（O）NH-， - （O）NHX-，其中X 是烷基-16或不存在，Y是N或O或不存在，并且R 3是烷基1-6; PAG是直链或支链的聚亚烷基二醇部分; 如果X存在，则R2是烷基-22封端部分，如果X不存在，则为烷基2-22; q是PAG上从1到最大分支数的数字; m为1-5。
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公开(公告)号：US07423014B2
公开(公告)日：2008-09-09
申请号：US11314309
申请日：2005-12-21
申请人： Nnochiri N. Ekwuribe , Christopher H. Price , James Gordon Still , Jennifer Ann Filbey , Aslam M. Ansari , Amy L. Odenbaugh , Balasingam Radhakrishnan
发明人： Nnochiri N. Ekwuribe , Christopher H. Price , James Gordon Still , Jennifer Ann Filbey , Aslam M. Ansari , Amy L. Odenbaugh , Balasingam Radhakrishnan
CPC分类号： C07K14/62 , A61K38/28 , A61K47/542 , A61K47/60
摘要： Methods of treating diabetes mellitus in a patient in need of such treatment include administering an effective amount of an insulin polypeptide-oligomer conjugate of formula V to the patient in order to treat diabetes mellitus in the patient. Methods according to the present invention may “activate” the liver, potentially restoring normal glucose homeostasis to individuals suffering from diabetes mellitus.
摘要翻译： 在需要这种治疗的患者中治疗糖尿病的方法包括向患者施用有效量的式V的胰岛素多肽 - 低聚物缀合物以便治疗患者的糖尿病。 根据本发明的方法可以“激活”肝脏，潜在地恢复患有糖尿病的个体的正常葡萄糖体内平衡。
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10.发明申请ARYL CARBAMATE OLIGOMERS FOR HYDROLYZABLE PRODRUGS AND PRODRUGS COMPRISING SAME 有权用于可水解产品的ARYL碳酸酯低聚物和包含其的原料公开(公告)号：US20080146778A1
公开(公告)日：2008-06-19
申请号：US12037445
申请日：2008-02-26
IPC分类号： C07K2/00 , C07C43/23 , C07C233/69 , C07C271/22
CPC分类号： C07C235/48 , C07C41/16 , C07C41/26 , C07C43/23 , C07C45/673 , C07C45/71 , C07C47/575 , C07C49/84 , C07C271/22 , C07C271/28 , C07K7/02 , C07K7/06 , C07C43/2055
摘要： The present invention provides a compound having a formula: where R1 is selected from the group consisting of alkyl, CH2(OC2H4)OCH3, and —(OC2H4)OCH3; n is 0-4; Olig is an oligomer having a formula: -L-O-PAGR.R2]q where L is a optional linker moiety selected from the group consisting of —CH2O—, —CH2OX—, —OX—, —C(O)—, —C(O)X, —NH—, —NHC(O)—, —XNHC(O)—, —NHC(O)X—, —C(O)NH—, —C(O)NHX—, and where X is alky1-6 or is not present, Y is N or O or is not present, and R3 is alkyl1-6; PAG is a linear or branched polyalkylene glycol moiety; R2 is an alkyl1-22 capping moiety if X is present or alkyl2-22 if X is not present; and q is a number from 1 to the maximum number of branches on PAG; and m is 1-5.
摘要翻译： 本发明提供具有下式的化合物：其中R 1选自烷基，CH 2（OC 2 H 2） OCH 3，和 - （OC 2 H 4 H）OCH 3; n为0-4; Olig是具有下式的低聚物：<？in-line-formula description =“In-line Formulas”end =“lead”？> LO-PAGR.R 其中L是选自-CH 2 O 2的任选的接头部分，其中L是选自-CH 2 - ，-O - ， - C（O） - ， - C（O）X，-NH-，-NHC（O） - ， - N - （O） -NHC（O）X - ， - C（O）NH - ， - C（O）NHX-，其中X是烷基，或不存在，Y是N或O或 不存在，R 3是烷基1-6。 PAG是直链或支链的聚亚烷基二醇部分; 如果X不存在，则R 2是烷基封端的封端部分，如果不存在X则为烷基2-22。 q是PAG上从1到最大分支数的数字; m为1-5。
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