公开(公告)号：US07470703B1

公开(公告)日：2008-12-30

申请号：US11210206

申请日：2005-08-23

申请人： Duane D. Miller ,  Bob M. Moore, II ,  Suni Mustafa ,  Dennis R. Feller ,  Supriya A. Bavadekar

发明人： Duane D. Miller ,  Bob M. Moore, II ,  Suni Mustafa ,  Dennis R. Feller ,  Supriya A. Bavadekar

IPC分类号： A61K31/4745 ,  C07D471/16

CPC分类号： C07D471/16

摘要： Yohimbine derivatives are disclosed having modification of the C-16 carboxyl group to include a sidechain and where the resulting derivative does not possess a second yohimbine pharmacophore (i.e., the compound is not a yohimbine dimer). The yohimbine derivatives of the present invention are preferably characterized by selective activity as α2c-AR antagonists. Use of the compounds, or pharmaceutical composition containing them, for treating or preventing an α2c adrenergic receptor mediated condition or disorder, and for antagonizing activity of an α2c adrenergic receptor are also disclosed.

摘要翻译： 公开了育亨宾衍生物，其具有C-16羧基的修饰以包括侧链，并且其中所得衍生物不具有第二育亨宾药效团（即，该化合物不是育亨宾二聚体）。 优选本发明的育亨宾衍生物的特征在于作为α2c-AR拮抗剂的选择性活性。 还公开了化合物或含有它们的药物组合物用于治疗或预防α2c肾上腺素能受体介导的病症或病症以及拮抗α2c肾上腺素能受体的活性的用途。

公开(公告)号：US06596734B1

公开(公告)日：2003-07-22

申请号：US10269438

申请日：2002-10-11

申请人： Dennis R. Feller ,  Duane D. Miller

发明人： Dennis R. Feller ,  Duane D. Miller

IPC分类号： C07D22102

CPC分类号： C07D217/20

摘要： The invention provides compounds of formula: wherein R1 is —NHS(O)mR, wherein R is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle; X is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxy, nitro, amino, and substituted amino; R2 is benzyl or benzyl substituted with one or more substituents selected from the group consisting of halo, CF3, hydroxy, nitro, alkoxy, substituted alkoxy, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, and substituted amino of formula —NHR' or —NR′R′, wherein each R′ is alkyl, substituted alkyl, —C(O)Y, —C(O)NHY, or —C(O)SY, wherein Y is alkyl or substituted alkyl; R3 is H or alkyl; n is 0-3; m is 1-2; p is 1-4; the sum of n and p is 1-4; and pharmaceutically acceptable salts thereof.

摘要翻译： 本发明提供下式的化合物：其中R1是-NHS（O）mR，其中R是烷基，取代的烷基，烷氧基，取代的烷氧基，环烷基，取代的环烷基，芳基，取代的芳基，杂芳基，取代的杂芳基，杂环或取代的杂环 ; X独立地选自卤素，烷基，取代的烷基，烷氧基，取代的烷氧基，羟基，硝基，氨基和取代的氨基; R 2是被一个或多个选自卤素，CF 3，羟基，硝基，烷氧基，取代的烷氧基，烷基，取代的烷基，环烷基，取代的环烷基，芳基，取代的芳基，杂芳基，取代的杂芳基， 杂环，取代的杂环，氨基和式-NHR'或-NR'R'的取代的氨基，其中每个R'是烷基，取代的烷基，-C（O）Y，-C（O）NHY或-C O）SY，其中Y是烷基或取代的烷基; R3是H或烷基; n为0-3; m是1-2; p为1-4; n和p的和为1-4; 及其药学上可接受的盐。

公开(公告)号：US4845121A

公开(公告)日：1989-07-04

申请号：US874148

申请日：1986-06-13

申请人： Donald T. Witiak ,  Sung K. Kim ,  Dennis R. Feller ,  Karl J. Romstedt

发明人： Donald T. Witiak ,  Sung K. Kim ,  Dennis R. Feller ,  Karl J. Romstedt

IPC分类号： C07D311/56

CPC分类号： C07D311/56

摘要： The present invention relates to novel benzopyranone aci-reductone compounds of the formula I wherein X and Y are selected from the group comprising H (except that X and Y are not both H, unless otherwise indicated) Cl or other halogen, OH, a straight or branched C.sub.1 -C.sub.6 alkyl or alkoxy group or phenyl or phenyloxy groups, such as, for example a phenyl or a tertiary butyl group. The invention also provides for compounds of the general formula I wherein X, Y=OCH.sub.2 O. ##STR1## The compounds of the invention are useful in the treatment or prevention of thromboembolic disorders.

摘要翻译： 本发明涉及式I的新型苯并吡喃酮缩合物化合物，其中X和Y选自H（除非另有说明，X和Y不能同时为H）Cl或其它卤素OH，直链 或支链C 1 -C 6烷基或烷氧基或苯基或苯氧基，例如苯基或叔丁基。 本发明还提供通式I的化合物，其中X，Y = OCH 2 O。 本发明的化合物可用于治疗或预防血栓栓塞性疾病。

公开(公告)号：US08133917B2

公开(公告)日：2012-03-13

申请号：US12911376

申请日：2010-10-25

申请人： Agnes M. Rimando ,  Dennis R. Feller ,  Wallace H. Yokoyama

发明人： Agnes M. Rimando ,  Dennis R. Feller ,  Wallace H. Yokoyama

IPC分类号： A61K31/075 ,  A61K38/00 ,  A01N65/00

CPC分类号： A61K31/704 ,  A23L33/105 ,  A23V2002/00 ,  A61K31/352 ,  A61K36/45 ,  A61K36/87 ,  A23V2200/3262 ,  A23V2250/21

摘要： Resveratrol, a stilbenoid antioxidant found in grapes, wine, peanuts and other berries, has been reported to have hypolipidemic properties. Resveratrol and its three analogs (pterostilbene, piceatannol and resveratrol trimethyl ether) were evaluated for their effects on the activation of the peroxisome proliferator-activated receptor alpha (PPARα) isoforms, a receptor shown to mediate the activity of lipid-lowering drugs such as the fibrates. The four stilbenes and ciprofibrate (positive control) were evaluated for the activation of endogenous PPARα in H4IIEC3 cells. Pterostilbene demonstrated the highest induction of PPARα demonstrating increases of 7- and 9-14 fold relative to control. The maximal responses to pterostilbene are similar to those obtained with the hypolipidemic drug, ciprofibrate; that is, pterostilbene acts as a PPARα agonist, like that of the fibrate class, and is a more effective hypolipidemic agent than resveratrol.

摘要翻译： 据报道，白藜芦醇是葡萄，葡萄酒，花生和其他浆果中发现的芪类抗氧化剂，具有降血脂性质。 评估白藜芦醇及其三种类似物（ter芪二烯，白藜芦醇和白藜芦醇三甲基醚）对过氧化物酶体增殖物激活受体α（PPARα）同工型的活化的影响，所述受体显示为介导降脂药物的活性，例如 贝特类。 评估了四苯并苯和环丙沙星（阳性对照）在H4IIEC3细胞中内源性PPARα的活化。 Pterostilbene表现出最高的PPARα诱导，显示相对于对照增加7和9-14倍。 对ter芪烯的最大反应与用降血脂药物环丙沙星获得的相似; 也就是说，ter芪烯作为PPARα激动剂，与贝特类相似，是比白藜芦醇更有效的降血脂药。

公开(公告)号：US06593341B2

公开(公告)日：2003-07-15

申请号：US10149953

申请日：2002-06-17

申请人： Dennis R. Feller ,  Duane D. Miller

发明人： Dennis R. Feller ,  Duane D. Miller

IPC分类号： C07D22102

CPC分类号： C07D217/18 ,  C07D217/20

摘要： The invention provides compounds useful as &bgr;3-adrenorecptor agonists and pharmaceutical compositions comprising such compounds. The invention further includes a method for stimulating, regulating, and modulating metabolism in fats of adipose tissue in mammals by administering an effective amount of a compound of the invention.

摘要翻译： 本发明提供了可用作β3肾上腺素摄取激动剂的化合物和包含这些化合物的药物组合物。 本发明还包括通过施用有效量的本发明化合物来刺激，调节和调节哺乳动物脂肪组织脂肪代谢的方法。

公开(公告)号：US4737504A

公开(公告)日：1988-04-12

申请号：US890490

申请日：1986-07-25

申请人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

发明人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

IPC分类号： C07D217/20 ,  A61K31/47

CPC分类号： C07D217/20

摘要： The present invention relates to novel 5-fluoro- and 8-fluoro-trimetoquinol compounds of the general formula I wherein X.sub.1 =F,X.sub.2 =H or X.sub.1 =H,X.sub.2 =F ##STR1## The present invention also relates to a process for making the 5-fluoro- and 8-fluoro-trimetoquinol compounds by condensation of an appropriately substituted phenethylamine to afford an appropriately substituted phenethylacetamide compound. The amides are cyclized to give appropriately substituted intermediate dihydroisoquinolines. Without isolation, the dihydroisoquinolines are reduced to give appropriately substituted tetrahydroisoqinolines. The hydrochloride salts of tetrahydroisoqinolines are prepared and subjected to hydrogenolysis, to give the fluorine substituted trimetoquinol compounds of the present invention. The present invention also encompasses the preparation of the phenethylamines by reducing appropriately substituted benzylcyanides and to the preparation of an intermediate benzylcyanide compound by converting a fluorine substituted methoxyphenol compound, under aminomethylation conditions into a N, N-dimethyl-4-hydroxy-3-methoxy-5-fluorobenzylamine. The benzylamine is converted to benzylnitrile and a functional group shuffle is carried out which yields the appropriately substituted benzylcyanide compound. In a composition aspect, the present invention encompasses novel pharmaceutical compositions comprising a compound of the formula I, together with a physiologically acceptable carrier or excipient, in an amount sufficient to increase .beta..sub.2 -adrenergic and antithrombotic activities while simultaneously decreasing the .beta..sub.1 -adrenergic activity in mammals, including humans. The compounds of the invention are useful in the treatment of pulmonary, cardiovascular or thromboembolic disorders.

摘要翻译： 本发明涉及通式I的新的5-氟 - 和8-氟 - 三甲基喹诺酮化合物，其中X1 = F，X2 = H或X1 = H，X2 = F。本发明还涉及一种 通过适当取代的苯乙胺的缩合制备5-氟 - 和8-氟 - 三甲基喹啉化合物，得到适当取代的苯乙基乙酰胺化合物。 使酰胺环化，得到适当取代的中间体二氢异喹啉。 不分离，将二氢异喹啉还原，得到适当取代的四氢异喹啉。 制备四氢异喹啉的盐酸盐并进行氢解，得到本发明的氟取代的三甲基喹诺酮化合物。 本发明还包括通过在氨基甲基化条件下将氟取代的甲氧基苯酚化合物转化成N，N-二甲基-4-羟基-3-甲氧基的方法，通过还原适当取代的苄基氰化物和制备中间体苄基氰化合物来制备苯乙胺 -5-氟苄胺。 将苄胺转化为苄基腈，进行官能团混洗，产生适当取代的苄基氰化合物。 在组合物方面，本发明包括新颖的药物组合物，其包含式I化合物以及生理上可接受的载体或赋形剂，其量足以增加β2-肾上腺素能和抗血栓形成活性，同时降低β1-肾上腺素能 哺乳动物，包括人类的活动。 本发明的化合物可用于治疗肺，心血管或血栓栓塞障碍。

公开(公告)号：US07119103B2

公开(公告)日：2006-10-10

申请号：US10964461

申请日：2004-10-13

申请人： Dennis R. Feller ,  Duane D. Miller

发明人： Dennis R. Feller ,  Duane D. Miller

IPC分类号： A61K31/472

CPC分类号： C07D405/06 ,  C07D217/18 ,  C07D217/20 ,  C07D491/04 ,  C07D513/04

摘要： The invention provides β3-adrenoreceptor agonists, pharmaceutical compositions comprising β3-adrenoreceptor agonist compounds, and methods of using such compounds for stimulating, regulating or modulating metabolism of fats in adipose tissue in animals.

摘要翻译： 本发明提供β3 - 肾上腺素受体激动剂，包含β3 - 肾上腺素受体激动剂化合物的药物组合物，以及使用这些化合物刺激，调节或调节脂肪中脂肪代谢的方法 动物组织。

公开(公告)号：US4855476A

公开(公告)日：1989-08-08

申请号：US167336

申请日：1988-03-14

申请人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

发明人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

IPC分类号： C07D217/20

CPC分类号： C07D217/20

摘要： The present invention relates to novel 5-fluoro- and 8-fluoro-trimetoquinol compounds of the general formula I wherein X.sub.1 =F, X.sub.2 =H or X.sub.1 =H, X.sub.2 =F ##STR1## The present invention also relates to a process for making the 5-fluoro- and 8-fluoro-trimetoquinol compounds by condensation of an appropriately substituted phenethylamine to afford an appropriately substituted phenlethylacetamide compound. The amides are cyclized to give appropriately substituted intermediate dihydroisoquinolines. Without isolation, the dihydroisoquinolines are reduced to give appropriately substituted tetrahydroisoquinolines. The hydrochloride salts of tetrahydroisoquinolines are prepared and subjected to hydrogenolysis, to give the fluorine substituted trimetoquinol compounds of the present invention. The present invention also encompasses the preparation of the phenethylamines by reducing appropriately substituted benzylcyanides and to the preparation of an intermediate benzylcyanide compound by converting a fluorine substituted methoxyphenol compound, under aminomethylation conditions into a N-N-dimethyl-4-hydroxy-3-methoxy-5-fluorobenzylamine. The benzylamine is converted to benzylnitrile and a functional group shuffle is carried out which yields the appropriately substituted benzylcyanide compound. In a composition aspect, the present invention encompasses novel pharmaceutical compositions comprising a compound of the formula I, together with a physiologically acceptable carrier or excipient, in an amount sufficient to increase .beta..sub.2 -adrenergic and antithrombotic activities while simultaneously decreasing the .beta..sub.1 -adrenergic activity in mammals, including humans. The compounds of the invention are useful in the treatment of pulmonary, cardiovascular or thromboembolic disorders.

摘要翻译： 本发明涉及通式I的新的5-氟 - 和8-氟 - 三甲基喹诺酮化合物，其中X1 = F，X2 = H或X1 = H，X2 = F。本发明还涉及一种 通过适当取代的苯乙胺的缩合制备5-氟 - 和8-氟 - 三甲基喹啉化合物，得到适当取代的苯乙酰基乙酰胺化合物。 使酰胺环化，得到适当取代的中间体二氢异喹啉。 不分离，将二氢异喹啉还原，得到适当取代的四氢异喹啉。 制备四氢异喹啉的盐酸盐并进行氢解，得到本发明的氟取代的三甲基喹诺酮化合物。 本发明还包括通过将氨基甲基化条件下的氟取代的甲氧基苯酚化合物转化成N-二甲基-4-羟基-3-甲氧基-5 - 氟苄胺。 将苄胺转化为苄基腈，进行官能团混洗，产生适当取代的苄基氰化合物。 在组合物方面，本发明包括新颖的药物组合物，其包含式I化合物以及生理上可接受的载体或赋形剂，其量足以增加β2-肾上腺素能和抗血栓形成活性，同时降低β1-肾上腺素能 哺乳动物，包括人类的活动。 本发明的化合物可用于治疗肺，心血管或血栓栓塞障碍。

公开(公告)号：US08252845B1

公开(公告)日：2012-08-28

申请号：US13363959

申请日：2012-02-01

申请人： Agnes M. Rimando ,  Dennis R. Feller ,  Wallace H. Yokoyama

发明人： Agnes M. Rimando ,  Dennis R. Feller ,  Wallace H. Yokoyama

IPC分类号： A61K31/075 ,  A61K38/00 ,  A01N65/00

CPC分类号： A61K31/704 ,  A23L33/105 ,  A23V2002/00 ,  A61K31/352 ,  A61K36/45 ,  A61K36/87 ,  A23V2200/3262 ,  A23V2250/21

摘要： Resveratrol has been reported to have hypolipidemic properties. We investigated whether resveratrol and its analogs: pterostilbene, piceatannol and resveratrol trimethyl ether, would activate the peroxisome proliferator-activated receptor alpha (PPARα) isoform. This nuclear receptor is proposed to mediate the activity of lipid-lowering drugs such as the fibrates. The four stilbenes and ciprofibrate (positive control) were evaluated for the activation of endogenous PPARα in H4IIEC3 cells transfected with a luciferase gene reporter construct. Pterostilbene demonstrated the highest induction of PPARα; the maximal response to pterostilbene was similar to that obtained with the hypolipidemic drug, ciprofibrate.

摘要翻译： 据报道，白藜芦醇具有降血脂性质。 我们调查了白藜芦醇及其类似物：ter芪烯，白藜芦醇和白藜芦醇三甲基醚是否会激活过氧化物酶体增殖物激活受体α（PPARα）同种型。 提议这种核受体介导降脂药物如贝特类药物的活性。 评估四种芪和环丙沙星（阳性对照）活化的荧光素酶基因报道构建体转染的H4IIEC3细胞内源性PPARα。 P il烯表现出最高的PPARα诱导; 对ter芪烯的最大反应与用降血脂药物环丙司酮获得的相似。

公开(公告)号：US20110060060A1

公开(公告)日：2011-03-10

申请号：US12911376

申请日：2010-10-25

申请人： Agnes M. Rimando ,  Dennis R. Feller ,  Wallace H. Yokoyama

发明人： Agnes M. Rimando ,  Dennis R. Feller ,  Wallace H. Yokoyama

IPC分类号： A61K31/09 ,  A61P3/06 ,  B65D69/00

CPC分类号： A61K31/704 ,  A23L33/105 ,  A23V2002/00 ,  A61K31/352 ,  A61K36/45 ,  A61K36/87 ,  A23V2200/3262 ,  A23V2250/21

摘要： Resveratrol, a stilbenoid antioxidant found in grapes, wine, peanuts and other berries, has been reported to have hypolipidemic properties. Resveratrol and its three analogs (pterostilbene, piceatannol and resveratrol trimethyl ether) were evaluated for their effects on the activation of the peroxisome proliferator-activated receptor alpha (PPARα) isoforms, a receptor shown to mediate the activity of lipid-lowering drugs such as the fibrates. The four stilbenes and ciprofibrate (positive control) were evaluated for the activation of endogenous PPARα in H4IIEC3 cells. Pterostilbene demonstrated the highest induction of PPARα demonstrating increases of 7- and 9-14 fold relative to control. The maximal responses to pterostilbene are similar to those obtained with the hypolipidemic drug, ciprofibrate; that is, pterostilbene acts as a PPARα agonist, like that of the fibrate class, and is a more effective hypolipidemic agent than resveratrol.

摘要翻译： 据报道，白藜芦醇是葡萄，葡萄酒，花生和其他浆果中发现的芪类抗氧化剂，具有降血脂特性。 评估白藜芦醇及其三种类似物（ter芪二烯，白藜芦醇和白藜芦醇三甲基醚）对过氧化物酶体增殖物激活受体α（PPARα）同工型的活化的影响，所述受体显示为介导降脂药物的活性，例如 贝特类。 评估了四苯并苯和环丙沙星（阳性对照）在H4IIEC3细胞中内源性PPARα的活化。 Pterostilbene表现出最高的PPARα诱导，显示相对于对照增加7和9-14倍。 对ter芪烯的最大反应与使用降血脂药物环丙沙星获得的类似; 也就是说，ter芪烯作为PPARα激动剂，与贝特类相似，是比白藜芦醇更有效的降血脂药。