公开(公告)号：US07772278B2

公开(公告)日：2010-08-10

申请号：US12237117

申请日：2008-09-24

Applicant: David S. Garvey ,  Ricky D. Gaston ,  L. Gordon Letts ,  Inigo Saenz de Tejada ,  Sang William Tam ,  Manuel Worcel

Inventor： David S. Garvey ,  Ricky D. Gaston ,  L. Gordon Letts ,  Inigo Saenz de Tejada ,  Sang William Tam ,  Manuel Worcel

IPC: A61K31/557 ,  C07C405/00

CPC classification number: A61K31/5575

Abstract: The invention describes novel nitrosated and/or nitrosylated prostaglandins, and novel compositions comprising at least one nitrosated and/or nitrosylated prostaglandin, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and/or at least one vasoactive agent. The invention also provides novel compositions comprising at least one prostaglandin and at least one S-nitrosothiol compound, and, optionally, at least one vasoactive agent. The prostaglandin is preferably a prostaglandin E1 compound, more preferably alprostadil, and the S-nitrosothiol compound is preferably S-nitrosoglutathione. The invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing cerebrovascular disorders, cardiovascular disorders, benign prostatic hyperplasia (BPH), glaucoma, peptic ulcers or for inducing abortions.

Abstract translation: 本发明描述了新的亚硝化和/或亚硝基化的前列腺素，以及包含至少一种亚硝化和/或亚硝基化的前列腺素的新组合物，以及任选的至少一种捐赠，转移或释放一氧化氮的化合物，提高内源性内皮水平的放松 因子，刺激一氧化氮的内源性合成或是一氧化氮合酶的底物和/或至少一种血管活性剂。 本发明还提供了包含至少一种前列腺素和至少一种S-亚硝基硫醇化合物和任选的至少一种血管活性剂的新型组合物。 前列腺素优选为前列腺素E1化合物，更优选前列地尔，S-亚硝基硫醇化合物优选为S-亚硝基谷胱甘肽。 本发明还提供用于治疗或预防男性和女性的性功能障碍的方法，用于增强男性和女性的性反应，以及用于治疗或预防脑血管疾病，心血管疾病，良性前列腺增生（BPH），青光眼，消化性溃疡或诱导 堕胎

公开(公告)号：US07754772B2

公开(公告)日：2010-07-13

申请号：US11134358

申请日：2005-05-23

Applicant: Richard A. Earl ,  Maiko Ezawa ,  Xinqin Fang ,  David S. Garvey ,  Ricky D. Gaston ,  Subhash P. Khanapure ,  L. Gordon Letts ,  Chia-En Lin ,  Ramani R. Ranatunge ,  Stewart K. Richardson ,  Joseph D. Schroeder ,  Cheri A. Stevenson ,  Shiow-Jyi Wey

Inventor： Richard A. Earl ,  Maiko Ezawa ,  Xinqin Fang ,  David S. Garvey ,  Ricky D. Gaston ,  Subhash P. Khanapure ,  L. Gordon Letts ,  Chia-En Lin ,  Ramani R. Ranatunge ,  Stewart K. Richardson ,  Joseph D. Schroeder ,  Cheri A. Stevenson ,  Shiow-Jyi Wey

IPC: A61K31/135 ,  C07C203/04

CPC classification number: C07D493/04 ,  C07C291/02 ,  C07C311/17 ,  C07C317/18 ,  C07C323/12 ,  C07C327/28 ,  C07D209/18 ,  C07D211/22 ,  C07D211/56

Abstract: The invention describes novel nitrosated nonsteroidal antiinflammatory drugs (NSAIDs) and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated NSAID, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated NSAID, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating gastrointestinal disorders; for facilitating wound healing; for treating and/or preventing gastrointestinal, renal and/or respiratory toxicities resulting from the use of nonsteroidal antiinflammatory compounds; for treating inflammatory disease states and/or disorders; and for treating and/or preventing ophthalmic diseases and/or disorders.

Abstract translation: 本发明描述了新型亚硝化非甾体抗炎药（NSAID）及其药学上可接受的盐，以及包含至少一种亚硝化NSAID的新组合物，以及任选地至少一种捐赠，转移或释放一氧化氮的化合物，刺激一氧化氮的内源性合成 升高内源性内源性松弛因子水平，或是一氧化氮合酶的底物和/或至少一种治疗剂。 本发明还提供了包含至少一种亚硝化NSAID和至少一种捐赠，转移或释放一氧化氮的化合物的新型组合物，提高内源性内皮衍生的舒张因子水平，刺激一氧化氮的内源性合成，或是一氧化氮的底物 合酶和/或至少一种治疗剂。 本发明还提供了包含至少一种亚硝化NSAID和任选的至少一种一氧化氮供体和/或至少一种治疗剂的新型试剂盒。 本发明还提供了治疗炎症，疼痛和发烧的方法; 用于治疗胃肠道疾病; 促进伤口愈合; 用于治疗和/或预防由使用非甾体抗炎化合物引起的胃肠道，肾脏和/或呼吸道毒性物质; 用于治疗炎性疾病状态和/或病症; 并用于治疗和/或预防眼科疾病和/或病症。

公开(公告)号：US07595313B2

公开(公告)日：2009-09-29

申请号：US12136531

申请日：2008-06-10

Applicant: David S. Garvey ,  L. Gordon Letts ,  Richard A. Earl ,  Maiko Ezawa ,  Xinqin Fang ,  Ricky D. Gaston ,  Subhash P. Khanapure ,  Chia-En Lin ,  Ramani R. Ranatunge ,  Cheri A. Stevenson ,  Shiow-Jyi Wey

Inventor： David S. Garvey ,  L. Gordon Letts ,  Richard A. Earl ,  Maiko Ezawa ,  Xinqin Fang ,  Ricky D. Gaston ,  Subhash P. Khanapure ,  Chia-En Lin ,  Ramani R. Ranatunge ,  Cheri A. Stevenson ,  Shiow-Jyi Wey

IPC: C07D285/24 ,  C07D417/04 ,  C07D513/10 ,  A61K31/549

CPC classification number: C07D285/30 ,  C07D285/28 ,  C07D285/32 ,  C07D417/04 ,  C07D417/06 ,  C07D513/10

Abstract: The invention describes novel compositions and kits comprising at least one nitric oxide enhancing diuretic compound, or pharmaceutically acceptable salts thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The invention also provides methods for (a) treating conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidative stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (l) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; (p) treating metabolic syndrome; (q) treating sexual dysfunctions; and (r) hyperlipidemia. The nitric oxide enhancing diuretic compounds comprise at least one nitric oxide enhancing group linked to the diuretic compound through one or more sites such as carbon, oxygen and/or nitrogen via a bond or moiety that cannot be hydrolyzed.

Abstract translation: 本发明描述了包含至少一种一氧化氮增强利尿剂或其药学上可接受的盐，和任选的至少一种一氧化氮增强化合物和/或至少一种治疗剂的新型组合物和试剂盒。 本发明还提供了（a）处理由过量水和/或电解质滞留导致的条件的方法; （二）治疗心血管疾病; （c）治疗血管性疾病; （d）治疗糖尿病; （e）治疗由氧化应激引起的疾病; （f）治疗内皮功能障碍; （g）治疗由内皮功能障碍引起的疾病; （h）治疗肝硬化; （j）治疗先兆子痫; （k）治疗骨质疏松症; （l）治疗肾病; （m）治疗外周血管疾病; （n）治疗门静脉高压; （o）治疗中枢神经系统疾病; （p）治疗代谢综合征; （q）治疗性功能障碍; 和（r）高脂血症。 一氧化氮增强利尿化合物包含通过一个或多个位点如碳，氧和/或氮通过不能水解的键或部分与利尿剂化合物连接的至少一个一氧化氮增强基团。

公开(公告)号：US07589124B2

公开(公告)日：2009-09-15

申请号：US11730886

申请日：2007-04-04

Applicant: L. Gordon Letts ,  David S. Garvey

Inventor： L. Gordon Letts ,  David S. Garvey

IPC: A61K31/34 ,  C07C229/42

CPC classification number: C07D295/185 ,  A61K45/06 ,  C07C229/42 ,  C07C317/18 ,  C07C323/12 ,  C07D493/04

Abstract: The invention provides novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions and kits comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

Abstract translation: 本发明提供新的亚硝化和/或亚硝基化的环氧合酶2（COX-2）选择性抑制剂和包含至少一种亚硝化和/或亚硝基化的环氧合酶2（COX-2）选择性抑制剂的新组合物和试剂盒，以及任选的至少一种化合物 捐赠，转移或释放一氧化氮，刺激一氧化氮的内源性合成，提高内源性内皮衍生的松弛因子水平，或者是一氧化氮合酶的底物和/或任选的至少一种治疗剂。 本发明还提供了治疗炎症，疼痛和发烧的方法; 用于治疗和/或改善COX-2选择性抑制剂的胃肠性质; 促进伤口愈合; 用于治疗和/或预防肾和/或呼吸毒性; 用于治疗和/或预防由环氧合酶-2水平升高引起的其他疾病; 并用于改善COX-2选择性抑制剂的心血管外形。

公开(公告)号：US07220749B2

公开(公告)日：2007-05-22

申请号：US10718060

申请日：2003-06-10

Applicant: L. Gordon Letts ,  David S. Garvey

Inventor： L. Gordon Letts ,  David S. Garvey

IPC: A61K31/495 ,  A61K31/216 ,  A61K31/34 ,  C07D241/04 ,  C07D493/04 ,  C07C229/42

CPC classification number: C07D295/185 ,  A61K45/06 ,  C07C229/42 ,  C07C317/18 ,  C07C323/12 ,  C07D493/04

Abstract: The invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent. The invention also provides novel compositions comprising at least one COX-2 selective inhibitor, that is optionally sitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent.

Abstract translation: 本发明描述了新的亚硝化和/或亚硝基化的环氧合酶2（COX-2）选择性抑制剂和包含至少一种亚硝化和/或亚硝基化的环氧合酶2（COX-2）选择性抑制剂的新组合物，和任选的至少一种可以提供的化合物 ，转移或释放一氧化氮，刺激一氧化氮的内源性合成，升高内源性内源性松弛因子水平，或者是一氧化氮合酶的底物和/或任选的至少一种治疗剂。 本发明还提供了包含至少一种COX-2选择性抑制剂（其任选被亚硝化和/或亚硝基化）和任选地至少一种一氧化氮供体和/或至少一种治疗剂的新型组合物。

公开(公告)号：US07211590B2

公开(公告)日：2007-05-01

申请号：US10631782

申请日：2003-08-01

Applicant: Xinqin Fang ,  David S. Garvey ,  L. Gordon Letts

Inventor： Xinqin Fang ,  David S. Garvey ,  L. Gordon Letts

IPC: C07D401/04 ,  A61K31/44

CPC classification number: C07D401/12

Abstract: The invention describes novel nitrosated proton pump inhibitor compounds and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated proton pump inhibitor compound, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated proton pump inhibitor compound, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated proton pump inhibitor compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating gastrointestinal disorders; facilitating ulcer healing; decreasing the recurrence of ulcers; improving gastroprotective properties, anti-Helicobacter pylori properties or antacid properties of proton pump inhibitors; decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds; treating bacterial infections and/or viral infections.

Abstract translation: 本发明描述了新的亚硝化质子泵抑制剂化合物及其药学上可接受的盐，以及包含至少一种亚硝化质子泵抑制剂化合物和任选的至少一种捐赠，转移或释放一氧化氮的化合物，刺激内源性硝酸合成的新型组合物 氧化物，提高内源性内源性水平的内源性松弛因子，或者是一氧化氮合酶的底物和/或至少一种治疗剂。 本发明还提供了包含至少一种亚硝化质子泵抑制剂化合物和至少一种捐赠，转移或释放一氧化氮的化合物的新型组合物，提高内源性内皮衍生的松弛因子水平，刺激一氧化氮的内源性合成或是底物 用于一氧化氮合酶和/或至少一种治疗剂。 本发明还提供了包含至少一种亚硝化质子泵抑制剂化合物和任选的至少一种一氧化氮供体和/或至少一种治疗剂的新型试剂盒。 本发明还提供了治疗胃肠道疾病的方法; 促进溃疡愈合; 减少溃疡复发; 改善胃保护性质，抗幽门螺旋杆菌性质或质子泵抑制剂的抗酸性; 降低或减少与使用非甾体抗炎化合物相关的胃肠道毒性; 治疗细菌感染和/或病毒感染。

公开(公告)号：US06852739B1

公开(公告)日：2005-02-08

申请号：US09512829

申请日：2000-02-25

Applicant: David S. Garvey ,  L. Gordon Letts ,  Sang William Tam

Inventor： David S. Garvey ,  L. Gordon Letts ,  Sang William Tam

IPC: A61K31/00 ,  A61K31/4184 ,  A61K31/433 ,  A61K31/437 ,  A61K31/4439 ,  A61K31/444 ,  A61K31/4706 ,  A61K31/506 ,  A61K45/06 ,  C07D401/12

CPC classification number: C07D401/12 ,  A61K31/00 ,  A61K31/4184 ,  A61K31/433 ,  A61K31/437 ,  A61K31/4439 ,  A61K31/444 ,  A61K31/4706 ,  A61K31/506 ,  A61K45/06 ,  A61K2300/00

Abstract: The present invention describes novel nitrosated and/or nitrosylated proton pump inhibitor compounds, and novel compositions comprising at least one proton pump inhibitor compound that is optionally substituted with at least one NO and/or N02 group, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one nonsteroidal antiinflammatory drug, selective COX-2 inhibitor, antacid, bismuth-containing reagent, acid-degradable antibacterial compound, and mixtures thereof. The present invention also provides methods for treating and/or preventing gastrointestinal disorders; facilitating ulcer healing; decreasing the recurrence of ulcers; improving gastroprotective properties, anti-Helicobacter pylori properties or antacid properties of proton pump-inhibitors; decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds; treating Helicobacter pylori and viral infections. The compounds and/or compositions of the present invention can also be provided in the form of a pharmaceutical kit.

Abstract translation: 本发明描述了新的亚硝化和/或亚硝化的质子泵抑制剂化合物，以及包含至少一种任选被至少一个NO和/或NO 2基团取代的至少一种质子泵抑制剂化合物的新组合物，和任选的至少一种化合物， 捐赠，转移或释放一氧化氮，刺激一氧化氮的内源性合成，提高内源性内皮衍生的松弛因子水平，或是一氧化氮合酶的底物和/或至少一种非甾体抗炎药，选择性COX-2抑制剂，抗酸剂 ，含铋试剂，酸降解抗菌化合物及其混合物。 本发明还提供了治疗和/或预防胃肠道疾病的方法; 促进溃疡愈合; 减少溃疡复发; 改善胃保护性质，抗幽门螺杆菌特性或质子泵抑制剂的抗酸性; 降低或减少与使用非甾体抗炎化合物相关的胃肠道毒性; 治疗幽门螺杆菌和病毒感染。 本发明的化合物和/或组合物也可以以药物试剂盒的形式提供。

公开(公告)号：US06579863B1

公开(公告)日：2003-06-17

申请号：US09689851

申请日：2000-10-13

Applicant: David S. Garvey ,  L. Gordon Letts ,  H. Burt Renfroe ,  Stewart K. Richardson

Inventor： David S. Garvey ,  L. Gordon Letts ,  H. Burt Renfroe ,  Stewart K. Richardson

IPC: A61K3156

CPC classification number: C07D451/06 ,  C07C313/36 ,  C07D311/22 ,  C07D451/10 ,  C07D471/04 ,  C07J5/00 ,  C07J7/00 ,  C07J31/00 ,  C07J71/00 ,  C07J71/0031

Abstract: Disclosed are (i) compounds of a steroid, a &bgr;-agonist, an anticholinergic, a mast cell stabilizer and a phosphodiesterase (PDE) inhibitor directly or indirectly linked to a NO or NO2 group or a group which stimulates endogenous production of NO or EDRF in vivo; (ii) compositions of steroids, &bgr;-agonists, anticholinergics, mast cell stabilizers and PDE inhibitors, which can optionally be substituted with at least one NO or NO2 moiety or a group which stimulates endogenous production of NO or EDRF in vivo, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NO−), or as the neutral species, nitric oxide (NO•) or that stimulates endogenous production of NO or EDRF in vivo; and (iii) uses for them in preventing and/or treating respiratory disorders.

Abstract translation: 公开的是（i）直接或间接连接到NO或NO 2基团或刺激NO或EDRF的内源性产生的基团的类固醇，β-激动剂，抗胆碱能药，肥大细胞稳定剂和磷酸二酯酶（PDE）抑制剂的化合物 体内; （ii）类固醇，β-激动剂，抗胆碱能药物，肥大细胞稳定剂和PDE抑制剂的组合物，其可任选地被至少一个NO或NO 2部分或刺激体内NO或EDRF内源性产生的基团取代;以及化合物 捐赠，转移或释放一氧化氮作为带电物质，即亚硝酸盐（NO +）或硝酰基（NO-），或作为中性物质，一氧化氮（NO））或刺激体内NO或EDRF的内源性产生; 和（iii）用于预防和/或治疗呼吸系统疾病。

公开(公告)号：US6057347A

公开(公告)日：2000-05-02

申请号：US931564

申请日：1997-09-16

Applicant: David S. Garvey ,  L. Gordon Letts ,  H. Burt Renfroe ,  Sang William Tam

Inventor： David S. Garvey ,  L. Gordon Letts ,  H. Burt Renfroe ,  Sang William Tam

IPC: C07D417/04 ,  A61K31/00 ,  A61K31/19 ,  A61K31/403 ,  A61K31/404 ,  A61K31/405 ,  A61K31/54 ,  A61K31/541 ,  A61K38/00 ,  A61K45/00 ,  A61P1/00 ,  A61P1/04 ,  A61P29/00 ,  A61P43/00 ,  C07C203/00 ,  C07C327/28 ,  C07C381/00 ,  C07D209/28 ,  C07D417/12 ,  C07J41/00 ,  C07K5/02 ,  A61K31/12 ,  C07C207/00 ,  C07C207/02 ,  C07C207/04

CPC classification number: C07D417/12 ,  A61K31/343 ,  A61K31/60 ,  C07C203/00 ,  C07C327/28 ,  C07C381/00 ,  C07D209/28 ,  C07J41/0055 ,  C07K5/0215 ,  A61K38/00

Abstract: Nonsteroidal antiinflammatory drugs which have been substituted with a nitrogen monoxide group; compositions comprising (i) a nonsteroidal antiinflammatory drug, which can optionally be substituted with a nitrogen monoxide group and (ii) a compound that directly donates, transfers or releases a nitrogen monoxide group (preferably as a charged species, particularly nitrosonium); and methods of treatment of inflammation, pain, gastrointestinal lesions and/or fever using the compositions are disclosed. The compounds and compositions protect against the gastrointestinal, renal and other toxicities that are otherwise induced by nonsteroidal antiinflammatory drugs.

公开(公告)号：US6051588A

公开(公告)日：2000-04-18

申请号：US425090

申请日：1995-04-19

Applicant: David S. Garvey ,  L. Gordon Letts ,  H. Burt Renfroe ,  Sang William Tam

Inventor： David S. Garvey ,  L. Gordon Letts ,  H. Burt Renfroe ,  Sang William Tam

IPC: A61K38/00 ,  C07C203/00 ,  C07C327/28 ,  C07C381/00 ,  C07D209/28 ,  C07D417/12 ,  C07J41/00 ,  C07K5/02 ,  C07D403/02 ,  A61K31/38 ,  A61K31/40 ,  A61K31/405 ,  A61K31/42 ,  C07D263/30 ,  C07D333/02 ,  C07D403/14

CPC classification number: C07D417/12 ,  C07C203/00 ,  C07C327/28 ,  C07C381/00 ,  C07D209/28 ,  C07J41/0055 ,  C07K5/0215 ,  A61K38/00

Abstract: A compound comprising a non-steroidal antiinflammatory agent to which is directly or indirectly linked an NO group, a pharmaceutical composition including the compounds and methods of treatment of pain and/or inflammation using the compounds and compositions are disclosed. Also disclosed is a composition comprising a non-steroidal antiinflammatory agent and a compound that donates, transfers or releases nitric oxide.

Abstract translation: 公开了一种化合物，其包含直接或间接连接NO基团的非甾体抗炎剂，包含该化合物的药物组合物和使用该化合物和组合物治疗疼痛和/或炎症的方法。 还公开了包含非甾体抗炎剂和捐赠，转移或释放一氧化氮的化合物的组合物。