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    Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
    1.
    发明授权
    Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use 有权
    硝化非甾体抗炎化合物，组合物和使用方法

    公开(公告)号：US08088762B2

    公开(公告)日：2012-01-03

    申请号：US12636316

    申请日：2009-12-11

    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: A61K31/54 ,  A61K31/44 ,  A61K31/425 ,  C07D498/02 ,  C07D295/02 ,  C07D333/22

    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 anti-inflammatory 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: 本发明描述了新的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，和任选的至少一种捐赠，转移或释放一氧化氮的化合物，刺激内源性合成 一氧化氮，提高内源性内源水平的内源性松弛因子，或者是一氧化氮合成酶的底物和/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。

    Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders
    4.
    发明授权
    Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders 失效
    亚硝化和亚硝化化合物及其组合物及其用于治疗呼吸系统疾病的用途

    公开(公告)号：US07345037B2

    公开(公告)日：2008-03-18

    申请号：US11604677

    申请日：2006-11-28

    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: A61K31/40 ,  C07D451/00

    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 β-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, β-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基团或基团上的基团的类固醇，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 其在体内刺激NO或EDRF的内源性产生; （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个部分取代，或刺激内源性产生NO 或EDRF，以及作为带电物质，即亚硝酸盐（硝酸）或硝酰基（NO +）的一氧化氮，或NOX + 作为中性物种，一氧化氮（NO））或者在体内刺激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。

    Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use
    6.
    发明授权
    Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use 失效
    亚硝化和亚硝基化H 2受体拮抗剂化合物，组合物和使用方法

    公开(公告)号：US07129251B2

    公开(公告)日：2006-10-31

    申请号：US11180790

    申请日：2005-07-14

    Applicant: David S. Garvey ,  L. Gordon Letts ,  Chia-En Lin ,  Tiansheng Wang

    Inventor： David S. Garvey ,  L. Gordon Letts ,  Chia-En Lin ,  Tiansheng Wang

    IPC: C07D295/14 ,  A61K31/445 ,  A61P1/04

    CPC classification number: C07D233/54 ,  C07D233/64 ,  C07D277/48 ,  C07D295/092 ,  C07D295/096

    Abstract: The invention describes novel nitrosated and/or nitrosylated H2 receptor antagonist compounds, and novel compositions comprising at least one H2 receptor antagonist compound that is optionally substituted with at least one NO and/or NO2 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, antacid, bismuth-containing reagent or anti-viral agent. The invention also describes methods for treating and/or preventing gastrointestinal disorders; improving gastroprotective properties of H2 receptor antagonists; decreasing the recurrence of ulcers; facilitating ulcer healing; preventing and/or treating inflammations and microbial infections, ophthalmic diseases and disorders, multiple sclerosis, and viral infections; and decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds.

    Abstract translation: 本发明描述了新的亚硝化和/或亚硝基化的H 2 O 2受体拮抗剂化合物，以及包含至少一种H 2受体拮抗剂化合物的新组合物，其任选被至少一个NO 和/或NO 2个基团，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，提高内源性内皮水平的内源性松弛因子，或者是 一氧化氮合酶的底物和/或至少一种非甾体抗炎药，抗酸剂，含铋试剂或抗病毒剂。 本发明还描述了治疗和/或预防胃肠道疾病的方法; 改善H 2受体拮抗剂的胃保护性质; 减少溃疡复发; 促进溃疡愈合; 预防和/或治疗炎症和微生物感染，眼科疾病和病症，多发性硬化和病毒感染; 并减少或减少与使用非甾体抗炎化合物相关的胃肠道毒性。

    Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
    7.
    发明授权
    Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use 失效

    公开(公告)号：US06706724B2

    公开(公告)日：2004-03-16

    申请号：US10024046

    申请日：2001-12-21

    Applicant: Subhash P. Khanapure ,  David S. Garvey ,  Richard A. Earl ,  Maiko Ezawa ,  Xinqin Fang ,  Ricky D. Gaston

    Inventor： Subhash P. Khanapure ,  David S. Garvey ,  Richard A. Earl ,  Maiko Ezawa ,  Xinqin Fang ,  Ricky D. Gaston

    IPC: A61K31435

    CPC classification number: C07D319/08 ,  A61K45/06 ,  C07D317/56 ,  C07D319/18 ,  C07D319/20 ,  C07D405/06

    Abstract: The invention describes novel substituted aryl compounds that are cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one 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, such as, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. 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 toxicity or other toxicities; 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.

    Nitrosated and nitrosylated potassium channel activators, compositions and methods of use
    8.
    发明授权
    Nitrosated and nitrosylated potassium channel activators, compositions and methods of use 失效
    亚硝化和亚硝基化钾通道激活剂，组合物和使用方法

    公开(公告)号：US06693122B2

    公开(公告)日：2004-02-17

    申请号：US10154916

    申请日：2002-05-28

    Applicant: David S. Garvey ,  Inigo Saenz de Tejada

    Inventor： David S. Garvey ,  Inigo Saenz de Tejada

    IPC: A61K3144

    CPC classification number: C07D213/82 ,  A61K31/4406 ,  A61K31/455

    Abstract: The present invention describes novel nitrosated and/or nitrosylated potassium channel activators, and novel compositions comprising at least one nitrosated and/or nitrosylated potassium channel activator, 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 present invention also provides novel compositions comprising at least one potassium channel activator, 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 vasoactive agent. The present 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 cardiovascular disorders, cerebrovascular disorders, hypertension, asthma, baldness, urinary incontinence, epilepsy, sleep disorders, gastrointestinal disorders, migraines, irritable bowel syndrome and sensitive skin.

    Abstract translation: 本发明描述了新的亚硝化和/或亚硝基化的钾通道激活剂，以及包含至少一种亚硝化和/或亚硝基化钾通道活化剂的新组合物，以及任选的至少一种捐赠，转移或释放一氧化氮的化合物，提高内源性水平 的内皮衍生的松弛因子，刺激一氧化氮的内源性合成或者是一氧化氮合酶和/或至少一种血管活性剂的底物。 本发明还提供了包含至少一种钾通道活化剂和至少一种捐赠，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，或者是用于 一氧化氮合酶和/或至少一种血管活性剂。 本发明还提供了治疗或预防男性和女性性功能障碍的方法，用于增强男性和女性的性反应，以及治疗或预防心血管疾病，脑血管障碍，高血压，哮喘，秃发，尿失禁，癫痫，睡眠障碍 胃肠道疾病，偏头痛，肠易激综合征和敏感性皮肤。

    Compositions and kits comprising alpha-adrenergic receptor antagonists and nitric oxide donors and methods of use
    10.
    发明授权
    Compositions and kits comprising alpha-adrenergic receptor antagonists and nitric oxide donors and methods of use 失效
    包含α-肾上腺素能受体拮抗剂和一氧化氮供体的组合物和试剂盒及使用方法

    公开(公告)号：US06294517B1

    公开(公告)日：2001-09-25

    申请号：US09145143

    申请日：1998-09-01

    Applicant: David S. Garvey ,  Joseph D. Schroeder ,  Inigo Saenz de Tejada

    Inventor： David S. Garvey ,  Joseph D. Schroeder ,  Inigo Saenz de Tejada

    IPC: A01N4354

    CPC classification number: C07D459/00 ,  A61K45/06 ,  C07C381/00 ,  C07D211/62 ,  C07D233/24 ,  C07D239/95 ,  C07D401/04 ,  C07D405/12 ,  Y10S514/929 ,  Y10S514/968

    Abstract: The present invention describes novel compositions and kits comprising alpha-adrenergic receptor antagonists and compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, or stimulate nitric oxide synthesis. In preferred embodiments, the alpha-adrenergic receptor antagonist is an alkaloid selected from the group consisting of rauwolscine, corynanthine, yohimbine, apoyohimbine, beta-yohimbine, yohimbol, pseudoyohimbine and epi-3&agr;-yohimbine, and the compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, or stimulates nitric oxide synthesis is selected from the group consisting of L-arginine, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine and S-nitroso-glutathione. In other embodiments, the present invention describes novel compositions comprising yohimbine and L-arginine. In still other embodiments, the invention describes novel compositions comprising yohimbine and L-arginine where the yohimbine is derived from yohimbe bark or Rauwolfia root. The novel compositions of the invention are useful for treating impotence in males and females.

    Abstract translation: 本发明描述了包含α-肾上腺素能受体拮抗剂和捐赠，转移或释放一氧化氮，提高内源性松弛因子的内源水平或刺激一氧化氮合成的化合物的新型组合物和试剂盒。 在优选的实施方案中，α-肾上腺素能受体拮抗剂是选自以下的生物碱：羊尿苷，色氨酸，育亨宾，去氨嘌呤，β-育亨宾，育亨宾，假蛋黄嘌呤和epi-3α-育亨宾，以及捐赠，转移或释放的化合物 一氧化氮提高内源性舒张因子的内源水平，或刺激一氧化氮合成选自L-精氨酸，S-亚硝基-N-乙酰半胱氨酸，S-亚硝基卡托普利，S-亚硝基高半胱氨酸，S 亚硝基半胱氨酸和S-亚硝基 - 谷胱甘肽。 在其它实施方案中，本发明描述了包含育亨宾和L-精氨酸的新型组合物。 在其它实施方案中，本发明描述了包含育亨宾和L-精氨酸的新型组合物，其中育亨宾衍生自yohimbe树皮或Rauwolfia根。 本发明的新型组合物可用于治疗男性和女性的阳。。

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