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    C-nitroso compounds and use thereof
    1.
    发明授权
    C-nitroso compounds and use thereof 失效
    C-亚硝基化合物及其用途

    公开(公告)号：US07030238B2

    公开(公告)日：2006-04-18

    申请号：US11052777

    申请日：2005-02-09

    申请人： Jonathan S. Stamler ,  Eric J. Toone

    发明人： Jonathan S. Stamler ,  Eric J. Toone

    IPC分类号： C07D265/02 ,  C07D267/04 ,  C07D279/02 ,  A61K31/5415 ,  A61K31/536

    CPC分类号： C07C207/00 ,  A61K31/00 ,  A61K31/195 ,  A61K2300/00

    摘要： A C-nitroso compound having a molecular weight ranging from about 225 to about 1,000 (from about 225 to about 600 for oral administration) on a monomeric basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, is useful as an NO donor. When the compound is obtained from a carbon acid with a pKa less than about 10, it provides vascular relaxing effect when used at micromolar concentrations and this activity is potentiated by glutathione to be obtained at nanomolar concentrations. When the compound is obtained from a carbon acid with a pKa ranging from about 15 to about 20, vascular relaxing effect is obtained at nanomolar concentrations without glutathione. The compound is preferably water-soluble and preferably contains a carbon alpha to the nitrosylated carbon which is part of a ketone group. In one embodiment, the C-nitroso compound is obtained by nitrosylation of a conventional drug or such drug modified to modify the carbon acid pKa thereof. When such drug is a nonsteroidal anti-inflammatory drug, the resulting C-nitroso compound functions as a COX-1 and COX-2 inhibitor without the deleterious effects associated with COX-1 inhibition but with the advantageous effects associated with COX-1 and COX-2 inhibition. One such C-nitroso compound is a nitrosoketoibuprofen. A specific example of this kind of compound is isolated as dimeric 2-[4′-(α-nitroso)isobutyrylphenyl]propionic acid. In another case, the C-nitroso compound contains the moiety where X is S, O or NR. One embodiment is directed to COX-2 inhibitors where a tertiary carbon atom and/or an oxygen atom and/or a sulfur atom is nitrosylated.

    摘要翻译： 单体基团的分子量范围为约225至约1,000（约225至约600）的C-亚硝基化合物，其中亚硝基连接到叔碳上，其通过碳的亚硝基化获得 pKa小于约25的酸可用作NO供体。 当化合物从pKa小于约10的碳酸获得时，当以微摩尔浓度使用时，其提供血管松弛效果，并且该活性由以纳摩尔浓度获得的谷胱甘肽加强。 当化合物由pKa为约15至约20的碳酸获得时，在没有谷胱甘肽的纳摩尔浓度下获得血管松弛效果。 该化合物优选是水溶性的并且优选地含有作为酮基的一部分的亚硝基化碳的碳α。 在一个实施方案中，C-亚硝基化合物通过常规药物的亚硝基化或经修饰以改性其碳酸pKa的药物而获得。 当这种药物是非甾体抗炎药物时，所得到的C-亚硝基化合物起COX-1和COX-2抑制剂的作用，而没有与COX-1抑制有关的有害作用，但具有与COX-1和COX相关的有益效果 -2抑制。 一种这样的C-亚硝基化合物是亚硝基基布洛芬。 这种化合物的具体实例被分离为二聚2- [4' - （α-亚硝基）异丁酰苯基]丙酸。 在另一种情况下，C-亚硝基化合物包含其中X是S，O或NR的部分。 一个实施方案涉及其中叔碳原子和/或氧原子和/或硫原子被亚硝酰化的COX-2抑制剂。

    C-nitroso compounds and use thereof
    3.
    发明授权
    C-nitroso compounds and use thereof 失效
    C-亚硝基化合物及其用途

    公开(公告)号：US06359182B1

    公开(公告)日：2002-03-19

    申请号：US09695934

    申请日：2000-10-26

    申请人： Jonathan S. Stamler ,  Eric J. Toone

    发明人： Jonathan S. Stamler ,  Eric J. Toone

    IPC分类号： C07D21190

    CPC分类号： C07C207/00 ,  A61K31/00 ,  A61K31/195 ,  A61K2300/00

    摘要： A C-nitroso compound having a molecular weight ranging from about 225 to about 1,000 (from about 225 to about 600 for oral administration) on a monomeric basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, is useful as an NO donor. When the compound is obtained from a carbon acid with a pKa less than about 10, it provides vascular relaxing effect when used at micromolar concentrations and this activity is potentiated by glutathione to be obtained at nanomolar concentrations. When the compound is obtained from a carbon acid with a pKa ranging from about 15 to about 20, vascular relaxing effect is obtained at nanomolar concentrations without glutathione. The compound is preferably water-soluble and preferably contains a carbon alpha to the nitrosylated carbon which is part of a ketone group. In one embodiment, the C-nitroso compound is obtained by nitrosylation of a conventional drug or such drug modified to modify the carbon acid pKa thereof When such drug is a nonsteroidal anti-inflammatory drug, the resulting C-nitroso compound functions as a COX-1 and COX-2 inhibitor without the deleterious effects associated with COX-1 inhibition but with the advantageous effects associated with COX-1 and COX-2 inhibition. One such C-nitroso compound is a nitrosoketoibuprofen. A specific example of this kind of compound is isolated as dimeric 2-[4′-(&agr;-nitroso)isobutyrylphenyl] propionic acid. In another case, the C-nitroso compound contains the moiety where X is S, O or NR One embodiment is directed to COX-2 inhibitors where a tertiary carbon atom and/or an oxygen atom and/or a sulfur atom is nitrosylated.

    摘要翻译： 单体基团的分子量范围为约225至约1,000（约225至约600）的C-亚硝基化合物，其中亚硝基连接到叔碳上，其通过碳的亚硝基化获得 pKa小于约25的酸可用作NO供体。 当化合物从pKa小于约10的碳酸获得时，当以微摩尔浓度使用时，其提供血管松弛效果，并且该活性由以纳摩尔浓度获得的谷胱甘肽加强。 当化合物由pKa为约15至约20的碳酸获得时，在没有谷胱甘肽的纳摩尔浓度下获得血管松弛效果。 该化合物优选是水溶性的并且优选地含有作为酮基的一部分的亚硝基化碳的碳α。 在一个实施方案中，C-亚硝基化合物通过常规药物的亚硝基化或经修饰以改变其碳酸pKα的药物而获得。当这种药物是非甾体抗炎药物时，所得的C-亚硝基化合物起COX- 1和COX-2抑制剂，没有与COX-1抑制相关的有害作用，但具有与COX-1和COX-2抑制相关的有利效果。 一种这样的C-亚硝基化合物是亚硝基基布洛芬。 这种化合物的具体实例被分离为二聚2- [4' - （α-亚硝基）异丁酰苯基]丙酸。 在另一种情况下，C-亚硝基化合物包含其中X是S，O或NR的部分。一个实施方案涉及COX-2抑制剂，其中叔碳原子和/或氧原子和/或硫原子被亚硝酰化。

    Reactive Oxygen Generating Enzyme Inhibitor With Nitric Oxide Bioactivity and Uses Thereof
    4.
    发明申请
    Reactive Oxygen Generating Enzyme Inhibitor With Nitric Oxide Bioactivity and Uses Thereof 有权
    具有一氧化氮活性的活性氧发生酶抑制剂及其用途

    公开(公告)号：US20100010019A1

    公开(公告)日：2010-01-14

    申请号：US12554249

    申请日：2009-09-04

    申请人： Jonathan S. Stamler ,  Eric J. Toone ,  Joshua M. Hare

    发明人： Jonathan S. Stamler ,  Eric J. Toone ,  Joshua M. Hare

    IPC分类号： A61K31/519 ,  A61P29/00

    CPC分类号： C07D487/04 ,  A61K31/519

    摘要： A reactive oxygen generating enzyme inhibitor with NO donor bioactivity, e.g., nitrated allopurinol, is useful to treat heart failure, stable angina, ischemic disorder, ischemic reperfusion injury, atherosclerosis, sickle cell disease, diabetes, Alzheimer's disease, Parkinson's disease, ALS and asthma and to obtain proper contraction of heart, skeletal and smooth muscle.

    摘要翻译： 具有NO供体生物活性的活性氧产生酶抑制剂，例如硝化别嘌呤醇，可用于治疗心力衰竭，稳定性心绞痛，缺血性障碍，缺血再灌注损伤，动脉粥样硬化，镰状细胞病，糖尿病，阿尔茨海默病，帕金森病，ALS和哮喘 并获得心脏，骨骼和平滑肌的适当收缩。

    Reactive oxygen generating enzyme inhibitor with nitric oxide bioactivity and uses thereof
    5.
    发明授权
    Reactive oxygen generating enzyme inhibitor with nitric oxide bioactivity and uses thereof 有权
    具有一氧化氮生物活性的活性氧发生酶抑制剂及其应用

    公开(公告)号：US07625907B2

    公开(公告)日：2009-12-01

    申请号：US11430986

    申请日：2006-05-10

    申请人： Jonathan S. Stamler ,  Eric J. Toone ,  Joshua M. Hare

    发明人： Jonathan S. Stamler ,  Eric J. Toone ,  Joshua M. Hare

    IPC分类号： A61K31/519 ,  A61P9/10 ,  C07D487/04

    CPC分类号： C07D487/04 ,  A61K31/519

    摘要： A reactive oxygen generating enzyme inhibitor with NO donor bioactivity, e.g., nitrated allopurinol, is useful to treat heart failure, stable angina, ischemic disorder, ischemic reperfusion injury, atherosclerosis, sickle cell disease, diabetes, Alzheimer's disease, Parkinson's disease, ALS and asthma and to obtain proper contraction of heart, skeletal and smooth muscle.

    摘要翻译： 具有NO供体生物活性的活性氧产生酶抑制剂，例如硝化别嘌呤醇，可用于治疗心力衰竭，稳定性心绞痛，缺血性障碍，缺血再灌注损伤，动脉粥样硬化，镰状细胞病，糖尿病，阿尔茨海默病，帕金森病，ALS和哮喘 并获得心脏，骨骼和平滑肌的适当收缩。

    C-nitroso compounds and use thereof
    6.
    发明授权
    C-nitroso compounds and use thereof 失效
    C-亚硝基化合物及其用途

    公开(公告)号：US07259250B2

    公开(公告)日：2007-08-21

    申请号：US11052141

    申请日：2005-02-08

    申请人： Jonathan S. Stamler ,  Eric J. Toone

    发明人： Jonathan S. Stamler ,  Eric J. Toone

    IPC分类号： C07D211/90 ,  C07D405/14 ,  C07D413/04 ,  C07D231/12 ,  A61P29/00

    CPC分类号： C07C245/04 ,  A61K31/00 ,  A61K31/195 ,  A61K31/785 ,  A61L31/10 ,  A61L31/16 ,  A61L2300/114 ,  A61L2300/606 ,  C07C207/00 ,  C07C207/04 ,  C07C219/06 ,  A61K2300/00

    摘要： A C-nitroso compound having a molecular weight ranging from 225 to 1,000 (from 225 to 600 for oral administration) on a monomeric basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, is useful as an NO donor. When the compound is obtained from a carbon acid with a pKa less than about 10, it provides vascular relaxing effect when used at micromolar concentrations and this activity is potentiated by glutathione to be obtained at nanomolar concentrations. When the compound is obtained from a carbon acid with a pKa ranging from about 15 to about 20, vascular relaxing effect is obtained at nanomolar concentrations without glutathione. In another embodiment, a biocompatible polymer incorporates a C-nitroso moiety.

    摘要翻译： 一种分子量范围为225〜1000（口服给药时为225〜600）的C-亚硝基化合物，其中亚硝基连接到叔碳上，其通过具有pKa的碳酸的亚硝化而得到 小于约25，可用作NO供体。 当化合物从pKa小于约10的碳酸获得时，当以微摩尔浓度使用时，其提供血管松弛效果，并且该活性由以纳摩尔浓度获得的谷胱甘肽加强。 当化合物由pKa为约15至约20的碳酸获得时，在没有谷胱甘肽的纳摩尔浓度下获得血管松弛效果。 在另一个实施方案中，生物相容性聚合物包含C-亚硝基部分。

    Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders
    9.
    发明授权
    Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders 有权
    以气体形式肺部输送含NO组的化合物，以治疗呼吸，心脏和血液疾病

    公开(公告)号：US06314956B1

    公开(公告)日：2001-11-13

    申请号：US09390215

    申请日：1999-09-08

    申请人： Jonathan S. Stamler ,  Eric J. Toone ,  Andrew J. Gow

    发明人： Jonathan S. Stamler ,  Eric J. Toone ,  Andrew J. Gow

    IPC分类号： A61M1500

    CPC分类号： C12N5/0641 ,  A61K31/197 ,  A61K31/21 ,  A61K33/00 ,  A61K33/04 ,  A61M2202/0275 ,  A61K2300/00

    摘要： Treatment of pulmonary disorders associated with hypoxemia and/or smooth muscle constriction comprises administering into the lungs as a gas a compound with an NO group which does not form NO2/NOx in the presence of oxygen or reactive oxygen species at body temperature. Treatment of cardiac and blood disorders, e.g., angina, myocardial infarction, heart failure, hypertension, sickle cell disease and clotting disorders, comprises administering into the lungs as a gas, a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO2/NOx in the presence of oxygen or reactive oxygen species at body temperature. Exemplary of the compound administered in each case is ethyl nitrite.

    摘要翻译： 与低氧血症和/或平滑肌收缩相关的肺部疾病的治疗包括在体温下在氧气或活性氧存在的情况下向肺中施用具有NO基团的化合物作为气体，所述NO组不形成NO 2 / NO x。 治疗心脏和血液疾病，例如心绞痛，心肌梗死，心力衰竭，高血压，镰状细胞病和凝血障碍，包括作为气体给予肺，与血红蛋白中的半胱氨酸反应和/或溶解于血液中的化合物和 具有在所述化合物中结合的NO基团，使得其在体温存在氧或活性氧的情况下不形成NO 2 / NO x。 在每种情况下施用的化合物的实例是亚硝酸乙酯。

    C-nitroso compounds and use thereof
    10.
    发明授权
    C-nitroso compounds and use thereof 有权
    C-亚硝基化合物及其用途

    公开(公告)号：US07785616B2

    公开(公告)日：2010-08-31

    申请号：US11822770

    申请日：2007-07-10

    申请人： Jonathan S. Stamler ,  Eric J. Toone

    发明人： Jonathan S. Stamler ,  Eric J. Toone

    IPC分类号： A61K31/785

    CPC分类号： C07C245/04 ,  A61K31/00 ,  A61K31/195 ,  A61K31/785 ,  A61L31/10 ,  A61L31/16 ,  A61L2300/114 ,  A61L2300/606 ,  C07C207/00 ,  C07C207/04 ,  C07C219/06 ,  A61K2300/00

    摘要： A C-nitroso moiety derived from a carbon acid with a pKa less than about 25 is bound in a biocompatible polymer as an ester or ether to a pendant hydroxyl group, as an ester to a pendant carboxylic acid or as an amine or amide to a pendant amine moiety. The polymer with c-nitroso moiety bound thereto can be coated on a medical device and/or used for prophylaxis of a patient at risk for restenosis. A c-nitroso moiety bound as amide to polyisobutylene amine substituted styrene copolymer is described in detail.

    摘要翻译： 衍生自pKa小于约25的碳酸的C-亚硝基部分作为酯或醚与作为酯的侧链羟基的生物相容性聚合物结合到侧羧酸或作为胺或酰胺与 侧胺部分。 具有结合到其上的C-亚硝基部分的聚合物可以涂覆在医疗装置上和/或用于预防具有再狭窄风险的患者。 详细描述了作为酰胺与聚异丁烯胺取代的苯乙烯共聚物结合的C-亚硝基部分。