National Institutes of Health, a Component of the US Dept. of Health & Human Services

The United States of America As Represented by the Department of Health

The United States of America As Represented by the Secretary of

Other

Medtronic Vascular, Inc.

The United States of America

University of Pittsburgh

Arizona Board of Regents on Behalf of the University of Arizona

Icn Pharmaceuticals, Inc.

Vivus, Inc.

Entremed, Inc.

The Government of the United States of America, As Represented by the

The United States of America As Represented by the Secretary of Health

Comedicus Incorporated

Larry K Keefer

Joseph A Hrabie

Joseph E Saavedra

Joseph Saavedra

David A Wink

Tambra M Dunams

Robert L Cafferata

Ernst V Arnold

Anthony L Fitzhugh

Xinhua Ji

Peter P Roller

Miki Akamatsu

David J Waterhouse

Virgil A Place

Marc Hendriks

Peiwen Cheng

Paul C Doherty, Jr

Eugene Tedeschi

William G Rice

Mark S Hanamoto

Anna E Maciag

Christian Bogdan

Frank DeRosa

Preeya Kapur

Frank De Rosa

Aloka Srinivasan

Daniel J Smith

Shawn J Green

Timothy R Billiar

Katrina M Miranda

Debashish Chakravarthy

Danae D Christodoulou

Thomas C Hutsell

Vandana Kumari

Debashree Basudhar

Daniela Andrei

Michel I P M Verhoeven

Michel L P M Verhoeven

Michael L Citro

Jean G Diodati

Lipu Kong

Ronald J Korthuis

Lucy M Anderson

Xia Xu

George Lunn

Harinath Chakrapani

Regina G Ziegler

Debra J Salmon

Ji Xinhua

Christian Freidrich-Alexander-Univ Bogdan

Disclosed is a nitric oxide-releasing polyvinylpyrrolidone-based polymer derived from N-vinylpyrrolidone monomer and at least one nitric oxide releasing NOgroup, in which the NOgroup is attached to a 2 pyrrolidinone group or a group derived therefrom in the N-vinylpyrrolidone monomer, and the polymer is optionally in combination with a substrate. The NO-releasing polymer can be part of a medical device or pharmaceutical composition and is useful for treating a biological disorder, such as healing a wound, restenosis, and/or promoting angiogenesis.

Nitric oxide-releasing diazeniumdiolated polyvinylpyrrolidone-based polymers, and compositions, medical devices, and uses thereof

Disclosed is a method of treating cancer in a patient comprising administering to the patient an effective amount of a diazeniumdiolated (NO-containing) compound or a pharmaceutically acceptable salt thereof, wherein the cancer cell has an elevated level of reactive oxygen species (ROS) and/or a decreased level of one or more of PRX1, PRX6, and OGG1, compared to a normal cell of the same tissue or tissue type. An example of a diazeniumdiolated compound is Formula (I), wherein X and Q are defined herein. Also disclosed are diazeniumdiolated compounds, pharmaceutical compositions, and methods of use including enhancing the chemotherapeutic treatment of chemotherapeutic agents and high energy radiation. 

Diazeniumdiolated compounds, pharmaceutical compositions, and method of treating cancer

Disclosed are hybrid compounds that release both nitric oxide and a moiety that inhibits poly (ADP-ribose) polymerase (PARP), e.g., a compound or a pharmaceutically acceptable salt thereof of formula (I), wherein Rand m-p are as described herein. Also disclosed are pharmaceutical compositions and methods of use including treating cancer and enhancing the chemotherapeutic treatment of chemotherapeutic agents and high energy radiation. 

Hybrid diazeniumdiolated compounds, pharmaceutical compositions, and method of treating cancer

Disclosed is a compound of the formula (I) or a pharmaceutically acceptable salt thereof: (I) in which R, R, R, and Rare defined herein and pharmaceutical compositions thereof. Further provided is a method of treating various disorders, such as a disorder selected from the group consisting of a cardiovascular disorder, cancer, chronic pain, alcohol dependence, and inflammation in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt of formula (I). 

Nitroxyl (HNO) releasing compounds and uses thereof in treating diseases

The invention described herein provides for novel nitric oxide-releasing polymers that comprise at least two adjacent units derived from acrylonitrile monomer units and containing at least one carbon-bound diazeniumdiolate. The diazeniumdiolated acrylonitrile-derived polymers can be used in medical devices therapeutically. Accordingly, the invention also provides a method of treating a biological disorder and a method of promoting angiogenesis that includes administering a medical device comprising a nitric oxide-releasing polymer comprising at least two adjacent units of acrylonitrile before exposure to nitric oxide and at least one nitric oxide releasing NOgroup, wherein the NOgroup is attached directly to the polyacrylonitrile backbone, to a specific location on or within the mammal in an amount effective to treat the biological disorder or promote angiogenesis.

Nitric oxide-releasing diazeniumdiolated compounds

The invention described herein provides for novel nitric oxide-releasing polymers that comprise at least two adjacent units derived from acrylonitrile monomer units and containing at least one carbon-bound diazeniumdiolate. The diazeniumdiolated acrylonitrile-derived polymers can be used in medical devices therapeutically. Accordingly, the invention also provides a method of treating a biological disorder and a method of promoting angiogenesis that includes administering a medical device comprising a nitric oxide-releasing polymer comprising at least two adjacent units of acrylonitrile before exposure to nitric oxide and at least one nitric oxide releasing NO&#x2014; group, wherein the NO&#x2014; group is attached directly to the polyacrylonitrile backbone, to a specific location on or within the mammal in an amount effective to treat the biological disorder or promote angiogenesis.

Nitric oxide-releasing diazeniumdiolated acrylonitrile-based polymers, and compositions, medical devices, and uses thereof

The present invention provides compound of the formula (I): in which at least two of R, R, R, R, R, and Rare NOM and related compounds, substrates, compositions, and methods of using such compounds and compositions to treat biological disorders in which a polyphasic release of nitric oxide would be beneficial.

Polydiazeniumdiolated cyclic polyamines with polyphasic nitric oxide release and related compounds, compositions comprising same and methods of using same

The invention relates to compounds capable of releasing nitric oxide wherein the compounds comprise a saccharide and at least one nitric oxide-releasing diazeniumdiolate [NO] functional group, which is bonded directly to a carbon atom of the saccharide, and methods for preparing the same. The invention further comprises the treatment of biological disorders treatable by the administration of nitric oxide.

Polysaccharide-derived nitric oxide-releasing carbon-bound diazeniumdiolates

Methods for enhancing detection by mass spectroscopy (MS) and/or chromatographic separability of carbonyl-containing compounds such as steroids are disclosed. Reaction of a carbonyl compound with a sulfonhydrazide compound provides a sulfonhydrazone with enhanced ionization efficiency during the electrospray ionization process. In a particularly disclosed embodiment, derivatization of catechol estrogens with p-toluenesulfonhydrazide enhances both detection by atmospheric pressure ionization-MS (API-MS), such as electron spray ionization-MS (ESI-MS) and separation by liquid chromatography (such as HPLC) under reverse phase conditions. In yet other embodiments, the sulfonhydrazone is further reacted with a sulfonyl halide under alkaline conditions to derivatize hydroxyl groups in the compound. Prior formation of the sulfonhydrazide derivative protects the carbonyl bond of the compound during subsequent alkaline reaction with the sulfonyl halide.

Methods for separation and detection of ketosteroids and other carbonyl-containing compounds

The present invention provides compound of the formula (I): in which at least two of R, R, R, R, R, and Rare NOM and related compounds substrates, compositions, and methods of using such compounds and compositions to treat biological disorders in which a polyphasic release of nitric oxide would be beneficial.

An implant or intravascular stent comprising a polymeric composition capable of releasing nitric oxide under physiological conditions. The polymeric composition comprises a polymer and at least one nitric oxide-releasing NOfunctional group bound to the polymer.

Nitric oxide-releasing medical devices

The present invention relates to nitric oxide-releasing amidine diazeniundiolates, compositions comprising same, methods of using same, and a method for preparing same from imidate diazeniumdiolates and primary or secondary amines.

Nitric oxide-releasing amidine diazeniumdiolates, compositions and uses thereof and method of making same

Extremely hydrophobic nitric oxide (NO) releasing polymers are disclosed. The extremely hydrophobic NO-releasing polymers provided are extensively cross-linked polyamine-derivatized divinylbenzene diazeniumdiolates. These polymers can be loaded with extremely high NO levels and designed to release NO in manners than mimic natural biological systems. The NO-releasing extremely hydrophobic polymers provided can maintain a sustained NO release for periods exceeding nine months. Also provided are related medical devices made using these NO-releasing extremely hydrophobic polymers.

Highly cross-linked, extremely hydrophobic nitric oxide-releasing polymers and methods for their manufacture and use

The invention provides NO- or NO-releasing imidate; and thioimidate, diazeniumdiolates, in which the NOfunctional group is bonded to a carbon atom. The imidate and thioimidate diazeniumdiolates are bound to a polymer or a substrate.

Nitric oxide-releasing imidate and thioimidate diazeniumdiolates

The present invention provides O-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates (1-[(2-carboxylato)pyrrolidin-1-yl]diazeniumdiolates) of the formula in which R and Rare as described herein. Also provided is a composition comprising such a compound and a carrier. The 1-[(2-carboxylato)pyrrolidin-1-yl]diazeniumdiolates compounds release nitric oxide under physiological conditions and are useful for treating biological disorders.

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Bethesda, MD, United States of America

Larry K Keefer