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

University of Pittsburgh

Vivus, Inc.

Arizona Board of Regents on Behalf of the University of Arizona

Joseph E Saavedra

Larry K Keefer

Virgil A Place

Joseph A Hrabie

David A Wink

Paul C Doherty, Jr

William G Rice

Mark S Hanamoto

Xinhua Ji

Peter P Roller

Anna E Maciag

Miki Akamatsu

Christian Bogdan

Aloka Srinivasan

Timothy R Billiar

Katrina M Miranda

Tambra M Dunams

Vandana Kumari

Debashree Basudhar

Daniela Andrei

Debra J Salmon

Harinath Chakrapani

Lucy M Anderson

Ji Xinhua

Christian Freidrich-Alexander-Univ Bogdan

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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Provided are O-glycosylated 1-substituted diazen-1-ium-1,2-diolates (O-glycosylated diazeniumdiolates) having the formula:in which R is a saccharide, which is attached to the Oof the compound by the anomeric carbon of a pyranose ring or a furanose ring.

O2-glycosylated 1-substituted diazen-1-ium-1,2-diolates

Diazeniumdiolates, wherein the N position is substituted by an inorganic or organic moiety and the O -oxygen is bound to a substituted or unsubstituted aromatic group, are provided. Also provided are O -glycosylated 1-substituted diazen-1-ium-1,2-diolates (O -glycosylated diazeniumdiolates) and O -substituted 1-&lsqb;(2-carboxylato)pyrrolidin-1-yl&rsqb;diazen-1-ium-1,2-diolates (1-&lsqb;(2-carboxylato)pyrrolidin-1-yl&rsqb;diazeniumdiolates). The O -aryl diazeniumdiolates are stable with respect to the hydrolytic generation of nitric oxide in neutral to acidic solutions and generate nitric oxide in basic or nucleophilic environments or microenvironments. Also provided are compositions, including pharmaceutical compositions, comprising such compounds and methods of using such compounds.

O2-arylated or O2-glycosylated 1-substituted diazen-1-ium-1,2-diolates and O2-substituted 1-&lsqb;(2-carboxylato) pyrrolidin-1-yl&rsqb; diazen-1-ium-1,2-diolates

A method of treatment for impotency is provided. The method involves the administration of nitric oxide by a nitric oxide-releasing agent capable of providing a penile erection-inducing amount of nitric oxide to the corpus cavernosum of the penis of an impotent male animal. Also provided is a nitric oxide delivery means for use in the method.

Use of nitric oxide-releasing agents to treat impotency

A polymeric composition capable of releasing nitric oxide under physiological conditions which includes a biopolymer, such as a peptide, polypeptide, protein, oligonucleotide or nucleic acid, to which is bound a nitric oxide-releasing N,O,functional group; pharmaceutical compositions comprising the polymeric composition; and methods of treating biological disorders in which dosage with nitric oxide is therapeutic.

Biopolymer-bound nitric oxide-releasing compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same

A method for the treatment of mammalian tissue injured or at risk of injury during sepsis or shock including the administration to a mammal a diazeniumdiolate which releases a therapeutically effective amount of nitric oxide sufficient to protect the tissue from sepsis- or shock-induced injury.

Selective prevention of organ injury is sepsis and shock using selective

There are disclosed N-substituted piperazine NONOate compounds having the structure: ##STR1## wherein M is a pharmaceutically acceptable cation, x is the valence of the cation, and R is selected from the group consisting of: an unsubstituted or substituted C.sub.1 -C.sub.20 straight chain alkyl, an unsubstituted or substituted C.sub.3 -C.sub.20 branched chain alkyl,an unsubstituted or substituted C.sub.2 -C.sub.20 straight chain alkenyl, an unsubstituted or substituted C.sub.3 -C.sub.20 branched chain alkenyl, a group of formula, ##STR2## a group of formula, ##STR3## a group of formula R.sup.4 --SO.sub.2 --, or a group of formula R.sup.5 --O--N.dbd.N(O)--. The compounds are potent nitric oxide releasing compounds.

N-substituted piperazine NONOates

Selective prevention of organ injury in sepsis and shock using selection

A polymeric composition capable of releasing nitric oxide under physiological conditions which includes a biopolymer, such as a peptide, polypeptide, protein, oligonucleotide or nucleic acid, to which is bound a nitric oxide-releasing N.sub.2 O.sub.2.sup.- functional group; pharmaceutical compositions comprising the polymeric composition; and methods of treating biological disorders in which dosage with nitric oxide is therapeutic.

Biopolymer-bound nitric oxide-releasing compositions, pharmaceutical

A polymeric composition capable of releasing nitric oxide including a polymer and a nitric oxide-releasing N.sub.2 O.sub.2.sup.- functional group bound to the polymer; pharmaceutical compositions including the polymeric composition; and methods for treating biological disorders in which dosage with nitric oxide is beneficial. The compositions can be used as and/or incorporated into implants, injectables, condoms, prosthesis coatings, patches, and the like for use in a wide variety of medical applications.

Polymer-bound nitric oxide/nucleophile adduct compositions,

There are disclosed cardiovascularly active compounds possessing antihypertensive properties, and pharmaceutical compositions containing these agents and a method of treating cardiovascular disorders with the compounds. The active components of the pharmaceutical compositions are compounds of formula I ##STR1## wherein R.sub.1 and R.sub.2 are independently chosen from straight chain and branched chain alkyl and olefinic groups, which may be unsubstituted or substituted; or R.sub.1 and R.sub.2 together with the nitrogen atom they are bonded to form a heterocyclic group; and R.sub.3 is a pharmaceutically acceptable organic group selected from alkyl and olefinic groups which may be unsubstituted or substituted, acyl, a sulfonyl, sulfinyl, sulfenyl, carbonate, or carbamate derivative; or R.sub.3 is a group of the formula--(CH.sub.2).sub.n ONN(O)NR.sub.1 R.sub.2, wherein n is 2-8, and R.sub.1 and R.sub.2 are as described above. Novel compounds are disclosed wherein at least one of R.sub.1, R.sub.2 and R.sub.3 is an olefinic group or heteroatom-substituted straight or branched chain alkyl or olefinic group. Novel methods of synthesizing the compounds are also disclosed.

Oxygen substituted derivatives of nucleophile-nitric oxide adducts as

Growing community of inventors

Thurmont, MD, United States of America

Joseph E Saavedra