US 20080293702Al (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2008/0293702 A1 Garvey (43) Pub. Date: NOV. 27, 2008 (54) NITRIC OXIDE ENHANCING PYRUVATE A61K 31/4245 (2006.01) COMPOUNDS, COMPOSITIONS AND A61K 31/42 (2006.01) METHODS OF USE C07D 273/00 (2006.01) C07D 413/04 (2006.01) (75) Inventor: David S. Garvey, Dover, MA (U S) A61 K 31/53 77 (200601) A61P 9/00 (2006.01) Correspondence Address: A 61p 9/06 (200601) WILMERHALE/NITROMED A 611) 9/10 (200601) 1875 PENNSYLVANIA AVE, NW A611) 9/12 (200601) WASHINGTON, DC 20006 (US) _ _ (52) US. Cl. .................... .. 514/222.5; 548/125; 514/364; (73) Assrgnee: NITROMED, INC., Lexington, 514/361; 544/138; 514/2362 MA (U S) (21) Appl. N0.: 12/096,867 (57) ABSTRACT (22) PCT F 11 e d: D e c_ 19, 2006 The invention provides novel compositions and kits compris ing at least one nitric oxide enhancing pyruvate compound, or (86) PCT NO; PCT M52006 /0 4819 4 a pharmaceutically acceptable salt thereof, and, optionally, at least one nitric oxide enhancing compound and/ or at least one § 371 (OX1), therapeutic agent. The invention also provides methods for (2)’ (4) Date; Jun_ 10, 2008 (a) treating cardiovascular diseases; (b) treating renovascular diseases; (0) treating diabetes; (d) treating diseases resulting Related US. Application Data from oxidative stress; (e) treating endothelial dysfunctions; (f) treating diseases caused by endothelial dysfunctions; (g) (60) Provisional application No. 60/753,971, ?led on Dec. treating cirrhosis; (h) treating pre-eclampsia; (j) treating 22, 2005. osteoporosis; (k) treating nephropathy; (l) treating peripheral vascular diseases; (m) treating portal hypertension (n) treat Publication Classi?cation ing reperfusion injury following ischemia; and/or (m) pre (51) Int. Cl. serving tissues, organs, organ parts and/or limbs. The nitric A61K 31/546 (2006.01) oxide enhancing pyruvate compounds comprise at least one C07D 271/08 (2006.01) nitroxide group. US 2008/0293702 A1 Nov. 27, 2008 NITRIC OXIDE ENHANCING PYRUVATE tuted With at least one heterocyclic nitric oxide donor group COMPOUNDS, COMPOSITIONS AND and/or at least one nitroxide group and pharmaceutically METHODS OF USE acceptable salts thereof. The pyruvate compound can be sub stituted With the heterocyclic nitric oxide donor group and/ or RELATED APPLICATIONS the nitroxide group through one or more sites such as oxygen [0001] This application claims priority under 35 USC § 1 19 (hydroxyl condensation), sulfur (sulfhydryl condensation) to US. Application No. 60/753,971 ?led Dec. 22, 2005; the and/or nitrogen via a bond or moiety that can be hydrolyZed. disclosure of Which is incorporated by reference herein in its The heterocyclic nitric oxide donors are furoxans, sydnon entirety. imines, oxatriaZole-5-ones and/or oxatriaZole-5-imines. The invention also provides compositions comprising the novel FIELD OF THE INVENTION compounds described herein in a pharmaceutically accept [0002] The invention provides novel compositions and kits able carrier. comprising at least one nitric oxide enhancing pyruvate com [0006] The invention is also based on the discovery that pound, or a pharmaceutically acceptable salt thereof, and, administering at least one pyruvate compound, comprising at optionally, at least one nitric oxide enhancing compound least one nitric oxide enhancing group (i.e. heterocyclic nitric and/ or at least one therapeutic agent. The invention also pro oxide donor group and/ or nitroxide group), and, optionally, at vides methods for (a) treating cardiovascular diseases; (b) least one nitric oxide enhancing compound can be used for the treating renovascular diseases; (c) treating diabetes; (d) treat targeted delivery of the compounds to organs, cells or tissues ing diseases resulting from oxidative stress; (e) treating containing the enZyme gamma-glutamyl transpeptidase and endothelial dysfunctions; (f) treating diseases caused by for the delivery of nitric oxide at the targeted site. Nitric oxide endothelial dysfunctions; (g) treating cirrhosis; (h) treating enhancing compounds include, for example, S-nitrosothiols, pre-eclampsia; (j) treating osteoporosis; (k) treating nephr nitrates, nitrates, N-oxo-N-nitrosamines, furoxans, sydnon opathy; (l) treating peripheral vascular diseases; (m) treating imines, SPM 3672, SPM 4757, SPM 5185, SPM 5186 and portal hypertension; (n) treating reperfusion injury folloWing analogues thereof, substrates of the various isoZymes of nitric ischemia; and/or (m) preserving tissues, organs, organ parts oxide synthase, and nitroxides. Thus, another embodiment of and/or limbs. The nitric oxide enhancing pyruvate com the invention provides compositions comprising at least one pounds comprise at least one heterocyclic nitric oxide donor nitric oxide enhancing pyruvate compound and at least one group and/or at least one nitroxide group. nitric oxide enhancing compound. The invention also pro vides for such compositions in a pharmaceutically acceptable BACKGROUND OF THE INVENTION carrier. [0003] Normal metabolic processes in vascular cells are [0007] The invention provides compositions comprising at associated With the generation of reactive oxygen intermedi least one nitric oxide enhancing pyruvate compound, and, ates that must be neutraliZed in order to limit oxidative dam optionally, at least one nitric oxide enhancing compound age and cellular dysfunction. In the setting of common dis and/or at least one therapeutic agent, including, but not lim orders or in the presence of common risk factors for numerous ited to, aldosterone antagonists, alpha-adrenergic receptor diseases reactive oxygen species (ROS) are generated in antagonists, angiotensin II antagonists, angiotensin-convert abundance and their rate of synthesis and ?ux typically ing enZyme (ACE) inhibitors, antidiabetic compounds, anti exceeds the capacity of endogenous antioxidant mechanisms. hyperlipidemic compounds, antioxidants, antithrombotic and For example, hypercholesterolemia, hyperglycemia (Keaney vasodilator compounds, [3-adrenergic antagonists, calcium et al, Circulation, 99:189-191 (1999)), cigarette smoking, channel blockers, digitalis, diuretics, endothelin antagonists, hyperhomocysteinemia, hypertension, and atherosclerosis hydralaZine compounds, H2 receptor antagonists, neutral are all accompanied by an increase in plasma and tissue ROS endopeptidase inhibitors, nonsteroidal antiin?ammatory generation. Superoxide anion, hydrogen peroxide, hydroxyl compounds (NSAIDs), phosphodiesterase inhibitors, potas radical, peroxynitrite, and lipid peroxides all increase in dis sium channel blockers, platelet reducing agents, proton pump eases resulting from oxidative stress. inhibitors, renin inhibitors, selective cyclooxygenase-2 [0004] It is believed that oxidative damage is mediated by (COX-2) inhibitors, and combinations of tWo or more thereof. intracellular redox-active metal reactions catalyZed by highly In one embodiment the at least one therapeutic agent is reactive oxygen species (i.e. hydroxyl radicals). The genera selected from the group consisting of an aldosterone antago tion of such reactive oxygen species depends on the availabil nist, an angiotensin II antagonist, an angiotensin-converting ity of their common precursor, the superoxide anion. Mito enZyme (ACE) inhibitors, a [3-adrenergic antagonist, a cal chondria, microsomes and other various enZyme systems are cium channel blocker, a diuretic, a hydralaZine compound knoWn to produce superoxide anion that reacts With nitric and a renin inhibitor. The invention also provides for such oxide at or near diffusion controlled rates to form the poWer compositions in a pharmaceutically acceptable carrier. ful oxidant peroxynitrite. At pH 7.4, peroxynitrite protonates [0008] Another embodiment of the invention provides to form peroxynitrous acid (pKa 6.6) Which decays homolyti compositions comprising at least one at least one nitric oxide cally to form hydroxyl and nitrogen dioxide radicals in addi enhancing pyruvate compound, and at least one therapeutic tion to a host of other ions. The extent to Which these later agent is selected from the group consisting of an aldosterone reactive ions and radicals can cause cellular damage and antagonist, an angiotensin II antagonist, an angiotensin-con death depends on the rate of formation of their peroxynitrite verting enZyme (ACE) inhibitor, a [3-adrenergic antagonist, a precursor. calcium channel blocker, a diuretic, a hydralaZine compound and a renin inhibitor. The invention also provides for such SUMMARY OF THE INVENTION compositions in a pharmaceutically acceptable carrier. [0005] The invention provides novel nitric oxide enhancing [0009] The invention provides methods for (a) treating car pyruvate compounds and derivatives thereof that are substi diovascular diseases; (b) treating renovascular diseases; (c) US 2008/0293702 A1 Nov. 27, 2008 treating diabetes; (d) treating diseases resulting from oxida [0011] These and other aspects of the invention are tive stress; (e) treating endothelial dysfunctions; (f) treating described in detail herein. diseases caused by endothelial dysfunctions; (g) treating cir rhosis; (h) treating pre-eclampsia; (j) treating osteoporosis; DETAILED DESCRIPTION OF THE INVENTION (k) treating nephropathy; (l) treating peripheral vascular dis [0012] As used throughout the disclosure, the folloWing eases; (m) treating portal hypertension; (n) treating reperfu temms, unless otherWise indicated, shall be understood to sion injury folloWing ischemia;