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Wo 2007/016677 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 8 February 2007 (08.02.2007) PCT WO 2007/016677 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/5377 (2006.01) kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (21) International Application Number: CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, PCT/US2006/030287 GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, (22) International Filing Date: 2 August 2006 (02.08.2006) LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MZ, NA, (25) Filing Language: English NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, (26) Publication Language: English UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 60/704,426 2 August 2005 (02.08.2005) US kind of regional protection available): ARIPO (BW, GH, 60/741,455 2 December 2005 (02.12.2005) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (71) Applicant (for all designated States except US): NI- European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, TROMED, INC. [US/US]; 125 Spring Street, Lexington, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, MA 02421-7801 (US). RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, (72) Inventors; and GN, GQ, GW, ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): ELLIS, James, L. [GB/US]; 2 1 Pearl Road, Boxford, MA 01921 (US). GAR- Published: VEY, David, S. [US/US]; 10 Grand Hill Drive, Dover, — without international search report and to be republished Massachusetts 02030 (US). upon receipt of that report (74) Agents: LEW, Belinda et al.; Wilmer Cutler Pickering For two-letter codes and other abbreviations, refer to the "G uid Hale and Dorr LLP, 1875 Pennsylvania Avernue, NW, ance Notes on Codes and Abbreviations" appearing at the beg in Washington, DC 20006 (US). ning of each regular issue of the PCT Gazette. (54) Title: NITRIC OXIDE ENHANCING ANTIMICROBIAL COMPOUNDS, COMPOSITIONS AND METHODS OF USE (57) Abstract: The invention describes compositions and kits comprising at least one nitric oxide enhancing group antimicrobial compound, or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitric oxide enhancing antimicrobial compound, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The invention also provides methods for (a) treating bacterial infections; (b) treating viral infections; (c) treating fungal infections; and (d) treating lesions. The antimicrobial compounds of the invention are preferably tobramycin, aztreonam, ciprofloxacin and doripenam. The nitric oxide enhancing antimicrobial compounds are substituted with at least one heterocyclic nitric oxide donor group and/or at least one nitroxide group. The nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donors. The heterocyclic nitric oxide donors are furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines. In one embodiment the methods of the invention are for the treatment of bacterial infections associated with pulmonary diseases such as cystic fibrosis and for treating Bacillus anthracis infections. NITRIC OXIDE ENHANCING ANTIMICROBIAL COMPOUNDS, COMPOSITIONS AND METHODS OF USE RELATED APPLICATIONS This application claims priority under 35 USC § 119 to U.S. Application No. 60/704,426 filed August 2, 2005; and U.S. Application No. 60/741,455 filed December 2, 2005; the disclosures of which are incorporated by reference herein in its entirety. FIELD OF THE INVENTION The invention describes compositions and kits comprising at least one nitric oxide enhancing group antimicrobial compound, or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitric oxide enhancing antimicrobial compound, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The invention also provides methods for (a) treating bacterial infections; (b) treating viral infections; (c) treating fungal infections; and (d) treating lesions. The antimicrobial compounds of the invention are preferably tobramycin, aztreonam, ciprofloxacin and doripenam. The nitric oxide enhancing antimicrobial compounds are substituted with at least one heterocyclic nitric oxide donor group and/or at least one nitroxide group. The nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donors. The heterocyclic nitric oxide donors are furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines. In one embodiment the methods of the invention are for the treatment of bacterial infections associated with pulmonary diseases such as cystic fibrosis and for treating Bacillus anthracis infections. BACKGROUND OF THE INVENTION Antimicrobial compounds are used to control infections, to treat life-threatening diseases and to reduce death and illness. However, many antimicrobial compounds and antiviral compounds are potent anti-infective agents and also cause toxic side-effects such as skin rashes, shock and other allergic responses, toxic effects on the stomach, liver and kidney. In addition the wide use of .antimicrobial compounds and antiviral compounds in the treatment of infections has caused the development of strains resistant to these drugs. Hence there is a need in the art for antimicrobial compounds that can be administered to treat infections and that have improved efficacy, lower toxicity, can be used at low dosages and reduce microbial resistance. The invention is directed to these, as well as other, important ends. SUMMARY OF THE INVENTION The invention provides novel nitric oxide enhancing antimicrobial compounds, or pharmaceutically acceptable salts thereof. The nitric oxide enhancing antimicrobial compounds are substituted with at least one heterocyclic nitric oxide donor group and/or at least one nitroxide group that is linked to the antimicrobial compound through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen via a bond or moiety that can be hydrolyzed. The heterocyclic nitric oxide donor groups preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines. The invention also provides compositions comprising the novel compounds described herein in a pharmaceutically acceptable earner. The invention is also based on the discovery that administering at least one nitric oxide enhancing antimicrobial compound or a pharmaceutically acceptable salt thereof, and, optionally, at least one nitric oxide enhancing compound improves the properties of the antimicrobial compound. Nitric oxide enhancing compounds include, for example, S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, furoxans, sydnonimines, SPM 3672, SPM 4757, SPM 5185, SPM 5186 and analogues thereof, substrates of the various isozymes of nitric oxide synthase, and nitroxides. Thus, another embodiment of the invention provides compositions comprising at least one nitric oxide enhancing antimicrobial compound and at least one nitric oxide enhancing compound. The invention also provides for such compositions in a pharmaceutically acceptable carrier. Another embodiment of the invention provides compositions comprising at least one nitric oxide enhancing antimicrobial compound, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent, including, but not limited to, aldosterone antagonists, α-adrenergic receptor antagonists, β-adrenergic agonists, anti- allergic compounds, antidiabetic compounds, anti-hyperlipidemic drugs, antitussive compounds, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antioxidants, antithrombotic and vasodilator drugs, β-adrenergic antagonists, bronchodilators, calcium channel blockers, diuretics, endothelin antagonists, expectorants, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, steroids, and combinations of two or more thereof. In one embodiment the at least one therapeutic agent is selected from the group consisting of a β-adrenergic agonist, an anti-allergic compound, an antitussive compound, an antioxidant, a bronchodilator, an expectorant, a H receptor antagonist, a nonsteroidal antiinflammatory compound (NSAIDs), a phosphodiesterase inhibitor, a proton pump inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitor and a steroid. The invention also provides for such compositions in a pharmaceutically acceptable carrier. Yet another embodiment of the invention provides methods for (a) treating bacterial infections; (b) treating viral infections; (c) treating fungal infections; and (d) treating lesions in a patient in need thereof comprising administering to the patient an effective amount of at least one nitric oxide enhancing antimicrobial compound, and, optionally, at least one nitric oxide enhancing compound. The methods
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