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WO 2011/103516 A2 25 August 2011 (25.08.2011) PCT

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WO 2011/103516 A2 25 August 2011 (25.08.2011) PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau I (10) International Publication Number (43) International Publication Date WO 2011/103516 A2 25 August 2011 (25.08.2011) PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/536 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) Number: International Application CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US201 1/025558 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 18 February 20 11 (18.02.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/305,862 18 February 2010 (18.02.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): THE GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, TRUSTEES OF PRINCETON UNIVERSITY ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, [US/US]; P.O. Box 36, 4 New South Building, Princeton, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, NJ 08544 (US). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors; and SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (75) Inventors/Applicants (for US only): KOYUNCU, Emre GW, ML, MR, NE, SN, TD, TG). [US/US]; 465 Meadow Road, Apt. 8302, Priceton, NJ 08540 (US). RABINOWITZ, Joshua, D. [US/US]; 17A Published: Hulfish Street, Princeton, NJ 08540 (US). SHENK, — without international search report and to be republished Thomas [US/US]; 12 Boundinot St., Princeton, NJ 08540 upon receipt of that report (Rule 48.2(g)) (US). — with sequence listing part of description (Rule 5.2(a)) (74) Agents: SOMERVILLE, Deborah, A. et al; Kenyon & Kenyon LLP, One Broadway, New York, NY 10004 (US). (54) Title: INHIBITORS OF LONG AND VERY LONG CHAIN FATTY ACID METABOLISM AS BROAD SPECTRUM ANTI-VIRALS Related genes and tested inhibitors ,v j < o Fig. 1 (57) Abstract: The present invention provides methods and compounds for treating viral infections using modulators of host cell enzymes relating to long chain fatty acid and lipid droplet metabolism. It includes a method of treating viral infections using triac- sin C and its relatives, analogues and derivatives as well as other inhibitors of long chain fatty acid metabolism and lipid droplet metabolism. INHIBITORS OF LONG AND VERY LONG CHAIN FATTY ACID METABOLISM AS BROAD SPECTRUM ANTI-VIRALS FIELD OF THE INVENTION [0001] The present invention provides methods and compounds for treating viral infections using modulators of host cell enzymes relating to long chain fatty acid and lipid droplet metabolism. It includes a method of treating viral infections using triacsin C and its relatives, analogues and derivatives as well as other inhibitors of long chain fatty acid metabolism and lipid droplet metabolism. STATEMENT OF GOVERNMENT INTEREST [0002] The invention was made with United States Government support under Grant Nos. AI068678 and CA85786 awarded by the National Institutes of Health. The Government has certain rights in this invention. BACKGROUND OF THE INVENTION [0003] There is a great unmet medical need for agents that more safely, effectively, and reliably treat viral infections, from HIV to the common cold. This includes a major need for better agents to treat human cytomegalovirus (where current agents suffer from significant toxicity and lack of efficacy), herpes simplex virus (where current agents are beneficial but provide incomplete relief), influenza A (where resistance to current agents is rampant), and hepatitis C virus (where many patients die from poor disease control). It further includes a major need for agents that work across a spectrum of viruses, facilitating their clinical use without necessarily requiring identification of the underlying pathogen. SUMMARY OF THE INVENTION [0004] The invention provides a method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is a compound of Formula I : wherein R1 is a carbon chain having from 3 to 23 atoms (including optional heteroatoms) in the chain, wherein the chain comprises 0-10 double bonds within the chain, and 0-4 heteroatoms within the chain, and wherein 0-8 of the carbon atoms of R1 are optionally substituted. If one or more optional heteroatoms occur within the R1 chain, in preferred embodiments each heteroatom is independently selected from O, S, and NR2, wherein R2 is Ci_ 1 selected from H, 6 alkyl, and C3 6 cycloalkyl. When the carbon atoms of R are substituted, it is preferred that from 0-8 hydrogen atoms along the chain may be replaced by a substituent selected from halo, OR2, SR2, lower alkyl, and cycloalkyl, wherein R2 is H, Ci_ alkyl, and C3-6 cycloalkyl. In certain preferred embodiments, R1 is unsubstituted (i.e., R1 is unbranched, and none of the hydrogens have been replaced by a substituent). In preferred embodiments for compounds of the formula I, R1 has a chain length of 8 to 12 atoms. More preferably, R1 has a total chain length of R1 has a chain length of 9 to 11 atoms. Most preferably R1 has a chain length of 10 atoms. In other preferred embodiments, R1 has 2 to 4 double bonds. In another embodiment of the invention, the compound of Formula I is a triacsin. In yet another embodiment of the invention, the compound of Formula I is triacsin C. In still another embodiment of the invention, the compound is an inhibitor of acyl-CoA synthetase long-chain family member 1 (ACSL1). In still another embodiment of the invention, the compound is an inhibitor of another enzyme inhibited by triacsin C, including without limitation arachidonoyl-CoA synthase or enzymes of triglyceride (TG) or cholesterol ester (CE) synthesis. [0005] Compounds of Formula I are broad spectrum antivirals useful for treating or preventing infection by a wide range of viruses. In one embodiment, the compounds of Formula I are used to treat or prevent viral infection by an enveloped virus. In certain embodiments of the invention, the compounds are used to treat or prevent infection by human cytomegalovirus (HCMV), herpes simplex virus- 1 (HSV-1), influenza A, or hepatitis C virus. [0006] The invention also provides a pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug; and a pharmaceutically acceptable carrier, wherein the compound is a compound of Formula I. [0007] In one embodiment, the invention provides a method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is a compound of formula V wherein X and Y are independently selected from N and CH; R i and R2' are independently selected from H, Ci_ alkyl which may be optionally substituted with F, OCH3 and OH, and Ci_6 cycloalkyl; Re and R are independently selected from H, and Ci_3 alkyl, or R6 and R taken together may form a C3-6 cycloalkyl, R3, R 4 and R are independently selected from H, Ci_6 alkyl which may be optionally substituted with F, OCH3 and OH, and Ci_6 cycloalkyl; additionally or alternatively, one of R6 or R may be taken together with R to form a C5-11 cycloalkyl ring. [0008] In one embodiment, the compound of formula V is avasimibe. In one embodiment the compound of formula V is an inhibitor of Acyl-CoA cholesterol acyltransferase (ACAT). [0009] In one embodiment, the invention provides a method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is selected from the group consisting of eflucimibe, pactimibe, Compound 1, Compound 21, Compound 12g, SMP-797, CL-283,546, and Wu-V-23. In one embodiment the compound inhibitor of Acyl-CoA cholesterol acyltransferase (ACAT). [0010] In one embodiment, the invention provides a method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is selected from the group consisting of PF- 1052, spylidone, rubimaillin, sespendole, terpendole C, Compound 7, Compound 8, Compound 9, vermisporin, beauveriolides, phenochalasins, isobisvertinol, and K97-0239. In one embodiment, the compound is PF-1052. In one embodiment, compound is spylidone. In one embodiment, the compound is rubimaillin. In one embodiment compound inhibits lipid droplet formation.
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