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(12) United States Patent (10) Patent No.: US 8.258,308 B2 Castro Palomino Laria Et Al

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(12) United States Patent (10) Patent No.: US 8.258,308 B2 Castro Palomino Laria Et Al USOO82583.08B2 (12) United States Patent (10) Patent No.: US 8.258,308 B2 Castro Palomino Laria et al. (45) Date of Patent: Sep. 4, 2012 (54) AMINONICOTINIC AND ISONICOTINIC W W 388f $3. ACD DERVATIVES AS DHODH INHIBITORS WO WO 2004/056747 T 2004 WO WO 2005, O75410 8, 2005 (75) Inventors: Julio Cesar Castro Palomino Laria, WO WO 2006/OO1961 1, 2006 Barcelona (ES); Montserrat Erra Sola, WO WO 2006/022442 3, 2006 Barcelona (ES); Maria Estrella Lozoya W. W. 39: 38. Toribio, Barcelona (ES); Eloisa WO WO 2008/09718O 8, 2008 Navarro Romero, Barcelona (ES) WO WO 2009/021696 2, 2009 WO WO 2009,153O43 12/2009 (73) Assignee: Laboratorios Almirall, S.A., Barcelona WO WO 2010/083975 T 2010 (ES) WO WO 2010/102824 9, 2010 WO WO 2010/102825 9, 2010 (*) Notice: Subject to any disclaimer, the term of this W. W. 23 Sg 233.9 patent is extended or adjusted under 35 U.S.C. 154(b) by 50 days. OTHER PUBLICATIONS (21) Appl. No.: 12/520,237 Silverman, R. “The Organic Chemistry of Drug Design and Drug Action.” 2004, Elsevier, pp. 29-32.* (22) PCT Filed: Dec. 21, 2007 HCAPLUS 1972: 10360. Patani, G. et al., Chem. Rev. 1996, vol. 96, pp. 3147-3176.* (86). PCT No.: PCT/EP2007/011401 Silverman, R. “The Organic Chemistry of Drug Design and Drug Action.” 2004, Elsevier, p. 9.* S371 (c)(1), U.S. Appl. No. 12/529,490, filed Feb. 9, 2010, Laria et al. (2), (4) Date: Sep. 9, 2009 Baughman, RP et al. “Leflunomide for Chronic Sarcoidosis.” Clini cal Research, 21:43-48 (2004). (87) PCT Pub. No.: WO2008/077639 Breedveld, FC et al. “Leflunomide: Mode of Action in the Treatment of Rheumatoid Arthritis.” Annals of the Rheumatic Diseases, 59: PCT Pub. Date: Jul. 3, 2008 841-849 (2000). (65) Prior Publication Data (Continued) US 201O/OO74898A1 Mar. 25, 2010 Primary Examiner — Janet Andres (30) Foreign Application Priority Data Assistant Examiner — Heidi Reese (74) Attorney, Agent, or Firm — Finnegan, Henderson Dec. 22, 2006 (ES) ................................... 20060325O Farabow, Garrett & Dunner, LLP Apr. 23, 2007 (ES) ................................... 2007O1086 (51) Int. Cl. (57) ABSTRACT C 242 3.08: The present disclosure relates to compounds of formula (I): CO7D 42L/00 (2006.01) A6 IK3I/44 (2006.01) Formula (I): (52) U.S. Cl. ..................... 54.6/318; 546/326; 546/268.1; 514/332 2. 2 (58) Field of ClassificationO A O Search ........................ None W -R See application file for complete search history. S. Gl (56) References Cited Ra \ s Gl U.S. PATENT DOCUMENTS Hin Z 5,780,592 A 7/1998 Müllner et al. O N 7,071,222 B2 7/2006 Bartlett et al. R 7,258,118 B2 8, 2007 Goede et al. MN N3 2003/0004171 A1 1/2003 Humphrey et al. O f 2006/0081246 A1 4/2006 Goede et al. G4 2011/0129445 A1 6/2011 Godessart Marina et al. Ca FOREIGN PATENT DOCUMENTS R1 EP O 780 128 6, 1997 WO WO97,34600 1, 1997 or a pharmaceutically acceptable salt or N-oxide thereof. W. W. S. 3E The present disclosure also relates to pharmaceutical compo WO WOOOf 76489 12/2000 sitions comprising the compounds of formula (I), and to their WO WO O2/O8O897 10, 2002 methods of use in therapy. WO WOO3,OOO325 1, 2003 WO WOO3,OO6425 1, 2003 WO WOO3,061742 T 2003 26 Claims, No Drawings US 8,258,308 B2 Page 2 OTHER PUBLICATIONS Gu, L. et al., “Preformulation Salt Selection. Physical Property Com parisons of the Tris (Hydroxymethyl) Aminomethane (THAM) Salts Dexter, DL et al. "Activity of a Novel 4-Quinolinecarboxylic Acid, of Four Analgesic/Anti-inflammatory Agents with the Sodium Salts NSC 3683906-Fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4- and the Free Acids.' Pharmaceutical Research, Kluwer Academic quinolinecarboxylic Acid Sodium Salt, against Experimental Publishers, New York, NY. vol. 4, No. 3, Jan. 1, 1987, pp. 255-257, Tumors.” Cancer Research, 45: 5563-5568 (Nov. 1985). XP0020993.48, ISSN: 0724-8741. Dimitrova, P. et al. “Restriction of DeNovo Primidine Biosynthesis International Search Report for International Application No. PCT/ Inhibits Th1 Cell Activation and Promotes Th2 Cell Differentiation.” EP2010/00 1549 dated May 31, 2010. The Journal of Immunology, 169:3392-3399 (2002). International Search Report for International Application No. PCT/ Fox, RI “Mechanism of Action of Leflunomide in Rheumatoid Arthritis.” The Journal of Rheumatology, 25, Supplement 53:20-26 EP2010/00 1548 dated Nov. 18, 2010. (1998). International Search Report for International Application No. PCT/ Haibel, J. et al. "Six Month Open Label Trial of Leflunomide in EP2010/001550 mailed Apr. 23, 2010. Active Ankylosing Spondylitis.” Annals of the Rheumatic Diseases, Stahl, PH. et al., “Tromethamine', Handbook of Pharmaceutical 64: 124-126 (2005). Salts Properties, Selection and Use, Jan. 1, 2002, pp. 324-325, International Search Report mailed Oct. 20, 2008, for International XPOO2214621. Application No. PCT/EP2008/006573 (WO 2009/021696). U.S. Appl. No. 12/999,698, filed Dec. 17, 2010, Godessart Marina et John, GT et al. “Leflunomide Therapy for Cytomegalovirus Disease al. in Renal Allograft Recipients.” Transplantation, 77(9): 1460-1461 U.S. Appl. No. 13/145,628, filed Jul. 21, 2011, Godessart Marina et (2003). al. Liu, S. etal. “Structures of Human Dihydroorotate Dehydrogenase in ClinialTrials.gov Identifier: NCT00637819, Sanofi-Aventis, Double Complex with Antiproliferative Agents.” Structure, 8(1): 25-33 blind, randomized, placebo controlled pilot study of leflunomide in (2000). systemic lupus erythematosus (SLE) (2008). Löffler, M. et al. “Dihydroorotat-ubiquinone oxidoreductase links International Search Report mailed Jul. 31, 2009, for International mitochondria in the biosynthesis of pyrimidine nucleotides.” Application No. PCT/EP2009/004404 (WO 2009/153043). Molecular and Cellular Biochemistry, 174: 125-129 (1997). International Search Report mailed Apr. 16, 2010, for International Manna, SK et al. “Leflunomide Suppresses TNF-Induced Cellular Application No. PCT/EP2010/000270 (WO 2010/083975). Responses: Effects on NF-kappaB. Activator Protein-1, c-Jun Kremer, JM "Methotrexate and leflunomide: Biochemical basis for N-Terminal Protein Kinase, and Apoptosis.” Journal of Immunology, combination therapy in the treatment of rheumatoid arthritis.” Semi 165:5962-5969 (2000). nars in Arthritis and Rheumatism, 29(1): 14-26 (1999). McRobert, L. et al. “RNA Interference (RNAi) Inhibits Growth of Kremer, JM “Concomitant Leflunomide Therapy in Patients with Plasmodium falciparum," Molecular & Biochemical Parasitology, Active Rheumatoid Arthritis despite Stable Doses of Methotrexate.” 19:273-278 (2002). Annals of Internal Medicine, 137(9): 726-733 (2002). Metzler, C. et al. “Maintenance of Remission with Leflunomide in Kulkarni, OP et al. “4SC-101, A Novel Small Molecule Wegener's Granulomatosis.” Rheumatology, 43:315-320 (2004). Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Miyaura, N. et al. “Palladium-Catalyzed Cross-Coupling Reactions Lupus Erythematosus in MRL-(Fas)lpr Mice.” The American Journal of Organoboron Compounds.” Chemical Reviews, 35:2457-2483 of Pathology, 176(6): 2840-2847 (2010). (1995). Leban, J. etal. "Biphenyl-4-ylcarbamoylthiophene carboxylic acids O'Connor, PW et al. “A Phase II Study of the Safety and Efficacy of as potent DHODH inhibitors.” Bioorganic & Medicinal Chemistry Teriflunomide in Multiple Sclerosis with Relapses.” Neurology, Letters, 16(2): 267-270 (2006). 66:894-900 (2006). Majithia, V. et al. “Successful Treatment of Sarcoidosis with Schläpfer, E. etal. "Anti-HIV-1 Activity of Leflunomide: a Compari Leflunomide.” Rheumatology, 42: 700-702 (2003). son with Mycophenolic Acid and Hydroxyurea.” AIDS, 17(11): Mehta, V. etal. “Leflunomide.” Indian J. Dermatol. Venereol. Leprol. 1613-1620 (2003). 75(4): 422-425 (2009). Silverman, E. et al. “Long-Term Open-Label Preliminary Study of Sanders, S. et al. “Leflunomide for the Treatment of Rheumatoid the Safety and Efficacy of Leflunomide in Patients with Polyarticular Arthritis and Autoimmunity.” American Journal of the Medical Sci Course Juvenile Rheumatoid Arthritis.” Arthritis & Rheumatism, ences, 323(4): 190-103(2002). 52(2): 554-562 (2005). Tlacuilo Parra, JA et al. “Leflunomide in the treatment of psoriasis: Urushibara, M. etal. “The Antirheumatic Drug Leflunomide Inhibits results of a phase II open trial.” British Journal of Dermatology, 150: Osteoclastogenesis by Interfering With Receptor Activator of NF-kB 970-976 (2004). Ligand-Stimulated Induction of Nuclear Factor of Activated T Cells Weinblatt, ME et al. "Pharmacokinetics, safety, and efficacy of com c1.” Arthritis & Rheumatism, 50(3): 794-804 (2004). bination treatment with methotrexate and leflunomide in patients English Language Derwent Abstract for WO 06/022442 (Mar. 2, with active rheumatoid arthritis.” Arthritis & Rheumatism, 42(7): 2006). 1322-1328 (Jul 1999). English Language Caplus Abstract for Spano, R. et al. "Preparation U.S. Appl. No. 13/501,847, filed Apr. 13, 2012, Boix Bernardini. and pharmacology of Some derivatives of 2-aminonicotinic.” International Search Report for International Application No. PCT/ Farmaco, Edizione Scientifica, Societa Chimica Italiana, Pavia, IT, EP2010/006283 (WO 2011/045059) dated Nov. 12, 2010. 26(9): 844-849 (1971). Batt, Douglas G., “Inhibitors of dihydroorotate dehydrogenase.” Spano, R. et al. "Preparation and pharmacology of some derivatives Expert Opinion on Therapeutic Patents, 9(1):41-54 (1999). of 2-aminonicotinic,” Farmaco, Edizione Scientifica, Societa Vyas, V. 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