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(12) United States Patent (10) Patent No.: US 8.436,005 B2 Liu Et Al

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(12) United States Patent (10) Patent No.: US 8.436,005 B2 Liu Et Al USOO8436005B2 (12) United States Patent (10) Patent No.: US 8.436,005 B2 Liu et al. (45) Date of Patent: May 7, 2013 (54) MACROCYCLIC PYRIMIDINEDERIVATIVES WO WOO 170673 A2 9, 2001 WO WOO23O890 A1 4, 2002 (75) Inventors: Egyal y Risi, WO WO2004.056784WO2004 103992 A1 12/2004T 2004 rene Drizin, Wadsworth, (US); John WO WO2005O14556 A1 2/2005 R. Koenig, Chicago, IL (US); Marlon WO WO2005040159 A1 5/2005 D. Cowart, Round Lake Beach, IL (US); WO WO2005040 167 A1 5, 2005 Chen Zhao, Libertyville, IL (US); Brian W W888. A. g: D. Wakefield, Vernon Hills, IL (US); WO WO2005082855 A1 9, 2005 Lawrence A. Black, Libertyville, IL WO WO2005097794 A1 10/2005 (US); Robert J. Altenbach, Chicago, IL WO WO2006021544 A1 3f2006 (US) WO WO2006040281 4/2006 WO WO2006O48750 A2 5, 2006 (73) Assignee: Abbott Laboratories, Abbott Park, IL WO WO20081.00565 A1 8/2008 (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Cowart et al. (Journal of Medicinal Chemistry (2008), 51(20), 6547 patent is extended or adjusted under 35 U.S.C. 154(b) by 415 days. 6557). Akdis, C., et al., “Histamine Receptors Are Hot in (21) Appl. No.: 12/413,168 Immunopharmacology.” European Journal of Pharmacology, 2006, vol. 533, pp. 69-76. (22) Filed: Mar. 27, 2009 Anquetin, G., et al., “Design, Synthesis and Activity Against Toxoplasma gondii, Plasmodium Spp., and Mycobacterium tubercu (65) Prior Publication Data losis of New 6-fluoroquinolones.” European Journal of Medicinal Chemistry, 2006, vol. 41 (12), pp. 1478-1493. US 2009/O2.53678A1 Oct. 8, 2009 Baas, J., et al., “Vitamin A Analogues. IV. Attempted Synthesis of 2,4,4-trimethyl-tetrahydrothiopyrone-3.” Tetrahedron, 1966, vol. 22 Related U.S. Application Data (1), pp. 285-291. Becker, D., et al., “A Short Synthesis of 1-Azaadamantan-4-One and (60) Provisional application No. 61/042,110, filed on Apr. the 4r and 4s Isomers of 4-Amino-1-AZaadamantane. Synthesis, 3, 2008. 1992, vol. 11, pp. 1080-1082. Bell, J., et al., “Involvement of Histamine H and H. Receptors in (51) Int. Cl. Scratching Induced by Histamine Receptor Agonists in BalbC Mice.” CO7D 403/04 (2006.01) British Journal of Pharmacology, 2004, vol. 142, pp. 374-380. CO7D40 L/04 (2006.01) Bennett, G., et al., “A Peripheral Mononeuropathy in Rat that Pro A 6LX3/57 (2006.01) duces Disorders of Pain Sensation like those Seen in Man.’ Pain, 1988, vol. 33 (1), pp. 87-107. (52) U.S. Cl. Bergmann, D., et al., “High Yields of Diazabicycloalkanes and USPC .................... 514/266.2: 514/266.23: 544/253 Oxazabicycloalkanes Containing Medium and Large Rings From (58) Field of Classification Search .................. 544/253; Rhodium-Catalysed Hydroformylation Reactions Without the Need 514/266.2, 266.23 for High Dilution Conditions.” Chemical Communications, 1999, See application file for complete search history. vol. 14, pp. 1279-1280. Blazejewski, J., et al., “Condensation of Alphabeta-Unsaturated (56) References Cited Amines with Perfluoroarenes,” Journal of the Chemical Society, 1980, pp. 2845-2850. U.S. PATENT DOCUMENTS Buckland, K., et al., “Histamine Induces Cytoskeletal Changes in 2.932,650 A 4/1960 Cope et al. Human Eosinophils via the H. Receptor.” British Journal of Pharma 3,247.206 A 4, 1966 Yost et al. cology, 2003, vol. 140, pp. 1117-1127. 3,299,068 A * 1/1967 Chinn ........................... 544,253 3,322,759 A 5, 1967 James et al. (Continued) 5,252,747 A 10, 1993 Chu et al. 5,442,044 A 8, 1995 Hoover et al. 2005, OO84446 A1 4/2005 Schmitt et al. Primary Examiner — Bruck Kifle 2005/01016O2 A1 5, 2005 Basha et al. (74) Attorney, Agent, or Firm — Lisa V. Mueller; Michael 2006, O199851 A1 9/2006 Kempfet al. 2008. O194538 A1 8, 2008 Cowart et al. Best & Friedrich LLP 2008. O194577 A1* 8, 2008 Cai et al. .................. 514, 252.14 2010/0298.289 A1 * 1 1/2010 Raphy et al. ............. 514,210.21 (57) ABSTRACT FOREIGN PATENT DOCUMENTS DE 2155671 C3 12/1981 Macrocyclic pyrimidine compounds, compositions compris DE 3726.908 A1 2, 1989 ing Such compounds, methods for making the compounds, EP 202062 A2 11, 1986 and methods of treating and preventing the progression of JP 2001O399.50 2, 2001 WO WO92O3415 3, 1992 diseases, conditions, and disorders using Such compounds WO WO9510519 4f1995 and compositions are described herein. WO WO9623782 8, 1996 WO WO9921855 A1 5, 1999 WO WO9940070 8, 1999 10 Claims, No Drawings US 8,436,005 B2 Page 2 OTHER PUBLICATIONS Einsiebel, J., et al., “Stereocontrolled Dopamine Receptor Binding Caubere, P. et al., “Condensations Aryniques D'enolates de and Subtype Selectivity of Clebopride Analogues Synthesized from Cetones.” Bulletin de la Societe Chimique de France, 1974, pp. Aspartic Acid.” Bioorganic & Medicinal Chemistry Letters, 2003, 1415-1420. vol. 13 (19), pp. 3293-3296. Chaplan, S., et al., “Quantitative Assessment of Tactile Allodynia in Esbenshade, T., et al., “Pharmacological and Behavioral Properties of the Rat Paw,” Journal of Neuroscience Methods, 1994, vol. 53, pp. A-349821, a Selective and Potent Human Histamine H. Receptor 55-63. Antagonist.” Biochemical Pharmacology, 2004, vol. 68 (5), pp. 933 Cianchi. F., et al., “The role of Cyclooxygenase-2 in Mediating the 945. 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The Preparation of Coudert, G., et al., “Synthesis of 2-(2-Oxoalkyl)-quinolines and 4-(2- 2-Arylcycloheptanones and 2-Aryl-2-Cycloheptenones.” Journal of Oxoalkyl)-quinolines.” Synthesis, 1976, vol. 11, pp. 764-766. the American Chemical Society, 1956, vol. 78, pp. 1184-1187. Crabb, T., et al., “Proton Magnetic Resonance Studies of Compounds Gutzmer, R., et al., “Histamine H4 Receptor Stimulation Suppresses with Bridgehead Nitrogen Atoms XII".” Tetrahedron, 1970, vol. IL-12p70 Production and Mediates Chemotaxis in Human 26, pp. 1217-1233. Monocyte-derived Dendritic Cells,” Journal of Immunology, 2005, Cross, L., et al., “IUPAC Commission on Nomenclature of Organic vol. 174 (9), pp. 5224-5232. Chemistry: Rules for the Nomenclature of Organic Chemistry, Sec Hamana, M., et al., “Studies on Tertiary Amine Oxides. XXXVII.) tion E: Stereochemistry.” Pure and Applied Chemistry, 1976, vol. 45, Reactions of Aromatic N-Oxides with Enol Ethers in the Presence of pp. 11-30. Benzoyl Chloride.” Chemical & Pharmaceutical Bulletin, 1970, vol. Culbertson, T., et al., “Quinolone Antibacterial Agents Substituted at 18 (1), pp. 26-31. the 7-position With Spiroamines. Synthesis and Structure-Activity Han. X., et al., “Palladium-Catalyzed Intramolecular Hydroalkyla Relationships,” Journal of Medicinal Chemistry, 1990, vol. 33 (8), tion of Alkenyl-B-Keto Esters, C.-Aryl Ketones, and Alkyl Ketones in pp. 2270-2275. the Presence of MeSiC1 or HCL.” European Journal of Organic Database Beilstein Beilstein Institute for Organic Chemistry, Frank Chemistry, 2004, vol. 10 (24), pp. 6333-6342. furt-Main, DE; 1946, Database accession No. BRN: 25240 N4-(2- Hanus, V., et al., “Stereoelectronic Effects on the Fragmentation of diethylamino-ethyl)-5,6,7,8-tetrahydro-quinazoline-2,4- 2.9-Diazabicyclo[4.4.0Decame Derivatives.” 1984, vol. 19 (9), pp. diyldiamine. 459-460. Database Beilstein Beilstein Institute for Organic Chemistry, Frank Higuchi, T., et al., “Pro-Drugs as Novel Drug Delivery Systems.” furt-Main, DE; 1946, Database accession No. BRN: 26451 N4-(3- American Chemical Society, 1975, Table of Contents. diethylamino-propyl)-5,6,7,8-tetrahydro-quinazoline-2,4- Honore, P. et al., “Interleukin-1 of Gene-Deficient Mice Show diyldiamine. Reduced Nociceptive Sensitivity in Models of Inflammatory and Database Beilstein Beilstein Institute for Organic Chemistry, Frank Neuropathic Pain but not Post-Operative Pain.” Behavioural Brain furt-Main, DE; 1946, XP002531327 Database accession No. BRN: Research, 2006, vol. 167 (2), pp. 355-364. 31092N4-(4-diethylamino-1-methyl-butyl)-5,6,7,8-tetrahydro Horner, L., et al., “Zur Kenntnis Der Elektroreduktiven Spaltungder quinazoline-2,4-dlyldiamine. N N-Bindung 2.” Justus Liebigs Annalender Chemie, 1978, vol. 9, Database Beilstein Beilstein Institute for Organic Chemistry, Frank pp. 1505-1517. furt-Main, DE; 1986, Database accession No. BRN: 5694631 CAS Huang, et al..."The Reaction of 2-chlorocyclohexanone with RN: 111896-83-44-Piperazin-1-yl-5,6,7,8-tetrahydro-quinazolin-2- Grignard Reagents and the Rearrangement of the Resulting ylamine; compound with(Z)-but-2-enedioic acid.
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