USOO6660832B1 (12) United States Patent (10) Patent No.: US 6,660,832 B1 Jefferson et al. (45) Date of Patent: Dec. 9, 2003 (54) MACROCYCLIC COMPOUNDS AND Bilodeau, M.T., et al., “Solid-Supported Synthesis of Imi PREPARATION METHODS THEREOF dazoles: A Stragegy for Direct Resin-Attachment to the Imidazole Core", J. Org. Chem., 1998, 63, 2800–2801. (75) Inventors: Elizabeth Jefferson, La Jolla, CA (US); Block, L., “Medicated Applications”, Remington's Pharma Eric Edward Swayze, Carlsbad, CA ceutical Sciences, 18th Ed., Gennaro (ed.), Mack Publishing (US) Co., Easton, PA, 1990, Ch. 87, 1596–1614. Bodanszky, M., et al., “Side Reactions in Peptide Synthesis. (73) Assignee: ISIS Pharmaceuticals, Inc., Carlsbad, 11. Possible Removal of the 9-Fluorenylmethyoxycarbonyl CA (US) Group by the Amino Components during Coupling, J. Org. Chem., 1979, 44, 1622–1625. (*) Notice: Subject to any disclaimer, the term of this Bomann, et al., “A Mild, Pyridine-Borane-Based Reductive patent is extended or adjusted under 35 Amination Protocol”, J. Org. Chem., 1995, 60,5995-5996. U.S.C. 154(b) by 0 days. Cheung, S.T., et al., “N-Methylamino acids in peptides Synthesis. VI. A method for determining the enantiomeric (21) Appl. No.: 09/378,529 purity of N-methylamino acids and their derivatives by ion-exchange chromatography as their C-terminal lysyl (22) Filed: Aug. 20, 1999 dipeptides”, Can. J. Chem., 1977, 55,911–915. (51) Int. Cl." .................................................. C07K 7/50 Chow, C.S., et al., “A Structural Basis for RNA-Ligand (52) U.S. Cl. ........................... 530/317; 514/11; 514/19; Interactions”, Chem. Rev., 1997, 97, 1489–1514. 514/159 Coste, J., et al., “Oxybenzotriazole Free Peptide Coupling (58) Field of Search ................................. 530/454, 474, Reagents for N-Methylated Amino Acids”, Tetrahedron Lett., 1991, 32, 1967-1970. 530/450, 317; 514/183, 11, 19 Coste, J., et al., “BROP: A New Reagent for Coupling (56) References Cited N-Methylated Amino Acids”, Tetrahedron Lett., 1990, 31, 669-672. U.S. PATENT DOCUMENTS Egorov, M.P., et al., “Some Aspects of Anionic O Com 3.687,808 A 8/1972 Merigan et al. ........... 435/91.3 plexes”, Chem. Rev., 1982, 82, 427–459. 5,741,462 A 4/1998 Nova et al. ................ 422/68.1 Enantioselective Synthesis of Beta-Amino Acids, Juarish, 5,751,629 A 5/1998 Nova et al. ................. 365/151 E., John Wiley & Sons, New York, N.Y. 1997. 5,770,455 A 6/1998 Cargill et al. ..... ... 436/518 Englisch, U., “Chemically Modified Oligonucleotides as 5,874.214 A 2/1999 Nova et al. .................... 435/6 Probes and Inhibitors', Angew. Chem. Int. Ed. Eng., 1991, 5,925,562 A 7/1999 Nova et al. .............. 435/287.1 30, 613-629. Feng, Y., et al., SNAr Cyclizations To Form Cyclic Pepti OTHER PUBLICATIONS domimetics of B-Turns, J. Am. Chem. Soc., 1998, 120, Corriveau Infectious Agents and Disease 2, 44-52, 1993.* 10768-10769. Gavini, Archiv der Pharmazie 333 (10) 341 6, 2000.* (List continued on next page.) Fudou, Journal of Antibiotics 54 (2) 149–52, 2001.* Juvvadi Journal of Peptide Research 53 (3) 244-51, 1999.* Primary Examiner-Christopher S. F. Low Avrahami, Biochemistry 40 (42) 12591-603, 2001.* ASSistant Examiner David Lukton Otvos, Protein Science 9 (4) 742–9, 2000.* (74) Attorney, Agent, or Firm Woodcock Washburn LLP Jefferson et al., Beta-Amino Acid Facilitates Macrocyclic (57) ABSTRACT Ring Closure in a Combinatorial Library, Tetrahedron Let ters, 40, pp. 7757-7760, 1999.* The present invention is directed to macrocyclic compounds Boggetto et al., Cyclic Peptides as Selective Substrates and of the formula (I) Suicide Substrate Precursors of Trypsin-like proteinases, Bull. Chim. Fr., 36(11), pp. 152–166, 1994.* (I) Feng et al., SNAr Cyclization to Form Cyclic Peptidomi metics of Beta-turns., J. Am. Chem. Soc., 120(41), pp. 10768-10769, 1998.* HN Kiselyov et al., Tetrahedron, 54 pp. 10635-10640, 1998.* Rama Rao et al., Chem. Rev., 95, pp. 2135-2167, 1995.* Marsh et al., J. Org. Chem., 62, pp. 6199-6202, 1997.* Angell, Y.M., et al., “Comparative Studies of the Coupling of N-Methylated, Sterically Hindered Amino Acids During Solid-Phase Peptide Synthesis”, Tetrahedron Lett., 1994, 35,5981-5984. Balasubramanian, S., et al., “Solid Phase Reductive Alky wherein Q, X, R and Rs are as defined herein. Compounds lation of Secondary Amines”, Tetrahedron Lett., 1996, 37, of the invention are useful for therapeutic and prophylactic 4819-4822. treatment of bacterial infection in mammals. Solid phase Beugelmans, R., et al., “The First Examples of Snar-based Synthetic procedures are provided effecting Synthesis of the Macrocyclisation: Synthesis of Model Carboxylate-Binding macrocyclic rings attached to a Solid Support. Pockets of Vancomycin, J. Chem. Soc., Chem. Commun., 1994,439. 31 Claims, 7 Drawing Sheets US 6,660,832 B1 Page 2 OTHER PUBLICATIONS Pearson, N.D. and Prescott, C.D., “RNA as a drug target', Fivush, A.M., et al., “AMEBA: An Acid Sensitive Aldehyde Chem. Biol., 1997, 97(4), 409–414. Resin for Solid Phase Synthesis”, Tetrahedron Lett., 1997, Pelter, A., et al., “Reductive Aminations of Ketones and 38, 7151-7154. Aldehydes using Borane-Pyridine”, J. Chem. Soc., Perkins Greene, T.W. and Wuts, P.G.M., Protective Groups in Trans I, 1984, 717–720. Organic Synthesis, 2" Ed., John Wiley & Sons, New York, Rama Rao, A.V., et al., “S.Ar Macrycyclisation: A New N.Y. 1991. Approach Towards the Synthesis of D-O-E Segment of Guichard, G., et al., “Preparation of N-Fmoc-Protected vancomycin, Tetrahedron lett., 1997, 38(42), 7433–7436. B°-and B-Amino Acids and Their Use as Building Blocks for the Solid-Phase Synthesis of B-Peptides”, Hell: Chem. Rama Rao, A.V., et al., “Studies Directed toward the Syn Acta., 1998, 81, 187-206. thesis of Vancomycin and Related Cyclin Peptides”, Chem. Hermann, T., “RNA as a drug target: chemical, modelling, Rev., 1995, 95, 2135-2167. and evolutionary tools”, Curr. Opin. Biotech., 1998, 9, Rich, D.H., “Bis(2-oxo-3-oxazolidinyl)phosphinic Chlo 66-73. ride (1) as a Coupling Reagent for N-Alkyl Amino Acids, Kearney, P.C., et al., “Solid-Phase Synthesis of 2-Ami J. Am. Chem. Soc., 1985, 107, 4342–4343. nothiazoles”, J. Org. Chem., 1998, 63, 196-200. Kiselyov, et al., “Solid Support Synthesis of 14-Membered Rudnic, E. et al., “Oral Solid Dosage Forms”, Remington's Macrocyles Containing the Thioether Bridge via SNAr Pharmaceutical Sciences, 18th Ed., Gennaro (ed.), Mack Methodology”, Tetrahedon, 1998, 54, 10635-10640. Publishing Co., Easton, PA, 1990, Ch. 89, 1633–1665. Kroschwitz, J.I., “Polynucleotides”, Concise Encyclopedia Sarantakis, et al., “Solid Phase Synthesis of Sec-Amides of Polymer Science and Engineering, 1990, John Wiley & and Removal from the Polymeric Support Under Mild Sons, New York, 858-859. Conditions”, Tetrahedron Lett., 1997, 38, 7325-7328. Longer, M. A. et al., “Sustained-Release Drug Delivery Swayze, E., “Secondary Amide-based Linkers for Solid Systems”, Remington's Pharmaceitucal Sciences, 18th Ed., Phase Organic Synthesis”, Tetrahedron Letters, 1997, Gennaro (ed.), Mack Publishing Co., Easton, PA, 1990, Ch. 38(49), 8465–8468. 91, 1676–1693. Marsh, I.R., et al., “Solid-Phase Total Synthesis of Oscil Wallis, M.G., et al., “The Binding of Antibiotics to RNA", lamide Y and Analogues”, J. Org. Chem., 1997, 62, Prog. Biophys. Molec. Biol., 1997, 67, 141–154. 61.99-62O3. Wei, G.P., et al., “Solid Phase Synthesis of Benzimidazolo McClinton, M.A., “Triethylamine Tris(hydrogen fluoride): nes”, Tetrahedron Letts., 1998, 39, 179-182. Applications in Synthesis”, Aldrichimica Acta, 1995, 28, Wenger, R.M., “270. Synthesis of Cyclosporine', Hell: 31-35. Meire, “The Woff Rearrangement of C-Diazo Carbonyl Chem. Acta., 1983, 66, 2672-2702. Compounds”, Angew. Chem. Int. Ed. Engl. 1975, 14, 32-43. Yoon, N.M., et al., “Selective Reductions. XIX. The Rapid Michael, K., “Designing Novel RNA Binders”, Chem. Eur: Reaction of Carboxylic Acids with Borane-Tetrahydrofu J., 1998, 4, 2091-2098. ran. A Remarkably Convenient Procedure for the Selective Moormann, A.E., “Reductive Amination of Piperidines with Conversion of Carboxylic Acids to the Corresponding Alco Aldehydes Using Borane-Pyridine', Synth. Commun., 1993, hols in the Presence of Other Functional Groups', J. Org. 23, 789-795. Chem., 1973, 38, 2786-2792. Nairn, et al., “Solutions, Emulsions, Suspensions and Boggetto, et al., “Cyclic peptides as Selective Substrates and Extracts”, Remington's Pharmaceutical Sciences, 18th Ed., Suicide Substrate precursors of trypsin-like proteinases,” Gennaro (ed.), Mack Publishing Co., Easton, PA, 1990, Ch. Bull. Soc. Chim. Fr., 1994, 131, 152–166. 83, 1519–1544. Nurgatin, et al., “Investigations in the 2,4,6-Trinitrothiophe Chemical Abstracts, 119(13), 1993, Columbus, OH, USA), nol Series. ... ", J. Org. Chem. USSR, 1983, 19, 343–346. 944; col. 1, the abstract No. 139765x, Wakselman, M., “New Ouyang, et al., “Solid Support Synthesis of 2-Substituted mechanism-based inactivators of trypsin-like proteinases,” Dibenzb,floxazepin-11(10H)-ones via S.Ar Methodology J. Med. Chem., 1993, 36(11), 1539–1547. on AMEBA Resin', Tetrahedron, 1999, 55, 2827–2834. Jefferson, E.A., et al., “B-amino acid facilitates macrocyclic Paradisi, C., “Arene Substitution via Nucleophilic Addition ring closure in a combinatorial library,” Tetra. Letts., 1999, to Electron Deficient Arenes”, Comprehensive Organic Syn 40, 7757-7760. thesis, Trost, B.M., et al., eds., Pergamon Press: Oxford, 1991, vol. 4, pp. 423–450. * cited by examiner U.S. Patent Dec. 9, 2003 Sheet 1 of 7 US 6,660,832 B1 R R b, C R d R ef ornoTBDMS Y---OH - - - loTBDMS -----OTBDMS - y - - R-M2 N ON ONo. O NH la-h 2a-h R- R 3 a Y: Emoc moC xNHFmoc ---- I - 3a-h 4-a-h ON R OTBDMS R R O h R2 O NS k R2 ŠO N-1S 9 R R4 HNOO,--Rs - - - HNO o, 1Rs O= F r NH NH y \ .