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(12) United States Patent (10) Patent No.: US 7.491,695 B2 Fraser Et Al

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(12) United States Patent (10) Patent No.: US 7.491,695 B2 Fraser Et Al USOO749 1695 B2 (12) United States Patent (10) Patent No.: US 7.491,695 B2 Fraser et al. (45) Date of Patent: *Feb. 17, 2009 (54) METHODS OF USING MACROCYCLIC S. Rudikoff, et al. Proc. Natl. Acad. Sci. USA (1982) 79, pp. 1979 MODULATORS OF THE GHRELIN 1983.* RECEPTOR J.-M. Cao et al. Trends Endocrin. Metab. (2006) 17(1), pp. 14-18.* Ahnfelt-Ronne et al. “Do Growth Hormone-Releasing Peptides Act (75) Inventors: Graeme L. Fraser, Québec (CA); as Ghrelin Secretagogues?” Endocrine 14(1): 133-135 (2001). Hamid R. Hoveyda, Québec (CA); Arcadi et al. “Electrophilic Cyclization of o-Acetoxy- and Mark L. Peterson, Québec (CA) o-Benzyloxyalkynylpyridines: An Easy Entry into 2,3-Disubsituted (73) Assignee: Tranzyme Pharma Inc., Quebec (CA) Furopyridines' Organic Letters 4(14): 2409-2412 (2002). Ariyasu et al. “Stomach is a Major Source of Circulating Ghrelin, and (*) Notice: Subject to any disclaimer, the term of this Feeding State Determines Plasma Ghrelin-Like Immunoreactivity patent is extended or adjusted under 35 Levels in Humans' The Journal of Clinical Endocrinology & U.S.C. 154(b) by 389 days. Metabolism 86(10): 4756-4758 (2001). Arvatet al. “Growth Hormone-Releasing Hormone and Growth Hor This patent is Subject to a terminal dis mone Secretagogue-Receptor Ligands' Endocrine 14(1): 35-43 claimer. (2001). (21) Appl. No.: 11/149,512 Backes et al. “Solid Support Linker Strategies' Current Opinion in Chemical Biology 1: 86-93 (1997). (22) Filed: Jun. 10, 2005 Baig et al. “Postoperative Ileus: A Review” Diseases of the Colon & Rectum 47: 516-526 (2002). (65) Prior Publication Data Baldanzi et al. “Ghrelin and des-acyl Ghrelin Inhibit Cell Death in US 2007/OO21331 A1 Jan. 25, 2007 Cardiomyocytes and Endothelial Cells through ERK1/2 and Pl 3-kinase/AKT The Journal of Cell Biology 159(6): 1029-1037 Related U.S. Application Data (2002). Baldwin et al. “Symbiotic Approach to Drug Design: (63) Continuation-in-part of application No. 10/872,142, Antihypertensive f3-Adrenergic Blocking Agents' Journal of Medici filed on Jun. 18, 2004. nal Chemistry 22(11): 1284-1290 (1979). (60) Provisional application No. 60/642.271, filed on Jan. Banks et al. “Extent and Direction of Ghrelin Transport Across the 7, 2005, provisional application No. 60/622,055, filed Blood-Brain Barrier Is Determined by its Unique Primary Structure” on Oct. 27, 2004, provisional application No. 60/621, The Journal of Pharmacology and Experimental Therapeutics 302: 642, filed on Oct. 26, 2004, provisional application No. 822-827 (2002). 60/479,223, filed on Jun. 18, 2003. Barreiro et al. “Developmental, State-Specific, and Hormonally (51) Int. Cl. Regulated Expression of Growth Hormone Secretagogue Receptor A6 IK 38/12 (2006.01) Messenger RNA in Rat Testis' Biology of Reproduction 68: 1631 CO7K 5/12 (2006.01) 1640 (2002). (52) U.S. Cl. ........................................... 514/9; 530/317 (Continued) (58) Field of Classification Search ....................... None See application file for complete search history. Primary Examiner Andrew DKosar (56) References Cited (74) Attorney, Agent, or Firm Myers Bigel Sibley & U.S. PATENT DOCUMENTS Sajovec, PA 6,548,501 B2 4/2003 Hakkinen 6,586,403 B1* 7/2003 Mathison et al. .............. 514/18 (57) ABSTRACT 6,852,722 B2 2/2005 Hakkinen FOREIGN PATENT DOCUMENTS The present invention provides novel conformationally-de EP 1 159964 12/2001 fined macrocyclic compounds that have been demonstrated to WO WOO1/25257 4/2001 be selective modulators of the ghrelin receptor (growth hor WO WO 04/111077 12, 2004 mone secretagogue receptor, GHS-R1a and Subtypes, iso WO WO 05/O12331 2, 2005 forms and variants thereof). Methods of synthesizing the WO WO 05/O12332 2, 2005 novel compounds are also described herein. These com OTHER PUBLICATIONS pounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medi W.-C. Qiu et al. J. Gastroenterol. (2008) 14(9), pp. 1419-1424.* J. Rudinger. In: Peptide Hormones, JA Parsons, Ed. (1976) 1-7.* cal conditions including, but not limited to, metabolic and/or D. Voet and J.G. Voet. Biochemistry, 2nd Edition.(1995), pp. 235 endocrine disorders, gastrointestinal disorders, cardiovascu 241.* lar disorders, obesity and obesity-associated disorders, cen D.E. Smilek, et al. Proc. Natl. Acad. Sci. USA (1991) 88, pp. 9633 tral nervous system disorders, genetic disorders, hyperprolif 9637.* erative disorders and inflammatory disorders. W.S. Messer, "Vasopressin and Oxytocin', web document updated Apr. 3, 2000; <http://www.neuroscipharm.utoledo.edu/MBC3320, vasopressin.htm>; 5 pages. 18 Claims, 21 Drawing Sheets US 7.491.695 B2 Page 2 OTHER PUBLICATIONS Adenosine 3', 3'-Monophosphate Production in Cells Expressing Transfected GHRH and GH Secretagogue Receptors' Endocrinol Barth et al. “Tailoring Ultraresins Based on the Cross-Linking of ogy 143(12): 4570-4582 (2002). Polyethylene Imines. Comparative Investigation of the Chemical Deghenghi et al. “GH-Releasing Activity of Hexarelin, A New Composition, the Swelling, the Mobility, the Chemical Accessibility, Growth Hormone Releasing Peptide. In iNfant and Adult Rats' Life and the Performance in Solid-Phase Synthesis of Very High Loaded Sciences 54(18): 1324-1328 (1994). Resins” Journal of Combinatorial Chemistry 6:340-349 (2004). Deghenghi et al. “Somatostatin Octapeptides (Lanreotide, Bedendietal. “cardiac Effects of Ghrelin and its Endogenous deriva Octreotide, Vapreotide, and their Analogs) Share the Growth Hor tives des-octanoyl Ghrelin and des-Gin'-ghrelin' European Journal mone-Releasing Peptide Receptor in the Human Pituitary Gland” of Pharmacology 476: 87-95 (2003). Endocrine 14(1): 29-33 (2001). Bednarek et al. "Structure-Function Studies on the New Growth Deghenghi et al. “Targeting the Ghrelin Receptor' Endocrine 22(1): Hormone-Releasing Peptide, Ghrelin: Minimal Sequence of Ghrelin 13-18 (2003). Necessary for Activation of Growth Hormone Secretagogue Recep Depoortere et al. “Interaction of the Growth Hormone-Releasing tor la” Journal of Medicinal Chemistry 43: 4370-4376 (2000). Peptides Ghrelin and Growth Hormone-Releasing Peptide-6 with the Birr et al. "Der O.C.-Dimethyl-3,5-dimethoxybenzyloxycarbonyl Motilin Receptor in the Rabbit Gastric Antrum” The Journal of (Ddz)-Rest, eine photo-undsäurelabile Stickstoff-Schutzgruppe für Pharmacology and Experimental Therapeutics 305: 660-667 (2003). die Peptidehemie” Liebigs Ann Chem 763: 162-172 (1972). Devi “Heterodimerization of G-Protein-Coupled Receptors: Phar Bossharth et al. “Palladium-Mediated Three-Component Sythesis of macology, Signaling and Trafficking Trends in Pharmacological FuroI2,3-bipyridones by One-Pot Coupling of 3-lodopyridones, Sciences 22(10): 532-537 (2001). Alkynes, and Organic Halides' Organic Letters 5(14): 2441-2444 Edholm et al. “Grehlin Stimulates Motility in the Small Intestine of (2003). Rats Through Intrinsic Cholinergic Neurons' Regulatory Peptides Bowers “Growth Hormone Releasing Peptides: Physiology and 121:25-30 (2004). Clinical Applications' Current Opinion in Endocrinology & Diabe Eggenweiler “Linkers for Solid-Phase Synthesis of Small Molecules: tes 7: 168-174 (2000). Coupling and Cleavage Techniques' DDT3(12): 552-560 (1998). Bowers et al. “Structure-Activity Relationships of a Synthetic Elias et al. “In Vitro Characterization of Four Novel Classes of Pentapeptide that Specifically Releases Growth Hormone in Vitro” Growth Hormone-Releasing Peptide' Endocrinology 136(12): 5694 Endocrinology 106(3): 663-667 (1980). 5699 (1995). Fehrentz et al. “Growth Hormone Secretagogues: Past, Present and Broglio et al. “Endocrine and Non-Edocrine Actions of Ghrelin' Future” Drugs 5(8): 804-814 (2002). Hormone Research 59: 109-117 (2003). Feighner et al. “Receptor for Motilin Identified in the Human Camannietal. “Growth Hormone-Releasing Peptides and Their Ana Gastrointestinal System” Science 284: 2184-2188 (1999). logs' Frontiers in Neuroendocrinology 19: 47-72 (1998). Frechet et al. “Use of Polymers as Protecting Groups in Organic Camilleri "Advances in Diabetic Gastroparesis' Reviews in Synthesis. II. Protection of Primary Alcohol Functional Groups” Gastroenterological Disorders 2(2): 47-56 (2002). Tetrahedron Letters 35: 3055-3056 (1975). Carlini et al. "Ghrelin Increases Anxiety-Like Behavior and Memory Fujino et al. “Ghrelin Induces Fasted Motor Activity of the Retention in Rats' Biochemical and Biophysical Research Commu Gastrointestinal Tract in Conscious Fed Rats' Journal of Physiology nications 299: 739-743 (2002). 550(1): 227-240 (2004). Carpino et al. “recent Developments in Ghrelin Receptor (GHS-R1a) Ghigo et al. “Orally Active Growth Hormone Secretagogues: State of Agonists and Antagonists' Expert Opinion in Ther: Patents 12(11): the Art and Clinical Perspectives' Trends in Clinical Practice. 1599-1618 (2002). Gross "A Concise Sterospecific Synthesis of Repinotan Carreira et al. "Agonist-Specific Coupling of Growth Hormone (BAYx3702)” Tetrahedron Letters 44: 8563-8565 (2003). Secretagogue Receptor Type 1a to Different Intracellular Signaling Halem et al. “Novel Analogs of Ghrelin: Physiological and Clinical Systems' Neuroendocrinology 79: 13-25 (2004). Implications' European Journal of Endocrinology 151: S71-S75 Casanueva et al. "Ghrelin: The Link Connection Growth with (2004). Metabolism and Energy Homeostatis” Reviews in Endocrine & Hansen, Jr. etal. “Chemoselective N-Ethylation of Boc Amino Acids Metabolic Disorders 3: 325-338 (2002). without Racemization” Journal of Organic Chemistry 50: 945-950 Cassoni et al. “Expression
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