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(12) United States Patent (10) Patent No.: US 6,979,750 B1 Scanlan Et Al USOO697975OB1 (12) United States Patent (10) Patent No.: US 6,979,750 B1 Scanlan et al. (45) Date of Patent: Dec. 27, 2005 (54) THYRONAMINEDERIVATIVES AND Cote, P., et al., “Thyronamine, a new inotropic agent: its ANALOGS AND METHODS OF USE cardiovascular effects and mechanism of action', THEREOF Cardiovascular Res. 8: 721-730, 1974. Dratman, M., “On the Mechanism if Action of Thyroxin, an (75) Inventors: Thomas S. Scanlan, San Francisco, CA Amino Acid Analog of Tyrosine”, J. theor: Biol., 46: 255 (US); Matthew E. Hart, San Francisco, 270, 1974. CA (US); David K. Grandy, Portland, Han, et al., “Synthesis of side chain-modified OR (US); James R. Bunzow, Portland, idothyronines”, Int. J. Peptide Protien Res., 30: 652-661, OR (US) 1987. Rozanov, C.B., et al., “Immunohistochemical Mapping of (73) Assignees: The Regents of the University of Brain Triiodothyronine Reveals Prominent Localization in California, Oakland, CA (US); Oregon Central Noradrenergic Systems”, Neuroscience, 74: 897 Health & Science University, Portland, 915, 1996. OR (US) Tomita, K., et al., “Synthesis and Biological Activity of Some Triiodinated Analogues of Thyroxine”, J. Biol. Chem. (*) Notice: Subject to any disclaimer, the term of this 219: 595-604, 1956. patent is extended or adjusted under 35 Biondi, B., et al., “Effects of Subclinical Thyroid Dysfunc U.S.C. 154(b) by 82 days. tion on the Heart', Ann Intern Med., 137: 904-914, 2002. Thibault, O., “Recherhes Sur la nature de la <<thyroxine (21) Appl. No.: 10/418,399 active>> . Renforcement immediate parla thyroxamine des effets de I adrénaline Sur divers muscles lisses', 1951 C.R. (22) Filed: Apr. 18, 2003 SOc. Chim. biol., 797-800. Meyer, T, et al., “Triiodothyronamine- A Beta-adrenergic (51) Int. Cl." ....................... C07C 211/27; A61K 31/35 Metabolite of Triiodothyronine?”, Horm. metabol. Res. 15: (52) U.S. Cl. ....................................... 564/374; 514/654 602-606, 1983. (58) Field of Search ................................ 564/355,374; Buu Hoi; N.P. et al., “Some Biological Effects of 514/654 Thyronamine”, Med. Pharmacol. exp. 15:17-23, 1966. Bunzow, J.R., et al., “Amphetamine, 3,4- (56) References Cited Methylenedioxymethamphetamine, LySergic Acid OTHER PUBLICATIONS Diethylamide, and Metabolites of the Catecholamine Neurotransmitters are Agonists of a Rat Trace Amine Recep Database CAPLUS on STN, Acc. No. 1971:135556, Fuller tor', Mol. Pharmacol. 60: 1181-1188, 2001. et al., J. of Medicinal Chemistry (1971), 14(4), p. 322-325 Borowsky, B., et al., “Trace amines: Identification of a (abstract.* family of mammalian G protein-coupled receptors', PrOC. Yen, P.M., “Physiological and Molecular Basis of Thyroid Natl. Acad. Sci. 98: 8966-8971, 2001. Hormone Action”, Physiol. Rey: 81: 1097-1142, 2001. Stöhr, R., “Synthese des Thyronamins”, Hoppe-Seyler Z. Falkenstein, E., et al., “Multiple Actions of Steroid physiol. Chem. 201: 142-149, 1931. Hormones-A Focus on Rapid, Nongenomic Effects”, Petit, L. et al., “A Synthesis of Thyronamine and its Lower Pharmacol. Rev. 52: 513-555, 2000. Homolog”, J. Org. Chem. 26: 3832-4, 1961. Walker, J.D., et al., “The novel effects of 3,5,3-triiodo-L- thyronine on myocyte contractile function and B-adrenergic Cody et al., “Molecular Structure and Biochemical Activity responsivneSS in dilated cardiomyopathy', J. Thorac. of 3,5,3'-Triiodothyronamine”, Endocrine Research, 10:91 Cardiovasc. Surg. 108: 672-679, 1994. 99, 1984. Sun, Z.-Q., et al., “Effects of thyroid hormone on action * cited by examiner potential and repolarizing currents in rat Ventricular myocytes”, Am. J. Physiol. Endocrinol. Metab. 278: E302 Primary Examiner-Brian Davis E307, 2000. (74) Attorney, Agent, or Firm-Woodcock Washburn LLP Hamilton, M.A., et al., “Safety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart (57) ABSTRACT Failure”, Am. J. Cardiol. 81: 443-447, 1998. Buu-Hoi, N.P., et al., “Thyronamine, a New Substance with Thyronamine derivatives and analogs, methods of using Long-acting positive Inotropic Effect”, Pharmacology 2: Such compounds, and pharmaceutical compositions contain 281-287, 1969. ing them are disclosed. Methods of preparing Such com Boissier, J.R., et al., “Differential Inotropic-Chronotropic pounds are also disclosed. Action of Thyronamine”, Eur: J. Pharmacol. 22: 141-149, 1973. 17 Claims, 15 Drawing Sheets U.S. Patent Dec. 27, 2005 Sheet 1 of 15 US 6,979,750 B1 NH2 HO O CO2H D-L, Il D- N - T a NH2 NH2 HO ok-co -- COH rT3 T w D-, i. w D-1, Il NH2 NH2 HO O CO2H HO O COH 3,3'-T2 Y / T. Ya 4. NH2 T Figure 1 U.S. Patent Dec. 27, 2005 Sheet 2 of 15 US 6,979,750 B1 OH AAD NH aaraara 2 HO HO L-DOPA dopamine --- m COH AAD a 1- as a s - NH ()n dy, (1)n lodo-thyronines lodo-thyronamines Figure 2 U.S. Patent Dec. 27, 2005 Sheet 3 of 15 US 6,979,750 B1 Figure 3 U.S. Patent Dec. 27, 2005 Sheet 4 of 15 US 6,979,750 B1 1OO T1AM A 2AM s 80 v. 3,3'-T2AM n 60 d C 40 U O -10 -9 -8 -7 -6 5 4 log Thyronamine(M) Figure 4 U.S. Patent Dec. 27, 2005 Sheet 5 of 15 US 6,979,750 B1 MRM of 8 Channels ES+ MRM of 8 Channels ES+ 356.1 > 339.1 356.1 > 339.1 12022002-7 5.19e7 12022002-6 2.7 4.41 e6 100 2.76 100- 73 % - % \ mirrt160"200"300' tririt triri 460" Ti, 660" Trinistric 660" O - 106"200"360---, --N--M "oo"500"Garriairfrar, 666 Time'" A B Figure 5A U.S. Patent Dec. 27, 2005 Sheet 6 of 15 US 6,979,750 B1 12022002-9 144 (2.665) Cm (134:154 Daughters of 100- ( ) 333.9 356ES 6.62e5 % - 2.9 23.0 244.9 293.3 329 340. 1 / 355.9 O f 7.8 1380 / / 256.9 284.8 V 303. 321, 1 355,3357 3838,388 100 120 40 160 180 200 220 240 260 280 300 320 340 360 380 400 102302-7 409 (7.524) - Daughters of Cm (400:420)00:42 338.8 356ES-3.92e4 100 % 2.9 3394 / 1944 22.6 338. 38 383.2 07.1| 133.0 - 17s. N970 2270 246.0 292.5/ N40340.2356.6 37.1 - 398.3 O 1324. F.T. 72442 267 2892, 320.8 \, (4-1-4 m) 00 () "is"iso"; "," "is")","ä", "go" miz Figure 5B U.S. Patent Dec. 27, 2005 Sheet 7 of 15 US 6,979,750 B1 12022002-10 139 (2.574) 100- Cm (133:148) 356. Parents of 212ES-- 2.96e5 % 338.9 355 357.4 292.8 -3584 387.8 462 omitry275.6 firm.,soo. 338.4 Yuk. kork. "/398.57 as- a m/z. 260 280 300 320 340 360 380 400 420 44() Figure 5C 1202.2002-11 139 (2.574) Cm (131:146) Parents22ES-- of 100 355.8 2.59e4 356.6--- % - 365 400.8 46.7 O "500"it.-1 "30 360 380 400 420 440 U.S. Patent Dec. 27, 2005 Sheet 8 of 15 US 6,979,750 B1 Figure 6A ---> ---"HO 2.1. ADMAO e--"HO dopamine DOPAC Figure 6B HO -- --- ()n ()n lodothyronamines : 1. MAO ; 2. AD t to:---- o-)-3- Ho-( )-O-()--" TETRAC TRAC thyroacetic acid U.S. Patent Dec. 27, 2005 Sheet 9 of 15 US 6,979,750 B1 Temperature (°C) 42.5 40.0 -H Control; i.p. - A - 18.75 mg/kg, i.p. -7- 37.5 mg/kg, i.p. -- 75 mg/kg, i.p. 35.0 32.5 300 Figure 7 U.S. Patent Dec. 27, 2005 Sheet 10 Of 15 US 6,979,750 B1 8ºun61-I 7Ápogeuo'o| (O.)'duuel U.S. Patent US 6,979,750 B1 U.S. Patent Dec. 27, 2005 Sheet 14 of 15 US 6,979,750 B1 008 009 eun61-IVz], ?anôlCIZI, U.S. Patent US 6,979,750 B1 US 6,979,750 B1 1 2 THYRONAMINEDERVATIVES AND There are, however, physiological effects of thyroid hor ANALOGS AND METHODS OF USE mone that are not readily explained by a transcription THEREOF regulation mode of action. These So-called “non-genomic effects are characterized by a rapid onset in response to This invention was made with Government support by hormone and/or insensitivity to translation inhibitors, Such Grant Nos. DK52798, DA10703, DA12408, and DAO7262 as cyclohexamide. Specific examples of Such effects include 09, awarded by the National Institutes of Health. The the rapid contractile response to T in cultured cardiac Government has certain rights in this invention. myocytes, the Shortening of the action potential with con comitant attenuation of repolarizing currents in Ventricular FIELD OF THE INVENTION 1O myocytes, and in Studies in animals. Falkenstein, E., et al., 2000, Pharmacol. Rev. 52, 513–555; Walker, J. D., et al., This invention generally relates to derivatives and analogs 1994, J. Thorac. Cardiovasc. Surg. 108, 672–679; Sun, of thyroid hormone. More specifically, the invention relates Z.-Q., et al., 2000, Am. J. Physiol. Endocrinol. Metab. 278, to thyronamine derivatives and analogs of thyroid hormone, E302-E307; Hamilton, M.A., et al., 1998, Am. J. Cardiol. pharmaceutical compositions containing the thyronamine 15 81, 443–447; Buu-Hoi, N. P., et al., 1969, Pharmacology 2, derivatives and analogs, methods of making the thy 281–287; Boissier, J. R., et al., 1973, Eur. J. Pharmacol. 22, ronamine derivatives and analogs and methods of use 141-149; Cote, P., et al., 1974, Cardiovascular ReS. 8, thereof. 721-730. The rapid rate of these effects suggests that they are mediated by receptors other than the nuclear TRS in BACKGROUND OF THE INVENTION response to a thyroid hormone.
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