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(12) Patent Application Publication (10) Pub. No.: US 2009/0118236A1 Erion Et Al

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US 200901 18236A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0118236A1 Erion et al. (43) Pub. Date: May 7, 2009 (54) NOVEL PHOSPHORUS-CONTAINING Publication Classification THYROMMETCS (51) Int. Cl. (76) Inventors: Mark D. Erion, Del Mar, CA (US); gt. 5% CR Hongjian Jiang, San Diego, CA A6II 3/662 CR (US); Serge H. Boyer, San Diego, ( .01) CA (US) C07F 9/59 (2006.01) A6IP5/4 (2006.01) Correspondence Address: 9."66 :08: STERNE KESSLER GOLDSTEIN & FOX P.L. L.C 9 9 C07F 9/58 (2006.01) 1100 NEW YORKAVENUE, N.W. C07F 9/38 (2006.01) WASHINGTON, DC 20005 (US) (52) U.S. Cl. ............. 514/89;568/15: 514/130; 514/119; 564/15: 514/114: 546/22:568/12: 514/110; (21) Appl. No.: 10/580,134 436/5O1 (22) PCT Filed: Nov. 19, 2004 (57) ABSTRACT The present invention relates to compounds of phosphonic (86). PCT No.: PCT/USO4/39024 acid containing T3 mimetics, Stereoisomers, pharmaceuti S371 (c)(1) cally acceptable salts, co-crystals, and prodrugs thereof and (2), (4).te: May 30, 2007 pharmaceutically acceptable salts and co-crystals of the pro s 9 drugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, Related U.S. Application Data hypercholesterolemia and hyperlipidemia, as well as associ (60) Provisional application No. 60/523,830, filed on Nov. ated conditions such as atherosclerosis, coronary heart dis 19, 2003, provisional application No. 60/598.524, ease, impaired glucose tolerance, metabolic syndromex and filed on Aug. 3, 2004. diabetes. Patent Application Publication US 2009/0118236 A1 suo?ouay?quattroou|ds?GISn030?0?IOH (Wu)uopel)uacu00 Patent Application Publication May 7, 2009 Sheet 2 of 13 US 2009/0118236 A1 strogouº?quatu90BIds?GISn0?0[0?OH 000||000|-|||00:0 1881·000Z |009 oog,Wdº 000! Patent Application Publication May 7, 2009 Sheet 3 of 13 US 2009/0118236 A1 strogouºXIquatu90elds?qsn03010t?OH (Wu)uopeljuabuoo Wdo Patent Application Publication May 7, 2009 Sheet 4 of 13 US 2009/0118236 A1 0001OQ||0|1:0||0:01000 (Wu)uopenuasuoo suo?obºx!quattroot:[ds?qsno30?ottroH 000Z 000|| 009 009?WCHO Patent Application Publication US 2009/0118236 A1 suo?obºYIquattrºog(?ís?QSnoão(ouIOH. (wu)uo?enueouoo Patent Application Publication US 2009/0118236 A1 '00OOOO[000||000|||'| suo?ouØYIquætuæðu?ds?QSn030?0?IOH Patent Application Publication May 7, 2009 Sheet 8 of 13 US 2009/0118236 A1 *;....….………………….•* *??..•* Lpumoduloo0410.101s210(IO30astrods0}{9SOGI ?oue?s??O?O ___________________)-------------¬---------~--~~"+"~~~~*)* (q)z+3) Sju??pa??10.194sæ?otIOu? • 02|| 0?y! 0892. () O |-24. 9. -or, {09 Patent Application Publication May 7, 2009 Sheet 9 of 13 US 2009/0118236 A1 j?540M).Bº??trôLipunoduloogo100JgGI (b)g'?? S?u}{pº??(0.(9)SO?OLIO(I? 00"| (6) ubleM. Jee Patent Application Publication May 7, 2009 Sheet 10 of 13 US 2009/0118236 A1 “….(…)-----------------6?0 (6) ubleNN jeeh Patent Application Publication May 7, 2009 Sheet 11 of 13 US 2009/0118236 A1 (p/68/6u)esop/1punodujo0. HOCHS)\le9H !"0?0'0100’0. (5uyuuin) -Odo be Patent Application Publication May 7, 2009 Sheet 12 of 13 US 2009/0118236 A1 (pffix||fiuu)asopLpunoduuoo 9 (5u/uuin) HOdeeH US 2009/011 8236 A1 May 7, 2009 NOVEL PHOSPHORUS-CONTAINING gland and specific regions of the hypothalamus as well as the THYROMMETCS developing brain and inner ear. In the rat and mouse liver, TRB-1 is the predominant isoform (80%). The TR isoforms FIELD OF THE INVENTION found in human and rat are highly homologous with respect to their amino acid sequences which suggest that each serves a 0001. The present invention is directed toward phosphonic specialized function. acid-containing compounds that are thyroid receptor ligands, 0006 TSH is an anterior pituitary hormone that regulates pharmaceutically acceptable salts, and to prodrugs of these thyroid hormone production. TSH formation and secretion is compounds as well as their preparation and uses for prevent in turn regulated by the hypothalamic thyrotropin releasing ing and/or treating metabolic diseases Such as obesity, NASH, factor (TRF). TSH controls the uptake of iodide by the thy hypercholesterolemia and hyperlipidemia as well as associ roid, the Subsequent release of iodinated thyronines from ated conditions such as atherosclerosis, coronary heart dis thyroglobulin (e.g., T3, T4) as well as possibly the intrapitu ease, impaired glucose tolerance and diabetes. The invention itary conversion of circulating T4 to T3. Compounds that is also related to the liver specific delivery of thyroid receptor mimic T3 and T4 can negatively regulate both TSH and TRF ligands and the use of these compounds for the prevention and secretion resulting in suppression of TSH levels and treatment of diseases responsive to modulation of T3-respon decreased levels of T3 and other iodinated thyronines. Nega sive genes in the liver. tive regulation of TSH is postulated based on co-transfection and knockout studies (Abel et al., J. Clin. Invest. 104, 291 BACKGROUND 300, (1999)) to arise through activation of the thyroid receptor 0002 The following description of the background is pro TRB, possibly the isoform TRB-2, which is highly expressed vided to aid in understanding, but is not admitted to be, or to in the pituitary. describe, prior art. All publications and their cited references 0007. The most widely recognized effects of THs are an are incorporated by reference in their entirety. increase in metabolic rate, oxygen consumption and heat 0003) Thyroid hormones (TH) are synthesized in the thy production. T3 treatment increases oxygen consumption in roid in response to thyroid stimulating hormone (TSH), isolated perfused liver and isolated hepatocytes. (Oh, et al., J. which is secreted by the pituitary gland in response to various Nutr. 125(1): 112-24 (1995); Oh, et al., Proc. Soc. Exp. Biol. stimulants (e.g., thyrotropin-releasing factor (TRF) from the Med. 207(3): 260-7 (1994)) Liver mitochondria from hyper hypothalamus). Thyroid hormones are iodinated O-aryl thyroid rats exhibit increased oxygen consumption (Carreras, tyrosine analogues excreted into the circulation primarily as et al., Am J Physiol Heart Circ Physiol. 281 (6):H2282-8 T4. T4 is rapidly deiodinated in the liver and kidney by (2001) and higher activities of enzymes in the oxidative path thyroxine 5'-deiodinase to T3, which is the most potent TH. ways (Dummler et al., Biochem J 317(3):913-8 (1996), T3 is metabolized to inactive metabolites via a variety of Schmehl, et al., FEBS Lett. 375(3):206-10 (1995), Harper et pathways, including pathways involving deiodination, glucu al., Can J. Physiol Pharmacol. 72(8):899-908 (1994)). Con ronidation, Sulfation, deamination, and decarboxylation. versely, mitochondria from hypothyroid rats show decreased Most of the metabolic pathways reside in the liver. oxygen consumption. Increased metabolic rates are associ 0004 THs have profound physiological effects in animals ated with increased mitochondrialgenesis and the associated and humans. Hyperthyroidism is associated with increased 2- to 8-fold increase in mitochondrial mRNA levels. Some of body temperature, general nervousness, weight loss despite the energy produced from the increased metabolic rate is increased appetite, muscle weakness and fatigue, increased captured as ATP (adenosine 5'-triphosphate), which is stored bone resorption and enhanced calcification, and a variety of or used to drive biosynthetic pathways (e.g., gluconeogen cardiovascular changes, including increased heart rate, esis, lipogenesis, lipoprotein synthesis). Much of the energy, increased stroke Volume, increased cardiac index, cardiac however, is lost in the form of heat (thermogenesis), which is hypertrophy, decreased peripheral vascular resistance, and associated with an increase in mitochondrial proton leak pos increased pulse pressure. Hypothyroidism is generally asso sibly arising from TH-mediated effects on mitochondrial ciated with the opposite effects. membrane, uncoupling proteins, enzymes involved in the 0005. The biological activity of THs is mediated largely inefficient sn-glycerol 3-phosphate shuttle Such as mitochon through thyroid hormone receptors (TRs). TRs belong to the drial sn-glycerol 3-phosphate dehydrogenase (mGPDH), receptor Superfamily known as nuclear receptors, which, and/or enzymes associated with proton leakage such as the along with its common partner, the retinoid X receptor, form adenine nucleotide transporter (ANT), Na/K-ATPase, heterodimers that act as ligand-inducible transcription fac Cat-ATPase and ATP synthase. tors. Like other nuclear receptors, TRS have a ligand binding 0008 THs also stimulate metabolism of cholesterol to bile domain and a DNA binding domain and regulate gene expres acids. Hypertyroidism leads to decreased plasma cholesterol sion through ligand-dependent interactions with DNA levels, which is likely due to increased hepatic LDL receptor response elements (thyroid response elements, TREs). Cur expression. Hypothyroidism is a well-established cause of rently, the literature shows that TRs are encoded by two hypercholesterolemia and elevated serum LDL. L-T3 is distinct genes (IRC. and TRB), which produce several iso known to lower plasma cholesterol levels. The effects of T3 forms through alternative splicing (Williams, Mol Cell Biol. are attributed to TRB since TRB-deficient mice are resistant to 20022):8329-42 (2000): Nagaya, et al. Biochem Biophy's Res T3-induced reduction in cholesterol levels. The effects on Commun 226(2):426-30 (1996)). The major isoforms that cholesterol levels have been postulated to result from direct have so far been identified are TRO-1, TRC-2, TRB-1 and effects on LDL receptor expression, enzymes involved in TRB-2. TRO-1 is ubiquitously expressed in the rat with high conversion of cholesterol to bile acids such as the rate-limit est expression in skeletal muscle and brown fat. TRB-1 is also ing enzyme cholesterol 7C.-hydroxylase (CYP7A) and/or ubiquitously expressed with highest expression in the liver, possibly enzymes involved in cholesterol synthesis such as brain and kidney.
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