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(12) Patent Application Publication (10) Pub. No.: US 2010/011 1901 A1 Gant Et Al US 201001 11901A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/011 1901 A1 Gant et al. (43) Pub. Date: May 6, 2010 (54) TRIAZOLE INHIBITORS OF AROMATASE A63/496 (2006.01) A 6LX 3/57 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA A 6LX 3/5.377 (2006.01) (US); Sepehr Sarshar, Cardiff by A638/46 (2006.01) the Sea, CA (US); Manouchehr M. A6II 3/69 (2006.01) Shahbaz, San Diego, CA (US) CI2N 5/00 (2006.01) A6IP35/00 (2006.01) Correspondence Address: A6IP5/00 (2006.01) GLOBAL PATENT GROUP - APX A6IP 5/00 (2006.01) 10411 Clayton Road, Suite 304 ST. LOUIS, MO 63131 (US) (52) U.S. Cl. ..................... 424/85.2: 548/262.2: 514/383; 514/328; 514/171; 514/300: 514/324; 514/217.08; (73) Assignee: AUSPEX 514/110: 514/62; 424/649; 514/34: 514/8: PHARMACEUTICALS, INC., 424/133.1; 424/144.1: 514/252.19; 514/266.1: Vista, CA (US) 514/234.5: 514/252.18; 424/94.6; 514/64; 435/375 (21) Appl. No.: 12/611,278 (22) Filed: Nov. 3, 2009 (57) ABSTRACT The present invention relates to new triazole modulators of Related U.S. Application Data aromatase activity, pharmaceutical compositions thereof, and (60) Provisional application No. 61/110,820, filed on Nov. methods of use thereof. 3, 2008. Publication Classification Formula I (51) Int. Cl. A6 IK 38/20 (2006.01) CO7D 249/08 (2006.01) A6 IK 3/496 (2006.01) A6 IK 3/445 (2006.01) A6 IK3I/56 (2006.01) A6 IK 3/437 (2006.01) A6 IK 3L/4535 (2006.01) A6 IK3I/55 (2006.01) A6 IK3I/66 (2006.01) A6 IK 33/24 (2006.01) A6 IK3I/704 (2006.01) A6 IK 38/14 (2006.01) A 6LX 39/395 (2006.01) US 2010/011 1901 A1 May 6, 2010 TRAZOLE INHIBITORS OF AROMATASE pain, vomiting, dyspnea, edema, eruption, skin, vaginal dis order, weight gain, cancer, depression, lethargy, thrombosis, and vaginal bleeding. 0001. This application claims the benefit of priority of Deuterium Kinetic Isotope Effect U.S. provisional application No. 61/110,820, filed Nov. 3, 0005. In order to eliminate foreign substances such as 2008, the disclosure of which is hereby incorporated by ref therapeutic agents, the animal body expresses various erence as if written herein in its entirety. enzymes, such as the cytochrome Paso enzymes (CYPs), 0002 Disclosed herein are new triazole compounds, phar esterases, proteases, reductases, dehydrogenases, and maceutical compositions made thereof, and methods to monoamine oxidases, to react with and convert these foreign modulate aromatase activity in a Subject are also provided for Substances to more polar intermediates or metabolites for the treatment of disorders such as breast tumors, endocrine renal excretion. Such metabolic reactions frequently involve disease, infertility, precocious puberty, male hypogonadism, the oxidation of a carbon-hydrogen (C H) bond to either a and McCune-Albright syndrome. carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. 0003. Anastrozole (Anastrol, Anastrozole, ICI-D 1033, The resultant metabolites may be stable or unstable under ZD 1033, Arimidex(R), 2-3-(2-cyano-2-propyl)-5-(1,2,4- physiological conditions, and can have substantially different triazol-1-ylmethyl)phenyl-2-methylpropiononitrile, is an pharmacokinetic, pharmacodynamic, and acute and long aromatase inhibitor. AnastroZole is commonly prescribed for term toxicity profiles relative to the parent compounds. For most drugs, such oxidations are generally rapid and ulti the treatment of breast tumors (Drug Report for Anastrozole, mately lead to administration of multiple or high daily doses. Thompson Investigational Drug Database (2008); Lonning et 0006. The relationship between the activation energy and al., Breast Cancer Research and Treatment 1998, 49 (Suppl. the rate of reaction may be quantified by the Arrhenius equa 1), S53-S57; Buzdar et al., Cancer, 2002, 95(9), 2006-2016: tion, k=Ae'. The Arrhenius equation states that, at a Cuzicket al., Drugs of Today 2005, 41(4), 227-239; Welling given temperature, the rate of a chemical reaction depends ton et al., Drugs 2002, 62(17), 24.83-2490; Howell et al., exponentially on the activation energy (E). Women's Health 2005, 1(3), 309-322: Nabholtz et al., Oncol 0007. The transition state in a reaction is a short lived state ogy, 2006, 7001), 1-12; and Nabholtz et al., Exp. Opin. Phar along the reaction pathway during which the original bonds macother: 2002, 3(9), 1329-1339). Anastrozole has also have stretched to their limit. By definition, the activation shown promise in treating endocrine disease, infertility, pre energy E for a reaction is the energy required to reach the cocious puberty, male hypogonadism, and McCune-Albright transition state of that reaction. Once the transition state is syndrome (Drug Report for Anastrozole, Thompson Investi reached, the molecules can either revert to the original reac gational Drug Database (2008); Graham, Exp. Op. Pharma tants, or form new bonds giving rise to reaction products. A cother. 2007, 8(14), 2347-2357; and Tredway et al., Fertility catalyst facilitates a reaction process by lowering the activa and Sterility, 2004, 82(6), 1587-1593). tion energy leading to a transition state. Enzymes are examples of biological catalysts. 0008 Carbon-hydrogen bond strength is directly propor tional to the absolute value of the ground-state vibrational 1. energy of the bond. This vibrational energy depends on the N mass of the atoms that form the bond, and increases as the 2 S. mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium (H), a C-D bond is stronger than the corresponding C–H bond. If a C-H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), then Substituting a deuterium for that protium Anastrozole will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The 0004 Anastrozole is extensively metabolised in the liver magnitude of the DKIE can be expressed as the ratio between via N-dealkylation, hydroxylation, and glucuronidation, with the rates of a given reaction in which a C H bond is broken, and the same reaction where deuterium is substituted for about 60% of the dose excreted in the urine as metabolites protium. The DKIE can range from about 1 (no isotope effect) (Wellington et al., Drugs 2002, 62(17), 24.83-2490; Nabholtz to very large numbers, such as 50 or more. Substitution of et al. Oncology 2006, 7001), 1-12: Lonning et al., Breast tritium for hydrogen results in yet a stronger bond than deu Cancer Research and Treatment 1998, 49 (Suppl. 1), S53 terium and gives numerically larger isotope effects S57). The mean terminal elimination half-life of anastrozole I0009 Deuterium (H or D) is a stable and non-radioactive is approximately 40-50 hours (Wellington et al., Drugs 2002, isotope of hydrogen which has approximately twice the mass 62(17), 24.83-2490; Tredway et al., Fertility and Sterility of protium ("H), the most common isotope of hydrogen. 2004, 82(6), 1587-1593; Cuzick, Drugs of Today 2005, 41(4), Deuterium oxide (DO or "heavy water) looks and tastes like 227-239). Anastrozole inhibits (in decreasing order of mag HO, but has different physical properties. nitude) CYP1A2, CYP2C8/9, and CYP3A4, and has no effect I0010. When pure DO is given to rodents, it is readily on CYP2A6 or CYP2D6 (Grimm et al., Drug Metab. Disp. absorbed. The quantity of deuterium required to induce tox 1997, 25(5), 598-602). Anastrazole administration is associ icity is extremely high. When about 0-15% of the body water ated with anorexia, asthenia, constipation, diarrhea, dyspep has been replaced by DO, animals are healthy but are unable sia, flushing, gastrointestinal disorders, headache, nausea, to gain weight as fast as the control (untreated) group. When US 2010/011 1901 A1 May 6, 2010 about 15-20% of the body water has been replaced with D.O. desired effect, (d) decrease the amount of a dose needed to the animals become excitable. When about 20-25% of the achieve a desired effect, (e) increase the formation of active body water has been replaced with DO, the animals become metabolites, if any are formed, (f) decrease the production of so excitable that they go into frequent convulsions when deleterious metabolites in specific tissues, and/or (g) create a stimulated. Skin lesions, ulcers on the paws and muzzles, and more effective drug and/or a safer drug for polypharmacy, necrosis of the tails appear. The animals also become very whether the polypharmacy be intentional or not. The deutera aggressive. When about 30% of the body water has been tion approach has the strong potential to slow the metabolism replaced with DO, the animals refuse to eat and become of anastroZole and attenuate interpatient variability. comatose. Their body weight drops sharply and their meta 0014 Novel compounds and pharmaceutical composi bolic rates drop far below normal, with death occurring at tions, certain of which have been found to inhibit aromatase about 30 to about 35% replacement with D.O.The effects are have been discovered, together with methods of synthesizing reversible unless more than thirty percent of the previous and using the compounds, including methods for the treat body weight has been lost due to D.O. Studies have also ment of aromatase-mediated disorders in a patient by admin shown that the use of DO can delay the growth of cancer cells istering the compounds.
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