US 2010.0143507A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/014.3507 A1 Gant et al. (43) Pub. Date: Jun. 10, 2010 (54) CARBOXYLIC ACID INHIBITORS OF Publication Classification HISTONE DEACETYLASE, GABA (51) Int. Cl. TRANSAMINASE AND SODIUM CHANNEL A633/00 (2006.01) A 6LX 3/553 (2006.01) A 6LX 3/553 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA A63L/352 (2006.01) (US); Sepehr Sarshar, Cardiff by A6II 3/19 (2006.01) the Sea, CA (US) C07C 53/128 (2006.01) A6IP 25/06 (2006.01) A6IP 25/08 (2006.01) Correspondence Address: A6IP 25/18 (2006.01) GLOBAL PATENT GROUP - APX (52) U.S. Cl. .................... 424/722:514/211.13: 514/221; 10411 Clayton Road, Suite 304 514/456; 514/557; 562/512 ST. LOUIS, MO 63131 (US) (57) ABSTRACT Assignee: AUSPEX The present invention relates to new carboxylic acid inhibi (73) tors of histone deacetylase, GABA transaminase, and/or PHARMACEUTICALS, INC., Sodium channel activity, pharmaceutical compositions Vista, CA (US) thereof, and methods of use thereof. (21) Appl. No.: 12/632,507 Formula I (22) Filed: Dec. 7, 2009 Related U.S. Application Data (60) Provisional application No. 61/121,024, filed on Dec. 9, 2008. US 2010/014.3507 A1 Jun. 10, 2010 CARBOXYLIC ACID INHIBITORS OF HISTONE DEACETYLASE, GABA TRANSAMNASE AND SODIUM CHANNEL 0001. This application claims the benefit of priority of Valproic acid U.S. provisional application No. 61/121,024, filed Dec. 9, 2008, the disclosure of which is hereby incorporated by ref 0004 Valproic acid is extensively metabolised via erence as if written herein in its entirety. microsomal glucuronide conjugation, mitochondrial 13-oxi 0002 Disclosed herein are new carboxylic acid com dation and cytochrome P450-dependent ()-, (c)-1)- and (c)-2)- pounds, pharmaceutical compositions made thereof, and oxidation (Perucca et al., CNS Drugs 2002, 16(10), 695-714). methods to inhibit histone deacetylase, gamma-aminobutyric Glucuronidation represents the major metabolic pathway in acid (GABA) transaminase and/or Sodium channel activity in mammals, although a number of oxidative pathways also a subject are also provided for, for the treatment of disorders operate and lead to the formation of a variety of hydroxy Such as epilepsy, migraine, Schizophrenia, autism, and bipo oxo-, and dicarboxylic acid metabolites (Perucca et al., CNS lar disorder. Drugs 2002, 16(10), 695-714). In addition, several mono- and 0003 Valproic acid (Abbott 44090, BRN 1750447, Depa polyunsaturated metabolites have also been reported (Retten kine(R), Ergenyl(R), HSDB 3582, AI3-10500, 2-propylvaleric meier et al., Xenobiotica 1987, 17(10), 1147-1157). Adverse acid, DepakeneR), Convulex(R), Stavzor R, Epival(R) 2-propy effects associated with valproic acid administration include: lpentanoic acid, is a histone deacetylase inhibitor, a GABA fatigue, dizziness, nausea, vomiting, tremor, hair loss, weight transaminase inhibitor, and a sodium channel inhibitor. Val gain and depression. Valproic acid inhibits fatty acid B-oxi proic acid is commonly prescribed for the treatment of dation; although the mechanism remains unknown. migraine (Drug Report for Valproate Semisodium, Thompson Investigational Drug Database (Aug. 12, 2008); and Mathew Deuterium Kinetic Isotope Effect et al., Arch. Neurol. 1995, 123(2), 281-6); epilepsy (Drug Report for Valproate Semisodium, Thompson Investigational 0005. In order to eliminate foreign substances such as Drug Database (Aug. 11, 2008); Drug Report for Sodium therapeutic agents, the animal body expresses various Valproate (oral, sustained release), Thompson Investiga enzymes, such as the cytochrome Paso enzymes (CYPs), tional Drug Database (Aug. 12, 2008); Drug Report for Val esterases, proteases, reductases, dehydrogenases, and proic Acid (delayed release), Thompson Investigational Drug monoamine oxidases, to react with and convert these foreign Database (Aug. 12, 2008); and Davis et al., Drugs 1994, Substances to more polar intermediates or metabolites for 47(2), 332-72); schizophrenia (Drug Report for Valproate renal excretion. Such metabolic reactions frequently involve Semisodium, Thompson Investigational Drug Database (Aug. the oxidation of a carbon-hydrogen (C H) bond to either a 12, 2008); Citrome et al., Psychiatr. Serv. 2000, 51, 634-638; carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. and Ko et al., Biological Psychiatry 1985, 20(2), 209-215): The resultant metabolites may be stable or unstable under autism (Plioplys A. Arch. Pediatr. Adolesc. Med., 1994, 148 physiological conditions, and can have substantially different (2), 220-2; and Drug Report for Valproate Semisodium, pharmacokinetic, pharmacodynamic, and acute and long Thompson Investigational Drug Database (Aug. 12, 2008)); term toxicity profiles relative to the parent compounds. For and bipolar disorder (Macritchie et al., Cochrane Database most drugs, such oxidations are generally rapid and ulti Syst. Rev. 2001, 3, CD003196; Drug Report for Valproic Acid mately lead to administration of multiple or high daily doses. (delayed release), Thompson Investigational Drug Database 0006. The relationship between the activation energy and (Aug. 12, 2008); Drug Report for Valproate Semisodium, the rate of reaction may be quantified by the Arrhenius equa Thompson Investigational Drug Database (Aug. 12, 2008); tion, k=Ae'. The Arrhenius equation states that, at a and McElroy et al., J. Clin. Psychopharmacol. 1992, 12(1 given temperature, the rate of a chemical reaction depends Suppl), 42S-52S). Valproic acid has also shown promise in exponentially on the activation energy (E). treating major depressive disorder (Davis et al., Psychophar 0007. The transition state in a reaction is a short lived state macol. Bull. 1996, 32(4), 647-52); familial adenomatous along the reaction pathway during which the original bonds polyposis (Drug Report for Valproic Acid (oral, cancer), have stretched to their limit. By definition, the activation Thompson Investigational Drug Database (Aug. 12, 2008)); energy E for a reaction is the energy required to reach the Solid tumors (Drug Report for Valproic Acid (oral, cancer), transition state of that reaction. Once the transition state is Thompson Investigational Drug Database (Aug. 12, 2008); reached, the molecules can either revert to the original reac and Munster et al., Journal of Clinical Oncology 2007, tants, or form new bonds giving rise to reaction products. A 25(15), 1979-1985); basal cell carcinoma (Drug Report for catalyst facilitates a reaction process by lowering the activa Valproic Acid (topical), Thompson Investigational Drug tion energy leading to a transition state. Enzymes are Database (Aug. 12, 2008)); psoriasis (Drug Report for Valp examples of biological catalysts. roic Acid (topical), Thompson Investigational Drug Database 0008 Carbon-hydrogen bond strength is directly propor (Aug. 12, 2008); and McLaughlin et al., Current Drug Tar tional to the absolute value of the ground-state vibrational gets—Inflammation &Allergy 2004, 3(2), 213-219); acne energy of the bond. This vibrational energy depends on the (Drug Report for Valproic Acid (topical), Thompson Investi mass of the atoms that form the bond, and increases as the gational Drug Database (Aug. 12, 2008)); and skin tumors mass of one or both of the atoms making the bond increases. (Drug Report for Valproic Acid (topical), Thompson Investi Since deuterium (D) has twice the mass of protium ("H), a gational Drug Database (Aug. 12, 2008); and Chung et al., C D bond is stronger than the corresponding C–H bond. Mol. Cancer. Ther. 2004, 3,317-325). If a C-H bond is broken during a rate-determining step in a US 2010/014.3507 A1 Jun. 10, 2010 chemical reaction (i.e. the step with the highest transition could effect the pharmacokinetic, pharmacologic and/or toxi state energy), then Substituting a deuterium for that protium cologic profiles of valproic acid in comparison with Valproic will cause a decrease in the reaction rate. This phenomenon is acid having naturally occurring levels of deuterium. known as the Deuterium Kinetic Isotope Effect (DKIE). The 0013 Based on discoveries made in our laboratory, as well magnitude of the DKIE can be expressed as the ratio between as considering the literature, valproic acid is Subject to meta the rates of a given reaction in which a C-H bond is broken, bolic oxidation at all of its C–H bonds. The current approach and the same reaction where deuterium is substituted for has the potential to prevent metabolism at these site. Other protium. The DKIE can range from about 1 (no isotope effect) sites on the molecule may also undergo transformations lead to very large numbers, such as 50 or more. Substitution of ing to metabolites with as-yet-unknown pharmacology/toxi tritium for hydrogen results in yet a stronger bond than deu cology. Limiting the production of these metabolites has the terium and gives numerically larger isotope effects. potential to decrease the danger of the administration of Such 0009 Deuterium (2H or D) is a stable and non-radioactive drugs and may even allow increased dosage and/or increased isotope of hydrogen which has approximately twice the mass efficacy. All of these transformations can occur through poly of protium ("H), the most common isotope of hydrogen. morphically-expressed enzymes, exacerbating interpatient Deuterium oxide (DO or “heavy water) looks and tastes like variability. Further, some disorders are best treated when the HO, but has different physical properties. Subject is medicated around the clock or for an extended 0010. When pure DO is given to rodents, it is readily period of time. For all of the foregoing reasons, a medicine absorbed. The quantity of deuterium required to induce tox with a longer half-life may result in greater efficacy and cost icity is extremely high. When about 0-15% of the body water savings. Various deuteration patterns can be used to (a) reduce has been replaced by DO, animals are healthy but are unable or eliminate unwanted metabolites, (b) increase the half-life to gain weight as fast as the control (untreated) group.