(12) Patent Application Publication (10) Pub. No.: US 2010/0055072 A1 Gant Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0055072 A1 Gant Et Al US 20100055072A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0055072 A1 Gant et al. (43) Pub. Date: Mar. 4, 2010 (54) 2-OXO-1,2-DIHYDRO-QUINOLINE Publication Classification MODULATORS OF IMMUNE FUNCTION (51) Int. Cl. A638/2 (2006.01) C07D 25/00 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA A6II 3/47 (2006.01) (US); Manoucher M. Shahbaz, A 6LX 39/395 (2006.01) Escondido, CA (US) (52) U.S. Cl. ....... 424/85.6; 546/157: 514/312; 424/85.5; 424/85.7; 424/133.1 Correspondence Address: (57) ABSTRACT GLOBAL PATENT GROUP - APX The present invention relates to new 2-oxo-1,2-dihydro 10411 Clayton Road, Suite 304 quinoline modulators of immune function, pharmaceutical ST. LOUIS, MO 63131 (US) compositions thereof, and methods of use thereof. (73) Assignee: AUSPEX Formula I PHARMACEUTICALS, INC., R R16 Vista, CA (US) R3 R R15 R4 R17 (21) Appl. No.: 12/552,663 Rs N O (22) Filed: Sep. 2, 2009 C O Related U.S. Application Data (60) Provisional application No. 61/093.943, filed on Sep. 3, 2008. US 2010/0055072 A1 Mar. 4, 2010 2-OXO-1,2-DIHYDRO-QUINOLINE given temperature, the rate of a chemical reaction depends MODULATORS OF IMMUNE FUNCTION exponentially on the activation energy (E). 0007. The transition state in a reaction is a short lived state along the reaction pathway during which the original bonds have stretched to their limit. By definition, the activation 0001. This application claims the benefit of priority of energy E for a reaction is the energy required to reach the U.S. provisional application No. 61/093.943, filed Sep. 3, transition state of that reaction. Once the transition state is 2008, the disclosure of which is hereby incorporated by ref reached, the molecules can either revert to the original reac erence as if written herein in its entirety. tants, or form new bonds giving rise to reaction products. A 0002 Disclosed herein are new substituted 2-oxo-1,2-di catalyst facilitates a reaction process by lowering the activa hydro-quinoline compounds, pharmaceutical compositions tion energy leading to a transition state. Enzymes are made thereof, and methods to modulate immune function examples of biological catalysts. activity in a subject are also provided for, for the treatment of 0008 Carbon-hydrogen bond strength is directly propor disorders such as multiple Sclerosis and autoimmune disor tional to the absolute value of the ground-state vibrational ders. energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the 0003 Laquinimod (ABR 215062; SAIK-MS; ABR mass of one or both of the atoms making the bond increases. 215062; SAIKMS: CAS #248281-84-7), 5-chloro-4-hy Since deuterium (D) has twice the mass of protium ("H), a droxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic C-D bond is stronger than the corresponding C–H bond. If acid ethyl-phenyl-amide, is an immune function modulator. a C-H bond is broken during a rate-determining step in a Laquinimod is currently under investigation for the treatment chemical reaction (i.e. the step with the highest transition of multiple sclerosis (Burton et al., Curr. Neurol. & Neurosc. state energy), then Substituting a deuterium for that protium Reports 2007, 7(3), 223-30; Tuvesson et al., Xenobiotica will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The 2005, 35(3), 293-304; Cohen et al., Int. J. Clin. Pract. 2007, magnitude of the DKIE can be expressed as the ratio between 61 (11), 1922-30). Laquinimod has also shown promise in therates of a given reaction in which a C H bond is broken, treating autoimmune disorders (TuVesson et al., Xenobiotica and the same reaction where deuterium is substituted for 2005, 35(3), 293-304). protium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. Substitution of tritium for hydrogen results in yet a stronger bond than deu terium and gives numerically larger isotope effects. 0009 Deuterium (H or D) is a stable and non-radioactive isotope of hydrogen which has approximately twice the mass NY - of protium (H), the most common isotope of hydrogen. 21 N Deuterium oxide (DO or “heavy water) looks and tastes like HO, but has different physical properties. 0010 When pure DO is given to rodents, it is readily C OH O absorbed. The quantity of deuterium required to induce tox icity is extremely high. When about 0-15% of the body water Laquinimod has been replaced by DO, animals are healthy but are unable to gain weight as fast as the control (untreated) group. When 0004 Laquinimod is subject to extensive oxidative about 15-20% of the body water has been replaced with D.O. metabolism by cytochrome Paso enzymes, particularly by the animals become excitable. When about 20-25% of the CYP3A4 (Tuvesson et al., Drug Metab. & Disp. 2005, 33(6), body water has been replaced with DO, the animals become 866-72). Primary metabolites include those formed by quino so excitable that they go into frequent convulsions when line hydroxylation at various sites, quinoline demethylation, stimulated. Skin lesions, ulcers on the paws and muzzles, and aniline de-ethylation, and aniline hydroxylation at the para necrosis of the tails appear. The animals also become very aggressive. When about 30% of the body water has been position (Tuvesson et al., Xenobiotica 2005, 35(3), 293-304). replaced with DO, the animals refuse to eat and become comatose. Their body weight drops sharply and their meta Deuterium Kinetic Isotope Effect bolic rates drop far below normal, with death occurring at 0005. In order to eliminate foreign substances such as about 30 to about 35% replacement with D.O.The effects are therapeutic agents, the animal body expresses various reversible unless more than thirty percent of the previous enzymes, such as the cytochrome Paso enzymes (CYPs), body weight has been lost due to DO Studies have also esterases, proteases, reductases, dehydrogenases, and shown that the use of DO candelay the growth of cancer cells and enhance the cytotoxicity of certain antineoplastic agents. monoamine oxidases, to react with and convert these foreign 0011 Deuteration of pharmaceuticals to improve pharma Substances to more polar intermediates or metabolites for cokinetics (PK), pharmacodynamics (PD), and toxicity pro renal excretion. Such metabolic reactions frequently involve files has been demonstrated previously with some classes of the oxidation of a carbon-hydrogen (C-H) bond to either a drugs. For example, the DKIE was used to decrease the hepa carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. totoxicity of halothane, presumably by limiting the produc The resultant metabolites may be stable or unstable under tion of reactive species such as trifluoroacetylchloride. How physiological conditions, and can have Substantially different ever, this method may not be applicable to all drug classes. pharmacokinetic, pharmacodynamic, and acute and long For example, deuterium incorporation can lead to metabolic term toxicity profiles relative to the parent compounds. For Switching. Metabolic Switching occurs when Xenogens, most drugs, such oxidations are generally rapid and ulti sequestered by Phase I enzymes, bind transiently and re-bind mately lead to administration of multiple or high daily doses. in a variety of conformations prior to the chemical reaction 0006. The relationship between the activation energy and (e.g., oxidation). Metabolic switching is enabled by the rela the rate of reaction may be quantified by the Arrhenius equa tively vast size of binding pockets in many Phase I enzymes tion, k=Ae'. The Arrhenius equation states that, at a and the promiscuous nature of many metabolic reactions. US 2010/0055072 A1 Mar. 4, 2010 Metabolic switching can lead to different proportions of or a salt, Solvate, or prodrug thereof, wherein: known metabolites as well as altogether new metabolites. 0016 R-R, are independently selected from the group This new metabolic profile may impart more or less toxicity. consisting of hydrogen and deuterium; and Such pitfalls are non-obvious and are not predictable a priori 0017 at least one of R-R, is deuterium. for any drug class. 0018 Certain compounds disclosed herein may possess 0012 Laquinimod is an immune function modulator. The carbon-hydrogen bonds of laquinimod contain a naturally useful immune function modulating activity, and may be used occurring distribution of hydrogen isotopes, namely "H or in the treatment or prophylaxis of a disorder in which immune protium (about 99.984.4%), H or deuterium (about function plays an active role. Thus, certain embodiments also 0.0156%), and H or tritium (in the range between about 0.5 provide pharmaceutical compositions comprising one or and 67 tritium atoms per 1018 protium atoms). Increased more compounds disclosed herein together with a pharma levels of deuterium incorporation may produce a detectable ceutically acceptable carrier, as well as methods of making Deuterium Kinetic Isotope Effect (DKIE) that could effect and using the compounds and compositions. Certain embodi the pharmacokinetic, pharmacologic and/or toxicologic pro ments provide methods for modulating immune function. files of laquinimod in comparison with laquinimod having Other embodiments provide methods for treating a immune naturally occurring levels of deuterium. function-mediated disorder in a patient in need of such treat 0013 Based on discoveries made in our laboratory, as well ment, comprising administering to said patient a therapeuti as considering the literature, laquinimod is metabolized in cally effective amount of a compound or composition accord humans at the quinoline ring, the N-methyl group, the N-ethyl ing to the present invention.
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