US 2010013 0582A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0130582 A1 Gant et al. (43) Pub. Date: May 27, 2010 (54) INDOLINONE MODULATORS OF Publication Classification DOPAMINE RECEPTOR (51) Int. Cl. A6II 3/40 (2006.01) C07D 209/34 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA A6IP 25/00 (2006.01) (US); Sepehr Sarshar, Cardiff by (52) U.S. Cl. ......................................... 514/418: 548/486 the Sea, CA (US) (57) ABSTRACT The present invention relates to new indolinone modulators of Correspondence Address: dopamine receptor, pharmaceutical compositions thereof, GLOBAL PATENT GROUP - APX and methods of use thereof. 10411 Clayton Road, Suite 304 ST. LOUIS, MO 63131 (US) Formula I (73) Assignee: AUSPEX PHARMACEUTICALS, INC., Vista, CA (US) (21) Appl. No.: 12/624,618 (22) Filed: Nov. 24, 2009 Related U.S. Application Data (60) Provisional application No. 61/117,250, filed on Nov. 24, 2008. US 2010/013 0582 A1 May 27, 2010 INDOLINONE MODULATORS OF monoamine oxidases, to react with and convert these foreign DOPAMINE RECEPTOR Substances to more polar intermediates or metabolites for renal excretion. Such metabolic reactions frequently involve the oxidation of a carbon-hydrogen (C H) bond to either a 0001. This application claims the benefit of priority of carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. U.S. provisional application No. 61/117,250, filed Nov. 24. The resultant metabolites may be stable or unstable under 2008, the disclosure of which is hereby incorporated by ref physiological conditions, and can have substantially different erence as if written herein in its entirety. pharmacokinetic, pharmacodynamic, and acute and long 0002 Disclosed herein are new indolinone compounds term toxicity profiles relative to the parent compounds. For and compositions and their application as pharmaceuticals most drugs, such oxidations are generally rapid and ulti for the treatment of disorders. Methods of modulation of mately lead to administration of multiple or high daily doses. dopamine receptor activity in a subject are also provided for 0006. The relationship between the activation energy and the treatment of disorders such as restless leg syndrome and the rate of reaction may be quantified by the Arrhenius equa Parkinson's disease. tion, k=Ae'. The Arrhenius equation states that, at a 0003 Ropinirole (Adartrel R., ReOuip(R), Requip XL(R), given temperature, the rate of a chemical reaction depends Ropark(R), SK&F 101468, SK&F 101468-A, CAS # 91374 exponentially on the activation energy (E). 20-8), 4-(2-(dipropylamino)ethyl)indolin-2-one, is a dopam 0007. The transition state in a reaction is a short lived state ine receptor agonist. Ropinirole is commonly prescribed for along the reaction pathway during which the original bonds the treatment of restless leg syndrome and Parkinson's dis have stretched to their limit. By definition, the activation ease. Drug Report for Ropinirole, Thompson Investigational energy E for a reaction is the energy required to reach the Drug Database (Sep. 15, 2008); Zesiewicz et al., Exp. Opin. transition state of that reaction. Once the transition state is Invest. Drugs, 1999, 8(5), 697-710; Rascol et al., Neurol. reached, the molecules can either revert to the original reac Disease Ther, 2004, 63 (Therapy of Parkinson's Disease (3rd tants, or form new bonds giving rise to reaction products. A Edition)), 153-162: Molnar et al., Drugs of Today, 2006, catalyst facilitates a reaction process by lowering the activa 42(9), 587-598; Matheson et al., Drugs, 2000, 60(1), 115 tion energy leading to a transition state. Enzymes are 137: Jost et al., J. Neurology, 2004, 251 (Suppl. 6), VI/ 13-VI/ examples of biological catalysts. 18; Jost et al., J. Neurology, 2006, 253 (Suppl. 4), IV/16-IV/ 0008 Carbon-hydrogen bond strength is directly propor 21: Jost et al., CNS Drug Rev., 2005, 11(3), 253-272; and tional to the absolute value of the ground-state vibrational Bogan et al., Exp. Opin. Pharmacother, 2008, 9(4), 611-623. energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the 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 N chemical reaction (i.e. the step with the highest transition state energy), then Substituting a deuterium for that protium will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The magnitude of the DKIE can be expressed as the ratio between O the rates of a given reaction in which a C H bond is broken, and the same reaction where deuterium is substituted for N H protium. The DKIE can range from about 1 (no isotope effect) Ropinirole 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 0004 Ropinirole is subject to CYP1A2- and CYP3A-me 0009 Deuterium (2H or D) is a stable and non-radioactive diated metabolic oxidation of the three methylene groups isotope of hydrogen which has approximately twice the mass alpha to the amine nitrogen to give N-despropyl and des of protium (H), the most common isotope of hydrogen. diisopropylamine metabolites, as well as hydroxylation of the Deuterium oxide (DO or “heavy water) looks and tastes like 7-position of the indolinone ring. Bloomeret al., Drug Metab. HO, but has different physical properties. Disp., 1997, 25(7), 840-844; Kaye et al., Clin. Pharmacoki I0010. When pure DO is given to rodents, it is readily net., 2000, 39(4), 243-254; Matheson et al., Drugs, 2000, absorbed. The quantity of deuterium required to induce tox 60(1), 115-137: Reavillet al., J. Pharm. Pharmacol., 2000, icity is extremely high. When about 0-15% of the body water 52(9), 1129-1135; and Ramji et al., Xenobiotica, 1999, 29(3), has been replaced by DO, animals are healthy but are unable 311-325. Adverse effects associated with ropinirole include to gain weight as fast as the control (untreated) group. When dizziness, drowsiness, fatigue, headache, heartburn, vomit about 15-20% of the body water has been replaced with D.O. ing, constipation, urinary frequency, mouth dryness, and the animals become excitable. When about 20-25% of the decreased libido. body water has been replaced with DO, the animals become so excitable that they go into frequent convulsions when Deuterium Kinetic Isotope Effect stimulated. Skin lesions, ulcers on the paws and muzzles, and 0005. In order to eliminate foreign substances such as necrosis of the tails appear. The animals also become very therapeutic agents, the animal body expresses various aggressive. When about 30% of the body water has been enzymes, such as the cytochrome Paso enzymes (CYPs), replaced with DO, the animals refuse to eat and become esterases, proteases, reductases, dehydrogenases, and comatose. Their body weight drops sharply and their meta US 2010/013 0582 A1 May 27, 2010 bolic rates drop far below normal, with death occurring at 0014 Novel compounds and pharmaceutical composi about 30 to about 35% replacement with D.O.The effects are tions, certain of which have been found to modulate dopam reversible unless more than thirty percent of the previous ine receptor have been discovered, together with methods of body weight has been lost due to D.O. Studies have also synthesizing and using the compounds, including methods shown that the use of DO can delay the growth of cancer cells for the treatment of dopamine receptor-mediated disorders in and enhance the cytotoxicity of certain antineoplastic agents. a patient by administering the compounds. 0011 Deuteration of pharmaceuticals to improve pharma 0015. In certain embodiments of the present invention, cokinetics (PK), pharmacodynamics (PD), and toxicity pro compounds have structural Formula I: files has been demonstrated previously with some classes of drugs. For example, the DKIE was used to decrease the hepa totoxicity of halothane, presumably by limiting the produc (I) tion of reactive species such as trifluoroacetylchloride. How ever, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic Switching. Metabolic Switching occurs when Xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching is enabled by the rela tively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori for any drug class. 0012 Ropinirole is a dopamine receptor agonist. The car bon-hydrogen bonds of ropinirole contain a naturally occur or a salt thereof, wherein: ring distribution of hydrogen isotopes, namely "H or protium 0016 R-R are independently selected from the group (about 99.984.4%), Hordeuterium (about 0.0156%), and H consisting of hydrogen and deuterium; and or tritium (in the range between about 0.5 and 67 tritium 0017 at least one of R-R is deuterium. atoms per 10' protium atoms). Increased levels of deuterium 0018 Certain compounds disclosed herein may possess incorporation may produce a detectable Deuterium Kinetic useful dopamine receptor modulating activity, and may be Isotope Effect (DKIE) that could effect the pharmacokinetic, used in the treatment or prophylaxis of a disorder in which pharmacologic and/or toxicologic profiles of such ropinirole dopamine receptor plays an active role.