US 20100152283A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0152283 A1 Gant (43) Pub. Date: Jun. 17, 2010 (54) TETRAHYDROCANNABINOL Publication Classification MODULATORS OF CANNABINOD (51) Int. Cl. RECEPTORS A63L/352 (2006.01) C07D 3II/80 (2006.01) (52) U.S. Cl. ......................................... 514/454; 549/390 (75) Inventor: Thomas G. Gant, Carlsbad, CA (US) (57) ABSTRACT The present invention relates to new tetrahydrocannabinol modulators of cannabinoid receptors, pharmaceutical com Correspondence Address: positions thereof, and methods of use thereof. GLOBAL PATENT GROUP - APX 10411 Clayton Road, Suite 304 ST. LOUIS, MO 63131 (US) Formula I (73) Assignee: AUSPEX PHARMACEUTICALS, INC., Vista, CA (US) (21) Appl. No.: 12/640,107 (22) Filed: Dec. 17, 2009 Related U.S. Application Data (60) Provisional application No. 61/138,517, filed on Dec. 17, 2008. US 2010/0152283 A1 Jun. 17, 2010 TETRAHYDROCANNABINOL abdominal pain, nausea, Vomiting, amnesia, anxiety, ataxia, MODULATORS OF CANNABINOD confusion, depersonalization, dizziness, euphoria, hallucina RECEPTORS tion, paranoid reaction, Somnolence, abnormal thinking, con junctivitis, hypotension, diarrhea, fecal incontinence, myal gia, depression, nightmares, speech difficulties, tinnitus, and 0001. This application claims the benefit of priority of vision difficulties. U.S. provisional application No. 61/138,517, filed Dec. 17, 2008, the disclosure of which is hereby incorporated by ref DEUTERIUM KINETIC ISOTOPE EFFECT erence as if written herein in its entirety. 0005. In order to eliminate foreign substances such as 0002 Disclosed herein are new tetrahydrocannabinol therapeutic agents, the animal body expresses various compounds, pharmaceutical compositions made thereof, and enzymes, such as the cytochrome Paso enzymes (CYPs), methods to modulate cannabinoid receptor activity in a Sub esterases, proteases, reductases, dehydrogenases, and ject are also provided for, for the treatment of disorders such monoamine oxidases, to react with and convert these foreign as chemotherapy-induced emesis, pain, neuropathic pain, Substances to more polar intermediates or metabolites for multiple Sclerosis, spasticity, Alzheimer's disease, nausea, renal excretion. Such metabolic reactions frequently involve Vomiting, affective disorders, anorexia nervosa, dementia, the oxidation of a carbon-hydrogen (C H) bond to either a major depressive disorder, cachexia, HIV wasting syndrome, carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. Tourette's syndrome, and emesis. The resultant metabolites may be stable or unstable under 0003 Dronabinol (Marinol R, THC, delta-9-tetrahydro physiological conditions, and can have substantially different cannabinol, delta-9-THC, SP-104, ElevatR, CompassiaR), pharmacokinetic, pharmacodynamic, and acute and long CAS # 1972-08-3), (-)-(6aR,10aR)-6,6,9-trimethyl-3-pen term toxicity profiles relative to the parent compounds. For tyl-6a, 7.8.10a-tetrahydro-6H-benzocchromen-1-ol, is a most drugs, such oxidations are generally rapid and ulti cannabinoid receptor agonist. Dronabinol is commonly pre mately lead to administration of multiple or high daily doses. scribed for the treatment of chemotherapy-induced emesis, 0006. The relationship between the activation energy and cachexia, emesis, and anorexia nervosa (Drug Report for the rate of reaction may be quantified by the Arrhenius equa Dronabinol, Thompson Investigational Drug Database (Aug. tion, k=Ae'. The Arrhenius equation states that, at a 12, 2008); Beal et al., J. Pain Symptom Management 1995, given temperature, the rate of a chemical reaction depends 10(2), 89-97: Meiri et al., Curr. Med. Res. Opin. 2007, 23(3), exponentially on the activation energy (E). 533-43; Struwe et al., Ann. Pharmacother: 1993, 27, 827-31; 0007. The transition state in a reaction is a short lived state and Volicer et al., Int. J. Geriatric Psych. 1997, 12,913-19). along the reaction pathway during which the original bonds Dronabinol has also shown promise in treating pain, neuro have stretched to their limit. By definition, the activation pathic pain, multiple Sclerosis, spasticity, Alzheimer's dis energy E for a reaction is the energy required to reach the ease, nausea; Vomiting, affective disorders, dementia, major transition state of that reaction. Once the transition state is depressive disorder, HIV wasting syndrome, Tourette's syn reached, the molecules can either revert to the original reac drome, asthma, and glaucoma (Drug Report for Dronabinol, tants, or form new bonds giving rise to reaction products. A Thompson Investigational Drug Database (Aug. 12, 2008); catalyst facilitates a reaction process by lowering the activa Ashton et al., Curr. Opin. Invest. Drugs 2008, 9(1), 65-75; tion energy leading to a transition state. Enzymes are Baker et al., Nature 2000, 404, 84-87; Beal et al., J. Pain examples of biological catalysts. Symptom Management 1995, 10(2), 89-97: Rice, Curr: Opin. 0008 Carbon-hydrogen bond strength is directly propor Invest. Drugs 2001, 203), 399-414; Struwe et al., Ann. Phar tional to the absolute value of the ground-state vibrational macother: 1993,27,827-31; and Volicer et al., Int. J. Geriatric energy of the bond. This vibrational energy depends on the Psych. 1997, 12,913-19). 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 Dronabinol 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 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 the rates of a given reaction in which a C H bond is broken, and the same reaction where deuterium is substituted for protium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. Substitution of 0004 Dronabinol is subject to CYP2C9-, CYP2C19-, and tritium for hydrogen results in yet a stronger bond than deu CYP3A4-mediated oxidation of the allylic methyl and meth terium and gives numerically larger isotope effects. ylene groups to form 11-hydroxy-delta-9-tetrahydrocannab I0009 Deuterium (H or D) is a stable and non-radioactive inol, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, isotope of hydrogen which has approximately twice the mass and 8-hydroxy-delta-9-tetrahydrocannabinol (Perez-Reyes, of protium (H), the most common isotope of hydrogen. J. Clin. Pharmacol. 1981, 21, 178S-189S; and Wall et al., Deuterium oxide (DO or “heavy water) looks and tastes like Clin. Pharmacol. Ther: 1983,34(3), 352-63). Adverse effects HO, but has different physical properties. associated with dronabinol administration include: asthenia, 0010 When pure DO is given to rodents, it is readily palpitations, tachycardia, Vasodilation, facial flushing, absorbed. The quantity of deuterium required to induce tox US 2010/0152283 A1 Jun. 17, 2010 icity is extremely high. When about 0-15% of the body water ings. Various deuteration patterns can be used to (a) reduce or has been replaced by DO, animals are healthy but are unable eliminate unwanted metabolites, (b) increase the half-life of to gain weight as fast as the control (untreated) group. When the parent drug, (c) decrease the number of doses needed to about 15-20% of the body water has been replaced with D.O. achieve a desired effect, (d) decrease the amount of a dose the animals become excitable. When about 20-25% of the needed to achieve a desired effect, (e) increase the formation body water has been replaced with DO, the animals become of active metabolites, if any are formed, (f) decrease the so excitable that they go into frequent convulsions when production of deleterious metabolites in specific tissues, and/ stimulated. Skin lesions, ulcers on the paws and muzzles, and or (g) create a more effective drug and/or a safer drug for necrosis of the tails appear. The animals also become very polypharmacy, whether the polypharmacy be intentional or aggressive. When about 30% of the body water has been not. The deuteration approach has the strong potential to slow replaced with DO, the animals refuse to eat and become the metabolism of dronabinol and attenuate interpatient vari comatose. Their body weight drops sharply and their meta ability. 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 cannab reversible unless more than thirty percent of the previous inoid receptors have been discovered, together with methods body weight has been lost due to D.O. Studies have also of synthesizing and using the compounds, including methods shown that the use of DO can delay the growth of cancer cells for the treatment of cannabinoid receptor-mediated disorders and enhance the cytotoxicity of certain antineoplastic agents. in a patient by administering the compounds as disclosed 0011 Deuteration of pharmaceuticals to improve pharma herein. cokinetics (PK), pharmacodynamics (PD), and toxicity pro 0015. In certain embodiments of the present invention, files has been demonstrated previously with some classes of compounds have structural Formula I: drugs. For example, the DKIE was used to decrease the hepa totoxicity of halothane, presumably by limiting the produc tion of reactive species such as trifluoroacetylchloride. How (I) 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.