(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 14 August 2008 (14.08.2008) WO 2008/098151 A2 (51) International Patent Classification: (74) Agent: GROETKEN, TroyA.; McAndrews, Held &MaI- A61K 47/48 (2006.01) A61P 25/00 (2006.01) loy, Ltd, 500 W Madison St., 34th Floor, Chicago, IL 60661 (US). (21) International Application Number: PCT/US2008/053363 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: 8 February 2008 (08.02.2008) AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (25) Filing Language: English IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, (26) Publication Language: English MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, (30) Priority Data: SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, 60/888,870 8 February 2007 (08.02.2007) US ZA, ZM, ZW (71) Applicant (for all designated States except US): KEM- (84) Designated States (unless otherwise indicated, for every PHARM, INC. [US/US]; 3015 Wind Ridge Drive, kind of regional protection available): ARIPO (BW, GH, Coralville, IA 52241 (US). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (72) Inventor; and European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (75) Inventor/Applicant (for US only): MICKLE, Travis C. FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, [US/US]; 3015 Wind Ridge Drive, Iowa City, IA 52241 NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, (US). CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). [Continued on next page] (54) Title: POLAR HYDROPHILIC PRODRUGS OF AMPHETAMINE AND OTHER STIMULANTS AND PROCESSES FOR MAKING AND USING THE SAME hArg-Ampvs. Lys-Amp 4 5 Time [h] Figure 1 (57) Abstract: Disclosed are polar, hydrophilic stimulant prodrug compositions comprising at least one stimulant chemically at tached to a polar hydrophilic ligand, a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed. Published: — without international search report and to be republished upon receipt of that report POLAR HYDROPHILIC PRODRUGS OF AMPHETAMINE AND OTHER STIMULANTS AND PROCESSES FOR MAKING AND USING THE SAME RELATED APPLICATIONS [001] This application claims priority to and benefit of U.S. provisional patent application No. 60/888870, filed on February 8, 2007, which is incorporated by reference in its entirety. FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [002] [Not Applicable] [MICROFICHE/COPYRIGHT REFERENCE] [003] [Not Applicable] BACKGROUND OF THE INVENTION [004] The present technology describes, in general, novel prodrugs/compositions of the stimulant amphetamine (i.e., l-phenylpropan-2-amine) as well as polar hydrophilic conjugates of amphetamine, salts thereof, other derivatives thereof, and combinations thereof. Additionally, the presently described technology also relates generally to the methods of making and using these new prodrugs/compositions. [005] Stimulants, including amphetamine and its derivatives, enhance the activity of the sympathetic nervous system and/or central nervous system (CNS) and are prescribed for the treatment of a range of conditions and disorders predominantly encompassing, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety and wakefulness. [006] Attention deficit hyperactivity disorder (ADHD) in children has been treated with stimulants for many years. However, more recently, the increase in the number of prescriptions for ADHD therapy in an adult population has, at times, outperformed the growth of the pediatric market. Although there are various drugs currently in use for the treatment of ADHD, such as methylphenidate (commercially available from, for example, Novartis International AG (located in Basel, Switzerland) under the trademark Ritalin®) and non-stimulant atomoxetine (commercially from Eli Lilly and Company (located in Indianapolis, IN) as Strattera®), amphetamine has been the forerunner in ADHD therapy. Moreover during classroom trials, non-stimulants have shown to be less effective in improving behavior and attention of ADHD afflicted children than amphetamine derivatives. [007] Initial drug therapy for ADHD was limited to fast acting immediate release formulations of stimulants (e.g., Dexedrine®, pure dextroamphetamine sulfate, commercially available from Smith Kline and French located in the United Kingdom) which triggered an array of potentially undesirable side effects including, for example, fast wear-off of the therapeutic effect of the stimulant active ingredient causing rebound symptoms, cardiovascular stress/disorders (e.g., increased heart rate, hypertension, cardiomyopathy), other side effects (e.g., insomnia, euphoria, psychotic episodes), addiction and abuse. [008] Behavioral deterioration (rebound/"crashing") is observed in a significant portion of children with ADHD as the medication wears off, typically in the afternoon or early evening. Rebound symptoms include, for example, irritability, crankiness, hyperactivity worse than in the unmedicated state, sadness, crying and in rare cases psychotic episodes. The symptoms may subside quickly or last several hours. Some patients may experience rebound/crashing so severe that treatment must be discontinued. Rebound/crashing effects can also give rise to addictive behavior by enticing patients to administer additional doses of stimulant with the intent to prevent anticipated rebound/crashing negative outcomes and side effects. [009] Stimulants, such as methylphenidate and amphetamine, have shown to exhibit noradrenergic and dopaminergic effects that can lead to cardiovascular events comprising, for example, increased heart rate, hypertension, palpitations, tachycardia and in isolated cases cardiomyopathy, stroke, myocardial infarction and sudden death. Consequently, currently available stimulants expose patients with pre-existing structural cardiac abnormalities or other severe cardiac indications to even greater health risks and are frequently not used or used with caution in this population. It is notable, however that the cardiovascular effects of stimulants, for example on heart rate and blood pressure, is dependent on the administered dose. As a result, a treatment which maintains the lowest effective stimulant blood concentrations for a therapeutically beneficial duration is believed to demonstrate fewer cardiovascular risks/side effects. [010] Amphetamine and many of its derivatives (e.g., methamphetamine, 3,4-methylenedioxy- methamphetamine/' Ε cstasy") are widely abused for various purposes such as euphoria, extended periods of alertness/wakefulness, or rapid weight loss or by actual ADHD patients who developed excessive self-dosing habits to prevent rebound symptoms from manifesting, for example, in anxiety or depression. The effects desired by potential abusers originated from the stimulation of the central nervous system and prompted a Schedule II or even Schedule I classification for amphetamine (d- and 1-amphetamine individually and any combination of both are Schedule II) and certain derivatives thereof after passage of the Controlled Substance Act (CSA) in 1970. Both classifications are defined by the high propensity for abuse. Schedule II drugs have an accepted medical use while Schedule I substances do not pursuant to the CSA. So far, all amphetamine products, including compositions with sustained release formulations and prodrugs thereof, are obligated to include a black box warning on the drug label to inform patients about the potential for amphetamine abuse and dependence. [Oil] It has been observed in the conventional art that most side effects of amphetamines are caused by a large initial spike in blood concentration of the stimulant which quickly erodes to levels below therapeutic effectiveness (typically within 4-6 hours). As a consequence, the high potency of dextroamphetamine (d-amphetamine) was subsequently modulated by a series of new drugs with increasingly sustained release profiles achieved by delivering amphetamine more slowly into the blood stream with the goal to create safer and less abusable treatment outcomes and regimens. The methods and technologies for generating smaller spikes in drug blood concentrations include, for example, use of mixed salts and isomer compositions (i.e., different salts of d- and less potent 1- amphetamine), extended/controlled/sustained release formulations (e.g., Adderall X® commercially available from Shire U.S., Inc. located in Wayne, PA) and, most recently, prodrugs of amphetamine (Vyvanse™ also commercially available from Shire). The ideal drug treatment option should produce stimulant blood concentrations within a narrow therapeutic window for an extended time duration followed by a prolonged fade-out period in order to minimize cardiovascular stress and behavioral deterioration, and would also exhibit anti-abuse properties. [012] Besides immediate release formulations, newer sustained release formulations have been developed with the objective to provide a therapeutic