US 2010O2.92336A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0292336A1 Mickle (43) Pub. Date: Nov. 18, 2010 (54) POLAR HYDROPHILIC PRODRUGS AND (60) Provisional application No. 60/869,375, filed on Dec. NON-STANDARDAMNO ACID 11, 2006, provisional application No. 60/888,870, CONUGATES OF AMPHETAMINE AND filed on Feb. 8, 2007. OTHER STIMULANTS AND PROCESSES FOR MAKING AND USING THE SAME Publication Classification (76) Inventor: Travis C. Mickle, Coralville, IA (51) Int. Cl. (US) A6II 3/16 (2006.01) Correspondence Address: C07C 237/00 (2006.01) MCANDREWS HELD & MALLOY, LTD A6IP 25/00 (2006.01) 500 WEST MADISON STREET, SUITE 3400 CHICAGO, IL 60661 (52) U.S. Cl. ......................................... 514/626; 564/196 (21) Appl. No.: 12/843,169 (22) Filed: Jul. 26, 2010 (57) ABSTRACT Disclosed are polar, hydrophilic stimulant prodrug composi Related U.S. Application Data tions comprising at least one stimulant chemically attached to (63) Continuation of application No. 11/953,668, filed on a polar hydrophilic ligand, a salt thereof, a derivative thereof, Dec. 10, 2007, now Pat. No. 7,776,917, Continuation or a combination thereof. Also disclosed are non-standard of application No. 12/028,152, filed on Feb. 8, 2008, amino acid conjugates of amphetamine. Methods of making now Pat. No. 7,772,222. and using the same are also disclosed. Patent Application Publication Nov. 18, 2010 Sheet 1 of 7 US 2010/0292336A1 --Arg-Ang: -)-Lys-A in -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- yS-A in OhAfg-Ang Patent Application Publication Nov. 18, 2010 Sheet 2 of 7 US 2010/0292336A1 E. Patent Application Publication Nov. 18, 2010 Sheet 3 of 7 US 2010/0292336A1 Lys-Amp vs. hArg-Amp 4 -(-Lys-Amp . 3. -Hh Arg-Amp Q Time (h Figure 5 240 gr. Patent Application Publication Nov. 18, 2010 Sheet 4 of 7 US 2010/0292336A1 Oral Study Lys-Amp vs. Sar-Amp -H S 3-Arts Oral Study Lys-Amp, hoit-Amp, and hArg(NO)-Amp --Lys-Ary - 3 -ti-Air -- Aig NC:3}-Ailp Patent Application Publication Nov. 18, 2010 Sheet 5 of 7 US 2010/0292336A1 Intranasal Study Amp, Lys-Amp, h Arg-Amp - - Annp -H Lys Amp -- harg Amp Intravenous d-Amp, Lys-Amp and hArg-Amp -- Armp -- Lys sh Arg O.5 15 2.5 3 Time (h) Figure 10 Patent Application Publication Nov. 18, 2010 Sheet 6 of 7 US 2010/0292336A1 : ra E. --harg-Amp - A - Orn-AImp O 2 4. 6 8. Time (h) Figure 11 Oral Study: Lys-Amp, h Arg-Amp, Orn-Asp and Cit-Amp ss --Lys-Ap --Arg-Ang: w - - Orr-Arnp - Cit-Aing Figure 12 Patent Application Publication Nov. 18, 2010 Sheet 7 of 7 US 2010/0292336A1 in tranasal Study: Amp, harg-Amp, Orn-Amp r -- Amp 3 --harg-Amp - " - Orn-Amp Figure 13 -- ci-3rip --Arg-Arp - " - ri-A) Figure 14 US 2010/0292336 A1 Nov. 18, 2010 POLAR HYDROPHILIC PRODRUGS AND available from, for example, Novartis International AG (lo NON-STANDARDAMNOACD cated in Basel, Switzerland) under the trademark Ritalin R.) CONUGATES OF AMPHETAMINE AND and non-stimulant atomoxetine (commercially from Eli Lilly OTHER STIMULANTS AND PROCESSES FOR and Company (located in Indianapolis, Ind.) as StratteraR), MAKING AND USING THE SAME amphetamine has been the forerunner in ADHD therapy. Moreover during classroom trials, non-stimulants have RELATED APPLICATIONS shown to be less effective in improving behavior and attention 0001. This application is a continuation of U.S. patent of ADHD afflicted children than amphetamine derivatives. application Ser. No. 11/953,668, filed on Dec. 10, 2007, 0008. Initial drug therapy for ADHD was limited to fast which claims priority to and benefit of U.S. provisional patent acting immediate release formulations of stimulants (e.g., application No. 60/869,375, filed on Dec. 11, 2006; and a Dexedrine(R), pure dextroamphetamine Sulfate, commercially continuation of U.S. patent application Ser. No. 12/028, 152, available from SmithKline and French located in the United filed on Feb. 8, 2008, which claims priority to and benefit of Kingdom) which triggered an array of potentially undesirable U.S. provisional patent application No. 60/888,870, filed on side effects including, for example, fast wear-off of the thera Feb. 8, 2007, which are all incorporated herein by reference in peutic effect of the stimulant active ingredient causing their entireties. rebound symptoms, cardiovascular stress/disorders (e.g., increased heart rate, hypertension, cardiomyopathy), other FEDERALLY SPONSORED RESEARCHOR side effects (e.g., insomnia, euphoria, psychotic episodes), DEVELOPMENT addiction and abuse. 0009 Behavioral deterioration (rebound/"crashing') is 0002. Not Applicable observed in a significant portion of children with ADHD as the medication wears off, typically in the afternoon or early MICROFICHEACOPYRIGHT REFERENCE evening. Rebound symptoms include, for example, irritabil 0003) Not Applicable ity, crankiness, hyperactivity worse than in the unmedicated state, sadness, crying and in rare cases psychotic episodes. BACKGROUND OF THE INVENTION The symptoms may subside quickly or last several hours. 0004. The present technology describes, in general, novel Some patients may experience rebound/crashing so severe prodrugs/compositions of the stimulant amphetamine (i.e., that treatment must be discontinued. Rebound/crashing 1-phenylpropan-2-amine). The present technology also effects can also give rise to addictive behavior by enticing describes polar hydrophilic conjugates of amphetamine, Salts patients to administer additional doses of stimulant with the thereof, other derivatives thereof, and combinations thereof, intent to prevent anticipated rebound/crashing negative out as well as non-standard amino acid conjugates of amphet comes and side effects. amine, salts thereof, other derivatives thereof, and combina 0010 Stimulants, such as methylphenidate and amphet tions thereof. Additionally, the presently described technol amine, have shown to exhibit noradrenergic and dopaminer ogy also relates generally to the methods of making and using gic effects that can lead to cardiovascular events comprising, these new prodrugs/compositions. for example, increased heart rate, hypertension, palpitations, 0005. The presently described technology in at least one tachycardia and in isolated cases cardiomyopathy, stroke, aspect is focused on a slow/Sustained controlled release com myocardial infarction and Sudden death. Consequently, cur position of amphetamine, in prodrug form, that allows slow/ rently available stimulants expose patients with pre-existing sustained/controlled delivery of the stimulant into the blood structural cardiac abnormalities or other severe cardiac indi system of a human or animal within a safe therapeutic win cations to even greater health risks and are frequently not used dow upon oral administration. At least some compositions/ or used with caution in this population. It is notable, however formulation of the current technology can lessen the rebound that the cardiovascular effects of stimulants, for example on effect, cardiovascular stress, addiction/abuse potential and/or heart rate and blood pressure, is dependent on the adminis other common stimulant side effects associated with amphet tered dose. As a result, a treatment which maintains the lowest amine and similar compounds. Such compositions may also effective stimulant blood concentrations for a therapeutically increase the duration of therapeutic efficacy, ease of applica beneficial duration is believed to demonstrate fewer cardio tion, patient compliance and/or any combination of these vascular risks/side effects. characteristics when administered, in particular, orally. 0011 Amphetamine and many of its derivatives (e.g., 0006 Stimulants, including amphetamine and its deriva methamphetamine, 3.4-methylenedioxy-methamphetamine? tives, enhance the activity of the sympathetic nervous system “Ecstasy”) are widely abused for various purposes such as and/or central nervous system (CNS) and are prescribed for euphoria, extended periods of alertness/wakefulness, or rapid the treatment of a range of conditions and disorders predomi weight loss or by actual ADHD patients who developed nantly encompassing, for example, attention deficit hyperac excessive self-dosing habits to prevent rebound symptoms tivity disorder (ADHD), attention deficit disorder (ADD), from manifesting, for example, in anxiety or depression. The obesity, narcolepsy, appetite Suppression, depression, anxiety effects desired by potential abusers originated from the stimu and wakefulness. lation of the central nervous system and prompted a Schedule 0007 Attention deficit hyperactivity disorder (ADHD) in II or even Schedule I classification for amphetamine (d-and children has been treated with stimulants for many years. 1-amphetamine individually and any combination of both are However, more recently, the increase in the number of pre Schedule II) and certain derivatives thereof after passage of scriptions for ADHD therapy in an adult population has, at the Controlled Substance Act (CSA) in 1970. Both classifi times, outperformed the growth of the pediatric market. cations are defined by the high propensity for abuse. Schedule Although there are various drugs currently in use for the II drugs have an accepted medical use while Schedule I sub treatment of ADHD, such as methylphenidate (commercially stances do not pursuant