USOO81 01661 B2 (12) United States Patent (10) Patent No.: US 8,101,661 B2 Mickle (45) Date of Patent: *Jan. 24, 2012 (54) POLAR HYDROPHILIC PRODRUGS AND W 388-39. 358. NON-STANDARDAMNO ACID CONUGATES OF AMPHETAMINE AND WO 2008/098151 8, 2008 OTHER STIMULANTS AND PROCESSES FOR OTHER PUBLICATIONS MAKING AND USING THE SAME European Patent Office, Communication dated Jun. 8, 2010, in EP Application No. 07869 098.9. (75) Inventor: Travis C. Mickle, Coralville, IA (US) Amy Sorter, Understanding ADHD Stimulant Abuse, Publication, Vitality Drug Free Work, 2002. (http://12.42.224.168/HealthyLiv (73) Assignee: KemPharm, Inc., North Libery, IA (US) ing family homeljan04 family homestimulantabuse.htm). International Preliminary Report on Patentability for PCT Interna (*) Notice: Subject to any disclaimer, the term of this tional Application No. PCT/US08/53363, dated Nov. 6, 2008. Davankova et al., “Synthesis and Pharmacological Properties of N patent is extended or adjusted under 35 Aminoacyl Derivatives of Beta Phenyl ISO Propylamine.” Pharma U.S.C. 154(b) by 0 days. ceutical Chemistry Journal, vol. 9, No. 3, 1975. G.C. Barrett, D.T. Elmore; Methods for Peptide Bonds Amino Acids This patent is Subject to a terminal dis and Peptides; 1st Edition, Cambridge University Press, UK, 1998, pp. claimer. 151-156. International Search Report and Written Opinion corresponding to (21) Appl. No.: 12/843,169 International Application Serial No. PCT/US08/53363, mailed Nov. 6, 2008, 19 pages. (22) Filed: Jul. 26, 2010 J. Jones; Amino Acid and Peptide Synthesis; 2nd Edition, Oxford University Press, UK, 2002, pp. 25-41. Musshoff, "Illegal or legitimate use? Precursor compounds to (65) Prior Publication Data amphetamine and methamphetamine.” Drug Metabolism Reviews US 2010/O2.92336A1 Nov. 18, 2010 2000 US, vol. 32, No. 1, pp. 15-44. Office Action in U.S. Appl. No. 11/953,668, dated Dec. 16, 2009. Office Action in U.S. Appl. No. 11/953,668, dated Jun. 5, 2009. Related U.S. Application Data Office Action in U.S. Appl. No. 11/953,668, dated Mar. 19, 2009. Office Action in U.S. Appl. No. 12/028, 152, dated Feb. 16, 2010. (63) Continuation of application No. 11/953,668, filed on Office Action in U.S. Appl. No. 12/028, 152, dated Feb. 23, 2010. Dec. 10, 2007, now Pat. No. 7,776,917, application Office Action in U.S. Appl. No. 12/028, 152, dated Mar, 20, 2009. No. 12/843,169, which is a continuation of application Office Action in U.S. Appl. No. 12/028, 152, dated Nov. 12, 2008. No. 12/028,152, filed on Feb. 8, 2008, now Pat. No. Office Action in U.S. Appl. No. 12/028, 152, dated Nov. 13, 2009. 7,772,222. The Drug Enforcement Administration Office of Diversion Control and Office of Congressional and Public Affairs Demand Reduction (60) Provisional application No. 60/888,870, filed on Feb. Section, Stimulant Abuse by School Age Children: A Guide for 8, 2007, provisional application No. 60/869,375, filed School Officials; Publication, Developed and Published by The Drug on Dec. 11, 2006. Enforcement Administration Office of Diversion Control and Office of Congressional and Public Affairs Demand Reduction Section; Jun. Int. C. 2001. (http://www.deadiversion.usdoj.gov/pubs/brochures/stimu (51) lant? stimulant abuse.htm). A6 IK3I/96 (2006.01) European Search Report for European Patent Application No. A6 IK3I/6 (2006.01) 07869098.9-2112, dated Dec. 10, 2009. A6IP 25/00 (2006.01) Notice of Allowance in U.S. Appl. No. 1 1/953,668, dated Apr. 7, (52) U.S. Cl. ........................................ 514/561; 514/613 2010. Notice of Allowance in U.S. Appl. No. 12/028, 152, dated Apr. 12, (58) Field of Classification Search .................. 514/561, 2010. 514f613 Berge et al., Pharmaceutical Salts, J. Pharm. Sci., 66(1):1-19 (1977). See application file for complete search history. Office Action in U.S. Appl. No. 12/473,903, dated Apr. 13, 2011. Office Action in U.S. Appl. No. 12/473.903, dated Aug. 4, 2010. (56) References Cited Office Action in U.S. Appl. No. 12/473,903, dated Sep. 15, 2010. Office Action in U.S. Appl. No. 12/477,616, dated Jun. 28, 2011. U.S. PATENT DOCUMENTS Structure-Activity Relationship and Drug Design, Remington's Pharmaceutical Sciences (Sixteenth Edition). Mack Publishing, 2,881,113 A 4, 1959 Millman 1980. pp. 420-425. 2,892,753. A 6, 1959 Schmidt 6,417, 184 B1 7, 2002 Ockert 6,475,494 B2 11/2002 Kaiko et al. Primary Examiner — Sreeni Padmanabhan 6,503.950 B1 1/2003 Ockert Assistant Examiner — Sahar Javanmard 6,525,062 B2 2/2003 Levine (74) Attorney, Agent, or Firm — McAndrews, Held & 6,696,066 B2 2, 2004 Kaiko et al. Malloy, Ltd. 7,105,486 B2 9, 2006 Mickle et al. 7,223,735 B2 5, 2007 Mickle et al. 7,772,222 B2 8, 2010 Mickle (57) ABSTRACT 7,776,917 B2 8, 2010 Mickle Disclosed are polar, hydrophilic stimulant prodrug composi 2005, OO38121 A1 2/2005 Mickle et al. 2005.0054561 A1 3/2005 Mickle et al. tions comprising at least one stimulant chemically attached to 2006/0177892 A1 8, 2006 De Frees a polar hydrophilic ligand, a salt thereof, a derivative thereof, or a combination thereof. Also disclosed are non-standard FOREIGN PATENT DOCUMENTS amino acid conjugates of amphetamine. Methods of making CN 1816346. A 8, 2006 and using the same are also disclosed. FR 1421130 3, 1966 WO O3,O72046 9, 2003 16 Claims, 5 Drawing Sheets U.S. Patent Jan. 24, 2012 Sheet 1 of 5 US 8,101,661 B2 Cia:g:A: Tire is Figure 2 U.S. Patent Jan. 24, 2012 Sheet 2 of 5 US 8,101,661 B2 Acs harg-Amp-citys-Amp fire is Figure 3 U.S. Patent Jan. 24, 2012 Sheet 3 of 5 US 8,101,661 B2 Lys-Amp vs. harg-Amp -8-Lys-Amp -a-harg-Amp is: {} Figure 6 U.S. Patent Jan. 24, 2012 Sheet 4 of 5 US 8,101,661 B2 U.S. Patent Jan. 24, 2012 Sheet 5 of 5 US 8,101,661 B2 intravenous d-Amp, Lys-Amp and harg-Amp 3. 3. O s: S. St. 3. s: { 3. ( 1. c Timeh) Figure 9 US 8,101,661 B2 1. 2 POLAR HYDROPHILIC PRODRUGS AND Initial drug therapy for ADHD was limited to fast acting NON-STANDARDAMNOACD immediate release formulations of stimulants (e.g., CONUGATES OF AMPHETAMINE AND Dexedrine(R), pure dextroamphetamine Sulfate, commercially OTHER STIMULANTS AND PROCESSES FOR available from SmithKline and French located in the United MAKING AND USING THE SAME Kingdom) which triggered an array of potentially undesirable side effects including, for example, fast wear-off of the thera RELATED APPLICATIONS peutic effect of the stimulant active ingredient causing rebound symptoms, cardiovascular stress/disorders (e.g., This application is a continuation of U.S. patent applica increased heart rate, hypertension, cardiomyopathy), other 10 side effects (e.g., insomnia, euphoria, psychotic episodes), tion Ser. No. 11/953,668, filed on Dec. 10, 2007 now U.S. Pat. addiction and abuse. No. 7,776,917, which claims priority to and benefit of U.S. Behavioral deterioration (rebound/"crashing) is observed provisional patent application No. 60/869,375, filed on Dec. in a significant portion of children with ADHD as the medi 11, 2006; and a continuation of U.S. patent application Ser. cation wears off, typically in the afternoon or early evening. No. 12/028, 152, filed on Feb. 8, 2008 now U.S. Pat. No. 15 Rebound symptoms include, for example, irritability, cranki 7,772,222, which claims priority to and benefit of U.S. pro ness, hyperactivity worse than in the unmedicated State, sad visional patent application No. 60/888,870, filed on Feb. 8, ness, crying and in rare cases psychotic episodes. The Symp 2007. toms may subside quickly or last several hours. Some patients may experience rebound/crashing so severe that treatment BACKGROUND OF THE INVENTION must be discontinued. Rebound/crashing effects can also give rise to addictive behavior by enticing patients to administer The present technology describes, in general, novel pro additional doses of stimulant with the intent to prevent antici drugs/compositions of the stimulant amphetamine (i.e., pated rebound/crashing negative outcomes and side effects. 1-phenylpropan-2-amine). The present technology also Stimulants, such as methylphenidate and amphetamine, describes polar hydrophilic conjugates of amphetamine, Salts 25 have shown to exhibit noradrenergic and dopaminergic thereof, other derivatives thereof, and combinations thereof, effects that can lead to cardiovascular events comprising, for as well as non-standard amino acid conjugates of amphet example, increased heart rate, hypertension, palpitations, amine, salts thereof, other derivatives thereof, and combina tachycardia and in isolated cases cardiomyopathy, stroke, tions thereof. Additionally, the presently described technol myocardial infarction and Sudden death. Consequently, cur ogy also relates generally to the methods of making and using 30 rently available stimulants expose patients with pre-existing these new prodrugs/compositions. structural cardiac abnormalities or other severe cardiac indi The presently described technology in at least one aspect is cations to even greater health risks and are frequently not used focused on a slow/Sustained controlled release composition or used with caution in this population. It is notable, however of amphetamine, in prodrug form, that allows slow/Sustained/ that the cardiovascular effects of stimulants, for example on controlled delivery of the stimulant into the blood system of a 35 heart rate and blood pressure, is dependent on the adminis human or animal within a safe therapeutic window upon oral tered dose.