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

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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

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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

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Figure 10 Patent Application Publication Nov. 18, 2010 Sheet 6 of 7 US 2010/0292336A1

: ra E. --harg-Amp - A - Orn-AImp

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Figure 11

Oral Study: Lys-Amp, h Arg-Amp, Orn-Asp and Cit-Amp

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Figure 12 Patent Application Publication Nov. 18, 2010 Sheet 7 of 7 US 2010/0292336A1

in tranasal Study: Amp, harg-Amp, Orn-Amp

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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 to the CSA. So far, all amphetamine US 2010/0292336 A1 Nov. 18, 2010 products, including compositions with Sustained release for the extractability of drug substance an additional undesirable mulations and prodrugs thereof, are obligated to include a property. It is also, at least in part, a reason for increased drug blackbox warning on the drug label to inform patients about diversion, especially evident by selling or trading of medica the potential for amphetamine abuse and dependence. tion by school children who are ADHD patients and in pos 0012. It has been observed in the conventional art that session of Sustained release amphetamine capsules. The most side effects of amphetamines are caused by a large obtained stimulants are then abused by classmates without initial spike in blood concentration of the stimulant which the disorder by either ingesting high doses or Snorting the quickly erodes to levels below therapeutic effectiveness (typi drug material after crushing it. cally within 4-6 hours). As a consequence, the high potency of (0015 U.S. Pat. No. 7,105,486 (to assignee New River dextroamphetamine (d-amphetamine) was Subsequently Pharmaceuticals, hereinafter the "486 patent) appears to modulated by a series of new drugs with increasingly sus describe compounds comprising a chemical moiety (namely tained release profiles achieved by delivering amphetamine 1-lysine) covalently attached to amphetamine, compositions more slowly into the blood stream with the goal to create safer thereof, and methods of using the same. Allegedly, these and less abusable treatment outcomes and regimens. The compounds and their compositions are useful for reducing or methods and technologies for generating Smaller spikes in preventing abuse and overdose of amphetamine. The 486 drug blood concentrations include, for example, use of mixed patent also describes that using any amino acid other than salts and isomer compositions (i.e., different salts of d- and 1-lysine (Table 46) will not give rise to the same in vivo less potent 1-amphetamine), extended/controlled/sustained properties demonstrated by 1-lysine-d-amphetamine (Lys release formulations (e.g., Adderall XRR) commercially Amp, VyvanseTM). Additionally, since lysine is a natural and available from Shire U.S., Inc. located in Wayne, Pa.) and, standard amino acid, the breakdown of the new prodrug most recently, prodrugs of amphetamine (VyvanseTM also occurs faster than desired to reduce the side effect profile. commercially available from Shire). The ideal drug treatment Thus, quick release of amphetamine from Such standard option should produce stimulant blood concentrations within amino acid conjugate compositions may cause an increase in a narrow therapeutic window for an extended time duration blood pressure and heart rate found in other conventional followed by a prolonged fade-out period in order to minimize stimulant treatments. As a result, there still exists a need cardiovascular stress and behavioral deterioration, and would within the art for a safer dosage form of amphetamine, and also exhibit anti-abuse properties. treatment regimen that is therapeutically effective and can 0013 Besides immediate release formulations, newersus provide Sustained release and Sustained therapeutic effect. tained release formulations have been developed with the objective to provide a therapeutic treatment option that offers BRIEF SUMMARY OF THE INVENTION the convenience of a single daily dosing regimen versus mul 0016. The presently described technology provides, in tiple quotidian administrations. Such formulations also have part, compositions comprising at least one amphetamine con the objective of imparting or rendering a euphoric response. jugated with a non-standard amino acid, or a salt thereof, Sustained release formulations commonly consist of drug which can diminish or eliminate pharmacological activity of particles coated with a polymer or polymer blend that delays the amphetamine until released in vivo. The non-standard and extends the absorption of the active drug substance by the amino acid conjugate(s) of the present technology is amphet gastrointestinal tract for a relatively defined period of time. amine in a prodrug form, and can be converted into its active Such formulations frequently embed the therapeutic agent/ form in the body by normal metabolic processes. Although active ingredient/drug within a hydrophilic hydrocolloid gel not wanting to be bound by any particular theory, one or more ling polymer matrix (e.g., hydroxypropyl methylcellulose, non-standard amino acid conjugates of the present technol hydroxypropyl cellulose or pullulan). This dosage formula ogy are believed to be safer than other sustained release forms tion in turn becomes a gel upon entering an acidic medium, as of amphetamine by providing controlled blood levels for a found in the stomach of humans and animals, thereupon prolonged period of time, thus preventing the rebound effect, slowly effusing the therapeutic agent/active ingredient/drug. cardiovascular stress and euphoria associated with conven However, the dosage formulation dissolves in an alkaline tional stimulant treatment options. medium, as found in the intestines of humans and animals, 0017. The presently described technology further pro concurrently liberating the drug more quickly in an uncon vides methods of controlled therapeutic delivery of amphet trolled manner. Some formulations, such as acrylic resins, amine compositions by oral administration. Release of acrylic latex dispersions, cellulose acetate phthalate, and amphetamine following oral administration of the non-stan hydroxypropyl methylcellulose phthalate, offer improved dard amino acid conjugates of the present technology can Sustained release in the intestines by being resistant to acidic occur gradually over an extended period of time thereby environments and dispensing the active ingredient only at eliminating unintended elevations (e.g., blood level concen elevated pH via a diffusion-erosion mechanism, either by tration spikes) of drug levels in the bloodstream of a human or themselves or mixed with hydrophilic polymers. animal patient. Again not wanting to be bound by any par 0014 Sustained release formulations have been moder ticular theory, it is also believed that such spikes in blood ately effective in providing an improved and extended dosage levels can lead to a euphoric drug “high” and cardiovascular form over immediate release tablets. Nonetheless, such for effects like increased blood pressure and heart rate. Addition mulations are potentially subject to inconsistent, erratic or ally, sustained blood levels are achieved within an effective premature release of the therapeutic agent due to failure of the therapeutic range for a longer duration than other conven polymer material, and they also usually allow easy extraction tional therapies, thereby preventing a rebound effect. of the active ingredient utilizing a simple physical procedure. 0018. At least some compositions comprising the amphet Since single daily dose formulations contain a greater amount amine prodrugs of the present technology are resistant to of amphetamine than immediate release formulations, they abuse by parenteral routes of administration, such as intrave are more attractive to potential abusers, consequently making nous 'shooting.” intranasal 'snorting,” or inhalation “smok US 2010/0292336 A1 Nov. 18, 2010

ing. that are often employed during illicit use. The present with a disorder or condition requiring the stimulation of the technology thus provides a stimulant based treatment modal patient's CNS (Central Nervous System), comprising the step ity and dosage form for certain disorders requiring the stimu of orally administering to the patient in need a composition lation of the CNS such as ADHD, ADD, obesity, narcolepsy, formulated for oral dosage comprising at least one non-stan appetite Suppressant, depression, anxiety, and wakefulness dard amino acid conjugate of amphetamine of the present with reduced or prevented abuse potential. Although not technology, wherein the blood levels of amphetamine in the wanting to be bound by any particular theory, it is believed patient's body can maintain a therapeutically effect level that the treatment of such CNS conditions as noted above with throughout a given day, and do not lead to behavioral dete compositions of the present technology results in Substan rioration or the rebound effect. tially decreased abuse liability as compared to existing stimu 0025. In another aspect, the presently described technol lant treatment modalities and dosage forms. ogy provides a method for treating a human or animal patient 0019. At least some compositions comprising the amphet with a disorder or condition requiring the stimulation of the amine prodrugs of the present technology can also be used for patient's CNS (Central Nervous System), comprising the step treating stimulant (cocaine, methamphetamine) abuse and of orally administering to the patient in need a composition addiction, for improving battle field alertness, and/or for formulated for oral dosage comprising at least one non-stan combating fatigue. dard amino acid conjugate of amphetamine of the present 0020. In a first aspect, the presently described technology technology, wherein the blood levels of amphetamine in the provides a composition comprising at least one non-standard patient's body are not unnecessarily elevated (i.e., blood level amino acid conjugate of amphetamine, a salt thereof, a spikes) thus preventing additional cardiovascular stress derivative thereof, or a combination thereof. Preferably, the through, for example, increased blood pressure and/or heart non-standard amino acid is covalently attached to amphet rate. amine through the C-terminus of the non-standard amino 0026. In another aspect, the presently described technol acid. The N-terminus or the side chain amino group of the ogy provides a method for treating a human or animal patient non-standard amino acid may be in a free and unprotected with a disorder or condition requiring the stimulation of the state, or in the form of a salt thereof. The non-standard amino patient's CNS, comprising orally administering to the patient acid moiety can be derived from a non-standard amino acid in need a composition formulated for oral dosage comprising that is either a dextro- (d-) or levo- (1-) form amino acid, at least one non-standard amino acid conjugate of amphet racemic amino acid, or a mixture thereof. amine, wherein the blood levels of amphetamine in the 0021. In accordance with some embodiments, non-stan patient's body can maintain a therapeutically effect level, but dard amino acids are used. Examples of preferred non-stan do not result in an euphoric effect (such as that observed with dard amino acids to be conjugated with the amphetamine abuse of amphetamines). include, but are not limited to, ornithine, homoarginine, sele 0027. In a further aspect, the presently described technol nomethionine, citrulline, sarcosine, homoserine, and homoc ogy provides a method for delivering amphetamine, compris itrulline. More preferred non-standard amino acids for at least ing providing a human or animal patient with a therapeuti Some embodiments of the present technology are homoargi cally effective amount of at least one non-standard amino acid nine and ornithine. Homoarginine is most preferred for at conjugate of amphetamine, which can provide a therapeuti least some embodiments of the present technology. cally bioequivalent area under the curve (AUC) when com 0022. The compositions of the present technology prefer pared to free amphetamine, but does not provide a maximum ably have no or a Substantially decreased pharmacological plasma concentration (C) which results in an increased activity when administered through injection or intranasal heart rate, increased blood pressure or drug related euphoria routes of administration. However, they remain orally bio when taken orally. available. The bioavailability can be a result of the hydrolysis 0028. In another aspect, the presently described technol of the covalent linkage following oral administration. ogy provides a composition for treating a human or animal Hydrolysis is time-dependent, thereby allowing amphet patient having attention deficit disorder or attention deficit amine and other metabolites Such as p-hydroxyamphetamine hyperactivity disorder, comprising amphetamine chemically and p-hydroxyephedrine to become available in its active attached to a polar hydrophilic ligand, a salt thereof, or a form over an extended period of time. In at least one further combination thereof. embodiment, release of amphetamine is diminished or elimi 0029. In an additional aspect, the presently described tech nated when the composition of the present technology is nology provides a composition for treating a human oranimal delivered by parenteral routes. patient having attention deficit disorder or attention deficit 0023 For example, in one embodiment, the composition hyperactivity disorder, comprising amphetamine chemically of the present technology maintains its effectiveness and attached to a polar hydrophilic ligand, a salt thereof, or a abuse resistance following the crushing of the tablet, capsule combination thereof, wherein the polar hydrophilic ligand is or other oral dosage form utilized to deliver the therapeutic homoarginine. component (i.e., active ingredient/drug) due to the inherent 0030. In a further aspect, the presently described technol controlled release components being a property of the com ogy provides a composition for treating a human or animal position not formulation. In contrast, conventional extended patient having attention deficit disorder or attention deficit release formulations used to control the release of amphet hyperactivity disorder, comprising amphetamine chemically amine are Subject to release of up to the entire amphetamine attached to a polar hydrophilic ligand, a salt thereof, or a content immediately following crushing. When the content of combination thereof, wherein the polar hydrophilic ligand is the crushed tablet is injected or snorted, the large dose of 1-homoarginine. amphetamine produces the “rush’ effect sought by addicts. 0031. In another aspect, the presently described technol 0024. In another aspect, the presently described technol ogy provides a composition for treating a human or animal ogy provides a method for treating a human or animal patient patient having attention deficit disorder or attention deficit US 2010/0292336 A1 Nov. 18, 2010

hyperactivity disorder, comprising amphetamine chemically attention deficit disorder or attention deficit hyperactivity attached to a polar hydrophilic ligand, a salt thereof, or a disorder, comprising a derivative of amphetamine chemically combination thereof, wherein the amphetamine is d-amphet attached to a polar hydrophilic ligand, a salt thereof, or a amine. combination thereof wherein the derivative of amphetamine 0032. In an additional aspect, the presently described tech is 1-amphetamine, methamphetamine, p-methoxyamphet nology provides a composition for treating a human oranimal amine, 3.4-methylenedioxyamphetamine, 2.3-methylene patient having attention deficit disorder or attention deficit dioxyamphetamine, 3.4-methylenedioxymethamphetamine, hyperactivity disorder, comprising amphetamine chemically 2,5-dimethoxy-4-methylamphetamine, 3,4,5-trimethoxyam attached to a polar hydrophilic ligand, a salt thereof, or a phetamine, 2,4,5-trimethoxyamphetamine, 2,3,4-tri combination thereof, wherein the salt thereof is an acefylli methoxyamphetamine, 2,3,5-trimethoxyamphetamine, 2.3, nate, 4-acetamidobenzoate, acetate, aceturate, adipate, ami 6-trimethoxyamphetamine, O 2.4.6- nosalicylate, ammonium, ascorbate, l-aspartate, benzoate, trimethoxyamphetamine. besylate, bicarbonate, borate, butyrate, calcium, camphocar 0038. In a further aspect, the present technology provides bonate, camphorate, d-camsylate, 1-camsylate, camsylate, a composition for treating a human or animal patient having carbonate, cholate, citrate, cypionate, decanoate, dichloroac attention deficit disorder or attention deficit hyperactivity etate, edentate, edisylate, estolate, esylate, ethyl Sulfate, disorder, comprising a derivative of amphetamine chemically fumarate, furate, fusidate, galactarate (mucate), galactur attached to a polar hydrophilic ligand, a salt thereof, or a onate, gallate, gentisate, gluceptate, gluconate, glucuronate, combination thereof wherein the derivative of amphetamine glutamate, glutarate, glycerophosphate, glycolate, hep is 1-amphetamine. tanoate (enanthate), hexanoate, hippurate, hybenzate, hydro 0039. In an additional aspect, the present technology pro bromide/bromide, hydrochloride/chloride, hydroxide, vides a composition for treating a human or animal patient hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- having attention deficit disorder or attention deficit hyperac lactate, lactobionate, laurate, lithium, magnesium, malate, tivity disorder, comprising a derivative of amphetamine d.1-malate, maleate, malonate, mandelate, meso-tartrate, chemically attached to a polar hydrophilic ligand, a salt mesylate, methanesulfonate, methylsulfate, myristate, napa thereof, or a combination thereof wherein wherein the salt disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, thereof is an acefyllinate, 4-acetamidobenzoate, acetate, orotate, oxalate, palmitate, pamoate, phenylpropionate, phos aceturate, adipate, aminosalicylate, ammonium, ascorbate, phate, picrate, pivalate, potassium, propionate, pyrophos 1-aspartate, benzoate, besylate, bicarbonate, borate, butyrate, phate, salicylate, salicylsulfate, sodium, Stearate, succinate, calcium, camphocarbonate, camphorate, d-camsylate, l-cam Sulfate, Sulfosalicylate, tannate, d-tartrate, 1-tartrate, d.l-tar Sylate, camsylate, carbonate, cholate, citrate, cypionate, trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri decanoate, dichloroacetate, edentate, edisylate, estolate, esy brophenate, triflate, undecylenate, Valerate, Valproate, Xin late, ethylsulfate, fumarate, furate, fusidate, galactarate (mu afoate, Zinc, and mixtures thereof. cate), galacturonate, gallate, gentisate, gluceptate, gluconate, 0033. In a further aspect, the presently described technol glucuronate, glutamate, glutarate, glycerophosphate, glyco ogy provides a composition for treating a human or animal late, heptanoate (enanthate), hexanoate, hippurate, hyben patient having attention deficit disorder or attention deficit Zate, hydrobromide/bromide, hydrochloride/chloride, hyperactivity disorder, comprising amphetamine chemically hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, attached to a polar hydrophilic ligand, a salt thereof, or a 1-lactate, d.l-lactate, lactobionate, laurate, lithium, magne combination thereof, wherein the salt thereof is a mesylate, a sium, malate, d.l-malate, maleate, malonate, mandelate, hydrochloride salt, a Sulfate, an oxalate, a triflate, a citrate, a meso-tartrate, mesylate, methanesulfonate, methylsulfate, malate, a tartrate, a phosphate, a nitrate, a benzoate, or a myristate, napadisilate, 2-napsylate, nicotinate, nitrate, mixture thereof. octanoate, oleate, orotate, oxalate, palmitate, pamoate, phe 0034. Another aspect of the present technology provides a nylpropionate, phosphate, picrate, pivalate, potassium, pro composition for treating a human or animal patient having pionate, pyrophosphate, Salicylate, salicylsulfate, Sodium, attention deficit disorder or attention deficit hyperactivity Stearate. Succinate, Sulfate, Sulfosalicylate, tannate, d-tartrate, disorder, comprising a derivative of amphetamine chemically 1-tartrate, d.l-tartrate, terephthalate, thiocyanate, thiosalicy attached to a polar hydrophilic ligand, a salt thereof, or a late, tosylate, tribrophenate, triflate, undecylenate, Valerate, combination thereof. valproate, Xinafoate, Zinc, and mixtures thereof. 0035. In an additional aspect, the present technology pro 0040. In an additional aspect, the present technology pro vides a composition for treating a human or animal patient vides a composition for treating a human or animal patient having attention deficit disorder or attention deficit hyperac having attention deficit disorder or attention deficit hyperac tivity disorder, comprising a derivative of amphetamine tivity disorder, comprising a derivative of amphetamine chemically attached to a polar hydrophilic ligand, a salt chemically attached to a polar hydrophilic ligand, a salt thereof, or a combination thereof wherein the polar hydro thereof, or a combination thereof wherein wherein the salt philic ligand is homoarginine. thereof is mesylate, a hydrochloride salt, a Sulfate, an oxalate, 0036. In a further aspect, the present technology provides a triflate, a citrate, a malate, a tartrate, a phosphate, a nitrate, a composition for treating a human or animal patient having a benzoate, or a mixture thereof. attention deficit disorder or attention deficit hyperactivity 0041 Another aspect of the present technology provides a disorder, comprising a derivative of amphetamine chemically composition for treating a human or animal patient having attached to a polar hydrophilic ligand, a salt thereof, or a attention deficit disorder or attention deficit hyperactivity combination thereof wherein the polar hydrophilic ligand is disorder, comprising at least one conjugate, a salt of the 1-homoarginine. conjugate, or a combination thereof, wherein the conjugate 0037. In another aspect, the present technology provides a comprises amphetamine or a derivative thereof and composition for treating a human or animal patient having homoarginine. US 2010/0292336 A1 Nov. 18, 2010

0042. In an additional aspect, the present technology pro 0051. In an additional aspect, the present technology pro vides a composition for treating a human or animal patient vides a composition for treating a human or animal patient having attention deficit disorder or attention deficit hyperac having attention deficit disorder or attention deficit hyperac tivity disorder, comprising at least one conjugate, a salt of the tivity disorder, comprising at least one conjugate, a salt of the conjugate, or a combination thereof, wherein the conjugate conjugate, or a combination thereof, wherein the conjugate, comprises amphetamine or a derivative thereof and the salt of the conjugate, or the combination thereof is present homoarginine, and wherein the amphetamine is d-amphet in the amount of from about 5 mg to about 250 mg. amine. 0052. In another aspect, the present technology provides a 0043. In a further aspect, the present technology provides composition for treating a human or animal patient having a composition for treating a human or animal patient having attention deficit disorder or attention deficit hyperactivity attention deficit disorder or attention deficit hyperactivity disorder, comprising at least one conjugate, a salt of the disorder, comprising at least one conjugate, a salt of the conjugate, or a combination thereof, wherein the conjugate, conjugate, or a combination thereof, wherein the conjugate the salt of the conjugate, or the combination thereof is present comprises amphetamine or a derivative thereof and 1-ho in the amount of from about 10 mg to about 100 mg. moarginine. 0053. In a further aspect, the present technology provides 0044. In another aspect, the present technology provides a a composition for treating a human or animal patient having composition for treating a human or animal patient having attention deficit disorder or attention deficit hyperactivity attention deficit disorder or attention deficit hyperactivity disorder, comprising at least one conjugate, a salt of the disorder, comprising at least one conjugate, a salt of the conjugate, or a combination thereof, wherein the conjugate, conjugate, or a combination thereof, wherein the conjugate is the salt of the conjugate, or the combination thereof is in an 1-homoarginine-d-amphetamine. amount Sufficient to provide a therapeutically bioequivalent 0045. In an additional aspect, the present technology pro AUC when compared to amphetamine alone, but does not vides a composition for treating a human or animal patient provide a C. Spike. having attention deficit disorder or attention deficit hyperac 0054. In another aspect, the present technology provides a tivity disorder, comprising at least one conjugate, a salt of the composition for treating a human or animal patient having conjugate, or a combination thereof, wherein the salt of the attention deficit disorder or attention deficit hyperactivity conjugate is 1-homoarginine-d-amphetamine hydrochloride. disorder, comprising at least one conjugate, a salt of the 0046. In a further aspect, the present technology provides conjugate, or a combination thereof, wherein the conjugate, a composition for treating a human or animal patient having the salt of the conjugate, or the combination thereof is in an attention deficit disorder or attention deficit hyperactivity amount Sufficient to provide a therapeutically bioequivalent disorder, comprising at least one conjugate, a salt of the AUC when compared to amphetamine alone, but does not conjugate, or a combination thereof, wherein the composition provide an equivalent C. has a reduced pharmacological activity when administered by 0055 Another aspect of the present technology provides a parenteral routes. method of treating a human or animal patient having attention 0047. In another aspect, the present technology provides a deficit disorder or attention deficit hyperactivity disorder, composition for treating a human or animal patient having comprising the step of orally administering to the patient a attention deficit disorder or attention deficit hyperactivity pharmaceutically effective amount of a composition compris disorder, comprising at least one conjugate, a salt of the ing amphetamine chemically attached to a polar hydrophilic conjugate, or a combination thereof, wherein the salt of the ligand, a salt thereof, or a combination thereof. conjugate is a mesylate, a hydrochloride salt, a Sulfate, an 0056. Other objects, advantages and embodiments of the oxalate, a triflate, a citrate, a malate, a tartrate, a phosphate, a invention are described below and will be obvious from this nitrate, a benzoate, or a mixture thereof. description and practice of the invention. 0048. In an additional aspect, the present technology pro vides a composition for treating a human or animal patient BRIEF DESCRIPTION OF SEVERAL VIEWS OF having attention deficit disorder or attention deficit hyperac THE DRAWINGS tivity disorder, comprising at least one conjugate, a salt of the 0057 FIG. 1 compares mean plasma concentrations conjugate, or a combination thereof, wherein the composition released from rats orally administered 1-homoarginine-d-am is in the form of a tablet, a capsule, a caplet, a troche, a phetamine or 1-lysine-d-amphetamine. lozenge, an oral powder, a solution, a oral film, a thin strip, or 0.058 FIG. 2 compares the relative blood levels of d-am a suspension. phetamine released from 1-homoarginine-d-amphetamine 0049. In a further aspect, the present technology provides and 1-lysine-d-amphetamine. a composition for treating a human or animal patient having 0059 FIGS.3 and 4 illustrate the difference in blood levels attention deficit disorder or attention deficit hyperactivity obtained from the study results shown in FIG. 2. disorder, comprising at least one conjugate, a salt of the 0060 FIG. 5 compares average plasma concentrations conjugate, or a combination thereof, wherein the composition from four (4) oral Studies of rats administered 1-homoargin is in the form or a chewable tablet, chewable troche, or chew ine-d-amphetamine or 1-lysine-d-amphetamine. able lozenge. 0061 FIG. 6 compares mean plasma concentrations 0050. In another aspect, the present technology provides a released from rats orally administered 1-citrulline-d-amphet composition for treating a human or animal patient having amine or 1-lysine-d-amphetamine. attention deficit disorder or attention deficit hyperactivity 0062 FIG. 7 compares mean plasma concentrations disorder, comprising at least one conjugate, a salt of the released from rats orally administered sarcosine-d-amphet conjugate, or a combination thereof, wherein the conjugate, amine or 1-lysine-d-amphetamine. the salt of the conjugate, or the combination thereof is present 0063 FIG. 8 compares the mean plasma concentrations of in the amount of from about 1 mg to about 500 mg. d-amphetamine released from rats orally administered 1-ho US 2010/0292336 A1 Nov. 18, 2010 mocitrulline-d-amphetamine, 1-homoarginine(NO)-d-am acid precursor refers to a molecule that can either chemically phetamine or 1-lysine-d-amphetamine. or metabolically breakdown into a naturally occurring amino 0064 FIG.9 compares the mean plasma concentrations of acid (standard or non-standard). As used herein, a “synthetic d-amphetamine released from rats intranasally administered amino acid is an amino acid that is not naturally occurring. d-amphetamine, 1-homoarginine-d-amphetamine or 1-lysine As used herein, an "amino alcohol refers to a derivative of an d-amphetamine. amino acid (standard or non-standard, natural or synthetic) 0065 FIG. 10 compares the mean plasma concentrations wherein the carboxylic acid group has been reduced to an of d-amphetamine released from rats intravenously adminis alcohol. tered d-amphetamine, 1-homoargine-d-amphetamine or 0074 As used herein, “amphetamine' shall mean any of 1-lysine-d-amphetamine. the sympathomimetic phenethylamine derivatives which 0066 FIG. 11 compares the mean plasma concentrations have central nervous system stimulantactivity, Such as but not of d-amphetamine released from rats orally administered limited to, amphetamine (a-methyl-phenethylamine), levo 1-homoarginine-d-amphetamine or 1-ornithine-d-amphet amphetamine, methamphetamine, p-methoxyamphetamine amine. (PMA), methylenedioxyamphetamine, 3.4-methylene 0067 FIG. 12 compares the mean plasma concentration of dioxyamphetamine (MDA), 2.3-methylenedioxyamphet d-amphetamine released from rats orally administered amine, 2,5-dimethoxy-4-methylamphetamine (DOM), 3,4- 1-lysine-d-amphetamine, 1-homoarginine-d-amphetamine, methylenedioxy-methamphetamine (MDMA), 3,4,5- 1-ornithine-d-amphetamine and 1-citrulline-d-amphetamine. trimethoxyamphetamine (TMA), 2,4,5- 0068 FIG. 13 compares the mean plasma concentration of trimethoxyamphetamine (TMA-2), 2,3,4- d-amphetamine released from rats intranasally administered trimethoxyamphetamine (TMA-3), 2,3,5- d-amphetamine, 1-homoarginine-d-amphetamine or 1-orni trimethoxyamphetamine (TMA-4), 2,3,6- thine-d-amphetamine. trimethoxyamphetamine (TMA-5), 2.4.6- 0069 FIG. 14 compares the mean plasma concentration of trimethoxyamphetamine (TMA-6), and methylphenidate. d-amphetamine released from rats intravenously adminis 0075 Please note that although the present technology tered d-amphetamine, 1-homoarginine-d-amphetamine or sometimes may be described with a reference to amphet 1-ornithine-d-amphetamine. amine only, amphetamine is merely used as an example. It should be understood that any method or composition of the DETAILED DESCRIPTION OF THE INVENTION presently described technology is not limited to amphet 0070 The presently described technology relates to novel amine. prodrugs/compositions of stimulants, including stimulants 0076. As used herein, “in a manner inconsistent with the chemically attached to polar hydrophilic ligands, salts manufacturer's instructions' or similar expression is meant to thereof, derivatives thereof, or combinations thereof. More include, but is not limited to, consuming amounts greater than specifically, the presently described technology is related, in amounts described on the label or ordered by a licensed Some embodiments, to compositions comprising non-stan physician, and/or altering by any means (e.g., crushing, dard amino acid conjugates of amphetamine, salts thereof, breaking, melting, separating etc.) the dosage formulation derivatives thereof, or combinations thereof. Methods of Such that the composition maybe injected, inhaled or Smoked. making and using the prodrugs/compositions of the present 0077. As used herein, the phrases such as “decreased.” technology are also disclosed. “reduced,” “diminished' or “lowered' is meant to include at 0071 Polar hydrophilic ligands suitable for the presently least a 10% change in pharmacological activity with greater described technology can take a number of forms. These percentage changes being preferred for reduction in abuse forms can be divided into several categories including non potential and overdose potential. For instance, the change standard amino acids, amino acid derivatives, amino acid may also be greater than 25%, 35%, 45%, 55%, 65%, 75%, precursors, amino alcohols, synthetic amino acid derivatives, 85%, 95%, 96%, 97%, 98%, 99%, or increments therein. phosphorylated carbohydrates, Sugar alcohols, phospholip 0078 Some abbreviations that may be used in the present ids, natural Substrates, and other hydrophilic groups or application include: DCC-dicyclohexylcarbodiimide, ligands. They can be in d-, 1- or racemic form, or a mixture NHS=N-hydroxysuccinimide, EtOAc=ethyl acetate, thereof along with a number of other possible enantiomeric/ MsOH-methanesulfonic acid, EDCl=1-ethyl-3-(3-dimethy diastereomeric forms depending on the ligands. For example, laminopropyl)carbodiimide, PyBrOP-bromo-tris-pyrroli the non-standard amino acid used to produce the stimulant dino phosphoniumhexafluorophosphate, NMM-N-methyl prodrug of the present technology can be either d- or 1-form morpholine or 4-methylmorpholine, TEA triethylamine, amino acid, racemic amino acid, or a mixture thereof. CDl-carbonyl diimidazole, IPAc-isopropyl acetate, 0072. As used herein, a “non-standard’ amino acid refers DEA diethylamine, BOP=(benzotriazol-1-yloxy)tris(dim to an amino acid that is not one of the “standard' twenty ethylamino)phosphonium hexafluorophosphate. amino acids. Non-standard amino acids may be derived from 0079. In accordance with some embodiments, the present either natural or synthetic sources. Non-standard amino acids technology provides stimulants such as amphetamine in a are non-essential and are not readily incorporated into pro prodrug form. More specifically, the stimulant prodrug com teins of natural origin. With the exception of selenocysteine prises at least one stimulant chemically attached to a polar and pyrrolysine, there are no known human genetic codons hydrophilic ligand, a salt thereof, a derivative thereof, or a that are translated into non-standard amino acids. Non-stan combination thereof. dard amino acids may be metabolites of other amino acids or 0080. In accordance with other embodiments, the amphet precursors in various metabolic pathways. amine prodrug of the present technology comprises at least 0073. As used herein, an "amino acid derivative' is a one non-standard amino acid covalently bonded or attached chemically modified version of a naturally occurring amino to amphetamine, which includes different forms or modified acid (standard or non-standard). As used herein, an "amino forms of sympathomimetic phenethylamine derivatives. US 2010/0292336 A1 Nov. 18, 2010

According to the presently described technology, any non orotate, oxalate, palmitate, pamoate, phenylpropionate, phos standard amino acid can be used to produce the amino acid phate, picrate, pivalate, potassium, propionate, pyrophos conjugate of amphetamine. The amino acid can be either the phate, Salicylate, Salicylsulfate, sodium, Stearate. Succinate, dextro- (d-) or levo- (1-) form of the amino acid, a racemic Sulfate, Sulfosalicylate, tannate, d-tartrate, 1-tartrate, d.l-tar mixture of the amino acid, or a mixture thereof. trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri 0081. According to the presently described technology, brophenate, triflate, undecylenate, Valerate, valproate, Xin polar hydrophilic molecules or ligands can be chemically (preferably covalently) attached to amphetamine (d-, 1-, or afoate, Zinc, and mixtures thereof. racemic form or a mixture thereof) to produce novel polar, I0084. Some of the preferred non-standard amino acid con hydrophilic prodrugs of amphetamine. Other stimulants (in jugates of amphetamine of the present technology can be cluding stimulant or stimulant-like drugs) can also be modi represented by the following general formula, fied with these ligands. Some examples of other stimulants include adrafinil, modafinil, aminorex, benzylpiperazine, cathinone, chlorphentermine, chlobenzorex, cyclopentam ine, diethylpropion, ephedrine, fenfluramine, 4-methyl-ami norex, methylone, methylphenidate, pemoline, phentermine, HN phenylephrine, propylhexadrine, pseudoephedrine, and Syn NH ephrine. Metabolites and derivatives of these and other stimu lants could also be modified with the same potential benefit. Examples of metabolites of amphetamine include p-hy droxyamphetamine and p-hydroxyephedrine. 0082 In some embodiments, non-standard amino acids are used to produce the amino acid conjugates of amphet amine. One group of preferred non-standard amino acids suitable for the presently described technology can be repre wherein R the side chain of any non-standard amino acid. sented by the following general formula: More preferably, R is homoarginine or ornithine due to their low toxicity profile in humans and animals. Examples of NH-CH(R)-COOH amphetamine derivatives of the present technology to which wherein R is a side chain of one of the non-standard amino non-standard amino acids, including but not limited to acids. In some preferred embodiments, R comprises the side homoarginine, can be chemically conjugated to are shown chain of ornithine ( CHCHCH-NH) or homoarginine below in Tables 1 and 2. ( CHCHCHCH-NH-(C—NH) NH). In some alter native embodiments, R can comprise the side chain of any TABLE 1 other non-standard amino acid. 0083. In accordance with some embodiments of the pres Amphetamine Derivatives ently described technology, the non-standard amino acid is attached to amphetamine to make the non-standard amino Structure Chemical Name acid conjugate of amphetamine or salts thereof. Preferably, (R) NH2 levoamphetamine the non-standard amino acid is covalently attached to amphet amine through the C-terminus of the amino acid. The N-ter minus or, when it is present, the side chain amino group of the amino acid may be in a free and unprotected State, or in the form of a salt thereof. Alternatively, in some embodiments, methamphetamine the non-standard amino acid can be attached to amphetamine N through the N-terminus. Examples of salts of non-standard amino acid conjugates of amphetamine that can be formed and administered to patients in accordance with the presently described technology include, but are not limited to, acefyl NH2 p-methoxyamphetamine (PMA) linate, 4-acetamidobenzoate, acetate, aceturate, adipate, ami nosalicylate, ammonium, ascorbate, l-aspartate, benzoate, besylate, bicarbonate, borate, butyrate, calcium, camphocar No bonate, camphorate, d-camsylate, 1-camsylate, camsylate, carbonate, cholate, citrate, cypionate, decanoate, dichloroac O NH 3.4-methylenedioxyamphetamine etate, edentate, edisylate, estolate, esylate, ethyl Sulfate, { (MDA) fumarate, furate, fusidate, galactarate (mucate), galactur onate, gallate, gentisate, gluceptate, gluconate, glucuronate, O glutamate, glutarate, glycerophosphate, glycolate, hep tanoate (enanthate), hexanoate, hippurate, hybenzate, hydro /- O 2,3-methylenedioxyamphetamine bromide/bromide, hydrochloride/chloride, hydroxide, O NH2 hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- lactate, lactobionate, laurate, lithium, magnesium, malate, d.1-malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylsulfate, myristate, napa disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, US 2010/0292336 A1 Nov. 18, 2010

TABLE 1-continued TABLE 2-continued Amphetamine Derivatives Trimethoxyamphetamine derivatives. Structure Chemical Name Structure Chemical Name H 3,4-methylenedioxymethampheta N 2,4,6-trimethoxyamphetamine NS mine (MDMA) O (TMA-6) NH2

NH 2,5-dimethoxy-4-methylampheta mine (DOM) No O Y--OY I0085 Examples of non-standard amino acids that are con templated for the presently described technology include, but are not limited to: ornithine, homoarginine, pyrrolysine, TABLE 2 lanthionine, 2-aminoisobutyric acid, dehydroalanine, 3-ala nine, homocysteine, homoserine, 2-oxoarginine, Y-aminobu Trimethoxyamphetamine derivatives. tyric acid (GABA), 4-amino butanoic acid, all phosphory Structure Chemical Name lated Standard amino acids, all hydroxylated Standard amino acids, all acetylated Standard amino acids, all Succinated Stan 3,4,5-trimethoxyamphetamine dard amino acids, all methylated Standard amino acids, 1.1-2. NH2 (TMA)TMA 6-diaminopimelic acid, 6-aminohexanoic acid, 1-2-aminoadi pate 6-semialdehyde, pipecolic acid, d-threo-2,4- diaminopentanoate, 2-amino-4-OXopentanoic acid, 1-erythro NoO 3,5-diaminohexanoic acid, (S)-5-amino-3-oxohexanoic acid, N'-hydroxy-l-lysine, N-acyl-l-lysine, 1-saccharopine, O 5-aminovaleric acid, N-methyl-l-lysine, N,N-dimethyl-1- N lysine, N.N.N-trimethyl-l-lysine, 3-hydroxy-N,N',N'- O NH 2,4,5-trimethoxyamphetamine trimethyl-l-lysine, 4-trimethylammoniobutanoic acid, 5-hy droxy-l-lysine, 1-citrulline, 2-oxo-4-hydroxy-5- 1. Or (TMA-2) aminovalerate, pyrrole-2-carboxylate, 1-erythro-4- No O hydroxyglutamic acid, trans-4-hydroxy-l-proline, 4-oxoproline, N-methylglycine (sarcosine), 3-sulfino-l-ala nine, O-acetyl-l-serine, selenomethionine, selenocysteine, 1. 2,3,4-trimethoxyamphetamine Se-methyl selenomethionine, Se-methyl selenocysteine, O (TMA-3) SelenocyStathionine, selenocysteine selenate, and cys O NH tathione. 0086. In accordance with at least some embodiments, the polar hydrophilic ligands Suitable for the present technology 1. r 2 contain at least one of the following functional groups: O hydroxyl, carboxylic acid, amine (primary or secondary), ketone or aldehyde, acetyl halide, phosphate, phosphonate, 1. 2,3,5-trimethoxyamphetamine sulfate, sulfonate, sulfonyl, sulfonamide, and thiol. These O (TMA-4) functional groups can be chemically attached to amphet amine, for example, through the primary amine of amphet NH2 amine to form the following chemical linkages: carbamate, thiocarbamate, amide, urea, phosphoramidate, phosphona midate, phosphoramide, Sulfamate, Sulfonamide, or thiourea. The final prodrug products of the present technology may be in a number of derivative forms such as salt forms depending on other functionality of the attached ligands and any depro 2,3,6-trimethoxyamphetamine tection steps that may or may not be necessary. (TMA-5) I0087 Salts of the stimulant chemically attached to the polar hydrophilic ligand that can be formed and utilized include, but are not limited to, acefyllinate, 4-acetamidoben Zoate, acetate, aceturate, adipate, aminosalicylate, ammo nium, ascorbate, l-aspartate, benzoate, besylate, bicarbonate, borate, butyrate, calcium, camphocarbonate, camphorate, d-camsylate, 1-camsylate, camsylate, carbonate, cholate, cit rate, cypionate, decanoate, dichloroacetate, edentate, edisy US 2010/0292336 A1 Nov. 18, 2010 late, estolate, esylate, ethylsulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glu -continued ceptate, gluconate, glucuronate, glutamate, glutarate, glyc O erophosphate, glycolate, heptanoate (enanthate), hexanoate, hippurate, hybenzate, hydrobromide/bromide, hydrochlo HO ride/chloride, hydroxide, hydroxybenzoate, iodide, isethion ate, d-lactate, l-lactate, d.l-lactate, lactobionate, laurate, lithium, magnesium, malate, d.l-malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, meth O H ylsulfate, myristate, napadisilate, 2-napsylate, nicotinate, hydroxyproline nitrate, octanoate, oleate, orotate, oxalate, palmitate, pamo O OH ate, phenylpropionate, phosphate, picrate, pivalate, potas sium, propionate, pyrophosphate, salicylate, salicylsulfate, Sodium, Stearate. Succinate, Sulfate, Sulfosalicylate, tannate, HO d-tartrate, 1-tartrate, d.l-tartrate, terephthalate, thiocyanate, --- thiosalicylate, tosylate, tribrophenate, triflate, undecylenate, statine Valerate, Valproate, Xinafoate, Zinc, and mixtures thereof. Fur ther, in accordance with some embodiments, the salts may be required in multiple forms (e.g., di-, tri-, or tetra-). Other derivative forms such as free base, free acid, or neutral forms HO OH may also be prepared depending on the polar hydrophilic ligand used. 0088. Examples of non-standard amino acids suitable for N'-hydroxy-lysine the presently described technology include homoarginine, citrulline, homocitrulline, hydroxyproline, 2-hydroxy-4- (methylthio)butanoic acid (HMB), homoserine, y-aminobu Se tyric acid, 3-alanine, taurine, glutathione, statine, homocys HO teine, selenomethionine, ornithine, sarcosine and --- combinations thereof. Structures of some non-standard amino acids are shown below. Selenomethionine

O HO -- N H N NH2 sarcosine HO r NH2 NH I0089. Examples of amino acids derivatives or precursors homoarginine Suitable in the presently described technology include isos O erine, N-(p-nitro-arginine, N-e.e-dimethyl-lysine, buthion ine, cysteic acid, ethionine, (2-amino ethyl) cysteine, cys HO NH2 tathionine, 2-amino-3-ethyoxybutanoic acid, methylserine, saccharopine, O-ethyl-threonine, and combinations thereof. Structures of some amino acids derivatives or precursors for ornithine use in the practice of the present technology are provided O below. H N NH2

HO r O O NH2 O homocitrulline O HO NH2 HO i -OH

SH OH NH2 O HO isoserine cysteic acid O O H N homocysteine HO OH O O NH2 HO N -- NH2 H NH2 O OH citrulline Saccharopine US 2010/0292336 A1 Nov. 18, 2010 10

-continued O NH2

HO OH HO NH2 in-l NH2 HO C-methylserine NH2 O NH alaninol HO serinol NH2 HO N N1 lysinol H H NH2 N-nitro-arginine 0092. Other polar hydrophilic ligands that can be used to O produce stimulant prodrugs of the present technology include phosphorylated carbohydrates, Sugar alcohols, phospholip N HO N ids, natural Substrates, and other hydrophilic groups. As used herein, phosphorylated carbohydrates refer to carbohydrates NH2 that occur in nature and have been either chemically, enzy N-e, e-dimethyl-lysine matically or biologically phosphorylated. A Sugar alcohol is derived from a Sugar that has had the aldehyde group of the Sugar reduced to an alcohol. Sugar alcohols are used heavily 0090. Examples of synthetic amino acids suitable for use in the Sugar Substitute area. Examples of Sugar alcohols Suit in the presently described technology include 2-amino-3- able for use in the presently described technology include guanidinopropionic acid, 2-amino-3-ureidopropioninc acid, mannitol, Sorbitol, erythritol, glycerol, isomalt, lactitol, 2-amino benzoic acid, 3-amino benzoic acid, 4-amino ben maltitol and Xylitol. Structures of some Sugar alcohols for use Zoic acid, 2-aminomethylbenzoic acid, 3-aminomethylben in the practice of the present technology are provided below: Zoic acid, 4-aminomethylbenzoic acid, 5-acetamido-2-ami nobenzoic acid, (3,4)-diamino benzoic acid, (3,5)-diamino benzoic acid, 2-amino-3-methoxybenzoic acid, 4-nitroan OH thranillic acid, and combinations thereof. Structures of some synthetic amino acids for use in the practice of the present arro HO OH technology are provided below. OH glycerol OH erythritol O l 0093I Phospholipids refer to naturally occurring mono- or --> H NH2 digylcerides that have been phosphorylated. As used herein, NH2 “natural substrates’ refer to polar molecules that are readily 2-amino-3-ureidopropionic acid found in humans and can include essential or non-essential O NH nutrients and biological components. Other hydrophilic groups or ligands include examples of compounds that occur in natural or are regarded as non-toxic and could not be H readily classified in the other groupings. NH2 0094. Examples of some natural substrates suitable for use 2-amino-3-guanidinopropionic acid in the presently described technology include carnitine, ben O Zoic acid, tartaric acid, biotin, citric acid, pantothenic acid and salts, choline, cystine dimer, lactic acid, niacin, ribofla OH vin, thiamine, Vitamin A, vitamin B, Vitamin D. Vitamin D., ascorbic acid, and combinations thereof. Structures of some preferred natural substrates for use in the practice of the HN present technology are provided below. 4-amino benzoic acid

HO O 0091 Examples of amino alcohols suitable for use in the O presently described technology include alaninol, indano, norephedrine, asparaginol, aspartimol, glutamol, leucinol, | - methioninol, phenylalaninol, prolinol, tryptophanol, Valinol, O N+ O OH OH isoleucinol, argininol, serinol, tyrosinol, threoninol, cys OH OH O teinol, lysinol, histidinol, and combinations thereof. Struc carnitine tures of Some amino alcohols for use in the practice of the citric acid present technology are provided below. US 2010/0292336 A1 Nov. 18, 2010 11

deprotection of benzoyl usually requires strong basic condi -continued tions such as in the presence of NaOMe. 0099 More specifically, using a non-standard amino acid and amphetamine as an example, the non-standard amino OH acid can be attached to amphetamine to make an amino acid conjugate of amphetamine or salts thereof in accordance with the presently described technology. Preferably, the amino benzoic acid acid is covalently attached to amphetamine through the C-ter minus of the amino acid. The N-terminus or the side chain amino group of the amino acid may be in a free and unpro 0095 Examples of other hydrophilic groups suitable for tected state, or in the form of a salt thereof. Alternatively, in use in the presently described technology include ethylene Some embodiments, the amino acid can be attached to diamine tetraacetic acid (EDTA), t-butylated hydroxyanisole amphetamine through the N-terminus. Examples of salts of (BHA), propionic acid, sorbic acid, erythorbic acid, methyl amino acid conjugates of amphetamine that can be formed paraben, propyl gallate, propyl paraben, thiodipropionic acid, and administrated to patients inaccordance with the presently propylene glycol, pyridoxine, adipic acid, Succinic acid, described technology include, but are not limited to, acefyl malic acid, acetoin, N-butyric acid, Vanillin, geraniol, methyl linate, 4-acetamidobenzoate, acetate, aceturate, adipate, ami anthranilate, benzoin, benzyl alcohol, and combinations nosalicylate, ammonium, ascorbate, 1-aspartate, benzoate, thereof. Structures of two representative hydrophilic groups besylate, bicarbonate, borate, butyrate, calcium, camphocar for use in the practice of the present technology are provided bonate, camphorate, d-camsylate, 1-camsylate, camsylate, below. carbonate, cholate, citrate, cypionate, decanoate, dichloroac etate, edentate, edisylate, estolate, esylate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galactur O H onate, gallate, gentisate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hep O tanoate (enanthate), hexanoate, hippurate, hybenzate, hydro bromide/bromide, hydrochloride/chloride, hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- -N-N-NOH 1. lactate, lactobionate, laurate, lithium, magnesium, malate, Sorbic acid O d.l-malate, maleate, malonate, mandelate, meso-tartrate, OH mesylate, methanesulfonate, methylsulfate, myristate, napa vanillin disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, palmitate, pamoate, phenylpropionate, phos 0096 Generally, to produce a stimulant prodrug of the phate, picrate, pivalate, potassium, propionate, pyrophos present technology, a selected polar hydrophilic ligand (e.g., phate, Salicylate, Salicylsulfate, sodium, Stearate. Succinate, a commercially available non-standard amino acid or amino Sulfate, Sulfosalicylate, tannate, d-tartrate, 1-tartrate, d.l-tar acid derivative) can be added to the stimulant (e.g. amphet trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri amine) in dextro, levo or racemic forms. Depending on the brophenate, triflate, undecylenate, Valerate, valproate, Xin polar hydrophilic ligand selected, one or more functional afoate, Zinc, and mixtures thereof. groups on the polar hydrophilic ligand may or may not need 0100. To conjugate an amino acid of the present technol to be protected prior to coupling the ligand with the stimulant. ogy, including non-standard amino-acids, with amphetamine, 0097. For example, to conjugate an amino acid with the one or more amino groups are preferably protected using amphetamine, the one or more amino groups are preferably agents described above before the amino acid is reacted with protected before the amino acid is reacted with amphetamine. amphetamine. The amino acid whose amino groups are pro Agents and methods for protecting amino groups in a reactant tected can be referred to as an N-protected amino acid. One are known in the art. Examples of protecting groups that may can either protect the amino groups in situ during the produc be used to protect the amino groups include, but are not tion process, or use commercially available N-protected limited to, fluorenylmethoxycarbonyl (Fmoc), t-butylcarbon amino acids directly. Preferably, the carboxylic acid group in ate (Boc), trifluoroacetate (TFA), acetate (Ac) and benzy the N-protected amino acid is activated by an acid activating loxycarbonyl (Z). After coupling with any standard coupling agent (sometimes also called coupling reagent) to help the procedure, deprotection can occur with a variety of strong reaction of the N-protected amino acid with amphetamine. acids to give the corresponding salt form. Saltforms may also General information about the reaction of amino acids to be switched by first free basing the product and then adding form peptide bonds can be found in, for example, G.C. Barett, any acid. Neutral, free base or anionic salts may also be D. T. Elmare, Amino Acids and Peptides, page 151-156, formed. Additional deprotection may be necessary in the case Cambridge University Press, UK (1st edition, 1998); Jones, of some polar hydrophilic ligands such as homoarginine and J., Amino Acid and Peptide Synthesis, pages 25-41, Oxford any protected urea derivative. These deprotections usually University Press, UK (2nd edition, 2002), which are incorpo occur under hydrogenation conditions. rated herein by reference in their entirety. 0098. For another example, coupling of carnitine (d-, 1-, or 0101 One category of acid activating agents (coupling racemic) to amphetamine may require protection of the reagents) well known in the art are carbodiimides. Examples hydroxyl group prior to coupling. In accordance with some of carbodiimide acid activating agents include, but are not embodiments, use of a silyl or benzoyl group to protect the limited to, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'- hydroxyl group would be preferred. Deprotection of the silyl dimethylaminopropyl)-carbodiimide (EDCI), and diisopro can occur in water or slightly acidic media. On the other hand, pylcarbodiimide (DIPCDI). Examples of other coupling US 2010/0292336 A1 Nov. 18, 2010 reagents that could be used include bromo-tris-pyrrolidino phosphoniumhexafluorophosphate, (benzotriazol-1-yloxy)- -continued tris-(dimethylamino)-phosphonium hexafluorophosphate, PCls/PhH, SOCl, NH 1-ethoxycarbonyl-2-ethoxy-1,2-di HN hydroquinoline, other phosphonium reagents, and uronium N SNO, 1. H., Pd/C, reagents. The use of appropriate acyl halide or anhydride is NH MeOHA also contemplated. HCI 0102 The N-protected amino acid conjugate of amphet 2. HCI in amine resulting from the reaction of the N-protected amino dioxane acid and amphetamine as described above can then be de- or un-protected with a strong acid to produce the corresponding final salt form of the amino acid conjugate of amphetamine. 0103 Scheme 1 below outlines an exemplary route for the O l synthesis of a derivative of amphetamine chemically attached N to homoarginine in accordance with the presently described O technology. In this exemplary reaction scheme, a dihydro chloride Salt form of homoarginine-amphetamine is pro N NH2 HCI duced. The procedure uses tert-butyloxycarbonyl (Boc) and nitro protected homoarginine (Boc-homoarginine(NO)) as NH the starting material. In this exemplary reaction scheme, the coupling agent EDC1 is added to Boc-homoarginine(NO) in dimethylformamide (DMF). N-hydroxysuccinamide (NHS) is then added to the reaction mixture. A stable, yet still acti vated, succinimidyl ester of Boc-homoarginine(NO) is H formed. Amphetamine is then added to the resulting Succin N imidyl ester of Boc-homoarginine(NO) to make the corre HC H2N sponding protected prodrug, Boc-homoarginine(NO)-am phetamine. This protected prodrug can be de- or un-protected using hydrogenation followed by a strong acid such as meth anesulfonic acid (MSOH) or hydrochloric acid to produce the 0104. The preparation of hArg-Amp required extensive prodrug of amphetamine, which is a dihydrochloride Salt of modifications to previously published methods and synthe homoarginine-amphetamine in this exemplary reaction ses. First, Boc-harg(NO)—OH required use of DMF to scheme. solubilize the material prior to reaction. Second, formation of Scheme 1 the free base of amphetamine was performed in situ and was not isolated. Also, the formation of the activated ester was HN performed in situ with the addition reaction following in the same reaction vessel. Homoarginine is different from many N NNO other standard and non-standard amino acids in that it NH requires a separate step of deprotection to remove the nitro group from the side chain. Failure to adequately protect homoarginine can lead to undesirable products that do not perform in vivo with respect to the desired therapeutic out comes discussed herein. O 0105 Examples of other solvents that can be used in the presently described technology include, but are not limited to, >ulO N OH isopropyl acetate (IPAC), acetone, and dichloromethane H (DCM), dimethylformamide (DMF), ethyl acetate, chloro form, dimethylsulfoxide, dioxane, diethyl ether, methylt-bu NHS, EDCI, DIPEA tyl ether, hexanes, heptane, methanol, ethanol, isopropanol, and butanol. A mixture of different solvents can also be used. Co-bases such as tertiary amines may or may not be added in the coupling reaction of the presently described technology. Example of suitable co-bases include, but are not limited to 4-methylmorpholine (NMM), triethylamine (TEA), ammo nia or any tertiary amine base. 0106 The amphetamine to be chemically attached to polar hydrophilic ligands of the presently described technology can be in d-form, 1-form, or racemic form, or can be a mixture thereof. In accordance with some embodiments of the pres ently described technology, d-amphetamine (dextroamphet amine) and a non-standard amino acid with a know toxicity O ul profile are preferably used to make an amphetamine prodrug. N Other preferred polar hydrophilic ligands to form d-amphet amine prodrugs include, for example, 1-carnitine, 1-saccha ropine, 1-lysinol, benzoic acid, citric acid, choline, EDTA, or US 2010/0292336 A1 Nov. 18, 2010

Succinic acid. In accordance with some other embodiments, the prodrugs of d-amphetamine can be used in combination -continued with a prodrug of 1-amphetamine or 1-amphetamine itself. 1 CH 3 0107 Scheme 2 below outlines an exemplary route for the Se synthesis of a derivative of amphetamine chemically attached to selenomethionine in accordance with the presently H described technology. The amphetamine prodrug produced N here is in a sulfate salt form. HN O

sulfate salt

0.108 Scheme 3 below outlines an exemplary route for the synthesis of a derivative of amphetamine chemically attached DCC, NHS He to statine in accordance with the presently described technol > - - - EtOAc ogy. The amphetamine prodrug produced here is in an HCl N salt form.

OH 1. EDCI, amphetamine --- 2. HCI

0109 Scheme 4 below outlines an exemplary route for the synthesis of a derivative of amphetamine chemically attached to isoserine in accordance with the presently described tech nology. The amphetamine prodrug produced here is in an NH2 MSOH Salt form.

Scheme 4 O O

> O ls N OH -->DCC, NHS H EtOAc 1. US 2010/0292336 A1 Nov. 18, 2010 14

-continued -continued O O O O O

N O N O1 > us H ~. -- O O O HN

O EtOAc He > 1,-,--O- > ul 1, -N O O 1. anhydrous l acid (HCl in O N N Hedioxane) H H 2. MSOH O anhydrous HN acid --- 1. O

O

O N H HN N O OH MSOHSalt

O OH 0110 Scheme 5 below outlines an exemplary route for the synthesis of a derivative of amphetamine chemically attached to saccharopine in accordance with the presently described technology. The amphetamine prodrug produced here is in OH various salt forms. HN

O Scheme 5

O o-(- H N HN O O HN O various salt forms

1. EDCI --- O 2. d-amphetamine 0111 Scheme 6 below outlines an exemplary route for the > ul OH synthesis of a derivative of amphetamine chemically attached O N to cyStathionine in accordance with the presently described technology. The amphetamine prodrug produced here is in an HCl Salt form. US 2010/0292336 A1 Nov. 18, 2010 15

Scheme 8 HNN SNO, DCC, NHS NH Hos O EtOAc 1. EDCI, amphetamine cr's -- 2. HC >ulO N OH H

H HNN N NNO Ji NH O

HN O >ulO N NN O H O O HN N n n NO NH HN O -- O >ul O O HC Salt O N n N R = OH or amphetamine H R = OH or amphetamine O O

EtOAc 0112 Scheme 7 below outlines an exemplary route for the He synthesis of a derivative of amphetamine chemically attached NH2 to O-ethyl-threonine in accordance with the presently described technology. The amphetamine prodrug produced HN here is in an HCl salt form. N n NO NH O Scheme 7 N > O us N H H r O HN 1. EDCI, amphetamine He n NO 2. HCI 1. H2/Pd, NH EtOAc >1. O 2. MSOH

HN 0113 Scheme 8 below outlines an exemplary route for the synthesis of a derivative of amphetamine chemically attached to 2-amino-3-guanidinopropionic acid in accordance with the MSOHSalt presently described technology. The amphetamine prodrug produced here is in an MsCH salt form. US 2010/0292336 A1 Nov. 18, 2010

0114 Scheme 9 below outlines an exemplary route for the synthesis of a derivative of amphetamine chemically attached to lysinol-carbamate in accordance with the presently Scheme 10 described technology. The amphetamine prodrug produced NH2 here is in an HCl salt form.

CDI, IPAc --

Fmoc O n N n BZ - -k H

CDI, IPAc l -- HN N1\ N > --- S. Fmoc NN O YB, - -k H

HN l N1\ N S. 1. amphetamine Her 2. DEA, NaOMe

Fmoc O n N n BZ H

1. amphetamine --- 2. HC l HN N H

OH HN

0116 Scheme 11 below outlines an exemplary route for the synthesis of amphetamine chemically attached to a phos phorylated carbohydrate in accordance with the presently described technology.

Scheme 11 O OH 1. Primary-OH protection HO 2. Secondary-OH protection 3. Primary-OH deprotection 0115 Scheme 10 below outlines an exemplary route for 4. Phosphorylation HO OH 5. Phosphate activation the synthesis of a derivative of amphetamine chemically 6. Amphetamine attached to lysinol-urea in accordance with the presently OH 7. Deprotection described technology. US 2010/0292336 A1 Nov. 18, 2010

-continued -continued O

N 1No O OH --~~~ H OH OH

HO OH

OH HO-PEO

0117 Scheme 12 below outlines an exemplary route for NH the synthesis of a derivative of amphetamine chemically attached to erythritol in accordance with the presently described technology.

Scheme 12 OH 1. CDI OTMS - - --> TMSO 2. d-amphetamine 0119 Scheme 14 below outlines an exemplary route for 3. acid the synthesis of a derivative of amphetamine chemically attached to benzoic acid using benzoyl chloride in accordance with the presently described technology.

d-amphetamine C Her

I0120 Scheme 15 below outlines an exemplary route for the synthesis of a derivative of amphetamine chemically attached to carnitine in accordance with the presently described technology. 0118 Scheme 13 below outlines an exemplary route for the synthesis of amphetamine chemically attached to a phos Scheme 15 pholipid in accordance with the presently described technol O Ogy. N He1. DCC, TEA 1. N O 2. d-amphetaminep 3. water Scheme 13 OTMS O ~so N OH >r OH O 1. Phosphate activation I0121 Scheme 16 below outlines an exemplary route for HO- O ---2. Amphetamine the synthesis of a derivative of amphetamine chemically OH attached to citric acid in accordance with the presently described technology. US 2010/0292336 A1 Nov. 18, 2010 18

-continued Scheme 16 R OH HO 1. DCC, NHS ca O O OH O --2. d-amphetamine R r 1N1 Null R" OH O O

R'' R = OH or amphetamine R = OH or amphetamine R" = OH or amphetamine R" = OH or amphetamine

0.124 Scheme 19 below outlines an exemplary route for the synthesis of a derivative of amphetamine chemically o,O OH 2O attached to Succinic acid in accordance with the presently described technology.

Scheme 19

1. BOP HO 2. d-amphetamine 0122) Scheme 17 below outlines an exemplary route for OH the synthesis of a derivative of amphetamine chemically attached to choline in accordance with the presently described technology. R

Scheme 17 O -- OH 1. CDI R = OH or amphetamine N1-11. 2. d-amphetamine R = OH or amphetamine

0.125 Scheme 20 below shows a general synthetic scheme when ornithine is used as the non-standard amino acid.

0123 Scheme 18 below outlines an exemplary route for the synthesis of amphetamine chemically attached to EDTA in accordance with the presently described technology. OH HN Scheme 18 O OH 2,5-diaminopentanoic acid 4. O

HO 1N1 Nulls OH - 1. BOP- - 2. d-amphetamine 1. Amino Protection -- O O NH2 2. Activation 3. Addition 4. Deprotection OH 1-phenylpropan-2-amine US 2010/0292336 A1 Nov. 18, 2010

-continued -continued NH2 -k MSOHA EtOAc H N HN O O ulO N 2,5-diamino-N- (1-phenylpropan-2-yl) pentanamide

NHOMs 0126. In accordance with some embodiments of the pres ently described technology, d-amphetamine (dextroamphet amine) is preferably used and 1-ornithine is a preferred non standard amino acid. In accordance with some other embodiments, the prodrug of d-amphetamine can be used in MsOHN combination with a prodrug of 1-amphetamine or 1-amphet amine itself. 0127. In accordance with some other preferred embodi ments, synthesis of Orn-Amp 1-ornithine-d-amphetamine) I0128 Besides ethyl acetate, examples of other solvents can be accomplished in two steps as shown in reaction that can be used in the presently described technology Scheme 21 below. The first step is the coupling of Boc-Orn include, but are not limited to, isopropyl acetate (IPAc), (Boc)-OH with d-amphetamine using EDC1. N-hydroxysuc acetone, and dichloromethane (DCM). A mixture of different cinimide (NHS) can be added to form an in-situ activated Solvents can also be used. When a polar solvent is required, ester with diisopropylethylamine (DIPEA) used as a co-base. water, dimethylformamide (DMF), 1,4-dioxane or dimethyl The product can then be subjected to deprotection with meth sulfoxide (DMSO) can be used. Co-bases such as tertiary anesulfonic acid which also forms the corresponding dime amines may or may not be added in the coupling reaction. Sylate salt. Examples of suitable co-bases include 4-methylmorpholine (NMM), triethylamine (TEA), etc. I0129. It is important to note that preparation of Orn-Amp requires additional experimentation compared to the prior art. It has been Surprisingly found that significant changes of the solubility in starting material of Boc-Orn(Boc)-OH required -k the use of DMF instead of less polar solvents stated previ ously. In addition, due to the unique solubility differences of Orn-Amp 2MsOH as compared to either Lys-Amp 2 HCl or Lys-Amp 2 MsOH, the procedures of the conventional art would not give rise to Orn-Amp 2 MsOH without significant > -ss experimentation. Also, formation of the free base of amphet amine was performed in situ and was not isolated. The for NHS, EDCI, DIPEA, mation of the activated ester was performed in situ with the DMF He addition reaction following in the same reaction vessel. Quite Surprisingly, these changes to solubility and reaction condi tions are not readily apparent from previously published pro cedures or from the overall structures themselves and were unpredictable and unexpected which lead to the discovery of -k the presently described technology. 0.130. In some other preferred embodiments of the present technology, 1-citrulline-d-amphetamine hydrochloride (Cit Amp) can be synthesized as shown in reaction Scheme 22 below in three overall steps. The first step involves the acti O ul vation of Boc-Cit-OH to form an activated ester using DCC N and NHS followed by the addition of d-amphetamine to pro duce the protected Boc-Cit-Amp. Deprotection using 4NHCl in dioxane gives the corresponding hydrochloride salt. US 2010/0292336 A1 Nov. 18, 2010 20

-continued O

HNls NH

DCC, NHS --- THF CIHN OH

I0131) Another example of the preparation of homoargin ine conjugates of amphetamine derivatives of the present NH2 technology is shown in the general pathway of Scheme 23.

HN NH2 1. Activating agent 2. Amphetamine derivative (PEA) 3. Deprotection

NH

HN l NH2

PEA HN O

I0132) Scheme 24 provides an exemplary route for the syn thesis of p-methoxyamphetamine (PMA) chemically attached to homoarginine.

HCI in dioxane HN NH, 1. NHS, DCC, THF NH2

° N O Orr O 3. H., Pd/C, HCI, MeOH > l OH 4. HCI, MeOH O US 2010/0292336 A1 Nov. 18, 2010 21

-continued -continued NH NH 1. NH2 1. NH2

O HN HN N O 1. O

0.133 Scheme 25 provides an exemplary route for the syn- 0135) Scheme 27 provides an exemplary route for the syn thesis of a methylenedioxyamphetamine derivative (example thesis of a trimethoxyamphetamine derivative (example shows 3.4-methylenedioxyamphetamine) chemically shows 3,4,5-trimethoxyamphetamine) chemically attached attached to homoarginine. to homoarginine. Scheme 27 -NO) 1. NHS, EDCI, NMM, DMF,NH2 ins, 1. NHS, EDCI, NMM, DMSO, NH2 O Orr -O NH2 3. H., Pd/C, HCI, EtOH, O O

> O OH 4. HOHCl, dioxane O l N OH O n l N H 3. H2, Pd/C, HCI, MeOH H O 4. HCI, MeOH

HN NH2 HN NH2

H N O O N

HN O ro X HN O O O 0134 Scheme 26 provides an exemplary route for the syn- -O thesiRN If 2.5-dimethoXV-4-methvlamphetamit R methylamphetamine ( DOM) 0.136 Scheme 28 provides an exemplary route for the syn Cnem1cally allached to nomoarg1n1ne. thesis of levoamphetamine chemically attached to homoargi nine.

Scheme 26 NO l NH, 1 NHS, DCC, 2-MeTHF ins, 1. NHS, EDCI, DIPEA, DMSO, O NH2

>uO N OH NMM > -- OH - S? - H O He3. H2, Pd/C, HCl, IPA, H2O H O 3. Epic, HCI, MeOH, 4. HCI, IPA 4. HCI,2 MeOH US 2010/0292336 A1 Nov. 18, 2010 22

0140 Standard amino acids such as lysine or glutamic -continued acid are not contemplated for the presently described tech NH nology. Because standard amino acids are essential parts of all dietary requirements, it would be expected that the pro HN l NH2 drug of the present technology conjugated with a standard amino acid would be released at a faster rate. By using non standard amino acids, synthetic amino acids, amino acid derivatives or precursors, or other polar hydrophilic ligands of the presently described technology, the release rate of amphetamine or another stimulant will be reduced due to the difference in overall digestion rate of the stimulant prodrug. 0.141. Once produced, the prodrug of amphetamine (or HN another stimulant) of the present technology can be adminis tered through oral routes of delivery and once administered will release the stimulant under digestive conditions. Due to the hydrophilic and polar nature of the prodrug and the slow 0.137. At least some compounds of the present technology, rate of hydrolysis of the chemical linkage as described above, including polar, hydrophilic stimulant prodrugs, have no or a should high levels of drug be administered either accidentally Substantially decreased pharmacological activity when or intentionally, the prodrug will be cleared by metabolic administered through alternative routes of administration and/or excretory pathways prior to releasing large amounts of including, but not limited to, injection or intranasal. However, the stimulant. Also, release of amphetamine (or another they remain orally bioavailable. The bioavailability can be a stimulant) over an extended period should alleviate or dimin result of the hydrolysis of the covalent linkage following oral ish drug induced side-effects that can limit or terminate administration. Hydrolysis of a chemical linkage is time amphetamine therapy. These side effects include increase in dependent, thereby allowing amphetamine and other metabo the heart and respiration rates, increased blood pressure, dila lites Such as p-hydroxyamphetamine and p-hydroxyephe tion of the pupils of the eyes, and decreased appetite. Other drine or another stimulant to become available in its active side effects include anxiety, blurred vision, sleeplessness, and form over an extended period of time. dizziness. Also, amphetamines and other stimulants are 0.138. Therefore, the prodrug compounds of the present power psychostimulants and are prone to substance abuse. technology can release amphetamine or another stimulant 0142. Substance abuse of stimulants is often characterized over an extended period and provide a therapeutically area by an escalation of events. First, a substantial “rush” or high under the curve (AUC) when compared to free amphetamine may be obtained from increasing oral dosages. Due to the or another stimulant (including other controlled release forms properties of these polar, hydrophilic prodrugs, these poten of amphetamine such as Adderall XRR) or VyvanseTM) with tial routes for abuse can be mitigated via the polar nature of little or no spike in maximum plasma concentration (C)) the prodrug. That is, once administered at higher than thera or equivalent C. Not wanting to be bound by any particular peutic levels, the body will excrete any remaining prodrug theory, it is believed that since non-standard amino acids and without breakdown into amphetamine. After oral amounts the other suitable polar hydrophilic ligands are used to pro exceed an attainable amount, other routes can be explored duce the prodrugs, the in vivo breakdown of the prodrugs by including Smoking, Snorting, or injection. In accordance with enzymes would occurata slower rate than, for example, when the presently described technology, release of amphetamine a standard amino acid is used to conjugate the stimulants. This or another stimulant would only occur under desired physi will allow the prodrugs of the present technology to release ological conditions. Preferably, non-oral routes of adminis amphetamine or other stimulants slowly and, preferably, only tration (e.g., intranasal or intravenous) do not break the pro under in vivo conditions. drug down to any appreciable extent. Also preferably, 0.139. As a person of ordinary skill in the art will under external means (chemical, enzymatic or other) will not break stand, drug products are considered pharmaceutical equiva the prodrug downto any appreciable extent either. The break lents if they contain the same active ingredient(s), are of the down ratio of the prodrug that can be achieved through exter same dosage form, route of administration and are identical in nal means is preferably less than about 50%, alternatively less strength or concentration. Pharmaceutically equivalent drug than about 25%, alternatively less than about 20%, alterna products are formulated to contain the same amount of active tively less than about 10%. ingredient in the same dosage form and to meet the same or 0143. The presently described technology utilizes cova compendial or other applicable standards (i.e., strength, qual lent modification of amphetamine by a non-standard amino ity, purity, and identity), but they may differ in characteristics acid, an amino acid derivative or any polar hydrophilic group Such as shape, scoring configuration, release mechanisms, to decrease its potential for causing behavioral deterioration packaging, excipients (including colors, flavors, preserva or the rebound effect. It is believed that since the amphet tives), expiration time, and, with certain limits, labeling. Drug amine is covalently modified to form the polar hydrophilic products are considered to be therapeutic equivalents only if conjugate of the present technology and releases slowly over they are pharmaceutical equivalents and if they can be the entire length of the day, little or no rebound effect can expected to have the same clinical effect and safety profile occur due to the slow continuous release of the active ingre when administered to patients under the conditions specified dient/drug/therapeutic component. in the labeling. The term “bioequivalent on the other hand, 0144 Compounds, compositions and methods of the pres describes pharmaceutical equivalent or pharmaceutical alter ently described technology are also believed to provide native products that display comparable bioavailability when reduced potential for rebound, reduced potential for abuse or studied under similar experimental conditions. addiction, and/or improve amphetamine's stimulant related US 2010/0292336 A1 Nov. 18, 2010 toxicities. By limiting the blood level spike, doses are kept at 0154 Another embodiment of the present technology is a levels required for a clinically significant effect without the composition that can reduce amphetamine toxicity, compris unnecessary levels administered with other therapies. It is ing at least one polar, hydrophilic prodrug of amphetamine of widely held that these spikes in blood levels can lead to the present technology wherein the polar hydrophilic moiety cardiovascular toxicity in the form of higher blood pressure can provide a plasma release curve which does not increase and rapid heart rate in addition to the euphoria encountered in above amphetamine's toxicity level when given at doses drug abuse. Also, with a full day therapy, the risk of re-dosing exceeding those within the therapeutic range of amphet is lowered, thus preventing additional toxicities or drug abuse amine. 1SSU.S. 0.155. Another embodiment of the present technology is a 0145 The polar, hydrophilic prodrugs of stimulants, composition that can reduce amphetamine toxicity, compris including, but not limited to, amphetamine prodrugs, of the ing at least one non-standard amino acid conjugate of amphet presently described technology could be used for any condi amine wherein the non-standard amino acid moiety can pro tion requiring the stimulation of the central nervous system vide a plasma release curve which does not increase above (CNS). These conditions include, for example, attention defi amphetamine's therapeutic level and does not cause blood cit hyperactivity disorder (ADHD), attention deficit disorder level spiking. (ADD), obesity, narcolepsy, appetite Suppressant, depres 0156 Another embodiment of the present technology is a Sion, anxiety, withdrawals (e.g., alcohol withdrawals or drug composition that can reduce bioavailability of amphetamine, withdrawals), and wakefulness. Some stimulants such as comprising at least one polar, hydrophilic prodrug of amphet amphetamine have also demonstrated usefulness in treating amine of the present technology wherein the amphetamine stimulant (e.g., cocaine, methamphetamine) abuse and addic prodrug can maintain a steady-state plasma release curve tion. Amphetamine stimulants have also been used exten which can provide a therapeutically effective bioavailability sively to improve battlefield alertness and to combat fatigue. but prevent spiking or increased plasma concentrations com 0146 Therefore, in accordance with some embodiments, pared to unconjugated amphetamine or amphetamine conju the presently described technology provides stimulant com gated with a standard amino acid when given at doses exceed positions comprising at least one polar, hydrophilic stimulant ing those within the therapeutic range of amphetamine. prodrug of the present technology. 0157 Another embodiment of the present technology is a 0147 In accordance with some other embodiments, the composition that can reduce bioavailability of amphetamine presently described technology provides amphetamine com or prevent a toxic release profile in a patient, comprising at positions comprising at least one amphetamine prodrug of the least one non-standard amino acid conjugate of amphetamine present technology. wherein the non-standard amino acid conjugate of amphet amine can maintain a steady-state plasma release curve which 0148 One embodiment is a composition that can prevent can provide a therapeutically effective bioavailability but pre behavioral deterioration of amphetamine dosing comprising vent spiking or increased plasma concentrations compared to at least one polar hydrophilic conjugate of amphetamine. unconjugated amphetamine or amphetamine conjugated with 0149 Another embodiment is a composition that can pre a standard amino acid. vent behavioral deterioration of amphetamine dosing com 0158 Another embodiment of the present technology is a prising at least one non-standard amino acid conjugate of composition comprising at least one polar, hydrophilic pro amphetamine. drug of amphetamine of the present technology that can pre 0150. Another embodiment is a composition for safely vent a C or equivalent C. Spike for amphetamine when delivering a stimulant, comprising a therapeutically effective taken by means other than orally while still providing a thera amount of at least one polar, hydrophilic prodrug of the stimu peutically effective bioavailability curve if taken orally. lant of the present technology wherein the polar hydrophilic 0159. Another embodiment of the present technology is a moiety can reduce the rate of absorption of the stimulant as composition comprising at least one non-standard amino acid compared to delivering the unconjugated Stimulant or the conjugate of amphetamine that can prevent a C or equiva stimulant conjugated to a standard amino acid, for example. lent C spike for amphetamine. 0151. Another embodiment is a composition for safely 0160 Another embodiment of the present technology is a delivering amphetamine, comprising a therapeutically effec composition comprising at least one non-standard amino acid tive amount of at least one non-standard amino acid conjugate conjugate of amphetamine that can prevent a C or equiva of amphetamine wherein the non-standard amino acid moiety lent C. Spike for amphetamine when taken by means other can reduce the rate of absorption of the amphetamine as than orally while still providing a therapeutically effective compared to delivering the unconjugated amphetamine or bioavailability curve if taken orally. amphetamine conjugated to a standard amino acid. 0.161 Another embodiment of the present technology is a 0152 Another embodiment of the present technology is a composition that can prevent a toxic release profile in a composition that can reduce amphetamine toxicity, compris patient comprising at least one polar, hydrophilic prodrug of ing at least one polar hydrophilic prodrug of amphetamine amphetamine of the present technology wherein the amphet wherein the non-standard amino acid moiety can release amine prodrug can maintain a steady-state plasma release amphetamine over the entire course of a day providing a curve which provides a therapeutically effective bioavailabil limited behavioral deterioration effect. ity but prevents spiking or increased plasma concentrations 0153. Another embodiment of the present technology is a compared to unconjugated amphetamine or amphetamine composition that can reduce amphetamine toxicity, compris conjugated with a naturally occurring and standard amino ing at least one non-standard amino acid conjugate of amphet acid. amine wherein the non-standard amino acid moiety can 0162 One or more embodiments of the present technol release amphetamine over the entire course of a day providing ogy provide stimulant such as amphetamine compositions a limited behavioral deterioration effect. which allow the stimulant to be therapeutically effective US 2010/0292336 A1 Nov. 18, 2010 24 when delivered at the proper dosage but reduces the rate of cants such as magnesium Stearate, calcium Stearate, Zinc absorption or extent of bioavailability of the stimulant when Stearate, powdered Stearic acid, hydrogenated vegetable oils, given at doses exceeding those within the therapeutic range of talc, polyethylene glycol, and mineral oil; colorants such as the stimulant. One or more embodiments of the present tech Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. nology also provide stimulant compositions wherein the 6, D&CYellow No. 10, or FD&C Blue No. 1 and other various polar hydrophilic moiety increases the rate of clearance of the certified color additives (See 21 CFR, Part 74); binders such stimulant when given at doses exceeding those within the as Sucrose, lactose, gelatin, starch paste, acacia, tragacanth, therapeutic range of the stimulant. poVidone, polyethylene glycol, Pullulan and corn Syrup; 0163. In one or more embodiments, the stimulant compo glidants such as colloidal silicon dioxide and talc; Surface sitions of the present technology have Substantially lower active agents such as sodium lauryl Sulfate, dioctyl Sodium toxicity compared to unconjugated Stimulant or the stimulant SulfoSuccinate, triethanolamine, polyoxyethylene Sorbitan, conjugated with a standard amino acid. In one or more poloxalkol, and quaternary ammonium salts; preservatives embodiments, the stimulant compositions of the present tech and Stabilizers; excipients such as lactose, mannitol, glucose, nology can reduce or eliminate the possibility of overdose by fructose, Xylose, galactose, Sucrose, maltose, Xylitol, Sorbitol, oral administration. In one or more embodiments, the stimu chloride, Sulfate and phosphate salts of potassium, Sodium, lant compositions of the present technology can reduce or and magnesium; and/or any other pharmaceutical additives eliminate the possibility of overdose by intranasal adminis known to those of skill in the art. In one preferred embodi tration. In one or more embodiments, the stimulant compo ment, a Sustained release formulation of the present technol sitions of the present technology can reduce or eliminate the ogy further comprises magnesium Stearate and Emerald possibility of overdose by injection. In one or more embodi Green Lake. ments, the stimulant compositions of the present technology 0167. The stimulant compositions, such as amphetamine can reduce or eliminate the possibility of overdose by inha compositions, of the present technology, which comprises at lation. least one polar, hydrophilic stimulant prodrug of the present 0164. In one or more embodiments, the polar, hydrophilic technology, can be further formulated with excipients, and prodrugs of stimulants, such as non-standard amino acid con may be manufactured according to any appropriate method jugates of amphetamine, of the present technology may fur known to those of skill in the art of pharmaceutical manufac ther comprise a polymer blend which comprises a hydrophilic ture. For instance, the stimulant prodrug and a hydrophilic polymer and/or a water-insoluble polymer. The polymers polymer may be mixed in a mixer with an aliquot of water to may be used according to industry standards to further form a wet granulation. The granulation may be dried to enhance the Sustained release/abuse resistant properties of the obtain hydrophilic polymer encapsulated granules of the stimulant prodrug of the present technology without reducing stimulant prodrug. The resulting granulation may be milled, the abuse resistance. For instance, a composition might screened, then blended with various pharmaceutical additives include: about 70% to about 100% stimulant prodrug of the Such as, for example, water insoluble polymers, and/or addi present technology by weight, from about 0.01% to about tional hydrophilic polymers. The formulation may then be 10% of a hydrophilic polymer (e.g. hydroxypropyl methyl tableted and may further be film coated with a protective cellulose), from about 0.01% to about 2.5% of a water-in coating which rapidly dissolves or disperses in gastric juices. soluble polymer (e.g. acrylic resin), from about 0.01% to (0168 It should be noted that the above additives are not about 1.5% of additives (e.g. magnesium Stearate), and from required for the stimulant composition of the present technol about 0.01% to about 1% colorant by weight. ogy to have Sustained release and abuse resistance properties. 0.165 Hydrophilic polymers suitable for use in the sus The stimulant prodrug of the present technology itself can tained release formulations include one or more natural or control the release of the stimulant into the digestive tract over partially or totally synthetic hydrophilic gums such as acacia, an extended period of time resulting in an improved profile gum tragacanth, locust bean gum, guar gum, or karayagum, when compared to immediate release combinations and pre modified cellulosic Substances such as methylcellulose, vention of abuse without the addition of the above additives. hydroxymethylcellulose, hydroxypropyl methylcellulose, In one or more embodiments of the present technology, no hydroxypropyl cellulose, hydroxyethylcellulose, carboxym further sustained release additives are required to achieve a ethylcellulose; proteinaceous Substances such as agar, pectin, blunted or reduced pharmacokinetic curve (e.g., reduced carrageen, and alginates; and other hydrophilic polymers euphoric effect) while achieving therapeutically effective Such as carboxypolymethylene, gelatin, casein, Zein, bento amounts of stimulant release when taken orally. nite, magnesium aluminum silicate, polysaccharides, modi 0169. The compounds and compositions of the presently fied starch derivatives, and other hydrophilic polymers described technology can be formulated into and adminis known to those of skill in the art, or a combination of such tered by a variety of dosage forms, preferably, through any polymers. These hydrophilic polymers gel and would dis oral routes of delivery. Once administered, the prodrugs will Solve slowly in aqueous acidic media thereby allowing the release amphetamine or another stimulant under digestive stimulant prodrug to diffuse from the gel in the stomach. conditions. Any biologically-acceptable dosage form known When the gel reaches the intestines it would dissolve in con to persons of ordinary skill in the art, now or in the future, and trolled quantities in the higher pH medium to allow further combinations thereof, are contemplated for use with the sustained release. Preferred hydrophilic polymers are the present technology. Examples of preferred dosage forms hydroxypropyl methylcelluloses Such as those manufactured include, without limitation, chewable tablets, quick dissolve by The Dow Chemical Company and known as Methocel tablets, effervescent tablets, reconstitutable powders, elixirs, ethers, such as Methocel E1 OM. liquids, Solutions, Suspensions, emulsions, tablets, multi 0166 Other formulations according to one or more layer tablets, bi-layer tablets, capsules, soft gelatin capsules, embodiments of the present technology may further comprise hard gelatin capsules, caplets, troches, lozenges, chewable pharmaceutical additives including, but not limited to, lubri lozenges, beads, powders, granules, particles, microparticles, US 2010/0292336 A1 Nov. 18, 2010 dispersible granules, cachets, thin Strips, oral films, transder than gum, tragacanth gum, guar gum, acacia gum, Arabic mal patches, and combinations thereof. Preferred dosage gum, polyacrylic acid, amylase, starch, dextrin, pectin, chitin, forms include, but are not limited to, capsules, thin Strips, fast chitosin, levan, elsinan, collagen, gelatin, Zein, gluten, Soy dissolving oral films and solution formulations. protein isolate, whey protein isolate, casein, and mixtures 0170 Formulations of the present technology suitable for thereof. oral administration can be presented as discrete units, such as 0177 Also, saliva stimulating agents, plasticizing agents, capsules, caplets or tablets. These oral formulations also can cooling agents, Surfactants, emulsifying agents, thickening comprise a solution or a suspension in an aqueous liquid or a agents, binding agents, Sweeteners, flavoring, coloring non-aqueous liquid. The formulation can be an emulsion, agents, preservatives, or taste masking resins may be Such as an oil-in-water liquid emulsion or a water-in-oil liquid employed in the oral films or thin strips. Preferred agents emulsion. The oils can be administered by adding the purified include: pullulan, triethanolamine Stearate, methyl cellulose, and sterilized liquids to a prepared enteral formula, which can starch, triacetin, polysorbate 80, Xanthan gum, maltitol, Sor then be placed in the feeding tube of a patient who is unable bitol and glycerol. to Swallow. 0.178 The presently described technology also contem 0171 If the capsule form is chosen, for example, excipi plates the use of biologically-acceptable carriers which may ents used in the capsule formulation could be broken up into be prepared from a wide range of materials. Without being four separate groups: bulk agent/binder, disintergrant, lubri limited thereto, such materials include diluents, binders and cant and carrier. A preferred capsule formulation comprises adhesives, lubricants, plasticizers, disintegrants, colorants, from about 50% to about 90% by weight of a bulk agent such bulking Substances, flavorings, Sweeteners and miscella as various types of microcrystalline cellulose, from about 1% neous materials such as buffers and adsorbents in order to to about 5% by weight of a disintegrant Such as croScarmel prepare a particular medicated composition. lose sodium, from about 0.5% to about 2.5% of a lubricant 0179 Binders may be selected from a wide range of mate Such as magnesium Stearate or other fatty acid salts. The rials such as hydroxypropylmethylcellulose, ethylcellulose, carrier can be either hard gelatin capsules, and preferably use or other suitable cellulose derivatives, povidone, acrylic and the Smaller sized ones such as #3 or #4 hard gelatin capsules. methacrylic acid co-polymers, pharmaceutical glaze, gums, 0172 Softgel or softgelatin capsules may be prepared, for milk derivatives, such as whey, starches, and derivatives, as example, by dispersing the formulation of the present tech well as other conventional binders known to persons skilled in nology in an appropriate vehicle (vegetable oils are com the art. Exemplary non-limiting solvents are water, ethanol, monly used) to form a high viscosity mixture. This mixture isopropyl alcohol, methylene chloride or mixtures and com can then be encapsulated with a gelatin based film using binations thereof. Exemplary non-limiting bulking Sub technology and machinery known to those in the soft gel stances include Sugar, lactose, gelatin, starch, and silicon industry. The individual units so formed are then dried to dioxide. constant weight. 0180 Preferred plasticizers may be selected from the 0173 Chewable tablets, for example, may be prepared by group consisting of diethyl phthalate, diethyl sebacate, tri mixing the formulations of the present technology with ethylcitrate, cronotic acid, propylene glycol, butyl phthalate, excipients designed to form a relatively soft, flavored, tablet dibutyl sebacate, castor oil and mixtures thereof, without dosage form that is intended to be chewed rather than swal limitation. As is evident, the plasticizers may be hydrophobic lowed. Conventional tablet machinery and procedures, that is as well as hydrophilic in nature. Water-insoluble hydrophobic both direct compression and granulation, i.e., or slugging, Substances, such as diethyl phthalate, diethyl sebacate and before compression, can be utilized. Those individuals castor oil are used to delay the release of water-soluble vita involved in pharmaceutical Solid dosage form production are mins, such as vitamin B and vitamin C. In contrast, hydro versed in the processes and the machinery used as the chew philic plasticizers are used when water-insoluble vitamins are able dosage form is a very common dosage form in the phar employed which aid indissolving the encapsulated film, mak maceutical industry. ing channels in the Surface, which aid in nutritional compo 0.174 Film-coated tablets, for example, may be prepared sition release. by coating tablets using techniques such as rotating pan coat 0181. It should be understood that in addition to the ingre ing methods or air Suspension methods to deposit a contigu dients particularly mentioned above, the formulations of the ous film layer on a tablet. present technology can include other Suitable agents such as 0175 Compressed tablets, for example, may be prepared flavoring agents, preservatives and antioxidants. Such anti by mixing the formulation of the present technology with oxidants would be food acceptable and could include, for excipients intended to add binding qualities to disintegration example, vitamin E, carotene, BHT or other antioxidants qualities. The mixture can be either directly compressed or known to those of skill in the art. granulated then compressed using methods and machinery 0182. Other compounds which may be included are, for known to those in the industry. The resultant compressed example, medically inert ingredients, e.g., Solid and liquid tablet dosage units are then packaged according to market diluent, such as lactose, dextrose, Saccharose, cellulose, need, i.e., unit dose, rolls, bulk bottles, blister packs, etc. starch or calcium phosphate for tablets or capsules, olive oil 0176 One preferred formulation of the polar hydrophilic or ethyl oleate for soft capsules and water or vegetable oil for prodrugs, such as non-standard amino acid conjugates of Suspensions or emulsions; lubricating agents such as silica, amphetamine, of the present technology is a fast dissolving talc, Stearic acid, magnesium or calcium Stearate and/or poly oral film or thin strip. Methods and other ingredients needed ethylene glycols; gelling agents such as colloidal clays; thick to make oral films or thin strips are known in the art. Potential ening agents such as gum tragacanth or sodium alginate, film forming agents include pullulan, hydroxypropylmethyl binding agents such as starches, arabic gums, gelatin, meth cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, ylcellulose, carboxymethylcellulose or polyvinylpyrroli polyvinyl alcohol, Sodium alginate, polyethylene glycol, Xan done; disintegrating agents such as starch, alginic acid, algi US 2010/0292336 A1 Nov. 18, 2010 26 nates or Sodium starch glycolate; effervescing mixtures; period. The doses may be uneven doses with regard to one dyestuff Sweeteners; wetting agents such as lecithin, another or with regard to the individual components at differ polysorbates or laurylsulphates; and other therapeutically ent administration times. acceptable accessory ingredients, such as humectants, preser 0189 Likewise, the compositions of the present technol vatives, buffers and antioxidants, which are known additives ogy may be provided in a blister pack or other Such pharma for such formulations. ceutical package. Further, the compositions of the present 0183 For oral administration, fine powders or granules technology may further include or be accompanied by indicia containing diluting, dispersing and/or Surface-active agents allowing individuals to identify the compositions as products may be presented in a draught, in water or a syrup, in capsules for a prescribed treatment. The indicia may additionally or Sachets in the dry state, in a non-aqueous Suspension include an indication of the above specified time periods for wherein suspending agents may be included, or in a suspen administering the compositions. For example, the indicia sion in water or a syrup. Where desirable or necessary, fla may be time indicia indicating a specific or general time of Voring, preserving, Suspending, thickening or emulsifying day for administration of the composition, or the indicia may agents can be included. be a day indicia indicating a day of the week for administra 0184 Liquid dispersions for oral administration may be tion of the composition. The blisterpack or other combination syrups, emulsions or Suspensions. The syrups may contain as package may also include a second pharmaceutical product. a carrier, for example, Saccharose or saccharose with glycerol 0190. It will be appreciated that the pharmacological and/or mannitol and/or Sorbitol. The Suspensions and the activity of the compositions of the present technology can be emulsions may contain a carrier, for example a natural gum, demonstrated using standard pharmacological models that agar, Sodium alginate, pectin, methylcellulose, carboxymeth are known in the art. Furthermore, it will be appreciated that ylcellulose or polyvinyl alcohol. the compositions of the present technology can be incorpo 0185. The dose range for adult or pediatric human beings rated or encapsulated in a suitable polymer matrix or mem will depend on a number of factors including the age, weight brane for site-specific delivery, or can be functionalized with and condition of the patient. Suitable oral dosages of the specific targeting agents capable of effecting site specific prodrugs of one stimulant of the presently described technol delivery. These techniques, as well as other drug delivery ogy can be the equivalents of those typically found in treat techniques, are well known in the art. ments using that stimulant. For example, typical dosages for 0191 In one or more embodiments of the present technol amphetamine salts can range from about 1 mg to about 100 ogy, the solubility and dissolution rate of the composition can mg, although higher dosages may be approved at later dates. be substantially changed under different physiological con Using the molecular weight of the prodrug of the present ditions encountered, for example, in the intestine, at mucosal technology, the release percentage (% release) of amphet Surfaces, or in the bloodstream. In one or more embodiments amine from the prodrug and desired dosage forms of the of the present technology, the solubility and dissolution rate required amphetamine, the following equation can be gener of the composition can Substantially decrease the bioavail ated: ability of the amphetamine, particularly at doses above those intended for therapy. In one embodiment of the present tech grams of a prodrug needed (dosage/molecular weight of amphetamine)(% release) (molecular weight of the nology, the decrease in bioavailability occurs upon intranasal prodrug) administration. In another embodiment, the decrease in bio availability occurs upon intravenous administration. 0186 Tablets, capsules, and other forms of presentation (0192 For each of the described embodiments of the provided in discrete units conveniently contain a daily dose, present technology, one or more of the following character or an appropriate fraction thereof, of one or more of the istics can be realized: The cardiovascular toxicity of the prodrug compounds of the invention. For example, the units amphetamine prodrug is Substantially lower than that of the may contain from about 1 mg to about 1000 mg, alternatively unconjugated amphetamine and amphetamine conjugated from about 5 mg to about 500 mg, alternatively from about 5 with a standard amino acid. The covalently bound polar mg to about 250 mg, alternatively from about 10 mg to about hydrophilic moiety, such as a non-standard amino acid moi 100 mg of one or more of the prodrug compounds of the ety, reduces or eliminates the possibility of behavioral dete presently described technology. rioration or the rebound effect. The covalently bound polar 0187. It is also possible for the dosage form of the present hydrophilic moiety reduces or eliminates the possibility of technology to combine any forms of release known to persons abuse by intranasal administration. The covalently bound of ordinary skill in the art. These conventional release forms polar hydrophilic moiety reduces the possibility of abuse by include immediate release, extended release, pulse release, injection. variable release, controlled release, timed release, Sustained 0193 The presently described technology further pro release, delayed release, long acting, and combinations vides methods for altering and/or delivering amphetamines thereof. The ability to obtain immediate release, extended and other stimulants in a manner that can decrease their release, pulse release, variable release, controlled release, potential for abuse. Methods of the present technology pro timed release, Sustained release, delayed release, long acting vide various ways to regulate pharmaceutical dosage through characteristics and combinations thereof is known in the art. conjugating stimulants such as amphetamine with polar 0188 Compositions of the present technology may be hydrophilic ligands, such as non-standard amino acids, of the administered in a partial, i.e., fractional dose, one or more present technology. times during a 24 hour period, a single dose during a 24 hour 0194 One embodiment provides a method for preventing period of time, a double dose during a 24 hour period of time, behavioral deterioration or the rebound effect by administer or more than a double dose during a 24 hour period of time. ing to a patient in need an amphetamine prodrug composition Fractional, double or other multiple doses may be taken of the present technology, which comprises at least one polar simultaneously or at different times during the 24 hour hydrophilic conjugate of amphetamine. US 2010/0292336 A1 Nov. 18, 2010 27

0.195 Another embodiment provides a method for pre maintain a steady-state plasma release curve which provides venting behavioral deterioration or the rebound effect by a therapeutically effective bioavailability but prevents spik administering to a patient in need an amphetamine prodrug ing or increased plasma concentrations compared to amphet composition of the present technology, which comprises at amine conjugated with a standard amino acid. least one non-standard amino acid conjugate of amphet 0204 Another embodiment provides a method for pre amine. Venting a C or equivalent C. Spike for amphetamine or 0196. Another embodiment provides a method for safely another stimulant while still providing a therapeutically delivering amphetamine or another stimulant comprising effective bioavailability curve comprising the step of admin providing a therapeutically effective amount of at least one istering to a patient at least one polar, hydrophilic prodrug of polar, hydrophilic prodrug of Stimulant of the present tech amphetamine or another stimulant of the present technology. nology wherein the polar hydrophilic moiety can reduce the 0205 Another embodiment provides a method for pre rate of absorption of amphetamine or another stimulant as Venting a C or equivalent C. Spike for amphetamine compared to delivering the unconjugated Stimulant or the while still providing a therapeutically effective bioavailabil stimulant conjugated with a standard amino acid, for ity curve comprising the step of administering to a patient at example. least one non-standard amino acid conjugate of amphet 0.197 Another embodiment provides a method for safely amine. delivering amphetamine comprising providing a therapeuti 0206. Another embodiment provides a method for pre cally effective amount of at least one non-standard amino acid venting a toxic release profile in a patient comprising admin conjugate of amphetamine wherein the non-standard amino istering to a patient at least one polar, hydrophilic stimulant acid moiety can reduce the rate of absorption of amphetamine prodrug of the present technology, wherein the stimulant as compared to delivering the unconjugated amphetamine or prodrug can maintain a steady-state plasma release curve amphetamine conjugated with a standard amino acid. which provides a therapeutically effective bioavailability but 0198 Another embodiment provides a method for reduc prevents spiking or increased plasma concentrations com ing stimulant toxicity comprising providing a patient with at pared to unconjugated Stimulant or the stimulant conjugated least one polar, hydrophilic prodrug of the stimulant of the to a standard amino acid, particularly when taken at doses present technology, wherein the polar hydrophilic moiety can above prescribed amounts. increase the rate of clearance of pharmacologically active 0207 Another embodiment of the present technology is a stimulant (i.e., released stimulant such as amphetamine) method for reducing or preventing abuse of a stimulant com when given at doses exceeding those within the therapeutic prising providing, administering, or prescribing a composi range of the stimulant. tion to a patient in need thereof, wherein said composition 0199 Another embodiment provides a method for reduc comprises at least one polar, hydrophilic stimulant prodrug of ing stimulant toxicity comprising providing a patient with at the present technology Such that the pharmacological activity least one polar, hydrophilic stimulant prodrug of the present of the stimulant is decreased when the composition is used in technology, wherein the polar hydrophilic moiety can provide a manner inconsistent with the manufacturer's instructions. a plasma release curve which does not increase above the 0208 Another embodiment of the present technology is a stimulant's toxicity level when given at doses exceeding those method for reducing or preventing abuse of a stimulant Such within the therapeutic range for the unconjugated Stimulant. as amphetamine comprising consuming at least one polar, 0200 Another embodiment provides a method for reduc hydrophilic prodrug of the stimulant of the present technol ing amphetamine cardiovascular toxicity comprising provid ogy, wherein said prodrug comprises the stimulant covalently ing a patient with at least one non-standard amino acid con attached to a polar hydrophilic ligand Such that the pharma jugate of amphetamine, wherein the amino acid moiety can cological activity of the stimulant is substantially decreased decrease the rate of release of amphetamine within the first a when the composition is used in a manner inconsistent with few hours of administration. the manufacturer's instructions. 0201 Another embodiment provides a method for reduc 0209 Another embodiment of the present technology is a ing amphetamine cardiovascular toxicity comprising provid method for reducing or preventing abuse of amphetamine ing a patient with at least one non-standard amino acid con comprising providing, administering, consuming, or pre jugate of amphetamine, wherein the amino acid moiety can scribing a composition to a patient in need thereof, wherein provide a plasma release curve which does not increase above said composition comprises at least one non-standard amino the amphetamine's cardiovascular toxicity level. acid conjugate of amphetamine Such that the pharmacologi 0202 Another embodiment provides a method for reduc cal activity of amphetamine is decreased when the composi ing bioavailability of stimulant a comprising providing at tion is used in a manner inconsistent with the manufacturer's least one polar, hydrophilic stimulant prodrug of the present instructions. technology, wherein the stimulant prodrug can maintain a 0210 Another embodiment of the present technology is a steady-state plasma release curve which provides a therapeu method of preventing behavioral deterioration or the rebound tically effective bioavailability but prevents spiking or effect of amphetamine or stimulant treatment comprising increased plasma concentrations compared to unconjugated providing, administering, or prescribing an amphetamine stimulant when given at doses exceeding those within the composition of the presently described technology to a therapeutic range for the unconjugated Stimulant or the stimu patient in need thereof, wherein said composition comprises lant conjugated with a standard diamino acid, for example. at least one polar hydrophilic prodrug of amphetamine that 0203. Another embodiment provides a method for reduc can decrease the potential of behavioral deterioration or the ing bioavailability of amphetamine or for preventing a toxic rebound effect from amphetamine or stimulant treatment. release profile of amphetamine in a patient, comprising pro 0211 Another embodiment of the present technology is a viding at least one non-standard amino acid conjugate of method of preventing behavioral deterioration or the rebound amphetamine, wherein the conjugated amphetamine can effect of amphetamine or stimulant treatment comprising US 2010/0292336 A1 Nov. 18, 2010 28 providing, administering, consuming, or prescribing an prodrug composition of the present technology to a patient, amphetamine composition of the presently described tech wherein said composition comprises at least one polar, hydro nology to a patient in need thereof, wherein said composition philic stimulant prodrug of the present technology that can comprises at least one non-standard amino acid conjugate of decrease the pharmacological activity of the stimulant when amphetamine that can decrease the potential of behavioral the composition is used in a manner inconsistent with the deterioration or the rebound effect from amphetamine or manufacturer's instructions. stimulant treatment. 0212 Another embodiment of the present technology is a 0219. Another embodiment is a method for reducing or method for reducing or preventing the euphoric effect of a preventing the euphoric effect of a stimulant comprising stimulant comprising providing, administering, or prescrib orally administering a stimulant prodrug composition of the ing to a human or animal in need thereof, a composition present technology to a patient in need thereof, wherein said comprising at least one polar, hydrophilic stimulant prodrug composition comprises at least one polar, hydrophilic pro of the present technology that can decrease the pharmacologi drug of the stimulant of the present technology that can cal activity of the stimulant when the composition is used in decrease the pharmacological activity of the stimulant when a manner inconsistent with the manufacturer's instructions. the composition is used in a manner inconsistent with the 0213 Another embodiment of the present technology is a manufacturer's instructions. method for reducing or preventing the euphoric effect of 0220. For one or more of the recited methods of the present amphetamine comprising providing, administering, or pre technology, the following properties may be achieved scribing to a human in need thereof, or consuming a compo through conjugating amphetamine to a polar hydrophilic sition comprising at least one non-standard amino acid con group or to a non-standard amino acid. In one embodiment, jugate of amphetamine that can decrease the pharmacological the cardiovascular toxicity or stress of the polar hydrophilic activity of amphetamine when the composition is used in a prodrug of, or non-standard amino acid conjugate of amphet manner inconsistent with the manufacturer's instructions. amine of the present technology may be lower than that of the 0214) Another embodiment of the present technology is a amphetamine when the amphetamine is delivered in its method for reducing or preventing the euphoric effect of a stimulant, comprising consuming a composition comprising unconjugated State, as a compound conjugated to a standard at least one polar, hydrophilic stimulant prodrug of the amino acid, or as a salt thereof. In another embodiment, the present technology that can decrease the pharmacological possibility of behavioral deterioration is reduced or elimi activity of the stimulant when the composition is used in a nated. In another embodiment, the possibility of abuse by manner inconsistent with the manufacturer's instructions. intranasal administration is reduced or eliminated. In another 0215. Another embodiment of the present technology is embodiment, the possibility of abuse by intravenous admin any of the preceding methods wherein the stimulant compo istration is reduced or eliminated. sition used is adapted for oral administration, and wherein the 0221) Another embodiment of the present technology pro stimulant prodrug is resistant to release the stimulant from the vides methods of treating various diseases or conditions polar hydrophilic moiety when the composition is adminis requiring the stimulation of the central nervous system (CNS) tered parenterally, such as intranasally or intravenously. Pref comprising administering compounds or compositions of the erably, the stimulant may be released from the polar hydro present technology which, optionally, further comprise com philic moiety in the presence of acid and/or enzymes present monly prescribed active agents for the respective illness or in the stomach, intestinal tract, or blood serum. Optionally, disease. For instance, one embodiment of the invention com the stimulant composition used may be in the form of a tablet, prises a method of treating attention deficit hyperactivity capsule, oral Solution, oral Suspension, thin Strip or other oral disorder (ADHD) comprising administering to a patient at dosage form discussed herein. least one polar, hydrophilic prodrug of amphetamine of the 0216. Another embodiment of the present technology is present technology. Another embodiment of the invention any of the preceding methods wherein the amphetamine com comprises a method of treating attention deficit hyperactivity position used is adapted for oral administration, and wherein disorder (ADHD) comprising administering to a patient at the amphetamine prodrug is resistant to release amphetamine least one non-standard amino acid conjugate of amphet from the non-standard amino acid moiety when the compo sition is administered parenterally, Such as intranasally or amine. Another embodiment provides a method of treating intravenously. Preferably, amphetamine may be released attention deficit disorder (ADD) comprising administering to from the non-standard amino acid moiety in the presence of a patient compounds or compositions of the invention. the intestinal tract. Optionally, the amphetamine composition 0222 Another embodiment of the invention provides a used may be in the form of a tablet, capsule, oral film, oral method of treating narcolepsy comprising administering to a Solution, oral Suspension, or other oral dosage form discussed patient compounds or compositions of the presently herein. described technology. 0217 For one or more of the recited methods, the compo 0223) The presently described technology and its advan sition of the present technology used may yield a therapeutic tages will be better understood by reference to the following effect without substantial euphoria. Preferably, the stimulant, examples. These examples are provided to describe specific Such as amphetamine, composition of the present technology embodiments of the present technology. By providing these can provide a therapeutically equivalent AUC when com specific examples, the applicants do not limit the scope and pared to the stimulant alone but does not provide a C, which spirit of the present technology. It will be understood by those results in euphoria or an equivalent C. skilled in the art that the full scope of the presently described 0218. Another embodiment of the present technology is a technology encompasses the Subject matter defined by the method for reducing or preventing abuse of stimulants such as claims appending this specification, and any alterations, amphetamine comprising orally administering a stimulant modifications, or equivalents of those claims. US 2010/0292336 A1 Nov. 18, 2010 29

Example 1 anhydrous MgSO. The product was recrystallized from EtOAc/hexane two times to give 2.36 g of desired protected Comparative Study of Pharmacokinetic Parameters product. of Released d-Amphetamine Following Administra 0228. The product was analyzed using 'H NMR (DMSO tion of a Polar Hydrophilic Prodrug of the Non-Stan d) 8. The result shows 0.9-1.1 (m, 3H, Amp CH), 1.1-1.2 dard Amino Acid Type (harg-Amp) and a Standard (m. 2H, harg Y CH), 1.2-1.5 (m. 13H, Boc CHh Arg B.ö Amino Acid Conjugate (VyvanseTM, Lys-Amp) CH), 2.55-2.75 (m. 2H, Amp B CH), 3.1 (m. 2H, harge 0224. The pharmacokinetic parameters of d-amphetamine CH), 3.75 (m. 1H, Amp C. CH), 3.95 (m. 1H, hArg C. CH), following oral administration of a non-standard amino acid 6.65 (t, 1H, hArg guanidino NH), 7.1-7.3 (m, 5H, Amp conjugate of the present technology and a standard amino Ar—H), 7.6-8.2 (brm, 2H, harg guanidine NH and amide acid conjugate, VyvanseM (Lys-Amp), commercially avail NH), 8.5 (brs, 1H, harg NH NO). These results are con able from Shire, Incorporated of Wayne, Pa. are studied in this sistent with the proposed structure. example. The non-standard amino acid conjugate used in this example is the hydrochloride salt of hArg-Amp. The results Example 3 are recorded in Table 3 below: Preparation of hArg-Amp-2 HCl (1-homoarginine-d- amphetamine dihydrochloride) TABLE 3 0229 Boc-harg(NO)-Amp (1.5 g) was dissolved in Non-standard amino HPLC grade MeCH (120 mL) and to the clear solution was Parameter Acid% amp' Vyvanse TM% total Amp? added the Pd/C catalyst (10%, Aldrich). A small stir bar was AUCo. 8, 94% 100% placed in the flask and the reaction mixture was stirred under AUCo. 4, 770, 100% a slow stream of hydrogen overnight after incorporating the AUC 95% 100% 5-6 NHCl in 2-propanol solution (1.5 mL). After the over ex 76% 100% 400% 100% night reaction, the solution was filtered and the Solvent evapo ex rated. The white crystalline product was dried under vacuum Percent amphetamine released relative to Vyvanse TM (at an equimolar concentration of to give 1.61 g of the Boc-harg-Amp intermediate product. amphetamine contained in the non-standard amino acid prodrug compared to the total amphetamine contained in Vyvanse TM) 0230. The product (1.6 g) was dissolved in 80 mL of *Percent amphetamine relative to 50 mg Vyvanse TM dose HPLC grade MeOH, and 5-6N HCl in 2-propanol (3.2 mL) was added to the solution. The reaction mixture was stirred 0225. The study shows that the C of a prodrug of the overnight, solvent removed and re-dissolved in minimum preset technology is significantly lower than that of amount of MeOH. The final product was crashed out with VyvanseM, a standard amino acid conjugate of d-amphet MTBE, and dried under vacuum at 30° C. for about 20 hours amine, which can lead to lower cardiovascular effects (blood to yield 1.12 g of a white powder. pressure, heart rate). Quick release (higher C) of amphet 0231. The white powder was analyzed using "H NMR amine has already demonstrated significant increases in (DMSO-d) 8. The result shows 0.9-1.1 (m, 3H, Amp CH), blood pressure and heart rate. In certain patient populations, 1.1-1.2 (m. 2H, harg Y CH), 1.35 (m. 2H, harg BCH), these cardiovascular side effects can be dose limiting or can 1.55(m, 2H, harg 8 CH), 2.75 (d. 2H, Amp BCH), 3.0 (m, cause the termination of stimulant therapy. 2H, hArg e CH), 3.75 (m, 1H, Amp C. CH), 4.05 (m. 1H, 0226. The pharmacokinetic parameters of d-amphetamine hArg C. CH), 7.1-7.2 (m, 5H, Amp Ar H), 7.2-7.8 (brm,3H, following parental administration of hArg-Amp and d-am amide NH, HCl), 8.0 (t, 1H, hArgguanidino NH), 8.2 (brs, phetamine are also studied. The study shows that little release 2H, amide or guanidino NH), 8.75 (d. 1H, amide NH); 'C of amphetamine (intranasal: <40% of AUC and <20% of NMR (DMSO-d) & 21.08 (Amp CH), 21.36 (hargy), 28.23 C, intravenous: <50% of AUC and <40% of C, when compared to d-amphetamine Sulfate) happens when harg (harg 8), 32.28 (harg B), 40.18 (Amp B), 42.19 (harge), Amp is taken through parental routes (intranasal, intrave 46.88 (Amp C.), 52.23 (harg C.), 126.54 (p-Ar), 128.52 nous) due to differences in enzymes encountered in the gut (m-Ar), 129.60 (o-Ar), 139.34 (Ar), 157.61 (C=O), 167.95 versus other routes. When Adderall XRR) or other controlled (guanidino C); M+1=306. These results are consistent with release formulations of amphetamine are injected or Snorted, the proposed structure. the pharmacokinetic parameters of the amphetamine are sig Example 4 nificantly altered and an individual can use these changes to produce euphoria. Preparation of Cit-Amp.HCl (1-citrulline-d-amphet amine hydrochloride) Example 2 0232 Boc-Cit-OH (0.500 g, 1.82 mmol) was dissolved in Preparation of Boc-hArg(NO)-Amp anhydrous THF. To this solution was added NHS (0.209 g, 1.82 mmol) followed by DCC (0.376g, 1.82 mmol). Result 0227 Boc-harg(NO)-OH (2.667 g., 8 mmol) was dis ing slurry was stirred at ambient temperature overnight. In a solved in DMF (25 mL). EDC1 (2.30 g, 12 mmol), NHS separate flask, d-amphetamine sulfate (0.306 g. 0.83 mmol) (1.012 g, 8.8 mmol), d-amphetamine (1.269 g, 9.6 mmol) and was suspended in THF (10 mL) and NMM (0.34 mL, 3.64 DIEA (1.138 g, 8.8 mmol) were then added sequentially. The mmol) was added. The activated ester was filtered directly clear reaction mixture was stirred at room temperature for 16 into the amphetamine Suspension and the resulting Suspen hrs. The reaction mixture was quenched with pH3 water (150 sion was stirred overnight. The reaction was quenched with mL), and the product was extracted with EtOAc (3x50 mL). 5% NaHCO and IPAc for 45 min. Organic solvent was then The combined extracts were washed with pH 3 water fol removed. The aqueous layer was then extracted 3 times with lowed by saturated NaCl. The EtOAc layer was dried over IPAc and the combined organics were washed with 5% acetic US 2010/0292336 A1 Nov. 18, 2010 30 acid, 5% NaHCO and 5% NaCl. The organic layer was then evaporated to dryness. Crude product was purified via column dried over NaSO and solvent was removed. Crude product chromatography (0-2.5% MeOH/DCM) to give 96 mg (0.32 was re-crystallized using IPAc/heptane to yield 200 mg of a mmol) of 1-hyPro(t-Bu)-d-Amp. white solid. HPLC: column: YMC ODS-AQ, 5um, 120 A, 0238 Hydroxyl-protected 1-hyPro(t-Bu)-d-Amp (96 mg, 4.6x250 mm; mobile phase: A=0.1% TFA/HO, B=0.1% 0.32 mmol) was cooled in an ice-bath and 5 mL of chilled TFA/MeCN; method: 0-15 min.: 85/15->60/40, 15-25 min.: TFA were added. The ice-bath was removed and the mixture 60/40->0/100; flow rate: 1 mL/min. UV detection: 230 nm, was stirred overnight. The solvent was evaporated and the retention time: 8.06 min. remaining residue was dissolved in 4 NHCl/dioxane. This 0233. 10 mL of 4N HCl in dioxane were added to the 200 process was repeated three times. The product was dried in mg (0.200 g) Boc-Cit-Amp. The mixture was stirred at room high vacuum to yield 90 mg (0.32 mmol) of 1-hyPro-d-Amp. temperature for 6 hours and solvent was removed. HC1. HPLC: column: YMC ODS-AQ, 5um, 120 A, 4.6x250 mm; mobile phase: A=0.1%TFA/HO, B=0.1%TFA/MeCN: Example 5 method: 0-15 min.: 85/15->60/40, 15-25 min.: 60/40->0/ Preparation of hCit-Amp.HCl (1-homocitrulline-d- 100; flow rate: 1 mL/min. UV detection: 230 nm, retention amphetamine hydrochloride) time: 9.61 min. 0234 Procedure as described for citrulline. However, 1,4- Example 7 dioxane was used during amino acid activation and coupling Preparation of Arg(NO)-Amp.2HCl (1-arginine reaction instead of THF. Crude product was purified via col (NO)-d-amphetamine dihydrochloride) umn chromatography (0-6.5% MeOH/DCM) to give 201 mg (0.49 mmol) of Boc-l-hCit-d-amphetamine (based on 500 mg 0239 Procedure as described for citruline. Crude product of Boc-1-hCit-OH). was purified via column chromatography (0-3.5% MeOH/ 0235. The Boc-protected Boc-1-hCit-d-Amp (110 mg. DCM) to give 471 mg (1.08 mmol) of Boc-l-Arg(NO)-d- 0.27 mmol) was cooled in an ice-bath and 10 mL of chilled 4 Amp (based on 1.000 g of Boc-l-Arg(NO)—OH). N HCl/dioxane were added. The mixture was stirred for 4 h 0240 Boc-protected Boc-Arg(NO)-d-Amp was depro and solvent was evaporated to dryness yielding 92 mg (0.27 tected using the procedure described for homocitrulline mmol) of 1-hCit-d-Amp.HC1. HPLC: column: YMC ODS yielding 442 mg (1.08 mmol) of l-Arg(NO)-d-Amp.HC1. AQ, 5um, 120 A, 4.6x250mm; mobile phase: A-0.1%TFA/ HPLC: column: YMCODS-AQ, 5um, 120 A, 4.6x250 mm: HO, B=0.1% TFA/MeCN; method: 0-15 min.: 85/15->60/ mobile phase: A=0.1% TFA/HO, B=0.1% TFA/MeCN: 40, 15-25 min.: 60/40->0/100; flow rate: 1 mL/min. UV method: 0-15 min.: 85/15->60/40, 15-25 min.: 60/40->0/ detection: 230 nm, retention time: 8.92 min. 100; flow rate: 1 mL/min. UV detection: 230 nm, retention time: 9.21 min. Example 6 Example 8 Preparation of hyPro-Amp.HCl (2-hydroxyproline-d- amphetamine hydrochloride) Preparation of Lys-ol-CO-Amp (1-lysinol-CO-d- amphetamine) 0236 Z-l-hyPro(t-Bu)-OH (1.000 g, 3.11 mmol) was dis solved in 15 mL of anhydrous THF. NHS (0.358 g., 3.11 0241 Boc-l-Lys(Z)-ol (500 mg, 1.36 mmol) was dis mmol) was added and the solution was stirred for 5 min. DCC solved in 10 mL of anhydrous dioxane. CD1 was added and (0.642 g, 3.11 mmol) was then added and the mixture stirred the mixture stirred overnight at ambient temperature. Solvent overnight at ambient temperature. In a separate flask, d-am was evaporated to dryness and the remaining oily residue was phetamine sulfate (0.521 g, 1.41 mmol) was suspended in 15 dissolved in 15 mL of anhydrous THF. Amphetamine sulfate mL of anhydrous THF and NMM (0.68 mL, 6.22 mmol) was (277 mg, 0.75 mmol) and EtN (0.40 mL, 2.86 mmol) were added. The mixture was stirred for 10 min. Subsequently, the added and the mixture was stirred overnight at 50° C. The prior prepared Succinimidyl ester was charged to the Suspen reaction was quenched with water and the aqueous layer sion through a sintered funnel and the mixture was stirred extracted with IPAc (3x75 mL). The combined organics were overnight. The reaction was quenched with 5% NaHCO washed with 5% HOAc, sat. NaHCO, sat. NaCl and 5% solution (75 mL). IPAc (25 mL) was added and the solution NaCl solution and dried over NaSO. Solvents were evapo stirred for 45 min. The mixture was concentrated by evapo rated to dryness yielding Boc-l-LyS(Z)-ol-CO-d-Amp as a rating most of the organic solvents. The aqueous layer was white foam. HPLC: column: YMC ODS-AQ, 5um, 120 A, extracted with IPAc (3x100 mL). The combined organics 4.6x250 mm; mobile phase: A=0.1% TFA/HO, B=0.1% were washed with 5% HOAc (1x100 mL), 5% NaHCO TFA/MeCN; method: 0-15 min.: 85/15->60/40, 15-25 min.: (1x100 mL) and 5% NaCl solution (2x100 mL), dried over 60/40->0/100; flow rate: 1 mL/min. UV detection: 230 nm, Na2SO and evaporated to dryness. Crude product was dis retention time: 20.59 min. solved in 10 mL of AcO at 60° C. and 10 mL water were added while hot. The mixture was kept overnight at ambient Example 9 temperature. White crystals formed which were filtered off, Preparation of BZ-Amp (benzamide-d-amphetamine) rinsed with water and dried in high vacuum to yield 877 mg (2.00 mmol) of Z-1-hyPro(tBu)-d-Amp. 0242 Amphetamine sulfate (1.000 g, 2.71 mmol) was 0237 Fully protected Z-1-hyPro(t-Bu)-d-Amp (500 mg, taken in 15 mL of anhydrous dioxane. NMM (1.36 mL, 12.34 1.14 mmol) was dissolved in 10 mL of MeOH. Pd/C (10 mmol) was added and the Suspension was cooled in an ice w.t.-% Pd, 250mg) was added and the mixture stirred over bath. Benzoyl chloride (0.57 mL, 4.93 mmol) was slowly night in hydrogen atmosphere at ambient temperature. The added and the mixture stirred overnight while warming to suspension was filtered through Celite(R) and solvent was ambient temperature. Solids were filtered off and rinsed with US 2010/0292336 A1 Nov. 18, 2010

dioxane. The white crystals were dried and then dissolved in C. CH), 4.1 (m. 1H, Orn C. CH), 7.1-7.4 (m, 5H, Amp Ar—H). IPA at 60° C. Water was added to the hot solution without These NMR shifts are consistent with the structure of Boc forming any precipitate. The mixture was kept for 4 h while Orn(Boc)-Amp. cooling to ambient temperature. White crystals formed which were filtered off and rinsed with water to give 317 mg (1.32 Example 13 mmol) of Bz-d-Amp. HPLC: column: YMCODS-AQ, 5um, Preparation of Orn-Amp.2MsOH (1-ornithine-d-am 120 A, 4.6x250 mm; mobile phase: A=0.1%TFA/HO, B=0. phetamine dimeSylate) 1% TFA/MeCN; method: 0-15 min.: 85/15->60/40, 15-25 min.: 60/40->0/100; flow rate: 1 mL/min. UV detection: 230 0247 Boc-Orn(Boc)-Amp (1.35 g, 3 mmol) was dissolved nm, retention time: 21.84 min. in EtOAc (200 mL) and to the slightly cloudy solution was added MsOH (0.43 mL, 6.6 mmol) drop wise. The reaction mixture became a clear Solution which was stirred at room Example 10 temperature for approximately 20 hrs. Solvent was removed and the residue was triturated in hexanes. Off-white solid Preparation of Carn-Amp (O-acetyl-l-carnitine-d- product was formed which was filtered under vacuum and amphetamine) washed with hexanes. The solid was dried in vacuum oven for 20 hrs to obtain 0.88g of Orn-Amp.2MsOH. 0243 O-Acetyl-l-carnitine.C1 (1.000 g, 4.17 mmol) was 0248. The product obtained was tested by 1H NMR dissolved in 12.5 mL of a mixture of DMF/dioxane?water (DMSO-d) 8. The result shows 1.1 (m, 3H, Amp C-CH), (2:2:1). NHS (0.528 g, 4.59 mmol) and DCC (0.947 g. 4.59 1.4-1.6 (m, 4H, Orn B, Y CH), 2.35 (s, 6H, CHSOHCH), mmol) were added and the mixture was stirred overnight at 2.6-2.8 (m, 4H, Amp B and Ornö), 3.75 (m. 1H, Amp C), 4.05 ambient temperature. Solvents were evaporated and the (m. 1H, Orn C), 7.1-7.3 (m, 5H, Amp Ar H), 7.6-8.5 (br remaining residue was dried overnight in high vacuum. The peaks, amide and amine); 'CNMR (DMSO-d) & 18.45 (Orn crude succinimidyl ester intermediate was dissolved in 20 mL Y), 21.49 (Orn B), 27.30 (Amp B), 37.38 (Amp CH), 37.77 of anhydrous DMF. Amphetamine sulfate (0.700 g, 1.90 (Amp C), 41.20 (Ornö), 51.54 (Orn C), 125.29 (p-Ar), 127.27 mmol) and NMM (0.92 mL, 8.34 mmol) were added and the (m-Ar), 129.17 (o-Ar), 137 (Ar), 166.58 (C=O); mixture stirred overnight. Solvent was evaporated to dryness M+1==250.7. These results are consistent with the proposed and the remaining residue was leached with IPA. Solvent was Structure. evaporated to yield Carn-d-Amp. Example 14 Example 11 Pharmacokinetic Study of hArg-Amp vs. Lys-Amp 0249 Male Sprague-Dawley rats were fasted overnight Preparation of Suc-Amp (Succinamide-d-amphet and dosed by oral gavage with either 1-homoarginine-d-am amine) phetamine (harg-Amp) or 1-lysine-d-amphetamine (Vy vanseTM, Lys-Amp). Water was provided ad libitum. Doses 0244. To a solution of succinic anhydride (1.1 eq) in DMF were calculated at an equivalent 1.5 mg/kg freebase equiva was added N-methyl morpholine (1.5 eq) and amphetamine lent of d-amphetamine. Plasma concentrations of d-amphet (1 eq). The resulting mixture was stirred at room temperature amine were measured using ELISA (Neogen Corp. Lexing for 18 hours, quenched with water and partitioned between ton, Ky.). EtOAc and water. Organics were combined, dried and solvent 0250 Mean plasma concentration curves (n=5) of d-am removed to obtain Suc-Amp (86% yield) as a white solid. phetamine released by 1-homoarginine-d-amphetamine or 1-lysine-d-amphetamine are shown in FIG.1. Pharmacokinet Example 12 ic(PK) parameters of this study are listed in Table 4.

Preparation of Boc-Orn(Boc)-Amp (1-Boc-ornithine TABLE 4 (Boc)-d-amphetamine) Pharmacokinetic Properties of hArg-Amp and Lys-Amp 0245 Boc-Orn(Boc)-OH (1.5 g. 4.518 mmol) was dis solved in DMF (15 mL). EDC1 (1.299 g, 6.777 mmol), NHS Vehicle % AUC T. Cmax % Tax % Ca. (0.572 g, 4.969 mmol), d-amphetamine (0.732 g, 5.422 Lys-Amp 100% 3h 44 ng/mL 100% 100% mmol) and DIEA (0.87 mL, 4.969 mmol) were then added hArg-Amp 99% 4h 44 ng/mL 13.3% 100% sequentially. The clear reaction mixture was stirred at room temperature for 16 hours (hrs). The reaction mixture was 0251. This pharmacokinetic (PK) study clearly demon quenched with pH 3 water (40 mL), and the product was strates a shift in the T for the polar hydrophilic prodrug of extracted with EtOAc (3x70 mL). The combined extracts the non-standard amino acid type (harg-Amp) compared to were washed with pH3 water, saturated NaHCO, followed by the standard amino acid (Lys-Amp). This shift may be due to water. The EtOAc layer was dried over anhydrous NaSO. a reduction in the rate of enzymatic hydrolysis of the amide Solvent was removed to obtain 1.82 g of protected amide as a bond of the non-standard amino acid attached to amphet white solid. amine vs. the standard amino acid attached to amphetamine. 0246 The white solid was analyzed by "H NMR (CDC1) 0252 FIGS. 2-4 represent different ways to view the data 6. The results show 1.1-1.2 (m, 3H, Amp C-CH), 1.3-1.5 (m, reflected in FIG. 1 and Table 4. As further discussed below, 18H, Boc CH), 1.6-1.8 (m, 4H, Orn B, Y CH), 2.75 (m, 2H, these figures highlight the differences of hArg-Amp over Amp B CH), 3.05-3.1 (m. 2H, Orn 8 CH), 3.2 (m. 1H, Amp Lys-Amp during the first several hours. US 2010/0292336 A1 Nov. 18, 2010 32

0253 FIG. 2 demonstrates the relative blood levels of d-amphetamine released from both Lys-Amp and harg-Amp. TABLE 6 The graph shows that equivalent blood levels do not occur until later time points and that blood levels do not appear to Oral Properties of Lys-Amp and Cit-Amp spike or have a more significant C than Lys-Amp. The Vehicle % AUC Tmax Cmax % Tax % Ca amount of d-amphetamine released from hArg-Amp is Lys-Amp 100% 1 h 59ng/mL 100% 100% gradual and maintains a more steady concentration over the Cit-Amp 95% 15 min. 129 ng/mL 25%. 21.9% duration of the study than did Lys-Amp. In contrast, Lys-Amp blood levels of released d-amphetamine “spiked at 3 hours and cleared more quickly than the blood levels obtained from Example 16 hArg-Amp. Pharmacokinetic Study of Lys-Amp, Sarcosine 0254 FIGS. 3 and 4 show the difference in blood levels Amp, hCit-Amp and harg(NO)-Amp obtained from the study described in FIG. 2. As is shown, the 0258 To compare the amount of release of d-amphet initial blood levels for both conjugates (Lys-Amp and harg amine among various polar hydrophilic prodrugs, sarcosine Amp) are very different, with hArg-Amp releasing amphet d-amphetamine (Sar-Amp), 1-homocitrulline-d-amphet amine at a more gradual rate. These differences in blood amine (hCit-Amp) and Phomoarginine(NO)-d- levels become less during the more critical duration of action amphetamine (harg(NO)-Amp) were dosed with Lys-Amp for stimulant treatments and more importantly, the differ in another oral pharmacokinetic study. Mean plasma concen ences are greater again at later time points suggesting that tration curves (n=5) of d-amphetamine released by the hArg-Amp maintains a more consistent dose of amphetamine amphetamine prodrugs are shown in FIGS. 7 and 8. Pharma when compared to Lys-Amp. The longer duration of release cokinetic parameters of this study are listed in Table 7 for hArg-Amp would suggest a much lower opportunity for behavioral deterioration to occur. TABLE 7 0255. Other oral studies have been conducted in a similar Oral Properties of Lys-Amp, h0lit fashion and are summarized in Table 5 below. The average PK Amp, Sar Amp and hArg(NO2)-Amp results for four (4) oral studies (n=30 per vehicle) are recorded in FIG. 5: Vehicle % AUC T. Cmax % Tax % Cna. Lys-Amp 100% 1 h 54 ng/mL 100% 100% TABLE 5 hCit-Amp 78% 1 h 57 ng/mL NA 105% Sar-Amp 33% 1 h 45 ng/mL NA 83% Average Results of 6 Oral Studies (n = 30 per compound hArg(NO-)-Amp 69% 1 h 59ng/mL NA 109% Vehicle % AUC T 96 T 96 C 96 AUCoa, Lys-Amp 100% 1 100% 100% 100% Example 17 hArg-Amp 81% 2-4h 200-400%. 69% 67% Intranasal Study of AMP Lys-Amp and harg-Amp 0259 Male Sprague-Dawley rats were fasted overnight and dosed by intranasal administration with either harg Example 15 Amp, Lys-Amp or d-amphetamine. Doses were calculated at an equivalent 1.5 mg/kg freebase equivalent of d-amphet Comparative Biological Study of Lys-Amp and Cit amine. Plasma concentrations of d-amphetamine were mea Amp Sured using ELISA. Mean plasma concentration curves (n=5) of d-amphetamine released by harg-Amp or Lys-Amp are 0256 To compare the amount of release of d-amphet shown in FIG. 9. Pharmacokinetic parameters of this study amine among various polar hydrophilic prodrugs, 1-citrulline are listed in Table 8. No significant release (<50%) was d-amphetamine (Cit-Amp) was dosed with Lys-Amp in observed in either harg-Amp or Lys-Amp and less release was observed within the first hour of administration (<25%). another oral pharmacokinetic study. Mean plasma concentra Observed levels from Lys-Amp are significantly higher than tion curves (n=5) of d-amphetamine released by Cit-Amp and previously published data. Lys-Ampare shown in FIG. 6. Pharmacokinetic parameters of this study are listed in Table 6. TABLE 8 0257 Direct comparison of polar hydrophilic prodrugs especially non-standard amino acid conjugates of amphet Intranasal Properties of d-Amp, harg-Amp and Lys-Amp amine (Cit and harg) demonstrate the significant ability to shift or change the pharmacokinetic properties versus the Vehicle % AUC Tmax Cmax % Tmax % Cna. standard amino acids. All non-standard amino acids studied d-Amp 100% 5 min. 779 ng/mL 100% 100% released amphetamine in an amount greater than 50%. hArg-Amp 42% O.S 71 ng/mL 600% 9% Homoarginine showed C levels far below that of lysine Lys-Amp 36% 3 h 79 ng/mL 3600% 10% and homoarginine and citrulline significantly shifted the T compared to Lys-Amp. These changes to the pharmacoki netic properties of amphetamine when conjugated to non Example 18 standard amino acids represent clinically significant changes Intravenous Study of d-Amp, hArg-Amp, Lys-Amp not described or demonstrated by Lys-Amp nor described or 0260 Male Sprague-Dawley rats were dosed by intrave demonstrated by other standard amino acids. nous administration through the tail vein with hArg-Amp, US 2010/0292336 A1 Nov. 18, 2010

Lys-Amp or d-amphetamine. Doses were calculated at an amphetamine when conjugated to non-standard amino acids equivalent 1.5 mg/kg freebase equivalent of d-amphetamine. represent clinically significant changes not described or dem Plasma concentrations of d-amphetamine were measured onstrated by Lys-Amp nor described or demonstrated by using ELISA. Mean plasma concentration curves (n=5) of other standard amino acids. d-amphetamine released by harg-Amp or Lys-Amp are shown in FIG. 10. TABLE 11 0261 Pharmacokinetic parameters of this study are listed in Table 9. No significant release (<15%) was observed in Oral Properties of Lys-Amp, hArg-Amp, Orn-Amp and Cit-Amp eitherharg-Amp or Lys-Ampthough hArg-Amp was signifi cantly less. Observed levels from Lys-Amp are significantly Vehicle % AUC Tmax Cmax % Tax % Cna. higher than previously published data. The initial spike in Lys-Amp 100% 1 h 59ng/mL 100% 100% hArg-Amp 68% 2h 27 ng/mL. 200% 46% d-amphetamine released from hArg-Amp cleared quickly. Orn-Amp 52% 1 h 32 ng/mL. 100% S4% Cit-Amp 95% 15 min. 129 ng/mL 25% 21.9% TABLE 9 Intravenous Properties of d-Amp, hArg-Amp and Lys-Amp Example 21 Vehicle % AUC Tmax Cmax % Tax %Cna. Intranasal Study of AMP harg-Amp, Orn-Amp d-Amp 100% 5 min. 554 ng/mL 100% 100% hArg-Amp 8% 5 min. 68 ng/mL. 100% 12% 0265 Male Sprague-Dawley rats were fasted overnight Lys-Amp 14% 15 min. 79 ng/mL 100% 14% and dosed by intranasal administration with either harg Amp, Orn-Amp or d-amphetamine. Doses were calculated at an equivalent 1.5 mg/kg freebase equivalent of d-amphet Example 19 amine. Plasma concentrations of d-amphetamine were mea Sured using ELISA. Mean plasma concentration curves (n=5) Biological Study of hArg-Amp and Orn-Amp of d-amphetamine released by hArg-Amp or Orn-Amp are 0262 To compare the amount of release of d-amphet shown in FIG. 13. Pharmacokinetic parameters of this study amine among various non-standard amino acids, 1-ornithine are listed in Table 12. No significant release (<25%) was d-amphetamine (Orn-Amp) was dosed in place of Lys-Amp observed in either harg-Amp or Orn-Amp. in Example 14 in another oral pharmacokinetic study. Mean plasma concentration curves (n=5) of d-amphetamine TABLE 12 released by harg-Amp or Orn-Amp are shown in FIG. 11. Pharmacokinetic parameters of this study are listed in Table Intranasal Properties of d-Amp, hArg-Amp and Orn-Amp 10. Vehicle % AUC Tmax Cmax % Tax % Cna. d-Amp 100% 15 min. 53 ng/mL 100% 100% TABLE 10 hArg-Amp 23% 2h 9 ng/mL 16.00% 1796 Orn-Amp 14% 2h 10 ng/mL 16.00% 19% Pharmacokinetic Properties of hArg-Amp and Orn-Amp Vehicle % AUC T. Cmax % Tax % Ca hArg-Amp 100% 4h 32 ng/mL. 100% 100% Example 22 Orn-Amp 78% 1 h 27 ng/mL. 25% 84% Intravenous Study of AMP harg-Amp, Orn-Amp 0266 Male Sprague-Dawley rats were dosed by intrave Example 20 nous administration through the tail vein with hArg-Amp, Orn-Amp or d-amphetamine. Doses were calculated at an Comparative Biological Study of Lys-Amp, harg equivalent 1.5 mg/kg freebase equivalent of d-amphetamine. Amp, Orn-Amp and Cit-Amp Plasma concentrations of d-amphetamine were measured 0263. To compare the amount of release of d-amphet using ELISA. Mean plasma concentration curves (n=5) of amine among various non-standard amino acids, 1-ornithine d-amphetamine released by harg-Amp or Orn-Amp are d-amphetamine (Orn-Amp), harg-Amp and 1-citrulline-d- shown in FIG. 14. Pharmacokinetic parameters of this study amphetamine (Cit-Amp) were dosed with Lys-Amp in are listed in Table 13. No significant release (<35%) was another oral pharmacokinetic study. Mean plasma concentra observed in either harg-Amp or Orn-Amp. The initial spike tion curves (n=5) of d-amphetamine released by harg-Amp, in d-amphetamine released from hArg-Amp cleared quickly Orn-Amp and Cit-Amp are shown in FIG. 12. Pharmacoki while as in the intranasal study, Orn-Amp had a slight netic parameters of this study are listed in Table 11. increase at the 2 hour point. 0264 Direct comparison of 3 non-standard amino acid TABLE 13 conjugates of amphetamine (Cit, Ornand harg) demonstrate the significant ability to shift or change the pharmacokinetic Intravenous Properties of d-Amp, hArg-Amp and Orn-Amp properties versus the standard amino acids. All non-standard Vehicle % AUC Tmax Cmax % Tax % Cna. amino acids studied released amphetamine in an amount d-Amp 100% 15 min. 396 ng/mL 100% 100% greater than 50%. Ornithine and homoarginine both showed hArg-Amp 41% 15 min. 135 ng/mL 100% 34% Clevels far below that of lysine and both homoarginine Orn-Amp 10% 15 min. 26 ng/mL. 100% 79% and citrulline significantly shifted the T compared to Lys Amp. These changes to the pharmacokinetic properties of US 2010/0292336 A1 Nov. 18, 2010 34

0267 Results of the studies in above examples clearly understood that the foregoing describes preferred embodi show an unexpected change in the oral pharmacokinetic prop ments of the invention and that modifications may be made erties exhibited by polar hydrophilic prodrugs, including non therein without departing from the spirit or scope of the standard amino acid conjugates of amphetamine. By chang invention as set forth in the appended claims. ing the polar hydrophilic group attached to amphetamine, the What is claimed is: conjugates are able to shift T. (earlier or later), modify 1. A composition for treating a human or animal patient curve shape, lower C, and raise C. In addition, the shift having attention deficit disorder or attention deficit hyperac in T for harg-Amp may be clinically significant in that tivity disorder, comprising amphetamine chemically attached many of the cardiovascular side effects and toxicity are to a polar hydrophilic ligand, a salt thereof, or a combination related to T, and C. The results demonstrate that by thereof. using these polar hydrophilic groups, including non-standard 2. The composition of claim 1, wherein the polar hydro amino acids, a shift in the T, with a lower C. occurs philic ligand is homoarginine. without changing AUC significantly. In addition, the slope of 3. The composition of claim 2, wherein the homoarginine uptakeofharg-Amp vs. Lys-Amp appears to be more gradual is 1-homoarginine. thus leading to a slower onset which could further alleviate 4. The composition of claim 1, wherein the amphetamine is side effects. d-amphetamine. 0268. The amphetamine conjugates listed above of the 5. The composition of claim 1, wherein the salt thereofisan present technology demonstrate that by using polar hydro acefyllinate, 4-acetamidobenzoate, acetate, aceturate, adi philic prodrugs, a shift in the T occurs while still retaining pate, aminosalicylate, ammonium, ascorbate, l-aspartate, AUC and potential clinical effect. By using polar hydrophilic benzoate, besylate, bicarbonate, borate, butyrate, calcium, prodrugs, we are able to demonstrate that harg-Amp shows camphocarbonate, camphorate, d-camsylate, 1-camsylate, little release via the IN (intranasal) and IV (intravenous) route camsylate, carbonate, cholate, citrate, cypionate, decanoate, yet still maintain a similar AUC. dichloroacetate, edentate, edisylate, estolate, esylate, ethyl 0269. In addition, the amphetamine conjugate, harg Sulfate, fumarate, furate, fusidate, galactarate (mucate), Amp, of the present technology demonstrates that by using galacturonate, gallate, gentisate, gluceptate, gluconate, glu non-standard amino acids, a shift in the Toccurs while still curonate, glutamate, glutarate, glycerophosphate, glycolate, retaining AUC and potential clinical effect. By using non heptanoate (enanthate), hexanoate, hippurate, hybenzate, standard amino acids, we are able to demonstrate that both hydrobromide/bromide, hydrochloride/chloride, hydroxide, hArg-Amp and Orn-Amp show little release via the IN (intra hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- nasal) and IV (intravenous) route yet still maintain a similar lactate, lactobionate, laurate, lithium, magnesium, malate, AUC. d.l-malate, maleate, malonate, mandelate, meso-tartrate, 0270. For example, value ranges for the pharmacokinetic mesylate, methanesulfonate, methylsulfate, myristate, napa parameters of amphetamine derivatives conjugated to disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, homoarginine after oral administration when compared to the orotate, oxalate, palmitate, pamoate, phenylpropionate, phos respective unconjugated amphetamine derivatives are pro phate, picrate, pivalate, potassium, propionate, pyrophos vided in Table 14. phate, Salicylate, Salicylsulfate, sodium, Stearate. Succinate, Sulfate, Sulfosalicylate, tannate, d-tartrate, 1-tartrate, d.l-tar TABLE 1.4 trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri brophenate, triflate, undecylenate, Valerate, valproate, Xin PK Parameter hArg-PEA' afoate, Zinc, and mixtures thereof. AUCo-12, SO-200% 6. The composition of claim 1, wherein the salt thereofisa AUC, SO-200% mesylate, a hydrochloride salt, a Sulfate, an oxalate, a triflate, AUC SO-200% Cmax 50-500% a citrate, a malate, a tartrate, a phosphate, a nitrate, a benzoate, Tmax 25-500% or a mixture thereof. T1/2 SO-200% 7. A composition for treating a human or animal patient PEA = derivative of amphetamine (phenethylamine analog) having attention deficit disorder or attention deficit hyperac PK Parameter for amphetamine derivative released from hArg-PEA conjugate expressed as tivity disorder, comprising a derivative of amphetamine percent of PK parameter for the unconjugated amphetamine derivative (both administered at equimolar doses) chemically attached to a polar hydrophilic ligand, a salt In no case shallC and T and T12 and any AUC value for any one harg-PEA conjugate thereof, or a combination thereof. all be within 80-125%. 8. The composition of claim 7, wherein the polar hydro 0271 The polar, hydrophilic amphetamine prodrug, such philic ligand is homoarginine. as a non-standard amino acid amphetamine conjugate, of the 9. The composition of claim 8, wherein the homoarginine present technology is chemically stable to in vitro hydrolysis is 1-homoarginine. of the amide linkage to prevent tampering or removing the 10. The composition of claim 7, wherein the derivative of amphetamine prior to oral ingestion. Also, the controlled amphetamine is 1-amphetamine, methamphetamine, p-meth release of amphetamine through oral administration of the oxyamphetamine, 3.4-methylenedioxyamphetamine, 2.3- polar, hydrophilic amphetamine prodrug, such as a non-stan methylenedioxyamphetamine, 3.4-methylenedioxymetham dard amino acid amphetamine conjugate, of the present tech phetamine, 2,5-dimethoxy-4-methylamphetamine, 3,4,5- nology is an inherent property of the molecule, not related to trimethoxyamphetamine, 2,4,5-trimethoxyamphetamine, the formulation. Therefore, the prodrug of the present tech 2,3,4-trimethoxyamphetamine, 2,3,5-trimethoxyamphet nology can be easily formulated to different dosage forms. amine, 2.3,6-trimethoxyamphetamine, or 2,4,6-tri 0272. The invention is now described in such full, clear, methoxyamphetamine. concise and exact terms as to enable any person skilled in the 11. The composition of claim 7, wherein the derivative of art to which it pertains, to practice the same. It is to be amphetamine is 1-amphetamine. US 2010/0292336 A1 Nov. 18, 2010

12. The composition of claim 7, wherein the salt thereof is 18. The composition of claim 14, wherein the salt of the an acefyllinate, 4-acetamidobenzoate, acetate, aceturate, adi conjugate is 1-homoarginine-d-amphetamine hydrochloride. pate, aminosalicylate, ammonium, ascorbate, 1-aspartate, 19. The composition of claim 14, wherein the composition benzoate, besylate, bicarbonate, borate, butyrate, calcium, has a reduced pharmacological activity when administered by camphocarbonate, camphorate, d-camsylate, 1-camsylate, parenteral routes. camsylate, carbonate, cholate, citrate, cypionate, decanoate, 20. The composition of claim 14, wherein the salt of the dichloroacetate, edentate, edisylate, estolate, esylate, ethyl conjugate is a mesylate, a hydrochloride salt, a Sulfate, an Sulfate, fumarate, furate, fusidate, galactarate (mucate), oxalate, a triflate, a citrate, a malate, a tartrate, a phosphate, a galacturonate, gallate, gentisate, gluceptate, gluconate, glu nitrate, a benzoate, or a mixture thereof. curonate, glutamate, glutarate, glycerophosphate, glycolate, 21. The composition of claim 14, wherein the composition heptanoate (enanthate), hexanoate, hippurate, hybenzate, is in the form of a tablet, a capsule, a caplet, a troche, a hydrobromide/bromide, hydrochloride/chloride, hydroxide, lozenge, an oral powder, a solution, a oral film, a thin strip, or hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- a Suspension. lactate, lactobionate, laurate, lithium, magnesium, malate, 22. The composition of claim 21, wherein the tablet, tro d.1-malate, maleate, malonate, mandelate, meso-tartrate, che, or lozenge is chewable. mesylate, methanesulfonate, methylsulfate, myristate, napa 23. The composition of claim 14, wherein the conjugate, disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, the salt of the conjugate, or the combination thereof is present orotate, oxalate, palmitate, pamoate, phenylpropionate, phos in the amount of from about 1 mg to about 500 mg. phate, picrate, pivalate, potassium, propionate, pyrophos 24. The composition of claim 23, wherein the conjugate, phate, Salicylate, Salicylsulfate, Sodium, Stearate. Succinate, the salt of the conjugate, or the combination thereof is present Sulfate, Sulfosalicylate, tannate, d-tartrate, 1-tartrate, d.l-tar in the amount of from about 5 mg to about 250 mg. trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri 25. The composition of claim 24, wherein the conjugate, brophenate, triflate, undecylenate, Valerate, Valproate, Xin the salt of the conjugate, or the combination thereof is present in the amount of from about 10 mg to about 100 mg. afoate, Zinc, and mixtures thereof. 26. The composition of claim 14, wherein the conjugate, 13. The composition of claim 7, wherein the salt thereof is the salt of the conjugate, or the combination thereof is in an a mesylate, a hydrochloride salt, a Sulfate, an oxalate, a tri amount Sufficient to provide a therapeutically bioequivalent flate, a citrate, a malate, a tartrate, a phosphate, a nitrate, a AUC when compared to amphetamine alone, but does not benzoate, or a mixture thereof. provide a C, spike. 14. A composition for treating a human or animal patient 27. The composition of claim 14, wherein the conjugate, having attention deficit disorder or attention deficit hyperac the salt of the conjugate, or the combination thereof is in an tivity disorder, comprising at least one conjugate, a salt of the amount Sufficient to provide a therapeutically bioequivalent conjugate, or a combination thereof; AUC when compared to amphetamine alone, but does not wherein the conjugate comprises amphetamine or a deriva provide an equivalent C. tive thereof and homoarginine. 28. A method of treating a human or animal patient having 15. The composition of claim 14, wherein the amphet attention deficit disorder or attention deficit hyperactivity amine is d-amphetamine. disorder, comprising the step of orally administering to the 16. The composition of claim 14, wherein the homoargin patient a pharmaceutically effective amount of the composi ine is 1-homoarginine. tion of any one of claim 1, 7 or 14. 17. The composition of claim 14, wherein the conjugate is 1-homoarginine-d-amphetamine. c c c c c