D-AMPHETAMINE COMPOUNDS, COMPOSITIONS, AND PROCESSES FOR MAKING AND USING SAME - Patent application

Abstract

JPEG2023501968000058.jpg2063 A composition comprising a d-amphetamine compound having this structure and at least one organic acid covalently bonded to d-amphetamine, or a salt thereof, a derivative thereof, or a combination thereof, is disclosed. Methods for making and using the same are also disclosed. The organic compound includes a heterocyclic nitrogen compound. Heterocyclic nitrogen compounds are commonly found in nature and are involved in several biological functions in plants and animals. Examples of heterocyclic nitrogen compounds for use in the practice of the present technology include, but are not limited to, pyridine derivatives, some of which play important roles in the metabolism of nicotinate and tryptophan. In these compounds, one carbon atom of the phenyl ring is generally replaced by a nitrogen atom.

Description

[Technical field]

[0001] Related Applications This patent application is related to and claims the benefit of priority to U.S. Non-Provisional Patent Application No. 16 / 667 / 807, filed October 29, 2019, the contents of which are incorporated by reference in their entirety into this disclosure.

[0002] Federally funded research and development [Not applicable] [Background technology]

[0003] 2. Background of the Invention The technology described herein relates to novel compounds and compositions of d-amphetamine (i.e., 1-phenylpropan-2-amine), its salts, its derivatives, or combinations thereof, including organic compounds covalently bound or attached to d-amphetamine. Methods of making and using the compounds and compositions of the technology are also disclosed.

[0004] Stimulants, including d-amphetamine and its derivatives, increase activity of the sympathetic nervous system and / or central nervous system (CNS) and are prescribed for the treatment of a variety of conditions and disorders, primarily including, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety, and wakefulness.

[0005] Children's attention deficit hyperactivity disorder (ADHD) has been treated with stimulants for many years. However, more recently, the increase in the number of prescriptions for ADHD treatment in the adult population has sometimes outpaced the growth of the pediatric market. There are various drugs currently used to treat ADHD, such as methylphenidate (e.g., commercially available under the trade name Ritalin® from Novartis International AG, located in Basel, Switzerland) and the non-stimulant atomoxetine (commercially available as Strattera® from Eli Lilly and Company, located in Indianapolis, IN), but d-amphetamine has become the pioneer of ADHD treatment.

[0006] Initial drug treatments for ADHD were limited to fast-acting immediate release formulations of stimulants (e.g., Dexedrine®, pure dextroamphetamine sulfate, commercially available from Smith Kline and French, located in the UK), which elicited a number of potentially undesirable side effects including rebound symptoms, cardiovascular stress / disorders (e.g., increased heart rate, hypertension, cardiomyopathy), other side effects (e.g., insomnia, euphoria, psychotic episodes), and rapid loss of therapeutic effect of the stimulant active ingredient, leading to addiction and abuse.

[0007] Behavioral deterioration (rebound / "crashing") is observed in a significant proportion of children with ADHD, typically in the afternoon or evening, as the medication wears off. Rebound symptoms include, for example, irritability, moodiness, hyperactivity worse than in the unmediated state, sadness, crying, and in rare cases, psychotic episodes. Symptoms may subside quickly or last for hours. Some patients may experience rebound / crashing so severe that treatment must be discontinued. The rebound / crashing effect may also trigger addictive behavior, with patients attempting to administer additional doses of stimulants in an attempt to prevent the expected negative outcomes and side effects of rebound / crashing.

[0008] It has been shown that stimulants such as methylphenidate and d-amphetamine exert noradrenergic and dopaminergic effects, which can lead to cardiovascular events, including, for example, increased heart rate, hypertension, palpitations, tachycardia, and in isolated cases, cardiomyopathy, stroke, myocardial infarction, and sudden death.As a result, currently available stimulants expose patients with existing structural cardiac abnormalities or other severe cardiac symptoms to greater health risks, and are not often used or used with caution in this population.However, it is worth noting that the cardiovascular effects of stimulants, for example, on heart rate and blood pressure, depend on the dose administered.As a result, it is believed that the treatment that maintains the lowest effective stimulant blood concentration for a therapeutically beneficial duration will demonstrate less cardiovascular risk.

[0009] d-amphetamine and many of its derivatives (e.g., methamphetamine, 3,4-methylenedioxy-methamphetamine / "ecstasy") are widely abused for various purposes such as euphoria, prolonged wakefulness / alertness, or rapid weight loss, or by actual ADHD patients who have developed excessive self-medication habits to avoid rebound symptoms, for example, with anxiety or depression. The effects desired by potential abusers are derived from stimulation of the central nervous system, prompting the Schedule II or even Schedule I classification of d-amphetamine (d- and ld-amphetamine individually and any combination of both are Schedule II) and certain of its derivatives after the passage of the Controlled Substances Act (CSA) in 1970. Both classifications are defined by a high propensity for abuse. Schedule II drugs have accepted medical uses, while Schedule I substances do not fall under the CSA. To date, all d-amphetamine products, including compositions containing extended release formulations of the drug, are required to include a black box warning on the drug label to inform patients about the potential for abuse and dependence of d-amphetamine.

[0010] Prior art has shown that most side effects of amphetamines are caused by a large initial spike in blood levels of the stimulant that quickly fades (typically within 4-6 hours) to levels below therapeutic efficacy. As a result, the high potency of dextroamphetamine (d-amphetamine) has been continually balanced by a series of new drugs with increasingly sustained release profiles achieved by delivering d-amphetamine more slowly into the bloodstream in an effort to create treatment outcomes and regimens that are safer and less prone to abuse. Methods and techniques for generating smaller spikes in drug blood concentrations include, for example, the use of mixed salt and isomer compositions (i.e., various salts of d- and the less potent l-amphetamine), extended / controlled / sustained release formulations of amphetamine / dextroamphetamine salts (e.g., Adderall XR®, available from Shire US, Inc., located in Wayne, PA), and prodrugs of lisdexamfetamine salts (Vyvanse®, also available from Shire).

[0011] As a result, there remains a need in the art for safer dosage forms of d-amphetamine and treatment regimens that are therapeutically effective and can provide sustained release and sustained therapeutic effect. Summary of the Invention [Means for solving the problem]

[0012] Summary of the Invention The technology described herein provides, in part, novel compounds and compositions of the stimulant d-amphetamine ("d-Amp", "dextroamphetamine"), its salts, other derivatives, and combinations thereof.

[0013] In some embodiments, the technology provides compounds and / or compositions comprising d-amphetamine and one or more organic compounds.In some embodiments of the technology, the organic compounds comprise heterocyclic nitrogen compounds.Heterocyclic nitrogen compounds are commonly found in nature and are involved in some biological functions in plants and animals.Examples of heterocyclic nitrogen compounds for use in implementing the technology include, but are not limited to, pyridine derivatives, some of which play an important role in the metabolism of nicotinate and tryptophan.In these compounds, one carbon of phenyl ring is generally replaced by nitrogen atom.

[0014] In some aspects of the present technology, the organic compound comprises an amino acid. An amino acid is a group consisting of a carboxyl (-COOH) and an amino (-NH 2Amino acids that may be used in the present technology may be natural, standard, non-standard, unusual, synthetic, and / or essential amino acids, and may be L- or D-amino acids, or combinations thereof. Examples of amino acids for use in the practice of the present technology include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, gamma-aminobutyric acid, 6-aminohexanoic acid, sarcosine, carnitine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, beta-alanine, beta-aminoisobutyric acid, beta-leucine, beta-lysine, beta-arginine, beta-tyrosine, beta-phenylalanine, isoserine, beta-glutamic acid. , β-tyrosine, β-dopa (3,4-dihydroxy-L-phenylalanine), 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methyl-alanine, L-abrine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, azetidine-2-carboxylic acid, pipecolic acid, allylglycine, cyclohexylglycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glycine ester, 2-(trifluoromethyl)-phenylalanine, 4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine, 2-chlorophenylglycine, 3-guanidino-propionic acid, 3,4-dehydro-proline, 2,3-Diaminobenzoic acid, 2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid, allo-isoleucine, tert-leucine, 3-phenylserine, isoserine, 3-aminopentanoic acid, 2-amino-octanedioic acid, 4-chloro-β-phenylalanine, β-homoproline, β-homoalanine, 3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid, 5-aminovaleric acid, 4-(dimethylamino)cinnamic acid, 2-pyridylalanine (2-Pal), and 3-pyridylalanine (3-Pal).

[0015] In some embodiments, the compound has formula IB

[0016] [ka] The structure is Wherein X is A-COO-R;

[0017] A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0018] R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl and m is an integer from 1 to 5. In one embodiment, the radical is selected from the group consisting of sulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, amino acid, and amino acid residue.

[0019] In some embodiments, the compound has the formula ID

[0020] [ka] The structure is

[0021] In the formula, X is A-CO-NR 1 R 2 and;

[0022] A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0023] R 1 and R 2are independently selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl, In some embodiments, the arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, amino acid, and amino acid residue.

[0024] It is to be understood that the carbon atom attached to Y is a chiral center when Y is not hydrogen.

[0025] [ka]

[0026] In some embodiments, the technology includes conjugates in which the chiral carbon has an R configuration. In other embodiments, the technology includes conjugates in which the chiral carbon has an S configuration. In other embodiments, the technology includes mixtures of stereoisomers in which some conjugates contain a chiral carbon with an R configuration and some conjugates contain a chiral carbon with an S configuration.

[0027] The technology described herein further provides a method for controlled therapeutic delivery of d-amphetamine compositions by oral administration. In at least one embodiment, the technology described herein focuses on slow / sustained controlled release compositions of d-amphetamine in compound form that allow slow / sustained / controlled delivery of the stimulant to the blood system of humans or animals within a safe therapeutic window upon oral administration. At least some compositions / formulations of the current technology can reduce rebound effects, cardiovascular stress, addiction / abuse potential, and / or other common stimulant side effects associated with d-amphetamine and similar compounds. Such compositions can also increase duration of therapeutic efficacy, ease of application, patient compliance, and / or any combination of these features, especially when administered orally.

[0028] The release of d-amphetamine after oral administration of the compound of the present technology can occur gradually over an extended period of time, thereby eliminating unintended excessive rapid rises in drug levels in the bloodstream of a human or animal patient (e.g., large blood level concentration spikes). Without being bound to any particular theory, it is believed that such spikes in blood levels can cause the euphoric drug to "get high," resulting in cardiovascular effects such as increased blood pressure and heart rate. Furthermore, sustained blood levels are achieved within the effective therapeutic range for a longer duration than other conventional treatments, thereby preventing rebound effects.

[0029] In some embodiments, the present technology provides certain d-amphetamine ("d-Amp", "dexamphetamine") compounds, compositions, or pharma- ceutically acceptable salts thereof, for example to provide at least one once-daily dose form of a d-amphetamine compound in a composition with unconjugated d-amphetamine that can provide both immediate and extended release PK profiles when compared to unconjugated d-amphetamine. In some cases, the release profile provides the ability of the compound or composition to be administered using dosing regimens not readily available with unconjugated d-amphetamine.

[0030] At least some compositions comprising d-amphetamine compounds of the present technology are resistant to abuse by parenteral administration routes such as intravenous "shooting", intranasal "snorting" or inhalation "smoking" that are often used during illicit use. Thus, the present technology provides stimulant-based treatment modalities and dosage forms for certain disorders that require CNS stimulation, such as ADHD, ADD, obesity, narcolepsy, appetite suppression, depression, anxiety, sleep disorders, excessive daytime sleepiness, insomnia, binge eating, and wakefulness with reduced or prevented abuse potential. Without being bound to any particular theory, it is believed that the compositions of the present technology provide substantially reduced abuse potential or abuse liability compared to existing stimulant treatment modalities and dosage forms.

[0031] At least some compositions comprising the d-amphetamine compounds of the present technology may also be used to treat stimulant substance (cocaine, methamphetamine) abuse and addiction, substance use disorders, improve battlefield alertness, and / or combat fatigue.

[0032] The compositions of the present technology preferably have no or substantially reduced pharmacological activity when administered by injection or intranasal administration route.However, they remain orally bioavailable with respect to d-amphetamine.Bioavailability may be the result of hydrolysis of the covalent bond between d-amphetamine and the remaining part of the conjugate after oral administration.Hydrolysis is time-dependent, which allows d-amphetamine and other metabolites such as p-hydroxyamphetamine and p-hydroxyephedrine to be available in their active form for a long period of time.In at least one further embodiment, the release of d-amphetamine is reduced or eliminated when compared to unconjugated d-amphetamine or when the compositions of the present technology are delivered by parenteral route.

[0033] For example, in one embodiment, the composition of the present technology maintains its efficacy and abuse resistance after crushing of the tablet, capsule, or other oral dosage form utilized to deliver the therapeutic component (i.e., active ingredient / drug) due to the controlled release component, which is a designed property of the composition, not the formulation. In contrast, conventional extended release formulations used to control the release of d-amphetamine are subject to release up to the entire d-amphetamine content immediately after crushing. When the content of the crushed tablet is injected or ingested, the large dose of d-amphetamine produces the "rush" effect sought by addicts.

[0034] Other objects, advantages and features of the invention will be described below, and will be apparent from the description and from the practice of the invention. [Brief description of the drawings]

[0035] [Figure 1] Oral PK curves comparing d-amphetamine sulfate and d-amphetamine-CO2CH2-nicotinate ethyl ester (AMP-CO2CH2-nicotinate (Et)).

[0036] [Diagram 2]Oral PK curves comparing lisdexamfetamine (LDX), d-amphetamine sulfate, d-amphetamine-CO2CH2-nicotinoyl-valinamide (AMP-CO2CH2-nicotinoyl-Val-NH2), d-amphetamine-CO2CH2-nicotinoyl-alanine methyl ester (AMP-CO2CH2-nicotinoyl-Ala-OMe), and (d-amphetamine-CO2CH2-nicotinoyl)2-serine methyl ester ((AMP-CO2CH2-nicotinoyl)2-Ser-OMe).

[0037] [Diagram 3] Oral PK curves comparing d-amphetamine sulfate and d-amphetamine-CO2CH2-nicotinoyl-serine (AMP-CO2CH2-nicotinoyl-Ser).

[0038] [Figure 4] Intravenous PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-nicotinate ethyl ester (AMP-CO2CH2-nicotinate (Et)).

[0039] [Diagram 5] Intravenous PK curves comparing lisdexamfetamine (LDX), d-amphetamine sulfate, d-amphetamine-CO2CH2-nicotinoyl-valinamide (AMP-CO2CH2-nicotinoyl-Val-NH2), and d-amphetamine-CO2CH2-nicotinoyl-alanine methyl ester (AMP-CO2CH2-nicotinoyl-Ala-OMe).

[0040] [Figure 6] Intranasal PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-nicotinate ethyl ester (AMP-CO2CH2-nicotinate (Et)).

[0041] [Figure 7]Intranasal PK curves comparing lisdexamfetamine (LDX), d-amphetamine sulfate, and d-amphetamine-CO2CH2-nicotinoyl-valinamide (AMP-CO2CH2-nicotinoyl-Val-NH2).

[0042] [Figure 8] Oral PK curves comparing d-amphetamine-CO2CH2-nicotinoyl-valinamide (AMP-CO2CH2-nicotinoyl-Val-NH2) and d-amphetamine-CO2CH2-isonicotinoyl-valinamide (AMP-CO2CH2-isonicotinoyl-Val-NH2).

[0043] [Figure 9] Oral PK curves comparing d-amphetamine-CO2CH2-nicotinate ethyl ester (AMP-CO2CH2-nicotinate (Et)) and d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate (Et)).

[0044] [Figure 10] Intravenous PK curves comparing d-amphetamine-CO2CH2-nicotinate ethyl ester (AMP-CO2CH2-nicotinate (Et)) and d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate (Et)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Detailed Description of the Invention The present technology generally describes novel compounds and compositions of the stimulant d-amphetamine, its salts, other derivatives, and combinations thereof. Additionally, the technology described herein generally relates to methods of making and using these novel compounds and compositions.

[0046] As used herein, "amino acid" refers to naturally occurring, standard, non-standard, unusual, synthetic, and / or essential amino acids, which may be L-amino acids or D-amino acids, or combinations thereof.

[0047] As used herein, "d-amphetamine" is intended to mean any of the sympathomimetic phenethylamine derivatives with central nervous system stimulant activity, including, but not limited to, d-amphetamine (alpha-methyl-phenethylamine), methamphetamine, p-methoxyamphetamine, methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,4,5-trimethoxyamphetamine, 3,4-methylenedioxy-methamphetamine, and methylphenidate.

[0048] As used herein, "in a manner inconsistent with the manufacturer's instructions" or similar phrases is meant to include, but is not limited to, consuming greater amounts than stated on the label or prescribed by a qualified physician, and / or altering the dosage formulation by any means (e.g., crushing, breaking, melting, separating, etc.) such that the composition may be injected, inhaled, or smoked.

[0049] As used herein, phrases such as "reduce," "reduce," "diminished," or "decreasing" are meant to include at least a 10% change in pharmacological activity, with greater percentage changes being preferred with respect to reduced abuse potential and overdose potential. For example, the change may also be greater than or increments within 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%.

[0050] As used herein, the term "substance use disorder" or "stimulant substance use disorder" or the acronym "SUD" can be characterized as the narrowing of maladaptive behaviors toward the acquisition and use of abused drugs at the expense of more positive behaviors maintained by other non-drug reinforcers. The success of any intervention can be measured, in part, by the extent to which it promotes re-direction of behavior away from the abused drug or toward non-drug reinforcers that are generally considered to be healthier. Pharmacological treatments, particularly agonist-like medications, have several properties that can promote such behavioral re-direction.

[0051] As used herein, the term "agonist medication" or "agonist replacement therapy" refers to drugs that are mechanistically similar to the drugs of abuse in terms of receptor-mediated and pharmacodynamic effects, but differ in terms of pharmacokinetic properties. Desirable attributes for agonist replacement therapy include receptor pharmacology overlap with the drug of abuse, oral bioavailability, slow onset of action, and long duration of action.

[0052] According to some embodiments, the present technology provides amphetamine in a compound form. More specifically, the amphetamine comprises at least one organic compound covalently bound or attached to the amphetamine.

[0053] In some embodiments, the compound has formula IB [ka] or a pharma- ceutically acceptable salt thereof,

[0054] Wherein X is A-COO-R;

[0055] A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0056] R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl and m is an integer from 1 to 5. In one embodiment, the radical is selected from the group consisting of sulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, amino acid, and amino acid residue.

[0057] In some embodiments, the compound has the formula ID

[0058] [ka] The structure is

[0059] In the formula, X is A-CO-NR 1 R 2 and;

[0060] A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0061] R 1 and R 2are independently selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl, In some embodiments, the arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, amino acid, and amino acid residue.

[0062] In some embodiments, the compound has formula IIB:

[0063] [ka] The structure is

[0064] In the formula, R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl In some embodiments, the arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, amino acid, and amino acid residue.

[0065] In some embodiments, the compound has formula IID:

[0066] [ka] The structure is

[0067] wherein Y is hydrogen and A is absent;

[0068] R 1 and R2 are independently selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl, In some embodiments, the arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, amino acid, and amino acid residue.

[0069] In some embodiments, the compound has the following structure:

[0070] [ka] AMP-CO with 2 CH 2 - Nicotinate (Et) or a pharmaceutical salt thereof.

[0071] In some embodiments, the compound has the following structure:

[0072] [ka] AMP-CO with 2 CH 2 -Nicotinoyl-Val-NH 2 or a pharmaceutical salt thereof.

[0073] In some embodiments, the compound has the following structure:

[0074] [ka] AMP-CO with 2 CH 2 -nicotinoyl-Ser or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments, the compound has the following structure:

[0076] [ka] AMP-CO with 2 CH 2 -nicotinoyl-Ala-OMe or a pharmaceutical salt thereof.

[0077] In some embodiments, the compound has the following structure:

[0078] [ka] (AMP-CO 2 CH 2 -nicotinoyl) 2 -Ser-OMe or a pharma- ceutically acceptable salt thereof.

[0079] In some embodiments, the pharma- ceutically acceptable salt of the compound is a single salt or a mixed salt, one or more of the salts being acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D, L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphorcarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, Ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate , salicylate, salicylic sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholate, lysinium, ammonium, troethamine, and mixtures thereof.

[0080] In some embodiments, the compound is a conjugate of d-amphetamine and has formula IB: [ka] The structure is

[0081] Wherein X is A-COO-R;

[0082] A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0083] R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, and / or arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0084] In some embodiments, the compound is a conjugate of d-amphetamine and has the formula ID

[0085] [ka] The structure is

[0086] In the formula, X is A-CO-NR 1 R 2 and;

[0087] A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0088] R 1 and R 2are independently selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl ... and / or arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0089] In some embodiments, the compound is a conjugate of d-amphetamine and has formula IIB:

[0090] [ka] The structure is

[0091] In the formula, R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfinyl, and arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0092] In some embodiments, the compound is a conjugate of d-amphetamine and has the formula IID:

[0093] [ka] The structure is

[0094] wherein Y is hydrogen and A is absent;

[0095] R1 and R 2 are independently selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl ... and arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0096] In some embodiments, the conjugate has the following structure:

[0097] [ka] AMP-CO with 2 CH 2 - Nicotinate (Et) or a pharmaceutical salt thereof.

[0098] In some embodiments, the conjugate has the following structure:

[0099] [ka] AMP-CO with 2 CH 2 -Nicotinoyl-Val-NH 2 or a pharmaceutical salt thereof.

[0100] In some embodiments, the conjugate has the following structure:

[0101] [ka] AMP-CO with 2 CH 2 -nicotinoyl-Ser or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, the conjugate has the following structure:

[0103] [ka] AMP-CO with 2 CH 2 -nicotinoyl-Ala-OMe or a pharmaceutical salt thereof.

[0104] In some embodiments, the conjugate has the following structure:

[0105] [ka] (AMP-CO 2 CH 2 -nicotinoyl) 2 -Ser-OMe or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the pharma- ceutically acceptable salt of the conjugate is a single salt or a mixed salt, wherein one or more of the salts are acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate. , L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphorcarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate Salt, fructose, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate The salt is selected from the group consisting of salts, salicylic sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholate, lysinium, ammonium, troethamine, and mixtures thereof.

[0107] In some embodiments, the amphetamine portion of the conjugate can be d-amphetamine or l-amphetamine.In other embodiments, the composition of the present technology comprises a mixture of d-amphetamine conjugates and l-amphetamine conjugates.In further embodiments, the mixture of conjugates can be a racemic mixture.It should be understood that the portion of the conjugate other than amphetamine can also have a chiral center, which creates additional stereoisomers.The composition of the present technology can comprise a single stereoisomer or any mixture of stereoisomers.

[0108] In some embodiments, X of the compound or conjugate is located at the C-3 or C-5 position of the pyridine ring. It should be understood that for symmetry reasons, C-3 is equivalent to C-5. [ka]

[0109] Some embodiments are compositions comprising conjugates of d-amphetamine. In some embodiments, the compositions are formulated for oral, suppository, powder for injection, intravenous, intranasal, or intrathecal administration. In yet another embodiment, the compositions formulated for oral administration are in a dosage form selected from the group consisting of solid forms, tablets, capsules, caplets, soft gels, suppositories, troches, lozenges, oral powders, solutions, syrups, oral films, thin strips, slurries, emulsions, elixirs, and suspensions. In yet another embodiment, the compositions further comprise one or more excipients, the excipients being selected from the group consisting of anti-adhesives, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof. In yet other aspects, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, and polyethylene glycol, and milk derivatives.In some embodiments, the conjugate is present in an amount per unit dose between about 0.1 mg and about 2000 mg per unit dose. In yet other embodiments, the conjugate is present in an amount per unit dose between about 0.1 mg and about 1000 mg per unit dose. In other embodiments, the conjugate is present in an amount per unit dose between about 0.5 mg and about 500 mg per unit dose. In further embodiments, the conjugate is present in an amount per unit dose between about 1 mg and about 250 mg per unit dose. In yet other embodiments, the conjugate is present in an amount per unit dose between about 1.5 mg and about 100 mg per unit dose. In yet another embodiment, the conjugate is present in an amount per unit dose between about 0.5 mg to about 2000 mg per unit dose, alternatively about 1 mg to about 2000 mg per unit dose, alternatively about 2 mg to about 2000 mg per unit dose, alternatively about 5 mg to about 2000 mg per unit dose, alternatively about 10 mg to about 2000 mg per unit dose, alternatively about 20 mg to about 2000 mg per unit dose, alternatively about 40 mg to about 2000 mg per unit dose, alternatively about 80 mg to about 2000 mg per unit dose, alternatively about 160 mg to about 2000 mg per unit dose, alternatively about 320 mg to about 2000 mg per unit dose, alternatively about 640 mg to about 2000 mg per unit dose, alternatively about 1280 mg to about 2000 mg per unit dose.In yet another embodiment, the conjugate is present in an amount of from about 0.1 mg to about 2000 mg per unit dose, alternatively from about 0.1 mg to about 1900 mg per unit dose, alternatively from about 0.1 mg to about 1800 mg per unit dose, alternatively from about 0.1 mg to about 1700 mg per unit dose, alternatively from about 0.1 mg to about 1600 mg per unit dose, alternatively from about 0.1 mg to about 1500 mg per unit dose, alternatively from about 0.1 mg to about 1400 mg per unit dose, or alternatively from about 0.1 mg to about 1500 mg per unit dose. is about 0.1 mg to about 1300 mg per unit dose, or about 0.1 mg to about 1200 mg per unit dose, or about 0.1 mg to about 1100 mg per unit dose, or about 0.1 mg to about 1000 mg per unit dose, or about 0.1 mg to about 900 mg per unit dose, or about 0.1 mg to about 800 mg per unit dose, or about 0.1 mg to about 700 mg per unit dose, or about 0.1 mg to about 600 mg per unit dose, or or about 0.1 mg to about 500 mg per unit dose, or about 0.1 mg to about 400 mg per unit dose, or about 0.1 mg to about 300 mg per unit dose, or about 0.1 mg to about 200 mg per unit dose, or about 0.1 mg to about 100 mg per unit dose, or about 0.1 mg to about 90 mg per unit dose, or about 0.1 mg to about 80 mg per unit dose, or about 0.1 mg to about 70 mg per unit dose, or about 0.1 mg to about 100 mg per unit dose, or about 0.1 mg to about 150 mg per unit dose, or about 0.1 mg to about 200 mg per unit dose, or about 0.1 mg to about 300 mg per unit dose, or about 0.1 mg to about 400 mg per unit dose, or about 0.1 mg to about 500 mg per unit dose, or about 0.1 mg to about 600 mg per unit dose, or about 0.1 mg to about 70 mg per unit dose, or about 0.1 mg to about 80 mg per unit dose, or about 0.1 mg to about 90 mg per unit dose, or about 0.1 mg to about 100 mg per unit dose, or about 0.1 mg to about 150 mg per unit dose, or about 0.1 mg to about 200 mg per unit dose, or about 0.1 mg to about 300 mg per unit dose, or about 0.1 mg to about 400 mg per unit dose, or about 0.1 mg to about 500 mg per unit dose, or about 0.1 mg to about 600 mg per unit dose, or about 0.1 mg to about 150 mg per unit dose, or about 0.1 mg to about 200 mg per unit dose, or about 0.1 mg to about 300 mg per unit dose, or about 0.1 mg to about 400 It is present in an amount per unit dose between about 0.1 mg to about 60 mg per dose, alternatively about 0.1 mg to about 50 mg per unit dose, alternatively about 0.1 mg to about 40 mg per unit dose, alternatively about 0.1 mg to about 30 mg per unit dose, alternatively about 0.1 mg to about 20 mg per unit dose, alternatively about 0.1 mg to about 10 mg per unit dose, alternatively about 0.1 mg to about 5 mg per unit dose, alternatively about 0.1 mg to about 1 mg per unit dose.

[0110] In some embodiments, the composition further comprises one or more additional pharmacological agents selected from the group consisting of stimulants, antidepressants, combinations thereof, and prodrugs thereof.In another embodiment, the composition further comprises one or more of unconjugated amphetamine, unconjugated methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, ethoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, or ziprasidone.In another embodiment, the composition further comprises unconjugated amphetamine, its isomer, or amphetamine conjugate. In yet another embodiment, the isomer of unconjugated amphetamine is unconjugated d-amphetamine.In another embodiment, the composition further comprises unconjugated methylphenidate, its isomer, or methylphenidate conjugate.In yet another embodiment, the isomer of unconjugated methylphenidate is unconjugated d-methylphenidate.In a further embodiment, the conjugate of methylphenidate is celdexmethylphenidate.

[0111] In some embodiments, the conjugate is provided in an amount sufficient to provide a similar or reduced AUC when compared to unconjugated d-amphetamine when administered orally at equimolar doses. In some embodiments, the conjugate is provided in an amount sufficient to provide a similar or reduced C when compared to unconjugated d-amphetamine when administered orally at equimolar doses. max In yet another embodiment, the conjugate is provided in an amount sufficient to provide a reduced C compared to unconjugated d-amphetamine when orally administered at equimolar doses. maxand in an amount sufficient to provide a similar or reduced AUC. In yet another embodiment, intranasal or intravenous administration of at least one conjugate provides a lower AUC and / or Cmax when compared to an equimolar amount of unconjugated d-amphetamine. In another embodiment, a composition comprising the conjugate provides a longer Tmax when compared to an equimolar amount of unconjugated d-amphetamine when orally administered. max In another embodiment, the composition comprising the conjugate is provided in an amount sufficient to provide a similar T when compared to unconjugated d-amphetamine when orally administered at equimolar doses. max Provided in a quantity sufficient to provide.

[0112] In some embodiments, compositions comprising the conjugate provide reduced abuse potential compared to unconjugated d-amphetamine. In other embodiments, compositions comprising the conjugate provide a longer T when compared to unconjugated d-amphetamine when administered at equimolar doses. max In another embodiment, the composition comprising the conjugate provides a similar T when compared to unconjugated d-amphetamine when administered at equimolar doses. max In yet another embodiment, the composition comprising the conjugate has an improved safety profile when compared to unconjugated d-amphetamine. In some embodiments, the composition comprising the conjugate produces reduced or no pharmacological activity when administered by parenteral route. In yet another embodiment, the composition comprising the conjugate has reduced plasma or blood concentration of released d-amphetamine when administered intranasally or intravenously compared to unconjugated d-amphetamine when administered in equimolar amount.

[0113] In some embodiments, the compositions comprising the conjugates have a lower AUC and / or C for d-amphetamine released from the conjugate when compared to an equimolar amount of unconjugated d-amphetamine following intravenous or intranasal administration of the composition to a subject. max In another embodiment, the composition comprising the conjugate exhibits a longer T for d-amphetamine released from the conjugate when compared to an equimolar amount of unconjugated d-amphetamine following intravenous or intranasal administration of the composition to a subject. max In some embodiments, upon administration to a subject, the composition comprising the conjugate provides a prolonged release of d-amphetamine in the subject as compared to the release of d-amphetamine upon administration of an equimolar amount of unconjugated d-amphetamine. In yet another embodiment, the composition comprising the conjugate exhibits less variability in inter- or intra-subject d-amphetamine plasma concentrations as compared to unconjugated d-amphetamine.

[0114] In some embodiments, some compounds of the present invention that contain a nicotinoyl moiety unexpectedly and unobviously provide different and / or improved d-amphetamine exposure in a subject following oral, intranasal, and / or intravenous administration when compared to compounds of the same structure but in which the nicotinoyl is replaced by an isonicotinoyl moiety. 2 CH 2 -Nicotinoyl-Val-NH2 is d-amphetamine-CO 2 CH 2 -Isonicotinoyl-Val-NH 2 In another embodiment, the d-amphetamine-CO 2 CH 2 - Nicotinate (Et) is d-amphetamine-CO 2 CH 2 -provides increased oral bioavailability of d-amphetamine compared to isonicotinate (Et). 2 CH2 - Nicotinate (Et) is AMP-CO 2 CH 2 -Reduces exposure to d-amphetamine after intravenous administration when compared to isonicotinate (Et).

[0115] Another embodiment of the present technology is a composition for treating a patient having a disorder or condition requiring stimulation of the patient's central nervous system, the composition having reduced abuse potential when administered compared to unconjugated d-amphetamine.

[0116] Another aspect of the present technology is a method of treating a patient having a disease, disorder, or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake, comprising administering to a patient in need thereof a pharma- ceutical effective amount of a composition comprising a conjugate of the present invention.

[0117] Another aspect of the present technology is a method of treating a patient having a disease, disorder, or condition mediated by increasing neurotransmitter concentrations at synapses, comprising administering to a patient in need thereof a pharma- ceutically effective amount of a composition comprising a conjugate of the present invention.

[0118] Another aspect of the present technology is a method for treating a patient with a disorder or condition that requires stimulation of the patient's central nervous system, comprising orally administering to a patient in need thereof a pharmacologic effective amount of a composition comprising the conjugate of the present invention.In some embodiments, the disease or condition is attention deficit hyperactivity disorder, attention deficit disorder, autism spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, bulimia, chronic fatigue syndrome, excessive daytime sleepiness, insomnia, schizophrenia, major depressive disorder, narcolepsy, postural orthostatic tachycardia syndrome, Tourette's syndrome, nervous tics, substance use disorder, apathy, depression, neurological injury, or obesity.In yet another embodiment, the disease or condition is attention deficit hyperactivity disorder.In yet another embodiment, the disease or condition is Tourette's syndrome or nervous tics.

[0119] As will be appreciated by those skilled in the art, drug products are considered to be pharmacopoeial equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration, and are identical in strength or concentration. Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and meet the same or official or other applicable specifications (i.e., strength, quality, purity, and identity), but they may differ in characteristics such as shape, scoring configuration, release mechanism, packaging, excipients (including dyes, flavors, preservatives), expiration date, and, to certain limits, labeling. Drug products are considered to be therapeutically equivalent only if they are pharmacopoeial equivalents and can be expected to have the same clinical efficacy and safety profile when administered to patients under conditions specified in the labeling. On the other hand, the term "bioequivalent" describes pharmacopoeial equivalents or pharmacopoeial substitute products that exhibit comparable bioavailability when studied under similar experimental conditions.

[0120] According to the technology described herein, the release of d-amphetamine after oral administration of the compounds of the technology described herein can occur under desired physiological conditions. Preferably, other routes of administration (e.g., intranasal or intravenous) do not degrade the compound to any appreciable extent. In some embodiments, the reduction in d-amphetamine exposure after intranasal and / or intravenous administration is 50%, 30%, 20%, <10%, etc., of the exposure after intranasal and / or intravenous administration of an equimolar dose of unconjugated d-amphetamine. Also, preferably, certain compounds or embodiments of the present invention resist the release of amphetamine via external means (chemical, enzymatic, or other). The degradation ratio of the compound that can be achieved through external means is preferably less than about 50%, alternatively less than about 25%, alternatively less than about 20%, alternatively less than about 10%.

[0121] It is also believed that embodiments of the compounds, compositions, and methods of the technology described herein provide a reduced likelihood of rebound, a reduced likelihood of abuse or addiction, and / or ameliorate stimulant-related toxicity of d-amphetamine.

[0122] The d-amphetamine compounds of the technology described herein could be used in any condition requiring stimulation of the central nervous system (CNS). These conditions include, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety, and wakefulness. d-amphetamine stimulants have also demonstrated utility in treating stimulant substance (e.g., cocaine, methamphetamine) abuse and addiction. d-amphetamine stimulants have also been used extensively to improve battlefield wakefulness and combat fatigue.

[0123] Thus, according to some embodiments, the technology described herein provides d-amphetamine compositions comprising at least one d-amphetamine compound of the present technology.

[0124] One embodiment is a composition comprising a d-amphetamine compound of the present technology that can prevent behavioral deterioration caused by d-amphetamine medication.

[0125] Another embodiment is a composition that allows for lower dosages of active pharmaceutical ingredients, including d-amphetamine compounds of the present technology.

[0126] Other formulations according to one or more embodiments of the present technology may contain, but are not limited to, lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, and mineral oil; color additives such as Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, or FD&C Blue No. 1, and various other certified color additives (21 CFR, Part 74); binders such as sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone polyethylene glycol, pullulan, and corn syrup; lubricants such as colloidal silicon dioxide and talc; surface active agents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol, and quaternary ammonium salts; preservatives and stabilizers; excipients such as lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, chlorides, sulfates, and phosphates of potassium, sodium and magnesium; and / or any other excipients known to one of skill in the art.

[0127] The d-amphetamine compositions of the present technology may be prepared according to any suitable method known to those of ordinary skill in the art of pharmaceutical manufacturing.

[0128] It should be noted that the above additives are not necessary for the d-amphetamine composition of the present technology to have sustained release in vivo properties. The d-amphetamine compound of the present technology is chemically stable to prevent d-amphetamine degradation or removal before oral ingestion. Also, the controlled release of d-amphetamine by oral administration of the d-amphetamine compound of the present technology is a designed property of the molecule and is not related to the formulation. Therefore, the compound of the present technology can be easily formulated into various dosage forms. In one or more embodiments of the present technology, no additional sustained release additives are necessary to achieve a blunted or reduced pharmacokinetic curve (e.g., reduced euphoric effect) while achieving a therapeutically effective amount of d-amphetamine release when taken orally.

[0129] The compounds and compositions of the technology described herein can be formulated into various dosage forms and administered by various dosage forms by any oral route of delivery. When administered, the compound releases d-amphetamine under digestive conditions. Any biologically acceptable dosage form known to those skilled in the art and combinations thereof are contemplated. Examples of preferred dosage forms include, but are not limited to, chewable tablets, fast-dissolving tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, granules, particles, microparticles, dispersible granules, cachets, oral films (e.g., fast-dissolving thin strips), and combinations thereof.

[0130] The formulations of the present technology suitable for oral administration can be presented as individual units, such as capsules, caplets, tablets, or oral films. These oral formulations can also include solutions or suspensions in aqueous or non-aqueous liquids. The formulations can be emulsions, such as oil-in-water liquid emulsions or water-in-oil liquid emulsions. Oil can be administered by adding purified and sterilized liquids to the prepared enteral formulation, which can then be placed in the feeding tube of patients who cannot swallow.

[0131] For example, when capsule form is selected, excipients used in capsule formulations can be divided into four separate groups: fillers / binders, disintegrants, lubricants, and carriers.Soft gel or soft gelatin capsules can be prepared, for example, by dispersing the formulation of the present technology in a suitable vehicle (vegetable oil is commonly used) to form a high-viscosity mixture.This mixture can then be encapsulated with a gelatin-based film using techniques and machines known to those skilled in the art of soft gel industry.The industrial units thus formed are then dried to constant weight.

[0132] For example, chewable tablets may be prepared by mixing the formulations of the present technology with excipients designed to form a relatively soft, flavored tablet dosage form that is intended to be chewed rather than swallowed. Conventional tablet machines and procedures can be utilized, both direct compression and granulation prior to compression, i.e., slugging. Individuals involved in pharmaceutical solid dosage form manufacturing are familiar with the processes and machinery used for chewable dosage forms, a very common dosage form in the pharmaceutical industry.

[0133] For example, film-coated tablets may be prepared by coating the tablet using techniques such as rotating pan coating or air suspension techniques to deposit a contiguous film layer onto the tablet.

[0134] For example, compressed tablets may be prepared by mixing the formulation of the present technology with excipients intended to add binding qualities to disintegration qualities. The mixture can be directly compressed or granulated and then compressed using methods and machines known to those skilled in the art. The resulting compressed tablet dosage units are then packaged according to market needs, i.e., unit dose, rolls, bulk bottles, blister packs, etc.

[0135] The methods and other ingredients required to make oral films or thin strips are known in the art. Potential film formers include pullulan, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, amylase, starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and mixtures thereof.

[0136] Saliva stimulants, plasticizers, cooling agents, surfactants, emulsifiers, thickeners, binders, sweeteners, flavoring agents, coloring agents, preservatives, or flavoring resins may also be used in the oral films or thin strips. Preferred agents include pullulan, triethanolamine stearate, methylcellulose, starch, triacetin, Polysorbate 80, xanthan gum, maltitol, sorbitol, and glycerol.

[0137] The technology described herein also contemplates the use of biologically acceptable carriers which can be prepared from a wide variety of materials, including, but not limited to, diluents, binders and adhesives, lubricants, plasticizers, disintegrants, colorants, bulking agents, flavoring agents, sweeteners, and miscellaneous materials, such as buffers and adsorbents, to prepare a particular pharmaceutical composition.

[0138] The binder may be selected from a wide range of materials, such as hydroxypropylmethylcellulose, ethylcellulose or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, milk derivatives such as whey, starch, and derivatives, and other conventional binders known to those skilled in the art.Exemplary non-limiting solvents are water, ethanol, isopropyl alcohol, methylene chloride, or mixtures and combinations thereof.Exemplary non-limiting bulk materials include sugar, lactose, gelatin, starch, and silicon dioxide.

[0139] Preferred plasticizers may be selected from the group consisting of, but not limited to, diethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid, propylene glycol, butyl phthalate, dibutyl sebacate, castor oil, and mixtures thereof. As will be apparent, the plasticizer may be hydrophobic as well as hydrophilic in nature. Water-insoluble hydrophobic substances such as diethyl phthalate, diethyl sebacate, and castor oil are known to be effective in preventing the formation of vitamin B 6 and vitamin C. In contrast, hydrophilic plasticizers are used when water-insoluble vitamins are used to aid in dissolving the encapsulation film and create channels on the surface to aid in the release of the nutritional composition.

[0140] It should be understood that in addition to the ingredients specifically mentioned above, the formulations of the present technology can include other suitable agents such as flavoring agents, preservatives, and antioxidants. Such antioxidants can be dietarily acceptable and can include, for example, vitamin E, carotene, BHT, or other antioxidants known to those skilled in the art.

[0141] Other compounds that may be included are, for example, medically inert ingredients, such as solid and liquid diluents, such as lactose, dextrose, saccharose, cellulose, starch, or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules, and water or vegetable oil for suspensions or emulsions; lubricants, such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; gelling agents, such as colloidal clays; thickening agents, such as tetrahydrofuran, ... These may include, for example, gum galactan or sodium alginate, binding agents such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates, or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; humectants such as lecithin, polysorbates, or lauryl sulfate; and other therapeutically acceptable auxiliary ingredients which are known additives for such formulations, such as humectants, preservatives, buffers, and antioxidants.

[0142] For oral administration, the powder or granules containing diluents, dispersants, and / or surface-active agents may be presented in a draught, in a solution or syrup, in a capsule or dry sachet, in a non-aqueous suspension which may contain a suspending agent, or as a suspension in a solution or syrup. Flavoring agents, preservatives, suspending agents, thickening agents, or emulsifying agents may be included as desired or necessary.

[0143] The liquid dispersion for oral administration may be a syrup, an emulsion, or a suspension. The syrup may contain as a carrier, for example, saccharose, or saccharose with glycerol and / or mannitol and / or sorbitol. The suspensions and emulsions may contain carriers, for example, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0144] Dose ranges for adults depend on several factors, including the age, weight, and condition of the patient. Suitable oral dosages of the compositions of the technology described herein can be similar to those typically seen with d-amphetamine treatment. Typical dosages for d-amphetamine salts can range from about 1 mg to about 500 mg, alternatively from about 1 mg to about 400 mg, alternatively from about 1 mg to about 300 mg, alternatively from about 1 mg to about 200 mg, alternatively from about 1 mg to about 100 mg, although higher dosages may be approved at a later date.

[0145] Tablets, capsules, oral films, and other forms of presentation provided in individual units conveniently contain one or more daily doses, or an appropriate fraction thereof, of the compounds of the present invention.

[0146] The dosage form of the present technology can also combine any form of release known to those skilled in the art.These conventional release forms include immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long-acting, and combinations thereof.The ability to obtain immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long-acting characteristics, and combinations thereof, is known in the art.

[0147] The compositions of the present technology may be administered in portions, i.e., in divided doses, one or more times during a 24 hour period, a single dose during a 24 hour period, double doses during a 24 hour period, or more than double doses during a 24 hour period. The divided, double, or other multiple doses may be taken simultaneously or at different times during a 24 hour period. The doses may be unequal doses relative to each other or to individual components at different administration times.

[0148] Similarly, the composition of the present technology may be provided in a blister pack or other such pharmaceutical package. Furthermore, the composition of the present technology may further include or be accompanied by an indicator that allows an individual to identify the composition as a product for a prescribed treatment. The indicator may further include an indication of the specified period for administering the composition. For example, the indicator may be an indicator indicating a specific or general time for administering the composition, or the indicator may be a date indicator indicating the day of the week for administering the composition. The blister pack or other combination package may also include a second pharmaceutical product.

[0149] It is understood that the pharmacological activity of the composition of the present technology can be demonstrated using standard pharmacological models known in the art.Furthermore, it is understood that the composition of the present technology can be incorporated or encapsulated in a polymer matrix or film suitable for site-specific delivery, or can be functionalized with a specific targeting agent that can bring about site-specific delivery.These techniques, as well as other drug delivery techniques, are well known in the art.

[0150] In one or more embodiments of the present technology, the solubility and dissolution rate of the composition can change substantially under various physiological conditions, such as those encountered in the intestine, on mucosal surface, or in bloodstream.In one or more embodiments of the present technology, the solubility and dissolution rate of the composition can substantially reduce the bioavailability of d-amphetamine, particularly at doses above the doses intended for treatment.In one embodiment of the present technology, the reduced bioavailability occurs during intranasal administration.In another embodiment, the reduced bioavailability occurs during intravenous administration.

[0151] The technology described herein further provides methods for modifying and / or delivering amphetamines in a manner that can reduce their abuse potential.

[0152] One embodiment provides a method for preventing behavioral deterioration or rebound effects by administering to a patient in need thereof a d-amphetamine composition of the present technology.

[0153] Another embodiment of the present technology is a method for reducing or preventing abuse of d-amphetamine, the method comprising providing, administering, consuming, or prescribing a composition to a patient in need thereof, wherein the composition comprises a d-amphetamine compound of the present invention such that the pharmacological activity of d-amphetamine is reduced when the composition is used in a manner inconsistent with the manufacturer's instructions.

[0154] Another embodiment of the present technology is a method of preventing behavioral deterioration or rebound effects of d-amphetamine or stimulant treatment comprising providing, administering, consuming, or prescribing a d-amphetamine composition of the technology described herein to a subject in need thereof, said composition comprising a d-amphetamine compound of the present invention capable of reducing the likelihood of behavioral deterioration or rebound effects from d-amphetamine or stimulant treatment.

[0155] Another embodiment of the present technology is any of the above methods, wherein the d-amphetamine composition used is adapted for oral administration and the d-amphetamine is resistant to release of the d-amphetamine from the organic acid moiety when the composition is administered parenterally, such as intranasally or intravenously.

[0156] Another embodiment of the present technology provides a method for treating various diseases or conditions requiring stimulation of the central nervous system (CNS), comprising administering a compound or composition of the present technology, optionally further comprising an active agent commonly prescribed for the respective disease or disorder.

[0157] In one embodiment, compositions comprising a d-amphetamine compound, a salt thereof, or a combination thereof provide immediate and extended release PK profiles when compared to unconjugated d-amphetamine.

[0158] A further embodiment of the present technology is a kit comprising individual doses of a therapeutically effective amount of a composition comprising a d-amphetamine compound, a conjugate, a salt thereof, or a combination thereof. In some embodiments, the kit is in a unit dose pack.

[0159] In one embodiment of the invention, the amphetamine conjugates, compounds, and / or compositions have increased d-amphetamine plasma concentrations compared to lisdexamfetamine dimesylate (or amphetamine sulfate) after at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 6 hours of oral administration. In another embodiment of the invention, the amphetamine conjugates, compounds, and / or compositions have reduced d-amphetamine plasma concentrations compared to d-amphetamine sulfate and similar d-amphetamine plasma concentrations compared to lisdexamfetamine dimesylate after at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 6 hours of oral administration. In another embodiment of the invention, the amphetamine conjugates, compounds, and / or compositions of the invention have reduced d-amphetamine plasma concentrations compared to lisdexamfetamine dimesylate or amphetamine sulfate after at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 6 hours of intravenous or intranasal administration.

[0160] The technology described herein and its advantages will be better understood by referring to the following examples and / or schemes. These examples and / or schemes are provided to describe specific embodiments of the technology. By providing these specific examples and / or schemes, the applicant does not limit the scope and spirit of the technology. EXAMPLES

[0161] General synthesis procedure:

[0162] [ka]

[0163] Amphetamine hemisulfate 1 was converted to chloromethyl carbamate 2 by addition of chloromethyl chloroformate. The chloromethyl carbamate of amphetamine 2 and the respective pyridine derivative were heated in acetone or acetonitrile with or without NaI to give the amphetamine conjugate. Subsequent deprotection may be required if applicable.

[0164] Specific steps:

[0165] AMP-CO 2 -CH 2 -Synthesis of nicotinate (Et)3f:

[0166] Table 1: Structure of conjugate 3f [Table 1]

[0167] AMP-CO 2 -CH 2 -Synthetic scheme for nicotinate (Et)3f: [ka]

[0168] Scheme 1: (a) ClCH 2 COCl, DIPEA, DCM; (b) Ethyl nicotinate, acetonitrile, 80-85°C

[0169] Step 1: Amphetamine chloromethyl carbamate, ClCH 2 OCO-AMP 2:

[0170] D-amphetamine hemisulfate (4.640 g, 25.18 mmol) in DCM (80 mL) was cooled in an ice-water bath. DIPEA (8.136 g, 62.95 mmol) was added. Chloromethyl chloroformate (4.221 g, 32.74 mmol) in DCM (20 mL) was then added over 15 min. The reaction was allowed to warm to room temperature over 30 min and then stirred for an additional 1.5 h. Then 5% aqueous NH 4 The reaction was quenched by adding Cl (40 mL). The DCM layer was separated and dried over sodium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 4:1) to give 4.9 g of 2 as a syrup that solidified when stored in a freezer. The yield was 85.5%.

[0171] Step 2: AMP-CO 2 CH 2 -Nicotinate (Et) 3f:

[0172] Amphetamine chloromethyl carbamate 2 (0.228 g, 1 mmol) and ethyl nicotinate in acetonitrile (8 mL) were heated at 80-85 °C for 8 h. The solvent was evaporated. The residue was dissolved in DCM (1 mL). TBME (15 mL) and hexane (15 mL) were then added. The top layer was decanted. The remaining syrup was treated three more times using the above procedure and then dried under vacuum to give 0.230 g of amorphous solid. The yield was 60.7%.

[0173] Conjugate AMP-CO 2 CH 2 -3-(3-pyridyl)alanine 5z and AMP-CO 2 CH 2 Synthesis of nicotinoyl-amino acids 6a-c:

[0174] Table 2: Structure of conjugate 5z [Table 2] Table 3: Structures of conjugates 6a-6c [Table 3]

[0175] AMP-CO 2 CH 2 Synthetic scheme for -3-(3-pyridyl)alanine 5z: [ka]

[0176] Scheme 2: (a) NaI, acetonitrile; (b) 4M HCl / dioxane followed by Dowex 1×8

[0177] 3-(3-pyridyl)-Boc-alanine tert-butyl ester 7z (0.226 g, 0.7 mmol) in acetonitrile (10 mL), ClCH 2 OCO-AMP 2 (0.180 g, 0.791 mmol), and NaI (0.111 g, 0.742 mmol) were refluxed for 1 h. The solid was filtered off. The filtrate was concentrated and dried in vacuum to give an amorphous solid. The solid in 4M HCl / dioxane (10 mL) was stirred at room temperature for 12 h. The solvent was evaporated to dryness and dried in vacuum to give an amorphous solid, which was dissolved in 8 mL of ethanol and treated twice with Dowex 1×8 (200-400, Cl form, 1 g and 0.5 g). The filtrate, after resin treatment, was concentrated and dried in vacuum to give 0.285 g of 5z as an amorphous solid. The yield was 94%.

[0178] Conjugate AMP-CO 2 CH 2 -Synthetic scheme for nicotinoyl-valine 6a: [ka] Scheme 3: (a) TEA / DCM; (b) 7a, NaI, acetonitrile; (c) 4M HCl / dioxane followed by Dowex 1×8

[0179] Step 1: Nicotinoyl-Val-OtBu 7a:

[0180] To valine t-butyl ester HCl salt (H-Val-OtBu HCl, 0.629 g, 3 mmol) in DCM (30 mL) was added Et 3 N (1.25 ml, 9 mmol) was added. Nicotinoyl chloride hydrochloride (0.534 g, 3 mmol) was added in 4 portions over 15 min in a water bath (room temperature). The reaction was stirred for 2 h. This was followed by 5% aqueous NH 4 The reaction was quenched by the addition of Cl (20 mL). The DCM layer was diluted with Na 2 SO 4 The mixture was dried at rt. The product was purified by silica gel column chromatography (3% MeOH / DCM). 0.822 g of 7a was obtained as a syrup. The yield was 98%.

[0181] Step 2: AMP-CO 2 CH 2 -Nicotinoyl-Val 6a:

[0182] Nicotinoyl-Val-OtBu 7a (0.31 g, 1.11 mmol) in acetonitrile (10 mL), ClCH 2 OCO-AMP 2 (0.291 g, 1.28 mmol), and NaI (0.176 g, 1.18 mmol) were refluxed for 1.5 h. The solid was filtered off. The filtrate was concentrated to give an amorphous solid. To this solid, 4M HCl / dioxane (8 mL) was added, and the mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness and dried in vacuum for 1 h. The resulting residue was dissolved in 8 mL of ethanol and treated twice with Dowex 1×8 (200-400, Cl form, 1 g and 0.5 g). The filtrate was concentrated after resin treatment and dried in vacuum to give 0.461 g of 6a as an amorphous solid. The yield was 93%.

[0183] Conjugates 6b and 6c were synthesized by a similar procedure to 6a.

[0184] Conjugate AMP-CO 2 CH2 Synthesis of nicotinoyl-amino acid esters 9i-9n:

[0185] Table 4: Structures of conjugates 9i-9n [Table 4]

[0186] Conjugate AMP-CO 2 CH 2 Synthetic scheme for -nicotinoyl-amino acid esters 9i-9n: [ka]

[0187] Scheme 4: (a) TEA / DCM; (b) 10i, NaI, acetonitrile followed by Dowex 1×8

[0188] Step 1: Nicotinoyl-Gly-OEt 10i:

[0189] To glycine ethyl ester HCl (H-Gly-Et HCl, 1.40 g, 10 mmol) in DCM (50 mL), 3 N (4.18 ml, 30 mmol) was added. Nicotinoyl chloride hydrochloride (1.78 g, 10 mmol) was added in seven portions over 30 min in a water bath (room temperature). The reaction was stirred for 2 h. This was followed by 5% aqueous NaHCO 3 (40 mL) was added to quench the reaction, followed by 50 ml of DCM. The DCM layer was further washed with 5% aqueous NaHCO 3 (40 mL), and then washed with Na 2 SO 4 The mixture was dried at rt. The product was purified by silica gel column chromatography (EtOAc). 1.59 g of 10a was obtained as a syrup. The yield was 76%.

[0190] Step 2: AMP-CO 2 -CH 2-Nicotinoyl-Gly-OEt 9i:

[0191] Nicotinoyl-Gly-OEt 10i (0.167 g, 0.8 mmol) in acetonitrile (8 mL), ClCH 2 OCO-AMP 2 (0.209 g, 0.92 mmol), and NaI (0.127 g, 0.848 mmol) were heated at 65° C. for 1 h. The solid was filtered off. The filtrate was concentrated to dryness, then dissolved in 6 mL of ethanol and treated twice with Dowex 1×8 (200-400, Cl form, 1 g and 0.5 g). The filtrate was concentrated to dryness after the resin treatment.

[0192] The residue was dissolved in DCM (1.5 mL) and TBME (25 mL) was added. The upper layer was decanted. The remaining solid was dissolved in DCM (15 mL) and concentrated to give a solid. After drying in vacuum, 0.314 g of 9i was obtained. The yield was 90%.

[0193] Conjugates 9j-9n were synthesized by a similar procedure to 9i.

[0194] Conjugate AMP-CO 2 CH 2 Synthesis of -nicotinoyl-amino acid amide 11c:

[0195] Table 5: Structure of conjugate 11c [Table 5]

[0196] AMP-CO 2 CH 2 -Nicotinoyl-Val-NH 2 Synthetic scheme for 11c: [ka]

[0197] Scheme 5: (a) TEA / DCM; (b) 12c, NaI, acetone, then Dowex 1×8

[0198] Step 1: Nicotinoyl-Val-NH 2 12c:

[0199] Valinamide HCl (H-Val-NH) in DCM (30 mL) 2 HCl, 0.458 g, 3 mmol), Et 3 N (1.062 g, 10.5 mmol) was added. Nicotinoyl chloride hydrochloride (0.587 g, 3.3 mmol) was added in three portions over 10 min under water bath (room temperature). The reaction was stirred for 1.5 h. The solvent was evaporated. The remaining solid was purified by silica column gel chromatography (8% MeOH / DCM) to give Et 3 A white solid containing N HCl was obtained. To the solid was added ethanol (10 mL) and the mixture was heated to reflux (the solid did not completely dissolve). The mixture was cooled to room temperature. The solid was collected after 2 hours, washed with ethanol (1 mL x 3) and dried in vacuum. 0.245 g of 12c was obtained. The yield was 36.9%.

[0200] Step 2: AMP-CO 2 CH 2 -Nicotinoyl-Val-NH 2 11c:

[0201] Nicotinoyl-Val-NH in acetone (6 mL) 2 12c (0.111 g, 0.5 mmol), ClCH 2 OCO-AMP 2 (0.137 g, 0.6 mmol), and NaI (0.086 g, 0.575 mmol) were refluxed for 1.5 h. The solid was filtered off. The filtrate was concentrated to dryness, and the resulting residue was dissolved in 6 mL of ethanol and treated twice with Dowex 1×8 (200-400, Cl form, 0.8 g and 0.4 g). The filtrate was concentrated after the resin treatment and dried in vacuum to give 0.218 g of 11c as an amorphous solid. The yield was 97%.

[0202] Amphetamine double conjugate (AMP-CO 2 CH2 -nicotinoyl) 2 Synthesis of -Ser-OMe 13b: [ka]

[0203] (AMP-CO 2 CH 2 -nicotinoyl) 2 -Ser-OMe 13b Synthesis scheme: [ka] Scheme 6: (a) Et 3 N / DCM; (b) 15b, NaI, acetone, then Dowex 1×8

[0204] Step 1: (Nicotinoyl) 2 -Ser-OMe 15b:

[0205] To serine methyl ester HCl (2.80 g, 18 mmol) in DCM (200 mL) was added Et 3 N (14.57 g, 144 mmol) was added. Nicotinoyl chloride hydrochloride (9.613 g, 54 mmol) was added in seven portions over 30 min in a water bath (room temperature). The reaction was stirred for 22 h. This was followed by 5% aqueous NH 4 The reaction was quenched by the addition of Cl (80 mL). The DCM layer was diluted with Na 2 SO 4 The mixture was dried at rt. The product was purified by silica gel column chromatography (EtOAc, then 7% MeOH / DCM). 3.99 g of 15b was obtained as a syrup. The yield was 67%.

[0206] Step 2: (AMP-CO 2 CH 2 -nicotinoyl) 2 -Ser-OMe 13b:

[0207] (nicotinoyl) in acetone (12 mL) 2-Ser-OMe 15b (0.165g, 0.5mmol), ClCH 2 OCO-AMP 2 (0.273 g, 1.2 mmol), and NaI (0.172 g, 1.15 mmol) were refluxed for 1.5 h. The solid was filtered off. The filtrate was concentrated to dryness and the resulting residue was dissolved in 8 mL of methanol and treated twice with Dowex 1×8 (200-400, Cl form, 1.5 g, 1 g). The filtrate was concentrated after the resin treatment and dried in vacuum to give 0.334 g of 13b as an amorphous solid. The yield was 85%.

[0208] The conjugates could be in various salt forms other than the chloride salt. [Table 10]

[0209] In the following aspect of the invention, 1 H-NMR and 13 C-NMR was performed using DMSO-d 6 The mass spectra were recorded on a Bruker Advance II 500 spectrometer with 0.1% formic acid-water / 0.1% formic acid-acetonitrile (no internal standard). Low-resolution ESI mass spectra were recorded on an Agilent 1290 HPLC and an Agilent 6420 QQQ triple mass spectrometer, run in positive ion mode using 0.1% formic acid-water / 0.1% formic acid-acetonitrile as the mobile base. HPLC was run on an Agilent 1200 series instrument using a YMC ODS-AQ (C-18, 4.6×250 mm, 5 μm, 120 Å) column and 0.1% TFA-water / 0.1% TFA-acetonitrile as the mobile base. [Table 11-1] [Table 11-2] NA: The compound is amorphous and the melting point could not be determined.

[0210] Example 1 Oral Pharmacokinetic Studies

[0211] Conjugates of d-amphetamine and comparator compounds of d-amphetamine sulfate or lisdexamfetamine dimesylate were dissolved in the appropriate vehicle and administered to rats via oral gavage at a dose of 5.6 μmol / kg. Whole blood samples were collected via retro-orbital bleeding at 0.25, 0.5, 1, 2, 4, and as needed 3 and 6 hours after dosing. Blood samples were centrifuged and the resulting plasma samples were collected for analysis of amphetamine concentrations by LC-MS / MS.

[0212] Oral pharmacokinetic plasma concentration-time profiles are shown in Figures 1-17. A summary of oral pharmacokinetic parameters is provided in Tables 6 and 7.

[0213] Table 6: Oral PK parameters for d-amphetamine conjugates administered to rats using a 4 hour time course. [Table 6] Table 7: Oral PK parameters for d-amphetamine conjugates administered to rats using a 6 hour time course. [Table 7]

[0214] Example 2 Intravenous pharmacokinetic studies

[0215] Conjugates of d-amphetamine and comparator compounds of d-amphetamine sulfate or lisdexamfetamine dimesylate were dissolved in the appropriate vehicle and administered at a dose of 5.6 μmol / kg by injecting the solution into the tail vein of rats. Whole blood samples were collected via retro-orbital bleeding at 5 min and 0.25, 0.5, 1, and 2 h after administration. Blood samples were centrifuged and the resulting plasma samples were collected for analysis of levorphanol concentrations by LC-MS / MS.

[0216] Intravenous pharmacokinetic d-amphetamine plasma concentration-time profiles are shown in Figures 18-26. A summary of intravenous d-amphetamine pharmacokinetic parameters is provided in Table 8. Table 8: Intravenous PK parameters for d-amphetamine conjugates administered to rats. [Table 8]

[0217] Example 3 Nasal pharmacokinetic studies

[0218] Conjugates of d-amphetamine and comparator compounds of d-amphetamine sulfate or lisdexamfetamine dimesylate were dissolved in the appropriate vehicle and administered to rats at a dose of 5.6 μmol / kg by slow dropwise addition of the respective dosing solutions to alternating nasal cavities. Whole blood samples were collected via retro-orbital bleeding 5 minutes and 0.25, 0.5, and 1 hour after dosing. Blood samples were centrifuged and the resulting plasma samples were collected for analysis of amphetamine concentrations by LC-MS / MS. The intranasal pharmacokinetic plasma concentration-time profiles are shown in Figures 27-35. A summary of the intranasal pharmacokinetic parameters is provided in Table 9.

[0219] Table 9: Intranasal PK parameters for d-amphetamine conjugates administered to rats [Table 9]

[0220] 8-10 unexpectedly and non-obviously show that some compounds of the invention containing a nicotinoyl moiety provide different and / or improved d-amphetamine exposure in subjects following oral, intranasal, and / or intravenous administration when compared to compounds of the same structure but in which the nicotinoyl is replaced with an isonicotinoyl moiety. 2-Nicotinoyl-Val-NH 2 However, d-amphetamine-CO 2 CH 2 -Isonicotinoyl-Val-NH 2 FIG. 9 shows that d-amphetamine-CO provides increased oral bioavailability of d-amphetamine compared to 2 CH 2 - Nicotinate (Et) is d-amphetamine-CO 2 CH 2 FIG. 10 shows that AMP-CO provides increased oral bioavailability of d-amphetamine compared to d-isonicotinate (Et). 2 CH 2 - Nicotinate (Et) is AMP-CO 2 CH 2 -shown to reduce exposure to d-amphetamine following intravenous administration when compared to isonicotinate (Et).

[0221] Further aspects and embodiments of the present technology are described in the following paragraphs.

[0222] One aspect of the present invention is a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is selected from the group consisting of an ester, a carboxylic acid, an amino acid, an amino acid residue, an amide, and derivatives thereof, and Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle. Another embodiment is a composition comprising the compound or a pharma- ceutically acceptable salt thereof.

[0223] Another aspect of the invention is a compound of formula IB: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is A-COO-R; A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycyclialkyl, polycycloalkylalkyl, and polyethylene glycol; R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, The compound is selected from the group consisting of aryl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. Another embodiment is a composition comprising the compound or a pharma- ceutically acceptable salt of the compound.

[0224] Another aspect of the present invention is a compound of formula ID: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is A-CO-NR 1 R 2 and; A is absent or, if present, is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol; R 1 and R 2are independently selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl ... The compound is selected from the group consisting of aryl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. Another embodiment is a composition comprising the compound or a pharma- ceutically acceptable salt of the compound.

[0225] Another embodiment of the invention is where A is absent and Y is hydrogen and the compound has formula IIB: [ka] or a pharma- ceutically acceptable salt thereof, wherein R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfon ... The compound is selected from the group consisting of rufinyl alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthio alkyl, cycloalkenyl, cycloalkenyl alkyl, cycloalkyl, cycloalkyl alkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkyl alkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroaryl alkyl, heteroaryl amino, heteroaryl carbonyl, heteroaryl carbonyl amino, heteroaryl oxo, heteroaryloxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycycloalkenyl, polycycloalkenyl alkyl, polycycloalkyl, polycycloalkyl alkyl, and polyethylene glycol. Another embodiment is a composition comprising the compound or a pharma- ceutically acceptable salt of the compound.

[0226] In another embodiment, A is absent and Y is hydrogen and the compound has formula IID: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 and R 2are independently selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl ... The compound is selected from the group consisting of aryl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. Another embodiment is a composition comprising the compound or a pharma- ceutically acceptable salt of the compound.

[0227] In yet another embodiment, the compound is: [ka] The compound has a structure selected from the group consisting of:

[0228] In one embodiment, the pharma- ceutically acceptable salt is acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, acetone, or glycerol. Benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphorcarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethylsulfate, furanate, fusidate, galactosylate, ethylsulfate, furate, fusidate, galactosylate, ethylsulfate, fusidate ...fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate, fusidate Talate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylic sulfate The salt is selected from the group consisting of salts, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholate, lysinium, ammonium, troethamine, and mixtures thereof.

[0229] In another embodiment, the compound is: [ka] The compound has a structure selected from the group consisting of:

[0230] An aspect of the present invention is a composition comprising any compound of the present invention or a pharma- ceutically acceptable salt of said compound. In one aspect, said composition is formulated for oral administration or suppository administration. In a further aspect, the composition formulated for oral administration is in a dosage form selected from the group consisting of solid forms, tablets, capsules, caplets, soft gels, suppositories, troches, lozenges, oral powders, solutions, syrups, oral films, thin strips, slurries, emulsions, elixirs, and suspensions. In another aspect, said composition further comprises one or more excipients, said excipients being selected from the group consisting of anti-adhesives, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof. In a further aspect, said binder is selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and milk derivatives.

[0231] In one embodiment, the compound is present in an amount per unit dose between about 0.1 mg and about 2000 mg per unit dose. In another embodiment, the compound is present in an amount per unit dose between about 0.5 mg and about 500 mg per unit dose. In a further embodiment, the compound is present in an amount per unit dose between about 1 mg and about 250 mg per unit dose. In yet another embodiment, the compound is present in an amount per unit dose between about 1.5 mg and about 100 mg per unit dose.

[0232] In one embodiment, the composition further comprises one or more additional pharmacological agents selected from the group consisting of stimulants, antidepressants, combinations thereof, and prodrugs thereof.In another embodiment, the composition further comprises one or more of methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, ethoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, ziprasidone, or one or more additional amphetamines, or any combination of the above.In a further embodiment, the one or more additional amphetamines are unconjugated amphetamines, amphetamine conjugates, amphetamine prodrugs, any isomers thereof, or any combination thereof. In yet another embodiment, the isomer of unconjugated amphetamine is unconjugated d-amphetamine.In a further embodiment, methylphenidate is unconjugated methylphenidate, a conjugate of methylphenidate, a prodrug of methylphenidate, any isomer thereof, or any combination thereof.In another embodiment, the isomer of unconjugated methylphenidate is unconjugated d-methylphenidate.In yet another embodiment, the conjugate of methylphenidate is celdexmethylphenidate.

[0233] In one embodiment, the compound is provided in an amount sufficient to provide a similar or reduced AUC when compared to unconjugated d-amphetamine when administered orally at equimolar doses. In another embodiment, the compound is provided in an amount sufficient to provide a similar or reduced C when compared to unconjugated d-amphetamine when administered orally at equimolar doses. max In yet another embodiment, the compound is provided in an amount sufficient to provide a reduced C compared to unconjugated d-amphetamine when orally administered at equimolar doses. maxand in an amount sufficient to provide a similar or reduced AUC. In one embodiment, intranasal or intravenous administration of the compound provides a reduced AUC and / or C when compared to an equimolar amount of unconjugated d-amphetamine. max In another embodiment, the compounds provide reduced abuse potential compared to unconjugated d-amphetamine.

[0234] One aspect of the invention is a kit comprising individual doses of a therapeutically effective amount of a composition comprising a compound according to claim 1, a pharmaceutical salt thereof, or a combination thereof.

[0235] One aspect of the invention is a method of treating a patient having a disorder or condition requiring stimulation of the central nervous system, or a disease, disorder, or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake, or a disease, disorder, or condition mediated by increasing neurotransmitter concentrations in synapses, comprising administering to a patient in need thereof a pharma- ceutically effective amount of the composition of claim 9. In another aspect, the composition has reduced abuse potential when administered compared to unconjugated d-amphetamine. In yet another embodiment, the disease or condition is attention deficit hyperactivity disorder, attention deficit disorder, autism spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, insomnia, schizophrenia, major depressive disorder, narcolepsy, postural orthostatic tachycardia syndrome, Tourette's syndrome, neurological tics, substance use disorder, apathy, depression, neurological injury, or obesity.

[0236] The techniques described herein are described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains to practice the same. It will be understood that the foregoing describes preferred embodiments of the invention and that modifications may be made therein without departing from the spirit or scope of the invention. The present invention provides, for example, the following items. (Item 1) Formula I:

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Claims

1. Formula IIB: 【Chemistry 45】 Or formula IID: 【Chemistry 46】 or a pharma- ceutically acceptable salt thereof, wherein R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, a is selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, and polycycloalkylalkyl; R 1 and R 2 are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, and polycycloalkylalkyl; A compound or a pharma- ceutically acceptable salt thereof.

2. The compound of formula IIB: 【Chemistry 41】 wherein R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalcohol. alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, and polycycloalkylalkyl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt of said compound.

3. The compound of claim 1, wherein the compound has formula IID: 【Chemistry 42】 wherein R １ and R ２ are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, and polycycloalkylalkyl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt of said compound. 【Request 4】 【Chemical 43】 A compound having a structure selected from the group consisting of:

5. The pharma- ceutically acceptable salt may be acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluconate, or the like. Septoate, D-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphorcarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethylsulfate, furanate, fusidate, galactarate, galactosylate ... Ronate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylic sulfate, sulfosalicylate , tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholate, lysinium, ammonium, troethamine, and mixtures thereof.

6. 【Catalogue 44】 A compound having a structure selected from the group consisting of:

7. 13. A composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt of said compound.

8. The composition of claim 7 , wherein the composition is formulated for oral or suppository administration.

9. 9. The composition of claim 8, wherein the composition formulated for oral administration is in a dosage form selected from the group consisting of solid forms, tablets, capsules, caplets, soft gels, suppositories, troches, lozenges, oral powders, solutions, syrups, oral films, thin strips, slurries, emulsions, elixirs, and suspensions.

10. 8. The composition of claim 7, wherein the composition further comprises one or more excipients selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, pigments, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

11. 11. The composition of claim 10, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and milk derivatives.

12. The composition of claim 7, wherein the compound is present in an amount per unit dose between 0.1 mg and 2000 mg per unit dose.

13. The composition of claim 12, wherein the compound is present in an amount per unit dose between 0.5 mg and 500 mg per unit dose.

14. The composition of claim 13, wherein the compound is present in an amount per unit dose between 1 mg and 250 mg per unit dose.

15. The composition of claim 14, wherein the compound is present in an amount per unit dose between 1.5 mg and 100 mg per unit dose.

16. 8. The composition of claim 7, wherein the composition further comprises one or more additional pharmacological agents selected from the group consisting of stimulants, antidepressants, combinations thereof, and prodrugs thereof.

17. 8. The composition of claim 7, wherein the composition further comprises one or more of methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, etoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, ziprasidone, or one or more additional amphetamines, or any combination thereof.

18. 18. The composition of claim 17, wherein the one or more additional amphetamines is unconjugated amphetamine, a conjugate of amphetamine, a prodrug of amphetamine, any isomer thereof, or any combination thereof.

19. 20. The composition of claim 18, wherein the isomer of unconjugated amphetamine is unconjugated d-amphetamine.

20. 20. The composition of claim 19, wherein the methylphenidate is unconjugated methylphenidate, a conjugate of methylphenidate, a prodrug of methylphenidate, any isomer thereof, or any combination thereof.

21. 21. The composition of claim 20, wherein the isomer of unconjugated methylphenidate is unconjugated d-methylphenidate.

22. 21. The composition of claim 20, wherein the conjugate of methylphenidate is celdexmethylphenidate.

23. 8. The composition of claim 7, wherein the compound is provided in an amount sufficient to provide a similar or reduced AUC when compared to unconjugated d-amphetamine when administered orally at an equimolar dose.

24. The compounds have similar or reduced C activity compared to unconjugated d-amphetamine when administered orally at equimolar doses. ｍａｘ The composition of claim 7 provided in an amount sufficient to provide.

25. The compound exhibited a decreased C compared to unconjugated d-amphetamine when administered orally at equimolar doses. ｍａｘ and in an amount sufficient to provide a similar or reduced AUC.

26. Intranasal or intravenous administration of the compound results in a decreased AUC and / or C when compared to an equimolar amount of unconjugated d-amphetamine. ｍａｘ The composition of claim 7 .

27. 8. The composition of claim 7, wherein the compound offers reduced abuse potential as compared to unconjugated d-amphetamine.

28. 13. A kit comprising individual doses of a therapeutically effective amount of a composition comprising the compound of claim 1, a pharmaceutical salt thereof, or a combination thereof.

29. 8. The composition of claim 7 for treating a patient having a disorder or condition requiring stimulation of the central nervous system, for treating a patient having a disease, disorder, or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake, or for treating a patient having a disease, disorder, or condition mediated by increasing neurotransmitter concentrations in synapses.

30. 30. The composition of claim 29, wherein the composition has reduced abuse potential when administered compared to unconjugated d-amphetamine.

31. 30. The composition of claim 29, wherein the disease or condition is attention deficit hyperactivity disorder, attention deficit disorder, autism spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, insomnia, schizophrenia, major depressive disorder, narcolepsy, postural orthostatic tachycardia syndrome, Tourette's syndrome, neurological tics, substance use disorder, apathy, depression, neurological injury, or obesity.

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