D-amphetamine compounds, compositions, and methods of making and using the same

Abstract

Disclosed are d-amphetamine compounds and compositions comprising at least one organic acid covalently bonded to d-amphetamine (having the structure of or salts thereof, derivatives thereof, or combinations thereof. Also disclosed are methods of making and using the same.

Description

[0001] Related applications

[0002] This patent application relates to and claims priority to U.S. Nonprovisional Patent Application Serial No. 16 / 667,807, filed October 29, 2019, the contents of which are hereby incorporated herein by reference in their entirety.

[0003] Federally funded research or development

[0004] [not applicable] Background of the Invention

[0006] The currently described technology relates to novel compounds and compositions of d-phenylpropylamine (i.e., 1-phenylpropane-2-amine), including organic compounds covalently bonded to or linked to d-phenylpropylamine, their salts, their derivatives, or combinations thereof. Methods for preparing and using the compounds and compositions of this technology are also disclosed.

[0007] Stimulants, including d-amphetamine and its derivatives, enhance the activity of the sympathetic and / or central nervous system (CNS) and are prescribed to treat a range of conditions and disorders, including, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety, and insomnia.

[0008] Stimulants have been used to treat attention deficit hyperactivity disorder (ADHD) in children for many years. However, recently, the increase in prescriptions for ADHD treatment in the adult population has sometimes outpaced the growth of the pediatric market. Although a variety of medications are currently available for treating ADHD, such as methylphenidate (available under the trademark Ritalin® from companies such as Novartis International AG (based in Basel, Switzerland)) and the non-stimulant atoxetine (available as Strattera® from Eli Lilly and Company (based in Indianapolis, IN)), d-amphetamine has been a pioneer in the treatment of ADHD.

[0009] Initial drug treatment for ADHD is limited to fast-acting, immediate-release stimulants (e.g., Dexedrine®, pure dextromethorphan sulfate, commercially available from Smith Kline and French in the UK), which can cause a range of potentially undesirable side effects, including, for example, rapid loss of therapeutic effect of the stimulant active ingredient, resulting in rebound symptoms, cardiovascular stress / disorders (e.g., increased heart rate, high blood pressure, cardiomyopathy), other side effects (e.g., insomnia, euphoria, psychotic episodes), addiction, and abuse.

[0010] As medication wears off, a significant portion of children with ADHD experience a behavioral deterioration (rebound / “breakdown”), typically in the afternoon or evening. Rebound symptoms include, for example, irritability, paranoia, hyperactivity more severe than in the unregulated state, sadness, crying, and, in rare cases, psychotic episodes. Symptoms may subside rapidly or last for several hours. Some patients may experience rebounds / breakdowns so severe that treatment must be discontinued. The rebound / breakdown effect can also induce addictive behavior by inducing patients to take additional doses of stimulants to prevent the anticipated negative consequences and side effects of the rebound / breakdown.

[0011] Stimulants, such as methylphenidate and d-amphetamine, have been shown to exhibit norepinephrine and dopaminergic effects, which can lead to cardiovascular events, including, for example, increased heart rate, hypertension, palpitations, tachycardia, and in individual cases, cardiomyopathy, stroke, myocardial infarction, and sudden death. Therefore, currently available stimulants expose patients with pre-existing structural cardiac abnormalities or other serious cardiac indications to even greater health risks and are often not used or used with caution in this population. However, it is worth noting that the cardiovascular effects of stimulants, such as their effects on heart rate and blood pressure, depend on the dose administered. Therefore, treatment that maintains the lowest effective blood concentration of stimulants for the duration of therapeutic benefit is considered to exhibit less cardiovascular risk.

[0012] D-Amphetamine and its many derivatives (e.g., methamphetamine, 3,4-methylenedioxy-metamphenicol / “ecstasy”) are widely abused for various purposes, such as euphoria, prolonged alertness / wakefulness, or rapid weight loss, or by actual ADHD patients who have developed an excessive self-administration habit to prevent rebound symptoms, such as during anxiety or depression. The desired effects for potential abusers stem from stimulation of the central nervous system, prompting the adoption of the Controlled Substance Act (CSA) in 1970, classifying d-amphetamine (d- and ld-amphetamine individually and any combination of both as Schedule II) and certain derivatives as Schedule II or even Schedule I. Both classifications are defined by a high propensity for abuse. Schedule II drugs have recognized medical uses, while Schedule I substances are not subject to the CSA. To date, all d-amphetamine products, including compositions and their sustained-release formulations, are mandated to include a boxed warning on the drug label to inform patients of the potential for d-amphetamine abuse and dependence.

[0013] It has been shown in conventional techniques that most side effects of amphetamines are caused by a large initial spike in blood concentration, which rapidly drops below therapeutic levels (typically within 4-6 hours). Therefore, a series of new drugs have subsequently modified the high potency of dextroamphetamine (d-amphetamine) to achieve a progressively increasing sustained release property by delivering d-amphetamine into the bloodstream more slowly, with the aim of creating safer and less abused treatment outcomes and regimens. Methods and techniques for producing a smaller spike in drug blood concentration include, for example, the use of mixed salt and isomer compositions (i.e., different salts of d-amphetamine and the less potent l-amphetamine), and extended / controlled / sustained-release formulations of amphetamine / d-amphetamine salts (e.g., Adderall XR). ® Available commercially from Shire US, Inc., located in Wayne, PA, and a prodrug of lisdexamfetamine salt (Vyvanse). ® It can also be purchased from Shire.

[0014] As a result, there remains a need in the field for safer d-amphetamine formulations and treatment regimens that are therapeutically effective and can provide sustained release and sustained therapeutic effect.

[0015] Invention Summary

[0016] The techniques described herein partially provide novel compounds and compositions of the stimulant d-amphetamine (“d-Amp”, “d-amphetamine”), its salts, other derivatives thereof, and combinations thereof.

[0017] In some aspects, this technology provides compounds and / or compositions comprising d-phenylpropylamine and one or more organic compounds. In some aspects of this technology, the organic compounds comprise heterocyclic nitrogen compounds. Heterocyclic nitrogen compounds are ubiquitous in nature and are associated with a variety of biological functions in plants and animals. Examples of heterocyclic nitrogen compounds used in the practice of this technology include, but are not limited to, pyridine derivatives, some of which play important roles in nicotinic acid and tryptophan metabolism. In these compounds, one carbon atom of the phenyl ring is typically replaced by a nitrogen atom.

[0018] In certain aspects of this technology, the organic compound comprises an amino acid. An amino acid is an organic compound containing a carboxyl (-COOH) and an amino (-NH2) group, as well as variable side chain groups. The amino acids that can be used in this technology can be natural, standard, non-standard, rare, synthetic, and / or essential amino acids, and can be L-amino acids or D-amino acids or combinations thereof. Examples of amino acids used in this technical practice 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, γ-aminobutyric acid, 6-aminohexanoic acid, sarcosine, carnitine, 2-aminoadipic acid, pantothenic acid, taurine, linolenic acid, and lanthanum. Amino acids, thiocysteine, cystathionine, homocysteine, β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β-DOPA (3,4-dihydroxy-L-phenylalanine), 2-aminoisobutyric acid, isovaleine, di-N-ethylglycine, N-methyl-alanine, L-abrine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxy Isoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, aziridine-2-carboxylic acid, pipercoic acid, allyl glycine, cyclohexyl glycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glycine ester, 2-(trifluoromethyl)-phenylalanine, 4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine, 2-chlorophenylglycine, 3-guanidinyl-propionic acid, 3,4-dehydro-proline, 2,3-diaminobenzoic acid, 2-amino-3-chlorobenzoic acid, 2-amino-5- Fluorobenzoic acid, alloleucine, tert-leucine, 3-phenylserine, isoserine, 3-aminovaleric acid, 2-amino-octanoic 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).

[0019] In some respects, the compound has the structure of formula IB:

[0020]

[0021] Where X is A-COO-R;

[0022] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0023] Where R is 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, arylsulfinyl Alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, polyethylene glycol, amino acids and amino acid residues.

[0024] In some respects, the compound has the structure of formula ID.

[0025]

[0026] Where X is A-CO-NR 1 R 2 ;

[0027] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0028] Where R 1 and R 2 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, arylsulfinyl Alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, polyethylene glycol, amino acids and amino acid residues.

[0029] It should be understood that if Y is not hydrogen, the carbon atom bonded to Y is a chiral center.

[0030]

[0031] In some aspects, the present technology comprises a conjugate wherein the chiral carbon has an R configuration. In other aspects, the present technology comprises a conjugate wherein the chiral carbon has an S configuration. In still other aspects, the present technology comprises a mixture of stereoisomers, some of which contain a chiral carbon having an R configuration and some of which contain a chiral carbon having an S configuration.

[0032] The currently described technology further provides a method for the controlled therapeutic delivery of d-amphetamine compositions via oral administration. In at least one aspect, the currently described technology focuses on slow / sustained-release compositions of d-amphetamine in compound form, which, upon oral administration, allow for the slow / sustained / controlled delivery of the stimulant into the bloodstream of a human or animal within a safe therapeutic window. At least some compositions / formulations of the present technology can mitigate rebound effects, cardiovascular stress, addiction / abuse potential, and / or other common stimulant side effects associated with d-amphetamine and similar compounds. When administered (particularly orally), such compositions can also increase the duration of therapeutic effect, ease of application, patient compliance, and / or any combination of these characteristics.

[0033] Following oral administration of the compound of this technology, the release of d-amphetamine occurs gradually over a prolonged period, thus eliminating unintended, excessively rapid increases in drug levels in the bloodstream of human or animal patients (e.g., large spikes in blood concentration). It is not intended to be bound by any particular theory, but rather that such spikes in blood levels could lead to euphoric "high" drug levels and cardiovascular effects such as increased blood pressure and heart rate. Furthermore, compared to other conventional therapies, sustained blood levels are achieved within the effective therapeutic range for a longer duration, thereby preventing rebound effects.

[0034] In some embodiments, this technology provides specific d-amphetamine (“d-Amp”, “d-amphetamine”) compounds, compositions, or pharmaceutically acceptable salts thereof to provide, for example, at least one once-daily dose form of a d-amphetamine compound bound to unconjugated d-amphetamine that, when compared to unconjugated d-amphetamine, can provide both immediate and prolonged release pharmacokinetic (PK) profiles. In some cases, the release profiles provide the ability to administer the compound or composition using dosing regimens that are not readily compatible with unconjugated d-amphetamine.

[0035] At least some compositions of d-amphetamine compounds incorporating this technology are tolerable for abuse via parenteral administration, such as intravenous “injection,” intranasal “sniffing,” or inhaled “smoking,” which are frequently used during illicit use. Therefore, this technology provides stimulant-based treatments and dosage forms for certain disorders requiring CNS stimulation, such as ADHD, ADD, obesity, narcolepsy, appetite suppression, depression, anxiety, sleep disorders, excessive daytime sleepiness, insomnia, bulimia, and sleeplessness, with reduced or prevented abuse potential. While not wishing to be bound by any particular theory, it is believed that compositions of this technology result in a significantly reduced abuse potential or tendency compared to existing stimulant treatments and dosage forms.

[0036] At least some compositions incorporating d-amphetamine compounds of this technology can also be used to treat stimulant (cocaine, methamphetamine) abuse and addiction, substance use disorders, enhance battlefield alertness, and / or combat fatigue.

[0037] When administered via injection or intranasal route, the compositions of this technology preferably have no pharmacological activity or significantly reduced pharmacological activity. However, in the case of d-amphetamine, they still possess oral bioavailability. Bioavailability can be the result of the hydrolysis of the covalent link between d-amphetamine and the remaining portion of the conjugate after oral administration. The hydrolysis is time-dependent, thus allowing d-amphetamine and other metabolites such as p-hydroxyamphetamine and p-hydroxyephedrine to become available in their active form over a prolonged period of time. In at least one other aspect, the release of d-amphetamine is reduced compared to unconjugated d-amphetamine, or the release of d-amphetamine is eliminated when the compositions of this technology are delivered via a parenteral route.

[0038] For example, in one aspect, after crushing tablets, capsules, or other oral dosage forms used to deliver the therapeutic component (i.e., the active ingredient / drug), the compositions of this technology maintain their efficacy and abuse resistance because the controlled-release component is a design feature of the composition, not the formulation. In contrast, conventional extended-release formulations used to control d-amphetamine release release up to the full amount of d-amphetamine immediately upon crushing. When the contents of the crushed tablet are injected or inhaled, the large dose of d-amphetamine produces the "thunder" effect sought by addicts.

[0039] Other objects, advantages and aspects of the invention are described below and will be apparent from this description and practice of the invention.

[0040] Brief description of several views in the attached diagram

[0041] Figure 1Compare the oral pharmacokinetic (PK) curves of d-amphetamine sulfate and d-amphetamine-CO2CH2-nicotinic acid ester ethyl ester (AMP-CO2CH2-nicotinic acid ester (Et)).

[0042] Figure 2 Oral pharmacokinetic (PK) curves of d-amphetamine (LDX), d-amphetamine sulfate, d-amphetamine-CO2CH2-nicotinyl-valamine (AMP-CO2CH2-nicotinyl-Val-NH2), d-amphetamine-CO2CH2-nicotinyl-alanine methyl ester (AMP-CO2CH2-nicotinyl-Ala-OMe), and (d-amphetamine-CO2CH2-nicotinyl)2-serine methyl ester ((AMP-CO2CH2-nicotinyl)2-Ser-OMe) were compared.

[0043] Figure 3 Compare the oral pharmacokinetic (PK) curves of d-phenylamphetamine sulfate and d-phenylamphetamine-CO2CH2-nicotinyl-serine (AMP-CO2CH2-nicotinyl-Ser).

[0044] Figure 4 Compare the intravenous PK curves of d-amphetamine (LDX) and d-amphetamine-CO2CH2-nicotinic acid ester ethyl ester (AMP-CO2CH2-nicotinic acid ester (Et)).

[0045] Figure 5 Compare the intravenous PK curves of d-amphetamine (LDX), d-amphetamine sulfate, d-amphetamine-CO2CH2-nicotinyl-valamine (AMP-CO2CH2-nicotinyl-Val-NH2), and d-amphetamine-CO2CH2-nicotinyl-alanine methyl ester (AMP-CO2CH2-nicotinyl-Ala-OMe).

[0046] Figure 6 Compare the intranasal PK curves of d-amylon (LDX) and d-amphetamine-CO2CH2-nicotinic acid ester ethyl ester (AMP-CO2CH2-nicotinic acid ester (Et)).

[0047] Figure 7 Intranasal PK curves of d-amphetamine (LDX), d-amphetamine sulfate and d-amphetamine-CO2CH2-nicotinyl-valamine (AMP-CO2CH2-nicotinyl-Val-NH2) were compared.

[0048] Figure 8Compare the oral pharmacokinetic (PK) curves of d-amphetamine-CO2CH2-nicotinyl-valamine (AMP-CO2CH2-nicotinyl-Val-NH2) and d-amphetamine-CO2CH2-isonicotinyl-valamine (AMP-CO2CH2-isonicotinyl-Val-NH2).

[0049] Figure 9 Compare the oral pharmacokinetic (PK) curves of d-amphetamine-CO2CH2-nicotinic acid ester (AMP-CO2CH2-nicotinic acid ester (Et)) and d-amphetamine-CO2CH2-isonicotinic acid ester (AMP-CO2CH2-isonicotinic acid ester (Et)).

[0050] Figure 10 Compare the intravenous PK curves of d-amphetamine-CO2CH2-nicotinic acid ester (AMP-CO2CH2-nicotinic acid ester (Et)) and d-amphetamine-CO2CH2-isonicotinic acid ester (AMP-CO2CH2-isonicotinic acid ester (Et)). Invention Details

[0052] This technology generally describes novel compounds and compositions of the stimulant d-amphetamine, its salts, other derivatives, and combinations thereof. Furthermore, the technology described herein also generally relates to methods for preparing and using these novel compounds and compositions.

[0053] As used in this article, “amino acid” refers to natural, standard, non-standard, rare, synthetic and / or essential amino acids, and may be L-amino acids or D-amino acids or combinations thereof.

[0054] As used in this article, "d-amphetamine" refers to any sympathomimetic phenethylamine derivative with central nervous system stimulant activity, including, but not limited to, d-amphetamine (α-methyl-phenethylamine), methamphetamine, p-methoxyamphetamine, methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,4,5-trimethoxyamphetamine, 3,4-methylenedioxy-methylamphetamine, and methylphenidate.

[0055] As used herein, “in a manner inconsistent with the manufacturer’s instructions” or similar expressions are intended to include, but are not limited to, consuming a quantity greater than that described on the label or prescribed by a licensed physician, and / or altering the dosage formulation by any means (e.g., crushing, breaking, melting, separating, etc.) such that the composition can be injected, inhaled, or smoked.

[0056] The phrases used herein, such as “decreased,” “reduced,” “less,” or “lower,” are intended to include at least a 10% change in pharmacological activity, with larger percentage changes preferred for reducing the potential for abuse and overdose. For example, changes may also be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or increments thereof.

[0057] As used in this article, the terms "substance use disorder" or "stimulant use disorder," or the acronym "SUD," can be characterized as maladaptive, regressive behaviors toward the acquisition and use of abusive substances at the expense of other, more constructive behaviors maintained by non-pharmacological supplements. The success of any intervention can be measured in part by the extent to which it promotes a shift away from abusive substances or toward a redistribution of behavior toward non-pharmacological supplements that are generally considered healthier. Pharmacological therapies, particularly stimulant-like drugs, possess many properties that can promote such a redistribution of behavior.

[0058] The terms "agonist drugs" or "agonist replacement therapy" used in this article are mechanistically similar to drugs of abuse in terms of receptor-mediated action and pharmacodynamic effects, but differ in pharmacokinetic properties. Desired attributes of agonist replacement therapy include overlapping receptor pharmacology with drugs of abuse, oral bioavailability, slow onset of action, and long duration of action.

[0059] According to some aspects, this technology provides amphetamine in the form of a compound. More specifically, the amphetamine comprises at least one organic compound covalently bonded to or linked to amphetamine.

[0060] In some respects, the compound has the structure of formula IB:

[0061]

[0062] Where X is A-COO-R;

[0063] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0064] Where R is 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, arylsulfinyl Alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, polyethylene glycol, amino acids and amino acid residues.

[0065] In some respects, the compound has the structure of formula ID.

[0066]

[0067] Where X is A-CO-NR 1 R 2 ;

[0068] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0069] Where R 1 and R 2 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, arylsulfinyl Alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, polyethylene glycol, amino acids and amino acid residues.

[0070] In some respects, the compound has the structure of formula IIB:

[0071]

[0072] Where R is 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, arylsulfinyl Alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, polyethylene glycol, amino acids and amino acid residues.

[0073] In some respects, the compound has the structure of formula IID:

[0074]

[0075] Where Y is hydrogen, and A does not exist.

[0076] And R 1 and R 2 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, arylsulfinyl Alkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, polyethylene glycol, amino acids and amino acid residues.

[0077] In some respects, the compound is AMP-CO2CH2-nicotinic acid ester (Et) having the following structure or a pharmaceutically acceptable salt thereof:

[0078] or .

[0079] In some respects, the compound is AMP-CO2CH2-nicotinyl-Val-NH2 or a pharmaceutical salt thereof having the following structure:

[0080] or .

[0081] In some respects, the compound is AMP-CO2CH2-nicotinyl-Ser or a pharmaceutically acceptable salt thereof having the following structure:

[0082] or .

[0083] In some respects, the compound is AMP-CO2CH2-nicotinyl-Ala-OMe or a pharmaceutical salt thereof having the following structure:

[0084] or .

[0085] In some respects, the compound is (AMP-CO2CH2-nicotinyl)2-Ser-OMe having the following structure or a pharmaceutically acceptable salt thereof:

[0086] or .

[0087] In some respects, pharmaceutically acceptable salts of the said compounds are single salts or mixed salts, wherein one or more of said salts are selected from acetates, L-aspartate salts, benzenesulfonates, bicarbonates, carbonates, D-camphorsulfonates, L-camphorsulfonates, citrates, ethanedisulfonates, formates, fumarates, gluconates, hydrobromide / bromine, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonates, pyrates, phosphates, succinates, sulfates, and bisulfates. D-Tartrate, L-Tartrate, D,L-Tartrate, Meso-Tartrate, Benzoate, Glucoheptanoate, D-Glucuronate, Hybenzate, Hydroxyethylsulfonate, Malonate, Methylsulfate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Orotica, Stearate, Toluenesulfonate, Thiocyanate, Acetylglycinate, N-Acetylglycine, Aminosalicylate, Ascorbate, Borate, Butyrate, Camphorate, Camphor Carbonate, Decanoate, Hexanoate, Cholic Acid Salts, cyclopentanepropionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactobionate, galacturonate, gallate, gentianate, glutamate, glutamate, glycerol phosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, sine naphthate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, naphthalene disulfonate, oleate, oxalate, palmitate, picrate, neopentanoate, propionate, pyrophosphate Phosphates, salicylates, salicylsulfates, sulfosalicylates, tannates, terephthalates, thiosalicylates, tribromophenates, valerates, valproate, adipate, 4-acetaminobenzoate, camphor sulfonate, octanoate, etolate, ethanesulfonate, glycolate, thiocyanate, undecenoate, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, aluminum salts, lithium salts, choline salts, lysinium salts, ammonium salts, troethamine, and mixtures thereof.

[0088] In some respects, the compound is a conjugate of d-phenylpropylamine and has the structure of formula IB:

[0089]

[0090] Where X is A-COO-R;

[0091] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0092] Where R is 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, aryl... The following are listed: alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroaryl alkyl, heteroaryl amino, heteroaryl carbonyl, heteroaryl carbonyl amino, heteroaryl oxo, heteroaryl oxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenyl alkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol.

[0093] In some respects, the compound is a conjugate of d-phenylpropylamine and has the structure of formula ID.

[0094]

[0095] Where X is A-CO-NR 1 R 2 ;

[0096] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0097] Where R 1 and R 2 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, aryl... The following are listed: alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroaryl alkyl, heteroaryl amino, heteroaryl carbonyl, heteroaryl carbonyl amino, heteroaryl oxo, heteroaryl oxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenyl alkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol.

[0098] In some respects, the compound is a conjugate of d-phenylpropylamine and has the structure of formula IIB:

[0099]

[0100] Where R is 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, aryl... The following are listed: alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroaryl alkyl, heteroaryl amino, heteroaryl carbonyl, heteroaryl carbonyl amino, heteroaryl oxo, heteroaryl oxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenyl alkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol.

[0101] In some respects, the compound is a conjugate of d-phenylpropylamine and has the structure of formula IID:

[0102]

[0103] Where Y is hydrogen, and A does not exist.

[0104] And R 1 and R 2 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, aryl... The following are listed: alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroaryl alkyl, heteroaryl amino, heteroaryl carbonyl, heteroaryl carbonyl amino, heteroaryl oxo, heteroaryl oxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenyl alkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol.

[0105] In some respects, the conjugate is AMP-CO2CH2-nicotinic acid ester (Et) having the following structure or a pharmaceutically acceptable salt thereof:

[0106] or .

[0107] In some respects, the conjugate is AMP-CO2CH2-nicotinyl-Val-NH2 or a pharmaceutical salt thereof having the following structure:

[0108] or .

[0109] In some respects, the conjugate is AMP-CO2CH2-nicotinyl-Ser or a pharmaceutically acceptable salt thereof having the following structure:

[0110] or .

[0111] In some respects, the conjugate is AMP-CO2CH2-nicotinyl-Ala-OMe or a pharmaceutical salt thereof having the following structure:

[0112] or .

[0113] In some respects, the conjugate is (AMP-CO2CH2-nicotinyl)2-Ser-OMe having the following structure or a pharmaceutically acceptable salt thereof:

[0114] or .

[0115] In some respects, the pharmaceutically acceptable salt of the conjugate is a single salt or a mixture of salts, wherein one or more salts are selected from acetates, L-aspartate salts, benzenesulfonates, bicarbonates, carbonates, D-camphorsulfonates, L-camphorsulfonates, citrates, ethanedisulfonates, formates, fumarates, gluconates, hydrobromide / bromine, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonates, pyrantel salts, phosphorus salts, etc. Salts, succinates, sulfates, hydrogen sulfates, D-tartrates, L-tartrates, D,L-tartrates, meso-tartrates, benzoates, glucohepanoates, D-glucuronates, hydroxyethyl sulfonates, malonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, stearates, toluenesulfonates, thiocyanates, theophylline salts, N-acetylglycine salts, aminosalicylates, ascorbic acid salts, borates, butyrates, camphorates, camphor carbon Salts, decanoates, hexanoates, cholates, cyclopentanepropionate, dichloroacetate, edetate, ethyl sulfate, furoate, fusidate, galactosidate, galacturonate, gallate, gentianate, glutamate, glutamate, glycerol phosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodides, sine, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, naphthalene disulfonate, oleate, oxalate, palmitate Picrates, neopentanoates, propionates, pyrophosphates, salicylates, salicylsulfates, sulfosalicylates, tannates, terephthalates, thiosalicylates, tribromophenolates, valerates, valproate, adipate, 4-acetaminobenzoate, camphor sulfonate, octanoate, etolate, ethanesulfonate, glycolate, thiocyanate, undecenoate, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, aluminum salts, lithium salts, choline salts, lysine onium salts, ammonium salts, aminobutanetriol salts, and mixtures thereof.

[0116] In some aspects, the amphetamine moiety of the conjugate may be d-amphetamine or l-amphetamine. In other aspects, the compositions of this technology comprise a mixture of d-amphetamine conjugates and l-amphetamine conjugates. In still other aspects, the mixture of conjugates may be a racemic mixture. It should be understood that the conjugate moiety other than amphetamine may also have a chiral center that produces additional stereoisomers. The compositions of this technology may comprise a single stereoisomer or any mixture of stereoisomers.

[0117] In some respects, the X of the compound or the conjugate is located at the C-3 or C-5 position of the pyridine ring. It should be understood that, for reasons of symmetry, C-3 is equivalent to C-5.

[0118]

[0119] Pyridine

[0120] In some aspects, the composition comprises a conjugate of d-amphetamine. In some aspects, the composition is formulated for oral, suppository, injectable powder, intravenous, intranasal, or intrathecal administration. In another aspect, the dosage form of the composition formulated for oral administration is selected from solid forms, tablets, capsules, capsule-shaped tablets, soft gels, suppositories, troche tablets, lozenges, oral powders, solutions, syrups, oral films, thin strips, pastes, emulsions, elixirs, and suspensions. In yet another aspect, the composition further comprises one or more excipients, wherein the excipients are selected from anti-adhesion agents, adhesives, coating agents, disintegrants, fillers, flavoring agents, dyes, coloring agents, flow aids, lubricants, preservatives, absorbents, sweeteners, derivatives thereof, and combinations thereof. In another aspect, the adhesive is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic acid and methacrylic acid copolymers, pharmaceutical glazes, gums, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, polyethylene glycol and milk derivatives.

[0121] In some aspects, the conjugate is present in an amount of about 0.1 mg to about 2000 mg / unit dose per unit dose. In another aspect, the conjugate is present in an amount of about 0.1 mg to about 1000 mg / unit dose per unit dose. In another aspect, the conjugate is present in an amount of about 0.5 mg to about 500 mg / unit dose per unit dose. In another aspect, the conjugate is present in an amount of about 1 mg to about 250 mg / unit dose per unit dose. In another aspect, the conjugate is present in an amount of about 1.5 mg to about 100 mg / unit dose per unit dose. In another aspect, the conjugate is present in an amount of about 0.5 mg to about 2000 mg / unit, alternatively about 1 mg to about 2000 mg / unit, alternatively about 2 mg to about 2000 mg / unit, alternatively about 5 mg to about 2000 mg / unit, alternatively about 10 mg to about 2000 mg / unit, alternatively about 20 mg to about 2000 mg / unit, alternatively about 40 mg to about 2000 mg / unit, alternatively about 80 mg to about 2000 mg / unit, alternatively about 160 mg to about 2000 mg / unit, alternatively about 320 mg to about 2000 mg / unit, alternatively about 640 mg to about 2000 mg / unit, alternatively about 1280 mg to about 2000 mg / unit. In another aspect, the conjugate is present in an amount of about 0.1 mg to 2000 mg / unit. The amount of each unit dose is present in mg / unit, alternatively about 0.1 mg to about 1900 mg / unit dose, alternatively about 0.1 mg to about 1800 mg / unit dose, alternatively about 0.1 mg to about 1700 mg / unit dose, alternatively about 0.1 mg to about 1600 mg / unit dose, alternatively about 0.1 mg to about 1500 mg / unit dose, alternatively about 0.1 mg to about 1400 mg / unit dose, alternatively about 0.1 mg to about 1300 mg / unit dose, alternatively about 0.1 mg to about 1200 mg / unit dose, alternatively about 0.1 mg to about 1100 mg / unit dose, alternatively about 0.1 mg to about 1000 mg / unit dose, alternatively about 0.1 mg to about 900 mg / unit dose, alternatively about 0.1 mg to about 800 mg / unit dose, alternatively about 0.1 mg. mg to about 700 mg / unit dose, alternatively about 0.1 mg to about 600 mg / unit dose, alternatively about 0.1 mg to about 500 mg / unit dose, alternatively about 0.1 mg to about 400 mg / unit dose, alternatively about 0.A dose of 1 mg to approximately 300 mg / unit, alternatively approximately 0.1 mg to approximately 200 mg / unit, alternatively approximately 0.1 mg to approximately 100 mg / unit, alternatively approximately 0.1 mg to approximately 90 mg / unit, alternatively approximately 0.1 mg to approximately 80 mg / unit, alternatively approximately 0.1 mg to approximately 70 mg / unit, alternatively approximately 0.1 mg to approximately 60 mg / unit, alternatively approximately 0.1 mg to approximately 50 mg / unit, alternatively approximately 0.1 mg to approximately 40 mg / unit, alternatively approximately 0.1 mg to approximately 30 mg / unit, alternatively approximately 0.1 mg to approximately 20 mg / unit, alternatively approximately 0.1 mg to approximately 10 mg / unit, alternatively approximately 0.1 mg to approximately 5 mg / unit, and alternatively approximately 0.1 mg to approximately 1 mg / unit.

[0122] In some aspects, the composition further comprises one or more additional pharmacological substances selected from stimulants, antidepressants, combinations thereof, and their prodrugs. In another aspect, the composition further comprises one or more of the following: unconjugated amphetamine, unconjugated methylphenidate, aripiprazole, atoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacin, haloperidol, levetiracetam, mecaramyl, etoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tebufenozide, topiramate, or ziprasidone. In another aspect, the composition further comprises unconjugated amphetamine, its isomers, or amphetamine conjugates. In yet another aspect, the isomer of unconjugated amphetamine is unconjugated d-amphetamine. In another aspect, the composition further comprises unconjugated methylphenidate, its isomers, or methylphenidate conjugates. In yet another aspect, the unconjugated methylphenidate isomer is unconjugated d-methylphenidate. In yet another aspect, the methylphenidate conjugate is serdexmethylphenidate.

[0123] In some aspects, providing the conjugate in a quantity sufficient to provide a similar or reduced AUC compared to unconjugated d-amphetamine when administered orally in an equimolar dose. In some aspects, providing the conjugate in a quantity sufficient to provide a similar or reduced CUC compared to unconjugated d-amphetamine when administered orally in an equimolar dose. max In another aspect, the conjugate is provided in an amount sufficient to provide a reduced C10 concentration compared to unconjugated d-amphetamine when administered orally in an equimolar dose.max And similar or reduced AUC. In another aspect, intranasal or intravenous administration of at least one conjugate provides a lower AUC and / or Cmax compared to an equimolar amount of unconjugated d-amphetamine. In another aspect, a composition comprising the conjugate is provided in an amount sufficient to provide a longer T than unconjugated d-amphetamine when administered orally in an equimolar dose. max In another aspect, a composition comprising the conjugate is provided in an amount sufficient to provide a similar T compared to unconjugated d-amphetamine when administered orally in an equimolar dose. max .

[0124] In some respects, compositions containing the conjugate offer a reduced potential for abuse compared to unconjugated d-amphetamine. In another respect, a composition containing the conjugate is provided in an amount sufficient to provide a longer Tg compared to unconjugated d-amphetamine when administered in an equimolar dose. max In another aspect, a composition comprising the conjugate is provided in an amount sufficient to provide a similar T compared to unconjugated d-amphetamine when administered in an equimolar dose. max In another respect, compositions containing the conjugate have an improved safety profile compared to unconjugated d-amphetamine. In some respects, compositions containing the conjugate produce reduced or negligible pharmacological activity when administered via the parenteral route. In another respect, compositions containing the conjugate have reduced plasma or blood concentrations of released d-amphetamine when administered intranasally or intravenously compared to unconjugated d-amphetamine when administered in equimolar amounts.

[0125] In some respects, after intravenous or intranasal administration of the composition to a subject, the composition containing the conjugate provides a lower AUC and / or C0.05 of d-amphetamine released from the conjugate compared to an equivalent molar amount of unconjugated d-amphetamine. max In another aspect, after intravenous or intranasal administration of the composition to a subject, the composition containing the conjugate provides a longer Tg of d-amphetamine released from the conjugate compared to an equivalent molar amount of unconjugated d-amphetamine. max In some respects, upon administration to subjects, the compositions containing the conjugate resulted in prolonged release of d-amphetamine in subjects compared to the release of d-amphetamine upon administration of an equivalent molar amount of unconjugated d-amphetamine. In another respect, the compositions containing the conjugate exhibited less variability in d-amphetamine plasma concentrations between or within subjects compared to unconjugated d-amphetamine.

[0126] In some respects, some compounds of the present invention containing the nicotinic moiety unexpectedly and non-obviously result in different and / or improved d-amphetamine exposure in subjects after oral, intranasal, and / or intravenous administration, compared to compounds having the same structure but with the nicotinic group partially replaced by the isonicotinic group. In one respect, d-amphetamine-CO2CH2-nicotinic acid-Val-NH2 provides increased oral bioavailability of d-amphetamine compared to d-amphetamine-CO2CH2-isonicotinic acid ester (Et). In another respect, d-amphetamine-CO2CH2-nicotinic acid ester (Et) provides increased oral bioavailability of d-amphetamine compared to d-amphetamine-CO2CH2-isonicotinic acid ester (Et). In yet another respect, AMP-CO2CH2-nicotinic acid ester (Et) reduces exposure to d-amphetamine after intravenous administration compared to AMP-CO2CH2-isonicotinic acid ester (Et).

[0127] Another aspect of this technology is a composition for treating patients suffering from disorders or conditions requiring stimulation of the patient's central nervous system, wherein the composition has a reduced potential for abuse when applied compared to unconjugated d-amphetamine.

[0128] Another aspect of this technology is a method of treating a patient suffering from a disease, disorder, or condition mediated by controlling, blocking, limiting, or inhibiting neurotransmitter uptake, the method comprising administering to the patient in need a pharmaceutically effective amount of the composition of the present invention containing conjugates.

[0129] Another aspect of this technology is a method of treating a patient suffering from a disease, disorder, or condition mediated by an increase in neurotransmitter concentrations at the synapse, the method comprising administering to the patient in need a pharmaceutically effective amount of the composition of the present invention containing the conjugate.

[0130] Another aspect of this technology is a method of treating a patient suffering from a disorder or condition requiring stimulation of the patient's central nervous system, the method comprising orally administering a pharmaceutically effective amount of the composition comprising the conjugate of the present invention to the patient in need. In some aspects, the disorder 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, orthostatic tachycardia syndrome, Tourette syndrome, neurotic tics, substance use disorder, somnolence, depression, neurological impairment, or obesity. In another aspect, the disorder or condition is attention deficit hyperactivity disorder. In yet another aspect, the disorder or condition is Tourette syndrome or neurotic tics.

[0131] As will be understood by those skilled in the art, pharmaceutical products are considered pharmaceutical equivalents if they contain the same active ingredient, have the same dosage form, route of administration, and the same strength or concentration. Pharmaceutically equivalent pharmaceutical products are formulated to contain the same amount of active ingredient in the same dosage form and meet the same or pharmacopoeial or other applicable standards (i.e., strength, mass, purity, and properties), but they may differ in characteristics such as shape, notched configuration, release mechanism, packaging, excipients (including colorants, flavoring agents, and preservatives), shelf life, and (with certain limitations) labeling. A pharmaceutical product is considered therapeutically equivalent only if it is a pharmaceutical equivalent and if it can be expected to have the same clinical effects and safety profile when administered to a patient under the conditions specified on the label. On the other hand, the term "bioequivalent" describes a pharmaceutical equivalent or pharmaceutical substitute that shows comparable bioavailability when studied under similar experimental conditions.

[0132] According to the currently described technology, the release of d-amphetamine following oral administration of the compounds of the currently described technology will occur under the desired physiological conditions. Preferably, other routes of administration (e.g., intranasal or intravenous) will not break down the compound to any perceptible extent. In some aspects, the reduction in d-amphetamine exposure following intranasal and / or intravenous administration is 50%, 30%, 20%, <10%, etc., compared to the exposure following intranasal and / or intravenous administration of an equimolar dose of unconjugated d-amphetamine. Furthermore, preferably, certain compounds or aspects of the invention will be resistant to the release of amphetamine by external means (chemical, enzymatic, or other). The breakdown rate of the compound that can be achieved by external means is preferably less than about 50%, alternatively less than about 25%, alternatively less than about 20%, alternatively less than about 10%.

[0133] It is also believed that embodiments of the compounds, compositions, and methods described in the present invention will provide reduced rebound potential, reduced abuse or addiction potential, and / or improve the stimulant-related toxicity of d-amphetamine.

[0134] The d-amphetamine compounds described in this technology can be used for 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 insomnia. D-amphetamine stimulants have also been shown to be effective in treating stimulant abuse and addiction (e.g., cocaine, methamphetamine). D-amphetamine stimulants have also been widely used to enhance battlefield alertness and combat fatigue.

[0135] Therefore, according to certain aspects, the currently described technology provides d-amphetamine compositions comprising at least one d-amphetamine compound of the present technology.

[0136] One aspect is a composition that can prevent behavioral deterioration caused by d-amphetamine administration, which contains the d-amphetamine compound of the present technology.

[0137] Another aspect is the creation of compositions that allow for lower doses of the active pharmaceutical ingredient, which contains the d-phenylpropanol compound of this technology.

[0138] Other formulations according to one or more aspects of this technology may further comprise pharmaceutical additives, including, but not limited to, lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oil, talc, polyethylene glycol, and mineral oil; colorants such as Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Yellow No. 10, or FD&C Blue No. 1, and various other certified color additives (see 21). CFR, part 74); binders such as sucrose, lactose, gelatin, starch paste, gum arabic, tragacanth, polyvinyl alcohol, pullulan, and corn syrup; gliding agents such as colloidal silica and talc; surfactants such as sodium lauryl sulfate, sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitol, polyhydroxyanisole, 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 pharmaceutical additives known to those skilled in the art.

[0139] The d-amphetamine composition of this technology can be manufactured by any suitable method known to those skilled in the art of pharmaceutical manufacturing.

[0140] It should be noted that the d-amphetamine compositions of this technology do not require the aforementioned additives to have sustained-release properties in vivo. The d-amphetamine compounds of this technology are chemically stable to prevent the destruction or removal of d-amphetamine prior to oral administration. Furthermore, the controlled release of d-amphetamine by oral administration of the d-amphetamine compounds of this technology is a molecular design property and is independent of formulation. Therefore, the compounds of this technology can be readily formulated into different dosage forms. In one or more aspects of this technology, no other sustained-release additives are required to achieve a desensitized or reduced pharmacokinetic profile (e.g., reduced euphoric effect) while simultaneously achieving a therapeutically effective amount of d-amphetamine release upon oral administration.

[0141] The compounds and compositions of the currently described technology can be formulated into a variety of dosage forms and administered via any oral delivery route. Upon administration, the compound will release d-phenylalanine under digestive conditions. This encompasses any biologically acceptable dosage form and combination thereof known to those skilled in the art. Examples of preferred dosage forms include, but are not limited to, chewable tablets, instant tablets, effervescent tablets, resoluble powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multilayer tablets, bilayer tablets, capsules, soft gelatin capsules, hard gelatin capsules, capsule-shaped tablets, lozenges, chewable lozenges, beads, powders, granules, particles, microparticles, dispersible particles, capsules, oral films (e.g., instant thin-film tablets), and combinations thereof.

[0142] Formulations suitable for oral administration can be presented as discrete units, such as capsules, capsule-shaped tablets, tablets, or oral films. These oral formulations can also be contained in solutions or suspensions in aqueous or non-aqueous liquids. The formulations can be emulsions, such as oil-in-water or water-in-oil emulsions. The oil can be administered as follows: a purified and sterilized liquid is added to a prepared enteral formulation, which can then be inserted into a feeding tube for a patient who cannot swallow.

[0143] For example, if a capsule form is chosen, the excipients used in the capsule formulation can be divided into four separate groups: bulk agent / binder, disintegrant, lubricant, and carrier. Soft gel or soft gelatin capsules can be prepared, for example, by dispersing the formulation of this technique in a suitable medium (typically vegetable oil) to form a high-viscosity mixture. This mixture can then be encapsulated with a gelatin-based film using techniques and machinery known to those skilled in the soft gel industry. The industrial unit thus formed is then dried to constant weight.

[0144] For example, chewable tablets can be prepared by mixing the formulation of this technology with an excipient designed to form a relatively soft, flavored tablet dosage form intended to be chewed rather than swallowed. Conventional tablet machinery and procedures can be used, including direct compression and granulation before compression, i.e., tableting. Individuals involved in the production of solid dosage forms of pharmaceuticals are proficient in the processes and machinery used, as chewable dosage forms are very common in the pharmaceutical industry.

[0145] For example, film-coated tablets can be prepared by coating the tablets using techniques such as rotary pan coating or air suspension methods to deposit a continuous film layer on the tablets.

[0146] For example, compressed tablets can be prepared by mixing the formulation of this technology with an excipient designed to improve disintegration quality and binding properties. The mixture can be directly compressed or granulated and then compressed using methods and machinery known to those skilled in the art. The resulting compressed tablets are then packaged according to market needs in dosage units, i.e., unit doses, rolls, bulk bottles, blister packs, etc.

[0147] Methods and other ingredients required for preparing oral films or thin-film tablets are known in the art. Potential film-forming agents include pullulan, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, polyacrylic acid, amylase, starch, dextrin, pectin, chitin, chitosan, fructan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and mixtures thereof.

[0148] In addition, saliva stimulants, plasticizers, coolants, surfactants, emulsifiers, thickeners, binders, sweeteners, flavoring agents, colorants, preservatives, or taste-masking resins can be used in oral films or thin-layer tablets. Preferred agents include pullulan, triethanolamine stearate, methylcellulose, starch, triacetin, polysorbate 80, xanthan gum, maltitol, sorbitol, and glycerin.

[0149] The techniques described here also encompass the use of biologically acceptable carriers, which can be prepared from a variety of materials. These are not limited to, but include diluents, binders and adhesives, lubricants, plasticizers, disintegrants, colorants, fillers, flavorings, sweeteners, and miscellaneous materials such as buffers and adsorbents, in order to prepare specific pharmaceutical compositions.

[0150] The adhesive can be selected from a variety of materials such as hydroxypropyl methylcellulose, ethyl cellulose 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 adhesives known to those skilled in the art. Exemplary non-limiting solvents are water, ethanol, isopropanol, dichloromethane, or mixtures thereof. Exemplary non-limiting fillers include sugars, lactose, gelatin, starch, and silica.

[0151] Preferred plasticizers may be selected from, but are not limited to, diethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid, propylene glycol, butyl phthalate, dibutyl sebacate, castor oil, and mixtures thereof. Obviously, plasticizers can be either hydrophobic or hydrophilic in nature. Water-insoluble hydrophobic substances such as diethyl phthalate, diethyl sebacate, and castor oil are used to delay the release of water-soluble vitamins such as vitamin B6 and vitamin C. Conversely, when using water-insoluble vitamins, hydrophilic plasticizers are used, which help dissolve the encapsulating film and form channels on the surface, which facilitates the release of the nutrient composition.

[0152] It should be understood that, in addition to the ingredients specifically mentioned above, formulations of this technology may include other suitable agents such as flavoring agents, preservatives, and antioxidants. Such antioxidants are food-acceptable and may include, for example, vitamin E, carotene, BHT, or other antioxidants known to those skilled in the art.

[0153] Other compounds that may be included are, for example, medically inert ingredients, such as solid and liquid diluents, such as lactose, dextrose, sucrose, 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 stearate, or calcium stearate and / or polyethylene glycol; gelling agents such as colloidal clay; thickeners such as gum arabic or sodium alginate; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginate, or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; humectants such as lecithin, polysorbate, or lauryl sulfate; and other therapeutically acceptable adjuvants, such as humectants, preservatives, buffers, and antioxidants, which are known additives used in such formulations.

[0154] For oral administration, fine powders or granules containing diluents, dispersants, and / or surfactants may be presented as: beverages, water or syrups, capsules or pods in a dry state, non-aqueous suspensions (which may include suspending agents), or suspensions in water or syrup. Flavoring agents, preservatives, suspending agents, thickeners, or emulsifiers may be included, if desired or necessary.

[0155] Liquid dispersions for oral administration can be syrups, emulsions, or suspensions. Syrups may contain, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol as a carrier. Suspensions and emulsions may contain carriers such as natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0156] The dosage range for adults will depend on many factors, including the patient's age, weight, and condition. A suitable oral dose of the compositions of the currently described technology may be an equivalent dose to those commonly found in d-amphetamine treatment. Typical dosage ranges for d-amphetamine salts may be 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 doses may be approved in the future.

[0157] Tablets, capsules, oral films, and other forms provided in discrete units conveniently contain a daily dose or suitable portion thereof of one or more compounds of the present invention.

[0158] The dosage forms of this technology may also be combined with any release profile known to those skilled in the art. These conventional release profiles include immediate release, extended release, pulsatile release, variable release, controlled release, timed release, sustained release, delayed release, long-acting, and combinations thereof. The ability to achieve immediate release, extended release, pulsatile release, variable release, controlled release, timed release, sustained release, delayed release, long-acting characteristics, and combinations thereof, is known in the art.

[0159] The compositions of this technology can be administered as follows: as partial doses, once or multiple times within a 24-hour period, as a single dose within a 24-hour period, as two doses within a 24-hour period, or as more than two doses within a 24-hour period. Partial doses, two doses, or other multiple doses can be administered simultaneously or at different times within a 24-hour period. The dosage may be non-uniform relative to each other or relative to individual components at different times of administration.

[0160] Similarly, the compositions of this technology can be provided in blister packs or other such pharmaceutical packages. Furthermore, the compositions of this technology may further include or be accompanied by markings that allow an individual to identify the composition as a product for prescribed treatment. The markings may additionally include indications regarding the specified time period for application of the composition. For example, the markings may be time markers indicating a specific or general time within a day for application of the composition, or the markings may be day markers indicating a day within a week for application of the composition. Blister packs or other combination packages may also include a second pharmaceutical product.

[0161] It should be understood that the pharmacological activity of the compositions of this technology can be demonstrated using standard pharmacological models known in the art. Furthermore, it should be understood that the compositions of this technology can be incorporated into or encapsulated in a suitable polymer matrix or membrane for site-specific delivery, or can be functionalized with specific targeting agents capable of achieving site-specific delivery. These techniques, as well as other drug delivery technologies, are well known in the art.

[0162] In one or more aspects of this technology, the solubility and dissolution rate of the composition can be significantly altered under different physiological conditions encountered (e.g., in the intestine, on the mucosal surface, or in the bloodstream). In one or more aspects of this technology, the solubility and dissolution rate of the composition can significantly reduce the bioavailability of d-amphetamine, particularly at doses higher than the intended therapeutic dose. In one aspect of this technology, the reduction in bioavailability occurs immediately after intranasal administration. In another aspect, the reduction in bioavailability occurs immediately after intravenous administration.

[0163] The technology described here further provides methods for altering and / or delivering amphetamine in a manner that can reduce its potential for abuse.

[0164] One aspect provides a method for preventing behavioral deterioration or rebound effects by administering a d-amphetamine composition of the present technology to a patient in need of it.

[0165] Another aspect of this technology is a method for reducing or preventing the abuse of d-amphetamine, comprising providing, administering, consuming, or prescribing a composition to a patient in need, wherein the composition comprises the 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.

[0166] Another aspect of this technology is a method for preventing behavioral deterioration or rebound effects from d-amphetamine or stimulant treatment, comprising providing, administering, consuming, or prescribing a d-amphetamine composition of the presently described technology to a patient in need, wherein the composition comprises the d-amphetamine compound of the present invention, which may reduce the potential for behavioral deterioration or rebound effects from d-amphetamine or stimulant treatment.

[0167] Another aspect of this technology is any of the methods described above, wherein the d-amphetamine composition used is suitable for oral administration, and wherein when the composition is administered parenterally, such as via the nose or intravenously, d-amphetamine can resist the release of d-amphetamine from the organic acid moiety.

[0168] Another aspect of this technology provides a method for treating various diseases or conditions that require stimulation of the central nervous system (CNS), comprising administering compounds or compositions of this technology, which optionally further comprise active agents commonly prescribed for the various diseases or conditions.

[0169] In one respect, compositions comprising d-amphetamine compounds, their salts, or combinations thereof provide immediate and prolonged release PK profiles compared to unconjugated d-amphetamine.

[0170] Another aspect of this technology is a kit containing an individual dose of a therapeutically effective amount of a compound, conjugate, salt thereof, or combination thereof containing d-amphetamine. In some aspects, the kit is in a unit dose packet.

[0171] In one aspect of the invention, the amphetamine conjugate, compound, and / or composition, upon oral administration, exhibits an increased d-amphetamine plasma concentration compared to levedexamethasone dimethylsulfonate (or alternatively, d-amphetamine sulfate) for at least 1 hour, at least 2 hours, at least 4 hours, or at least 6 hours. In other aspects of the invention, the amphetamine conjugate, compound, and / or composition, upon oral administration, exhibits a decreased d-amphetamine plasma concentration compared to d-amphetamine sulfate and a similar d-amphetamine plasma concentration compared to levedexamethasone dimethylsulfonate for at least 1 hour, at least 2 hours, at least 4 hours, or at least 6 hours. In yet another aspect of the invention, the amphetamine conjugate, compound, and / or composition of the invention, upon intravenous or intranasal administration, exhibits a decreased d-amphetamine plasma concentration compared to levedexamethasone dimethylsulfonate or amphetamine sulfate for at least 1 hour, at least 2 hours, at least 4 hours, or at least 6 hours.

[0172] The presently described technology and its advantages will be better understood by referring to the following embodiments and / or solutions. These embodiments and / or solutions are provided to illustrate specific aspects of the technology. By providing these specific embodiments and / or solutions, the applicant does not limit the scope and spirit of the technology.

[0173] General synthesis procedure:

[0174]

[0175] Amphetamine hemisulfate 1 is converted to chloromethyl carbamate 2 by adding chloromethyl chloroformate. Chloromethyl carbamate 2 of amphetamine and the corresponding pyridine derivative are heated in acetone or acetonitrile with or without NaI to produce an amphetamine conjugate. Subsequent deprotection may be necessary, if applicable.

[0176] Specific procedures:

[0177] Synthesis of AMP-CO2-CH2-nicotinic acid ester (Et) 3f:

[0178] Table 1: Structure of conjugate 3f

[0179]

[0180] Synthesis scheme of AMP-CO2-CH2-nicotinic acid ester (Et) 3f:

[0181]

[0182] Option 1: (a) ClCH2COCl, DIPEA, DCM; (b) Ethyl nicotinic acid, acetonitrile, 80-85℃

[0183] Step 1: Chloromethyl carbamate of amphetamine, ClCH2OCO-AMP 2:

[0184] D-phenylpropylamine 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. Then, methyl chloroformate (4.221 g, 32.74 mmol) in DCM (20 mL) was added over 15 min. The reaction was warmed to room temperature over 30 min and then stirred for another 1.5 h. The reaction was then quenched by adding 5% NH4Cl aqueous solution (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 produce 4.9 g of syrup, which solidified upon storage in a refrigerator. The yield was 85.5%.

[0185] Step 2: AMP-CO2CH2-nicotinic acid ester (Et) 3f:

[0186] Amphetamine chloromethyl carbamate 2 (0.228 g, 1 mmol) and ethyl nicotinate in acetonitrile (8 mL) were heated at 80–85 °C for 8 hours. The solvent was evaporated. The residue was dissolved in DCM (1 mL). Then TBME (15 mL) and hexane (15 mL) were added. The supernatant was decanted. The remaining syrup was treated three more times using the above procedure, and then dried under vacuum to produce 0.230 g of amorphous solid. The yield was 60.7%.

[0187] Synthesis of conjugates AMP-CO2CH2-3-(3-pyridyl)alanine 5z and AMP-CO2CH2-nicotinyl-amino acid 6a-c:

[0188] Table 2: Structure of conjugate 5z

[0189]

[0190] Table 3: Structures of conjugates 6a-6c

[0191]

[0192] Synthetic scheme for AMP-CO2CH2-3-(3-pyridyl)alanine 5z:

[0193]

[0194] Option 2: (a) NaI, acetonitrile; (b) 4M HCl / dioxane, then Dowex 1x8

[0195] 7 z of 3-(3-pyridyl)-Boc-alanine tert-butyl ester (0.226 g, 0.7 mmol), ClCH₂OCO-AMP₂ (0.180 g, 0.791 mmol), and NaI (0.111 g, 0.742 mmol) in acetonitrile (10 mL) were refluxed for 1 hour. The solid was filtered off. The filtrate was concentrated and dried under vacuum to produce an amorphous solid. The solid in 4 M HCl / dioxane (10 mL) was stirred at room temperature for 12 hours. The solvent was evaporated to dryness and dried under vacuum to produce an amorphous solid, which was dissolved in 8 mL of ethanol and treated twice with Dowex 1 x 8 (200-400, Cl form, 1 g and 0.5 g). The resin-treated filtrate was concentrated and dried under vacuum to produce 5 z of 0.285 g as an amorphous solid. The yield was 94%.

[0196] Synthetic scheme of conjugate AMP-CO2CH2-nicotinyl-valine 6a:

[0197]

[0198] Option 3: (a) TEA / DCM; (b) 7a, NaI, acetonitrile; (c) 4M HCl / dioxane, then Dowex 1x8

[0199] Step 1: Nicotinyl-Val-OtBu 7a:

[0200] Et3N (1.25 mL, 9 mmol) was added to valine tert-butyl ester HCl salt (H-Val-OtBu HCl, 0.629 g, 3 mmol) in DCM (30 mL). Nicotinyl chloride hydrochloride (0.534 g, 3 mmol) was added in four fractions over 15 min in a water bath (room temperature). The reaction was stirred for 2 h. Subsequently, 20 mL of 5% NH4Cl aqueous solution was added to quench the reaction. The DCM layer was dried over Na2SO4. The product was purified by silica gel column chromatography (3% MeOH / DCM). 0.822 g of 7a was given as syrup. The yield was 98%.

[0201] Step 2: AMP-CO2CH2-nicotinyl-Val 6a:

[0202] Nicotinyl-Val-OtBu 7a (0.31 g, 1.11 mmol), ClCH2OCO-AMP 2 (0.291 g, 1.28 mmol), and NaI (0.176 g, 1.18 mmol) in acetonitrile (10 mL) were refluxed for 1.5 h. The solid was filtered off. The filtrate was concentrated to produce an amorphous solid. 4 M HCl / dioxane (8 mL) was added to the solid, and the mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness and then dried under vacuum for 1 h. The resulting residue was dissolved in 8 mL of ethanol and treated twice with a Dowex resin (1 x 8) (200-400, Cl form, 1 g and 0.5 g). The resin-treated filtrate was concentrated and dried under vacuum to produce 0.461 g of amorphous solid 6a. The yield was 93%.

[0203] Conjugates 6b and 6c were synthesized using a procedure similar to that for 6a.

[0204] Synthesis of the conjugate AMP-CO2CH2-nicotinyl-amino acid ester 9i-9n:

[0205] Table 4: Structure of conjugates 9i-9n

[0206]

[0207] Synthetic scheme for the conjugate AMP-CO2CH2-nicotinyl-amino acid ester 9i-9n:

[0208]

[0209] Option 4: (a) TEA / DCM; (b) 10i, NaI, acetonitrile, then Dowex 1x8

[0210] Step 1: Nicotinyl-Gly-OEt 10i:

[0211] Et3N (4.18 ml, 30 mmol) was added to glycine ethyl ester HCl (H-Gly-Et HCl, 1.40 g, 10 mmol) in DCM (50 mL). Nicotinyl chloride hydrochloride (1.78 g, 10 mmol) was added in seven fractions over a water bath (room temperature) for 30 min. The reaction was stirred for 2 h. Subsequently, 5% NaHCO3 aqueous solution (40 mL) was added to quench the reaction, followed by 50 mL of DCM. The DCM layer was further washed with 5% NaHCO3 aqueous solution (40 mL) and dried over Na2SO4. The product was purified by silica gel column chromatography (EtOAc). 1.59 g of syrup 10a was obtained. The yield was 76%.

[0212] Step 2: AMP-CO2-CH2-nicotinyl-Gly-OEt 9i:

[0213] Nicotinyl-Gly-OEt 10i (0.167 g, 0.8 mmol), ClCH2OCO-AMP2 (0.209 g, 0.92 mmol), and NaI (0.127 g, 0.848 mmol) in acetonitrile (8 mL) were heated at 65 °C for 1 hour. The solid was filtered off. The filtrate was concentrated to dryness and then dissolved in 6 mL of ethanol and treated twice with Dowex 1 x 8 (200-400, Cl form, 1 g and 0.5 g). The resin-treated filtrate was concentrated to dryness. The residue was dissolved in DCM (1.5 mL) and TBME (25 mL) was added. The supernatant was decanted. The remaining solid was dissolved in DCM (15 mL) and concentrated to produce a solid. After vacuum drying, 0.314 g of 9i was given. The yield was 90%.

[0214] Conjugate 9j-9n was synthesized using a procedure similar to that of 9i.

[0215] Synthesis of the conjugate AMP-CO2CH2-nicotinyl-amino acid amide 11c:

[0216] Table 5: Structure of conjugate 11c

[0217]

[0218] Synthetic scheme of AMP-CO2CH2-nicotinyl-Val-NH2 11c:

[0219]

[0220] Option 5: (a) TEA / DCM; (b) 12c, NaI, acetone, then Dowex 1x8

[0221] Step 1: Nicotinyl-Val-NH2 12c:

[0222] Et3N (1.062 g, 10.5 mmol) was added to valine amide HCl (H-Val-NH2 HCl, 0.458 g, 3 mmol) in DCM (30 mL). Nicotinyl chloride hydrochloride (0.587 g, 3.3 mmol) was added in three fractions over 10 min in a water bath at room temperature. The reaction was stirred for 1.5 h. The solvent was evaporated. The remaining solid was purified by silica gel column chromatography (8% MeOH / DCM) to produce a white solid containing Et3N HCl. Ethanol (10 mL) was added to the solid, and the mixture was heated to reflux (the solid did not completely dissolve). The mixture was cooled to room temperature. After 2 hours, the solid was collected, washed with ethanol (1 mL x 3), and dried under vacuum. 0.245 g of 12c was given. The yield was 36.9%.

[0223] Step 2: AMP-CO2CH2-nicotinyl-Val-NH2 11c:

[0224] The nicotinyl-Val-NH2 12c (0.111 g, 0.5 mmol), ClCH2OCO-AMP2 (0.137 g, 0.6 mmol), and NaI (0.086 g, 0.575 mmol) in acetone (6 mL) 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 a Dowex resin (1 x 8) (200-400, Cl form, 0.8 g and 0.4 g). The resin-treated filtrate was concentrated and vacuum dried to yield 0.218 g of 11c as an amorphous solid. The yield was 97%.

[0225] Synthesis of amphetamine bisconjugate (AMP-CO2CH2-nicotinyl)2-Ser-OMe 13b:

[0226]

[0227] Synthetic scheme of (AMP-CO2CH2-nicotinyl)2-Ser-OMe 13b:

[0228]

[0229] Option 6: (a) Et3N / DCM; (b) 15b, NaI, acetone, then Dowex 1x8

[0230] Step 1: (nicotinyl)2-Ser-OMe 15b:

[0231] Et3N (14.57 g, 144 mmol) was added to serine methyl ester HCl (2.80 g, 18 mmol) in DCM (200 mL). Nicotinyl chloride hydrochloride (9.613 g, 54 mmol) was added in seven fractions over a water bath (room temperature) for 30 min. The reaction was stirred for 22 h. Subsequently, 80 mL of 5% NH4Cl aqueous solution was added to quench the reaction. The DCM layer was dried over Na2SO4. The product was purified by silica gel column chromatography (EtOAc, then 7% MeOH / DCM). 3.99 g of 15b was given as syrup. The yield was 67%.

[0232] Step 2: (AMP-CO2CH2-nicotinyl)2-Ser-OMe 13b:

[0233] The mixture was refluxed for 1.5 h in acetone (12 mL) with (nicotinyl)-2-Ser-OMe 15b (0.165 g, 0.5 mmol), ClCH₂OCO-AMP₂ (0.273 g, 1.2 mmol), and NaI (0.172 g, 1.15 mmol). 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 a Dowex 1x8 resin (200-400, Cl form, 1.5 g, 1 g). The resin-treated filtrate was concentrated and dried under vacuum to yield 0.334 g of 13b as an amorphous solid. The yield was 85%.

[0234] Conjugates can be in different salt forms other than hydrochloride.

[0235]

[0236] For the following aspects of the invention, DMSO- was used on a Bruker Advance II 500 spectrometer. d 6 Record as solvent (without internal standard) 1 H-NMR and 13C-NMR. Low-resolution ESI mass spectra were recorded on an Agilent 1290 HPLC and an Agilent 6420 QQQ Triple mass spectrometer, run in cation mode using 0.1% formic acid-water / 0.1% formic acid-acetonitrile as the mobile phase. HPLC was run on an Agilent 1200 series instrument with a YMC ODS-AQ (C-18, 4.6x250 mm, 5µm, 120Å) column using 0.1% TFA-water / 0.1% TFA-acetonitrile as the mobile phase.

[0237]

[0238] NA: The compound is amorphous and its melting point cannot be determined.

[0239] Example 1: Oral Pharmacokinetic Study

[0240] The conjugates of d-amphetamine and the comparative compounds, d-amphetamine sulfate or levodopam dimethyl sulfonate, were dissolved in a suitable medium and administered to rats via oral feeding at a dose of 5.6 μmol / kg. Whole blood samples were collected via retro-orbital bleeding at 0.25, 0.5, 1, 2, and 4 hours post-administration, and optionally at 3 and 6 hours post-administration. The blood samples were centrifuged, and the resulting plasma samples were collected for analysis of amphetamine concentrations by LC-MS / MS.

[0241] Oral pharmacokinetic plasma concentration-time curves are shown in Figure 1-3 The oral pharmacokinetic parameters are summarized in Tables 6 and 7, 8 and 9.

[0242] Table 6: Oral pharmacokinetic parameters of d-amphetamine conjugate administered in rats over a 4-hour time course.

[0243]

[0244] Table 7: Oral pharmacokinetic parameters of d-amphetamine conjugate administered in rats over a 6-hour time course.

[0245]

[0246] Example 2: Intravenous Pharmacokinetic Study

[0247] A d-amphenicol conjugate and a comparative compound, either d-amphenicol sulfate or levofloxacin dimethylsulfonate, were dissolved in a suitable medium and administered to rats via tail vein injection at a dose of 5.6 μmol / kg. Whole blood samples were collected via retroorbital aspiration at 5 minutes and 0.25, 0.5, 1, and 2 hours post-administration. Blood samples were centrifuged, and the resulting plasma samples were collected for analysis of levonoricol concentrations by LC-MS / MS.

[0248] Intravenous pharmacokinetics of d-amphetamine plasma concentration-time curves were shown in the figure. Figure 4 , 5 The intravenous pharmacokinetic parameters of d-amphetamine are summarized in Table 8.

[0249] Table 8: Intravenous PK parameters of d-amphetamine conjugates administered in rats

[0250]

[0251] Example 3: Intranasal Pharmacokinetic Study

[0252] The conjugates of d-amphetamine and the comparative compounds, d-amphetamine sulfate or levodopam-methylsulfonate, were dissolved in a suitable medium and administered to rats at a dose of 5.6 μmol / kg as follows: the individual dosing solutions were slowly added dropwise and alternately introduced into the nostrils. Whole blood samples were collected via retro-orbital aspiration at 5 minutes and at 0.25, 0.5, and 1 hour post-administration. The blood samples were centrifuged, and the resulting plasma samples were collected for analysis of amphetamine concentrations by LC-MS / MS.

[0253] Intranasal pharmacokinetic plasma concentration-time curves were shown Figure 6 , 7 The summary of intranasal pharmacokinetic parameters is provided in Table 9.

[0254] Table 9: Intranasal PK parameters of d-amphetamine conjugates administered in rats

[0255]

[0256] Figure 8-10 It is noted that, compared to compounds having the same structure but with the nicotinic group partially replaced by the isonicotinic group, some compounds of the present invention containing the nicotinic group moiety unexpectedly and non-obviously resulted in different and / or improved d-amphetamine exposure in subjects after oral, intranasal and / or intravenous administration. Figure 8This demonstrates that d-amphetamine-CO2CH2-nicotinic acid-Val-NH2 provides increased oral bioavailability of d-amphetamine compared to d-amphetamine-CO2CH2-isonicotinic acid-Val-NH2. Figure 9 This demonstrates that d-amphetamine-CO2CH2-nicotinic acid ester (Et) provides increased oral bioavailability of d-amphetamine compared to d-amphetamine-CO2CH2-isonicotinic acid ester (Et). Figure 10 This demonstrates that, compared to AMP-CO2CH2-isonicotinic acid ester (Et), AMP-CO2CH2-nicotinic acid ester (Et) reduces exposure to d-phenylpropanol after intravenous administration.

[0257] Other aspects and implementations of this technology are described in the following paragraphs.

[0258] One aspect of the present invention is a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0259]

[0260] Wherein X is selected from esters, carboxylic acids, amino acids, amino acid residues, amides, and their derivatives, and Y is selected from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocyclic. Another aspect is a composition comprising said compound or a pharmaceutically acceptable salt of said compound.

[0261] Another aspect of the invention is a compound having the structure of formula IB or a pharmaceutically acceptable salt of said compound:

[0262]

[0263] Where X is A-COO-R;

[0264] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0265] Where R is 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, aryl... The compounds include alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroarylalkyl, heteroarylamino, heteroaryl carbonyl, heteroaryl carbonylamino, heteroaryl oxo, heteroaryloxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, and polyethylene glycol. Another aspect is a composition comprising said compounds or pharmaceutically acceptable salts of said compounds.

[0266] Another aspect of the invention is a compound having the structure of formula ID or a pharmaceutically acceptable salt of said compound:

[0267]

[0268] Where X is A-CO-NR 1 R 2 ;

[0269] Where A is absent, or when present, is selected from 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 Acyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cyclohexaalkyl, cyclohexaalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl and polyethylene glycol; and

[0270] Where R 1 and R 2 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, aryl... The compounds include alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroarylalkyl, heteroarylamino, heteroaryl carbonyl, heteroaryl carbonylamino, heteroaryl oxo, heteroaryloxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, and polyethylene glycol. Another aspect is a composition comprising said compounds or pharmaceutically acceptable salts of said compounds.

[0271] Another aspect of the invention is a compound or a pharmaceutically acceptable salt of said compound, wherein A is absent, Y is hydrogen, and said compound has the structure of formula IIB:

[0272]

[0273] Where R is 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, aryl... The compounds include alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroarylalkyl, heteroarylamino, heteroaryl carbonyl, heteroaryl carbonylamino, heteroaryl oxo, heteroaryloxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, and polyethylene glycol. Another aspect is a composition comprising said compounds or pharmaceutically acceptable salts of said compounds.

[0274] Another aspect is a compound or a pharmaceutically acceptable salt of said compound, wherein A is absent, Y is hydrogen, and said compound has the structure of formula IID:

[0275]

[0276] Where R 1 and R 2Independently 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, aryl... The compounds include alkyl sulfinyl alkyl, aryl sulfonyl, aryl sulfonyl amino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkoxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl alkenyl, heteroarylalkyl, heteroarylamino, heteroaryl carbonyl, heteroaryl carbonylamino, heteroaryl oxo, heteroaryloxy, heteroaryl sulfinyl, heteroaryl sulfonyl, heteroaryl thio, polycyclic alkenyl, polycyclic alkenylalkyl, polycyclic alkyl, polycyclic alkylalkyl, and polyethylene glycol. Another aspect is a composition comprising said compounds or pharmaceutically acceptable salts of said compounds.

[0277] In another respect, the compound has a structure selected from the following:

[0278] , , , , and .

[0279] In one aspect, the pharmaceutically acceptable salt is selected from acetates, L-aspartate, benzenesulfonates, bicarbonates, carbonates, D-camphorsulfonates, L-camphorsulfonates, citrates, ethanedisulfonates, formates, fumarates, gluconates, hydrobromide / bromine, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonates, pyrates, phosphates, succinates, sulfates, and hydrogen sulfates. Salts, D-tartrates, L-tartrates, D,L-tartrates, meso-tartrates, benzoates, glucohepanoates, D-glucuronates, hydroxyethyl sulfonates, malonates, methyl sulfates, 2-naphthalene sulfonates, nicotinates, nitrates, orotates, stearates, toluene sulfonates, thiocyanates, acetophylline salts, N-acetylglycine salts, aminosalicylates, ascorbic acid salts, borates, butyrates, camphorates, camphor carbonates, decanoates, hexanoates Cholic acid salts, cyclopentane propionate, dichloroacetate, edetate, ethyl sulfate, furoate, fusidate, galactosidate, galacturonate, gallate, gentianate, glutamate, glutamate, glycerol phosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, sine, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, naphthalene disulfonate, oleate, oxalate, palmitate, picrates Neopentanoate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribromophenolate, valerate, valproate, adipate, 4-acetaminobenzoate, camphor sulfonate, octanoate, etolate, ethanesulfonate, glycolate, thiocyanate, undecenoate, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, aluminum salt, lithium salt, choline salt, lysine onium salt, ammonium salt, aminobutanetriol salt, and mixtures thereof.

[0280] In another aspect, the compound has a structure selected from the following:

[0281] , , , , and .

[0282] One aspect of the invention is a composition comprising any compound of the invention or a pharmaceutically acceptable salt of said compound. In one aspect, the composition is formulated for oral or suppository administration. In another aspect, the composition formulated for oral administration is in a dosage form selected from: solid forms, tablets, capsules, capsule-shaped tablets, soft gels, suppositories, sugar tablets, lozenges, oral powders, solutions, syrups, oral films, thin-layer tablets, pastes, emulsions, elixirs, and suspensions. In another aspect, the composition further comprises one or more excipients selected from anti-adhesion agents, binders, coating agents, disintegrants, fillers, flavoring agents, dyes, colorants, flow aids, lubricants, preservatives, absorbents, sweeteners, derivatives thereof, and combinations thereof. In another aspect, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical enamels, gums, and emulsion derivatives.

[0283] In one aspect, the compound is present in an amount of about 0.1 mg to about 2000 mg per unit dose. In another aspect, the compound is present in an amount of about 0.5 mg to about 500 mg per unit dose. In another aspect, the compound is present in an amount of about 1 mg to about 250 mg per unit dose. In yet another aspect, the compound is present in an amount of about 1.5 mg to about 100 mg per unit dose.

[0284] In one aspect, the composition further comprises one or more additional pharmacological substances selected from stimulants, antidepressants, combinations thereof, and prodrugs thereof. In another aspect, the composition further comprises one or more of methylphenidate, aripiprazole, atoxetine, baclofen, clonidine, desipramine, dihydrobufenazine, guanifacin, haloperidol, levetiracetam, mecaramylamine, metoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, bufenazine, topiramate, ziprasidone, or one or more additional amphetamines, or any combination thereof. In another aspect, the one or more additional amphetamines are unconjugated amphetamines, amphetamine conjugates, amphetamine prodrugs, any isomers thereof, or any combination thereof. In another aspect, the unconjugated amphetamine isomer is unconjugated d-amphetamine. In another aspect, the methylphenidate is unconjugated methylphenidate, a methylphenidate conjugate, a methylphenidate prodrug, any isomer thereof, or any combination thereof. In another aspect, the unconjugated isomer of methylphenidate is unconjugated d-methylphenidate. In another aspect, the methylphenidate conjugate is methylphenidate.

[0285] In one aspect, the compound is provided in an amount sufficient to provide a similar or reduced AUC compared to unconjugated d-amphetamine when administered orally in an equimolar dose. In another aspect, the compound is provided in an amount sufficient to provide a similar or reduced CUC compared to unconjugated d-amphetamine when administered orally in an equimolar dose. max In another aspect, the compound is provided in an amount sufficient to provide a reduced C10 concentration compared to unconjugated d-amphetamine when administered orally in an equimolar dose. max And similar or reduced AUC. In one aspect, intranasal or intravenous administration of the compound provides a reduced AUC and / or C when compared to an equivalent molar amount of unconjugated d-amphetamine. max In another respect, compared to unconjugated d-amphetamine, the compound offers reduced abuse potential.

[0286] One aspect of the present invention is a kit comprising an individually therapeutically effective amount of a composition, said composition comprising a compound having the structure of Formula I, a pharmaceutically acceptable salt thereof, or a combination thereof: Formula I, wherein X is selected from esters, carboxylic acids, amino acids, amino acid residues, amides, and their derivatives, and Y is selected from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocyclic.

[0287] One aspect of the invention is a method for treating a patient with a disorder or condition requiring stimulation of the central nervous system, a method for treating a patient with a disease, disorder, or condition mediated by controlling, blocking, limiting, or inhibiting neurotransmitter uptake, or a method for treating a patient with a disease, disorder, or condition mediated by increasing neurotransmitter concentrations at synapses, said method comprising the step of administering a pharmaceutically effective amount of a composition to the patient in need, said composition comprising a compound having the structure of Formula I or a pharmaceutically acceptable salt of said compound: Formula I, wherein X is selected from esters, carboxylic acids, amino acids, amino acid residues, amides, and their derivatives, and Y is selected from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocyclic. In another aspect, the composition has a reduced potential for abuse upon application compared to unconjugated d-amphetamine. In another aspect, 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, orthostatic tachycardia syndrome, Tourette syndrome, neurotic tic disorders, substance use disorder, somnolence, depression, neurological impairment, or obesity.

[0288] The described technique is now presented in such complete, clear, concise, and precise terminology that any person skilled in the art can implement it. It should be understood that preferred aspects of the invention have been described above, and modifications may be made therein without departing from the spirit or scope of the invention.

Claims

1. A compound having a structure selected from the following, or a pharmaceutically acceptable salt of said compound: , , , and .

2. The compound according to claim 1, wherein the pharmaceutically acceptable salt is selected from acetate, L-aspartate, benzenesulfonate, bicarbonate, carbonate, D-camphorsulfonate, L-camphorsulfonate, citrate, ethanedisulfonate, formate, fumarate, gluconate, hydrobromide / bromine, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, methanesulfonate, pyrate, phosphate, and amber. Salts, sulfates, hydrogen sulfates, D-tartrates, L-tartrates, D,L-tartrates, meso-tartrates, benzoates, glucohepanoates, D-glucuronates, phenacetinates, hydroxyethyl sulfonates, malonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, stearates, toluenesulfonates, thiocyanates, theophylline salts, N-acetylglycine salts, aminosalicylates, ascorbic acid salts, borates, butyrates, camphorates, camphor carbonates Decanoate, Hexanoate, Cholate, Cyclopentanepropionate, Dichloroacetate, Edelweiss, Ethyl Sulfate, Furoate, Fusidate, Galactobionate, Galacturonate, Gallate, Gentianate, Glutamate, Glutarate, Glyceryl Phosphate, Heptanate, Hydroxybenzoate, Hippurate, Phenylpropionate, Iodides, Sinnaphthaleneate, Lactobionate, Laurate, Maleate, Mandelate, Myristate, Naphthalene Disulfonate, Oleate, Oxalate, Palmitate, Bitterness Salts, neopentanoates, propionates, pyrophosphates, salicylates, salicylsulfates, sulfosalisates, tannates, terephthalates, thiosalicylates, tribromophenolates, valerates, valproate, adipate, 4-acetaminobenzoate, camphor sulfonate, octanoate, etolate, ethanesulfonate, glycolates, thiocyanates, undecenoate, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, aluminum salts, lithium salts, choline salts, lysine onium salts, ammonium salts, aminobutanetriol salts, and mixtures thereof.

3. The compound according to claim 2, wherein the compound has a structure selected from the following: , , , and .

4. A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt of the compound.

5. The composition according to claim 4, wherein the composition is formulated for oral or suppository administration.

6. The composition according to claim 5, wherein the composition formulated for oral administration is selected from the dosage forms of solid form, solution, emulsion and suspension.

7. The composition according to claim 5, wherein the composition formulated for oral administration is selected from the dosage forms of tablets, capsules, lozenges, oral powders, syrups, oral films, and elixirs.

8. The composition according to claim 5, wherein the composition formulated for oral administration is selected from the dosage forms of: soft gel, sugar tablet, capsule tablet, thin-film tablet and paste.

9. The composition of claim 4, wherein the composition further comprises one or more excipients, wherein the excipients are selected from anti-adhesives, adhesives, coating agents, disintegrants, fillers, flavoring agents, colorants, flow aids, preservatives, and combinations thereof.

10. The composition of claim 4, wherein the composition further comprises one or more excipients, wherein the excipients are selected from dyes, lubricants, absorbents, sweeteners, and combinations thereof.

11. The composition according to claim 9 or 10, wherein the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic acid and methacrylic acid copolymers, pharmaceutical glazes, gums and whey.

12. The composition according to claim 4, wherein the compound is present in an amount from 0.1 mg to 2000 mg / unit dose.

13. The composition of claim 12, wherein the compound is present in an amount from 0.5 mg to 500 mg / unit dose.

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

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

16. The composition of claim 4, wherein the composition further comprises one or more additional pharmacological substances selected from stimulants, antidepressants, and combinations thereof.

17. The composition of claim 4, wherein the composition further comprises one or more of aripiprazole, atoxine, baclofen, clonidine, desipramine, dihydrobufenazine, guanifaxine, haloperidol, levetiracetam, mecaramine, metoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, bufenazine, topiramate, ziprasidone, or one or more of unconjugated amphetamines, amphetamine conjugates, or any combination thereof.

18. The composition of claim 17, wherein the unconjugated amphetamine is unconjugated d-amphetamine.

19. A kit comprising an individually therapeutically effective amount of a composition, said composition comprising the compound of claim 1, a pharmaceutically acceptable salt thereof, or a combination thereof.

20. Use of the composition according to claim 4 for the preparation of a medicament for treating disorders or conditions requiring stimulation of the central nervous system, for treating diseases, disorders or conditions mediated by controlling, blocking, limiting or inhibiting neurotransmitter uptake, or for treating diseases, disorders or conditions mediated by increasing neurotransmitter concentrations in synapses.

21. The use according to claim 20, wherein the disease or condition is attention deficit hyperactivity disorder, autism spectrum disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, schizophrenia, postural orthostatic tachycardia syndrome, substance use disorder, or neurological injury.

22. The use according to claim 20, wherein the disease or condition is attention deficit disorder, autism, Asperger's disorder, pervasive developmental disorder, insomnia, schizophrenia, major depressive disorder, narcolepsy, Tourette syndrome, neurotic tic, or somnolence.

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