d-amphetamine compounds, compositions, and processes for producing and using them.

Abstract

To provide a d-amphetamine compound, a composition, as well as a process for producing and using the same.SOLUTION: Compositions comprising a d-amphetamine compound, a composition including at least one organic acid covalent bonded to d-amphetamine, salts thereof, derivatives thereof, or combinations thereof are disclosed. Methods for producing and using them are also be disclosed. Organic compounds include heterocyclic nitrogen compounds. Heterocyclic nitrogen compounds are commonly found in nature and are involved in several biological functions in plants and animals. Examples of heterocyclic nitrogen compounds for use in the implementation of the present technology include, but are not limited to, for example, pyridine derivatives, some of which play an important role in the metabolism of nicotinate and tryptophan. In these compounds, one carbon of the phenyl ring is generally replaced by a nitrogen atom.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related applications This patent application relates to and claims priority from U.S. Nonprovisional Patent Application No. 16 / 667 / 804, filed on 29 October 2019, and the contents of that U.S. Nonprovisional Patent Application are incorporated in their entirety by reference.

[0002] Research and development funded by the federal government [Not applicable] [Background technology]

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

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

[0005] Childhood attention deficit hyperactivity disorder (ADHD) has been treated with stimulants for many years. More recently, however, the increase in prescriptions for ADHD treatment in the adult population has sometimes outpaced the growth of the pediatric market. Methylphenidate (e.g., Novartis) There are various drugs currently used to treat ADHD, such as International AG (marketed under the trademark Ritalin® by Basel, Switzerland) and the non-irritant atomoxetine (commercially sold as Stratella® by Eli Lilly and Company (located in Indianapolis, IN)), but d-amphetamine is the pioneer in the treatment of ADHD.

[0006] Early drug treatment for ADHD was limited to rapid-acting, immediate-release formulations of stimulants that could induce a number of potential undesirable side effects, including rebound symptoms, cardiovascular stress / disorders (e.g., increased heart rate, hypertension, cardiomyopathy), other side effects (e.g., insomnia, euphoria, psychotic episodes), addiction and abuse, and rapid loss of the therapeutic effect of the stimulant active ingredient (e.g., Dexedrine®, pure dextroamphetamine sulfate, marketed by Smith Kline and French, located in the UK).

[0007] Behavioral deterioration (rebound / "crushing") is observed in a significant percentage of children with ADHD, typically in the afternoon or evening, as medication is discontinued. Rebound symptoms may include, for example, irritability, irritability, hyperactivity worse than in the unmediated state, grief, crying, and, in rare cases, psychotic episodes. Symptoms may subside quickly or last for several hours. Some patients may experience rebound / crushing so severe that treatment must be discontinued. Rebound / crushing effects may lead to additional doses being prescribed to prevent the negative outcomes and side effects of anticipated rebound / crushing. Attempting to administer stimulants could potentially trigger addictive behavior.

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

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

[0010] In the prior art, it has been shown that most of the side effects of amphetamine are caused by a large initial spike in the blood concentration of the stimulant that rapidly dissipates to levels lower than the therapeutic efficacy (typically within 4 - 6 hours). As a result, the high efficacy of dextroamphetamine (d-amphetamine) has been continuously modulated by a series of new drugs with a gradually increasing sustained release profile that deliver d-amphetamine more slowly into the bloodstream for the purpose of creating a more safe and less abuse - prone treatment outcome and regimen. Methods and techniques for generating smaller spikes in drug blood concentration include, for example, the use of mixed salts and isomeric compositions (i.e., various salts of d- and the less potent l-amphetamine), long - term / controlled / sustained release formulations of amphetamine / dextroamphetamine salts (e.g., Adderall XR® commercially available from Shire U.S., Inc., located in Wayne, PA), and prodrugs of lysdexamphetamine salts (also Vyvanse® commercially available from Shire).

[0011] As a result, there remains a need in the art for a safer dosage form of d-amphetamine, as well as treatment regimens that are therapeutically effective and can provide sustained release and a sustained therapeutic effect. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0012] SUMMARY OF THE INVENTION The technology described herein, in part, provides novel compounds, as well as compositions of the stimulant d-amphetamine (「d-Amp」, 「dextroamphetamine」), its salts, other derivatives, and combinations thereof.

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

[0014] In some aspects of this technology, the organic compound includes an amino acid. An amino acid is an organic compound containing both a carboxyl (-COOH) and an amino (-NH2) group, along with various side chain groups. The amino acids that may be used in this technology may be natural, standard, non-standard, synthetic, and / or essential amino acids, and may be L-amino acids, D-amino acids, or combinations thereof. Examples of amino acids for use in implementing this technology include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, norleucine, 3-nitrotyrosine, pyroglutamic acid, nitroarginine, ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, gamma-aminobutyric acid, 6-aminohexanoic acid, sarcosine, carnitine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine, β-phenylalanine Lanine, isoserine, β-glutamic acid, β-tyrosine, β-dopa (3,4-dihydroxy-L-phenylalanine), 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methylalanine, L-abulin, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, azetidine-2-carboxylic acid, pipecoric acid, allylglycine, cyclohexylglycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glycine ester, 2-(trifluoromethyl)-phenylalanine, 4-(hydroxymethyl)-phenylalanine, 4-aminophenylalanine, 2-chlorophenylglycine, 3-guanidino-propionic acid, 3,4-dehydro-proline, 2,It contains 3-diaminobenzoic acid, 2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid, allo-isoleucine, tert-leucine, 3-phenylserine, isoserine, 3-aminopentanoic acid, 2-aminooctanodioic acid, 4-chloro-β-phenylalanine, β-homoproline, β-homoalanine, 3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid, 5-aminovaleric acid, 4-(dimethylamino)cinnamic acid, 2-pyridylalanine (2-Pal), and 3-pyridylalanine (3-Pal).

[0015] In some embodiments, the compound is of formula IA

[0016] [ka] Having a structure,

[0017] In the formula, X is A-COO-R;

[0018] A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0019] R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, A Selected from the group consisting of arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues. It will be selected.

[0020] In some embodiments, the compound is of formula IC

[0021] [ka] Having a structure,

[0022] In the formula, X is A-CO-NR 1 R 2 and;

[0023] A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0024] R 1 and R 2Independently, hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, hetero Selected from the group consisting of loarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues.

[0025] It should be understood that the carbon atom attached to Y is a chiral center if Y is not a hydrogen atom. It should also be understood that in certain embodiments, X is attached to at least one of C-2, C-3, C-4, C-5, and / or C-6.

[0026] [ka]

[0027] In some embodiments, the technology includes conjugates in which the chiral carbon has an R configuration. In other embodiments, the technology includes conjugates in which the chiral carbon has an S configuration. In other embodiments, the technology includes a mixture of stereoisomers in which some conjugates contain a chiral carbon having an R configuration and some conjugates contain a chiral carbon having an S configuration.

[0028] The techniques described herein further provide a method for the controlled therapeutic delivery of d-amphetamine compositions by oral administration. In at least one embodiment, the techniques described herein focus on slow-rapid / sustained controlled-release compositions of d-amphetamine in compound form that enable slow-rapid / sustained / controlled delivery of stimulants to the human or animal blood system within the therapeutic concentration range when administered orally. At least some compositions / formulations of the current techniques can reduce rebound effects, cardiovascular stress, the potential for addiction / abuse, and / or other common stimulant side effects associated with d-amphetamine and similar compounds. Such compositions may also increase the duration of therapeutic effect, ease of application, patient compliance, and / or any combination of these characteristics, especially when administered orally.

[0029] The release of d-amphetamine after oral administration of the compound in this technology can be induced gradually over a long period, thereby eliminating unintended excessive rapid increases in drug levels in the bloodstream of human or animal patients (e.g., large spikes in blood concentration). While not adhering to any particular theory, such spikes in blood levels may make euphoric drugs "high" and lead to cardiovascular effects such as increased blood pressure and heart rate. Furthermore, sustained blood levels are achieved for a longer duration and within an effective therapeutic range than other conventional treatments, thereby preventing rebound effects.

[0030] In some embodiments, the technology provides specific d-amphetamine ("d-Amp", "dexamfetamine") compounds, compositions, or pharmaceutically acceptable salts thereof to provide at least one once-daily dose form of d-amphetamine compound in a composition having unconjugated d-amphetamine, for example, that can provide both immediate and long-release PK profiles compared to unconjugated d-amphetamine. In some cases, the release profile of the compound or composition administered using a dosing regimen not readily available with unconjugated d-amphetamine is To provide capabilities.

[0031] At least some compositions of this technology, including the d-amphetamine compound, are resistant to abuse via parenteral administration routes such as intravenous "shooting," intranasal "snoring," or inhalation "smoking," which are frequently used in illegal 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 states of arousal with reduced or prevented potential for abuse. Without adhering to any particular theory, the compositions of this technology are considered to result in substantially reduced potential for abuse or abuse compared to existing stimulant treatments and dosage forms.

[0032] At least some compositions of this technology, including the d-amphetamine compound, can also be used to treat stimulant (cocaine, methamphetamine) abuse and addiction, substance use disorders, improve alertness on the battlefield, and / or combat fatigue.

[0033] When administered by injection or intranasal route, the compositions of this technology are preferably devoid of pharmacological activity or substantially reduced in pharmacological activity. However, they remain orally bioavailable with respect to d-amphetamine. Bioavailability may be a result of hydrolysis of the covalent linkage between d-amphetamine and the remainder of the conjugate after oral administration. Hydrolysis is time-dependent, thereby allowing d-amphetamine and other metabolites such as p-hydroxyamphetamine and p-hydroxyephedrine to be available in their active form for extended periods. In at least one further embodiment, the release of d-amphetamine is reduced or eliminated when the compositions of this technology are delivered via parenteral routes, compared to unconjugated d-amphetamine.

[0034] For example, in one embodiment, the compositions of this technology maintain their efficacy and abuse tolerance after crushing of tablets, capsules, or other oral dosage forms used to deliver the therapeutic component (i.e., active ingredient / drug) due to a controlled-release component, which is a designed property of the composition rather than the formulation itself. In contrast, conventional long-release formulations used to control the release of d-amphetamine are subjected to release up to the total d-amphetamine content immediately after crushing. When the content of a crushed tablet is injected or swallowed, a large dose of d-amphetamine produces the "rush" effect desired by the addict.

[0035] Other objects, advantages, and aspects of the present invention are described below and will be evident from this description and from the practice of the present invention. [Brief explanation of the drawing]

[0036] [Figure 1]Oral PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-valineamide (AMP-CO2CH2-isonicotinoyl-Val-NH2), and d-amphetamine-CO2CH2-isonicotinoyl-ethylalanine ethyl ester (AMP-CO2CH2-isonicotinoyl-Ala-OEt).

[0037] [Figure 2] Oral PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-isoleucine (AMP-CO2CH2-isonicotinoyl-Ile), and d-amphetamine-CO2CH2-isonicotinoyl-glutamate (AMP-CO2CH2-isonicotinoyl-Glu).

[0038] [Figure 3] Oral PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinoyl-threonine (AMP-CO2CH2-isonicotinoyl-Thr).

[0039] [Figure 4] Oral PK curves comparing d-amphetamine sulfate and d-amphetamine-CO2CH2-isonicotinate-tert-butyl ester (AMP-CO2CH2-isonicotinate (tBu)).

[0040] [Figure 5] Oral PK curves comparing d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinoyl-sarcosine (AMP-CO2CH2-isonicotinoyl-Sar), and d-amphetamine-CO2CH2-isonicotinoyl-glycine (AMP-CO2CH2-isonicotinoyl-Gly).

[0041] [Figure 6]Oral PK curves comparing d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinoyl-morpholine (AMP-CO2CH2-isonicotinoyl-morpholine), and d-amphetamine-CO2CH2-isonicotinoyl-serine (AMP-CO2CH2-isonicotinoyl-Ser).

[0042] [Figure 7] Oral PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-leucine (AMP-CO2CH2-isonicotinoyl-Leu), and d-amphetamine-CO2CH2-isonicotinoyl-beta-alanine ethyl ester (AMP-CO2CH2-isonicotinoyl-β-Ala-OEt).

[0043] [Figure 8] Oral PK curves comparing d-amphetamine sulfate and d-amphetamine-CO2CH2-isonicotinoyl-proline (AMP-CO2CH2-isonicotinoyl-Pro).

[0044] [Figure 9] Oral PK curves comparing d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinoyl-N-methyl-L-alanine (AMP-CO2CH2-isonicotinoyl-N-Me-Ala), and d-amphetamine-CO2CH2-isonicotinoyl-glycyl-alanine (AMP-CO2CH2-isonicotinoyl-Gly-Ala).

[0045] [Figure 10] Oral PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-leucine methyl ester (AMP-CO2CH2-isonicotinoyl-Leu-OMe), and d-amphetamine-CO2CH2-isonicotinoyl-isoleucine methyl ester (AMP-CO2CH2-isonicotinoyl-Ile-OMe).

[0046] [Figure 11] Oral PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-leucinamide (AMP-CO2CH2-isonicotinoyl-Leu-NH2), and d-amphetamine-CO2CH2-isonicotinoyl-alanine isopropyl ester (AMP-CO2CH2-isonicotinoyl-Ala-OiPr).

[0047] [Figure 12] Oral PK curves comparing d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinoyl-ornithine (AMP-CO2CH2-isonicotinoyl-Orn), and d-amphetamine-CO2CH2-isonicotinoyl-alanine (AMP-CO2CH2-isonicotinoyl-Ala).

[0048] [Figure 13] Oral PK curves comparing d-amphetamine sulfate and d-amphetamine-CO2CH2-isonicotinoyl-valinemethyl ester (AMP-CO2CH2-isonicotinoyl-Val-OMe).

[0049] [Figure 14] Oral PK curves comparing d-amphetamine sulfate and d-amphetamine-CO2CH2-isonicotinoyl-aspartate (AMP-CO2CH2-isonicotinoyl-Asp).

[0050] [Figure 15] Oral PK curves comparing d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinoyl-valine (AMP-CO2CH2-isonicotinoyl-Val), and d-amphetamine-CO2CH2-isonicotinoyl-phenylalanine (AMP-CO2CH2-isonicotinoyl-Phe).

[0051] [Figure 16]Intravenous PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-valineamide (AMP-CO2CH2-isonicotinoyl-Val-NH2), and d-amphetamine-CO2CH2-isonicotinoyl-alanine ethyl ester (AMP-CO2CH2-isonicotinoyl-Ala-OEt).

[0052] [Figure 17] Intravenous PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-threonine (AMP-CO2CH2-isonicotinoyl-Thr), and d-amphetamine-CO2CH2-isonicotinoyl-isoleucine (AMP-CO2CH2-isonicotinoyl-ILe).

[0053] [Figure 18] Intravenous PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-phenylalanine (AMP-CO2CH2-isonicotinoyl-Phe), and d-amphetamine-CO2CH2-isonicotinate-tert-butyl ester (AMP-CO2CH2-isonicotinate(tBu)).

[0054] [Figure 19] Intravenous PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-sarcosine (AMP-CO2CH2-isonicotinoyl-Sar), and d-amphetamine-CO2CH2-isonicotinoyl-glycine (AMP-CO2CH2-isonicotinoyl-Gly).

[0055] [Figure 20]Intravenous PK curves comparing d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinoyl-valine methyl ester (AMP-CO2CH2-isonicotinoyl-Val-OMe), and d-amphetamine-CO2CH2-isonicotinoyl-morpholine (AMP-CO2CH2-isonicotinoyl-morpholine).

[0056] [Figure 21] Intravenous pharmacokinetic curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinoyl-leucine (AMP-CO2CH2-isonicotinoyl-Leu).

[0057] [Figure 22] Intravenous pharmacokinetic curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-valine (AMP-CO2CH2-isonicotinoyl-Val), and d-amphetamine-CO2CH2-isonicotinoyl-proline (AMP-CO2CH2-isonicotinoyl-Pro).

[0058] [Figure 23] Intranasal PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinoyl-valineamide (AMP-CO2CH2-isonicotinoyl-Val-NH2).

[0059] [Figure 24] Intranasal PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-threonine (AMP-CO2CH2-isonicotinoyl-Thr), and d-amphetamine-CO2CH2-isonicotinoyl-isoleucine (AMP-CO2CH2-isonicotinoyl-Ile).

[0060] [Figure 25]Intranasal PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinate-tert-butyl ester (AMP-CO2CH2-isonicotinate (tBu)), and d-amphetamine-CO2CH2-isonicotinoyl-phenylalanine (AMP-CO2CH2-isonicotinoyl-Phe).

[0061] [Figure 26] Intranasal PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-sarcosine (AMP-CO2CH2-isonicotinoyl-Sar), and d-amphetamine-CO2CH2-isonicotinoyl-glycine (AMP-CO2CH2-isonicotinoyl-Gly).

[0062] [Figure 27] Intranasal PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinoyl-leucine (AMP-CO2CH2-isonicotinoyl-Leu).

[0063] [Figure 28] Intranasal PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinoyl-proline (AMP-CO2CH2-isonicotinoyl-Pro), and d-amphetamine-CO2CH2-isonicotinoyl-valine (AMP-CO2CH2-isonicotinoyl-Val).

[0064] [Figure 29] Intranasal PK curves comparing d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinoyl-valine methyl ester (AMP-CO2CH2-isonicotinoyl-Val-OMe), and d-amphetamine-CO2CH2-isonicotinoyl-morpholine (AMP-CO2CH2-isonicotinoyl-morpholine).

[0065] [Figure 30] Oral PK curves comparing d-amphetamine-CO2CH2-nicotinoyl-serine (AMP-CO2CH2-nicotinoyl-Ser) and d-amphetamine-CO2CH2-isonicotinoyl-serine (AMP-CO2CH2-isonicotinoyl-serine).

[0066] [Figure 31] Intranasal PK curves comparing d-amphetamine-CO2CH2-nicotinate ethyl ester (AMP-CO2CH2-nicotinate(Et)) and d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate(Et)).

[0067] [Figure 32] Intravenous pharmacokinetic curves comparing d-amphetamine-CO2CH2-nicotinoyl-valineamide (AMP-CO2CH2-nicotinoyl-Val-NH2) and d-amphetamine-CO2CH2-isonicotinoyl-valineamide (AMP-CO2CH2-isonicotinoyl-Val-NH2).

[0068] [Figure 33] Oral PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinate (AMP-CO2CH2-isonicotinate), and d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate(Et)).

[0069] [Figure 34] Oral PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinate (AMP-CO2CH2-isonicotinate).

[0070] [Figure 35]Intravenous PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate(Et)).

[0071] [Figure 36] Intravenous pharmacokinetic curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinate (AMP-CO2CH2-isonicotinate).

[0072] [Figure 37] Intranasal PK curves comparing lisdexamfetamine (LDX) and d-amphetamine-CO2CH2-isonicotinate (AMP-CO2CH2-isonicotinate).

[0073] [Figure 38] Nasal PK curves comparing d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate(Et)).

[0074] [Figure 39] Intranasal PK curves comparing lisdexamfetamine (LDX), d-amphetamine sulfate, d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate (Et)), and d-amphetamine-CO2CH2-isonicotinate (AMP-CO2CH2-isonicotinate).

[0075] [Figure 40] Intranasal PK curves comparing lisdexamfetamine (LDX), d-amphetamine-CO2CH2-isonicotinate ethyl ester (AMP-CO2CH2-isonicotinate (Et)), and d-amphetamine-CO2CH2-isonicotinate (AMP-CO2CH2-isonicotinate). [Modes for carrying out the invention]

[0076] Detailed description of the invention This technology generally describes novel compounds and compositions of the irritant d-amphetamine, their salts, other derivatives, and combinations thereof. Furthermore, the technology described herein generally relates to methods for preparing and using these novel compounds and compositions.

[0077] As used herein, “amino acids” means natural, standard, non-standard, abnormal, synthetic, and / or essential amino acids, and may be L-amino acids, D-amino acids, or combinations thereof.

[0078] As used herein, "d-amphetamine" means any of the sympathetic-mimicking phenethylamine derivatives having central nervous system stimulant activity, including but not limited to d-amphetamine (alpha-methylphenethylamine), methamphetamine, p-methoxyamphetamine, methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,4,5-trimethoxyamphetamine, 3,4-methylenedioxy-methamphetamine, and methylphenidate.

[0079] As used herein, “in a manner inconsistent with the manufacturer’s instructions” or similar expressions mean, but are not limited to, consuming an amount greater than that described on the label or directed by a qualified physician, and / or altering the drug formulation by any means (e.g., crushing, destroying, melting, separating, etc.) so that the composition can be injected, inhaled, or smoked.

[0080] As used herein, phrases such as “decrease,” “reduce,” “be reduced,” or “lower” mean a change of at least 10% of the pharmacological activity, with a larger percentage change being preferred in relation to the reduction of the potential for abuse and the potential for overdose. For example, the change may also be greater than or equal to 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, or 99%, or an increment within that range.

[0081] As used herein, the terms “substance use disorder” or “stimulant use disorder” or the acronym “SUD” can be characterized as a narrowing of maladaptive behaviors toward the acquisition and use of abused substances at the expense of more positive behaviors maintained by other non-pharmacological supplements. The success of any intervention can be measured in part by the extent to which it facilitates a reversal of behavior toward non-pharmacological supplements that are generally considered to lead to abstinence from abused substances or better health. Pharmacological treatments, particularly agonist-like medications, possess several properties that can facilitate such behavioral reversals.

[0082] As used herein, the terms “agonist therapy” or “agonist replacement therapy” refer to drugs that are mechanistically similar to abused drugs in terms of receptor-mediated and pharmacodynamic effects, but differ in terms of pharmacokinetic properties. Desirable attributes of agonist replacement therapy include overlapping receptor pharmacology with that of abused drugs, oral bioavailability, slow onset of action, and long duration of action.

[0083] In some embodiments, the technology provides amphetamine in compound form. More specifically, the amphetamine comprises at least one organic compound covalently bonded to or attached to the amphetamine.

[0084] In some embodiments, the compound is of formula A

[0085] [ka] Having the structure or a pharmaceutically acceptable salt thereof,

[0086] In the formula, X is selected from the group consisting of esters, carboxylic acids, amino acids, amino acid residues, amide groups, and derivatives thereof, and Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycles.

[0087] In some embodiments, the compound is of formula IA

[0088] [ka] Having a structure,

[0089] In the formula, X is A-COO-R;

[0090] A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

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

[0092] In some embodiments, the compound is of formula IC

[0093] [ka] Having a structure,

[0094] In the formula, X is A-CO-NR 1 R 2 and;

[0095] A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0096] R 1 and R 2Independently, hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, hetero Selected from the group consisting of loarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues.

[0097] In some embodiments, the compound is of formula IIA:

[0098] [ka] Having a structure,

[0099] In the formula, R is selected from the group consisting of hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol, amino acid, and amino acid residue.

[0100] In some embodiments, the compound has the formula IIC:

[0101]

Chemical formula

[0102] where Y is hydrogen and A is absent,

[0103] R 1 and R2 Independently, hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylamonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl Selected from the group consisting of polysulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues.

[0104] In some embodiments, the compound is IIE:

[0105] [ka] Having a structure,

[0106] In the formula, R is independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylal Selected from the group consisting of coxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxy, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues.

[0107] In some embodiments, the compound is of formula IIF:

[0108] [ka] Having a structure,

[0109] In the formula, R 1 and R 2Independently, hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl Selected from the group consisting of polysulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues.

[0110] In some embodiments, the compound is of formula I [ka] The formula has the structure or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of esters, carboxylic acids, amino acids, amino acid residues, amide groups, and derivatives thereof, and Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle.

[0111] In a further embodiment, one or more substituents X can be attached to the pyridine ring, each X independently forming A-COO-R and A-CO-NR. 1 R 2 Selected from the group.

[0112] In a further embodiment, two or more substituents X can be attached to the pyridine ring, each X independently forming A-COO-R and A-CO-NR. 1 R 2 Selected from the group.

[0113] In some embodiments, the compound has the following structure:

[0114] [ka] It is an AMP-CO2CH2-isonicotinate or a salt thereof that has the following properties:

[0115] In some embodiments, the compound has the following structure:

[0116] [ka] It is AMP-CO2CH2-isonicotinate (tBu) or a salt thereof that contains [the specified compound].

[0117] In some embodiments, the compound has the following structure:

[0118] [ka] It is AMP-CO2CH2-isonicotinoyl-morpholine or a salt thereof that contains

[0119] In some embodiments, the compound has the following structure:

[0120] [ka] It is AMP-CO2CH2-isonicotinoyl-Val-NH2 or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Val-NH2.

[0121] In some embodiments, the compound has the following structure:

[0122] [ka] It is AMP-CO2CH2-isonicotinoyl-Ile or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Ile.

[0123] In some embodiments, the compound has the following structure:

[0124] [ka] It is AMP-CO2CH2-isonicotinoyl-Thr or a salt thereof.

[0125] In some embodiments, the compound has the following structure:

[0126] [ka] It is AMP-CO2CH2-isonicotinoyl-Gly or a salt thereof that contains

[0127] In some embodiments, the compound has the following structure:

[0128] [ka] It is AMP-CO2CH2-isonicotinoyl-Sar or a salt thereof, which has the properties of AMP-CO2CH2-isonicotinoyl-Sar.

[0129] In some embodiments, the compound has the following structure:

[0130] [ka] It is AMP-CO2CH2-isonicotinoyl-Leu or a salt thereof that contains AMP-CO2CH2-isonicotinoyl-Leu.

[0131] In some embodiments, the compound has the following structure:

[0132] [ka] AMP-CO2CH2-isonicotinoyl-Pro or a salt thereof possessing these properties.

[0133] In some embodiments, the compound has the following structure:

[0134] [ka] It is AMP-CO2CH2-isonicotinoyl-Ile-OMe or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Ile-OMe.

[0135] In some embodiments, the compound has the following structure:

[0136] [ka] AMP-CO2CH2-isonicotinoyl-Ala-OiPr or a salt thereof is a salt of AMP-CO2CH2-isonicotinoyl-Ala-OiPr.

[0137] In some embodiments, the compound has the following structure:

[0138] [ka] It is AMP-CO2CH2-isonicotinoyl-Leu-NH2 or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Leu-NH2.

[0139] In some embodiments, the compound has the following chemical structure:

[0140] [ka] It is AMP-CO2CH2-isonicotinoyl-Leu-OMe or a salt thereof.

[0141] In some embodiments, the compound has the following structure:

[0142] [ka] AMP-CO2CH2-isonicotinoyl-Ala or a salt thereof possessing these properties.

[0143] In some embodiments, the compound has the following structure:

[0144] [ka] It is AMP-CO2CH2-isonicotinoyl-Orn or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Orn.

[0145] In some embodiments, the compound has the following structure:

[0146] [ka] AMP-CO2CH2-isonicotinoyl-Val-OMe or a salt thereof has the properties of AMP-CO2CH2-isonicotinoyl-Val-OMe.

[0147] In some embodiments, the compound has the following structure:

[0148] [ka] It is AMP-CO2CH2-isonicotinoyl-Asp or a salt thereof, which has the properties of AMP-CO2CH2-isonicotinoyl-Asp.

[0149] In some embodiments, the compound has the following structure:

[0150] [ka] It is AMP-CO2CH2-isonicotinoyl-Ser or a salt thereof.

[0151] In some embodiments, the compound has the following structure: [ka] It is AMP-CO2CH2-isonicotinoyl-Val or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Val.

[0152] In some embodiments, the compound has the following structure:

[0153] [ka] It is AMP-CO2CH2-isonicotinoyl-N-Me-Ala or a salt thereof that has the following properties:

[0154] In some embodiments, the compound has the following structure:

[0155] [ka] AMP-CO2CH2-isonicotinoyl-Glu or a salt thereof is a compound containing AMP-CO2CH2-isonicotinoyl-Glu.

[0156] In some embodiments, the compound has the following structure:

[0157] [ka] AMP-CO2CH2-isonicotinoyl-Gly-Ala or a salt thereof has the following properties:

[0158] In some embodiments, the compound has the following structure:

[0159] [ka] It is AMP-CO2CH2-isonicotinoyl-Phe or a salt thereof.

[0160] In some embodiments, the compound has the following structure: [ka] It is an AMP-CO2CH2-picolinate (Me) or a salt thereof that has [a specific characteristic].

[0161] In some embodiments, the pharmaceutically acceptable salts of the compound are single salts or mixed salts, one or more of which are acetate, L-aspartate, besilate, bicarbonate, carbonate, D-cansylate, L-cansylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotine Salt, nitrate, orotate, stearate, tosylate, thiocyanate, acetophilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidicate, galactarate, galacturonate, gallate, gentisinate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, me Selected from the group consisting of tansulfonates, myristicates, napadisylates, oleates, oxalates, palmitates, picrinates, pivalates, propions, pyrophosphates, salicylates, salicyl sulfates, sulfosalicylates, tannates, terephthalates, thiosalicylates, tribrophenates, valersates, valproates, adipines, 4-acetamidebenzoates, cansilates, octanoates, estates, esylates, glycolates, thiocyansates, undecylenates, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholineates, lysinium, ammonium, troetamines, and mixtures thereof. ru.

[0162] In some embodiments, the compound is a conjugate of d-amphetamine, and formula IA

[0163] [ka] Having a structure,

[0164] In the equation, X is A-COO-R;

[0165] A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0166] R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroaryl Selected from the group consisting of rukenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0167] In some embodiments, the compound is a conjugate of d-amphetamine, and the formula is IC

[0168] [ka] Having a structure,

[0169] In the formula, X is A-CO-NR 1 R 2 and;

[0170] A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;

[0171] R 1 and R 2Independently, hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, A Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0172] In some embodiments, the compound is a conjugate of d-amphetamine, and formula IIA

[0173] [ka] Having a structure,

[0174] In the formula, R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulf Selected from the group consisting of honyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0175] In some embodiments, the compound is a conjugate of d-amphetamine, and formula IIC:

[0176] [ka] Having a structure,

[0177] In the formula, Y is hydrogen, and A does not exist.

[0178] R1 and R 2 These are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulf Selected from the group consisting of honyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol.

[0179] In some embodiments, the compound is a conjugate of d-amphetamine, IIE:

[0180] [ka] Having a structure,

[0181] In the formula, R is independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylal Selected from the group consisting of coxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxy, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues.

[0182] In some embodiments, the compound is a conjugate of d-amphetamine, and formula IIF:

[0183] [ka] Having a structure,

[0184] In the formula, R 1 and R 2Independently, hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl Selected from the group consisting of polysulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkyl, polyethylene glycol, amino acids, and amino acid residues.

[0185] In some embodiments, the compound is a conjugate of d-amphetamine, and formula I [ka] Having the structure or a pharmaceutically acceptable salt thereof,

[0186] In the formula, X is selected from the group consisting of esters, carboxylic acids, amino acids, amino acid residues, amide groups, and derivatives thereof, and Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycles.

[0187] In some embodiments, the conjugate has the following structure:

[0188]

Chemical formula

[0189] In some embodiments, the conjugate has the following structure:

[0190]

Chemical formula

[0191] In some embodiments, the conjugate has the following structure:

[0192]

Chemical formula

[0193] In some embodiments, the conjugate has the following structure:

[0194]

Chemical formula

[0195] In some embodiments, the conjugate has the following structure:

[0196] [Chemical formula] and is AMP-CO2CH2-isonicotinoyl-Ile or a salt thereof.

[0197] In some embodiments, the conjugate has the following structure:

[0198] [Chemical formula] and is AMP-CO2CH2-isonicotinoyl-Thr or a salt thereof.

[0199] In some embodiments, the conjugate has the following structure:

[0200] [Chemical formula] and is AMP-CO2CH2-isonicotinoyl-Gly or a salt thereof.

[0201] In some embodiments, the conjugate has the following structure:

[0202] [Chemical formula] and is AMP-CO2CH2-isonicotinoyl-Sar or a salt thereof.

[0203] In some embodiments, the conjugate has the following structure:

[0204] [Chemical formula] and is AMP-CO2CH2-isonicotinoyl-Leu or a salt thereof.

[0205] In some embodiments, the conjugate has the following structure:

[0206] [ka] AMP-CO2CH2-isonicotinoyl-Pro or a salt thereof possessing these properties.

[0207] In some embodiments, the conjugate has the following structure:

[0208] [ka] AMP-CO2CH2-isonicotinoyl-Ile-OMe or a salt thereof .

[0209] In some embodiments, the conjugate has the following structure:

[0210] [ka] AMP-CO2CH2-isonicotinoyl-Ala-OiPr or a salt thereof is a salt of AMP-CO2CH2-isonicotinoyl-Ala-OiPr.

[0211] In some embodiments, the conjugate has the following structure:

[0212] [ka] It is AMP-CO2CH2-isonicotinoyl-Leu-NH2 or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Leu-NH2.

[0213] In some embodiments, the conjugate has the following chemical structure:

[0214] [ka] It is AMP-CO2CH2-isonicotinoyl-Leu-OMe or a salt thereof.

[0215] In some embodiments, the conjugate has the following structure:

[0216] [ka] AMP-CO2CH2-isonicotinoyl-Ala or a salt thereof possessing these properties.

[0217] In some embodiments, the conjugate has the following structure:

[0218] [ka] It is AMP-CO2CH2-isonicotinoyl-Orn or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Orn.

[0219] In some embodiments, the conjugate has the following structure:

[0220] [ka] AMP-CO2CH2-isonicotinoyl-Val-OMe or a salt thereof has the properties of AMP-CO2CH2-isonicotinoyl-Val-OMe.

[0221] In some embodiments, the conjugate has the following structure:

[0222] [ka] It is AMP-CO2CH2-isonicotinoyl-Asp or a salt thereof, which has the properties of AMP-CO2CH2-isonicotinoyl-Asp.

[0223] In some embodiments, the conjugate has the following structure:

[0224] [ka] It is AMP-CO2CH2-isonicotinoyl-Ser or a salt thereof.

[0225] In some embodiments, the conjugate has the following structure: [ka] It is AMP-CO2CH2-isonicotinoyl-Val or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Val.

[0226] In some embodiments, the conjugate has the following structure:

[0227] [ka] It is AMP-CO2CH2-isonicotinoyl-N-Me-Ala or a salt thereof that has the following properties:

[0228] In some embodiments, the conjugate has the following structure:

[0229] [ka] AMP-CO2CH2-isonicotinoyl-Glu or a salt thereof.

[0230] In some embodiments, the conjugate has the following structure:

[0231] [ka] It is AMP-CO2CH2-isonicotinoyl-Gly-Ala or a salt thereof that has the properties of AMP-CO2CH2-isonicotinoyl-Gly-Ala.

[0232] In some embodiments, the conjugate has the following structure:

[0233] [ka] It is AMP-CO2CH2-isonicotinoyl-Phe or a salt thereof.

[0234] In some embodiments, the conjugate has the following structure: [ka] It is an AMP-CO2CH2-picolinate (Me) or a salt thereof that has [a specific characteristic].

[0235] In some embodiments, the pharmaceutically acceptable salt of the conjugate is a single salt or a mixed salt, one or more salts being acetate, L-aspartate, besilate, bicarbonate, carbonate, D-cansylate, L-cansylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acetulinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate Salt, frate, fusidicate, galactarate, galacturonate, gallate, gentisinate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristicate, napadisylate, oleate, oxalate, palmitate, picrinate, pivalate, propionate, pyrophosphate, salicylic acid Selected from the group consisting of salts, salicyl sulfates, sulfosalicylates, tannates, terephthalates, thiosalicylates, tribrophenates, valers, valproates, adipines, 4-acetamidebenzoates, cansylates, octanoates, estates, esylates, glycolates, thiocyans, undecylenates, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholineates, lysinium, ammonium, troetamines, and mixtures thereof.

[0236] In some embodiments, the amphetamine portion of the conjugate may be d-amphetamine or l-amphetamine. In other embodiments, the composition of the Art comprises a mixture of d-amphetamine conjugates and l-amphetamine conjugates. In further embodiments, the mixture of conjugates may be a racemic mixture. It should be understood that the non-amphetamine portion of the conjugate may also have chiral centers that create additional stereoisomers. The composition of the Art may contain a single stereoisomer or any mixture of stereoisomers.

[0237] In some embodiments, X of the compound or conjugate is located at the C-2 or C-4 position of the pyridine ring. In further embodiments, two or more independently selected X are attached to the pyridine ring at the C-2, C-3, C-4, C-5, and / or C-6 positions. For reasons of symmetry, it should be understood that with respect to a particular substitution pattern of X, C-3 may be equivalent to C-5, and C-2 may be equivalent to C-6. [ka]

[0238] In some embodiments, the composition comprises a conjugate of d-amphetamine. In some embodiments, the composition is formulated for oral, suppository, infusion powder, intravenous, intranasal, or intrathecal administration. In yet another embodiment, the composition formulated for oral administration is in dosage forms selected from the group consisting of solid form, tablets, capsules, caplets, soft gels, suppositories, lozenges, oral powders, solutions, syrups, oral films, thin strips, slurries, emulsions, elixirs, and suspensions. In yet another embodiment, the composition further comprises one or more excipients, the excipients selected from the group consisting of anti-adhesives, binders, coatings, disintegrants, fillers, fragrances, dyes, pigments, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, and combinations thereof. In yet another embodiment, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, and polyethylene glycol, as well as milk derivatives.

[0239] In some embodiments, the conjugate is present in an amount per unit dose between approximately 0.1 mg and approximately 2000 mg. In yet another embodiment, the conjugate is present in an amount per unit dose between approximately 0.1 mg and approximately 1000 mg. In yet another embodiment, the conjugate is present in an amount per unit dose between approximately 0.5 mg and approximately 500 mg. In yet another embodiment, the conjugate is present in an amount per unit dose between approximately 1 mg and approximately 250 mg. In yet another embodiment, the conjugate is present in an amount per unit dose between approximately 1.5 mg and approximately 100 mg. In yet another embodiment, the conjugate is present in an amount per unit dose between approximately 0.5 mg and approximately 2000 mg, or approximately 1 mg and approximately 2000 mg, or approximately 2 mg and approximately 2000 mg, or approximately 5 mg and approximately 2000 mg, or approximately 10 mg and approximately 2000 mg, or approximately 20 mg and approximately 2000 mg, or approximately 40 mg and approximately 2000 mg, or approximately 80 mg and approximately 2000 mg, or approximately 160 mg and approximately 2000 mg, or approximately 320 mg and approximately 2000 mg, or approximately 640 mg and approximately 2000 mg, or approximately 1280 mg and approximately 2000 mg.In yet another embodiment, the conjugate is approximately 0.1 mg to approximately 2000 mg per unit dose, or approximately 0.1 mg to approximately 1900 mg per unit dose, or approximately 0.1 mg to approximately 1800 mg per unit dose, or approximately 0.1 mg to approximately 1700 mg per unit dose, or approximately 0.1 mg to approximately 1600 mg per unit dose, or approximately 0.1 mg to approximately 1500 mg per unit dose, or approximately 0.1 mg to approximately 1400 mg per unit dose, or approximately 0.1 mg to approximately 1300 mg per unit dose, or approximately 0.1 mg to approximately 1200 mg, or approximately 0.1 mg to 1100 mg per unit dose, or approximately 0.1 mg to 1000 mg per unit dose, or approximately 0.1 mg to 900 mg per unit dose, or approximately 0.1 mg to 800 mg per unit dose, or approximately 0.1 mg to 700 mg per unit dose, or approximately 0.1 mg to 600 mg per unit dose, or approximately 0.1 mg to 500 mg per unit dose, or approximately 0.1 mg to 400 mg per unit dose, or approximately 0.1 mg to 300 mg per unit dose, or per unit dose. It exists in amounts per unit dose ranging from approximately 0.1 mg to approximately 200 mg, or approximately 0.1 mg to approximately 100 mg per unit dose, or approximately 0.1 mg to approximately 90 mg per unit dose, or approximately 0.1 mg to approximately 80 mg per unit dose, or approximately 0.1 mg to approximately 70 mg per unit dose, or approximately 0.1 mg to approximately 60 mg per unit dose, or approximately 0.1 mg to approximately 50 mg per unit dose, or approximately 0.1 mg to approximately 40 mg per unit dose, or approximately 0.1 mg to approximately 30 mg per unit dose, or approximately 0.1 mg to approximately 20 mg per unit dose, or approximately 0.1 mg to approximately 10 mg per unit dose, or approximately 0.1 mg to approximately 5 mg per unit dose, or approximately 0.1 mg to approximately 1 mg per unit dose.

[0240] In some embodiments, the composition further comprises one or more additional pharmacological substances selected from the group consisting of stimulants, antidepressants, combinations thereof, and their prodrugs. In other embodiments, the composition further comprises one or more of the following: unconjugated amphetamine, unconjugated methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, etoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, or ziprasidone. In other embodiments, the composition further comprises unconjugated amphetamine, its isomers, or amphetamine conjugates. In yet another embodiment, the isomer of the unconjugated amphetamine is unconjugated d-amphetamine. In yet another embodiment, the composition further comprises unconjugated methylphenidate, its isomers, or a methylphenidate conjugate. In yet another embodiment, the isomer of the unconjugated methylphenidate is unconjugated d-methylphenidate. In yet another embodiment, the conjugate of methylphenidate is celdexmethylphenidate.

[0241] In some embodiments, the conjugate is provided in an amount sufficient to provide a similar or reduced AUC compared to unconjugated d-amphetamine when administered orally at an equimolar dose. max It is provided in an amount sufficient to provide. In yet another embodiment, the conjugate has reduced C compared to unconjugated d-amphetamine when administered orally in equimolar doses. maxand provided in an amount sufficient to provide a similar or reduced AUC. In yet another embodiment, intranasal or intravenous administration of at least one conjugate provides a lower AUC and / or Cmax compared to equimolar amounts of unconjugated d-amphetamine. In yet another embodiment, the composition comprising the conjugate provides a longer T150 compared to unconjugated d-amphetamine when administered orally in equimolar doses. max It is provided in an amount sufficient to provide. In another embodiment, the composition containing the conjugate provides similar T when administered orally in equimolar doses compared to unconjugated d-amphetamine. max It is provided in sufficient quantity to serve.

[0242] In some embodiments, the composition containing the conjugate provides reduced abuse potential compared to unconjugated d-amphetamine. In other embodiments, the composition containing the conjugate provides longer T-rates compared to unconjugated d-amphetamine when administered in equimolar doses. max It is provided in an amount sufficient to provide. In another embodiment, the composition containing the conjugate provides similar T when administered in equimolar doses compared to unconjugated d-amphetamine. max It is provided in an amount sufficient to provide. In yet another embodiment, the composition containing the conjugate has an improved safety profile compared to unconjugated d-amphetamine. Some embodiments In this case, the composition containing the conjugate produces reduced or minimal pharmacological activity when administered via parenteral routes. In yet another embodiment, the composition containing the conjugate has reduced plasma or blood concentrations of released d-amphetamine when administered intranasally or intravenously compared to unconjugated d-amphetamine when administered in equimolar amounts.

[0243] In some embodiments, a composition containing a conjugate has a lower AUC and / or C2 with respect to d-amphetamine released from the conjugate compared to equimolar amounts of unconjugated d-amphetamine after intravenous or intranasal administration of the composition to a subject. max In another embodiment, the composition comprising the conjugate provides a longer T with respect to d-amphetamine released from the conjugate, compared to equimolar amounts of unconjugated d-amphetamine after intravenous or intranasal administration of the composition to a subject. max The present invention provides that, in some embodiments, upon administration to a subject, the composition containing the conjugate results in a longer-lasting release of d-amphetamine in the subject compared to the release of d-amphetamine upon administration of an equimolar amount of unconjugated d-amphetamine. In yet another embodiment, the composition containing the conjugate exhibits less variability in inter-subject or intra-subject d-amphetamine plasma concentrations compared to unconjugated d-amphetamine.

[0244] Another aspect of this technology is a composition for treating patients with disorders or conditions requiring stimulation of the patient's central nervous system, which has reduced abuse potential when administered compared to unconjugated d-amphetamine.

[0245] Another aspect of the present technology is a method for treating a patient having a disease, disorder, or condition mediated by controlling, preventing, limiting, or inhibiting the uptake of neurotransmitters, the method comprising administering a pharmaceutically effective amount of a composition comprising the conjugate of the present invention to the patient in need.

[0246] Another aspect of the present technology is a method for treating a patient having a disease, disorder, or condition mediated by an increase in neurotransmitter concentration at synapses, comprising administering a pharmaceutically effective amount of a composition comprising the conjugate of the present invention to the patient in need.

[0247] Another aspect of the present technology is a method for treating a patient having a disorder or condition requiring stimulation of the patient's central nervous system, comprising orally administering a pharmaceutically effective amount of a 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 nervosa, chronic fatigue syndrome, excessive daytime sleepiness, insomnia, schizophrenia, major depressive disorder, narcolepsy, postural orthostatic tachycardia syndrome, Tourette syndrome, neurotic tics, substance use disorder, apathy, depression, neurological disorders, or obesity. In yet 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.

[0248] As those skilled in the art will understand, drug products are considered pharmaceutically equivalent if they contain the same active ingredient(s), are in the same dosage form and route of administration, and have the same strength or concentration. Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or official or other applicable standards (i.e., strength, quality, purity, and identity), but they may differ in features such as shape, scoring configuration, release mechanism, packaging, excipients (including colorants, fragrances, and preservatives), expiration date, and, to certain limits, labeling. A substance is considered a therapeutic equivalent only if it is a substance and can be expected to have the same clinical efficacy and safety profile when administered to a patient under the conditions specified on the label. The term "biological equivalent," on the other hand, describes a pharmaceutical equivalent or pharmaceutical substitute product that exhibits equivalent bioavailability when studied under similar experimental conditions.

[0249] According to the techniques described herein, the release of d-amphetamine after oral administration of the compounds of the techniques described herein can occur under desired physiological conditions. Preferably, other routes of administration (e.g., intranasal or intravenous) do not degrade the compound to any recognizable degree. In some embodiments, the reduction of d-amphetamine exposure after intranasal and / or intravenous administration is 50%, 30%, 20%, <10%, etc., of the exposure after intranasal and / or intravenous administration of an equimolar dose of unconjugated d-amphetamine. Preferably, certain compounds or embodiments of the present invention resist amphetamine release via external means (chemical, enzymatic, or otherwise). The degradation ratio of the compound that can be achieved through external means is preferably less than about 50%, or less than about 25%, or less than about 20%, or less than about 10%.

[0250] Embodiments of compounds, compositions, and methods of the techniques described herein may offer reduced likelihood of rebound, reduced likelihood of abuse or addiction, and / or improved stimulant-related toxicity of d-amphetamine.

[0251] The d-amphetamine compounds of the techniques described herein could be used in any condition requiring stimulation of the central nervous system (CNS). These conditions include, for example, attention-deficit hyperactivity disorder (ADHD), attention-deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety, and arousal. D-amphetamine stimulants have also demonstrated usefulness in treating stimulant (e.g., cocaine, methamphetamine) abuse and addiction. D-amphetamine stimulants have also been widely used to improve alertness and combat fatigue in battlefield situations.

[0252] Accordingly, according to certain embodiments, the techniques described herein provide a d-amphetamine composition comprising at least one d-amphetamine compound of the techniques of the present invention.

[0253] One embodiment is a composition comprising the d-amphetamine compound of the present technology, which can prevent behavioral deterioration caused by d-amphetamine administration.

[0254] Another embodiment is a composition that enables lower doses of the active pharmaceutical ingredient containing the d-amphetamine compound of the present technology.

[0255] Other formulations according to one or more embodiments of this technology include, but are not limited to, lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oil, talc, polyethylene glycol, and mineral oil; Emerald Green Lake, FD&C Red No. 40, FD&C Yellow Colorants such as No. 6, D&C Yellow No. 10, or FD&C Blue No. 1, and various other certified colorants (see 21 CFR, Part 74); binders such as sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone polyethylene glycol, pullulan, and corn syrup; lubricants such as colloidal silicon dioxide and talc; surfactants such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalcol, and quaternary ammonium salts; preservatives and stabilizers; lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, It may further contain excipients such as maltose, xylitol, sorbitol, chlorides, sulfates, and potassium, sodium, and magnesium phosphates; and / or any other pharmaceutical additives known to those skilled in the art.

[0256] The d-amphetamine composition of this technology may be manufactured according to any suitable method known to those skilled in the art in the field of pharmaceutical manufacturing.

[0257] It should be noted that the above-mentioned additives are not necessary for the d-amphetamine composition of this technology to have sustained-release in vivo properties. The d-amphetamine compound of this technology is chemically stable to prevent denaturation or removal of d-amphetamine before oral administration. Furthermore, the controlled release of d-amphetamine upon oral administration of the d-amphetamine compound of this technology is a designed molecular property and is not related to the formulation. Therefore, the compound of this technology can be easily formulated into various dosage forms. In one or more embodiments of this technology, further sustained-release additives are not required to achieve a blunted or reduced pharmacokinetic curve (e.g., reduced euphoric effect) while achieving therapeutically effective d-amphetamine release upon oral administration.

[0258] The compounds and compositions of the art described herein can be formulated into various dosage forms and administered by various dosage forms via any oral route of delivery. Upon administration, the compounds release d-amphetamine under digestive conditions. Any bioacceptable dosage forms and combinations thereof known to those skilled in the art are intended. Examples of preferred dosage forms, but not limited to, include chewable tablets, fast-dissolving tablets, effervescent tablets, reconstituteable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multilayer tablets, double-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, granules, particles, particulates, dispersible granules, cachets, oral films (e.g., fast-dissolving thin strips), and combinations thereof.

[0259] Formulations of this technology suitable for oral administration can be presented as individual units, such as capsules, caplets, tablets, or oral films. These oral formulations may also include solutions or suspensions in aqueous or non-aqueous liquids. The formulations may be emulsions, such as oil-in-water or water-in-oil emulsions. The oil can be administered by adding a purified and sterilized liquid to a prepared enteral formulation, which can then be placed into a feeding tube for patients who are unable to swallow.

[0260] For example, when a capsule form is selected, the excipients used in the capsule formulation can be divided into four distinct groups: fillers / binders, disintegrants, lubricants, and carriers. Soft gels or soft gelatin capsules may be prepared, for example, by dispersing the formulation of this technology in a suitable vehicle (vegetable oil is commonly used) to form a high-viscosity mixture. This mixture can then be encapsulated in a gelatin-based film using techniques and machinery known to those skilled in the soft gel industry. The industrial units thus formed are then dried to a certain weight.

[0261] For example, chewable tablets may be prepared by mixing the formulation of this technology with excipients designed to form a relatively soft, flavored tablet dosage form intended to be chewed rather than swallowed. Conventional tableting machines and procedures, namely direct compression and pre-compression granulation, i.e., slugging, can be utilized. Individuals involved in the manufacture of solid pharmaceutical dosage forms are familiar with the processes and machinery used for chewable dosage forms, which are very common in the pharmaceutical industry.

[0262] For example, film-coated tablets are made by depositing adjacent film layers onto the tablet. The tablets may be prepared by coating them using techniques such as the rotary pan coating method or the air suspension method.

[0263] For example, compressed tablets may be prepared by mixing the formulation of this technology with excipients intended to add binding quality to the disintegration quality. The mixture can be compressed directly or granulated and then compressed using methods and machinery known to those skilled in the art. The resulting compressed tablet dosing units can then be packaged according to market needs, i.e., in unit doses, rolls, bulk bottles, blister packs, etc.

[0264] Methods and other components necessary for preparing oral film formulations or thin strip formulations are known in the art. Potential film-forming agents include pullulan, hydroxypropyl methylcellulose, hydroxypropylcellulose, 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, levan, elcinan, collagen, gelatin, zein, gluten, soy protein isolates, whey protein isolates, casein, and mixtures thereof.

[0265] Furthermore, salivary stimulants, plasticizers, coolants, surfactants, emulsifiers, thickeners, binders, sweeteners, flavorings, colorants, preservatives, or flavor-correcting resins may be used in oral films or thin strips. Preferred agents include pullulan, triethanolamine stearate, methylcellulose, starch, triacetin, Polysorbate 80, xanthan gum, maltitol, sorbitol, and glycerol.

[0266] The techniques described herein also envision the use of bioacceptable carriers that can be prepared from a wide range of materials. Such materials, though not limited to them, include diluents, binders, and adhesives, lubricants, plasticizers, disintegrants, colorants, bulking agents, flavoring agents, sweeteners, and a variety of other materials, such as buffers and adsorbents, for preparing specific medicinal compositions.

[0267] The binder may be selected from a wide range of materials, including hydroxypropyl methylcellulose, ethylcellulose, or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, milk derivatives such as whey, starch, and derivatives, as well as other conventional binders known to those skilled in the art. Exemplary non-limiting solvents include water, ethanol, isopropyl alcohol, methylene chloride, or mixtures and combinations thereof. Exemplary non-limiting bulking materials include sugars, lactose, gelatin, starch, and silicon dioxide.

[0268] Preferred plasticizers may be selected from the group consisting of, but are not limited to, diethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid, propylene glycol, butyl phthalate, dibutyl sebacate, castor oil, and mixtures thereof. As is obvious, plasticizers may be hydrophobic and 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. In contrast, hydrophilic plasticizers are used when water-insoluble vitamins are used, to help dissolve the encapsulation film, create channels on the surface, and facilitate the release of the nutrient composition.

[0269] In particular, it should be understood that, in addition to the ingredients mentioned above, formulations of this technology may also contain other appropriate agents such as flavorings, preservatives, and antioxidants. Such antioxidants are found in food. These may include, for example, vitamin E, carotene, BHT, or other antioxidants known to those skilled in the art.

[0270] Other compounds that may be included are, for example, medically inert ingredients, such as solid and liquid diluents, such as lactose, dextrose, saccharose, cellulose, starch, or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules, and water or vegetable oil for suspensions or emulsions; lubricants, such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; gelling agents, such as colloidal clay; thickeners, such as tungsten. Gacantho gum or sodium alginate; binding agents, such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrating agents, 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 adjuncts that are known additives to such preparations, such as humectants, preservatives, buffers, and antioxidants.

[0271] For oral administration, fine powders or granules containing diluents, dispersants, and / or surfactants may be present in liquid medicine (draught), liquid or syrup, capsules, or in a dry state. It may be presented in a sachet, in a non-aqueous suspension which may contain a suspending agent, or as a suspension of an aqueous or syrup formulation. Flavoring agents, preservatives, suspending agents, thickeners, or emulsifiers may be included if desired or necessary.

[0272] Liquid dispersants for oral administration may be syrups, emulsions, or suspensions. Syrups may contain, for example, saccharose, or saccharose together with glycerol and / or mannitol and / or sorbitol as a carrier. Suspensions and emulsions may contain a carrier such as natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0273] The dosage range for adults depends on several factors, including the patient's age, weight, and condition. Appropriate oral doses of the compositions of the techniques described herein can be equivalent to those typically seen in d-amphetamine treatments. Typical doses for d-amphetamine salts may range from approximately 1 mg to 500 mg, or approximately 1 mg to 400 mg, or approximately 1 mg to 300 mg, or approximately 1 mg to 200 mg, or approximately 1 mg to 100 mg, although higher doses may be approved at a later date.

[0274] Tablets, capsules, oral films, and other forms provided in individual units conveniently contain one or more daily doses or appropriate proportions of the compounds of the present invention.

[0275] The dosage forms of this technology can also be combined with any form of release known to those skilled in the art. These conventional release forms include immediate release, long-term release, pulsed release, variable release, controlled release, timed release, sustained release, delayed release, long-acting release, and combinations thereof. The ability to obtain immediate release, long-term release, pulsed release, variable release, controlled release, timed release, sustained release, delayed release, long-acting features, and combinations thereof is known in the art.

[0276] The composition of this technology may be administered in part, i.e., in divided doses, once or more times within a 24-hour period, as a single dose, a double dose, or more than a double dose within a 24-hour period. Divided, double, or other multiple doses may be taken simultaneously or at different times within a 24-hour period. Doses may be administered at different times. The dosage may be uneven for all or for each individual component.

[0277] Similarly, the compositions of the present technology may be provided in blister packs or other such pharmaceutical packaging. Furthermore, the compositions of the present technology may further include, or be accompanied by, indicators that enable an individual to identify the composition as a product for a prescribed treatment. The indicators may further include instructions for the above-specified period for administering the composition. For example, the indicators may be indicators indicating a specific or general time for administering the composition, or the indicators may be indicators of dates indicating the day of the week for administering the composition. The blister packs or other combination packaging may also contain a second pharmaceutical product.

[0278] It is understood that the pharmacological activity of the compositions of this technology can be demonstrated using standard pharmacological models known in the art. Furthermore, it is understood that the compositions of this technology can be incorporated into polymer matrices or membranes suitable for site-directed delivery, encapsulated, or functionalized with specific target agents that can result in site-directed delivery. These techniques, as well as other drug delivery techniques, are well known in the art.

[0279] In one or more embodiments of this technology, the solubility and dissolution rate of the composition can be substantially altered under various physiological conditions encountered, for example, in the intestines, on mucosal surfaces, or in the bloodstream. In one or more embodiments of this technology, the solubility and dissolution rate of the composition can substantially reduce the bioavailability of d-amphetamine, particularly at doses exceeding the dose intended for therapeutic purposes. In one embodiment of this technology, the reduction in bioavailability occurs during intranasal administration. In another embodiment, the reduction in bioavailability occurs during intravenous administration.

[0280] The techniques described herein further provide methods for altering and / or delivering amphetamines in a manner that can reduce their potential for abuse.

[0281] One embodiment provides a method for preventing behavioral deterioration or rebound effects by administering the d-amphetamine composition of the present technology to a patient in need.

[0282] Another aspect of the present technology is a method for reducing or preventing the abuse of d-amphetamine, the method comprising providing, administering, consuming or prescribing a composition to a patient in need thereof, wherein the composition contains the d-amphetamine compound of the present invention such that the pharmacological activity of d-amphetamine is reduced if the composition is used in a manner inconsistent with the manufacturer's instructions for use.

[0283] Another aspect of the present technology is a method for preventing behavioral deterioration or rebound effects from d-amphetamine or stimulant treatment, the method comprising providing, administering, consuming or formulating a d-amphetamine composition of the technology described herein to a subject in need thereof, wherein the composition comprises a d-amphetamine compound of the present invention that can reduce the possibility of behavioral deterioration or rebound effects from d-amphetamine or stimulant treatment.

[0284] Another aspect of the present technology is any of the preceding methods, wherein the d-amphetamine composition used is adapted for oral administration, and the d-amphetamine is resistant to the release of d-amphetamine from the organic acid moiety when the composition is administered parenterally, such as intranasally or intravenously.

[0285] Another aspect of this technology is a method for treating various diseases or conditions requiring stimulation of the central nervous system (CNS), which may be prescribed as needed for each disease or condition. The present invention provides a method comprising administering a compound or composition of the present technology that further contains an activator.

[0286] In one embodiment, a composition comprising a d-amphetamine compound, a salt thereof, or a combination thereof provides immediate and long-release PK profiles compared to unconjugated d-amphetamine.

[0287] A further embodiment of the present technology is a kit comprising individual doses of therapeutically effective amounts of a composition comprising a d-amphetamine compound, a conjugate thereof, a salt thereof, or a combination thereof. In some embodiments, the kit is contained in a unit dose pack.

[0288] In one aspect of the present invention, an amphetamine conjugate, compound, and / or composition has an increased d-amphetamine plasma concentration compared to lisdexamfetamine dimesylate (or amphetamine sulfate) after oral administration for at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 6 hours. In another aspect of the present invention, an amphetamine conjugate, compound, and / or composition has a decreased d-amphetamine plasma concentration compared to d-amphetamine sulfate and a similar d-amphetamine plasma concentration compared to lisdexamfetamine dimesylate after oral administration for at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 6 hours. In yet another aspect of the present invention, an amphetamine conjugate, compound, and / or composition of the present invention has a decreased d-amphetamine plasma concentration after intravenous or intranasal administration compared to lisdexamfetamine dimesylate or amphetamine sulfate for at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 6 hours.

[0289] The technology and its advantages described herein will be better understood by referring to the following examples and / or schemes. These examples and / or schemes are provided to describe specific aspects of the technology. By providing these specific examples and / or schemes, the applicant does not limit the scope and spirit of the technology. [Examples]

[0290] General synthesis procedure: [ka]

[0291] Amphetamine hemisulfate 1 was converted to chloromethyl carbamate 2 by adding chloromethyl chloroformate. The chloromethyl carbamate of amphetamine 2 and their respective pyridine derivatives were heated in acetone or acetonitrile with or without NaI to obtain amphetamine conjugates. Subsequent deprotection was performed as applicable. , it may be necessary.

[0292] Specific steps:

[0293] 1. Synthesis of AMP-CO2CH2-isonicotinates 3a-e:

[0294] Table 1: Structure of conjugates 3a-e [Table 1]

[0295] [ka]

[0296] Scheme 1: (a) ClCH2COCl, DIPEA, DCM; (b) Isonicotinate, Acetonitrile, 80-85°C

[0297] a) Synthesis of AMP-CO2-CH2-isonicotinate (tBu) 3a and AMP-CO2-CH2-isonicotinate 3e:

[0298] [ka]

[0299] Step 1: Chloromethyl carbamate of amphetamine, ClCH2OCO-AMP 2:

[0300] [ka]

[0301] D-amphetamine hemisulfate (4.640 g, 25.18 mmol) in DCM (80 mL) was cooled in an ice bath. DIPEA (8.136 g, 62.95 mmol) was added. Then, chloromethyl chloroformate (4.221 g, 32.74 mmol) in DCM (20 mL) was added over 15 minutes. The reaction mixture was warmed to room temperature over 30 minutes, and then stirred for a further 1.5 hours. The reaction was then quenched by adding 5% aqueous NH4Cl (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 obtain 4.9 g of syrup, which solidified when stored in a freezer. The yield was 85.5%.

[0302] Step 2: AMP-CO2CH2-isonicotinate (tBu)3a:

[0303] Chloromethyl 2-carbamate (0.342 g, 1.5 mmol) and t-butyl isonicotinate (0.806 g, 4.5 mmol) of amphetamine were heated in acetonitrile (10 mL) at 80-85°C for 8 hours. The solvent was evaporated. The residue was dissolved in DCM (1.5 mL) and TBME (60 mL) was added. The upper layer was decanted. The remaining syrup was treated twice using the above procedure and then vacuum-dried to obtain 0.462 g of amorphous solid. The yield was 76%.

[0304] Step 3: AMP-CO2-CH2-Isonicotinic acid 3e:

[0305] [ka]

[0306] Scheme 2: (a) 4M HCl / Dioxane

[0307] 3a (0.300 g, 0.74 mmol) was stirred in 4M HCl / dioxane (8 mL) for 21 hours. The solvent was evaporated to obtain a solid, which was then simultaneously evaporated with DCM (15 mL x 2) and vacuum-dried. The obtained solid was dissolved in ethanol (5.5 mL) and TBME (15 mL) was added. The formed precipitate was collected after 4 hours, washed with TBME / ethanol (4:1, 1 mL x 3), and vacuum-dried. 0.146 g of solid was obtained, with a yield of 56%.

[0308] b) Conjugates 3b to d were prepared using the same synthesis method as 3a.

[0309] 2. Synthesis of AMP-CO2CH2-isonicotinamide 4a and 4b:

[0310] [ka] [ka]

[0311] Scheme 3: (a) Nicotinamide, NaI, acetone, then Dowex 1×8

[0312] a) Synthesis of AMP-CO2CH2-isonicotinoylmorpholine 4b:

[0313] [ka]

[0314] N-isonicotinoylmorpholine (0.135 g, 0.7 mmol), ClCH2OCO-AMP2 (0.188 g, 0.826 mmol), and NaI (0.113 g, 0.756 mmol) were refluxed in acetone (8 mL) for 1 hour. The solid was filtered off. The filtrate was concentrated to dryness and then dissolved in EtOH (6 mL). The solution was treated twice with a Dowex 1×8 filter (200-400 ohms, Cl form, 1 g and 0.5 g). The filtrate after resin treatment was concentrated and vacuum-dried to obtain 0.278 g of 4b as an amorphous solid. The yield was 94%.

[0315] b) Conjugate 4a was prepared using the same synthesis method as 4b, with a yield of 84%.

[0316] 3. Synthesis of conjugate AMP-CO2CH2-isonicotinoyl-amino acids or AMP-CO2CH2-isonicotinoyl-peptides 5a-y:

[0317] [ka]

[0318] Table 2: Structure of conjugates 5a-5y [Table 2-1] [Table 2-2]

[0319] a) Synthesis of AMP-CO2CH2-isonicotinoyl-Thr 5s: [ka]

[0320] Scheme 4: (a) TEA / DCM; (b) 7s, NaI, acetone; (c) 4M HCl / dioxane, then Dowex 1×8, preparative HPLC

[0321] Step 1: Isonicotinol-Thr(tBu)-OtBu 7s:

[0322] Et3N (1.062 g, 10.5 mmol) was added to Ot-butyl-threonine t-butyl ester (H-Thr(tBu)-OtBu, 0.694 g, 3 mmol) in DCM (50 mL). Isonicotinol chloride hydrochloride (0.801 g, 4.5 mmol) was added in four portions over 15 minutes in a water bath (room temperature). The reaction mixture was stirred for 2 hours. Subsequently, the reaction was quenched by adding 5% aqueous NH4Cl (20 mL). The DCM layer was dried over Na2SO4. The product was purified by silica gel column chromatography (4% MeOH / DCM). 0.894 g of 7s was obtained as syrup. The yield was 88.6%.

[0323] Step 2: AMP-CO2CH2-Isonicotinol-Thr 5s:

[0324] Isonicotinol-Thr(tBu)-OtBu 7s (0.269 g, 0.8 mmol), ClCH2OCO-AMP 2 (0.219 g, 0.96 mmol), and NaI (0.138 g, 0.92 mmol) were refluxed in acetone (10 mL) for 1.5 hours. The solid was filtered off. The filtrate was concentrated and purified by silica gel column chromatography (siRNA, followed by 8% MeOH / DCM) to obtain an amorphous solid. This solid was then treated with 4M HCl / dioxane (10 mL) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated to dryness, and the mixture was vacuum-dried for 1 hour. The resulting residue was dissolved in 8 mL of ethanol and treated with Dowex 1×8 (200-400, Cl form, 1.2 g). After resin treatment, the filtrate was concentrated and further purified by preparative HPLC, and 0.133 g of 5s was obtained as an amorphous solid. It was obtained. The yield was 37%.

[0325] b) Synthesis of AMP-CO2CH2-isonicotinoyl-Ile 5t: [ka]

[0326] Scheme 5: (a) TEA / DCM; (b) 7t, NaI, acetone; (c) 4M HCl / dioxane, then Dowex 1×8

[0327] Step 1: Isonicotinol-Ile-OtBu 7t:

[0328] Et3N (1.821 g, 18 mmol) was added to isoleucine tert-butyl ester HCl (H-Ile-OtBu HCl, 0.671 g, 3 mmol) in DCM (50 mL). Isonicotinol chloride hydrochloride (0.961 g, 5.4 mmol) was added to a water bath (room temperature) in four portions over 15 minutes. The reaction mixture was stirred for 2 hours. Subsequently, the reaction was quenched by adding 5% aqueous NH4Cl (20 mL). The DCM layer was dried over Na2SO4. The product was purified by silica gel column chromatography (4-5% MeOH / DCM). 0.780 g of 7 tons was obtained as syrup. The yield was 90%.

[0329] Step 2: AMP-CO2CH2-Isonicothinoyl-Ile 5t:

[0330] Isonicotinol-Ile-OtBu 7t (0.234 g, 0.8 mmol), ClCH2OCO-AMP 2 (0.219 g, 0.96 mmol), and NaI (0.138 g, 0.92 mmol) were refluxed in acetone (10 mL) for 1.5 hours. The solid was filtered off. The filtrate was concentrated to obtain a solid. 15 mL of siRNA / hexane (2:1) was added to the solid. The solid was collected, washed with siRNA / hexane (2:1, 2 mL x 2), and vacuum dried. The solid in 4 M HCl / dioxane (8 mL) was stirred at room temperature for 4 hours. The solvent was evaporated to dryness, and the mixture was vacuum-dried to obtain an amorphous solid. This solid was dissolved in 6 mL of ethanol and treated twice with a Dowex 1×8 filter (200-400 ethanol, Cl form, 1 g and 0.5 g). The filtrate was concentrated after resin treatment and vacuum-dried to obtain 0.337 g of 5t as an amorphous solid. The yield was 86%.

[0331] c) Conjugates 5a-5r and 5u-5y were synthesized using the same procedure as for 5s and 5t.

[0332] 4. Synthesis of the conjugate AMP-CO2CH2-isonicotinoyl-amino acid esters 9a~9h:

[0333] Table 3: Structure of conjugates 9a-9h [Table 3-1] [Table 3-2]

[0334] a) AMP-CO2CH2-Isonicotinol-Leu-OMe 9a: [ka]

[0335] Scheme 6: (a) TEA / DCM; (b) 10a, NaI, acetone, then Dowex 1×8

[0336] Step 1: Isonicotinol-Leu-OMe 10a:

[0337] 10a was prepared using the same procedure as 7t, and purified by silica gel chromatography column (7% MeOH / DCM) to obtain 0.212 g of syrup (1 mmol scale). The yield was 84.7%.

[0338] Step 2: AMP-CO2-CH2-Isonicotinol-Leu-OMe 9a:

[0339] Isonicotinol-Leu-OMe 10a (0.212 g, 0.85 mmol), ClCH2OCO-AMP 2 (0.232 g, 1.02 mmol), and NaI (0.147 g, 0.98 mmol) were refluxed in acetone (10 mL) for 1.5 hours. The solid was filtered off. The filtrate was concentrated to dryness and then dissolved in 7 mL of methanol, and treated twice with a Dowex 1×8 filter (200-400 ohms, Cl form, 1 g and 0.5 g). The filtrate was concentrated after resin treatment and vacuum-dried to obtain 0.381 g of 9a as an amorphous solid. The yield was 94%.

[0340] b) Conjugates 9b to 9h were synthesized using the same procedure as in 9a.

[0341] 5. Synthesis of conjugates AMP-CO2CH2-isonicotinoyl-amino acid amides and AMP-CO2CH2-nicotinoyl-amino acid amides 11a and 11b:

[0342] Table 4: Structure of conjugates 11a and 11b [Table 4]

[0343] a) Synthesis of AMP-CO2CH2-isonicotinoyl-Val-NH211a: [ka]

[0344] Scheme 7: (a) TEA / DCM; (b) 12a, NaI, acetone, then Dowex 1×8

[0345] Step 1: Isonicotinol-Val-NH212a:

[0346] Valinamide HCl (H-Val-NH2HCl, 0.763 g, 5 mmol) in DCM (60 mL) was mixed with Et3N (3.036 g, 30 mmol). Isonicotinol chloride hydrochloride (1.602 g, 9 mmol) was added in five portions over 20 minutes in a water bath (room temperature). The reaction mixture was stirred for 1 hour. Subsequently, 5% aqueous NH4Cl (20 mL) was added to quench the reaction, and the mixture was stirred for 10 minutes. The DCM was evaporated, leaving the solid in the aqueous solution. The solid was collected by filtration, washed with water (5 mL x 2) and siRNA (3 mL), and vacuum dried. 0.514 g of 12a was obtained. The yield was 46%.

[0347] Step 2: AMP-CO2CH2-Isonicotinoyl-Val-NH211a:

[0348] Isonicotinoyl-Val-NH212a (0.155 g, 0.7 mmol), ClCH2OCO-AMP 2 (0.191 g, 0.84 mmol), and NaI (0.121 g, 0.805 mmol) were refluxed in acetone (8 mL) for 2 hours. The solid was filtered off. The filtrate was concentrated to obtain a solid. 5 mL of siRNA was added to the solid. The solid was collected, washed with siRNA (1 mL × 2), and vacuum-dried. The solid was dissolved in 6 mL of methanol and treated twice with a Dowex 1 × 8 filter (200-400 Hz, Cl form, 1 g and 0.5 g). The filtrate was concentrated after resin treatment and vacuum-dried to obtain 0.247 g of 11a as an amorphous solid. The yield was 78.6%.

[0349] 6. Synthesis of amphetamine double conjugate 13a: [ka]

[0350] a) Synthesis of (AMP-CO2CH2-isonicotinoyl)2-Ser-OMe 13a: [ka]

[0351] Scheme 9: (a) EDCI / DMAP / DCM; (b) 15a, NaI, acetone, then Dowex 1×8

[0352] Step 1: (Isonicotinol) 2-Ser-OMe 15a:

[0353] N-isonicotinoyl serine methyl ester 14a (0.318 g, 1.42 mmol), isonicotinic acid (0.175 g, 1.42 mmol), and DMAP (0.035 g, 0.284 mmol) were added to a 25 mL DCM (water bath) with EDCI (0.327 g, 1.704 mmol) at room temperature. The reaction mixture was stirred for 24 hours. Subsequently, the reaction was quenched by adding 10 mL of 5% aqueous NH4Cl. The DCM layer was dried over Na2SO4. The product was purified by silica gel column chromatography (3-7% MeOH / DCM). 0.342 g of 15a was obtained as an amorphous solid. The yield was 73%.

[0354] Step 2: (AMP-CO2CH2-Isonicotinol)2-Ser-OMe 13a:

[0355] (Isonicotinoyl) 2-Ser-OMe 15a (0.165 g, 0.5 mmol), ClCH2OCO-AMP 2 (0.273 g, 1.2 mmol), and NaI (0.172 g, 1.15 mmol) were refluxed in acetone (12 mL) for 1.5 hours. The solid was filtered off. The filtrate was concentrated to obtain a syrup. 20 mL of siRNA was added to the syrup. The liquid was decanted after shaking the flask for several minutes. The remaining semi-solid was dissolved in 8 mL of methanol and treated with Dowex 1 × 8 (200-400, Cl form, 2 g). The filtrate was concentrated after resin treatment and vacuum-dried to obtain 0.325 g of 13a as an amorphous solid. The yield was 82.8%.

[0356] The conjugate could be in various salt forms other than chloride salts. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0357] In the following embodiments of the present invention, 1 H-NMR and 13 C-NMR was performed using DMSO-d6. The ESI mass spectra were recorded using a Bruker Advance II 500 spectrometer (without internal standards) as the medium. Low-resolution ESI mass spectra were recorded using an Agilent 1290 in cation mode with 0.1% formic acid-water / 0.1% formic acid-acetonitrile as the mobile phase. The data was recorded using HPLC and an Agilent 6420 QQQ triple mass spectrometer. HPLC was performed on an Agilent 1200 Series instrument using a YMC ODS-AQ (C-18, 4.6 × 250 mm, 5 μm, 120 Å) column and 0.1% TFA-water / 0.1% TFA-acetonitrile as the mobile phase. [Table 12-1] [Table 12-2] NA: The compound is amorphous, and its melting point could not be determined.

[0358] (Example 1) Oral pharmacokinetic studies

[0359] d-amphetamine conjugates and comparator compounds of d-amphetamine sulfate or lisdexamfetamine dimesylate were dissolved in a suitable vehicle and administered to rats via oral force-feeding at a dose of 5.6 μmol / kg. Whole blood samples were collected via post-orbital hemorrhage at 0.25, 0.5, 1, 2, 4, and optionally 3 and 6 hours after administration. Blood samples were centrifuged, and plasma samples obtained were collected for analysis of amphetamine concentrations by LC-MS / MS.

[0360] Oral pharmacokinetic plasma concentration-time profiles are shown in Figures 1-17. An overview of oral pharmacokinetic parameters is provided in Tables 5 and 6.

[0361] Table 5: Oral PK parameters for d-amphetamine conjugate administered to rats using a 4-hour time course. [Table 5]

[0362] Table 6: Oral PK parameters for d-amphetamine conjugate administered to rats using a 6-hour time course. [Table 6-1] [Table 6-2]

[0363] Table 7: Oral PK parameters for d-amphetamine conjugate administered to rats using an 8-hour time course. [Table 7]

[0364] (Example 2) Intravenous pharmacokinetic studies

[0365] d-amphetamine conjugates and comparator compounds of d-amphetamine sulfate or lisdexamfetamine dimesylate were dissolved in a suitable vehicle and administered to rats at a dose of 5.6 μmol / kg by injection of the solution into the tail vein. Whole blood samples were collected via post-orbital hemorrhage 5 minutes after administration, and at 0.25, 0.5, 1, and 2 hours later. Blood samples were centrifuged, and plasma samples obtained were collected for analysis of levorphanol concentration by LC-MS / MS.

[0366] The intravenous pharmacokinetic d-amphetamine plasma concentration-time profiles are shown in Figures 18-26. A summary of the intravenous pharmacokinetic parameters of d-amphetamine is provided in Table 8.

[0367] Table 8: Intravenous PK parameters for d-amphetamine conjugate administered to rats [Table 8]

[0368] (Example 3) Nasal pharmacokinetic studies

[0369] d-amphetamine conjugates and comparator compounds of d-amphetamine sulfate or lisdexamfetamine dimesylate were dissolved in a suitable vehicle and administered to rats at a dose of 5.6 μmol / kg by slowly dropping each drug solution into the nasal cavity alternately. Whole blood samples were collected via post-orbital hemorrhage 5 minutes after administration, and at 0.25, 0.5, and 1 hour later. Blood samples were centrifuged, and plasma samples obtained were collected for analysis of amphetamine concentrations by LC-MS / MS.

[0370] The intranasal pharmacokinetic plasma concentration-time profiles are shown in Figures 27-35. A summary of the intranasal pharmacokinetic parameters is provided in Table 9.

[0371] Table 9: Intranasal PK parameters for d-amphetamine conjugate administered to rats using a 1-hour time course. [Table 9]

[0372] Table 10: Intranasal PK parameters for d-amphetamine conjugate administered to rats using a 4-hour time course. [Table 10]

[0373] Figures 30-32 unexpectedly and non-obviously show that some compounds of the present invention containing an isonicotinoyl moiety result in different and / or improved d-amphetamine exposure after oral, intranasal, and / or intravenous administration in subjects, compared to compounds of the same structure but in which the isonicotinoyl moiety is replaced by a nicotinoyl moiety. For example, Figure 30 shows that d-amphetamine-CO2CH2-isonicotinoyl-Ser provides increased oral bioavailability of d-amphetamine compared to d-amphetamine-CO2CH2-nicotinoyl-Ser. Figure 31 shows that AMP-CO2CH2-isonicotinate(Et) reduces exposure to d-amphetamine after intranasal administration compared to AMP-CO2CH2-nicotinate(Et). Figure 32 shows that AMP-CO2CH2-isonicotinoyl-Val-NH2 reduces d-amphetamine exposure after intravenous administration compared to AMP-CO2CH2-nicotinoyl-Val-NH2.

[0374] Further aspects and embodiments of this technology are described in the following paragraphs.

[0375] Some aspects of the present invention include formula I: [ka] The composition comprises a compound having the structure of the formula or a pharmaceutically acceptable salt of the compound, wherein X is selected from the group consisting of esters, carboxylic acids, amino acids, amino acid residues, amides, and derivatives thereof, and Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle. In another embodiment, the composition comprises the compound or a pharmaceutically acceptable salt of the compound.

[0376] Another aspect is formula IA: [ka] The compound comprises a compound having the structure of or a pharmaceutically acceptable salt of said compound, wherein X is A-COO-R; A is absent or present, if present, is an alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, allulamino, allolaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, a Selected from the group consisting of arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;R stands for 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, aryl cycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxy; The compound is selected from the group consisting of so, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. In another embodiment, the composition comprises the compound or a pharmaceutically acceptable salt of the compound.

[0377] Another aspect is formula IC: [ka] A compound having the structure A-CO-NR or a pharmaceutically acceptable salt of the said compound, where X is A-CO-NR 1 R 2A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol; R 1 and R 2Independently, 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, aryl Aryl sulfinyl, aryl sulfinyl alkyl, aryl sulfonyl, aryl sulfonylamino, aryl thio, aryl thioalkyl, cycloalkenyl, cycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycyclo The compound is selected from the group consisting of rukenyl alkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. In another embodiment, the composition comprises the compound or a pharmaceutically acceptable salt of the compound.

[0378] Another embodiment is one in which A is absent, Y is hydrogen, and the compound is of formula IIA: [ka] A compound having the structure of , or a pharmaceutically acceptable salt of said compound, where R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, aryls Selected from the group consisting of ruffinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. In another embodiment, the composition comprises the compound or a pharmaceutically acceptable salt of the compound.

[0379] Another embodiment is one in which A is absent, Y is hydrogen, and the compound is of formula IIC: [ka] A compound having the structure, a pharmaceutically acceptable salt of the compound, wherein R 1 and R 2These are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, The compounds are selected from the group consisting of arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. In another embodiment, the composition comprises the compound or a pharmaceutically acceptable salt of the compound.

[0380] In one embodiment, the compound is: [ka] [ka] [ka] The structure is selected from the group consisting of the following. In another embodiment, the composition comprises the compound or a pharmaceutically acceptable salt of the compound.

[0381] In another embodiment, any pharmaceutically acceptable salt of the above compound is acetate, L-aspartate, besilate, bicarbonate, carbonate, D-cansilate, L-cansilate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesilate, pamoate, phosphate, succinate, sulfate, bisulfate, D-alcohol Sulfate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acephrine, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, hexanoate, kohl Salts, cypionates, dichloroacetates, edentates, ethyl sulfates, frates, fusidicates, galactarates, galacturonic acid, gallates, gentisinates, glutamates, glutarates, glycerophosphates, heptanoates, hydroxybenzoates, hippurates, phenylpropionates, iodides, xinafoates, lactobionates, laurates, maleates, mandelates, methanesulfons, myristicates, napadisylates Salt, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicyl sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipine, 4-acetamidebenzoate, cansilate, octanoate, estrate, esylate, glycolate, thiocyanate, undecylenate, sodium The group consists of potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, ammonium, troetamine, and mixtures thereof.

[0382] In another embodiment, the compound is: [ka] [ka] [ka] It has a structure selected from the group consisting of the following.

[0383] In another embodiment, the composition comprises the compound or a pharmaceutically acceptable salt of the compound.

[0384] In another embodiment, the composition is formulated for oral or suppository administration. In yet another embodiment, the composition formulated for oral administration is in dosage forms selected from the group consisting of solids, tablets, capsules, caplets, soft gels, suppositories, lozenges, oral powders, solutions, syrups, oral films, thin strips, slurries, emulsions, elixirs, and suspensions. In yet another embodiment, the composition further comprises one or more excipients, the excipients selected from the group consisting of anti-adhesives, binders, coatings, disintegrants, fillers, fragrances, dyes, pigments, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, and combinations thereof. In yet another embodiment, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylate copolymers, pharmaceutical glazes, gums, and milk derivatives.

[0385] In another embodiment, the compound is present in an amount per unit dose between approximately 0.1 mg and approximately 2000 mg. In yet another embodiment, the compound is present in an amount per unit dose between approximately 0.5 mg and approximately 500 mg. In yet another embodiment, the compound is present in an amount per unit dose between approximately 1 mg and approximately 250 mg. In yet another embodiment, the compound is present in an amount per unit dose between approximately 1.5 mg and approximately 100 mg.

[0386] In another embodiment, the composition further comprises one or more additional pharmacological substances selected from the group consisting of stimulants, antidepressants, combinations thereof, and their prodrugs. In another embodiment, the composition further comprises methylphenidate, aripiprazole, and The present invention includes one or more of tomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, etoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, and ziprasidone, or one or more of additional amphetamines, or any combination thereof. In a further embodiment, one or more additional amphetamines are unconjugated amphetamines, amphetamine conjugates, amphetamine prodrugs, any isomers thereof, or any combination thereof. In another embodiment, the isomer of unconjugated amphetamine is unconjugated d-amphetamine. In yet another embodiment, methylphenidate is unconjugated methylphenidate, a conjugate of methylphenidate, a prodrug of methylphenidate, any isomer thereof, or any combination thereof. In yet another embodiment, an isomer of unconjugated methylphenidate is unconjugated d-methylphenidate. In yet another embodiment, a conjugate of methylphenidate is celdexmethylphenidate.

[0387] In one embodiment, 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 embodiment, the compound provides a similar or reduced C2 compared to unconjugated d-amphetamine when administered orally in an equimolar dose. max It is provided in an amount sufficient to provide. In yet another embodiment, the compound is provided in an amount that reduces C compared to unconjugated d-amphetamine when administered orally in equimolar doses. max and provided in an amount sufficient to provide a similar or reduced AUC. In one embodiment, intranasal or intravenous administration of at least one compound results in a reduced AUC and / or C2 compared to equimolar amounts of unconjugated d-amphetamine. max In another embodiment, the compound provides reduced abuse potential compared to unconjugated d-amphemine.

[0388] One aspect of the present invention is a method for treating a patient having a disorder or condition requiring stimulation of the central nervous system, or a patient having a disease, disorder or condition mediated by controlling, preventing, limiting or inhibiting neurotransmitter uptake, or a patient having a disease, disorder or condition mediated by increasing neurotransmitter concentrations in synapses, the method comprising the step of administering a pharmaceutically effective amount of the composition of the present invention to a patient in need thereof.

[0389] In one embodiment, the composition has reduced abuse potential when administered compared to unconjugated d-amphetamine. In another embodiment, the disease or condition is attention-deficit hyperactivity disorder, attention-deficit disorder, autism spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, insomnia, schizophrenia, major depressive disorder, narcolepsy, postural orthostatic tachycardia syndrome, Tourette syndrome, neurotic tics, substance use disorder, apathy, depression, neurological disorder, or obesity.

[0390] One aspect of the present invention is a kit comprising individual doses of therapeutically effective amounts of compositions comprising any compound of the present invention, a pharmaceutically effective salt thereof, or a combination thereof.

[0391] One aspect of the present invention is formula I: [ka] A compound having the structure of or a pharmaceutically acceptable salt of said compound, wherein X is selected from the group consisting of esters, carboxylic acids, amino acids, amino acid residues, amides, and derivatives thereof, and Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle.

[0392] In another embodiment, the pharmaceutically acceptable salts are acetate, L-aspartate, besilate, bicarbonate, carbonate, D-cansilate, L-cansilate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesilate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, Benzoate, gluceptate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acephylline, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, flute, fusidicate, galamine Cutalates, galacturonic acid, gallates, gentisinates, glutamates, glutarates, glycerophosphates, heptanoates, hydroxybenzoates, hippurates, phenylpropionates, iodides, xinafoates, lactobionates, laurates, maleates, mandelates, methanesulfonates, myristates, napadisylates, oleates, oxalates, palmitates, picrinates, pivalates, propions, pyrophosphates, salicylates, salicyl sulfates Selected from the group consisting of salts, sulfosalicylates, tannates, terephthalates, thiosalicylates, tribrophenates, valersate, valproates, adipines, 4-acetamidebenzoates, cansilates, octanates, estates, esylates, glycolates, thiocyansates, undecylenates, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholineates, lysinium, ammonium, troetamines, and mixtures thereof.

[0393] In another embodiment, X is located at the C-2 or C-4 position of the pyridine ring. In yet another embodiment, X is located at two or more of the C-2, C-3, C-4, C-5, or C-6 positions of the pyridine ring. In yet another embodiment, the compound is [ka] It has the structure of [the object].

[0394] In a further embodiment, the compound is [ka] It has the structure, in the formula R, R 1 , or R 2These are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulf The compound is selected from the group consisting of honyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. In yet another embodiment, the compound is [ka] It has the structure of [the object].

[0395] The technologies described herein are described in complete, clear, concise, and precise terms so that those skilled in the art in which they relate can implement them. It should be understood that the foregoing describes preferred embodiments of the invention, and that modifications thereto may be made without departing from the spirit or scope of the invention. The present invention provides, for example, the following items: (Item 1) Formula I: [ka] A compound having the structure of the formula or a pharmaceutically acceptable salt of the said compound, wherein X is selected from the group consisting of esters, carboxylic acids, amino acids, amino acid residues, amides, and derivatives thereof. Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle. A compound or a pharmaceutically acceptable salt of said compound. (Item 2) Formula IA: [ka] A compound described in item 1 having the structure of the said compound, or a pharmaceutically acceptable salt of the said compound, wherein X is A-COO-R; A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol; R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl Selected from the group consisting of polychloropropyl glycol, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. A compound or a pharmaceutically acceptable salt of said compound. (Item 3) Formula IC: [ka] A compound described in item 1 having the structure of the said compound, or a pharmaceutically acceptable salt of the said compound, wherein X is A-CO-NR 1 R 2 and; A is either absent or present, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, Selected from the group consisting of arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol; R 1 and R 2These are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulf Selected from the group consisting of honyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. A compound or a pharmaceutically acceptable salt of said compound. (Item 4) A is absent, Y is hydrogen, and the compound is of formula IIA: [ka] The formula has a structure where R is hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, aryl Selected from the group consisting of polysulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. The compounds listed in item 2, or pharmaceutically acceptable salts of said compounds. (Item 5) A is absent, Y is hydrogen, and the compound is of formula IIC: [ka] It has the structure, in the formula, R 1 and R 2These are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl Selected from the group consisting of polychloroethylene glycol, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. The compounds listed in item 3 or pharmaceutically acceptable salts of said compounds. (Item 6) [ka] [ka] [ka] A compound having a structure selected from the group consisting of the following. (Item 7) The aforementioned pharmaceutically acceptable salts are acetate, L-aspartate, besylate, and bicarbonate. Carbonate, D-cansylate, L-cansylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hibenzate, isethionic acid Salt, malonate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acephyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, frate, fusidicate, galactarate, galacturonate, gallate, gentisinate, Compounds listed in Item 1, selected from the group consisting of glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristicate, napadisylate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicyl sulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipine, 4-acetamidobenzoate, cansylate, octanoate, estrate, esylate, glycolate, thiocyanate, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholineate, lysinium, ammonium, troetamine, and mixtures thereof. (Item 8) [ka] [ka] A compound having a structure selected from the group consisting of the following. (Item 9) A composition comprising the compound described in item 1 or a pharmaceutically acceptable salt of said compound. (Item 10) The composition according to item 9, wherein the composition is formulated for oral or suppository administration. (Item 11) The composition according to item 10, wherein the composition, which is formulated for oral administration, is in a dosage form selected from the group consisting of solid form, tablets, capsules, caplets, soft gels, suppositories, lozenges, oral powders, solutions, syrups, oral films, thin strips, slurries, emulsions, elixirs, and suspensions. (Item 12) The composition according to item 10, wherein the composition further comprises one or more excipients, the excipients being selected from the group consisting of anti-adhesives, binders, coatings, disintegrants, fillers, fragrances, dyes, pigments, lubricants, preservatives, adsorbents, sweeteners, and combinations thereof. (Item 13) The composition according to item 12, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, milk derivatives, and combinations thereof. (Item 14) The composition according to item 9, wherein the compound is present in an amount per unit dose between approximately 0.1 mg and approximately 2000 mg per unit dose. (Item 15) The composition according to item 13, wherein the compound is present in an amount per unit dose between approximately 0.5 mg and approximately 500 mg per unit dose. (Item 16) The composition according to item 15, wherein the compound is present in an amount per unit dose between approximately 1 mg and approximately 250 mg per unit dose. (Item 17) The composition according to item 16, wherein the compound is present in an amount per unit dose between approximately 1.5 mg and approximately 100 mg per unit dose. (Item 18) The composition according to item 9, wherein the composition further comprises one or more additional pharmacological substances selected from the group consisting of stimulants, antidepressants, combinations thereof, and prodrugs thereof. (Item 19) The composition according to item 9, further comprising one or more of methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, etoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, ziprasidone, or one or more additional amphetamines, or any combination thereof. (Item 20) The composition according to item 19, wherein the one or more additional amphetamines are unconjugated amphetamines, amphetamine conjugates, amphetamine prodrugs, any isomers thereof, or any combination thereof. (Item 21) The composition according to item 20, wherein the isomer of the unconjugated amphetamine is unconjugated d-amphetamine. (Item 22) The composition according to item 19, wherein the methylphenidate is unconjugated methylphenidate, a conjugate of methylphenidate, a prodrug of methylphenidate, any isomer thereof, or any combination thereof. (Item 23) The composition according to item 22, wherein the isomer of the unconjugated methylphenidate is unconjugated d-methylphenidate. (Item 24) The composition according to item 22, wherein the methylphenidate conjugate is celdexmethylphenidate. (Item 25) The composition according to item 9, wherein the compound is provided in an amount sufficient to provide a similar or reduced AUC compared to unconjugated d-amphetamine when administered orally in equimolar doses. (Item 26) When the aforementioned compound is administered orally in an equimolar dose, the unconjugated d-amphetamine Compared to min, similar or reduced C max The composition described in item 9, provided in an amount sufficient to provide. (Item 27) The compound showed a reduced C content compared to unconjugated d-amphetamine when administered orally in equimolar doses. max The composition described in item 9, provided in an amount sufficient to provide a similar or reduced AUC. (Item 28) Intranasal or intravenous administration of the aforementioned compound resulted in a reduced AUC and / or C2 compared to equimolar amounts of unconjugated d-amphetamine. max The composition described in item 9, which provides the following. (Item 29) The composition according to item 9, wherein the compound provides reduced abuse potential compared to unconjugated d-amphetamine. (Item 30) A method for treating a patient having a disorder or condition requiring stimulation of the central nervous system, or a patient having a disease, disorder or condition mediated by controlling, preventing, limiting or inhibiting the uptake of neurotransmitters, or a patient having a disease, disorder or condition mediated by increasing the concentration of neurotransmitters in synapses, wherein the method comprises the step of administering a pharmaceutically effective amount of the composition described in item 9 to the patient in need. (Item 31) The method according to item 30, wherein the composition has reduced abuse potential when administered compared to unconjugated d-amphetamine. (Item 32) The method according to item 30, wherein the disease or condition is attention-deficit hyperactivity disorder, attention-deficit disorder, autism spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, insomnia, schizophrenia, major depressive disorder, narcolepsy, orthostatic tachycardia syndrome, Tourette syndrome, neurotic tics, substance use disorder, apathy, depression, neurological disorder, or obesity. (Item 33) A kit comprising individual doses of therapeutically effective amounts of compositions containing the compounds described in item 1, their pharmaceutically active salts, or combinations thereof. (Item 34) Formula I: [ka] A compound having the structure or a pharmaceutically acceptable salt of the said compound, In the formula, X is selected from the group consisting of esters, carboxylic acids, amino acids, amino acid residues, amides, and their derivatives. Y is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle. A compound or a pharmaceutically acceptable salt of said compound. (Item 35) The aforementioned pharmaceutically acceptable salts are acetate, L-aspartate, besilate, bicarbonate, carbonate, D-cansilate, L-cansilate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesilate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluconate Septate, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acephylline, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethylsulfate, frate, fusidicate, galactarate, galactus Glycerinate, gallate, gentisinate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristicate, napadisylate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylate, sulfosalicylate Compounds described in item 34, selected from the group consisting of tannates, terephthalates, thiosalicylates, tribrophenates, valers, valproates, adipines, 4-acetamidebenzoates, cansilates, octanates, estates, esylates, glycolates, thiocyans, undecylenates, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholineates, lysinium, ammonium, troetamines, and mixtures thereof. (Item 36) The compound described in item 34, wherein X is located at the C-2 or C-4 position of the pyridine ring. (Item 37) The compound according to item 34, wherein X is located at two or more positions of the C-2, C-3, C-4, C-5, or C-6 of the pyridine ring. (Item 38) The aforementioned compound, [ka] A compound having the structure described in item 34. (Item 39) The aforementioned compound, [ka] It has the structure, in the formula R, R 1 , or R 2 These are independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, and Compounds described in item 38, selected from the group consisting of arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxy, heteroaryloxy, heteroarylsulfinyl, heterolioarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol. (Item 40) The aforementioned compound, [ka] A compound having the structure described in item 39.

Claims

【Request Item 1】 【Chemistry 115】 A compound having the structure or a pharmaceutically acceptable salt of the said compound, In the formula, R, R1, or R2 can be independently hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, aryl Compounds selected from the group consisting of polycycloalkenylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, and polycycloalkylalkyl, or pharmaceutically acceptable salts of said compounds.

2. The aforementioned pharmaceutically acceptable salts include acetate, L-aspartate, besilate, bicarbonate, carbonate, D-cansilate, L-cansilate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesilate, pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, and gluceptate. Salt, D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acephyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphor carbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethylsulfate, frate, fusidicate, galactarate, galacturonate, gall Glycerinate, gentisinate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristicate, napadisylate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylate, sulfosalicylate, tannate, tereph A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of talates, thiosalicylates, tribrophenates, valersates, valproates, adipines, 4-acetamidebenzoates, cansilates, octanates, estates, esylates, glycolates, thiocyans, undecylenates, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholineates, lysinium, ammonium, troetamine, and mixtures thereof.

3. The aforementioned compound, 【Chemistry 116】 A compound according to claim 1 or 2, having the structure of the compound or a pharmaceutically acceptable salt thereof.

4. A composition comprising the compound described in 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 in a dosage form selected from the group consisting of solid form, tablets, capsules, caplets, soft gels, suppositories, lozenges, troches, oral powders, solutions, syrups, oral films, thin strips, slurries, emulsions, elixirs, and suspensions.

7. The composition according to claim 6, wherein the composition further comprises one or more excipients, the excipients being selected from the group consisting of anti-adhesives, binders, coatings, disintegrants, fillers, fragrances, dyes, pigments, lubricants, preservatives, adsorbents, sweeteners, and combinations thereof.

8. The composition according to claim 7, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and combinations thereof.

9. The composition according to claim 4, wherein the compound is present in an amount per unit dose between 0.1 mg and 2000 mg per unit dose.

10. The composition according to claim 9, wherein the compound is present in an amount per unit dose between 0.5 mg and 500 mg per unit dose.

11. The composition according to claim 10, wherein the compound is present in an amount per unit dose between 1 mg and 250 mg per unit dose.

12. The composition according to claim 11, wherein the compound is present in an amount per unit dose between 1.5 mg and 100 mg per unit dose.

13. The composition according to claim 4, wherein the composition further comprises one or more additional pharmacological substances selected from the group consisting of stimulants, antidepressants, combinations thereof, and prodrugs thereof.

14. The composition according to claim 4, further comprising one or more of methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamillamine, metoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, ziprasidone, or one or more additional amphetamines, or any combination thereof.

15. The composition according to claim 14, wherein the one or more additional amphetamines are unconjugated amphetamines, amphetamine conjugates, amphetamine prodrugs, any isomers thereof, or any combination thereof.

16. The composition according to claim 15, wherein the isomer of the unconjugated amphetamine is unconjugated d-amphetamine.

17. The composition according to claim 16, wherein the methylphenidate is unconjugated methylphenidate, a conjugate of methylphenidate, a prodrug of methylphenidate, any isomer thereof, or any combination thereof.

18. The composition according to claim 17, wherein the isomer of the unconjugated methylphenidate is unconjugated d-methylphenidate.

19. The composition according to claim 18, wherein the methylphenidate conjugate is celdexmethylphenidate.

20. The composition according to claim 4, wherein the compound is provided in an amount sufficient to provide a similar or reduced AUC compared to unconjugated d-amphetamine when administered orally in equimolar doses.

21. When the compound is administered orally in equimolar doses, it exhibits similar or reduced C content compared to unconjugated d-amphetamine. ｍａｘ The composition according to claim 4, provided in an amount sufficient to provide.

22. The compound showed a reduced C content compared to unconjugated d-amphetamine when administered orally in equimolar doses. ｍａｘ The composition according to claim 4, provided in an amount sufficient to provide a similar or reduced AUC.

23. When the aforementioned compound is administered intranasally or intravenously, compared to equimolar amounts of unconjugated d-amphetamine, the AUC and / or C2 levels are reduced. ｍａｘ The composition according to claim 4, which provides the following:

24. The composition according to claim 4, wherein the compound provides reduced abuse potential compared to unconjugated d-amphetamine.

25. The composition according to claim 4 for treating a patient having a disorder or condition requiring stimulation of the central nervous system; the composition according to claim 8 for treating a patient having a disease, disorder or condition mediated by controlling, preventing, limiting or inhibiting neurotransmitter uptake; or the composition according to claim 8 for treating a patient having a disease, disorder or condition mediated by increasing neurotransmitter concentrations in synapses.

26. The composition according to claim 25, wherein the composition has a reduced potential for abuse when administered compared to unconjugated d-amphetamine.

27. The composition according to claim 25, wherein the disease or condition is attention deficit hyperactivity disorder, attention deficit disorder, autism spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, insomnia, schizophrenia, major depressive disorder, narcolepsy, orthostatic tachycardia syndrome, Tourette's syndrome, neurotic tics, substance use disorder, apathy, depression, neurological disorder, or obesity.

28. A kit comprising individual doses of therapeutically effective amounts of a composition comprising the compound described in claim 1, a pharmaceutically acceptable salt thereof, or a combination thereof.

Images