Vinylene phenylethylamines as neurotransmitter releasers

Abstract

The present disclosure provides monoamine neurotransmitter releasers and / or monoamine uptake inhibitor compounds that have biogenic amine transporter activity but lack substantial activity at the 5-HT2 receptor subtype. The phenethylamine compounds or vinylogous phenethylamine compounds of the present disclosure are useful in treating diseases, conditions, and / or disorders mediated by the activity of one or more monoamine neurotransmitters.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 335,191, filed May 12, 2016. The disclosure of such related provisional application is hereby incorporated by reference in its entirety.

[0002] Government Rights in This Invention

[0003] This invention was made with government support under Grant No. R01-12970 awarded by the National Institute on Drug Abuse (NIDA) of the National Institutes of Health. The government has certain rights in this invention.

[0004] field

[0005] The present disclosure relates to phenethylamine compounds (including vinylogous phenethylamines) useful as monoamine neurotransmitter releasers, methods of using phenethylamine compounds in therapeutic or therapeutic regimens, and pharmaceutical compositions containing such compounds.

[0006] Specifically, the present disclosure relates to compounds that are monoamine neurotransmitter releasers capable of functioning as dual dopamine and serotonin (DA / 5HT) releasers or dopamine releasers and serotonin uptake inhibitors. The present disclosure also relates to pharmaceutical compositions comprising one or more dual DA / 5HT releasers or dopamine releasers and serotonin uptake inhibitors, which may also comprise one or more additional therapeutic agents. The present disclosure also relates to methods for treating various diseases, conditions, and / or disorders that respond to administration of dual DA / 5HT releasers or dopamine releasers and serotonin uptake inhibitors, such as substance abuse, depression, and other similar conditions or neurological diseases.

[0007] Description of related art

[0008] The plasma membrane biogenic amine transporter (BAT) regulates neuronal signaling in the central nervous system by transporting previously released monoamine neurotransmitters—dopamine, norepinephrine, and 5-hydroxytryptamine (DA, NE, and 5-HT, transported via DAT (dopamine transporter), NET (norepinephrine transporter), and SERT (5-hydroxytryptamine transporter), respectively—from synapses back to the neuronal cytoplasm. Ligands that interact with BAT are divided into two major categories: reuptake inhibitors and substrate-type releasers. Both types of ligands increase extracellular neurotransmitter concentrations, but act via different mechanisms. Reuptake inhibitors bind to transporters and block transporter-mediated reuptake of neurotransmitters. Substrate-type releasers bind to substrate sites on transporters, are transported to the interior of neurons, and promote neurotransmitter efflux through carrier-mediated exchange. Disturbances in BAT function play an important role in the pathophysiology of many neurological diseases such as depression, anxiety, Parkinson's disease, schizophrenia, and psychostimulant addiction.

[0009] Psychostimulants, such as cocaine and methamphetamine, are addictive drugs that target BAT in the central and peripheral nervous systems to cause various harmful physiological effects in humans. A potential strategy for treating psychostimulant addiction is known as agonist replacement therapy, whereby patients are administered less potent and less addictive stimulant drugs. BAT releasers represent a class of compounds that are evaluated as potential agonist drugs.

[0010] Several studies have demonstrated the ability of S(+)-amphetamine to

[0011]

[0012] It has high selectivity for releasing DA relative to 5-HT, acting as an agonist therapy for stimulant dependence.

[0013] Chronic treatment with S(+)-amphetamine in rhesus monkeys resulted in a selective, dose-dependent reduction in cocaine self-administration compared to food-maintained responding using progressive-ratio, choice, and two-stage regimens. In a double-blind, placebo-controlled clinical trial, treatment with S(+)-amphetamine resulted in a reduction in cocaine use, consistent with other clinical trials testing agonist treatments. However, a significant limitation of the use of S(+)-amphetamine as a drug is its potential for abuse due to activation of mesolimbic dopamine neurons.

[0014] Previous evidence suggests that the loss of both DA and 5-HT is associated with withdrawal symptoms, and that an increase in extracellular 5-HT can counteract the stimulant and reinforcing effects of DA (a dual-deficit model of stimulant addiction). One potential advantage of using dual DA / 5-HT releasers as agonist drugs is their ability to provide the necessary stimulant-like properties (i.e., DA release) for therapeutic efficacy while reducing abuse liability (5-HT release). Thus, multiple lines of evidence suggest that elevated 5-HT can reduce drug-seeking behavior. In vivo studies in rats have revealed that 5-HT release reduces the stimulant effects of amphetamine-type drugs, and for example, fenfluramine (a 5-HT releaser) dose-dependently attenuates cue-reinstated cocaine-seeking behavior. The reduction in drug-seeking behavior observed in rats translates to humans, as fenfluramine significantly reduces cocaine craving in abstinent cocaine-dependent patients. Furthermore, in preliminary clinical trials, co-administration of the anorectic phentermine (DA releaser) and fenfluramine (Fen-Phen) has shown promise in treating cocaine and alcohol dependence, thus supporting the use of dual DA / 5-HT releasers as therapeutic agents. However, Fen-Phen and other similar neurotransmitter releasers also have activities that are often associated with adverse effects.

[0015] There is a need in the art for neurotransmitter releasers and / or uptake inhibitors that are useful in the treatment of substance abuse and provide other therapeutic effects with little or no activity at off-target sites that are typically associated with the adverse effects of known compounds that are effective as neurotransmitter releasers and / or uptake inhibitors.

[0016] Overview

[0017] The present disclosure relates to compounds useful as neurotransmitter releasers and / or uptake inhibitors. Such compounds and pharmaceutical compositions comprising them may have therapeutic benefits in the treatment of obesity, sleep disorders, neurological diseases, depression, anxiety, ADHD, and substance use disorders (including stimulant addiction such as cocaine addiction and methamphetamine addiction, and alcohol addiction). The present disclosure provides pharmaceutical compositions comprising the compounds and methods for synthesizing such compounds. In addition, the present disclosure includes the treatment of diseases, conditions, and / or disorders that respond to the administration of monoamine releasers and / or monoamine uptake inhibitors.

[0018] In one aspect, present disclosure provides phenylethylamine compounds that can work as monoamine neurotransmitter releasers and / or uptake inhibitors. In some respects, compound can work as dual dopamine / 5-hydroxytryptamine (DA / 5HT) releasers. In other aspects, compound can work as a releaser of a transporter and a blocker or uptake inhibitor of another transporter. By way of example, in some aspects, compound can work as dopamine releasers and 5HT uptake inhibitors. In addition, compounds of present disclosure provide therapeutic benefits without substantially any adverse reactions from the activity at 5-hydroxytryptamine-2 receptor subtypes.

[0019] In another aspect, the present disclosure provides phenethylamine compounds according to Formula I:

[0020]

[0021] Where A is C 3-4 Alkynyl or C 2-4 Alkenyl; R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof. Preferably, the compound of Formula I will be able to act as a monoamine neurotransmitter releaser and / or a monoamine uptake inhibitor.

[0022] In another aspect, the present disclosure provides vinylogous phenethylamine compounds according to Formula II:

[0023]

[0024] where R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; R 6 and R 7 Each independently selected from H or C1-3 Alkyl; R 8 Selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof. Preferably, the compound of Formula II will be capable of acting as a monoamine neurotransmitter releaser and / or monoamine uptake inhibitor.

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising a phenethylamine compound according to Formula I or Formula II and a pharmaceutically acceptable carrier.

[0026] In a further aspect, the present disclosure provides methods of treating diseases, conditions and / or disorders that respond to the activity of monoamine transporter uptake inhibitors and / or monoamine transporter substrate-releasing agents, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a phenethylamine compound according to Formula I or Formula II. Such methods provide therapeutic benefit to the subject without substantial adverse effects from activity at serotonin-2 receptor subtypes.

[0027] Detailed description

[0028] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Like numbers refer to like elements throughout.

[0029] The present disclosure provides monoamine neurotransmitter uptake inhibitor and / or releaser compounds that have biogenic amine transporter activity but lack substantial activity at the 5-HT2 receptor subtype.

[0030] In one aspect, the present disclosure provides phenethylamine compounds according to Formula I:

[0031]

[0032] Where A is C 3-4 Alkynyl or C 2-4 Alkenyl; R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0033] In some embodiments, A is C 2-4 In other embodiments, A is C 3-4 Alkynyl, and R 10 and R 11 is H. In another embodiment, R 10 and R 11 Is H and / or R 1 -R 5 At least three of are H. In another embodiment, R 1 -R 5 At least four of are H. In further embodiments, the alkyl group is unsubstituted.

[0034] In another aspect, the present disclosure provides vinylogous phenethylamine compounds according to Formula II:

[0035]

[0036] where R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; R 6 and R 7 Each independently selected from H or C 1-3 Alkyl; R 8 Selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0037] In some embodiments, R 10 and R 11 Is H and / or R 1 -R 5 At least three of are H. In another embodiment, R 1 -R 5 At least four of are H. In further embodiments, the alkyl group is unsubstituted.

[0038] As used herein, the term "alkyl" means a saturated straight or branched chain hydrocarbon group, which may be optionally substituted. In certain embodiments, alkyl refers to a group containing 1 to 3 carbon atoms ("C1-3 alkyl"). In other embodiments, alkyl refers to a group containing 1 to 2 carbon atoms ("C1-2 alkyl"), or a group containing 2 to 3 carbon atoms ("C2-3 alkyl"). In specific embodiments, alkyl refers to methyl, trifluoromethyl, ethyl, propyl, or isopropyl.

[0039] In one embodiment, the vinylogous phenethylamine has the structure of Formula IIa:

[0040]

[0041] The term "optionally substituted" refers to a moiety which optionally contains one or more different substituent groups, such as, by way of possible example, one or more of the following substituent groups, which does not preclude the desired pharmaceutical action: halogen (e.g., Cl, F, Br, and I); haloalkyl (e.g., CF3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, or CF2); CF3; hydroxy; amino; carboxylate; formamido; alkylamino; alkoxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.

[0042] As used herein, the term "alkenyl" refers to an alkyl moiety in which at least one saturated C-C bond is replaced by a double bond. In certain embodiments, alkenyl refers to a group containing 2 to 4 carbon atoms ("C2-4 alkenyl"). In other embodiments, alkenyl refers to a group containing 2 to 3 carbon atoms ("C2-3 alkenyl"), or a group containing 3 to 4 carbon atoms ("C3-4 alkenyl").

[0043] As used herein, the term "alkynyl" refers to an alkyl moiety in which at least one saturated CC bond is replaced by a triple bond. In certain embodiments, alkynyl refers to a group containing 3 to 4 carbon atoms ("C3-4 alkynyl").

[0044] As used herein, the term "alkoxy" refers to a straight or branched chain alkyl group attached by an oxygen atom (i.e., -O-alkyl), wherein alkyl is as described above. In certain embodiments, alkoxy refers to an oxygen-attached group containing from 1 to 3 carbon atoms ("C1-3 alkoxy").

[0045] As used herein, the term "halo" or "halogen" means fluorine, chlorine, bromine, or iodine.

[0046] The term "alkylthio" as used herein refers to a thio group having one or more alkyl substituents, wherein alkyl is as defined above.

[0047] As used herein, the term "amino" refers to a moiety represented by the structure NR2, and includes primary amines, and secondary and tertiary amines substituted with alkyl groups (i.e., alkylamino groups). Thus, R2 can represent two hydrogen atoms, two alkyl moieties, or one hydrogen atom and one alkyl moiety.

[0048] As used herein, the term "derivative" means a compound formed starting from a similar starting compound by attaching another molecule or atom to the starting compound. Furthermore, according to the present disclosure, a derivative encompasses one or more compounds formed starting from a precursor compound by adding one or more atoms or molecules or by combining two or more precursor compounds.

[0049] As used herein, the term "prodrug" means any compound that, when administered to a mammal, is converted in whole or in part to a compound of the present disclosure.

[0050] As used herein, the term "active metabolite" means a physiologically active compound produced by the metabolism of a compound of the present disclosure or a prodrug thereof when such compound or prodrug is administered to a mammal.

[0051] The compound of the present disclosure can be included in a pharmaceutical composition comprising a phenylethylamine compound according to Formula I or Formula II and a pharmaceutically acceptable carrier. Such a pharmaceutical composition can be useful in treating or alleviating a disease, condition or disorder in response to the administration of a monoamine releaser and / or a monoamine uptake inhibitor, without substantially causing undesirable effects. Such a disease, condition or disorder can include obesity, sleep disorders, neurological diseases, depression, anxiety, ADHD and substance use disorders including psychostimulant addiction such as cocaine addiction and methamphetamine addiction and alcohol addiction.

[0052] The term "psychostimulant" refers to a broadly defined class of compounds or drugs that stimulate the central and peripheral nervous systems, producing a range of effects in humans, including cardiovascular stimulation, elevated mood, and reduced sleep needs. At higher doses or after longer periods of use, psychostimulants can lead to a range of disordered thought processes, including severe psychotic episodes. Examples of psychostimulants include cocaine, methamphetamine, methylphenidate, amphetamines, substituted amphetamines, phentermine, diethylpropion, phendimetrazine, benzphetamine, and 3,4-methylenedioxymethamphetamine.

[0053] The term "dual dopamine / 5-hydroxytryptamine (DA / 5HT) releaser" refers to a compound that can act as at least a portion of a substrate-type releaser for both dopamine and 5-hydroxytryptamine. Substrate-type releasers are bound to substrate sites on transporters such as dopamine and 5-hydroxytryptamine transporters, are transported to neuron interior, and promote neurotransmitter outflow by carrier-mediated exchange. Such dual dopamine / 5-hydroxytryptamine (DA / 5HT) releaser compounds can provide the therapeutic effect of stimulant-type releasers, while minimally enhancing because dopamine release provides the stimulant-like properties that are considered to be required for therapeutic efficacy, and 5HT release is considered to reduce abuse tendency. Dual dopamine / 5-hydroxytryptamine (DA / 5HT) releaser compounds can be active in both uptake inhibition and release assays.

[0054] The term "reuptake inhibitor" refers to a compound that binds to a transporter and blocks the transporter-mediated reuptake of a monoamine neurotransmitter.

[0055] As used herein, the term "monoamine" encompasses monoamine neurotransmitters and neuromodulators. Specifically, it is used to refer to dopamine, norepinephrine, and serotonin. Monoamine transporters facilitate the reuptake or reabsorption of these monoamines into the presynapses of an individual.

[0056] As used herein, the terms "therapeutically effective amount" or "therapeutically effective dose" are interchangeable and refer to a concentration of a compound according to the present disclosure, or a biologically active variant thereof, sufficient to elicit the desired therapeutic effect according to the methods of treatment described herein.

[0057] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier conventionally used in the art to facilitate the storage, administration and / or healing effects of a biologically active agent.

[0058] The present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a phenethylamine according to Formula I:

[0059]

[0060] Where A is C 3-4 Alkynyl or C 2-4 Alkenyl; R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0061] The present disclosure also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a vinylogous phenethylamine according to Formula II:

[0062]

[0063] where R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; R 6 and R 7 Each independently selected from H or C 1-3 Alkyl; R 8 Selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0064] The compounds according to Formula I and Formula II are preferably capable of acting as dual dopamine / 5-hydroxytryptamine (DA / 5HT) releasers or as dopamine releasers and 5HT uptake inhibitors. The compounds of the present disclosure are useful in methods for treating or delaying the progression of diseases, conditions and / or disorders that are alleviated by inhibiting monoamine reuptake in a patient or by selectively binding to one or more monoamine transporters.

[0065] As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, alleviate, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition.

[0066] As used herein, the term "subject" refers to a human or any non-human animal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). In many embodiments, the subject is a human. The subject can be a patient, which refers to a human being presented to a medical provider for diagnosis or treatment of a disease, condition, and / or disorder. The terms "subject" and "individual" or "patient" are used interchangeably herein. A subject may be suffering from or afflicted with a disease, condition, or disorder, but may or may not display symptoms of the disease, condition, or disorder.

[0067] The present disclosure specifically provides methods of treating diseases, conditions, or disorders that are responsive to monoamine transporter uptake inhibitors and / or monoamine transporter substrate-releasing agents, comprising administering to a subject in need thereof a therapeutically effective amount of a phenethylamine compound according to Formula I or Formula II, or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0068] The compounds of the present disclosure avoid the effects of the previously known monoamine transporter uptake inhibitors and / or monoamine transporter substrate-releasing agents on the 5HT receptors, particularly on the 5HT 2b Receptors and 5HT 2a This lack of substantial activity at "off-target" sites allows for the reduction or attenuation of adverse reactions from administering the monoamine transporter uptake inhibitors and / or monoamine transporter substrate-releasing agents disclosed herein to a subject in need of treatment for a disease, condition, and / or disorder that can be modulated by activity at a biogenic amine transporter.

[0069] Diseases, conditions and / or disorders to be treated with the phenylethylamines of the present disclosure may include obesity, sleep disorders, neurological diseases, depression, anxiety, ADHD, and substance use disorders (including stimulant addiction such as cocaine addiction and methamphetamine addiction, and alcohol addiction). In embodiments, the condition or disorder is stimulant addiction, more specifically, psychostimulant addiction.

[0070] In one aspect of the present disclosure, there is provided a method of treating psychostimulant addiction, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the structure of Formula I:

[0071]

[0072] Where A is C 3-4 Alkynyl or C 2-4 Alkenyl; R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0073] In another aspect of the present disclosure, there is provided a method of treating psychostimulant addiction, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the structure of Formula II:

[0074]

[0075] where R 6 and R 7 Each independently selected from H or C 1-3 Alkyl, and R 8 Selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0076] The phenylethylamine compounds disclosed herein as active agents may contain chiral centers that may be in the (R) configuration or the (S) configuration, or may contain mixtures thereof. Therefore, the present disclosure also includes stereoisomers of the compounds described herein, where applicable, individually or mixed in any proportion. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques by reacting enantiomeric starting materials, or by separating isomers of the compounds disclosed herein. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis-isomers or trans-isomers that span a double bond. Other isomers are contemplated in the compounds of the present disclosure. Isomers may be used in pure form or in admixture with other isomers of the compounds described herein.

[0077] Various methods for preparing optically active forms and determining activity are known in the art. Such methods include the standard assays described herein and other similar assays well known in the art. Examples of methods that can be used to obtain optical isomers of compounds according to the present disclosure include the following:

[0078] i) physical separation of crystals, whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used specifically when crystals of the individual enantiomers are present (i.e., the material is a conglomerate) and the crystals are visually distinct;

[0079] ii) simultaneous crystallization, whereby the individual enantiomers are crystallized separately from a solution of the racemate, which is only possible if the racemate is an aggregate in the solid state;

[0080] iii) enzymatic resolution, whereby racemates are partially or completely separated by virtue of the different rates for the reaction of the enantiomers with an enzyme;

[0081] iv) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure synthetic precursor or an enantiomerically enriched synthetic precursor of the desired enantiomer;

[0082] v) chemical asymmetric synthesis, whereby the desired enantiomer is synthesized from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

[0083] vi) diastereoisomer separation, whereby the racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization on the basis of their now more distinct structural differences, and the chiral auxiliary is later removed to obtain the desired enantiomer;

[0084] vii) primary and secondary asymmetric transformations whereby diastereomers from the racemate equilibrate to give rise to a preponderance in solution of the diastereomer from the desired enantiomer, or whereby preferential crystallization of the diastereomer from the desired enantiomer disturbs the equilibrium so that ultimately, in principle, all of the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then liberated from the diastereomers;

[0085] viii) kinetic resolution, including the partial or complete resolution (or further resolution of partially resolved compounds) of racemates by means of unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions;

[0086] ix) enantiospecific synthesis from non-racemic precursors, whereby the desired enantiomer is obtained from achiral starting materials and wherein the stereochemical integrity is not compromised or only minimally compromised during the synthesis;

[0087] x) Chiral liquid chromatography, whereby the enantiomers of the racemate are separated in a liquid mobile phase by virtue of their different interactions with the stationary phase. The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce different interactions;

[0088] xi) chiral gas chromatography, whereby the racemate is volatilized and the enantiomers are separated by means of their different interactions in the gaseous mobile phase with a column containing a stationary non-racemic chiral adsorbent phase;

[0089] xii) extraction using a chiral solvent, whereby enantiomers are separated by virtue of preferential solubility of one enantiomer in a particular chiral solvent; and

[0090] xiii) Transport across a chiral membrane, whereby the racemate is placed in contact with a membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force, such as a concentration or pressure difference, results in preferential transport across the membrane barrier. The separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass.

[0091] Optionally, the compound can be provided in an enantiomerically enriched composition, e.g., a mixture of enantiomers in which one enantiomer is present in excess, particularly to the extent of 60% or more, 75% or more, 90% or more, 95% or more, or 98% or more, including 100%.

[0092] The compounds of the present disclosure may be used per se or in the form of pharmaceutically acceptable esters, amides, salts, solvates, prodrugs, or isomers. For example, the compounds may be provided as pharmaceutically acceptable salts. If used, salts of pharmaceutical compounds should be both pharmacologically acceptable and pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be conveniently used to prepare the free active compound or its pharmaceutically acceptable salt and are not excluded from the scope of the present disclosure.

[0093] Such pharmacologically acceptable salts and pharmaceutically acceptable salts can be prepared by the reaction of drugs with organic or inorganic acids, using the standard methods described in detail in the literature. Examples of pharmaceutically acceptable salts of compounds useful according to the present disclosure include acid addition salts. However, salts of non-pharmaceutically acceptable acids can be useful, for example, in the preparation and purification of compounds. Suitable acid addition salts according to the present disclosure include organic and inorganic acids. Preferred salts include those formed by hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and isethionic acid. Other useful acid addition salts include propionic acid, glycolic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, and the like. Specific examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0094] While the compounds of the present disclosure can be administered in their original chemical form, it is preferred that the compounds be delivered as pharmaceutical formulations. Accordingly, the present disclosure provides pharmaceutical compositions comprising at least one compound capable of acting as a dual DA / 5-HT releaser or a DA releaser and 5HT reuptake inhibitor. Thus, the formulations of the present disclosure comprise a compound of Formula I or a compound of Formula II, as described above, or a pharmaceutically acceptable ester, amide, salt, or solvate thereof, and one or more pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

[0095] "Pharmaceutically acceptable carrier" is intended to be a carrier conventionally used in the art to facilitate storage, administration, and / or healing effects of an agent. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not overly harmful to the recipient thereof. The carrier may also reduce any undesirable side effects of the agent. Such carriers are known in the art.

[0096] The adjuvant or auxiliary component used in the preparation of the present disclosure can include any pharmaceutical ingredient generally considered to be acceptable in this area, such as adhesive, filler, lubricant, disintegrant, diluent, surfactant, stabilizer, preservative, flavoring and coloring agent, and analog. Compositions can also include diluent, buffer, adhesive, disintegrant, thickening agent, lubricant, preservative (including antioxidant), flavoring, masking agent, inorganic salt (such as sodium chloride), antimicrobial (such as benzalkonium chloride), sweetener, antistatic agent, surfactant (such as, from BASF available polysorbate such as " Tween 20 " and " Tween 80 ", and pluronics such as F68 and F88), dehydrated sorbitol ester, lipid (such as, phospholipid such as lecithin and other phosphatidylcholines, phosphatidylethanolamine, fatty acid and fatty ester, steroid (such as cholesterol)) and chelating agent (such as, EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and / or additives suitable for use in the compositions according to the present disclosure are listed in “Remington: The Science & Practice of Pharmacy,” 19th edition, Williams & Williams, (1995); in “Physician's Desk Reference,” 52nd edition, Medical Economics, Montvale, NJ (1998); and in “Handbook of Pharmaceutical Excipients,” 3rd edition, Ed. AH Kibbe, Pharmaceutical Press, 2000.

[0097] The pharmaceutical formulations according to the present disclosure are suitable for various modes of delivery, including oral administration, parenteral administration (including intravenous, intramuscular, subcutaneous, intradermal and transdermal), topical administration (including dermal, buccal, and sublingual), and rectal administration. The most useful and / or beneficial mode of administration may vary depending on the condition of the recipient and the disorder being treated.

[0098] Pharmaceutical preparation can be easily made into available unit dosage form, and thus such preparation can be prepared by any method generally known in the pharmaceutical field.In general, such preparation method comprises (by various methods) by activating agent, for example according to the compound of formula I of the present disclosure or the compound of formula II (or its pharmaceutically acceptable ester, amide, salt or solvate) and suitable carrier or other adjuvant combination, and described carrier or adjuvant can be made up of one or more compositions.Then the combination of active component and one or more adjuvants is physically treated, for example, to present the preparation of suitable form for delivering (for example, being shaped as tablet or forming aqueous suspension).

[0099] The pharmaceutical preparation according to the present disclosure that is suitable as oral dosage form can take various forms, such as tablet, capsule, caplet and thin slice (comprising fast dissolving or effervescent), each containing a predetermined amount of activating agent.Preparation can also be in the form of powder or granule, solution or suspension in aqueous liquid or non-aqueous liquid and as liquid emulsion (oil-in-water and water-in-oil).Activating agent can also be sent as bolus (bolus), electuary (electuary) or paste.It is generally understood that the preparation method of above dosage form is generally known in the art, and any such method will be suitable for preparing the corresponding dosage form used in the sending of the compound according to the present disclosure.

[0100] Tablets comprising a compound according to the present disclosure can be manufactured by any standard process known to those skilled in the art, such as, for example, by compression or molding, optionally with one or more adjuvants or auxiliary ingredients. The tablets can be optionally coated or scored, and can be formulated to provide slow release or controlled release of the active agent.

[0101] Solid dosage form can be formulated to provide the delayed release of activating agent, for example, by applying coating.Delayed release coating is known in the art, and the dosage form comprising such delayed release coating can be prepared by any known suitable method.Such method generally comprises, after preparing solid dosage form (for example tablet or caplet), applying delayed release coating composition.Applying can be carried out by for example airless spraying, fluidized bed coating, use coating pan or similar method.The material used as delayed release coating can be polymeric in nature, for example cellulosic material (for example, cellulose butyrate phthalate, hydroxypropyl methylcellulose phthalate and carboxymethyl ethyl cellulose), and polymer and copolymer of acrylic acid, methacrylic acid and ester thereof.

[0102] Solid dosage forms according to the present disclosure can also be sustained-release (that is, releasing active agent over an extended period of time), and can also or may not be delayed-release. Sustained-release formulations are known in the art, and are usually prepared by dispersing the drug in gradually degradable material or hydrolyzable material, for example, in a matrix of insoluble plastics, hydrophilic polymers or fatty compounds. Alternatively, the solid dosage form can be coated with such material.

[0103] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which can also include other agents, such as antioxidants, buffers, antibacterials, and solutes that make the preparation and the recipient's blood isotonic with intention. Preparations can include aqueous and non-aqueous sterile suspensions comprising suspending agents and thickening agents. Such preparations for parenteral administration can be presented in unit dose containers or multidose containers such as, for example, sealed ampoules and vials, and can be stored in freeze-dried (lyophilized) conditions, only needing to add sterile liquid carriers such as water (for injection) immediately before use. Instant injection solutions and suspensions can be prepared by sterile powders, granules, and tablets of previously described kinds.

[0104] Compound according to the present disclosure can also be transdermal administered, wherein activating agent is incorporated into the laminated structure (commonly referred to as " patch ") that is suitable for keeping close contact with the epidermis of recipient for the time period of continuous extension.Typically, such patch is obtainable as single layer " drug in adhesive " patch or as multilayer patch, in which activating agent is contained in the layer separated from the adhesive layer.Two types of patches also comprise backing layer and lining usually, and this lining is removed before being attached to the skin of recipient.Transdermal drug delivery patch can also be included in the reservoir below the backing layer, and this reservoir is separated from the skin of recipient by semipermeable membrane and adhesive layer.Transdermal drug delivery can occur by passive diffusion, or can use electrical transport or iontophoresis to promote.

[0105] Formulations for rectal delivery of compounds of the present disclosure include rectal suppositories, creams, ointments, and liquids. Suppositories can be presented as active agents in combination with carriers commonly known in the art, such as polyethylene glycol. Such dosage forms can be designed to disintegrate rapidly or over an extended period of time, and the time to complete disintegration can be in the range of from a short period of time, such as about 10 minutes, to an extended period of time, such as about 6 hours.

[0106] The compound of formula I or formula II above can be formulated in a composition, including those suitable for oral administration, buccal administration, rectal administration, topical administration, nasal administration, ophthalmic administration or parenteral administration (including intraperitoneal injection, intravenous injection, subcutaneous injection or intramuscular injection). The composition can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art.

[0107] Method of preparation typically includes the step that makes the compound of formula I or the compound of formula II combine with the carrier that comprises (constitutes) one or more auxiliary components.Usually, composition is by making the compound of the present disclosure combine with liquid carrier to form solution or suspension, or selectively, makes the compound of the present disclosure combine with the formulation component that is suitable for forming solid, optionally granular product, and then, if approval, product is shaped into the delivery form of expectation and prepares.When being particle, the solid preparation of the present disclosure will typically include the particle with the size in the scope from about 1 nanometer to about 500 microns.Usually, for being intended for the solid preparation used intravenously, the diameter of particle will typically in the scope from about 1nm to about 10 microns.

[0108] The amount of the compound of Formula I or the compound of Formula II in the formulation will vary depending on the particular compound chosen, the dosage form, the target patient population, and other considerations, and will be readily determined by one skilled in the art.

[0109] The amount of the compound of Formula I or the compound of Formula II in the formulation will be that amount required to deliver a therapeutically effective amount of the compound to a patient in need thereof to obtain at least one therapeutic effect associated with the compounds of the present disclosure. In practice, this will vary widely depending on the specific compound, its activity, the severity of the condition to be treated, the patient population, the stability of the formulation, etc.

[0110] The treatment methods according to the present disclosure generally comprise administering a therapeutically effective amount of a compound of Formula I or a compound of Formula II, optionally in a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, wherein the therapeutically effective amount is preferably sufficient to achieve the release of dopamine and serotonin or to achieve the release of dopamine and the inhibition of the uptake of serotonin. The therapeutically effective amount is also preferably sufficient to provide the patient with relief of the symptoms of the disease, condition, or disorder for which the patient is being treated.

[0111] Generally, the compositions will contain any amount of a Compound of the Disclosure from about 1% by weight to about 99% by weight, typically from about 5% to about 70% by weight, and more typically from about 10% to about 50% by weight, and will also depend on the relative amounts of excipients / additives contained in the composition.

[0112] In specific embodiments, the compound of Formula I or the compound of Formula II, or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof, can be used in combination with other biologically active agents typically considered useful for treating the diseases, conditions, and / or disorders discussed herein. Such biologically active agents for use in combination with the phenethylamine compounds of the present disclosure can include, for example, antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclics, serotonin norepinephrine reuptake inhibitors, and norepinephrine and dopamine reuptake inhibitors (NDRIs), monoamine oxidase inhibitors (MAOIs), mood stabilizers, anti-narcolepsy agents, or antipsychotics. Example

[0113] The present disclosure also encompasses methods of preparing compounds having structures as disclosed herein. In order to obtain compounds that are effective as dual DA and 5-HT releasers, available information on 1-naphthyl-2-aminopropane (PAL-287 (PAL, Phenyl Amine Library)) as a comparative compound was evaluated. PAL-287,

[0114]

[0115] Release of radiolabeled neurotransmitters from DAT, SERT, and NET, where EC 50The values ​​were 12.6 nM, 3.4 nM, and 11.1 nM, respectively (Table 1). In vivo microdialysis experiments in rats confirmed the in vitro data by showing that PAL-287 (1-3 mg / kg Lv.) increased extracellular DA and 5-HT in the frontal cortex, with a greater effect on 5-HT (464% increase compared to 133% increase). Furthermore, in rats, PAL-287 caused significantly less locomotor stimulation than S(+)-amphetamine, which is 71-fold more potent at releasing DA than 5-HT; importantly, high doses of PAL-287 did not cause cortical 5-HT depletion. In rhesus monkeys trained to self-administer cocaine, PAL-287 produced a dose-dependent decrease in cocaine self-administration and significantly reduced cocaine-maintained responding relative to food at 1.0 mg / kg / h. In general, data collected with the non-amphetamine analog PAL-287 support the hypothesis that dual DA / 5-HT releasers possess the therapeutic effects of amphetamine-type releasers while being minimally potentiating.

[0116] Therefore, a series of phenylethylamines were synthesized and their transporter activities were evaluated. Four groups of phenylethylamine analogs were synthesized, as shown below.

[0117]

[0118] The I group is made up of racemic alkynyl isostere (isostere) 4 and two chiral isosteres S-4 and R-4. The II group is made up of racemic and chiral (E)-alkenyl isostere (6, S-6, R-6), and the III group is made up of corresponding (Z)-alkenyl isostere (8, S-8, R-8). The analogs (10, 11) of the IV group have a less carbon between the phenyl ring and the amine group. All analogs are synthesized in three steps or four steps by commercially available materials. Scheme 1 shows the synthesis of (S)-stereoisomers from Group I-Group III.

[0119]

[0120] To synthesize Group I alkynes S-4, commercially available alcohols R-3 are converted to tosylates, which undergo configurational inversion to azide displacement, which is reduced under Staudinger conditions to provide S-4. The same commercially available starting alcohols R-3 are selectively reduced with lithium aluminum hydride (LAH) or Lindlar catalyst to provide the corresponding (E)-olefins or (Z)-olefins, R-5 and R-7, respectively. These olefins are then converted to amines S-6 and S-8, respectively, using the same three-step tosylation / azide formation / Staudinger reduction steps. The (R) stereoisomers and racemates of Groups I-III are synthesized using the same pathway starting with the corresponding commercially available (S)-alcohols and racemic alcohols, respectively.

[0121] Scheme 2 shows the synthesis of Group IV vinylogous phenethylamines (10, 11) from commercially available alcohol 9 using the same route as the compounds synthesized in Scheme 1, except that mesylation was performed instead of tosylation due to stability issues.

[0122]

[0123] Scheme 2: Synthesis of Group IV Analogs

[0124] According to the protocol developed by Rothman and collaborators (Rothman, et al., Eur. J. Pharmacol. 2002, 447 (1), 51), BAT activity was measured using synaptosomes prepared from rat brain homogenate. Compounds were first screened in uptake inhibition and release assays to determine the exact mode of drug action. Compounds that were active in both assays were releasers, while compounds that were only active in the uptake inhibition assay were uptake inhibitors. The active compounds were then fully characterized by running 8-point concentration response curves in an assay corresponding to their mechanism of action. Substrate reversal experiments were performed to verify substrate activity. As previously described, analogs were tested for their activity at 5-hydroxytryptamine-2 receptor subtypes (5-HT) using an in vitro calcium mobilization assay in transfected HEK293 cells. 2A , 5-HT 2B , 5-HT 2C These receptors are relevant to the pharmacology of drugs of abuse because 5-HT 2A Agonists are considered hallucinogenic, and 5-HT agonists have been associated with valvular heart disease and pulmonary hypertension; activity at these receptors would be considered off-target. 2C Agonists of α-glucose agonist may be beneficial as potential pharmacotherapy for drug abuse and appetite suppression.

[0125] Table 1 shows the transporter data for the analogs. All compounds were active as DAT and NET releasers, with varying potencies, and all except two compounds, 10 and 11, were active as SERT releasers. At DAT, the Group I alkynes had similar potencies, with S-4 being the most potent, with an EC of 0. 50 The alkynes also had similar potency at SERT, with R-4 being the most potent, with an EC 50 The value was 288 nM. At NET, alkyne R-4 was the most effective (EC 50 =496 nM), and 4 was the least potent (EC 50 =2980 nM). Group II (E)-olefins were effective at all three transporters, EC 50 The values ​​were less than 540 nM. At DAT, Group II (E)-olefins had similar potency, with R-6 being the least potent (EC 50 =540 nM), and S-6 was the most effective, EC 50 The value is 206nM.

[0126] At SERT and NET, S-6 was the most active compound in the group, with EC 50 The values ​​were 40 nM and 138 nM, respectively. At DAT, Group III (Z)-olefins were less than 1500 nM, with S-8 being the most potent at 304 nM. At SERT, analogs 8 and S-8 had similar potency, with 8 being slightly more potent (EC 50 =646 nM). At NET, S-8 was the most potent analog, with an EC 50 The value was 170 nM. Group IV analogs were inactive at SERT and were relatively weak releasers at DAT, with 10 being the most potent (EC 50 =666 nM). However, both analogs had similar potency at NET (EC 50 ≈300nM).

[0127] Table 1

[0128] Structure-activity relationships of a series of vinylogous amphetamine analogs for the release of radiolabeled substrates from DAT, SERT, and NET

[0129]

[0130] In Table 1, a:EC 50 Values ​​were determined as described below, and each value is the mean ± SD (n = 3); b: Calcium mobilization EC 50Values ​​were determined as described below; c: Data from Rothman, RB; Blough, BE; Baumann, MH Trends Pharmacol. Sci. 2006, 27(12), 612; IA = inactive at 10 μM.

[0131] From a structure-activity perspective, all compounds are substrates for the transporter, suggesting that the transporter can transport larger structures than previously thought. With the exception of Group IV, all compounds are dual DA / 5-HT releasers, but with varying degrees of transporter selectivity. Group I alkynes do not exhibit great selectivity for releasing 5-HT compared to DA, as racemic analogs 4 and R-4 are only 2.6-fold and 2.3-fold more potent at DAT, respectively. S-4 is essentially equivalent at DAT and SERT. Group II alkenes are all more selective at SERT relative to DAT, with 5-fold greater potency at SERT. This group is interesting because the activities at the transporter are very similar, indicating that there is no difference between the chiral isomers R-6 and S-6 and the racemate 6. Group III (Z)-alkenes are similar to Group I-alkynes in that the analogs do not show great SERT / DAT selectivity. Racemic analogs 8 and R-8 have similar potency in releasing 5-HT relative to DA (1.4-fold and 1.2-fold, respectively), whereas 5-8 is slightly more potent in releasing DA relative to 5-HT (2.2-fold). Removal of the carbon between the olefin and the amine (Group IV) results in analogs that are selective at DAT and NET. These compounds are inactive at SERT, indicating that they cannot bind to the transport site; this activity profile suggests that the compounds may be weak agonists.

[0132] In some studies, NE release has been found to be almost parallel to DA release, with slightly higher potency. Although most vinylogous analogs follow the DA / NE release trend, several compounds show selectivity for either DAT or NET. Group I racemic alkyne 4 is 3 times more effective in releasing DA than NE, EC 50 The values ​​were 997 nM and 2980 nM, respectively. Analog S-4 followed the typical trend at DAT and NET, with EC 50 values ​​were 660 nM and 496 nM, respectively, whereas for analog R-4, the activities at DAT and NET were reversed, with EC 50 The values ​​were 443 nM and 784 nM, respectively. All group II (E)-olefins and two group III (Z)-olefins followed the typical trend; however, group III (Z)-olefin R-8 showed a 6.7-fold selectivity for releasing NE relative to releasing DA, EC 50The values ​​were 211 nM and 1416 nM, respectively. Two analogs of Group IV, 10 and 11, were more potent at NET than at DAT, but had different selectivities (2.2-fold and 3.7-fold, respectively).

[0133] Compared with the other three groups, group II (E)-olefins were the most active compounds. The most effective analogues at DAT, SERT and NET were (E)-olefin S-6, EC 50 The values ​​were 206 nM, 40 nM, and 138 nM, respectively. This analog retains the same configuration as S(+)-amphetamine, with the same number of carbons between the phenyl and amine groups as PAL-287, and a similar spatial conformation to PAL-287 compared to the more sterically hindered (Z)-olefin. Although PAL-287 was 10-fold more potent than S-6 at all three transporters, the compounds shared some activity characteristics. S-6 had a 5-fold higher potency for 5-HT / DA release, similar to the comparative compound PAL-287, which had a 3.7-fold selectivity. S-6 was 3.5-fold more potent for 5-HT release compared to NE release, similar to the 3.3-fold selectivity of PAL-287, and the two compounds had nearly equal potency for DA / NE release.

[0134] The vinylogous analogs of the present disclosure were also evaluated for their activity in 5-HT using an in vitro calcium mobilization assay. 2A , 5-HT 2B and 5-HT 2C The analogs had varying degrees of weak activity at all three receptors, making them more like S(+)-amphetamine (inactive in all three assays) than PAL-287 (Table 1). Previous functional studies revealed that PAL-287 has a strong agonist activity at 5-HT receptors. 2A Receptors and 5-HT 2B The receptor is a full agonist (EC 50 = 466 nM and 40 nM, respectively), and in 5-HT 2C Partial agonist (EC 50 =2.3nM, E MAX =20%) in 5-HT 2A At present, the vinylogous analogs are not as effective as PAL-287, as most of them are inactive (S-6, 10, 11) or have EC > 10 μM. 50 The remaining analogs had potencies in the micromolar range. 50 value and 102% E MAXThe analog S-8 was the most potent and efficacious analog. Racemic analog 8 had similar potency (EC 50 =1860 nM) and efficacy (E MAX =90%). The only other active compounds were alkyne S-4 and racemic alkene 6, which had 2.7-fold and 3-fold decreases in potency, respectively, compared to 8. These compounds were also not as potent and had E in the lower 80% range. MAX Value. 2B All analogs were inactive. This is interesting because PAL-287 is 2B It is active as an agonist, EC 50 The value is 40nM. 2C Only group III (Z)-olefins 8 and S-8 were weak agonists, with activity less than that of the control 5-HT E at 10 μM. MAX The most active transporter compound (S-6) was inactive at all three receptors, indicating that this compound may not produce the typical effects associated with agonist activity at the 5-HT2 receptor. Analog S-6 was also inactive in the in vitro 5-HT2 calcium mobilization assay, indicating no potential in vivo effects.

[0135] The experimental synthesis and activity studies are described in detail below.

[0136] Example 1

[0137]

[0138] 1-Methyl-4-phenyl-but-3-ynylamine (4).

[0139] Under N 2, at 0 ℃, slowly add the p-toluenesulfonyl chloride (1.03g, 5.40mmol) in pyridine (1mL) into the stirred solution of known alcohol R-3 (432mg, 2.70mmol) in pyridine (1.7mL).Allow reaction mixture to slowly heat to room temperature and then stir overnight.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until it reaches room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the crude toluenesulfonic acid ester as brown oil that is polluted by some unreacted starting materials.

[0140] To the stirred solution of the crude toluenesulfonic acid ester (849mg, 2.70mmol) in DMF (9mL), add NaN (702mg, 10.8mmol), and allow the suspension to be stirred vigorously overnight. Reactant mixture is poured in water and ether, and stirring continues 20min. Biphasic mixture is distributed in separating funnel. Water layer is extracted twice with ether, and the organic extract water washed twice and with salt water washing once, through Na sO dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 258mg (52% yield) is provided.

[0141] Under N 2, in the stirred solution of the azide (158mg, 0.853mmol) in THF (4.5mL), PPh is added 3 (449mg, 1.71mmol).Then water (0.53mL) is added dropwise, and the reaction mixture is stirred overnight. The reaction mixture is diluted with ethyl acetate and water. Biphasic mixture is distributed in a separating funnel. Water layer is extracted twice with EtOAc, and the organic extract water and salt water washing merged are washed with Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (with 10%MeOH / CH 2 Cl 2 to 20%MeOH / CH 2 Cl 2 gradient elution), 114mg (84% yield) of amine 4 as light yellow oil is provided. 1 H NMR (CDCl3, 300 MHz) δ 7.42-7.39 (m, 2H), 7.29-7.27 (m, 3H), 3.24-3.14 (m, 1H), 2.56-2.37 (qd mixed with br.s, 4H), 1.21 (d, J = 6.0 Hz, 3H); 13 C NMR(CDCl3,75MHz)ppm 131.6,128.2,127.8,123.6,87.1,82.7,46.4,30.3,22.7; MS(APCI)(M+1) + 160.2, found 160.1. The hydrochloride salt has a melting point of 131°C-132°C; Anal.(C 11 H 14 ClN)C,H,N.

[0142] Example 2

[0143] (1S)-1-Methyl-4-phenyl-but-3-ynylamine (S-4).

[0144]

[0145] Under N 2, at 0 ℃, to the stirred solution of known alcohol R-3 (580mg, 3.62mmol) in pyridine (2mL), slowly add the p-toluenesulfonyl chloride (1.38g, 7.24mmol) in pyridine (1.6mL).Allow reaction mixture to slowly heat to room temperature and then stir overnight.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until it reaches room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate to provide 949mg (83% yield) as the crude toluenesulfonic acid ester of white solid.

[0146] In the stirred solution of the crude toluenesulfonic acid ester (949mg, 3.02mmol) in DMF (10mL), add NaN (787mg, 12.1mmol), and allow the suspension to be stirred vigorously overnight.Reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted twice with ether, and the organic extract water washed twice and with salt water washing once, through Na sO dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 490mg (88% yield) is provided.

[0147] Under N2, PPh3 (1.39g, 5.30mmol) was added to a stirred solution of azide (490mg, 2.65mmol) in THF (14mL). Water (1.7mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The two-phase mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluted with 10% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient) provided 261mg (62% yield) of amine S-4 as a light yellow oil. [α] 20 D +11.4 g / mL (c 0.0007, MeOH); 1 H NMR (CD3OD, 300MHz) δ7.40-7.36 (m, 2H), 7.31-7.28 (m, 3H), 3.14-3.05 (m, 1H), 2.48-2.46 (m, 2H), 1.21 (d, J = 6.0Hz, 3H);13 C NMR(CDCl3,75MHz)ppm 131.6,128.2,127.7,123.7,87.3,82.6,46.4,30.7,23.0; MS(APCI)(M+1) + 160.2, found 160.1. The hydrochloride salt has a melting point of 141°C-142°C; Anal. (C 11 H 14 ClN·0.2H2O)C,H,N.

[0148] Example 3

[0149] (1R)-1-Methyl-4-phenyl-but-3-ynylamine (R-4).

[0150]

[0151] Under N 2, at 0 ℃, slowly add the p-toluenesulfonyl chloride (1.33g, 7.00mmol) in pyridine (1.5mL) in the stirred solution of known alcohol S-3 (560mg, 3.50mmol) in pyridine (2mL).Allow reaction mixture to slowly heat to room temperature and then stir and spend the night.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until it reaches room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the crude toluenesulfonic acid ester as brown oil that is polluted by some unreacted starting materials.

[0152] In the stirring solution of the crude toluenesulfonic acid ester in DMF (11mL), add NaN (826mg, 12.7mmol), and allow the suspension to be stirred vigorously overnight.Reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted twice with ether, and the organic extract water washed twice and with salt water washing once, through Na sO dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 370mg (63% yield) is provided.

[0153] Under N2, PPh3 (1.05g, 4.00mmol) was added to a stirred solution of azide (370mg, 2.00mmol) in THF (11mL). Water (1.3mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The two-phase mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluted with 10% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient) provided 213mg (67% yield) of amine R-4 as a light yellow oil. [α] 20 D -4.2 g / mL (c 0.0050, MeOH); 1 H NMR(CDCl3,300MHz)δ7.43-7.40(m,2H),7.29-7.27(m,3H),3.24-3.14(m,1H),2 .44(qd,J=54.0,42.0,24.0,6.0Hz,2H),1.81(br.s,2H),1.22(d,J=6.0Hz,3H); 13 C NMR(CDCl3,75MHz)ppm 131.6,128.2,127.7,123.7,87.3,82.6,46.5,30.6,23.0; MS(APCI)(M+1) + 160.2, found 160.0. The hydrochloride salt has a melting point of 143°C-144°C; Anal. (C 11 H 14 ClN)C,H,N.

[0154] Example 4

[0155] (3E)-1-Methyl-4-phenyl-but-3-enylamine (6).

[0156]

[0157] Under N2, at 0 ℃, to the stirred solution of LAH (12.5mL, 1M in THF, 12.5mmol) in dry THF (15mL), slowly add the alcohol 3a (500mg, 3.12mmol) in dry THF (3mL). Note: due to H2 gas evolution causes bubbling. After bubbling stops, the reaction mixture is slowly warmed to room temperature, and then reflux continues for 5h. After cooling to room temperature, then cooling to 0 ℃, by continuously adding 0.47mL H2O, 0.47mL 3M aqueous HCl, 1.4mL H2O and 1.4mL 3M aqueous HCl, carefully quench the reaction mixture. Note: due to H2 gas evolution, cause violent heat release and bubbling. After bubbling stops, the quenched reaction mixture is slowly warmed to room temperature, stirring continues for 30min, and is transferred to a separating funnel. The aqueous layer was extracted twice with ether, and the combined organic extracts were washed with saturated aqueous NaHCO 3 , water, and brine, dried over Na 2 SO 4 , and filtered. Concentration under reduced pressure provided 446 mg (88% yield) of crude (E)-olefin 5 as a clear oil.

[0158] Under N 2, at 0 ℃, to the stirred solution of (E)-alkene 5 (738mg, 4.55mmol) in pyridine (3mL), slowly add the p-toluenesulfonyl chloride (1.73g, 9.10mmol) in pyridine (1.6mL).Allow reaction mixture to slowly heat to room temperature and then stir and spend the night.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until it reaches room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the crude toluenesulfonic acid ester as brown oil that is polluted by some unreacted starting materials.

[0159] In the stirring solution of the crude toluenesulfonic acid ester in DMF (15mL), add NaN (1.18g, 18.2mmol), and allow the suspension to be stirred vigorously overnight.Reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted with ether twice, and the organic extract water washed twice and with salt water washing once, through Na sO dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 640mg (75% yield) is provided.

[0160] Under N 2, PPh is added in the stirred solution of the azide (640mg, 3.42mmol) in THF (18mL) (1.79g, 6.84mmol).Then water (2.1mL) is added dropwise, and the reaction mixture is stirred overnight. The reaction mixture is diluted with ethyl acetate and water. Biphasic mixture is distributed in a separating funnel. Water layer is extracted twice with EtOAc, and the organic extract water and salt water washing merged are washed with Na 2 SO 4 dry, and filter. Under reduced pressure, concentrate, then by the flash chromatography on silica gel (with 10%MeOH / CH 2 Cl 2 to 20%MeOH / CH 2 Cl 2 gradient elution), 404mg (73% yield) of amine 6 as white solid is provided. 1 H NMR(CDCl3,300MHz)δ7.37-7.17(m,5H),6.44(d,J=15.0Hz,1H),6.23-6.13(m,1H),3.09- 2.98(m,1H),2.34-2.25(m,1H),2.23-2.13(m,1H),1.83(br.s,2H),1.12(d,J=6.0Hz,3H); 13 C NMR(CDCl3,75MHz)ppm 137.5,132.5,128.5,127.4,127.1,126.1,46.9,43.6,23.4; MS(APCI)(M+1) + 162.2, found 162.2. The hydrochloride salt has a melting point of 147°C-148°C; Anal.(C 11 H 16 ClN·0.1H2O)C,H,N.

[0161] Example 5

[0162] (1S,3E)-1-Methyl-4-phenyl-but-3-enylamine (S-6).

[0163]

[0164] Under N2, at 0 ℃, to the stirred solution of LAH (12.5mL, 1M in THF, 12.5mmol) in dry THF (15mL), slowly add the alcohol R-3 (500mg, 3.12mmol) in dry THF (3mL).Note: due to H2 gas evolution causes bubbling.After bubbling stops, the reaction mixture is slowly warmed to room temperature, and then reflux continues for 5h.After cooling to room temperature, then cooling to 0 ℃, by continuously adding 0.47mL H2O, 0.47mL 3M aqueous HCl, 1.4mL H2O and 1.4mL 3M aqueous HCl, carefully quench the reaction mixture.Note: due to H2 gas evolution, cause violent heat release and bubbling.After bubbling stops, the reaction mixture of quenching is slowly warmed to room temperature, stirring continues for 30min, and is transferred in separating funnel. The aqueous layer was extracted twice with ether, and the combined organic extracts were washed with saturated aqueous NaHCO 3 , water, and brine, dried over Na 2 SO 4 , and filtered. Concentration under reduced pressure provided 417 mg (82% yield) of crude (E)-olefin R-5 as a clear oil.

[0165] Under N 2, at 0 ℃, to the stirred solution of (E)-alkene R-5 (417mg, 2.57mmol) in pyridine (2mL), slowly add the tosyl chloride (980mg, 5.14mmol) in pyridine (1mL).Allow reaction mixture to slowly heat to room temperature and then stir and spend the night.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until reaching room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the crude toluenesulfonic acid ester as brown oil that is polluted by some unreacted starting materials.

[0166] In the stirring solution of the crude toluenesulfonic acid ester in DMF (8.6mL), add NaN (670mg, 10.3mmol), and allow the suspension to be stirred vigorously overnight.Reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted twice with ether, and the organic extract water washed twice and with salt water washing once, through Na sO dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 440mg (91% yield) is provided.

[0167] Under N2, PPh3 (1.23g, 4.70mmol) was added to a stirred solution of azide (440mg, 2.35mmol) in THF (12mL). Water (1.5mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The two-phase mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluted with 10% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient) provided 190mg (50% yield) of amine S-6 as a clear oil. [α] 20 D +24.1 g / mL (c 0.0039, MeOH); 1 H NMR(CDCl3,300MHz)δ7.37-7.17(m,5H),6.45(d,J=15.0Hz,1H),6.26-6.13(m,1H),3.09- 3.01(m,1H),2.34-2.25(m,1H),2.23-2.13(m,1H),1.80(br.s,2H),1.12(d,J=6.0Hz,3H); 13 C NMR(CDCl3,75MHz)ppm137.5,132.5,128.5,127.4,127.1,126.1,46.9,43.6,23.4; MS(APCI)(M+1) + 162.2, found 162.3. The hydrochloride salt has a melting point of 172°C-173°C; Anal.(C 11 H 16 ClN)C,H,N.

[0168] Example 6

[0169] (1R,3E)-1-Methyl-4-phenyl-but-3-enylamine (R-6).

[0170]

[0171] Under N2, at 0 ℃, to the stirred solution of LAH (12.5mL, 1M in THF, 12.5mmol) in dry THF (15mL), slowly add the alcohol S-3 (500mg, 3.12mmol) in dry THF (3mL).Note: due to H2 gas evolution causes bubbling.After bubbling stops, the reaction mixture is slowly warmed to room temperature, and then reflux continues for 5h.After cooling to room temperature, then cooling to 0 ℃, by continuously adding 0.47mL H2O, 0.47mL 3M aqueous HCl, 1.4mL H2O and 1.4mL 3M aqueous HCl, carefully quench the reaction mixture.Note: due to H2 gas evolution, cause violent heat release and bubbling.After bubbling stops, the quenched reaction mixture is slowly warmed to room temperature, stirring continues for 30min, and is transferred in a separating funnel. The aqueous layer was extracted twice with ether, and the combined organic extracts were washed with saturated aqueous NaHCO 3 , water, and brine, dried over Na 2 SO 4 , and filtered. Concentration under reduced pressure provided 500 mg (99% yield) of crude (E)-olefin S-5 as a white solid.

[0172] Under N 2, at 0 ℃, to the stirred solution of (E)-alkene S-5 (500mg, 3.08mmol) in pyridine (2.1mL), slowly add the p-toluenesulfonyl chloride (1.17g, 6.16mmol) in pyridine (1mL).Allow reaction mixture to slowly heat to room temperature and then stir and spend the night.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until it reaches room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the crude toluenesulfonic acid ester as brown oil that is polluted by some unreacted starting materials.

[0173] In the stirring solution of the crude toluenesulfonic acid ester in DMF (10mL), add NaN (800mg, 12.3mmol), and allow the suspension to be stirred vigorously overnight.Reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted twice with ether, and the organic extract water washed twice and with salt water washing once, through Na sO dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 370mg (64% yield) is provided.

[0174] Under N2, PPh3 (1.04g, 3.96mmol) was added to a stirred solution of azide (370mg, 1.98mmol) in THF (10mL). Water (1.2mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The two-phase mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluted with 10% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient) provided 146mg (46% yield) of amine R-6 as a clear oil. [α] 20 D -5.7 g / mL (c 0.0021, MeOH); 1 H NMR (CDCl3, 300MHz) δ7.38-7.20(m,5H),6.45(d,J=15.0Hz,1H),6.24-6.16(m,1H),3.12-3.01(m,1H),2.37-2.17(br.m,4H),1.15(d,J=6.0Hz,3H); 13 C NMR(CDCl3,75MHz)ppm 137.4,132.7,128.5,127.2,126.1,47.0,43.3,23.1; MS(APCI)(M+1) + 162.2, found 162.2. The hydrochloride salt has a melting point of 172°C-174°C; Anal.(C 11 H 16 ClN·0.1H2O)C,H,N.

[0175] Example 7

[0176] (3Z)-1-Methyl-4-phenyl-but-3-enylamine (8).

[0177]

[0178] In a Paar bottle, a mixture of alcohol 3 (900 mg, 5.62 mmol), Lindela catalyst (720 mg, 80 wt.%) and quinoline (9 mL, 76.4 mmol) in MeOH (250 mL) was shaken at 43 psi in a Paar hydrogenator for 3 h. The mixture was filtered through diatomaceous earth, washed with MeOH, and then concentrated under reduced pressure. The residue was dissolved in CH Cl and 10% aqueous HCl. The two-phase mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with CH Cl and the combined organic extracts were washed twice with 10% aqueous HCl and once with brine, dried over Na SO and filtered. Concentration under reduced pressure provided crude (Z)-olefin 7 as a brown oil contaminated with ~10% fully saturated compound.

[0179] Under N 2, at 0 ℃, slowly add the tosyl chloride (2.14g, 11.2mL) in pyridine (4mL) in the stirring solution of the crude (Z)-alkene 7 in pyridine (2mL).Allow reaction mixture to slowly heat to room temperature and then stir and spend the night.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until reaching room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the crude toluenesulfonic acid ester as orange oil of 1.74g (97% yield).

[0180] In the stirred solution of the crude toluenesulfonic acid ester (1.74g, 5.50mmol) in DMF (18mL), add NaN (1.43g, 22.0mmol).After stirring overnight, reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.With water layer ether extraction twice, and the organic extract water washing twice and with salt water washing once, through Na sO dry, and filter.Under reduced pressure concentrate, then by the flash chromatography on silica gel (with 5%EtOAc / hexane wash-out), provide the azide as clarifying oily thing that uses without any further purification.

[0181] Under N2, PPh3 (2.89g, 11.0mmol) was added to a stirred solution of the azide in THF (29mL). Water (3.4mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The biphasic mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluted with 5% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient, then 100% MeOH) provided 367mg (41% yield) of amine 8 as a light yellow oil. The hydrochloride salt has a melting point of 115°C-117°C; 1 H NMR (CD3OD, 300MHz) δ7.38-7.25(m,5H),6.69(d,J=12.0Hz,1H),5.71-5.63(m,1H),3.44-3.38(m,1H),2.78-2.57(m,2H),1.29(d,J=6.0Hz,3H); 13 C NMR(CD3OD,75MHz)ppm 138.1,134.1,129.8,129.6,128.3,127.4,126.5,49.2,34.6,18.5; MS(ESI)(M+1) + 162.2, found 162.2 (free base); Anal. (C 11 H 16 ClN)C,H,N.

[0182] Example 8

[0183] (1S,3Z)-1-Methyl-4-phenyl-but-3-enylamine (S-8).

[0184]

[0185] In a Paar bottle, a mixture of alcohol R-3 (350 mg, 2.18 mmol), Lindela catalyst (280 mg, 80 wt.%) and quinoline (3.5 mL, 29.6 mmol) in MeOH (200 mL) was shaken at 43 psi in a Paar hydrogenator for 3 h. The mixture was filtered through diatomaceous earth, washed with MeOH, and then concentrated under reduced pressure. The residue was dissolved in CH Cl and 10% aqueous HCl. The two-phase mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with CH Cl and the combined organic extracts were washed twice with 10% aqueous HCl and once with brine, dried over Na SO and filtered. Concentration under reduced pressure provided the crude (Z)-alkene R-7 as a brown oil contaminated with 10% fully saturated compounds.

[0186] Under N 2, at 0 ℃, slowly add the tosyl chloride (831mg, 4.36mmol) in pyridine (1mL) in the stirring solution of the rough (Z)-alkene R-7 in pyridine (1mL).Allow reaction mixture to slowly heat to room temperature and then stir and spend the night.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until it reaches room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and with salt water washing once, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the rough toluenesulfonic acid ester as orange oil.

[0187] In the stirring solution of the crude toluenesulfonic acid ester in DMF (3.7mL), add NaN (291mg, 4.48mmol).After stirring overnight, reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted with ether twice, and the organic extract water that merges is washed twice and with salt water washing once, through Na SO Drying, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (with 5%EtOAc / hexane wash-out), provide the azide as clarifying oil that uses without any further purification.

[0188] To a stirred solution of the azide in THF (5.9 mL) was added PPh (588 mg, 2.24 mmol) under N2. Water (0.7 mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The biphasic mixture was partitioned in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluting with a 5% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient, then 100% MeOH) provided 118 mg (65% yield) of amine S-8 as a clear, thick oil. The hydrochloride salt has a melting point of 83°C-84°C; [α] 20 D -27.9 g / mL (c 0.0014, MeOH); 1 H NMR (CD3OD, 300MHz) δ7.38-7.23(m,5H),6.69(d,J=12.0Hz,1H),5.71-5.63(m,1H),3.44-3.33(m,1H),2.77-2.56(m,2H),1.29(d,J=6.0Hz,3H); 13 C NMR(CD3OD,75MHz)ppm138.1,134.1,129.8,129.5,128.3,126.5,49.2,34.6,18.5; MS(ESI)(M+1) + 162.2, measured 162.4; Anal.(C 11 H 16 ClN·0.45H2O)C,H,N.

[0189] Example 9

[0190] (1R,3Z)-1-Methyl-4-phenyl-but-3-enylamine (R-8).

[0191]

[0192] In a Paar bottle, a mixture of alcohol S-3 (350 mg, 2.18 mmol), Lindela catalyst (280 mg, 80 wt.%) and quinoline (3.5 mL, 29.6 mmol) in MeOH (200 mL) was shaken at 43 psi in a Paar hydrogenator for 3 h. The mixture was filtered through celite, washed with MeOH, and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and 10% aqueous HCl. The biphasic mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were washed twice with 10% aqueous HCl and once with brine, dried over Na2SO4, and filtered. Concentration under reduced pressure provided crude (Z)-olefin S-7 as a brown oil contaminated with ~10% fully saturated compound.

[0193] Under N 2, at 0 ℃, slowly add the tosyl chloride (831mg, 4.36mmol) in pyridine (1mL) in the stirring solution of the crude (Z)-alkene S-7 in pyridine (1mL).Allow reaction mixture to slowly heat to room temperature and then stir and spend the night.Reaction mixture is poured in the conical flask containing ice and 10% aqueous HCl, use CH 2 Cl 2 to help transfer, and stir until it reaches room temperature.Biphasic mixture is distributed in separating funnel.With water layer CH 2 Cl 2 extract twice, and the organic extract merging is washed three times with 10% aqueous HCl, washed once with water, and washed once with salt water, through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate and provide the crude toluenesulfonic acid ester as orange oil.

[0194] In the stirring solution of the crude toluenesulfonic acid ester in DMF (3.7mL), add NaN (291mg, 4.48mmol).After stirring overnight, reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted with ether twice, and the organic extract water that merges is washed twice and with salt water washing once, through Na SO Drying, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (with 5%EtOAc / hexane wash-out), provide the azide as clarifying oil that uses without any further purification.

[0195] To a stirred solution of the azide in THF (5.9 mL) was added PPh (588 mg, 2.24 mmol) under N2. Water (0.7 mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The biphasic mixture was partitioned in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluting with a 5% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient, then 100% MeOH) provided 102 mg (56% yield) of amine R-8 as a clear, thick oil. The hydrochloride salt had a melting point of 83°C-84°C; [α] 20 D +20 g / mL (c 0.00085, MeOH); 1 HNMR (CD3OD, 300MHz) δ7.38-7.22(m,5H),6.69(d,J=12.0Hz,1H),5.71-5.63(m,1H),3.44-3.33(m,1H),2.77-2.56(m,2H),1.29(d,J=6.0Hz,3H); 13 C NMR(CD3OD,75MHz)ppm 138.1,134.1,129.8,129.5,128.3,126.5,49.2,34.6,18.5; MS(ESI)(M+1) + 162.2, found 162.2 (free base); Anal. (C 11 H 16 ClN·0.5H2O)C,H,N.

[0196] Example 10

[0197] (2E)-1-Methyl-3-phenyl-prop-2-enylamine (10).

[0198]

[0199] Under N2, at 0 ℃, to the stirred solution of LAH (13.7mL, 1M in THF, 13.7mmol) in dry THF (17mL), slowly add the alcohol 9 (500mg, 3.42mmol) in dry THF (3mL). Note: due to H2 gas evolution causes bubbling. After bubbling stops, the reaction mixture is slowly warmed to room temperature, and then reflux continues for 5h. After being cooled to room temperature, then cooled to 0 ℃, by continuously adding 0.52mL H2O, 0.52mL 3M aqueous HCl, 1.6mL H2O and 1.6mL 3M aqueous HCl, carefully quench the reaction mixture. Note: due to H2 gas evolution, cause violent heat release and bubbling. After bubbling stops, the quenched reaction mixture is slowly warmed to room temperature, stirring continues for 30min, and is transferred in a separating funnel. The aqueous layer was extracted twice with ether, and the combined organic extracts were washed with saturated aqueous NaHCO 3 , water, and brine, dried over Na 2 SO 4 , and filtered. Concentration under reduced pressure provided the crude (E)-olefin as a clear oil.

[0200] Under N , at 0 ℃ to CH c l (34mL) in the stirring solution of the rough (E)-alkene, add NEt (0.95mL, 6.84mmol) and MsCl (0.40mL, 5.13mmol).Reaction mixture is stirred at 0 ℃ and continues 1h, and then stirring at room temperature continues 1h, after this, uses saturated aqueous NaHCO quencher, and water and CH c l dilution.Biphasic mixture is distributed in separating funnel.With water layer CH c l Extract twice, and with the organic extract water and salt water washing that merges, through Na sO dry, and filter.Under reduced pressure, concentrate and provide the rough mesylate as brown oil that uses without any purification.

[0201] In the stirring solution of the crude mesylate in DMF (11mL), add NaN (891mg, 13.7mmol).After stirring overnight, reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted twice with ether, and the organic extract water merging is washed twice and with salt water washing once, through Na SO Drying, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 570mg (96% yield) is provided.

[0202] Under N 2, in the stirred solution of the azide (570mg, 3.29mmol) in THF (17.3mL), add PPh 3 (1.73g, 6.58mmol).Then dropwise add water (2.1mL), and the reaction mixture is stirred overnight.The reaction mixture is diluted with ethyl acetate and water. Biphasic mixture is distributed in a separating funnel. Water layer is extracted twice with EtOAc, and the organic extract water and salt water washing merged are through Na 2 SO 4 dry, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (with 5%MeOH / CH 2 Cl 2 to 20%MeOH / CH 2 Cl 2 gradient, then 100%MeOH wash-out), 70mg (14% yield) of amine 11 as clear oil are provided. 1 H NMR(CDCl3,300MHz)δ7.38-7.20(m,5H),6.48(d,J=18.0Hz,1H),6.20(dd,J=15.0,6.0Hz,1H),3.72-3.64(m,1H),2.00(br.s,2H),1.26(d,J=6.0Hz,3H); 13 C NMR(CDCl3,75MHz)ppm 135.7,128.5,128.2,127.3,126.3,49.3,23.7; MS(ESI)(M+1) + 148.2, found 146.2. The hydrochloride salt has a melting point of 151°C-152°C; Anal.(C 10 H 14 ClN)C,H,N.

[0203] Example 11

[0204] (2Z)-1-Methyl-3-phenyl-prop-2-enylamine (11).

[0205]

[0206] In a Paar bottle, a mixture of alcohol 9 (100 mg, 0.684 mmol), Lindela catalyst (80 mg, 80 wt.%) and quinoline (1.1 mL, 9.31 mmol) in MeOH (100 mL) was shaken at 43 psi in a Paar hydrogenator for 4 h. The mixture was filtered through celite and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and 10% aqueous HCl. The biphasic mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were washed twice with 10% aqueous HCl and once with brine, dried over Na2SO4, and filtered. Concentration under reduced pressure provided the crude (Z)-olefin as a brown oil contaminated with ~10% of the fully saturated compound.

[0207] Under N , at 0 ℃ to CH c l (6.8mL) in the stirring solution of the rough (Z)-alkene, add NEt (0.19mL, 1.36mmol) and MsCl (0.16mL, 2.04mmol).Reaction mixture is stirred at 0 ℃ and continues 1h, and then stirring at room temperature continues 1h, after this, uses saturated aqueous NaHCO quencher, and water and CH c l dilution.Biphasic mixture is distributed in separating funnel.With water layer CH c l Extract twice, and with the organic extract water and salt water washing that merges, through Na sO dry, and filter.Under reduced pressure, concentrate and provide the rough mesylate as brown oil that uses without any purification.

[0208] In the stirring solution of the crude mesylate in DMF (2.3mL), add NaN (177mg, 2.73mmol).After stirring overnight, reaction mixture is poured in water and ether, and stirring continues 20min.Biphasic mixture is distributed in separating funnel.Water layer is extracted twice with ether, and the organic extract water merging is washed twice and with salt water washing once, through Na SO Drying, and filter.Under reduced pressure, concentrate, then by the flash chromatography on silica gel (eluting with 5%EtOAc / hexane), the azide as clarifying oil of 118mg (100% yield) is provided.

[0209] Under N2, to a stirred solution of azide (118 mg, 0.682 mmol) in THF (3.6 mL) was added PPh3 (357 mg, 1.36 mmol). Water (0.43 mL) was then added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The biphasic mixture was distributed in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentrated under reduced pressure, then flash chromatography on silica gel (eluted with 5% MeOH / CH2Cl2 to 20% MeOH / CH2Cl2 gradient, then 100% MeOH) provided 46.2 mg (46% yield) of amine 12 as a clear oil. The hydrochloride salt has a melting point of 149°C-151°C; 1 H NMR(CD3OD,300MHz)δ7.48-7.45(m,2H),7.37-7.28(m,3H),6.77(d,J=15.0Hz ,1H),6.26(dd,J=15.0,6.0Hz,1H),4.11-4.02(m,1H),1.50(d,J=9.0Hz,3H); 13 C NMR(CD3OD,75MHz)ppm 137.1,135.5,129.8,129.6,127.8,126.9,50.7,19.6; MS(APCI)(M+1) + 148.2, found 146.3 (free base); Anal. (C 10 H 14 ClN)C,H,N.

[0210] Example 12

[0211] Bioassay

[0212] Dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) assays

[0213] All animal studies were conducted in facilities fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), and the experiments were conducted in accordance with the Institutional Care and Use Committee (IACUC) of the National Institute on Drug Abuse Intramural Research Program (NIDA IRP). Rats were euthanized by CO2 anesthesia, and the brains were processed to produce synaptosomes as previously described (Rothman, RB, et al., Eur. J. Pharmacol. 2002, 447 (1), 51.). Synaptosomes were prepared from rat striatum for DAT determination, while synaptosomes were prepared from whole brain minus striatum and cerebellum for NET determination and SERT determination.

[0214] For uptake inhibition assays, 5 nM [ 3 H]DA, 10 nM [ 3 H] norepinephrine (NE) and 5 nM [ 3 H]5-HT was used to assess transport activity at DAT, NET, and SERT. Unlabeled blockers were included to prevent competitive transporter uptake [ 3 H] transmitter, the selectivity of the uptake assay was optimized for a single transporter. The uptake inhibition assay was performed by adding 100 μl of tissue suspension to a solution containing the test drug and [ 3 The uptake inhibition assay was terminated by rapid vacuum filtration through a Whatman GF / B filter and the retained radioactivity was quantified by liquid scintillation counting. Concentration-response curves were generated to obtain IC 50 value.

[0215] For release assays, 9 nM [ 3 H]1-methyl-4-phenylpyridinium ([ 3 H] MPP+) was used as a radiolabeled substrate for DAT and NET, while 5 nM [ 3 H] 5-HT was used as a substrate for SERT. All buffers used in the release assays contained 1 μM reserpine to block vesicular uptake of the substrate. Uptake by competitive transporters was prevented by including an unlabeled blocker. 3 H]MPP+ or [ 3[H] 5-HT, the selectivity of the release assay is optimized for a single transporter. Synaptosomes are preloaded with radiolabeled substrate in Krebs-phosphate buffer for 1 h (steady state). The release assay is initiated by adding 850 μL of preloaded synaptosomes to 150 μL of test drug. Release is terminated by vacuum filtration, and the retained radioactivity is quantified as described for uptake inhibition. Concentration-response curves are generated to obtain EC 50 value.

[0216] Substrate reversal experiments were performed to verify substrate activity. 80 The release capacity of the test compound is tested at a concentration of 1:1. If the test agent is a release agent, an uptake inhibitor reduces the effect of the test agent. If the test agent is an uptake inhibitor, then adding a second uptake inhibitor results in either no change or an increased effect in the release assay.

[0217] Calcium mobilization assay

[0218] Using stably expressed human 5-HT 2A The HEK293 cells of the receptor. One day before the assay, the cells were plated in a 96-well black wall assay plate in DMEM-HG supplemented with 10% fetal bovine serum, 100 units of penicillin and streptomycin and 15mM HEPES with 40,000 cells / well. The cells were incubated overnight at 37°C, 5% CO. Before the assay, according to the manufacturer's instructions, calcium 5 dye (Molecular Devices) was reconstructed. The reconstructed dye was diluted 1:40 in preheated (37°C) assay buffer (1X HBSS, 20mM HEPES, 2.5mM probenecid, pH 7.4, at 37°C). The growth medium was removed, and the cells were gently washed with the preheated (37°C) assay buffer of 100 μL. The cells were incubated at 37°C, 5% CO in the diluted calcium 5 dye of 200 μL for 45 minutes. Serial dilutions of test compounds were prepared in 1% DMSO / assay buffer, aliquoted into 96-well polypropylene plates, and warmed to 37°C. Following the dye loading incubation period, cells were pretreated with 25 μL of 9% DMSO / assay buffer and incubated at 37°C for 15 min. Following the pretreatment incubation period, plates were incubated with II (Molecular Devices). Calcium-mediated fluorescence changes were monitored every 1.52 seconds over a 60-second period, where II At the 19-second time point, 25 μL of the test compound dilution was added (excitation at 485 nm, detection at 525 nm). Peak kinetic reduction (SoftMax, Molecular Devices) relative fluorescence units (RFU) were plotted against compound concentration. Data were fitted to an appropriate three-parameter logarithmic curve to generate EC 50 Value (GraphPad Prism 6.0, GraphPad Software, Inc., San Diego, CA). 5-HT 2B and 5-HT 2C Calcium mobilization assay using stable 5-HT 2B and 5-HT 2C HEK293 cells were run in the same manner except that 35,000 cells / well were used instead of 40,000 cells / well. The results are set forth in Table 1 above.

[0219] As variously set forth herein with respect to features, aspects, and embodiments thereof, in particular implementations, the present disclosure may be constructed to comprise, consist of, or consist essentially of some or all of such features, aspects, and embodiments, as well as elements and components thereof aggregated to form various additional embodiments of the present disclosure. The present disclosure accordingly contemplates such features, aspects, and embodiments, or selected one or more thereof, in various permutations and combinations, within the scope of the present disclosure.

[0220] While the present disclosure has been described herein with reference to particular aspects, features, and illustrative embodiments, it will be understood that the utility of the disclosure is not limited thereby, but on the contrary extends to and encompasses numerous other variations, modifications, and alternative embodiments, which will suggest themselves to those skilled in the art as claimed and are intended to be broadly construed and understood to include all such variations, modifications, and alternative embodiments within the spirit and scope thereof.

[0221] This application also covers the following projects:

[0222] 1). A compound having a structure according to formula I:

[0223]

[0224] Where A is C 3-4 Alkynyl or C 2-4 Alkenyl; R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 alkyl;

[0225] or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0226] 2) The compound according to item 1), wherein A is C 2-4 Alkenyl.

[0227] 3) The compound according to item 1), which is represented by the structure of Formula II:

[0228]

[0229] where R 6 and R 7 Each independently selected from H or C 1-3 Alkyl, and R 8 Selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0230] 4). The compound according to item 3), wherein R 10 and R 11 It’s H.

[0231] 5) The compound according to item 3), which is selected from (3E)-1-methyl-4-phenyl-but-3-enylamine, (3Z)-1-methyl-4-phenyl-but-3-enylamine and stereoisomers thereof.

[0232] 6) The compound according to item 3), which is represented by formula IIa:

[0233]

[0234] or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0235] 7). The compound according to item 1), wherein A is C 3-4 Alkynyl.

[0236] 8). The compound according to item 1), wherein A is a C3 alkynyl group and R 10 and R 11 It’s H.

[0237] 9). A pharmaceutical composition comprising the compound described in item 1) and a pharmaceutically acceptable carrier.

[0238] 10). A pharmaceutical composition comprising the compound described in item 3) and a pharmaceutically acceptable carrier.

[0239] 11). A pharmaceutical composition comprising the compound according to item 5) and a pharmaceutically acceptable carrier.

[0240] 12). A pharmaceutical composition comprising the compound according to item 6) and a pharmaceutically acceptable carrier.

[0241] 13). A method of treating a disease, condition and / or disorder responsive to a monoamine transporter uptake inhibitor and / or a monoamine transporter substrate-releasing agent, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula I:

[0242]

[0243] Where A is C 3-4 Alkynyl or C 2-4 Alkenyl; R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0244] 14). The method according to item 13), wherein A is C 2-4 Alkenyl.

[0245] 15). The method according to item 14), wherein the compound is represented by the structure of formula II:

[0246]

[0247] where R6 and R 7 Each independently selected from H or C 1-3 Alkyl, and R 8 Selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0248] 16). The method according to item 15), wherein R 10 and R 11 It’s H.

[0249] 17) The method according to item 15), wherein the compound is selected from (3E)-1-methyl-4-phenyl-but-3-enylamine, (3Z)-1-methyl-4-phenyl-but-3-enylamine and stereoisomers thereof.

[0250] 18). The method according to item 15), wherein the compound is represented by formula IIa:

[0251]

[0252] or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0253] 19). The method according to item 13), wherein A is C 3-4 Alkynyl.

[0254] 20). The method according to item 13), wherein A is a C3 alkynyl group and R 10 and R 11 It’s H.

[0255] 21). The method according to item 13), wherein the disease, condition or disorder is obesity, sleep disorder, neurological disease, depression, anxiety, ADHD, stimulant addiction, or alcohol addiction.

[0256] 22). A method for treating stimulant addiction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula II:

[0257]

[0258] R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; R 6 and R 7 Each independently selected from H or C 1-3 Alkyl; R 8 Selected from H, OH, optionally substituted C 1-3 Alkyl, optionally substituted C 1-2 Alkoxy, optionally substituted C 2-3 Alkenyl, optionally substituted C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0259] 23). The method according to item 22), wherein the compound is represented by formula IIa:

[0260]

[0261] or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer thereof.

[0262] 24). The method according to item 22), wherein the stimulant addiction is cocaine addiction.

Claims

1. A pharmaceutical composition comprising a compound selected from the following formula or a pharmaceutically acceptable salt or isomer thereof and a pharmaceutically acceptable carrier:

2. A pharmaceutical composition comprising a compound represented by Formula IIa or a pharmaceutically acceptable salt or isomer thereof and a pharmaceutically acceptable carrier:

3. Compounds having the structure of Formula I: Where A is C 3-4 Alkynyl or C 2-4 Alkenyl; R 1 -R 5 and R 9 Each independently selected from H, OH, C 1-3 Alkyl, C 1-2 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 Alkyl; or a pharmaceutically acceptable salt or isomer thereof Use in the preparation of a medicament for treating a disease, condition and / or disorder responsive to a monoamine transporter uptake inhibitor and / or a monoamine transporter substrate-releasing agent, wherein the compound or a pharmaceutically acceptable salt or isomer thereof is administered to a subject in need thereof in a therapeutically effective amount; wherein the compound is not 4. The method according to claim 3, wherein A is C 2-4 Alkenyl.

5. The use according to claim 3, wherein the compound or a pharmaceutically acceptable salt or isomer thereof is a compound represented by the structure of Formula II: in i)R 6 is a C1 alkyl group and R 7 and R 8 is H; or ii) R 7 is a C1 alkyl group and R 6 and R 8 is H; or iii) R 8 is a C1 alkyl group and R 6 and R 7 is H; or iv) R 6 、R 7 and R 8 For H.

6. The use according to claim 5, wherein R 10 and R 11 It’s H.

7. The use according to claim 5, wherein the compound or a pharmaceutically acceptable salt or isomer thereof is selected from (3E)-1-methyl-4-phenyl-but-3-enylamine, (3Z)-1-methyl-4-phenyl-but-3-enylamine and stereoisomers thereof.

8. The use according to claim 5, wherein the compound or a pharmaceutically acceptable salt or isomer thereof is a compound represented by Formula IIa: or a pharmaceutically acceptable salt or isomer thereof.

9. The method according to claim 3, wherein A is C 3-4 Alkynyl.

10. The method according to claim 3, wherein A is a C3 alkynyl group and R 10 and R 11 It’s H.

11. The use of claim 3, wherein the disease, condition or disorder is obesity, a sleep disorder, a neurological disease, depression, anxiety, ADHD, stimulant addiction, or alcohol addiction.

12. Compounds according to the structure of Formula II: R 1 -R 5 and R 9 Each independently selected from H, OH, C 1-3 Alkyl, C 1-2 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; R 6 and R 7 Each independently selected from H or C 1-3 Alkyl; R 8 Selected from H, OH, C 1-3 Alkyl, C 1-2 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, halogen, amino, CN, CF3 and NO2; and R 10 and R 11 Is H or C 1-3 Alkyl; or a pharmaceutically acceptable salt or isomer thereof Use in the preparation of a medicament for treating stimulant addiction, when the medicament is administered, the compound or a pharmaceutically acceptable salt or isomer thereof is administered to a subject in need thereof in a therapeutically effective amount.

13. The use according to claim 12, wherein the compound or a pharmaceutically acceptable salt or isomer thereof is a compound represented by Formula IIa: or a pharmaceutically acceptable salt or isomer thereof.

14. The use of claim 13, wherein the stimulant addiction is cocaine addiction.

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