JP2906085B2 - Methods of treatment with biologically active tropane derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Acceptance Issues The present invention relates to the National Institute for Drug Abuse.
of Drug Abuse), R01-DA-06301-02 and p5
0-Made with federal assistance awarded as DA06634. The federal government has certain rights in the invention.

Background Art The tropane skeleton is the basic structural unit leading to compounds with various central nervous system (CNS) activities. Due to its rigid nature, there is the possibility of producing highly selective compounds. This application binds selectively to monoamine neurotransmitters and treats major depression, Parkinson's disease, attention deficit (AD
The present invention relates to the synthesis of a tropane derivative effective for the treatment of D).

Two important central nervous system neurotransmitters are serotonin (5-HT) and dopamine (DA). Together with norepinephrine and epinephrine, these neurotransmitters contain a group known as monoamines. 5-HT and DA are involved in many diseases, such as depression, Parkinson's disease, ADD, obesity, and cocaine addiction.

The main depression is one of the common mental illnesses, affecting 5-10% of the population. The disease is characterized by extreme changes in mood and is also associated with mental illness. It is generally known that most antidepressants work significantly to modulate monoamine neurotransmitters, including DA, 50-HT and norepinephrine. 3 such as imipramine
Cyclic antidepressants are the most commonly used drugs for treating depression. It is believed that the ability of the drug to inhibit norepinephrine uptake by neurons is a major factor in their efficacy.

In recent years, many new types of antidepressants have been developed. Two of the compounds are commercially available in the United States, trazodone and fluoxetine. Both of these compounds act on the regulation of 5-HT. Trazodone increases the effect of 5-HT and fluoxetine selectively suppresses 5-HT reuptake. 3-Chloroimipramine, which inhibits both 5-HT and norepinephrine reuptake, is widely used in Europe and Canada. Other notable and tested antidepressants include fluvoxamine, citalopran, dimerdin, bupropion, and fomifensin. These drugs all suppress the mechanism of monoamine uptake, but differ in the selectivity between dopamine, 5-HT, and norepinephrine carriers.

Other syndromes also respond to antidepressants. For example (1)
Severe anxiety syndrome, characterized by a panic response, and (2) threat, both of which respond to 5-HT selective drugs. Monoamine uptake blockers are also effective in treating chronic pain, neuralgia, migraine, sleep apnea, fibromyopathy, and responsive enteritis syndrome.

Parkinson's disease affects about 1% of the population over the age of 65,
Leads to serious neurological illness. The main clinical features of the disease are disruption of motor function: walking, language, diet,
It is a confusion of operation that requires other techniques. The disease has been found to be the result of dopamine deficiency in the basal ganglia. That is, agents that can increase dopamine levels have an effective capacity for treating Parkinson's disease. The most effective drug in this regard is levodopa, which acts as a biogenesis precursor for dopamine.

Recently, attention has been focused on the treatment of attention deficit (ADD). Children with this disease are physically very active, but feel very difficult when they require long periods of attention. In addition, these children tend to be academically inferior and can be destructive. In addition, their behavior persists in adulthood in altered forms. The disease appears to be related to the action of monoamines in the cerebral cortex, which is involved in controlling attention. Many stimulants such as dextroamphetamine, methylphenidate hydrochloride, tricyclic antidepressants, antipsychotics, clonidine and the like have been used as agents for controlling this disease. Many of these drugs work with monoamine uptake transporters.

Another disease in which inhibitors of monoamine transport are effective treatments is obesity. Generally, sympathomimetics (ie,
Monoamines that increase synaptic levels) promote weight loss by suppressing appetite.
Drugs such as mazindol, which act as sympathomimetics by blocking monoamine uptake, are effective in treating obesity.

 Cocaine has the following structural formula:

The basic ring structure of this cocaine is of the tropane ring type.

It has long been known that cocaine and cocaine-related compounds function as inhibitors of dopamine reuptake and may lead to compounds with enhanced properties. In recent years, new and very potent cocaine analogues have been created based on the tropane structure (Abraham et al., Journal of Medical Chemistry, 1992, 35, 141;
Boja et al., European Journal of Pharmacology, 1990,183,329; Boja et al., European Journal of Pharmacology, 1991,194,133; Carroll
Et al., Journal of Medical Chemistry, 19
92,35,969; Carroll et al., Journal of Medical Chemistry, 1992,35,1813; Carroll et al., Journal of Medical Chemistry, 1992,35,2497; Cli
ne et al., Journal of Pharmacology and
Experimental Salaputics, 1992, 26
0,1174; Cline et al., Synapse, 1992, 12, 37; Kozikowski
Et al., Medical Chemistry Research, 1991, 1,31.
2; Kozikowski et al., Journal of Medical Chemistry, 1992, 35, 4764; Lewin et al., Journal of Medical
Medical Chemistry, 1992, 35, 135; Madras et al., Moleculer Pharmacology, 1989, 36, 518). All of these compounds are based on the tropane skeleton and have a tendency to bind selectively to the dopamine transporter.
Certain structural changes can lead to compounds that bind very selectively to dopamine reuptake sites (Carrol
l et al., Journal of Medical Chemistry, 1
992,35,2497). However, all of these tropane derivatives are very similar to each other because they are derived from cocaine as a starting material.

If the tropamine ring system is modified at the aryl moiety as described below, it is 5 times less than the DA transporter.
-Compounds that selectively bind by binding to the HT transporter can be produced. These modified tropanes (as described below) preferentially bind to the 5-HT transporter, thus increasing synaptic levels of 5-HT.
This is useful for treating diseases associated with 5-HT action. Similarly, synthesis can selectively block the DA transporter, creating tropane analogs that selectively increase DA synaptic levels.

In principle, the tropane skeleton is ideally suited for making highly selective compounds due to its rigid structure. Also, tropane derivatives have rather limited conformational flexibility. Such derivatives can be altered by appropriate structural changes to analogs that preferentially bind to either the 5-HT or DA reuptake sites. The novel chemical method referred to in the prior patent application related to the present application can produce a wider range of tropane analogs than before and have a novel structure having selective biological activity be able to.

Therefore, the main object of the present invention is to provide 5-HT or DA
To provide a novel method for the synthesis of tropane analogs, which are selective inhibitors of any of the reuptake of tropane.

Another main object of the present invention is to produce a range of tropane analogs that can be studied as therapeutics for chronic depression.

Another object of the invention is to provide a broad range of tropane derivatives that are systematically used and tested to determine structure-activity relationships for binding with dopamine, 5-HT and norepinephrine transporters. To provide.

Yet another object of the present invention is to provide a system for treating a disease capable of altering patient treatment with a compound that selectively binds to 5-HT or DA reuptake sites and prevents neurotransmission at those sites. To provide.

SUMMARY OF THE INVENTION Provided are derivatives of the biologically active tropane ring system that selectively bind to 5-HT or DA reuptake sites and lead to compounds useful for treating depression, Parkinkins disease, ADD and obesity .

Will be described.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1, FIG. 2, FIG. 3 and FIG. 4 show the ability of various analogs of the present invention to bind to 5-HT or DA transporters. These results demonstrate analogs with three different types of selectivity: DA selectivity, 5-HT selectivity, and non-selectivity.

DETAILED DESCRIPTION OF THE INVENTION The focus of the present invention lies in the use of tropane derivatives of the general formula

Here, R ₁ is an aromatic group, which may be 1-naphthyl, 2-naphthyl, phenyl, a C ₁ to C ₈ alkylaryl group or an indole group, preferably isopropylphenyl and a naphthyl group . R ₂ and R ₃ are as follows: That is, one of R ₂ and R ₃
When one is a hydrogen atom, the others are not hydrogen atoms, and R ₂ and R ₃ are each a ketone, (O = C-R _2-3 )
(O = C-R _2-3 ) is selected from phosphonate, sulfone, cyano, oxazole and imidazole. Preferably also, R ₂ and R ₃ are each a group selected from ketones, esters, C ₁ -C ₈ alkyls and alkoxys. _Me is generally a hydrogen atom, lower (C ₁ to C ₈ )
It may be described as R ₄ which may be alkyl.

The most preferred compounds that can be used in the method of the present invention are those represented by the following formula:

Here, alkyl of R is not C ₁ C _8, Ar is an aryl group.

The synthesis of the tropane derivative is performed by the following general formula.
The final step experimental approach is detailed in the earlier patent. For earlier processes, see Davies et al., Journal of
Organic Chemistry, 1991, 56, 5696.

Basically, in the process in this case, the 3-aryltropane derivative converts 8-azabicyclo [3.2.1] oct-2-ene with an aryl Grignard reagent and a copper (I) and / or copper (II) salt catalyzing agent. It is prepared by reacting in the presence of an amount. The 3-aryltropane derivative starting material is optionally prepared by decomposition of a functionalized vinyldiazomethane using a decomposition catalyst, preferably a rhodium catalyst, in the presence of certain pyrroles, preferably in the presence of a substantial excess of its stoichiometric amount. , Can be manufactured. The catalyst may be a copper, palladium, silver salt catalyst. This gives a bicyclic intermediate containing a tropane ring system, which is later converted to 8-azabicyclo [3.2.1] oct-2-ene. As such, it can be used as a starting material and used to react with an aryl Grignard reagent, which provides a synthetic route to the unique cocaine analogs of the present invention.

The starting material for this method is 8-azabicyclo [3.2.1] oct-2-ene, which has the following structural formula:

Here, R is a C ₁ to C ₈ alkyl group and C ₁ to C ₈
Is a group selected from oxyalkyl radicals of C _8. In other words, the 2-position component may be functionally substituted with a ketone group or an ester group.

HUW MLDavies, one of the present inventors, has previously disclosed the synthesis of 8-azabicyclo [3.2.1] oct-2-ene of the above formula. In this regard, Davies
Et al., "A New Entry to the Tropane System by Reaction of Rhodium (II) Acetate-Stabilized Vinyl Carbenoid with Pyrrole", Tetrahedron Letters, vol. 30, no. 35, pp. 46
53-4656, (1989); District ACS Conference in New Orleans
December 1990 Abstract, "Single Electron Withdrawing Group for Vinyl Carbenoid Chemistry, Approach to Tropan Alkaloids", Davies et al., American Chemical Society, Dec. 5-7.1990, pp. 181-182; Davies et al. , "Synthesis of ± ferrugin and anhydrous ecgonine methyl ester by tandem cyclopropanation / corpoarrangement", Journal of Organic Memories, 1991,
Vol., 56, pp. 5696-5700. These Davies
It is understood that the subject matter of the literature by them et al is cited here and the details of the description are not necessary. However, preferred processes not specifically described in the above references are described here for completeness.

Starting material for Grignard addition, ie, 8-
The synthesis of azabicyclo [3.2.1] oct-2-ene uses as a first step a decomposition process of a functionalized vinyl diazomethane of the formula:

The decomposition process is in the presence of at least a stoichiometric amount of pyrrole of the following structural formula Here, Z is carried out in the presence of a functional group protector and an effective amount of a decomposition catalyst selected from rhodium, copper, palladium, and a silver salt to obtain an intermediate bicyclic compound.

In the above formula, R is a C ₁ to C ₈ alkyl group and
C ₁ to a group selected from oxyalkyl radicals of C _8.
Preferably, R is an alkyl group which has a ketone group at the 2-position of the finally obtained cocaine analog as described below. In pyrrole, Z is a functional protector such as trimethylsilylethyl, but a conventional tertiary butyl group can also be used as this functional protector.

The amount of pyrrole in this first reaction system requires at least a stoichiometric amount, preferably more than the stoichiometric amount, for example 2 to 5 times, as compared with vinyldiazomethane. This excess is preferred to achieve high yields of the intermediate bicyclic compound. This is because vinyldiazomethane decomposes into a very reactive intermediate, a vinyl carbenoid, which degrades rapidly unless captured using excess stoichiometric amounts of pyrrole. Resulting in.

The pyrrole can be prepared by a conventionally known method described in the Journal of Organic Chemistry, 1991, Vol., 56. The reaction is preferably
It is carried out at 25 ° C to 100 ° C, preferably at 80 ° C. When gradually adding vinyldiazomethane to pyrrole,
This reaction can also be performed at 25 ° C. Pressure does not matter in this reaction.

As mentioned above, the reaction is carried out in the presence of an effective amount of a cracking catalyst selected from rhodium, copper, palladium and silver salts.
Among these, the preferred catalyst is a rhodium salt, and may be rhodium (II) acetate, mandelate, trifluoroacetate, hexanoate, pivalate or octanoate. At present, the most preferred catalyst is rhodium octanoate, which can give the desired product in high yield. The amount of this catalyst can be used in the range from 0.25 mol% to 2.0 mol%, preferably 1.0 mol%, based on vinyldiazomethane.

The reaction time is not critical and can vary from a few minutes to several hours (when added dropwise). 8-
Other carbon atoms of the azabicyclo [3.2.1] oct-2-ene may contain substituents other than hydrogen (eg, one or more of the other carbon atoms of the bicyclic system may be a lower alkyl It may contain a substituent).
This is because more substituted pyrrole or vinyldiazomethane may be used as a starting material.

The reaction of this first step produces a bicyclic intermediate compound which is hydrogenated, deprotected, and reductively methylated by the previously described 8-azabicyclo [3.2.1] oct-2-amine.
It is converted to en. This hydrogenation, removal of the deprotecting group, and reductive methylation are all known steps, and therefore need not be described in detail.

Here, R is methyl, the protecting group used is trimethylsilyl, and the intermediate is methyl 8- (2- (trimethyl-silyl) ethoxycarbonyl) -8-azabicyclo [3.2.1] oct-2,6-diene. -2- Oate.

The reaction is preferably carried out in the presence of a solvent, preferably a non-polar solvent. Preferred nonpolar solvents for this reaction include pentane, hexane, benzene, and the like. Other suitable non-polar solvents can be used as long as they can dissolve the basic reactant. There is no particular limitation on the exact solvent,
It can be used as long as it is virtually non-polar.

For details of hydrogenation, removal of deprotecting groups, and reductive methylation, see the aforementioned Journal of Organic Chemistry, 1991, Vol. 56. There,
That the catalytic hydrogenation is a Wilkinson-catalyzed process, that the deprotecting group is generated using, for example, tertiary butylammonium fluoride, and that the yield of 8-azabicyclo [3.2.1] oct-2 is as high as 95%. -To produce enes. This compound is purified by silica gel column chromatography as described in the above-mentioned references.

Then 8-azabicyclo [3.2.1] oct-2-ene is used as starting material for the process of the invention.
The structural formula of 8-azabicyclo [3.2.1] oct-2-ene described above can be obtained by reacting an aryl Grignard reagent in the presence of a catalytically effective amount of a copper salt with a biologically active Was found to be converted to a new cocaine analog. This copper salt is copper (II) or copper (II
I) It may be a catalyst.

As described above, 8-azebicyclo [3.2.1] oct-
2-R group ene to no C ₁ than is the oxy group of C _8, it is preferable rather an alkyl group of C ₁ to C _8. This is because the substitution at the 2-position is preferably a ketone substitution rather than an ester substitution. Ketones work well in copper-catalyzed reactions, are more metabolically stable as explained in the biological activity section below,
And it has the same binding site activity. The Grignard addition reaction is carried out in a suitable non-polar organic solvent, preferably in ether or tetrahydrofuran.

As the Grignard reagent (ArMgX), a suitable arylmagnesium halide is used. The aryl group phenyl, substituted phenyl, alkyl aryl C ₁ to C _8, polyaryl example anthracite reels, may be an alkyl poly aryl. Alkyl magnesium halides (C ₁ to C ₈ ) can also be used. The "X" component represents a halogenated group, preferably bromide. The copper salt may be a copper (II) or copper (III) salt, for example, copper bromide dimethyl sulfide.
It is preferable that the amount of the Grignard reagent exceeds the stoichiometric amount to ensure the reaction. Reasonably high yields are obtained by using up to about 4-fold excess Grignard reagent. The amount of copper salt catalyst ranges from 5 to 20% (mole), preferably 15% (mole) of the amount of Grignard reagent. The reaction for producing a preferable ketone is carried out according to the following reaction formula.

As can be seen, the reaction product consists of a mixture of two structural isomers. One is where the two-component position is above (a), and the other is where the two-component position is below (b). The most preferred analogs are those in which R is alkyl and therefore the 2-position is a ketone component, and are structural isomers in which the ketone group is in the upper position. These are more active in binding evaluations compared to the structural isomer with the ketone group in the lower position, and in some cases,
Shows 200 times higher activity.

Other process conditions need to be mentioned. This reaction is not particularly limited in temperature, and can be performed at any temperature from 0 ° C. or lower to room temperature or higher. Further, the reaction is preferably performed in an inert gas atmosphere. This reaction is rapid and takes a few minutes
Can be done in 12 hours range. Further, it is preferable to carry out the reaction under stirring in order to carry out the reaction completely. After the reaction is completed, it is quenched, for example, with HCl / ice, and the desired compound is extracted with ether. As described in the examples, purification can be performed by conventional silica gel chromatography.

The compound is administered orally, parenterally, intravenously, and the like. The preferred method of administration is oral administration. The dosage is 4 micrograms to 50 milligrams per kilogram of body weight,
More usually it is between 20 micrograms and 15 milligrams.

The novel tropane analog synthesized by the vinyl carbenoid method described above was tested for its ability to interact with 5-HT and dopamine transporters by two assays. Thus, displacement of radioligand binding to the transporter site and direct suppression of 5-HT and dopamine uptake in rapidly dissociated fetal and adult rat neurons were evaluated. These assays are known to be associated with transport sites in the human brain. In this binding experiment, [ ¹²⁵ I] RT
Low concentrations of I-55 (a tropane analog recently synthesized by Carroll's group (Boja et al., European Journal of Pharmacology, 1991, 184, 329))
-20 pM) to label the dopamine transporter in rat fibrous membrane. On the other hand, 5-HT transporters in rat procortex were labeled using [ ³ H] paroxetine (Harbert et al., European Journal of Pharmacology, 1985, 118, 107). To date, 34 analogues have been tested for binding. That is, their ability for binding and incorporation was evaluated, and the results are shown in Table 1 below.

In Table 1, the general formula is depicted in the first part of the present application, ie in the first part of the detailed description of the invention. The code names, WF-1 to WF-35, are simply internal reference numbers and are abbreviations for "Wake Forest-1". Two analogs, WF-11, are abbreviated PTT, and WF-31 is abbreviated PIT.

The binding affinity of tropane in the dopamine transporter is based on earlier patent applications for cocaine addiction therapeutics. In the subsequent patent application, WF-1 to WF-5,
The binding affinities for 7-9, 11 were reported as background evidence. Since then, WF-1-5, 7-9, 11, 13, 18,
Literature showing binding affinities for 19, 22, 23, 25 has been published (Davies et al., European Journal of Pharmacology-Molecular Pharmacology, 1993, 244, 93).

FIG. 1 shows displacement of [ ¹²⁵ I] RTI-55 binding by cocaine with four tropane analogs, PTT, PIT, WF-23 and WF-.
It is shown in comparison with 33. This provides information on how these compounds bind to the dopamine transporter. These data are 2
The two 2-naphthyl analogs, WF-23 and WF-33, are the most effective, followed by PTT, indicating that it is. In contrast, PIT shows less ability to displace [ ¹²⁵ I] RTI-55 than cocaine. In comparison of IC ₅₀ values (Table 1), WF-23 and WF-33 were 90
0-1300 fold, PTT 20 fold, indicating that PTT has greater capacity than cocaine in binding to dopamine transporter. In contrast, PIT shows that binding to the dopamine transporter is 2.5 times worse than cocaine.

FIG. 2 shows how the selectivity of these analogs is determined in [ ³ H] loxetine binding experiments. This leads to information on how these compounds bind to the 5-HT transporter. Again, the two 2-naphthyl analogs, WF-23 and WF-33
Is similar to [ ^125I ] RTI-55 binding (Figure 1),
It was most effective for [ ³ H] paroxetine binding. However, while these compounds have comparable capacity for displacement of [ ¹²⁵ I] RTI-55 binding, WF-33 is more potent than WF-23 for displacement of [ ³ H] paroxetine binding. 4 times less ability. Furthermore, the two phenyl analogs, PTT and PIT is reversed if the position of the ^[125 I] RTI-55 binding for the displacement of ^[3 H] paroxetine binding, PIT whereas ^[3 H] displacement of paroxetine binding , PTT was more effective than cocaine, indicating that PTT was almost equivalent to cocaine in terms of displacement of [ ³ H] paroxetine binding (FIG. 2). The IC ₅₀ values (Table 1), respectively 480 times more cocaine in the 5-HT Toranshipota site Both WF-23 and WF-33, are shown to be 140 times more effective. On the other hand, PIT was 8 times more effective than cocaine and PTT was 2 times more effective than cocaine. Table 1 shows the binding capacity ratio for all analogs for the dopamine and 5-HT transporters (higher numbers indicate a correspondingly higher dopamine transporter capacity). According to these data, PIT has relatively high selectivity for 5-HT, and PTT and PTI have relatively high selectivity for dopamine transporters. In contrast, WF-23, like cocaine, has little selectivity between the two transporters. However, the capacity for both transporters is 500 to 800 times that of cocaine.

The synthesis of tropane analogs from vinyl carbenoid precursors results in racemic compounds. Therefore, all of the above binding studies have been performed using racemic compounds. When WF-23 was separated into two stereoisomers by a chiral HPLC column, the active isomer showed an IC ₅₀ estimate of 0.03 nM for [ ¹²⁵ I] RTI-55, while the inactive isomer showed IC ₅₀ values of 113 nm (the values in Table 1 of WF-23 (1) and WF-33 (2), reference). These results indicate not only that the stereoisomers can be separated by a chiral HPLC column, but that the active isomer has a very high capacity. The active isomer of WF-23 is also effective for [ ³ H] paroxetine binding, and the selectivity of the active and inactive isomers is the same as a racemic mixture of WF-23. Generally, isomers having R ₂ in the upper position are more active, and compounds where R ₂ is a ketone are more active.

This incorporation experiment was also performed on some selected analogs, confirming the results of the binding experiments. In these experiments, isolated cells from fetal and adult rat brain were used, and the striatum was used to assess dopamine uptake, and the frontal cortex was used to assess 5-HT uptake. FIG. 3 shows the inhibition of [ ³ H] dopamine uptake into striatal cells by cocaine and selected tropane analogs. These results were equivalent to the binding evaluation. That, WF-23 is the most competent analogs to inhibit uptake of dopamine, followed WF-11 is to, WF-31 were those significantly inferior in ^[3 H] inhibited uptake dopamine. [ ³ H] 5-HT incorporation experiments in cortical cells (FIG. 4) support the results of this binding evaluation, indicating that WF-
Both 23 and WF-31 have shown to be significantly more effective than cocaine in blocking [ ³ H] 5-HT incorporation. That is, the selectivity of these tropane analogs was confirmed as determined by binding evaluation by this uptake evaluation. For example, WF-11 was 140 times more effective in suppressing dopamine uptake than 5-HT uptake. On the other hand, WF-31 was 120 times more effective in suppressing 5-HT uptake than dopamine uptake. Both were somewhat larger than the ratios determined in the binding experiments (Table 1). In contrast, WF-23, when evaluated as a racemic mixture or as its active stereoisomer, is only 3-4 regardless of the evaluation method in which the dopamine: 5-HT ratio was used.
Met.

In addition to the isopropylphenyl derivative WF-31, the ethylphenyl derivative WF-9 and the 1- (4-methylnaphthyl) derivative WF-27 also clearly show significant selectivity for 5-HT transporters with respect to binding and inhibition. . A common feature of these derivatives is that they contain some extended functionality in a plane perpendicular to the aromatic ring. This structural change leads to a novel biological activity of tropane compounds with the potential to develop new classes of antidepressants. The general activity of a series of analogs at the monoamine transporter site has proven useful in the treatment of diseases associated with impaired monoamine balance, such as Parkinkin's disease, ADD and obesity.

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Childers, Stephen Earl. 27106, Winston-Salem, North Carolina, USA, Brookmere Lane 5029 (72) Inventor Bennett, Barbara, United States 27157, North Carolina, Winston-Salem, Bo Uman Gray School of Medicine, Medical Center Boulevard, Department of Physiology and Pharmacology (No address) (58) Fields surveyed (Int. Cl. ⁶ , DB name) A61K 31/435 C07D 451/02 CA (STN) WPIL (DERWENT)

Claims (12)

(57) [Claims] An agent for selectively blocking the incorporation of 5-HT, comprising as an active ingredient an effective amount of a 3-aryltropane of the following general formula or a derivative thereof or a structural isomer thereof: Composition: Here, R1 is an aromatic group, 1-naphthyl,
Selected from 2-naphthyl, phenyl, C1 to C8 alkylaryl or indole; R2 and R3
Are the same or different and are selected from a hydrogen atom and C1 to C8 ketones, provided that R2 and
R3 is not simultaneously a hydrogen atom; R4 is methyl, a hydrogen atom or a lower alkyl group. 2. The pharmaceutical composition according to claim 1, wherein R2 is a ketone. 3. The pharmaceutical composition according to claim 1, wherein R2 is a beta isomer. 4. A pharmaceutical composition for selectively blocking 5-HT incorporation, comprising an effective 5-HT inhibitory amount of a 3-aryltropane derivative having the following structural formula: Here, R is a C1 to C8 alkyl group, and Ar is an aromatic ring. 5. The pharmaceutical composition according to claim 2, wherein the 3-aryltropane derivative is contained at a dose of 1 μg / Kg to 15 mg / Kg. 6. The method according to claim 2, wherein the oral dosage of the 3-aryltropane derivative is 20 μg / Kg to 15 mg / Kg.
A pharmaceutical composition as described. 7. A pharmaceutical composition for selectively blocking dopamine uptake, comprising an effective amount of a 3-aryltropane of the following general formula or a derivative thereof or a structural isomer thereof as an active ingredient: : Here, R1 is an aromatic group, 1-naphthyl,
Selected from 2-naphthyl, phenyl, C1 to C8 alkylaryl or indole; R2 and R3
Are the same or different and are selected from a hydrogen atom and C1 to C8 ketones, provided that R2 and
R3 is not simultaneously a hydrogen atom; R4 is methyl, a hydrogen atom or a lower alkyl group. 8. The pharmaceutical composition according to claim 7, wherein R2 is a ketone. 9. The pharmaceutical composition according to claim 7, wherein R2 is a beta isomer. 10. The method according to claim 5, wherein the effective amount of the 3-aryltropane derivative represented by the following general formula is contained as an active ingredient.
Pharmaceutical compositions for selectively blocking HT uptake: Here, R is a C1 to C8 alkyl group, and Ar is an aromatic ring. 11. The pharmaceutical composition according to claim 8, wherein the dose of the 3-aryltropane derivative is 1 μg / Kg to 15 mg / Kg. 12. The pharmaceutical composition according to claim 8, wherein the oral composition contains 20 μg / Kg to 15 mg / Kg of the 3-aryltropane derivative.