KR910006124B1 - Melatonin analogues - Google Patents

Abstract

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Description

[Name of invention]

Melatonin homologue

[Brief Description of Drawings]

1 shows the spatial orientation of a compound of the invention having a melatonin antagonist activity, wherein the longitudinal axis of the indole moiety and the 2-aryl substituent are multiplanar as described herein,

FIG. 2 shows a closely related homologue whose vertical axis is assumed to exhibit no melatonin antagonistic activity as a single plane as described herein.

FIG. 3a is a concentration-response showing melatonin antagonistic activity of one of the preferred compounds of the invention and FIG. 3b is a Schild diagram.

Detailed description of the invention

[Background of invention]

[Field of Invention]

The present invention relates to novel 2-aryl substituted-N-acetyltryptamines having pharmacological action, for example melatonin antagonistic activity, and methods of their synthesis.

[Technology Background]

Melatonin, or 5-methoxy-N-acetyltrytamine, is the major hormone of the pineal gland. Synthesis and secretion of melatonin exhibits a 24-hour cycle rhythm that varies with season and age, such as adolescence and senescence. Rhythm is believed to be the result of endogenous mechanisms and the role of the environment, in particular the exposure of mammals to light that inhibits melatonin synthesis and secretion. Melatonin is considered a hormonal regulator of photoperiodic changes. Evidence suggests that melatonin is involved in the regulation of 24-hour rhythm and various neuronal and endothelial functions. Melatonin is associated with a number of human diseases, particularly those related to lifelong abnormalities. Researchers have suggested that melatonin is administered to mitigate or prevent the impairment of 24-hour rhythms due to rapid turnaround in time zones, such as jet lag, or changes in work shifts from night to day. European Patent Application No. 0 126 630).

It has been suggested that melatonin modulates the sun-shortening effect on the symptom of winter depression in seasonal emotional disorders (SAD), and that the symptoms of SAD are due to melatonin secretion in a slightly odd or unusually sensitive group. Rosenthal et al., J. Neural Transm. (1986) [suppl] 21: 257-267. Thus, in Science, Vol. 235, pages 352-354, Lewy uses daylight to suppress melatonin production in humans at night, indicating that this treatment reverses depressive symptoms in SAD patients.

Melatonin homologues have been studied for their effects on the germ line, specifically on the gonad suppression action and on the inhibition of the release of progesterone (LH) [Flaugh et al. Journal of Medicinal Chemistry, (1979) 22: 63-69. ].

Life Sciences, Frohn et al., Vol. 27, pp. 2043-2046, Pergamon Press and Clemens et al. J. Neursl Transm. (1986) [suppl] 21: 451-459 describe melatonin homologues in which the action of the melatonin homologue is related to the structure. Homologs with improved metabolic stability are described, for example 2-methyl-6,7-dichloromelatonin.

(1975) Life Sci, 17: 1167-1168 by Howard and Hadley, melatonin responses of various indoleamines including melatonin and 5-methoxy-N-acetyltrytamine by frog skin lightening In vitro methods have been reported to measure. Of the compounds described in this paper, only N-acetyltryptamine and N-acetylserotonin have been reported to have `` melatonin blocking activity ''.

Evr. By Dubocovich. J. Pharmacol. 105: 193-194, 1984 also reported that N-acetyltryptamine competitively antagonizes the inhibitory effects of melatonin in the retina of chickens, thereby enhancing melatonin blocking activity in a more sensitive in vitro method than that used by Howard and Hadley. It was reported.

Therefore, it is clear that the development of melatonin homologues and the use of such melatonin homologues for the treatment of lifespan, nerves and endocrine abnormalities in the human body is a continuing concern.

[Summary of invention]

The present invention has a melatonin antagonistic activity or agonist activity, and provides novel compounds of the general formula (I).

Wherein each R is independently selected from the group consisting of hydrogen, halogen such as fluoro and chloro and lower alkyl groups, ie C ₁ -C ₄ alkyl groups such as methyl, ethyl, n-propyl and isopropyl R ¹ is an aryl group having 4 to 14 carbon atoms (including a heteroaryl group), for example, a phenyl, thienyl, furanyl, pyridyl or naphthyl group, and R ² is hydrogen, lower alkyl, ie C _Is selected from the group of _1- C ₄ alkyl groups and phenyl groups, R ³ is hydrogen, halogen, for example fluoro and chloro, hydroxy, lower alkyl, ie C ₁ -C ₄ alkyl groups, lower alkoxy, ie C ₁ -C ₄ alkoxy and phenoxy group, R ⁴ is hydrogen, halogen, for example fluoro and chloro, hydroxy, lower alkyl, ie C ₁ -C ₄ alkyl, lower alkoxy, ie C ₁ -C ₄ is selected from the group consisting of alkoxy and phenoxy, R ⁵ is, for hydrogen, halogen, for example, fluorene And a le chloro, hydroxy, lower alkyl, i.e. C ₁ -C ₄ alkyl, lower alkoxy, or C ₁ -C ₄ is selected from the group consisting of alkoxy and phenoxy, R ⁶ is, for hydrogen, halogen, for example fluoro And chloro, hydroxy, lower alkyl, ie C ₁ -C ₄ alkyl, lower alkoxy, ie C ₁ -C ₄ alkoxy and phenoxy, A is oxygen, sulfur or nitrogen, m is 1-3 N is an integer of 1 to 3, x is 0 or 1, y is 1 when A is oxygen or sulfur, and y is 2 when A is nitrogen.

Each of R is hydrogen, R ² is a lower alkyl group, m is 1, n is 2 and x is preferably 0. R ¹ is more preferably selected from the group consisting of hydrocarbyl groups such as phenyl and naphthyl, for example phenyl.

These compounds have melatonin activity or antagonistic activity and may be associated with parallax fatigue, depression, and 24-hour cycles or seasonal rhythms and / or functions regulated by the amount of melatonin in the body and / or hormone melatonin It is useful for treating abnormalities.

In the compound of the present invention, the vertical axis of the indole ring and the 2-aryl substituent is preferably multiplanar. That is, the longitudinal axis of the indole portion (see A in FIG. ¹ ) is preferably oriented so as to be in a plane different from R ¹ (see B in FIG. 1). To achieve this orientation R ¹ must be connected to the indole moiety by methylene or polymethylene bridges, ie m is an integer from 1 to 3 but not zero. Since R ¹ is a `` bulky '' group, this multi-plane orientation of the compounds of the invention is advantageous in terms of energy.

Melatonin antagonists in the case of 2-phenyl N-acetyltrytamine shown in FIG. 2, in which the longitudinal axis of the indole moiety and the 2-phenyl substituent (see C in FIG. 2) are single plane in structure. Vaginal activity is not observed.

In particular, R ¹ may be selected from the group consisting of phenyl, thienyl, furanyl, pyridyl, pyrrolyl and other aromatic and heteroaromatic groups of five or six membered single rings.

The groups may also be substituted by various functional groups. In particular, such substituents may be selected from the group consisting of hydroxy, nitro, azido, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl groups, said heteroatoms being halogen, nitrogen, oxygen, sulfur And it is selected from the group consisting of phosphorus, the hydrocarbyl group is 1 to 12 carbon atoms. R ¹ may also be a polyphenyl group such as biphenyl and similar polyaromatic and poly heteroaromatic groups.

R ¹ may also be selected from the group consisting of organic groups having fused aromatic rings, ie groups consisting of carbon atom pairs or groups of at least two rings sharing carbon and nitrogen atoms.

R ¹ are preferably a fused aromatic ring of up to three, R ¹ is more preferably a two fused aromatic rings. Examples of suitable groups as R ¹ include naphthyl, anthracyl, phenanthryl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzotriazolyl, triazolo pyradinyl, benzoxazolyl, benzothiazolyl, ben Yoxadiazolyl, benzopyranyl, quinolyl, phthalazinyl, furinyl, naphthothienyl, indolinyl, kinrizinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnaolinyl, and the like. .

The groups can also be substituted by various functional groups. In particular, such substituents may be selected from the group consisting of hydroxy, nitro, azido, sulphonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl groups, said heteroatoms being halogen, nitrogen, oxygen, sulfur And it is selected from the group consisting of phosphorus, the hydrocarbyl group is 1 to 12 carbon atoms.

The compounds can be prepared as described in the Examples below.

Specific preferred compounds within the scope of the present invention include the following compounds.

2-benzyl-N-acetyltrytamine

2-benzyl-5-bromo-N-acetyltrytamine

2-benzyl-5-hydroxy-N-acetyltrytamine

2-benzyl-5-methoxy-N-acetyltrytamine

2- (2-chlorobenzyl) -N-acetyltrytamine

2- (2-methylbenzyl) -N-acetyltrytamine

2- (2-nitrobenzyl) -N-acetyltrytamine

2- (1-naphthyl) methyl-N-acetyltrytamine

2- (2-thienylmethyl) -N-acetyltrytamine

Preferred embodiments of the present invention are directed to the treatment of a disease wherein treating or inhibiting melatonin function or affecting a 24-hour cycle rhythm by administering to the patient suffering from any disease a therapeutically effective amount of one or more compounds of the invention. It becomes a treatment method.

Another preferred embodiment of the present invention is to administer a therapeutically effective amount of one or more compounds of the present invention to one or more lifelong disease patients, such as lifelong diseases such as seasonal emotional disorders (SAD), sleep disorders and Treatment of symptoms such as combustible conditions and fatigue associated with disturbances in sleep / weather cycles (eg jet lag, night shift workers, etc.).

Another suitable embodiment of the present invention is to administer a therapeutically effective amount of one or more compounds of the invention to one or more lifelong disease patients such as lifelong diseases, such as seasonal emotional disorders (SAD), sleep diseases and It can be used to treat symptoms such as mask conditions and fatigue associated with disturbances in sleep / weather cycles (eg, jet lag, night shift workers, etc.).

Another suitable embodiment of the present invention relates to the conversion of melatonin function by the administration of one or more therapeutically effective amounts of a compound of the invention to one or more psychotic patients or influenced by melatonin and a 24-hour cycle rhythm. It is a method of treating various psychotic diseases such as emotional disorders (manic and depression), alcoholism and stress.

Another preferred embodiment of the invention is due to altered melatonin function by administering a therapeutically effective amount of one or more compounds of the invention to one or more endocrine-related disease patients or patients seeking to cause endocrine-related diseases or to melatonin and A method for treating or causing various endocrine-related diseases affected by biological rhythms, especially endocrine-related diseases related to genital maturation and function control, such as idiopathic delayed puberty, premature birth and infertility. In addition, the melatonin active compounds of the present invention can be used to treat or prevent glaucoma by administering at least one effective amount of the melatonin active compound in the present invention to lower intraocular pressure and control body weight.

Finally, preferred embodiments of the present invention use melatonin active substances to control the reproduction cycle by administering to the animal at least one effective amount of a compound of the present invention.

In general, the pharmacologically effective daily dosage may be from 0.01 mg / kg / day to 100 mg / kg, preferably from 0.1 mg / kg / day to 25 mg / kg / day, of course in any specific case. In choosing a dosage suitable for the subject, care should be taken in consideration of the patient's weight, general state of health, metabolism, age, and other factors affecting the response to the drug. Particularly preferred dosage is 1.0 mg / kg / day.

Another embodiment of the present invention is to provide a pharmaceutical composition in the form of a dosage unit consisting of about 2 mg to 500 mg of the compound of the above general formula.

The pharmaceutical composition may be in a form suitable for oral use such as, for example, tablets, water-soluble or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, or syrups or elixirs.

Compositions for oral use can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, which compositions contain one or more reagents selected from the group consisting of sweetening, flavoring, coloring and preservatives. Pharmaceutically good, delicious formulations are provided. Tablets contain the active ingredient and pharmaceutically acceptable nontoxic excipients suitable for the manufacture of tablets.

These excipients are, for example, inert diluents (e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate), coarse and disintegrants (e.g. corn starch, or alginic acid), binders (e.g. starch, gelatin, Or gum arabic) and lubricants (eg, stearic acid, magnesium, stearic acid, or talc). Tablets may not be coated or may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract. In this way, it is possible to provide sustained activity over a long period of time.

Formulations for oral use include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or the active ingredient in an oil medium such as peanut oil, liquid paraffin or olive oil. It may also be formulated as a soft gelatin capsule mixed with.

Aqueous suspensions contain the active ingredient and excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth rubber and gum arabic, and dispersants or wetting agents are naturally occurring phospholipids, eg For example lecithin or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxy-cetanol, or ethylene Condensation products of oxides with partial esters derived from fatty acids and hexitols, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as poly It may be oxyethylene sorbitan monooleate . The demandable suspension also contains one or more preservatives such as ethyl benzoate, benzoic acid n-propyl or benzoic acid p-hydroxy, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose. It may also contain os, saccharin or sodium cyclamate or calcium cyclamate.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in a mixture with the dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified above. Additional excipients may be present, such as sweetening, flavoring and coloring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain protective, preservative and flavoring and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable, eg, an aqueous suspension for sterile injectable. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Sterile injectables may also be sterile injectable solutions or suspensions in a parenterally acceptable non-toxic diluent or solvent, for example a solution in 1,3-butanediol.

Pharmaceutical compositions of the invention also include compositions for transdermal administration and / or intranasal administration. Accordingly, the compounds of the present invention may be formulated with penetration enhancers, such as 1-n-dodecylazacyclopentan-2-one or other penetration enhancers, described in US Pat. Nos. 3,991,203 and 4,122,170. The content is referenced to describe penetration enhancers that may be included in the transdermal or intranasal compositions of the present invention.

The pharmaceutical composition may be tableted or otherwise formulated such that 5 to 95 parts by weight of active ingredient is present relative to 100 parts by weight of the composition. Dosage unit forms generally contain from about 1 mg to about 100 mg of the active ingredient of the general formula described above.

It is clear from the foregoing discussion that the compositions of the present invention can be administered orally or parenterally. The term parenteral, as used herein, includes subcutaneous injection, intravenous, intramuscular or intrasternal injection or infusion techniques.

In order to demonstrate the method by which the present invention can be carried out, the following examples are described. However, the examples are for illustrative purposes and the present invention is not to be considered limited to any particular material or condition of the examples.

Example 1

Preparation of 2-benzyl-N-acetyltrytamine

Tryptamine 8.0 gm (0.05 M), benzaldehyde 5.8 gm (0.055 M), and 440 mL of 0,125 N sulfuric acid were mixed together and then heated to 70-75 ° C. for 24 h in a stirred 1 liter round bottom flask. The resulting precipitate was filtered and recrystallized in ethanol solution made basic with ammonium hydroxide. The melting point of the resulting organic amine was 168-174 ° C.

4.10 gm (0.026 m) of the above product (1-benzyl-tetra-hydrocarboline hydrochloride) was mixed with 600 mg of carbon based 10% palladium, 30 ml of glacial acetic acid and 180 ml of deionized water. This mixture was placed in a gas reservoir of about 6934.08 gm / cm ² (1001bs / in ² ) hydrogenation heated to 35 ° C. The reaction was continued for 6 hours and then cooled to room temperature overnight. The mixture was filtered and the filtrate was extracted with dichloromethane. The aqueous solution was then treated with ammonium hydroxide and the resulting precipitate was filtered off, washed with water and dried. Melting point was 159-163 degreeC.

Yield: 2.2 gm (54%)

0.3 gm (0.0012 M) of the product (2-benzyltryptamine) was dissolved in ethyl acetate and then made basic by the addition of drops of ammonium hydroxide. 50 mg of potassium carbonate was added along with 0.3 ml acetic anhydride (0.01 M).

The mixture was stirred at room temperature under nitrogen atmosphere for 15 minutes. Water was added and the organic phase was separated. It was washed with brine and then dried using magnesium sulfate. Concentration gave a residue, which was purified by column chromatography (C-18 colour, methanol / water gradient) to give 0.075 gm (21%) of 2-benzyl-n-acetyltrytamine.

Elemental Analysis Values:

Found (%): C; 77.94, H; 6.89, N; 9.39

Theoretical value (%): C; 78.05, H; 6.89, N; 9.58

Example 2

Preparation of 2-benzyl-5-methoxy-N-acetyltrytamine

5-methoxy trytamine was used instead of trytamine (Example 1) to obtain the compound.

Example 3

Preparation of 2- (4-methoxy) benzyl-N-acetyltrytamine

The compound was obtained using p-methoxybenzaldehyde instead of benzaldehyde (Example 1).

Example 4

Preparation of 2- (4-methyl) benzyl-N-acetyltrytamine

The compound was obtained using p-tolualdehyde instead of benzaldehyde (Example 1).

Example 5

Preparation of 2- (1-naphthyl) methyl-N-acetyltrytamine

The compound was obtained using 1-naphthaldehyde instead of benzaldehyde (Example 1).

Melatonin Receptor Assay

Melatonin has been shown to inhibit dopamine release from rabbit retinas through specific receptor mechanisms (Dubocovich, 1983, Nature, 306: 782-784 and 1985, J. Pharmacol. Exp. Ther. 234: 395- 401). Competitive antagonists are expected to prevent dopamine release from being reduced by melatonin and shift the melatonin concentration-response curve to higher concentrations.

Methods: The method of Dubokovichi, 1985 was used to show melatonin receptor antagonist activity. Dopamine release was induced simply in vitro by electric field stimulation (3 μs, 2 min, 2 mA, 2 msec.) Of rabbit retinal fragments previously labeled with ³ H-dopamine. Release was measured as a percentage of the spontaneous release concentration measured before and after total tissue radio-stimulation released during stimulation. Two stimuli (S ₁ and S ₂ ) durations were applied at 40 minute intervals in each experiment. The results are expressed as the ratio of release at S ₂ to release at S ₁ .

In the control experiment, various concentrations of melatonin were present during S ₂ , and release was attenuated compared to that shown in S ₁ . To test antagonistic activity, compounds were added 40 minutes before S ₁ and were present throughout the rest of the experiments involving the addition of melaconin during the S ₂ period. Preliminary experiments were conducted with compound alone for S ₂ to test any direct effect of the compound on dopamine release.

Example 6

Examples of the compound 1 did not have a significant direct effect on the natural dopamine release or stimulate dopamine release when tested at a concentration of 0.1-10μM (compound alone, as shown in the figure is controlled ratio S ₂ / S ₁ Could not be adjusted). Increasing concentrations (lpM - 100nM) of melatonin in the presence of S ₂ is decreased gradually the S ₂ / S ₁ ratio. The concentration of melatonin (IC ₁₀ ) which inhibited release by 50% was 0.04 nM.

As shown in Figure 3a, the effect of any given melatonin concentration is reduced by increasing the concentration of this compound, and the melatonin concentration-response curve has shifted to the right (increasing the IC ₁₀ value). As shown in FIG. 3A, melatonin was absent (empty sign) or present at various concentrations (filled sign) during S ₂ . Compound (N-0774) of Example 1 was present at concentrations of 0.1 μM (▲), 1μM (■), or 10μM (◆) in both S ₁ and S ₂ . The affinity constant for antagonists (KB) could be estimated from the Schild plots shown in Figure 3b [Arunlakshana and Schild, 1959. Br. J. Pharmacol, 14: 48-58), the KB calculated for this compound is known to be 20 nM.

Conclusion: The compound of Example 1, 2-benzyl-N-acetyltrytamine, is a potent and competitive antagonist at the melatonin receptor.

Example 7

The activity of compound 1-5 was tested using the melatonin receptor assay described above. Compounds did not inhibit ³ H-dopamine release from the rabbit retina only when present during the S ₂ electrical stimulation period. However, all of the compounds significantly antagonized the activity of 0.1 nM melatonin to inhibit ³ H-dopamine release as shown in the Higi table.

TABLE 1

* (n) number of experimental observations

Claims (23)

The compound of the following general formula (I).

Wherein each R is independently selected from the group consisting of hydrogen, halogen and lower alkyl groups, R ¹ is an aryl group having 4 to 14 carbon atoms, and R ² is selected from the group consisting of hydrogen, lower alkyl and phenyl groups R ³ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy group, and R ⁴ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkoxy, lower alkoxy and phenoxy group R ⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy group, and R ⁶ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy group Is selected, A is oxygen, sulfur or nitrogen, m is an integer from 1 to 3, n is an integer from 1 to 3, x is 0 or 1, y is 1 when A is oxygen or sulfur, and A is Y is 2 when is nitrogen. ^2. A compound according to claim 1 wherein each R is hydrogen, R ² is a lower alkyl group, m is 1, n is 2 and x is 0. 3. A compound according to claim 2, wherein R ¹ is a hydrocarbyl group. ^4. A compound according to claim ³ , wherein R ³ , R ⁴ , R ⁵ and R ₆ are hydrogen. The compound of claim 4, wherein R ¹ is selected from the group consisting of phenyl, naphthyl, p-methyl phenyl and p-methoxy phenyl groups. ^4. A compound according to claim 3, wherein R ³ is a methoxy group and R ⁴ , R ⁵ and R ⁶ are hydrogen. 7. A compound according to claim 6, wherein R ¹ is a phenyl group. A compound according to claim 5, wherein R ¹ is a phenyl group. A compound according to claim 5, wherein R ¹ is a naphthyl group. A compound according to claim 5, wherein R ¹ is a p-methyl phenyl group. A compound according to claim 5, wherein R ¹ is a p-methoxy phenyl group. (a) reacting a trytamine compound of formula (II) with an aldehyde of formula (III) in the presence of an acid to obtain an I-benzyl tetrahydrocarboline compound of formula (IV)

Wherein each R is independently selected from the group consisting of hydrogen, halogen and lower alkyl groups, R ¹ is an aryl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are independently hydrogen, halogen, hydroxy , Lower alkyl and alkoxy groups) (b) reducing the carboline in step (a) to obtain a compound of formula (V)

Wherein R, R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are as defined above. (c) acetylating the compound of step (b) to obtain 2-aryl substituted N-acetyltrytamine of formula (VI)

(Wherein R, R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above), wherein the 2-aryl-substituted N-acetyltrytamine is prepared. 13. The method of claim 12, wherein each R is hydrogen. The method of claim 13, wherein R ³ is methoxy and R ⁴ , R ⁵ and R ⁶ are hydrogen. The method of claim 13, wherein R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. The method of claim 15, wherein R ¹ is p-methoxybenzyl. The method of claim 15, wherein R ¹ is p-methylbenzyl. The method of claim 15, wherein R ¹ is naphthyl. The method of claim 15, wherein R ¹ is benzyl. The method of claim 14, wherein R ¹ is benzyl. A pharmaceutical composition for the treatment of mental disorders associated with melatonin function comprising at least one compound of the general formula (I) as an active ingredient or affected by melatonin and a 24-hour rhythm.

Wherein each R is independently selected from the group consisting of hydrogen, halogen, and lower alkyl groups, R ¹ is an aryl group having 4 to 14 carbon atoms, and R ² is a group consisting of hydrogen, lower alkyl and phenyl groups R ³ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy group, and R ⁴ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenyl group R ⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy group, and R ⁶ is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy group Is selected, A is oxygen, sulfur or nitrogen, m is an integer from 1 to 3, n is an integer from 1 to 3, x is 0 or 1, y is 1 when A is oxygen or sulfur, and A is Y is 2 when is nitrogen. The composition of claim 21, wherein the disease is a lifelong disease. The composition of claim 21 wherein the disease is an endocrine disease.

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