JPH10101644A - Pineal hormone agonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful for prophylaxis and treat ment of cancers, etc., maintaining physiological activity, excellent in chemical stability and metabolic stability, by introducing a trifluoromethyl group into an indole parent nucleus of melatonin. SOLUTION: This compound is shown by the formula (R<1> is a 1-4C alkyl or a phenyl which may contain a substituent group; R<2> is H or a 1-4C alkyl) such as a compound capable of acting as a component melatonin agonist. The compound of the formula is produced, for example, by using melatonin (N- acetyl-5-methoxytryptamine), N-benzoyl-5-methoxy tryptamine or their derivative as a raw material and treating these compounds with an electrophilic trifluoromethylating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel compound having a pineal hormone action.

[0002]

2. Description of the Related Art Melatonin (N-acetyl-5-methoxytryptamine) is a substance isolated from bovine pineal gland as a substance that degrades amphibian melanophre and has various physiological actions. It has been revealed. For example, it has been suggested to be involved in signal conversion on the retina, control of gene expression by retinal clock signals, and transmission of light and dark signals from the retina to the pineal gland (Molecular Medic.
ine, Vol. 33, pp. 830-831, 1996; Reppert, SM et a
l., Cell, 83, 1059-1062, 1995), and have also been shown to regulate the production of bioactive factors involved in immunity and cell proliferation. Recently, various melatonin receptors have been cloned and their properties and localization have been elucidated.
(Reppert, SM et al., Proc. Natl. Acad. Sci., US
A, 92, 8734-8738, 1995).

The application of melatonin as a medicament is described, for example, in Stein Hilbar's review (Deutsche Apothe
ker Zeitung, 136. Jahrgang, No. 20, 16.5, pp. 1647-1
654, 1996). However, it has been pointed out that melatonin is a chemically unstable substance and has problems in metabolic stability and bioavailability in vivo. For this reason, compounds in which melatonin is chemically modified for the purpose of stably and sustainably expressing the pharmacological action of melatonin have been proposed (for example, US Pat. No. 5,071,875). Development is in progress.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a melatonin agonist. More specifically, it is an object of the present invention to provide a substance having an affinity for the melatonin receptor and having the same physiological action on the melatonin system as melatonin. Another object of the present invention is a compound having the above characteristics,
An object of the present invention is to provide a substance having excellent chemical stability and metabolic stability in a living body. Still another object of the present invention is to provide a medicine containing a substance having the above-mentioned characteristics as an active ingredient.

[0005]

The present inventors have made intensive efforts to solve the above-mentioned problems. As a result, when a trifluoromethyl group was introduced into the indole nucleus of melatonin, the physiological activity of melatonin was substantially maintained. It has been found that chemical and metabolic stability can be greatly improved. The present invention has been completed based on the above findings.

That is, the present invention provides the following formula:

Embedded image (Wherein, R ¹ represents a C _1-4 alkyl group or a phenyl group which may have a substituent, and R ² represents a hydrogen atom or a C _1-4 alkyl group). Is what you do. According to another aspect of the present invention there is provided a medicament comprising the above compound, preferably in the form of a pharmaceutical composition.
The medicament of the present invention can be used as a prophylactic and / or therapeutic agent for diseases caused or associated with melatonin dysfunction. According to still another aspect of the present invention, there is provided a method for preventing and / or treating a disease caused or related to a melatonin dysfunction, comprising a step of administering an effective amount of the above compound to mammals including humans. Methods; use of the compounds for the manufacture of the pharmaceutical compositions; and inventions of the compounds that are melatonin agonists.

[0007]

In the above formula, R ¹ is C _1-4 (C ₁ -C 1)
And (4) alkyl groups or phenyl groups which may have a substituent. The alkyl group may be linear or branched. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group sec-butyl group, te
Any of rt-butyl groups and the like may be used. Of these, a methyl group is preferred. As the phenyl group, an unsubstituted phenyl group can be suitably used, but one or more, preferably one, substituent may be present on the phenyl ring. Examples of the substituent on the phenyl group include a halogen atom such as a fluorine atom, a chloro atom and a bromine atom, a C _1-4 alkyl group, a C atom such as a trifluoromethyl group.
Substituents selected from the group consisting of _1-4 halogenated alkyl groups, C _1-4 alkoxy groups, substituted or unsubstituted amino groups, nitro groups, and acyl groups such as acetyl groups can be exemplified.

R ² represents a hydrogen atom or a C _1-4 alkyl group.
The alkyl group may be linear or branched.
For example, any of a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group and a tert-butyl group may be used. R ² is preferably a hydrogen atom or a methyl group, and particularly preferably a case where R ² is a hydrogen atom. Particularly preferred among the compounds of the present invention are the following compounds.

[0009]

Embedded image

The compound of the present invention may have one or more asymmetric carbon atoms in the molecule depending on the type of R ¹ and R ² , and any optical isomer based on the asymmetric carbon is All are included in the scope of the present invention. In addition, any mixture of isomers such as optical isomers and diastereoisomers, racemates, and the like are also included in the scope of the present invention. Further, it may exist as any hydrate or solvate.

The compounds of the present invention include, for example, melatonin
Using (N-acetyl-5-methoxytryptamine), N-benzoyl-5-methoxytryptamine or a derivative thereof as a raw material, an electrophilic trifluoromethylating agent (for example, S- (trifluoromethyl ) -3,7-
dinitrodibenzothiophenium trifluoromethanesulfonat
e, MEC-12: Umemoto, T., Chem. Rev., 96, 1757-1777,
1996, etc.). Alternatively, a 2-haloindole derivative can be used as a raw material and converted to a 2-trifluoromethylindole derivative by reacting with a reagent such as trifluoromethylated copper (Wiemers, DM et al., J. Am. Che
m. Soc., 108, 832, 1986; Miller, JA et al., J. O.
rg. Chem., 58, 2637, 1993).

The compound having a substituted phenyl group as R ¹ is obtained by subjecting melatonin to trifluoromethylation by the above-mentioned method, removing the acetyl group on the terminal amino group by hydrolysis, and then removing the corresponding substituted benzoyl chloride. Can be easily produced by reacting Synthesis of a substituent at the indole 3-position of a compound in which R ² is a C _1-4 alkyl group, for example, a methyl group, is described in, for example, U.S. Patent Nos. 4,084,444, 4,614,807, and 4,997.
This can be performed according to the method described in, for example, Japanese Patent No. 845. However, the method for producing the compound of the present invention is not limited to the above method. In addition, by referring to the above general description and the specific description of the examples, if necessary, by appropriately modifying or altering these methods, those skilled in the art can easily produce the compound of the present invention. Will be understood.

The compounds of the present invention have the property of acting as agonists for the melatonin receptor. The existence of a control system and a transmission system in a living body in which melatonin is involved (the term “melatonin system” is used as a concept including all these systems in this specification) has been clarified. The present invention is useful as a preventive and / or therapeutic agent for diseases in mammals, preferably humans, caused or associated with various melatonin dysfunctions. That the compound of the present invention has an affinity for the melatonin receptor, and that it acts as a melatonin agonist,
For example, U.S. Pat.Nos. 5,071,875 and 5,420,108, Missbach, M. et al., J. Biol. Chem., 271, p.
It can be easily confirmed by the method described in p. The effects of the compounds of the present invention on the melatonin system are described, for example, in Eur. J. Pharmaco
l., 105, 193, 1984; Nature, 306, 782-784, 1983; FA
SEB J., 2, 2765-2773, 1988; J. Pharmacol. Exp. The
r., 246, 902, 1988; J. Rev. Physiol., 24, 41-95, 19
81; Biol. Psychiat., 23, 405-425, 1988, etc.

The medicament of the present invention can be used, for example, as a sedative, anxiolytic or antipsychotic drug for central nervous system diseases. In addition, prevention of insomnia, abnormal sleep / wake rhythms, depression, eating disorders, epilepsy, Parkinson's disease, senile dementia, various mental diseases associated with aging, Alzheimer's disease, diseases related to cerebral circulation, and / or the like. Or it can be used for treatment. Further, it may be used for the prevention and / or treatment of diseases involving immunity and growth factors, for example, diseases such as malignant tumor, immunodeficiency, rheumatism, soliosis, acne, seborrhea and the like. Furthermore, the medicament of the present invention may be used for promoting hair growth, preventing hair loss, or eliminating so-called jet lag.

The compound of the present invention may be administered as a medicament itself. Preferably, the compound of the present invention is orally or non-administered using the compound as an active ingredient and a pharmaceutical additive by a method well known to those skilled in the art. It can be administered as an oral pharmaceutical composition. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups.Pharmaceutical compositions suitable for parenteral administration include: For example, injections, suppositories,
Examples include inhalants, eye drops, nasal drops, transdermal absorbents, ointments, creams, patches, and the like. Pharmaceutical additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, diluents,
Base, solubilizer or solubilizer, tonicity agent, pH adjuster,
Stabilizers, propellants, and adhesives can be used,
An appropriate one can be selected and used according to the form of the pharmaceutical composition.

The dose of the medicament of the present invention is not particularly limited.
The appropriate dose can be selected according to the purpose of prevention or treatment, the type of disease to be applied, the age and symptoms of the patient, the administration route, and the like. It can be used in the range of about 0.01 to 100 mg per day. Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to these Examples.

[0017]

【Example】

 Example 1: Preparation of compound 1

Embedded image 232 mg (1 mmol) of melatonin (3) was dissolved in DMF (5 mL), and pyridine (0.1 mL) was added. S- (Trifluoromethyl) -3,7-dinitrodibenzothiophenium trifluoromethanesulfonate (MEC-12, 492 mg, 1 mmol) was added, and the mixture was stirred overnight at room temperature. After the precipitate was filtered, DMF was distilled off under reduced pressure. The residue was poured into 2N HCl and extracted with methylene chloride. The organic layer was washed with brine and dried over Na ₂ SO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : AcOEt = 1: 1) to obtain compound 1 (120 mg, 40%). Colorless needles (CH ₂ Cl ₂ / hexane); mp 110-112 ° C. ¹ H-NMR (CDCl ₃ ) δ 8.29 (brs, 1H), 7.31 (d, 1H, J = 8.8 H)
z), 7.11 (d, 1H, J = 2.2 Hz), 7.01 (dd, 1H, J = 2.6,8.8 H
z), 5.54 (brs, 1H), 3.87 (s, 3H), 3.55 (q, 2H, J = 6.5 H
z), 3.09 (t, 2H , J = 6.2 Hz), 1.93 (s, 3H) M + 300 Anal Calcd for C 14 H 15 N 2 O 2 F 3 · 1 / 4H 2 O, C: 55.17, H:
5.13, N: 9.19; Found C: 55.24, H: 4.92, N: 9.20

Example 2: Preparation of compound 2

Embedded image Compound 1 (100 mg) obtained in Example 1 was dissolved in EtOH (5 mL), 2 N HCl (5 mL) was added, and the mixture was refluxed overnight. The solvent was distilled off under reduced pressure to obtain a crude amino compound. After adding a small amount of pyridine and drying under reduced pressure and azeotropically evaporating water, the residue was dissolved in methylene chloride (10 mL) and pyridine (4 mL). Benzoyl chloride (50 mg) in methylene chloride (2 mL)
The solution was added and stirred at room temperature for 4 hours. Reaction solution is 2 N
HCl and extracted with methylene chloride. The organic layer was washed with water, 1 N NaHCO ₃ , water, brine, and dried over Na ₂ SO ₄ . After evaporating the solvent, the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : AcOEt = 10: 1) to obtain compound 2 (70 mg, 58%). Colorless needles (CH ₂ Cl ₂ / hexane); mp 144-145 ° C. ¹ H-NMR (CDCl ₃ ) δ 8.27 (brs, 1H), 7.65 (d, 2H, J = 8.4 H)
z), 7.47 (t, 1H, J = 7.4 Hz), 7.38 (t, 2H, J = 7.7 Hz), 7.
31 (d, 1H, J = 8.2 Hz), 7.09 (d, 1H, J = 2.6 Hz), 6.99 (d
d, 1H, J = 2.4,9 Hz), 6.22 (brt, 1H), 3.77 (q, 2H, J = 6.5
Hz), 3.70 (s, 3H), 3.22 (t, 2H, J = 6.6 Hz) Anal Calcd for C ₁₉ H ₁₇ N ₂ O ₂ F ₃ C 62.98, H 4.73, N 7.7
3; Found C 62.72, H 4.55, N 8.01.

Example 3 Preparation of Compound 2 (Alternative Method)

Embedded image 5-Methoxytryptamine (4) (5.26 mmol) was dissolved in methylene chloride (30 mL) and pyridine (2 mL), and benzoyl chloride (740 mg) in methylene chloride (5
mL) solution and stirred overnight at room temperature. Reaction solution 2
Drained into N HCl and extracted with methylene chloride. The organic layer was washed with water, 1N NaHCO ₃ , water, and brine, dried over Na ₂ SO ₄ , and the solvent was evaporated to give Compound 5 (1.48 g, 96%). ¹ H-NMR (CDCl ₃ ) δ 7.98 (brs, 1H), 7.68 (d, 2H, J = 8 H
z), 7.47 (t, 1H, J = 7.3 Hz), 7.38 (t, 2H, J = 7.5 Hz), 7.
28 (d, 1H, J = 8.8 Hz), 7.06 (d, 1H, J = 2.2 Hz), 7.05 (d, 1
H, J = 2.6 Hz), 6.88 (dd, 1H, J = 2.6,8.8 Hz), 6.23 (br
s, 1H), 3.80 (q, 2H, J = 6.3 Hz), 3.78 (s, 3H), 3.07 (t,
2H, J = 6.5 Hz).

Compound 5 (800 mg) was dissolved in DMF (25 mL), and pyridine (0.4 mL) was added. MEC-12 (1.34 g) was added, and the mixture was stirred overnight at room temperature. After the precipitate was filtered, DMF was distilled off under reduced pressure. The residue was poured into 2N HCl and extracted with methylene chloride. The organic layer was washed with brine and dried over Na ₂ SO _4. After evaporating the solvent, the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : AcOEt 10: 1) to obtain compound 2 (120 mg, 12%).

[0021]

The compound of the present invention acts as a melatonin agonist, and thus is useful as a medicament for preventing and / or treating diseases caused by or related to melatonin dysfunction, such as abnormal sleep / wake rhythms and cancer. It is.

Claims (5)

[Claims] 1. The following formula: (Wherein, R ¹ represents a C _1-4 alkyl group or a phenyl group which may have a substituent, and R ² represents a hydrogen atom or a C _1-4 alkyl group). 2. The compound according to claim 1, wherein R ¹ is a C _1-4 alkyl group or an unsubstituted phenyl group, and R ² is a hydrogen atom. 3. A medicament comprising the compound according to claim 1 or 2 as an active ingredient. 4. Use as a preventive and / or therapeutic agent for diseases caused or associated with melatonin dysfunction.
The medicament according to item 1. 5. The compound according to claim 1, which is a melatonin agonist.