New indole derivatives are melatonin receptor binders useful to treat e.g. sleep disturbance, stress, anxiety, depression, cardiovascular diseases, digestive system disorders, schizophrenia, panic attack, obesity and insomnia

摘要

#CMT# #/CMT# Indole derivatives (I), their enantiomers, diastereomers and their acid/base addition salts are new. #CMT# : #/CMT# Indole derivatives of formula (I), their enantiomers, diastereomers and their acid/base addition salts are new. R 11-6C alkyl, 3-8C cycloalkyl or 3-8C cycloalkyl-1-6C alkyl, preferably alkyl; NR 2R 35-8 membered heterocycle, preferably piperidinyl; and n : 2-6, preferably 2. An independent claim is included for the preparation of (I). #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Hypnotic; Tranquilizer; Antidepressant; Cardiovascular-Gen; Gastrointestinal-Gen; Neuroleptic; Anorectic; Anticonvulsant; Antidiabetic; Antiparkinsonian; Nootropic; Antimigraine; Neuroprotective; Endocrine-Gen; Contraceptive; Immunomodulator; Cytostatic. #CMT#MECHANISM OF ACTION : #/CMT# Melatonin receptor binder. The affinity of (I) to bind with melatonin receptors MT1 and MT2 was tested using 2-[ 1> 2> 5>I]-iodomelatonin as reference radioligand. The results showed that (I) exhibited an inhibition constant value of less than 1 mu M. #CMT#USE : #/CMT# (I) are useful to treat melatonin disorders, sleep disturbance, stress, anxiety, major or seasonal depression, cardiovascular diseases, digestive system disorders, insomnia and fatigueness due to jetlag, schizophrenia, panic attack, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders associated with normal aging or disease, migraine, memory loss, Alzheimer's disease, cerebral circulation disturbance, sexual dysfunction, as ovulation inhibitors, as immunomodulators and to treat cancers (claimed). #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of (I) comprises condensation reaction of an acid chloride of formula R 1COCl or its anhydride with 2-(5-methoxy-1H-indol-3-yl)-ethylamine of formula (II) to obtain an amide of formula (III), treating (III) with tosyl chloride under a basic medium to obtain a sulfonyl derivative of formula (IV), demethylation of (IV) to form an alcohol compound of formula (V), condensation of a chloride derivative of formula R 2R 3N-(CH 2) n-Cl to obtain an indole derivative of formula (VI) and subjecting (VI) to the action of magnesium to obtain (I). #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 0.01 mg to 1 g per 24 hours, orally, parenterally, nasally, per/trans cutaneously, rectally, perlingually, ocularly or respiratorily. #CMT#SPECIFIC COMPOUNDS : #/CMT# 3 Compounds (I) are specifically claimed i.e. N-(2-{5-[2-(1-piperidinyl)ethoxy]-1H-indol-3-yl}ethyl)acetamide of formula (Ia), N-(2-{5-[2-(1-piperidinyl)ethoxy]-1H-indol-3-yl}ethyl)propanamide and N-(2-{5-[2-(1-piperidinyl)ethoxy]-1H-indol-3-yl}ethyl)butanamide. #CMT#EXAMPLE : #/CMT# N-(2-{5-hydroxy-1-[4-methylphenynsulfonyl]-1H-indol-3-yl}ethyl)acetamide (0.36 g) was dissolved in dimethylformamide (10 ml) and potassium bicarbonate (0.4 g) and 1-(2-chloroethyl) piperidine hydrochloride (0.2 g) were added. The reaction mixture was stirred at 80[deg] C for 48 hours. The reaction mixture was worked up to obtain N-(2-{1-[(4-methylphenyl)sulfonyl]-5-[2-(1-piperidinyl)ethoxy]-1H-indol-3-yl}ethyl)acetamide. N-(2-{1-[(4-Methylphenyl)sulfonyl]-5-[2-(1-piperidinyl)ethoxy]-1H-indol-3-yl}ethyl)acetamide (0.66 g) was dissolved in methanol (15 ml). Magnesium (0.51 g) was added the solution and the reaction mixture was stirred for 20 hours. The reaction mixture was further worked up to obtain N-(2-{5-[2-(1-piperidinyl)ethoxy]-1H-indol-3-yl}ethyl)acetamide.