Heterocyclic compounds for treating or preventing disorers caused by reduced neurotransmission of serotonin, norephnephrine or dopamine

Abstract

A heterocyclic compound represented by the general formula (1) or a salt thereof:wherein m, I, and n respectively represent an integer of 1 or 2; X represents —O— or —CH2—;R1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group;R2 and R3, which are the same or different, each independently represent hydrogen or a lower alkyl group; or R2 and R3 are bonded to form a cyclo-C3-C8 alkyl group; andR4 represents an aromatic group or a heterocyclic group, whereinthe aromatic or heterocyclic group may have one or more arbitrary substituent(s).

Description

TECHNICAL FIELD[0001]The present invention relates to a novel heterocyclic compound.BACKGROUND ART[0002]Three monoamines known as serotonin, norepinephrine, and dopamine function as neurotransmitters in vivo. Therefore, drugs having inhibitory effects on the reuptake of these monoamines have been used widely as therapeutic drugs for diseases associated with the central or peripheral nervous system.[0003]Most of drugs previously used in the treatment of depression selectively inhibit the reuptake of norepinephrine or serotonin. Examples of such drugs include imipramine (first-generation antidepressant), maprotiline (second-generation antidepressant), selective serotonin reuptake inhibitors (SSRIs, third-generation antidepressants) typified by fluoxetine, and serotonin and / or norepinephrine reuptake inhibitors (SNRIs, fourth-generation antidepressants) typified by venlafaxine (S. Miura, Japanese Journal of Clinical Psychopharmacology, 2000, 3: 311-318).[0004]However, all of these drug...

AI Technical Summary

Benefits of technology

[0005]An object of the present invention is to provide a drug that has a wide therapeutic spectrum and can exert sufficient therapeutic effects in a short period, compared with antidepressants known in the art.

[0182]Examples of the isotope that can be incorporated in the compound of the present invention include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine isotopes such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, and 36Cl. These particular isotope-labeled compounds of the present invention containing any of the isotopes and / or other isotopes of other atoms, for example, radioisotope (e.g., 3H and 14C)-incorporated compounds, are useful in assay for the distribution of drugs and / or substrates in tissues. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferable because of their easy preparation and detectability. Furthermore, substitution by heavier isotopes such as heavy hydrogen (i.e., 2H) can be expected to bring about particular therapeutic advantages attributed to improved metabolic stability, for example, increased in-vivo half-life, or reduced necessary doses. The isotope-labeled compounds of the present invention can be prepared generally by substituting an unlabeled reagent by an easily obtainable isotope-labeled reagent by a method disclosed in the reaction formulas and / or Examples below.

[0199]The heterocyclic compound of the present invention has excellent bioavailability, weak inhibitory activity on metabolic enzymes in the liver, few side effects, and excellent safety.

[0200]The heterocyclic compound of the present invention is excellent in transfer into the brain.

[0203]The heterocyclic compound of the present invention has reuptake inhibitory effects on 1, 2, or 3 monoamines (serotonin, norepinephrine, and dopamine) and is therefore effective for treating various disorders associated with the reduced neurotransmission of serotonin, norepinephrine, or dopamine.

Problems solved by technology

However, all of these drugs require a period as long as 3 weeks or longer for exerting their therapeutic effects and, in addition, fail to exert sufficient therapeutic effects on approximately 30% of patients with depression (Phil Skolnick, European Journal of Pharmacology, 1999, 375: 31-40).

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