Indole derivatives having a 2-phenyl-ethanolamino-substituted lo

Details Indole derivatives having a 2-phenyl-ethanolamino-substituted lo Indole derivatives having a 2-phenyl-ethanolamino-substituted lo

1997-05-29

1998-10-06

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514411, 514866, 514909, 548431, 548506, A61K 3140, C07D20914

Patent

active

058176896

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP95/02400 filed Nov. 27, 1995.


TECHNICAL FIELD

The present invention relates to a novel indole derivative having a potent .beta..sub.3 -adrenergic receptor-stimulating activity with excellent adrenoceptor selectivity.


BACKGROUND ART

It has been known that .beta.-receptor of sympathetic nerve has two sub-types, i.e. .beta..sub.1 -receptor and .beta..sub.2 -receptor. At the present, .beta..sub.1 -adrenergic receptor-stimulating agents have been clinically used as a cardiac function promoter or a vasopressor, and .beta..sub.2 -adrenergic receptor-stimulating agents have been used as a bronchodilator, respectively.
Recently, there has been found and isolated .beta..sub.3 -adrenergic receptor as the third subtype of .beta.-adrenergic receptor, which is 1118-1121 (1989)!. The .beta..sub.3 -adrenergic receptor exists at brown adipose cells, and has been estimated to show a thermogenetic activity by decomposing lipids of white adipose cells adhering to the subcutaneous tissues or the internal organs, and hence, .beta..sub.3 -adrenergic receptor has been suggested to be connected with one of the causes of obesity. Besides, it has been reported that the crisis of the non-insulin-dependent diabetes mellitus may also be related with .beta..sub.3 -adrenergic receptor.
When a .beta..sub.3 -adrenergic receptor-stimulating agent acts on the .beta..sub.1 -adrenergic receptor and .beta..sub.2 -adrenergic receptor subtypes as well, there might be some side effects such as hyperfunction of heart, tremor of hands and foot, etc. Thus, it has been desired to develop a drug having a potent .beta..sub.3 -adrenergic receptor-stimulating activity but having no .beta..sub.1 -adrenergic receptor- and .beta..sub.2 -adrenergic receptor-stimulating activities, or having a weak .beta..sub.1 - and .beta..sub.2 -adrenergic receptor-stimulating activity. In the present description and claims, a compound having such properties is occasionally expressed as "a compound having an excellent adrenoceptor selectivity".
As a .beta..sub.3 -adrenergic receptor-stimulating agent, there have been disclosed BRL35135 oxy!acetic acid methyl ester hydrobromide; Japanese Patent Second Publication (Kokoku) No. 26744/1988 and European Patent Publication No. 23385}, SR-58611A {(R,S)-N-(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-(3-chlo rophenyl)-2-hydroxyethanamine hydrochloride; Japanese Patent First Publication (Kokai) No. 66152/1989 and European Patent Publication No. 255415}, etc. However, these BRL35135 and SR-58611A are completely different from the compounds of the present invention as mentioned below in that these compounds are not indole derivatives.
The indole compounds as listed in Table 1 are also known.


TABLE 1 __________________________________________________________________________ Pharmacological Chemical Structure Activity Literature __________________________________________________________________________ ##STR2## .beta..sub.2 -Adrenergic receptor-stimul ating activity German Patent Publication No. 3407861 ##STR3## Central nervous system inhibitory activity British Patent Publication No. 61,428 ##STR4## Antibacterial activity J. Org. Chem. 56 4403-4407 (1991) ##STR5## .beta..sub.2 -Adrenergic receptor-stimul ating activity Japanese Patent Second Publication (Kokoku) No. 2653/1971 ##STR6## .beta..sub.2 -Adrenergic receptor-stimul ating activity Japanese Patent First Publication (Kokai) No. 139041/1977 ##STR7## .beta..sub.2 -Adrenergic receptor-stimul ating activity J. Med. Chem. 25, 670-379 (1982) __________________________________________________________________________
However, these compounds are chemical-structurally different from the compounds of the present invention in having two substituents on the benzene ring and having no-substituent on the indole nucleus. Besides, these literatures have never suggest that these compounds have .beta..sub.3 -adrenergic receptor-stimulating activity.
The following compounds are known to have a

REFERENCES:
patent: 4055658 (1977-10-01), Kreighbaum et al.
Bobzin et al., "Aromatic Alkaloids from the Marine Sponge Chelonaplysilla", J. Org. Chem., 56, 4403-4407 (1991).
Chemical Abstract, 78, 431, 71665s (1973).
Clifton et al., "Arylethanolamines Derived from Salicylamide with .alpha.-and .beta.-Adrenoceptor Blocking Activities. Preparation of Lebetalol, Its Enantiomers, and Related Salicylamides", 25, 670-679 (1982).
Jackman et al., "Some tryptamine derivatives: Pharmacol., 17, 742-746 (1965).
Chemical Abstract, 96, 726, 142543k (1982).
Chemical Abstract, 109, 666, 128763n (1988).
Kato et al., CA 122:239540, May 8, 1995.
Patent Abstracts of Japan for JP 06345731, 1994.

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