Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-04-24
2000-05-30
Lee, Howard C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514656, 514741, 514866, 514909, 564305, 564462, A61K 31135, C07C 49255, C07C 49753, C07C21302, C07C21774
Patent
active
06069176&
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel phenylethanolamine compounds with a .beta.3 adrenergic receptor stimulating effect which are useful as drugs, and to their pharmacologically acceptable salts.
PRIOR ART
Sympathetic nerve .beta. receptors include the subtypes .beta.1, .beta.2 and .beta.3, among which it is believed that the .beta.1 receptors are present mainly in the heart, and the .beta.2 receptors are present in the trachea, uterus, bladder and vascular smooth muscle. Also, the .beta.3 receptors are believed to be present on the cell surfaces of brown adipocytes and white adipocytes and in the enteric canal (Land, A. M. et al.: Nature, 214, 597-598 (1967). Emorine, L. J. et al.: Science, 245, 1118-1121 (1989)).
Current clinical applications of .beta.1 adrenergic receptor agonists include their use as cardiac function promoters or vasopressors, and those of .beta.2 adrenergic receptor agonists include their use as bronchial dilators, prophylactics against impending premature birth, or therapies for urinary incontinence. In addition, .beta.3 adrenergic receptor agonists have been reported useful as antiobestic and antidiabetic drugs because they promote fat decomposition and energy consumption, and as therapies for accelerated gastrointestinal motility because they suppress it (J. Med. Chem. 35, 3081-3084 (1992). Br. J. Pharmacol. 100, 831-839 (1990)).
Drugs which are known to act selectively on .beta.3 adrenergic receptors include 2-amino-1-phenylethanol compounds, such as BRL35135 [(R*R*)-(.+-.)-[4-[2-[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]phenox y]acetic acid methyl ester hydrobromide salt: Japanese Patent Publication No. 26744 of 1988 and European Patent Publication No. 23385], and SR58611A [(RS)-N-(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-(3-chlor ophenyl)-2-hydroxyethanamine hydrochloride: Japanese Laid-open Patent Publication No. 66152 of 1989 and European Laid-open Patent Publication No. 255415].
It has been reported that BRL35135 has a lypolytic and hypoglycemic effect while SR58611A has a potent suppressing effect on spontaneous locomotion of rat colon (Drugs of the Future, 18, 529-549 (1993)).
The .beta.2 adrenergic receptor agonist clenbuterol hydrochloride acts directly on bladder detrusor muscle .beta.2 receptors, having a relaxing effect on the bladder detrusor muscle (The autonomic nervous system, 26, 380-387 (1989)), and therefore finds clinical use as a therapy for urinary incontinence. However, there are problems associated with this treatment for urinary incontinence, because of side-effects including finger tremor and palpitation.
It is an object of the present invention to provide novel phenylethanolamine compounds and their pharmacologically acceptable salts, which have a strong .beta.3 adrenergic stimulating effect and high .beta.3 receptor selectivity, and which can be used as prophylactics and/or treatments for accelerated or spasmodic gastrointestinal motility, as well as obesity and diabetes, and pollakisuria; urinary incontinence and other forms of dysuria.
It is another object of the invention to provide a process for producing such phenylethanolamine compounds and their pharmacologically acceptable salts.
It is a further object of the invention to provide pharmaceutical compositions containing such phenylethanolamine compounds and their pharmacologically acceptable salts as active components thereof.
The present inventors have carried out diligent research aimed at discovering compounds which differ in chemical structure from the widely known .beta.3 adrenergic agonists and which have a potent .beta.3-selective .beta.3 adrenergic receptor stimulating effect. As a result it was found that newly synthesized novel phenylethanolamine compounds satisfy these conditions. It was further found that these compounds of the invention have a potent relaxing effect on rat bladder detrusor muscle, and the present invention was thus completed.
DISCLOSURE OF THE INVENTION
The phenylethanolamine compounds of the invention are
REFERENCES:
patent: 3803232 (1974-04-01), Rodriguez et al.
patent: 4350685 (1982-09-01), Ali et al.
patent: 4755505 (1988-07-01), Winkley et al.
Rosenbaum et al., "Lack of beta-3-Adreneric Effect on Lipolysis in Human Subcutaneous Adipose Tissue", Journal of Clinical Endocrinology and Metabolism, vol. 77: 352-355, 1993.
Airapetyan et al., Arm. Khim. Zh., 40(1): 40-44, 1987.
DeMeglio et al., "Sintesi E Studio Farmacologico Di Derivati Dell'Orciprenalina E Del Salbutamolo", Farmaco, Ed. Sci., vol. 35(3): 203-230, 1980.
Brouty-Boye, G. 1979, Chemical Abstracts vol. 93, 1980 p. 666.
Hiratsuka Kozo
Hukuzaki Atsusi
Iizuka Hiroyuki
Matsumoto Toshifumi
Matsunaga Kouichi
Lee Howard C.
Mitsubishi-Tokyo Pharmaceuticals, Inc.
LandOfFree
Phenylethanolamine compounds useful as .beta. 3 agonists, proces does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Phenylethanolamine compounds useful as .beta. 3 agonists, proces, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Phenylethanolamine compounds useful as .beta. 3 agonists, proces will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1910768