Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-02-04
1997-06-17
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540594, A61K 3155, C07D40112, C07D40312, C07D40512
Patent
active
056397488
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US92/06538 filed Aug. 5, 1992.
FIELD OF THE INVENTION
This invention relates to novel substituted 2,3,4,5-tetrahydro-1H-3-benzazepine compounds having .alpha.-adrenergic receptor antagonist activity.
BACKGROUND OF THE INVENTION
The autonomic nervous system is separated into the cholinergic and adrenergic nervous systems. Norepinephrine, the neurotransmitter of the adrenergic nervous system, exerts its activity by interaction with receptors (adrenoceptors) on the effector organs or on the nerve endings. The adrenoceptors are of two primary types: .alpha. and .beta.. Based upon selectivity of the receptors for a series of agonists and antagonists, the a adrenoceptors have been subdivided into .alpha..sub.1 and .alpha..sub.2 subtypes.
A large amount of experimental evidence now supports the view that the .alpha..sub.2 subtype is a heterogeneous adrenoceptor class. (For a general review see Timmermans and Van Zwieten, J. Med. Chem., 25, 1389 (1982)). Experiments using 6-chloro-9-(3-methyl-2-butenyloxy)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzaz epine (SK&F 104078) demonstrated that the classical adrenoceptors are heterogeneous and can be divided into SK&F 104078-insensitive and SK&F 104078-sensitive .alpha..sub.2 adrenoceptors. The latter variously are referred to as postjunctional .alpha..sub.2 adrenoceptors or, preferably, .alpha..sub.3 adrenoceptors, U.S. Pat. No. 4,683,229, Jul. 28, 1987.
As one of the primary regulators of peripheral vascular tone, .alpha. adrenoceptors long have been the targets of efforts to develop agents effective in changing vascular tone for use in treating diseases, such as hypertension, in which alterations in vascular resistance produce therapeutic benefits. Antihypertensive compounds presently in clinical use that function via interaction with a adrenoceptors include methyldopa, clonidine, and prazosin. Efforts to modulate sympathetic tone through interactions with a adrenoceptors have resulted in several compounds that interact somewhat selectively with .alpha..sub.1 or .alpha..sub.2 adrenoceptors. Selective agonists include phenylephrine and methoxamine which preferentially activate .alpha..sub.1 receptors; and clonidine, .alpha.-methyl-norepinephrine, and tramazoline which preferentially activate .alpha..sub.2 adrenoceptors. Examples of selective .alpha.-adrenoceptor antagonists include prazosin which has high selectivity for .alpha..sub.1 adrenoceptors; and the .alpha..sub.2 -selective blockers yohimbine and rauwolscine.
U.S. Pat. No. 4,469,634, dated Sep. 4, 1984, describes allyloxy- and allythio-2,3,4,5-tetrahydro-1H-3-benzazepines useful as intermediates for preparing .alpha..sub.2 adrenoceptor affinity resins and as antihypertensive agents.
U.S. Pat. No. 4,683,229 dated Jul. 28, 1987, describes 6-halo-9-alkenyloxy-2,3,4,5-tetrahydro-1H-3-benzazepines having .alpha..sub.3 -selective antagonist activity.
U.S. Pat. No. 4,265,890 dated May 5, 1981, describes mercapto substituted-2,3,4,5-tetrahydro-1H-3-benzazepines having dopamine receptor blocking activity.
SUMMARY OF THE INVENTION
The present invention resides in the discovery that certain substituted-2,3,4,5,-tetrahydro-1H-3-benzazepine compounds are .alpha.-adrenoceptor antagonists. Presently preferred compounds of the invention include: -3-benzazepine, epine, enzazepine, methyl-9-[2-(1H-pyrazol-1-yl)ethoxy]-1H-3-benzazepine, -9-(1H-1,2,4-triazol-1-ylmethoxy)-1H-3-benzazepine, e, -3-benzazepine, methyl-1H-3-benzazepine, 3-methyl-1H-3-benzazepine, enzazepine, chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-ylmethyl)-1H-3-benzazepi ne, -1H-3-benzazepine, and -1H-3-benzazepine; or a pharmaceutically acceptable salt thereof.
The most preferred compound of the invention is 6-chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine or a pharmaceutically acceptable salt thereof.
In a further aspect of the invention there are provided methods of antagonizing a adrenoceptors in mammals, including humans, that comprise administering internally to a subject an effective amoun
REFERENCES:
patent: 4233217 (1980-11-01), Shetty
patent: 4265890 (1981-05-01), Holden et al.
patent: 4469634 (1984-09-01), DeMarinis
patent: 4683229 (1987-07-01), DeMarinis et al.
Medicinal Chemistry (2nd Ed.) by Alfred Burger (Editor), pp. 72-78 (1960).
Journal of Medicinal Chemistry, vol. 25, No. 12, pp. 1389-1401, 1982, Timmermans et al.
Journal of Medicinal Chemistry, vol. 27, No. 7, pp. 918-921, 1984, DeMarinis et al.
DeMarinis Robert Michael
Pfeiffer Francis Richard
Bernhardt Emily
Lentz Edward T.
McCarthy Mary E.
SmithKline Beecham Corporation
Venetianer Stephen
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