Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-07-08
1992-02-18
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548526, 548527, 548525, C07D40706, A61K 3140
Patent
active
050895192
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to alpha-2-adrenergic antagonists useful in the treatment of depression, metabolic disorders (e.g. obesity or diabetes), glaucoma, migraine and hypertension.
BACKGROUND OF THE INVENTION
The adrenergic nervous system plays a major role in the innervation of heart, blood vessel and smooth muscle tissue. Compounds capable of interacting with receptor sites within the adrenergic nervous system can initiate a variety of physiological responses. including vasoconstriction, vasodilation, and increased or decreased heart rate (chronotropic), contractility (inotropic) and metabolic activity. In the past, various adrenergic compounds have been employed to affect these and other physiological responses. However, many adrenergic compounds do not possess significant selectivity to enable desirable interactions with adrenergic receptor sites. That is, these adrenergic compounds do not demonstrate a high degree of specificity for differing receptor types within the adrenergic nervous system in order to obtain a desired physiological response separate from other possible, and perhaps less desirable, responses of the system.
DISCLOSURE OF THE INVENTION
It has now been determined that a new class of compounds, as herein defined, demonstrate an ability to selectively inhibit (antagonists) alpha-2-adrenergic receptors which are mainly distributed on the membranes of central and peripheral adrenergic neurons and on the tissues innervated thereby.
Through inhibitory interaction with the alpha-adrenergic receptor in the peripheral nervous system, one can modulate the function of adrenergic neurons and hemodynamic equilibrium which is therapeutically useful in a multitude of cardiovascular indications such as hypertension, congestive heart failure, and a variety of vascular spastic conditions. Furthermore, the alpha-adrenergic antagonists are useful in certain neurological and psychiatric disorders such as depression.
The present invention includes compounds represented by the formula: ##STR3## wherein X is O or S; hydrogen, hydroxy, halo, loweralkoxy, thioalkoxy and loweralkyl; or R.sub.1 and R.sub.2 taken together can form a methylenedioxy or ethylenedioxy bridge; ##STR4## wherein Y is O or S, R.sub.6 is hydrogen, methoxy or halo and m is 0 or 1; phenyl ring is substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; and pyrrolidine ring; or a pharmaceutically acceptable salt thereof.
It will be appreciated that the compounds of the present invention contain asymmetric carbon atoms and it is to be understood that the invention includes both the racemic mixture as well as the optically active derivatives.
As used herein, the term "loweralkoxy" refers to alkoxy groups containing 1 or 2 carbon atoms.
As used herein, the term "thioalkoxy" refers to --SR" wherein R" is an alkyl residue containing 1 or 2 carbon atoms.
As used herein, the term "loweralkyl" means straight or branched chain saturated hydrocarbon radicals having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl and iso-propyl.
As used herein, the term "substituted phenyl" means a phenyl ring with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino and --SR.sub.7 wherein R.sub.7 is loweralkyl.
As used herein, the term "halo" or "halogen" means fluorine, iodine, bromine or chlorine.
The term "pharmaceutically acceptable salts" refers to the pharmaceutically acceptable, relatively nontoxic, inorganic or organic acid addition salts of the compounds of this invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the free base with a suitable organic or inorganic acid. Representative salts include the hydrochloride, hydrobromide, sulfate, phosphate, nitrate, bisulfate, acetate, oxalate, valerte, oleate, palmitrate, methanesulfonate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fum
REFERENCES:
patent: 4066648 (1978-01-01), Oka et al.
patent: 4647579 (1987-03-01), Kabbe et al.
Arendsen David L.
DeBernardis John F.
Zelle Robert E.
Abbott Laboratories
Chang Celia
Ivy C. Warren
Janssen Jerry F.
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