Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-10-09
1999-11-16
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544284, 544291, A61K 31505, C07D40114, C07D40514
Patent
active
059858850
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 2-piperidine (4-substituted) derivatives of 4-amino-6,7-dimethoxyquinazolines. These compounds are useful in the treatment of hypertension, congestive heart failure, prostate hypertrophy, various urinary tract disorders and pathological symptoms caused by hyperactivity or dysfunctioning of the noradrenergic neural system.
2. Description of the Related Art
The hypotensive activity of a variety of quinazoline-piperazine derivatives is well known. For example, U.S. Pat. No. 3,511,836 describes the hypotensive activity of 4-amino-6,7-dialkoxy-2-(piperazine-(4-substituted)-1-yl)quinazolines, in which the substituent in the 4-position of the piperazine is a benzoyl or furyl group; U.S. Pat. No. 4,001,237 describes the hypotensive activity of analogous derivatives in which the 4-substituent is an oxazolyl, thiazolyl, isoxazolyl or isothiazolyl group; U.S. Pat. No. 4,188,390 describes the hypotensive activity of analogous derivatives in which the 4-substituent is, inter alia, a group such as 1,4-benzodioxan-2-carbonyl.
BRIEF SUMMARY OF THE INVENTION
The subject of the invention is new 2-piperidine(4-substituted) derivatives of 4-amino-6,7-dimethoxy-quinazoline which may be represented by the general formula (I) indicated below ##STR2## in which: Ar is methoxy, ethoxy or methyl group mono-substituted with a methoxy or methyl group a methoxy or methyl group
The compounds of the present invention have been shown to be powerful antagonists to noradrenergic receptors (alpha.sub.1A and alpha.sub.1B receptor subtypes) and serotonergic receptors, and can therefore be used to advantage in treating various human illnesses, whether at the level of the cardiovascular system, in particular for treating hypertension, as well as in the urogenital apparatus, for example, in the treatment of prostate hypertrophy, various urinary tract problems and, in general, the pathological manifestations caused by hyperactive or disfunctioning adrenergic receptors.
DETAILED DESCRIPTION OF THE INVENTION
One of the advantages of the new piperidine-quinazoline derivatives of the invention over previously known piperazine-quinazoline compounds having hypotensive activity is that, as they do not contain the piperazine nucleus in their chemical structure, their use should eliminate the potential danger of neurotoxic manifestations in patients with renal failure or central nervous system disorders.
A further advantage is the absence from their chemical structure of the carbonyl-piperazine bond which is susceptible to in vivo enzymatic hydrolysis. In effect, compounds with a high bioavailability and duration of action are obtained. This allows the therapeutic dose to be reduced, for a given effectiveness and, consequently, any undesirable side-effects will be reduced.
In addition to the powerful hypotensive effect demonstrated by the compounds of the invention linked to the blocking of the alpha.sub.1 adrenergic receptor, they can also display an antagonistic effect on seratonin receptors which are widely present in some peripheral tissues such as the vascular musculature and the thrombocytes, thereby also blocking the amplification effect of seratonin on the vasoconstrictive and thrombocytic-aggregation activity of catecholamines.
Pharmaceutical forms of the compounds of the invention may be prepared by conventional techniques in the form of, for example, tablets, capsules, suspensions, solutions, suppositories or patches, and may be administered orally, parenterally, rectally or transdermally, or in other suitable ways to obtain the therapeutic effect such as, for example, as solid preparations for oral use having a protracted action which allow the controlled release of the active ingredient over time.
The active ingredient is usually administered to the patient in a reference dose which may vary from 0.001 to 1 mg/kg bodyweight per dose. In the case of parenteral administration it is preferable to use a hydrosoluble salt of the compound in question such a
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Campbell, S.F., and Plews, R.M. J. Med. Chem. 30, 1794-1798, 1987.
Makovec Francesco
Peris Walter
Rovati Lucio Claudio
Rovati Luigi Angelo
Balasubramanian V
Rotta Research Laboratorium S.p.A.
Shah Mukund J.
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