Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-06-28
1992-09-15
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514183, 514212, 514317, 514428, 514508, 540450, 540597, 540610, 546193, 546205, 546241, 546275, 548569, 564254, A61K 31445, C07D21104
Patent
active
051478790
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel hydroximic acid halides, the preparation of the same, pharmaceutical compositions containing the above novel compounds as active ingredient as well as the use of the said compounds in the therapy of diabetic angiopathy.
BACKGROUND ART
One of the most frequent metabolism diseases is diabetes mellitus, the main symptom of which is the disturbance of the balance of carbohydrate metabolism in the organism. Diabetes mellitus is often accompanied by pathological vascular deformations, e.g. vasoconstrictions in the limbs, pathological deformation of the eyeground vessels, etc. Though, in addition to insulin a large number of effective drugs are known, in the field of the treatment of diabetic angiopathy associated with the basic disease, results provided by the commercially available compositions are quite poor. This situation is caused by the phenomenon that diabetes mellitus results in changes of the vascular adrenergic receptors, and consequently, medical treatment with the commercially available drugs results in adrenegic reaction different from those taking place in the blood vessels of non-diabetic patients. (Nature New Biology, 243, No. 130, 276/1973/; Szemeszet, 111, 23/1974/; Endocrinology, 93, 752/1973/). The adrenergic receptors of blood vessels in diabetic patients undergo a transformation into beta receptors due to the quantitative increase of the metabolism. For the receptor transformation, the release of a modulator is responsible (Amer.J.Physiol., 218, 869/1970/). After addition of the modulator to the alpha organ the alpha agonists will not be active any more as the receptor is transformed into beta.
The original alpha sensibility may be recovered by adding a special beta blocking agent into the organism.
In case of qualitative alteration of the metabolism in model or human in vivo diabetes the alpha agonists, e.g. noradrenalin, remain effective, this effect, however, may be compensated by the addition of beta blocking agents. This is the first functional change which is detectable in diabetes, e.g. by addition of Alloxane (Hexahydropirimidin-tetraon), 24 hours after the administration. In case of diabetes an imperfect alpha-beta receptor transformation--possibly due to the formation of an alternative, so-called "Falsch" modulator--serves as starting point of the pathological changes.
DISCLOSURE OF THE INVENTION
It has been found that the novel compounds of the formula (I) wherein being substituted with hydroxy, and form a 5-8 membered ring optionally containing additional nitrogen and/or oxygen atom, which ring may also be condensed with a benzene ring, R.sup.3 is hydrogen, phenyl, naphtyl or piridyl optionally substituted with one or more halo or alkoxy, the healthy blood vessels, but show a strong effect on the adrenergic receptors deformed by the diabetes mellitus. This effect appears in the first line as a selective beta-blocking effect, consequently, the compounds of the general formula (I) are useful in medical influencing of diabetic angiopathy.
The common beta-blocking agents <Inderal, 1-(methyl-ethyl-amino)-3-(1-naphtalenyloxy)-2-propanol, Visken, 4,5-dihydro-2-(5-methyl-2-/1-methyl-ethyl-phenoxy/-methyl)-1H-imidazol> are contraindicated in the therapy of diabetic angiopathy.
Diabetes selective adrenergic receptor blocking compounds are described in Hungarian Patent No. 177,578, "Process for preparing novel OF-(3-amino-2-hydroxypropyl)-amidoxim derivatives". An other object of the invention is the process for preparing the compounds of the general formula (I) and the salts thereof. According to the process
a) an aldoxim of the general formula (III) wherein R.sup.3, R.sup.4, R.sup.5, m and n are as defined above, is reacted in the presence of a base with an amine of the general formula (IV/A) and (IV/B), resp., wherein R.sup.1 and R.sup.2 are as defined above and X is halo, or
b) an aldoxim of the general formula (III), wherein R.sup.1, R.sup.2 R.sup.3, m and n are as specified above, is reacted with epichlorohydrine and
REFERENCES:
patent: 4187220 (1980-02-01), Takacs et al.
patent: 4308399 (1981-12-01), Takacs et al.
Almasi Attila
Balazs Bela
Blasko Gyorgy
Boross Maria
braham Lajos
Biorex Kutato-Fejleszto KFT
Chang Celia
Ivy C. Warren
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