Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-16
1999-02-23
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3135
Patent
active
058744614
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the national stage of application Ser. No. PCT/EP 95/05174, filed on Dec. 21, 1995, which in turn claims priority from EP 94.203.775.5, filed on Dec. 28, 1994.
The present invention is concerned with the use of an the manufacture of a medicament for the therapeutic or prophylactic treatment of humans suffering from aging of, or degenerative diseases of the vascular and nervous system which are associated with oxidative stress. disclosed in EP-0,145,067 as .beta.-1 blocking agents having therapeutic potential for treating hypertension. Nebivolol, which consists of a racemic mixture of (RSSS) and (SRRR) generically disclosed therein. Nebivolol is disclosed specifically in EP-0,334,429, and therein the (SRRR) enantiomer is shown to be a potent and selective .beta.-1 blocking agent, whereas the (RSSS) enantiomer is shown not to be a potent .beta.-1 blocking agent, but a potentiator for a series of antihypertensive agents such as atenolol, propanolol, prazosin, hydralazine and, interestingly, also its own (SRRR) enantiomer. In the meantime subsequent investigations have shown that several beneficial haemodynamic effects of nebivolol which distinguish it from other .beta.-1 blocking agents, e.g. that it acutely lowers blood pressure in spontaneous hypertensive rats, decreases total peripheral vascular resistance and augments stroke volume in anaesthesized dogs, are also largely attributable to the (RSSS) enantiomer.
Experiments now show that have potent antioxidant activity both in vitro and in vivo. Apparently, this is only the second group of .beta.-1 blockers after carvedilol and its metabolites to exhibit antioxidant properties in vitro and in vivo, with this difference that the .alpha.,.alpha.'-imino potent. In view of their antioxidant properties, have therapeutical utility in the treatment of degenerative diseases as well as aging of the vascular and nervous system which are caused by oxidative stress.
Consequently, the present invention is concerned with the use of the pharmaceutically acceptable acid addition salts, the stereochemically isomeric forms, and any mixtures of said derivatives, salts and stereoisomers, for the manufacture of a medicament for the therapeutic or prophylactic treatment of humans suffering from aging of, or degenerative diseases of the vascular and nervous system which are associated with oxidative stress, said derivatives having the formula (I): ##STR1## wherein R.sup.1 and R.sup.3 each independently represent fluoro, hydroxy or hydrogen, R.sup.2 and R.sup.4 each independently represent hydrogen or hydroxy, and each asterisk indicates a stereogenic center.
The invention also concerns a method of treating patients suffering from aging of or degenerative diseases of the vascular and nervous system which are associated with oxidative stress, by administering to said patients an derivative effective in improving, halting, retarding or palliating the course and/or effects of said aging and degenerative diseases.
The compounds wherein R.sup.1 and R.sup.3 represent hydroxy, and R.sup.2 and R.sup.4 represent hydrogen, were thought to be the main metabolites formed from the corresponding compounds wherein R.sup.1 and R.sup.3 represent fluoro, but very recent findings show that they are not. Nevertheless, these pseudo-metabolites do have potent anti-oxidant activity.
Specific compounds according to the invention include: racemic mixture of which is generically known as nebivolol, its individual enantiomers, (RSSS) and (SRRR) ino!-methyl!-6-hydroxy-2-chroman-methanol ethanedioate (1:1); and ino!methyl!-6-hydroxy-2-chroman-methanol ethanedioate (1:1).
The compounds of formula (I) may be prepared following the procedures described in EP-0,145,067 and EP-0,334,429. As they have basic properties, these compounds may be converted into their pharmaceutically acceptable acid addition salt forms by treatment with an appropiate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or h
REFERENCES:
G. Vandeplassche et al., "Cytoprotective Effects of Nebivolol", Drug Investigation, vol. 3 (Suppl. 1): 134-136, 1991.
L.M.A.B. Van Bortel et al., "Antihypertensive treatment and vessel wall properties of large arteries", Basic Res. Cardiol., vol. 86, Suppl. 1, pp. 91-95, 1991.
Salvetti et al., "What Effect Does Blood Pressure Control Have on the Progression Toward Renal Failure?", American Journal of Kidney Diseases, vol. 21, No. 6, Suppl. 3, Jun. 1993, pp. 10-15.
P.M. Vanhoutte, "Endothelium, .beta.-Blockers and Vascular Protection", Drug Investigation 3 (Suppl. 1): 201-203, 1991.
EP A 0 334 429, Sep. 1989, European Patent Office, The United States equivalent of this EPO application is pending as Serial No. 07/825,488.
de Chaffoy de Courcelles Didier Robert Guy Gabriel
Lesage Anne Simone Josephine
Leysen Josepha Eduarda Maria Francisca
Appollina Mary A.
Janssen Pharmaceutica N.V.
Reamer James H.
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