Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-24
1999-12-07
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514356, 546286, 546321, C07D21180, A61K 31435
Patent
active
059984481
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel combination preparations for the prevention and treatment of vascular disorders, in particular of cardiovascular and cerebrovascular disorders, containing dihydropyridines which have calcium antagonist activity, acetylsalicylic acid nitroesters and vitamins, and, if appropriate, also further auxiliaries or active compounds.
The individual elements of the combination according to the invention and its therapeutic actions on the vascular system are well known. This applies in particular to the calcium antagonist active compounds and to acetylsalicylic acid, subsequently called ASA, and some of its derivatives. It is furthermore known that, for example, ASA or calcium antagonist dihydropyridines such as nifedipine and also combinations of these active compounds possess a positive synergistic effect on thrombogenesis (cf. E. Dong et al., Effects of the combination of Aspirin and Nifedipine on platelet aggregation and thrombogenesis, Chin. J. Cardiol. 18 (5), 301 (1990)). It was not possible however, to achieve a reduction of already present lesions using dihydropyridines.
Combinations of parenterally administered nitroglycerin with nifedipine, isosorbide dinaitrate, heparin and ASA show a clearly antiarrhythmic effect on unstable angina pectoris at the end of the first week of treatment, which also persists on further treatment with a lower dose (cf. T. E. Dobrotvorskaya et al., Antiarrhythmic effect of Cordaron in patients with unstable angina pectoris and myocardial infarction, Klin. Med. (Mosk.) 67 (II) (1993)).
The positive synergistic actions of ASA in combination with nifedipine were tested and confirmed in numerous clinical investigations (cf. I. Coma-Canella, Detection of restenosis with dobutamine stress after coronary angioplasty, Am. Heart J. 124 (5), 1196 (1992)); J. P. Nunes et al., The effect of low dose Aspirin on blood pressure in treated hypertensive patients, RIC SCI (Suppl. 90), Abstract 526 (1991); I. B. Kovacs, Addition of Nifedipine to Aspirin improves platelet reactivity in cardiac patients who fail to respond to Aspirin alone, Thromb. Haemost, 69 (6), 634 (1993); H. Darius et al., Beeinflussung der Thrombozytenfunktion bei diagnostischen und therapeutischen Eingriffen in der Cardiologie [Effect of platelet function on diagnostic and therapeutic interventions in cardiology], 80 (Suppl. 5), (1991)).
ASA is only employed for the prophylaxis of thromboembolic and cardiovascular events. ASA derivatives which are cleaved in vivo into ASA and nitrogen oxides are also known and should have fewer gastrointestinal side effects with the same potency of action as ASA (cf. WO 92/01668, 6.2.1992).
The positive effects of vegetable gingko preparations and of vitamins, in particular of vitamins A, B, C and E, are also known from numerous publications.
The invention relates to new combinations of dihydropyridines of the general formula (I) ##STR2## in which R.sup.1 represents cyano or alkyl having 1 to 4 C atoms, which is optionally substituted by hydroxyl, or the radical OCH.sub.2 CH.sub.2 NH.sub.2, alkyl having 1 to 4 C atoms, which is optionally substituted by alkoxy having 1 to 4 C atoms or by an N-methylbenzyl radical, hydrogen, nitro, trifluoromethyl, chlorine or the radical OCHF.sub.2 or together with the phenyl, ring represent the radical ##STR3## with acetylsalicylic acid nitroesters of the formula (II) ##STR4## in which A represents oxygen or NH, atoms, a cycloalkylene radical having 3 to 7 C atoms or an aralkylene radical having 7 to 12 C atoms and B, C, D, E and .beta.-carotene, and, if appropriate, gingko extract as a further active compound component.
Active compounds of interest from the dihydropyridines class which may be mentioned are nifedipine, amlodipine, nimodipine, nitrendipine and nisoldipine.
For the treatment of cerebrovascular disorders, combination therapy with nimodipine is particularly to be recommended. For treatment of cardiovascular disorders, combinations which contain nifedipine or amlodipine are of particular interest.
Those combinations
REFERENCES:
Dong et al., Chin. J. Cariol. 18 (5), 301 (1990).
Dobrotvorskaya et al., Klin.Med. (Mosk.) 67 (II) (1993) (English Summary appears on page 43 of the reference.).
Coma-Canella et al., Am.Heart.J. 124 (5), 1196 (1992).
Nunes et al., RIC SCI Suppl. 90, Abstract 526 (1991).
Kovacs et al., Throm.Haemost 69 (6), 634 (1993).
Darius et al., Z. Kardiol. 80 (Suppl. 5) (1991) (English Summary appears on page 47 of this reference.).
Tison et al., Am.J.Hypertension, 46S-49S (1994).
Fetkovska et al., Am.J.Hypertension , 98S-101S (1993).
Tison et al., Blood Pres.Suppl., 57-60 (1994).
Folts et al., Med.Sci.Symp.Ser., 165-71 (1993).
English Abstract of Dong et al., Chin J. Cariol. 18 (5), 301 (1990).
Kurka Peter
Lesur Eva
Lockhoff Oswald
Neuser Dieter
Perzborn Elisabeth
Bayer Aktiengeselechaft
Davis Zinna Northington
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