Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-11
2004-09-21
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S356000, C546S321000
Reexamination Certificate
active
06794399
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Applications
This invention which could continuously maintain hypotension; with activation of competitive &bgr;-adrenoreceptor and calcium channel blocking agent; induced vasorelaxing effect; with calcium channel antagonist and &bgr;-adrenoreceptor antagonist activity, is a series of 1,4-dihydropiridine derivatives chemically with guaiacoxypropanolamine and/or phenoxypropanolamine moiety.
2. Background of the Invention
Serious and pernicious hypertensive subjects could obtain rapid hypotension by treatment with nifedipine, yet too rapid or strong effect could result in tachycardia. In later experiments, it is found that while administrating vasodilator, provision of &bgr;-adrenoceptor blocking agent to subjects could inhibit tachycardia induced by sympathetic excitation. Clinical reports have shown that in the treatment of angina pectoris and hypertension, combination therapy of, &bgr;-adrenoceptor blocking agent and calcium entry blocking agent has advantage efficacy over any one of those drugs (Fitzsimons, T. J.,
J. Hypertens.,
5, pp. S11-S15, 1987).
In most original hypertension subjects, their peripheral circulation usually have a much higher resistance than normal. Though directly effective vasodilator could reduce the resistance, therefore these drugs could induce unwanted effects, including reflex tachycardia due to baroreceptor activation which may impair the hypotensive effect by blood vessel contraction; tachycardia; increase of cardiac output. Some reports have already pointed out that &bgr;-adrenoceptor blocking agent could inhibit tachycardia due to sympathetic excitation after administration of vasodilator.
Nifedipine is a peripheral vasodilator with 1,4-dihydropiridine ring. It is effective on the cardiac blood vessels, including vasodilatation, where it functions by directly inhibit the result of calcium ion inflow in vessel's smooth muscle cell membrane. Theoretically, combination therapy of calcium entry blocking agent and &bgr;-adrenoceptor blocking agent may result in two different cardiac suppression effect. Nevertheless, reports have demonstrated that though nifedipine would increase the heart rate and renin level in hypertensive subjects, these effects could be inhibited by concurrent administration of PROPRANOLOL. Furthermore, it has been observed that there is coordinating effect of this combination therapy in lowering the blood pressure.
DESCRIPTION OF THE PRIOR ART
To overcome the tachycardia tendency due to the direct effect of peripheral vasodilator, the inventor has tried designing a chemical compound which has both vasodilatation and, &bgr;-adrenoceptor blocking agent activation effects. VANIDILOL, previously described as a &bgr;-blocking agent, is chemically with a guaiacoxypropanolamines moiety, while this synthesized vanidipinedilol of this inventor, which belongs to the derivative of VANIDILOL, has been demonstrated in a series of experiment and indicates that it has both &bgr;-adrenoceptor blocking and added calcium channel blocking effects.
Furthermore, Asano, M. (
J. Pharmacol,
296, pp. 204-211, 1990) has suggested YM-16151-1, and Shibasaki, K. (
Gen. Pharmac.
29, pp. 545-550, 1997) has demonstrated YM 430. Though both these two compounds have &bgr;-adrenoceptor blocking effects as shown in
FIG. 1
, their structures are different from this invention.
SUMMARY OF THE INVENTION
Therefore, this invention will attempt to undergo structural embellishment, using VANIDILOL as the fundamental key structure. The main purpose is to embellish aldehyde at the 4 position on VANIDILOL, and introduce a dihydropyridine ring that with vasodilatation effect.
This invention will also make use of various pharmacological experiments to demonstrate that these 1,4-dihydropiridine derivatives chemically with guaiacoxypropanolamine and/or phenoxypropanolamine moiety could continuously maintain hypotension; with activation of competitive &bgr;-adrenoreceptor and calcium channel blocking agent; induced vasorelaxing effect; and with activation of calcium channel antagonist and, &bgr;-adrenoreceptor antagonist.
This invention will further demonstrate that by having 1,4-dihydropiridine derivative chemically with guaiacoxypropanolamine or phenoxypropanolamine moiety as the main component and adding necessary excipients to form various pharmacological compounds that is therapeutically efficient.
REFERENCES:
Jhy-Chong Liang, et al, “Labedipinedilol-A: . . . ”, Drug Development Research, 2000, Wiley-Liss, Inc., vol. 49, pp. 94-108.*
CA 94:167456, Baldwin et al. 1981.*
CA 84:150511, Ger. offen 2,405,658 1976.*
CA 116:173968, Yan et al 1992.*
CA 135:282947, Yeh et al. 2001.*
CA 133:68681, Liang et al. 2000.*
CA 132:137107, Chen 2000.
Birch & Stewart Kolasch & Birch, LLP
Coppins Janet L
Rotman Alan L.
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