Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-12-14
1999-01-05
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546321, 546322, A61K 3144, C07D21380
Patent
active
058563466
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel, potent, very short-acting calcium antagonists of the dihydropyridine type with high vascular selectivity. The compounds of the invention are very effective in lowering blood pressure, and, due to their very short duration of action, are highly efficient for obtaining steerable blood pressure control after intravenous administration. The present invention also relates to processes for preparation of these compounds as well as suitable pharmaceutical compositions for their administration. Furthermore the invention also relates to the use of the compounds of the invention for medical treatment.
BACKGROUND OF THE INVENTION
Steerable blood pressure control is of great importance in many acute clinical situations, e.g. in the majority of patients undergoing cardiac surgery, cerebral surgery , orthopedic surgery or microsurgery. Under such conditions it is often important to rapidly and safely lower blood pressure to a pre-specified level, keeping it there for a pre-determined time, and then rapidly normalizing it again.
Although some drugs are presently used in the clininc for such purpose, none of them are really adequate for efficient blood pressure control.
The drugs most commonly used for this indications are sodium nitroprusside, nitroglycerine and nicardipine. Sodium nitroprusside is an old, potent and very short-acting compound wich in most countries is the only drug available with a suitable profile of acion, i.e. mainly causing arterial dilation. However, several serious side effects limit its usefulness. The main disadvantage being the risk of cyanide intoxication. A second disadvantage is its effects on regional myocardial blood flow in patients with coronary artery disease. Nitroglycerine is also very short-acting, but has too low potency to be really effective except in high doses which also causes unwanted lowering of cardiac output. Nicardipine, which is a calcium antagonist of the dihydropyridine type, has high vascular selectivity and high potency, but the effect duration is too long, as usually is the case for this class of compounds.
Thus, there exist today a clear medical need for new short-acting, steerable antihypertensive drugs for intravenous administration. The compounds of the present invention are useful for this purpose.
PRIOR ART
Hypotensive calcium antagonists of the dihydropyridine type are now well established for prophylaxis and treatment of various cardiovascular diseases (Opic LH. Clinical use of Calcium channel antagonist Drugs. Kluwer Academic Publ. 1990. ISBN O-7923-0872-7). The main impetus in their development has been to identify safe, highly potent drugs with long duration of action. However, no efforts in the direction of developing short-acting dihydropyridines have been made.
A few compounds of similar type to those of the present invention have earlier been described (EP 0 474 129 A2; Tetrahedron Letters 32, 5805-8, (1991); Tetrahedron Letters 33, 7157-60, (1992)).
The following compounds are described: 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichlorophenyl)-3,5-pyridinedicarboxylat e, 1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-3,5-pyridinedicarbox ylate, 1,4-dihydro-2,6-dimethyl-4-phenyl-3,5-pyridinedicarboxylate 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-3,5-pyridinedicarboxylate, 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-3,5-pyridinedicarboxylate, 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-3,5-pyridinedicarboxylate, 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-3,5-pyridinedicarboxylate, 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-3,5-pyridinedicarboxylate.
These compounds were prepared in order to fascilitate the synthesis of pure enantiomers of conventional, long-acting dihydropyridines and have not been described for medical use.
1,5-Benzothiazepine derivatives have been described (EP 0 416 479 A1) for use as short-acting calcium antagonists, for treating patients with critical cardiovascular diseases.
DESCRIPTION OF THE INVENTION
It has now been found that 1,4-dihydropyridines of t
REFERENCES:
patent: 3799934 (1974-03-01), Meyer et al.
patent: 4154839 (1979-05-01), Wehinger et al.
Chemical Abstracts, vol. 117(1),abst. No. 7808n,Jul. 6,1992.
Andersson Kjell Hjalmar
Nordlander Margareta
Westerlund Rolf Christer
Astra Aktiebolag
Rotman Alan L.
LandOfFree
Short-acting dihydropyridines does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Short-acting dihydropyridines, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Short-acting dihydropyridines will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-862653