Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-07-29
1998-12-22
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514428, 548533, A61K 3140, C07D20708, C07D20712
Patent
active
058520473
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/IE95/00012 filed Jan. 24, 1995.
The invention relates to pharmaceutical products.
The term "ACE inhibitor" as used in this specification refers to pharmacologically active ACE inhibitor compounds which relieve, or act as prophylactic against cardiovascular disease including hypertension, cardiac failure, arrhythmias (irregular heart beats) and angina pectoris (pain in the heart muscle).
BACKGROUND OF THE INVENTION
ACE inhibitors act directly on the renin-angiotensin system. By inhibiting the angiotensin converting enzyme (ACE) they produce a decrease in blood pressure that can be sustained. ACE inhibitors also have a vasodilator effect which reduces peripheral resistance, increases natriuresis (the loss of sodium via the kidneys) and improves renal blood flow thereby assisting the antihypertensive (blood pressure lowering) effect.
The ACE inhibitors improve many of the haemodynamic parameters that are changed in congestive heart failure by inhibiting the formation of the vasoconstrictor, angiotensin II. They lower systemic arteriolar resistance through vasodilatation thus reducing the after load. Heart output and the cardiac index increase thereby increasing the stroke work and stroke volume. The resistance of the kidney vasculature is reduced which improves kidney blood flow leading to an increase in sodium loss via the kidneys thereby increasing body fluid loss which helps to reduce the blood volume returning to the heart. The removal of angiotensin II's stimulatory effect on aldosterone secretion also helps kidney sodium loss--for treatment in cardiac failure (heart failure).
Aspirin has been widely used for many years as an analgesic/anti-pyretic and anti-inflammatory agent. As such, it is a most useful drug. In more recent years, however, it has been discovered that aspirin has a powerful anti-platelet effect. Platelets are microscopic particles within the blood that, under certain circumstances, can stick together to form a thrombus (clot). Aspirin prevents the sticking together of platelets and thus helps prevent the occurrence of heart attack or its complications.
SUMMARY OF THE INVENTION
According to the invention there is provided a pharmaceutical product comprising a salicylate of an esterifiable ACE inhibitor.
The term "salicylate" as used in this specification refers to a salicylate or a salt, ester, derivative, complex thereof, or salts of the ester, derivative or complex having anti-platelet activity.
The term "esterifiable" as used in this specification means the formation of an ester, a thioester, an amide or an anhydride.
In a particularly preferred embodiment of the invention the product is formed by esterification of an esterifiable ACE inhibitor with acetylsalicylic acid.
Preferably the ACE inhibitor is captopril.
Alternatively the ACE inhibitor may be a primary amine such as Lisinopril. In this case the aspirinate may be formed by amide formation processes.
The ACE inhibitor may also be a secondary amine such as Enalapril, Enaliprilat, Perindopril, Perindoprilat, Quinapril or Ramipril. In this case, the aspirinate may be formed by amidation processes.
In another aspect the invention provides a process for preparing a pharmaceutical product of the invention which comprises esterifying an esterifiable ACE inhibitor such as a captopril with acetylsalicylic acid to form a thioester.
The invention further provides a process for preparing a pharmaceutical product of the invention which comprises forming an amide from an amine ACE inhibitor such as Lisinopril with acetylsalicylic acid.
The invention also provides a process for preparing a pharmaceutical product of the invention which comprises forming an anhydride from a secondary amine ACE inhibitor selected from Enalapril, Enaliprilat, Perindopril, Perindoprilat, Quinapril, and Ramipril with acetylsalicylic acid.
The invention also provides a process for preparing Captopril-S-aspirinate comprising the steps of: salicylic acid; captopril aspirinate.
In one embodiment of the invention, the phenol hydrox
Byrne William
Rynne Andrew
Cal International Limited
Oswecki Jane C.
Richter Johann
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