Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-08-10
2000-07-25
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514605, 560 12, A01N 4106, A01K 3118, C07C30300, C07C30700
Patent
active
060937440
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF INVENTION
This invention relates to chemical compounds having pharmacological activity, to pharmaceutical compositions which include these compounds, and to pharmaceutical methods of treatment using the compounds. More particularly, this invention concerns certain N-acyl sulfamic acid esters with improved physical properties which inhibit the enzyme and acyl-coenzyme A:cholesterol acyltransferase (ACAT).
The compounds of the instant invention show increased chemical stability over those of U.S. Pat. No. 5,245,068.
The compounds of the instant invention show improved physical properties (such as aqueous solubility, decreased lipophilicity, and improved dissolution rates) over those disclosed in U.S. Pat. No. 5,491,172.
U.S. patent application Ser. No. 60/003,03 filed Aug. 3, 1995, teaches other methods of using the compounds taught in U.S. Pat. No. 5,491,172. Both of these are incorporated herein by reference.
In recent years the role which elevated blood plasma levels of cholesterol plays in pathological conditions in man has received much attention. Deposits of cholesterol in the vascular system have been indicated as causative of a variety of pathological conditions including coronary heart disease.
Initially, studies of this problem were directed toward finding therapeutic agents which would be effective in lowering total serum cholesterol levels. It is now known that cholesterol is transported in the blood in the form of complex particles consisting of a core of cholesteryl esters plus triglycerides and a variety of types of protein which are recognized by specific receptors. For example, cholesterol is carried to the sites of deposit in blood vessels in the form of low density lipoprotein cholesterol (LDL cholesterol) and away from such sites of deposit by high density lipoprotein cholesterol (HDL cholesterol).
Following these discoveries, the search for therapeutic agents which control serum cholesterol turned to finding compounds which are more selective in their action; that is, agents which are effective in elevating the blood serum levels of HDL cholesterol and/or lowering the levels of LDL cholesterol. While such agents are effective in moderating the levels of serum cholesterol, they have little or no effect on controlling the initial absorption of dietary cholesterol in the body through the intestinal wall.
In intestinal mucosal cells, dietary cholesterol is absorbed as free cholesterol which must be esterified by the action of the enzyme, acyl-CoA:cholesterol acyltransferase (ACAT) before it can be packaged into the chylomicrons which are then released into the blood stream. Thus, therapeutic agents which effectively inhibit the action of ACAT prevent the intestinal absorption of dietary cholesterol into the blood stream or the reabsorption of cholesterol which has been previously released into the intestine through the body's own regulatory action.
The present invention relates to methods of using the novel compounds to lower plasma cholesterol and/or lipoprotein(a), Lp(a), and more particularly to methods and agents to lower their plasma concentrations to achieve therapeutic benefit.
SUMMARY OF THE INVENTION
The present invention is compounds of the formula ##STR2## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is hydrogen, alkyl, or alkoxy; phenyl; CO.sub.2 R.sup.1, (CH.sub.2).sub.1-10 Z or NR.sup.7 R.sup.8 ; --Y--(CH.sub.2).sub.0-5 Z, or optionally substituted by one or more moieties selected from --CN, NO.sub.2, halogen, OR.sup.1, NR.sup.9 R.sup.10, and CO.sub.2 R.sup.1 ; R.sup.10 are each independently selected from hydrogen, alkyl, and unsubstituted or substituted phenyl, or attached to form a ring selected from: R.sup.15, and R.sup.16 are each independently selected from hydrogen, alkyl, and unsubstituted or substituted phenyl; R.sup.11 is hydrogen, alkyl, unsubstituted or substituted phenyl, above and Y is phenyl or a bond; independently hydrogen, alkyl, phenyl, substituted phenyl, or the side chain of a naturally occurring amino acid; substituted p
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Sliskovic et al., "Inhibitors of Acyl-Co-A:cholesterol O-Acyl Transferase (ACAT) as Hypocholesterolemic Agents. 6. The First Water-Soluble ACAT Inhibitor with Lipid-Regulating Activity", J. Med. Chem., vol. 37, 1994, pp. 560-562.
Lee Helen Tsenwhei
Picard Joseph Armand
Roark William Howard
Roth Bruce David
Sliskovic Drago Robert
Anderson Elizabeth M.
Shah Mukund J.
Truong Tamthom N.
Warner-Lambert & Company
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