Hydroxylated metabolites and derivatives of doxazosin as anti-atherosclerosis agents

Abstract: This invention relates to the use of certain hydroxylated metabolites and derivatives of doxazosin and their pharmaceutically acceptable acid addition salts for retarding the development of atherosclerosis in a mammal. Such compounds are useful for reducing atherosclerotic plaque involvement and for retarding and reducing both lipid deposition fibrosis in the development of atherosclerotic plaques.

Description: This invention relates to the use of certain hydroxylated metabolites and derivatives of doxazosin (4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)-piperazin-1-yl]-6,7-dimethoxyquinazoline), and their pharmaceutically acceptable acid addition salts for retarding the development of arterial disease in mammals, and, more specifically, for suppressing lipid deposition and fibrosis in the development of atherosclerotic plaques and thus reducing atherosclerotic plaque involvement in mammals. Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease has been described in detail by Ross and Glomset in New England Journal of Medicine 295 , 369-377 (1976). The earliest stage in this sequence is the formation of "fatty streaks (plaques) in the carotid, coronary and cerebral arteries and in the aorta. These, in turn, give rise to development of the "fibrous plaque", which coisists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extracellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "complicated lesion" which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscular spasm that characterize advanced atherosclerosis. Statistical evidence suggests that hyperlipidemia and hypertension are primary risk factors in causing atherosclerosis., Treatment of atherosclerosis is, therefore, approached by attempts to control hypertension and hyperlipidemia by dietary or pharmacological means. Some success has been achieved in reducing the incidence and severity of atherosclerosis by strict adherence to a prudent diet, by lowering plasma lipids with drugs or with ileal bypass surgery and by lowering systemic blood pressure with diet or drugs. However, coronary heart disease remains a threat, even to individuals striving to control their risk factors. It has been speculated that every individual in the United States has some degree of atherosclerosis. This fact, along with the high associated mortality and the inadequacy of the present treatment methods, establishes the need for anti-atherosclerotic agents. Doxazosin, its pharmaceutically acceptable acid addition salts and the use of doxazosin and such salts as regulators of the cardiovascular system, particularly in the treatment of hypertension, are referred to in U.S.-A-4,188,390. The use of doxazosin as an anti-atherosclerosis agent is referred to in U.S.-A-4,758,569. Elliot et al ., Am. J. Cardio 59 , p. 78G-81G (1987), refer to two hydroxylated metabolites of doxazosin, in particular, the 5'-hydroxy and 6'-hydroxy metabolites. S. F. Campbell, in U.K. Patent Application No. 8605551, published as GB 2171997A refers to the 5'-, 6'-, 7'- and 8'- hydroxy derivatives of doxazosin and their use in the treatment of hypertension and congestive heart failure. Doxazosin, an inhibitor of α-adrengic receptors, is effective in treating hypertension and in lowering serum lipid levels in mammals. The present inventors have found that doxazosin inhibits aortic lipid infiltration and fibrosis In cholesterol fed rabbits and that this effect is independent of the lowering of blood pressure or serum lipid levels, This independent inhibition of aortic lipid infiltration and fibrosis by doxazosin is believed to be caused by the anti-oxidant properties of certain hydroxylated metabolites of doxazosin, and, in particular, the ability of these metabolites to inhibit the oxidative uptake of low density lipoproteins (LDL) by macrophages. The present invention relates to the use of a compound of formula I or of a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for suppressing lipid deposition or fibrosis in the development of atherosclerotic lesions, or for reducing atherosclerotic lesions in a mammal having atherosclerosis. The terms "5'-hydroxy metabolite of doxazosin," "6'-hydroxy metabolite of doxazosin," "7'-hydroxy metabolite of doxazosin," and "8'-hydroxy metabolite of doxazosin," as used herein, refer to compounds of the formula I wherein the hydroxy group is attached to, respectively, the carbon atom labelled 5', 6', 7' and 8'. A preferred embodiment of the present invention is the method described above wherein the 7'-hydroxy metabolite of doxazosin is administered. The present invention also relates to a pharmaceutical composition in a form adapted for transdermal administration for suppressing lipid deposition or fibrosis in the development of atherosclerotic lesions, or reducing atherosclerotic lesions in a mammal having atherosclerosis, comprising an atherosclerotic lesion reducing or fibrosis suppressing or lipid deposition suppressing effective amount of compound of the formula, I, or a pharmaceutically acceptable salt thereof, and a transdermally- acceptable diluent or carrier. The compounds of the formula I and their pharmaceutically acceptable acid addition salts may be prepared as described in GB-A-2,171,977, referred to above, or by variations of the methods described therein that will be obvious to those skilled in the art. Examples of pharmaceutically acceptable acid addition salts of compounds of the formula I are the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, gluconate, methane sulfate, ethane sulfate, benzenesulfonate and p-toluene-sulfonate salts of such compounds. The compounds of formula I and their pharmaceutically acceptable acid addition salts can be administered transdermally. For purposes of transdermal administration, the dosage form of the particular compound may include, by way of example, solutions, lotions, ointments, creams, gels, suppositories, rate-limiting sustained release formulations and devices therefor. Such dosage forms comprise the particular compound and may include ethanol, water, penetration enhancers and inert carriers such as gel-producing materials, mineral oil, emulsifying agents, benzyl alcohol and the like, Specific transdermal flux enhancing compositions are referred to in U.S.-A-5196410.

Claims: The use of a compound of the formula (I):- or of a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for suppressing lipid deposition or fibrosis in the development of atherosclerotic lesions, or for reducing atherosclerotic lesions in a mammal having atherosclerosis. The use according to claim 1, wherein the hydroxy group in compound (I) is in the 7'-position. The use according to claim 1, wherein the hydroxy group is in the 6'-position. A pharmaceutical composition in a form adapted for transdermal administration, comprising a compound of the formula (I) or pharmaceutically acceptable acid addition salt thereof as defined in claim 1 and a transdermally - effective diluent or carrier. A composition as claimed in claim 4 in the form of a solution, lotion, ointment, cream, gel, or suppository. A composition as claimed in claims 4 or 5 which comprises ethanol, penetration enhancers, gel-producing materials, mineral oil, emulsifying agents or benzyl alcohol.

Inventors: SWINDELL ARCHIE CALHOUN, WONG SAMUEL SIU-MING, SWINDELL, ARCHIE CALHOUN, WONG, SAMUEL SIU-MING
Applicants: PFIZER, PFIZER INC.
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61P9, C07D405