Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1991-01-21
1992-07-21
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
548375, 558405, C07D47114, C07D48714, A61K 31505
Patent
active
051324245
DESCRIPTION:
BRIEF SUMMARY
INTRODUCTION
This invention relates to new pyrazolo-pyrrolo-pyrimidine-dione (PPPD) derivatives as new compounds per se, and to their use as drugs to inhibit or control the ACAT (acyl CoA:cholesterol acyltransferase) enzyme to help a warm-blooded animal, including human patient to correct and regulate abnormal cholesterol metabolism rates in the animal cell system. More particularly, this invention provides some 2,4,6-trisubstituted-pyrazolo[1.5]-a[3,4-d]pyrimidine-5,8-dione (PPPD) derivative compounds per se, as active ingredients in pharmaceutical formulations to be used as anti-atherosclerotic drug medicines where the ACAT enzyme inhibition is desired, and to a method of using these new compounds as anti-atherosclerotic drug compounds in a valuable, warm-blooded animal patient including humans.
BACKGROUND OF THE INVENTION AND INFORMATION STATEMENT
Along with the HMG-CoA reductase (see Illingworth, D. R., "Specific . . . as hypocholesterolemic agents in humans", Mevinolin and Compactin" in Pharmacological Control of Hyperlipidaemia, J. R. Prous, Science Publishers (1986), pp. 231-249) and 7-alpha hydroxylase (see Cighetti, G. et al, "The effect . . . cholesterol 7-alpha hydroxylase . . . animals" in Life Science, 33 (1983), pp. 2483-2488) enzymes, acylCoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26), which latter enzyme is found in virtually all tissue but demonstrating highest activity in tissues such as the liver, intestine, adrenal and atherosclerotic arterial tissue, is known to be one of the major regulators of cholesterol metabolism in warm-blooded animal cells. Since the accumulation of esterified cholesterol is one of the characteristic features of atherosclerotic plaque (see Bell, F. P., "Arterial Cholesterol Esterification . . . Inhibition By Drugs", in Pharmacological Control of Hyperlipidaemia (1986), J. R. Prous, Science Publishers, pp. 409-422), the regulation of the ACAT enzyme activity is believed to be of significant importance in the treatment of atherosclerosis and related diseases in valuable animals including humans.
The ACAT enzyme is a constitutive protein in the endoplasmic reticulum and as such can be dramatically influenced by alterations in membrane fatty acid composition, phospholipid composition and cholesterol content (see Bell, F. P., supra; Doolittle, G. M. et al, "Solubilization . . . of AcylCoA:cholesterol Acyltransferase" in Biochemistry, 21 (1982), pp. 674-679, and Brenneman, D. E. et al, "Effects of Dietary Fat . . . Microsomes" J. Lipid Research, 18 (1977), pp. 583-591). It is recognized in the art that when such alteration or modifications in membrane fatty acid composition are extensive enough to alter membrane fluidity a number of cellular functions, which include among others, carrier-mediated transport, the properties of certain membrane-bound enzymes, binding to insulin and opiate receptors, etc., are affected.
An example of a known drug that has been shown to change the fluidity of membranes and is also an ACAT enzyme inhibitor is the tranquilizer, chlorpromazine (see Keefe, E. B. et al, "Alteration . . . By Chlorpromazine . . . ", Gastroenterology, 79, (1980), pp. 22-231; Ogiso, T. et al, "Fluidity . . . Chlorpromazine . . . Membrane", in Biochim. Biophys. Acta, 649 (1981), pp. 325-335 and Bell, F. P., "Effect of Chlorpromazine . . . Synthesis" in Exp. Molec. Pathol., 38 (1983), pp. 336-346). Chlorpromazine is also known to have blood platelet aggregation inhibition properties (see Jain, M. K. et al, "Correlation of Inhibitors . . . Bilayer" in Thrombosis Res., 13 (1978), pp. 1067-1075).
Other known drug compounds which also have ACAT enzyme inhibiting activity include the sedative-tranquilizer, diazepam, and the beta-blocker compound propanolol (see Bell, F. P., "Effects . . . Propanol . . . on ACAT Activity . . . Vitro", in J. Cardiovasc. Pharmacol., 7 (1985), pp. 437-442).
6-Cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin e-5,8(6H)-dione, utilized as a starting material to prepare compounds of this invention, was once comme
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Bell Frank P.
Larsen Scott D.
Bernhardt L.
Shah Mukund J.
Steele Gregory W.
The Upjohn Company
Williams, Jr. Sidney B.
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