American Home Products Corporation

Donald P Strike

Thomas Joseph Commons

William Floyd Fobare

Richard Eric Mewshaw

Wenling Kao

Hassan Mahmoud Elokdah

Guy A Schiehser

Theodore S Sulkowski

Arthur Attilio Santilli

Sie-Yearl Chai

Jerauld S Skotnicki

Wen-Ling Kao

Amedeo A Failli

Anthony C Scotese

Kevin Anthony Memoli

Robert J Steffan

John R Potoski

Robert L Morris

Jay Scott Shumsky

Daniel M Teller

Christa M LaClair

Richard L Fenichel

Susan T Nielsen

Bruce A Steinbaugh

Patrick M Andrae

Susan M Andrews

Richard L Fenichei

Substituted tetrahydro-pyrimidine-2(1H)-thione HDL-C elevators useful as antiatherosclerotic agents

This invention provides compounds of formula 1 having the structure

Substitued tetrahydro-1,3,5-triazin-2&lsqb;1H&rsqb;-thiones as anti-atherosclerotic agents

This invention provides compounds of formula 1 having the structure ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each independently, hydrogen, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenylalkyl, alkoxy, aryloxy, fluoroalkoxy, trifluoromethyl, alkylthio, alkylsulfony, --SCF.sub.3, nitro, alkylamino, or dialkylamino;

Substituted tetrahydro-1,3,5-triazin-2[1H]-thiones as

Inhibition of the enzymes cholesterol ester hydrolase (CEH) and/or acyl coenzyme A: cholesterol acyltransferase (ACAT) results in the inhibition of the esterification of cholesterol and are therefore implicated in the inhibition of absorption of cholesterol and thus can lower serum cholesterol levels. Compounds of the formula: ##STR1## where Z is ##STR2## or --Ar.sup.1 --(CR.dbd.CR).sub.1-3 --Ar.sup.2, --AR.sup.1 --NR.sup.7 --AR.sup.2 and A is a linking group inhibit the enzymes CEH and/or ACAT (in vitro) and inhibit absorption of cholesterol.

Tris carbamic acid esters: inhibitors of cholesterol absorption

The compound of formula I: ##STR1## wherein R is phenyl or phenyl optionally substituted with one or more groups selected from halogen, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, hydroxy, alkanoyloxy, aroyloxy or arylalkanoyloxy; R.sup.3 is alkyl, aryl or arylalkyl; or a pharmaceutically acceptable salt thereof, are use for increasing HDL blood levels.

2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives

The compound of formula I: ##STR1## in which R.sup.1 is alkyl or alkenyl; R.sup.2 is alkyl and R.sup.3 and R.sup.4 are, independently, hydrogen or alkyl; or R.sup.2 is hydrogen and R.sup.3 and R.sup.4 taken together are ortho substituted trimethylene or tetramethylene are useful for increasing blood serum HDL levels.

2-thioxo-imidazolidin-4-one derivatives

The compound of formula I ##STR1## in which R.sup.1 is alkyl, alkenyl, aryl or arylalkyl; R.sup.2 is alkyl, R.sup.3 is a halogen and R.sup.4 is hydrogen; or R.sup.2 is hydrogen, R.sup.3 is a halogen, and R.sup.4 is alkyl are useful for increasing blood serum HDL levels.

The compound of formula I ##STR1## in which R.sup.1 is alkyl; and R is alkyl, naphthyl, benzhydryl, fluorophenylmethyl, phenethyl, 1-(fluorophenyl)ethyl, 5-chloro-2-methoxyphenyl, trifluoromethoxyphenyl, trifluoromethylphenyl, methylsulfanylphenyl or pyridyl are useful for increasing blood serum HDL levels.

The compound of formula I ##STR1## in which R is alkynyl; and X and Y are, independently, alkyl, halo, perfluoralkyl, perfluoralkoxy, or, taken together, X and Y are ortho substituted trimethylene or tetramethylene are useful for increasing blood serum HDL levels.

The compounds of the formula: ##STR1## in which X is ##STR2## where R.sup.7 is hydrogen, alkyl, hydroxy, alkanoyloxy, hydroxyalkyl, hydroxycarbonyl, alkoxycarbonyl, phenyl or substituted phenyl, in which the substituent is alkyl, alkoxy, halo, nitro, cyano, haloalkyl, perhaloalkyl or dialkylaminoalkyl; R.sup.8 is hydrogen or alkyl or R.sup.7 and R.sup.8 taken together are polymethylene; R.sup.9 is hydrogen, alkyl, phenyl or substituted phenyl, in which the substituent is alkyl, alkoxy, halo, nitro, cyano or perhaloalkyl; R.sup.10 is hydrogen, alkyl or gemdialkyl; n is one of the integers 0, 1 or 2; and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are, independently, hydrogen, alkyl, alkoxy, halo, nitro, cyano or perhaloalkyl, alkoxycarbonyl or hydroxycarbonyl; and when X is --NR.sup.9 -- or R.sup.7 is an amino alkyl group, a pharmaceutically acceptable salt thereof; are useful as inhibitors of cholesterol ester hydrolase.

Cholesterol ester hydrolase inhibitors

A method for increasing blood serum HDL cholesterol levels in a mammal in need of increased HDL cholesterol blood serum levels, which comprises administering to said mammal, an effective amount of a compound of formula I: ##STR1## wherein R is phenyl or phenyl optionally substituted with one or more groups selected from halogen, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, hydroxy, alkanoyloxy, aroyloxy or arylalkanoyloxy; R.sup.3 is alkyl, aryl or arylalkyl; or a pharmaceutically acceptable salt thereof.

2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives for

A method for increasing the HDL cholesterol concentration in the blood of a mammal in need of increased HDL cholesterol blood concentration, which comprises administering to said mammal, orally or parenterally, a compound of formula I: ##STR1## wherein R is alkyl; a substituted or unsubstituted aromatic N, O or S heterocycle; substituted or unsubstituted aryl, arylalkyl, benzhydryl or indanyl, in which the substituents are one to three members independently selected from the group consisting of alkyl, alkoxy, alkylthio, alkenyl, alkynyl, halo, perfluoroalkyl, perfluoroalkyl or hydroxy; and R.sup.1 is aryl, alkyl, alkenyl, alkynyl or substituted aryl where the substituents are one to three members independently selected from the group consisting of alkyl, alkoxy, alkylthio, alkenyl, alkynyl, halo, perfluoroalkyl, perfluoroalkoxy or hydroxy.

Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of

The compounds of the formula: ##STR1## in which ##STR2## where R.sup.7 is hydrogen, alkyl, hydroxy, alkanoyloxy, hydroxyalkyl, hydroxycarbonyl, alkoxycarbonyl, phenyl or substituted phenyl, in which the substituent is alkyl, alkoxy, halo, nitro, cyano, haloalkyl, perhaloalkyl or dialkylaminoalkyl; R.sup.8 is hydrogen or alkyl or R.sup.7 and R.sup.8 taken together are polymethylene; R.sup.9 is hydrogen, alkyl, phenyl or substituted phenyl, in which the substituent is alkyl, alkoxy, halo, nitro, cyano or perhaloalkyl; R.sup.10 is hydrogen, alkyl or gemdialkyl; n is one of the integers 0, 1 or 2; and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are, independently, hydrogen, alkyl, alkoxy, halo, nitro, cyano or perhaloalkyl, alkoxycarbonyl or hydroxycarbonyl; and when X is --NR.sup.9 -- or R.sup.7 is an amino alkyl group, a pharmaceutically acceptable salt thereof; are useful as inhibitors of cholesterol ester hydrolase.

A compound of formula A: ##STR1## wherein R.sup.1 and R.sup.2 are, independently, hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, alkyl, alkoxy, --CO.sub.2 H, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonyloxy, mono or dialkylaminocarbonyl, or mono or dialkylaminocarbonyloxy; R.sup.3 is hydrogen or alkyl; R.sup.4 is alkyl, cycloalkylalkyl or phenylalkyl or substituted phenylalkyl, and the substituent on the benzene ring is alkyl, alkoxy, halo, nitro, cyano, trifluoromethyl or phenyl, are anti-cholesterolemic agents.

Dibenzofuranyl N-alkyl carbamates

The compounds of the formula: ##STR1## in which X, Y and Z are, independently, hydrogen, halogen, hydroxy, nitro, cyano, carboxyl, trifluoromethyl, phenyl, amino, alkylamino, dialkylamino, alkyl, alkoxy or phenylalkyloxy; R.sub.1 is thienyl, imidazolyl, thiazolyl, pyridinyl, quinolinyl, pyrimidinyl, pyrazinyl, benzamidazolyl, phenylalkylpiperidinyl or morpholino or athaae analogous hetercyclic groups with from one to three substituents selected from halogen, hydroxy, nitro, cyano, carboxyl, trifluoromethyl, phenyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms; R.sub.2 is hydrogen, alkyl, cycloalkyl, phenyl, benzyl or substituted phenyl or benzyl in which said substituent is alkyl, alkoxy, halogen, cyano, trifluoromethyl amino, nitro, alkylamino or dialkylamino; and a pharmaceutically acceptable salt thereof; are ACAT inhibitors, some of which possess antioxidant properties.

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St. Davids, PA, United States of America

Donald P Strike