Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity

A compound of formula (I2):

• wherein:
• R1 is hydrogen, C1-6alkyl, C3-6cycloalkyl or aryl;
• R2 and R5 are independently hydrogen, a branched or unbranched C1-6alkyl, hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C1-6alkoxy, aryl C1-6alkoxy, (C1-C4 alkyl)3Si, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a, C3-6cycloalkyl, aryl or aryl C1-6 alkylS(O)a, wherein a is 0-2;
• and wherein any aryl group may be optionally substituted by one or two substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkoxy, and cyano;
• R3 is hydrogen, alkyl, halo, C1-6alkoxy or C1-6 alkylS-;
• R4 is methyl or aryl;
• R6 is hydrogen, C1-6 alkyl, or arylC1-6 alkyl;
• wherein R5 and R2 may form a ring with 2-7 carbon atoms and wherein R6 and R2 may form a ring with 3-6 carbon atoms;
• n=0 or 1
• or a pharmaceutically acceptable salt or a prodrug thereof.

One or more compounds chosen from:

• N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine;
• N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-valine;
• N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-methyl-D-valine;
• N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-lysine;
• N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3 -[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycylglycine;
• and
• N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycine.

A combination of a compound according to formula (I) or (I2)

• wherein:
• R1 is hydrogen, C1-6alkyl, C3-6cycloalkyl or aryl;
• R2 and R5 are independently hydrogen, a branched or unbranched C1-6alkyl, C3-6cycloalkyl or aryl;
• wherein said C1-6alkyl may be optionally substituted by one or more hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C1-6alkoxy, aryl C1-6alkoxy, (C1-C4 alkyl)3Si, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a, C3-6cycloalkyl, aryl or aryl C1-6 alkylS(O)a, wherein a is 0-2;
• and wherein any aryl group may be optionally substituted by one or two substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkoxy, and cyano;
• R3 is hydrogen, alkyl, halo, C1-6alkoxy or C1-6 alkylS-;
• R4 is methyl or aryl;
• R6 is hydrogen, C1-6 alkyl, or arylC1-6 alkyl;
• wherein R5 and R2 may form a ring with 2-7 carbon atoms and wherein R6 and R2 may form a ring with 3-6 carbon atoms;
• n=0 or 1;
• or a pharmaceutically acceptable salt or a prodrug thereof
• wherein:
• R1 is hydrogen, C1-6alkyl, C3-6cycloalkyl or aryl;
• R2 and R5 are independently hydrogen, a branched or unbranched C1-6alkyl, hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C1-6alkoxy, aryl C1-6alkoxy, (C1-C4 alkyl)3Si, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a, C3-6cycloalkyl, aryl or aryl C1-6 alkylS(O)a, wherein a is 0-2;
• and wherein any aryl group may be optionally substituted by one or two substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkoxy, and cyano;
• R3 is hydrogen, alkyl, halo, C1-6alkoxy or C1-6 alkylS-;
• R4 is methyl or aryl;
• R6 is hydrogen, C1-6 alkyl, or arylC1-6 alkyl;
• wherein R5 and R2 may form a ring with 2-7 carbon atoms and wherein R6 and R2 may form a ring with 3-6 carbon atoms;
• n=0 or 1;
• or a pharmaceutically acceptable salt or a prodrug thereof with a PPAR alpha and/or gamma agonist.

A combination of a compound according to formula (I) or (I2)

• wherein:
• R1 is hydrogen, C1-6alkyl, C3-6cycloalkyl or aryl;
• R2 and R5 are independently hydrogen, a branched or unbranched C1-6alkyl, C3-6cycloalkyl or aryl;
• wherein said C1-6alkyl may be optionally substituted by one or more hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C1-6alkoxy, aryl C1-6alkoxy, (C1-C4 alkyl)3Si, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a, C3-6cycloalkyl, aryl or aryl C1-6 alkylS(O)a, wherein a is 0-2;
• and wherein any aryl group may be optionally substituted by one or two substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkoxy, and cyano;
• R3 is hydrogen, alkyl, halo, C1-6alkoxy or C1-6 alkylS-;
• R4 is methyl or aryl;
• R6 is hydrogen, C1-6 alkyl, or arylC1-6 alkyl;
• wherein R5 and R2 may form a ring with 2-7 carbon atoms and wherein R6 and R2 may form a ring with 3-6 carbon atoms;
• n=0 or 1;
• or a pharmaceutically acceptable salt or a prodrug thereof
• wherein:
• R1 is hydrogen, C1-6alkyl, C3-6cycloalkyl or aryl;
• R2 and R5 are independently hydrogen, a branched or unbranched C1-6alkyl, hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C1-6alkoxy, arylC1-6alkoxy, (C1-C4 alkyl)3Si, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a, C3-6cycloalkyl, aryl or arylC1-6alkylS(O)a, wherein a is 0-2;
• and wherein any aryl group may be optionally substituted by one or two substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkoxy, and cyano;
• R3 is hydrogen, alkyl, halo, C1-6alkoxy or C1-6 alkylS-;
• R4 is methyl or aryl;
• R6 is hydrogen, C1-6 alkyl, or arylC1-6 alkyl;
• wherein R5 and R2 may form a ring with 2-7 carbon atoms and wherein R6 and R2 may form a ring with 3-6 carbon atoms;
• n=0 or 1;
• or a pharmaceutically acceptable salt or a prodrug thereof with an HMG Co-A reductase inhibitor.