Novel 2-Azetidinone Derivatives As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemic Conditions

A compound of formula (I2):

• wherein:
• X is —CH2—, —CH2CH2—, or —CH2CH2CH2—;
• R1 is H, C1-6 alkyl, C3-6cycloalkyl or aryl;
• R2 and R3 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, carbamoyl, carboxy, C1-6alkoxy, (C1-C4alkyl)3Si, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2-amino, C1-6alkylS(O)a wherein a is 0-2, C3-6cycloalkyl or aryl;
• and wherein any aryl group may be optionally substituted by one or two substituents selected from halo, hydroxy, cyano, C1-6alkyl OF and C1-6alkoxy;
• R4 is hydrogen, C1-6 alkyl, or arylC1-6 alkyl;
• wherein R3 and R2 may form a ring with 3-7 carbon atoms and wherein R4 and R2 may form a ring with 2-6 carbon atoms;
• and
• R5 is selected from hydrogen, halo, nitro, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C1-6 alkyl, C1-6alkoxy, C1-6 alkanoyl, C1-6 alkanoyloxy, N—(C1-6 alkyl)amino, N,N—(C1-6 alkyl)2-amino, C1-6alkanoylamino, N—(C1-6 alkyl)carbamoyl, N,N—(C1-6alkyl)2-carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl and N,N—(C1-6 alkyl)2sulphamoyl;
• or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

One or more compounds selected from:

• N-({4-[(2R,3R)-3-{[2-(1,3-Benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine;
• N-({4-[(2R,3R)-3-{[2-(1,3-Benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-methyl-D-valine;
• N-({4-[(2R,3R)-3-{[(2R)-2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-methyl-D-valine;
• and
• N-({4-[(2R,3R)-3-{[(2R)-2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine.

A compound of the formula (XVI):

• wherein:
• X is —CH2—, —CH2CH2—, or —CH2CH2CH2—;
• R1 is hydrogen, C1-6 alkyl, C3-6cycloalkyl or aryl;
• R5 is selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C1-6alkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2-amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2-carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl and N,N—(C1-6alkyl)2sulphamoyl;
• and
• R7 is an hydroxy group or a C1-4 alkoxy group.

A process for preparing a compound of formula (I)

• wherein:
• X is —CH2— —CH2CH2— or —CH2CH2CH2—;
• R1 is H, C1-6 alkyl, C3-6cycloalkyl or aryl;
• R2 and R3 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, carbamoyl, carboxy, C1-6alkoxy, (C1-C4alkyl)3Si N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2-amino, C1-6alkylS(O)a wherein a is 0-2, C3-6cycloalkyl or aryl;
• and wherein any aryl group may be optionally substituted by one or two substituents selected from halo, hydroxy, cyano, C1-6alkyl, and C1-6alkoxy;
• R4 is hydrogen, C1-6 alkyl, or arylC1-6 alkyl;
• wherein R3 and R2 may form a ring with 3-7 carbon atoms and wherein R4 and R2 may form a ring with 2-6 carbon atoms;
• and
• R5 is selected from hydrogen, halo, nitro, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C1-6 alkyl, C1-6alkoxyl, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6 alkyl)2-amino, C1-6alkanoylamino, N—(C1-6 alkyl)carbamoyl, N,N—(C1-6alkyl)2-carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl and N,N—(C1-6 alkyl)2sulphamoyl;
• or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises any of the steps:
• Process 1) reacting a compound of formula (II2):
• with a compound of formula (III):
• wherein L is a displaceable group;
• or
• Process 2) reacting an acid of formula (IV2):
• or an activated derivative thereof;
• with an amine of formula (V):
• or
• Process 3):
• reacting an acid of formula (VI2):
• or an activated derivative thereof, with an amine of formula (VII):
• or
• Process 4):
• reducing a compound of formula (VIII2):
• or
• Process 5):
• reacting a compound of formula (IX2):
• with a compound of formula (X):
• wherein L is a displaceable group;
• or
• Process 6):
• reacting a compound of formula (XI2):
• wherein L is a displaceable group;
• with a compound of formula (XII):
• or
• Process 7):
• De-esterifying a compound of formula (XIII2)
• wherein the group C(O)OR is an ester group.