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

A compound of formula (I2):

• wherein:
• X=—CH2—, —CH2CH2—, or —CH2CH2 CH2—;
• Y=—CH2— or O;
• Y1=—CH2— or O;
• Wherein at least one of Y and Y1 is —CH2—;
• R1=H, C1-6 alkyl, C3-6cycloalkyl or aryl;
• R1 is hydrogen, 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, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-C6 alkylcarbonylamino 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, C1-6alkyl or C1-6alkoxy;
• 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, 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, cyano, C1-6alkyl or 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;
• 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)2amino, 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 wherein n is 0, 1, 2 or 3;
• or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

A compound according to any of the preceding claims, wherein,

• R1 is hydrogen;
• R2 and R3 are hydrogen or a branched or unbranched C1-6alkyl;
• wherein said C1-6alkyl is substituted by C3-6cycloalkyl, aryl or amino;
• R4 is hydrogen.

A compound according to any of the preceding claims wherein,

• R1 is hydrogen;
• R2 and R3 are hydrogen or a branched or unbranched C1-6alkyl;
• wherein said C1-6alkyl is substituted by C3-6cycloalkyl;
• R4 is hydrogen.

One or more compound chosen from:

• N—({4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-lysine;
• N-({4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-b,b-dimethyl-D-phenyl alanine;
• and
• N-({4-[(2R,3R)-3-{[(2R or S)-2-(2,3-Dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine ammoniate;
• N-({4-[(2R,3R)-3-{[(2R or S)-2-(2,3-dihydro-1-benzofuran-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 or S)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-valine;
• N-({4-[(2R,3R)-3-{[(2R or S)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-4-cyano-D-phenylalanine;
• N-({4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-N6,N6-dimethyl-L-lysine;
• N-({4-[(2R,3R)-3-{[(2R or S)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydxoxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-methyl-D-isovaline;
• N-({4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycylglycine.

A compound of the (XVI):

• Wherein:
• X=—CH2—, —CH2CH2—, or —CH2CH2 CH2—;
• Y=—CH2— or O;
• Y1=—CH2— or O;
• Wherein at least one of Y and Y1 is —CH2—;
• 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 wherein n is 0, 1, 2 or 3;
• R7 is an hydroxy group or a C1-4 alkoxy group.

A process for preparing a compound of formula (I) 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)) comprising any of the steps of:

• Process 1) reacting a compound of formula (II):
• with a compound of formula (III):
• (III)
• wherein L is a displaceable group;
• Process 2) reacting an acid of formula (IV):
• or an activated derivative thereof;
• with an amine of formula (V):
• Process 3):
• reacting an acid of formula (VI):
• or an activated derivative thereof, with an amine of formula (VII):
• Process 4):
• reducing a compound of formula (VIII):
• Process 5):
• reacting a compound of formula (IX):
• with a compound of formula (X):
• wherein L is a displaceable group;
• Process 6):
• reacting a compound of formula (XI):
• wherein L is a displaceable group;
• with a compound of formula (XII):
• Process 7):
• De-esterifying a compound of formula (XIII)
• wherein the group C(O)OR is an ester group.