US 2010/0168075 A1 · Novel 2-Azetidinone Derivatives As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemic Conditions

Abstract

The application relates to novel 2-azetidinone derivatives of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof. The compounds are cholesterol absorption inhibitors and are useful in the treatment of hyperlipidaemic conditions, including atherosclerosis, Alzheimers' disease and cholesterol associated tumours. The application also relates to pharmaceutical formulations comprising such compounds and to processes for their preparation.

A compound of formula (I):

wherein:
R1 and R2 are, independently, 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-C6alkylcarbonylamino, 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 of and C1-6alkoxy;
R3 is halo, hydroxy, C1-6alkyl, C1-6alkoxy or C1-6alkylS(O)a wherein a is 0 to 2;
wherein R3 is independently optionally substituted on carbon by one or more halo, C1-6alkoxy or hydroxy;
R4 is halo, nitro, cyano, hydroxy, amino, carboxy, formyl, carbamoyl, carbamoyloxy, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkenyloxy, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl-N-(C1-6alkyl)amino, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-N-(C1-6alkyl)amino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkyl)carbamoyloxy, N,N-(C1-6alkyl)2carbamoyloxy, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, C1-6alkoxycarbonyl-N-(C1-6alkyl)amino, C1-6alkoxycarbonyloxy, C1-6alkoxycarbonylamino, ureido, N′-(C1-6alkyl)ureido, N-(C1-6alkyl)ureido, N′,N′-(C1-6alkyl)2ureido, N′-(C1-6alkyl)-N-(C1-6alkyl)ureido, N′,N′-(C1-6alkyl)2-N-(C1-6alkyl)ureido, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl or phenyl;
wherein R4 is independently optionally substituted on carbon by one or more halo, C1-6alkoxy, hydroxy, amino, carboxy, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl-N-(C1-6alkyl)amino, phenyl, phenoxy, benzoyl, phenylC1-6alkyl or phenylC1-6alkoxy;
R5 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonyl, C1-10alkanoyl, C1-10alkanoyloxy, N-(C1-10alkyl)amino, N,N-(C1-10alkyl)2amino, N,N,N-(C1-10alkyl)3ammonio, C1-10alkanoylamino, N-(C1-10alkyl)carbamoyl, N,N-(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N-(C1-10alkyl)sulphamoyl, N,N-(C1-10alkyl)2sulphamoyl, N-(C1-10alkyl)sulphamoylamino, N,N-(C1-10alkyl)2sulphamoylamino, C1-10alkoxycarbonylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl-(C1-10alkylene)e-R29-(C1-10alkylene)f-, heterocyclyl-(C1-10alkylene)g-R30-(C1-10alkylene)h-, carboxy, sulpho, sulphino, phosphono, —P(O)(OR31)(OR32), —P(O)(OH)(OR31), —P(O)(OH)(R31) or —P(O)(OR31)(R32) wherein R31 and R32 are independently selected from C1-6alkyl;
wherein R5 may be optionally substituted on carbon by one or more R33;
and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by R34;
or R5 is a group of formula (IA):
wherein:
Z is —N(R35)—, —N(R35)C(O)—, —O—, or —S(O)a—;
wherein a is 0-2 and R35 is hydrogen or C1-4alkyl;
R15 is hydrogen or C1-4alkyl;
R16 and R17 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, —P(O)(OR36)(OR37), —P(O)(OH)(OR36), —P(O)(OH)(R36) and —P(O)(OR36)(R37), wherein R36 and R37 are independently selected from C1-6alkyl;
wherein R16 and R17 may be independently optionally substituted on carbon by one or more R38;
and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by R39;
R18 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkanoyl, C1-10alkanoyloxy, N-(C1-10alkyl)amino, N,N-(C1-10alkyl)2amino, C1-10alkanoylamino, N-(C1-10alkyl)carbamoyl, C1-10alkoxycarbonyl, N,N-(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N-(C1-10alkyl)sulphamoyl, N,N-(C1-10alkyl)2sulphamoyl, N-(C1-10alkyl)sulphamoylamino, N,N-(C1-10alkyl)2sulphamoylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl-(C1-10alkylene)e-R40-(C1-10alkylene)f- or heterocyclyl-(C1-10alkylene)g-R41-(C1-10alkylene)h-, carboxy, sulpho, sulphino, phosphono, —P(O)(OR42)(OR43), —P(O)(OH)(OR42), —P(O)(OH)(R42) and —P(O)(OR42)(R43) wherein R42 and R43 are independently selected from C1-6alkyl;
wherein R18 may be optionally substituted on carbon by one or more R44;
and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by R45;
or R18 is a group of formula (IB):
wherein:
R19 is hydrogen or C1-4alkyl;
R20 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, —P(O)(OR46)(OR47), —P(O)(OH)(OR46), —P(O)(OH)(R46) and —P(O)(OR46)(R47), wherein R46 and R47 are independently selected from C1-6alkyl;
where R20 may be independently optionally substituted on carbon by one or more R48;
and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by R49;
R21 is selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonyl, C1-10alkanoyl, C1-10alkanoyloxy, N-(C1-10alkyl)amino, N,N-(C1-10alkyl)2amino, N,N,N-(C1-10alkyl)3ammonio, C1-10alkanoylamino, N-(C1-10alkyl)carbamoyl, N,N-(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N-(C1-10alkyl)sulphamoyl, N,N-(C1-10alkyl)2sulphamoyl, N-(C1-10alkyl)sulphamoylamino, N,N-(C1-10alkyl)2sulphamoylamino, C1-10alkoxycarbonylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl-(C1-10alkylene)e-R50-(C1-10alkylene)f-, heterocyclyl-(C1-10alkylene)g-R51-(C1-10alkylene)h-, carboxy, sulpho, sulphino, phosphono, —P(O)(OR52)(OR53), —P(O)(OH)(OR52), —P(O)(OH)(R52) and —P(O)(OR53)(R53) wherein R52 and R53 are independently selected from C1-6alkyl;
wherein R21 may be independently optionally substituted on carbon by one or more R54;
and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by R55;
p is 1-3;
wherein the values of R16 may be the same or different;
q is 0-1;
r is 0-3;
wherein the values of R17 may be the same or different;
z is 0-3;
wherein the values of R20 may be the same or different;
R33, R38, R44, R48 and R54 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkanoyl, C1-10alkanoyloxy, C1-10alkoxycarbonyl, N-(C1-10alkyl)amino, N,N-(C1-10alkyl)2amino, N,N,N-(C1-10alkyl)3ammonio, C1-10alkanoylamino, N-(C1-10alkyl)carbamoyl, N,N-(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N-(C1-10alkyl)sulphamoyl, N,N-(C1-10alkyl)2sulphamoyl, N-(C1-10alkyl)sulphamoylamino, N,N-(C1-10alkyl)2sulphamoylamino, C1-10alkoxycarbonylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl-(C1-10alkylene)e-R56-(C1-10alkylene)f-, heterocyclyl-(C1-10alkylene)g-R57-(C1-10alkylene)h-, carboxy, sulpho, sulphino, amidino, phosphono, —P(O)(OR58)(OR59), —P(O)(OH)(OR58), —P(O)(OH)(R58) and —P(O)(OR59)(R59), wherein R58 and R59 are independently selected from C1-6alkyl;
wherein R33, R38, R44, R48 and R54 may be independently optionally substituted on carbon by one or more R60;
and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by R61;
R34, R39, R45, R49, R55 and R61 are independently selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, benzyl, phenethyl, benzoyl, phenylsulphonyl and phenyl;
R29, R30, R40, R41, R50, R51, R56 and R57 are independently selected from —O—, —NR62—, —S(O)x—, —NR62C(O)NR63—, —NR62C(S)NR63—, —OC(O)N═C—, —NR62C(O)— and —C(O)NR62—;
wherein R62 and R63 are independently selected from hydrogen and C1-6alkyl, and x is 0-2;
R60 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;
and
e, f, g and h are independently selected from 0-2;
R6 is hydrogen, alkyl, c-alkyl or aryl;
and
c is 1, 2, 3, 4 or 5;
or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof;
provided that compounds of formula (I) are not compounds of formula A
wherein:
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-C6alkylcarbonylamino, 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 and C1-6alkoxy;
R2 and R5 are independently hydrogen, a branched or unbranched 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-C4alkyl)3Si, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a, C1-6alkanoylamino, C3-6cycloalkyl, aryl or aryl C1-6alkylS(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 and C1-6alkoxy;
R3 is hydrogen, alkyl, halo, C1-6alkoxy or C1-6alkylS—;
R4 is hydrogen, C1-6alkyl, halo or C1-6alkoxy;
and
R6 is hydrogen, C1-6alkyl, or arylC1-6alkyl;
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;
or N-{[4-((2R,3R)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxo-1-phenylazetidin-2-yl)phenoxy]acetyl}glycine.

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

Life of this patent

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

Life of this patent

Abstract

Claims32