Alpha-substituted beta-aminoethyl phosphonate derivatives

A method for decreasing plasma levels of apo (a), lipoprotein(a), apo B, LDL cholesterol and total cholesterol comprising administering to a subject an effective amount of a compound of formula (Ia):

• 39
• or a compound of formula (Ib):
• 40
• in which:
• X1, X2, X3, X4 and X5 are independently hydrogen, hydroxy, hydroxymethyl, C1-C3 alkoxymethyl straight or branched C1-C8 alkyl, straight or branched C1-C8 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, norbornyl, adamantyl, amino, primary or secondary amino substituted with C1-C3 alkyl, cyano, halogen, and nitro;
• or
• X2 may be combined with X3, or X4 may be combined with X5, to form a 5- to 6-membered alkylidenedioxy ling optionally substituted with a C1-C4 alkyl group;
• or
• X4 may be combined with X5 to form a 5- to 6-membered alkylidene ring optionally substituted with a C1-C4 alkyl group;
• R1 and R2, are independently hydrogen or a straight or branched C1-C6 alkyl;
• B is CH2 or CH2—CH2;
• n is zero or 1;
• Z0 H, straight or branched C1-C4 alkyl, C1-C4 alkylcarbonyl, or C-C4 perfluoroalkylcarbonyl;
• m is zero or an integer from 1 to 4;
• Het is an optionally substituted heteroaryl group comprising at least one nitrogen atom;
• for a compound of formula (Ia), Y1, Y2 and Y3 are independently hydrogen or C1-C4 alkyl and for a compound of formula (Ib), Y3 is hydrogen or C1-C4 alkyl;
• or a pharmaceutically acceptable salt thereof.

A method for treatment of thrombosis comprising administering to a patient in need of such treatment an effective amount of a compound of formula (Ia):

• 41
• or a compound of formula (Ib):
• 42
• in which:
• X1, X2, X3, X4 and X5 are independently hydrogen, hydroxy, hydroxymethyl, C1-C3 alkoxymethyl straight or branched C1-C8 alkyl, straight or branched C1-C8 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, norbornyl, adamantyl, amino, primary or secondary amino substituted with C1-C3 alkyl, cyano, halogen, and nitro;
• or
• X2 may be combined with X3, or X4 may be combined with X5, to form a 5- to 6-membered alkylidenedioxy ring optionally substituted with a C1-C4 alkyl group;
• or
• X4 may be combined with X5 to form a 5- to 6-membered alkylidene ring optionally substituted with a C1-C4 alkyl group;
• R1 and R2, are independently hydrogen or a straight or branched C1-C6 alkyl;
• B is CH2 or CH2—CH2;
• n is zero or 1;
• Z0 is H, straight or branched C1-C4 alkyl, C1-C4 alkylcarbonyl, or C1-C4 perfluoroalkylcarbonyl;
• m is zero or an integer from 1 to 4;
• Het is an optionally substituted heteroaryl group comprising at least one nitrogen atom;
• for a compound of formula (Ia), Y1, Y2 and Y3 are independently hydrogen or C1-C4 alkyl and for a compound of formula (Ib), Y3 is hydrogen or C1-C4 alkyl;
• or a pharmaceutically acceptable salt thereof.

A method for the treatment of restenosis following angioplasty comprising administering to a patient in need of such treatment an effective amount of a compound of formula (Ia):

• 43
• or a compound of formula (Ib):
• 44
• in which:
• X1, X2, X3, X4 and X5 are independently hydrogen, hydroxy, hydroxymethyl, C1-C3 alkoxymethyl straight or branched C1-C8 alkyl, straight or branched C1-C8 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, norbornyl, adamantyl, amino, primary or secondary amino substituted with C1-C3 alkyl, cyano, halogen, and nitro;
• or
• X2 may be combined with X3, or X4 may be combined with X5, to form a 5- to 6-membered alkylidenedioxy ring optionally substituted with a C1-C4 alkyl group;
• or
• X4 may be combined with X5 to form a 5- to 6-membered alkylidene ring optionally substituted with a C1-C4 alkyl group;
• R1 and R2, are independently hydrogen or a straight or branched C1-C6 alkyl;
• B is CH2 or CH2—CH2;
• n is zero or 1;
• Z0 is H, straight or branched C1-C4 alkyl, C1-C4 alkylcarbonyl, or C1-C4 perfluoroalkylcarbonyl;
• m is zero or an integer from 1 to 4;
• Het is an optionally substituted heteroaryl group comprising at least one nitrogen atom;
• for a compound of formula (Ia), Y1, Y2 and Y3 are independently hydrogen or C1-C4 alkyl and for a compound of formula (Ib), Y3 is hydrogen or C1-C4 alkyl;
• or a pharmaceutically acceptable salt thereof.

A method for the prevention and/or treatment of atherosclerosis comprising administering to a patient in need of such treatment an effective amount of a compound of formula (Ia):

• 45
• or a compound of formula (Ib):
• 46
• in which:
• X1, X2, X3, X4 and X5 are independently hydrogen, hydroxy, hydroxymethyl, C1-C3 alkoxymethyl straight or branched C1-C8 alkyl, straight or branched C1-C8 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, norbornyl, adamantyl, amino, primary or secondary amino substituted with C1-C3 alkyl, cyano, halogen, and nitro;
• or
• X2 may be combined with X3, or X4 may be combined with X5, to form a 5- to 6-membered alkylidenedioxy ring optionally substituted with a C1-C4 alkyl group;
• or
• X4 may be combined with X5 to form a 5- to 6-membered alkylidene ring optionally substituted with a C1-C4 alkyl group;
• R1 and R2, are independently hydrogen or a straight or branched C1-C6 alkyl;
• B is CH2 or CH2—CH2;
• n is zero or 1;
• Z0 is H, straight or branched C1-C4 alkyl, C1-C4 alkylcarbonyl, or C1-C4 perfluoroalkylcarbonyl;
• m is zero or an integer from 1 to 4;
• Het is an optionally substituted heteroaryl group comprising at least one nitrogen atom;
• for a compound of formula (Ia), Y1, Y2 and Y3 are independently hydrogen or C1-C4 alkyl and for a compound of formula (Ib), Y3 is hydrogen or C1-C4 alkyl;
• or a pharmaceutically acceptable salt thereof.