1. A composition comprising:
(a) at least one lipid modulating agent; and
(b) at least one substituted azetidinone compound or substituted \u03b1-lactam compound or salt or solvate thereof.
2. The composition according to claim 1, wherein the substituted azetidinone compound is represented by Formula (I):
or pharmaceutically acceptable salts or solvates thereof, wherein in Formula (I) above:
Ar1 and Ar2 are independently selected from the group consisting of aryl and R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X, Y and Z are independently selected from the group consisting of \u2014CH2\u2014, \u2014CH(lower alkyl)- and \u2014C(dilower alkyl)-;
R and R2 are independently selected from the group consisting of \u2014O6, \u2014O(CO)R5, \u2014O(CO)OR9 and\u2014O(CO)NR6R7 ;
R1 and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, \u2014OR6, \u2014O(CO)R6, \u2014O(CO)OR9, \u2014O(CH2)1-5OR6, \u2014O(CO)NR6R7, \u2014NR6R7, \u2014NR6(CO)R7, \u2014NR6(CO)OR9, \u2014NR6(CO)NR7R8, \u2014NR6SO2R9, \u2014COOR6, \u2014CONR6R7, \u2014COR,6, \u2014SO2NR6R7, S(O)0-2R9, \u2014O(CH2)1-10\u2014COOR6, \u2014O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, \u2014CH\u2550CH\u2014COOR6, \u2014CF3, \u2014CN, \u2014NO2 and halogen;
R5 is 1-5 substituents independently selected from the group consisting of \u2014OR6, \u2014O(CO)R6, \u2014O(CO)OR9, \u2014O(CH2)1-5OR6, \u2014O(CO)NR6R7, \u2014NR6R7, \u2014NR6(CO)R7, \u2014NR6(CO)OR9, \u2014NR (CO)NR7R8, \u2014NR6 SO2R9, \u2014COOR6, \u2014CONR6R7, \u2014COR6, \u2014SO2NR6R7, S(O)0-2R9, \u2014O(CH2)1-10\u2014COOR6, \u2014O(CH2), 1-10CONR6R7, -(lower alkylene)COOR6 and \u2014CH\u2550CH\u2014COOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl.
3. The composition according to claim 1, wherein the substituted azetidinone compound is represented by Formula (II) below:
or pharmaceutically acceptable salt or solvate thereof.
4. The composition according to claim 1, wherein the lipid modulating agent is selected from the group consisting of synthetic HDL, phospholipids, phospholipids in combination with HDL associated and biologically active peptides derived therefrom, reverse lipid transport (RLT) peptides, enzymes associated with HDL, and apo E, alone or formulated in combination with liposomes or emulsions.
5. The composition according to claim 1, wherein the lipid modulating agent is a synthetic HDL complex comprising recombinant apolipoprotein A-I Milano and 1-palmitoyl-2-oleoyl phosphatidyl choline complex.
6. A composition comprising: (a) at least one lipid modulating agent; and (b) a compound represented by Formula (II) below:
or pharmaceutically acceptable salt or solvate thereof.
7. A therapeutic combination comprising: (a) a first amount of at least one lipid modulating agent; and (b) a second amount of at least one substituted azetidinone compound or substituted \u03b2-lactam compound or pharmaceutically acceptable salt or solvate thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a subject.
8. A pharmaceutical compositions for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a subject, comprising a therapeutically effective amount of a composition or therapeutic combination of claim 1 and a pharmaceutically acceptable carrier.
9. A method of treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a subject, comprising the step of administering to a mammal in need of such treatment an effective amount of a composition or therapeutic combination of claim 1.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of Formula I:
wherein
L is (C5-C8)cycloalkyl; phenyl optionally substituted by 1-4 (C1-C4)alkyl; \u2014(CH2)n\u2014 where n is 1, 2, or 4-10; \u2014C(Rx)2\u2014; or \u2014CH2\u2014C(Rx)2\u2014CH2\u2014; where each Rx is independently OH, or \u2014CH2O-Sac;
each X is independently O, S, NH, triazole; or a direct bond;
each m is 0 or 1;
each R1 is independently H or (C1-C20)alkyl; and
each Amph is independently a moiety of Formula A:
wherein
Y is CH2 or a direct bond;
each R2, R3, and R4 is independently H, OH, or O-Sac; and
each Sac is independently a monosaccharide, disaccharide, or trisaccharide;
wherein the compound has at least 4 Sac groups.
2. The compound of claim 1 wherein each R1 is (C1-C20)alkyl.
3. The compound of claim 1 wherein Y is a direct bond.
4. The compound of claim 1 wherein at least two of R2, R3 and R3 are O-Sac and each Sac is a disaccharide.
5. The compound claim 1 wherein the compound is a compound of Formula III:
6. The compound claim 1 wherein the compound is a compound of Formula XII:
where each R2 is independently an oxygen linked monosaccharide, disaccharide, trisaccharide.
7. The compound claim 6 wherein the compound is:
8. The compound claim 1 wherein the compound is a compound of Formula XIII:
9. The compound claim 8 wherein the compound is:
10. The compound claim 1 wherein the compound is a compound of Formula XIV:
where each R2 is independently a monosaccharide, disaccharide, trisaccharide.
11. The compound claim 10 wherein the compound is:
12. A compound of Formula I:
Amph-X-L-X-Amph\u2003\u2003(I)
wherein
L is (C5-C8)cycloalkyl; phenyl optionally substituted by 1-4 (C1-C4)alkyl; \u2014(CH2)n\u2014 where n is 1-10; \u2014C(Rx)2\u2014; or \u2014CH2\u2014C(Rx)2\u2014CH2\u2014; where each Rx is independently H, OH, or \u2014CH2O-Sac;
each X is independently O, S, NH, CH2, triazole; or a direct bond; and
each Amph is independently a moiety of Formula A:
wherein
Y is CH2 or a direct bond;
each R2, R3, and R4 is independently H, OH, or O-Sac; and
each Sac is independently a monosaccharide, disaccharide, or trisaccharide;
wherein the compound has at least 4 Sac groups.
13. The compound claim 12 wherein the compound is a compound of Formula VII:
wherein each X is independently O, S, NH, CH2, or triazole; and n is \u22121, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
14. The compound claim 13 wherein the compound is a compound of Formula VIII:
wherein each X is S, O, CH2, or
15. The compound of claim 1 wherein a plurality of the compounds form a micelle in water comprising about 6 to about 15 molecules of the compound.
16-20. (canceled)
21. A compound of Formula I:
where L is \u2014(CH2)n\u2014 where n is 1-10; (C5-C8)cycloalkyl; a phenyl diradical optionally substituted by 1, 2, 3, or 4 (C1-C4)alkyl groups; \u2014C(Rx)2\u2014; or \u2014CH2\u2014C(Rx)2\u2014CH2\u2014; where each Rx is independently H, OH, or \u2014CH2O-Sac;
each X is independently O, S, NH, CH2, triazole, or a direct bond;
each m is 0 or 1;
each R1 is independently (C5-C20)alkyl; and
each Amph is independently a moiety of Formula A:
wherein
Y is CH2 or a direct bond;
each R2, R3, and R4 is independently H, OH, or O-Sac; and
each Sac is independently an oxygen-linked monosaccharide, disaccharide, or trisaccharide where the compound of Formula I has at least 4 Sac groups.