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US 2006/0069080 A1Published application
Combinations of substituted azetidinones and CB1 antagonists
OwnerEnrico Veltriinventor
Life of this patent
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Abstract
The present invention provides compositions, therapeutic combinations and methods including: (a) at least one selective CB1 antagonist; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity, metabolic syndrome and lowering plasma levels of sterols or 5α-stanols.
Claims39
A composition comprising:
- (a) at least one selective CB1 receptor antagonist;
- and
- (b) at least one cholesterol lowering compound.
A composition comprising:
- (a) at least one selective CB1 receptor antagonist;
- and
- (b) at least one sterol absorption inhibitor or at least one 5α-stanol absorption inhibitor.
A composition comprising:
- (a) at least one selective CB1 receptor antagonist or a pharmaceutically acceptable salt, solvate, or ester thereof;
- and
- (b) at least one substituted azetidinone compound or substituted α-lactam compound or a pharmaceutically acceptable salt, solvate, or ester thereof.
A composition comprising:
- (a) at least one selective CB1 receptor antagonist or a pharmaceutically acceptable salt, solvate, or ester thereof;
- and
- (b) at least one sterol absorption inhibitor represented by Formula (I):
- or pharmaceutically acceptable salts, solvate, or esters 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 —CH2—, —CH(lower alkyl)- and —C(di-lower alkyl)-;
- R and R2 are independently selected from the group consisting of —OR6, —OC(O)R6, —OC(O)OR9 and —OC(O)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, —OR6, —OC(O)R6, —OC(O)OR9, —O(CH2)1-5OR6, —OC(O)NR6R7, —NR6R7, —NR6C(O)R7, —NR6C(O)OR9, —NR6C(O)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, —CH═CH—COOR6, —CF3, —CN, —NO2 and halogen;
- R5 is 1-5 substituents independently selected from the group consisting of —OR6, —OC(O)R6, —OC(O)OR9, —O(CH2)1-5OR6, —OC(O)NR6R7, —NR6R7, —NR6C(O)R7, —NR6C(O)OR9, —NR6C(O)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and —CH═CH—COOR6;
- 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.
17 more elements
A composition comprising:
- (a) at least one selective CB1 receptor antagonist;
- and
- (b) a compound represented by Formula (II) below:
- or a pharmaceutically acceptable salt, solvate, or ester thereof.
1 more element
A therapeutic combination comprising:
- (a) a first amount of at least one selective CB1 receptor antagonist;
- and
- (b) a second amount of at least one cholesterol lowering compound or pharmaceutically acceptable salt, solvate, or ester 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, metabolic syndrome, or lowering a concentration of a sterol in plasma of a subject.
1 more element
A therapeutic combination comprising:
- (a) a first amount of at least one selective CB1 receptor antagonist or a pharmaceutically acceptable salt, solvate, or ester thereof;
- and
- (b) a second amount of at least one sterol absorption inhibitor or at least one 5α-stanol absorption inhibitor, or a pharmaceutically acceptable salt, solvate or ester 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, metabolic syndrome, or lowering a concentration of a sterol in plasma of a subject.
1 more element
A therapeutic combination comprising:
- (a) a first amount of at least one selective CB1 receptor antagonist or a pharmaceutically acceptable salt, solvate, or ester thereof;
- and
- (b) a second amount of at least one substituted azetidinone compound or substituted β-lactam compound or salt, solvate, or ester 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, metabolic syndrome, or lowering a concentration of a sterol in plasma of a subject.
1 more element
A therapeutic combination comprising:
- (a) a first amount of at least one selective CB1 receptor antagonist or a pharmaceutically acceptable salt, solvate, or ester thereof;
- and
- (b) a second amount of at least one sterol absorption inhibitor represented by Formula (I):
- or pharmaceutically acceptable salts, solvate, or esters 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 —CH2—, —CH(lower alkyl)- and —C(di-lower alkyl)-;
- R and R2 are independently selected from the group consisting of —OR6, —OC(O)R6, —OC(O)OR9 and —OC(O)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, —OR6, —OC(O)R6, —OC(O)OR9, —O(CH2)1-5OR6, —OC(O)NR6R7, —NR6R7, —NR6C(O)R7, —NR6C(O)OR9, —N R6C(O)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, —CH═CH—COOR6, —CF3, —CN, —NO2 and halogen;
- R5 is 1-5 substituents independently selected from the group consisting of —OR6, —OC(O)R6, —OC(O)OR9, —O(CH2)1-5OR6, —OC(O)NR6R7, —NR6R7, —NR6C(O)R7, —NR6C(O)OR9, —NR6C(O)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and —CH═CH—COOR6;
- 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;
- 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, metabolic syndrome, or lowering a concentration of a sterol in plasma of a subject.
18 more elements
A therapeutic combination comprising:
- (a) a first amount of at least one selective CB1 receptor antagonist or a pharmaceutically acceptable salt, solvate, or ester thereof;
- and
- (b) a second amount of a compound represented by Formula (II) below:
- or a pharmaceutically acceptable salt, solvate, or ester 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, metabolic syndrome, or lowering a concentration of a sterol in plasma of a subject.
2 more elements
A composition comprising:
- (a) rimonabant;
- and
- (b) at least one cholesterol lowering compound or salt, solvate, or ester thereof.
A composition comprising:
- (a) rimonabant;
- and
- (b) at least one sterol absorption inhibitor or at least one 5α-stanol absorption inhibitor, or a pharmaceutically acceptable salt, solvate, or ester thereof.
A composition comprising:
- (a) rimonabant;
- and
- (b) at least one substituted azetidinone compound or substituted β-lactam compound or a pharmaceutically acceptable salt, solvate, or ester thereof.
A composition comprising:
- (a) rimonabant;
- and
- (b) at least one sterol absorption inhibitor represented by Formula (I):
- or pharmaceutically acceptable salts, solvate, or esters 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 —CH2—, —CH(lower alkyl)- and —C(di-lower alkyl)-;
- R and R2 are independently selected from the group consisting of —OR6, —OC(O)R6, —OC(O)OR9 and —OC(O)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 O 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, —OR6, —OC(O)R6, —OC(O)OR9, —O(CH2)1-5OR6, —OC(O)NR6R7, —NR6R7, —NR6C(O)R7, —NR6C(O)OR9, —NR6C(O)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, —CH═CH—COOR6, —CF3, —CN, —NO2 and halogen;
- R5 is 1-5 substituents independently selected from the group consisting of —OR6, —OC(O)R6, —OC(O)OR9, —O(CH2)1-5OR6, —OC(O)NR6R7, —NR6R7, —NR6C(O)R7, —NR6C(O)OR9, —NR6C(O)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and —CH═CH—COOR6;
- 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.
17 more elements
A composition comprising:
- (a) rimonabant;
- and
- (b) a compound represented by Formula (II) below:
- or a pharmaceutically acceptable salt, solvate, or ester thereof.
1 more element
A method of treating or preventing a vascular condition, diabetes, obesity, metabolic syndrome, 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 rimonabant and ezetimibe.
Dependencies are inferred from the claim text.