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US 8,802,661 B2Granted
C-28 amides of modified C-3 betulinic acid derivatives as HIV maturation inhibitors
AssigneeBristol-Myers Squibb Company
InventorsAlicia Regueiro-Ren, Zheng Liu, Jacob Swidorski, Nicholas A. Meanwell, Sing-Yuen Sit, Jie Chen, Yan Chen, Ny Sin
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Abstract
Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, modified C-3 and C-28 betulinic acid derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors. These compounds are useful for the treatment of HIV and AIDS.
Claims22
A compound which is selected from the group of:
- a compound of formula I
- a compound of formula II
- a compound of formula III
- wherein R1 is isopropenyl or isopropyl;
- J and E are —H or —CH3;
- E is absent when the double bond is present;
- X is a phenyl or heteroaryl ring substituted with A, wherein A is at least one member selected from the group of —H, -halo, -alkyl, -alkoxy, —COOR2 and -hydroxyl wherein R2 is —H—C1-6 alkyl, or substituted —C1-6 alkyl;
- Y is selected from the group of —COOR2, —C(O)NR2SO2R3, —C(O)NR2SO2NR2R2, —SO2NR2R2, —NR2SO2R2, —C1-6 cycloalkyl-COOR2, —C1-6 alkenyl-COOR2, —C1-6 alkynyl-COOR2, —C1-6 alkyl-COOR2, —NHC(O)(CH2)n—COOR2, —SO2NR2C(O)R2, -tetrazole, B(OH)2 and —CONHOH wherein n=1-6 and wherein R3 is C1-6 alkyl;
- and
- Z is —CONR4R5;
- R4 is selected from the group of H, C1-6 alkyl, and C1-6 alkyl-OH;
- R5 is selected from the group of H, C1-6 alkyl, substituted-alkyl, C1-6 alkyl-R6, C2-6 alkyl-R7, SO2R8, SO2NR9R10;
- R6 is selected from phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, SO2R11, SO2NR12R13, C1-6 cycloalkyl, substituted C1-6 cycloalkyl, SO3H, COOR14, C(O)NR15R16;
- R7 is selected from OR17, N+(O−)R18R19, NR20(COR21) and NR22R23;
- or R4 and R5 are taken together to form a cycle selected from the group of:
- R22 and R23 are selected from the group of H, C1-6 alkyl, substituted-alkyl, C1-6 alkyl-R32, C2-6 alkyl-R33, SO2R8, SO2NR9R10;
- R32 is selected from phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, SO2R11, SO2NR12R13, C1-6 cycloalkyl, substituted C1-6 cycloalkyl, SO3H, COOR14, C(O)NR15R16,
- R33 is selected from OR17, N+(O−)R18R19, NR20(COR21) and NR9R10;
- or R22 and R23 are taken together to form a cycle selected from the group of:
- R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R27, R29, R30 and R31 are each independently selected from the group of H, C1-6 alkyl, substituted-alkyl, C1-6 cycloalkyl and substituted C1-6 cycloalkyl;
- R24, R26 and R28 are selected from the group of H, alkyl, substituted alkyl, COOR29, COONR30R31;
- and
- R25 is selected from the group of alkyl, substituted alkyl, COOR29, COONR30R31;
- and pharmaceutically acceptable salts thereof.
21 more elements
A compound which is selected from the group consisting of:
- and pharmaceutically acceptable salts thereof.
A compound which is selected from the group consisting of:
- and pharmaceutically acceptable salts thereof.
A compound which is selected from the group consisting of:
- and pharmaceutically acceptable salts thereof.
An intermediate compound which is selected from the group of:
- wherein A is selected from the group of —H, -halo, -alkyl, -alkoxy, —COOR2 and -hydroxyl, wherein R2 is —H, —C1-6 alkyl, or substituted C1-6 alkyl,
- wherein R4 is selected from the group of H, C1-6 alkyl, and C1-6 alkyl-OH;
- wherein R5 is selected from the group of H, C1-6 alkyl, substituted-alkyl, C1-6 alkyl-R6, C2-6 alkyl-R7, SO2R8, SO2NR9R10;
- wherein R6 is selected from phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, SO2R11, SO2NR12R13, C1-6 cycloalkyl, substituted C1-6 cycloalkyl, SO3H, COOR14, C(O)NR15R16;
- wherein R7 is selected from OR17, N+(O−)R18R19, NR20(COR21) and NR22R23;
- wherein R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 are each independently selected from the group of H, C1-6 alkyl, substituted-alkyl, C1-6 cycloalkyl and substituted C1-6 cycloalkyl;
- wherein R22 and R23 are selected from the group of H, C1-6 alkyl, substituted-alkyl, C1-6 alkyl-R32, C2-6 alkyl-R33, SO2R8, SO2NR9R10;
- wherein R32 is selected from phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, SO2R11, SO2NR12R13, C1-6 cycloalkyl, substituted C1-6 cycloalkyl, SO3H, COOR14, C(O)NR15R16,
- and wherein R33 is selected from OR17, N+(O−)R18R19, NR20(COR21) and NR9R10.
6 more elements
An intermediate compound with the structure:
Dependencies are inferred from the claim text.