Antibacterial agents: high-potency myxopyronin derivatives
View Patent ↗The invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein Ya, Yb, R1, R2, and G are as described in the specification, as well as compositions comprising a compound of formula (I). The compounds are useful as inhibitors of bacterial RNA polymerase and as antibacterial agents.
1. A method of inhibiting a bacterial RNAP, comprising contacting a bacterial RNA polymerase with a compound of compound formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or —CH 3 ;
R 2 is hydrogen or —C 1 -C 6 straight or branched alkyl;
one of Y a and Y b is hydrogen or C 1 -C 4 straight alkyl, and the other of Y a and Y b is C 1 -C 10 straight or branched alkyl, C 2 -C 12 straight or branched hydroxyalkyl, C 2 -C 12 straight or branched alkenyl, C 2 -C 12 straight or branched hydroxyalkenyl, phenyl, C 7 -C 12 aralkyl, C 7 -C 12 (aryl)hydroxyalkyl, C 6 -C 12 heteroaralkyl, C 6 -C 12 (heteroaryl)hydroxyalkyl, or Y a and Y b are taken together with their intervening atom to form a 4-6 membered ring having 0-1 ring heteroatoms selected from nitrogen, oxygen or sulfur, said ring optionally substituted by one or two C 1 -C 6 alkyl, C 2 -C 6 alkenyl or hydroxyalkyl groups, wherein an alkyl, aryl or heteroaryl moiety of Y a and Y b optionally is substituted with 1-3 groups independently selected from halo, —C 1 -C 6 hydroxyalkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 trifluoroalkoxy, —CN, —C 1 -C 4 alkoxycarbonyl, —C 1 -C 4 alkylcarbonyl, —S(C 1 -C 4 alkyl), and —SO 2 (C 1 -C 4 alkyl);
G is —CH═CH—NHC(O)—R 3 , —CH═CH—NHC(S)—R 3 , —CH 2 CH 2 NHC(O)—R 3 , —CH 2 CH 2 NHC(S)—R 3 , —CH 2 NHNHC(O)—R 3 , or —CH 2 NHNHC(S)—R 3 ;
R 3 is C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 4 ) 2 ; and
each R 4 is independently hydrogen or —C 1 -C 6 alkyl;
provided that, when Y a is hydrogen and Y b is —CH 2 CH 2 CH 2 CH 3 , or when Y a is —CH 3 and Y b is —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH═C(CH 3 ) 2 , —CH 2 CH 2 CH(OH)C(CH 3 )═CHCH 2 CH═CHCH 3 , or —CH 2 CH 2 CH(OH)C(CH 3 )═CHCH 2 CH═CHCH 2 CH 3 , then G is other than —CH═CH—NHC(O)—OCH 3 ; and
provided that, when Y a is —CH 3 and Y b is —CH 2 CH 2 CH 2 CH 3 , then G is other than —CH 2 CH 2 —NHC(O)—OCH 3 .
2. A method of inhibiting a bacterial RNAP, comprising contacting a bacterial RNAP with a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or —CH 3 ;
R 2 is hydrogen or —C 1 -C 6 straight or branched alkyl;
one of Y a and y b is hydrogen or C 1 -C 4 straight alkyl, and the other of Y a and Y b is C 1 -C 10 straight or branched alkyl, C 2 -C 12 straight or branched hydroxyalkyl, C 2 -C 12 straight or branched alkenyl, C 2 -C 12 straight or branched hydroxyalkenyl, phenyl, C 7 -C 12 aralkyl, C 7 -C 12 (aryl)hydroxyalkyl, C 6 -C 12 heteroaralkyl, C 6 -C 12 (heteroaryl)hydroxyalkyl, or Y a and Y b are taken together with their intervening atom to form a 4-6 membered ring having 0-1 ring heteroatoms selected from nitrogen, oxygen or sulfur, said ring optionally substituted by one or two C 1 -C 6 alkyl, C 2 -C 6 alkenyl or hydroxyalkyl groups, wherein an alkyl, aryl or heteroaryl moiety of Y a and Y b optionally is substituted with 1-3 groups independently selected from halo, —C 1 -C 6 hydroxyalkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 trifluoroalkoxy, —CN, —C 1 -C 4 alkoxycarbonyl, —C 1 -C 4 alkylcarbonyl, —S(C 1 -C 4 alkyl), and —SO 2 (C 1 -C 4 alkyl;
G is —CH═CH—NHC(O)—R 3 , —CH═CH—NHC(S)—R 3 , —CH 2 ,CH 2 ,NHC(O)—R 3 , —CH 2 ,CH 2 ,NHC(S)—R 3 , —CH 2 ,NHNHC(O)—R 3 , or —CH 2 NHNHC(S)—R 3 ;
each R 3 is independently C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 4 ) 2 ; and
each R 4 is independently hydrogen or —C 1 -C 6 alkyl;
provided that, when Y a is hydrogen and Y b is —CH 2 CH 2 CH 2 CH 3 , or when Y a is —CH 3 and Y b is —CH 2 CH 2 ,CH═C(CH 3 ) 2 , —CH 2 CH 2 CH(OH)C(CH 3 )═CHCH 2 CH═CHCH 3 , or —CH 2 CH 2 CH(OH)C(CH 3 )═CHCH 2 CH═CHCH 2 CH 3 , then G is other than —CH═CH—NHC(O)—OCH 3 ;
and provided that, when Y a is —CH 3 and Y b is —CH 2 CH 2 CH 3 or —CH 2 CH 2 CH 2 CH 3 , then G is other than —CH═CH—NHC(O)—(C 1 -C 6 alkyl), —CH═CH—NHC(O)—O(C 1 -C 6 alkyl), —CH═CH—NHC(O)—N(R 4 ) 2 , and —CH 2 CH 2 —NHC(O)—O(C 1 -C 6 alkyl).
3. The method of claim 1 wherein the bacterial RNAP is from Mycobacterium tuberculosis, Mycobacterium avium, Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Enterobacter cloacae, Clostridium difficile, Acinetobacter baumannii , or Escherichia coli.
4. A method of treating a bacterial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or —CH 3 ;
R 2 is hydrogen or —C 1 -C 6 straight or branched alkyl;
one of Y a and Y b is hydrogen or C 1 -C 4 straight alkyl, and the other of Y a and Y b is C 1 -C 10 straight or branched alkyl, C 2 -C 12 straight or branched hydroxyalkyl, C 2 -C 12 straight or branched alkenyl, C2-C 12 straight or branched hydroxyalkenyl, phenyl, C 7 -C 12 aralkyl, C 7 -C 12 (aryl)hydroxyalkyl, C 6 -C 12 heteroaralkyl, C 6 -C 12 (heteroaryl)hydroxyalkyl, or Y a and Y b are taken together with their intervening atom to form a 4-6 membered ring having 0-1 ring heteroatoms selected from nitrogen, oxygen or sulfur, said ring optionally substituted by one or two C 1 -C 6 alkyl, C 2 -C 6 alkenyl or hydroxyalkyl groups, wherein an alkyl, aryl or heteroaryl moiety of Y a and Y b optionally is substituted with 1-3 groups independently selected from halo, —C 1 -C 6 hydroxyalkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 trifluoroalkoxy, —CN, —C 1 -C 4 alkoxycarbonyl, —C 1 -C 4 alkylcarbonyl, —S(C 1 -C 4 alkyl), and —SO 2 (C 1 -C 4 alkyl);
G is —CH═CH—NHC(O)—R 3 , —CH═CH—NHC(S)—R 3 , —CH 2 ,CH 2 ,NHC(O)—R 3 , —CH 2 ,CH 2 ,NHC(S)—R 3 , —CH 2 ,NHNHC(O)—R 3 , or —CH 2 NHNHC(S)—R 3 ;
each R 3 is independently C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 4 ) 2 ; and
each R 4 is independently hydrogen or —C 1 -C 6 alkyl;
provided that, when Y a is hydrogen and Y b is —CH 2 CH 2 CH 2 CH 3 , or when Y a is —CH 3 and Y b is —CH 2 CH 2 ,CH═C(CH 3 ) 2 , —CH 2 CH 2 CH(OH)C(CH 3 )═CHCH 2 CH═CHCH 3 , or —CH 2 CH 2 CH(OH)C(CH 3 )═CHCH 2 CH═CHCH 2 CH 3 , then G is other than —CH═CH—NHC(O)—OCH 3 ;
and provided that, when Y a is —CH 3 and Y b is —CH 2 CH 2 CH 3 or —CH 2 CH 2 CH 2 CH 3 , then G is other than —CH═CH—NHC(O)—(C 1 -C 6 alkyl), —CH═CH—NHC(O)—O(C 1 -C 6 alkyl), —CH═CH—NHC(O)—N(R 4 ) 2 , and —CH 2 CH 2 —NHC(O)—O(C 1 -C 6 alkyl).
5. The method of claim 4 wherein the bacterial infection is associated with Mycobacterium tuberculosis, Mycobacterium avium, Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Enterobacter cloacae , or Clostridium difficile, Acinetobacter baumannii , or Escherichia coli.
6. A composition comprising:
(a) from about 0.25 mg/ml to about 5 mg/ml of a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or —CH 3 ;
R 2 is hydrogen or —C 1 -C 6 straight or branched alkyl;
one of Y a and Y b is hydrogen or C 1 -C 4 straight alkyl, and the other of Y a and Y b is C 1 -C 10 straight or branched alkyl, C 2 -C 12 straight or branched hydroxyalkyl, C 2 -C 12 straight or branched alkenyl, C 2 -C 12 straight or branched hydroxyalkenyl, phenyl, C 7 -C 12 aralkyl, C 7 -C 12 (aryl)hydroxyalkyl, C 6 -C 12 heteroaralkyl, C 6 -C 12 (heteroaryl)hydroxyalkyl, or Y a and Y b are taken together with their intervening atom to form a 4-6 membered ring having 0-1 ring heteroatoms selected from nitrogen, oxygen or sulfur, said ring optionally substituted by one or two C 1 -C 6 alkyl, C 2 -C 6 alkenyl or hydroxyalkyl groups, wherein an alkyl, aryl or heteroaryl moiety of Y a and Y b optionally is substituted with 1-3 groups independently selected from halo, —C 1 -C 6 hydroxyalkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 trifluoroalkoxy, —CN, —C 1 -C 4 alkoxycarbonyl, —C 1 -C 4 alkylcarbonyl, —S(C 1 -C 4 alkyl), and —SO 2 (C 1 -C 4 alkyl);
G is —CH═CH—NHC(O)—R 3 , —CH═CH—NHC(S)—R 3 , —CH 2 CH 2 NHC(O)—R 3 , —CH 2 CH 2 NHC(S)—R 3 , —CH 2 NHNHC(O)—R 3 , or —CH 2 NHNHC(S)—R 3 ;
R 3 is C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 4 ) 2 ; and
each R 4 is independently hydrogen or —C 1 -C 6 alkyl;
(b) about 5% to about 20% dimethylacetamide; and
(c) about 4% to about 16% Cremophor EL.
7. The composition of claim 6 which comprises from about 0.5 mg/ml to about 3 mg/ml of the compound of formula I or a pharmaceutically acceptable salt thereof; about 5% to about 15% dimethylacetamide; and about 4% to about 12% Cremophor EL.
8. The composition of claim 6 which comprises about 2 mg/ml of the compound of formula I or a pharmaceutically acceptable salt thereof; about 9% dimethylacetamide; and about 8% Cremophor EL.
9. The composition of claim 6 wherein the compound of formula I is a compound of the following formula Ia:
wherein: R e is H, methyl, or ethyl, which methyl or ethyl is optionally is substituted with hydroxy, —C 1 -C 4 alkoxy, or halo; Y a is H or methyl; and R 1 is H or methyl.