11-deoxy azalide antibacterials
Antibacterial compounds having formula (I) and formula (II) and salts, prodrugs, and salts of prodrugs thereof, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis or treatment of bacterial infections using the compounds are disclosed.
1. A compound, or a salt, thereof, having formula (I)
one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—;
R 1 is hydrogen, C 1 -alkyl, or R 9 ;
R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety;
R 3 is hydrogen and R 4 is —OH, —OR 10 , —OC(O)OR 10 , —OC(O)NH 2 , —OC(O)NHR 11 , —OC(O)NR 11 R 12 , —OCH 2 R 13 , —OC(O)OCH 2 R 13 , —OC(O)NHCH 2 R 13 , or —OC(O)N(CH 2 R 13 ) 2 ; or
R 3 and R 4 together are ═O;
R 5 is hydrogen, R 14 , —C(O)OR 14 , —C(O)NH 2 , —C(O)NHR 15 , —C(O)NR 15 R 16 , —CH 2 R 17 , —C(O)OCH 2 R 17 , —C(O)NHCH 2 R 17 , or —C(O)N(CH 2 R 17 ) 2 ;
one of R 6 or R 7 is hydrogen and the other is —OH, —OR 18 , —OC(O)R 18 , —OC(O)OR 18 , —OC(O)NH 2 , —OC(O)NHR 19 , —OC(O)NR 19 R 20 , —OCH 2 R 21 , or —OC(O)OCH 2 R 21 ; or
R 6 and R 7 together are ═O or —CH 2 O—;
R 8 is hydrogen, R 22 , —C(O)OR 22 , —C(O)NH 2 , —C(O)NHR 23 , —C(O)NR 23 R 24 , —CH 2 R 25 , —C(O)OCH 2 R 25 , —C(O)NHCH 2 R 25 , or —C(O)N(CH 2 R 25 ) 2 ; or
R 1 is R 9 , and R 8 and R 9 together are —CH 2 — or —C(O)—;
R 10 , R 14 , R 18 , and R 22 are independently alkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and OR 33 ;
R 11 , R 12 , R 15 , R 16 , R 19 , R 20 , R 23 , and R 24 , are independently alkyl, cycloalkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, cycloalkyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 ; or
R 11 and R 12 together, R 15 and R 16 together, R 19 and R 20 together, and R 23 and R 24 together are each independently C 3 -C 6 -alkylene, C 5 -C 6 -alkylene interrupted with one moiety selected from the group consisting of —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, and —SO 2 —, C 3 -C 6 -alkylene substituted with one substituent selected from the group consisting of —OH, —O(alkyl), —OR 33 , ═O, —NH 2 , —NH(alkyl), and —N(alkyl) 2 , or C 5 -C 6 -alkylene interrupted with one moiety selected from the group consisting of —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, and —SO 2 — and substituted with one substituent selected from the group consisting of aryl, heteroaryl, heterocyclyl, —OH, —O(alkyl), —OR 33 , ═O, —NH 2 , —NH(alkyl), and —N(alkyl) 2 ;
R 13 , R 17 , R 21 , and R 25 are independently alkyl interrupted with one or two or three moieties independently selected from the group consisting of —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, and —SO 2 — or alkyl interrupted with one or two or three moieties independently selected from the group consisting of —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, and —SO 2 — and substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, heterocyclyl —OH, —O(alkyl), —OR 33 , ═O, —NH 2 , —NH(alkyl), and —N(alkyl) 2 ;
R 33 is alkyl substituted with one substituent selected from the group consisting of aryl, —OH, —O(alkyl), —S(alkyl), —S(O)(alkyl), and —SO 2 (alkyl); and
X 1 is hydrogen or fluoride.
2. The compound of claim 1 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen, C 1 -alkyl, or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; or R 3 and R 4 together are ═O; R 5 is hydrogen, R 14 , —C(O)OR 14 , —C(O)NH 2 , —C(O)NHR 15 , —C(O)NR 15 R 16 ; one of R 6 or R 7 is hydrogen and the other is —OH; or R 6 and R 7 together are ═O; R 8 is hydrogen, R 22 , —C(O)OR 22 , —C(O)NH 2 , —C(O)NHR 23 , or —C(O)NR 23 R 24 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 — or —C(O)—; R 14 and R 22 are independently alkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 ; R 15 , R 16 , R 23 , and R 24 are independently alkyl, cycloalkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, cycloalkyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 , or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , —OH, —O(alkyl), and —OR 33 ; R 33 is alkyl substituted with one substituent selected from the group consisting of aryl, —OH, —O(alkyl), —S(alkyl), —S(O) (alkyl), and —SO 2 (alkyl); and X 1 is hydrogen or fluoride.
3. The compound of claim 2 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen, C 1 -alkyl, or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; or R 3 and R 4 together are ═O; R 5 is hydrogen or R 14 ; one of R 6 or R 7 is hydrogen and the other is —OH; or R 6 and R 7 together are ═O; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 14 and R 22 are independently alkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl; and
X 1 is hydrogen or fluoride.
4. The compound of claim 3 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen, C 1 -alkyl, or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; or R 3 and R 4 together are ═O; R 5 is hydrogen or R 14 ; one of R 6 or R 7 is hydrogen and the other is —OH; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 14 and R 22 are independently alkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl; and X 1 is hydrogen or fluoride.
5. The compound of claim 4 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen, C 1 -alkyl, or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; or R 3 and R 4 together are ═O; R 5 is hydrogen or R 14 ; R 6 is hydrogen; R 7 is —OH; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 14 and R 22 are independently alkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl; and X 1 is hydrogen or fluoride.
6. The compound of claim 5 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen, C 1 -alkyl, or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; R 5 is hydrogen or R 14 ; R 6 is hydrogen; R 7 is —OH; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 14 and R 22 are independently alkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl; and X 1 is hydrogen or fluoride.
7. The compound of claim 6 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; R 5 is hydrogen; R 6 is hydrogen; R 7 is —OH; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 22 is alkyl, —(CH 2 )alkenyl, —(CH 2 )alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, or —(CH 2 )alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl; and X 1 is hydrogen or fluoride.
8. The compound of claim 7 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; R 5 is hydrogen; R 6 is hydrogen; R 7 is —OH; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 22 is alkyl, —(CH 2 )alkenyl, alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl, or —(CH 2 )alkenyl substituted with one substituent selected from the group consisting of aryl and heteroaryl; and X 1 is hydrogen or fluoride.
9. The compound of claim 8 having formula (I) or formula (II), in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen or R 9 ; R 2 is hydrogen or R P , in which R P is a hydroxyl protecting moiety; R 3 is hydrogen and R 4 is —OH; R 5 is hydrogen; R 6 is hydrogen; R 7 is —OH; R 8 is hydrogen, methyl, ethyl, phenylmethyl, (pyridin-3-yl)methyl, prop-2-enyl, 3-(quinolin-3-yl)-prop-2-enyl, 3-(isoquinolin-3-yl)-prop-2-enyl, 3-(5-(2-methyl-2H-tetrazol-5-yl)-thien-2-yl)-prop-2-enyl, 3-(5-(pyrimidin-2-yl)-thien-2-yl)-prop-2-enyl, 3-(5-(pyridin-2-yl)-thien-2-yl)-prop-2-enyl, (3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methyl, (3-(phenyl)-4,5-dihydroisoxazol-5-yl)methyl, (3-(pyridin-2-yl)-4,5-dihydroisoxazol-5-yl)methyl, or (phenylmethoxy)carbonyl; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; and X 1 is hydrogen or fluoride.
10. The compound of claim 1 having formula (I) in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen or R 9 ; R 2 , R 5 , and R 6 are hydrogen; R 7 is —OH; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 22 is alkyl, —(CH 2 )alkenyl, alkyl substituted with one substituent selected from the group consisting of phenyl and 4,5-dihydroisoxazolyl, in which the 4,5-dihydroisoxazolyl is substituted with phenyl, and the phenyl is further substituted with one halo substituent, or —(CH 2 )alkenyl substituted with pyridyl, in which the pyridyl is fused with phenyl; and X 1 is hydrogen.
11. The compound of claim 1 having formula (I) in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is hydrogen or R 9 ; R 2 , R 5 , and R 6 are hydrogen; R 7 is —OH; R 8 is hydrogen, R 22 , or —C(O)OR 22 ; or R 1 is R 9 , and R 8 and R 9 together are —CH 2 —; R 22 is C 1 -alkyl, —(CH 2 )—C 2 -alkenyl, C 1 -alkyl substituted with one substituent selected from the group consisting of phenyl and 4,5-dihydroisoxazolyl, in which the 4,5-dihydroisoxazolyl is substituted with phenyl, and the phenyl is further substituted with one halo substituent, or —(CH 2 )—C 2 -alkenyl substituted with pyridyl, in which the pyridyl is fused with phenyl; and X 1 is hydrogen.
12. The compound of claim 11 in which A 1 is —N(R 8 )—, B 1 is —CH 2 —; R 1 , R 2 , R 5 , and R 6 are hydrogen; R 7 is —OH; R 8 is hydrogen, methyl, prop-2-enyl, (3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methyl, 3-(quinolin-3-yl)-prop-2-enyl, or (phenylmethyoxy)carbonyl; and X 1 is hydrogen.
13. The compound of claim 11 in which A 1 is —CH 2 —, B 1 is —N(R 8 )—; R 1 , R 2 , R 5 , and R 6 are hydrogen; R 7 is —OH; R 8 is hydrogen, methyl, prop-2-enyl, (3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methyl, 3-(quinolin-3-yl)-prop-2-enyl, or (phenylmethyoxy)carbonyl; and X 1 is hydrogen.
14. The compound of claim 11 in which one of A 1 and B 1 is —CH 2 —, and the other is —N(R 8 )—; R 1 is R 9 ; R 2 , R 5 , and R 6 are hydrogen; R 7 is —OH; R 8 and R 9 together are —CH 2 —; and X 1 is hydrogen.
15. A composition for treatment of bacterial infections in a fish or a mammal comprising a therapeutically effective amount of a compound of claim 1 .
16. A method for treatment of bacterial infections in a fish or a mammal comprising administering to the fish or the mammal a therapeutically effective amount of a compound of claim 1 .
17. A compound of claim 1 , or a therapeutically acceptable salt thereof, which is
(2R,3S,5S,8R,10S,11R,12S,13S,14R)-2-ethyl-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-6-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside;
(2R,3S,5S,8R,10S,11R,12S,13S,14R)-6-allyl-2-ethyl-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-6-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside;
(2R,3S,5S,8R,10S,11R,12S,13S,14R)-2-ethyl-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-((2E)-3-quinolin-3-ylprop-2-enyl)-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-6-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside;
(2R,3S,5S,8R,10S,11R,12S,13S,14R)-2-ethyl-6-((3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methyl)-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-6-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside;
benzyl (2R,3S,5S,8R,10S,11R,12S,13S,14R)-13-((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy)-2-ethyl-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)-oxy)-1-oxa-6-azacyclopentadecane-6-carboxylate;
(2S,4S,5R,8R,9S,10S,11R,12R,14R)-5-ethyl-4-hydroxy-2,4,8,10,12,14-hexamethyl-7-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-6,17-dioxa-1-azabicyclo(10.3.2)heptadec-9-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside;
(2R,3S,5S,8S,10S,11R,12S,13S,14R)-2-ethyl-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-6-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside;
(2R,3S,5S,8S,10S,11R,12S,13S,14R)-2-ethyl-3,10-dihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-6-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside;
(2R,3S,5S,8R,10S,11R,12S,13S,14R)-2-ethyl-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-11-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-7-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside; or
(2R,3S,5R,8S,10S,11R,12S,13S,14R)-2-ethyl-3,10-dihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-((3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy)-1-oxa-7-azacyclopentadecan-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside.