Rifamycin derivatives
View Patent ↗Novel rifamycin derivatives of formula I (both hydroquinone and corresponding quinone (C 1 -C 4 ) forms): or their salts, hydrates or prodrugs thereof, wherein: a preferred R comprises hydrogen, acetyl; L is a linker, a preferred linker group elements selected from any combination of 1 to 5 groups shown FIG. 1 , provided L is not wherein R 1 is H, methyl or alkyl. The inventive compounds exhibit valuable antibiotic properties. Formulations having these compounds can be used in the control or prevention of infectious diseases in mammals, both humans and non-humans. In particular, the compounds exhibit a pronounced antibacterial activity, even against multiresistant strains of microbes.
1. A compound having a structural formula I:
a pharmaceutically acceptable salt thereof, wherein:
R is hydrogen or acetyl,
L is a linker selected from one or any combination of two or three of the following:
(a) (C 1 -C 6 )alkylene,
(b) (C 3 -C 8 )cycloalkylene,
(c) arylene,
(d) heteroarylene,
(e) bivalent heterocyclic group containing 1 to 3 heteroatoms,
(f) —(═O)—,
(g) —C(═N—O—R 11 )—, wherein R 11 represents hydrogen, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 alkyl),
(h) —C═N—,
(i) —O—,
(j) —S(O) n —, wherein n is number between 0 and 2, and
(k) —N(R 12 )—, wherein R 12 represents hydrogen, (C 1 -C 6 )alkyl. or substituted (C 1 -C 6 alkyl),
wherein the carbon or nitrogen atoms of the linker group are substituted by 0 to 3 substituents selected from (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, heterocycloalkyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino. hydroxyl, or (C 1 -C 6 )alkoxy; and provided L is not
wherein R 1 is H, C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl.
2. The compound of claim 1 , wherein L is a linker group selected from one or any combination of two to three of the following structural elements:
3. A method of treating a bacterial infection in a subject comprising administering to the subject an effective amount of the compound of claim 1 .
4. The method of claim 3 , wherein the bacterial infection is caused by a drug-resistant bacterium.
5. A compound having a formula selected from the group consisting of:
a. (R/&)-3-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-rifamycin S:
b. (R/S)-3-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-amino}-rifamycin S:
c. (R/S)-3-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-methyl-amino}-rifamycin S:
d. (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-piperazin-1-yl}-rifamycin S:
e. (S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl-oxycarbonyl]-piperazin-1-yl}-rifamycin S:
f. (R/S)-3-4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl-carbonyl]-amino}-piperidin-1-yl)-rifamycin S:
g. (S)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-carbamoyl}-piperidin-1-yl)-rifamycin S:
h. (R/S)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-carbamoyl}-piperidin-1-yl)-rifamycin S:
i. (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-piperidin-1-yl}-rifamycin S:
j. 3-[5-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-rifamycin S:
k. 3-[7-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-2,7-diaza-spirol[4.4]non-2-yl]-rifamycin S:
l. (R/S,R/S)-3-{3-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-piperidin-3-yl]-pyrrolidin-1-yl}-rifamycin S:
m. (R/S)-3-{3-[4-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-piperazin-1-yl]-pyrrolidin-1-yl}-rifamycin S:
n. (R/S, R/S)-3-{3-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-piperidin-3 -ylamino]-pyrrolidin-1-yl}-rifamycin S:
o. (R, S)-3-{3-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-pyrrolidin-3-ylamino]-pyrrolidin-1-yl}-rifamycin S and (S, S)-3-{3-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-pyrrolidin-3-ylamino]-pyrrolidin-1-yl}-rifamycin S:
p. (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-pyrrolidin-3-yl]-piperazin-1-yl}-rifamycin S:
q. (R/S, S)-3-{3-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-pyrrolidin-3-ylamino]-piperidin-1-yl}-rifamycin S:
r. (S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylamino]-piperidin-1-yl}-rifamycin S:
s. (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylamino]-piperidin-1-yl}-rifamycin S:
t. (R/S)-3-(4-{[1-(3-Carboxy-1-cyclopropl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-(N-methyl-amino)}-piperidin-1-yl)-rifamycin S:
u. (R)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-pyrrolidin-3-yloxyimino]-piperidin-1-yl}-rifamycin S:
v. (S)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-pyrrolidin-3-ylamino]-methyl}-piperidin-1-yl)-rifamycin S:
6. A compound having a formula selected from the group consisting of:
a. (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethoxy]-piperidin-1-yl}-rifamycin S:
b. (R/S)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-piperidin-1-yl)-rifamycin S:
c. (R)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3 -ylmethyl]-methyl-amino}-piperidin-1-yl)-rifamycin S:
d. (R/S)-3-(4-{1-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-cyclopropylamino}-piperidin-1-yl)-rifamycin S:
e. (R/S)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-3-trifluoromethyl-pyrrolidin-3-ylmethyl]-amino}-piperidin-1-yl)-rifamycin S:
f. (R)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-piperidin-1-yl)-rifamycin S:
g. (R/S)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-piperidin-1-yl)-rifamycin S:
h. (S)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-piperidin-1-yl)-rifamycin S:
i. (R)-3-(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-piperidin-1-yl)-rifamycin SV:
j. (R)-3-(4-{1-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-cyclopropylamino}-piperidin-1-yl)-rifamycin SV:
7. A compound having a formula selected from the group consisting of:
a. 3-{[4-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-piperazin-1-yl-imino]-methyl}-rifamycin SV:
b. (R/S)-3-({4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-piperazin-1-ylimino}-methyl)-rifamycin SV:
c. (S)-3-({4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl-oxycarbonyl]-piperazin-1-yl-imino}-methyl)-rifamycin SV:
d. (R/S)-3-[(4-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-piperidin-1-ylimino)-methyl]-rifamycin SV:
e. (R/S)-3-({4-[1-(3-Carboxy-1-cyclopropl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethoxy]-piperidin-1-ylimino}-methyl)-rifamycin SV:
f. (S)-3-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-hydrazinomethyl}-rifamycin SV:
g. (R/S)-3 -{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-hydrazinomethyl}-rifamycin SV:
h. (R/S)-3-{[1-(3-Carboxy-1-cyclopropl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-hydrazinomethyl}-rifamycin SV:
i. (R/S)-3-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-(N-methyl-hydrazino)-methyl}-rifamycin SV:
j. (R/S)-3-({3-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-piperidin-4-yl]-pyrrolidin-1-ylimino}-methyl)-rifamycin SV (2014) and (R/S)-3-({4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-piperidin-1-ylimino}-methyl)-rifamycin SV (2015):
k. 3-{[5-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin-8-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylimino]-methyl}-rifamycin SV:
l. (R/S, R/S)-3-({3 -[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-piperidin-3-yl]-pyrrolidin-1-ylimino}-methyl)-rifamycin SV:
m. (R/S)-3-({4-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl]-piperazin-1-ylimino}-methyl)-rifamycin SV:
n. (S)-3-{[1-(3-Carboxy-1-cyclopropl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yloxyimino]-methyl}-rifamycin SV:
8. A compound having a formula selected from the group consisting of:
a. (S)-3-({[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-methyl)-rifamycin S:
b. (R)-3-({[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-methyl)-rifamycin S:
c. (S)-3-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl-aminomethyl]-rifamycin SV:
d. (R/S)-3-{[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylamino]-methyl}-rifamycin SV:
e. (R/S)-3-({[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-H-quinolizine-8-yl)-pyrrolidin-3-yl]-methyl-amino}-methyl)-rifamycin SV:
f. (S)-3-({[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-methyl)-rifamycin SV:
g. (R)-3-({[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-H-quinolizine-8-yl)-pyrrolidin-3-ylmethyl]-amino}-methyl)-rifamycin SV:
h. 3-[2-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-2,8-diaza-spiro[4.5]dec-8-ylmethyl]-rifamycin SV: