Rifamycin analogs and uses thereof
View Patent ↗The present invention features rifamycin analogs that can be used as therapeutics for treating or preventing a variety of microbial infections. In one form, the analogs are acetylated at the 25-position, as is rifamycin. In another form, the analogs are deacetylated at the 25-position. In yet other forms, benzoxazinorifamycin, benzthiazinorifamycin, and benzdiazinorifamycin analogs are derivatized at various positions of the benzene ring, including 3′-hydroxy analogs, 5′-halo and/or alkoxy analogs, and various 4′- and/or 6′-substituents that incorporate a cyclic amine moiety.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein
(a) A is H, OH, O—(C 1-6 alkyl), O—(C 1-4 alkaryl), O—(C 6-12 aryl), O—(C 1-9 heteroaryl), or O—(C 1-4 alkheteroaryl);
W is O, S, or NR 1 , wherein R 1 is H, C 1-6 alkyl, C 1-4 alkaryl, or C 1-4 alkheteroaryl;
X is H or COR 2 , wherein R 2 is C 1-6 alkyl, which can be substituted with 1-5 OH groups, O—(C 3-7 alkyl), which can be substituted with 1-4 OH groups, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, wherein each alkyl carbon is bonded to no more than one oxygen atom;
Y is H, Hal, or OR Y3 , wherein R Y3 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl; and
each of R 4 and R 4′ is H or has the formula:
with the proviso that R 4 and R 4′ cannot be H at the same time, wherein
when each of m and n is 1:
each of R 5 and R 6 is H, or R 5 and R 6 together are ═O;
R 7 and R 10 together form a single bond or a C 1-3 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), R 7 and R 12 together form a single bond or a
C 1-2 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), R 7 and R 14 together form a single bond or a C 1 linkage, or R 7 and R 16 together form a single bond or a C 1 linkage, wherein R 23 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, COR 24b , CO 2 R 24a , CONR 24a R 24b , CSR 24b , COSR 24a , CSOR 24a , CSNR 24a R 24b , SO 2 R 24a , or SO 2 NR 24a R 24b , wherein R 24a is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, R 24b is H, C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, or R 24a and R 24b together form a C 2-6 linkage, optionally containing a non-vicinal O;
R 8 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, R 8 and R 12 together form a single bond, or R 8 and R 9 together are ═O or ═N—OR 18 , wherein R 18 is H, C 1-6 alkyl, C 1-4 alkaryl, or C 1-4 alkheteroaryl;
R 9 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, or R 9 and R 8 together are ═O or ═N—OR 18 , wherein R 18 is as previously defined;
R 10 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, R 10 and R 7 together form a single bond or a C 1-3 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), R 10 and R 11 together are ═O, R 10 and R 16 together form a C 1-2 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), or R 10 and R 17 together form a C 1-3 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined;
R 11 is H, or R 11 and R 10 together are ═O;
R 12 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, R 12 and R 7 together form a single bond or a C 1-2 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), R 12 and R 8 together form a single bond, or R 12 and R 16 together form a C 24 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined;
R 13 is H, C 1-6 alkyl, C 1-4 alkaryl, or C 1-4 alkheteroaryl;
R 14 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, or R 14 and R 7 together form a single bond or a C 1 linkage;
R 15 is H, C 1-6 alkyl, C 1-4 alkaryl, or C 1-4 alkheteroaryl;
R 16 is H, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, C 1-9 heteroaryl, C 1-4 alkaryl, C 1-4 alkheteroaryl, R 16 and R 7 together form a bond or a C 1 alkyl linkage, R 16 and R 12 together form a C 2-4 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), or R 16 and R 10 together form a C 1-2 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined; and
R 17 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, COR 19 , CO 2 R 19 , CONHR 19 , CSR 19 , COSR 19 , CSOR 19 , CSNHR 19 , SO 2 R 19 , or SO 2 NHR 19 , wherein R 19 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, or R 17 and R 10 together form a C 1-3 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined,
and
when m is 0 and n is 1:
R 7 and R 10 together form a single bond or a C 1-4 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), R 7 and R 12 together form a single bond or a C 1-3 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), or R 7 and R 14 together form a single bond or a C 1-2 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined;
each of R 8 and R 9 is H;
R 10 is H or R 10 and R 7 together form a single bond or a C 1-4 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined;
R 11 is H;
R 12 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, R 12 and R 7 together form a single bond or a C 1-3 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), R 12 and R 13 together form a —CH 2 CH 2 — linkage, or R 12 and R 16 together form a C 2-4 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined;
R 13 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, or R 13 and R 12 together form a —CH 2 CH 2 — linkage;
R 14 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, or R 14 and R 7 together form a single bond or a C 1-2 linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined;
R 15 is H, C 1-6 alkyl, C 1-4 alkaryl, or C 1-4 alkheteroaryl;
R 16 is H, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, C 1-9 heteroaryl, C 1-4 alkaryl, C 1-4 alkheteroaryl, or R 16 and R 12 together form a C 2-4 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R 23 ), wherein R 23 is as previously defined; and
R 17 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, COR 19 , CO 2 R 19 , CONHR 19 , CSR 19 , COSR 19 , CSOR 19 , CSNHR 19 , SO 2 R 19 , or SO 2 NHR 19 , wherein R 19 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl,
or
(b) A is OH;
X is H;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and R 4′ cannot be H, R 21 is H, C 1-6 alkyl, C 6-12 aryl, C 1-9 heteroaryl, C 1-4 alkaryl, or C 1-4 alkheteroaryl, R 20 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, COR 19 , CO 2 R 19 , CONHR 19 , CSR 19 , COSR 19 , CSOR 19 , CSNHR 19 , SO 2 R 19 , or SO 2 NHR 19 , wherein R 19 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl,
or
(c) A is OH;
X is COCH 3 ;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and
R 4′ cannot be H, R 21 is H, C 1-6 alkyl, C 6-12 aryl, C 1-9 heteroaryl, C 1-4 alkaryl, or C 1-4 alkheteroaryl, R 20 is H, C 1-6 alkyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, COR 19 , CO 2 R 19 , CONHR 19 , CSR 19 , COSR 19 , CSOR 19 , CSNHR 19 , SO 2 R 19 , or SO 2 NHR 19 , wherein R 19 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl,
or
(d) A is H or OH;
X is H or COCH 3 ;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and R 4′ cannot be H;
or
(e) A is H or OH;
X is H or COCH 3 ;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and R 4′ cannot be H, R 22 is H, C 1-6 alkyl, C 6-12 aryl, C 1-9 heteroaryl, C 1-4 alkaryl, C 1-4 alkheteroaryl, R 20 is H, C 1-6 aryl, C 1-4 alkaryl, C 1-4 alkheteroaryl, COR 24 , CO 2 R 24 , CONHR 24 , CSR 24 , COSR 24 , CSOR 24 , CSNHR 24 , SO 2 R 24 , or SO 2 NHR 24 , wherein R 24 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, and each of r and s is, independently, 1-2,
or
(f) A is H or OH;
X is H or COCH 3 ;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and R 4′ cannot be H, T is O, S, NR 26 , or a bond, where each of R 21 , R 25 , and R 26 is H, C 1-6 alkyl, C 6-12 aryl, C 1-9 heteroaryl, C 2-9 heterocyclyl, C 1-4 alkaryl, or C 1-4 alkheteroaryl, or R 25 and R 26 together form a 3-8-membered ring, with the ring optionally containing a non-vicinal oxygen,
or
(g) A is H or OH;
X is H or COCH 3 ;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and R 4′ cannot be H, R 27 is H, C 1-6 alkyl, C 1-4 alkaryl, or C 1-4 alkheteroaryl; R 28 is H, C 1-6 alkyl, C 6-12 aryl, C 1-9 heteroaryl, C 2-9 heterocyclyl, C 1-4 alkaryl, C 1-4 alkheteroaryl, OR 24b , or NR 24a R 24b , wherein R 24a is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, R 24b is H, C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, or R 24a and R 24b together form a C 2-6 linkage, optionally containing a non-vicinal O; and each of r and s is, independently, 1-2,
or
(h) A is H or OH;
X is H or COCH 3 ;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and R 4′ cannot be H, ═E is ═O or (H,H), R 22 is H, C 1-6 alkyl, C 6-12 aryl, C 1-9 heteroaryl, C 1-4 alkaryl, C 1-4 alkheteroaryl, COR 24 , CO 2 R 24 , CONHR 24 , CSR 24 , COSR 24 , CSOR 24 , CSNHR 24 , SO 2 R 24 , or SO 2 NHR 24 , wherein R 24 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl, r is 1-2, and s is 0-1,
or
(i) A is H or OH;
X is H or COCH 3 ;
W and Y are defined as above; and
each of R 4 and R 4′ is H or has the formula:
wherein both R 4 and R 4′ cannot be H,
wherein said C 1-9 heteroaryl is selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxatriazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, triazyl, benzofuranyl, isobenzofuranyl, benzothienyl, indole, indazolyl, indolizinyl, benzisoxazolvl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphtyridinyl, phthalazinyl, phenanthrolinyl, purinyl, and carbazolyl.
2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 1 .
3. A method of treating bacterial infection or a condition caused by a bacterial infection in an animal, said method comprising administering to said animal the compound of claim 1 in an amount sufficient to treat said infection or said condition.
4. The method of claim 3 , wherein said compound is administered orally, topically, intravenously, intramuscularly, or subcutaneously.
5. The method of claim 3 , wherein said animal is a human.
6. The method of claim 3 , wherein said condition is selected from the group consisting of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, bone and joint infections, and hospital-acquired lung infections.
7. The method of claim 3 , wherein said infection is a persistent infection.
8. The method of claim 3 , wherein said infection is an ear infection.
9. The method of claim 3 , wherein said bacterial infection is an intracellular infection.
10. The method of claim 3 , wherein said infection is caused by a Gram-positive coccus.
11. The method of claim 3 , wherein said infection is caused by N. gonorrhoeae.
12. The method of claim 3 , wherein said infection is caused by C. difficile.
13. The method of claim 3 , wherein said infection is caused by C. pneumoniae.
14. The method of claim 3 , wherein said infection is caused by H. pylori.
15. The method of claim 14 , wherein said medicament further comprises a proton pump inhibitor or bismuth preparation.
16. The method of claim 3 , wherein said bacterial infection is caused by a bacterium selected from the group consisting of Anaplasma bovis, A. caudatum, A. centrale, A. marginale A. ovis, A. phagocytophila, A. platys, Bartonella bacilliformis, B. clarridgeiae, B. elizabethae, B. henselae, B. henselaephage, B. quintana, B. taylorii, B. vinsonii, Borrelia afzelii, B. andersonii, B. anserina, B. bissettii, B. burgdorferi, B. crocidurae, B. garinii, B. hermsii, B. japonica, B. miyamotoi, B. parkeri, B. recurrentis, B. turdi, B. turicatae, B. valaisiana, Brucella abortus, B. melitensis, C. psittaci, C. trachomatis, Cowdria ruminantium, Coxiella burnetii, Ehrlichia canis, E. chaffeensis, E. equi, E. ewingii, E. muris, E. phagocytophila, E. platys, E. risticii, E. ruminantium, E. sennetsu, Haemobartonella canis, H. felis, H. muris, Mycoplasma arthriditis, M. buccale, M. faucium, M. fermentans, M. genitalium, M. hominis, M. laidlawii, M. lipophilum, M. orale, M. penetrans, M. pirum, M. pneumoniae, M. salivarium, M. spermatophilum, Rickettsia australis, R. conorii, R. felis, R. helvetica, R. japonica, R. massiliae, R. montanensis, R. peacockii, R. prowazekii, R. rhipicephali, R. rickettsii, R. sibirica, R. typhi and the bacterium of Mycobacterium ssp.
17. The method of claim 3 , wherein said method further comprises a second agent selected from the group consisting of: antifungal agent, antiviral agent, antibacterial agent, and antiprotozoan agent.