US2010273765A1PendingUtilityA1
Rifamycin analogs and uses thereof
Est. expiryDec 23, 2023(expired)· nominal 20-yr term from priority
Inventors:John H. Van DuzerArthur F. MichaelisWilliam B. GeissDouglas G. StaffordJoseph RakerXiang Y. YuJames M. SiedleckiYingfei Yang
A61P 3/06A61P 9/10A61P 9/00A61P 7/02A61P 29/00A61P 31/04A61P 33/02A61P 31/12A61P 31/00A61P 31/10A61P 19/08A61P 19/02A61P 17/00C07D 519/00C07D 498/18C07D 513/18A61P 1/04C07D 513/22C07D 498/22C07D 471/20
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Claims
Abstract
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, 4′- and/or 6′ halo and/or alkoxy analogs, and various 5′ substituents that incorporate a cyclic amine moiety.
Claims
exact text as granted — not AI-modified1 . 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 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;
Z is H, Hal, or OR Z3 , wherein R Z3 is C 1-6 alkyl, C 6-12 aryl, C 1-4 alkaryl, C 1-9 heteroaryl, or C 1-4 alkheteroaryl; and
R 4 has the formula:
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 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, 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 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, Y, and Z are defined as above; and
R 4 is selected from the group consisting of:
wherein 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 , 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, Y, and Z are defined as above; and
R 4 is selected from the group consisting of:
wherein 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, 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, Y, and Z are defined as above; and
R 4 is
with the proviso that one or both of Y and Z are Hal;
or
(e) A is H or OH;
X is H or COCH 3 ;
W, Y, and Z are defined as above; and
R 4 is
wherein 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, and r is 1-2,
or
(f) A is H or OH;
X is H or COCH 3 ;
W, Y, and Z are defined as above; and
R 4 is
wherein R 21 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
(g) A is H or OH;
X is H or COCH 3 ;
W, Y, and Z are defined as above; and
R 4 is
wherein =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
(h) A is H or OH;
X is H or COCH 3 ;
W, Y, and Z are defined as above; and
R 4 is
2 . The compound of claim 1 , wherein said compound is selected from the group consisting of:
wherein
A′ is
B′ is
C′ is
D′ is
E′ is
F′ is
G′ is
H′ is
I′ is
J′ is
K′ is
L′ is
M′ is
N′ is
O′ is
P′ is
Q′ is
R′ is
and S′ is
3 . The compound of claim 1 , wherein said compound is
4 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 1 .
5 . A method of treating or preventing a microbial infection or a condition caused by a microbial infection in an animal, said method comprising administering to said animal the compound of claim 1 in an amount sufficient to treat or prevent said infection or said condition.
6 . The method of claim 5 , wherein said compound is administered orally, topically, intravenously, intramuscularly, or subcutaneously.
7 . The method of claim 5 , wherein said animal is a human.
8 . The method of claim 5 , 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.
9 . The method of claim 5 , wherein said infection is a persistent infection.
10 . The method of claim 5 , wherein said infection is an ear infection.
11 . The method of claim 5 , wherein said microbial infection is a protozoan, bacterial, viral, or fungal infection.
12 . The method of claim 5 , wherein said microbial infection is an intracellular infection.
13 . The method of claim 5 , wherein said infection is caused by a Gram-positive coccus.
14 . The method of claim 5 , wherein said infection is caused by N. gonorrhoeae.
15 . The method of claim 5 , wherein said infection is caused by C. difficile.
16 . The method of claim 5 , wherein said infection is caused by C. pneumoniae.
17 . The method of claim 5 , wherein said infection is caused by H. pylori.
18 . The method of claim 17 , wherein said medicament further comprises a proton pump inhibitor or bismuth preparation.
19 . The method of method of claim 5 , wherein said microbial 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. henselae phage, 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 , and R. typhi.
20 . The method of method of claim 5 , wherein said method further comprises a second agent selected from the group consisting of: antifungal agent, antiviral agent, antibacterial agent, and antiprotozoan agent.
21 . A method for treating or preventing the development of an atherosclerosis-associated disease in a patient in need thereof, said method comprising administering to said patient the compound of claim 1 in an amount effective to treat or prevent the development of said atherosclerosis-associated disease in said patient.
22 . The method of claim 21 , further comprising the step of administering to said patient a second agent selected from the group consisting of: anti-inflammatory agent, antibacterial agent, platelet aggregation inhibitor, anticoagulant, antipyretic, and lipid lowering agent.
23 . The method of claim 21 , wherein, prior to administration of said compound, said patient is diagnosed as having said atherosclerosis-associated disease.Cited by (0)
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