US 7,488,726 B2
Rifamycin analogs and uses thereof
John H. Van Duzer, Georgetown, Mass. (US); James M. Siedlecki, Burlington, Mass. (US); and Xiang Y. Yu, Acton, Mass. (US)
Assigned to ActivBiotics Pharma, LLC, Tucker, Ga. (US)
Filed on Nov. 02, 2006, as Appl. No. 11/591,971.
Claims priority of provisional application 60/732963, filed on Nov. 03, 2005.
Prior Publication US 2007/0105849 A1, May 10, 2007
Int. Cl. C07D 498/14 (2006.01); C07D 491/14 (2006.01); A61K 31/542 (2006.01); A61K 31/5383 (2006.01); A61P 31/04 (2006.01); A61P 31/10 (2006.01)
U.S. Cl. 514—224.5  [514/229.5; 514/252.1; 540/458] 17 Claims
 
1. A compound having the formula:

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt thereof, wherein
(a) A is H, OH, O—(C1-6 alkyl), O—(C1-4 alkaryl), O—(C6-12 aryl), O—(C1-9 heteroaryl), or O—(C1-4 alkheteroaryl);
W is O, S, or NR1, wherein R1 is H, C1-6 alkyl, C1-4 alkaryl, or C1-4 alkheteroaryl;
X is H or COR2, wherein R2 is C1-6 alkyl, which can be substituted with 1-5 OH groups, O—(C3-7 alkyl), which can be substituted with 1-4 OH groups, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, wherein each alkyl carbon is bonded to no more than one oxygen atom;
Y is H, Hal, or ORY3, wherein RY3 is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
with the proviso that R4 and R4′ cannot be H at the same time, wherein
when each of m and n is 1:
each of R5 and R6 is H, or R5 and R6 together are ═O;
R7 and R10 together form a single bond or a C1-3 linkage, which optionally contains a non-vicinal O, S, or N(R23), R7 and R12 together form a single bond or a
C1-2 linkage, which optionally contains a non-vicinal O, S, or N(R23), R7 and R14 together form a single bond or a C1 linkage, or R7 and R16 together form a single bond or a C1 linkage, wherein R23 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, COR24b, CO2R24a, CONR24aR24b, CSR24b, COSR24a, CSOR24a, CSNR24aR24b, SO2R24a, or SO2NR24aR24b, wherein R24a is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, R24b is H, C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, or R24a and R24b together form a C2-6 linkage, optionally containing a non-vicinal O;
R8 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, R8 and R12 together form a single bond, or R8 and R9 together are ═O or ═N—OR18, wherein R18 is H, C1-6 alkyl, C1-4 alkaryl, or C1-4 alkheteroaryl;
R9 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, or R9 and R8 together are ═O or ═N—OR18, wherein R18 is as previously defined;
R10 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, R10 and R7 together form a single bond or a C1-3 linkage, which optionally contains a non-vicinal O, S, or N(R23), R10 and R11 together are ═O, R10 and R16 together form a C1-2 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), or R10 and R17 together form a C1-3 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined;
R11 is H, or R11 and R10 together are ═O;
R12 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, R12 and R7 together form a single bond or a C1-2 linkage, which optionally contains a non-vicinal O, S, or N(R23), R12 and R8 together form a single bond, or R12 and R16 together form a C24 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined;
R13 is H, C1-6 alkyl, C1-4 alkaryl, or C1-4 alkheteroaryl;
R14 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, or R14 and R7 together form a single bond or a C1 linkage;
R15 is H, C1-6 alkyl, C1-4 alkaryl, or C1-4 alkheteroaryl;
R16 is H, C1-6 alkyl, C1-6 alkoxy, C6-12 aryl, C1-9 heteroaryl, C1-4 alkaryl, C1-4 alkheteroaryl, R16 and R7 together form a bond or a C1 alkyl linkage, R16 and R12 together form a C2-4 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), or R16 and R10 together form a C1-2 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined; and
R17 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, COR19, CO2R19, CONHR19, CSR19, COSR19, CSOR19, CSNHR19, SO2R19, or SO2NHR19, wherein R19 is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, or R17 and R10 together form a C1-3 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined,
and
when m is 0 and n is 1:
R7 and R10 together form a single bond or a C1-4 linkage, which optionally contains a non-vicinal O, S, or N(R23), R7 and R12 together form a single bond or a C1-3 linkage, which optionally contains a non-vicinal O, S, or N(R23), or R7 and R14 together form a single bond or a C1-2 linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined;
each of R8 and R9 is H;
R10 is H or R10 and R7 together form a single bond or a C1-4 linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined;
R11 is H;
R12 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, R12 and R7 together form a single bond or a C1-3 linkage, which optionally contains a non-vicinal O, S, or N(R23), R12 and R13 together form a —CH2CH2— linkage, or R12 and R16 together form a C2-4 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined;
R13 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, or R13 and R12 together form a —CH2CH2— linkage;
R14 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, or R14 and R7 together form a single bond or a C1-2 linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined;
R15 is H, C1-6 alkyl, C1-4 alkaryl, or C1-4 alkheteroaryl;
R16 is H, C1-6 alkyl, C1-6 alkoxy, C6-12 aryl, C1-9 heteroaryl, C1-4 alkaryl, C1-4 alkheteroaryl, or R16 and R12 together form a C2-4 alkyl linkage, which optionally contains a non-vicinal O, S, or N(R23), wherein R23 is as previously defined; and
R17 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, COR19, CO2R19, CONHR19, CSR19, COSR19, CSOR19, CSNHR19, SO2R19, or SO2NHR19, wherein R19 is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl,
or
(b) A is OH;
X is H;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 and R4′ cannot be H, R21 is H, C1-6 alkyl, C6-12 aryl, C1-9 heteroaryl, C1-4 alkaryl, or C1-4 alkheteroaryl, R20 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, COR19, CO2R19, CONHR19, CSR19, COSR19, CSOR19, CSNHR19, SO2R19, or SO2NHR19, wherein R19 is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl,
or
(c) A is OH;
X is COCH3;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 andR4′ cannot be H, R21 is H, C1-6 alkyl, C6-12 aryl, C1-9 heteroaryl, C1-4 alkaryl, or C1-4 alkheteroaryl, R20 is H, C1-6 alkyl, C1-4 alkaryl, C1-4 alkheteroaryl, COR19, CO2R19, CONHR19, CSR19, COSR19, CSOR19, CSNHR19, SO2R19, or SO2NHR19, wherein R19 is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl,
or
(d) A is H or OH;
X is H or COCH3;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 and R4′ cannot be H;
or
(e) A is H or OH;
X is H or COCH3;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 and R4′ cannot be H, R22 is H, C1-6 alkyl, C6-12 aryl, C1-9 heteroaryl, C1-4 alkaryl, C1-4 alkheteroaryl, R20 is H, C1-6 aryl, C1-4 alkaryl, C1-4 alkheteroaryl, COR24, CO2R24, CONHR24, CSR24, COSR24, CSOR24, CSNHR24, SO2R24, or SO2NHR24, wherein R24 is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, and each of r and s is, independently, 1-2,
or
(f) A is H or OH;
X is H or COCH3;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 and R4′ cannot be H, T is O, S, NR26, or a bond, where each of R21, R25, and R26 is H, C1-6 alkyl, C6-12 aryl, C1-9 heteroaryl, C2-9 heterocyclyl, C1-4 alkaryl, or C1-4 alkheteroaryl, or R25 and R26 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 COCH3;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 and R4′ cannot be H, R27 is H, C1-6 alkyl, C1-4 alkaryl, or C1-4 alkheteroaryl; R28 is H, C1-6 alkyl, C6-12 aryl, C1-9 heteroaryl, C2-9 heterocyclyl, C1-4 alkaryl, C1-4 alkheteroaryl, OR24b, or NR24aR24b, wherein R24a is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, R24b is H, C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, or R24a and R24b together form a C2-6 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 COCH3;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 and R4′ cannot be H, ═E is ═O or (H,H), R22 is H, C1-6 alkyl, C6-12 aryl, C1-9 heteroaryl, C1-4 alkaryl, C1-4 alkheteroaryl, COR24, CO2R24, CONHR24, CSR24, COSR24, CSOR24, CSNHR24, SO2R24, or SO2NHR24, wherein R24 is C1-6 alkyl, C6-12 aryl, C1-4 alkaryl, C1-9 heteroaryl, or C1-4 alkheteroaryl, r is 1-2, and s is 0-1,
or
(i) A is H or OH;
X is H or COCH3;
W and Y are defined as above; and
each of R4 and R4′ is H or has the formula:

OG Complex Work Unit Drawing
wherein both R4 and R4′ cannot be H,
wherein said C1-9 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.