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US 7,678,791 B2Granted
Nitroheteroaryl-containing rifamycin derivatives
AssigneeCumbre IP Ventures, L.P.
InventorsCharles Z. Ding, In Ho Kim, Jiancheng Wang, Zhenkun Ma, Yafei Jin, Keith D. Combrink, Genliang Lu, A. Simon Lynch
Life of this patent
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Abstract
Substituted rifamycin derivatives in which a nitroimidazole, nitrothiazole or nitrofuran pharmacophore is covalently bonded to a rifamycin, methods of using the rifamycin derivatives, and pharmaceutical compositions containing the rifamycin derivatives are disclosed. Methods of synthesizing these substituted rifamycin derivatives are also disclosed. The rifamycin derivatives possess antibacterial activity, and are effective against a number of human and veterinary pathogens in the treatment of bacterial diseases.
Claims7
A compound of structural formula (I) as defined below:
- or their pharmaceutically acceptable salt thereof,
- wherein R1 is a hydrogen or acetyl group, G is a structure of formula II, III, IV or V:
- wherein, in formula II, III, IV or V, Q is N— or CR2—, which is bonded to a linkage group “L”, which in turn is bonded to a structure
- and R2 is a group selected from hydrogen, (C1-C6)alkyl, aryl, heteroaryl, or heterocycloalkyl group;
- L is a bond, or a linker group selected from one or a combination of two to five of the following groups:
- 1) (C1-C6)alkylene,
- 2) (C3-C8)cycloalkylene,
- 3) arylene,
- 4) heteroarylene,
- 5) heterocycloalkylene containing 1 to 3 heteroatoms,
- 6) —C(═O)—,
- 7) —C(═N—O—R3)—,
- 8) —C═N—,
- 9) —O—,
- 10) —S(O)n—, wherein n is number between 0 and 2,
- 11) —N(R4)—,
- wherein the carbon or nitrogen atoms of the linker group are unsubstituted or are independently substituted by 1 to 3 substituents selected from (C1-C6)alkyl, (C1-C6)alkyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxyl, (C1-C6)alkoxy or heterocycloalkyl group;
- R3 and R4 are independently a group selected from hydrogen, substituted or unsubstituted (C1-C6)alkyl, aryl, heteroaryl or heterocycloalkyl group;
- and
- structure
- is a structural formula VI, VII, VIII or IX:
- wherein Y is a bond which is bonded to linkage group “L”, defined as above;
- and Z is a carbon (—CR7R8—), carbonyl (—C(O)—), amide (—C(O)NH—), sulfonamide (—S(O2)N—), or a heteroatom selected from N, O, S, SO or SO2;
- wherein R5, R6, R7, and R8 are independently a group selected from hydrogen, (C1-C6)alkyl, aryl, heteroaryl, or heterocycloalkyl group;
- R5 and R6, R7 and R8 can join together to form a five to seven-member ring system optionally containing one to three heteroatoms, and
- wherein if R1 is an acetyl group, G is II, Q is N—, and L is —C(═O)—, then
- is not VIII in which R5 and R6 are hydrogen.
24 more elements
A compound selected from:
- a. 4-Deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,
- b. 4-Deoxy-3,4-[2-spiro-[1-[(5-nitro-thiazol-2-ylcarbamoyl)-methyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,
- c. 3′-Hydroxy-5′-[4-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-1-piperazinyl]benzoxazinorifamycin,
- d. 3-[[[4-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-1-piperazinyl]imino]methyl]rifamycin SV,
- e. 4-Deoxy-3,4-[2-spiro-[1-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,
- f. 3-{4-[4-(6-Nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-benzyl]-piperazin-1-yl}rifamycin S,
- g. 4-Deoxy-3,4-[2-[4-(6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]]-(1H)-imidazo-rifamycin SV,
- h. 3-{4-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-benzoyl]-piperazin-1-yl}rifamycin S,
- i. 4-Deoxy-3,4-[2-spiro-[1-[4-[6S-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,
- j. 3-{4-[4-[(65)-(2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperazin-1-yl}rifamycin S,
- k. 3-{4-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-benzyl]-piperazin-1-yl}rifamycin S,
- l. 3′-Hydroxy-5′-[4-[4-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1-piperazinyl]benzoxazinorifamycin,
- m. 4-Deoxy-3,4-[2-spiro-[1-[3-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,
- n. 3-{4-[3-(6S-(2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperazin-1-yl}rifamycin S,
- o. 3′-Hydroxy-5′-[4-[3-(65′-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1-piperazinyl]benzoxazinorifamycin,
- p. 3-[[[4-[4-(6S-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-piperazin-1-yl]imino]methyl]rifamycin SV,
- q. 4-Deoxy-3,4-[2-spiro-[1-[[4-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-phenoxy]-acetyl]-piperidin-4-yl]-(1H)-imidazo-(2,5-dihydro)rifamycin S,
- r. 3-[4-[1-[4-(6S-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1H-[1,2,3]triazol-4-ylmethyl]-piperazin-1-yl]rifamycin S,
- s. 3′-Hydroxy-5′-[4-[1-[4-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1H-[1,2,3]triazol-4-ylmethyl]-piperazin-1-yl]-benzoxazinorifamycin,
- t. 3′-Hydroxy-5′-{4-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}-benzoxazinorifamycin,
- u. 3-(2-{4-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}) Rifamycin S,
- v. 3-[4-(2-{4-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}-acetyl)-piperazin-1-yl]-rifamycin S,
- w. 4-Deoxy-3,4-[2-spiro-[1-[2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-acetyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,
- x. 2-[4-(2-Bromo-4-nitro-imidazol-1-ylmethyl)-4-hydroxy-piperidin-1-yl]-rifamycin S,
- y. 3-{4-[2-(6S-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-acetyl]-piperazin-1-yl}-rifamycin S, and
- z. 3-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-piperazin-1-yl]rifamycin S.
23 more elements
Dependencies are inferred from the claim text.