Inhibitors of β-lactamases and uses therefor
First Claim
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1. A method of treating a bacterial infection comprising administering to an animal suffering from such an infection an effective amount of a compound having the formula:
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(OH)2—
B—
R
(1)wherein;
R is naphthalene, phenanthrene, or has one of the following formulas;
wherein;
ring system (2), (3), (4), (5), (6), (7), (8), (9) or (10) is aromatic or nonaromatic;
the atom center * is (R) or (S) in the case of chiral compounds;
positions 1, 2, 3, 4, 5, 6, 7 or 8 each independently is C, N, O or S;
R1 through R6 each independently is a lone pair, H, B(OH)2, a halogen atom, CF3, CH2CF3, CCl3, CH2CCl3, CBr3, CH2CBr3, NO2, lower alkyl, CO2H, CHCHCOOH, CH2CH2CH2COOH, SO3H, PO3H, OSO3H, OPO3H, OH, NH2, CONH2, COCH3, OCH3, or phenyl boronic acid, except that R2, R3, R4, R5 and R6 cannot all simultaneously be H, R2 cannot be lower alkyl when R3, R4, R5 and R6 are H, R3 cannot be NH2, OH or lower alkyl when R2, R4, R5 and R6 are H, and R4 cannot be lower alkyl when R2, R3, R5 and R6 are H;
R7 is a lone pair, H, B(OH)2, a halogen atom, CF3, CCl3, CBr3, CH2CF3, CH2CCl3, CH2CBr3, NO2, CONH2, COCH3, OCH3, lower alkyl, aryl, aryl substituted with one or more substituents R8, heteroaryl, or heteroaryl substituted with one or more substituents R8;
each R8 is independently a lone pair, H, B(OH)2, a halogen atom, CF3, CCl3, CBr3, CH2CF3, CH2CCl3, CH2CBr3, NO2, lower alkyl, O, N, S, OH, NH2, N(CH3)2, N(CH3)CH2CH3, NCOCH3, COOH, CHCHCOOH, CH2CH2CH2COOH, CONH2, COCH3, OCH3, OCl or phenyl boronic acid;
X is O, NH, NCH3 orY is OH, NH2, NCH3, N(CH3)2, NHCOCH3 or NHCOCH2COOH; and
R9 is a lone pair, H, B(OH)2, a halogen atom, CF3, CCl3, CBr3CH2CF3, CH2CCl3, CH2CBr3, NO2, CO2H, CHCHCOOH, CH2CH2CH2COOH, SO3H, PO3H, OSO3H, OPO3H, OH, NH2, CONH2, COCH3, OCH3, phenyl boronic acid, lower alkyl, or a side chain of a standard amino acid;
or a pharmaceutically acceptable salt thereof.
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Abstract
The invention provides novel non-β-lactam inhibitors of β-lactamases. In particular, the invention provides such inhibitors which are boronic acids of formula (1) which is set forth in the specification. These compounds may be used with β-lactam antibiotics to treat 62 -lactam-antibiotic-resistant bacterial infections. These compounds are also antibacterial by themselves. Finally, the invention provides a pharmaceutical composition comprising these compounds.
25 Citations
3 Claims
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1. A method of treating a bacterial infection comprising administering to an animal suffering from such an infection an effective amount of a compound having the formula:
-
(OH)2—
B—
R
(1)wherein; R is naphthalene, phenanthrene, or has one of the following formulas;
wherein; ring system (2), (3), (4), (5), (6), (7), (8), (9) or (10) is aromatic or nonaromatic;
the atom center * is (R) or (S) in the case of chiral compounds;
positions 1, 2, 3, 4, 5, 6, 7 or 8 each independently is C, N, O or S;
R1 through R6 each independently is a lone pair, H, B(OH)2, a halogen atom, CF3, CH2CF3, CCl3, CH2CCl3, CBr3, CH2CBr3, NO2, lower alkyl, CO2H, CHCHCOOH, CH2CH2CH2COOH, SO3H, PO3H, OSO3H, OPO3H, OH, NH2, CONH2, COCH3, OCH3, or phenyl boronic acid, except that R2, R3, R4, R5 and R6 cannot all simultaneously be H, R2 cannot be lower alkyl when R3, R4, R5 and R6 are H, R3 cannot be NH2, OH or lower alkyl when R2, R4, R5 and R6 are H, and R4 cannot be lower alkyl when R2, R3, R5 and R6 are H;
R7 is a lone pair, H, B(OH)2, a halogen atom, CF3, CCl3, CBr3, CH2CF3, CH2CCl3, CH2CBr3, NO2, CONH2, COCH3, OCH3, lower alkyl, aryl, aryl substituted with one or more substituents R8, heteroaryl, or heteroaryl substituted with one or more substituents R8;
each R8 is independently a lone pair, H, B(OH)2, a halogen atom, CF3, CCl3, CBr3, CH2CF3, CH2CCl3, CH2CBr3, NO2, lower alkyl, O, N, S, OH, NH2, N(CH3)2, N(CH3)CH2CH3, NCOCH3, COOH, CHCHCOOH, CH2CH2CH2COOH, CONH2, COCH3, OCH3, OCl or phenyl boronic acid;
X is O, NH, NCH3 or Y is OH, NH2, NCH3, N(CH3)2, NHCOCH3 or NHCOCH2COOH; and
R9 is a lone pair, H, B(OH)2, a halogen atom, CF3, CCl3, CBr3CH2CF3, CH2CCl3, CH2CBr3, NO2, CO2H, CHCHCOOH, CH2CH2CH2COOH, SO3H, PO3H, OSO3H, OPO3H, OH, NH2, CONH2, COCH3, OCH3, phenyl boronic acid, lower alkyl, or a side chain of a standard amino acid;
or a pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3)
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Specification
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Current AssigneeNorthwestern University
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Original AssigneeNorthwestern University
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InventorsShoichet, Brian, Weston, Scott
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Primary Examiner(s)Weddington, Kevin E.
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Application NumberUS09/587,794Time in Patent Office763 DaysField of Search514/64, 514/330, 514/340, 514/451, 514/456, 514/481, 514/543, 514/199US Class Current514/64CPC Class CodesA61K 2300/00 Mixtures or combinations of...A61K 31/18 Sulfonamides compounds cont...A61K 31/34 having five-membered rings ...A61K 31/38 having sulfur as a ring het...A61K 31/40 having five-membered rings ...A61K 31/405 Indole-alkanecarboxylic aci...A61K 31/69 Boron compoundsA61K 33/22 Boron compoundsA61P 31/04 Antibacterial agentsA61P 43/00 Drugs for specific purposes...
