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US 9,315,495 B2Granted
Antibacterial agents: aryl myxopyronin derivatives
AssigneesRutgers, The State University of New Jersey, Provid Pharmaceuticals, Inc.
InventorsRichard H. Ebright, Yon W. Ebright, Juan Shen, James Bacci, Anne-Cecile Hiebel, William Solvibile, Christopher Self, Gary Olson
Life of this patent
Estimating the term…
Abstract
The invention provides compounds of formula la, lb and Ic: [Formula Ia, Ib, and Ic] and salts thereof, wherein variables are as described in the specification, as well as compositions comprising a compound of formula Ia-Ic, methods of making such compounds, and methods of using such compounds, e.g., as inhibitors of bacterial RNA polymerase and as antibacterial agents.
Claims10
A compound of formula Ia, Ib or Ic:
- or a salt thereof, wherein:
- W is sulfur, oxygen, or nitrogen;
- X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;
- one of R1 and R2 is C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, aryloxy, heteroaryloxy, or NRaNb, wherein any C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C1-C5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C1-C5 alkyl, or C1-C5 alkoxy, wherein any C1-C5 alkyl and C1-C5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy;
- or
- one of R1 and R2 is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy;
- and the other of R1 and R2 is absent or is one of H, halogen, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy, wherein any C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy;
- R3 is absent, or is one of H, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- R4 is absent, or is one of H, halogen, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- V′, W′, X′, Y′, and Z′ are individually carbon or nitrogen;
- wherein at least three of V′, W′, X′, Y′, and Z′ are carbon;
- one of R1′ and R2′ is C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, aryloxy, heteroaryloxy, or NRaRb, wherein any C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C1-C5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C1-C5 alkyl, or C1-C5 alkoxy, wherein any C1-C5 alkyl and C1-C5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy;
- or
- one of R1′ and R2′ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy;
- and the other of R1′ and R2′ is absent or is one of H, halogen, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy, wherein any C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy;
- R3′, R4′, and R5′ are each independently absent, H, halogen, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- W″ is sulfur, oxygen, or nitrogen;
- U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;
- one of R1″ and R2″ is C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, aryloxy, heteroaryloxy, or NRaRb, wherein any C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C1-C5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C1-C5 alkyl, or C1-C5 alkoxy, wherein any C1-C5 alkyl and C1-C5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy;
- or
- one of R1″ and R2″ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, alkyl, C2-C10 alkenyl, or C1-C10 alkoxy;
- and the other of R1″ and R2″ is absent or is one of H, halogen, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy, wherein any C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy;
- R3′ is absent or is one of H, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- R4″, R5″, and R6″ are each independently absent, H, halogen, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- R5 and R6 are individually H or methyl;
- G is one of —CH═CH—NHC(O)—R7, —CH═CH—NHC(S)—R7, —CH2CH2NHC(O)—R7, —CH2CH2NHC(S)—R7, —CH2NHNHC(O)—R7, or —CH2NHNHC(S)—R7;
- R7 is one of C1-C6 alkyl, —O(C1-C6 alkyl), —S(C1-C6 alkyl), or —N(R8)2;
- each R8 is independently one of hydrogen or —C1-C6 alkyl;
- R9 is C1-C10 alkyl or C2-C10 alkenyl, wherein any C1-C10 alkyl or C2-C10 alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NRaRb;
- each Ra is C1-C10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy;
- and
- each Rb is H or C1-C10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C1-C5 alkoxy.
29 more elements
The compound of formula Ia′, Ib′ or Ic′:
- or a salt thereof, wherein:
- W is sulfur, oxygen, or nitrogen;
- X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;
- one of R1 and R2 is C1-C8 alkyl or C1-C8 alkoxy optionally substituted by at least one of halogen, hydroxy, alkoxy, or furanyl;
- and the other of R1 and R2 is absent or is one of H, halogen, or C1-C8 alkyl or C1-C8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;
- R3 is absent, or is one of H, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- R4 is absent, or is one of H, halogen, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- V′, W, X′, Y′, and Z′ are individually carbon or nitrogen;
- wherein at least four of V′, W′, X′, Y′, and Z′ are carbon;
- one of R1′ and R2′ is C1-C5 alkyl or C1-C8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy, or furanyl;
- and the other of R1′ and R2′ is absent, or is one of H, halogen, or C1-C8 alkyl or C1-C8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;
- R3′, R4′, and R5′ each is absent, or each of R3′, R4′, and R5′ is one of is H, halogen, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- W″ is sulfur, oxygen, or nitrogen;
- U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;
- one of R1″ and R2″ is C1-C8 alkyl or C1-C5 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy, or furanyl;
- and the other of R1″ and R2″ is absent, or is one of H, halogen, or C1-C8 alkyl or C1-C8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;
- R3″ is absent or is one of H, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- R4″, R5″, and R6″ each is absent, or each of R4″, R5″, and R6″ is H, halogen, C1-C2 alkyl, or halogen-substituted C1-C2 alkyl;
- and
- R5 and R6 are individually H or methyl;
- G is one of —CH═CH—NHC(O)—R7, —CH═CH—NHC(S)—R7, —CH2CH2NHC(O)—R7, —CH2CH2NHC(S)—R7, —CH2NHNHC(O)—R7, or —CH2NHNHC(S)—R7, R7 is one of C1-C6 alkyl, —O(C1-C6 alkyl), —S(C1-C6 alkyl), or —N(R8)2;
- and
- each R8 is independently one of hydrogen or —C1-C6 alkyl.
20 more elements
A compound selected from
- and salts thereof.
Dependencies are inferred from the claim text.