Inhibitors of RNase P proteins as antibacterial compounds
AssigneeMessage Pharmaceuticals
InventorsTony Giordano, Michael A. Sturgess, Samala J. Rao
Life of this patent
Estimating the term…
Abstract
The present invention features compounds useful for inhibiting RNase P activity. These compounds can be used as therapeutics for treating or preventing a variety of bacterial infections. The compounds belong to several classes including mono- and bis-guanylhydrazones, guanylhydrazone mimetics, and benzothiazolium compounds. Exemplary compounds are compounds of formula I: Y—(NR′)k—U1—(NR″)I—A—(NR1)m—U2—(NR2)n—Z I with substituents as described herein.
Claims27
A method of killing or inhibiting the growth of bacteria, said method comprising contacting bacteria or a site susceptible to bacterial growth with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula I:
- Y—(NR′)k—U1—(NR″)—A—(NR1)m—U2—(NR2)n—Z I
- or a derivative, salt, racemic mixture, mixture of E/Z isomers, or mixture of diastereomers thereof;
- wherein U1 and U2 are independently carbonyl, thiocarbonyl, or sulfonyl;
- k, l, m, and n are independently 0 or 1;
- A is a linker of 1, 2, 3, 4, 5, 6, 7, or 8 atoms that is optionally substituted with a group selected from alkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, alkaryl, and heteroaryl;
- R′, R″, R1, and R2 are independently H, alkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, or heteroaryl;
- Y is selected from the group consisting of formulas II, III, IV, V, VI, VII, VIII, IX, and X;
- and Z is selected from the group consisting of substituted phenyl and formulas II, III, IV, V, VI, VII, VIII, IX, X, and XI:
- wherein each R3, R4, R5, R7, R8, or R9 is independently H, alkyl, aralkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, or heteroaryl;
- and each R6 is H, or alkyl;
- wherein said substituted phenyl group comprises hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, quaternary amino, nitro, alkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, or heteroaryl;
- provided that when A is propylene or substituted phenylene, k and n are both 1, and l and m are both 0, Z and Y are not both formula II.
A method of killing or inhibiting the growth of bacteria, said method comprising contacting bacteria or a site susceptible to bacterial growth with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula I:
- Y—(NR′)k—U1—(NR″)—A—(NR1)m—U2—(NR2)n—Z I
- or a derivative, salt, racemic mixture, mixture of E/Z isomers, or mixture of diastereomers thereof, wherein U1 and U2 are independently carbonyl, thiocarbonyl, or sulfonyl;
- k, l, m, and n are independently 0 or 1;
- A is a linker of 1, 2, 3, 4, 5, 6, 7, or 8 atoms that is optionally substituted with a group selected from alkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, alkaryl, and heteroaryl;
- R′, R″, R1, and R2 are independently H, alkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, or heteroaryl;
- Y is selected from the group consisting of formulas II, III, IV, V, VI, VII, VIII, IX, and X:
- wherein each R3, R4, R5, R7, R8, or R9 is independently H, alkyl, aralkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, or heteroaryl;
- and R6 is H, or alkyl;
- and Z is
- wherein A1 is a bond or a linker of 1 or 2 atoms, and Q is aryl or heteroaryl.
A method of killing or inhibiting the growth of bacteria, said method comprising contacting bacteria or a site susceptible to bacterial growth with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula I:
- Y—(NR′)k—U1—(NR″)1—A—(NR1)m—U2—(NR2)n—Z I
- or a derivative, salt, racemic mixture, mixture of E/Z isomers, or mixture of diastereomers thereof, wherein U1 and U2 are independently carbonyl, thiocarbonyl, or sulfonyl;
- k, l, m, and n are independently 0 or 1;
- A is a linker of 1, 2, 3, 4, 5, 6, 7, or 8 atoms that is optionally substituted with a group selected from alkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, alkaryl, and heteroaryl;
- R′, R″, R1, and R2 are independently H, alkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, or heteroaryl;
- Y is selected from the group consisting of formulas II, III, IV, V, VI, VII, VIII, and IX:
- wherein each R3, R4, R5, R7, R8, or R9 is independently H, alkyl, aralkyl, heteroalkyl, alkene, heteroalkene, alkyne, heteroalkyne, aryl, or heteroaryl;
- and R6 is H, alkyl, aralkyl, heteroalkyl, or aryl;
- and Z is selected from the group consisting of formulas XII, XIII, XIV XV, and XVI:
- wherein A1, B1, C1, D1, E1, F1, G1, H1, J1, K1, V1, W1, and Z1 are independently C, CR13, or NR14;
- X1, is CR15, NR16, O, or S;
- Y1 is C or N;
- and R10, R11, R12, R13, R14, R15, and R16 are independently H, alkyl, aryl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, nitro, or halogen.
A method of killing or preventing the growth of bacteria, said method comprising contacting bacteria or a site susceptible to bacterial growth with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula XVIII:
- or a derivative, salt, racemic mixture, mixture of diastereomers thereof, wherein R1 and R5 are independently lower alkyl;
- R2, R3, and R4, are independently H or lower alkyl;
- R6 is aryl, heteroaryl or C(O)R7, wherein R7 is alkyl, aryl, or substituted allyl;
- X is OR8, SR9, or NR10R11, wherein R8, R9, and R10, and R11 are alkyl, alkenyl, or aryl, or X and R6 taken together are a heterocyclic ring;
- and Z1 and Z2 are independently alkyl, aryl, alkenyl, alkynyl, halogen, cyano, nitro, or OR12, wherein R12 is alkyl, alkenyl, or aryl, or SR13, where R13 is alkyl, alkenyl, aryl, or NR14R15, where R14 and R15 are independently alkyl, alkenyl, or aryl, or Z1 and Z2 taken together form a ring that is optionally substituted.
A method of killing or preventing the growth of bacteria, said method comprising contacting bacteria or a site susceptible to bacterial growth with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula XIX:
- or a derivative, salt, racemic mixture, or mixture of diastereomers thereof, wherein R1 and R3 are independently lower alkyl;
- R2 is H or lower alkyl;
- R4 is aryl, heteroaryl or C(O)R5, wherein R5 is alkyl, aryl, or substituted allyl;
- X is OR6, SR7, or NR8R9, wherein R6, R7, R8, and R9 are independently alkyl, alkenyl or aryl or X and R4 taken together form a heterocyclic ring;
- and Z1 and Z2 are independently alkyl, aryl, alkenyl, alkynyl, halogen, cyano, nitro, or OR10, where R10 is alkyl, alkenyl, aryl, or SR11, where R11 is alkyl, alkenyl, aryl, or NR12R13, where R12 and R13 are independently alkyl, alkenyl, or aryl, or Z1 and Z2 taken together form a ring that is optionally substituted.
Dependencies are inferred from the claim text.