Prolines as antimicrobial agents
AssigneesMerck & Co., Inc., Cubist Pharmaceuticals, Inc.
InventorsMilton L. Hammond, Aaron H. Leeman, Milana Maletic, Gina M. Santorelli, Sherman T. Waddell, John Finn, Michael Morytko, Siya Ram, Dennis Keith
Life of this patent
Estimating the term…
Abstract
Transfer ribonucleic acid (tRNA) synthetase inhibitors, salts, and pharmaceutically acceptable compositions thereof of the general formula: wherein Ar is aryl and heteroaryl; L is —C(O)N(Q)CH2—, or —CR10R11OCR12R13—; Q is hydrido, —(CH2)mCO2H and —(CH2)mCO2CH3, m is 1, 2, 3, and 4; R1, R2, R9, R10, R11, R12 and R13 are hydrido or lower alkyl; wherein Het is a heterocyclic moiety, the inhibitors are suitable for use as antimicrobial agents.
Claims37
A compound of the general formula:
- (a) wherein Ar is selected from the group consisting of substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
- (b) wherein L is selected from the group consisting of —C(O)N(Q)CH2—, and —CR10R11OCR12R13—;
- wherein Q is selected from the group consisting of hydrido, —(CH2)mCO2H and —(CH2)mCO2CH3;
- wherein m is selected from the group consisting of 1, 2, 3, and 4;
- (c) wherein each of R1, R2, R9, R10, R11, R12 and R13 is independently selected from the group consisting of hydrido and lower alkyl;
- (d) wherein each of R3, R4, R5, R6, R7, and R8 is independently selected from the group consisting of hydrido, acyl, amino, cyano, acyloxy, acylamino, carboalkoxy, carboxyamido, carboxy, halo, alkyl, heteroaryl, heterocyclyl, alkoxy, aryloxy, N-sulfonylcarboxyamido, N-acylamino, hydroxy, aryl, and cycloalkyl, —O(CH2)nCO2R17, —O(CH2)nCONHSO2R18, —(CH2)nCO2R19, —(CH2)nCONHSO2R20, —(O)NHCH(R22)CO2R21, and —N(R23)(CH2)nCO2R24;
- alternatively, each of R3 and R4 together, R5 and R6 together, and R7 and R8 together are independently selected from the group consisting of
- wherein each of R14, R15 and R16 are independently selected from the group consisting of hydrido, alkyl and carboxy substituted alkyl;
- provided that at least five of R3, R4, R5, R6, R7, and R8 are independently hydrido;
- (e) wherein Hat is selected from the group consisting of
- wherein X is selected from the group consisting of N and CR27;
- wherein Y is selected from the group consisting of NH, S and O;
- wherein Z is selected from the group consisting of N and CR28;
- wherein each of R25, R26, R27, and R28 is independently selected from the group consisting of nitro, halo, hydroxy, lower amino, lower alkyl, lower alkoxy, lower carboalkoxy and carboxy;
- and pharmaceutically-acceptable salts thereof;
- and wherein each of R29, R30, and R31 is selected from the group consisting of hydrido, alkyl aryl, nitro and amino.
A pharmaceutical composition comprising a therapeutically-effective amount of an active compound and a pharmaceutically-acceptable carrier, said active compound selected from a family of compounds of the Formula:
- (a) wherein Ar is selected from the group consisting of substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
- (b) wherein L is selected from the group consisting of —C(O)N(Q)CH2—, and —CR10R11OCR12R13—;
- wherein Q is selected from the group consisting of hydrido, —(CH2)mCO2H and —(CH2)mCO2CH3;
- wherein m is selected from the group consisting of 1, 2, 3, and 4;
- (c) wherein each of R1, R2, R9, R10, R11, R12 and R13 is independently selected from the group consisting of hydrido and lower alkyl;
- (d) wherein each of R3, R4, R5, R6, R7, and R8 is independently selected from the group consisting of hydrido, acyl, amino, cyano, acyloxy, acylamino, carboalkoxy, carboxyamido, carboxy, halo, alkyl, heteroaryl, heterocyclyl, alkoxy, aryloxy, N-sulfonylcarboxyamido, N-acylamino, hydroxy, aryl, and cycloalkyl, —O(CH2)nCO2R17, —O(CH2)nCONHSO2R18, —(CH2)nCO2R19, —(CH2)nCONHSO2R20, —C(O)NHCH(R22)CO2R21, and —N(R23)(CH2)nCO2R24;
- alternatively, each of R3 and R4 together, R5 and R6 together, and R7 and R8 together are independently selected from the group consisting of
- wherein each of R14, R15 and R16 are independently selected from the group consisting of hydrido, alkyl and carboxy substituted alkyl;
- provided that at least five of R3, R4, R5, R6, R7, and R8 are independently hydrido;
- (e) wherein Hat is selected from the group consisting of
- wherein X is selected from the group consisting of N and CR27;
- wherein Y is selected from the group consisting of NH, S and O;
- wherein Z is selected from the group consisting of N and CR28;
- wherein each of R25, R26, R27, and R28 is independently selected from the group consisting of nitro, halo, hydroxy, lower amino, lower alkyl, lower alkoxy, lower carboalkoxy and carboxy;
- wherein each of R29, R30, and R31 is selected from the group consisting of hydrido, alkyl, aryl, nitro and amino;
- and pharmaceutically-acceptable salts thereof.
A compound of the formula
- selected from the Table
- L R5 N (S)—CONHCH2 H 1 (S)—CONHCH2 (R,S) OH 1 (S)—CONHCH2 (R,S)—CN 1 (S)—CONHCH2 (R,S)—OCH2Ph 1 (S)—CONHCH2 ═O 1 (S)—CONHCH2 H 2 (S)—CONHCH2 ═NNH2 1 (S)—CONHCH2 (R,S)-tetrazole 1 (S)—CONHCH2 ═NOH 1 (S)—CONHCH2 ═NOCH3 1 (S)—CONHCH2 ═NOCH2CO2H 1 (R)-CONHCH2 H 1 (R)-CONHCH2 (R)-OH 1 (S)—CONHCH2 (S)—OH 1 (S)—CONHCH2 (R)-OH 1 (S)—CH2OCH2 H 1 (S)—CONHCH2 CH2CO2H 1
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound of the formula
A compound of the formula
A compound of the formula
A compound of the formula
A compound of the formula
A compound of the formula
Dependencies are inferred from the claim text.