Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections

A composition comprising:

• at least one antibiotic selected from the group consisting of Amoxicillin, Amikacin, Aztreonam, Ciprofloxacin, Clindamycin, Chloramphenicol, Colistin, Cefpirome, Ceftriaxone, Cefotaxime, Daptomycin, Erythromycin, Cefepime, Cefixime, Fosfomycin, Cefuroxime, Imipenem, Linezolid, Meropenem, Piperacillin, Cefpodoxime, Rifampicine, Synercid, Tigecycline, Vancomycin, Sulbactam, Ceftaroline, Cefiderocol (S-649266), and BAL30072;
• and
• at least one compound selected from the group consisting of a compound of formula (I), a racemate of the formula (I) compound, an enantiomer of the formula (I) compound, a diastereoisomer of the formula (I) compound, a geometric isomer of the formula (I) compound, and a pharmaceutically acceptable salt of the formula (I) compound
• wherein:
• R is —SO3H or CF2CO2H;
• R1 is H, CH2—NH2, CONH2, or a 5-membered heteroaryl comprising at least two nitrogen;
• A-B is
• or
• A is CH2 and B is C═NOR4;
• wherein:
• R2 is a hydrogen atom;
• or a saturated or partially unsaturated or totally unsaturated or aromatic 4- to 10-membered heterocycle comprising at least one nitrogen atom that is unsubstituted or substituted by one or more T1;
• R3 is H or oxazolyl;
• or
• R2 and R3 together with the carbon atom to which they are linked form a cycle that is
• wherein Y is S or O, and R5 is (C2-C3)alkyl-N H2;
• R4 is —(CH2)2NH2 or —CH2CONH2;
• T1, identical or different, independently represents a fluorine atom;
• —(CH2)mOQ1;
• —(CH2)m—CN;
• —(CH2)m—OC(O)Q1;
• —(CH2)m—C(O)OQ1;
• —(CH2)m—OC(O)OQ1;
• —(CH2)m—OC(O)NQ1Q2;
• —(CH2)m—C(O)NQ1Q2;
• —(CH2)m—C(O)ONQ1Q2;
• —(CH2)m—C(O)NQ1OQ2;
• —(CH2)m—C(O)NQ1-NQ1Q2;
• —(CH2)m—NQ1C(O)Q2;
• —(CH2)m—NQ1S(O)2NQ1Q2;
• —(CH2)m—NQ1S(O)2Q2;
• —(CH2)m—S(O)2NQ1Q2;
• —(CH2)m—NQ1C(O)OQ2;
• —(CH2)m—NQ1C(O)NQ1Q2;
• —(CH2)m—NQ1Q2;
• —(CH2)m—NH—C(NHQ3)=NQ4;
• —(CH2)m—NH—CH═NQ3;
• —(CH2)m—C(NHQ3)=NQ4;
• —(X)—(CH2)pOQ1;
• —(X)—(CH2)n—CN;
• —(X)—(CH2)p—OC(O)Q1;
• —(X)—(CH2)n—C(O)OQ1;
• —(X)—(CH2)p—OC(O)OQ1;
• —(X)—(CH2)p—OC(O)NQ1Q2;
• —(X)—(CH2)n—C(O)NQ1Q2;
• —(X)—(CH2)n—C(O)ONQ1Q2;
• —(X)—(CH2)n—C(O)NQ1OQ2;
• —(X)—(CH2)n—C(O)NQ1-NQ1Q2;
• —(X)—(CH2)p—NQ1C(O)Q2;
• —(X)—(CH2)p—NQ1S(O)2NQ1Q2;
• —(X)—(CH2)p—NQ1S(O)2Q2;
• —(X)—(CH2)p—S(O)2NQ1Q2;
• —(X)—(CH2)p—NQ1C(O)OQ2;
• —(X)—(CH2)p—NQ1C(O)NQ1Q2;
• —(X)—(CH2)p—NQ1Q2;
• —(X)—(CH2)p—NH—C(NHQ3)=NQ4;
• —(X)—(CH2)p—NH—CH═NQ3;
• —(X)—(CH2)n—C(NHQ3)=NQ4;
• —C(O)—(CH2)nOQ1;
• —C(O)—(CH2)n—CN;
• —C(O)—(CH2)n—OC(O)Q1;
• —C(O)—(CH2)n—C(O)OQ1;
• —C(O)—(CH2)n—OC(O)OQ1;
• —C(O)—(CH2)n—OC(O)NQ1Q2;
• —C(O)—(CH2)n—C(O)NQ1Q2;
• —C(O)—(CH2)n—C(O)ONQ1Q2;
• —C(O)—(CH2)n—C(O)NQ1OQ2;
• —C(O)—(CH2)n—C(O)NQ1-NQ1Q2;
• —C(O)—(CH2)n—NQ1C(O)Q2;
• —C(O)—(CH2)n—NQ1S(O)2NQ1Q2;
• —C(O)—(CH2)n—NQ1S(O)2Q2;
• —C(O)—(CH2)n—S(O)2NQ1Q2;
• —C(O)—(CH2)n—NQ1C(O)OQ2;
• —C(O)—(CH2)n—NQ1C(O)NQ1Q2;
• —C(O)—(CH2)n—NQ1Q2;
• —C(O)—(CH2)n—NH—C(NHQ3)=NQ4;
• —C(O)—(CH2)n—NH—CH═NQ3;
• or —C(O)—(CH2)n—C(NHQ3)=NQ4;
• or
• T1, identical or different, independently represents an unsubstituted or substituted by one or more T2, —(CH2)m—(4-, 5- or 6-membered saturated, partially or totally unsaturated or aromatic heterocycle);
• —(X)—(CH2)m—(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle);
• (C1-C3)-alkyl;
• (C1-C3)-fluoroalkyl;
• —(X)—(C1-C3)-alkyl;
• —(X)—(C1-C3)-fluoroalkyl;
• —(CH2)m—(C3-C6)-cycloalkyl;
• —(X)—(CH2)m—(C3-C6)-cycloalkyl;
• —(CH2)m—(C3-C6)-cyclofluoroalkyl;
• —(X)—(CH2)m—(C3-C6)-cyclofluoroalkyl;
• —C(O)—(CH2)m—(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle);
• —C(O)—(C1-C3)-alkyl;
• —C(O)—(C1-C3)-fluoroalkyl;
• —C(O)O—(C1-C3)-fluoroalkyl;
• —C(O)—(CH2)m—(C3-C6)-cycloalkyl;
• —C(O)—(CH2)m—(C3-C6)-cycloalkyl;
• —C(O)—(CH2)m—(C3-C6)-cyclofluoroalkyl;
• or —C(O)—(CH2)m—(C3-C6)-cyclofluoroalkyl;
• Q1 and Q2, identical or different, independently represent a hydrogen atom;
• —(CH2)r—NHQ3;
• —(CH2)r—NH—C(NHQ3)=NQ4;
• —(CH2)r—NH—CH═NQ3;
• (CH2)n—C(NHQ3)=NQ4;
• —(CH2)r—OQ3;
• —(CH2)n—CONHQ3;
• an unsubstituted or substituted by one or more T2, (C1-C3)-alkyl;
• (C1-C3)-fluoroalkyl;
• or a saturated, partially or totally unsaturated, or aromatic-(CH2)m—(4-, 5- or 6-membered heterocycle comprising at least one nitrogen atom);
• or
• Q1, Q2 and the nitrogen atom to which they are bonded, form together an unsubstituted or substituted by one or more T2, saturated or partially unsaturated 4-, 5- or 6-membered heterocycle comprising 1, 2 or 3 heteroatoms;
• Q3 and Q4, identical or different, independently represent a hydrogen atom or (C1-C3)-alkyl;
• T2, identical or different, independently represents —OH;
• —NH2;
• —CONH2;
• m, identical or different, independently represents 0, 1, 2 or 3;
• n, identical or different, independently represents 1, 2 or 3;
• p, identical or different, independently represents 2 or 3;
• and
• r is 1, 2 or 3 when the (CH2)r is directly linked to a carbon atom or 2 or 3 otherwise;
• X, identical or different, independently represents O, S, S(O), S(O)2, or N(Q3);
• and
• at least one of R2 and R3 is different from H;
• and R2 and R3 are not simultaneously H;
• and at least one of R1, R2, and R3 is different from H.

A kit for the treatment or prevention of bacterial infections by the simultaneous, separate or sequential administration of components of the kit to a patient in need thereof, the kit components comprising:

• at least one antibiotic selected from the group consisting of Amoxicillin, Amikacin, Aztreonam, Ciprofloxacin, Clindamycin, Chloramphenicol, Colistin, Cefpirome, Ceftriaxone, Cefotaxime, Daptomycin, Erythromycin, Cefepime, Cefixime, Fosfomycin, Cefuroxime, Imipenem, Linezolid, Meropenem, Piperacillin, Cefpodoxime, Rifampicine, Synercid, Tigecycline, Vancomycin, Sulbactam, Ceftaroline, Cefiderocol (S-649266), and BAL30072;
• and
• at least one compound selected from the group consisting of a compound of formula (I), a racemate of the formula (I) compound, an enantiomer of the formula (I) compound, a diastereoisomer of the formula (I) compound, a geometric isomer of the formula (I) compound, and a pharmaceutically acceptable salt of the formula (I) compound
• wherein:
• R is —SO3H or CF2CO2H;
• R1 is H, CH2—NH2, CONH2, or a 5-membered heteroaryl comprising at least two nitrogen;
• A-B is
• or
• A is CH2 and B is C═NOR4;
• wherein:
• R2 is a hydrogen atom;
• or a saturated or partially unsaturated or totally unsaturated or aromatic 4- to 10-membered heterocycle comprising at least one nitrogen atom that is unsubstituted or substituted by one or more T1;
• R3 is H or oxazolyl;
• or
• R2 and R3 together with the carbon atom to which they are linked form a cycle that is
• wherein Y is S or O, and R5 is (C2-C3)alkyl-NH2;
• R4 is —(CH2)2NH2 or —CH2CONH2;
• T1, identical or different, independently represents a fluorine atom;
• —(CH2)mOQ1;
• —(CH2)m—CN;
• —(CH2)m—OC(O)Q1;
• —(CH2)m—C(O)OQ1;
• —(CH2)m—OC(O)OQ1;
• —(CH2)m—OC(O)NQ1Q2;
• —(CH2)m—C(O)NQ1Q2;
• —(CH2)m—C(O)ONQ1Q2;
• —(CH2)m—C(O)NQ1OQ2;
• —(CH2)m—C(O)NQ1-NQ1Q2;
• —(CH2)m—NQ1C(O)Q2;
• —(CH2)m—NQ1S(O)2NQ1Q2;
• —(CH2)m—NQ1S(O)2Q2;
• —(CH2)m—S(O)2NQ1Q2;
• —(CH2)m—NQ1C(O)OQ2;
• —(CH2)m—NQ1C(O)NQ1Q2;
• —(CH2)m—NQ1Q2;
• —(CH2)m—NH—C(NHQ3)=NQ4;
• —(CH2)m—NH—CH═NQ3;
• —(CH2)m—C(NHQ3)=NQ4;
• —(X)—(CH2)pOQ1;
• —(X)—(CH2)n—CN;
• —(X)—(CH2)p—OC(O)Q1;
• —(X)—(CH2)n—C(O)OQ1;
• —(X)—(CH2)p—OC(O)OQ1;
• —(X)—(CH2)p—OC(O)NQ1Q2;
• —(X)—(CH2)n—C(O)NQ1Q2;
• —(X)—(CH2)n—C(O)ONQ1Q2;
• —(X)—(CH2)n—C(O)NQ1OQ2;
• —(X)—(CH2)n—C(O)NQ1-NQ1Q2;
• —(X)—(CH2)p—NQ C(O)Q2;
• —(X)—(CH2)p—NQ1S(O)2NQ1Q2;
• —(X)—(CH2)p—NQ1S(O)2Q2;
• —(X)—(CH2)p—S(O)2NQ1Q2;
• —(X)—(CH2)p—NQ1C(O)OQ2;
• —(X)—(CH2)p—NQ1C(O)NQ1Q2;
• —(X)—(CH2)p—NQ1Q2;
• —(X)—(CH2)p—NH—C(NHQ3)=NQ4;
• —(X)—(CH2)p—NH—CH═NQ3;
• —(X)—(CH2)n—C(NHQ3)=NQ4;
• —C(O)—(CH2)nOQ1;
• —C(O)—(CH2)n—CN;
• —C(O)—(CH2)n—OC(O)Q1;
• —C(O)—(CH2)n—C(O)OQ1;
• —C(O)—(CH2)n—OC(O)OQ1;
• —C(O)—(CH2)n—OC(O)NQ1Q2;
• —C(O)—(CH2)n—C(O)NQ1Q2;
• —C(O)—(CH2)n—C(O)ONQ1Q2;
• —C(O)—(CH2)n—C(O)NQ1OQ2;
• —C(O)—(CH2)n—C(O)NQ1-NQ1Q2;
• —C(O)—(CH2)n—NQ1C(O)Q2;
• —C(O)—(CH2)n—NQ1S(O)2NQ1Q2;
• —C(O)—(CH2)n—NQ1S(O)2Q2;
• —C(O)—(CH2)n—S(O)2NQ1Q2;
• —C(O)—(CH2)n—NQ1C(O)OQ2;
• —C(O)—(CH2)n—NQ1C(O)NQ1Q2;
• —C(O)—(CH2)n—NQ1Q2;
• —C(O)—(CH2)n—NH—C(NHQ3)=NQ4;
• —C(O)—(CH2)n—NH—CH═NQ3;
• or —C(O)—(CH2)n—C(NHQ3)=NQ4;
• or
• T1, identical or different, independently represents an unsubstituted or substituted by one or more T2, —(CH2)m—(4-, 5- or 6-membered saturated, partially or totally unsaturated or aromatic heterocycle);
• —(X)—(CH2)m—(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle);
• (C1-C3)-alkyl;
• (C1-C3)-fluoroalkyl;
• —(X)—(C1-C3)-alkyl;
• —(X)—(C1-C3)-fluoroalkyl;
• —(CH2)m—(C3-C6)-cycloalkyl;
• —(X)—(CH2)m—(C3-C6)-cycloalkyl;
• —(CH2)m—(C3-C6)-cyclofluoroalkyl;
• —(X)—(CH2)m—(C3-C6)-cyclofluoroalkyl;
• —C(O)—(CH2)m—(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle);
• —C(O)—(C1-C3)-alkyl;
• —C(O)—(C1-C3)-fluoroalkyl;
• —C(O)O—(C1-C3)-fluoroalkyl;
• —C(O)—(CH2)m—(C3-C6)-cycloalkyl;
• —C(O)—(CH2)m—(C3-C6)-cycloalkyl;
• —C(O)—(CH2)m—(C3-C6)-cyclofluoroalkyl;
• or —C(O)—(CH2)m—(C3-C6)-cyclofluoroalkyl;
• Q1 and Q2, identical or different, independently represent a hydrogen atom;
• —(CH2)r—NHQ3;
• —(CH2)r—NH—C(NHQ3)=NQ4;
• —(CH2)rNH—CH═NQ3;
• (CH2)n—C(NHQ3)=NQ4;
• —(CH2)rOQ3;
• —(CH2)n—CONHQ3;
• an unsubstituted or substituted by one or more T2, (C1-C3)-alkyl;
• (C1-C3)-fluoroalkyl;
• or a saturated, partially or totally unsaturated, or aromatic-(CH2)m—(4-, 5- or 6-membered heterocycle comprising at least one nitrogen atom);
• or
• Q1, Q2 and the nitrogen atom to which they are bonded, form together an unsubstituted or substituted by one or more T2, saturated or partially unsaturated 4-, 5- or 6-membered heterocycle comprising 1, 2 or 3 heteroatoms;
• Q3 and Q4, identical or different, independently represent a hydrogen atom or (C1-C3)-alkyl;
• T2, identical or different, independently represents —OH;
• —NH2;
• —CONH2;
• m, identical or different, independently represents 0, 1, 2 or 3;
• n, identical or different, independently represents 1, 2 or 3;
• p, identical or different, independently represents 2 or 3;
• and
• r is 1, 2 or 3 when the (CH2)r is directly linked to a carbon atom or 2 or 3 otherwise;
• X, identical or different, independently represents O, S, S(O), S(O)2, or N(Q3);
• and
• at least one of R2 and R3 is different from H;
• and R2 and R3 are not simultaneously H;
• and at least one of R1, R2, and R3 is different from H.