Potentiators of antibacterial activity

A pharmaceutical composition comprising:

• (i) an antibiotic;
• and
• (ii) a compound of formula (A-II):
• or a pharmaceutically acceptable derivative thereof,
• wherein A′ is CH2, oxygen, NH or N-(C1-C4 alkyl);
• B′ and W are independently:
• (i) hydrogen, Ar′, (C1-C10)-straight or branched alkyl, (C2-C10)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkyl substituted (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkenyl substituted (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, or Ar′ substituted (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl wherein, in each case, any one of the CH2 groups of said alkyl, alkenyl or alkynyl chains may be optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO2, N, and NR,
• wherein R is selected from the group consisting of hydrogen, (C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar′ group;
• or
• wherein Q′ is hydrogen, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl or alkynyl;
• and
• T′ is Ar′ or substituted 5-7 membered cycloalkyl with substituents at positions 3 and 4 which are independently selected from the group consisting of oxo, hydrogen, hydroxyl, O-(C1-C4)-alkyl, and O-(C2-C4)-alkenyl;
• wherein Ar′ is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl;
• or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl;
• and
• wherein Ar′ may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O[(C1-C4)-straight or branched alkyl], O[(C2-C4)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, N-[(C1-C5)-straight or branched alkyl or (C2-C5)-straight or branched alkenyl)carboxamides, N,N-di[(C1-C5)-straight or branched alkyl or (C2-C5)-straight or branched alkenyl)]carboxamides, N-morpholinocarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, O—X, CH2—(CH2)q—X, O—(CH2)q—X, (CH2)q—O—X, and CH═CH—X;
• wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl;
• and
• q is 0-2;
• G is U′;
• M is either oxygen or CH-U′;
• provided that if G is hydrogen, then M is CH-U′ or if M is oxygen, then G is U′;
• wherein U′ is hydrogen, O[(C1-C4)-straight or branched alkyl] or O[(C2-C4)straight or branched alkenyl], (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl[(C1-C4)-alkyl or (C2-C4)-alkenyl]-Y or Y;
• wherein Y is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrolidinyl, 1,3-dioxolyl, 2-imidazolinyl, imidazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl, and heterocyclic aromatic groups as defined for Ar′ above;
• and
• wherein Y may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O[(C1-C4)-straight or branched alkyl], O[(C2-C4)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, and carboxyl;
• J is hydrogen, (C1-C2) alkyl or benzyl;
• K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl, or J′ and K are taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of O, S, SO and SO2;
• m is 0-3;
• and
• wherein said compound is not a compound of formula (A-I).

A pharmaceutical composition comprising:

• (i) an antibiotic;
• (ii) a pharmaceutically acceptable carrier;
• and
• (iii) a compound having the formula (B-I):
• or a pharmaceutically acceptable derivative thereof, wherein:
• A is CH2, oxygen, or NR1;
• wherein R1, B and D are independently:
• hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl substituted (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, or Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;
• wherein any one of the CH2 groups of said alkyl chain in R1, B and D is optionally replaced by O, S, SO, SO2 or NR;
• wherein R is hydrogen, (C1-C4) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl chain to form a ring, and wherein said ring is optionally fused to Ar;
• J is selected from hydrogen, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, or —CH2Ar;
• K is selected from (C1-C4)-straight or branched alkyl, —CH2Ar, or cyclohexylmethyl;
• or
• J and K are taken together with the nitrogen and carbon atoms to which they are respectively bound to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from O, S, SO and SO2;
• Z is O or S;
• Y is O or N;
• wherein
• when Y is O, then R1 is a lone pair and R2 is selected from Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl;
• and
• when Y is N, then R1 and R2 are independently selected from the group consisting of Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl;
• or R1 and R2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;
• wherein Ar is a carboxylic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl;
• wherein Ar is optionally substituted with one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, —SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O-[(C1-C6)-straight or branched alkyl], O[(C3-C4)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, —NR3R4, carboxyl, N-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl, O-Z, CH2—(CH2)q-Z, O—(CH2)q-Z, (CH2)q-Z-O-Z, or CH═CH-Z;
• wherein R3 and R4 are independently selected from (C1-C6)-straight or branched alkyl, (C3-C6) straight or branched alkenyl or alkynyl, hydrogen or benzyl;
• or wherein R3 and R4 are taken together to form a 5-6 membered heterocyclic ring;
• wherein Z is selected from 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl;
• wherein q is 0-2;
• and
• n is 0 or 1.

A pharmaceutical composition comprising:

• (i) an antibiotic;
• and
• (ii) a compound of formula (C-I):
• or a pharmaceutically acceptable salt thereof, wherein:
• R1, B and D are independently:
• hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl substituted (C3-C6) straight or branched alkenyl of alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;
• provided that R1 is not hydrogen;
• wherein any one of the CH2 groups of said alkyl chains in R1, B and D is optionally replaced by O, S, SO, SO2 or NR;
• wherein R is hydrogen, (C1-C6) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl chain to form a ring, and wherein said ring is optionally fused to Ar;
• wherein each Ar is independently selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
• and
• wherein each Ar is optionally and independently substituted with one to three substituents independently selected from hydrogen, halogen, hydroxyl, nitro, —SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6) straight or branched alkyl, O-((C1-C6) straight or branched alkyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, —NR5R6, carboxyl, N-(C1-C6 straight or branched alkyl or C3-C5 straight or branched alkenyl) carboxamides, N,N-di-((C1-C6) straight or branched alkyl or (C3-C5) straight or branched alkenyl), carboxamides, morpholinyl, piperidinyl, O-M, CH2—(CH2)q-M, O—(CH2)q-M, (CH2)q—O-M, and CH═CH-M;
• wherein R5 and R6 are independently selected from the group consisting of hydrogen, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, benzyl or R5 and R6 are taken together to form a 5-7 membered heterocyclic ring;
• M is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, 2-methylthioazoyl, thiazoyl, 2-thienyl, 3-thienyl, 4-thienyl and pyrimidyl;
• and
• q is 0-2;
• J is selected from the group consisting of (C1-C6) straight or branched alkyl, (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, and Ar-substituted (C3-C6) straight or branched alkenyl of alkynyl, and cyclohexylmethyl;
• K is selected from the group consisting of (C1-C6) straight or branched alkyl, Ar-substituted (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, and Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;
• or
• J and K are taken together with the nitrogen and carbon atoms to which they are respectfully bound to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from O, S, SO and SO2;
• X is selected from the group consisting of Ar, —OR2, and —N(R3)R4;
• wherein R2 has the same definition as R1;
• R3 and R4 independently have the same definitions as B and D;
• or R3 and R4 are taken together to form a 5-7 membered heterocyclic aliphatic or aromatic ring;
• and
• m is 0 or 1.

A pharmaceutical composition comprising:

• (i) an antibiotic;
• (ii) a pharmaceutically acceptable carrier;
• and
• (iii) compound having the formula (D-I):
• or a pharmaceutically acceptable derivative thereof, wherein A, B, and C are independently:
• hydrogen, (C1-C6)-straight or branched alkyl, 0-(C1-C6)-straight or branched alkyl, (CH2)n—Ar, Y(CH2)n—Ar or halogen, wherein:
• n is 0-4;
• Y is O, S, or NR1;
• R1 is (C1-C6)-straight or branched alkyl or hydrogen;
• wherein each Ar is independently selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, peridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl;
• wherein each Ar optionally contains one to three substituents independently selected from hydrogen, hydroxyl, halogen, nitro, SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, 0-(C1-C6)-straight or branched alkyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl and NR2R3 or NR2R3 carboxamides;
• wherein R2 and R3 are independently selected from hydrogen, (C1-C5)-straight or branched alkyl or benzyl;
• wherein D is selected from hydrogen or (CH2)m-E, wherein:
• E is Ar or NR4R5;
• m=1-3;
• and
• R4 and R5 are independently selected from hydrogen, alkyl (C1-C5 straight or branched) or (CH2)Ar or can be taken together to form a 5 or 6 membered heterocyclic ring;
• wherein X is O or NR6, wherein:
• R6 is selected from hydrogen, (C1-C6)-straight or branched alkyl or (CH2)m—Ar;
• m=1-3;
• wherein J and K are independently (C1-C6)-straight or branched alkyl or Ar-substituted with (C1-C6)-straight or branched alkyl or wherein J and K are taken together to form a five or six membered ring or a five or six membered benzo-fused ring;
• wherein M is (C1-C6)-straight or branched alkyl or Ar;
• and
• wherein the stereochemistry at carbon 1 and carbon 2 is R or S.