HEPTOSE DERIVATIVES FOR USE IN THE TREATMENT OF BACTERIAL INFECTIONS
Compounds having the general formula (I) pharmaceutical compositions containing them for use in inhibiting bacterial heptose biosynthesis and thereby lowering or suppressing bacterial virulence.
1 . Compounds having the general formula (I)
wherein,
Carbon-2 is in D-manno-heptose or D-gluco-heptose configuration or as a mixture of both;
Carbon-6 is in D-glycero-heptose configuration;
X is O, S, CH 2 , CHF, CF 2 or NH;
Y is H or P(O)(OZ1)(OZ2), P(O)(OZ1)(NHZ2) or SO 2 (OZ1);
Z1 and Z2, identical or different, are H, (C 1 -C 6 )alkyl, n-octadecanoyl, (C 1 -C 6 )fluoroalkyl, CH 2 O(CO)O(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)O(CO)O(C 1 -C 6 )alkyl, CH 2 O(CO)O(C 1 -C 6 )fluoroalkyl, CH 2 O(CO)(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)O(CO)(C 1 -C 6 )alkyl, CH 2 O(CO)(C 1 -C 6 )fluoroalkyl, CH 2 CH(O-n-decanoyl)CH 2 S-n-dodecanoyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, CH 2 CH 2 S(CO)(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)(CO)O(C 1 -C 6 )alkyl, CH 2 (CO)O(C 1 -C 6 )alkyl; phenyl optionally substituted by one or several identical or different groups R; 4-6 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S, optionally substituted by one or several identical or different groups R; or mono-, di- or trivalent cation such as lithium, sodium, potassium, magnesium, calcium, cesium, barium, ammonium, to form a phosphate salt; Z1 and Z2 may form a 4-10 membered cycle with each other, optionally including those selected from the group comprising CH 2 CH 2 CH(m-chlorophenyl or pyridyl), CH 2 CH 2 CH(O(CO)(C 1 -C 6 )alkyl);
W1 and W2 identical or different, optionally linked with each other, are selected from the group consisting of H, F, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OR a , (C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a , and SO 2 NR a R b , CONR a OR b , N(OR b )COR a all the above members of the group representing W1 or W2 being optionally substituted by one, two or three identical or different groups R, which may form a cycle with each other;
R a , R b and R e , identical or different, are selected from the group consisting of H, (C 1 -C 6 )alkyl, C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl and 4-6 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S; R a , R b and R e may form a cycle with each other optionally including 1-3 heteroatoms selected from N, O and S, illustrative examples of saturated nitrogen containing heterocycles within the definition of NRaRb include those selected from the group comprising, pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl.
R is selected from the group consisting of halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R C , NR a SO 2 R b , S(O) n R a , and SO 2 NR a R b , CONR a OR b , N(OR b )COR a ; all the above members of the group representing R being optionally substituted by one or several identical or different groups R′, which may form a cycle with each other;
R′ is selected from the group consisting of halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a , and SO 2 NR a R b , CONR a OR b , N(OR b )COR a ;
n is 0, 1 or 2;
their N-oxide derivatives,
in their racemic, scalemic (non racemic mixtures), enantiomeric or geometric forms, and their addition salts thereof with acids and bases,
to the exclusion of the following compounds:
Methyl (6R/S)—C-ethyl-α-D-glycero-pyranoside;
D/L-Glycero-D-manno-heptose-7-phosphate, and methyl α-D-manno-heptopyranoside-7-phosphate;
—O-L-glycero-α-D-manno-heptopyranosyl-(1→7)-L-glycero-D-manno-heptopyranose Methyl 7-O-L-glycero-α-D-manno-heptopyranosyl-L-glycero-α-D-matmo-heptopyranose;
Methyl 7-O-L-glycero-α-D-manno-heptopyranosyl-L-gdycero-α-D-manno-heptopyranoside;
Allyl 6-O-(L-glycero-α-D-manno-heptopyranosyl)-α-D-glycero-pyrano side;
Methyl 7-O-(2-aminoethyl)phosphoryl-L-glycero-α-D-manno-heptopyranoside; and
with the proviso that when X is O and Y is H, W1 and W2 may not form a double bond with each other when W1 is a linking bond and W2 is (O)(D/L-Glycero-D-manno-hepto-1,5-pyranone); when W1 is H then W2 is different from OH, OCH 3 , CH 2 CH(CH 3 )OH, CH 2 C(O)CH3, or when W2 is H then W1 is different from OH, OCH 3 , OBn, OCH 2 CH═CH 2 , CH 2 CH(CH 3 )OH, CH 2 C(O)CH 3 , SC 2 H 5 , (N-Benzylcarbamoyl)-3-propyloxy, 3-(Perfluorooctyppropanyl-oxybutanyloxy.
2 . The compounds according to claim 1 , in which at least one of W1 and W2 is H, and X is O, S, CH 2 or NH, and Y is H, P(O)(OZ1)(OZ2) or P(O)(OZ1)(NHZ2).
3 . The compounds according to claim 1 , in which X is O and Y is H.
4 . The compounds according to claim 1 , in which W1 and W2 are H.
5 . The compounds according to claim 1 , in which X is CH 2 , CHF or CF 2 and Y is P(O) (OZ1) (OZ2).
6 . The compounds according to claim 1 , which are drugs.
7 . The compounds according to claim 1 , which are inhibitors of bacterial heptose synthesis.
8 . Pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula (I) in association with a pharmaceutically acceptable carrier, the formula (I) comprising:
wherein
Carbon-2 is in D-manno-heptose or D-glycero-heptose configuration or as a mixture of both;
Carbon-6 is in D-glycero-heptose configuration.,
X is O, S, CH 2 , CHF, CF, or NH;
Y is H or P(O)(OZ1)(OZ2), P(O)(OZ1)(NHZ2) or SO 2 (OZ1);
Z1 and Z2, identical or different, are H, (C 1 -C 6 )alkyl, n-octadecanoyl, (C 1 -C 6 )fluoroalkyl, CH 2 O(CO)O(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)O(CO)O(C 1 -C 6 )alkyl, CH 2 O(CO)O(C 1 -C 6 )fluoroalkyl, CH 2 O(CO)(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)O(CO)(C 1 -C 6 )alkyl, CH 2 O(CO)(C 1 -C 6 )fluoroalkyl, CH 2 CH(O-n-decanoyl)CH 2 S-n-dodecanoyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 )alkynyl, CH 2 CH 2 S(CO)(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)(CO)O(C 1 -C 6 )alkyl, CH 2 (CO)O(C 1 -C 6 )alkyl; phenyl; 4-6 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S;
W1 and W2 identical or different, are selected from the group consisting of H, F, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OR a , (C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a , and SO 2 NR a R b , CONR a OR b , N(OR b )COR a all the above members of the group representing W1 or W2;
R a , R b and R c , identical or different, are selected from the group consisting of H, (C 1 -C 6 )alkyl, C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl and 4-6 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S; R a , R b and R c may form a cycle with each other.
R is selected from the group consisting of halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a and SO 2 NR a R b , CONR a OR b , N(OR b )COR a ; all the above members of the group representing R;
R′ is selected from the group consisting of halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a and SO 2 NR a R b , CONR a OR b , N(OR b )COR a ;
n is 0, 1 or 2;
their N-oxide derivatives,
in their racemic, scalemic (non racemic mixtures), enantiomeric or geometric forms,
and their addition salts thereof with acids and bases,
to the exclusion of the following compounds:
Methyl (6R/S)—C-ethyl-α-D-glycero-pyranoside;
D/L-Glycero-D-manno-heptose-7-phosphate, and methyl α-D-manno-heptopyranoside-7 phosphate;
—O-L-glycero-α-D-manno-heptopyranosyl-(1→7)-L-glycero-D-manno-heptopyranose Methyl 7-O-L-glycero-α-D-manno-heptopyranosyl-L-glycero-α-D-manno-heptopyranose;
Methyl 7-O-L-glycero-α-D-manno-heptopyranosyl-L-glycero-α-D-manno-heptopyranoside;
Allyl 6-O-(L-glycero-α-D-manno-heptopyranosyl)-α-D-gluco-pyranoside;
Methyl 7-O-(2-aminoethyl)phosphoryl-L-glycero-α-D-manno-heptopyranoside; and
with the proviso that when X is O and Y is H, W1 and W2 may not form a double bond with each other when W1 is a linking bond and W2 is (O)(D/L-Glycero-D-manno-hepto-1,5-pyranone); when W1 is H then W2 is different from OH, OCH 3 CH 7 CH(CH 2 )OH, CH 2 C(O)CH3, or when W2 is H then W1 is different from OH, OCH 3 , OBn, OCH 2 CH═CH 2 ; and CH 2 CH(CH 3 )OH, CH 2 C(O)CH 3 , SC 2 H 5 , (N-Benzylcarbamoyl)-3-propyloxy, 3-(Perfluorooctyl)propanyl-oxybutanyloxy.
9 . The pharmaceutical compositions according to claim 8 formulated to be administered under oral, parenteral, and injectable routes, with individual doses appropriate for the patient to be treated.
10 . The pharmaceutical compositions according to claim 8 , in combination with at least one antibacterial.
11 . The pharmaceutical compositions according to claim 8 , in combination with at least one antivirulence agent.
12 . The pharmaceutical compositions according to claim 8 , in combination with one or more drug(s) reinforcing the host innate immunity.
13 . The pharmaceutical compositions according to claim 8 , preventing or therapeutically treating severe infections due to Gram-negative bacteria able to disseminate in blood such as the non-limiting following species (spp.): Escherichia coli, Enterobacter, Salmonella, Shigella, Pseudomonas, Acinetobacter, Neisseria, Klebsiella, Serratia, Citrobacter, Proteus, Yersinia, Haemophilus, Legionella, Moraxella and Helicobacter pylori.
14 . A method of preventing or treating a bacterial infection in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of general formula (I)
wherein,
Carbon-2 is in D-manno-heptose or D-gluco-heptose configuration or as a mixture of both;
Carbon-6 is in D-glycero-heptose configuration;
Y is H or P(O)(OZ1)(OZ2), P(O)(OZ1)(NHZ2) or SO 2 (OZ1);
Z1 and Z2, identical or different, are H, (C 1 -C 6 )alkyl, n-octadecanoyl, (C 1 -C 6 )fluoroalkyl, CH 2 O(CO)O(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)O(CO)O(C 1 -C 6 )alkyl, CH 2 O(CO)O(C 1 -C 6 )fluoroalkyl, CH 2 O(CO)(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)O(CO)(C 1 -C 6 )alkyl, CH 2 O(CO)(C 1 -C 6 )fluoroalkyl, CH 2 CH(O-n-decanoyl)CH 2 S-n-dodecanoyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, CH 2 CH 2 S(CO)(C 1 -C 6 )alkyl, CH((C 1 -C 6 )alkyl)(CO)O(C 1 -C 6 )alkyl, CH 2 (CO)O(C 1 -C 6 )alkyl; 4-6 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S;
W1 and W2, identical or different, are selected from the group consisting of H, F, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OR a , (C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a , and SO 2 NR a R b , CONR a OR b , N(OR b )COR a all the above members of the group representing W1 or W2;
R a , R b and R c , identical or different, are selected from the group consisting of H, (C 1 -C 6 )alkyl, C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl and 4-6 membered monocyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S; R a , R b and R c may form a cycle with each other
R is selected from the group consisting of halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a , and SO 2 NR a R b , CONR a OR b , N(OR b )COR a ; all the above members of the group representing R;
R′ is selected from the group consisting of halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )fluoroalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocycle containing 1-5 heteroatoms selected from N, O and S; CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , OCO 2 R a , NR a CONR b R c , NR a SO 2 R b , S(O) n R a , and SO 2 NR a R b , CONR a OR b , N(OR b )COR a ;
n is 0, 1 or 2;
their N-oxide derivatives,
the compound in their racemic, scalemic (non racemic mixtures), enantiomeric or geometric forms,
and their addition salts thereof with acids and bases,
to the exclusion of the following compounds:
Methyl (6R/S)—C-ethyl-α-D-gluco-pyranoside;
D/L-Glycero-D-manno-heptose-7-phosphate, and methyl α-D-manno-heptopyranoside-7 phosphate;
—O-L-glycero-α-D-manno-heptopyranosyl-(1→7)-L-glycero-D-manno-heptopyranose Methyl 7-O-L-glycero-α-D-manno-heptopyranosyl-L-glycero-α-D-manno-heptopyranose;
Methyl 7-O-L-glycero-α-D-manno-heptopyranosyl-L-glycero-α-D-manno heptopyranoside;
Allyl 6-O-(L-glycero-α-D-manno-heptopyranosyl)-α-D-gluco-pyranoside;
Methyl 7-O-(2-aminoethyl)phosphoryl-L-glycero-α-D-manno-heptopyranoside; and
with the proviso that when X is O and Y is H, W1 and W2 may not form a double bond with each other when W1 is a linking bond and W2 is (O)(D/L-Glycero-D-manno-hepto-1,5-pyranone); when W1 is H then W2 is different from OH, OCH 3 , CH 2 CH(CH 3 )OH, CH 2 C(O)CH3, or when W2 is H then W1 is different from OH, OCH 3 , OBn, OCH 2 CH═CH 2 ; and CH 2 CH(CH 3 )OH, CH 2 C(O)CH 3 , SC 2 H 5 , (N-Benzylcarbamoyl)-3-propyloxy, 3-(Perfluorooctyl)propanyl-oxybutanyloxy.
15 . The method according to claim 14 , wherein W1 and/or W2 is H, and X is O, S, CH 2 or NH, and Y is H, P(O)(OZ1)(OZ2) or P(O)(OZ1)(NHZ2).
16 . The method according to claim 14 , wherein X is O and Y is H.
17 . The method according to claim 14 , wherein W1 and W2 are H.
18 . The method according to claim 14 , wherein X is CH 2 , CHF or CF 2 and Y is P(O) (OZ1) (OZ2).
19 . The method according to claim 14 , wherein R a , R b and/or R is a saturated nitrogen containing heterocycle of formula NRaRb selected from the group consisting of pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, and morpholinyl.
20 . The method according to claim 14 , wherein the compound is an inhibitor of bacterial heptose synthesis.
21 . The method according to claim 14 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
22 . The method according to claim 14 , further comprising administering the pharmaceutical compound orally, parenterally, or by injection at a therapeutically effective dose.
23 . The method according to claim 14 , further comprising administering at least one additional antimicrobial compound.
24 . The method according to claim 23 , wherein the antimicrobial is a natural, hemisynthetic or synthetic antibacterial or antivirulence agent.
25 . The method according to claim 24 , wherein the antimicrobial is a peptide.
26 . The method according to claim 14 , further comprising administering one or more drugs for reinforcing the patient's innate immunity.
27 . The method according to claim 14 , wherein the bacterial infection comprises gram negative bacteria.
28 . The method according to claim 27 , wherein the gram negative bacteria are Escherichia coli, Enterobacter, Salmonella, Shigella, Pseudomonas, Acinetobacter, Neisseria, Klebsiella, Serratia, Citrobacter, Proteus, Yersinia, Haemophilus, Legionella, Moraxella, Helicobacter pylori or combinations thereof.
29 . The method according to claim 14 , wherein the patient is a human.
30 . The method according to claim 14 , further comprising administering 0.1 to 10 g of the compound per day.