Novel substituted succinic acid metallo-beta-lactamase inhibitors and their use in treating bacterial infections

A compound represented by formula I:

• 228
• including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof, wherein:
• M1 and M2 are independently selected from:
• (a) Hydrogen,
• (e) Pharmaceutically acceptable cation,
• (f) Pharmaceutically acceptable esterifing group;
• and
• (g) A negative charge;
• R1 and R2 are independently selected from the following:
• (d) Hydrogen, provided that R1 and R2 are not hydrogen at the same time;
• (e) a C1 to C16 straight, branched or unsaturated alkyl group substituted with 0 to 2 Rq groups and substituted with 0 to 3 Rx groups and optionally interrupted by one of the following O, S, SO2, —C(O)—,
• (f) —C(O)—NRa—, —CO2—;
• (c) a group of the formula:
• 229
• wherein
• —A— represents a single bond, C1 to C8 straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 Rx groups and optionally interrupted by one of the following O, S, SO2, —C(O)—, —C(O)—NRa—, —CO2—;
• 230
• represents:
• (1) a C6 to C14 aryl group;
• (2) a C3 to C10 alicyclic group;
• (3) a C3 to C14 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfir;
• (4) a C3 to C10 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
• or
• (d) a group of the formula:
• 231
• wherein:
• —A— is as defined above;
• A′ is a single bond, O, S, or a C1 to C6 straight, branched or unsaturated alkyl group optionally substituted with 1-2 Rx groups and optionally interrupted by one of the following groups O, S, SO2, —C(O)—, —C(O)—NRa—, —CO2—;
• 232
• are independently selected from:
• (1) a C6 to C10 aryl group;
• (2) a C3 to C8 alicyclic group;
• (3) a C2 to C9 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
• (4) a C3 to C8 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
• provided that at least one Rq group is present in R1 or R2 and that when more than one Rq is present the total number of cationic nitrogen atoms does not exceed 8;
• the total number of cationic nitrogen atoms can be charged balanced by M1 and/or M2 or by M1 and/or M2 in combination with an appropriate number of Y−;
• wherein:
• Rq is —E—Q+Y−;
• Y− is a pharmaceutically acceptable anionic group;
• E is —(CH2)m—X—(CH2)n—;
• m is 0 to 6;
• n is 0 to 6 (but when E is attached to an aromatic ring n is 1-6);
• X is a bond, O, S, SO2, —C(O)—, —C(O)—N(Ra)—, —C(O)O—, —CH═CH— or —C≡C—, provided that when X is O, S, —C(O)—N(Ra)— or —C(O)O—, then n is 2 to 6
• and Q+, attached to the (CH2)n terminus of E is:
• (1) a cationic group selected from the following:
• 233
• wherein:
• Ru and Rv are independently hydrogen or C1-6 alkyl optionally substituted with 1 to 2 Ry;
• Rw is hydrogen or C1-6 alkyl optionally substituted with 1 to 2 Rx;
• Ru and Rv when bonded to the same nitrogen atom may together be a C3-6 alkyl radical, which when taken together with the intervening atoms form a ring;
• Two Ru groups on separate nitrogen atoms may together comprise a C2-5 alkyl radical, which when taken together with the intervening atoms form a ring;
• Ru, Rv and Rw when bonded to the same nitrogen atom may together form a C6-10 tertiary alkyl radical, which with N+ forms a bicyclic ring;
• (2) A dicationic group:
• 234
• wherein:
• E1 is —(CH2)p—Z—(CH2)r—;
• p and r are independently 1 to 4;
• Z is a bond, O, S, SO2, —C(O)—, —C(O)O—**, —CH═CH—, —C≡C—, or
• 235
• Provided that when Z is O or S, p is 2 to 4 and r is 2 to 4 and when Z is
• 236
• or —C(O)O—**, r is 2 to 4;
• wherein ** denotes the atom which is bonded to the —(CH2)r— moiety of E1 above;
• Q1 is selected from the following:
• 237
• Q2 is selected from the following:
• 238
• Ru, Rv and Rw are independently selected and defined as above,
• And in addition, in the case where two Ru groups on separate nitrogen atoms are joined to form a ring as defined above, two Rv groups on the same two separate nitrogen atoms may also comprise a C1-5 alkyl radical to form together with the intervening atoms a bicyclic ring;
• an example of such is:
• 239
• (5) A tricationic group selected from the following:
• 240
• wherein:
• Each E1 is as defined above, but selected independently;
• Each Q1 is as defined above, but selected independently;
• Each Q2 is as defined above, but selected independently;
• Ru, Rv and Rw are defined as in the definition of Q+ item (2) above and selected independently;
• or
• (6) A tetracationic group selected from the following:
• 241
• wherein:
• Each E1 is as defined above, but selected independently;
• Each Q1 is as defined above, but selected independently;
• Each Q2 is as defined above, but selected independently;
• Ru, Rv and Rw are defined as in the definition of Q+ item (2) above and selected independently;
• where each Rx is independently selected from the group consisting of:
• (f) F, Cl, Br, I,
• (g) CF3,
• (h) ORb,
• (i) CN,
• (j) —C(O)—Rc,
• (f) —S(O2)—Rf,
• (g) —C(O)—ORa
• (h) —O—C(O)—Rc,
• (i) —S—Rb,
• (j) —N(Ra)—C(O)—Rc,
• 242
• (q) —N(Ra)—C(O)—ORf,
• (r) —S(O)—Rf,
• (s) —N(Ra)—S(O2)—Rf,
• (t) NO2, and
• (u) C1 to C8 straight, branched or unsaturated alkyl optionally substituted with one of the substituents (a) through (t) above;
• (v) —CH2-aryl wherein the aryl is optionally substituted with one of the substituents (a) through (t) above;
• or two adjacent Rx groups on an aromatic ring may consist of the following divalent moiety, —O—CH2—O—;
• wherein:
• Ra is H, C1 to C6 alkyl optionally substituted with Ry;
• Rb is H, C1 to C6 alkyl optionally substituted with Ry, CH2-aryl, or aryl, said aryls optionally substituted with 1-2 Ry groups;
• Rc is H, C1 to C6 alkyl optionally substituted with Ry, CF3, or aryl, said aryl optionally substituted with 1-2 Ry groups;
• Rd and Re are independently hydrogen, C1 to C4 alkyl optionally substituted with Ry, or Rd and Re taken together may represent a 3 to 5-membered alkyl radical to form a ring, or Rd and Re taken together may represent a 2 to 4-membered alkyl radical interrupted by O, S, SO or SO2 to form a ring;
• Rf is C1 to C6 alkyl optionally substituted with Ry, or aryl, said aryl optionally substituted with 1-2 Ry groups;
• and
• Ry is —OH, —OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.