Patent EA-001296-B1 (EA)
Title: Carbapenem antibacterial compounds, compounds containing such compounds and methods of trteatment
Inventor: WILKENING ROBERT R
IPC: A61K31/454
Filed: 1997-04-21
Abstract: 1. A compound represented by formula I:   or a pharmaceutically acceptable salt thereof, wherein:  R<1> represents H or methyl; CO2M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group; P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; each R is independently selected from: -R*; -Q; hydrogen; halo; -CN; -NO2; -NR<a>R<b>; -OR<c>; -SR<c>; -C(O)NR<a>R<b>; -C(O)OR<h>; -S(O)R<c>; -SO2R<c>; -SO2NR<a>R<b>; -NR<a>SO2R<b>; -C(O)R<a>; -OC(O)R<a>; -OC(O)NR<a>R<b>; -NR<a>C(O)NR<b>R<c>; -NR<a>CO2R<h>; -OCO2R<h>; -NR<a>C(O)R<b>; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<d> groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four R<d> groups; with the proviso that at least one R is present which contains at least one positive charge; each R<a>, R<b> and R<c> independently represents hydrogen, -R*, -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<d> groups, or -C3-7 cycloalkyl, unsubstituted or substituted with one to four R<d> groups;  or R<a> and R<b> taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR<c>, where R<c> as defined above, or -C(O)-, while said ring being unsubstituted or substituted with one to four R<i> groups;  or R<b> and R<c> taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR<a>, where R<a> as defined above, or -C(O)-, while said ring being unsubstituted or substituted with one to four R<i> groups; each R<d> independently represents halo; -CN; -NO2-; -NR<e>R<f>; -OR<g>; -SR<g>; -CONR<e>R<f>; -COOR<g>; -SOR<g>; -SO2R<g>; -SO2NR<e>R<f>; -NR<e>SO2R<f>; -COR<e>; -NR<e>COR<f>; -OCOR<e>; -OCONR<e>R<f>; -NR<e>CONR<f>R<g>; -NR<e>CO2R<h>; -OCO2R<h>; -C(NR<e>)NR<f>R<g>; -NR<e>C(NH)NR<f>R<g>; -NR<e>C(NR<f>)R<g>; -R* or -Q; R<e>, R<f> and R<g> represent hydrogen; -R*; -C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R<i> groups; or R<e> and R<f> taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NR<g>, where R<g> as defined above, said ring being unsubstituted or substituted with one to four R<i> groups; each R<i> independently represents halo; -CN; -NO2; phenyl; -NHSO2R<h>; -OR<h>; -SR<h>; -N(R<h>)2; -N<+>(R<h>)3; -C(O)N(R<h>)2; -SO2N(R<h>)2; heteroaryl; heteroarylium; -CO2R<h>; -C(O)R<h>; -OCOR<h>; -NHCOR<h>; guanidinyl; carbamimidoyl or ureido; each R<h> independently represents hydrogen, a -C1-6 straight or branched-chain alkyl group, a -C3-6 cycloalkyl group or phenyl, or when two R<h> groups are present, said R<h> groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3; Q is selected from the group consisting of:   wherein: a and b are integers 1, 2 or 3; L<-> is a pharmaceutically acceptable counterion; α represents O, S or NR
; β, δ, λ, μ and σ represent CR<t>, N or N<+>R
, provided that no more than one of β, δ, λ, μ and σ is N<+>R
 and provided that there are 2 or more carbon atoms in the ring; R* is selected from the group consisting of:   wherein: d represents O, S or NR<k>; e, g, x, y and z represent CR<m>, N or N<+>R<k>, provided that no more than one of e, g, x, y and z in any given structure represents N<+>R<k>; R<k> represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<i> groups; or -(CH2)nQ where n = 1, 2 or 3 and Q is as previously defined; each R<m> independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO2; -NR<n>R<o>; -OR<n>; -SR<n>; -CONR<n>R<o>; -COOR<h>; -SOR<n>; -SO2R<n>; -SO2NR<n>R<o>; -NR<n>SO2R<o>; -COR<n>; -NR<n>COR<o>; -OCOR<n>; -OCONR<n>R<o>; -NR<n>CO2R<h>; -NR<n>CONR<o>R<h>; -OCO2R<h>; -CNR<n>NR<o>R<h>; -NR<n>CNHNR<o>R<h>; -NR<n>C(NR<o>)R<h>; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<i> groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four R<i> groups; and -(CH2)nQ where n and Q are as defined above; R<n> and R<o> represent hydrogen, phenyl; -C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R<i> groups; each R
 independently represents hydrogen; phenyl or -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<i> groups; each R<t> independently represents hydrogen; halo; phenyl; -CN; -NO2, -NR<u>R<v>; -OR<u>; -SR<u>; -CONR<u>R<v>; -COOR<h>; -SOR<u>; -SO2R<u>; -SO2NR<u>R<v>; -NR<u>SO2R<v>; -COR<u>; -NR<u>COR<v>; -OCOR<u>; -OCONR<u>R<v>; -NR<u>CO2R<v>; -NR<u>CONR<v>R<w>; -OCO2R<v>; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<i> groups; R<u> and R<v> represent hydrogen or -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<i> groups; or R<u> and R<v> together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR<w> or -C(O)-, said ring being unsubstituted or substituted with one to four R<i> groups; each R<w> independently represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R<i> groups; C3-6 cycloalkyl optionally substituted with one to four R<i> groups; phenyl optionally substituted with one to four R<i> groups, or heteroaryl optionally substituted with 1-4 R<i> groups; or R<h> and R<w> taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3; R<x> represents hydrogen or a C1-8 straight- or branched-chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NR<w>, N<+>R<h>R<w>, or -C(O)-, said chain being unsubstituted or substituted with one to four substituents selected of halo, CN, NO2, OR<w>, SR<w>, SOR<w>, SO2R<w>, NR<h>R<w>, N<+>(R<h>)2R<w>, -C(O)-R<w>, C(O)NR<h>R<w>, SO2NR<h>R<w>, CO2R<w>, OC(O)R<w>, OC(O)NR<h>R<w>, NR<h>C(O)R<w>, NR<h>C(O)NR<h>R<w>, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R<i> groups or with one to two C1-3 straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R<i> groups; R<y> and R<z> represent hydrogen; phenyl; -C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R<i> groups, and optionally interrupted by O, S, NR<w>, N<+>R<h>R<w> or -C(O)-; or R<x> and R<y> together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NR<w>, N<+>R<h>R<w> or -C(O)-, unsubstituted or substituted with 1-4 R<i> groups, and when R<x> and R<y> together represent a 4-6 membered ring as defined above, R<z> is as defined above or R<z> represents an additional saturated 4-6 membered ring fused to the ring represented by R<x> and R<y> taken together, optionally interrupted by O, S, NR<w> or -C(O)-, said rings being unsubstituted or substituted with one to four R<i> groups. 2. A compound in accordance with claim 1, wherein CO2M represents a carboxylate anion. 3. A compound in accordance with claim 1, wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R<d> groups. 4. A compound in accordance with claim 3, wherein one R represents a group containing a positively charged moiety and the remaining R groups are hydrogen. 5. A compound in accordance with claim 1, wherein the R groups contain from 1-3 positive charges. 6. A compound in accordance with claim 5, wherein the R groups contain two positive charges, balanced by a carboxylate anion and a negatively charged counterion. 7. A compound in accordance with claim 1, wherein one R group represents a -C1-6 straight or branched chain alkyl group, substituted with one to four R<d> groups, wherein one R<d> group represents -R* or Q. 8. A compound in accordance with claim 1, wherein Q is selected from the group consisting of:   9. A compound in accordance with claim 8, wherein Q represents:   L, a and b are as originally defined, and R<x> represents a member selected from the group consisting of: hydrogen, C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NR<w>, N<+>R<h>R<w>, or -C(O)-, said chain being unsubstituted or substituted with one to four substituents selected of halo, CN, NO2, OR<w>, SR<w>, SOR<w>, SO2R<w>, NR<h>R<w>, N<+>(R<h>)2R<w>, -C(O)-R<w>, C(O)NR<h>R<w>, SO2NR<h>R<w>, CO2R<w>, OC(O)R<w>, OC(O)NR<h>R<w>, NR<h>C(O)R<w>, NR<h>C(O)NR<h>R<w>, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R<i> groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R<i> groups, and R<h>, R<i> and R<w> are as originally defined. 10. A compound in accordance with claim 1, wherein Q represents -N<+>R<x>R<y>R<z>, wherein R<x>, R<y> and R<z> are as originally defined. 11. A compound in accordance with claim 1, wherein one R* group is present and is selected from:   and d represents NR<k>; R<k> represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CR<m> or N<+>R<k>, where R<k> as defined above and R<m> representing hydrogen. 12. A compound in accordance with claim 1, wherein: CO2M represents a carboxylate anion; one R group, which is attached to the naphthosultam platform, contains at least one positively