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US 7,683,049 B2Granted
Carbapenem antibacterials with gram-negative activity and processes for their preparation
AssigneeFOB Synthesis, Inc.
InventorsWoo-Baeg Choi, Ewa Kowalik
Life of this patent
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Abstract
The present invention provides β-methyl carbapenem compounds and pharmaceutical compositions useful in the treatment of bacterial infections and methods for treating such infections using such compounds and/or compositions, wherein the compounds are generally of the Formulae The invention includes administering an effective amount of a carbapenem compound or salt and/or prodrug thereof to a host in need of such a treatment.
Claims42
A carbapenem compound of the formula I:
- or pharmaceutically acceptable salts or prodrugs thereof, wherein:
- R is H or alkyl;
- R1 is H or alkyl;
- M is H or a group such that CO2M is a carboxylic acid, a carboxylate anion balanced by a counterion or a charged Ri or Q group of the compound of formula I, a pharmaceutically acceptable ester group, or a carboxylic acid protected by a protecting group;
- P is selected from the group consisting of hydrogen, hydroxyl, halogen or hydroxyl protected by a hydroxyl protecting group;
- and
- Y1 is selected from the group consisting of hydrogen;
- halogen;
- —CN;
- —NO2;
- —NRaRb;
- —ORc;
- —SRc;
- —C(O)NRaRb;
- —C(O)ORh;
- S(O)Rc;
- —SO2Rc;
- —SO2NRaRb;
- —NRaSO2Rb;
- —C(O)Ra;
- —OC(O)Ra;
- OC(O)NRaRb;
- —NRaC(O)NRbRc;
- —NRaCO2Rh;
- —OCO2Rh;
- NRaC(O)Rb;
- C1-6 straight- or branched-chain alkyl that are substituted or unsubstituted with one to four Rd groups;
- alkylaryl, -A-(CH2)n-Q and C3-7 cycloalkyl, substituted or unsubstituted with one to four Rd groups;
- Y2 is selected from the group consisting halogen;
- —CN;
- —NO2;
- —NRaRb;
- —ORc;
- —SRc;
- —C(O)NRaRb;
- —C(O)ORh;
- S(O)Rc;
- —SO2Rc;
- —SO2NRaRb;
- —NRaSO2Rb;
- —C(O)Ra;
- —OC(O)Ra;
- OC(O)NRaRb;
- —NRaC(O)NRbRc;
- —NRaCO2Rh;
- —OCO2Rh;
- NRaC(O)Rb;
- C1-6 straight- or branched-chain alkyl that are substituted with one to four Rd groups;
- alkylaryl, -A-(CH2)n-Q and C3-7 cycloalkyl, substituted or unsubstituted with one to four Rd groups, wherein:
- A is O, S, NH, NCH3, NR, or —CH2—;
- n is 0, 1, 2 or 3;
- each Ra, Rb and Rc is independently selected from hydrogen, —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or —C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups;
- or Ra and Rb taken together with any intervening atoms is a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRc, or —C(O)—, the ring being unsubstituted or substituted with one to four Ri groups;
- or Rb and Rc taken together with any intervening atoms is a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NRa, with Ra as defined above, or —C(O )—, the ring being unsubstituted or substituted with one to four Ri groups;
- each Rd is independently halogen;
- —CN;
- —NO2;
- —NReRf;
- —ORg;
- —SRg;
- —CONReRf;
- —COORg;
- —SORg;
- —SO2Rg;
- —SO2NReRf;
- —NReSO2Rf;
- —CORe;
- —NReCORf;
- —OCORe;
- —OCONReRf;
- NReCONRfRg;
- —NReCO2Rh;
- —OCO2Rh;
- —C(NRe)NRfRg;
- NReC(NH)NRfRg or —NReC(NRf)Rg;
- each Re, Rf and Rg is selected from hydrogen;
- —Rh;
- —C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups or Re and Rf taken together with any intervening atoms is a 4-6 membered saturated ring optionally interrupted by one to three of O, S, —C(O)— or NRg with Rg as defined above, the ring being unsubstituted or substituted with one to four Ri groups;
- each Ri is independently selected from halogen;
- —CN;
- —NO2;
- phenyl;
- —NHSO2Rh;
- —ORh, —SRh;
- —N(Rh)2;
- —N+(Rh)3;
- —C(O)N(Rh)2;
- SO2N(Rh)2;
- heteroaryl;
- heteroarylium;
- —CO2Rh;
- —C(O)Rh;
- —OCORh;
- NHCORh;
- guanidinyl;
- carbamimidoyl or ureido;
- each Rh is independently selected from hydrogen, a —C1-6 straight or branched-chain alkyl group, a —C3-C6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh 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;
- each Q is selected from the group consisting of:
- wherein:
- a and b are 1, 2 or 3;
- L− is a pharmaceutically acceptable counterion;
- α is O, S or NRs;
- β, δ, λ, μ, and σ are independently CRt, N;
- each Rs is independently selected from hydrogen;
- phenyl or C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
- each Rt is independently selected from hydrogen;
- halo;
- phenyl;
- —CN;
- —NO2;
- —NRuRv;
- —ORu;
- —SRu;
- CONRuRv;
- —COORh;
- —SORu;
- —SO2Ru;
- —SO2NRuRv;
- —NRuSO2Rv;
- —CORu;
- —NRuCORv;
- —OCORu;
- —OCONRuRv;
- —NRuCO2Rv;
- —NRuCONRvRw;
- —OCO2Rv;
- —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
- each Ru and Rv is independently selected from hydrogen or —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups or Ru and Rv together with any intervening atoms is a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRw or —C(O)—, the ring being unsubstituted or substituted with one to four Ri groups;
- each Rw is independently selected from hydrogen;
- —C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
- C3-6 cycloalkyl optionally substituted with one to four Ri groups;
- phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1-4 Ri groups;
- or Rh and Rw 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;
- each Rx is independently hydrogen or a C1-8 straight- or branched chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, or —C(O)—, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRw, SORw, SO2Rw, NRhRw, —C(O)—Rw, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four Ri 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 Ri groups;
- each Ry and Rz is independently selected from hydrogen;
- phenyl;
- —C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by O, S, NRw or —C(O)— or Rx and Ry together with any intervening atoms is a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRw or —C(O)—, unsubstituted or substituted with 1-4 Ri groups,
- or, when Rx and Ry together are a 4-6 membered ring, Rz is an additional saturated 4-6 membered ring fused to the Rx and Ry ring, optionally interrupted by O, S, NRw or —C(O)—, the rings being unsubstituted or substituted with one to four Ri groups.
135 more elements
A carbapenem compound of the formula II,
- or pharmaceutically acceptable salts thereof, wherein:
- R1 is hydrogen or methyl;
- P is hydrogen or hydroxyl;
- M is H or a group such that CO2M is a carboxylic acid, a carboxylate anion balanced by a counterion, a pharmaceutically acceptable ester group, or a carboxylic acid protected by a protecting group;
- Y1 is H or R2, wherein R2 is H or C1-C4 alkyl;
- and
- Y2 is —(CH2)n-A, wherein n is 0-4 and A is —CN, —OR2, —SR2, —N(R2)2, CO2R2, C(O)—N(R2)2, —C(O)—NR2SO2N(R2)2, NR2SO2N(R2)2, NH—C(═NR2)—N(R2)2, —S—C(═NR2)—N(R2)2, wherein each R2 is independently H or C1-C4 alkyl.
4 more elements
A carbapenem compound of the formula IV,
- or pharmaceutically acceptable salts thereof, wherein:
- R1 is H or methyl;
- P is hydrogen or hydroxyl;
- n=0-4;
- M is H or a group such that CO2M is a carboxylic acid, a carboxylate anion balanced by a counterion, a pharmaceutically acceptable ester group, or a carboxylic acid protected by a protecting group;
- and
- B is —OR2, —SR2, —CO2R2, CO—N(R2)H, —CO—NR2SO2N(R2)2, NR2SO2N(R2)2, NH—C(═NR2)—N(R2)2, —S—C(═NR2)—N(R2)2, wherein each R2 is independently H or C1-C4 alkyl.
4 more elements
A carbapenem compound of the formula V,
- or pharmaceutically acceptable salts thereof, wherein:
- R1 is hydrogen or methyl;
- P is hydrogen or hydroxyl;
- M is H or a group such that CO2M is a carboxylic acid, a carboxylate anion balanced by a counterion, a pharmaceutically acceptable ester group, or a carboxylic acid protected by a protecting group;
- Z is —O, —S, —N(R2);
- and
- each Y3and Y4 is independently hydrogen or —(CH2)n-A, wherein n=0-4 and A is selected from —N(R2)2, —CO2R2, —CO—N(R2)2, —CO—NR2SO2N(R2)2, NR2SO2N(R2)2, NH—C(═NR2)—N(R2)2, —S—C(═NR2)—N(R2)2, wherein each R2 is H or C1-C4 alkyl.
4 more elements
A method of preventing or treating an infection by a gram negative bacteria in a host comprising administering to the host a therapeutic amount of a compound of claim l, optionally in a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.