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US-12616670-B2 - N-phenyl-3-mercaptopropanamide derivatives as metallo-beta-lactamase inhibitors for the treatment of bacterial infections

US12616670B2US 12616670 B2US12616670 B2US 12616670B2US-12616670-B2

Abstract

The present invention related to novel inhibitors of metallo-β-lactamases of formula (I) wherein R 1 is an optionally substituted aryl group of an optionally substituted heteroaryl group, and the use thereof in the treatment of bacterial infections, especially in combination with β-lactam antibiotics.

Inventors

  • Rolf W. Hartmann
  • Jelena Konstantinovic
  • Jörg Haupenthal
  • Anna K. Hirsch
  • Andreas M. Kany
  • Cansu Kaya
  • Samir Yahiaoui
  • Thomas Wichelhaus
  • Eugen Proschak

Assignees

  • HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH

Dates

Publication Date
20260505
Application Date
20210323
Priority Date
20200323

Claims (20)

  1. 1 . A compound of formula (I): wherein R 1 is a substituted phenyl group or a substituted heteroaryl group containing 5 or 6 ring atoms selected from C, O, N and S, wherein the substituents are independently selected from groups of formula —O—C 1-6 alkyl, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —COOH, —COOMe, —COMe, —NHSO 2 Me, —SO 2 NMe 2 , —SO 2 NCNH 2 NH 2 , —CH 2 N(CH 2 CH 3 ) 2 , —SO 2 NHCONH 2 , —SO 2 NHC(NH)NH 2 , —CH 2 N(CH 2 CH 2 ) 2 NCH 3 , —SO 3 H, —SO 2 NH 2 , —CONH 2 , —CH 2 NH 2 , —CN, —S—C 1-6 alkyl, NHAc, —SO 2 —N(CH 2 CH 2 ) 2 O, —NHCONH 2 , —SO 2 Me and cyclopropyl, or a pharmaceutically acceptable salt thereof.
  2. 2 . A compound according to claim 1 , wherein R 1 is an optionally substituted phenyl group.
  3. 3 . A compound according to claim 1 , wherein group R 1 is substituted by one, two or three substituents.
  4. 4 . A compound according to claim 1 , wherein group R 1 is substituted by one or two substituents.
  5. 5 . A compound selected from the following compounds, or a salt thereof: wherein R 2 is —COOH, —NHSO 2 Me, —OH or —COOMe; R 3 is —OH, —COOH, —NHSO 2 Me, —CH 2 NH 2 , —NO 2 , —SO 3 H or —CH 2 N(CH 2 CH 3 ) 2 ; and R 4 is —OH, —NH 2 , —COOH, —COOMe, —COMe, —SO 2 NMe 2 , —SO 2 —N(CH 2 CH 2 ) 2 O, —SO 2 NHCONH 2 , —SO 2 NHC(NH)NH 2 or —CH 2 N(CH 2 CH 2 ) 2 NCH 3 .
  6. 6 . A pharmaceutical composition comprising a compound according to claim 1 and optionally one or more carrier substances and/or one or more adjuvants.
  7. 7 . The pharmaceutical composition according to claim 6 , further comprising a β-lactam antibiotic.
  8. 8 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a β-lactam antibiotic.
  9. 9 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a pharmaceutical composition according to claim 6 , and a β-lactam antibiotic.
  10. 10 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a pharmaceutical composition according to claim 7 .
  11. 11 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a β-lactam antibiotic: wherein R 1 is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, O, N and S, wherein the optional substituents are independently selected from fluorine, chlorine, bromine and iodine and groups of formula —OH, —O—C 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —COOH, —COOMe, —COMe, —NHSO 2 Me, —SO 2 NMe 2 , —SO 2 NCNH 2 NH 2 , —CH 2 N(CH 2 CH 3 ) 2 , —SO 2 NHCONH 2 , —SO 2 NHC(NH)NH 2 , —CH 2 N(CH 2 CH 2 ) 2 NCH 3 , —SO 3 H, —SO 2 NH 2 , —CONH 2 , —CH 2 NH 2 , —CN, —C 1-6 alkyl, —SH, —S—C 1-6 alkyl, NHAc, —SO 2 —N(CH 2 CH 2 ) 2 O, —NO 2 , —C≡CH, —NHCONH 2 , —SO 2 Me and cyclopropyl.
  12. 12 . The method according to claim 11 , wherein R 1 is an optionally substituted phenyl group.
  13. 13 . The method according to claim 11 , wherein group R 1 is substituted by one, two or three substituents.
  14. 14 . The method according to claim 11 , wherein group R 1 is substituted by one or two substituents.
  15. 15 . The method according to claim 11 , wherein the optional substituents are independently selected from Cl, —OH, —NH 2 , —COOH, —COOMe, —COMe, —NHSO 2 Me, —SO 2 NMe 2 , —CH 2 NH 2 , —NO 2 , —SO 2 —N(CH 2 CH 2 ) 2 O, —SO 3 H, —CH 2 N(CH 2 CH 3 ) 2 , —SO 2 NHCONH 2 , —SO 2 NHC(NH)NH 2 , —CH 2 N(CH 2 CH 2 ) 2 NCH 3 and —SO 2 NCNH 2 NH 2 .
  16. 16 . A pharmaceutical composition comprising a compound according to claim 5 and optionally one or more carrier substances and/or one or more adjuvants.
  17. 17 . The pharmaceutical composition according to claim 16 , further comprising a β-lactam antibiotic.
  18. 18 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 5 , or a pharmaceutically acceptable salt thereof, in combination with β-lactam antibiotic.
  19. 19 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a pharmaceutical composition according to claim 16 , and a β-lactam antibiotic.
  20. 20 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a pharmaceutical composition according to claim 17 .

Description

This application is a National Stage Application pursuant to 35 U.S.C. § 371, of United States International Application No. PCT/EP2021/057461, filed Mar. 23, 2021, which claims priority to European Patent Application No. 20164855.7, filed Mar. 23, 2020. The entire contents of which are incorporated herein by reference in their entirety. The present invention relates to novel N-aryl mercaptopropionamides and the use thereof as inhibitors of metallo-β-lactamases. In combination with β-lactam antibiotics, these compounds are useful in the treatment of infections, especially due to antibiotic-resistant bacteria. Antibiotic resistance is a severely intensifying threat to human health, as it leads to diseases that are extremely difficult to cure. Over the years, many bacteria have established various ways of resistance including the secretion of beta-lactamases, which are enzymes able to hydrolyze the β-lactam ring of highly effective antibiotics such as penicillins, cephalosporins, carbapenems and monobactams (Proschak, E. et al, (2015) J. Med. Chem. 58, 3626-3630). The affected bacteria include important pathogens such as Pseudomonas aeruginosa and Enterobacterales (e.g. Escherichia coli). Since their first discovery, β-lactam antibiotics are still the most used antibacterial drugs, especially for infections caused by these bacteria. However, their efficacy is threatened by above-mentioned beta-lactamases. The two most significant categories of beta-lactamases are based on their catalytic mechanism. Class A, C and D contain serine beta-lactamases (SBLs) which cleave the β-lactam ring by a nucleophilic attack of the serine residue, whereas class B contains metallo-beta-lactamases (MBLs) bearing one or two zinc cations in the active site and hydrolyze the active center of β-lactam antibiotics by a nucleophilic water molecule (Bush, K., Bradford, P. A. (2019). Nat. Rev. Microbiol. 17, 459-460). Beta-lactamases belonging to class B are further divided into B1, B2 and B3 based on their sequence identity. B1 MBLs contain the largest number of clinically relevant members, including VIMs (Verona integrin-encoded MBLs), IMPs (Imipenemase) and NDMs (New Delhi MBLs) (Mojica, M. F., Bonomo, R. A., & Fast, W. (2016). Current drug targets, 17, 1029-1050). There are many variants of each of these members, since the selective pressure continues to initiate the evolution of resistance. Some of the common features they share are low sequence identity, exhibition of a similar protein fold, and having a broad substrate profile. IMP enzymes are the first isolated member of MBLs. Up to today, more than 47 variants of IMP-1 have been identified, which are mostly encoded by P. aeruginosa. IMP-7 showed high resistance to late-generation carbapenems meropenem and imipenem (Navaratnam, P. et al, (2002). Antimicrobial agents and chemotherapy, 46, 3286-3287). VIM-type MBLs constitute the second major subgroup after IMPs, which has first been isolated from P. aeruginosa. The initial biochemical characterization of VIM-1 showed that it exhibits a broad substrate specificity including all β-lactam antibiotics except monobactams (Docquier J-D. et al, (2000). Antimicrob Agents Chemother, 44, 3003-3007). NDM type MBLs form the third main type with more than 15 variants. It has spread to nearly every continent worldwide and has become a tremendous threat to the world (McKenna M. (2013). Nature, 499, 394-396). Although it has been known for a shorter time than the other two, the crystal structure of NDM-1 was reported in 2011 (Rao, Z. et. al, (2011). Prot Cell. 2, 384-94). The structure displays two catalytic zinc ions bound as dinuclear center in the active site and it provided considerable insight into ligand recognition by NDM-1. Given that the pipeline of new antibiotics is virtually empty, an alternative way to treat infections caused by multi-drug resistant pathogens is through design of novel beta-lactamase inhibitors. These inhibitors usually have no intrinsic antibacterial activity but restore the activity of currently used β-lactam antibiotics by inhibiting beta-lactamases. There are numerous SBL inhibitors in clinical use, whereas class B1 MBL inhibitors remain challenging to progress further. The fact that MBLs can hydrolyze almost all β-lactam antibiotics, including carbapenem, is the main drawback for the development of new structures. Moreover, it is difficult to make a generalization based on the active site, as there is a high sequence variation within this subfamily and the β-lactam substrates are quite diverse. Even though many potent inhibitors were reported in literature, their effect is usually restricted to only one of the MBL types within the sub-class. However, it is advantageous to have broad-spectrum inhibitors that are active against most of the relevant members belonging to this class. The beta-lactamases found in Gram-positive organisms are often extracellular enzymes. However, in Gram-negative organisms, beta-lactam