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EP-4741399-A1 - LINCOSAMIDE ANTIBIOTICS AND USES THEREOF

EP4741399A1EP 4741399 A1EP4741399 A1EP 4741399A1EP-4741399-A1

Abstract

Provided are lincosamide compounds for the treatment of infectious diseases. The lincosamides described herein are modified at the amino acid (southern) region. The lincosamides may have further modification at the C-1 and C-7 positions of the aminooctose (northern) region, thus distinguishing them from lincomycin and clindamycin. Also provided are methods for preparing the lincosamide compounds, pharmaceutical compositions comprising the lincosamide compounds, and methods of treating infectious diseases using the disclosed lincosamide compounds.

Inventors

  • MYERS, ANDREW, G.
  • MITCHELTREE, Matthew James
  • SILVESTRE, KATHERINE J.

Assignees

  • President And Fellows Of Harvard College

Dates

Publication Date
20260513
Application Date
20180810

Claims (15)

  1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: P is independently hydrogen or a protecting group; A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; B is a carbocyclyl or heterocyclyl ring; R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A , -N(R A ) 2 , or -SR A ; preferably, R 1 is -SR A , -SCH 3 , R 7 is hydrogen or unsubstituted alkyl; or A and R 7 are joined to form a substituted or unsubstituted heterocyclic ring; R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, - C(=NR A )R A , -C(=NR A )OR A , -C(=NR A )N(R A ) 2 , -C(=O)R A , -C(=O)OR A , -C(=O)N(R A ) 2 , - S(O) 2 R A , or a nitrogen protecting group; preferably, R 8 is hydrogen or methyl; each occurrence of R 9 is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A , -N(R A ) 2 , -SR A , -CN, -SCN, -C(=NR A )R A , -C(=NR A )OR A , - C(=NR A )N(R A ) 2 , -C(=O)R A , -C(=O)OR A , -C(=O)N(R A ) 2 , -NO 2 , -NR A C(=O)R A , - NR A C(=O)OR A , -NR A C(=O)N(R A ) 2 , -NR A C(=NR A )N(R A ) 2 , -OC(=O)R A , -OC(=O)OR A , - OC(=O)N(R A ) 2 , -NR A S(O) 2 R A , -OS(O) 2 R A , or -S(O) 2 R A ; or two R 9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; p is 0-4; and each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; preferably, each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted hetaralkyl, -C(=NR A )N(R A ) 2 , -C(=O)OR A , or -C(=O)N(R A ) 2 .
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, R 2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, -OR A , -N 3 , -N(R A ) 2 , -SR A , -CN, - SCN, -C(=NR A )R A , -C(=NR A )OR A , -C(=NR A )N(R A ) 2 , -C(=O)R A , -C(=O)OR A , - C(=O)N(R A ) 2 , -NO 2 , -NR A C(=O)R A , -NR A C(=O)OR A , -NR A C(=O)N(R A ) 2 , - NR A C(=NR A )N(R A ) 2 , -OC(=O)R A , -OC(=O)OR A ,-OC(=O)N(R A ) 2 , -NR A S(O) 2 R A , - OS(O) 2 R A , or -S(O) 2 R A ; R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic; R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic; R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic; and R 6a , R 6b , and R 6c are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, or substituted or unsubstituted acyl; preferably, A is of the formula:
  3. The compound of claim 1, wherein the compound is of Formula (I-a): or wherein the compound is of Formula (I-b): wherein: X is O, S, NR 9 or C(R 9 ) 2 ; Y is O, S, NR 9 , C(R 9 ) 2 , CR 9 , CH 2 , or CH; n is 0 or 1; and = represents a single or double bond; wherein preferably: Y is C(R 9 ) 2 , CR 9 , CHR 9 , CH 2 , or CH; or wherein the compound is of Formula (I-c): wherein preferably: Y is C(R 9 ) 2 , CR 9 , CHR 9 , CH 2 , or CH; or wherein the compound is of Formula (I-d): wherein preferably: Y is C(R 9 ) 2 , CR 9 , CHR 9 , CH 2 , or CH; or wherein the compound is of Formula (I-e): wherein p is 0-2. wherein preferably: Y is C(R 9 ) 2 , CR 9 , CHR 9 , CH 2 , or CH; or wherein the compound is of Formula (I-f): or wherein the compound is of Formula (I-g): or wherein the compound is of Formula (I-h): or wherein the compound is of Formula (I-i): or wherein the compound is of Formula (I-j): wherein p is 0-2; wherein preferably: Y is C(R 9 ) 2 , CR 9 , CHR 9 , CH 2 , or CH; or wherein the compound is of Formula (I-k): or wherein the compound is of Formula (I-1): or wherein the compound is of Formula (I-m): or a pharmaceutically acceptable salt thereof; wherein preferably, n is 1.
  4. The compound of claim 2, wherein the compound is of Formula (I-n): or a pharmaceutically acceptable salt thereof, wherein: X is O, S, NR 9 or C(R 9 ) 2 ; Y is O, S, NR 9 , C(R 9 ) 2 , CR 9 , CHR 9 , CH 2 , or CH; n is 0 or 1; and - - - represents a single or double bond; or wherein the compound is of Formula (I-o): or wherein the compound is of Formula (I-p): or wherein the compound is of Formula (I-q): or wherein the compound is of Formula (I-r): wherein: R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, -OR A , -N 3 , -N(R A ) 2 , -SR A , -CN, -SCN, -C(=NR A )R A , -C(=NR A )OR A , - C(=NR A )N(R A ) 2 , -C(=O)R A , -C(=O)OR A , -C(=O)N(R A ) 2 , -NO 2 , -NR A C(=O)R A , - NR A C(=O)OR A , -NR A C(=O)N(R A ) 2 , -NR A C(=NR A )N(R A ) 2 , -OC(=O)R A , -OC(=O)OR A ,-OC(=O)N(R A ) 2 , -NR A S(O) 2 R A , -OS(O) 2 R A , or -S(O) 2 R A , or R 1a and R 1b are joined to form a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted carbocyclic ring; preferably, R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, -OR A , -OS(O) 2 R A , -N 3 , -N(R A ) 2 , or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; or wherein the compound is of Formula (I-s): wherein: R A is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted hetaralkyl; or wherein the compound is of Formula (I-t): or wherein the compound is of Formula (I-u): or wherein the compound is of Formula (I-v): or a pharmaceutically acceptable salt thereof; wherein preferably, n is 1.
  5. The compound of any of claims 2-4, or a pharmaceutically acceptable salt thereof, wherein: Y is NR 9 , C(R 9 ) 2 , CR 9 , CHR 9 , CH 2 , or CH.
  6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: FSA-24039 FSA-24041 FSA-22091 FSA-24040 FSA-24035 FSA-24036 FSA-27049 FSA-212034 FSA-213061 FSA-213064 FSA-214009a FSA-214009b FSA-211030 FSA-211064 FSA-501076 FSA-501099 FSA-504059 FSA-504062 FSA-507051 FSA-507007 FSA-507041 FSA-507031 FSA-507056 FSA-511019 FSA-511020 FSA-511071 FSA-511072 FSA-511073 FSA-511074 FSA-507052 FSA-507057 FSA-507053 FSA-507060 FSA-509019 FSA-507061 FSA-511044 FSA-511045 FSA-511046 FSA-511077 FSA-511078 FSA-511080 FSA-510001 FSA-510002 FSA-510003 FSA-510006 FSA-510011 FSA-510012 FSA-511033 FSA-510021 FSA-510022 FSA-510065 FSA-510072 FSA-510073 FSA-503001 FSA-503002 FSA-503003 FSA-503004 FSA-503073 FSA-502002 FSA-504049 FSA-504050 FSA-504063 FSA-504057 FSA-511100 FSA-512011 FSA-512012 FSA-512075 FSA-512076 FSA-512077 FSA-512079b FSA-512079c FSA-512080b FSA-512080c FSA-512081a or FSA-512081b .
  7. A pharmaceutical composition comprising a compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  8. A kit comprising a compound of any of claims 1-6, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 7, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.
  9. A compound of any of claims 1-6, or a pharmaceutical composition of claim 7 for use in a method of treating an infectious disease comprising administering an effective amount of a compound of any of claims 1-6, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 7, to a subject in need thereof; wherein preferably the infectious disease is a bacterial infection or a parasitic infection.
  10. The compound or pharmaceutical composition of of claim 9, wherein the bacterial infection is an infection caused by a Gram positive bacteria or by a Gram negative bacteria; preferably wherein the bacterial infection is a Staphylococcus infection, a Streptococcus infection, an Enterococcus infection, an Acetinobacter infection, a Clostridium infection, a Bacterioides infection, an Escherichia infection, a Pseudomonas infection, a Klebsiella infection, a Haemophilus infection, a C. difficile infection or a B. fragilis infection.
  11. A method of killing or inhibiting the growth of a microorganism comprising contacting the microorganism in vitro with an effective amount of a compound of any of claims 1-6, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 7, to a subject in need thereof.
  12. A method of preparing a compound of Formula (I): or a salt thereof, the method comprising coupling a compound of Formula (A): or salt thereof, with a compound of Formula (B), to yield a compound of Formula (I), wherein A, P, B, R 1 , R 7 , R 8 , R 9 , and p are as defined in claim 1.
  13. The method of claim 12, further comprising adding an amide coupling reagent; preferably, the amide coupling reagent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), or a combination thereof.
  14. A compound of Formula (C): or salt thereof, wherein: Y is O, S, NR 9 , C(R 9 ) 2 , CR 9 , CH 2 , or CH; R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, - C(=NR A )R A , -C(=NR A )OR A , -C(=NR A )N(R A ) 2 , -C(=O)R A , -C(=O)OR A , -C(=O)N(R A ) 2 , - S(O) 2 R A , or a protecting group; each occurrence of R 9 is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A , -N(R A ) 2 , -SR A , -CN, -SCN, -C(=NR A )R A , -C(=NR A )OR A , - C(=NR A )N(R A ) 2 , -C(=O)R A , -C(=O)OR A , -C(=O)N(R A ) 2 , -NO 2 , -NR A C(=O)R A , - NR A C(=O)OR A , -NR A C(=O)N(R A ) 2 , -NR A C(=NR A )N(R A ) 2 , -OC(=O)R A , -OC(=O)OR A , - OC(=O)N(R A ) 2 , -NR A S(O) 2 R A , -OS(O) 2 R A , or -S(O) 2 R A ; or two R 9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; p is 0-3; n is 0 or 1; - - - represents a single or double bond; and each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.
  15. A method of preparing a compound of Formula (C-4): or a salt thereof, the method comprising ring closing metathesis of a compound of Formula (D): or salt thereof, wherein R 8 , R 9 , R 11 , p, and n are as defined in claim 13; and R B is hydrogen or methyl; preferably, the method further comprises allylation of a compound of Formula (E): or salt thereof, to provide the compound of Formula (D).

Description

RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Applications, U.S.S.N. 62/543,808, filed August 10, 2017; U.S.S.N. 62/557,893, filed September 13, 2017; U.S.S.N. 62/558,143, filed September 13, 2017; U.S.S.N. 62/568,657, filed October 5, 2017; U.S.S.N. 62/585,271, filed November 13, 2017; and U.S.S.N. 62/650,822, filed March 30, 2018. The entire content of each is incorporated herein by reference. BACKGROUND Emerging resistance to existing antibiotics is rapidly developing as a crisis of global proportions, especially for infections originating from drug-resistant Gram-negative bacteria. Pathogenic bacteria can transmit genes coding for antibiotic resistance both vertically (to their progeny) and horizontally (to neighboring bacteria of different lineages), and as a result antibiotic resistance can evolve quickly, particularly in nosocomial (hospital) settings. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. More than 99,000 people die annually in the U.S. from healthcare-associated infections, more than all casualties from car accidents, HIV, and breast cancer combined, creating an estimated burden of up to $45 billion in U.S. healthcare costs. See, e.g., Klevens et al., Public Health Rep (2007) 122:160-166. The current crisis is exacerbated by decreased research in the development of new antibiotics by most major pharmaceutical companies. See, e.g., Projan, Curr. Opin. Microbiol. (2003) 6:427-430. The current rate of introduction of new antibiotics does not adequately address growing resistance, and with the ease of international travel and increasing population densities, the need for innovation in the field has never been higher. The lincosamides are a class of antibiotics that prevent bacteria growth by interfering with the synthesis of proteins. They bind to the 23s portion of the 50S subunit of bacterial ribosomes and cause premature dissociation of the peptidyl-tRNA from the ribosome. Lincosamides do not interfere with protein synthesis in human cells (or those of other eukaryotes) because human ribosomes are structurally different from those of bacteria. The first lincosamide to be discovered was lincomycin, but the use of lincomycin as an antibiotic has been largely superseded by clindamycin, which exhibits improved antibacterial activity. Clindamycin also exhibits some activity against parasitic protozoa and has been used to treat toxoplasmosis and malaria. Lincosamides are typically used to treat Staphylococcus and Streptococcus infections but have also proved to be useful in treating Bacteroides fragilis and other anaerobic infections. They are used in the treatment of toxic shock syndrome and thought to directly block the M protein production that leads to the severe inflammatory response. Target bacteria may alter the drug's binding site leading to resistance (similar to resistance found with macrolides and streptogramins). The resistance mechanism is methylation of the 23s binding site. If this occurs, then the bacteria are resistant to both macrolides and lincosamides. In rare instances, enzymatic inactivation of clindamycin has also been reported. In addition, lincosamide antibiotics are associated with pseudomembranous colitis caused by Clostridium difficile (C. difficile). Pseudomembranous colitis is inflammation of the colon associated with an overgrowth of C. difficile. This overgrowth of C. difficile is most often related to recent lincosamide antibiotic use. For example, clindamycin, currently the only lincosamide in clinical use, carries a black-box warning for its tendency to promote C. difficile-associated diarrhea (CDAD). Accordingly, the discovery and development of new antibiotics effective against drug-resistant bacteria, particularly lincosamides, represents a currently unmet medical need. SUMMARY A powerful synthetic platform for the discovery of new synthetic lincosamide antibiotics is disclosed herein. This platform enables the production of lincosamides bearing unprecedented modifications to both constituent halves of the lincosamides, namely the aminooctose (northern) and amino-acid (southern) portions. Lincosamides generated using this platform demonstrate potent activity against high-priority, clinically relevant pathogens including clindamycin- and azithromycin-resistant strains of S. aureus, S. pneumoniae, and E. faecalis-strains against which effective new antibiotics are in demand. Moreover, the disclosed lincosamides show potential promise as safer alternatives to clindamycin, owing to a diminished negative impact on commensal gut flora due to increased activity against C. difficile. The disclosed synthetic lincosamides also demonstrate activity against Gram-negative pathogens like E. coli. In one aspect, the present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein: P is independently hydrogen or a protecting group;A is substituted or unsubstituted carbocy