Teixobactin analogue and use thereof
Pharmaceuticals, and specifically a Teixobactin analogue and use thereof. A pharmaceutical composition having the compound and use of the compound and the pharmaceutical composition thereof inhibits the growth and/or reproduction of Gram-positive bacteria or Mycobacterium tuberculosis . A compound has Formula (Ia) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
1. A compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
wherein:
R 9 is H, deuterium, C 1-6 alkyl or C 1-6 haloalkyl;
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is independently C 1-10 alkyl, hydroxy C 1-6 alkyl or H 2 NC(═O)—C 1-6 alkyl, wherein C 1-10 alkyl is unsubstituted or substituted with 1, 2 or 3 substituents, and the substituent is independently selected from deuterium, F, Cl, Br, OH, NH 2 , C 1-6 alkyl or C 2-6 alkenyl;
R 8 is —R 10 , —R 11 -L 1 -R 12 or —R 13 -L 2 -R 14 -L 3 -R 15 ;
each of L 1 , L 2 and L 3 is independently —(CH 2 ) q —, —O—, or —S—;
q is 0, 1 or 2;
each of R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is independently C 6-10 aryl or 5-10 membered heteroaryl, wherein each C 6-10 aryl and 5-10 membered heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from deuterium, F, Cl, Br, I, CN, OH, C 1-6 alkoxy, C 6-10 aryl or 5-6 membered heteroaryl;
A is —(CR a R b ) p —;
p is 1, 2, 3, 4, 5 or 6;
each R a and R b is independently H, deuterium, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, carboxy C 1-6 alkyl or 3-6 membered heterocyclyl-C 1-6 alkylene;
R is R 16 or —P 4 -L 4 -R 17 ;
P 4 is C 1-6 alkylene;
L 4 is —O—, —S—, —NR d — or —NR e C(═O)—;
each R d and R e is independently H, deuterium or C 1-6 alkyl
each of R 16 and R 17 is H, deuterium, F, Cl, Br, I, CN, OH, NH 2 , —SH, C 1-8 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl or C 6-10 aryl, wherein each C 1-8 alkyl and C 6-10 aryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R x ; and
each R x is independently deuterium, F, Cl, Br, I, OH, NH 2 , —C(═O)OH, —SH, C 1-6 alkoxy or C 1-6 alkylamino.
2. The compound of claim 1 having Formula (II) or a stereoisomer, a tautomer, an N-oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
3. The compound of claim 1 , wherein R 9 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.
4. The compound of claim 1 , wherein:
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is independently C 1-8 alkyl, hydroxy C 1-4 alkyl or H 2 NC(═O)—C 1-4 alkyl, wherein C 1-8 alkyl is unsubstituted or substituted with 1, 2 or 3 substituents, and the substituent is independently selected from deuterium, F, Cl, Br, OH, NH 2 , C 1-4 alkyl or C 2-4 alkenyl; or
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, hydroxymethyl, hydroxyethyl, H 2 NC(═O)—CH 2 —, H 2 NC(═O)—CH 2 CH 2 — or H 2 NC(═O)—(CH 2 ) 3 —, wherein each methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl is independently unsubstituted or substituted with 1, 2 or 3 substituents, and the substituent is independently selected from deuterium, F, Cl, Br, OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, vinyl or allyl.
5. The compound of claim 1 , wherein:
each of R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is independently C 6-10 aryl or 5-10 membered heteroaryl, wherein each C 6-10 aryl and 5-10 membered heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from deuterium, F, Cl, Br, I, CN, OH, C 1-4 alkoxy, C 6-10 aryl or 5-6 membered heteroaryl; or
each of R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is independently phenyl, naphthyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridyl, pyrazinyl, benzofuranyl, benzimidazolyl, benzothienyl, indolyl, purinyl, quinolinyl or isoquinolinyl, wherein each phenyl, naphthyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridyl, pyrazinyl, benzofuranyl, benzimidazolyl, benzothienyl, indolyl, purinyl, quinolinyl and isoquinolinyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from deuterium, F, Cl, Br, I, CN, OH, methoxy, ethoxy, phenyl or 5-6 membered heteroaryl.
6. The compound of claim 1 , wherein:
each of R 16 and R 17 is independently H, deuterium, F, Cl, Br, I, OH, NH 2 , —SH, C 1-6 alkyl, C 1-4 haloalkyl, or C 6-10 aryl, wherein each C 1-6 alkyl and C 6-10 aryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R x ; or
each of R 16 and R 17 is independently H, deuterium, F, Cl, Br, I, CN, OH, NH 2 , —SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, —CH═CH 2 , —CH═CHCH 3 , —CH 2 CH═CH 2 , —CH 2 F, —CF 3 , —CHF 2 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —(CH 2 ) 2 CF 3 , —(CH 2 ) 2 CHF 2 , —(CH 2 ) 2 CH 2 F or phenyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridyl or pyrazinyl; wherein each methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl and phenyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R x .
7. The compound of claim 1 , wherein each R a and R b is independently H, deuterium, F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, carboxyl C 1-4 alkyl, or 5-6 membered heterocyclyl-C 1-4 alkylene.
8. The compound of claim 1 , wherein:
each R a and R b is independently H, deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, vinyl, methoxy, ethoxy, trifluoromethyl, —CHF 2 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CH 2 CF 3 , —(CH 2 ) 2 CHF 2 , —(CH 2 ) 3 CHF 2 , hydroxymethyl, —CH 2 CH 2 OH, aminomethyl, —CH 2 CH 2 NH 2 , cyanomethyl, carboxymethyl, —(CH 2 ) 2 -morpholine or —(CH 2 ) 2 -pyrrole;
each R d and R e is independently H, deuterium, methyl, ethyl, n-propyl or isopropyl; and
P 4 is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 —, —CH 2 CH 2 CH 2 CH 2 — or —CH 2 (CH 2 ) 3 CH 2 —.
9. The compound of claim 1 , wherein:
each R x is independently deuterium, F, Cl, Br, I, OH, NH 2 , —C(═O)OH, —SH, C 1-4 alkoxy or C 1-4 alkylamino; or
each R x is independently deuterium, F, Cl, Br, I, OH, NH 2 , —C(═O)OH, —SH, methoxy, ethoxy, n-propyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy or methylamino.
10. The compound of claim 1 having one of the following structures:
or a stereoisomer, a tautomer, an N-oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
11. A pharmaceutical composition comprising:
the compound of claim 1 , and
optionally, a pharmaceutically acceptable carrier, adjuvant, vehicle, or a combination thereof.
12. The pharmaceutical composition of claim 11 , further comprising:
one or more other therapeutic agents,
wherein the other therapeutic agents are selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, antiprotozoal agents, antihelminthic agents and combinations thereof.
13. A method of managing, treating or lessening a bacterial infectious disease in a subject, the method comprising:
administering to the subject a therapeutically effective amount of the compound of claim 1 .
14. The method of claim 13 , wherein
the bacterial infection is a Gram-positive bacterial infection or a Mycobacterium tuberculosis infection; or
the bacteria is Streptococcus, Staphylococcus, Enterococcus, Corynebacterium, Listeria, Bacillus, Erysipelothrix, Actinomycetes, Helicobacter pylori, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium avium intracellulare, Staphylococcus aureus, Staphylococcus epidermidis, Neisseria gonorrhoeae, Neisseria meningitidis, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus bovis, Streptococcus pneumoniae, Haemophilus, Pseudomonas aeruginosa, Bacillus anthracis or Bacillus subtilis.
15. A method of managing, treating or lessening a bacterial infectious disease in a subject, the method comprising:
administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 11 .
16. The method of claim 15 , wherein:
the bacterial infection is a Gram-positive bacterial infection or a Mycobacterium tuberculosis infection; or
the bacteria is Streptococcus, Staphylococcus, Enterococcus, Corynebacterium, Listeria, Bacillus, Erysipelothrix, Actinomycetes, Helicobacter pylori, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium avium intracellulare, Staphylococcus aureus, Staphylococcus epidermidis, Neisseria gonorrhoeae, Neisseria meningitidis, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus bovis, Streptococcus pneumoniae, Haemophilus, Pseudomonas aeruginosa, Bacillus anthracis or Bacillus subtilis.