Polycyclic indoline and indolenine compounds
View Patent ↗The present invention relates to indoline and indolenine alkaloid compounds. In particular, indoline and indolenine alkaloid compounds of the invention have antibacterial activity and/or are capable of re-sensitizing the susceptibility of methicillin-resistant S. aureus to a β-lactam antibiotic. The present invention also relates to a method for producing and using the same.
1. A compound of the formula:
wherein
a is 0, 1 or 2;
each R 1 is independently halide;
each of R 2 , R 3 and Z 1 is independently hydrogen, alkyl or a nitrogen protecting group, provided at most only one of Z 1 or R 3 is a nitrogen protecting group; and
Z 2 is hydrogen, alkyl, a nitrogen protecting group, heteroalkyl or a carbonyl group.
2. The compound according to claim 1 , wherein a is 1 or 2.
3. The compound according to claim 1 , wherein each of R 1 is independently selected from the group consisting of hydrogen, Cl, Br, and F.
4. The compound according to claim 1 of the formula:
wherein R 2 , R 3 , Z 1 and Z 2 are those defined in claim 1 ; and each of X 1 and X 2 is independently selected from the group consisting of hydrogen, Cl, Br and F, provided at least one of X 1 and X 2 is not hydrogen.
5. The compound according to claim 4 , wherein X 2 is F.
6. The compound according to claim 4 , wherein X 1 is Cl.
7. The compound according to claim 1 , wherein Z 2 is selected from a moiety of the group consisting of: —C(═O)R a , —C(═O)[CH 2 ] 2 CCH, —C(═O)CH 2 NH-tBoc, —C(═O)CH 2 NH 2 , —C(═O)[CH 2 ] 5 NHC(═O)[CH 2 ] 2 —Y 1 , —C(═O)[CH 2 ] 3 Y 2 , —C(═O)[CH 2 ] 2 CO 2 H, —C(═O)CF 3 , —C(═O)Y 3 , -tBoc, —SO 2 —Ar 1 , —C(═O)NHY 4 , and a guanidine derivative of the formula —C(═NR x )—NR y R z where each of R x , R y and R z is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, and heteroalkyl; R a is alkyl or haloalkyl, Ar 1 is aryl or heteroaryl, Y 1 is 5,5-difluoro-7,9-dimethyl-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-3-yl, Y 2 is (3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl, Y 3 is cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, aryl, heteroaryl and Y 4 is alkyl, heterocycloalkyl or (heterocycloalkyl)alkyl.
8. The compound according to claim 7 , wherein R a is methyl, ethyl, heptyl, trifluoromethyl.
9. The compound according to claim 7 , wherein Ar 1 is selected from the group consisting of 4-chlorophenyl, 1-methyl-1H-imidazol-4-yl and 6-chloropyridin-3-yl.
10. The compound according to claim 7 , wherein Y 3 is selected from the group consisting of 4,4-difluorocyclohexyl, 4-chlorophenyl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(2,2,2-trifluoroacetyl)piperidin-4-yl, 1-(2,2,2-trifluoroacetyl)azetidin-3-yl, 6-chloropyridin-3-yl and (morpholino)methyl.
11. The compound according to claim 7 , wherein Y 4 is selected from the group consisting of methyl, tetrahydro-2H-pyran-4-yl and tetrahydrofuran-2-yl)methyl.
12. An antibiotic composition comprising a compound of claim 1 .
13. The antibiotic composition of claim 12 further comprising a β-lactam antibiotic.
14. The antibiotic composition of claim 13 further comprising a β-lactamase inhibitor or other resistance-modifying agent or a combination thereof.
15. A method for treating bacterial infection in a subject comprising administering to the subject in need of such a treatment a therapeutically effective amount of a compound of claim 1 .
16. A method for treating methicillin-resistant Staphylococci aureus infection in a subject comprising administering to the subject having a MRSA infection a therapeutically effective amount of a composition comprising a compound of claim 1 and a β-lactamase inhibitor.
17. The method of claim 16 , wherein the β-lactamase inhibitor comprises amoxicillin, clavulanic acid, cefazolin, meropenem, or a combination thereof.