Synthetic rocaglates with broad-spectrum antiviral activities and uses thereof
AssigneesMemorial Sloan Kettering Cancer Center, Philipps-Universitat Marburg
InventorsHANS-GUIDO WENDEL, ARNOLD GRUNWELLER
Life of this patent
Estimating the term…
Abstract
Described herein are compositions, uses thereof, and methods for treating a viral infection in a host cell or organism infected by the virus, such as coronaviruses, Zika virus, Lassa virus, Crimean Congo hemorrhagic fever virus, hepatitis E virus, and other RNA viruses. Also described herein are synthetic rocaglate compositions, uses thereof, and methods for reducing or inhibiting translation initiation of a messenger ribonucleic acid (mRNA) of a virus in a host cell or organism infected by the virus.
Claims24
A method of treating a viral infection in a host cell or organism infected by a virus, the method comprising administering to the cell or organism a therapeutically effective amount of a pharmaceutical composition comprising a synthetic rocaglate composition or a pharmaceutically acceptable salt thereof, wherein the synthetic rocaglate composition comprises a compound represented by formula (I)
- wherein
- R1, R3, and R5 are each independently H, alkyl, —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2-P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2-P(O)(O-alkyl)(O-alkyl), or (CO)-alkyl, or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2-P(O)(OH)(O-alkyl), wherein at least one of R1, R3, and R5 is H, —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2-P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2-P(O)(O-alkyl)(O-alkyl), or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2-P(O)(OH)(O-alkyl);
- R2 and R4 are each independently H, alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)-alkyl, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, NH(CO)-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
- R6 is alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)-alkyl, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, NH(CO)-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
- R7 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
- R8 and R9 are each independently H, OH, alkyl, halo, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, or NH(CO)-alkyl;
- R10 is H, alkyl, (CO)-alkyl, or (CO)NRaRb;
- R11 and R12 are each independently H, OH, alkyloxy, cycloalkyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxy, or heteroaryloxy;
- Ra and Rb are each H or alkyl, or Ra and Rb, together with the nitrogen atom they are attached, form a heterocycloalkyl group;
- and
- n is an integer from 0 to 4,
- or a pharmaceutically acceptable salt thereof.
-5. (canceled)
-8. (canceled)
(canceled)
A method for reducing or inhibiting translation initiation of a messenger ribonucleic acid (mRNA) of a virus in a host cell or organism infected by the virus, the method comprising administering to the cell or organism a therapeutically effective amount of a pharmaceutical composition comprising a synthetic rocaglate composition or a pharmaceutically acceptable salt thereof, wherein the synthetic rocaglate composition comprises a compound represented by formula (I)
- wherein
- R1, R3, and R5 are each independently H, alkyl, —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2-P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2-P(O)(O-alkyl)(O-alkyl), or (CO)-alkyl, or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2-P(O)(OH)(O-alkyl), wherein at least one of R1, R3, and R5 is H, —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), —CH2-P(O)(OH)(O-alkyl), —P(O)(O-alkyl)(O-alkyl), —CH2-P(O)(O-alkyl)(O-alkyl), or a pharmaceutically acceptable salt of —P(O)(OH)(OH), —CH2-P(O)(OH)(OH), —P(O)(OH)(O-alkyl), or —CH2-P(O)(OH)(O-alkyl);
- R2 and R4 are each independently H, alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)-alkyl, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, NH(CO)-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
- R6 is alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)-alkyl, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, NH(CO)-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
- R7 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with alkyl, halo, nitro, OH, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, and NRaRb;
- R8 and R9 are each independently H, OH, alkyl, halo, O-alkyl, SH, S-alkyl, CN, haloalkyl, O-haloalkyl, NRaRb, (CO)OH, (CO)O-alkyl, SO2NRaRb, (CO)NRaRb, or NH(CO)-alkyl;
- R10 is H, alkyl, (CO)-alkyl, or (CO)NRaRb;
- R11 and R12 are each independently H, OH, alkyloxy, cycloalkyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxy, or heteroaryloxy;
- Ra and Rb are each H or alkyl, or Ra and Rb, together with the nitrogen atom they are attached, form a heterocycloalkyl group;
- and
- n is an integer from 0 to 4,
- or a pharmaceutically acceptable salt thereof.
-33. (canceled)
-59. (canceled)
Dependencies are inferred from the claim text.