Deuterated protease inhibitors
Compounds and treatment methods with compounds exhibiting antiviral activity and/or inhibition of viral replication against viruses, particularly those belonging to the picornavirus-like supercluster, including coronavirus having a formula: or a prodrug or pharmaceutically-acceptable salt thereof, where: each X comprises at least one cyclic moiety directly attached to the oxygen or connected via an alkyl linkage, where at least one of the linkage and/or the X moiety comprises a deuterium substitution; and Z is selected from the group consisting of aldehydes and bisulfite salts, or the ester or carbamate prodrugs thereof.
1. A deuterated compound having the structure of formula I, or a prodrug or pharmaceutically-acceptable salt thereof:
where:
each X is at least one cyclic moiety directly attached to the oxygen or connected via an alkyl linkage, where at least one of the linkage and/or the cyclic moiety comprises a deuterium substitution; and
Z is selected from the group consisting of aldehydes and bisulfite salts, or the ester or carbamate prodrugs thereof.
2. The compound, salt, or prodrug of claim 1 , wherein Z is —CHO, —SO 3 Na, —CH(OH)SO 3 − Na + , —(C═O)(C═O)NHbenzyl, or —CH [O(C═O)R w ]SO 3 − Na + , where R w is an alkyl or arylalkyl.
3. The compound, salt, or prodrug of claim 1 , wherein said compound is a prodrug wherein Z comprises an ester or carbamate moiety.
4. The compound, salt, or prodrug of claim 1 , wherein X is a substituted or unsubstituted C 3 -C 10 cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, or a substituted or unsubstituted C 6-10 aryl group.
5. The compound, salt, or prodrug of claim 1 , wherein said alkyl linkage comprises a branched or unbranched and substituted or unsubstituted C 1 -C 6 alkyl linkage.
6. The compound, salt, or prodrug of claim 1 , wherein X—O has a structure selected from the group consisting of:
7. The compound, salt, or prodrug of claim 1 , having the structure of formula:
or a prodrug or pharmaceutically-acceptable salt thereof, where each of R a and R b , independently, is hydrogen or deuterium, provided that at least one of R a or R b is a deuterium atom, optionally wherein at least one R a is a halogen.
8. The compound, salt, or prodrug of claim 7 , wherein at least one R a is a halogen.
9. The compound, salt, or prodrug of claim 7 , wherein each of said R a and R b groups are deuterium.
10. The compound, salt, or prodrug of claim 1 , said compound comprising a deuterated formula selected from the group consisting of:
11. The compound, salt or prodrug of claim 1 , wherein said compound is a deuterated formula from Table 2:
TABLE 2
Compound
Z
X
1 2 3 4 5
CHO CH(OH)SO 3 Na CH(O(C═O)CH 3 )SO 3 Na CH(O(C═O)n-pentyl)SO 3 Na (C═O)(C═O)NHbenzyl
6 7 8
CHO CH(OH)SO 3 Na CH(O(C═O)n-pentyl)SO 3 Na
9 10 11
CHO CH(OH)SO 3 Na CH(O(C═O)n-pentyl)SO 3 Na
12. A kit comprising a compound, salt, or prodrug according to claim 1 ; and instructions for administering said compound to a subject in need thereof.
13. The kit of claim 12 , wherein the compound, salt, or prodrug is provided in unit dosage form.
14. The kit of claim 12 , wherein the compound, salt, or prodrug is provided in a first container, said kit further comprising a carrier in a second container; and instructions for preparing said compound, salt, or prodrug for administration to said subject.