Hydrogen sulfide precursors and conjugates thereof
The present invention provides methods of forming hydrogen sulfide. The methods include contacting a precursor compound with an unmasking agent; wherein the precursor compound comprises a hydrogen sulfide releasing moiety and a masked nucleophile; and wherein the contacting is conducted under conditions sufficient for cyclization of the precursor compound via lactone or lactam formation; thereby releasing hydrogen sulfide from the precursor compound. Hydrogen sulfide precursor compounds according to Formula I are also described, as well as methods for treating diseases and conditions using hydrogen sulfide precursors.
1. A compound according to Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
subscripts a and b are each 1;
each subscript c is 0;
L 1 and L 2 are each a bond;
R 1 and R 2 are taken together to form C 6 -C 10 aryl, which is optionally substituted with 1-3 R 4 ;
each R 4 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 aminoalkyl, C 1 -C 6 aminoalkoxy, C 3 -C 6 cycloalkyl;
R 3 is O;
W is O;
Y is a bond and R 10 is H, or
Y is —S— and R 10 is selected from the group consisting of C 1 -C 6 alkyl and (C 6 -C 10 aryl)-(C 1 -C 6 alkyl), wherein C 1 -C 6 alkyl and (C 6 -C 10 aryl)-(C 1 -C 6 alkyl) are optionally substituted with 1-5 R 10a , or wherein C 1 -C 6 alkyl and (C 6 -C 10 aryl)-(C 1 -C 6 alkyl) optionally substituted with —OR′ wherein R′ is C 1-6 alkyl;
Z is selected from the group consisting of —C(═O)R 6 , —C(═O)OR 6 , —(CH 2 ) x OR 6 , —(CH 2 ) x (C(═O)OR 6 , —(CH 2 ) x OC(═O)R 6 , —(CH 2 ) x OP(═O)(OR 6 ) x , —OP(═O)(OR 6 ) x , —P(═O)(OR 6 ) x , and R 7 , wherein each subscript x is independently 0, 1, 2, 3, or 4;
each R 8 is independently selected from the group consisting of H and C 1 -C 6 alkyl,
each R 9 is independently C 1 -C 6 alkyl,
wherein one R 8 is optionally taken together with one R 9 to form a double bond;
each R 10a is independently selected from the group consisting of C 1 -C 6 alkyl, —C(═O)OR 5 , —NR 5 C(═O)OR 5 , and a moiety —W—Z;
each R 5 is independently selected from the group consisting of H and C 1 -C 4 alkyl;
each R 6 is independently selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, and C 3 -C 4 cycloalkyl; and
R 7 is a monosaccharide or a non-steroidal anti-inflammatory drug, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, naproxen, sulindac, aceclofenac, salicylates, indomethacin, flurbiprofen, diclofenac, ketorolac, etodolac, fenoprofen, flufenamic acid, ketoprofen, mefenamic acid, diflunisal, tolmetin, ketorolac, aspirin, and lumiracoxib.
2. The compound of claim 1 , wherein Z is selected from the group consisting of —C(═O)R 6 , —C(═O)OR 6 , —(CH 2 ) x OR 6 , —(CH 2 ) x C(═O)OR 6 , —(CH 2 ) x OC(═O)R 6 , —(CH 2 ) x OP(═O)(OR 6 ) x , —OP(═O)(OR 6 ) x , and —P(═O)(OR 6 ) x , wherein each subscript x is independently 0, 1, 2, 3, or 4.
3. The compound of claim 1 , wherein:
Z is —C(═O)R 6 and R 6 is C 1 -C 4 alkyl; or
wherein Z is R 7 and R 7 is the non-steroidal anti-inflammatory drug.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure according to Formula Ia:
wherein:
subscript d is 0, 1, or 2.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure according to Formula Ib:
wherein subscripts d and e are independently 0, 1, or 2; and
each R 10a is independently selected from the group consisting of C 1 -C 6 alkyl, —C(═O)OR 5 , and —NR 5 C(═O)OR 5 .
6. The compound of claim 1 , which is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
7. The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound according claim 1 and a pharmaceutically acceptable excipient.