Mitochondria-targeted dicarbonyl sequestering compounds

1. A compound of Formula 1:

A-L-B   Formula 1

or a pharmaceutically acceptable salt thereof, wherein:

A is a dicarbonyl sequestering moiety that is a substituted aryl group selected from substituted phenyl, biphenyl and naphthalenyl; or a substituted heteroaryl group selected from substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, chromanyl, 2-phenylchromanyl, 3-phenylchromanyl, 4-phenylchromanyl, chromen-4-onyl, 2-phenylchromen-4-onyl, 3-phenylchromen-4-onyl, coumarinyl, 3-phenylcoumarinyl, 4-phenylcoumarinyl and 1,8-bis[2-chromanyl]-6-benzo[7]annuleonyl;

wherein the substituted aryl group, or the substituted heteroaryl group comprises two or more substituent groups independently selected from —NH 2 , —NHR 1 , —NR 1 R 1 , — 1 X—NH 2 , — 1 X—NHR 1 , —O—NH 2 , —O—NHR 1 , — 1 X—O—NH 2 , — 1 X—O—NHR 1 , —NR′—NHR′, — 1 X—NR′—NHR′, and —NHC(O)R 1 ;

and

wherein the substituted aryl group, or the substituted heteroaryl group may optionally comprise one or more optional substituent groups selected from

—C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, -halogen, — 1 X—OH, — 1 X—O—R 1 , —CO 2 H, — 1 X—CO 2 H, —CO 2 R 1 , — 1 X—CO 2 R 1 , — 1 X—O—C(O)—R 1 , —CH(OH)—C(O)—R 1 , —CO 2 H, — 1 X—CH(OH)—C(O)—R 1 , —CHO, —C(O)—R 1 , —C(O)NH 2 , —C(O)NHR 1 , —SO 2 NH 2 and —SO 2 NHR 1 ; and

wherein

each R 1 is independently selected from —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl and Formula 2:

wherein each group R 2 -R 4 is independently selected from —H, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, -halogen, —OH, — 1 X—OH, —O—C 1-6 alkyl, — 1 X—O—C 1-6 alkyl, —NR′R′, — 1 X—NR′R′, — 1 X—NH—C 1-6 alkyl, —O—NH 2 , —O—NH—C 1-6 alkyl, — 1 X—O—NH 2 , — 1 X—O—NH—C 1-6 alkyl, —NR′—NHR′, — 1 X—NR′—NHR′, —NHC(O)—C 1-6 alkyl, —O—C(O)—C 1-6 alkyl, —CO 2 H, — 1 X—CO 2 H, —CO 2 C 1-6 alkyl, — 1 X—CO 2 C 1-6 alkyl, — 1 X—O—C(O)—C 1-6 alkyl, —CH(OH)—C(O)—C 1-6 alkyl, —CHO, —C(O)—C 1-6 alkyl, — 1 X—CH(OH)—C(O)—C 1-6 alkyl, —C(O)NH 2 , —C(O)NH C 1-6 alkyl, —SO 2 NH 2 and —SO 2 NH C 1-6 alkyl;

each R′ is independently selected from —H and —C 1-6 alkyl; and

each 1 X is independently selected from C 1-6 alkylene, C 2-6 alkenylene and C 2-6 alkynylene;

L is a linker moiety of Formula 6:

—(Z 1 ) m —X 1 —(Z 2 ) t —   Formula 6

 wherein:

Z 1 and Z 2 are independently selected from O, NR 12 , NR 12 -C(O), C(O)NR 12 , O—C(O), C(O)—O and S;

X 1 is selected from C 1 -C p alkylene, C 2 -C p alkenylene, C 2 -C p alkynylene and C 3 -C p cycloalkylene;

each of m and t is independently selected from 0 or 1;

wherein p=30 and wherein X 1 is optionally substituted with one or more functional groups independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfonyl, alkylsulfonyl, carboxyalkyl, cyano, oxy, amino, alkylamino, aminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl; and

B is a mitochondrial targeting moiety that is a lipophilic cation selected from:

(i) a quaternary phosphonium cation;

(ii) a 1,4a,8-triaza-2,3,4,5,6,7-hexahydro-1H-napthalene compound; and

(iii) a Rhodamine compound of Formula 13:

wherein R 22 , R 23 and R 24 are independently selected from —H and —C 1 -C 6 alkyl;

R 26 and R 27 are independently selected from —H or —CH 3 ;

R 28 is selected from —CO 2 R 29 , —O—C(O)—R 29 , —C(O)—NHR 29 and —NH—C(O)—R 29 ; and

one of R 25 and R 29 is a bond to the linker L and the other of R 25 and R 28 is selected from —H and —C 1 -C 6 alkyl.

2. A compound of Formula 1 or pharmaceutically acceptable salt thereof according to claim 1 , wherein A is a substituted aryl group of Formula 3:

wherein two or more of R 7 -R 11 are independently selected from —NH 2 , —NHR 1 , —NR 1 R 1 , —C 1-6 alkylene-NH 2 , —C 1-6 alkylene-NHR 1 , —O—NH 2 , —O—NHR 1 , —C 1-6 alkylene-O—NH 2 , —C 1-6 alkylene-O—NHR 1 , —NHCOR1, —NR′—NHR′ and —C 1-6 alkylene —NR′—NHR′; and

the remaining groups R 7 -R 11 are independently selected from —H, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, -halogen, —C 1-6 alkylene-OH, —C 1-6 alkylene-O—R 1 , —CO 2 H, —C 1-6 alkylene-CO 2 H, —CO 2 R 1 , —C 1-6 alkylene-CO 2 R 1 , —C 1-6 alkylene-O—C(O)—R 1 , —CH(OH)—C(O)—R 1 , —C 1-6 alkylene-CH(OH)—C(O)—R 1 , —CHO, —C(O)—R 1 , —C(O)NH 2 , —C(O)NHR 1 , —SO 2 NH 2 and —SO 2 NHR 1 .

3. A compound of Formula 1 or pharmaceutically acceptable salt thereof according to claim 1 , wherein B is a mitochondrial targeting moiety of Formula 10:

wherein:

D is phosphorous; and

each of R 15 , R 16 and R 17 is independently selected from substituted or unsubstituted alkyl, benzyl, aryl and heteroaryl.

4. A compound of Formula 1 or pharmaceutically acceptable salt thereof according to claim 1 , wherein B is a triphenylphosphonium cation.

5. A compound of Formula 1 or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is:

wherein An − represents an optional pharmaceutically acceptable anion.

6. A compound of Formula 1 or pharmaceutically acceptable salt thereof according to claim 2 , wherein R 7 =—H, R 10 =—H, and R 11 =—H, and R 8 and R 9 are independently selected from —OH, —OR 1 , —NH 2 , —NHR 1 , —C 1-6 alkylene-NH2, —C 1-6 alkylene-NHR 1 , —O—NH 2 , —O—NHR 2 , —C 1-6 alkylene-O—NH 2 , —C 1-6 alkylene-O—NHR 1 , —NHCOR 1 and —O—C(O)—R 1 .

7. A compound of Formula 1 or pharmaceutically acceptable salt thereof according to claim 1 , wherein -L- is a linker moiety of Formula 7:

—(Z 1 ) m (C 1 -C p ) alkylene-   Formula 7.

8. A compound Formula 1 or pharmaceutically acceptable salt thereof according to claim 3 , wherein the compound is a salt of Formula 15:

wherein:

each of R 15 , R 16 and R 17 is independently selected from substituted or unsubstituted alkyl, benzyl, aryl and heteroaryl; and

the compound optionally further includes a pharmaceutically acceptable anion.

9. A compound of formula 1, or a pharmaceutically acceptable salt thereof, according to claim 1 , for use in the preservation of organ and tissue for surgical transplants, or in the storage of blood.

10. A compound of Formula 1 or a pharmaceutically acceptable salt thereof according to claim 1 , for use as a mass spectrometry probe.

11. A compound of Formula 1 or pharmaceutically acceptable salt thereof according to claim 1 , for use as a medicament.

12. A pharmaceutical composition comprising: a compound of Formula 1 or a pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient, carrier or diluent.

13. A method of reversing, alleviating, or inhibiting the progress of a disease or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1, according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or condition is diabetes.

14. A method according to claim 13 , wherein the disease or condition is hyperglycemic diabetes.

15. A method of labelling a biological molecule for mass spectrometry detection comprising contacting said molecule with a compound according to claim 1 .

16. A method according to claim 15 wherein said biological molecule comprises a dicarbonyl group.