Thiadiazole Compounds and Uses Thereof
Thiadiazole compounds, compositions, bioconjugates, and methods for targeting and photoactivation at target sites.
1 . A compound of Formula I
where R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 1 -C 10 acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R 6 )E, and —(CH 2 ) a N(R 5 )CSN(R 6 )E; or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 , together with the carbon atoms to which they are attached, independently form alicyclic or heterocyclic structures wherein a combination of R 1 and R 2 , or a combination of R 2 and R 3 , or a combination of R 3 and R 4 is selected from —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )—O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O—, and —N═N—S—;
each of b and c independently varies from 0 to 3;
X is selected from —O—, —NR 11 —, —S—, —SO—, and —SO 2 —;
R 5 to R 11 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxyalkyl, C 5 -C 10 heteroaryl, C 1 -C 10 acyl, halogen, nitro, cyano, —(CH 2 ) a OR 12 , —(CH 2 ) a CO 2 R 12 , —(CH 2 ) a NR 12 R 13 , —NR 13 COR 12 ; —(CH 2 ) a CONR 12 R 13 , —(CH 2 ) a SR 12 , —(CH 2 ) a SOR 12 , —(CH 2 ) a SO 2 R 12 , —(CH 2 ) a CON(R 12 )E, —(CH 2 ) a N(R 12 )COE, —(CH 2 ) a N(R 12 )CON(R 13 )E, and —(CH 2 ) a N(R 12 )CSN(R 13 )E;
a varies from 0 to 10;
R 12 and R 13 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxyalkyl, C 5 -C 10 heteroaryl, and C 1 -C 10 acyl; and
each E is independently either hydrogen or a targeting moiety that binds to a target.
2 . The compound of claim 1 wherein Formula I forms a structure of Formula II
wherein R 2 and R 3 of Formula I are combined to form A, and A is selected from —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )—O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O—, and —N═N—S—; and
R 1 and R 4 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 1 -C 10 acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 )SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, (CH 2 ) a N(R 5 )CON(R)E, and —(CH 2 ) a N(R 5 )CSN(R 6 )E.
3 . The compound of claim 1 wherein Formula I forms a structure of Formula III
wherein R 1 and R 2 of Formula I are combined to form B, and B is selected from —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )—O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O—, and —N═N—S—; and
R 3 and R 4 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 1 -C 10 acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, (CH 2 ) a N(R 5 )CON(R)E, and —(CH 2 ) a N(R 5 )CSN(R 6 )E.
4 . The compound of claim 1 wherein Formula I forms a structure of Formula IV
wherein R 3 and R 4 of Formula I are combined to form D, and D is selected from —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )—O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O—, and —N═N—S—; and
R 1 and R 2 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 1 -C 10 acyl, halogen, nitro, cyano, —CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, (CH 2 ) a N(R 5 )CON(R)E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E; and
R 5 to R 11 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 1 -C 10 hydroxylakyl, C 1 -C 10 alkoxyalkyl, C 5 -C 10 heteroaryl, C 1 -C 10 acyl, halogen, nitro, cyano, —(CH 2 ) a OR 12 , —(CH 2 ) a CO 2 R 12 , —(CH 2 ) a NR 12 R 13 , —NR 13 COR 12 ; —(CH 2 ) a CONR 12 R 13 , —(CH 2 ) a SR 12 , —(CH 2 ) a SOR 12 , —(CH 2 ) a SO 2 R 12 , —(CH 2 ) a CON(R 12 )E, —(CH 2 ) a N(R 12 )COE, —(CH 2 ) a N(R 12 )CON(R 13 )E, and —(CH 2 ) a N(R 12 )CSN(R 13 )E.
5 . The compound of claim 1 wherein Formula I forms a structure of Formula V
wherein R 2 and R 3 of Formula I are combined to form A, and A is —(CH 2 ) b X(CH 2 ) c —; b is 2, and c is 1; X is —NR 11 —; R 4 is hydrogen; R 1 is hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 1 -C 10 acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R 6 )E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E; and
R 5 , R 6 , and R 11 are independently selected from hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, C 1 -C 10 hydroxylakyl, and C 1 -C 10 alkoxyalkyl.
6 . The compound of claim 1 , wherein E, if present, is independently selected from whole or fragmented somatostatin receptor binding molecules, whole or fragmented ST receptor binding molecules, whole or fragmented neurotensin receptor binding molecules, whole or fragmented bombesin receptor binding molecules, whole or fragmented CCK receptor binding molecules, whole or fragmented steroid receptor binding molecules, and whole or fragmented carbohydrate receptor binding molecules.
7 . The compound of claim 1 further comprising at least one of an electron donating group, an electron withdrawing group, a lipophilic group, or a hydrophilic group.
8 . A biocompatible composition comprising a compound of claim 1 , and a biocompatible excipient.
9 . The composition of claim 8 wherein the excipient is at least one of a buffer, emulsifier, surfactant, or electrolyte.
10 . A biologic photoactivation method comprising
administering to a target tissue in an animal an effective amount of a biocompatible composition comprising a compound represented by the formula E-L-Ar, wherein Ar is a bicyclic or tricyclic thiadiazole, E is either hydrogen or a targeting moiety that binds to a target, and L is a single bond or a linking moiety that does not substantially reduce a targeting function of E and does not substantially reduce photosensitivity of Ar; and
photoactivating the compound by exposing the target tissue to electromagnetic radiation having a wavelength between about 300 nm and about 950 nm.
11 . The method of claim 10 wherein the compound is a compound of claim 1 .
12 . The method of claim 10 further comprising allowing the compound to accumulate in the target tissue before exposing the tissue to light.
13 . The method of claim 10 wherein the composition administered is in a range of about 0.1 mg/kg body weight to about 500 mg/kg body weight.
14 . The method of claim 10 wherein the composition is administered in a range of about 0.5 mg/kg body weight to about 2 mg/kg body weight.
15 . The method of claim 10 wherein the composition is administered by a route selected from parenteral, enteral, topical, aerosol, subdermal, subcutaneous, inhalation, and combinations thereof.
16 . The method of claim 10 resulting in a necrotic effect, an antimicrobial effect, an apoptotic effect, or a combination thereof.
17 . The method of claim 10 wherein the compound is in a form selected from at least one of liposomes, micelles, microcapsules, or microparticles.
18 . The method of claim 10 wherein the composition is parenterally administered to the target tissue in a concentration in a range of 1 nM to 0.5 M.
19 . The method of claim 10 wherein the composition is administered in a form selected from an aerosol spray, a cream, a gel, and a solution.