CARBONIC ANHYDRASE INHIBITORS WITH ANTIMETASTATIC ACTIVITY
Derivatized coumarin-based pharmaceutical compositions and methods to use them are provided. The compositions are characterized in that they inhibit the activity of tumor-related CAIX and CAXII to a greater degree than they inhibit the activity of CAI and CAII. The compositions can be used to suppress tumor growth and/or suppress tumor metastases in a mammal.
1 .- 30 . (canceled)
31 . A method for treating a mammal having hypoxic or metastatic cancer, the method comprising administering to the mammal a pharmaceutical composition in an amount that is capable of inhibiting human carbonic anhydrase IX and XII while leaving carbonic anhydrase I and II substantially unaffected, wherein the pharmaceutical composition comprises a compound of Formula V and a pharmaceutically acceptable excipient:
wherein,
G is (1) a glycosyl group, (2) a non-glycosyl group selected from the group of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and aryl or (3) a heterocyclic sugar according to the following general formula:
a is a single bond, or a double bond;
b is a single bond, or a double bond;
X 1 and X 2 are independently O or S;
X 3 is —O—, —NH—, —S—, or a single bond;
X 4 is —N—, or —C—;
X 5 are X 6 are independently —N—, —C—, or —O—;
n=0, or 1.
R 1 ═H; and
R 2 ; R 3 ; R 4 ; R 5 ; R 6 and R 7 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or halogen.
32 . The method of claim 31 wherein X 1 , X 2 and X 3 are all O.
33 . The method of claim 31 wherein R 2 is CH 3 .
34 . The method of claim 31 , wherein R 3 , R 4 and R 5 are each hydrogen.
35 . The method of claim 31 selected from the group consisting of:
36 . A method for treating hypoxic or metastatic cancer in a subject in need thereof comprising administering to the subject a pharmaceutical composition in an amount that is capable of inhibiting human carbonic anhydrase IX and XII while leaving carbonic anhydrase I and II substantially unaffected, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a compound or a salt thereof selected from the following group:
2′,4′,6′-trimethyl-1-(2-(2-oxo-2H-chromen-7-yloxy)ethyl)pyridine;
7-(pent-4-ynyloxy)-2H-chromen-2-one hexacarbonyldicobalt;
7-(prop-2-ynyloxy)-2H-chromene-2-thione hexacarbonyldicobalt;
7-(prop-2-ynyloxy)-2H-chromen-2-one hexacarbonyldicobalt;
N-(4-methyl-2-oxo-2H-chromen-7-yl)-4′-methylbenezenesulfonimde;
7-(prop-2-ynyloxy)-2H-chromene-2-thione;
7-(allyloxy)-2H-chromene-2-thione;
2-(2-oxo-2H-chromen-7-yloxy)ethylcarbamate;
1-(4-(4-((2-oxo-2H-chromen-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-tetrahydro-5-(hydroxymethyl)furan-2-yl)-5-methylpyrimidine-2,4(1H,3H)dione;
7-[(1′H-1′,2′,3′-triazol-4′-yl)methoxy]-2H-chromen-2-one;
6-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one
6-((1-(2-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-5-chromen-2-one;
6-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-5-chromen-2-one;
6-((1-(2-iodophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-5-chromen-2-one;
7-(2′,4′,6′-trimethylpyridinium)-4-methyl-2H-chromen-2-one;
7-(2′,4′,6′-trimethylpyridinium)-4-methyl-2H-chromen-2-one perchlorate;
4-methyl-7-(4-((2-oxo-2H-chromen-7-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-2H-chromen-2-one;
6-(tert-Butyldimethylsilyloxy)-2H-chromen-2-one;
7-(tert-Butyldimethylsilyloxy)-2H-chromen-2-one;
6-(tert-Butyldimethylsilyloxy)-2H-chromene-2-thione;
7-(tert-Butyldimethylsilyloxy)-2H-chromene-2-thione;
6-Hydroxy-2H-chromene-2-thione;
6-Hydroxy-2H-chromene-2-thione;
4-(Allyloxy)-2H-chromen-2-one;
6-(Allyloxy)-2H-chromen-2-one;
7-(Allyloxy)-2H-chromen-2-one;
4-(Allyloxy)-2H-chromene-2-thione;
6-(Allyloxy)-2H-chromene-2-thione;
7-(2′-hydroxyethoxy)-2H-chromen-2-one;
2′-(2-Oxo-2H-chromen-7-yloxy)ethyl 4″-methylbenzenesulfonate;
7-(2′-Fluoroethoxy)-2H-chromen-2-one;
N-(4-Methyl-2-oxo-2H-chromen-7-yl)acetamide;
1-(3′,5′-dimethylphenyl)-3-(4-methyl-2-oxo-2H-chromen-7-yl)urea;
tert-Butyl 4-methyl-2-oxo-2H-chromen-7-ylcarbamate;
37 . The method of claim 31 , further comprising treating the mammal with additional anticancer agents.
38 . The method of claim 36 , wherein the mammal is also treated with additional anticancer agents.
39 . The method of claim 31 wherein the mammal has breast cancer, lung carcinoma, pancreatic carcinoma, renal carcinoma, ovarian, prostate or cervical carcinoma, glioblastoma, colorectal carcinoma.
40 . The method of claim 31 wherein the mammal is a human.
41 . The method of claim 36 wherein the mammal has breast cancer, lung carcinoma, pancreatic carcinoma, renal carcinoma, ovarian, prostate or cervical carcinoma, glioblastoma, colorectal carcinoma.
42 . The method of claim 36 wherein the mammal is a human.
43 . A compound selected from the following group:
2′,4′,6′-trimethyl-1-(2-(2-oxo-2H-chromen-7-yloxy)ethyl)pyridine;
7-(pent-4-ynyloxy)-2H-chromen-2-one hexacarbonyldicobalt;
7-(prop-2-ynyloxy)-2H-chromene-2-thione hexacarbonyldicobalt;
7-(prop-2-ynyloxy)-2H-chromen-2-one hexacarbonyldicobalt;
N-(4-methyl-2-oxo-2H-chromen-7-yl)-4′-methylbenezenesulfonimde;
7-(prop-2-ynyloxy)-2H-chromene-2-thione;
7-(allyloxy)-2H-chromene-2-thione;
2-(2-oxo-2H-chromen-7-yloxy)ethylcarbamate;
1-(4-(4-((2-oxo-2H-chromen-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-tetrahydro-5-(hydroxymethyl)furan-2-yl)-5-methylpyrimidine-2,4(1H,3H)dione;
7-[(1′H-1′,2′,3′-triazol-4′-yl)methoxy]-2H-chromen-2-one;
6-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one
6-((1-(2-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-5-chromen-2-one;
6-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-5-chromen-2-one;
6-((1-(2-iodophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-5-chromen-2-one;
7-(2′,4′,6′-trimethylpyridinium)-4-methyl-2H-chromen-2-one;
7-(2′,4′,6′-trimethylpyridinium)-4-methyl-2H-chromen-2-one perchlorate;
4-methyl-7-(4-((2-oxo-2H-chromen-7-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-2H-chromen-2-one;
6-(tert-Butyldimethylsilyloxy)-2H-chromen-2-one;
7-(tert-Butyldimethylsilyloxy)-2H-chromen-2-one;
6-(tert-Butyldimethylsilyloxy)-2H-chromene-2-thione;
7-(tert-Butyldimethylsilyloxy)-2H-chromene-2-thione;
6-Hydroxy-2H-chromene-2-thione;
6-Hydroxy-2H-chromene-2-thione;
4-(Allyloxy)-2H-chromen-2-one;
6-(Allyloxy)-2H-chromen-2-one;
7-(Allyloxy)-2H-chromen-2-one;
4-(Allyloxy)-2H-chromene-2-thione;
6-(Allyloxy)-2H-chromene-2-thione;
7-(2′-hydroxyethoxy)-2H-chromen-2-one;
2′-(2-Oxo-2H-chromen-7-yloxy)ethyl 4″-methylbenzenesulfonate;
7-(2′-Fluoroethoxy)-2H-chromen-2-one;
N-(4-Methyl-2-oxo-2H-chromen-7-yl)acetamide;
1-(3′,5′-dimethylphenyl)-3-(4-methyl-2-oxo-2H-chromen-7-yl)urea;
tert-Butyl 4-methyl-2-oxo-2H-chromen-7-ylcarbamate;
44 . A pharmaceutical composition comprising a compound of claim 43 or a salt thereof and a pharmaceutically acceptable excipient.