Inhibitors of carbonic anhydrase IX
View Patent ↗Novel radiopharmaceuticals that are useful in diagnostic imaging and therapeutic treatment of disease characterized by over expression of CA-IX comprise a complex that contains a sulfonamide moiety which is capable of binding the active catalytic site of CA-IX, and a radionuclide adapted for radioimaging and/or radiotherapy:
1. A complex of formula I, its stereoisomer or pharmaceutically acceptable salt:
wherein:
V is a bond, O, C═O, C(═X)—NH, a group of
or a group of
wherein X is O or S; U is a bond or a group of (O—CH 2 —CH 2 —O) p —CH 2 —CH 2 wherein p is an integer ranging from 1 to 3;
each W is independently a bond, O, or NH;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
m is an integer ranging from 0 to 6;
n is an integer ranging from 0 to 6;
Metal represents a radionuclide selected from the group consisting of 99m Tc, 68 Ga, 62 Cu, 111 In, 186 Re, 188 Re, 90 Y, 212 Bi, 211 At, 89 Sr, 166 Ho, 153 Sm, 67 Cu, 64 Cu, 100 Pd, 212 Pb, 109 Pd, 68 Ga, 94 Tc, 105 Rh, 95 Ru, 177 Lu, and 170 Lu; and
Chelate represents a chelating moiety that coordinates with said radionuclide to form said complex, and the Chelate is selected from the group consisting of tetra-azacyclododecanetetra-acetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), bis(pyridin-2-ylmethyl)amine (DPA), quinolinemethylamino acetic acid (QAA), bis(isoquinolinemethyl)amine, bis(quinolinemethyl)amine (DQA), pyridine-2-ylmethylamino acetic acid (PAMA), isoquinolin-3-ylmethylamino acetic acid, bis(thiazol-2-ylmethyl)amine (DTK), and thiazol-2-ylmethylamino acetic acid (MTMA), bis(N-carboxymethylimidazoylamine) (DCMI), bis(N-1,1-dimethoxyethylimidazoylamine) (DMEI), bis(N-methylimidazoylamine) (DMI) and bis(N-hydroxyethylimidazoylamine) (DHI).
2. The complex of claim 1 wherein said radionuclide is selected from the group consisting of 99m Tc, 186 Re, 188 Re, 90 Y, 64 Cu, 177 Lu, 68 Ga and 111 In.
3. The complex of claim 1 wherein said radionuclide is gamma emitting or positron emitting.
4. A method of imaging tissue of a mammal which expresses CA IX comprising administering to said mammal an effective amount of a complex or compound selected from the group consisting of formulae I, II, III, IV and V, its stereoisomer or pharmaceutically acceptable salt:
wherein in formula I:
V is a bond, O, C═O, C(═X)—NH, a group of
or a group of
wherein X is O or S; U is a bond or a group of (O—CH 2 —CH 2 —O) p —CH 2 —CH 2 wherein p is an integer ranging from 1 to 3;
each W is independently a bond, O, or NH;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
m is an integer ranging from 0 to 6;
n is an integer ranging from 0 to 6;
Metal represents a radionuclide selected from the group consisting of 99m Tc, 68 Ga, 62 Cu, 111 In, 186 Re, 188 Re, 90 Y, 212 Bi, 211 At, 89 Sr, 166 Ho, 153 Sm, 67 Cu, 64 Cu, 100 Pd, 212 Pb, 109 Pd, 67 Ga, 94 Tc, 105 Rh, 95 Ru, 177 Lu, and 170 Lu; and
Chelate represents a chelating moiety that coordinates with said radionuclide to form said complex, and the Chelate is selected from the group consisting of tetra-azacyclododecanetetra-acetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), bis(pyridin-2-ylmethyl)amine (DPA), quinolinemethylamino acetic acid (QAA), bis(isoquinolinemethyl)amine, bis(quinolinemethyl)amine (DQA), pyridine-2-ylmethylamino acetic acid (PAMA), isoquinolin-3-ylmethylamino acetic acid, bis(thiazol-2-ylmethyl)amine (DTK), and thiazol-2-ylmethylamino acetic acid (MTMA), bis(N-carboxymethylimidazoylamine) (DCMI), bis(N-1,1-dimethoxyethylimidazoylamine) (DMEI), bis(N-methylimidazoylamine) (DMI) and bis(N-hydroxyethylimidazoylamine) (DHI);
wherein in formula II:
V 1 is selected from the group consisting of a bond, O, NH, O—(CH 2 —CH 2 —O) q , a group of
a group of CHR 6 —CO and CHR 6 —CO—NH—CHR 6 —CO wherein R 6 is lower alkyl substituted with carboxylic acid, sulfonic acid, sulfuric acid, phosphonic acid, phosphinic acid, phosphoric acid, amine, guanidine, amidine or N-containing heterocycle, and combinations thereof;
W is a bond, O, or NH;
W 1 and W 2 are independently a bond, NH, C═X, or a group of
wherein X is O or S;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
Z 1 is a bond, aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
m is an integer ranging from 0 to 8;
n is an integer ranging from 0 to 8;
q is an integer ranging from 1 to 6; and
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected;
wherein in formula III:
V 1 and V 2 are independently selected from the group consisting of a bond, O, NH, O—(CH 2 —CH 2 —O) q , a group of
a group of CHR 6 —CO or CHR 6 —CO—NH—CHR 6 —CO wherein R 6 is lower alkyl substituted with carboxylic acid, sulfonic acid, sulfuric acid, phosphonic acid, phosphinic acid, phosphoric acid, amine, guanidine, amidine or N-containing heterocycle, and combinations thereof;
W 1 is a bond, NH, C═X, or a group of
wherein X is O or S;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
Z 1 is a bond, aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
m is an integer ranging from 0 to 8;
n is an integer ranging from 0 to 8;
q is an integer ranging from 1 to 6;
y is an integer ranging from 0 to 6; and
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected; and
wherein in formula IV:
V 1 is selected from the group consisting of a bond, O, NH, O—(CH 2 —CH 2 —O) q , a group of
a group of CHR 6 —CO or CHR 6 —CO—NH—CHR 6 —CO wherein R 6 is lower alkyl substituted with carboxylic acid, sulfonic acid, sulfuric acid, phosphonic acid, phosphinic acid, phosphoric acid, amine, guanidine, amidine or N-containing heterocycle, and combinations thereof;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
n is an integer ranging from 0 to 8;
q is an integer ranging from 1 to 6; and
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected; and
wherein in formula V:
X is O or S;
m is an integer ranging from 0 to 8;
n is an integer ranging from 0 to 8;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected; and
R 7 is H or lower alkyl.
5. The method of claim 4 further comprising determining the level of CA IX in said tissue.
6. The method of claim 4 further comprising monitoring the changes of the level of CA IX in said tissue over a period of time.
7. The method of claim 4 wherein said administration is carried out intravenously.
8. A method of treating a mammal suffering a disease which is characterized by over expression of CA IX, the method comprising administering to said mammal a therapeutically effective amount of a complex or compound selected from the group consisting of formulae I, II, III, IV and V, its stereoisomer or pharmaceutically acceptable salt:
wherein in formula I:
V is a bond, O, C═O, C(═X)—NH, a group of
or a group of
wherein X is O or S; U is a bond or a group of (O—CH 2 —CH 2 —O) p —CH 2 —CH 2 wherein p is an integer ranging from 1 to 3;
each W is independently a bond, O, or NH;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
m is an integer ranging from 0 to 6;
n is an integer ranging from 0 to 6;
Metal represents a radionuclide selected from the group consisting of 99m Tc, 68 Ga, 62 Cu, 111 In, 186 Re, 188 Re, 90 Y, 212 Bi, 211 At, 89 Sr, 166 Ho, 153 Sm, 67 Cu, 64 Cu, 100 Pd, 212 Pb, 109 Pd, 67 Ga, 94 Tc, 105 Rh, 95 Ru, 177 Lu, and 170 Lu; and
Chelate represents a chelating moiety that coordinates with said radionuclide to form said complex, and the Chelate is selected from the group consisting of tetra-azacyclododecanetetra-acetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), bis(pyridin-2-ylmethyl)amine (DPA), quinolinemethylamino acetic acid (QAA), bis(isoquinolinemethyl)amine, bis(quinolinemethyl)amine (DQA), pyridine-2-ylmethylamino acetic acid (PAMA), isoquinolin-3-ylmethylamino acetic acid, bis(thiazol-2-ylmethyl)amine (DTK), and thiazol-2-ylmethylamino acetic acid (MTMA), bis(N-carboxymethylimidazoylamine) (DCMI), bis(N-1,1-dimethoxyethylimidazoylamine) (DMEI), bis(N-methylimidazoylamine) (DMI) and bis(N-hydroxyethylimidazoylamine) (DHI);
wherein in formula II:
V 1 is selected from the group consisting of a bond, O, NH, O—(CH 2 —CH 2 —O) q , a group of
a group of CHR 6 —CO and CHR 6 —CO—NH—CHR 6 —CO wherein R 6 is lower alkyl substituted with carboxylic acid, sulfonic acid, sulfuric acid, phosphonic acid, phosphinic acid, phosphoric acid, amine, guanidine, amidine or N-containing heterocycle, and combinations thereof;
W 1 is a bond, NH, C═X, or a group of
wherein X is O or S;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
Z 1 is a bond, aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
m is an integer ranging from 0 to 8;
n is an integer ranging from 0 to 8;
q is an integer ranging from 0 to 6; and
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected;
wherein in formula III:
V 1 and V 2 are independently selected from the group consisting of a bond, O, NH, O—(CH 2 —CH 2 —O) q , a group of
a group of CHR 6 —CO or CHR 6 —CO—NH—CHR 6 —CO wherein R 6 is lower alkyl substituted with carboxylic acid, sulfonic acid, sulfuric acid, phosphonic acid, phosphinic acid, phosphoric acid, amine, guanidine, amidine or N-containing heterocycle, and combinations thereof;
W 1 is a bond, NH, C═X, or a group of
wherein X is O or S;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
Z 1 is a bond, aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
m is an integer ranging from 0 to 8;
n is an integer ranging from 0 to 8;
q is an integer ranging from 1 to 6;
y is an integer ranging from 0 to 6; and
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected; and
wherein in formula IV:
V 1 is selected from the group consisting of a bond, O, NH, O—(CH 2 —CH 2 —O) q , a group of
a group of CHR 6 —CO or CHR 6 —CO—NH—CHR 6 —CO wherein R 6 is lower alkyl substituted with carboxylic acid, sulfonic acid, sulfuric acid, phosphonic acid, phosphinic acid, phosphoric acid, amine, guanidine, amidine or N-containing heterocycle, and combinations thereof;
Z is an aromatic, bicyclic aromatic, heteroaromatic, bicyclic heteroaromatic or heterocyclic ring;
n is an integer ranging from 0 to 8;
q is an integer ranging from 1 to 6; and
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected; and
wherein in formula V:
X is O or S;
m is an integer ranging from 0 to 8;
n is an integer ranging from 0 to 8;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, carboxyl, halogen, alkyl, alkoxy, and substituted or unsubstituted amino wherein at least one halogen is selected; and
R 7 is H or lower alkyl.
9. The complex of claim 2 wherein said radionuclide is selected from the group consisting of 99m Tc, 186 Re, and 188 Re.