Back to results
US 2022/0169669 A1Published application
High-affinity cu(i) ligands and methods of use thereof
AssigneeGeorgia Tech Research Corporation
InventorsChristoph J. FAHRNI, M. Thomas MORGAN
Life of this patent
Estimating the term…
Abstract
Several dimethylphosphine sulfide- and phosphine-containing compounds have been discovered that chelate copper(I) with high affinity. In certain embodiments, the compounds can be used to quantify copper(I) in complex biological systems. In another embodiment, the compounds can be used for the treatment of copper(I)-related illnesses and conditions. In still other embodiments, the compounds are ratiometric probes.
Claims24
A compound defined according to formula (I) as follows:
- wherein:
- A is any aromatic system including but not limited to anthracene, azepine, benzene, benzimidazole, benzofuran, benzothiophene, bifuran, biphenyl, bipyridyl, bithiophene, chrysene, cinnoline, cyclopentadienyl, 9,9-dimethyl-xanthene, ferrocene, furan, imidazole, indazole, indole, indoxazine, isoquinoline, isothiazole, isoxazole, methylimidazole, methylindole, naphthalene, oxadiazole, oxazole, phenanthrene, phenanthroline, phthalazine, pteridine, pyrazole, pyrazine, pyrene, pyridine, pyrilium, pyrimidine, pyrrole, quinoline, quinolone, quinoxaline, quinazoline, thiadiazole, thiazole, thiophene, triazole, or xanthene;
- R1 and R2 are independently selected from —H, -halogen, —NH2, —CONH2, —NO2, —CH3, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —C1-C30 alkyl which can be optionally substituted with R4, an aromatic system optionally substituted with R4, a polycyclic aromatic system optionally substituted with R4, a carbocycle or heterocycle optionally substituted with R4, a polycyclic carbocycle or heterocycle optionally substituted with R4, —(C1-C30 alkyl)-carbocycle or heterocycle optionally substituted by R4, —(C1-C30 alkyl)-polycyclic carbocycle or heterocycle optionally substituted by R4;
- R3 is selected from —C1-C30 alkyl, —NH(C1-C30 alkyl), —N(C1-C30 alkyl)2, —O(C1-C30 alkyl)OH, or —S(C1-C30 alkyl)SH;
- and
- R4 is selected from halogen, —NO2, —NH2, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), N(C1-C30 alkyl)(C1-C30 alkyl), —CONH2, —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —COOH, —C1-C30 alkyl;
- or an enantiomer, polymorph or salt thereof.
4 more elements
A compound defined according to formula (II) as follows:
- wherein:
- A and B are independently any aromatic system including but not limited to anthracene, azepine, benzene, benzimidazole, benzofuran, benzothiophene, bifuran, biphenyl, bipyridyl, bithiophene, chrysene, cinnoline, cyclopentadienyl, 9,9-dimethyl-xanthene, ferrocene, furan, imidazole, indazole, indole, indoxazine, isoquinoline, isothiazole, isoxazole, methylimidazole, methylindole, naphthalene, oxadiazole, oxazole, phenanthrene, phenanthroline, phthalazine, pteridine, pyrazole, pyrazine, pyrene, pyridine, pyrilium, pyrimidine, pyrrole, quinoline, quinolone, quinoxaline, quinazoline, thiadiazole, thiazole, thiophene, triazole, or xanthene;
- X is selected from —O—, —S—, —N(H)—, —N(alkyl)-, —C1-C30 alkyl-, —C1-C30 alkyl-O—C1-C30 alkyl-, —C1-C30 alkyl-N—C1-C30 alkyl-, or —C1-C30 alkyl-S—C1-C30 alkyl-;
- R1 and R2 are independently selected from —H, halogen, —NH2, —CONH2, —NO2, —CH3, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), C1-C30 alkyl which can be optionally substituted with R4, an aromatic system optionally substituted with R4, a polycyclic aromatic system optionally substituted with R4, a carbocycle or heterocycle optionally substituted with R4, a polycyclic carbocycle or heterocycle optionally substituted with R4, —(C1-C30 alkyl)-carbocycle or heterocycle optionally substituted by R4, —(C1-C30 alkyl)-polycyclic carbocycle or heterocycle optionally substituted by R4;
- R3 is selected from —C1-C30 alkyl, —NH(C1-C30 alkyl), —N(C1-C30 alkyl)2, —O(C1-C30 alkyl)OH, or —S(C1-C30 alkyl)SH;
- and
- R4 is selected from -halogen, —NO2, —NH2, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), N(C1-C30 alkyl)(C1-C30 alkyl), —CONH2, —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —COOH, —C1-C30 alkyl;
- or an enantiomer, polymorph or salt thereof.
5 more elements
A compound defined according to formula (III) as follows:
- wherein:
- A and B are independently any aromatic system including but not limited to anthracene, azepine, benzene, benzimidazole, benzofuran, benzothiophene, bifuran, biphenyl, bipyridyl, bithiophene, chrysene, cinnoline, cyclopentadienyl, 9,9-dimethyl-xanthene, furan, imidazole, indazole, indole, indoxazine, isoquinoline, isothiazole, isoxazole, methylimidazole, methylindole, naphthalene, oxadiazole, oxazole, phenanthrene, phenanthroline, phthalazine, pteridine, pyrazole, pyrazine, pyrene, pyridine, pyrilium, pyrimidine, pyrrole, quinoline, quinolone, quinoxaline, quinazoline, thiadiazole, thiazole, thiophene, triazole, or xanthene;
- X is selected from —O—, —S—, —N(H)—, —N(alkyl)-, —C1-C30 alkyl-, —C1-C30 alkyl-O—C1-C30 alkyl-, —C1-C30 alkyl-N—C1-C30 alkyl-, or —C1-C30 alkyl-S—C1-C30 alkyl-;
- R1 and R2 are independently selected from —H, -halogen, —NH2, —CONH2, —NO2, —CH3, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), C1-C30 alkyl which can be optionally substituted with R4, an aromatic system optionally substituted with R4, a polycyclic aromatic system optionally substituted with R4, a carbocycle or heterocycle optionally substituted with R4, a polycyclic carbocycle or heterocycle optionally substituted with R4, —(C1-C30 alkyl)-carbocycle or heterocycle optionally substituted by R4, —(C1-C30 alkyl)-polycyclic carbocycle or heterocycle optionally substituted by R4;
- R3 is selected from —C1-C30 alkyl, —NH(C1-C30 alkyl), —N(C1-C30 alkyl)2, —O(C1-C30 alkyl)OH, or —S(C1-C30 alkyl)SH;
- and
- R4 is selected from -halogen, —NO2, —NH2, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —CONH2, —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —COOH, —C1-C30 alkyl;
- and
- n is selected from zero to five;
- or an enantiomer, polymorph or salt thereof.
7 more elements
A compound defined according to formula (IV) as follows:
- wherein:
- A is any aromatic system including but not limited to anthracene, azepine, benzene, benzimidazole, benzofuran, benzothiophene, bifuran, biphenyl, bipyridyl, bithiophene, chrysene, cinnoline, cyclopentadienyl, 9,9-dimethyl-xanthene, ferrocene, furan, imidazole, indazole, indole, indoxazine, isoquinoline, isothiazole, isoxazole, methylimidazole, methylindole, naphthalene, oxadiazole, oxazole, phenanthrene, phenanthroline, phthalazine, pteridine, pyrazole, pyrazine, pyrene, pyridine, pyrilium, pyrimidine, pyrrole, quinoline, quinolone, quinoxaline, quinazoline, thiadiazole, thiazole, thiophene, triazole, or xanthene;
- R1 is independently selected from —H, -halogen, —NH2, —CONH2, —NO2, —CH3, —SO3H, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —COOH, C1-C30 alkyl which can be optionally substituted with R4, an aromatic system optionally substituted with R4, a polycyclic aromatic system optionally substituted with R4, a carbocycle or heterocycle optionally substituted with R4, a polycyclic carbocycle or heterocycle optionally substituted with R4, —(C1-C30 alkyl)-carbocycle or heterocycle optionally substituted by R4, —(C1-C30 alkyl)-polycyclic carbocycle or heterocycle optionally substituted by R4;
- R2 is independently selected from —H, -halogen, —NH2, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —C(S)SH, —C(O)SH, —COO(C1-C30 alkyl), any aromatic system including but not limited to triazole, tetrazole, imidazole, pyrazole, pyridine, pyrimidine optionally substituted with R4, a polycyclic aromatic system optionally substituted with R4, a carbocycle or heterocycle optionally substituted with R4, a polycyclic carbocycle or heterocycle optionally substituted with R4, —(C1-C30 alkyl)-carbocycle or heterocycle optionally substituted by R4, —(C1-C30 alkyl)-polycyclic carbocycle or heterocycle optionally substituted by R4, -(phosphanediylbis(methylene))bis(dimethylphosphine sulfide), -dimethylphosphine sulfide, —P(R5)2, —P(S)(R5)2, or —P(O)(R5)2;
- R3 is selected from —C1-C30 alkyl, —NH(C1-C30 alkyl), —N(C1-C30 alkyl)2, —O(C1-C30 alkyl)OH, or —S(C1-C30 alkyl)SH;
- and
- R4 is selected from -halogen, —NO2, —NH2, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —CONH2, —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —COOH, or —C1-C30 alkyl;
- and
- R5 is selected from —OH, —SH, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), N(C1-C30 alkyl)(C1-C30 alkyl), —C1-C30 alkyl which can be optionally substituted with R4, any aromatic system optionally substituted with R4, a carbocycle or heterocycle optionally substituted with R4, or a polycyclic carbocycle or heterocycle optionally substituted with R4;
- or an enantiomer, polymorph or salt thereof.
7 more elements
A compound defined according to formula (V) as follows:
- wherein:
- A is any monocyclic or polycyclic saturated or unsaturated aliphatic or heteroaliphatic system including but not limited to azetidine, aziridine, cyclobutane, cyclobutene, cyclohexane, cyclohexene, cyclopropane, cylopropene, cyclopentene, cyclopentane, oxetane, norbornane, norbornene, piperidine, pyrrolidine, pyrimidine, tetrahydrofuran, thietane, thiolane, thiolane, thiolane-1-oxide, thiolane-1,1-dioxide;
- and
- R1 and R2 are independently selected from —H, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —SO3H, —COOH, —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —CON—(C1-C30 alkyl)-N—(C1-C30 alkyl)-OH, —CONH2, —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —C1-C30 alkyl which can be optionally substituted with R4, an aromatic system optionally substituted with R4, a polycyclic aromatic system optionally substituted with R4, a carbocycle or heterocycle optionally substituted with R4, a polycyclic carbocycle or heterocycle optionally substituted with R4, —(C1-C30 alkyl)-carbocycle or heterocycle optionally substituted by R4, —(C1-C30 alkyl)-polycyclic carbocycle or heterocycle optionally substituted by R4, -1,3-dimethyl-1,3,2-diazaphospholidine 2-sulfide, (phosphanediylbis(methylene))bis(dimethylphosphine sulfide), or -dimethylphosphine sulfide;
- R3 is selected from —C1-C30 alkyl, —NH(C1-C30 alkyl), —N(C1-C30 alkyl)2, —O(C1-C30 alkyl)OH, or —S(C1-C30 alkyl)SH;
- and
- R4 is selected from -halogen, —NO2, —NH2, —O—(C1-C30 alkyl), —NH—(C1-C30 alkyl), —S—(C1-C30 alkyl), —N(C1-C30 alkyl)(C1-C30 alkyl), —CONH2, —CON(C1-C30 alkyl)(C1-C30 alkyl), —SO2(C1-C30 alkyl), —SO2N(C1-C30 alkyl)(C1-C30 alkyl), —OH, —SH, —COO(C1-C30 alkyl), —COOH, —C1-C30 alkyl;
- or an enantiomer, polymorph or salt thereof.
5 more elements
A compound defined according to formula (VI) as follows:
- or an enantiomer, polymorph or salt thereof.
A compound defined according to formula (VII) as follows:
- or an enantiomer, polymorph or salt thereof.
A compound selected from the group consisting of ammonium 3,4-bis(bis((dimethylphosphorothioyl)methyl)phosphaneyl)benzenesulfonate;
- 3,4-bis(bis((dimethylphosphorothioyl)methyl)phosphaneyl)benzoic acid;
- N-(2-aminoethyl)-3,4-bis(bis((dimethylphosphorothioyl)methyl)phosphaneyl)benzamide;
- N-(2-aminoethyl)-3,4-bis(bis((dimethylphosphorothioyl)methyl)phosphaneyl)benzamide tethered to a bioconjugate;
- ((pyridine-3,4-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- 3-(3,4-bis(bis((dimethylphosphorothioyl)methyl)phosphaneyl)pyridin-1-ium-1-yl)propane-1-sulfonate;
- ((pyridazine-4,5-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- ((pyrazine-2,3-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- substituted ((thiophene-2,3-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- substituted 4,5-bis(bis((dimethylphosphorothioyl)methyl)phosphaneyl)furan-2-carboxylic acid;
- substituted (((1-methyl-1H-imidazole-4,5-diyl)bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- substituted ((thiazole-4,5-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((oxybis(2,1-phenylene))bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((thiobis(2,1-phenylene))bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((azanediylbis(2,1-phenylene))bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((9,9-dimethyl-9H-xanthene-4,5-diyl)bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- substituted ((quinolin-8-ylphosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (((2-(dimethylphosphorothioyl)phenyl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (((2-mercaptophenyl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (([1,1′-biphenyl]-2,2′-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((2-mercaptophenyl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (([1,1′-biphenyl]-2,2′-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- ((cyclopent-1-ene-1,2-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((2,5-dihydro-1H-pyrrole-3,4-diyl)bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((2,5-dihydrofuran-3,4-diyl)bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- ((cyclohex-1-ene-1,2-diylbis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((1,2,5,6-tetrahydropyridine-3,4-diyl)bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- 4,5-bis(bis((dimethylphosphorothioyl)methyl)phosphaneyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide;
- (((2-(dimethylphosphorothioyl)-5-(2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]thieno[2,3-f]quinolin-10-yl)thiophen-3-yl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (((5-(13,13-dimethyl-2,3,5,6,7,13-hexahydro-1H-indeno[2,1-f]pyrido[3,2,1-ij]quinolin-11-yl)thiophene-2,3-diyl)bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide);
- (((3-(bis((dimethylphosphorothioyl)methyl)phosphaneyl)-5-(5-(4-(dimethylamino)phenyl)thiazol-2-yl)thiophen-2-yl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (E)-2-(3-(bis((dimethylphosphorothioyl)methyl)phosphaneyl)-2-mercaptostyryl)-1,3,3-trimethyl-3H-indol-1-ium;
- (((3-(1,3-dimethyl-2-sulfido-1,3,2-diazaphospholidin-2-yl)thiophen-2-yl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (E)-(((5-(4-(dimethylamino)styryl)-3-(dimethylphosphorothioyl)thiophen-2-yl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (E)-(((5-(4-(dimethylamino)styryl)-3-(dimethylphosphorothioyl)thiophen-2-yl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- (((5′-(4-(dimethylamino)phenyl)-4-(dimethylphosphorothioyl)-[2,2′-bithiophen]-5-yl)phosphanediyl)bis(methylene))bis(dimethylphosphine sulfide);
- and (((4-(6-(dimethylamino)benzo[b]thiophen-2-yl)-1,2-phenylene)bis(phosphanetriyl))tetrakis(methylene))tetrakis(dimethylphosphine sulfide).
33 more elements
Dependencies are inferred from the claim text.