Back to results
US 6,906,050 B2Granted
Substituted porphyrin and azaporphyrin derivatives and their use in photodynamic therapy, radioimaging and MRI diagnosis
AssigneeMiravant Pharmaceuticals, Inc.
InventorByron C. Robinson
Life of this patent
Estimating the term…
Abstract
Substituted porphyrin and azaporphyrin deviations with various substitutents in the 12- and 17-positions of the porphyrin skeleton as pharmaceutical agents for use in photodynamic therapy, MRI diagnosis, and radiodiagnostics.
Claims30
A compound of formula II:
- wherein R1-R11 can be the same or different and are selected from:
- H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH═CH(aryl), CH═CHCH2N(CH3)2, or a functional group of molecular weight of less than about 100,000 daltons;
- CH═CHCH2N+(CH3)3A, CH═N(alkyl)2A, or N(alkyl)3+A, where A is a charge balancing ion;
- CN, OH, CHO, COCH3, CO(alkyl), CO2H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)O-alkyl, CH(CH3)O-alkoxy, and CH(CH3)O-aryl;
- (CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
- C(X)2C(X)3, where X is a halogen;
- CO2R12, where R12 is selected from a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
- (CH2)nOH, or (CH2)nOR13, where R13 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- (CH2)nCO2R14, (CHX)nCO2R14, or (CX2)nCO2R14, where X is a halogen and R14 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalky;, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
- CONH(R15), CONHNH(R15), CO(R15), CON(R15)2, CON(R15)(R16), (CH2)nCONH(R15), (CH2)nCONHNH(R15), (CH2)nCON(R15)2, (CH2)nCOR15, (CH2)nCON(R15)(R16), (CX2)nCONH(R15), (CX2)nCON(R15)2, (CX2)nCON(R15)(R16) (CX2)nCOR15, (CH2)nCONHNH(R15), (CX2)nCONHNH(R15), (CHX)nCONH(R15), (CHX)nCONHNH(R15), (CHX)nCON(R15)2, (CHX)nCON(R15)(R16) where X is a halogen and R15 and R16 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or Polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- S(R17), (CH2)nS(R17), (CH2)nNH(R17), (CH2)nNH(R17), (CH2)nR17, (CH2)nN(R17)(R18), or (CH2)nN(R17)(R18)(R19)+A where R17, R18 and R19 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids, an amino acid ester, an amino acid amide provided —NH(R17) is part of the amino acid, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, a functional group of less than about 100,000 daltons, or where R17, R18 and R19 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
- (CH2)nOPO2OR20, (CH2)nPO(OR20)2, (CH2)nPO2R20, or (CH2)nPOR20 where R20 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- (CH2)nNHCOR21, or (CH2)nNHNHCOR21, where R21 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- SO3R22, SO2NHR22, SO2N(R22)2, SO2NHNHR22 or SO2R22, where R22 is select H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, and NHR22 can be an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
- Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
- R1—R2, R3—R4, R6—R7, R9—R10, R4—R5, R5—R6, R7—R8, R8—R9, R10—R11, or R11—R1, may also possess the atoms necessary to form ring systems, which themselves may possess heteroatoms that may bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons;
- with the proviso that at least one of the R1-R11 groups is linked via an organic group that has as part or all of its structure a group Q, which is an amine, an ester, an ether or an amide link, to a complexing agent of general formula IIa, IIb, IIc, IId, IIe:
- wherein R24 is selected from a hydrogen, a straight or branched chain C1-C7 alkyl group, a phenyl or benzyl group;
- L1, L2, L3, L4, independently of one another, are selected from a hydrogen atom or a metal ion equivalent of an element of the atomic numbers 20-32, 37-39, 42-51, or 57-83, which may be radioactive, provided that at least two of L1, L2, L3 and L4 are metal ion equivalents, that other anions are present to compensate for optionally present charges on the porphyrin, and free carboxyhic acid groups that are not required for complexing are optionally present as salts with physiologically compatible inorganic cations, or organic cations, or as esters or amides;
- and wherein
- M is 2H or a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, and Mg2+.
18 more elements
A compound of formula IIA:
- wherein R1-R6 can be the same or different and are selected from:
- H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH═CH(aryl), CH═CHCH2N(CH3)2, or a functional group of molecular weight of less than about 100,000 daltons;
- CH═CHCH2N+(CH3)3A, CH═N(alkyl)2A, or N(alkyl)3+A, where A is a charge balancing ion;
- CN, OH, CHO, COCH3, CO(alkyl), CO2H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)O-alkyl, CH(CH3)O-alkoxy, or CH(CH3)O-aryl;
- (CH2)nO-alkoxy, or (CH2)nO-aIkyl, where n is an integer from 0 to 8;
- C(X)2C(X)3, where X is a halogen;
- CO2R7, where R7 is selected from a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
- (CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- (CH2)nCO2R9, (CHX)nCO2R9, or (CX2)nCO2R9, where X is a halogen and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
- CONH(R10), CONHNH(R10), CO(R10), CON(R10)2, CON(R10)(R11), (CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10, (CH2)nCON(R10)(R11), (CX2)nCONH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(R11), (CX2)nCOR10, (CH2)nCONHNH(R10), (CX2)nCONHNH(R10), (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, or (CHX)nCON(R10)( R11), where X is a halogen and R10 and R11 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- S(R12), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nNHNH(R12), (CH2)nN(R12)2, (CH2)nN(R12)(R13), or (CH2)nN(R12)(R13)(R14)+A, where R12, R13 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids, an amino acid ester, or an amino acid amide provided —NH(R13) is part of the amino acid, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, a functional group of less than about 100,000 daltons, or where R12, R13 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
- (CH2)nOPO2OR15, (CH2)nPO(OR15)2, (CH2)nPO2R15, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- (CH2)nNHCOR16, or (CH2)nNHNHCOR16, where R16 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
- SO3R17, SO2NHR17, SO2N(R17)2, SO2NHNHR17 or SO2R17, where R17 is select H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, a functional group of less than about 100,000 daltons, and NHR17 can be an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue;
- Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
- and
- R1—R2, and R3—R4 may also possess the atoms necessary to form ring systems, which themselves may possess heteroatoms that may bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons;
- with the proviso that at least one of the R1-R4 groups is linked via an organic group that has as part or all of its structure a group Q, which is an amine, an ester, an ether or an amide link, to a complexing agent of general formula IIa, IIb, IIc, IId, IIe:
- wherein R24 is selected from a hydrogen, a straight or branched chain C1-C7 alkyl group, a phenyl or benzyl group;
- L1, L2, L3, L4, independently of one another, are selected from a hydrogen atom or a metal ion equivalent of an element of the atomic numbers 20-32, 37-39, 42-51, or 57-83, which may be radioactive, provided that at least two of L1, L2, L3 and L4 are metal ion equivalents, that other anions are present to compensate for optionally present charges on the porphyrin, and free carboxylic acid groups that are not required for complexing are optionally present as salts with physiologically compatible inorganic cations, or organic cations, or as esters or amides;
- and wherein
- M is 2H or a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, and Mg2+.
19 more elements
Dependencies are inferred from the claim text.