Mayo Foundation for Medical Education and Research
Regents of the University of Minnesota
대리인 / 주소
Fish & Richardson P.C.
인용정보
피인용 횟수 :
5인용 특허 :
99
초록
An agent, composition and method for the treatment, prophylaxis and/or diagnosis of proliferative disorders, which is highly and efficiently absorbed at the site of abnormal cellular proliferation is disclosed.
대표청구항▼
What is claimed is: 1. A compound of the formula (I): or its enantiomer, diastereomer or its pharmaceutically acceptable salt, wherein: (i) the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co--N bonds and one covalent Co--N bond,
What is claimed is: 1. A compound of the formula (I): or its enantiomer, diastereomer or its pharmaceutically acceptable salt, wherein: (i) the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co--N bonds and one covalent Co--N bond, wherein, in the case of the dative bond, the valence of nitrogen is completed either with a double bond with an adjacent ring carbon or with a hydrogen; (ii) the dotted line in the chemical structure indicates either a double or single bond such that the double bond does not over-extend the valence of the element and, in the case of a single bond, the valence is completed with hydrogen; (iii) X is hydrogen, cyano, halogen, haloalkyl, NO, NO2, NO3, phosphonate, PR15R16R17, NH2, NR15R16, OH, OR15, SR15, SCN, N3, OC(O)R15, C(O)2R15, C(O)R15, OC(O)NR15R16, C(O)2NR15R16, C(O)NR15R16, P(O)2OR15, S(O)2R15, a purine or pyrimidine nucleoside or nucleoside analog, adenosyl, 5-FU, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, amino acid, peptide, protein, carbohydrate, heteroalkyl, heterocycle, heteroaryl or alkylheteroaryl; (iv) M is a monovalent heterocycle or heteroaromatic, which is capable of binding to the adjacent sugar ring, and forming a dative bond with Co+3; (v) K is O, S, NJ1, C(OH)H, CR100R101 or C(R100)V8Z8; (vi) E is O or S; (vii) G1 is hydrogen, alkyl, acyl, silyl, phosphate or L-T; (viii) Y1, Y2, Y3, Y4, Y5, Y6 and Y7 independently are O, S or NJ2; (ix) V1, V2, V3, V4, V5, V6, V7 and V8 independently are O, S, NJ3, CR102R103 or a direct bond; (x) Z1, Z2, Z3, Z4, Z5, Z7 and Z8 independently are R104 or L-T; (xi) each L is independently a direct bond or linker, of a singular molecular weight, to one or more T moieties, and that does not significantly impair the ability of the TC-or IF-binding carrier to bind to a transcobalamin receptor, optionally when bound to a transport protein; (xii) each T independently comprises the residue of a diagnostic agent effective for the diagnosis of a proliferative disorder, optionally bound though a chelating moiety; (xiii) at least one of Z1, Z2, Z3, Z4, Z5, Z7, Z8, K and G1 is L-T; (xiv) J1, J2 and J3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy or amine; (xv) R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heteroalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO2, SO3, carboxylic acid, C1-6 carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine; (xvi) R13 and R14 optionally can form a double bond; (xvii) R15, R16 and R17 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl group, heteroalkyl, heterocycle or heteroaromatic; and (xviii) R100, R101, R102, R103, and R104 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO2, SO3, thioalkyl or amino; (xix) wherein at least one of Y, R, G, E, K, M and V is not as it is found in natural vitamin B12; and (xx) wherein at least one-L-T is independently a poly-L-lysine-NR'(CH((CH2)4 --NHR')CONR')mR', wherein each R' is independently hydrogen, lower alkyl or T; and m is 2-20. 2. A compound of the formula (I): or its enantiomer, diastereomer or its pharmaceutically acceptable salt, wherein: (i) the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co--N bonds and one covalent Co--N bond, wherein, in the case of the dative bond, the valence of nitrogen is completed either with a double bond with an adjacent ring carbon or with a hydrogen; (ii) the dotted line in the chemical structure indicates either a double or single bond such that the double bond does not over-extend the valence of the element and, in the case of a single bond, the valence is completed with hydrogen; (iii) X is hydrogen, cyano, halogen, haloalkyl, NO, NO2, NO3, phosphonate, PR15R16R17, NH2, NR15R16, OH, OR16, SR15, SCN, N3, OC(O)R15, C(O)2R15, C(O)R15, OC(O)NR15R16, C(O)2NR15R16, C(O)NR15R16, P(O)2OR15, S(O)2R15, a purine or pyrimidine nucleoside or nucleoside analog, adenosyl, 5-FU, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, amino acid, peptide, protein, carbohydrate, heteroalkyl, heterocycle, heteroaryl or alkyiheteroaryl; (iv) M is a monovalent heterocycle or heteroaromatic, which is capable of binding to the adjacent sugar ring, and forming a dative bond with Co+3; (v) K is O, S, NJ1, C(OH)H, CR100R101 or C(R100)V8Z8; (vi) E is O or S; (vii) G1 is hydrogen, alkyl, acyl, silyl, phosphate or L-T; (viii) Y1, Y2, Y3, Y4, Y5, Y6 and Y7 independently are O, S or NJ2; (ix) V1, V2, V3, V4, V5, V6, V7 and V8 independently are O, S, NJ3, CR102R103 or a direct bond; (x) Z1, Z2, Z3, Z4, Z5, Z7 and Z8 independently are R104 or L-T; (xi) each L is independently a direct bond or linker, of a singular molecular weight, to one or more T moieties, and that does not significantly impair the ability of the TC-or IF-binding carrier to bind to a transcobalamin receptor, optionally when bound to a transport protein; (xii) each T independently comprises the residue of a diagnostic agent effective for the diagnosis of a proliferative disorder, optionally bound though a chelating moiety; (xiii) at least one of Z1, Z2, Z3, Z4, Z5, Z7, Z8, K and G1 is L-T; (xiv) J1, J2 and J3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy or amine; (xv) R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heteroalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO2, SO3, carboxylic acid, C1-6 carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine; (xvi) R13 and R14 optionally can form a double bond; (xvii) R15, R16 and R17 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl group, heteroalkyl, heterocycle or heteroaromatic; and (xviii) R100, R101, R102, R103, and R104 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO2, SO3, thioalkyl or amino; (xix) wherein at least one of Y, R, G, E, K, M and V is not as it is found in natural vitamin B12; and (xx) wherein at least one-L-T is independently a polyamine residue of the formula--NR'(alkylene-NR')nalkyleneNR'R', wherein each R' is independently hydrogen, lower alkyl or T and n is 1-20. 3. A compound of the formula (I): or its enantiomer, diastereomer or its pharmaceutically acceptable salt, wherein: (i) the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co--N bonds and one covalent Co--N bond, wherein, in the case of the dative bond, the valence of nitrogen is completed either with a double bond with an adjacent ring carbon or with a hydrogen; (ii) the dotted line in the chemical structure indicates either a double or single bond such that the double bond does not over-extend the valence of the element and, in the case of a single bond, the valence is completed with hydrogen; (iii) X is hydrogen, cyano, halogen, haloalkyl, NO, NO2, NO3, phosphonate, PR15R16R17, NH2, NR15R16, OH, OR15, SR15, SCN, N3, OC(O)R15, C(O)2R15, C(O)R15, OC(O)NR15R16, C(O)2NR15R16, C(O)NR15R16, P(O)2OR15, S(O)2R15, a purine or pyrimidine nucleoside or nucleoside analog, adenosyl, 5-FU, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, amino acid, peptide, protein, carbohydrate, heteroalkyl, heterocycle, heteroaryl or alkyiheteroaryl; (iv) M is a monovalent heterocycle or heteroaromatic, which is capable of binding to the adjacent sugar ring, and forming a dative bond with Co+3; (v) K is O, S, NJ1, C(OH)H, CR100R101 or C(R100)V8Z8; (vi) E is O or S; (vii) G1 is hydrogen, alkyl, acyl, silyl, phosphate or L-T; (viii) Y1, Y2, Y3, Y4, Y5, Y6 and Y7 independently are O, S or NJ2; (ix) V1, V2, V3, V4, V5, V6, V7 and V8 independently are O, S, NJ3, CR102R103 or a direct bond; (x) Z1, Z2, Z3, Z4, Z5, Z7 and Z8 independently are R104 or L-T; (xi) each L is independently a direct bond or linker, of a singular molecular weight, to one or more T moieties, and that does not significantly impair the ability of the TC-or IF-binding carrier to bind to a transcobalamin receptor, optionally when bound to a transport protein; (xii) each T independently comprises the residue of a diagnostic agent effective for the diagnosis of a proliferative disorder, optionally bound though a chelating moiety; (xiii) at least one of Z1, Z2, Z3, Z4, Z5, Z7, Z8, K and G1 is L-T; (xiv) J1, J2 and J3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy or amine; (xv) R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heteroalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO2, SO3, carboxylic acid, C1-6 carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine; (xvi) R13 and R14 optionally can form a double bond; (xvii) R15, R16 and R17 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl group, heteroalkyl, heterocycle or heteroaromatic; and (xviii) R100, R101, R102, R103, and R104 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO2, SO3, thioalkyl or amino; (xix) wherein at least one of Y, R, G, E, K, M and V is not as it is found in natural vitamin B12; (xx) wherein at least one-L-T is independently a poly-L-lysine-NR'(CH((CH2)4 --NHR')CONR')mR', wherein each R' is independently hydrogen, lower alkyl or T; and m is 2-20; and (xxi) wherein at least one T is a detectable radionuclide. 4. A compound of the formula (I): or its enantiomer, diastereomer or its pharmaceutically acceptable salt, wherein: (i) the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co--N bonds and one covalent Co--N bond, wherein, in the case of the dative bond, the valence of nitrogen is completed either with a double bond with an adjacent ring carbon or with a hydrogen; (ii) the dotted line in the chemical structure indicates either a double or single bond such that the double bond does not over-extend the valence of the element and, in the case of a single bond, the valence is completed with hydrogen; (iii) X is hydrogen, cyano, halogen, haloalkyl, NO, NO2, NO3, phosphonate, PR15R16R17, NH2, NR15R16, OH, OR15, SR15, SCN, N3, OC(O)R15, C(O)2R15, C(O)R15, OC(O)NR15R16, C(O)2NR15R16, C(O)NR15R16, P(O)2OR15, S(O)2R15, a purine or pyrimidine nucleoside or nucleoside analog, adenosyl, 5-FU, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, amino acid, peptide, protein, carbohydrate, heteroalkyl, heterocycle, heteroaryl or alkyiheteroaryl; (iv) M is a monovalent heterocycle or heteroaromatic, which is capable of binding to the adjacent sugar ring, and forming a dative bond with Co+3; (v) K is O, S, NJ1, C(OH)H, CR100R101 or C(R100)V8Z8; (vi) E is O or S; (vii) G1 is hydrogen, alkyl, acyl, silyl, phosphate or L-T; (viii) Y1, Y2, Y3, Y4, Y5, Y6 and Y7 independently are O, S or NJ2; (ix) V1, V2, V3, V4, V5, V6, V7 and V8 independently are O, S, NJ3, CR102R103 or a direct bond; (x) Z1, Z2, Z3, Z4, Z5, Z7 and Z8 independently are R104 or L-T; (xi) each L is independently a direct bond or linker, of a singular molecular weight, to one or more T moieties, and that does not significantly impair the ability of the TC-or IF-binding carrier to bind to a transcobalamin receptor, optionally when bound to a transport protein; (xii) each T independently comprises the residue of a diagnostic agent effective for the diagnosis of a proliferative disorder, optionally bound though a chelating moiety; (xiii) at least one of Z1, Z2, Z3, Z4, Z5, Z7, Z8, K and G1 is L-T; (xiv) J1, J2 and J3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy or amine; (xv) R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heteroalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO2, SO3, carboxylic acid, C1-6 carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine; (xvi) R13 and R14 optionally can form a double bond; (xvii) R15, R16 and R17 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl group, heteroalkyl, heterocycle or heteroaromatic; and (xviii) R100, R101, R102, R103, and R104 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO2, SO3, thioalkyl or amino; (xix) wherein at least one of Y, R, G, E, K, M and V is not as it is found in natural vitamin B12; (xx) wherein at least one-L-T is independently a polyamine residue of the formula--NR'(alkylene-NR')nalkyleneNR'R', wherein each R' is independently hydrogen, lower alkyl or T and n is 1-20; and (xxi) wherein at least one T is a detectable radionuclide. 5. The compound of claim 2 or 4, wherein--NR'(alkylene-NR')nalkyleneNR' is selected from the group consisting of--NR'(CH2)3NR'(CH2)4NR'(CH2 )3NR'R';--NR'(CH2)3NR'(CH2)4NR'R'; decamethylene tetraamine and pentamethylene hexamine. 6. A pharmaceutical composition for the diagnosis of a proliferative disorder in a host comprising a compound of claim 1, 2, 3, and 4, or the pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. 7. A pharmaceutical composition for the diagnosis of a proliferative disorder in a host comprising a compound of claim 1, 2, 3, and 4, or the pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in combination with one or more other diagnostic agent(s). 8. The pharmaceutical composition of claim 6, wherein the host is a human. 9. The pharmaceutical composition of claim 7, wherein the host is a human.
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