Patent ID: 6548663
Filing Date: 2003-04-15
Classification: A61K,B01J,C07D,C07K,C40B

Abstract:
A method of imaging formation of new blood vessels in a patient comprising:(1) administering a diagnostically effective amount of a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent to a patient by injection or infusion; and (2) imaging the area of the patient wherein the desired formation of new blood vessels is located, wherein the diagnostic radiopharmaceutical, MRI contrast agent, or X-ray contrast agent comprises: i) a radioisotope selected from the group consisting of: 99mTc, 95Tc, 111In, 62Cu, 64Cu, 67Ga, or a paramagnetic metal ion, selected from the group consisting of: Gd(III), Dy(III), Fe(III), and Mn(II), or a metal selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir; and ii) a compound of the formula: (Q)dâ€”Lnâ€”Ch or (Q)dâ€”Lnâ€”(Ch)dâ€²wherein, Q is a compound of Formula (I): wherein:one of R or R1 is selected from a bond to Ln or (CH2)1-4 or an NH bond to Ln and the other of R or R1 is selected from C1-4 alkyl, benzyl or phenethyl; R2 is selected from benzimidazole or imidazole; R3 is selected from H, C1-4 alkyl or benzyl; R4 is selected from H, C1-4 alkyl or benzyl; d is selected from 1, 2 and 3; Ln is a linking group having the formula: (CR6R7)gâ€”(W)hâ€”(CR6aR7a)gâ€²â€”(Z)kâ€”(W)hâ€²â€”(CR8R9)gâ€³â€”(W)hâ€³â€”(CR8aR9a)gâ€²â€³â€”(W)hâ€²â€³â€”(CR8bR9b)gâ€³â€³provided that g+h+gâ€²+k+hâ€²+gâ€³+hâ€³+gâ€²â€³ is other than 0;W is independently selected at each occurrence from the group: O, S, NH, NHC(&boxH;O), C(&boxH;O)NH, C(&boxH;O), C(&boxH;O)O, OC(&boxH;O), NHC(&boxH;S)NH, NHC(&boxH;O)NH, SO2, (OCH2CH2)s, (CH2CH20)sâ€², (OCH2CH2CH2)sâ€³, (CH2CH2CH2O)t, and (aa)tâ€²; aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substitued with 0-3 R10, C3-10 cycloalkyl substituted with 0-3 R10, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R10; R6, R6a, R7, R7a, R8, R8a, R8b, R9, R9a and R9b are independently selected at each occurrence from the group: H, &boxH;O, COOH, SO3H, PO3H, C1-C5alkyl substituted with 0-3 R10, aryl substituted with 0-3 R10, benzyl substituted with G-3 R10, and C1-C5 alkoxy substituted with 0-3 R10, NHC(&boxH;O)R11, C(&boxH;O)NHR11, NHC(&boxH;O)NHR11, NHR11, R11, and a bond to Ch; R10 is independently selected at each occurrence from the group: a bond to Ch COOR11, OH, NHR11, C(&boxH;O)NHR11, NH(C&boxH;O)R11,SO3H, PO3H, &boxH;O, R11, aryl substituted with 0-3 R11, C1-5 alkyl substituted with 0-1 R12, C1-5 alkoxy substituted with 0-1 R12, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R11; R11 is independently selected at each occurrence from the group: H, C1-C10 alkyl substituted with 0-1 R12, aryl substituted with 0-1 R12, a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R12, C3-10 cycloalkyl substituted with 0-1 R12, polyalkylene glycol substituted with 0-1 R12, carbohydrate substituted with 0-1 R12, cyclodextrin substituted with 0-1 R12, amino acid substituted with 0-1 R12 polycarboxyalkyl substituted with 0-1 R12 polyazaalkyl substituted with 0-1 R12, peptide substituted with 0-1 R12, wherein the peptide is comprised of 2-10 amino acids, and a bond to Ch; R12 is a bond to Ch; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; hâ€² is selected from 0, 1, 2, 3, 4, and 5; hâ€³ is selected from 0, 1, 2, 3, 4, and 5; hâ€²â€³ is selected from 0, 1, 2, 3, 4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; gâ€² is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; gâ€³ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; gâ€²â€³ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; gâ€³â€³ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; sâ€² is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; sâ€³ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; tâ€² is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Ch is a metal bonding unit having a formula selected from the group: A1, A2, A3, A4, A5, A6, A7, and A8 are independently selected at each occurrence from the group: NR13, NR13R14, S, SH, S(Pg), O, OH, PR13, PR13R14, P(O)R15R16, CO2H and a bond to Ln; E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C1-C10 alkyl substituted with 0-3 R17, aryl substituted with 0-3 R17, C3-10 cycloalkyl substituted with 0-3 R17, heterocyclo-C1-10 alkyl substituted with 0-3 R17, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0-3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0-3 R17, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R17; R13 and R14 are each independently selected from the group: a bond to Ln, hydrogen, C1-C10 alkyl substituted with 0-3 R17, aryl substituted with 0-3 R17, C1-10 cycloalkyl substituted with 0-3 R17, heterocyclo-C1-10 alkyl substituted with 0-3 R17, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0-3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0-3 R17, a 5-10 membered heterocyclic ring system having 14 heteroatoms independently selected from N, S, and O and substituted with 0-3 R17, and an electron, provided that when one of R13 or R14 is an electron, then the other is also an electron; alternatively, R13 and R14 combine to form &boxH;C(R20)(R21); R15 and R16 are each independently selected from the group: a bond to Ln, â€”OH, C1-C10 alkyl substituted with 0-3 R17, C1-C10 alkyl substituted with 0-3 R17, aryl substituted with 0-3 R17, C1-10 cycloalkyl substituted with 0-3 R17, heterocyclo-C1-10 alkyl substituted with 0-3 R17, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0-3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0-3 R17, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R17; R17 is independently selected at each occurrence from the group: a bond to Ln, &boxH;O, F, Cl, Br, I, â€”CF3, â€”CN, â€”CO2R18, â€”C(&boxH;O)R18, â€”C(&boxH;O)N(R18)2, â€”CHO, â€”CH2OR18, â€”OC(&boxH;O)R18, â€”OC(&boxH;O)OR18a, â€”OR18, â€”OC(&boxH;O)N(R18)2, â€”NR19C(&boxH;O)R18, â€”NR19C(&boxH;O)OR18a, â€”NR19C(&boxH;O)N(R18)2, â€”NR19SO2N(R18)2, â€”NR19SO2R18a, â€”SO3H, â€”SO2R18a, â€”SR18, â€”S(&boxH;O)R18a, â€”SO2N(R18)2, â€”N(R18)2, â€”NHC(&boxH;S)NHR18, &boxH;NOR18, NO2, â€”C(&boxH;O)NHOR18, â€”C(&boxH;O)NHNR18R18a, â€”OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C5 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6 alkoxyalkyl, aryl substituted with 0-2 R18, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O; R18, R18a, and R19 are independently selected at each occurrence from the group: a bond to Ln, H, C1-C6 alkyl, phenyl, benzyl, C1-C6 alkoxy, halide, nitro, cyano, and trifluoromethyl; Pg is a thiol protecting group; R20 and R21 are independently selected from the group: H, C1-C10 alkyl, â€”CN, â€”CO2R25, â€”C(&boxH;O)R25, â€”C(&boxH;O)N(R25)2, C2-C10 1-alkene substituted with 0-3 R23, C2-C10 1-alkyne substituted with 0-3 R23, aryl substituted with 0-3 R23, unsaturated 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R23, and unsaturated C3-10 carbocycle substituted with 0-3 R23; alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H, R24, C1-C10 alkyl substituted with 0-3 R24, C2-C10 alkenyl substituted with 0-3 R24, C2-C10 alkynyl substituted with 0-3 R24, aryl substituted with 0-3 R24, a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R24, and C3-10 carbocycle substituted with 0-3 R24; alternatively, R22, R23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O; a and b indicate the positions of optional double bonds and n is 0 or 1; R24 is independently selected at each occurrence from the group: &boxH;O, F, Cl, Br, I, â€”CF3, â€”CN, â€”CO2R25, â€”C(&boxH;O)R25, â€”C(&boxH;O)N(R25)2, â€”N(R25)3+, â€”CH20R25, â€”OC(&boxH;O)R25, â€”OC(&boxH;O)OR25a, â€”OR25, â€”OC(&boxH;O)N(R25)2, â€”NR26C(&boxH;O)R25, â€”NR26C(&boxH;O)OR25a, â€”NR26C(&boxH;O)N(R25)2, â€”NR26SO2N(R25)2, â€”NR26SO2R25a, â€”SO3H, â€”SO2R25a, â€”SR25, â€”S(&boxH;O)R25a, â€”SO2N(R25)2, â€”N(R25)2, &boxH;NOR25, â€”C(&boxH;O)NHOR25, â€”OCH2CO2H, and 2-(1-morpholino)ethoxy; and, R25, R25a, and R26 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl; and a pharmaceutically acceptable salt thereof.