Patent EA-000742-B1 (EA)
Title: Stable reagents for the preparation of radiopharmaceuticals
Inventor: SWORIN MICHAEL
IPC: A61K31/00
Filed: 1996-06-07
Abstract: 1. A reagent for preparing a radiopharmaceutical comprising a biologically active group connected to a stable hydrazone group, optionally having a linking group between said stable hydra zone and said biologically active group. 2. The reagent of claim 1 having a linking group between said stable hydrazone and said biologically active group. 3. The reagent of claim 2 having the formula (Q)d'Ln-Hz and pharmaceutically acceptable salts thereof wherein Q is a biologically active group; d' is 1-20; Ln is a linking group of formula M<1>-[Y<1>(CR<55>R<56>)f(Z<1>)f"Y<2>]f'M<2> wherein M<1> is -[(CH<2>)gZ<1>]g'(CR<55>R<56>)g"-; M<2> is -(CR<55>R<56>)g"-[Z<1>(CH2)g]g'-; g is independently 0-10; g' is independently 0-1; g" is independently 0-10; f is independently 0-10; f' is independently 0-10; f" is independently 0-1; Y<1> and Y<2>, are independently selected at each occurrence from a bond, O, NR<56>, C=O, C(=O)O, OC(=O)O, C(=O)NH-, C=NR<56>, S, SO, SO2, SO3, NHC(=O), (NH)2C(=O), (NH)2C=S; Z<1> is independently selected at each occurrence from a C6-C14  saturated, partially saturated, or aromatic carbocyclic system, substituted with 0-4 R<57>; and a heterocyclic system, substituted with 0-4 R<57>; R<55> and R<56> are independently selected at each occurrence from hydrogen; C1-C10 alkyl substituted with 0-5 R<57>; alkaryl wherein the aryl is substituted with 0-5 R<57>; R<57> is independently selected at each occurrence from the group hydrogen, OH, NHR<58>, C(=O)R<58>, OC(=O)R<58>, OC(=O)OR<58>, C(=O)OR<58>, C(=O)NR<58>, C [triple bond] N, SR<58>, SOR<58>, SO2R<58>, NHC(=O)R<58>, NHC(=O)NHR<58>, NHC(=S)NHR<58>;or, alternatively, when attached to an additional molecule Q, R<57> is independently selected at each occurrence from the group: O, NR, C=O, C(=O)O, OC(=O)O, C(=O)N-, C=NR<58>, S, SO, SO2, SO3, NHC(=O), (NH)2C(=O), (NH)2C=S; and, R<58> is independently selected at each occurrence from the group: hydrogen; C1-C6 alkyl; benzyl, and phenyl; Hz is a stable hydrazone of formula   wherein R<40> is independently selected at each occurrence from the group: a bond to Ln, C1-C10 alkyl substituted with 0-3 R<52>, aryl substituted with 0-3 R<52>, cycloaklyl substituted with 0-3 R<52>, heterocycle substituted with 0-3 R<52>, heterocycloalkyl substituted with 0-3 R<52>, aralkyl substituted with 0-3 R<52> and alkaryl substituted with 0-3 R<52>; R<41> is independently selected from the group: hydrogen, aryl substituted with 0-3 R<52>, C1-C10 alkyl substituted with 0-3 R<52>, and a heterocycle substituted with 0-3 R<52>; R<52> is independently selected at each occurrence from the group: a bond to Ln, =O, F, Cl, Br, I, -CF3, -CN, -CO2R<53>, -C(=O)R<53>, -C(=O)N(R<53>)2, -CHO, -CH2OR<53>, -OC (=O)R<52>, -OC(=O)OR<53a>, -OR<53>, -OC(=O)N(R<53>)2, -NR<53>C(=O)R<53>, -NR<54>C(=O)OR<53a>, -NR<53>C(=O)N(R<53>)2, -NR<54>SO2N(R<53>)2, -NR<54>SO2R<53a>, -SO3H, -SO2R<53a>, -SR<53>, -S(=O)R<53a>, -SO2N(R<53>)2, -N(R<53>)2, -NHC(=NH)NHR<53>, -C(=NH)NHR<53>, NOR<53>, NO2, -C(=O)NHOR<53>, -C(=O)NHNR<53>R<53a>, -OCH2CO2H, 2-(1-morpholino)ethoxy; R<53>, R<53a>, and R<54> are each independently selected at each occurrence from the group: hydrogen, C1-C6 alkyl, and a bond to Ln; R<80> and R<81> are independently selected from the group H; C1-C10 alkyl; -CN; -CO2R<85>; -C(=O)R<85>; -C(=O)N(R<85>)2; C2-C10 1-alkene substituted with 0-3 R<84>; C2-C10 1-alkyne substituted with 0-3 R<84>; aryl substituted with 0-3 R<84>; unsaturated heterocycle substituted with 0-3 R<84>; and unsaturated carbocycle substituted with 0-3 R<84>; provided that when one of R<80> and R<81> is H or alkyl, then the other is not H or alkyl; or, alternatively, R<80> and R<81>, may be taken together with the shown divalent carbon radical to form   wherein R<82> and R<83> may be independently selected from the group: H; R<84>; C1-C10 alkyl substituted with 0-3 R<84>; C2-C10 1-alkenyl substituted with 0-3 R<84>; C2-C10 1-alkynyl substituted with 0-3 R<84>; aryl substituted with 0-3 R<84>; heterocycle substituted with 0-3 R<84>; and carbocycle substituted with 0-3 R<84>; or, alternatively, R<82>, R<83> may be taken together to form a fused aromatic or heterocyclic ring; a and b indicate the positions of optional double bonds and n is 0 or 1, R<84> is independently selected at each occurrence from the group: =O, F, Cl, Br, I, -CF3, -CN, -CO2R<85>, -C(=O)R<85>, -C(=O)N(R<85>)2, -N(R<85>)3+, -CH2OR<85>, -OC(=O)R<85>, -OC(=O)OR<85a>, -OR<85>, -OC(=O)N(R<85>)2, -NR<85>C(=O)R<85>, -NR<86>C(=O)OR<85a>, -NR<85>C(=O)N(R<85>)2, -NR<86>SO2N(R<85>)2, -NR<86>SO2R<85a>, -SO3H, -SO2R<85a>, -SR<85>, -S(=O)R<85a>, -SO2N(R<85>)2, -N(R<85>)2, -NHC(=NH)NHR<85>, -C (=NH)NHR<85>, =NOR<85>, -C(=O)NHOR<85>, -CH2CO2H, 2-(1-morpholino)ethoxy; and R<85>, R<85a> and R<86> are each independently selected at each occurrence from the group:hydrogen, C1-C6 alkyl. 4. The reagent of claim 3 wherein Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists, IIb/IIIa receptor ligands, fibrin binding peptides, leukocyte binding peptides, chemotactic peptides, somatostatin analogs, and selectin binding peptides; d' is 1 to 3; Ln is: -(CR<55>R<56>)g"-[Y<1>(CR<55>R<56>)ffY<2>]f'-(CR<55>R<56>) g"-, wherein g" is 0-5; f is 0-5; f' is 1-5; Y<1> and Y<2>, are independently selected at each occurrence from: O, NR<56>, C=O, C(=O)O, OC(=O)O, C(=O)NH-, C=NR<56>, S, SO, SO2, SO3, NHC(=O), (NH)2C(=O), (NH)2C=S; R<55> and R<56> are independently selected at each occurrence from hydrogen, C1-C10 alkyl, and alkaryl; Hz is a stable hydrazone of formula   wherein R<40> is independently selected at each occurrence from the group: aryl substituted with 0-3 R<52>, and heterocycle substituted with 0-3 R<52>; R<41> is independently selected from the group: hydrogen, aryl substituted with 0-1 R<52>, C1-C3 alkyl substituted with 0-1 R<52>, and a heterocycle substituted with 0-1 R<52>; R<52> is independently selected at each occurrence from the group: a bond to Ln, -CO2R<53>, -CH2OR<53>, -SO3H, -SO2R<53a>, -N(R<53>)2, -NHC(=NH)NHR<53>, and -OCH2CO2H; R<53>, R<53a> are each independently selected at each occurrence from the group: hydrogen and C1-C3 alkyl; R<80> is independently selected at each occurrence from the group: -CO2R<85>; C2-C5 1-alkene substituted with 0-3 R<84>; C2-C5 1-alkyne substituted with 0-3 R<84>; aryl substituted with 0-3 R<84>; unsaturated heterocycle substituted with 0-3 R<84>; R<81> is independently selected at each occurrence from the group: H and C1-C5 alkyl; or, alternatively, R<80> and R<81>, when taken together with the indicated divalent carbon radical form   wherein R<82> and R<83> may be independently selected from the group: H and R<84>; or, alternatively, R<82>, R<83> may be taken together to form a fused aromatic or heterocyclic ring; a and b indicate the positions of optional double bonds and n is 0 or 1, R<84> is independently selected at each occurrence from the group -CO2R<85>, -C(=O)N(R<85>)2, -CH2OR<85>, -OC(=O)R<85>, -OR<85>, -SO3H, -N(R<85>)2, -OCH2CO2H; R<85> is independently selected at each occurrence from the group hydrogen, C1-C3 alkyl. 5. The reagent of claim 4 wherein Q represents a biologically active molecule selected from the group: IIb/IIIa receptor antagonists and chemotactic peptides; d' is 1; Ln is: -(CR<55>R<56>)g"-[Y<1>(CR<55>R<56>)ffY<2>]f'-(CR<55>R<56>) g"-, wherein g" is 0-5; f is 0-5; f' is 1-5; Y<1> and Y<2>, are independently selected at each occurrence from O, NR<56>, C=O, C(=O)O, OC(=O)O, C(=O)NH-, C=NR<56>, S, NHC(=O), (NH)2C(=O), (NH)2C=S;  R<55> and R<56> hydrogen; Hz is a stable hydrazone of formula   wherein R<40> is independently selected at each occurrence from the group: heterocycle substituted with R<52>; R<41> is hydrogen; R<52> is a bond to Ln; R<80> is independently selected from the group:-CO2R<85>; C2-C3 1-alkene substituted with 0-1 R<84>; aryl substituted with 0-1 R<84>; unsaturated heterocycle substituted with 0-1 R<84>; R<81> is H; R<84> is independently selected at each occurrence from the group: -CO2R<85>; -OR<85>; -SO3H; -N(R<85>)2; R<85> is independently selected at each occurrence from the group: H and methyl. 6. The reagents of claim 3 that are:             7. A kit for preparing a radiopharmaceutical comprising: (a) a predetermined quantity of a sterile, pharmaceutically acceptable reagent of any of claims 1-6; (b) a predetermined quantity of one or more sterile, pharmaceutically acceptable ancillary ligand(s); (c) a predetermined quantity of a sterile, pharmaceutically acceptable reducing agent; and (d) optionally, a predetermined quantity of a sterile, pharmaceutically acceptable component selected from the group: transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids and bacteriostats. 8. A kit for preparing a radiopharmaceutical comprising: (a) a predetermined quantity of a sterile, pharmaceutically acceptable reagent of any of claims 1-6; (b) a predetermined quantity of two sterile, pharmaceutically acceptable ancillary ligand(s); (c) a predetermined quantity of a sterile, pharmaceutically acceptable reducing agent; and (d) optionally, a predetermined quantity of a sterile, pharmaceutically acceptable component selected from the group: transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids and bacteriostats. 9. A stable hydrazone compound useful for the synthesis of the reagents of Claim 1 having the formula: R<44> (C=O)s(R<45>)N-N=CR<80>R<81> Wherein s is 0 or 1; R<44> is selected from the group aryl substituted with 1 R<59> and heterocycle substituted with 1 R<59>; R<45> is selected from the group hydrogen and C1-C6 alkyl, R<59> is a chemically reactive moiety selected from the group alkyl substituted with halogen; acid anhydride; acid halide; active ester; isothiocyanate; maleimide; R<80> and R<81> are independently selected from the group H; C1-C10 alkyl; -CN; -CO2R<85>; -C(=O)R<85>; -C(=O)N(R<85>)2; C2-C10 1-alkene substituted with 0-3 R<84>; C2-C10