Patent EA-000636-B1 (EA)
Title: Ternary radiopharmaceutical complexes
Inventor: EDWARDS DAVID SCOTT
IPC: A61K51/08
Filed: 1996-04-03
Abstract: 1. A radiopharmaceutical comprising a transition metal radionuclide, a transition metal chelator, a biologically active group connected to said chelator, a first ancillary ligand, a second ancillary ligand capable of stabilizing the radiopharmaceutical, optionally having a linking group between said chelator and said biologically active group. 2. A radiopharmaceutical of Claim 1 having a linking group between said chelator and said biologically active group. 3. A radiopharmaceutical of Claim 2 of formula: [(Q)d', Ln-Ch']x-Mt(AL1)y(AL2)z (1) wherein: Q is a biologically active molecule; d' is 1 to 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 -[(CH2)gZ<l>]g'-(CR<55>R<56>)g''-,x 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>, at each occurrence, are independently selected from: a bond, O, NR<56>, C=O. C(=O)O, OC(=O)O, C(=O)NH-, C=NR<56>, S, SO, S02, S03, 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 ring system, substituted with 0-4 R<57>; and a heterocyclic ring system, optionally 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(=0)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<58>, C=O, C(=O)O, OC(=O)O, C(=O)N-, OC=MR<58>. S, SO, S02, S03, 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; x and y are independently 1 or 2; z is independently 1-4; Mt is a transition metal radionuclide selected from the group: <99m>Tc, <186>Re and <188>Re; Ch' is a radionuclide metal chelator coordinated to transition metal radionuclide Mt, and is independently selected at each occurrence, from the group: R<40>N=N<+>=, R<40>R<41>N-N=, R<40>N=, and R<40>N=N(H)-, 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, -CHO20R<53>, -OC(=O)R<53>, -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>, -S02N(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; AL1 is a first ancillary ligand which is functionalized aminocarboxylate; AL2 is an ancillary ligand capable of stabilizing the radiopharmaceutical selected from the group: A<9> and A<10>-W-A<11>, wherein: A<9> is independently selected at each occurrence from the group: PR<61>R<62>R<63> and AsR<61>R<62>R<63>; A<10> and A<11>- are independently selected at each occurrence from the group: PR<61>R<62>and AsR<61>R<62>; W is a spacer group selected from the group: C1-C10 alkyl substituted with 0-3 R<70>, aryl substituted with 0-3 R<70>. cycloaklyl substituted with 0-3 R<70>, heterocycle substituted with 0-3 R<70> heterocycloalkyl substituted with 0-3 R<70>, aralkyl substituted with 0-3 R<70> and alkaryl substituted with 0-3 R<70>; R<61>, R<62>, and R<63> are independently selected at each occurrence from the group: C1-C10 alkyl substituted with 0-3 R<70>, aryl substituted with 0-3 R<70>, cycloalkyl substituted with 0-3 R<70>. heterocycle substituted with 0-3 R<70>, aralkyl substituted with 0-3 R<70>, alkaryl substituted with 0-3 R<70> and arylalkaryl substituted with 0-3 R<70>; R<70> is independently selected at each occurrence from the group: F, Cl, Br. I, -CF3, -CN, -C02R<71>- -C(=O)R<71>, -C(=O)N(R<71>)2, -CH2OR<71>, -OC(=O)R<71>, -OC(=O)OR<71a>, -OR<71>, -OC(==O)N(R<71>)2, - -NR<71>C(=O)OR<71>, -NR<71>C(=O)N(R<71>)2. SO3-, -NR<71>SO2N(R<71>)2, -NR<71>SO2R<71a>, -SO3H. -SO2R<71>, -S(=O)R<71>, -SO2N(R<71>)2. -N(R<71>), -N(R<71>)3+, -NHC(=NH)NHR<71>, -C (=NH)NHR<71>, =NOR<71>, N02. -C (=O)NHOR<71>, -C(=O)NHNR<71>R<71a>, -OCH2C02H; and R<71> and R<71a> are independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl; and pharmaceutically acceptable salts thereof. 4. A radiophamiaceutical 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>R5<6>)g''-[Y<l>(CR<55>R<56>)fY<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>, at each occurrence, are independently selected 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; x and y are independently 1 or 2; z is independently 1-2; MT is <99m>Tc; Ch' is a radionuclide metal chelator coordinated to transition metal radionuclide Mt and is independently selected at each occurrence, from the group: R<40>N=N<+>=, R<40>R<41>N-N=, R<40>N=, and R<40> N=N(H)-; 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 R5<2>; R<52> is independently selected at each occurrence from the group: a bond to Ln, -CO2R<53>. -CH2 OR<53>, -SO3H -SO2R<53>-, -N(R<53>)2, -N(R<53>)3<+>, -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; AL1 is selected from the group: pyrones, pyridinones, and functionalized aminocarboxylates; AL2 is selected from the group: A<9> and A<10>-W-A<11>, wherein: A<9> is PR<61>R<62>R<63>; A<10> and A<11> are PR<61>R<62>; W is a spacer group selected from the group: C1-C3 alkyl substituted with 0-3 R<70>, aryl substituted with 0-3 R<70>, and heterocycle substituted with 0-3 R<70>; R<61>, R<62>, and R<63> are independently selected at each occurrence from the group: C1-C3 alkyl substituted with 0-3 R<70>, aryl substituted with 0-3 R<70>, and heterocycle substituted with 0-3 R<70>; R<70> is independently selected at each occurrence from the group: -C02R<71>, -OR<71>, -S03 and -S03H; and R<71> is hydrogen. 5. A radiopharmaceutical 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<l>(CR<55>R<56>)fY<2>]f'-(CR<55>R<56>)g'', wherein: g" is 0-5; f is 0-5; f'is 1-5; Y<1> and y2, at each occurrence, are independently selected 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> are hydrogen; x and y are 1; z is 1; Ch'- is a radionuclide inetal chelator coordinated to transition inetal radionuclide MT. and is independently selected at each occurrence, from the group: R<40>N=N<+>=, and R<40>R<41>N-N=; 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; AL1 is tricine; AL2 is PR<61>R<62>R<63>, wherein R<61>, R<62>, and R<63> are independently selected at each occurrence from the group: C1-C3 alkyl substituted with 0-3 R<70>, aryl substituted with 0-3 R<70>; R<70> is independently selected at each occurrence from the group: -CO2H, -OH, -SO3H, -SO3-. 6. The radiopharmaceutical of Claim 3 wherein: Q is   d' is 1; Ln is attached to Q at the carbon atom designated with a * and has the formula: -(C=O)NH(CH2)5C(=O)NH-; Ch'- is   or   and is attached to Ln at the carbon atom designated with a *; Mt is <99m>Tc; AL1is tricine; AL2 is PR<61>R<62>R<63>, wherein R<61>, R<62> and R<63> are each phenyl bearing an SO3H or SO3<-> group in the meta position; and x, y and z are 1. 7. The radiopharmaceutical of Claim 3 wherein: Q is   d- is 1; LN is attached to Q at the carbon atom designated with a * and has the formula: -(C=O)NH(CH2)5C(=O)NH-; Ch' is   or   and is attached to Ln at the carbon atom designated with a *; Mt. is <99m>Tc, AL1 is tricine; A L2 is PR<61>R<62> R<63>, wherein R<61> is phenyl, R<62> and R<63> are each phenyl bearing an SO3H or SO3<-> group in the meta position; and x, y and z are 1. 8. The radiopharmaceutical of Claim 3 wherein: Q is   d' is 1; Ln is attached to Q at the carbon atom designated with a * and has the formula: -(C=O)NH(CH2)5C(=O)NH-; Ch' is   or   and is attached to Ln at the carbon atom designated with a *; Mt. is <99m>Tc, AL1 is tricine; A L2 is PR<61>R<62> R<63>, wherein R<61> and R<62> are each