WO1998043678B1 - Tetraaza- or n2s2- complexants, and their use in radiodiagnostics or radiotherapy - Google Patents

Tetraaza- or n2s2- complexants, and their use in radiodiagnostics or radiotherapy

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Publication number
WO1998043678B1
WO1998043678B1 PCT/US1998/005858 US9805858W WO9843678B1 WO 1998043678 B1 WO1998043678 B1 WO 1998043678B1 US 9805858 W US9805858 W US 9805858W WO 9843678 B1 WO9843678 B1 WO 9843678B1
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Prior art keywords
hydrogen
independently selected
nitrogen
hydroxyl
sulfur
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PCT/US1998/005858
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French (fr)
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WO1998043678A2 (en
WO1998043678A3 (en
Inventor
Sudhakar Kasina
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Neorx Corp
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Publication date
Application filed by Neorx Corp filed Critical Neorx Corp
Priority to DE69837038T priority Critical patent/DE69837038T2/en
Priority to CA002284653A priority patent/CA2284653C/en
Priority to JP54176898A priority patent/JP2002500629A/en
Priority to EP98912032A priority patent/EP0971748B1/en
Publication of WO1998043678A2 publication Critical patent/WO1998043678A2/en
Publication of WO1998043678A3 publication Critical patent/WO1998043678A3/en
Publication of WO1998043678B1 publication Critical patent/WO1998043678B1/en

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Abstract

The present invention provides for substituted metal chelating compounds in which at least two of the chelating atoms are nitrogen which are directly attached to aromatic rings and one or more of those nitrogen atoms has attached thereto a substituent other than hydrogen, and methods for making and using these compounds. Another aspect of the invention provides for the use of the chelation compounds described above in methods for diagnostic and therapeutic purposes. A diagnostic method is described for detecting the presence or absence of a target site within a mammalian host. This method comprises providing to cells a diagnostically effective dose of a compound of the present invention which contains a metal radionuclide, such as 99mTc and/or 111In, and detecting the biodistribution of the radionuclide. A therapeutic method is described for delivering a radionuclide, such as ?186Re/188Re, 90Y, and 153¿Sm, to a target site within a mammalian host. This method comprises providing to cells a therapeutically effective dose of a chelate compound of the present invention.

Claims

87AMENDED CLAIMS[received by the International Bureau on 5 February 1999 (05.02.99); original claims 1-16 replaced by new claims 1-18 (8 pages)]
1. A compound of the formula:
Figure imgf000003_0001
wherein: n = 0 or 1 ;
R\ and R2 are independently selected from hydrogen, =0, with the proviso that both are not =0, - (CH2)m-Z where m is 0-10 and Z represents a conjugation group or targeting moiety, and - (CH2)m-W where m is 0-10 and W represents a hydrolyzable group, or R\ and R2 are taken together to form a cyclic anhydride or a benzene ring;
R3 is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, - (CH_2)m -Z or - (CH2)m-W;
R4 and R5 are attached at one or more of the ring positions and are independently selected from hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, - (CH2)m -Z and - (CH2)m -W;
R and R are independently selected from hydrogen with the proviso that both are not hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, - (CH2)m -Z, -(CH2)m -W and
Figure imgf000003_0002
where Q represents a multivalent acid functionality group able to coordinate with metal ions, and p = 0 to 1; R12 and Rι3 are independently selected from hydrogen, hydroxyl, carboxyl, phosphoric, and hydrocarbon radicals having from 1-10 carbon atoms, and physiologically acceptable salts of the acid radicals; X, X', Y and Y' are independently selected from carbon, nitrogen, oxygen and sulfur to independently form 5 or 6 member aromatic rings wherein the remaining ring atoms are carbon;
A and A' are independently selected from sulfur and nitrogen, where sulfur may bear a hydrogen or a sulfur protecting group, or where A and A' are both sulfur, A and A' may be joined together by a bond; where a nitrogen may bear a hydrogen; or where A or A' is nitrogen, A may bear R8 or R10 or both and A' may bear R9 or Ru or both, wherein R8, 'R9, R10 and Ru are independently selected from lower alkyl, alkoxy, halogen, hydroxyl, nitro, - (CH2)m -Z, -(CH2)m -W and
R12 ~-(CH2)p -C— Q;
I Rl3 or R8 and R10 may be joined to form a cyclic anhydride or Re, and Rj j may be joined to form a cyclic anhydride; or when A and A' are both nitrogen, R10 and Rn may be joined to form T, where T is
Figure imgf000004_0001
and n is 0 to 1, and Rj' and R2' are independently selected from hydrogen, =O, with the proviso that both are not =O, -(CH2)m-Z, or Rj' and R2' are taken together to form a cyclic anhydride or a benzene ring; and R3' is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, -(CH2)m-Z or -(CH2)m-W; and the compound has at least one Z, W or Q.
2. A compound according to claim 1, wherein:
Rj, and R2 are independently selected from hydrogen, =O, with the proviso that both are not =O, and -(CH2)m-Z where m is 0-10 and Z represents a conjugation group or targeting moiety, or Rj and R2 are taken together to form a cyclic anhydride or a benzene ring;
R3 is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro or -(CH2)m-Z; 89
R4 and R5 are attached at one or more of the ring positions and are independently selected from hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro and -(CH2)m-Z;
R6 and R are independently selected from hydrogen with the provision that both are not hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro and -(CH2)m-Z or
R12
— (CH2)P -C— Q; I Rl3
X, X', Y and Y' are independently selected from carbon, nitrogen and sulfur to form 5 or 6 member aromatic rings wherein the remaining ring atoms are carbon;
A and A' are independently selected from sulfur and nitrogen, where sulfur may bear a hydrogen or a sulfur protecting group, or where A and A' are both sulfur, A and A' may be joined together by a bond; where a nitrogen may bear a hydrogen; or where A or A' is nitrogen, A may bear Rg or Rio or both and A' may bear Ro or Ru or both, wherein Rg, Ro, Rio and Ru are independently selected from lower alkyl, alkoxy, halogen, hydroxyl, nitro, -(CH2)m-Z and
R12
— (CH2)P -C— Q; I Rl3 or Rg and Rio may be joined to form a cyclic anhydride or R9 and Ri 1 may be joined to form a cyclic anhydride; or when A and A' are both nitrogen, Rio and Ru may be joined to form T, where T is
Figure imgf000005_0001
and n is 0 to 1, and Ri' and R2' are independently selected from hydrogen, =O, with the proviso that both are not =O, and -(CH2)m-Z; or R and R2' are taken together to form a cyclic anhydride or a benzene ring; and R3' is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro or -(CH2)m-Z; and said compound has at least one Z or Q. 90
3. A compound according to claim 2, wherein n = 1; Rj, R2, R3 are hydrogen; R and R5 are independently selected from hydrogen and -(CH2)m-Z; R6 and R are
R12
— (CH2)P -C— Q 1 R13 where p = 0, Rι2 and Rι are hydrogen, Q is a multivalent acid functionality capable of coordinating with metal ions; A and A' are both nitrogen, wherein A bears Rg or Rio or both, and A' bears R9 or Rπ or both, wherein Rg, R9, Rio and Ru are
Figure imgf000006_0001
where Q is independently selected from a phosphonic acid and a carboxylic acid, p = 0, and Rι2 and Rι3 are hydrogen; or Rg and Rio may be joined to form a cyclic anhydride or R9 and Ru may be joined to form a cyclic anhydride; or Rι0 and Ru may be joined to form T wherein n is 1, and Ri', R2' and R3' are hydrogen.
4. A compound according to claim 2, wherein n = 0; Ri and R2 are taken together to form a benzene ring; R4 and R5 are independently selected from hydrogen and -(CH2)m-Z; Rg and R are
R12
— (CH2)P -C— Q
I
R13
wherein Q is independently selected from a phosphonic acid and a carboxylic acid, p = 0, and Rι2 and Rι3 are hydrogen; A and A' are both nitrogen and Rio and Ru are joined to form T, wherein n=0, R\ and R2' are taken together to form a benzene ring and Rg and R9 are
R12
— (CH2)P -C— Q
I
R13 91
wherein Q may be independently selected from a phosphonic acid and a carboxylic acid, p = 0, and R12 and Rι3 are hydrogen.
5. A compound according to claim 2, wherein n = 1; Ri, R2 and R are hydrogen; R4, and R5 are independently selected from hydrogen and -(CH2) - ; R6 and R are
Figure imgf000007_0001
wherein Q is independently selected from a phosphonic acid and a carboxylic acid, p = 0, and R12 and Rι3 are hydrogen; A and A' are both nitrogen, R8, R9, Rι0 and Ru are independently selected from -(CH2)m-Z, wherein m is 0 to 10 and Z is a targeting moiety, and
R12
— (CH2)P -C— Q I Rl3 wherein Q is independently selected from a phosphonic acid and a carboxylic acid, p = 0, and R12 and Rι3 are hydrogen, with the proviso that said compound has at least one Z.
6. A compound according to claim 5, wherein Z is a targeting moiety selected from antibody fragments, biotin or annexin.
7. A compound according to claim 1, wherein:
Ri and R2 are independently selected from hydrogen, =O, with the proviso that both are not =O, and -(CH2)m-W where m is 0-10 and W represents a hydrolyzable group, or Ri and R2 are taken together to form a cyclic anhydride or a benzene ring;
R3 is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro or -(CH )m-W;
R4 and R5 are attached at one or more of the ring positions and are independently selected from hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro and -(CH2)m-W; 92
R and R7 are independently selected from hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, -(CH2)m-W and
R12 — (CH2)P -C— Q;
I Rl3
A and A' are independently selected from sulfur and nitrogen, where sulfur may bear a hydrogen or a sulfur protecting group, or where A and A' are both sulfur, A arid A' may be joined together by a bond; where a nitrogen may bear a hydrogen; or where A or A' is nitrogen, A may bear Rg or Rio or both and A' may bear R9 or Rπ or both, wherein Rg, R9, Rio and Ru, are independently selected from lower alkyl, alkoxy, halogen, hydroxyl, nitro, -(CH2)m-W and
R12 — (CH2)P -C— Q;
I Rl3 or Rg and Rio may be joined to form a cyclic anhydride or R9 and Rπ may be joined to form a cyclic anhydride; or when A and A' are both nitrogen, Rio and Ru may be joined to form T, where T is
Figure imgf000008_0001
and n is 0 to 1, and R and R2' are independently selected from hydrogen, =0 with the proviso that both are not =O, and -(CH2)m-W where m is 0-10 and W represents a hydrolyzable group, or Ri' and R2' are taken together to form a cyclic anhydride or a benzene ring; and R3' is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro and -(CH2)m-W; and said compound has at least one W.
8. A compound according to claim 7, wherein n = 1; Rj, R2 and R3 are hydrogen; R4 and R5 is independently selected from hydrogen and -(CH2)m-W; R and R7 are
R12
— (CH2)P -C— Q I Rl3 wherein Q are independently selected from a phosphonic acid and a carboxylic acid, p = 0, and R12 and Rι3 are hydrogen; A or A' may be independently selected from a sulfur containing a protecting group, and nitrogen, with the proviso that both A and A' are not sulfur; and when A or A' is nitrogen, Rg and Rio are independently selected from hydrogen and -(CH2)m-W, wherein m is 1 to 10 and W is a hydrolyzable group, with the proviso that both are not hydrogen.
9. A compound of claim 8 wherein W is selected from the group consisting of ester, carbamate and nitrile.
10. A compound according to any one of claims 2 to 9, wherein X, X', Y and Y' are all carbon.
11. The title compound of any one of examples I through XI.
12. A complex comprising a compound according to any one of claims 1 to 11, with a radionuclide metal or an oxide or nitride thereof.
13. A complex according to claim 12, wherein the radionuclide is a radionuclide of technetium, copper, rhenium, lead, bismuth, ruthenium, rhodium, yttrium, samariun, indium, gold, gadolinium, holmium, lutetium, ytterbium or palladium.
14. A complex according to claim 13, wherein the radionuclide is a radionuclide of technetium, rhenium, indium, holmium or yttrium. 94
64
15. A complex according to claim 13, wherein the radionuclide is Cu,
67^ 90v 97n 99n r 105^, 109 , l l lτ 153c 159^ , 166u 175_, 177τ 186D 188D
Cu, Y, Ru, Tc, Rh, Pd, In, Sm, Gd, Ho, Yb, Lu, Re, Re,
198 199 203
Au, A. u, P™b, 212 Pb or 212 B„i..
16. A complex according to claim 14, wherein the radionuclide is Tc,
186^ Re, 188, R,e, l l lτ In, lόό^ Ho or 90v Y.
17. A complex according to any one of claims 12, 13, 14, 15 or 16 for use in a diagnostic or therapeutic method.
18. A complex according to any one of claims 12, 13, 14, 15 or 16 for use in the manufacture of a medicament.
PCT/US1998/005858 1997-03-28 1998-03-26 Tetraaza- or n2s2- complexants, and their use in radiodiagnostics or radiotherapy WO1998043678A2 (en)

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