Process for production of heterodimers of glutamic acid
View Patent ↗A manufacturing process for the preparation of radiolabeled compounds of formula (I) includes reacting compounds of formula (II) with a source of readionuclide of a halogen in the presence of an oxidant under acidic condition, wherein: *I is 123 I, 124 I, 125 I or 131 I; R is lower alkyl, optionally substituted with one or more fluorine atoms; Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 , (CH 2 ) p ; Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , (CH 2 ) p ; R′ is H, C(O), S(O) 2 , C(O) 2 ; Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6; and p is 0, 1, 2, 3, 4, 5 or 6.
1. A compound of formula (II):
wherein
R is lower alkyl, optionally substituted with one or more fluorine atoms;
Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
Y is O, NR′, S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
or Q and Y together are —NR′C(O)NR′—;
R′ is H, C(O), S(O) 2 , or C(O) 2 ;
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl;
m is 1,2,3,4 or 5;
n is 0, 1, 2, 3, 4, 5 or 6; and
p is 2, 3, 4, 5 or 6.
2. The compound of claim 1 , wherein Y is O, NR′, C(O) 2 , (CH 2 ) p .
3. The compound of claim 1 , wherein Y is (CH 2 ) p and Q is NR′.
4. The compound of claim 1 , wherein R′ is H.
5. The compound of claim 1 , wherein Z is C 4 alkyl.
6. The compound of claim 1 , wherein Z is substituted benzyl.
7. The compound of claim 1 , wherein m is 4.
8. The compound of claim 1 , wherein n is 0.
9. The compound of claim 1 which is:
10. A stable composition comprising a radiolabeled compound of the formula (I)
and a pharmaceutically acceptable excipient under acidic conditions
wherein:
*I is 123 I, 124 I, 125 I, or 131 I;
R is lower alkyl, optionally substituted with one or more fluorine atoms;
Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
Y is O, NR′, S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
or Q and Y together are —NR′C(O)NR′—;
R′ is H, C(O), S(O) 2 , or C(O) 2 ;
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl;
m is 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3, 4, 5 or 6; and
p is 2, 3, 4, 5 or 6.
11. The stable composition of claim 10 , wherein Y is O, NR′, C(O) 2 , or (CH 2 ) p .
12. The stable composition of claim 10 , wherein Y is (CH 2 ) p and Q is NR′.
13. The stable composition of claim 10 , wherein R′ is H.
14. The stable composition of claim 10 , wherein Z is C 4 alkyl.
15. The stable composition of claim 10 , wherein Z is substituted benzyl.
16. The stable composition of claim 10 , wherein the pharmaceutically acceptable excipient comprises an ascorbate/ascorbic acid and a stabilizing amount of a gentisate stabilizer selected from gentisic acid and soluble, pharmaceutically acceptable salts thereof.
17. The stable composition of claim 16 , wherein the ascorbate/ascorbic acid is present at about 6% and the gentisate is present at about 3%.
18. The stable composition of claim 10 , wherein the acidic conditions have a pH from 4.5 to 5.5.
19. The stable composition of claim 10 having less than 5% free iodine.
20. The stable composition of claim 10 which is iodine-free.
21. A compound that is:
wherein:
R is lower alkyl, optionally substituted with one or more fluorine atoms; and
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl.
22. The compound of claim 21 , wherein Z is C 4 alkyl.
23. The compound of claim 21 , wherein Z is substituted benzyl.
24. A stable composition comprising a radiolabeled compound of the formula (I)
and a pharmaceutically acceptable excipient under acidic conditions;
wherein:
*I is 123 I, 124 I, 125 I, or 131 I;
R is lower alkyl, optionally substituted with one or more fluorine atoms;
Q is C(O), O, NR′, S, S(O) 2 , or C(O) 2 ;
Y is O, NR′, C(O)N(R′), S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
or Q and Y together are —NR′C(O)NR′—;
R′ is H, C(O), S(O) 2 , or C(O) 2 ;
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl;
m is 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3, 4, 5 or 6 and p is 2, 3, 4, 5, or 6.
25. The stable composition of claim 24 , wherein the compound is:
and
a pharmaceutically acceptable excipient under acidic conditions
wherein:
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl, and
*I is 123 I, 124 I, 125 I, or 131 I.
26. The stable composition of claim 24 , wherein Z is C 4 alkyl.
27. The stable composition of claim 24 , wherein Z is substituted benzyl.
28. The stable composition of claim 24 , wherein the pharmaceutically acceptable excipient comprises an ascorbate/ascorbic acid and a stabilizing amount of a gentisate stabilizer selected from gentisic acid and soluble, pharmaceutically acceptable salts thereof.
29. The stable composition of claim 28 , wherein the ascorbate/ascorbic acid is present at about 6% and the gentisate is present at about 3%.
30. The stable composition of claim 24 , wherein the acidic conditions have a pH from 4.5 to 5.5.
31. The stable composition of claim 24 having less than 5% free iodine.
32. The stable composition of claim 24 which is iodine-free.