Metal complexes of tetraazamacrocycle derivatives
View Patent ↗Improved methods for synthesizing bifunctional chelates of tetraazamacrocycle derivatives and intermediates thereof are disclosed as well as novel tetraazamacrocycle derivatives and intermediates thereof.
1. A compound of Formula:
wherein,
T is a metal ion selected from the group consisting of alkali metals, alkaline earth metals, and transition metals bearing (+1) or (+2) charges;
R 11 , R 22 and R 33 are independently selected from the group consisting of —CH 2 CO 2 R 5 , —CH 2 ArOR 5 , —CH 2 SR 5 , —CH 2 PO 3 H 2 , CH 2 SO 3 H, —CH 2 Ar(OR 5 ) 2 , —CH 2 Ar(OR 5 )R 6 and —CH 2 Ar(OR 5 ) 2 R 6 ;
R 44 is —CH 2 ArOR 7 , —CH(R 5 )CO 2 R 7 , —CH 2 Ar(OR 7 ) 2 , —CH 2 Ar(OR 7 )R 5 , or —CH 2 Ar(OR 7 ) 2 R 3 ;
R 5 , R 6 and R 7 are independently H, alkyl or substituted alkyl,
R 8 is selected from a group consisting of acyl, optionally substituted aryl and heteroaryl, alkoxy, hydroxy, halo, amino, nitro, thiols, disulfides, carbohydrates, vitamins, and combinations thereof;
Ar is an optionally substituted phenyl, pyrimidinyl or pyridinyl; and
Y is a counter ion selected from the group consisting of the halides, methanesulfonate, trifluoroacetate, trifluormethanesulfonate and p-toluenesulfonate.
2. The compound of claim 1 wherein R 11 , R 22 and R 33 are independently selected from the group consisting of —CH 2 CO 2 R 5 , —CH 2 ArOR 5 , —CH 2 SR 5 , —CH 2 PO 3 H 2 , CH 2 SO 3 H, —CH 2 Ar(OR 5 ) 2 , —CH 2 Ar(OR 5 )R 6 and —CH 2 Ar(OR 5 ) 2 R 6 wherein, R 5 and R 6 are independently hydrogen, alkyl or substituted alkyl, and Ar is an optionally substituted phenyl, pyrimidinyl or pyridinyl.
3. The compound of claim 2 wherein R 5 and R 6 are independently H, t-Bu, Et or Me.
4. The compound of claim 3 wherein R 11 , R 22 and R 33 are independently —CH 2 CO 2 R 5 ; and R 5 is hydrogen or alkyl.
5. The compound of claim 4 wherein each R 11 , R 22 and R 33 is —CH 2 C(O)O-t-butyl.
6. The compound of claim 1 wherein,
R 7 is hydrogen or alkyl;
R 8 is selected from a group consisting of carboxylic acids, ethers, alcohols, fluorides, aryl, amino acids, peptides, carbohydrates, vitamins, thiols, disulfides, amines, pyridines, pyrimidines, imidazoles, triazoles, and one or more in combination.
7. The compound of claim 1 wherein R 44 is —CH 2 Ar(OR 5 )NO 2 or —CH(CO 2 R 5 )(CH 2 ) 4 NH(CO 2 )CH 2 Ar.
8. The compound of claim 7 wherein R 5 is t-butyl; R 7 and R 8 are independently hydrogen or a lower (C 1-4 ) alkyl.
9. The compound of claim 1 wherein T is an alkali or alkaline earth metal.
10. The compound of claim 9 wherein T is sodium.
11. The compound of claim 1 wherein, T is sodium and Y is bromide.
12. The compound of claim 1 wherein,
T is sodium;
R 11 , R 22 and R 33 are identical, selected from the group consisting of —CH 2 CO 2 R 5 , —CH 2 ArOR 5 , —CH 2 SR 5 , —CH 2 PO 3 H 2 , CH 2 SO 3 H, —CH 2 Ar(OR 5 ) 2 , —CH 2 Ar(OR 5 )R 6 and —CH 2 Ar(OR 5 ) 2 R 6 ; and
Y is bromide.
13. The compound of claim 12 wherein R 11 , R 22 and R 33 are independently —CH 2 CO 2 R 5 ; and R 5 is hydrogen or alkyl.
14. The compound of claim 13 wherein each of R 11 , R 22 and R 33 is —CH 2 C(O)O-t-butyl.
15. The compound of claim 1 wherein R 11 , R 22 and R 33 are independently —CH 2 CO 2 R 5 ; and R 44 is —CH 2 Ar(OR 5 )NO 2 or —CH(CO 2 R 6 )—(CH 2 ) 4 NHCO 2 CH 2 Ar.
16. The compound of claim 15 , wherein Ar is phenyl, T is sodium and Y is bromide.
17. The compound of claim 1 wherein T is an alkali metal ion; R 5 is t-butyl; R 7 and R 5 are independently hydrogen or a lower (C 1-4 alkyl and Y is a halide ion.
18. The compound of claim 1 corresponding to the structure:
1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid,
10-[(2-t-butoxy-5-nitrophenyl)methyl]-tri-t-butyl ester, sodium bromide complex.
19. The compound of claim 1 corresponding to the structure:
2-{[2′,2″-(1,4,7,10-Tetraaza-cyclododecane-1,4,7-triyl)triacetic acid]-10-yl}-6-[(benzyloxycarbonyl)-amino]hexanoic acid, tetra-t-butyl este, sodium bromide complex.