US 5,705,637 AGranted

Polyazacycloalkane compounds

AssigneeNycomed Imaging AS

InventorsLisa Schultze, Alan Ray Bulls

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Abstract

The present invention relates to tribenzylcyclen compounds of formula I ##STR1## (where R is hydrogen, or a C.sub.1-12 alkyl group optionally substituted by hydroxy, alkoxy or aryl groups or R is an amphiphilic aralkyl group comprising a N, S, O or P interrupted C.sub.2-25 alkylene chain, e.g. a polyalkylene oxide chain or R provides a bridge to a second tribenzylcyclen group, but with the proviso that R is other than benzyl; X is CHR.sub.1, or where R is hydrogen two X groups may each represent CO groups; and R.sub.1 is hydrogen, a C.sub.1-6 alkyl group optionally substituted by hydroxy, alkoxy or carboxy groups or an aralkyl group having 1 to 6 carbons in the alkyl moiety and optionally. substituted in the aryl moiety by alkyl, alkoxy, hydroxy or isothiocyanate groups). These compounds are useful in the preparation of DO3A, N-substituted-1,4,7,10-tetraazacyclododecane-N',N",N'"-triacetic acids, and the phosphonic acid analogs.

A process for the preparation of a compound comprising at least one of the following steps:

(a) reacting a diamine of formula II
PhCH.sub.2 NHCHR.sub.1 CHR.sub.1 NHCH.sub.2 Ph (II)
(wherein R.sub.1 is hydrogen, a C.sub.1-6 alkyl group optionally substituted by hydroxy, alkoxy or carboxy groups or an aralkyl group having 1 to 6 carbons in the alkyl moiety and optionally substituted in the aryl moiety by alkyl, alkoxy, hydroxy or isothiocyanate groups) with a diamine of formula III
YN(CH.sub.2 Ph)CHR.sub.1 CHR.sub.1 NHY (III)
(where Y is CH.sub.2 COLv or COCH.sub.2 Lv and Lv is a leaving group) to yield a compound of formula IV or V ##STR6## (b) reacting a triamine of formula VI
Z.sub.1 NHCHR.sub.1 CHR.sub.1 N(Z.sub.2)CHR.sub.1 CHR.sub.1 NHZ.sub.3(VI)
with a monoamine of formula VII
Z.sub.4 N(CHR.sub.1 COLv).sub.2 (VII)
to yield a compound of formula VIII ##STR7## (wherein R.sub.1 is is hydrogen, a C.sub.1-6 alkyl group optionally substituted by hydroxy, alkoxy or carboxy groups or an aralkyl group having 1 to 6 carbons in the alkyl moiety and optionally substituted in the aryl moiety by alkyl, alkoxy, hydroxy or isothiocyanate groups, one of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is a hydrogen atom and the others are benzyl groups);
(c) reducing a compound of formula IV, V or VIII to yield a compound of formula IX ##STR8## (wherein R.sub.1 is hydrogen, a C.sub.1-6 alkyl group optionally substituted by hydroxy, alkoxy or carboxy groups or an aralkyl group having 1 to 6 carbons in the alkyl moiety and optionally substituted in the aryl moiety by alkyl, alkoxy, hydroxy or isothiocyanate groups;
(d) reacting a compound of formula IX with a compound of formula X
Lv--R.sup.1 (X)
(where Lv is a leaving group and R.sup.1 is a C.sub.1-12 alkyl group optionally substituted by hydroxy, alkoxy or aryl groups or an amphiphilic aralkyl group comprising a N, S, O or P interrupted C.sub.2-25 alkylene chain, or where Lv--R.sup.1 is a cyclic or unsaturated compound nucleophilically substitutable by an amine nitrogen to yield an N-attached R group other than hydrogen);
(e) reacting a monoamine of formula XI
LvCHR.sub.1 CHR.sub.1 NR.sup.2 CHR.sub.1 CHR.sub.1 Lv (XI)
(where R.sup.2 is hydrogen, or a C.sub.1-12 alkyl group optionally substituted by hydroxy, alkoxy or aryl groups or an amphiphilic aralkyl group comprising a N, S, O or P interrupted C.sub.2-25 alkylene chain, or a nitrogen protecting group) with a triamine of formula VI, and if required deprotecting the R.sup.2 -substituted in the resulting tribenzylcyclen.

13 more elements

Abstract

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