# US 5,705,637 A · Polyazacycloalkane compounds

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- Number: US 5,705,637 A
- Document ID: US5705637A
- Status: Granted
- Kind: A
- Application number: 08/790,855
- Filed: 1997-02-03
- Granted: 1998-01-06
- Earliest claimed: 1995-06-07
- Assignees: Nycomed Imaging AS
- Inventors: Lisa Schultze; Alan Ray Bulls
- Web page: https://patentgrep.com/patent/US5705637A

## CPC

- C07D 257/02: not condensed with other rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 4)

A process for the production of DO3A or DO3A analog chelating agents, said process comprising the following steps
(1) (a) reacting a diantide of formula XII
Z.sub.1 NHCHR.sub.1 CHR.sub.1 NH.sub.2 (XII)
with a diamine of formula XIII
YNZ.sub.2 CHR.sub.1 CHR.sub.1 NHY (XIII)
(where R.sub.1 and Y are as defined in claim 4, and one of Z.sub.1 and Z.sub.2 is hydrogen and the other is a benzyl group),
or (b) reacting a trimnine of formula XIV
Z.sub.1 NHCHR.sub.1 CHR.sub.1 NZ.sub.2 CHR.sub.1 CHR.sub.1 NH.sub.2(XIV)
with a monoamine of formula XV or XVI
Z.sub.3 N(CH.sub.2 COLv).sub.2 (XV)
Z.sub.3 N(CHR.sub.1 CHR.sub.1 Lv).sub.2 (XVI)
(where R.sub.1 and Lv are as defined in claim 4, one of Z.sub.1, Z.sub.2 and Z.sub.3 is a benzyl group and the other two are hydrogen atoms),
and (c) where necessary reducing the cyclic dione thus produced to yield N-benzyl-cyclen;
(2) reacting the N-benzyl-cyclen to introduce acid groups at the unsubstituted ring nitrogens;
(3) debenzylating the N-acid substituted product; and
(4) if desired, N-alkylating the debenzylated product.

### Claim 3 (depends on 2)

A process as claimed in claim 2 wherein in step (4) the debenzylated product is N-alkylated to introduce a hydroxyalkyl group.