Method for imaging mammalian tissue using 1-substituted- 4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs

A method for the preparation of 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane analogs, comprising:

• reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacatal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane.
• reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,
• removing the ester groups of 1-formyl, 4,7,10-triscarboxymethyl- 1,4,7, 10-tetraazacyclododecane tris-t-butylester with strong acid.

A method for the preparation of a tetraazacyclo compound having formula I:

• ##STR22## or a pharmaceutically acceptable salt thereof, wherein Y is ##STR23## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, or alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR24## wherein G is ##STR25## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR26## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,
• R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and
• X is chloro, bromo or iodo,
• wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups, comprising:
• reacting 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

A method of preparing compounds having formula I ##STR28## or a pharmaceutically acceptable salt thereof. wherein Y is ##STR29## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenylalkyl or substituted phenylalkyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups ##STR30## wherein G is ##STR31## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR32## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

• R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and
• X is chloro, bromo or iodo,
• wherein the ten substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:
• reacting a compound having formula II:
• ##STR33## with a reactive acid derivative having formula III:
• ##STR34## wherein X is a readily displaceable group such as chlorine, bromine or iodine, and
• displacing X.

A method for the preparation of 1,4,7-triscarboxymethyl-10-(2'-hydroxypropyl)-1,4,7,10-tetraazacyelododeca ne comprising:

• reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,
• reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,
• removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid to yield 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane
• reacting 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane with propylene oxide, acidify the product, apply to a carbon exchange resin and elute with ammonia.

A method for the preparation of gadolinium (III), comprising:

• reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,
• reacting the 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7.10-tetraazacyclododecane tris-t-butylester,
• removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid to yield 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane,
• reacting the 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane with propylene oxide, acidify the product, apply to a carbon exchange resin, elute with ammonia, and reacting with Gd(OAC).sub.3.4H.sub.2 O.

A method for the preparation of 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane analogs which forms a stable, charge neutral, complex when combined with a paramagnetic ion of a lanthanide element, comprising:

• reacting 1,4,7,10 tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,
• reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,
• removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid.

A method for the preparation of a tetraazacyclo compound which forms a stable, charge neutral, complex when combined with a paramagnetic ion of a lanthanide element, having formula I:

• ##STR42## or a pharmaceutically acceptable salt thereof, wherein Y is ##STR43## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, or alkoxy having from one to five carbon atom, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR44## wherein G is ##STR45## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR46## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,
• R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and
• X is chow, bromo or iodo,
• wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising;
• reacting 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 1,4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

A method of preparing compounds having formula I:

• ##STR48## or a pharmaceutically acceptable salt thereof, said compounds form a stable, charge neutral, complex when combined with a paramagnetic ion of a lanthanide element,
• wherein Y is ##STR49## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenylalkyl or substituted phenylalkyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR50## ##STR51## wherein G is ##STR52## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR53## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,
• R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and
• X is chloro, bromo or iodo,
• wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:
• reacting a compound having formula II:
• ##STR54## with a reactive acid derivative having formula III:
• ##STR55## whereto X is a readily displaceable group such as chlorine, bromine or iodine and
• displacing X.

A method for the preparation of asymmetric 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane analogs, comprising:

• reacting 1,4,7,10 tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10tetraazatricyclo(5.5.1.0)tridecane,
• reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 1,4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,
• removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid.

A method for the preparation of an asymmetric tetraazacyclo compound having formula I:

• ##STR63## or a pharmaceutically acceptable salt thereof, wherein Y is ##STR64## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, or alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR65## wherein G is ##STR66## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR67## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,
• R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and
• X is chloro, bromo or iodo,
• wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:
• reacting 1,4,7,10 tetraazatricyclo(5.5,1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and
• reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

A method of preparing asymmetric compounds having formula I:

• ##STR69## or a pharmaceutically acceptable salt thereof, said compounds form, wherein Y is ##STR70## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenylalkyl or substituted phenylalkyl alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups ##STR71## wherein G is ##STR72## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR73## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,
• R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and
• X is chloro, bromo or iodo,
• wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:
• reacting a compound having formula II:
• ##STR74## with a reactive acid derivative having formula III:
• ##STR75## wherein X is a readily displaceable group such as chlorine, bromine or iodine and
• displacing X.