METALLIC CHELATES OF MACROCYCLIC POLYAMINOCARBOXYLIC DERIVATIVES AND THEIR APPLICATION TO DIAGNOSTIC IMAGERY

摘要

1. Chelate compound of cation of paramagnetic metal and composition of formula I: where m is 1 or 2, R' is H, (C1-C4) alkyl or hydroxyalkyl radical, CH2-COOH or CH2-CONZ1Z2, wherein Z1 and Z2 are independently from one another, H, or (C1-C4) alkyl radical, optionally hydroxylated, | or R' is HOOC-CH-(CH2)m-CONHR radical, R is a radical where a is 1 or 2, Z is a bond, CH2, CH2CONH or (CH2)2NHCO, Z' is a bond, O, S, NQ, CH2, CO, CO-NQ, NQ-CO, NQ-CO-NQ or CO-NQ-CH2-CONQ, Z" is CO-NQ, NQ-CO or CO-NQ-CH2-CO-NQ, NQ-CO-CH2-NQ-CO, where Q is H or a (C1-C4) alkyl radical, optionally hydroxylated, R1, R2, R3, R4, R5 are independently selected from H, Br, Cl, I, CO-NQ1Q2 or N(Q1)-CO-Q2 and Q1 and Q2. identical or different, selected from (C2-C6) alkyl groups, optionally hydroxylated and in which can be included an oxygen atom , so that Q1 and Q2 comporrisetogether from 4 to 10 OH groups, wherein at least one, but not more than 2 R1, R2, R3, R4, R5 radicals are amido-groups, and pharmacologically acceptable salt thereof with inorganic and organic bases. 2. Chelate compound of cation of paramagnetic metal and the salt thereof according to claim 1 of formula I, where: m is 2, | R' is HOOC-CH-(CH2)2CONHR, CH2-COOH or CH2-CONZ1Z2, a is 1, Z is a bond, CH2, or CH2CONH, Z' is CONH, NHCO, CONH-CH2-CONH, or NHCONH, Z" is CONH or CONH-CH2-CONH, then R2=R4=CONQ1Q2 or R3=CONQ1Q2, and R1, R2, R4, R5 are H, Br, Cl or I, or Z" is NHCO, then R2=R4=N(Q1)COQ2 and R1, R3 and R5 are H, Br, I or Cl, or R3=N(Q1)-COQ2, and R1, R2, R4, R5 are H, Br, Cl or I. 3. Chelate compound of cation of paramagnetic metal and and the salt thereof according to claim 2 of formula I, where: | R' is HOOC-CH-(CH2)2CONHR or CH2COOH, Z' is CONH, NHCONH, or CONH-CH2-CONH, Z" is CONH, or CONH-CH2-CONH, R1, R3 and R5 are, all three, Br or I, R2 and R4 are CONQ1Q2, where Q1 and Q2 are selected from hydroxylated (C2-C6) alkyl groups, comprising together 6-10 OH groups, or from 4 to 8 OH groups, if Q1 and/or Q2 are interrupted by an oxygen atom. 4. Chelate compound of cation of paramagnetic metal and the salt thereof according to claim 3 of formula I, where: | R' is HOOC-CH-(CH2)2CONHR, Z is CH2 or CH2CONH, Z' is CONH, NHCONH. 5. Chelate compound of cation of paramagnetic metal and the salt thereof according to claim 4 of formula I, where: | R' is CH2CO2H or HOOC-CH-(CH2)2CONHR, Z' and Z'' are CONH. 6. Chelate compound of cation of paramagnetic metal and the salt thereof according to claim 1 of formula I, where: m is 2, | R' is HOOC-CH-(CH2)2CONHR a is 2 Z is CH2 or CH2CONH, Z' is CONH or NHCO, Z" is CONH, or CONH-CH2-CONH, R1, R3 and R5 are, all three, Br or I, then R2 and R4 are both CONQ1Q2, or R3 is CONQ1Q2, and R1, R2, R4, R5 are H, Br, Cl or I. 7. Chelate compound of cation of paramagnetic metal and the salt thereof according to claim 1 of formula I, where: m is 1, | R' is 2 HOOC-CH-(CH2)2CONHR a is 1 Z is CH2 or CH2CONH, Z' is CONH, Z" is CONH, or CONH-CH2-CONH, R1, R3 and R5 are Br, R2 and R4 are CONQ1Q2, where Q1 and Q2 are selected from hydroxylated (C2-C6) alkyl groups, comprising together 6-10 OH groups. 8. Chelate compound according to one of claims 1 to 7, where a cation of a metal is Gd 3+. 9. Chelate compound of gadolinium and the salt thereof according to claim 1 of formula I, where: m is 2, | R' is 2 HOOC-CH-(CH2)2CONHR, and R is 10. Chelate compound of gadolinium and the salt thereof according to claim 1, of formula I, where: m is 2, | R' is 2 HOOC-CH-(CH2)2CONHR, where Z" is CONH-CH2CONH and Q1 and Q2 are CH2(CHOH)4CH2OH, then either Z is CH2 and R3 and R5 are I, or Z is CH2CONH and R1, R3 and R5 are Br, or Z" is CONH, Z is CH2 or CH2CONH, and d R1, R3 and R5 are Br and Q1 is CH2(CHOH)4CH2OH and Q2 is CH2CHOH-CH2OH or CH2(CHOH)4CH2OH. 11. A contrast product for diagnostic magnetic resonance imagery comprising an effective amount of the chelate compoundin a phatmaceutically acceptable carrier according to one of the preceding claims. 12. A product for scintigraphy comprising chelate compound of a cation of a metal marked by a radioactive isotope and compositions of the formula where: m is 1 or 2, R' is H, (C1-C4) alkyl or hydroxyalkyl radical, CH2-COOH or CH2-CONZ1Z2, wherein Z1 and Z2 are independently from one another, H, or (C1-C4) alkyl radical, optionally hydroxylated, or | R' is HOOC-CH-(CH2)m-CONHR, R is a radical where: a is 1 or 2, Z is a bond, CH2, CH2CONH or (CH2)2NHCO, Z' is a bond, O, S, NQ, CH2, CO, CO-NQ, NQ-CO, NQ-CO-NQ or CO-NQ-CH2-CONQ, Z" is CO-NQ, NQ-CO or CO-NQ-CH2-CO-NQ, NQ-CO-CH2-NQ-CO where Q is H or an (C1-C4) alkyl radical, optionally hydroxylated, R1, R2, R3, R4, R5 are independently selected from H, Br, Cl , I, CO-NQ1Q2 or N(Q1)-CO-Q2 and Q1 and Q2, identical or different, selected from (C2-C6) alkyl groups, optionally hydroxylated and in which can be included an oxygen atom , so that Q1 and Q2 comporrisetogether from 4 to 10 OH groups, wherein at least one, but not more than 2 R1, R2, R3, R4, R5 radicals are amido-groups, and pharmacologically acceptable salt thereof with inorganic and organic bases.