Biotin diaminoderivatives and their conjugates with macrocyclic chelating agents
View Patent ↗Formula (I) compounds are described: Formula (I) where the radicals are as defined in the description, processes for their preparation, and their uses for the preparation of conjugates with radionuclides for use in human and animal therapy and diagnostics, particularly for the diagnosis and therapy of pathological conditions such as tumors.
1. A compound of formula (I):
where:
A is CH 2 or CO;
B is H, CHO or COOH; with the proviso that:
when A is CH 2 , Q is a —(CH 2 ) n — group, in which n is an integer from 4 to 12, in which case R is absent; when A is CO, Q is selected from the group consisting of —(CH 2 ) a —CH(R—)—(CH 2 ) b —, where a and b are, independently, integers from 0 to n−1 and R is defined as below;
W is a C 1 -C 12 alkylene or C 2 -C 12 alkenylene linear chain or a functionalized polyethylene glycol; or a C 6 -C 10 aromatic residue; or a glycofuranose residue; or
W, alone or together with the nitrogen atom supporting the —(CH 2 ) c —NHR′ and —(CH 2 ) d —NHR″ chains, is a heterocyclic group with 5 or 6 members containing one or more heteroatoms selected from O, N, S;
when W is an aromatic residue, an heterocyclic group or a sugar moiety, the nitrogen atom supporting the —(CH 2 ) c —NHR′ and —(CH 2 ) d —NHR″ chains is optionally absent and the —(CH 2 ) c —NHR′ and —(CH 2 ) d —NHR″ chains are directly and independently bonded to the carbon or nitrogen atoms of the aromatic and heterocyclic rings or to oxygen atoms of the glycofuranose residue;
c and d independently are integers from 3 to 10;
R′ and R″ are, independently, −Λ, where −Λ is a formula (II) macrocycle:
where Y are the same or different and are selected from the group consisting of hydrogen, straight or branched C 1 -C 4 alkyl, —(CH 2 ) m —COOH, where m is an integer from 1 to 3;
X is hydrogen, or the —CH 2 —U group, where U is selected from methyl, ethyl, p-aminophenyl, or X is the —(CHJ) 0 -Z group, where o is an integer from 1 to 5, J is hydrogen, methyl or ethyl, Z is a heterocyclic group with 5 or 6 members containing one or more heteroatoms selected from O, N—R 1 , R 1 being a hydrogen atom or a linear or branched C 1 -C 4 alkyl group, and S; or Z is selected from —NH 2 , —NH—C(═NH—)—NH 2 , or —S—R 2 where R 2 is a linear or branched C 1 -C 4 alkyl group;
p is the integer 2 or 3;
R is selected from the group consisting of linear or branched C 1 -C 4 alkyl, cycloalkyl, heterocycle or —(CH 2 ) q -T, where T is selected from the group consisting of S—CH 3 , —OH, or —COOH, and q is 0, 1 or 2.
2. The compound of Formula (I) according to claim 1 , where independently A is CH 2 , B is H, Q is —(CH 2 ) n —, where n is an integer from 4 to 8, preferably 6, c and d are both 3 or 6, R′ and R″ are −Λ where Y is always —CH 2 —COOH; X is hydrogen, and p is 2.
3. A complex of a compound of Formula (I) according to claim 1 with a radioisotope.
4. The complex according to claim 3 , where the radioisotope is selected from the group consisting of Fe-52, Mn-52m, Co-55, Cu-64, Ga-67, Ga-68, Tc-99m, In-111, I-123, I-125, I-131, P-32, Sc-47, Cu-67, Y-90, Pd-109, Ag-111, I-131, Pm-149, Re-186, Re-188, At-211, Bi-212, Bi-213, Rh-105, Sm-153, Lu-177, and Au-198.
5. The complex according to claim 3 , where Q is —(CH 2 ) n —, n is an integer from 4 to 8, preferably 6, Y is —CH 2 —COOH and the radioisotope is Y-90.
6. A pharmaceutical and/or diagnostic composition containing a compound according to claim 1 in a mixture with suitable vehicles and/or excipients.
7. A pharmaceutical and/or diagnostic composition containing a complex according to claim 3 in a mixture with suitable vehicles and/or excipients.
8. Kit comprising one pharmaceutical or diagnostic composition according to claim 6 .
9. Kit comprising one pharmaceutical or diagnostic composition complex according to claim 3 .