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CN-117715912-B - Macrocyclic ligands with picolinate groups, complexes thereof and medical uses

CN117715912BCN 117715912 BCN117715912 BCN 117715912BCN-117715912-B

Abstract

The present invention relates to novel macrocyclic ligands substituted with at least one picolinate group, to radioactive complexes thereof and to their use in medical imaging and/or therapy, in particular in interventional radiology. The invention also relates to a novel process for preparing the ligands according to the invention, and also to intermediates for their preparation.

Inventors

  • Olivier Russo
  • William Pauli Battard
  • Olivier Fogel
  • Sarah katoon

Assignees

  • 法国加柏公司

Dates

Publication Date
20260512
Application Date
20220729
Priority Date
20210730

Claims (12)

  1. 1. A compound having the general formula (I): (I) Wherein R is a group having the formula (II): –C≡C-Ph-L1-(CH 2 ) n -L2 (II) Wherein the method comprises the steps of L1 represents Ph or-C.ident.C-or CH 2 , L2 represents H or Ph, -N is between 4 and 12, Or one of its pharmaceutically acceptable salts.
  2. 2. The compound of claim 1 having formula (I) selected from the group consisting of: 。
  3. 3. A complex of a compound of formula (I) or one of its pharmaceutically acceptable salts as claimed in any one of claims 1 and 2 with a chemical element M, wherein M is a radioactive element selected from the group consisting of ： 44 Sc(III)、 47 Sc(III)、 111 In(III)、 152 Tb(III)、 155 Tb(III)、 149 Tb(III)、 161 Tb(III)、 64 Cu(III)、 61 Cu(III)、 67 Cu(II)、 68 Ga(III)、 90 Y(III)、 153 Sm(III)、 166 Ho(III)、 177 Lu(III)、 52 Mn and 225 Ac (III).
  4. 4. A complex according to claim 3 selected from the group consisting of: Wherein M is selected from 177 Lu(III)、 90 Y (III) and 111 In (III), Wherein M is 90 Y (III), And Wherein M is 90 Y (III).
  5. 5. A pharmaceutical composition comprising a compound according to any one of claims 1 and 2 and optionally one or more pharmaceutically acceptable excipients.
  6. 6. A pharmaceutical composition comprising the complex of claim 3 and optionally one or more pharmaceutically acceptable excipients.
  7. 7. The pharmaceutical composition of claim 5, further comprising iodinated oil.
  8. 8. A pharmaceutical composition comprising the following compounds: Or it comprises the following complexes: 。
  9. 9. use of a complex according to claim 3 for the preparation of a medical imaging agent.
  10. 10. Use of a pharmaceutical composition according to claim 5 for the preparation of a medical imaging agent.
  11. 11. A process for the preparation of a compound having the general formula (I): (I) The general formula (I) as defined in any one of claims 1 to 2, which process comprises a stage of functionalizing a compound having the following general formula (IX): (IX), To form a compound having the following general formula (X): (X), Wherein E 2 is C 1 -C 4 alkyl; A stage of deprotection of the compound of general formula (X) to give a compound of general formula (XI): (XI) And A stage of functionalizing the compound of formula (XI) to obtain a compound of formula (I): e 2 and E 3 are C 1 -C 4 alkyl groups and X is a mesylate group.
  12. 12. The method of claim 11, wherein the C 1 -C 4 alkyl is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl.

Description

Macrocyclic ligands with picolinate groups, complexes thereof and medical uses Technical Field The present invention relates to novel macrocyclic ligands and also complexes thereof, in particular radioactive complexes, and their use in medical imaging and/or in therapy, in particular in interventional radiology. The invention also relates to a novel process for preparing the ligand as according to the invention, and also to intermediates for its preparation. Background The need for targeted and personalized therapies in oncology has led to the development of new therapeutic strategies based on early detection tools in combination with more specific and efficient vectorized therapies. Interventional radiology is a very promising direction in personalized medicine. It makes it possible to combine the accurate diagnosis of lesions or tumors and/or their immediate treatment in a single same series of events, this combination being guided and controlled by the images. It is described as a minimally invasive procedure and can therefore be performed on an outpatient basis, which results in a saving of many costly hospitalization days and achieving an effectiveness generally comparable to conventional procedures. Thus, interventional radiology may be used as a surrogate or extension to conventional surgical therapies. Interventional radiology makes it possible to access lesions or tumors located within the body, thereby performing diagnostic (e.g., sampling) or therapeutic actions. Imaging with fluoroscopy, echography, scanner or MRI allows for accurate positioning, guidance and optimal control of the medical procedure. Thus, there is a need for novel molecules that can be used in medical imaging and/or therapy, in particular in interventional radiology. More particularly, there is a need for ligands that are capable of achieving chemical elements, in particular metal complexation, in order to obtain complexes that are useful in medical imaging and/or therapy, in particular for interventional radiology. Such ligands must be stable in human serum in particular and must complex metals sufficiently strongly so that the latter reach their targets without diffusing into other sensitive organs or tissues such as bones, lungs and kidneys. Disclosure of Invention It is an object of the present invention to provide novel ligands capable of achieving complexation of chemical elements, in particular radioactive elements. It is a further object of the present invention to provide novel complexes, in particular radioactive complexes. It is an object of the present invention to provide ligands and/or complexes that are particularly useful in medical imaging and/or therapy, in particular in cancer treatment. It is another object of the present invention to provide a pharmaceutical composition comprising a complex capable of achieving medical imaging, targeting and/or treatment of cancer. It is an object of the present invention to provide a novel process for preparing these ligands. Starting from the studies described in WO 2017/109217 and Le far et al (Inorganic Chemistry [ inorganic chemistry ], vol.57, stage 4, pages 2051-2063, 2018), the inventors developed novel ligands with high affinity for certain metals, especially rare earth metals, whose complexes are very stable and exhibit high kinetic inertness. In addition, these complexes can be readily radiolabeled and then exhibit satisfactory radiochemical yields and satisfactory radiochemical purity. These complexes can also be incorporated into iodinated oils in a stable manner and with good reproducibility, exhibiting biodistribution characteristics that enable their use in cancer therapy. The present invention relates to a compound having the following general formula (I): Wherein R is a group having the formula (II): –C≡C-Ph-L1-(CH2)n-L2(II) Wherein the method comprises the steps of L1 represents Ph or-C.ident.C-or CH 2, L2 represents H or Ph or alkylphenyl, -N is between 4 and 12, Or one of its pharmaceutically acceptable salts. According to a preferred embodiment, the invention relates to a compound having the general formula (I), wherein the group R is selected from: -a group R wherein l1=ch 2, n=7 and l2=h, which corresponds to the structure: -a group R wherein l1=ph, n=8 and l2=h, which corresponds to the structure: -a group R wherein l1= -c≡c-, n=8 and l2=ph, which corresponds to the following structure: and one of its pharmaceutically acceptable salts. The present inventors have developed novel ligand-metal complexes (also known as chelate complexes) starting from the pyclen macrocyclic (3,6,9,15-tetraazabicyclo [9.3.1] pentadecane-1 (15), 11, 13-triene) which are differently substituted with acetate and/or picolinate (6-methylene-2-picolinic acid) groups. The pyclen macrocycle has the formula: As with the complexes described in WO 2017/109217, the complexes according to the invention show good thermodynamic stability as well as good kinetic inertness. These complex