Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings

Definitions

• the selectivity of the macrocycle with respect to a given substrate depends on the nature, the number and the relative position of the chelating arms. Most applications require the attachment of macrocycles, either on a solid support or on an antibody.
• the synthesis of molecules containing both a complex site, such as a nitrogenous macrocycle carrying adequate chelating arms, and a reactive termination allowing grafting onto an antibody or onto a solid support has been the subject of numerous publications and requests. patent over the past decade.
• bifunctional chelating agents BCA or BFC
• BCA bifunctional chelating agents
• Another approach consists in introducing the arm allowing grafting on a carbon atom of the macrocyclic skeleton then the chelating arms on the nitrogen atoms.
• the latter seems better suited to the synthesis of these bifunctional chelating agents because it allows on the one hand to conserve the four secondary amino functions without altering the properties of the macrocycle and on the other hand easily attach four chelating arms during a stage of total functionalization.
• This approach was applied in the synthesis of numerous bifunctional chelating agents, some of which, represented in FIG. 1, are used in clinical trials on human and / or marketed beings (BAT, p-NCS-Bz-DOTA, p -NH 2 -Bz-DOTA).
• BAT bifunctional chelating agents
• Free ligands mono- or di- C-functionalized with acid or amino groups have also been obtained from these complexes 47 "50.
• Bismacrocycles have also been synthesized in this way 51.
• the subsequent functionalization of the cyclam carrying an amino group for example allows access to new macrocycles C-substituted 52.
• the yields observed during cyclization reactions vary from 15 to 75% depending on the compounds targeted.
• the disadvantages of the method lie in the elimination of the metal ion which requires conditions limiting the choice of functional group introduced and in its impossibility to be adapted to the cyclene series
• the use of Fe III as a support has recently made it possible to obtain several C-arylated cyclenes with yields of 40% to 70% 53,54 .
• the inventors have therefore sought to develop a new process for the preparation of C-functionalized tetraazacycloalkanes.
• the subject of the invention is a process for the preparation of a compound of formula (I):
• one of the groups A or B represents a radical -CH 2 - and the other group represents, or else a radical -CH (R ') - CH 2 - in which R' represents either a saturated aliphatic radical or unsaturated having from 1 to 12 carbon atoms, leaves a radical - (CH 2 ) n-0-R ⁇ ⁇ in which n represents an integer between 0 and 4 and R-) 'represents a hydrogen atom or a radical saturated or unsaturated aliphatic having from 1 to 8 carbon atoms, i.e.
• R and R1 identical or different, independently of one another represent a hydrogen atom or a radical chosen from methyl, ethyl, linear or branched propyl or butyl, linear or branched radicals and preferably represent a hydrogen atom or a methyl radical, to form a compound of formula (IV): in which D, R and R1 are as defined above;
• step (b) during which the compound of formula (IV) obtained in step (a) reacts with the compound of formula (V):
• step (c) during which the compound of formula (VI) obtained in step (b) undergoes an acid treatment to form said compound of formula (I).
• saturated or unsaturated aliphatic radical containing from 1 to 12 carbon atoms is meant in the definitions of R ', R ", Ri' and R-i" described above, in particular alkyl radicals, and alkenyl radicals.
• alkyl radicals more particularly denoted for R ', R “, Ri” and Ri ", the methyl, ethyl, propyl, 1-methyl ethyl, butyl, 1-methyl propyl, 2-methyl propyl, 1, 1- radicals. dimethyl ethyl, pentyl, 1-methyl butyl, 2-methyl butyl, 1-ethyl propyl, 1, 1-dimethyl propyl, 2,2-dimethyl propyl or 1, 2-dimethyl propyl.
• alkenyl radicals more particularly denoted for R ', R ", Ri' and Ri"
• the vinyl 1-propenyl, 1-methyl ethenyl, 2-propenyl, 1- butenyl, 1-methyl 1-propenyl, 2-methyl 1-propenyl, 2-butenyl, 1-pentenyl, 1- methyl 1 -butenyl, 2-methyl 1 -butenyl, 3-methyl 1 -butenyl, 1, 1-dimethyl 1- propenyl, 2,2-dimethyl 1-propenyl or 1, 2-dimethyl 1-propenyl, 2-pentenyl, 2-methyl 2-butenyl.
• the process as defined above allows direct synthesis of functionalized C-tetraazacycloalkanes, which are macrocycles with high added value. It proceeds in only three stages, starting from commercially available compounds. None of the three stages requires special conditions: high dilution, inert atmosphere, long reaction times, ... unlike all the syntheses described so far. It is general and allows the preparation of cyclams, cyclenes, but also of 1,4,7,10-tetraazatridecanes (2223) C- functionalized. The yields are very high (71-87% in the cyclam series) for such compounds.
• This compound of formula (VII) constitutes another object of the present invention.
• the present invention also relates to the compounds of formula (la):
• alkyl radical linear or branched, comprising from 1 to 15 carbon atoms, a [hetero (aryl)] alkyl radical comprising from 7 to 12 carbon atoms; or
• V represents an OH radical, or an OR 3 radical (in which R 3 represents an alkyl radical containing from 1 to 6 carbon atoms, and more particularly from 1 to
• step (d) can be obtained by an appropriate treatment, within the reach of those skilled in the art.
• the present invention also relates to the process for the preparation of the compounds of formula (I ') comprising the additional step (d) defined above. More particularly, the invention also relates to the compounds capable of being obtained by subjecting the compounds of formula (la) to the abovementioned functionalization step (d), namely the compounds of formula (la 1 ) below :
• Example A Synthesis of 1,4,8,1-methyl tetraazacyclotetradecane-6-carboxylate (compound 5).
• Example B Synthesis of 1, 4,8,11 -tetraazacyclotetradecane-6-carboxylic acid (compound 6).
• This product is obtained according to a procedure identical to that described in Example A stage (b), from 1 g (5.48 mmol) of compound 12 prepared in the preceding stage, 1.42 g (5.48 mmol ) of 3-bromo-2- (bromomethyl) propanoate methyl, and 3.80 g (27.45 mmol) of K2CO3.
• This product is obtained according to a procedure identical to that described in Example A stage (b) from 26.2 g (0.12 mol) of compound 1.54.9 g (0.12 mol) of compound 16 and 86 g (0.62 mol) of K 2 C0 3 .
• the red oil obtained is purified by chromatography on an alumina column (eluent CH 2 CI 2 ).
• This product is obtained according to a procedure identical to that described in Example I from 7.7 g (35.6 mmol) of compound 9 and 21, 66 g (176.2 mmol) of 2-chloro-N , N-dimethylacetamide.
• the red oil obtained is purified by chromatography on an alumina column (eluent CH 2 CI 2 / MeOH-98/2).
• Example K preparation of (1, 4,7,10-tetra- (N, N-dimethylcarbamoylmethyl) -1 • (1, 4,7,10-tetraazacvclotridéc-5-yl) -allyloxymethane (compound 21)

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2001
  • 2001-09-28 FR FR0112550A patent/FR2830253B1/fr not_active Expired - Fee Related
• 2002
  • 2002-09-27 US US10/490,948 patent/US7312327B2/en not_active Expired - Fee Related
  • 2002-09-27 JP JP2003532478A patent/JP4699693B2/ja not_active Expired - Fee Related
  • 2002-09-27 WO PCT/FR2002/003319 patent/WO2003029228A1/fr not_active Ceased
  • 2002-09-27 EP EP02783226A patent/EP1430036A1/fr not_active Withdrawn
  • 2002-09-27 CA CA002461344A patent/CA2461344A1/fr not_active Abandoned

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