Dendritic chelated compounds, methods for making the same and pharmaceutical compositions containing the same

• US 8,404,216 B2
• Filed: 10/09/2007
• Issued: 03/26/2013
• Est. Priority Date: 10/09/2006
• Status: Expired due to Fees

• Current Assignee: Centre National De La Recherche Scientifique, Université Louis Pasteur
• Original Assignee: Centre National De La Recherche Scientifique, Université Louis Pasteur
• Inventors: Felder-Flesch, Delphine, Bertin, Annabelle, Steibel, Jrme
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): SCHLIENTZ, LEAH H
• Application Number:
  US12/444,817
• Publication Number:
  US 20100104512A1
• Time in Patent Office: 1,995 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.3, 424/9.36, 424/9.361, 424/9.362, 424/9.363, 424/9.364, 424/9.365
• US Class Current: 424/9.361
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07C 229/16 to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• CPC Class Codes: C07C 229/76 Metal complexes of amino carboxylic acids
• CPC Class Codes: C07C 237/08 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07D 215/48 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07F 9/6524 having four or more nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C08G 83/002 Dendritic macromolecules

Abstract

The invention relates to dendritic chelated compounds, to methods for producing the same and to pharmaceutical compositions containing the same. The dendritic chelated complexes of the present invention have the following formula (I): [[MC]E_n-[D]_m-X_1p1X_2p2X_3p3X_4p4]_z⁻zB⁺ (I), where m is a magnetic or scintigraphic marker, C is a chelating agent of the marker M, E is a spacer, n=0 or 1, D is compound capable of forming a dendritic structure, m is an integer equal to 1 or 2 or 4, X₁ is a group increasing the complex lipophily, p1 is an integer from 0 to 12, X₂ is a group increasing the complex specificity for a particular organ, p2 is an integer equal to 1 or 2 or 4, X₃ is a group having a therapeutic activity, p3 is an integer equal to 0, 1, 2 or 4, X₄ is a CH₃ group, p4 is an integer from 0 to 12, B is a counter-ion, z is an integer equal to 0, 1, 2, 3 or 4. The invention can be used in the field of pharmacy, more precisely in medical imaging.

Claims

1. A dendritic chelated complex of the following formula I:

[[MC]-E_n-[D]_m-X_1p1 X_2p2 X_3p3 X_4p4]^z−

zB⁺ 

 

Formula I

wherein;

M is a magnetic or scintigraphic marker,

C is a chelating agent for the magnetic marker M,

[MC] is a chelate of the magnetic-marker M,

E is a spacer,

n=0 or 1,

[D] is a dendritic structure, the core of which comprises at least one group derived from benzyl alcohol or from a benzyl amine, the benzyl ring of which is substituted at positions 3, 4, 5 with chains composed of polyethylene glycol units,

m is an integer equal to 1 or 2 or 4,

X₁ is a group for increasing the lipophilicity of the complex,

p1 is an integer equal to 0 to 12, limits included,

X₂ is a group for increasing the specificity of the complex for a particular organ,

p2 is an integer equal to 0, 1, 2 or 4, limits included,

X₃ is a group having a therapeutic activity,

p3 is an integer equal to 0, 1, 2 or 4, limits included,

X₄ is a CH₃ group,

p1+p2+p3+p4=3 when m=1 or p1+p2+p3+p4=6 when m=2 or p1+p2+p3+p4=12 when m=4,

p4 is an integer equal to 0 to 12, limits included,

B is a counterion,

z is an integer equal to 0, 1, 2, 3 or 4.

2. The complex according to claim 1, wherein the chelating agent C is diethylenetriaminepentaacetic acid (DTPA), a catechol-derived tripod or an 8-hydroxyquinoline-derived tripod.

3. The complex according to claim 1 wherein each dendrite of the dendritic structure [D] is a polyethylene glycol chain comprising 3 or 4 ethylene glycol units.

4. The complex according to claim 1, wherein m=1.

5. The complex according to claim 1, wherein m=2 or 4.

6. The complex according to claim 1, wherein:

n=p1=p2=p3=0,

X₄ is CH₃,

p4=6,

each dendrite of the dendritic structure [D] is a chain comprising 3 ethylene glycol units,

m=2,

C is diethylenetriaminepentaacetic acid,

M is Gd³⁺,

B is Na⁺, and

z=1

of formula II-1 below;

7. The complex according to claim 1, characterized in that:

n=p1=p2=p3=0,

X₄ is CH₃,

p4=6,

each dendrite of the dendritic structure [D] is a polyethylene glycol chain having 3 ethylene glycol units,

m=2,

C is diethylenetriaminepentaacetic acid,

M is Mn²⁺,

B is Na⁺, and

z=2,

of formula II-2 below;

8. The complex according to claim 1, wherein:

n=p1=p2=p3=0,

X₄ is CH₃,

p4=6,

each dendrite of the dendritic structure [D] is a polyethylene glycol chain having 3 ethylene glycol units,

m=2,

C is diethylenetriaminepentaacetic acid,

M is 99 mTc³⁺,

B is Na⁺, and

z=1,

of formula II-3 below;

9. The complex according to claim 1, wherein:

C is a catechol-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain having 3 or 4 ethylene glycol units,

m=1,

M is Gd³⁺,

p1=p2=p3=0,

X₄ is CH₃,

p4=3,

B is Na⁺, and

z=3.

10. The complex according to claim 1, wherein:

C is a catechol-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain having 3 or 4 ethylene glycol units,

m=1

M is Mn²⁺,

p1=p2=p3=0,

X₄ is CH₃,

p4=3,

B is Na⁺, and

z=4.

11. The complex according to claim 1, wherein:

C is a catechol-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain having 3 or 4 ethylene glycol units,

m=1,

M is 99 mTc³⁺,

p1=p2=p3=0

X₄ is CH₃,

p4=3,

B is Na⁺, and

z=3.

12. The complex according to claim 1, wherein:

C is an 8-hydroxyquinoline-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=1,

M is Gd³⁺,

p1=p2=p3=0,

X₄ is CH₃,

p4=3,

and

z=0.

13. The complex according to any claim 1, wherein:

C is an 8-hydroxyquinoline-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=1,

M is Mn²⁺,

p1=p2=p3=0,

X₄ is CH₃,

p4=3,

B is Na⁺, and

z=1.

14. The complex according to any claim 1, wherein:

C is an 8-hydroxyquinoline-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=1,

M is 99 mTc³⁺,

p1=p2=p3=0,

X₄ is CH₃,

p4=3,

and

z=0.

15. The complex according to claim 1, wherein:

C is a catechol-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

M is Gd³⁺,

p4=6 when m=2 or p4=12 when m=4,

B is Na⁺, and

z=3.

16. The complex according to claim 1, wherein:

C is a catechol-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

M is Mn²⁺,

p4=6 when m=2 or p4=12 when m=4,

B is Na⁺, and

z=4.

17. The complex according to claim 1, wherein:

C is a catechol-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

M is 99 mTc³⁺,

p1=p2=p3=0,

X₄ is CH₃,

p4=6 when m=2 or p4=12 when m=4,

B is Na⁺, and

z=3.

18. The complex according to claim 1, wherein:

C is an 8-hydroxyquinoline-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

M is Gd³⁺,

p1=p2=p3=0,

X₄ is CH₃,

p4=6 when m=2 or p4=12 when m=4,

and

z=0.

19. The complex according to claim 1, wherein:

C is an 8-hydroxyquinoline-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

M is Mn²⁺,

p1=p2=p3=0,

X₄ is CH₃,

p1=p2=p3=0,

X₄ is CH₃,

p4=6 when m=2 or p4=12 when m=4,

B is Na⁺, and

z=1.

20. The complex according to claim 1, wherein:

C is an 8-hydroxyquinoline-derived tripod,

n=1,

E is an ethylenediamine or butanediamine chain,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

M is 99 mTc³⁺,

p1=p2=p3=0,

X₄ is CH₃,

p1=p2=p3=0,

X₄ is CH₃,

p4=6 when m=2 or p4=12 when m=4,

and

z=0.

21. The complex according to claim 1, wherein:

n=p2=p3=p4=0,

M is Gd³⁺,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=1,

C is diethylenetriaminepentaacetic acid,

X₁ is a tert-butyl (tBu) group,

p1=3,

B is Na⁺, and

z=1.

22. The complex according to claim 1, wherein:

n=p2=p3=p4=0,

M is Mn²⁺,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=1,

C is diethylenetriaminepentaacetic acid,

X₁ is a tert-butyl (tBu) group,

p1=3,

B is Na⁺, and

z=2.

23. The complex according to claim 1, wherein:

n=p2=p3=p4=0,

M is 99 mTc³⁺,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=1,

C is diethylenetriaminepentaacetic acid,

X₁ is a tert-butyl (tBu) group,

p1=3,

B is Na⁺, and

z=1.

24. The complex according to claim 1, wherein:

n=p2=p3=p4=0,

M is Gd³⁺,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

C is diethylenetriaminepentaacetic acid,

X₁ is a tert-butyl (tBu) group,

p1=6 when m=2 or p1=12 when m=4,

B is Na⁺, and

z=1.

25. The complex according to claim 1, wherein:

n=p2=p3=p4=0,

M is Mn²⁺,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

C is diethylenetriaminepentaacetic acid,

X₁ is a tert-butyl (tBu) group,

p1=6 when m=2 and p1=12 when m=4,

B is Na⁺, and

z=2.

26. The complex according to claim 1, wherein:

n=p2=p3=p4=0,

M is 99 mTc³⁺,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=2 or 4,

C is diethylenetriaminepentaacetic acid,

X₁ is a tert-butyl (tBu) group,

p1=6 when m=2 or p1=12 when m=4,

B is Na⁺, and

z=1.

27. The complex according to claim 1, wherein:

n=p3=p4=0,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

C is diethylenetriaminepentaacetic acid,

M is Gd³⁺,

m=1,

X₁ is a tert-butyl (tBu) group,

p1=2,

X₂ is L-dopamine,

p2=1,

B is Na⁺, and

z=1.

28. The complex according to claim 1, wherein:

n=p3=p4=0,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

C is diethylenetriaminepentaacetic acid,

M is Mn²⁺,

m=1,

X₁ is a tert-butyl (tBu) group,

p1=2,

X₂ is L-dopamine,

p2=1,

B is Na⁺, and

z=2.

29. The complex according to claim 1, wherein:

n=p3=p4=0,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

C is diethylenetriaminepentaacetic acid,

M is 99 mTc³⁺,

m=1,

X₁ is a tert-butyl (tBu) group,

p1=2,

X₂ is L-dopamine,

p2=1,

B is Na⁺, and

z=1.

30. The complex according to claim 1, wherein:

n=p3=p4=0,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

C is diethylenetriaminepentaacetic acid,

M is Gd³⁺,

m=2,

X₁ is a tert-butyl (tBu) group,

p1=4,

X₂ is L-dopamine,

p2=2,

B is Na⁺, and

z=1.

31. The complex according to claim 1, wherein:

n=p3=p4=0,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

C is diethylenetriaminepentaacetic acid,

M is Mn²⁺,

m=2,

X₁ is a tert-butyl (tBu) group,

p1=4,

X₂ is L-dopamine,

p2=2,

B is Na⁺, and

z=2.

32. The complex according to claim 1, wherein:

n=p3=p4=0,

each dendrite of the dendritic structure [D] is a chain comprising 3 or 4 ethylene glycol units,

C is diethylenetriaminepentaacetic acid,

M is 99 mTc³⁺,

m=2,

X₁ is a tert-butyl (tBu) group,

p1=4,

X₂ is L-dopamine,

p2=2,

B is Na⁺, and

z=1.

33. The complex according to claim 1, wherein:

C is either diethylenetriaminepentaacetic acid, or a catechol-derived or 8-hydroxyquinoline-derived tripod,

n=0 or 1,

E is an ethylenediamine chain or butanediamine chain when n=1,

each dendrite of the structure [D] is a chain comprising 3 or 4 ethylene glycol units,

m=1 or 2 or 4,

M is Gd³⁺, or Mn²⁺, or 99 mTc³⁺,

X₁ is a tert-butyl (tBu) group,

p1 is an integer equal to between 0 and 12, limits included,

X₂ is L-dopamine,

p2 is an integer equal to 0, 1, 2 or 4, limits included,

X₃ is a therapeutic agent,

p3 is an integer equal to 0, 1, 2 or 4, limits included,

p4=0,

B is Na⁺, and

z=0, 1, 2, 3 or 4.

34. A method for synthesizing the complex according to claim 6, comprising the following steps:

a) reaction of triethylene glycol monomethyl ether with tosyl chloride,

b) reaction of the tosylate obtained in step a) with methyl 3,4,5-trihydroxybenzoate,

c) reduction of the product obtained in step b), preferably with LiAlH₄, so as to obtain the corresponding alcohol,

d) bromination of the product obtained in step c),

e) reaction of the product obtained in step d) with methyl 3,5-dihydroxybenzoate,

f) reaction of the product obtained in step e), preferably with LiAlH₄,

g) reaction of the product obtained in step with diethylenetriaminepentaacetic dianhydride,

h) reaction of the product obtained in step g) with Gd chloride or Mn chloride or pertechnetate.

35. A method for synthesizing the complex according to claim 21, comprising the following steps:

a) synthesis of tert-butoxytriethylene glycol from tert-butanol,

b) reaction of the product obtained in step a) with tosyl chloride,

c) reaction of the tosylate obtained in step b) with methyl 3,4,5-trihydroxybenzoate,

d) reduction of the product obtained in step c), preferably with LiAlH₄, so as to obtain the corresponding alcohol,

e) reaction of the product obtained in step d) with diethylenetriaminepentaacetic dianhydride,

f) reaction of the product obtained in step e) with Gd chloride or Mn chloride or pertechnetate.

36. A method for synthesizing the complex according to claim 27 comprising the following steps:

a) synthesis of tert-butoxytriethylene glycol from tert-butanol,

b) reaction of the product obtained in step a) with tosyl chloride,

a′

) reaction of methyl 3,4,5-trihydroxybenzoate with acetic anhydride,

b′

) reaction of the product obtained in step a′

) with allyl bromide,

c′

) basic hydrolysis of the product obtained in step b′

), preferably with potassium carbonate,

d′

) reaction of the product obtained in step c′

) with the tosylate obtained in step b),

e′

) deprotection of the alcohol function of the product obtained in step d′

),

a″

) protection of L-dopamine with Fmoc chloride

b″

) reaction of the product obtained in step a″

) with allyl bromide,

c″

) reaction of the product obtained in step b″

) with morpholine,

d″

) esterification of the product obtained in step c″

),

e″

) saponification of the product obtained in step d″

),

f″

) esterification of the product obtained in step e″

) with the product obtained in step e′

),

g″

) reduction of the product obtained in step f″

) so as to obtain the corresponding alcohol,

h″

) reaction of the product obtained in step g″

) with diethylenetriaminepentaacetic dianhydride,

i″

) reaction of the product obtained in step h″

) with Gd (III), chloride, Mn (II) chloride or pertechnetate.

37. A method for synthesizing the complex according to claim 30, comprising the following steps:

a) synthesis of tert-butoxytriethylene glycol from tert-butanol,

b) reaction of the product obtained in step a) with tosyl chloride,

a′

) reaction of methyl 3,4,5-trihydroxybenzoate with acetic anhydride,

b′

) reaction of the product obtained in step a′

) with allyl bromide,

c′

) basic hydrolysis of the product obtained in step b′

) with potassium carbonate,

d′

) reaction of the product obtained in step c′

) with the tosylate obtained in step b),

e′

) deprotection of the alcohol function of the product obtained in step d′

),

a″

) protection of L-dopamine with Fmoc chloride,

b″

) reaction of the product obtained in step a″

) with allyl bromide,

c″

) reaction of the product obtained in step b″

) with morpholine,

d″

) esterification of the product obtained in step c″

),

e″

) saponification of the product obtained in step d″

),

f″

) esterification of the product obtained in step e″

) with the product obtained in step e′

),

g″

) reduction of the product obtained in step f″

), preferably with LiAlH₄, so as to obtain the corresponding alcohol,

h″

) bromination of the product obtained in step g″

),

i″

) reaction of the product obtained in step h″

) with methyl 3,5-dihydroxybenzoate,

j″

) reduction of the product obtained in step i″

), preferably with LiAlH₄, so as to obtain the corresponding alcohol,

k″

) reaction of the product obtained in step j″

) with diethylenetriaminepentaacetic dianhydride,

l″

) reaction of the product obtained in step k″

) with Gd (III) chloride, Mn (II) chloride or pertechnetate.

38. A pharmaceutical composition, comprising at least one complex as claimed in claim 1, in a pharmaceutically acceptable excipient.

39. A method for the detection of neurodegenerative diseases selected from the group consisting of Alzheimer'"'"'s disease, Parkinson'"'"'s disease and multiple sclerosis comprising administering the pharmaceutical composition of claim 38 to a subject in need of said detection.

40. The complex according to claim 1, wherein M is chosen from Gd³⁺, Mn²⁺ and 99 mTc³⁺ ions.

41. A dendritic chelated complex according to claim 1, wherein X₁ is a tert-butyl (tBu) group.

42. A dendritic chelated complex according to claim 1, wherein X₂ is a group for increasing the specificity of the complex for the brain.

43. A dendritic chelated complex according to claim 1, wherein X₂ is a L-dopamine group.

44. A dendritic chelated complex according to claim 1, wherein X₃ is a group having a therapeutic activity for neurodegenerative diseases.

45. A dendritic chelated complex according to claim 1, wherein X₃ is a group having a therapeutic activity for neurodegenerative diseases chosen in the group of Alzheimer'"'"'s disease, Parkinson'"'"'s disease and multiple sclerosis.

46. A dendritic chelated complex according to claim 1, wherein B is Na⁺ or K⁺.