Dendritic Chelated Compounds, Methods for Making the Same and Pharmaceutical Compositions Containing the Same
First Claim
1. A dendritic chelated complex of the following formula I:
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[[MC]-En-[D]m-X1p1X2p2X3p3X4p4]z−
z B+
Formula Iwherein;
M is a magnetic or scintigraphic marker, preferably chosen from Gd3+, Mn2+ and 99mTc3+ ions,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, preferably a tert-butyl (tBu) group,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, preferably for the brain, such as L-dopamine,p2 is an integer equal to 0, 1, 2 or 4, limits included,X3 is a group having a therapeutic activity, preferably for neurodegenerative diseases such as Alzheimer'"'"'s disease, Parkinson'"'"'s disease and multiple sclerosis,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, preferably Na+ or K+,z is an integer equal to 0, 1, 2, 3 or 4.
1 Assignment
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Accused Products
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]En-[D]m—X1p1X2p2X3p3X4p4]z− z B+ (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.
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Citations
40 Claims
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1. A dendritic chelated complex of the following formula I:
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[[MC]-En-[D]m-X1p1X2p2X3p3X4p4]z−
z B+
Formula Iwherein; M is a magnetic or scintigraphic marker, preferably chosen from Gd3+, Mn2+ and 99mTc3+ ions, 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, preferably a tert-butyl (tBu) group, 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, preferably for the brain, such as L-dopamine, p2 is an integer equal to 0, 1, 2 or 4, limits included, X3 is a group having a therapeutic activity, preferably for neurodegenerative diseases such as Alzheimer'"'"'s disease, Parkinson'"'"'s disease and multiple sclerosis, 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, preferably Na+ or K+, z is an integer equal to 0, 1, 2, 3 or 4. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
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7. The complex according to claim 1, characterized in that:
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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;
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8. The complex according to claim 1, wherein:
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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 99mTc3+, B is Na+, and z=1, of formula II-3 below;
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9. The complex according to claim 1, wherein:
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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.
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10. The complex according to claim 1, wherein:
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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.
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11. The complex according to claim 1, wherein:
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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 99mTc3+, p1=p2=p3=0 X4 is CH3, p4=3, B is Na3+, and z=3.
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12. The complex according to claim 1, wherein:
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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, B is Na3+, and z=0.
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13. The complex according to any claim 1, wherein:
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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 Na3+, and z=1.
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14. The complex according to any claim 1, wherein:
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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 99mTc3+, p1=p2=p3=0, X4 is CH3, p4=3, B is Na3+, and z=0.
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15. The complex according to claim 1, wherein:
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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 Na3+, and z=3.
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16. The complex according to claim 1, wherein:
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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 Na3+, and z=4.
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17. The complex according to claim 1, wherein:
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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 99mTc3+, p1=p2=p3=0, X4 is CH3, p4=6 when m=2 or p4=12 when m=4, B is Na3+, and z=3.
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18. The complex according to claim 1, wherein:
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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, B is Na3+, and z=0.
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19. The complex according to claim 1, wherein:
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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 Na3+, and z=1.
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20. The complex according to claim 1, wherein:
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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 99mTc3+, 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 Na3+, and z=0.
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21. The complex according to claim 1, wherein:
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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.
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22. The complex according to claim 1, wherein:
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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.
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23. The complex according to claim 1, wherein:
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n=p2=p3=p4=0, M is 99mTc3+, 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.
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24. The complex according to claim 1, wherein:
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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.
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25. The complex according to claim 1, wherein:
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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.
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26. The complex according to claim 1, wherein:
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n=p2=p3=p4=0, M is 99mTc3+, 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.
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27. The complex according to claim 1, wherein:
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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.
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28. The complex according to claim 1, wherein:
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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.
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29. The complex according to claim 1, wherein:
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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 99mTc3+, m=1, X1 is a tert-butyl (tBu) group, p1=2, X2 is L-dopamine, p2=1, B is Na+, and z=1.
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30. The complex according to claim 1, wherein:
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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.
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31. The complex according to claim 1, wherein:
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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.
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32. The complex according to claim 1, wherein:
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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 99mTc3+, m=2, X1 is a tert-butyl (tBu) group, p1=4, X2 is L-dopamine, p2=2, B is Na+, and z=1.
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33. The complex according to claim 1, wherein:
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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 99mTc3+, 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.
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34. A method for synthesizing the complex according to claim 6, comprising the following steps:
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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 f) with diethylenetriaminepentaacetic dianhydride, h) reaction of the product obtained in step g) with Gd chloride or Mn chloride or pertechnetate.
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35. A method for synthesizing the complex according to claim 21, comprising the following steps:
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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.
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36. A method for synthesizing the complex according to claim 27 comprising the following steps:
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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 chlorideb″
) 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.
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37. A method for synthesizing the complex according to claim 30, comprising the following steps:
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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.
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38. A pharmaceutical composition, comprising at least one complex as claimed in claim 1, in a pharmaceutically acceptable excipient.
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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.
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40. A method for treating a neurodegenerative disease selected from the group consisting of Alzheimer'"'"'s disease, Parkinson'"'"'s disease or multiple sclerosis comprising administering the pharmaceutical composition of claim 38 to a subject in need of said treatment.
Specification