Methods of radiofluorination of biologically active vectors

FIELD: chemistry.

SUBSTANCE: invention refers to the conjugates of formula (V)

or (VI) : wherein X is -CO-NH- or -O-; their use as radiopharmaceuticals, processes for their preparation, and synthetic intermediates used in such processes.

EFFECT: use as radiopharmaceuticals.

25 cl, 15 ex

 

The text descriptions are given in facsimile form.

1. How radiotolerance, enabling the th interaction of the compounds of formula (I) with the compound of the formula (II):


or the compounds of formula (III) with the compound of the formula (IV)


where R1 represents an aldehyde group;
R2 represents hydrazide;
R3 represents aminoxy;
R4 represents an aldehyde group, a ketone group, a protected aldehyde, such as acetal-protected ketone, such as ketal, or functional group, such as a diol or N-terminal serine residue, which can be quickly and efficiently oxidized to the aldehyde or ketone using an oxidizing agent;
obtaining the conjugate of formula (V) or (VI) respectively:


where X represents-CO-NH - or-O-;
Y represents N; and
the linker group in the compounds of formula (II), (IV), (V) and (VI) selected from



where n is an integer from 0 to 20;
m is an integer from 1 to 10;
p is an integer 0 or 1;
Z represents O or S; and
the vector is a molecule with affinity to the biological target, representing the peptide.

2. How radiotolerance involving communication connection is of formula (VII):

with the compound of the formula (VIII), (X) or (XI):


,
where n is an integer from 0 to 20;
m is an integer from 1 to 10;
X represents-O-;
Y represents H, to obtain the compounds of formula (XII, XIV, XV), respectively:



where n is an integer from 0 to 20;
m is an integer from 1 to 10;
X represents-O-;
Y represents N; and
the vector is a molecule with affinity to the biological target, representing the peptide.

3. How radiotolerance, including interaction of the compounds of formula (XVI):

where Y represents H,
with the compound of the formula (XX):

obtaining the compounds of formula (XXIV):

where Y represents N; and
the vector is a molecule with affinity to the biological target, representing the peptide.

4. The method according to any one of claims 1 to 3, where the vector is a peptide Arg-Gly-Asp or its equivalent.

5. The method according to claim 4, where the vector contains the code

6. The method according to claim 4, hgevector has the formula (A):

where X7represents a-NH2or

where a is an integer from 1 to 10, and preferably is 1.

7. The compound of formula (II):

where R2 represents a hydrazide; and
the linker group is a

where n is an integer from 1 to 20.

8. The compound of formula (XX):

9. The compound of formula (IV),

where R4 represents an aldehyde group, a ketone group, a protected aldehyde, such as acetal-protected ketone, such as Catal,
the linker group in the compounds of formula (IV) selected from



where n is an integer from 0 to 20;
m is an integer from 1 to 10;
p is an integer 0 or 1;
Z represents O or S;
provided that in compounds of formula (IV), the linker does not represent phenyl.

10. The compound of formula (VIII), (X) or (XI):



where n is an integer from 0 to 20;
m is an integer from 1 to 10;
S submitted the a-O-;
Y represents N;
provided that in compounds of formula (X) n is not equal to 0.

11. The compound of formula (I):

where R1 represents an aldehyde group;
or of the formula (III);

where R3 represents aminoxy;
in which the vector has the formula (A):

where X7represents a-NH2or

where a is an integer from 1 to 10, or a vector is a (Cys disulfide1-6): -CH2CONH(CH2)5CO-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2.

12. Connection claim 11, where the vector is a peptide Arg-Gly-Asp.

13. The connection according to item 11 or 12, where the vector has the formula (A):

where X7represents a-NH2or

where a is an integer from 1 to 10, and preferably is 1.

14. The compound of formula (V):

or of the formula (VI):

where X represents-CO-NH - or-O-;
Y represents N;
the linker group in the compounds of formulas (V) and (VI) selected from



where n is an integer from 0 to 20;
m represents Soboh is an integer from 1 to 10;
p is an integer 0 or 1;
Z represents O or S; and
the vector has the formula (A):

where X7represents a-NH2or

where a is an integer from 1 to 10, or a vector is a (Cys disulfide1-6): -CH2CONH(CH2)5CO-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2.

15. The compound of formula (XII), (XIV) and (XV)



where n is an integer from 0 to 20;
m is an integer from 1 to 10;
X represents-O-;
Y represents N; and
the vector has the formula (A):

where X7represents a-NH2or

where a is an integer from 1 to 10, or a vector is a (Cys disulfide1-6): -CH2CONH(CH2)5CO-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2.

16. The compound of formula (XXIV):

where Y represents N;
and the vector has the formula (A):

where X7represents a-NH2or

where a is an integer from 1 to 10.

17. The compound according to any one of p-16, where the vector, not only is em a peptide Arg-Gly-Asp.

18. The connection 17, where the vector contains the fragment:

19. The connection 17, where the vector has the formula (A):

where X7represents a-NH2or

where a is an integer from 1 to 10, and preferably is 1.

20. The compound of the formula:

21. Radiopharmaceutical composition for use in the method of imaging in vivo, containing an effective amount of a compound according to any one of p-20 together with one or more pharmaceutically acceptable adjuvant, excipient or diluent.

22. The compound according to any one of p-20 for diagnostic imaging.

23. The use of compounds according to any one of p-20 for the manufacture of radiopharmaceutical agents for use in the method of visualization in vivo.

24. A method of obtaining images of a human or animal, comprising introducing into a specified body of the compounds according to any one of p-20 and obtaining images of at least portions of the said body, in which the specified connection was distributed using PET (positron emission tomography).

25. Method of monitoring the effect of treatment of the human or animal drug to combat a condition associated with the th cancer, preferably angiogenesis, including an introduction to the specified body compounds according to any one of p-20 and the detection of seizure specified conjugate cell receptors, and specified the introduction and detection is possible, but is preferably carried out before, during and after treatment indicated medicine.



 

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12 cl, 2 tbl

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2 tbl, 1 ex, 2 dwg

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3 cl, 3 tbl, 1 ex

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8 cl, 8 tbl, 25 ex

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11 cl, 1 tbl, 8 ex

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11 ex

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3 cl, 2 tbl, 10 ex

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11 cl, 3 tbl, 3 dwg, 2 ex

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5 cl, 1 tbl, 14 ex

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11 cl, 1 dwg, 9 ex

FIELD: organic chemistry, chemical technology.

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EFFECT: improved preparing method.

1 tbl, 4 ex

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