N3S1 chelator-folate derivatives, preparation method thereof and composition for diagnosis or treatment of cancer containing the same as an active ingredient

Patent metadata

Field	Value
Publication number	US-9365599-B2
Application number	US-201314063724-A
Country	US
Kind code	B2
Filing date	Oct 25, 2013
Priority date	Oct 26, 2012
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

Novel N 3 S 1 chelator-folate derivatives, a preparation method thereof, and a composition for diagnosis and treatment of tumor including the same as an active ingredient are provided. The novel N 3 S 1 chelator-folate derivatives or a pharmaceutically acceptable salt thereof are easily introduced into the cells using receptor binding to tumor expressing α-folate receptor (α-FR). Accordingly, the folate derivatives, labeled with radioisotope such as technetium, or rhenium, can be advantageously used for the diagnosis and treatment of tumor using tumor imaging and irradiation from the isotope, and therefore, can be widely used for the purpose of labeling a variety of radiopharmaceuticals.

First claim

What is claimed is:

1. A N 3 S 1 chelator-folate derivative expressed by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:

wherein, R is hydroxy or amine;
R 1 is nonbonding,

 wherein Aaa is any one selected from 1 to 3 amino acids, and derivatives thereof;
l is an integer between 1 and 10;
m is an integer between 1 and 10;
n is an integer between 1 and 10;
o is an integer between 1 and 20;
R 2 is amino acid selected from a group consisting of alanine, arginin, asparagine, aspartic acid, cystine, glutaric acid, glutamine, glycine, histidine, iso-leucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
R 3 is

R 4 is halogen, hydroxy or amine;
R 5 is alkyl between C 1 and C 4 ; and
P is an integer between 1 and 4.

2. The N 3 S 1 chelator-folate derivative or pharmaceutically acceptable salt thereof as set forth in claim 1 ,
wherein
R is hydroxy or amine;
R 1 is nonbonding,

 wherein
Aaa is any one selected from 1 to 3 amino acids, D-form amino acid, and derivative thereof;
l is an integer between 1 and 4;
m is an integer between 1 and 4;
n is an integer between 1 and 6; and
o is an integer between 1 and 10,

R 2 is amino acid selected from a group consisting of alanine, arginin, asparagine, aspartic acid, cystine, glutaric acid, glutamine, glycine, hisitidine, iso-leucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
R 3 is

R 4 is fluoro, hydroxy or amine;
R 5 is methyl or ethyl; and
P is an integer between 1 and 4.

3. A method for preparation of the N 3 S 1 chelator-folate derivative of claim 1 , comprising, as represented by Reaction Formula 1 below;
preparing folate derivative of Chemical Formula 4 by allowing the folic acid derivative of Chemical Formula 2 to react with a compound of Chemical Formula 3 (step 1); and
preparing a compound of Chemical Formula 1 by removing resin, which is solid phase support of the folate derivative of Chemical Formula 4 prepared at step 1 under acidic condition (step 2):

wherein,
resin is solid phase support; and
Trt is trityl group.

4. The method of claim 3 , wherein the compound represented by Chemical Formula 3 of the Reaction Formula 1 is prepared by a method comprising, as represented by Reaction Formula 2 below;
preparing a compound represented by Chemical Formula 5 by allowing lysine protected with Alloc protecting group to react with cysteine protected with Fmoc protecting group (step 1);
preparing a compound represented by Chemical Formula 7 by allowing the compound of Chemical Formula 5 prepared at step 1 to react with a compound represented by Chemical Formula 6 (step 2);
preparing a compound represented by Chemical Formula 9 by allowing the compound of Chemical Formula 7 prepared at step 2 to react with a compound represented by Chemical Formula 8 (step 3); and
preparing a compound represented by Chemical Formula 3, by allowing the compound of Chemical Formula 9 prepared at step 3 to react with a compound represented by Chemical Formula 10 (step 4):

wherein,
resin is solid phase support;
Alloc is allylcarbamate;
Fmoc is fluorenylmethyloxycarbonyl group; and
Trt is trityl group.

5. A preparation method of the N 3 S 1 chelator-folate derivative of claim 1 , comprising, as represented by Reaction Formula 3 below:
preparing folate derivative of Chemical Formula 4 by allowing pteroic acid derivative of Chemical Formula 11 to react with a compound of Chemical Formula 12 (step 1); and
preparing a compound of Chemical Formula 1 by removing resin, which is solid phase support of the folate derivative of Chemical Formula 4 prepared at step 1, under acidic condition (step 2):

wherein,
resin is solid phase support; and
Trt is trityl group.

6. The method of claim 5 , wherein the compound represented by Chemical Formula 12 of the Reaction Formula 3is prepared by a method comprising, as represented by Reaction Formula 4 below:
preparing a compound represented by Chemical Formula 14, by allowing a compound represented by Chemical Formula 3 to be conjugated with glutamic acid represented by Chemical Formula 13 (step 1); and
preparing a compound represented by Chemical Formula 12 by deprotecting the compound of Chemical Formula prepared at step 1 (step 2):

wherein,
resin is solid phase support;
Fmoc is fluorenylmethyloxycarbonyl group; and
Trt is trityl group.

7. The method of claim 3 , wherein the solid phase support is Wang resin or Merrifield resin.

8. The N 3 S 1 chelator-folate derivative of claim 1 , further labeled with radioisotope.

9. The radioisotope-labeled N 3 S 1 chelator-folate derivative of claim 8 , wherein the radioisotope is technetium or rhenium.

10. A method for preparation of a radioisotope-labeled complex, comprising transchelating the N 3 S 1 chelator-folate derivative of claim 8 , using ligand exchange reaction kit.

11. A composition for diagnosis of tumor, comprising the radioisotope-labeled N 3 S 1 chelator-folate derivative of claim 8 as an active ingredient.

12. A composition for treatment of tumor, comprising the radioisotope-labeled N 3 S 1 chelator-folate derivative of claim 8 as an active ingredient.

13. A kit for radioisotope-labeling the N 3 S 1 chelator-folate derivative of claim 1 .

Assignees

• Korea Atomic Energy Res

Inventors

• Hong Young-Don
• Choi Sun Ju
• Lee So-Young
• Lim Jae Cheong
• Lee Dong Eun

Classifications

• C07D475/04 Primary

  with a nitrogen atom directly attached in position 2 · CPC title

• C07F13/00 Primary

  Compounds containing elements of Groups 7 or 17 of the Periodic Table · CPC title

• A61K47/48076

  Human Necessities · mapped topic

• A61K47/547

  Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent · CPC title