Dicabba-analogues of octreotide

A compound and chiral carbon technology, applied in the field of analog derivatives of octreotide, can solve problems such as short half-life and clinical use restrictions of somatostatin

Inactive Publication Date: 2011-06-08
ADVANCED ACCELERATOR APPLICATIONS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the clinical use of somatostatin is limited due to many disadvantages such as its short half-life in blood (<3 minutes)

Method used

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  • Dicabba-analogues of octreotide
  • Dicabba-analogues of octreotide
  • Dicabba-analogues of octreotide

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0076] Linear heptapeptide Fmoc-Hag 3 (Allyl amino acid)-1-Nal 7 -D-Trp 8 -Lys 9 -Thr 10 -Hag 14 -Thr(ol) 15 Synthesis

[0077] Peptides were prepared in Teflon reactors with porous polystyrene membranes using the Fmoc-SPPS method on pre-swelled H-L-Thr(tBu)-ol-2-chlorotriphenyl resin.

[0078] Coupling steps were performed by adding 2 equivalents of protected amino acid, activated by HATU and 4 equivalents of NMMDMF solution, followed by stirring for 45 minutes for each coupling and monitored by qualitative tests using ninhydrin (Kaiser test).

[0079] Once the synthesis of the linear peptide was complete, microlysis was performed on 5 mg of resin. This resin uses TFA / H 2 Treated with O / 1,2-ethanedithiol (EDT) / phenol (94:2:2:2; 3h) and filtered, the solution was concentrated under reduced pressure and washed with Et 2O precipitated peptides, centrifuged, dissolved in water and lyophilized. Analysis of Fmoc-protected crude peptides by RP-HPLC [Phenomenex Jupiter C18 ...

example 2

[0082] Synthesis of cyclic unsaturated peptides of structural formula (1), wherein -Λ is H, R=benzyl, R 1 is a chemical bond, CH 2 is the D configuration, CH 3 It is L configuration, X=1-Nal, Y=D-Trp, W=Lys, Z=Thr, R 2 =-NHThr(ol)

[0083] The heptapeptide on resin was re-swelled in anhydrous DCM for 2 hours. The reactor was heated to 45 °C and a solution of the second generation Grubbs catalyst, [(L)(L')X 2 Ru=CHR wherein L is a phosphine ligand, L' is a heterocyclic carbene (1,3-bis(2,4,6-trimethylphenyl)-imidazole-2-ylidene) (1,3-dimesityl-imidazol -2-ylidene), X is a Cl atom and R is a phenyl] (0.5 molar equivalent), and the suspension was stirred for 24 hours. The resin was washed with DCM, DMF and MeOH, followed by swelling with DMF. Fmoc-Hag was deprotected with 20% piperidine, and the cyclic peptide coupled to Fmoc-D-Phe was as described previously. This cyclic peptide was deprotected and isolated from the resin as previously described. with Et 2 O concentrate...

example 3

[0086] Synthesis of the unsaturated cyclic peptide of structural formula (1), wherein-Λ is a chelating group DOTA, R=benzyl, R 1 is a chemical bond, CH 2 is the D configuration, CH 3 It is L configuration, X=1-Nal, Y=D-Trp, W=Lys, Z=Thr, R 2 =-NHThr(ol)

[0087] As described in Example 2, the Fmoc-D-Phe of formula I bonded to the resin 2 The deprotection of the peptide was carried out with 20% piperidine; then 2 molar equivalents of DOTA-tri-(t-Bu) ester in DMF, 2 molar equivalents of HATU in DMF and then 4 molar equivalents of NMM were added to in the resin. The equivalent is calculated based on a resin substitution rate of 0.5 mmol / g. The DOTA-conjugated peptide was separated from the resin after the resin was washed for 45 minutes. The tri-(t-Bu)DOTA-protecting group was isolated together with the peptide. The crude peptide was dissolved in water and lyophilized, then purified by RP-HPLC (20%-60% of B in 20 minutes; yield: 29%).

[0088] ESI-MS: found [M+H] + 1417....

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Abstract

Analogues of octreotide, their preparation and use are described.

Description

technical field [0001] The present invention relates to analog derivatives of octreotide. Background technique [0002] Somatostatin-14 (SRIF-14) is a cyclic tetradetrapeptide (formula 1) containing a disulfide bridge between two cysteine ​​residues; [0003] [0004] Formula 1: SRIF-14 [0005] SRIF-14 is an important regulator of endocrine and exocrine, and inhibits the release of various other hormones such as glucagon, growth hormone (GH), insulin, gastrin, and others. [0006] Furthermore, based on its distribution in various regions of the brain and spinal cord, somatostatin is thought to play a role in nerve transmission. [0007] According to their structure, phylogenetic and pharmacological properties, SRIF receptors can be divided into two main types: SRIF receptors including sst2, sst3, sst5 1 and SRIF including receptors sst1 and sst4 2 . [0008] However, the clinical use of somatostatin is limited due to many disadvantages such as its short half-life in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/08A61K31/38C07K14/655A61P35/00A61P19/02A61P19/08
CPCC07K14/6555A61K38/00A61K31/38A61K51/088A61P19/02A61P19/08A61P29/00A61P35/00
Inventor 毛罗·金南内施德博拉·达多纳亚历山德拉·迪查尼
Owner ADVANCED ACCELERATOR APPLICATIONS SA
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