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Oligopeptide having marrow hemopoiesis protection function, preparation thereof, pharmaceutical composition containing the oligopeptide and use

A technology of bone marrow hematopoiesis and composition, which is applied in the field of medicine, can solve the problems of poor feasibility of large-scale production, high synthesis investment, and difficulty in developing into practical drugs, and achieve the effect of poor purity and ideal purity

Inactive Publication Date: 2012-05-23
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there have been some design and synthesis of SP4 transformations, such as sequentially changing the peptide bond (CONH) in the molecule to an isosteric pseudo-peptide bond (Pseudo-Peptide), such as CONH→CH2NH [Gaudron, S et al., Stem Cells, 1999, 17:100-106]; a certain residue substitution, such as Homo-Ser→Ser [Thierry, J et al., J Pept Sci, 2001, 7:284 -293] and partial introduction of the Freidinger ring structure into the peptide chain [Kumar, S et al., J Org Chem, 2005, 70: 5946-5953] and other forms, although the biological stability of SP4 was improved on the basis of retaining the original activity, However, due to the high investment in synthesis, it is only of academic significance, and the feasibility of large-scale production is poor, so it is difficult to develop into practical drugs.

Method used

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  • Oligopeptide having marrow hemopoiesis protection function, preparation thereof, pharmaceutical composition containing the oligopeptide and use
  • Oligopeptide having marrow hemopoiesis protection function, preparation thereof, pharmaceutical composition containing the oligopeptide and use
  • Oligopeptide having marrow hemopoiesis protection function, preparation thereof, pharmaceutical composition containing the oligopeptide and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The synthesis of embodiment 1 Ac-Ser-Asp-Lys-Pro-NHEt (1)

[0067] ①Synthesis of Boc-Pro-acetophenone (Pac)-resin

[0068] Weigh 10g (5mmol) Pac-resin (substitution equivalent 0.5mmol / g, particle size 100-200 mesh, crosslinking degree 1%), three times (15mmol) moles of Boc-Pro-OH, three times the moles of K 2 CO 3 and 1 / 10 mole (0.5 mmol) of KI were mixed together with 150 mL of DMF in a round bottom flask. Under the conditions of heating and rotating in an air bath at 70°C, the reaction was carried out for 24 hours. The reaction suspension was transferred to a filter with a suction filter sand plate, and washed 5 times with DMF at 60° C., about 50 mL each time. This was followed by diafiltration with the following solvents (× times): 95% EtOH × 3, DMF × 3, 50% EtOH / H 2 O×3, anhydrous EtOH×3, anhydrous Et 2 O×2. After the solvent was drained, the resin was taken out and air-dried to constant weight under infrared light at about 50°C. Weighed Boc-Pro-OCH 2 - 10.6...

Embodiment 2

[0084] Example 2 (2) Synthesis

[0085] ① Synthesis of Fmoc-Lys(Boc)-Pac-resin

[0086] Since the Fmoc group cannot tolerate K 2 CO 3 / 60°C, in this example, DIEA equivalent to Fmoc-Lys(Boc)-OH was used instead of K 2 CO 3 , the temperature was changed to room temperature, the reaction time was extended to 35h, and all the other operations were identical to the conditions of (1) in Example 1. As a result, 11.57 g of Fmoc-Lys(Boc)-Pac-resin was obtained, with a weight gain of 1.57 g (theoretical amount: 1.938 g), and an actual yield of 81%.

[0087] ②Synthesis of Ac-Ser(tBu)-Asp(tBu)-Lys(Boc)-Pac-resin

[0088] Take 2g of Fmoc-Lys(Boc)-Pac-resin, and obtain 2.25g of Acated fully protected resin according to the conditions of Example 1 (3)-(6).

[0089] ③ piperidine aminolysis to remove the resin, preparation of

[0090] The above fully protected tripeptide resin was mixed with 8mL piperidine and 8mL THF in a sealable reaction tube and rotated on an air bath at 50°C f...

Embodiment 3

[0093] Example 3 Synthesis of Ac-Ser-Asp-Lys-NHEt (3)

[0094] The synthesis method and conditions are the same as in Example 1. Finally, 311 mg of product 3 (theoretical amount: 410 mg) was obtained, with a total yield of 75.8%, and the structure confirmed by FAB-MS: 418.4 (M+H).

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Abstract

The invention discloses an oligopeptide chemical compound containing a neighboring structure of acid residues and alkaline residues, a method for synthesizing the oligopeptide chemical compound by a crossed matching strategy and medicine compounds containing the oligopeptide chemical compound. The oligopeptide chemical compound is proved to have the activity for protecting marrow hematogenesis functions through influences of oligopeptide products on GM forming and BFUE forming and influences on death rate of irradiating Gamma ray on mice, and the invention can prepare medicament for protecting marrow hematogenesis stem cells from being injured by chemotherapy medicines and radiotherapy.

Description

technical field [0001] The present invention relates to a class of oligopeptide compounds containing an acidic residue and a basic residue adjacent structure, a preparation method for this type of oligopeptide compound, a pharmaceutical composition containing this type of oligopeptide compound, and a preparation for protecting bone marrow hematopoietic stem cells from The application of chemotherapeutic drugs and drugs for radiotherapy damage belongs to the technical field of medicine. Background technique [0002] At present, 60% to 70% of tumor patients need radiotherapy and chemotherapy. Generally, reasonable radiotherapy and chemotherapy 2 to 4 weeks after surgery can kill "metastasis" in time and effectively resist tumor recurrence and metastasis. Whether radiotherapy and chemotherapy can persist The key is the protection of bone marrow hematopoietic function. However, many anti-tumor chemotherapeutic drugs cause different degrees of bone marrow suppression, which init...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K5/10A61K38/07A61K38/08A61P43/00A61P35/00
Inventor 王德心韩香林浩冯鹤鹤韩俊领孟恒星
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI