阅读说明：本技术 一种多臂型peg化奥利万星衍生物及其制备 (Multi-arm PEG (polyethylene glycol) oritavancin derivative and preparation thereof ) 是由 张安林 邓泽平 成佳 于 2018-06-26 设计创作，主要内容包括：本发明利用多臂PEG无毒、易于结合的特性,分别把四臂PEG,六臂PEG和多臂PEG与奥利万星连接起来。多臂PEG负载的奥利万星的前药不仅具有良好的水溶性,最重要的特征在一条多臂PEG链能够与多个奥利万星残基相连,药物的负载率大大提高,并且它大大延长了药物的半衰期,使其在血浆中的存在时间显著增加,从而提高疗效。(The invention utilizes the characteristics of non-toxicity and easy combination of multi-arm PEG to respectively connect the four-arm PEG, the six-arm PEG and the multi-arm PEG with oritavancin. The multi-arm PEG-loaded oritavancin prodrug has good water solubility, and the most important characteristic is that one multi-arm PEG chain can be connected with a plurality of oritavancin residues, so that the drug loading rate is greatly improved, and the half-life period of the drug is greatly prolonged, so that the existence time of the drug in plasma is remarkably prolonged, and the curative effect is improved.)

1. A multi-arm PEG oritavancin derivative has a structural formula as follows:

wherein n is the number of branches, n is an integer from 1 to 3, m is the average number of monomer units (-OCH2CH2-) on each arm of the multi-arm PEG, and m is an integer from 24 to 250.

2. A multi-Arm pegylated oritavancin derivative according to claim 1, having a four-Arm structure when n ═ 1, 4 Arm-PEGm-oritavancin-II structural formula as follows:

wherein m is the average number of monomer units (-OCH2CH2-) on each arm of the multi-arm PEG, and m is an integer of 24-250.

3. The pegylated oritavancin derivative according to claim 1, wherein when n-2, it has a six-armed structure, and 6 Arm-PEGm-oritavancin-II has the following structural formula:

wherein m is the average number of monomer units (-OCH2CH2-) on each arm of the multi-arm PEG, and m is an integer of 24-250.

4. The pegylated oritavancin derivative of claim 1, wherein when n-3, it has a multiarm structure, and 8 Arm-PEGm-oritavancin-II has the following structural formula:

wherein m is the average number of monomer units (-OCH2CH2-) on each arm of the multi-arm PEG, and m is an integer of 24-250.

5. A process for the preparation of a multi-arm pegylated oritavancin derivative of claim 1, via the synthetic route:

wherein step 1(4or 6or 8) -Arm-PEGm-OH-I reacts with adipic anhydride and DMAP in DMF to obtain (4or 6or 8) -Arm-PEGm-GA-II; step 2(4or 6or 8) -Arm-PEGm-GA-II reacts with oritavancin under the action of a condensing agent to obtain a PEG-typed oritavancin derivative (4or 6or 8) -Arm-PEGm-oritavancin-III.

6. The method for preparing the multi-arm PEGylated oritavancin derivative as claimed in claim 5, wherein step1 is performed at a reaction temperature of 100-120 ℃ for a reaction time of 8-12h in DMF as a solvent.

7. The multi-arm PEGylated oritavancin derivative according to claim 5, wherein step2 is performed by using N, N-dimethylformamide as a solvent, and DIC (diisopropylcarbodiimide) and 4-PPY (4-N, N-lutidine) as condensing agents, at a reaction temperature of 0-35 ℃ and a reaction time of 12-24 hours.

8. The use of a multi-arm pegylated oritavancin derivative according to any one of claims 1-4 for the preparation of a medicament for the treatment of acute bacterial skin and skin structure infections.

Technical Field

The invention relates to the field of medicine synthesis, in particular to a multi-arm PEG (polyethylene glycol) oritavancin derivative, a preparation method thereof and application thereof in preparation of medicines for treating acute bacterial skin and skin structure infection.

Background

In recent years, with the increase of the application of antibacterial drugs, the problem of drug resistance of bacteria is becoming more serious, and the proportion of MRSA in skin infection is increasing year by year. Vancomycin, teicoplanin and the like are generally used clinically to treat severe infections caused by MRSA. However, the rapid emergence of vancomycin-resistant strains has made the search for new anti-MRSA antibacterial agents urgent.

Oritavancin is a second generation glycopeptide antibacterial drug developed on the basis of vancomycin, and is the first and only one single-dose antibacterial drug approved by the FDA for the treatment of abssssis. The approval of oritavancin represents a significant advance in the treatment of acute bacterial skin and skin structure infections.

Oritavancin (oritavancin) is a novel glycopeptide antibacterial drug developed by medicins, is approved by the Food and Drug Administration (FDA) to be marketed in 2014 at 8-6 months, and has a trade name of orabativ. The medicine can be used for treating Acute Bacterial Skin and Skin Structure Infection (ABSSSIS) caused by sensitive gram-positive bacteria (including methicillin-resistant Staphylococcus aureus (MRSA)).

The antibacterial action mechanism of oritavancin is to inhibit the formation of bacterial cell walls by blocking transglycosylation in the process of peptidoglycan biosynthesis. In a clinical test involving 1987 patients with ABSSSIS, the safety and effectiveness of oritavancin were evaluated, and the results showed that the activity of oritavancin was comparable to vancomycin; research shows that oritavancin has good antibacterial activity on gram-positive bacteria including vancomycin insensitivity, drug-resistant staphylococcus, enterococcus and the like, can reduce the generation of drug resistance, and has a multiple action mechanism for preventing the generation of the drug resistance. The most common adverse reactions of oritavancin are osteomyelitis, hypersensitivity, hypoglycemia, tenosynovitis, myalgia, bronchospasm, wheezing, anemia, eosinophilia, erythema, extravasation, induration, pruritus, rash, peripheral edema, urticaria, angioedema, erythema multiforme, pruritus, leukocytoclasis vasculitis and the like. And because a plurality of reaction sites (10 secondary amino groups or primary amino groups or amide groups, 9 hydroxyl groups and one carboxyl group) are arranged in the structure of the oritavancin compound and can participate in various reactions, the positioning modification of oritavancin by chemical bonds is difficult to realize in the prior art so as to reduce toxic and side effects. At present, the most effective method for reducing the side effect of the medicament is to reduce the administration times and dosage, which can not solve the problem of toxic and side effect of the medicament fundamentally and reduce the medicament effect.

Polyethylene glycol (PEG) is a water-soluble polyether of low molecular weight obtained by the gradual addition polymerization of ethylene oxide and water or ethylene glycol. The low molecular weight poly-ethylene glycol is colorless, odorless and hygroscopic viscous liquid, has ether chains and hydroxyl groups in molecules, has unique solubility and good biocompatibility, and has important application prospect in the fields of medicines, materials, engineering and the like. While the conventional linear chain PEG has only two terminal modification groups, when the linear chain PEG is connected with a small molecule drug, the loading capacity is very limited, and the multi-arm type PEG has more than 2 modifiable terminals. The multi-arm PEG chain can be connected with a plurality of medicines, and the loading rate of the medicines is greatly improved.

Disclosure of Invention

In order to solve the problems, the invention utilizes the characteristics of non-toxicity and easy combination of multi-arm PEG and takes adipic acid as a bridging bond to respectively connect four-arm PEG, six-arm PEG, multi-arm PEG and oritavancin through a combined condensing agent. The process can realize the fixed-point modification of primary ammonia on oritavancin by multi-arm PEG, so that modification sites are defined, the interference of modification isomers is avoided, and the in-vivo and in-vitro activity of the medicament can be well reserved; the modified product has uniform composition and stable property, is convenient for quality control, reduces potential safety risk caused by the modified isomer, greatly improves the yield and reduces the cost.

The multi-arm PEG-loaded oritavancin prodrug has good water solubility, and the most important characteristic is that one multi-arm PEG chain can be connected with a plurality of oritavancin residues, so that the drug loading rate is greatly improved, and the half-life period of the drug is greatly prolonged, so that the existence time of the drug in plasma is remarkably prolonged, and the curative effect is improved.

A multi-arm PEG oritavancin derivative has a structural formula as follows:

wherein n is the number of branches and n is an integer of 1 to 3. m is the average number of monomer units (-OCH2CH2-) on each arm of the multi-arm PEG, and m is an integer of 24-250.

Further, the multi-Arm PEGylated oritavancin derivative has the following structure, namely the structural formula of 4 Arm-PEGm-oritavancin-II is as follows:

the structural formula of 6 Arm-PEGm-oritavancin-II is as follows:

the structural formula of 8 Arm-PEGm-oritavancin-II is as follows:

wherein m is the average number of monomer units (-OCH2CH2-) on each arm of the multi-arm PEG, and m is an integer of 24-250.

Further, the synthetic route is shown in figure 1.

Wherein step 1(4or 6or 8) -Arm-PEGm-OH-I reacts with adipic anhydride and DMAP in DMF to obtain (4or 6or 8) -Arm-PEGm-GA-II; step 2(4or 6or 8) -Arm-PEGm-GA-II reacts with oritavancin under the action of a condensing agent to obtain a PEG-typed oritavancin derivative (4or 6or 8) -Arm-PEGm-oritavancin-III. The step1 is carried out under the condition of taking DMF as a solvent at the reaction temperature of 100 ℃ and 120 ℃ for 8-12 h. The step2 is carried out by taking N, N-dimethylformamide as a solvent, DIC (diisopropylcarbodiimide) and 4-PPY (4-N, N-dimethylpyridine) as a condensing agent at the reaction temperature of 0-35 ℃ for 12-24 h. The use of the multi-arm pegylated oritavancin derivative for the preparation of a medicament for the treatment of acute bacterial skin and skin structure infections.

The invention has the following beneficial effects:

1. the multi-arm PEG modified oritavancin has the advantages that the drug water solubility is enhanced, the half-life period is prolonged, the toxic and side effects of the drug are reduced, and the drug activity is increased;

2. the loading rate of the drug is greatly improved, and the half-life period of the drug is greatly prolonged, so that the existence time of the drug in blood plasma is obviously prolonged, and the curative effect is improved.

3. Adipic acid is taken as a bridging bond, and four-arm PEG, six-arm PEG, multi-arm PEG and oritavancin are respectively connected through a combined condensing agent. The process can realize the fixed-point modification of primary ammonia on oritavancin by multi-arm PEG, so that modification sites are defined, the interference of modification isomers is avoided, and the in-vivo and in-vitro activity of the medicament can be well reserved; the modified product has uniform composition and stable property, is convenient for quality control, reduces potential safety risk caused by the modified isomer, greatly improves the yield and reduces the cost.

Drawings

Figure 1 is the preparation of multi-arm oritavancin derivatives.

Detailed Description

The conjugates of the present invention and their preparation are described below with reference to examples, which are not intended to limit the present invention, the scope of which is defined by the claims.