阅读说明：本技术 含有异吲哚啉酮衍生物混合物的组合物及其用途 (Composition containing isoindolinone derivative mixture and application thereof ) 是由 向飞 张斌 于 2019-12-17 设计创作，主要内容包括：本发明提供了一种含有互不相同的第一异吲哚啉酮衍生物与第二异吲哚啉酮衍生物混合物的组合物,所述异吲哚啉酮衍生物的具体定义见说明书。本发明所述的混合物能协同地增强白钻等植物的提取物对沃氏葡萄球菌等细菌的抑制作用。(The invention provides a composition containing a mixture of a first isoindolinone derivative and a second isoindolinone derivative which are different from each other, wherein the isoindolinone derivative is specifically defined in the specification. The mixture of the invention can synergistically enhance the inhibition effect of the extract of the plants such as the rhinestone on the bacteria such as staphylococcus wowensis and the like.)

1. A composition comprising a mixture of a first isoindolinone derivative and a second isoindolinone derivative, which are different from each other and are selected from the group consisting of compounds 1 to 44 shown below:

2. the composition according to claim 1, wherein the mass ratio of the first isoindolinone derivative to the second isoindolinone derivative in the composition is between 0.01:1 and 100: 1.

3. The composition of claim 1 or 2, wherein said composition further comprises a plant extract.

4. The composition of claim 3, wherein said plant extract is an extract of a plant selected from the group consisting of Cissus quadrangularis, Gynura paniculata, Ainsliaea fragrans, Tiger, Anoectochilus roxburghii, and Chaihoufeng.

5. The composition of claim 1 or 2, wherein said composition is formulated as an oral solid dosage form.

6. The composition of claim 5, wherein said oral solid dosage form is one selected from the group consisting of a tablet, a capsule and a capsule.

7. Use of a composition according to claim 1 or 2 for the preparation of a medicament for the treatment of bacterial infectious diseases.

8. Use according to claim 7, characterized in that said bacterial infectious disease is a disease caused by an infection with a bacterium selected from the group consisting of Staphylococcus wowensis, Staphylococcus lugdunensis, Acinetobacter lodoi, Propionibacterium acnes, Achromobacter xylosoxidans, Staphylococcus saprophyticus, Mycobacterium avium, Staphylococcus pasteurii, Moraxella oshimurii, Serratia marcescens, Staphylococcus haemolyticus, Streptococcus viridis, Proteus mirabilis, Coccocus radiculoides, Aeromonas hydrophila, Rosemotonia pilei, Citrobacter discrepant, Streptococcus salivarius, Acinetobacter baumannii.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a composition containing a mixture of isoindolinone derivatives and application thereof.

Background

Nosocomial infections are a significant problem affecting hospital medical quality. With the continuous development and progress of modern medical technology, a large amount of antibacterial drugs are used, and the drug-resistant strains of clinical pathogenic bacteria are continuously increased. Therefore, the improvement of the antibacterial activity of the existing drugs can help to improve the treatment effect of the patients with bacterial infection.

A series of isoindolinones with antibacterial activity were synthesized by El-Gohary NS et al (ArchPharm (Weinheim) 2015 Sep; 348(9): 666-80.). Research by Vicente T et al proves that isoindolinone compounds with the structure shown in formula I have certain inhibition effect on mycobacterium avium (Arch Intern Med.1993 Feb22; 153(4): 534).

The plant extract is rich in a plurality of components with antibacterial activity, for example, the extracts of plants such as the populus nymphs and the like (the report of tropical biology, 2019,10(03): 226;) 230. the extracts of the plants such as the blumea riparia, the rhinestone, the illicium verum, the aeolian milkvetch root, the sinoacutus hexapetalus mongholicus, the kadsura longipedunculata, the anoectochilus roxburghii, the typhonium giganteum, the rhynchophyllum giganteum, the stringy euphorbia root, the typhonium giganteum, the fraxinellus pallidus, the cudrania cochinchinensis, and the like have certain antibacterial activity.

It is well known that the therapeutic effects of Chinese herbs are manifested by the synergistic action of a series of compounds (effective components) with similar structures. Therefore, a compound group which can generate synergistic action with the plant extract is searched, and a new way is provided for treating difficult and complicated diseases by combining Chinese and western medicine.

Disclosure of Invention

The invention aims to provide a composition containing a mixture of a first isoindolinone derivative and a second isoindolinone derivative which are different from each other, wherein the mixture can generate synergistic antibacterial effect with extracts of plants such as rhinestone, panax notoginseng, typhonium giganteum, cutworm, anoectochilus roxburghii, caulis seu folium japonicae and the like.

In order to achieve the above object, one aspect of the present invention provides a composition comprising a mixture of a first isoindolinone derivative and a second isoindolinone derivative, which are different from each other and selected from the group consisting of compounds 1 to 44 shown below:

in one aspect, the mass ratio of the first isoindolinone derivative to the second isoindolinone derivative in the composition of the invention is preferably 0.01:1 to 100: 1.

In another aspect, the composition of the present invention preferably further comprises a plant extract.

Further preferably, the plant extract of the present invention is an extract of one selected from the group consisting of boehmeria platyphylla, gynura segetum, typhonium giganteum, tiger hair, anoectochilus roxburghii, and lindera glauca.

In another aspect, the composition of the present invention can be prepared into oral solid preparation.

More preferably, the oral solid preparation of the present invention is one selected from the group consisting of tablets, capsules and capsules.

In another aspect, the present invention provides the use of a composition as described above for the preparation of a medicament for the treatment of a bacterial infectious disease.

Preferably, the bacterial infectious disease according to the present invention is a disease caused by infection with a bacterium selected from the group consisting of Staphylococcus Wauteri, Staphylococcus lugdunensis, Acinetobacter lodoides, Propionibacterium acnes, Achromobacter xylosoxidans, Staphylococcus saprophyticus, Mycobacterium avium, Staphylococcus pasteuri, Moraxella oshimurium, Serratia marcescens, Corynebacterium parvum, Staphylococcus haemolyticus, Streptococcus viridis, Proteus mirabilis, Coccocus radiculoides, Aeromonas hydrophila, Rosemotonia pilei, Citrobacter difficile, Streptococcus salivarius, and Acinetobacter baumannii.

In-vitro test results show that the isoindolinone derivative mixture can generate synergistic antibacterial effect with extracts of various plants such as rhinestone, panax notoginseng, typhonium giganteum, cutworm, anoectochilus roxburghii, lysimachia foenum-graecum and the like

Detailed Description

The following description of the embodiments is only intended to aid in the understanding of the method of the invention and its core ideas. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The following description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

Preparation example 1 preparation of plant extract

Drying the dried plant material at 40 deg.C by ultrasonic extraction, pulverizing, sieving with 40 mesh sieve, and placing into self-sealing bag. Before the test, 50g of the dried plant powder was weighed and added with different organic solvents for ultrasonic extraction (as shown in table 1), and the extraction was repeated 3 times for 60min each time. Filtering, concentrating to dry, and storing in a refrigerator at 4 deg.C for use.

TABLE 1 organic solvent for ultrasonic extraction of different plant extracts

Test example 1 Effect of the mixture of isoindolinone derivatives on the antibacterial Activity of plant extracts

The inhibition of various bacteria by the test substances ① - ③ shown below is determined by a method disclosed by Lemna hexandra et al (food and fermentation industry, 2017,43(02): 232-238.).

(1) ① test drug prepared by mixing isoindolinone derivative compounds X and Y (X, Y is selected from 1-44, and X is not equal to Y) at a specific mass ratio (R)₁) Mixing, namely MIX (X-Y), ②, the plant extract (PEZ, Z is selected from 1-6) obtained in preparation example 1, ③, ① and ②, and mixing according to the mass ratio (R)₂) The resulting mixture was designated MIX (X-Y-PEZ).

(2) Test method

① preparing test sample solution by taking a certain amount of test substance, using DMF as solvent, and adopting a specific multiple continuous dilution method to prepare test sample solution with 6 concentrations.

② bacterial suspension is prepared by inoculating activated strain to liquid culture medium (no agar), shake-culturing, calculating bacterial colony number by plate dilution method, and adjusting bacterial suspension concentration to 10 with sterile physiological saline⁷CFU/mL。

③ agar-hole diffusion method for determining antibacterial activity comprises cooling the sterilized culture medium to 50 deg.C, adding 6mL of bacterial suspension, mixing, pouring into a culture dish with diameter of 9cm, standing for 46min, uniformly perforating (diameter of 7mm) on the cured culture medium with an aseptic perforator, marking, adding 40 μ L of sample solution into each hole, DMF as blank control, culturing the bacteria at 37 deg.C for 18h, measuring and recording the diameter (mm) of the zone of inhibition, repeating for 3 times, averaging to obtain the result, and calculating the Inhibition Ratio (IR) of the strain to be tested according to the following formula.

For MIX (X-Y) and PEZ, IR is plotted against the log (c)) of the total concentration of MIX (X-Y) versus the tested concentration (ng/mL) of PEZThe concentrations of the test substances at the time of the occurrence of the specific inhibition of fa were calculated from the linear regression equation and each concentration was designated as IC_fa(A)And IC_fa(PEZ). For MIX (X-Y-PEZ), the concentration of MIX (X-Y) in MIX (X-Y-PEZ) at which inhibition of a particular fa occurs is calculated according to a linear regression equation using IR plotted against the logarithm of the concentration (ng/mL) of MIX (X-Y) therein, and is designated IC_fa(mixA)。

The Combination Index (CI) at which a specific fa inhibitory rate is produced is calculated according to the following formula.

When CI <1, it means that there is synergism, the smaller the CI, the stronger the synergism.

TABLE 2.1 inhibitory Effect of the test substances on Staphylococcus Wauteri

TABLE 2.2 inhibitory Effect of the test substances on Staphylococcus lugdunensis

TABLE 2.3 inhibition of Acinetobacter lofoii by test substances

TABLE 2.4 inhibition of Propionibacterium acnes by test substances

TABLE 2.5 inhibition of Achromobacter xylosoxidans by test substances

TABLE 2.6 inhibitory Effect of test substances on Staphylococcus saprophyticus

TABLE 2.7 inhibitory Effect of test substances on M.avium

TABLE 2.8 inhibitory Effect of the test substances on Staphylococcus pasteurii

TABLE 2.9 inhibitory Effect of the test substances on Ouslomanra

TABLE 2.10 inhibition of Serratia marcescens by the test substances

TABLE 2.11 inhibitory Effect of the test substances on Corynebacterium glutamicum

TABLE 2.12 inhibition of Staphylococcus hemolyticus by the test substances

TABLE 2.13 inhibition of Streptococcus viridis by test substances

TABLE 2.14 inhibition of Proteus mirabilis by test substances

TABLE 2.15 test substance inhibition of Cockera rhizophila

TABLE 2.16 inhibition of Aeromonas hydrophila by test substances

TABLE 2.17 test substance inhibition of Ralstonia pickettii

TABLE 2.18 inhibition of Citrobacter difficile by test substances

TABLE 2.19 inhibition of Streptococcus salivarius by the test substances

TABLE 2.20 inhibition of Acinetobacter baumannii by test substances