阅读说明：本技术 含有氮杂双环衍生物的组合物及其用途 (Compositions containing azabicyclo derivatives and uses thereof ) 是由 向飞 赵震震 于 2019-10-21 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两种氮杂双环衍生物的混合物的组合物,具体的氮杂双环衍生物的定义如说明书所示。所述混合物能与金花茶、南蛇藤、半夏、白花蛇舌草、柘木、峨参等植物的提取物产生协同的抗肿瘤作用。(The invention provides a composition containing a mixture of two different azabicyclo derivatives, wherein the definition of the specific azabicyclo derivative is shown in the specification. The mixture can produce synergistic antitumor effect with extracts of Camellia Chysantha, Celastrus orbiculatus, rhizoma Pinelliae, herba Hedyotidis Diffusae, lignum Cudraniae Tricuspidatae, and Anthriscus sylvestris.)

1. A composition comprising a mixture of first and second azabicyclic derivatives, different from each other, selected from compounds 1-48:

2. the composition of claim 1, wherein the mass ratio of the first azabicyclo derivative to the second azabicyclo derivative 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 Camellia Chysantha, Celastrus orbiculatus, pinellia ternata, Hedyotis diffusa, Cudrania tricuspidata, and Anthriscus sylvestris.

5. The composition of claim 1 or 2, wherein said composition is formulated as a liquid or solid formulation.

6. The composition of claim 5, wherein said liquid formulation is one selected from the group consisting of oral liquid and injection.

7. The composition according to claim 5, wherein the solid preparation is one selected from the group consisting of capsules, tablets and granules.

8. Use of a composition according to claim 1 or 2 for the preparation of a medicament for the treatment of a tumour.

9. The use according to claim 9, wherein the tumor is one selected from the group consisting of lung cancer, colon cancer, leukemia, melanoma, nasopharyngeal carcinoma, ovarian cancer, breast cancer, liver cancer, stomach cancer and prostate cancer.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a composition containing an azabicyclo derivative and a polyhydroxy compound and application thereof.

Background

Tumors (tumors) are one of the most threatening diseases to human health. According to WHO statistics, about 800 million new cases per year and about 700 million people die of malignant tumor are on average newly increased worldwide, and this data is increasing year by year. The three methods for treating tumors in western medicine clinical practice are surgical resection, radiotherapy and chemotherapy. However, although the traditional chemotherapy drugs prolong the survival time of patients, strong adverse reactions and drug resistance are generated, so that research for searching new drugs for treating tumors becomes a hot spot in the current research field.

Azabicycles are structural mother nuclei common to a number of antitumoral active compounds, and specific examples are found in, but not limited to, Rageot D et al (J Med chem.2018Nov 21; 61(22): 10084) and Duan Z et al (MolPharmacol.2007Nov; 72(5): 1137-45).

The extracts reported in the literatures contain the anti-tumor active ingredients, and the anti-tumor active ingredients include, but are not limited to, blueberry, Chinese sage, grifola frondosa, ophthalmia indica, acanthopanax sessiliflorus, abelmoschus manihot, camellia chrysantha, celastrus orbiculatus, pinellia ternate, oldenlandia diffusa, tsugeki, anthriscus sylvestris, african kalimeris, Auricularia, euphorbia pekinensis, brown algae, radix tetrastigme and Tibet wormwood.

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 two different azabicyclo derivatives, wherein the mixture can generate a synergistic antitumor effect with extracts of camellia chrysantha, celastrus orbiculatus, pinellia ternate, oldenlandia diffusa, tsugeki, anthriscus sylvestris and the like.

In order to achieve the above objects, according to one aspect of the present invention, there is provided a composition comprising a mixture of first and second azabicyclic derivatives selected from compounds 1-48 shown below, which are different from each other:

in one aspect, the mass ratio of the first azabicyclo derivative to the second azabicyclo derivative in the mixture of the invention is preferably between 0.01:1 and 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 plant selected from camellia chrysantha, celastrus orbiculatus, pinellia ternate, oldenlandia diffusa, cudrania tricuspidata and anthriscus sylvestris.

On the other hand, the composition of the invention can be prepared into liquid preparation or solid preparation.

More preferably, the liquid preparation of the present invention is one selected from oral liquid and injection, and the solid preparation is one selected from capsule, tablet and granule.

In another aspect, the present invention provides the use of a composition as described above in the manufacture of a medicament for the treatment of a tumour.

More preferably, the tumor of the present invention is one selected from lung cancer, colon cancer, leukemia, melanoma, nasopharyngeal cancer, ovarian cancer, breast cancer, liver cancer, stomach cancer and prostate cancer.

In vitro test results show that the mixture of the invention can synergistically enhance the inhibition effect of the plant extract on the proliferation of related tumor cells.

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 plant dry powder is weighed, 10-20 times (v/w) of water is added for ultrasonic extraction, 60min each time, and the extraction is repeated for 3 times. Filtering, concentrating, and storing in refrigerator at 4 deg.C.

The plant material is one selected from blueberry (PE1), Chinese sage (PE2), grifola frondosa (PE3), ophthalmia indica (PE4), acanthopanax sessiliflorus (PE5), abelmoschus manihot (PE6), golden camellia (PE7), celastrus orbiculatus (PE8), pinellia ternate (PE9), oldenlandia diffusa (PE10), cudrania tricuspidata (PE11), anthriscus sylvestris (PE12), African mukul fruit (PE13), Auricularia fuscosuccinea (PE14), euphorbia pekinensis (PE15), brown algae (PE16), radix tetrastigme (PE17) and Tibetan capillaris thunbergii (PE 18).

Test example 1 Effect of mixture containing azabicyclo derivative on the Effect of plant extracts on inhibiting tumor cell proliferation

The present invention employs the method disclosed by Deng K et al (Cancer Biol ther.2019; 20(1):52-64) to evaluate the inhibition of proliferation of different tumor cells by the following subjects:

a test substance (i): the compound X and the compound Y are selected from the compounds 1 to 48 in different mass ratios (R)₁) The mixture is marked as mixture X-Y, wherein X, Y is selected from 1-48, and X is not equal to Y.

A test object (c): the plant extract prepared in preparation example 1 was designated PEZ (Z is selected from 7 to 12).

Tested object (c): the test substance (R) and the test substance (C) are in a specific mass ratio₂) The resulting mixture, mixture X-Y-PEZ.

The Inhibition Rate (IR) of each test substance on the proliferation of the relevant tumor cells was calculated according to the following formula.

IR＝(1-RCV)×100％。

RCV in the above formula represents the relative cell viability measured according to the method disclosed by Deng K et al (Cancer Biol ther.2019; 20(1): 52-64).

For the test substances (i) and (ii), IR is used to plot the logarithm (log (c)) of the total concentration of the mixture and the concentration (ng/mL) of the plant extract, and the concentration of each test substance at which the inhibition of specific fa occurs is calculated according to the linear regression equation and is recorded as IC_fa(A)And IC_faB). For the test object c, the logarithm of the total concentration (ng/mL) of the compound X and the compound Y in the test object c is plotted by IR, and the total concentration of the compound X and the compound Y in the test object c at the time of generating the inhibition rate of the specific fa is calculated according to a linear regression equation and is recorded as 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 Effect of mixtures of azabicyclo derivatives on plant extracts on the inhibition of proliferation of Lung cancer H1299 cell lines

TABLE 2 effects of mixtures of azabicyclo derivatives on the inhibition of proliferation of the colon cancer HCT-116 cell line by plant extracts

TABLE 2.3 Effect of mixtures of azabicyclo derivatives on plant extract inhibition of proliferation of leukemia U937 cell line

TABLE 2.4 Effect of mixtures of azabicyclo derivatives on the proliferation of melanoma OCM-1 cell lines by plant extracts

TABLE 2.5 Effect of mixtures of azabicyclo derivatives on plant extract inhibition of proliferation of HNE1 cell line in nasopharyngeal carcinoma

TABLE 2.6 Effect of mixtures of azabicyclo derivatives on the inhibition of ovarian cancer A2780 cell line proliferation by plant extracts

TABLE 2.7 Effect of mixtures of azabicyclo derivatives on the inhibition of proliferation of the Breast cancer T47D cell line by plant extracts

TABLE 2.8 Effect of mixtures of azabicyclo derivatives on plant extracts inhibiting the proliferation of hepatoma HepG-2 cell line

TABLE 2.9 Effect of mixtures of azabicyclo derivatives on plant extract inhibition of proliferation of gastric carcinoma 7901 cell line

TABLE 2.10 Effect of mixtures of azabicyclo derivatives on the inhibition of the proliferation of the prostate cancer DU145 cell line by plant extracts

TABLE 2.11 Effect of mixtures of azabicyclo derivatives on plant extracts on the inhibition of proliferation of Lung cancer A549 cell lines

TABLE 2.12 Effect of mixtures of azabicyclo derivatives on plant extracts inhibiting proliferation of the colon cancer CT26 cell line

TABLE 2 effects of mixtures of azabicyclo derivatives on the inhibition of the proliferation of the leukemia K562 cell line by plant extracts

TABLE 2.14 Effect of mixtures of azabicyclo derivatives on plant extract inhibition of proliferation of melanoma A375 cell line

TABLE 2.15 Effect of mixtures of azabicyclo derivatives on the proliferation of plant extracts for the inhibition of nasopharyngeal carcinoma CNE-2 cell lines

TABLE 2.16 Effect of mixtures of azabicyclo derivatives on the inhibition of ovarian cancer SK-OV-3 cell line proliferation by plant extracts

TABLE 2.17 Effect of mixtures of azabicyclo derivatives on the inhibition of proliferation of breast cancer MDA-MB-231 cell lines by plant extracts

TABLE 2.18 Effect of mixtures of azabicyclo derivatives on plant extracts inhibiting the proliferation of the cell line of hepatocarcinoma SMMC-7721

TABLE 2 effects of mixtures of azabicyclo derivatives on the inhibition of gastric carcinoma SGC-7901 cell line proliferation by plant extracts

TABLE 2.20 Effect of mixtures of azabicyclo derivatives on plant extract inhibition of prostate cancer PC-3 cell line proliferation