WO2010081266A1 - A new use of tetrahydropalmatine - Google Patents

Abstract

A new use of tetrahydropalmatine, which is the use of tetrahydropalmatine of formula (I) or its pharmaceutically acceptable salts in preparing medicament for inhibiting tumor cells proliferation in eucaryon and in preparing medicament for preventing and/or treating tumor. The results of the test in nude mice show that tetrahydropalmatine may inhibit the tumor growth effectively and the volume of the tumor is markedly smaller than the negative control. So tetrahydropalmatine which has been widely used in ease pain has excellent anti- tumor activity and may be used in preparing medicament for treating cancer, especially lung cancer. This invention expands the pharmaceutical uses of tetrahydropalmatine.

Description

 New use of tetrahydropalmatine

 This invention relates to new uses of tetrahydropalmatine.

Background technique

 Corydalis is the dry tubers of the poppy plant, the genus Corydalis, which has the effect of promoting blood circulation, benefiting gas and relieving pain. Its main chemical component is alkaloid, of which tetrahydropalmatine (structural formula is shown in formula I) is a tertiary amine alkaloid with the strongest analgesic effect, analgesic, sedative, sleep aid and stability, especially for the gastrointestinal system. The resulting dull pain is effective. At present, tetrahydropalmatine has been used as an analgesic and sleepless non-prescription drug, such as tetrahydropalmatine sulfate tablets and Qiangtongning. However, none of them reported on anti-tumor.

式 I

Formula I

 Lung cancer is a common malignant tumor of the lung, and its mortality rate has been the highest in cancer mortality. Most lung cancers originate from the bronchial mucosa. In recent years, with the influence of smoking and various environmental factors, the incidence and mortality of lung cancer have risen rapidly in countries around the world, especially in industrialized countries. Chemotherapy can be used alone in advanced lung cancer cases to relieve symptoms or to be combined with surgery and radiotherapy to prevent cancer metastasis, recurrence, and cure. Commonly used chemotherapeutic drugs are cyclophosphamide, 5-fluorouracil, mitomycin (:, doxorubicin, procarbazine, vincristine, methotrexate, nitrosourea, cisplatin, etc.). However, there is currently no clinically safe and effective treatment for lung cancer.

Invention disclosure

 It is an object of the present invention to provide new uses of tetrahydropalmatine.

The use of the tetrahydropalmatine provided by the present invention is: the tetrahydropalmatine or the drug thereof of the formula I Application of a physiologically acceptable salt in the preparation of a medicament for inhibiting proliferation of eukaryotic tumor cells

式 I

Formula I

 The tetrahydropalmatine may be a left-handed body, a right-handed body or a racemate, and is preferably a drusen of the formula II;

式 II

Formula II

 The present invention also protects a drug which inhibits proliferation of eukaryotic tumor cells, and its active ingredient is tetrahydropalmatine of the formula I or a pharmaceutically acceptable salt thereof.

 The eukaryotic organism described in the present invention is a mammal.

 The tumor cells are cancer cells; the cancer cells may specifically be breast cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer A cell, a nasopharyngeal cancer cell, a colon cancer cell, a bladder cancer cell, an anal cancer cell, or a rectal cancer cell; preferably a lung cancer cell.

 The novel use of the tetrahydropalmatine provided by the present invention is also: The use of tetrahydropalmatine or a pharmaceutically acceptable salt thereof represented by the formula (I) for the preparation of a medicament for preventing and/or treating a tumor.

The tetrahydropalmatine may be a left-handed body, a right-handed body or a racemate, and is preferably a left-handed tamarindine represented by the formula. The tumor cells are cancer cells; the cancer cells may specifically be breast cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer A cell, a nasopharyngeal cancer cell, a colon cancer cell, a bladder cancer cell, an anal cancer cell, or a rectal cancer cell; preferably a lung cancer cell.

 It is also within the scope of the present invention to use a tetrahydropalmatine or a pharmaceutically acceptable salt thereof represented by Formula I as an active ingredient for the prevention and/or treatment of a tumor.

 The preventive and/or therapeutic tumor drug can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, jetting, nasal drops, eye drops, infiltration, absorption, physical or chemical mediated methods; Other substances are mixed or wrapped and introduced into the body.

 An antitumor drug containing tetrahydropalmatine or a pharmaceutically acceptable salt thereof as an active ingredient, and if necessary, one or more pharmaceutically acceptable carriers may be added to the above drug. The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.

 The preventive and/or therapeutic tumor drug prepared by using tetrahydropalmatine or a pharmaceutically acceptable salt thereof can be prepared into various forms such as an injection, a tablet, a powder, a granule, a capsule, an oral solution, an ointment, a cream, and the like. The above various dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field.

 The following examples are provided to facilitate a better understanding of the invention but are not intended to limit the invention.

DRAWINGS

 Fig. 1 is a schematic diagram showing the tumor size in nude mice of each group on the 28th day after administration, wherein the blank in the positive control group represents tumor disappearance.

The best way to implement the invention

 The experimental methods in the following examples are conventional methods unless otherwise specified.

 Example 1. Effect of tetrahydropalmatine on proliferation of human lung cancer cells

 Tumor cell line: human lung cancer cell line A549 (Shanghai Institute of Cell Biology, Chinese Academy of Sciences);

 Test animals: Male BALB/c nude mice (SPF grade, Institute of Experimental Animals, Chinese Academy of Medical Sciences), aged 4-6 weeks, 24 animals;

 The animal's body weight range at the start of administration: 16-18 g, and the animal's initial body weight is not more than or less than 20% of the average body weight;

Positive control: cisplatin injection (ra Keding Medical Co., Ltd., batch number: M071881);

 Negative control: 0.9% sodium chloride injection (physiological saline).

 The specific steps are as follows:

 (1) Culture of tumor cells

The human lung cancer cell line A549 was suspended and cultured in RPMI 1640 medium (containing penicillin 100 U/mL, streptomycin 100 U /mL) containing 10% calf serum, and placed in a cell culture at 37 ° C, 5% CO ₂ . Cultivate in the box.

 It is passed every 3 days. After 24 hours of subculture, the cells were subjected to the logarithmic growth phase for the next test.

 (2) Establishment of a nude mouse xenograft model

 The logarithmic growth phase A549 cells were collected and centrifuged, and counted after staining with a mass percentage of 0.4% trypan blue solution.

With the above RPMI 1640 medium to adjust the cell concentration ΙχΙΟ ⁷ / ml, and at 0.2ml / only right armpits of nude mice, tumor-bearing murine prepared.

 The tumor was grown to about lg, and the mice were inoculated to prepare F1 generation tumor-bearing mice.

Tumor-bearing animals with strong tumor growth and no ulceration and good health were taken, and tumors were taken under aseptic conditions to prepare 3nmi ³ , which was inoculated into the right axilla of each animal.

The tumor growth was observed after inoculation in nude mice. When the tumor volume was 100-300 mm ³ , the tumor size and body weight were screened. The tumor volume was too large and no tumorigenicity was selected.

 Tumor-bearing mice were randomly divided into: negative control group, positive control group and tetrahydropalmatine group, each group

8 rats were then given different drugs in groups.

 (3) Preparation of test samples

 Negative control group: normal saline was administered;

 Tetrahydropalmatine group: L-Tallowhosin (Chengdu Cisco Hua Biotechnology Co., Ltd.), the intragastric dose is lOOmg I kg body weight;

 Positive control group: 0.5 mg I ml of cisplatin solution was administered, and the intraperitoneal dose was: 0.1 ml/lOg body weight.

 (4) Method of administration

Route and frequency of administration: Tetrahydropalmatine and negative control were administered intragastrically once a day, and the positive control was administered intraperitoneally once a week. Duration of administration: 4 weeks (5) Experimental results:

 During the test, the long diameter, short diameter and body weight of the tumor were measured and recorded by vernier calipers twice a week from the time of grouping and administration, including the first dose and the last dose, the tumor volume was calculated and the tumor growth between the groups was compared. The difference in the curves, the tumor size in the nude mice of each group on the 28th day after administration is shown in Fig. 1.

 Calculate the tumor volume according to the following formula:

V=l/2x long diameter X short diameter ² ― evaluation of curative effect based on tumor volume

Relative tumor volume (RTV) and relative tumor proliferation rate T/C % were calculated according to the following formula: RTV=Vt/V ₀

 Vt : daily measurement of tumor volume obtained by tumor

 Vo: initial tumor volume (before administration)

 T/C% = RTV average of the administration group / RTV average of the control group χ 100%

 The experimental results of each group of nude mice were statistically analyzed using the Τ test method in biostatistics. The results are shown in Table 1.

 ' Table 1 Relative to tumor volume (RTV) of tetrahydropalmatine on human lung cancer

 And significant differences within each group (Ρ) results

Among them, the "Ρ" value was significantly different from the negative control group. Table 2 Relative tumor proliferation rate of tetrahydropalmatine on human lung cancer (T/C%) Time/day 3 7 10 14 18 22 25 28 Negative pair 72.6543 49.3087 26.5509 24.3323 20.1204 18.2441 16.0161 16.6303 Corydalis 87.6830 73.4258 31.8297 21.2873 14.781 1 21.5647 17.3453 21.9651 The above results indicate that tetrahydropalmatine has a good inhibitory effect on human lung cancer in vivo. In vivo experiments in nude mice showed that tetrahydropalmatine can effectively inhibit tumor growth, and the tumor volume is significantly smaller than the negative control. It can be seen that tetrahydropalmatine, which has been widely used for analgesic action, has excellent antitumor activity, and the results indicate that tetrahydropalmatine can be used for the preparation of a medicament for treating lung cancer. The invention broadens the field of medical application of tetrahydropalmatine.

Industrial application

 In vivo anti-cancer effects of tetrahydropalmatine on human lung cancer xenograft models using nude mice indicate that tetrahydropalmatine can effectively inhibit tumor growth. Moreover, since tetrahydropalmatine is a marketed drug, its toxicity is low, so the discovery not only broadens the medicinal range of tetrahydropalmatine, but also is very promising to develop into a new type of highly effective, low-toxic anti-tumor drug, especially anti-tumor. Drugs for lung cancer.

Claims

Rights request  1. The use of tetrahydropalmatine or a pharmaceutically acceptable salt thereof of formula I for the preparation of a medicament for inhibiting proliferation of eukaryotic tumor cells;

(Formula I).  2. The use according to claim 1, wherein: the tetrahydropalmatine is a levofosine of the formula II;

(Formula II).  3. The use according to claim 1 or 2, wherein: the eukaryote is a mammal; the tumor cell is a cancer cell; and the cancer cell is a breast cancer cell, a liver cancer cell, a pancreatic cancer cell, Lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer cells, nasopharyngeal cancer cells, colon cancer cells, bladder cancer cells, anal cancer cells or rectal cancer cells  4. The use according to claim 3, wherein: said cancer cells are lung cancer cells. A drug for inhibiting proliferation of a eukaryotic tumor cell, wherein the active ingredient is tetrahydropalmatine of the formula I or a pharmaceutically acceptable salt thereof. The drug according to claim 5, wherein: the eukaryote is a mammal; the tumor cell is a cancer cell; and the cancer cell is a breast cancer cell, a liver cancer cell, a pancreatic cancer cell, a lung cancer cell , brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer cells, nasopharyngeal cancer cells, colon cancer cells, bladder cancer cells, anal cancer cells or rectal cancer cells.  The drug according to claim 6, wherein the cancer cell is a lung cancer cell.  8. Use of tetrahydropalmatine or a pharmaceutically acceptable salt thereof of formula I for the preparation of a medicament for the prevention and/or treatment of a tumor.  9. The use according to claim 8, wherein: the tetrahydropalmatine is a levofosine of the formula II.  10. Use according to claim 8 or 9, characterized in that the tumor is cancer. 11. The use according to claim 10, wherein the cancer is breast cancer, liver cancer, pancreatic cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, stomach cancer, nasopharyngeal cancer, Colon cancer, bladder cancer, anal cancer or rectal cancer.  12. The use according to claim 11, wherein the cancer is lung cancer.  A medicament for preventing and/or treating a tumor, which comprises the compound of the formula I or a pharmaceutically acceptable salt thereof.  The drug according to claim 13, wherein the tumor is cancer; the cancer is breast cancer, liver cancer, pancreatic cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, Gastric cancer, nasopharyngeal cancer, colon cancer, bladder cancer, anal cancer or rectal cancer.  The drug according to claim 14, wherein the cancer is lung cancer.  The medicine according to any one of claims 13 to 15, wherein the pharmaceutical preparation comprises an injection, a tablet, a powder, a granule, a capsule, an oral liquid, a cream, and a cream.