WO2011131102A1

WO2011131102A1 - Preparation method of lactone and use thereof

Info

Publication number: WO2011131102A1
Application number: PCT/CN2011/072779
Authority: WO
Inventors: 陈悦; 张泉; 卢亚欣; 翟佳黛; 丁亚辉; 龙菁; 范洪霞; 张浩亮; 王淼; 马维维
Original assignee: 天津尚德药缘科技有限公司; 南开大学
Priority date: 2010-04-23
Filing date: 2011-04-14
Publication date: 2011-10-27
Also published as: CN102234258B; CN102234258A

Abstract

Disclosed is a preparation method of a sphaelactone which is prepared form parthenolide sphaelactone as raw material and a suitable acid as catalyst in suitable solvent at suitable reaction temperature and the yield is more than 60%. Also disclosed are uses of the sphaelactone and pharmaceutical composition comprising the sphaelactone and pharmaceutically acceptable carrier in preparation of drugs for treating cancer.

Description

Preparation method of serotonin and its use

Technology domain

The present invention relates to the field of pharmaceutical technology, and in particular to a method for preparing a lactone-containing lactone and a pharmaceutical composition thereof for treating cancer or adjuvant treatment of tumors using the medicament as an active ingredient, and use thereof, and the medicament And group ^ in the preparation of anti-cancer or adjuvant anti-cancer drugs.

Background technique

The tumor is extremely human. There are about 2 million cancer patients in China, and 1.6 million new cases are issued each year. This is a big anti-tumor research, which is an extremely challenging and significant field in the field of combat. In the past, the treatment methods focused on the eradication and killing of cancer cells. At present, the anticancer drugs commonly used in clinical practice are mainly fine drugs, and such anticancer drugs have poor selectivity, strong side effects, and easy to produce drug resistance. It is a typical double-sided blade drug, and it is difficult to eradicate cancer. Many cancers have a higher recurrence rate. The high recurrence rate of malignant tumors has been a problem for the tumor doctors. More and more studies have confirmed that there are a few tumor stem cells in the tumor. They are usually in the Tweman cycle, have low sensitivity to chemotherapy drugs, and are the source of tumor recurrence. Therefore, the discovery of cancer stem cells brings new targets to cancer treatment, and drug research for cancer stem cells provides a possibility to completely cure cancer.

In recent years, the search for anticancer activity from natural products has become a hot spot for the development of anticancer drugs. In the past 20 years, 61% of the new chemical entities of small drugs introduced worldwide have been traced back to natural products. The rate of occurrence of natural products in certain therapeutic areas is very high: 78% of antibacterials ^ and 74% of anti-tumorization are not natural products, or derived from a natural product, proven to be natural products in anti-cancer drugs The unique role of discovery has regained great attention. Traditional chemotherapeutic drugs for treating tumors have drug resistance problems, especially tumor stem cells are less sensitive. The anti-cancer Chinese medicine is highly effective ^ ^, and it is possible to screen out drugs that can effectively kill cancer stem cells and thus treat malignant tumors. The sesquiterpene lactone compound ParthenoMe is a compound extracted from the white chrysanthemum that was originally used to treat skin infections, rheumatism and migraine. Recent studies have shown that parthenolide can inhibit the growth of cancer cells such as prostate cancer, breast cancer, gastric cancer, leukemia, kidney cancer, lung cancer, colon adenocarcinoma, and medulloblastoma, in the white chrysanthemum Ester can also treat cancer caused by ultraviolet rays. Its effect ^ ί Li study found that parthenolide can inhibit the activation of the transcription factor F-κΒ, its activity may be mainly derived from the p65/NF-KB subunit Cys38 on the sulfhydryl group and the lactone lactone Michael addition Response, since NF-κΒ is an important gene regulating tumor invasion, metastasis, and drug resistance, inhibition of F-κΒ activation may increase the sensitivity of tumors to apoptosis induced by tumor suppressor. Recently, Dr. Jordan, CT and colleagues at the University of Rochester Medical School in New York found that parthenolide can specifically eliminate stem cells that cause acute and chronic myeloid leukemia without damaging normal stem cells, which may be fundamentally To curb the recurrence of leukemia, the unique mechanism of action of parthenolide has attracted extensive attention.

The guaiacol-like sesquiterpene lactones of the genus Lactone are reported in the literature [J. Nat. Prod. 1993, 56, 90-98; Bioorg. Med. Chem. Lett. 2003, 11, 1503-1510 The synthesis method has a low yield (13-26%) and many side reactions, and the catalyst used in the ruthenium reaction is a boron trifluoride etherate compound, and the boron trifluoride is flammable, highly toxic, and highly corrosive. It greatly limits the industrial application. The preparation method of the lactone lactone needs to be further improved to improve its production rate, and the iL^ invention also finds a new medicinal use of the lactone-containing lactone.

Summary of the invention

The structure of the lactone lactone is as follows: structural formula (I), ^^ is C ₁₅ H ₂₀ O ₃ , and the amount of ^^ is 248, and the trait is a white amorphous powder.

The present invention provides a process for the manufacture of Lactuctone and a novel pharmaceutical use of Lactone. The present invention provides a process for the preparation of the lactone-containing lactone of the above formula (I) which comprises preparing the lactone lactone under the catalysis of a suitable acid catalyst in a suitable solvent.

Preferably, the above method for producing lactone comprises the following steps:

Weigh *t amount of parthenolide and acid catalyst, add appropriate solvent, stir for 0.5-48 hours, pour the liquid into the appropriate amount of ice water, extract, wash, dry, decompress the lactone.

More preferably, the above method for producing lactone comprises the following steps:

Weigh the amount of small chrysanthemum lactone and acid catalyst, add appropriate solvent, stir at appropriate temperature (-5 °C ~ 110 °C), 0. 548 hours, pour the liquid into the appropriate amount of ice water, Extracted with ethyl acetate, organically washed with appropriate amount of sodium bicarbonate and brine, dried in an appropriate amount of sodium sulphate, and decompressed 3⁄43⁄41 ^caprolactone. In order to obtain pure 4 oxime lactone, the pure product can be purified by stone column chromatography.

In the above method, the organic solvent is preferably one or more selected from the group consisting of tetrahydrofuran, diethyl ether, benzene, toluene, dichlorodecane and chloroform.

The acid catalyst is preferably selected from one or more of the group consisting of mercaptosulfonic acid, p-phthalic acid, trifluoroacetic acid and acetic acid.

In the above method, the solvent is one of toluene, tetrahydrofuran or dichlorosilane.

In the above method, the acid catalyst ^ is a confrontation! ^ Translation.

The invention also provides the use of the lactide-containing lactone for preparing a medicament for treating cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, He Jie Jinlinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-Hodgkin's lymphoma, neuroma, melanoma, bladder cancer, ovarian cancer, sputum cancer or Kaposi's sarcoma.

The present invention also provides a drug group for treating cancer, which does not contain an effective amount of a lactone-containing lactone and a pharmaceutically acceptable carrier, wherein the cancer is leukemia, breast cancer, prostate cancer, large Intestinal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, ^^ cancer, colorectal cancer, cervical cancer, non-Hodgkin, cancer Glioma, melanoma, bladder cancer, ovarian cancer, sputum cancer or Kaposi's sarcoma.

The present invention also provides a use of a group containing a lactone lactone for the preparation of a medicament for treating cancer or for adjuvant treatment of cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal tract Cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer, cervical cancer, non-Hodgkin's cancer, glioma, melanoma, bladder cancer, ovarian cancer, sickle Adenocarcinoma or Kaposi's sarcoma.

The lactone lactone of the present invention can be directly lactolactone after being prepared into a medicament for treating cancer

^ h , or in the form of a drug group containing lactones ^]. The drug group should not contain 0.1 - 99%, 0.5 - 90% by weight of the lactone lactone, and the rest are pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable carriers and / or! Agent.

The pharmaceutically acceptable carrier or excipient is one or more solid, semi-solid and liquid diluents, i^ cattle and pharmaceutical preparations. The pharmaceutical composition of the present invention is used in the form of a unit weight. The medicament of the present invention can be administered in both injection and oral administration, and the injection can be intravenous or intramuscular.

Have ^

The preparation method of the lactone-containing lactone provided by the invention solves the technical defect that the preparation yield of the lactone lactone is low, and the yield of the lactone lactone is more than 60%, and the present invention now contains a new pharmaceutical use of the lactone. Lactyl lactone has a significant effect on the treatment of cancer, and it has no obvious killing effect on normal cells.

Real ^ Γ

In order to understand the present invention, the present invention will be further illustrated by the following examples without restricting the invention. Example 1: Preparation of Lactone

At room temperature, 500 mg of parthenolide and 34 mg of ruthenium ruthenium were dissolved in 50 mL of hydrazine and returned to 1⁄2 12 hours. The solution was poured into an appropriate amount of ice water, extracted with ethyl acetate, and then acetic acid B The ester layer was washed with 200 mL of 5% sodium hydrogen hydride and 300 mL of brine, then dried with 7 g of sodium sulphate, and the crude product of decomposed lactone was decompressed, followed by stone column chromatography (petroleum ether: acetic acid). Ethyl ester = 80: 20) 300 mg of lactone lactone was obtained in a yield of 60%.

The prepared spectrum of the lactone-containing lactone I history data ^ (under the mouth:

_3⁄4 MR (CDC1 ₃ , 400 MHz) δ 6.14 (d, J= 3.2 Hz, 1H), 5.45 (d, J= 2.8 Hz, 1H), 3.76 (t, J= 10.4Hz, 1H), 2.61-2.68 ( m, 3H), 1.98-2.36 (m, 6H), 1.67-1.77 (m, 2H), 1.62 (s, 3H), 1.28 (s, 3H); ¹³ C NMR (CDC1 ₃ , 100 MHz) δ 168.8, 137.8, 130.8, 129.9, 118.6, 83.5, 79.2, 57.6, 48.5, 37.2, 33.9, 29.1, 24.8, 22.9, 21.7.

The spectral data indicates that the compound prepared by the method of Example 1 is a caprolactone of the formula (I). Example 2: Pharmacological action of leucine lactone

Various cancer cells were prepared into 2xl0 ⁵ /mL cell suspension, added to the round bottom fine cultivating plate, respectively added with lactone, each test concentration of 5 wells, placed at 37 ° C, 5% CO 2 humidity ^ cattle culture 18 In the hour, the degree of (A) was measured by the MT method at the wavelength of 570 酶, and the inhibitory effect of the present invention on the test cancer cells was calculated.

Table 1 Inhibitory activity of IC5 and smear organisms on various cancer cells (IC ₅₀ , μΜ )

ASPC-1 6.1

HT-29 9.8

HeLa 7.6

GL15 4.5

B16F1 3.4

T24 4.4

SKOV3 2.4

SW579 12.2

PC-3 14.2

Among them HL-60, K562, MCF-7, SW620, A549, HepG-2, Ec9706, SGC7901, SW1116, A498, ASPC-1, HT-29, HeLa, GL15, B16F1, T24, SKOV3, SW579, PC-3 Respectively express acute leukemia, Zhu, chronic leukemia, fine breast cancer, breast cancer, cancer cell line, cancer cell, liver cancer cell line, esophageal cancer cell line, gastric cancer cell line, colon cancer cell line, kidney cancer Fine Zhu, ^^ Cancer Fine Zhu, Colon Cancer Fine Zhu, Cervical Cancer Fine Zhu, M Female Fine J Tumor Cell Line, Melanoma Cell Line, Bladder Cancer Fine Zhu, Ovarian Cancer Cell Line, Sickle Adenocarcinoma Strain, prostate cancer, fine Zhu.

The activity test results showed that the selected cells showed strong inhibitory activity on the test cells, while the JJ^ normal cells showed obvious killing effects.

Example 3: Injection containing lactone lactone

The galactolide prepared in Example 1 was dissolved in a small amount of DMSO, and water was injected as usual, and the mixture was sterilized by potting and sterilized to prepare an injection.

Example 4: Ten doses of Lactone

After the lactone lactone prepared in Example 1 was dissolved in a small amount of DMSO, it was dissolved in sterile water for injection, dissolved by stirring, filtered through a sterile suction funnel, and then sterilely filtered, and dispensed in an ampoule. After low temperature freeze-drying, the powder is injected aseptically.

Example 5: 4 points of containing lactone lactone The concentration of the lactone-containing lactone prepared in Example 1 and the excipient in a weight ratio of 9:1 was prepared as a powder.

Example 6: Tablets containing Lactone

The ratio of the lactone-containing lactone prepared in Example 1 to the excipient in a weight ratio of 5:1; granulated tablet, ^lactone lactone tablet.

Example 7: Oral solution containing lactone lactone

The lactone-containing lactone prepared in Example 1 was prepared into a regular solution by using a conventional oral liquid preparation method.

Example 8: Limbs containing lactone lactone

The ratio of the lactone-containing lactone prepared in Example 1 to the excipient in a weight ratio of 5:1 was prepared as follows; Example 9: Limbs containing lactone

The ratio of the lactone-containing lactone prepared in Example 1 to the excipient in a weight ratio of 3:1 was prepared as follows. The use and method of the present invention have been described by way of specific examples. Those skilled in the art can learn from other aspects of the present invention, such as changing materials, processes, and the like, and the related changes are not deviated from the content of the present invention. All similar substitutions and modifications will be apparent to those skilled in the art. It is obvious that it is included in the scope of the present invention.

Claims

Claim

A process for the preparation of a lactone, which comprises preparing a lactone lactone under the catalysis of an acid catalyst in a suitable solvent.

2. The method according to claim 1, the method is as follows: fc

3. The method according to claim 1 or 2, wherein the method comprises the following steps

Weigh *t amount of parthenolide and acid catalyst, add appropriate solvent, stir the reaction at -5 ° C ~ 110 ° C for 0.5 8 hours, pour the liquid into an appropriate amount of ice water, ethyl acetate extraction, Organically washed with appropriate amount of sodium bicarbonate and ^^ saline, dried in an appropriate amount of sodium citrate, decompressed

Laughter lactone.

4. The method of claim 2 or 3, further comprising the step of purifying:

Purification of the L-lactone lactone obtained by 3⁄4 ^ by stone column chromatography

The method according to any one of claims 1 to 4, wherein the organic solvent is one or more selected from the group consisting of benzene, toluene, dichlorodecane, chloroform, tetrahydrofuran and diethyl ether, preferably toluene, two One of chlorodecane and tetra-argon.

6. The method according to any one of claims 1 to 4, wherein the acid catalyst is selected from the group consisting of one or more selected from the group consisting of sulfhydryl, quinone, trifluoroacetic acid, and acetic acid, preferably acid.

7. Use of a lactose-containing lactone for the preparation of a medicament for treating cancer.

8. The use according to claim 7, wherein the cancer is leukemia, breast cancer, prostate cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer , ^^ cancer, colorectal cancer, cervical cancer, non-Hodgkin's cancer, glioma, melanoma, bladder cancer, ovarian cancer, sputum cancer or Kaposi's sarcoma.

9. A group of drugs for treating cancer. This group contains an effective amount of containing lactone and a drug. A school-acceptable carrier, wherein the cancer is leukemia, breast cancer, prostate cancer, λ ^ cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer , colorectal cancer, cervical cancer, non-Hodgkin's cancer, glioma, melanoma, bladder cancer, ovarian cancer, sputum cancer or Kaposi's sarcoma.

10. The use of the composition of claim 9 for the preparation of a medicament for treating cancer or for adjuvant treatment of cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, carcinoma, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney Cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-Hodgkin's lymphoma, neuroma, melanoma, bladder cancer, ovarian cancer, 曱^^ cancer or Kapos Western sarcoma.