WO2011131102A1 - Méthode de synthèse d'une lactone et ses applications - Google Patents

Méthode de synthèse d'une lactone et ses applications Download PDF

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Publication number
WO2011131102A1
WO2011131102A1 PCT/CN2011/072779 CN2011072779W WO2011131102A1 WO 2011131102 A1 WO2011131102 A1 WO 2011131102A1 CN 2011072779 W CN2011072779 W CN 2011072779W WO 2011131102 A1 WO2011131102 A1 WO 2011131102A1
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WO
WIPO (PCT)
Prior art keywords
cancer
lactone
preparation
group
leukemia
Prior art date
Application number
PCT/CN2011/072779
Other languages
English (en)
Chinese (zh)
Inventor
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
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Publication date
Application filed by 天津尚德药缘科技有限公司, 南开大学 filed Critical 天津尚德药缘科技有限公司
Publication of WO2011131102A1 publication Critical patent/WO2011131102A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • 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.
  • 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.
  • the treatment methods focused on the eradication and killing of cancer cells.
  • 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.
  • 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.
  • cancer cells such as prostate cancer, breast cancer, gastric cancer, leukemia, kidney cancer, lung cancer, colon adenocarcinoma, and medulloblastoma
  • parthenolide can inhibit the activation of the transcription factor F- ⁇ , 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- ⁇ is an important gene regulating tumor invasion, metastasis, and drug resistance, inhibition of F- ⁇ activation may increase the sensitivity of tumors to apoptosis induced by tumor suppressor.
  • 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.
  • 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.
  • the above method for producing lactone comprises the following steps:
  • the above method for producing lactone comprises the following steps:
  • 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.
  • the solvent is one of toluene, tetrahydrofuran or dichlorosilane.
  • 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 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 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
  • 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 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,
  • the lactone lactone of the present invention can be directly lactolactone after being prepared into a medicament for treating cancer
  • 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.
  • 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.
  • Example 2 Pharmacological action of leucine lactone
  • 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.
  • 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 1 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
  • 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.
  • 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;
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode de synthèse d'une sphaélactone obtenue à partir de parthénolide sphaélactone au titre de produit de départ et d'un acide adapté au titre de catalyseur, dans un solvant adapté à une température réactionnelle adaptée, le rendement étant supérieur à 60 %. La présente invention concerne également des applications de la sphaélactone et une composition pharmaceutique comprenant la sphaélactone et un vecteur de qualité pharmaceutique dans l'élaboration de médicaments destinés au traitement du cancer.
PCT/CN2011/072779 2010-04-23 2011-04-14 Méthode de synthèse d'une lactone et ses applications WO2011131102A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010153685.5 2010-04-23
CN2010101536855A CN102234258B (zh) 2010-04-23 2010-04-23 含笑内酯的制备方法

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WO2011131102A1 true WO2011131102A1 (fr) 2011-10-27

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WO (1) WO2011131102A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104211669B (zh) * 2013-06-05 2018-01-19 天津尚德药缘科技股份有限公司 含笑内酯衍生物，及其制备方法和用途
WO2015006893A1 (fr) * 2013-07-15 2015-01-22 天津尚德药缘科技有限公司 Utilisations d'un composé lactone sesquiterpénique et son dérivé dans la préparation de médicaments
CN104382894A (zh) * 2014-11-24 2015-03-04 中国医学科学院血液病医院（血液学研究所） 含笑内酯在制备治疗耐药白血病的药物中的用途
CN111803489B (zh) * 2020-07-10 2021-08-06 温州医科大学附属第一医院 含笑内酯及其衍生物在垂体腺瘤治疗中的应用
CN114948939A (zh) * 2022-04-29 2022-08-30 浙江百越生物技术有限公司 小白菊内酯在制备辅助抗癌药物中的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101978959A (zh) * 2010-10-18 2011-02-23 天津尚德药缘科技有限公司 含笑内酯及其衍生物用于治疗癌症的用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101978959A (zh) * 2010-10-18 2011-02-23 天津尚德药缘科技有限公司 含笑内酯及其衍生物用于治疗癌症的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OSE CASTANEDA ACOSTA ET AL.: "Biomimetic transformations of parthenolide", JOURNAL OF NATURAL PRODUCTS, vol. 56, no. 1, 1993, pages 90 - 98 *

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CN102234258A (zh) 2011-11-09
CN102234258B (zh) 2013-12-11

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