WO2008031357A1 - (3z)-3-(1h-pyrrol-2-ylmethylene)-1,3-dihydro-2h-indol-2-one utile dans la fabrication de médicaments pour traiter les cancers - Google Patents

(3z)-3-(1h-pyrrol-2-ylmethylene)-1,3-dihydro-2h-indol-2-one utile dans la fabrication de médicaments pour traiter les cancers Download PDF

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Publication number
WO2008031357A1
WO2008031357A1 PCT/CN2007/070649 CN2007070649W WO2008031357A1 WO 2008031357 A1 WO2008031357 A1 WO 2008031357A1 CN 2007070649 W CN2007070649 W CN 2007070649W WO 2008031357 A1 WO2008031357 A1 WO 2008031357A1
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WO
WIPO (PCT)
Prior art keywords
compound
cancer
cancer cells
pyrrol
dihydro
Prior art date
Application number
PCT/CN2007/070649
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English (en)
Chinese (zh)
Inventor
Long Yu
Haoxing Zhang
Qingyu Lang
Lisha Tang
Jia Li
Original Assignee
Fudan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fudan University filed Critical Fudan University
Priority to CNA200780018662XA priority Critical patent/CN101448494A/zh
Publication of WO2008031357A1 publication Critical patent/WO2008031357A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • Mitosis is a very important stage in the cell cycle process.
  • the difference between a tumor and a normal cell is infinite hyperplasia, that is, mitosis loses its normal regulation.
  • Most tumors occur due to genomic instability caused by mitosis.
  • Genomic instability is caused by chromosome instability.
  • Chromosomal instability is a characteristic marker of cancer.
  • Abnormal chromosome segregation, central granule replication and segregation can lead to abnormalities in the number of chromosomes per cell, ie aneuploidy, increased chance of heterozygous deletion, loss of tumor suppressor gene or increased number of proto-oncogenes Disrupts cell life metabolism and signaling, increasing the chance of cancer.
  • Kinase plays an important role in the completion of mitosis and cell cycle regulation, and thus has become a research hotspot in molecular biology. Summary of the invention
  • the anticancer drug contains 0.001 to 99% by weight (more preferably 0.01 to 90% by weight;) a compound of the formula I and a pharmaceutically acceptable carrier or excipient.
  • the medicament is also for inhibiting phosphokinase Aurora-B.
  • the anticancer drug is an injection, granule, capsule, solution or tablet.
  • the cancer is selected from the group consisting of liver cancer, colon cancer, gastric cancer, and lung cancer.
  • the tumor cells are selected from the group consisting of liver cancer cells, colon cancer cells, gastric cancer cells, and lung cancer cells.
  • the application amount is from 0.1 mg/kg to 20 mg/kg of body weight per day.
  • the present invention provides the use of a compound having the structure described below for the preparation of an anticancer drug.
  • salts include: salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, as well as esters, carbamates or other conventional "prodrugs" (when given in this form) In the case of medicine, it can be converted into an active part in the body).
  • the compound s2 can be used for the preparation of an anticancer drug.
  • the present invention detects the action of the compound s2 on tumor cells and cancer cells according to a standard MTS assay, and the results show that the s2 of the present invention is applicable to various tumor cells and cancer cells, such as liver cancer cells, colon cancer cells, gastric cancer cells, lung cancer cells, and the like. , have a killing or inhibition effect.
  • the compound s2 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This further confirmed that the compound s2 of the present invention has an effect of inhibiting malignant tumors.
  • Aik2 mainly plays a role in the mitosis of cells.
  • Aik2 As a chromosome-associated protein, it is involved in the regulation of the interaction between the centromere and the spindle microtubule. At the metaphase to the late stage, Aik2 migrates from the centromere to the middle zone of the cell, and is distributed at the end of the cell plate and the posterior mitotic bridge. Post-mitotic events are associated with chromosome segregation and cytokinesis. Mutation of Aik2 inhibits the formation of dividing sulcus and leads to the formation of multinucleated cells. Aik2 is located at 17ql3, this region is abnormal in a variety of human cancer cells, and Aik2 is highly expressed in abnormally ploidy colon cancer cell lines. Therefore, researchers are looking for molecules that interact with Aik2 and use them as antitumor drugs.
  • the effective application amount is from 0.1 mg/kg to 20 mg/kg of body weight per day.
  • the antitumor drug prepared may be an injection or a tablet or the like.
  • the present invention can provide different effects when administered (administered;) therapeutically.
  • these materials can be formulated in a non-toxic, inert, andpharmaceutically acceptable aqueous carrier medium, wherein the pH is usually from about 5 to about 8, preferably from about 6 to about 8, although the pH may be The nature of the formulation and the condition to be treated vary.
  • the formulated pharmaceutical compositions can be administered by conventional routes including, but not limited to, intramuscular, intraperitoneal, subcutaneous, intradermal, intratumoral, or topical administration.
  • s2 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carrier include, but are not limited to;: saline, buffer, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical preparation should be matched to the mode of administration.
  • the s2 of the present invention can be prepared in the form of an injection, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • compositions such as injections, solutions, tablets and capsules are preferably prepared under sterile conditions.
  • the amount of active ingredient administered is a therapeutically effective amount, for example from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day.
  • the s2 of the present invention can also be used with other therapeutic agents.
  • a therapeutically effective amount of s2 can be administered to a mammal, wherein the therapeutically effective dose is typically at least about 10 micrograms per kilogram of body weight, and in most cases no more than about 80 milligrams per kilogram.
  • the body weight preferably the dose is from about 500 micrograms per kilogram of body weight to about 2 milligrams per kilogram of body weight.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. Cancer has become the first cause of death, and the substances that kill tumors and cancer cells have become biomedical Research hotspots in the pharmaceutical industry.
  • the s2 of the present invention has a killing or inhibiting effect on various tumor cells and cancer cells; meanwhile, the compound s2 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This all proves that the compound s2 of the present invention has an effect of inhibiting malignant tumors.
  • the compound s2 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier to prepare an anticancer drug to inhibit the continued growth of the tumor.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the human Aurora-B protein kinase (NCBI accession number NP-004208) was cloned, expressed and purified using the E. coli expression system for high-throughput screening experiments. Using radioisotope techniques, AuroraB phosphorylated substrate MBP (UPSTATE company, CAT # 13-110, lot # 27845 ), the ⁇ - 33 ⁇ solution of [ ⁇ - 33 ⁇ ] - ⁇ the transfer covalently bound in the end thereof, Its Ser is phosphorylated to produce the substrate 33 P-MBP with isotopic labeling. Finally, the activity of the enzyme was detected by counting the scintillation liquid by counting with a liquid scintillation counter, and the inhibition of the activity of the different compounds was observed to initially evaluate the activity of the compound.
  • AuroraB phosphorylated substrate MBP UPSTATE company, CAT # 13-110, lot # 27845
  • the activity of the enzyme was detected by counting the scintillation liquid by counting with a liquid scintillation counter,
  • Seed plate 1000 cells / hole
  • mice liver cancer H22 ascites was diluted 1:4 with physiological saline (cell concentration: about 1-2 ⁇ 10 7 cells/ml), and each mouse was inoculated with 0.2 ml under the right iliac crest, randomly grouped, and set:
  • the drug was administered from the next day after the inoculation, and the administration volume was 0.5 ml/20 g body weight, and continuous intraperitoneal injection was performed for 7 days.
  • the animals were sacrificed by cervical dislocation 10 days after inoculation, and the tumor pieces were dissected and weighed, and the results were judged. The results are shown in Fig. 2. After inoculation of s2, the tumor weight of the mice decreased significantly, and the more s2 inoculated, the more obvious the tumor weight decreased.
  • the pharmaceutical composition in the form of a tablet is prepared by a conventional technique by mixing the following components and then directly compressing the tablet, and the formulation is as follows:

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

Abstract

L'invention concerne l'utilisation de (3Z)-3-(1H-pyrrol-2-ylmethylene)-1,3-dihydro-2H-indol-2-one dans la fabrication de médicaments pour traiter les cancers. Le composé précité permet d'inhiber des cellules cancéreuses du foie, du côlon, des poumons et de l'estomac et de la phosphokinase Aurora-B. Le composé de cette invention peut être formulé sous forme de compositions pharmaceutiques anticancéreuses comportant des excipients pharmaceutiquement acceptables pour supprimer des croissances tumorales continues.
PCT/CN2007/070649 2006-09-07 2007-09-07 (3z)-3-(1h-pyrrol-2-ylmethylene)-1,3-dihydro-2h-indol-2-one utile dans la fabrication de médicaments pour traiter les cancers WO2008031357A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNA200780018662XA CN101448494A (zh) 2006-09-07 2007-09-07 (3z)-3-(1h-吡咯-2-基亚甲基)-1,3-二氢-2h-吲哚-2-酮在制备抗癌药物中的应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200610030914.8 2006-09-07
CN2006100309148A CN101112371B (zh) 2006-09-07 2006-09-07 化合物s2在制备抗癌药物中的应用

Publications (1)

Publication Number Publication Date
WO2008031357A1 true WO2008031357A1 (fr) 2008-03-20

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Application Number Title Priority Date Filing Date
PCT/CN2007/070649 WO2008031357A1 (fr) 2006-09-07 2007-09-07 (3z)-3-(1h-pyrrol-2-ylmethylene)-1,3-dihydro-2h-indol-2-one utile dans la fabrication de médicaments pour traiter les cancers

Country Status (2)

Country Link
CN (2) CN101112371B (fr)
WO (1) WO2008031357A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1365972A (zh) * 2001-01-19 2002-08-28 中国人民解放军军事医学科学院毒物药物研究所 吲哚类衍生物及其抗肿瘤用途
US6492389B1 (en) * 1998-07-21 2002-12-10 Thomas Jefferson University Small molecule inhibitors of BCL-2 proteins

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6492389B1 (en) * 1998-07-21 2002-12-10 Thomas Jefferson University Small molecule inhibitors of BCL-2 proteins
CN1365972A (zh) * 2001-01-19 2002-08-28 中国人民解放军军事医学科学院毒物药物研究所 吲哚类衍生物及其抗肿瘤用途

Also Published As

Publication number Publication date
CN101112371B (zh) 2010-11-17
CN101112371A (zh) 2008-01-30
CN101448494A (zh) 2009-06-03

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