CN105418508A - Compound with breast cancer prevention activity, and preparation method and use thereof - Google Patents
Compound with breast cancer prevention activity, and preparation method and use thereof Download PDFInfo
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- CN105418508A CN105418508A CN201511003880.9A CN201511003880A CN105418508A CN 105418508 A CN105418508 A CN 105418508A CN 201511003880 A CN201511003880 A CN 201511003880A CN 105418508 A CN105418508 A CN 105418508A
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- compound
- breast cancer
- formula
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
The invention discloses a compound with breast cancer prevention activity, and a preparation method and a use thereof. A result of in vitro MMT antitumor activity evaluation shows that the above compound of formula I has a substantial inhibition effect on human breast cancer cell strains MCF-7, 4T1, MDA-MB-231 and MCF-7B. The compound has breast cancer prevention activity, can be used to prepare breast cancer treatment medicines, has good exploitation application prospect, and can be widely applied in clinic and medical science researches.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to mammary cancer.Specifically, the present invention relates to compound with anti-breast cancer activity and preparation method thereof.
Background technology
According to the World Health Organization (WHO) statistics, the whole world has 6,000,000 people to die from cancer every year, and annual new cases about have 1,000 ten thousand people.Relevant department of China statistics has 1,300,000 people to die from cancer every year, and new cases are about 1,600,000 people, and annual economy damage reaches hundred billion yuan.
" the up-to-date seniority among brothers and sisters table of the Chinese population cause of the death " is provided to show according to national treatment and prevention of tumour research office, mortality of malignant tumors occupies various cause of the death second, due to the severe contamination of global environment and the change of dietetic life form, malignant tumour has the trend risen further.2000, Chinese Urban Residents pathogenesis of cancer number was 180-200 ten thousand, and death toll is 1,500,000, and occupy city cause of the death first place, rank is followed successively by: lung cancer, liver cancer, cancer of the stomach, colorectal carcinoma, the esophageal carcinoma.
And one of mammary cancer modal malignant tumour that is women, according to statistics, its sickness rate accounts for 7% ~ 10% of women's whole body malignant tumour, is only second to cervical cancer, but has the tendency exceeding cervical cancer in recent years, and in ascendant trend year by year.The whole world about has 1,200,000 women to suffer from mammary cancer every year, has 500,000 women to die from mammary cancer.Estimate according to medical expert, by 2010, global mammary cancer year neopathy number of cases will reach about 1,400,000.Mammary cancer hotspot, the whole world is North America and Northern Europe, and China is not the district occurred frequently of mammary cancer, but average annual growth exceeds national 1 ~ 2 percentage point occurred frequently, with the speed increase of annual 3%.In big city, mammary cancer has accounted for first of women's Cancer Mortality, and morbidity presents rejuvenation trend, and the mortality ratio of China's mammary cancer also rises 39.32% thus, becomes cancer mortality in China city in recent years and to rise the fastest tumour.Therefore mammary cancer becomes the number one killer threatening women's health gradually, control and the research of mammary cancer is also become gradually to the problem of whole world scientist's growing interest.Chemotherapy is one of important means of current cancer clinical treatment, with the method such as operative treatment, radiotherapy, belongs to the Main Means of oncotherapy.Mammary cancer is one of the most effective tumour for the treatment of with chemotherapy in solid tumor, and chemotherapy occupies an important position in whole treatment.Therefore searching effective antitumour compound has crucial meaning for the treatment of mammary cancer.
The invention discloses a kind of compound with anti-breast cancer activity, can be used for preparing anti-breast cancer medicines.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, a kind of formula I with anti-breast cancer activity is provided.
Another object of the present invention is to provide the method for the compound of preparation formula I.
Another object of the present invention is to provide the compound containing formula I and is jointly used for the treatment of mammary cancer as the medicinal compositions of effective constituent and one or more pharmaceutically acceptable carrier, vehicle or thinners.
The compound that the present invention has formula I structure has following structural formula:
Formula I of the present invention is synthesized by following steps:
Such as formula the purposes of compound in preparation treatment anti-breast cancer medicines of I structure.
Further, described formula I can with pharmaceutically acceptable carrier or mixed with excipients prepare acceptable pharmaceutical preparation clinically.
Further, described pharmaceutical preparation is oral Preparation; Muscle or intravenous administration formulation.
Further, described oral Preparation is tablet, capsule, granule, sustained release preparation, dripping pill.
Compd A and compd B react, and obtain Compound C, then obtain Compound D with SOCl2 through acyl chloride reaction, and Compound D and compd E obtain such as formula compound shown in I through amidate action.
The present invention is found by external MTT antineoplastic activity evaluation, the compound of formula I structure also has significant restraining effect to the growth of MCF-7 cell strainHJ2mm, 4T1, MDA-MB-231, MCF-7B, and it suppresses the IC50 value of this 4 strain Growth of Cells to be respectively 1.06 ± 0.03 μm, 3.15 ± 0.34 μm, 2.42 ± 0.41 μm, 1.01 ± 0.13 μm.Therefore, the compound of formula I structure for the preparation of anti-breast cancer medicines, can have good development prospect.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Accompanying drawing explanation
Fig. 1 is the formula I for preparing of the present invention
1hNMR schemes.
Fig. 2 is the structural formula of the formula I that the present invention prepares.
Fig. 3 is the syntheti c route of the formula I that the present invention prepares.
Embodiment
Embodiment 1:
6.03g (15mmol) compd A 50mL tetrahydrofuran (THF) is dissolved in 100mL round-bottomed flask, then adds 2mmol dimethyl formamide, 20mmol compd B, then stir 70 DEG C of following coronites, react 5 hours.Add 100mL tetrahydrofuran (THF) again, with time washing of distilled water 100mL × 3, anhydrous sodium sulfate drying, concentrating under reduced pressure organic phase, finally adopt silica gel column chromatography separate mode to purify, eluent is petrol ether/ethyl acetate=2:1, obtains oily compound C, ESI-MS, m/e=546.10 ([M+NH
4]
+).
Dissolved by 15mmol Compound C 50mL tetrahydrofuran (THF), then add 50mmol triethylamine, then under nitrogen protection, drip thionyl chloride 25mmol at 10 DEG C, dropping limit, limit is stirred, and naturally rises to room temperature after 20 minutes, continues stirring 0.5 hour.With saturated aqueous common salt 100mL × 3 time washing reaction liquid, anhydrous sodium sulfate drying, concentrating under reduced pressure organic phase, finally adopt silica gel column chromatography separate mode to purify, eluent is petrol ether/ethyl acetate=2:1, obtains Compound D, ESI-MS, m/e=564.07 ([M+NH
4]
+).
Get 10mmol Compound D to be dissolved in 20mL toluene, add 10mmol thionyl chloride, stirred at ambient temperature reacts 30 minutes, after add 3mmolTEA, 10mmol compd E and at room temperature stirring reaction 5 hours.In reaction mixture impouring 100mL frozen water, stir, extract with the ethylene dichloride of 50mL × 3, merge extraction phase, salt water washing once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain resistates, then column chromatography purification, obtain the sterling of I, ESI-MS, m/z=585.16 ([M-H]
-).
Its physical properties:
1H-NMR:δH(DMSO):6.06(d,1H),6.67(d,1H),6.69(d,1H),7.24(d,1H),7.31(d,1H),7.31(d,1H),7.47(s,1H),7.60(s,1H),7.64(s,1H),7.67(s,1H),7.67(s,1H),7.69(t,1H),7.71(d,1H),7.80(d,1H),7.82(d,1H),8.0(d,1H),8.06(d,1H)，8.07(d,1H)，8.20(s,1H)，8.20(s,1H)，8.47(s,1H)，12.4(s,1H)，12.4(s,1H)。
Ultimate analysis: theoretical value: C:62.88, H:3.37, N:10.19, O:6.98.
Measured value: C:62.85, H:3.35, N:10.18, O:7.01.
Embodiment 2:
The maximum tolerance test of formula I of the present invention:
Getting the mouse 40 of body weight 20 ± 2g, male and female half and half, is the suspension of 100mg/ml by 0.8mg/20g gavage such as formula the concentration of I, the death condition of animal in Continuous Observation 30 days, result, in 30 days, all animal feeding activities are normal, do not have death, LD do not detected
50, think that it is nontoxic.
Embodiment 3:
The test of the Anti-tumor angiogenesis of compound described in formula I of the present invention
Chemical combination I is evaluated to the growth-inhibiting effect of Breast cancer lines by mtt assay.
1, main agents and method:
Be in the cell of growth logarithmic phase: MCF-7 cell strainHJ2mm, 4T1, MDA-MB-231, MCF-7B (are bought from Chinese Academy of Sciences's cell bank with 1.5 × 10
4concentration kind is in 96 orifice plates.) suck original substratum after cell cultures 24h is adherent.Test is divided into blank group, drug treating group.Blank group changes 1640 substratum containing 10% foetal calf serum; Drug treating group is changed and is contained the substratum that concentration is the Compound I of 100 μm, 50 μm, 10 μm, 1 μm, 0.1 μm, 0.01 μm, 0.001 μm.After cultivating 48h, add the MTT of concentration 5mg/mL, continue to be put in CO
24h cultivated by incubator, then 100 μ L supernatant liquors are sucked along nutrient solution top, add 100 μ LDMSO, 10min is placed in dark place, microplate reader (Sunrise Products) is utilized to measure light absorption value (wavelength 570nm), and calculating cell stock position according to light absorption value, 6 repeating holes are established in each process.Cell survival rate (%)=Δ OD
drug treating/ Δ OD
blank× 100.
2, result: the growth of Compound I to MCF-7 cell strainHJ2mm, 4T1, MDA-MB-231, MCF-7B has significant restraining effect.This compound suppresses the IC of MCF-7 cell strainHJ2mm, 4T1, MDA-MB-231, MCF-7B growth
50value is respectively 1.06 ± 0.03 μm, 3.15 ± 0.34 μm, 2.42 ± 0.41 μm, 1.01 ± 0.13 μm.
Shown by above-described embodiment, the growth of Compound I of the present invention to MCF-7 cell strainHJ2mm, 4T1, MDA-MB-231, MCF-7B has good restraining effect.Prove thus, formula I of the present invention has anti-breast cancer activity, can with preparing anti-breast cancer medicines.
Claims (6)
1. the compound of a formula I structure:
2. synthesize the method for the compound of the formula I structure that claim 1 defines, comprise the following steps:
3. the compound of formula I structure is preparing the purposes in treatment anti-breast cancer medicines as defined in claim 1.
4. application according to claim 3, is characterized in that: described formula I can with pharmaceutically acceptable carrier or mixed with excipients prepare acceptable pharmaceutical preparation clinically.
5. application according to claim 4, is characterized in that: described pharmaceutical preparation is oral Preparation; Muscle or intravenous administration formulation.
6. application according to claim 5, is characterized in that: described oral Preparation is tablet, capsule, granule, sustained release preparation, dripping pill.。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511003880.9A CN105418508A (en) | 2015-12-28 | 2015-12-28 | Compound with breast cancer prevention activity, and preparation method and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511003880.9A CN105418508A (en) | 2015-12-28 | 2015-12-28 | Compound with breast cancer prevention activity, and preparation method and use thereof |
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| Publication Number | Publication Date |
|---|---|
| CN105418508A true CN105418508A (en) | 2016-03-23 |
Family
ID=55497113
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|---|---|---|---|
| CN201511003880.9A Pending CN105418508A (en) | 2015-12-28 | 2015-12-28 | Compound with breast cancer prevention activity, and preparation method and use thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418527A (en) * | 2015-12-28 | 2016-03-23 | 青岛友诚高新技术有限公司 | Compound with ductal breast cancer prevention activity, and preparation method and use thereof |
| CN105601532A (en) * | 2016-01-14 | 2016-05-25 | 青岛友诚高新技术有限公司 | Hypotensively active compound and preparation method thereof |
| CN115368263A (en) * | 2022-09-01 | 2022-11-22 | 南开大学 | Synthesis of cinnamic acid amide derivative and pharmaceutical application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104470902A (en) * | 2012-07-19 | 2015-03-25 | 南京英派药业有限公司 | N-(3-heteroarylaryl)-4-arylarylcarboxamtdes and analogs as hedgehog pathway inhibitors and use thereof |
-
2015
- 2015-12-28 CN CN201511003880.9A patent/CN105418508A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104470902A (en) * | 2012-07-19 | 2015-03-25 | 南京英派药业有限公司 | N-(3-heteroarylaryl)-4-arylarylcarboxamtdes and analogs as hedgehog pathway inhibitors and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| 温瑞兴等: "《药理学实验教程 2014年5月第1版第1印》", 31 May 2014, 北京工业大学出版社 * |
| 赵建庄等: "《有机化学2014年1月第1版第1印》", 31 January 2014, 北京林业出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418527A (en) * | 2015-12-28 | 2016-03-23 | 青岛友诚高新技术有限公司 | Compound with ductal breast cancer prevention activity, and preparation method and use thereof |
| CN105601532A (en) * | 2016-01-14 | 2016-05-25 | 青岛友诚高新技术有限公司 | Hypotensively active compound and preparation method thereof |
| CN115368263A (en) * | 2022-09-01 | 2022-11-22 | 南开大学 | Synthesis of cinnamic acid amide derivative and pharmaceutical application thereof |
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Application publication date: 20160323 |
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