CN103483187A - 4-oxethyl-2-hydroxyl-6-methyl benzoic acid as well as medicinal composition and application thereof - Google Patents
4-oxethyl-2-hydroxyl-6-methyl benzoic acid as well as medicinal composition and application thereof Download PDFInfo
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Abstract
The invention discloses 4-oxethyl-2-hydroxyl-6-methyl benzoic acid with a structure shown in a formula (1) as well as a medicinal composition and an application thereof. The compound is capable of significantly killing and/or inhibiting the various tumour cells of human and animals in vivo and in vitro, the compound has a significant combined antitumour effect with clinic antitumour medicines, and the compound or the pharmaceutically acceptable salts thereof can be applied to preparation of antitumour medicines, antitumour medicine compositions, combined antitumour medicine compositions or auxiliary antitumour healthcare products. The compound is capable of significantly promoting the apoptosis and necrosis of cancer cells, adjusting the growth cycle of cancer cells, and inhibiting the proliferation of cancer cells. The compound has no significant toxicity on the ponderal growth and organ development of mice under an effective anticancer dosage, or the toxic effect significance of the compound is lower than clinic anticancer medicines such as cyclophosphamide and 5-fluorouracil.
Description
Technical field
The invention belongs to chemical field of medicaments, particularly relate to a kind of 4-oxyethyl group-2-hydroxyl-6-tolyl acid and medicinal compositions and application.
Background technology
Cancer is a major disease of serious threat human health and life security, has become first cause of the death of the mankind at present.According to global cancer statistical report, within 2008, global new cases of cancer is 1266.1 ten thousand examples, dead 756.4 ten thousand examples; The Cancer in China new cases are 281.6 ten thousand examples, dead 195.8 ten thousand examples." 2012 Chinese tumour registration annual report " discloses, China's new cases of cancer 3,120,000 in 2012, and average per minute has 6 people to be diagnosed as malignant tumour.The sickness rate of cancer is also rising, and cancer has become a main hygienic issues of serious threat people ' s health and life security.
Cancer is still a kind of obstinate disease in the world at present.The chemotherapy of cancer, as the systemic treatment measure, occupies epochmaking status in the treatment of cancer, is also thoroughly to solve from now on the hope of cancer therapy problem.
The cancer chemotherapeutic drug used at present clinically, the problems such as a lot of medicines exist that toxic side effect is large, uncertain therapeutic efficacy is fixed, poor selectivity and cancer cells resistance, be very limited cancer chemotherapy application and effect clinically.Therefore, the exploitation curative effect is clear and definite, safety low-poison, the chemotherapeutics that particularly has the selectivity antitumous effect, is important directions and the urgent task of PTS research.
Summary of the invention
Based on this, the purpose of this invention is to provide a kind of 4-oxyethyl group with antitumor action-2-hydroxyl-6-tolyl acid.
Concrete technical scheme is as follows:
There is the 4-oxyethyl group of formula (1) structure-2-hydroxyl-6-tolyl acid (4-ethoxy-2-hydroxy-6-methylbenzoic acid) or pharmacy acceptable salt,
Another object of the present invention is to provide a kind of antitumor medicine composition.
Concrete technical scheme is as follows:
A kind of antitumor medicine composition, its activeconstituents comprises above-mentioned 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its pharmacy acceptable salt.
In some embodiment, the formulation of this pharmaceutical composition is therein: injection liquid, powder injection, tablet, oral liquid, capsule, granule or electuary.
Another object of the present invention is to provide a kind of associating antitumor medicine composition.
Concrete technical scheme is as follows:
A kind of associating antitumor medicine composition, its activeconstituents comprises above-mentioned 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its pharmacy acceptable salt, and at least one in 5 FU 5 fluorouracil, taxol, cis-platinum or endoxan.
Another object of the present invention is to provide the application of above-mentioned 4-oxyethyl group-2-hydroxyl-6-tolyl acid.
Concrete technical scheme is as follows:
Above-mentioned 4-oxyethyl group-2-hydroxyl-6-tolyl acid or the application of its pharmacy acceptable salt in preparing antitumor drug.
In some embodiment, described tumour is any in following human tumor therein: human breast carcinoma, prostate cancer, lung cancer, cancer of the stomach, cervical cancer, colorectal carcinoma, liver cancer, ovarian cancer, leukemia, neuroma, sarcoma.
Another object of the present invention is to provide the application of above-mentioned 4-oxyethyl group-2-hydroxyl-6-tolyl acid in auxiliary anti-tumor health care product.
Concrete technical scheme is as follows:
The application in auxiliary anti-tumor health care product of above-mentioned 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its pharmacy acceptable salt.
A kind of auxiliary anti-tumor health care product, its activeconstituents comprises above-mentioned 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its pharmacy acceptable salt.Should assist the formulation of anti-tumor health care product to be: tablet, oral liquid, capsule, granule or electuary.
Advantage of the present invention is as follows:
4-oxyethyl group of the present invention-2-hydroxyl-6-tolyl acid (4-ethoxy-2-hydroxy-6-methylbenzoic acid) compound is the new texture material, can carry out chemosynthesis by phase-transfer-catalyzed reactions; This compound or its salt class can be used as antitumor chemotherapeutic agent, or as the antineoplastic pharmaceutical compositions of antitumor activity composition, and as auxiliary anti-tumor health care product.Human and animal's multiple cancer cells is killed and/or suppressed to the external energy of 4-oxyethyl group-2-hydroxyl-6-tolyl acid significance, as human breast carcinoma, prostate cancer, lung cancer, cancer of the stomach, cervical cancer, colorectal carcinoma, liver cancer cell, and murine sarcoma, liver cancer, lung carcinoma cell etc.In this chemical combination object, the balb/c nude mice is transplanted to Human Lung Cancer and human liver cancer, and murine sarcoma and the rat liver cancer of Kunming mouse and the transplanting of ICR mouse, the tumours such as mice lung cancer that the C57BL/6J mouse is transplanted, the growth-inhibiting effect that all there is significance.The antineoplastic chemotherapy medicine of this compound and clinical use in vitro and/or all have the combination and cooperation antitumor action in body.This compound has the selectivity antitumous effect, the susceptibility difference of different carcinoma cell strain, and liver cancer cell is very responsive to this compound.This compound energy significance promotes the propagation of cancer cell-apoptosis, adjusting Cancer Cell cycle and differentiation, anticancer.This compound, under effective antitumor dosage, is grown without significance toxicity the body weight gain of mouse and internal organs, or the toxic action significance lower than clinical cancer therapy drug as cyclophosphamide and 5-fluorouracil.
The accompanying drawing explanation
The mass spectrum that Fig. 1 is formula (1) compound;
The nucleus magnetic hydrogen spectrum figure that Fig. 2 is formula (1) compound;
Nuclear-magnetism carbon spectrogram and DEPT spectrogram that Fig. 3 is formula (1) compound;
Fig. 4 is the dose-effect curve figure of formula of the present invention (1) compound to different tumor cell lines;
Time m-effect, dose-effect relationship graphic representation that Fig. 5 is formula of the present invention (1) compound anticancer experiment in vitro;
When Fig. 6 is formula of the present invention (1) compound anti-tumor in vivo (NCI-H460) test, the tumour relative volume (RTV) of different time points;
When Fig. 7 is formula of the present invention (1) compound anti-tumor in vivo (NCI-H460) test, the relative appreciation rate of the tumour of different time points (%);
Fig. 8 is the NCI-H460 tumor weight after formula of the present invention (1) compound administration 10 times;
When Fig. 9 is formula of the present invention (1) compound anti-tumor in vivo (QGY-7703) test, the tumour relative volume (RTV) of different time points;
When Figure 10 is formula of the present invention (1) compound anti-tumor in vivo (QGY-7703) test, the relative proliferation rate of the tumour of different time points (%);
When Figure 11 is formula of the present invention (1) compound anti-tumor in vivo (QGY-7703) experiment end, the exemplary embodiment lock of each group;
When Figure 12 is formula of the present invention (1) compound anti-tumor in vivo (QGY-7703) experiment end, the tumour photo of each treated animal;
When Figure 13 is formula of the present invention (1) compound anti-tumor in vivo (QGY-7703) experiment end, the spleen photo of each treated animal;
The flow cytometer detected result (QGY-7703) that Figure 14 is formula of the present invention (1) compound solvent control;
The flow cytometer detected result (QGY-7703) that Figure 15 is formula of the present invention (1) compound;
Figure 16 is that formula of the present invention (1) compound (D4,50 μ M) is in the Western of QGY-7703 Blot detected result;
Figure 17 is that formula of the present invention (1) compound (D1,200 μ M) is in the Western of HCT-116 Blot detected result;
Figure 18 is that formula of the present invention (1) compound (D2,150 μ M) is in the Western of MCF-7 Blot detected result;
Figure 19 is that formula of the present invention (1) compound (D1,200 μ M) is in the Western of A-549 Blot detected result;
To be formula of the present invention (1) compound combine anti-A-549 function of tumor to Figure 20 with 5 FU 5 fluorouracil external;
To be formula of the present invention (1) compound combine anti-A-549 function of tumor to Figure 21 with cis-platinum external.
Embodiment
The present invention is further elaborated by the following examples.
Embodiment 1: the synthetic and Structural Identification of compound 4-oxyethyl group shown in formula (1)-2-hydroxyl-6-tolyl acid (4-ethoxy-2-hydroxy-6-methylbenzoic acid)
1, preparation method
Phase-transfer catalysis is synthesized and column chromatography for separation
Utilize phase-transfer-catalyzed reactions, under sodium hydroxide exists, 2,4-dihydroxyl-6-tolyl acid and ethyl sulfate (mol ratio is 0.2:0.18), at the two octadecyl methyl amine Benzyl Chloride quaternary ammonium salts of catalyzer HA-1() react 3h in 60-65 ℃ under effect.After completion of the reaction, be cooled to 25 ℃, pour in frozen water, with dilute hydrochloric acid, adjust pH value to neutral, separate organic layer; Toluene extraction 2 times for water layer, merge organic layer; Washing organic layer 3 times, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent toluene, product adopts the silica gel column chromatography technology to carry out separation and purification again, obtains compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid.
2, Structural Identification
The mass spectrum (as shown in Figure 1) of compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid;
The nucleus magnetic hydrogen spectrum figure (as shown in Figure 2) of compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid;
The nuclear-magnetism carbon spectrogram of compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid and DEPT spectrogram (as shown in Figure 3).
Embodiment 2: the biological experiment result of formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid
Below by the concrete experiment of part illustration illustrate formula of the present invention (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid (in following chart, with D6B2 or D, mean, lower with; D1 is that 200 μ M, D2 are that 150 μ M, D3 are that 100 μ M, D4 are that 50 μ M, D5 are 25 μ M) have significance and selectivity antitumor action, with the synergistic antitumor effect of clinical antitumor drug, with and toxicological safety, Antitumor Mechanism.
1, the anti-cancer effect in vitro of 4-oxyethyl group-2-hydroxyl-6-tolyl acid:
Test method: formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid dissolves with DMSO, by ultimate density, is that 25,50,100,150,200 μ M carry out external anticancer test.Collect the logarithmic phase mankind or animal tumor cell, after the perfect medium suspendible, be inoculated in 6 orifice plates, every hole adds the 2ml cell suspension.37 ℃, 5%CO
2incubator was cultivated after 24 hours, got 3 porocytes and counted the cell count as 0 hour; Suck the nutrient solution in all the other holes, then by design, add respectively the complete culture solution 2ml that contains respective concentration formula (1) compound, establish the DMSO solvent control simultaneously.It is parallel that every concentration and DMSO control group are done 9 holes, cell after dosing in 37 ℃, 5%CO
2incubator continues to cultivate.24h, 48h, 72h after dosing, every concentration is collected respectively 3 porocytes and is counted, and calculates mean value and the standard deviation of cell count, draws cell growth curve, carries out the significant difference check.Adopt 96 orifice plates to cultivate simultaneously, with mtt assay, measure the OD value of drug treating after 24,48 and 72 hours, observe the time m-effect relation of medicine.
Result: formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid all has the significance antitumous effect to human breast cancer cell strain MCF-7, human lung cancer cell lines A-549, human colon cancer cell strain HCT-116, human hepatoma cell strain QGY-7703 etc.This compound has significant difference to the inhibiting rate of different carcinoma cell, and human liver cancer cell QGY-7703 is very responsive to this compound.200 μ M concentration, 72 hours, this compound was respectively 95.07%, 78.26%, 50.39% and 51.84% to the inhibiting rate of QGY-7703, MCF-7, A-549 and HCT-116, has obvious dose-response relationship, its half-inhibition concentration (IC
50) be respectively 70 μ M, 135 μ M, 190 μ M and 200 μ M.72 hours external anticancer the results are shown in Figure 4.In other Anticancer Activity in vitro shaker test, formula (1) compound treatment cancer cells is after 72 hours, see under the microscope to human cervical carcinoma cell Hela, gastric carcinoma cells SGC-7901, Human Prostate Cancer Cells PC-3, Proliferation of Human Ovarian Cell SKOV-3, human leukemia cell K-562 and HL-60, human glioma cell U-251 etc. have significance vitro inhibition or killing action (at present temporarily not to these cell strains carry out dose-effect relationship and the time m-effect relation research).
This compound under various dose to the dose-effect relationship figure of human liver cancer cell QGY-7703 anti-cancer effect in vitro and the time m-effect relation figure (mtt assay) see Fig. 5.
2, the vivo antitumor effect of mankind's maxicell lung cancer NCI-H460 that 4-oxyethyl group-2-hydroxyl-6-tolyl acid is transplanted the balb/c nude mice
Test method: male balb/c nude mice (body weight 16～18g), every right side back subcutaneous vaccination mankind maxicell lung cancer NCI-H460 cell suspension 0.1ml(5 * 10
7cells/ml).After cancer cells the 12nd day of inoculation, the subcutaneous visible tumour of naked eyes that occurs of most of mouse.With vernier caliper measurement, calculate the gross tumor volume of every mouse.Tumor-bearing mice is divided into to DMSO control group and formula (1) compound administration group, every group of 8 tumor-bearing mices at random by the gross tumor volume size.Formula (1) compound is with the pure DMSO preparation of aseptic mass spectrum, and dosage is 30mg/kg; Control group mice gives the DMSO of equal volume.The second day of mouse from grouping starts intraperitoneal injection, administration every other day 1 time, and 1 gross tumor volume of every 4 days mensuration and body weight, calculate the relative volume of tumour, the relative appreciation rate of tumour.After administration 10 times, put to death mouse, complete tumour, liver,spleen,kidney and the testis peeled off, measure tumor weight and each organ weights, calculates tumor weight inhibiting rate and each organ coefficient.
Result: 4-oxyethyl group-2-hydroxyl-6-tolyl acid to the inhibition of NCI-H460 tumour the results are shown in Figure 6, Fig. 7, Fig. 8.4-oxyethyl group-2-hydroxyl-6-tolyl acid energy significance suppresses the growth (p<0.05) of Human Lung Cancer NCI-H460, during off-test, the weight inhibiting rate of tumour is 43.51%, the relative appreciation rate of tumour is 51.96%, the tumor weight of administration group, tumour relative volume and negative control group (mean with NC, lower same) relatively, be significance decline (p<0.05).
3, the antitumous effect of 4-oxyethyl group-2-hydroxyl-6-tolyl acid to transplantability human liver cancer QGY-7703 in nude mouse
Test method: to raise the female balb/c nude mice (body weight 16～18g) of 1 week through adaptability, every in back, right side subcutaneous vaccination QGY-7703 cell suspension 0.1ml(1 * 10
8cells/ml).Nude mice is raised in the SPF laboratory.After cancer cells the 21st day of inoculation, the subcutaneous visible tumour of naked eyes that occurs of mouse.With major diameter and the transverse diameter of vernier caliper measurement mouse tumor, calculate gross tumor volume.Tumor-bearing mice is divided into to DMSO solvent control group, 5 FU 5 fluorouracil (5-Fu) positive drug control group and formula (1) compound administration group at random according to the gross tumor volume size, every group of totally 6 tumor-bearing mices.After 4-oxyethyl group-2-hydroxyl-6-tolyl acid dissolves with the pure DMSO of aseptic mass spectrum, then, with the aseptic PBS dilution of equal-volume, dosage is 20mg/kg; Solvent control group mouse gives the DMSO/PBS(1:1 of equal volume); 5-Fu is with equal-volume DMSO dilution, and the 5-Fu using dosage is 30mg/kg.The second day of mouse from grouping starts intraperitoneal injection, administration every other day 1 time, 1 gross tumor volume of every 4 days mensuration and body weight.After administration 12 times, put to death mouse, complete tumour, the liver,spleen,kidney peeled off, measure tumor weight, Mouse Weight and each organ weights.
Result: formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid to the inhibition of QGY-7703 tumour the results are shown in Figure 9, Figure 10, Figure 11.Formula (1) compound energy significance suppresses the growth (p<0.05) of human liver cancer QGY-7703, during off-test, the weight inhibiting rate of tumour is 69.83%, the relative appreciation rate of tumour is 30.84%, the tumor weight of administration group, tumour relative volume and control group relatively, are significance decline (p<0.05).This compound is better than the restraining effect to lung cancer to the restraining effect significance of human liver cancer.When experiment finishes, Figure 12 is shown in by the QGY-7703 tumour photo of each group.
Murine sarcoma S-180, the rat liver cancer H-22 of 4-oxyethyl group-2-hydroxyl-6-tolyl acid to Kunming mouse and the transplanting of ICR mouse, and the mice lung cancer 3ll that the C57BL/6J mouse is transplanted all has the vivo antitumor effect (p<0.05) of significance, and there is dose-effect relationship.
4, the toxic action of 4-oxyethyl group-2-hydroxyl-6-tolyl acid to nude mice
Experimental technique: in nude mouse, in anticancer test, at each time point of measuring gross tumor volume, simultaneously measure the body weight of mouse; When off-test, put to death mouse, complete taking-up mouse liver, spleen, kidney, testis (male mouse) are also weighed, and calculate each organ coefficient.
(1) impact of male mouse body weight and internal organs being grown
The body weight (g) of the male balb/c mouse of table 1. different time points
*：P<0.05
Result: after administration 4 times, formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid presents restraining effect to weight of mice.
The organ coefficient of the male balb/c mouse of table 2.
*:P<0.05
Result: formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid can affect liver and the Development of The Spleen of male nude mouse, but does not affect kidney and the testicualr development of male mice.
(2) impact of female mice death, body weight and internal organs being grown
The body weight (g) of the female balb/c mouse of table 3. different time points
2 mouse of #:5-Fluracil group, death in the 20th day, separately have 3 skeletonizes, dying;
*: since the 8th day, 5 FU 5 fluorouracil and D6B2 organized the body weight significance lower than the solvent control group, P<0.05;
Result: cancer therapy drug 5 FU 5 fluorouracil and formula (1) compound energy significance affects Mouse Weight and grows, and 5 FU 5 fluorouracil affects significance higher than this compound to Mouse Weight.At the 20th day of experiment, the 5-Fu group had 2 animals because of exhaustion death, 3 mouse extreme exhaustions was separately arranged and dying.Formula (1) compound treated animal is still bouncing, nothing death when off-test.
The organ coefficient of the female balb/c mouse of table 4.
*：P<0.05
Result: 4-oxyethyl group-2-hydroxyl-6-tolyl acid can affect the female mice kidney and grow, and 5 FU 5 fluorouracil energy significance affects spleen and the kidney growth (Figure 13 is shown in by the spleen photo of respectively organizing mouse) of mouse.This compound to the development impact significance of Mouse Weight and internal organs lower than the cancer therapy drug 5 FU 5 fluorouracil.
5, the impact of 4-oxyethyl group-2-hydroxyl-6-tolyl acid on apoptosis of tumor cells and cell cycle:
Experimental technique: liver cancer cell QGY-7703, after formula (1) compound treatment 48h, adopts flow cytometer (FACS) to detect cell cycle and apoptosis situation.The results are shown in Figure 14 and Figure 15.
Result: formula (1) compound energy significance promotes the necrosis and apoptosis of cancer cells, when the drug treating group is 100 μ M, 150 μ M and 200 μ M at dosage, the DNA fragment peak (P2) that Apoptosis and necrosis forms is respectively 13.5%, 24.7% and 32.7%, obvious dose-effect relationship is arranged, significance is higher than 6.8% of control group, and this compound significance postpones G0/G1 and G2/M peak value and the cell cycle distribution ratio of cancer cells, obviously affect differentiation and the cycle of cancer cells.
6,4-oxyethyl group-2-hydroxyl-6-tolyl acid is on apoptosis marker protein Cleaved Caspase-3 and Cleaved PARP level, and the impact expressed of PTEN Tumor Suppressor Gene:
Experimental technique: liver cancer cell QGY-7703, colon cancer cell HCT-116, breast cancer cell MCF-7, lung carcinoma cell A-549 are through formula (1) compound treatment after 24 hours, collecting cell, cracking, adjustment protein concentration, adopt Western Blot technical measurement.The results are shown in Figure 16, Figure 17, Figure 18, Figure 19 (SP means positive control Staurosporine, and SP1 is 50nM, and SP2 is 100nM).
Result: 4-oxyethyl group-2-hydroxyl-6-tolyl acid energy significance promotes the formation of apoptosis sign primer Cleaved PARP in liver cancer cell QGY-7703, colon cancer cell HCT-116, to the formation of Cleaved PARP in breast cancer cell MCF-7, lung carcinoma cell A-549 without effect.This compound does not affect the Cleaved Caspase-3 level of cancer cells and the expression of PTEN yet.
7, the synergistic antitumor effect of 4-oxyethyl group-2-hydroxyl-6-tolyl acid and other cancer therapy drug:
In anticancer test, compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid and cancer therapy drug 5 FU 5 fluorouracil, taxol and cis-platinum have the external synergistic antitumor effect of significance in vitro.The results are shown in Table 5, table 6 and Figure 20, Figure 21.
Test method: in external anticancer test, the D6B2 group of the positive cancer therapy drug group of negative control group, a dosage, 3 dosage and the D6B2 of three dosage are set and add positive cancer therapy drug group, after dosing, 72 hours collecting cell countings, calculate inhibiting rate and carry out statistical study.
The In-vitro Inhibitory Effect (n=3, x ± s) of table 5.D6B2 associating 5-Fu to people's lung cancer cell A-549
With control group, compare,
*p<0.05,
*p<0.01; With 5-FU, compare,
△p<0.05,
△ △p<0.01.
Table 6D6B2 combination with cisplatin (DDP) to the restraining effect of lung cancer cell A-549 (n=3,
)
With control group, compare,
*p<0.05,
*p<0.01; With DDP, compare,
△p<0.05,
△ △p<0.01.
Taxol is when 1nM concentration, the external inhibiting rate to MCF-7 is 28.85%, D6B2 inhibiting rate to MCF-7 when concentration is 100 μ M is 15.38%, inhibiting rate to MCF-7 during the two combined action is that 52.16%, 4-oxyethyl group-2-hydroxyl-6-tolyl acid and taxol have significance combination and cooperation anti-cancer effect in vitro to human breast cancer cell MCF-7 in vitro.
In anticancer test, 4-oxyethyl group-2-hydroxyl-6-tolyl acid has in vivo and combines inhibition rat liver cancer H-22 with endoxan in vivo.Endoxan is when 40mg/kg, and to the inhibiting rate of rat liver cancer H-22, being 75.83%, D6B2 when the 40mg/kg, the inhibiting rate to H-22 is 38.99%, and the two is combined while using, and combines the group mouse there are no tumor growth.
Embodiment 3:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid and sodium bicarbonate carry out neutralization reaction under heating condition, then with soda ash solution, adjust pH value to 7.0-7.5, heating, evaporation, crystallization form the sodium salt Sodium4-ethoxy-2-hydroxy-6-methylbenzoate of formula (1) compound, can be water-soluble.Formula (1) compound also can form salt with other alkali ion or group.
Embodiment 4:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid, dissolve with a small amount of DMSO, injects routinely water, the essence filter, and injection liquid is made in the embedding sterilizing.
Embodiment 5:
The sodium salt Sodium4-ethoxy-2-hydroxy-6-methylbenzoate of formula (1) compound, be dissolved in water for injection routinely, the essence filter, and injection liquid is made in the embedding sterilizing.
Embodiment 6:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its esters, after dissolving with a small amount of ethanol, methyl alcohol or distilled water, filter with aseptic suction funnel, more aseptic essence filter, is sub-packed in ampoule, and after frozen drying, aseptic sealing by fusing obtains powder injection.
Embodiment 7:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its esters, the ratio needed in preparation adds vehicle, makes pulvis.
Embodiment 8:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its esters, the ratio needed in preparation adds vehicle, and pelletizing press sheet is made tablet.
Embodiment 9:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its esters, the oral liquid method for making is made oral liquid routinely.
Embodiment 10:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its esters, the ratio needed in preparation adds vehicle, makes capsule or granule or electuary.
Embodiment 11:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its esters, add food or other carrier in the ratio of product needed, makes healthcare products or other functional articles.
Embodiment 12:
Formula (1) compound 4-oxyethyl group-2-hydroxyl-6-tolyl acid or its esters, need by treatment, with other antitumor drug, is mixed in proportion, and makes various preparations, forms the combined with antineoplastic compositions.
The above embodiment only part has expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (7)
1. there is the 4-oxyethyl group of formula (1) structure-2-hydroxyl-6-tolyl acid or pharmacy acceptable salt,
2. an antitumor medicine composition, is characterized in that, its activeconstituents comprises 4-oxyethyl group claimed in claim 1-2-hydroxyl-6-tolyl acid or its pharmacy acceptable salt.
3. pharmaceutical composition according to claim 2, is characterized in that, the formulation of this pharmaceutical composition is: injection liquid, powder injection, tablet, oral liquid, capsule, granule or electuary.
4. combine antitumor medicine composition for one kind, it is characterized in that, its activeconstituents comprises 4-oxyethyl group claimed in claim 1-2-hydroxyl-6-tolyl acid or its pharmacy acceptable salt, and at least one in 5 FU 5 fluorouracil, taxol, cis-platinum or endoxan.
5. 4-oxyethyl group claimed in claim 1-2-hydroxyl-6-tolyl acid or the application of its pharmacy acceptable salt in preparing antitumor drug.
6. application according to claim 5, is characterized in that, described tumour is any in following human tumor: human breast carcinoma, prostate cancer, lung cancer, cancer of the stomach, cervical cancer, colorectal carcinoma, liver cancer, ovarian cancer, leukemia, neuroma, sarcoma.
7. 4-oxyethyl group claimed in claim 1-2-hydroxyl-6-tolyl acid or its pharmacy acceptable salt application in auxiliary anti-tumor health care product.
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| CN201310390817.XA CN103483187B (en) | 2013-08-30 | 2013-08-30 | 4-ethyoxyl-2-hydroxyl-6-methyl benzoic acid and Pharmaceutical composition thereof and application |
| PCT/CN2014/000808 WO2015027669A2 (en) | 2013-08-30 | 2014-08-29 | Phenyl-substituted compound, pharmaceutical composition and uses thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015027669A3 (en) * | 2013-08-30 | 2015-04-23 | 香港科技大学 | Phenyl-substituted compound, pharmaceutical composition and uses thereof |
| CN114948927A (en) * | 2021-02-20 | 2022-08-30 | 江苏九基生物科技有限公司 | Application of 3-benzofuranone derivative containing benzylidene in preparation of antitumor drugs |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6434913A (en) * | 1987-07-31 | 1989-02-06 | Mitsubishi Chem Ind | Antitumor agent |
| CN103102264A (en) * | 2013-01-07 | 2013-05-15 | 四川大学 | Preparation method of salicylic acid compound |
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| CN103483187B (en) * | 2013-08-30 | 2016-08-24 | 香港科技大学 | 4-ethyoxyl-2-hydroxyl-6-methyl benzoic acid and Pharmaceutical composition thereof and application |
-
2013
- 2013-08-30 CN CN201310390817.XA patent/CN103483187B/en not_active Expired - Fee Related
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2014
- 2014-08-29 WO PCT/CN2014/000808 patent/WO2015027669A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6434913A (en) * | 1987-07-31 | 1989-02-06 | Mitsubishi Chem Ind | Antitumor agent |
| CN103102264A (en) * | 2013-01-07 | 2013-05-15 | 四川大学 | Preparation method of salicylic acid compound |
Non-Patent Citations (1)
| Title |
|---|
| 美国化学会: "339546-91-7", 《REGISTRY 数据库》, 6 June 2001 (2001-06-06), pages 1 - 3 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015027669A3 (en) * | 2013-08-30 | 2015-04-23 | 香港科技大学 | Phenyl-substituted compound, pharmaceutical composition and uses thereof |
| CN114948927A (en) * | 2021-02-20 | 2022-08-30 | 江苏九基生物科技有限公司 | Application of 3-benzofuranone derivative containing benzylidene in preparation of antitumor drugs |
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| WO2015027669A2 (en) | 2015-03-05 |
| CN103483187B (en) | 2016-08-24 |
| WO2015027669A3 (en) | 2015-04-23 |
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