CN104151304A - New triazole compound - Google Patents
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- CN104151304A CN104151304A CN201410355339.3A CN201410355339A CN104151304A CN 104151304 A CN104151304 A CN 104151304A CN 201410355339 A CN201410355339 A CN 201410355339A CN 104151304 A CN104151304 A CN 104151304A
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Abstract
The invention relates to a new triazole compound (shown in a formula I) and salt thereof. Experiments prove that the new triazole compound can inhibit growth of tumour cells and can be used for preparing an anti-tumour drug; the new triazole compound can generate salt with alkali metals such as Na, K, Me and Ca, can generate salt with organic bases such as methylamine, ethylamine, dimethylamine, methyl alcohol amine, ethanol amine, tromethamine, conray, diethylamine and triethylamine and has good effects of inhibiting liver cancer and growth of melanoma cells, and vascular irritation experiments prove that the new triazole compound has no hemolysis or irritation and can be prepared into injection for clinical use. The formula (I) is described in the specification.
Description
Technical field
The present invention relates to a kind of new compound with inhibition tumor cell growth, have water-solublely preferably, can be prepared into injection liquid and be used for the treatment of tumour.
Background technology
Tumour is the serious disease of harm humans health, and the preventing and controlling of tumour are the emphasis in medical research field always.At present, due to problems such as the environmental pollutions bringing in industrial development, the mankind's living environment quality constantly declines, and causes the sickness rate of tumor disease and lethality rate constantly to rise.Radiotherapy, chemotherapy are the Main Means for the treatment of at present tumour.But chemotherapy, radiotherapy, having suppressed in cancer cells is grown also to have suppressed Normocellular growth, have reduced immunity of organisms, cause new complication.The specifics for the treatment of tumor disease can not be satisfactory, and clinical cytotoxic drug selectivity used is not high at present, causes, to Normocellular pernicious killing and wounding, having limited its application.Therefore, find important directions new, become international field of medicaments without the antitumor drug of wound, acellular toxic action.
The present invention relates to a kind of new compound, experimental results show that to have good activity through external, anti-tumor in vivo, process dissolubility test proves to have water-soluble preferably, proves to be prepared into injection for treating tumour through haemolysis and vascular stimulation tests.
disclosure of the invention
The invention provides a kind of antineoplastic compound, is a kind of new compound and salt thereof, is specially formula (I) compound or its pharmacy acceptable salt:
And the reaction of above-claimed cpd basic metal and organic bases obtains salt.
This compound can be obtained by reaction scheme below.
Compound 1,7 in upper reaction scheme experimental results show that the effect with good inhibition tumor cell growth through antineoplastic in vitro and in vivo.
Specific embodiment:
Embodiment 1: the preparation of compound:
1, compound 4 is synthetic:
Accurately take 33.6 and digest compound 3, be dissolved in the THF of 300.0mL and the DMF mixing solutions of 50.0mL, stir 30 minutes under ice bath, a small amount of 4.0 grams of sodium hydrides (60%) that add in batches, finish rear continuation and stir 30 minutes.Accurately take 40.8 and digest compound 2, be dissolved in the THF of 300.0mL, this solution is added drop-wise in above-mentioned reaction solution, dropwise rear continuation reaction 1 hour, be then naturally warming up to room temperature, be heated to 60 DEG C and continue reaction 3 hours.Stopped reaction, adds the distilled water of 300.0mL, then regulates pH to 7 between 8 with saturated ammonium chloride solution.Suction filtration, distilled water wash for filter cake (100.0mL × 3), obtains 46.7 and digests compound 4 after ethyl alcohol recrystallization, and productive rate is 72%.HNMR(400Hz，DMSO)：?8.21(s，1H)，8.08(s，1H)，7.51(s，1H)，7.48(d，J＝8.2Hz，2H)，7.21(s，1H)，7.17(d，J＝8.0Hz，1H)，7.07(d，J＝8.0Hz，1H)，6.67(d，J＝8.8Hz，2H)，6.57(d，J＝8.2Hz，2H)，6.48(d，J＝8.8Hz，2H)，4.52(s，2H)，4.42-4.40(m，1H)，4.21-3.99(m，2H)，3.92-3.90(m，2H)，3.62(t，J＝3.6Hz，4H)，3.58(t，J-3.6Hz，4H)；MS(m/z)：649.5。
2, compound 5 is synthetic:
Accurately take 32.4 and digest compound 4 and be dissolved in 200.0mL dehydrated alcohol, under agitation add 2.8 grams of potassium hydroxide, be then heated to 80 DEG C of reactions 30 minutes.Add 11.3 grams of 3-methyl bromoethyl ketones, continue reaction 5 hours.Stopped reaction, cooling reaction solution is to room temperature, and the solvent of half volume is removed in underpressure distillation, then pour 500.0mL distilled water into reaction solution, have Precipitation, suction filtration, filter cake distilled water wash, obtains 24.3 and digests compound 5 after re-crystallizing in ethyl acetate, productive rate is 67.5%.HNMR(400Hz，DMSO)：8.21(s，1H)，8.08(s，1H)，7.51(s，1H)，7.48(d，J＝8.2Hz，2H)，7.21(s，1H)，7.17(d，J＝8.0Hz，1H)，7.07(d，J＝8.0Hz，1H)，6.67(d，J＝8.8Hz，2H)，6.57(d，J＝8.2Hz，2H)，6.48(d，J＝8.8Hz，2H)，4.62(m，1H)，4.52(s，2H)，4.42-4.40(m，1H)，4.21-4.39(m，2H)，3.92-3.90(m，2H)，3.62(t，J＝3.6Hz，4H)，3.58(t，J＝3.6Hz，4H)，2.09(s，3H)，1.40(d，J＝2.4Hz，3H)；MS(m/z)：720.5。
3, compound 6 is synthetic:
Digest compound 5 by 21.6 and be dissolved in the anhydrous methanol of 200.0mL, in ice bath, stir 30 minutes, add 1.7 grams of sodium borohydrides in batches on a small quantity, then reaction solution is moved to and under room temperature, continue reaction 1 hour.Stopped reaction, add 10.0mL ammonium chloride saturated solution and 100.0mL distilled water to reaction solution, methyl alcohol is wherein removed in underpressure distillation, add again the distilled water of 100.0mL, ethyl acetate extraction (100.0mL L × 3), merge organic phase, underpressure distillation remove ethyl acetate obtain 17.2 can compound 6, productive rate 79.6%.HNMR(400Hz，DMSO)：8.21(s，1H)，8.08(s，1H)，7.51(s，1H)，7.48(d，J＝8.2Hz，2H)，7.21(s，1H)，7.17(d，J＝8.0Hz，1H)，7.07(d，J＝8.0Hz，1H)，6.67(d，J＝8.8Hz，2H)，6.57(d，J＝8.2Hz，2H)，6.48(d，J＝8.8Hz，2H)，4.52(s，2H)，4.42-4.40(m，1H)，4.21-4.39(m，2H)，4.01(m，1H)，3.92-3.90(m，2H)，3.84(m，1H)，3.62(t，J＝3.6Hz，4H)，3.58(t，J＝3.6Hz，４H)，1.30(d，J＝2.4Hz，3H)，1.21(d，J＝2.8Hz，3H)；MS(m/z)：722.6。
4, compound 7 is synthetic:
Digest 6,2.5 grams of Succinic anhydrieds of compound by 14.4, the DMAP of 0.06 gram and 3.0 grams of triethylamines join in the THF of 100.0mL, at 60 DEG C, react and spend the night.Stopped reaction, cooling reaction solution is to room temperature, underpressure distillation, except desolventizing obtains thick product, adds 100.0mL acetic acid ethyl dissolution, adds the dilute hydrochloric acid 30mL of 1.0N, stir stratification after 10 minutes, organic layer washes (50.0mL × 3) with water, anhydrous sodium sulfate drying, and underpressure distillation is except desolventizing, digest compound 7 with obtaining 15.9 after re-crystallizing in ethyl acetate, productive rate is 98%.90.9％。HNMR(400Hz，DMSO)：8.21(s，1H)，8.08(s，1H)，7.51(s，1H)，7.48(d，J＝8.2Hz，2H)，7.21(s，1H)，7.17(d，J＝8.0Hz，1H)，7.07(d，J＝8.0Hz，1H)，6.67(d，J＝8.8Hz，2H)，6.57(d，J＝8.2Hz，2H)，6.48(d，J＝8.8Hz，2H)，4.75(m，1H)，4.52(s，2H)，4.42-4.40(m，1H)，4.35(m，1H)，4.21-4.39(m，2H)，3.92-3.90(m，2H)，3.62(t，J＝3.6Hz，4H)，3.58(t，J＝3.6Hz，4H)，2.69(t，J＝3.2Hz，2H)，2.52(t，J＝3.2Hz，2H)，1.40(d，J＝2.8Hz，3H)，1.30(d，J＝2.4Hz，3H)；MS(m/z)：822.6。
5, compound 1 is synthetic:
The compound of 15.0 grams 7 is joined in 50.0mL dehydrated alcohol, under room temperature, vigorous stirring, dissolve completely.1.7 grams of anhydrous sodium carbonates are dissolved in the distilled water of 10.0mL, are then added drop-wise in above-mentioned reaction solution, at this moment, in reaction solution, have bubble to emerge, after dropwising, continue reaction 1 hour.Stopped reaction, the solvent of half volume is removed in underpressure distillation, at room temperature, stir downhill reaction drop and add 100mL acetone, stirs 30 minutes, has precipitation generation.Suction filtration, washing with acetone for filter cake (50.0mL × 3), obtains 12.5 and digests compound 1 after vacuum-drying, and productive rate is that 81.1%, HPLC purity is more than 99.0%.HNMR(400Hz，DMSO)：8.21(s，1H)，8.08(s，1H)，7.51(s，1H)，7.48(d，J＝8.2Hz，2H)，7.21(s，1H)，7.17(d，J＝8.0Hz，1H)，7.07(d，J＝8.0Hz，1H)，6.67(d，J＝8.8Hz，2H)，6.57(d，J＝8.2Hz，2H)，6.48(d，J＝8.8Hz，2H)，4.75(m，1H)，4.52(s，2H)，4.42-4.40(m，1H)，4.35(m，1H)，4.21-3.99(m，2H)，3.92-3.90(m，2H)，3.62(t，J＝3.6Hz，4H)，3.58(t，J＝3.6Hz，4H)，2.69(t，J＝3.2Hz，2H)，2.52(t，J＝3.2Hz，2H)，1.49(d，J＝2.8Hz，3H)，1.30(d，J＝2.4Hz，3H)；MS(m/z)：844.6。
Embodiment 2: the anti-tumor activity of compound 1
(1) external inhibition test (replacing the compound 1 in embodiment 1 with code name SZY1402 in test)
Experiment material:
Medicine and reagent: SZY1402
RPMI1640 substratum: GIBCO company produces.
New-born calf serum (super), Hangzhou Sijiqing Biological Engineering Material Co., Ltd..
Trypsinase, Sigma company produces.
Cell strain: human hepatoma cell strain SMMC-7721, human lung adenocarcinoma cell line A549, human glioma cell line U251, Human gastric carcinoma cell line BGC-823
Instrument: CO
2incubator (Forma3110, USA), Bechtop (Ha Dong joins BCN-1360B), microplate reader (Bio-Rad550, USA), inverted microscope (Nikon TE2000, Japan), Tissue Culture Flask (Costar, USA), 96 porocyte culture plates (Costar, USA).
Experimental technique:
Medicine and reagent preparation: one bag of RPMI1640 substratum adds water one liter, adds 2 grams of sodium bicarbonates, and 100,000 unit penicillin and 100mg Streptomycin sulphate, regulate pH value to 7.4, with 0.22 μ m degerming membrane filtration degerming.95ml substratum adds deactivation new-born calf serum 5ml and is complete culture solution.Trypsinase is made into 0.25% solution with D-hanks damping fluid, and after filtration sterilization, 4 DEG C save backup.
Accurately take SZY1402 100mg, be added in the 1.5ml centrifuge tube of sterilizing, add DMSO1ml, be made into 100mg/ml stoste ,-20 DEG C of freezing preservations.After melting before use, get in right amount and be diluted to respective concentration application with complete culture solution.
Cell cultures and going down to posterity: the equal adherent culture of all cells is in containing in 10ml complete culture solution Tissue Culture Flask, in 37 DEG C, 5%CO
2, full closing under humidity cultivate.After at the bottom of cell covers with bottle, wash twice with sterilizing D-hanks liquid, add 0.25% trypsin digestion and cell 2 minutes, outwell trypsinase, after jog cell can come off completely, add after complete culture solution 30ml, dispel cell with transfer pipet, be sub-packed in 3 new Tissue Culture Flasks, continue to cultivate.
Drug treating: get one bottle, the cell that just covered with, collecting cell after tryptic digestion, with transfer pipet piping and druming evenly, get two cell suspension Trypan Blues, living cell counting number under microscope, adjusts cell number to 1 × 10 with complete culture solution
5individual cells/ml.In 96 porocyte culture plates, every hole adds 100 μ l cell suspensions, and culture plate is placed in to CO
2in incubator, cultivate 12 hours, after taking out culture plate, in every hole, add the complete culture solution of 100 μ l containing different concns SZY1402, make medicine final concentration be respectively 80.0,60.0,45.0,33.8 and 25.3 μ g/ml, each concentration is established 4 parallel holes, separately establishing 4 porocytes adds not pastille complete culture solution to make negative control hole, 4 porocytes add containing the complete culture solution of vincristine(VCR) makes positive control, and vincristine(VCR) final concentration is 5 μ g/ml.After adding medicine, culture plate vibrates and mixes on microwell plate vibrator, is placed in CO
2in incubator, continue to cultivate 48 hours.Take out culture plate, every hole adds the MTT liquid of 10 μ l 5mg/ml, vibration mixes, continue to cultivate 4 hours, discard original fluid, add DMSO 150 μ l in every hole, fully vibration is to dissolve bluish voilet crystallization, in Bio-Rad 550 microplate reader, measure the photoabsorption in each hole, measure wavelength 570nm, reference wavelength 630nm.
Calculate the inhibiting rate of medicine on cell proliferation according to each hole OD value:
Do straight-line regression according to the inhibiting rate that the logarithm of drug level is corresponding, obtain straight-line equation, calculate inhibiting rate corresponding drug level 50% time and be the 503nhibiting concentration (IC of SZY1402 to tumour cell
50).
Under above-mentioned similarity condition, measure the IC of every strain cell
50, every strain cell experiment continuously in triplicate.
Experimental result:
Half 503nhibiting concentration (the IC of table 1SZY1402 to different tumor cell lines
50, μ g/ml)
(2) inhibition test in body
Experiment material:
Medicine and reagent: SZY1402 (compound 1 in embodiment 1), white powder.
Cyclophosphamide for injection, Hengrui Medicine Co., Ltd., Jiangsu Prov.'s product.
Animal and knurl strain: SPF level Kunming kind small white mouse, body weight 18～22g, is provided conformity certification number by Shandong Luye Pharmaceutical Co., Ltd.'s animal center: SYXK (Shandong) 20030020.SPF level C57BL/6 inbred mouse, body weight 18～22g.Mouse H22 liver cancer, B16 melanoma are all drawn from Beijing institute of materia medica of the Chinese Academy of Medical Sciences.
Instrument: CO
2incubator (Forma 3110, USA), Bechtop (BCN-1360, east, Harbin connection), inverted microscope (Nikon).
Experiment 1:H22 liver cancer
H22 liver cancer is got the ascites preservation of going down to posterity after Kunming mouse intraperitoneal inoculation.Get the H22 liver cancer tumor-bearing mice that ascites goes down to posterity the 10th, de-cervical vertebra is put to death mouse, and sterilization skin of abdomen, draws oyster white ascites with asepsis injector, adjusts tumour cell concentration as 1 × 107 cell/ml taking injection physiological saline.With cotton ball soaked in alcohol sterilization Kunming mouse right side armpit skin, in the above-mentioned tumor cell suspension 0.2ml of subcutaneous vaccination, conventional raising.
Grouping and administration: 50 of tumor-bearing mices, be divided at random 5 groups by body weight, 10 every group, be respectively model group, endoxan group, SZY1402 10,30,90mg/kg group.Each group mouse is pressed dosage shown in table 2 and mode administration, and endoxan group only gives endoxan one time in abdominal cavity in lotus knurl second day, and SZY1402 organizes equal every day of tail intravenously administrable 1 time, continuous 10 days.Administration volume 20ml/kg body weight.After last administration 24 hours, de-cervical vertebra was put to death mouse, weighs, and strips tumor tissue and weighs, and calculates tumour inhibiting rate.
Result with
represent significant difference comparison between organizing with t inspection.
Result shows, the SZY1402 continuous intravenous injection of 30mg/kg 10 days is inhibited to the growth of mice transplanted tumor H22 liver cancer.In table 2:
The restraining effect of table 2SZY1402 to mouse H22 liver cancer growth
With model group comparison:
*, P < 0.05;
*, P < 0.01.
Experiment 2:B16 melanoma
B16 melanoma is in the C57BL/6 mouse oxter subcutaneous vaccination preservation of going down to posterity.The B16 melanoma tumor-bearing mice of preservation that selection tumor growth is good, nothing is downright bad or go down to posterity in oxter liquefaction, de-cervical vertebra is put to death mouse, after 75% alcohol-pickled sterilization, the aseptic tumor tissue of getting, add the injection physiological saline of 5 times of volumes (W/V), grind to form homogenate by tissue homogenizer system, obtain tumor cell suspension with 200 order stainless steel sift net filtrations of sterilizing.The same to be inoculated in C57BL/6 mouse armpit subcutaneous, conventional raising.
Grouping and administration: 50 of tumor-bearing mices, be divided at random 5 groups by body weight, 10 every group, be respectively model group, endoxan group, SZY1402 10,30,90mg/kg group.Each group mouse is pressed dosage shown in table 3 and mode administration, and endoxan group only gives endoxan one time in abdominal cavity in lotus knurl second day, each group of SZY1402 equal every day of tail intravenously administrable 1 time, continuous 10 days.Administration volume 20ml/kg body weight.After last administration 24 hours, de-cervical vertebra was put to death mouse, weighs, and strips tumor tissue and weighs, and calculates tumour inhibiting rate.
Result with
represent significant difference comparison between organizing with t inspection.
Result shows, the SZY1402 group continuous intravenous injection of 30mg/kg 10 days is inhibited to the melanomatous growth of mice transplanted tumor B16.In table 3:
The restraining effect of table 3 SZY1402 to the growth of mouse B16 melanoma
With model group comparison:
*, P < 0.05;
*, P < 0.01.
Embodiment 4: adopt the injection liquid that in embodiment 1 prepared by compound 1:
Accurately taking compound 1 prepared by embodiment 1 by recipe quantity puts in a container, add appropriate water for injection, be stirred to entirely molten, and regulate pH to 8.5-8.8, and inject water to 4000ml, add 2g needle-use activated carbon, boil 15min, suction filtration decarburization, solution is through 0.22 μ m filtering with microporous membrane, solution embedding in glass ampoule (every containing compound 1:94mg) preparation through 115 DEG C of pressurization sterilizing 30min.
Injection liquid hemolytic and irritation test in embodiment 5: embodiment 4
The test of liquid hemolytic:
External hemolytic test: to filling the lower concentration and the high density (0.63mg/mL and 1.88mg/mL) that add respectively injection liquid prepared by the embodiment 4 of inequality in each drug liquid tube of 2% red blood corpuscle suspension, each drug liquid tube do not produce hemolytic action in 3 hours.The outer hemolytic negative of injecting fluid prepared by embodiment 4 is described.Concrete experimental technique and experimental result are as follows:
1, the preparation of tested medicine:
(1) high dose group: get 1 bottle of injection liquid (4mL:94mg/ bottle) prepared by embodiment 4, be diluted to 6.25mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 0.5mL, make into the solution that concentration is 1.88mg/mL.
(2) low dose group: getting above-mentioned concentration is the solution 2mL of 1.88mg/mL, is diluted to 6mL with 0.9% (0.9g/100ml) sodium chloride injection, is diluted to the solution that concentration is 0.63mg/mL.
2, medication:
The preparation of (1) 2% red blood corpuscle suspension:
Get rabbit blood number milliliter, put into and fill containing the triangular flask jolting of granulated glass sphere 10 minutes, remove Fibrinogen, make into defibrinated blood.Then be divided in several centrifuge tubes, 0.9% sodium chloride injection of 10 times of amounts of every Guan Jiayue, shakes up, centrifugal (1500 revs/min, 15 minutes), remove supernatant liquor, the red blood corpuscle of precipitation is again with 0.9% sodium chloride injection washing 2-3 time, until the not aobvious redness of supernatant liquor.Gained red blood corpuscle is made into 2% suspension with 0.9% sodium chloride injection, is for experiment.
Get 7 of the uniform clean tube of caliber size (every Guan Junshe parallel pipe), after numbering, add successively 2% red blood corpuscle suspension, 0.9% sodium chloride injection, water for injection and tested liquid by proportional quantity shown in table 9 with transfer pipet, after mixing, put immediately in 37 DEG C of thermostat containers and carry out incubation, start to observe once every 15 minutes, after 1 hour, observed once every 1 hour, observe altogether 3 hours.In table 5:
The preparation numbering of table 5:2% red blood corpuscle suspension
Note: wherein 1-5 pipe is trial-product pipe, the negative control tube of the 6th pipe, the positive control tube of the 7th pipe.
(2) result is observed:
As solution in test is clear and bright redness, it is residual or have a small amount of red corpuscle residual that the pipe end, is acellular, indicates haemolysis generation; As red corpuscle all sinks, supernatant liquid achromatism and clarity, shows to occur without haemolysis.As having red-brown or reddish-brown flocks in solution, after jolting, do not disperse, show to have red blood cell condensation to occur.If any the phenomenon of red blood cell condensation, need further to judge to be true cohesion or pseudo agglutination.If condensation product can be uniformly dispersed again after test tube vibration, or aggregation is placed on wave carrier piece, drip 2 0.9% sodium chloride injections at cover glass edge, to examine under a microscope, cohesion red corpuscle can be pseudo agglutination by the person of breaking up; If condensation product is not shaken loose or is not true cohesion by the person of breaking up on slide.
3, result is judged
When negative control pipe occurs without haemolysis and cohesion, when positive control pipe has haemolysis to occur, if the solution in tested property management did not produce haemolysis and cohesion in 3 hours, tested material can be injected use; If the solution in tested property management produced haemolysis and (or) cohesion in 3 hours, tested material should not be injected use.
4, test-results
Adding respectively lower concentration is that each drug liquid tube of 0.63mg/mL and the high density injection liquid solution that is 1.88mg/mL all do not produce hemolytic action, external hemolytic negative in 3 hours.Refer to following table 6 and table 7.
Table 6: injection liquid (high dose group) hemolytic test-results (visual inspection)
Note: "+" represents full haemolysis, "-" represents not haemolysis; The negative control tube of the 6th pipe, the positive control tube of the 7th pipe.
Table 7: injection liquid (low dose group) hemolytic test-results (visual inspection)
Note: "+" represents full haemolysis, "-" represents not haemolysis; The negative control tube of the 6th pipe, the positive control tube of the 7th pipe.
Injection liquid vascular stimulation tests
Rabbit vascular stimulation tests: 8 of healthy new zealand rabbits are selected in test, adopt consubstantiality left and right sides ear self-contrast method, left side auricular vein is injected tested medicine, administration volume 5ml/kg body weight, each administration group gives injection liquid prepared by the embodiment 4 of corresponding dosage, low dose group and high dose group dosage are respectively 3.15mg/kgbw and 9.4mg/kgbw, (calculate its lower concentration and high density is respectively 0.63mg/mL and 1.88mg/mL by concentration, that 0.7-1.4 times and 2-4 times by concentration intended in a clinical intravenous drip), auris dextra gives equal-volume 0.9% (0.9g/100ml) sodium chloride injection and compares, once a day, for three days on end.8 rabbits are subject to after the high density and lower concentration of reagent successively, then give respectively 0.9% sodium chloride injection.Respectively get 2 rabbits of low dosage and high dosage and within 48 hours after last administration, cut open inspection, 4 rabbits of remaining lower concentration and high density are cutd open inspection after 2 week decubation of last administration finishes.8 animal ears blood vessel profiles are more clear as a result, and rabbit ear thickness is even, has no obvious change; Histopathologic examination, animal ears blood vessel is there are no the change of toxicology meaning.Illustrate that injection liquid vascular stimulation tests prepared by embodiment 4 conforms with the regulations.Concrete experimental technique and experimental result are as follows:
1, the preparation of tested material:
(1) high dose group: get 2 bottles of injection liquids (4mL: 94mg/ bottle) prepared by embodiment 4, be diluted to 100.0mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 8mL, make into the solution that concentration is 1.88mg/mL.
(2) low dose group: getting above-mentioned concentration is the solution 30mL of 1.88mg/mL, is diluted to 90.0mL with 0.9% sodium chloride injection, is diluted to the solution that concentration is 0.63mg/mL.
2, animal is weighed: before administration and after last administration, within 48 hours and 14 days, respectively weigh once.
3, overview and animal are drawn materials:
Before administration every day, observe and record the reaction at animal and intravascular injection position, after last administration 48 hours, the high density of the tested medicine of sacrificed by exsanguination and 2 new zealand rabbits of lower concentration respectively, visual inspection is also recorded after the reaction of vascular tissue, from basal part of the ear portion cut two rabbit ears (first cut left ear, after cut auris dextra, and mark), then one section of rabbit ear sample of clip is fixed on that in 10% neutral formalin solution, (sample is about 8cm, wide about 1cm respectively; Distal end otch is apart from the about 0.5cm of the first pinprick place, and proximal part otch is apart from the about 2cm of the 3rd pinprick place, and hanging wire end is proximal part).Respectively leave the high density of tested medicine and 2 animals of lower concentration and continue to observe to after last administration 14 days, carry out following pathologic finding: taking the first pinprick as boundary, far-end is cut one section; Taking the 3rd pinprick as boundary, near-end is cut two sections; Blood vessel crosscut when film-making, routine paraffin wax flaking, the about 4-5 μ of slice thickness m, H-E dyeing, then carries out histopathologic examination.
4, result is judged
Comprehensively judge according to the result of visual inspection and pathologic finding.
5, test-results
5.1 visual inspections:
The front visual inspection of administration every day the reaction of recording animal blood vessels injection site, during administration, in the Some Animals administration side of the visible tested medicine high density of naked eyes and lower concentration and control sides rabbit ear inserting needle position vascular epidermis, outside takes on a red color, and area is by 0.1cm × 0.2cm to 0.2cm × 1.0cm.After last administration 48 hours, the bilateral rabbit ear blood vessel profile of 4 rabbits of the high density of tested medicine and lower concentration was more clear, and rabbit ear thickness is even, has no obvious change, refers to table 12 and table 13.Within after last administration 14 days, cut open the inspection high density of tested medicine and 4 rabbits of lower concentration, bilateral rabbit ear blood vessel profile is more clear, and rabbit ear thickness is even, has no obvious change.
5.2 pathologic findings:
4 rabbits of the high density of tested medicine and lower concentration are cutd open inspection for 48 hours after last administration, and 4 rabbits of the high density of remaining tested medicine and lower concentration are cutd open inspection after 2 week decubation finished.Histopathologic examination is showed no vascular tissue the reaction of the significant stimulation such as sex change or necrosis.The results are shown in Table 8 and table 9:
Table 8: injection liquid (high dose group) is to rabbit ear vascular stimulation reaction (48 hours visual inspection results after last administration)
Table 9: injection liquid (low dose group) is to rabbit ear vascular stimulation reaction (48 hours visual inspection results after last administration)
These results suggest that injection liquid prepared by the compound 1 in employing embodiment 1 shows to have good security through hemolytic and vascular stimulation tests, the suitable injection liquid that is prepared into is in clinical use.
Claims (3)
1. suc as formula the compound of structure shown in (I):
。
2. compound according to claim 1, the salt generating with Alkali-Metal Na, K, Me, Ca, and react with organic bases Trometamol, thanomin, diethanolamine, trolamine, diethylamine, triethylamine, Portugal's amine, dimethylamine, methylamine etc. the salt obtaining.
Described in claim 1,2 compound in the purposes of preparing in Hepatoma therapy and melanoma medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410355339.3A CN104151304B (en) | 2014-07-23 | 2014-07-23 | A kind of triazole class compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110819703A (en) * | 2018-08-07 | 2020-02-21 | 上海恒润达生生物科技有限公司 | Method for evaluating safety of CART cells |
| CN111138421A (en) * | 2019-12-26 | 2020-05-12 | 上海英诺富成生物科技有限公司 | Antifungal water-soluble compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008089185A2 (en) * | 2007-01-16 | 2008-07-24 | Enzon Pharmaceuticals, Inc. | Posaconazole polymer conjugates and methods of treatment using posaconazole and polymer conjugates thereof |
| CN101830847A (en) * | 2010-05-18 | 2010-09-15 | 苏州麦迪仙医药科技有限公司 | Anticancer compound and preparation method thereof |
| WO2013036866A1 (en) * | 2011-09-07 | 2013-03-14 | The Johns Hopkins University | Itraconazole analogs and use thereof |
-
2014
- 2014-07-23 CN CN201410355339.3A patent/CN104151304B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008089185A2 (en) * | 2007-01-16 | 2008-07-24 | Enzon Pharmaceuticals, Inc. | Posaconazole polymer conjugates and methods of treatment using posaconazole and polymer conjugates thereof |
| CN101830847A (en) * | 2010-05-18 | 2010-09-15 | 苏州麦迪仙医药科技有限公司 | Anticancer compound and preparation method thereof |
| WO2013036866A1 (en) * | 2011-09-07 | 2013-03-14 | The Johns Hopkins University | Itraconazole analogs and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| 张娜，等: "靶向血管内皮生长因子及其受体的抗肿瘤药物研究进展", 《国际药学研究杂志》, vol. 39, no. 2, 30 April 2012 (2012-04-30), pages 137 - 142 * |
| 王秀云，等: "靶向血管内皮生长因子/血管内皮生长因子受体-2的血管生成抑制剂", 《药学进展》, vol. 37, no. 1, 31 December 2013 (2013-12-31), pages 8 - 16 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110819703A (en) * | 2018-08-07 | 2020-02-21 | 上海恒润达生生物科技有限公司 | Method for evaluating safety of CART cells |
| CN111138421A (en) * | 2019-12-26 | 2020-05-12 | 上海英诺富成生物科技有限公司 | Antifungal water-soluble compound and preparation method and application thereof |
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