CN104151304B - A kind of triazole class compounds - Google Patents
A kind of triazole class compounds Download PDFInfo
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- CN104151304B CN104151304B CN201410355339.3A CN201410355339A CN104151304B CN 104151304 B CN104151304 B CN 104151304B CN 201410355339 A CN201410355339 A CN 201410355339A CN 104151304 B CN104151304 B CN 104151304B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
A kind of noval chemical compound (shown in Formulas I) and salt thereof, experiment proves to suppress the growth of tumor cell, is used for preparing antitumor drug.Salt can be generated with Alkali-Metal Na, K, Me, Ca etc., salt can be generated with organic base methylamine, ethamine, dimethylamine, carbinolamine, ethanolamine, trometamol, Portugal's amine, diethylamine, triethylamine etc., there is preferably suppression hepatocarcinoma and the effect of melanoma cell growth, and intravascular irritant experiment proves without haemolysis and zest, can be prepared as injection Clinical practice
Description
Technical field
The present invention relates to a kind of noval chemical compound with suppression growth of tumour cell, there is preferable water solublity, can be prepared as injection for treating tumor.
Background technology
Tumor is the serious disease of harm human health, and the preventing and controlling of tumor are always the emphasis in medical research field.At present, due to problems such as the environmental pollutions that brings in industrial development, the living environment quality of the mankind constantly declines, and causes the sickness rate of tumor disease constantly to rise with fatality rate.Radiotherapy, chemotherapy are the Main Means treating tumor at present.But chemotherapy, radiotherapy also inhibits Normocellular growth while inhibiting cancer cell development, reduce immunity of organisms, cause new complication.The specific drug for the treatment of tumor disease is not satisfactory, and the most clinical cytotoxic drug selectivity used is the highest, causes Normocellular pernicious killing, limits its application.Therefore, important directions new, that hurtless measure, the antitumor drug of acellular toxic action become international field of medicaments is found.
The present invention relates to a kind of noval chemical compound, through external, anti-tumor in vivo experiment proof, there is preferable activity, prove that there is preferable water solublity through dissolubility test, prove to can be prepared as injection for treating tumor through haemolysis and vascular stimulation tests.
Disclosure of the invention
The invention provides a kind of antitumoral compounds, be a kind of new compound and salt thereof, specially formula (I) compound or its pharmaceutically acceptable salt:
And above-claimed cpd alkali metal and organic base reaction obtain salt.
This compound can be obtained by following reaction scheme.
Compound 1,7 in upper reaction scheme proves the effect with preferably suppression growth of tumour cell through the experiment of antineoplastic in vitro and in vivo.
Specific embodiment:
Embodiment 1: the preparation of compound:
1, the synthesis of compound 4:
Accurately weigh 33.6 g of compound 3, in the DMF mixed solution of THF and 50.0mL being dissolved in 300.0mL, stir 30 minutes under ice bath, 4.0 grams of sodium hydrides (60%) of the most a small amount of addition, after finishing, continue stirring 30 minutes.Accurately weigh 40.8 g of compound 2, be dissolved in the THF of 300.0mL, this solution is added drop-wise in above-mentioned reactant liquor, drip complete follow-up continuous reaction 1 hour, then warm naturally 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 between pH to 7 to 8 with saturated ammonium chloride solution.Sucking filtration, filter cake, with distilled water wash (100.0mL × 3), obtains 46.7 g of compound 4 after ethyl alcohol recrystallization, productivity is 72%.nullHNMR(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, the synthesis of compound 5:
Accurately weigh 32.4 g of compound 4 to be dissolved in 200.0mL dehydrated alcohol, under agitation add 2.8 grams of potassium hydroxide, be then heated to 80 DEG C and react 30 minutes.Add 11.3 grams of 3-homomartonites, continue reaction 5 hours.Stopped reaction, cooling reactant liquor to room temperature, decompression is distilled off the solvent of half volume, then pour 500.0mL distilled water into reactant liquor, have Precipitation, sucking filtration, filter cake distilled water wash, obtains 24.3 g of compound 5 after re-crystallizing in ethyl acetate, productivity is 67.5%.nullHNMR(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, the synthesis of compound 6:
21.6 g of compound 5 are dissolved in the absolute methanol of 200.0mL, stir 30 minutes in ice bath, 1.7 grams of sodium borohydrides of the most a small amount of addition, then reactant liquor moves to continue under room temperature reaction 1 hour.Stopped reaction, 10.0mL ammonium chloride saturated solution and 100.0mL distilled water is added to reactant liquor, decompression is distilled off methanol therein, add the distilled water of 100.0mL, ethyl acetate extraction (100.0mL L × 3), merge organic facies, decompression be distilled off ethyl acetate obtain 17.2 can compound 6, productivity 79.6%.nullHNMR(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, the synthesis of compound 7:
By 6,2.5 grams of succinic anhydrides of 14.4 g of compound, the DMAP of 0.06 gram and 3.0 grams of triethylamines join in the THF of 100.0mL, react overnight at 60 DEG C.Stopped reaction, cooling reactant liquor is to room temperature, decompression is distilled off solvent and obtains thick product, adds 100.0mL acetic acid ethyl dissolution, adds the dilute hydrochloric acid 30mL of 1.0N, stratification after stirring 10 minutes, organic layer washes (50.0mL × 3) with water, and anhydrous sodium sulfate is dried, and decompression is distilled off solvent, with obtaining 15.9 g of compound 7 after re-crystallizing in ethyl acetate, productivity is 98%.90.9%.nullHNMR(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, the synthesis of compound 1:
The compound 7 of 15.0 grams is joined in 50.0mL dehydrated alcohol, room temperature, be stirred vigorously under be completely dissolved.1.7 grams of natrium carbonicum calcinatums are dissolved in the distilled water of 10.0mL, are then added drop-wise in above-mentioned reactant liquor, at this moment, reactant liquor has bubble emerge, wait to drip complete follow-up continuous reaction 1 hour.Stopped reaction, decompression is distilled off the solvent of half volume, at room temperature, stirring downhill reaction drop add 100mL acetone, stir 30 minutes, has precipitation generation.Sucking filtration, filter cake, with washing with acetone (50.0mL × 3), obtains 12.5 g of compound 1 after vacuum drying, productivity is 81.1%, and HPLC purity is more than 99.0%.nullHNMR(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 culture medium: GIBCO company produces.
New-born calf serum (super), Hangzhou Sijiqing Biological Engineering Material Co., Ltd..
Trypsin, Sigma company produces.
Cell strain: human hepatoma cell strain SMMC-7721, human A459 lung cancer cell line, human glioma cell line U251, Human gastric carcinoma cell line BGC-823
Instrument: CO2Incubator (Forma3110, USA), superclean bench (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 preparation of reagents: RPMI1640 culture medium one bag adds water one liter, add 2 grams of sodium bicarbonate, 100,000 units of Penicillin and 100mg streptomycin, and regulation pH value is to 7.4, degerming with the 0.22 degerming membrane filtration of μm.95ml culture medium adds inactivation new-born calf serum 5ml and is complete culture solution.Trypsin D-hanks buffer is made into 0.25% solution, and after filtration sterilization, 4 DEG C save backup.
Accurately weigh SZY1402 100mg, be added in the 1.5ml centrifuge tube of sterilizing, add DMSO1ml, be made into 100mg/ml stock solution ,-20 DEG C of freezen protective.Take after melting before use and be diluted to respective concentration application with complete culture solution in right amount.
Cell is cultivated and passes on: the equal adhere-wall culture of all cells is in containing in 10ml complete culture solution Tissue Culture Flask, in 37 DEG C, 5%CO2, full conjunction cultivate under humidity.Cell cover with bottle at the bottom of after wash twice with sterilizing D-hanks liquid, add 0.25% trypsin digestion and cell 2 minutes, outwell trypsin, after jog cell can completely fall off, after adding complete culture solution 30ml, dispel cell with pipet, it is sub-packed in 3 new Tissue Culture Flasks, continues to cultivate.
Drug treating: take one bottle of the cell just covered with, collects cell after trypsinization, with pipet piping and druming uniformly, take two cell suspension Trypan Blues, in counted under microscope number of viable cells, adjusts cell number to 1 × 10 with complete culture solution5Individual cells/ml.In 96 porocyte culture plates, every hole adds 100 μ l cell suspension, and culture plate is placed in CO2Incubator is cultivated 12 hours, in every hole, the 100 μ l complete culture solution containing variable concentrations SZY1402 is added after taking out culture plate, medicine final concentration is made to be respectively 80.0,60.0,45.0,33.8 and 25.3 μ g/ml, each concentration sets 4 parallel holes, separately set 4 porocytes to add not pastille complete culture solution and make negative control hole, the complete culture solution that 4 porocytes add containing vincristine makees positive control, the final concentration of 5 μ g/ml of vincristine.After adding medicine, culture plate vibrates mixing on microwell plate agitator, is placed in CO2Incubator continues cultivate 48 hours.Take out culture plate, every hole adds the MTT liquid of 10 μ l 5mg/ml, vibration mixing, continue to cultivate 4 hours, discard original fluid, add DMSO 150 μ l in every hole, fully vibration is to dissolve bluish violet crystallization, the light measuring each hole in Bio-Rad 550 microplate reader absorbs, and measures wavelength 570nm, reference wavelength 630nm.
Suppression ratio according to each hole OD value calculating medicine cell proliferation:
The suppression ratio that logarithm according to drug level is corresponding makees rectilinear regression, obtains linear equation, and the drug level calculating suppression ratio corresponding when 50% is the SZY1402 503nhibiting concentration (IC to tumor cell50)。
The IC of every strain cell is measured under above-mentioned similarity condition50, every strain cell experiment continuously repeats three times.
Experimental result:
The table 1S,ZY1,402 half 503nhibiting concentration (IC to different tumor cell lines50, μ g/ml)
(2) internal inhibition test
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 tumor strain: SPF level Kun Ming mice, body weight 18～22g, Shandong Luye Pharmaceutical Co., Ltd.'s animal center provide, the quality certification number: SYXK (Shandong) 20030020.SPF level C57BL/6 inbred mouse, body weight 18～22g.Mice H22 hepatocarcinoma, B16 melanoma are all quoted from Beijing institute of materia medica of the Chinese Academy of Medical Sciences.
Instrument: CO2Incubator (Forma 3110, USA), superclean bench (BCN-1360, east, Harbin joins), inverted microscope (Nikon).
Experiment 1:H22 hepatocarcinoma
H22 hepatocarcinoma takes ascites after Kunming mouse intraperitoneal inoculation and passes on preservation.Taking the H22 hepatocarcinoma tumor-bearing mice that ascites passes on the 10th, de-cervical vertebra puts to death mice, and skin of abdomen of sterilizing draws milky ascites with asepsis injector, and adjusting tumor cell concentration with injection normal saline is 1 × 107 cell/ml.With armpit skin on the right side of cotton ball soaked in alcohol sterilization Kunming mouse, in subcutaneous vaccination above-mentioned tumor cell suspension 0.2ml, conventional raising.
Packet and be administered: tumor-bearing mice 50, be randomly divided into 5 groups by body weight, often group 10, respectively model group, cyclophosphamide group, the 10 of SZY1402,30,90mg/kg group.Each group mice dosage and mode as shown in table 2 are administered, and cyclophosphamide group gives a cyclophosphamide in lotus tumor second day only abdominal cavity, SZY1402 group tail intravenously administrable equal every day 1 time, continuous 10 days.It is administered volume 20ml/kg body weight.Last is administered latter 24 hours, and de-cervical vertebra puts to death mice, weighs, strips tumor tissue and weigh, and calculates tumour inhibiting rate.
Result withRepresenting, between organizing with t inspection, significant difference compares.
Result shows, the SZY1402 continuous intravenous injection of 30mg/kg 10 days, and the growth to mice transplanted tumor H22 hepatocarcinoma is inhibited.It is shown in Table 2:
The table 2SZY1402 inhibitory action to mice H22 liver cancer growth
Compare with model group:*, P ＜ 0.05；**, P ＜ 0.01.
Experiment 2:B16 melanoma
B16 melanoma passes on preservation in the oxter subcutaneous vaccination of C57BL/6 mice.Select the B16 melanoma tumor-bearing mice that tumor growth is good, pass on preservation without downright bad or liquefaction oxter, de-cervical vertebra puts to death mice, after 75% alcohol-pickled sterilization, aseptic take tumor tissue, add the injection normal saline of 5 times of volumes (W/V), grind to form homogenate by Potter-Elvehjem Tissue Grinders system, obtain tumor cell suspension with 200 mesh stainless steel sift net filtrations of sterilizing.Ibid it is inoculated in C57BL/6 mouse armpit subcutaneous, conventional raising.
Packet and be administered: tumor-bearing mice 50, be randomly divided into 5 groups by body weight, often group 10, respectively model group, cyclophosphamide group, the 10 of SZY1402,30,90mg/kg group.Each group mice dosage and mode as shown in table 3 are administered, and cyclophosphamide group gives a cyclophosphamide in second day only abdominal cavity of lotus tumor, each group tail intravenously administrable equal every day of SZY1402 1 time, continuous 10 days.It is administered volume 20ml/kg body weight.Last is administered latter 24 hours, and de-cervical vertebra puts to death mice, weighs, strips tumor tissue and weigh, and calculates tumour inhibiting rate.
Result withRepresenting, between organizing with t inspection, significant difference compares.
Result shows, the SZY1402 group continuous intravenous injection of 30mg/kg 10 days, the growth to mice transplanted tumor B16 melanoma is inhibited.It is shown in Table 3:
Table 3 SZY1402 inhibitory action to mice B16 Melanoma Growth
Compare with model group:*, P ＜ 0.05；**, P ＜ 0.01.
Embodiment 4: the injection of compound 1 preparation in employing embodiment 1:
The compound 1 accurately weighing embodiment 1 preparation by recipe quantity is put in a container, add appropriate water for injection, stirring is to the most molten, and regulate pH to 8.5-8.8, inject water to 4000ml, add 2g needle-use activated carbon, boil 15min, sucking filtration decarburization, solution through 0.22 μm filtering with microporous membrane, solution embedding in glass ampule (every 1:94mg Han compound) preparation through 115 DEG C pressurize sterilizing 30min.
Embodiment 5: injection hemolytic and irritation test in embodiment 4
Liquid hemolytic is tested:
Hemolysis in vitro is tested: being separately added into low concentration and the high concentration (0.63mg/mL and 1.88mg/mL) of the injection of embodiment 4 preparation of inequality in each the drug liquid tube fill 2% erythrocyte suspension, each drug liquid tube did not produce haemolysis 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 test medicine:
(1) high dose group: the injection (4mL:94mg/ bottle) 1 bottle of Example 4 preparation, is diluted to 6.25mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 0.5mL, makes into the solution that concentration is 1.88mg/mL.
(2) low dose group: take the solution 2mL that above-mentioned concentration is 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% erythrocyte suspension:
Take Sanguis Leporis seu oryctolagi number milliliter, put in the triangular flask filled containing bead and shake 10 minutes, remove Fibrinogen, make into defibrinated blood.Then it is divided in several centrifuge tubes, 0.9% sodium chloride injection of every Guan Jiayue 10 times amount, shakes up, centrifugal (1500 revs/min, 15 minutes), remove supernatant, the erythrocyte of precipitation washs 2-3 time with 0.9% sodium chloride injection again, till supernatant does not shows redness.Gained erythrocyte is made into 0.9% sodium chloride injection the suspension of 2%, is for experiment.
Take the uniform clean tube of caliber size 7 (often pipe is all provided with parallel pipe), after numbering, it is sequentially added into 2% erythrocyte suspension, 0.9% sodium chloride injection, water for injection and tested medicinal liquid with pipet proportional quantity as shown in table 9, put immediately after mixing in 37 DEG C of calorstats and carry out incubation, start to observe once every 15 minutes, after 1 hour, observed once every 1 hour, observe 3 hours altogether.It is shown in Table 5:
The preparation numbering of table 5:2% erythrocyte suspension
Note: wherein 1-5 pipe is test sample pipe, the 6th pipe is negative control pipe, and the 7th pipe is positive control pipe.
(2) result is observed:
As in test, solution is clear and bright redness, acellular residual at the bottom of pipe or have a small amount of erythrocyte to remain, i.e. indicate that haemolysis occurs；As erythrocyte all sinks, supernatant fluid achromatism and clarity, show to occur without haemolysis.As solution has brownish red or rufous flocculent deposit, do not disperse after shaking, show have red blood cell condensation to occur.If any the phenomenon of red blood cell condensation, true cohesion or pseudo agglutination need to be judged further.If condensation product can be uniformly dispersed again after test tube vibrates, or is placed on wave carrier piece by aggregation, dripping 2 0.9% sodium chloride injections at coverslip edge, examine under a microscope, cohesion erythrocyte can be pseudo agglutination by the person of breaking up；If condensation product is not shaken and dissipates or be not true cohesion by the person of breaking up on slide.
3, result judges
When negative control pipe occurs without haemolysis and cohesion, and when positive control pipe has haemolysis to occur, if the solution in tested property management did not produce haemolysis and cohesion in 3 hours, then tested material can inject use；If the solution in tested property management produced haemolysis and (or) cohesion in 3 hours, then tested material should not inject use.
4, result of the test
Each the drug liquid tube being separately added into the injection solution that low concentration is 0.63mg/mL and high concentration is 1.88mg/mL did not the most produce haemolysis, hemolysis in vitro negative in 3 hours.Refer to table 6 below and table 7.
Table 6: injection (high dose group) hemolytic result of the test (perusal)
Note: "+" representing full haemolysis, "-" represents not haemolysis；6th pipe is negative control pipe, and the 7th pipe is positive control pipe.
Table 7: injection (low dose group) hemolytic result of the test (perusal)
Note: "+" representing full haemolysis, "-" represents not haemolysis；6th pipe is negative control pipe, and the 7th pipe is positive control pipe.
Injection vascular stimulation tests
Rabbit vascular stimulation tests: healthy new zealand rabbit 8 is selected in test, use consubstantiality left and right sides ear self-contrast method, left side auricular vein injection test medicine, it is administered volume 5ml/kg body weight, each administration group gives the injection of embodiment 4 preparation of corresponding dosage, low dose group and high dose group dosage are 3.15mg/kg bw and 9.4mg/kg bw respectively, (calculate its low concentration by concentration and high concentration is respectively 0.63mg/mL and 1.88mg/mL, it it is 0.7-1.4 times and 2-4 times of a clinical intravenous drip plan concentration), 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 give by after the high concentration of reagent and low concentration successively, then give 0.9% sodium chloride injection respectively.2 rabbits respectively taking low dosage and high dose cut open inspection for latter 48 hours in last administration, and 4 rabbits of remaining low concentration and high concentration cut open inspection after last 2 week convalescent period of administration terminates.8 animal ears vessel profile are more visible as a result, and rabbit ear thickness is uniform, have no substantially change；Histopathologic examination, animal ears blood vessel there are no the change of toxicological significance.Illustrate that injection vascular stimulation tests prepared by embodiment 4 meets regulation.Concrete experimental technique and experimental result are as follows:
1, the preparation of tested material:
(1) high dose group: the injection (4mL: 94mg/ bottle) 2 bottles of Example 4 preparation, is diluted to 100.0mL with 0.9% (0.9g/100ml) sodium chloride injection after sucking-off 8mL, makes into the solution that concentration is 1.88mg/mL.
(2) low dose group: take the solution 30mL that above-mentioned concentration is 1.88mg/mL, be diluted to 90.0mL with 0.9% sodium chloride injection, be diluted to the solution that concentration is 0.63mg/mL.
2, animal is weighed: administration is front and last is administered and respectively weighs once for latter 48 hours and 14 days.
3, overview is drawn materials with animal:
Observe before being administered every day and record animal and the reaction at intravascular injection position, last is administered latter 48 hours, the high concentration of difference sacrificed by exsanguination test medicine and 2 new zealand rabbits of low concentration, perusal after recording the reaction of vascular tissue, double rabbit ear (first cut left ear, then cut auris dextra, and labelling) is cut from basal part of the ear portion, one section of rabbit ear specimen of clip is fixed in 10% neutral formalin solution that (specimen is about 8cm, wide about 1cm the most respectively；Distal end otch is at the first pinprick about 0.5cm, and proximal part otch is at the 3rd pinprick about 2cm, and hanging wire end is proximal part).High concentration and 2 animals of low concentration of respectively leaving test medicine continue to observe to latter 14 days of last administration, carry out following pathologic finding: with the first pinprick as boundary, and far-end cuts one section；With the 3rd pinprick as boundary, near-end cuts two-stage nitration；During film-making, blood vessel is crosscutting, routine paraffin wax flaking, slice thickness about 4-5 μm, and H-E dyes, and then carries out histopathologic examination.
4, result judges
Result according to perusal and pathologic finding carries out comprehensive descision.
5, result of the test
5.1 perusals:
It is administered front perusal every day and records the reaction of animal blood vessels injection site, in during administration, the Some Animals of test medicine high concentration and low concentration seen from naked eyes is administered side 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.Being administered latter 48 hours at last, the bilateral rabbit ear vessel profile of the high concentration of test medicine and the 4 of low concentration rabbits is more visible, and rabbit ear thickness is uniform, has no substantially change, refers to table 12 and table 13.Last is administered high concentration and 4 rabbits of low concentration cuing open inspection test medicine for latter 14 days, and bilateral rabbit ear vessel profile is more visible, and rabbit ear thickness is uniform, has no substantially change.
5.2 pathologic findings:
The high concentration of test medicine and the 4 of low concentration rabbits are administered in last and within latter 48 hours, cut open inspection, and the remaining high concentration of test medicine and 4 rabbits of low concentration cut open inspection after 2 week convalescent period terminated.Histopathologic examination is showed no vascular tissue has the significant stimulation such as degeneration or necrosis to react.The results are shown in Table 8 and table 9:
Table 8: rabbit ear vascular stimulation is reacted (last is administered latter 48 hours visual results) by injection (high dose group)
Table 9: rabbit ear vascular stimulation is reacted (last is administered latter 48 hours visual results) by injection (low dose group)
These results suggest that the injection of compound 1 preparation used in embodiment 1 shows have good safety through hemolytic and vascular stimulation tests, be suitably prepared as injection at Clinical practice.
Claims (3)
1. the compound of structure as shown in formula (I):
。
2. the sodium salt of compound described in claim 1.
3. the purposes in preparation treatment hepatocarcinoma and melanoma medicine of the compound described in claim 1,2.
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