CN103665046A - Ruthenium complex as well as preparation method and application thereof - Google Patents
Ruthenium complex as well as preparation method and application thereof Download PDFInfo
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- CN103665046A CN103665046A CN201210319799.1A CN201210319799A CN103665046A CN 103665046 A CN103665046 A CN 103665046A CN 201210319799 A CN201210319799 A CN 201210319799A CN 103665046 A CN103665046 A CN 103665046A
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- RTLIGSBOOHDFJU-UHFFFAOYSA-N C[NH+](C1CC1)[O-] Chemical compound C[NH+](C1CC1)[O-] RTLIGSBOOHDFJU-UHFFFAOYSA-N 0.000 description 1
- NKUPMAYFFJGPTI-UHFFFAOYSA-N OCNC1CC1 Chemical compound OCNC1CC1 NKUPMAYFFJGPTI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a ruthenium complex containing a pyridine derivative as well as a preparation method and an application of the ruthenium complex. The structural formula of the complex is shown in the formula (I). The preparation method comprises the steps: grinding a reaction initiator trans-[RuCl4(SOR1R2)2][(SOR1R2)2H] into fine powder; stirring the initiator and ligand or performing ultrasonic oscillation in a reaction solvent, wherein the molar rate of the initiator to the ligand is 1:2-1:8 and the reaction temperature is 25-80 DEG C; or carrying out backflow; filtering precipitate formed after ultrasonic oscillation, and washing with acetone and diethyl ether; and drying by a silicon rubber dryer and keeping overnight. According to the preparation method of the ruthenium complex, the reaction time is short and the yield is high; and by using the prepared NA MI-A derivate, the anti-metastasis pesticide effect of Lewis experimental lung-cancer mice is significant, and the toxicity is low.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of with band substituent pyridine ruthenium complexe and its preparation method and application.
Background technology
Lung cancer is China male sex sickness rate and mortality ratio is the highest, the malignant tumour of women's mortality ratio time high (sickness rate is up to mammary cancer).Annual death reaches hundreds of thousands of them, is the healthy maximum cancer of harm China.And lung cancer early symptom is not obvious, the patients with lung cancer of discovery mostly is late period and has shifted.At present except early operation excision, without active drug treatment means.Mostly be the treatment of comfort property.Tumour patient is mainly died from the transfer of tumour and the toxicity of antitumour drug.Clinical conventional anticarcinogen, except killing cancer cells, has larger toxicity to normal cell, and with serious side effects such as bone marrow depression, resistance.Patient dies from the transfer of cancer and the toxicity of anticarcinogen (bone marrow depression) more.Preparation has anti-lung cancer, Metastasis in Breast Cancer new compound active, low toxicity is the long-term objective that China researches and develops anticarcinogen always.
V2
NAMI-A-trans-[RuCl
4(DMSO) HIm] [H
2im] (DMSO=bis-first class sulfoxides, Im=imidazoles) anti metastasis compound (chemical structure of V2-NAMI-A) of obtaining for Europe screening in recent years.Its anti-metastasis rate to mice lung cancer and mammary cancer can reach 80%, and toxicity is lower, without the common bone marrow depression side effect of antitumour drug, has good Prospect of R & D.NAMI-A completes I clinical trial phase and enters II clinical trial phase [Zhang little Nian in Holland, Liu Yanan, Yang Xiaoxin, Liu Jie. the signal path of ruthenium complexe inducing apoptosis of tumour cell and mechanism of action thereof. chemical progress, 2011.23 (5): p.983-990. beam sunlight is magnificent, Bi Wei, Liang Guogang, the preparation and the Hydrolytic Mechanism kinetics that contain the anti metastasis NAMI-A derivative of pyridine. Chinese Journal of Inorganic Chemistry, 2011.27 (4): p.595-603.].The NAMI-A derivative of bibliographical information is mainly imidazoles in NAMI-A by binuclear compound of the replacements such as N-Methylimidazole, ammonia, pyrazine and pyrazine or derivatives thereof bridge joint etc., above compound has all been applied for Patents [Sava, G.M.E.A.G., Ruthenium Dimeric Complexes Stuitable As Antimetastatic and Antineoplastic Agents.2005.Patent No.:US6,921,824, B1].
The present invention has prepared the new ruthenium complexe that contains pyridine derivate, and the application of above-mentioned ruthenium complexe in antitumor and anti metastasis is provided.
Summary of the invention
One of object of the present invention provides a kind of new ruthenium complexe.
The technical scheme that realizes above-mentioned purpose is as follows.
A ruthenium complexe with following general formula (I),
Wherein,
R
1, R
2independently be selected from separately:
1) C1-C8 alkyl,
2) the C1-C8 alkyl that 1,2 or 3 H are replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different,
3) C5-C7 aromatic nucleus,
4) the C5-C7 aromatic nucleus that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different;
L is selected from:
1) nitrogenous C1-C8 alkyl,
2) the nitrogenous C1-C8 alkyl that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different,
3) nitrogenous 6 yuan of aromatic nucleus,
4) nitrogenous 6 yuan of aromatic nucleus that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different,
5) nitrogenous 5 yuan of aromatic nucleus,
6) nitrogenous 5 yuan of aromatic nucleus that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, sulfonic group, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different.
In an embodiment therein, R
1for C1-C8 alkyl, R
2for C5-C7 aromatic nucleus.
In an embodiment therein, L is pyridine, pyrazine or pyridazine.
In an embodiment therein, L is imidazoles or pyrazoles.
Another object of the present invention is to provide the preparation method of a plurality of anti metastasis ruthenium complexees.The ruthenium complexe aqueous solution of preparation has the Hydrolytic Mechanism identical with NAMI-A (comprising 2 step dechlorination hydrolysis reaction and de-DMSO hydrolysis reaction), but the stability of the solution of most compounds is stronger than NAMI-A, and antimetastatic activity is higher, and toxicity is lower.
Another object of the present invention is to provide and can improves the preparation method that ruthenium complexe and derivative thereof are prepared yield, shortened preparation time.
The preparation method of above-mentioned ruthenium complexe comprises the following steps:
1) by start material trans-[RuCl
4(SOR
1r
2)
2] [(SOR
1r
2)
2h] grind to form fine powder;
2) by initiator and part stirring in reaction solvent, sonic oscillation or the backflow with above-mentioned L structure, stirring, vibration or return time are 10min-20h; The mol ratio of initiator and part is 1:2-1:8; Temperature of reaction 25-80 ℃;
3) sedimentation and filtration forming after sonic oscillation, with acetone and ether washing, silica dehydrator spends the night, and obtains described ruthenium complexe and derivative thereof respectively.
In an embodiment therein, described reaction solvent is one or more in methyl alcohol, ethanol, acetone, chloroform.
A further object of the present invention is to provide the application of above-mentioned ruthenium complexe in anti metastasis.
Concrete technical scheme is as follows:
The application of above-mentioned ruthenium complexe in the medicine of preparation treatment tumour or metastases, or the application in the medicine of preparation prevention and curing oncoma transfer.
In an embodiment therein, described tumour is mammary cancer, lung cancer, intestinal cancer, liver cancer, gastrointestinal cancer, ovarian cancer, carcinoma of the pancreas, laryngocarcinoma, carcinoma of testis, nasopharyngeal carcinoma or leukemia.
Another object of the present invention is to provide a kind of medicinal compositions for the treatment of tumour or metastases.
Concrete technical scheme is as follows:
Treat a medicinal compositions for tumour or metastases, include by above-mentioned ruthenium complexe and pharmaceutically acceptable carrier and form.
In an embodiment therein, described medicinal compositions also includes other anticarcinogen or antioxidant halfcystine, xitix and protein formulation as injection albumin.Described compound can be combined use with one or more other anticarcinogens.Also can combine use as injection albumin etc. with antioxidant halfcystine, xitix and protein formulation, to increase drug effect.
The tumor cure dose of above-mentioned ruthenium complexe is 25-500mg/kg/ days, and administering mode is oral, injection, target injection.The formulation of described compound, pharmaceutical composition is tablet, injection, pill, pulvis, capsule, microcapsule, suppository.In formulation, can comprise one or more anticarcinogens (as cis-platinum, taxol and derivative, Ro 2-9757 etc.).Described liquid dosage form can be used the method solubilising that adds polysorbas20-80, span 20-80, DMSO, glycerine or 1,2-PD.Described compound can be combined use as injected albumin with protein formulation, to reduce toxicity.Described compound also can shift for prophylaxis of tumours.I.e. administration in advance occurs and metastases to prevent tumour.
Compare with existing correlation technique, this preparation method also has following beneficial effect:
1.trans-[RuCl
4(SOR
1r
2)
2] [(SOR
1r
2)
2h] in acetone with Im(imidazoles) react for solid-liquid reaction, be ground into fine powder and can make reaction more even;
Sonic oscillation, improve temperature of reaction compare with the method for stirring at room can fast reaction speed, improve and prepare yield;
3. the derivative aqueous solution of preparing has the Hydrolytic Mechanism identical with NAMI-A and (comprises 2 step dechlorination hydrolysis reaction and de-SOR
1r
2hydrolysis reaction); The dechlorination hydrolysis rate of majority of compounds is slower than NAMI-A, and activity of resisting tumor metastasis species lifetime in solution is long.
4. the stability of solution of the derivative that prepared by part is stronger and antimetastatic activity is high, toxicity is low than NAMI-A.
Embodiment
Initiator trans-[RuCl
4(DMSO)
2] [(DMSO)
2h] press patent documentation method preparation [Alessio, E.M., G.; Pocar, S.; Sava, G.; Spinelli, S., US Patent 5409893.1995].The material obtaining is confirmed as follows:
Physicochemical property are as follows:
Outward appearance: red transparent crystals
Molecular formula: C
8h
25cl
4o
4ruS
4
Molecular weight: 556.40
Fusing point: 120 ℃.
Embodiment 1[H (3-BrPy)] [trans-RuCl
4(DMSO) preparation (3-BrPy)] (compound 1, L=3-BrPy, 3-bromopyridine)
Take initiator trans-[RuCl
4(DMSO)
2] [(DMSO)
2h] 0.10g (0.18mmol) grinds to form fine powder, is dissolved in 8ml acetone, adds 0.07ml (0.72mmol) 3-bromopyridine.Ultrasonic reaction 3 hours, after the orange powder filter of generation, respectively with acetone and ether washing, silica dehydrator spends the night.Obtain orange powder: 0.10g.Productive rate: 87%.
The title complex obtaining (compound 1) physico-chemical property is described below: form: safran needle-like crystallite.Molecular weight: 638.01.Fusing point: 181-183 ℃.Molecular formula: C
12h
15cl
4br
2n
2oRuS.Ultimate analysis calculated value: C 22.59, H 2.37, and N 4.39%; Determination of elemental analysis value: C 22.93, H 2.29, and N 4.42%.UV/Vis(25℃，H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：293(3280)，396(3980)，462(480)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3091,3047,1616,1556,1514,1462,1448,1417,1200,1144,1107,1076,1022,430.
1h-NMR composes (DMSO-d
6) δ: 8.83ppm, 8.65ppm, 8.24ppm, 7.54ppm ,-1.90ppm ,-12.86ppm.
Embodiment 2[H (4-BrPy)] [trans-RuCl
4(DMSO) preparation (4-BrPy)] (compound 2, L=4-BrPy, 4-bromopyridine)
4-bromopyridine is unstable, after must processing with 4-bromopyridine hydrochloride, is converted into 4-bromopyridine.
Conversion process: get 4-bromopyridine hydrochloride 1g and be dissolved in 5ml water.Use 0.5molL
-1naOH solution adjust pH, makes it to be greater than 6.Use 3ml chloroform extraction, take out chloroform layer (lower floor).Use respectively again 3ml chloroform re-extract, three extraction liquids are merged, use anhydrous Na
2sO
4dehydration, standby (Refrigerator store).
Take initiator trans-[RuCl
4(DMSO)
2] [(DMSO)
2h] 0.11g (0.20mmol), be dissolved in 8ml acetone, add the above-mentioned reserve liquid of 2ml.Ultrasonic reaction 3 hours, finally generates safran pressed powder.Filter, respectively with acetone and ether washing.Silica dehydrator spends the night.Obtain safran pressed powder: 0.084g.Yield: 67%.
Title complex physico-chemical property is described below: form: safran crystallite.Molecular formula: C
l2h
15c1
4br
2n
2oRuS.Molecular weight: 638.01.Fusing point: 179 ℃ of variable colors, 250 ℃ of carbonizations.Ultimate analysis calculated value: C 22.59, H 2.37, and N 4.39%; Determination of elemental analysis value: C 22.65, H 2.45, and N 4.26%.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：288(5210)，397(4010)，462(540)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3215,3083,3050,1613,1585,1506,1477,1413,1213,1194,1074,1055,1011,429.
1h-NMR composes (DMSO-d
6) δ: 10.08ppm, 8.69ppm, 8.11ppm ,-0.92ppm ,-12.83ppm.
Embodiment 3[H (3-ClPy)] [trans-RuCl
4(DMSO) preparation (3-ClPy)] (compound 3, L=3-ClPy, 3-chloropyridine)
Preparation method is identical with embodiment 1.Productive rate: 71.37%.
Title complex physico-chemical property is described below: form: safran crystallite; Molecular formula: C
12h
15cl
6n
2oRuS; Molecular weight: 549.11; Ultimate analysis calculated value: C 26.25, H 2.75, and N 5.10%; Measured value: C 26.25, H 2.87, and N 4.71%.UV/Vis(25℃，H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：290(3480),396(4000),462(490)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3089,3050,2916,1516 (vs), 1465,1452,1421,1073,1022,430 (s).
1h-NMR composes (DMSO-d
6) δ: 8.76ppm, 8.62ppm, 8.11ppm, 7.60ppm ,-1.96ppm ,-12.85ppm.
Embodiment 4[H (3-IPy)] [trans-RuCl
4(DMSO) preparation (3-IPy)] (compound 4, L=3-IPy, 3-iodine pyridine)
Preparation method is identical with embodiment 1.Productive rate: 86.47%.
Title complex physico-chemical property is described below: form: safran crystallite.Molecular formula: C
l2h
15c
14i
2n
2oRuS.Molecular weight: 732.02.Fusing point: 180 ℃ of variable colors, 210 ℃ of carbonizations.Ultimate analysis calculated value: C 19.69, H 2.07, and N 3.83%; Determination of elemental analysis value: C 19.45, H 1.96, and N 3.30%.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：280(6340)，397(3620)，463(470)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3086,1614,1549,1510,1444,1413,1086,1043,1023,428.
1h-NMR composes (DMSO-d
6) δ: 11.98ppm, 9.06ppm, 8.77ppm, 8.59ppm, 7.58ppm ,-1.93ppm ,-12.86ppm.
Embodiment 5[H (4-IPy)] [trans-RuCl
4(DMSO) preparation (4-IPy)] (compound 5, L=4-IPy, 4-iodine pyridine)
Preparation method is identical with embodiment 1.Productive rate 30%.Molecular formula: C
l2h
15c
14i
2n
2oRuS.Molecular weight: 732.02.Fusing point: 170 ℃ of variable colors, 240 ℃ of carbonizations.Ultimate analysis calculated value: C 19.69, H 2.07, and N 3.83%; Determination of elemental analysis value: C 19.71, H 1.98, and N 3.38%.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：396(4450)，462(580)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3004,2917,1614 (vs), 1584 (vs), 1475 (vs), 1410 (vs), 1359,1316,1220,1196,1076,1056,1031,435.
1h-NMR composes (DMSO-d
6) δ: 13.17ppm, 8.56ppm, 8.43ppm ,-1.03ppm ,-12.85ppm.
Embodiment 6[H (3-CNPy)] [trans-RuCl
4(DMSO) preparation (3-CNPy)] (compound 6, L=3-CNPy, nicotinonitrile)
Preparation method is identical with embodiment 1.Productive rate: 72%.
Title complex physico-chemical property is described below: form: orange needle-like crystallite.Molecular formula: C
14h
15cl
4n
4oRuS.Molecular weight: 530.24.Fusing point: 205 ℃ of variable colors, 225 ℃ of carbonizations.Ultimate analysis calculated value: C 31.71, H 2.85, and N 10.57%; Determination of elemental analysis value: C 31.87, H 2.78, N10.38%.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：294(3130)，397(4170)，465(490)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3095,3062,2245,1633,1606,1550,1464,1414,1190,1068,1026,432.
1h-NMR composes (DMSO-d
6) δ: 13.78ppm, 9.06ppm, 8.87ppm, 8.40ppm, 7.71ppm ,-1.36ppm ,-12.97ppm.
Embodiment 7[H (4-CNPy)] [trans-RuCl
4(DMSO) preparation (4-CNPy)] (compound 7, L=4-CNPy, 4-cyanopyridine)
Preparation method is identical with embodiment 1.Productive rate: 71%.
Title complex physico-chemical property is described below: form: orange needle-like crystallite.Molecular formula: C
14h
15cl
4n
4oRuS.Molecular weight: 530.24.Fusing point: 185 ℃ (deepening), 260 ℃ of carbonizations.Ultimate analysis calculated value: H 2.85, C 31.71, and N 10.57; Determination of elemental analysis value: H 2.85, C 32.30, and N 10.33%.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：280(6890)，317(3280),396(4380),466(500)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3092,3048,2241,1607,1591,1488,1414,1222,1196,1067,1022,463,429.
1h-NMR composes (DMSO-d
6) δ: 8.86ppm, 7.93ppm ,-0.88ppm ,-12.55ppm.
Embodiment 8[H (3-AcPy)] [trans-RuCl
4(DMSO) preparation (3-AcPy)] (compound 8, L=3-AcPy, 3-acetylpyridine)
Preparation method is identical with embodiment 1.Productive rate: 70%.
Title complex physico-chemical property is described below: form: orange needle-like crystallite; Molecular formula: C
16h
21cl
4n
2o
3ruS; Molecular weight: 564.3; Fusing point: 173-175 ℃.Ultimate analysis calculated value: C 34.06, H 3.75, and N 4.96; Determination of elemental analysis value: C 34.29, H 3.50, and N 4.76.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：294(2890)，396(3980)，462(470)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3086,3062,2920,1700,1631,1600,1539,1273,1201,1090,1023,432.
1h-NMR composes (DMSO-d
6) δ: 12.86ppm, 9.28ppm, 8.97ppm, 8.66ppm, 7.91ppm, 2.71ppm, 0.88ppm ,-1.45ppm ,-12.69ppm.
Embodiment 9[H (4-AcPy)] [trans-RuCl
4(DMSO) preparation (4-AcPy)] (compound 9, L=4-AcPy, 4-acetylpyridine)
Preparation method is identical with embodiment 1.Productive rate: 73%.
Title complex physico-chemical property is described below: form: safran needle-like crystallite; Molecular formula: C
16h
21cl
4n
2o
3ruS; Molecular weight: 564.3; Fusing point: 175-180 ℃.Ultimate analysis calculated value: C 34.06, H 3.75, and N 4.96%; Determination of elemental analysis value: C 34.62, H 3.83, and N 4.70%.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：283(6660)，393(4460)，462(570)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3060,3019,2920,1705,1636,1600,1551,1500,1414,1364,1256,1077,1025,435.
1h-NMR composes (DMSO-d
6) δ: 8.96ppm, 8.08ppm, 2.68ppm, 0.49ppm ,-1.30ppm ,-12.70ppm.
Embodiment 10[H (iso-nicotinamide)] [trans-RuCl
4(DMSO) preparation (iso-nicotinamide)] (compound 10, L=iso-nicotinamide, Isonicotinamide)
Preparation method is identical with embodiment 1.Productive rate: 87%.
Title complex physico-chemical property is described below: form: orange crystallite.Molecular formula: C
14h
19cl
4n
4o
3ruS.Molecular weight: 566.28.Fusing point: 231-237 ℃ (carbonization decomposition).Ultimate analysis calculated value: C 29.69, H 3.38, and N 9.89%; Determination of elemental analysis value: C 29.88, H 3.35, and N 9.48%.UV/Vis(25℃,H
2O)，λmax，nm(ε,L·mol
-1·cm
-1)：300(3820)，395(4090)，462(520)。Diffuse reflectance infrared spectroscopy peak (cm
-1): 3400,3147,1711,1399,1119,1024,427.
Embodiment 11[H (3,5-Cl
2py)] [trans-RuCl
4(DMSO) (3,5-Cl
2py)] (compound 11, L=3,5-Cl
2py, 3,5-dichloropyridine)
Preparation method is identical with embodiment 1.Yield: 85.39%.
Title complex physico-chemical property is described below: form: safran crystallite; Molecular formula: C
12h
13cl
8n
2oRuS; Molecular weight: 618; Fusing point: 180-205 ℃ (carbonization decomposition); Ultimate analysis calculated value: C 23.32, H 2.12, and N 4.53; Measured value: C 23.17, H 2.12, and N 4.54%.UV/Vis(25℃,H
2O)λmax，nm(ε,L·mol
-1·cm
-1)：400(4060),467(480)。
Embodiment 12 pharmacological evaluation
Pharmacological evaluation: mouse species is C57BL/6, female, hero half and half, body weight 19 ± 2g.Mouse is at isolation animal indoor feeding.Fluorescent lamp lighting, 12 hours light and shades alternately.22 ± 2 ℃ of temperature, relative humidity 40-60%, 6-10 time/h blows.The subcutaneous aseptic inoculation Mice Bearing Lewis Lung Cancer of the right armpit of mouse tumor cell suspension 0.2ml/ only, is divided at random 5 groups by the weight of animals after inoculation 24h, and establishes physiological saline control group and NAMI-A positive controls.NAMI-A group is all established 25mgkg with 1 group of compound
-1and 35mgkg
-1two dosage groups.Model group is 10 mouse, and all the other each groups are 9 mouse.Quantitatively take each tested medicine (keeping in Dark Place in moisture eliminator), before use with physiological saline through sonic oscillation be dissolved to clear and bright liquid by aseptic filter membrane degerming after for abdominal injection.Each treated animal all, in postvaccinal the 9th day, starts administration after the inoculation position of knurl strain touches knurl body, and administration volume is 20mlkg
-1body weight.Administration every day 1 time, successive administration is administration 3 times again the next day after 6 days, and administration is 9 times altogether.The isopyknic physiological saline of model group abdominal injection.Each is organized mouse and within the 21st day, weighs, puts to death after inoculation, peels off knurl body and lungs and weighs respectively.Then lungs are put in Bouin ' s liquid and fixed and within 10 days, directly observe afterwards, add up animal number of elements and the lung cancer metastasis kitchen range quantity of respectively organizing mouse lungs surface generation lung cancer metastasis.Calculate and respectively organize the inhibiting rate (administration group Pulmonary metastasis focuses quantity/model group Pulmonary metastasis focuses quantity * 100%) that the tumor suppression percentage of primary tumo(u)r and the lungs index of each treated animal (lung weight in wet base/body weight) and lung shift.Tumor-inhibiting action calculates average knurl heavy (X ± SD) and the heavy inhibiting rate of knurl of each treated animal as follows.
The heavy inhibiting rate (%)=(1-T/C) * 100% of knurl
The heavy C=model control group of T=administration group knurl knurl weight
Each is organized knurl weight, lung cancer metastasis kitchen range quantity and lungs index and all with mean ± standard deviation, represents, each dosage group of administration compares with model control group respectively, with t-check, carry out statistical study, the tumour inhibiting rate of each administration group and lung metastasis inhibition rate all represent with percentage.
The tumour inhibiting rate of 2.3NAMI-A derivative
The tumour inhibiting rate experimental result of the new compound of NAMI-A and preparation is listed in table 1.In table 1, the tumour inhibiting rate of NAMI-A two dosage groups is respectively 11%, 36%.The tumour inhibiting rate of the new compound that other is prepared, in 11%-40% left and right, is more or less the same with the tumour inhibiting rate of NAMI-A.The tumour inhibiting rate of NAMI-A derivative is not high, and its Main Function is anti metastasis.
Table 1NAMI-A and derivative [H (L)] [trans-RuCl thereof
4(DMSO) (the L)] tumor-inhibiting action to Lewis lung cancer mouse
Note: with model group comparison, * P<0.05, * * P<0.01
The anti-metastasis rate of 2.4NAMI-A derivative
The anti-metastasis rate experimental result of the new compound of NAMI-A and preparation is listed in table 2.
Table 2NAMI-A and derivative [H (L)] [trans-RuCl thereof
4(DMSO) (L)] the anti-metastasis effect to Lewis lung cancer mouse
Note: with model group comparison, * P<0.05, * * P<0.01
Mouse after the strain of inoculation Lewis lung cancer knurl 21 days, there is lung and shift in model group 100% mouse, and metastasis is point-like.The large and small dosage group of NAMI-A and compound 1 all has the transferance of significant anti-lung, the results detailed in Table 2.In table 2, the anti-metastasis rate of NAMI-A various dose is respectively 81%, 86%.The anti-metastasis rate of the new compound various dose of preparation is 45% to 85%.The high resistance rate of transform of the single dose of the new compound of each preparation is all more than 70%.Be noted that NAMI-A to the anti-metastasis rate of mammary cancer mouse (nude mice) apparently higher than Lewis lung cancer mouse.And because the toxicity of this compounds is low, without bone marrow depression side effect.Develop into having good prospects of new antitumor drug.
The tumour inhibiting rate experimental result of another group new compound of NAMI-A and each preparation is listed in table 3.In table 3, the tumour inhibiting rate of NAMI-A two dosage groups is respectively 28%, 57%.The tumour inhibiting rate of the new compound 1 of preparation, in 20%-31% left and right, is more or less the same with the tumour inhibiting rate of NAMI-A.The tumour inhibiting rate of NAMI-A derivative is not high, and its Main Function is anti metastasis.
Table 3NAMI-A and derivative [H (L)] [trans-RuCl thereof
4(DMSO) (the L)] tumor-inhibiting action to Lewis lung cancer mouse
Note: with model group comparison, * P<0.05, * * P<0.01
In table 4, the anti-metastasis rate of NAMI-A various dose is respectively 64%, 73%.The anti-metastasis rate of the new compound various dose of preparation is 28% to 75%.The anti-metastasis rate of the single dose of 2 new compounds of preparation is all more than 60%.
Table 4NAMI-A and derivative [H (L)] [trans-RuCl thereof
4(DMSO) (L)] the anti-metastasis effect to Lewis lung cancer mouse
Note: with model group comparison, * P<0.05, * * P<0.01
In table 4, remove the 35mgkg of NAMI-A
-1dosage group has outside a dead mouse, and all the other each dosage groups are even without dead.The toxicity of new compound that shows NAMI-A and preparation is all lower.The hypotoxicity of NAMI-A derivative is due to a little less than it compares with cis-platinum with the binding ability of target molecule albumen, and this is in conjunction with reversible.The first phase clinical pharmacology experimental result of NAMI-A shows, its main side effects is that bleb (blister) appears in a few patients arm, after drug withdrawal, can recover.Different from clinical conventional anticarcinogen, hypotoxicity is the major advantage of NAMI-A and derivative thereof.
The above embodiment has only 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 (10)
1. a ruthenium complexe with following general formula (I),
Wherein,
R
1, R
2independently be selected from separately:
1) C1-C8 alkyl,
2) the C1-C8 alkyl that 1,2 or 3 H are replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different,
3) C5-C7 aromatic nucleus,
4) the C5-C7 aromatic nucleus that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different;
L is selected from:
1) nitrogenous C1-C8 alkyl,
2) the nitrogenous C1-C8 alkyl that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different,
3) nitrogenous 6 yuan of aromatic nucleus,
4) nitrogenous 6 yuan of aromatic nucleus that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different,
5) nitrogenous 5 yuan of aromatic nucleus,
6) nitrogenous 5 yuan of aromatic nucleus that 1,2 or 3 H can be replaced by halogen, cyano group, sulfydryl, hydroxyl, carboxyl, sulfonic group, methoxyl group, acyl group, amido, amino (primary, secondary, uncle), above-mentioned 2 or 3 substituting groups can be the same or different.
2. ruthenium complexe according to claim 1, is characterized in that, R
1for C1-C8 alkyl, R
2for C5-C7 aromatic nucleus.
3. ruthenium complexe according to claim 1, is characterized in that, L is pyridine, pyrazine or pyridazine.
4. ruthenium complexe according to claim 1, is characterized in that, L is imidazoles or pyrazoles.
5. the preparation method of ruthenium complexe described in claim 1-4, is characterized in that, comprises the following steps:
1) by start material trans-[RuCl
4(SOR
1r
2)
2] [(SOR
1r
2)
2h] grind to form fine powder;
2) by initiator and part stirring in reaction solvent, sonic oscillation or the backflow with the arbitrary described L structure of claim 1-4, stirring, vibration or return time are 10min-20h; The mol ratio of initiator and part is 1:2-1:8; Temperature of reaction 25-80 ° of C;
3) sedimentation and filtration forming after sonic oscillation, with acetone and ether washing, silica gel drier dried overnight, obtains described ruthenium complexe and derivative thereof respectively.
6. preparation method according to claim 5, described reaction solvent is one or more in methyl alcohol, ethanol, acetone, chloroform.
7. the application of the ruthenium complexe described in claim 1-4 in the medicine of preparation treatment tumour or metastases, or the application in the medicine of preparation prevention and curing oncoma transfer.
8. application according to claim 7, is characterized in that, described tumour is mammary cancer, lung cancer, intestinal cancer, liver cancer, gastrointestinal cancer, ovarian cancer, carcinoma of the pancreas, laryngocarcinoma, nasopharyngeal carcinoma, carcinoma of testis or leukemia.
9. treat a medicinal compositions for tumour or metastases, include ruthenium complexe and pharmaceutically acceptable carrier described in claim 1-4 any one.
10. medicinal compositions according to claim 9, is characterized in that, also includes other anticarcinogen or antioxidant halfcystine, xitix and protein formulation as injection albumin.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744518A (en) * | 2015-02-11 | 2015-07-01 | 中国中医科学院中药研究所 | Metallic ruthenium complex as well as preparation method and application thereof |
| CN109126899A (en) * | 2018-09-26 | 2019-01-04 | 上海克琴科技有限公司 | A method of increasing ruthenium metal olefin metathesis catalyst stability in the solution |
| CN113150033A (en) * | 2021-02-10 | 2021-07-23 | 中国中医科学院中药研究所 | Artemisinin ruthenium metal complex and preparation method and medical application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990013553A1 (en) * | 1989-05-05 | 1990-11-15 | Boehringer Mannheim Italia S.P.A. | Ruthenium(iii) complexes as antineoplastic agents |
| US6221905B1 (en) * | 1996-07-02 | 2001-04-24 | Sigea S.R.L. | Salts of anionic complexes of RU(III), as antimetastatic and antineoplastic agents |
| US6921824B1 (en) * | 1999-04-19 | 2005-07-26 | Sigea S.R.L. | Ruthenium dimeric complexes suitable as antimetastatic and antineoplastic agents |
-
2012
- 2012-08-31 CN CN201210319799.1A patent/CN103665046A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990013553A1 (en) * | 1989-05-05 | 1990-11-15 | Boehringer Mannheim Italia S.P.A. | Ruthenium(iii) complexes as antineoplastic agents |
| US6221905B1 (en) * | 1996-07-02 | 2001-04-24 | Sigea S.R.L. | Salts of anionic complexes of RU(III), as antimetastatic and antineoplastic agents |
| US6921824B1 (en) * | 1999-04-19 | 2005-07-26 | Sigea S.R.L. | Ruthenium dimeric complexes suitable as antimetastatic and antineoplastic agents |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744518A (en) * | 2015-02-11 | 2015-07-01 | 中国中医科学院中药研究所 | Metallic ruthenium complex as well as preparation method and application thereof |
| CN104744518B (en) * | 2015-02-11 | 2018-08-07 | 中国中医科学院中药研究所 | Ruthenium complex and its preparation method and application |
| CN109126899A (en) * | 2018-09-26 | 2019-01-04 | 上海克琴科技有限公司 | A method of increasing ruthenium metal olefin metathesis catalyst stability in the solution |
| CN113150033A (en) * | 2021-02-10 | 2021-07-23 | 中国中医科学院中药研究所 | Artemisinin ruthenium metal complex and preparation method and medical application thereof |
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