CN106361753A - Allopurinol derivative and application thereof to preparing anti-tumor medicine - Google Patents

Allopurinol derivative and application thereof to preparing anti-tumor medicine Download PDF

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Publication number
CN106361753A
CN106361753A CN201610996656.2A CN201610996656A CN106361753A CN 106361753 A CN106361753 A CN 106361753A CN 201610996656 A CN201610996656 A CN 201610996656A CN 106361753 A CN106361753 A CN 106361753A
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formula
group
tumor
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medicine
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曹艳
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Abstract

The invention discloses an allopurinol derivative in the formula (II) and application of the allopurinol derivative to preparing anti-tumor medicine, and particularly relates to application of the allopurinol derivative in the formula (II) to liver cancer, lung cancer, glioma, gastric cancer, ovarian cancer, breast cancer and leukemia.

Description

A kind of allopurinol derivatives and its purposes in preparing antitumor drug
Technical field
The present invention relates to a kind of allopurinol derivatives formula () and its purposes in preparing antitumor drug, more particularly, to A kind of allopurinol derivatives formula () answering in hepatocarcinoma, pulmonary carcinoma, glioma, gastric cancer, ovarian cancer, breast carcinoma, leukemia With.
Background technology
Cancer be the great subject under discussion of life science, malignant tumor seriously threaten the mankind life quality become the mankind be good for First killer of health.The mankind, always in the research constantly carrying out antitumor drug, find new and effective, low toxicity anti-for many years The focus of tumour medicine always medicine research and development both at home and abroad.Countries in the world are all paid much attention to the screening of antitumor drug, put into Substantial amounts of human and material resources, financial resources, (chemosynthesis, natural product and fermentable produce substantial amounts of compound every year Thing) through screening anti-tumor medicine.Micromolecular compound has critical role in tumor research and development.There is substantial amounts of little point every year Sub- chemical entities are devised and carry out the different screening active ingredients adapting to disease drug, but due to designing the initial of compound Purpose and the difference of designer's research interest, the exploitation of a lot of compounds is not comprehensive, and much outstanding pharmacological effect function is not Can be developed, on the other hand, because newly-designed compound is typically all protected in the form of compound patent, more extensively There is patent barrier for non-patentee in the purposes exploitation of general ground, commercial value is low.
Application No. 200980139583.3, invention entitled pyrazolo [3,4] pyrimidine-4-yl derivant and its treatment sugar The compounds of this invention structural formula is disclosed in the patent of purposes of urine disease and obesity
Also disclose structural identification data and its purposes in terms of diabetes and obesity of compound.
Content of the invention
It is an object of the invention to provide a kind of allopurinol derivatives formula () and its use in preparing antitumor drug On the way, more particularly, to a kind of allopurinol derivatives formula () are in hepatocarcinoma, pulmonary carcinoma, glioma, gastric cancer, ovarian cancer, breast carcinoma, white Application in disorders of blood.Allopurinol derivatives formula ()
()
Compound, its salt or its solvated compounds representing.
Further, purposes in preparing antitumor drug for the formula ().
Further, described tumor is malignant tumor, and described malignant tumor is solid tumor or non-physical knurl.
Preferably, described solid tumor is hepatocarcinoma, pulmonary carcinoma, glioma, gastric cancer, ovarian cancer, breast carcinoma, described non-physical Tumor is leukemia.
Further, purposes in preparing tumor complicated thrombocytopenia medicine for the formula ().
Further, purposes in the spleen enlargement medicine that preparation treatment bel-7402 cell causes for the formula ().
Further, formula () and Capecitabine use in conjunction.
The present invention not administration to allopurinol derivatives formula () or the compositionss comprising allopurinol derivatives formula () Mode is particularly limited, and representational method of application includes (but being not limited to): oral, parenteral (intravenouss, intramuscular or Subcutaneous) and local administration.Solid dosage formss for oral administration include capsule, tablet, pill, powder and granule.At this In a little solid dosage formss, allopurinol derivatives formula () are mixed with least one conventional inert excipients (or carrier), such as citric acid Sodium or dicalcium phosphate, or mix with following compositions: (a) filler or bulking agent, such as starch, Lactose, sucrose, glucose, manna Alcohol and silicic acid；(b) binding agent, such as hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and Arab Glue；(c) wetting agent, such as glycerol；(d) disintegrating agent, such as agar, Calcium Carbonate, potato starch or tapioca, alginic acid, certain A little composition silicate, sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, such as quaternary ammonium compound；(g) moistening Agent, such as spermol and glyceryl monostearate；(h) adsorbent, such as Kaolin；(i) lubricant, such as Talcum, stearic acid Calcium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate.In capsule, tablet and pill, dosage form also can comprise to buffer Agent.
Wherein, gastrointestinal administration preparation is presently the most common administration form, and convenient experimental operation, therefore, this Carry out the test of pesticide effectiveness of allopurinol derivatives formula () using gastric infusion in bright specific embodiment, it is not intended that, not Fast 01 derivatives formula () antineoplastic administration form is only limitted to gastrointestinal administration, and those skilled in the art can be according to allopurinol The physicochemical properties of derivant formula (), in conjunction with being actually needed of Modern preparations technology and sufferer, be prepared into injection, The several formulations such as scalp absorbable preparation, implantation preparation, thus expanding its route of administration, and improve target-oriented drug or are prevented effectively from Unnecessary toxic and side effects.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture. Except active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent adopting in this area, such as water or other solvent, increases Solvent and emulsifying agent, example knows ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethylformamide And oil, the particularly mixture of Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or these materials Deng.
In addition to these inert diluents, compositionss also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste Agent, correctivess and spice.
Except active ingredient beyond the region of objective existence, suspension can comprise suspending agent, such as ethoxylation isooctadecane alcohol, polyoxyethylene mountain Mixture of pears alcohol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection compositionss can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or emulsion, and for being again dissolved into the sterilized powder of aseptic Injectable solution or dispersion liquid.Suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyhydric alcohol and its suitable mixture.
Dosage form for the compounds of this invention of local administration includes ointment, powder, patch, propellant and inhalant. Active component aseptically with physiologically acceptable carrier and any preservative, buffer agent, or if necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable other drugs administering drug combinations.
Obviously, the above according to the present invention, according to ordinary technical knowledge and the means of this area, without departing from this Under the premise of bright above-mentioned basic fundamental thought, modification, replacement or the change of other various ways can also be made.
Specific embodiment
Allopurinol derivatives formula () Structural Identification result and Chinese patent (Shen used in the specific embodiment of the invention Please number be 200980139583.3) open consistent.Hplc measures purity more than 95%.
Embodiment 1:mtt(tetrazolium bromide) inhibitory action to different tumor cells for method mensure allopurinol derivatives formula ().
First, cell strain
Human lung carcinoma cell a549, human liver cancer cell smmc-7721, human liver cancer cell bel-7402, neuroglia cell of human tumor is thin Born of the same parents u251, human large cell lung cancer cell nci-h460, human gastric adenocarcinoma bgc-823, human gastric adenocarcinoma sgc-7901, people's ovum Nest adenocarcinoma cell sk-ov-3, human breast cancer cell mcf-7, people chronic myelogenous leukemia cell k562.
2nd, main solution is prepared:
1.pbs buffer:
nacl 8g、kcl 0.2g、na2hpo41.44g、kh2po40.24g, adjusts ph 7.4, constant volume 1l.
2. trypsin solution:
0.25% trypsin+0.02%edta, uses pbs buffer, and 0.22 μm of membrane filtration is degerming, and 4 DEG C standby.
3.rpmi 1640 cell culture fluid:
(1) 10.4g/ bag rpmi 1640 culture powder molten to tri-distilled water, magnetic agitation 20min；
(2) add 2g nahco3, continue stirring 10min；
(3) add penicillin solution (2 × 105U/ml) 0.5ml, Streptomycin Solution (2 × 105U/ml) 0.5ml；
(4) add 100ml inactivated fetal bovine serum；
(5) add 1mol/l hcl, adjust ph to 7.2, constant volume 1l；
(6) filtration sterilization.
4. test medicine gradient solution:
(1) allopurinol derivatives formula () gradient solution: (final dmso after allopurinol derivatives formula () are dissolved with a small amount of dmso Content is within 0.1%), it is configured to 100 μ g/ml with rpmi 1640 cell culture fluid, half-and-half dilution is configured to 8 concentration ladders Degree, it may be assumed that 128,64,32,16,8,4,2,1 μ g/ml, uses front preparation.
(2) cisplatin gradient solution: Cisplatin Injection is configured to 100 μ g/ml with rpmi 1640 cell culture fluid is half-and-half dilute Release and be configured to 8 Concentraton gradient, be i.e. 128,64,32,16,8,4,2,1 μ g/ml, use front preparation.
3rd, experiment packet:
Medicine group (referring to experimental procedure part) to be measured
Positive control medicine group (compared with drug test group, adds the medicine to be measured of Concentraton gradient to be changed to add Concentraton gradient Cisplatin)
Matched group (compared with drug test group, adds the medicine to be measured of Concentraton gradient to be changed to add the rpmi 1640 of not drug containing Cell culture fluid)
Blank group (compared with matched group, is not added with cell)
4th, experimental procedure:
1. take the logarithm the cell of trophophase, trypsinization, rpmi 1640 cell culture fluid adjust concentration of cell suspension be 6 × 104Individual/ml.In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 DEG C, 5% co224h is cultivated, cell pastes in incubator Wall.
2. remove rpmi 1640 cell culture fluid, add rpmi 1640 cell culture fluid of the medicine to be measured of Concentraton gradient 100 μ l, each concentration sets 6 parallel holes.96 orifice plates after dosing are placed in 37 DEG C, 5% co2Cultivate 48h in incubator, be inverted The action effect of basis of microscopic observation medicine.
Discard culture fluid after 3.96 orifice plate centrifugations, carefully rushed after 2 ~ 3 times with pbs, add the rpmi containing 0.5% mtt 1640 cell culture fluid 100 μ l, continues culture 4h.
4. remove supernatant, every hole adds 150 μ l dimethyl sulfoxide, puts low-speed oscillation 10min on shaking table, so that formazan is tied Brilliant fully dissolving.
5. measure the optical density (od value) in each hole at enzyme-linked immunosorbent assay instrument 490nm.
6. parallel hole od value is represented with mean ± sd, calculates suppression ratio formula: [(odMatched group-odBlank group)-(odDrug study group- odBlank group)]/(odMatched group-odBlank group)*100%.
7. adopt graphpad prism 5 data processing software, by drawing amount effect curve calculation of half inhibitory concentration (ic50).
5th, experimental result
Allopurinol derivatives formula () all have good In-vitro Inhibitory Effect, ic to 10 kinds of human tumor cell lines50(see Table 1) is equal Within 15 μ g/ml.Compared with positive drug cisplatin, a549, u251, sgc-7901, sk-ov-3, mcf-7, k562 are suppressed Particularly sensitive, cisplatin is weaker than to smmc-7721, bel-7402, nci-h460 and bgc-823 inhibition.Mtt method equally measures Allopurinol derivatives formula () pyridine replaces with the compound of phenyl ring to a549, k562, u251, bel-7402, nci-h460 Inhibitory action, result display sensitivity is far below allopurinol derivatives formula ().
Table 1 formula () and cisplatin are to 10 kinds of human tumor cells ic50Value
Embodiment 2:bel-7402 transplanted human hepatocellular carcinoma mouse model is studied
First, set up human liver cancer nude mouse xenotransplant cancer model
Spf level balb/c nude mice, male, 4 week old, people's bel-7402 hepatoma carcinoma cell nude mice model of learning from else's experience becomes tumor, then passes through nude mice Generation 2 tumor mass more than generation, are cut into about 2*2*2mm, are inoculated in nude mice armpit using the trocar subcutaneous, set up human liver cancer nude mice allosome Transplanting cancer model.
2nd, dosage regimen
With length and the width of each animal tumor of vernier caliper measurement, by formula: v=1/2*ab2Calculate tumor volume, treat tumor volume length extremely About 100mm3Start to be administered, all animals are randomly divided into model group, positive drug Capecitabine group (400mg/kg), formula by tumor volume () height (100mg/kg), in (50mg/kg), low (25mg/kg) dosage group, drug combination group (Capecitabine 100mg/kg and Formula () 25mg/kg), every group 8, each group gastric infusion, dosage is l0ml/kg, 1 time/d, successive administration 14d.
3rd, Testing index and data analysiss
1. general indicator
Observe animal behavior, reaction, diet and death condition after being administered, weigh the weight of animals.All groups 1 day before administration (d0) before taking blood within the and 16th day, (d16) weighs in.
2. peripheral blood cells detection
Pluck eyeball and take blood within 16th day, take 0.2ml in 0.5mlep pipe (first plus 20 μ l edta-2k), turn upside down mixed hook, blood cell Instrument meter calculates peripheral blood cells situation, including leukocyte (wbc), erythrocyte (rbc), platelet (plt) number.
3. organ coefficient
Pluck and take liver, kidney, spleen to weigh after eyeball takes blood, calculate organ coefficient as follows.Organ coefficient (%)=internal organs Weight/body weight * 100%.Body weight refers to the 16th day take body weight before blood.
4. knurl weight and tumour inhibiting rate
Pluck after eyeball takes blood, strip tumor mass, analytical balance claims knurl weight, calculate tumour inhibiting rate as follows.
The average knurl weight of the average knurl weight-administration group of tumour inhibiting rate %=(model group) average knurl weight * of/model group 100%.
5. data analysiss
Data analysiss are carried out to testing result using graphpad prism 5 data processing software.
4th, testing result
1. general indicator
After all group administrations, death in mice, and mice behavior, reaction, diet aspect also do not find obvious exception.Each group Significant difference (p > 0.05) in other and model group comparing bulk weight average.Different group bel-7402 transplanted human hepatocellular carcinoma Mice Bodies Weight situation is shown in Table 2.
The different group bel-7402 transplanted human hepatocellular carcinoma Mouse Weight situation of table 2 (N=8)
Note: * is compared p < 0.05 * * and is compared p < 0.01 with model group with model group
2. peripheral blood cells detection
Compare with model group, there was no significant difference for other each groups wbc and rbc counting, and formula () high dose group plt counts notable Higher than model group.The high, medium and low dosage group of formula () and drug combination group do not affect wbc and rbc, formula () high dose group The rising of plt quantity can be caused.Because model group plt quantity is substantially less than normal value, so the liter of plt quantity is a height of beneficial Effect.Bel-7402 transplanted human hepatocellular carcinoma mouse peripheral blood situation is shown in Table 3.
The different group bel-7402 transplanted human hepatocellular carcinoma mouse peripheral blood situation of table 3 (N=8)
Note: * is compared p < 0.05 * * and is compared p < 0.01 * * * with model group and compared p < 0.001 with model group with model group
3. organ coefficient
Compare with model group, there was no significant difference for other each group liver coefficients and Kidney coefficients, formula () high dose group and connection Share medicine group Spleen coefficient and be substantially less than model group.The high, medium and low dosage group of formula () and drug combination group do not affect liver Coefficient and Kidney coefficients, formula () high dose group and drug combination group can cause Spleen coefficient to reduce.Different groups bel- 7402 transplanted human hepatocellular carcinoma mice organs coefficients are shown in Table 4.
The different group bel-7402 transplanted human hepatocellular carcinoma mice organs coefficient of table 4 (N=8)
Group Liver coefficient Kidney coefficients Spleen coefficient
Model group 5.92±0.72 1.61±0.21 0.77±0.10
Capecitabine group 6.03±0.28 1.53±0.17 0.72±0.21
Formula () high dose group 5.75±0.35 1.56±0.14 0.46±0.10***
Formula () middle dose group 5.82±0.49 1.60±0.20 0.59±0.10
Formula () low dose group 5.68±0.61 1.63±0.20 0.67±0.16
Drug combination group 6.02±0.39 1.63±0.13 0.44±0.10***
Note: * is compared p < 0.05 * * and is compared p < 0.01 with model group with model group
4. knurl weight and tumour inhibiting rate
Compare with model group, in addition to formula () low dose group, the equal significance of other each group knurl weights reduces, and illustrate that tumor killing effect is aobvious Write.Formula () high dose group tumour inhibiting rate is slightly above Capecitabine group, and formula () middle dose group and drug combination group tumour inhibiting rate are lower slightly In Capecitabine group, but no difference of science of statistics.Different group bel-7402 transplanted human hepatocellular carcinoma mice knurl weights and tumour inhibiting rate are shown in Table 5.
The different group bel-7402 transplanted human hepatocellular carcinoma mice knurl weight of table 5 and tumour inhibiting rate (N=8)
Group Knurl weight (g) Tumour inhibiting rate (%)
Model group 1.25±0.21 -
Capecitabine group 0.70±0.22*** 44.0%
Formula () high dose group 0.68±0.16*** 45.6%
Formula () middle dose group 0.77±0.36** 38.4%
Formula () low dose group 1.11±0.23 11.2%
Drug combination group 0.72±0.24** 42.4%
Note: * is compared p < 0.05 * * and is compared p < 0.01 * * * with model group and compared p < 0.001 with model group with model group
Show according to the study, nude mice model tumor model has obvious dependency with the medication effect of clinical treatment, can be relatively The clinical efficacy of good forecast medicine.Thus it can be deduced that formula () can be applied as antitumor drug.Drug combination group is adopted Applied as antitumor drug with the formula () and Capecitabine each testing result formula () joint Capecitabine of low dosage Have under more excellent curative effect or equivalent therapeutic effect and can reduce Capecitabine consumption.Additionally, formula () high dose group is significantly raised Platelet counts explanation can be applicable to prepare in tumor complicated thrombocytopenia medicine.

Claims (7)

1. a kind of allopurinol derivatives formula ()
()
Compound, its salt or its solvated compounds representing.
2. purposes in preparing antitumor drug for the formula () as claimed in claim 1.
3. purposes as claimed in claim 2, is characterized in that, described tumor is malignant tumor, and described malignant tumor is solid tumor Or non-physical knurl.
4. purposes as claimed in claim 3, is characterized in that, described solid tumor is hepatocarcinoma, pulmonary carcinoma, glioma, gastric cancer, ovum Nest cancer, breast carcinoma, described non-physical knurl is leukemia.
5. purposes in preparing tumor complicated thrombocytopenia medicine for the formula () as claimed in claim 1.
6. use in the spleen enlargement medicine that preparation treatment bel-7402 cell causes for the formula () as claimed in claim 1 On the way.
7. the purposes as described in claim 2,5 or 6, is characterized in that, described formula () and Capecitabine use in conjunction.
CN201610996656.2A 2016-11-13 2016-11-13 Allopurinol derivative and application thereof to preparing anti-tumor medicine Pending CN106361753A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047288A1 (en) * 2003-11-10 2005-05-26 Arrow Therapeutics Limited Pyrazolopyrimidines as anti - hepatits c agents
WO2007024294A2 (en) * 2005-05-03 2007-03-01 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
CN102171213A (en) * 2008-08-04 2011-08-31 阿斯利康(瑞典)有限公司 Pyrazolo [3, 4] pyrimidin-4-yl derivatives and their uses to treat diabetes and obesity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047288A1 (en) * 2003-11-10 2005-05-26 Arrow Therapeutics Limited Pyrazolopyrimidines as anti - hepatits c agents
WO2007024294A2 (en) * 2005-05-03 2007-03-01 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
CN102171213A (en) * 2008-08-04 2011-08-31 阿斯利康(瑞典)有限公司 Pyrazolo [3, 4] pyrimidin-4-yl derivatives and their uses to treat diabetes and obesity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YONG LI等: "Discovery of Novel Allopurinol Derivatives with Anticancer Activity and Attenuated Xanthine Oxidase Inhibition", 《MOLECULES》 *

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Application publication date: 20170201