CN106749265A - A kind of allopurinol derivatives and its purposes in antineoplastic is prepared - Google Patents
A kind of allopurinol derivatives and its purposes in antineoplastic is prepared Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- 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
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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
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- 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
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Abstract
The invention discloses a kind of allopurinol derivatives formula（Ⅳ）And its purposes in antineoplastic is prepared, more particularly to a kind of allopurinol derivatives formula（Ⅳ）Application in liver cancer, lung cancer, glioma, stomach cancer, oophoroma, breast cancer, leukaemia.
Description
Technical field
The present invention relates to a kind of allopurinol derivatives formula（Ⅳ）And its purposes in antineoplastic is prepared, more particularly to
A kind of allopurinol derivatives formula（Ⅳ）Answering in liver cancer, lung cancer, glioma, stomach cancer, oophoroma, breast cancer, leukaemia
With.
Background technology
Cancer is the great subject under discussion of life science, and the life quality that malignant tumour seriously threatens the mankind is strong as the mankind
First killer of health.The mankind are constantly carrying out the research of antineoplastic always for many years, find new and effective, low toxicity anti-
Tumour medicine is always the focus of medicine research and development both at home and abroad.Screening of the countries in the world to antineoplastic is all paid much attention to, input
Substantial amounts of human and material resources, financial resources, there is a substantial amounts of compound every year（Chemical synthesis, natural products and microbial fermentation are produced
Thing）By screening anti-tumor medicine.Micromolecular compound has critical role in tumour research and development.There is substantial amounts of small point every year
Sub- chemical entities are devised and carry out the screening active ingredients of different adaptation disease drugs, but due to designing the initial of compound
The difference of purpose and designer's research interest, the exploitation of many compounds is not comprehensive, and many outstanding pharmacological effect functions are 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 in the purposes exploitation of general ground, commercial value is low for non-patentee.
Application No. 200980139583.3, entitled pyrazolo [3,4] pyrimidine-4-yl derivative and its treatment sugar
The compounds of this invention structural formula is disclosed in the patent of the purposes of urine disease and obesity
Also disclose the structural identification data and its purposes in terms of diabetes and obesity of compound.
The content of the invention
It is an object of the invention to provide a kind of allopurinol derivatives formula（Ⅳ）And its use in antineoplastic is prepared
On the way, more particularly to a kind of allopurinol derivatives formula（Ⅳ）In liver cancer, lung cancer, glioma, stomach cancer, oophoroma, breast cancer, white
Application in blood disease.Allopurinol derivatives formula（Ⅳ）
（Ⅳ）
The compound of expression, its salt or its solvated compounds.
Further, formula（Ⅳ）Purposes in antineoplastic is prepared.
Further, the tumour is malignant tumour, and the malignant tumour is solid tumor or non-physical knurl.
Preferably, the solid tumor is liver cancer, lung cancer, glioma, stomach cancer, oophoroma, breast cancer, the non-physical
Knurl is leukaemia.
Further, formula（Ⅳ）Purposes in tumor complicated decrease of platelet medicine is prepared.
Further, formula（Ⅳ）Purposes in the spleen enlargement medicine that treatment Bel-7402 cells cause is prepared.
Further, formula（Ⅳ）With capecitabine use in conjunction.
The present invention is not to allopurinol derivatives formula（Ⅳ）Or comprising allopurinol derivatives formula（Ⅳ）Composition administration
Mode is particularly limited, and representational method of application includes（But it is not limited to）：Orally, parenteral（Intravenous, intramuscular or
It is subcutaneous）And local administration.Solid dosage forms for being administered orally includes capsule, tablet, pill, powder and granule.At this
In a little solid dosage forms, allopurinol derivatives formula（Ⅳ）With at least one conventional inert excipients（Or carrier）Mixing, such as citric acid
Sodium or Dicalcium Phosphate, or mix with following compositions：（a）Filler or bulking agent, such as starch, lactose, sucrose, glucose, sweet dew
Alcohol and silicic acid；（b）Adhesive, such as hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arab
Glue；（c）NMF, such as glycerine；（d）Disintegrant, such as agar, calcium carbonate, farina 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）Wetting
Agent, such as cetanol and glycerin monostearate；（h）Adsorbent, such as kaolin；（i）Lubricant, such as talcum, stearic acid
Calcium, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate.In capsule, tablet and pill, formulation also can be comprising buffering
Agent.
Wherein, gastrointestinal administration preparation is presently the most common administration form, and convenient experimental operation, therefore, this hair
Allopurinol derivatives formula is carried out using gastric infusion in bright specific embodiment（Ⅳ）The test of pesticide effectiveness, it is not intended that, not
Fast 01 derivatives formula（Ⅳ）Antineoplastic administration form is only limitted to gastrointestinal administration, and those skilled in the art can be according to Allopurinol
Derivative formula（Ⅳ）Physicochemical properties, with reference to being actually needed for Modern preparations technology and sufferer, be prepared into injection,
The several formulations such as scalp absorbable preparation, implantation preparation, so as to expand its method of administration, and improve target-oriented drug or are prevented effectively from
Unnecessary toxic and side effect.
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 include the inert diluent routinely used in this area, such as water or other solvents, increase
Solvent and emulsifying agent, example know ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3-BDO, dimethylformamide
And oil, the particularly mixture of cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these materials
Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste
Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, such as ethoxylation isooctadecane alcohol, polyoxyethylene
Mixture of sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection composition can comprising physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or emulsion, and for being dissolved into the aseptic powdery of aseptic Injectable solution or dispersion liquid again.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
Formulation 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, 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 of the invention, according to the ordinary technical knowledge and means of this area, is not departing from this hair
Under the premise of bright above-mentioned basic fundamental thought, the modification of other diversified forms can also be made, is replaced or is changed.
Specific embodiment
Allopurinol derivatives formula used in the specific embodiment of the invention（Ⅳ）Structural Identification result and Chinese patent（Shen
Please number be 200980139583.3）It is open consistent.HPLC determines purity more than 95%.
Embodiment 1：MTT（Tetrazolium bromide）Method determines allopurinol derivatives formula（Ⅳ）To the inhibitory action of different tumour cells.
First, cell line
Human lung cancer cell A549, human liver cancer cells Hep G2, Human hepatoma cell line Bel-7402, neuroglia cell of human knurl 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 line Bcap-37, people's chronic myelogenous leukemia cell K562.
2nd, main solution is prepared：
1.PBS buffer solutions：
NaCl 8g、KCl 0.2g、Na2HPO4 1.44g、KH2PO40.24g, adjusts ph 7.4, constant volume 1L.
2. trypsin solution：
0.25% trypsase+0.02%EDTA, is prepared with PBS, and 0.22 μm of membrane filtration is degerming, and 4 DEG C standby.
The cell culture fluids of 3.RPMI 1640：
（1）The culture powder of 10.4g/ bags RPMI 1640 is molten into tri-distilled water, magnetic agitation 20min；
（2）Plus 2g NaHCO3, continue to stir 10min；
（3）Plus penicillin solution（2×105U/mL）0.5mL, Streptomycin Solution（2× 105U/mL）0.5mL；
（4）Plus 100ml inactivated fetal bovine serums；
（5）Plus 1mol/L HCl, adjust PH to 7.2, constant volume 1L；
（6）Filtration sterilization.
4. test medicine gradient solution：
（1）Allopurinol derivatives formula（Ⅳ）Gradient solution：Allopurinol derivatives formula（Ⅳ）After being dissolved with a small amount of DMSO（Final DMSO
Content is within 0.1%）, 100 μ g/ml are configured to the cell culture fluids of RPMI 1640, half-and-half dilution is configured to 8 concentration ladders
Degree, i.e.,：128th, 64,32,16,8,4,2,1 μ g/ml, use preceding preparation.
（2）Cis-platinum gradient solution：Cisplatin injections are configured to 100 μ g/ml with the cell culture fluids of RPMI 1640, half-and-half dilute
Release and be configured to 8 concentration gradients, i.e., 128,64,32,16,8,4,2,1 μ g/ml use preceding preparation.
3rd, experiment packet：
Medicine group to be measured（Referring to experimental procedure part）
Positive control medicine group（Compared with drug test group, the medicine to be measured of concentration gradient is added to be changed to add concentration gradient
Cis-platinum）
Control group（Compared with drug test group, the medicine to be measured of addition concentration gradient is changed to add the RPMI 1640 of not drug containing
Cell culture fluid）
Blank group（Compared with control group, cell is not added with）
4th, experimental procedure：
1. take the logarithm the cell in growth period, Trypsin Induced, the cell culture fluids of RPMI 1640 adjust concentration of cell suspension be 6 ×
104Individual/mL.Add the μ L of cell suspension 100 per hole in 96 well culture plates, put 37 DEG C, 5% CO224h, cell patch are cultivated in incubator
Wall.
2. the cell culture fluids of RPMI 1640 are removed, the cell culture fluids of RPMI 1640 of the medicine to be measured of concentration gradient are added
100 μ L, each concentration sets 6 parallel holes.96 orifice plates after by dosing are placed in 37 DEG C, 5% CO248h is cultivated in incubator, is inverted
The action effect of basis of microscopic observation medicine.
Nutrient solution is discarded after the centrifugation of 3.96 orifice plates, after carefully rushing 2 ~ 3 times with PBS, the RPMI containing 0.5% MTT is added
The μ L of 1640 cell culture fluid 100, continue to cultivate 4h.
4. supernatant is removed, 150 μ L dimethyl sulfoxide (DMSO)s are added per hole, put low-speed oscillation 10min on shaking table, tie formazan
Brilliant fully dissolving.
5. the optical density in each hole is measured at enzyme-linked immunosorbent assay instrument 490nm（OD values）.
6. parallel hole OD values represent with mean ± SD, calculate inhibiting rate formula：[(ODControl group-ODBlank group)-(ODDrug study group-
ODBlank group)]/(ODControl group-ODBlank group)*100%。
7. using the data processing softwares of GraphPad Prism 5, by drawing amount effect curve calculation of half inhibitory concentration
（IC50）.
5th, experimental result
Allopurinol derivatives formula（Ⅳ）There are good In-vitro Inhibitory Effect, IC to 10 kinds of human tumor cell lines50（It is shown in Table 1）
Within 14 μ g/ml.Compared with positive drug cis-platinum, particularly sensitive is suppressed to A549, U251, SK-OV-3, MCF-7, K562,
Cis-platinum is weaker than to SMMC-7721, SGC-7901, Bel-7402, NCI-H460 and BGC-823 inhibition.Mtt assay is equally determined
Allopurinol derivatives formula（Ⅳ）Pyridine replaces with the compound of phenyl ring to A549, K562, U251, Bel-7402, NCI-H460
Inhibitory action, as a result shows that sensitiveness is far below allopurinol derivatives formula（Ⅳ）.
The formula of table 1（Ⅳ）With cis-platinum to 10 kinds of human tumor cells IC50Value
Embodiment 2：Bel-7402 transplanted human hepatocellular carcinomas mouse model is studied
First, human liver cancer nude mouse xenotransplant cancer model is set up
SPF grades of Balb/c nude mice, male, 4 week old, people's Bel-7402 HCC nude mice models of learning from else's experience are passed into knurl, then through nude mice
2 tumor mass more than generation of generation, is cut into about 2*2*2mm, and it is subcutaneous to be inoculated in nude mice armpit using trochar, sets up human liver cancer nude mice allosome
Transplanting cancer model.
2nd, dosage regimen
With the length and width of vernier caliper measurement each animal knurl, by formula：V=1/2*ab2Knurl volume is calculated, treats that knurl volume is long extremely
About 100mm3Start administration, all animals are randomly divided into model group, positive drug capecitabine group by knurl volume（400mg/kg）, formula
（Ⅳ）It is high（100mg/kg）, in（50mg/kg）, it is low（25mg/kg）Dosage group, drug combination group（Capecitabine 100mg/kg and
Formula（Ⅳ）25mg/kg）, every group 8, each group gastric infusion, dosage is l0ml/kg, 1 time/d, successive administration 14d.
3rd, Testing index and data analysis
1. general indicator
Animal behavior, reaction, diet and death condition after observation administration, weigh the weight of animals.All groups 1 day before administration
（d0）Before blood being taken with the 16th day（d16）Weigh in.
2. PBC detection
Pluck eyeball and take blood within 16th day, take 0.2ml and managed in 0.5mlEP（First plus 20 μ L EDTA-2K）In, turn upside down mixed hook, blood cell
Instrument meter calculates PBC situation, including leucocyte（WBC）, red blood cell（RBC）, blood platelet（PLT）Number.
3. organ coefficient
Pluck eyeball and take and take liver, kidney, spleen after blood and weigh, organ coefficient is calculated as follows.Organ coefficient (%)=internal organs
Weight/body weight * 100%.Body weight refers to the 16th day and takes body weight before blood.
4. knurl weight and tumour inhibiting rate
Pluck after eyeball takes blood, strip tumor mass, assay balance claims knurl weight, tumour inhibiting rate is calculated as follows.
Tumour inhibiting rate %=（The average average knurl weight of knurl weight-administration group of model group）The average knurl weight * 100% of/model group.
5. data analysis
Data analysis is carried out to testing result using the data processing softwares of GraphPad Prism 5.
4th, testing result
1. general indicator
There is not death in mouse after all group administrations, and mouse behavior, reaction, diet aspect also do not find obvious exception.Each group
Do not compare body weight with model group and do not occur significant difference（P>0.05）.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 situations of table 2（n=8）
Note：* P is compared with model group<0.05 * * compare P with model group<0.01
2. PBC detection
Compare with model group, there was no significant difference for other each group WBC and RBC countings, formula（Ⅳ）High dose group PLT counts notable
Higher than model group.Formula（Ⅳ）High, medium and low dosage group and drug combination group do not influence WBC and RBC, formula（Ⅳ）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 situations are shown in Table 3.
The different group Bel-7402 transplanted human hepatocellular carcinoma mouse peripheral blood situations of table 3（n=8）
Note：* P is compared with model group<0.05 * * compare P with model group<0.01 * * * compare P with model group<0.001
3. organ coefficient
Compare with model group, there was no significant difference for other each group liver coefficients and Kidney coefficients, formula（Ⅳ）High, middle dose group and
Drug combination group Spleen coefficient is substantially less than model group.Formula（Ⅳ）High, medium and low dosage group and drug combination group do not influence liver
Dirty coefficient and Kidney coefficients, formula（Ⅳ）High, middle dose group and drug combination group can cause the 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 coefficients of table 4（n=8）
| Group | Liver coefficient | Kidney coefficients | Spleen coefficient |
| Model group | 5.92±0.72 | 1.61±0.21 | 0.77±0.1 |
| Capecitabine group | 6.03±0.28 | 1.53±0.17 | 0.72±0.21 |
| Formula（Ⅳ）High dose group | 6.01±0.62 | 1.57±0.17 | 0.5±0.09** |
| Formula（Ⅳ）Middle dose group | 5.78±0.54 | 1.63±0.2 | 0.53±0.1* |
| Formula（Ⅳ）Low dose group | 5.9±0.36 | 1.73±0.13 | 0.75±0.14 |
| Drug combination group | 5.99±0.52 | 1.66±0.14 | 0.47±0.1*** |
Note：* P is compared with model group<0.05 * * compare P with model group<0.01
4. knurl weight and tumour inhibiting rate
Compare with model group, each equal conspicuousness reduction of group knurl weight illustrates that tumor killing effect is notable.Formula（Ⅳ）High dose group tumour inhibiting rate
Higher than capecitabine group, drug combination group tumour inhibiting rate is suitable with capecitabine group.Different group Bel-7402 transplanted human hepatocellular carcinomas are small
Mouse knurl weight and tumour inhibiting rate are shown in Table 5.
The different group Bel-7402 transplanted human hepatocellular carcinoma mouse knurl weights of table 5 and tumour inhibiting rate（n=8）
| Group | Knurl weight（g） | Tumour inhibiting rate（%） |
| Model group | 1.25±0.21 | - |
| Capecitabine group | 0.7±0.22*** | 44.0% |
| Formula（Ⅳ）High dose group | 0.63±0.2*** | 49.6% |
| Formula（Ⅳ）Middle dose group | 0.85±0.16** | 32.0% |
| Formula（Ⅳ）Low dose group | 0.9±0.14* | 28.0% |
| Drug combination group | 0.69±0.24*** | 44.8% |
Note：* P is compared with model group<0.05 * * compare P with model group<0.01 * * * compare P with model group<0.001
Show according to the study, nude mice model tumor model has obvious correlation with the medication effect of clinical treatment, can be compared with
The clinical efficacy of good forecast medicine.It is possible thereby to deduce, formula（Ⅳ）Can be as antineoplastic application.Drug combination group is adopted
With the formula of low dosage（Ⅳ）With each testing result formula of capecitabine（Ⅳ）Joint capecitabine is used as antineoplastic application
With capecitabine consumption can be reduced under more excellent curative effect or equivalent therapeutic effect.Additionally, formula（Ⅳ）High dose group is significantly raised
Platelet counts explanation can be applied to prepare in tumor complicated decrease of platelet medicine.
Claims (7)
1. a kind of allopurinol derivatives formula（Ⅳ）
（Ⅳ）
The compound of expression, its salt or its solvated compounds.
2. formula as claimed in claim 1（Ⅳ）Purposes in antineoplastic is prepared.
3. purposes as claimed in claim 2, it is characterized in that, the tumour is malignant tumour, and the malignant tumour is solid tumor
Or non-physical knurl.
4. purposes as claimed in claim 3, it is characterized in that, the solid tumor is liver cancer, lung cancer, glioma, stomach cancer, ovum
Nest cancer, breast cancer, the non-physical knurl are leukaemia.
5. formula as claimed in claim 1（Ⅳ）Purposes in tumor complicated decrease of platelet medicine is prepared.
6. formula as claimed in claim 1（Ⅳ）Use in the spleen enlargement medicine that treatment Bel-7402 cells cause is prepared
On the way.
7. the purposes as described in claim 2,5 or 6, it is characterized in that, described formula（Ⅳ）With capecitabine use in conjunction.
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