CN110684062B - Medicine for treating non-small cell lung cancer and preparation method thereof - Google Patents

Medicine for treating non-small cell lung cancer and preparation method thereof Download PDF

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CN110684062B
CN110684062B CN201910992671.3A CN201910992671A CN110684062B CN 110684062 B CN110684062 B CN 110684062B CN 201910992671 A CN201910992671 A CN 201910992671A CN 110684062 B CN110684062 B CN 110684062B
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lung cancer
small cell
cell lung
tumor
compound
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CN110684062A (en
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唐乾
李玲兢
曹洪玉
王立皓
郑学仿
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Dalian University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Abstract

The invention belongs to the field of pharmacy, and discloses a medicament for treating non-small cell lung cancer and a preparation method thereof. Relates to an improved purine derivative or pharmaceutically acceptable salt thereof, a preparation method and application thereof, wherein the structure of the derivative is shown as formula I, wherein X is 1 Or X 2 Independently selected from H, C1-5 alkyl, fluoro, chloro, bromo, fluoro C1-5 alkyl, and said X 1 And X 2 At least one is selected from fluoro or fluoroalkyl; said fluorinated C1-5 alkyl group is preferably a perfluorinated C1-5 alkyl group; the experimental result shows that the compound has excellent anti-tumor effect, especially shows excellent selectivity on tumor inhibition of non-small cell lung cancer, and has good clinical application prospect.

Description

Medicine for treating non-small cell lung cancer and preparation method thereof
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a medicine for treating non-small cell lung cancer, and more particularly relates to a purine derivative, and a preparation method and medical application thereof.
Background
Lung cancer is one of the most common malignancies in china. According to the pathological type, the lung cancer is divided into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC), wherein the NSCLC accounts for 80 to 85 percent. As most lung cancer patients are diagnosed at the middle and late stages, the optimal surgical treatment opportunity is lost, and only systemic treatment is taken as the main treatment. Therefore, drug therapy is becoming the main treatment for advanced NSCLC, and as such, research on the treatment of lung cancer, especially non-small cell lung cancer, has been a focus and is one of the most rapidly progressing tumors.
Among the therapeutic approaches for non-small cell lung cancer, molecular targeted therapy has become a research focus in recent years, such as Epidermal Growth Factor Receptor (EGFR) inhibitors, anti-angiogenic drugs, anaplastic Lymphoma Kinase (ALK) inhibitors, and the like. The advent of targeted therapeutic drugs has brought the treatment of lung cancer into the era of "individualized treatment" or "precision treatment". For example, EGFR-targeted TKI that promotes apoptosis of cells by inhibiting activation of tyrosine kinase domain in lung cancer, and monoclonal antibody inhibitors such as gefitinib, erlotinib, etc. The results of a number of large phase iii clinical trials indicate that PES in patients after EGFR-TKI treatment is significantly longer in advanced NSCLC patients with EGFR sensitive mutations than in chemotherapy patients. In another example, the inhibitor targeting tumor angiogenesis as a therapeutic target firstly generates new blood vessels in the early stage of tumor formation, and Vascular Endothelial Growth Factor (VEGF) is an important angiogenesis inducer, is recognized as one of the most important factors for promoting angiogenesis, and plays an important role in the generation of new blood vessels, and the generation, development and metastasis of tumors. VEGF inhibits angiogenesis-related endothelial cells, inhibits the generation of tumor neovascularization, and achieves the anti-tumor purpose, such as bevacizumab.
However, despite the fact that targeted therapy is a relatively new treatment for non-small cell lung cancer, chemotherapy remains the cornerstone of advanced NSCLC treatment. As known from related research reports, the survival period, the tolerance and the like of the sensitive population with gene mutation without progress are better than those of chemotherapy, but the targeted therapy is still difficult to surpass the chemotherapy in the overall survival time. Combination chemotherapy regimens based on platinum drugs have long been demonstrated to control and improve the symptoms and prolong survival of patients with advanced NSCLC compared to best support therapy. A Meta analysis result in the journal of American medical society of 2004 shows that the effect of the platinum-based two-drug combination therapy is better than that of the single-drug therapy or the three-drug combination therapy, thereby establishing the position of the platinum-based two-drug combination therapy in the treatment of the advanced NSCLC. A large number of phase I clinical trials have demonstrated that the 3 rd generation chemotherapeutic drugs in combination with cisplatin or carboplatin are effective in treating advanced NSCLC, and these include paclitaxel, docetaxel, gemcitabine, pemetrexed, vinblastine, vinorelbine, etoposide and albumin paclitaxel, which are widely used clinically. However, the curative effect of chemotherapy for advanced lung cancer is still very limited, taking the 3 rd generation chemotherapy drug in combination with platinum drug to treat advanced NSCLC as an example, the objective remission rate of the chemotherapy is 17-22%, the disease progression free survival time (PFS) of advanced patients is 4-6 months, the median survival time (OS) is 7.4-8.1 months, the 1-year survival rate is 31-36%, and the 2-year survival rate is 10-13%.
Based on the above background, research and development of more new drugs with good tumor inhibition effect for treating lung cancer, especially non-small cell lung cancer, and expanded therapeutic approaches become pursuits for continuous efforts of researchers in the tumor field.
Disclosure of Invention
The present invention is directed to solving the above technical problems.
The first objective of the present invention is to provide a novel drug for treating non-small cell lung cancer based on the prior art, and the inventors have provided a novel purine derivative based on long-term research and molecular structure design and improvement of anti-tumor chemical drugs, specifically, based on structural improvement of gemcitabine, a commonly used drug for anti-non-small cell lung cancer, and introduced guanine groups. To this end, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002238762200000021
wherein, X 1 Or X 2 Independently selected from H, C1-5 alkyl, fluoro, chloro, bromo, fluoro C1-5 alkyl, and said X 1 And X 2 At least one is selected from fluoro or fluoroalkyl; the fluorinated C1-5 alkyl group is preferably a perfluoroC 1-5 alkyl group.
Preferably, the compound of formula I is selected from the following compounds I-a to I-f:
Figure BDA0002238762200000022
the pharmaceutically acceptable salt is a salt of the compound of formula I with an inorganic acid or an organic acid, and may be, for example, a salt of the compound of formula I with hydrochloric acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, or malic acid.
The second purpose of the invention is to provide a synthetic method of the compound shown in the formula I, and the synthetic route is as follows:
Figure BDA0002238762200000031
wherein R1 is selected from tBuCO-, meCO-, bz-; r2 is selected from C1-5 alkyl and aryl.
Further, the preparation method specifically comprises the following steps:
adding guanine, hexamethyl disilazane and ammonium sulfate into an organic solvent A, heating and refluxing until a reaction solution is clear, continuously keeping the reaction for 0.5-1 h, cooling to room temperature, concentrating under reduced pressure to separate out a solid, adding an organic solvent B into the solid to dissolve the solid, then adding a compound shown in the formula II, heating and refluxing for 5-10 h, cooling to room temperature, adding ethyl acetate and water, standing for layering, washing with saturated saline water for three times, concentrating an organic phase, drying, and concentrating under reduced pressure to remove the solvent to obtain a compound shown in the formula III;
and (2) adding the compound shown in the formula III into an organic solvent C, adding alkali, reacting for 1-3 hours at 60-90 ℃, filtering, adding ethyl acetate and water, standing for layering, washing an organic phase with saturated saline solution for three times, drying, concentrating under reduced pressure, and purifying an obtained substrate by using flash column chromatography to obtain the compound shown in the formula I.
The compound of formula II as a reactant in the above synthesis method can be prepared by a synthesis method known in the art, for example, a method described in documents such as patents CN200680047128.7 and CN 200680047128.7.
In some embodiments of the present invention, preferably, the organic solvent a is selected from methanol, ethanol, acetonitrile, dichloromethane, dichloroethane; the organic solvent B is selected from toluene, xylene, DMSO and DMF; the organic solvent C is selected from methanol or ethanol.
Further, the molar ratio of the compound of formula II, guanine, hexamethyldisilazane, and ammonium sulfate in step (1) is 1.1 to 2.
In other embodiments of the present invention, preferably, the base in step (2) is selected from any one of triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; the molar ratio of the compound of formula III to the base is 1.
The third purpose of the invention is to provide a pharmaceutical composition, which comprises the compound of formula I or the pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials; the pharmaceutically acceptable auxiliary materials include, but are not limited to, one or more combinations selected from the following: cellulose derivatives, polyvinylpyrrolidone, polyethylene glycol, mannitol, xylitol, starch, cyclodextrin, magnesium stearate, ethyl p-hydroxybenzoate; particularly preferred are cellulose derivatives including microcrystalline cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, and the like.
Furthermore, another object of the present invention is to provide the use of the compound of formula I or its pharmaceutically acceptable salt, or the pharmaceutical composition as described above for the preparation of a medicament for the treatment of tumors, preferably non-small cell lung cancer.
In the above medical application, the pharmaceutical composition can be prepared into a suitable pharmaceutical preparation according to the condition of an animal and the application site so as to facilitate administration, and the administration time and the administration frequency of the pharmaceutical composition of the present invention are determined according to the specific diagnosis result of the condition of an animal. For example, a mouse treatment regimen is applied to a human, and the effective dose of all drugs to the human can be converted to the effective dose of the drug to the mouse.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel purine derivative, and experiments show that the obtained compound has excellent antitumor effect, and particularly shows excellent selectivity on inhibition of non-small cell cancer tumors. Has good clinical application prospect.
Detailed Description
The invention is described in more detail below with reference to specific examples, without limiting the scope of the invention. Unless otherwise specified, the experimental methods adopted by the invention are all conventional methods, and experimental equipment, materials, reagents and the like used in the experimental method can be obtained from commercial sources.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art and are intended to be within the scope of the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated herein by reference.
Example 1
Specific preparation examples of the compounds of the present invention:
(1) Preparation of Compound I-a:
Figure BDA0002238762200000051
step (1) was a process in which guanine (226.5mg, 1.5mmol), hexamethyldisilazane (80.5mg, 0.5 mmol), ammonium sulfate (26.4 mg, 0.2mmol) were added to 50mL of dichloromethane, the mixture was heated under reflux until the reaction mixture became clear, the reaction was continued for 0.5h, the mixture was cooled to room temperature, concentrated under reduced pressure to precipitate a solid, an organic solvent B was added to the solid to dissolve the solid, 3, 5-acetyl-2-deoxy-2, 2-difluoro-D-ribofuranose-1-p-toluenesulfonate (408mg, 1mmol) was then added to the solid, the mixture was heated under reflux for 8 hours, the mixture was cooled to room temperature, 30mL of ethyl acetate and 30mL of water were added thereto, the mixture was layered, washed with saturated brine (30 mL. Times.3), the organic phase was concentrated, dried, and the solvent was removed by concentration under reduced pressure to obtain 322mg of the compound of formula III (yield: 83.2%).
Step (2), the compound of formula III (322mg, 0.832mmol) was added to 35mL of toluene, sodium carbonate was added, reaction was carried out at 75 ℃ for 1.5 hours, suction filtration was carried out, 30mL of ethyl acetate and 30mL of water were added, standing was carried out for separation, the organic phase was washed three times with saturated brine, dried, concentrated under reduced pressure, and the resulting substrate was purified by silica gel flash column chromatography (eluent petroleum ether: ethyl acetate = 5) to obtain 231.8mg of the compound of formula I (HPLC purity: 95.4%). The overall yield of the two-step reaction was 76.5%.
1 HNMR(DMSO-d6)：δ10.27(s，1H)，8.92(s，1H)，8.76(s，1H)，7.62(s，1H)， 6.67(br，2H)，4.07(s，1H)，3.72(m，1H)，3.62(t，1H)，3.54(m，2H)；
LC-MS：303。
The compounds I-b-I-f are further synthesized by the method, and the synthetic route is as follows:
Figure BDA0002238762200000052
the structure, reactants, yield and characterization data of the compound are shown in table 1.
Table 1: production results of Compounds 1-b to I-f
Figure BDA0002238762200000053
Figure BDA0002238762200000061
Experiment one:
the compound of the invention has the proliferation inhibiting effect on in vitro cultured lung cancer cells and the influence on human normal cells
Taking lung cancer cells (non-small cell lung cancer cells A549, large cell lung cancer cells NCI-H460, squamous lung cancer cells HTB-8 and human lung squamous cell carcinoma cells QG-5) in logarithmic growth phase and human normal liver cells L02 to inoculate on a 96-hole culture plate, wherein the inoculation amount of each hole is 3000-4000/100 uL and 6000/100 uL respectively; aseptically collecting 15mL of venous blood of a healthy donor, performing heparin anticoagulation, separating mononuclear cells by using a Ficoll density gradient centrifugation method, preparing a single cell suspension by using RPMI1640 containing 10% fetal calf serum, adjusting the cell concentration to be 2 multiplied by 105/mL, and inoculating the single cell suspension to a 96-hole culture plate, wherein each hole is 100uL. After the cells of each culture plate are cultured for 24 hours, adding the compounds I-a to I-f and gemcitabine of the invention at different concentrations into an experimental group, and preparing three multiple wells for each concentration; and adding 100uL of nutrient solution into the negative control group, and adding 100uL of nutrient solution into the blank control hole for zero setting of the instrument. After different time of action (48 h and 72 h), 20uL of MTT (methanol to methanol) of 5mg/mL is added into each well, the culture is continued for 4h, the supernatant is thrown off, and 150uL of dimethyl sulfoxide is added into each well. The absorbance value (A570) of each 570nm well was measured by a microplate reader (BIO-RAD product), and the average value of each group was calculated to calculate the inhibition: inhibition = (1-experimental group a 570/control group a 570) × 100%. Statistical analysis was performed with SPSS13.0 and IC50 was calculated.
As a result: the compound prepared by the invention has obvious proliferation inhibition effect on the lung cancer cells, and has small inhibition effect on normal human liver cells and peripheral blood lymphocytes (Table 2). The compound prepared by the invention has obvious selective inhibition effect on tumor cells.
Table 2: the results of the antitumor drug effect of the compound
Figure BDA0002238762200000062
And (4) conclusion: the compound prepared by the invention can obviously inhibit non-small cell lung cancer cells A549, large cell lung cancer cells NCI-H460, lung squamous carcinoma cells HTB-8 and human lung squamous cell carcinoma cells QG-5 cultured in vitro, and particularly has the inhibition activity on the non-small cell lung cancer cells A549 which is greatly better than gemcitabine, and has small inhibition effect on human normal liver cells LO2 and peripheral blood lymphocytes, thereby showing obvious selectivity. Therefore, the compound can be used for treating lung cancer, especially non-small cell lung cancer.
Experiment two
Pharmacodynamic test for inhibiting mouse transplantation tumor
Combining with the results of cell experiments, the inventors further performed animal model studies on compounds with better inhibition effect on lung cancer cells, specifically:
1. test materials:
medicine preparation: liquid lipid composition prepared from gemcitabine, four compounds I-a, I-d and I-e
Animals: clean grade C57BL/6N mice.
Tumor species: mouse transplantation tumor Lewis lung cancer cell strain.
2. The test method comprises the following steps:
male C57BL/6N mice weighing 18 to 22g were divided into five groups at random, and 10 mice were each group, and were set as a normal saline control group and five groups of the above four compounds. The Lewis lung cancer is killed by dislocation of the neck, C57BL/6N tumor-bearing mice (tumor-inducing mice) growing for 12d are inoculated subcutaneously, fresh tumor tissues are taken aseptically, cell homogenate is prepared by a tissue grinder, the content of living cells is adjusted to 2 x 107/mL by using physiological saline, and the tumor-bearing mice are inoculated subcutaneously in the right axilla of the C57BL/6N mice, and each tumor-bearing mouse is inoculated with 0.1mL.
The administration method comprises the following steps: the gemcitabine, the compounds I-a, I-d and I-e are administrated to four groups of mice by intraperitoneal injection from the 2 nd day of inoculation, the dose is 1 time per day, each administration dose is 10mg/kg, and the administration is continuously carried out for 14 days; the control group was given an equal amount of physiological saline 1 time a day, and was also injected continuously for 14 days.
24h after the last administration, the animals were sacrificed, and the tumor mass and body weight were weighed to calculate the tumor weight inhibition ratio according to the following formula:
tumor weight inhibition (%) = (1-tumor weight of test group/tumor weight of saline control group) × 100%.
Statistical analysis was performed using the SPSS10.0 software, and experimental data for body weight and tumor weight were expressed as x ± s, and differences between each administration group and the saline control group were compared by one-way analysis of variance.
3. Inhibition of mouse graft tumors:
table 3: tumor inhibition rate of the compound and gemcitabine on Lewis lung cancer
Figure BDA0002238762200000071
Figure BDA0002238762200000081
From the results in Table 3, it can be seen that the liquid lipid composition of the compounds I-a, I-d and I-e has a tumor weight inhibition ratio of 71-86% for Lewis lung cancer, which is significantly better than gemcitabine (tumor inhibition ratio of 65.2% for Lewis lung cancer), and has a more excellent tumor inhibition effect, which may be exhibited by the combination of the specific chemical substance and the specific composition of the present invention; the experimental results show that the compound provided by the invention has excellent clinical application prospect, and provides a new effective medication way for treating tumors, particularly non-small cell lung cancer.
The embodiments described above are only preferred embodiments of the invention, and are not all possible embodiments for the practical implementation of the invention. It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims (1)

1. Compounds I-a to I-f:
Figure FDA0003867230040000011
the application of the compound in preparing the medicine for treating the tumor is characterized in that the tumor is non-small cell lung cancer.
CN201910992671.3A 2019-10-18 2019-10-18 Medicine for treating non-small cell lung cancer and preparation method thereof Active CN110684062B (en)

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IL77133A (en) * 1984-12-04 1991-01-31 Lilly Co Eli Antineoplastic pharmaceutical compositions containing pentofuranoside derivatives,some new such compounds and their preparation
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ES2932354T3 (en) * 2017-07-28 2023-01-18 Bristol Myers Squibb Co Cyclic dinucleotides as anticancer agents

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