CN110698484A - Pyrazolo [1,5-a ] pyrimidine-containing derivative, pharmaceutical composition and application - Google Patents

Pyrazolo [1,5-a ] pyrimidine-containing derivative, pharmaceutical composition and application Download PDF

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CN110698484A
CN110698484A CN201911118557.4A CN201911118557A CN110698484A CN 110698484 A CN110698484 A CN 110698484A CN 201911118557 A CN201911118557 A CN 201911118557A CN 110698484 A CN110698484 A CN 110698484A
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pyrazolo
amino
derivative
trifluoromethyl
pharmaceutical composition
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刘瑾
卢久富
葛红光
王芹
宋娟
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Shaanxi University of Technology
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia

Abstract

The invention discloses a compound containing pyrazolo [1,5-a ]]Pyrimidine derivatives, pharmaceutical compositions and uses. The derivative of the invention is 2-amino-7-trifluoromethyl pyrazolo [1,5-a]Pyrimidine derivatives in which Ar is a substituent1And Ar2Selected from furyl, pyrrolyl, thienyl, phenyl, pyridyl, naphthyl or quinolyl, or Ar1And Ar2Optionally substituted with 1 to 5 identical or different R1Substitution; r1Optionally selected from hydrogen, hydroxy, fluoro, chloro, bromo, iodo, nitro, amino, cyano, methyl, ethyl, propyl, propenyl, allyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or dimethylamino.The medicinal composition is an excipient which is prepared by taking the derivative as an active ingredient and is acceptable in pharmacy. The derivative and the medicinal composition have obvious inhibiting effect on human gastric cancer cells and lung cancer cells, and are particularly used for preparing medicaments for treating and/or preventing gastric cancer, colon cancer and leukemia.

Description

Pyrazolo [1,5-a ] pyrimidine-containing derivative, pharmaceutical composition and application
Technical Field
The invention belongs to the field of medicines, and particularly relates to a 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative, a medicinal composition containing the derivative as an active ingredient, and application of the derivative and the medicinal composition in preparation of medicines, particularly antitumor medicines.
Background
Cancer, also known as malignant tumor, is a common disease and frequently encountered disease seriously harming human health, is second to the second largest killer of cardiovascular diseases, and the treatment of cancer is very urgent. Although tens of chemotherapy and adjuvant anticancer drugs have been used clinically so far, and some of them have been cured at a relatively high rate, most drugs only have the effect of relieving the disease. Therefore, overcoming cancer is also a subject of much attention in the world. A great deal of manpower and material resources are invested in research and development of anti-cancer drugs in all countries. Although there are many anti-tumor drugs in clinical practice, the current tumor therapeutic drugs still have the disadvantages of poor selectivity, high toxicity and easy generation of drug resistance, so that the development of anti-tumor drugs with high selectivity, low toxicity and difficult generation of drug resistance is an urgent task and challenge for scientists.
In the process of modern drug development, nitrogen-containing heterocyclic drugs play an important role. Pyrazolopyrimidine compounds, as structural analogs of purine alkaloids, can specifically bind to nucleotides, protein receptors, protein kinases and the like, can regulate cell signal transduction and cell cycle, and have wide biological activity. Researches show that the pyrazolo [1,5-a ] pyrimidine compound has wide pharmacological activity, such as medicinal values of antianxiety, antibiosis, antiphlogosis, analgesia, antitumor and the like, so that the pyrazolo [1,5-a ] pyrimidine compound becomes one of hot spots of research in the field of medicine at present. In the field of anti-tumor research, a compound containing a pyrazolo [1,5-a ] pyrimidine structural unit can be used as a key protein, enzyme and receptor action target of tumor cell signal transduction, such as a cyclin kinase 2(CDK2) inhibitor, a cell cycle detection kinase 1(CHK1) inhibitor, a Pim kinase inhibitor, a deoxyribonucleic acid (DNA) binding molecule, a B-Raf kinase inhibitor, a vascular endothelial growth factor receptor 2(VEGFR-2) kinase inhibitor, a protein kinase CK2 inhibitor and the like, and can inhibit tumor cell proliferation and induce tumor cell apoptosis. Therefore, it is necessary to prepare compounds containing pyrazolo [1,5-a ] pyrimidine structural units and study their biological activities.
Disclosure of Invention
The invention aims to provide a novel 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative.
It is still another object of the present invention to provide a pharmaceutical composition comprising the above-mentioned 2-amino-7-trifluoromethylpyrazolo [1,5-a ] pyrimidine derivative as an active ingredient.
The invention further aims to provide the application of the 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative and a medicinal composition.
The invention is realized by the following steps that 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative has a structural formula shown as the following formula (I):
Figure BDA0002274765510000021
in the formula (I), Ar1And Ar2Selected from furyl, pyrrolyl, thienyl, phenyl, pyridyl, naphthyl or quinolyl, or Ar1And Ar2Optionally substituted with 1 to 5 identical or different R1Substitution;
wherein R is1Optionally selected from hydrogen, hydroxy, fluoro, chloro, bromo, iodo, nitro, amino, cyano, methyl, ethyl, propylAlkenyl, allyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, or dimethylamino.
The present invention further provides a pharmaceutical composition comprising the above 2-amino-7-trifluoromethylpyrazolo [1,5-a ] pyrimidine derivative as an active ingredient or a pharmaceutically acceptable excipient therefor.
The invention further discloses application of the pyrimidine derivative or the medicinal composition in preparing medicaments for treating and/or preventing proliferative diseases.
The invention further discloses application of the pyrimidine derivative or the medicinal composition in preparing a medicament for treating and/or preventing cancer.
The invention further discloses application of the pyrimidine derivative or the medicinal composition in preparing medicaments for treating and/or preventing gastric cancer, colon cancer and leukemia.
The invention overcomes the defects of the prior art and provides a 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative, a medicinal composition containing the derivative as an active ingredient, and application of the derivative and the medicinal composition in preparing medicaments, in particular in preparing antitumor medicaments.
The invention takes pyrazolo [1,5-a ] pyrimidine group as a mother nucleus, carries out structural modification on the group, and obtains a series of 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine compounds, wherein the specific reaction process is as follows:
Figure BDA0002274765510000031
the above synthetic route describes the 2-amino-7-trifluoromethylpyrazolo [1,5-a ] of the invention]Preparation of the pyrimidines, all starting materials are prepared by the means described in the synthetic route, by methods well known to those of ordinary skill in the art of organic chemistry or are directly commercially available. All final derivatives of the invention are prepared by the methods described in the synthetic routes above or by methods analogous thereto, these methods being organic chemistryAs is well known to those of ordinary skill in the art. Substituents Ar of all compounds in the scheme1And Ar2As defined in the specification.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects: through in vitro inhibition activity tests of human gastric cancer cells MKN45, human colon cancer cells HT29 and human leukemia cells K562, the 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative has a remarkable inhibition effect on human gastric cancer cells and lung cancer cells, and is particularly used for preparing medicines for treating and/or preventing gastric cancer, colon cancer and leukemia.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the following examples, NMR spectra of compounds were measured using BrukeraRx-600 and mass spectra were measured using Agilent6460 QQQ; all reagents used were analytically or chemically pure.
Example 1
Step A preparation of 2- (substituted benzylidene) malononitrile (a)
Adding 100mL of ethanol solution of malononitrile (20.00g, 302.7mmol) into 150mL of ethanol solution of 2, 4-difluoro substituted benzaldehyde (51.6g, 363.3mmol), adding 10mL of triethylamine, stirring at room temperature for reaction for 3h, separating out a large amount of solid in the reaction process, filtering, washing a filter cake with cold ethanol for three times, and drying to obtain 49.2g of yellow solid, namely 2- (substituted benzylidene) malononitrile (a);
step B2- (substituted benzyl) malononitrile (B)
Adding 2- (substituted benzylidene) malononitrile (199.8mmol) into 200mL of dried tetrahydrofuran for dissolution, slowly adding a mixed solution of 150mL of tetrahydrofuran and 24mL of glacial acetic acid of sodium cyanoborohydride (15.1g,240.0mmol), stirring at room temperature for reaction for 7h, removing the solvent by reduced pressure evaporation, adding 300mL of water into the mixture, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, removing most of the solvent by organic phase reduced pressure evaporation, cooling, generating a large amount of solid, filtering, and drying to obtain a light yellow solid 3, namely the 2- (substituted benzyl) malononitrile (b);
step C4- (substituted benzyl) -1H-pyrazole-3, 5-diamine (C)
2- (substituted benzyl) malononitrile (156.1mmol) was added to 150mL of ethanol to dissolve, and 85% hydrazine hydrate (12.0g,191.8mmol) was added slowly. Refluxing for 5H, evaporating under reduced pressure to remove most of the solvent, cooling, generating a large amount of solid, filtering, and drying to obtain a light yellow solid, namely 4- (substituted benzyl) -1H-pyrazole-3, 5-diamine (c);
step D general Synthesis of novel pyrazolo [1,5-a ] pyrimidines
4- (substituted benzyl) -1H-pyrazole-3, 5-diamine (2.00mmol) and 4,4, 4-trifluoro-1- (4-aryl) butane-1, 3-dione (2.20mmol) were added to a reaction flask, and the mixture was heated to 170 ℃ to melt and react for 1.5H. Cooling the reaction mixture to room temperature, crushing the obtained solid, and recrystallizing the crushed solid by methanol to obtain the 2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative.
In this example, the substituent in 2, 4-difluoro-substituted benzaldehyde is reacted with 2-amino-7-trifluoromethylpyrazolo [1,5-a ]]Ar in pyrimidine derivatives1The groups are directly related correspondingly; aryl group of 4,4, 4-trifluoro-1- (4-aryl) butane-1, 3-dione and 2-amino-7-trifluoromethylpyrazolo [1,5-a ]]Ar in pyrimidine derivatives2Directly corresponding to the correlation.
This example is a general procedure for the preparation of 2-amino-7-trifluoromethylpyrazolo [1,5-a ] pyrimidine derivatives, which are prepared accordingly to give specific 2-amino-7-trifluoromethylpyrazolo [1,5-a ] pyrimidine derivatives, based on the selection of 2, 4-difluoro-substituted benzaldehyde and 4,4, 4-trifluoro-1- (4-aryl) butane-1, 3-dione.
More specific examples are as follows:
EXAMPLE 13- (2, 4-difluorobenzyl) -5- (4-methylphenyl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-2-amine (compound 1)
1H NMR(600MHz,CDCl3)δ8.00(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,4H),6.80(m,2H),4.30(s,2H),4.08(s,2H),2.44(s,3H);MS(ESI)m/z(%):419.1[M+H]+.
EXAMPLE 23- (2, 4-difluorobenzyl) -5- (4-methoxyphenyl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-2-amine (compound 2)
Figure BDA0002274765510000061
1H NMR(600MHz,CDCl3)δ8.07(d,J=8.7Hz,2H),7.38–7.28(m,2H),7.03(d,J=8.7Hz,2H),6.87–6.74(m,2H),4.29(s,2H),4.07(s,2H),3.89(s,3H);MS(ESI)m/z(%):435.1[M+H]+
EXAMPLE 33- (2, 4-difluorobenzyl) -5- (4-fluorophenyl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-2-amine (compound 3)
Figure BDA0002274765510000062
MS(ESI)m/z(%):423.1[M+H]+
EXAMPLE 43- (2, 4-dichlorobenzyl) -5- (4-methylphenyl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-2-amine (compound 4)
Figure BDA0002274765510000063
1H NMR(600MHz,CDCl3)δ7.98(d,J=7.5Hz,2H),7.40(s,1H),7.36–7.27(m,4H),7.15(d,J=8.3Hz,1H),4.31(s,2H),4.17(s,2H),2.43(s,3H);MS(ESI)m/z(%):451.1[M+H]+
EXAMPLE 53- (2, 4-dichlorobenzyl) -5- (4-methoxyphenyl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-2-amine (compound 5)
Figure BDA0002274765510000064
1H NMR(600MHz,CDCl3)δ8.05(d,J=8.7Hz,2H),7.41(d,J=1.7Hz,1H),7.31(s,1H),7.26(d,J=5.1Hz,1H),7.15(dd,J=8.3,1.7Hz,1H),7.02(d,J=8.7Hz,2H),4.27(s,2H),4.16(s,2H),3.89(s,3H);MS(ESI)m/z(%):467.1[M+H]+
EXAMPLE 63- (2, 4-dichlorobenzyl) -5- (4-fluorophenyl) -7- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-2-amine (compound 6)
Figure BDA0002274765510000071
MS(ESI)m/z(%):455.1[M+H]+
EXAMPLE 2 preparation of tablets of the pharmaceutical composition
The tablet comprises the following components:
Figure BDA0002274765510000072
the preparation process of the tablet comprises the following steps: sieving and fully mixing the compound 1, starch and microcrystalline cellulose, adding the mixed powder into a hydroxymethyl cellulose solution, uniformly mixing, sieving to prepare wet granules, drying at 50-60 ℃, sieving sodium carboxymethyl starch, magnesium stearate and talcum powder in advance, adding the granules into the granules, and tabletting.
EXAMPLE 3 preparation of an injection of the pharmaceutical composition
Mixing the components, filtering until the pH value is 7.5-8.5, wherein the concentration of filtrate is 1 mg/ml, subpackaging 2 ml per ampoule, and sterilizing to obtain the injection.
Effects of the embodiment
Pyrazolo [1,5-a ] pyrimidine derivatives according to example 1 of the present invention were screened for their activity in inhibiting human gastric cancer cell MKN45, human colon cancer cell HT29 and human leukemia cell K562 in vitro.
Digesting the cells cultured in a culture bottle until the cells are in the logarithmic phase of the logarithmic phase with pancreatin, stopping digestion with a culture solution containing 10% of serum, centrifuging at 800rpm for 8min, removing the supernatant, uniformly blowing the supernatant with the culture solution containing 10% of serum, adjusting the concentration of cell suspension with the culture solution, adding the mixture into a 96-well plate, wherein 100uL of cells are not added in each hole except for a1 hole which is a blank hole in the 96-well plate, and the concentration of the cells is about 1 multiplied by 104Perwell (cell concentration can be adjusted), placed at 37 deg.C and 5% CO2Incubate for 24 hours. Dissolving 50(L DMSO) of tested drug (about 2 mg) in DMSO, adding 950(L culture solution, diluting, mixing to obtain 2mg/mL liquid medicine, diluting with 24-well plate to obtain 5 drugs with different concentrations, such as 100, 20, 4, 0.8, and 0.16 (g/mL. the culture solution in 96-well plate with embedded cells is forcibly thrown out, adding 3 wells for each concentration liquid medicine, wherein the growth of two rows and two columns of cells around the plate are greatly influenced by environment, and the plate is used as blank cell well, placing 96-well plate in 37 deg.C and 5% CO2Was cultured in an incubator for 72 hours. Forcibly draining the liquid from the 96-well plate, adding 200(L physiological saline for washing to remove the residual drug) per well, draining the liquid, diluting the 5% MTT liquid prepared in advance with the culture solution to 0.5% MTT solution, adding the diluted MTT into the 96-well plate at 37 deg.C and 5% CO per well, and standing2The culture chamber of (2) was incubated for 4 hours to promote completion of the reaction. After 4 hours, the liquid in the 96-well plate is forcibly thrown out, 100(L DMSO) is added into each well, the mixture is placed on a magnetic oscillator to be oscillated for 3min, after the crystals are fully dissolved, the crystals are placed into an enzyme-linked immunosorbent assay to determine the result, and the medicine IC can be obtained by a Bliss method50The value is obtained.
The results of human gastric cancer cell MKN45, human colon cancer cell HT29, and human leukemia cell K562 with sorafenib as a positive control are shown in table 1 below:
TABLE 1
As is clear from the test results in Table 1, the anti-tumor activity of the pyrazolo [1,5-a ] pyrimidine derivative is equivalent to or superior to that of the control drug Sorafenib, and the compound of the general formula (I) has good in-vitro anti-tumor activity. The compounds have good development and application prospects of antitumor drugs.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (5)

1. A2-amino-7-trifluoromethyl pyrazolo [1,5-a ] pyrimidine derivative is characterized in that the structural formula of the derivative is shown as the following formula (I):
Figure FDA0002274765500000011
in the formula (I), Ar1And Ar2Selected from furyl, pyrrolyl, thienyl, phenyl, pyridyl, naphthyl or quinolyl, or Ar1And Ar2Optionally substituted with 1 to 5 identical or different R1Substitution;
wherein R is1Optionally selected from hydrogen, hydroxy, fluoro, chloro, bromo, iodo, nitro, amino, cyano, methyl, ethyl, propyl, propenyl, allyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or dimethylamino.
2. A pharmaceutical composition comprising an active ingredient which is the 2-amino-7-trifluoromethylpyrazolo [1,5-a ] pyrimidine derivative according to claim 1 or a pharmaceutically acceptable excipient therefor.
3. Use of a pyrimidine derivative as defined in claim 1 or a pharmaceutical composition as defined in claim 2 in the manufacture of a medicament for the treatment and/or prophylaxis of proliferative diseases.
4. Use of a pyrimidine derivative as defined in claim 1 or a pharmaceutical composition as defined in claim 2 in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
5. Use of a pyrimidine derivative according to claim 1 or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for the treatment and/or prophylaxis of gastric cancer, colon cancer and leukaemia.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028263A1 (en) * 2011-08-24 2013-02-28 Glaxosmithkline Llc Pyrazolopyrimidine derivatives as pi3 kinase inhibitors
CN104250252A (en) * 2013-06-28 2014-12-31 上海捷森药物化学科技有限公司 Pyrazolo[1,5-a]miazine compound and its preparation method and medical use
CN105001242A (en) * 2014-04-23 2015-10-28 盛世泰科生物医药技术(苏州)有限公司 Heterocyclic compound as protein tyrosinase inhibitor
CN109311887A (en) * 2016-04-06 2019-02-05 溶酶体治疗股份有限公司 Pyrazolo [1,5-a] pyrimidine radicals benzamide compound and they treatment medical conditions in purposes
CN109414442A (en) * 2016-04-04 2019-03-01 洛克索肿瘤学股份有限公司 (S) liquid preparation of-N- (5- ((R) -2- (2,5- difluorophenyl)-pyrrolidin-1-yl)-pyrazolo [1,5-A] pyrimidin-3-yl) -3- hydroxyl pyrrolidine -1- formamide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028263A1 (en) * 2011-08-24 2013-02-28 Glaxosmithkline Llc Pyrazolopyrimidine derivatives as pi3 kinase inhibitors
CN104250252A (en) * 2013-06-28 2014-12-31 上海捷森药物化学科技有限公司 Pyrazolo[1,5-a]miazine compound and its preparation method and medical use
CN105001242A (en) * 2014-04-23 2015-10-28 盛世泰科生物医药技术(苏州)有限公司 Heterocyclic compound as protein tyrosinase inhibitor
CN109414442A (en) * 2016-04-04 2019-03-01 洛克索肿瘤学股份有限公司 (S) liquid preparation of-N- (5- ((R) -2- (2,5- difluorophenyl)-pyrrolidin-1-yl)-pyrazolo [1,5-A] pyrimidin-3-yl) -3- hydroxyl pyrrolidine -1- formamide
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