CN113292484B - 3- (4-methylpiperidine-1-yl) -3-benzylurea compound and analogue, preparation method and application thereof - Google Patents
3- (4-methylpiperidine-1-yl) -3-benzylurea compound and analogue, preparation method and application thereof Download PDFInfo
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Abstract
3- (4-methylpiperidine-1-yl) -3-benzylurea compounds and analogues thereof, a preparation method and application thereof, which belong to the technical field of medicine, in particular to the preparation of the 3- (4-methylpiperidine-1-yl) -3-benzylurea compounds and the analogues thereof and the application thereof in preparing antitumor drugs. The structural general formula of the related 3- (4-methylpiperidine-1-yl) -3-benzylurea compound and analogues thereof is shown as the following formula I, wherein n =0-2,R 1 、R 2 Each independently being methoxy, ethoxy, isobutoxy, fluoro, chloro, 2- (1-methylpiperazin-4-yl) ethoxy or trifluoromethoxy, R 3 、R 4 Each independently hydrogen or 1-methylpiperazin-4-yl. The compound of the invention has simple and convenient synthesis method, is suitable for industrial production, shows the antitumor activity of the compound through biological activity test, and is applied to the preparation of antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a 3- (4-methylpiperidine-1-yl) -3-benzylurea compound and an analogue thereof, a preparation method thereof, and application of the compound as a protein tyrosine kinase inhibitor in preparation of antitumor drugs.
Background
The morbidity and mortality of various tumors in China have a remarkably rising trend in recent years, the tumors with the highest morbidity and mortality in men are lung cancer, and women are breast cancer and lung cancer. Unhealthy living habits such as smoking, excessive drinking, insufficient physical activities and the like, haze, and working and living pressure brought to people by rapid development and social transformation of the economic society have no negligible influence on health, and the rising trend of death rate of lung cancer, liver cancer, colorectal cancer and breast cancer related to environment and life style is more obvious (FENG R-M, ZONG Y-N, CAO S-M, et al. Cancer Communications,2019,39 (1): 22-33).
Among the many targets associated with tumor cell growth and apoptosis, a large number of them belong to Protein Tyrosine Kinase (PTK). PTKs are largely classified into receptor-type PTKs and non-receptor-type PTKs. Receptor-type PTKs typically have an extracellular binding domain capable of binding to a particular substrate, a transmembrane domain, and an intracellular kinase domain capable of binding to and phosphorylating a substrate. Common receptor-type PTKs are mainly: the epidermal growth factor receptor (EGFR; erbB-1, HER1) family, including ErbB-1 (EGFR), erbB-2 (HER-2), erbB-3 (HER-3) and ErbB-4 (HER-4), is highly expressed in epithelial cell tumors; the VEGFR family, including VEGFR-1 (FLT-1), VEGFR-2 (FLK-1) and VEGFR-3 (FLT-4), is overexpressed in many tumor tissues and plays a key role in tumor angiogenesis; platelet Derived Growth Factor Receptor (PDGFR) family, including PDGFR- α and PDGFR- β, PDGFR can act on endothelial cells and stromal cells through a variety of effects to promote angiogenesis; the Fibroblast Growth Factor (FGFR) family, including FGFR-1, FGFR-2, FGFR-3 and FGFR-4, is a pleiotropic growth factor capable of regulating cell division, proliferation, migration and differentiation, and the receptors play an important role in angiogenesis. There are also the Insulin Receptor (IR) family, the myosin receptor kinase (TRK) family, the Hepatocyte Growth Factor Receptor (HGFR) family, and the leukocyte tyrosine kinase (ltk) family, which play an important role in the signaling, metastasis and angiogenesis within tumor cells (Fujii m.int.j.clin.oncol.2014, 19.
Non-receptor PTKs are usually present in the cytosol or bind to transmembrane receptors inside the cell membrane, with no extracellular structure. It performs signal transduction functions through cytokine receptors, T cell receptors and other signaling pathways, and mainly includes the families SRC, ABL, JAK, ACK, CSK, FAK, FRK, TEC and SYK (Li Xin, gao Jinheng, chen Guoliang, shenyang university of pharmacy, 2011,28 (12): 1005-1012).
Disclosure of Invention
The invention aims to provide a 3- (4-methylpiperidin-1-yl) -3-benzylurea compound and an analogue thereof (formula I), a prodrug of the compound and the analogue, a pharmaceutically active metabolite and a pharmaceutically acceptable salt thereof, a preparation method and application in preparing medicines for treating and/or preventing tumor diseases related to BRaf kinase, VEGFR-2, PDGFR-beta, epidermal growth factor receptor and mitogen activated extracellular signal-regulated kinase (MEK), such as small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, colorectal cancer, breast cancer, ovarian cancer and renal cell carcinoma.
Wherein n =0,1 or 2;
R 1 、R 2 each independently of the others is hydrogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, halogen beingSubstituted C1-C4 alkoxy, halogen, nitro, amino or C1-C4 alkylamino; r 1 、R 2 May be one or more.
Further, the present invention relates to compounds represented by formula I, prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof:
n =0,1 or 2;
R 1 、R 2 each independently is methoxy, ethoxy, isobutoxy, fluoro, chloro, 2- (1-methylpiperazin-4-yl) ethoxy or trifluoromethoxy;
further, the following compounds are preferred in the present invention:
HA01:1- (4-methylpiperidin-1-yl) -1- (4-ethoxybenzyl) -3- (4-isobutoxybenzyl) urea;
HA02:1- (4-methylpiperidin-1-yl) -1- (4-fluorophenethyl) -3- (4-isobutoxyphenyl) urea;
HA03:1- (4-methylpiperidin-1-yl) -1- (4-fluorobenzyl) -3- (4-isobutoxyphenyl) urea;
HA04:1- (4-methylpiperidin-1-yl) -1- (4-fluorobenzyl) -3- (4-isobutoxyphenylethyl) urea;
HA05:1- (4-methylpiperidin-1-yl) -1- (4-isobutoxybenzyl) -3- (4-fluorobenzyl) urea;
HA06:1- (4-methylpiperidin-1-yl) -1- { 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzyl } -3- (4-trifluoromethoxyphenyl) urea;
HA07:1- (4-methylpiperidin-1-yl) -1- { 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzyl } -3- (3-chloro-4-fluorophenyl) urea.
A pharmaceutical composition comprising as active ingredient a compound of the invention, prodrugs and pharmaceutically active metabolites thereof, and a compound of any one of the pharmaceutically acceptable salts of the above compounds, and a pharmaceutically acceptable carrier or diluent.
"pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological potency and properties of the compounds of formula I and are formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 2- , , , , , , , , , , , , , , , , , , , , , </xnotran> Edetate, pyruvate, alpha-ketoglutarate, alginate, cyclopentanepropionate, 3-phenylpropionate, 3-cyclohexylpropionic acid, 2-naphthoate, 2-naphthalenesulfonate, pamoate, lauryl sulfate, glycerophosphate, lauryl sulfate, pectin oleate, and the like. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts of organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine salts and the like, also, basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides and the like. Preferred acids for the formation of acid addition salts include hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, sulfanilic acid.
The invention also relates to pharmaceutical compositions for inhibiting tyrosine kinases and serine kinases, which compositions comprise a compound of formula I or a derivative or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
"pharmaceutically acceptable" such as pharmaceutically acceptable carriers, excipients, prodrugs, etc., means pharmacologically acceptable and substantially non-toxic to a patient to whom a particular compound is administered.
"pharmaceutically active metabolite" refers to a pharmaceutically acceptable and effective metabolite of a compound of formula I.
The term "halogen" as used in the present invention includes fluorine, chlorine, bromine or iodine.
The compounds of the invention can be administered to a patient by various methods, such as orally in capsules or tablets, as sterile solutions or suspensions, and in some cases, intravenously in the form of solutions. The free base compounds of the present invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.
The compound provided by the invention is used as a novel structural type BRAF (Vascular endothelial growth factor receptor), VEGFR (Vascular endothelial growth factor receptor), PDGFR (Platelet-derived growth factor receptor), EGFR (epidermal growth factor receptor) and mitogen-activated extracellular signal-regulated kinase (MEK), has the characteristics of novel structural type, capability of acting on a plurality of MEK (extracellular signal-regulated kinase) targets and the like, can be used for treating or preventing BRAF (Vascular endothelial growth factor receptor) -2 (VEGFR-2 ) and PDGF-beta (Platelet-derived growth factor receptor-beta, PDGFR-2) and the like, and can be used for treating or preventing colorectal cancer and the like, and can be used for developing small cell tumor-related diseases, such as small cell tumor, small cell tumor cell, breast cancer, ovarian cancer and mitogen-activated cell tumor-mediated tumor cell tumor diseases.
The preparation method of the compound comprises the following steps:
the preparation route of the compounds HA 01-HA 05:
preparation routes of compounds HA 06-HA 07:
the compound can be combined with protein tyrosine kinases such as EGFR, VEGFR and the like in a reversible mode, and blocks a downstream signal path of a related growth factor receptor, so that related physiological activities such as tumor cell proliferation, differentiation, metastasis and the like are inhibited. And can further induce tumor cell apoptosis.
The invention has the following effects: the invention develops an N-4-methylpiperidine-1-substituted urea compound serving as an antitumor drug and has a novel skeleton structure. Compared with positive control drugs, the compound has similar anti-tumor cell proliferation activity, better flexibility of the structure of the compound and better membrane penetration and absorption.
Detailed Description
Synthetic examples
Example 1: preparation of 1- (4-methylpiperidin-1-yl) -1- (4-ethoxybenzyl) -3- (4-isobutoxybenzyl) urea (HA 01):
preparing by adopting a first route;
step I: weighing 4-ethoxybenzylamine (3.02g, 20mmol) 1-methylpiperidine-4-one (2.26g, 20mmol) and placing the mixture into a 100mL flask, adding 40mL MeOH, stirring and dissolving, adding AcOH (0.3g, 5mmol), stirring and reacting at room temperature for 1h, weighing sodium cyanoborohydride, adding the sodium cyanoborohydride into the flask in batches, and discharging a large amount of gas. TLC confirmed the reaction was complete, methanol was evaporated under reduced pressure to give a paste, 2mol/L EtOH was added and dissolved with stirring, DCM was used for extraction, the organic phase was collected, washed with water and saturated brine, and the solvent was evaporated under reduced pressure to give N- (1-methylpiperidin-4-yl) -4-ethoxybenzylamine 4.22g as a yellow oily liquid with a yield of 84.95%.
Step II: triphosgene (0.20g, 0.067mmol) was weighed into a flask, and 10mL of DCM was added and dissolved with stirring. Substituted p-isobutoxybenzylamine (0.36g, 2mmol) is weighed and dissolved in 10mL DCM, slowly added into the flask dropwise at room temperature, and a large amount of solid is separated out after dropwise addition. Triethylamine (0.40g, 4 mmol) was weighed into 10mL DCM and slowly added dropwise to the flask at room temperature, and the solid gradually dissolved. Weighing N- (4-methylpiperidin-1-yl) -N- (4-ethoxybenzyl) amine, dissolving in 10mL DCM, dropwise adding into a bottle, stirring at room temperature for 1h after the dropwise adding is finished, and monitoring the reaction by TLC. Stopping the reaction, transferring the reaction solution into a separating funnel, washing with 50mL multiplied by 3 times of water, back-extracting with saturated salt solution, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and then separating and purifying by column chromatography to obtain 0.43g of a target product, namely a white solid (HA 01), with the yield of 31.6%; m.p.:116.9 to 117.5 ℃; MS:454.4[ deg. ] M + H] + ,452.4[M-H] - ； 1 H NMR(400MHz,Chloroform-d)δ7.16–7.09(m,2H),7.03–6.96(m,2H),6.87–6.73(m,4H),4.56(t,J＝5.5Hz,1H),4.41(tt,J＝11.6,4.5Hz,1H),4.31(s,2H),4.27(d,J＝5.4Hz,2H),4.02(q,J＝7.0Hz,2H),3.69(d,J＝6.6Hz,2H),2.92–2.83(m,2H),2.27(s,3H),2.15–1.99(m,3H),1.70(dtd,J＝28.2,11.8,3.7Hz,4H),1.42(t,J＝7.0Hz,3H),1.02(d,J＝6.7Hz,6H)。
Example 2: preparation of 1- (4-methylpiperidin-1-yl) -1- (4-fluorophenethyl) -3- (4-isobutoxyphenyl) urea (HA 02)
Referring to the preparation method of example 1, 0.3g of a white solid was obtained in a yield of 23.4%; m.p.:127.3 to 128.1 ℃; MS:428.3[ 2 ] M + H] + ，450.2[M+Na] + ，426.7[M-H] - ； 1 H NMR(400MHz,Chloroform-d)δ7.21(dd,J＝8.4,5.5Hz,2H),7.15–7.08(m,2H),7.07–6.98(m,2H),6.86–6.79(m,2H),6.01(s,1H),4.07(tt,J＝11.5,4.5Hz,1H),3.69(d,J＝6.6Hz,2H),3.43(t,J＝7.6Hz,2H),2.99–2.85(m,4H),2.31(s,3H),2.14–1.96(m,4H),1.84(td,J＝12.0,3.8Hz,2H),1.02(d,J＝6.7Hz,6H)。
Example 3: preparation of 1- (4-methylpiperidin-1-yl) -1- (4-fluorobenzyl) -3- (4-isobutoxyphenyl) urea (HA 03)
Referring to the preparation method of example 1, 0.38g of white solid was obtained with a yield of 30.6%; m.p.:151.1-152.8 ℃; MS:414.4[ mu ] M + H] + ,436.3[M+Na] + ； 1 H NMR(400MHz,Chloroform-d)δ7.34–7.28(m,2H),7.16–7.03(m,4H),6.78(dd,J＝9.0,3.9Hz,2H),6.07(s,1H),4.47(s,2H),4.38(tq,J＝12.9,4.6Hz,1H),3.74–3.63(m,2H),2.90(d,J＝10.2Hz,2H),2.28(d,J＝3.9Hz,3H),2.16–2.02(m,3H),1.76(dtd,J＝16.6,12.5,10.9,6.3Hz,4H),1.00(dd,J＝7.0,3.9Hz,6H)。
Example 4: preparation of 1- (4-methylpiperidin-1-yl) -1- (4-fluorobenzyl) -3- (4-isobutoxyphenylethyl) urea (HA 04)
Referring to the preparation method of example 1, 0.32g of white solid was obtained in 24.2% yield; m.p. 88.9-90.3 ℃; MS:442.4[ 2 ] M + H] + ； 1 H NMR(400MHz,Chloroform-d)δ7.07(dd,J＝8.5,5.4Hz,2H),7.00–6.86(m,4H),6.76–6.69(m,2H),4.34–4.21(m,3H),4.18(t,J＝5.5Hz,1H),3.67(d,J＝6.5Hz,2H),3.39(q,J＝6.5Hz,2H),2.93–2.85(m,2H),2.64(t,J＝6.7Hz,2H),2.28(s,3H),2.09(tdd,J＝13.4,9.6,5.1Hz,3H),1.67(td,J＝11.5,10.5,3.6Hz,4H),1.03(d,J＝6.7Hz,6H)。
Example 5: preparation of 1- (4-methylpiperidin-1-yl) -1- (4-isobutoxybenzyl) -3- (4-fluorobenzyl) urea (HA 05)
The preparation was obtained with reference to example 1, 0.49g of white solid is obtained, and the yield is 38.2%; m.p. 131.4-132.6 ℃; MS:428.3[ deg. ] M +H] + ,426.2[M-H] - ； 1 H NMR(400MHz,Chloroform-d)δ7.12(d,J＝8.4Hz,2H),7.07–6.99(m,2H),6.96–6.87(m,2H),6.87–6.80(m,2H),4.65(t,J＝5.7Hz,1H),4.45(tt,J＝10.9,5.8Hz,1H),4.34–4.25(m,4H),3.70(d,J＝6.5Hz,2H),3.00–2.91(m,2H),2.33(s,3H),2.19(td,J＝11.3,4.4Hz,2H),2.08(dp,J＝13.4,6.7Hz,1H),1.86–1.74(m,4H),1.04(d,J＝6.7Hz,6H)。
Example 6: preparation of 1- (4-methylpiperidin-1-yl) -1- { 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzyl } -3- (4-trifluoromethoxyphenyl) urea (HA 06)
Preparing by adopting a second route;
step I: weighing 2-chloroethanol (20.63g, 250mmol), vanillin (15.22g, 100mmol), anhydrous potassium carbonate (K) 2 CO 3 ) (69g, 0.5 mol), potassium iodide (0.166g, 1mmol) was placed in a 250mL round bottom flask, 100mL of N, N-Dimethylformamide (DMF) was added and stirred at 80 deg.C for 24h, and the reaction was monitored by Thin Layer Chromatography (TLC). The reaction was stopped, the reaction solution was poured into a 1L beaker, and 750mL of water was added and stirred until anhydrous K 2 CO 3 Completely dissolved, the liquid was transferred to a separatory funnel, EA150 mL. Times.4 extractions, the organic phases were combined, washed with 2mol/L sodium hydroxide (NaOH) solution 200 mL. Times.2, once with 200mL water, once with 200mL saturated brine, and anhydrous sodium sulfate (Na. Sub. 2 SO 4 ) Drying, filtering, distilling and concentrating under reduced pressure, precipitating solid, adding PE, anhydrous ether, filtering, washing filter cake with anhydrous ether, and drying to obtain light yellow solid 4- (2-hydroxyethoxy) -3-methoxybenzaldehyde 9.66g with yield 49.27%.
Step II: 4- (2-hydroxyethoxy) -3-methoxybenzaldehyde (19.6 g, 100mmol) and NaOH (6 g, 150mmol) were weighed out in a 250mL round-bottom flask, and 50mL of water and 50mL of Tetrahydrofuran (THF) were added and stirred. 4-tosyl chloride (TsCl) (20.02g, 105mmol) was weighed out and dissolved in 50mL THF, added dropwise to the round-bottomed flask in an ice-water bath, and after the addition was completed, the temperature was slowly raised to room temperature, stirred overnight, and the reaction was monitored by TLC (VEA: VPE = 1:1). The reaction was stopped, filtered, and the filter cake was washed with THF and water in sequence and dried to give 25.26g of [ (4-formyl-2-methoxyphenoxy) ethyl ] 4-methylbenzenesulfonic acid as a white solid in 72.15% yield.
Step III: n-methylpiperazine (3.3g, 33mmol) was weighed into a 100mL round-bottomed flask and anhydrous K was added 2 CO 3 (13.8 g, 100mmol), 4-methylbenzenesulfonic acid [ (4-formyl-2-methoxyphenoxy) ethyl group]Ester (10.51g, 30mmol) was placed in the round bottom flask, 40mL acetonitrile was added, the reaction was stirred at 70 deg.C overnight, and the reaction was monitored by TLC. The reaction was stopped, concentrated by distillation under reduced pressure, 60mL of water was added to the round-bottomed flask, and stirred until anhydrous K was obtained 2 CO 3 After complete dissolution, the liquid was transferred to a separatory funnel, EA X3 times extracted, the organic phases were combined, washed once with 50mL of saturated brine, anhydrous Na 2 SO 4 Drying, and distilling off the solvent under reduced pressure to obtain 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] ethanol as a yellow oily liquid]Benzaldehyde 7.95g, yield 95.20%.
Step IV: hydroxylamine hydrochloride (2.29g, 33mmol) and sodium bicarbonate (2.77g, 33mmol) were weighed into a50mL eggplant-shaped bottle, 30mL of water was added, and the reaction was stirred at room temperature for half an hour to release a large amount of gas. Weighing 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy]Benzaldehyde (8.62g, 30mmol) was placed in a 100ml flask and dissolved by adding 30ml ethanol (EtOH) with stirring, a hydroxylamine hydrochloride solution was added to the flask with stirring and reacted at room temperature for 3h, monitored by tlc (DCM: meOH = 20). The reaction was stopped, etOH was distilled off under reduced pressure, cooled to room temperature, EA50mL X3 times extracted, the organic phases combined, washed with 50mL of saturated brine, anhydrous Na 2 SO 4 Drying, filtering, and distilling off the solvent under reduced pressure to obtain yellow solid 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy]Benzaldehyde oxime 8.56g, yield 97.26%.
And V: weighing 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy]Benzaldoxime (8.8g, 30mmol) was placed in a 250mL eggplant-shaped bottle, dissolved by adding 50mL EtOH, and 60mL of a 5mol/L NaOH solution was added in ice bath. Weighing nickel-aluminum alloy (10 g), adding into a flask in batches under ice bath, discharging a large amount of gas to fully perform the reaction, analyzing by TLC (DCM: meOH = 20) 2 SO 4 Drying, filtering, and distilling off the solvent under reduced pressure to obtain yellow liquid 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy]7.86g of benzylamine, yield 93.78%,MS：280.2([M+H] + )。
step VI: 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzylamine (5.58g, 20mmol) 1-methylpiperidin-4-one (2.26g, 20mmol) was weighed and placed in a 100mL flask, 40mL of MeOH was added and stirred to dissolve, acOH (0.3g, 5mmol) was added and stirred at room temperature for 1 hour, sodium cyanoborohydride (1.26g, 20mmol) was weighed and added to the flask in portions, and a large amount of gas was discharged. After confirming the completion of the reaction by TLC, methanol was evaporated under reduced pressure to give a paste, which was dissolved by adding 2mol/L EtOH under stirring, DCM was used for extraction, and the organic phase was collected, washed with water, washed with saturated brine, and the solvent was evaporated under reduced pressure to give 6.02g of N- (1-methylpiperidin-4-yl) -3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzylamine as a yellow liquid in a yield of 80.15%.
Step VII: triphosgene (0.20g, 0.067mmol) was weighed into a flask, and 10mL of DCM was added and dissolved with stirring. Substituted p-trifluoromethylaniline (0.30g, 2mmol) was weighed and dissolved in 10mL DCM, slowly added dropwise to the flask at room temperature, and after the dropwise addition was completed, a large amount of solid was precipitated. Triethylamine (0.40g, 4 mmol) was weighed into 10mL DCM and slowly added dropwise to the flask at room temperature, and the solid gradually dissolved. Weighing N- (1-methylpiperidin-4-yl) -3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy]Benzylamine (0.75g, 2mmol), dissolved in 10mL DCM, was added dropwise to the flask, after the addition was complete, the mixture was stirred at room temperature for 1h, and the reaction was monitored by TLC. Stopping the reaction, transferring the reaction solution into a separating funnel, washing with 50mL multiplied by 3 times of water, back-extracting with saturated salt solution, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and then separating and purifying by column chromatography to obtain 0.35g of white solid (HA 07), wherein the yield is 30.2%; m.p.:122.6-123.5 ℃; MS:580.3[ mu ] M + H] + ； 1 H NMR(400MHz,Chloroform-d)δ7.19–7.11(m,2H),7.10–7.02(m,2H),6.94–6.78(m,3H),6.36(s,1H),4.49–4.38(m,3H),4.15(t,J＝6.1Hz,2H),3.84(s,3H),2.87(t,J＝6.1Hz,2H),2.65(s,4H),2.49(s,4H),2.29(d,J＝1.8Hz,6H),2.14(ddd,J＝14.8,11.6,5.8Hz,4H),1.84–1.69(m,4H)。
Example 7: preparation of 1- (4-methylpiperidin-1-yl) -1- { 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzyl } -3- (3-chloro-4-fluorophenyl) urea (HA 07)
By reference to the preparation of example 6, white was obtained0.36g of a colored solid (HA 07), yield 32.8%; m.p.:133.8-135.2 ℃; MS:548.3[ deg. ] M + H] + ,546.2[M-H] - ； 1 H NMR(400MHz,Chloroform-d)δ7.38(dd,J＝6.6,2.6Hz,1H),6.99–6.83(m,4H),6.80(d,J＝1.9Hz,1H),6.34(d,J＝6.7Hz,1H),4.41(s,3H),4.19–4.11(m,2H),3.84(s,3H),2.95–2.84(m,4H),2.70–2.60(m,4H),2.54–2.45(m,4H),2.29(d,J＝2.5Hz,6H),2.13(td,J＝11.4,3.6Hz,2H),1.85–1.68(m,4H)。
Pharmacological examples
Example 8: inhibitory Activity of test Compounds on cell proliferation of A549, MCF7, HCT116, and PC3
(1) Experimental Material
Cell line: a549, MCF7, HCT116 and PC3 cells are respectively paved on a 96-well plate at the density of 1500, 2200, 800 and 2000 cells/well, and are used after 100ul and 24h.
The test compounds were dissolved in DMSO and diluted with culture medium to five different concentrations of 50. Mu.M, 20. Mu.M, 10. Mu.M, 5. Mu.M, 2.5. Mu.M and stored at-20 ℃ until use, with the final concentration of DMSO in the culture medium being less than 0.1%.
Positive control drug: sorafenib (sorafenib).
MTT: dissolved in PBS to be 2mg/mL, store at-20 ℃.
(2) Experimental method
A549, MCF7, HCT116, and PC3 cells were selected by MTT method to evaluate the antitumor proliferation activity of the test sample. A549, HCT116 and PC3 cell strains were cultured in RPMI 1640 medium containing 10% bovine serum (FBS), and MCF-7 cell strains were cultured in DMEM medium containing 10% bovine serum (FBS). When the cells proliferated to 80-90% they were pooled and subsequently subcultured for no more than 20 passages, and then they were acclimatized for 24h before the next disposal. These cells were placed in a 96-well plate and then were subjected to the following analysis to 5% CO 2 Was incubated overnight in a humidified environment and temperature controlled at 37 ℃. After 24h, adding differentConcentration of representative compounds of the invention. After an additional 24h of incubation, MTT (2 mg/mL) was added and incubation continued for 4h. The culture medium was removed, the crystals were dissolved in DMSO, and the absorbance was measured at a wavelength of 570nm using a microplate reader (TECAN SPECTRA, wetDar, germany). According to the formula: cell growth inhibition rate = (1-drug group OD value/control group OD value) × 100%, cell growth inhibition rate under corresponding concentration is calculated, and IC corresponding to test compound is calculated according to logarithmic curve of inhibition rate of different concentrations and cells of test compound 50 The value is obtained.
In the prepared compound, HA 01-HA 05 HAs better anti-tumor cell proliferation activity compared with HA06 and HA07 with piperazine structures. IC of compound HA01 to four tumor cell strains 50 Both reached 10. Mu.M or less, and the IC of HA04 and HA05 on MCF7 cell line 50 Even lower to 5. Mu.M or less. Comparison of HA03 to HA05 shows that the inhibitory activity of the compounds is optimal when the carbon chain length n = 1. Comparison of HA01 to HA05 shows R 2 When the substituent is 4-fluorine substitution, the compound has stronger inhibitory activity on MCF7 cells.
Formulation examples
The following formulation examples are merely illustrative of the scope of the invention and are not to be construed as limiting in any way. The active compounds described in the following examples refer to the compounds HA-01 to HA07 prepared in the above examples.
Example 9: tablet formulation
25-1000mg of active compound, 45mg of starch, 35mg of microcrystalline cellulose, 4mL of polyvinylpyrrolidone (as a 10% aqueous solution), 4.5mg of sodium carboxymethylcellulose, 0.5mg of magnesium stearate, and 1mg of talc.
Example 10: suspending agent formulation
0.1-1000mg of active compound, 50mg of sodium carboxymethylcellulose, 1.25mg of syrup, 0.1mg of sodium benzoate, 25mg of flavoring agent, 5mg of coloring agent and 5mL of pure water.
Example 11: aerosol formulations
0.25mg of active compound, 25-75mL of ethanol and 70mg of propellant 22 (chlorodifluoromethane).
Example 12: suppository formula
250mg of active compound, 2000mL of saturated fatty acid glycerides.
Example 13: injectable formulation
50mg of active compound, 1000mL of isotonic saline solution.
Example 14: ointment formulation
0.025g of micronized active compound, 10g of liquid paraffin and 100g of soft white wax.
Example 15: ointment formulations
0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin and 100g of soft white wax.
Example 16: oil-in-water cream formulation
0.025g of active compound, 5g of hexadecanol, 5g of glycerin monostearate, 10g of liquid paraffin, 2g of cetyl polyoxyethylene ether, 0.1g of citric acid, 0.2g of sodium citrate, 35g of propylene glycol and water until the weight is 100g.
Example 17: oil-in-water cream formulation
0.025g of micronized active compound, 15g of soft white wax, 5g of liquid paraffin, 5g of cetyl alcohol, 2g of Sorbimcarol stearate (Tween 65, grade of specific pharmaceutical excipients), 0.5g of sorbitan monostearate, 0.2g of sorbic acid, 0.1g of citric acid, 0.2g of sodium citrate, and water to 100g.
Example 18: water-in-oil cream formulation
0.025g of active compound, 35g of soft white wax, 5g of liquid paraffin, 5g of sorbitan sesquioleate, 0.2g of sorbic acid, 0.1g of citric acid and 0.2g of sodium citrate, and water is added until the weight is 100g.
Example 19: lotion formulation
0.25g of active compound, 0.5mL of isopropanol, 3mg of carboxyvinyl polymer, 2mg of NaOH, and 1g of water.
Example 20: suspension formulation for injection
10mg of the active compound, sodium carboxymethylcellulose 7mg, naCl 7mg, polyoxyethylene (20) sorbitan monooleate 0.5mg, benzyl alcohol 8mg, and sterile water to 1mL.
Example 21: aerosol formulation for oral and nasal inhalation
0.1% w/w of active compound, 0.7% w/w of sorbitan trioleate, 24.8% w/w of trichlorofluoromethane, 24.8% w/w of dichlorotetrafluoroethane, 49.6% w/w of dichlorodifluoromethane.
Example 22: atomized solution formulation
7mg of active compound, 5mg of propylene glycol, and water to 10g.
Example 23: powder formulations for inhalation
Gelatine capsules were filled with a mixture of the following ingredients, micronised active compound 0.1mg, lactose 20mg and the powder was inhaled with the aid of an inhalation device.
Example 24: powder formulations for inhalation
The spheronized powder was loaded into a multi-dose powder inhaler containing 0.1mg of micronized active compound per dose.
Example 25: powder formulations for inhalation
The spheronized powder was loaded into a multi-dose powder inhaler containing 0.1mg of micronized active compound and 1mg of micronized lactose per dose.
Example 26: capsule formulation
1.0mg of active compound, 321mg of small sugar spheres, 6.6mg of Aquacoat ECD, 0.5mg of acetyl tributyl citrate, 0.1mg of Tween-80, 100-55.5 mg of Eudragit L, 1.8mg of triethyl citrate, 8.8mg of talcum powder and 0.lmg of defoamer MMSg.
Example 27: capsule body-slimming formula
2.0mg of active compound, 305mg of small sugar spheres, 5.0mg of Aquocoat ECD 30.0mg, 0.4mg of acetyl tributyl citrate, 0.14mg of Tween-80, 12.6mg of Eudragit NE30D, 12.6mg of Eudragit S100.6 mg and 0.l6mg of talcum powder.
Example 28: enema formula
2mg of active compound, 25mg of sodium carboxymethylcellulose, 0.5mg of disodium ethylenediaminetetraacetate, 0.8mg of methyl p-hydroxybenzoate, 0.2mg of propyl p-hydroxybenzoate, 7mg of sodium chloride, 1.8mg of citric acid, 0.01mg of tween-80 and purified water to be 1mL.
Example 29: formulations containing liposomes
A. Preparation of the instillation formulation
Dipalmitoyl lecithin (45 mg), dimyristoyl lecithin (7 mg), dipalmitoyl phosphatidyl glycerol (1 mg) and active compound (5 mg) were placed in a glass tube, all components were dissolved in chloroform and N was used 2 Adding an aqueous solution (0.9% NaCl) to the lipid to form liposomes at a temperature above the phase inversion temperature of the lipid, the resulting suspension containing liposomes ranging in size from very small vesicles to 2 μm.
B. Preparation of formulations for inhalation
Liposomes were prepared as in example A, with an aqueous solution containing 10% lactose at a lactose to lipid ratio of 7:3. The liposome suspension was frozen with dry ice and freeze-dried, and the dried product was micronized, and the Mass Mean Aerodynamic Diameter (MMAD) of the resulting particles was about 2 μm.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. Any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention, without departing from the technical solution of the present invention, still belong to the protection scope of the technical solution of the present invention.
Claims (7)
1. A3- (4-methylpiperidin-1-yl) -3-benzylurea compound and a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:
HA02:1- (4-methylpiperidin-1-yl) -1- (4-fluorophenethyl) -3- (4-isobutoxyphenyl) urea;
HA03:1- (4-methylpiperidin-1-yl) -1- (4-fluorobenzyl) -3- (4-isobutoxyphenyl) urea;
HA04:1- (4-methylpiperidin-1-yl) -1- (4-fluorobenzyl) -3- (4-isobutoxyphenylethyl) urea;
HA06:1- (4-methylpiperidin-1-yl) -1- { 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzyl } -3- (4-trifluoromethoxyphenyl) urea;
HA07:1- (4-methylpiperidin-1-yl) -1- { 3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy ] benzyl } -3- (3-chloro-4-fluorophenyl) urea;
2. a pharmaceutical composition comprising the compound of any one of 3- (4-methylpiperidin-1-yl) -3-benzylurea compound and a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier or diluent.
3. The pharmaceutical composition of claim 2, which is a pharmaceutical composition for inhibiting tyrosine kinase and serine threonine kinase.
4. A process for preparing 3- (4-methylpiperidin-1-yl) -3-benzylurea compound and pharmaceutically acceptable salt thereof according to claim 1, wherein the process for preparing 3- (4-methylpiperidin-1-yl) -3-benzylurea compound comprises the following preparation route:
the preparation route of the compounds HA 02-HA 04 is as follows:
the preparation route of the compounds HA 06-HA 07 is as follows:
5. use of a 3- (4-methylpiperidin-1-yl) -3-benzylurea compound according to claim 1 and pharmaceutically acceptable salts thereof or a pharmaceutical composition according to any one of claims 2 to 3 for the preparation of a BRaf kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor or mitogen-activated extracellular signal-regulated kinase inhibitor.
6. The use of the 3- (4-methylpiperidin-1-yl) -3-benzylurea compound according to claim 1 and pharmaceutically acceptable salts thereof or the pharmaceutical composition according to any one of claims 2 to 3 for the preparation of a medicament for the treatment of tumors.
7. The use of claim 6, wherein the neoplasm comprises lung cancer, liver cancer, melanoma, colon cancer, rectal cancer, breast cancer, ovarian cancer, and renal cancer.
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