CN113292515B - Urea compound containing piperazine group and preparation method and application thereof - Google Patents

Urea compound containing piperazine group and preparation method and application thereof Download PDF

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CN113292515B
CN113292515B CN202110624640.XA CN202110624640A CN113292515B CN 113292515 B CN113292515 B CN 113292515B CN 202110624640 A CN202110624640 A CN 202110624640A CN 113292515 B CN113292515 B CN 113292515B
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urea
methoxy
ethoxy
benzyl
piperazin
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CN113292515A (en
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胡春
侯世澄
韩英妹
王润
张新庚
赵紫雅
李茉
郑洁
董佳怡
向奕霏
李涛
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a urea compound containing piperazine groups, a preparation method and application thereof, in particular to 1-aryl-3- { 3-methoxy-4- [2- (4-phenylpiperazin-1-yl) ethoxy]Benzyl } urea compounds, a preparation method thereof and application thereof in preparing antitumor drugs. The 1-aryl-3- { 3-methoxyl-4- [2- (4-phenylpiperazin-1-yl) ethoxy]The structural general formula of the benzyl urea compound, prodrug thereof, pharmaceutically active metabolite thereof and pharmaceutically acceptable salt thereof is shown as follows: n can be 0 or 1; r1Can be methyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, nitro, dimethylamino, fluoro, chloro or 3-chloro-4-fluoro; r2Can be 2, 3-dichloro or 4-methoxy; the compound of the invention has simple and convenient synthesis method, is suitable for industrial production, shows that the compound has anti-tumor activity by biological activity test, and can be applied to the preparation of anti-tumor drugs.

Description

Urea compound containing piperazine group and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 1-aryl-3- { 3-methoxy-4- [2- (4-phenylpiperazine-1-yl) ethoxy ] benzyl } urea compound, a preparation method thereof, and application thereof as RAF kinase, RAS kinase and MEK kinase inhibitors in preparation of antitumor drugs.
Background
Cancer is becoming an important factor threatening human life and health from its inception. According to relevant statistics, cancer has now become the second leading cause of death in humans. Especially in the last thirty years, the prevalence of cancer and the number of deaths has shown a dramatic trend in china. With the development of molecular biology technology, the pathogenesis of tumors is gradually clarified, and a plurality of different action targets are gradually discovered. Among the several lines of targets associated with tumor cell growth and apoptosis, protein kinases dominate (zhonghong Wang, Philip a. cole. methods in Enzymology,2014,548: 1-21).
The protein serine threonine kinase mainly exists in cytoplasm and mainly executes downstream signal conduction of growth factors, thereby realizing a series of physiological changes of regulating and controlling cell proliferation, apoptosis and the like. Common protein serine threonine kinases mainly include: RAF family including A-BAF, B-RAF, C-RAF, RAF; the mitogen-activated extracellular signal-regulated kinase (MEK) family, including MEK1 and MEK 2; the ERK (extracellular regulated protein kinases) family, including ERK1 and ERK 2; RAF, MEK and ERK kinases together constitute the RAS kinase downstream pathway, and this signaling pathway plays a crucial role in tumor cell proliferation, apoptosis and metastasis (Robert Roskoski. pharmaceutical Research,2019,142: 151-. Further common protein serine threonine kinases are PI 3K; akt, and the like.
Protein silk threonine kinase inhibitors which have been approved for clinical use today represent Sorafenib (Sorafenib), Regorafenib (Regorafenib), Dabrafenib (Dabrafenib) and others (Scott a. foster,1Daniel m. whalen,2 aysxetlogulozen, et al. cancer Cell 2016,29: 477-. However, these drugs have various degrees of side effects and most of them develop mutation resistance after long-term administration (Xiaoyun Lu, Jeff B. Smaill, and Ke Ding.J.Med.chem.2020,63,19, 10726-10741). Therefore, the continuous development of novel protein serine threonine kinase inhibitors has great significance for the treatment of related cancers.
Disclosure of Invention
The invention aims to provide a piperazine group-containing urea compound shown as a formula I, a prodrug and a pharmaceutically acceptable salt thereof, a preparation method of the compound and application of the compound as an RAF kinase, RAS kinase and MEK kinase inhibitor in treating cancers.
Figure BDA0003100536950000021
Wherein n is 0, 1 or 2;
R1、R2each independently is hydrogen, C1-C4 alkyl, halogen substituted C1-C4 alkyl, C1-C4 alkoxy, halogen substituted C1-C4 alkoxy, halogen, nitro, amino or C1-C4 alkylamino; at the same time, R1、R2May be one or more;
further, the compounds represented by formula I, prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, according to the present invention:
n is 0 or 1;
R1is methyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, nitro, dimethylamino, fluoro, chloro or 3-chloro-4-fluoro;
R2is 2, 3-dichloro or/and methoxy.
Further, the compound of the present invention is any one of the following compounds:
HE 01: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-ethoxybenzyl) urea;
HE 02: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethoxyphenyl) urea;
HE 03: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-chloro-4-fluorophenyl) urea;
HE 04: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-trifluoromethylphenyl) urea;
HE 05: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-nitrophenyl) urea;
HE 06: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-dimethylaminobenzyl) urea;
HE 07: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxyphenyl) urea;
HE 08: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethylphenyl) urea;
HE 09: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxybenzyl) urea;
HE 10: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-chlorophenyl) urea;
HE 11: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-fluorophenyl) urea;
HE 12: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-fluorobenzyl) urea;
HE 13: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-tolyl) urea;
HE 14: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-chloro-4-fluorophenyl) urea;
HE 15: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethoxyphenyl) urea;
HE 16: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-trifluoromethylphenyl) urea;
HE 17: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-ethoxybenzyl) urea;
HE 18: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxyphenyl) urea;
HE 19: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-tolyl) urea;
HE 20: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-dimethylaminobenzyl) urea;
HE 21: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-nitrophenyl) urea;
HE 22: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethylphenyl) urea.
A pharmaceutical composition comprising as active ingredient a compound according to the invention, prodrugs and pharmaceutically active metabolites thereof, and a compound of any one of the above compounds in a pharmaceutically acceptable salt thereof, 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. Acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, perchlorate, thiocyanate, bisulfate, persulfate, borate, formate, acetate, propionate, valerate, pivalate, hexanoate, heptanoate, octanoate, isooctanoate, undecanoate, laurate, palmitate, stearate, oleate, cyclopropionate, oxalate, malonate, succinate, maleate, fumarate, adipate, azelate, acrylate, strawberry, crotonate, glatironate, itaconate, sorbate, cinnamate, glycolate, lactate, malate, tartrate, citrate, tartrate, mandelate, diphenoxylate, troponate, ascorbate, gluconate, glucoheptonate, mandelate, dibenzolate, trogoplate, ascorbate, gluconate, glucoheptonate, and the like, Glucarate, mannonate, lactobionate, benzoate, phthalate, paraththalate, furoate, nicotinate, isonicotinate, salicylate, acetylsalicylate, caseinate, gallate, caffeate, ferulate, picrate, camphorate, camphorsulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, p-toluenesulfonate, sulfanilate, sulfamate, taurate, 2-hydroxyethanesulfonate, glycinate, alaninate, valine, leucine, isoleucine, phenylalanine, tryptophan, caseinate, aspartate, asparagine, glutamate, lysine, glutamine, methionine, serine, threonine, cysteine, proline, histidine, arginine, and salts thereof, 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 with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and the like, and 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 a pharmaceutical composition for inhibiting tyrosine kinase and serine threonine kinase, which comprises the compound shown in the formula I or the derivative or the pharmaceutically applicable 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 of the invention is used as BRAF kinase, Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-derived growth factor receptor (PDGFR), Epidermal Growth Factor Receptor (EGFR) and mitogen-activated extracellular signal-regulated kinase (MEK) with novel structure types, can be used for treating or preventing BRAF kinase, Vascular endothelial growth factor receptor-2 (VEGFR-2) Platelet-derived growth factor receptor-beta (FR-beta) and epidermal growth factor receptor (PDGF-beta) with multiple targets, MEK) related tumor diseases such as small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, colorectal cancer, breast cancer, ovarian cancer and renal cell carcinoma, and has good application value and development and application prospects.
The preparation method of the piperazine group-containing urea compound comprises the following preparation routes:
Figure BDA0003100536950000051
the urea compound containing piperazine group, the prodrug and the pharmaceutically active metabolite thereof, and the pharmaceutically acceptable salt or the pharmaceutical composition can inhibit the function of RAF family kinase, thereby blocking the downstream conduction of the related signal path thereof and realizing the inhibition of tumor cell proliferation. In addition, the compound can also inhibit the polymerization of the periscopic protein, thereby inhibiting the mitosis process of tumor cells and achieving the aim of inhibiting the growth of tumors.
The urea compound containing piperazine group, prodrug and active metabolite thereof, and pharmaceutically acceptable salt or pharmaceutical composition are applied to preparation of inhibitors of BRaf kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor or mitogen-activated extracellular signal-regulated kinase.
The invention has the beneficial effects that:
the urea compound containing piperazine group provided by the invention has a brand new skeleton structure, and is simple in preparation process and low in cost. Has good anti-tumor cell proliferation activity, and has better activity compared with the anti-tumor drugs on the market. Is a potential anti-tumor drug active component.
Detailed Description
The present invention is described in detail by the following examples. It should be understood, however, that the present invention is not limited to the following examples which are specifically set forth.
Example 1: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-ethoxybenzyl) urea (HE01)
Step I: weighing 2-chloroethanol (20.63g, 250mmol), vanillin (15.22g, 100mmol) and anhydrous potassium carbonate (K)2CO3) (69g, 0.5mol), 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 K2CO3Completely dissolveAfter decomposition, the liquid was transferred to a separatory funnel, EA 150 mL. times.4 extractions, and 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)2SO4) 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 (19.6g, 100mmol) and NaOH (6g, 150mmol) were weighed into 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, suction filtration was carried out, and the filter cake was washed with THF and water in this order 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: 1- (2, 3-dichlorophenyl) piperazine hydrochloride (8.03g, 30mmol) was weighed into a 100mL round bottom flask and anhydrous K was added2CO3(13.8g, 100mmol), 4-methylbenzenesulfonic acid [ (4-formyl-2-methoxyphenoxy) ethyl]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. Stopping reaction, distilling under reduced pressure, concentrating, adding 60mL water into round bottom flask, stirring to anhydrous K2CO3After 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 Na2SO4Drying, and distilling off the solvent under reduced pressure to obtain a yellowish solid 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl]11.59g of ethoxy benzaldehyde, yield 94.4%.
Step IV: hydroxylamine hydrochloride (2.29g, 33mmol) and sodium bicarbonate (2.77g, 33mmol) were weighed into a50mL eggplant-shaped flask, 30mL of water was added, the reaction was stirred at room temperature for half an hour, and a large amount of gas was evolved. Weighing 3-formazanOxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl]Ethoxy } benzaldehyde (12.27g, 30mmol) was placed in a 100ml flask and 30ml ethanol (EtOH) was added and dissolved with stirring, hydroxylamine hydrochloride solution was added to the flask with stirring and reacted at room temperature for 3h, monitored by TLC (DCM: EA ═ 1: 1). 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 Na2SO4Drying, filtering and decompressing to evaporate the solvent to obtain white solid 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazine-1-yl]Ethoxy } benzaldehyde oxime 10.72g, yield 92.73%.
Step V: weighing 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazine-1-yl]Ethoxy } benzaldoxime (12.73g, 30mmol) was placed in a 250mL eggplant-shaped bottle, dissolved by adding 50mL EtOH, and 60mL of 5mol/L NaOH solution was added under ice bath. Weighing nickel aluminum alloy (10g), 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 is 20:1), after confirming that the reaction is completely performed, filtering out nickel powder participating in the reaction by suction filtration (note that the reaction cannot be dried, and the reaction can be natural), distilling out EtOH under reduced pressure, EA50mL X3 times extracting water phase, combining organic phases, washing with 50mL saturated saline solution once, and washing with anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure to obtain light yellow solid 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl]Ethoxy } benzylamine 10.48g, yield 85.2%.
Step VI: solid phosgene (dicloromethyl carbonate) (0.20g, 0.67mmol) was weighed into a 100mL eggplant-shaped flask, 10mL DCM was added and dissolved with stirring at room temperature, p-ethoxybenzylamine (0.30g, 2mmol) was weighed and dissolved in 12mL DCM and added to the flask with stirring at room temperature, and solid was gradually precipitated. Triethylamine (0.40g, 4mmol) was weighed into 12mL DCM and added to the flask with stirring at room temperature, and the solid gradually dissolved to give a clear solution. Weighing 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazine-1-yl]Ethoxy } benzylamine (0.82g, 2mmol) was dissolved in 12mL DCM and added dropwise to the flask with stirring at room temperature, TLC monitored for complete conversion of the substituted benzylamine, the reaction was transferred to 125mL separatory funnel, washed three times with 50mL water, once with 50mL saturated brine, and washed with anhydrous Na2SO4Drying, filtering and evaporating to drynessThe solvent obtained oily liquid, and the column chromatography separation obtained the target product 0.57g, yield 48.5%; ESI-MS (M/z) 587.5([ M + H)]+；1H NMR(400MHz,DMSO-d6)δ7.30(q,J＝5.0,4.3Hz,2H),7.16(dq,J＝9.5,3.1Hz,3H),6.93(d,J＝8.2Hz,1H),6.89–6.81(m,3H),6.76(dd,J＝8.3,1.9Hz,1H),6.30(q,J＝5.7Hz,2H),4.16(dd,J＝6.0,1.8Hz,4H),4.07(t,J＝5.9Hz,2H),3.99(q,J＝7.0Hz,2H),3.73(s,3H),3.00(t,J＝4.6Hz,4H),2.76(t,J＝5.9Hz,2H),2.66(d,J＝15.0Hz,4H),1.31(t,J＝7.0Hz,3H)；m.p.：46.9-148.3℃。
Example 2: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethoxyphenyl) urea (HE02)
Completing the step I to the step V by adopting the method of the embodiment 1 to obtain 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazine-1-yl ] ethoxy } benzylamine;
step VI: solid phosgene (trichloromethyl carbonate) (0.20g, 0.67mmol) was weighed into a 100mL eggplant-shaped flask, 10mL of LPCM was added and dissolved with stirring at room temperature, p-trifluoromethoxyaniline (0.35g, 2mmol) was weighed and dissolved in 12mL of DCM, and added to the flask with stirring at room temperature, and a solid was gradually precipitated. Triethylamine (0.40g, 4mmol) was weighed into 12mL DCM and added to the flask with stirring at room temperature, and the solid gradually dissolved to give a clear solution. Weighing the prepared 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazine-1-yl]Ethoxy } benzylamine (0.82g, 2mmol) was dissolved in 12mL DCM and added dropwise to the flask with stirring at room temperature, TLC monitored for complete conversion of the substituted benzylamine, the reaction was transferred to 125mL separatory funnel, washed three times with 50mL water, once with 50mL saturated brine, dried over Na2SO4Drying, filtering and evaporating the solvent to obtain oily liquid, and performing column chromatography to obtain a white solid 0.17g with a yield of 13.9%; ESI-MS (M/z):613.1([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.55–7.47(m,2H),7.35–7.26(m,2H),7.25–7.20(m,2H),7.15(dd,J＝6.4,3.3Hz,1H),7.00–6.89(m,2H),6.82(dd,J＝8.2,2.0Hz,1H),6.59(t,J＝5.8Hz,1H),4.23(d,J＝5.7Hz,2H),4.08(t,J＝5.9Hz,2H),3.76(s,3H),2.99(t,J＝4.8Hz,4H),2.77(t,J＝5.9Hz,2H),2.68(s,4H)；m.p.：172.6-174.0℃。
Example 3: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-chloro-4-fluorophenyl) urea (HE03)
Referring to the preparation method of example 2, 0.72g of white solid was obtained with a yield of 61.9%; ESI-MS (M/z) 581.2([ M + H)]+),603.0([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.78(dd,J＝6.8,2.4Hz,1H),7.35–7.18(m,4H),7.14(dd,J＝6.4,3.2Hz,1H),6.99–6.90(m,2H),6.82(dd,J＝8.2,2.0Hz,1H),6.63(t,J＝5.9Hz,1H),4.22(d,J＝5.7Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),2.99(t,J＝4.8Hz,4H),2.76(t,J＝5.9Hz,2H),2.68(d,J＝5.3Hz,4H)；m.p.：168.1-169.2℃。
Example 4: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-trifluoromethylphenyl) urea (HE04)
Referring to the preparation method of example 2, 0.83g of a white solid was obtained in a yield of 59.5%; ESI-MS (M/z) 597.2([ M + H)]+),619.0([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.99(d,J＝2.0Hz,1H),7.53(dd,J＝8.5,1.7Hz,1H),7.45(t,J＝7.9Hz,1H),7.34–7.27(m,2H),7.23(dd,J＝7.8,1.4Hz,1H),7.14(dd,J＝6.4,3.3Hz,1H),6.99–6.92(m,2H),6.83(dd,J＝8.2,1.9Hz,1H),6.69(t,J＝5.9Hz,1H),4.25(d,J＝5.7Hz,2H),4.08(t,J＝5.9Hz,2H),3.77(s,3H),2.99(t,J＝4.7Hz,4H),2.77(t,J＝5.9Hz,2H),2.68(s,4H)；m.p.：169.2-170.5℃。
Example 5: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-nitrophenyl) urea (HE05)
Referring to the preparation method of example 2, 0.83g of yellow solid was obtained with a yield of 72.2%; ESI-MS (M/z):574.2([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.53(t,J＝2.2Hz,1H),7.75(dd,J＝7.7,1.7Hz,1H),7.67(dd,J＝8.4,2.3Hz,1H),7.51(t,J＝8.2Hz,1H),7.29(q,J＝5.0,4.3Hz,2H),7.14(dt,J＝6.5,3.4Hz,1H),7.00–6.92(m,2H),6.84(dd,J＝8.2,2.0Hz,1H),6.75(t,J＝5.8Hz,1H),4.08(t,J＝5.9Hz,2H),3.77(s,3H),2.99(t,J＝4.8Hz,3H),2.77(t,J＝5.9Hz,2H),2.66(dd,J＝14.9,8.9Hz,4H)；m.p.：143.4-145.2℃。
Example 6: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-dimethylaminobenzyl) urea (HE06)
Referring to the preparation method of example 1, 0.69g of white solid was obtained with a yield of 58.8%; ESI-MS (M/z) 586.2([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ7.30(d,J＝6.5Hz,2H),7.15(dd,J＝6.4,3.3Hz,1H),7.11–7.05(m,2H),6.93(d,J＝8.1Hz,1H),6.87(d,J＝1.9Hz,1H),6.76(dd,J＝8.2,1.9Hz,1H),6.71–6.63(m,2H),6.23(dt,J＝19.4,5.9Hz,2H),4.16(d,J＝5.9Hz,2H),4.11(d,J＝5.8Hz,2H),4.07(t,J＝5.9Hz,2H),3.73(s,3H),3.00(t,J＝4.8Hz,4H),2.85(s,6H),2.76(t,J＝5.9Hz,2H),2.68(d,J＝5.7Hz,4H)；m.p.：109.5-111.3℃。
Example 7: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxyphenyl) urea (HE07)
Referring to the preparation method of example 2, 0.57g of white solid was obtained with a yield of 50.9%; ESI-MS (M/z) 559.2([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.33–7.26(m,4H),7.14(dd,J＝6.3,3.3Hz,1H),6.97–6.92(m,2H),6.84–6.79(m,3H),6.41(t,J＝5.9Hz,1H),4.21(d,J＝5.8Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),3.69(s,3H),2.99(t,J＝4.7Hz,4H),2.76(t,J＝5.9Hz,2H),2.68(s,4H)；m.p.：159.4-161.2℃。
Example 8: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethylphenyl) urea (HE08)
Referring to the preparation method of example 2, 0.59g of white solid was obtained in 49.4% yield; ESI-MS (M/z) 597.2([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.96(d,J＝2.3Hz,1H),7.59(qd,J＝9.1,2.3Hz,4H),7.30(dd,J＝6.2,2.7Hz,2H),7.14(dt,J＝6.0,2.9Hz,1H),6.99–6.92(m,2H),6.83(dt,J＝8.3,2.2Hz,1H),6.69(q,J＝5.2Hz,1H),4.25(dd,J＝6.0,2.4Hz,2H),4.08(td,J＝6.0,2.4Hz,2H),3.76(s,3H),2.99(s,4H),2.81–2.74(m,2H),2.68(s,4H)；m.p.：196.2-198.2℃。
Example 9: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxybenzyl) urea (HE09)
Referring to the preparation method of example 1, 0.67g of a white solid was obtained, 58.4%; ESI-MS (M/z):573.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ7.34–7.27(m,2H),7.20–7.13(m,3H),6.93(d,J＝8.2Hz,1H),6.89–6.84(m,3H),6.75(dd,J＝8.2,2.0Hz,1H),6.31(q,J＝6.0Hz,2H),4.15(d,J＝5.9Hz,4H),4.06(t,J＝5.9Hz,2H),3.72(s,6H),2.99(t,J＝4.6Hz,4H),2.76(t,J＝5.9Hz,2H),2.67(m,4H)；m.p.：142.4-144.3℃。
Example 10: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-chlorophenyl) urea (HE10)
Referring to the preparation method of example 2, 0.51g of white solid was obtained with a yield of 45.2%; ESI-MS (M/z):563.1([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.47–7.40(m,2H),7.32–7.23(m,4H),7.15(dd,J＝6.4,3.3Hz,1H),6.97–6.91(m,2H),6.82(dd,J＝8.2,2.0Hz,1H),6.57(t,J＝5.9Hz,1H),4.22(d,J＝5.7Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),2.99(t,J＝4.8Hz,4H),2.77(t,J＝5.9Hz,2H),2.68(s,4H)；m.p.：153.7-156.2℃。
Example 11: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-fluorophenyl) urea (HE11)
Referring to the preparation method of example 2, 0.50g of white solid was obtained with a yield of 45.7%; ESI-MS (M/z):547.3([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),7.45–7.38(m,2H),7.30(q,J＝4.8,4.1Hz,2H),7.15(dd,J＝6.3,3.3Hz,1H),7.06(t,J＝8.9Hz,2H),6.99–6.92(m,2H),6.82(dd,J＝8.2,2.0Hz,1H),6.51(t,J＝5.9Hz,1H),4.22(d,J＝5.8Hz,2H),4.08(t,J＝5.9Hz,2H),3.76(s,3H),2.99(t,J＝4.7Hz,4H),2.77(t,J＝5.9Hz,2H),2.68(s,4H)；m.p.：168.0-170.6℃。
Example 12: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-fluorobenzyl) urea (HE12)
Reference toThe preparation of example 2 gave 0.59g of a white solid in 52.5% yield; ESI-MS (M/z) 561.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ7.36–7.26(m,4H),7.19–7.10(m,3H),6.94(d,J＝8.2Hz,1H),6.87(d,J＝1.9Hz,1H),6.76(dd,J＝8.2,2.0Hz,1H),6.40(dt,J＝24.6,6.0Hz,2H),4.21(d,J＝6.0Hz,2H),4.16(d,J＝5.9Hz,2H),4.07(t,J＝5.9Hz,2H),3.73(s,3H),3.00(t,J＝4.8Hz,4H),2.76(q,J＝5.8Hz,2H),2.72–2.61(m,4H)；m.p.：153.8-155.7℃。
Example 13: preparation of 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-tolyl) urea (HE13)
Referring to the preparation method of example 2, 0.61g of a white solid was obtained with a yield of 56.1%; ESI-MS (M/z) 543.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.33–7.25(m,4H),7.15(dd,J＝6.3,3.3Hz,1H),7.02(d,J＝8.1Hz,2H),6.98–6.90(m,2H),6.82(dd,J＝8.2,1.9Hz,1H),6.49(t,J＝5.9Hz,1H),4.21(d,J＝5.7Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),2.99(t,J＝4.8Hz,4H),2.76(t,J＝5.9Hz,2H),2.70–2.58(m,4H),2.22(s,3H)；m.p.：164.5-166.1℃
Example 14: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-chloro-4-fluorophenyl) urea (HE14)
Steps I to II were carried out in the same manner as in example 1 to obtain 4-methylbenzenesulfonic acid [ (4-formyl-2-methoxyphenoxy) ethyl ] ester.
Step III: 1- (4-methoxyphenyl) piperazine hydrochloride (6.86g, 30mmol) was weighed into a 100mL flask, and anhydrous K was added2CO3(13.8g, 100mmol), 4-methylbenzenesulfonic acid [ (4-formyl-2-methoxyphenoxy) ethyl]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. Stopping reaction, distilling under reduced pressure, concentrating, adding 60mL water into round bottom flask, stirring to anhydrous K2CO3After 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 Na2SO4Drying, and distilling off the solvent under reduced pressure to obtain a yellowish solid 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl]Ethoxy benzaldehyde (10.33 g) in a yield of 92.95%.
Step IV: hydroxylamine hydrochloride (2.29g, 33mmol) and sodium bicarbonate (2.77g, 33mmol) were weighed into a50mL eggplant-shaped flask, 30mL of water was added, the reaction was stirred at room temperature for half an hour, and a large amount of gas was evolved. Weighing 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl]Ethoxy } benzaldehyde (11.11g, 30mmol) was placed in a 100ml flask and 30ml ethanol (EtOH) was added and dissolved with stirring, hydroxylamine hydrochloride solution was added to the flask with stirring and reacted at room temperature for 3h, monitored by TLC (DCM: EA ═ 1: 1). 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 and anhydrous Na2SO4Drying, filtering and decompressing to evaporate the solvent to obtain white solid 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl]Ethoxy } benzaldoxime 10.50g, yield 90.81%.
Step V: weighing 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl]Ethoxy } benzaldehyde oxime (11.56g, 30mmol) was placed in a 250mL eggplant-shaped bottle and dissolved by adding 50mL EtOH and 60mL of 5mol/L NaOH solution was added under ice bath. Weighing nickel aluminum alloy (10g), 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 is 20:1), after confirming that the reaction is completely performed, filtering out nickel powder participating in the reaction by suction filtration (note that the reaction cannot be dried, and the reaction can be natural), distilling out EtOH under reduced pressure, EA50mL X3 times extracting water phase, combining organic phases, washing with 50mL saturated saline solution once, and washing with anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure to obtain light yellow solid 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl]Ethoxy } benzylamine 11.38, yield 94.04%.
Step VI: solid phosgene (trichloromethyl carbonate) (0.20g, 0.67mmol) was weighed out and placed in a 100mL eggplant-shaped flask, 10mL of LPCM was added and dissolved under stirring at room temperature, 3-chloro-4-fluoroaniline (0.29g, 2mmol) was dissolved in 12mL of DCM and added to the flask under stirring at room temperature, and solid was gradually precipitated. Triethylamine (0.40g, 4mmol) was weighed into 12mL DCM and added to the flask with stirring at room temperature, and the solid gradually dissolvedAnd (4) decomposing to obtain a clear solution. Weighing 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazine-1-yl]Ethoxy } benzylamine (0.82g, 2mmol) was dissolved in 12mL of LPCM, added dropwise to the flask with stirring at room temperature, TLC was used to monitor completion of conversion of the substituted benzylamine, the reaction solution was transferred to a 125mL separatory funnel, washed three times with 50mL of water, washed once with 50mL of saturated saline, and washed with anhydrous Na2SO4Drying, filtering and evaporating the solvent to obtain oily liquid, and performing column chromatography to obtain 0.78g of white solid with the yield of 60.9%; ESI-MS (M/z) 543.7([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.78(dd,J＝6.8,2.4Hz,1H),7.31–7.20(m,2H),6.97–6.79(m,7H),6.64(t,J＝5.8Hz,1H),4.22(d,J＝5.8Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),3.68(s,3H),3.01(dd,J＝6.3,3.6Hz,4H),2.73(t,J＝5.9Hz,2H),2.63(t,J＝4.9Hz,4H)；m.p.：173.2-174.1℃。
Example 15: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethoxyphenyl) urea (HE15)
Referring to the preparation method of example 14, 0.95g of a white solid was obtained in a yield of 82.7%; ESI-MS (M/z) 575.6([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.54–7.47(m,2H),7.23(d,J＝8.6Hz,2H),6.99–6.92(m,2H),6.88(d,J＝9.1Hz,2H),6.82(td,J＝6.6,6.1,3.2Hz,3H),6.59(t,J＝5.8Hz,1H),4.23(d,J＝5.7Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),3.68(s,3H),3.01(t,J＝4.9Hz,4H),2.73(t,J＝5.9Hz,2H),2.63(t,J＝5.0Hz,4H)；m.p.：149.1-150.2℃。
Example 16: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-trifluoromethylphenyl) urea (HE16)
Referring to the preparation method of example 14, 0.68g of white solid was obtained with a yield of 60.9%; ESI-MS (M/z) 559.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.99(s,1H),7.56–7.41(m,2H),7.23(d,J＝7.6Hz,1H),7.00–6.93(m,2H),6.88(d,J＝8.9Hz,2H),6.85–6.79(m,3H),6.69(t,J＝5.9Hz,1H),4.24(d,J＝5.7Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),3.68(s,3H),3.01(t,J＝4.9Hz,4H),2.73(t,J＝5.9Hz,2H),2.63(t,J＝4.9Hz,4H)；m.p.：156.1-157.5℃
Example 17: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-ethoxybenzyl) urea (HE17)
Step I to step V were carried out by the method of example 14 to obtain 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzylamine.
Step VI: solid phosgene (dicloromethyl carbonate) (0.20g, 0.67mmol) was weighed into a 100mL eggplant-shaped flask, 10mL of LPCM was added and dissolved under stirring at room temperature, and 4-ethoxybenzylamine (0.30g, 2mmol) was dissolved in 12mL of DCM and added to the flask under stirring at room temperature, and a solid was gradually precipitated. Triethylamine (0.40g, 4mmol) was weighed into 12mL DCM and added to the flask with stirring at room temperature, and the solid gradually dissolved to give a clear solution. Weighing 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazine-1-yl]Ethoxy } benzylamine (0.82g, 2mmol) was dissolved in 12mL of LPCM, added dropwise to the flask with stirring at room temperature, TLC was used to monitor completion of conversion of the substituted benzylamine, the reaction solution was transferred to a 125mL separatory funnel, washed three times with 50mL of water, washed once with 50mL of saturated saline, and washed with anhydrous Na2SO4Drying, filtering and evaporating the solvent to obtain oily liquid, and performing column chromatography to obtain white solid HE170.24g with yield of 21.9%; ESI-MS (M/z) 549.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ7.21–7.12(m,2H),6.94–6.74(m,9H),6.30(q,J＝5.7Hz,2H),4.15(d,J＝5.8Hz,4H),4.07(t,J＝5.9Hz,2H),3.99(q,J＝6.9Hz,2H),3.73(s,3H),3.68(s,3H),3.01(t,J＝5.0Hz,4H),2.73(t,J＝5.9Hz,2H),2.64(d,J＝5.0Hz,4H),1.31(t,J＝7.0Hz,3H)；m.p.：156.1-157.5℃。
Example 18: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxyphenyl) urea (HE18)
Referring to the preparation method of example 14, 0.67g of a white solid was obtained in a yield of 64.3%; ESI-MS (M/z) 521.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.34–7.27(m,2H),6.97–6.78(m,9H),6.41(t,J＝5.9Hz,1H),4.21(d,J＝5.8Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),3.69(d,J＝6.4Hz,6H),3.01(t,J＝5.0Hz,4H),2.73(t,J＝5.9Hz,2H),2.63(t,J＝5.0Hz,4H)；m.p.：165.5-166.5℃。
Example 19: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-tolyl) urea (HE19)
According to the production method of example 14, 0.71g was obtained, yield 70.3%; ESI-MS (M/z) 505.6([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.32–7.23(m,2H),7.02(d,J＝8.2Hz,2H),6.95(d,J＝8.2Hz,1H),6.92(d,J＝2.0Hz,1H),6.90–6.85(m,2H),6.83–6.78(m,3H),6.45(t,J＝5.8Hz,1H),4.20(d,J＝5.8Hz,2H),4.06(t,J＝5.9Hz,2H),3.75(s,3H),3.67(s,3H),3.00(t,J＝4.9Hz,4H),2.73(t,J＝5.9Hz,2H),2.63(t,J＝5.0Hz,4H),2.21(s,3H)；m.p.：146.1-146.7℃。
Example 20: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-dimethylaminobenzyl) urea (HE20)
Referring to the preparation method of example 17, 0.3g of a white solid was obtained in a yield of 27.4%; ESI-MS (M/z) 548.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ7.08(d,J＝8.2Hz,2H),6.94–6.86(m,4H),6.84–6.74(m,3H),6.67(d,J＝8.4Hz,2H),6.23(dt,J＝19.6,6.0Hz,2H),4.16(d,J＝5.8Hz,2H),4.13–4.04(m,4H),3.73(d,J＝1.2Hz,3H),3.68(d,J＝1.2Hz,3H),3.01(t,J＝4.9Hz,4H),2.85(s,6H),2.73(t,J＝5.9Hz,2H),2.63(d,J＝5.1Hz,4H)；m.p.：142.4-143.3℃。
Example 21: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-nitrophenyl) urea (HE21)
Referring to the preparation method of example 14, yellow solid 0.33 was obtained with a yield of 30.8%; ESI-MS (M/z):536.4([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.52(t,J＝2.2Hz,1H),7.75(ddd,J＝8.1,2.3,0.9Hz,1H),7.66(ddd,J＝8.2,2.2,1.0Hz,1H),7.50(t,J＝8.2Hz,1H),6.99–6.70(m,8H),4.25(d,J＝5.8Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),3.67(s,3H),3.01(t,J＝4.9Hz,4H),2.73(t,J＝5.9Hz,2H),2.63(t,J＝4.9Hz,4H)；m.p.：159.8-161.4℃。
Example 22: preparation of 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethylphenyl) urea (HE22)
Referring to the preparation method of example 14, 0.71g of a white solid was obtained, 63.6%; ESI-MS (M/z) 559.3([ M + H)]+)；1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.59(q,J＝8.7Hz,4H),7.00–6.92(m,2H),6.91–6.78(m,5H),6.70(t,J＝5.8Hz,1H),4.24(d,J＝5.7Hz,2H),4.07(t,J＝5.9Hz,2H),3.76(s,3H),3.68(s,3H),3.01(t,J＝4.8Hz,4H),2.74(t,J＝5.9Hz,2H),2.63(t,J＝4.8Hz,4H)；m.p.：146.2-147.9℃。
Figure BDA0003100536950000131
Figure BDA0003100536950000141
Figure BDA0003100536950000151
Pharmacological examples
Example 23: inhibitory Activity of test Compounds on proliferation of A549, MCF7, HCT-116, PC3 cells
(1) Experimental Material
Cell line: a549 cells, MCF7 cells, HCT-116 cells and PC3 cells are respectively paved in 96-well plates at the density of 1500, 2200, 800 and 2000 cells per well, each well is 100ul, and the cells are used after 24 h.
Code HE01-HE22 target compound: dissolved in DMSO, 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 ℃ for use, the final concentration of DMSO in the culture medium is less than 0.1%.
Positive control drug: sorafenib (sorafenib).
MTT: dissolved in PBS to 2mg/mL and stored at-20 ℃.
(2) Experimental methods
Using MTT squareA549, MCF7, HCT-116, and PC3 cells were selected to evaluate the anti-tumor proliferation activity of test samples. A549, HCT-116 and PC3 cell lines were cultured in RPMI 1640 medium containing 10% bovine serum (FBS), and MCF-7 cell lines 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 plated in 96-well plates and then incubated in a medium containing 5% CO2Was incubated overnight in a humidified environment and temperature controlled at 37 ℃. After 24h, various concentrations of representative compounds of the invention were added. After an additional 24h of incubation, MTT (2mg/mL) was added and incubation continued for 4 h. 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: the cell growth inhibition rate is (1-drug group OD value/control group OD value) × 100%, the cell growth inhibition rate under the corresponding concentration is calculated, and the IC corresponding to the tested compound is calculated according to the logarithmic curve of the inhibition rate of the tested compound to the cell and the different concentrations of the tested compound50The value is obtained. Representative compounds of the invention were tested according to the methods described above.
Figure BDA0003100536950000161
Figure BDA0003100536950000171
Figure BDA0003100536950000181
Most of the 22 compounds prepared in the way have good proliferation inhibition activity on A549 and HCT116 cell strains, wherein HE01 and HE13 have IC (integrated Circuit) of four tumor cell strains50All reach below 10 μ M, IC of HE01, HE02, HE03, HE04, HE11 and HE13 for HCT116 cell line50Are all less than 5 μ M, in particular compoundsIC of HE11 on HCT116 cells50It is as low as 3.25. + -. 0.38. mu.M. IC of HE01, HE06, HE14 on A549 cell line50Also to or less than 5 μ M, wherein the IC of compound HE14 on A549 cell line50As low as 3.55. + -. 0.29. mu.M.
The substituent on the benzene ring in the phenylpiperazine structure has great influence on the antitumor activity of the compound, when R is2When the substituents were changed from 2, 3-dichloro substitution of HE01 to HE13 to 4-methoxy substitution of HE14 to HE22, the proliferation inhibitory activity against A549 and HCT116 cell lines was slightly reduced, but the proliferation inhibitory activity against MCF7 and PC3 cell lines was greatly reduced. When R is1When the substituent contains a fluorine atom, such as fluorine, trifluoromethyl, trifluoromethoxy and the like, the growth inhibitory activity of HCT116 cell line tends to be good. In addition, R1When the electron donating group is relatively weak, such as HE13 substituted by methyl, the compound has better tumor cell proliferation inhibition activity. R1When the end is substituted by benzyl, the end has relatively larger substituents, such as ethoxy and dimethylamino, and the improvement of the overall activity is better shown.
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 are the compounds HE-01 to HE22 prepared in the above examples.
Example 24: 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 25: 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 and 5mg of coloring agent, and pure water is added to the volume of 5 mL.
Example 26: aerosol formulations
0.25mg of active compound, 25-75mL of ethanol and 70mg of propellant 22 (chlorodifluoromethane).
Example 27: suppository formula
250mg of active compound, 2000mL of saturated fatty acid glycerides.
Example 28: injectable formulation
50mg of active compound, 1000mL of isotonic saline solution.
Example 29: ointment formulation
0.025g of micronized active compound, 10g of liquid paraffin, and 100g of soft white wax.
Example 30: ointment formulation
0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin and 100g of soft white wax.
Example 31: oil-in-water cream formulation
0.025g of active compound, 5g of cetyl alcohol, 5g of glycerol 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 to 100 g.
Example 32: 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 of the particular pharmaceutical excipient grade), 0.5g of sorbitan monostearate, 0.2g of sorbic acid, 0.1g of citric acid, 0.2g of sodium citrate, and water to 100 g.
Example 33: 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 100 g.
Example 34: lotion formulation
0.25g of active compound, 0.5mL of isopropanol, 3mg of carboxyvinyl polymer, 2mg of NaOH and water to 1 g.
Example 35: suspension formulation for injection
10mg of active compound, 7mg of sodium carboxymethylcellulose, 7mg of NaCl, 0.5mg of polyoxyethylene (20) sorbitan monooleate, 8mg of benzyl alcohol, and sterile water to 1 mL.
Example 36: aerosol formulation for oral and nasal inhalation
0.1% w/w active compound, 0.7% w/w sorbitan trioleate, 24.8% w/w trichlorofluoromethane, 24.8% w/w dichlorotetrafluoroethane and 49.6% w/w dichlorodifluoromethane.
Example 37: atomized solution formulation
7mg of active compound, 5mg of propylene glycol, water to 10 g.
Example 38: 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 39: 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 40: 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 41: capsule formulation
1.0mg of active compound, 321mg of small sugar spheres, 306.6 mg of Aquacoat ECD, 0.5mg of acetyl tributyl citrate, 800.1 mg of Tween-800, 100-5517.5 mg of Eudragit L, 1.8mg of triethyl citrate, 8.8mg of talcum powder and 0.lmg of antifoaming agent MMS.
Example 42: capsule seedling formula
2.0mg of active compound, 305mg of small sugar spheres, Aquocoat ECD 305.0 mg, acetyl tributyl citrate 0.4mg, Tween-800.14 mg, Eudragit NE 30D 12.6mg, Eudragit S10012.6 mg, talc 0.l6 mg.
Example 43: enema formula
2mg of active compound, 25mg of sodium carboxymethylcellulose, 0.5mg of disodium ethylenediaminetetraacetate, 0.8mg of methylparaben, 0.2mg of propylparaben, 7mg of sodium chloride, 1.8mg of citric acid, 800.01 mg of tween-tween and 1mL of pure water.
Example 44: formulations containing liposomes
A. Preparation of the instillation formulation
Dipalmitoyl lecithin (45mg), dimyristoyl lecithin (7mg), dipalmitoyl phosphatidyl glycerol (1mg) and active compound (5mg) were placed in a glass tube, all components were dissolved in chloroform and N was used2A lipid film is formed on the surface of the glass tube by evaporating most of the solvent and then reducing the pressure, and then, an aqueous solution (0.9% NaCl) is added to the lipid to form liposomes at a temperature higher than the phase inversion temperature of the lipid, and the resulting suspension contains liposomes having a size ranging 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 7:3 lactose to lipid ratio. 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. A urea compound containing piperazine group and its pharmaceutically acceptable salt shown in formula I, wherein the structure of formula I is as follows:
Figure FDA0003576969680000011
wherein n is 0, 1 or 2;
R1、R2each independently hydrogen, C1-C4 alkyl, halogen substituted C1-C4 alkyl, C1-C4 alkoxy, halogen substituted C1-C4 alkoxyHalogen, nitro, amino or C1-C4 alkylamino; at the same time, R1、R2May be one or more.
2. The piperazine group-containing urea compound and the pharmaceutically acceptable salts thereof according to claim 1, wherein in formula I:
n is 0 or 1;
R1is methyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, nitro, dimethylamino, fluoro, chloro or 3-chloro-4-fluoro;
R2is 2, 3-dichloro or/and methoxy.
3. The piperazine group-containing urea compound and the pharmaceutically acceptable salts thereof according to claim 2, wherein the compound is any one of the following compounds:
HE 01: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-ethoxybenzyl) urea;
HE 02: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethoxyphenyl) urea;
HE 03: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-chloro-4-fluorophenyl) urea;
HE 04: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-trifluoromethylphenyl) urea;
HE 05: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-nitrophenyl) urea;
HE 06: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-dimethylaminobenzyl) urea;
HE 07: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxyphenyl) urea;
HE 08: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethylphenyl) urea;
HE 09: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxybenzyl) urea;
HE 10: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-chlorophenyl) urea;
HE 11: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-fluorophenyl) urea;
HE 12: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-fluorobenzyl) urea;
HE 13: 1- { 3-methoxy-4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-tolyl) urea;
HE 14: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-chloro-4-fluorophenyl) urea;
HE 15: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethoxyphenyl) urea;
HE 16: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-trifluoromethylphenyl) urea;
HE 17: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-ethoxybenzyl) urea;
HE 18: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-methoxyphenyl) urea;
HE 19: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-tolyl) urea;
HE 20: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-dimethylaminobenzyl) urea;
HE 21: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (3-nitrophenyl) urea;
HE 22: 1- { 3-methoxy-4- {2- [4- (4-methoxyphenyl) piperazin-1-yl ] ethoxy } benzyl } -3- (4-trifluoromethylphenyl) urea;
Figure FDA0003576969680000021
Figure FDA0003576969680000031
4. a pharmaceutical composition comprising, as an active ingredient, a compound of any one of the piperazine group-containing urea compounds of any one of claims 1 to 3 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.
5. A method for preparing piperazine-group-containing urea compounds and pharmaceutically acceptable salts thereof according to claim 1, wherein the piperazine-group-containing urea compounds are prepared by the following route:
Figure FDA0003576969680000041
6. use of a urea compound containing a piperazine group according to any one of claims 1 to 3, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, 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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CN110054584A (en) * 2019-05-28 2019-07-26 沈阳药科大学 1- aryl -3- { 4- [(pyridine -2- ylmethyl) sulfenyl] phenyl } carbamide compounds and application

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CN102775385A (en) * 2011-05-10 2012-11-14 湖南有色凯铂生物药业有限公司 N-substituted phenyl-N'-substituted heterocyclic urea compounds and application of same as anti-cancer drugs
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