Diarylguanidine derivatives having anti-lymphoma function, and preparation method and application thereof
By introducing the amlodipine structure into a diarylguanidine derivative, a simple chain-like guanidine-based BTK inhibitor was developed, which solved the problems of poor selectivity and drug resistance of existing BTK inhibitors, and achieved efficient inhibition of B lymphoma cells and simple synthesis.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HENAN UNIV OF SCI & TECH
- Filing Date
- 2026-03-19
- Publication Date
- 2026-05-29
AI Technical Summary
Existing BTK inhibitors suffer from poor selectivity, leading to side effects and drug resistance due to target mutations in the treatment of B-cell lymphoma. There is a need to develop highly effective and selective BTK inhibitors.
By incorporating the amlodipine structure into diarylguanidine derivatives, compounds with anti-B lymphoma activity are generated through a one-step photoreaction based on a simple chain guanidine, simplifying the synthesis process and improving the reaction yield.
This diarylguanidine derivative exhibits good anti-proliferative activity against B-cell lymphoma (Ramos cells), with an IC50 value superior to most first-line drugs, and its synthesis method is simple with a yield as high as 88%.
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Figure CN122103014A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of compound synthesis technology, specifically relating to diarylguanidine derivatives with anti-lymphoma function, their preparation methods, and applications. Background Technology
[0002] Lymphoma, an immune system tumor, is one of the most common malignant tumors worldwide, ranking first among hematological malignancies. In recent years, the main targeted drugs for treating B-cell lymphoma, such as Ibrutinib, inhibit Bruton's tyrosine kinase (BTK). Currently, six BTK inhibitors have been approved for marketing globally and have become the best choice for treating hematological malignancies and some autoimmune diseases. Five of these are covalent (irreversible) BTK inhibitors. Although covalent BTK inhibitors have been widely used in clinical treatment of B-cell lymphoma and have achieved significant therapeutic effects, they still have some side effects due to poor selectivity, such as rash, diarrhea, joint pain, atrial fibrillation, hypertension, bruising, and bleeding. In addition, drug resistance caused by target mutations is another serious problem in their clinical use. The only non-covalent (reversible) BTK inhibitor, Pirtobrutinib (Jaypirca), was approved by the FDA in January 2023. As a highly selective BTK inhibitor, it is used to treat relapsed or refractory mantle cell lymphoma. Developing novel, highly effective, and selective BTK inhibitors has always been a hot topic in the research of B-cell lymphoma treatment drugs and has very important academic significance. Summary of the Invention
[0003] To comprehensively address the above problems, this invention introduces the amlodipine structure into the molecular structure to prepare a diarylguanidine derivative with certain antitumor activity. This diarylguanidine derivative exhibits significant anti-B lymphoma activity, particularly showing good performance against Ramos cells, and is expected to be used for the treatment of B lymphoma.
[0004] To achieve the above objectives, the first aspect of the present invention provides a diarylguanidine derivative with anti-lymphoma function, the chemical name of which is 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate, and its structural formula is as follows: Wherein, R is any one of 2-fluorophenyl, 2-trifluoromethylphenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2-fluoro-4-trifluoromethylphenyl, 2,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, and 2,4,6-trifluorophenyl; Ar represents substituted phenyl, pyridine, or substituted pyridine.
[0005] A second aspect of this invention provides a method for preparing a diarylguanidine derivative with anti-lymphoma function, comprising: Step 1: React phenolic compounds with 4-bromonitrobenzene in DMF solution to prepare 4-nitrodiphenyl ether compounds; Step 2: Place 4-nitrodiphenyl ether compounds in an iron-containing ethanol solution to prepare 4-aminodiphenyl ether compounds; Step 3: Place 4-aminodiphenyl ether compounds and phenyl thioisocyanate in a tetrahydrofuran solution to react and prepare 1-(4-phenoxyphenyl)-3-phenylurea compounds; Step 4: React 1-(4-phenoxyphenyl)-3-phenylurea compounds with amlodipine under light conditions to obtain the target compound 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate ester.
[0006] Preferably, step 1 specifically includes: 4-Bromonitrobenzene, phenolic compounds, and potassium carbonate in a molar ratio of 1:2:1.1 were added to a round-bottom flask containing DMF and reacted. The resulting reaction mixture was placed in an ice-water bath, and the precipitated solid was filtered and washed to obtain 4-nitrodiphenyl ether compounds.
[0007] Preferably, step 2 specifically includes: 4-Nitrodiphenyl ether compounds, ammonium chloride, and iron powder were added to a mixed solvent containing ethanol and water. The reaction mixture was heated under reflux and cooled. The iron powder was filtered out, the mixture was collected, extracted, and the filtrate was evaporated to dryness to obtain 4-aminodiphenyl ether compounds.
[0008] Preferably, the molar ratio of 4-nitrodiphenyl ether compound, ammonium chloride, and iron powder is 1:3:3.
[0009] Preferably, step 3 specifically includes: 4-Aminodiphenyl ether compounds and phenyl isothiocyanate were added to a round-bottom flask containing tert-butanol. The reaction mixture was then heated to reflux. After the reaction was stopped, the reaction mixture was cooled, evaporated, washed, and dried to obtain clean 1-(4-phenoxyphenyl)-3-phenylthiourea compounds.
[0010] Preferably, the molar ratio of 4-aminodiphenyl ether compounds and phenyl isothiocyanate is 1:2.
[0011] Preferably, step 4 specifically includes: 1-(4-phenoxyphenyl)-3-phenylthiourea compounds, amlodipine, and potassium carbonate were added to a mixed solvent of ethanol and water and reacted. After the reaction, the mixture was extracted and dried. The crude product was separated and purified to obtain the final product, 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate compounds.
[0012] Preferably, in step 4, the molar ratio of 1-(4-phenoxyphenyl)-3-phenylthiourea compound, amlodipine, and potassium carbonate is 1:1.5:2, and the molar ratio of ethanol to water is 9:1.
[0013] A third aspect of the present invention provides the use of the diarylguanidine derivatives described above in the preparation of anti-lymphoma drugs.
[0014] Compared with the prior art, the beneficial effects of the present invention are: 1. The BTK inhibitor uses a simple chain-like guanidine as its hinge region structure, which distinguishes it from existing inhibitor molecules with nitrogen-containing heterocycles as their parent core.
[0015] 2. It exhibits good anti-proliferative activity against B lymphoma cells (Ramos cells), with an IC50 value of 0.061 mm, which is superior to most first-line clinical drugs.
[0016] 3. Unlike the complex nitrogen-containing heterocyclic structures of existing BTK inhibitors, a simple synthetic method for generating the target compound in one step by using chain-like guanidine compounds is proposed, with a high reaction yield, reaching up to 88%. Attached Figure Description
[0017] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof.
[0018] In the attached diagram: Figure 1 The HCl spectrum of compound 1; Figure 2The C spectrum of compound 1; Figure 3 The HCl spectrum of compound 2; Figure 4 The C spectrum of compound 2; Figure 5 The F spectrum of compound 2; Figure 6 The HCl spectrum of compound 3; Figure 7 The C spectrum of compound 3; Figure 8 The F spectrum of compound 3; Figure 9 The HCl spectrum of compound 4; Figure 10 The C spectrum of compound 4; Figure 11 The F spectrum of compound 4; Figure 12 The HCl spectrum of compound 5; Figure 13 The C spectrum of compound 5; Figure 14 The HCl spectrum of compound 6; Figure 15 This is the C spectrum of compound 6. Detailed Implementation
[0019] The following combination Figures 1-15 The preferred embodiments of the present invention are described herein. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.
[0020] Raw materials and reagents: Unless otherwise specified, all raw materials and reagents used in this article are commercially purchased.
[0021] 4-Bromonitrobenzene, phenol, phenyl isothiocyanate, tert-butanol, amlodipine, 4-bromonitrobenzene, 4-trifluoromethylphenol, 4-bromonitrobenzene, 2-fluorophenol, and 4-fluorophenol were all purchased from Anhui Zesheng Technology Co., Ltd.
[0022] Potassium carbonate, DMF, ammonium chloride, iron powder, and ethanol were all purchased from Shanghai Maclean Biochemical Technology Co., Ltd.
[0023] A diarylguanidine derivative with anti-lymphoma function, chemically named 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate, has the following structural formula: Wherein, R is any one of 2-fluorophenyl, 2-trifluoromethylphenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2-fluoro-4-trifluoromethylphenyl, 2,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, and 2,4,6-trifluorophenyl; Ar represents substituted phenyl, pyridine, or substituted pyridine.
[0024] A method for preparing a diarylguanidine derivative with anti-lymphoma function, comprising: Step 1: Add 4-bromonitrobenzene, phenolic compounds, and potassium carbonate in a molar ratio of 1:2:1.1 to a round-bottom flask containing DMF. Let the reaction proceed overnight. Stop the reaction when no further changes are observed. Place the reaction mixture in an ice-water bath. Filter and wash the precipitated solid to obtain the product, 4-nitrodiphenyl ether compounds.
[0025] Step 2: Add 4-nitrodiphenyl ether compounds, ammonium chloride, and iron powder in a molar ratio of 1:3:3 to a mixed solvent containing ethanol and water in a 3:1 ratio. Heat the reaction mixture under reflux for 2-3 hours. Stop the reaction when no further changes are observed. Cool the reaction solution, filter out the iron powder, collect the mixture, extract with dichloromethane, and evaporate the filtrate to obtain 4-aminodiphenyl ether compounds.
[0026] Step 3: Add 4-aminodiphenyl ether compounds and phenyl isothiocyanate in a 1:2 ratio to a round-bottom flask containing tert-butanol. Then heat the reaction mixture under reflux for 4 hours. Monitor the reaction until phenyl isothiocyanate is completely consumed, then stop the reaction, cool the reaction solution, evaporate the solvent, wash with hydrochloric acid, dry, and evaporate the solvent to obtain clean 1-(4-phenoxyphenyl)-3-phenylthiourea compounds.
[0027] Step 4: 1-(4-phenoxyphenyl)-3-phenylthiourea compounds, amlodipine, and potassium carbonate were added in a ratio of 1:1.5:2 to a Shrek tube containing a 9:1 mixture of ethanol and water. The reaction mixture was placed under blue light and stirred at room temperature for 20 hours. The reaction was stopped when TLC showed no further change. The mixture was then extracted with dichloromethane and dried over anhydrous Na2SO4. The crude product was purified by silica gel column chromatography to obtain the final product, 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate.
[0028] The present invention relates to the use of diarylguanidine derivatives prepared by the method described above for the preparation of anti-lymphoma drugs.
[0029] Example 1: Step 1: Add 4-bromonitrobenzene (0.40 g, 2 mmol), phenol (0.38 g, 4 mmol), and potassium carbonate (0.30 g, 2.2 mmol) to a round-bottom flask containing DMF (60 mL). Let the reaction stand overnight. Stop the reaction when no further changes are observed. Place the reaction mixture in an ice-water bath. Filter and wash the precipitated solid to obtain the product 4-nitrodiphenyl ether (0.42 g, 98%).
[0030] Step 2: Add 4-nitrodiphenyl ether (0.39 g, 1.8 mmol), ammonium chloride (0.29 g, 5.4 mmol), and iron powder (0.30 g, 5.4 mmol) to a mixed solvent containing ethanol and water in a 3:1 ratio (60 mL). Heat the reaction mixture under reflux for 2-3 hours. Stop the reaction when no further changes are observed. Cool the reaction mixture, filter out the iron powder, collect the mixture, extract with dichloromethane, and evaporate the filtrate to obtain 4-aminodiphenyl ether (0.31 g, 92%).
[0031] Step 3: Add 4-aminodiphenyl ether (0.28 g, 1.5 mmol) and phenyl isothiocyanate (0.41 g, 3 mmol) to a round-bottom flask containing tert-butanol (45 mL). Then heat the reaction mixture under reflux for 4 hours. Monitor the reaction until the 4-aminodiphenyl ether is completely consumed. Stop the reaction, cool the reaction mixture, evaporate the solvent, wash with hydrochloric acid, dry, and then evaporate the solvent to obtain clean 1-(4-phenoxyphenyl)-3-phenylthiourea (0.46 g, 95%).
[0032] Step 4: Add 0.32 g, 1 mmol of 1-(4-phenoxyphenyl)-3-phenylthiourea, 0.61 g, 1.5 mmol of amlodipine, 0.28 g, 2 mmol of potassium carbonate, and 2 mg of photocatalyst (6H-dipyridine[1,2-e:2',1'-i]purine-6-one) to a Shrek tube containing a mixed solvent of ethanol and water (9:1, 30 mL). Place the reaction mixture under blue light and stir at room temperature for 20 hours. The reaction was stopped when TLC detection showed no further change. The product was then added to the reaction system, followed by extraction with dichloromethane and drying with anhydrous Na2SO4. The crude product was purified by silica gel column chromatography to obtain the final product 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate (0.57 g, 82%).
[0033] Example 2: Step 1: Add 4-bromonitrobenzene (0.40 g, 2 mmol), 4-trifluoromethylphenol (0.65 g, 4 mmol), and potassium carbonate (0.30 g, 2.2 mmol) to a round-bottom flask containing DMF (60 mL). Let the reaction stand overnight. Stop the reaction when no further changes are observed. Place the reaction mixture in an ice-water bath and filter and wash the precipitated solid to obtain the product 1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (0.55 g, 97%).
[0034] Step 2: Add 1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (0.51 g, 1.8 mmol), ammonium chloride (0.29 g, 5.4 mmol), and iron powder (0.30 g, 5.4 mmol) to a mixed solvent containing ethanol and water in a 3:1 ratio (60 mL). Heat the reaction mixture under reflux for 2-3 hours. Stop the reaction when no further changes are observed. Cool the reaction mixture, filter out the iron powder, collect the mixture, extract with dichloromethane, and evaporate the filtrate to obtain 4-(4-(trifluoromethyl)phenoxy)aniline (0.43 g, 95%).
[0035] Step 3: Add 4-(4-(trifluoromethyl)phenoxy)aniline (0.38 g, 1.5 mmol) and phenyl isothiocyanate (0.41 g, 3 mmol) to a round-bottom flask containing tert-butanol (45 mL). Then heat the reaction mixture under reflux for 4 hours. Monitor the reaction until the 4-aminodiphenyl ether is completely consumed. Stop the reaction, cool the reaction mixture, evaporate the solvent, wash with hydrochloric acid, dry, and then evaporate the solvent to obtain clean 1-phenyl-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)thiourea (0.55 g, 95%).
[0036] Step 4: 1-Phenylene-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)thiourea (0.39 g, 1 mmol), amlodipine (0.61 g, 1.5 mmol), potassium carbonate (0.28 g, 2 mmol), and photocatalyst (6H-dipyridine[1,2-e:2',1'-i]purine-6-one) 2 mg were added to a Shrek tube containing a mixed solvent of ethanol and water (9:1, 30 mL). The reaction mixture was placed under blue light and stirred at room temperature for 20 hours. The reaction was stopped when TLC detection showed no further change. The product was then added to the reaction system, followed by extraction with dichloromethane and drying with anhydrous Na2SO4. The crude product was purified by silica gel column chromatography to obtain the final product 3-ethyl-5-methyl(Z)-4-(2-chlorophenyl)-6-methyl-2-((2-(3-phenyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)guanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylic acid ester (0.64 g, 84%).
[0037] Example 3: Step 1: Add 4-bromonitrobenzene (0.40 g, 2 mmol), 2-fluorophenol (0.45 g, 4 mmol), and potassium carbonate (0.30 g, 2.2 mmol) to a round-bottom flask containing DMF (60 mL). Let the reaction stand overnight. Stop the reaction when no further changes are observed. Place the reaction mixture in an ice-water bath. Filter and wash the precipitated solid to obtain the product 1-fluoro-2-(4-nitrobenzoxy)benzene (0.45 g, 96%).
[0038] Step 2: Add 1-fluoro-2-(4-nitrophenoxy)benzene (0.42 g, 1.8 mmol), ammonium chloride (0.29 g, 5.4 mmol), and iron powder (0.30 g, 5.4 mmol) to a mixed solvent containing ethanol and water in a 3:1 ratio (60 mL). Heat the reaction mixture under reflux for 2-3 hours. Stop the reaction when no further changes are observed. Cool the reaction mixture, filter out the iron powder, collect the mixture, extract with dichloromethane, and evaporate the filtrate to obtain 4-(2-fluorophenoxy)aniline (0.35 g, 95%).
[0039] Step 3: Add 4-(2-fluorophenoxy)aniline (0.30 g, 1.5 mmol) and phenyl isothiocyanate (0.41 g, 3 mmol) to a round-bottom flask containing tert-butanol (45 mL). Then heat the reaction mixture under reflux for 4 hours. Monitor the reaction until the 4-aminodiphenyl ether is completely consumed. Stop the reaction, cool the reaction mixture, evaporate the solvent, wash with hydrochloric acid, dry, and then evaporate the solvent to obtain clean 1-(4-(2-fluorophenoxy)phenyl)-3-phenylthiourea (0.49 g, 97%).
[0040] Step 4: 1-(4-(2-fluorophenoxy)phenyl)-3-phenylthiourea (0.34 g, 1 mmol), amlodipine (0.61 g, 1.5 mmol), potassium carbonate (0.28 g, 2 mmol), and photocatalyst (6H-dipyridine[1,2-e:2',1'-i]purine-6-one) 2 mg were added to a Shrek tube containing a mixed solvent of ethanol and water (9:1, 30 mL). The reaction mixture was placed under blue light and stirred at room temperature for 20 hours. The reaction was stopped when TLC detection showed no further change. The product was then added to the reaction system, followed by extraction with dichloromethane and drying with anhydrous Na2SO4. The crude product was purified by silica gel column chromatography to obtain the final product 3-ethyl-5-methyl(Z)-4-(2-chlorophenyl)-2-((2-(2-(4-(2-fluorophenoxy)phenyl)-3-phenylguanidinyl)ethoxy)methyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester (0.61 g, 85%).
[0041] Example 4: Step 1: Add 4-bromonitrobenzene (0.40 g, 2 mmol), 4-fluorophenol (0.45 g, 4 mmol), and potassium carbonate (0.30 g, 2.2 mmol) to a round-bottom flask containing DMF (60 mL). Let the reaction stand overnight. Stop the reaction when no further changes are observed. Place the reaction mixture in an ice-water bath. Filter and wash the precipitated solid to obtain the product 1-fluoro-4-(4-nitrobenzoxy)benzene (0.45 g, 96%).
[0042] Step 2: Add 1-fluoro-4-(4-nitrophenoxy)benzene (0.42 g, 1.8 mmol), ammonium chloride (0.29 g, 5.4 mmol), and iron powder (0.30 g, 5.4 mmol) to a mixed solvent containing ethanol and water in a 3:1 ratio (60 mL). Heat the reaction mixture under reflux for 2-3 hours. Stop the reaction when no further changes are observed. Cool the reaction mixture, filter out the iron powder, collect the mixture, extract with dichloromethane, and evaporate the filtrate to obtain 4-(4-fluorophenoxy)aniline (0.35 g, 95%).
[0043] Step 3: Add 4-(4-fluorophenoxy)aniline (0.30 g, 1.5 mmol) and phenyl isothiocyanate (0.41 g, 3 mmol) to a round-bottom flask containing tert-butanol (45 mL). Then heat the reaction mixture under reflux for 4 hours. Monitor the reaction until the 4-aminodiphenyl ether is completely consumed. Stop the reaction, cool the reaction mixture, evaporate the solvent, wash with hydrochloric acid, dry, and then evaporate the solvent to obtain clean 1-(4-(4-fluorophenoxy)phenyl)-3-phenylthiourea (0.49 g, 97%).
[0044] Step 4: 1-(4-(4-fluorophenoxy)phenyl)-3-phenylthiourea (0.34 g, 1 mmol), amlodipine (0.61 g, 1.5 mmol), potassium carbonate (0.28 g, 2 mmol), and photocatalyst (2 mg) were added to a Shrek tube containing a mixed solvent of ethanol and water (9:1, 30 mL). The reaction mixture was placed under blue light and stirred at room temperature for 20 hours. The reaction was stopped when TLC detection showed no further change. The product was then added to the reaction system, followed by extraction with dichloromethane and drying with anhydrous Na2SO4. The crude product was purified by silica gel column chromatography to obtain the final product 3-ethyl-5-methyl(Z)-4-(2-chlorophenyl)-2-((2-(2-(4-(4-fluorophenoxy)phenyl)-3-phenylguanidinyl)ethoxy)methyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester (0.61 g, 85%).
[0045] Example 5: Step 1: Add 4-bromonitrobenzene (0.40 g, 2 mmol), phenol (0.38 g, 4 mmol), and potassium carbonate (0.30 g, 2.2 mmol) to a round-bottom flask containing DMF (60 mL). Let the reaction stand overnight. Stop the reaction when no further changes are observed. Place the reaction mixture in an ice-water bath. Filter and wash the precipitated solid to obtain the product 4-nitrodiphenyl ether (0.42 g, 98%).
[0046] Step 2: Add 4-nitrodiphenyl ether (0.39 g, 1.8 mmol), ammonium chloride (0.29 g, 5.4 mmol), and iron powder (0.30 g, 5.4 mmol) to a mixed solvent containing ethanol and water in a 3:1 ratio (60 mL). Heat the reaction mixture under reflux for 2-3 hours. Stop the reaction when no further changes are observed. Cool the reaction mixture, filter out the iron powder, collect the mixture, extract with dichloromethane, and evaporate the filtrate to obtain 4-aminodiphenyl ether (0.31 g, 92%).
[0047] Step 3: Add 4-aminodiphenyl ether (0.28 g, 1.5 mmol) and 4-isothiocyanopyridine (0.41 g, 3 mmol) to a round-bottom flask containing tert-butanol (45 mL). Then heat the reaction mixture under reflux for 4 hours. Monitor the reaction until the 4-aminodiphenyl ether is completely consumed. Stop the reaction, cool the reaction mixture, evaporate the solvent, wash with hydrochloric acid, dry, and then evaporate the solvent to obtain clean 1-(4-phenoxyphenyl)-3-(pyridin-4-yl)thiourea (0.45 g, 92%).
[0048] Step 4: 1-(4-phenoxyphenyl)-3-(pyridin-4-yl)thiourea (0.32 g, 1 mmol), amlodipine (0.61 g, 1.5 mmol), potassium carbonate (0.28 g, 2 mmol), and photocatalyst (6H-dipyridin[1,2-e:2',1'-i]purine-6-one) 2 mg were added to a Shrek tube containing a mixed solvent of ethanol and water (9:1, 30 mL). The reaction mixture was placed under blue light and stirred at room temperature for 20 hours. The reaction was stopped when TLC detection showed no further change. The product was then added to the reaction system, followed by extraction with dichloromethane and drying with anhydrous Na2SO4. The crude product was purified by silica gel column chromatography to obtain the final product 3-ethyl-5-methyl(Z)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(4-phenoxyphenyl)-3-(pyridin-4-yl)guanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylic acid ester (0.61 g, 88%).
[0049] Example 6: Step 1: Add 4-bromonitrobenzene (0.40 g, 2 mmol), phenol (0.38 g, 4 mmol), and potassium carbonate (0.30 g, 2.2 mmol) to a round-bottom flask containing DMF (60 mL). Let the reaction stand overnight. Stop the reaction when no further changes are observed. Place the reaction mixture in an ice-water bath. Filter and wash the precipitated solid to obtain the product 4-nitrodiphenyl ether (0.42 g, 98%).
[0050] Step 2: Add 4-nitrodiphenyl ether (0.39 g, 1.8 mmol), ammonium chloride (0.29 g, 5.4 mmol), and iron powder (0.30 g, 5.4 mmol) to a mixed solvent containing ethanol and water in a 3:1 ratio (60 mL). Heat the reaction mixture under reflux for 2-3 hours. Stop the reaction when no further changes are observed. Cool the reaction mixture, filter out the iron powder, collect the mixture, extract with dichloromethane, and evaporate the filtrate to obtain 4-aminodiphenyl ether (0.31 g, 92%).
[0051] Step 3: Add 4-aminodiphenyl ether (0.28 g, 1.5 mmol) and 1-(4-isothiocyanate phenyl)ethane-1-one (0.53 g, 3 mmol) to a round-bottom flask containing tert-butanol (45 mL). Then heat the reaction mixture under reflux for 4 hours. Monitor the reaction until the 4-aminodiphenyl ether is completely consumed. Stop the reaction, cool the reaction mixture, evaporate the solvent, wash with hydrochloric acid, dry, and then evaporate the solvent to obtain clean 1-(4-acetylphenyl)-3-(4-phenoxyphenyl)thiourea (0.51 g, 94%).
[0052] Step 4: 1-(4-acetylphenyl)-3-(4-phenoxyphenyl)thiourea (0.36 g, 1 mmol), amlodipine (0.61 g, 1.5 mmol), potassium carbonate (0.28 g, 2 mmol), and photocatalyst (6H-dipyridine[1,2-e:2',1'-i]purine-6-one) 2 mg were added to a Shrek tube containing a mixed solvent of ethanol and water (9:1, 30 mL). The reaction mixture was placed under blue light and stirred at room temperature for 20 hours. The reaction was stopped when TLC detection showed no further change. The product was then added to the reaction system, followed by extraction with dichloromethane and drying with anhydrous Na2SO4. The crude product was purified by silica gel column chromatography to obtain the final product 3-ethyl-5-methyl(Z)-2-((2-(3-(4-acetylphenyl)-2-(4-phenoxyphenyl)guanidinyl)ethoxy)methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester (0.63 g, 85%).
[0053] Experimental section: 1. Cell viability assay Compound 1 was used to detect its inhibition of tyrosine BTK using an enzyme-linked immunosorbent assay (ELISA). Its antiproliferative activity against Ramos B lymphoma cells was tested using the CellTiter-Glo method, with a compound concentration of 10 mg. The activity results are shown in Table 1 below. Table 1. Results of studies on the anti-cancer cell activity and anti-BTK kinase activity of typical compound 1 BTK kinase Ramos 1 0.204 mm 0.061 mm The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.
Claims
1. A diarylguanidine derivative with anti-lymphoma function, characterized in that, The chemical name of this diarylguanidine derivative is 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-aryloxyphenyl)-3-arylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate, and its structural formula is as follows: Wherein, R is any one of 2-fluorophenyl, 2-trifluoromethylphenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2-fluoro-4-trifluoromethylphenyl, 2,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, and 2,4,6-trifluorophenyl; Ar is any one of substituted phenyl, pyridine, or substituted pyridine.
2. A method for preparing a diarylguanidine derivative with anti-lymphoma function, characterized in that, include Step 1: React phenolic compounds with 4-bromonitrobenzene in DMF solution to prepare 4-nitrodiphenyl ether compounds; Step 2: Place 4-nitrodiphenyl ether compounds in an iron-containing ethanol solution to prepare 4-aminodiphenyl ether compounds; Step 3: Place 4-aminodiphenyl ether compounds and phenyl thioisocyanate in a tetrahydrofuran solution to react and prepare 1-(4-phenoxyphenyl)-3-phenylurea compounds; Step 4: React 1-(4-phenoxyphenyl)-3-phenylurea compounds with amlodipine under light conditions to obtain the target compound 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate ester.
3. The method for preparing the diarylguanidine derivative with anti-lymphoma function according to claim 1, characterized in that, Step 1 is as follows: 4-Bromonitrobenzene, phenolic compounds, and potassium carbonate in a molar ratio of 1:2:1.1 were added to a round-bottom flask containing DMF and reacted. The resulting reaction mixture was placed in an ice-water bath, and the precipitated solid was filtered and washed to obtain the product, 4-nitrodiphenyl ether compounds.
4. The method for preparing the diarylguanidine derivative with anti-lymphoma function according to claim 3, characterized in that, Step 2 is as follows: 4-Nitrodiphenyl ether compounds, ammonium chloride, and iron powder were added to a mixed solvent containing ethanol and water. The reaction mixture was heated under reflux and cooled. The iron powder was filtered out, the mixture was collected, extracted, and the filtrate was evaporated to dryness to obtain 4-aminodiphenyl ether compounds.
5. The method for preparing the diarylguanidine derivative with anti-lymphoma function according to claim 4, characterized in that, The molar ratio of 4-nitrodiphenyl ether compounds, ammonium chloride, and iron powder is 1:3:
3.
6. The method for preparing the diarylguanidine derivative with anti-lymphoma function according to claim 5, characterized in that, Step 3 specifically involves: 4-Aminodiphenyl ether compounds and phenyl isothiocyanate were added to a round-bottom flask containing tert-butanol. The reaction mixture was then heated to reflux. After the reaction was stopped, the reaction mixture was cooled, evaporated, washed, and dried to obtain clean 1-(4-phenoxyphenyl)-3-phenylthiourea compounds.
7. The method for preparing the diarylguanidine derivative with anti-lymphoma function according to claim 6, characterized in that, The molar ratio of 4-aminodiphenyl ether compounds to phenyl isothiocyanate is 1:
2.
8. The method for preparing the diarylguanidine derivative with anti-lymphoma function according to claim 7, characterized in that, Step 4 specifically involves: 1-(4-phenoxyphenyl)-3-phenylthiourea compounds, amlodipine, and potassium carbonate were added to a mixed solvent of ethanol and water and reacted. After the reaction, the mixture was extracted and dried. The crude product was separated and purified to obtain the final product 3-ethyl-5-methyl-(E)-4-(2-chlorophenyl)-6-methyl-2-((2-(2-(3-phenoxyphenyl)-3-phenylguanidinyl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate.
9. The method for preparing the diarylguanidine derivative with anti-lymphoma function according to claim 10, characterized in that, In step 4, the molar ratio of 1-(4-phenoxyphenyl)-3-phenylthiourea compound, amlodipine, and potassium carbonate is 1:1.5:2, and the molar ratio of ethanol to water is 9:
1.
10. Use of the diarylguanidine derivative as described in claim 1 in the preparation of an anti-lymphoma drug.