1-aryl-3-(heterocycle-substituted phenyl) urea compounds, and preparation method and application thereof

Abstract

The application discloses a 1-aryl-3-(heterocyclic-substituted phenyl) urea compound and a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to a 1-aryl-3-{4-{1-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolano[4,5-d][1,2]diazepin-5-yl]methyl}phenyl} urea compound and a preparation method thereof and application thereof in preparation of antitumor drugs. The structural general formula of the 1-aryl-3-(heterocyclic-substituted phenyl) urea compound is as follows: Y is CH2 or CO; R is selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, halogen-substituted C1-C4 alkyl, halogen-substituted C1-C4 alkoxy, phenyl, and naphthyl formed by combining with the phenyl; and R can be one or more. The synthesis method of the compound is simple, suitable for industrial production, and biological activity test shows that the compound has antitumor activity and can be applied to preparation of antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to 1-aryl-3-{4-{1-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza -5-yl]methyl}phenyl}urea compounds, their preparation methods, and their applications in the preparation of antitumor drugs. Background Technology

[0002] Cancer refers to malignant tumor cells formed when normal cells undergo gene abnormalities under the influence of various carcinogenic factors, resulting in carcinogenesis. It has biological characteristics such as abnormal cell differentiation and proliferation, uncontrolled growth, invasiveness, and metastasis. Its occurrence is a complex process involving multiple factors and multiple steps.

[0003] The development of cancer treatment strategies is a matter of great concern today. Currently, anti-tumor drugs can cure or control many types of tumors, but overall, they have not yet reached a satisfactory stage. In recent years, with the development of multidisciplinary approaches, we have gained a deeper understanding of the mechanisms of tumor development and the mechanisms of action of anti-tumor drugs, including cytotoxic anti-tumor drugs and small-molecule targeted anti-tumor drugs. However, many tumor cells develop drug resistance during chemotherapy. Therefore, while improving the efficacy of existing drugs and reducing side effects, it is also necessary to synthesize new small-molecule drugs and develop novel, low-toxicity, and effective anti-tumor drugs.

[0004] Urea compounds play an important role in the development of antitumor drugs because urea can form multiple stable hydrogen bonds with proteins and receptor targets. This stable drug-target interaction gives urea compounds good biological activity and drug properties. Typical antitumor drugs, such as sorafenib, lenvatinib, and regorafenib, are all marketed drugs with a diarylurea structure (Zheng A, Chevalier N, Calderoni M, Dubuis G, Dormond O, Ziros PG, Sykiotis GP, Widmann C. CRISPR / Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma. Oncotarget, 2019, 10(66):7058-7070.).

[0005] The structure of sorafenib:

[0006]

[0007] Structure of lenvatinib:

[0008]

[0009] The structure of regorafenib:

[0010] Summary of the Invention

[0011] The primary objective of this invention is to provide a 1-aryl-3-(heterocyclic substituted phenyl)urea compound as shown in Formula I, or a pharmaceutically acceptable salt thereof:

[0012]

[0013] Y is CH2 or CO;

[0014] R is selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, halogen-substituted C1-C4 alkyl, halogen-substituted C1-C4 alkoxy, phenyl, and naphthyl with the attached phenyl group; R can be one or more.

[0015] Furthermore, R is selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, halogen, phenyl, and naphthyl group formed by the attached phenyl group; R can be one or more.

[0016] Furthermore, R is selected from 4-chloro-3-trifluoromethyl, 4-methoxy, 4-fluoro, 3-chloro-4-fluoro, 4-methyl, 4-trifluoromethoxy, 4-chloro, 4-phenyl, 4-trifluoromethyl, 3-trifluoromethyl, 3-methyl, and the naphthyl-1-yl group formed by the attached phenyl group.

[0017] The following compounds are preferred in this invention:

[0018] 1-(4-chloro-3-trifluoromethylphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0019] 1-(4-methoxyphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0020] 1-(3-trifluoromethylphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0021] 1-(4-fluorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0022] 1-(3-chloro-4-fluorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0023] 1-(p-Tolyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0024] 1-(4-trifluoromethoxyphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0025] 1-(4-chlorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0026] 1-(naphthyl-1-yl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0027] 1-(biphenyl-4-yl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] -5-yl]methyl}phenyl}urea;

[0028] 1-(4-Fluorophenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} [5-carbonyl]phenylurea;

[0029] 1-(4-trifluoromethoxyphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} [5-carbonyl]phenylurea;

[0030] 1-(3-trifluoromethylphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} [5-carbonyl]phenylurea;

[0031] 1-(3-Chloro-4-fluorophenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} [5-carbonyl]phenylurea;

[0032] 1-(3-Methylphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} -5-carbonyl]phenyl}urea.

[0033] A pharmaceutical composition comprising a compound of Formula I of the present invention as an active ingredient, a prodrug and a pharmaceutically active metabolite thereof, a compound of any one of its pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier or diluent.

[0034] "Pharmaceutical acceptable salt" refers to a conventional acid addition salt or base addition salt that retains the biological potency and properties of the compound represented by Formula I and is formed with a suitable nontoxic organic or inorganic acid or organic or inorganic base. Acid addition salts include hydrochlorides, hydrobroms, hydroiodates, nitrates, phosphates, sulfates, perchlorates, thiocyanates, hydrogen sulfates, persulfates, borates, formates, acetates, propionates, valerates, neovalerates, hexanoates, heptanoates, octanoates, isooctanoates, undecanoates, laurates, palmitates, stearates, oleates, cyclopropionates, oxalates, malonates, succinates, maleates, fumarates, adipates, azelaates, acrylates, strawberry salts, crotonates, tigrinates, itacrates, sorbates, cinnamates, glycolates, lactates, malates, tartrates, citrates, tartrites, mandelates, diphenylglycolates, tropine, ascorbate, gluconate, glucono-p-ethyl, gluconate, mannitol, lactobionate, benzoates, phthalates, paraphthalates, furoate, nicotinic acid, and isonicotinic acid. Salicylate, acetylsalicylate, butyrate, gallate, caffeate, ferulic acid, picrate, camphorate, camphor sulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, p-toluenesulfonate, p-aminobenzenesulfonate, aminosulfonate, taurine, 2-hydroxyethanesulfonate, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartate, asparagine, glutamate, lysine, glutamine, methionine, serine, threonine, cysteine, proline, histidine, arginine, edetate, pyruvate, α-ketoglutarate, alginate, cyclopentanepropionate, 3-phenylpropionate, 3-cyclohexylpropionic acid, 2-naphthylcarboxate, 2-naphthylsulfonate, dihydroxynaphthylate, lauryl sulfate, glycerol phosphate, lauryl sulfate, pectin esters, etc. Alkaline salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts of organic bases such as dicyclohexylamine salts and N-methyl-D-glucosamine salts. Furthermore, the basic nitrogen-containing group can be quaternized with reagents such as lower alkyl halides, such as chloro, bromine, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides, such as chloro, bromine, and iodides of decyl, lauryl, myristyl, and stearoyl groups; and aralkyl halides, such as bromides of benzyl and phenethyl groups. Preferred acids for forming acid addition salts include hydrochloric acid, acetates, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, and p-aminobenzenesulfonic acid.

[0035] The present invention also relates to pharmaceutical compositions that inhibit tyrosine kinases and serine / threonine kinases, the compositions comprising a compound or derivative of Formula I or a pharmaceutically suitable acid addition salt thereof and a pharmaceutically acceptable carrier.

[0036] "Pharmaceutical acceptable" refers to pharmaceutically acceptable carriers, excipients, prodrugs, etc., which are pharmacologically acceptable and substantially non-toxic to patients who are given the specific compound.

[0037] "Pharmaceutically active metabolites" refer to the metabolites of pharmaceutically acceptable and effective Formula I compounds.

[0038] The term "halogen" as used in this invention includes fluorine, chlorine, bromine, and iodine.

[0039] The compounds of this invention can be administered to patients by various methods, such as oral administration as capsules or tablets, as sterile solutions or suspensions, and in some cases, intravenous injection as solutions. The free base compounds of this invention can be formulated and administered as pharmaceutically suitable acid addition salts.

[0040] The following process summarizes the preparation steps of the compounds of the present invention:

[0041]

[0042]

[0043] In the synthetic route, R represents the corresponding group at the position of the compound shown in Formula I.

[0044] The present invention also provides the use of the 1-aryl-3-(heterocyclic substituted phenyl)urea compound of Formula I or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of A549 cell, A375 cell, MCF-7 cell and HeLa cell proliferation inhibitors.

[0045] This invention also provides the use of 1-aryl-3-(heterocyclic substituted phenyl)urea compounds of Formula I, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the preparation of antitumor drugs. The tumors include lung cancer, melanoma, breast cancer, human cervical cancer, and ovarian cancer.

[0046] The beneficial effects of this invention are:

[0047] This invention discloses a series of novel 1-aryl-3-(heterocyclic substituted phenyl)urea compounds. These compounds exhibit varying degrees of inhibitory activity against tumor cell lines such as A549 (lung cancer cells), A375 (melanoma cells), MCF-7 (breast cancer cells), and HeLa (human cervical cancer cells) in in vitro experiments, and can be further applied to the research and preparation of anti-tumor drugs. This invention provides new strategies and potential drugs for cancer treatment. The synthetic methods of the compounds in this invention are simple and suitable for industrial production. Detailed Implementation

[0048] The present invention will be further described in detail below with reference to specific embodiments. However, this should not be construed as limiting the scope of the above-described subject matter of the present invention to the following embodiments; all technologies implemented based on the content of the present invention fall within the scope of the present invention.

[0049] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents and instruments used, unless otherwise specified, are all commercially available conventional reagent products.

[0050] Example 1: 1-(4-chloro-3-trifluoromethylphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methylphenylurea (TT01)

[0051] Step a: Preparation of (3aR,6R,6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-ol

[0052] 10.0 g (66.7 mmol) of D-ribose was weighed and placed in a flask. Acetone (50 mL) was added, and sulfuric acid (0.5 mL) was slowly added dropwise under ice bath conditions. The mixture was stirred at room temperature for 1.5 h, and then triethylamine (TEA) was added to neutralize the reaction solution to neutral. After evaporating the acetone under reduced pressure, the product was separated by silica gel column chromatography (PE:EA = 2:1) to obtain 11.87 g of a pale yellow viscous liquid, with a yield of 93.7%.

[0053] Step b: Preparation of [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-yl]methyl-p-methylbenzenesulfonate

[0054] Weigh (3aR,6R,6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-ol (11.87 g, 62.4 mmol) into a flask, add 20 mL of pyridine to dissolve, and weigh p-toluenesulfonyl chloride (TsCl, 14.28 g, 74.9 mmol) and dissolve in 50 mL of pyridine (Py). Slowly add the solution to the reaction mixture under ice bath conditions. After the addition is complete, stir the mixture overnight at room temperature. Dilute the reaction solution with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, distill off most of the ethyl acetate under reduced pressure, and separate by column chromatography (PE:EA = 5:1) to obtain 14.00 g of white solid, yield 67.3%.

[0055] Step c: (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza Preparation

[0056] [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-yl]methyl p-toluenesulfonate (0.35 g, 1.0 mmol), methylhydrazine sulfate (0.17 g, 1.2 mmol), acetonitrile (2 mL), and triethylamine (0.55 mL, 4.0 mmol) were added to a flask and reacted overnight at 35 °C under nitrogen protection with stirring. After most of the acetonitrile was distilled off under reduced pressure, column chromatography (PE:EA = 2:1) was performed to obtain 0.133 g of a pale yellow waxy solid, with a yield of 66.3%. 1 H NMR (400MHz, CDCl3) δ4.88–4.86(m,1H),4.86–4.81(m,1H),4.80–4.73(m,1H),4.27(m,J=2.1,0. 9Hz,1H),2.75–2.71(m,1H),2.36(dd,J=11.3,2.0Hz,1H),2.34(s,3H),1.47(s,3H),1.35(s,3H). 13 C NMR (100MHz, CDCl3) δ111.42,91.50,82.78,82.73,78.76,59.98,46.24,26.02,24.54.MS:201.1([M+H] + ).

[0057] Step d: (3aR,4R,8R,8aR)-2,2,6-trimethyl-5-(4-nitrobenzyl)hexahydro-4H-4,8-epoxy[1,3]dioxanepentane[4,5-d][1,2]diaza Preparation

[0058] Weigh (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza (2 g, 10 mmol) of p-nitrobenzyl bromide (2.6 g, 12 mmol) and potassium carbonate (6.0 g, 45 mmol) were placed in a 100 mL round-bottom flask. A stir bar was added, followed by 35 mL of acetonitrile. A drying tube was added, and the mixture was refluxed at 60 °C for 48 h. After the reaction was complete, the mixture was extracted three times with 50 mL of ethyl acetate, washed three times with 50 mL of water, and washed three times with 50 mL of saturated brine. The mixture was dried, and after most of the ethyl acetate was distilled off under reduced pressure, it was separated by column chromatography (PE:EA = 6:1) to obtain 2.5 g of a yellow solid, yield 74.5%; Mp: 190.3-192.5 °C; MS: 336.1 ([M+H)). + ).

[0059] Step e: 4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methyl}aniline

[0060] Weigh (3aR,4R,8R,8aR)-2,2,6-trimethyl-5-(4-nitrobenzyl)hexahydro-4H-4,8-epoxy[1,3]dioxanepentane[4,5-d][1,2]diaza 3.35 g (10 mmol), ferric chloride hexahydrate (0.27 g, 1 mmol), and 1 g activated carbon were placed in a 100 mL round-bottom flask. A stir bar was added, followed by 25 mL of anhydrous ethanol. The temperature was set to 80 °C. Under heating and stirring conditions, hydrazine hydrate (3.03 mL, 50 mmol) was added dropwise, and the mixture was refluxed for 12 h. After most of the ethanol was distilled off under reduced pressure, the mixture was separated by column chromatography (PE:EA = 3:1) to obtain 1.25 g of a yellow solid, yield 40.9%; Mp: 161.1-163.2 °C; MS: 328.1 ([M+Na)). + ).

[0061] Step f: 1-(4-chloro-3-trifluoromethylphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza Preparation of 5-yl]methylphenylurea (TT01)

[0062] Weigh 0.2 g (0.66 mmol) of triphosgene (BTC) and 10 mL of dichloromethane (DCM) into a flask. Slowly add a dichloromethane solution of 0.39 g (2 mmol) of 4-chloro-3-trifluoromethylaniline, followed by a dichloromethane solution of 0.4 g (4 mmol) of triethylamine, and then a dichloromethane solution of 4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] A solution of 0.31 g (1 mmol) of [-5-yl]methyl}aniline in dichloromethane was reacted overnight at room temperature with stirring. After most of the dichloromethane was distilled off under reduced pressure, 0.48 g of a white solid was obtained by column chromatography (DCM:EA = 15:1), yield 90.6%; Mp: 120.1-123.3 °C. 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 8.81 (s, 1H), 8.11 (d, J = 2.4Hz, 1H), 7.63 (dd, J = 8 .8,2.5Hz,1H),7.58(d,J=8.8Hz,1H),7.42(d,J=8.3Hz,2H),7.23(d,J=8.2Hz,2H),4. 67(s,2H),4.28–4.23(m,1H),4.19–4.14(m,1H),3.92–3.78(m,2H),2.99(dd,J=11.8, 2.1Hz,1H),2.39(s,3H),2.37–2.32(m,1H),1.27(s,3H),1.22(s,3H); MS:527.1([M+H] + ).

[0063] Example 2: 1-(4-methoxyphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methyl}phenyl}urea (TT02)

[0064] Following the preparation method of Example 1, but replacing 4-chloro-3-trifluoromethylaniline in step f with 4-methoxyaniline, 0.23 g of white solid was obtained, with a yield of 50.6%; Mp: 174.7-186.4℃; 1H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.44 (s, 1H), 7.39 (d, J = 8.5Hz, 2H), 7.35 (d,J=9.0Hz,2H),7.20(d,J=8.4Hz,2H),6.86(d,J=9.0Hz,2H),4.67(s,2H),4. 30–4.21(m,1H),4.19–4.14(m,1H),3.93–3.78(m,2H),3.71(s,3H),3.00(dd, J=11.7,2.1Hz,1H),2.40(s,3H),2.38–2.34(m,1H),1.28(s,3H),1.23(s,3H). 13 C NMR(101MHz,DMSO-d6)δ154.90,153.16,139.25,131.21,130.17,120.43,118.50,114.44,11 0.81,92.79,83.37,82.69,79.05,55.63,49.93,42.43,42.19,26.43,24.83; MS:455.0([M+H] + ).

[0065] Example 3: 1-(3-trifluoromethylphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methyl}phenyl}urea (TT03)

[0066] Following the preparation method of Example 1, but replacing 4-chloro-3-trifluoromethylaniline with 3-trifluoromethylaniline in step f, 0.34 g of white solid was obtained, with a yield of 69.0%; Mp: 169.0-171.6℃; 1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.77(s,1H),8.02(s,1H),7.56(d,J=9.1Hz,1H),7 .53–7.47(m,1H),7.43(d,J=8.4Hz,2H),7.30(d,J=7.5Hz,1H),7.23(d,J=8.5Hz,2H),4 .67(s,2H),4.30–4.22(m,1H),4.20–4.13(m,1H),3.94–3.80(m,2H),3.00(dd,J=11.8, 2.1Hz,1H),2.40(s,3H),2.38–2.33(m,1H),1.28(s,3H),1.22(s,3H); MS:493.1([M+H] + ).

[0067] Example 4: 1-(4-fluorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methylphenylurea (TT04)

[0068] Following the preparation method of Example 1, but replacing 4-chloro-3-trifluoromethylaniline with 4-fluoroaniline in step f, 0.32 g of white solid was obtained, with a yield of 72.3%; Mp: 189.4-190.7℃; 1 H NMR(400MHz, CDCl3)δ7.46(s,1H),7.30(s,1H),7.28–7.23(m,2H),7.19–7.07(m,4 H),6.95–6.84(m,2H),4.85(d,J=5.5Hz,1H),4.74(d,J=5.6Hz,1H),4.53–4.48(m, 1H),4.34–4.29(m,1H),4.01–3.92(m,1H),3.88–3.78(m,1H),3.17(dd,J=11.9,2. 1Hz,1H),2.49(s,3H),2.35–2.28(m,1H),1.39(s,3H),1.28(s,3H); MS:440.9([MH] + ).

[0069] Example 5: 1-(3-chloro-4-fluorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methylphenylurea (TT05)

[0070] Following the preparation method of Example 1, but replacing 4-chloro-3-trifluoromethylaniline with 3-chloro-4-fluoroaniline in step f, 0.31 g of a white solid was obtained, with a yield of 65.0%; Mp: 204.7-206.5 °C; 1 H NMR (400MHz, DMSO-d6) δ8.84 (s, 1H), 8.73 (s, 1H), 7.80 (dd, J = 6.8, 2.4Hz, 1H), 7. 40(d,J=8.5Hz,2H),7.37–7.25(m,2H),7.22(d,J=8.5Hz,2H),4.77–4.58(m,2H), 4.36–4.20(m,1H),4.19–4.06(m,1H),3.97–3.75(m,2H),3.00(dd,J=11.7,2.1Hz ,1H),2.40(s,3H),2.38–2.34(m,1H),1.28(s,3H),1.23(s,3H); MS:477.0([M+H] + ).

[0071] Example 6: 1-(p-Tolyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methyl}phenyl}urea (TT06)

[0072] Following the preparation method of Example 1, but replacing 4-chloro-3-trifluoromethylaniline in step f with 4-methylaniline, 0.37 g of white solid was obtained, with a yield of 84.4%; Mp: 200.5-202.4℃; 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),8.51(s,1H),7.39(d,J=8.5Hz,2H),7.32(d,J= 8.4Hz,2H),7.21(d,J=8.5Hz,2H),7.07(d,J=8.2Hz,2H),4.71–4.63(m,2H),4.28–4 .23(m,1H),4.19–4.14(m,1H),3.88–3.79(m,2H),3.00(dd,J=11.7,2.1Hz,1H),2.4 0(s,3H),2.38–2.34(m,1H),2.24(s,3H),1.28(s,3H),1.23(s,3H); MS:439.0([M+H] + ).

[0073] Example 7: 1-(4-trifluoromethoxyphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] The preparation of 5-yl]methyl}phenyl}urea (TT07) was carried out according to the preparation method of Example 1, except that 4-chloro-3-trifluoromethylaniline in step f was replaced with 4-trifluoromethoxyaniline to obtain 0.43 g of white solid, yield 84.6%; Mp: 175.8-176.7℃. 1 H NMR (400MHz, CDCl3) δ7.71 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 9.0Hz, 2H), 7.20–7.13 (m, 4H),7.05(d,J=9.1Hz,2H),4.86(d,J=5.6Hz,1H),4.76(d,J=5.5Hz,1H),4.54–4.49( m,1H),4.36–4.31(m,1H),3.99–3.91(m,1H),3.85–3.78(m,1H),3.19(dd,J=11.9,2. 1Hz,1H),2.50(s,3H),2.36–2.30(m,1H),1.41(s,3H),1.30(s,3H); MS:509.0([M+H] + ).

[0074] Example 8: 1-(4-chlorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza Preparation of 5-yl]methyl}phenyl}urea (TT08)

[0075] Following the preparation method of Example 1, but replacing 4-chloro-3-trifluoromethylaniline in step f with 4-chloroaniline, 0.37 g of a white solid was obtained, with a yield of 80.6%; Mp: 202.0-203.5℃; 1H NMR (400MHz, CDCl3) δ7.52 (s, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.8Hz, 2H), 7.20–7. 13(m,6H),4.88(d,J=5.5Hz,1H),4.75(d,J=5.6Hz,1H),4.55–4.50(m,1H),4.3 5–4.30(m,1H),4.02–3.94(m,1H),3.89–3.81(m,1H),3.18(dd,J=11.9,2.1Hz, 1H),2.52(s,3H),2.37–2.30(m,1H),1.39(s,3H),1.28(s,3H); MS:459.0([M+H] + ).

[0076] Example 9: 1-(naphthyl-1-yl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza Preparation of 5-yl]methylphenylurea (TT09)

[0077] Following the preparation method of Example 1, but replacing 4-chloro-3-trifluoromethylaniline in step f with 1-naphthylamine, 0.35 g of white solid was obtained, with a yield of 73.8%; Mp: 210.1-211.6℃; 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.4Hz,1H),7.72(d,J=7.6Hz,1H),7.56(d,J=6.9Hz,2H),7.46 –7.23(m,5H),7.13(d,J=8.5Hz,2H),7.07(d,J=8.2Hz,2H),4.78(d,J=5.6Hz,1H),4.67(d,J=5. 6Hz,1H),4.50–4.39(m,1H),4.24–4.19(m,1H),3.92–3.83(m,1H),3.78–3.67(m,1H),3.07(dd, J=11.7,2.1Hz,1H),2.41(s,3H),2.25–2.19(m,1H),1.37(s,3H),1.25(s,3H); MS:475.1([M+H] + ).

[0078] Example 10: 1-(biphenyl-4-yl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] Preparation of 5-yl]methylphenylurea (TT10)

[0079] Following the preparation method of Example 1, and replacing 4-chloro-3-trifluoromethylaniline in step f with 4-aminobiphenyl, 0.44 g of white solid was obtained, with a yield of 88.0%; Mp: 168.7-169.3℃. 1 H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 7.52–7.34 (m, 8H), 7.33 (d, J = 3.2Hz, 1H), 7.30–7.24 (m, 1H), 7. 23(d,J=5.8Hz,2H),7.18(s,1H),6.57(d,J=4.7Hz,0H),4.86(d,J=5.5Hz,1H),4.74(d,J=5.6Hz,1 H),4.53(s,1H),4.32(d,J=2.1Hz,1H),3.97(d,J=11.7Hz,1H),3.83(d,J=11.7Hz,1H),3.16(dd,J =11.9,2.1Hz,1H),2.49(s,3H),2.31(d,J=11.7Hz,1H),1.40(s,3H),1.29(s,3H); MS:501.0([M+H] + ).

[0080] Example 11: 1-(4-fluorophenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} Preparation of 5-carbonyl]phenyl]urea (TT11)

[0081] Following the preparation method of step ac in Example 1, (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza was obtained. (Compound 4 in the synthetic route)

[0082] Step g: (4-Nitrophenyl)[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza Preparation of 5-yl]methyl ketone

[0083] Weigh p-nitrobenzoic acid (1.67 g, 10 mmol) into a 50 mL round-bottom flask, add 15 mL of dichloromethane, and under ice bath conditions, add sulfoxide (0.89 g, 7.5 mmol). Stir at room temperature for 1 h, then add pyridine (1.67 mL, 20 mmol) and (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza (1.0 g, 5 mmol), reacted for 24 h. Extracted three times with 20 mL dichloromethane, washed once with saturated sodium bicarbonate, washed three times with 20 mL water, and washed once with saturated sodium chloride. 1.2 g of white solid was given, yield 68.7%; Mp: 162.6–165.7 °C; MS: 350.0 ([M+H)). + ).

[0084] Step h: 4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxanepentano[4,5-d][1,2]diaza] Preparation of 5-yl]methyl}aniline

[0085] Weigh out (4-nitrophenyl)[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza] 3.35 g (10 mmol) of 5-yl methyl ketone, 0.056 g (0.2 mmol) of ferric chloride hexahydrate, and 2.8 g of activated carbon were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous ethanol was added. The temperature was set to 80 °C. Under heating and stirring conditions, 0.44 g (7 mmol) of hydrazine hydrate was added dropwise, and the mixture was refluxed for 12 h. After filtration and distillation off most of the ethanol under reduced pressure, the solid was separated by column chromatography (PE:EA = 4:1) to obtain 0.4681 g of a yellow solid, yield 52.3%; Mp: 143.3-145.5 °C; MS: 320.2 ([M+H)). + ).

[0086] Step i: 1-(4-fluorophenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} Preparation of 5-carbonyl]phenyl]urea (TT11)

[0087] Weigh 0.2 g (0.66 mmol) of triphosgene and 10 mL of dichloromethane into a flask. Slowly add a dichloromethane solution of 0.22 g (2 mmol) of p-fluoroaniline, followed by a dichloromethane solution of 0.4 g (4 mmol) of triethylamine, and then a dichloromethane solution of 4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxanepentano[4,5-d][1,2]diaza]dioxane. A solution of 0.32 g (1 mmol) of [-5-yl]methyl}aniline in dichloromethane was reacted overnight at room temperature with stirring. After most of the dichloromethane was distilled off under reduced pressure, 0.42 g of a white solid was obtained by column chromatography (DCM:EA = 15:1), yield 92.4%; Mp: 190.0-190.9 °C. 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.65 (s, 1H), 7.42 (d, J = 8.4Hz, 2H), 7.22– 7.20(m,2H),7.19–7.17(m,2H),6.93–6.83(m,2H),5.54–5.49(m,1H),5.00–4 .94(m,1H),4.80–4.73(m,1H),4.34–4.29(m,1H),3.56(dd,J=12.1,2.7Hz,1H ),2.84(s,3H),2.59–2.47(m,1H),1.36(s,3H),1.30(s,3H); MS:457.1([M+H] + ).

[0088] Example 12: 1-(4-trifluoromethoxyphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} Preparation of 5-carbonyl]phenyl]urea (TT12)

[0089] Following the preparation method of Example 11, but replacing p-fluoroaniline in step i with 4-trifluoromethoxyaniline, 0.47 g of white solid was obtained, with a yield of 92.8%; Mp: 130.4-132.0 °C; 1H NMR (400MHz, CDCl3) δ7.74 (s, 1H), 7.43 (d, J = 8.4Hz, 2H), 7.34 (d, J = 9.0Hz, 2H) ,7.21(s,1H),7.20–7.10(m,2H),7.07(d,J=8.4Hz,2H),5.58–5.48(m,1H),5.0 3–4.98(m,1H),4.83–4.78(m,1H),4.38–4.33(m,1H),3.57(dd,J=11.6,2.7Hz, 1H),2.87(s,3H),2.64–2.56(m,1H),1.37(s,3H),1.31(s,3H); MS:523.1([M+H] + ).

[0090] Example 13: 1-(3-trifluoromethylphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} Preparation of 5-carbonyl]phenyl]urea (TT13)

[0091] Following the preparation method of Example 11, but replacing p-fluoroaniline in step i with 3-trifluoromethylaniline, 0.42 g of white solid was obtained, with a yield of 82.9%; Mp: 182.3-184.0 °C; 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),7.89(s,1H),7.63(s,1H),7.55(d,J=8.8Hz,1H ),7.44(d,J=8.4Hz,2H),7.34–7.26(m,1H),7.27–7.20(m,3H),5.58–5.48(m,1H) ,5.05–4.99(m,1H),4.87–4.81(m,1H),4.39–4.34(m,1H),3.60(dd,J=12.0,2.8H z,1H),2.89(s,3H),2.70–2.62(m,1H),1.37(s,3H),1.31(s,3H); MS:507.1([M+H] + ).

[0092] Example 14: 1-(3-chloro-4-fluorophenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} Preparation of 5-carbonyl]phenyl]urea (TT14)

[0093] Following the preparation method of Example 11, but replacing p-fluoroaniline in step i with 3-chloro-4-fluoroaniline, 0.39 g of white solid was obtained, with a yield of 79.5%; Mp: 151.4-154.3 °C; 1 H NMR (400MHz, CDCl3) δ7.91(s,1H),7.84(s,1H),7.42(d,J=8.6Hz,2H),7.34(dd,J= 6.5,2.7Hz,1H),7.17(d,J=8.2Hz,2H),7.11–7.01(m,1H),7.00–6.87(m,1H),5.59 –5.42(m,1H),5.01–4.93(m,1H),4.83–4.73(m,1H),4.37–4.30(m,1H),3.54(dd,2 H),2.83(s,3H),2.57(d,J=12.3Hz,1H),1.36(s,3H),1.30(s,3H);MS:491.1([M+H] + ).

[0094] Example 15: 1-(3-methylphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza} Preparation of 5-carbonyl]phenyl]urea (TT15)

[0095] Following the preparation method of Example 11, but replacing p-fluoroaniline with m-toluidine in step i, 0.31 g of a white solid was obtained, with a yield of 68.3%; Mp: 198.9-202.8 °C; 1 H NMR (400MHz, CDCl3) δ7.78 (s, 1H), 7.54 (s, 1H), 7.42 (d, J = 8.6Hz, 2H), 7.22 (d,J=4.7Hz,2H),7.12(d,J=8.6Hz,2H),6.98(d,J=7.8Hz,2H),5.60–5.45(m ,1H),5.00–4.93(m,1H),4.79–4.72(m,1H),4.33–4.28(m,1H),3.56(dd,2H) ,2.83(s,3H),2.56–2.48(m,1H),1.36(s,3H),1.30(s,3H); MS:453.1([M+H] + ).

[0096]

[0097]

[0098]

[0099] Example 16: Pharmacological Example

[0100] Experimental methods:

[0101] a. Cell resuscitation

[0102] Cryopreservation tubes containing melanoma cells A375, non-small cell lung cancer cells A549, human cervical cancer cells HeLa, and human breast cancer cells MCF-7 were removed from the liquid nitrogen container and thawed by shaking in a 37°C water bath. The thawed cryopreservation solution was transferred to 15mL centrifuge tubes containing culture medium, centrifuged at 1050rpm for 3min, the supernatant was discarded, and 1mL of complete culture medium was added to resuspend the cells. The cells were then seeded into 75mL culture flasks pre-filled with warm complete culture medium. After shaking the culture flasks to ensure even distribution of cells, they were incubated in a 37°C, 5% CO2 incubator. Cell morphology and growth were observed periodically.

[0103] b. Cell passage

[0104] When the cells in the culture flask reach 80%-90% confluence, discard the culture medium, add 3 mL of 0.25% trypsin solution, and incubate at 37°C for 2 min. Add 6 mL of culture medium to stop the digestion, repeatedly pipetting the cells from the flask wall to transfer them to a 15 mL centrifuge tube. Centrifuge at 1050 rpm for 3 min, discard the supernatant, and resuspend the cells in complete culture medium containing 10% fetal bovine serum to prepare a single-cell suspension. Mix thoroughly and count the cells. (Prepare 100 μL 2-5 * 10^10 cells / mL) 3 Inoculate one well per 96-well plate, filling the edge wells with sterile PBS to avoid edge effects. Incubate at 37°C with 5% CO2 for 24 hours.

[0105] c. Cytotoxicity and proliferation inhibition

[0106] After 24 hours of incubation in the 96-well culture plates, the culture medium was discarded, and 200 μL of complete culture medium containing the samples was replaced for another 72 hours. Three to five concentration gradients were set up for each sample group, with three replicates for each concentration. 20 μL of MTT solution (5 mg / mL, prepared with PBS, pH 7.4) was added to each well, and incubation continued for 4 hours. 150 μL of DMSO was added to each well, and the plates were shaken for 3 minutes to fully dissolve the crystals. The absorbance of each well was measured at 490 nm, 570 nm, or 630 nm using a microplate reader, and the results were recorded. The cell drug response (concentration required to achieve 50% maximum cellular effect, EC50) was also recorded. 50 The experimental data were obtained by calculation using the software GraphPad Prism 8.0.1.

[0107] Experimental results:

[0108]

[0109] Of the 15 compounds mentioned above, all exhibited varying degrees of inhibitory activity against tumor cell proliferation in A549, MCF-7, A375, and HeLa cell lines. TT01 showed significant inhibitory activity against A549 cell line, while TT02 and TT14 showed significant inhibitory activity against HeLa cell line. 50 All were below 10 μM.

[0110] Formulation Examples

[0111] The following formulation examples are merely illustrative of the scope of protection of the present invention and are not intended to limit it in any way. The active compounds mentioned in the following examples refer to compounds TT01-TT15 obtained in the above examples.

[0112] Example 17: Tablet Formulation

[0113] The active compound is 25-1000 mg, starch is 45 mg, microcrystalline cellulose is 35 mg, polyvinylpyrrolidone (10% aqueous solution) is 4 mL, sodium carboxymethyl cellulose is 4.5 mg, magnesium stearate is 0.5 mg, and talc is 1 mg.

[0114] Example 18: Suspension Formulation

[0115] 0.1-1000 mg of active compound, 50 mg of sodium carboxymethyl cellulose, 1.25 mg of syrup, 0.1 mg of sodium benzoate, 25 mg of flavoring agent, 5 mg of coloring agent, and add pure water to 5 mL.

[0116] Example 19: Aerosol Formulation

[0117] 0.25 mg of active compound, 25-75 mL of ethanol, and 70 mg of propellant 22 (dichlorofluoromethane).

[0118] Example 20: Suppository Formulation

[0119] 250 mg of active compound and 2000 mL of saturated fatty acid glycerides.

[0120] Example 21: Injectable Formulation

[0121] 50 mg of the active compound, 1000 mL of isotonic salt solution.

[0122] Example 22: Ointment Formulation

[0123] 0.025g of micronized active compound, 10g of liquid paraffin, and soft white wax to a total of 100g.

[0124] Example 23: Ointment Formulation

[0125] 0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin, and soft white wax to 100g.

[0126] Example 24: Water-in-oil cream formulation

[0127] 0.025g of active compound, 5g of cetyl alcohol, 5g of glyceryl monostearate, 10g of liquid paraffin, 2g of cetyl alcohol polyoxyethylene ether, 0.1g of citric acid, 0.2g of sodium citrate, 35g of propylene glycol, and water to 100g.

[0128] Example 25: Water-in-oil cream formulation

[0129] 0.025g of micronized active compound, 15g of soft white wax, 5g of liquid paraffin, 5g of cetyl alcohol, 2g of Sorbimacrogolstearate (Tween 65 of a specific pharmaceutical excipient grade), 0.5g of dehydrated sorbitan monostearate, 0.2g of sorbic acid, 0.1g of citric acid, 0.2g of sodium citrate, and water to 100g.

[0130] Example 26: Oil-in-water cream formulation

[0131] 0.025g of active compound, 35g of soft white wax, 5g of liquid paraffin, 5g of dehydrated sorbitol sesquioleate, 0.2g of sorbic acid, 0.1g of citric acid, 0.2g of sodium citrate, and water to 100g.

[0132] Example 27: Lotion Formulation

[0133] 0.25 g of active compound, 0.5 mL of isopropanol, 3 mg of carboxyvinyl polymer, 2 mg of NaOH, and water to 1 g.

[0134] Example 28: Formulation of a suspension for injection

[0135] 10 mg of active compound, 7 mg of sodium carboxymethyl cellulose, 7 mg of NaCl, 0.5 mg of polyoxyethylene (20) dehydrated sorbitan monooleate, 8 mg of benzyl alcohol, and sterile water to 1 mL.

[0136] Example 29: Aerosol Formulation for Oral and Nasal Inhalation

[0137] The active compound was 0.1% w / w, sorbitan trioleate was 0.7% w / w, trichlorofluoromethane was 24.8% w / w, dichlorotetrafluoroethane was 24.8% w / w, and dichlorodifluoromethane was 49.6% w / w.

[0138] Example 30: Formulation of atomizing solution

[0139] Add 7 mg of the active compound and 5 mg of propylene glycol to water to a final volume of 10 g.

[0140] Example 31: Powder Formulation for Inhalation

[0141] Fill a capsule with a mixture of the following ingredients: 0.1 mg of micronized active compound and 20 mg of lactose. Inhale the powder using an inhalation device.

[0142] Example 32: Powder Formulation for Inhalation

[0143] The spherical powder is packed into a multi-dose powder inhaler, with each dose containing 0.1 mg of micronized active compound.

[0144] Example 33: Powder Formulation for Inhalation

[0145] The spheroidized powder is loaded into a multi-dose powder inhaler, each dose containing 0.1 mg of micronized active compound and 1 mg of micronized lactose.

[0146] Example 34: Capsule Formulation

[0147] Active compound 1.0 mg, small sugar spheres 321 mg, Aquacoat ECD 30 6.6 mg, acetylated tributyl citrate 0.5 mg, Tween-80 0.1 mg, Eudragit L 100-55 17.5 mg, triethyl citrate 1.8 mg, talc 8.8 mg, defoamer MMS 0.1 mg.

[0148] Example 35: Capsule Formulation of Vaccines

[0149] Active compound 2.0 mg, small sugar globules 305 mg, Aquocoat ECD 30 5.0 mg, acetylsalicylic acid tributyl ester 0.4 mg, Tween-80 0.14 mg, Eudragit NE30D 12.6 mg, Eudragit S100 12.6 mg, talc 0.16 mg.

[0150] Example 36: Enema Formulation

[0151] Add 2 mg of active compound, 25 mg of sodium carboxymethyl cellulose, 0.5 mg of disodium EDTA, 0.8 mg of methylparaben, 0.2 mg of propylparaben, 7 mg of sodium chloride, 1.8 mg of citric acid, and 0.01 mg of Tween-80 to pure water to 1 mL.

[0152] Example 37: Formulation containing liposomes

[0153] A. Preparation of the drip formulation

[0154] Dipalmitoyl lecithin (45 mg), dimyristoyl lecithin (7 mg), dipalmitoyl phosphatidylglycerol (1 mg), and the active compound (5 mg) were placed in a glass tube. All components were dissolved in chloroform, and most of the solvent was evaporated with N2. Then, the pressure was reduced, thereby forming a lipid film on the surface of the glass tube. An aqueous solution (0.9% NaCl) was added to the lipid, and liposomes were formed at a phase inversion temperature higher than that of the lipid. The resulting suspension contained liposomes ranging in size from very small vesicles to 2 μm.

[0155] B. Preparation of inhalation formulations

[0156] Liposomes were prepared according to Example A, wherein the aqueous solution contained 10% lactose, and the ratio of lactose to lipids was 7:3. The liposome suspension was frozen with dry ice and then freeze-dried to micronize the dried product, resulting in particles with a mass-average aerodynamic diameter (MMAD) of approximately 2 μm.

[0157] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any other way. Any person skilled in the art may make changes or modifications to the above-disclosed technical content to create equivalent embodiments. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A 1-aryl-3-(heterocyclic substituted phenyl)urea compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of Formula I is as follows: ； Y is CH2 or CO; R is selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, halogen-substituted C1-C4 alkyl, halogen-substituted C1-C4 alkoxy, phenyl, and naphthyl with the attached phenyl group; R is one or more.

2. The 1-aryl-3-(heterocyclic substituted phenyl)urea compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, In Formula I, R is selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, halogen, phenyl, and naphthyl group formed by the attached phenyl group; R can be one or more.

3. The 1-aryl-3-(heterocyclic substituted phenyl)urea compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, In Formula I, R is selected from 4-chloro-3-trifluoromethyl, 4-methoxy, 4-fluoro, 3-chloro-4-fluoro, 4-methyl, 4-trifluoromethoxy, 4-chloro, 4-phenyl, 4-trifluoromethyl, 3-trifluoromethyl, 3-methyl, and the naphthyl group formed by the phenyl group to which it is attached.

4. The 1-aryl-3-(heterocyclic substituted phenyl)urea compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that, The 1-aryl-3-(heterocyclic substituted phenyl)urea compound is any one of the following compounds: 1-(4-chloro-3-trifluoromethylphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(4-methoxyphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(3-trifluoromethylphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(4-fluorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(3-chloro-4-fluorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(p-Tolyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(4-trifluoromethoxyphenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(4-chlorophenyl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(naphthyl-1-yl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(biphenyl-4-yl)-3-{4-{[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-yl]methyl}phenyl}urea; 1-(4-Fluorophenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-carbonyl]phenyl}urea; 1-(4-trifluoromethoxyphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-carbonyl]phenyl}urea; 1-(3-trifluoromethylphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-carbonyl]phenyl}urea; 1-(3-chloro-4-fluorophenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-carbonyl]phenyl}urea; 1-(3-Methylphenyl)-3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diaza-5-carbonyl]phenyl}urea.

5. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any one of the 1-aryl-3-(heterocyclic substituted phenyl)urea compounds of claims 1-4 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or diluent.

6. The use of the 1-aryl-3-(heterocyclic substituted phenyl)urea compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug.

7. Use of the pharmaceutical composition according to claim 5 in the preparation of an antitumor drug.

8. The application according to claim 7, characterized in that, The tumors mentioned are selected from lung cancer, melanoma, breast cancer, and cervical cancer.

9. The method for preparing the 1-aryl-3-(heterocyclic substituted phenyl)urea compound of claim 4 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: ； In the synthetic route, R is the corresponding group at the corresponding position of the compound described in claim 4.

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