CN114573581B - 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound and preparation and application thereof - Google Patents

5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound and preparation and application thereof Download PDF

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CN114573581B
CN114573581B CN202210322190.3A CN202210322190A CN114573581B CN 114573581 B CN114573581 B CN 114573581B CN 202210322190 A CN202210322190 A CN 202210322190A CN 114573581 B CN114573581 B CN 114573581B
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pyrimidine
trione
fluorophenyl
methyl
bis
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CN114573581A (en
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胡春
谢倩
李乐瑢
王宇航
文杰
杨小力
黄二芳
彭子俊
姚语桐
林柔嘉
金逸丹
邓杰元
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Shenyang Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] of the present invention]Pyrimidine compounds, and preparation and application thereof, and belongs to the technical field of medicines. The 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ]]The structural general formula of the pyrimidine compound is shown as the formula (I): r is R 1 Independently selected from hydrogen, fluorine; r is R 2 Independently selected from hydrogen, methyl, benzyl; r is R 3 、R 4 Independently selected from hydrogen, methyl, cyclopropyl, 2-dimethylaminoethyl, 3-morpholinopropyl, 3-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-trifluoromethylphenyl, 2-furanmethyl, or R 3 、R 4 Together with the nitrogen atom to which they are attached, form morpholinyl. The compound has simple synthesis method, is suitable for industrial production, and has antitumor activity as shown by biological activity test, and can be used for preparing antitumor drugs.

Description

5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound and preparation and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound, and preparation and application thereof.
Background
Malignant tumor is a serious disease, seriously threatens human health, has plagued human for many years, and is a big factor for preventing human life from increasing. With the discovery of oncogenes and cancer suppressor genes and elucidation of cell signaling pathways, the understanding of the canceration mechanism of cells by humans is greatly enriched, and by analyzing the functions of oncogene products, many oncoproteins are found at different sites of normal cell signaling pathways, which play an important role in promoting cell division and proliferation (Klein G.science,1987 (4833): 1539-1545).
The mitogen-activated protein kinase MAPK signaling pathway is a very important information transfer chain in cells. The MAPK pathway has three signaling processes: MAPK, MAPK kinase (MEK or MKK), and MAPK kinase (MEKK or MKK). These three kinases are activated in sequence and together regulate a variety of important physiological/pathological effects such as cell growth, differentiation, stress, inflammatory response, etc., which are the disaster areas (Orton RJ, sturm OE, vyshemirsky V, calder M, gilbert DR, kolch W.the Biochemical journal 2005,392 (2): 249-61) that induce tumor production. The common MAPK signal pathways in human body mainly comprise an extracellular signal kinase (ERK 1/2) signal pathway, a c-Jun-N-terminal kinase (JNK)/Stress Activated Protein (SAPK) signal pathway, a p38MAPK signal pathway, mitogen activated extracellular signal regulated kinase (MEK) and the like, and the MAPK pathway inhibitor small-molecule drugs on the market at present mainly comprise:
Trametinib (Trametinib) is a MEK inhibitor drug with anticancer activity, which can inhibit the activity of MEK1 and MEK2 kinases. Trametinib has achieved good results in phase III clinical trials on metastatic melanoma harboring the BRAF V600E mutation. In this mutation, the valine amino acid at position 600 of the BRAF protein has been replaced by glutamic acid, thus rendering the mutant BRAF protein constitutively active (Flaherty KT, inanth JR, daud A, gonzalez R, kefford RF, sosman J, et al, the New England Journal of medicine.2012,367 (18): 1694-703).
Bimetainib (binimeinib) is a selective inhibitor of MEK and was developed by Array Biopharma for the treatment of a variety of cancers. Binimeinib is, MEK is a central kinase in the pro-tumor MAPK pathway. Inappropriate activation of this pathway has been shown to occur in many cancers. Month 6 of 2018, it was approved by the FDA in combination with encouraging for the treatment of unresectable or metastatic BRAF V600E or V600K mutation positive melanoma patients (Koelblinger P, dornbierer J, dummer R.Fuure oncology.2017,13 (20): 1755-1766).
Sorafenib (Sorafenib) is an orally available Raf kinase inhibitor that directly inhibits Raf kinase activity, blocks signaling of the Ras pathway, and also acts on platelet-derived growth factor receptors and vascular endothelial growth factor receptors to down-regulate the expression level of p-MEK, thereby blocking the downstream Ras-Raf-MEK-ERK pathway. The incidence of sorafenib-induced lethal adverse reactions such as gastrointestinal distress, skin toxicity, etc. is extremely low (Wilhelm SM, carter C, tang L, et al cancer research 2004,64 (19): 7099-7109).
Dabrafenib (Dabrafenib) is a drug for treating non-operable or metastatic melanoma, and can specifically act on B-Raf V600E Domain, blocking MAPK pathway, inhibiting tumor cell growth and proliferation, and promoting apoptosis. And researches show that the combination of the B-Raf kinase inhibitor and the MEK inhibitor can regulate parallel channels causing adverse reactions of the B-Raf inhibitor, and the combination of the B-Raf kinase inhibitor and the MEK inhibitor can improve response speed and reduce toxicity. Patients often develop resistance to dabrafenib faster, and thus this problem can be solved by co-administration with the MEK inhibitor trimetinib (Khoja L, hogg d. Expert Review of Anticancer therapy.2015,112 (6): 536-545).
Disclosure of Invention
The invention aims to provide a 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound, and preparation and application thereof, wherein the compound is specifically a 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione compound, and the application of the compound in preparing medicines for treating or/and preventing tumor diseases related to MAPK channels such as B-Raf kinase, ras/Raf/MEK/ERK signal channels, p38MAPK signal channels, JNK-SAPK signal channels and the like correspondingly comprises the application of the compound in the aspect of resisting tumors as a multi-target inhibitor.
A 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound, a prodrug and pharmaceutically active metabolite thereof, and pharmaceutically acceptable salts thereof, as shown in formula I:
R 1 independently selected from hydrogen, halogen;
R 2 independently selected from hydrogen, C1-C4 alkyl, benzyl;
R 3 、R 4 independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 2-dimethylaminoethyl, 3-morpholinopropyl, C1-C3 alkyl-substituted phenyl, halogen-substituted C1-C3 alkyl-substituted phenyl, or R 3 、R 4 Together with the nitrogen atom to which they are attached, form morpholinyl.
Further, the compounds of formula I, prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, as described herein:
R 1 independently selected from hydrogen, fluorine;
R 2 independently selected from hydrogen, methyl, benzyl;
R 3 、R 4 independently selected from hydrogen, methyl, cyclopropyl, 2-dimethylaminoethyl, 3-morpholinopropyl, 3-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-trifluoromethylphenyl, 2-furanmethyl, or R 3 、R 4 Together with the nitrogen atom to which they are attached, form morpholinyl.
Further, the present invention is preferably the following compounds:
6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T01) having the structural formula I-1:
6-benzyl-5- { [2- (dimethylamino) ethyl ] amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T02) having the structural formula I-2:
6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- (methylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T03), having the structural formula I-3:
5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T04) having the structural formula I-4:
1, 3-bis (4-fluorophenyl) -8-methyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T05) having the structural formula I-5:
1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T06) having the structural formula I-6:
5- [ (3-chloro-4-fluorophenyl) amino ] -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T07), having the structural formula shown in the following formula I-7:
1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T08), having the structural formula I-8:
1, 3-bis (4-fluorophenyl) -5- [ (furan-2-ylmethyl) amino ] -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (T09), having the structural formula I-9:
1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (T10) having the structural formula I-10:
6-benzyl-8-methyl-5- [ (3-morpholinopropyl) amino ] -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T11), having the structural formula I-11:
6-benzyl-5- (cyclopropylamino) -8-methyl-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T12), having the structural formula I-12:
6-benzyl-8-methyl-5-morpholinyl-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T13) having the structural formula I-13:
6-benzyl-5- { [2- (dimethylamino) ethyl ] amino } -8-methyl-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T14), having the structural formula I-14:
6, 8-dimethyl-5- [ (3-morpholinopropyl) amino ] -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T15), having the structural formula I-15:
a pharmaceutical composition comprising as active ingredient a compound of the invention, a prodrug thereof and a pharmaceutically active metabolite thereof, and any one of its pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier or diluent.
"pharmaceutically acceptable salts" refer to conventional acid or base addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed with non-toxic organic or inorganic acids or organic or inorganic bases. The acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, perchlorate, thiocyanate, bisulfate, persulfate, borate, formate, acetate, propionate, valerate, pivalate, caproate, enanthate, caprylate, isooctanoate, undecanoate, laurate, palmitate, stearate, oleate, cyclopropanoate, oxalate, malonate, succinate, maleate, fumarate, adipate, azelate, acrylate, strawberry, crotonate, tiglate, itaconic acid, sorbate, cinnamate, glycolate, lactate, malate, tartrate, citrate, bitartrate, mandelate, dibenzoglycolate, tropinate, ascorbate, gluconate, glucoheptonate glucose di-, mannose-, lactose-, benzoate-, phthalate-, terephthalic-, furcate-, nicotinate-, isonicotinate-, salicylate-, acetylsalicylate-, caseinate-, gallate-, cafte-, ferulate-, picrate-, camphorate-, camphorsulfonate-, ethanesulfonate-, propanesulfonate-, phenylsulfonate-, p-toluenesulfonate-, sulfanilate-, sulfamate-, taurate-, 2-hydroxyethanesulfonate-, glycinate-, alaninate-, valine-, leucine-, isoleucine-, phenylalanine-, tryptophan-, tyrosine-, aspartic-, asparagine-, glutamic-, lysine-, glutamine-, methionine-, serine-, threonine-, cysteine-, proline-, histidine-, arginine-, proline-, and, edetate, pyruvate, alpha-ketoglutarate, alginate, cyclopentane propionate, 3-phenylpropionate, 3-cyclohexylpropionic acid, 2-naphthoate, 2-naphthalenesulfonate, pamoate, lauryl sulfate, glycerophosphate, lauryl sulfate, pectate. Preferred acids for use in forming the acid addition salts include hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, and sulfanilic acid. Base addition salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts of organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides.
The invention also relates to a pharmaceutical composition for inhibiting MEK kinase and B-RAF kinase, which comprises a compound shown as a formula I or a derivative thereof or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
"pharmaceutically acceptable" such as pharmaceutically acceptable carriers, excipients, prodrugs, refers to those that are pharmacologically acceptable and substantially non-toxic to the patient to whom the particular compound is administered.
"pharmaceutically active metabolite" refers to a metabolite of a compound of formula I that is pharmaceutically acceptable and effective.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
The compounds of the invention may be administered to a patient by various methods, including oral administration in capsules or tablets, in sterile solutions or suspensions, and in some cases, may be administered intravenously in solution. 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 disclosed by the invention is used as a novel-structure type small-molecule inhibitor related to MAPK signal paths such as a B-Raf kinase, a Ras/Raf/MEK/ERK signal path, a p38MAPK signal path, a JNK-SAPK signal path and the like, has the characteristics of novel structure type, can act on a plurality of targets and the like, can be used for preparing medicines for treating or preventing tumor diseases related to MAPK paths such as a B-Raf kinase, a Ras/Raf/MEK/ERK signal path, a p38MAPK signal path, a JNK-SAPK signal path and the like, such as lung cancer, liver cancer, melanoma, colon cancer, rectal cancer, breast cancer, ovarian cancer, cervical cancer and renal cancer, and has good application value and development and application prospect.
The preparation route of the compound of the invention comprises the following steps:
the compound T01-T15, pharmaceutically acceptable salts and prodrugs thereof have the functions of acting on Ras/Raf/MEK/ERK signal paths and inhibiting the phosphorylation of ERK1/2, thereby achieving the purpose of inhibiting the proliferation of tumor cells.
The invention has the beneficial effects that:
the invention provides a novel structure of an anti-tumor compound, which has potential patent drug value, simple and convenient preparation route of the compound, easy synthesis and low cost. Compared with the medicines on the market, the preparation has more remarkable anti-tumor cell proliferation activity.
Detailed Description
The invention will be described in detail with the following examples. However, it should be understood that the invention is not limited to the following examples specifically recited. Example 1: preparation of 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T01)
Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, p-fluoroaniline (8.89 g, 80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30 minutes, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30 minutes, p-fluoroaniline (8.89 g, 80 mmol) was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of methylene chloride was distilled off under reduced pressure, and after stirring with 5% HCl solution for 5-10min, a large amount of solids were produced, the solids were filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-di-p-fluorobenzourea as a white solid in a yield of 18.5g, 93.16%.
Step II: 1, 3-Di-p-fluorobenzourea (4.96 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 3.87g of 1, 3-bis (4-fluorophenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 61.18% yield.
Step III: 1, 3-bis (4-fluorophenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (5.12 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are reacted completely, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain yellow solid of 5.12g of 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione with the yield of 94.43 percent.
Step IV: 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.34 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in 3.16g yield 95.96%.
Step V: 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (1.65 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether were weighed into a 100mL three-necked round bottom flask, heated to 256 ℃ on a heating mantle, followed by reflux reaction for 40min, after TLC monitoring the reaction completion, the reaction solution was poured into 30mL petroleum ether to precipitate a large amount of solid, suction filtration, drying and purification by column chromatography to obtain pure 6-benzyl-5-hydroxy-1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione as a white solid with a yield of 2.00g and a yield of 82.07%.
Step VI: 6-benzyl-5-hydroxy-1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (3.39 g,6.95 mmol), triethylamine (1.06 g,10.44 mmol), 0.1g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was measured to dissolve p-toluenesulfonyl chloride (2.54 g,10.17 mmol) into the flask, the solution was slowly dropped into the flask, stirred at room temperature for 10min and heated to reflux for 5h, TLC monitored the reaction was complete. The solvent is removed by distillation under reduced pressure, a large amount of solid is stirred by adding ethyl acetate, pumping filtration and drying are carried out, thus obtaining the product 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl p-toluenesulfonate, the off-white solid is obtained, the yield is 4.22g, and the yield is 94.63%.
Step VII: weighing 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.91 g,1.41 mmol), N-aminopropyl morpholine (0.28 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of N-butanol were reacted in a 50mL round bottom flask, heated to 120℃and refluxed for 8h, and TLC monitored the reaction to completion. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T01), white solid, yield 0.33g, 38.13%; m.p.:112.4-116.2 ℃; MS 614.4[ M+H ]] + ； 1 HNMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.2Hz,1H),7.53(dd,J＝8.9,4.9Hz,2H),7.40–7.23(m,8H),7.15(dd,J＝7.4,4.1Hz,3H),4.01(s,2H),3.46(s,4H),3.26–3.30(m,2H),2.75(s,3H),2.18(s,6H),1.56(s,2H)。
Example 2: preparation of 6-benzyl-5- { [2- (dimethylamino) ethyl ] amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T02)
The compound 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 1.
Step VII: weighing 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] ]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.91 g,1.41 mmol), N-dimethylethylenediamine (0.17 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of N-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered, repeatedly washed by methanol and dried to obtain the 6-benzyl-5- { [2- (dimethylamino) ethyl]Amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T02), white solid, yield 0.31g, 39.43%; m.p.:85.7-95.3 ℃; MS 558.22992[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.11(t,J＝4.6Hz,1H),7.55–7.50(m,2H),7.41–7.36(m,4H),7.35–7.31(m,2H),7.27–7.23(m,2H),7.16–7.11(m,3H),4.05(s,2H),3.37–3.27(m,2H),2.75(s,3H),2.25(t,J＝6.1Hz,2H),1.95(s,6H)。
Example 3: preparation of 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- (methylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T03)
The compound 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 1.
Step VII: weighing 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.91 g,1.41 mmol), 40% aqueous methylamine (0.17 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- (methylamino) pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T03), as a white solid, 0.52g yield 73.68%; m.p.:257.9-262.0 ℃; MS 501.17163[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.03(q,J＝5.3Hz,1H),7.58–7.49(m,2H),7.41–7.24(m,8H),7.18–7.11(m,3H),4.07(s,2H),2.90(d,J＝5.3Hz,3H),2.75(s,3H)。
Example 4: preparation of 5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T04)
The compound 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 1.
Step V: weighing 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.65 g,5 mmol), diethyl malonate (0.96 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 1.39g yield, 69.97% yield; m.p.:246.3-253.6 ℃; MS 398.09290[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ12.00(s,1H),7.60–7.54(m,2H),7.43–7.34(m,6H),5.63(s,1H),2.73(s,3H)。
Step VI: 1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (2.66 g,6.69 mmol), triethylamine (1.06 g,10.44 mmol), 0.1g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (2.54 g,10.17 mmol) in the flask, the solution was slowly dropped into the flask, stirred at room temperature and heated to reflux for 5h, TLC monitored the reaction was complete. The solvent is distilled off under reduced pressure, a large amount of solid is stirred by adding ethyl acetate, suction filtration and drying are carried out, thus obtaining the product 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl p-toluenesulfonate, the yield is 3.49g, and the yield is 94.62%.
Step VII: weighing 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidin-5-yl-p-methylbenzenesulfonate (0.83 g,1.5 mmol), 3-chloro-4-trifluoromethylaniline (0.38 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were burned at a 50mL round bottomIn the flask, heat to 120℃and reflux for 8h, TLC monitored reaction complete. After the reaction solution is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered, repeatedly washed by methanol, and dried to obtain the 5- { [ 3-chloro-4- (trifluoromethyl) phenyl]Amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T04), white solid, yield 0.56g, 64.94% yield; m.p.:265.2-269.7 ℃; MS 575.08948[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),7.78–7.65(m,3H),7.61–7.53(m,2H),7.46–7.31(m,6H),5.65(s,1H),2.74(s,3H)。
Example 5: preparation of 1, 3-bis (4-fluorophenyl) -8-methyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T05)
The compound 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 4.
Step VII: weighing 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] ]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.83 g,1.5 mmol), 3-trifluoromethylaniline (0.31 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered, repeatedly washed by methanol, and dried to obtain the 1, 3-bis (4-fluorophenyl) -8-methyl-5- { [3- (trifluoromethyl) phenyl]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T05), white solid, yield 0.62g, 76.48%; m.p.:197.2-201.3 ℃; MS 541.12878[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.59(s,1H),7.70–7.53(m,6H),7.46–7.32(m,6H),5.60(s,1H),2.74(s,3H)。
Example 6: preparation of 1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T06)
The compound 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 4.
Step VII: weighing 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.83 g,1.5 mmol), 4-trifluoromethylaniline (0.31 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered, repeatedly washed by methanol, and dried to obtain the 1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethyl) phenyl ]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T06), a white solid, 0.65g yield 80.18%; m.p.:199.0-201.7 ℃; MS 541.12787[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.74(s,1H),7.77–7.73(m,2H),7.61–7.51(m,4H),7.45–7.32(m,6H),5.81(s,1H),2.74(s,3H)。
Example 7:5- [ (3-chloro-4-fluorophenyl) amino ] -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (T07):
the compound 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 4.
Step VII: weighing 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.83 g,1.5 mmol), 3-chloro-4-fluoroaniline (0.29 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 5- [ (3-chloro-4-fluorophenyl) amino]-1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T07), as a white solid, 0.56g, 71.13% yield; m.p.:250.3-254.2 ℃; MS 525.09283[ M+H ] ] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),7.60–7.52(m,3H),7.49–7.31(m,8H),5.47(s,1H),2.73(s,3H)。
Example 8:1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (T08):
the compound 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 4.
Step VII: weighing 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.83 g,1.5 mmol), 4-trifluoromethoxyaniline (0.35 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered, repeatedly washed by methanol, and dried to obtain the 1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethoxy) phenyl]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T08), white solid, yield 0.62g, 74.28%; m.p.:212.7-220.2 ℃; MS 557.12305[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.49(s,1H),7.60–7.52(m,2H),7.47–7.30(m,10H),5.56(s,1H),2.73(s,3H)。
Example 9: preparation of 1, 3-bis (4-fluorophenyl) -5- [ (furan-2-ylmethyl) amino ] -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T09)
The compound 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 4.
Step VII: weighing 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.83 g,1.5 mmol), 2-furanmethanamine (0.19 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 1, 3-bis (4-fluorophenyl) -5- [ (furan-2-ylmethyl) amino]-8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T09), as a white solid, 0.43g yield, 60.17%; m.p.:195.2-198.4 ℃;MS:477.13617[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝5.6Hz,1H),7.62–7.48(m,3H),7.41–7.26(m,6H),6.43–6.36(m,2H),5.40(s,1H),4.41(d,J＝5.5Hz,2H),2.68(s,3H)。
example 10: preparation of 1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T10)
The compound 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared by the method of example 4.
Step VII: weighing 1, 3-bis (4-fluorophenyl) -8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.83 g,1.5 mmol), N-aminopropyl morpholine (0.28 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of N-butanol were reacted in a 50mL round bottom flask, heated to 120℃and refluxed for 8h, and TLC monitored the reaction to completion. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T29), as a white solid, 0.41g yield 52.21%; m.p.:91.8-93.6 ℃; MS 524.2[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.69(t,J＝5.3Hz,1H),7.51(dd,J＝8.9,4.8Hz,2H),7.38(dd,J＝8.7,4.5Hz,4H),7.32(d,J＝9.2Hz,2H),5.25(s,1H),3.56(t,J＝4.6Hz,4H),3.18(q,J＝6.4Hz,2H),2.68(s,3H),2.35(s,6H),1.73(p,J＝6.8Hz,2H)。
Example 11: preparation of 6-benzyl-8-methyl-5- [ (3-morpholinopropyl) amino ] -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T11)
Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, aniline (7.45 g,80 mmol) was weighed into 40mL of methylene chloride, and it was dropped into the bottle with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and it was dropped into the bottle over 30min, aniline (7.4 g,80 mmol) was again weighed into 40mL of methylene chloride, and it was dropped into the bottle again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of the methylene chloride was distilled off under reduced pressure, and a large amount of solid was produced after stirring with 5% HCl solution for 5-10min, and the solid was filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-diphenylurea as a white solid in a yield of 16.17g and a yield of 93.25%.
Step II: 1, 3-diphenylurea (4.25 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 3.75g of 1, 3-diphenylpyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 66.90% yield.
Step III: 1, 3-Diphenyl pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (4.54 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain 4.58g of yellow solid 6-chloro-1, 3-diphenyl pyrimidine-2, 4 (1H, 3H) -diketone, wherein the yield is 94.64%.
Step IV: 6-chloro-1, 3-diphenylpyrimidine-2, 4 (1H, 3H) -dione (2.99 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux reaction was complete after 8 hours. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-methylamino-1, 3-diphenylpyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 2.76g, 94.09%.
Step V: 6-methylamino-1, 3-diphenyl pyrimidine-2, 4 (1H, 3H) -dione (1.47 g,5 mmol), diethyl benzylmalonate (1.50 g,6 mmol) and 15g diphenyl ether are weighed into a 100mL three-necked round bottom flask, heated to 256 ℃ on a heating jacket, reflux reacted for 40min, after TLC monitoring the reaction of the raw materials is complete, the reaction solution is poured into 30mL petroleum ether, a large amount of solid is separated out, suction filtration and column chromatography purification is carried out after drying to obtain pure 6-benzyl-5-hydroxy-1, 3-diphenyl-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione as a white solid with the yield of 1.39g and the yield of 61.57%.
Step VI: 6-benzyl-5-hydroxy-1, 3-diphenyl-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (2.42 g,5.36 mmol), triethylamine (1.06 g,10.44 mmol), 0.1g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (2.54 g,10.17 mmol) in the conical flask, the solution was slowly dropped into the flask, stirred at room temperature for 10min and heated to reflux for 5h, TLC monitored reaction was complete. The solvent is distilled off under reduced pressure, a large amount of solid is stirred by adding ethyl acetate, pumping filtration and drying are carried out, thus obtaining the product 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl p-toluenesulfonate, the yield is 3.07g, and the yield is 94.62%.
Step VII: weighing 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.91 g,1.5 mmol), N-aminopropyl morpholine (0.28 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of N-butanol were reacted in a 50mL round bottom flask, heated to 120℃and refluxed for 8h, and TLC monitored the reaction to completion. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 6-benzyl-8-methyl-5- [ (3-morpholinopropyl) amino]-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T11), as a white solid, 0.4g in 46.16% yield; m.p.:180.6-185.1 ℃; MS 578.27502[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.06(t,J＝5.2Hz,1H),7.57–7.37(m,8H),7.36–7.23(m,4H),7.20–7.10(m,3H),4.01(s,2H),3.44(t,J＝4.5Hz,4H),3.35–3.26(m,3H),2.71(s,3H),2.18(t,J＝4.5Hz,4H),2.13(t,J＝6.8Hz,2H),1.54(p,J＝6.9Hz,2H)。
Example 12: preparation of 6-benzyl-5- (cyclopropylamino) -8-methyl-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T12)
The compound 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared using the procedure of example 11.
Step VII: weighing 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-toluenesulfonate (0.91 g,1.5 mmol), cyclopropylamine (0.12 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 6-benzyl-5- (cyclopropylamino) -8-methyl-1, 3-diphenyl pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T12), white solid, yield 0.29g, 39.41%; m.p.:152.7-159.4 ℃; MS 491.20706[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.32(d,J＝3.5Hz,1H),7.57–7.37(m,8H),7.35–7.23(m,4H),7.20–7.10(m,3H),4.33(s,2H),2.71(s,3H),2.66–2.58(m,1H),0.63(d,J＝6.7Hz,2H),0.56–0.46(m,2H)。
Example 13: preparation of 6-benzyl-8-methyl-5-morpholinyl-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T13)
The compound 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared using the procedure of example 11.
Step VII: weighing 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.91 g,1.5 mmol), morpholine (0.17 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of n-butanol were reacted in a 50mL round bottom flask, heated to 120℃and refluxed for 8h, and TLC monitored the reaction to completion. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 6-benzyl-8-methyl-5-morpholinyl-1, 3-diphenyl pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T13), white solid, yield 0.29g,yield 37.14%; m.p.:85.3-89.7 ℃; MS 521.21753[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ7.48(d,J＝8.1Hz,2H),7.42–7.22(m,8H),7.18(dd,J＝12.5,6.9Hz,4H),7.09–6.98(m,1H),4.06(d,J＝15.5Hz,1H),3.95(d,J＝15.5Hz,1H),3.30(s,3H),3.08–2.87(m,4H)。
Example 14: preparation of 6-benzyl-5- { [2- (dimethylamino) ethyl ] amino } -8-methyl-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T14)
The compound 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-methylbenzenesulfonate was prepared using the procedure of example 11.
Step VII: weighing 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.91 g,1.5 mmol), N-dimethylethylenediamine (0.17 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of N-butanol were reacted in a 50mL round bottom flask, heated to 120deg.C and refluxed for 8h, and TLC monitored the reaction was complete. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered, repeatedly washed by methanol and dried to obtain the 6-benzyl-5- { [2- (dimethylamino) ethyl]Amino } -8-methyl-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T14), white solid, yield 0.34g, 43.45%; m.p.:181.4-186.4 ℃; MS 522.24884[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.16(t,J＝4.7Hz,1H),7.56–7.41(m,8H),7.36–7.26(m,4H),7.19–7.12(m,3H),4.07(s,2H),3.38–3.33(m,2H),2.73(s,3H),2.28(t,J＝6.2Hz,2H),1.97(s,6H)。
Example 15: preparation of 6, 8-dimethyl-5- [ (3-morpholinopropyl) amino ] -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T15)
The compound 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 11.
Step V: 6-methylamino-1, 3-diphenyl pyrimidine-2, 4 (1H, 3H) -dione (1.47 g,5 mmol), diethyl methylmalonate (1.04 g,6 mmol) and 15g diphenyl ether are weighed into a 100mL three-necked round bottom flask, heated to 256 ℃ on a heating jacket, reflux reacted for 40min, after TLC monitoring the reaction of the raw materials is complete, the reaction solution is poured into 30mL petroleum ether, a large amount of solid is separated out, suction filtration and column chromatography purification are carried out after drying to obtain pure 6-methyl-5-hydroxy-1, 3-diphenyl-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione as a white solid with the yield of 1.05g and the yield of 55.94%.
Step VI: 6-methyl-5-hydroxy-1, 3-diphenyl-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (2.51 g,6.66 mmol), triethylamine (1.06 g,10.44 mmol), 0.1g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (2.54 g,10.17 mmol) in the conical flask, the solution was slowly dropped into the flask, stirred at room temperature for 10min and heated to reflux for 5h, TLC monitored reaction was complete. The solvent was distilled off under reduced pressure, ethyl acetate was added and a large amount of solid was stirred, suction filtration and drying were carried out to obtain the product 6-benzyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate as an off-white solid in a yield of 3.34g and a yield of 94.62%.
Step VII: weighing 6-methyl-1, 3-diphenyl-8-methyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl-p-methylbenzenesulfonate (0.79 g,1.5 mmol), N-aminopropyl morpholine (0.28 g,1.95 mmol), triethylamine (0.23 g,2.25 mmol) and 15mL of N-butanol were reacted in a 50mL round bottom flask, heated to 120℃and refluxed for 8h, and TLC monitored the reaction to completion. After the reaction liquid is cooled to room temperature, a large amount of crystals are separated out, the crystals are filtered out, repeatedly washed by methanol, and dried to obtain the 6, 8-dimethyl-5- [ (3-morpholinopropyl) amino ]-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (T15), white solid, yield 0.29g, 38.54%; m.p.:82.4-84.3 ℃; MS 502.2[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.62–8.64(m 1H),7.51–7.41(m,8H),7.34–7.28(m,2H),3.52(t,J＝4.6Hz,4H),3.43(q,J＝6.5Hz,2H),2.68(s,3H),2.36–2.24(m,6H),2.06(s,3H),1.65(p,J＝7.0Hz,2H)。
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Pharmacological examples
Example 16: inhibitory Activity of test Compounds on MCF7, A375, SK-Mel-2 cell proliferation
(1) Experimental materials
Cell line: MCF7, A375, SK-Mel-2 cells were plated in 96-well plates at densities of 4000, 5000, 4000 per well, 200ul per well, 24h later.
Numbering T01-T15 target compounds: dissolving in DMSO, diluting with culture solution to obtain six different concentrations of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM, and storing at-20deg.C until the final concentration of DMSO in culture solution is lower than 0.1%.
Positive control drug: 5-Fluorouracil (5-Fu, fluoraracil).
MTT: the solution was dissolved at 2mg/mL in PBS and stored at-20 ℃.
(2) Experimental method
MCF7, A375 and SK-Mel-2 cells are selected to evaluate the antitumor proliferation activity of the samples for test by MTT method. MCF7, A375, SK-Mel-2 cell lines were cultured on DMEM medium containing 10% calf serum (FBS). Cells were pooled when they had proliferated to 80-90% and then subcultured for no more than 20 passages, and then allowed to acclimate for 24 hours before the next treatment. These cells were plated onto 96-well plates and then plated onto plates containing 5% CO 2 Culturing in incubator at 37 deg.c until the cell adhesion is complete. After 24 hours, various concentrations of the inventive representative compound were added. After further culture for 24 hours, MTT (2 mg/mL) was added thereto and the culture was continued for 4 hours. The culture medium was removed, the crystals were dissolved in DMSO and absorbance was measured at 570nm wavelength using a microplate reader (Thermo Multiskan GO, thermo Fisher, usa). According to the formula: cell growth inhibition = (1-drug group)OD value/control OD value) ×100%, calculating cell growth inhibition rate at corresponding concentration, calculating IC corresponding to the tested compound according to different concentrations of the tested compound and inhibition rate versus cell curve 50 Values. Representative compounds of the present invention were determined as described above.
Of the 15 compounds obtained above, most showed moderate tumor cell proliferation inhibition activity against MCF-7, A375 and SK-MEL-2 cell lines, wherein T06 showed strong proliferation inhibition activity against MCF7, A375 and SK-MEL-2, IC 50 As low as 24.02.+ -. 0.45. Mu.M, 25.81.+ -. 0.69. Mu.M and 29.28.+ -. 0.53. Mu.M.
Formulation examples
The following formulation examples merely illustrate the scope of the invention, but are not to be construed as limiting in any way. The active compounds described in the examples below refer to the compounds T01 to T15 prepared in the examples described above.
Example 17: tablet formulation
25-1000mg of active compound, 45mg of starch, 35mg of microcrystalline cellulose, 4mL of polyvinylpyrrolidone (10% aqueous solution), 4.5mg of sodium carboxymethylcellulose, 0.5mg of magnesium stearate and 1mg of talcum.
Example 18: suspending agent formula
Active compound 0.1-1000mg, sodium carboxymethylcellulose 50mg, syrup 1.25mg, sodium benzoate 0.1mg, flavoring agent 25mg, colorant 5mg, and pure water to 5mL.
Example 19: aerosol formulation
0.25mg of active compound, 25-75mL of ethanol, and 70mg of propellant 22 (chlorodifluoromethane).
Example 20: suppository formula
250mg of active compound and 2000mL of saturated fatty acid glyceride.
Example 21: injectable formulation
50mg of active compound, 1000mL of isotonic saline solution.
Example 22: ointment formula
Micronizing active compound 0.025g, liquid paraffin 10g, and softening white wax to 100g.
Example 23: ointment formula
0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin and adding white wax to 100g.
Example 24: oil-in-water cream formulation
Active compound 0.025g, hexadecanol 5g, glyceryl monostearate 5g, liquid paraffin 10g, cetyl polyoxyethylene ether 2g, citric acid 0.1g, sodium citrate 0.2g, propylene glycol 35g, and water to 100g.
Example 25: oil-in-water cream formulation
Micronizing active compound 0.025g, soft white wax 15g, liquid paraffin 5g, hexadecanol 5g,Sorbimacrogol stearate (Tween 65 of specific pharmaceutical adjuvant grade) 2g, sorbitan monostearate 0.5g, sorbic acid 0.2g, citric acid 0.1g, sodium citrate 0.2g, and water to 100g.
Example 26: water-in-oil cream formulation
Active compound 0.025g, white soft wax 35g, liquid paraffin 5g, sorbitan sesquioleate 5g, sorbic acid 0.2g, citric acid 0.1g, sodium citrate 0.2g, and water to 100g.
Example 27: lotion formulation
Active compound 0.25g, isopropanol 0.5mL, carboxyvinyl polymer 3mg, naOH 2mg, add water to 1g.
Example 28: suspension formulations for injection
10mg of active compound, 7mg of sodium carboxymethyl cellulose, 7mg of NaCl, 0.5mg of polyoxyethylene (20) sorbitan monooleate, 8mg of benzyl alcohol and 1mL of sterile water.
Example 29: 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 30: atomized solution formulation
7mg of active compound, 5mg of propylene glycol and 10g of water are added.
Example 31: powder formulations for inhalation
The gelatin capsule is filled with a mixture of 0.1mg of micronised active compound, 20mg of lactose and the powder is inhaled by means of an inhalation device.
Example 32: powder formulations for inhalation
The spheroidized powder is loaded into a multi-dose powder inhaler, each dose containing 0.1mg of micronized active compound.
Example 33: powder formulations for inhalation
The spheroidized powder was charged to a multi-dose powder inhaler, each dose containing 0.1mg of micronized active compound and 1mg of micronized lactose.
Example 34: capsule formulation
1.0mg of active compound, 321mg,Aquacoat ECD 30 6.6mg mg of small sugar ball, 0.5mg of acetyl tributyl citrate, 1.8mg of tween-80 0.1mg,Eudragit L100-55.5 mg of triethyl citrate, 8.8mg of talcum powder and 0.lmg of defoamer MMS.
Example 35: capsule seedling formula
2.0mg of active compound, 305mg,Aquocoat ECD 30 5.0mg mg of small sugar ball, 0.4mg of acetyl tributyl citrate, 80 0.14mg,Eudragit NE30D 12.6mg,Eudragit S100 12.6mg of tween and 0.6 mg of talcum powder.
Example 36: enema formula
2mg of active compound, 25mg of sodium carboxymethyl cellulose, 0.5mg of disodium ethylenediamine tetraacetate, 0.8mg of methylparaben, 0.2mg of propylparaben, 7mg of sodium chloride, 1.8mg of citric acid, 0.01mg of tween-80 and 1mL of pure water are added.
Example 37: liposome-containing formulations
A. Preparation of instillation formulations
Dipalmitoyl lecithin (45 mg), dimyristoyl lecithin (7 mg), dipalmitoyl phosphatidylglycerol (1 mg) and active compound (5 mg) were placed in a glass tube, and all components were dissolvedIn chloroform, with N 2 The lipid was added with an aqueous solution (0.9% NaCl) and liposomes were formed at a temperature above the inversion temperature of the lipid, and the resulting suspension contained liposomes ranging in size from very small vesicles to 2. Mu.m.
B. Preparation of formulations for inhalation
Liposomes were prepared as in example A, wherein the aqueous solution contained 10% lactose at a lactose to lipid ratio of 7:3. The liposome suspension was frozen with dry ice and freeze-dried, and the dried product was micronised, the mass average aerodynamic diameter (MMAD) of the resulting particles being about 2 μm.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the invention in any way, and any person skilled in the art may make modifications or alterations to the disclosed technical content to the equivalent embodiments. Any simple modification, equivalent variation and variation of the above embodiments according to the technical substance of the present invention still belongs to the protection scope of the technical solution of the present invention.

Claims (5)

  1. A 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following compounds:
    6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    6-benzyl-5- { [2- (dimethylamino) ethyl]Amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    6-benzyl-1, 3-bis (4-fluorophenyl) -8-methyl-5- (methylamino) pyrido [2,3-d]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    5- { [ 3-chloro-4- (trifluoromethyl) phenyl group]Amino } -1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    1, 3-bis (4-fluorophenyl) -8-methyl-5- { [3- (trifluoromethyl) phenyl group]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethyl) phenyl group]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    5- [ (3-chloro-4-fluorophenyl) amino group]-1, 3-bis (4-fluorophenyl) -8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    1, 3-bis (4-fluorophenyl) -8-methyl-5- { [4- (trifluoromethoxy) phenyl group]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    1, 3-bis (4-fluorophenyl) -5- [ (furan-2-ylmethyl) amino group]-8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    1, 3-bis (4-fluorophenyl) -8-methyl-5- [ (3-morpholinopropyl) amino group]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    6-benzyl-8-methyl-5- [ (3-morpholinopropyl) amino group]-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    6-benzyl-5- (cyclopropylamino) -8-methyl-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    6-benzyl-8-methyl-5-morpholinyl-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    6-benzyl-5- { [2- (dimethylamino) ethyl]Amino } -8-methyl-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione;
    6, 8-dimethyl-5- [ (3-morpholinopropyl) amino group]-1, 3-diphenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1)H,3H,8H) -a trione.
  2. 2. A pharmaceutical composition comprising as an active ingredient a compound of any one of the 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidines according to claim 1 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.
  3. 3. Use of a 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting MCF-7, a375, SK-MEL-2 tumor cell growth.
  4. 4. Use of a pharmaceutical composition according to claim 2 for the preparation of a medicament for inhibiting MCF-7, a375, SK-MEL-2 tumor cell growth.
  5. 5. The use of a 5-substituted amino-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of cancer, said cancer being melanoma, breast cancer.
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WO2006124874A2 (en) * 2005-05-12 2006-11-23 Kalypsys, Inc. Inhibitors of b-raf kinase
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