CN114456166B - 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine compound and preparation and application thereof - Google Patents

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

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CN114456166B
CN114456166B CN202210330914.9A CN202210330914A CN114456166B CN 114456166 B CN114456166 B CN 114456166B CN 202210330914 A CN202210330914 A CN 202210330914A CN 114456166 B CN114456166 B CN 114456166B
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pyrimidine
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CN114456166A (en
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胡春
谢倩
孟艳丽
李乐瑢
吴阳灿
文杰
杨小力
王宇航
刘晓平
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Shenyang Pharmaceutical University
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    • 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
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Abstract

The 5-substituted amino-3-methylpyrido [2,3-d ] of the present invention]Pyrimidine compounds, and preparation and application thereof, and belongs to the technical field of medicines. The compound is specifically 5-substituted amino-3-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione compounds have the structural general formula shown in formula (I): r is R 1 Hydrogen, methyl or ethyl; r is R 2 Is hydrogen, methyl, benzyl, 2-methylbenzyl; r is R 3 Is isopropyl, cyclopropyl, dimethylaminoethyl, 3-morpholinopropyl, 3-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-trifluoromethylphenyl, pyridin-2-yl, 4-methylpyridin-2-yl, 2- (methoxycarbonyl) phenyl, 3-carboxyphenyl, 2-oxo-2- (p-toluylamino) ethyl, 2-oxo-2- (o-toluylamino) ethyl or 3- [ (3-morpholinopropyl) carbamoyl]Phenyl. The synthesis method of the compound is simple and convenient, is suitable for industrial production, and the biological activity test shows that the compound has anti-tumor activity and can be applied to anti-tumor drugs.

Description

5-substituted amino-3-methylpyrido [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-3-methylpyrido [2,3-d ] pyrimidine compound, and preparation and application thereof.
Background
MAPK (mitogen-activated protein kinase, MAPK) is a serine/threonine kinase family that plays a central role in various reactions that transduce extracellular signals into cells. The MAPK family is divided into two major classes: exemplary MAPK and atypical MAPK. Exemplary MAPKs include extracellular signal-regulated kinase 1/2 (ERK 1/2), c-Jun amino (N) -terminal kinase 1/2/3 (JNK 1/2/3), p38 subtype, and ERK5. Atypical MAPKs include ERK3/4, ERK7/8 and Nemo-like kinase (NLK). All eukaryotic organisms have multiple MAPK pathways, a tertiary kinase model, including MAPK kinase (MKKK), MAPK kinase (MKK) and MAPK, which synergistically regulate gene expression, mitosis, metabolic growth, motility, survival, apoptosis and differentiation (Coulombe P, rodier G, et al mol Cell Biol,2003, 23:4542-4558).
The MAPK family has been reported to be involved in the proliferative growth of cancer cells in different states. Such as: the MAPK pathway has been shown to play a key role in angiogenesis and metastasis; the MAPK pathway is inversely related to ROS regulated vascular inflammation; increased p38 and ERK1/2 activity may be associated with endothelial apoptosis; inhibition of p38 or ERK1/2 has been shown to prevent TNF- α -induced increases in human pulmonary microvascular endothelial cell permeability. (Perander M, aberg E, et al biochem J,2008, 411:613-622)
The MAPK pathway inhibitor small molecule drugs that have been marketed at present mainly include:
trametinib (Trametinib) is an oral small molecule ATP non-competitive selective MEK1 and MEK2 inhibitor. In preclinical studies, phosphorylated extracellular signal-regulated kinase (Perk) -1/2 was effectively inhibited. The same is true for V600E and V600K mutant patients, and was approved by the FDA for treatment of BRAF mutant metastatic melanoma in month 5 of 2013 (Grimuldi.AM.Simerone E.Asclerto P A.Current Opinion in oncology.2014,26 (2): 196-203.).
Selumetinib (Selumetinib) is a mitogen-activated protein kinase 1 and 2 (MEK 1/2) inhibitor developed by Adilikang for the treatment of tumors associated with neurofibromatosis and various cancers. Approved for use in symptomatic, inoperable pediatric patients with type i neurofibromatosis older than 2 years. MEK1/2 is an upstream regulator of the extracellular signal-related kinase (ERK) pathway, both MEK and ERK being components of the RAF-MEK-ERK pathway regulated by RAS, which is activated in many cancers (Markham A, keam SJ. Drugs.2020,80 (8): 931-937.).
Disclosure of Invention
The invention aims to provide a 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine compound, and preparation and application thereof, in particular to an application of a 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione compound in preparing medicines for treating or/and preventing tumor diseases related to B-Raf kinase, ras/Raf/MEK/ERK signal channels, p38MAPK signal channels, JNK-SAPK signal channels and other MAPK channels, and the application of the 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione compound in anti-tumor aspect as a multi-target inhibitor.
5-substituted amino-3-methylpyrido [2,3-d ] pyrimidines, prodrugs and pharmaceutically active metabolites thereof and pharmaceutically acceptable salts thereof, as shown in formula I;
Figure BDA0003572213870000021
R 1 is hydrogen, C1-C4 alkyl;
R 2 is hydrogen, C1-C4 alkyl, benzyl, C1-C4 alkyl substituted benzyl;
R 3 is C1-C6 alkyl, C1-C4 alkyl-substituted phenyl, halogen-substituted C1-C4 alkyl-substituted phenyl, carboxy-substituted phenyl, amino-substituted C1-C4 alkyl-substituted phenyl, pyridyl, C1-C4 alkyl-substituted pyridyl, amino-substituted C1-C6 alkyl, C1-C4 alkoxy-substituted C1-C4 alkyl, amino-substituted C1-C4 acyl;
R 1 、R 2 and R is 3 May be one or more.
Further, the compounds of formula I, prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, as described herein:
R 1 hydrogen, methyl or ethyl;
R 2 is hydrogen, methyl, benzyl or 2-methylbenzyl;
R 3 is isopropyl, cyclopropyl, dimethylaminoethyl, 3-morpholinopropyl, 3-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-trifluoromethylphenyl, pyridin-2-yl, 4-methylpyridin-2-yl, 2- (methoxycarbonyl) phenyl, 3-carboxyphenyl, 2-oxo-2- (p-toluylamino) ethyl, 2-oxo-2- (o-toluylamino) ethyl or 3- [ (3-morpholinopropyl) carbamoyl ]Phenyl.
Further, the present invention is preferably the following compounds:
6-benzyl-5- (isopropylamino) -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 01), having the structural formula I-1:
Figure BDA0003572213870000031
6-benzyl-5- (cyclopropylamino) -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 02), having the structural formula I-2:
Figure BDA0003572213870000032
6-benzyl-5- { [2- (dimethylamino) ethyl ] amino } -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 03), having the structural formula I-3:
Figure BDA0003572213870000033
6-benzyl-1, 3, 8-trimethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 04), having the structural formula I-4:
Figure BDA0003572213870000034
5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 05), having the structural formula I-5:
Figure BDA0003572213870000035
1,3, 8-trimethyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 06) having the formula I-6:
Figure BDA0003572213870000041
5- [ (3-chloro-4-fluorophenyl) amino ] -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 07) having the structural formula I-7:
Figure BDA0003572213870000042
1,3, 8-trimethyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 08), having the formula I-8:
Figure BDA0003572213870000043
1,3, 8-trimethyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 09), having the structural formula I-9:
Figure BDA0003572213870000044
1,3, 8-trimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQM 10) having the structural formula I-10:
Figure BDA0003572213870000045
1,3, 8-trimethyl-5- [ (4-methylpyridin-2-yl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQM 11), having the structural formula I-11:
Figure BDA0003572213870000051
methyl 2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoate (XQM) having the structural formula I-12:
Figure BDA0003572213870000052
n- (p-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] acetamide (XQM 13) having the structural formula I-13:
Figure BDA0003572213870000053
n- (o-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] acetamide (XQM 14) having the structural formula I-14:
Figure BDA0003572213870000054
1,3,6, 8-tetramethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM) having the structural formula I-15:
Figure BDA0003572213870000061
3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoic acid (XQM) having the structural formula I-16:
Figure BDA0003572213870000062
n- (3-morpholinopropyl) -3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzamide (XQM 17) having the structural formula I-17:
Figure BDA0003572213870000063
5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1-ethyl-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM), having the structural formula I-18:
Figure BDA0003572213870000064
1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 19), having the formula I-19:
Figure BDA0003572213870000071
5- [ (3-chloro-4-fluorophenyl) amino ] -1-ethyl-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM) having the structural formula I-20:
Figure BDA0003572213870000072
1-ethyl-3, 8-dimethyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 21), having the formula I-21:
Figure BDA0003572213870000073
1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM) having the formula I-22:
Figure BDA0003572213870000074
1-ethyl-3, 8-dimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQM) having the structural formula I-23:
Figure BDA0003572213870000075
methyl 2- [ (1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoate (XQM) having the structural formula I-24:
Figure BDA0003572213870000081
1-ethyl-3, 8-dimethyl-5- [ (4-methylpyridin-2-yl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQM 25), having the structural formula I-25:
Figure BDA0003572213870000082
6-benzyl-1-ethyl-3, 8-dimethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM) having the structural formula I-26:
Figure BDA0003572213870000083
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 salt" refers 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, wherein: 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 forming acid addition salts include hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, p-aminobenzenesulfonic 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/and preventing cancer 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:
Figure BDA0003572213870000101
the compound XQM-XQM, 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 tumor cell proliferation.
The invention has the beneficial effects that:
the invention provides a novel structure of an anti-tumor compound, which has potential patent drug value, and the corresponding compound has simple preparation route, 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-5- (isopropylamino) -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 01)
Step I: 6-chloro-3-methyluracil (4.80 g,30 mmol), potassium carbonate (4.98 g,36 mmol), TBAB (0.2 g,0.6 mmol), 3mL of water and 50mL of acetone were weighed into a 250mL round bottom flask, stirred at room temperature until the solids dissolved before separating out the solids, and then a solution of dimethyl sulfate (4.16 g,33 mmol) dissolved in 10mL of acetone was slowly dropped into the flask, stirred slightly and refluxed for 2 hours. After the TLC monitoring reaction is completed, filtering out solid, decompressing and distilling mother liquor to obtain white solid, pulping by diethyl ether, filtering out solid again to obtain the product 6-chloro-1, 3-dimethyluracil, white solid, yield 5.10g and yield 91.70%.
Step II: 6-chloro-1, 3-dimethyluracil (2.61 g,15.00 mmol), aqueous methylamine (40%) solution (1.51 g,19.50 mmol), TEA (3.04 g,30.00 mmol) and 15mL ethanol were weighed into a 100mL round bottom flask and reacted overnight under stirring and refluxing. TLC monitored the reaction to completion, after distilling off ethanol under reduced pressure, 10mL of diethyl ether was added to slurry, the solid was filtered off, and dried to give 1, 3-dimethyl-6- (methylamino) pyrimidine-2, 4 (1H, 3H) -dione as a pale yellow solid in a yield of 2.33g, 91.67%.
Step III: 1, 3-dimethyl-6- (methylamino) pyrimidine-2, 4 (1H, 3H) -dione (1.69 g,10 mmol), diethyl benzylmalonate (3.25 g,13 mmol) and 10.00g diphenyl ether were weighed into a 50mL three-necked round bottom flask, heated to 256 ℃ on a heating mantle, refluxed for 40min, after TLC monitoring the reaction completion of the starting material, the reaction solution was poured into 20mL petroleum ether to precipitate a solid, suction filtration, dried and purified by column chromatography to obtain pure 6-benzyl-5-hydroxy-1, 3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione as a white solid in a yield of 1.05g, yield 44.29%.
Step IV: 6-benzyl-5-hydroxy-1, 3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (5.79 g,17.71 mmol), triethylamine (2.51 g,24.8 mmol), 0.11g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (4.04 g,21.26 mmol) into the flask, the solution was slowly dropped into the flask, stirred at room temperature for 10min and then heated to reflux for 5h, TLC monitoring 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, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl p-toluenesulfonate, the yield is 4.42g and 94.62%.
Step V: weighing 6-benzyl-1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.81 g,10 mmol), isopropylamine (0.65 g,11 mmol), 15mL n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, and column chromatographyPurifying to obtain pure 6-benzyl-5- (isopropylamino) -1,3, 8-trimethyl pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, in 0.81g yield, 35.43%; m.p, 171.4-176.0 ℃; MS 369.19052[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.13(d,J＝9.0Hz,1H),7.20–7.28(m,2H),7.17–7.08(m,3H),3.92(s,2H),3.77–3.66(m,1H),3.41(s,6H),3.20(s,3H),1.01(d,J＝6.2Hz,6H)。
Example 2: preparation of 6-benzyl-5- (cyclopropylamino) -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 02)
The compound 6-benzyl-1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 1;
step V: weighing 6-benzyl-1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.81 g,10 mmol), cyclopropylmethylamine (0.63 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-5- (cyclopropylamino) -1,3, 8-trimethylpyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, 0.79g yield 35.22%; m.p, 177.2-178.0 ℃; MS 367.17505[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.42(d,J＝3.4Hz,1H),7.18–7.27(m,2H),7.07–7.16(m,3H),4.30(s,2H),3.41(s,6H),3.18(s,3H),2.60–2.63(m,1H),0.69–0.60(m,2H),0.45–0.55(m,2H)。
Example 3: preparation of 6-benzyl-5- { [2- (dimethylamino) ethyl ] amino } -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 03)
The compound 6-benzyl-1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 1;
step V: weighing 6-benzyl-1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidin-5-yl-p-toluenesulfonate (4.81 g,10 mmol), N1, N1-dimethylethane-1, 2-diamine (0.97 g,11 mmol), 15mL N-butanol at 50In a mL round bottom flask, heat reflux for 8h, solid formation, TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-5- { [2- (dimethylamino) ethyl]Amino } -1,3, 8-trimethylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, 0.91g yield 37.09%; m.p, 140.8-142.1 ℃; MS 398.31[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.24(t,J＝4.6Hz,1H),7.19–7.28(m,2H),7.07–7.17(m,3H),4.01(s,2H),3.41(s,6H),3.25–3.34(m,2H),3.19(s,3H),2.27(t,J＝6.1Hz,2H),2.01(s,6H)。
Example 4: preparation of 6-benzyl-1, 3, 8-trimethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 04)
The compound 6-benzyl-1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 1;
step V: weighing 6-benzyl-1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.81 g,10 mmol), N-aminopropyl morpholine (1.58 g,11 mmol), 15mL N-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-1, 3, 8-trimethyl-5- [ (3-morpholinopropyl) amino]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, 1.03g in yield 39.21%; m.p, 168.3-174.4 ℃; MS 454.24268[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.17(t,J＝5.2Hz,1H),7.19–7.28(m,2H),7.07–7.17(m,3H),3.98(s,2H),3.47(t,J＝4.5Hz,4H),3.41(s,6H),3.27(q,J＝6.4Hz,2H),3.20(s,3H),2.21(t,J＝4.5Hz,4H),2.17(t,J＝6.9Hz,2H),1.56(p,J＝6.8Hz,2H)。
Example 5:
preparation of 5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 05)
The compound 1, 3-dimethyl-6- (methylamino) pyrimidine-2, 4 (1 h,3 h) -dione was prepared by the method of example 1;
step III: 1, 3-dimethyl-6- (methylamino) pyrimidine-2, 4 (1H, 3H) -dione (3.38 g,20 mmol), diethyl malonate (4.16 g,26 mmol) and 20.00g diphenyl ether were weighed into a 50mL three-necked round bottom flask, heated to 256 ℃ on a heating mantle and then refluxed for 40min, after TLC monitoring the reaction of the starting materials was complete, the reaction solution was poured into 20mL petroleum ether to precipitate a large amount of solid, and after suction filtration and drying, 5-hydroxy-1, 3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione was obtained as a white solid with a yield of 3.89g and a yield of 88.29%.
Step IV: 5-hydroxy-1, 3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (4.20 g,17.71 mmol), triethylamine (2.51 g,24.8 mmol), 0.11g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (4.04 g,21.26 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. Removing the solvent by distillation under reduced pressure, adding ethyl acetate, stirring to obtain a large amount of solid, suction filtering, and drying to obtain the product 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl p-toluenesulfonate, and obtaining the yellow-white solid with the yield of 4.28g and the yield of 95.82%
Step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (3.91 g,10 mmol), 3-chloro-4-trifluoromethylaniline (2.15 g,11 mmol), 15mL n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction was complete. Suction filtering, drying and purifying by column chromatography to obtain pure 5- { [ 3-chloro-4- (trifluoromethyl) phenyl]Amino } -1,3, 8-trimethylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, 1.11g in yield, 35.81%; m.p, 266.5-268.8 ℃; MS:.415.07635[ M+H ] ] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.70(s,1H),7.73(d,J＝10.4Hz,2H),7.65(d,J＝8.8Hz,1H),5.54(s,1H),3.45(s,3H),3.42(s,3H),3.24(s,3H)。
Example 6: preparation of 1,3, 8-trimethyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 06)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 4-trifluoromethylaniline (1.77 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 1,3, 8-trimethyl-5- { [4- (trifluoromethyl) phenyl]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, in a yield of 0.87g, 31.35%; m.p, 206.2-213.2 ℃; MS 381.11520[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),7.76(d,J＝8.4Hz,2H),7.51(d,J＝8.3Hz,2H),5.72(s,1H),3.45(s,3H),3.42(s,3H),3.24(s,3H)。
Example 7: preparation of 5- [ (3-chloro-4-fluorophenyl) amino ] -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 07)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] ]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 3-chloro-4-fluoroaniline (1.60 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction was complete. Suction filtering, drying, and purifying by column chromatography to obtain pure 5- [ (3-chloro-4-fluorophenyl) amino]-1,3, 8-trimethylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, in 0.92g yield, 36.31%; m.p, 194.5-197.9 ℃; MS 365.07977[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),7.55–7.41(m,2H),7.27–7.34(m,1H),5.36(s,1H),3.45(s,3H),3.40(s,3H),3.23(s,3H)。
Example 8: preparation of 1,3, 8-trimethyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 08)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 3-trifluoromethylaniline (1.77 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 1,3, 8-trimethyl-5- { [3- (trifluoromethyl) phenyl]Amino } pyrido [2,3-d ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, 1.11g in yield 39.45%; m.p, 213.6-216.4 ℃; MS 381.11514[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),7.70–7.54(m,4H),5.50(s,1H),3.45(s,3H),3.41(s,3H),3.24(s,3H)。
Example 9: preparation of 1,3, 8-trimethyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 09)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 4-trifluoromethoxyaniline (1.95 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 1,3, 8-trimethyl-5- { [4- (trifluoromethoxy) phenyl]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1 h,3h,8 h) -trione, as a white solid, 0.87 yield, 30.91%; m.p, 210.9-213.2 ℃; MS 397.10986[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.62(s,1H),7.38–7.45(m,4H),5.46(s,1H),3.45(s,3H),3.41(s,3H),3.23(s,3H)。
Example 10: preparation of 1,3, 8-trimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 10)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
Step (a)V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 2-aminopyridine (1.03 g,11 mmol), 15mL n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 1,3, 8-trimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, in 0.81g yield, 32.11%; m.p, 252.6-256.2 ℃; MS 314.12317[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.67(s,1H),8.35(d,J＝4.9Hz,1H),7.73–7.75(m,1H),7.44(s,1H),7.03(d,J＝8.0Hz,2H),3.45(s,3H),3.42(s,3H),3.23(s,3H)。
Example 11: preparation of 1,3, 8-trimethyl-5- [ (4-methylpyridin-2-yl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 11)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 4-methyl-2-aminopyridine (1.19 g,11 mmol), 15mL n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 1,3, 8-trimethyl-5- [ (4-methylpyridin-2-yl) amino ]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, 1.12g yield 38.12%; m.p, 248.6-250.2 ℃; MS 328.13882[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.61(s,1H),8.19(d,J＝5.1Hz,1H),7.43(s,1H),6.90–6.83(m,2H),3.45(s,3H),3.42(s,3H),3.22(s,3H),2.30(s,3H)。
Example 12: preparation of methyl 2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoate (XQM)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), methyl 2-aminobenzoate (1.67 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidin-5-yl) amino groups]Methyl benzoate, white solid, yield 0.79g, 31.15%; m.p, 237.1-240.2 ℃; MS 371.13315[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.39(s,1H),7.94(d,J＝7.7Hz,1H),7.63(s,2H),7.26(s,1H),5.75(s,1H),3.84(s,3H),3.43(s,3H),3.40(s,3H),3.24(s,3H)。
Example 13: preparation of N- (p-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] acetamide (XQM 13)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 2-amino-N- (p-tolyl) acetamide (1.80 g,11 mmol), 15mL of N-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored the reaction was complete. Suction filtering, drying, purifying by column chromatography to obtain pure product, white solid N- (p-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2, 3-d)]Pyrimidin-5-yl) amino groups]Acetamide, 1.12g, 36.51%; m.p, 271.7-275.4 ℃; MS 384.16632[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.10(s,1H),9.61(t,J＝5.3Hz,1H),7.47(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),6.38(s,1H),4.19(d,J＝5.3Hz,2H),3.43(s,3H),3.26(s,3H),2.25(s,3H)。
Example 14: preparation of N- (o-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] acetamide (XQM 14)
The compound 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 5;
step V: weighing 1,3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] ]Pyrimidine-5-yl tosylate (4.20 g,10 mmol), 2-amino-N- (o-tolyl) acetamide (1.80 g,11 mmol), 15mL N-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, purifying by column chromatography to obtain pure product, white solid N- (o-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2, 3-d)]Pyrimidin-5-yl) amino groups]Acetamide, yield 1.04g, 35.71%; m.p, 279.6-284.3 ℃; MS 384.16611[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.63(s,1H),9.54(s,1H),7.95(s,3H),7.44(s,1H),7.16(dd,J＝37.2,12.7Hz,3H),6.44(s,1H),4.40–4.19(m,2H),3.44(s,3H),3.26(s,3H),2.89(s,9H),2.73(s,9H),2.22(s,3H)。
Example 15: preparation of 1,3,6, 8-tetramethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM)
The compound 1, 3-dimethyl-6- (methylamino) pyrimidine-2, 4 (1 h,3 h) -dione was prepared by the method of example 1;
step III: 1, 3-dimethyl-6- (methylamino) pyrimidine-2, 4 (1H, 3H) -dione (3.38 g,20 mmol), diethyl 2-methylmalonate (4.52 g,26 mmol) and 20.00g diphenyl ether were weighed into a 50mL three-necked round bottom flask, heated to 256 ℃ on a heating mantle and then refluxed for 40min, after TLC monitoring the reaction of the starting materials was complete, the reaction solution was poured into 20mL petroleum ether to precipitate a large amount of solid, and after suction filtration and drying, 5-hydroxy-1, 3,6, 8-tetramethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione was obtained as a white solid in a yield of 3.69g and a yield of 86.15%.
Step IV: 5-hydroxy-1, 3,6, 8-tetramethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (4.45 g,17.71 mmol), triethylamine (2.51 g,24.8 mmol), 0.11g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (4.04 g,21.26 mmol) in the 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 1,3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl 4-methylbenzenesulfonate, the off-white solid with the yield of 4.57g and the yield of 97.73%.
Step V: weighing 1,3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl 4-methylbenzenesulfonate (4.05 g,10 mmol), N-aminopropylmorpholine (1.58 g,11 mmol), 15mL of N-butanol were heated under reflux in a 50mL round bottom flask for 8h, and solid formed with complete reaction monitored by TLC. Suction filtering, drying, and purifying by column chromatography to obtain pure 1,3,6, 8-tetramethyl-5- [ (3-morpholinopropyl) amino]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, in 0.88g yield, 32.51%; m.p, 176.0-177.6 ℃; MS 378.2[ M+H ] ] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.77–8.72(m,1H),3.55(t,J＝4.6Hz,4H),3.44–3.39(m,3H),3.38(s,3H),3.37(s,2H),3.18(d,J＝1.9Hz,3H),2.34(s,2H),2.32(s,2H),2.31(s,2H),2.01(d,J＝2.4Hz,3H),1.66(p,J＝7.0Hz,2H)。
Example 16: preparation of 3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoic acid (XQM)
The compound 1,3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl 4-methylbenzenesulfonate was prepared by the method of example 15;
step V: weighing 1,3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl 4-methylbenzenesulfonate (4.05 g,10 mmol), 3-aminobenzoic acid (1.51 g,11 mmol), 15mL of n-butanol were heated under reflux in a 50mL round bottom flask for 8h, and solid formed with complete reaction monitored by TLC. Suction filtering, drying, purifying by column chromatography to obtain pure product, and white solid 3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidin-5-yl) amino groups]Benzoic acid, yield 0.91g, 31.25%; m.p, 254.5-256.1 ℃; MS 371.1[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),10.28(s,1H),7.56(d,J＝7.6Hz,1H),7.39 7.42(m,1H),7.34(s,1H),7.16(dd,J＝8.0,2.1Hz,1H),3.50(s,3H),3.47(s,3H),1.91(s,3H),1.53(s,3H)。
Example 17: preparation of N- (3-morpholinopropyl) -3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzamide (XQM 17)
The compound 1,3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl 4-methylbenzenesulfonate was prepared by the method of example 15;
Step V: weighing 1,3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl 4-methylbenzenesulfonate (4.05 g,10 mmol), 3-amino-N- (3-morpholinopropyl) benzamide (2.90 g,11 mmol), 15mL of N-butanol were heated in a 50mL round bottom flask and refluxed for 8h, and solids formed, and TLC monitored the reaction was complete. Suction filtering, drying, purifying by column chromatography to obtain pure product, white solid N- (3-morpholinopropyl) -3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2, 3-d)]Pyrimidin-5-yl) amino groups]Benzamide, yield 1.21g, yield 32.13%; m.p, 106.2-107.3 ℃; MS 497.3[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H),8.44–8.46(m,1H),7.45(d,J＝7.7Hz,1H),7.35–7.37(m,1H),7.30–7.32(m,1H),7.03(dd,J＝7.9,2.2Hz,1H),3.56(t,J＝4.6Hz,4H),3.50(s,3H),3.47(s,3H),3.28(d,J＝6.4Hz,2H),3.22(s,3H),2.37–2.33(m,4H),2.31(d,J＝7.2Hz,2H),1.66(q,J＝7.0Hz,2H),1.52(s,3H)。
Example 18: preparation of 5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1-ethyl-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM)
Step I: 6-chloro-3-methyluracil (4.80 g,30 mmol), potassium carbonate (4.98 g,36 mmol), TBAB (0.2 g,0.6 mmol), 3mL of water and 50mL of acetone were weighed into a 250mL round bottom flask, stirred at room temperature until the solids dissolved before separating out the solids, and then a solution of diethyl sulfate (5.09 g,33 mmol) dissolved in 10mL of acetone was slowly dropped into the flask, stirred and refluxed for 2 hours. After completion of the reaction by TLC, the solid was filtered off, the mother liquor was distilled under reduced pressure to give a white solid, which was slurried with diethyl ether and the solid was filtered off again to give 6-chloro-1-ethyl-3-methylpyrimidine-2, 4 (1 h,3 h) -dione as a white solid in a yield of 4.69g, 87.73%.
Step II: 6-chloro-1-ethyl-3-methylpyrimidine-2, 4 (1H, 3H) -dione (4.70 g,25.00 mmol), aqueous methylamine (40%) solution (2.52 g,32.50 mmol), TEA (5.06 g,50.00 mmol) and 40mL ethanol were weighed into a 250mL round bottom flask and stirred at reflux overnight. TLC monitored the reaction to completion, after distilling off ethanol under reduced pressure, about 20mL of diethyl ether was added to slurry, the solid was filtered off, and dried to give 1-ethyl-3-methyl-6- (methylamino) pyrimidine-2, 4 (1H, 3H) -dione as a pale yellow solid, yield 3.66g, 88.79%.
Step III: 1-ethyl-3-methyl-6- (methylamino) pyrimidine-2, 4 (1H, 3H) -dione (3.66 g,20 mmol), diethyl malonate (4.16 g,26 mmol) and 30.00g diphenyl ether were weighed into a 100mL three-necked round bottom flask, heated to 256 ℃ on a heating mantle and then refluxed for 40min, after TLC monitoring the reaction completion of the starting material, the reaction solution was poured into 30mL petroleum ether to precipitate a solid, and the solid was suction-filtered and dried to obtain 1-ethyl-5-hydroxy-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione as a white solid in a yield of 4.54g and a yield of 93.77%.
Step IV: 1-ethyl-5-hydroxy-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (4.27 g,17.71 mmol), triethylamine (2.51 g,24.8 mmol), 0.11g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (4.04 g,21.26 mmol) in the flask, the solution was slowly dropped into the flask, stirred at room temperature for 10min and then heated to reflux for 5h, TLC monitored the reaction was complete. The solvent is removed by distillation under reduced pressure, ethyl acetate is added, the solid is stirred, suction filtration and drying are carried out, and the product 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl p-toluenesulfonate is obtained, the yellowish white solid is obtained, the yield is 4.66g, and the yield is 95.12%.
Step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.05 g,10 mmol), 3-chloro-4-trifluoromethylaniline (2.15 g,11 mmol), 15mL n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction was complete. Suction filtering, drying, purifying by column chromatography to obtain pure product, and purifying by white solid 5- { [ 3-chloro-4- (trifluoromethyl) phenyl]Amino } -1-ethyl-3, 8-dimethylpyrido [2 ],3-d]pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, 1.01g, 33.01%; m.p, 198.1-201.1 ℃; MS 428.09195[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.67(s,1H),7.81–7.58(m,3H),5.53(s,1H),4.00(q,J＝6.9Hz,2H),3.42(s,3H),3.23(s,3H),1.30(t,J＝6.9Hz,3H)。
Example 19: preparation of 1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 19)
The compound 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 18;
step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.05 g,10 mmol), 4-trifluoromethylaniline (1.77 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, purifying by column chromatography to obtain pure product, white solid 1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethyl) phenyl ]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, yield 0.89g, 31.23%; m.p, 183.3-186.1 ℃; MS 395.13086[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),7.75(d,J＝8.6Hz,2H),7.50(d,J＝8.3Hz,2H),5.72(s,1H),4.00(q,J＝6.9Hz,2H),3.43(s,3H),3.23(s,3H),1.31(t,J＝6.9Hz,3H)。
Example 20: preparation of 5- [ (3-chloro-4-fluorophenyl) amino ] -1-ethyl-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 20)
The compound 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 18;
step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.05 g,10 mmol), 3-chloro-4-fluoroaniline (1.59 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction was complete. Suction filtering, drying, and purifying by column chromatography to obtain pure productWhite solid 5- [ (3-chloro-4-fluorophenyl) amino group]-1-ethyl-3, 8-dimethylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, yield 0.91g, 33.51%; m.p, 229.1-231.3 ℃; MS 379.09543[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.45(s,1H),7.53(dd,J 1 ＝6.6,J 2 ＝2.6Hz,1H),7.44–7.46(m,1H),7.29-7.33(m,1H),5.35(s,1H),3.99(q,J＝6.9Hz,2H),3.40(s,3H),3.22(s,3H),1.29(t,J＝6.9Hz,3H)。
Example 21: preparation of 1-ethyl-3, 8-dimethyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 21)
The compound 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 18;
step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.05 g,10 mmol), 3-trifluoromethylaniline (1.77 g,11 mmol), 15mL of n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, purifying by column chromatography to obtain pure product, white solid 1-ethyl-3, 8-dimethyl-5- { [3- (trifluoromethyl) phenyl]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, yield 0.93g, yield 32.15%; m.p, 209.5-212.0 ℃; MS 395.13174[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.69(s,1H),7.79–7.45(m,4H),5.49(s,1H),4.00(q,J＝6.9Hz,2H),3.42(s,3H),3.23(s,3H),1.30(t,J＝6.9Hz,3H)。
Example 22: preparation of 1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 22)
The compound 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 18;
step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] ]Pyrimidin-5-yl-p-toluenesulfonate (4.05 g,10 mmol), 4-trifluoromethoxyaniline (1.95 g,11 mmol), 15mL of n-butanol was heated at reflux in a 50mL round bottom flask for 8h, and solid formed as monitored by TLC for completion of the reaction. Suction filtering, drying, purifying by column chromatography to obtain pure product, white solid 1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethoxy) phenyl]Amino } pyrido [2,3-d]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, 1.03g yield, 31.27%; m.p, 172.4-175.6 ℃; MS 411.12637[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.59(s,1H),7.41(s,4H),5.46(s,1H),3.99(q,J＝6.9Hz,2H),3.41(s,3H),3.22(s,3H),1.30(t,J＝6.9Hz,3H)。
Example 23: preparation of 1-ethyl-3, 8-dimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 23)
The compound 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 18;
step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.05 g,10 mmol), 2-aminopyridine (1.03 g,11 mmol), 15mL n-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed, and TLC monitored reaction completion. Suction filtering, drying, purifying by column chromatography to obtain pure product, white solid 1-ethyl-3, 8-dimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, 1.11g yield, 35.67% yield; m.p, 261.8-263.5 deg.c; MS:328.13977[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.65(s,1H),8.36(s,1H),7.75(s,1H),7.46(s,1H),7.05(d,J＝8.5Hz,2H),4.00(s,2H),3.44(s,3H),3.25(s,3H),1.51–1.02(m,3H)。
Example 24: preparation of methyl 2- [ (1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoate (XQM)
The compound 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 18;
step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidin-5-yl-p-toluenesulfonic acidEsters (4.05 g,10 mmol), methyl anthranilate (1.66 g,11 mmol), 15mL of n-butanol were heated under reflux in a 50mL round bottom flask for 8h with solid formation and TLC monitored completion of the reaction. Suction filtering, drying, purifying by column chromatography to obtain pure product, and white solid 2- [ (1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidin-5-yl) amino groups]Methyl benzoate, yield 1.08g, yield 32.31%; m.p, 196.2-198.4 ℃; MS 385.14984[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.38(s,1H),7.93(d,J＝7.9Hz,1H),7.70–7.59(m,2H),7.23–7.26(m,1H),5.67(s,1H),3.99(q,J＝6.9Hz,2H),3.84(s,3H),3.41(s,3H),3.24(s,3H),1.30(t,J＝6.9Hz,3H)。
Example 25: preparation of 1-ethyl-3, 8-dimethyl-5- [ (4-methylpyridin-2-yl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 25)
The compound 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl p-toluenesulfonate was prepared by the method of example 18;
step V: weighing 1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.05 g,10 mmol), 4-methyl-2-aminopyridine (1.19 g,11mmol,15mL n-butanol in a 50mL round bottom flask, heating reflux for 8h, solid formation, TLC monitoring reaction complete, suction filtration, drying, column chromatography purification to obtain pure product, white solid 1-ethyl-3, 8-dimethyl-5- [ (4-methylpyridin-2-yl) amino]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, yield 0,88g, 31.24%; m.p, 249.5-251.9 ℃; MS 342.15543[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ11.60(s,1H),8.21(d,J＝5.1Hz,1H),7.45(s,1H),6.88(s,2H),3.99(q,J＝6.9Hz,2H),3.43(s,3H),3.24(s,3H),2.31(s,3H),1.30(t,J＝6.9Hz,3H)。
Example 26: preparation of 6-benzyl-1-ethyl-3, 8-dimethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQM 26)
The compound 1-ethyl-3-methyl-6- (methylamino) pyrimidine-2, 4 (1 h,3 h) -dione was prepared by the method of example 18;
step III: 1-ethyl-3-methyl-6- (methylamino) pyrimidine-2, 4 (1H, 3H) -dione (3.66 g,20 mmol), diethyl benzyl malonate (6.50 g,26 mmol) and 30.00g diphenyl ether were weighed into a 100mL three-necked round bottom flask, heated to 256 ℃ on a heating mantle, refluxed 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 and drying to obtain 6-benzyl-1-ethyl-5-hydroxy-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione as a white solid in a yield of 4.62g and a yield of 91.09%.
Step IV: 6-benzyl-1-ethyl-5-hydroxy-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (6.04 g,17.71 mmol), triethylamine (2.51 g,24.8 mmol), 0.11g DMAP and 15mL acetonitrile were weighed into a 100mL round bottom flask, 5mL acetonitrile was taken to dissolve p-toluenesulfonyl chloride (4.04 g,21.26 mmol) in the Erlenmeyer 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, suction filtration and drying are carried out, thus obtaining the product 6-benzyl-1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidine-5-yl p-toluenesulfonate, the yield is 4.68g, and the yield is 94.66%.
Step V: weighing 6-benzyl-1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ]]Pyrimidine-5-yl tosylate (4.95 g,10 mmol), N-aminopropyl morpholine (1.58 g,11 mmol), 15mL N-butanol in a 50mL round bottom flask, heated to reflux for 8h, solid formed and TLC monitored reaction completion. Suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-1-ethyl-3, 8-dimethyl-5- [ (3-morpholinopropyl) amino]Pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione, as a white solid, in 0.98g yield, 32.14%; m.p, 34.1-135.1 ℃; MS 468.3[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.14(t,J＝5.2Hz,1H),7.23–7.25(m,2H),7.11–7.13(m,3H),3.97(d,J＝7.4Hz,4H),3.47(t,J＝4.6Hz,4H),3.42(s,3H),3.26(q,J＝6.5Hz,2H),3.19(s,3H),2.21(t,J＝4.6Hz,4H),2.17(t,J＝6.9Hz,2H),1.56(q,J＝6.8Hz,2H),1.27(t,J＝6.9Hz,3H)。
Figure BDA0003572213870000221
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Figure BDA0003572213870000231
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Figure BDA0003572213870000241
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Figure BDA0003572213870000251
Pharmacological examples
Example 27
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.
Target compounds numbered XQM 01-XQM: 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 Constant temperature 37 DEG CIs cultured in the incubator until the cell wall is completely attached. 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 ratio= (1-drug group OD value/control group OD value) ×100%, calculating cell growth inhibition ratio at corresponding concentration, calculating IC corresponding to the test compound according to different concentrations of the test compound and inhibition ratio log curve to cells 50 Values. Representative compounds of the present invention were determined as described above.
Figure BDA0003572213870000261
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Figure BDA0003572213870000271
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Figure BDA0003572213870000281
Of the 26 compounds obtained above, most compounds have inhibitory effect on proliferation of A549, A375 and SK-MEL-2 tumor cells, wherein XQM01 and XQM10 have effect on IC of MCF7 cell strain 50 The values are 9.97+ -0.59 mu M and 10.25+ -0.39 mu M, respectively, which is significantly better than the positive control 5-F uracil (IC) 50 =13.42±0.54 μm), and XQM01 and XQM showed moderate proliferation-inhibiting activity on both malignant melanoma cells a375 and SK-MEL-2.
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 XQM to XQM prepared in the examples above.
Example 28: 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 29: 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 30: aerosol formulation
0.25mg of active compound, 25-75mL of ethanol, and 70mg of propellant 22 (chlorodifluoromethane).
Example 31: suppository formula
250mg of active compound and 2000mL of saturated fatty acid glyceride.
Example 32: injectable formulation
50mg of active compound, 1000mL of isotonic saline solution.
Example 33: ointment formula
Micronizing active compound 0.025g, liquid paraffin 10g, and softening white wax to 100g.
Example 34: 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 35: 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 36: 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 37: 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 38: lotion formulation
Active compound 0.25g, isopropanol 0.5mL, carboxyvinyl polymer 3mg, naOH 2mg, add water to 1g.
Example 39: 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 40: 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 41: atomized solution formulation
7mg of active compound, 5mg of propylene glycol and 10g of water are added.
Example 42: 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 43: 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 44: 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 45: 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 46: 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 47: 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 48: 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, all components were dissolved in chloroform, and N was used 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 (6)

  1. A 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following compounds:
    6-benzyl-5- (isopropylamino) -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    6-benzyl-5- (cyclopropylamino) -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    6-benzyl-5- { [2- (dimethylamino) ethyl ] amino } -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    6-benzyl-1, 3, 8-trimethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1,3, 8-trimethyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    5- [ (3-chloro-4-fluorophenyl) amino ] -1,3, 8-trimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1,3, 8-trimethyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1,3, 8-trimethyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1,3, 8-trimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1,3, 8-trimethyl-5- [ (4-methylpyridin-2-yl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    methyl 2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoate;
    n- (p-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] acetamide;
    n- (o-tolyl) -2- [ (1, 3, 8-trimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] acetamide;
    1,3,6, 8-tetramethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoic acid;
    N- (3-morpholinopropyl) -3- [ (1, 3,6, 8-tetramethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzamide;
    5- { [ 3-chloro-4- (trifluoromethyl) phenyl ] amino } -1-ethyl-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    5- [ (3-chloro-4-fluorophenyl) amino ] -1-ethyl-3, 8-dimethylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1-ethyl-3, 8-dimethyl-5- { [3- (trifluoromethyl) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1-ethyl-3, 8-dimethyl-5- { [4- (trifluoromethoxy) phenyl ] amino } pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    1-ethyl-3, 8-dimethyl-5- (pyridin-2-ylamino) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    methyl 2- [ (1-ethyl-3, 8-dimethyl-2, 4, 7-trioxo-1, 2,3,4,7, 8-hexahydropyrido [2,3-d ] pyrimidin-5-yl) amino ] benzoate;
    1-ethyl-3, 8-dimethyl-5- [ (4-methylpyridin-2-yl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;
    6-benzyl-1-ethyl-3, 8-dimethyl-5- [ (3-morpholinopropyl) amino ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione.
  2. 2. A pharmaceutical composition comprising as an active ingredient a compound of any one of the 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine compounds and pharmaceutically acceptable salts thereof according to claim 1 and a pharmaceutically acceptable carrier or diluent.
  3. 3. The use of a 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine compound of claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting MCF7, a375, and 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 MCF7, a375 and SK-MEL-2 tumor cell growth.
  5. 5. The use of a 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the preparation of a medicament for the treatment of cancer, said cancer being melanoma or breast cancer.
  6. 6. The use of the pharmaceutical composition according to claim 2, for the preparation of a medicament for the treatment of cancer, said cancer being melanoma, breast cancer.
CN202210330914.9A 2022-03-30 2022-03-30 5-substituted amino-3-methylpyrido [2,3-d ] pyrimidine compound and preparation and application thereof Active CN114456166B (en)

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