CN108129486B - Pyrimidone derivatives and uses thereof - Google Patents
Pyrimidone derivatives and uses thereof Download PDFInfo
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- CN108129486B CN108129486B CN201810075170.4A CN201810075170A CN108129486B CN 108129486 B CN108129486 B CN 108129486B CN 201810075170 A CN201810075170 A CN 201810075170A CN 108129486 B CN108129486 B CN 108129486B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Abstract
The invention relates to a pyrimidone derivative and application thereof. The pyrimidone derivative is a compound shown as a formula I,or a pharmaceutically acceptable salt thereof. Through activity inhibition experiments, the following results are found: the pyrimidone derivative provided by the invention has a remarkable activity inhibition effect on dihydroorotate dehydrogenase of plasmodium falciparum. The invention lays a foundation for preparing novel antimalarial drugs.
In the formula I, R1Is C1～C6A linear, branched or cyclic alkyl group of (a), or an amino group; a is a 5-6 membered saturated or unsaturated carbocyclic group.
Description
Technical Field
The invention relates to a pyrimidone derivative and application thereof.
Background
Malaria is an insect-mediated infectious disease caused by parasitic plasmodium that seriously harms human health and is still one of the most serious parasitic diseases in the world to date.
Hitherto, clinically applied antimalarial drugs mainly comprise chloroquine, artemether, arteether and other artemisinin derivatives, pyrimethamine, sulfadoxine and the like, and the drugs have the defects of difficult avoidance of toxic and side effects, poor selectivity, easy generation of drug resistance and the like. With the rapid development of life science and technology, the development of anti-drugs with good therapeutic effect and small toxic and side effects has become an important direction for the research of the current novel anti-malaria drugs by taking some signal transduction pathway key enzymes related to malaria as drug screening targets.
Disclosure of Invention
The invention designs and synthesizes a series of pyrimidone derivatives. The in vitro activity inhibition experiment shows that: the pyrimidone derivative designed by the invention has obvious activity inhibition effect on dihydroorotate dehydrogenase of plasmodium falciparum, and lays a foundation for preparing novel antimalarial drugs.
An object of the present invention is to provide a pyrimidone derivative having a novel structure.
The pyrimidone derivative is a compound shown as a formula I, or a pharmaceutically acceptable salt thereof:
in the formula I, R1Is C1～C6Linear, branched or cyclic alkyl, or amino (NH)2) (ii) a A is a 5-6 membered saturated or unsaturated carbocyclic group.
It is another object of the present invention to provide a composition.
The composition comprises a compound shown in formula I or a pharmaceutically acceptable salt thereof and a suitable diluent or/and a filler.
The invention further discloses an application of the pyrimidone derivative (the compound shown in the formula I or the pharmaceutically acceptable salt thereof) or the composition thereof. Namely the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing a dihydroorotate dehydrogenase inhibitor of plasmodium falciparum; or the like, or, alternatively,
use of a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a suitable diluent or filler for the manufacture of a medicament for the treatment of a disease mediated by the dihydroorotate dehydrogenase from plasmodium falciparum.
In addition, the invention also aims to provide a method for preparing the compound shown in the formula I.
The method comprises the following steps:
(1) a step of preparing a compound shown in a formula II by using diethyl malonate as a starting material and reacting the diethyl malonate with chloroacetyl chloride;
(2) the compound shown in the formula II and corresponding arylamine
Reacting to obtain a compound shown in a formula III;
(3) hydrolyzing the compound shown in the formula III to obtain a compound shown in a formula IV;
(4) a compound of formula IV with R1-NH2Reacting to obtain a compound shown as a formula V; and the combination of (a) and (b),
(5) and (3) performing cyclization reaction on the compound shown in the formula V and paraformaldehyde to obtain a target object (the compound shown in the formula I).
Wherein R is1And A are as defined above.
Detailed Description
In a preferred embodiment of the present invention, R1Is C1～C3Linear, branched or cyclic alkyl, or amino (NH)2)；
In a more preferred embodiment, R1Is methyl, ethyl, n-propyl, cyclopropyl or amino (NH)2)。
In another preferred embodiment of the present invention, A is
Wherein the labeled positions of the curves are substitution positions, and the "mother ring" to which A is connected is a "and" relationship.
In a further preferred embodiment of the invention, the composition may also comprise a suitable cellulose preparation or calcium phosphate (e.g. tricalcium phosphate or calcium hydrogen phosphate, etc.), and a suitable binder (e.g. starch paste, corn starch, wheat starch, rice starch or potato starch, etc.). If desired, disintegrating agents and/or suitable coatings to resist gastric juices, and the like may also be added.
The composition provided by the invention can be prepared into various dosage forms and is administrated in an oral or injection mode.
The invention is further illustrated by the following examples, which are intended only for a better understanding of the contents of the invention. The examples given therefore do not limit the scope of the invention in any way.
Example 1
Synthesis of 3-methyl-1- (2-naphthyl) -2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione (compound shown as formula Ia)
(1) Synthesis of ethyl 2- (2-naphthylamino) -4-carbonyl-4, 5-dihydrofuran-3-carboxylate (compound represented by formula IIIa):
adding 3mmol of sodium hydrogen (with the purity of 60%) and 1.8mL of anhydrous Tetrahydrofuran (THF) into a 50mL flask, dropwise adding a 3mL anhydrous THF solution of 6mmol of diethyl malonate under an ice-water bath, dropwise adding a 3mL anhydrous THF solution of 3mmol of chloroacetyl chloride after 10 minutes, and stirring at the temperature of 40-45 ℃ for at least 1 hour;
under the condition of room temperature, dropwise adding 2-naphthylamine into the reaction liquid, stirring at 45-55 ℃ for at least 12 hours, adjusting the pH of the reaction liquid to 6-7 by using a 5% diluted hydrochloric acid solution, extracting by using ethyl acetate, washing for 2 times by using saturated saline, concentrating an organic layer, drying, and carrying out silica gel column chromatography (petroleum ether: ethyl acetate is 1: 1, v/v) to obtain white powder (the compound shown in the formula IIIa) with the yield of 40%.
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.02-7.90(m,4H),7.63-7.51(m,3H),4.75(s, 2H),4.25(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H).
(2) Synthesis of 2- (2-naphthylamino) -4-carbonyl-4, 5-dihydrofuran-3-carboxylic acid (compound shown as formula IVa)
Under ice bath conditions, 3mmol of the compound of formula IIIa was dissolved in methanol: water 5: 1 (total 18mL), adding 15mmol of lithium hydroxide monohydrate, stirring for half an hour, removing the ice bath, heating to 55-60 ℃, keeping the state for at least 12 hours, spin-drying methanol, adding a little water and 5% diluted hydrochloric acid to adjust the pH value of the reaction solution to 4-5, separating out a large amount of off-white solid, and performing suction filtration and drying to obtain the compound shown in the formula IVa with the yield of 80%.
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.55(s,1H),8.11-7.93(m,4H),7.72-7.41(m, 3H),4.68(s,2H).
(3) Synthesis of 2- (2-naphthylamino) -4-carbonyl-4, 5-dihydrofuran-3-carboxamide (compound shown in formula Va)
10mL of dichloromethane, 1.2mmol of 1-hydroxybenzotriazole, 1.2mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.2mmol of aqueous methylamine solution are added in sequence to 1mmol of the compound shown in the formula IVa, the mixture is placed in a round-bottomed flask, stirred at room temperature overnight, saturated sodium bicarbonate solution is added in sequence, the mixture is washed with saturated brine, an organic layer is concentrated and dried, and silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1, v/v) is carried out to obtain a white solid (the compound shown in the formula Va), wherein the yield is 25%.
1H NMR(400MHz,CDCl3)δ12.71(s,1H),8.80(d,J＝5.6Hz,1H),8.05-7.95(m,4H),7.60-7.53(m,3H),3.90(s,2H),3.31(s,3H).
(4) Synthesis of target Compound (Compound represented by formula Ia)
The compound represented by formula Va (100mg, 1.0mmol) and paraformaldehyde (10mg, 1.2mmol) were dissolved in anhydrous ethanol (4mL), and sodium hydroxide (17mg, 1.2mmol) was added. The mixture was stirred at room temperature for 1 hour and then kept at 70 ℃ for at least 8 hours, heating was stopped, suction filtration was performed, the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (ethyl acetate: petroleum ether: 1: 3) to obtain 36mg of a white solid (the objective compound, the compound represented by formula Ia) with a yield of 34.6%.
1H NMR(400MHz,CDCl3):δ8.11-7.90(m,4H),7.51-7.33(m,3H),5.61(s,2H),4.73(s,2H), 3.27(s,3H).
13C NMR(100MHz,CDCl3)δ191.1,183.4,165.5,135.4,133.3,132.3,129.8,128.4,128.2, 127.5,127.2,124.2,123.6,97.6,86.3,77.8,38.5.
LC-MS(ESI)calcd for C17H14N2O3[M+H]+295.10,found 295.17.
Example 2
Synthesis of 1- (2-naphthyl) -3-ethyl-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5- (1H,6H) -dione (Compound represented by formula Ib):
the same conditions and procedures as in example 1 were repeated except that an aqueous solution of ethylamine was used instead of the aqueous methylamine solution in example 1 (in step (3)), to obtain a white solid (the compound represented by formula Ib) in a yield of 37.3%.
1H NMR(400MHz,CDCl3):δ8.03-7.73(m,4H),7.60-7.42(m,3H),5.51(s,2H),4.88(s,2H), 3.05(q,J＝7.6 3H),1.33(t,J＝7.6 3H).
13C NMR(100MHz,CDCl3)δ193.6,182.4,162.3,135.4,133.3,132.3,131.8,128.4,128.2, 127.5,127.2,124.2,123.6,97.6,38.6,38.5,14.9.
LC-MS(ESI)calcd for C18H16N2O3[M+H]+309.02,found 309.09.
Example 3
Synthesis of 1- (2, 3-dihydro-1H-inden-5-yl) -3-ethyl-2, 3-dihydrofuro [2,3-d ] pyrimidine-4.5 (1H,6H) -dione (Compound of formula Ic):
the conditions and procedures were the same as in example 1 except that the compound represented by the formula c was used instead of 2-naphthylamine in example 1 (in step (1)), and an aqueous ethylamine solution was used instead of the aqueous methylamine solution in example 1 (in step (3)), to obtain a white solid (the compound represented by the formula Ic) in a yield of 39.1%.
1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.0Hz,1H),7.27(s,1H),7.16(d,J＝8.0Hz,1H), 4.22(q,J＝7.2Hz,2H),4.17(s,2H),3.65(s,2H),2.89(t,J＝7.6Hz,4H),2.09-2.02(m,2H),1.26 (t,J＝7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ190.9,183.5,165.6,145.7,144.2,135.8,125.4,123.6,121.6, 97.1,88.3,59.7,38.4,32.8,32.4,25.7,14.9.
LC-MS(ESI)calcd for C17H18N2O3[M+H]+299.13,found 299.17.
Example 4
Synthesis of 1- (2-naphthyl) -3-propyl-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione (Compound represented by formula Id):
the conditions and procedure were the same as in example 1 except that an aqueous solution of n-propylamine was used instead of the aqueous methylamine solution in example 1 (in step (3)), to give a white solid (the compound represented by the formula Id) in a yield of 27.6%.
1H NMR(400MHz,DMSO-d6):δ7.92-7.84(m,4H),7.56-7.29(m,3H),4.51(s,2H),3.57(s, 2H),3.05(q,J＝6.4,2H),1.69-1.63(m,2H),1.33(t,J＝7.2,3H)
13C NMR(100MHz,DMSO-d6)δ193.6,182.4,162.3,135.4,133.3,132.3,131.8,128.4,128.2, 127.5,127.2,124.2,123.6,97.6,38.6,38.5,14.9.
LC-MS(ESI)calcd for C17H18N2O3[M+H]+323.13,found 323.17.
Example 5
Synthesis of 1- (2-naphthyl) -3-cyclopropyl-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione (Compound represented by formula Ie):
the same conditions and procedures as in example 1 were repeated except that an aqueous solution of cyclopropylamine was used instead of the aqueous solution of methylamine in example 1 (in step (3)), to give a white solid (the compound represented by the formula Ie) in a yield of 35.3%.
1H NMR(400MHz,DMSO-d6)δ8.08-7.93(m,4H),7.69-7.54(m,3H),3.89(s,2H),3.64(s, 2H),2.82-2.77(m,1H),0.78-0.73(m,2H),0.56-0.50(m,2H).
13C NMR(100MHz,CDCl3)δ193.7,181.2,167.5,134.9,133.4,131.8,129.9,127.9,127.2, 126.5,121.7,123.5,120.5,99.4,83.6,77.4,29.7,21.6,6.5.
LC-MS(ESI)calcd for C19H16N2O3[M+H]+321.10,found 321.13.
Example 6
Synthesis of 1- (2-naphthyl) -3-amino-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione (Compound represented by formula If):
(1) 1mmol of the compound of formula IVa was added with 6mL of dichloromethane and 1mmol of N, N' -Carbonyldiimidazole (CDI) in this order and stirred at room temperature for about 1 h. Then 1.2mmol of 80% hydrazine hydrate solution was added. After the reaction was completed, filtration was carried out, the filter cake was dried and purified by column chromatography (EA: methanol 10:1, v/v) to obtain a product as a brown solid with a yield of 27%;
(2) dissolving 1mmol of the compound represented by the formula Vf in 5mL of absolute ethanol, adding 1.2mmol of sodium hydroxide solid, stirring the mixed solution at room temperature for 1 hour, adding 1.2mmol of paraformaldehyde, keeping the temperature at 70 ℃ for at least 8 hours, stopping heating, performing suction filtration, concentrating the filtrate under reduced pressure, and separating by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 3) to obtain a white solid (the target compound represented by the formula If) with the yield of 13.2%.
1H NMR(400MHz,CDCl3):δ10.33(s,2H),7.83-7.67(m,4H),7.65-7.43(m,3H),5.51(s, 2H),4.88(s,2H).
13C NMR(100MHz,CDCl3)δ194.7,185.4,162.7,133.5,132.6,131.5,132.2,128.4,128.2, 127.5,127.2,124.2,120.3,87.3,79.9,76.2.
LC-MS(ESI)calcd for C16H13N3O3[M+H]+296.10,found 296.13.
Example 7
The in vitro inhibition effect experiment of the compound provided by the invention on the activity of plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is as follows:
the screening method comprises the following steps: DHODH (dihydroorotate dehydrogenase) catalyzes the oxidation of its natural substrate DHO (dihydroorotate) to Orotate under certain conditions. Under the catalysis of DHODH, firstly two H + and e-of substrate DHO are transferred to coenzyme FMN, and then reduced FMNH2Electrons are transferred to free coenzyme CoQ. The free coenzyme CoQ finally transfers electrons to a chromogenic substrate DCIP, and the DCIP is reduced. DCIP has maximum light absorption at 600nm, while DCIP in the reduced state has no light absorption at 600 nm. The degree of oxidation of the substrate DHO can be judged according to the degree of reduction of the absorbance. The degree of oxidation of the substrate DHO in unit time is the initial rate of the enzymatic reaction. After addition of the inhibitor, the initial rate of the enzymatic reaction decreases. The procedure of the PfDHODH experiment employed DSM1 as a positive control, with at least three replicates per experiment. IC (integrated circuit)50Values were calculated using Originpro 8.0.
The IC of the compounds of formulae Ia to If for inhibition of PfDHODH activity was tested according to the screening method described above50(. mu.M), the specific results are shown in Table 1.
TABLE 1
Claims (8)
1. A pyrimidone derivative which is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
in the formula I, R1Is C1～C6A linear, branched or cyclic alkyl group of (a), or an amino group; a is a 5-6 membered saturated or unsaturated carbocyclic group.
2. A pyrimidone derivative according to claim 1, wherein R is1Is C1～C3A linear, branched or cyclic alkyl group, or an amino group.
3. A pyrimidone derivative according to claim 2, wherein R is1Is methyl, ethyl, n-propyl, cyclopropyl or amino.
4. A pyrimidone derivative according to claim 1, wherein a is
5. A pyrimidone derivative which is 3-methyl-1- (2-naphthyl) -2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione, 1- (2-naphthyl) -3-ethyl-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5- (1H,6H) -dione, 1- (2, 3-dihydro-1H-inden-5-yl) -3-ethyl-2, 3-dihydrofuran [2,3-d ] pyrimidine-4.5 (1H,6H) -dione, 1- (2-naphthyl) -3-propyl-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione, 1- (2-naphthyl) -3-cyclopropyl-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione, or 1- (2-naphthyl) -3-amino-2, 3-dihydrofuran [2,3-d ] pyrimidine-4, 5(1H,6H) -dione.
6. A composition comprising a pyrimidone derivative according to any of claims 1 to 5 and a diluent or/and a filler.
7. Use of a pyrimidone derivative according to any one of claims 1 to 5 for the preparation of a dihydroorotate dehydrogenase inhibitor of plasmodium falciparum.
8. Use of a composition according to claim 6 for the manufacture of a medicament for the treatment of a disease mediated by dihydroorotate dehydrogenase from plasmodium falciparum.
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