CN108129486B - Pyrimidone derivatives and their uses - Google Patents

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

Pyrimidone derivatives and their uses

technical field

The present invention relates to a pyrimidone derivative and its use.

Background technique

Malaria is a vector-borne infectious disease caused by the parasitic Plasmodium parasite that seriously endangers human health and is still one of the most serious parasitic diseases in the world.

So far, the clinically used antimalarial drugs mainly include artemisinin derivatives such as chloroquine, artemether and arteether, pyrimethamine and sulfadoxine, etc. These drugs have unavoidable side effects, poor selectivity and easy to produce Disadvantages such as drug resistance. With the rapid development of life science and technology, some key enzymes of malaria-related signal transduction pathways are used as drug screening targets, and the development of anti-drugs with good therapeutic effect and less toxic and side effects has become an important direction in the research of new anti-malarial drugs. .

SUMMARY OF THE INVENTION

The present invention designs and synthesizes a series of pyrimidone derivatives. It is found through the in vitro activity inhibition experiment that the pyrimidone derivatives designed in the present invention have significant activity inhibition effect on the dihydroorotate dehydrogenase of Plasmodium falciparum, which lays a foundation for the preparation of new antimalarial drugs.

An object of the present invention is to provide a pyrimidone derivative with a novel structure.

The pyrimidinone derivative of the present invention is the compound shown in formula I, or a pharmaceutically acceptable salt thereof:

In formula I, R ₁ is a C ₁ -C ₆ linear, branched or cyclic alkyl group, or an amino group (NH ₂ ); A is a 5- to 6-membered saturated or unsaturated carbocyclic group.

Another object of the present invention is to provide a composition.

The composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a suitable diluent or/and filler.

Another object of the present invention is to disclose a use of the above-mentioned pyrimidone derivatives (the compound represented by formula I or a pharmaceutically acceptable salt thereof) or a composition thereof. That is, the application of a compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a dihydroorotate dehydrogenase inhibitor of Plasmodium falciparum; or,

Use of a composition comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof and a suitable diluent or filler in the preparation of a medicament for treating diseases mediated by dihydroorotate dehydrogenase of Plasmodium falciparum .

In addition, another object of the present invention is to provide a method for preparing the compound represented by formula I.

The method includes the following steps:

(1) take diethyl malonate as starting raw material, react by diethyl malonate and chloroacetyl chloride, prepare the step of compound shown in formula II;

反应，得到式III所示化合物的步骤；(2) The compound represented by formula II and the corresponding aromatic amine

Reaction, the step that obtains the compound shown in formula III;

(3) compound shown in formula III obtains the step of compound shown in formula IV through hydrolysis reaction;

(4) the step of reacting the compound represented by formula IV with R ₁ -NH ₂ to obtain the compound represented by formula V; and,

(5) The step of obtaining the target compound (the compound represented by formula I) through cyclization reaction between the compound represented by formula V and paraformaldehyde.

Wherein, the definitions of R ₁ and A are the same as those described above.

Detailed ways

In a preferred technical solution of the present invention, R ₁ is a C ₁ -C ₃ linear, branched or cyclic alkyl group, or an amino group (NH ₂ );

In a more preferred technical solution, R ₁ is methyl, ethyl, n-propyl, cyclopropyl or amino (NH ₂ ).

其中曲线标注位为取代位，且 A与其相连的“母环”为“并”的关系。In another preferred technical solution of the present invention, A is

The position marked on the curve is the substitution position, and the "mother ring" connected with A is the relationship of "union".

In yet another preferred technical solution of the present invention, the composition may also include suitable cellulose preparations or calcium phosphates (such as tricalcium phosphate or calcium hydrogen phosphate, etc.), and suitable binders (such as starch paste) , corn starch, wheat starch, rice starch or potato starch, etc.). If desired, disintegrants and/or suitable coatings to resist gastric juices, etc. may also be added.

The composition provided by the present invention can be made into various dosage forms and administered orally or by injection.

The present invention will be further described below through examples, and the purpose is only to better understand the content of the present invention. Therefore, the examples given do not limit the scope of protection of the present invention in any way.

Example 1

Synthesis of 3-methyl-1-(2-naphthyl)-2,3-dihydrofuro[2,3-d]pyrimidine-4,5(1H,6H)-dione (compound of formula Ia)

(1) Synthesis of 2-(2-naphthylamino)-4-carbonyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester (compound represented by formula IIIa):

3 mmol of sodium hydrogen (purity of 60%) and 1.8 mL of anhydrous tetrahydrofuran (THF) were added to a 50 mL flask, and 6 mmol of diethyl malonate in 3 mL of anhydrous THF solution was added dropwise under an ice-water bath, and after 10 minutes Add dropwise a solution of 3 mmol of chloroacetyl chloride in 3 mL of anhydrous THF, and stir at 40°C to 45°C for at least 1 hour;

At room temperature, add 2-naphthylamine dropwise to the above reaction solution, stir at 45°C to 55°C for at least 12 hours, adjust the pH of the reaction solution to 6-7 with 5% dilute hydrochloric acid solution, and use ethyl acetate. Extraction, washed twice with saturated brine, the organic layer was concentrated, dried, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate=1:1, v/v) to obtain a white powder (the compound represented by formula IIIa) with a yield of 40 %.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.47(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 of formula IVa)

Under ice bath conditions, dissolve 3 mmol of the compound of formula IIIa in a mixed solution of methanol: water = 5:1 (total 18 mL), then add 15 mmol of lithium hydroxide monohydrate, stir for half an hour, remove the ice bath, and heat to 55℃～60℃, and kept in this state for at least 12 hours, spin dry methanol, add a little water and 5% dilute hydrochloric acid to adjust the pH value of the reaction solution to 4-5, and precipitate a large amount of off-white solid, suction filtration and dry The compound represented by formula IVa was obtained with a yield of 80%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.47(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 represented by formula Va)

1 mmol of the compound represented by formula IVa was added successively to 10 mL of dichloromethane, 1.2 mmol of 1-hydroxybenzotriazole, and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide The hydrochloride and 1.2 mmol methylamine aqueous solution were placed in a round-bottomed flask, stirred overnight at room temperature, sequentially added with saturated sodium bicarbonate solution, washed with saturated brine, the organic layer was concentrated, dried, and subjected to silica gel column chromatography (petroleum ether: acetic acid) Ethyl ester=5:1, v/v) to obtain a white solid (compound represented by formula Va), with a yield of 25%.

¹ H NMR (400MHz, CDCl ₃ ) δ 12.71 (s, 1H), 8.80 (d, J=5.6 Hz, 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 of formula Va (100 mg, 1.0 mmol) and paraformaldehyde (10 mg, 1.2 mmol) were dissolved in absolute ethanol (4 mL) and sodium hydroxide (17 mg, 1.2 mmol) was added. The mixture was stirred at room temperature for 1 hour, then kept at 70°C for at least 8 hours, the heating was stopped, suction filtered, the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:3) to obtain 36 mg of white Solid (target compound, compound represented by formula Ia), yield 34.6%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11-7.90 (m, 4H), 7.51-7.33 (m, 3H), 5.61 (s, 2H), 4.73 (s, 2H), 3.27 (s, 3H) .

¹³ C NMR (100 MHz, CDCl ₃ ) δ 191.1, 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 C ₁₇ H ₁₄ N ₂ O ₃ [M+H] ⁺ 295.10, found 295.17.

Example 2

1-(2-naphthyl)-3-ethyl-2,3-dihydrofuro[2,3-d]pyrimidine-4,5-(1H, 6H)-dione (compound of formula Ib) synthesis:

Except for replacing the methylamine aqueous solution in Example 1 with an ethylamine aqueous solution (in step (3)), other conditions and steps were the same as in Example 1 to obtain a white solid (compound represented by formula Ib) with a yield of 37.3%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.03-7.73 (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).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 193.6, 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 C ₁₈ H ₁₆ N ₂ O ₃ [M+H] ⁺ 309.02, found 309.09.

Example 3

1-(2,3-Dihydro-1H-inden-5-yl)-3-ethyl-2,3-dihydrofuro[2,3-d]pyrimidine-4.5(1H,6H)-dione ( The synthesis of compound shown in formula Ic):

Except replacing 2-naphthylamine in Example 1 with the compound shown in formula c (in step (1)), and replacing the methylamine aqueous solution in Example 1 with an aqueous ethylamine solution (in step (3)), other conditions and steps In the same manner as in Example 1, a white solid (the compound represented by formula Ic) was obtained in a yield of 39.1%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 4.22 (q, J=7.2 Hz ,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) .

¹³ C NMR (100 MHz, CDCl ₃ ) δ 190.9, 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 C ₁₇ H ₁₈ N ₂ O ₃ [M+H] ⁺ 299.13, found 299.17.

Example 4

Synthesis of 1-(2-naphthyl)-3-propyl-2,3-dihydrofuro[2,3-d]pyrimidine-4,5(1H, 6H)-dione (compound of formula Id) :

Except for replacing the methylamine aqueous solution in Example 1 with n-propylamine aqueous solution (in step (3)), other conditions and steps are the same as in Example 1 to obtain a white solid (compound represented by formula Id) with a yield of 27.6%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.92-7.84 (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)

¹³ C NMR (100MHz, DMSO-d ₆ ) δ 193.6, 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 C ₁₇ H ₁₈ N ₂ O ₃ [M+H] ⁺ 323.13, found 323.17.

Example 5

1-(2-naphthyl)-3-cyclopropyl-2,3-dihydrofuro[2,3-d]pyrimidine-4,5(1H, 6H)-dione (compound of formula Ie) synthesis:

Except replacing the methylamine aqueous solution in embodiment 1 with cyclopropylamine aqueous solution (in step (3)), other conditions and steps are the same as embodiment 1, obtain white solid (compound shown in formula Ie), productive rate 35.3%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.08-7.93(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).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 193.7, 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 C ₁₉ H ₁₆ N ₂ O ₃ [M+H] ⁺ 321.10, found 321.13.

Example 6

Synthesis of 1-(2-naphthyl)-3-amino-2,3-dihydrofuro[2,3-d]pyrimidine-4,5(1H, 6H)-dione (compound of formula If):

(1) 1 mmol of the compound represented by formula IVa was added successively to 6 mL of dichloromethane and 1 mmol of N,N'-carbonyldiimidazole (CDI), and the mixture was stirred at room temperature for about 1 h. Then 1.2 mmol of 80% hydrazine hydrate solution was added. After the reaction, filter, dry the filter cake and purify by column chromatography (EA: methanol = 10: 1, v/v), the product is a brown solid, the yield is 27%;

(2) 1 mmol of the compound represented by formula Vf is dissolved in 5 mL of absolute ethanol, 1.2 mmol of sodium hydroxide solid is added, the mixed solution is stirred at room temperature for 1 hour, 1.2 mmol of paraformaldehyde is added, and at 70° C., the state is maintained for at least 8 After 1 hour, the heating was stopped, filtered with suction, the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:3) to obtain a white solid (target compound, compound represented by formula If) with a yield of 13.2%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.33 (s, 2H), 7.83-7.67 (m, 4H), 7.65-7.43 (m, 3H), 5.51 (s, 2H), 4.88 (s, 2H) .

¹³ C NMR (100 MHz, CDCl ₃ ) δ 194.7, 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 C ₁₆ H ₁₃ N ₃ O ₃ [M+H] ⁺ 296.10, found 296.13.

Example 7

The experiment of the in vitro inhibitory effect of the compounds provided by the invention on the activity of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is as follows:

Screening method: DHODH (dihydroorotate dehydrogenase) can catalyze the oxidation of its natural substrate DHO (dihydroorotate) to Orotate under certain conditions. Under the catalysis of DHODH, the two H+ and e- of the substrate DHO are firstly transferred to the coenzyme FMN, and then the reduced FMNH ₂ transfers electrons to the free coenzyme CoQ. The free coenzyme CoQ finally transfers electrons to the chromogenic substrate DCIP, which is reduced. DCIP has a maximum light absorption at 600 nm, 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 decrease in absorbance. The degree of oxidation of the substrate DHO per unit time is the initial rate of the enzymatic reaction. After adding the inhibitor, the initial rate of the enzymatic reaction decreased. DSM1 was used as a positive control during the PfDHODH experiment, and at least three parallels were set for each experiment. _IC50 values were calculated using Originpro 8.0.

According to the above screening method, the IC ₅₀ (μM) of the compounds represented by formulas Ia to If inhibiting the activity of PfDHODH was tested. The specific results are shown in Table 1.

Table 1

Claims (8)

1. a pyrimidone derivative, is the compound shown in formula I, or its pharmaceutically acceptable salt:

In formula I, R ₁ is a C ₁ -C ₆ linear, branched or cyclic alkyl group, or an amino group; A is a 5- to 6-membered saturated or unsaturated carbocyclic group. 2 . The pyrimidinone derivative according to claim 1 , wherein R ₁ is a C ₁ -C ₃ linear, branched or cyclic alkyl group, or an amino group. 3 . 3. The pyrimidinone derivative of claim 2, wherein R ₁ is methyl, ethyl, n-propyl, cyclopropyl or amino. 4. The pyrimidinone derivative of claim 1, wherein A is

5. A pyrimidinone derivative, characterized in that the pyrimidinone derivative 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-dihydrofuro[2,3-d]pyrimidine-4,5-(1H, 6H )-dione, 1-(2,3-dihydro-1H-inden-5-yl)-3-ethyl-2,3-dihydrofuro[2,3-d]pyrimidine-4.5(1H, 6H )-dione, 1-(2-naphthyl)-3-propyl-2,3-dihydrofuro[2,3-d]pyrimidine-4,5(1H, 6H)-dione, 1-( 2-naphthyl)-3-cyclopropyl-2,3-dihydrofuro[2,3-d]pyrimidine-4,5(1H,6H)-dione, or 1-(2-naphthyl)- 3-Amino-2,3-dihydrofuro[2,3-d]pyrimidine-4,5(1H,6H)-dione. 6. A composition comprising the pyrimidinone derivative of any one of claims 1 to 5 and a diluent or/and a filler. 7. Use of the pyrimidinone derivative according to any one of claims 1 to 5 in the preparation of a dihydroorotate dehydrogenase inhibitor of Plasmodium falciparum. 8. The use of the composition according to claim 6 in the preparation of a medicament for the treatment of diseases mediated by the dihydroorotate dehydrogenase of Plasmodium falciparum.