CN114805339B

CN114805339B - Pyrroloquinoline quinone derivative or pharmaceutically acceptable salt thereof, preparation method and application

Info

Publication number: CN114805339B
Application number: CN202110114354.9A
Authority: CN
Inventors: 王广基; 甄乐; 许亚文; 王健鲲
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2021-01-27
Filing date: 2021-01-27
Publication date: 2024-02-27
Anticipated expiration: 2041-01-27
Also published as: CN114805339A

Abstract

The invention discloses a pyrroloquinoline quinone derivative with a structure shown as a formula (I) or pharmaceutically acceptable salts thereof, a preparation method and application. The derivatives have excellent solubility and/or permeability, are obviously superior to PQQ and PQQ salts (commercial disodium salt), and show ideal drug effects in anti-inflammatory, anti-diabetic and anti-metabolic disease models, and are superior to the PQQ and PQQ salts (commercial disodium salt).

Description

Pyrroloquinoline quinone derivative or pharmaceutically acceptable salt thereof, preparation method and application

Technical Field

The invention relates to the field of biological medicine, in particular to a pyrroloquinoline quinone derivative or pharmaceutically acceptable salt thereof, a preparation method and application.

Background

Pyrroloquinoline quinone (pyrroloquinoline quinone, PQQ) has been demonstrated to be an important nutrient for mammals, with a wide range of physiological and pharmacological activities including growth promotion, antioxidant, antidiabetic, neuroprotective effects, and the like. However, the presence of three carboxylic acid groups in the molecular structure of PQQ results in poor solubility and permeability. Carboxylic acids can solve the solubility problem by salifying, but the salt forms of PQQ are diverse and complex, such as monosodium, disodium, trisodium and tetrasodium salts. Wherein only the disodium salt exists in various hydrated forms such as the trihydrate and the pentahydrate; the solubility of the trihydrate is about 3mg/mL in water, and the solubility in artificial gastric juice is reduced by 40 times; pentahydrate has poor stability and crystallinity, which is unfavorable for drug development (cryst. Growth des.2017, 17, 4118). Although salt formation is possible to partially solve the problem of solubility, the tricarboxylic acid structure of PQQ causes that the salt exists in a negative ion form under physiological conditions, which greatly hinders the osmotic absorption process in the gastrointestinal tract. Esterification of carboxylic acids of PQQ is currently the primary means of improving its lipid solubility and permeability, with the activity of trimethyl derivatives (PQQ-TME) reported in general (J. Gastroenterol. Hepatol.1993,8, 342;ACS Chem.Neurosci.2018,9, 2898). However, PQQ-TME is hardly soluble in water, affecting its drug properties.

Disclosure of Invention

The invention aims to: the object of the present invention is to provide pyrroloquinoline quinone derivatives or pharmaceutically acceptable salts thereof. After the structure of the PQQ is modified, the solubility and/or permeability of the obtained derivative are improved obviously, and the derivative has ideal anti-inflammatory and anti-metabolic disease drug effect.

The invention aims to provide a preparation method and application of the pyrroloquinoline quinone derivative or the pharmaceutically acceptable salt thereof.

The technical scheme is as follows: the invention provides a pyrroloquinoline quinone derivative with a structure shown as a formula (I) or pharmaceutically acceptable salt thereof,

R ¹ selected from: H. C1-C8 alkyl, C1-C6 cycloalkyl, allyl or benzyl;

R ² selected from: C1-C18 alkyl, C1-C6 cycloalkyl, -COOR ³ Substituted C1-C8 alkyl or X-NH-substituted C1-C8 alkyl;

R ³ selected from: H. C1-C8 alkyl, C1-C6 cycloalkyl, allyl or benzyl;

x is selected from: h or an amino protecting group.

Further, R ¹ Selected from: H. C1-C4 alkyl, C1-C6 cycloalkyl, allyl or benzyl;

R ² selected from: C1-C18 alkyl, C1-C6 cycloalkyl, -COOR ³ Substituted Cl-C8 alkyl or X-NH-substituted C1-C8 alkyl;

R ³ selected from: H. C1-C4 alkyl or benzyl;

x is selected from: H. t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, acetyl, isobutyryl or benzoyl.

Further, the method comprises the steps of,

the pyrroloquinoline quinone derivative with the structure shown in the formula (I) or pharmaceutically acceptable salt thereof is any one of the following:

a pharmaceutical composition comprising a therapeutically effective amount of a pyrroloquinoline quinone derivative of the structure shown in formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.

The preparation method of the pyrroloquinoline quinone derivative with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof is shown in the following synthetic route:

wherein the R is ¹ 、R ² 、R ³ Is defined in accordance with claim 1;

(1) Alkylation reaction is carried out on PQQ to obtain a compound II;

(2) The compound II is subjected to reduction reaction to obtain a compound III;

(3) The compound III is subjected to an acylation reaction to obtain a compound I;

(4) If the compound I synthesized in the step (3) contains an amino protecting group, the derivative containing free amino or amino salification can be obtained through deprotection.

Further, the solvent used in step (1): acetonitrile, tetraHydrofuran, acetone, 2-butanone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, water or a mixed solvent optionally composed of these solvents; the alkylating agent used is R ¹ Y, wherein Y is chloro, bromo, iodo, p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate; the reaction temperature is from 0℃to 180℃and preferably from 20℃to 80 ℃.

Further, the solvent used in step (2): dichloromethane, ethyl acetate, chloroform, acetonitrile, tetrahydrofuran, acetone, 2-butanone, methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, water, 10% aqueous ammonium chloride solution, 30% aqueous ammonium chloride solution, or a mixed solvent optionally composed of these solvents; the reducing agent used: lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, zinc powder, iron powder, sodium thiosulfate, sodium pyrosulfate, sodium sulfite, sodium bisulfite, sodium dithionite, or a mixed reagent optionally composed of these agents; the reaction temperature is-20℃to 100℃and preferably 0℃to 50 ℃.

Further, the solvent used in step (3): dichloromethane, ethyl acetate, chloroform, acetonitrile, tetrahydrofuran, acetone, 2-butanone, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, water or a mixed solvent optionally composed of these solvents; the acylating agent is acid, ester, acyl chloride or anhydride; the reaction temperature is-20℃to 100℃and preferably 0℃to 50 ℃.

The application of pyrroloquinoline quinone derivatives with the structure shown in the formula (I) or pharmaceutically acceptable salts thereof in medicines for treating anti-inflammatory and anti-metabolic diseases.

The beneficial effects are that: the derivatives have excellent solubility and/or permeability, are obviously superior to PQQ and PQQ salts (commercial disodium salt), and show ideal drug effects in anti-inflammatory, anti-diabetic and anti-metabolic disease models, and are superior to the PQQ and PQQ salts (commercial disodium salt).

Drawings

FIG. 1 is a diagram of Compound 4 ¹ H NMR spectrum;

FIG. 2 is a diagram of Compound 15 ¹ H NMR spectrum;

FIG. 3 is a diagram of Compound 16 ¹ H NMR spectrum;

fig. 4 is blood glucose levels in the OGTT experiment.

Detailed Description

Example 1

Synthesis of PQQ trimethyl ester: a single-necked flask was taken, PQQ (3.3 g,10 mmol) was dissolved in DMF (200 mL), followed by small multiple additions of potassium carbonate (6.9 g,50 mmol) and stirring for 1 hour. Dimethyl sulfate (25 g) was added dropwise to the reaction suspension at room temperature, and the reaction was continued at room temperature for 5 days after the completion of the addition. After DMF was distilled off by an oil pump, water (200 mL) was added to the residue and the mixture was made acidic with 4N hydrochloric acid, and the reaction mixture was stirred at room temperature for 6 hours, followed by suction filtration to give PQQ trimethyl ester as an orange solid (3.17 g, yield 85%).

Reduction of PQQ trimethyl ester: a single-necked flask was taken, PQQ trimethyl ester (1.86 g,5 mmol) was suspended in acetonitrile (100 mL), and 1M sodium dithionite solution (100 mL) was added thereto, and stirred at room temperature overnight. The reaction solution was directly suction-filtered, and the cake was dried to obtain reduced PQQ trimethyl ester (1.9 g), which was directly used in the next reaction without purification.

Synthesis of Compound 1: the intermediate from the previous step (187 mg,0.5 mmol) was placed in a two-necked flask and methylene chloride (2 mL) was added to the flask under nitrogen; the suspension was stirred in an ice bath, a solution of acetyl chloride (157 mg,2 mmol) in dichloromethane (2 mL) and triethylamine (220 mg) were added sequentially, warmed naturally and reacted overnight. The reaction was quenched with water (2 mL), the organic phase was separated, the aqueous phase extracted with dichloromethane, the organic phases combined and evaporated to dryness, and the residue was purified by column chromatography (PE: ea=10:1-2:1) to give compound 1 (155 mg, 68%). ¹ H NMR(300MHz，Chloroform-d)δ12.67(s，1H)，8.93(s，1H)，7.33(s，1H)，4.19(s，3H)，4.07(s，3H)，4.02(s，3H)，2.57(s，3H)，2.51(s，3H).

Example 2

With reference to the method of example 1, the following will be carried outReplacement of acetyl chloride in example 1 with palmitoyl chloride produced compound 2 (319 mg, 75%). ¹ H NMR(300MHz，Chloroform-d)δ12.67(s，1H)，8.94(s，1H)，7.32(s，1H)，4.20(s，3H)，4.06(s，3H)，4.03(s，3H)，2.83(t，J＝7.6Hz，2H)，2.75(t，J＝7.5Hz，2H)，1.91(dt，J＝14.3，7.2Hz，4H)，1.30(d，J＝8.3Hz，54H)，0.90(t，J＝6.3Hz，6H).

Example 3

Referring to the procedure of example 1, substitution of acetyl chloride in example 1 with benzoyl chloride produced compound 3 (230 mg, 79%). ¹ H NMR(300MHz，Chloroform-d)δ12.74(s，1H)，8.96(s，1H)，8.47-8.11(m，4H)，7.95-6.91(m，7H)，4.21(s，3H)，4.01(s，3H)，3.82(s，3H).

Example 4

A reduced PQQ trimethyl ester was prepared by the method of example 1.

Synthesis of Compound 4: the intermediate from the previous step (187 mg,0.5 mmol) was placed in a two-necked flask and methylene chloride (5 mL) was added to the flask under nitrogen; the suspension was stirred in an ice bath under nitrogen flow, and monoethyl succinate (292 mg,2 mmol), EDCI (383 mg,2 mmol) and DMAP (48 mg) were added successively, warmed naturally and reacted overnight. The reaction was quenched with water (2 mL), the organic phase was separated, the aqueous phase extracted with dichloromethane, the organic phases combined and evaporated to dryness, and the residue was chromatographed on a column to give compound 4 (132 mg, 42%). ¹ H NMR(300MHz，Chloroform-d)δ12.64(s，1H)，8.92(s，1H)，7.39(d，J＝2.3Hz，1H)，4.23(t，4H)，4.18(s，3H)，4.07(s，3H)，4.02(s，2H)，3.19(t，J＝7.3Hz，2H)，3.12(t，J＝7.5，5.8Hz，2H)，2.95(t，J＝7.3Hz，2H)，2.86(t，J＝7.5，5.8Hz，2H)，1.36-1.31(m，3H)，1.31-1.25(m，3H).

Example 5

Referring to the procedure of example 4, the substitution of monoethyl succinate in example 4 with monobenzyl succinate produced compound 5 (192 mg, 51%). ¹ H NMR(300MHz，Chloroform-d)δ12.66(s，1H)，8.93(s，1H)，7.63-7.20(m，11H)，5.20(d，J＝8.1Hz，3H)，4.19(s，2H)，4.02(s，4H)，3.22(t，J＝7.2Hz，2H)，3.14(t，J＝6.6Hz，1H)，3.02(t，J＝7.2Hz，2H)，2.92(t，J＝7.4，5.8Hz，2H).

Example 6

Referring to the procedure of example 4, substituting monoethyl succinate in example 4 with Boc-glycine produced compound 6 (100 mg, 29%). ¹ H NMR(300MHz，Chloroform-d)δ12.66(s，1H)，8.92(s，1H)，7.43(s，1H)，5.52(d，J＝19.5Hz，2H)，4.45(d，J＝5.9Hz，2H)，4.38(d，J＝6.1Hz，2H)，4.19(s，3H)，4.08(s，3H)，4.02(s，3H)，1.50(d，J＝3.3Hz，18H).

Example 7

Referring to the procedure of example 4, substituting monoethyl succinate in example 4 with Boc-alanine produced compound 7 (118 mg, 33%). ¹ H NMR(300MHz，Chloroform-d)δ12.66(s，1H)，8.93(s，1H)，7.47(s，1H)，5.67(s，1H)，5.39(s，1H)，5.20-4.50(m，2H)，4.20(s，3H)，4.05(s，3H)，4.02(s，3H)，1.82(d，J＝7.2Hz，3H)，1.74(d，J＝7.3Hz，2H)，1.50(s，16H).

Example 8

Referring to the procedure of example 4, substituting monoethyl succinate in example 4 with Boc-valine produced compound 8 (154 mg, 40%). ¹ H NMR(300MHz，Chloroform-d)δ12.64(s，1H)，8.93(s，1H)，7.46(s，1H)，5.53(d，J＝8.9Hz，1H)，5.41(d，J＝8.8Hz，1H)，4.72(dd，J＝9.2，4.0Hz，1H)，4.59(dd，J＝8.8，5.5Hz，1H)，4.19(s，2H)，4.06(s，3H)，4.01(s，2H)，2.82-2.60(m，1H)，2.45(p，J＝6.6Hz，1H)，1.51(d，J＝10.0Hz，18H)，1.27-1.10(m，12H).

Example 9

Referring to the procedure of example 4, substituting monoethyl succinate in example 4 with Boc-2-methylalanine produced compound 9 (230 mg, 62%). ¹ H NMR(300MHz，Chloroform-d)δ12.61(s，1H)，8.93(s，1H)，7.98-7.49(m，1H)，5.51(s，1H)，5.40(s，1H)，4.21(s，3H)，4.04(s，3H)，4.02(s，3H)，1.98(s，6H)，1.84(s，6H)，1.51(s，10H)，1.49(s，9H).

Example 10

Referring to the procedure of example 4, substituting monoethyl succinate in example 4 with Boc-phenylalanine produced compound 9 (230 mg, 62%). ¹ H NMR(300MHz，Chloroform-d)δ12.69(s，1H)，8.98(s，1H)，7.67-6.58(m，12H)，5.69(d，J＝8.6Hz，1H)，5.29(s，1H)，5.03-4.81(m，2H)，4.21(s，3H)，4.03(s，3H)，3.89(s，3H)，3.50(dd，J＝12.9，5.1Hz，1H)，3.43-3.26(m，2H)，1.42(s，16H).

Example 11

Referring to the procedure of example 8, dimethyl sulfate in example 8 was replaced with allyl bromide to obtain PQQ triallyl ester, which was then reduced and acylated to obtain compound 11. ¹ H NMR(300MHz，CDCl ₃ )δ12.59(s，1H)，8.94(s，1H)，7.50(s，1H)，6.31-5.96(m，3H)，5.64-5.38(m，6H)，5.38-5.29(m，2H)，5.08(d，J＝6.0Hz，2H)，4.97(t，J＝6.6Hz，2H)，4.91(d，J＝5.6Hz，2H)，4.75-4.46(m，2H)，2.82-2.57(m，1H)，2.57-2.35(m，1H)，1.51(s，9H)，1.48(s，9H)，1.28-1.08(m，12H).

Example 12

Referring to the procedure of example 9, dimethyl sulfate in example 9 was replaced with allyl bromide to obtain PQQ triallyl ester, which was then reduced and acylated to obtain compound 12. ¹ H NMR(300MHz，CDCl ₃ )δ12.53(s，1H)，8.92(s，1H)，7.79(s，1H)，6.27-5.93(m，3H)，5.63-5.26(m，8H)，5.08(d，J＝5.9Hz，2H)，5.01-4.82(m，4H)，1.96(s，6H)，1.83(s，6H)，1.48(s，9H)，1.47(s，9H).

Example 13

Referring to the procedure of example 9, dimethyl sulfate in example 9 was replaced with benzyl bromide to prepare PQQ tribenzyl ester, which was then reduced and acylated to obtain compound 13. ¹ H NMR(300MHz，Chloroform-d)δ13.11-11.33(m，1H)，8.95(s，1H)，7.85(s，1H)，7.72-7.06(m，15H)，5.59(s，2H)，5.58-5.21(m，6H)，1.83(d，J＝7.8Hz，12H)，1.48(d，J＝14.1Hz，18H).

Example 14

Referring to the method of example 10, the method of example 10Dimethyl sulfate is replaced by benzyl bromide, PQQ tribenzyl ester is prepared first, and finally compound 14 is obtained through reduction and acylation. ¹ H NMR(300MHz，Chloroform-d)δ12.68(s，1H)，8.98(s，1H)，7.84-6.88(m，23H)，5.72(d，J＝8.5Hz，1H)，5.62(s，2H)，5.46(d，J＝18.2Hz，3H)，5.20(dd，J＝25.6，9.9Hz，2H)，5.08-4.78(m，2H)，3.72(dd，J＝14.5，4.9Hz，1H)，3.50(dd，J＝14.1，4.5Hz，1H)，3.28(ddd，J＝23.1，14.1，9.1Hz，2H)，1.44(s，9H)，1.39(s，9H).

Example 15

Synthesis of Compound 15: compound 8 (100 mg) was suspended in ethyl acetate (2 mL), to which was added dropwise a 2N hydrogen chloride/ethyl acetate solution (2 mL), and stirred at room temperature overnight. The reaction solution was suction-filtered, and the filter cake was washed with ethyl acetate to give compound 15 (69 mg). ¹ H NMR(300MHz，DMSO-d ₆ )δ12.64(s，1H)，8.99(d，J＝34.2Hz，6H)，8.77(s，1H)，7.58(d，J＝2.1Hz，1H)，4.80(s，1H)，4.43(s，1H)，4.13(s，3H)，3.97(s，6H)，2.75-2.54(m，2H)，1.36-1.15(m，12H).

Example 16

Synthesis of Compound 16: compound 9 (100 mg) was suspended in ethyl acetate (2 mL), to which was added dropwise a 2N hydrogen chloride/ethyl acetate solution (2 mL), and stirred at room temperature overnight. The reaction solution was suction-filtered, and the filter cake was washed with ethyl acetate to give compound 16 (77 mg). ¹ H NMR(300MHz，DMSO-d ₆ )δ12.60(s，1H)，9.25(s，6H)，8.74(s，1H)，7.55(s，1H)，4.13(s，3H)，3.98(s，6H)，1.93(s，6H)，1.87(s，6H).

The solvent, the reducing agent, the acylating agent, the alkylating agent, and the like in each of the above examples may be replaced as necessary.

Example 17

Determination of Compound solubility

The experimental method comprises the following steps:

(1) kinetic solubility: dissolving the compound in DMSO to prepare stock solution (10 mM); the stock was diluted to 100 μm with PBS buffer (ph=7.0); after incubating the mixture in a water bath at 37℃for 1 hour, the mixture was centrifuged for 30 minutes (maximum relative centrifugal force: 2800 g), and the drug concentration in the supernatant was measured by HPLC.

(2) Equilibrium solubility: the solubility of the compounds in the solution was determined by shake flask method. The compound, 20 μmol, was precisely weighed into different vials, added with artificial intestinal fluid (ph=6.8) and equilibrated with shaking, and the drug concentration was calculated at this time as measured by HPLC until no more change in the amount dissolved.

The experimental results are shown in the following table:

experimental results show that the solubility of the compounds 15 and 16 is significantly better than that of PQQ, the disodium salt of PQQ and the trimethyl ester of PQQ.

Example 18

Determination of Compound permeability (Caco-2 cell model)

Inoculating Caco-2 cells on a 12 or 24-hole polyethylene terephthalate film, and simulating an intestinal epithelial absorption barrier of a human body after the cells grow and differentiate into an intact cell monolayer (more than 21 days); membrane integrity was assessed by measuring the transmembrane resistance. Transport buffer: HBSS buffer containing 10mM HEPES and 15mM glucose, wherein the dosing solution ph=6.5; the receiver ph=7.4 and contained 1% bsa.

Experimental operation: drug-containing transport buffer was added, 1-and 2-hour receiving chamber solutions (100 μl) were collected and acetonitrile (400 μl) was added to perform protein precipitation and stabilize the compound while blank transport buffer (100 μl) was supplemented. Drugs were applied to the top side (a) and the base side (B), respectively, and the permeability was measured. And finally, taking buffer solutions at two sides in the experiment, and calculating the total dosage and the recovery rate.

The experimental results are shown in the following table:

experimental results show that the permeability of the compounds 15 and 16 is significantly better than that of the disodium salt and trimethyl ester of PQQ.

Example 19

Evaluation of anti-inflammatory Activity of Compounds (LPS-induced in vitro inflammation model)

LPS was used to induce RAW264.7 cell inflammation model. RAW264.7 cells (8×10 cells) with good growth state were selected ⁴ Per mL) was inoculated in 96-well plates, 6 wells per group, and cultured for 24h. Blank (+dmem broth), LPS stimulated (+1 μg/mL) and dosing groups (lps+drug) were set, each group was 3-multiplexed, incubated for 24h after dosing, and supernatants were used for Griess assay to detect NO (table 1) (xn-methyl-L-arginine (L-NMMA) is a broad spectrum inhibitor of NOs, and competed with L-arginine for binding to NOs, thereby inhibiting NO production).

The experimental results are shown in the following table:

experimental results show that the in vitro anti-inflammatory activity of compounds 1, 4, 8, 15 and 16 is significantly better than that of the disodium salt of PQQ.

EXAMPLE 20 oral glucose tolerance test OGTT

C57BL/6J mice (4 weeks old, 4 weeks of adaptive feeding) were fasted for 6 hours after 8 weeks of high fat diet (D12492, research Diets inc.); the weight and fasting blood glucose of the mice are measured and grouped, and 6 mice are grouped in each group; administration begins immediately after grouping. The positive control group was selected from commercial metformin hydrochloride (250 mg/kg, intragastric, once daily); the administration group selected from PQQ disodium salt, PQQ trimethyl ester and compound 15 (30. Mu. Mol/kg, gastric lavage, once daily); the blank group was filled with distilled water.

On the 6 th week of administration, fasting was performed on the morning, and blood was taken from the caudal apex after 6 hours of fasting, and fasting blood glucose was measured. 2g/kg glucose solution was administered by gavage, and blood glucose was collected from the tail tips 15min,30min,60min,90min and 120min after sugar stimulation, respectively, and blood glucose was measured.

The experimental results are shown in figure 4.

Claims

1. A pyrroloquinoline quinone derivative or a pharmaceutically acceptable salt thereof, characterized by; is any one of the following:

2. a pharmaceutical composition comprising a therapeutically effective amount of one or more pyrroloquinoline quinone derivatives, or pharmaceutically acceptable salts thereof, as claimed in claim 1, together with a pharmaceutically acceptable carrier or adjuvant.

3. A process for the preparation of pyrroloquinoline quinone derivatives or pharmaceutically acceptable salts thereof according to claim 1, wherein: the synthetic route is as follows:

wherein R is ¹ Selected from: a methyl group;

R ² selected from: methyl group,

(1) Alkylation reaction is carried out on PQQ to obtain a compound II; the alkylating agent used is R ¹ Y, wherein Y is chloro, bromo, iodo, p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate;

(3) The compound III is subjected to an acylation reaction to obtain a compound I; the acylating agent is acid, ester, acyl chloride or anhydride;

4. A process for the preparation of pyrroloquinoline quinone derivatives or pharmaceutically acceptable salts thereof according to claim 3, wherein: the solvent used in step (1): acetonitrile, tetrahydrofuran, acetone, 2-butanone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, waterOr a mixed solvent optionally composed of these solvents; the alkylating agent used is R ¹ V, wherein Y is chloro, bromo, iodo, p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate; the reaction temperature is 0 ℃ to 180 ℃.

5. A process for the preparation of pyrroloquinoline quinone derivatives or pharmaceutically acceptable salts thereof according to claim 3, wherein: the solvent used in step (2): dichloromethane, ethyl acetate, chloroform, acetonitrile, tetrahydrofuran, acetone, 2-butanone, methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, water, 10% aqueous ammonium chloride solution, 30% aqueous ammonium chloride solution, or a mixed solvent optionally composed of these solvents; the reducing agent used: lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, zinc powder, iron powder, sodium thiosulfate, sodium pyrosulfate, sodium sulfite, sodium bisulfite, sodium dithionite, or a mixed reagent optionally composed of these agents; the reaction temperature is-20 ℃ to 100 ℃.

6. A process for the preparation of pyrroloquinoline quinone derivatives or pharmaceutically acceptable salts thereof according to claim 3, wherein: the solvent used in step (3): dichloromethane, ethyl acetate, chloroform, acetonitrile, tetrahydrofuran, acetone, 2-butanone, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, water or a mixed solvent optionally composed of these solvents; the acylating agent is acid, ester, acyl chloride or anhydride; the reaction temperature is-20 ℃ to 100 ℃.

7. Use of a pyrroloquinoline quinone derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of anti-inflammatory and anti-metabolic diseases.