CN113861111B

CN113861111B - N-aryl-4-sulfur (selenium) ethyl multi-membered ring [ C ] -1-pyridone derivative and synthetic method and application thereof

Info

Publication number: CN113861111B
Application number: CN202111390916.9A
Authority: CN
Inventors: 陈万里; 杨真; 朱英红
Original assignee: Zhejiang University of Technology ZJUT
Current assignee: Zhejiang University of Technology ZJUT
Priority date: 2021-11-23
Filing date: 2021-11-23
Publication date: 2023-05-26
Anticipated expiration: 2041-11-23
Also published as: CN113861111A

Abstract

The invention discloses an N-aryl-4-sulfur (selenium) ethyl multi-membered ring [ C ] -1-pyridone derivative, a synthesis method and application thereof. The invention provides a novel compound with anti-fibrosis bioactivity, namely an N-aryl-4-sulfur (selenium) ethyl multi-ring-o [ C ] -1-pyridone derivative, which has the advantages of novel structure, simple and easy synthesis operation, mild reaction conditions and good compatibility for various substituents. And the compounds have better anti-fibrosis biological activity than pirfenidone.

Description

N-aryl-4-sulfur (selenium) ethyl multi-membered ring [ C ] -1-pyridone derivative and synthetic method and application thereof

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to an N-aryl-4-sulfur (selenium) ethyl multi-membered ring [ C ] -1-pyridone derivative, and a synthesis method and application thereof.

Background

Idiopathic pulmonary fibrosis (Idiopathic Pulmonary Fibrosis, IPF) is a progressive chronic disease with a causative agent, an unknown pathogenesis, and interstitial pneumonia as a major pathological change. Extensive fibrosis stiffens lung tissue, has reduced compliance, is heterogeneous in clinical manifestations and disease progression, is primarily manifested by chronic progressive ventilation dysfunction and varying degrees of hypoxia, late complications manifest as respiratory failure and pulmonary heart disease, and there is currently no means of complete cure, organ transplantation being the sole choice for many end-stage fibrotic diseases. The disease has various inducing factors, complex pathogenesis and undefined action targets, so that the development work of the anti-fibrosis drugs is very slow. At present, only two medicines, namely pirfenidone and nidazole, are marketed for treating mild to moderate fibrosis diseases, and the treatment effect is only to delay the disease process and reduce the risk of acute exacerbation.

Of these, pirfenidone (5-methyl-1-phenyl-2- [1H ] -pyridone) is the first oral small molecule drug marketed worldwide for the treatment of fibrotic diseases. Developed by Marnac, inc. in the United states, the product has a broad spectrum of anti-fibrosis effects and is currently marketed in Japan and Europe as a drug for treating pulmonary fibrosis. However, although pirfenidone has clinically shown anti-inflammatory, antioxidant and anti-fibrotic effects, it has drawbacks of lower efficacy, too fast metabolic rate, high dosage and great side effects. Therefore, pirfenidone is still not an ideal anti-fibrotic drug.

At present, the treatment of fibrosis diseases is considered as one of the main medical challenges nowadays, and the characteristics of high morbidity and low survival rate make the clinical development of novel anti-fibrosis drugs with lower toxicity, better activity and stronger drug effect particularly significant. Therefore, there is still a need for further structural optimization of pirfenidone (CN 105998018A, CN 105998016) or for new design of novel anti-fibrosis drugs with high efficiency and low toxicity.

Disclosure of Invention

The invention aims to provide a novel compound N-aryl-4-sulfur (selenium) ethyl multi-ring-o [ C ] -1-pyridone derivative with anti-fibrosis biological activity and a synthesis method thereof. The invention synthesizes N-aryl-4-sulfur (selenium) ethyl multi-ring [ C ] -1-pyridone derivative by brand new design, namely, N-aryl-4-bromoethyl multi-ring [ C ] -1-pyridone is taken as a substrate to react with diphenyl disulfide or diphenyl diselenide compound to finally obtain the target product, and the compound has better anti-fibrosis biological activity than similar compounds.

In order to solve the problems, the invention adopts the following technical scheme:

an N-aryl-4-thio (seleno) ethyl multi-membered cyclo [ C ] -1-pyridone derivative represented by general formula (III):

wherein, the ring A is a five-membered ring or a six-membered ring or a seven-membered ring; r is R ¹ Y is thioether or selenoether structure, R ¹ Is phenyl or substituted phenyl, Y is thio or seleno; r is R ² Is one of hydrogen, methoxy, trifluoromethyl, chlorine or methyl.

The N-aryl-4-sulfur (selenium) ethyl multi-membered ring [ C ] -1-pyridone derivative shown in the general formula (III) is prepared by the following synthesis method:

(1) A compound represented by formula (I) and PBr ₃ Reacting in a first organic solvent at room temperature to convert into a compound shown as a formula (II); the reaction time is preferably 3-5 hours; the first organic solvent is at least one of dichloromethane and diethyl ether, and preferably a mixture of dichloromethane and diethyl ether is used as the first organic solvent;

(2) Under an inert atmosphere, preferably under a nitrogen atmosphere, a compound represented by the formula (II) and (R) ¹ Y) ₂ Reacting sodium borohydride in a second organic solvent at room temperature to obtain a target compound shown as a formula (III); the reaction time is preferably 5-10 hours; the second organic solvent is any one of ethanol, methanol, tetrahydrofuran or a mixture of methanol and tetrahydrofuran, and ethanol is preferably used as the second organic solvent.

The target compound represented by the formula (III) can be obtained by purification by: after the reaction in the step (2) is finished, the reaction solution is concentrated by rotary evaporation, and water and CH are added ₂ Cl ₂ Extracting for multiple times, washing with saturated saline (30 ml), drying with anhydrous magnesium sulfate, and performing silica gel column chromatography with the following developing agent: and V (petroleum ether) to V (ethyl acetate) =3:1, collecting eluent containing the target compound, spin-evaporating to remove the solvent, and drying to obtain the target compound shown in the product (III).

The invention takes anti-fibrosis drug pirfenidone as a lead compound, and on the basis of keeping pyridone parent nucleus, five-membered ring or six-membered ring or seven-membered ring is incorporated on 5 and 6 positions of pyridone, and different polysubstituted arylthio and selenoethyl structures are introduced on 4 positions, and N-phenyl is substituted to obtain a series of N-aryl-4-thio (selen) ethyl multi-membered cyclo [ C ] -1-pyridone derivatives.

Preferably, ring a is a benzene ring.

Preferably, R ¹ Is para-chloro substituted phenyl or ortho-nitro substituted phenyl.

Preferably, R ² Is para-substituted methoxy; or para-substituted trifluoromethyl; or ortho-or meta-or para-substituted chlorine; or ortho-or meta-substituted methyl.

For example, in a preferred embodiment of the invention, ring A is a six-membered ring, R ¹ Is phenyl, R ² Is ortho-position or meta-position or para-position substituted chlorine. In a preferred embodiment of the invention, ring A is a five-membered ring, R ¹ Is phenyl, R ² Is ortho-substituted methyl. In a preferred embodiment of the invention, ring A is a six-membered ring, R ¹ Is phenyl, R ² Is para-substituted trifluoromethyl or para-substituted methoxy. In a preferred embodiment of the invention, ring A is a six-membered ring, R ¹ R is para-chloro substituted phenyl ² Is para-substituted chlorine. In a preferred embodiment of the invention, ring A is a benzene ring, R ¹ R is para-chloro substituted phenyl ² Is hydrogen. In a preferred embodiment of the invention, ring A is a six-membered ring, R ¹ R is para-chloro substituted phenyl ² Is para-substituted methoxy. In a preferred embodiment of the invention, ring A is a six-membered ring, R ¹ Is ortho-nitro substituted phenyl, R ² Is para-substituted methoxy.

The invention determines N-aryl-4-sulfur (selenium) ethyl multi-membered ring-o [ C ] by MTT method]IC of-1-pyridone derivative ₅₀ The values, the pirfenidone is used as a positive control, and the results show that the compounds have better anti-fibrosis biological activity than the pirfenidone, and have application prospects in preparing anti-fibrosis medicines.

In particular, when ring A is a benzene ring, R ¹ Is phenyl, R ² In the case of hydrogen, the N-aryl-4-thio (seleno) ethyl polycyclo [ C]The anti-fibrotic activity of the 1-pyridone derivative is 76 times that of pirfenidone.

In addition, when ring A is a six-membered ring, R ¹ R is para-chloro substituted phenyl ² In the case of para-position substitution of chlorine, the N-aryl-4-thio (seleno) ethyl multi-membered ring-o [ C]The anti-fibrotic activity of the 1-pyridone derivative is 66 times that of pirfenidone.

Compared with the technology, the invention has the technical effects that:

the invention provides a novel compound with anti-fibrosis bioactivity, namely an N-aryl-4-sulfur (selenium) ethyl multi-ring-o [ C ] -1-pyridone derivative, which has the advantages of novel structure, simple and easy synthesis operation, mild reaction conditions and good compatibility for various substituents. And the compounds have better anti-fibrosis biological activity than pirfenidone.

It will be appreciated by those skilled in the art that the objects and advantages that can be achieved with the present invention are not limited to the above-described specific ones, and that the above and other objects that can be achieved with the present invention will be more clearly understood from the following detailed description.

Drawings

FIG. 1 is a schematic illustration of an N-aryl-4-thio (seleno) ethyl polycyclo [ C ] polymer prepared in accordance with example 1 of the present invention]-1-pyridone derivative A ₁ A kind of electronic device ¹ H spectrogram;

FIG. 2 is a schematic illustration of an N-aryl-4-thio (seleno) ethyl polycyclo [ C ] polymer prepared in accordance with example 1 of the present invention]-1-pyridone derivative A ₁ A kind of electronic device ¹³ C, spectrogram;

FIG. 3 is a N-aryl-4-thio (seleno) ethyl-polycyclo [ C ] produced in example 3 of the invention]-1-pyridone derivative A ₃ A kind of electronic device ¹ H spectrogram;

FIG. 4 is a schematic illustration of an N-aryl-4-thio (seleno) ethyl polycyclo [ C ] polymer prepared in accordance with example 3 of the present invention]-1-pyridone derivative A ₃ A kind of electronic device ¹³ C, spectrogram;

FIG. 5 is a N-aryl-4-thio (seleno) ethyl-polycyclo [ C ] produced in example 11 of the invention]-1-pyridone derivative A ₁₁ A kind of electronic device ¹ H spectrogram;

FIG. 6 is a N-aryl-4-thio (seleno) ethyl polycycloo [ C ] produced in example 11 of the invention]-1-pyridone derivative A ₁₁ A kind of electronic device ¹³ C, spectrogram;

FIG. 7 is a N-aryl-4-thio (seleno) ethyl polycycloo [ C ] produced in example 23 of the invention]-1-pyridone derivative A ₂₃ A kind of electronic device ¹ H spectrogram;

FIG. 8 is a N-aryl-4-thio (seleno) ethyl polycycloo [ C ] produced in example 23 of the invention]-1-pyridone derivative A ₂₃ A kind of electronic device ¹³ C, spectrogram;

FIG. 9 is a N-aryl-4-thio (seleno) ethyl polycycloo [ C ] produced in example 25 of the invention]-1-pyridone derivative A ₂₅ A kind of electronic device ¹ H spectrogram;

FIG. 10 is a schematic illustration of an N-aryl-4-thio (seleno) ethyl polycyclo [ C ] polymer prepared in example 25 of the invention]-1-pyridone derivative A ₂₅ A kind of electronic device ¹³ C, spectrogram;

FIG. 11 shows the general structural formula of N-aryl-4-thio (seleno) ethyl multi-membered cyclo [ C ] -1-pyridone derivative prepared by the example of the present invention.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

Example 1

2-o-chlorophenyl-4- (2-hydroxyethyl) -5,6,7, 8-tetrahydrocycio [ C ] was added to a 25ml single neck round bottom flask]Pyridin-1 (2H) -one (1.52 g,5 mmol), (V (CH) ₂ Cl) : V(Et ₂ O) =1:1, 8 ml), dropwise addition of PBr in dichloromethane (2 ml) ₃ (1.5 eqiv,7.5 mmol) stirring at room temperature. After TLC monitoring the reaction, slowly pouring the mixture into 20 ml ice water to quench the reaction, regulating the reaction to be alkalescent by sodium hydroxide solution, extracting the mixture for multiple times by methylene dichloride, washing the mixture by saturated saline water and anhydrous Mg ₂ SO ₄ Drying, concentrating, and performing silica gel column chromatography with the developing agent: v (petroleum ether): V (ethyl acetate) =4:1, to give substrate a as a yellow solid in 80% yield.

N ₂ In a 25ml double round bottom flask under atmosphere, the compound diphenyl disulfide (1.1 eqiv,0.33 mmol), absolute ethanol (5 ml) and sodium borohydride were added(1.3 eqiv,0.39 mmol) stirring at room temperature followed by addition of substrate a (0.3 mmol) in absolute ethanol (3 ml). After TLC monitoring the reaction, removing the solvent by rotary evaporation, adding water and dichloromethane for extraction, washing with saturated saline solution and anhydrous Mg ₂ SO ₄ Drying, concentrating, and performing silica gel column chromatography with the developing agent: v (Petroleum ether): V (ethyl acetate) =3:1, to give yellow solid A ₁ The yield was 80%. Physical Properties of the product, ¹ H spectrum, ¹³ The C spectrum and high resolution data are as follows:

(A ₁ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.56-7.53 (m, 1H), 7.39-7.32 (m, 5H), 7.29 (t, J＝7.32 Hz, 2H), 7.22-7.18 (m, 1H), 6.84 (s, 1H), 3.08 (t, J＝7.68 Hz, 2H), 2.71 (td, J ₁ ＝7.30 Hz, J ₂ ＝2.30 Hz, 2H), 2.61-2.59 (m, 2H), 2.54-2.52 (m, 2H), 1.78-1.74 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.08, 147.08, 138.79, 135.88, 131.86, 131.71, 130.43, 129.89, 129.72, 129.48, 129.00, 128.76, 127.72, 126.36, 116.95, 34.00, 29.33, 26.46, 24.09, 21.92, 21.72; HRMS (ESI+) calculated for C ₂₃ H ₂₂ ClNOS [M + H] ⁺ 396.1183, found 396.1180.

example 2

Experimental procedures see example 1. Obtaining pale yellow solid A ₂ The yield was 95%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₂ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.42-7.40 (m, 3H), 7.37-7.33 (m, 2H), 7.31-7.27 (m, 3H), 7.20 (t, J = 7.16 Hz, 1H), 6.95 (s, 1H), 3.09 (t, J = 7.30 Hz, 2H), 2.70 (t, J = 7.30 Hz, 2H), 2.58-2.56 (m, 2H), 2.52-2.50 (m, 2H), 1.78-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.19, 146.88, 142.18, 135.76, 134.60, 131.59, 130.02, 129.66, 128.99, 128.69, 128.25, 127.13, 126.37, 125.00, 117.14, 33.96, 29.31, 26.39, 24.17, 21.87, 21.73; HRMS (ESI+) calculated for C ₂₃ H ₂₂ ClNOS [M + H] ⁺ 396.1183, found 396.1184.

example 3

Experimental procedures see example 1. Obtaining a pale yellow oily matter A ₃ The yield was 83%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₃ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.43 (d, J = 8.70 Hz, 2H), 7.34-7.27 (m, 6H), 7.22-7.18 (m, 1H), 6.95 (s, 1H), 3.08 (t, J = 7.25 Hz, 2H), 2.70 (t, J = 7.25 Hz, 2H), 2.58-2.57 (m, 2H), 2.52-2.49 (m, 2H), 1.77-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.24, 148.80, 139.65, 135.74, 133.74, 131.68, 129.60, 129.18, 128.96, 128.59, 127.96, 126.33, 117.07, 33.94, 29.25, 26.35, 24.16, 21.84, 21.71; HRMS (ESI+) calculated for C ₂₃ H ₂₂ ClNOS [M + H] ⁺ 396.1183, found 396.1180.

example 4

Experimental procedures see example 1. Obtaining a pale yellow oily matter A ₄ Yield 78%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₄ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.37-7.27 (m, 5H), 7.21-7.14 (m, 4H), 6.99 (s, 1H), 3.08 (t, J = 7.36 Hz, 2H), 2.70 (t, J = 7.36 Hz, 2H), 2.60-2.58 (m, 2H), 2.53-2.50 (m, 2H), 2.41 (s, 3H), 1.78-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.47, 146.49, 141.22, 139.08, 135.87, 132.23, 129.65, 128.95, 128.91, 128.79, 128.49, 127.31, 126.30, 123.59, 116.70, 34.06, 29.35, 26.36, 24.19, 21.93, 21.81, 21.27; HRMS (ESI+) calculated for C ₂₄ H ₂₅ NOS [M + H] ⁺ 376.1729, found 376.1728.

example 5

Experimental procedures see example 1. A brown oil A is obtained ₅ The yield was 65%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₅ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.35-7.33 (m, 4H), 7.29 (t, J = 7.46 Hz, 3H), 7.20 (t, J = 7.29 Hz, 1H), 7.16 (d, J = 7.37 Hz, 1H), 6.84 (s, 1H), 3.10-3.06 (m, 2H), 2.71-2.69 (m, 2H), 2.62-2.59 (m, 2H), 2.55-2.52 (m, 2H), 2.15 (s, 3H), 1.80-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.24, 146.63, 140.56, 135.90, 135.21, 132.14, 130.93, 129.60, 128.99, 128.68, 128.61, 127.33, 126.90, 126.31, 116.68, 34.04, 29.22, 26.40, 24.15, 21.96, 21.80, 17.76; HRMS (ESI+) calculated for C ₂₄ H ₂₅ NOS [M + H] ⁺ 376.1729, found 376.1732.

example 6

Experimental procedures see example 11. A white oil A was obtained ₆ The yield was 50%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₆ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.36-7.28 (m, 7H), 7.22-7.17 (m, 2H), 6.85 (s, 1H), 3.05-2.98 (m, 3H), 2.91-2.87 (m, 1H), 2.72-2.69 (m, 4H), 2.14 (s, 3H), 1.90-1.88 (m, 2H), 1.68-1.59 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.41, 153.28, 140.90, 135.82, 135.11, 134.25, 133.18, 130.95, 129.86, 129.03, 128.69, 127.25, 126.92, 126.45, 116.26, 34.87, 32.61, 30.87, 29.96, 26.33, 26.25, 26.15, 17.70; HRMS (ESI+) calculated for C ₂₅ H ₂₇ NOS [M + H] ⁺ 390.1886, found 390.1880.

example 7

Experimental procedures see example 1. A brown oil A is obtained ₇ The yield was 82%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₇ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.35-7.32 (m, 4H), 7.30-7.27 (m, 3H), 7.21-7.18 (m, 1H), 7.16 (d, J = 7.47 Hz, 1H), 6.90 (s, 1H), 3.10-3.07 (m, 2H), 2.93-2.84 (m, 4H), 2.70 (t, J = 7.50 Hz, 2H), 2.16 (s, 3H), 2.12 (t, J = 7.50 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 159.78, 154.80, 140.41, 135.81, 135.25, 134.67, 133.07, 130.93, 129.55, 128.97, 128.72, 127.38, 126.88, 126.30, 115.27, 33.90, 32.76, 30.44, 29.95, 23.23, 17.71; HRMS (ESI+) calculated for C ₂₃ H ₂₃ NOS [M + K] ⁺ 390.1886, found 384.1394.

example 8

Experimental procedures see example 1. To give a milky oil A ₈ The yield was 90%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₈ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.73 (d, J = 8.36 Hz, 2H), 7.52 (d, J = 8.36 Hz, 2H), 7.34-7.32 (m, 2H), 7.28 (t, J = 7.55 Hz, 2H), 7.21-7.18 (m, 1H), 6.98 (s, 1H), 3.09 (t, J = 7.29 Hz, 2H), 2.71 (t, J = 7.29 Hz, 2H), 2.59-2.56 (m, 2H), 2.53-2.50 (m, 2H), 1.77-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.05, 147.02, 144.07, 135.70, 131.23, 129.94 (q, J = 32.64 Hz), 129.57, 128.91, 128.67, 127.07, 126.30, 126.13 (q, J = 3.54 Hz),123.70 (q, J = 271.65 Hz), 117.34, 33.86, 29.20, 26.32, 24.11, 21.77, 21.63; HRMS (ESI+) calculated for C ₂₄ H ₂₂ F ₃ NOS [M + Na] ⁺ 452.1266, found 452.1263.

example 9

Experimental procedures see example 1. Obtain white solid A ₉ The yield was 90%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₉ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.35 (d, J = 7.29 Hz, 2H), 7.30-7.27 (m, 4H), 7.20 (t, J = 7.29 Hz, 1H), 6.98 (d, J = 2.82 Hz, 2H), 6.96 (s, 1H), 3.85 (s, 3H), 3.08 (t, J = 7.49 Hz, 2H), 2.70 (t, J = 7.49 Hz, 2H), 2.60-2.57 (m, 2H), 2.52-2.49 (m, 2H), 1.77-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.68, 159.09, 146.43, 135.90, 134.25, 132.49, 129.69, 128.97, 128.44, 127.68, 126.33, 116.65, 114.30, 55.55, 34.11, 29.36, 26.38, 24.25, 21.96, 21.84; HRMS (ESI+) calculated for C ₂₄ H ₂₅ NO ₂ S [M + H] ⁺ 392.1678, found 392.1678.

example 10

Experimental procedures see example 1. Obtain white solid A ₁₀ Yield 78%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₀ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.54 (dd, J ₁ = 8.17 Hz, J ₂ = 0.67 Hz, 1H),7.74-7.70 (m, 1H), 7.60-7.51 (m, 4H), 7.45-7.36 (m, 5H), 7.30-7.27 (m, 2H), 7.21 (t, J = 7.27 Hz, 1H), 7.07 (s, 1H), 3.25 (t, J = 7.50 Hz, 2H), 3.04 (t, J = 7.37 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.59, 141.29, 136.25, 135.78, 132.57, 130.88, 129.80, 129.26, 129.08, 128.98, 128.05, 127.05, 126.84, 126.71, 126.39, 122.40, 114.05, 33.80, 29.74; HRMS (ESI+) calculated for C ₂₃ H ₁₉ NOS [M + Na] ⁺ 380.1079, found 380.1075.

example 11

Experimental procedures see example 1. Obtaining pale yellow solid A ₁₁ The yield was 70%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₁ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.55-7.49 (m, 3H), 7.39-7.37 (m, 2H), 7.34-7.32 (m, 1H), 7.28-7.25 (m, 3H), 6.83 (s, 1H), 3.05 (t, J = 7.60 Hz, 2H), 2.79-2.75 (m, 2H), 2.61-2.58 (m, 2H), 2.50-2.47 (m, 2H), 1.77-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 160.97, 146.98, 138.72, 132.93, 131.77, 131.46, 130.33, 129.81, 129.70, 129.39, 129.06, 128.59, 127.65, 127.08, 117.67, 30.17, 27.40, 26.28, 24.00, 21.83, 21.65; HRMS (ESI+) calculated for C ₂₃ H ₂₂ ClNOSe[M + H] ⁺ 444.0628, found 444.0626.

example 12

Experimental procedures see example 1. Obtaining pale yellow solid A ₁₂ The yield was 73%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₂ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.50-7.48 (m, 2H), 7.42-7.37 (m, 3H), 7.29-7.26 (m, 4H), 6.94 (s, 1H), 3.06 (t, J = 7.60 Hz, 2H), 2.77 (t, J = 7.33 Hz, 2H), 2.58-2.55 (m, 2H), 2.49-2.46 (m, 2H), 1.76-1.74 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.18, 146.87, 142.20, 134.60, 132.94, 131.43, 130.03, 129.67, 129.13, 128.64, 128.25, 127.17, 127.13, 124.99, 117.93, 30.23, 27.58, 26.31, 24.16, 21.86,21.74; HRMS (ESI+) calculated for C ₂₃ H ₂₂ ClNOSe[M + H] ⁺ 444.0628, found 444.0626.

example 13

Experimental procedures see example 1. Yellow oil A was obtained ₁₃ The yield was 74%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₃ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.49-7.43 (m, 2H), 7.43 (d, J = 8.65 Hz, 2H), 7.32 (d, J = 8.64 Hz, 2H), 7.27-7.25 (m, 3H), 6.95 (s, 1H), 3.06 (t, J = 7.55 Hz, 2H), 2.77 (t, J = 7.58 Hz, 2H), 2.57-2.55 (m, 2H), 2.48-2.46 (m, 2H), 1.75-1.73 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.25, 146.81, 139.68, 133.76, 132.93, 131.53, 129.68, 129.21, 129.11, 128.57, 127.97, 127.16, 117.88, 30.20, 27.61, 26.28, 24.17, 21.85, 21.73; HRMS (ESI+) calculated for C ₂₃ H ₂₂ ClNOSe[M + Na] ⁺ 466.0447, found 466.0442.

example 14

Experimental procedures see example 1. Yellow oil A was obtained ₁₄ Yield 61%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₄ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.50-7.48 (m, 2H), 7.33-7.25 (m, 6H), 7.16 (d, J = 7.54 Hz, 1H), 6.86 (s, 1H), 3.05 (t, J = 7.21 Hz, 2H), 2.76 (t, J = 7.62 Hz, 2H), 2.62-2.57 (m, 2H), 2.51-2.49 (m, 2H), 2.15 (s, 3H), 1.78-1.75 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.18, 146.60, 140.52, 135.17, 132.88, 131.91, 130.88, 129.73, 129.08, 128.63, 128.49, 127.27, 127.09, 126.86, 117.48, 30.08, 27.57, 26.26, 24.10, 21.89, 21.75, 17.74; HRMS (ESI+) calculated for C ₂₄ H ₂₅ NOSe[M + H] ⁺ 424.1174, found 424.1182.

example 15

Experimental procedures see example 1. Yellow oil A was obtained ₁₅ The yield was 50%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₅ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.50 (d, J = 3.00 Hz, 2H), 7.32-7.26 (m, 6H), 7.17 (d, J = 7.06 Hz, 1H), 6.84 (s, 1H), 3.02-2.96 (m, 3H), 2.90-2.86 (m, 1H), 2.77 (t, J = 7.23 Hz, 2H), 2.65-2.63 (m, 2H), 2.14(s, 3H), 1.90-1.85 (m, 2H), 1.63-1.56 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.33, 153.23, 140.85, 135.04, 134.15, 133.05, 132.96, 130.88, 129.63, 129.10, 128.63, 127.17, 126.86, 117.04, 32.57, 31.69, 29.84, 28.39, 26.26, 26.20, 26.07, 17.69; HRMS (ESI+) calculated for C ₂₅ H ₂₇ NOSe[M + H] ⁺ 438.1330, found 438.1339.

example 16

Experimental procedures see example 1. A brown oil A is obtained ₁₆ Yield 79%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₆ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.50-7.48 (m, 2H), 7.34-7.26 (m, 6H), 7.16 (d, J = 7.40 Hz, 1H), 6.89 (s, 1H), 3.06 (t, J = 7.11 Hz, 2H), 2.93-2.88 (m, 2H), 2.83 (t, J = 7.39 Hz, 2H), 2.77 (t, J = 7.39 Hz, 2H), 2.16 (s, 3H), 2.11 (quint, J = 7.59 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 159.74, 154.76, 140.41, 135.24, 134.47, 133.03, 132.83, 130.90, 129.69, 129.09, 128.69, 127.36, 127.10, 126.87, 116.04, 32.67, 30.83, 30.40, 27.46, 23.22, 17.72; HRMS (ESI+) calculated for C ₂₃ H ₂₃ NOSe[M + Na] ⁺ 432.0837, found 432.0847.

example 17

Experimental procedures see example 1. Obtaining a pale yellow oily matter A ₁₇ Yield 79%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₇ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.53 (dd, J ₁ = 1.34 Hz, J ₂ = 8.59 Hz, 1H), 7.71-7.68 (m, 1H), 7.55-7.50 (m, 6H), 7.45-7.41 (m, 3H), 7.28-7.25 (m, 3H), 7.06 (s, 1H), 3.22 (t, J = 7.29 Hz, 2H), 3.11 (t, J = 7.51 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.54, 141.24, 136.14, 132.95, 132.49, 130.65, 129.59, 129.22, 129.08, 129.10, 128.98, 128.00, 127.12, 126.97, 126.63, 122.36, 114.80, 30.57, 27.32; HRMS (ESI+) calculated for C ₂₃ H ₁₉ NOSe[M + Na] ⁺ 428.0524, found 428.0525.

example 18

Experimental procedures see example 1. Yellow solid A was obtained ₁₈ Yield 78%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₈ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.50-7.48 (m, 2H), 7.29-7.25 (m, 5H), 6.98-6.96 (m, 3H), 3.85 (s, 3H), 3.05 (t, J = 7.53 Hz, 2H), 2.76 (t, J = 7.48 Hz, 2H), 2.58-2.55 (m, 2H), 2.48-2.45 (m, 2H), 1.75-1.73 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.67, 159.07, 146.44, 134.26, 132.98, 132.34, 129.77, 129.11, 128.38, 127.68, 127.13, 117.47, 114.30, 55.55, 30.27, 27.71, 26.29, 24.23, 21.94, 21.84; HRMS (ESI+) calculated for C ₂₄ H ₂₅ NO ₂ Se[M + Na] ⁺ 462.0942, found 462.0955.

example 19

Experimental procedures see example 1. Yellow oil A was obtained ₁₉ The yield was 80%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₁₉ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.43-7.39 (m, 4H), 7.31(d, J = 8.43 Hz, 2H), 7.21 (t, J = 8.45 Hz, 2H), 6.93 (s, 1H), 3.02 (t, J = 7.50 Hz, 2H), 2.74 (t, J = 7.50 Hz, 2H), 2.57-2.54 (m, 2H), 2.47-2.44 (m, 2H), 1.75-1.72 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.16, 146.63, 139.59, 134.31, 133.72, 133.40, 131.46, 129.20, 129.16, 128.61, 127.89, 127.84, 117.64, 30.04, 27.96, 26.24, 24.12, 21.78, 21.66; HRMS (ESI+) calculated for C ₂₃ H ₂₁ Cl ₂ NOSe[M + Na] ⁺ 500.0058, found 500.0072.

example 20

Experimental procedures see example 1. Yellow solid A was obtained ₂₀ The yield was 67%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₂₀ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.24 (d, J = 8.18 Hz, 1H), 7.50-7.48 (m, 2H), 7.40 (d, J = 8.70 Hz, 2H), 7.34-7.28 (m, 3H), 7.02 (s, 1H), 3.08 (t, J = 7.28 Hz, 2H), 2.83 (t, J = 7.28 Hz, 2H), 2.59-2.55 (m, 4H), 1.79-1.75(m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.31, 147.13, 146.60, 139.58, 133.98, 133.58, 132.57, 131.57, 129.34, 129.13, 129.06, 128.00, 126.53, 125.77, 117.57, 28.34, 26.52, 25.83, 24.26, 21.91, 21.77; HRMS (ESI+) calculated for C ₂₃ H ₂₁ ClN ₂ O ₃ Se[M + Na] ⁺ 511.0298, found 511.0320.

example 21

Experimental procedures see example 1. Obtaining a pale yellow oily matter A ₂₁ The yield was 89%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₂₁ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.54 (d, J = 7.95 Hz, 1H), 7.72-7.68 (m, 1H), 7.56-7.50 (m, 4H), 7.45-7.40 (m, 5H), 7.21 (d, J = 8.50 Hz, 2H),7.05 (s, 1H), 3.20 (t, J = 7.29 Hz, 2H), 3.17 (t, J = 7.47 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.54, 141.27, 136.10, 134.40, 133.44, 132.57, 130.75, 129.30, 129.27, 129.09, 128.08, 127.86, 127.08, 126.81, 126.70, 122.32, 114.62, 30.52, 27.81; HRMS (ESI+) calculated for C ₂₃ H ₁₈ ClNOSe[M + Na] ⁺ 462.0134, found462.0144.

example 22

Experimental procedures see example 1. Yellow oil A was obtained ₂₂ The yield was 75%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₂₂ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.54 (dd, J ₁ = 0.68 Hz, J ₂ = 8.15 Hz, 1H), 8.23 (dd, J ₁ = 1.13 Hz, J ₂ = 8.22 Hz, 1H), 7.77-7.69 (m, 1H), 7.70 (d, J = 7.98 Hz, 1H), 7.56-7.47 (m, 3H), 7.44-7.37 (m, 5H), 7.30-7.26 (m, 1H), 7.05 (s, 1H), 3.25 (t, J = 7.22 Hz, 2H), 3.17 (t, J = 6.96 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.34, 146.78, 141.00, 135.92, 133.42, 132.60, 132.53, 130.68, 129.16, 129.07, 128.96, 127.97, 127.07, 126.66, 126.60, 126.25, 125.52, 122.23, 114.22, 28.54, 25.48; HRMS (ESI+) calculated for C ₂₃ H ₁₈ N ₂ O ₃ Se[M + Na] ⁺ 473.0375, found 473.0392.

example 23

Experimental procedures see example 1. Obtain white solid A ₂₃ The yield was 95%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₂₃ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.41 (d, J = 8.49 Hz, 2H), 7.29-7.22 (m, 4H), 6.98-6.97 (m, 3H), 3.85 (s, 3H), 3.03 (t, J = 7.42 Hz, 2H), 2.74 (t, J = 7.42 Hz, 2H), 2.59-2.56 (m, 2H), 2.48-2.45 (m, 2H), 1.76-1.74 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.66, 159.10, 146.30, 134.42, 134.20, 133.46, 132.33, 129.28, 128.51, 127.95, 127.65, 117.25, 114.33, 55.55, 30.18, 28.12, 26.31, 24.23, 21.92, 21.82; HRMS (ESI+) calculated for C ₂₄ H ₂₄ ClNO ₂ Se [M + Na] ⁺ 496.0553, found 496.0566.

example 24

Experimental procedures see example 1. Yellow solid A was obtained ₂₄ The yield was 87%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₂₄ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.29 (d, J = 8.27 Hz, 1H), 7.53-7.49 (m, 2H), 7.35-7.25 (m, 3H), 7.05 (s, 1H), 6.97 (d, J = 8.83 Hz, 2H), 3.84 (s, 3H), 3.09 (t, J = 7.33 Hz, 2H), 2.85 (t, J = 7.33 Hz, 2H), 2.62-2.59 (m, 4H), 1.82-1.77 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 161.67, 159.15, 147.04, 146.17, 134.11, 133.56, 132.73, 132.33, 129.10, 128.78, 127.66, 126.50, 125.68, 117.06, 114.37, 55.56, 28.35, 26.48, 25.89, 24.28, 21.96, 21.83; HRMS (ESI+) calculated for C ₂₄ H ₂₄ N ₂ O ₄ Se[M + Na] ⁺ 507.0793, found 507.0805.

example 25

Experimental procedures see example 1. Yellow oil A was obtained ₂₅ The yield was 73%. The product is ¹ H、 ¹³ The C spectrum, and high resolution data are as follows:

(A ₂₅ ) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.54-7.52 (m, 1H), 7.42 (d, J = 8.29 Hz, 2H), 7.39-7.31 (m, 3H), 7.22 (d, J = 8.29 Hz, 2H), 6.82 (s, 1H), 3.02 (t, J = 7.60 Hz, 2H), 2.75 (t, J = 7.60 Hz, 2H), 2.61-2.58 (m, 2H), 2.49-2.47 (m, 2H), 1.77-1.74 (m, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 160.97, 146.90, 138.68, 134.36, 133.38, 131.75, 131.48, 130.35, 129.85, 129.37, 129.21, 128.71, 127.90, 127.67, 117.48, 30.08, 27.79, 26.31, 24.01, 21.81, 21.63; HRMS (ESI+) calculated for C ₂₃ H ₂₁ Cl ₂ NOSe [M + Na] ⁺ 500.0057, found 500.0064.

the substrate, the obtained product and the yield of the product in the reactions of examples 1 to 25 are shown in the following table.

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For the N-aryl-4-thio (seleno) ethyl multi-membered ring [ C ] prepared in the above example]-1-pyridone derivatives were assayed for anti-fibrotic bioactivity as follows: selecting embryo fibroblast NIH3T3 of mouse as research object, taking pirfenidone as positive control, and adopting MTT method to examine synthetic N-aryl-4-sulfur (selenium) ethyl multi-ring-o [ C ]]Intensity of inhibition of NIH3T3 cell proliferation by 1-pyridone derivatives by IC ₅₀ The values can be compared for differences in biological activity between the series of compounds.

The anti-fibrosis bioactivity assay examples of the present invention are as follows:

using MTT colorimetric method, using DMEM medium containing 10% foetal calf serum for mouse embryo fibroblast, and containing 5% CO at 37deg.C ₂ And (5) culturing the humidified cells in a culture box. NIH3T3 cells were seeded in 96-well plates, 10000 cells per well, and culture was continued for 12 h. After the cells are attached, the cells are changed into N-aryl-4-sulfur (selenium) ethyl multi-membered ring with different concentrationsC]-medium of 1-pyridone derivative and pirfenidone containing 10% fetal bovine serum, 5 multiplex wells were set per concentration. After 48 hours of incubation, 10% MTT solution (20, uL) was added to each well, after 4 hours, MTT was aspirated, and MTT solution DMSO (100, uL) was added to each well until complete dissolution of MTT. 15 After min, OD values were determined at 570nm using an enzyme-labeled instrument, and data were processed with GraphPadprism 8.0 to give pirfenidone and N-aryl-4-thio (selenium) ethyl-polycyclo [ C ]]IC of-1-pyridone derivative ₅₀ Values. The results obtained are given in the following table:

from the above table, it can be concluded that the N-aryl-4-thio (seleno) ethyl-multi-cyclic-o [ C ] -1-pyridone derivatives prepared according to the examples of the present invention have anti-fibrotic life activity:

(1) The activity of the vast majority of the compounds in the series is superior to that of the positive control pirfenidone, which indicates that the series of compounds are helpful for improving the anti-fibrosis biological activity.

(2) In general, when ring A is a benzene ring, the compound activity is optimal, wherein compound A ₁₀ Is 76 times more active than pirfenidone; the activity of the compound with the ring A being a six-membered ring is better than that of a five-membered ring and a seven-membered ring, and the seven-membered ring is slightly better than the five-membered ring.

(3) The compound R ² Has a certain promotion effect on biological activity, and has a certain promotion effect on R ² As can be seen from the comparison of the activity of the chlorine substituents in ortho-or meta-or para-position, the meta-chlorine substituents are better than the ortho-and para-positions, wherein the compound A ₂ 、A ₁₂ Is 16 and 25 times more active than pirfenidone, respectively.

(4) In the ether-containing compound, R ¹ Y is thioether or selenoether structure, when R ¹ When the compound is p-chlorophenyl seleno, the activity of the compound is better than that of other polysubstituted phenylseleno. Wherein Compound A ₁₉ Is 66 times more active than pirfenidone.

The present invention is not limited to the above-described specific embodiments, and various modifications and variations are possible. Any modification, equivalent replacement, improvement, etc. of the above embodiments according to the technical substance of the present invention should be included in the protection scope of the present invention.

Claims

An n-aryl-4-thio (seleno) ethyl-multi-membered-cyclo [ C ] -1-pyridone derivative, characterized by the following general formula (iii):

wherein ring A is a benzene ring; YR (Yttrium barium titanate) ¹ Is thioether or selenoether structure, R ¹ Phenyl, p-chloro substituted phenyl or o-nitro substituted phenyl, Y is S or Se; r is R ² Is one of hydrogen, methoxy, trifluoromethyl, chlorine or methyl.
2. An N-aryl-4-thio (seleno) ethyl multi-membered ring o [ C ] according to claim 1]-1-pyridone derivatives, characterized in that R ² Is para-substituted methoxy.
3. An N-aryl-4-thio (seleno) ethyl multi-membered ring o [ C ] according to claim 1]-1-pyridone derivatives, characterized in that R ² Is a para-substituted trifluoromethyl group.
4. An N-aryl-4-thio (seleno) ethyl multi-membered ring o [ C ] according to claim 1]-1-pyridone derivatives, characterized in that R ² Is ortho-or meta-or para-substituted chlorine.
5. An N-aryl-4-thio (seleno) ethyl multi-membered ring o [ C ] according to claim 1]-1-pyridone derivatives, characterized in that R ² Methyl substituted in ortho or meta position.
6. The method for synthesizing an N-aryl-4-thio (seleno) ethyl multi-membered cyclo [ C ] -1-pyridone derivative according to any one of claims 1 to 5, comprising the steps of:

(1) A compound represented by formula (I) and PBr ₃ Reacting in a first organic solvent at room temperature to convert into a compound shown as a formula (II); the first organic solvent is at least one of dichloromethane and diethyl ether;

(2) Under inert atmosphere, the compound shown as the formula (II) and (R) ¹ Y) ₂ Reacting sodium borohydride in a second organic solvent at room temperature to obtain a target compound shown as a formula (III); the second organic solvent is any one of ethanol, methanol, tetrahydrofuran or a mixture of methanol and tetrahydrofuran;

wherein ring A is a benzene ring; YR (Yttrium barium titanate) ¹ Is thioether or selenoether structure, R ¹ Phenyl, p-chloro substituted phenyl or o-nitro substituted phenyl, Y is S or Se; r is R ² Is one of hydrogen, methoxy, trifluoromethyl, chlorine or methyl.
7. The N-aryl-4-thio (seleno) ethyl multi-membered ring of claim 6 [ C]A process for synthesizing a 1-pyridone derivative, wherein ring A is a benzene ring, R ¹ Is phenyl, R ² Is hydrogen.
8. The use of an N-aryl-4-thio (seleno) ethyl multi-membered cyclo [ C ] -1-pyridone derivative as claimed in any one of claims 1 to 5 for the preparation of an anti-fibrotic medicament.