CN117143040A - A kind of cyclobutenedionyl benzoxazole derivative and its preparation method and application - Google Patents

Abstract

The invention provides a cyclobutenedione benzoxazole derivative, a preparation method and application thereof, and particularly relates to a cyclobutenedione benzoxazole derivative with a structure shown in a formula (I). Experimental results show that the cyclobutenedione benzoxazole derivative provided by the invention has better P2Y ₁₄ Receptor antagonistic activity as a P2Y inhibitor ₁₄ Therapeutic agents for receptor-related diseases.

Description

A kind of cyclobutenedionyl benzoxazole derivative and its preparation method and application

Technical field

The present invention relates to the technical field of medicinal chemistry, and in particular to a preparation method and application of a cyclobutenedionyl benzoxazole derivative.

Background technique

P2Y ₁₄ receptor (P2Y ₁₄ R) is a member of the P2Y receptor. When P2Y ₁₄ R is stimulated, it can promote the release of mediators from mast cells and inflammation of renal leap cells, and increase the hypersensitivity and neutralization of microglia. The motility of neutrophils; and can inhibit the release of metalloproteinases and tumor necrosis factors from astrocytes. P2Y ₁₄ receptor antagonists have good innovation and application prospects in the field of drug development for liver fibrosis, arthritis, acute kidney injury, neural pain and other related diseases. P2Y ₁₄ R activation is closely related to intracellular cAMP content, and cAMP can prevent the activation of NLRP3 inflammasome. Therefore, P2Y ₁₄ R may regulate the inflammatory response through NLRP3 inflammasome. In chronic liver diseases, fibrosis is a major prognostic factor, but effective anti-fibrotic treatments are lacking. The latest research [1] shows that the activation of ERK induced by P2Y ₁₄ is the main reason for the pro-fibrotic effect of HSCs (44).

Benzoxazole is an important pharmacophore in modern drug discovery. A large number of benzoxazole compounds have been successfully developed. The inventor's research group has only disclosed benzoxazole derivatives with multiple structures and used them in P2Y ₁₄ receptors. Anti-caking agents, the inhibitory effects of these compounds need to be further improved. Moreover, the poor solubility of existing compounds in aqueous solutions limits their clinical application.

Contents of the invention

In view of this, the present invention discloses a cyclobutenedionyl benzoxazole derivative and its preparation method and application. The prepared cyclobutenedionyl benzoxazole derivative has good antagonism to P2Y ₁₄ Receptor activity and activity in treating liver fibrosis and other related diseases. Cyclobutenedione benzoxazole is an important pharmacophore in drugs. Utilizing the principle of activity superposition, after introducing the cyclobutenedione benzoxazole group into many small molecule drugs, its activity is greatly improved. improvement, and has low toxicity, high bioavailability, good biocompatibility and efficacy. Cyclobutenedionyl benzoxazoles have a wide range of biological activities.

The present invention adopts the following technical solutions:

A cyclobutenedionyl benzoxazole derivative having a structure shown in formula (I): Wherein, R is a ring, preferably an alicyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic ring or a substituted heterocyclic ring; further preferably, the R is an aliphatic ring, a benzene ring, a substituted benzene ring or a heterocyclic ring, such as 5 to 6 membered Heterocycle; more preferably, R is cyclopropane, cyclobutane, cyclohexane, cyclopentane, benzene ring and substituted benzene ring. In substituted aromatic rings and substituted heterocyclic rings, the substituents are independently selected from one or more of alkyl, alkoxy, haloalkyl, and haloalkoxy. The preferred substituents are independently selected from methyl, ethyl, One or more of methoxy group, fluorine atom, chlorine atom, trifluoromethyl group and trifluoromethoxy group. Preferably, R is a substituted benzene ring, and the compound has good P2Y14 receptor antagonist activity.

In some specific embodiments of the invention, the cyclobutenedionyl benzoxazole derivative has any of the following structures:

Formula (HDB-1)/> Formula (HDB-2)

Formula (HDB-3)/> Formula (HDB-4)

Formula (HDB-5)/> Formula (HDB-6)

Formula (HDB-7)/> Formula (HDB-8)

Formula (HDB-9)/> Formula (HDB-10)

Formula (HDB-11)/> Formula (HDB-12)

Formula (HDB-13)/> Formula (HDB-14)

Type (HDB-15)/> Formula (HDB-16)

Formula (HDB-17).

The invention provides a method for preparing the above-mentioned cyclobutenedionyl benzoxazole derivatives, which includes the following steps: preparing 3-(benzo[d]oxazole-6-ylamino)-4-methoxycyclobutane -3-ene-1,2-dione reacts with RNH ₂ to obtain the cyclobutenedionyl benzoxazole derivative. Preferably, the reaction temperature is room temperature to 100°C, and the reaction time is 5 to 60 minutes; further preferably, the reaction temperature is 50 to 70°C, and the reaction time is 15 to 30 minutes.

The reaction equation of the above preparation method is as follows:

The ranges of R ₁ and R ₂ are the same as above and will not be repeated here.

The invention discloses the application of the above-mentioned cyclobutenedionyl benzoxazole derivatives or pharmaceutically acceptable salts thereof in preparing drugs for treating P2Y ₁₄ receptor-related diseases, such as liver fibrosis and other related diseases.

The present invention discloses the use of the above-mentioned cyclobutenedionyl benzoxazole derivatives or pharmaceutically acceptable salts thereof in the preparation of P2Y ₁₄ receptor anticaking agents or in the preparation of anti-inflammatory drugs.

The invention discloses a drug for treating P2Y ₁₄ receptor-related diseases, which uses the above-mentioned cyclobutenedionyl benzoxazole derivative or its pharmaceutically acceptable salt as an active ingredient. It further includes auxiliary materials; the auxiliary materials may be pharmaceutically acceptable auxiliary materials.

The above-mentioned treatment of liver fibrosis provided by the present invention can also be used in combination with other drugs for treating related diseases.

Compared with the prior art, the present invention provides cyclobutenedionyl benzoxazole derivatives. Experimental results show that the cyclobutenedionedionyl benzoxazole derivatives provided by the invention have better therapeutic effect on P2Y. ₁₄ receptor-related diseases such as liver fibrosis.

Description of the drawings

Figure 1 shows the relative inhibition rate of P2Y ₁₄ receptor.

Figure 2 shows serum ALT and AST levels.

Figure 3 shows the results of HE staining and Masson staining.

Detailed ways

In order to further illustrate the present invention, the cyclobutenedionyl benzoxazole derivatives provided by the present invention and their preparation methods and applications are described in detail below in conjunction with the examples. The raw materials used in the present invention are commercially available products, and the specific preparation operations and performance tests are conventional techniques.

Synthesis example

Dissolve 1.34g (10 mmol) benzo[d]oxazole-6-amine in methanol, and add 1.42g (10 mmol) 3,4-dimethoxycyclobutane-3-en-1,2- dione, and the mixture was stirred at 65 °C for 24 h. When the reaction was complete, the crude product was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spun down under reduced pressure. The product was purified by silica gel column chromatography, eluting with dichloromethane:methanol (50:1), to give 1.95 g of 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut- 3-ene-1,2-dione.

Example 1

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(p-toluidine)cyclobut-3-ene-1,2-dione: Dissolve 0.642g (6 mmol) p-toluidine In methanol, add 0.732g (3 mmol) 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione, and mix the mixture Stir at 65°C for 24 hours. When the reaction was complete, the crude product was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spun down under reduced pressure. The product was purified by silica gel column chromatography, eluting with dichloromethane:methanol (100:1) to give 3-(benzo[d]oxazole-6-amino)-4-(p-toluylamino)cyclobutan-3 -ene-1,2-dione.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 7.65 – 7.55 (m,2H), 7.19 – 7.11 (m, 2H), 6.95 – 6.85 (m, 3H) , 2.32 (d, J = 1.3 Hz, 3H); ¹³ CNMR (101 MHz, DMSO-d6) δ 183.43, 158.24, 148.33, 143.51, 143.14, 139.51,139.28, 137.54, 130.10, 126.9 7, 126.50, 124.83, 119.88, 117.66, 115.83, 105.06, 17.90.

Example 2

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(phenylamino)cyclobut-3-en-1,2-one: 6 mmol aniline, 3 mmol 3-(benzo[ d] Oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione is used as the raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 2H), 8.66 (s, 1H), 8.47 (s, 2H), 8.03 (d, J = 2.1 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.29 (dd, J= 8.6, 2.2 Hz, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 183.00, 181.54, 169.41,164.34, 154.33, 150.61 , 137.72, 135.48, 120.97, 116.05, 101.17, 53.99, 50.55,22.78.

Example 3

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(cyclobutylamino)cyclobut-3-ene-1,2-dione: 6 mmol cyclobutylamine, 3 mmol 3 -(benzo[d]oxazole-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione is used as the raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.66 (s, 1H), 8.00 (s, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.30 (dd, J = 8.6, 2.2 Hz, 1H), 4.55 (q, J = 8.3 Hz, 1H), 2.37 – 2.27 (m, 2H), 2.07 (td, J = 9.5, 2.7 Hz, 2H), 1.75 – 1.61 (m, 2H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 180.88, 168.71, 163.59,154.28, 150.62, 137.83, 135.43, 120.92, 116.13, 101.21, 49.27, 32.09, 14.45.

Example 4

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(bicyclo[1.1.1]pentane-1-amino)cyclobut-3-ene-1,2-dione: based on 6 mmol bicyclo[1.1.1]-1-pentylamine hydrochloride, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2 -Diketone is the raw material, and the synthesis method is shown in Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.76 (d, J ¹³ C NMR (101 MHz) ,DMSO-d ₆ ) δ 182.85, 167.08, 165.90, 154.45, 150.48, 137.41, 136.55, 135.85,130.92, 129.10, 126.90, 125.19, 122.78, 120.88, 116.72, 101.99, 18.27.

Example 5

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(o-tolylamino)cyclobut-3-ene-1,2-dione: 6 mmol o-methylaniline, 3 mmol 3- (Benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione is used as the raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 9.95 (s, 1H), 8.69 (s, 1H), 8.04 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 39.7 Hz,5H), 7.09 (s, 1H), 2.50 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 182.23, 182.13, 166.31, 165.82, 154.54, 150.51, 138.92, 137.30, 135.92, 129.86, 123.88,120.98, 119.06, 116.59, 101.83.

Example 6

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(m-toluylamino)cyclobut-3-ene-1,2-dione: 6 mmol m-toluaniline, 3 mmol 3- (Benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione is used as the raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 9.91 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.76 (s, 1H) ), 7.27 (d, J = 13.8 Hz, 4H), 6.89 (s,1H), 2.31 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 182.22, 182.14, 166.34, 165.76,154.52 , 150.51, 139.23, 138.85, 137.35, 135.89, 129.69, 124.64, 120.97,119.60, 116.57, 116.26, 101.81, 21.62.

Example 7

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(cyclopentylamino)cyclobut-3-en-1,2-one: 6 mmol cyclopentylamine, 3 mmol 3 -(benzo[d]oxazole-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione is used as the raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.65 (s, 1H), 8.04 (s, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.29 (dd, J = 8.6, 2.1 Hz, 1H), 4.40(q, J = 6.5 Hz, 1H), 2.01 – 1.93 (m, 2H), 1.75 – 1.68 (m, 2H), 1.62 – 1.53(m, 4H). ¹³ C NMR (101 MHz, DMSO-d6) δ 184.24, 180.62, 169.19, 163.64, 154.24,150.64, 137.90, 135.33, 120.93, 115.98, 101.09, 56.06, 3 4.21, 23.64.

Example 8

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(cyclohexylamino)cyclobut-3-en-1,2-one: 6 mmol cyclohexanamine, 3 mmol 3- (Benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione is used as the raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.65 (s, 1H), 8.04 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 8.6, 2.2 Hz, 1H), 3.87(s, 1H), 1.94 (s, 2H), 1.73 (s, 2H), 1.57 (d, J = 12.3 Hz, 1H), 1.40 – 1.25( m, 5H). ¹³ C NMR (101 MHz, DMSO-d6) δ 184.03, 180.56, 169.01, 163.64, 154.24,150.64, 137.90, 135.33, 120.93, 115.96, 101.08, 53.14, 34.05, 25.18, 24.48.

Example 9

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione: 6 mmol 4-trifluoromethylaniline, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione as raw materials, synthesized See Example 1 for the method.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (d, J = 3.9 Hz, 2H), 8.69 (s, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.78 ( d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H). ¹³ C NMR (101 MHz, DMSO-d6) δ 182.98,182.05, 166.66, 165.80, 154.62, 150.42, 142.57, 137.05, 136.14, 127.14,126.21, 123.38, 120.96, 119.02, 116.79, 102.08.

Example 10

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((4-chlorophenyl)amino)cyclobut-3-ene-1,2-dione: 6 mmol p-chloroaniline, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione was used as raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (d, J = 45.4 Hz, 2H), 8.70 (s, 1H), 8.01 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.37 (dt,J = 15.5, 7.1 Hz, 3H), 7.12 (d, J = 7.5 Hz, 1H). ¹³ C NMR (101 MHz, DMSO-d6) δ165 .92, 154.60, 150.46, 140.54, 137.17, 131.45, 123.36, 120.97, 118.77,117.56, 116.74, 101.99.

Example 11

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((4-ethylphenyl)amino)cyclobut-3-ene-1,2-dione: with 6 mmol 4- Ethylphenyl, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione as raw material, see the examples for the synthesis method 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.89 (s, 1H), 8.68 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H ), 7.39 (d, J = 8.3 Hz, 3H), 7.22 (s,2H), 2.57 (q, J = 9.5, 8.6 Hz, 2H), 1.17 (s, 3H). ¹³ C NMR (101 MHz, DMSO -d6) δ182.19, 182.00, 166.28, 165.52, 154.48, 150.51, 139.52, 137.39, 136.60,135.84, 129.05, 120.95, 119.23, 116.51, 101.7 4, 27.98, 16.13.

Example 12

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione: 6 mmol m-trifluoromethylaniline, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione as raw materials, synthesized See Example 1 for the method.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 2H), 8.70 (s, 1H), 7.97 (d, J = 22.1 Hz, 2H), 7.77 (s, 1H), 7.63 (d, J = 23.3 Hz, 2H), 7.40 (s,2H). ¹³ C NMR (101 MHz, DMSO-d6) δ 183.43, 158.24, 148.33, 143.51, 143.14,139.51, 139.28, 137.54, 13 0.10, 126.97 , 126.50, 124.83, 119.88, 117.66,115.83, 105.06, 17.90.

Example 13

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-(cyclopropylamino)cyclobut-3-en-1,2-one: 6 mmol cyclopropylamine, 3 mmol 3 -(benzo[d]oxazole-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione is used as the raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.65 (s, 1H), 7.98 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), ¹³ CNMR (101 MHz, DMSO-d6) δ 181.27, 170.93, 164.11, 154.27, 150.58, 137.83, 135.40, 120.86, 26.52, 7.51.

Example 14

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((3-chlorophenyl)amino)cyclobut-3-ene-1,2-dione: using 6 mmol m-chloroaniline, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione was used as raw material. For the synthesis method, see Example 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.23 (d, J = 44.4 Hz, 2H), 8.70 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.78 ( d, J = 8.6 Hz, 1H), 7.70 (s,1H), 7.42 – 7.33 (m, 3H), 7.12 (d, J = 7.8 Hz, 1H). ¹³ C NMR (101 MHz, DMSO-d6) δ166 .28, 165.92, 154.60, 150.45, 140.53, 137.16, 136.05, 134.24, 131.46, 123.37, 120.97, 118.78, 117.58, 116.76, 102.02.

Example 15

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((3-ethylphenyl)amino)cyclobut-3-ene-1,2-dione: 6 mmol m-ethyl aniline, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione as raw material, see Example 1 for the synthesis method.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (d, J = 65.9 Hz, 2H), 8.69 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.32 (d, J = 44.9 Hz, 3H), 6.97 (s,1H), 6.66 (s, 1H), 4.40 (s, 1H), 3.77 (s, 3H), 1.23 (s, 1H). ¹³ C NMR (101 MHz, DMSO-d6) δ 183.43, 158.24, 148.33, 143.73, 142.08, 139.28, 138.78, 137.54,129.58, 125.81, 121.20, 119.88, 119.43, 117 .66, 105.06, 28.97, 15.60.

Example 16

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((2-ethylphenyl)amino)cyclobut-3-ene-1,2-dione: 6 mmol ortho-ethyl aniline, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione as raw material, see Example 1 for the synthesis method.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H), 9.49 (s, 1H), 8.67 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.6, 2.2 Hz, 1H), 7.30 (dd, J = 7.9, 1.3 Hz, 1H), 7.25 (dd, J = 7.5, 1.6Hz , 1H), 7.22 – 7.15 (m, 1H), 7.12 (td, J = 7.4, 1.4 Hz, 1H), 2.76 (q, J =7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H) . ¹³ C NMR (101 MHz, DMSO-d6) δ 182.79,182.35, 167.30, 165.89, 154.41, 150.49, 137.51, 135.80, 135.24, 128.91,126.76, 125.65, 123. 57, 120.86, 116.69, 101.92, 49.06, 24.05, 14.56 .

Example 17

Synthesis of 3-(benzo[d]oxazole-6-amino)-4-((3-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione: 6 mmol m Methoxyaniline, 3 mmol 3-(benzo[d]oxazol-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione as raw material, see the examples for the synthesis method 1.

The NMR data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.89 (s, 1H), 8.67 (s, 1H), 8.03 (s, 1H), 7.77 (s, 1H ), 7.30 (d, J = 20.6 Hz, 4H), 6.92 (d,J = 6.9 Hz, 1H), 2.61 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d6) δ 182.18, 166.36,165.71 , 154.50, 150.52, 145.57, 138.89, 137.36, 135.88, 129.74, 123.50,120.97, 118.42, 116.51, 101.76, 28.63, 15.78.

The product structural formulas of the above examples are shown in Table 1.

Example 18 P2Y ₁₄ R Antagonistic Activity Test

The HEK293 cell line stably expressing human P2Y ₁₄ receptor was purchased from Keygen Biotech. Approximately 24 hours before assay, cells were seeded in 384 ^- well plates at a density of 1 × 10 cells per well. The culture medium was discarded before the assay, and serum-free culture medium was used instead. IBMX (500 μM) and Ro 20-1724 (100 μM) were added to inhibit the activity of PDEs. The AC agonist Forskolin (30 μM) was used to stimulate the production of cAMP in cells. Different levels were added in advance. Concentrations of cyclobutenedionyl benzoxazole derivatives (0.0001, 0.001, 0.01, 0.1, 1, 10, 100 nM, aqueous solution), with PPTN (CAS number: 1160271-30-6) as a positive control. At the same time, 10 μM of P2Y ₁₄ receptor agonist UDPG was added. After 30 minutes, detect the intracellular cAMP content according to the instructions of the cAMP GloTM Assay Kit (PROMEGA Co. Ltd, USA), and calculate the IC ₅₀ based on the cAMP content.

value and the relative inhibition rate of P2Y ₁₄ receptor. The results are shown in Figure 1 and Table 2.

Example 19 Experiment on the Alleviation of Liver Fibrosis by P2Y ₁₄ R New Antagonist

The animal model experiment itself is a conventional technique and complies with the relevant requirements of Soochow University. Male C57BL/6 mice, 6-8 weeks old, weighing 20-25g, have free access to water and food, 12 hours of lighting per day, and an ambient temperature of 25±2°C. The mice were randomly divided into 4 groups: sham operation control group, model control group, positive control group (magnesium isoglycyrrhizinate 20 mg/kg), and HDB-1 group (HDB-1 10 mg/kg). Common bile duct ligation was used to construct a mouse fibrosis model. The common bile duct was separated after laparotomy and ligated twice with 5-0 silk thread. The sham operation group had the same steps as the model group except for no ligation; the treatment group was treated on the second day after bile duct ligation. Intraperitoneal injection was given once a day, and the sham operation control group was injected with the same dose of normal saline until the end of the modeling; 14 days later, the eyeballs were removed to collect blood and use ALT and AST kits to measure serum ALT and AST levels. The results are shown in Figure 2, ^** P <0.01, ^*** P <0.001, compared with the model group. The mice were sacrificed to obtain liver tissue for fixation for HE staining and Masson staining. The results are shown in Figure 3.

Example 20 In vivo pharmacokinetic study of new P2Y ₁₄ R antagonists

Twelve healthy SD male rats, weighing approximately 220 g, were adaptively fed for 5 days, with free access to food and water. Fasted overnight before the experiment, and randomly divided into 2 groups (n=6). Compound HDB-1 was administered via intragastric administration at 20 mg/kg; the administration volume was 0.2 mL/100g; and 2 mg/kg was administered via tail vein; the administration volume was 0.2 mL/100g. Respectively before administration (0 h), 10min, 20min, 30min, 45min, 1h, 75min, 90min, 2h, 4h, 6h, 8h, 12h after intragastric administration; 2min, 5min, 10min, Continuously collect blood from the fundus venous plexus into heparin-treated EP tubes at 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, and 8 h. Centrifuge the whole blood at 8000 rpm for 5 minutes, separate the plasma samples and store them at -80°C. Use LC-MS/MS (Shimadzu LCMS-8030) to analyze and determine the drug concentration in the plasma, and use WinNonlin Professional V6.3 non-departmental model. Analyze pharmacokinetic parameters. The results are shown in Table 3. The results show that HDB1 has good metabolic stability and oral bioavailability.

It can be seen from the above examples that the cyclobutenedione derivative provided by the present invention has a structure represented by formula (I). Experimental results show that the cyclobutenedione derivatives provided by the present invention have good P2Y ₁₄ receptor antagonistic activity, in vivo anti-inflammatory activity and pharmacokinetic properties, and can be used as a preparation for the treatment of P2Y ₁₄ receptor-related inflammatory diseases. Drug Applications.

The description of the above embodiments is only used to help understand the method and its core idea of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of the claims of the present invention.

Claims (10)

1. A cyclobutenedioyl benzoxazole derivative having a structure represented by formula (I):

wherein R is a ring.

2. The cyclobutenedione benzoxazole derivative according to claim 1, wherein R is an aliphatic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic ring or a substituted heterocyclic ring.

3. The cyclobutenedione benzoxazole derivative according to claim 2, wherein R is an aliphatic ring, a benzene ring, a substituted benzene ring or a heterocyclic ring.

4. The cyclobutenedione benzoxazole derivative according to claim 2, wherein the substituents are independently selected from one or more of alkyl, alkoxy, haloalkyl and haloalkoxy groups in the substituted aromatic ring or the substituted heterocyclic ring.

5. The method for producing a cyclobutenedione benzoxazole derivative according to claim 1, comprising the steps of: 3- (benzo [ d)]Oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione and RNH ₂ And (3) reacting to obtain the cyclobutenedioyl benzoxazole derivative.

6. The process for producing a cyclobutenedione benzoxazole derivative as claimed in claim 5, wherein the reaction temperature is from room temperature to 100℃for a period of from 5 to 60 minutes.

7. The process for preparing P2Y from a cyclobutenedioyl benzoxazole derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 ₁₄ Use of a therapeutic agent for a receptor-related disease.

8. The preparation or use of a cyclobutenedioyl benzoxazole derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1P2Y ₁₄ Use of a receptor anticaking agent.

9. Use of a cyclobutenedioyl benzoxazole derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the manufacture of an anti-inflammatory medicament.

10. Treatment of P2Y ₁₄ A drug for receptor-related diseases, which comprises the cyclobutenedioyl benzoxazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.