CN117143040A - Cyclobutene-diketo-benzoxazole derivative as well as preparation method and application thereof - Google Patents

Cyclobutene-diketo-benzoxazole derivative as well as preparation method and application thereof Download PDF

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CN117143040A
CN117143040A CN202310963871.2A CN202310963871A CN117143040A CN 117143040 A CN117143040 A CN 117143040A CN 202310963871 A CN202310963871 A CN 202310963871A CN 117143040 A CN117143040 A CN 117143040A
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benzoxazole derivative
cyclobutenedione
ring
oxazol
benzo
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李环球
胡庆华
王辉
周梦泽
钟芬
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Suzhou University
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    • C07—ORGANIC CHEMISTRY
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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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

Cyclobutene-diketo-benzoxazole derivative as well as preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method and application of a cyclobutenedione benzoxazole derivative.
Background
P2Y 14 Receptor (P2Y) 14 R) is one of the members of the P2Y receptor when P2Y 14 When R is excited, the medicine can promote mast cells to release mediators and kidney leap cell inflammation, and improve the hypersensitivity of microglia cells and the chemotaxis of neutrophils; and inhibit the release of metalloproteinases and tumor necrosis factor by astrocytes. P2Y 14 The receptor antagonist has good innovation and application prospect in the field of drug development of related diseases such as liver fibrosis, arthritis, acute kidney injury, neuropathic pain and the like. P2Y 14 R activation is closely related to intracellular cAMP levels, whereas cAMP prevents activation of NLRP3 inflammatory corpuscles, thus P2Y 14 R may regulate the inflammatory response through NLRP3 inflammatory bodies. In chronic liver disease, fibrosis is a major factor in determining prognosis, but there is a lack of effective anti-fibrosis treatment. Recent research [ 1]]Indicating that P2Y 14 Activation of induced ERK is the primary cause of pro-fibrosis in HSCs (44).
Benzoxazoles are important pharmacophores in modern drug discovery, a large number of benzoxazoles have been successfully developed, and the inventors' subject group only discloses benzoxazole derivatives of various structures and used for P2Y 14 The inhibitory effect of these compounds is further improved. And the characteristic that the existing compounds are poorly dissolved in aqueous solution limits the clinical application of the compounds.
Disclosure of Invention
In view of the above, the invention discloses a cyclobutenedione benzoxazole derivative, a preparation method and application thereof, and the prepared cyclobutenedione benzoxazole derivative has better antagonism to P2Y 14 Receptor activity and activity for treating liver fibrosis and other related diseases. The cyclobutenedione benzoxazole is an important pharmacophore in the medicine, and after the cyclobutenedione benzoxazole groups are introduced into a plurality of small molecular medicines by utilizing the activity superposition principle, the activity of the cyclobutenedione benzoxazole is greatly improved, and the cyclobutenedione benzoxazole has low toxicity, high bioavailability, good biocompatibility and good curative effect. Cyclobutene-diketo-benzoxazole compoundsHas wide biological activity.
The invention adopts the following technical scheme:
a cyclobutenedioyl benzoxazole derivative having a structure represented by formula (I):wherein R is a ring, preferably an aliphatic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic ring or a substituted heterocyclic ring; further preferably, the R is an alicyclic ring, a benzene ring, a substituted benzene ring or a heterocyclic ring, such as a 5-to 6-membered heterocyclic ring; still more preferably, R is a cyclopropane, a cyclobutane, a cyclohexane, a cyclopentane, a benzene ring, or a substituted benzene ring. In the substituted aromatic ring and the substituted heterocycle, the substituent is independently selected from one or more of alkyl, alkoxy, halogenated alkyl and halogenated alkoxy, and the preferable substituent is independently selected from one or more of methyl, ethyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl and trifluoromethoxy. Preferably, R is a substituted benzene ring, and the P2Y14 receptor antagonistic activity of the compound is better.
In some embodiments of the invention, the cyclobutenedioyl benzoxazole derivative has any one of the following structures:
formula (HDB-1)>(HDB-2)
Formula (HDB-3)>(HDB-4)
Formula (HDB-5)>(HDB-6)
Formula (HDB-7)>(HDB-8)
Formula (HDB-9)>(HDB-10)
Formula (HDB-11)>(HDB-12)
Formula (HDB-13)>(HDB-14)
Formula (HDB-15)>(HDB-16)
Formula (HDB-17).
The invention provides a preparation method of the cyclobutenedione benzoxazole derivative, which comprises the following steps: 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. Preferably, the reaction temperature is room temperature to 100 ℃ and the reaction time is 5 to 60 minutes; further preferred isThe reaction temperature is 50-70 ℃ and the reaction time is 15-30 minutes.
The reaction equation of the preparation method is as follows:
the R is 1 、R 2 The ranges of (2) are the same and are not described in detail herein.
The invention discloses a preparation method of the cyclobutenedione benzoxazole derivative or the pharmaceutically acceptable salt thereof for preparing P2Y 14 The application of the receptor-related diseases such as liver fibrosis and other related diseases in the medicaments.
The invention discloses a preparation method of the cyclobutenedioyl benzoxazole derivative or pharmaceutically acceptable salt thereof or the preparation method is used as P2Y 14 Receptor anticaking agents, or in the preparation of anti-inflammatory agents.
The invention discloses a method for treating P2Y 14 The receptor-related disease drug comprises the cyclobutenedioyl benzoxazole derivative or the pharmaceutically acceptable salt thereof as an active ingredient. Further comprises auxiliary materials; the auxiliary material can be pharmaceutically acceptable auxiliary material.
The medicine for treating liver fibrosis can be combined with other medicines for treating related diseases.
Compared with the prior art, the invention provides the cyclobutenedione benzoxazole derivative, and the experimental result shows that the cyclobutenedione benzoxazole derivative provided by the invention has better treatment effect on P2Y 14 Activity of receptor-related diseases such as liver fibrosis and the like.
Drawings
FIG. 1 is P2Y 14 Relative inhibition of the receptor.
FIG. 2 shows serum ALT and AST levels.
FIG. 3 shows HE staining and Masson staining results.
Detailed Description
In order to further illustrate the present invention, the following describes in detail the cyclobutenedioyl benzoxazole derivative provided by the present invention, and the preparation method and application thereof. The raw materials adopted by the invention are commercial products, and the specific preparation operation and performance test are conventional technologies.
Synthesis example
1.34g (10 mmol) of benzo [ d ] oxazol-6-amine are dissolved in methanol, 1.42g (10 mmol) of 3, 4-dimethoxycyclobut-3-ene-1, 2-dione are added and the mixture is stirred for 24h at 65 ℃. 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 dried under reduced pressure. The product was purified by column chromatography on silica gel with dichloromethane: methanol (50:1) to give 1.95g of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione.
Example 1
Synthesis of 3- (benzo [ d ] oxazol-6-amino) -4- (p-toluylamino) cyclobut-3-ene-1, 2-dione: 0.642g (6 mmol) of p-toluidine are dissolved in methanol, 0.732g (3 mmol) of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione are added and the mixture is stirred for 24 hours at 65 ℃. 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 dried under reduced pressure. The product was purified by column chromatography on silica gel with dichloromethane: methanol (100:1) to give 3- (benzo [ d ] oxazol-6-amino) -4- (p-toluylamino) cyclobut-3-ene-1, 2-dione.
The nuclear magnetic 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 C NMR (101 MHz, DMSO-d6) δ 183.43, 158.24, 148.33, 143.51, 143.14, 139.51, 139.28, 137.54, 130.10, 126.97, 126.50, 124.83, 119.88, 117.66, 115.83, 105.06, 17.90。
example 2
Synthesis of 3- (benzo [ d ] oxazol-6-amino) -4- (phenylamino) cyclobut-3-en-1, 2-one: starting from 6 mmol of aniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 ] oxazol-6-amino) -4- (cyclobutylamino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of cyclobutylamine, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 ] oxazol-6-amino) -4- (bicyclo [1.1.1] pentane-1-amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of bicyclo [1.1.1] -1-pentylamine hydrochloride, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 = 8.5 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.24 – 7.16 (m, 2H), 7.06 (t, J = 6.8 Hz, 1H), 2.37 (s, 3H). 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 ] oxazol-6-amino) -4- (o-tolylamino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of o-methylaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 ] oxazol-6-amino) -4- (m-toluylamino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of m-methylaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 ] oxazol-6-amino) -4- (cyclopentylamino) cyclobut-3-en-1, 2-one: starting from 6 mmol of cyclopentylamine, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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, 34.21, 23.64。
example 8
Synthesis of 3- (benzo [ d ] oxazol-6-amino) -4- (cyclohexylamino) cyclobut-3-en-1, 2-one: starting from 6 mmol of cyclohexane amine, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 ] oxazol-6-amino) -4- ((4- (trifluoromethyl) phenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmole of 4-trifluoromethylaniline, 3 mmole of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 ] oxazol-6-amino) -4- ((4-chlorophenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of p-chloroaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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) δ 165.92, 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 ] oxazol-6-amino) -4- ((4-ethylphenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of 4-ethylphenyl, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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) δ 182.19, 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, 101.74, 27.98, 16.13。
example 12
Synthesis of 3- (benzo [ d ] oxazol-6-amino) -4- ((3- (trifluoromethyl) phenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of m-trifluoromethylaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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, 130.10, 126.97, 126.50, 124.83, 119.88, 117.66, 115.83, 105.06, 17.90。
example 13
Synthesis of 3- (benzo [ d ] oxazol-6-amino) -4- (cyclopropylamino) cyclobut-3-en-1, 2-one: starting from 6 mmol of cyclopropylamine, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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), 7.29 (d, J = 8.0 Hz, 1H), 3.12 (tq, J = 7.1, 3.6 Hz, 1H), 0.79 (td, J = 7.2, 4.9 Hz, 2H), 0.70 – 0.65 (m, 2H). 13 C NMR (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 ] oxazol-6-amino) -4- ((3-chlorophenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of m-chloroaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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) δ 166.28, 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 ] oxazol-6-amino) -4- ((3-ethylphenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of m-ethylaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 ] oxazol-6-amino) -4- ((2-ethylphenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of o-ethylaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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, 1.6 Hz, 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 ] oxazol-6-amino) -4- ((3-methoxyphenyl) amino) cyclobut-3-ene-1, 2-dione: starting from 6 mmol of m-methoxyaniline, 3 mmol of 3- (benzo [ d ] oxazol-6-ylamino) -4-methoxycyclobut-3-ene-1, 2-dione, the synthesis is described in example 1.
The nuclear magnetic 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 structural formula of the product of the above example is shown in table 1.
Example 18P 2Y 14 R antagonistic Activity test
Stable expression of human P2Y 14 HEK293 cells of the receptorPurchased from Keygen Biotech. Cells were 1X 10 per well approximately 24 hours prior to assay 4 The density of individual cells was seeded in 384 well plates. The medium was discarded before the measurement, instead of serum-free medium, IBMX (500. Mu.M) and Ro 20-1724 (100. Mu.M) were added to inhibit PDEs activity, AC agonist Forskolin (30. Mu.M) was used to stimulate cellular cAMP production, and different concentrations of cyclobutenedione benzoxazole derivatives (0.0001, 0.001, 0.01, 0.1, 1, 10, 100 nM, aqueous solution) were added in advance, respectively, with PPTN (CAS No. 1160271-30-6) as a positive control. At the same time add 10. Mu.M P2Y 14 The receptor agonist UDPG. After 30min, the intracellular cAMP content was measured according to the cAMP GloTM Assay kit (PROMEGA Co. Ltd, USA) protocol, and IC was calculated from the cAMP content 50
Value sum P2Y 14 The relative inhibition of the receptors and the results are shown in fig. 1 and table 2.
EXAMPLE 19P 2Y 14 Experiments on alleviation of liver fibrosis by novel R antagonists
The animal model experiment is a conventional technology and meets the related requirements of the university of Suzhou. Male C57BL/6 mice, with weight of 20-25g, free water diet, and illumination for 12h each day, at 25+ -2deg.C for 6-8 weeks. Mice were randomly divided into 4 groups: the sham operation control group, the model control group, the positive control group (magnesium isoglycyrrhizate 20 mg/kg) and the HDB-1 group (HDB-1 10 mg/kg). Constructing a mouse fibrosis model by using common bile duct ligation, separating a common bile duct after opening an abdomen, ligating twice by using 5-0 silk threads, and performing other steps of a sham operation group except that the sham operation group is not ligatured, wherein the steps are the same as those of the model group; the treatment group is injected into the abdominal cavity for 1 time every day after the bile duct ligation, and the sham operation control group is injected with the same dose of physiological saline until the molding is finished; after 14 days, the ALT and AST kit is used for taking out the blood from the eyeballs, the serum ALT and AST levels are measured, the result is shown in figure 2, ** P＜0.01， *** P< 0.001, compared to model group. Mice were sacrificed to obtain liver tissue fixation for HE staining and Masson staining, the results are shown in fig. 3.
EXAMPLE 20P 2Y 14 In vivo pharmacokinetic studies of novel R antagonists
12 healthy SD male rats weighing about 220g were fed adaptively for 5 days with free diet. The experiment was fasted overnight and randomized into 2 groups (n=6). Compound HDB-1 was administered by gavage at 20 mg/kg; the administration volume is 0.2 mL/100g; 2 mg/kg by tail vein; the administration volume was 0.2. 0.2 mL/100g. Before administration (0 h), 10min, 20min, 30min, 45min, 1h, 75min, 90min, 2h, 4h, 6h, 8h, 12h after gastric lavage administration; 2min, 5min, 10min, 30min, 45min, 1h, 2h, 4h, 6h, 8h of fundus venous plexus after intravenous injection administration was continuously bled in heparin-treated EP tubes. Whole blood was centrifuged at 8000 rpm for 5min, plasma samples were taken and stored at-80 ℃, plasma drug concentrations were determined by LC-MS/MS (Shimadzu LCMS-8030) analysis, and pharmacokinetic parameters were analyzed using WinNonlin Professional V6.3.3 non-department model. The results are shown in Table 3, and the results show that HDB1 has better metabolic stability and oral bioavailability.
As is clear from the above examples, the cyclobutenedione derivatives provided by the invention have a structure shown in formula (I). Experimental results show that the cyclobutenedione derivatives provided by the invention have better P2Y 14 Receptor antagonistic activity, anti-inflammatory activity in vivo and pharmacokinetic properties, useful for the preparation of P2Y 14 Use of a therapeutic agent for a receptor-related inflammatory disease.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various changes and modifications can be made herein without departing from the principles of the invention, which are also intended to fall within the scope of the appended claims.

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.
CN202310963871.2A 2023-08-02 2023-08-02 Cyclobutene-diketo-benzoxazole derivative as well as preparation method and application thereof Pending CN117143040A (en)

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