CN113264928B - Dihydropyrazole thiazole derivative and preparation method and application thereof - Google Patents

Dihydropyrazole thiazole derivative and preparation method and application thereof Download PDF

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CN113264928B
CN113264928B CN202110563549.1A CN202110563549A CN113264928B CN 113264928 B CN113264928 B CN 113264928B CN 202110563549 A CN202110563549 A CN 202110563549A CN 113264928 B CN113264928 B CN 113264928B
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CN113264928A (en
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李青山
张朕
杨潇潇
曹培常
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Hefei University of Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention discloses a dihydropyrazole thiazole derivative, a preparation method and application thereof, wherein the dihydropyrazole thiazole derivative has the following general formula:wherein R is 1 Selected from 4-Br, 4-F, 4-CH 3 、3‑CH 3 、2‑CH 3 Or 3,4,5-3OCH 3 ；R 2 Selected from OCH 3 、CH 3 F or Br. The dihydropyrazolothiazole derivative has good anti-inflammatory activity on RAW264.7 cells with LPS induced inflammation.

Description

Dihydropyrazole thiazole derivative and preparation method and application thereof
Technical Field
The invention relates to a dihydropyrazole thiazole derivative, in particular to a dihydropyrazole thiazole derivative, a preparation method and application thereof. The dihydropyrazolothiazole derivative has good anti-inflammatory activity on RAW264.7 cells with LPS induced inflammation.
Background
Dihydropyrazoles are extremely important nitrogen-containing five-membered heterocyclic compounds, which are important structural motifs found in many pharmaceutically active compounds, which possess a variety of important biological activities such as anticancer, antifungal, antiviral, antitubercular, antiinflammatory, etc. activities. Naturally occurring bioactive flavonoids and isoflavones and appropriately substituted α, β -unsaturated ketones are useful as ideal sources for obtaining dihydropyrazoles in nature. Because the dihydropyrazoles are mostly chiral rings, the characteristic is very important, and the substitution on the rings and the conformation of the molecules are more abundant and have better biological activity potential.
Thiazole nuclei are very important heterocycles among many biologically active compounds, making them one of the most widely studied heterocycles. Thiazole plays a vital role in many pharmaceutical structures, such as anti-tumor, antiviral, antifungal, antiparasitic, anti-inflammatory, antiulcer and insecticidal. Many reports have announced the use of thiazole core structures in drug design and the development of novel therapeutic agents. Thiazole rings have played a variety of roles in the recognition and optimization of lead compounds as part of a variety of five-membered heterocycles, including as pharmacophores and biological allele line elements and as spacers. Also, the presence of thiazole rings as part of the drug structure can affect its physicochemical and pharmacokinetic properties.
The invention adopts a design strategy of 'combined pharmacophore', introduces an active pharmacophore-thiazole ring into a 3, 5-diaryl-4, 5-dihydro-pyrazole framework with good activity, screens and synthesizes a novel structure with high efficiency and low toxicity as a candidate compound of an anti-inflammatory drug.
Disclosure of Invention
The invention aims to provide a dihydropyrazole thiazole derivative, a preparation method and application thereof. The dihydropyrazolothiazole compound has good anti-inflammatory activity on RAW264.7 cells with LPS induced inflammation.
The RAW264.7 cells are mouse mononuclear macrophages, often used in cell inflammation experiments to detect the anti-inflammatory activity of compounds.
The dihydropyrazole thiazole derivative has the following structural general formula:
wherein R is 1 Selected from 4-Br, 4-F, 4-CH 3 、3-CH 3 、2-CH 3 Or 3,4,5-OCH 3 ；R 2 Selected from OCH 3 、CH 3 F or Br.
Further, the structural formula of the dihydropyrazolothiazole derivative is preferably as follows:
the preparation method of the dihydropyrazole thiazole derivative comprises the following steps:
step 1: dissolving benzaldehyde derivative A (10 mmol) in 40mL of absolute ethyl alcohol, slowly dropwise adding 5mL of 10% NaOH solution, adding acetophenone derivative B (10 mmol), stirring at normal temperature for reaction, monitoring the reaction progress by TLC, and separating out a product in a solid form after the reaction is performed for about 3 hours; after the reaction is finished, standing, suction filtering, and recrystallizing with ethanol to obtain chalcone derivative C;
the structural formula of the benzaldehyde derivative A is as follows:
the structural formula of the acetophenone derivative B is as follows:
the structural formula of the chalcone derivative C is as follows:
wherein R is 1 Selected from 4-Br, 4-F, 4-CH 3 、3-CH 3 、2-CH 3 Or 3,4,5-OCH 3 ；R 2 Selected from OCH 3 、CH 3 F or Br.
Step 2: dissolving dried chalcone derivative C (10 mmol) in 40mL of ethanol, adding 3-4mL of N, N-Dimethylformamide (DMF) to assist dissolution if the solubility is poor, then adding 12mmol of thiosemicarbazide and about 1g of KOH solid, heating to 75 ℃ for refluxing, monitoring the reaction progress by TLC, pouring the reaction solution into about 150mL of ice water after 12H of reaction, automatically separating out the product, standing, filtering and washing with petroleum ether and a small amount of water to obtain the compound D, namely the 3, 5-diaryl-4, 5-dihydro-1H-pyrazole-carbosulfamide derivative.
Wherein R is 1 Selected from 4-Br, 4-F, 4-CH 3 、3-CH 3 、2-CH 3 Or 3,4,5-OCH 3 ；R 2 Selected from OCH 3 、CH 3 F or Br.
Step 3: compound D (4 mmol) is dissolved in 30mL of ethanol, 3-4mL of N, N-Dimethylformamide (DMF) can be added for assisting dissolution if the solubility is poor, then 6mmol of chloroacetone is added, stirring is carried out at room temperature for 4h, the reaction is continuously detected by TLC, after the reaction is finished, the reaction solution is concentrated in vacuo, and column chromatography (ethyl acetate: petroleum ether=1:4, v/v) is adopted for separation and purification to obtain the target compound.
In step 1, the ratio of the amounts of the substances of the benzaldehyde derivative A and the acetophenone derivative B was 1:1.
In step 2, 1.2 mmole of thiosemicarbazide was added per 1 mmole of chalcone derivative C.
In step 3, the mass ratio of the compound D to the chloroacetone is 1:1.5.
The application of the dihydropyrazole thiazole derivative is in the preparation of anti-inflammatory drugs. The anti-inflammatory drug has good anti-inflammatory activity on RAW264.7 cells with LPS induced inflammation.
Drawings
FIG. 1 is the inhibition of LPS-induced NO release by compounds 1-21 (1. Mu.M) from RAW264.7 inflammatory cells.
FIG. 2 shows the inhibition of NO release by LPS-induced RAW264.7 inflammatory cells by a more toxic compound (1. Mu.M) and a control drug.
FIG. 3 is the inhibition of LPS-induced NO release from RAW264.7 inflammatory cells by less toxic compounds (10. Mu.M) and control drugs.
Detailed Description
The technical scheme of the present invention will be further described in detail by the following specific examples, but it should be noted that the scope of the present invention is not limited by any of these examples.
Example 1: preparation of 2- (5- (4-bromophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 1)
1. A150 mL round bottom flask was taken, 4-bromobenzaldehyde A (1.850 g,10 mmol) was dissolved in 40mL absolute ethanol, then 5mL 10% NaOH was slowly added dropwise, and 4-fluoroacetophenone B (1.3831 g,10 mmol) was added. The reaction was stirred at room temperature for about 3 hours and monitored by TLC for progress of the reaction, and the product precipitated as a solid. After the reaction is completed, standing, suction filtering, and recrystallizing with ethanol to obtain chalcone derivative C.
2. A150 mL round bottom flask is taken, a dried chalcone derivative C (3.051 g,10 mmol) is dissolved in 40mL of ethanol, 3-4mL of N, N-Dimethylformamide (DMF) can be added for assisting in dissolution, 12mmol of thiosemicarbazide and about 1g of KOH solid are added, the mixture is heated to 75 ℃ for refluxing, the TLC monitors the reaction progress, after 12H of reaction, the reaction solution is poured into about 150mL of ice water, the product is automatically separated out, standing, suction filtration and washing with petroleum ether and a small amount of water are carried out, and the 3, 5-diaryl-4, 5-dihydro-1H-pyrazole-carbosulfamide derivative D is obtained.
3. A150 mL round bottom flask was taken, compound D (1.513 g,4 mmol) was dissolved in 30mL of ethanol, 3-4mL of N, N-Dimethylformamide (DMF) was added to aid dissolution, then chloroacetone (555 mg,6 mmol) was added, stirring was carried out at room temperature for 4h and the reaction was continuously examined by TLC, after completion of the reaction, the reaction solution was concentrated in vacuo and separated and purified by column chromatography (ethyl acetate: petroleum ether=1:4, v/v) to give the objective compound 1. Product 1 was a yellow-green solid with a yield of 21.5% and a melting point of 132-135 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.80–7.68(m,2H),7.53–7.42(m,2H),7.25–7.19(m,2H),7.15–7.08(m,2H),6.20(q,J＝1.1Hz,1H),5.63(dd,J＝12.0,5.9Hz,1H),3.87(dd,J＝17.3,12.0Hz,1H),3.20(dd,J＝17.4,5.9Hz,1H),2.19(d,J＝1.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)164.81,162.39,150.07,149.44,140.63,131.89,128.30,128.22,127.99,127.66,121.51,115.96,115.74,103.70,63.70,43.50,17.61.HR-MS(ESI):calcd for C 19 H 15 BrFN 3 S,[M+H] + ,416.0232；found 416.0231.
Example 2: preparation of 2- (5- (4-bromophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 2)
The preparation method is the same as in example 1. 4-methoxyacetophenone was used instead of 4-fluoroacetophenone to give a brown solid with a yield of 24.3% and a melting point of 142-147 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.76–7.66(m,2H),7.56–7.41(m,2H),7.28–7.23(m,2H),7.01–6.91(m,2H),6.17(t,J＝1.1Hz,1H),5.78(s,1H),3.87(s,4H),3.23(dd,J＝17.3,5.3Hz,1H),2.27–2.16(m,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)165.08,160.97,151.08,149.32,140.86,131.83,128.03,127.95,124.02,121.39,114.11,103.37,63.48,55.40,43.64,17.61.HR-MS(ESI):calcd for C 20 H 18 BrN 3 OS,[M+H] + ,428.0432；found 428.0429.
Example 3: preparation of 2- (5- (4-bromophenyl) -3- (4-methylphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 3)
The preparation method is the same as in example 1. 4-methylacetophenone is used to replace 4-fluoroacetophenone to obtain a yellowish green solid with a yield of 26.8% and a melting point of 192-197 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.68–7.63(m,2H),7.48–7.44(m,2H),7.26(t,J＝7.8Hz,5H),6.18(q,J＝1.1Hz,1H),5.80(s,1H),3.91(dd,J＝17.4,11.8Hz,1H),3.25(dd,J＝17.4,5.3Hz,1H),2.42(s,3H),2.23(s,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)164.97,151.29,149.35,140.84,140.10,131.83,129.39,128.04,126.33,121.40,103.50,63.50,43.53,21.51,17.61.ESI MS(m/z):412.0479(C 20 H 18 BrN 3 S,[M+H]).HR-MS(ESI):calcd for C 20 H 18 BrN 3 S,[M+H] + ,412.0483；found 412.0479.
Example 4: preparation of 2- (5- (4-bromophenyl) -3- (4-bromophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 4)
The preparation method is the same as in example 1. 4-bromoacetophenone is used for replacing 4-fluoroacetophenone to obtain a yellowish green solid with the yield of 27.5 percent and the melting point of 165-170 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.65–7.55(m,4H),7.50–7.45(m,2H),7.27(d,J＝9.1Hz,2H),6.21(d,J＝1.2Hz,1H),5.93(s,1H),3.91(dd,J＝17.5,11.6Hz,1H),3.25(dd,J＝17.4,4.8Hz,1H),2.24(s,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)164.57,149.95,149.45,140.51,131.89,130.29,127.98,127.74,123.98,121.56,103.86,63.77,43.22,17.59.HR-MS(ESI):calcd for C 19 H 15 Br 2 N 3 S,[M+H] + ,475.9432；found 475.9433.
Example 5: preparation of 2- (5- (4-bromophenyl) -3- (3-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 5)
The preparation method is the same as in example 1. 3-methoxyacetophenone was used instead of 4-fluoroacetophenone to give a yellow solid with a yield of 27.4% and a melting point of 164-169 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.52–7.44(m,2H),7.39–7.31(m,2H),7.32–7.22(m,6H),7.05–6.90(m,1H),6.20(q,J＝1.1Hz,1H),5.86(s,1H),3.89(s,5H),3.26(dd,J＝17.4,5.2Hz,1H),2.24(s,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)164.79,159.74,151.01,149.39,140.71,132.65,131.86,129.71,128.02,119.03,115.82,111.24,103.69,63.64,55.40,43.51,17.60.HR-MS(ESI):calcd for C 20 H 18 BrN 3 OS,[M+H] + ,428.0432；found 428.0424.
Example 6: preparation of 2- (5- (4-bromophenyl) -3- (3-methylphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 6)
The preparation method is the same as in example 1. 3-methylacetophenone was used instead of 4-fluoroacetophenone to give a yellow solid with a yield of 30.2% and a melting point of 192-197 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.60(s,1H),7.55(d,J＝7.6Hz,1H),7.49–7.45(m,2H),7.34(t,J＝7.6Hz,1H),7.29(s,4H),7.27(s,1H),6.20(t,J＝1.2Hz,1H),5.96(s,1H),3.94(dd,J＝17.6,11.7Hz,1H),3.29(dd,J＝18.0,4.5Hz,1H),2.42(s,3H),2.26(s,3H). 13 CNMR(101MHz,CDCl 3 )δ(ppm)164.87,151.33,149.37,140.77,138.39,131.85,131.22,130.67,128.58,128.01,126.90,123.58,121.43,103.58,63.52,43.52,21.42,17.60.HR-MS(ESI):calcd for C 20 H 18 BrN 3 S,[M+H] + ,412.0483；found 412.0521.
Example 7: preparation of 2- (5- (4-bromophenyl) -3- (3-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 7)
The preparation method is the same as in example 1. 3-fluoro acetophenone was used instead of 4-fluoro acetophenone to give a yellow solid with a yield of 28.7% and a melting point of 165-169 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.49(m,J＝11.2,9.1,2.1Hz,4H),7.40(td,J＝7.9,5.6Hz,1H),7.27–7.22(m,2H),7.12(m,J＝8.3,2.7,1.0Hz,1H),6.22(q,J＝1.1Hz,1H),5.80(s,1H),3.89(dd,J＝17.4,12.0Hz,1H),3.23(dd,J＝17.4,5.6Hz,1H),2.26–2.16(m,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)164.57,161.66,149.84,149.44,140.50,133.58,131.92,130.32,127.97,122.07,121.57,116.77,116.55,113.12,112.89,103.95,63.77,43.30,17.58.HR-MS(ESI):calcd for C 19 H 15 BrFN 3 S,[M+H] + ,416.0232；found 416.0234.
Example 8: preparation of 2- (5- (4-bromophenyl) -3- (3-bromophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 8)
The preparation method is the same as in example 1. 3-bromoacetophenone was used instead of 4-fluoroacetophenone to give a yellow solid with a yield of 23.5% and a melting point of 169-174 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.91(q,J＝3.0,2.4Hz,1H),7.65(m,J＝8.5,3.8,2.4Hz,1H),7.58–7.51(m,1H),7.47(m,J＝8.6,2.5Hz,2H),7.34–7.26(m,2H),7.26–7.20(m,2H),6.23–6.20(m,1H),5.81(s,1H),3.94–3.81(m,1H),3.22(dd,J＝17.4,5.4Hz,1H),2.31–2.18(m,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)164.49,149.44,140.43,133.40,132.53,131.92,130.19,129.14,127.94,124.81,122.89,121.59,103.97,63.75,43.18,17.57.HR-MS(ESI):calcd for C 19 H 15 Br 2 N 3 S,[M+H] + ,475.9432；found 475.9429.
Example 9: preparation of 2- (5- (4-bromophenyl) -3- (2-methylphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 9)
The preparation method is the same as in example 1. 2-methylacetophenone is used to replace 4-fluoroacetophenone, so that a yellow solid is obtained, the yield is 24.3%, and the melting point is 143-148 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.49–7.45(m,2H),7.33(m,J＝10.0,7.0,1.5Hz,3H),7.28–7.21(m,3H),6.20(q,J＝1.1Hz,1H),5.65(dd,J＝12.1,5.5Hz,1H),3.97(dd,J＝17.2,11.9Hz,1H),3.32(dd,J＝17.2,5.6Hz,1H),2.72(s,3H),2.20(d,J＝1.1Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ(ppm)165.27,151.84,149.48,140.83,138.28,131.84,129.91,129.04,128.53,128.02,125.85,121.39,103.67,62.66,45.67,23.71,17.65.HR-MS(ESI):calcd for C 20 H 18 BrN 3 S,[M+H] + ,412.0483；found 412.0478.
Example 10: preparation of 2- (5- (4-bromophenyl) -3- (2-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 10)
The preparation method is the same as in example 1. 2-methoxyacetophenone was used instead of 4-fluoroacetophenone to give a yellow solid with a yield of 22.6% and a melting point of 123-128 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.01(dd,J＝7.8,1.8Hz,1H),7.49–7.44(m,2H),7.41–7.35(m,1H),7.27–7.21(m,2H),7.03(td,J＝7.6,1.0Hz,1H),6.93(dd,J＝8.4,0.9Hz,1H),6.18(t,J＝1.0Hz,1H),5.57(dd,J＝11.9,5.8Hz,1H),4.03(dd,J＝18.3,12.0Hz,1H),3.84(s,3H),3.40(dd,J＝18.3,5.9Hz,1H),2.19(d,J＝1.0Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ(ppm)165.24,157.82,151.31,149.34,141.14,131.73,131.11,129.18,128.09,121.22,120.93,120.55,111.48,103.40,63.68,55.41,46.73,17.64.HR-MS(ESI):calcd for C 20 H 18 BrN 3 OS,[M+H] + ,428.0432；found 428.0434.
Example 11: preparation of 2- (5- (4-bromophenyl) -3- (2-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 11)
The preparation method is the same as in example 1. 2-fluoro acetophenone was used instead of 4-fluoro acetophenone to give a yellow solid with a yield of 24.6% and a melting point of 150-155 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.05(td,J＝7.7,1.8Hz,1H),7.52–7.34(m,3H),7.28–7.21(m,4H),7.12(m,J＝11.6,8.3,1.2Hz,1H),6.21(q,J＝1.1Hz,1H),5.79(s,1H),4.02(m,J＝18.2,11.9,2.7Hz,1H),3.39(m,J＝18.1,5.6,3.0Hz,1H),2.23(s,3H). 13 CNMR(101MHz,CDCl 3 )δ(ppm)164.76,161.99,159.48,149.43,147.85,140.65,131.85,131.38,128.77,128.00,124.47,121.45,119.50,119.39,116.53,116.31,103.82,63.69,63.66,45.64,17.60.HR-MS(ESI):calcd for C 19 H 15 BrFN 3 S,[M+H] + ,416.0232；found 416.0203.
Example 12: preparation of 2- (5- (4-bromophenyl) -3- (2-bromophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 12)
The preparation method is the same as in example 1. 2-bromoacetophenone was used instead of 4-fluoroacetophenone to give a yellow solid with a yield of 27.5% and a melting point of 124-126 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.67(m,J＝16.8,7.9,1.5Hz,2H),7.50–7.45(m,2H),7.39(td,J＝7.6,1.3Hz,1H),7.28–7.23(m,2H),6.24–6.16(m,1H),5.71(s,1H),4.10(dd,J＝17.7,11.9Hz,1H),3.44(dd,J＝17.7,5.7Hz,1H),2.20(d,J＝1.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)164.88,151.59,149.38,140.35,134.18,132.57,131.86,130.84,130.61,129.83,128.69,128.06,127.49,126.36,121.60,103.94,64.11,50.88,46.08,17.56.HR-MS(ESI):calcd for C 19 H 15 Br 2 N 3 S,[M+H] + ,475.9432；found 475.9437.
Example 13: preparation of 2- (5- (4-fluorophenyl) -3- (2-bromophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 13)
The preparation method is the same as in example 1. 4-fluorobenzaldehyde is used for replacing 4-bromobenzaldehyde, 2-bromoacetophenone is used for replacing 4-fluoroacetophenone, and brown solid is obtainedThe yield was 26.3% and the melting point was 88-93 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.69(dd,J＝7.8,1.7Hz,1H),7.62(dd,J＝8.1,1.2Hz,1H),7.34(td,J＝7.6,1.3Hz,1H),7.27–7.19(m,3H),7.14(d,J＝7.8Hz,2H),6.16(d,J＝1.4Hz,1H),5.63(dd,J＝11.9,5.7Hz,1H),4.07(dd,J＝17.6,11.9Hz,1H),3.42(dd,J＝17.6,5.7Hz,1H),2.32(s,3H),2.18(d,J＝1.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ(ppm)164.93,163.43,160.98,151.57,149.38,137.03,134.17,132.66,130.85,130.56,128.05,127.47,121.60,115.71,115.50,103.86,64.04,50.87,46.21,17.58.HR-MS(ESI):calcd for C 19 H 15 BrFN 3 S,[M+H] + ,416.0232；found 416.0218.
Example 14: preparation of 2- (5- (4-fluorophenyl) -3- (2-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 14)
The preparation method is the same as in example 1. 4-fluorobenzaldehyde is used for replacing 4-bromobenzaldehyde, 2-methoxyacetophenone is used for replacing 4-fluoroacetophenone, and a dark green solid is obtained, the yield is 29.6%, and the melting point is 99-104 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.98(dd,J＝7.8,1.8Hz,1H),7.35(m,J＝8.4,7.3,1.8Hz,1H),7.32–7.29(m,2H),7.03–6.97(m,3H),6.91(dd,J＝8.4,1.1Hz,1H),6.14(q,J＝1.1Hz,1H),5.56(dd,J＝11.8,5.7Hz,1H),4.00(dd,J＝18.2,11.9Hz,1H),3.82(s,3H),3.38(dd,J＝18.2,5.8Hz,1H),2.16(d,J＝1.1Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ(ppm)170.33,168.34,165.91,163.09,156.55,154.24,143.39,136.27,134.06,133.30,125.90,125.72,120.48,120.27,116.84,108.46,108.44,68.81,60.45,51.90,22.44.HR-MS(ESI):calcd for C 20 H 18 FN 3 OS,[M+H] + ,368.1233；found 368.1238.
Example 15: preparation of 2- (5- (4-methylphenyl) -3- (2-bromophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 15)
The preparation method is the same as in example 1. 4-methyl benzaldehyde is used for replacing 4-bromobenzaldehyde, 2-bromoacetophenone is used for replacing 4-fluoroacetophenone, and a yellowish green solid is obtained, the yield is 25.7%, and the melting point is 82-86 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.69(dd,J＝7.8,1.7Hz,1H),7.62(dd,J＝8.1,1.2Hz,1H),7.34(td,J＝7.6,1.3Hz,1H),7.27–7.19(m,3H),7.14(d,J＝7.8Hz,2H),6.16(d,J＝1.4Hz,1H),5.63(dd,J＝11.9,5.7Hz,1H),4.07(dd,J＝17.6,11.9Hz,1H),3.42(dd,J＝17.6,5.7Hz,1H),2.32(s,3H),2.18(d,J＝1.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)170.11,156.66,154.28,144.47,142.07,139.42,138.00,136.11,135.86,134.36,132.91,131.41,126.16,108.91,69.57,51.28,25.41,21.94.HR-MS(ESI):calcd for C 20 H 18 BrN 3 S,[M+H] + ,412.0483；found 412.0470.
Example 16: preparation of 2- (5- (4-methylphenyl) -3- (2-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 16)
The preparation method is the same as in example 1. 4-methylbenzaldehyde is used for replacing 4-bromobenzaldehyde, 2-methoxyacetophenone is used for replacing 4-fluoroacetophenone, and a pale yellow solid is obtained, the yield is 28.5%, and the melting point is 140-143 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.98(dd,J＝7.8,1.8Hz),7.33(m,J＝8.3,7.3,1.8Hz),7.24–7.19(m),7.14–7.08(m),7.02–6.97(m),6.89(dd,J＝8.4,1.1Hz),6.11(q,J＝1.1Hz),5.53(dd,J＝11.9,5.7Hz),3.99(dd,J＝18.2,11.9Hz),3.80,3.38(dd,J＝18.2,5.8Hz),2.31,2.16(d,J＝1.1Hz). 13 C NMR(101MHz,CDCl 3 )δ(ppm)165.36,157.84,151.34,149.37,139.12,137.01,130.90,129.31,126.21,120.87,120.86,111.45,103.06,64.03,55.40,46.96,21.16,17.70.HR-MS(ESI):calcd for C 21 H 21 N 3 OS,[M+H] + ,364.1484；found 364.1495.
Example 17: preparation of 2- (5- (3, 4, 5-trimethoxyphenyl) -3- (2-bromophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 17)
The preparation method is the same as in example 1.3, 4, 5-methoxybenzaldehyde is used for replacing 4-bromobenzaldehyde, 2-bromoacetophenone is used for replacing 4-fluoroacetophenone, and a pale yellow solid is obtained, the yield is 30.5%, and the melting point is 126-131 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.64(m,J＝14.2,7.9,1.5Hz,2H),7.36(td,J＝7.6,1.2Hz,1H),7.24(td,J＝7.7,1.7Hz,1H),6.57(s,2H),6.18(q,J＝1.0Hz,1H),5.59(dd,J＝11.8,5.4Hz,1H),4.02(dd,J＝17.7,11.8Hz,1H),3.82(d,J＝1.2Hz,9H),3.48(dd,J＝17.6,5.4Hz,1H),2.20(d,J＝1.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)165.13,153.40,151.77,149.46,137.24,136.85,134.15,132.78,130.79,130.56,127.50,121.64,103.87,103.12,64.90,60.82,56.12,46.15,17.67.HR-MS(ESI):calcd for C 22 H 22 BrN 3 O 3 S,[M+H] + ,488.0643；found 488.0644.
Example 18: preparation of 2- (5- (3, 4, 5-trimethoxyphenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 18)
The preparation method is the same as in example 1.3, 4, 5-methoxybenzaldehyde is used for replacing 4-bromobenzaldehyde, 4-fluoroacetophenone is used for replacing 4-fluoroacetophenone, so that a pale yellow solid is obtained, the yield is 29.6%, and the melting point is 187-190 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.82–7.59(m,2H),7.14–7.01(m,2H),6.52(s,2H),6.18(t,J＝1.2Hz,1H),5.55(dd,J＝11.9,6.0Hz,1H),3.81(d,J＝5.1Hz,10H),3.24(dd,J＝17.3,6.0Hz,1H),2.20(d,J＝1.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ(ppm)165.18,164.88,162.39,153.48,150.43,149.42,137.28,128.34,127.77,115.94,115.72,103.68,103.01,64.58,60.81,56.13,43.74,17.65.HR-MS(ESI):calcd for C 22 H 22 FN 3 O 3 S,[M+H] + ,428.1444；found 428.1464.
Example 19: preparation of 2- (5- (3-methylphenyl) -3- (2-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 19)
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The preparation method is the same as in example 1. 3-methylbenzaldehyde is used for replacing 4-bromobenzaldehyde, 2-methoxyacetophenone is used for replacing 4-fluoroacetophenone, and a yellow solid is obtained, the yield is 30.5%, and the melting point is 98-100 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.01(dd,J＝7.8,1.8Hz,1H),7.34(m,J＝8.9,7.4,1.8Hz,1H),7.20(t,J＝7.6Hz,1H),7.16–7.12(m,2H),7.06(d,J＝7.5Hz,1H),7.01(td,J＝7.6,1.0Hz,1H),6.91(dd,J＝8.4,1.0Hz,1H),6.13(d,J＝1.2Hz,1H),5.53(dd,J＝12.0,5.8Hz,1H),4.01(dd,J＝18.2,12.0Hz,1H),3.81(s,3H),3.39(dd,J＝18.2,5.9Hz,1H),2.33(s,3H),2.18(d,J＝1.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)165.39,157.84,151.36,149.39,142.06,138.27,130.93,129.22,128.50,128.19,126.88,123.27,120.87,111.46,103.09,64.20,55.40,47.02,21.53,17.71.HR-MS(ESI):calcd for C 21 H 21 N 3 OS,[M+H] + ,364.1484；found 364.1482.
Example 20: preparation of 2- (5- (2-methylphenyl) -3- (2-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 20)
The preparation method is the same as in example 1. 2-methylbenzaldehyde is used for replacing 4-bromobenzaldehyde, 2-methoxyacetophenone is used for replacing 4-fluoroacetophenone, and a yellow solid is obtained, the yield is 31.6%, and the melting point is 110-112 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.00(dt,J＝7.8,1.5Hz,1H),7.34(m,J＝8.6,7.3,1.5Hz,1H),7.21–7.11(m,4H),7.00(m,J＝7.5,1.2Hz,1H),6.90(dd,J＝8.4,1.2Hz,1H),6.14(t,J＝1.2Hz,1H),5.71(m,J＝12.1,6.3,1.2Hz,1H),4.04(m,J＝18.1,12.1,1.2Hz,1H),3.81(d,J＝1.2Hz,3H),3.27(m,J＝18.1,6.3,1.2Hz,1H),2.50(s,2H),2.16(t,J＝1.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)165.24,157.81,151.27,149.43,140.18,134.68,130.93,130.56,129.24,127.16,126.43,125.46,120.88,111.45,103.10,61.61,55.42,45.97,19.68,17.67.HR-MS(ESI):calcd for C 21 H 21 N 3 OS,[M+H] + ,364.1484；found 364.1483.
Example 21: preparation of 2- (5- (3-methylphenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-methylthiazole (Compound 21)
The preparation method is the same as in example 1. 3-methylbenzaldehyde is used for replacing 4-bromobenzaldehyde, 4-methoxyacetophenone is used for replacing 4-fluoroacetophenone, and a pale yellow solid is obtained, the yield is 31.8%, and the melting point is 130-132 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.70–7.66(m,2H),7.20(t,J＝7.5Hz,1H),7.14–7.10(m,2H),7.08–7.04(m,1H),6.94–6.89(m,2H),6.13(q,J＝1.0Hz,1H),5.57(dd,J＝11.9,5.7Hz,1H),3.84(s,4H),3.21(dd,J＝17.2,5.7Hz,1H),2.32(s,3H),2.17(d,J＝1.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ(ppm)165.21,160.85,151.17,149.36,141.78,138.42,128.60,128.35,127.97,126.77,124.28,123.22,114.05,103.04,63.98,55.39,43.91,21.51,17.68.HR-MS(ESI):calcd for C 21 H 21 N 3 OS,[M+H] + ,364.1484；found 364.1475.
Example 22: culture of RAW264.7 cells
We selected mouse mononuclear macrophage RAW264.7 cells for culture. RAW264.7 cells were cultured in DMEM high-sugar culture medium containing 10% of fresh calf serum and 100U/mL penicillin, streptomycin, and the incubator culture conditions were set to 5% CO 2 The cells were changed every other day at 37℃and observed for growth every day. Discarding when RAW264.7 cells grow to 70-80% fusion degreeRemoving old cell culture solution, washing cells with PBS for 2 times, adding 0.25% trypsin, observing cell morphology change under an inverted microscope, when cytoplasmatic retraction, cytokinesis and cell gap enlargement occur, discarding digestive juice, immediately adding cell culture solution containing 10% serum to stop digestion, sucking culture solution with a straw, repeatedly gently blowing off adherent cells to make them fall off and suspend, adjusting cell density to appropriate, inoculating into new culture dish, placing into 5% CO 2 Culturing in an incubator at 37 ℃.
Example 23: evaluation of anti-inflammatory Activity of Dihydropyrazole thiazole derivatives (Compounds 1 to 21) on mouse mononuclear macrophage RAW264.7
We used the MTT method to determine cytotoxicity of compounds 1-21 against LPS-induced mouse mononuclear macrophage RAW 264.7. RAW264.7 cells in the logarithmic growth phase were seeded into 96-well plates with about 10000 cells per well. After 16h incubation in the incubator, LPS pretreatment was added for 1 hour, followed by the addition of compounds 1-21, and 6 duplicate wells were placed per compound. After 24h of incubation, the medium was aspirated and the MTT solution was added and incubation continued for 3h. Dimethyl sulfoxide was then added and shaken on a shaker for 10min. Finally, the absorbance (OD value) of the solution was measured at 550nm using a microplate reader, and the effect of each drug on the cell activity was calculated.
Based on the results of MTT, the appropriate concentration of compounds 1-21 was selected. RAW264.7 cells in the logarithmic growth phase were seeded into 48-well plates. After 16h incubation in the incubator, LPS pretreatment was added for 1 hour, followed by the addition of compounds 1-28, and 3 multiplex wells were set for each compound. After 24 hours of culture, the culture medium supernatant solution is sucked, transferred into a 96-well plate, NO detection reagent is sequentially added, after 5 minutes of reaction, the absorbance (OD value) of the solution is detected at 550nm by using an enzyme-labeled instrument, and the concentration of NO in each well is calculated according to a standard curve. The measured inhibition of NO release by Compounds 1-21 and the control drugs indomethacin and celecoxib for RAW264.7 are shown in FIGS. 1, 2 and 3. As can be seen from fig. 1, 2 and 3, compounds 1 to 21 have various degrees of inhibitory effects on the NO release of LPS-induced RAW264.7 inflammatory cells. Compounds 2, 10, 12, 15, 16, 20 all had good inhibitory effect at an action concentration of 1. Mu.M, and compounds 14, 20, 21 had good inhibitory effect at an action concentration of 10. Mu.M. Taken together, compound 20 has good inhibitory effects at both 1 μm and 10 μm concentrations, even in excess of the positive control drug, and is therefore a promising potential compound in the direction of eliminating inflammation.

Claims (1)

1. The application of the dihydropyrazolothiazole derivative in preparing anti-inflammatory drugs is characterized in that: the dihydropyrazolothiazoles are selected from compounds with the following structures:
the anti-inflammatory drug has good anti-inflammatory activity on RAW264.7 cells with LPS induced inflammation.
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