Steroid chalcone and ester derivatives thereof and preparation method and application thereof

Abstract

The invention discloses steroid chalcone and ester derivatives thereof, the structural formula of the derivatives is as shown in the formula (I), R1 is hydrogen or halogen group, R2 is hydrogen or a C1-3 alkoxy group, and R3 is hydrogen, a halogen group, a benzyloxy group, a mercaptomethyl group, a C1-3 alkyl group or a C1-3 alkoxy group. The steroid chalcone and the ester derivative thereof provided by the invention are simple to prepare, raw materials are easy to obtain, meanwhile, good anti-inflammatory activity is realized, the selectivity is higher, the cytotoxicity is lower, the steroidchalcone and the ester derivative thereof disclosed by the invention have a very strong inhibition effect on nitric oxide (NO) generated by lipopolysaccharide (LPS)-induced mouse peritoneal macrophageRAW 264.7 cells, particularly, the IC50 value of the compound 7 is close to that of dexamethasone, the dexamethasone derivative has an obvious inhibition effect on inflammatory factors TNF-alpha, IL-6 and PGE-2 released by RAW 264.7 cells, has lower toxicity to the cells than dexamethasone, has important significance in preparation of drugs for preventing and treating inflammation-related diseases, and can be widely applied to preparation of drugs for resisting inflammatory diseases.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a steroidal chalcone and its ester derivatives as well as a preparation method and application thereof. Background technique

[0002] In recent years, chalcone compounds have shown more and more important roles in drug research and biology. Compounds containing chalcone structures have strong physiological activities and have attracted more and more attention from researchers. Chalcones have good biological activities such as anti-tumor, anti-inflammation, anti-angiogenesis, antibacterial and antimalarial. Its basic skeleton is 1,3-diaryl-2-propen-1-one, which contains two aromatic rings separated by α, β unsaturated ketone, and the biological activity of chalcone depends on this unique structure. Previous studies have shown that the properties of the substituents on the benzene ring and their conformations in the core structure play a crucial role in the activ...

Examples

Embodiment 1

[0041] Embodiment 1: the synthesis of compound 1

[0042] Compound 1 provided in this example is: 3β-3-phenylacrylate-pregn-5-en-17β-yl-3'-(p-benzyloxy)-phenylpropyl-2'-ene-1' -ketone, its structural formula is as follows:

[0043]

[0044] The preparation method of compound 1 is as follows:

[0045] (1) Preparation of intermediate 1-1:

[0046] Will replace benzaldehyde: (2.12g),, equimolar pregnenolone (3.16g), 10% NaOH solution (3g NaOH dissolved in 10mL water) and absolute ethanol solution (30mL) were mixed, stirred and reacted for 48h at 25°C, filtered, washed, dried, and recrystallized from ethanol to obtain intermediate Body 1-1:

[0047]

[0048] (2) Preparation of compound 1

[0049]Weigh intermediate 1-1 (5.10g, 0.01mol) and place it in a 50mL round bottom flask, add cinnamic acid (2.96g, 0.02mol), dissolve in anhydrous dichloromethane (25mL), add DMAP (0.12g , 1mmol) as a catalyst, reacted in an ice bath for 30 minutes, slowly added EDCI (0.38g, 2mmol...

Embodiment 2

[0051] Example 2: Synthesis of compound 2.

[0052] Compound 2 provided in this example is: 3β-3-phenylacrylate-pregn-5-en-17β-yl-3'-(p-methoxy)-phenylpropyl-2'-ene-1' - Ketone, its structural formula is as follows:

[0053]

[0054] The preparation method of compound 2 except the R of substituted benzaldehyde 3 Except for methoxyl group, all the other raw materials, consumption and operation steps are consistent with Example 1. and end up with:

[0055] Yellow solid powder, yield 51.23%, M.p.: 164.4-167.3℃.IR(KBr,cm -1 ): 1700.18(C=O), 1677.34, 1644.76, 1597.74, 1573.53, 1510.91, 1451.52, 1172.76(C-O), 1098.08(C-O). 1 HNMR (600MHz, δppm, CDCl 3 ):7.68(d,1H,J=16.20Hz,C=CH),7.51–7.56(m,5H,C=CH,Ar-H),7.33–7.41(m,3H,Ar-H),6.91( d,2H,J=8.40Hz,Ar-H),6.67(d,1H,J=16.20Hz,CH=C),6.43(d,1H,J=16.20Hz,CH=C),5.42(s, 1H,C 6 -H),4.72-4.79(m,1H,C 3α -H),3.84(s,3H,C 4″ -OCH 3 ),2.85(m,1H,C 17α -H),1.04(s,3H,C 10 -CH 3 ),0.65(s,3H,C 13 -CH 3 ). 13 C NMR (ppm, CDCl 3 ):200.2...

Embodiment 3

[0056] Example 3: Synthesis of compound 3 Compound 3 provided in this example is: 3β-3-phenylacrylate-pregna-5-en-17β-yl-3'-(p-methyl)-phenylpropyl- 2'-en-1'-one, its structural formula is as follows:

[0057]

[0058] The preparation method of compound 3 except the R of substituted benzaldehyde 3 Except for methyl, all the other raw materials, consumption and operation steps are consistent with Example 1. and end up with:

[0059] Yellow powder, yield 58.37%, M.p.:188.2189.7℃.IR(KBr,cm -1 ): 1708.30(C=O), 1679.80, 1644.25, 1604.25, 1585.0, 1487.06, 1450.53, 1174.51(C-O), 1097.16(C-O). 1 HNMR (600MHz, δppm, CDCl 3 ):7.68(d,1H,J=16.20Hz,C=CH),7.49–7.56(m,3H,C=CH,Ar-H),7.46(d,1H,J=7.80Hz,Ar-H) ,7.33–7.41(m,3H,Ar-H),7.20(d,2H,J=7.80Hz,Ar-H),6.75(d,1H,J=16.20Hz,CH=C),6.43(d, 1H, J=16.20Hz, CH=C), 5.42(s, 1H, C 6 -H),4.71-4.79(m,1H,C 3α -H),2.86(m,1H,C 17α -H),2.38(s,3H,C 4″ -CH 3 ),1.04(s,3H,C 10 -CH 3 ),0.65(s,3H,C 13 -CH 3 ). 13 C NMR (ppm, CDCl 3 ):200.38,16...

technical field

[0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a steroidal chalcone and its ester derivatives as well as a preparation method and application thereof. Background technique

[0002] In recent years, chalcone compounds have shown more and more important roles in drug research and biology. Compounds containing chalcone structures have strong physiological activities and have attracted more and more attention from researchers. Chalcones have good biological activities such as anti-tumor, anti-inflammation, anti-angiogenesis, antibacterial and antimalarial. Its basic skeleton is 1,3-diaryl-2-propen-1-one, which contains two aromatic rings separated by α, β unsaturated ketone, and the biological activity of chalcone depends on this unique structure. Previous studies have shown that the properties of the substituents on the benzene ring and their conformations in the core structure play a crucial role in the activ...

Examples

Embodiment 1

[0041] Embodiment 1: the synthesis of compound 1

[0042] Compound 1 provided in this example is: 3β-3-phenylacrylate-pregn-5-en-17β-yl-3'-(p-benzyloxy)-phenylpropyl-2'-ene-1' -ketone, its structural formula is as follows:

[0043]

[0044] The preparation method of compound 1 is as follows:

[0045] (1) Preparation of intermediate 1-1:

[0046] Will replace benzaldehyde: (2.12g),, equimolar pregnenolone (3.16g), 10% NaOH solution (3g NaOH dissolved in 10mL water) and absolute ethanol solution (30mL) were mixed, stirred and reacted for 48h at 25°C, filtered, washed, dried, and recrystallized from ethanol to obtain intermediate Body 1-1:

[0047]

[0048] (2) Preparation of compound 1

[0049]Weigh intermediate 1-1 (5.10g, 0.01mol) and place it in a 50mL round bottom flask, add cinnamic acid (2.96g, 0.02mol), dissolve in anhydrous dichloromethane (25mL), add DMAP (0.12g , 1mmol) as a catalyst, reacted in an ice bath for 30 minutes, slowly added EDCI (0.38g, 2mmol...

Embodiment 2

[0051] Example 2: Synthesis of compound 2.

[0052] Compound 2 provided in this example is: 3β-3-phenylacrylate-pregn-5-en-17β-yl-3'-(p-methoxy)-phenylpropyl-2'-ene-1' - Ketone, its structural formula is as follows:

[0053]

[0054] The preparation method of compound 2 except the R of substituted benzaldehyde 3 Except for methoxyl group, all the other raw materials, consumption and operation steps are consistent with Example 1. and end up with:

[0055] Yellow solid powder, yield 51.23%, M.p.: 164.4-167.3℃.IR(KBr,cm -1 ): 1700.18(C=O), 1677.34, 1644.76, 1597.74, 1573.53, 1510.91, 1451.52, 1172.76(C-O), 1098.08(C-O). 1 HNMR (600MHz, δppm, CDCl 3 ):7.68(d,1H,J=16.20Hz,C=CH),7.51–7.56(m,5H,C=CH,Ar-H),7.33–7.41(m,3H,Ar-H),6.91( d,2H,J=8.40Hz,Ar-H),6.67(d,1H,J=16.20Hz,CH=C),6.43(d,1H,J=16.20Hz,CH=C),5.42(s, 1H,C 6 -H),4.72-4.79(m,1H,C 3α -H),3.84(s,3H,C 4″ -OCH 3 ),2.85(m,1H,C 17α -H),1.04(s,3H,C 10 -CH 3 ),0.65(s,3H,C 13 -CH 3 ). 13 C NMR (ppm, CDCl 3 ):200.2...

Embodiment 3

[0056] Example 3: Synthesis of compound 3 Compound 3 provided in this example is: 3β-3-phenylacrylate-pregna-5-en-17β-yl-3'-(p-methyl)-phenylpropyl- 2'-en-1'-one, its structural formula is as follows:

[0057]

[0058] The preparation method of compound 3 except the R of substituted benzaldehyde 3 Except for methyl, all the other raw materials, consumption and operation steps are consistent with Example 1. and end up with:

[0059] Yellow powder, yield 58.37%, M.p.:188.2189.7℃.IR(KBr,cm -1 ): 1708.30(C=O), 1679.80, 1644.25, 1604.25, 1585.0, 1487.06, 1450.53, 1174.51(C-O), 1097.16(C-O). 1 HNMR (600MHz, δppm, CDCl 3 ):7.68(d,1H,J=16.20Hz,C=CH),7.49–7.56(m,3H,C=CH,Ar-H),7.46(d,1H,J=7.80Hz,Ar-H) ,7.33–7.41(m,3H,Ar-H),7.20(d,2H,J=7.80Hz,Ar-H),6.75(d,1H,J=16.20Hz,CH=C),6.43(d, 1H, J=16.20Hz, CH=C), 5.42(s, 1H, C 6 -H),4.71-4.79(m,1H,C 3α -H),2.86(m,1H,C 17α -H),2.38(s,3H,C 4″ -CH 3 ),1.04(s,3H,C 10 -CH 3 ),0.65(s,3H,C 13 -CH 3 ). 13 C NMR (ppm, CDCl 3 ):200.38,16...

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