A kind of forskolin aromatic derivative and its preparation method and application

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a forskolin aromatic derivative, a preparation method and an application thereof. The forskolin aromatic derivative has a chemical structure shown in formula (I), and is obtained by an open reaction of forskolin and palladium acetate in tetrahydrofuran to obtain a forskolin cycloalkenyl ether intermediate 2. The forskolin cycloalkenyl ether intermediate 2 is reacted with aryl iodide, silver acetate, copper acetate and palladium acetate in dry dichloroethane to obtain a forskolin aromatic derivative 3. The forskolin aromatic derivative obtained by the present invention contains a cycloalkenyl ether structure, and this new structure gives this type of derivative excellent anti-inflammatory activity.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a forskolin aromatic derivative and a preparation method and application thereof. Background Art

[0002] Forskolin is a complex hemiarthane-type plant diterpenoid. Based on its activity as a cyclic adenosine monophosphate (cAMP) cyclase activator, it is used to treat a variety of diseases. Natural forskolin is currently only found in the cork layer of the root of the endangered plant Coleus forskohlii. Forskolin analogs or derivatives reported in the literature have various pharmacological activities such as anti-tumor, anticoagulant, and antihypertensive.

[0003] Summary of the invention

[0004] In view of this, the purpose of the present invention is to provide a forskolin aromatic derivative and a preparation method and application thereof. The structure of this type of compound contains a cyclic ether structure, and this new structure is expected to give this type of derivative excellent anti-inflammatory activity.

[0005] The present invention provides a forskolin aromatic derivative, which has a structure shown in formula (I):

[0006]

[0007] Here, R represents one of phenyl, p-chlorophenyl, p-methoxyphenyl, p-tert-butylphenyl and p-trifluoromethoxyphenyl.

[0008] Furthermore, the forskolin aromatic derivative has a structure as shown in any one of Formulae 3a to 3e:

[0009]

[0010] in,

[0011] When R is phenyl, the forskolin aromatic derivative is a compound having a structure shown in Formula 3a;

[0012] When R is p-chlorophenyl, the forskolin aromatic derivative is a compound having a structure shown in Formula 3b;

[0013] When R is p-methoxybenzene, the forskolin aromatic derivative is a compound having a structure shown in Formula 3c;

[0014] When R is p-tert-butylphenyl, the forskolin aromatic derivative is a compound having a structure shown in Formula 3d;

[0015] When R is p-trifluoromethoxyphenyl, the forskolin aromatic derivative is a compound having a structure shown in Formula 3e;

[0016] The present invention also provides a method for preparing a forskolin aromatic derivative, comprising the following steps:

[0017] Forskolin is reacted with palladium acetate in tetrahydrofuran to obtain forskolin cyclopentane intermediate 2. Forskolin cyclopentane intermediate 2 is reacted with aryl iodide, silver acetate, copper acetate, palladium acetate in dry dichloroethane to obtain forskolin aromatic derivative 3.

[0018] Wherein, the reaction formula of the reaction is:

[0019]

[0020] Here, R represents one of phenyl, p-chlorophenyl, p-methoxyphenyl, p-tert-butylphenyl and p-trifluoromethoxyphenyl.

[0021] Specifically, the preparation method comprises the following steps:

[0022] S1. Forskolin is dissolved in tetrahydrofuran, palladium acetate is added, and the reaction is carried out in an open state to obtain a first reaction solution. The first reaction solution is cooled, concentrated under reduced pressure, diluted with an organic solvent, washed with water, washed with saturated brine, dried over MgSO4, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid forskolin cyclohexene ether intermediate 2, wherein the molar ratio of forskolin to palladium acetate is 1:0.2;

[0023] S2. Dissolve the forskolin cycloalkenyl ether intermediate 2 in dry dichloroethane, add aryl iodide, silver acetate, copper acetate and palladium acetate in sequence, and react under argon protection to obtain a second reaction liquid. After cooling the second reaction liquid, concentrate it under reduced pressure, dilute it with an organic solvent, wash it with water and saturated brine in sequence, dry it with MgSO4, concentrate it under reduced pressure, and then perform column chromatography to obtain a white solid forskolin aromatic derivative 3, wherein the molar ratio of the forskolin cycloalkenyl ether intermediate 2, aryl iodide, silver acetate, copper acetate and palladium acetate is 1:2:1.2:2:0.5; wherein the aryl iodine is one of iodobenzene, p-chloroiodobenzene, p-methoxyiodobenzene, p-tert-butyliodobenzene and p-trifluoromethoxyiodobenzene.

[0024] Preferably, in step S1 of the above preparation method, the reaction temperature is 40° C. and the reaction time is 24 h.

[0025] Preferably, in step S2 of the above preparation method, the reaction temperature is 60° C. and the reaction time is 24 h.

[0026] Preferably, in the above preparation method, the organic solvent is at least one of ethyl acetate, diethyl ether and benzene.

[0027] The present invention also provides the use of the forskolin aromatic derivatives in the preparation of anti-inflammatory drugs.

[0028] Compared with the prior art, the present application provides a new class of compounds, forskolin aromatic derivatives, and preparation methods and applications thereof. The compound structure contains a cyclic ether structure, and this new structure gives this class of derivatives excellent anti-inflammatory activity, which can be used in the preparation of anti-inflammatory drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[0030] Figure 1 The NMR of the forskolin aromatic derivative (3a) provided in Example 2 of the present invention is 1 H spectrum;

[0031] Figure 2 The NMR of the forskolin aromatic derivative (3a) provided in Example 2 of the present invention is 13 C spectrum;

[0032] Figure 3 The NMR of the forskolin aromatic derivative (3b) provided in Example 3 of the present invention is 1 H spectrum;

[0033] Figure 4 The NMR of the forskolin aromatic derivative (3b) provided in Example 3 of the present invention is 13 C spectrum. DETAILED DESCRIPTION

[0034] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] Example 1

[0036] 82 mg (0.2 mmol) of forskolin was dissolved in tetrahydrofuran (2 ml), and then 5 mg (0.02 mmol) of palladium acetate was added and reacted at 40° C. for 24 hours. The reaction solution was concentrated under reduced pressure and column chromatography (petroleum ether: ethyl acetate = 2:1) was performed to obtain 77 mg of a white solid, i.e., forskolin cyclopentane ether intermediate 2 (yield = 85%).

[0037] 1H NMR (400MHz, CDCl3): δ5.26(d,J=3.8Hz,1H,H-7),4.48(d,J=2.9Hz,1H,H-15),4.47(d,J=3.7Hz,1H,H-1),4.29(m,2H,H-6,1-OH),4 .27(d,J=2.9Hz,1H,H-15),2.66(d,J=18.9Hz,1H,H-12),2.53(d,J=18.9Hz,1H,H-12),2.17(s,3H,7-OCOCH3),2.16–2.14(m,1H,H- 5),2.05(td,J=13.9,3.0Hz,1H,H-2e),1.91(td,J=13.5,3.5Hz,1H,H-3a),1.82(s,1H,6-OH),1.56(s,3H,8-CH3),1.54(s,3H,10-C H3),1.51(dd,J=3.3,3.1Hz,1H,H-2a),1.34(s,3H,13-CH3),1.28(s,3H,4e-CH3),1.10(t,J=3.1Hz,1H,H-3e),1.06(s,3H,4a-CH3). 13 C NMR (100MHz, CDCl3) δ200.0,169.6,157.1,88.3,84.7,79.4,75.7,73.0,69.7,69.5,4 9.3,43.7,42.8,36.0,34.7,33.0,25.9,24.8,24.4,21.2,21.0,19.6.HRMS(ESI):m / z calcd for C 22 H 33 O7:409.2226; found:409.2228[M+H] + .

[0038] Example 2

[0039] 41 mg (0.1 mmol) of forskolin cyclopentane intermediate 2 was dissolved in dry dichloroethane (2 ml), and then 41 mg of iodobenzene (0.2 mmol), 20 mg (0.12 mmol) of silver acetate, 40 mg (0.2 mmol) of copper acetate, and 8 mg (0.05 mmol) of palladium acetate were added, and the mixture was reacted at 60° C. for 24 hours under argon protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and column chromatography (dichloromethane: petroleum ether = 1:1) was performed to obtain 38 mg of a white solid, i.e., forskolin aromatic derivative 3a (yield 78%).

[0040] 1H NMR(400MHz,Chloroform-d)δ7.43(d,J=7.7Hz,2H,ArH),7.26(t,J=7.6Hz,2H,ArH),7.15-7.09(m,1H,ArH),5.53(s,1H,H-14),5.21(d,J =3.8Hz,1H,H-7),4.42(t,J=3.5Hz,1H,H-1),4.20(t,J=2.9Hz,1H,H-6),3.65(s,1H,1-OH),2.65(d,J=18.9Hz,1H,H-12),2.56(d,J=19.0H z,1H,H-12),2.24(d,J=2.8Hz,1H,H-5),2.07(s,3H,7-OCOCH3),2.05-1.97(m,1H),1.87(td,J=13.8,13.3,3.2Hz,1H),1.79(s,1H,6-OH), 1.53(s,3H,CH3),1.50(s,3H,CH3),1.47-1.44(m,1H),1.36(s,3H,CH3),1.21(s,3H,CH3),1.06(dt,J=13.1,3.3Hz,1H),1.01(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ200.2,169.5,150.5,133.6,128.6,128.3,126.9,101.1,89.0,79.6,75.8,72. 9,70.8,69.5,49.5,44.3,44.0,36.3,34.7,33.4,25.9,24.5,24.4,21.2,21.1,19.8.HRMS(ESI):m / z calcd for C 28 H 36 O7Na:507.2353; found:507.2366[M+Na] + .

[0041] Example 3

[0042] Example compound 3b was prepared according to the method of Example 2 above, using p-chloroiodobenzene instead of iodobenzene.

[0043] 3b: Yield: 82%, 1H NMR(400MHz,Chloroform-d)δ7.50(d,J=8.4Hz,2H,ArH),7.31(d,J=8.3Hz,2H,ArH),5.56(s,1H,H-14),5.25(d,J=3.8Hz,1H,H-7),4. 50(p,J=2.2Hz,1H,H-1),4.32(d,J=2.8Hz,1H,H-6),3.53(s,1H,1-OH),2.74(d,J=19.0Hz,1H,H-12),2.64(d,J=19.0Hz,1H,H-12),2.2 9(d,J=2.6Hz,1H,H-5),2.16(s,3H,CH3),2.10(dt,J=14.1,2.9Hz,1H),1.96(td,J=13.5,3.3Hz,1H),1.88(s,1H,6-OH),1.62(s,3H,C H3),1.59(s,3H,CH3),1.56(q,J=5.3,3.3Hz,1H),1.44(s,3H,CH3),1.31(s,3H,,CH3),1.18(dt,J=13.3,3.3Hz,1H),1.10(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ200.0,169.5,151.1,132.4,132.2,129.5,128.7,99.9,89.2,79.7,75.7,7 2.9,70.8,69.4,49.4,44.3,44.1,36.3,34.7,33.5,25.9,24.4,21.2,21.1,19.8.HRMS(ESI):m / z calcd for C 28 H 35 O7ClNa:541.1964; found:541.1974[M+Na] + .

[0044] Example 4

[0045] Example compound 3c was prepared according to the method of Example 2 above, using p-methoxyiodobenzene instead of iodobenzene.

[0046] 3c: Yield 81%, 1H NMR(400MHz,Chloroform-d)δ7.49-7.43(m,2H,ArH),6.91-6.82(m,2H,ArH),5.55(s,1H,H-14),5.28(d,J=3.9Hz,1H,H-7),4.50(t,J=3 .3Hz,1H,H-1),4.30(t,J=2.7Hz,1H,H-6),3.81(s,1H,1-OH),3.80(s,3H,ArOCH3),2.72(d,J=19.0Hz,1H,H-12),2.63(d,J=19.0Hz,1H,H -12),2.33(d,J=2.7Hz,1H,H-5),2.14(s,3H,7-OCOCH3),2.08(dt,J=13.9,2.7Hz,1H),1.98(td,J=13.5,3.1Hz,1H),1.85(s,1H,6-OH),1 .61(s,3H,CH3),1.56(s,3H,CH3),1.56-1.52(m,1H),1.42(s,3H,CH3),1.29(s,3H,CH3),1.15(dt,J=12.9,3.1Hz,1H),1.09(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ200.4,169.5,158.4,148.9,129.5,126.2,114.0,100.7,89.0,79.6,75.8,73. 0,70.8,69.5,55.3,49.7,44.2,44.0,36.3,34.7,33.5,25.9,24.4,21.3,21.2,19.8.HRMS(ESI):m / z calcdfor C 29 H 38 O8Na:537.2459; found:537.2464[M+Na] + .

[0047] Example 5

[0048] Example Compound 3d was prepared according to the method of Example 2 above, using p-tert-butyl iodobenzene instead of iodobenzene.

[0049] 3d: yield 83%, 1H NMR(400MHz,Chloroform-d)δ7.52-7.41(m,2H,ArH),7.40-7.33(m,2H,ArH),5.60(s,1H,H-14),5.29(d,J=3.8Hz,1H,H-7),4.50(d,J= 3.8Hz,1H,H-1),4.32(d,J=2.8Hz,1H,H-6),3.83(s,1H,1-OH),2.73(d,J=19.0Hz,1H,H-12),2.65(d,J=18.9Hz,1H,H-12),2.35(d,J=2. 7Hz,1H,H-5),2.16(s,3H,7-OCOCH3),2.14-2.07(m,1H),2.00(td,J=13.4,3.1Hz,1H),1.88(s,1H,6-OH),1.63(s,3H,CH3),1.63–1.59( m,1H),1.58(s,3H,CH3),1.45(s,3H,CH3),1.32(s,9H,CH3,CH3,CH3),1.31(s,3H,CH3),1.18(dt,J=13.2,3.3Hz,1H),1.10(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ200.4,169.4,149.8,149.8,130.7,128.0,125.5,101.1,89.0,79.7,75.7,73.0,70. 9,69.5,49.6,44.3,43.9,36.3,34.7,34.5,33.4,31.3,25.9,24.5,24.4,21.3,21.1,19.9.HRMS(ESI):m / z calcd forC 32 H 44 O7Na:563.2979; found:563.2991[M+Na] + .

[0050] Example 6

[0051] Example compound 3e was prepared according to the method of Example 2 above, using p-trifluoromethoxyiodobenzene instead of iodobenzene.

[0052] 3e: yield 80%, 1H NMR(400MHz,Chloroform-d)δ7.57(d,J=8.5Hz,2H,ArH),7.17(d,J=8.3Hz,2H,ArH),5.57(s,1H,H-14),5.23(d,J=3.8Hz,1H,H-7),4.46 (d,J=3.6Hz,1H,H-1),4.30(d,J=3.1Hz,1H,H-6),3.45(s,1H,1-OH),2.72(dd,J=19.0,1.1Hz,1H,H-12),2.63(dd,J=18.9,1.1Hz,1H,H- 12),2.25(d,J=2.8Hz,1H,H-5),2.14(s,3H,7-OCOCH3),2.08(dt,J=14.2,2.9Hz,1H),1.92(td,J=13.7,3.4Hz,1H),1.83(s,1H,6-OH),1 .60(s,3H,CH3),1.57(s,3H,CH3),1.55-1.51(m,1H),1.43(s,3H,CH3),1.28(s,3H,CH3),1.15(dt,J=13.1,3.4Hz,1H),1.05(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ200.0,169.5,151.3,132.5,129.6,121.1,99.7,89.2,79.7,75.6,72.9,70.8 ,69.5,49.3,44.3,44.1,36.3,34.7,33.4,31.5,30.2,25.9,24.4,21.2,21.1,19.8.HRMS(ESI):m / z calcd forC 29 H 35 O8Na:591.2182; found:591.2188[M+Na] + .

[0053] In order to better understand the essence of the present invention, the pharmacological experimental results of the inhibitory effect of the forskolin ester derivatives provided by the present invention on the NO release of RAW264.7 cells induced by LPS are used below to illustrate its new use in the field of anti-tumor drug research. The pharmacological examples give some activity data of representative compounds. It must be noted that the pharmacological examples of the present invention are used to illustrate the present invention rather than to limit the present invention. Simple improvements made to the present invention according to the essence of the present invention all belong to the scope of protection claimed in the present invention.

[0054] Drug Example 1: Inhibitory activity of compounds 3a-3d and dexamethasone on LPS-induced NO release in RAW264.7 macrophages

[0055] RAW264.7 macrophages were cultured at 1×10 5 The cells were inoculated at a density of 100 μg / mL on a 96-well plate and incubated in a 37°C, 5% CO2 incubator for 24 hours. This experiment set up a control group, an LPS-induced group, a positive control dexamethasone (DEX) group, and an experimental group. The positive control group and the experimental group were added with 0.2, 1.0, 5.0, and 25.0 μM of the test compound 3a-3d or DEX to be tested to treat the RAW264.7 macrophages. After 4 hours of placement, 10 μL of culture medium was added to the control group, and LPS (1.0 μg / mL) was added to the other groups to induce the cells. The cells were incubated for 24 hours, centrifuged, and the supernatant of the cells was collected. The release of NO was determined by a nitric oxide kit, and the IC was calculated using Graphpad5 software. 50 The MTT method was used to detect the effects of the compounds at 20 μM on the growth of RAW264.7 macrophages.

[0056] Table 1 Inhibitory activity of compounds 3a-3d and dexamethasone on LPS-induced NO release in RAW264.7 macrophages

[0057]

[0058]

[0059] As shown in Table 1, the forskolin ester derivatives provided by the present invention have important biological activities. The inhibitory activity test of LPS-induced RAW 264.7 macrophage NO release shows that the forskolin ester derivatives of the structure shown in formula (1) have good inhibitory activity on LPS-induced RAW264.7 macrophage NO release. The inhibitory effects of compounds 3a-3e in the examples are significantly better than those of the positive control drug dexamethasone, and there is no obvious cytotoxicity, so they may be developed into new anti-inflammatory drugs.

[0060] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Application of a forskolin aromatic derivative in the preparation of anti-inflammatory drugs; The structure of the forskolin aromatic derivative is shown in the following formula: in, R represents one of phenyl, p-chlorophenyl, p-methoxyphenyl, p-tert-butylphenyl and p-trifluoromethoxyphenyl.

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