Huperzine derivatives, preparation methods thereof and applications thereof in anti-gout drugs

Abstract

The present application relates to the technical field of gout treatment, and more specifically, it relates to a serrata huperzine derivative, a preparation method thereof, and its application in anti-gout drugs. In the first aspect, the present application discloses a serrata huperzine derivative compound having the general formula (I) below; in the second aspect, the present application discloses a preparation method of the above-mentioned serrata huperzine derivative; in the third aspect, the serrata huperzine derivative of the present application can be used in gouty arthritis, and such serrata huperzine derivatives represented by 3k and 3q significantly inhibit the release of IL-1β induced by sodium urate at a concentration of 30 μM. Compared with the clinical anti-inflammatory drugs hydrocortisone, indomethacin, and colchicine, the serrata huperzine derivatives of the present application have a good balance between high inhibitory activity and low cytotoxicity, and have good application prospects. #imgabs0#

Description

Technical Field

[0001] The present application relates to the technical field of gout treatment, and more specifically, to a compound of a scutellaria baicalensis derivative, a preparation method thereof, and an application thereof in anti-gout drugs. Background Art

[0002] Gout, a metabolic disease closely associated with high uric acid levels and the accumulation of urate crystals, has become the second most common metabolic disease in my country, second only to diabetes. By the first decade of this century, over 17 million people in my country suffered from gout, primarily among the elderly. With the aging population in my country, the number of gout patients is expected to increase annually, with an annual growth rate of 9.7%. Gout not only damages joints and affects the kidneys, but is also closely linked to conditions such as hypertension, hyperlipidemia, and coronary heart disease. Therefore, preventing and controlling the occurrence and progression of gout has become a pressing social issue.

[0003] Gout is a common metabolic disease caused by the deposition of monosodium urate crystals in joints and soft tissues, with hyperuricemia being a prerequisite for its development. Its clinical features include severe joint pain, swelling, and active inflammation. Current clinical treatments for gout focus primarily on relieving pain and inflammation. Currently, colchicine is the first-line drug for the treatment of acute gout attacks, but it is not suitable for patients with kidney and liver diseases, and long-term use can produce serious adverse reactions. Therefore, there is an urgent need for safe, effective, and low-cost compounds for the treatment of gout. Summary of the Invention

[0004] The purpose of the present invention is to provide a safe, effective and low-cost compound for treating gout, as well as a method for preparing the compound and its use in anti-gouty arthritis drugs.

[0005] In the first aspect, the serrata huperzine derivative compound provided in this application adopts the following technical solution:

[0006] A huperzine derivative, the structural formula of which includes the compound represented by formula (I), or includes isomers, tautomers, enantiomers, diastereomers, mixtures or pharmaceutically acceptable salts of the compound represented by formula (I);

[0007] The general structural formula of formula (I) is:

[0008]

[0009] Where R 1 It includes any one of a hydrogen atom, an alkyl group, a halogen, a haloalkyl group, a hydroxyl group, a nitro group, a hydroxyalkyl group, an ester group and an aldehyde group.

[0010] Preferably, the derivative includes any compound of formula (II), or includes an isomer, tautomer, enantiomer, diastereomer, mixture or pharmaceutically acceptable salt of the compound represented by formula (II);

[0011]

[0012] Preferably, the derivative includes any compound of formula (III), or includes an isomer, tautomer, enantiomer, diastereomer, mixture or pharmaceutically acceptable salt of the compound represented by formula (III);

[0013]

[0014] Preferably, the derivative includes any compound of formula (IV), or includes an isomer, tautomer, enantiomer, diastereomer, mixture or pharmaceutically acceptable salt of the compound represented by formula (IV);

[0015]

[0016] In a second aspect, the present application provides a method for preparing the above-mentioned huperzine derivative compound:

[0017] The synthesis process of huperzine derivatives is shown in formula (V):

[0018]

[0019] Under base catalysis, compound 2 acts as an aryl reagent to arylate compound 1 to obtain compound 3, thereby obtaining a serrata huperzine derivative. Compound 1 is serrata huperzine, and compound 2 is a diaryliodonium salt.

[0020] Preferably, the synthesis process of huperzine derivatives is shown in formula (VI):

[0021] wherein the base is one or more of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, cesium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium phosphate, sodium hydride, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, and pyridine;

[0022] The solvent is one or more of methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, toluene, chlorobenzene, fluorobenzene, and xylene;

[0023] The reaction temperature is 30℃–140℃;

[0024]

[0025] Preferably, the synthesis process of huperzine derivatives is shown in formula (VII):

[0026] wherein the base is one or more of cesium carbonate, sodium hydroxide, cesium hydroxide, N,N-diisopropylethylamine, and N,N-dimethylaniline;

[0027] The solvent is one or more of 1,2-dichloroethane, toluene, chlorobenzene, fluorobenzene, and xylene;

[0028] The reaction temperature is 80℃–140℃;

[0029]

[0030] Preferably, the synthesis process of the scutellaria huperzine derivative is shown in formula (VIII):

[0031] The base is cesium carbonate;

[0032] The solvent is toluene;

[0033] The reaction temperature is 120°C;

[0034]

[0035] Thirdly, the above-mentioned huperzine derivatives of the present application can be used in anti-gout drugs and have good anti-gouty arthritis activity.

[0036] Most huperzine derivatives can significantly inhibit the release of the inflammatory factor IL-1β induced by sodium urate. Commonly used clinical anti-inflammatory drugs include hydrocortisone, indomethacin, and colchicine. Hydrocortisone and indomethacin have low cytotoxicity but weak inhibitory ability against inflammatory factors. In contrast, colchicine, while exerting anti-inflammatory activity, also has a significant killing effect on normal cells.

[0037] Compared with hydrocortisone and indomethacin, most of the serrata huperzine derivatives of the present application have higher inhibitory activity under the premise of lower cytotoxicity; compared with colchicine, under the premise of equivalent or even slightly better activity, the serrata huperzine derivatives of the present application have obvious cytotoxicity advantages and lower toxicity, and have a good balance between high inhibitory activity and low cytotoxicity, and have good application prospects.

[0038] This application has the following beneficial effects:

[0039] The present invention provides a serrata huperzine derivative and a simple preparation method thereof. The synthesized serrata huperzine derivative has a good effect on gouty arthritis, has stronger efficacy or higher safety than clinical drugs, and has good application prospects. DETAILED DESCRIPTION

[0040] The present application is further described in detail below with reference to the embodiments.

[0041] Example

[0042] In a first aspect, the present invention discloses a huperzine derivative, characterized in that the general structural formula is as shown in formula (I):

[0043]

[0044] Wherein R is any one of a hydrogen atom, an alkyl group, a halogen, a haloalkyl group, a hydroxyl group, a nitro group, a hydroxyalkyl group, an ester group and an aldehyde group.

[0045] In a second aspect, the present application discloses a method for preparing a phenylpropanoid compound having the structural formula (I) above. The synthesis process of the serrata huperzine derivative is shown in formula (V):

[0046]

[0047] To a 25 mL sealed tube, add scutellaria serrata (compound 1) (54.0 mg, 0.2 mmol), diaryliodonium salt (compound 2) (129.0 mg, 0.3 mmol), cesium carbonate (97.7 mg, 0.3 mmol), and toluene (2.0 mL) in sequence, then place the sealed tube in an oil bath at 120°C and stir for 48 h to obtain a reaction solution.

[0048] The solvent in the reaction solution was then removed under reduced pressure to obtain a crude product. The crude product was separated on a silica gel column (n-hexane:ethyl acetate = 4:1) to obtain the target compound 3, a scutellaria serrata derivative, in a yield of 32-70%.

[0049] Under base catalysis, compound 2 acts as an aryl reagent to arylate compound 1 to obtain compound 3, thereby obtaining a serrata huperzine derivative. Compound 1 is serrata huperzine, and compound 2 is a diaryliodonium salt.

[0050] The specific structure of the compound 3 is shown in formula (II):

[0051]

[0052] When R is H, the resulting compound is 3a in formula (2);

[0053] When R is 4-F, the resulting compound is 3b in formula (2);

[0054] When R is 4-Cl, the resulting compound is 3c in formula (2);

[0055] When R is 4-Br, the resulting compound is 3d in formula (2);

[0056] When R is 4-CF3, the resulting compound is 3e in formula (2);

[0057] When R is 4-CH3, the resulting compound is 3f in formula (2);

[0058] When R is 4-OCH3, the resulting compound is 3g in formula (2);

[0059] When R is 4-COOMe, the resulting compound is 3h in formula (2);

[0060] When R is 4-CHO, the resulting compound is 3i in formula (2);

[0061] When R is 2-Cl, the resulting compound is 3j in formula (2);

[0062] When R is 2-Br, the resulting compound is 3k in formula (2);

[0063] When R is 2-CH3, the resulting compound is 3l in formula (2);

[0064] When R is 3-Br, the resulting compound is 3m in formula (2);

[0065] When R is 3-CH3, the resulting compound is 3n in formula (2);

[0066] When R is 3-NO2, the resulting compound is 3o in formula (2);

[0067] When R is 3,5-CH3, the resulting compound is 3p in formula (2);

[0068] When R is 2,4,6-CH3, the resulting compound is 3q in formula (2).

[0069] The characterization data of compounds 3a-3q are shown below:

[0070] Compound 3a: (5R,9R,11R)-N,N,7-trimethyl-2-phenoxy-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine.

[0071] 11H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.6 Hz, 1H), 7.37 (m, 2H), 7.16 (overlapped, 3H), 6.60 (d, J = 8.6 Hz, 1H), 5.99 (dt, J = 17.0, 10.1 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.21 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.1, 2.0 Hz, 1H), 3.09 (dd, J = 17.8, 5.2 Hz, 1H), 2.93 (dd, J = 10.0, 4.0 Hz 1H), 2.90 (d, J = 17.5 Hz, 1H), 2.45 (overlapped, 2H), 2.43 (s, 6H), 1.65 (d, J = 17.5 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (125 MHz, CDCl3) δ 161.7, 155.0, 154.6, 140.9, 140.3, 133.3, 131.4, 129.8 (×2), 125.4, 124.5, 121.0 (×2), 116.1, 108.6, 61.3, 46.2, 45.9, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 347.2135 [M+H] + 。

[0072] Compound 3b: (5R,9R,11R)-2-(4-fluorophenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine.

[0073] 11H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.6 Hz, 1H), 7.13 (m, 2H), 7.06 (m, 2H), 6.60 (d, J = 8.6 Hz, 1H), 5.98 (dt, J = 17.0, 10.0 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.21 (dd, J = 17.0, 2.0 Hz, 1H), 5.04 (dd, J = 10.0, 2.0 Hz, 1H), 3.07 (dd, J = 17.8, 5.2 Hz, 1H), 2.94 (dd, J = 10.0, 4.0 Hz, 1H), 2.91 (d, J = 17.2 Hz, 1H), 2.45 (overlapped, 2H), 2.43 (s, 6H), 1.64 (d, J = 17.2 Hz, 1H), 1.50 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 161.6, 159.5 (d, J = 243.4 Hz), 154.8, 150.2, 140.8, 140.2, 133.3, 131.4, 125.2, 122.5 (×2) (d, J = 8.3 Hz), 116.3 (×2) (d, J = 23.3 Hz), 116.0, 108.4, 61.2, 46.1, 45.8, 39.7 (×2), 39.4, 34.0, 22.9. HRMS (ESI) m / z 365.2037 [M+H] + 。

[0074] Compound 3c: (5R,9R,11R)-2-(4-chlorophenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine.

[0075] 11H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.6 Hz, 1H), 5.98 (dt, J = 17.0, 10.4 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.04 (dd, J = 10.4, 2.0 Hz, 1H), 3.06 (dd, J = 17.8, 5.2 Hz, 1H), 2.87 (dd, J = 10.4, 4.0 Hz, 1H), 2.84 (d, J = 17.3 Hz, 1H), 2.39 (overlapped, 2H), 2.36 (s, 6H), 1.65 (d, J = 17.3 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 161.2, 155.0, 153.2, 140.9, 140.4, 133.4, 132.0, 129.7 (×2), 129.5, 1:25.4, 122.2 (×2), 116.1, 109.0, 61.9, 46.2, 45.9, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 381.1735 [M+H] + .

[0076] ​​​​​1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.6 Hz, 1H), 5.97 (dt, J = 17.0, 10.0 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.0, 2.0 Hz, 1H), 3.06 (dd, J = 17.8, 5.2 Hz, 1H), 2.94 (dd, J = 10.0, 4.0 Hz, 1H), 2.91 (d, J = 16.8 Hz, 1H), 2.46 (overlapped, 2H), 2.37 (s, 6H), 1.59 (d, J = 16.8 Hz, 1H), 1.44 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 161.1, 155.0, 153.7, 140.8, 140.5, 133.4, 132.7 (×2), 131.5, 125.3, 122.8 (×2), 117.1, 116.2, 109.1, 61.5, 46.2, 45.9, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 425.1233 [M+H] + 。

[0078] Compound 3e: (5R,9R,11R)-N,N,7-trimethyl-2-(4-(trifluoromethyl)phenoxy)-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0079] 11H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.5 Hz, 1H), 5.98 (dt, J = 17.0, 10.1 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.0, 2.0 Hz, 1H), 3.07 (dd, J = 17.6, 5.2 Hz, 1H), 2.95 (dd, J = 10.0, 4.0 Hz, 1H), 2.92 (d, J = 17.5 Hz, 1H), 2.46 (overlapped, 2H), 2.44 (s, 6H), 1.66 (d, J = 17.5 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 160.4, 157.6, 155.1, 140.7, 140.6, 133.4, 132.5, 127.2 (×2) (q, J = 3.7 Hz), 126.1 (q, J = 32.7 Hz), 125.7 (q, J = 272.7 Hz), 125.3, 120.6 (×2), 116.2, 109.8, 61.4, 46.3, 45.8, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 415.1989 [M+H] + 。

[0080] Compound 3f: (5R,9R,11R)-N,N,7-trimethyl-2-(p-tolyloxy)-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0081] 11H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.5 Hz, 1H), 5.98 (dt, J = 17.0, 10.0 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.04 (dd, J = 10.0, 2.0 Hz, 1H), 3.09 (dd, J = 17.6, 5.2 Hz, 1H), 2.93 (dd, J = 10.0, 4.0 Hz, 1H), 2.90 (d, J = 17.2 Hz, 1H), 2.45 (overlapped, 2H), 2.36 (s, 6H), 2.35 (s, 3H), 1.65 (d, J = 17.2 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 162.1, 155.0, 152.2, 140.9, 140.2, 134.2, 133.3, 130.3 (×2), 129.5, 125.4, 121.0 (×2), 116.1, 108.2, 61.4, 46.2, 45.9, 39.8 (×2), 39.5, 34.1, 23.0, 21.0. HRMS (ESI) m / z 361.2275 [M+H] + .

[0082] Compound 3g: (5R,9R,11R)-2-(4-methoxyphenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0083] 11H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.7 Hz, 1H), 5.98 (dt, J = 17.0, 10.1 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.1, 2.0 Hz, 1H), 3.81 (s, 3H), 3.08 (dd, J = 17.6, 5.2 Hz, 1H), 2.93 (dd, J = 10.4, 4.0 Hz, 1H), 2.90 (d, J = 16.8 Hz, 1H), 2.45 (overlapped, 2H), 2.44 (s, 6H), 1.69 (d, J = 16.8 Hz, 1H), 1.50 (s, 3H). 13 13C NMR (125 MHz, CDCl3) δ 162.4, 156.6, 154.9, 147.9, 140.8, 140.2, 133.3, 130.7, 125.4, 122.3 (×2), 116.2, 114.9 (×2), 107.9, 61.0, 55.7, 46.1, 45.9, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 377.2223 [M+H] + 。

[0084] Compound 3h: Methyl 4 - (((5R,9R,11R)-5-(dimethylamino)-7-methyl-11-vinyl-5,6,9,10-tetrahydro-5,9-methanocycloocta[b]pyridin-2-yl)oxy)benzoate

[0085] 11H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.5 Hz, 1H), 5.99 (dt, J = 17.0, 10.0 Hz, 1H), 5.38 (d, J = 5.2 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.0, 2.0 Hz, 1H), 3.91 (s, 3H), 3.08 (dd, J = 17.6, 5.2 Hz, 1H), 2.94 (dd, J = 10.4, 4.0 Hz, 1H), 2.91 (d, J = 17.2 Hz, 1H), 2.45 (overlapped, 2H), 2.43 (s, 6H), 1.67 (d, J = 17.2 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (125 MHz, CDCl3) δ 166.8, 160.4, 158.9, 155.2, 140.8, 140.6, 133.4, 132.7, 131.6 (×2), 125.8, 125.3, 119.9 (×2), 116.1, 110.0, 61.3, 52.2, 46.3, 45.9, 39.9 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 405.2168 [M+H] + 。

[0086] Compound 3i: 4 - (((5R,9R,11R)-5-(dimethylamino)-7-methyl-11-vinyl-5,6,9,10-tetrahydro-5,9-methanocycloocta[b]pyridin-2-yl)oxy)benzaldehyde

[0087] 11H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.5 Hz, 1H), 5.98 (dt, J = 17.0, 10.0 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 5.23 (dd, J = 17.0, 2.0 Hz, 1H), 5.06 (dd, J = 10.0, 2.0 Hz, 1H), 3.07 (dd, J = 17.6, 5.2 Hz, 1H), 2.95 (dd, J = 10.4, 4.0 Hz, 1H), 2.92 (d, J = 17.2 Hz, 1H), 2.46 (overlapped, 2H), 2.45 (s, 6H), 1.67 (d, J = 17.2 Hz 1H), 1.51 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 191.1, 160.2, 160.0, 155.2, 140.8, 140.6, 133.4, 132.3, 131.8 (×2), 128.3, 125.3, 120.3 (×2), 116.3, 110.4, 61.7, 46.2, 45.8, 39.8 (×2), 39.4, 34.0, 23.0. HRMS (ESI) m / z 375.2065 [M+H] + .

[0088] Compound 3j: (5R,9R,11R)-2-(2-chlorophenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine (3j)

[0089] 11H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 8.0, 1.8 Hz, 1H), 7.28 (m, 1H), 7.22 (dd, J = 8.0, 1.8 Hz, 1H), 7.15 (ddd, J = 8.0, 7.2, 1.8 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 5.99 (dt, J = 17.0, 10.0 Hz, 1H), 5.37 (d, J = 5.3 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.0, 2.0 Hz, 1H), 3.06 (dd, J = 17.8, 5.3 Hz, 1H), 2.93 (dd, J = 10.0 Hz, 4.0 Hz, 1H), 2.90 (d, J = 16.8 Hz, 1H), 2.45 (overlapped, 2H), (2.44 (s, 6H), 1.67 (d, J = 16.8 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (125 MHz, CDCl3) δ 160.8, 154.9, 150.4, 140.9, 140.4, 133.3, 131.2, 130.7, 127.9, 127.0, 125.7, 125.3, 123.3, 116.1, 108.4, 61.1, 46.1, 45.9, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 381.1726 [M+H] + 。

[0090] Compound 3k: (5R,9R,11R)-2-(2-bromophenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0091] 11H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.30 (td, J = 7.6, 1.6 Hz, 1H), 7.19 (dd, J = 8.0, 1.6 Hz, 1H), 7.06 (td, J = 7.6, 1.6 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 5.98 (dt, J = 17.0, 10.1 Hz, 1H), 5.36 (d, J = 5.2 Hz, 1H), 5.20 (dd, J = 17.0, 2.0 Hz, 1H), 5.03 (dd, J = 10.0, 2.0 Hz, 1H), 3.06 (dd, J = 17.8, 5.2 Hz, 1H), 2.93 (dd, J = 10.0, 4.0 Hz 1H), 2.90 (d, J = 17.2 Hz, 1H), 2.43 (overlapped, 2H), 2.42 (s, 6H), 1.65 (d, J = 17.2 Hz, 1H), 1.50 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 160.7, 154.9, 151.6, 140.9, 140.4, 133.8, 133.3, 131.7, 128.6, 125.9, 125.3, 123.1, 116.1, 116.0, 108.6, 61.3, 46.2, 45.9, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 425.1219 [M+H] + 。

[0092] Compound 3l: (5R,9R,11R)-N,N,7-trimethyl-2-(o-tolyloxy)-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0093] 11H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 1H), 7.16 (m, 2H), 7.02 (m, 2H), 6.44 (d, J = 8.6 Hz, 1H), 6.00 (dt, J = 17.0, 10.0 Hz, 1H), 5.38 (d, J = 5.3 Hz, 1H), 5.21 (dd, J = 17.0, 2.0 Hz, 1H), 5.04 (dd, J = 10.0, 2.0 Hz, 1H), 3.10 (dd, J = 17.8, 5.3 Hz, 1H), 2.93 (dd, J = 10.0, 4.0 Hz, 1H), 2.90 (d, J = 16.8 Hz, 1H), 2.38 (overlapped, 2H), 2.42 (s, 6H), 2.23 (s, 3H), 1.63 (d, J = 16.8 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 161.7, 155.1, 152.8, 141.0, 140.2, 133.4, 131.5, 131.1, 130.7, 127.2, 125.4, 124.9, 121.4, 116.0, 107.5, 61.2, 46.3, 46.0, 39.8 (×2), 39.6, 34.2, 23.0, 16.6. HRMS (ESI) m / z = 361.2299 [M+H] + .

[0094] Compound 3m: (5R,9R,11R)-2-(3-bromophenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0095] 11H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.32 (overlapped, 2H), 7.23 (t, J = 8.1 Hz, 1H), 7.10 (dd, J = 6.4, 5.2 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.98 (dt, J = 17.0, 10.1 Hz, 1H), 5.38 (d, J = 5.2 Hz, 1H), 5.22 (d, J = 13.2 Hz, 1H), 5.06 (d, J = 10.1 Hz, 1H), 3.08 (dd, J = 17.7, 5.2 Hz, 1H), 2.94 (dd, J = 8.0, 5.2 Hz, 1H), 2.91 (d, J = 17.6 Hz, 1H), 2.52 (overlapped, 2H), 2.45 (s, 6H), 1.67 (s, 1H), 1.52 (s, 3H). 13 13C NMR (125 MHz, CDCl3) δ 161.0, 155.4, 155.0, 141.0, 140.5, 133.3, 130.8, 130.1, 127.5, 125.3, 124.3, 122.7, 119.7, 116.2, 109.2, 61.6, 46.1, 45.8, 39.8 (×2), 39.5, 34.1, 23.0. HRMS (ESI) m / z 425.1217 [M+H] + 。

[0096] Compound 3n: (5R,9R,11R)-N,N,7-trimethyl-2-(m-tolyloxy)-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0097] 11H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.6 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 6.96 (overlapped, 3H), 6.57 (d, J = 8.6 Hz, 1H), 5.99 (dt, J = 17.0, 10.1 Hz, 1H), 5.38 (d, J = 5.3 Hz, 1H), 5.21 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.1, 2.0 Hz, 1H), 3.10 (dd, J = 17.8, 5.3 Hz, 1H), 2.94 (dd, J = 10.1, 4.0 Hz, 1H), 2.90 (d, J = 17.2 Hz, 1H), 2.47 (overlapped, 2H), 2.4 (s, 6H), 2.35 (s, 3H), 1.65 (d, J = 17.2 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (125 MHz, CDCl3) δ 161.9, 155.0, 154.5, 140.9, 140.2, 140.0, 133.3, 131.2, 129.5, 127.2, 125.4, 121.7, 118.0, 116.1, 108.4, 61.3, 46.2, 45.9, 39.8 (×2), 39.5, 34.1, 23.0, 21.5. HRMS (ESI) m / z 361.2268 [M+H] + 。

[0098] Compound 3o: (5R,9R,11R)-N,N,7-trimethyl-2-(3-nitrophenoxy)-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0099] 11H NMR (600 MHz, CDCl3) δ 8.07 (m, 1H), 8.03 (overlapped, 2H), 7.52 (m, 2H), 6.81 (d, J = 8.5 Hz, 1H), 5.98 (dt, J = 17.0, 10.0 Hz, 1H), 5.38 (ddd, J = 6.0, 2.9, 1.5 Hz, 1H), 5.24 (d, J = 17.0 Hz, 1H), 5.07 (d, J = 10.0 Hz, 1H), 3.05 (dd, J = 18.0, 5.4 Hz, 1H), 2.95 (dd, J = 10.0, 4.2 Hz, 1H), 2.93 (d, J = 16.2 Hz, 1H), 2.46 (overlapped, 8H), 1.71 (s, 1H), 1.53 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 160.3, 155.1, 154.9, 149.1, 140.8, 140.5, 133.4, 132.6, 130.0, 127.3, 125.3, 119.1, 116.3, 109.9, 62.5, 46.1, 45.8, 39.9 (×2), 39.4, 34.0, 31.7, 23.0. HRMS (ESI) m / z 392.1967 [M+H] + 。

[0100] Compound 3p: (5R,9R,11R)-2-(3,5-dimethylphenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0101] 11H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.6 Hz, 1H), 6.82 (s, 1H), 6.77 (s, 2H), 6.54 (d, J = 8.6 Hz, 1H), 6.00 (dt, J = 17.0, 10.0 Hz, 1H), 5.38 (d, J = 5.1 Hz, 1H), 5.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.05 (dd, J = 10.0, 2.0 Hz, 1H), 3.10 (dd, J = 17.8, 5.1 Hz, 1H), 2.94 (dd, J = 10.0, 4.0 Hz, 1H), 2.90 (d, J = 17.3 Hz, 1H), 2.47 (overlapped, 2H), 2.43 (s, 6H), 2.31 (s, 6H), 1.65 (d, J = 17.3 Hz, 1H), 1.51 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 162.0, 155.0, 154.5, 141.0, 140.2, 139.7 (×2), 133.3, 131.1, 126.4, 125.4, 118.7 (×2), 116.1, 108.2, 61.3, 46.2, 45.9, 39.8 (×2), 39.5, 34.1, 23.0, 21.5 (×2). HRMS (ESI) m / z 413.1987 [M+K] + 。

[0102] Compound 3q: (5R,9R,11R)-2-(mesityloxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine

[0103] 1H NMR (400MHz, CDCl3) δ7.75(d,J=8.6Hz,1H),6.89(s,2H),6.26(d,J=8.6Hz,1H),6.01(dt,J=16 .9,10.1Hz,1H),5.38(d,J=5.2Hz,1H),5.20(dd,J=17.0,2.0Hz,1H),5.04(dd,J=10.0,2.0Hz, 1H),3.10(dd,J=17.8,5.2Hz,1H),2.92(dd,J=10.4,4.0Hz,1H),2.88(d,J=17.2Hz,1H),2.44( overlapped,2H),2.41(s,6H),2.29(s,3H),2.10(s,6H),1.62(d,J=17.2Hz,1H),1.50(s,3H). 13 C NMR (100MHz, CDCl3) δ161.3,155.0,148.3,141.0,140.1,134.5,133.2,130.8×2,130.1,129.5(×2) ,125.3,115.8,105.6,61.1,46.1,45.9,39.7(×2),39.4,34.1,22.9,20.8,16.7(×2).HRMS(ESI)m / z 389.2591[M+H] + .

[0104] Thirdly, the huperzine derivatives prepared in the examples of this application can be used in anti-gout drugs. A series of huperzine derivatives, represented by compounds 3k and 3q, exhibited strong inhibitory effects on sodium urate-induced IL-1β release and low cytotoxicity, which is of great significance for the development of highly active anti-gouty arthritis drugs.

[0105] Evaluation of the inhibitory effect of compounds on IL-1β at (30 μM)

[0106] In this example, THP-1 cells in the logarithmic growth phase were first treated with phorbol ester to induce differentiation. LPS and compounds were then added to pre-incubate the cells. Finally, sodium urate was added to induce the production of inflammatory factors. After 24 hours, the cell supernatant was collected to detect the IL-1β content.

[0107] The results are shown in Table 1

[0108] Table 1: Evaluation of the inhibitory effect of 3a-3q on IL-1β at 30 μM

[0109]

[0110]

[0111] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A serrata huperzine derivative, characterized in that: The structural formula is a compound represented by formula (I); The general structural formula of formula (I) is: The compound of formula (I) is specifically any one of the compounds of formula (II): When R 1 When is H, the resulting compound is 3a in formula (2); When R 1 When it is 4-F, the obtained compound is 3b in formula (2); When R 1 When it is 4-Cl, the resulting compound is 3c in formula (2); When R 1 When it is 4-Br, the resulting compound is 3d in formula (2); When R 1 When it is 4-CF3, the resulting compound is 3e in formula (2); When R 1 When it is 4-CH3, the resulting compound is 3f in formula (2); When R 1 When it is 4-OCH3, the obtained compound is 3g in formula (2); When R 1 When it is 4-COOMe, the obtained compound is 3h in formula (2); When R 1 When it is 4-CHO, the obtained compound is 3i in formula (2); When R 1 When it is 2-Cl, the resulting compound is 3j in formula (2); When R 1 When it is 2-Br, the resulting compound is 3k in formula (2); When R 1 When it is 2-CH3, the resulting compound is 3l in formula (2); When R 1 When it is 3-Br, the resulting compound is 3m in formula (2); When R 1 When it is 3-CH3, the resulting compound is 3n in formula (2); When R 1 When it is 3-NO2, the resulting compound is 3o in formula (2); When R 1 When it is 3,5-CH3, the resulting compound is 3p in formula (2); When R 1 When it is 2,4,6-CH3, the obtained compound is 3q in formula (2).

2. The serrata huperzine derivative according to claim 1, characterized in that The derivative is any compound of formula (III):

3. The serrata huperzine derivative according to claim 2, characterized in that The derivative is any compound of formula (IV):

4. The method for preparing a huperzine derivative according to claim 1, wherein: The synthesis process of huperzine derivatives is shown in formula (V): Where R 2 and R 1 Same definition.

5. Use of the serrata huperzine derivative according to claim 1 in the preparation of an anti-gout drug, which has anti-gouty arthritis activity.

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