Huperzine serratum derivative, preparation method thereof and application of huperzine serratum derivative in anti-gout drugs

Abstract

The invention relates to the technical field of gout treatment, in particular to a huperzine derivative, a preparation method of the huperzine derivative and application of the huperzine derivative in anti-gout drugs. In a first aspect, the present application discloses huperzine derivative compounds of general formula (I); on the second aspect, the invention discloses a preparation method of the huperzine derivative. On the third aspect, the huperzine derivative can be applied to gouty arthritis, the huperzine derivative represented by 3k and 3q remarkably inhibits release of IL-1beta induced by sodium urate at the concentration of 30 mu M, and compared with clinical anti-inflammatory drugs such as hydrocortisone, indometacin and colchicine, the huperzine derivative has the advantages that the anti-inflammatory effect is good, and the anti-inflammatory effect is good. The huperzine derivative disclosed by the invention well gives consideration to high inhibitory activity and low cytotoxicity, and has a good application prospect. # imgabs0 #

Description

Technical Field

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

[0002] Gout is a metabolic disease closely related to high uric acid and urate crystal deposition. It has become the second largest metabolic disease in my country after diabetes. As of the first decade of this century, there were more than 17 million gout patients in my country, most of whom were elderly people. With the aggravation of my country's aging population, the number of gout patients will increase year by year, and is growing at an annual growth rate of 9.7%. Gout not only causes joint damage and affects the kidneys, but is also closely related to diseases such as hypertension, hyperlipidemia, and coronary heart disease. Therefore, the prevention and treatment of the occurrence and development of gout has become a hot issue that needs to be solved in society.

[0003] Gout is a common metabolic disease caused by the deposition of monosodium urate crystals in joints and soft tissues, and hyperuricemia is a prerequisite for its development. Its clinical characteristics include severe joint pain, swelling and active inflammation. Currently, the clinical treatment of gout mainly focuses 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 will produce serious adverse reactions. Therefore, there is an urgent need for safe, effective and low-cost gout treatment compounds. 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 application in anti-gouty arthritis drugs.

[0005] In the first aspect, the huperzine derivative compound provided in the present application adopts the following technical scheme:

[0006] A huperzine derivative, the structural formula of which includes the compound represented by formula (I), or includes the isomer tautomerism, enantiomer, diastereomer, mixture form or pharmaceutically acceptable salt 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 halogenated alkyl 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 form 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 form 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 form 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 the catalysis of a base, compound 2 is used as an aryl reagent to carry out oxyarylation of compound 1 to obtain compound 3, that is, a serrata huperzine derivative. Compound 1 is serrata huperzine, and compound 2 is a diaryl iodide salt.

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

[0021] 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°C–140°C;

[0024]

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

[0026] 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°C–140°C;

[0029]

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

[0031] wherein the base is cesium carbonate;

[0032] The solvent is toluene;

[0033] The reaction temperature is 120°C;

[0034]

[0035] In a third aspect, 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 of the huperzine derivatives can significantly inhibit the release of 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 on inflammatory factors; in contrast, colchicine has a greater killing effect on normal cells while exerting anti-inflammatory activity.

[0037] Compared with hydrocortisone and indomethacin, most of the scutellaria baicalensis 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 scutellaria baicalensis 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 huperzine serrata derivative and a simple preparation method thereof. The synthesized huperzine serrata derivative has a good effect on gouty arthritis, has a stronger efficacy or higher safety than clinical drugs, and has a good application prospect. DETAILED DESCRIPTION

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

[0041] Example

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

[0043]

[0044] In the formula, R is any one of a hydrogen atom, an alkyl group, a halogen, a halogenated alkyl group, a hydroxyl group, a nitro group, a hydroxyalkyl group, an ester group and an aldehyde group.

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

[0046]

[0047] To a 25 mL sealed tube, add huperzine (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 to react for 48 hours 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 by silica gel column (n-hexane: ethyl acetate = 4:1) to obtain the target compound 3, i.e., a huperzine derivative, in a yield of 32-70%.

[0049] Under the catalysis of a base, compound 2 is used as an aryl reagent to carry out oxyarylation of compound 1 to obtain compound 3, that is, a serrata huperzine derivative. Compound 1 is serrata huperzine, and compound 2 is a diaryl iodide 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 obtained 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 31 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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, 125.4, 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] Compound 3d: (5R,9R,11R)-2-(4-bromophenoxy)-N,N,7-trimethyl-11-vinyl-9,10-dihydro-5,9-methanocycloocta[b]pyridin-5(6H)-amine.

[0077] (c 1.0, DCM); 11H 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM); 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), 2.43 (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] (c 1.0, DCM); 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] (c 1.0, DCM); 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] (c 1.0, DCM) 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 the present application can be used in anti-gout drugs. Among them, a series of huperzine derivatives represented by compounds 3k and 3q have good inhibitory effects on sodium urate-induced IL-1β release and low cytotoxicity, which is of great significance for the development of anti-gouty arthritis drugs with good activity.

[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, then LPS and compounds were added to pre-incubate the cells, and finally sodium urate was added to induce the production of inflammatory factors, and the cell supernatant was collected after 24 hours to detect the content of IL-1β.

[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 modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A huperzine derivative, characterized in that: The structural formula includes the compound represented by formula (I), or includes the isomer tautomerism, enantiomer, diastereomer, mixture form or pharmaceutically acceptable salt of the compound represented by formula (I); The general structural formula of formula (I) is: Where R 1 It includes any one of a hydrogen atom, an alkyl group, a halogen, a halogenated alkyl group, a hydroxyl group, a nitro group, a hydroxyalkyl group, an ester group and an aldehyde group.

2. The huperzine derivative according to claim 1, characterized in that The derivatives include any compound of formula (II), or include isomer tautomerism, enantiomer, diastereomer, mixture form or pharmaceutically acceptable salt of the compound represented by formula (II); 3. The huperzine derivative according to claim 2, characterized in that The derivatives include any compound of formula (III), or include isomer tautomerism, enantiomer, diastereomer, mixture form or pharmaceutically acceptable salt of the compound represented by formula (III); 4. The serrata huperzine derivative according to claim 3, characterized in that The derivatives include any compound of formula (IV), or include isomer tautomerism, enantiomers, diastereomers, mixture forms or pharmaceutically acceptable salts of the compound represented by formula (IV); 5. The method for preparing the huperzine derivative according to claim 1, characterized in that: The synthesis process of huperzine derivatives is shown in formula (V): Under the catalysis of a base, compound 2 is used as an aryl reagent to carry out oxyarylation of compound 1 to obtain compound 3, that is, a serrata huperzine derivative. Compound 1 is serrata huperzine, and compound 2 is a diaryl iodide salt.

6. The method for preparing the huperzine derivative according to claim 1, characterized in that: The synthesis process of huperzine derivatives is shown in formula (VI): 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; 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; The reaction temperature is 30°C–140°C; 7. The method for preparing the huperzine derivative according to claim 6, characterized in that: The synthesis process of huperzine derivatives is shown in formula (VII): The base is one or more of cesium carbonate, sodium hydroxide, cesium hydroxide, N,N-diisopropylethylamine, and N,N-dimethylaniline; The solvent is one or more of 1,2-dichloroethane, toluene, chlorobenzene, fluorobenzene and xylene; The reaction temperature is 80°C–140°C; 8. The method for preparing the huperzine derivative according to claim 7, characterized in that: The synthesis process of huperzine derivatives is shown in formula (VIII): wherein the base is cesium carbonate; The solvent is toluene; The reaction temperature is 120°C; 9. Use of the huperzine derivative according to claim 1 in an anti-gout drug, which has anti-gouty arthritis activity.

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