Uses of tetrahydrofuran-type lignan compounds

Abstract

The invention discloses a use of a tetrahydrofuran lignan compound. The tetrahydrofuran lignan compound is a monotetrahydrofuran lignan compound having a chemical structure shown in formula I: or a ditetrahydrofuran lignan compound having a chemical structure shown in formula II:; the use refers to using the tetrahydrofuran lignan compound or at least one of its stereoisomers, precursor compounds, deuterated substances, and pharmaceutically acceptable esters as an active ingredient for preparing a phosphodiesterase 4 inhibitor, which is further expected to be used as an active ingredient for preparing a drug for preventing and / or treating related diseases mediated by phosphodiesterase 4 and preparing a cosmetic for improving skin sensitivity, and has broad application prospects.

Description

Technical Field

[0001] The invention relates to a new use of tetrahydrofuran type lignan compounds and belongs to the technical field of medicine. Background Art

[0002] Cyclic nucleotide phosphodiesterases (PDEs) are a super enzyme family that catalyzes the hydrolysis of cAMP and cGMP, and are composed of 21 different genes. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are two second messengers that play an important role in cell metabolism. PDEs can be divided into 11 different PDE families (PDE1-11) based on their substrate specificity and amino acid sequence. Among them, PDE4 is a highly cAMP-specific phosphodiesterase that contains four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. Studies have shown that inhibiting PDE4 can improve the degradation of intracellular cAMP, thereby activating PKA and affecting downstream pathways such as CREB / ATF-1 and NF-κB, leading to a decrease in the synthesis of inflammatory cytokines and an increase in anti-inflammatory cytokines; PDE4 is widely distributed in various human tissues and cells, such as the brain, kidney, cardiomyocytes, endothelial cells, and immune cells. Due to its organ specificity, PDE4 is involved in the regulation of cognitive function, can promote the expression of proinflammatory cytokines and chemokines in inflammatory cells (including peripheral blood mononuclear cells, macrophages, neutrophils, natural killer cells, basophils and lymphocytes), regulate vascular smooth muscle proliferation, vasodilation and cardiac contraction; PDE4A, PDE4B and PDE4D are also involved in the generation of hematological malignancies, central nervous system tumors, breast tumors, lung tumors and prostate tumors; animal models of Alzheimer's disease, stroke, etc. have confirmed that PDE4 is also a therapeutic target for the central nervous system. A potential target for diseases; a variety of compounds that act as PDE4 inhibitors have been disclosed in the prior art, but the usefulness of several first-generation PDE4 inhibitors, such as rolipram and piramilast, has been limited due to their undesirable side effects, including nausea and vomiting due to their effects on PDE4 in the central nervous system, and gastric acid secretion due to their effects on PDE4 in the gastric parietal cells of the stomach; therefore, the development of new PDE4 inhibitors with a larger safety window and better safety is of great significance.

[0003] Psoriasis is a multifactorial, intractable inflammatory skin disease characterized by the appearance of scaly, red plaques on frequently abraded parts of the body (such as the extensor parts of the limbs and scalp) and is accompanied by a variety of comorbidities, which seriously affect the patient's quality of life. The immunopathogenesis of psoriasis involves a variety of inflammatory mediators, including tumor necrosis factor (TNF-α), interleukins (IL-12, IL-17, IL-22, IL-23), and interferon (IFN)-γ. The treatment of psoriasis varies, from topical corticosteroids, retinoids, and calcipotriol, to oral conventional systemic therapy as a broad immunosuppressant, to biological therapy targeting specific cytokines. Among them, topical corticosteroids are the most commonly used, but their long-term side effects, such as skin atrophy and stretch marks, limit their use. In 2022, Zoryve (roflumilast) 0.3% cream was approved for the treatment of localized plaque psoriasis, proving that PDE4 inhibitors have great potential in the treatment of psoriasis, but Zoryve still has the side effects of roflumilast, such as nausea, diarrhea, loss of appetite, and mild weight loss. Therefore, there is still a need to develop drugs for the treatment of psoriasis in the clinic, and providing a highly effective and safe drug for the treatment of psoriasis is of great clinical significance.

[0004] Atopic dermatitis is a common allergic skin disease, which is mainly manifested by severe itching of the skin, dryness, erythema, papules and other symptoms, affecting a wide range of people including infants, adolescents and adults. Persistent itching of the skin can cause severe sleep disorders, which not only interferes with daily activities, but also seriously reduces the quality of life and brings a heavy burden to patients. At present, the first-line treatment option for atopic dermatitis is still steroid anti-inflammatory drugs, such as corticosteroids (such as prednisone, dexamethasone and fludrocortisone). Although these corticosteroids can relieve the symptoms of atopic dermatitis, their long-term use will cause adverse reactions such as skin redness, thinning, atrophy and growth retardation. As a topical anti-inflammatory drug, crisaborole was approved by the FDA in 2016 and was launched in the United States in early 2017 for the treatment of mild to moderate atopic dermatitis in adults and children aged 2 years and above, proving that PDE4 inhibitors also have great potential in the treatment of atopic dermatitis.

[0005] Skin sensitivity refers to a skin condition that is susceptible to a variety of factors and induces subjective sensory symptoms, that is, the skin is highly reactive, poorly tolerant, and even prone to allergies, such as allergies caused by cosmetic raw materials. Sensitive skin mainly occurs on the face, as well as other parts such as the hands, feet, and scalp. The main characteristics of skin sensitivity are that it is drier than normal skin, prone to tightness and redness; it can produce itching, desquamation, and even burning and stinging sensations when slightly stimulated. Inflammatory response is an important factor in sensitive skin. When the skin is sensitive and uncomfortable, it is more susceptible to external irritants and allergens, resulting in skin inflammation. There is currently no specific treatment for skin sensitivity. PDE4 plays an important role in a variety of skin inflammatory diseases. Therefore, the development of PDE4 inhibitors to relieve skin sensitivity is also of great significance.

[0006] Naturally derived tetrahydrofuran lignans are secondary metabolites formed by the oxidative polymerization of two molecules of phenylpropanoid units. They are mainly found in plants of the Lauraceae, Magnoliaceae, Piperaceae, Cucurbitaceae, Myristicaceae, Thymelaeaceae, Asteraceae, Oleaceae, Caprifoliaceae, and Aristolochiaceae families. They are not only widely distributed in plants, but also have low toxicity. However, there have been no relevant research reports on the use of tetrahydrofuran lignan compounds as PDE4 inhibitors. Summary of the invention

[0007] In view of the above problems existing in the prior art, the object of the present invention is to provide a new use of tetrahydrofuran-type lignan compounds to broaden the application scope of such compounds.

[0008] The tetrahydrofuran-type lignan compound of the present invention has a chemical structure as shown in Formula I:

[0009] Monotetrahydrofuran-type lignan compounds or compounds having a chemical structure shown in Formula II:

[0010] The di-tetrahydrofuran-type lignan compounds, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are independently selected from H, unsubstituted or halogen-substituted C 1 ~C 6 Alkoxy, unsubstituted or halogen-substituted C 3 ~C 6 Cycloalkoxy; R 7 is selected from hydroxy, unsubstituted or halogen-substituted C 1 ~C 6 Carboxylic acid group, R 8Selected from H or hydroxyl; the use refers to using the tetrahydrofuran-type lignan compound or at least one of its stereoisomers, precursor compounds, deuterated substances, and pharmaceutically acceptable esters as an active ingredient for preparing a phosphodiesterase 4 (PDE4) inhibitor.

[0011] In one embodiment, the use refers to using the phosphodiesterase 4 inhibitor as an active ingredient in the preparation of a drug for preventing and / or treating diseases mediated by phosphodiesterase 4.

[0012] According to a further embodiment, the related diseases include at least one of inflammatory diseases, allergic diseases, cardiovascular diseases, neurological and mental disorders and malignant tumors.

[0013] In a further embodiment, the inflammatory disease comprises at least one of asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, and the allergic disease comprises atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, chronic glomerulonephritis, endotoxic shock, cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, diabetes, pneumoconiosis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, simple lichen, pruritus of the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and generalized pyoderma, endogenous or exogenous acne, rosacea, Beghet's The present invention relates to a method for treating a patient with a heart disease or a psychiatric disorder, wherein the patient has at least one of: a heart attack, a heart attack, a heart failure, an idiopathic dilated cardiomyopathy, an acute myocardial infarction, myocardial ischemia-reperfusion injury, and ischemic pulmonary hypertension; the method comprises: treating a patient with a heart disease or a psychiatric disorder, wherein the patient has at least one of: ... a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure, a heart failure

[0014] In a preferred embodiment, the use refers to using the phosphodiesterase 4 inhibitor as an active ingredient in the preparation of a drug for preventing and / or treating psoriasis or atopic dermatitis mediated by phosphodiesterase 4.

[0015] In one embodiment, the use refers to using the phosphodiesterase 4 inhibitor as an active ingredient in the preparation of cosmetics for improving skin sensitivity.

[0016] In one embodiment, the cosmetic consists of phases A, B, C, and D, wherein: phase A consists of water, disodium EDTA, glycerin, panthenol, butylene glycol, hyaluronic acid, and sodium hyaluronate; phase B consists of a moisturizer, squalane, caprylic / capric triglyceride, polydimethylsiloxane, and the tetrahydrofuran-type lignan compound, wherein the moisturizer is a mixture of polyglyceryl-6 distearate, jojoba esters, polyglyceryl-3 beeswax ester, and cetyl alcohol; phase C is an emulsifier, which is selected from polyacrylamide, C 13 -C 14 At least one of isoparaffin and laureth-7; phase D is composed of a preservative and antibacterial agent and ceramide liposomes, the preservative and antibacterial agent is composed of 1,3-propylene glycol, 1,2-hexanediol and caprylhydroxamic acid, and the ceramide liposomes is composed of ceramide 3, hydrogenated lecithin, cholesterol, octyldodecanol, glycerin and water.

[0017] In one embodiment, the preparation of the cosmetic comprises the following steps:

[0018] 1) Pre-disperse sodium hyaluronate evenly, then add the remaining raw materials constituting phase A, stir evenly, and heat to 80-85° C. for standby use;

[0019] 2) Add the raw materials of phase B, first heat to 80-85°C, then add to phase A under stirring, and then homogenize at 10000-12000 rpm;

[0020] 3) cooling the mixture homogenized in step 2) to 50° C., then adding phase C, and homogenizing at 7000-8000 rpm;

[0021] 4) Cooling the mixture homogenized in step 3) to 45° C., then adding phase D and stirring evenly to obtain the product.

[0022] In a preferred embodiment, in 100 parts by mass of the cosmetic, phase A accounts for 85.3 parts by mass, phase B accounts for 12 parts by mass, phase C accounts for 0.9 parts by mass, and phase D accounts for 1.8 parts by mass.

[0023] In a further preferred embodiment, in 100 parts by mass of the cosmetic, phase A is composed of 80.71 parts by mass of water, 0.05 parts by mass of disodium EDTA, 2.0 parts by mass of glycerin, 0.5 parts by mass of panthenol, 2.0 parts by mass of butylene glycol, 0.03 parts by mass of hyaluronic acid and 0.01 parts by mass of sodium hyaluronate; phase B is composed of 2.0 parts by mass of moisturizer, 2.0 parts by mass of squalane, 2.0 parts by mass of caprylic / capric triglyceride, 2.0 parts by mass of polydimethylsiloxane and 4.0 parts by mass of the tetrahydrofuran-type lignan compound, phase C is composed of 0.9 parts by mass of emulsifier, and phase D is composed of 0.8 parts by mass of preservative and antibacterial agent and 1.0 parts by mass of ceramide liposome.

[0024] In a preferred embodiment, in the general formula of the tetrahydrofuran-type lignan compound, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are independently selected from H or methoxy; R 7 is selected from hydroxyl or acetyl, R 8 Selected from H or hydroxyl.

[0025] In a further preferred embodiment, the tetrahydrofuran-type lignan compound is selected from at least one of the following compounds:

[0026]

[0027]

[0028] In one embodiment, the tetrahydrofuran-type lignan compounds are obtained by chemical synthesis or extraction from plants.

[0029] In a preferred embodiment, the tetrahydrofuran-type lignan compounds are extracted and separated from Magnolia biondii Pamp. buds.

[0030] The definitions of the terms used in this invention are as follows:

[0031] The term "C 1 ~C 6 The term "alkyl" includes methyl, ethyl, propyl, butyl, pentyl and hexyl, preferably methyl or ethyl.

[0032] The term "C 3 ~C 6 "Cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0033] The term "compound having PDE4 inhibitory activity" refers to a compound capable of inhibiting phosphodiesterase 4 and its isoforms.

[0034] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including conformational isomers, optical isomers, and the like.

[0035] The term "precursor compound" refers to a compound that is inactive in vitro but can be converted into the active ingredient of the present invention by metabolism or chemical reaction in vivo, thereby exerting its pharmacological effect.

[0036] The drug of the present invention can be administered to patients by various routes of administration, including but not limited to oral, transdermal, intramuscular, subcutaneous and intravenous injection.

[0037] The dosage form of the drug of the present invention is not limited, as long as it is a dosage form that can effectively enable the active ingredients to reach the body, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, granules, pills, powders, pastes, pills, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches, etc.; oral dosage forms are preferred, such as: capsules, tablets, oral liquids, granules, pills, powders, pills, pastes, etc.

[0038] In addition to the main active ingredients, the medicine and / or cosmetics of the present invention may also contain a small amount of secondary ingredients that do not affect the active ingredients and / or pharmaceutically acceptable carriers and various necessary excipients for preparations. For example, when the medicine is an oral dosage form, it may contain commonly used excipients such as adhesives, fillers, diluents, compressed tablets, lubricants, disintegrants, colorants, flavoring agents and wetting agents, and the tablets may be coated if necessary. Suitable fillers include cellulose, mannitol, lactose and other similar fillers; suitable disintegrants include starch, polyvinyl pyrrolidone and starch derivatives, such as sodium starch glycolate; suitable lubricants include, for example, magnesium stearate; suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

[0039] The present invention also contemplates the use of pharmaceutically acceptable deuterated compounds or other non-radioactive substituted compounds of the compounds. Deuteration is the replacement of one or more or all hydrogens in the active molecular groups of the drug with the isotope deuterium, which is non-toxic and non-radioactive, and is about 6 to 9 times more stable than carbon-hydrogen bonds. It can block metabolic sites and prolong the half-life of the drug, thereby reducing the therapeutic dose, while not affecting the pharmacological activity of the drug, and is therefore considered to be an excellent modification method.

[0040] The term "ester" means that the hydroxy group (if present) in the compounds of the present invention has been converted to the corresponding ester using, for example, an inorganic or organic anhydride, acid or acid chloride.

[0041] The term "pharmaceutically acceptable ester" refers to esters of the compounds of the invention that are pharmacologically acceptable and substantially non-toxic to the subject to which they are administered. More specifically, these esters retain the biological effectiveness and properties of the compounds of the invention and act as prodrugs that, when administered in vivo, are metabolized or cleaved in a manner that produces the parent compound. Examples of esters include, inter alia, the following groups: (1) carboxylates; (2) sulfonates, such as alkyl- or arylalkyl-sulfonates (e.g. methanesulfonate); (3) phosphonates; (4) monophosphates, diphosphates or triphosphates (including phosphoramidates); (5) carbamates (e.g. N-methylcarbamate); (6) carbonates obtained by esterification of a hydroxyl group (e.g. methyl carbonate), the ester group including, for example, a straight-chain or branched alkyl group (e.g. ethyl, n-propyl, tert-butyl, n-butyl, methyl, propyl, isopropyl, butyl, isobutyl or pentyl), an alkoxyalkyl group (e.g. methoxymethyl, acetoxymethyl and 2,2-dimethylpropionyloxymethyl), an aralkyl group (e.g. benzyl), an aryloxyalkyl group (e.g. phenoxymethyl), an aryl group (e.g. optionally substituted with, for example, halogen, C 1 ~C 4 Alkyl or C 1 ~C 4 phenyl substituted with alkoxy or amino).

[0042] The compounds of the present invention can be esterified by various conventional methods, including reacting an appropriate anhydride, carboxylic acid or acyl chloride with the alcohol group of the compounds of the present invention. For example, an appropriate anhydride can be reacted with an alcohol in the presence of a base such as 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine to promote acylation. In addition, a suitable carboxylic acid can be reacted with an alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water-soluble dehydrating agents for driving the reaction by removing water and an optional acylation catalyst. Esterification can also be carried out using an appropriate carboxylic acid. The reaction of an acyl chloride with an alcohol can also be carried out. When the compounds of the present invention contain a number of free hydroxyl groups, those groups that are not converted to prodrug functional groups can be protected (e.g., using tert-butyl-dimethylsilyl) and then deprotected. Moreover, enzymatic methods can be used to selectively phosphorylate or dephosphorylate alcohol functional groups. Those skilled in the art will readily know how to successfully implement these and other known alcohol esterification methods.

[0043] Compared with the prior art, the present invention has the following significant beneficial effects:

[0044] The research results of the present invention show that the tetrahydrofuran-type lignan compounds can effectively inhibit the activity of phosphodiesterase 4, and therefore are expected to be used as active ingredients for preparing phosphodiesterase 4 inhibitors, and further as active ingredients for preparing drugs for preventing and / or treating related diseases mediated by phosphodiesterase 4, and are particularly useful for preparing drugs for preventing and / or treating psoriasis or atopic dermatitis mediated by phosphodiesterase 4, and have significant medicinal value; in addition, the research results of the present invention also show that the tetrahydrofuran-type lignan compounds can also effectively improve skin sensitivity, and can be used to prepare cosmetics for improving skin sensitivity, and have broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1a The curve showing the relationship between the inhibition rate of compound WCH-3 on PDE4 and its concentration;

[0046] Figure 1b The curve showing the relationship between the inhibition rate of compound WCH-10 on PDE4 and its concentration;

[0047] Figure 2a The relationship curve between the skin lesion area and severity index (PASI score) of compounds WCH-3 and WCH-10 and the administration time of psoriasis mice stimulated by imiquimod is shown; in the figure: * indicates that compared with the model group, P < 0.05; ** indicates that compared with the model group, P < 0.01; *** indicates that compared with the model group, P < 0.001;

[0048] Figure 2b The relationship curve between the erythema score of the compound WCH-3 and WCH-10 in the back lesions of psoriasis mice stimulated by imiquimod and the administration time is shown; in the figure: * means P<0.05 compared with the model group; ** means P<0.01 compared with the model group; *** means P<0.001 compared with the model group;

[0049] Figure 2c The relationship curve between the scale score of the back lesions of psoriasis mice stimulated by imiquimod and the administration time of the compounds WCH-3 and WCH-10 is shown; in the figure: * indicates that compared with the model group, P < 0.05; ** indicates that compared with the model group, P < 0.01; *** indicates that compared with the model group, P < 0.001;

[0050] Figure 2d The relationship curve between the thickness score of the back lesions of psoriasis mice stimulated by imiquimod and the administration time of the compounds WCH-3 and WCH-10 is shown; in the figure: * indicates that compared with the model group, P < 0.05; ** indicates that compared with the model group, P < 0.01; *** indicates that compared with the model group, P < 0.001;

[0051] Figure 3a The effect of compounds WCH-3 and WCH-10 on the back lesion score of mice in the skin allergic reaction induced by 2,4-dinitrochlorobenzene (DNCB) is shown; in the figure: * indicates that compared with the model group, P < 0.05; ** indicates that compared with the model group, P < 0.01; *** indicates that compared with the model group, P < 0.001;

[0052] Figure 3b The effect of compounds WCH-3 and WCH-10 on the scale score of the back skin lesions of mice in the skin allergic reaction induced by 2,4-dinitrochlorobenzene (DNCB) is shown; in the figure: * indicates that compared with the model group, P < 0.05; ** indicates that compared with the model group, P < 0.01; *** indicates that compared with the model group, P < 0.001;

[0053] Figure 3c The effect of compounds WCH-3 and WCH-10 on the epidermal exfoliation score in the back skin lesions of mice in the skin allergic reaction induced by 2,4-dinitrochlorobenzene (DNCB) is shown; in the figure: * indicates that compared with the model group, P < 0.05; ** indicates that compared with the model group, P < 0.01; *** indicates that compared with the model group, P < 0.001;

[0054] Figure 3d The effect of compounds WCH-3 and WCH-10 on the erythema score in the back skin lesions of mice in the skin allergic reaction induced by 2,4-dinitrochlorobenzene (DNCB) is shown; in the figure: * indicates that compared with the model group, P < 0.05; ** indicates that compared with the model group, P < 0.01; *** indicates that compared with the model group, P < 0.001;

[0055] Figure 3e The effects of compounds WCH-3 and WCH-10 on edema scores in back skin lesions of mice in 2,4-dinitrochlorobenzene (DNCB)-induced skin allergic reactions are shown; in the figure: * indicates P<0.05 compared with the model group; ** indicates P<0.01 compared with the model group; *** indicates P<0.001 compared with the model group. DETAILED DESCRIPTION

[0056] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0057] The preparation method of the tetrahydrofuran-type lignan compounds described in the following examples is as follows:

[0058] Take 10 kg of dried Magnolia biondii Pamp. buds, crush them, and use about 10 times the amount of 95% ethanol to heat and reflux for 3 times, 2 hours each time, combine the extracts, and concentrate under reduced pressure until there is no alcohol taste;

[0059] Add 10L of purified water to the extract for suspension, then extract with equal volumes of petroleum ether and ethyl acetate three times in sequence, combine the ethyl acetate extracts, and concentrate under reduced pressure to obtain an ethyl acetate extract;

[0060] Add MCI filler and mix the sample, and separate it by MCI column chromatography, eluting with 20%, 40%, 60%, 70%, and 95% ethanol in sequence, and finally washing the column with acetone to obtain 9 components (recorded as Fr.1-9);

[0061] The component Fr.2 was subjected to secondary separation by silica gel column chromatography, and gradient elution was performed with petroleum ether-ethyl acetate (10:1-4:1) to obtain 9 fractions (referred to as Fr.2-1-9);

[0062] Fraction Fr.2-9 was separated by gel column chromatography [methanol-water (70:30)] to obtain compound WCH-8;

[0063] The fraction Fr.2-3 was separated by semi-preparative HPLC (acetonitrile-water 43:57, volume flow rate 3 mL / min) to obtain compound WCH-7 (t R =9.75min);

[0064] The fraction Fr.2-4 was separated by semi-preparative HPLC (acetonitrile-water 43:57, volume flow rate 3 mL / min) to obtain compound WCH-9 (t R =8.11min);

[0065] Recrystallize component Fr.3 from methanol to obtain compound WCH-5;

[0066] The component Fr.3 was subjected to secondary separation by silica gel column chromatography, and gradient elution was performed with dichloromethane-methanol (100:1 to 10:1) to obtain 8 fractions (referred to as Fr.3-1 to 8);

[0067] The fraction Fr.3-6 was subjected to MCI column chromatography and gradient eluted with methanol-water (30:70 to 100:0) to obtain three fractions (referred to as Fr.3-6-1 to 3);

[0068] The fraction Fr.3-6-1 was subjected to ODS column chromatography and gradient eluted with methanol-water (30:70 to 100:0) to obtain three fractions (denoted as Fr.3-6-1-A to C);

[0069] The fraction Fr.3-6-1-A was subjected to polyamide column chromatography and gradient eluted with ethanol-water (0:100 to 100:0) to obtain 5 fractions (referred to as Fr.3-6-1-Aa to e);

[0070] The fraction Fr.3-6-1-Ab was separated by semi-preparative HPLC [methanol-water (53:47), volume flow rate 3 mL / min] to obtain compound WCH-4 (t R =10.10min) and WCH-6(t R =14.62min);

[0071] The fraction Fr.3-6-1-Ac was separated by semi-preparative HPLC [methanol-water (47:53), volume flow rate 3 mL / min] to obtain compound WCH-1 (t R =11.30min);

[0072] The fraction Fr.3-6-1-Ad was separated by gel column chromatography [methanol-water (70:30)] to obtain Fr.3-6-1-Ad-1 and compound WCH-10;

[0073] Fr.3-6-1-Ae and Fr.3-6-1-Ad-1 were combined and then separated by gel column chromatography [methanol-water (70:30)] to obtain 7 fractions Fr.3-6-1-Ae-1 to 7, among which: Fr.3-6-1-Ae-6 is compound WCH-3, and Fr.3-6-1-Ae-7 is compound WCH-2;

[0074] Fr.3-6-1-Ae-3 was separated by semi-preparative HPLC [acetonitrile-water (25:75), volume flow rate 3 mL / min] to obtain compound WCH-11.

[0075]

[0076] (+)-pinoresinol(WCH-1):white solid,ESI-MS m / z:359[M+H] + ,341[MH 2 O+H] + ,molecular formula:C 20 H 22 O 6 ,molecular weight:358. 1 H-NMR (CDCl 3 ,600MHz)δ H:6.90(2H,d,J=1.9Hz,H-10,10'),6.89(2H,d,J=8.0Hz,H-13,13'),6.82(2H,dd,J=1.7,8.2Hz,H-14,14'),5.60(2H,s,H-2×OH),4.74(2H, d,J=4.3Hz,H-2,6),4.25(2H,dd,J=6.9,9.1Hz,H-4e,8e),3.91(6H,s,H-2×OMe),3.88(2H,dd,J=3.7,9.3Hz,H-4a,8a),3.10(2H,m,H-1,5). 13 C-NMR (CDCl 3 ,151MHz)δ C :146.83(2C-11,11'),145.37(2C-12,12'),133.05(2C-9,9'),119.11(2C-14,14'),114.39(2C-13,13'),108.72(2C-10,10'),86.02(2C-2,6),71.82(2C-4,8),56.10(2C-2×OMe),54.31(2C-1,5). The above data are basically consistent with those reported in the literature, so the compound is identified as (+)-pinoresinol[Natural product letters.2002;16(5):359-63.].

[0077]

[0078] Medioresinol B(WCH-2):white solid,ESI-MS m / z:389[M+H] + ,371[MH 2 O+H] + ,molecular formula:C 21 H 24 O 7 ,molecular weight:388. 1 H-NMR (CDCl 3 ,600MHz)δ H:6.89(1H,d,J=1.8Hz,H-10), 6.89(1H,d,J=8.1Hz,H-13), 6.82(1H,dd,J=1.7,8.2Hz, H-14),6.57(1H,d,J=1.5Hz,H-10'),6.50(1H,d,J=1.8Hz,H-14'),5.78(1H,s,H-OH), 5.59(1H,s,H-OH),4.74(2H,d,J=5.1Hz,H-2,6),4.26(2H,m,H-4e,8e),3.88(2H,dd,J =3.7,9.3Hz,H-4a,8a),3.91(3H,s,H-OMe),3.88(6H,s,H-2×OMe),3.08(2H,m,H-1,5). 13 C-NMR (CDCl 3 ,151MHz)δ C :152.65(C-13'),149.44(C-11'),146.83(C-11),145.40(C-12),137.61(C-9'),134.95( C-12'),132.99(C-9),119.16(C-14),114.39(C-13),108.71(C-10),105.60(C-10'),101 .84(C-14'),86.03(C-2),85.84(C-6),72.10(C-8),71.87(C-4),61.11(C-OMe),56.11(C-OMe),56.07(C-OMe),54.33(C-1),54.29(C-5). The above data are basically consistent with those reported in the literature, so the compound was identified as medioresinol B [Chemical&Pharmaceutical Bulletin.2017;65(9):840].

[0079]

[0080] (+)-4”-de-O-methylmagnolin(WCH-3):white solid,ESI-MS m / z:403[M+H] + , 385[MH 2 O+H] + ,molecular formula:C 22 H 26 O 7 ,molecular weight:402. 1 H-NMR (CDCl 3,600MHz)δ H :6.91(1H,d,J=1.6Hz,H-10'),6.88(1H,dd,J=1.6,8.3Hz,H-14'),6.85(1H ,d,J=8.2Hz,H-13'),6.59(2H,s,H-10,14),5.49(1H,s,H-OH),4.77(1H,d, J=4.8Hz,H-2),4.72(1H,d,J=5.0Hz,H-6),4.31(2H,m,H-4e,8e),3.90(9H, s,H-3×OMe),3.89(2H,m,H-4a,8a),3.88(3H,s,H-OMe),3.11(2H,m,H-1,5). 13 C-NMR (CDCl 3 ,151MHz)δ C :149.35(C-11'),148.79(C-12'),147.29(2C-11,13),134.42(C-12),133.64(C-9'),132.27(C-9), 118.37(C-14'),111.19(C-13'),109.37(C-10'),102.84(2C-10,14),86.30(C-6),85.88(C-2),72. 03(C-8),71.80(C-4),56.53(2C-2×OMe),56.11(C-OMe),56.09(C-OMe),54.56(C-5),54.25(C-1). The above data are basically consistent with those reported in the literature, so the compound is identified as (+)-4"-de-O-methylmagnolin[Phytochemistry.1995;39(5):1027-30.].

[0081]

[0082] De-4'-O-methylyangabin(WCH-4):white solid,ESI-MS m / z:433[M+H] + , 415[MH 2 O+H] + ,molecular formula:C 23 H 28 O 8 ,molecular weight:432. 1 H-NMR (CDCl 3 ,600MHz)δ H:6.58(2H,s,H-10',14'),6.57(2H,s,H-10,14),5.49(1H,s,H-OH),4.75(1H,d,J=4.5Hz,H-6),4.73(1H,d,J=4.5Hz,H-2),4.2 9(2H,m,H-4e,8e),3.92(2H,m,H-4a,8a),3.90(6H,s,H-2×OMe),3.88(6H,s,H-2×OMe),3.84(3H,s,H-OMe),3.10(2H,m,H-1,5). 13 C-NMR (CDCl 3 ,150MHz)δ C :153.59(2C-11,13),147.30(2C-11',13'),137.63(C-12),136.93(C-9),134.45(C-12'),132 .19(C-9'),102.95(2C-10',14'),102.85(2C-10,14),86.22(C-2),86.12(C-6),72.07(C-8),7 2.03(C-4),61.01(C-OMe),56.53(2C-2×OMe),56.35(2C-2×OMe),54.53(C-5),54.51(C-1). The above data are basically consistent with those reported in the literature, so the compound was identified as de-4'-O-methylyangabin [Phytochemistry. 1993; 32(6):1421-1424].

[0083]

[0084] (+)-magnolin(WCH-5):yellowishoil,ESI-MS m / z:417[M+H] + ,399[MH 2 O+H] + ,molecular formula:C 23 H 28 O 7 ,molecular weight:416. 1 H-NMR (CDCl 3 ,600MHz)δ H:6.90(1H,d,J=1.8Hz,H-10'),6.87(1H,dd,J=1.7,8.3Hz,H-14'),6.83(1H,d,J=8.2Hz,H-13') ,6.56(2H,s,H-10,14),4.75(1H,d,J=4.5Hz,H-2),4.73(1H,d,J=4.5Hz,H-6),4.27(2H,m,H-4e, 8e), 3.91(2H,m,H-4a,8a),3.89(3H,s,H-OMe),3.86(9H,s,H-3×OMe),3.82(3H,s,H-OMe),3.10(2H,m,H-1,5). The above data are basically consistent with those reported in the literature, so the compound was identified as (+)-magnolin[Luo Huiwei. Research on chemical components and pharmacological activities of magnolia. South-Central University for Nationalities; 2013:51].

[0085]

[0086] (+)-eudesmin(WCH-6):yellow solid,ESI-MS m / z:387[M+H] + ,369[MH 2 O+H] + ,molecular formula:C 22 H 26 O 6 ,molecular weight:386. 1 H-NMR (CDCl 3 ,600MHz)δ H :6.91(2H,d,J=1.5Hz,H-10,10'),6.88(2H,dd,J=1.7,8.2Hz,H-14,14'),6.84(2H,d,J=8.2Hz,H-13,13'),4 .76(2H,d,J=4.1Hz,H-2,6),4.26(2H,dd,J=6.8,9.0Hz,H-4e,8e),3.88(2H,m,H-4a,8a),3.90(6H,s,H-2×OCH 3 ),3.88(3H,s,H-2×OCH 3 ),3.12(2H,m,H-1,5). The above data are basically consistent with those reported in the literature, so the compound was identified as (+)-eudesmin[Biotechnology&BioprocessEngineering.2010;15(3):400-406].

[0087]

[0088] 9'-O-acetyl-(7R,8S,7'R,8'R)-fargesol(WCH-7):yellow solid,HR-ESI–MS atm / z:431.1717(calculated for C 23 H 27 O 8 ,431.1711[M-H] - ). 1 H-NMR(CDCl 3 ,600MHz)δ H :6.89(1H,d,J=1.7Hz,H-2'),6.88(1H,d,J=8.1Hz,H-5'),6.86(1H,brd,H-2),6.83(1H,dd,J=8.1 / 1.6Hz,H-5'),6.81(2H,m,H-5,6),4.50(1H,d,J=7.8Hz,H-7'),4.61(1H,dd,J=8.2 / 3.0Hz,H-7),3.87(3H,s,H-OMe),3.86(3H,s,H-OMe),3.91(3H,s,H-OMe),3.97(1H,dd,J=7.2,9.4Hz,H-9a),4.33(1H,dd,J=4.1,9.4Hz,H-9b),1.90(3H,s,H-COCH 3 ). 13 C-NMR(CDCl 3 ,150MHz)δ C :135.2(C-1),109.5(C-2),149.4(C-3),149.0(C-4),111.1(C-5),119.0(C-6),76.0(C-7),50.1(C-8),70.2(C-9),133.2(C-1’),108.8(C-2’),146.7(C-3’),145.4(C-4’),114.4(C-5’),119.5(C-6’),84.2(C-7’),49.2(C-8’),61.2(C-9’),170.9( CO CH 3 ),20.9(CO CH 3 ),56.1(C-OMe),56.1(C-OMe),56.1(C-OMe). The above data are basically consistent with those reported in the literature, so the compound is identified as 9'-O-acetyl-(7R,8S,7'R,8'R)-fargesol.[Natural Product Research,2022,2147166.]

[0089]

[0090] 7R,8S,7'S,8'R-3,4,3',4'-tetramethoxy-9,7'-dihydroxy-8.8',7.O.9'-lignan(WCH-8):yellow solid,ESI-MS m / z:387[MH 2 O+H] + ,molecular formula:C 22 H 28 O 7 ,molecular weight:404. 1 H-NMR (CD 3 OD,600MHz)δ H :7.05(1H,d,J=1.2Hz,H-2'),6.99(1H,d,J=1.2Hz,H-2),6.93-6.95(4H,H-5,5 ',6,6'),4.57(1H,d,J=8.7Hz,H-7'),4.54(1H,d,J=9.0Hz,H-7),3.87(3H,s,H -OMe),3.86(3H,s,H-OMe),3.875(6H,s,H-2×OMe),3.77(1H,dd,J=6.3,9.2Hz, H-9b),3.62-3.67(3H,m,H-9a,9'b,9'a),2.65(1H,m,H-8'),2.31(1H,m,H-8). 13 C-NMR (CD 3 OD,151MHz)δ C:150.57,150.53(2C-3,3'),150.23,150.16(2C-4,4'),137.55(C-1'),135.54(C-1),120.63(C-6'),120.40(C -6),112.69(C-5'),112.60(C-5),111.55(C-2),111.33(C-2'),85.59(C-7),77.36(C-7'),71.21(C-9'),63.29 (C-9), 56.49 (C-OMe), 56.46 (2C-2×OMe), 56.43 (C-OMe), 55.91 (C-8), 52.74 (C-8'). The above data are basically consistent with those reported in the literature, so the compound was identified as 7R, 8S, 7'S, 8'R-3, 4, 3', 4'-tetramethoxy-9, 7'-dihydroxy-8.8', 7.O.9'-lignan [Chemical & Pharmaceutical Bulletin. 2007; 55(1): 137-9.].

[0091]

[0092] 9'-O-acetyl-(7S,8R,7S,8S)-(-)-fargesol(WCH-9):yellowish solid,ESI-MSm / z:445[MH] - ,molecular formula:C 24 H 30 O 8 ,molecular weight:446. 1 H-NMR (CDCl 3 ,600MHz)δ H :6.83-6.96(6H,H-Ar),4.53(1H,d,J=7.7Hz,H-7),4.51(1H,d,J=7.1Hz,H-7 '),4.29(1H,dd,J=4.4,9.1Hz,H-9a),3.96(1H,dd,J=7.5,9.0Hz,H-9b),3.8 4(3H,s,H-OMe),3.82(3H,s,H-OMe),3.81(3H,s,H-OMe),3.80(3H,s,H-OMe) ,3.76(2H,m,H-9'),2.50(1H,m,H-8'),2.12(1H,m,H-8),1.82(3H,s,H-Me). 13 C-NMR (CDCl 3,151MHz)δ C :172.47(C=O),150.53(C-4,4'),150.23(C-3'),150.09(C-3),137.33(C-1'),135.30(C-1),120.48(C- 6'),120.36(C-6),112.75(C-5),112.69(C-5'),111.49(C-2),111.37(C-2'),85.72(C-7'),76.34(C-7) ,71.34(C-9),64.94(C-9'),56.51(C-OMe),56.50(C-OMe),56.47(C-OMe),56.42(C-OMe),51.26(C-8),50.31(C-8'),20.58(C-Me). The above data are basically consistent with those reported in the literature, so the compound is identified as 9'-O-acetyl-(7S,8R,7S,8S)-(-)-fargesol[Chem Pharm Bull.2002;50(4):541-3.].

[0093]

[0094] Lariciresinol dimethyl ether(WCH-10):yellowish solid,ESI-MS m / z:777[2M+H] + ,357[MH 2 OH] - ,molecular formula:C 22 H 28 O 6 ,molecular weight:388. 1 H-NMR (CDCl 3 ,600MHz)δ H :6.71-6.88(6H,H-Ar),4.82(1H,d,J=6.6Hz,H-7'),3.74-4.07(4H,H-9,9'),3,88( 3H,s,H-OMe),3,87(6H,s,H-2×OMe),3,86(3H,s,H-OMe),2.43-2.96(4H,H-7,8,8'). 13 C-NMR (CDCl 3 ,151MHz)δ C:149.24(C-3),149.11(C-4),148.57(C-3'),147.61(C-4'),135.55(C-1),133.09(C-1 '),120.63(C-6'),118.17(C-6),112.06(C-5'),111.46(C-2'),111.14(C-5),109.09(C -2), 82.90(C-7), 73.10(C-9'), 61.13(C-9), 56.09(C-OMe), 56.06(C-OMe), 56.04(C-OMe), 52.71(C-8), 42.49(C-8'), 33.41(C-7'). The above data are basically consistent with those reported in the literature, so the compound is identified as lariciresinol dimethyl ether [Phytochemistry. 1998; 47(7): 1437-9.].

[0095]

[0096] 3-furanmethanol-tetrahydro-2-(4-hydroxy-3',5'-dimethoxyphenyl)-4-[(3”,4”,5”-trimethoxyphenyl)methyl]-(2R,3S,4S)-rel-(WCH-11):yellowish solid,EI-MS m / z:434[M] + ,molecular formula:C 23 H 30 O 8 ,molecular weight:434. 1 H-NMR (CDCl 3 ,600MHz)δ H:6.57,6.41(2H each,s,H-2,6;H-2,6'),4.82(1H,d,J=6.0Hz,H-7'),4.07(1H,m,H-9b),3.95(1H,m,H-9'b),3.93(1H,m,H-7b),3.88( 6H,s,H-2×OMe),3.86(6H,s,H-2×OMe),3.85(3H,s,H-OMe),3.80(1H,m,H-9'a),3.77(1H,m,H-9a),2.75(1H,m,H-8),2 .57(1H,m,H-7a),2.45(1H,m,H-8'). The above data are basically consistent with those reported in the literature, so the compound was identified as 3-ethanol-tetrahydro-2-(4-hydroxy-3',5'-dimethoxyphenyl)-4-[(3",4",5"-trimethoxyphenyl)methyl]-(2R,3S,4S)-furan[Phytochemistry.1993;35(1):209-15].

[0097] Example 1: Determination of PDE4 inhibitory activity

[0098] The inhibitory activity of WCH-1 to WCH-11 compounds against PDE4 was determined using the phosphodiesterase proximity assay (SPA).

[0099] This assay detects the hydrolase activity of PDE4 [ 3 H]-cAMP hydrolysis products [ 3 The scintillation light excited by the combination of [H]-AMP and scintillation microbeads under the chelation of metal ions is used to identify the effect of the tetrahydrofuran-type lignan compounds (such as WCH-1 to WCH-11 compounds) of the present invention on the hydrolysis activity of PDE4.

[0100] The volume of the entire enzymatic reaction system was 125 μL, and the assay buffer (50 mM Tris pH 7.5, 8.3 mM MgCl) was used. 2 , 1.7 mM EGTA) to prepare a protein solution with a concentration of 0.01-0.06 ng / μL. The specific experimental steps are as follows:

[0101] SPA reaction buffer was used to prepare protein solution (working concentration was 0.01-0.06 ng / μL) and compounds of corresponding concentrations; during the test, the reaction system of each well was 125 μL, and 10 μL of the tetrahydrofuran-type lignan compound solution (the final concentration of DMSO was not more than 1%), 80 μL of the above protein solution and 10 μL of [ 3 H]-cAMP (final concentration of 0.005 μCi / μL); after incubation at 30°C for 10 minutes, 25 μL of phosphodiesterase SPA scintillation beads were added to terminate the reaction; after standing at room temperature for 20 minutes, luminescence was measured using a liquid scintillation counter MicroBeta2; all experimental data were analyzed using GraphPad Prism version 8.0 (GraphPad Inc.); detailed results are shown in Table 1.

[0102] Table 1. Inhibition rate of different concentrations of tetrahydrofuran lignans on PDE4

[0103]

[0104]

[0105] Note: N / A means no inhibition; * means inhibition rate is 1% to 30%; ** means inhibition rate is 31% to 60%; *** means inhibition rate is 61% to 90%.

[0106] From the results shown in the above table, it can be seen that compounds WCH-1 to WCH-11 have significant inhibitory activity against PDE4 at a concentration of 10 μM.

[0107] Figure 1a and Figure 1b The dependence of the inhibitory activity of compounds WCH-3 and WCH-10 on PDE4 on their concentrations is shown. Figure 1a and Figure 1b Visible: Compound WCH-3 (IC 50 =3.06 μM) and WCH-10 (IC 50 =4.04 μM) all had significant inhibitory activity against PDE4.

[0108] Example 2: Preparation of skin lotion from compound WCH-3

[0109] Prepare the body lotion as follows:

[0110] 1) After pre-dispersing the sodium hyaluronate evenly, add the remaining raw materials of phase A, stir evenly, and heat to 80-85°C for standby use;

[0111] 2) Add the raw materials of phase B, heat to 80-85°C, add to phase A under stirring, and then homogenize at 10000-12000 rpm for 5 minutes;

[0112] 3) cooling the mixture homogenized in step 2) to 50° C., then adding phase C, and homogenizing at 7000-8000 rpm for 3 min;

[0113] 4) cooling the mixture homogenized in step 3) to 45° C., then adding phase D (solid powder needs to be pre-dissolved before adding), and stirring evenly;

[0114] The components and ratios of phases A to D are shown in Table 2.

[0115] Table 2 Formula of body lotion

[0116]

[0117]

[0118] Example 3: Preparation of skin lotion from compound WCH-10

[0119] The only difference between this embodiment and embodiment 2 is that the WCH-3 compound is replaced by the WCH-10 compound, and the rest of the contents are the same as those described in embodiment 2.

[0120] Comparative Example: Preparation of comparative body lotion

[0121] The only difference between this comparative example and Example 2 is that phase B does not contain tetrahydrofuran-type lignan compounds (WCH-3 compounds), and the rest of the contents are the same as those described in Example 2.

[0122] Example 4: Evaluation of the therapeutic effects of compounds WCH-3 and WCH-10 on imiquimod-stimulated psoriasis in mice

[0123] Experimental purpose: To detect the therapeutic effect of the tetrahydrofuran-type lignan compounds described in the present invention on imiquimod-induced psoriasis in mice.

[0124] Experimental animals: Female BALB / c mice.

[0125] Experimental groups: blank group, model group, WCH-3 group, and WCH-10 group.

[0126] Experimental method: Before the start of the experiment (ie, day 0), the mice were depilated; on days 1 to 5, after the mice were depilated, imiquimod (60 mg per day) was applied to the back skin for modeling, and applied once a day; on days 6 to 15, the drug was applied for treatment, and the application method (calculated based on 10 days of drug treatment) was as follows: imiquimod was applied at around 9:00 am every day, and the residual imiquimod on the back was wiped off at around 15:00 pm, and then the treatment drug was applied (model group, 4% compound WCH-3 group or 4% compound WCH-10 group, the amount of ointment applied was 60 mg ointment / day).

[0127] From the beginning of modeling to the end of the experiment, the skin on the back of the animals was photographed every morning, and the mouse model was scored and recorded according to the Psoriasis Lesion Area and Severity Index (PASI):

[0128] ① Erythema scoring standard: 0 is no erythema, 1 is erythema with light red color, 2 is erythema with red color, 3 is red erythema with red color.

[0129] The spots are dark red, with 4 points indicating very deep erythema;

[0130] ② Scaling scoring criteria: 0 is no scale on the surface, 1 is part of the lesion surface covered with scales, 2 is most of the lesion surface covered with scales, 3 is almost all of the lesion is covered with scales, the scales are layered, 4 is the skin is not completely covered with scales, and 5 is the skin is not completely covered with scales.

[0131] The damaged part is completely covered with scales;

[0132] ③Thickness scoring standard: 0 points means the lesion is flush with the normal skin, 1 point means the lesion is slightly higher than the normal skin surface, 2 points means the lesion is moderately raised, 3 points means the lesion is thickened and obviously raised, and 4 points means the lesion is highly thickened and obviously raised.

[0133] For detailed experimental results, please refer to Figure 2a to Figure 2d As shown by Figure 2a to Figure 2d The results show that compared with the model group, the skin lesions in the drug group showed significant reduction in scaling, erythema and PASI scores starting from the 5th day (P<0.05).

[0134] Example 5: Evaluation of the therapeutic effect of compound WCH-3 or WCH-10 on delayed hypersensitivity reaction in mice stimulated by 2,4-dinitrochlorobenzene (DNCB)

[0135] Experimental purpose: To detect the therapeutic effect of the tetrahydrofuran-type lignan compounds described in the present invention on DNCB-stimulated atopic dermatitis in mice.

[0136] Experimental animals: 50 female Balb / C mice;

[0137] Experimental groups: blank group, model group, 4% WCH-3 group, 4% WCH-10 group and positive drug crisaborole group (containing 2% crisaborole);

[0138] Experimental method: Before the experiment (i.e., day 0), the mice were depilated.

[0139] Week 1: The blank group was smeared with 200 μL of acetone: olive oil (3:1) solution, and the other groups were smeared with 200 μL of acetone: olive oil (3:1) solution containing 1% DNCB, and sensitization was performed twice a week (sensitization on the 1st and 4th days);

[0140] Week 2: The blank group was smeared with 200 μL of acetone: olive oil (3:1) solution, and the other groups were smeared with 200 μL of acetone: olive oil (3:1) solution containing 0.4% DNCB to induce allergic reaction (stimulation on the 1st and 4th days);

[0141] Week 3: The blank group was smeared with 200 μL of acetone: olive oil (3:1) solution and matrix milk; the model group was smeared with 200 μL of acetone: olive oil (3:1) solution containing 0.4% DNCB and matrix milk; the drug group was smeared with samples and dexamethasone in addition to 200 μL of acetone: olive oil (3:1) solution containing 0.4% DNCB. The drugs were administered five times a week and photographed on the 7th day (DNCB was applied on the 1st and 4th days, and the drugs were administered on the remaining 5 days);

[0142] The same procedure was performed in the fourth, fifth, and sixth weeks, and the extent of skin lesions was evaluated on the 42nd day.

[0143] Scoring criteria for delayed allergic reaction skin lesions:

[0144] 1) Erythema or hemorrhage: 3 points for deep red or fiery red, 2 points for clearly visible, 1 point for dark red, and 1 point for faintly visible or pink;

[0145] 2) Edema or papules: 3 points if the swelling is significantly higher than the skin surface, 2 points if the swelling is clearly higher than the skin surface but not significantly higher than the skin surface, and 1 point if the swelling is barely noticeable higher than the epidermis;

[0146] 3) Scaling or dryness: diffuse superficial and / or many deep exfoliations were scored as 3 points, many superficial and / or some deeper exfoliations were scored as 2 points, and a few superficial exfoliations were scored as 1 point;

[0147] 4) Epidermal exfoliation or scratches: thick scaly coverage was 3 points, flaky scaling, thin coverage was 2 points, and bran-like scaling was 1 point.

[0148] For detailed experimental results, please refer to Figures 3a to 3e As shown by Figures 3a to 3eThe results show that compared with the model group, WCH-3 and WCH-10 had significant differences in the total score and each sub-item score of skin lesions (P<0.001), and the therapeutic effect was equivalent to that of the positive drug crisaborole group.

[0149] Example 6: Test on improving skin sensitivity function

[0150] Screening of experimenters: The screening was conducted by comparing the two sides of the nose.

[0151] 50 μL of 10% (w / w) lactic acid aqueous solution was applied to the nasolabial groove on either side, and normal saline was applied to the other side. The subjects were asked about their subjective symptoms at 30 seconds, 2.5 minutes, and 5 minutes, and the symptoms were recorded.

[0152] The pain was scored on a 4-point scale: 0 for no pain, 1 for mild pain, 2 for moderate pain, and 3 for severe pain).

[0153] Subtract the total scores of the two sides (10% lactic acid side and normal saline control side), and the difference of ≥3 points is considered as positive lactic acid stinging reaction. The subjects with positive lactic acid stinging reaction are selected as qualified subjects for the next test.

[0154] Sample test: The above-mentioned subjects with positive lactic acid stinging reaction were randomly divided into 14 groups (20-50 years old, half male and half female), 5 people in each group, wherein the control group did not use any product, and the test group used the moisturizing lotion prepared in Example 2 or Example 3 or the comparative example, one bottle each time, once a day. The test period was 28 days, and the lactic acid stinging test was performed on the first day (D0), the fourteenth day (D14) and the twenty-eighth day (D28) of the selected test, and the skin moisture content was tested by a skin moisture meter.

[0155] The detailed experimental results are shown in Tables 3 and 4.

[0156] Table 3 Average scores of lactic acid stinging test in each group of subjects

[0157] Body lotion D0 D14 D28 Example 2 7.35±0.63 4.35±0.71 3.54±0.25 Example 3 7.98±0.51 5.81±0.64 4.35±0.79 Comparative Example 7.19±1.20 7.32±0.67 7.61±1.48

[0158] From the results shown in Table 3, it can be seen that the lactic acid stinging test scores of the lotions prepared in Example 2 and Example 3 showed a significant decrease with the extension of the use time, indicating that the skin sensitivity of the subjects decreased and a better skin barrier could be formed; while the lotions prepared in the comparative example lacked the tetrahydrofuran-type lignan compounds (compounds WCH-3 or WCH-10) described in the present invention, so there was no decrease in the skin sensitivity score, indicating that the comparative example lotions had no skin repair performance.

[0159] Table 4 Average skin moisture content of subjects in each group

[0160] Body lotion D0 D14 D28 Example 2 Preparation Example 1 53.85±0.37 59.78±0.19 67.89±1.35 Example 3 Preparation Example 2 52.15±0.42 58.88±0.75 64.17±0.75 Comparative Example Comparative Preparation Example 1 50.47±0.83 53.02±0.57 49.37±1.61

[0161] From the results shown in Table 4, it can be seen that in the lotion test groups prepared by Example 2 and Example 3, the skin moisture content of the subjects was significantly improved, corresponding to the lactic acid stinging score, indicating that the skin barrier function of the subjects in each example was significantly improved, the skin condition was improved, and the water retention capacity was enhanced; while in the lotion prepared in the comparative example, due to the lack of the tetrahydrofuran-type lignan compound (compound WCH-3 or WCH-10) described in the present invention, there was no decrease in the skin water retention capacity score, and the comparative example lotion had no skin repair performance.

[0162] Combining the results in Table 3 and Table 4, it can be shown that the tetrahydrofuran-type lignan compounds described in the present invention have a significant effect in improving skin sensitivity.

[0163] The above experimental results show that the tetrahydrofuran lignan compounds of the present invention have significant inhibitory activity on PDE4 enzyme. The representative compounds WCH-3 and WCH-10 inhibit PDE4 at the enzyme level with IC 50 They are 3.06μM and 4.04μM respectively; and in the pharmacodynamic experiments, the representative compounds WCH-3 and WCH-10 both showed the ability to effectively reduce skin damage in mice with psoriasis induced by imiquimod and mice with delayed allergic reactions stimulated by DNCB, and had a clear therapeutic effect on psoriasis and delayed allergic reactions.

[0164] Finally, it is necessary to explain here that the above embodiments are only used to further illustrate the technical solution of the present invention in detail and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by technicians in this field based on the above content of the present invention all fall within the scope of protection of the present invention.

Claims

1. A use of a tetrahydrofuran-type lignan compound, characterized in that: The tetrahydrofuran-type lignan compound has the following chemical structure: The monotetrahydrofuran-type lignan compound; the use refers to using the tetrahydrofuran-type lignan compound to prepare a drug for preventing and / or treating psoriasis.

2. The use according to claim 1, characterized in that: The medicine also contains pharmaceutically acceptable carriers and / or auxiliary materials necessary for preparation.

3. The use according to claim 2, characterized in that: The preparations include tablets, capsules, oral liquids, lozenges, granules, pills, powders, ointments, pills, suspensions, powders, solutions and injections.

4. The use according to claim 2, characterized in that: The preparations include suppositories, ointments, plasters, creams, sprays, drops and patches.

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