Use of diterpene compound derivatives or their salts in the preparation of pharmaceuticals for the prevention and treatment of atopic dermatitis.

Abstract

The present application provides a use of a diterpene compound derivative or its salt in the preparation of a medicine for preventing and treating atopic dermatitis. The small molecule diterpene compound derivative or its salt has a significant role in preventing and treating atopic dermatitis, and shows good preventive and therapeutic roles in both mouse AD models induced by OXA or MC903, and can suppress the situation in which the skin lesion score of the mouse lesion increases, the ear thickness increases, the ear swelling worsens, and the mast cell number increases, and further, can reduce the serum IgE concentration and improve the degree of itching. It is found that such compounds can be used for the prevention and treatment of atopic dermatitis, providing a novel preventive and therapeutic concept and an effective medicine for the treatment of atopic dermatitis.

Description

[Technical Field]

[0001] This application relates to the field of biopharmaceutical technology, and more specifically to the use of small molecule diterpene compound derivatives or salts thereof in the preparation of pharmaceuticals for the prevention and treatment of atopic dermatitis. [Background technology]

[0002] Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease associated with the immune system. Because patients often have other atopic conditions such as allergic rhinitis and asthma, it is considered a systemic disease. The clinical manifestations of AD are diverse, but its basic characteristics include dry skin, chronic eczematous dermatitis, and severe itching.

[0003] The onset of Alzheimer's disease (AD) is closely related to genetic and environmental factors. A history of allergic diseases in family members, such as the father or mother, is the strongest risk factor for this disease, and genetic factors primarily affect skin barrier function and immune balance. Patients with this disease often have many immunological abnormalities, among which Th2 activation is a key feature, as well as weakened or destroyed skin barrier function, such as a decrease or deficiency of filaggrin in the epidermis. Environmental factors include climate change, lifestyle changes, improper bathing, and exposure to infectious agents and allergens. Modern lifestyles (excessive hygiene, Western diet, etc.) and environmental exposures (environmental pollution, passive smoking, etc.) may cause abnormalities in the immune system and skin barrier through epigenetic modifications, potentially contributing to the development of AD. Psychological factors (e.g., stress, anxiety, depression, etc.) also play a role in the development of AD.

[0004] The exact pathogenesis of Alzheimer's disease (AD) is still unclear, but current studies suggest that immune abnormalities, skin barrier dysfunction, and skin microbiota disorder are important contributing factors. Th2 inflammation is a fundamental characteristic of AD, and IL-4 and IL-13 are key cytokines that mediate the onset of AD, primarily produced by Th2 cells, basophils, and innate lymphoid cells. In the chronic phase of AD, mixed inflammatory infiltration of Th1, Th17, and Th22 cells is also observed in skin lesions. TSLP, produced by keratinocytes, is also an important cytokine that mediates AD pruritus. Skin barrier dysfunction due to gene mutations such as Filaggrin makes it easier for external environmental substances (e.g., microorganisms and allergens) to penetrate the epidermis and initiate Th2 inflammation, with Langerhans cells and cutaneous dendritic cells participating in this process through allergen presentation. Th2 inflammatory factors can suppress the expression of keratinocyte barrier-related proteins and further disrupt skin barrier function. AD skin lesions and seemingly normal skin promote the progression of skin inflammation, accompanied by disturbances in the skin bacterial colony, primarily manifested as increased Staphylococcus aureus colonization and decreased bacterial colony diversity, as well as resulting metabolic and other functional abnormalities. Repeated scratching is a significant cause of exacerbation and persistence of skin inflammation, as it stimulates keratinocytes to produce inflammatory mediators, triggers the release of autoantigens, and can lead to the production of IgE against these autoantigens. Non-immune factors, such as neuroendocrine elements, can also be involved in the development and progression of skin inflammation.

[0005] Currently, there are no drugs that can effectively cure Alzheimer's disease (AD). Conventional treatments only aim to alleviate or eliminate clinical symptoms, eliminate triggers and / or aggravating factors, reduce and prevent relapses, reduce or mitigate complications, and thereby improve the patient's quality of life. Although significant progress has been made in the treatment of AD over the past few decades, existing treatment options still struggle to meet clinical needs. Clinical treatment strategies still primarily consist of topical medications, oral glucocorticosteroids, and immunosuppressants. Commonly used drugs include glucocorticosteroids (TCS), calcineurin inhibitors (TCI), and targeted therapies such as PDE4 inhibitors, Jak inhibitors, and biologics such as Dupilumab monoclonal antibodies, which have been approved in recent years. Crisabolol ointment, a topical PDE4 inhibitor developed by Anacor Pharmaceuticals, was approved for sale by the FDA (trade name: Eucrisa®) and the EMA (trade name: Staquis®) in December 2016 and March 2020, and was approved for import and sale in China (trade name: Staquis®) in July 2020. It is used for topical treatment of mild to moderate Alzheimer's disease patients aged 2 years and older. Other companies are also developing topical PDE4 inhibitors, including Difamilast (OPA-15406, MM36) developed by Otsuka Pharmaceutical. On March 27, 2020, two top-line results from evaluation and treatment of mild to moderate AD stage III clinical trials held in Japan were published, both reaching major endpoints. In January 2020, Corectim (delgocitinib) ointment, jointly developed by Japan Tobacco and Torii Pharmaceutical, was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) under the Japanese Ministry of Health, Labour and Welfare. It is used for the topical treatment of mild to moderate Alzheimer's disease (AD) in adults and is the first topical JAK inhibitor to treat AD worldwide. Currently, many JAK inhibitors for treating AD are in the late stages of development.First-generation JAK inhibitors target multiple JAKs; for example, Lilly's Olumiant® (Baricitinib) is used for severe Alzheimer's disease (AD). Second-generation or next-generation JAK inhibitors selectively target JAKs and include Abbvie's Rinvoq® (Upadacitinib) and Pfizer's Abrocitinib, both used for moderate to severe AD. However, due to safety concerns of regulatory bodies regarding JAK inhibitors, listing applications for three JAK inhibitors used for AD have frequently been delayed by the FDA. Dupilumab Injection (trade name: Dupixent®), jointly developed by Sanofi and REGN, is a monoclonal antibody that inhibits the specific binding of the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complex, thereby suppressing IL-4 and IL-13 signaling. It is the first targeted biologic for the treatment of moderate to severe Alzheimer's disease (AD) to be approved by the FDA and EMA worldwide. This product was approved by the NMPA on June 19, 2020, for the treatment of moderate to severe AD in adults (trade name: Dapiltool), and on September 9, it was approved for use in adolescents aged 12 and older and adults with moderate to severe AD. The approval and marketing of dupilumab signifies the arrival of the era of AD treatment with biologics. On June 22, LEO Pharma announced that its interleukin-13 inhibitor, Adtralza (Tralokinumab), had been approved for use in the European Union for the treatment of Alzheimer's disease (AD). Adtralza is the world's first monoclonal antibody therapy to be specifically targeted at interleukin-13 and approved for use in the treatment of AD. In July 2020, the FDA accepted Tralokinumab's Biologics License Application (BLA). Tralokinumab was licensed to LEO Pharma from Astrazeneca in July 2016.Currently, Lilly is also developing Lebrikizumab, a drug of the same type as targeted interleukin-13, which was obtained through Lilly's purchase of Dermira in early 2020 for a total price of approximately $1.1 billion. On August 16, Lilly reported that its target IL-13 monoclonal antibody therapy, Lebrikizumab, had reached both the primary endpoint and all important secondary endpoints in two key Phase III clinical trials, ADvocate 1 and ADvocate 2. In addition, Nemolizumab, a human monoclonal antibody targeting the IL-31 receptor A from Maruho (authorized by Chugai Pharmaceutical in September 2016), is also progressing to late-stage clinical trials. In recent years, many new drugs have been listed on the market for Alzheimer's disease (AD). However, due to safety concerns with targeted drugs and the high cost of biopharmaceuticals, these tend to be considered last resort treatments. Low-cost, widely used topical or oral systemic therapies are preferred, and these factors can be major obstacles to new drugs entering the treatment market and becoming dominant.

[0006] Therefore, given the limitations of conventional technologies in treating Alzheimer's disease (AD), developing more treatment options for AD is highly significant. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] This application provides for the use of small molecule diterpene compound derivatives or salts thereof in the preparation of pharmaceuticals for the prevention and treatment of atopic dermatitis. [Means for solving the problem]

[0008] In one embodiment, the present application provides a use of a diterpene compound derivative or a salt thereof in the preparation of a pharmaceutical for the prevention and treatment of atopic dermatitis, wherein the structure of the diterpene compound derivative is represented by formula I.

[0009] [ka]

[0010] (However, R1 and R2 are independently substituted or unsubstituted alkyl groups.) The molecular structure of the small molecule diterpene compound derivative represented by formula I relating to this application, and the method for synthesizing the same, are disclosed in WO2018153235A1.

[0011] In some preferred embodiments of the present application, the substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, for example, a C1, C2, C3, C4, C5, C6, C7, or C8 alkyl group.

[0012] In this application, the substituted alkyl group is selected from C1-C5 alkyl groups (e.g., C1, C2, C3, C4, C5) whose substituents are halogen-substituted.

[0013] In this application, the alkyl group is a linear or side-chain alkyl group.

[0014] In some preferred embodiments, R1 and R2 are independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group, an isobutyl group, an n-heptyl group, an n-octyl group, or an n-hexyl group.

[0015] In some more preferred embodiments, R1 and R2 are independently a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0016] In one embodiment, the diterpene compound derivative is one of the following compounds.

[0017] [ka]

[0018] In some preferred embodiments, the salt includes tartrate, stearate, oxalate, citrate, lactate, sorbate, fumarate, formate, acetate, benzoate, benzenesulfonate, ethanesulfonate, resinate, trifluoroacetate, maleate, methanesulfonate, fumarate, amino acid salt, nicotinate, phosphate, sulfate, hydrochloride or hydrobromide.

[0019] In the present application, any of the salts of the diterpene compound derivatives has the effect of preventing and treating atopic dermatitis. In the present application, any of the salts of the diterpene compound derivatives can be converted into a stabilized free base by adjusting the pH value during the preparation process of the preparation to exert the medicinal effect, and can well exert the action effect of the diterpene compound derivative during the use process, and has a good therapeutic effect on atopic dermatitis.

[0020] In the present application, the diterpene compound derivative or its salt can improve the degree of skin itching in terms of preventing and treating atopic dermatitis.

[0021] In the present application, the diterpene compound derivative or its salt can reduce the serum IgE concentration (for example, reduce the serum IgE concentration of mice with atopic dermatitis) in terms of preventing and treating atopic dermatitis.

[0022] In the present application, the dosage form of the pharmaceutical product is any one of pharmaceutically acceptable dosage forms.

[0023] In some preferred embodiments, the dosage form includes any one of a suspending agent, a granule, a capsule, a powder, a tablet, an emulsion, a solution, a drop, an injection, a suppository, an enema, an aerosol, a spray, a patch or a drop.

[0024] In some preferred embodiments, the pharmaceutical product further includes a pharmaceutically acceptable adjuvant.

[0025] In some preferred embodiments, the auxiliary agent includes one or a combination of at least two of the following: carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH adjusters, antioxidants, antimicrobial agents, or buffers. The combination of at least two may be, for example, a combination of a diluent and an excipient, a combination of a binder and a wetting agent, or a combination of an emulsifier and a solubilizer, and any other combination is selectable and is not described herein exhaustively.

[0026] In some preferred embodiments, the pharmaceutical is a drug that relieves or eliminates itching caused by atopic dermatitis. [Effects of the Invention]

[0027] Compared to the prior art, this invention has the following beneficial effects.

[0028] In this application, it is discovered for the first time that small molecule diterpene compound derivatives represented by formula I or their salts have a role in preventing and treating severe atopic dermatitis. They show a good preventive and therapeutic role in mouse AD models induced by either OXA or MC903, suppressing the improvement of skin lesion scores, ear thickening, worsening of ear swelling, and increase in mast cells in mice, as well as reducing serum IgE concentration and improving the degree of itching. This indicates that such compounds can be used for the prevention and treatment of atopic dermatitis, providing a novel preventive and therapeutic concept and effective drugs for the treatment of atopic dermatitis. [Brief explanation of the drawing]

[0029] [Figure 1A] This figure shows the changes in skin lesion scores over time in the OXA-induced mouse AD model in Example 1. [Figure 1B] This figure shows the skin lesion score results on day 24 of the OXA-induced mouse AD model in Example 1. [Figure 2A]This figure shows the change in ear thickness over time in the OXA-induced mouse AD model in Example 1. [Figure 2B] This figure shows the ear thickness results on day 24 of the OXA-induced mouse AD model in Example 1. [Figure 3A] This figure shows the changes in skin lesion scores over time in the OXA-induced mouse AD model in Example 2. [Figure 3B] This figure shows the skin lesion score results on day 24 of the OXA-induced mouse AD model in Example 2. [Figure 4A] This figure shows the change in ear thickness over time in the OXA-induced mouse AD model in Example 2. [Figure 4B] This figure shows the ear thickness results on day 24 of the OXA-induced mouse AD model in Example 2. [Figure 5A] This figure shows the results of the immunohistochemical Ki67 positivity rate in the OXA-induced mouse AD model in Example 2. [Figure 5B] This figure shows the results of the immunohistochemical ICAM-1 positivity rate in the OXA-induced mouse AD model in Example 2. [Figure 5C] This figure shows the results of the immunohistochemical VCAM-1 positivity rate in the OXA-induced mouse AD model in Example 2. [Figure 6A] This figure shows the gray value statistical results for detecting ICAM-1 expression levels in Western Blot in Example 2. [Figure 6B] This figure shows the gray value statistical results for detecting VCAM-1 expression levels in Western Blot in Example 2. [Figure 7] This figure shows the results of ear swelling in the MC903-induced mouse AD model in Example 3. [Figure 8A] This figure shows the epidermal thickness results for the MC903-induced mouse AD model in Example 3. [Figure 8B] This figure shows the dermal thickness results of the MC903-induced mouse AD model in Example 3. [Figure 8C]It is a figure showing the result of the overall ear thickness of the MC903-induced mouse AD model in Example 3. [Figure 9] It is a figure showing the result of the mast cell count of the MC903-induced mouse AD model in Example 3. [Figure 10A] It is a figure showing the result of the histopathological score of the MC903-induced mouse AD model in Example 3. [Figure 10B] It is a figure showing the result of the histopathological parakeratosis score of the MC903-induced mouse AD model in Example 3. [Figure 10C] It is a figure showing the result of the histopathological epidermal defect score of the MC903-induced mouse AD model in Example 3. [Figure 10D] It is a figure showing the result of the histopathological dermal papilla hypertrophy score of the MC903-induced mouse AD model in Example 3. [Figure 10E] It is a figure showing the result of the histopathological capillary proliferation score of the MC903-induced mouse AD model in Example 3. [Figure 10F] It is a figure showing the result of the histopathological inflammatory infiltration score of the MC903-induced mouse AD model in Example 3. [Figure 11] It is a figure showing the result of detecting the serum IgE concentration by ELISA in Example 3. [Figure 12] It is a figure showing the statistical result of the scratching frequency on the 10th day of the MC903-induced mouse AD model in Example 4.

Mode for Carrying Out the Invention

[0030] Note: Compared with the blank, && , ### , [Figure 12] , <0​​​​​​​​​​​​​​​​​

[0031] The technical proposal of this application will be further described below with reference to specific embodiments. Those skilled in the art will find that the above embodiments are merely for the purpose of understanding this application and should not be considered as specifically limiting it.

[0032] The experimental animals used in the following examples are SPF-level BALB / c mice (7 weeks old or older, female).

[0033] The standard skin lesion scores for the following examples are shown in Table 1, and the standard histopathological scores are shown in Table 2.

[0034] [Table 1]

[0035] [Table 2]

[0036] The reagents used in the following examples are compounds 1 to 8, provided by Suzhou Pharmavan Co., Ltd. (prepared by the preparation method disclosed in WO2018153235A1), and their molecular structures are as follows.

[0037] [ka]

[0038] Example 1 This example investigates the preventive and therapeutic effects of the eight small molecule diterpene compound derivatives described above on an OXA-induced AD model, and includes the following:

[0039] The day of group assignment was defined as day 0. Mice were randomly divided into 11 groups: blank (NC) group, model (OXA) group, blank castor oil (solvent) group, compound 1 administration group, compound 2 administration group, compound 3 administration group, compound 4 administration group, compound 5 administration group, compound 6 administration group, compound 7 administration group, and compound 8 administration group. There were 5 animals in each group. Model construction processing was performed for all groups except the NC group. Day 0: 20 μL / ear of 0.8%-OXA solution was applied to the auricle of each ear. Days 7, 10, 12, 14, 17, 19, 21, and 23: 20 μL / ear of 0.4%-OXA solution was applied to the auricle of each ear. All groups except the NC group and OXA group were administered the test subjects. The drug was administered from day 7 to day 23, once daily, by rubbing it onto the auricles of both ears of the mice, with 50 μL applied to each ear for a total of 100 μL. The design of the administration method and subject dosage for model construction is shown in Table 3. During the study period, the condition of the animals was observed, a skin lesion score was applied to the auricle (referencing the skin lesion score standards in Table 1), and ear thickness was measured.

[0040] [Table 3]

[0041] As shown in Figures 1A and 1B, during the study period (Figure 1A), the OXA group consistently showed higher skin lesion scores in mice compared to the NC group. At the end of the study (Figure 1B), the skin lesion scores, from highest to lowest, were in the following order: OXA group > solvent group > compound 8 group > compound 3 group > compound 2 group > compound 4 group > compound 5 group = compound 6 group = compound 7 group > compound 1 group > NC group. As can be seen from the statistical results of the skin lesion score data on day 24, there was a statistical difference in the OXA group compared to the NC group, and there was a statistical difference in all of the compound 1, 5, 6, and 7 groups compared to the solvent group. OXA induction clearly improves the skin lesion score in mice, but compounds 1, 5, 6, and 7 can effectively reduce the skin lesion score.

[0042] As shown in Figures 2A and 2B, throughout the study period (Figure 2A), the OXA group consistently showed higher right ear thickness compared to the NC group. At the end of the study (Figure 2B), the right ear thickness, from largest to smallest, was in the following order: OXA group > solvent group > compound 8 group > compound 3 group > compound 2 group > compound 4 group > compound 7 group > compound 6 group > compound 5 group > compound 1 group > NC group. As can be seen from the statistical results of the right ear thickness data on day 24, there was a statistical difference in the OXA group compared to the NC group, and a statistical difference in all of the compound 1-7 groups compared to the solvent group. While OXA induction clearly improves ear thickness in mice, compounds 1-7 can effectively improve ear thickness.

[0043] As can be seen from the results of this embodiment, compounds 1, 5, 6, and 7 can clearly improve OXA-induced AD-like lesions in mice.

[0044] Example 2 This example investigates the preventive and therapeutic effects of small molecule diterpene compound derivatives on an OXA-induced AD model, and includes the following:

[0045] The day of group assignment was defined as day 0. Mice were randomly divided into five groups: a blank (NC) group, a model (OXA) group, a blank cream (solvent) group, a 0.1% compound 1 cream group, and a 0.5% compound 1 cream group. The NC group consisted of 5 animals, while each of the other groups consisted of 10 animals. Model construction was performed for all groups except the NC group. Day 0: 20 μL of 0.8% OXA solution was applied to the auricle of each ear. Days 7, 10, 12, 14, 17, 19, 21, and 23: 20 μL of 0.4% OXA solution was applied to the auricle of each ear. All groups except the NC and OXA groups were administered the subject. The drug was administered from day 7 to day 23, once daily, by smearing it onto the auricles of both ears of the mice, with 50 μL applied to each ear for a total of 100 μL. The design of the administration method and subject dosage for model construction is shown in Table 4. During the study period, the condition of the animals was observed, a skin lesion score was performed on the auricles (referencing the skin lesion score standards in Table 1), and ear thickness was measured. After euthanasia of the mice, ear tissue was sampled and subjected to immunohistochemistry and Western Blot detection.

[0046] [Table 4]

[0047] As shown in Figures 3A and 3B, throughout the study period (Figure 3A), the OXA group consistently showed higher skin lesion scores compared to the NC group. At the end of the study (Figure 3B), the skin lesion scores were, from highest to lowest, in the order of OXA group > solvent group > 0.5%-compound 1 cream group > 0.1%-compound 1 cream group > NC group. As can be seen from the statistical results of the skin lesion score data on day 24, there was a statistical difference in the OXA group compared to the NC group, and statistical differences in both the 0.1%-compound 1 cream group and the 0.5%-compound 1 cream group compared to the solvent group. OXA induction clearly improves the skin lesion score in mice, but compound 1 can effectively reduce the skin lesion score.

[0048] As shown in Figures 4A and 4B, throughout the study period (Figure 4A), the OXA group consistently showed higher right ear thickness compared to the NC group. At the end of the study (Figure 4B), the right ear thickness, from largest to smallest, was in the following order: OXA group > solvent group > 0.1%-compound 1 cream group > 0.5%-compound 1 cream group > NC group. As can be seen from the statistical results of the right ear thickness data on day 24, there was a statistical difference in the OXA group compared to the NC group, and a statistical difference in both the 0.1%-compound 1 cream group and the 0.5%-compound 1 cream group compared to the solvent group. While OXA induction clearly improves ear thickness in mice, compound 1 can effectively improve ear thickness.

[0049] As shown in Figures 5A to 5C, immunohistochemical results showed that when comparing the OXA group and the NC group, the Ki67 positivity rate was significantly increased (statistically different), and the ICAM-1 and VCAM-1 positivity rates also increased. Compared to the OXA group, the solvent group showed a slight increase in Ki67 and ICAM-1 positivity rates and a slight decrease in VCAM-1. Compared to the solvent group, the 0.1% and 0.5% Compound 1 cream groups showed a decrease in both Ki67 positivity rates (statistically different), and both ICAM-1 and VCAM-1 were decreased. As shown in Figures 6A and 6B, the results of detecting ICAM-1 and VCAM-1 protein expression in Western Blot were consistent with the immunohistochemical results. OXA induction accelerates the proliferation of basal cells (Ki67) in the epidermis of mouse skin and increases the amount of intracutaneous adhesion molecules (ICAM-1 and VCAM-1), but Compound 1 can effectively suppress excessive epidermal proliferation and abnormal expression of adhesion factors.

[0050] As can be seen from the results of this example, compound 1 can clearly improve OXA-induced AD-like lesions in mice.

[0051] Example 3 This example investigates the preventive and therapeutic effects of small molecule diterpene compound derivatives on an MC903-induced AD model, and includes the following:

[0052] The day of group assignment was defined as day 0. Mice were divided into five groups: blank (NC) group, model (MC903) group, blank cream (solvent) group, 0.1% compound 1 cream group, and 0.5% compound 1 cream group. There were 10 animals in each group. Model construction was performed on all groups except the NC group. From day 0 to day 10: 20 μL of 0.1 nmol / μL MC903 solution was applied to the right auricle once daily. All groups except the NC and MC903 groups were administered the subject. From day 3 to day 10, administration was performed once daily, with 50 μL applied to the right auricle of each mouse. The design of the administration method and dosage for model construction is shown in Table 5. The condition of the animals was observed throughout the study period. After euthanizing the mice, ear tissue samples were taken, and the degree of ear swelling, skin thickness, mast cell count, and histopathological analysis were performed. Blood samples were also taken and detected using ELISA.

[0053] [Table 5]

[0054] As shown in Figure 7, MC903 induction leads to ear swelling in mice, but compound 1 can improve the ear swelling in mice.

[0055] As shown in Figures 8A, 8B, and 8C, analysis of the measurement results of epidermal, dermal, and overall ear thickness in scan images of ear tissue revealed that MC903 induction significantly thickened the epidermis and dermis of mouse skin, but compound 1 could effectively mitigate this epidermal and dermal thickening.

[0056] As shown in Figure 9, ear tissue sections were stained with toluidine blue, and then mast cells were counted. As can be seen from the results, treatment with compound 1 can clearly reduce the number of mast cells.

[0057] After HE staining of ear tissue, the extent of the lesions was analyzed histopathologically, and the results of the score (referencing the histopathological score standards in Table 2) were analyzed. It was found that MC903 induction resulted in an increase in skin lesions in mice, an improvement in the pathology score (Figure 10A), increased epidermal parakeratosis (Figure 10B), the appearance of epidermal defects (Figure 10C), clear dermal papillary thickening (Figure 10D), increased capillary proliferation in the dermis (Figure 10E), and clear inflammatory infiltration (Figure 10F). Treatment with compound 1 can effectively improve the extent of AD-like lesions induced by MC903.

[0058] As shown in Figure 11, ELISA detection of serum IgE concentration revealed that compound 1 suppresses serum IgE concentration.

[0059] As can be seen from the results of this embodiment, compound 1 can clearly improve mouse AD-like lesions induced by MC903.

[0060] Example 4 This example investigates the preventive and therapeutic effects of small molecule diterpene compound derivatives on pruritic symptoms in an MC903-induced AD model, and includes the following:

[0061] The day of group assignment was defined as day 0. Mice were randomly divided into five groups: blank (NC) group, model (MC903) group, blank cream (solvent) group, 0.1% compound 1 cream group, and 0.5% compound 1 cream group. There were 10 animals in each group. Model construction was performed on all groups except the NC group. From day 0 to day 10: 20 μL of 0.1 nmol / μL MC903 solution was applied to the right auricle once daily. All groups except the NC and MC903 groups were administered the subject. From day 3 to day 10, 50 μL was applied to the right auricle of the mouse once daily. The administration method and dosage design for model construction were the same as in Example 3. One day before the end of the experiment, the mice were imaged, and the number of scratches within 15 minutes after mouse model construction was analyzed using video.

[0062] The scratching frequency results (shown in Figure 12) clearly show that MC903 induction significantly increases the scratching frequency in mice and worsens itching, but it has been found that treatment with compound 1 can effectively improve the itching condition in mice.

[0063] Tests in the examples revealed, for the first time in this application, that small molecule diterpene compound derivatives represented by formula I or their salts have a significant preventive and therapeutic effect on atopic dermatitis, with the reduction of skin lesion scores being the main indicator of efficacy. Typical compounds are, for example, compounds 1, 5, 6, and 7 in the examples, and the structure of these compounds is characterized by the substitution of the thiazole amino group with a bisalkyl group. On the other hand, compounds 2, 3, 4, and 8 in the examples, characterized by single substitution at the thiazole amino group, were unable to exert a significant preventive and therapeutic effect on atopic dermatitis (with the reduction of skin lesion scores being the main indicator of efficacy), suggesting that the single substitution structure may weaken the affinity between the molecule and the receptor.

[0064] While the present application has illustrated the use of the diterpene compound derivative or its salt in pharmaceuticals for the prevention and treatment of atopic dermatitis using the above-described examples, the applicant declares that the present application is not limited to the above-described examples, and that it does not mean that the present application must be implemented in accordance with the above-described examples. Those skilled in the art should understand that any improvements to the present application, equivalent substitutions and additions of auxiliary components to the raw materials selected in the present application, and selection of specific forms are all included within the scope of protection and disclosure of the present application.

Claims

1. A pharmaceutical product comprising a diterpene compound derivative or a salt thereof, for the prevention and treatment of atopic dermatitis, wherein the structure of the diterpene compound derivative is shown in formula I. 【Chemistry 1】 (However, R １ and R ２ (These are independently a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.) A medicine used to prevent and treat atopic dermatitis.

2. The diterpene compound derivative is one of the following compounds: The pharmaceutical product according to claim 1. 【Chemistry 2】

3. The salts include tartrate, stearate, oxalate, citrate, lactate, sorbate, fumarate, formate, acetate, benzoate, benzenesulfonate, ethanesulfonate, resinate, trifluoroacetate, maleate, methanesulfonate, fumarate, amino acid salt, nicotinate, phosphate, sulfate, hydrochloride, or hydrobromide. The pharmaceutical product according to claim 1.

4. The dosage form of the aforementioned pharmaceutical product is one of the pharmacodynamically acceptable dosage forms. The aforementioned dosage form includes one of the following: a suspension agent, granules, capsules, powders, tablets, emulsions, solutions, drops, injections, suppositories, enemas, aerosols, sprays, patches, or drops. The pharmaceutical product according to claim 1.

5. The aforementioned pharmaceutical further comprises a pharmacodynamically acceptable adjuvant. The pharmaceutical product according to claim 1.

6. The aforementioned auxiliary agent includes one or a combination of at least two of the following: carrier, diluent, excipient, filler, binder, wetting agent, disintegrant, emulsifier, solubilizer, osmotic pressure regulator, surfactant, coating material, colorant, pH adjuster, antioxidant, antibacterial agent, or buffering agent. The pharmaceutical product according to claim 5.

7. The aforementioned pharmaceutical product is a drug that relieves or eliminates itching caused by atopic dermatitis. The pharmaceutical product according to claim 1.

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