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WO2023202439A1 - 二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用 - Google Patents

二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用 Download PDF

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WO2023202439A1
WO2023202439A1 PCT/CN2023/087767 CN2023087767W WO2023202439A1 WO 2023202439 A1 WO2023202439 A1 WO 2023202439A1 CN 2023087767 W CN2023087767 W CN 2023087767W WO 2023202439 A1 WO2023202439 A1 WO 2023202439A1
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group
compound
atopic dermatitis
application according
salt
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English (en)
French (fr)
Inventor
杨飞
李栋
俞云会
冯海梅
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Suzhou Pharmavan Co Ltd
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Suzhou Pharmavan Co Ltd
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Priority to US18/859,069 priority Critical patent/US20250275949A1/en
Priority to JP2024562350A priority patent/JP2025512582A/ja
Priority to EP23791094.8A priority patent/EP4512400A1/en
Publication of WO2023202439A1 publication Critical patent/WO2023202439A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • This application belongs to the field of biomedical technology, and specifically relates to the application of a small molecule diterpene compound derivative or its salt in the preparation of drugs for preventing and treating atopic dermatitis.
  • AD Atopic dermatitis
  • dermatitis is an immune-related chronic, relapsing, inflammatory skin disease. Because patients often have allergic rhinitis, asthma and other atopic diseases, it is considered a systemic disease.
  • the clinical manifestations of AD are diverse, with dry skin, chronic eczematoid dermatitis and severe itching as its basic characteristics.
  • AD Alzheimer's disease
  • Th2 activation is an important feature.
  • They may also have weakened or damaged skin barrier function, such as the reduction or absence of filaggrin in the epidermis.
  • Environmental factors include climate change, lifestyle changes, incorrect bathing, infection and allergen stimulation, etc.
  • Modern lifestyle overly hygienic, Western-style diet, etc.
  • environmental exposure environmental pollution, passive smoking, etc.
  • AD psychological factors
  • psychological factors also play a certain role in the onset of AD.
  • Th2-type inflammation is the basic feature of AD.
  • IL-4 and IL-13 are important cytokines that mediate the pathogenesis of AD. They are mainly produced by Th2 cells, basophils, and type 2 innate lymphoid cells. .
  • TSLP produced by keratinocytes is also an important cytokine that mediates AD itch.
  • Skin barrier dysfunction caused by gene mutations such as Filaggrin makes it easy for external environmental substances (such as microorganisms and allergens) to invade the epidermis and initiate Th2-type inflammation.
  • Langerhans cells and skin dendritic cells are involved through the presentation of allergens. This process.
  • Th2-type inflammatory factors can inhibit the expression of keratinocyte barrier-related proteins and further damage the skin barrier function.
  • AD skin lesions and normal-appearing skin are often accompanied by skin flora disorders, mainly manifested by increased Staphylococcus aureus colonization and decreased bacterial diversity, as well as the resulting metabolic and other functional abnormalities, which promote the progression of skin inflammation. Repeated scratching is an important reason for the aggravation and persistence of skin inflammation.
  • Scratching promotes keratin Forming cells produce inflammatory mediators, which can also lead to the release of self-antigens and the production of IgE against self-antigens.
  • Non-immune factors such as neuro-endocrine factors can also be involved in the occurrence and development of skin inflammation.
  • AD Alzheimer's disease
  • Existing treatments only alleviate or eliminate clinical symptoms, eliminate triggering and/or aggravating factors, reduce and prevent recurrence, and reduce or alleviate comorbidities, thereby improving the patient's quality of life.
  • Clinical treatment strategies are still based on topical medications, oral glucocorticoids and immunosuppressants.
  • Commonly used drugs include glucocorticoids (TCS), calcineurin inhibitors (TCI), and targeted drugs such as PDE4 inhibitors, Jak inhibitors, and biological agents such as Dupilumab monoclonal antibody that have been approved in recent years.
  • the topical PDE4 inhibitor cristorole ointment developed by Anacor Pharmaceuticals obtained FDA approval in December 2016 and March 2020 (trade name: ) and EMA (trade name ) was approved for marketing, and was approved for import in my country in July 2020 (trade name: Sutamin/ ), for the topical treatment of patients 2 years of age and older with mild to moderate AD.
  • Other companies are also developing topical PDE4 inhibitors, including Difamilast (OPA-15406, MM36) developed by Otsuka Pharmaceuticals.
  • Otsuka Pharmaceuticals On March 27, 2020, two phase III clinical trials in Japan were announced to evaluate the treatment of mild to moderate AD. The top-line results all met the primary endpoint.
  • the first generation of JAK inhibitors targeting multiple JAK targets, such as Eli Lilly’s (Baricitinib) for severe AD; second- or next-generation JAK inhibitors that target selective JAKs, including AbbVie’s (Upadacitinib, Upadacitinib) and Pfizer's Abrocitinib, respectively, for moderate to severe AD.
  • Eli Lilly Baricitinib
  • next-generation JAK inhibitors that target selective JAKs, including AbbVie’s (Upadacitinib, Upadacitinib) and Pfizer's Abrocitinib, respectively, for moderate to severe AD.
  • Dupilumab injection (trade name: ) is a monoclonal antibody that inhibits the specific binding of the IL-4R ⁇ subunit shared by IL-4 and IL-13 receptor complexes and inhibits the signaling of IL-4 and IL-13. It is also the first monoclonal antibody in the world to obtain FDA and EMA approves targeted biologics for the treatment of moderate to severe AD. This product was approved by the NMPA for the treatment of moderate to severe AD in adults on June 19, 2020 (trade name: Dalbitux). On September 9, the indication for moderate to severe AD was approved for adolescents and adults aged 12 and above. The approval of dupilumab marks the arrival of the era of biologic treatment of AD.
  • Adtralza Tralokinumab
  • Adtralza is the world's first specific targeting interleukin 13 approved to treat AD. of monoclonal antibody therapy.
  • BLA Bio Products License Application
  • Tralokinumab was licensed by Leo Pharma from AstraZeneca in July 2016.
  • Eli Lilly is also developing Lebrikizumab, a similar drug targeting interleukin 13. This monoclonal antibody was acquired by Eli Lilly in early 2020 when it acquired Dermira for a total price of approximately US$1.1 billion.
  • the present application provides the application of a small molecule diterpene compound derivative or a salt thereof in the preparation of a medicine for preventing and treating atopic dermatitis.
  • this application provides the use of a diterpene compound derivative or a salt thereof in the preparation of a medicine for preventing and treating atopic dermatitis, wherein the structure of the diterpene compound derivative is as shown in Formula I:
  • R 1 and R 2 are independently substituted or unsubstituted alkyl.
  • the substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, such as C1, C2, C3, C4, C5, C6, C7 or C8 alkyl .
  • the substituted alkyl group has a substituent selected from halogen-substituted C1-C5 (for example, C1, C2, C3, C4, C5) alkyl group.
  • the alkyl group is a linear or branched alkyl group.
  • R1 and R2 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert -butyl, isobutyl, n-heptyl, n-octyl, or n-hexyl base.
  • R1 and R2 are independently methyl, ethyl, n-propyl, or isopropyl.
  • the diterpene derivative is any one of the following compounds:
  • the salts include tartrate, stearate, oxalate, citrate, lactate, sorbate, fumarate, formate, acetate, benzoate Salt, benzenesulfonate, ethanesulfonate, resinate, trifluoroacetate, maleate, methanesulfonate, fumarate, amino acid salt, nicotinate, phosphate, sulfate, Hydrochloride or hydrobromide.
  • the salts of the diterpene derivatives have the effect of preventing and treating atopic dermatitis.
  • the salts of the diterpene derivatives in this application can be converted into The stable free base exerts its medicinal effect, enabling it to exert the effects of diterpenoid derivatives well during the application process, and has a good therapeutic effect on atopic dermatitis.
  • the diterpene compound derivative or its salt can improve the degree of skin itching in preventing and treating atopic dermatitis.
  • the diterpene compound derivative or its salt can reduce the serum IgE concentration in preventing and treating atopic dermatitis (for example, reducing the serum IgE concentration in mice with atopic dermatitis).
  • the dosage form of the drug is any pharmaceutically acceptable dosage form.
  • the dosage forms include suspensions, granules, capsules, powders, tablets, emulsions, solutions, pills, injections, suppositories, enemas, aerosols, sprays, patches Any of the dosage forms or drops.
  • the medicament further includes pharmaceutically acceptable excipients.
  • the excipients include carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surface Any one or a combination of at least two of active agents, coating materials, colorants, pH adjusters, antioxidants, bacteriostatic agents or buffers.
  • the combination of at least two kinds for example, the combination of diluent and excipient, the combination of binder and wetting agent, the combination of emulsifier and co-solvent, etc., any other combinations can be selected, and will not be discussed here. Let’s go over them one by one.
  • the drug is a drug that relieves or eliminates itching caused by atopic dermatitis.
  • Figure 1A shows the changes in skin lesion scores over time in the OXA-induced mouse AD model in Example 1.
  • Figure 1B is a graph showing the skin lesion score results on the 24th day of the OXA-induced mouse AD model in Example 1.
  • Figure 2A shows the changes in ear thickness over time in the OXA-induced mouse AD model in Example 1.
  • Figure 2B is a graph showing the ear thickness results on the 24th day of the OXA-induced mouse AD model in Example 1.
  • Figure 3A shows the changes in skin lesion scores over time in the OXA-induced mouse AD model in Example 2.
  • Figure 3B is a graph showing the skin lesion score results on the 24th day of the OXA-induced mouse AD model in Example 2.
  • Figure 4A shows the changes in ear thickness over time in the OXA-induced mouse AD model in Example 2.
  • Figure 4B is a graph showing the ear thickness results on the 24th day of the OXA-induced mouse AD model in Example 2.
  • Figure 5A is a graph showing the immunohistochemistry Ki67 positive rate results of the OXA-induced mouse AD model in Example 2.
  • Figure 5B is a diagram showing the immunohistochemical ICAM-1 positive rate results of the OXA-induced mouse AD model in Example 2.
  • Figure 5C is a graph showing the immunohistochemical VCAM-1 positive rate results of the OXA-induced mouse AD model in Example 2.
  • Figure 6A is a graph showing the gray value statistical results of Western Blot detection of ICAM-1 expression in Example 2.
  • Figure 6B is a graph showing the gray value statistical results of Western Blot detection of VCAM-1 expression in Example 2.
  • Figure 7 is a graph showing the results of ear swelling in MC903-induced mouse AD model in Example 3.
  • Figure 8A is a graph showing the epidermal thickness results of the MC903-induced mouse AD model in Example 3.
  • Figure 8B is a graph showing the dermal thickness results of the MC903-induced mouse AD model in Example 3.
  • Figure 8C is a graph showing the results of the total ear thickness of the MC903-induced mouse AD model in Example 3.
  • Figure 9 is a graph showing the mast cell counting results of the MC903-induced mouse AD model in Example 3.
  • Figure 10A is a diagram showing the histopathological scoring results of the MC903-induced mouse AD model in Example 3.
  • Figure 10B is a graph showing the histopathological parakeratosis score results of the MC903-induced mouse AD model in Example 3.
  • Figure 10C is a graph showing the histopathological epidermal defect scoring results of the MC903-induced mouse AD model in Example 3.
  • Figure 10D is a graph showing the histopathological dermal papilla thickening score results of the MC903-induced mouse AD model in Example 3.
  • Figure 10E is a graph showing the histopathological capillary proliferation score results of the MC903-induced mouse AD model in Example 3.
  • Figure 10F is a graph showing the histopathological inflammatory infiltration score results of the MC903-induced mouse AD model in Example 3.
  • Figure 11 is a graph showing the results of ELISA detection of serum IgE concentration in Example 3.
  • Figure 12 is a graph showing the statistical results of the number of scratches on the 10th day of the MC903-induced mouse AD model in Example 4.
  • mice SPF grade BALB/c mice ( ⁇ 7 weeks old, female).
  • the skin lesion scoring standards involved in the following examples are shown in Table 1, and the histopathological scoring standards are shown in Table 2.
  • the skin lesion score of each animal is the sum of the three index scores.
  • the reagents involved in the following examples are Compound 1 to Compound 8, which are provided by Suzhou Huyun New Drug Research and Development Co., Ltd. (prepared by the preparation method disclosed in WO2018153235A1), and their molecular structures are as follows:
  • the grouping day is defined as day 0.
  • the mice were randomly divided into 11 groups: blank control (NC) group, model (OXA) group, blank castor oil (vehicle) group, compound 1 administration group, compound 2 administration group, compound 3 administration group, compound 4
  • Day 0 Apply 0.8%-OXA solution to the auricles of both ears, 20 ⁇ L of each ear.
  • Days 7, 10, 12, 14, 17, 19, 21, and 23 Apply 0.4%-OXA solution to the auricles of both ears, 20 ⁇ L of each ear.
  • test substance was administered to all groups except the NC group and OXA group. Administration was started from the 7th day to the 23rd day, once a day, applied to the auricles of both ears of the mice, 50 ⁇ L for each ear, and a total of 100 ⁇ L for each ear.
  • the modeling administration method and test substance dosage design are shown in Table 3. During the test, the status of the animals was observed, skin lesions were scored on the auricles (see Table 1 for skin lesion scoring standards), and ear thickness was measured.
  • the grouping day is defined as day 0.
  • the mice were randomly divided into 5 groups: blank control (NC) group, model (OXA) group, blank cream (vehicle) group, 0.1%-Compound 1 cream group, and 0.5%-Compound 1 cream group.
  • Days 7, 10, 12, 14, 17, 19, 21, and 23 Apply 0.4%-OXA solution to the auricles of both ears, 20 ⁇ L of each ear.
  • the test substance was administered to all groups except the NC group and OXA group.
  • the immunohistochemistry results show that compared with the NC group, the positive rate of Ki67 in the OXA group increased significantly (with statistical differences), and the positive rate of ICAM-1 and VCAM-1 increased; compared with the OXA group , the positive rates of Ki67 and ICAM-1 in the vehicle group increased slightly, and VCAM-1 decreased slightly; compared with the vehicle group, the positive rates of Ki67 in the 0.1% and 0.5%-Compound 1 cream groups both decreased (statistical difference), and ICAM-1 , VCAM-1 were all reduced.
  • Figure 6A and Figure 6B the results of Western Blot detection of ICAM-1 and VCAM-1 protein expression were consistent with the immunohistochemistry results.
  • OXA induction can accelerate the proliferation of basal cells in the mouse skin epidermis (Ki67) and increase the adhesion molecules (ICAM-1 and VCAM-1) in the skin.
  • Compound 1 can effectively inhibit epidermal hyperplasia and abnormal expression of adhesion factors.
  • the grouping day is defined as day 0.
  • the mice were randomly divided into 5 groups: blank control (NC) group, model (MC903) group, blank cream (vehicle) group, 0.1%-Compound 1 cream group, and 0.5%-Compound 1 cream group. 10 animals per group. Except for the NC group, all other groups were subjected to modeling treatment.
  • Day 0 to Day 10 Apply 20 ⁇ L of 0.1 nmol/ ⁇ L-MC903 solution to the auricle of the right ear, once a day. Except NC group and MC903 The test substance was administered to all groups outside the group. The administration was from the 3rd day to the 10th day, once a day, and 50 ⁇ L was applied to the auricle of the right ear of the mice.
  • MC903 induction can significantly swell the ears of mice, and compound 1 can effectively improve the ear swelling of mice.
  • MC903 induction can significantly thicken the epidermis and dermis of mouse skin, and compound 1 can effectively slow down the Thickening of epidermis and dermis.
  • MC903 induction can increase the skin lesions of mice and increase the pathological scores (Figure 10A ), epidermal parakeratosis increased (Fig. 10B), epidermal defects appeared (Fig. 10C), dermal papillae thickened significantly (Fig. 10D), capillaries proliferated in the dermis (Fig. 10E), and obvious inflammatory infiltration appeared (Fig. 10F) .
  • Compound 1 treatment can effectively improve the degree of AD-like lesions induced by MC903.
  • the grouping day is defined as day 0.
  • the mice were randomly divided into 5 groups: blank control (NC) group, model (MC903) group, blank cream (vehicle) group, 0.1%-Compound 1 cream group, and 0.5%-Compound 1 cream group. 10 animals per group. Except for the NC group, all other groups were subjected to modeling treatment.
  • Day 0 to Day 10 Apply 20 ⁇ L of 0.1 nmol/ ⁇ L-MC903 solution to the auricle of the right ear, once a day.
  • the test substance was administered to all groups except the NC group and MC903 group.
  • the administration was from the 3rd day to the 10th day, once a day, and 50 ⁇ L was applied to the right ear pinna of the mice.
  • the modeling administration method and dosage design are the same as those in Example 3.
  • the mice were videotaped one day before the end of the experiment, and the video analysis was performed on the number of scratches made by the mice within 15 minutes after the model was established.
  • the scratching number results show that MC903 induction can significantly increase the number of scratching times in mice and intensify itching. Compound 1 treatment can effectively improve the itching condition in mice.

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Abstract

本申请提供一种二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用，所述小分子二萜化合物衍生物或其盐具有显著的防治特应性皮炎的作用，其对OXA或MC903诱导的小鼠AD模型均显示出良好的防治作用，可抑制小鼠病变的皮损评分升高、耳厚度增厚、耳肿胀加剧及肥大细胞增多情况，还可降低血清中IgE浓度，改善瘙痒程度，表明该类化合物可用于防治特应性皮炎，为特应性皮炎的治疗提供了一种新的防治思路和有效药物。

Description

二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用 技术领域
本申请属于生物医药技术领域，具体涉及一种小分子二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用。
背景技术
特应性皮炎(Atopic Dermatis，AD)是一种免疫相关的慢性、复发性、炎症性皮肤病。由于患者常合并过敏性鼻炎、哮喘等其他特应性疾病，故被认为是一种系统性疾病。AD的临床表现多种多样，以皮肤干燥、慢性湿疹样皮炎和剧烈瘙痒为其基本特征。
AD的发病与遗传和环境等因素关系密切。父母亲等家族成员有过敏性疾病史是本病的最强风险因素，遗传因素主要影响皮肤屏障功能与免疫平衡。本病患者往往有多种免疫学异常，其中Th2的活化为重要特征，还可有皮肤屏障功能减弱或破坏如表皮中聚丝蛋白(filaggrin)减少或缺失。环境因素包括气候变化、生活方式改变、不正确的洗浴、感染原和变应原刺激等。现代生活方式(过于卫生、西式饮食等)及环境暴露(环境污染、被动吸烟等)等可能通过表观遗传修饰引起免疫系统与皮肤屏障异常，参与AD的发病。此外，心理因素(如精神紧张、焦虑、抑郁等)也在AD的发病中发挥一定作用。
虽然AD的确切发病机制尚不清楚，但目前研究认为，免疫异常、皮肤屏障功能障碍、皮肤菌群紊乱等因素是本病发病的重要环节。Th2型炎症是AD的基本特征，IL-4和IL-13是介导AD发病的重要细胞因子，主要由Th2细胞、嗜碱性粒细胞和2型固有淋巴样细胞(innate lymphoid cells)等产生。在AD的慢性期，皮损中还可见Th1、Th17和Th22的混合炎症浸润。角质形成细胞产生的TSLP也是介导AD瘙痒的重要细胞因子。Filaggrin等基因突变导致的皮肤屏障功能障碍使外界环境物质(如微生物和过敏原)易于侵入表皮而启动Th2型炎症，朗格汉斯细胞和皮肤树突细胞通过对变应原的提呈参与了这一过程。Th2型炎症因子可以抑制角质形成细胞屏障相关蛋白的表达，进一步破坏皮肤屏障功能。AD皮损和外观正常皮肤常伴有以金黄色葡萄球菌定植增加和菌群多样性下降为主要表现的皮肤菌群紊乱，以及所导致的代谢等功能异常，促进了皮肤炎症的进展。反复搔抓是导致皮肤炎症加重和持续的重要原因，搔抓促使角质 形成细胞产生炎症介质，也会导致自身抗原释放，产生针对自身抗原的IgE。非免疫性因素如神经—内分泌因素也可参与皮肤炎症的发生和发展。
目前没有可有效根治AD的药物，现有治疗方法仅是缓解或消除临床症状，消除诱发和/或加重因素，减少和预防复发，减少或减轻合并症，以此提高患者的生活质量。尽管在过去的几十年里，AD的治疗取得了显著进展，但现有的治疗选择仍旧难以满足临床需求。临床治疗策略仍然以局部外用药，口服糖皮质激素和免疫抑制剂为主。常用药物包括糖皮质激素(TCS)、钙调神经磷酸酶抑制剂(TCI)以及近年来获批的PDE4抑制剂、Jak抑制剂以及生物制剂如Dupilumab单抗等靶向药。Anacor制药公司开发的局部PDE4抑制剂克立硼罗软膏于2016年12月和2020年3月相续获得FDA(商品名为)和EMA(商品名为)批准上市，并于2020年7月在我国获进口批准上市(商品名为舒坦明/)，用于2岁及以上轻度至中度AD患者的局部外用治疗。其他公司也正在开发局部PDE4抑制剂，包括大冢制药开发的Difamilast(OPA-15406，MM36)，2020年3月27日公布了在日本开展的两项评估治疗轻度至中度AD III期临床的顶线结果，均达主要终点。2020年1月，日本烟草和鸟居制药共同开发的Corectim(delgocitinib)软膏获得日本厚生劳动省下属医药医疗器械综合机构(PMDA)批准，用于局部治疗成人轻度至中度AD，成为全球首款治疗AD的JAK局部外用药物。目前有多款治疗AD的JAK抑制剂处于晚期阶段。第一代JAK抑制剂，靶向多个JAK靶点，如礼来的(Baricitinib，巴瑞替尼)用于重度AD；第二代或下一代JAK抑制剂，靶向选择性JAK，包括艾伯维的(Upadacitinib，乌帕替尼)和辉瑞的Abrocitinib分别用于中度至重度AD。但由于监管机构对JAK抑制剂安全性担忧，3款JAK抑制剂用于AD适应症的上市申请屡遭FDA延期审查。由赛诺菲和再生元联合开发的度普利尤单抗注射液(商品名为)是一款可抑制IL-4和IL-13受体复合物共享的IL-4Rα亚单位特异性结合而抑制IL-4和IL-13的信号传导的单抗，也是全球首款获得FDA及EMA批准治疗中重度AD的靶向生物制剂。该产品已于2020年6月19日获NMPA批准用于治疗成人中重度AD(商品名为达必妥)，9月9日，12岁及以上青少年及成人的中重度AD适应症获批。度普利尤单抗的获批上市标志着AD生物制剂治疗时代已经到来。6月22日，丹麦利奥制药公司宣布，白介素13抑制剂Adtralza(Tralokinumab)已在欧盟获批可用于治疗AD适应症，Adtralza是全球首个特异性靶向白介素13获批治疗AD 的单克隆抗体疗法。2020年07月FDA已受理Tralokinumab的生物制品许可申请(BLA)。Tralokinumab是利奥制药2016年7月从阿斯利康授权获得。当前，礼来公司也正在研发一款靶向白介素13的同类型药物Lebrikizumab，该单抗是礼来2020年初以总价约11亿美元价格收购Dermira获得。8月16日，礼来宣布，其开发的靶向IL-13的单克隆抗体疗法Lebrikizumab，在两项关键性Ⅲ期临床试验ADvocate 1和ADvocate 2中均达到了主要终点和所有关键次要终点。此外，Maruho公司的靶向阻断IL-31受体A人源化单克隆抗体Nemolizumab(2016年9月从中外制药获得授权)也进入到晚期临床试验阶段。近年来AD药物市场陆续有新药上市，然而，由于靶向药物的安全性问题和生物制剂的价格昂贵，它们更倾向于被作为最后一道治疗方案，而低成本、通用的局部或口服全身治疗药物是首选的一线药物，这些因素都可能成为新药进入治疗市场占领主导地位的巨大障碍。
因此，现有技术中关于治疗AD的策略还很有限，开发出更多的AD的治疗途径是非常有意义的。
发明内容
本申请提供一种小分子二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用。
一方面，本申请提供一种二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用，其中，所述二萜化合物衍生物的结构如式I所示：
其中，R1和R2独立地为取代或未取代的烷基。
本申请所涉及的式Ⅰ所示的小分子二萜化合物衍生物的分子结构及其合成方法已在WO2018153235A1中公开。
在本申请的一些优选实施方案中，所述取代或未取代的烷基为取代或未取代的C1-C8的烷基，例如C1、C2、C3、C4、C5、C6、C7或C8烷基。
在本申请中，所述取代的烷基，其取代基选自卤素取代的C1-C5(例如C1、 C2、C3、C4、C5)的烷基。
在本申请中，所述烷基为直链或支链烷基。
在一些优选实施方案中，R1和R2独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基或正己基。
在一些更优选实施方案中，R1和R2独立地为甲基、乙基、正丙基或异丙基。
在一个实施方案中，所述二萜化合物衍生物为如下化合物中的任意一种：
在一些优选实施方案中，所述盐包括酒石酸盐、硬脂酸盐、草酸盐、枸橼酸盐、乳酸盐、山梨酸盐、延胡索酸盐、甲酸盐、乙酸盐、苯甲酸盐、苯磺酸盐、乙磺酸盐、树脂酸盐、三氟乙酸盐、马来酸盐、甲磺酸盐、富马酸盐、氨基酸盐、烟酸盐、磷酸盐、硫酸盐、盐酸盐或氢溴酸盐。
在本申请中，所述二萜化合物衍生物的盐均具有防治特应性皮炎的效果，在本申请中所述二萜化合物衍生物的盐在其制剂制备中均可通过调节pH值转换成稳定的游离碱发挥药效，使得其在应用过程中能够良好地发挥二萜化合物衍生物的作用效果，具有较好的特应性皮炎治疗效果。
在本申请中，所述二萜化合物衍生物或其盐在防治特应性皮炎方面，能够改善皮肤瘙痒程度。
在本申请中，所述二萜化合物衍生物或其盐在防治特应性皮炎方面，能够降低血清IgE浓度(例如降低特应性皮炎小鼠血清IgE浓度)。
在本申请中，所述药物的剂型为药学上可接受的任意一种剂型。
在一些优选实施方案中，所述剂型包括混悬剂、颗粒剂、胶囊剂、散剂、片剂、乳剂、溶液剂、滴丸剂、注射剂、栓剂、灌肠剂、气雾剂、喷雾剂、贴 剂或滴剂中的任意一种。
在一些优选实施方案中，所述药物还包括药学上可接受的辅料。
在一些优选实施方案中，所述辅料包括载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。所述至少两种的组合例如稀释剂和赋形剂的组合、粘合剂和润湿剂的组合、乳化剂和助溶剂的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。
在一些优选实施方案中，所述药物为缓解或消除特应性皮炎引起的瘙痒的药物。
相对于现有技术，本申请具有以下有益效果：
本申请首次发现式Ⅰ所示的小分子二萜化合物衍生物或其盐具有显著的防治特应性皮炎的作用，其对OXA或MC903诱导的小鼠AD模型均显示出良好的防治作用，可抑制小鼠病变的皮损评分升高、耳厚度增厚、耳肿胀加剧及肥大细胞增多情况，还可降低血清中IgE浓度，改善瘙痒程度，这表明该类化合物可用于防治特应性皮炎，为特应性皮炎的治疗提供了一种新的防治思路和有效药物。
附图说明
图1A是实施例1中OXA诱导小鼠AD模型的皮损评分随时间的变化情况。
图1B是实施例1中OXA诱导小鼠AD模型的第24天皮损评分结果图。
图2A是实施例1中OXA诱导小鼠AD模型的耳厚度随时间的变化情况。
图2B是实施例1中OXA诱导小鼠AD模型的第24天耳厚度结果图。
图3A是实施例2中OXA诱导小鼠AD模型的皮损评分随时间的变化情况。
图3B是实施例2中OXA诱导小鼠AD模型的第24天皮损评分结果图。
图4A是实施例2中OXA诱导小鼠AD模型的耳厚度随时间的变化情况。
图4B是实施例2中OXA诱导小鼠AD模型的第24天耳厚度结果图。
图5A是实施例2中OXA诱导小鼠AD模型的免疫组化Ki67阳性率结果图。
图5B是实施例2中OXA诱导小鼠AD模型的免疫组化ICAM-1阳性率结果图。
图5C是实施例2中OXA诱导小鼠AD模型的免疫组化VCAM-1阳性率结果图。
图6A是实施例2中Western Blot检测ICAM-1表达量的灰度值统计结果图。
图6B是实施例2中Western Blot检测VCAM-1表达量的灰度值统计结果图。
图7是实施例3中MC903诱导小鼠AD模型的耳肿胀度结果图。
图8A是实施例3中MC903诱导小鼠AD模型的表皮厚度结果图。
图8B是实施例3中MC903诱导小鼠AD模型的真皮厚度结果图。
图8C是实施例3中MC903诱导小鼠AD模型的全耳厚度结果图。
图9是实施例3中MC903诱导小鼠AD模型的肥大细胞计数结果图。
图10A是实施例3中MC903诱导小鼠AD模型的组织病理学评分结果图。
图10B是实施例3中MC903诱导小鼠AD模型的组织病理学角化不全评分结果图。
图10C是实施例3中MC903诱导小鼠AD模型的组织病理学表皮缺损评分结果图。
图10D是实施例3中MC903诱导小鼠AD模型的组织病理学真皮乳头增厚评分结果图。
图10E是实施例3中MC903诱导小鼠AD模型的组织病理学毛细血管增生评分结果图。
图10F是实施例3中MC903诱导小鼠AD模型的组织病理学炎症浸润评分结果图。
图11是实施例3中ELISA检测血清IgE浓度的结果图。
图12是实施例4中MC903诱导小鼠AD模型的第10天抓挠次数统计结果图。
图注：与空白对照组比较，*p＜0.05，**p＜0.01，***p＜0.001；与模型组比较，#p＜0.05，##p＜0.01，###p＜0.001；与溶媒组比较，&p＜0.05，&&p＜0.01，&&&p＜0.001。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
下述实施例所涉及的实验动物为SPF级BALB/c小鼠(≥7周龄，雌性)。
下述实施例所涉及的皮损评分标准见表1，组织病理学评分标准见表2。
表1皮损评分标准
注：每只动物皮损评分为三个指标分值总和。
表2组织病理学评分标准
注：每个指标单独进行评分。
下述实施例所涉及的试剂为化合物1-化合物8，由苏州沪云新药研发股份有限公司提供(其通过WO2018153235A1中公开的制备方法制备得到)，其分子结构如下所示：

实施例1
本实施例探究如上所述8个小分子二萜化合物衍生物对OXA诱导AD模型的防治效果，包括以下内容：
分组当天定义为第0天。将小鼠随机分为11组：空白对照(NC)组、模型(OXA)组、空白蓖麻油(溶媒)组、化合物1给药组、化合物2给药组、化合物3给药组、化合物4给药组、化合物5给药组、化合物6给药组、化合物7给药组、化合物8给药组，每组5只动物。除NC组外其余每组均进行造模处理。第0天：0.8％-OXA溶液分别涂抹两耳耳廓，每耳20μL。第7，10，12，14，17，19，21，23天：0.4％-OXA溶液分别涂抹两耳耳廓，每耳20μL。除NC组和OXA组外均进行受试物给药。给药从第7天开始至第23天，每天1次，涂抹于小鼠两耳耳廓，每耳50μL，每只共100μL。造模给药方法及受试物剂量设计见表3。试验期间观察动物状态，对耳廓进行皮损评分(见表1皮损评分标准)，测量耳厚度。
表3处理方法和剂量设计表
如图1A和图1B所示，试验期间(图1A)，与NC组相比，OXA组小鼠皮损评分一直较高。试验结束时(图1B)，皮损评分从高到低依次是：OXA组＞溶媒组＞化合物8组＞化合物3组＞化合物2组＞化合物4组＞化合物5组＝化合物6组＝化合物7组＞化合物1组＞NC组。第24天皮损评分数据的统计学结果表明，与NC组相比，OXA组有统计学差异；与溶媒组相比，化合物1、5、6、7组均有统计学差异。OXA诱导可使小鼠皮损评分显著升高，化合物1、5、6、7可有效降低皮损评分。
如图2A和图2B所示，试验期间(图2A)，与NC组相比，OXA组小鼠右耳厚度一直较高。试验结束时(图2B)，右耳厚度从大到小依次是：OXA组＞溶媒组＞化合物8组＞化合物3组＞化合物2组＞化合物4组＞化合物7组＞化合物6组＞化合物5组＞化合物1组＞NC组。第24天右耳厚度数据的统计学结果表明，与NC组相比，OXA组有统计学差异；与溶媒组相比，化合物1～7组均有统计学差异。OXA诱导可使小鼠耳厚度显著增加，化合物1～7可有效改善耳厚度。
本实施例结果表明，化合物1、5、6、7可显著改善OXA诱导小鼠产生的AD样病变。
实施例2
本实施例探究小分子二萜化合物衍生物对OXA诱导AD模型的防治效果，包括以下内容：
分组当天定义为第0天。将小鼠随机分为5组：空白对照(NC)组、模型(OXA)组、空白乳膏(溶媒)组、0.1％-化合物1乳膏组、0.5％-化合物1乳膏组。NC组5只动物，其余每组10只动物。除NC组外其余每组均进行造模处理。第0天：0.8％-OXA溶液分别涂抹两耳耳廓，每耳20μL。第7，10，12，14，17，19，21，23天：0.4％-OXA溶液分别涂抹两耳耳廓，每耳20μL。除NC组和OXA组外均进行受试物给药。给药从第7天开始至第23天，每天1次，涂抹于小鼠两耳耳廓，每耳50μL，每只共100μL。造模给药方法及受试物剂量设计见表4。试验期间观察动物状态，对耳廓进行皮损评分(表1皮损评分标准)，测量耳厚度。小鼠安乐死后，耳组织留样，进行免疫组化和Western Blot检测。
表4处理方法和剂量设计表

如图3A和图3B所示，试验期间(图3A)，与NC组相比，OXA组小鼠皮损评分一直较高。试验结束时(图3B)，皮损评分从高到低依次是：OXA组＞溶媒组＞0.5％-化合物1乳膏组＞0.1％-化合物1乳膏组＞NC组。第24天皮损评分数据的统计学结果表明，与NC组相比，OXA组有统计学差异；与溶媒组相比，0.1％-化合物1乳膏组、0.5％-化合物1乳膏组均有统计学差异。OXA诱导可使小鼠皮损评分显著升高，化合物1可有效降低皮损评分。
如图4A和图4B所示，试验期间(图4A)，与NC组相比，OXA组小鼠右耳厚度一直较高。试验结束时(图4B)，右耳厚度从大到小依次是：OXA组＞溶媒组＞0.1％-化合物1乳膏组＞0.5％-化合物1乳膏组＞NC组。第24天右耳厚度数据的统计学结果表明，与NC组相比，OXA组有统计学差异；与溶媒组相比，0.1％-化合物1乳膏组、0.5％-化合物1乳膏组均有统计学差异。OXA诱导可使小鼠耳厚度显著增加，化合物1可有效改善耳厚度。
如图5A-图5C所示，免疫组化结果显示OXA组与NC组相比，Ki67阳性率明显增加(有统计学差异)，ICAM-1、VCAM-1阳性率增加；与OXA组相比，溶媒组Ki67、ICAM-1阳性率略增加，VCAM-1略降低；与溶媒组相比，0.1％和0.5％-化合物1乳膏组Ki67阳性率均降低(统计学差异)，ICAM-1、VCAM-1均降低。如图6A和图6B所示，Western Blot检测ICAM-1、VCAM-1蛋白表达的结果与免疫组化结果一致。OXA诱导可使小鼠皮肤表皮的基底细胞增殖加快(Ki67)，皮肤内黏附分子(ICAM-1和VCAM-1)增多，化合物1可有效抑制表皮过度增生、黏附因子异常表达。
本实施例结果表明，化合物1可显著改善OXA诱导小鼠产生的AD样病变。
实施例3
本实施例探究小分子二萜化合物衍生物对MC903诱导AD模型的防治效果，包括以下内容：
分组当天定义为第0天。将小鼠随机分为5组：空白对照(NC)组、模型(MC903)组、空白乳膏(溶媒)组、0.1％-化合物1乳膏组、0.5％-化合物1乳膏组。每组10只动物。除NC组外其余各组均进行造模处理。第0天至第10天：0.1nmol/μL-MC903溶液涂抹右耳耳廓20μL，每天一次。除NC组和MC903 组外均进行受试物给药，给药从第3天开始至第10天，每天1次，涂抹于小鼠右耳耳廓50μL。造模给药方法及剂量设计见表5。试验期间观察动物状态。小鼠安乐死后，耳组织留样进行耳肿胀度测量、皮肤厚度测量、肥大细胞计数、组织病理学分析，血液留样进行ELISA检测。
表5处理方法和剂量设计表
如图7所示，MC903诱导可使小鼠耳朵肿胀明显，化合物1可有效改善小鼠耳肿胀情况。
如图8A、图8B和图8C所示，通过对耳组织扫描图表皮、真皮及全耳厚度的测量结果进行分析，MC903诱导可使小鼠皮肤表皮、真皮明显增厚，化合物1可有效减缓表皮、真皮的增厚。
如图9所示，耳组织切片甲苯胺蓝染色后，对肥大细胞进行计数，结果表明化合物1治疗可明显降低肥大细胞数量。
将耳组织进行HE染色后，组织病理学分析病变程度，通过对评分(见表2组织病理学评分标准)结果分析后可知，MC903诱导可使小鼠皮肤病变增多，病理评分升高(图10A)，表皮角化不全增加(图10B)，表皮出现缺损(图10C)，真皮乳头增厚明显(图10D)，真皮中毛细血管增生(图10E)，并出现明显的炎症浸润(图10F)。化合物1治疗可有效改善上述MC903诱导的AD样病变程度。
如图11所示，ELISA检测血清IgE浓度的结果，表明化合物1抑制血清中IgE浓度。
本实施例结果表明，化合物1可显著改善MC903诱导小鼠产生的AD样病变。
实施例4
本实施例探究小分子二萜化合物衍生物对MC903诱导AD模型瘙痒症状的防治效果，包括以下内容：
分组当天定义为第0天。将小鼠随机分为5组：空白对照(NC)组、模型(MC903)组、空白乳膏(溶媒)组、0.1％-化合物1乳膏组、0.5％-化合物1乳膏组。每组10只动物。除NC组外其余各组均进行造模处理。第0天至第10天：0.1nmol/μL-MC903溶液涂抹右耳耳廓20μL，每天一次。除NC组和MC903组外均进行受试物给药，给药从第3天开始至第10天，每天1次，涂抹于小鼠右耳耳廓50μL。造模给药方法及剂量设计同实施例3。试验结束前一天对小鼠进行录像，视频分析小鼠造模后15min内的抓挠次数。
抓挠次数结果(如图12所示)表明MC903诱导可使小鼠抓挠次数显著增加，瘙痒加剧，化合物1治疗可有效改善小鼠瘙痒情况。
通过实施例中的试验，以降低皮损评分为主要药效指标，本申请首次发现式Ⅰ所示的小分子二萜化合物衍生物或其盐具有显著的防治特应性皮炎的作用，典型化合物如实施例中的化合物1、化合物5、化合物6和化合物7，这些化合物的结构特点为噻唑氨基上被双烷基取代。而实施例中的化合物2、化合物3、化合物4和化合物8，这些化合物的结构特点为噻唑氨基上单取代，则不能发挥显著的抗治特应性皮炎作用(以降低皮损评分为主要药效指标)，可能是单取代结构减弱了分子与受体的亲和力。
申请人声明，本申请通过上述实施例来说明本申请的二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请所选用原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (10)

  1. 一种二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用，其中，所述二萜化合物衍生物的结构如式I所示：
    其中，R1和R2独立地为取代或未取代的烷基。
  2. 根据权利要求1所述的应用，其中，所述取代或未取代的烷基为取代或未取代的C1-C8的烷基。
  3. 根据权利要求1或2所述的应用，其中，R1和R2独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基或正己基。
  4. 根据权利要求3所述的应用，其中，R1和R2独立地为甲基、乙基、正丙基或异丙基。
  5. 根据权利要求1-4中任一项所述的应用，其中，所述二萜化合物衍生物为如下化合物中的任意一种：
  6. 根据权利要求1-5中任一项所述的应用，其中，所述盐包括酒石酸盐、硬脂酸盐、草酸盐、枸橼酸盐、乳酸盐、山梨酸盐、延胡索酸盐、甲酸盐、乙酸盐、苯甲酸盐、苯磺酸盐、乙磺酸盐、树脂酸盐、三氟乙酸盐、马来酸盐、 甲磺酸盐、富马酸盐、氨基酸盐、烟酸盐、磷酸盐、硫酸盐、盐酸盐或氢溴酸盐。
  7. 根据权利要求1-6中任一项所述的应用，其中，所述药物的剂型为药学上可接受的任意一种剂型；
    优选地，所述剂型包括混悬剂、颗粒剂、胶囊剂、散剂、片剂、乳剂、溶液剂、滴丸剂、注射剂、栓剂、灌肠剂、气雾剂、喷雾剂、贴剂或滴剂中的任意一种。
  8. 根据权利要求1-7中任一项所述的应用，其中，所述药物还包括药学上可接受的辅料。
  9. 根据权利要求8所述的应用，其中，所述辅料包括载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。
  10. 根据权利要求1所述的应用，其中，所述药物为缓解或消除特应性皮炎引起的瘙痒的药物。
PCT/CN2023/087767 2022-04-22 2023-04-12 二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用 Ceased WO2023202439A1 (zh)

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