WO2021179959A1 - Pharmaceutical composition comprising jak3/jak1/tbk1 inhibitor and methotrexate and use thereof - Google Patents

Pharmaceutical composition comprising jak3/jak1/tbk1 inhibitor and methotrexate and use thereof Download PDF

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WO2021179959A1
WO2021179959A1 PCT/CN2021/078693 CN2021078693W WO2021179959A1 WO 2021179959 A1 WO2021179959 A1 WO 2021179959A1 CN 2021078693 W CN2021078693 W CN 2021078693W WO 2021179959 A1 WO2021179959 A1 WO 2021179959A1
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jak1
jak3
methotrexate
pharmaceutical composition
pharmaceutically acceptable
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PCT/CN2021/078693
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French (fr)
Chinese (zh)
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方征宇
鲁先平
王庆文
周游
山松
虎义平
钟福波
何娟
戴嘉婧
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深圳微芯生物科技股份有限公司
成都微芯药业有限公司
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a drug combination comprising JAK3/JAK1/TBK1 inhibitor and methotrexate, and its use and method for treating autoimmune diseases, especially rheumatoid arthritis.
  • Autoimmune diseases refer to diseases caused by the body's immune response to self-antigens and damage to its own tissues.
  • Common autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn’s disease, systemic lupus erythematosus, Multiple sclerosis, type I diabetes, allergic diseases, chronic obstructive pulmonary disease, asthma, leukemia, lymphoma diseases, etc.
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • the etiology of the disease is unknown.
  • the peak age of the disease is between 30 and 50 years old. Generally, there are more women than men.
  • the overall incidence rate in my country is 0.32% to 0.36%.
  • Methotrexate (methotrexate, MTX) has the following structure, and its chemical name is: S-(+)-N-2-[4-[[(2,4-diamino-6pteridinyl)methyl]methan Amino]benzoyl]glutamic acid.
  • MTX is a classic disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA. It is recommended by major rheumatology societies and guidelines worldwide as the first choice for early RA.
  • DMARD disease-modifying anti-rheumatic drug
  • MTX reduces the chemotaxis of neutrophils by inhibiting the synthesis of thymine and inhibits the release of inflammatory cytokines, thereby alleviating disease symptoms and slowing the progression of joint damage. Since RA cannot be cured, the safety of long-term use of the drug requires special attention. Clinical studies have confirmed that the main side effects of long-term use of MTX are gastrointestinal reactions, bone marrow suppression, liver damage, kidney damage, etc.
  • JAKs are a small family in the superfamily of non-receptor tyrosine protein kinases in the cytoplasm, including four known members of JAK1, JAK2, JAK3 and TYK2. JAKs function by interacting with tyrosine kinase-related receptors and transcription factor signal transducers and activators of transcription (STAT): the tyrosine kinase-related receptors on the cell membrane do not themselves Kinase activity, but the intracellular segment has the binding site of JAKs.
  • STAT transcription factor signal transducers and activators of transcription
  • the tyrosine residues of various target proteins are phosphorylated by the activation of the bound JAKs to realize the signal from the outside of the cell. Transfer to the cell; after activation of JAKs, the tyrosine residues on the catalytic receptor undergo phosphorylation modification and then form a "parking site" with the surrounding amino acid sequence.
  • the STAT protein is recruited to this "parking site", and finally JAKs catalyze the phosphorylation modification of STAT protein.
  • the activated STAT protein enters the nucleus in the form of a dimer and binds to the target gene to regulate gene transcription.
  • JAK3 is specifically expressed in hematopoietic cells by binding to the ⁇ co-chain ( ⁇ c) of cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 , Regulate cell signal transduction.
  • JAK1 can interact with IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN- ⁇ , IFN- ⁇ , IL-6 in the gp130 family, and other receptors containing ⁇ c, etc. Combine.
  • JAK1 and JAK3 are considered to be more related to immune regulation.
  • the abnormal activation of the two is involved in a variety of autoimmune diseases (including but not limited to lymphoma, arthritis, psoriasis, Crohn’s disease, erythema). Lupus, etc.) play a key role in the etiology and course of the disease. Therefore, the development of inhibitors of JAK1 and JAK3 has become a hot spot in the treatment of RA.
  • autoimmune diseases including but not limited to lymphoma, arthritis, psoriasis, Crohn’s disease, erythema).
  • Lupus, etc. play a key role in the etiology and course of the disease. Therefore, the development of inhibitors of JAK1 and JAK3 has become a hot spot in the treatment of RA.
  • TBK1 (TANK binding kinase 1) is a serine/threonine kinase that activates its substrates IRF3 and IRF7 transcription factors by directly phosphorylating specific sites, and induces them to localize to the nucleus to promote the transcription of type I IFN genes.
  • the expression of type I IFN may cause damage to the body.
  • RANKL/NF ⁇ B is considered to be one of the most important signaling pathways for osteoclast differentiation.
  • Increased levels of soluble RANKL in the synovial fluid of RA patients cause abnormal activation of NF ⁇ B, which will lead to an increase in the number of activated osteoclasts, excessive bone resorption and Increased risk of bone destruction.
  • Studies have shown that the activation of NF ⁇ B can be enhanced by the kinase activity of TBK1, and inhibition of TBK1 activity can inhibit RANKL-induced osteoclast differentiation.
  • the compound represented by formula (I) is a new molecular entity drug exclusively discovered by Shenzhen Chips Biotechnology Co., Ltd., with a novel mechanism.
  • Patent (CN105399685A) and literature (Shan S., et al. 2019, IntImmunopharmacol. 77:105914.) studies have shown that the compound represented by formula (I) is a selective inhibitor of JAK3/JAK1/TBK1, through the target Inhibition reduces the activation of STATs and IRF3, thereby inhibiting the activation of CD4 + T cells, the function of helper T cells 17, the expression of type I interferon (interferon, IFN), and the receptor activator of nuclear factor ⁇ B.
  • Nuclear factor kappa B ligand (RANKL) induces osteoclast differentiation to achieve the therapeutic effect of alleviating RA.
  • MTX and JAK3/JAK1/TBK1 inhibitors are different in the mechanism of alleviating RA.
  • the present invention combines these two drugs with different mechanisms. It is unexpectedly found that the two have a significant synergistic effect on RA, which can reduce Single drug dose, reduce the patient's drug tolerance and reduce possible adverse reactions to provide new and better medication options.
  • the inventors unexpectedly discovered through research that the combination of MTX or its pharmaceutically acceptable salt with JAK3/JAK1/TBK1 inhibitors has a synergistic effect for RA and other autoimmune diseases.
  • the first aspect of the present invention provides a pharmaceutical composition containing MTX or a pharmaceutically acceptable salt thereof and a JAK3/JAK1/TBK1 inhibitor.
  • the pharmaceutical composition can effectively alleviate autoimmunity including RA
  • the treatment effect of the symptoms of sexual diseases is significantly better than the effect of any single component.
  • JAK3/JAK1/TBK1 inhibitors used in the present invention include the compounds described in CN105399685A, the entire contents of which are incorporated herein by reference.
  • the compound in CN105399685A includes a compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,
  • R 1 is halogen or C1-C6 alkyl
  • R 2 is one or more substituents selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkane Carbonyl and C1-C6 alkylamino;
  • R 3 is hydrogen or halogen
  • R 4 is hydrogen or C1-C4 alkyl
  • X is NH, O or S
  • Y is CO or S(O) 2 ;
  • Z is a covalent bond, CH 2 or (CH 2 ) 2 ;
  • n is an integer from 1 to 4.
  • Ring A is a benzene ring, a pyridine ring or a piperidine ring.
  • the JAK3/JAK1/TBK1 inhibitor is N-(3-(5-chloro-2-(4-fluoro-3-(N-methacrylamido)phenylamino)pyrimidinyl-4 -Amino)propyl)-4-cyanobenzamide, its structural formula is as shown in formula (II):
  • the pharmaceutical composition according to the present invention comprises a JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof.
  • the weight ratio of the MTX or its pharmaceutically acceptable salt (calculated as MTX) to the JAK3/JAK1/TBK1 inhibitor is 1:100-1:500.
  • the effective dose of the MTX or its pharmaceutically acceptable salt is 0.1 mg/kg to 0.5 mg/kg.
  • the effective dose of the JAK3/JAK1/TBK1 inhibitor is 20-100 mg/kg; preferably 15-90 mg/kg; most preferably 20-80 mg/kg.
  • the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof can be administered separately, simultaneously or sequentially.
  • halogen refers to fluorine, chlorine, bromine, and iodine; preferably fluorine, chlorine, and bromine; most preferably chlorine.
  • the alkyl group refers to a saturated branched or branched chain hydrocarbon group; in particular, C1-C4 alkyl refers specifically to methyl, ethyl, propyl, isopropyl, butyl, 1-isobutyl, 2- Isobutyl, tert-butyl; the C1-C6 alkyl group includes a 5-carbon alkyl group and a 6-carbon alkyl group in addition to the aforementioned C1-C4 alkyl group, and specific examples thereof will not be repeated here.
  • the alkyl group in the compound of the present invention may be optionally substituted or unsubstituted, and the substituent may include an alkyl group, a halogen, an alkoxy group, a hydrocarbyl group, a hydroxyl group, and the like.
  • the "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” in the present invention refers to an acid addition salt prepared by reacting the compound represented by the aforementioned formula (I) or MTX with a pharmaceutically acceptable acid, or A salt formed by the reaction between a compound having an acidic group and a pharmaceutically acceptable base.
  • the pharmaceutically acceptable acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.) and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, Tartaric acid, citric acid or benzoic acid, etc.);
  • the pharmaceutically acceptable base is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, ammonia or ammonium bicarbonate.
  • the stereoisomers include conformational isomers, enantiomers and diastereomers.
  • composition of the present invention may also include pharmaceutically acceptable excipients.
  • compositions according to the present invention can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions).
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oils, etc.
  • adsorption promoters such as lactose, white sugar, sodium chloride, glucose
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc; binders, Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
  • carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc
  • binders Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol
  • disintegrants such as agar and kelp powder.
  • the solution and suspension can be sterilized, and it is best to add an appropriate amount of sodium chloride, glucose or glycerin, etc., to make an injection that is isotonic with blood.
  • any carriers commonly used in the art can also be used.
  • usual dissolving agents, buffering agents and analgesics can also be added.
  • the content of the JAK3/JAK1/TBK1 inhibitor of the present invention and methotrexate or its pharmaceutically acceptable salt in the pharmaceutical composition is not particularly limited, and can be selected in a wide range, usually alone can be a mass percentage 1-45%, preferably 1-30% by mass.
  • the present invention provides a medicine kit containing the above-mentioned pharmaceutical composition.
  • the MTX and JAK3/JAK1/TBK1 inhibitors are unit preparations with the same or different specifications, respectively, and the preparations are not particularly limited and can be any preparations, especially those described in the present invention above. Dosage form.
  • the MTX and JAK3/JAK1/TBK1 inhibitors are preferably provided in separate containers.
  • the weight ratio of the MTX to the JAK3/JAK1/TBK1 inhibitor is 1:100 to 1:500.
  • the MTX and JAK3/JAK1/TBK1 inhibitor are administered simultaneously, separately or sequentially.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicine for treating autoimmune diseases.
  • the autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia, lymph Tumor disease and so on.
  • the present invention provides a method for treating autoimmune diseases, which includes the step of administering a therapeutically effective amount of the above-mentioned pharmaceutical composition or kit to a patient in need.
  • composition and kit of the present invention can be prepared by conventional methods in the art.
  • the autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia, lymph Tumor disease and so on.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a JAK3/JAK1/TBK1 inhibitor and methotrexate, which has a synergistic effect for autoimmune diseases including RA.
  • the present invention also relates to a kit containing the pharmaceutical composition, so that the JAK3/JAK1/TBK1 inhibitor and methotrexate can be administered separately or simultaneously.
  • the pharmaceutical composition or the kit according to the present invention can reduce a single drug dose, thereby reducing toxicity, reducing the patient's drug tolerance and reducing possible adverse reactions, and providing new and better drug options for autoimmune diseases.
  • Figure 1 The efficacy of MTX and JAK3/JAK1/TBK1 inhibitors in the CIA rat model.
  • Figure 2 H&E staining and microscopic observation of the sections of the knee joint (Figure 2A) and ankle joint (Figure 2B) of CIA rats after the administration.
  • the present invention discloses the combination of MTX or its pharmaceutically acceptable salt and JAK3/JAK1/TBK1 inhibitor and its use in the treatment of autoimmune diseases including RA.
  • SD rats Three-month-old male Sprague Dawley (SD) rats were purchased from Guangdong Medical Experimental Animal Center.
  • Bovine type II collagen and incomplete Freund's adjuvant were purchased from Chondrex.
  • JAK3/JAK1/TBK1 inhibitor N-(3-(5-chloro-2-(4-fluoro-3-(N-methacrylamido)phenylamino)pyrimidinyl-4-amino)propyl) -4-Cyanobenzamide, code CS12192) was synthesized by Shenzhen Microchip Biotechnology Co., Ltd.; methotrexate was purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Tissue fixative solution and EDTA decalcification solution were purchased from Salarbio.
  • Hematoxylin and eosin staining solutions were purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.
  • test animals were numbered and divided into 5 groups, each with 8 animals, including the normal control group, model group, MTX group, CS12192 group and MTX+CS12192 group. Gavage was started on the day of the second immunization.
  • the MTX group was given 0.2 mg MTX per kilogram of body weight once a day; the CS12192 group was given 40 mg per kilogram of body weight twice a day and CS12192; the MTX+CS12192 group was given 0.2 mg per kilogram of body weight per day.
  • MTX once, and give 40mg CS12192 per kilogram of body weight twice a day.
  • the front and back paws of each test animal were collected, fixed in tissue fixative for 24 hours, and 3 days after decalcification treatment, paraffin embedding and sectioning were performed, and the tissue was cut into 5 ⁇ m thick.
  • the sections were deparaffinized and stained with H&E.
  • the pathological changes of the knee joint and ankle joint tissues of the tested animals were observed under the microscope, including whether the synovial tissue was proliferated, whether inflammatory cells were infiltrated, and whether there was granulation tissue formation.
  • the average inflammation scores of the two single-drug groups of MTX and CS12192 were 4.14 and 4, respectively.
  • the P values were 0.027 and 0.018, respectively.
  • MTX+CS12192 is the combination medication group.
  • the average inflammation score at the end of the experiment is 1.86.
  • the P value is 0.00010, indicating that the combination medication has a statistically significant improvement in the condition of CIA; while the combination medication group and MTX and MTX have a P value of 0.00010. Comparing the two single-drug groups of CS12192 (P values were 0.020 and 0.0093), there were still statistical or significant statistical differences.
  • Figure 1B shows the changes in the weight of the animals recorded in the experiment. Due to the development of the disease, the average weight of the model group at the end of the experiment was significantly lower than that of the blank control group, and the average weight gain of each administration group was higher than that of the model group. improve.
  • Figure 2 shows that the knee joints and ankle joints of each group of animals were collected after the administration, fixed, sliced and H&E stained, and then the pathological changes were observed under a microscope.
  • Figure 2A is the knee joint
  • Figure 2B is the ankle joint.
  • significant disease changes can be observed in the model: synovial tissue abnormal proliferation, massive inflammatory cell infiltration and granulation tissue formation; CS12192 or MTX alone
  • the improvement of the disease by the drug can be observed, but a certain amount of synovial tissue abnormal proliferation or inflammatory cell infiltration can still be found; while in the CS12192+MTX combined drug group, the pathological features of arthritis are basically not found.
  • the combination of MTX and JAK3/JAK1/TBK1 inhibitors can achieve a significant synergistic effect that is superior to that of single drugs in collagen-induced arthritis rat models. There are no obvious side effects in animal models, and the safety is acceptable.

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Abstract

A pharmaceutical composition comprising a JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof and use thereof. The present invention specifically relates to use of a combination of a JAK3/JAK1/TBK1 inhibitor and methotrexate in treating autoimmune diseases, especially rheumatoid arthritis. The combined administration regimen increases the efficacy by means of the synergy between the drugs, thereby reducing the dosage of a single drug, reducing toxicity, reducing the drug tolerance of patients and reducing possible adverse reactions, and is expected to provide a new and better administration option for autoimmune diseases including RA.

Description

一种包含JAK3/JAK1/TBK1抑制剂和甲氨蝶呤的药物组合物及其用途A pharmaceutical composition containing JAK3/JAK1/TBK1 inhibitor and methotrexate and uses thereof 技术领域Technical field
本发明属于医药技术领域，具体涉及一种包含JAK3/JAK1/TBK1抑制剂和甲氨蝶呤的药物组合及其在治疗自身免疫性疾病尤其是类风湿性关节炎中的用途和使用方法。The invention belongs to the technical field of medicine, and specifically relates to a drug combination comprising JAK3/JAK1/TBK1 inhibitor and methotrexate, and its use and method for treating autoimmune diseases, especially rheumatoid arthritis.
背景技术Background technique
自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织损害所引起的疾病，常见的自身免疫性疾病包括类风湿性关节炎、银屑病、克罗恩病、系统性红斑狼疮、多发性硬化症、Ⅰ型糖尿病、过敏性疾病、慢性阻塞性肺病、哮喘、白血病、淋巴瘤疾病等。Autoimmune diseases refer to diseases caused by the body's immune response to self-antigens and damage to its own tissues. Common autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn’s disease, systemic lupus erythematosus, Multiple sclerosis, type I diabetes, allergic diseases, chronic obstructive pulmonary disease, asthma, leukemia, lymphoma diseases, etc.
类风湿性关节炎(rheumatoid arthritis,RA)是一种以多关节、对称性、侵袭性的关节滑膜炎症和可能累及关节外器官为特征的慢性、自身免疫性疾病。该疾病病因未明，发病高峰年龄在30～50岁之间，一般女性多于男性，在我国总体发病率为0.32％～0.36％。Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by multi-joint, symmetrical and aggressive joint synovial inflammation and possible involvement of extra-articular organs. The etiology of the disease is unknown. The peak age of the disease is between 30 and 50 years old. Generally, there are more women than men. The overall incidence rate in my country is 0.32% to 0.36%.
数据表明，如未及时治疗，约75％的患者在发病2年内即可出现骨破坏，由此造成关节僵硬、畸形和功能严重受损，进而可能导致劳动能力丧失甚至残疾。这将使患者生活水平下降、期望寿命降低，并给患者本人、家庭和社会带来巨大的经济负担。Data shows that, if not treated in time, about 75% of patients will experience bone destruction within 2 years of onset, resulting in joint stiffness, deformity and severe impairment of function, which may lead to loss of work ability and even disability. This will reduce the living standards of patients, reduce life expectancy, and bring a huge economic burden to the patients themselves, their families and society.
甲氨蝶呤(methotrexate,MTX)具有如下结构，其化学名称为：S-(+)-N-2-[4-[[(2,4-二氨基-6蝶啶基)甲基]甲氨基]苯甲酰基]谷氨酸。Methotrexate (methotrexate, MTX) has the following structure, and its chemical name is: S-(+)-N-2-[4-[[(2,4-diamino-6pteridinyl)methyl]methan Amino]benzoyl]glutamic acid.
Figure PCTCN2021078693-appb-000001
Figure PCTCN2021078693-appb-000001
MTX是一款经典的用于RA治疗的改善病情抗风湿药(disease-modifying anti-rheumatic drug,DMARD)，被全球各大风湿病学会、指南推荐为早期RA的首选用药。作为一种叶酸还原酶抑制剂，MTX通过抑制胸腺嘧啶的合成减少中性粒细胞的趋化作用，抑制炎性细胞因子的释放，从而发挥缓解疾病症状和减缓关节损伤进展的作用。由于RA尚不能被治愈，药物长期使用的安全性需要特别关注。临床研究已经证实，长期使用MTX的毒副作用主要为胃肠道反应、骨髓抑制、肝损伤、肾损伤等。MTX is a classic disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA. It is recommended by major rheumatology societies and guidelines worldwide as the first choice for early RA. As a folate reductase inhibitor, MTX reduces the chemotaxis of neutrophils by inhibiting the synthesis of thymine and inhibits the release of inflammatory cytokines, thereby alleviating disease symptoms and slowing the progression of joint damage. Since RA cannot be cured, the safety of long-term use of the drug requires special attention. Clinical studies have confirmed that the main side effects of long-term use of MTX are gastrointestinal reactions, bone marrow suppression, liver damage, kidney damage, etc.
JAKs(Janus kinases)是胞浆内非受体酪氨酸蛋白激酶超家族中的一个小家族，包括JAK1、JAK2、JAK3和TYK2四个已知成员。JAKs通过与酪氨酸激酶相关受体和转录因子信号转导子和转录激活子(signal transducer and activator of transcription,STAT)的相互作用发挥功能：细胞膜上的酪氨酸激酶相关受体本身不具有激酶活性，但胞内段具有JAKs的结合位点，受体与配体结合后，通过与之相结合的JAKs的活化来磷酸化各种靶蛋白的酪氨酸残基以实现信号从胞外到胞内的传递；JAKs激活后催化受体上的酪氨酸残基发生磷酸化修饰继而与周围的氨基酸序列形成“停泊位点”，STAT蛋白被招募到这种“停泊位点”，最后，JAKs催化STAT蛋白发生磷酸化修饰，活化的STAT蛋白以二聚体的形式进入细胞核内与靶基因结合，调控基因的转录。JAKs (Janus kinases) are a small family in the superfamily of non-receptor tyrosine protein kinases in the cytoplasm, including four known members of JAK1, JAK2, JAK3 and TYK2. JAKs function by interacting with tyrosine kinase-related receptors and transcription factor signal transducers and activators of transcription (STAT): the tyrosine kinase-related receptors on the cell membrane do not themselves Kinase activity, but the intracellular segment has the binding site of JAKs. After the receptor binds to the ligand, the tyrosine residues of various target proteins are phosphorylated by the activation of the bound JAKs to realize the signal from the outside of the cell. Transfer to the cell; after activation of JAKs, the tyrosine residues on the catalytic receptor undergo phosphorylation modification and then form a "parking site" with the surrounding amino acid sequence. The STAT protein is recruited to this "parking site", and finally JAKs catalyze the phosphorylation modification of STAT protein. The activated STAT protein enters the nucleus in the form of a dimer and binds to the target gene to regulate gene transcription.
JAK3特异性地在造血细胞表达，通过与IL-2、IL-4、IL-7、IL-9、IL-15、IL-21等细胞因子受体复合物的γ共链(γc)相结合，调节细胞信号传导。JAK1可与IL-10、IL-19、IL-20、IL-22、IL-26、IL-28、IFN-α、IFN-γ、gp130家族中的IL-6以及含γc的其它受体等结合。在JAKs家族中，JAK1和JAK3被认为更多地与免疫调节有关，二者的异常活化在多种自身免疫疾病(包括但不限于淋巴瘤、关节炎、银屑病、克罗恩病、红斑狼疮等)的病因、病程中发挥关键作用，因此，JAK1和JAK3的抑制剂的开发成为RA等治疗领域的热点。JAK3 is specifically expressed in hematopoietic cells by binding to the γ co-chain (γc) of cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 , Regulate cell signal transduction. JAK1 can interact with IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 in the gp130 family, and other receptors containing γc, etc. Combine. In the JAKs family, JAK1 and JAK3 are considered to be more related to immune regulation. The abnormal activation of the two is involved in a variety of autoimmune diseases (including but not limited to lymphoma, arthritis, psoriasis, Crohn’s disease, erythema). Lupus, etc.) play a key role in the etiology and course of the disease. Therefore, the development of inhibitors of JAK1 and JAK3 has become a hot spot in the treatment of RA.
TBK1(TANK binding kinase 1)一种是丝氨酸/苏氨酸激酶，通过直接磷酸化特异性位点激活其底物IRF3和IRF7转录因子，诱导它们定位至细胞核来推动I型IFN基因的转录，过量的I型IFN表达可能造成机体损伤。此外，RANKL/NFκB被认为是破骨细胞分化最重要的信号通路之一，RA患者关节液中的可溶性RANKL水平升高，使NFκB异常激活，会导致活化破骨细胞数量增加、骨吸收过度和骨破坏风险增加。已有研究表明，NFκB的活化可被TBK1的激酶活性增强，而通过抑制TBK1活性可抑制RANKL诱导的破骨细胞分化。TBK1 (TANK binding kinase 1) is a serine/threonine kinase that activates its substrates IRF3 and IRF7 transcription factors by directly phosphorylating specific sites, and induces them to localize to the nucleus to promote the transcription of type I IFN genes. The expression of type I IFN may cause damage to the body. In addition, RANKL/NFκB is considered to be one of the most important signaling pathways for osteoclast differentiation. Increased levels of soluble RANKL in the synovial fluid of RA patients cause abnormal activation of NFκB, which will lead to an increase in the number of activated osteoclasts, excessive bone resorption and Increased risk of bone destruction. Studies have shown that the activation of NFκB can be enhanced by the kinase activity of TBK1, and inhibition of TBK1 activity can inhibit RANKL-induced osteoclast differentiation.
式(I)所示化合物是深圳微芯生物科技股份有限公司独家发现的新分子实体药物，机制新颖。专利(CN105399685A)和文献(Shan S.,et al.2019,IntImmunopharmacol.77:105914.)研究表明式(I)所示化合物是一种JAK3/JAK1/TBK1选择性抑制剂，通过对靶点的抑制减少STATs和IRF3的活化，从而抑制CD4 +T细胞的活化、辅助性T细胞17的功能、I型干扰素(interferon,IFN)的表达及核因子κB受体激动剂配体(receptor activator of nuclear factor kappa B ligand,RANKL)诱导的破骨细胞分化，达到缓解RA的疗效。 The compound represented by formula (I) is a new molecular entity drug exclusively discovered by Shenzhen Chips Biotechnology Co., Ltd., with a novel mechanism. Patent (CN105399685A) and literature (Shan S., et al. 2019, IntImmunopharmacol. 77:105914.) studies have shown that the compound represented by formula (I) is a selective inhibitor of JAK3/JAK1/TBK1, through the target Inhibition reduces the activation of STATs and IRF3, thereby inhibiting the activation of CD4 + T cells, the function of helper T cells 17, the expression of type I interferon (interferon, IFN), and the receptor activator of nuclear factor κB. Nuclear factor kappa B ligand (RANKL) induces osteoclast differentiation to achieve the therapeutic effect of alleviating RA.
综上，MTX和JAK3/JAK1/TBK1抑制剂在缓解RA的机制上具有差异化。目前未见有将二者联合应用于RA和其他自身免疫性疾病治疗的研究，本发明将这两种不同机制的药物进行组合，意外地发现二者对RA具有显著的协同疗效，可为降低单个药物剂量、降低患者的药物耐受并减少可能的不良反应提供新的更好的用药选择。In summary, MTX and JAK3/JAK1/TBK1 inhibitors are different in the mechanism of alleviating RA. At present, there is no research on the combined application of the two in the treatment of RA and other autoimmune diseases. The present invention combines these two drugs with different mechanisms. It is unexpectedly found that the two have a significant synergistic effect on RA, which can reduce Single drug dose, reduce the patient's drug tolerance and reduce possible adverse reactions to provide new and better medication options.
发明内容Summary of the invention
本发明人通过研究意外发现：将MTX或其药学上可接受的盐与JAK3/JAK1/TBK1抑制剂联用，用于RA和其他自身免疫性疾病具有协同疗效。The inventors unexpectedly discovered through research that the combination of MTX or its pharmaceutically acceptable salt with JAK3/JAK1/TBK1 inhibitors has a synergistic effect for RA and other autoimmune diseases.
因此，本发明的第一个方面提供一种含MTX或其药学上可接受的盐和JAK3/JAK1/TBK1抑制剂的药物组合物，利用该药物组合物可有效缓解包括RA在内的自身免疫性疾病的症状，其治疗效果显著优于任意单一组份的效果。Therefore, the first aspect of the present invention provides a pharmaceutical composition containing MTX or a pharmaceutically acceptable salt thereof and a JAK3/JAK1/TBK1 inhibitor. The pharmaceutical composition can effectively alleviate autoimmunity including RA The treatment effect of the symptoms of sexual diseases is significantly better than the effect of any single component.
本发明中所用的JAK3/JAK1/TBK1抑制剂包括描述于CN105399685A中的化合物，其全部内容引入本文作为参考。The JAK3/JAK1/TBK1 inhibitors used in the present invention include the compounds described in CN105399685A, the entire contents of which are incorporated herein by reference.
具体而言，CN105399685A中的化合物包括为式(I)所示化合物或其立体异构体或其药学上可接受的盐，Specifically, the compound in CN105399685A includes a compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021078693-appb-000002
Figure PCTCN2021078693-appb-000002
其中，in,
R 1为卤素或C1-C6烷基； R 1 is halogen or C1-C6 alkyl;
R 2为一个或多个取代基，所述取代基选自氢、羟基、氰基、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6的卤代烷基、C1-C6的烷基羰基和C1-C6烷基氨基； R 2 is one or more substituents selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkane Carbonyl and C1-C6 alkylamino;
R 3为氢或卤素； R 3 is hydrogen or halogen;
R 4为氢或C1-C4烷基； R 4 is hydrogen or C1-C4 alkyl;
X为NH、O或S；X is NH, O or S;
Y为CO或S(O) 2； Y is CO or S(O) 2 ;
Z为共价键、CH 2或(CH 2) 2； Z is a covalent bond, CH 2 or (CH 2 ) 2 ;
n为1到4的整数；n is an integer from 1 to 4;
环A为苯环、吡啶环或哌啶环。Ring A is a benzene ring, a pyridine ring or a piperidine ring.
更优选的，所述JAK3/JAK1/TBK1抑制剂为N-(3-(5-氯-2-(4-氟-3-(N-甲基丙烯酰胺基)苯基氨基)嘧啶基-4-氨基)丙基)-4-氰基苯甲酰胺，其结构式如式(II)所示：More preferably, the JAK3/JAK1/TBK1 inhibitor is N-(3-(5-chloro-2-(4-fluoro-3-(N-methacrylamido)phenylamino)pyrimidinyl-4 -Amino)propyl)-4-cyanobenzamide, its structural formula is as shown in formula (II):
Figure PCTCN2021078693-appb-000003
Figure PCTCN2021078693-appb-000003
根据本发明的药物组合物，其包含JAK3/JAK1/TBK1抑制剂和甲氨蝶呤或其药学上可接受的盐。The pharmaceutical composition according to the present invention comprises a JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof.
所述MTX或其可药用盐(以MTX计)与所述JAK3/JAK1/TBK1抑制剂的重量比为1：100～1：500。The weight ratio of the MTX or its pharmaceutically acceptable salt (calculated as MTX) to the JAK3/JAK1/TBK1 inhibitor is 1:100-1:500.
所述MTX或其可药用盐(以MTX计)的有效剂量为0.1mg/kg～0.5mg/kg。The effective dose of the MTX or its pharmaceutically acceptable salt (calculated as MTX) is 0.1 mg/kg to 0.5 mg/kg.
所述JAK3/JAK1/TBK1抑制剂的有效剂量为20～100mg/kg；优选15～90mg/kg；最优选为20～80mg/kg。The effective dose of the JAK3/JAK1/TBK1 inhibitor is 20-100 mg/kg; preferably 15-90 mg/kg; most preferably 20-80 mg/kg.
根据本发明的药物组合物，所述JAK3/JAK1/TBK1抑制剂和甲氨蝶呤或其可药用盐可以分开、同时或依次施用。According to the pharmaceutical composition of the present invention, the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof can be administered separately, simultaneously or sequentially.
根据本发明，其中，所述卤素是指氟、氯、溴、碘；优选氟、氯、溴；最优选氯。According to the present invention, wherein the halogen refers to fluorine, chlorine, bromine, and iodine; preferably fluorine, chlorine, and bromine; most preferably chlorine.
所述烷基是指饱和的支链或支链烃基；特别地，C1-C4烷基具体是指甲基、乙基、丙基、异丙基、丁基、1-异丁基、2-异丁基、叔丁基；所述C1-C6烷基除了前述C1-C4烷基以外，还包括5碳烷基和6碳烷基，其具体例子在此不再赘述。本发明化合物中的烷基可以是任选取代或未取代的，取代基可以包括烷基、卤素、烷氧基、烃基、羟基等。The alkyl group refers to a saturated branched or branched chain hydrocarbon group; in particular, C1-C4 alkyl refers specifically to methyl, ethyl, propyl, isopropyl, butyl, 1-isobutyl, 2- Isobutyl, tert-butyl; the C1-C6 alkyl group includes a 5-carbon alkyl group and a 6-carbon alkyl group in addition to the aforementioned C1-C4 alkyl group, and specific examples thereof will not be repeated here. The alkyl group in the compound of the present invention may be optionally substituted or unsubstituted, and the substituent may include an alkyl group, a halogen, an alkoxy group, a hydrocarbyl group, a hydroxyl group, and the like.
本发明所述的“可药用盐”或“药学上可接受的盐”是指前述式(I)所示化合物或MTX与药学上可接受的酸进行反应制得的酸加成盐，或者其中具有酸性基团的化合物和药学上可接受的碱反应生成的盐。其中，所述的药学上可接受的酸较佳的选自无机酸(如盐酸、硫酸、磷酸或氢溴酸等)，和有机酸(如草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸或苯甲酸等)；所述药学上可接受的碱较佳的选自氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠、碳酸氢钾、氨水或碳酸氢铵等。The "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" in the present invention refers to an acid addition salt prepared by reacting the compound represented by the aforementioned formula (I) or MTX with a pharmaceutically acceptable acid, or A salt formed by the reaction between a compound having an acidic group and a pharmaceutically acceptable base. Among them, the pharmaceutically acceptable acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.) and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, Tartaric acid, citric acid or benzoic acid, etc.); the pharmaceutically acceptable base is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, ammonia or ammonium bicarbonate.
所述立体异构体包括构象异构体，对映异构体和非对应异构体。The stereoisomers include conformational isomers, enantiomers and diastereomers.
本发明的上述药物组合物还可包含药学上可接受的辅料。The above-mentioned pharmaceutical composition of the present invention may also include pharmaceutically acceptable excipients.
根据本发明的药物组合物可以制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。The pharmaceutical composition according to the present invention can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions).
为了使片剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂。例 如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油等；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。如果需要的话，还可以用通常的涂渍材料使片剂作为糖衣片剂、肠衣片剂、涂膜片剂(如涂明胶膜片剂)、双层膜片剂及多层片剂。In order to shape the pharmaceutical composition in the form of a tablet, any excipient known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrant, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.; disintegration inhibitors, such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oils, etc.; adsorption promoters, such as quaternary amine bases and sodium lauryl sulfate, etc.; wetting agents, such as glycerin, starch, etc.; adsorbents, such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and lubricants , Such as pure talc, stearate, boric acid powder and polyethylene glycol. If necessary, the tablets can also be made into sugar-coated tablets, enteric-coated tablets, film-coated tablets (such as gelatin film-coated tablets), double-film tablets, and multi-layer tablets with usual coating materials.
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。In order to shape the pharmaceutical composition in the form of pills, any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc; binders, Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
为了制备针剂形式的药物组合物，可将溶液和悬浮液消毒，并最好加入适量的氯化钠，葡萄糖或甘油等，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。In order to prepare a pharmaceutical composition in the form of an injection, the solution and suspension can be sterilized, and it is best to add an appropriate amount of sodium chloride, glucose or glycerin, etc., to make an injection that is isotonic with blood. When preparing injections, any carriers commonly used in the art can also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan and the like. In addition, usual dissolving agents, buffering agents and analgesics can also be added.
本发明的JAK3/JAK1/TBK1抑制剂和甲氨蝶呤或其药学上可接受的盐在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常独自可为质量百分比1-45％，较佳的为质量百分比1-30％。The content of the JAK3/JAK1/TBK1 inhibitor of the present invention and methotrexate or its pharmaceutically acceptable salt in the pharmaceutical composition is not particularly limited, and can be selected in a wide range, usually alone can be a mass percentage 1-45%, preferably 1-30% by mass.
进一步的，本发明提供了一种药盒，它含有上述药物组合物。Further, the present invention provides a medicine kit containing the above-mentioned pharmaceutical composition.
本发明的药盒中，所述MTX与JAK3/JAK1/TBK1抑制剂分别是具有相同或不同规格的单位制剂，所述制剂没有特殊的限制，可以是任何制剂，尤其优选上述本发明所记载的剂型。In the kit of the present invention, the MTX and JAK3/JAK1/TBK1 inhibitors are unit preparations with the same or different specifications, respectively, and the preparations are not particularly limited and can be any preparations, especially those described in the present invention above. Dosage form.
根据本发明，所述MTX与JAK3/JAK1/TBK1抑制剂优选分别置于单独容器中提供。According to the present invention, the MTX and JAK3/JAK1/TBK1 inhibitors are preferably provided in separate containers.
所述MTX与JAK3/JAK1/TBK1抑制剂的重量比为1：100～1：500。The weight ratio of the MTX to the JAK3/JAK1/TBK1 inhibitor is 1:100 to 1:500.
其中，所述MTX与JAK3/JAK1/TBK1抑制剂同时、分别或依次给药。Wherein, the MTX and JAK3/JAK1/TBK1 inhibitor are administered simultaneously, separately or sequentially.
本发明同时提供了上述药物组合物在制备治疗自身免疫性疾病的药物中的用途。The present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicine for treating autoimmune diseases.
所述自身免疫性疾病包括类风湿性关节炎、银屑病、克罗恩病、系统性红斑狼疮、多发性硬化症、Ⅰ型糖尿病、过敏性疾病、慢性阻塞性肺病、哮喘、白血病、淋巴瘤疾病等。The autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia, lymph Tumor disease and so on.
最后，本发明提供了一种治疗自身免疫性疾病的方法，其包括向有需要的患者施用治疗有效量的上述药物组合物或药盒的步骤。Finally, the present invention provides a method for treating autoimmune diseases, which includes the step of administering a therapeutically effective amount of the above-mentioned pharmaceutical composition or kit to a patient in need.
本发明的药物组合物及药盒可以通过本领域的常规方法进行制备。The pharmaceutical composition and kit of the present invention can be prepared by conventional methods in the art.
所述自身免疫性疾病包括类风湿性关节炎、银屑病、克罗恩病、系统性红斑狼疮、多发性硬化症、Ⅰ型糖尿病、过敏性疾病、慢性阻塞性肺病、哮喘、白血病、淋巴瘤疾病等。The autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia, lymph Tumor disease and so on.
有益效果Beneficial effect
本发明涉及一种包含JAK3/JAK1/TBK1抑制剂和甲氨蝶呤的药物组合物，其用于包括RA在内的自身免疫性疾病具有协同增效的作用。The present invention relates to a pharmaceutical composition comprising a JAK3/JAK1/TBK1 inhibitor and methotrexate, which has a synergistic effect for autoimmune diseases including RA.
本发明还涉及包含所述药物组合物的药盒，使得其中JAK3/JAK1/TBK1抑制剂和甲氨蝶呤可以单独或同时给药。The present invention also relates to a kit containing the pharmaceutical composition, so that the JAK3/JAK1/TBK1 inhibitor and methotrexate can be administered separately or simultaneously.
根据本发明的药物组合物或者药盒可以降低单个药物剂量、从而降低毒性、降低患者的药物耐受并减少可能的不良反应，为自身免疫性疾病提供新的更好的用药选择。The pharmaceutical composition or the kit according to the present invention can reduce a single drug dose, thereby reducing toxicity, reducing the patient's drug tolerance and reducing possible adverse reactions, and providing new and better drug options for autoimmune diseases.
附图说明Description of the drawings
图1 MTX与JAK3/JAK1/TBK1抑制剂在CIA大鼠模型中的药效。Figure 1 The efficacy of MTX and JAK3/JAK1/TBK1 inhibitors in the CIA rat model.
图2给药结束后CIA大鼠膝关节(图2A)和踝关节(图2B)切片的H&E染色及显微观察。Figure 2 H&E staining and microscopic observation of the sections of the knee joint (Figure 2A) and ankle joint (Figure 2B) of CIA rats after the administration.
具体实施方式Detailed ways
本发明公开了MTX或其可药用盐和JAK3/JAK1/TBK1抑制剂的组合及其在治疗包括RA在内的自身免疫性疾病中的用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明的范围之内。本部分意在对本发明所述应用和药用组合物的较佳实施例进行描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用和药用组合物进行改动或适当变更与组合，来实现和应用本发明技术。The present invention discloses the combination of MTX or its pharmaceutically acceptable salt and JAK3/JAK1/TBK1 inhibitor and its use in the treatment of autoimmune diseases including RA. Those skilled in the art can learn from the content of this article and appropriately improve the process Parameter realization. It should be particularly pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the scope of the present invention. This section is intended to describe the preferred embodiments of the applications and pharmaceutical compositions of the present invention. The relevant personnel can obviously modify or modify the applications and pharmaceutical compositions described herein without departing from the content, spirit and scope of the present invention. Appropriate changes and combinations are used to realize and apply the technology of the present invention.
实验部分Experimental part
实验材料：Experimental Materials:
三月龄雄性Sprague Dawley(SD)大鼠购自于广东省医学实验动物中心。Three-month-old male Sprague Dawley (SD) rats were purchased from Guangdong Medical Experimental Animal Center.
牛Ⅱ型胶原和不完全弗氏佐剂购自于Chondrex公司。Bovine type II collagen and incomplete Freund's adjuvant were purchased from Chondrex.
JAK3/JAK1/TBK1抑制剂(N-(3-(5-氯-2-(4-氟-3-(N-甲基丙烯酰胺基)苯基氨基)嘧啶基-4-氨基)丙基)-4-氰基苯甲酰胺，代号CS12192)由深圳微芯生物科技股份有限公司合成；甲氨蝶呤购自于上海源叶生物科技有限公司。JAK3/JAK1/TBK1 inhibitor (N-(3-(5-chloro-2-(4-fluoro-3-(N-methacrylamido)phenylamino)pyrimidinyl-4-amino)propyl) -4-Cyanobenzamide, code CS12192) was synthesized by Shenzhen Microchip Biotechnology Co., Ltd.; methotrexate was purchased from Shanghai Yuanye Biotechnology Co., Ltd.
组织固定液和EDTA脱钙液购自于Salarbio公司。苏木素和伊红染色液购自于北京中山金桥生物技术有限公司。Tissue fixative solution and EDTA decalcification solution were purchased from Salarbio. Hematoxylin and eosin staining solutions were purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.
实验方法：experimental method:
将牛Ⅱ型胶原加入等体积不完全弗氏佐剂乳化，通过尾根注射建立SD大鼠胶原诱导关节炎(collagen induced arthritis,CIA)模型，第一次免疫当天(记为第0天)每只注射0.2mL，第二次免疫(第7天)每只注射0.1mL。一般第10天开始肿胀发病，第13～14天到达发病高峰，第21天肿胀开始减退、关节变形。Add bovine type II collagen to an equal volume of incomplete Freund’s adjuvant for emulsification, and establish a collagen-induced arthritis (CIA) model in SD rats by tail-root injection. On the day of the first immunization (denoted as day 0) each animal 0.2 mL was injected, and the second immunization (day 7) was injected with 0.1 mL each. Generally, swelling begins on the 10th day and reaches the peak on the 13th to 14th day. The swelling begins to decrease and the joint deforms on the 21st day.
将受试动物编号后分为5组、每组各8只，包括正常对照组、模型组、MTX组、CS12192组和MTX+CS12192组。第二次免疫当天开始灌胃给药，其中MTX组每天每千克体重给0.2mg MTX一次；CS12192组每天2次，每次每千克体重给40mg CS12192；MTX+CS12192组每天每千克体重给0.2mg MTX1次，并每天2次每次每千克体重给40mg CS12192。The test animals were numbered and divided into 5 groups, each with 8 animals, including the normal control group, model group, MTX group, CS12192 group and MTX+CS12192 group. Gavage was started on the day of the second immunization. The MTX group was given 0.2 mg MTX per kilogram of body weight once a day; the CS12192 group was given 40 mg per kilogram of body weight twice a day and CS12192; the MTX+CS12192 group was given 0.2 mg per kilogram of body weight per day. MTX once, and give 40mg CS12192 per kilogram of body weight twice a day.
于第二次免疫当天开始评分，采用16分制：前后四肢，每肢4分：关节严重红肿或关节变形4分；关节重度红肿为3分；关节中度红肿为2分；关节有红色斑点或轻度肿胀为1分；无红肿为0分。Start scoring on the day of the second immunization, using a 16-point system: front and rear limbs, 4 points for each limb: 4 points for severe joint swelling or joint deformity; 3 points for severe joint swelling and swelling; 2 points for moderate joint swelling and red spots; red spots on joints Or mild swelling is 1 point; no redness is 0 point.
给药及评分结束后，采集各受试动物前后爪，在组织固定液中固定24小时，脱钙处理3天后，进行石蜡包埋和切片，将组织切成5μm厚。切片脱蜡后进行H&E染色，镜下观察各受试动物膝关节和踝关节组织的病理变化，包括滑膜组织是否增生、炎症细胞是否浸润及是否有肉芽组织形成。After the administration and scoring, the front and back paws of each test animal were collected, fixed in tissue fixative for 24 hours, and 3 days after decalcification treatment, paraffin embedding and sectioning were performed, and the tissue was cut into 5 μm thick. The sections were deparaffinized and stained with H&E. The pathological changes of the knee joint and ankle joint tissues of the tested animals were observed under the microscope, including whether the synovial tissue was proliferated, whether inflammatory cells were infiltrated, and whether there was granulation tissue formation.
实验结果：Experimental results:
实验开始后19天结束，如图1A所示，模型组动物在实验结束时的平均炎症评分为8.6，相对空白对照组具有显著的统计学差异(P＝0.00014)，表明CIA病理模型构建成功。到实验结束时，MTX和CS12192两个单药组的平均炎症评分分别为4.14和4，与模型组相比，P值分别为0.027和0.018，具统计学差异，说明上述剂量的两单药在CIA大鼠中均具有一定疗效。MTX+CS12192为联合用药组，实验结束时的平均炎症评分为1.86，相较于模型组，P值为0.00010，表明联合用药对CIA病情有显著统计学意义的改善；而联合用药组与MTX和CS12192两单药组比较(P值分别为0.020和0.0093)，仍具有统计学或显著统计学差异。图1B为实验中所记录的各组动物体重变化，由于病情发展，模型组在实验结束时，平均体重明显低于空白对照组，而各给药组的平均体重增长情况均较模型组有所改善。The experiment ended 19 days after the start of the experiment. As shown in Figure 1A, the average inflammation score of the model group animals at the end of the experiment was 8.6, which was significantly different from the blank control group (P=0.00014), indicating that the CIA pathological model was successfully constructed. By the end of the experiment, the average inflammation scores of the two single-drug groups of MTX and CS12192 were 4.14 and 4, respectively. Compared with the model group, the P values were 0.027 and 0.018, respectively. There was a statistical difference. All have certain curative effect in CIA rats. MTX+CS12192 is the combination medication group. The average inflammation score at the end of the experiment is 1.86. Compared with the model group, the P value is 0.00010, indicating that the combination medication has a statistically significant improvement in the condition of CIA; while the combination medication group and MTX and MTX have a P value of 0.00010. Comparing the two single-drug groups of CS12192 (P values were 0.020 and 0.0093), there were still statistical or significant statistical differences. Figure 1B shows the changes in the weight of the animals recorded in the experiment. Due to the development of the disease, the average weight of the model group at the end of the experiment was significantly lower than that of the blank control group, and the average weight gain of each administration group was higher than that of the model group. improve.
图2为给药结束后，采集各组动物膝关节和踝关节，经固定、切片和H&E染色后，在显微镜下观察病理变化。图2A为膝关节，图2B为踝关节，相对于空白对照组，造模组可观察到显著的病情变化：滑膜组织异常增生、大量炎性细胞浸润和肉芽组织形成；CS12192或MTX的单药组中，可观察到药物对病情的改善，但仍可发现一定量的滑膜组织异常增生或炎性细胞浸润；而CS12192+MTX的联合用药组中，基本未发现关节炎的病理特征。Figure 2 shows that the knee joints and ankle joints of each group of animals were collected after the administration, fixed, sliced and H&E stained, and then the pathological changes were observed under a microscope. Figure 2A is the knee joint, and Figure 2B is the ankle joint. Compared with the blank control group, significant disease changes can be observed in the model: synovial tissue abnormal proliferation, massive inflammatory cell infiltration and granulation tissue formation; CS12192 or MTX alone In the drug group, the improvement of the disease by the drug can be observed, but a certain amount of synovial tissue abnormal proliferation or inflammatory cell infiltration can still be found; while in the CS12192+MTX combined drug group, the pathological features of arthritis are basically not found.
综上，MTX与JAK3/JAK1/TBK1抑制剂的联合用药在胶原诱导关节炎大鼠模型中可以取得优于单药的显著协同疗效，在动物模型中未出现明显毒副作用，安全性可接受。In summary, the combination of MTX and JAK3/JAK1/TBK1 inhibitors can achieve a significant synergistic effect that is superior to that of single drugs in collagen-induced arthritis rat models. There are no obvious side effects in animal models, and the safety is acceptable.
以上对本发明提供的包含MTX和JAK3/JAK1/TBK1抑制剂的组合及其应用进行了详细的介绍，本文中应用了具体实施例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想，包括最佳方式，并且也使得本领域的任何技术人员都能够实践本发明，包括制造和使用任何装置或系统，和实施任何结合的方法。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定，并可包括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有不是不同于权利要求文字表述的结构要素，或者如果它们包括与权利要求的文字表述无实质差异的等同结构要素，那么这些其他实施例也应包含在权利要求的范围内。The combination of MTX and JAK3/JAK1/TBK1 inhibitor provided by the present invention and its application are described in detail above. Specific examples are used in this article to illustrate the principle and implementation of the present invention. The description of the above examples is only It is used to help understand the method and the core idea of the present invention, including the best mode, and also enables any person skilled in the art to practice the present invention, including manufacturing and using any device or system, and implementing any combined method. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims, and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements that are not different from the literal expression of the claims, or if they include equivalent structural elements that are not substantially different from the literal expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims (10)

  1. 一种药物组合物，其特征在于，其包含JAK3/JAK1/TBK1抑制剂和甲氨蝶呤(MTX)或其药学上可接受的盐。A pharmaceutical composition characterized in that it comprises a JAK3/JAK1/TBK1 inhibitor and methotrexate (MTX) or a pharmaceutically acceptable salt thereof.
  2. 根据权利要求1所述的药物组合物，其特征在于，所述JAK3/JAK1/TBK1抑制剂为式(I)所示化合物或其立体异构体或其药学上可接受的盐：The pharmaceutical composition according to claim 1, wherein the JAK3/JAK1/TBK1 inhibitor is a compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021078693-appb-100001
    Figure PCTCN2021078693-appb-100001
    其中，in,
    R 1为卤素或C1-C6烷基； R 1 is halogen or C1-C6 alkyl;
    R 2为一个或多个取代基，所述取代基选自氢、羟基、氰基、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6的卤代烷基、C1-C6的烷基羰基和C1-C6烷基氨基； R 2 is one or more substituents selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkane Carbonyl and C1-C6 alkylamino;
    R 3为氢或卤素； R 3 is hydrogen or halogen;
    R 4为氢或C1-C4烷基； R 4 is hydrogen or C1-C4 alkyl;
    X为NH、O或S；X is NH, O or S;
    Y为CO或S(O) 2； Y is CO or S(O) 2 ;
    Z为共价键、CH 2或(CH 2) 2； Z is a covalent bond, CH 2 or (CH 2 ) 2 ;
    n为1到4的整数；n is an integer from 1 to 4;
    环A为苯环、吡啶环或哌啶环。Ring A is a benzene ring, a pyridine ring or a piperidine ring.
  3. 根据权利要求2所述的药物组合物，其特征在于，所述JAK3/JAK1/TBK1抑制剂为N-(3-(5-氯-2-(4-氟-3-(N-甲基丙烯酰胺基)苯基氨基)嘧啶基-4-氨基)丙基)-4-氰基苯甲酰胺，其结构式如式(II)所示：The pharmaceutical composition according to claim 2, wherein the JAK3/JAK1/TBK1 inhibitor is N-(3-(5-chloro-2-(4-fluoro-3-(N-methylpropene) Amido)phenylamino)pyrimidinyl-4-amino)propyl)-4-cyanobenzamide, the structural formula of which is shown in formula (II):
    Figure PCTCN2021078693-appb-100002
    Figure PCTCN2021078693-appb-100002
  4. 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述JAK3/JAK1/TBK1抑制剂和甲氨蝶呤或其药学上可接受的盐混合存在于所述药物组合物中或二者包含于所述组合物的不同部分，以使得JAK3/JAK1/TBK1抑制剂和甲氨蝶呤或其药学上可接受的盐可以同时或分开使用。The pharmaceutical composition according to any one of claims 1 to 4, wherein the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are mixed in the pharmaceutical composition Either or both are included in different parts of the composition, so that the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof can be used simultaneously or separately.
  5. 一种药盒，其特征在于，其包含治疗有效量的权利要求1-4中任一项所述的药物组合物。A kit, characterized in that it contains a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1-4.
  6. 根据权利要求5所述的药盒，其特征在于，所述JAK3/JAK1/TBK1抑制剂与甲氨蝶呤或其药学上可接受的盐分别是具有相同或不同规格的单位制剂。The kit according to claim 5, wherein the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are unit preparations with the same or different specifications, respectively.
  7. 根据权利要求5-6任一项所述的药盒，其特征在于，所述JAK3/JAK1/TBK1抑制剂与甲氨蝶呤或其药学上可接受的盐分别置于单独容器中提供。The kit according to any one of claims 5-6, wherein the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are provided in separate containers.
  8. 根据权利要求5-7任一项所述的药盒，其特征在于，按照JAK3/JAK1/TBK1抑制剂50mg/kg，以MTX计，甲氨蝶呤或其药学上可接受的盐0.1mg/kg～0.5mg/kg来确定所述药盒中提供的甲氨蝶呤或其药学上可接受的盐与JAK3/JAK1/TBK1抑制剂的用量。The kit according to any one of claims 5-7, wherein according to the JAK3/JAK1/TBK1 inhibitor 50mg/kg, in terms of MTX, methotrexate or its pharmaceutically acceptable salt 0.1mg/kg kg-0.5 mg/kg to determine the dosage of methotrexate or its pharmaceutically acceptable salt and JAK3/JAK1/TBK1 inhibitor provided in the kit.
  9. 根据权利要求1-4任一项所述的药物组合物或权利要求5-8任一项所述的药盒在制备治疗自身免疫性疾病的药物中的用途。Use of the pharmaceutical composition according to any one of claims 1 to 4 or the kit according to any one of claims 5-8 in the preparation of a medicament for the treatment of autoimmune diseases.
  10. 根据权利要求9所述的用途，其中所述自身免疫性疾病包括类风湿性关节炎、银屑病、克罗恩病、系统性红斑狼疮、多发性硬化症、Ⅰ型糖尿病、过敏性疾病、慢性阻塞性肺病、哮喘、白血病、淋巴瘤疾病。The use according to claim 9, wherein the autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn’s disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic diseases, Chronic obstructive pulmonary disease, asthma, leukemia, lymphoma disease.
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