CN111297866B - Pharmaceutical composition containing JAK3/JAK1/TBK1 inhibitor and methotrexate and application thereof - Google Patents

Pharmaceutical composition containing JAK3/JAK1/TBK1 inhibitor and methotrexate and application thereof Download PDF

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CN111297866B
CN111297866B CN202010156766.4A CN202010156766A CN111297866B CN 111297866 B CN111297866 B CN 111297866B CN 202010156766 A CN202010156766 A CN 202010156766A CN 111297866 B CN111297866 B CN 111297866B
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jak1
jak3
methotrexate
pharmaceutically acceptable
pharmaceutical composition
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CN111297866A (en
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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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Chengdu Weixin Pharmaceutical Co ltd
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Shenzhen Chipscreen Biosciences Co Ltd
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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
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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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract

The invention provides a pharmaceutical composition containing a JAK3/JAK1/TBK1 inhibitor and methotrexate or pharmaceutically acceptable salts thereof and application thereof, and particularly relates to application of the JAK3/JAK1/TBK1 inhibitor and methotrexate in treatment of autoimmune diseases, particularly rheumatoid arthritis. The combined medication scheme provided by the invention increases the curative effect through the synergistic effect among the medicines, thereby reducing the dosage of a single medicine, reducing the toxicity, reducing the medicine tolerance of a patient and reducing possible adverse reactions, and is expected to provide a new and better medication selection for autoimmune diseases including RA.

Description

Pharmaceutical composition containing JAK3/JAK1/TBK1 inhibitor and methotrexate and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing a JAK3/JAK1/TBK1 inhibitor and methotrexate, and application and a using method thereof in treatment of autoimmune diseases, particularly rheumatoid arthritis.
Background
The autoimmune disease refers to a disease caused by the damage of self tissues due to the immune reaction of the body to self antigens, and common autoimmune diseases comprise rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic diseases, chronic obstructive pulmonary disease, asthma, leukemia, lymphoma and the like.
Rheumatoid Arthritis (RA) is a chronic, autoimmune disease characterized by polyarticular, symmetrical, aggressive synovial inflammation of the joints 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, common women are more than men, and the total morbidity in China is 0.32 to 0.36 percent.
The data indicate that, if not promptly treated, bone destruction occurs in about 75% of patients within 2 years of disease, resulting in joint stiffness, deformity, and severely impaired function, which may lead to loss of labor or even disability. This will lead to a reduction in the patient's living standard, a reduction in the expected life span, and a huge economic burden on the patient himself, the family and the society.
Methotrexate (MTX) has the following structure, with its chemical name: s- (+) -N-2- [4- [ [ (2, 4-diamino-6 pteridinyl) methyl ] methylamino ] benzoyl ] glutamic acid.
Figure BDA0002404338730000011
MTX is a classic disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA, recommended by various world college of rheumatology guidelines as the first choice for early RA. As a folate reductase inhibitor, MTX exerts the effects of alleviating disease symptoms and slowing the progression of joint damage by inhibiting the synthesis of thymine to reduce chemotaxis of neutrophils and inhibit the release of inflammatory cytokines. Safety of long-term use of drugs requires special attention, since RA cannot be cured yet. Clinical studies have confirmed that the toxic and side effects of long-term use of MTX are mainly gastrointestinal reactions, bone marrow suppression, liver injury, kidney injury, and the like.
The JAKs (janus kinases) are a small family of the intracytoplasmic non-receptor tyrosine protein kinase superfamily, including four known members of JAK1, JAK2, JAK3 and TYK 2. The JAKs function by interacting with tyrosine kinase-associated receptors and transcription factor signal transducers and transcriptional activators (STATs): tyrosine kinase related receptors on cell membranes have no kinase activity per se, but the intracellular segments have binding sites for JAKs, and after the receptors are combined with ligands, tyrosine residues of various target proteins are phosphorylated through activation of the JAKs combined with the receptors so as to realize signal transmission from the extracellular part to the intracellular part; after the JAKs are activated, tyrosine residues on a catalytic receptor are subjected to phosphorylation modification, then the phosphorylation modification and the surrounding amino acid sequences form a 'docking site', STAT proteins are recruited to the 'docking site', finally, the JAKs catalyze the STAT proteins to be subjected to phosphorylation modification, and the activated STAT proteins enter a cell nucleus in a dimer form to be combined with target genes so as to regulate the transcription of the genes.
JAK3 is specifically expressed in hematopoietic cells and regulates cell signaling by binding to the gamma-co-chain (yc) of cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK1 binds to 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 yc, among others. In the JAKs family, JAK1 and JAK3 are thought to be more involved in immune regulation, and abnormal activation of both plays a key role in the etiology and course of various autoimmune diseases (including but not limited to lymphoma, arthritis, psoriasis, crohn's disease, lupus erythematosus, etc.), and therefore, the development of inhibitors of JAK1 and JAK3 has been a hotspot in the therapeutic field of RA and the like.
TBK1(TANK binding kinase 1) is serine/threonine kinase, which activates its substrates IRF3 and IRF7 transcription factors by direct phosphorylation of specific sites, induces them to be positioned to cell nucleus to promote the transcription of type I IFN gene, and excessive type I IFN expression may cause body damage. In addition, RANKL/nfkb is considered to be one of the most important signaling pathways for osteoclast differentiation, and an increase in soluble RANKL level in synovial fluid of RA patients leads to abnormal activation of nfkb, which leads to an increase in the number of activated osteoclasts, bone resorption, and bone destruction risk. It has been shown that activation of NF κ B is enhanced by kinase activity of TBK1, while RANKL-induced osteoclast differentiation is inhibited by inhibition of TBK1 activity.
The compound shown in the formula (I) is a new molecular entity drug which is exclusively discovered by Shenzhen micro-core biotechnology limited company, and has a novel mechanism. Researches of patents (CN105399685A) and literatures (Shan S., et al.2019, Intimmunopharmacol.77: 105914) show that the compound shown as the formula (I) is a JAK3/JAK1/TBK1 selective inhibitor, and the activation of STATs and IRF3 is reduced through the inhibition of targets, so that CD4 is inhibited+Activation of T cells, function of helper T cells 17, expression of type I Interferon (IFN), and osteoclast differentiation induced by receptor activator of nuclear factor kappa B ligand (RANKL), achieving the therapeutic effect of alleviating RA.
Taken together, MTX and JAK3/JAK1/TBK1 inhibitors are differentiated in the mechanism of alleviating RA. At present, the research of jointly applying the two medicines to the treatment of RA and other autoimmune diseases is not available, the invention combines the two medicines with different mechanisms, and the invention unexpectedly finds that the two medicines have obvious synergistic curative effect on RA, and can provide new and better medication options for reducing single medicine dosage, reducing medicine tolerance of patients and reducing possible adverse reactions.
Disclosure of Invention
The inventor unexpectedly discovers through research that: the MTX or the pharmaceutically acceptable salt thereof is combined with JAK3/JAK1/TBK1 inhibitors, and the compound has synergistic curative effect on RA and other autoimmune diseases.
Therefore, the first aspect of the invention provides a pharmaceutical composition containing MTX or a pharmaceutically acceptable salt thereof and JAK3/JAK1/TBK1 inhibitor, which can effectively relieve symptoms of autoimmune diseases including RA and has a treatment effect remarkably superior to that of any single component.
Inhibitors of JAK3/JAK1/TBK1 for use in the present invention include the compounds described in CN105399685A, the entire contents of which are incorporated herein by reference.
Specifically, the compound in CN105399685A comprises a compound shown as a formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,
Figure BDA0002404338730000031
wherein the content of the first and second substances,
R1is halogen or C1-C6 alkyl;
R2is one or more substituents selected from the group consisting of hydrogen, hydroxy, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylcarbonyl, and C1-C6 alkylamino;
R3is hydrogen or halogen;
R4is hydrogen or C1-C4 alkyl;
x is NH, O or S;
y is CO or S (O)2；
Z is a covalent bond, CH2Or (CH)2)2；
n is an integer of 1 to 4;
ring A is a benzene ring, a pyridine ring or a piperidine ring.
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 having the formula (II):
Figure BDA0002404338730000041
a pharmaceutical composition according to the invention comprising a JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof.
The weight ratio of the MTX or pharmaceutically acceptable salt thereof (as MTX) to the JAK3/JAK1/TBK1 inhibitor is 1: 100-1: 500.
the effective dose of the MTX or the pharmaceutical salt thereof (calculated by MTX) is 0.1 mg/kg-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 to 80 mg/kg.
According to the pharmaceutical composition of the invention, the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof may be administered separately, simultaneously or sequentially.
According to the invention, wherein halogen means fluorine, chlorine, bromine, iodine; preferably fluorine, chlorine, bromine; most preferred is chlorine.
The alkyl refers to a saturated branched or branched hydrocarbon group; in particular, C1-C4 alkyl specifically means 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 are not described herein again. The alkyl groups in the compounds of the present invention may be optionally substituted or unsubstituted, and the substituents may include alkyl, halogen, alkoxy, hydrocarbyl, hydroxy, and the like.
The "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" of the present invention refers to an acid addition salt prepared by reacting a compound represented by the formula (I) or MTX with a pharmaceutically acceptable acid, or a salt formed by reacting a compound having an acid group with a pharmaceutically acceptable base. Wherein, 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 water or ammonium bicarbonate, etc.
The stereoisomers include conformational isomers, enantiomers and diastereomers.
The pharmaceutical composition of the invention may further comprise pharmaceutically acceptable excipients.
The pharmaceutical composition according to the present invention can be prepared into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like.
For shaping the pharmaceutical composition in tablet form, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerin tristearate, coconut oil, hydrogenated oil and the like; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, etc.; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. If desired, the tablets may also be provided as sugar-coated tablets, enteric-coated tablets, film-coated tablets (e.g., gelatin-coated tablets), bilayer-coated tablets, and multilayer tablets using conventional coating materials.
For shaping the pharmaceutical composition in the form of a pill, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like; disintegrating agents, such as agar and kelp powder.
For the preparation of pharmaceutical compositions in the form of injection solutions, the solutions and suspensions may be sterilized and, preferably, suitable amounts of sodium chloride, glucose or glycerol, etc., may be added to prepare an injection solution which is isotonic with blood. In the preparation of injection, any carrier commonly used in the art may 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, conventional lytic agents, buffers, analgesics, and the like may be added.
The content of the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and generally can be 1 to 45% by mass alone, preferably 1 to 30% by mass.
Further, the present invention provides a kit comprising the above pharmaceutical composition.
In the kit of the present invention, the MTX and JAK3/JAK1/TBK1 inhibitors are unit preparations having the same or different specifications, and the preparation is not particularly limited and may be any preparation, and the dosage form described in the above-mentioned present invention is particularly preferable.
According to the present invention, the MTX and JAK3/JAK1/TBK1 inhibitors are preferably provided separately in separate containers.
The weight ratio of the MTX to the JAK3/JAK1/TBK1 inhibitor is 1: 100-1: 500.
wherein the MTX is administered simultaneously, separately or sequentially with a JAK3/JAK1/TBK1 inhibitor.
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating autoimmune diseases.
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 diseases, etc.
Finally, the present invention provides a method of treating an autoimmune disease comprising the step of administering to a patient in need thereof a therapeutically effective amount of the above pharmaceutical composition or kit.
The pharmaceutical compositions and kits of the present invention may be prepared by methods conventional in the art.
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 diseases, etc.
Advantageous effects
The invention relates to a pharmaceutical composition containing a JAK3/JAK1/TBK1 inhibitor and methotrexate, which has a synergistic effect on autoimmune diseases including RA.
The invention also relates to kits comprising the pharmaceutical compositions such that the JAK3/JAK1/TBK1 inhibitor and methotrexate may be administered separately or simultaneously.
The pharmaceutical composition or the kit according to the invention can reduce the dosage of a single drug, thereby reducing toxicity, reducing drug tolerance of patients and reducing possible adverse reactions, and provides a new and better drug choice for autoimmune diseases.
Drawings
FIG. 1 shows the efficacy of MTX and JAK3/JAK1/TBK1 inhibitors in a rat model of CIA.
FIG. 2H & E staining and microscopic observation of sections of the knee joint (FIG. 2A) and ankle joint (FIG. 2B) of CIA rats after the end of dosing.
Detailed Description
The invention discloses a combination of MTX or pharmaceutically acceptable salts thereof and JAK3/JAK1/TBK1 inhibitors and application thereof in treating autoimmune diseases including RA, and a person skilled in the art can use the contents to realize the combination by appropriately improving process parameters. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the present invention has been described in terms of preferred embodiments of the uses and pharmaceutical compositions described herein, it will be apparent to those skilled in the art that variations and modifications can be made in the uses and pharmaceutical compositions described herein, or in the practice or use of the techniques described herein, as appropriate, without departing from the spirit and scope of the invention.
Experimental part
Experimental materials:
three month old male Sprague Dawley (SD) rats were purchased from the center of medical laboratory animals, Guangdong province.
Bovine type II collagen and incomplete Freund's adjuvant were purchased from Chondrex corporation.
The JAK3/JAK1/TBK1 inhibitor (N- (3- (5-chloro-2- (4-fluoro-3- (N-methylacrylamido) phenylamino) pyrimidinyl-4-amino) propyl) -4-cyanobenzamide, code number CS12192) was synthesized by Shenzhen Microcore Biotech GmbH; methotrexate is purchased from Shanghai-derived leaf Biotech, Inc.
Tissue fixative and EDTA decalcification solutions were purchased from Salarbio. Hematoxylin and eosin staining solutions were purchased from jin Qiao biotechnology, Inc. of Zhongshan, Beijing.
The experimental method comprises the following steps:
bovine type II collagen is added into an equal volume of incomplete Freund's adjuvant for emulsification, a Collagen Induced Arthritis (CIA) model of SD rats is established by tail root injection, 0.2mL is injected into each rat on the first immunization day (marked as day 0), and 0.1mL is injected into each rat on the second immunization day (day 7). Generally, swelling starts to occur on day 10, the peak of the disease occurs on days 13-14, and swelling starts to decline and joint deformation starts on day 21.
The test animals were numbered and divided into 5 groups of 8 animals each, including a normal control group, a model group, an MTX group, a CS12192 group, and an MTX + CS12192 group. Gavage administration was started on the day of the second immunization, wherein the MTX group was administered 0.2mg MTX per kg body weight per day; CS12192 group administered 40mg of CS12192 per kg of body weight 2 times a day; the MTX + CS12192 group was administered 0.2mg MTX1 times per kg body weight per day and 40mg CS12192 times per kg body weight 2 times per day.
Scoring was started on the day of the second immunization, using a 16 point scale: four limbs before and after, 4 points per limb: severe swelling of joints or joint deformity divided by 4; the severe red swelling of the joint is 3 points; the moderate red swelling of the joint is 2 points; red spots or slight swelling of the joints were scored as 1; the grade of the powder was 0.
After the administration and scoring, the front and rear paws of each animal were collected, fixed in a tissue fixing solution for 24 hours, decalcified for 3 days, embedded in paraffin and sectioned, and the tissues were cut into 5 μm thick pieces. And (4) carrying out H & E staining after the section is dewaxed, and observing pathological changes of knee joint and ankle joint tissues of each tested animal under a microscope, wherein the pathological changes comprise whether synovial tissues are proliferated, whether inflammatory cells are infiltrated and whether granulation tissues are formed.
The experimental results are as follows:
at the end of 19 days after the start of the experiment, as shown in fig. 1A, the average inflammation score of the model group animals at the end of the experiment was 8.6, which is significantly different from that of the blank control group (P ═ 0.00014), indicating that the CIA pathological model was successfully constructed. By the end of the experiment, the mean inflammation scores of the two monotherapies MTX and CS12192 were 4.14 and 4, respectively, and the P values were 0.027 and 0.018, respectively, compared to the model group, with statistical differences, indicating that both monotherapies at the above doses have a certain therapeutic effect in CIA rats. MTX + CS12192 is a combined medicine group, the average inflammation score at the end of the experiment is 1.86, and compared with a model group, the P value is 0.00010, which shows that the combined medicine has significant statistical significance on the improvement of the CIA disease condition; the combined drug group still has statistical or significant statistical differences compared with the two single drug groups MTX and CS12192 (P values of 0.020 and 0.0093, respectively). FIG. 1B shows the body weight changes of animals recorded in the experiment, and the average body weight of the model group at the end of the experiment is significantly lower than that of the blank control group due to the disease development, and the average body weight increase of each administration group is improved compared with that of the model group.
FIG. 2 shows that after the administration, the knee joints and ankle joints of each group of animals were collected, fixed, sectioned and H & E stained, and then pathological changes were observed under a microscope. In fig. 2A, the knee joint and in fig. 2B, the ankle joint were observed as distinct disease changes in the model group relative to the placebo group: abnormal synovial tissue proliferation, massive inflammatory cell infiltration and granulation tissue formation; in the single medicine group of CS12192 or MTX, the improvement of the disease condition by the medicine can be observed, but a certain amount of abnormal hyperplasia of synovial tissue or inflammatory cell infiltration can be still found; in the combined medicine group of CS12192+ MTX, no pathological features of arthritis were found.
In conclusion, the combination of MTX and JAK3/JAK1/TBK1 inhibitor can obtain a remarkable synergistic curative effect superior to that of a single drug in a collagen-induced arthritis rat model, has no obvious toxic or side effect in the animal model, and is acceptable in safety.
The combinations provided by the present invention and including MTX and JAK3/JAK1/TBK1 inhibitors and uses thereof are described in detail above, and the principles and embodiments of the present invention are described herein using specific examples, which are included to help understand the methods of the present invention and their core concepts, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The scope of the invention is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims (8)

1. A pharmaceutical composition for the treatment of rheumatoid arthritis, comprising a JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof; the JAK3/JAK1/TBK1 inhibitorIs N- (3- (5-chloro-2- (4-fluoro-3- (N-methylacrylamido) phenylamino) pyrimidinyl-4-amino) propyl) -4-cyanobenzamide or pharmaceutically acceptable salt thereof, and the structural formula is shown as (A)
Figure DEST_PATH_IMAGE001
) Shown in the figure:
Figure 161469DEST_PATH_IMAGE002
formula (A), (B) and
Figure 923364DEST_PATH_IMAGE001
）。
2. the pharmaceutical composition for the treatment of rheumatoid arthritis according to claim 1, wherein said JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are present in admixture in said pharmaceutical composition or are both contained in different parts of said composition, such that JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof can be used simultaneously or separately.
3. A kit for the treatment of rheumatoid arthritis, comprising a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1-2.
4. The kit for treating rheumatoid arthritis according to claim 3, wherein said JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are unit preparations having the same or different specifications, respectively.
5. The kit for treating rheumatoid arthritis according to any one of claims 3-4, wherein said JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are provided separately in separate containers.
6. The kit for treating rheumatoid arthritis according to any one of claims 3 to 4, wherein the amount of the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof provided in the kit is determined in accordance with 50 mg/kg of the JAK3/JAK1/TBK1 inhibitor and 0.1mg/kg to 0.5mg/kg of methotrexate or a pharmaceutically acceptable salt thereof.
7. Use of a pharmaceutical composition according to any one of claims 1-2 in the manufacture of a medicament for the treatment of rheumatoid arthritis.
8. Use of a kit according to any one of claims 3 to 6 in the manufacture of a medicament for the treatment of rheumatoid arthritis.
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CN112675177A (en) * 2020-12-28 2021-04-20 南方医科大学珠江医院 Pharmaceutical composition containing inhibitor and methotrexate and preparation method and application thereof
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