Method for treating moderate to severe active rheumatoid arthritis in patient

Abstract

A method for treating moderate to severe active rheumatoid arthritis in a patient, which method comprises administering, to the patient, a therapeutically effective amount of a compound as shown in 001, a stereoisomer, racemate, tautomer, isotopic marker, prodrug thereof or a pharmaceutically acceptable salt thereof; and the patient responds poorly to methotrexate. The compound as shown in formula 001 has the below structure.

Description

Methods of treating patients with moderate to severe active rheumatoid arthritis TECHNICAL FIELD

[0001] The present invention relates to the field of medicinal chemistry, in particular, the present invention relates to a method of treating patients with moderate to severe active rheumatoid arthritis. BACKGROUND

[0002] Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease characterized by non-suppurative inflammation of joints and joint tissues, mainly manifested as synovial inflammation, eventually leading to damage of various tissues such as cartilage, ligament and tendon of joints, and multiple organs. Studies have shown that a variety of immune cells are involved in and mediate autoimmune inflammation in RA patients, including T / B lymphocytes, macrophages, neutrophils, etc. Meanwhile, a large number of studies have also proved that cytokines are directly related to RA diseases, such as interleukins (IL-1 / IL-6, etc.), TNF-α, etc. There is a need in the art to develop a new type of protein kinase, cytokine inhibitor, so as to improve the treatment effect of related diseases.

[0003] SUMMARY

[0004] To improve the above technical problems, the present invention provides a method of treating patients with moderate to severe active rheumatoid arthritis.

[0005] The present disclosure relates to a method of treating patients with moderate to severe active rheumatoid arthritis, comprising administering to the patient a therapeutically effective amount of a compound as shown in formula 001, stereoisomer, racemic isomer, tautomer, isotopically labeled, prodrug or pharmaceutically acceptable salt thereof.

[0006] The patient is poorly responsive to methotrexate;

[0007] The compound as shown in formula 001 is as follows:

[0008] The compounds of the present application are directed to interleukin-1 receptor associated kinases (IRAK). IRAK includes, but is not limited to, IRAK1 (interleukin-1 receptor associated kinase-1), IRAK2 (interleukin-1 receptor associated kinase-2), IRAK-M (interleukin-1 receptor associated kinase-M), and IRAK4 (interleukin-1 receptor associated kinase-4), or a combination thereof. It has been found that interleukin-1 receptor associated kinases IRAK, particularly IRAK4, are associated with diseases such as inflammation, cancer, sepsis, autoimmune diseases, metabolic disorders, genetic disorders, immunodeficiency disorders, disorders associated with cell death, destructive bone disorders, thrombin-induced platelet aggregation, liver diseases, and the like, and IRAK, particularly IRAK4, is a target for treating these diseases. Preferably, the inflammation includes, but is not limited to, rheumatoid, rheumatoid arthritis, systemic lupus erythematosus, conjunctivitis, osteoarthritis, chronic gouty arthritis, synovitis of the joint. The description of IRAK above is incorporated by reference in its entirety from International Patent Application No. PCT / CN2019 / 128347.

[0009] In one embodiment, the compound is a compound of Formula 001.

[0010] In one embodiment, the patient is diagnosed with rheumatoid arthritis according to the 2010 American College of Rheumatology (ACR) and / or the European League Against Rheumatism (EULAR) classification criteria.

[0011] In one embodiment, the patient with moderate to severe active rheumatoid arthritis has no less than 6 tender joints (TJC) and no less than 6 swollen joints (SJC) based on a 68 / 66 joint count. In one embodiment, the patient has an erythrocyte sedimentation rate (ESR) greater than 28 mm / h and / or a C-reactive protein (CRP) greater than 10 mg / L. In one embodiment, the patient with moderate to severe active rheumatoid arthritis has no less than 6 tender joints (TJC) and no less than 6 swollen joints (SJC) based on a 68 / 66 joint count; and the patient has an erythrocyte sedimentation rate (ESR) greater than 28 mm / h and / or a C-reactive protein (CRP) greater than 10 mg / L. In another embodiment, joints that have undergone major surgical treatment or intra-articular injection of glucocorticoids or hyaluronic acid within the previous 6 weeks are not counted in the TJC and SJC counts.

[0012] In one embodiment, the patient has been on methotrexate continuously for no less than 12 weeks prior to the first administration of the compound, and the patient has been on a stable dose of oral methotrexate for no less than 4 weeks, the stable dose being 7.5 to 20 mg / week. In one embodiment, the method further comprises administering a stable dose of methotrexate, the stable dose being 7.5 to 20 mg / week. In one embodiment, the stable dose of methotrexate is administered concurrently with the administration of the compound to the patient, the stable dose being 7.5 to 20 mg / week.

[0013] In one embodiment, the patient is not one who has or has had other inflammatory joint diseases or autoimmune diseases (such as gout, psoriatic arthritis, reactive arthritis, spondyloarthropathies, systemic lupus erythematosus, ulcerative colitis, mixed connective tissue disease, etc.) other than rheumatoid arthritis, secondary Sjogren's syndrome.

[0014] In one embodiment, the patient is not one who has used any of the following drugs or treatments prior to the administration of the compound of the present application:

[0015] a) has used potent opioid drugs (including but not limited to oxycodone, oxymorphone, fentanyl, levorphanol, buprenorphine, methadone, hydromorphone, and morphine) within 4 weeks prior to the administration of the compound of the present application;

[0016] b) has used any JAK inhibitor drugs within 4 weeks prior to the administration of the compound of the present application;

[0017] c) has used other disease-modifying antirheumatic drugs (DMARDs) or biologies other than methotrexate (MTX) prior to the administration of the compound of the present application: has used antimalarials (chloroquine, hydroxychloroquine, etc.), sulfasalazine, penicillamine, oral gold preparations, cyclosporine, azathioprine, cyclophosphamide, etanercept, etc. within 4 weeks prior to the administration of the compound of the present application; has used botanicals (including Chinese patent medicines and / or Chinese herbal medicines such as tripterygium preparations, total glucosides of paeony, sinomenine, etc.) within 4 weeks prior to the administration of the compound of the present application; has used leflunomide within 8 weeks prior to the administration of the compound of the present application; has used TNF-a inhibitors (fusion proteins) within 4 weeks, TNF-a inhibitors (monoclonal antibodies) or abatacept within 12 weeks, tocilizumab within 10 weeks, rituximab within 24 weeks, or other biologies within 5 half-lives prior to the administration of the compound of the present application;

[0018] d) has received or is scheduled to receive intra-articular, intramuscular, intravenous, trigger point or tender point, intrabursal, or intrasynovial corticosteroid therapy within 4 weeks prior to the administration of the compound of the present application and during the study.

[0019] In one embodiment, the patient is not one who has not responded to JAK inhibitor therapy for more than 8 weeks.

[0020] In one embodiment, the patient is not a patient with rheumatoid arthritis joint function activity classification IV or wheelchair or bedridden.

[0021] In one embodiment, the patient is not a patient with a history of lymphoproliferative disease, or various signs or symptoms suggesting lymphoproliferative disease, including abnormal lymph node enlargement or hepatosplenomegaly.

[0022] In one embodiment, the compound of formula 001, stereoisomer, racemic isomer, tautomer, isotopically labeled, prodrug or pharmaceutically acceptable salt thereof is administered orally, parenterally or other routes of administration. Preferably, oral or parenteral administration. In a preferred embodiment, the compound is administered orally.

[0023] In one embodiment, the compound is administered at a daily dose of 40 mg per subject. In one embodiment, the compound is administered at a daily dose of 80 mg per subject.

[0024] In one embodiment, the compound is administered once a day. In one embodiment, the compound is administered twice a day.

[0025] In one embodiment, the compound is administered continuously for 12 weeks. In one embodiment, the compound is administered continuously for 8 weeks. In one embodiment, the compound is administered continuously for 4 weeks.

[0026] International Patent Application No. PCT / CN2019 / 128347 also discloses that experiments show that the compound of the present application can effectively inhibit interleukin-1 receptor associated kinase (especially IRAK4) and cytokine TNF-a, and the compound of the present application can be applied to the treatment of various diseases related to the interleukin-1 receptor associated kinase (especially IRAK4) and cytokine TNF-a. In addition, experiments also show that the structure of the compound of the present application has good inhibitory effect on IRAK4 kinase, and has excellent selectivity to other kinases. Animal experiments show that the compound of the present application shows excellent exposure and retention time in animals; cytokine TNF-a shows excellent inhibition in LPS-induced human PBMC; and also shows excellent effect in the in vivo model of LPS-induced Balb / c female mice releasing TNF-a. The above suggests that the compound of the present application may have good effect on treating moderate to severe active rheumatoid arthritis. DETAILED DESCRIPTION

[0027] The technical solutions of the present application will be further described in detail below in combination with specific examples.

[0028] The starting materials and reagents used in the following examples are either commercially available or can be prepared by known methods unless otherwise indicated.

[0029] The terms

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this subject matter belongs.

[0031] It is understood that one of ordinary skill in the art can select substituents and substitution patterns for compounds of the application to produce compounds that are chemically stable, and that can be synthesized by techniques known in the art and as set forth below. If substituted by more than one substituent group, it is understood that the multiple groups can be on the same carbon or on different carbons, as long as a stable structure results.

[0032] As used herein, each chiral carbon atom (chiral center) in all compounds of the application can optionally be in the R or S configuration, or a mixture of R and S configurations, unless otherwise indicated.

[0033] As used herein, the terms "comprising", "including", "containing", are interchangeable and are used herein to mean including, but not limited to.

[0034] It is understood that all features described herein (including in the following claims) and / or illustrated in the drawings are intended to be combinable unless otherwise explicitly stated. In the following, the application will be described with regard to the enclosed drawings.

[0035] Active ingredient

[0036] The term "pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present application with acids, and suitable acids which form salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, picric, methanesulfonic, benzenesulfonic, benzenesulfonic, and the like; as well as aspartic acid, glutamic acid and the like. One preferred class of salts is the metal salts of the compounds of the present application with bases, and suitable bases which form salts include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate and the like; ammonia, triethylamine, diethylamine and the like.

[0037] The compounds of formula 001 according to the present application can be converted into their pharmaceutically acceptable salts by conventional methods, for example, a solution of the corresponding acid can be added to a solution of the above-mentioned compounds, and the salt formed can be isolated by removing the solvent after complete salification.

[0038] Therapeutic methods

[0039] The present application also provides a method of treating rheumatoid arthritis using the compounds of the present application.

[0040] In the present application, the term "treatment" refers to any treatment of a disease in a mammal, including, but not limited to: (a) inhibiting the disease, i.e., slowing or arresting the development of clinical symptoms; and / or (b) relieving the disease, i.e., causing the regression of clinical symptoms, and / or (c) alleviating or eliminating the disease and / or its attendant symptoms.

[0041] Methods of administration

[0042] In the present application, "therapeutically effective amount" refers to an amount that produces a functional or a biological activity and is acceptable to a human and / or an animal. It should be understood by those skilled in the art that the "therapeutically effective amount" can vary depending on the form of the pharmaceutical composition, the route of administration, the adjuvants used in the drug, the severity of the disease, and the use of other drugs in combination, and the like.

[0043] Examples

[0044] It should be understood that the following examples are merely illustrative and explanatory in nature and are not to be construed as limiting the scope of the present application.

[0045] Unless otherwise indicated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods. Examples of the following preparation methods can be found in Chinese Patent Application No. 202210179789.6, which is incorporated by reference herein in its entirety.

[0046] Example 1

[0047] Preparation of compound

[0048] 1. Synthesis of compound 3

[0049] 15℃, to a solution of compound 1 (50 g) in dichloromethane (500 mL) was added DMAP (42.5 g), compound 2 (63.4 g), and triethylamine (63.9 g) sequentially, and stirred at 25℃ for 18 hours. To the reaction solution was added dichloromethane (200 mL) and washed with water (300 mL*2), 1M dilute hydrochloric acid (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3 (98 g, yield: 99%).

[0050] 2. Synthesis of compound 4

[0051] 15℃, to a solution of compound 3 (50 g) in tetrahydrofuran (300 mL) was added 1M dilute hydrochloric acid (300 mL) and stirred at 25℃ for 20 hours. Cooled to 0℃, adjusted to PH = 9 with 1M sodium hydroxide solution, extracted with ethyl acetate (200 mL*3), and the extract was washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with petroleum ether (150 mL) to give compound 4 (39 g, yield 91%).

[0052] 3. Synthesis of compound 5 & 6

[0053] -40℃, to a solution of methyl magnesium bromide (85.8 mL) in tetrahydrofuran (500 mL) was added a solution of compound 4 (34.5 g) in tetrahydrofuran (200 mL) dropwise, and stirred at -40℃ for 4 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (500 mL*3), and the extract was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 5 (4.3 g, yield 10%), compound 6 (7.0 g, yield 17%) and mixture 12 g.

[0054] Compound 5

[0055] 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.52-4.41 (m, 1H), 2.44 (s, 3H), 1.95-1.80 (m, 2H), 1.77-1.61 (m, 4H), 1.46-1.35 (m, 2H), 1.19 (s, 3H).

[0056] Compound 6

[0057] 1H NMR (400 MHz, CDC13): δ 7.79 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.74-4.64 (m, 1H), 2.44 (s, 3H), 1.92-1.79 (m, 2H), 1.77-1.62 (m, 4H), 1.49-1.38 (m, 2H), 1.23 (s, 3H).

[0058] 4. Synthesis of compound 8

[0059] To the solution of compound 7 (2.0 g) in concentrated sulfuric acid (12 mL, 98%) was added dropwise a mixed solution of nitric acid (1.6 mL, 70%) in concentrated sulfuric acid (1.6 mL, 98%) at -15 °C. After the addition, the mixture was stirred at -15 °C for 2 h. The reaction solution was slowly poured into ice water and stirred for 5 min. The solid was collected by suction filtration, washed with water, and dried under reduced pressure to give compound 8 (2.5 g, yield: 97%).

[0060] 5. Synthesis of compound 9

[0061] To the solution of compound 8 (2.0 g) in DMF (20 mL) was added hydrazine hydrate (2.4 mL, 98%) at room temperature. After the addition, the mixture was heated to 120 °C and stirred for 16 h. The mixture was slowly poured into ice water and stirred. The solid was collected by suction filtration, washed with water, and concentrated under reduced pressure to give compound 9 (1.3 g, yield: 67%).

[0062] 6. Synthesis of compound 10

[0063] Compound 9 (12.4 g) and palladium on carbon (7 g, 10%) were sequentially added to 400 mL of ethyl acetate at 15 °C. After the addition, the mixture was stirred under hydrogen gas protection at 15 °C for 18 h. The palladium on carbon was filtered off from the reaction solution, and the filtrate was concentrated and evaporated to dryness to give compound 10 (10.4 g, yield 99%).

[0064] 7. Synthesis of compound 12

[0065] EDCI.HC1 (2.6 g) was added to the solution of compound 10 (1.5 g) and compound 11 (1.4 g) in Py (15 mL) at 25 °C. The reaction solution was stirred at 25 °C for 16 h. The reaction solution was concentrated and evaporated to dryness. The residue was slurried with MeOH / H20 = 20 mL / 20 mL to give compound 12 (1.3 g, yield 48%).

[0066] 8. Synthesis of compound 001, i.e., 2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide

[0067] 25 °C, cesium carbonate (985 mg) was added to a solution of compound 12 (300 mg) and compound 5 (344 mg) in 5 mL of DMF, the reaction was stirred at 90 °C for 16 h. The reaction was added to 30 mL of water, extracted with ethyl acetate (10 mL*3), the organic phase was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography column (CH3CN:H2O (0.1% NH4HCO3) = 15-45%, UV: 214 nm, flow rate: 15 ml / min) to give compound 001 (70 mg, yield 17%).

[0068] 1H NMR (400 MHz, DMSO-d6): δ 14.16 (s, 1H), 8.78 (s, 1H), 8.34 (s, 1H), 8.32-8.30 (m, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 4.45 (s, 1H), 4.43-4.40 (m, 1H), 3.95 (s, 3H), 2.53 (s, 3H), 2.09-2.00 (m, 4H), 1.68-1.58 (m, 4H), 1.22 (s, 3H). LCMS: Rt = 3.646 min, [M+H]+= 411.1.

[0069] Example 2 - Use of the compounds of the application for the treatment of moderate to severe active rheumatoid arthritis

[0070] The following is a randomized, double-blind, placebo and positive control, parallel design phase II clinical trial to evaluate the efficacy and safety of compound 001 of the application in patients with moderate to severe active rheumatoid arthritis who have an inadequate response to methotrexate.

[0071] The above has described specific embodiments of the present application. It needs to be understood that the present application is not limited by the above embodiments, and the above embodiments and descriptions in the specification are only for illustrating the principles of the present application. Those skilled in the art can make various non-essential changes and improvements to the present application without departing from the concept of the present application, and these all fall within the scope of the present application.

Claims

1. A method of treating moderate to severe active rheumatoid arthritis in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula 001, a stereoisomer, a racemic isomer, a tautomer, an isotopically-labeled material, a prodrug, or a pharmaceutically acceptable salt thereof; said patient is not responding to methotrexate; 2. The method of claim 1, said patient with moderate to severe active rheumatoid arthritis has no less than 6 tender joints (TJC) and no less than 6 swollen joints (SJC) based on a 68 / 66 joint count; and, The compound of formula 001 is as follows: said patient has an erythrocyte sedimentation rate (ESR) greater than 28 mm / h and / or a C-reactive protein (CRP) greater than 10 mg / L.

3. The method of claim 1 or 2, said patient has been continuously using methotrexate for no less than 12 weeks prior to the first administration of the compound, and said patient has been orally administered a stable dose of methotrexate for no less than 4 weeks, said stable dose is 7.5 to 20 mg / week.

4. The method of claim 3, further comprising administering a stable dose of methotrexate, said stable dose is 7.5 to 20 mg / week.

5. The method of claims 1-4, wherein the compound is administered orally.

6. The method of claims 1-5, wherein the compound is administered at a daily dose of 40 mg / day or 80 mg / day.

7. The method of claims 1-6, wherein the compound is administered once a day or twice a day.

8. The method of claims 1-7, wherein the compound is administered continuously for 12 weeks.

9. The method of claims 1-8, wherein the compound is a compound of Formula 001. ​

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