Therapeutic agent for rheumatoid arthritis

Abstract

Provided is a highly safe therapeutic agent for rheumatoid arthritis that produces effects after a short administration period, exhibits strong efficacy, and is effective for human rheumatoid arthritis.　The therapeutic agent for rheumatoid arthritis contains (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3, 4-d]pyrimidine-2-yl)amino)pyridine-3-yl)piperazine-2-one or a pharmaceutically acceptable salt thereof.

Description

Rheumatoid arthritis treatment

[0001] The present invention relates to a therapeutic agent for rheumatoid arthritis, which contains, as an active ingredient, (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one or a pharmaceutically acceptable salt thereof.

[0002] Rheumatoid arthritis (RA) is a chronic inflammatory systemic autoimmune disease of unknown etiology. It is characterized by symmetric synovitis, which leads to cartilage damage and joint destruction, and may be accompanied by numerous extra-articular manifestations. RA is generally a progressive disease, and long-term patients experience arthritis, joint destruction, physical disability, reduced life expectancy, and worsening symptoms. The disease can develop at any age, with the highest incidence occurring in people in their 40s to 60s. Anti-rheumatic drugs, also known as disease-modifying antirheumatic drugs (DMARDs), do not suppress the inflammation itself, but rather control the activity of RA by modifying the immune abnormalities associated with RA. DMARDs are the first-line treatment for patients with RA. Known DMARDs include methotrexate and salazosulfapyridine, which are administered after a diagnosis of rheumatoid arthritis, as well as biological agents such as TNF inhibitors and IL-6 inhibitors, which are administered to patients who do not respond well to these drugs. However, even with the use of these DMARDs, less than 40% of patients achieve remission of clinical symptoms, and the progression of joint destruction cannot be completely prevented. Furthermore, treatment that improves subjective symptoms, including pain, is also important for rheumatoid arthritis patients, and there is a need for drugs that reduce disease activity and pain from the early stages of administration of investigational drugs.

[0003] It is also known that Janus kinase inhibitors (JAK inhibitors) such as filgotinib are effective against rheumatoid arthritis (Non-Patent Document 1). However, JAK inhibitors have the problem that they require long-term administration to exhibit efficacy, and their efficacy is not sufficient.

[0004] Patent Document 1 discloses many compounds having CDK4 / 6 inhibitory activity, and describes that they are useful as preventive or therapeutic drugs for, for example, rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer. However, there is no specific description regarding the therapeutic effect of these compounds on rheumatoid arthritis in humans.

[0005] Ann Rheum Dis 2017; 76;1009-1019

[0006] International Publication No. 2016 / 194831

[0007] An object of the present invention is to provide a highly safe therapeutic agent for rheumatoid arthritis that requires a short administration period until the effect is exhibited, has a high efficacy, and is effective against rheumatoid arthritis in humans.

[0008] As a result of extensive research, the present inventors have found that a composition containing a certain amount of (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one (hereinafter referred to as "Compound 1"), one of the compounds having CDK4 / 6 inhibitory activity described in Patent Document 1, exhibits excellent clinical efficacy against human rheumatoid arthritis, is effective with short-term administration, and is safe, and have completed the present invention.

[0009] That is, the present invention encompasses, for example, the following concepts. [Item 1-1] A therapeutic agent for rheumatoid arthritis containing (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one or a pharmaceutically acceptable salt thereof. [Item 1-2] Use of (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for rheumatoid arthritis. [Item 1-3] A method for treating rheumatoid arthritis, comprising administering (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one or a pharmaceutically acceptable salt thereof to a subject suffering from rheumatoid arthritis. [Item 1-4] (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one or a pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis. [Item 2] The therapeutic agent for rheumatoid arthritis according to Item 1-1, the use according to Item 1-2, the method according to Item 1-3, or the compound according to Item 1-4, wherein the daily dosage of the compound is 10 to 200 mg. [Item 3] The therapeutic drug for rheumatoid arthritis according to Item 1-1, the use according to Item 1-2, the method according to Item 1-3, or the compound according to Item 1-4, wherein the daily dose of the compound is 30 to 125 mg. [Item 4] The therapeutic drug for rheumatoid arthritis according to any one of Items 1-1 to 3, the use according to any one of Items 1-2 to 3, the method according to any one of Items 1-3 to 3, or the compound according to any one of Items 1-4 to 3, which is administered once a day. [Item 5] The therapeutic drug for rheumatoid arthritis according to any one of Items 1-1 to 4, the use according to any one of Items 1-2 to 4, the method according to any one of Items 1-3 to 4, or the compound according to any one of Items 1-4 to 4, which is used in combination with another therapeutic drug for rheumatoid arthritis.[Item 6] The therapeutic drug, use, method, or compound for treating rheumatoid arthritis according to Item 5, wherein the "other therapeutic drug for rheumatoid arthritis" is a disease-modifying antirheumatic drug (DMARD). [Item 7] The therapeutic drug, use, method, or compound for treating rheumatoid arthritis according to Item 5, wherein the "other therapeutic drug for rheumatoid arthritis" is a biological preparation. [Item 8] The therapeutic drug, use, method, or compound for treating rheumatoid arthritis according to Item 5, wherein the "other therapeutic drug for rheumatoid arthritis" is a JAK inhibitor.

[0010] According to the present invention, a highly safe therapeutic drug for rheumatoid arthritis is provided, which has been shown to be clinically effective against rheumatoid arthritis in humans and is effective after short-term administration.

[0011] In the examples, the percentage of subjects who showed improvement in ACR20 is shown. The percentage for each administration group is shown on the horizontal axis as the vertical axis. In the examples, the percentage of subjects who showed improvement in DAS28-CRP is shown. The percentage for each administration group is shown on the horizontal axis as the vertical axis. In the examples, the VAS scale pain score is shown. The rate of change from baseline (day 1 of administration) in the VAS scale pain score for each administration group is shown on the horizontal axis as the vertical axis. In the examples of the present invention, the TJC is shown. The rate of change from baseline (day 1 of administration) in the TJC for each administration group is shown on the horizontal axis as the vertical axis.

[0012] Hereinafter, embodiments of the present invention will be described in detail.

[0013] The abbreviations used in the text represent the following: ACR20: An evaluation standard established by the American College of Rheumatology, which is the percentage of cases in which both TJC and SJC improved by 20% or more and three or more of the other five evaluation items improved by 20% or more among the seven items in the ACR Core Set (TJC, SJC, patient's pain assessment (by VAS; VAS scale pain score), PGA (by VAS), EGA (by VAS), patient's physical function assessment (by HAQ), and CRP). TJC: tender joint count SJC: swollen joint count VAS: evaluation score based on a visual analog scale PGA: patient's global assessment of disease activity EGA: evaluator global assessment of disease activity CRP: C-reactive protein (acute phase reactant) HAQ: Health Assessment Questionnaire Assessment Questionnaire) DAS28: Disease Activity Score for 28 specific joints. When CRP (mg / dL) is used (DAS28-CRP), the calculation formula is defined as follows: DAS28-CRP = 0.56 x √(TJC) + 0.28 x √(SJC) + 0.36 x Ln((CRP) x 10 + 1) + 0.14 x (PGA) (1-10 scale) + 0.96 (Note: Ln is the natural logarithm).

[0014] The present invention relates to a therapeutic agent for treating rheumatoid arthritis, which contains (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one (Compound 1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] In the present invention, Compound 1 can be converted into a pharmaceutically acceptable salt thereof, for example, inorganic acid salts such as hydrochloride and phosphate, organic acid salts such as acetic acid and fumaric acid, amino acid salts such as lysine and aspartic acid, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts with organic bases such as ethylamine and piperidine, and ammonium salts.

[0016] In the present invention, the pharmaceutically acceptable salts of Compound 1 also include solvates with pharmaceutically acceptable solvents such as water and ethanol.

[0017] Compound 1 of the present invention or a pharmaceutically acceptable salt thereof can be produced by known methods (for example, the method described in Patent Document 1).

[0018] The dose of Compound 1 or a pharmaceutically acceptable salt thereof when used as a therapeutic agent for rheumatoid arthritis of the present invention is 10 to 200 mg per day, preferably 20 to 180 mg, more preferably 30 to 125 mg, even more preferably 60 to 90 mg, and particularly preferably 75 mg.

[0019] The therapeutic drug for rheumatoid arthritis of the present invention is used in various dosage forms, such as tablets, pills, granules, powders, fine granules, dry syrup, and capsules.

[0020] The therapeutic agent for rheumatoid arthritis of the present invention may contain additives such as excipients and binders that are commonly used in the above dosage forms, in addition to Compound 1. In the case of tablets, the formulation may contain an excipient such as lactose, a binder such as hydroxypropylmethylcellulose, a disintegrant such as sodium starch glycolate, and a lubricant such as magnesium stearate.

[0021] The therapeutic drug for rheumatoid arthritis of the present invention can be prepared according to a method known to those skilled in the art. When the drug is made into a tablet, Compound 1, an excipient, and a binder are wet granulated using purified water or the like, and then mixed with a disintegrant and a lubricant, followed by tableting.

[0022] The therapeutic agent for rheumatoid arthritis of the present invention is preferably administered orally.

[0023] The therapeutic agent for rheumatoid arthritis of the present invention can be used in combination with existing pharmaceuticals used in the treatment of rheumatoid arthritis, such as by simultaneous administration, sequential administration, or administration with a certain time interval. Examples of existing pharmaceuticals used in the treatment of rheumatoid arthritis include nonsteroidal anti-inflammatory drugs such as loxoprofen, steroids such as prednisolone, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and salazosulfapyridine, biological agents such as infliximab, adalimumab, tocilizumab, etanercept, and abatacept, and JAK inhibitors such as tofacitinib, baricitinib, and filgotinib. Among the various biological agents, infliximab, adalimumab, etanercept, and the like are classified as TNF inhibitors. Furthermore, tocilizumab and the like are classified as IL-6 inhibitors, and abatacept and the like are classified as T-cell selective costimulation modulators. As an example, the present invention may relate to a combination pharmaceutical composition or kit for treating rheumatoid arthritis, comprising (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one (Compound 1) or a pharmaceutically acceptable salt thereof as active ingredients, and other existing rheumatoid arthritis treatments, particularly methotrexate, etanercept, or tofacitinib. The present invention may also relate to the use of (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one (Compound 1) or a pharmaceutically acceptable salt thereof for the manufacture of a combination pharmaceutical composition or kit for treating rheumatoid arthritis, comprising other therapeutic agents for rheumatoid arthritis. Other existing rheumatoid arthritis treatments can be used at concentrations normally used in the treatment of rheumatoid arthritis.

[0024] When used as a therapeutic agent for rheumatoid arthritis, Compound 1 is preferably administered once a day, but can also be administered twice or three times a day.

[0025] In one embodiment, the present invention includes a method for treating rheumatoid arthritis by administering Compound 1 or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment, the present invention includes the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating rheumatoid arthritis in a subject in need thereof.

[0027] The present invention will be described in more detail below with reference to examples. However, these examples are merely examples shown for the convenience of explanation, and the present invention is not limited to these examples in any sense.

[0028] Example 1: Clinical trial in patients with rheumatoid arthritis 1. Test method Thirty-two patients with rheumatoid arthritis (six patients in each compound 1 group at each dose, two patients in each placebo group at each dose) were orally administered 10, 25, 75, or 175 mg of compound 1 or placebo once daily for seven days (double-blind study). 2. Evaluation items Evaluation items included disease activity and pain-related items (DAS28-CRP, ACR20, VAS scale pain score, TJC) as efficacy indicators, vital signs (blood pressure, pulse rate, body temperature, respiratory rate), physical findings, electrocardiogram, hematological tests, changes in blood biochemistry tests, and severity and frequency of adverse events as safety indicators, and the plasma concentration of compound 1 over time (PK) as pharmacokinetics indicators. For DAS28-CRP, improvement or non-improvement was assessed based on the difference between the values ​​on Day 1 and Day 7 of administration, according to the criteria shown in Table 1 (EULAR assessment criteria).

[0029]

[0030] The presence or absence of improvement was determined based on the ACR20 on days 1 and 7 of administration. The VAS scale pain score change rate is the rate of change in the score on day 7 of administration relative to the score on day 1 of administration. The TJC change rate is the rate of change in the value on day 7 of administration relative to the value on day 1 of administration.

[0031] 3. Analysis Results (1) Efficacy Figure 1 shows the percentage of subjects in each administration group who showed improvement in ACR20 after 7 days of oral administration. The percentage of subjects who showed improvement was higher in the 25 mg, 75 mg, and 175 mg groups compared to placebo, demonstrating excellent efficacy in improving rheumatoid arthritis. The 75 mg group showed particularly remarkable improvement, with 60% of subjects showing improvement. Figure 2 shows the percentage of subjects in each administration group who showed improvement in DAS28-CRP after 7 days of oral administration. The percentage of subjects who showed improvement was higher in the 25 mg, 75 mg, and 175 mg groups compared to placebo, demonstrating excellent efficacy in improving rheumatoid arthritis. The 75 mg group showed particularly remarkable improvement, with 80% of subjects showing improvement. Figure 3 shows the rate of change in VAS scale pain score for each administration group after 7 days of oral administration. The 25 mg, 75 mg, and 175 mg groups showed a higher score reduction rate than placebo, indicating an excellent effect in improving rheumatoid arthritis. The 75 mg group showed a particularly notable effect, with a change rate of -40%. Figure 4 shows the TJC change rate for each group after 7 days of oral administration. The 25 mg, 75 mg, and 175 mg groups showed a higher score reduction rate than placebo, indicating an excellent effect in improving rheumatoid arthritis. The 75 mg group showed a particularly notable effect, with a change rate of -40%. (2) Safety At any dose, no notable events were observed in vital signs, electrocardiograms, or physical findings, or clear changes in hematological or blood biochemistry tests. Adverse events were reported in two patients (5 events) in the 10 mg group, two patients (3 events) in the 25 mg group, two patients (3 events) in the 75 mg group, and one patient (1 event) in the 175 mg group. However, all were mild to moderate in severity, with no severe adverse events. Existing CDK4 / 6 inhibitors (palbociclib and abemaciclib) frequently experience the side effect of neutropenia (palbociclib: 80.2% (package insert), abemaciclib: 42.2% (package insert)). On the other hand, with Compound 1, neutrophil counts remained constant from day 1 to day 7 of administration and throughout the three-day follow-up period after the end of administration (until day 10, counting from day 1 of administration). Neutropenia and a decrease in neutrophil count were not observed, regardless of dose.(3) Pharmacokinetics The plasma concentration half-life of Compound 1 on day 7 from the start of administration in each administration group was 12.9 hours for 10 mg, 11.9 hours for 25 mg, 14.6 hours for 75 mg, and 10.4 hours for 175 mg, and was the longest for the 75 mg formulation.

[0032] Example 2: Pharmacological test using synovial cells (in vitro) The synovial cells used in the test were derived from patients with rheumatoid arthritis. During the test, the synovial cells were stimulated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the effect of Compound 1 was measured. As a result, after stimulation with TNF-α and IL-1β, and compared with the control without Compound 1, Compound 1 inhibited the proliferation of synovial cells in a dose-dependent manner by 5% when 10 nM was added, 14% when 30 nM was added, 19% when 100 nM was added, 27% when 300 nM was added, and 35% when 1000 nM was added. Furthermore, the secretion of the pro-inflammatory mediator granulocyte-macrophage colony-stimulating factor (GM-CSF) was dose-dependently inhibited by 17% when 8 nM of Compound 1 was added, 25% when 40 nM was added, 48% when 200 nM was added, and 65% when 1000 nM was added, compared to the control group after stimulation with TNF-α and IL-1β without Compound 1. Furthermore, the secretion of matrix metalloproteinase-3 (MMP-3), a mediator involved in tissue destruction, was dose-dependently inhibited by 14% when 10 nM of Compound 1 was added, 21% when 30 nM was added, 37% when 100 nM was added, 60% when 300 nM was added, and 63% when 1000 nM was added, compared to the control group after stimulation with TNF-α and IL-1β without Compound 1.

[0033] Example 3: Distribution test in synovial cells (in vitro) Cultured cells were used for synovial cells and bone marrow cells. Compound 1 was applied, and the intracellular concentration in synovial cells and bone marrow cells and the concentration in the culture medium were measured. As a result, compound 1 was highly selectively distributed to synovial cells, while its distribution in bone marrow cells remained extremely low compared to its distribution in synovial cells (distribution ratio between synovial cells and bone marrow cells was 84:16). Palbociclib, a known CDK4 / 6 inhibitor with the same mechanism of action, did not show specific distribution (distribution ratio between synovial cells and bone marrow cells was 43:57), and compound 1 showed a different distribution characteristic.

[0034] Example 4: Combination Test with Methotrexate (In Vivo) The effect of the combination of Compound 1 and methotrexate was measured using a rat adjuvant-induced arthritis (AIA) model. The effect was evaluated by Arthritis Score. As a result, the combination of Compound 1 (30 mg / kg / day) and methotrexate (0.075 mg / kg / day) showed a much higher effect than the effect of Compound 1 alone or the effect of methotrexate alone. Compared to the control, the score was reduced by 33% with Compound 1 alone, 59% with methotrexate alone, and 86% with the combination of Compound 1 and methotrexate. On the other hand, in this test, no decrease in bone marrow cell count was observed even when Compound 1 was used in combination with methotrexate.

[0035] Example 5: Combination test with etanercept (in vivo) The effect of the combination of compound 1 and etanercept was measured using a mouse anti-collagen antibody-induced arthritis (CAIA) model. The effect was evaluated by Arthritis Score. As a result, when compound 1 (50 mg / kg / day) and etanercept (10 mg / kg / day) were used in combination, the effect was far greater than the effect shown by compound 1 alone or etanercept alone. Compared to the control, the score was reduced by 64% when compound 1 alone, 62% when etanercept alone, and 97% when compound 1 and etanercept were used in combination.

[0036] Example 6: Combination test with tofacitinib (in vivo) The effect of the combination of Compound 1 and tofacitinib was measured using a rat AIA model. The effect was evaluated by Arthritis Score. As a result, the combined use of Compound 1 (30 mg / kg / day) and tofacitinib (30 mg / kg / day) showed a much higher effect than the effect shown by Compound 1 alone or the effect shown by tofacitinib alone. Compared to the control, the score was reduced by 40% with Compound 1 alone, 67% with tofacitinib alone, and 92% with the combined use of Compound 1 and tofacitinib.

[0037] The results of the Examples show that Compound 1 is effective against rheumatoid arthritis in humans, the effect of which was particularly high in the 75 mg administration group, and there were no safety issues at any dose.

[0038] The present invention is extremely useful as a therapeutic agent for rheumatoid arthritis.

Claims

1. A therapeutic agent for rheumatoid arthritis comprising (R)-1-(6-((6-(1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one or a pharma- ceutically acceptable salt thereof.

2. The therapeutic drug for rheumatoid arthritis according to claim 1, wherein the daily dose of said compound is 10 to 200 mg.

3. The therapeutic drug for rheumatoid arthritis according to claim 1, wherein the daily dose of said compound is 30 to 125 mg.

4. A therapeutic agent for rheumatoid arthritis according to any one of claims 1 to 3, which is administered once a day.

5. The drug for treating rheumatoid arthritis according to any one of claims 1 to 4, which is used in combination with another drug for treating rheumatoid arthritis.

6. The drug for treating rheumatoid arthritis according to claim 5, wherein the "other drug for treating rheumatoid arthritis" is a disease-modifying antirheumatic drug (DMARDs).

7. The drug for treating rheumatoid arthritis according to claim 5, wherein the "other drug for treating rheumatoid arthritis" is a biological agent.

8. The drug for treating rheumatoid arthritis according to claim 5, wherein the "other drug for treating rheumatoid arthritis" is a JAK inhibitor.

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