USE OF GLUTARIMIDE DERIVATIVE FOR OVERCOMING STEROID RESISTANCE AND TREATING DISEASES ASSOCIATED WITH ABERRANT INTERFERON GAMMA SIGNALING

Abstract

The present invention relates to the medicine, in particular, to a new drug effective for the treatment of diseases associated with aberrant interferon gamma signaling, such as Sjögren's syndrome, dermatomyositis, systemic lupus erythematosus, or systemic sclerosis; for the treatment of patients suffering from cough; and for the treatment of disorders in steroid-resistant patients, such as asthma, rheumatoid arthritis, systemic lupus erythematosus, and gastrointestinal diseases, by administering a compound 1-(2-(1H-imidazol-4-yl)ethyl) piperidin-2,6-dione

##STR00001##

The invention provides the creation of a new effective drug for overcoming steroid resistance.

Claims

1.-14. (canceled)

15. A method of treating a cough interferon gamma signaling, comprising administering a therapeutically effective amount of a compound 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the formula: ##STR00011## or a pharmaceutically acceptable salt thereof to a body.

16. The method according to claim 15, wherein the compound is administered at a dose of 10-200 mg/day.

17. The method according to claim 15, wherein the compound is administered 1-2 times a day.

18.-27. (canceled)

28. A method of treating a disease associated with aberrant interferon gamma signaling, comprising administering a therapeutically effective amount of a compound 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the formula: ##STR00012## or a pharmaceutically acceptable salt thereof.

29. The method according to claim 28, wherein the disease associated with aberrant interferon gamma signaling is asthma, Sjögren's syndrome, dermatomyos, systemic lupus erythematosus, or systemic sclerosis.

30. The method according to claim 28, wherein the compound is administered at a dose of 10-200 mg/day.

31. The method according to claim 28, wherein the compound is administered 1-2 times a day.

32. A method for treating a disorder in steroid resistant patients, comprising administering a therapeutically effective amount of a compound 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the formula: ##STR00013## or a pharmaceutically acceptable salt thereof, provided that the said disorder is not directed to the treatment of cough.

33. The method according to claim 32, wherein the disorder associated with the development of steroid resistance is asthma, rheumatoid arthritis, systemic lupus erythematosus, or gastrointestinal diseases.

34. The method according to claim 32, wherein the compound is administered at a dose of 10-200 mg/day.

35. The method according to claim 32, wherein the compound is administered 1-2 times a day.

36. A method for treating a disorder in steroid resistant patients, comprising administering a therapeutically effective amount of a compound 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the formula: ##STR00014## or a pharmaceutically acceptable salt thereof, provided that the said disorder is not directed to the treatment of cough.

37. The method according to claim 36, wherein the disorder associated with the development of steroid resistance is asthma, rheumatoid arthritis, systemic lupus erythematosus, or gastrointestinal diseases.

38. The method according to claim 36, wherein the compound is administered at a dose of 10-200 mg/day.

39. The method according to claim 36, wherein the compound is administered 1-2 times a day.

40. A combination for the treatment of a disorder in a steroid resistant patient, comprising a therapeutically effective amount of a compound 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the formula: ##STR00015## or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a steroid, provided that the said disorder is not directed to the treatment of cough.

41. The combination according to claim 40, wherein the steroid is a corticosteroid.

42. The combination according to claim 40, wherein the disorder is asthma, rheumatoid arthritis, systemic lupus erythematosus, or gastrointestinal diseases.

43. A method for treating a disorder in a steroid resistant patient, comprising administering a combination according to claim 40 to the body.

44. The method according to claim 43, wherein the compound and steroid are administered simultaneously or separately.

45. The method according to claim 43, wherein the compound is administered at a dose of 10-200 mg/day.

46. The method according to claim 43, wherein the compound is administered 1-2 times a day.

Description

DESCRIPTION OF DRAWINGS

[0033] FIG. 1. The number of patients who responded to baseline therapy with inhaled glucocorticosteroids against the background of the administration of Compound 1 or placebo.

[0034] FIG. 2. The effect of the IFN-γ level (pg/ml) at the time of trial inclusion on an absolute increase (L) in forced expiratory volume in the first second (FEV1) (week 12 vs. week 0) in patients who received baseline steroid therapy and Compound 1 at a dose of 100 mg (designated as “Baseline steroid therapy+Compound 1, 100 mg”) and in patients who received baseline steroid therapy and placebo (designated as “Baseline steroid therapy+placebo”). Compound 1: For each point, n is the number of patients falling into a given subgroup depending on the type of therapy and the IFN-γ level.

[0035] FIG. 3. Response to therapy (a change in FEV1 (L), week 12 vs. week 0) in patients who received baseline steroid therapy and Compound 1 at a dose of 100 mg (designated as “Baseline steroid therapy +Compound 1, 100 mg”) and in patients who received baseline steroid therapy and placebo (designated as “Baseline steroid therapy +placebo”), depending on the IFN-γ level at the time of inclusion.

[0036] FIG. 4. A change in the concentration of interferon-γ-dependent cytokine CXCL10 (interferon-gamma-induced protein IP10) in the patients' blood plasma during administration of Compound 1 or placebo in combination with baseline steroid therapy, depending on the IFN-γ level at the time of inclusion (difference between levels at week 12 and week 0).

[0037] FIG. 5. A change in the concentration of interferon-γ in the patients' blood plasma during administration of Compound 1 or placebo in combination with baseline steroid therapy, depending on the IFN-γ level at the time of inclusion (difference between levels at week 12 and week 0).

DETAILED DISCLOSURE OF THE INVENTION

[0038] The preparation of Compound 1, which is the subject matter of the present invention, and a number of other chemical compounds is described in WO 2014/168522. The present patent application describes glutarimide derivatives with antiviral action, their use for the treatment of rhinosinusitis and other upper respiratory tract diseases.

[0039] WO 2015/072893 describes the use of Compound 1 for the treatment of diseases associated with the development of eosinophilic inflammation, including eosinophilic asthma. However, the development of eosinophilic inflammation is characteristic mainly of steroid-sensitive forms of asthma, whereas the bronchoalveolar lavage (BAL) in therapeutically resistant patients who received therapy with high doses of systemic corticosteroids showed a large number of neutrophils, i.e. steroid-resistant patients had predominantly neutrophilic inflammation [Turato G., Baraldo S., Zuin R. The laws of attraction: chemokines, neutrophils and eosinophils in severe exacerbations of asthma. Thorax. 2007; 62(6):465-466].

[0040] In clinical studies of the activity of Compound 1, which is the subject matter of the present invention, it has been unexpectedly found that the therapeutic use of Compound 1 effectively increases the number of responders to standard corticosteroid therapy and also suppresses aberrant interferon gamma signaling. The overcoming of corticosteroid resistance cannot be predicted or explained by the ability of Compound 1 to exert an antiviral effect or suppress eosinophilic inflammation.

[0041] Thus, Compound 1 has a previously unknown pharmacological activity associated with the effect on aberrant interferon gamma signaling and increases the response of patients to corticosteroid therapy, which indicates the potential applicability of Compound 1 for the treatment of diseases associated with aberrant interferon gamma signaling, such as Sjögren's syndrome, dermatomyositis, systemic lupus erythematosus, or systemic sclerosis, for the treatment of patients with cough, and for the treatment of disorders in steroid-resistant patients, such as asthma, rheumatoid arthritis, systemic lupus erythematosus, and gastrointestinal diseases.

[0042] Terms and Definitions

[0043] The term “glucocorticosteroids” or “glucocorticoids” means steroid hormones from the subclass of corticosteroids and/or their synthetic analogs.

[0044] The term “corticosteroids” includes the subclass of steroid hormones and/or synthetic analogs thereof.

[0045] The term “Compound 1” refers to a compound 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione, which is also represented by the structural formula:

##STR00010##

[0046] The term “steroid resistance” means a disease condition in which the steroid therapy, which is as a rule effective in the treatment of patients with said disease, is ineffective. Steroid-resistant patients include, but are not limited to, patients who do not or poorly, or insufficiently respond to therapy with systemic or oral corticosteroids according to response routine parameters.

[0047] The term “pharmaceutically acceptable salts” or “salts” includes salts of active compounds, prepared with relatively non-toxic acids. Examples of pharmaceutically acceptable non-toxic salts include salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic, citric or malonic acid, or prepared by other methods used in this field. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formiate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, hemi-fumarate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate (tosylate), undecanate, valerate and the like.

[0048] The terms “treatment” and “therapy” encompass the treatment of pathological conditions in mammals, preferably in humans, and include: a) reducing, b) blocking (arresting) the course of a disease, c) alleviating disease severity, i.e. inducing disease regression, d) reversing a disease or condition to which the term applies, or one or more symptoms of the disease or condition.

[0049] The terms “prophylaxis” and “prevention” encompass the elimination of risk factors, and prophylactic treatment of subclinical stages of a disease in mammals, preferably in humans, aimed at reducing the likelihood of the occurrence of clinical stages of the disease. The selection of patients for prophylactic therapy is based on factors that are known to be associated with an increased risk of progressing to clinical stages of the disease, compared with general population. Preventive therapy includes a) primary prevention and b) secondary prevention. Primary prevention is defined as prophylactic treatment of patients with a disease that has not reached clinical stage. Secondary prevention is the prevention of recurrence of the same or similar clinical condition of the disease.

[0050] Method for the Therapeutic Use of Compounds

[0051] The subject matter of the invention also includes the administration a therapeutically effective amount of a compound according to the invention to a subject in need of appropriate treatment. A therapeutically effective amount means the amount of a compound that when administered or delivered to a patient most likely provides a desired response of the patient to the treatment (prophylaxis). The required exact amount may vary from subject to subject, depending on the age, body weight, and general condition of the patient, disease severity, a method of drug administration, use in combination with other drugs, and the like.

[0052] A compound according to the invention or a pharmaceutical composition comprising the compound can be administered to a patient in any amount (preferably, the daily dose of the active substance is up to 0.2 g per patient per day, most preferably the daily dose is 10-200 mg/day, preferably 100 mg) and by any route of administration (preferably by oral route of administration) that is effective for the treatment or prophylaxis of a disease.

[0053] After mixing a drug with a specific suitable pharmaceutically acceptable carrier at a desired dosage, compositions according to the invention can be administered to humans or other animals orally, parenterally, topically, and the like.

[0054] The administration can be made both once and several times a day, week (or any other time interval), or from time to time. In addition, the compound can be administered to a patient every day for a specified period of days (e.g., 2-10 days), followed by a period without administration (e.g., 1-30 days).

[0055] When the compound according to the invention is used as part of a combination therapy, the dose of each of the combination therapy components is administered over a desired treatment period. The compounds of the combination therapy can be administered to the patient's body simultaneously both in the form of a dosage containing all the components and in the form of individual dosages of the components.

[0056] Use of Compound 1 in Combination Therapy

[0057] Although Compound 1 according to the invention can be administered as an individual active pharmaceutical agent, it can also be used in combination with one or more other agents; in particular, the other agent can be a glucocorticosteroid, a leukotriene receptor antagonist, a bronchodilator, a monoclonal antibody, etc. The therapeutic agents, when administered in combination, can be administered in different dosage forms simultaneously or sequentially at different times, or the therapeutic agents can be combined in a single dosage form.

[0058] The phrase “combination therapy” as related to the compound of the invention used in combination with other pharmaceutical agents means simultaneous or sequential administration of all agents such that a beneficial effect of the drug combination will be provided in any way. Co-administration implies, in particular, co-delivery, for example, in one tablet, capsule, injection or another form having a fixed ratio of active substances, as well as simultaneous delivery in several, separate dosage forms for each compound, respectively.

[0059] Thus, Compound 1 of the invention can be administered in combination with additional therapies known to those skilled in the prevention and treatment of corresponding diseases, including the use of antibacterial, cytostatic and cytotoxic drugs, medical preparations for suppressing symptoms or side effects of one of the drugs.

[0060] If the dosage form is a fixed dose, such a combination comprises a compound according to the invention within an acceptable dosage range. Compound 1 of the invention can also be administered to a patient sequentially with other agents, if a combination of these drugs is not possible. The invention is not limited to a certain sequence of administration; the compound of the invention can be administered to a patient concurrently or at any time before or after the administration of another drug.

EXAMPLES

[0061] Preparation of the compound according to the invention The preparation of Compound 1, which is the subject matter of the present invention, and a number of other chemical compounds, is described in WO 2014/168522. This patent application describes glutarimide derivatives with antiviral action, their use for the treatment of rhinosinusitis and other upper respiratory tract diseases.

[0062] Characterization of the biological activity of the compound according to the invention

[0063] The biological activity of Compound 1, which is the subject matter of the present invention, has been studied in extensive preclinical trials, and in a multicenter, double-blind, randomized Phase II clinical trial over a 12-week period of treatment of patients with bronchial asthma. The therapeutic use of Compound 1 has been shown to effectively increase the number of responders to standard therapy with inhaled corticosteroids. The overcoming of resistance to inhaled corticosteroids cannot be predicted or explained by the ability of Compound 1 to exert antiviral effects or suppress eosinophilic inflammation.

Example 1. Study of the Activity of Compound 1 in a Clinical Trial

[0064] In a multicenter, double-blind, randomized, parallel-group Phase II clinical trial study on evaluation of the effectiveness and safety of various doses of Compound 1 over placebo in a 12-week treatment of patients with bronchial asthma (PULM-XC8-02, NCT03450434), it has been unexpectedly found that the therapeutic use of Compound 1 effectively increases the number of responders to standard therapy with inhaled corticosteroids. Thus, Compound is potentially useful for the therapy of diseases associated with the development of steroid resistance, in particular for the treatment of steroid-resistant asthma.

[0065] In the clinical trial, eligible patients were randomized 1:1:1:1 to one of four groups: [0066] Compound 1 at a dose of 2 mg per day; [0067] Compound 1 at a dose of 10 mg per day; [0068] Compound 1 at a dose of 100 mg per day; and [0069] Placebo.

[0070] During the study therapy phase, patients received Compound 1 or placebo for 12 weeks against the background of baseline steroid therapy with low doses of inhaled corticosteroids. Compound 1 or placebo was administered orally once a day, 30 minutes before breakfast.

[0071] A clinically significant effect was obtained at a dose of Compound 1 of 100 mg per day.

[0072] An exploratory analysis of the results of the clinical trial in patients with bronchial asthma showed that Compound 1 effectively increased the number of responders to standard therapy. For example, the use of baseline steroid therapy and placebo led to an increase in FEV1 by 100 ml or more in only 13 patients out of 29, while the use of baseline steroid therapy and Compound 1 resulted in a response in 20 patients out of 29, thus allowing a significant increase in the number patients with a response to baseline steroid therapy (FIG. 1). Thus, one of the effects of the use of Compound 1 is the overcoming of the resistance to corticosteroids, which is the backbone of the baseline therapy of patients enrolled in the clinical trial.

[0073] To study the effect of the IFN-γ baseline level in patients with asthma, the results obtained in the clinical study were additionally analyzed; the patients' response to therapy was studied depending on their IFN-γ baseline level in the blood at the time of trial inclusion (determined by the Bio-Plex Pro Human Chemokine Panel Assay (Bio-Rad)).

[0074] The patients' response to baseline therapy in the groups of baseline steroid therapy and placebo decreased with an increase in the IFN-γ baseline level (FIG. 2). The use of baseline steroid therapy in patients with an IFN-γ level >100 pg/ml did not lead to a positive change in respiratory function, as determined by a change in FEV1 (an observed decrease of 0.1 L or more, FIG. 2), i.e. these patients showed resistance to steroid therapy (the lack of positive response to therapy). The use of Compound 1 at a dose of 100 mg per day administered against the background of baseline steroid therapy provided a significantly greater and clinically significant response to therapy in patients, especially in those with an IFN-γ level more than 100 pg/ml (FIG. 3). This fact indicates the overcoming of steroid resistance that can be caused, inter alia, by aberrant IFN-γ signaling.

[0075] Moreover, in the clinical trial, Compound 1 was also analyzed for its effect on IFN-γ signal transduction. It was shown that Compound 1 administered against the background of baseline steroid therapy suppressed the concentration of interferon-γ-dependent cytokine CXCL10 (interferon-gamma-induced protein IP10) in patients with an IFN-γ baseline level >100 pg/ml, while the group of patients received placebo against the background of baseline steroid therapy had a slight increase in the level of CXCL10 (FIG. 4). In addition, the therapeutic use of Compound 1 against the background of baseline therapy also led to negative dynamics of IFN-γ concentrations in the blood plasma of patients compared with the use of only baseline therapy and placebo, regardless of the IFN-γ level at the time of inclusion (FIG. 5). Thus, the suppression of steroid resistance induced by the use of Compound 1 could potentially be associated with an effect on the aberrant activity (signaling) of IFN-γ.

Example 2. Study of the Activity of Compound 1 in a Model of Acute Oxazolone-Induced intestinal inflammation

[0076] The activity of Compound 1 in a model of acute oxazolone-induced ulcerative colitis was studied using the standard method [Immunity. 2002. P. 629-638].

[0077] In the study, female balb/c mice (6-8 weeks old) were used. Compound I was administered intragastrically, three times: 1 hour, 25 hours, and 49 hours after rectal administration of oxazolone. The body weight of the animals was measured before and 24, 48 and 72 hours after administration of oxazolone. The intestinal wall damage was evaluated under a microscope 72 hours after administration of oxazolone, according to the following score scale:

[0078] 0=no damage,

[0079] 1=hyperemia, no ulcers,

[0080] 2=hyperemia, thickening of the intestinal wall, no ulcers,

[0081] 3=one ulcer without thickening of the intestinal wall,

[0082] 4=2 or more sites of ulceration or inflammation,

[0083] 5=2 or more serious sites of ulceration and inflammation, or one site of ulceration/inflammation, extending >1 cm along the length of the colon, and

[0084] 6-10=damage covers>2 cm long the length of the colon, the score is increased by 1 for each additional 1 cm of involvement.

[0085] All data were analyzed by descriptive statistics: arithmetic mean (M) and standard error of the arithmetic mean (m). The Shapiro-Wilk test was used to check the normality of the distribution of the obtained experimental data. A normal distribution was analyzed with 1-way ANOVA (with Dunnett's post-analysis) to assess intergroup differences. A non-normal distribution was analyzed with 1-way ANOVA (with Tukey's post-analysis) to compare several groups. Differences were determined at a confidence level of 5%. The results of study are shown in Tables 1 and 2.

TABLE-US-00001 TABLE 1 Effect of Compound 1 on damage of the colon wall in the murine model of acute oxazolone-induced ulcerative colitis (M ± m, n = 10) The degree of large intestine Dose, wall damage, Groups mg/kg n score Intact — 10 0.00 ± 0.00 Control — 10 2.11 ± 0.26* Compound 1 0.3 10 1.70 ± 0.30 3 10 1.89 ± 0.31 30 10 1.40 ± 0.16& Prednisone 10 10 1.80 ± 0.25 Note: *—statistical significance (P < 0.05) vs. the intact group &—statistical significance (P < 0.05) vs. the control group

TABLE-US-00002 TABLE 2 Effect of Compound I on body weight of the animals in the mouse model of acute oxazolone-induced ulcerative colitis (M ± m, n = 10) Body weight, g 24 hours 48 hours 72 hours Dose, Before after after after Group mg/kg n administration of oxazolone Intact — 10 19.1 ± 0.4 19.1 ± 0.3 19.4 ± 0.4 19.5 ± 0.4 Control — 10 18.9 ± 0.5  17.2 ± 0.3* 16.6 ± 0.3  16.1 ± 0.3* Compound I 0.3 10 19.0 ± 0.6 17.9 ± 0.2 17.5 ± 0.3 16.9 ± 0.2 3 10 18.7 ± 0.4 17.9 ± 0.3 17.6 ± 0.2 16.7 ± 0.2 30 10 19.8 ± 0.6   18.8 ± 0.2&   18.4 ± 0.4&   18.4 ± 0.5& Prednisone 10 10 19.0 ± 0.4 18.5 ± 0.4 17.9 ± 0.4 17.3 ± 0.6 Note: *statistical significance (P < 0.05) vs. the intact group &statistical significance (P < 0.05) vs. the control group

[0086] The results of the study showed that Compound I, when administered intragastrically, reduced the degree of damage of the colon wall and prevented weight loss in animals. Thus, Compound I had a therapeutic effect in the murine model of ulcerative colitis. Compound 1 was not inferior to prednisolone by intensity of action.

Example 3. Study of the Activity of Compound 1 in a Guinea Pig Model of Cough Induced by Inhalation of Citric Acid and IFN-γ.

[0087] The activity of Compound I in a model of cough in guinea pigs, which was induced by inhalation of citric acid and IFN-γ, was studied in accordance with the method [Am J Respir Crit Care Med. 2018. V. 198(7). P. 868-879].

[0088] In the study, guinea pigs of the Aguti line were used. All experimental animals were inhaled with a citric acid solution (0.3 M) prepared in physiological saline, for 8 minutes. The pathology control group and the groups receiving therapy were inhaled with IFN-γ (10 pg/kg) for 3 minutes at 7 hours before the inhalation of citrate. Compound 1 was administered intragastrically once, immediately after inhalation of IFN-γ, i.e. 7 hours before inhalation of the citric acid solution. The antitussive activity was evaluated by counting the number of coughing fits within 8 minutes from the start of inhalation of citric acid. All data were analyzed by descriptive statistics: arithmetic mean (M) and standard error of the arithmetic mean (m). The Shapiro-Wilk test was used to check the normality of the distribution of the obtained experimental data. A normal distribution was analyzed with 1-way ANOVA (with Dunnett's post-analysis) to assess intergroup differences. A non-normal distribution was analyzed with 1-way ANOVA (with Tukey's post-analysis) to compare several groups. Differences were determined at a confidence level of 5%. The results of study are shown in Tables 1 and 2.

[0089] The results of the study are given in Table 3.

[0090] The results of the study showed that Compound 1, when administered intragastrically, reduced the number of coughing movements. Thus, Compound I had a therapeutic effect in a guinea pig model of acute and subacute viral cough induced by inhalation of citric acid and IFN-γ.

TABLE-US-00003 TABLE 3 Effect of Compound 1 on the number of cough movements in the guinea pig model of viral cough induced by inhalation of citric acid and IFN-γ (M ± m, n = 5). The number of coughing Dose, movements within 8 Groups mg/kg n minutes Intact — 5 0 Citrate + placebo — 5 24.0 ± 3.2 Control — 5 34.6 ± 2.9 (Citrate + IFN-γ) Compound 1 1.4 5 19.2 ± 2.7& 14 5 18.4 ± 2.9& Note: &—statistical significance (P <0.05) vs. the control group