WO2023177328A1 - Bisamide derivative of dicarboxylic acid for use in restoring the external respiratory function after coronavirus infection - Google Patents
Bisamide derivative of dicarboxylic acid for use in restoring the external respiratory function after coronavirus infection Download PDFInfo
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Classifications
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the present invention relates to medicine and concerns rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, preferably the treatment of respiratory and neurological symptoms, maintenance of working capacity and exercise tolerance by using a bisamide derivative of dicarboxylic acid.
- the invention provides a new effective drug for rehabilitation therapy of patients who have undergone COVID-19 and are suffering from the consequences of the infection.
- Shortness of breath and severe weakness after exercise are the most common consequences of COVID-19: 6 months after the infection has resolved, shortness of breath occurs in 20% of patients who have had moderate disease and 30% of patients who have had severe disease [Chopra V. et al., Sixty-Day Outcomes Among Patients Hospitalized With COVID-19 // Ann Intern Med. 2021. v. 174. Mb 4. pp. 576-578., DOI: 10.7326/M20-5661; Huang C. et al., 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study // The Lancet. 2021. v. 397. Mb 10270. pp.
- SARS and COVID-19 have comparable probabilities of developing respiratory dysfunction 12 months after infection (23.7% for SARS and 33% for COVID-19), as well as comparable probabilities of persistent fibrotic lung injury (27.8% patients who have had SARS and 38% patients who have had COVID-19)[Hui D. S. et al., Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors // Thorax. 2005a. v. 60. N° 5.
- SARS severe acute respiratory syndrome
- the present invention relates to the use of a bisamide derivative of dicarboxylic acid for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, preferably for the treatment of respiratory and neurological symptoms, maintaining working capacity and exercise tolerance.
- the object of the present invention is to develop a new drug effective for rehabilitation therapy of the consequences of coronavirus infection, including those associated with pathological changes in the respiratory system, preferably for the treatment of respiratory and neurological symptoms, maintaining working capacity and exercise tolerance.
- the technical result of this invention is the use of a compound that promotes the restoration of respiratory function for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory system, preferably for the treatment of respiratory and neurological symptoms, maintaining working capacity and exercise tolerance.
- Treamide a compound that is N,N'-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide or its salt, hydrate, solvate, as a compound that promotes the restoration of respiratory function.
- the invention also includes a method for treating the consequences of coronavirus infection, which comprises administering to said organism a pharmaceutical composition comprising N,N'-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide.
- a pharmaceutical composition comprising N,N'-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide.
- Such consequences associated with pathological changes in the respiratory organs in some non-limiting embodiments of the invention, are respiratory and neurological symptoms, as well as fatigue, decreased work capacity and exercise tolerance.
- the organism is a human or an animal.
- N,N’-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide compound (hereinafter referred to as compound 1) is known and described in WO 2014/168523 Al.
- the object of the present invention is the use of N,N’-bis[2-(lH-imidazol- 2-yl)ethyl]pentanediamide compound of formula or salt, hydrate or solvate thereof for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs.
- pathological changes in the respiratory organs may be associated with respiratory and neurological symptoms, impairment of working capacity and impairment of exercise tolerance.
- Another object of the invention is a pharmaceutical composition for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, comprising a therapeutically effective amount of N,N-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide compound of formula or salt, hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
- a further object of the invention is the use of N,N-bis[2-(lH-imidazol-2- yl)ethyl]pentanediamide compound of formula salt, hydrate or solvate thereof for preparing a pharmaceutical composition.
- pathological changes in the respiratory organs can preferably be associated with respiratory and neurological symptoms, impairment of working capacity and exercise tolerance.
- the object of the invention is a method of rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, comprising administering to said organism N,N-bis[2-(lH-imidazol- 2-yl)ethyl]pentanediamide compound of formula salt, hydrate or solvate thereof, or the aforementioned pharmaceutical composition based thereon.
- Fig. 1 Relative change in DLCO (in %) in patients treated with Compound 1 compared to those receiving placebo.
- Fig- 2. Violin plots of a) absolute (in L) and b) relative change in TLC (in %) in patients treated with Compound 1 compared to those receiving placebo.
- Fig- 3. Violin plots of changes in lung damage area according to CT (in %) in patients treated with Compound 1 compared with those receiving placebo.
- Fig. 4 Change in dyspnea on the Borg scale (difference after/before the 6- minute walk test) in patients treated with Compound 1 compared with those receiving placebo.
- Compound 1 is described in application WO 2014/168523 Al. Said patent application describes dicarboxylic acid bisamide derivatives suitable for use as metal chelators in the treatment of a wide variety of diseases.
- WO 2016/190785A1 describes the use of Compound 1 to stimulate the regeneration of epithelial and/or connective tissues of the male reproductive system. It was shown that Compound 1 reduces the intensity of morphological changes in the regeneration and normalization of the structure of prostate tissue in chronic abacterial prostatitis (CAP) and benign prostatic hyperplasia (BPH).
- CAP chronic abacterial prostatitis
- BPH benign prostatic hyperplasia
- Compound 1 refers to N,N’-bis[2-(lH-imidazol-2- yl)ethyl]pentanediamide compound represented by the structural formula:
- solvate is used to describe a molecular complex containing the compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol.
- solvent molecules such as ethanol.
- hydrate is used when said solvent is water.
- salts includes salts of active compounds that are prepared with relatively non-toxic acids.
- 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 acids, or obtained by other methods known in the art, for example by ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate (mesylate), 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, peroxine sodium
- treatment encompass pathological conditions in mammals, preferably in humans, and include: a) reduction, b) blocking (arresting) the course of the disease, c) alleviation of disease severity, i.e. induction of regression of the disease, d) reversing the disease or condition to which the term is applied, or one or more symptoms of the disease or condition.
- prophylaxis encompasses the elimination of risk factors as well as the prophylactic treatment of subclinical stages of disease in mammals, preferably humans, aimed at reducing the likelihood of occurrence of clinical stages of the disease.
- Patients for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increased risk of clinical stages of the disease compared with the general population.
- Preventive therapy includes a) primary prevention, and b) secondary prevention.
- Primary prevention is defined as prophylactic treatment of patients who have not yet reached the clinical stage of the disease. Secondary prevention is the prevention of the recurrence of the same or similar clinical condition of the disease.
- Compound 1 is promising for the treatment of post-COVID syndrome, and more specifically, for the treatment of respiratory and neurological symptoms after coronavirus infection.
- symptoms may include, but are not limited to, cough, shortness of breath, pain in breathing, sensory disturbances manifested by burning sensation, stinging, goosebumps on the skin surface; thermoregulation impairment, sleep disturbances, fatigue, depression, panic attacks, anxiety, episodes of weakness.
- compound 1 is promising for restoration and maintenance of working capacity and exercise tolerance after coronavirus infection.
- the subject matter of this invention also includes administering to a subject in need of appropriate treatment a therapeutically effective amount of the compound of the invention.
- a therapeutically effective amount is meant such amount of the compound administered or delivered to a patient that will most likely result in the patient’s desired response to treatment (prophylaxis).
- the exact amount required may vary from subject to subject, depending on age, body weight and general condition of the patient, disease severity, method of drug administration, combined use with other drugs, and the like.
- Compound 1, or a pharmaceutical composition comprising Compound 1 can be administered to a patient in any amount (preferably, the daily dose of the active substance for humans is 25-200 mg/day) and by any route of administration (oral administration is preferred), effective for treatment or prevention of the disease.
- compositions After mixing Compound 1 with a specific suitable pharmaceutically acceptable carrier at the desired dosage, the compositions can be administered to humans or other animals orally, parenterally, topically, etc.
- Administration may be carried out either as a single dose or several times a day, a week (or any other time interval), or from time to time.
- the compound may be administered to patient’s body daily for a specified period (e.g., 14-30 days) followed by a period without drug administration (e.g., 1-30 days).
- each of the components of the combination therapy is performed during the desired treatment period.
- the compounds which are components of the combination therapy can be administered to patient’s body both simultaneously, as a dosage containing all the components, and in the form of individual dosages of the components.
- Compound 1 of this invention can be administered as a single active pharmaceutical agent, it can also be used in combination with one or more other agents, in particular, the other agent may be a glucocorticosteroid, leukotriene receptor antagonist, bronchodilator, monoclonal antibody etc.
- the therapeutic agents may be different dosage forms administered simultaneously or sequentially at different times, or the therapeutic agents may be combined into a single dosage form.
- combination therapy in respect of compound 1 in combination with other pharmaceutical agents, means simultaneous or sequential administration of all agents, which in one way or another will provide a beneficial effect of drug combination.
- Co-administration implies, in particular, joint delivery, for example, in a single tablet, capsule, injection or other form having a fixed ratio of active substances, as well as simultaneous delivery in several, separate dosage forms for each compound, respectively.
- compositions of the present invention can be carried out in combination with additional therapies known to those skilled in the art of prevention and treatment of related diseases, comprising use of antibacterial preparations, preparations to suppress symptoms or side effects of one of the drugs.
- the dosage form is a fixed dose, such a combination uses the compound of the invention in an acceptable dosage range.
- Compound 1 can be administered to the patient's body sequentially with other agents, when the combination of these drugs is not possible.
- the invention is not limited to the sequence of administration; the compound of the present invention may be administered to the patient simultaneously, before or after administration of another drug.
- Compound 1 Biological activity of Compound 1 was studied in a Phase II, multicentre, double-blind, randomized, clinical trial over a 4-week period in patients with COVID- 19-induced injury of respiratory system.
- the therapeutic use of Compound 1 for 4 weeks has been shown to be effective in suppressing the development of lung damage, restoring respiratory function and increasing exercise tolerance in patients who underwent the acute phase of CO VID-19.
- Fig. 1 shows the relative change in DLCO (%) in patients treated with Compound 1 at a dose of 50 mg (indicated as "Compound 1”) and in patients treated with placebo (indicated as "Placebo") at >35 days after the onset of Covid- 19 symptoms.
- n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
- FIG. 2 shows violin plots of a) absolute (in L) and b) relative change in TLC (in %) in patients received Compound 1 at a dose of 50 mg (indicated as "Compound 1”) and in patients received placebo (indicated as "Placebo"), with an initial DLCO ⁇ 80%.
- n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
- FIG.3 shows violin plots of changes in the area of lung damage according to CT (in %) in patients treated with Compound 1 at a dose of 50 mg (indicated as “Compound 1”) and in patients treated with placebo (indicated as "Placebo"), with an initial DLCO level ⁇ 80%.
- n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
- Fig. 4 shows change in dyspnea on the Borg scale (difference after/before the 6-minute walk test) in patients treated with Compound 1 at a dose of 50 mg (indicated as "Compound 1") and in patients treated with placebo (indicated as "Placebo"), with an initial DLCO level ⁇ 80%.
- the value n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
- Compound 1 helps to restore exercise tolerance and daily activities in patients who have had an acute coronavirus infection.
- Compound 1 was also analyzed for its effect on the restoration of psycho-emotional stability of patients according to the King scoring questionnaire for interstitial lung diseases (KBILD). It was shown that Compound 1 seems to accelerate the recovery of psycho-emotional stability in patients, which is associated with the restoration of respiratory function and exercise tolerance, and not the direct pharmacological action of the drug.
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Abstract
The present invention concerns rehabilitation therapy of the consequences of coronavirus infection, in particular consequences associated with pathological changes in the respiratory organs, and more particularly the treatment of respiratory and neurological symptoms, fatigue, maintaining working capacity and exercise tolerance by using a bisamide derivative of dicarboxylic acid of formula (I). The invention provides an effective drug for rehabilitation therapy of patients who have undergone COVID-19 and are suffering from the consequences of the infection.
Description
BISAMIDE DERIVATIVE OF DICARBOXYLIC ACID FOR USE IN RESTORING THE EXTERNAL RESPIRATORY FUNCTION
AFTER CORONAVIRUS INFECTION
FIELD OF THE INVENTION
The present invention relates to medicine and concerns rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, preferably the treatment of respiratory and neurological symptoms, maintenance of working capacity and exercise tolerance by using a bisamide derivative of dicarboxylic acid. The invention provides a new effective drug for rehabilitation therapy of patients who have undergone COVID-19 and are suffering from the consequences of the infection.
BACKGROUND OF THE INVENTION
Beginning in December 2019, a new SARS-CoV-2 coronavirus has caused an outbreak of respiratory disease called COVID-19 in nearly every country in the world [Wang D. et al., Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China//JAMA. 2020. v. 323. N° 11. pp. 1061-1069., DOI: 10.1001/jama.2020.1585]. As progress has been made in the treatment of acute coronavirus infection and the rate of deaths from the disease has declined, evidence has begun to emerge about the long-term consequences of COVID- 19 infection [Lechowicz K. et al., COVID-19: The Potential Treatment of Pulmonary Fibrosis Associated with SARS-CoV-2 Infection//! Clin Med. 2020. v. 9. N° 6., DOI: 10.3390/jcm9061917],
In observational studies, it has been shown that 30 to 70% of patients suffer long-term effects lasting 4 to 12 weeks from diagnosis [Huang C. et al., 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study//The Lancet. 2021. v. 397. N° 10270. pp. 220-232., DOI: 10.1016/S0140-6736(20)32656-8], and in about 10-20% of cases complete recovery does not occur even in 6 months [Gorna R. et al., Long COVID guidelines need to reflect lived experience//The Lancet. 2020.
-6736(20)32705-7; Huang C. et al., 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study // The Lancet. 2021. v. 397. N° 10270. pp. 220-232., DOI: 10.1016/S0140-6736(20)32656-8; M M. et al., Long-COVID: An evolving problem with an extensive impact // South African medical journal=Suid-Afrikaanse tydskrif vir geneeskunde. 2020. v. 111. Na L, DOI: 10.7196/SAMJ.2020.V1 l lil 1.15433], The National Institute for Health and Clinical Excellence (NICE) classification uses the term "ongoing symptomatic COVID- 19" for symptoms of COVID-19 lasting 4 to 12 weeks; for symptoms lasting more than 12 weeks after a COVID-19 infection, not explained by an alternative diagnosis,
capable of changing over time, disappearing and reappearing, affecting many body systems, the term “post-COVID syndrome” has been introduced. The terms "post- COVID syndrome" or "post-COVID condition" are also included in the International Classification of Diseases (ICD-10, heading code U09.9)
A document Daniel Munblit et al. described a number of symptoms that are typical for those who have had a coronavirus infection (Risk factors for long-term consequences of COVID-19 in hospitalized adults in Moscow using the ISARIC Global follow-up protocol: StopCOVID cohort study February 2021b DOI: 10.1101/ 2021.02.17.21251895).
It seems that the key factors determining the development of long-term consequences of infection are the presence and severity of external respiration disfunction, associated with the preservation of persistent lung damage [Chun H. J. et al., Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS- CoV-2 infection (PASC) // medRxiv. 2021. C. 2021.01.31.21250870., DOI: 10.1101/2021.01.31.21250870; Qin W. et al., Diffusion capacity abnormalities for carbon monoxide in patients with COVID-19 at 3 -month follow-up // Eur Respir J. 2021. v. 58.
1. C. 2003677., DOI: 10.1183/13993003.03677-2020; Wu X. et al., 3- month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study // Lancet Respir Med. 2021. v. 9. N° 7. pp. 747-754., DOI: 10.1016/S2213 -2600(21)00174-0], Patients with impaired respiratory function tend to have more severe respiratory symptoms and reduced exercise tolerance [Chun H. J. et al., Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2 infection (PASC) // medRxiv. 2021. C. 2021.01.31.21250870., DOI: 10.1101/2021.01.31.21250870; Wu X. et al., 3-month, 6- month, 9-month, and 12-month respiratory outcomes in patients following COVID-19- related hospitalisation: a prospective study // Lancet Respir Med. 2021. v. 9. N° 7. pp. 747-754., DOI: 10.1016/S2213 -2600(21)00174-0], as well as a lower probability of spontaneous resolution of fibrotic lung injuries [Chun H. J. et al., Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2 infection (PASC)//medRxiv. 2021. C. 2021.01.31.21250870., DOI: 10.1101/2021.01.31.21250870; Qin W. et al., Diffusion capacity abnormalities for carbon monoxide in patients with COVID-19 at 3-month follow-up // Eur Respir J. 2021. v. 58. N° 1. C. 2003677., DOI: 10.1183/13993003.03677-2020], In the guidelines of the Ministry of Health of the Russian Federation, the restoration of respiratory functions is defined as the main goal of patient rehabilitation (according to the interim guidelines "Medical rehabilitation for a new coronavirus infection (COVID 19)", Version 2 of 07/31/2020).
Shortness of breath and severe weakness after exercise are the most common consequences of COVID-19: 6 months after the infection has resolved, shortness of breath occurs in 20% of patients who have had moderate disease and 30% of patients who have had severe disease [Chopra V. et al., Sixty-Day Outcomes Among Patients Hospitalized With COVID-19 // Ann Intern Med. 2021. v. 174. Mb 4. pp. 576-578., DOI: 10.7326/M20-5661; Huang C. et al., 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study // The Lancet. 2021. v. 397. Mb 10270. pp. 220- 232., DOI: 10.1016/S0140-6736(20)32656-8], Similar results were obtained in a survey of 488 people conducted 60 days after the diagnosis of COVID-19: shortness of breath was the most common symptom, which was observed in 32% of the respondents [Chopra V. et al., Sixty-Day Outcomes Among Patients Hospitalized With CO VID-19 // Ann Intern Med. 2020., DOI: 10.7326/M20-5661], A similar situation is observed in the case of mild and moderate forms of COVID-19, during the observation of 150 patients pronounced dyspnea was observed in 37% of patients after 30 days and in 30% of patients after 60 days after diagnosis [Carvalho-Schneider C. et al., Follow-up of adults with noncritical COVID-19 two months after symptom onset // Clinical Microbiology and Infection. 2020. v. 0. Mb 0., DOI: 10.1016/j.cmi.2020.09.052], Shortness of breath and other respiratory symptoms are not only among the most common, but also among the most persistent effects of COVID-19. According to large-scale observational studies, the probability of spontaneous resolution of dyspnea within 6 months after the disease does not exceed 20% [Munblit D. et al., Risk factors for long-term consequences of COVID-19 in hospitalised adults in Moscow using the ISARIC Global follow-up protocol: StopCOVID cohort study // medRxiv. 2021. C. 2021.02.17.21251895., DOI: 10.1101/2021.02.17.21251895],
Among patients with reduced respiratory function, the prevalence of dyspnea is significantly higher than in patients with normal DLCO (diffusing capacity for carbon monoxide) values. In addition, extensive epidemiological studies have shown that in patients having respiratory symptoms the prevalence of neurological symptoms is 4 times higher [Munblit D. et al., Risk factors for long-term consequences of COVID-19 in hospitalised adults in Moscow using the ISARIC Global follow-up protocol: StopCOVID cohort study // medRxiv. 2021. C. 2021.02.17.21251895., DOI: 10.1101/2021.02.17.21251895], Thus, it is reasonable to assume that, at least in some patients, the development of neurological symptoms is associated with impaired respiratory function.
It is important to note that the recovery of patients who have had COVID-19 occurs during the first 9-12 months after the disease. Thus, within 6 months after the disease, patients have a significant decrease in the degree of lung damage, as shown by
computed tomography, accompanied by the restoration of forced vital capacity (FVC) and total lung capacity. 9 months after infection, 70% have complete resolution of lung injury [Wu X. et al., 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study // Lancet Respir Med. 2021. v. 9.
7. pp. 747-754., DOI: 10.1016/S2213 -2600(21)00174-0],
However, 9 months after infection, 30-35% of patients still have residual lung damage and 15% of patients experience reduced exercise tolerance.
In view of the similarity of the pathogenesis of SARS and COVID-19 coronavirus infections, it is reasonable to make prediction of subsequent dynamics and long-term consequences of COVID-19 basing on data obtained from patients who underwent SARS. However, it is also important to note that SARS and COVID-19 have comparable probabilities of developing respiratory dysfunction 12 months after infection (23.7% for SARS and 33% for COVID-19), as well as comparable probabilities of persistent fibrotic lung injury (27.8% patients who have had SARS and 38% patients who have had COVID-19)[Hui D. S. et al., Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors // Thorax. 2005a. v. 60. N° 5. pp. 401-409., DOI: 10.1136/thx.2004.030205; Hui D. S. et al., The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors // Chest. 2005. v. 128. N° 4. pp. 2247-2261., DOI: 10.1378/chest.128.4.2247], In the course of long-term observations of patients who underwent SARS-CoV-1 coronavirus infection, it was found that the severity and prevalence of impaired respiratory function and residual lung damage decrease during the first 12 months after the disease [Hui D. S. et al., Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors // Thorax. 2005b. v. 60. N° 5. pp. 401-409., DOI: 10.1136/thx.2004.030205; Zhao X., Nicholls J. M., Chen Y.-G. Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling // J Biol Chem. 2008. v. 283. N° 6. pp. 3272-3280., DOI: 10.1074/jbcM708033200] and remain unchanged over the next 14 years [Zhang P. et al., Correction: Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study // Bone Res. 2020. v. 8. p. 34., DOI: 10.1038/s41413-020- 00113-1], Thus, for patients who have had COVID-19 and are suffering from the longterm consequences of infection, rehabilitation will be most effective during the first 6-9 months after the disease, and after 12 months there is practically no resolution of the long-term consequences of the infection.
Based on the analysis of data on the condition of patients who have undergone COVID-19, during the first 6 months after the disease rehabilitation therapy should be aimed at the early restoration of the external respiratory function. Restoration of external respiratory function within the first 6 months after illness will increase the likelihood of complete resolution of residual lung injury and prevent the development of fibrosis, a late but potentially fatal consequence of COVID-19. In addition, therapy aimed at normalizing external respiratory function will ensure the restoration of exercise tolerance and the preservation of the patient's ability to work.
Thus, based on the literature data, it can be concluded that in clinical practice there is a pronounced need for drugs for rehabilitation of patients after past coronavirus infection. Rehabilitation of patients will reduce the severity of residual respiratory symptoms, restore exercise tolerance, the ability to work and self-care.
The present invention relates to the use of a bisamide derivative of dicarboxylic acid for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, preferably for the treatment of respiratory and neurological symptoms, maintaining working capacity and exercise tolerance.
SUMMARY OF THE INVENTION
The object of the present invention is to develop a new drug effective for rehabilitation therapy of the consequences of coronavirus infection, including those associated with pathological changes in the respiratory system, preferably for the treatment of respiratory and neurological symptoms, maintaining working capacity and exercise tolerance.
The technical result of this invention is the use of a compound that promotes the restoration of respiratory function for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory system, preferably for the treatment of respiratory and neurological symptoms, maintaining working capacity and exercise tolerance.
The specified technical result is achieved by using Treamide, a compound that is N,N'-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide
or its salt, hydrate, solvate, as a compound that promotes the restoration of respiratory function.
Said technical result is also achieved by using N,N’-bis[2-(lH-imidazol-2-
yl)ethyl]pentanediamide compound or its salt, hydrate, solvate (Compound 1) to obtain a pharmaceutical composition for the treatment of the consequences of coronavirus infection, preferably associated with pathological changes in the respiratory system, preferably for the treatment of respiratory and neurological symptoms, fatigue, maintaining working capacity and exercise tolerance.
The invention also includes a method for treating the consequences of coronavirus infection, which comprises administering to said organism a pharmaceutical composition comprising N,N'-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide. Such consequences associated with pathological changes in the respiratory organs, in some non-limiting embodiments of the invention, are respiratory and neurological symptoms, as well as fatigue, decreased work capacity and exercise tolerance. In particular embodiments of the invention, the organism is a human or an animal.
N,N’-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide compound (hereinafter referred to as compound 1) is known and described in WO 2014/168523 Al.
Thus, the object of the present invention is the use of N,N’-bis[2-(lH-imidazol- 2-yl)ethyl]pentanediamide compound of formula
or salt, hydrate or solvate thereof for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs. Preferably, pathological changes in the respiratory organs may be associated with respiratory and neurological symptoms, impairment of working capacity and impairment of exercise tolerance.
Another object of the invention is a pharmaceutical composition for rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, comprising a therapeutically effective amount of N,N-bis[2-(lH-imidazol-2-yl)ethyl]pentanediamide compound of formula
or salt, hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
A further object of the invention is the use of N,N-bis[2-(lH-imidazol-2-
yl)ethyl]pentanediamide compound of formula
salt, hydrate or solvate thereof for preparing a pharmaceutical composition.
At the same time, pathological changes in the respiratory organs can preferably be associated with respiratory and neurological symptoms, impairment of working capacity and exercise tolerance.
Also, the object of the invention is a method of rehabilitation therapy of the consequences of coronavirus infection associated with pathological changes in the respiratory organs, comprising administering to said organism N,N-bis[2-(lH-imidazol- 2-yl)ethyl]pentanediamide compound of formula
salt, hydrate or solvate thereof, or the aforementioned pharmaceutical composition based thereon.
DESCRIPTION OF THE DRAWINGS
Fig. 1. Relative change in DLCO (in %) in patients treated with Compound 1 compared to those receiving placebo.
Fig- 2. Violin plots of a) absolute (in L) and b) relative change in TLC (in %) in patients treated with Compound 1 compared to those receiving placebo.
Fig- 3. Violin plots of changes in lung damage area according to CT (in %) in patients treated with Compound 1 compared with those receiving placebo.
Fig. 4. Change in dyspnea on the Borg scale (difference after/before the 6- minute walk test) in patients treated with Compound 1 compared with those receiving placebo.
DETAILED DESCRIPTION OF THE INVENTION
Compound 1 is described in application WO 2014/168523 Al. Said patent application describes dicarboxylic acid bisamide derivatives suitable for use as metal chelators in the treatment of a wide variety of diseases.
WO 2016/190785A1 describes the use of Compound 1 to stimulate the regeneration of epithelial and/or connective tissues of the male reproductive system. It
was shown that Compound 1 reduces the intensity of morphological changes in the regeneration and normalization of the structure of prostate tissue in chronic abacterial prostatitis (CAP) and benign prostatic hyperplasia (BPH).
In further studies of Compound 1, it was unexpectedly found that the therapeutic use of Compound 1 helps to restore respiratory function and increase exercise tolerance in patients who underwent the acute phase of COVID-19. These data indicate the potential utility of Compound 1 for the treatment of COVID-19-induced lung tissue injury, restoration of respiratory function and exercise tolerance.
TERMS AND DEFINITIONS
The term «Compound 1» refers to N,N’-bis[2-(lH-imidazol-2- yl)ethyl]pentanediamide compound represented by the structural formula:
The term "solvate" is used to describe a molecular complex containing the compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when said solvent is water.
The term "pharmaceutically acceptable salts" or "salts" includes salts of active compounds that are 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 acids, or obtained by other methods known in the art, for example by ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, 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, semi-fumarate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate (tosylate), undecanate, valeriate and the like.
The terms "treatment", "therapy" encompass pathological conditions in mammals, preferably in humans, and include: a) reduction, b) blocking (arresting) the
course of the disease, c) alleviation of disease severity, i.e. induction of regression of the disease, d) reversing the disease or condition to which the term is applied, or one or more symptoms of the disease or condition.
The term "prophylaxis", "prevention" encompasses the elimination of risk factors as well as the prophylactic treatment of subclinical stages of disease in mammals, preferably humans, aimed at reducing the likelihood of occurrence of clinical stages of the disease. Patients for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increased risk of clinical stages of the disease compared with the general population. Preventive therapy includes a) primary prevention, and b) secondary prevention. Primary prevention is defined as prophylactic treatment of patients who have not yet reached the clinical stage of the disease. Secondary prevention is the prevention of the recurrence of the same or similar clinical condition of the disease.
Compound 1 is promising for the treatment of post-COVID syndrome, and more specifically, for the treatment of respiratory and neurological symptoms after coronavirus infection. Such symptoms may include, but are not limited to, cough, shortness of breath, pain in breathing, sensory disturbances manifested by burning sensation, stinging, goosebumps on the skin surface; thermoregulation impairment, sleep disturbances, fatigue, depression, panic attacks, anxiety, episodes of weakness.
Also, compound 1 is promising for restoration and maintenance of working capacity and exercise tolerance after coronavirus infection.
METHOD OF THERAPEUTIC USE OF THE COMPOUND
The subject matter of this invention also includes administering to a subject in need of appropriate treatment a therapeutically effective amount of the compound of the invention. By a therapeutically effective amount is meant such amount of the compound administered or delivered to a patient that will most likely result in the patient’s desired response to treatment (prophylaxis). The exact amount required may vary from subject to subject, depending on age, body weight and general condition of the patient, disease severity, method of drug administration, combined use with other drugs, and the like.
Compound 1, or a pharmaceutical composition comprising Compound 1, can be administered to a patient in any amount (preferably, the daily dose of the active substance for humans is 25-200 mg/day) and by any route of administration (oral administration is preferred), effective for treatment or prevention of the disease.
After mixing Compound 1 with a specific suitable pharmaceutically acceptable carrier at the desired dosage, the compositions can be administered to humans or other animals orally, parenterally, topically, etc.
Administration may be carried out either as a single dose or several times a day,
a week (or any other time interval), or from time to time. Moreover, the compound may be administered to patient’s body daily for a specified period (e.g., 14-30 days) followed by a period without drug administration (e.g., 1-30 days).
When the compound of the invention is used as part of a combination therapy regimen, dosing each of the components of the combination therapy is performed during the desired treatment period. The compounds which are components of the combination therapy can be administered to patient’s body both simultaneously, as a dosage containing all the components, and in the form of individual dosages of the components.
USE OF COMPOUND 1 IN COMBINATION THERAPY
Although Compound 1 of this invention can be administered as a single active pharmaceutical agent, it can also be used in combination with one or more other agents, in particular, the other agent may be a glucocorticosteroid, leukotriene receptor antagonist, bronchodilator, monoclonal antibody etc. In the case of oral coadministration, the therapeutic agents may be different dosage forms administered simultaneously or sequentially at different times, or the therapeutic agents may be combined into a single dosage form.
The phrase "combination therapy" in respect of compound 1 in combination with other pharmaceutical agents, means simultaneous or sequential administration of all agents, which in one way or another will provide a beneficial effect of drug combination. Co-administration implies, in particular, joint delivery, for example, in a single tablet, capsule, injection or other form having a fixed ratio of active substances, as well as simultaneous delivery in several, separate dosage forms for each compound, respectively.
Thus, administration of Compound 1 of the present invention can be carried out in combination with additional therapies known to those skilled in the art of prevention and treatment of related diseases, comprising use of antibacterial preparations, preparations to suppress symptoms or side effects of one of the drugs.
If the dosage form is a fixed dose, such a combination uses the compound of the invention in an acceptable dosage range. Compound 1 can be administered to the patient's body sequentially with other agents, when the combination of these drugs is not possible. The invention is not limited to the sequence of administration; the compound of the present invention may be administered to the patient simultaneously, before or after administration of another drug.
EXAMPLES
Preparation of compound 1
Preparation of Compound 1, which is the subject matter of the present invention, as well as a number of other chemical compounds, is described in application
WO 2014/168523 Al. Said patent application describes dicarboxylic acid bisamide derivatives suitable for use as metal chelators.
Characterization of biological activity of compound 1
Biological activity of Compound 1 was studied in a Phase II, multicentre, double-blind, randomized, clinical trial over a 4-week period in patients with COVID- 19-induced injury of respiratory system. The therapeutic use of Compound 1 for 4 weeks has been shown to be effective in suppressing the development of lung damage, restoring respiratory function and increasing exercise tolerance in patients who underwent the acute phase of CO VID-19.
Investigation of Compound 1 activity in the course of clinical study
In Phase II, multicenter, double-blind, randomized, parallel-group clinical trial evaluating the efficacy and safety of various doses of Compound 1 versus placebo over a 4-week period in patients with COVID-19-induced injury of respiratory system (NCT04527354), it was found that the therapeutic use of Compound 1 effectively promotes suppression of the development of lung damage, restores respiratory function and increases exercise tolerance in patients after acute phase of COVID-19. Thus, Compound 1 is potentially applicable for the treatment of COVID-19-induced lung tissue damage, restoration of respiratory function and exercise tolerance.
During the clinical trial, patients who met the eligibility criteria were randomized to one of two groups in a 1 : 1 ratio.
Compound 1 at a dose of 50 mg per day
Placebo
At the study therapy stage, patients received Compound 1 or placebo for 4 weeks in connection with the recommended standard medical rehabilitation program in a day hospital or outpatient setting (according to the interim guidelines "Medical Rehabilitation for Novel Coronavirus Infection (COVID 19)", Version 2 of 07.31. 2020). Compound 1 or placebo was administered orally once a day, 30 minutes before a meal.
Analysis of the results of clinical study in patients who underwent the acute phase of CO VID-19 showed that Compound 1 effectively restores respiratory functions (relative increase in diffusing capacity of the lungs (DLCO) is > 10%). Confirmation can be found in Fig. 1, which shows the relative change in DLCO (%) in patients treated with Compound 1 at a dose of 50 mg (indicated as "Compound 1") and in patients treated with placebo (indicated as "Placebo") at >35 days after the onset of Covid- 19 symptoms. For each area of the diagram, the value n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
In addition, there was a significant difference in the increase in total lung capacity (TLC). Fig. 2 shows violin plots of a) absolute (in L) and b) relative change in TLC (in %) in patients received Compound 1 at a dose of 50 mg (indicated as "Compound 1") and in patients received placebo (indicated as "Placebo"), with an initial DLCO < 80%. For each area of the diagram, the value n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
Also, there was a significant decrease in the area of lung damage. Fig.3 shows violin plots of changes in the area of lung damage according to CT (in %) in patients treated with Compound 1 at a dose of 50 mg (indicated as "Compound 1") and in patients treated with placebo (indicated as "Placebo"), with an initial DLCO level < 80%. For each area of the diagram, the value n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
Thus, one of the effects of using Compound 1 is the restoration of respiratory function in patients included in the study.
The use of Compound 1 also led to the restoration of COVID-19-induced decrease in exercise tolerance. After 4 weeks of therapy, patients treated with Compound 1 were characterized by a significantly greater reduction in the degree of dyspnea after 6 minutes of walking, compared with patients in the placebo group. Fig. 4 shows change in dyspnea on the Borg scale (difference after/before the 6-minute walk test) in patients treated with Compound 1 at a dose of 50 mg (indicated as "Compound 1") and in patients treated with placebo (indicated as "Placebo"), with an initial DLCO level < 80%. For each area of the diagram, the value n is the number of patients. Designations of tests used to compare medians (median (Iq; 3q)): m - median test; qr - quantile (median) regression.
Thus, the use of Compound 1 helps to restore exercise tolerance and daily activities in patients who have had an acute coronavirus infection.
Moreover, in the course of clinical study, Compound 1 was also analyzed for its effect on the restoration of psycho-emotional stability of patients according to the King scoring questionnaire for interstitial lung diseases (KBILD). It was shown that Compound 1 seems to accelerate the recovery of psycho-emotional stability in patients, which is associated with the restoration of respiratory function and exercise tolerance, and not the direct pharmacological action of the drug.
Claims
1. Use of N,N’-6Hc[2-(lH-imidazol-2-yl)ethyl]pentanediamide compound of formula
or salt, hydrate or solvate thereof for rehabilitation therapy of the consequences of coronavirus infection.
2. The use according to claim 1, wherein the consequences of coronavirus infection are pathological changes in the respiratory organs.
3. The use according to claim 1, wherein the consequences of coronavirus infection include respiratory and neurological symptoms, fatigue, impairment of working capacity and impairment of exercise tolerance.
4. A method for rehabilitation therapy of the consequences of coronavirus infection, comprising administering to said organism N,N'-bis[2-(lH-imidazol-2- yl)ethyl]pentanediamide compound of formula
solvate thereof.
5. The method according to claim 4, wherein the consequences of coronavirus infection are pathological changes in the respiratory organs.
6. The method according to claim 4, wherein the consequences of coronavirus infection include respiratory and neurological symptoms, fatigue, impairment of working capacity and impairment exercise tolerance.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2022106931A RU2022106931A (en) | 2022-03-17 | APPLICATION OF BISAMIDE DICARBOXYLIC ACID DERIVATIVE TO RESTORATION OF EXTERNAL RESPIRATORY FUNCTION AFTER CORONAVIRUS INFECTION | |
| RU2022106931 | 2022-03-17 |
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| WO2023177328A1 true WO2023177328A1 (en) | 2023-09-21 |
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| PCT/RU2023/050050 WO2023177328A1 (en) | 2022-03-17 | 2023-03-16 | Bisamide derivative of dicarboxylic acid for use in restoring the external respiratory function after coronavirus infection |
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