CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is filed under 35 U.S.C. § 371 as the U.S. national phase of International Patent Application No. PCT/GB2018/053591, filed Dec. 11, 2018, which designated the United States, and which claims the benefit of priority to GB Patent Application No. 1720622.8 filed Dec. 11, 2017, and to GB Patent Application No. 1720624.4 filed Dec. 11, 2017, and to GB Patent Application No. 1802354.9 filed Feb. 13, 2018, and to GB Patent Application No. 1802353.1 filed Feb. 13, 2018. each of which is hereby incorporated by reference in its entirety including all tables, figures, and claims.

FIELD OF THE INVENTION

This invention relates to organic compounds and their use as pharmaceuticals, more specifically, to a novel use of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof, namely in the prevention or reduction of acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND OF THE INVENTION

A large number of cytokines participate in the inflammatory response, including interleukin-1 (IL-1), IL6, IL-8 and TNF-α. Overproduction of cytokines such as IL-1 and TNF-α are implicated in a wide variety of diseases, including acute exacerbations of chronic obstructive pulmonary disease (AECOPD).

Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases. International patent application WO2005/009973 discloses various pyrazole- and imidazole-based compounds or pharmaceutically acceptable derivatives thereof that have cytokine inhibitory activity. It discloses such compounds can be used to treat conditions associated with p38 kinases, especially p38α and β kinases, including chronic obstructive pulmonary disease (COPD). WO2005/009973 discloses 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide as one such novel pyrazole-based p38 kinase inhibitor and describes processes for its preparation. 3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide has the following chemical structure:



This compound is also known as BCT197.

Chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are distinct indications or at least concern distinct disease states that require different treatment. Acute exacerbations of COPD are associated with increased mortality, accelerated decline in lung function, and impaired quality of life.

WO 2013/139809 discloses the use of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide and pharmaceutically acceptable derivatives thereof and use of these compounds in treating AECOPD. A single oral dose of 3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide was administered and the effect on recovery of AECOPD to the stable disease state was studied. A single dose administered orally accelerates the recovery to the stable disease state.

It has surprisingly been found that the dosage regimens of the present invention are particularly effective for preventing or reducing the rate of recurrent acute exacerbations of COPD.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a pharmaceutical composition for the treatment of a human patient suffering from COPD, comprising administering to the patient an effective dose or doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose, and repeating the administration to the patient of the effective dose or doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof after a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus of at least 1 month from the start of the preceding administration.

Hereafter, reference to 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide will include reference to the compound per se and pharmaceutically acceptable derivatives thereof.

In a second aspect, the present invention provides a pharmaceutical composition for the treatment of a human patient suffering from COPD, comprising administering to the patient three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose, and repeating the administration to the patient of the three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide thereof after a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus of at least 1 month from the start of the preceding administration.

In a third aspect, the invention provides a method for the prevention or reduction in the rate of acute exacerbations of COPD in a human patient, comprising administering to the human patient three separate therapeutically effective doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose, and repeating the administration to the patient of the three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide after a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus of at least 1 month from the start of the preceding administration.

In a fourth aspect, the invention provides a method for the prevention or reduction in the rate of acute exacerbations of COPD in a human patient, comprising: (a) administering to the human patient three separate therapeutically effective doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose; (b) discontinuing the administration to the patient with 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide for a period of at least 1 month (measured from the start of the preceding administration); and (c) administering to the human patient three separate therapeutically effective doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose.

In a fifth aspect, the present invention provides a pharmaceutical composition for the treatment of a human patient suffering from an acute exacerbation of COPD or at risk of developing an acute exacerbation of COPD, comprising administering to the patient an effective dose or doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose, and repeating the administration to the patient of the effective dose or doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl benzamide or a pharmaceutically acceptable derivative thereof after a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus of at least 1 month from the start of the preceding administration.

In a sixth aspect, the present invention provides a pharmaceutical composition for the prevention of a reoccurrence of an acute exacerbation of COPD in a human patient suffering from an acute exacerbation of COPD, comprising administering to the patient three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose. The human patient may not suffer from a reoccurrence of an acute exacerbation of COPD for at least 30 days after the last dose of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide in the administration, or at least 60 days, or at least 90 days, or at least 120 days, or at least 150 days, or at least 180 days. The administration to the patient of the three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide may be repeated after a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus of at least 1 month from the start of the preceding administration.

In a seventh aspect, the present invention provides a pharmaceutical composition for the prevention of a treatment failure of an acute exacerbation of COPD in a human patient suffering from an acute exacerbation of COPD, comprising administering to the patient three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose. The human patient may not suffer from a treatment failure within 1 day after the last dose of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide in the administration, preferably within 2 days, more preferably within 5 days, more preferably within 7 days, most preferably within 14 days after the last dose of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide in the administration. The administration to the patient of the three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide may be repeated after a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus of at least 1 month from the start of the preceding administration.

The invention also provides a kit comprising at least one, or at least three, therapeutically effective dose of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof, and instructions for treating a human patient in accordance with any of the above numbered aspects of the invention, said instructions comprising directions for administering the at least one dose, or at least three, in accordance with any of the above numbered aspects of the invention.

Essentially, the treatment of the present invention is a prophylactic treatment of AECOPD. It amounts to a low frequency maintenance therapy for preventing or reducing AECOPD. The administration of the composition of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide for the first time (i.e., the single or course of multiple doses that are administered over the initial period of not longer than seven days) will be known as the first administration. This is essentially a period of administration whereafter treatment ceases (the “hiatus”) and there is no treatment with 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide until a further period of administration takes place after the at least one month. The repeat period of administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide that takes place at least 1 month after the start of the first administration will be known as the second administration. Any additional administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide that takes place after the second administration will be known as further or numbered administrations (e.g., the third, fourth, fifth administration, etc.).

Within a period of administration, i.e., in the first administration, the patient will take one or more doses. These will be referred to a single dose or a course of doses (where a plurality of doses is taken).

Thus, in a preferred embodiment, within each period of administration, i.e., the first, second or third, a course of three separate doses are taken for the period of not longer than seven days.

In a further preferred embodiment, within each period of administration, i.e., the first, second or third, a course of three separate doses are taken for the period of not longer than five days.

With regard to any preceding aspect of the invention, the 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus prior to the repeat administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide is preferably at least 2 months, preferably about 3 months from the start of the preceding administration. The treatment hiatus can also be longer, for example, at least 4, 5 or 6 months after the start of the preceding administration. Most preferably, the repeat administration (i.e., second, third, fourth, etc., administration) is taken about 3 months (+ or −1 week) after the start of the preceding administration.

The 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide treatment hiatus prior to the repeat administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide is preferably less than 7 months, more preferably less than 6 months, more preferably less than 5 months, more preferably less than 4 months after the start of the preceding administration.

Preferably the composition or method according to any aspect above comprises administering three separate doses of a pharmaceutical composition comprising 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide, wherein the dosing is on days 1, 4 and 7. In a highly preferred embodiment of the invention, the composition or method according to any aspect above comprises administering three separate doses of a pharmaceutical composition comprising 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof, over a period of five days with at least one day between every dose administration.

In a most preferred embodiment, the composition or method according to any aspect above comprises administering three separate doses of a pharmaceutical composition comprising 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof, wherein the dosing is on days 1, 3 and 5.

In the above embodiments, the three separate doses constitute the administration relating to the first, second, third or further administration as defined above. Thus, each “administration” of the three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide is then punctuated by the treatment hiatus when defined. Then a further “administration” of three doses may take place, followed by a further treatment hiatus, and so forth. Such sequential administrations followed by the treatment hiatus preferably results in the effective reduction or elimination of further acute exacerbations of COPD.

Preferably the composition or method according to any aspect above comprises administering the second administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide three months after the start of the first administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof.

Further repeat administrations may take place after the first and second administrations of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof. For example, the repeat administrations of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide may be chronic. Therefore, the patient may take first, second, third, fourth, . . . n administrations, where n is an integer of 5 to 150.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has classified the severity of airflow limitation in COPD based on post-bronchodilator FEV1into four categories: GOLD 1-GOLD 4. Pocket guide to COPD diagnosis, management and prevention, A guide for health care professionals, Global Initiative for Chronic Obstructive Lung Disease, Inc, 2016. The composition, methods and kits of the present invention are intended to be particularly useful in the treatment of COPD 3 and COPD 4, and also in COPD 2 patients who are about to extend into COPD 3 or COPD 4, i.e., used to prevent GOLD 3 and 4 stage disease. It is known that with each exacerbation, patients are less likely to reach baseline levels of respiratory function. This leads to a vicious cycle wherein the more severe the acute exacerbations a patient has, the longer the exacerbations will take to remit, and the less likely to return to the pre-exacerbation health, leading to increasing susceptibility to more frequent acute exacerbations, getting worse each time, decreasing quality of life. This can be fatal. It is in these specific patients, the optional additional fourth dose may be given in addition to the previous three doses, but within the same 7 day period.

The invention also provides a kit comprising at least six separate therapeutically effective doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof, and instructions for treating a human patient suffering from COPD, said instructions comprising directions for administering the first, second and third doses separately over a period of not longer than seven days with at least one day between every dose administration, and directions for administering the fourth, fifth and sixth doses separately over a period of not longer than seven days with at least one day between every dose administration, said fourth dose being administered at least 1 month after the administration of the first dose.

The invention also provides a kit comprising three separate therapeutically effective doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide, and instructions for treating a human patient suffering from AECOPD, said patient having <2% blood eosinophils, said instructions comprising directions for administering said doses separately over a period of not longer than seven days with at least one day between every dose administration. In a preferred embodiment the dosing is on days 1, 3 and 5.

In a preferred embodiment, there is provided a pharmaceutical composition for the treatment of a human patient suffering from COPD, comprising administering to the patient three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose; stopping administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide for a period of about 3 months (+ or −1 week), and administering to the patient a further three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose.

In a further preferred embodiment, there is provided a method for the prevention or reduction in the rate of acute exacerbations of COPD in a human patient, comprising administering to the patient three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose; stopping administration of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide for a period of about 7 to 13 weeks, more preferably 10 to 12 weeks, and administering to the patient a further three doses of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide over a period of not longer than seven days with at least one day between every dose.

