WO2018197638A1

WO2018197638A1 - Novel use of (5r)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-d-prolinamide

Info

Publication number: WO2018197638A1
Application number: PCT/EP2018/060791
Authority: WO
Inventors: Mike TROWER
Original assignee: Nerre Therapeutics Limited
Priority date: 2017-04-27
Filing date: 2018-04-26
Publication date: 2018-11-01

Abstract

Use of the compound (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl]-2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D- prolinamide or pharmaceutically acceptable salts thereof and pharmaceutical compositions containing it for the treatment of chronic cough and to combinations for such a use.

Description

NOVEL USE OF

(5R)-5-[5-[{2-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]-2-METHYLPROPANOYL}(METHYL)AMINO]-4-(4-FLUORO-2-METHYL PHENYL)-2-PYRIDINYL]-2-METHYL-D-PROLINAMIDE

FIELD OF THE INVENTION

This invention relates to the new use of the compound (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or pharmaceutically acceptable salts thereof and pharmaceutical compositions containing it for the treatment of chronic cough and to combinations for such a use.

BACKGROUND OF THE INVENTION

WO2009/138393 describes a number of polyamide pyridine compounds derivatives having NK1 antagonist activity, including the (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide) having the following chemical structure (I).

The compound (I) and pharmaceutically acceptable salts thereof are described in the aforementioned specifications as antagonists of tachykinin receptors, including substance P (SP) and other neurokinin receptors, both in vitro and in vivo and are thus of use in the treatment of conditions mediated by tachykinins, including Substance P (SP) and other neurokinins.

Particularly, the compound (I), and pharmaceutically acceptable salts or solvates thereof are described as useful in the treatment of central nervous system (CNS) disorders.

We have now surprisingly found that the compound (I) or pharmaceutically acceptable salts thereof are also useful in the treatment of chronic cough or chronic refractory cough.

Furthermore we have found that the compound (I) or pharmaceutically acceptable salts thereof are useful in the treatment of acute cough.

Cough is a defensive reflex action of the respiratory system that is activated to clear the upper airways (Chung & Pavord, Lancet 2008; 371:1364-74). However, excessive coughing is the commonest reason for patients seeking medical care (Burt & Schappert, Vital and health statistics. Series 13, Data from the National Health Survey 2004; (157):l-70; Schappert & Burt, Series 13, Data from the National Health Survey 2006; (159):l-66) and has a significant impact on patient quality of life (French et al., Archives of internal medicine 1998; 158(15):1657-61; French et al., Chest 2005; 127(6):1991-8).

Acute cough is the commonest new presentation in primary care and is commonly associated with viral upper respiratory tract infections, where this symptom usually resolves spontaneously within a 3 week period. It is also the symptom most associated with acute exacerbations and hospitalisations with asthma and COPD (Morice et al., Thorax. 2006, 61 Suppl l:il-24).

Chronic coughing (in which persists in a troublesome form for more than eight weeks duration) however may affect up to 12% of the UK population (Ford et al., Thorax 2006; 61(ll):975-9) and 18% of the US (Barbee et al., Chest. 1991; 99(l):20-6), afflicts women more often than men and generally has an onset from middle age (Ford et al., Thorax 2006; 61(ll):975-9; Irwin et al., The American review of respiratory disease 1981; 123(4 Pt l):413-7; Irwin et al., Chest 2006; 129(1 Suppl):lS-23S; Janson et al., The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology 2001; 18(4):647-54). Chronic coughing may be associated with many conditions including interstitial lung diseases (also called parenchymal diseases) such as: emphysema, idiopathic pulmonary fibrosis (IPF) and sarcoidosis; airway diseases such as asthma, chronic bronchitis, chronic postnasal drip, eosinophilic bronchitis and chronic obstructive pulmonary disease(COPD); chronic infections such as: bronchiectasis, tuberculosis, cystic fibrosis; tumours such as: bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours; cardiovascular disease such as: left ventricular failure, pulmonary infarction, aortic aneurysm; other diseases such as: reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis; drug related such as: administration of angiotensin-converting enzyme inhibitors (Chung & Pavord, Lancet 2008; 371:1364-74). Chronic coughing has been shown to have significant physical, social and psychological consequences (Birring et al., Thorax 2003; 58(4):339-43; French et al., Chest 2002; 121(4):1123-31). Patients often suffer complications such as chest and abdominal pains, retching and vomiting, urinary incontinence and even cough syncope. Many are embarrassed and stigmatised by this symptom and therefore avoid public places and social gatherings. Depression scores in this patient population have been found to be comparable to those seen in other serious chronic illnesses such as rheumatoid arthritis and sickle cell disease (Dicpinigaitis et al., Chest 2006; 130(6):1839-43).

Clinicians cannot identify a treatable cause for chronic cough in about 40% of patients (Haque et al., Chest 2005; 127(5):1710-3); as a result the treatment options for these chronic treatment-refractory cough patients are very limited. To date the only drug therapies that have been shown to be effective in randomised controlled trials in this patient group are morphine (Morice et al., American journal of respiratory and critical care medicine 2007; 175(4):312-5) and gabapentin (Ryan et al., Lancet. 2012; 380(9853):1583- 9). Other studies have suggested treatments such as amitriptyline and pregabalin (Halum et al., The Laryngoscope 2009; 119(9):1844-7) may be of help, but all these available pharmacological treatment choices are frequently associated with intolerable side effects such as drowsiness, tiredness, gastrointestinal disturbances, and some of these agents, such as for example morphine, are also addictive.

It is hypothesised that the basis of chronic cough is from hypersensitivity of peripheral airway sensory afferent neurons and neurons centrally in the brainstem that, together, govern the cough reflex, resulting in enhanced cough in response to otherwise trivial stimuli or in the absence of an initiating event (Canning et al; CHEST Expert Cough Panel. Chest 2014 Dec; 146(6):1633-48)

Thus there is an urgent need to identify new, effective and well-tolerated therapies for this debilitating condition to alleviate patient suffering.

SUMMARY OF THE INVENTION

The solution provided by the present invention is the use of the compound of formula (I) or f cough.

Specifically, in a first aspect, the invention provides a method of treatment of cough which comprises administering to a human in need thereof an effective amount of (5R)-5- [5-[{2-[3, 5-bis (trifluoromethyl) phenyl]-2-methylpropanoyl} (methyl) amino]-4-(4-fluoro- 2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or a pharmaceutically acceptable salt thereof.

In a further aspect thereof, the invention provides the use of (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic cough.

In a yet further aspect thereof, the invention provides (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or a pharmaceutically acceptable salt thereof for use in the treatment of chronic cough.

In another aspect, the invention provides a pharmaceutical composition comprising (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or a pharmaceutically acceptable salt thereof for use in the treatment of chronic cough.

In a further aspect, the present invention provides a combination which comprises (a) 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or a pharmaceutically acceptable salt thereof and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of chronic cough. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of (5R)-5-[5-[{2-[3,5-bis (trifluoromethyl) phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic cough.

(5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl]-2-methylpropanoyl} (methyl) amino]-

4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide) or a pharmaceutically acceptable salt thereof has the following chemical structure (I).

The wedge shaped bond indicates that the bond is above the plane of the paper and it is referred to as β configuration. The broken bond indicates that the bond is below the plane of the paper and is in the a configuration.

The compound (I) or its pharmaceutically acceptable salts may be prepared by the processes described in International Patent Application No. WO2009/138393, which is incorporated herein by reference.

Specifically, the Examples 1 and 2 of WO2009/138393 describe the synthesis of the compound (I) as free base and as hydrochloride salt respectively.

The Example 7 of WO2009/138393 describes the synthesis of anhydrous crystalline Form 1 of compound of formula (I).

The anhydrous crystalline Form 1 of compound of formula (I) exhibits the XRPD pattern provided in Table 1. The XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Ka X-radiation. Table 1

The Examples 8-11 of WO2009/138393 describes the compound of formula(I) as tartrate, benzoate, citrate and bis hydrochloride salt respectively.

It will be appreciated that for use in medicine, the salts of the compound (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with pharmaceutically acceptable organic or inorganic acids.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably pharmaceutically acceptable salts of the compound of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids. Salts having a non-pharmaceutically acceptable anion are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.

Certain salts of the compound (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that salts of the compound (I) may exist in tautomeric forms and these are also included within the scope of the present invention.

The compound (I) may form acid addition salts with one or more equivalents of the acid. The present invention may employ all possible stoichiometric and non-stoichiometric forms thereof in the formulations of the invention.

The compound (I) or pharmaceutically acceptable salts thereof may exist in the form of a solvate.

It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallised. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate".

Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, ethanol, /^'so-propyl alcohol, and V-methyl pyrrolidinone may be used to form solvates. Methods for the identification of solvated include, but are not limited to, NMR and microanalysis.

The compound (I) or pharmaceutically acceptable salts thereof may exist in different polymorphic forms.

Polymorphism is defined as the ability of an element or compound to crystallise in more than one distinct crystalline phase. Thus, polymorphs are distinct solids sharing the same molecular formula, however since the properties of any solid depends on its structure, different polymorphs may exhibit distinct physical properties such as different solubility profiles, different melting points, different dissolution profiles, different thermal and/or photostability, different shelf life, different suspension properties and different physiological absorption rate. Inclusion of a solvent in the crystalline solid leads to solvates, and in the case of water as a solvent, hydrates.

Included within the compound (I) are all solvates (including hydrates) and polymorphs of the compound (I) or pharmaceutically acceptable salts thereof. The compound (I) or pharmaceutically acceptable salts or solvates thereof has now been determined to be useful in the treatment of cough.

Thus, in one embodiment, the invention provides the compound (I) or pharmaceutically acceptable salts or solvates thereof for use in the treatment of chronic cough,

In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide for use in the treatment of chronic cough.

In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide anhydrous crystalline Form 1 for use in the treatment of chronic cough.

In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide hydrochloride for use in the treatment of chronic cough.

In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide bus-hydrochloride for use in the treatment of cough.

In a further embodiment, the invention provides a method for the treatment of chronic cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or pharmaceutically acceptable salts thereof.

In a further embodiment, the invention provides a method for the treatment of chronic cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide.

In a further embodiment, the invention provides a method for the treatment of chronic cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide anhydrous crystalline Form

1.

In a further embodiment, the invention provides a method for the treatment of chronic cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide) hydrochloride.

In a further embodiment, the invention provides a method for the treatment of chronic cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide bis hydrochloride. In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide for use in the treatment of chronic refractory cough.

In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide anhydrous crystalline Form 1 for use in the treatment of chronic refractory cough.

In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide hydrochloride for use in the treatment of chronic refractory cough.

In a further embodiment, the invention provides (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide bus-hydrochloride for use in the treatment of refractory cough.

In a further embodiment, the invention provides a method for the treatment of chronic refractory cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or pharmaceutically acceptable salts thereof.

In a further embodiment, the invention provides a method for the treatment of chronic refractory cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D- prolinamide.

In a further embodiment, the invention provides a method for the treatment of chronic refractory cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D- prolinamide anhydrous crystalline Form 1.

In a further embodiment, the invention provides a method for the treatment of chronic refractory cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D- prolinamide) hydrochloride.

In a further embodiment, the invention provides a method for the treatment of chronic refractory cough which comprises administering to a human in need thereof an effective amount of 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D- prolinamide bis hydrochloride.

In one embodiment, the invention provides a compound of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of acute cough. In one embodiment, the invention provides a compound of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of chronic refractory cough.

All numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about."

The term "acute cough" refers to cough which persists in a troublesome form for upto three weeks.

The term "chronic cough" refers to cough which persists in a troublesome form for more than eight weeks.

As used herein, the term "chronic refractory cough" refers to cough which persists in a troublesome form for more than eight weeks and for which there is either no objective evidence of an underlying cause as determined after routine clinical investigation (idiopathic) or a cough that did not respond to standard treatment for the identified underlying cause (Gibson & Vertigan, 2015).

As used herein, the term "chronic refractory cough" is interchangeable with the terms "refractory chronic cough", "chronic unexplained cough", "chronic undiagnosed cough", "chronic idiopathic cough", "cough hypersensitivity syndrome", or "chronic treatment- resistant cough" and is intended to have the same meaning.

It should be understood that the terms "a" and "an" as used herein refer to "one or more" of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise.

As used herein, the terms "treatment," "treating," and the like, refer to obtaining a desired pharmacologic, physiologic, dermatologic or cosmetic effect. The effect may be prophylactic in terms of completely or partially preventing a condition or disease or disorder or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a condition or disease or disorder and/or adverse symptom or effect attributable to the condition or disease or disorder.

"Treatment," thus, for example, covers any treatment of a condition or disease in a mammal, particularly in a human, and includes: (a) preventing the condition or disease, disorder or symptom thereof from occurring in a subject which may be predisposed to the condition or disease or disorder but has not yet been diagnosed as having it; (b) inhibiting the condition or disease, disorder or symptom thereof, such as, arresting its development; and (c) relieving, alleviating or ameliorating the condition or disease or disorder or symptom thereof, such as, for example, causing regression of the condition or disease or disorder or symptom thereof.

As used herein, the term "effective amount" means that amount of a drug or a therapeutic agent or a pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher, clinician or veterinarian. As used herein, "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" mean a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be pharmaceutically-acceptable e.g. of sufficiently high purity.

The term "combination" as used herein refers to either a fixed combination in one dosage unit form, or non-fixed combination.

The term "fixed combination" means that the active ingredients, e.g. a compound of formula (I) or pharmaceutically acceptable salt thereof and a combination partner (e.g. another "therapeutic agent" or "co-agent" as explained below) are both administered to a patient simultaneously in the form of a single entity or dosage.

The term "non-fixed combination" means that the active ingredients, e.g. a compound (I) or pharmaceutically acceptable salt thereof and a combination partner, ((e.g. another

"therapeutic agent" or "co-agent" as explained below) are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no, specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the compound (I) and the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The patient to be treated using the invention described herein is preferably a human.

In one embodiment of the present invention, chronic cough is chronic refractory cough.

Chronic cough is a common symptom in people who develop interstitial lung diseases (ILDs)(Brown, 2006; 129(1 Suppl):180S-185S), such as sarcoidosis, emphysema and idiopathic pulmonary fibrosis (IPF).

The term interstitial lung diseases (ILDs), also known as diffuse parenchymal lung disease (DPLD), refers to a group of lung diseases affecting the interstitium (the tissue and space around the air sacs of the lungs). The interstitium is a lace-like network of tissue that extends throughout both lungs. The interstitium provides support to the lungs' microscopic air sacs (alveoli). Tiny blood vessels travel through the interstitium, allowing gas exchange between blood and the air in the lungs. Normally, the interstitium is so thin it cannot be seen on chest X-rays or computerised tomography (CT) scans.

All forms of ILD cause thickening of the interstitium. The thickening can be due to inflammation, scarring, or extra fluid (edema). Some forms of ILD are short-lived; others are chronic and irreversible.

ILDs include idiopathic pulmonary fibrosis (IPF), a chronic, progressive form of fibrosis (scarring) of the interstitium. Cough is estimated to be present in 84% of patients with IPF, is more prevalent in patients who have never smoked or who have more advanced disease and is an independent predictor of disease progression (Ryerson et al., Respirology 2011;16:969-75).

IPF is a progressive and usually fatal course with a medium survival of 2-3 years following diagnosis; its cause is unknown. Patients with IPF are usually between 50 to 70 years old and the incidence is lower in women (7.4 cases per 100,000 per year) then men (10.7 cases per 100,000 per year). The incidence, prevalence and death increase with age. At present, no pharmacological therapy is able to cure the disease and most treatment strategies have been based on eliminating or suppressing the inflammatory component though the condition responds poorly to immunosuppressive therapies. Recently however two drugs with anti-fibrotic activity, pirfenidone and nintedanib, have been shown in placebo controlled clinical trials to slow, but not halt disease progression.

ILDs may also include:

-Idiopathic interstitial pneumonias (IPP) such as nonspecific interstitial pneumonia, desquamative interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, lymphoid interstitial pneumonia, combined pulmonary fibrosis and emphysema syndrome (CPFE);

-Environmental and occupational diseases that are due to hypersensitivity for example: pneumoconiosis such as asbestosis, silicosis, and due to coal dust, beryllium, hard metal dust exposure, and extrinsic allergic alveolitis for example 'bird fancier's lung, radiation fibrosis syndrome, or due to exposure to bacteria and molds such as with mycoplasma pneumonia;

-Multi-system diseases that are associated with autoimmune diseases for example: connective tissue diseases such as systemic sclerosis, sarcoidosis, rheumatoid arthritis, Wegener's granulomatosis; certain muscle diseases such as polymyositis, dermatomyositis, and the anti-synthetase syndrome, or as a result of drug reactions for example with amiodarone, methotrexate and bleomycin;

-Rare lung diseases for example: pulmonary alveolar proteinosis, pulmonary histiocytosis, pulmonary eosinophilia and idiopathic pulmonary haemosiderosis,

Hermansky-Pudlak syndrome, tuberose sclerosis (lymphangioleiomyomatosis);

-Genetic or inherited diseases for example: familial pulmonary fibrosis (FPF) or familial interstitial pneumonia (FIP);

-Bronchiolitis Obliterans Syndrome following lung transplantation.

Treatment of chronic cough in interstitial lung diseases (ILDs) such as IPF, emphysema and sarcoidosis remains problematic for both patients and physicians, particularly in the later stages of the condition when it may be associated with increasingly severe breathlessness. In such cases, palliative therapy using conventional anti-tussive agents such as opiate-derived preparations often proves to be of limited benefit.

Thus, according to a further embodiment of the present invention, chronic cough is due or associated with interstitial lung diseases (ILDs).

In another embodiment, the present invention provides a method of treatment of chronic cough due or associated with sarcoidosis, emphysema or idiopathic pulmonary fibrosis (IPF) comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I ) or pharmaceutically acceptable salts thereof. In another embodiment, the present invention provides a method of treatment of chronic cough due or associated with sarcoidosis, comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof. In another embodiment, the present invention provides a method of treatment of chronic cough due or associated with emphysema comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof. In another embodiment, the present invention provides a method of treatment of chronic cough due or associated with emphysema comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof. Chronic cough is also a common symptom in people who develop airway diseases such as asthma, chronic bronchitis, chronic postnasal drip, eosinophilic bronchitis and chronic obstructive pulmonary disease; chronic infections such as: bronchiectasis, tuberculosis, cystic fibrosis; tumours such as: bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours; cardiovascular disease such as: left ventricular failure, pulmonary infarction, aortic aneurysm; other diseases such as: reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis; drug related such as: administration of angiotensin-converting enzyme inhibitors: other diseases such as: reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis; drug related such as: administration of angiotensin- converting enzyme inhibitors.

Thus, according to a further embodiment of the present invention, chronic cough is due or associated with asthma, chronic bronchitis, chronic postnasal drip, eosinophilic bronchitis and chronic obstructive pulmonary disease (COPD) or cough is upper airways cough syndrome (UACS).

In a further embodiment, the present invention provides a method of treatment of chronic cough due or associated with asthma, chronic bronchitis, chronic postnasal drip, eosinophilic bronchitis and chronic obstructive pulmonary disease (COPD) or upper airways cough syndrome (UACS), comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof.

Thus, according to a further embodiment of the present invention, chronic cough is due or associated with chronic infections such as bronchiectasis, tuberculosis, cystic fibrosis.

In a further embodiment, the present invention provides a method of treatment of chronic cough due or associated with chronic infections such as bronchiectasis, tuberculosis, cystic fibrosis, comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I ) or pharmaceutically acceptable salts thereof.

Thus, according to a further embodiment of the present invention, chronic cough is due or associated with tumours such as bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours.

In a further embodiment, the present invention provides a method of treatment of chronic cough due or associated with tumours such as bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours, comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof. Thus, according to a further embodiment of the present invention, chronic cough is due or associated with cardiovascular disease such as left ventricular failure, pulmonary infarction, aortic aneurysm.

In a further embodiment, the present invention provides a method of treatment of chronic cough due or associated with cardiovascular disease such as left ventricular failure, pulmonary infarction, aortic aneurysm, comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof. Thus, according to a further embodiment of the present invention, chronic cough is due or associated with reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis.

In a further embodiment, the present invention provides a method of treatment of chronic cough due or associated with reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis, comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof.

In a further embodiment, the present invention provides of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic cough due or associated with sarcoidosis, emphysema or idiopathic pulmonary fibrosis, with asthma, chronic bronchitis, chronic postnasal drip, eosinophilic bronchitis and chronic obstructive pulmonary disease (COPD), with chronic infections such as bronchiectasis, tuberculosis, cystic fibrosis, with lung tumours such as bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours, with cardiovascular disease such as left ventricular failure, pulmonary infarction or aortic aneurysm.

In a further embodiment, the present invention provides of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic cough due or associated with idiopathic pulmonary fibrosis (IPF) or with lung tumours such as bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours or with chronic obstructive pulmonary disease (COPD). Further, the compound of formula (I) and salts thereof are suitable for use in a method of treating pulmonary fibrosis of Interstitial lung diseases (ILDs)such as idiopathic pulmonary fibrosis.

Moreover, in a still further aspect provided is a method for treatment of pulmonary fibrosis, such as idiopathic pulmonary fibrosis comprising administering to a human in need thereof a therapeutically effective amount of the compound of formula (I).

In one embodiment, the human is a paediatric patient.

The activity of the compound of formula(I) or pharmaceutically acceptable salts thereof can be assessed in assays for mechanisms that can underlie the cough pathology and are thus important in determining the potential of compound of formula(I) or pharmaceutically acceptable salts thereof as an anti-tussive agent. These include assays of neuronal immunomodulation/ hypersensitivity using both isolated airway sensory nerves or/ and in vivo models. In addition the anti-tussive utility of compound of formula(I) or pharmaceutically acceptable salts thereof can be investigated in clinical studies.

Pharmaceutical compositions for use in accordance with the present invention may be formulated in a conventional manner for use in human and veterinary medicine using one or more pharmaceutically acceptable carriers or excipients.

Thus, the compound (I) or its pharmaceutically acceptable salts may be formulated for oral, buccal, parenteral, and topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For buccal administration the composition may take the form of tablets or formulated in conventional manner.

The compound (I) or its pharmaceutically acceptable salts may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compound (I) or its pharmaceutically acceptable salts can be formulated for dermal administration.

Dermal administration may include topical application or transdermal administration.

Transdermal application can be accomplished by suitable patches, emulsions, ointments, solutions, suspensions, pastes, foams, aerosols, lotions, creams or gels as is generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of specific permeability enhancers. Topical compositions can likewise take one or more of these forms. One or more active compounds may be present in association with one or more non-toxic pharmaceutically acceptable auxiliaries such as excipients, adjuvants (e.g. buffers), carriers, inert solid diluents, suspending agents, preservatives, fillers, stabilizers, anti-oxidants, food additives, bioavailability enhancers, coating materials, granulating and disintegrating agents, binding agents etc., and, if desired, other active ingredients.

The pharmaceutical composition may be formulated, for example, for immediate release, sustained release, pulsed release, two or more step release, or depot or any other kind of release.

The manufacture of the pharmaceutical compositions according to the present subject matter may be performed according to methods known in the art and will be explained in further detail below. Commonly known and used pharmaceutically acceptable auxiliaries as well as further suitable diluents, flavorings, sweetening agents, coloring agents etc. may be used, depending on the intended mode of administration as well as particular characteristics of the active compound to be used, such as solubility, bioavailability etc. Any non-toxic, inert, and effective topical, oral, etc. pharmaceutically acceptable carrier may be used to formulate the compositions described herein. Well-known carriers used to formulate other topical therapeutic compositions for administration to humans are useful in these compositions. Examples of these components that are well known to those of skill in the art are described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association)

International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the "Inactive Ingredient Guide", U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, January 1996, the contents of which are hereby incorporated by reference in their entirety. Examples of such useful cosmetically acceptable excipients, carriers and diluents include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO, which are among those suitable for use herein.

These additional other inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman's: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990) and Remington's Pharmaceutical Sciences,

17th Ed., Mack Publishing Co., Easton, Pa. (1990), both of which are incorporated by reference herein in their entirety.

In an embodiment, the present topical compositions are formulated in a serum, a gel cream, a lotion, a cream, an ointment, a gel, an aerosol, a foam, a foamable liquid, a solution (solubilized system), a paste, a suspension, a dispersion, an emulsion, a skin cleanser, a milk, a mask, a solid stick, a bar (such as a soap bar), an encapsulated formulation, a microencapsulated formulation, microspheres or nanospheres or vesicular dispersions, or other cosmetically acceptable topical dosage form. In the case of vesicular dispersions, the vesicles may be composed of lipids, which can be of the ionic or nonionic type, or a mixture thereof. The formulation can comprise one or more of an aqueous formulation and/or an anhydrous formulation.

In another embodiment, the present topical cosmetic composition in accordance with the subject matter described herein can comprise or consist of an anhydrous formulation, an aqueous formulation, or an emulsion.

For intranasal administration, the compound (I) or its pharmaceutically acceptable salts may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.

A proposed dose of the compound (I) is approximately 1 to 50 mg per day. Preferably, it is 5 to 50 mg per day, more preferably 5 mg, 20 mg, 30mg or 50 mg per day.

In one embodiment, the dose of the compound (I) is 1 mg per day or 5 mg per day or 20 mg per day.

In a further embodiment, the dose of the compound (I) is 30 mg or 50 mg per day.

It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration.

If desired, other therapeutic agents can be employed in conjunction with those provided in the above-described compositions. The amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.

The pharmaceutical compositions of the present invention may be given in a single dose or multiple doses daily.

In one embodiment, the compound (I) and its pharmaceutically acceptable salts is administered orally once daily.

In an embodiment, the present compositions may be topically applied once or multiple times per day. In an embodiment, the present compositions are topically applied from one to four times daily. For example, starting with once daily and progressing to more frequent applications, if needed, is one strategy.

In an embodiment, the present compositions are topically applied from one to six times daily, for example, in the morning, at noon, in the afternoon, and/or in the evening.

It is understood, however, that a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; and the form of administration. One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.

Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first- pass metabolism, elimination rate constant, half-life, and mean residence time are well known in the art.

The optimal formulations can be determined by one skilled in the art depending upon considerations such as the particular ingredients and the desired dosage. See, for example,

Remington's Pharmaceutical Sciences, 18th ed. (1990, Mack Publishing Co., Easton, PA 18042), pp. 1435-1712, and "Harry's Cosmeticology", 8th ed. (2000, Chemical Publishing Co., Inc., New York, N.Y. 10016), the disclosure of each of which is hereby incorporated by reference herein in its entirety. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance.

In particular, the ability to formulate compositions capable of long term storage, without pre-mixing or compounding requirements prior to application, are also contemplated. Specifically, the present compositions remain unexpectedly stable in storage for periods including between about 3 months and about 3 years, about 3 months and about 2.5 years, between about 3 months and about 2 years, between about 3 months and about 20 months, and alternately any time period between about 6 months and about 18 months.

Thus, in another aspect, the invention provides a pharmaceutical composition comprising (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or a pharmaceutically acceptable salt thereof for use in the treatment of chronic cough. In another embodiment, the invention provides a pharmaceutical composition comprising (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide for use in the treatment of chronic cough.

In a further embodiment, the invention provides a pharmaceutical composition comprising (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide anhydrous crystalline Form 1 for use in the treatment of chronic cough.

In another embodiment, the invention provides a pharmaceutical composition comprising (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide hydrochloride for use in the treatment of chronic cough.

In another embodiment, the invention provides a pharmaceutical composition comprising (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide bis hydrochloride for use in the treatment of chronic cough.

In another aspect, the invention provides a pharmaceutical composition comprising (5R)-5-[5-[{2-[3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide or a pharmaceutically acceptable salt thereof for use in the treatment of chronic refractory cough.

In an other embodiment, the invention provides a pharmaceutical composition comprising (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide for use in the treatment of chronic refractory cough.

In a further embodiment, the invention provides a pharmaceutical composition comprising (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide anhydrous crystalline Form 1 for use in the treatment of chronic refractory cough.

In another embodiment, the invention provides a pharmaceutical composition comprising (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide hydrochloride for use in the treatment of chronic refractory cough.

In another embodiment, the invention provides a pharmaceutical composition comprising (5 R) -5- [5- [{2- [3, 5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide bis hydrochloride for use in the treatment of chronic refractory cough.

It will be appreciated by those skilled in the art that the compound (I) or pharmaceutically acceptable salts thereof according to the invention may advantageously be used in combination with one or more other therapeutic agents.

The compound (I) or pharmaceutically acceptable salts thereof and the other pharmaceutically active agent(s) may be administered together in a fix combination or separately (i.e. non fix combination). When administered separately, this may occur separately or sequentially in any order and treatment regimens in which the agents are not necessarily administered by the same route of administration may also occur.

The amounts of the compound (I) or pharmaceutically acceptable salts thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

In a further embodiment, the present invention provides a combination which comprises (a) 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4- (4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of chronic cough.

In a further embodiment, the present invention provides a combination which comprises (a) 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4- (4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) anhydrous crystalline Form 1 and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of chronic cough.

In a further embodiment, the present invention provides a combination which comprises (a) 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4-

(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide hydrochloride and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of chronic cough.

(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide bis hydrochloride and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use the treatment of chronic cough.

In a further embodiment, the present invention provides a method of treatment of chronic cough which comprises administering to a human in need thereof an effective amount of a combination which comprises (a) 5R)-5-[5-[{2-[3,5- bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) In a further embodiment, the present invention provides a method of treatment of chronic cough which comprises administering to a human in need thereof an effective amount of a combination which comprises (a) 5R)-5-[5-[{2-[3,5- bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of Formula (I) as anhydrous crystalline Form 1 and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s). In a further embodiment, the present invention provides a combination which comprises (a) 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4- (4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of acute cough.

In a further embodiment, the present invention provides a combination which comprises (a) 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4- (4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of chronic refractory cough.

(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide hydrochloride and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of chronic refractory cough.

(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide bis hydrochloride and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use the treatment of chronic refractory cough.

In a further embodiment, the present invention provides a method of treatment of chronic refractory cough which comprises administering to a human in need thereof an effective amount of a combination which comprises (a) 5R)-5-[5-[{2-[3,5- bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) In a further embodiment, the present invention provides a method of treatment of chronic refractory cough which comprises administering to a human in need thereof an effective amount of a combination which comprises (a) 5R)-5-[5-[{2-[3,5- bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of Formula (I) as anhydrous crystalline Form 1 and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s).

Examples of suitable therapeutic agents which may be used in combination of the compound (I) or pharmaceutically acceptable salts thereof include for instance with leukotriene receptor antagonists such as montelukast and zafirlukast; voltage-gated sodium channel blockers such as lidocaine, GSK-2339345, benzonatate and CNV1014802; dual N- methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 agonist such as dextromethorphan; NMDA receptor antagonists such as memantine; opioids such as codeine and morphine; GABA analogues for example gabapentin and pregabalin; GABA-B receptor agonist such as baclofen; norepinephrine and serotonin reuptake inhibitors such as amytripyline; Nociceptin/orphanin FQ (NOP)-l agonists such as SCH486757; P2X3 purinergic receptor antagonists such as AF-219 (also called MK-7264 and gefapixant), AF- 130, BAY1817080 and BLU-5937; Histamine-1 receptor antagonists such as chlorpheniramine, azelastine, mizolastine, loratadine and cetirizine; anticholinergic drugs such as caramiphen edisylate; secreto lytic/mucolytic agents such as ambroxol, DWJ-13 0 and HOB-048; Vanilloid-1 (TRPV-1) receptor antagonists such as PAC-14028, VR-611 and

XEND-0501; Vanilloid-4 (TRPV-4) receptor antagonists such as GSK2798745, TRPM8 agonists such as menthol; homocysteine analogs such as erdosteine; corticosteroids such as budesonide and fluticasone; TRPAl receptor antagonists such as HC-030031 and GRC- 17536; p2-Agonists such as salbutamol; muscarinic receptor antagonists such as ipratropium bromide; proton pump inhibitors such as ranitidine and omeprazole; BK K+ channel inhibitors such as theophylline; mast cell stabilisers such as disodium cromoglycate (for example PA101); phosphodiesterase-(PDE)-4 inhibitors for example apremilast; cannabinoid receptor agonists such as CP55940 and JWH133; agonists of the nicotinic class of acetylcholine receptors (nAChRs) such as ATA-101 (also called TC-5619), ATA-104 and ATA-105), tyrosine kinase inhinitors such as nintedanib; anti-fibrotic/ anti-inflammatory agents such as pirfenidone; NK-1 (for example aprepitant, netupitant, OPK88002, rolapitant, SCH900978, serlopitant and tradipitant) and/or NK-2 or/and NK-3 antagonists or inhibitors of their cognate ligands NK-A and NK-B, inhibitors of SP for example anti-SP antibody; those of uncharacterised or unknown mechanism including levodropropizine, chlophedianol, carbetapentane (also known as pentoxyverine), levocloperastine, moguisteine, AG-1321001, CCP-01/05/06/07/08, AGPPC-709 and LPCN-1087.

In one embodiment, the present invention provides a combination which comprises 5R)- 5- [5- [{2- [3,5-bis(trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino] -4-(4-fluoro- 2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) or a pharmaceutically acceptable salt thereof and (b) a second drug substance and optionally one or more pharmaceutically acceptable excipient(s) for the treatment of chronic cough.

In a further embodiment, the present invention provides a combination of the compound(I) or a pharmaceutically acceptable salt thereof with a second drug substance which is selected from is selected from a leukotriene receptor antagonist, voltage-gated sodium channel blockers, dual N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 agonists, NMDA receptor antagonists, opioids, GABA analogues, GABA-B receptor agonist, Nociceptin/orphanin FQ (NOP)-l, P2X3 purinergic receptor antagonists, Histamine-1 receptor antagonists, anticholinergic drugs, secretolytic/mucolytic agents, Vanilloid-1 (TRPV-1) receptor antagonists, Vanilloid-4 (TRPV-1) receptor antagonists, homocysteine analogs, corticosteroids TRPAl receptor antagonists, 2-Agonists, muscarinic receptor antagonists, proton pump inhibitors, BK K+ channel inhibitors, phosphodiesterase-(PDE)-4 inhibitors; cannabinoid receptor agonists, agonists of the nicotinic class of acetylcholine receptors (nAChRs), tyrosine kinase inhibitors, anti-fibrotic/ anti-inflammatory agents, NK- 1 and/or NK-2 or/and NK-3 antagonists or inhibitors of their cognate ligands NK-A and NK- B, inhibitors of SP and optionally one or more pharmaceutically acceptable excipient(s) for the treatment of chronic cough.

In a further embodiment, the present invention provides a combination of the compound(I) or a pharmaceutically acceptable salt thereof with a second drug substance which is selected from P2X3 purinergic receptor antagonists such as: BAY1817080,

AF-219

r en one

or deuterium-substituted pirfenidone;

Substituted imidazopyridine compounds including of general formula

wherein:

Rlis selected from the group consisting of cyano, halogen, methyl, and ethyl;

R2is selected from the group consisting of hydrogen, halogen, methyl, and ethyl;

R3is selected from the group consisting of halogen, methyl, and ethyl;

R4is selected from the group consisting of hydrogen, halogen, methyl, ethyl, and methoxy;

as to R5and R6:

R5and R6are independently selected from the group consisting of hydrogen, Cl-C6-alkyl, and hydroxy-Cl-C6-alkyl; or

R5and R6, together with the nitrogen to which they are both attached, form a 5- or 6- member heterocycloalkyl, wherein:

the heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and Cl-C4-alkyl; R7 and R8 are independently selected from the group consisting of hydrogen and C1-C4- alkyl;

R9 is selected from the group consisting of Cl-C6-alkyl, C3-C6-cycloalkyl, Cl-C6-alkyl-C3- C6-cycloalkyl, halo-Cl-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy, and Cl-C6-alkoxy-Cl-C6- alkyl; and

X is selected from a bond, CH2, and 0.

or mast cell stabilisers such as disodium cromoglycate or GABA analogues such as gabapentin or pregabalin or opioids such as codeine and morphine, and optionally one or more pharmaceutically acceptable excipient(s)for the treatment of chronic refractory cough or chronic cough.

The following examples illustrate the invention without limiting the scope thereof.

EXAMPLES

Cough assays:

The effect of the compound of formula(I) or a salt thereof on the excitability of neurons associated with the cough reflex are assessed by measuring membrane voltage changes from isolated, primary vagal sections from both human and the guinea-pig which is a nonclinical species that has a cough reflex similar to humans. Specifically, the ability of compound of formula(I) anhydrous crystalline Form 1 to inhibit in a concentration- dependent fashion the depolarization of these isolated vagus axons by Substance P (the cognate agonist of the NK-1 receptor) and NK-1 agonists is assessed.

Methods: Guinea-pigs are sacrificed by overdose of pentobarbitone (200mg/kg i.p.) and vagus nerve trunks and ganglia are dissected. Human vagus nerve trunks are dissected from whole lungs, unsuitable for transplantation; appropriate consents for use of this tissue is obtained. In vitro, isolated guinea-pig and human vagus nerve sections of approx. 15mm in length are mounted onto a 'grease-gap' recording system. The nerve segments are perfused constantly with Krebs-Heinseleit (KH) solution at 37°C bubbled with 95% 0₂/5%

CO₂. Levels of depolarisation are amplified and recorded on a chart recorder. The vagal sections are first exposed to vehicle control for 2 minutes to demonstrate that it has no effect on the membrane excitability. In the first stage of the study, a strength of Substance P/ selective NK-1 agonist (0.01 to 10 uM) that induces depolarisation is determined by exposing the vagal nerves to this concentration range each for 2 mins while measurements are taken; the sections are washed between each increasing exposure. In the second stage, the vagal sections are then pre-incubated with vehicle or compound of formula(I) anhydrous crystalline Form 1 in a dose range from (1.0 nM to 10 uM dissolved in vehicle) each for 5 minutes and then at each concentration investigated the Substance P/ NK-1 agonist (at the concentration determined in the first part of the study) stimulus is added and the levels of depolarisation are measured. For each concentration of compound of formula(I) anhydrous crystalline Form 1 tested, after the 2 mins period the vagal sections are re-washed to remove the compound, and the Substance P/ NK-1 agonist (at the concentration determined in the first part of the study) is re-added to demonstrate maintained viability and responsiveness of the preparations. Dose-response depolarisation curves are prepared from the data collected for both the guinea-pig and human vagal nerve preparations to confirm the inhibitory activity on membrane excitability of compound of formula(I) anhydrous crystalline Form 1 induced by Substance P/ selective NK-1 agonist.

The effect of the compound of formula(I) or a salt thereof or the compound of formula(I) anhydrous crystalline Form 1 on cough is also assessed in vivo in the rabbit or cat following bilateral microinjection into the nucleus tractus solitarii (NTS) brainstem region that is associated with the cough reflex.

Methods: New Zealand white rabbits (2.5 -3.5kg) or cats (4-5 kg) are anesthetized with sodium pentobarbitone. Following cannulation of the trachea, catheters are inserted into a femoral artery to enable monitoring of arterial blood pressure and femoral vein for drug administration. Atropine (0.1 to 0.15 mg/kg intravenously) is administered to reduce reflex airway secretions. The right or left-side phrenic nerve that originates in the neck (C3-C5) is then dissected to enable recordings of the efferent neuronal activity. The prone animal is fixed by a stereotaxic head holder and vertebral clamps, and the dorsal surface of medulla is exposed by an occipital craniotomy. Arterial blood pressure, respiratory rate, end-tidal CO2 and body temperature are continuously monitored (temperature is maintained at 38.0±0.5°C by a heating pad). The electromyographic_(EMG) activity of abdominal muscles is also measured with bipolar insulated wire electrodes. The integrated phrenic and abdominal measurements that enable determination of inspiratory and expiratory activities characterising coughing, are logged on chart recorder. Cough is mechanically incited by inserting a thin flexible nylon fibre through the tracheal cannula and undertaking tracheobronchial stimulation by moving it backwards and forwards against the airway walls about once a second for ~5-20 seconds. To establish a stable cough baseline ~20 consecutive cough stimulation trials, separated by ~1 min, are conducted. Then bilateral microinjections of either vehicle or compound of formula(I) anhydrous crystalline Form 1 (vehicle control and lOmM) are made into the caudal NTS in a volume of 30-50 nl via a glass micropipette (tip diameter 10-40 um). Post the microinjections, two cough stimulation trials are undertaken at each of 5, 20, 60, 120 and 180 minutes. Fluorescent latex beads that are suspended in the injectate are used to label the injection sites. After the experimental procedure is completed, the medulla is sectioned and examined under light and UV microscopy for confirmation of the location of the injection site. Cough-related variables are measured before and 10 minutes after the bilateral microinjections. These variables, that include peak cough-related total duration of the respiratory cycle, phrenic amplitude, peak abdominal activity, and number of coughs induced by each stimulation, are used for subsequent statistical analysis. The anti-tussive activity of compound of formula(I) or salts thereof or the compound of formula (I) anhydrous crystalline Form 1 is thereby as confirmed using this approach.

All animal testing protocols and procedures are performed in accordance with relevant local and national regulations. Clinical Study

The anti-tussive efficacy and safety of compound of formula(I) anhydrous crystalline Form 1, is evaluated in a double-blind, randomised, placebo-controlled study involving repeated dosing in adult male and female patients with a diagnosis of chronic refractory cough for at least one year. Subjects entering the study must have a daytime cough frequency of ≥15 coughs/ hour, as assessed using an ambulatory cough monitor over a period of 24 hours during the screening period.

The objectives of the study are as follows: Primary - to evaluate the efficacy of 5 mg, 30 mg, and 50 mg compound of formula(I) anhydrous crystalline Form 1 versus placebo in reducing daytime objective cough frequency. Secondary: To evaluate the efficacy of 5 mg, 30 mg, and 50 mg compound of formula(I) anhydrous crystalline Form 1 versus placebo in:

Reducing night-time objective cough frequency, and subject assessed cough severity and urge to cough, and improving quality of life, and subject perception of change of cough frequency and severity. To assess the safety and tolerability of 5 mg, 30 mg, and 50 mg compound of formula(I) anhydrous crystalline Form 1 versus placebo over 12 weeks dosing.

The study is a four-arm (placebo, 5 and 30 and 50 mg administered orally once daily), 12-week dosing period study with a 4 week follow-up period. There are 8 scheduled clinic visits; Screening, Baseline/Day 1, Weeks 1, 2, 4, 8, and 12, and Week 16 follow-up.

The following instruments are used to assess efficacy:

· Subjects are fitted with an ambulatory cough monitor to record objective cough frequency over 24 hours.

• Leicester Cough Questionnaire (LCQ-Acute): to be completed by the subjects at the clinic. The LCQ-Acute is a 19 item questionnaire that assesses cough-related quality of life. It has 3 domains (physical, psychological and social). The total score range is 3-21 and domain scores range from 1-7; a higher score indicates a better quality of life.

• Global Rating of Change for Cough Frequency & Severity Scale: to be completed by the subjects at the clinic.

• Cough Severity VAS and Urge-to-Cough VAS: both to be completed by the subjects at the clinic. The VAS is a 100 mm scale on which patients indicate either their severity of cough or urge-to-cough. Study Endpoints are as follows:

Primary Efficacy:

• Change in objective daytime cough frequency at Week 4 compared to Baseline Secondary Efficacy:

• Change in objective daytime cough frequency at Weeks 1, 2, 8, 12 and 16 compared to Baseline

• Change in objective night-time cough frequency at Weeks 1, 2, 4, 8, 12 and 16 compared to Baseline

• Change in the Cough Severity VAS at Weeks 1, 2, 4, 8, 12 and 16 compared to Baseline

• Change in the Urge-to-Cough VAS at Weeks 1, 2, 4, 8, 12 and 16 compared to Baseline

• Change in the LCQ-Acute score (total and three domain scores) at Weeks 1, 2, 4, 8, 12 and 16 compared to Baseline

• Global Rating of Change in Cough Frequency and Severity at Weeks 1, 2, 4, 8, 12 and 16

Subjects are randomized in a 1:1:1:1 ratio (Placebo, 5 mg, 30 mg, and 50 mg compound of formula(I) anhydrous crystalline Form 1) with 60 subjects per treatment group. For this clinical study the statistical analysis used is a two-sided type I error of 0.05, not adjusted for multiple comparisons against placebo, with the primary analysis of objective cough frequency conducted via repeated measures analysis of variance.

Claims

1. (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]- 4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula(I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic cough.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the chronic cough is chronic refractory cough.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use of claim 1, wherein the chronic cough is due or associated with sarcoidosis, emphysema or idiopathic pulmonary fibrosis(IPF).

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use of claim 1, wherein the chronic cough is due or associated with asthma, chronic bronchitis, chronic postnasal drip, eosinophilic bronchitis and chronic obstructive pulmonary disease(COPD).

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use of claim 1, wherein the chronic cough is due or associated with chronic infections such as bronchiectasis, tuberculosis, cystic fibrosis.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use of claim 1, wherein the chronic cough is due or associated with lung tumours such as bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use of claim 1, wherein the chronic cough is due or associated with cardiovascular disease such as left ventricular failure, pulmonary infarction, aortic aneurysm.

8. The compound of formula (I) for use of claim 1, wherein the chronic cough is due or associated with reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis.

9. The compound of formula (I) for use of claim 1, wherein the chronic cough is due or associated with reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis.

10. A composition which comprises (a) 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoylj(methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide of formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more therapeutic agent(s) and optionally one or more pharmaceutically acceptable excipient(s) for use in the treatment of chronic cough.

11. A composition for use as claimed in claim 10, wherein the cough is chronic refractory cough.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1-9, wherein the pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride or bis hydrochloride.

13. 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]- 4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) for use as claimed in any one of claim 1-9.

14. 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl) amino]- 4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide of formula (I) anhydrous crystalline Form 1 for use as claimed in any one of claim 1-9.

15. A composition for use according to claims 10 and 11, wherein the pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride or bis hydrochloride.

16. A composition for use according to claims 10 and 11 , wherein the compound of formula (I) is 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide.

17. A composition for use according to claims 10 and 11 , wherein the compound of formula (I) is 5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl) amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2- methyl-D-prolinamide anhydrous crystalline Form 1.