WO2018185701A1

WO2018185701A1 - Trpv4 antagonists as antitussive agents

Info

Publication number: WO2018185701A1
Application number: PCT/IB2018/052365
Authority: WO
Inventors: James L. KREINDLER; Steven John PASCOE
Original assignee: Glaxosmithkline Intellectual Property (No.2) Limited
Priority date: 2017-04-06
Filing date: 2018-04-05
Publication date: 2018-10-11

Abstract

Invented is a method of treating cough; including acute cough, sub-acute cough and chronic cough, in a mammal in need thereof which comprises the administration of a therapeutically effective amount of a selected TRPV4 antagonist to such mammal.

Description

TRPV4 ANTAGONISTS AS ANTITUSSIVE AGENTS

FIELD OF THE INVENTION

This invention relates to a method of treating cough; including acute cough, sub-acute cough and chronic cough in a mammal, suitably a human, by administration of a selected TRPV4 antagonist and pharmaceutical compositions containing the same. Suitably, the method relates to methods of treating cough; including acute cough, sub-acute cough and chronic cough by the administration of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)- 7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

TRPV4 is a member of the Transient Receptor Potential (TRP) superfamily of cation channels and is activated by heat, demonstrating spontaneous activity at physiological temperatures (Guler et al., 2002. J Neurosci 22: 6408-6414). Consistent with its polymodal activation property TRPV4 is also activated by hypotonicity and physical cell stress/pressure (Strotmann et al., 2000. Nat Cell Biol 2: 695-702), through a mechanism involving

phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid generation (Vriens et al., 2004. Proc Natl Acad Sci U S A 101 : 396-401 ). In addition, amongst other mechanisms proposed, tyrosine kinase activity may also regulate TRPV4 (Wegierski et al., 2009. J Biol Chem. 284: 2923-33).

Heart failure results in the decreased ability of the left ventricle to pump blood into the peripheral circulation as indicated by a reduced ejection fraction and/or left ventricular dilation. This increases the left ventricular end diastolic pressure resulting in enhanced pulmonary blood pressures. This places the septal barrier, which separates the circulatory aqueous environment and the alveolar airspaces of the lung, at risk. Increased pulmonary pressure results in the flow of fluid from the pulmonary circulation into the alveolar space resulting in lung edema/congestion, as is observed in patients with congestive heart failure.

TRPV4 is expressed in the lung (Delany et al., 2001 . Physiol. Genomics 4: 165-174) and has been shown to mediate Ca²⁺ entry in isolated endothelial cells and in intact lungs (Jian et al., 2009 Am J Respir Cell Mol Biol 38: 386-92). Endothelial cells are responsible for forming the capillary vessels that mediate oxygen/carbon dioxide exchange and contribute to the septal barrier in the lung. Activation of TRPV4 channels results in contraction of endothelial cells in culture and cardiovascular collapse in vivo (Willette et al., 2008 J Pharmacol Exp Ther 325: 466-74), at least partially due to the enhanced filtration at the septal barrier evoking lung edema and hemorrage (Alvarez et al., 2006. Circ Res 99: 988- 95). Indeed filtration at the septal barrier is increased in response to increased vascular and/or airway pressures and this response is dependent on the activity of TRPV4 channels (Jian et al., 2008 Am J Respir Cell Mol Biol 38: 386-92). Overall this suggests a clinical benefit of inhibiting TRPV4 function in the treatment of heart failure associated lung congestion.

Additional benefit is suggested in inhibiting TRPV4 function in pulmonary-based pathologies presenting with symptoms including lung edema/congestion, infection, inflammation, pulmonary remodeling and/or altered airway reactivity. A genetic link between TRPV4 and chronic obstructive pulmonary disorder (COPD) has recently been identified (Zhu et al., 2009. Hum Mol Genetics, 18: 2053-62) suggesting potential efficacy for TRPV4 modulation in treatment of COPD with or without coincident emphysema. Enhanced TRPV4 activity is also a key driver in ventilator-induced lung injury (Hamanaka et al., 2007. Am J Physiol 293: L923-32) and it is suggested that TRPV4 activation may underlie pathologies involved in acute respiratory distress syndrome (ARDS), pulmonary fibrosis and asthma (Liedtke & Simon, 2004. Am J Physiol 287: 269-71 ). A potential clinical benefit for TRPV4 blockers in the treatment of sinusitis, as well as allergic and non-allergic rhinitis is also supported (Bhargave et al., 2008. Am J Rhinol 22:7^ 2).

TRPV4 has been shown to be involved in Acute Lung Injury (ALI). Chemical activation of TRPV4 disrupts the alvelor septal blood barrier potentially leading to pulmonary edema (Alvarez et al, Circ Res. 2006 Oct 27;99(9):988-95. TRPV4 is a necessary step in a process known to cause or worsen ALI in humans (Hamanaka et al, Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L923-32).

Furthermore, TRPV4 has in recent years been implicated in a number of other physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide significant clinical benefit. These include various aspects of pain (Todaka et al., 2004. J Biol Chem 279: 35133-35138; Grant et al., 2007. J Physiol 578: 715-733; Alessandri-Haber et al., 2006. J Neurosci 26: 3864-3874), genetic motor neuron disorders (Auer-Grumbach et al., 2009. Nat Genet. PMID: 20037588; Deng et al., 2009. Nat Genet PMID: 20037587;

Landoure et al., 2009. Nat Genet PMID: 20037586), cardiovascular disease (Earley et al., 2005. Circ Res 97: 1270-9; Yang et al., 2006. Am. J Physiol. 290:L1267-L1276), and bone related disorders; including osteoarthritis (Muramatsu et al., 2007. J. Biol. Chem. 282: 32158- 67), genetic gain-of function mutations (Krakow et al., 2009. Am J Hum Genet 84: 307-15; Rock et al., 2008 Nat Genet 40: 999-1003) and osteoclast differentiation (Masuyama et al. 2008. Cell Metab 8: 257-65).

The compounds of the invention are disclosed in International Application No. PCT/US2012/042622, having an International filing date of June 15, 2012; International Publication Number WO 2013/012500 and an International Publication date of January 24, 2013. The compound 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 - oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is disclosed therein as Example 147. International Publication Number WO 2013/012500 does not indicate the compounds disclosed therein in the treatment of cough; including acute cough, sub-acute cough and chronic cough.

The present invention concerns a novel therapeutic use of a known class of TRPV4 antagonist compounds.

SUMMARY OF THE INVENTION

This invention relates to a method of treating cough; including acute cough, sub-acute cough, and chronic cough, in a mammal, suitably a human, in need thereof which comprises administering to such mammal, suitably a human, a therapeutically effective amount of a compound of Formula (I):

(I)

wherein:

Ri is hydrogen, Ci_-3alkyl, CH₂OH, CH₂-0-CH₃, CH₂OCH₂Ph, CH₂CN, CN, halo or C(0)OCH₃; R₂ is independently hydrogen, CN, CF₃, halo, S0₂Ci.₃alkyl, Ci-₃alkyl or CZCH;

R₃ is hydrogen, Ci-₂alkyl, CF₃ or OH;

R₄ is hydrogen, halo or Ci-₃alkyl;

X is CR₄ or N;

A is (CH₂)_n - Het; or A is (CH₂)n-(CRaRb)-(CH₂)m-Het;

R_a is hydrogen or Ci_-3alkyl, wherein the Ci_-3alkyl may be further substituted with one or more halos;

R_b is Ci_-3alkyl; or R_a and R_b together with the carbon atom they are attached form a C₃-6cycloalkyl group; or one of the carbon atoms in the C₃-6cycloalkyl group formed by R_a and R_b may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C₃-6cycloalkyl group formed by R_a and R_b may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group;

Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci. salkyl, CN, CH₂F, CHF₂, CF₃, C₃.₆cycloalkyl, (CH₂)_n-0-Ci.₃alkyl, (CH₂)_n-phenyl, (CH₂)_n- pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci_-3alkyl, CH(OH)-Ci_-5alkyl, C(CH₃)₂ - R₅, C(0)N(CH₃)p, N(Ci.₃alkyl)p, NH₂, C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, or pyrazolyl; wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci-₃alkyl or CF₃; and the Ci_-5alkyl and C₃.₆cycloalkyl substituent on the Het may be further substituted by CN or OH;

R₅ is CN, 0-Ci.₄alkyl, (CH₂)_m - OH, (CH₂)_P - O - C(O) - O - Ci_-5alkyl, or 0-(CH₂)_p-0 -R₆; R₆ is Ci.₄alkyl or P(0)₂(CH₃)₂;

n is independently 0, 1 or 2;

m is independently 0, 1 or 2; p is independently 1 or 2; and

y is 1 , 2 or 3;

or a pharmaceutically acceptable salt thereof. Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.

Also, included in the present invention are methods of co-administering the compounds of the invention with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to methods of treating cough; including acute cough, sub-acute cough and chronic cough, in a human, in need thereof which comprises administering to such human a therapeutically effective amount of a compound of Formula (I) or a

pharmaceutically acceptable salt thereof as described above. Suitably the compound is 1 - (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof. The compound 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)- 7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is represented by the following structure:

"Alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of carbon member atoms. For example, Ci-₄ alkyl refers to an alkyl group having from 1 to 4 carbon member atoms. Alkyl groups may be straight or branched.

Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl, (n-propyl and isopropyl), and butyl (n-butyl, isobutyl, s-butyl, and t- butyl). "Cycloalkyl" refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of carbon member atoms. For example, C₃-6cycloalkyl refers to a cycloalkyl group having from 3 to 6 carbon member atoms. Unsaturated cycloalkyl groups have one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic. Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

When used herein, the terms 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.

"Substituted" in reference to a group indicates that one or more hydrogen atoms, suitably from 1 to 5 hydrogen atoms, suitably from 1 to 3 hydrogen atoms, attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers or diastereomeric mixtures. All such isomeric forms are included within the present invention, including mixtures thereof.

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds according to Formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively.

In certain embodiments, compounds according to Formula (I) may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. Examples of such bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine,

ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.

As used herein, the term "a compound of Formula (I)" or "the compound of Formula (I)" refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed from crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The compounds according to Formula (I) and pharmaceutically acceptable salts thereof may contain isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹ P, ³²P, ³⁵S, ¹⁸F, ³⁶CI, ¹²³l and ¹²⁵l.

Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are

incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵l isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in International Publication Number WO 2013/012500, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. Representative Embodiments of the Compounds of Formula (I).

In one embodiment:

Ri is hydrogen, d.₃alkyl, CH₂OH, CH₂-0-CH₃, CH₂OCH₂Ph, CH₂CN, CN, halo or C(0)OCH₃; R₂ is independently hydrogen, CN, CF₃, halo, S0₂Ci.₃alkyl, Ci-₃alkyl or CZCH;

R₃ is hydrogen, Ci-₂alkyl, CF₃ or OH;

R₄ is hydrogen, halo or Ci-₃alkyl;

X is CR₄ or N;

A is (CH₂)_n - Het;

or A is (CH₂)n-(CR_aRb)-(CH₂)_m-Het;

R_a is hydrogen or Ci-₃alkyl, wherein the Ci-₃alkyl may be further substituted with one or more halos;

R_b is Ci-₃alkyl;

or R_a and R_b together with the carbon atom they are attached form a C₃.₆cycloalkyl group; or one of the carbon atoms in the C₃.₆cycloalkyl group formed by R_a and R_b may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group;

or one of the carbon atoms in the C₃.₆cycloalkyl group formed by R_a and R_b may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group;

Het is

Wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci. salkyl, CN, CH₂F, CHF₂, CF₃, C₃.₆cycloalkyl, (CH₂)_n-0-Ci.₃alkyl, (CH₂)_n-phenyl, (CH₂)_n- pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci_₃alkyl, CH(OH)-Ci_-5alkyl, C(CH₃)₂ - R₅, C(0)N(CH₃)p, N(Ci-₃alkyl)_p, NH₂, C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, or pyrazolyl; wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci_₃alkyl or CF₃; and the Ci_-5alkyl and C₃.₆cycloalkyl substituent on the Het may be further substituted by CN or OH; R₅ is CN, 0-Ci.₄alkyl, (CH₂)m - OH, (CH₂)_P - O - C(O) - O - Ci_-5alkyl, or 0-(CH₂)_P-0 -R₆;

R₆ is Ci.₄alkyl or P(0)₂(CH₃)2;

n is independently 0, 1 or 2;

m is independently 0, 1 or 2;

p is independently 1 or 2; and

y is 1 , 2 or 3.

In another embodiment:

Ri is hydrogen, d.₃alkyl, CH₂OH, CH₂-0-CH₃, CH₂OCH₂Ph, CH₂CN, CN, halo or C(0)OCH₃; R₂ is independently hydrogen, CN, CF₃, halo, S0₂Ci-₃alkyl, Ci-₃alkyl or CZCH;

R₃ is hydrogen, Ci-₂alkyl, CF₃ or OH;

R₄ is hydrogen, halo or Ci-₃alkyl;

X is CR₄ or N;

A is (CH₂)_n - Het;

or A is (CH₂)_n-(CR_aRb)-(CH₂)_m-Het;

R_b is Ci-₃alkyl;

Het is

Wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci- ₅alkyl, CN, CH₂F, CHF₂, CF₃, C₃.₆cycloalkyl, (CH₂)_n-0-Ci-₃alkyl, (CH₂)_n-phenyl, (CH₂)_n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci.₃alkyl, C(CH₃)₂-OH, C(CH₃)₂-0-CH₃, C(CH₃)₂-CN, C(CH₃)₂-CH₂OH, C(CH₃)₂-CH₂-0-C(0)-0-Ci.₅alkyl, C(0)N(CH₃)_p, N(Ci.₃alkyl)_p, NH₂,

C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci_-3alkyl or CF₃;

and the Ci_₅alkyl and C₃-₆cycloalkyl substituent on the Het may be further substituted by CN or OH;

n is independently 0, 1 or 2;

m is independently 0, 1 or 2;

p is independently 1 or 2; and

y is 1 , 2 or 3.

In another embodiment:

Ri is hydrogen, Ci_-3 alkyl or CH₂OH;

R₂ is CN;

R₃ is hydrogen;

X is N;

A is (CH₂)_n - Het;

or A is (CH₂)n-(CRaRb)-(CH₂)m-Het;

R_b is Ci.₃alkyl;

or R_a and R_b together with the carbon atom they are attached form a C₃.₆ cycloalkyl group; or one of the carbon atoms in the C₃.₆cycloalkyl group formed by R_a and R_b may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group;

Het is

Wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci. ₅alkyl, CN, CH₂F, CHF₂, CF₃, C₃.₆cycloalkyl, (CH₂)_n-0-Ci-₃alkyl, (CH₂)_n-phenyl, (CH₂)_n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci.₃alkyl, C(CH₃)₂-OH, C(CH₃)₂-0-CH₃, C(CH₃)₂-CN, C(CH₃)₂-CH₂OH, C(CH₃)2-CH2-0-C(0)-0-Ci-₅alkyl, C(0)N(CH₃)_P, N(Ci.₃alkyl)_p, NH₂,

C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci-₃ alkyl or CF₃;

and the Ci-₅ alkyl and C₃.₆cycloalkyl substituent on the Het may be further substituted by CN or OH;

n is independently 0 or 1 ;

m is independently 0 or 1 ;

p is independently 1 or 2; and

y is 1 or 2.

In yet another embodiment:

Ri is hydrogen, Ci-₃alkyl or CH₂OH;

R₂ is CN;

R₃ is hydrogen;

X is N;

A is (CH₂)_n - Het;

or A is (CH₂)n-(CR_aR_b)-(CH₂)_m-Het;

R_b is Ci-₃alkyl;

Het is

Wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci- ₅alkyl, CN, CH₂F, CHF₂, CF₃, C₃.₆cycloalkyl, (CH₂)_n-0-Ci.₃alkyl, (CH₂)_n-phenyl, (CH₂)_n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci.₃alkyl, C(CH₃)₂-OH, C(CH₃)₂-0-CH₃, C(CH₃)₂-CN, C(CH₃)₂-CH₂OH, C(CH₃)₂-CH₂-0-C(0)-0-Ci.₅alkyl, C(0)N(CH₃)_p, N(Ci.₃alkyl)_p, NH₂,

C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci_-3alkyl, or CF₃;

n is independently 0 or 1 ;

m is independently 0 or 1 ;

p is independently 1 or 2;and

y is 1 or 2;

In yet another embodiment:

Ri is hydrogen, Ci_-3alkyl or CH₂OH;

R₂ is CN;

R₃ is hydrogen;

X is N;

A is (CH₂)_n - Het;

Het is

Wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci. ₅alkyl, CN, CH₂F, CHF₂, CF₃, C₃.₆cycloalkyl, (CH₂)_n-0-Ci-₃alkyl, (CH₂)_n-phenyl, (CH₂)_n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci_₃alkyl, C(CH₃)₂-OH, C(CH₃)₂-0-CH₃, C(CH₃)₂-CN, C(CH₃)₂-CH₂OH, C(CH₃)₂-CH₂-0-C(0)-0-Ci.₅alkyl, C(0)N(CH₃)_p, N(Ci.₃alkyl)_p, NH₂,

C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci_₃alkyl, or CF₃;

and the Ci_-5alkyl and C₃.₆cycloalkyl substituent on the Het may be further substituted by CN or OH;

n is independently 0 or 1 ;

p is independently 1 or 2; and

y is 1 or 2.

In yet another embodiment:

Ri is hydrogen, Ci-₃alkyl or CH₂OH; R₂ is CN;

R₃ is hydrogen;

X is N;

A is (CH₂)_n - Het;

Het is

Wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci. salkyl, CN, CH₂F, CHF₂, CF₃, C₃-₆cycloalkyl, , (CH₂)_n-0-Ci.₃alkyl, (CH₂)_n-phenyl, (CH₂)_n- pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci_-3alkyl, C(CH₃)₂-OH, C(CH₃)₂-0-CH₃, C(CH₃)₂- CN, C(CH₃)₂-CH₂OH, C(CH₃)₂-CH₂-0-C(0)-0-Ci.₅alkyl, C(0)N(CH₃)_p, N(Ci.₃alkyl)_p, NH₂, C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci-₃alkyl, or CF₃;

n is 0;

p is independently 1 or 2; and

y is 1 or 2.

It is to be understood that embodiments of the present invention includes all combinations of particular groups described hereinabove. The compounds of the invention are prepared generally according to the procedures in International Publication Number WO 2013/012500.

Biological Activity Chronic cough is highly prevalent worldwide and is highly impactful on the quality of life for suffers, with typical cough rates of 10-50 coughs per hour, during waking hours. It is hypothesized that chronic cough reflects a state of neuronal hypersensitivity involving exaggerated spinal and cortical responses to afferent sensory signals in a manner similar to chronic pain. Activation of TRPV4 channels in vivo causes ATP release and triggers afferent sensory signals from the lung through binding of ATP to P2X3 channels, resulting in cough (Bonvini, JACI, 2016). ATP levels are increased in exhaled breath of patients with diseases associated with cough, for example COPD (Basoglu, Chest, 2015). Recently a P2X3 antagonist has demonstrated high level efficacy in reducing chronic cough and improving quality of life scores in a phase 2 clinical trial (Abdulqawi, Lancet, 2015). These clinical data along with data from pre-clinical models suggests a role for TRPV4 receptors in generating cough. TRPV4 receptors are expressed in airway smooth muscle cells (McAlexander, JPET, 2014), in airway epithelial cells (Delany, Physiol Genomics, 2001 ), and in sensory neurons in the lung, including Ad-fibers from airway specific afferent neurons (Bonvini, JACI, 2016). Taken together, these data suggest a potential therapeutic role for TRPV4 antagonists in cough; including acute cough, sub-acute cough and chronic cough.

Abdulqawi R, et al. Lancet. 2015 Mar 28; 385(9974):1 198-1205.

• Basoglu OK, et al., Chest. 2015 Aug; 148(2):430-5.

· Bonvini SJ, et al., J Allergy Clin Immunol. 2016 Jul;138(1 ):249-261 .e12.

• Delany NS, et al., Physiol Genomics. 2001 Jan 19;4(3): 165-74.

• McAlexander MA, et al., J Pharmacol Exp Ther. 2014 Apr;349(1 ):1 18-25.

The compounds of Formula (I), suitably 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, are tested for their ability to treat cough in vivo in pre-clinical models in which cough is induced, for example the guinea pig model cited in Bonvini et al. above. The efficacy of compounds of Formula (I), suitably 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 - oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile or a

pharmaceutically acceptable salt thereof, are tested for their ability to treat cough; including acute cough, sub-acute cough and chronic cough, in people using the objective cough monitoring and specific quality of life instruments as cited in Abdulqawi et al.

The compound, 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- 1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is also known as GSK2798745. ClinicalTrials.gov Identifier: NCT03372603 - indicates a clinical trial titled: A Study to Assess the Effectiveness and Side Effects of GSK2798745 in Participants With Chronic Cough.

Ligand-gated assay:

TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium. The resulting changes in intracellular calcium were monitored using a calcium selective fluorescent dye Fluo4 (MDS Analytical Technologies). Dye loaded cells were initially exposed to test compound to verify a lack of agonist activity. Cells were subsequently activated by addition of an agonist and inhibition of the agonist-induced activation was recorded. Human embryonic kidney 293 cells stably expressing the macrophage scavenger receptor class II (HEK-293-MSR-II) and transduced with 1 %

BacMam (J. P. Condreay, S.M. Witherspoon, W.C. Clay and T.A. Kost, Proc Natl Acad Sci 96 (1999), pp. 127-132) virus expressing the human TRPV4 gene were plated at 15000 cells/well in a volume of 50 μΙ_ in a 384 well poly-D lysine coated plate. Cells were incubated for 24 hours at 37 degrees and 5% C0₂. Media was then aspirated using a Tecan Plate- washer and replaced with 20 μΙ_ of dye loading buffer: HBSS, 500 uM Brilliant Black (MDS Analytical Technologies), 2 uM Fluo-4. Dye loaded plates were then incubated in the dark at room temperature for 1 -1.5 hours. 10 μΙ_ of test compound diluted in HBSS (HBSS with 1 .5 mM Calcium Chloride, 1 .5 mM Magnesium Chloride and 10 mM HEPES. pH 7.4), + 0.01 % Chaps was added to the plate, incubated for 10 min at room temperature in the dark and then 10 μΙ_ of agonist was added at a final concentration equal to the agonist EC₈o. Calcium release was measured using the FLIPRtetra (MDS Analytical Technologies) or FLIPR384 (MDS Analytical Technologies).

All compounds of Formula (I) tested in International Publication Number WO

2013/012500 demonstrated TRPV4 biological activity with IC₅₀ ranges from 0.1 nM - 0.5 μΜ. The compound: 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa- 3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile demonstrated TRPV4 biological activity with IC₅o between 0.1 -10 nM.

Methods of Use

The compounds of the invention are TRPV4 antagonists, and maybe useful in the treatment or prevention of cough; including acute cough, sub-acute cough and chronic cough, in a mammal, suitably a human. Suitably 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, can be used in the treatment of cough; including acute cough, sub-acute cough and chronic cough. Accordingly, an aspect the invention is directed to methods of treating or preventing such conditions.

The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof, suitably 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 - oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile or a

pharmaceutically acceptable salt thereof, to a patient in need thereof.

As used herein, "treating", and derivatives thereof, in reference to a condition means: (1 ) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

The term "treating" and derivatives thereof refers to therapeutic therapy. Therapeutic therapy is appropriate to alleviate symptoms or to treat at early signs of disease or its progression.

The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be determined by the skilled artisan.

As used herein, "patient" or "subject" refers to a human or other mammal. Suitably the patient or subject is a human. The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, optic, intravaginal, and intranasal administration. Suitably the administration is oral. Suitably the administration is parenteral.

The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors. It will be further understood that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose. Preferred dosages are 1 - 500 mg once daily or BID per person.

Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, include the preparation of phosphates, amides, ethers, esters, thioesters, carbonates, and carbamate. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.

In an embodiment, this invention provides a method of treating cough; including acute cough, sub-acute cough and chronic cough, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a pharmaceutical combination of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof; and at least one further active ingredient. Suitably, the 1 -(((5S,7S)-3- (5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7- yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. Suitably the amount of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from: 1.0mg; 1 .1 mg, 1.2mg, 1 .3mg, 1 .4mg, 1 .5mg, 1 .6mg, 1 .7mg, 1 .8mg, 1.9mg, 2.0mg, 2.1 mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1 mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1 mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1 mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1 mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1 mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1 mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1 mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, and 10.0mg. Suitably, the amount of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- 1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from 2.4mg and 4.8mg. Suitably the amount of 1-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile monohydrate is 2.4mg. Suitably the amount of 1 -(((5S,7S)- 3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7- yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is 4.8mg.

In an embodiment, this invention provides method of treating cough; including acute cough, sub-acute cough and chronic cough, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a pharmaceutical combination of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, and at least one further active ingredient, wherein 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

In an embodiment, this invention provides a combination of 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof; and at least one further active ingredient for use in therapy. Suitably, the 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. Suitably the amount of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1- oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from: 1 .0mg; 1 .1 mg, 1 .2mg, 1 .3mg, 1 .4mg, 1.5mg, 1 .6mg, 1 .7mg, 1 .8mg, 1 .9mg, 2.0mg, 2.1 mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1 mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1 mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1 mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1 mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1 mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1 mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1 mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, and 10.0mg. Suitably, the amount of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from 2.4mg and 4.8mg. Suitably the amount of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile monohydrate is 2.4mg. Suitably the amount of 1 -(((5S,7S)- 3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7- yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is 4.8mg.

In an embodiment, this invention provides a combination of 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, and at least one further active ingredient, wherein 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized 1 - (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

An aspect of this invention provides a method of treating a disease state selected from: cough, acute cough, sub-acute cough, and chronic cough, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating cough in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. An aspect of this invention provides a method of treating acute cough in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. An aspect of this invention provides a method of treating sub-acute cough in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. An aspect of this invention provides a method of treating chronic cough in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In an embodiment, this invention provides a method of treating cough; including acute cough, sub-acute cough and chronic cough, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of 1- (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof. Suitably, the 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. Suitably the amount of 1 -(((5S,7S)-3-(5- (2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from: 1.0mg; 1 .1 mg, 1 .2mg, 1 .3mg, 1.4mg, 1 .5mg, 1.6mg, 1 .7mg, 1 .8mg, 1.9mg, 2.0mg, 2.1 mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1 mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1 mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1 mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1 mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1 mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1 mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1 mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, and 10.0mg. Suitably, the amount of 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from 2.4mg and 4.8mg.

Suitably the amount of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- 1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is 2.4mg. Suitably the amount of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is 4.8mg.

In an embodiment, this invention provides a method of treating cough; including acute cough, sub-acute cough and chronic cough, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of 1 - (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, wherein 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized 1 - (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of as disease state selected from: cough, acute cough, sub-acute cough and chronic cough.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cough.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of acute cough. An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of sub-acute cough.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic cough.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from: cough, acute cough, sub-acute cough and chronic cough.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cough. An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of acute cough. An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of sub-acute cough.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of chronic cough.

In an embodiment, this invention provides for the use of 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from: cough, acute cough, sub-acute cough, and chronic cough. Suitably, the 1 -(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. Suitably the amount of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from: 1 .0mg; 1 .1 mg, 1.2mg, 1 .3mg, 1 .4mg, 1 .5mg, 1 .6mg, 1 .7mg, 1.8mg, 1 .9mg, 2.0mg, 2.1 mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1 mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1 mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1 mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1 mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1 mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1 mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1 mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, and 10.0mg. Suitably, the amount of 1- (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from 2.4mg and 4.8mg. Suitably the amount of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile monohydrate is 2.4mg. Suitably the amount of 1 -(((5S,7S)- 3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7- yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is monohydrate 4.8mg.

In an embodiment, this invention provides for the use of 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)- 1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof in the manufacture of a medicament for the treatment of a disease state selected from: cough, acute cough, sub-acute cough, and chronic cough, wherein 1-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-

1 - oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. An aspect of this invention provides a pharmaceutical composition for use in the treatment of cough; including, acute cough, sub-acute cough and chronic cough, in humans comprising a compound of Formula (I), or a pharmaceutically acceptably salt thereof.

In an embodiment, this invention provides a pharmaceutical composition for use in the treatment of a disease state selected from: cough, acute cough, sub-acute cough, and chronic cough, in humans comprising 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-

2- OXO-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof. Suitably, the 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. Suitably the amount of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from: 1 .0mg; 1 .1 mg, 1.2mg, 1 .3mg, 1 .4mg, 1 .5mg, 1 .6mg, 1 .7mg, 1.8mg, 1 .9mg, 2.0mg, 2.1 mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1 mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1 mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1 mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1 mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1 mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1 mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1 mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, and 10.0mg. Suitably, the amount of 1- (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is selected from 2.4mg and 4.8mg. Suitably the amount of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile monohydrate is 2.4mg. Suitably the amount of 1 -(((5S,7S)- 3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7- yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile monohydrate is 4.8mg.

In an embodiment, this invention provides a pharmaceutical composition for use in the treatment of a disease state selected from: cough, acute cough, sub-acute cough, and chronic cough, in humans containing 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2- oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof wherein 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- 1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

Compositions

The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 0.1 mg to 1000 mg.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically-acceptable excipient" means 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 of sufficiently high purity to render it pharmaceutically-acceptable.

The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g.

microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

The compounds may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonists, HMG-CoA reductase inhibitors, dual non-selective β-adrenoceptor and a-| -adrenoceptor antagonists, type-5

phosphodiesterase inhibitors, and renin inhibitors.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following

Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Experimental Details Example 1 - Capsule Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.

Table I

INGREDIENTS

1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile

Mannitol

Talc

Magnesium Stearate

Example 2 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1 .5% by weight of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile, in 10% by volume propylene glycol in water.

Example 3 - Tablet Composition

The sucrose, microcrystalline cellulose and a non-peptide TPO agonist, as shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.

Table II

INGREDIENTS

1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7

methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)

1 H-benzo[d]imidazole-6-carbonitrile

Microcrystalline cellulose

Sucrose

Starch

Talc

stearic acid

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

A method of treating a disease state selected from: cough, acute cough, subacute cough and chronic cough in a mammal in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I):

(I)

wherein:

R₃ is hydrogen, Ci-₂alkyl, CF₃ or OH;

R₄ is hydrogen, halo or Ci-₃alkyl;

X is CR₄ or N;

A is (CH₂)_n - Het; or A is (CH₂)n-(CR_aRb)-(CH₂)_m-Het;

R_a is hydrogen or Ci_₃alkyl, wherein the Ci_₃alkyl may be further substituted with one or more halos;

R_b is Ci-₃alkyl; or R_a and R_b together with the carbon atom they are attached form a C₃.₆cycloalkyl group; or one of the carbon atoms in the C₃.₆cycloalkyl group formed by R_a and R_b may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C₃.₆cycloalkyl group formed by R_a and R_b may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group; Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci. salkyl, CN, CH₂F, CHF₂, CF₃, C₃-₆cycloalkyl, (CH₂)n-0-Ci.₃alkyl, (CH₂)_n-phenyl, (CH₂)_n- pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci_-3alkyl, CH(OH)-Ci_-5alkyl, C(CH₃)₂ - R₅, C(0)N(CH₃)p, N(Ci-₃alkyl)_p, NH₂, C(0)NH₂, oxetane, oxetane-CH₃, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, or pyrazolyl; wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH₃, Ci_₃alkyl or CF₃; and the Ci_-5alkyl and C₃.₆cycloalkyl substituent on the Het may be further substituted by CN or OH;

n is independently 0, 1 or 2;

m is independently 0, 1 or 2;

p is independently 1 or 2; and

y is 1 , 2 or 3;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the mammal is a human.

3. The method of claim 1 wherein the compound is 1 -(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7- yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile,

or a pharmaceutically acceptably salt thereof.

4. The method of clam 2 wherein the compound is 1 -(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazole-6-carbonitrile,

or a pharmaceutically acceptably salt thereof.

5. The method of claim 4 wherein the compound is administered orally.

6. The method of claim 4 wherein the compound is administered parenterally.

7. A method of treating a disease state selected from: cough, acute cough, sub-acute cough and chronic cough in a human in need thereof, which comprises: administering to such human a therapeutically effective amount of a pharmaceutical combination of:

a) a compound as disclosed in claim 3 or a pharmaceutically acceptable salt thereof; and

b) at least one further active ingredient.

8. A pharmaceutical combination as claimed in claim 7 for use in therapy.

9. A compound of Formula (I), as defined in claim 1 , or a pharmaceutically

acceptable salt thereof for use in the treatment of as disease state selected from: cough, acute cough, sub-acute cough and chronic cough.

10. 1-(((5S,7S)-3-(5-(2-Hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile,

or a pharmaceutically acceptably salt thereof for use in the treatment of a disease state selected from: cough, acute cough, sub-acute cough and chronic cough.

1 1. Use of a compound of Formula (I), as defined in claim 1 , or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disease state selected from: cough, acute cough, sub-acute cough and chronic cough.

12. Use of 1 -(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa- 3-azaspiro[4.5]decan-7-yl)meth l)-1 H-benzo[d]imidazole-6-carbonitrile,

or a pharmaceutically acceptably salt thereof in the manufacture of a medicament for use in the treatment of a disease state selected from: cough, acute cough, subacute cough and chronic cough.

13. A pharmaceutical composition for use in the treatment of a disease state selected from: cough, acute cough, sub-acute cough and chronic cough in humans comprising 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 - oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazole-6-carbonitrile,

or a pharmaceutically acceptably salt thereof.