WO2009074519A1

WO2009074519A1 - Combinations of pyrazolyl or isoxazolyl p2x7 modulators with further therapeutic agents

Info

Publication number: WO2009074519A1
Application number: PCT/EP2008/066891
Authority: WO
Inventors: Anton Duval Michel; Daryl Simon Walter
Original assignee: Glaxo Group Limited
Priority date: 2007-12-12
Filing date: 2008-12-05
Publication date: 2009-06-18
Also published as: GB0724258D0

Abstract

The present invention relates to combination comprising a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof: together with a further therapeutic agent or agents. The pyrazolyl (I) and isoxazolyl (IA) compounds of formula (I) and (IA) are thought to be P2X7 receptor antagonists, i.e. to modulate P2X7 receptor function and to be capable of antagonizing the effects of ATP at the P2X7 receptor. The further therapeutic agent can e.g. be methotrexate, an NSAID, a TNFα inhibitor, sulfasalazine, a statin, or an anti-CD20 monoclonal antibody, e.g. for the treatment of rheumatoid arthritis; or can be e.g. paracetamol, an opioid, pregabalin, gabapentin, gabapentin enacarbil, or carbamazepine, e.g. for inflammatory or neuropathic pain.

Description

Combinations of Pyrazolyl or Isoxazolyl P2X7 Modulators with Further

Therapeutic Agents

The present invention relates to combinations of heterocyclic (pyrazolyl or isoxazolyl) derivatives which modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor (P2X7 receptor antagonists) together with a further therapeutic agent or agents; to pharmaceutical compositions containing the combinations; and to the use of such combinations in therapy.

The P2X7 receptor is a ligand-gated ion-channel which is expressed in cells of the hematopoietic lineage, e.g. macrophages, microglia, mast cells, and lymphocytes (T and B) (see, for example, CoIIo, et al. Neuropharmacology, Vol.36, pp1277-1283 (1997)), and is activated by extracellular nucleotides, particularly adenosine triphosphate (ATP). Activation of P2X7 receptors has been implicated in giant cell formation, degranulation, cytolytic cell death, CD62L shedding, regulation of cell proliferation, and release of proinflammatory cytokines such as interleukin 1 beta (IL- 1 β) (e.g. Ferrari, et al., J. Immunol., Vol.176, pp3877-3883 (2006)) and tumour necrosis factor alpha (TNFα) (e.g. Hide, et al. Journal of Neurochemistry, Vol.75, pp965-972 (2000)). P2X7 receptors are also located on antigen presenting cells, keratinocytes, parotid cells, hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells. Furthermore, the P2X7 receptor is expressed by presynaptic terminals in the central and peripheral nervous systems and has been shown to mediate glutamate release in glial cells (Anderson, C. et al. Drug. Dev. Res., Vol.50, page 92 (2000)).

The localisation of the P2X7 receptor to key cells of the immune system, coupled with its ability to release important inflammatory mediators from these cells suggests a potential role of P2X7 receptor antagonists in the treatment of a wide range of diseases including pain and neurodegenerative disorders. Recent preclinical in vivo studies have directly implicated the P2X7 receptor in both inflammatory and neuropathic pain (Dell'Antonio et al., Neurosci. Lett., Vol.327, pp87-90 (2002),. Chessell, IP., et al., Pain, VoM 14, pp386-396 (2005), Honore et al., J. Pharmacol. Exp. Then, Vol.319, p1376-1385 (2006)) while there is in vitro evidence that P2X7 receptors mediate microglial cell induced death of cortical neurons (Skaper, S. D., et a/.,Glia, Vol.54, p234-242 (2006)). In addition, up-regulation of the P2X7 receptor has been observed around β-amyloid plaques in a transgenic mouse model of Alzheimer's disease (Parvathenani, L. et al. J. Biol. Chem., Vol.278(15), pp13309- 13317 (2003)).

The present invention provides combinations which modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor (P2X7 receptor antagonists).

In a first aspect of the invention there is provided, a combination comprising:

a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) wherein:

R¹ and R² represent C_1-6 alkyl, phenyl, or a C₃.₆ cycloalkyl, any of which is optionally substituted with 1 , 2 or 3 halogen atoms;

R³ and R⁴ independently represent hydrogen or C_1-3 alkyl;

R⁵, R⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, halogen, cyano, C_1-6 alkyl,

C_2-6 alkenyl, C₂-₆ alkynyl, C_3-6 cycloalkyl or phenyl, and any of said C_1-6 alkyl, C_2-6 alkenyl, C₂.₆ alkynyl, C_3-6 cycloalkyl or phenyl is optionally substituted with 1 , 2 or 3 halogen atoms; or R⁸ and R⁹ together with the carbon atoms to which they are attached form a benzene ring which is optionally substituted with 1 , 2 or 3 halogen atoms; or R⁴ and R⁵ together with the carbon atoms to which they are attached form a C₅_₇ cycloalkyl; with the proviso that when R⁵ and R⁹ are both selected from hydrogen or fluorine, at least one of R⁵, R⁷ and R⁸ is a halogen atom, or R⁶, R⁷ and R⁸ are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R⁶,

R⁷ and R⁸ is methyl or CF₃; or

a compound of formula (IA) or a pharmaceutically acceptable salt thereof:

(IA) wherein:

R^1a and R^2a represent Ci.₆ alkyl, phenyl, or a C_3-B cycloalkyl, any of which may be optionally substituted with 1 , 2 or 3 halogen atoms;

R^3a, R^4a, R^5a, R^6a and R^7a independently represent hydrogen, halogen, cyano, Ci_-6 alkyl, C_2-6 alkenyl, C₂.₆ alkynyl, C_3-6 cycloalkyl or phenyl, and any of said Ci_₆ alkyl, C₂.₆ alkenyl, C₂-₆ alkynyl, C_3-6 cycloalkyl or phenyl is optionally substituted with 1 , 2 or 3 halogen atoms; or R^6a and R^7a together with the carbon atoms to which they are attached form a benzene ring which is optionally substituted with 1 , 2 or 3 halogen atoms; with the proviso that when R^3a and R^7a are both selected from hydrogen or fluorine, at least one of R^4a, R^5a and R^Sa is a halogen atom, or R^4a, R^5a and R^6a are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R^4a, R^5a and R^6a is methyl or CF₃;

together with a further therapeutic agent or agents.

The pyrazole compounds of formula (I) or pharmaceutically acceptable salts thereof, and the isoxazole compounds of formula (IA) or pharmaceutically acceptable salts thereof, as defined herein, and their uses as P2X7 receptor antagonists, are disclosed in copending PCT applications PCT/EP2007/055518 and PCT/EP2007/055521 respectively, both filed on 5 June 2007, and both published on 13 December 2007 as WO 2007/141267 A1 and WO 2007/141269 A1 respectively.

In one embodiment of the invention, the further therapeutic agent or agents may be medicaments claimed to be useful in the treatment of a condition which is mediated by P2X7 receptors as described herein.

Suitable examples of other such therapeutic agents may include a β2-agonist (also known as β2 adrenoceptor agonists; e.g. formoterol) and/or a corticosteroid (e.g. budesonide, fluticasone (e.g. as propionate or furoate esters), mometasone (e.g. as furoate), beclomethasone (e.g. as 17-propionate or 17,21 -dipropionate esters), ciclesonide, triamcinolone (e.g. as acetonide), flunisolide, rofleponide or butixocort (e.g. as propionate ester), for the treatment of a respiratory disorder (such as asthma or chronic obstructive pulmonary disease (COPD)), e.g. as described in WO 2007/008155 and WO 2007/008157.

A further therapeutic agent may include a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin) for the treatment of a cardiovascular disorder (such as atherosclerosis), e.g. as described in WO 2006/083214.

A further therapeutic agent may include a non-steroid anti-inflammatory drug (NSAID; e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g. paracetamol, loxoprofen or aceclofenac; in particular celecoxib, paracetamol, ibuprofen or diclofenac) for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain), e.g. as described in WO 2005/025571. Celecoxib (a COX-2 inhibitor) can for example be administered orally at a dosage regimen of 100 mg or 200 mg (measured as the free base) once or twice daily.

A further therapeutic agent may in particular include a tumour necrosis factor α (TNFα) inhibitor (e.g. etanercept or an anti- TNFα antibody such as infliximab and adalimumab) (e.g. for parenteral administration such as subcutaneous or intravenous administration), for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain), e.g. as described in WO 2004/105798.

A further therapeutic agent may in particular include an anti-CD20 monoclonal antibody (e.g. for parenteral such as intravenous administration), such as ofatumumab (HuMax-CD20 ™, developed in part by Genmab AS) (e.g. ofatumumab for intravenous administration), rituximab, PRO70769, AME-133 (Applied Molecular Evolution), or hA20 (Immunomedics, Inc.); in particular ofatumumab or rituximab. This further therapeutic agent can e.g. be for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory pain). A further therapeutic agent may include 2-hydroxy-5- [ [4- [ (2- pyridinylamino) sulfonyl] phenyl] azo] benzoic acid (sulfasalazine) for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/105797.

A further therapeutic agent may in particular include N-[4-[[(2, 4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]- L-glutamic acid (methotrexate) for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/105796.

A further therapeutic agent may include an inhibitor of pro TNFα convertase enzyme (TACE) for the treatment of an inflammatory disease or disorder (such as rheumatoid arthritis or osteoarthritis; in particular rheumatoid arthritis), e.g. as described in WO 2004/073704.

A further therapeutic agent may in particular include:

a) sulfasalazine; b) a statin (e.g. for oral administration), such as atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, crilvastatin, dalvastatin, rosuvastatin, tenivastatin, fluindostatin, velostatin, dalvastatin, nisvastatin, bervastatin, pitavastatin, rivastatin, glenvastatin, eptastatin, tenivastatin, flurastatin, rosuvastatin or itavastatin; c) a glucocorticoid agent (e.g. for oral or skin-topical administration), such as dexamethasone, methylprednisolone, prednisolone, prednisone and hydrocortisone; d) an inhibitor of p38 kinase (e.g. for oral administration); e) an anti-IL-6-receptor antibody, e.g. an anti-IL-6-receptor monoclonal antibody (e.g. for parenteral such as intravenous administration); f) anakinra; g) an anti-IL-1 (e.g. I L-1 β) monoclonal antibody (e.g. for parenteral such as intravenous administration); h) an inhibitor of JAK3 protein tyrosine kinase; i) an anti-macrophage colony stimulation factor (M-CSF) monoclonal antibody; or j) an anti-CD20 monoclonal antibody (e.g. for parenteral such as intravenous administration), such as rituximab, ofatumumab (HuMax-CD20 ™, developed in part by Genmab AS) (e.g. ofatumumab for intravenous administration), PRO70769, AME- 133 (Applied Molecular Evolution), or hA20 (Immunomedics, Inc.); in particular rituximab or ofatumumab;

for the treatment of an I L- 1 (e.g. IL-1 β) mediated disease (such as rheumatoid arthritis or osteoarthritis, and/or inflammatory or neuropathic pain; in particular rheumatoid arthritis), e.g. as described in WO 2006/003517.

In a particular embodiment of the invention, when the further therapeutic agent includes a non-steroid anti-inflammatory drug (NSAID) (e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g. paracetamol, loxoprofen or aceclofenac; in particular celecoxib, paracetamol, ibuprofen or diclofenac), then the non-steroid anti-inflammatory drug and/or the combination comprising the non-steroid anti-inflammatory drug is for the treatment of an inflammatory disease or disorder.

Alternatively, in one further embodiment of the invention, the further therapeutic agent does not include a non-steroid anti-inflammatory drug (NSAID) (e.g. ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; or e.g. paracetamol, loxoprofen or aceclofenac).

Additionally or alternatively, in one further embodiment of the invention, the further therapeutic agent does not include ethanol, cocaine, nicotine, or an opioid (typically a dependence-inducing opioid, e.g. morphine). In a more particular embodiment, the further therapeutic agent does not include an opioid (typically a dependence-inducing opioid, e.g. morphine), or nicotine, or a dependence-inducing CNS depressant (e.g. ethanol), or a dependence-inducing psychostimulant (e.g. cocaine). In a still more particular embodiment, the further therapeutic agent does not include a dependence- inducing agent (e.g. an opioid such as morphine, or nicotine, or a dependence- inducing CNS depressant such as ethanol, or a dependence-inducing psychostimulant such as cocaine). CNS means central nervous system. Additionally or alternatively, in one further embodiment of the invention, the further therapeutic agent does not include a cancer chemotherapeutic agent.

In a particular embodiment of the invention, the further therapeutic agent or agents can be a therapeutic agent or agents capable of treating inflammatory pain, such as paracetamol and/or an opioid (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol). This/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s), can be for the treatment of inflammatory pain, e.g. in a mammal such as a human.

For example, in the present combination, paracetamol can be administered at a human oral dosage regimen of 500 mg to 1000 mg (e.g. 500 mg, 650 mg or 1000 mg, in particular 650 mg) of paracetamol (measured as the free base / free compound), administered two, three or four times daily.

In a particular embodiment of the invention, the further therapeutic agent or agents can be a therapeutic agent or agents capable of treating neuropathic pain, such as: - an opioid (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol),

- a monoamine reuptake inhibitor (such as duloxetine or amytriptyline),

- pregabalin, - gabapentin,

- gabapentin enacarbil (XP13512), and/or

- carbamazepine.

This/these therapeutic agent(s), and/or the combination comprising this/these therapeutic agent(s), can be for the treatment of neuropathic pain, e.g. in a mammal such as a human.

For example, in the present combination, pregabalin can be administered orally e.g. for neuropathic pain; e.g. at a human oral dosage regimen of 150 mg to 600 mg total pregabalin per day (measured as the free base), split between two to three doses per day. For example, for postherpetic neuralgia (a neuropathic pain condition), pregabalin can be administered at a starting oral dosage regimen of 150 mg total pregabalin per day (split between 2 or 3 doses per day), escalating (e.g. in about one week) to an oral dosage regimen of 300 mg pregabalin total per day, and optionally escalating up to a maximum oral dosage regimen of 600 mg total pregabalin per day. For painful diabetic neuropathy (another neuropathic pain condition), an oral dosage regimen of 150 mg to 300 mg total pregabalin per day can be administered. For fibromyalgia, an oral dosage regimen of 150 mg to 450 mg (e.g. 300 or 450 mg) total pregabalin per day can be administered. Pregabalin can e.g. be administered separately from the compound of formula (I) or (IA) or the salt thereof.

For example, in the present combination, gabapentin can be administered orally, e.g. for neuropathic pain. Oral dosage units can e.g. contain 100 mg, 300 mg, 400 mg, 600 mg or 800 mg of gabapentin (measured as the free base/acid). The gabapentin dosage regimen for neuropathic pain can e.g. be from 300 mg once, twice or three times per day up to a total dose of 3600 mg / day. Some gradual up-titration of the dosage regimen is usually performed. For example, for peripheral neuropathic pain in adults, gabapentin therapy can be initiated by titrating the dose thus: day 1 = 300 mg of gabapentin (measured as the free base/acid) once a day, day 2 = 300 mg two times a day, and day 3 = 300 mg three times a day; alternatively the starting dose can be 900 mg / day of gabapentin (measured as the free base/acid), administered as three equally divided doses. Thereafter, e.g. based on individual patient response and tolerability, the dose can be further increased, typically in 300 mg / day increments every 2-3 days, up to a maximum total dose of 3600 mg / day of gabapentin (measured as the free base/acid). Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a total dose of 1800 mg / day is typically one week, to reach 2400 mg / day is typically a total of 2 weeks, and to reach 3600 mg / day is typically a total of 3 weeks. Gabapentin can e.g. be administered separately from the compound of formula (I) or (IA) or the salt thereof.

For example, in the present combination, gabapentin enacarbil (XP13512, (±)-1-([(α- isobutanoyloxyethoxy)carbonyl]-aminomethyl)-1-cyclohexane acetic acid, which is a prodrug of gabapentin) can be administered orally, e.g. to a human, e.g. separately from the compound of formula (I) or (IA) or the salt thereof. In one embodiment, gabapentin enacarbil (XP13512) is for example administered orally, e.g. to a human such as a human adult, e.g. at a total daily dose having an equivalent molar quantity of gabapentin enacarbil as the molar quantity present in 900 mg / day to 3600 mg / day of gabapentin (see e.g. page 81 lines 24-32 of WO 02/100347). A 600 mg dose of gabapentin enacarbil (measured as the free acid) contains the molar equivalent of 312 mg of gabapentin. See also K.C. Cundy et al., "Clinical Pharmacokinetics of XP13512, a Novel Transported Prodrug of Gabapentin", J. CHn. Pharmacol., 2008, e-publication 30 September 2008, incorporated herein by reference, and the Materials and Methods - Formulation and Study Designs sections therein, for examples of some oral doses, dosage regimens and formulations of XP13512 used in human pharmacokinetic studies.

In a particular embodiment of the invention, when the further therapeutic agent includes an opioid (such as morphine, fentanyl, oxycodone, tramadol, hydrocodone, hydromorphone, oxymorphone, methadone or buprenorphine; in particular morphine, fentanyl, oxycodone, or tramadol), then the opioid and/or the combination comprising the opioid is for the treatment of pain, in particular inflammatory or neuropathic pain, e.g. in a mammal such as a human.

When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.

The individual components of the combination of the invention (i.e. the compound of formula (I) or (IA) or the salt thereof, and the further therapeutic agent or agents) may be present as separate pharmaceutical formulations / compositions, or may be present as a combined pharmaceutical formulation / composition (e.g. may be together in a single combined oral dosage form, e.g. a single combined tablet or capsule). The individual components of this combination can for example be administered either sequentially in separate pharmaceutical formulations / compositions (e.g. oral), or simultaneously in separate or combined pharmaceutical formulation(s) / composition(s) (e.g. oral); in a particular embodiment they are administered sequentially in separate pharmaceutical formulations / compositions (e.g. oral).

The combinations referred to herein may optionally be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined herein together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof is used in combination with a second (further) therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone.

As used herein, the term "alkyl" (when used as a group or as part of a group) refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, d-6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms. Examples of alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, n-hexyl and i-hexyl.

As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms wherein at least once carbon- carbon bond is a double bond. Examples of alkenyl include, but are not limited to ethenyl, propenyl, n-butenyl, i-butenyl, n-pentenyl and i-pentenyl.

As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms wherein at least once carbon- carbon bond is a triple bond. Examples of alkynyl include, but are not limited to ethynyl, propynyl, butynyl, i-pentynyl, n-pentynyl, i-hexynyl and n-hexynyl.

The term 'cycloalkyl' unless otherwise stated means a closed 3 to 8 membered non- aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.

In one embodiment of the invention, the compound of formula (I) is other than Λ/-[1- (4-bromophenyl)propyl]-2-(3,5-dimethyl-1 H-pyrazol-4-yl)acetamide.

In certain embodiments of the invention, R¹ and R² independently represent unsubstituted C^₆ alkyl, trifluoromethyl, phenyl or a C₃_₆ cycloalkyl. In one embodiment, R¹ and R² independently represent unsubstituted C^₆ alkyl or trifluoromethyl. In another embodiment, R¹ and R² independently represent methyl or trifluoromethyl. In a further embodiment, R¹ represents trifluoromethyl and R² represents methyl.

In certain embodiments of the invention, R³ and R⁴ independently represent hydrogen or methyl. In one embodiment, R³ and R⁴ both represent hydrogen.

In certain embodiments of the invention, R⁵, R⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, halogen, cyano, trifluoromethyl or unsubstituted Ci_₆ alkyl. In a further embodiment, R⁵, R⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, halogen, cyano, methyl or trifluoromethyl. In one embodiment, R⁵, R⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, chlorine, fluorine, bromine, methyl or trifluoromethyl.

In one embodiment of the invention there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² independently represent unsubstituted C_1-6 alkyl, trifluoromethyl, phenyl or a C_3-6 cycloalkyl;

R³ and R⁴ independently represent hydrogen or methyl;

R⁵, R⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, halogen, cyano, trifluoromethyl or unsubstituted C_1-6 alkyl; or R⁴ and R⁵ together with the carbon atoms to which they are attached form a C_5-7 cycloalkyl; with the proviso that when R⁵ and R⁹ are both selected from hydrogen or fluorine, at least one of R⁶, R⁷ and R⁸ is a halogen atom, or R⁶, R⁷ and R⁸ are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R⁶,

R⁷ and R⁸ is methyl or CF₃; together with a further therapeutic agent or agents.

In a further embodiment, there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² independently represent methyl or trifluoromethyl;

R³ and R⁴ both represent hydrogen; and

R⁵, R⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, halogen, trifluoromethyl or methyl; with the proviso that when R⁵ and R⁹ are both selected from hydrogen or fluorine, at least one of R⁵, R⁷ and R⁸ is a halogen atom, or R⁶, R⁷ and R⁸ are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R⁶,

Particular compounds of formula (I) include the compounds of Examples 1-37 as shown below, or a pharmaceutically acceptable salt thereof.

In certain embodiments of the invention, R^1a and R^2a independently represent unsubstituted Ci-s alkyl, trifluoromethyl, phenyl or a C_3-6 cycloalkyl. In one embodiment, R^1a and R^2a independently represent unsubstituted Ci-6 alkyl or trifluoromethyl. In another embodiment, R^1a and R^2a independently represent methyl or trifluoromethyl. In a further embodiment, R^1a represents trifluoromethyl and R^2a represents methyl. In yet a further embodiment, R^1a and R^2a both represent methyl.

In certain embodiments of the invention, R^3a, R^4a, R^5a, R^6a and R^7a independently represent hydrogen, halogen, cyano, trifluoromethyl or unsubstituted C_1-6 alkyl. In a further embodiment, R^3a, R^4a, R^5a, R⁶³ and R^7a independently represent hydrogen, halogen, cyano, methyl or trifluoromethyl. In one embodiment, R^3a, R^4a, R^5a, R^6a and R^7a independently represent hydrogen, chlorine, fluorine, bromine, methyl or trifluoromethyl.

In one embodiment of the invention there is provided a combination comprising a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein: R^1a and R^2a independently represent unsubstituted Ci_-6 alkyl, trifluoromethyl, phenyl or a C₃.₆ cycloalkyl; and

R^3a, R^4a, R^5a, R^6a and R^7a independently represent hydrogen, halogen, cyano, trifluoromethyl or unsubstituted Ci_-6 alkyl; with the proviso that when R^3a and R^7a are both selected from hydrogen or fluorine, at least one of R^4a, R^5a and R^Sa is a halogen atom, or R^4a, R^5a and R^6a are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R^4a, R^5a and R^6a is methyl or CF₃; together with a further therapeutic agent or agents.

In a further embodiment, there is provided a combination comprising a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein: R^1a and R^2a independently represent methyl or trifluoromethyl; and R^3a, R^4a, R^5a, R^6a and R^7a independently represent hydrogen, halogen, trifluoromethyl or methyl; with the proviso that when R^3a and R^7a are both selected from hydrogen or fluorine, at least one of R^4a, R^5a and R^6a is a halogen atom, or R^4a, R^5a and R^6a are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R^4a, R^5a and R^6a is methyl or CF₃; together with a further therapeutic agent or agents.

In another embodiment, there is provided a combination comprising a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein:

R^1a and R^2a both represent methyl; and

R^3a, R^4a, R^5a, R^6a and R^7a independently represent hydrogen, halogen, trifluoromethyl or methyl; with the proviso that when R^3a and R^7a are both selected from hydrogen or fluorine, at least one of R^4a, R^5a and R^6a is a halogen atom, or R^4a, R^5a and R^6a are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of

R^4a, R^5a and R^6a is methyl or CF₃; together with a further therapeutic agent or agents.

Particular compounds of formula (IA) include the compounds of Examples 1 A-38A as shown below, or a pharmaceutically acceptable salt thereof.

Antagonists of P2X7 may be useful in preventing, treating, or ameliorating a variety of pain states (e.g. neuropathic pain, inflammatory pain (e.g. chronic), or visceral pain), inflammation and neurodegeneration, in particular Alzheimer's disease. P2X7 antagonists may also constitute useful therapeutic agents in the management of rheumatoid arthritis and inflammatory bowel disease.

Compounds of formula (I) or (IA) or salts thereof, within the combinations of the present invention, modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor ("P2X7 receptor antagonists"), and may be competitive antagonists, inverse agonists, or negative allosteric modulators of P2X7 receptor function.

Certain compounds of formula (I) and/or (IA) may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds of formula (I) and/or (IA) may be used as salts, in which case the salts should be pharmaceutically acceptable. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19.

When a compound of formula (I) or (IA) is basic, in one embodiment a pharmaceutically acceptable salt is formed from a pharmaceutically acceptable acid such as an inorganic or organic acid. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.

Examples of pharmaceutically acceptable salts include those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.

The compounds of formula (I) or (IA) or pharmaceutically acceptable salts thereof may be prepared in crystalline or non-crystalline form (e.g. in crystalline or amorphous solid form), and, in particular if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope solvates (e.g. hydrates) of compounds of formula (I) or (IA) or pharmaceutically acceptable salts thereof, for example stoichiometric solvates (e.g. hydrates) as well as compounds or salts containing variable amounts of solvent (e.g. water).

Certain compounds of formula (I) and/or (IA) or salts thereof may be capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

The combinations of the subject invention may also include isotopically-labeled compounds or salts, which are identical to those recited in formula (I) and/or (IA) or salts thereof,, 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 most commonly found in nature. Examples of isotopes that can be incorporated into the compounds or salts within the combinations of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, 11 C, 14C, 18F, 1231 and 1251.

Compounds within the combinations 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-labeled compounds or salts within the combinations of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are potentially useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are for example optionally chosen for their (in some cases) ease of preparation and detectability. 11 C and 8F isotopes can be useful in PET (positron emission tomography), and 1251 isotopes can be useful in SPECT (single photon emission computerized tomography). PET and SPECT can be useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can sometimes afford certain effects resulting from greater metabolic stability, for example increased in vivo half- life or reduced dosage requirements and, hence, may be chosen in some circumstances, lsotopically labeled compounds of formula (I) and/or (IA) or salts thereof within this invention are in one embodiment and in some cases prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting an available isotopically labeled reagent for a non-isotopically labeled reagent.

In a further particular embodiment of the invention, the compound of formula (I) and/or (IA) or the pharmaceutically acceptable salt thereof is not a radioactive isotopically-labelled compound or salt. In a particular embodiment, the compound or salt is not an isotopically-labelled compound or salt. Preparation of compounds of formula (I)

(I)

Compounds of formula (I), wherein the variables are defined above, and salts and solvates thereof may be prepared by the methodology described hereinafter.

Compounds of formula (I) may be prepared by the following processes which comprise:

(a) Coupling of a carboxylic acid of formula (2) (or an activated derivative thereof) with an amine of formula (3) (see Scheme 1 ), wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as defined above. Compounds (2) and (3) are optionally protected;

(b) Deprotecting a compound of formula (I) which is protected. Examples of protecting groups and the means for their removal can be found in T.W. Greene and P. G. M. Wuts 'Protective Groups in Organic Synthesis' (J.Wiley and Sons, 3^rd Ed. 1999); or

(c) Interconversion of compounds of formula (I) to other compounds of formula (I). Examples of conventional interconversion procedures include epimerisation, oxidation, reduction, alkylation, aromatic substitution, nucleophilic substitution, amide coupling and ester hydrolysis. Scheme 1.

The coupling of an acid of formula (2) and an amine of formula (3) typically comprises the use of activating agents, such as water soluble carbodiimide or polymer-supported carbodiimide, 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7- azabenzotriazole (HOAt), and optionally a suitable base such as a tertiary alkylamine (e.g. diisopropylethylamine, N-ethyl morpholine, triethylamine) or pyridine, in a suitable solvent such as DMF and/or dichloromethane and at a suitable temperature e.g. between 0⁰C and room temperature. Alternatively the coupling of (2) and (3) may be accomplished by treatment with O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate and a suitable tertiary alkylamine such as diisopropylethylamine in a suitable solvent such as dimethylformamide at a suitable temperature such as room temperature. Where the compound of formula (2) is an activated derivative (e.g. acid chloride, mixed anhydride, active ester (e.g. O-acyl- isourea)), process (a) typically comprises treatment of said activated derivative with an amine (Ogliaruso, M.A.; Wolfe, J. F. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.B: The Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp442-8; Beckwith, A.L.J, in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.B: The Chemistry of Amides (Ed. Zabricky, J.) (John Wiley and Sons, 1970), pp 73 ff.

Representative methods for the preparation of compounds of formula (2) are shown in Schemes 2-3 below: Scheme 2

Wherein R¹ and R² are as defined above and P² represents a suitable protecting group such as C_1-6 alkyl, and L¹ represents a suitable leaving group such as a halogen atom (e.g. iodine, chlorine or bromine).

An analogous process has been described previously (US 4,146,721 ).

Step (i) typically comprises the use of a suitable solvent such as a dioxane/water mixture or dimethyl formamide and a suitable base such as potassium hydroxide or sodium hydride at a suitable temperature e.g. between 0⁰C and room temperature.

Step (ii) typically comprises the use of hydrazine (7) or a salt (e.g. HCI) thereof in a suitable solvent such as ethanol. The reaction mixtures are typically heated at a suitable temperature such as reflux temperature.

Step (iii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as use of an appropriate hydroxide salt (e.g. lithium hydroxide) in an appropriate solvent such as a mixture of tetrahydrofuran and water at a suitable temperature such as 50⁰C, or use of an appropriate acid (e.g. trifluoroacetic acid) in an appropriate solvent such as dichloromethane at a suitable temperature such as room temperature. Scheme 3

(13) (14)

Step (vi)

Wherein R¹ and R² are as defined above, P³ represents a suitable protecting group such as 2-(trimethylsilyl)ethoxymethyl, X represents a suitable exchangeable group such as halogen (e.g. bromine or iodine) and L² represents a suitable leaving group such as a sulphonate ester (e.g. methanesulphonyl ester).

Step (i) typically comprises treatment with a suitable protecting group using a suitable reagent such as {2-[(chloromethyl)oxy]ethyl}(trimethyl)silane chloride in a suitable solvent such as a tetrahydrofuran with a suitable base such as sodium hydride at a suitable temperature such as 5°C.

Step (ii) typically comprises treatment of (10) with a suitable alkyl lithium species such as n-butyl lithium and a suitable carbonylating agent such as dimethylformamide in a suitable solvent such as tetrahydrofuran and at a suitable temperature such as between -78°C and room temperature. Step (iii) typically comprises reduction of (1 1 ) using a suitable reducing agent such as sodium borohydride in a suitable solvent such as ethanol and at a suitable temperature such as between 0⁰C and room temperature.

Step (iv) typically comprises treatment of (12) with a suitable sulphonyl chloride such as methanesulphonyl chloride and a suitable base such as triethylamine in a suitable solvent such as dichloromethane and at a suitable temperature such as between O⁰C and room temperature.

Step (v) typically comprises treatment of (13) with a suitable cyanide salt such as potassium cyanide in a suitable solvent such as dimethylsulphoxide and at a suitable temperature such as between room temperature and 8O⁰C.

Step (vi) typically comprises treatment of (14) with a suitable acid such as 5N hydrochloric acid in a suitable solvent such as 1 ,4-dioxane at a suitable temperature such as 100⁰C.

Compounds of the general formulae (3), (4), (5), (7), and (9) are typically either available from commercial sources or can be prepared by a person skilled in the art using methods described in the chemical literature (or using analogous methods).

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

Preparation of compounds of formula (IA)

(IA)

Compounds of formula (IA), wherein the variables are defined above, and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention. Compounds of formula (IA) may be prepared by the following processes which comprise:

(a) Coupling of a carboxylic acid of formula (2) (or an activated derivative thereof) with an amine of formula (3) (see Scheme 1 ), wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷, are as defined above. Compounds (2) and (3) are optionally protected;

(c) Interconversion of compounds of formula (I) to other compounds of formula (I). Examples of conventional interconversion procedures include epimerisation, oxidation, reduction, alkylation, aromatic substitution, nucleophilic substitution, amide coupling and ester hydrolysis.

Scheme 1.

The coupling of an acid of formula (2) and an amine of formula (3) typically comprises the use of activating agents, such as water soluble carbodiimide or polymer-supported carbodiimide, 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7- azabenzotriazole (HOAt), and optionally a suitable base such as a tertiary alkylamine (e.g. diisopropylethylamine, N-ethyl morpholine, triethylamine) or pyridine, in a suitable solvent such as DMF and/or dichloromethane and at a suitable temperature e.g. between O⁰C and room temperature. Alternatively the coupling of (2) and (3) may be accomplished by treatment with O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate and a suitable tertiary alkylamine such as diisopropylethylamine in a suitable solvent such as dimethylformamide at a suitable temperature such as room temperature. Where the compound of formula (2) is an activated derivative (e.g. acid chloride, mixed anhydride, active ester (e.g. O-acyl- isourea)), process (a) typically comprises treatment of said activated derivative with an amine (Ogliaruso, M.A.; Wolfe, J. F. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.B: The Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp442-8; Beckwith, A.L.J, in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.B: The Chemistry of Amides (Ed. Zabricky, J.J(John Wiley and Sons, 1970), pp 73 ff.

A representative method for the preparation of compounds of formula (2) is shown in Scheme 2 below:

Scheme 2

wherein R¹ and R² are as defined above and P² represents a suitable protecting group such as Ci_-6 alkyl, and L¹ represents a suitable leaving group such as a halogen atom (e.g. iodine, chlorine or bromine).

Step (ii) typically comprises the use of hydroxylamine (7) or a salt (e.g. HCI) thereof in a suitable solvent such as ethanol. The reaction mixtures are typically heated at a suitable temperature such as 65°C. Step (iii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as use of an appropriate hydroxide salt (e.g. lithium hydroxide) in an appropriate solvent such as a mixture of tetrahydrofuran and water at a suitable temperature such as 5O⁰C, or use of an appropriate acid (e.g. trifluoroacetic acid) in an appropriate solvent such as dichloromethane at a suitable temperature such as room temperature.

Compounds of formulae (3), (4), (5) and (7) are typically either available from commercial sources or can be prepared by a person skilled in the art using methods described in the chemical literature (or using analogous methods).

Clinical Indications

It is believed that, as the compounds of formula (I) or (IA) or the pharmaceutically acceptable salts thereof within the combinations of the present invention modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor, combinations containing these compounds they may be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.

The chronic articular pain condition can be rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis (ankylosing spondylitis), gouty arthritis or juvenile arthritis.

The inflammatory pain condition can be rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis (ankylosing spondylitis) or fibromyalgia.

In particular, the compounds of formula (I) or (IA) or pharmaceutically acceptable salts thereof, and/or the combinations of the present invention, may be useful in the treatment or prevention of pain (e.g. inflammatory pain) in arthritis, such as pain (e.g. inflammatory pain) in rheumatoid arthritis or osteoarthritis.

Pain associated with functional bowel disorders includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.

The neuropathic pain condition can be: diabetic neuropathy (e.g. painful diabetic neuropathy), sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, or lumbar radiculopathy; or pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions. Alternatively, the neuropathic pain condition can be: include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia), or an absence of or deficit in selective sensory pathways (hypoalgesia).

The acute pain condition can be post-surgical pain or dysmenorrhea (e.g. primary dysmenorrhea).

Other conditions which could potentially be treated by combinations of the present invention include fever, inflammation, immunological diseases, abnormal platelet function diseases (e.g. occlusive vascular diseases), impotence or erectile dysfunction; bone disease characterised by abnormal bone metabolism or resorbtion; hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAID's) such as cyclooxygenase-2 (COX-2) inhibitors, cardiovascular diseases; neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence-inducing agent such as opiods (e.g. morphine), CNS (central nervous system) depressants (e.g. ethanol), psychostimulants (e.g. cocaine), or nicotine; complications of Type I diabetes, kidney dysfunction, liver dysfunction (e.g. hepatitis, cirrhosis), gastrointestinal dysfunction (e.g. diarrhoea), colon cancer, overactive bladder and urge incontinence. Depression and alcoholism could potentially also be treated by compounds of the present invention. Inflammation and the inflammatory conditions associated with said inflammation include arthritis (in particular rheumatoid arthritis or osteoarthritis), skin conditions (e.g. sunburn, burns, eczema, dermatitis, allergic dermatitis, psoriasis), meningitis, ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis), inflammatory lung disorders (e.g. asthma, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD, which includes bronchitis and/or emphysema), or airways hyperresponsiveness); gastrointestinal tract disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, or gastrointestinal reflux disease); organ transplantation and other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, polymyositis, tendinitis, bursitis, and Sjogren's syndrome. Inflammation or an inflammatory condition associated with said inflammation can in particular be arthritis (e.g. rheumatoid arthritis or osteoarthritis).

Immunological diseases include autoimmune diseases, immunological deficiency diseases or organ transplantation.

Bone diseases characterised by abnormal bone metabolism or resorbtion include osteoporosis (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cacchexia, calculosis, lithiasis (especially urolithiasis), solid carcinoma, gout and ankylosing spondylitis, tendinitis and bursitis.

Cardiovascular diseases include hypertension or myocardiac ischemia; atherosclerosis; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).

Neurodegenerative diseases include dementia, particularly degenerative dementia (such as senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, or motor neuron disease; in particular Alzheimer's disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment e.g. associated with ageing, particularly age associated memory impairment.

The neurodegenerative disease, e.g. to be treated by the compound of formula (I) or (IA) or a salt thereof or by the combination, can for example be degenerative dementia (in particular Alzheimer's disease), vascular dementia (in particular multi- infarct dementia), or mild cognitive impairment (MCI) e.g. MCI associated with ageing such as age associated memory impairment.

The combinations of the present invention may also be useful as neuroprotectants and in the treatment of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.

The combinations of the present invention may also be useful in the treatment of malignant cell growth and/or metastasis, and myoblastic leukaemia.

Complications of Type 1 diabetes include diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma, nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.

Kidney dysfunction includes nephritis, glomerulonephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome.

It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.

According to a further aspect of the invention, we therefore provide a combination as defined herein for use in human or veterinary medicine and/or for use in therapy.

According to another aspect of the invention, we provide a combination as defined herein for use in the treatment or prevention (e.g. treatment) of a condition which is mediated by P2X7 receptors. The combination can be for use in the treatment or prevention (e.g. treatment) of pain, inflammation (e.g. rheumatoid arthritis or osteoarthritis) or a neurodegenerative disease, in particular for use in the treatment of inflammatory pain, neuropathic pain, visceral pain, rheumatoid arthritis or osteoarthritis; e.g. in a mammal such as a human.

According to a further aspect of the invention, we provide a method of treating a human or animal (e.g. rodent e.g. rat) subject, for example a human subject, suffering from a condition which is mediated by P2X7 receptors, for example a condition or disease disclosed herein (in particular pain, inflammation, rheumatoid arthritis, osteoarthritis or a neurodegenerative disease, more particularly pain such as inflammatory pain, neuropathic pain or visceral pain), which comprises administering to said subject an effective amount of a combination as defined herein.

According to a further aspect of the invention we provide a method of treating a human or animal (e.g. rodent e.g. rat) subject, for example a human subject, suffering from pain, inflammation (e.g. rheumatoid arthritis or osteoarthritis), or a neurodegenerative disease (more particularly rheumatoid arthritis or osteoarthritis, and/or pain such as inflammatory pain, neuropathic pain or visceral pain), which method comprises administering to said subject an effective amount of a combination as defined herein.

According to a yet further aspect of the invention we provide a method of treating a human or animal (e.g. rodent e.g. rat) subject, for example a human subject, suffering from inflammatory pain, neuropathic pain or visceral pain (e.g. pain, such as inflammatory pain, in arthritis (e.g. rheumatoid arthritis or osteoarthritis)), which method comprises administering to said subject an effective amount of a combination as defined herein.

According to a further aspect of the invention we provide a method of treating a subject, for example a human subject, suffering from Alzheimer's disease which method comprises administering to said subject an effective amount of a combination as defined herein.

According to another aspect of the invention, we provide the use of a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of a condition which is mediated by the action of P2X7 receptors, for example a condition or disease disclosed herein, e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human. According to another aspect of the invention we provide the use of a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of pain (e.g. inflammatory pain, neuropathic pain or visceral pain), inflammation (e.g. rheumatoid arthritis or osteoarthritis), or a neurodegenerative disease; e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.

According to another aspect of the invention we provide the use of a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of inflammatory pain, neuropathic pain or visceral pain (in particular inflammatory pain or neuropathic pain; such as inflammatory pain in arthritis such as rheumatoid arthritis or osteoarthritis); e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.

In one aspect of the invention we provide the use of a combination as defined herein for the manufacture of a medicament for the treatment or prevention (e.g. treatment) of Alzheimer's disease; e.g. in a mammal such as a human or rodent e.g. human or rat e.g. human.

In order to use a combination as defined herein for the treatment of humans and other mammals it can optionally be formulated in accordance with pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention there is provided a pharmaceutical composition comprising a combination as defined herein, adapted for use in human or veterinary medicine.

In order to use a combination as defined herein in therapy, they it can optionally be formulated into a pharmaceutical composition in accordance with pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a combination as defined herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising the combination of the invention, and/or a pharmaceutical composition comprising a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (but not comprising the further therapeutic agent(s)), which may be prepared by admixture, e.g. at ambient temperature and/or at atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may e.g. be in the form of a tablet, a capsule, an oral liquid preparation, a powder, a granule, a lozenge, a reconstitutable powder, an injectable or infusable solution or suspension, or a suppository.

An orally administrable pharmaceutical composition comprising the combination of the invention, and/or an orally administrable pharmaceutical composition comprising a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (but not comprising the further therapeutic agent(s)), are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain one or more excipients, such as a binding agent (e.g. hydroxypropylmethylcellulose or povidone), a filler (e.g. lactose monohydrate, anhydrous lactose, and/or microcrystalline cellulose), a lubricant e.g. tabletting lubricant (e.g. magnesium stearate or calcium stearate), a disintegrant (e.g. croscarmellose sodium),,and/or an acceptable wetting agent. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and/or, if desired, flavourings or colourants.

For parenteral administration, fluid unit dosage forms are typically prepared utilising a compound or salt within the combination of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound or salt within the combination, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound or salt within the combination can e.g. be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. In one embodiment, adjuvant(s) such as a local anaesthetic, preservative(s) and/or buffering agent(s) are dissolved in the vehicle. To enhance the stability, the composition can e.g. be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are typically prepared in substantially the same manner, except that the compound within the combination is suspended in the vehicle instead of being dissolved, and sterilization is not usually accomplished by filtration. The compound or salt within the combination can be sterilised e.g. by exposure to ethylene oxide, before suspension in a sterile vehicle. In one embodiment, a surfactant or wetting agent is included in the composition, e.g. to facilitate uniform distribution of the compound or salt within the combination.

In one embodiment, the composition contains from 0.1% to 99% (by weight of the composition), in particular from 0.1 to 60% or from 1 to 60% or from 10 to 60% by weight, of the active material (e.g. the compound of formula (I) or (IA) or pharmaceutically acceptable salt of the invention), e.g. depending on the method of administration. The carrier(s) and/or excipient(s) contained in the composition can for example be present in from 1 % to 99.9%, e.g. from 10% to 99%, by weight of the composition.

The dose of the compound of formula (I) or (IA) or the pharmaceutically acceptable salt thereof within the combination, e.g. as used in the treatment of the aforementioned disorders, may vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses (e.g. orally-administrable unit doses) may be 0.05 to 2000 mg or 0.05 to 1000 mg, for example 0.05 to 200 mg, or may be for example 0.3 to 2000 mg or 10 to 2000 mg or 10 to 1000 mg or 20 to 1000 mg such as 20 to 40 mg, of the compound of formula (I) or (IA) or the pharmaceutically acceptable salt thereof. In one embodiment, such unit doses are typically administered once a day, or more than once a day (e.g. twice a day); e.g. orally and/or e.g. to a human. Such therapy may for example extend for a number of days, weeks, months or years.

EXAMPLES

The following Descriptions and Examples illustrate the preparation of compounds of Formula (I) and Formula (IA) but are not intended to be limiting.

Example 1 Λ/-[(2-Chloro-4-fluorophenyl)methyl]-2-[3-methyl-5-(2-methylpropyl)-1 H- pyrazol-4-yl]acetamide (E1)

[3-Methyl-5-(2-methylpropyl)-1 H-pyrazol-4-yl]acetic acid (0.170 g, 0.43 mmol, prepared as described below) was dissolved in a mixture of dimethylformamide (1 ml) and dichloromethane (3 ml) and and to this was added water soluble carbodiimide (0.099 g, 0.52 mmol), 1 -hydroxybenzotriazole (0.070 g, 0.52 mmol), and N-ethyl morpholine (0.164 ml, 1.29 mmol). The mixture was stirred for 10 minutes and then [(2-chloro-4-fluorophenyl)methyl]amine (0.082 g, 0.52 mmol) was added. The mixture was stirred overnight at room temperature and then saturated aqueous sodium hydrogen carbonate (2 ml) was added to the mixture. After stirring for a further 10 minutes the organic phase was separated by filtration through a hydrophobic frit. The aqueous layer was washed with a further aliquot of dichloromethane (2-3 ml) and the organic phase was again separated and then the combined organic phases were evaporated to give the crude product as a yellow oil. The crude material was purified by mass-directed automated HPLC to give the pure product as a white solid after freeze-drying of the collected product fractions (0.080 g).

LC/MS [M+H]⁺ = 338 retention time = 2.32 minutes.

The [3-methyl-5-(2-methylpropyl)-1 /-/-pyrazol-4-yl]acetic acid used in the above procedure was obtained by hydrolysis of the corresponding ester (ethyl [3-methyl-5- (2-methylpropyl)-1 H-pyrazol-4-yl]acetate). Ethyl [3-methyl-5-(2-methylpropyl)-1 H- pyrazol-4-yl]acetate was in turn prepared by the reaction of ethyl 3-acetyl-6-methyl-4- oxoheptanoate (see preparative details below) with hydrazine hydrate. Appropriate methodologies to prepare these or analgous compounds have been described previously (e.g. US 4, 146, 721 ). Ethyl 3-acetyl-6-methyl-4-oxoheptanoate was prepared in the following manner: 6-methyl-2,4-heptanedione (0.711 g, 5.0 mmol) was dissolved in dioxane (2 ml) and water (1 ml) and then cooled to 0⁰C. To this was added, in a dropwise fashion, a solution of potassium hydroxide (0.281 g, 5.0 mmol) in water (2 ml). The mixture was then warmed to room temperature and stirred for 15 minutes. A solution of ethyl bromoacetate (0.554 ml, 5.0 mmol) in dioxane (1 ml) was then added dropwise and the mixture was stirred overnight at room temperature. The organic phase was separated and the aqueous phase was further extracted with ethyl acetate (2 x 10 ml). The combined organic fractions were dried over anhydrous sodium sulphate then filtered and evaporated to give a pale yellow oil. This material was purified by automated flash-silica column chromatography (Biotage SP4™), eluting with a gradient of 0-20% ethyl acetate in hexane, to give ethyl [3-methyl-5-(2-methylpropyl)- 1H-pyrazol-4-yl]acetate (0.343 g) as a colourless oil.

Examples 2-3

In a manner analogous to that described for Example 1 above the compounds tabulated below (Table 1 ) were prepared by substituting the appropriate diketones for the 6-methyl-2,4-heptanedione used in the above procedure. All of the diketones required to prepare the examples listed in Table 1 are available from commercial sources or can be prepared using routes described previously in the chemical literature,

Table 1

Example 4 Λ/-[(2-Chloro-4-fluorophenyl)methyl]-2-(3,5-dimethyl-1 H-pyrazol-4- yl)acetamide (E4)

/V-[(2-Chloro-4-fluorophenyl)methyl]-2-(3,5-dimethyl-1 /-/-pyrazol-4-yl)acetamide was prepared in an analogous method to that described for the preparation of Λ/-[(2- chloro-4-fluorophenyl)methyl]-2-[3-methyl-5-(2-methylpropyl)-1 /-/-pyrazol-4- yl]acetamide (E1) but using (3,5-dimethyl-1 H-pyrazol-4-yl)acetic acid in the place of [3-methyl-5-(2-methylpropyl)-1 H-pyrazol-4-yl]acetic acid. LC/MS [M+H]⁺ = 296 retention time = 1.83 minutes.

Examples 5-29

In a manner analogous to that described for Example 4 above the compounds tabulated below (Table 2) were prepared by substituting the appropriate amines for the [(2-chloro-4-fluorophenyl)methyl]amine used in the above procedure. All of the amines required to prepare the examples listed inTable 2 are available from commercial sources or can be prepared using routes described previously in the chemical literature,

Table 2

Example 30 Λ/-[(2-Chloro-4-fluorophenyl)methyl]-2-(3,5-diethyl-1 H-pyrazol-4- yl)acetamide (E30)

(3,5-Diethyl-1 H-pyrazol-4-yl)acetic acid (0.260 g, -1 mmol), prepared as described below) was dissolved in a mixture of dimethylformamide (0.5 ml) and dichloromethane (5 ml) and to this was added water soluble carbodiimide (0.230 g, 1.2 mmol), 1-hydroxybenzotriazole (0.162 g, 1 .2 mmol), and N-ethyl morpholine (0.458 ml, 3.6 mmol). The mixture was stirred for 10 minutes and then [(2-chloro-4- fluorophenyl)methyl]amine (0.239 g, 1.5 mmol) was added. The mixture was stirred for -22 hrs at room temperature and then saturated aqueous sodium hydrogen carbonate (3 ml) was added to the mixture. After stirring for a further 10 minutes the organic phase was separated by filtration through a hydrophobic frit. The aqueous layer was washed with a further aliquot of dichloromethane (~1 ml) and the organic phase was again separated and then the combined organic phases were evaporated to give the crude product as an orange oil. The crude material was purified by mass- directed automated HPLC to give the pure product as an off-white solid after freeze- drying of the collected product fractions (0.049 g). LC/MS [M+H]⁺ = 324 retention time = 2.08 minutes.

The (3,5-Diethyl-1 H-pyrazol-4-yl)acetic acid used in the above method was prepared as follows:

(i) 3,5-Heptanedione (2.03 ml, 15.0 mmol) was dissolved in dimethylformamide (10 ml) and cooled to 0⁰C using an ice-bath. Sodium hydride (60% in oil, 0.630 g, 15.75 mmol) was then added slowly in portions and then the mixture was allowed to warm to room temperature and stirred for ~ 30 minutes. The mixture was then treated with f-butyl bromoacetate (2.21 ml, 15.0 mmol) and stirred overnight (-18 hrs) at room temperature. The mixture was concentrated, azeotroping with toluene to remove as much dimethylformamide as possible, and the residue was partitioned between water (-20 ml) and ethyl acetate (-20 ml). The organic layer was separated and the aqueous phase was acidified to ~pH5 using 2N aqueous hydrogen chloride then further extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried over sodium sulphate, filtered and concentrated to give a yellow oil. The oil was purified by automated (Biotage SP4™) flash-silica gel column chromatography, eluting with a 0-10% gradient of ethyl acetate in hexane, to give pure 1 ,1- dimethylethyl 4-oxo-3-propanoylhexanoate (2.15 g) as a yellow oil. (ii) 1 ,1 -Dimethylethyl 4-oxo-3-propanoylhexanoate (1.08 g, 4.46 mmol) was dissolved in ethanol (15 ml) and treated with hydrazine hydrate (0.857 ml, 17.66 mmol). The mixture was heated to reflux at 95°C for 6 hrs then cooled to room temperature and left to stand over a weekend. Most of the ethanol was removed in vacuo and the remaining residue was partitioned between dichloromethane (10 ml) and water (5 ml). The organic layer was separated using a hydrophobic frit and the aqueous layer was further extracted with dichloromethane (2 x 10 ml). The combined organic extracts were concentrated to give 1 ,1-dimethylethyl (3,5-diethyl- 1H-pyrazol-4-yl)acetate (1.08 g) as a pale yellow oil which was used in the next step without further purification.

(iii) 1 ,1-dimethylethyl (3,5-diethyl-1 H-pyrazol-4-yl)acetate (1 .07 g, 4.49 mmol) was dissolved in dichloromethane (~2 ml) and treated with trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 3.5 hrs and then evaporated in vacuo, azeotroping with toluene to remove traces of trifluoroacetic acid, to give crude (3,5- diethyl-1 H-pyrazol-4-yl)acetic acid (1.52 g) as a dark orange/brown oil which was used without any further purification.

Example 31 2-(3,5-Diethyl-1 H-pyrazol-4-yl)-/V-[(2,3,4- trif luorophenyl)methyl]acetamide (E31 )

2-(3,5-Diethyl-1 H-pyrazol-4-yl)-Λ/-[(2,3,4-trifluorophenyl)methyl]acetamide was prepared in a manner analogous to that described for the synthesis of Λ/-[(2-chloro-4- fluorophenyl)methyl]-2-(3,5-diethyl-1 H-pyrazol-4-yl)acetamide (example 30) above but using [(2,3,4-trifluorophenyl)methyl]amine in the place of [(2-chloro-4- fluorophenyl)methyl]amine. LC/MS [M+H]⁺ = 326 retention time = 2.04 minutes.

Example 32 2-[3,5-Bis(1-methylethyl)-1 H-pyrazol-4-yl]-Λ/-[(2-chloro-4- fluorophenyl)methyl]acetamide (E32)

2-[3,5-Bis(1 -methylethyl)-1 H-pyrazol-4-yl]-Λ/-[(2-chloro-4- fluorophenyl)methyl]acetamide was prepared in a manner analogous to that described for the synthesis of Λ/-[(2-chloro-4-fluorophenyl)methyl]-2-(3,5-diethyl-1 H- pyrazol-4-yl)acetamide (example 30) above but using 2,6-dimethyl-3,5-heptanedione in the place of 3,5-heptanedione. LC/MS [M+H]⁺ = 352 retention time = 2.35 minutes.

Example 33 2-[3_!5-Bis(1-methylethyl)-1 H-pyrazol-4-yl]-Λ/-[(2,3,4- trifluorophenyl)methyl]acetamide (E33)

2-[3,5-Bis(1-methylethyl)-1 H-pyrazol-4-yl]-A/-[(2,3,4-trifluorophenyl)methyl]acetamide was prepared in a manner analogous to that described for the synthesis of Λ/-[(2- chloro-4-fluorophenyl)methyl]-2-(3,5-diethyl-1 H-pyrazol-4-yl)acetamide (example 30) above but using 2,6-dimethyl-3,5-heptanedione in the place of 3,5-heptanedione and using [(2,3,4-trifluorophenyl)methyl]amine in the place of [(2-chloro-4- fluorophenyl)methyl]amine.

LC/MS [M+H]⁺ = 354 retention time = 2.31 minutes.

Example 34 Λ/-[(2-Chloro-4-fluorophenyl)methyl]-2-[3-methyl-5-(trifluoromethyl)-1 H- pyrazol-4-yl]acetamide (E34)

A mixture of crude [3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]acetic acid (0.187 g, 0.9 mmol, prepared as described below) in dichloromethane (10 ml) was treated with 1-hydroxybenzotriazole hydrate (0.149 g, 1.1 mmol), Λ/-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (0.21 1 g, 1.1 mmol) and Λ/-ethyl morpholine (0.35 ml, 2.7 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. [(2-Chloro-4-fluorophenyl)methyl]amine (0.128 g, 0.8 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane and the organic solution was washed sequentially with saturated aqueous sodium hydrogen carbonate, water, citric acid, water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC and the resulting solid was triturated with ether/hexane, collected and dried to give Λ/-[(2-chloro-4-fluorophenyl)methyl]-2-[3-methyl-5-(trifluoromethyl)-1 /-/-pyrazol-4- yl]acetamide (E34) LC/MS [M+H]⁺ = 350, retention time = 2.46 minutes.

3-Methyl-5-(trifluoromethyl)-1 /-/-pyrazol-4-yl]acetic acid used in the above procedure was prepared as follows:

(i) A solution of 4-bromo-3-methyl-5-(trifluoromethyl)-1 H-pyrazole (11.45 g, 50 mmol) in tetrahydrofuran (250 ml) was stirred at 5°C under argon. Sodium hydride (60% dispersion in oil, 2.0 g, 50 mmol) was added portionwise and the reaction mixture was stirred at 5⁰C for 10 minutes. {2-[(Chloromethyl)oxy]ethyl}(trimethyl)silane chloride (8.33 g, 8.9 ml, 50 mmol) was added dropwise and the reaction was stirred at 5⁰C for 90 minutes. The reaction was quenched by the careful addition of water and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, and then dried and evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexanes (1 :20 - 1 :10) to give a mixture of 4-bromo-5-methyl-3- (trifluoromethyl)-i -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole and 4-bromo-3- methyl-5-(trifluoromethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole (13.55 g) which was used in the next step.

(ii) A solution of 4-bromo-5-methyl-3-(trifluoromethyl)-1 -({[2- (trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole and 4-bromo-3-methyl-5- (trifluoromethyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole (10 g, 28 mmol) in tetrahydrofuran (150 ml) was stirred at -78⁰C under argon. n-Butyl lithium (1 1.2 ml, 2.5M solution in hexanes, 28 mmol) was added and the reaction was stirred at -78⁰C for 30 minutes. Λ/,Λ/-Dimethylformamide (4.1 g, 4.3 ml, 56 mmol) was added dropwise and the reaction was stirred at -78⁰C for 30 minutes and then warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was cooled to O⁰C and the reaction was quenched with citric acid solution. The solution was extracted with ethyl acetate, the organic layer was separated, washed with water and brine, and then dried and evaporated to give a mixture of 5-methyl-3- (trifluoromethyl)-i -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole-4-carbaldehyde and 3-methyl-5-(trifluoromethyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole-4- carbaldehyde (8.34 g) which was used in the next step.

(iii) A solution of 5-methyl-3-(trifluoromethyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1 H-pyrazole-4-carbaldehyde and 3-methyl-5-(trifluoromethyl)-1 -({[2- (trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole-4-carbaldehyde (1 1 .4 g, 37 mmol) in ethanol (100 ml) was stirred at room temperature. Sodium borohydride (0.700 g, 18.5 mmol) was added portionwise with ice-water cooling. The suspension was stirred at room temperature for 30 minutes and then cooled in an ice-water bath and quenched by the cautious addition of citric acid solution. Ethyl acetate was added and the mixture was stirred at room temperature for 5 minutes and the organic solvent was evaporated. The resulting solution was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/n-hexanes (1 :4- 1 :1 ) to give a mixture of [5-methyl-3-(trifluoromethyl)-1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazol-4-yl]methanol and [3-methyl-5-

(trifluoromethyl)-i -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazol-4-yl]methanol (7.7 g)-

(iv) A solution of [5-methyl-3-(trifluoromethyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1 H-pyrazol-4-yl]methanol and [3-methyl-5-(trif luoromethyl)-1 -({[2- (trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazol-4-yl]methanol (3.1 g, 10 mmol) in dichloromethane (50 ml) was stirred at 5⁰C under argon. Triethylamine (2.02g, 2.8 ml, 20 mmol) was added followed by methanesulfonyl chloride (1.37 g, 0.9 ml, 12 mmol) and the reaction was stirred at 5⁰C for 4 hours. The solution was washed with water and the organic layer was separated, then washed sequentially with citric acid, water and brine. The solution was dried over anhydrous magnesium sulphate, then filtered and evaporated to give a mixture of 4-(chloromethyl)-5-methyl-3- (trifluoromethyl)-i -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole and 4- (chloromethylJ-S-methyl-S-^rifluoromethylJ-i-^^-^rimethylsilylJethylJoxyJmethy^-I H- pyrazole (3.3 g) which was used in the next step. (v) A solution of 4-(chloromethyl)-5-methyl-3-(trifluoromethyl)-1 -({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole and 4-(chloromethyl)-3-methyl-5- (trifluoromethyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-pyrazole (3.3 g, 10 mmol) in dimethylsulfoxide (20 ml) was treated with potassium cyanide( 0.650 g, 10 mmol) and the mixture was heated at 8O⁰C for 5 hours. The reaction was cooled to room temperature, diluted with water and the solution was extracted with chloroform. The organic extracts were combined, then washed with water and then with brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (1 :10 — 1 :2) to give a mixture of [5-methyl-3-(trifluoromethyl)-1- ({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 /-/-pyrazol-4-yl]acetonitrile and [3-methyl-5- (trifluoromethyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 /-/-pyrazol-4-yl]acetonitrile (0.597 g) which was used in the next step.

(vi) A mixture of [5-methyl-3-(trifluoromethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1H-pyrazol-4-yl]acetonitrile and [3-methyl-5-(trifluoromethyl)-1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1 /-/-pyrazol-4-yl]acetonitrile (0.597 g, 1 .9 mmol) in dioxane (4 ml) and hydrochloric acid (5N, 4ml) was heated at reflux for 24 hours. Additional hydrochloric acid (5N, 2 ml) was added and the reaction was heated at reflux for a further 6 hours. After cooling to room temperature the solvent was evaporated and the residue was co-evaporated with toluene and ether. The residue was dried to give crude 3-methyl-5-(trifluoromethyl)-1 /-/-pyrazol-4-yl]acetic acid which was used in subsequent reactions without further purification.

Examples 35-36

In a manner analogous to that described for Example 34 above the compounds tabulated below (Table 3) were prepared by substituting the appropriate amine (or salt thereof) for the [(2-chloro-4-fluorophenyl)methyl]amine used in the above procedure. All of the amines required to prepare the examples listed in Table 3 are available from commercial sources or can be prepared using routes described previously in the chemical literature unless stated otherwise,

Table 3

Example 37 2-(3,5-Dimethyl-1 H-pyrazol-4-yl)-Λ/-[1 ,2,3,4-tetrahydro-1 ^■ naphthalenyl]acetamide (E37)

(3,5-Dimethyl-1 H-pyrazol-4-yl)acetic acid (0.100 g, 0.35 mmol) was dissolved in dichloromethane (10 ml) and to this was added water soluble carbodiimide (0.162 g, 0.84 mmol), 1 -hydroxybenzotriazole (0.1 14 g, 0.84 mmol), N-ethyl morpholine (0.413 ml, 3.25 mmol), and (1 S)-1 ,2,3,4-tetrahydro-1-naphthalenylamine (0.124 g, 0.52 mmol). The mixture was stirred overnight at room temperature and then diluted with more dichloromethane (10 ml) and washed with saturated aqueous sodium hydrogen carbonate (20 ml). The organic phase was separated by filtration through a hydrophobic frit and evaporated to give the crude product as a yellow solid. The crude material was purified by mass-directed automated HPLC to give pure 2-(3,5- dimethyl-1 /-/-pyrazol-4-yl)-Λ/-[1 ,2,3,4-tetrahydro-1-naphthalenyl]acetamide as a white solid after freeze-drying of the collected product fractions (0.029 g). LC/MS [M+H]⁺ = 284 retention time = 2.00 minutes. Example 1A Λ/-[(2-Chloro-4-fluorophenyl)methyl]-2-(3,5-dimethyl-4- isoxazolyl)acetamide (E1A)

(3,5-Dimethyl-4-isoxazolyl)acetic acid (0.100 g, 0.64 mmol, purchased from commercial sources) was dissolved in anhydrous dimethylformamide (3 ml) and to this was added water soluble carbodiimide (0.148 g, 0.773 mmol), 1- hydroxybenzotriazole (0.104 g, 0.77 mmol), N-ethyl morpholine (0.246 ml, 1.93 mmol), and [(2-chloro-4-fluorophenyl)methyl]amine (0.1 17 g). The mixture was stirred at room temperature (22⁰C) for 18 hrs and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure Λ/-[(2-chloro-4-fluorophenyl)methyl]-2-(3,5-dimethyl-4-isoxazolyl)acetamide (0.135 g) as a white solid. LC/MS [M+H]⁺ = 297, retention time = 2.46 minutes.

Example 2A N-[(2-Bromo-4-fluorophenyl)methyl]-2-(3,5-dimethyl-4- isoxazolyl)acetamide (E2A)

(3,5-Dimethyl-4-isoxazolyl)acetic acid (0.051 g, 0.33 mmol) was dissolved in dichloromethane (4 ml) and to this was added water soluble carbodiimide (0.059 g, 0.31 mmol), 1-hydroxybenzotriazole (0.041 g, 0.31 mmol), N-ethyl morpholine (0.156 ml, 1.24 mmol), and [(2-bromo-4-fluorophenyl)methyl]amine (0.075 g, 0.31 mmol). The mixture was stirred at room temperature for 5 hrs and then the mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate and 2N aqueous hydrogen chloride. The organic layer was filtered through a hydrophobic frit and evaporated to give the crude product. The crude material was purified by mass- directed automated HPLC to give pure Λ/-[(2-bromo-4-fluorophenyl)methyl]-2-(3,5- dimethyl-4-isoxazolyl)acetamide (0.061 g) as a white solid. LC/MS [M+H]⁺ = 341 , retention time = 2.57 minutes.

Examples 3A-36A In a manner analogous to that described for Example 2A above the compounds tabulated below (Table 1 ) were prepared by substituting the appropriate amines for the [[(2-bromo-4-fluorophenyl)methyl]amine used in the above procedure. All of the amines required to prepare the examples listed in Table 1 are available from commercial sources or can be prepared using routes described previously in the chemical literature..

Table 1

Example 37A 2-[3,5-Bis(1-methylethyl)-4-isoxazolyl]-/V-[(2-chloro-4- fluorophenyl)methyl]acetamide (E37A)

A solution of [(2-chloro-4-fluorophenyl)methyl]amine (0.073 g, 0.46 mmol) in dichloromethane (1 ml) was added to a solution of [3,5-bis(1 -methylethyl)-4- isoxazolyl]acetic acid (0.100 g, 0.47 mmol, prepared as described below), water soluble carbodiimide (0.087 g, 0.46 mmol), 1 -hydroxybenzotriazole (0.061 g, 0.46 mmol), and N-ethyl morpholine (0.240 ml, 1.88 mmol) in dichloromethane (4 ml). The mixture was stirred overnight at room temperature and then washed with saturated aqueous sodium hydrogen carbonate solution, and the organic phase was separated by filtration through a hydrophobic frit. Evaporation gave the crude product which was purified by mass-directed automated HPLC to give pure 2-[3,5-bis(1- methylethyl)-4-isoxazolyl]-Λ/-[(2-chloro-4-fluorophenyl)methyl]acetamide as a white solid after freeze-drying of the collected product fractions (0.067 g). LC/MS [M+H]⁺ = 353.11 retention time = 3.03 minutes.

The [3,5-bis(1-methylethyl)-4-isoxazolyl]acetic acid used in the above method was prepared as follows:

(i) 2,6-Dimethyl-3,5-heptanedione (2.34 ml, 15.0 mmol) was dissolved in dimethylformamide (10 ml) and cooled to 0°C using an ice-bath. Sodium hydride (60% in oil, 0.630 g, 15.75 mmol) was then added slowly in portions and then the mixture was allowed to warm to room temperature and stirred for - 30 minutes. The mixture was then treated with f-butyl bromoacetate (2.21 ml, 15.0 mmol) and stirred overnight (-18 hrs) at room temperature. The mixture was concentrated, azeotroping with toluene to remove as much dimethylformamide as possible, and the residue was partitioned between water (-20 ml) and ethyl acetate (-20 ml). The organic layer was separated and the aqueous phase was acidified to ~pH5 using 2N aqueous hydrogen chloride then further extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried over sodium sulphate, filtered and concentrated to give a yellow oil. The oil was purified by automated (Biotage SP4) flash-silica gel column chromatography, eluting with a 0-10% gradient of ethyl acetate in hexane, to give pure 1 ,1-dimethylethyl 5-methyl-3-(2-methylpropanoyl)-4- oxohexanoate (3.17 g) as a yellow oil.

(ii) A mixture of 1 ,1-dimethylethyl 5-methyl-3-(2-methylpropanoyl)-4-oxohexanoate (1.52 g, 5.63 mmol) and potassium carbonate (1.55 g, 11.26 mmol) in ethanol (75 ml) was treated with hydroxylamine hydrochloride (0.582 g, 8.45 mmol) and the resulting mixture was then heated at 65°C for a total of 3 hrs. The ethanol was evaporated in vacuo and the remaining residue was partitioned between dichloromethane and water. The aqueous layer was made slightly basic by addition of saturated aqueous sodium hydrogen carbonater solution and then the organic layer was separated using a hydrophobic frit. Evaporation of the solvent gave the crude product which was purified by flash-silica gel column chromatography, eluting with a 0-8% gradient of ethyl acetate in hexane, to give pure 1 ,1-dimethylethyl [3,5-bis(1 -methylethyl)-4- isoxazolyl]acetate (0.567 g) as a clear oil. (iii) 1 ,1 -dimethylethyl [3,5-bis(1-methylethyl)-4-isoxazolyl]acetate (0.567 g, 2.1 mmol) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 2.5 hrs and then evaporated in vacuo, azeotroping with toluene to remove all of the trifluoroacetic acid, to give [3,5- bis(1 -methylethyl)-4-isoxazolyl]acetic acid (0.447 g) which was used without any further purification. LC/MS [M+H]⁺ = 212.04 retention time = 2.23 minutes.

Example 38A Λ/-[(2-Chloro-4-fluorophenyl)methyl]-2-(3,5-diethyl-4- isoxazolyl)acetamide (E38A)

Λ/-[(2-chloro-4-fluorophenyl)methyl]-2-(3,5-diethyl-4-isoxazolyl)acetamide was prepared in a manner analogous to that described for the synthesis of 2-[3,5-bis(1- methylethyl)-4-isoxazolyl]-Λ/-[(2-chloro-4-fluorophenyl)methyl]acetamide (example

37A) above but using 3,5-heptanedione in the place of 2,6-dimethyl-3,5- heptanedione.

LC/MS [M+H]⁺ = 325.22 retention time = 2.77 minutes.

Mass-directed automated HPLC

Purification by mass-directed automated HPLC was carried out using the following apparatus and conditions:

Hardware

Waters 2525 Binary Gradient Module

Waters 515 Makeup Pump

Waters Pump Control Module Waters 2767 Inject Collect

Waters Column Fluidics Manager

Waters 2996 Photodiode Array Detector

Waters ZQ Mass Spectrometer

Gilson 202 fraction collector Gilson Aspec waste collector

Software

Waters MassLynx version 4 SP2

Column

The columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm

(small scale) and 30mm x 100mm (large scale). The stationary phase particle size is

5μm.

Solvents

A : Aqueous solvent = Water + 0.1 % Formic Acid

B : Organic solvent = Acetonitrile + 0.1 % Formic Acid

Make up solvent = Methanol : Water 80:20 Needle rinse solvent = Methanol

Methods

There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises a 10- minute gradient followed by a 3.5 minute column flush and re-equilibration step.

Large/Small Scale 1.0-1.5 = 5-30% B

Large/Small Scale 1.5-2.2 = 15-55% B

Large/Small Scale 2.2-2.9 = 30-85% B

Large/Small Scale 2.9-3.6 = 50-99% B Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)

Flow rate

All of the above methods have a flow rate of either 20mls/min (Small Scale) or 40mls/min (Large Scale).

Liquid Chromatography / Mass Spectrometry

Analysis of the above Examples by Liquid Chromatography / Mass Spectrometry (LC/MS) was carried out using the following apparatus and conditions:

Hardware Agilent 1 100 Gradient Pump Agilent 1 100 Autosampler Agilent 1 100 DAD Detector Agilent 1 100 Degasser Agilent 1 100 Oven

Agilent 1 100 Controller Waters ZQ Mass Spectrometer Sedere Sedex 85

Software

Waters MassLynx version 4.0 SP2

Column

The column used is a Waters Atlantis, the dimensions of which are 4.6mm x 50mm. The stationary phase particle size is 3μrm.

Solvents

A : Aqueous solvent = Water + 0.05% Formic Acid B : Organic solvent = Acetonitrile + 0.05% Formic Acid

Method

The generic method used has a 5 minute runtime.

The above method has a flow rate of 3ml/mins. The injection volume for the generic method is 5ul. The column temperature is 30deg. The UV detection range is from 220 to 330nm. Pharmacological data

Compounds of the invention may be tested for in vitro biological activity at the P2X7 receptor in accordance with the following studies:

Ethidium Accumulation Assay

Studies were performed using NaCI assay buffer of the following composition (in mM): 140 NaCI, HEPES 10, /V-methyl-D-glucamine 5, KCI 5.6, D-glucose 10, CaCI₂ 0.5 (pH 7.4). HEK293 cells, expressing human recombinant P2X7 receptors, were grown in poly-L-lysine pretreated 96 well plates for 18-24 h. (The cloning of the human P2X7 receptor is described in US 6,133,434). The cells were washed twice with 350μl of assay buffer before addition of 50μl of test compound. The cells were then incubated at room temperature (19-21⁰C) for 30 min before addition of ATP and ethidium (100μM final assay concentration). The ATP concentration was chosen to be close to the EC_8O for the receptor type and was 1 mM for studies on the human P2X7 receptor. Incubations were continued for 8 or 16 min and were terminated by addition of 25μl of 1.3M sucrose containing 5mM of the P2X7 receptor antagonist reactive black 5 (Aldrich). Cellular accumulation of ethidium was determined by measuring fluorescence (excitation wavelength of 530nm and emission wavelength of 620nm) from below the plate with a Canberra Packard Fluorocount (Pangbourne, LJK) or a Flexstation.il (Molecular Devices). Antagonist PlC₅₀ values for blocking ATP responses were determined using iterative curve fitting techniques.

Fluorescent Imaging Plate Reader (FLIPR) Ca Assay

Studies were performed using NaCI assay buffer of the following composition (in mM) for human P2X7: NaCI 137; HEPES 20; KCI; 5.37; NaHCO₃4.17; CaCI₂ 1 ; MgSO₄ 0.5; and 1g/L of D-glucose (pH 7.4). HEK293 cells, expressing human recombinant P2X7 receptors, were grown in poly-L-lysine pretreated 384 well plates for 42-48h. (The cloning of the human P2X7 receptor is described in US 6,133,434). The cells were washed three times with 80μl of assay buffer, loaded for 1 h at 37°C with 2μM Fluo4 (Teflabs), washed three times again, and left with 30μl buffer before the addition of 10 μl of 4x concentrated test compound. The cells were then incubated at room temperature for 30 mins before addition (online, by FLIPR384 or FLIPR3 instrument (Molecular Devices)) of Benzoylbenzoyl-ATP (BzATP) 60μM final assay concentration. The BzATP concentration was chosen to be close to the EC_8O for the receptor type. Incubations and reading were continued for 90sec, and intracellular calcium increase was determined by measuring fluorescence (excitation wavelength of 488nm and emission wavelength of 516nm) from below the plate, with FLIPR CCD camera. Antagonist pi C₅₀ values for blocking BzATP responses were determined using iterative curve fitting techniques.

The compounds of Examples 1-37 and 1A-38A were tested in the FLIPR Ca Assay and/or the Ethidium Accumulation Assay for human P2X7 receptor antagonist activity and found to have plC50 values > 4.7 in the FLIPR Ca Assay and/or plC50 values > 5.5 in the Ethidium Accumulation Assay.

Claims

1. A combination comprising:

a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) wherein:

R³ and R⁴ independently represent hydrogen or Ci_-3 alkyl;

R⁵, R⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, halogen, cyano, Ci_-6 alkyl,

C_2-6 alkenyl, C₂.₆ alkynyl, C_3-6 cycloalkyl or phenyl, and any of said Ci_-6 alkyl, C_2-6 alkenyl, C₂-₆ alkynyl, C_3-6 cycloalkyl or phenyl is optionally substituted with 1 , 2 or 3 halogen atoms; or R⁸ and R⁹ together with the carbon atoms to which they are attached form a benzene ring which is optionally substituted with 1 , 2 or 3 halogen atoms; or R⁴ and R⁵ together with the carbon atoms to which they are attached form a C_5-7 cycloalkyl; with the proviso that when R⁵ and R⁹ are both selected from hydrogen or fluorine, at least one of R⁶, R⁷ and R⁸ is a halogen atom, or R⁶, R⁷ and R⁸ are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R⁶,

R⁷ and R⁸ is methyl or CF₃; or

a compound of formula (IA) or a pharmaceutically acceptable salt thereof:

(IA) wherein:

R^1a and R^2a represent C₁^ alkyl, phenyl, or a C_3-6 cycloalkyl, any of which may be optionally substituted with 1 , 2 or 3 halogen atoms;

R^3a, R^4a, R^5a, R^6a and R^7a independently represent hydrogen, halogen, cyano, C_1-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C₃_₆ cycloalkyl or phenyl, and any of said C-ι_₆ alkyl, C₂-e alkenyl, C₂-₆ alkynyl, C₃_₆ cycloalkyl or phenyl is optionally substituted with 1 , 2 or 3 halogen atoms; or R^6a and R^7a together with the carbon atoms to which they are attached form a benzene ring which is optionally substituted with 1 , 2 or 3 halogen atoms; with the proviso that when R^3a and R^7a are both selected from hydrogen or fluorine, at least one of R^4a, R^5a and R^6a is a halogen atom, or R^4a, R^5a and R^6a are selected from the group consisting of hydrogen, methyl and CF₃ and one, but not more than one, of R^4a, R^5a and R^6a is methyl or CF₃;

together with a further therapeutic agent or agents.

2. A combination as defined in claim 1 wherein said compound is a compound of Examples 1 -37, or Examples 1 A-38A; or a pharmaceutically acceptable salt thereof.

3. A combination as claimed in claim 1 or 2, wherein when the further therapeutic agent includes a non-steroid anti-inflammatory drug (NSAID), the nonsteroid anti-inflammatory drug is for the treatment of an inflammatory disease or disorder.

4. A combination as claimed in claim 1 , 2 or 3, wherein the further therapeutic agent does not include ethanol, cocaine, nicotine, or an opioid such as morphine.

5. A combination as claimed in claim 4, wherein the further therapeutic agent does not include nicotine, or an opioid such as morphine, or a dependence-inducing central nervous system depressant such as ethanol, or a dependence-inducing psychostimulant such as cocaine.

6. A combination as claimed in claim 5, wherein the further therapeutic agent does not include a dependence-inducing agent.

7. A combination as claimed in any one of claims 1 to 6, wherein the further therapeutic agent does not include a cancer chemotherapeutic agent.

8. A combination as claimed in any one of claims 1 to 7, wherein:

(i) the further therapeutic agent or agents includes a β2 adrenoceptor agonist and/or a corticosteroid, for the treatment of a respiratory disorder; or

(ii) the further therapeutic agent includes a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor for the treatment of a cardiovascular disorder; or

(iii) the further therapeutic agent includes a non-steroid anti-inflammatory drug (NSAID), for the treatment of an inflammatory disease or disorder; and/or

(iv) the further therapeutic agent includes a tumour necrosis factor α (TNFα) inhibitor for the treatment of an inflammatory disease or disorder; and/or

(v) the further therapeutic agent includes 2-hydroxy-5- [ [4- [ (2- pyridinylamino) sulfonyl] phenyl] azo] benzoic acid (sulfasalazine) for the treatment of an inflammatory disease or disorder; and/or

(vi) the further therapeutic agent includes N-[4-[[(2, 4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]- L-glutamic acid (methotrexate) for the treatment of an inflammatory disease or disorder; and/or

(vii) the further therapeutic agent includes an inhibitor of pro TNFα convertase enzyme (TACE) for the treatment of an inflammatory disease or disorder; and/or

(viii) the further therapeutic agent includes: a) sulfasalazine; b) a statin; c) a glucocorticoid agent; d) an inhibitor of p38 kinase; e) an anti-IL-6-receptor antibody; f) anakinra; g) an anti-IL-1 monoclonal antibody; h) an inhibitor of JAK3 protein tyrosine kinase; i) an anti-macrophage colony stimulation factor (M-CSF) monoclonal antibody; or j) an anti-CD20 monoclonal antibody; for the treatment of an IL-1 mediated disease.

9. A combination as claimed in claim 3 or 8, wherein, when the further therapeutic agent includes a non-steroid anti-inflammatory drug (NSAID), the non- steroid anti-inflammatory drug is ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib.

10. A combination as claimed in claim 8, wherein:

(i) the further therapeutic agent or agents includes a β2 adrenoceptor agonist being formoterol; and/or a corticosteroid being budesonide, fluticasone as the propionate or furoate ester, mometasone furoate, beclomethasone as the 17-propionate or 17,21-dipropionate ester, ciclesonide, triamcinolone acetonide, flunisolide, rofleponide, or butixocort as the propionate ester; for the treatment of a respiratory disorder; or

(ii) the further therapeutic agent includes a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor for the treatment of a cardiovascular disorder, wherein the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor is atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin; or

(iii) the further therapeutic agent includes a non-steroid anti-inflammatory drug

(NSAID) for the treatment of an inflammatory disease or disorder; wherein the nonsteroid anti-inflammatory drug (NSAID) is ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; and/or

(iv) the further therapeutic agent includes a tumour necrosis factor α (TNFα) inhibitor for the treatment of an inflammatory disease or disorder, wherein the tumour necrosis factor α (TNFα) inhibitor is etanercept, the anti-TNFα antibody infliximab, or the anti- TNFα antibody adalimumab; and/or (v) the further therapeutic agent includes 2-hydroxy-5- [ [4- [ (2- pyridinylamino) sulfonyl] phenyl] azo] benzoic acid (sulfasalazine) for the treatment of an inflammatory disease or disorder; and/or

(viii) the further therapeutic agent includes: a) sulfasalazine; b) a statin, which is atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, crilvastatin, dalvastatin, rosuvastatin, tenivastatin, fluindostatin, velostatin, dalvastatin, nisvastatin, bervastatin, pitavastatin, rivastatin, glenvastatin, eptastatin, tenivastatin, flurastatin, rosuvastatin or itavastatin; c) a glucocorticoid agent which is dexamethasone, methylprednisolone, prednisolone, prednisone or hydrocortisone; d) an inhibitor of p38 kinase; e) an anti-IL-6-receptor antibody; f) anakinra; g) an anti-IL-1 monoclonal antibody; h) an inhibitor of JAK3 protein tyrosine kinase; i) an anti-macrophage colony stimulation factor (M-CSF) monoclonal antibody; or j) an anti-CD20 monoclonal antibody being rituximab or HuMax-CD20 (ofatumumab); for the treatment of an IL-1 mediated disease.

11. A combination as claimed in claim 10, wherein:

(i) the further therapeutic agent or agents includes a β2 adrenoceptor agonist being formoterol; and/or a corticosteroid being budesonide, fluticasone as the propionate or furoate ester, mometasone furoate, beclomethasone as the 17-propionate or 17,21-dipropionate ester, ciclesonide, triamcinolone acetonide, flunisolide, rofleponide, or butixocort as the propionate ester; for the treatment of asthma or chronic obstructive pulmonary disease; or (ii) the further therapeutic agent includes a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor for the treatment of atherosclerosis, wherein the 3- hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor is atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin; or

(iii) the further therapeutic agent includes a non-steroid anti-inflammatory drug (NSAID) for the treatment of an inflammatory disease or disorder being rheumatoid arthritis or osteoarthritis; wherein the non-steroid anti-inflammatory drug (NSAID) is ibuprofen, naproxen, aspirin, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketoprofen, ketoralac, oxaprozin, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, lumaricoxib, meloxicam, etoricoxib or parecoxib; and/or

(iv) the further therapeutic agent includes a tumour necrosis factor α (TNFα) inhibitor for the treatment of an inflammatory disease or disorder being rheumatoid arthritis or osteoarthritis, wherein the tumour necrosis factor α (TNFα) inhibitor is etanercept, the anti-TNFα antibody infliximab, or the anti-TNFα antibody adalimumab; and/or

(v) the further therapeutic agent includes 2-hydroxy-5- [ [4- [ (2- pyridinylamino) sulfonyl] phenyl] azo] benzoic acid (sulfasalazine) for the treatment of an inflammatory disease or disorder being rheumatoid arthritis; and/or

(vi) the further therapeutic agent includes N-[4-[[(2, 4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]- L-glutamic acid (methotrexate) for the treatment of an inflammatory disease or disorder being rheumatoid arthritis; and/or

(vii) the further therapeutic agent includes an inhibitor of pro TNFα convertase enzyme (TACE) for the treatment of an inflammatory disease or disorder being rheumatoid arthritis; and/or

(viii) the further therapeutic agent includes: a) sulfasalazine; b) a statin, which is atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, crilvastatin, dalvastatin, rosuvastatin, tenivastatin, fluindostatin, velostatin, dalvastatin, nisvastatin, bervastatin, pitavastatin, rivastatin, glenvastatin, eptastatin, tenivastatin, flurastatin, rosuvastatin or itavastatin; c) a glucocorticoid agent which is dexamethasone, methylprednisolone, prednisolone, prednisone or hydrocortisone; d) an inhibitor of p38 kinase; e) an anti-IL-6-receptor antibody; f) anakinra; g) an anti-IL-1 monoclonal antibody; h) an inhibitor of JAK3 protein tyrosine kinase; i) an anti-macrophage colony stimulation factor (M-CSF) monoclonal antibody; or j) an anti-CD20 monoclonal antibody being rituximab or HuMax-CD20 (ofatumumab); for the treatment of an IL-1 mediated disease being rheumatoid arthritis.

12. A pharmaceutical composition which comprises a combination as defined in claim 1 or claim 2 and a pharmaceutically acceptable carrier or excipient.

13. A combination as defined in claim 1 or claim 2 for use in therapy.

14. A method of treating a human or animal subject suffering from pain, inflammation or a neurodegenerative disease, which method comprises administering to said subject an effective amount of a combination as defined in claim 1 or claim 2.

15. Use of a combination as defined in claim 1 or claim 2 for the manufacture of a medicament for the treatment or prevention of pain, inflammation or a neurodegenerative disease.

16. Use as claimed in any claim 15, for the manufacture of a medicament for the treatment or prevention of inflammatory pain, neuropathic pain, visceral pain, rheumatoid arthritis or osteoarthritis.