NEW USE 921

The present invention relates to the use of a P2X ₇ antagonist in the treatment of a mood disorder.

The P2X ₇ receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X ₇ receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the processing and release of cytokines such as interleukin-lβ (IL- lβ) and IL- 18 and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes). For this reason P2X ₇ antagonists have been prepared as compounds for use in the treatment of inflammatory and immune diseases, such as rheumatoid arthritis.

Patients suffering from chronic immune -mediated and inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease may also experience a mood disorder such as depression (major depressive disorder), anxiety symptoms, lack of sleep, fatigue and loss of the ability to concentrate on both menial and complex tasks. As such, this collection of conditions forms part of the syndrome of sickness behaviour, which is manifest as a co-morbidity and contributing factor to further decline in patient well-being. In such instances, mood disorders such as depression may relate to disability, physical appearance and psychological factors. Treatment of depression in rheumatoid arthritis patients has been managed by administration with tryclic anti-depressants e.g. amitriptyline, and selective serotonin reuptake inhibitors e.g. paroxetine.

The present invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament for use in treating a mood disorder.

Without wishing to imply that the effects of a P2X ₇ antagonist in the treatment of a mood disorder may occur due to a single biological process, one rationale surrounding P2X ₇ antagonism involves inhibition of IL-I β and IL- 18 production. As applicable to rheumatoid arthritis, during joint inflammation and infection, IL-lβ and IL18 are released at the periphery where they may act both locally, systemically and centrally. The central effects of IL-lβ, in addition to induction of behavioural changes are to induce fever by binding brain type I IL-I receptors, where it may activate members of the mitogen- activated protein kinase family, which include p38, JNK, ERK1/2 (Neuroscience (2005), 134: 921-932). IL-lβ has been shown to evoke ATP and adenosine release from rat hippocampal slices (J. Neuroimmunol. (2004), 151:33-39) and may induce IL-lβ dependent depression via glutamate receptor activation and the p38 MAPK kinase pathway.

In the context of the present specification, the term Mood Disorder includes: 1) depressive disorder(s), including but not limited to a) major depressive disorder(s) and dysthymic disorder(s) and b) bipolar depression and/or bipolar mania including but not limited to bipolar I, including but not limited to those with manic, depressive or mixed episodes, and bipolar II, c) cyclothymiac's disorder(s); d) depressive disorder(s) due to a general medical condition; 2) anxiety disorder(s) including but not limited to panic disorder(s) without agoraphobia, panic disorder(s) with agoraphobia, agoraphobia without history of panic disorder(s), specific phobia, social phobia, obsessive-compulsive disorder(s), stress related disorder(s), posttraumatic stress disorder(s), acute stress disorder(s), generalized anxiety disorder(s) and generalized anxiety disorder(s) due to a general medical condition; and 3) sleep disorder(s).

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament for use in treating a depressive disorder. Depressive disorders that may be treated according to this embodiment include, but are not limited to major depressive disorder(s), dysthymic disorder(s), psychosomatic disorder(s) and depressive disorder(s) due to a general medical condition.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament for use in treating a depressive disorder due to a general medical condition.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament for use in treating an anxiety disorder. Anxiety disorders that may be treated according to this embodiment include, but are not limited to, panic disorder(s) without agoraphobia, panic disorder(s) with agoraphobia, agoraphobia without history of panic disorder(s), specific phobia, social phobia, obsessive-compulsive disorder(s), stress related disorder(s), posttraumatic stress disorder(s), acute stress disorder(s), generalized anxiety disorder(s) and generalized anxiety disorder(s) due to a general medical condition.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament for use in treating sickness behaviour. In the context of the present specification sickness behaviour is defined as a mood disorder that occurs as a secondary indication to a chronic primary disease. Examples of chronic primary diseases include cardiovascular diseases (e.g. atherosclerosis and hypertension), diabetes, cancer, arthritic diseases (e.g. rheumatoid arthritis) and inflammatory bowel disease (e.g. Crohn's disease). Examples of sickness behaviour include depression (major depressive disorder), anxiety symptoms, lack of sleep, fatigue and loss of the ability to concentrate on both menial and complex tasks.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament, wherein the medicament is for use in treating a patient having rheumatoid arthritis and a mood disorder.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament, wherein the medicament is for use in treating a patient having rheumatoid arthritis and, in co-morbidity, a mood disorder.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament, wherein the medicament is for use in treating a patient having rheumatoid arthritis and, in co-morbidity, a depressive disorder.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament, wherein the medicament is for use in treating a patient having inflammatory bowel disease and a mood disorder.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament, wherein the medicament is for use in treating a patient having Crohn's disease and, in co-morbidity, a mood disorder.

In one embodiment, the invention provides the use of a P2X ₇ antagonist in the manufacture of a medicament, wherein the medicament is for use in treating a patient having Crohn's disease and, in co-morbidity, a depressive disorder.

In one embodiment the invention provides the use a P2X ₇ antagonist in the manufacture of a medicament, wherein the medicament is for administration to a patient at risk of developing a mood disorder. An example of a patient at risk of developing a mood disorder is a patient having a primary disease (e.g. rheumatoid arthritis or inflammatory bowel disease (e.g. Crohn's disease)) and is at risk of developing a mood disorder in comorbidity.

In one embodiment, the present invention provides a P2X ₇ antagonist for the treatment of a mood disorder.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a depressive disorder. Depressive disorders that may be treated according to this embodiment include, but are not limited to major depressive disorder(s), dysthymic

disorder(s), psychosomatic disorder(s) and depressive disorder(s) due to a general medical condition.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a depressive disorder due to a general medical condition.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of an anxiety disorder. Anxiety disorders that may be treated according to this embodiment include, but are not limited to, panic disorder(s) without agoraphobia, panic disorder(s) with agoraphobia, agoraphobia without history of panic disorder(s), specific phobia, social phobia, obsessive-compulsive disorder(s), stress related disorder(s), posttraumatic stress disorder(s), acute stress disorder(s), generalized anxiety disorder(s) and generalized anxiety disorder(s) due to a general medical condition.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of sickness behaviour. In the context of the present specification sickness behaviour is defined as a mood disorder that occurs as a secondary indication to a chronic primary disease. Examples of chronic primary diseases include cardiovascular diseases (e.g. atherosclerosis and hypertension), diabetes, cancer, arthritic diseases (e.g. rheumatoid arthritis) and inflammatory bowel disease (e.g. Crohn's disease). Examples of sickness behaviour include depression (major depressive disorder), anxiety symptoms, lack of sleep, fatigue and loss of the ability to concentrate on both menial and complex tasks.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a patient having rheumatoid arthritis and a mood disorder.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a patient having rheumatoid arthritis and, in co-morbidity, a mood disorder.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a patient having rheumatoid arthritis and, in co-morbidity, a depressive disorder.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a patient having inflammatory bowel disease and a mood disorder.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a patient having Crohn's disease and, in co-morbidity, a mood disorder.

In one embodiment, the invention provides a P2X ₇ antagonist for the treatment of a patient having Crohn's disease and, in co-morbidity, a depressive disorder.

An antagonist of the P2X ₇ receptor is a compound or other substance that is capable of preventing, whether fully or partially, activation of the P2X ₇ receptor. Methods for assaying for P2X ₇ receptor antagonism are known in the art, for example from WO

01/42194 which describes an assay based on the observation that when the P2X ₇ receptor is activated using a receptor agonist in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of intracellular DNA-bound ethidium bromide is observed. Thus, an increase in fluorescence can be used as a measure of P2X ₇ receptor activation and therefore to quantify the effect of a compound or substance on the P2X ₇ receptor.

In WO 01/42194, the assay is carried out by taking a 96-well flat bottomed microtitre plate and filling the wells with 250 μl of test solution comprising 200 μl of a suspension of THP-I cells (2.5 x 10 ⁶ cells/ml) containing 10 ^"4 M ethidium bromide, 25 μl of a high potassium buffer solution containing 10 ^"5 M benzoylbenzoyl adenosine triphosphate (bbATP, a known P2X ₇ receptor agonist), and 25 μl of the high potassium buffer solution containing 3 x 10 ^"5 M test compound. The plate is covered with a plastics sheet and incubated at 37 ⁰ C for one hour. The plate is then read in a Perkin-Elmer fluorescent plate reader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20 nm. For the

purposes of comparison, bbATP (a P2X ₇ receptor agonist) and pyridoxal 5-phosphate (a P2X ₇ receptor antagonist) are used separately in the test as controls. From the readings obtained, a pICso figure is calculated for the test compound, this figure being the negative logarithm of the concentration of test compound necessary to reduce the bbATP agonist activity by 50%. A pICso figure greater than 5.5 is normally indicative of an antagonist.

Examples of P2X ₇ receptor antagonists which may be used in accordance with the present invention are described in WO 00/61569, WO 01/42194, WO 01/44170, WO 01/44213, WO 01/46200, WO 01/94338, WO 03/041707, WO 03/042190, WO 03/042191, WO 03/080579, WO 04/058270, WO 04/058731, WO 04/074224, WO 04/099146, WO 04/106305, WO05/009968, US2005/0171195, WO2005/111003, US2006/0025614, WO2006/059945, WO2006/086229, WO2006/110516, WO2007/056046, WO2007/056091, WO2005/014555, WO2005/019182, WO2006/102588, WO2006/102610 and WO2007/028022, the entire contents of which are incorporated herein by reference .

In an embodiment of the present invention the P2X ₇ receptor antagonist is an adamantyl derivative, for example as described in WO 00/61569, WO 01/42194, WO 01/44170 and WO 03/41707.

In an embodiment of the present invention, the P2X ₇ receptor antagonist is an adamantyl derivative of formula

(I) wherein m represents 1, 2 or 3;

A represents C(O)NH or NHC(O);

Y represents N or CH;

X represents a bond, CO, (CH ₂ ) _1-6 , O(CH ₂ ) _1-6 , (CH ₂ ) _1-6 NH(CH ₂ ) _1-6 , (CH ₂ ) _1-6 O(CH ₂ ) _1-6 ,

NH(CH ₂ ) _1-6 ; 5 Z represents NR ² R ³ ;

R ¹ represents halogen, cyano, nitro, amino, hydroxyl, Ci-C ₆ alkyl or C ₃ -Cs cycloalkyl, which alkyl or cycloalkyl group can be optionally substituted by one or more fluorine atoms;

R ² and R ³ each independently represent a hydrogen atom, Ci-C ₆ alkyl or C ₃ -C ₈ cycloalkyl,o which alkyl or cycloalkyl group can be optionally substituted by one or more groups selected from hydroxyl, halogen or Ci-C ₆ alkoxy, or R ² and R ³ together with the nitrogen atom to which they are attached form a 3- to 9- membered saturated mono- or bicyclic heterocyclic ring comprising from 1 to 2 nitrogen atoms and optionally an oxygen atom, which heterocyclic ring can be optionallys substituted by one or more groups selected from hydroxyl, halogen or Ci-C ₆ alkoxy; or a pharmaceutically acceptable salt thereof.

Adamantyl derivatives of formula (I) may be prepared according to known chemistry, for example by methods according or analogous to those described in WO 00/61569, WOo 01/42194, WO 01/44170 and WO 03/41707.

The P2Xγ receptor antagonist used in the present invention may be capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the active ingredient and mixtures thereof including racemates.5 Tautomers and mixtures thereof also form an aspect of the present invention. Moreover, it will be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms.

In another embodiment of the present invention, the P2X ₇ receptor antagonist is selectedo from

2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-N- (tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide,

2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 ]dec- 1 -ylmethyl)- benzamide, (i?)-2-Chloro-5-[3-[(2-hydroxy- 1 -methylethyl)amino]propyl]-N-

(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide,

2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tric yclo[3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide,

2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3. 3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)benzamide,

2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3 .3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide,

2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-N-(tricyclo[ 3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide, 2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-N-(tricyclo[3 .3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)-benzamide,

2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tr icyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide,

2-Chloro-5 -[ [2- [ [2-( 1 -methyl- lH-imidazol-4-yl)ethyl] amino]ethyl] amino]-N- (tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide,

2-Chloro-5-piperazin- 1 -ylmethyl-N-(tricyclo[3.3.1.1 ]dec- 1 -ylmethyl)-benzamide, 2-Chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, 2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricy clo[3.3.1.1 ]dec-l- ylmethyl)-benzamide, 2-Chloro-5-(piperidin-4-ylsulfinyl)-N-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide,

5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-λ/-(tricyclo[ 3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-4-pyridinecarboxamide,

2-Chloro-5 - [3 - [ [( li?)-2-hydroxy- 1 -methylethyl]amino]propyl] -N- (tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-3-pyridinecarboxamide,

5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-4- pyridinecarboxamide,

5-Chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3 .1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)- 4-pyridinecarboxamide, 5-Chloro-2-[3-[[(25)-2-hydroxypropyl]amino]propyl]-N-(tricyc lo[3.3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)-4-pyridinecarboxamide,

λ/-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbon yl)phenyl]- tricyclo[3.3.1.1 ³ ' ⁷ ]decane- 1 -acetamide, or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts include, where applicable, acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salt; and salts prepared from pharmaceutically acceptable inorganic and organic bases. Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and bismuth salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, cyclic amines like arginine, betaine, choline and the like.

Examples of P2X ₇ receptor antagonists that may be employed in accordance with the present invention include:-

2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-7V - (tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, dihydrochloride

2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-λ/-(tricyc lo[3.3.1.1 ]dec- 1 -ylmethyl)- benzamide, hydrochloride

(i?)-2-Chloro-5-[3-[(2-hydroxy- 1 -methylethyl)amino]propyl]-7V- (tricyclo[3.3.1.1 ³ ' ⁷ ]dec-l-ylmethyl)-benzamide, hydrochloride

2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tric yclo[3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide, acetate (1:1) salt 2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3. 3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)benzamide, hydrochloride

2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-7V-(tricyclo[ 3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide, hydrochloride

2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-7V-(tricyclo [3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide, acetate (1:1) salt

2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-7V-(tricyclo[ 3.3.1.1 ³ ' ⁷ ]dec- 1 - ylmethyl)-benzamide

2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tr icyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 ■ ylmethyl)-benzamide, hydrochloride 2-Chloro-5-[[2-[[2-(l-methyl-lH-imidazol-4-yl)ethyl]amino]et hyl]amino]-N-

(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide

2-Chloro-5-piperazin- 1 -ylmethyl-N-(tricyclo[3.3.1.1 ]dec- 1 -ylmethyl)-benzamide, dihydrochloride

2-Chloro-5-(4-piperidinyloxy)-7V-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, hydrochloride

2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tr icyclo[3.3.1.1 ]dec-l- ylmethyl)-benzamide, hydrochloride

2-Chloro-5-(piperidin-4-ylsulfinyl)-λ/-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide

5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3. 3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)-4-pyridinecarboxamide,

5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-4- pyridinecarboxamide, hydrochloride

5-Chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3 .1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)- 4-pyridinecarboxamide, hydrochloride

5-Chloro-2-[3-[[(25)-2-hydroxypropyl]amino]propyl]-N-(tricyc lo[3.3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)-4-pyridinecarboxamide, dihydrochloride, and

λ/-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbon yl)phenyl]- tricyclo[3.3.1.1 ³ ' ⁷ ]decane- 1 -acetamide, hydrochloride.

In one embodiment of the invention the P2X ₇ antagonist is 2-Chloro-5-[[2-(2-hydroxy- ethylamino)-ethylamino]-methyl]-7V-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X ₇ antagonist is 2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-7V - (tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide dihydrochloride.

In one embodiment of the invention the P2X ₇ antagonist is 2-Chloro-5-[3-[(3- hydroxypropyl)amino]propyl]-λ/-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X ₇ antagonist is 2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-λ/-(tricyclo[ 3.3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)-benzamide hydrochloride.

In one embodiment of the invention the P2X ₇ antagonist is 2-Chloro-5-[3- (methylamino)propyl]-7V-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X ₇ antagonist is 2-Chloro-5-[3-(methylamino)propyl]-7V-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)- benzamide hydrochloride.

In one embodiment of the invention the P2X ₇ antagonist is 2-Chloro-5-[2-(3- hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec-l-ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X ₇ antagonist is 2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-7V- (tricyclo[3.3.1.1 ³ ' ⁷ ]dec-l-ylmethyl)-benzamide, acetate (1:1) salt.

In one embodiment of the invention the P2X ₇ antagonist is 2-Chloro-5-[2-[2-[(2- hydroxyethyl)amino]ethoxy]ethoxy]-7V-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X ₇ antagonist is 2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N- (tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide, hydrochloride.

In another embodiment the P2X ₇ anatgonist is a quinoline derivative, for example as described in WO 2003/080579, WO 2004/106305, WO 2005/009968 and WO2006/059945, the entire contents of which are incorporated herein by reference.

In another embodiment of the present invention, the P2X ₇ receptor antagonist is selected from:

6-Chloro-2-(l -piperazinylmethyl)-7V-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-5- quinolinecarboxamide, (e.g. as a hydrochloride salt) 6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-λ/-(tricycl o[3.3.1.1 ³ ' ⁷ ]dec-l- ylmethyl)-5-quinolinecarboxamide

λ/-[6-chloro-2-[[4-(2-hydroxyethyl)-l-piperazinyl]methyl]-5 -quinolinyl]- tricyclo[3.3.1.1 ³ ' ⁷ ]decane- 1 -acetamide

N- [2- [2- [(3 -Hydroxypropyl)amino] ethyl]-6-methyl-5 -quinolinyl]- tricyclo[3.3.1.1 ³ ' ⁷ ]decane-l-acetamide, (e.g. as a dihydrochloride salt)

N- [6-chloro-2- [methyl[3 -(methylamino)propyl] amino] -5 -quinolinyl] - cyclohexaneacetamide, (e.g. as a dihydrochloride salt)

6-Chloro-N-(cyclohexylmethyl)-2-(3 -hydroxy- l-azetidinyl)-5-quinolinecarboxamide

λ/-[6-Chloro-2-[4-(lH-tetrazol-5-yl)butyl]-5-quinolinyl] -cyclohexaneacetamide (βi?)-λ/-[6-Chloro-2-[methyl[3-(methylamino)propyl]amino]- 5-quinolinyl]-β-methyl- benzenepropanamide

2,4-Dichloro-N-[6-chloro-2-(l-piperazinyl)-5-quinolinyl]- benzenepropanamide l-[6-Chloro-5-[[[2-(2,6-dichlorophenyl)ethyl]amino]carbonyl] -2-quinolinyl]- 4- piperidinecarboxylic acid

N-[(3S)-l-[6-Chloro-5-[[(tricyclo[3.3.1.1 ³ ' ⁷ ]dec-l-ylmethyl)amino]carbonyl]-2- quinolinyl] -3 -piperidinyl] -β-alanine

3-[6-Chloro-5-[[(tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)amino]carbonyl]-2-quinolinyl]- benzoic acid 6-Chloro-2-[4-(lH-tetrazol-5-yl)butyl]-N-(tricyclo[3.3.1.1 ³ ' ⁷ ]dec-l-ylmethyl)- 5- quinolinecarboxamide, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the P2X ₇ receptor antagonist is selected from:

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-(4,5-dihydro-3,5-d ioxo-l,2,4-triazin-2(3H)- yl)-benzamide

2-Chloro-5-(4,5-dihydro-3,5-dioxo-l,2,4-triazin-2(3H)-yl)-N- (tricyclo[3.3.1.1 ³ ' ⁷ ]dec- 1 -ylmethyl)-benzamide 2-Chloro-5-[4,5-dihydro-4-(2-methoxyethyl)-5-oxo-lH-l,2,4-tr iazol-l-yl]-N-[(l- hydroxycycloheptyl)methyl]-benzamide

2-Chloro-5-[4,5-dihydro-4-[(2R)-2-hydroxy-3-methoxypropyl ]-3,5-dioxo-l,2,4- triazin-2(3H)-yl]-N-[(l-hydroxycycloheptyl)methyl]-benzamide

2-Chloro-5-[l-(3-fluoro-2-hydroxypropyl)-lH-imidazol-4-yl ]-N-[(l- hydroxy cycloheptyl)methyl] -benzamide

λ/-[l-[[(Cyanoamino)(5-quinolinylimino)methyl]amino]-2,2 -dimethylpropyl]-3,4- dimethoxy-benzeneacetamide

N- [ 1 - [ [ 1 -(Cyanoamino)-2-(2-methylphenyl)ethylidene] amino] -2,2-dimethylpropyl]- benzeneacetamide 3-[[5-(2,3-Dichlorophenyl)-lH-tetrazol-l-yl]methyl]-pyridine , (e.g. as a monohydrochloride salt) l-(2,3-Dichlorophenyl)-N-[(2-methylphenyl)methyl]-l//-tetraz ol-5-amine

1 -Methyl-2,2-diphenyl-cyclopropanecarboxylic acid, 2-(5-quinolinyl)hydrazide l-(2,3-Dichlorophenyl)-5-[(3-pyridinylmethyl)amino]-lH-pyraz ole-4-carbonitrile

(4i?,55)-re/-2-[(3-Chloro-4-fluorophenyl)methyl]-4,5-dihy dro-4,5-diphenyl-lH- imidazole, (e.g. as a mono(trifluoroacetate) salt)

3 - [[ 1 -(2-Hydroxyethyl)-3 -methyl-5 -phenyl- 1 H-pyrazol-4-yl]methyl]-N-(3 - methoxyphenyl)-benzamide 5,6,7,8-Tetrahydro-7-(phenylmethyl)-N-(tricyclo[3.3.1.13,7]d ec-l-ylmethyl)- pyrido [3 ,4-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating a mood disorder, which comprises administering to a patient in need thereof, a therapeutically effective amount of a P2X ₇ antagonist. Mood disorders that may be treated according to this aspect of the invention include those herein before described with respect to the use of a P2X ₇ antagonist in the manufacture of a medicament for use treating a mood disorder.

In one embodiment the invention provides a method of treating a mood disorder in a patient having both a mood disorder and rheumatoid arthritis, which comprises administering to the patient a therapeutically effective amount of a P2X ₇ antagonist.

In one embodiment the invention provides a method of preventing or reducing the effects of a mood disorder in a patient having rheumatoid arthritis which comprises administering to a patient in need thereof a therapeutically effective amount of a P2X ₇ antagonist

In one embodiment the invention provides a method of treating a mood disorder in a patient having both a mood disorder and inflammatory bowel disease (e.g. Crohn's disease), which comprises administering to the patient a therapeutically effective amount of a P2X ₇ antagonist.

In one embodiment the invention provides a method of preventing or reducing the effects of a mood disorder in a patient having inflammatory bowel disease (e.g. Crohn's disease),

which comprises administering to a patient in need thereof a therapeutically effective amount of a P2X ₇ antagonist

In order to use the P2X ₇ antagonist, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition that comprises the P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier . Depending on the mode of administration, the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition. The pharmaceutical compositions may be administered for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

In one embodiment of the invention the P2X ₇ antagonist is administered in a pharmaceutical composition suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between O.lmg and Ig of active ingredient.

In another embodiment of the invention the P2X ₇ antagonist is administered in a pharmaceutical composition suitable for intravenous, subcutaneous or intramuscular injection. Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg ^"1 to 100 mgkg ^"1 of the compound, for example in the range of 0.1 mgkg ^"1 to 20 mgkg ^"1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The present invention further provides a pharmaceutical composition comprising a P2X ₇ antagonist for the treatment of a mood disorder. Mood disorders that may be treated according to this aspect of the invention include those herein before described with respect to the use of a P2X ₇ antagonist in the manufacture of a medicament for use in treating a mood disorder.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvent, diluent or carrier for the treatment of a mood disorder.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvent, diluent or carrier, for the treatment of a depressive disorder. Depressive disorders that may be treated according to this embodiment include, but are not limited to major depressive disorder(s), dysthymic disorder(s), psychosomatic disorder(s) and depressive disorder(s) due to a general medical condition.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a depressive disorder due to a general medical condition.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of an anxiety disorder. Anxiety disorders that may be treated according to this embodiment include, but are not limited to, panic disorder(s) without agoraphobia, panic disorder(s) with agoraphobia, agoraphobia without history of panic disorder(s), specific phobia, social phobia, obsessive-compulsive disorder(s), stress related disorder(s), posttraumatic stress disorder(s), acute stress disorder(s), generalized anxiety disorder(s) and generalized anxiety disorder(s) due to a general medical condition.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of sickness behaviour. In the context of the present specification sickness behaviour is defined as a mood disorder that occurs as a secondary indication to a chronic primary disease. Examples of chronic primary diseases include cardiovascular diseases (e.g. atherosclerosis and hypertension), diabetes, cancer, arthritic diseases (e.g. rheumatoid arthritis) and inflammatory bowel disease (e.g. Crohn's disease). Examples of sickness behaviour include depression (major depressive disorder), anxiety symptoms, lack of sleep, fatigue and loss of the ability to concentrate on both menial and complex tasks.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having rheumatoid arthritis and a mood disorder.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having rheumatoid arthritis and, in co-morbidity, a mood disorder.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having rheumatoid arthritis and, in co-morbidity, a depressive disorder.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having inflammatory bowel disease and a mood disorder.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having Cohn's disease and, in co-morbidity, a mood disorder.

In one embodiment, the invention provides a pharmaceutical composition comprising a P2X ₇ antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having Crohn's disease and, in co-morbidity, a depressive disorder.

One measure for assessing the efficay of a pharmaceutical on a patient is to measure their quality of life using a questionnaire.

Patients with chronic and debilitating diseases such as rheumatoid arthritis typically suffer from a deterioration in their health-related quality of life which can be partly attributed to mood disorders that are secondary to the major illness. Therefore assessment of the efficacy of a pharmaceutical product such as a P2X ₇ antagonist in the treatment of rheumatoid arthritis would usually include an assessment of health-related quality of life using one or more validated questionnaires. One such questionnaire is the SF-36 questionnaire (Ware JE Jr, Kosinski M, Bjorner JB, Turner-Bowker DM, Gandel, B & Maruish ME. User's manual for the SF-36v2 Health), which is suitable for use in many chronic disease areas such as Rheumatoid Arthritis and includes a Mental Component Summary score that addresses the health domains of Mental Health, Role-emotional, Social Functioning and Vitality thereby providing data on the patient's psychological well-being. More specific and in-depth data on the effect of a treatment on mood disorders, whether as a primary illness or secondary to a chronic illness, could be determined from questionnaires such as the Hospital Anxiety and Depression Scale (Zigmond AS, Snaith RP, Acta Psychiatr Scand. 1983;67:361-370) and the Centre for Epidemiological Studies Depression Scale (Radloff, L. S. The CES-D scale: A self-report depression scale for research in the general population. Applied Psychological Measurement, 1977; 1:385-401).