WO2009019503A2 - P2x7 antagonists for use in the treatment of mood disorders - Google Patents

P2x7 antagonists for use in the treatment of mood disorders Download PDF

Info

Publication number
WO2009019503A2
WO2009019503A2 PCT/GB2008/050640 GB2008050640W WO2009019503A2 WO 2009019503 A2 WO2009019503 A2 WO 2009019503A2 GB 2008050640 W GB2008050640 W GB 2008050640W WO 2009019503 A2 WO2009019503 A2 WO 2009019503A2
Authority
WO
WIPO (PCT)
Prior art keywords
antagonist
disorder
chloro
tricyclo
ylmethyl
Prior art date
Application number
PCT/GB2008/050640
Other languages
French (fr)
Other versions
WO2009019503A3 (en
Inventor
Martin Braddock
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2009019503A2 publication Critical patent/WO2009019503A2/en
Publication of WO2009019503A3 publication Critical patent/WO2009019503A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • 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).
  • cytokines such as interleukin-l ⁇ (IL- l ⁇ ) and IL- 18 and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and
  • 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.
  • depression major depressive disorder
  • anxiety symptoms depression
  • lack of sleep sleep
  • fatigue loss of the ability to concentrate on both menial and complex tasks.
  • 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.
  • 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.
  • 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 ⁇ and IL- 18 production.
  • IL-l ⁇ and IL18 are released at the periphery where they may act both locally, systemically and centrally.
  • IL-l ⁇ 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-l ⁇ has been shown to evoke ATP and adenosine release from rat hippocampal slices (J. Neuroimmunol. (2004), 151:33-39) and may induce IL-l ⁇ dependent depression via glutamate receptor activation and the p38 MAPK kinase pathway.
  • 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).
  • depressive disorder(s) including but not limited to a) major depressive disorder(
  • 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.
  • 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.
  • 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.
  • the invention provides the use of a P2X 7 antagonist in the manufacture of a medicament for use in treating sickness behaviour.
  • sickness behaviour is defined as a mood disorder that occurs as a secondary indication to a chronic primary disease.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a P2X 7 antagonist for the treatment of a mood disorder.
  • 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.
  • the invention provides a P2X 7 antagonist for the treatment of a depressive disorder due to a general medical condition.
  • 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.
  • the invention provides a P2X 7 antagonist for the treatment of sickness behaviour.
  • sickness behaviour is defined as a mood disorder that occurs as a secondary indication to a chronic primary disease.
  • 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).
  • 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.
  • the invention provides a P2X 7 antagonist for the treatment of a patient having rheumatoid arthritis and a mood disorder.
  • 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.
  • the invention provides a P2X 7 antagonist for the treatment of a patient having inflammatory bowel disease and a mood disorder.
  • the invention provides a P2X 7 antagonist for the treatment of a patient having Crohn's disease and, in co-morbidity, a mood disorder.
  • 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.
  • ethidium bromide a fluorescent DNA probe
  • the assay is carried out by taking a 96-well flat bottomed microtitre plate and filling the wells with 250 ⁇ l of test solution comprising 200 ⁇ l of a suspension of THP-I cells (2.5 x 10 6 cells/ml) containing 10 "4 M ethidium bromide, 25 ⁇ l of a high potassium buffer solution containing 10 "5 M benzoylbenzoyl adenosine triphosphate (bbATP, a known P2X 7 receptor agonist), and 25 ⁇ l 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.
  • bbATP a P2X 7 receptor agonist
  • pyridoxal 5-phosphate a P2X 7 receptor antagonist
  • 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 .
  • 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.
  • the P2X 7 receptor antagonist is an adamantyl derivative of formula
  • 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 ,
  • 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 P2X ⁇ 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.
  • 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,
  • 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.
  • 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-
  • 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.
  • P2X 7 receptor antagonists examples include:-
  • 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.
  • 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.
  • the P2X 7 antagonist is 2-Chloro-5-[3-[(3- hydroxypropyl)amino]propyl]- ⁇ /-(tricyclo[3.3.1.1 3 ' 7 ]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof.
  • the P2X 7 antagonist is 2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]- ⁇ /-(tricyclo[3.3.1.1 3 ' 7 ]dec-l- ylmethyl)-benzamide hydrochloride.
  • 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.
  • the P2X 7 antagonist is 2-Chloro-5-[3-(methylamino)propyl]-7V-(tricyclo[3.3.1.1 3 ' 7 ]dec- 1 -ylmethyl)- benzamide hydrochloride.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the P2X 7 receptor antagonist is selected from:
  • the P2X 7 receptor antagonist is selected from:
  • 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.
  • 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.
  • 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
  • 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.
  • a mood disorder in a patient having both a mood disorder and inflammatory bowel disease (e.g. Crohn's disease)
  • inflammatory bowel disease e.g. Crohn's disease
  • 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
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • sickness behaviour is defined as a mood disorder that occurs as a secondary indication to a chronic primary disease.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • rheumatoid arthritis 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.

Abstract

Use of a P2X 7antagonist for use in treating a mood disorder, wherein the mood disorder is a depressive or an anxiety disorder, and wherein the mood disorder may be associated with rheumatoid arthritis or inflammatory bowel disease.

Description

NEW USE 921
The present invention relates to the use of a P2X7 antagonist in the treatment of a mood disorder.
The P2X7 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 P2X7 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 P2X7 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 P2X7 antagonist in the manufacture of a medicament for use in treating a mood disorder. Without wishing to imply that the effects of a P2X7 antagonist in the treatment of a mood disorder may occur due to a single biological process, one rationale surrounding P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 antagonist for the treatment of a mood disorder.
In one embodiment, the invention provides a P2X7 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 P2X7 antagonist for the treatment of a depressive disorder due to a general medical condition.
In one embodiment, the invention provides a P2X7 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 P2X7 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 P2X7 antagonist for the treatment of a patient having rheumatoid arthritis and a mood disorder.
In one embodiment, the invention provides a P2X7 antagonist for the treatment of a patient having rheumatoid arthritis and, in co-morbidity, a mood disorder. In one embodiment, the invention provides a P2X7 antagonist for the treatment of a patient having rheumatoid arthritis and, in co-morbidity, a depressive disorder.
In one embodiment, the invention provides a P2X7 antagonist for the treatment of a patient having inflammatory bowel disease and a mood disorder.
In one embodiment, the invention provides a P2X7 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 P2X7 antagonist for the treatment of a patient having Crohn's disease and, in co-morbidity, a depressive disorder.
An antagonist of the P2X7 receptor is a compound or other substance that is capable of preventing, whether fully or partially, activation of the P2X7 receptor. Methods for assaying for P2X7 receptor antagonism are known in the art, for example from WO
01/42194 which describes an assay based on the observation that when the P2X7 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 P2X7 receptor activation and therefore to quantify the effect of a compound or substance on the P2X7 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 106 cells/ml) containing 10"4M ethidium bromide, 25 μl of a high potassium buffer solution containing 10"5M benzoylbenzoyl adenosine triphosphate (bbATP, a known P2X7 receptor agonist), and 25 μl of the high potassium buffer solution containing 3 x 10"5M test compound. The plate is covered with a plastics sheet and incubated at 37 0C 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 P2X7 receptor agonist) and pyridoxal 5-phosphate (a P2X7 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 P2X7 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 P2X7 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 P2X7 receptor antagonist is an adamantyl derivative of formula
Figure imgf000008_0001
(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, (CH2)1-6, O(CH2)1-6, (CH2) 1-6NH(CH2)1-6, (CH2) 1-6O(CH2)1-6,
NH(CH2)1-6; 5 Z represents NR2R3;
R1 represents halogen, cyano, nitro, amino, hydroxyl, Ci-C6 alkyl or C3-Cs cycloalkyl, which alkyl or cycloalkyl group can be optionally substituted by one or more fluorine atoms;
R2 and R3 each independently represent a hydrogen atom, Ci-C6 alkyl or C3-C8 cycloalkyl,o which alkyl or cycloalkyl group can be optionally substituted by one or more groups selected from hydroxyl, halogen or Ci-C6 alkoxy, or R2 and R3 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-C6 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 P2X7 receptor antagonist is selectedo from 2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-N- (tricyclo[3.3.1.13'7]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[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide,
2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide,
2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)benzamide,
2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide, 2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide,
2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide,
2-Chloro-5 -[ [2- [ [2-( 1 -methyl- lH-imidazol-4-yl)ethyl] amino]ethyl] amino]-N- (tricyclo[3.3.1.13'7]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[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, 2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.1 ]dec-l- ylmethyl)-benzamide, 2-Chloro-5-(piperidin-4-ylsulfinyl)-N-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide,
5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-Λ/-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-4-pyridinecarboxamide,
2-Chloro-5 - [3 - [ [( li?)-2-hydroxy- 1 -methylethyl]amino]propyl] -N- (tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-3-pyridinecarboxamide, 5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-4- pyridinecarboxamide,
5-Chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)- 4-pyridinecarboxamide, 5-Chloro-2-[3-[[(25)-2-hydroxypropyl]amino]propyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-4-pyridinecarboxamide,
Λ/-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]- tricyclo[3.3.1.13'7]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 P2X7 receptor antagonists that may be employed in accordance with the present invention include:-
2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-7V- (tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, dihydrochloride
2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-Λ/-(tricyclo[3.3.1.1 ]dec- 1 -ylmethyl)- benzamide, hydrochloride (i?)-2-Chloro-5-[3-[(2-hydroxy- 1 -methylethyl)amino]propyl]-7V- (tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, hydrochloride
2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide, acetate (1:1) salt 2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)benzamide, hydrochloride
2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-7V-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide, hydrochloride
2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-7V-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide, acetate (1:1) salt
2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-7V-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-benzamide
2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tricyclo[3.3.1.13'7]dec- 1 ■ ylmethyl)-benzamide, hydrochloride 2-Chloro-5-[[2-[[2-(l-methyl-lH-imidazol-4-yl)ethyl]amino]ethyl]amino]-N-
(tricyclo[3.3.1.13'7]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[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, hydrochloride
2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.1 ]dec-l- ylmethyl)-benzamide, hydrochloride
2-Chloro-5-(piperidin-4-ylsulfinyl)-Λ/-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide
5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-4-pyridinecarboxamide,
5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-4- pyridinecarboxamide, hydrochloride
5-Chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)- 4-pyridinecarboxamide, hydrochloride 5-Chloro-2-[3-[[(25)-2-hydroxypropyl]amino]propyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-4-pyridinecarboxamide, dihydrochloride, and
Λ/-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]- tricyclo[3.3.1.13'7]decane- 1 -acetamide, hydrochloride.
In one embodiment of the invention the P2X7 antagonist is 2-Chloro-5-[[2-(2-hydroxy- ethylamino)-ethylamino]-methyl]-7V-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X7 antagonist is 2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-7V- (tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide dihydrochloride.
In one embodiment of the invention the P2X7 antagonist is 2-Chloro-5-[3-[(3- hydroxypropyl)amino]propyl]-Λ/-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X7 antagonist is 2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-Λ/-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide hydrochloride.
In one embodiment of the invention the P2X7 antagonist is 2-Chloro-5-[3- (methylamino)propyl]-7V-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X7 antagonist is 2-Chloro-5-[3-(methylamino)propyl]-7V-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)- benzamide hydrochloride.
In one embodiment of the invention the P2X7 antagonist is 2-Chloro-5-[2-(3- hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X7 antagonist is 2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-7V- (tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, acetate (1:1) salt. In one embodiment of the invention the P2X7 antagonist is 2-Chloro-5-[2-[2-[(2- hydroxyethyl)amino]ethoxy]ethoxy]-7V-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment the P2X7 antagonist is 2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N- (tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, hydrochloride.
In another embodiment the P2X7 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 P2X7 receptor antagonist is selected from:
6-Chloro-2-(l -piperazinylmethyl)-7V-(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-5- quinolinecarboxamide, (e.g. as a hydrochloride salt) 6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-Λ/-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-5-quinolinecarboxamide
Λ/-[6-chloro-2-[[4-(2-hydroxyethyl)-l-piperazinyl]methyl]-5-quinolinyl]- tricyclo[3.3.1.13'7]decane- 1 -acetamide
N- [2- [2- [(3 -Hydroxypropyl)amino] ethyl]-6-methyl-5 -quinolinyl]- tricyclo[3.3.1.13'7]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[3.3.1.13'7]dec-l-ylmethyl)amino]carbonyl]-2- quinolinyl] -3 -piperidinyl] -β-alanine
3-[6-Chloro-5-[[(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)amino]carbonyl]-2-quinolinyl]- benzoic acid 6-Chloro-2-[4-(lH-tetrazol-5-yl)butyl]-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)- 5- quinolinecarboxamide, or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention, the P2X7 receptor antagonist is selected from:
2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-(4,5-dihydro-3,5-dioxo-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[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide 2-Chloro-5-[4,5-dihydro-4-(2-methoxyethyl)-5-oxo-lH-l,2,4-triazol-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//-tetrazol-5-amine
1 -Methyl-2,2-diphenyl-cyclopropanecarboxylic acid, 2-(5-quinolinyl)hydrazide l-(2,3-Dichlorophenyl)-5-[(3-pyridinylmethyl)amino]-lH-pyrazole-4-carbonitrile (4i?,55)-re/-2-[(3-Chloro-4-fluorophenyl)methyl]-4,5-dihydro-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]dec-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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 antagonist
In order to use the P2X7 antagonist, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition that comprises the P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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 P2X7 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).

Claims

C L A I M S
1. Use of a P2X7 antagonist in the manufacture of a medicament for use in treating a mood disorder.
2. Use of a P2X7 antagonist as claimed in claim 1, wherein the mood disorder is a depressive disorder.
3. Use of a P2X7 antagonist as claimed in claim 1, wherein the mood disorder is an anxiety disorder.
4. Use of a P2X7 antagonist in the manufacture of a medicament, wherein the medicament is for use in treating a patient having rheumatoid arthritis and a mood disorder.
5. A pharmaceutical composition comprising a P2X7 antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier for the treatment of a mood disorder.
6. A pharmaceutical composition comprising a P2X7 antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having rheumatoid arthritis and a mood disorder.
7. A pharmaceutical composition comprising a P2X7 antagonist and a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment of a patient having inflammatory bowel disease and a mood disorder.
8. A method of treating a mood disorder, which comprises administering to a patient in need thereof, a therapeutically effective amount of a P2X7 antagonist.
9. 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 P2X7 antagonist.
PCT/GB2008/050640 2007-08-03 2008-07-30 P2x7 antagonists for use in the treatment of mood disorders WO2009019503A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95371507P 2007-08-03 2007-08-03
US60/953,715 2007-08-03

Publications (2)

Publication Number Publication Date
WO2009019503A2 true WO2009019503A2 (en) 2009-02-12
WO2009019503A3 WO2009019503A3 (en) 2009-06-04

Family

ID=39934508

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050640 WO2009019503A2 (en) 2007-08-03 2008-07-30 P2x7 antagonists for use in the treatment of mood disorders

Country Status (1)

Country Link
WO (1) WO2009019503A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012110190A1 (en) 2011-02-17 2012-08-23 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2012163792A1 (en) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2012163456A1 (en) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1310493A1 (en) * 2001-11-12 2003-05-14 Pfizer Products Inc. N-adamantylalkyl benzamide derivates as p2x7-receptor antagonists
US20050147604A1 (en) * 2003-04-17 2005-07-07 Neuronova Ag Means and methods for diagnosing and treating affective disorders
WO2006003517A1 (en) * 2004-06-29 2006-01-12 Warner-Lambert Company Llc Combination therapies utilizing benzamide inhibitors of the p2x7 receptor
WO2006102588A1 (en) * 2005-03-24 2006-09-28 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2006110516A1 (en) * 2005-04-11 2006-10-19 Abbott Laboratories Acylhydrazide p2x7 antagonists and uses thereof
WO2007056091A2 (en) * 2005-11-09 2007-05-18 Abbott Laboratories 2-phenyl-2h-pyraz0le derivatives as p2x7 receptor antagonists and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1310493A1 (en) * 2001-11-12 2003-05-14 Pfizer Products Inc. N-adamantylalkyl benzamide derivates as p2x7-receptor antagonists
US20050147604A1 (en) * 2003-04-17 2005-07-07 Neuronova Ag Means and methods for diagnosing and treating affective disorders
WO2006003517A1 (en) * 2004-06-29 2006-01-12 Warner-Lambert Company Llc Combination therapies utilizing benzamide inhibitors of the p2x7 receptor
WO2006102588A1 (en) * 2005-03-24 2006-09-28 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2006110516A1 (en) * 2005-04-11 2006-10-19 Abbott Laboratories Acylhydrazide p2x7 antagonists and uses thereof
WO2007056091A2 (en) * 2005-11-09 2007-05-18 Abbott Laboratories 2-phenyl-2h-pyraz0le derivatives as p2x7 receptor antagonists and uses thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BARDEN N ET AL: "Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder" AMERICAN JOURNAL OF MEDICAL GENETICS, PART B: NEUROPSYCHIATRIC GENETICS 20060605 US, vol. 141, no. 4, 5 June 2006 (2006-06-05), pages 374-382, XP002519789 ISSN: 1552-4841 1552-485X *
BIRD HOWARD ET AL: "Paroxetine versus amitriptyline for treatment of depression associated with rheumatoid arthritis: A randomized, double blind, parallel group study" JOURNAL OF RHEUMATOLOGY, vol. 27, no. 12, December 2000 (2000-12), pages 2791-2797, XP008103825 ISSN: 0315-162X *
FULLER-THOMSON E ET AL: "Depression and inflammatory bowel disease: Findings from two nationally representative Canadian surveys" INFLAMMATORY BOWEL DISEASES 200608 US, vol. 12, no. 8, August 2006 (2006-08), pages 697-707, XP002520291 ISSN: 1078-0998 1536-4844 *
PARKER J C ET AL: "Management of Depression in Rheumatoid Arthritis: A Combined Pharmacologic and Cognitive-Behavioral Approach" ARTHRITIS CARE AND RESEARCH 20031215 US, vol. 49, no. 6, 15 December 2003 (2003-12-15), pages 766-777, XP008103822 ISSN: 0893-7524 *
ZHANG LEI ET AL: "Lithium regulates P2X7 receptor expression and ATP activation in astrocytes: A novel therapeutic target in the treatment of bipolar disorder?" NEUROPSYCHOPHARMACOLOGY, vol. 30, no. Suppl. 1, December 2005 (2005-12), pages S246-S247, XP008103757 & 44TH ANNUAL MEETING OF THE AMERICAN-COLLEGE-NEUROPSYCHOPHARMACOLOGY; WAIKOLOA, HI, USA; DECEMBER 11 -15, 2005 ISSN: 0893-133X *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012110190A1 (en) 2011-02-17 2012-08-23 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2012163792A1 (en) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use
WO2012163456A1 (en) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Novel p2x7r antagonists and their use

Also Published As

Publication number Publication date
WO2009019503A3 (en) 2009-06-04

Similar Documents

Publication Publication Date Title
EP2836211B1 (en) Treatment of PTSD and impulse control disorders
US10195213B2 (en) Chemical entities that kill senescent cells for use in treating age-related disease
TWI511728B (en) Pharmaceutical combination comprising atypical antipsychotic drug and taar1 agonist
US9808448B2 (en) Pharmaceutical compounds and use of same in cancer and tauopathies
EA009732B1 (en) Diaryl and arylheteroaryl urea derivatives as modulators of the 5-htserotonin receptor useful for the prophylaxis and treatment of disorders related thereto
KR20140097459A (en) Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
JP2013526544A (en) Heterocyclic sulfone mGluR4 allosteric enhancer, composition, and method of treating neurological dysfunction
US20100041668A1 (en) Compositions and methods for treating thrombocytopenia
JP6076498B2 (en) Pyrimido [4,5-B] quinoline-4,5 (3H, 10H) -dione as a nonsense mutation inhibitor
TW201717939A (en) Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
TW200817393A (en) Compounds and compositions as hedgehog pathway modulators
CA2687528C (en) Trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-n,n-dimethylcarbamoyl-cyclohexylamine for treating acute mania
JP2007537207A (en) Use of ghrelin antagonists for the treatment of certain central nervous disease
US20210379043A1 (en) Combination treatment of liver disorders
US20220288048A1 (en) Pimavanserin for treating schizophrenia or for treating psychosis secondary to neurodegenerative disorders or depressive disorder
US20230120819A1 (en) Methods and compositions for treating acute lung injury and acute respiratory distress syndrome
TWI427065B (en) Antibacterial quinoline derivatives
RU2304436C2 (en) Using derivatives of n-phenyl-2-pyrimidineamine against mastocyte-base diseases similar to allergic disturbance
WO2009019503A2 (en) P2x7 antagonists for use in the treatment of mood disorders
TW201102068A (en) Treatment of ophthalmologic disorders mediated by alpha-carbonic anhydrase isoforms
JP2020510071A (en) Treatment of idiopathic pulmonary fibrosis
JP2022533981A (en) Method of treating chronic spontaneous urticaria with a Bruton's tyrosine kinase inhibitor
JP7406264B2 (en) Cyanoaryl-aniline compounds for the treatment of skin disorders
TW202313050A (en) Combination therapies
KR20210062023A (en) Composition comprising CRAC inhibitor and corticosteroid and method of use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08776232

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08776232

Country of ref document: EP

Kind code of ref document: A2