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Novel Methods Neue Verfahren Nouvelles Méthodes (19) & (11) EP 2 120 936 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/439 (2006.01) A61P 11/06 (2006.01) 22.06.2011 Bulletin 2011/25 A61P 11/08 (2006.01) (21) Application number: 08707469.6 (86) International application number: PCT/EP2008/000782 (22) Date of filing: 31.01.2008 (87) International publication number: WO 2008/101591 (28.08.2008 Gazette 2008/35) (54) NOVEL METHODS NEUE VERFAHREN NOUVELLES MÉTHODES (84) Designated Contracting States: (74) Representative: Srinivasan, Ravi Chandran AT BE BG CH CY CZ DE DK EE ES FI FR GB GR J.A. Kemp & Co. HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT 14 South Square RO SE SI SK TR Gray’s Inn Designated Extension States: London WC1R 5JJ (GB) AL BA MK RS (56) References cited: (30) Priority: 21.02.2007 US 902843 P WO-A-2005/097126 WO-A-2005/115462 (43) Date of publication of application: • MOLFINO N A: "DRUGS IN CLINICAL 25.11.2009 Bulletin 2009/48 DEVELOPMENT FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE" RESPIRATION, (73) Proprietor: Almirall, S.A. KARGER, BASEL, CH, vol. 72, no. 1, 2005, pages 08022 Barcelona (ES) 105-112, XP008050164 ISSN: 0025-7931 • ALABASTER V A: "DISCOVERY & (72) Inventor: BELETA SUPERVIA, Jorge DEVELOPMENT OF SELECTIVE M3 E-08173 Sant Cugat del Valles (ES) ANTAGONISTS FOR CLINICAL USE" LIFE SCIENCES, PERGAMON PRESS, OXFORD, GB, vol. 60, no. 13/14, 1997, pages 1053-1060, XP001056370 ISSN: 0024-3205 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 120 936 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 120 936 B1 2 Description ness, drowsiness, and respiratory depression. It has been found that cholinesterase inhibitors, which inhibit Field of the Invention the breakdown of acetylcholine, are beneficial in Alzhe- imer’s disease and dementia, thus a physician may wish [0001] The invention relates to novel methods of anti- 5 to avoid anticholinergic drugs in such patients if feasible. cholinergic therapy, particularly for respiratory diseases Acetylcholine has a complicated role in Parkinson’s dis- such as asthma and chronic obstructive pulmonary dis- ease patients. It is believed to have a role in facilitating ease (COPD), without causing the class- related adverse dopamine release, possibly through actions at the M4 effects of antimuscarinic compounds. and M5 muscarinic receptors in the brain, and on this 10 basis, cholinesterase inhibitors are sometimes pre- Background of the Invention scribed for Parkinson’s patients; yet especially before the advent of levodopa, anticholinergics were used to treat [0002] Aclidinium (3(R)-(2- hydroxy-2,2-dithien-2-ylac- the symptoms of Parkinson’s disease, possibly by block- etoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2] oc- ing the dopamine inhibiting activity of the M1 muscarinic tane) is a potent muscarinic receptor antagonist de-15 receptors. scribed, e.g., in WO 01/04118, WO 05/115467, WO [0006] Older patients are more likely to experience un- 05/115466, and WO 05/115462 the contents of which desired anticholinergic effects because their bodies pro- applications are incorporated herein by reference. Aclid- duce less acetylcholine. Also, cells in many parts of the inium is a long-acting bronchodilator intended for admin- body (such as the digestive tract) in older patients may istration by inhalation for treatment of respiratory diseas- 20 have fewer acetylcholine receptors. Thus, the acetylcho- es, especially asthma and COPD), currently in clinical line produced is less likely to have an effect, and the trials. effect of anticholinergic drugs is correspondingly greater. [0003] Currently available muscarinic receptor antag- Moreover, older patients may have reduced kidney onists include tiotropium ((1α,2β,4β,7β)-7-[(2-hydroxy- and/or liver function, and so may be prone to increased 2,2-dithienylacetoxy]-9,9-dimethyl-3-oxa-9-azoniatricy- 25 serum concentrations of many anticholinergic drugs,. As clo[3.3.1.02,4]nonane), ipratropium methyl-([8- 8-(1- discussed below, a number of commonly prescribed methylethyl)-8-azoniabicyclo[3.2.1]oct-3-yl]3-hydroxy- medications have anticholinergic effects, so patients who 2-phenyl-propanoate), and glycopyrrolate ((1,1-dime- are taking multiple medications with anticholinegic side thyl-2,3,4,5-tetrahydropyrrol-3-yl) 2-cyclopentyl-2-hy- effects may be at elevated risk. Older men in particular droxy-2-phenyl-acetate). 30 may suffer adverse effects, because the urinary difficul- [0004] Acetylcholine is a neurotransmitter associated ties associated with anticholinergic activity may exacer- with parasympathetic innervation in the body and also bate or be exacerbated by an enlarged or obstructed with transmissions in the brain. It helps control the func- prostate. Overall, anticholinergic side effects are among tioning of the heart, blood vessels, airways, and organs the most common drug-related negative effects experi- of the urinary and digestive tracts. It is also involved in 35 enced by elderly people. memory, learning, and concentration. Antimuscarinic [0007] Currently marketed antimuscarinics may be un- compounds inhibit the effects of acetylcholine on mus- suitable for use in patients having a susceptibility to con- carinic receptors, which are by far the most common type ditions that may be exacerbated by systemic anticholin- of cholinergic receptors in the body. Compounds that in- ergic effects. Levels of systemic anticholinergic activity hibit acetylcholine activity at the M3 muscarinic receptors 40 that may be easily tolerated in a young, healthy person in the airways are very useful in the treatment of respi- may be unacceptable in such patients. Conditions that ratory diseases, as they inhibit the acetylcholine- mediat- may be exacerbated by systemic anticholinergic effects ed contraction of smooth muscle in the airways, resulting include schizophrenia, glaucoma, dry eyes, enlarged or in bronchodilation, and also reduce mucus secretion in obstructed prostate, narrowing or obstructon of the small the lungs. 45 intestine, enlarged colon, chronic constipation, enlarged [0005] One problem with the use of antimuscarinic lower esophagus, heart disease (especially any condi- compounds in the treatment of respiratory diseases, tion that may be aggravated by tachycardia, for example however, is the risk of side effects related to systemic restenosis or plaque in the coronary arteries, propensity suppression of cholinergic activity. These can include, toarrhythmias, damage resulting from prior heart attacks, for example, dry mouth, throat irritation, decreased50 and congestive heart failure), Parkinson’s disease, sweating, increased pupil size, blurred vision, increased Alzheimer’s disease, dementia, and myasthenia gravis. intraocular pressure, increased heart rate, chest pain, Antimuscarinics may also present special risks when co- decreased gastric motility, constipation difficulty starting administered with drugs which have anticholinergic ef- and continuing to urinate, and loss of bladder control due fects, for example atypical antipsychotics or tricyclic anti- to overflow incontinence. Anticholinergic activity can also 55 depressants. Antihistamines, particularly first generation have effects on the central nervous system, such as im- sedating antihistamines such as diphenhydramine, may paired concentration, confusion, agitation, anxiety, delir- bind muscarinic receptors in addition to histamine type- ium, attention deficit, impaired memory, light-headed- 1 receptors, and so may also have anticholinergic effects. 2 3 EP 2 120 936 B1 4 In extreme cases, anticholinergic drugs can trigger anti- Typically, the patient is suffering from or susceptible to cholinergic delerium, a medical emergency character- one or more conditions selected from ized by hot, dry skin, dry mucus membranes, dilated pu- pils, absent bowel sounds, and tachycardia. Finally, sys- a. schizophrenia, impaired concentration, confusion, temically active antimuscarinics may interfere with the 5 agitation, delirium, attention deficit, impaired mem- action of drugs intended to enhance acetylcholine func- ory, respiratory depression. tion, for example cholinesterase inhibitors and choliner- b. glaucoma, dry eye, increased pupil size, blurred gic agonists. vision, increased intraocular pressure, [0008] Accordingly, there is a need for antimuscarinic c. enlarged or obstructed prostate, difficulty urinat- therapy, particularly for respiratory diseases, especially 10 ing, overflow incontinence, asthma and chronic obstructive pulmonary disease d. narrowing or obstruction of the small intestine, en- (COPD), which does not cause the class- related adverse larged colon, chronic constipation, enlarged lower effects of systemically active antimuscarinic compounds. esophagus, decreased gastric motility, constipation, WO 2005/115462 relates to a combination which com- e. dry mouth, throat irritation, impaired sweating prises (a) a PDE4 inhibitor and (b) an antagonist of M3 15 f. cardiovascular disease (including any of resteno- muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dith- sis, arteriosclerosis, prior stroke or heart attack, con- ien- 2- ylacetoxy)- 1 (3- phenoxypropyl)- 1- azoniabicyclo
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