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Soft Anticholinergic Zwitterions Weiche Anticholinerge Zwitterionen Zwitterions Anticholinergiques Moderes

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Soft Anticholinergic Zwitterions Weiche Anticholinerge Zwitterionen Zwitterions Anticholinergiques Moderes (19) & (11) EP 1 957 451 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 207/10 (2006.01) C07D 451/10 (2006.01) 19.10.2011 Bulletin 2011/42 A61K 31/40 (2006.01) A61K 31/439 (2006.01) A61P 11/00 (2006.01) A61P 11/06 (2006.01) (2006.01) (2006.01) (21) Application number: 06837428.9 A61P 13/10 A61P 27/08 (22) Date of filing: 13.11.2006 (86) International application number: PCT/US2006/043966 (87) International publication number: WO 2007/059021 (24.05.2007 Gazette 2007/21) (54) SOFT ANTICHOLINERGIC ZWITTERIONS WEICHE ANTICHOLINERGE ZWITTERIONEN ZWITTERIONS ANTICHOLINERGIQUES MODERES (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-2005/000815 WO-A-2006/066928 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR • WU, WHEI-MEI ET AL: "Pharmacokinetic and Pharmacodynamic Evaluations of the (30) Priority: 10.11.2005 US 735206 P Zwitterionic Metabolite of a New Series of N- Substituted Soft Anticholinergics" (43) Date of publication of application: PHARMACEUTICAL RESEARCH , 22(12), 20.08.2008 Bulletin 2008/34 2035-2044 CODEN: PHREEB; ISSN: 0724-8741, [Online] 26 September 2005 (2005-09-26), (73) Proprietor: Bodor, Nicholas S. XP002426085 ISSN: 1573-904X Retrieved from Bal Harbour, FL 33154 (US) the Internet: URL:http://www.springerlink.com/ content/tq 341467ww302m87/> [retrieved on (72) Inventor: Bodor, Nicholas S. 2007-03-19] Bal Harbour, FL 33154 (US) • BANHOLZER, R. ET AL: "Synthesis of anticholinergically active N- (74) Representative: Hedley, Nicholas James Matthew alkylnorscopolamines and their quaternary salts et al with particular consideration of the Kilburn & Strode LLP bronchospasmolytic compound (-)-N- 20 Red Lion Street ethylnorscopolamine methobromide (Ba 253 London BR)" ARZNEIMITTEL-FORSCHUNG , 35(1A), WC1R 4PJ (GB) 217-28 CODEN: ARZNAD; ISSN: 0004-4172, 1985, XP001249054 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 1 957 451 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 957 451 B1 Description [0001] Various anticholinergic compounds have been previously described but are not optimal. [0002] Muscarinic receptor antagonists are frequently used therapeutic agents that inhibit the effects of acetylcholine 5 by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells as well as in peripherial ganglia and in the central nervous system (CNS). However, their side effects, which can include dry mouth, photophobia, blurred vision, urinary hesitancy and retention, decreased sweating, drowsiness, dizziness, restlessness, irritability, disorientation, hallucinations, tachycardia and cardiac arrhythmias, nausea, consti- pation, and severe allergic reactions, often limit their clinical use, and even topical anticholinergics can cause the same 10 unwanted side effects. Glycopyrrolate and triotropium are among the quaternary ammonium anticholinergics, which have reduced CNS-related side effects as they cannot cross the blood-brain barrier; however, because glycopyrrolate (or, presumably, tiotropium) is eliminated mainly as unchanged drug or active metabolite in the urine, its administration is problematic in young or elderly patients and especially in uraemic patients. To increase the therapeutic index of anticholinergics, the soft drug approach has been applied in a number of different designs starting from various lead 15 compounds over the past 20 years, but there is a need for yet other new soft anticholinergics. These novel muscarinic antagonists, just as all other soft drugs, are designed to elicit their intended pharmacological effect at the site of application, but they do not need to be further metabolized upon entering the systemic circulation and they are rapidly eliminated from the body, resulting in reduced systemic side effects and increased therapeutic index. [0003] Arzneimittel-Forschung, 35 (1A), 217 - 228, 1985, XP 002425584 discloses anticholinergically active quaternary 20 salts of scopolamine derivatives.SUMMARY [0004] New soft anticholinergic agents, pharmaceutical compositions containing them, processes for their preparation and methods for eliciting an anticholinergic response, especially for treating an inflammatory or obstructive disease of the respiratory tract or for treating overactive bladder, are provided. [0005] In one exemplary embodiment, there is provided a compound having the formula 25 30 35 [0006] In other exemplary embodiments, processes for preparing the compound are provided. 40 [0007] In other exemplary embodiments, there are provided pharmaceutical compositions comprising the compound of the foregoing formula and pharmaceutically acceptable carriers therefor; pharmaceutical combinations comprising the compound of the foregoing formula and an anti-inflammatory corticosteroid, a betamimetic agent or an antialleric agent. 45 BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIG. 1 is a graph showing the time course of action of different anticholinergics, including Compounds (w) and (aa), 50 on electrically stimulated guinea pig trachea. FIG. 2 is a graph showing the time course of the effect of different anticholingerics including Compounds (w) and (aa), after wash out of the test drug on electrically stimulated guinea pig trachea. DETAILED DESCRIPTION 55 [0009] Throughout this specification, the following definitions, general statements and illustrations are applicable: [0010] The patents, published applications, and scientific literature referred to herein establish the knowledge of those with skill in the art. Any conflict between any reference cited herein and the specific teachings of this specification shall 2 EP 1 957 451 B1 be resolved in favor of the latter. Likewise, any conflict between an art-understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter. [0011] As used herein, whether in a transitional phrase or in the body of a claim, the terms "comprise(s)" and "com- prising" are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously 5 with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term "comprising" means that the composition includes at least the recited features or components, but may also include additional features or components. [0012] The terms "consists essentially of" or "consisting essentially of" have a partially closed meaning, that is, they 10 do not permit inclusion of steps or features or components which would substantially change the essential characteristics of a process or composition; for example, steps or features or components which would significantly interfere with the desired properties of the compound or compositions described herein, i.e., the process or composition is limited to the specified steps or materials and those which do not materially affect its basic and novel characteristics. The basic and novel features herein are the provision of a compound of formula (Ib) and combinations of this compound with other 15 drugs, particularly with antiinflammatory steroids, especially loteprednol etabonate or etiprednol dichloroacetate, and most especially in the case of loteprenol etabonate (LE) further including an inactive metabolite enhancing agent for the LE as further defined hereinafter. [0013] The terms "consists of" and "consists" are closed terminology and allow only for the inclusion of the recited steps or features or components. 20 [0014] As used herein, the singular forms "a," "an" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. [0015] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" or "approximately" is used herein to modify a numerical 25 value above and below the stated value by a variance of 20%. [0016] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value of the numerical range, including the endpoints of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value of the numerical range, including 30 the endpoints of the range. As an example, a variable which is described as having values between 0 and 2, can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous. [0017] In the specification and claims, the singular
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