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(12) United States Patent (10) Patent No.: US 6,890,920 B2 Richards Et Al

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(12) United States Patent (10) Patent No.: US 6,890,920 B2 Richards Et Al USOO6890920B2 (12) United States Patent (10) Patent No.: US 6,890,920 B2 Richards et al. (45) Date of Patent: May 10, 2005 (54) QUATERNARY AMMONIUM COMPOUNDS GB O94O540 10/1963 WO WO951O269 4/1995 (75) Inventors: Ivan Richards, Kalamazoo, MI (US); WO WO9510270 4/1995 Sue K. Cammarata, Portage, MI (US); W W: 6.1. Craig D. Wegner, Mundelein, IL (US); Michael Hawley, Kalamazoo, MI (US); WO WOO235.245 5/2002 Mark Peter Warchol, Kalamazoo, MI OTHER PUBLICATIONS S.US); MarkWE KontinMawi, W. Libertvville, R n ILZOO Eglen et al, Trends in Pharmacological Sciences, MI (US); Karen Patrice Kolbasa, 22(8);409–414 (200 1). Schoolcraft, MI (US); Malcolm Wilson Gould, International Journal of Pharmaceutics, Moon. Kalamazoo, MI (US); 33(1-3):201–217 (1986)-Abstract only. Dominique Bonafoux. St. Louis. MO Stewart et al, The Journal of Urology, 115:558-559 (1976). (US); Sergey Gregory Wolfson. Ruffman, Journal of International Medical Research, Chesterfield, MO (US); Patrick James SE " ","En Journal of Pharmacology Lennon, Webster Groves,G MO (US)(US 368:223–230 (1999).s s (73) Assignee: Pharmacia & Upjohn Company, Postlind et al, Drug and Metabolism Disposition, Peapack, NJ (US) 26(4):289–293 (1998). Nilvebrant et al., Pharmacology & Toxicology, 81:169-172 (*) Notice: Subject to any disclaimer, the term of this (1997). patent is extended or adjusted under 35 Weber, Annals of Allergy, 65:348-350 (1990). U.S.C. 154(b) by 41 days. * cited by examiner (21) Appl. No.: 10/280,906 Primary Examiner Thomas McKenzie 9 (74) Attorney, Agent, or Firm-Dinsmore & Shohl LLP (22) Filed: Oct. 25, 2002 (57) ABSTRACT (65) Prior Publication Data Novel quaternary ammonium compounds of the formula US 2003/0158176 A1 Aug. 21, 2003 OR Related U.S. Application Data 21 4 R1 (60) Provisional application No. 60/348,930, filed on Oct. 26, Rs - H -R2 2001, provisional application No. 60/361979, filed on Mar. S V 1n-NN 6, 1992, and provisional application No. 60/391,521, filed C R3 on Jun. 25, 2002. X (51) Int. Cl." ................... C07D 295/096; CO7C 215/54; 21 A61K 31/40; A61K 31/14; A61P 11/06 S. (52) U.S. Cl. .................. 514/212.01; 514/317; 514/428; SS-X 514/546; 514/547; 514/643; 540/609; 546/240; R6 R7 548/575; 560/140; 564/283 (58) Field of Search ............................ 514/212.01, 317, and any Stereoisomers thereof, wherein R, R and R 514/428, 546, 547, 643; 540/609; 546/240; independently represent C-C alkyl, optionally Substituted 548/575; 560/140; 564/283 with phenyl or hydroxyl, or both, and wherein any two of R, R and R may form a ring together with the quaternary (56) References Cited ammonium nitrogen; R represents -H, -CH, or -CO U.S. PATENT DOCUMENTS RA-1, wherein R4-1 represents -(C-C, alkyl), -(C-C, alkoxy), or -NRR, wherein R and R indepen 2,592,191 A 4/1952 Ruddy dently represent -H or -(C-C alkyl); Rs, R. and R, 3,480,623 A 11/1969 Consonniet al. independently represent -H, -OCH, -OH, -CONH2, 3,505,337 A 4/1970 Zeile et al. -SONH, -F, -Cl, -Br, -I, -CF, O -(C-C, 5,096.8905,036,098 A 3/19927/1991 CrossKimura et etal. al. alkyl),Ikvl optionallytionall substitutedbstituted with one or ttwo -OH,OH 5,382,600 A 1/1995 Jonsson et al. -(C-C, alkoxy), -COOH, or -CO-O-(C-C, alkyl); 5,559,269 A 9/1996 Johansson et al. and X represents an anion of a pharmaceutically acceptable 5,922,914 A 7/1999 Gage et al. acid, the compounds for use as medicaments, use of the 6,538,035 B2 * 3/2003 Gilberg et al.............. 514/650 compounds for the manufacture of Specific medicaments, and pharmaceutical compositions comprising the com FOREIGN PATENT DOCUMENTS pounds. The present invention also concerns a method of CA 2066248 8/1998 treatment involving administration of the compounds. DE O106643 6/1974 EP O418716 3/1991 29 Claims, 7 Drawing Sheets U.S. Patent May 10, 2005 Sheet 1 of 7 US 6,890,920 B2 Crd 8.SS |----- NN N JnO?87Jnou99?7ZInO?8 OZ"| 000 eSne peoueuu effe JewW FIGURE U.S. Patent May 10, 2005 Sheet 2 of 7 US 6,890,920 B2 SSOCOOOOOOOK Syst site SS &KOOO.C.SSSSSSSSSSS 3. RSSSSSSSSSSSSSS eas s 2. i 55 CO severy Preserverses XXX SSSRSSY X8. X SSSSSSK S&S&S s CCCCCCCCXXCis a c 5 622 ww.y 2 SRSSRSRRSRSRSSRSSRS2 SSSSSSSSSSSSSSOld SSSSSSSSSSSSSSS)CCC i s s s S eSne peduleuuefeJewW U.S. Patent May 10, 2005 Sheet 5 of 7 US 6,890,920 B2 unO??7ZInO?9JnO??Zu?uu0), eSne peoueuuefe JewV FIGURE 5 U.S. Patent May 10, 2005 Sheet 6 of 7 US 6,890,920 B2 CN - w - - S5SS O) S.a S.5 S.St 5E O c. v. st V o o v OO 1 O O co S O) E H w CN as -1-1 1. O O SO O O S. O CN CN r S2 (Tuffd) uoyeueouoo eused FIGURE 6 U.S. Patent May 10, 2005 Sheet 7 of 7 US 6,890,920 B2 50 wn ------0.1 mg/mL g 40 -- 0.5mg/mL Sh -h- 1.0mg/mL S 30 s 3 20 1 O O FIGURE 7 US 6,890,920 B2 1 2 QUATERNARY AMMONIUM COMPOUNDS used by inhalation to produce bronchodilation. I pratropium is 8-isopropylnoratropine methobromide and is disclosed in This application claims the benefit of U.S. Provisional U.S. Pat. No. 3,505,337. Patent Application No. 60/348930, filed 26 Oct. 2001, U.S. Yono Metal, European Journal of Pharmacology (1999) Provisional Patent Application No. 60/361979, filed 6 Mar. 368:223–230, is concerned with the pharmacological effects 2002, and U.S. Provisional Patent Application No. 60/391 of tolterodine, an antimuscarinic drug, in isolated human 521, filed Jun. 25, 2002, and the entire disclosures of which urinary bladder Smooth muscle. are herein incorporated by reference. Ruffmann R et al, The Journal of International Medical Research (1998) 16:317-330, reviews use of flavoxate TECHNICAL FIELD hydrochloride or alternative compounds, Such as terodiline The present invention concerns a novel class of quater hydrochloride and emepronium bromide, in the treatment of nary ammonium compounds, pharmaceutical compositions urge incontinence. containing the Same, the compounds for use as Stewart B H et al, The Journal of Urology (1976) medicaments, and use of the compounds for the manufacture 115:558-559 discloses therapy of mild to moderate stress of Specific medicaments. The present invention also con 15 urinary incontinence with a combination of phenylpropano cerns a method of treatment involving administration of the lamine hydrochloride, chlorpheniramine maleate, and iso compounds. propamide iodide in a Sustained release capsule. The novel compounds are useful as antimuscarinic agents. WO95/10269 and WO95/10270 disclose the use of R In particular, the novel compounds are useful for the treat and S-terodiline, respectively, as drugs for treating condi ment of asthma, a group of breathing disorders termed tions related to the compounds activities as anticholinergic Chronic Obstructive Pulmonary Disease (COPD), allergic agents. rhinitis, and rhinorrhea due to the common cold. Despite the above advances in the art, it is desirable to BACKGROUND OF THE INVENTION develop novel pharmaceutical compounds that further 25 improve the quality of life for a large number of individuals. U.S. Pat. No. 5,382,600 discloses (substituted) 3,3- diphenylpropylamines useful for treating urinary inconti SUMMARY OF THE INVENTION nence. In particular, it discloses 2-(1R)-3- For these and other purposes, it is an object of the present (diisopropylamino)-1-phenylpropyl)-4-methylphenol, also invention to provide highly efficient pharmaceutical com known as N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- pounds for treatment of asthma. 3-phenylpropylamine, with the generic name of tolterodine, It is also an object of the present invention to provide as being useful to treat urinary incontinence. Tolterodine is highly efficient pharmaceutical compounds for treatment of the compound of Example 22 of U.S. Pat. No. 5,382,600. Chronic Obstructive Pulmonary Disease (COPD). It is preferred that tolterodine is prepared by the processes It is a further object of the present invention to provide of International Publication WO98/29402 (U.S. Pat. No. 35 highly efficient pharmaceutical compounds for treatment of 5,922,914). allergic rhinitis. HPostlind etal, Drug Metabolism and Disposition, 26(4): It is an object of the present invention to provide highly 289-293 (1998) discloses that tolterodine is a muscarinic efficient pharmaceutical compounds for treatment of rhin receptor antagonist. It is presently being Sold in a number of orrhea due to the common cold. different countries for treatment of urinary incontinence 40 It is also an object of the present invention to provide under the name DetrolE), marketed by Pharmacia. When pharmaceutically effective 3,3-diphenylpropylamine deriva tolterodine is used to treat urinary incontinence it is admin tives having an increased residence time in lung upon istered perorally as a tablet. The major, active metabolite of pulmonary administration. tolterodine is the 5-hydroxymethyl derivative of tolterodine. 45 It is an object of the present invention to provide a novel U.S. Pat. No. 5,559,269 and H Postlind et al, Drug class of 3,3-diphenylpropylamine derivatives having favor Metabolism and Disposition, 26(4): 289-293 (1998) dis able properties. close hydroxytolterodine. U.S. Pat. No. 5,559,269 discloses this compound as being useful to treat urinary incontinence. For these and other objects that will be evident from the Pharmacol.
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