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(12) United States Patent (10) Patent No.: US 8.481,518 B2 Wood (45) Date of Patent: Jul

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(12) United States Patent (10) Patent No.: US 8.481,518 B2 Wood (45) Date of Patent: Jul USOO8481.518B2 (12) United States Patent (10) Patent No.: US 8.481,518 B2 WOOd (45) Date of Patent: Jul. 9, 2013 (54) QUATERNARY ANTIMUSCARINIC FOREIGN PATENT DOCUMENTS COMPOUNDS FOR THE TREATMENT OF WO WO98/OO133 1, 1998 BLADDER DISEASES WO WO98/OO138 1, 1998 WO WOO245711 A1 * 6, 2002 (75) Inventor: Ronald W. Wood, Rochester, NY (US) OTHER PUBLICATIONS (73) Assignee: University of Rochester, Rochester, NY Disse et al. (Life Sciences, 1993, 52/5-6:537-544).* (US) Deaney et al., JNeurolNeurosurg Psychiatry, abstract, 1998,65:957 958.* (*) Notice: Subject to any disclaimer, the term of this Walter et al., Neurourology and Urodynamics, 18:447-453, 1999.* patent is extended or adjusted under 35 Kuo, H.C. J. Formos. Med. Assoc. (May 2001), 100(5), 309-14 U.S.C. 154(b) by 1721 days. (abstract).* Chuang et al., Journal of Urology, (Oct. 2009), 182(4), 1393-400.* (21) Appl. No.: 10/542,501 "Anticholinergic Therapy: The State of the Art. Proceedings of a Symposium Held in Stratford-Upon Avon Sep. 8-9, 1986.” (22) PCT Filed: Jan. 15, 2004 Higgenbottam et al., eds. Postgrad. Med. J. 63(Suppl 1): 1-86 and Poster Abstracts and Discussion 63(Suppl 1): 1A-31A (1987). (86). PCT No.: PCT/US2OO4/OOO961 Autret et al., “Plasma Levels of Oxybutynine Chloride in Children.” Eur: J. Clin. Pharmacol. 46:83-85 (1994). S371 (c)(1), Barbalias, G.A., “Interstitial Cystitis: Bladder Training with (2), (4) Date: Jan. 10, 2006 Intravesical Oxybutynin.” J. Urol. 163:1818-1822 (2000). Brendler et al., “Topical Oxybutynin Chloride for Relaxation of (87) PCT Pub. No.: WO2004/064789 Dysfunctional Bladders.”.J. Urol. 141: 1350-1352 (1989). PCT Pub. Date: Aug. 5, 2004 Brown et al., “Proceedings of the National Institute of Diabetes and Digestive and Kidney Diseases International Symposium on (65) Prior Publication Data Epidemiologic Issues in Urinary Incontinence in Women.” Am. J. Obstet. Gynecol. 188:S77-S88 (2003). US 2006/O154951A1 Jul. 13, 2006 Chen et al., “Pulmonary Effects of the Cocaine Pyrolysis Product, Methylecgonidine, in Guinea Pigs.” Life Sciences 56(1):7-12 (1995). Related U.S. Application Data Davilla, G.W., “Advances in Anticholinergic Therapy Delivery Sys tems.” Urology Times, pp. 1-2 (Jun. 2002). (60) sial application No. 60/441,391, filed on Jan. Disse et al., “Ba 679 BR, A Novel Long-Acting Anticholinergic Bronchodilator.” Life Sciences 52:537-544 (1993). Disse et al., “Tiotropium (SpirivatM): Mechanistical Considerations (51) Int. Cl. and Clinical Profile in Obstructive Lung Disease.” Life Sciences A6 IK3I/33 (2006.01) 64(6/7);457-464 (1999). A61 K3I/00 (2006.01) Eichel et al., “Assessment of Murine Bladder Permeability with (52) U.S. C. Fluorescein: Validation With Cyclophosphamide and Protemine.” USPC ...................................... 514/183; 514/211.01 Urology 58(1): 113-118 (2001). (58) Field of Classification Search El-Fawal et al., Airway Smooth Muscle Relaxant Effects of the Cocaine Pyrolysis Product, Methylecgonidine.” J. Pharm. Exp. Ther. USPC .......................................................... 514f183 272(3):991-996 (1995) See application file for complete search history. Gearien, J.E., "Cholinergics, Acetylcholinesterases, and Antispasmodics.” Foye, W.O., eds. Principles of Medicinal Chem (56) References Cited istry, Lean and Febiger, Philadelphia, PA, Chapter 15, pp. 323-341 (1989). U.S. PATENT DOCUMENTS Fransta et al., “Implementing an Incontinence Management Protocol 2.648,667 A 8, 1953 Sternbach in Long-Term Care.” J. Gerontological Nursing 29(8):46-53 (2003). 4467,095 A 8, 1984 Treves et al. Heller et al., “Muscarinic Receptor Agonists and Antagonists.” 5,001,160 A 3, 1991 McPherson et al. 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Attorney, Agent, or Firm — LeClairRyan, a 6,063,808 A * 5/2000 Fabiano et al. ... 514,424 Professional Corporation 6,110,972 A * 8/2000 Fabiano et al. ... 514,643 6,124.354 A * 9/2000 Akerblom et al. .. 514,530 (57) ABSTRACT 6,171,298 B1* 1/2001 Matsuura et al. ... 604/891.1 6,183,461 B1* 2/2001 Matsuura et al. ... ... 604,502 The present invention relates to a method for treating bladder 6,204.285 B1* 3/2001 Fabiano et al. ............... 514,424 disease, including urinary incontinence, which involves intra 6,482,837 B1 1 1/2002 Wood vesical administration of quaternary antimuscarinic com 83 R $398 E. al pounds having longer duration of effect and fewer side effects 6,974,820 B2 * 12/2005 Aberg ........................... 514/278 than standard treatments. RE39,820 E 9, 2007 Banholzer et al. 2006/0160887 A1* 7/2006 Yamagata et al. ............ 514,431 32 Claims, No Drawings US 8,481,518 B2 Page 2 OTHER PUBLICATIONS Interstitial Cystitis Association (Abstract and Poster Presentation) (2 Green et al., “Urinary Incontinence in Subacute Care-A Retrospec pp.). tive Analysis of Clincal Outcomes and Costs.” MJA 178:550-553 Abood, “The Psychotomimetic Glycolate Esters,” in Burger, ed., (2003). Drugs Affecting the Central Nervous System vol. 2, Chapter 4, New Greenfield et al., “The Use of Intravesical Oxybutynin Chloride in York: Marcel Dekker, Inc., pp. 127-167 (1968). Children with Neurogenic Bladder.” J. Urol. 146:532-534 (1991). Abood, "Anticholinergics.” Chap 15 in Psychotropic Agents, Part III: Gross, H.J., “Ipratropium Bromide.” New Eng. J. Med. 319:486-494 Alcohol and Psychomimetics, Psychotropic Effects of Central Acting (1988). Drugs, F. Hoffmeister et al., eds. 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Krishnan, K.R., "A Double-Blind, Randomized, Placebo-Controlled, Bonner et al., “Identification of a Family of Muscarinic Acetylcholine Parallel Group, Multicenter Study of Intravesical Oxybutynin.” Receptor Genes.” Science 237:527-532, Erratum 1556, 1628 (1987). Neurourol. And Urodyn. 15:307-308 (1996) (Abstract #32). Bonner et al., "Cloning and Expression of the Human and Rat m3 Langtry et al., "Terodiline. A Review of its Pharmacological Proper Muscarinic Acetylcholine Receptor Genes.” Neuron 1:403-410 ties, and Therapeutic Use in the Treatment of Urinary Incontinence.” (1988). Drugs 40(5):748-761 (1990). Brown, 'Atropine, Scopolamine, and Related Antimuscarinic Madersbacher et al., "Control of Detrusor Hyperreflexia by the Drugs.” in Goodman et al., eds. The Pharmacological Basis of Intravesical Instillation of Oxybutynine Hydrochloride.” Paraplegia Therapeutics, Eighth Edition, New York: Macmillan Publishing Co., 29:84-90 (1991). pp. 150-165 (1990). Martin et al., “Pyrolysis and Volatilization of Cocaine.” J. Anal. Buckley et al., "Antagonist Binding Properties of Five Cloned Toxicol. 13:158-162 (1989). Muscarinic Receptors Expressed in CHO-K1 Cells.” Molecular Norman et al., "Tiotropium Bromide, Treatment of COPD Pharmacology 35:469-476 (1989). Bronchodilator Muscarinic Antagonist.” Drugs of the Future Carroll et al., “Probes for the Cocaine Receptor. Potentially Irrevers 25(7):693-699 (2000). Olesen et al., "Calcitonin Gene-Related Peptide Receptor Antagonist ible Ligands for Dopamine Transporter.” J. Med. Chem. 35:1813 BIBN 4096 BS for the Acute Treatment of Migraine.” N. Engl. J. 1817 (1992). Med. 350(11): 1104-1110 (2004). Carter et al., Analogues of Oxybutynin. Synthesis and Pietzko et al., “Influences of Trospium Chloride and Oxybutynin on Antimuscarinic and Bladder Activity of Some Substituted 7-Amino Quantitative EEG in Healthy Volunteers.” Eur: J. Clin. Pharmacol. 1-hydroxy-5-heptyn-2-ones and Related Compounds, J. Med. Chem. 47:337-343 (1994). 34:3065-3074 (1991). Scheidweiler et al., “Pharmacokinetics and Pharmacodynamics of Cereda et al., “Synthesis and Biological Evaluation of New Methylecgonidine, a Crack Cocaine Pyrolyzate.” J. Pharm. Exp. Antimuscarinic Compounds with Amidine Basic Centers. A Useful Ther. 307(3): 1179-1187 (2003). Bioisosteric Replacement of Classical Cationic Heads.” J. Med. Sessions et al., "Continuous Bladder Infusion Methods for Voiding Chem. 33:2108-2113 (1990). Function in the Ambulatory Mouse.” Urology 60(4):707-713 (2002). Comer et al., "Clocinnamox: A Novel, Systemically-Active, Irrevers Shih et al., "Labor Costs Associated with Incontinence in Long-Term ible Opioid Antagonist.” The Journal of Pharmacology and Experi Care Facilities.” Urology 62(3):442-446 (2003). mental Therapeutics 262(3): 1051-1056 (1992). Takahashi et al., “Effect of Ba 679 BR, A Novel Long-Acting Connor et al., "Early Cystometrograms Can Predict the Response to Anticholinergic Agent, On Cholinergic Neurotransmission in Guinea Intravesical Instillation of Oxybutynin Chloride in Pigs and Human Airways.” Am. J. Resp. Crit. Care Med. 150: 1640 Myelomeningocele Patients.” The Journal of Urology 151:1045 1645 (1994). 1047 (1994). Thuroff et al., “Randomized, Double-Blind, Multicenter Trial on Davies et al., “Novel 2-Substituted Cocaine Analogs: Binding Prop Treatment of Frequency, Urgency and Incontinence Related to Detru erties at Dopamine Transport Sites in Rat Striatum.” European Jour sor Hyperactivity: Oxybutynin Versus Propantheline Versus Pla nal of Pharmacology Molecular Pharmacology Section 244:93-97 cebo.”.J.
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