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Wo 2009/151712 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 17 December 2009 (17.12.2009) WO 2009/151712 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07C 219/22 (2006.01) A61K 31/221 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/222 (2006.01) A61P 43/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, (21) International Application Number: EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, PCT/US2009/037980 HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 23 March 2009 (23.03.2009) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, (25) Filing Language: English SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, (26) Publication Language: English UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/039,1 66 25 March 2008 (25.03.2008) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): AUS- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, PEX PHARMACEUTICALS. INC. [US/US]; 1261 TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Liberty Way, Suite C, Vista, CA 9208 1 (US). ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), (72) Inventors; and OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, (75) Inventors/Applicants (for US only): GANT, Thomas, G. MR, NE, SN, TD, TG). [US/US]; 1261 Liberty Way, Suite C, Vista, CA 92081 (US). SARSHAR, Sepehr [US/US]; 1261 Liberty Way, Published: Suite C, Vista, CA 92081 (US). — without international search report and to be republished (74) Agent: BENNETT, Dennis, A.; Global Patent Group, upon receipt of that report (Rule 48.2(g)) LLC, 104 11 Clayton Road, Suite 304, St. Louis, MO 63 13 1 (US). (54) Title: SUBSTITUTED PHENYLCYCLOHEXYLGLYCOLATES (57) Abstract: Disclosed herein are substituted phenylcyclohexylglycolate-based muscarinic acetylcholine receptor modulators of Formula (I), processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof. SUBSTITUTED PHENYLCYCLOHEXYLGLYCOLATES [0001] This application claims the benefit of priority of United States provisional application No. 61/039,166, filed March 25, 2008, the disclosure of which is hereby incorporated by reference as if written herein in its entirety. [0002] The present invention is directed to phenylcyclohexylglycolate-based muscarinic acetylcholine receptor modulators, pharmaceutically acceptable salts and prodrugs thereof, the chemical synthesis thereof, and medical use of such compounds for the treatment and/or management of urinary incontinence, overactive bladder, enuresis, hyperhidrosis, neuropathic bladder, neurogenic bladder, detrusor overactivity, postoperative pain related to indwelling bladder catheter, nephrotuberculosis, refractory hot flashes in cancer patients, and/or any disorder which can lessened, alleviated, or prevented by administering a muscarinic acetylcholine receptor modulator. [0003] Oxybutynin (Oxytrol®, Ditropan XL®, Lyrinel XL®, Ditropan®, Ditrospam®, and Urotrol®), 4-diethylaminobut-2-ynyl-2-cyclohexyl-2-hydroxy-2-phenyl-ethanoate, is an orally or transdermally administered antispasmodic and anticholinergic agent. Oxybutynin is commonly prescribed to relieve urinary and bladder disorders, including, but not limited to, urinary incontinence (Reinberg et al, J Urol 2003, 169(1), 317-9), overactive bladder (Davila GW, Clin Interv Aging 2006, 1(2), 99-105; Lam et al., Clin Interv Aging 2007, 2(3), 337-45; Schaefer W, IntJ Urol 2007, 14(7), 670; Sand et al., BJU Int 2007, 99(4), 836-44), enuresis (Weaver et al., J Fam Health Care 2007, 17(5), 159-61; Zaffanello et al., Minera UrolNefrol 2007, 59(2), 199-205), neuropathic bladder (Tharion et al., Scientific WorldJ 2007, 22, 1683-90), nephrotuberculosis (Zuban et al., Urologiia 2006, (5), 37-40), neurogenic bladder (Bennet et al., J Urol 2004, 171(2ptl), 749-51; O'Leary et al., J Spinal Cord Med 2003, 26(2), 159-62), and detrusor overactivity (Arisco et al., Nat Clin Pract Urol 2007, 4(10), 538-9; Diokno et al., Urol Clin North Am 2006, 33(4), 439-45). Further, oxybutynin is effective in treating and/or managing postoperative pain related to an indwelling bladder catheter (Tauzin-Fin et al., Br J Anaesth 2007, 99(4), 572-5), hyperhidrosis (Lefrandt et al., Neth J Med 2007, 65(9), 356; Schollhammer et al., Arch Dermatol 2007, 143(4), 544-5), and refractory hot flashes in cancer patients (Sexton et al., Menopause 2007, 14(3PtI), 505-9). Oxybutynin acts as a competitive antagonist of acetylcholine at muscarinic receptors, resulting in relaxation of smooth muscle. Oxybutynin [0004] Oxybutynin is extensively metabolized, primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. Metabolites include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and N- desethyloxybutynin, which is pharmacologically active. The active metabolite, N- desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in-vitro studies. Oxybutynin is administered as a racemic mixture of (R) and (S) oxybutynin enantiomers. For orally administered oxybutynin, N- desethyloxybutynin is largely responsible for the systemic side effects, particularly dry mouth and central nervous system side effects. Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite. Only small amounts of CYP3A4 are found in skin, limiting pre- systemic metabolism during transdermal absorption. There is noticeable interpatient variability with respect to the elimination half-life of oxybutynin. Oxybutynin, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis. Oxybutynin should also be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis. Oxybutynin should be used with caution in patients with hepatic or renal impairment. Common oxybutynin-correlated side effects include, but are not limited to, dry mouth, constipation, and abnormal vision, pruritus (transdermal), site rash (transdermal), and macules (transdermal). [0005] Disclosed herein is a compound having structural Formula I : (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein: R 1-R3 1 are independently selected from the group consisting of hydrogen and deuterium; and at least one of R1-R31 is deuterium. [0006] Also disclosed herein are pharmaceutical compositions comprising at least one of the compounds disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with one or more pharmaceutically acceptable excipients or carriers. [0007] Also disclosed herein are articles of manufacture and kits containing compounds as disclosed herein. By way of example only a kit or article of manufacture can include a container (such as a bottle) with a desired amount of at least one compound (or pharmaceutical composition of a compound) as disclosed herein. Further, such a kit or article of manufacture can further include instructions for using said compound (or pharmaceutical composition of a compound) disclosed herein. The instructions can be attached to the container, or can be included in a package (such as a box or a plastic or foil bag) holding the container. [0008] Additionally, disclosed herein are methods of modulating smooth muscle function and tone. [0009] In certain embodiments, a method for the treatment, prevention, or amelioration of one or more symptoms of a muscarinic acetylcholine receptor-mediated disorder in a subject by administering a therapeutically effective amount of a compound as disclosed herein. [0010] In other embodiments said muscarinic acetylcholine receptor-mediated disorder is selected from the group consisting of urinary incontinence, overactive bladder, enuresis, hyperhidrosis, neuropathic bladder, neurogenic bladder, detrusor overactivity, postoperative pain related to indwelling bladder catheter, nephrotuberculosis, and refractory hot flashes in cancer patients. [0011] In further embodiments said muscarinic acetylcholine receptor-mediated disorder is urinary incontinence. [0012] In certain embodiments said muscarinic acetylcholine receptor-mediated disorder is overactive bladder. [0013] In certain embodiments said histamine receptor-mediated disorder can be ameliorated by modulating muscarinic acetylcholine receptors. [0014] In further embodiments, said method comprises a compound disclosed herein and one or more pharmaceutically acceptable carriers. [0015] In yet further embodiments said method further comprise another therapeutic agent. [0016] In other embodiments said therapeutic agent is selected from the group consisting of: urinary antispasmodics, urologicals, hyperhidrosis treatments, non-steroidal anti-inflammatory
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