(12) United States Patent
`Meese et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 7,384,980 B2
`Jun. 10, 2008
`
`US007384980B2
`
`(54) DERIVATIVES OF
`3,3-DIPHENYLPROPYLAMINES
`
`(75)
`
`Inventors: Claus Meese, Monheim (DE); Bengt
`Sparf, Trangsund (CH)
`
`(73) Assignee: Schwarz Pharma AG, Monheim (DE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 156 days.
`
`(21) Appl.No.: 11/201,756
`
`(22)
`
`Filed:
`
`Aug. 10, 2005
`
`(65)
`
`Prior Publication Data
`
`US 2006/0270738 A1
`
`Nov. 30, 2006
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/766,263, filed on
`Jan. 27, 2004, now Pat. No. 7,230,030, which is a
`continuation of application No. 09/700,094, filed as
`application No. PCT/EP99/03212 on May 11, 1999,
`now Pat. No. 6,713,464.
`
`(30)
`
`Foreign Application Priority Data
`
`May 12, 1998
`
`(EP)
`
`................................ .. 98108608
`
`(51)
`
`Int. Cl.
`(2006.01)
`A01N 37/12
`(2006.01)
`A01N 37/44
`(2006.01)
`A61K 31/22
`(2006.01)
`C07D 69/00
`(52) U.S. Cl. ...................................... .. 514/551; 560/140
`(58) Field of Classification Search ............... .. 514/551;
`560/ 140
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`2,556,636 A
`2,567,245 A
`2,676,964 A
`3,261,841 A
`3,446,901 A
`4,988,730 A
`5,382,600 A
`5,559,269 A
`5,686,464 A
`5,922,914 A
`6,310,248 B2
`6,313,132 B1
`6,517,864 B1
`6,566,537 B2
`6,630,162 B1
`6,689,916 B2
`6,713,464 B1
`6,770,295 B1
`6,783,769 B1
`6,809,214 B2
`6,809,225 B2
`6,858,650 B1
`6,890,920 B2
`
`6/1951 Sperber et al.
`9/1951 Sperber et al.
`4/1954 Sperber et al.
`7/1966 Zenitz
`5/1969 Macclesfield
`1/1991 Korbonits et al.
`1/1995 Jonsson et al.
`9/1996 Johansson et al.
`11/1997 Johansson et al.
`7/1999 Gage et al.
`10/2001 Andersson et al.
`11/2001 Johansson et al.
`2/2003 Orup Jacobsen et al.
`5/2003 Andersson et al.
`10/2003 Nilvebrant et al.
`2/2004 Andersson et al.
`3/2004 Meese et al.
`8/2004 Kreilgard et al.
`8/2004 Arth et al.
`10/2004 Meese
`10/2004 Donsbach et al.
`2/2005 Meese
`5/2005 Richards et al.
`
`6,911,217 B1
`2003/0124179 A1
`2003/0152624 A1
`2003/0158176 A1
`2004/0064821 A1
`2004/0186061 A1
`2005/0004223 A1
`
`6/2005 Gren et al.
`7/2003 Jacobsen et al.
`8/2003 Aldrich et al.
`8/2003 Richards et al.
`4/2004 Rousselle
`9/2004 Meese et al.
`1/2005 Slatter et al.
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`GB
`GB
`GB
`GB
`GB
`
`830193
`766207
`925 468
`1216318
`325 571
`667 852
`831799
`872233
`948321
`957073
`1019 358
`1 077 912
`1 128 819
`624 117
`627 139
`685 696
`689 835
`690 274
`692 931
`
`2/1952
`12/1952
`3/1955
`5/1966
`7/1989
`8/1995
`6/1996
`4/1997
`12/1997
`5/1998
`7/2000
`2/2001
`9/2001
`5/1949
`7/1949
`1/1953
`4/1953
`4/1953
`6/1953
`
`(Continued)
`OTHER PUBLICATIONS
`
`Abrams et al., “Tolterodine, a new antimuscarinic agent: as effective
`but better tolerated than oxybutynin in patients with an overactive
`bladder,” 1998, Br. J. Urol. 81:801-810.
`
`(Continued)
`
`Primary Examiner—Zachary C Tucker
`(74) Attorney, Agent, or Firm—Kenyon & Kenyon LLP
`
`(57)
`
`ABSTRACT
`
`The invention concerns novel derivatives of 3,3-diphenylpro-
`pylamines, methods for their preparation, pharmaceutical
`compositions containing the novel compounds, and the use of
`the compounds for preparing drugs. More particularly, the
`invention relates to novel prodrugs of antimuscarinic agents
`with superior pharmacokinetic properties compared to exist-
`ing drugs such as oxybutynin and tolterodine, methods for
`their preparation, pharmaceutical compositions containing
`them, a method of using said compounds and compositions
`for the treatment of urinary incontinence, gastrointestinal
`hyperactivity (irritable bowel syndrome) and other smooth
`muscle contractile conditions.
`
`16 Claims, 1 Drawing Sheet
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0001
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0001
`
`

`
`US 7,384,980 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`
`1025041
`GB
`1 169 944
`GB
`1 169 945
`GB
`W0 89/06644
`W0
`W0 93/23025
`W0
`W0 94/11337
`W0
`W0 96/12477
`W0
`W0 98/03067
`W0
`W0 98/43942
`W0
`W0 98/56359
`W0
`W0 99/58478
`W0
`W0 00/12069
`W0
`W0 00/27364
`W0
`W0 01/34139
`W0
`W0 02/11702
`W0
`W0 02/089773
`W0
`W0 03/002059
`W0
`W0 03/007918
`W0
`W0 03/020241
`W0
`W0 03/021271
`W0
`W0 03/026564
`W0
`W0 03/035599
`W0
`W0 03/039464
`W0
`W0 03/063834
`W0
`W0 03/099268
`W0
`W0 03/103637
`W0
`W0 03/106421
`W0
`W0 W0 2004/019892
`
`2/1964
`11/1969
`11/1969
`7/1989
`11/1993
`5/1994
`5/1996
`1/1998
`10/1998
`12/1998
`11/1999
`3/2000
`5/2000
`5/2001
`2/2002
`11/2002
`1/2003
`1/2003
`3/2003
`3/2003
`4/2003
`5/2003
`5/2003
`8/2003
`12/2003
`12/2003
`12/2003
`3/2004
`
`OTHER PUBLICATIONS
`
`Abstracts from the 261‘ Annual Meeting of the International Incon-
`tinence Society, Aug. 27-30, 1996, Gillberg et al., abstract 33, Neu-
`rology and Urodynamics 15:308-309.
`Anderson et al., “Once daily controlled versus immediate release
`oxybutynin chloride for urge urinary incontinence,” 1999, J. Urol.
`161:1809-1812.
`Andersson et al., “Pharmacological treatment of urinary inconti-
`nence,” in Abrams P., Khoury S., Wein A. (Eds), Incontinence, 2nd
`International Consultation on Incontinence, Plymouth, Plymbridge
`Distributors Ltd, UK, Plymouth, 2002, pp. 479-511.
`Andersson, “Antimuscarinics for treatment of overactive bladder,”
`2004, Lancet Neurol. 3:46-53.
`Andersson & Hedlund, “Pharmacological perspective on the physi-
`ology of the lower urinary tract,” 2002, Urology 60(Suppl. 5A): 13-
`20.
`Andersson & Wein, “Pharmacology of the lower urinary tract: basis
`for current and future treatments of urinary incontinence,” 2004,
`Pharmacol. Rev. 56:581-631.
`Appell et al., “Prospective randomized controlled trial of extended
`release oxybutynin chloride and tolterodine tartrate in the treatment
`of overactive bladder: results of the OBJECT study,” 2001, Mayo
`Clinic Proceedings 76:358-363.
`Breidenbach et al., “Pharmacodynamic profiling of the novel
`antimuscarinic drug fesoterodine on rat bladder,” 2002, Proceedings
`of the International Continence Society, 32:449.
`Brynne et al.,
`Influence of CYP2D6 polymorphism on the
`pharmacokinetics and pharmacodynarnics oftolterodine, 1998, Clin.
`Pharmacol. Thera. 63:529-539.
`Brynne et al., “Tolterodine does not affect the human in vivo metabo-
`lism of the probe drugs caffeine, debrisoquine, and omeprazole,”
`1999, Br. J. Clin. Pharmacol. 47:145-150.
`the metabolism of
`Brynne
`et
`al.,
`“Fluoxetine
`inhibits
`tolterodine—pharmacokinetic implications and proposed clinical
`relevance,” 1999, Br. J. Clin. Pharn1acol. 48:553-563.
`Brynne et al., “Ketoconazole inhibits the metabolism oftolterodine in
`subjects with deficient CYP2D6 activity,” 1999, Br.
`J. Clin.
`Pharmacol. 48:564-572.
`Cawello et al., “Multiple dose pharn1acokinetics of fesoterodine in
`human subjects,” 2002, Nauyn-Schmiedeberg’s Arch. Pharmacol.
`365 (Suppl. 1):428, 2002.
`
`Chancellor et al., “A comparison of the effects on saliva output of
`oxybutynin chloride and tolterodine tartrate,” 2001, Clinical Thera-
`peutics 23:753-760.
`Chapple & Udo, “Delay to maximum effect in overactive bladder
`patients treated with oxybutynin or tolterodine,” 2000, European
`Urology 37(Suppl. 2):84, abstract 335 from the XVth Congress ofthe
`European Association of Urology, Brussels, Belgium, Apr. 12-15,
`2000.
`Chapple et al., “Fesoterodine a new effective and well-tolerated
`antimuscarinic for the treatment of urgency-frequency syndrome:
`results of a Phase II controlled study,” 2004, Proceedings of the
`International Continence Society, 34: 142.
`Clemett & Jarvis, “Tolterodine: a review of its use in the treatment of
`overactive bladder,” 2001, Drugs & Aging 18:277-304.
`Teuvo et al “Extended release tolterodine compared with immediate
`release tolterodine for the treatment of overactive bladder,” 2000,
`European Urology 37(Suppl. 2):84, abstract 334 from the XVth
`Congress of the European Association of Urology, Brussels, Bel-
`gium, Apr. 12-15, 2000.
`Van Kerrebroeck et al ., “Tolterodine once daily: superior efficacy and
`tolerability in the treatment ofthe overactive bladder,” 200 1, Urology
`57:414-421.
`Van Kerrebroeck et al., “Clinical efficacy and safety of tolterodine
`compared to oxybutynin in patients with overactive bladder,” 1997,
`Neurourol. Urodyn. 16:478-479, abstract No. 91 from the 27th
`Annual meeting of the International Continence Society, Yokohama,
`Japan, Sep. 1997.
`Versi et al., “Dry mouth with conventional and controlled release
`oxybutynin in urinary incontinence,” 2000, Obstet. Gynecol. 95 1718-
`721.
`Wefer et al., “Tolterodine: an overview,” 2001, World Journal of
`Urology 19, 312-318.
`Nilvebrant et al., European Journal of Pharmacology, 327(1997) pp.
`195-207.
`Nilvebrant et al., Pharmacology and Toxicology, vol. 81, pp. 169-
`172, 1997.
`Nilvebrant et al., Life Sciences, vol. 60 (13/14), pp. 1129-1 136, 1997.
`Postlind et al., Drug Metabolism and Disposition, vol. 26 (4), pp.
`289-293, 1998.
`Andersson et al., Drug Metabolism and Disposition, vol. 26 (6), pp.
`528-535, 1998.
`Brynne et al., J. Clin. Pharm. Ther., vol. 35 (7), pp. 287-295 1997.
`Cole, “Fesoterodine, an advanced antimuscarinic for the treatment of
`overactive bladder: A safety update,” 2004, Drugs of the Future
`29:715-720.
`Committee for Proprietary Medicinal Products, “The assessment of
`the potential for QT interval prolongation by non-cardiovascular
`medicinal products,” CPMP/986/96, Dec. 17, 1997.
`Detrol® package insert, Pharmacia & Upjohn Co., Apr. 2004.
`Diokno et al., “Tolterodine (Detrol®) improves incontinence and
`nocturia in urological based study,” Apr. 1999, J. Urol. 161 (4
`Suppl):256, abstract 987.
`Ekstrom et al., “Effects of tolterodine on bladder function in healthy
`volunteers,” Journal ofUrology 153(Suppl.):394A, abstract 662 from
`the 19d‘ Annual Meeting ofthe American Urological Association, Las
`Vegas, Apr. 23-28, 1995.
`Gardner & Altman, “Confidence intervals rather than P values: esti-
`mation rather than hypothesis testing,” 1986, Br. Med. J. 2921746-
`750.
`Gillberg et al., “Tolterodine, a new agent with tissue effect selectivity
`for urinary bladder,” 1994, Neurourology and Urodynamics 13 1435-
`436, abstract 60B from International Continence Society 24d‘ Annual
`Meeting, Prague, Czech Republic, Aug. 1994.
`Gillberg et al., “Comparison of the in vitro and in vivo profiles of
`tolterodine with those of subtype-selective muscarinic receptor
`antagonists,” 1998, European Journal of Pharmacology 3491 285-
`292.
`Hills et al., “Tolterodine,” 1998, Drugs 55:813-820.
`Jonas et al., “Efficacy and safety of two doses of tolterodine versus
`placebo in patients with detrusor overactivity and symptoms of fre-
`quency, urge incontinence, and urgency: urodynamic evaluation,”
`1997, World J. Urol. 15:144-151.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0002
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0002
`
`

`
`US 7,384,980 B2
`Page 3
`
`Kang et al., “Cardiac ion channel effects of Tolterodine,” 2004, J.
`Pharmacol. Exper. Thera. 3081935-940.
`Kershen & Hsieh, “Preview of new drugs for overactive bladder and
`incontinence: darifenacin, solifenacin, trospium, and duloxetine,”
`Curr. Urol. Rep. 5:359-367, 2004.
`der Darstellung von
`Klosa,
`“Eine Neue Synthesemethode
`Diarylalkylaminen,” 1966, Journal fiir Praktische Chemie 4:312-334
`(in German) with English translation.
`Klosa, “Eine Neue Synthese von Diphenylisopropylaminen,” 1966,
`Journal fr Praktische Chemie 4:335-340 (in German, with English
`translation).
`Larsson et al., “Tolterodine in the treatment of overactive bladder:
`analysis of the pooled phase II safety and efficacy data,” 1999, Urol-
`ogy 53:990-998.
`Lipinski, et al ., “Experimental and computational approaches to esti-
`mate solubility and permeability in drug discovery and development
`settings” Elsevier Advanced Drug Delivery Reviews vol. 23, pp.
`3-25, 1997.
`Millard et al ., “Clinical efficacy and safety oftolterodine compared to
`placebo in detrusor overactivity,” 1999, J. Urol. 161:1551-1555.
`Modiri et al., “Effect of muscarinic antagonists on micturition pres-
`sure measured by cystometry in normal, conscious rats,” 2002, Urol-
`ogy 59:963-968.
`Naerger et al., “Effect of tolterodine on electrically induced contrac-
`tions of isolated human detrusor muscle from stable and unstable
`bladders,” 1995, Neurourology and Urodynamics 14:524-526,
`abstract 76 from International Continence Society 25d‘ Annual Meet-
`ing, Sydney, Australia, Oct. 1995.
`Netzer, et al., “Screening lead compounds for QT interval prolonga-
`tion” Drug Discovery Today vol. 6, No. 2, pp. 78-84, Jan. 2001.
`Nilsson et al., “Comparison of a 10 mg controlled release oxybutynin
`tablet with a 5 mg oxybutynin tablet in urge incontinence patients,”
`1997, Neurourol. Urodyn. 16:533-542.
`Nilvebrant & Sparf, “Receptor binding profiles of some selective
`muscarinic antagonists,” 1988, European Journal of Pharmacology
`151 :83-96.
`Nilvebrant & Sparf, “Differences between Binding Affinities of some
`Antimuscarinic Drugs in the parotid Gland and those in the Urinary
`Bladder and Ileum” Acta Pharmacol. et toxicol. vol. 53, No. 4, pp.
`304-313, Oct. 1983.
`“The in vitro pharmacological profile of
`Nilvebrant et al.,
`tolterodine—a new agent for the treatment of urinary urge inconti-
`nence,” 1994, Neurourology and Urodynamics 131433-435, abstract
`60A from International Continence Society 24d‘ Annual Meeting,
`Prague, Czech Republic, Aug. 1994.
`Nilvebrant et al., “Tolterodine is not subtype (ml-m5) selective but
`exhibits functional bladder selectivity in vivo,” 1996, Neurourology
`and Urodynamics 151310-311, abstract 34 from the 26th Annual
`Meeting of the International Continence Society, Athens, Greece,
`Aug. 27-30, 1996.
`Nilvebrant, “Tolterodine and terodiline—different pharmacological
`profiles,” pp. 141-142, abstract 181a, from the 27th Annual meeting
`of the International Continence Society, Yokohama, Japan, Sep.
`1997.
`Nilvebrant et al “Tissue distribution of tolterodine and its metabo-
`lites: low penetration into the central nervous system,” 2000, Euro-
`
`pean Urology 37(Suppl. 2): 84, abstract 333 from the XVth Congress
`of the European Association of Urology, Brussels, Belgium, Apr.
`12-15, 2000.
`Nilvebrant, “The mechanism ofaction oftolterodine,” 2000, Reviews
`in Contemporary Pharmacotherapy 11:13-27.
`Olsson et al., “Food increases the bioavailability of tolterodine but
`not effective exposure,” 2001, J. Clin. Pharmacol. 41:298-304.
`Olsson & Szamosi, “Food does not influence the pharmacokinetics of
`a new extended release formulation of tolterodine for once daily
`treatment of patients with overactive bladder,” 2001, Clinical
`Pharmacokinetics 40: 135-143.
`Olsson & Szamosi, “Multiple dose pharmacokinetics of a new once
`daily extended release formulation versus
`immediate release
`tolterodine,” 2001, Clinical Pharmacokinetics 40:227-235.
`Pharmacology/Toxicology Review from Application No. 21-518,
`Center for Drug Evaluation and Research, pp. 1-3, 2001.
`Rentzhog et al., “Efficacy and safety of tolterodine in patients with
`detrusor instability: a dose ranging study,” 1998, Br. J. Urol. 81:42-
`48.
`Roy, et al., “HERG, a Primary Human Ventricular Target of the
`Nonsedating Antihistamine Terfenadine” Circulation vol. 94, No. 4,
`pp. 817-823, Aug. 15, 1996.
`Sachse et al., “Pharmacodynamics of multiple dose treatment with
`the novel
`antimuscarinic drug fesoterodine,” 2002, Nauyn-
`Schmiedeberg’s Arch. Pharmacol. 365 (Suppl. 1):413.
`Sachse et al., “Safety and pharmacokinetics of the novel bladder-
`selective antimuscarinic drug fesoterodine in populations ofdifferent
`age or gender,” 2002, Proceedings of the International Continence
`Society, 32:441.
`Sachse et al., “Safety and pharmacokinetics of the novel bladder-
`selective antimuscarinic fesoterodine in populations of different eth-
`nic origin,” 2003, Proceedings of the International Continence Soci-
`ety, 33:377.
`Sachse et al., “Dose-proportional pharmacokinetics of the new
`antimuscarinic fesoterodine,” 2003, Nauyn-Schmiedeberg’s Arch.
`Pharmacol. 367 (Suppl. 1):446.
`Sachse et al., “Pharmacodynamics and pharmacokinetics of ascend-
`ing multiple oral doses ofthe novel, bladder-selective antimuscarinic
`fesoterodine,” 2003, Eur. Urol. Suppl 2:111.
`Sachse et al., “Concomitant food intake does not significantly influ-
`ence
`the pharmacokinetics of
`the
`novel,
`bladder-selective
`antimuscarinic fesoterodine,” 2004, Proceedings of the International
`Continence Society, 34:580.
`Sachse et al.,
`“Safety,
`tolerability and pharmacokinetics of
`fesoterodine in patients with hepatic impairment,” 2004, Proceedings
`of the International Continence Society, 34:585.
`Sachse et al.,
`“Safety,
`tolerability and pharmacokinetics of
`fesoterodine after co-treatment with the potent cytochrome P450
`3A4 inhibitor ketoconazole,” 2004, Proceedings of the International
`Continence Society, 34:586.
`Sachse et al., “Clinical pharmacological aspects ofthe novel bladder-
`selective antimuscarinic fesoterodine,” 2004, Progres en Urologie,
`14 (Suppl. 3):58.
`Stahl et al., “Urodynamic and other effects of tolterodine: a novel
`antimuscarinic drug for the treatment of detrusor overactivity,” 1995,
`Neurourol. Urodyn. 141647-55.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0003
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0003
`
`

`
`U S. Patent
`
`Jun. 10,2008
`
`US 7,384,980 B2
`
`F4(3.1
`
`
`
`
`
`FORMATIONasTHEACTIVEMETABDLITEFROMDIFFERENTPRODRUGSavHUMANLIVERs9(%)IN1n
`
`
`
`
`
`dmdo+oH
`
`3VO‘l'OH
`
`1oqo.
`
`9mo~
`
`emu
`
`o
`l"~
`
`0
`D
`
`o
`In
`
`O
`1"
`
`o
`IO
`
`2mo.-
`
`100
`
`on
`
`Jana-um: agqgssod ‘mam ;o [34,]
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0004
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0004
`
`

`
`1
`DERIVATIVES OF
`3,3-DIPHENYLPROPYLAMINES
`
`US 7,384,980 B2
`
`2
`
`lower absorption/bioavailability, leading to pre-systemic side
`effects or interactions due to non-absorbed antimuscarinic
`drug. In a method to circumvent this disadvantage, different
`prodrugs of the metabolite have been synthesized and tested
`for their antimuscarinic activity, potential absorption through
`biological membranes and enzymatic cleavage.
`
`BRIEF SUMMARY OF THE INVENTION
`
`It is an object of the present invention to provide novel
`derivatives of 3,3-diphenylpropylamines. It is a further object
`of the present invention to provide new derivatives of 3,3-
`diphenylpropylarnines which will be more useful as prodrugs
`for treatment of urinary incontinence and other spasmogenic
`conditions that are caused by muscarinic mechanisms while
`avoiding the disadvantage of a too low absorption through
`biological membranes of the drugs or an unfavourable
`metabolism.
`
`A further object of the invention is to provide novel pro-
`drugs of antimuscarinic agents with superior pharmacoki-
`netic properties compared to present drugs as oxybutynin and
`tolterodine, methods for preparing thereof, pharmaceutical
`compositions containing them, a method of using said com-
`pounds and compositions for the treatment of urinary incon-
`tinence, gastrointestinal hyperactivity (irritable bowel syn-
`drome) and other smooth muscle contractile conditions.
`According to the present invention, novel 3 ,3 -diphenylpro-
`pylamines are provided, which are represented by the general
`formulae I and VII‘
`
`O — R’
`
`Formula I
`
`X
`
`R — O
`
`A
`
`A
`
`0
`
`0A
`
`A
`
`HO
`
`X
`
`Formula VII’
`
`This application is a continuation of U.S. patent applica-
`tion Ser. No. 10/766,263, filed Jan. 27, 2004, now U.S. Pat.
`No. 7,230,030, which is a continuation of U.S. patent appli-
`cation Ser. No. 09/700,094, filed Jan. 2, 2001, now U.S. Pat.
`No. 6,713,464, which is a 371 ofPCT/EP99/03212, filed May
`1 1, 1999.
`The present invention relates to novel derivatives of 3,3-
`diphenylpropylarnines, methods for their preparation, phar-
`maceutical compositions containing the novel compounds,
`and the use of the compounds for preparing drugs.
`
`BACKGROUND OF THE INVENTION
`
`In man, normal urinary bladder contractions are mediated
`mainly through cholinergic muscarinic receptor stimulation.
`There is reason to believe that muscarinic receptors mediate
`not only normal bladder contractions, but also the main part of
`the contractions in the overactive bladder resulting in symp-
`toms such as urinary frequency, urgency and urge inconti-
`nence. For this reason, antimuscarinic drugs have been pro-
`posed for the treatment of bladder overactivity.
`Among the antimuscarinic drugs available on the market,
`oxybutynin is currently regarded as the gold standard for
`pharmacological treatment of urge incontinence and other
`symptoms related to bladder overactivity. The effectiveness
`of oxybutynin has been demonstrated in several clinical stud-
`ies, but the clinical usefulness of oxybutynin is limited due to
`antimuscarinic side effects. Dryness of the mouth is the most
`common experienced side effect which may be severe enough
`to result in poor compliance or discontinuation of Treatment
`(Anders son, K.-E., 1988, Current concepts in the treatment of
`disorders of micturition, Drugs 35, 477-494; Kelleher et al.
`1 994).
`Tolterodine is a new, potent and competitive, muscarinic
`receptor antagonist intended for the treatment ofurinary urge
`incontinence and detrusor hyperactivity. Preclinical pharma-
`cological data show that tolterodine exhibits a favourable
`tissue selectivity in vivo for the urinary bladder over the effect
`on the salivation (Nilvebrant et al., 1997, Tolterodine—a new
`bladder-selective antimuscarinic agent, Eur. J. Pharmacol.
`327 (1997), 195-207), whereas oxybutynin exhibits the
`reversed selectivity. Tolterodine is equipotent to oxybutynin
`at urinary bladder muscarinic receptors and the favourable
`tissue selectivity of tolterodine demonstrated in the preclini-
`cal studies has been confirmed in clinical studies. Thus a good
`clinical efficacy has been combined with a very low number
`of incidences of dry mouth and antimuscarinic side effects.
`A major metabolite of tolterodine, the 5-hydroxymethyl
`derivative is also a potent muscarinic receptor antagonist and
`the pharmacological in vitro and in vivo profiles of this
`metabolite are almost identical to those of tolterodine (Nil-
`vebrant et al., 1997, Eur. J. Pharmacol. 327 (1997), 195-207).
`Combined pharmacological and pharmacokinetic data indi-
`cate that it is most likely that the metabolite gives a major
`contribution to the clinical effect in most patients.
`WO 94/1 1337 proposes the active metabolite oftolterodine
`as a new drug for urge incontinence. Administration of the
`active metabolite directly to patients has the advantage com-
`pared to tolterodine that only one active principle (com-
`pound) has to be handled by the patient which normally
`should result in a lower variation in efiicacy and side effects
`between patients and lower risk of interaction with other
`drugs.
`However, the introduction of an additional hydroxy group
`in the tolterodine results in an increased hydrophilic property
`of the new compounds (3,3-diphenylpropylamines) com-
`pared to the parent compounds which normally results in a
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`O
`/K
`
`T
`(CH2)n
`1
`
`o
`
`YO
`
`O
`
`X
`
`60
`
`HO
`
`A
`
`A
`
`65
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0005
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0005
`
`

`
`US 7,384,980 B2
`
`3
`wherein R and R‘ are independently selected from
`a) hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, substituted or
`unsubstituted benzyl, allyl or carbohydrate; or
`b) formyl, C1-C6 alkylcarbonyl, cycloalkylcarbonyl, substi-
`tuted or unsubstituted arylcarbonyl, preferably benzoyl; or
`c) C1-C6 alkoxycarbonyl, substituted or unsubstituted ary-
`loxycarbonyl, benzoylacyl, benzoylglycyl, a substituted or
`unsubstituted amino acid residue; or
`
`d)
`
`wherein R4 and R5 independently represent hydrogen, C1-C6
`alkyl, substituted or unsubstituted aryl, preferably substituted
`or unsubstituted phenyl, benzyl or phenoxyalkyl wherein the
`alkyl residue has 1 to 4 carbon atoms and wherein R4 and R5
`may form a ring together with the amine nitrogen; or
`6)
`
`Ra
`>—N—so3—
`R7
`
`wherein R6 and R7 independently represent C1-C6 alkyl, sub-
`stituted or unstubstituted aryl, preferably substituted or
`unsubstituted phenyl, benzyl or phenoxyalkyl wherein the
`alkyl residue has 1 to 6 carbon atoms; or
`f) an ester moiety of inorganic acids,
`g) —SiRaRbR6, wherein Ra, R1,, R6 are independently
`selected from C1-C4 alkyl or aryl, preferably phenyl,
`with the proviso that R‘ is not hydrogen, methyl or benzyl if R
`is hydrogen,
`X represents a tertiary amino group of formula la
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Formula la
`
`45
`
`wherein R8 and R9 represent non-aromatic hydrocarbyl
`groups, which may be the same or different and which
`together contain at least three carbon atoms, and wherein R8
`and R9 may form a ring together with the amine nitrogen,
`Y and Z independently represent a single bond between the
`(CH2)n group and the carbonyl group, O, S or NH,
`A represents hydrogen (IH) or deuterium (2H),
`n is 0 to 12
`and
`
`their salts with physiologically acceptable acids, their free
`bases and, when the compounds can be in the form of
`optical isomers, the racemic mixture and the individual
`enantiomers.
`
`The aforementioned compounds can form salts with physi-
`ologically acceptable organic and inorganic acids. Further-
`more,
`the aforementioned compounds comprise the free
`
`50
`
`55
`
`60
`
`65
`
`4
`
`bases as well as the salts thereof. Examples of such acid
`addition salts include the hydrochloride, hydrobromide and
`the like.
`
`When the novel compounds are in the form of optical
`isomers, the invention comprises the racemic mixture as well
`as the individual isomers as such.
`
`Preferably each of R8 and R9 independently signifies a
`saturated hydrocarbyl group, especially saturated aliphatic
`hydrocarbyl groups such as C1_8-alkyl, especially C1_5 -alkyl,
`or adamantyl, R8 and R9 together comprising at least three,
`preferably at least four carbon atoms.
`According to another embodiment ofthe invention, at least
`one of R8 and R9 comprises a branched carbon chain.
`Presently preferred tertiary amino groups X in formula I
`include the following groups a) to h):
`
`—N
`
`—N
`
`CH(CH3)2
`
`CH(CH3)2
`
`CH3
`
`C(CH3)3
`
`CH3
`
`—N
`
`C(CH3)3CH3CH3
`
`H3C
`
`CH3
`
`—N
`
`H3C
`
`CH3
`
`H3C
`
`CH3
`
`—N
`
`H3C
`
`CH3
`
`CH3
`—N
`
`3)
`
`b)
`
`0)
`
`d)
`
`5)
`
`0
`
`g)
`
`11)
`
`Group a) is particularly preferred.
`The aforementioned tertiary amino groups X are described
`in W0 94/ l 1337 and the compounds according to the present
`invention can be obtained by using the corresponding starting
`compounds.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0006
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0006
`
`

`
`US 7,384,980 B2
`
`5
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG. 1 shows formulation of the active metabolite from
`
`different prodrugs by human liver S9 (%) in l h. In the
`compounds according to the present invention,
`the term
`“alkyl” preferably represents a straight-chain or branched-
`chain hydrocarbon group having 1 to 6 carbon atoms. Such
`hydrocarbon groups may be selected from methyl, ethyl,
`propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. The term
`“cycloalkyl” denotes a cyclic hydrocarbon group having 3 to
`10 carbon atoms which may be substituted conveniently.
`The term “substituted or unsubstituted benzyl” denotes a
`benyl group —CH2—C6H5 which is optionally substituted by
`one or more substituents on the phenyl ring. Suitable substitu-
`ents are selected from alkyl, alkoxy, halogen, nitro and the
`like. Suitable halogen atoms are fluorine, chlorine and iodine
`atoms. Preferred substituted benzyl groups are 4-methylben-
`zyl, 2-methylbenzyl, 4-methoxybenzyl, 2-methoxybenzyl,
`4-nitrobenzyl, 2-nitrobenzyl, 4-chlorobenzyl and 2-chlo-
`robenzyl.
`In the compounds according to the present invention the
`term “C1-C6 alkylcarbonyl” denotes a group R—C(:O)—
`wherein R is an alkyl group as defined hereinbefore. Preferred
`C1-C6 alkylcarbonyl groups are selected from acetyl, propio-
`nyl,
`isobutyryl, butyryl, valeroyl and pivaloyl. The term
`“cyclo-alkylcarbonyl” denotes
`a group R—C(:O)—
`wherein R is a cyclic hydrocarbon group as defined herein-
`before. The same counts to the selected carbonyl groups.
`The term “aryl” denotes an aromatic hydrocarbon group
`such as phenyl-(C6H5—), naphthyl-(C1OH7—), anthryl-
`(C 14H9—), etc. Preferred aryl groups according to the present
`invention are phenyl and naphthyl with phenyl being particu-
`larly preferred.
`The term “benzoyl” denotes an acyl group of the formula
`—CO—C6H5, wherein the phenyl ring may have one or more
`substituents.
`
`Preferred sub stituents ofthe aryl group and in particular of
`the phenyl group are selected from alkyl, alkoxy, halogen and
`nitro. As substituted benzoyl groups 4-methylbenzoyl, 2-me-
`thylbenzoyl, 4-methoxybenzoyl, 2-methoxybenzoyl, 4-chlo-
`robenzoyl, 2-chlorobenzoyl, 4-nitrobenzoyl and 2-nitroben-
`zoyl may be mentioned.
`The term “C1-C6 alkoxycarbonyl” refers to a group ROC
`(:O)— wherein R is an alkyl group as defined hereinbefore.
`Preferred C1-C6 alkoxycarbonyl groups are selected from
`CH3C(:O)—, C2H5—OC(:O)—, C3H7C(:O)— and
`(CH3)3COC(:O)— and alicyclic alkyloxycarbonyl.
`The term “amino acid residue” denotes the residue of a
`
`naturally occurring or synthetic amino acid. Particularly pre-
`ferred amino acid residues are selected from the group con-
`sisting ofglycyl, valyl, leucyl, isoleucyl, phenylalanyl, prolyl,
`seryl, threonyl, methionyl, hydroxyprolyl.
`The amino acid residue may be substituted by a suitable
`group and as substituted amino acid residues, benzoylglycyl
`and N-acetylglycyl may be mentioned.
`The term “carbohydrate” denotes the residue of a polyhy-
`droxy aldehyde or polyhydroxy ketone of the formula
`21114
`C”H O or C,1(H2O),1 and correponding carbohydrate groups
`are, for example, described in Aspinal, The Polysaccharides,
`New York: Academic Press 1982, 1983 . A preferred carbohy-
`drate group in the compounds according to the present inven-
`tion is a glucuronosyl group, in particular a l[3-D-glucurono-
`syi group.
`The term “LG” as used herein denotes a leaving group
`selected from halogenides, carboxylates, imidazolides and
`the like.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`The term “Bn” as used herein denotes a benzyl group.
`Suitable ester moieties of inorganic acids may be derived
`from inorganic acids such as sulfuric acid and phosphoric
`acid.
`
`Preferred compounds according to the present invention
`are:
`
`A) Phenolic monoesters represented by the general formulae
`II and II‘
`
`Formula II
`
`Formula II’
`
`Ofi/(CH2)n/k0
`
`wherein R1 represents hydrogen, C1-C6 alkyl or phenyl.
`Particularly preferred phenolic monoesters are listed
`below:
`
`(:)-formic acid 2-(3-diisopropylamino-l-phenylpropyl)-
`4-hydroxymethylphenyl ester,
`(:)-acetic acid 2-(3 -diisopropylamino-l -phenylpropyl)-4-
`hydroxymethylphenyl ester,
`(:)-propionic acid 2-(3 -diisopropylamino-l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(1)-n-butyric acid 2-(3 -diisopropylamino-l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(1)-isobutyric acid 2-(3 -diisopropylamino-l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`R-(+)-isobutyric acid 2-(3 -diisopropylamino-l -phenyl-
`propyl)-4-hydroxymethylphenyl ester,
`(1)-2,2-dimethylpropionic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyl ester,
`(1)-2-acetamidoacetic acid 2-(3 -diisopropylarnino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(1)-cyclopentanecarboxylic acid 2-(3-diisopropylamino-
`l-phenylpropyl)-4 -hydroxymethylphenyl ester,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0007
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0007
`
`

`
`US 7,384,980 B2
`
`7
`(1)-cyclohexanecarboxylic acid 2-(3 -diisopropylamino-l -
`phenylpropyl)-4-hydroxymethylphenyl ester,
`(:)-benzoic acid 2-(3 -diisopropylamino- l -phenylpropyl)-
`4-hydroxymethylphenyl ester,
`R- (+)-benzoic acid 2-(3 -diisopropylamino- l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(:)-4 -methylbenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-2 -methylbenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(1)-2-acetoxybenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(1)-l -naphthoic acid 2-(3 -diisopropylamino- l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(:)-2 -naphthoic acid 2-(3 -diisopropylamino- l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(1)-4-chlorobenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-4 -methoxybenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-2 -methoxybenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-4 -nitrobenzoic acid 2-(3 -diisopropylamino-l -phenyl-
`propyl)-4-hydroxymethylphenyl ester,
`(:)-2 -nitrobenzoic acid 2-(3 -diisopropylamino-l -phenyl-
`propyl)-4-hydroxymethylphenyl ester,
`(1)-malonic acid bis-[2-(3 -diisopropylamino-l -phenyl-
`propyl) -4 -hydroxymethyl -phenyl] ester,
`(:)-succinic acid bis-[2-(3 -diisopropylamino-l -phenyl-
`propyl) -4 -hydroxymethyl -phenyl] ester,
`(1)-pentanedioic acid bis-[2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4 -hydroxymethyl-phenyl] ester,
`(1)-hexanedioic acid bis-[2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4 -hydroxymethyl-phenyl] ester.
`B