Drugs of the Future 1999. 24(8): 871-874
`Cnpyrightib 1999 PROU5 SCIENCE
`ccc: 0377-2282/99
`
`YM-905
`
`Treatment of Urinary incontinence
`Muscarinic M3 Antagonist
`
`YM-53705 (as monohydrochloride)
`
`1(S)-Phenyl-1,2,3,4-tetrahydroisoquinoline-2—carboxy|ic acid 3(Fi)-quinuclidinyl ester monosuccinate
`
`0 N
`0
`
`O
`
`O,
`N
`
`H020
`
`COEH
`
`I
`
`2522
`C23H N 0 .c4Hfio4
`
`Mol wt: 480.5660
`
`CAS: 180272-14-4 (undefined isomer, free base)
`CAS: 1802?2-15-5 (undefined isomer, oxalate)
`CAS: 180272-16-6 (undefined isomer. monohydrochloride)
`CAS: 180463-39-7 (as monohydrochloride)
`
`EN: 249699
`
`Synthesis
`
`YM-905 has been obtained by two related ways:
`Scheme 1.
`1) The benzoylation of 2-phenyiethyiamine (I) with
`benzoyl chloride (II) and triethylamlne in chloroform, or
`with benzoic acid (Ill), DPPA and triethyiamine in DMF,
`gives the corresponding benzamide (IV), which is
`cyclized by means of POCI3 and P205 in refluxing xylene
`and reduced with NaBH4 in ethanoi, yielding racemic
`1—phenyl—t,2,3,4—tetrahydroisoquinoline (V). The reaction
`of (V) with ethyl chloroformate by means of K2003 in chlo-
`roform affords racemic 1-phenyl-1,2,3.4-tetrahydroiso-
`quinoline-2-carboxylic acid ethyl ester (Vt), which is
`transesterified with quinuclidine-3(H)-cl (VII) by means of
`NaH in refluxing toluene to provide the quinuclidinyl ester
`(VIII) as a diastereomeric mixture. This mixture is
`resolved by chiral HPLC. giving the target compound as
`a pure enantiomer (1).
`2) The racemic 1-phenyl-1,2,3,4-tetrahydroisoquino-
`line (V) can also be submitted to optical resolution with
`(+)-tartaric acid to give 1(S)-phenyl-1,2,3.4-tetrahydroiso-
`quinoline (IX) (1), which is condensed with ethyl chloro-
`formate by means of K2CO3 in chloroform to afford 1(8)-
`
`phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid
`ethyl ester (Vi). This compound is transesteriiied with
`quinuclidine-3(Fi‘)-oi (Vll) by means of NaH in refluxing
`toluene to directly provide the pure enantiorner (1, 2).
`
`Introduction
`
`Urinary incontinence is uncontroiable and can be
`caused by various factors such as neurologic disease
`(e.g., Alzheimer's disease) or weak pelvic muscles.
`Approximately 800,000 older Americans living at home
`are incontinent, which limits their daily activities. Severat
`anticholinergic drugs are available for the treatment of uri-
`nary incontinence. including oxybutinin. propiverine and
`tolterodine. These drugs act by blocking the action of
`acetylcholine at postganglionic cholinergic sites, thereby
`increasing bladder capacity by reducing the number of
`motor impulses reaching the detrusor muscle. New ther-
`apeutic approaches under study for the treatment of uri-
`nary incontinence are shown in Table I.
`In an attempt to develop more bladder-selective mus-
`carinic M3 receptor antagonists for use in the therapy of
`urinary incontinence, researchers at Yamanouchi pre-
`pared a series of 1,2,3,4-tetrahydro-2-isoquinolinecan
`boxyiate derivatives. One compound in the series,
`YM-53705, exhibited high affinity for this receptor and
`good selectivity for inhibition of rhythmic bladder contrac-
`tions versus salivary secretion (1). Pharmacological stud-
`ies were subsequently conducted with the monosuccinate
`YM-905.
`
`Pharmacological Actions
`
`YM-905 exhibits high affinity for human muscarinic
`m1, m2 and ma receptors. with respective K’. values of 25,
`120 and 10 nM. The M3 receptor-mediated. carbacho|-
`induced increase in intracellular Ca2+ Eevels in mouse sali-
`vary gland cells was antagonized by YM-905. tclterodine,
`
`
`N. Meaty, J. Caslafier. Prous Science, P.O. Box 540, 08030
`Barcelona, Spain.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2046 - 0001
`
`

`
`372
`
`YM-905
`
`Scheme 1; Synthesis of YM-905
`
`0
`
`(U)
`
`U)
`
`TEA
`
`DPPA.TEA
`
`,1“/®N
`E)” O
`
`(Iv)
`
`1) POCI3, P205
`-—-—--—----—-—----------—y-
`2) NaBl'_l4
`
`C|C0,_Et
`
`(+)-tartaric acid
`
`Cl
`
`N
`
`O
`
`N
`
`HO,
`(VII) 0 NW]/DEt
`
`O
`
`0 (
`
`Vi)
`
`O
`
`”
`
`NaH
`
`Chirat HPLC
`
`O N
`
`O,’
`\"/ 1
`0
`
`oxybutynin and atropine, with pKB values of 7.4, 9.3, 9.0
`and 9.9, respectively, whereas the responses in guinea
`pig detrusor muscle celis were antagonized by YM-905.
`tolterodine and oxybutynin with pKB values of 8.5, 8.9 and
`8.6, respectiveiy. Also, carbachol-evoked contractions of
`guinea pig detrusor muscle cells were antagonized by
`YM—905, tolterodine, oxybutynin and atropine with pA2
`values of 7.1, 8.1, 7.4 and 8.4, respectively. When tested
`in anesthetized mice, both YM-Q05 and oxybutynin
`potently inhibited carbachol-induced increases in baldder
`pressure at doses of 0.1-1 mg/kg i.v. in contrast, only oxy-
`butynin was associated with potent inhibition of carba-
`chol-stimulated salivation at these doses (3, 4).
`The effects of YM-905 on colonic function have also
`
`been investigated in vitro and in vivo. The compound
`potently inhibited carbachol-induced guinea pig colon
`
`contractions in a competitive manner (pA2 = 7.5).
`inhibition of defecation induced by bethanechol, neostig-
`mine and nicotine in rats was observed at oral doses of
`
`YM-905 of 1-30 mg/kg. Title compound was also able to
`inhibit restraint stress-induced defecation (EDSO = 4.0
`mgikg po.) and diarrhea, a model of irritable bowel syn-
`drome (IBS). As above (3, 4), YM-905 was shown to
`inhibit M3 receptor—mediated intracellular Ca2+ mobiliza-
`tion in guinea pig colonic longitudinal muscle cells
`(pKa = 8.4) to a significantly greater extent than in mouse
`salivary gland cells (pKB = 7.4). The results from these
`latter studies indicate that YM-905 may also be useful in
`the treatment of colonic motor dysfunction such as in IBS
`(5, 6).
`‘(M905 is currently in phase II trials in the U.S. and
`Europe for the treatment of urinary incontinence (7).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2046 - 0002
`
`

`
`Drugs Fut 1999, 24(8)
`
`873
`
`Nippon Shinyaku
`
`Preregistered
`
`Anticholinergic: calcium antagonist
`
`Table I: Drugs in clinical trials for urinary incontinence (Praus Science Ensemble database).
`Compound
`Manufacturer
`Phase
`Mechanism of Action
`1. inaperisone HCI
`Hokuriku; Yamanouchi
`Preregistered
`Muscle relaxant
`. (Fiiran, Inapen)
`2. Temiverine HCI
`(Urespan)
`3. Darilenacin
`4. Duloxetine oxalate
`5. (S)-Oxybutynin
`S. I-(HP-197
`7. NC-1800
`9. NS-49
`9. YM-905
`10. ZD-6169
`11. Ftesiniferatoxin
`12. Saredutant
`13. HCT-1026
`
`Pfizer
`Lilly, Shionogi
`Sepracor
`Kyorin
`Nippon Cherniphar
`Nippon Shinyaku; Sanofi Synthélabo; Abbott
`Yamanouchi
`Astrazeneca
`Afferon; Mundipharma
`Sanofi Synthélabo
`NicOx
`
`Phase III
`Phase III
`Phase llftll
`Phase II
`Phase I]
`Phase I!
`Phase ii
`Phase II
`Phase II
`Phase II
`Phase Ilil
`
`Muscarinic M3 antagonist
`5-HT and NE reuptake inhibitor
`Anticholinergic
`Muscarinic M1 and M3 antagonist
`Centratly acting agent
`oc,A- adrenoceptor agonist
`Muscarinic M3 antagonist
`Potassium channel activator
`Vanilloid compound"
`Tachykinin NK2 antagonist
`Nitric oxide donor
`
`0
`
`N
`
`: 7
`
`CH3
`
`‘Hm
`
`0 H30 CH3
`
`K (CH3
`O \
`\ “x/C”:
`
`-
`
`HCI
`H O2
`
`H0
`
`H3C
`
`\
`
`2
`H N
`
`y\
`
`0/\/\N’ 3
`CH
`
`H
`
`I
`2
`co H
`co
`
`HO
`
`0
`
`§ N
`F
`V
`
`CH3
`
`0
`
`N'[:;\N
`(6)
`
`E?
`
`2
`
`CO H
`
`H
`
`,N
`H3C\
`’/S\\
`
`if
`
`OH
`F
`
`NH?
`
`(8)
`
`“Cl
`
`
`
`C!
`
`(1 2)
`
`Cl
`
`*De5ensitizer of overactive afferent neurones
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2046 - 0003
`
`

`
`874
`
`Manutacturer
`
`Yamanouchi Pharmaceutical C0,. Ltd. (JP).
`
`References
`1. Takeuchi, M., Naito, R., Yonetoku. Y., Ikeda. K., Isomura, Y.
`1,2,3,4-Tetrahydro-2-isoquinotinecarboxytate derivatives: A
`novel class of selective muscarinic antagonists.
`tit. 213th AC5
`Natl Meet (April 13-17, San Francisco) 1997. Abst MEDI 046.
`
`2. Takeuchi, M.. Naito. R. Hayakawa, M. et al. (Yamanouchi
`Pharmaceutical Co. Ltd.). Novet qutnuctidine derivs. and medici-
`nal cornpsn. thereof. EP 801067, W0 9620194.
`
`3. lkeda, K., Kobayashi. S.. Suzuki, M.. Miyata, K., Takeuchi, tu‘|.,
`Yamada, T., Honda. K. Effect of YM905, a novel muscarinic
`receptor antagonist, on salivary gland and btadden Jpn J
`Pharmacot 1998, 76(Supp|. 1): Abst P-442.
`
`YM-905
`
`4. lkeda, K., Suzuki. M., Kobayashi, S., Takeuchi. M., Miyata, K.,
`Yamada, T., Honda, K. YM905, a novel antimuscarinic agent dis-
`plays tissue preference for the urinary bladder M3 receptor.
`FASEB J 1999, 13(4, Part 1): Abs! 157.8.
`
`5. Suzuki, M., lkeda, K., Kobayashi, 5., Miyata, K., Takeuchi, M.,
`Yamada, T., Honda, K. Preventive effect of YM905 on stress—
`induced defecation and diarrhea in rats through the muscarinic
`receptor antagonism. Jpn J Pharmaco! 1998, 76(Supp|. 1): Abst
`P-443.
`
`6. Kobayashi, 3., lkeda, K., Suzuki, M., Miyata, K., Yamada, T.,
`Honda. K. Antagonist protites of the novet antimuscarinic agents
`YM905 and darifenacin in the digestive tract. FASEB J 1999,
`135. Part 2): Abst 626.4.
`
`7. YM-905 development status. Yamanouchi Pharmaceutical
`C0,, Ltd. Company Communication July 8, 1999.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2046 - 0004