Cyclic urea derivatives as potent NK1 selective antagonists
`Ho-Jane Shue, a Xiao Chen, a Neng-Yang Shih, a,* David J. Blythin, a Sunil Paliwal, a
`Ling Lin, a Danlin Gu, a John H. Schwerdt, a Sapna Shah, a Gregory A. Reichard, a,/C160
`John J. Piwinski, a Ruth A. Duffy, b Jean E. Lachowicz, b Vicki L. Coffin, b Fei Liu, c
`Amin A. Nomeir, c Cynthia A. Morgan b and Geoffrey B. Varty b
`aChemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
`bCNS Biology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
`cDepartment of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road,
`Kenilworth, NJ 07033, USA
`Received 14 April 2005; revised 24 May 2005; accepted 25 May 2005
`Available online 12 July 2005
`Abstract—A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK 1 receptor
`antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are
`also described herein.
`/C2112005 Elsevier Ltd. All rights reserved.
`Substance P is a member of the tachykinin family of neu-
`rotransmitters that selectively binds to the NK 1 receptor.
`Substance P has been implicated in a number of patho-
`logical disorders in the central nervous system (CNS)
`and peripheral tissues,
`1,2 including pain, inflammation,
`depression, emesis and cough. 3–6 Consequently, an
`antagonist of the NK 1 receptor has potential therapeutic
`use in the treatment of cough, 6 inflammation,7 asthma,8
`pain,9 chemotherapy-induced emesis, 10 migraine,11 anxi-
`ety, and depression. 12 Recently, Emend was approved
`for the treatment of CINV (chemotherapy-induced nau-
`sea and vomiting), and several NK
`1 antagonists are in
`clinical trails for anxiety and depression. 13
`Herein, we report the discovery of novel cyclic urea
`derivatives 2 and 3 as potent and selective NK
`1 antago-
`nists that are orally active and have good CNS penetra-
`tion. These cyclic ureas provide structural novelty while
`possessing the minimal pharmacophoric elements of
`phenylglycinol-derived NK
`1 antagonists of type 1.14
`The racemic 4,4-disubstituted-2-imidazolidinones ( 2a–j)
`shown in Table 1 were prepared by the synthetic route
`illustrated in Scheme 1. 15 Alkylation of 3,5-bis(trifluo-
`romethyl)benzyl alcohol 4 with 2-iodo- N-methoxy-N-
`methylacetamide 5, which was prepared in acetone from
`its chloride derivative using sodium iodide, afforded
`Weinreb amide 6. The coupling of Weinreb amide 6 with
`phenyllithium gave the ketone 7 in excellent yield (80%).
`Treatment of ketone 7 with trimethylsilyl cyanide and
`ammonia in presence of zinc iodide afforded amine–
`nitrile intermediate 7a, which was subsequently reduced
`without isolation to give the diamine compound 8. The
`Bioorganic & Medicinal Chemistry Letters 15 (2005) 3896–3899
`0960-894X/$ - see front matter /C2112005 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.bmcl.2005.05.111
`* Corresponding author. Tel.: +1 908 740 3530; fax: +1 908 740
`7305; e-mail: neng-yang.shih@spcorp.com
`/C160Present address: Department of Chemistry, Pfizer Global Research
`and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105, USA.
`HELSINN EXHIBIT 2063
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 4
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`cyclization of diamine 8 in the presence of N,N0-carbon-
`yldiimidazole (CDI) afforded the unsubstituted urea
`compound 2a. An alternative four-step sequence to com-
`pound 2a from compound 4 in higher overall yield has
`previously been reported. 16 Treatment of compound 8
`with 1 equiv of ketone/aldehyde in the presence of a
`reducing agent, such as sodium triacetoxyborohydride,
`or an alkylating reagent, followed by CDI cyclization
`afforded the N-substituted cyclic ureas 2f–j. In order to
`determine the effect of the absolute stereochemistry on
`binding activity, compound 2a was resolved to the enan-
`tiomers 2b and 2c by chiral HPLC on a Daicel Chiralpak
`AD
`/C210column. The assignment of absolute configuration
`of enantiomer 2c was made based on the established chi-
`ral synthesis. 16 The chiral N-methylated compounds ( 2d
`and 2e) were prepared by alkylation of the chiral com-
`pound 2c with methyl iodide in the presence of sodium
`hydride in N,N-dimethylformamide.
`The in vitro NK 1 binding and in vivo NK 1 agonist-
`induced gerbil foot-tapping (GFT) inhibition data for
`4,4-disubstituted-2-imidazolidinones ( 2a–j) are listed in
`Table 1 . The NK
`1 binding assay determines the affinity
`of these compounds ( 2a–j) toward the NK 1 receptor
`while the GFT inhibition measures the potency of these
`compounds antagonizing an NK
`1 receptor-mediated
`CNS effect. As shown in Table 1 , the unsubstituted five
`membered urea analogue 2a exhibited good NK 1 bind-
`ing affinity ( Ki = 16 nM). It was noted that enantiomer
`2c (R-isomer) had higher affinity for the NK 1 receptor
`than the enantiomer 2b (S-isomer) (6 vs 330 nM). In
`addition, compound 2c was active in the GFT assay
`(54% inhibition of foot-tapping at 1 mg/kg po after a
`2 h pretreatment time) which demonstrated CNS pene-
`tration and NK
`1 antagonist activity. In order to under-
`stand the importance of the urea NH protons for
`affinity, the N-methyl derivatives of 2c were synthesized.
`When the hindered NH of the urea ring was methylated
`(2d), the binding affinity was greatly reduced
`(Ki = 94 nM). On the other hand, when the less hindered
`NH was methylated ( 2e), retention of the binding affin-
`ity was observed ( Ki = 8 nM). This suggested that the
`NH proton adjacent to the tertiary position of the cyclic
`urea is more important for NK
`1 receptor binding. Con-
`sequently, substitutions at the less hindered NH were
`further explored. We found that a polar amide side
`chain improved potency (e.g., 2f, Ki = 4 nM). Further
`increase in polarity from a neutral substitution to basic
`amino group containing side chains, significantly im-
`proved NK
`1 affinity and in some cases ( 2g and 2i)
`picomolar binding was achieved. Both the acyclic 2g
`and cyclic ( 2h–j) amine side chains were well tolerated
`and the position of the basic nitrogen did not significant-
`ly affect the binding ( 2g, Ki = 0.7 nM and 2j, Ki = 1 nM).
`The best representative of the amine side chain contain-
`ing compounds was analogue 2h, which bound with high
`affinity ( Ki = 1 nM) and produced good activity (68%
`inhibition) in the GFT assay.
`A series of racemic six-membered cyclic urea derivatives
`(3a–g) were prepared by the synthetic route shown in
`Scheme 2 15 and their biological data are listed in Table
`2. The chiral compounds 3a and 3b were prepared by
`Table 1. NK1 receptor binding affinity and GFT inhibition for
`compounds 2a–j
`Compounda R1 R2 NK1
`b Ki
`(nM)
`GFTb
`(%inh.)
`2a –H –H 16 NT c
`2b (S) –H –H 332 NT c
`2c (R)– H – H 6 5 4
`2d (R) –CH 3 –H 94 NT c
`2e (R) –H –CH 3 80
`2f –H 41 8
`2g –H 0.7 23
`2h –H 16 8
`2i –H 0.5 15
`2j –H 10
`a Unless defined as ( R)o r( S), the compounds in the table are racemic.
`b See Ref. 17–20.
`c NT = not tested.
`Scheme 1. Reagent and conditions: (a) KN(TMS) 2/THF, 0–25 /C176C,
`18 h, 60%; (b) PhLi/THF, /C078 /C176C, 1.5 h then rt, 80%; (c) TMSCN/
`ZnI2/THF, rt, 1 h, filtered, concd then NH 3/MeOH, 45 /C176C, 2 h then
`filtered, concd; (d) LiAlH 4/ether, /C078 /C176C then rt, 18 h, 25–35% from 7;
`(e) CDI/THF, rt, 18 h, 97%; (f) ketone, aldehyde/NaBH(OAc) 3/
`CH2Cl2, rt or NaBH 3CN/MeOH or alkyl halide/DMF.
`H.-J. Shue et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3896–3899 3897
`Page 2 of 4
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`the chiral HPLC separation of the racemic mixture 3a,b
`on a Daicel Chiralpak AS /C210column.
`As shown in Table 2 , the six-membered ureas also
`exhibited good NK 1 receptor binding affinities. Similar
`to five-membered urea derivatives, the activity of six-
`membered urea derivatives also resided mostly in the
`R-isomer, for an example, compound 3b (R-isomer,
`Ki = 9 nM) versus compound 3a (S-isomer, Ki =
`350 nM). However, compound 3b was found to be
`inactive in GFT assay. This may be due to a poorer
`pharmacokinetic profile of the latter. Based on the
`SAR of the five-membered ureas, the substitutions at
`the less hindered NH were subsequently explored in
`the six-membered series. The N-methyl derivative 3c
`and acetylpiperidine derivative 3d retained the binding
`while the pyran analogue 3e showed improvement in
`both binding ( K
`i = 3 nM), and in vivo activity (47%
`inhibition). As previously observed with five-mem-
`bered analogues, incorporation of basic amine side
`chains ( 3f,g) improved the binding, and in the case
`of methyl-piperidine analogue ( 3g), sub-nanomolar
`NK1 affinity ( Ki = 0.5 nM) was achieved. The analogue
`3g showed the best GFT activity (56% inhibition) in
`the six-membered urea series which was comparable
`to the most potent five-membered series analogues 2c
`and 2h.
`In conclusion, we have identified a novel series of cyclic
`urea derivatives of structures 2 and 3 as potent NK
`1
`antagonists. Several compounds in these series exhibit
`good NK 1 selectivity, are orally active and have good
`brain penetration. For example, compound 2c (SCH
`388714) showed an excellent selectivity (NK 2,
`NK3 >1 lM), good oral bioavailability (69% in rat)
`and it displayed very good brain penetration (brain/plas-
`ma ratio 4 in rat). Further details of the SAR effort to
`improve potency of this class of NK 1 antagonist will
`be reported in due course.
`References and notes
`1. Guard, S.; Watson, S. P. Neurochem. Int.1991, 18, 149.
`2. Otsuka, M.; Yoshioka, K. Physiol. Rev.1993, 73, 229.
`3. Lowe, J. A., III Med. Res. Rev.1996, 16, 527.
`4. Ho¨kfelt, T.; Pernow, B.; Wahren, J. J. Intern. Med.2001,
`249, 27.
`5. McLean, S. Med. Res. Rev.1996, 16, 297.
`6. Sekizawa, K.; Jia, Y. X.; Ebihara, T.; Hirose, Y.;
`Hirayama, Y.; Sasaki, H. Pulm. Pharmacol.1996, 9, 323.
`7. Seward, E. M.; Swain, C. J. Expert Opin. Ther. Patents
`1999, 9, 571.
`8. Maggi, C. A.; Giachetti, A.; Dey, R. D.; Said, S. I.
`Physiol. Rev.1995, 75, 277.
`9. Yonehara, N.; Yoshimura, M. Pain 2001, 92, 259.
`10. Gardner, C.; Perren, M. Neuropharmacology 1998, 37,
`1643.
`11. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri,
`M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.;
`Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattershall, F. D.;
`Rupniak, N. M. J.; Williams, A. R.; Rycroft, W.; Harg-
`reaves, R.; MacIntyre, D. E. J. Med. Chem.1998, 41, 4607.
`12. Saria, A. Eur. J. Pharmacol.1999, 375, 51.
`13. Duffy, R. A. Exp. Opin. Emerg. Drugs2004, 9,9 .
`Scheme 2. Reagent and conditions: (a) PhCH 2Br, Et 3N/THF/80 /C176C,
`48 h, 46%; (b) LDA/ICH 2CN/THF, /C078 /C176Ct o /C020 /C176C, 51%; (c) LAH/
`THF, /C078 /C176C to rt, 64%; (d) t-BOC-anhydride/20% Pd(OH) 2–C,
`H2, 50 psi, 18 h, 85%; (e) Ag 2O/DMF, 3,5-bis(trifluoromethyl)benzyl
`bromide, rt, 18 h, 64%; (f) HCl/Et 2O, rt, 18 h, 99%; (g) CDI/THF, 0–
`25 /C176C, 18 h, 48–63%; (h) ketone/HOAc/NaBH 3CN/MeOH, or CH 3I/
`K2CO3/DMF or R 2CH2Br/DMF.
`Table 2. NK1 receptor binding affinity and GFT inhibition for
`compounds 3a–g
`Compounda R1 R2 NK1
`b Ki
`(nM)
`GFTb
`(%inh.)
`3a (S) –H –H 350 NT c
`3b (R)– H – H 9 0
`3c –H –CH 3 14 18
`3d –H 91 6
`3e –H 34 7
`3f –H 22
`3g –H 0.5 56
`a Unless defined as ( R)o r( S), the compounds in the table are racemic.
`b See Ref. 17–20.
`c NT = not tested.
`3898 H.-J. Shue et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3896–3899
`Page 3 of 4
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`14. Swain, C. J.; Cascieri, M. A.; Owens, A.; Saari, W.;
`Sadowski, S.; Strader, C.; Teall, M.; Van Niel, M. B.;
`Williams, B. J. Bioorg. Med. Chem. Lett.1994, 4, 2161.
`15. For more experimental details see: Shih, N.-Y.; Shue,
`H.-J.; Reichard, G. A.; Paliwal, S.; Blythin, D. J.;
`Piwinski, J. J.; Xiao, D.; Chen, X. PCT Int. Appl. WO
`0144200, 2001.
`16. Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg,
`I.; Majmundar, S.; Wang, C.; Tiberi, R.; McPhail, A. T.;
`Piwinski, J. J.; Shih, N.-Y. Org. Lett.2003, 23, 4249.
`17. NK
`1 assay: Binding data are the average of two or three
`independent determinations. Receptor binding assays were
`performed on membrane preparations from CHO cells in
`which recombinant human NK 1 receptors were expressed.
`[3H]-Sar-Met Substance P was used as the ligand for the
`NK1 assay, at concentrations near the experimentally
`derived Kd value. Ki values were obtained using the Cheng
`and Prusoff equation.
`18. The NK 1 agonist GR73632 (3 pmol in 5 ll) was admin-
`istered centrally to female Mongolian gerbils via icv
`injection. Immediately following recovery from the anes-
`thesia, gerbils were placed into clear Plexiglas boxes for
`5 min, and the duration of foot tapping was measured.
`Foot tapping was defined as rhythmic, repetitive tapping
`of the hind feet. NK
`1 antagonists were administered orally
`in 0.4% methylcellulose in distilled water at a dose of 1 mg/
`kg (unless otherwise stated) at various pretreatment times
`prior to injection of GR73632. Data are expressed as a
`percent decrease (% inhibition) in the amount of time
`spent foot tapping compared to vehicle-treated controls.
`19. Cascieri, M. A.; Macleod, A. M.; Underwood, D.; Shiao,
`L.-L.; Ber, E.; Sadowski, S.; Yu, H.; Merchant, K. J.;
`Swain, C. J.; Strader, C. D.; Fong, T. M. J. Biol. Chem.
`1994, 269, 6587.
`20. Rupniak, N. M. J.; Williams, A. R. Eur. J. Pharmacol.
`1994, 265, 179.
`H.-J. Shue et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3896–3899 3899
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