Pergamon
`Bioorganic & Medicinal Chemistry Letters, Vol. 7, No. 3, pp. 347-350, 1997
`Copyright © 1997 Elsevier Science Ltd
`Printed in Great Britain. All rights reserved
`0960-894X/97 $17.00 + 0.00 PII: S0960-894X(96)00623-3
`STUDIES ON THE ACTIVE CONFORMATION OF NK1 ANTAGONIST CGP 49823. PART 1.
`SYNTHESIS OF CONFORMATIONALLY RESTRICTED ANALOGS.
`Siem J. Veenstra*, Kathleen Hauser and Claudia Betschart§
`Research Deparm~ent, Pharmaceuticals Division. CIBA-GEIGY AG, CH-4002 Basel, Switzerland. Fax: +41 61 696 33 35;
`§) Present address: Ciba-Geigy Japan Ltd. International Research Laboratories, 10-66 Miyuki-cho, Takarazuka 665, Japan.
`Abstract. Five conformationally restricted analogs of CGP 49823 have been synthesized. Comparison of their
`in vinv activities indicates an active conformation of CGP 49823 in which the two aromatic rings of the
`benzyl and the benzoyl groups are in proximity of each other. © 1997, Elsevier Science Ltd. All rights reserved.
`In earlier publicationsl, 2 we described the discovery and the structure-activity relationship (SAR) of CGP
`49823 ((+)-1, Chart), a potent, centrally and orally active NK1 receptor antagonist. It was shown that both the
`3,5-disubstituted tertiary benzamide and the C-2 benzyl substituent moieties are particularly important for high
`binding affinity to the NK1 receptor. This benzyl substituent is optinaal in terms of the distance between the
`aromatic moiety and the piperidine ring. The benzyl group may contain lipophilic substituents at 3- and/or 4-
`positions. The substituent at C-4 seems less critical for high binding affinity to the NK1 receptor, since it may be
`replaced by much smaller groups, such as acetamide 1.
`In this paper we wish to present our studies designed to determine the contbrmation of the C-2 benzyl side
`chain when bound to the NK1 receptor. For this purpose two types of restricted analogs of (+)-1 were
`synthesized. The conformational freedom of the benzyl group was reduced via the introduction of benzylic
`methyl substituent like in 2 and 3. In the compounds 4, 5 and 6 the position of the beuzylic phenyl ring is fixed
`by an additional bridging methylene group.
`Chart
`0 ~F'R2 2
`0
`(+)-1, CGP 49823 2 3
`R~"N ).f...R2 R, N N- 'k....T,,~" N D H ii.i ',~ H "rf ''n2 o .a2 o o
`4 5 6
`*) Fax: +41 61 696 33 35," e-mail: sienl.veenstra(~ chbs.mhs.ciba.conl
`RI= CH2 x~N
`R2= ~
`347
`HELSINN EXHIBIT 2046
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
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`348 S.J. VEENSTRA et al.
`Chemistry. Compounds 2 and 3 were synthesized according to Scheme 1. Ketoester 8, prepared from 7, was
`condensed with [3-alanine ethyl ester and subsequently cyclized in a Dieckmann-type ring closure to give 93.
`Reduction with magnesium in methanol, decarboxylation in refluxing aqueous HC1 followed by acylation with
`3,5-dimethylbenzoyl chloride, gave a 1:1 mixture of the 4-piperidones 10 and 11. Both diastereomers were
`separated by chromatography on silica gel. An X-ray analysis of ketone 10 (Fig.) 4 proved its relative
`stereochemistry. Reductive amination of 10 and 11 respectively with quinolin-4-yl-methylamine 5 gave in each
`case a ca. 1:1 mixture of cis- and trans-substituted aminopiperidines, from which 2 and 3 were isolated by
`chromatography on silica gel, respectively.
`Scheme I
`[~ ~r ~ b ~ c,d COCI a • CO2Et I~ 94% 45% 49%
`OH 3 CH 3 H (~H3
`7 8 9
`H3C % J~
`O H~N.~ e,d P 2 I
`22%
`10 O + G~
`O e,d • 3
`21%
`11 O
`Fig. X-ray crystal structure of 10.
`Reagents and conditions: (a) malonic acid monoethyl ester, BuLi, THF6; (b) i: H2NCH~CH2CO2Et, toluene, azeotropical removal
`of water; ii: NaOEt, EtOH, reflux; (c) i: Mg, MeOH, 45°C; ii: 6N HCI, reflux; iii: 3,5-dimethylbenzoyl chloride, CH2C12 aq.
`NaHCO3; (d) chromatographic separation on silica gel; (e) i: quinolin-4-yl-meOlylamine, toluene; ii: NaCNBH 3.
`The key bridged intermediates 14, 17 and 18, required for the synthesis of targets 4, 5 and 6, were
`synthesized according to Scheme 2. The starting material 12 was obtained by a literature procedure 7 followed by
`protection of the carbonyl function as a 1,3-dioxolane. Replacement of the N-benzyl protective group with the
`3,5-dimethylbenzoyl moiety and elimination of the hydroxyl group via its tosyl ester gave the olefm 13.
`Palladium catalyzed reductive arylation of the double bond with iodobenzene 8 tbllowed by deprotection of the
`carbonyl function yielded the ketone 14. The unsaturated ketone 17 was synthesized by the following procedure.
`Oxidation of the alcohol 12 and replacement of the benzyl group with the 3,5-dimethylbenzoyl moiety gave
`ketone 15, which was converted to the enol triflate 169. Palladium catalyzed coupling with PhZnC110 gave, after
`acid hydrolysis, the unsaturated ketone 17. The highly stereoselective palladium catalyzed hydrogenation of 17
`gave 18 in excellent yield. The two step reductive amination procedure of ketones 14, 17 and 18 with quinolin-4-
`yl-methylamine 5 (in analogy to Scheme 1) tailed, presumably due to steric hindrance.
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`The active conformation of CGP 49823--I 349
`Scheme 2
`"N
`a,b,c,d) O.-.~.~N 1~ A r .~ Ar = O 21% 74%
`"Bn O
`12 13 14 O
`72%~ g,a,b
`CO h iJ a ) 0 • 0 ) 0 O 98% ..~Ar 56% .[l. Ar 54%
`O O "rr "Ar "r[" Ar
`15 16 17 0 18 0
`Reagents and conditions: (a) Pal/C, H 2, MeOH; (b) 3,5-dimed~ylbenzoyl chloride, NEt3, CHzCI2, DMAP; (c) THF, BuLi, TsCI; (d)
`tBuOK, DMSO; (e) Phi, Pd(OAc)2, PPh3, Bu4NI, HCOOK, DMF; (f) 6N HCI aq., THF; (g) DCC, H3PO4, DMSO; (h) LiN(iPr) 2,
`HMPT, THF, PhN(SO2CF3)2; (i) PhZnCl (prepared in situ from PhLi and ZnCI2), Pd(PPha)4, THF.
`An alternative five step procedure leading to 4, 5 and 6 was therefore devised and is exemplified by the
`conversion of 14 to 4 (Scheme 3). Reduction of the carbonyl function gave a ca. 2:3 mixture of the axial and
`equatorial alcohols, respectively. After conversion to their respective mesylates, the desired axial derivative 19
`was purified via chromatography on silica gel. Correct stereochemical assignment was assured via NMR studies.
`Reaction of 19 with lithium azide in DMF gave 20, which was reduced to the amine 21 by catalytic
`hydrogenation. Conversion to the Schifl's base of quinoline-4-carboxaldehyde by azeotropic removal of water
`and subsequent NaBH4 reduction yielded the 6-exo-phenyl-8-aza-bicyclo[3,2,1]octanyl amine derivative 4. The
`endo epimer 6 and the unsaturated 6-phenyl-8-azabicyclo[3,2,1]-oct-6-enylamine derivative 5 were prepared in a
`similar way from 18 and 17, respectively.
`Scheme 3
`) • • ) 4
`33% ~ N '~ Ar 98% N 92% H~ N 66%
`19 O 2O O 21 O
`Reagents and conditions: (a) NaBH4, EtOH; (b) MsCI, NEt3, CH2C12; (c) separation via chromatography on silica gel; (d) LiN~,
`DMF; (e) 10% Pal/C, H 2, MeOH; (I3 PPh3, THF, H2 Ol 1; (g) qumoline-4-cm-boxaldehyde, toluene.
`Table Compound IC50 [nM] 12
`(+)-1 12
`(_+)-2 3O
`(_+)-3 23OO
`(+)-4 44
`(+)-5 1000
`(-+)-6 640
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`350 S.J. VEENSTRA et al.
`Results and discussion. The methyl substituted analog 2 has a ca. 80 times higher affmity to the NKI receptor 12
`than its diastereomer 3 (Table), and reaches the potency of (+)-1. A common phenomenon of N-acyl-2-alkyl
`piperidines is the axial position of the C-2 alkyl substituent 13, this is confirmed by the X-ray structure of 10. The
`C-2 benzyl group of (+)-1 may rotate, but rotational conformers, which have a hydrogen atom (being the
`smallest substituent) positioned above the piperidine ring are strongly preferred, thus minimizing 1,3-diaxial
`interactions. The introduction of a methyl group at the benzylic position as shown in the diastereomers 2 and 3
`will restrict the rotational freedom of the benzyl group to effectively one rotational conformer, where the
`hydrogen atom lies above the piperidine ring and the phenyl ring is either positioned towards the amide
`functionality (2) or protrudes out in space (3).
`Comparison of the binding affinities of the bridged analogs 4, 5 and 6 provides a sinailar picture (Table). The
`exo derivative 4, with the phenyl ring positioned towards the amide functionality, shows the highest affinity to
`the NKI receptor. Compounds 5 and 6 are substantially weaker.
`In conclusion, two types of contbrmationally restricted analogs of (+)-1, either with an additional methyl
`group at the benzylic position of the side chain, or with a bridging methylene group, as in the 8-aza-
`bicyclo[3,2,1]octanes, were synthesized. The comparison of their relative binding affinities to the NKI receptor
`produced strong evidence for an active conformation of (+)-1, where the benzyl side chain is oriented towards
`the 3,5-dimethylbenzamide group.
`Acknowledgement: We wish to thank Ursula Btitzberger, Priska Schmid and Ronny Haener tbr technical
`assistance, Grety Rihs for X-ray analysis and Dr. Tammo WinNer for NMR spectroscopical analysis.
`References and notes.
`(1) Ofner, S.; Hauser, K.; Schilling, W.; Vassout, A.; Veenstra, S.J. Bioorg. Med. Chem. Lett. 1996, 6, 1623.
`(2) Veenstra, S.J.; Hauser, K.; Schilling, W.; Betschart, C.; Ofner, S. Bioorg. Med. Chem. Lett. submitted.
`(3) (a) Becker, H. G. 0. J. Prakt. Chem. 1961, 284, 294. (b) Schultz, A.G.; Shannon, P.J.; Tobin, P.S.J.
`Org. Chem. 1979, 44, 291.
`(4) Detailed X-ray crystallographic data for 10 have been deposited at the Cambridge Crystallographic Data
`Centre.
`(5) Work, T. S. J. Chem. Soc. 1942, 426.
`(6) Katagiri, N.; Kato, T.; Nakano, J. Chem. Pharm. Bull. 1982, 30, 2440.
`(7) Markwell, R. E.; Hadley, M. S.; Blaney, F. E. EP 95262 (1983).
`(8) (a) Brunner, H.; Kramler, K. Synthesis 1991, 12, 1121. (b) Larock, R.C.; Johnson, P.L.J. Chem. Soc.
`Chem. Commun. 1989, 18, 1368.
`(9) McMurry, J.E.; Scott, W.J. Tetrahedron Lett. 1983, 24, 979.
`(10) McCague, R. Tetrahedron Lett. 1987, 28, 701.
`(i 1) PPh3 was used for reduction of the azide functionality in the preparation of 5.
`(12) For experimental details see: Bittiger, H. and Heid, J. "The retina, a part of the central nervous system
`with a very high density of 3H-Substance P binding sites", in Substance P - Dublin 1983, Proc. Int. Syrup.
`(1983), pp. 198-199, Skrabanek, P.; Powell, D., Eds.; Boole Press Ltd.; Dublin, 1983.
`(13) (a) Paulsen, H.; Todt, K.; Ripperger, H. Chem. Ber. 1968, 101, 3365. (b) Chow, Y.L.; Colon, C.J.; Tam,
`J.N.S. Can. J. Chem. 1968, 46, 2821.
`(Received in Belgium 9 November 1996; accepted 26 December 1996)
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