Synthesis and NK1/NK2 receptor activity of substituted-4(Z)-(methoxyimino)pentyl-1-piperazines

Article abstract of DOI:10.1016/S0960-894X(00)00464-9

A series of 5-[(3,5-bis(trifluoromethyl)phenyl)methoxy]-3-(3,4-dichlorophenyl)-4(Z)-(meth oxyimino)pentyl-1-piperazines was prepared and their affinity for the NK₁ and NK₂ receptors investigated. Compounds 7f, 10o, 10r, and 10s were

Full text of DOI:10.1016/S0960-894X(00)00464-9

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2333±2335
Synthesis and NK1/NK2 Receptor Activity of
Substituted-4(Z)-(methoxyimino)pentyl-1-piperazines
Pauline C. Ting,* Joe F. Lee, John C. Anthes, Neng-Yang Shih and John J. Piwinski
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-1300, USA
Received 9 June 2000; accepted 7 August 2000
AbstractÐA series of 5-[(3,5-bis(tri¯uoromethyl)phenyl)methoxy]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl-1-piperazines
was prepared and their anity for the NK1 and NK2 receptors investigated. Compounds 7f, 10o, 10r, and 10s were found to be our
most potent inhibitors. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Biological screening5 of directed targets and synthetic
Substance P (SP), neurokinin A (NKA), and neurokinin
B (NKB) are members of a family of neuropeptides that
share a common C-terminal sequence of Phe-X-Gly-
Leu-Met-NH2 and are found throughout the central
and peripheral nervous systems.1 These peptides exert
their biological e€ect through three neurokinin receptors
(NK1, NK2, and NK3), which are each G-protein linked
to secondary messenger systems. Although each neurokinin
can act as an agonist at all three receptor subtypes,
substance P (SP), neurokinin A (NKA), and neurokinin
B (NKB) have the highest anity for the NK1, NK2, and
NK3 receptor, respectively.2 The neurokinins may play
an important role in a number of disease states including
migraine, emesis, pain, arthritis, depression, anxiety,
and asthma.3 In particular, it is believed that both SP and
NKA are responsible for the excessive mucus secretion,
airway constriction, and plasma extravasation found in
the pathology of asthma.4 Therefore, our goal was to dis-
cover a compound which could block both the NK1 and
NK2 receptors as a therapy for the treatment of asthma.
intermediates in the program identi®ed oxime 1 to be a
potent dual NK1 and NK2 receptor antagonist.6 In this
communication, we describe a series of analogues in
which the piperidine ring has been replaced by an array
of substituted piperazines.
Results and Discussion
The target piperazines 7a±f were prepared as the race-
mates by the synthetic route shown in Scheme 1.7 1,4-
Addition of ethyl 1,3-dithiolane-2-carboxylate (2) to
methyl trans-3,4-dichlorocinnamate gave the diester 3.8
Reduction of the diester 3 with lithium aluminum
hydride and selective protection of the less hindered
primary alcohol a€orded the t-butyldimethylsilyl ether
4. Alkylation of alcohol 4 with 3,5-bis(tri¯uoromethyl)
benzyl bromide and removal of the silyl protecting
group yielded compound 5. Hydrolysis of the dithiane 5,9
treatment with methoxylamine,10 and Swern oxidation11
provided aldehyde 6. Reductive amination12 with alde-
hyde 6 produced the piperazines 7a±f.
The biological activity of piperazines 7a±f are summarized
in Table 1. These results indicate that the unsubstituted
piperazine 7a, the alkylsubstituted piperazines 7b and 7c,
and the arylsubstituted piperazines 7d and 7e all bind to
the NK1 receptor in favor of the NK2 receptor. In this set
of analogues, only the (pyrrolidinocarbonylmethyl)piper-
azine 7f stands out as a dual NK1/NK2 antagonist.
Additional analogues based on the (pyrrolidinocarbonyl-
methyl)piperazine lead structure 7f are reported in
*Corresponding author. Tel.: +1-908-740-3534; fax: +1-908-740-
7152; e-mail: pauline.ting@spcorp.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00464-9

2334
P. C. Ting et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2333±2335
Table 1. NK1 and NK2 antagonistic activity of the piperazines 7a±f
Table 2. These compounds were prepared by reductive
amination of key aldehyde 6 with TROC-protected
piperazine. Removal of the TROC moiety with zinc
under bu€ered pH conditions avoided oxime iso-
merization which was observed under acidic condi-
tions.13 The analogues 10a±k in Table 2 include a broad
range of variation at the terminal amine position. Alkyl-
ation of piperazine 7a in a parallel synthesis manner14 gave
target analogues 10a±k. Relative to the standard 7f, none
of the piperazine analogues 10a±k shows improved
potency as a dual NK1/NK2 antagonist.
Compd
R
NK1
Ki (nM)a
NK2
Ki (nM)a
7a
7b
7c
7d
7e
7f
H
Me
Cyclohexyl
Ph
30
61
53
181
70
14
738
200
128
978
217
21
The analogues 10m±w focus on a more speci®c struc-
ture±activity study of 7f. Replacement of the pyrrolidine
ring 7f with the smaller azetidine ring as in 10m or 10n
retains both NK1 and NK2 potency. The 3-position of
pyrrolidine can be substituted with a hydroxy moiety as
2-Pyrimidinyl
N-PyrrolidinylCOCH2
aValues are means of two experiments.
Table 2. NK1 and NK2 antagonistic activity of the piperazines l0a±w
Compd
R
NK1
Ki (nM)
NK2
Ki (nM)
Compd
R
NK1
Ki (nM)a
NK2
Ki (nM)a
10a
82
62
82
208
259
170
7f
14 (Æ7)
23 (Æ5)
22 (Æ5)
21 (Æ7)
33 (Æ8)
31 (Æ3)
10b
10c
10m
10n
(iPr)2N
10d
39
382
10o
16 (Æ4)
30 (Æ10)
10e
10f
10g
125
113
20
>680
368
10p
10q
10r
9 (Æ2)
14 (Æ2)
14 (Æ4)
48 (Æ25)
95 (Æ26)
13 (Æ2)
266
10h
10i
24
409
566
10s
10t
13 (Æ4)
24 (Æ6)
24 (Æ6)
26 (Æ8)
125
10j
136
136
>680
477
10u
10v
13 (Æ3)
38 (Æ21)
52 (Æ8)
10k
47 (Æ24)
10w
19 (Æ4)
28 (Æ6)
aValues are the means of three experiments; standard deviation is given in parentheses.

P. C. Ting et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2333±2335
2335
Figure 1. (a) LiN(TMS)2, THF, 78ꢀC, methyl trans-3,4-dichlorocinnamate, 87%; (b) LiAlH4, THF, 0ꢀC±23ꢀC, 92%; (c) t-BuMe2SiCl, Et3N,
DMAP, THF, 0ꢀC±23ꢀC, 96%; (d) KN(TMS)2, THF, 3,5-bis(tri¯uoromethyl)benzyl bromide, 0ꢀC±23ꢀC, 88%; (e) HF, CH3CN, 100%; (f)
Hg(ClO4)2, CaCO3, THF, H2O, 100%; (g) MeONH2-HCl, NaOAc, EtOH, H2O, Á, 58% of Z isomer and 25% of E isomer; (h) ClCOCOCl,
DMSO, CH2Cl2, Et3N, 100%; (i) substituted piperazine, NaCNBH3, CF3CH2OH, 3 A sieves, 20±40%.
References and Notes
in 10o and maintain biological activity. However, the
larger acetamide group as in 10p or the dimethylamino
group as in 10q both tend to decrease NK2 potency but
not NK1 potency. The 2-position of the pyrrolidine is
tolerant to substitution by a hydroxymethyl moiety as
in the stereoisomers 10r and 10s or a carboxamide moiety
as in 10t and retains the dual neurokinin antagonist pro-
®le. In comparison to the hydroxypiperidine analogue
10u, the hydroxymethylpiperidine 10v shows a slight
decrease in both NK1 and NK2 potency. The morpholine
analogue 10w possesses potent dual NK1/NK2 activity.
1. Otsuka, M.; Yoshioka, K. Physiolog. Rev. 1993, 73, 229.
2. Regoli, D.; Boudon, A.; Fauchere, J-L. Pharmacolog. Rev.
1994, 46, 551.
3. Longmore, J.; Swain, C. J.; Hill, R. G. Drug News Perspect.
1995, 8, 5.
4. Maggi, C.; Giachetti, A.; Dey, R.; Said, S. Physiolog. Rev.
1995, 75, 277.
5. Binding data are the average of two or three independent
determinations. Receptor binding assays were performed on
membrane preparations containing recombinant human NK1
or NK2 receptors in CHO cells. [3H]Sar SP and [3H]NKA were
used as the ligands for the NK1 and NK2 receptor assays
respectively, at the experimentally derived Kd values. Ki values
were obtained according to the Cheng and Prusso€ equation.
6. Reichard, G. A.; Ball, Z. T.; Aslanian R.; Anthes, J. C.; Shih,
N.-Y.; Piwinski, J. P. Bioorg. Med. Chem. Lett. 2000, 10, 2329.
Conclusion
In conclusion, we have found that the 4-hydroxy-4-
phenylpiperidine ring of compound 1 can be replaced
by a totally di€erent structural subunitÐthe (pyrrolidi-
nocarbonylmethyl)piperazine 7f. Modi®cation of the
pyrrolidine ring of 7f with a hydroxy group retains bio-
logical activity, and analogues such as 10o, 10r, and 10s
are equipotent to 1 as a dual NK1/NK2 antagonist.
Further structure±activity relationship studies will be
reported in future publications.
1
7. All synthesized compounds were fully characterized by H
NMR, 13C NMR, and high-resolution mass spectroscopy.
8. Grobel, B. T.; Seebach, D. Synthesis 1977, 357.
9. Bernardi, R.; Ghiringhelli, D. J. Org. Chem. 1987, 52, 5021.
10. The E and Z oxime isomers were separated by ¯ash chro-
matography on silica gel.
11. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2480.
12. Borch, R. F.; Berstein, M. D.; Dupont Durst, H. J. Am.
Chem. Soc. 1971, 93, 2897.
13. Just, G.; Grozinger, K. Synthesis 1976, 457.
14. Our parallel synthesis procedure was to react 11 di€erent
amines with bromoacetyl bromide in separate vials and sub-
sequently treat with piperazine 7a. The reaction mixtures
underwent water work up, extraction, and analysis by mass
spectroscopy.
Acknowledgements
We would like to thank Mr. Z. Zhan and Mr. Christian
Richard for conducting the NK1 and NK2 receptor
binding assays.