Synthesis of substituted 4(Z)-(methoxyimino)pentyl-1-piperidines as dual NK1/NK2 inhibitors

Article abstract of DOI:10.1016/S0960-894X(00)00702-2

The NK₁ and NK₂ receptor activity of a series of 5-[(3,5-bis(trifluoromethyl)phenyl)methoxy]-3-(3,4-dichlorophenyl)-4(Z)- (methoxyimino)pentyl-1-piperidines was evaluated. Compounds 11d, 11e, 11f, 12a, and 12k were found to be our most potent inhibitors.

Full text of DOI:10.1016/S0960-894X(00)00702-2

Bioorganic & Medicinal Chemistry Letters 11 (2001) 491±494
Synthesis of Substituted 4(Z)-(Methoxyimino)pentyl-1-piperidines
as Dual NK1/NK2 Inhibitors
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 1November 2000; accepted 4 December 2000
AbstractÐThe NK1 and NK2 receptor activity of a series of 5-[(3,5-bis(tri¯uoromethyl)phenyl)methoxy]-3-(3,4-dichlorophenyl)-
4(Z)-(methoxyimino)pentyl-1-piperidines was evaluated. Compounds 11d, 11e, 11f, 12a, and 12k were found to be our most potent
inhibitors. # 2001Elsevier Science Ltd. All rights reserved.
Introduction
The tachykinins are 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 system.1 There exists three G-protein linked
neurokinin receptors (NK1, NK2, and NK3) through
which the biological e€ects are transmitted. Although
each neurokinin can act as an agonist at all three
receptors, 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 neuro-
kinins may play an important role in several disease
states, which include migraine, emesis, pain, arthritis,
depression, anxiety, and asthma.3 Our research interest
lies in the theory that both SP and NKA are responsible
for the excessive mucus secretion, airway constriction,
and plasma extravasation found in the pathology of
asthma.4
Results and Discussion
The substituted 4(Z)-(methoxyimino)pentyl-1-piperidines
were prepared as the racemates by the synthetic route
outlined in Scheme 1. Reductive amination6 of N-benzyl-
4-piperidone (2) and subsequent hydrogenation7 provided
amine 3. Coupling of amine 3 with 1-[[3,5-bis(tri¯uoro-
methyl)phenyl]methoxy]-3-(3,4-dichlorophenyl)-5-formyl-
2(Z)-pentanone O-methyl-oxime (4)8 produced the ana-
logues 5.9 The synthesis of compounds 9 began with the
protection of 4-hydroxymethylpiperidine (6) as its t-BOC
derivative. Swern oxidation10 of 6 followed by reductive
amination and acid catalyzed removal of the t-BOC
group a€orded amine 8. Addition of amine 8 to aldehyde
4 yielded the targets 9.
Our goal was to design and synthesize a compound that
will block both the NK1 and NK2 receptors as a means
of alleviating asthma. Compound 1 was identi®ed as a
potent dual NK1 and NK2 receptor antagonist.5 In this
communication, we describe a series of analogues that
have diverse substituents at the 4-position of the piper-
idine ring.
The NK1 and NK2 biological activity of piperidines
10a±f are reported in Table 1.11 Replacement of the
4-hydroxy-4-phenylpiperidine subunit of 1 with the
4-(carbon linked amide)piperidines 10a or 10b increases
NK1 potency, but appears to decrease NK2 potency.
*Corresponding author. Fax: +1-908-740-7152; e-mail: pauline.
ting@spcorp.com
0960-894X/01/$ - see front matter # 2001Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00702-2

492
P. C. Ting et al. / Bioorg. Med. Chem. Lett. 11 (2001) 491±494
Table 1. NK1 and NK2 antagonistic activity of the piperidines 10a±f
The 4-(nitrogen linked amide)piperidines 10c±e show
greatly reduced NK2 activity. In this set of racemic
analogues, only the hydroxyamino substituted piper-
idine 10f is equipotent to our lead structure 1.
Additional analogues that have a second piperidine or
pyrrolidine ring attached to the 4-position of the piper-
idine are summarized in Table 2. The piperidone 11a12
shows increased potency for both the NK1 and NK2
receptors relative to the 4-hydroxy-4-phenylpiperidine
1. Similarly, the corresponding pyrrolidone analogue
11f and the thiopyrrolidine analogue 11g both retain
this desired dual NK1/NK2 pro®le. In contrast, the
pyrrolidine analogue 11h reduces NK2 potency to a
much greater extent than NK1 potency. Introduction of
a hydroxy moiety on the piperidine ring as in 11b or the
pyrrolidine ring as in 11i retains NK1 and NK2 activity. A
carboxyamide group can also be added to the piperidine
ring as in 11d or the pyrrolidine ring as in 11e and produces
potent NK1 and NK2 receptor anity. However, a less
polar carboxyester substituent as in 11c or a carbamate
substituent as in 11j shows decreased biological activity.
Compd
R
NK1 Ki (nM)a
8 (Æ3)
NK2 Ki (nM)a
10a
67
10b
10c
10d
6 (Æ2)
1 8 Æ( 4)
112
59
144
137
In Table 3 our analogues that have a methylene linker
between the two piperidine rings are tabulated. The
parent piperidone 12a and the pyrrolidone analogue 12d
possess increased NK1 and NK2 potency relative to our
lead structure 1. The thiopiperidone 12c and the
reduced piperidine analogue 12b are slightly less active.
Alkylation at the a-position of the piperidone 12a gives
analogues 12e±h. Steric size appears to be detrimental to
biological activity as evident by the benzyl analogue
12e. Hydroxy groups are well-tolerated as in analogue
12h. When the second piperidine ring is a morpholine
ring as in 12i, NK1 activity is retained and NK2 activity
10e
44
146
10f
24 (Æ7)
16 (Æ8)
aValues are means of two experiments. If values are means of three
experiments, standard deviation is given in parentheses.
Scheme 1. (a) Substituted amine, NaCNBH3, CF3CH2OH,
3
A
sieves, 42±83%; (b) H2, Pd/C, MeOH, 83±100%; (c) 1-[[3,5-bis(tri-
¯uoromethyl)phenyl]methoxy]-3-(3,4-dichlorophenyl)-5-formyl-2(Z)-pentanone O-methyloxime, 3 A sieves, NaCNBH3, CF3CH2OH, 32±63%; (d)
(t-BOC)2O, CH2Cl2, 100%; (e) ClCOCOCl, DMSO, CH2Cl2, Et3N, 100%; (f) CF3COOH, CH2Cl2, 100%.

P. C. Ting et al. / Bioorg. Med. Chem. Lett. 11 (2001) 491±494
493
decreases slightly. Substitution at the 2-position of the
piperidine ring indicates that the hydroxyethyl side chain
of 12k is more active than the hydroxymethyl side chain
of 12j. Compounds 12l±p vary the size and polarity of
the moiety at the 3-position of the piperidine ring, and
none of these analogues are as potent as the piperidone
12a.
Table 3. NK1 and NK2 antagonistic activity of the piperidines 12a±p
Compd
R
NK1 Ki (nM)a
1 0 (Æ3)
NK2 Ki (nM)a
12 (Æ2)
Table 2. NK1 and NK2 antagonistic activity of the piperidines 11a±j
12a
12b
12c
36 (Æ23)
20 (Æ7)
26 (Æ4)
23 (Æ6)
Compd
R
NK1 Ki (nM)a
1 8 (Æ4)
NK2 Ki (nM)a
4 (Æ1)
11a
12d
12e
8 (Æ3)
21( Æ6)
11b
11c
1 4 (Æ3)
15 (Æ6)
69
91
117
20
12f
1 4 (Æ5)
26 (Æ7)
11d
1 3 (Æ4)
10 (Æ3)
12g
1
3
58
11e
11f
1 3 (Æ3)
9 (Æ2)
11 (Æ3)
7 (Æ2)
12h
12i
7 (Æ4)
16 (Æ8)
1 4 (Æ10)
39 (Æ11)
11g
1 6 (Æ3)
23 (Æ8)
12j
20
53
12k
1 3 (Æ3)
14 (Æ3)
11h
11i
36
4
195
12l
38
47
1
6
12m
50 (Æ30)
39 (Æ9)
11j
1 9 (Æ7)
67 (Æ19)
aValues are means of two experiments. If values are means of three
experiments, standard deviation is given in parentheses.
(continued on next page)

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P. C. Ting et al. / Bioorg. Med. Chem. Lett. 11 (2001) 491±494
Acknowledgements
Table 3 (continued)
Compd
R
NK1 Ki (nM)a
1 7 (Æ3)
NK2 Ki (nM)a
33 (Æ5)
The authors would like to thank Mr. Z. Zhan and Mr.
Christian Richard for conducting the NK1 and NK2
receptor binding assays.
12n
References and Notes
1. Otsuka, M.; Yoshioka, K. Phys. 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 Per-
spectives 1995, 8, 5.
12o
12p
25 (Æ10)
1 6 (Æ1
27 (Æ18)
4. Maggi, C.; Giachetti, A.; Dey, R.; Said, S. Phys. Rev. 1995,
75, 277.
28 (
)
Æ7)
5. Reichard, G. A.; Ball, Z. T.; Aslanian, R.; Anthes, J. C.; Shih,
N.-Y.; Piwinski, J. P. Bioorg. Med. Chem. Lett. 2000, 10, 2329.
6. Borch, R. F.; Bernstein, M. D.; Dupont Durst, H. J. Am.
Chem. Soc. 1971, 93, 2897.
aValues are means of two experiments. If values are means of three
experiments, standard deviation is given in parentheses.
7. Hartung, W. H.; Simono€, R. Org. React. 1953, 7, 263.
8. Ting, P. C.; Lee, J. F.; Anthes, J. C.; Shih, N.-Y.; Piwinski,
J. P. Bioorg. Med. Chem. Lett. 2000, 10, 2333.
Conclusion
1
9. All synthesized compounds were fully characterized by H
In conclusion, the left hand region of our lead NK1/
NK2 inhibitor structure 1 appears to be quite tolerant
to structural modi®cations. We have found that the
4-hydroxy-4-phenyl substituent of piperidine 1 can be
replaced by a piperidone ring as in compounds 11a and
12a. From this structure±activity relationship study,
several diverse analogues including compounds 11d,
11e, 11f, and 12k were found to be our most potent dual
inhibitors. The results of our e€orts to further optimize
the biological pro®le of this series of dual NK1/NK2
antagonists will be forthcoming.
NMR, 13C NMR, and high-resolution mass spectroscopy.
10. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2480.
11. 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.
12. Miller, S. C. W.O. Patent 94/10 146, 1994; Chem. Abstr.
1994, 122, 105675.