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 eects 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 anity 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 aorded 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.
0960-894X/01/$ - see front matter # 2001Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00702-2