4,4-Disubstituted cyclohexylamine NK(1) receptor antagonists I.

Article abstract of DOI:10.1016/S0960-894X(02)00249-4

A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.

Full text of DOI:10.1016/S0960-894X(02)00249-4

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1755–1758
4,4-Disubstituted Cyclohexylamine NK1 Receptor Antagonists I
Jason M. Elliott,a,* Jose L. Castro,a Gary G. Chicchi,c Laura C. Cooper,a Kevin Dinnell,a
Gregory J. Hollingworth,a Mark P. Ridgill,a Wayne Rycroft,b Marc M. Kurtz,c
Duncan E. Shaw,a Christopher J. Swain,a Kwei-Lan Tsaoc and Lihu Yangd
aDepartment of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
bDepartment of Pharmacology, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
cDepartment of Biochemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
dDepartment of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 15 January 2002; revised 28 March 2002; accepted 9 April 2002
Abstract—A series of novel 4,4-disubstituted cyclohexylamine based NK1 antagonists is described. The effect of changes to the C1–
C4 relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identifica-
tion of compounds with high affinity and good in vivo duration of action. # 2002 Elsevier Science Ltd. All rights reserved.
Substance P (SP) is a member of the tachykinin family
of neuropeptides which binds selectively to the NK1
receptor. The release of SP has been implicated in the
pathogenesis of a wide range of disease conditions,
including neurogenic inflammation, transmission of
pain, emesis and depression.1
cyclohexane
2
suggests that the N-[3,5-bis(tri-
fluoromethyl)benzyl]phenylacetamide in 2 provides the
key elements for binding to the NK1 receptor; the
cyclohexane (which would be predicted to adopt a chair
conformation with the bulky C-1 substituent equatorial)
serves to deliver these elements. This paper describes the
initial work on optimisation of the N-[3,5-bis(tri-
fluoromethyl)benzyl]phenylacetamide and the stereo-
chemical requirements for NK1 binding.
Compounds were synthesised from ketones 3 by reduc-
tive amination with 4-(4-fluorophenyl)piperidine. In
most cases, the reactions were not stereoselective, lead-
ing to mixtures of isomers where the amine and linker L
were either cis- or trans- to one another (Scheme 1).
The key elements for high-affinity binding in known
NK1 antagonists (such as 1, hNK1 IC50 0.2 nM) are two
aromatic rings flanking
a
heteroatom.2 Targeted
screening has now identified the 1,1-disubstituted cyclo-
hexane 2 as a high affinity ligand (hNK1 IC50 0.34 nM).
Data (not shown) for binding of 2 to mutant receptors
show that it occupies the same site as antagonists such
as 1. Comparison of the structures of quinuclidine 1 and
Scheme 1. Reagents and conditions: (i) 4-(4-fluorophenyl)piperidine,
NaCN(BH3), ZnCl2, MeOH, rt or 4-(4-fluorophenyl)piperidine, NaB-
H(OAc)3, 1,2-dichloroethane, rt; (ii) separate isomers.
*Corresponding author. Fax: +44-1279-440390; e-mail: jason_elliott@
merck.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00249-4

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J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1755–1758
The syntheses of the ketones 3 with ester and amide
linkers are shown in Scheme 2. Dialkylation of methyl
phenylacetate with methyl acrylate, followed by in situ
cyclisation and ester hydrolysis gave the key acid 4.
Curtius rearrangement of acid 4 with diphenylphos-
phoryl azide gave the amine 5. Acid 4 and amine 5 were
used to prepare amides and esters. The syntheses of key
amine and acid components which are not commercially
available are shown in Scheme 3.
Reduction of the phenylglycine adduct 10 gave the cor-
responding a-hydroxymethyl derivative (Scheme 6).
Table 1 summarises the effect of modifications to the
amide linker of 2. Throughout, trans-isomers have
higher affinity than the corresponding cis-isomers. A
Protection of ketone 6, followed by DIBAL-H reduc-
tion, hydrolysis and further reduction gave the alcohol 7
(Scheme 4). Acylation with 3,5-bis(trifluoromethyl)-
benzoyl chloride introduced the ester linker. Methyle-
nation of this ester with dimethyl titanocene3 followed
by hydrogenation or hydroboration gave the corre-
sponding a-methyl and a-hydroxymethyl ethers.
Reductive amination of 6 followed by hydrogenation of
the nitrile led to the amine 8 as a mixture of cis-
and trans-isomers. Further reductive amination with
3,5-bis(trifluoromethyl)benzaldehyde and separation of
isomers gave individual cis- and trans-secondary amines.
Similarly, amine 8 was acylated with 3,5-bis(trifluoro-
methyl)benzoyl chloride and separated to give the
corresponding amides.
Compounds without a heteroatom in the linker were
prepared via a modified Julia coupling4 of the sulfone 9
(Scheme 5).
Scheme 4. Reagents and conditions: (i) HOCH2CH2OH, pTsOH,
PhCH3, reflux; (ii) DIBAL-H, PhCH3, ꢁ78 ꢀC; (iii) NaBH4, EtOH, rt;
(iv) 3,5-(CF3)2PhCOCl, CH2Cl2, rt; (v) HCl, H2O, acetone, reflux; (vi)
ꢀ
.
Cp2TiMe2, PhCH3, 90 C; (vii) BH3 THF, THF, rt; (viii) H2O2,
NaOH, THF, H2O, rt; (ix) H2, Pd/C, EtOAc, EtOH, rt; (x) 4-(4-
fluorophenyl)piperidine, NaCN(BH3), ZnCl2, MeOH, rt; (xi) H2, Pd/
C, HCl, MeOH, rt; (xii) 3,5-(CF3)2PhCHO, NaCNBH3, ZnCl2,
MeOH, rt; (xiii) separate isomers.
Scheme 2. Reagents and conditions: (i) methyl acrylate, NaH, DMF,
0 ꢀC to rt; (ii) LiOH, MeOH, THF, H2O, reflux; (iii) HCl, H2O, rt; (iv)
RNH2, 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC), 1-hydroxybenzotriazole (HOBT), Et3N, DMF, rt or RNH2,
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), Et3N, CH2Cl2,
rt; (v) (COCl)2, DMF, PhCH3, rt; (vi) ROH, DMAP, PhCH3, reflux;
(vii) (PhO)2PON3, Et3N, PhCH3, 90 ꢀC; (viii) HCl, H2O, reflux; (ix)
RCO2H, EDC, HOBT, Et3N, DMF, rt.
Scheme 5. Reagents and conditions: (i) 2,20-dithiobis(benzothiazole),
Bu3P, THF, rt; (ii) OXONE1, Al2O3, CHCl3, reflux; (iii) LiHMDS, 8-
phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde, THF, ꢁ78 ꢀC to
rt; (iv) HCl, H2O, acetone, reflux; (v) 4-(4-fluorophenyl)piperidine,
NaBH(OAc)3, 1,2-dichloroethane, rt; (vi) H2, Pd(OH)2, MeOH, rt.
Scheme 3. Reagents and conditions: (i) NaH, MeI, DMF, rt; (ii)
LiOH, THF, MeOH, H2O, rt; (iii) (PhO)2PON3, Et3N, PhCH3, 90 ꢀC;
(iv) HCl, Et2O, rt; (v) paraformaldehyde, NaHCO3, DMSO, 45 ꢀC.

J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1755–1758
1757
number of different linkers are tolerated, most notably
the amides 2 and 15, the amine 17 and ether 23. The
relatively poor affinity of the propyl linker 24 (hNK1
IC50 40 nM) shows that a heteroatom in the chain is
beneficial. This could be because the heteroatom intro-
duces a conformational bias which favours binding, or
due to participation of the heteroatom in a hydrogen
bond to the receptor.
The large substituent at the 1-position of the cyclohex-
ane locks the conformation of the ring, determining
which of the gem-substituents is axial and which is
equatorial.6 Thus, the 1-substituent indirectly deter-
mines the conformation of the key parts of the mole-
cule. The differences in affinity between the cis- and
trans-isomers for the compounds in Table 1 demon-
strates that the conformation in which the phenyl is
axial and the linker is equatorial (trans-isomer) is
necessary for good affinity. In contrast, the low affinity
cis-isomers have the phenyl group equatorial and the
linker axial.
This series has obvious similarities to the gem-piperidine
series which has been extensively studied (Table 2).7 In
these compounds the geminal centre is free to invert, but
NMRstudies show that compounds with ether based
linkers adopt a conformation in which the phenyl group
is axial, giving good affinity (25, hNK1 IC50 0.95 nM).
This is similar to the conformation adopted by the
trans-cyclohexane compounds (2). In contrast, model-
ling studies on gem-piperidines with amide based linkers
suggest that the preferred solution conformation has the
phenyl group equatorial, resulting in low affinity (26,
hNK1 IC50 130 nM). This is similar to the conformation
adopted by the cis-cyclohexane compounds (11).
Scheme 6. Reagents and conditions: (i) LiBH4, THF, rt.
Table 1. Linker replacements
Introduction of methyl or hydroxymethyl substituents
onto the lead amide and ether linkers is tolerated (Table
3). In the case of ether 28, the hydroxymethyl sub-
stituent improves affinity. The amide 29 was separated
by chiral HPLC (Chirobiotic V; MeOH/Et3N/AcOH;
100:0.1:0.1; 1 mL/min; 260 nm) into its component
enantiomers 29a and 29b. Interestingly, the difference in
affinities for the two compounds is modest when com-
pared to most other series of NK1 antagonists where
enantiomers show large differences in affinity.8 It is also
notable that achiral dimethyl substitution is well toler-
ated (30, 33).
Compd
-L-
Stereochemistry
hNK1 IC50 (nM)a
11
2
cis-
150ꢂ80
trans-
0.34ꢂ0.10
The in vivo CNS penetration of selected compounds
was assessed in gerbils by their ability to block the foot-
tapping response induced by central infusion of the
NK1-selective agonist GR73632.9 In this assay, 2 is
12
13
cis-
trans-
250ꢂ26
6.3ꢂ2.5
14
15
cis-
trans-
85ꢂ46
0.70ꢂ0.44
Table 2. Effect of conformation
16
17
cis-
trans-
82ꢂ0
Compd
Structurea
hNK1 IC50 (nM)b
1.7ꢂ0.6
25
0.95ꢂ0.41
18
19
cis-
trans-
140ꢂ49
2.5ꢂ0.6
26
2
130ꢂ80
20
21
cis-
trans-
50% @ 1000
120ꢂ99
0.34ꢂ0.10
22
23
cis-
trans-
59ꢂ18
4.2ꢂ1.9
11
150ꢂ80
24
1:1 cis- and trans-
40ꢂ3
aNR2=4-(4-fluorophenyl)piperidinyl; Ar=3,5-(CF3)2Ph.
bDisplacement of [125I]-labelled substance P from the cloned receptor
expressed in CHO cells. Data are meanꢂSD (n=3).5
aDisplacement of [125I]-labelled substance P from the cloned receptor
expressed in CHO cells. Data are meanꢂSD (n=3).5

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J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1755–1758
Table 3. Linker substitution
cyclohexylamine. Throughout, there is a clear pref-
erence for trans- relative stereochemistry across the
cyclohexane ring, which is consistent with the results for
the related gem-piperidine series. A heteroatom in the
linking chain is beneficial, although this can be as part
of either an amide or an ether. Substitution on the side
chain with methyl, dimethyl or hydroxymethyl groups is
well tolerated. Combining these features gives a range of
compounds with high affinity. The a-methyl amide 32
also shows long duration of action in an animal model
of central NK1 activity.
Compd
-A-
R1
R2
Stereo
hNK1
IC50 (nM)a
References and Notes
23
27
28
H
CH3
CH2OH
H
H
H
4.2ꢂ1.9
5.3ꢂ2.5
(ꢂ)-
(ꢂ)-
1. Seward, E. M.; Swain, C. J. Exp. Opin. Ther. Pat. 1999, 9,
571.
0.75ꢂ0.21
2. Swain, C. J.; Seward, E. M.; Cascieri, M. A.; Fong, T. M.;
Herbert, R.; MacIntyre, D. E.; Merchant, K. J.; Owen, S. N.;
Owens, A. P.; Sabin, V.; Teall, M.; VanNiel, M. B.; Williams,
B. J.; Sadowski, S.; Strader, C.; Ball, R. G.; Baker, R. J. Med.
Chem. 1995, 38, 4793.
2
H
CH3
CH3
CH3
CH3
CH2OH
H
H
H
H
CH3
H
0.34ꢂ0.10
0.77ꢂ0.11
0.35ꢂ0.11
1.5ꢂ0.7
29
29a
29b
30
31
(ꢂ)-
(+)-
(ꢁ)-
0.62ꢂ0.23
0.29ꢂ0.09
3. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392.
(ꢂ)-
4. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetra-
hedron Lett. 1991, 32, 1175.
5. Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Bansal,
A.; Swain, C. J.; Seward, E. M.; Frances, B.; Burns, D.; Stra-
der, C. D. Mol. Pharmocol. 1992, 42, 458.
15
32
33
34
H
CH3
CH3
CH2OH
H
H
CH3
H
0.70ꢂ0.44
0.63ꢂ0.45
0.49ꢂ0.24
0.44ꢂ0.11
(ꢂ)-
(ꢂ)-
6. 1H NMRexperiments (400 MHz, CD 3OD) show that, in
both isomers, the cyclohexyl ring adopts a chair conformation
with the C-1 hydrogen axial. In cis-isomers (such as 11),
NOE’s are seen from the o-hydrogens of the 4-phenyl group to
both axial and equatorial C-3 hydrogens, indicating that the 4-
phenyl group is equatorial. In trans-isomers (such as 2),
NOE’s are seen from the o-hydrogens of the 4-phenyl group to
the equatorial C-3 hydrogens and to the axial C-2 hydrogens,
indicating that the 4-phenyl group is axial.
7. Stevenson, G. I.; Huscroft, I.; MacLeod, A. M.; Swain,
C. J.; Cascieri, M. A.; Chicchi, G. G.; Graham, M. I.; Harri-
son, T.; Kelleher, F. J.; Kurtz, M.; Ladduwahetty, T.; Mer-
chant, K. J.; Metzger, J. M.; MacIntyre, D. E.; Sadowski, S.;
Sohal, B.; Owens, A. P. J. Med. Chem. 1998, 41, 4623.
8. For example, the 2R,3R enantiomer of 1 displays a 1000-
fold loss in affinity.2
aDisplacement of [125I]-labelled substance P from the cloned receptor
expressed in CHO cells. Data are meanꢂSD (n=3).5
moderately active when the NK1 agonist challenge
immediately follows dosing (ID50 1.9 mg/kg iv), but has
poor duration of action (15% inhibition at 3 mg/kg iv
when the NK1 agonist challenge is given 2 h after dos-
ing). The a-methyl amide 32 shows the most promising
in vivo profile; it has affinity similar to 2 and shows
similar blockade of foot-tapping immediately following
dosing (ID50 1.7 mg/kg iv). However, activity improves
after 2 h (ID50 0.6 mg/kg iv), suggesting slow brain
penetration, and is maintained to 24 h (ID50 1.8 mg/kg
iv).
9. Rupniak, N. M. J.; Tattersall, F. D.; Williams, A. R.;
Rycroft, W.; Carlson, E.; Cascieri, M. A.; Sadowski, S.; Ber,
E.; Hale, J. J.; Mills, S. G.; MacCoss, M.; Seward, E.;
Huscroft, I.; Owen, S.; Swain, C. J.; Hill, R. G.; Hargreaves,
R . J.Eur. J. Pharmacol. 1997, 326, 201.
In conclusion, we have explored the effect of changes to
C1–C4 relative stereochemistry on the cyclohexane ring
and replacements for the amide linker of a new series of
high affinity NK1 antagonists based on 4,4-disubstituted