Discovery of a novel, potent and orally active series of γ-lactams as selective NK1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.05.082

Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious γ-lactam series of selective NK₁ antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.

Full text of DOI:10.1016/j.bmcl.2008.05.082

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4168–4171
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel, potent and orally active series of
NK1 antagonists
c-lactams as selective
a
a
a
a
Sunil Paliwal a, , Gregory A. Reichard , Sapna Shah , Michelle Laci Wrobleski , Cheng Wang ,
Carmine Stengone a, Hon-Chung Tsui a, Dong Xiao a, Ruth A. Duffy b, Jean E. Lachowicz b, Amin A. Nomeir c,
Geoffrey B. Varty b, Neng-Yang Shih a
*
a Chemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b CNS Biology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
c Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a car-
Received 25 April 2008
Revised 19 May 2008
Accepted 19 May 2008
Available online 24 May 2008
bon resulted in the discovery of a novel, potent and orally more efficacious c-lactam series of selective
NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with
high binding affinity and excellent oral CNS activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
NK1
Substance P
Emesis
CNS
Lactam
The mammalian tachykinin Substance P (SP) has been impli-
cated in a number of pathological conditions in the central nervous
system (CNS) and peripheral tissues including pain, inflammation,
depression, anxiety, emesis and nausea.1 SP preferentially binds to
the NK1 receptor. Therefore, an antagonist of the NK1 receptor has
potential therapeutic use in the treatment of a variety of central
and peripheral diseases.
The resulting c-lactam compound 2 was prepared and evaluated
for biological response.5
F3C
F3C
O
O
NH
NH
Recently, we reported a novel series of cyclic urea derivatives as
potent and selective NK1 receptor antagonists that are orally active
and have good CNS penetration.2 SAR evaluation in this series led
to the identification of a five-membered unsubstituted urea ana-
logue 1 as the lead compound.2b Compound 1 exhibited sub-nano-
molar binding affinity for the NK1 receptor (Ki = 0.6 nM) and
moderate oral CNS activity (57% inhibition of foot tapping at
1 mg/kg po following a 4 h pretreatment time) in the in vivo gerbil
foot tapping (GFT) inhibition assay.3
Metabolism studies of 1 indicated hydroxylation at the carbon
next to urea nitrogen as the major route of metabolism. In an effort
to alter the metabolic processing of the urea ring, while improving
the biology of the compound, we sought to replace the urea nitro-
gen adjacent to the site of oxidative metabolism of 1 with a carbon.
N
O
O
H
CF3
CF3
site for hydroxylation
1
2
The synthesis of the unsubstituted
c-lactam 2 is outlined in
Scheme 1. Hydrolysis of chiral amino amide 36 to amino acid by
heating with barium hydroxide, followed by treatment with Boc-
anhydride provided Boc-protected amino acid 4.7 Reaction of 4
with triphosgene afforded useful Boc–NCA intermediate 5.8 Subse-
quent reduction of 5 with lithium borohydride followed by oxida-
tion with sodium hypochlorite provided aldehyde 6. Horner-
Emmons olefination of 6 with methyl diethylphosphonoacetate
followed by hydrogenation gave the compound 7. Cyclization of
7 in presence of trimethylaluminum and subsequent deprotection
* Corresponding author. Tel.: +1 908 740 2603; fax: +1 908 740 7305.
E-mail address: sunil.paliwal@spcorp.com (S. Paliwal).
provided the desired c
-lactam 2.9
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.082

S. Paliwal et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4168–4171
4169
Ph
NH2
Ph
Ph
NBoc
Ph
NH
F3C
F3C
F3C
F3C
O
O
O
O
O
O
a, b
NHBoc
OH
a, b
c
NH
O
O
CF3
CF3
CF3
CF3
F3C
CH3
2a, 2b
3
4
8
O
9
c, b
Ph
NBoc
Ph
F3C
Ph
NH
Ph
NH
d, e
O
O
O
O
F3C
F3C
NHBoc
O
O
H
O
CF3
CF3
O
O
CF3
CF3
N3
O
5
6
10
Ph
Ph
d
e
F3C
F3C
O
O
f, g
h
NHBoc
NBoc
Ph
Ph
NH
O
F3C
F3C
O
O
CF3
CF3
MeO2C
NH
7
8
O
O
CF3
CF3
H2N
HO
Ph
F3C
2d
2c
i
O
g
NH
f
O
CF3
2
Ph
R
Ph
NH
F3C
F3C
O
O
NH
Scheme 1. Reagents and conditions: (a) Ba(OH)2, H2O, 156 °C, 72 h; (b) (Boc)2O,
THF, rt, 18 h, 65% over two steps; (c) (CCl3O)2CO, i-Pr2EtN, CH2Cl2, 0 °C, 15 min, then
rt, 18 h; (d) LiBH4, THF, 0 °C, 15 min, then rt, 18 h; (e) TEMPO, NaOCl, NaBr, satd aq
NaHCO3, EtOAc, 0 °C, 1.5 h, 92% over three steps; (f) (C2H5O)2P(O)CH2CO2CH3, NaH,
THF, 0 °C, 15 min, then rt, 2.5 h, 92%; (g) H2, 10% Pd/C, 1 atm, rt, 18 h, 91%; (h)
(CH3)3Al, toluene, 0 °C, 15 min, then rt, 30 min, 84%; (i) TFA, CH2Cl2, rt, 2.5 h, 84%.
O
O
CF3
CF3
HN
HN
O
SO2CH3
2g, 2h
R = CH3; 2e, 2f
R = C2H5; 2i, 2j
Ph
NH
c
-Lactam 2 retained high NK1 binding affinity (Ki = 1 nM) and
F3C
O
maintained good selectivity over NK2 and NK3 receptors.10 More-
over, lactam 2 demonstrated superior oral activity compared to 1
(GFT inhibition at 1 mg/kg: 2 = 92, 78, 47%; 1 = 35, 57, 48% follow-
ing 2, 4, 6 h pretreatment times, respectively).
h
2d
O
CF3
N
i
O
We next investigated substitutions effect at the carbon alpha to
2k, 2l
Ph
NH
F3C
the carbonyl of the
c-lactam 2. The syntheses of the a-substituted
O
c
-lactam analogues 2a–o are shown in Scheme 2. Alkylation of
Boc-protected lactam 8 with methyl iodide using LDA followed
by separation of isomers by column chromatography and subse-
O
CF3
2m, 2n
N
O
quent deprotection with trifluoroacetic acid afforded
a-methyl
substituted lactams 2a and 2b. Treatment of the anion derived
from 8 with trisyl azide and subsequent deprotection provided
the desired azide substituted compound 9 and a side product 10.
Reduction of 10 with lithium borohydride yielded a diastereomeric
mixture of hydoxy-lactam 2c. Hydrogenation of azide-lactam 9
afforded amino-lactam 2d as a mixture of diastereomers. Acylation
of 2d with acetyl chloride and propionyl chloride followed by sep-
aration of isomers provided compounds 2e, 2f and 2i, 2j, respec-
tively. Similarly, treatment of amine 2d with methanesulfonyl
chloride and separation of isomers afforded compounds 2g and
2h. Alkylation and subsequent cyclization of amine 2d with ethyl
4-bromobutyrate in presence of trimethylaluminum followed by
separation of isomers by HPLC on a Chiracel ODÒ column afforded
five-membered cyclic amide substituted analogues 2k and 2l. Acyl-
ation of amine 2d with 5-chlorovaleryl chloride followed by subse-
quent cyclization upon heating with sodium hydride in THF at
60 °C provided six-membered cyclic amide substituted analogues
2m and 2n. Cyclization of amine 11 with 1,4-dibromobutane affor-
ded cyclic amine compound 2o.
Ph
NH
Ph
NH
F3C
F3C
O
O
j
O
O
CF3
CF3
H2N
N
11
2o
Scheme 2. Reagents and conditions: (a) i—0.5 M LDA, THF, À78 °C, 1 h, then CH3I,
ii—separation of isomers; (b) 4 M HCl/dioxane, CH2Cl2, 0 °C, 3 h, 2a (17%) and 2b
(36%) over two steps; (c) 0.5 M KHMDS, THF, À78 °C, 30 min, trisyl azide, À78 °C,
4 h, AcOH, separate desired two compounds, then step b, 9 (30%) and 10 (22%) over
two steps; (d) LiBH4, THF, rt, 6 h, 83%; (e) H2, 10% Pd/C, 1 atm, rt, 24 h, 68%; (f) i—
RCOCl, i-Pr2EtN, CH2Cl2, 0 °C, 15 min, then rt, 18 h, ii—separation of isomers; (g)
CH3SO2Cl, i-Pr2EtN, CH2Cl2, 0 °C, 15 min, then rt, 2 h, 2g (39%) and 2h (28%); (h) i—
2 M AlMe3, toluene, 0 °C to rt, 15 min, ethyl 4-bromobutyrate, 100 °C, 18 h; ii—
separation of isomers by HPLC on a Chiralcel ODÒ column eluting with 10% hexane/
90% IPA, 2k (35%) and 2l (18%); (i) i—5-chlorovaleryl chloride, Et3N, CH2Cl2, 0 °C,
5 min, then rt, 18 h, ii—NaH, THF, 0 °C, 5 min, then 60 °C, 5 h; iii—separation of
isomers by HPLC on a Chiralcel ODÒ column eluting with 10% hexane/90% IPA, 2m
(42%) and 2n (19%); (j) 1,4-dibromobutane, toluene, 110 °C, 48 h, 36%.
The in vitro NK1 receptor binding and in vivo GFT inhibition
data for
a-substituted c-lactams 2a–o are listed in Table 1. All
compounds having a Ki below 1 nM.
group provided diastereomers 2a and 2b. Diastereomer 2a having
a-Substitution by a methyl
the compounds except two (2c and 2d) were tested as single iso-
mer.12 It can be seen that high affinity is generally achieved, most

4170
S. Paliwal et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4168–4171
Table 1
group cis to the phenyl group exhibited superior GFT inhibition
activity than the other diastereomer 2j.
NK1 receptor binding affinity and GFT inhibition for compounds 2a–o
In addition to the acyclic, the cyclic amides such as lactams 2k–n
were also found to be well tolerated. Compared to six-membered
cyclic amides 2m and 2n, corresponding five-membered cyclic
amides 2k and 2l, respectively, demonstrated better GFT inhibition
profile. As previously seen with acyclic analogues, the cyclic amides
2k and 2m having the cyclic amide groups cis relative to the phenyl
displayed greater GFT inhibition activity than the corresponding
trans isomers 2l and 2n, respectively. The reason for generally supe-
rior GFT profile seen with isomer having a cis configuration than
trans between the R1 group and phenyl is not clear. Among all the
cyclic amides tested, five-membered amide 2k exhibited the best
combination of high NK1 affinity (Ki = 0.2 nM) and excellent oral
activity (>98% GFT inhibition following 2–6 h pretreatment). Re-
moval of the carbonyl group of 2k provided compound 2o which
maintained good NK1 activity (Ki = 0.4 nM) but displayed decreased
GFT inhibition activity.
Ph
F3C
O
NH
O
CF3
R1
Compounda
R1
NK1 Ki (nM)
GFTc (% inh.)
b
t = 2 h
t = 4 h
t = 6 h
2
2a
–H
0.6
0.7
92
77
78
85
47
44
CH3
2b
2c
2d
2e
2f
2.0
0.5
0.4
0.3
0.9
0.6
2.6
0.3
0.3
11
27
5
2
35
13
94
97
58
15
97
16
36
1
CH3
OH
11
91
71
43
0
NH2
94
80
10
0
NHAc
NHAc
NHSO2CH3
NHSO2CH3
Similar to the unsubstituted
tams retained good selectivity over other neurokinin receptors.
For example, 2e: NK2 = 1.4% inhibition at 3 M, NK3 = 43% inhibi-
tion at 10 M; 2k: NK2 = 28% inhibition at 3 M, NK3 Ki = 1254 nM.
In conclusion, changing urea to -lactam core structure resulted
c-lactam 2 the a-substituted lac-
l
2g
2h
2i
l
l
c
in the discovery of a novel and potent series of selective NK1 antag-
onists with significantly improved in vivo activity. Optimization of
the c-lactam lead compound 2 by a-substitution provided com-
pounds 2e and 2k which display high NK1 affinity (Ki 6 0.3 nM)
and excellent oral activity (>90% GFT inhibition following 2–6 h
pretreatment).
84
83
90
19
NH(CO)CH2CH3
2j
NH(CO)CH2CH3
O
2k
2l
0.2
0.5
0.2
0.2
0.4
100
49
74
20
100
46
37
26
60
98
39
63
56
45
N
O
References and notes
N
O
1. (a) Duffy, R. A. Exp. Opin. Emerg. Drugs 2004, 9, 9; (b) Seward, E. M.; Swain, C. J.
Exp. Opin. Ther. Pat. 1999, 9, 571.
2. (a) Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D. J.; Paliwal, S.; Lin, L.; Gu, D.;
Schwerdt, J. H.; Shah, S.; Reichard, G. A.; Piwinski, J. J.; Duffy, R. A.; Lachowicz, J.
E.; Coffin, V. L.; Liu, F.; Nomeir, A. A.; Morgan, C. A.; Varty, G. B. Bioorg. Med.
Chem. Lett. 2005, 15, 3896; (b) Shue, H.-J.; Chen, X.; Schwerdt, J. H.; Paliwal, S.;
Blythin, D. J.; Lin, L.; Gu, D.; Lin, L.; Wang, C.; Reichard, G. A.; Wang, H.;
Piwinski, J. J.; Duffy, R. A.; Lachowicz, J. E.; Coffin, V. L.; Nomeir, A. A.; Morgan,
C. A.; Varty, G. B.; Shih, N-Y. N.-Y. Bioorg. Med. Chem. Lett. 2006, 16, 1065.
3. Gerbil foot tapping (GFT) inhibition assay measures the potency of compounds
to antagonize an NK1-receptor mediated CNS effect (GFT) induced by an NK1
agonist administered centrally. Gerbil foot tapping inhibition assay: the NK1
2m
2n
N
O
N
2o
78
N
agonist GR73632 (3 pmol in
5 ll) was administered centrally to female
Mongolian gerbils via icv injection. Immediately following recovery from the
anesthesia, gerbils were placed into clear Plexiglas boxes for 5 min, and the
duration of foot tapping was measured. Foot tapping was defined as rhythmic,
repetitive tapping of the hind feet. NK1 antagonists were administered orally in
0.4% methylcellulose in distilled water at a dose of 1 mg/kg (unless otherwise
stated) at various pretreatment times prior to injection of GR73632. Data are
expressed as a percent decrease (% inhibition) in the amount of time spent foot
tapping compared to vehicle-treated controls.4
a
Compounds 2c and 2d are mixture of diasteromers; all other analogues are
single isomer.
b
c
See Ref. 13.
See Ref. 3.
a cis configuration of methyl group relative to the phenyl group
exhibited better binding and GFT inhibition activity than the dias-
teromer 2b. Though methyl substituted lactam 2a possessed good
potency and oral efficacy, it did not display any advantage over the
unsubstituted lactam lead compound 2.
We next evaluated the effect of
Introduction of a hydroxyl group (2c) and an amino group (2d) at
the -position slightly improved the NK1 affinity compared to the
4. Rupniak, N. M. J.; Williams, A. R. Eur. J. Pharmacol. 1994, 265, 179.
5. This work was presented in part at the 234th National Meeting of the American
Chemical Society, Boston, MA, August 19–23, 2007; MEDI 422.
6. Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg, I.; Majmundar, S.; Wang,
C.; Tiberi, R.; McPhail, A. T.; Piwinski, J. J.; Shih, N.-Y. Org. Lett. 2003, 23, 4249.
7. Attempt to directly hydrolyze amino amide 1 to corresponding amino acid
under acidic condition by heating with concentrated hydrochloric acid was
unsuccessful. This result is consistent with Seebach’s observation with similar
substrates (see Studer, A.; Seebach, D. Liebigs Ann. Chem. 1995, 2, 217).
Seebach’s solution to this problem was a four steps procedure utilizing an
intermediate benzamide for anchimeric assistance. Herein, we report that
a-substitution by polar groups.
a
lead compound 2 but resulted in significantly reduced GFT inhibi-
tion activity. The acetylation of the amino group of compound 2d
provided compounds 2e and 2f with high NK1 affinity (2e,
Ki = 0.3 nM and 2f, Ki = 0.9 nM) and excellent GFT profile (2e,
>90% inhibition and 2f, >70% inhibition following 2–6 h pretreat-
ment). Surprisingly, methyl sulfonamides 2g and 2h did not show
good in vivo activity. Extension of methyl to ethyl amides 2i and 2j
retained excellent in vitro activity (Ki = 0.3 nM for both). Interest-
ingly, these diastereomers showed different GFT profile despite
the same binding affinity. Diastereomer 2i having ethyl amide
hindered
a,a-disubstituted amino amide can be cleaved to respective amino
acids in one step by heating amino amide with barium hydroxide at 156 °C.
8. Urethane-protected N-carboxy anhydrides (UNCA) have been reported as
useful intermediates for peptide synthesis (see Fuller, W. D.; Chen, M. P.;
Shabankareh, M.; Blair, R. K. J. Am. Chem. Soc. 1990, 112, 7414). The reports of
UNCA to date have been restricted to
procedure for their synthesis is acylation of the corresponding NCA. We
found that -disubstituted UNCA derivative (Boc–NCA) can be prepared from
corresponding amino acid by first treatment of the amino acid with Boc
anhydride and then reaction with triphosgene.
a-amino acids and the standard
a,a
9. Taschner, M. J.; Huang, Y.; El-Alali, A.; Chen, L.; Youngs, W. J. Tetrahedron Lett.
1992, 33, 2765.

S. Paliwal et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4168–4171
4171
10. NK2 = 0.1% inhibition at 3
l
M; Ki (NK3) = 3815 nM.11
CH(R1) group to the o-hydrogens of the phenyl group, suggesting R1 group is
trans to phenyl.
11. NK2 and NK3 binding assays: binding data are the average of two or three
independent determinations. Receptor binding assays were performed on
membrane preparations from CHO cells in which recombinant human NK2 and
NK3 receptors were expressed. [3H]-Neurokinin A and [125I]-neurokinin B were
used as the ligands for the NK2and NK3 receptor assays, at concentrations near
their experimentally derived Kd value. Ki values were obtained using the Cheng
and Prusoff equation.
13. NK1 binding assay: Binding data are the average of two or three
independent determinations. Receptor binding assay was performed on
membrane preparations from CHO cells in which recombinant human
NK1 receptor was expressed. [3H]-Sar-Met Substance
P was used as the
ligand for the NK1 assay, at concentrations near the experimentally
derived Kd value. Ki values were obtained using the Cheng and Prusoff
equation.14
12. Configuration of R1 group was assigned based on the NOE experiments. In cis-
isomers, NOEs are seen from the CH hydrogen of the CH(R1) group to one of the
methylene (CH2) hydrogen of the ether side chain, indicating R1 group is cis to
phenyl. In trans-isomers, NOEs are observed from the CH hydrogen of the
14. Cascieri, M. A.; Macleod, A. M.; Underwood, D.; Shiao, L.-L.; Ber, E.; Sadowski,
S.; Yu, H.; Merchant, K. J.; Swain, C. J.; Strader, C. D.; Fong, T. M. J. Biol. Chem.
1994, 269, 6587.