Synthesis and evaluation of CCR5 antagonists containing modified 4-piperidinyl-2-phenyl-1-(phenylsulfonylamino)-butane

Article abstract of DOI:10.1016/j.bmcl.2004.12.044

Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for good anti-viral activity.

Full text of DOI:10.1016/j.bmcl.2004.12.044

Bioorganic & Medicinal Chemistry Letters 15 (2005) 977–982
Synthesis and evaluation of CCR5 antagonists containing
modified 4-piperidinyl-2-phenyl-1-(phenylsulfonylamino)-butane
Shrenik K. Shah,a,* Natalie Chen,a Ravindra N. Guthikonda,a Sander G. Mills,a
Lorraine Malkowitz,b Martin S. Springer,b Sandra L. Gould,b Julie A. DeMartino,b
Anthony Carella,c Gwen Carver,c Karen Holmes,c William A. Schleif,c Renee Danzeisen,c
Daria Hazuda,c Joseph Kessler,c Janet Lineberger,c Michael Miller,c
Emilio A. Eminic and Malcolm MacCossa
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Immunology and Rheumatology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA
Received 26 October 2004; revised 14 December 2004; accepted 15 December 2004
Available online 19 January 2005
Abstract—Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-
piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with
some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for
good anti-viral activity.
Ó 2004 Elsevier Ltd. All rights reserved.
The chemokine receptor CCR5 is the primary co-recep-
tor used by M-tropic (or R5) strains of human immuno-
deficiency virus (HIV) along with CD4 to gain entry into
immune system cells. CXCR4, another member of the
chemokine receptor family, is utilized by the T-tropic
(or X4) strains.1 The R5 virus predominates in the early
stages of HIV infection in vivo and is present through-
out the course of the disease, whereas the X4 virus is
present only during the later stage of the disease. The
beneficial effect of blocking CCR5 as a treatment for
HIV infection has been inferred from human genetic
studies. Individuals who lack functional CCR5 receptors
on their cell surfaces, due to a 32 bp deletion in their
CCR5 gene, are highly resistant to HIV infection2 and
infected heterozygous patients display a significantly de-
layed progression to clinical AIDS.3 More recently effi-
cacy of CCR5 antagonists was demonstrated in human
clinical studies.4 CCR5 is a member of the seven trans-
membrane G-protein coupled receptor family, which
has provided many important targets for drug discov-
ery. These observations have led to efforts in many lab-
oratories to identify CCR5 antagonists as new therapies
for HIV infection.5
Previous reports from these laboratories have described
the discovery of low molecular weight CCR5 antagonists
containing a 4-(piperidin-1-yl)-2-phenyl-1-(phenylsulfon-
ylamino)butane framework.6 SAR studies around this
lead identified 1 with an IC50 = 2 nM in a CCR5 binding
assay, which had minimal anti-viral activity in an in vitro
HIV replication assay.7 However, introduction of a benz-
ylic methyl at C-2 and modification of the ethylamino-
CBZ to an allylamino-4-nitro-CBZ group afforded 2,
which had good anti-viral activity.8 In order to improve
the potency, selectivity, and pharmacokinetic properties,
analogs where the backbone was restrained as a pyrrol-
idine ring have been prepared.9 Herein we report on an
alternative approach (3) where the carbamate of 2 is con-
strained by linking the N-alkyl group (a) with the benz-
ylic carbon atom or (b) with the piperidine ring and
discuss the synthesis, CCR5 affinity, and anti-viral activ-
ity of these novel analogs.
Keywords: CCR5 antagonist; Anti-HIV; Piperidine.
*
The general synthesis of this class of compounds
(Scheme 1) was described recently and was based on
Corresponding author. Tel.: +1 732 594 7988; fax: +1 732 594
5790; e-mail: shrenik_shah@merck.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.044

978
S. K. Shah et al. / Bioorg. Med. Chem. Lett. 15 (2005) 977–982
Et
N
O
O2N
O
N
O
N
O
O
O
Me
Ph
O
N
S
O
N
S
N
Me
Me
1
2
CCR5 IC50 = 2 nM
CCR5 IC50 = 1 nM
Antiviral IC90 = 3 nM
Ar
O
O
a
N
R
O
N
O
Me
b
N
S
Me
3
reductive amination of the key aldehyde intermediates,
5, with 4-substituted piperidines.6 This convergent ap-
proach was very useful for the present work because
we only had to synthesize the desired bicyclic piperidine
prior to the final coupling step. Initially, some of the
analogs were made using the racemic aldehyde 5b, with
the compounds having good activity being remade
using the chiral aldehyde 5c, which then allowed separa-
tion of the individual diastereomers by chromatography.
The starting chiral acids (4a and 4c) were obtained by
resolution of the racemic acids with (S)-(À)-a-methyl-
benzylamine.6,8
with (R) stereochemistry was preferred, only (R) isomers
were prepared in the subsequent disubstituted series.
The same three step sequence starting with (1R,2S)-
norephidrine (7a) gave (4S,5R) oxazolinone (10a), which
upon reaction with 5a yielded 13. The (1R,2R) isomer 7b
was prepared by inversion of the hydroxyl center of
(1S,2R)-norephidrine (7c) in a three step procedure.10
7b was converted to 10b, which was reacted with 5a to
provide the (4R,5R) isomer 14.
The synthesis of bicyclic piperidine 16, where the alkyl
group is connected to the piperidine, is shown in Scheme
3. The indole N of 5-azaindole (15), prepared by a liter-
ature procedure,11 was protected as a Boc derivative and
the product was hydrogenated using PtO2. Reductive
amination of 16 with 5a and 5b furnished 17 and 18 as
mixtures of diastereomers, respectively. Removal of
the Boc group from 18 gave the free amine 19, which
was acylated to afford 20–22 also as mixtures of isomers.
Reaction of 16 with chiral aldehyde 5c formed two dia-
stereomers, which could be separated by chromatogra-
The preparation of piperidines with a cyclic carbamate
substituent at C-4 is depicted in Scheme 2. Both
(R)- and (S)-1-phenylethanolamine (6a and 6b) were
individually reacted with Boc-piperidone (8) and each
aminoalcohol product was cyclized using phosgene.
Removal of the Boc protecting group gave 9a and 9b.
Reductive amination of 9a and 9b with 5a furnished
the test compounds 11 and 12, respectively. Since 11
O
R
R
CO2H
N
H
a,b
4a R = H (S)
4b R = Me (Racemic)
4c R = Me (S)
c,d
O
O
O
O
R
R
H
S
S
N
Me
N
Me
e,f
O
5a R = H (S)
5b R = Me (Racemic)
5c R = Me (S)
g
O
O
R
N
S
N
Me
Scheme 1. Reagents: (a) (COCl)2, CH2Cl2; (b) MeNH2, CH2Cl2; (c) DIBAL-H, THF; (d) PhSO2Cl, iPr2NEt, CH2Cl2; (e) OsO4, NMO, t-BuOH,
acetone, H2O; (f) NaIO4, THF, H2O; (g) amineÆHCl, Na(OAc)3BH, iPr2Net, DCE, or CH2Cl2.

S. K. Shah et al. / Bioorg. Med. Chem. Lett. 15 (2005) 977–982
979
O
1
HO HN
R
N Boc
a
OH
b,c
O
N
R
NH
R
NH2
O
N Boc
.HCl
2
8
6a R = H (R)
6b R = H (S)
9a R = H (R)
9b R = H (S)
d
7a R = Me (1 R,2S)
7b R = Me (1 R, 2R)
10a R = Me (4S,5R)
10b R = Me (4R, 5R)
5a
O
O
R
N
O
O
H
N
S
N
Me
11 R = H (R)
12 R = H (S)
13 R = Me (4S,5R)
14 R = Me (4R,5R)
(R)
(S)
H
H
H
OH
e,f
OH
O
g
Me
N
Me
NH2
(R)
Me
Me
NH2
H
H
H
(R)
7c
7b
Scheme 2. Reagents: (a) Na(OAc)3BH, DCE; (b) COCl2, Et3N; (c) HCl, EtOAc; (d) Na(OAc)3BH, iPr2Net, DCE; (e) Ac2O, toluene; (f) HCl,
toluene; (g) 4 N HCl, H2O, toluene.
phy to isolate individual stereoisomers 23a and 23b.
Acid treatment of 23a and 23b individually and reacyl-
ation with 4-nitro-CBZ-Cl gave 24a and 24b, respectively.
(1 and 2) are listed in Table 1. Among the analogs with
a cyclic carbamate (11–14) the stereoisomers 11 and 13
were preferred and had about a 10-fold better affinity
than the other isomers. However, the best compound
was still much less active than 1, thus indicating that this
construction did not allow the proper orientation of the
pharmacophores for binding.
The fused piperidines 26 (Scheme 4) were prepared from
Boc-piperidone (8). Michael addition of the pyrrolidine
enamine of 8 to ethyl acrylate gave 25. Reaction of 25
with an amine and Na(OAc)3BH formed the lactam
and subsequently the protecting group was removed
with HCl/ethyl acetate to yield 26. Final reductive ami-
nation of 5b with 26 using Na(OAc)3BH afforded the
test compounds 27–29 as mixtures of diastereomers.
The perhydro azaindole series (17–24b) provided better
orientation and both 18 and 21 had comparable activity
to 2 in the binding assay. Since 18 and 21 each contained
four stereoisomers, the individual isomers 23a,b and
24a,b with S stereochemistry at the quaternary center
were synthesized. Both 23b and 24b were as good as 2
in the CCR5 binding assay but their anti-viral activity
The receptor binding and anti-viral activities of the
newly synthesized compounds along with the two leads
NO2
HN
NO2
NMe2
Me
b
a
N
15
N
O
N
O
c,d
Boc
N
Boc
N
H
O
N
Me
O
5a-c
R
f,g
N
S
H
19-22,
e
23a-b, 24a-b
N
H
(See Table 1)
16
17 R = H
18 R = Me
Scheme 3. Reagents: (a) Me2NCH(OMe)2, DMF, 90 °C; (b) H2, 10% Pd/C, EtOH, 60 °C; (c) (Boc)2O, DMAP, MeCN; (d) H2, PtO2, EtOH, HOAc;
(e) Na(OAc)3BH, iPr2NEt, DCE; (f) HCl, EtOAc; (g) chloroformate or acid chloride, Et3N, CH2Cl2.

980
S. K. Shah et al. / Bioorg. Med. Chem. Lett. 15 (2005) 977–982
R
c,d
N
NH
.HCl
a,b
O
N Boc
O
N Boc
O
EtO2C
8
25
26
Scheme 4. Reagents: (a) pyrrolidine, p-TsOH, benzene, Dean–Stark trap, 80 °C; (b) ethyl acrylate, benzene, Dean–Stark trap, 80 °C; (c) H2O, reflux;
(d) RNH2, Na(OAc)3BH, DCE; (e) HCl, EtOAc.
Table 1. CCR5 binding affinity and anti-viral activity of synthesized compounds
O
O
R
N
S
N
Me
No.
R
H
CCR5 IC50 (nM)a
Anti-viral IC90 (nM)b
N
Et
N
1
2
NDc
Cbz
N
N
2
Me
1
3
p-NO2-Cbz
O
N
O
Ph
N
11
H
31.9
ND
H
N
N
(R)
O
O
Ph
N
12
13
H
H
>100
ND
ND
H
(S)
(R)
O
O
O
H
Ph
N
H
36.7
Me
(S)
N
N
(R)
Ph
O
H
N
H
14
H
H
350
ND
Me
(R)
N
Boc
17
18
19
16
11
ND
111
ND
N
N
Boc
HN
Me (R/S)
Me (R/S)
N
>2000
N

S. K. Shah et al. / Bioorg. Med. Chem. Lett. 15 (2005) 977–982
981
Table 1 (continued)
No.
R
CCR5 IC50 (nM)a
Anti-viral IC90 (nM)b
N
N
Cbz
20
21
Me (R/S)
Me (R/S)
9
>300
111
N
N
p-NO2-Cbz
3.6
N
O
N
22
Me (R/S)
6.4
111
N
Ph
N
Boc
23a
Me
>2000
ND
N
N
Isomer A
N
Boc
23b
24a
Me
Me
2
100
300
Isomer B
N
p-NO2-Cbz
21
N
N
Isomer A
N
p-NO2-Cbz
24b
27
Me
2
28
10
33
>300
333
Isomer B
Me
O
N
Me (R/S)
Me (R/S)
N
Ph
28
O
N
N
p-NO2-Ph
O
29
Me (R/S)
5.3
333
N
N
a The assay used recombinant CCR5 receptors expressed on CHO cell membranes and 125I-MIP-1a as the ligand. IC50 values are the average of three
experiments, where standard errors were <15% in a single assay. See footnote 20 of Ref. 12 for assay protocol.
b The assay has been described in Ref. 13.
c ND = Not determined.
was significantly lower. This result clearly demonstrates
that CCR5 binding affinity is not sufficient for anti-viral
activity and other features such as rate of dissociation
from the receptor or some physical property might be
important. Among the fused lactams, 28 and 29 both
displayed moderate CCR5 affinity, but also lacked
anti-viral activity.
Three types of bicyclic replacements for the 4-alkyl-
amino-piperidine moiety of the lead were evaluated for

982
S. K. Shah et al. / Bioorg. Med. Chem. Lett. 15 (2005) 977–982
Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.; Schleif,
W. A.; Emini, E. A. Bioorg. Med. Chem. Lett. 2001, 11,
2475.
their CCR5 activity and perhydro-5-azaindole deriva-
tives were found to have low nanomolar affinity for
the receptor. However, these compounds (23b and 24b)
were significantly less active as anti-viral agents suggest-
ing that activity in the CCR5 binding assay is not the
sole determinant of the anti-HIV activity. The lower
affinity of these bicyclic analogs has also provided valu-
able insights about the preferred orientation of the alkyl
and carbamate groups for chemokine binding and espe-
cially anti-HIV activity. We have used this information
to design other rigid structures with improved potency
and selectivity and these results were disclosed
recently.14
8. Caldwell, C. G.; Chen, P.; Finke, P. E.; Shankaran, K.;
Meurer, L. C.; Oates, B.; Dorn, C. P., Jr.; MacCoss, M.;
Mills, S. G.; DeMartino, J. A.; Gould, S. L.; Malkowitz,
L.; Siciliano, S. J.; Springer, M. S.; Braun, J.; Chen, Q.;
Hajdu, R.; Kwei, G.; Carella, A.; Carver, G.; Danzeisen,
R.; Hazuda, D.J.; Holmes, K.; Kessler, J.; Lineberger, J.;
Miller, M.; Emini, E. A.; Schleif, W. A. Abstract of
Papers, 220th ACS National Meeting, Washington, DC,
August 24–29, 2000; American Chemical Society: Wash-
ington, DC, 2000; MEDI 120.
9. Hale, J. J.; Budhu, R. J.; Holson, E. B.; Finke, P. E.;
Oates, B.; Mills, S. G.; MacCoss, M.; Gould, S. L.;
DeMartino, J. A.; Springer, M. S.; Siciliano, S.; Malko-
witz, L.; Schleif, W.; Hazuda, D.; Miller, M.; Kessler, J.;
Danzeisen, R.; Holms, K.; Lineberger, J.; Carella, A.;
Carver, G.; Emini, E. Bioorg. Med. Chem. Lett. 2001, 11,
2741.
References and notes
1. For a review of the co-receptors see: Fauci, A. S. Nature
1996, 384, 529.
2. Liu, R.; Paxton, W. A.; Choe, S.; Ceradini, D.; Martin, S.
R.; Horuk, R.; MacDonald, M. E.; Stuhlmann, H.; Koup,
R. A.; Landau, N. R. Cell 1996, 86, 367.
10. Dowd, W.; Krauss, R. C.; Freiter, E. R. U.S. Patent
4,237,304, 1980; Chem. Abstr. 1981.
11. Robinson, R. P.; Donahue, K. M. J. Org. Chem. 1991, 56,
4805.
3. Michael, N. L.; Chang, G.; Louie, L. G.; Mascola, J. R.;
Dondero, D.; Birx, D. L.; Sheppard, H. W. Nature Med.
1997, 3, 338.
4. (a) Palani, A.; Shapiro, S.; Clader, J. W.; Greenlee, W. J.;
Blythin, D.; Cox, K.; Wagner, N. E.; Strizki, J.; Baroudy,
B. M.; Dan, N. Bioorg. Med. Chem. Lett. 2003, 13, 705; (b)
Baroudy, B. M. In AIDS-14th International Conference,
Part I, New Drugs, New Targets Symposium, Barcelona,
Spain, July 7–12, 2002.
12. Hale, J. J.; Budhu, R. J.; Mills, S. G.; MacCoss, M.;
Malkowitz, L.; Siciliano, S.; Gould, S. L.; DeMartino, J.
A.; Springer, M. S. Bioorg. Med. Chem. Lett. 2001, 11,
1437.
13. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.;
Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski,
L.; Schleif, W.; Blau, C.; Miller, M. D. Science 2000, 287,
646.
14. (a) Shen, D.-M.; Shu, M.; Willoughby, C. A.; Shah, S.;
Lynch, C. L.; Hale, J. J.; Mills, S. G.; Chapman, K. T.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Siciliano, S. J.; Lyons, K.; Pivnichny, J. V.; Kwei, G.
Y.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.;
Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.;
Miller, M. D.; Emini, E. A. Bioorg. Med. Chem. Lett.
2004, 14, 941; (b) Shankaran, K.; Donnelly, K. L.; Shah,
S. K.; Guthikonda, R. N.; MacCoss, M.; Mills, S. G.;
Gould, S. L.; Malkowitz, L.; Siciliano, S. J.; Springer, M.
S.; Carella, A.; Carver, G.; Hazuda, D.; Holmes, K.;
Kessler, J.; Lineberger, J.; Miller, M. D.; Emini, E. A.;
Schleif, W. A. Bioorg. Med. Chem. Lett. 2004, 14, 3419.
5. For a review see: Kazmierski, W.; Bifulco, N.; Yang, H.;
Boone, L.; DeAnda, F.; Watson, C.; Kenakin, T. Bioorg.
Med. Chem. 2003, 11, 2663.
6. Finke, P. E.; Meurer, L. C.; Oates, B.; Mills, S. G.;
MacCoss, M.; Malkowitz, L.; Springer, M. S.; Daugherty,
B. L.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.;
Carella, A.; Carver, G.; Holmes, K.; Danzeisen, R.;
Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.; Schleif,
W. A.; Emini, E. A. Bioorg. Med. Chem. Lett. 2001, 11, 265.
7. Finke, P. E.; Oates, B.; Mills, S. G.; MacCoss, M.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Carella, A.; Carver, G.; Holmes, K.; Danzeisen, R.;