N-Alkyl-5H-pyrido[4,3-b]indol-1-amines and derivatives as novel urotensin-II receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.08.054

High throughput screening of our compound collection led to the discovery of a novel series of N-alkyl-5H-pyrido[4,3-b]indol-1-amines as urotensin-II receptor antagonists. Synthesis, initial structure and activity relationships, functional and animal ortholog activities of the series are described.

Full text of DOI:10.1016/j.bmcl.2008.08.054

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4936–4939
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
N-Alkyl-5H-pyrido[4,3-b]indol-1-amines and derivatives as novel
urotensin-II receptor antagonists
c
c
c
b
a
Yonghui Wang a, , Zining Wu , Brian F. Guida , Sarah K. Lawrence , Michael J. Neeb , Ralph A. Rivero ,
*
Stephen A. Douglas b, Jian Jin b,
*
a Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
b Cardiovascular and Urogenital CEDD, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
c Molecular Discovery Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
High throughput screening of our compound collection led to the discovery of a novel series of N-alkyl-
5H-pyrido[4,3-b]indol-1-amines as urotensin-II receptor antagonists. Synthesis, initial structure and
activity relationships, functional and animal ortholog activities of the series are described.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 July 2008
Revised 13 August 2008
Accepted 15 August 2008
Available online 22 August 2008
Keywords:
Urotensin-II receptor antagonist
UT antagonist
Pyridoindole amine
Competitive
Reversible
Functional antagonist
Human urotensin-II (hU-II), the most potent mammalian vaso-
constrictor identified to date,1 and its cognate receptor hUT (for-
merly known as human GPR-14) are proposed to be involved in
the (dys)regulation of cardiorenal function.2 Together, they have
been implicated in the etiology of numerous cardiorenal and
metabolic diseases including hypertension,3 heart failure,4,5 ath-
erosclerosis,6 renal failure,7 and diabetes.8 The impressive pharma-
cological activity of U-II has stimulated a great deal of interest in
developing small molecule UT modulators. Several non-peptidic
UT ligands (1–3, Fig. 1) have recently been reported.9,10 Herein,
we describe the discovery of a novel series of N-alkyl-5H-pyr-
ido[4,3-b]indol-1-amines as UT antagonists.
High throughput screening (HTS) of our compound collection
using a fluorometric imaging plate reader (FLIPR) assay (measuring
inhibition of hU-II induced [Ca2+]i-mobilization in HEK293 cells
expressing human recombinant UT receptor)11 identified com-
pound 4 as a submicromolar antagonist (pIC50 = 6.3). The tricyclic
compound 4 also showed good hUT binding affinity (pKi = 8.1)
in a [125I]hU-II radioligand binding assay using HEK293 cell
membranes stably expressing human recombinant UT receptors.11
The hUT binding assay was used as the primary assay for SAR
exploration.
The synthesis of N-alkyl-5H-pyrido[4,3-b]indol-1-amines
started with commercially available phenylhydrazine 5 and 4-hy-
droxy-2(1H)-pyridinone 6 (Scheme 1). Heating 5 and 6 in diphenyl
ether (DPE) gave 4-(2-phenylhydrazino)-2(1H)-pyridinone, which
underwent Fischer indole cyclization under reflux condition to af-
ford 2,5-dihydro-1H-pyrido[4,3-b]indol-1-one 7.12 Refluxing 7 in
neat POCl3, followed by HCl treatment produced the key interme-
diate, 1-chloro-5H-pyrido[4,3-b]indole 8. Nucleophilic aromatic
substitution of 8 with a variety of amines under conventional or
microwave heating led to 5H-pyrido[4,3-b]indol-1-amines 9.12 N-
Alkylation of 8 with alkyl halides under ultrasonic condition
formed 1-chloro-5-alkyl-5H-pyrido[4,3-b]indoles 10,13 which
upon nucleophilic aromatic substitution with different amines
afforded 5-alkyl-5H-pyrido[4,3-b]indol-1-amines 11.
N-Alkyl-1H-pyrido[2,3-b]indol-4-amines 14 were prepared
from 4-chloro-9H-pyrido[2,3-b]indoles 13 via nucleophilic aro-
matic substitution with N-alkylamines (Scheme 2). The 4-chloro
compounds 13 can be synthesized from 9H-pyrido[2,3-b]indole
1-oxides which can be made from the corresponding 9H-pyr-
ido[2,3-b]indoles or a
-carbolines 12.14
We first explored the amino side-chain moiety by preparing
analogs containing a variety of N-alkyl or aromatic amines. For
straight chain alkylamines ( 4, 9a–9d), hUT binding affinity in-
creases with the length of alkyl side-chain, e.g., Et < Pr < Bu, Pent,
Hex (Table 1). Branched alkylamines (9e–9g) are also allowed
* Corresponding author. Tel.: +1 610 917 6678; fax: +1 610 917 7391.
E-mail address: yonghui.2.wang@gsk.com (Y. Wang).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.054

Y. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4936–4939
4937
Cl
O
N
Cl
O
N
H
N
N
H
O
N
Cl
N
N
O
O
N
O
O
2
1
HN
N
N
N
Cl
N
O
N
H
Cl
4
3
Figure 1. Examples of non-peptidic UT ligands (1–3) and HTS hit 4.
ilar trend was observed with aromatic amines (9l–9o), e.g.,
phenyl ꢀ phenethyl < thienylmethyl, benzyl. In general, less steri-
cally hindered amines exhibited good hUT binding affinity. For het-
eroalkyl amines, oxygen-containing analogs (9p–9r) showed good
hUT binding affinities while nitrogen-containing compounds (9s
and 9t) were found to have no binding affinity. Furthermore, amide
containing side chains (9u and 9v) completely abolished binding
affinity. Also notable is that compared to secondary amino groups,
the tertiary amino groups (9w and 9x) showed much less hUT
binding affinity.
O
H
N
O
H
N
a
+
NH2
N
H
N
HO
N
H
7
5
6
2 R
N
Cl
1 R
N
c
b
The SAR of other parts of the tricyclic molecule was subse-
quently explored (Table 2). While 5-methyl (11a) and 5-isopropyl
(11b) had good hUT binding affinity, 5-benzyl (11c) showed poor
binding affinity. All three compounds had less binding affinity to
hUT compared to 4 (where 3R = H). Tricyclic analogs with the pyr-
ido-nitrogen at 4-position (or N-alkyl-1H-pyrido[2,3-b]indol-4-
amines) were tested in the hUT binding assay. Compared to the
corresponding analogs with pyrido-nitrogen at 2-position, these
4-pyrido tricyclic compounds were found to have less hUT binding
affinity (comparing 4 to 14d, 9p to 14e, 9i to 14f, and 9k to 14g).
For 4-pyrido tricyclic compounds, substituents on indole phenyl
ring (14h–14j) were well-tolerated with hUT binding pKi’s of 7.2,
7.3, and 7.5, respectively.
In addition to high hUT binding affinity, the tricyclic com-
pounds showed good functional activities in a hUT FLIPR assay
(Table 3). For example, compound 4 was found to be a competitive
and reversible antagonist with a pA2 of 7.0.15 The tricyclic com-
pounds were also evaluated for their cross-species activities and
found to be active in a cat UT binding assay16 (Table 3). For exam-
ple, compound 4 showed cat UT binding pKi of 6.2. However, these
tricyclic compounds were inactive or much less active in a rat UT
binding assay.17
N
H
N
H
8
9
d
2 R
N
1 R
Cl
N
N
c
N
3 R
N
3 R
10
11
Scheme 1. Reagents and conditions: (a) i—DPE, heating (Dean-Stark); ii—DPE,
reflux; (b) i—POCl3, reflux; ii—HCl, heating (33% yield for two steps); (c) 1R2RNH,
heating; (d) 3RX, KOH, TBAI, toluene, ultrasound.
but hUT binding affinity decreases dramatically when a branch is
located at a-position of alkylamines. The trend was also observed
for cycloalkyl amines (9h–9k). For example, both cyclopropyl
amine and cyclohexyl amine were found to have little or no bind-
ing affinity while the corresponding cyclopropylmethyl amine and
cyclohexylmethyl amine showed high hUT binding affinity. A sim-
2 R
N
1 R
Cl
c
a, b
4 R
4 R
4 R
N
N
N
N
H
N
N
H
H
14
13
12
Scheme 2. Reagents and conditions: (a) 30% H2O2, HOAc, heating; (b) POCl3, DMF, rt; (c) 1R2RNH, heating.

4938
Y. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4936–4939
Table 1
Table 3
SAR of the amino side-chain moiety
cat UT binding and hUT FLIPR data
2 R
N
15
cat UT binding pKia
hUT FLIPR pA2
1 R
Compound
4
6.2
6.4
6.7
5.9
5.8
5.6
6.0
5.5
6.0
7.0
—
—
7.0
—
6.9
7.7
6.8
—
N
9c
9d
9f
9g
9i
9m
9o
11a
N
H
Compound
1R-N-2R
hUT binding (pKi)a
9a
9b
4
Et-NH
Pr-NH
Bu-NH
5.8
7.6
8.4
8.4
8.2
6.1
8.0
7.9
5.6
8.2
<5.1
8.0
<5.1
7.9
7.0
7.6
7.7
7.9
7.1
a
Mean of at least two determinations; pKi was calculated from Ki using formula,
pKi = ÀlogKi; for Ki determination, see Ref. 9e.
9c
9d
9e
9f
9g
9h
9i
Pent-NH
Hex-NH
(1-Me)Bu-NH
(2-Me)Bu-NH
(3-Me)Bu-NH
c-Pr-NH
c-Pr-CH2-NH
c-Hex-NH
M1, M2, M3, M4, M5, CXCR2) and about 400-fold selective for
hUT over hERG (binding pIC50 = 5.8). However, compound
showed potent cytochrome P450 inhibition of the 2D6 (pIC50
4
=
9j
8.1) and 3A4 (pIC50 = 7.0) isoforms. In an in vivo rat iv/po pharma-
cokinetic (PK) study (0.49 mg/kg iv, 0.97 mg/kg po), compound 4
showed high clearance, short half life, and low oral bioavailability
(Clb = 110 mL/min/kg, T1/2 = 1.3 h, F = 11%).
In summary, we discovered a novel series of N-alkyl-5H-pyr-
ido[4,3-b]indol-1-amines and derivatives as urotensin-II receptor
antagonists. Tractable SAR was demonstrated through analog syn-
thesis. The compounds in the series exhibited high hUT binding
affinity and functional and ortholog activities. The preliminary data
suggests that this series constitutes a reasonable starting point for
further lead optimization.
9k
9l
c-Hex-CH2-NH
Ph-NH
9m
9n
9o
9p
9q
9r
9s
9t
9u
9v
9w
9x
Bn-NH
Ph-(CH2)2-NH
thienyl-CH2-NH
(2-OMe)Et-NH
(2-OEt)Et-NH
(tetrahydro-2-furanyl)-CH2-NH
[2-N(Me)2]Et-NH
[2-(4-morpholinyl)]Et-NH
(2-acetylamino)Et-NH
(2-aminocarbonyl)Et-NH
(2-OMe)Et-NMe
<5.1
<5.1
<5.1
<5.1
<5.1
6.1
(Bu)2N
References and notes
a
Mean of at least two determinations; pKi was calculated from Ki using formula,
pKi = ÀlogKi; for Ki determination, see Ref. 9e.
1. Ames, R. S.; Sarau, H. M.; Chambers, J. K.; Willette, R. N.; Aiyar, N. V.; Romanic,
A. M.; Louden, C. S.; Foley, J. J.; Sauermelch, C. F.; Coatney, R. W.; Ao, Z.; Disa, J.;
Holmes, S. D.; Stadel, J. M.; Martin, J. D.; Liu, W. S.; Glover, G. I.; Wilson, S.;
McNulty, D. E.; Ellis, C. E.; Elshourbagy, N. A.; Shabon, U.; Trill, J. J.; Hay, D. W.;
Ohlstein, E. H.; Bergsma, D. J.; Douglas, S. A. Nature 1999, 401, 282.
2. Douglas, S. A.; Dhanak, D.; Johns, D. G. Trends Pharmacol. Sci. 2004, 25, 76.
3. (a) Matsushita, M.; Shichiri, M.; Imai, T.; Iwashina, M.; Tanaka, H.; Takasu, N.;
Hirata, Y. J. Hypertens. 2001, 19, 2185; (b) Cheung, B. M.; Leung, R.; Man, Y. B.;
Wong, L. Y. J. Hypertens. 2004, 22, 1341.
Table 2
SAR of the 3R, 4R, and pyridine regions
2 R
N
1 R
2
1
X
9
6
4. Russell, F. D.; Meyers, D.; Galbraith, A. J.; Bett, N.; Toth, I.; Kearns, P.; Molenaar,
P. Am. J. Physiol. 2003, 285, H1576.
3
4 R8
7
Y4
5. (a) Douglas, S. A.; Tayara, L.; Ohlstein, E. H.; Halawa, N.; Giaid, A. Lancet 2002,
359, 1990; (b) Ng, L. L.; Loke, I.; O’Brien, R. J.; Squire, I. B.; Davies, J. E. Circulation
2002, 106, 2877;; (c) Richards, A. M.; Nicholls, M. G.; Lainchbury, J. G.; Fisher,
S.; Yandle, T. G. Lancet 2002, 360, 545;; (d) Lapp, H.; Boerrigter, G.; Costello-
Boerrigter, L. C.; Jaekel, K.; Scheffold, T.; Krakau, I.; Schramm, M.; Guelker, H.;
Stasch, J. P. Int. J. Cardiol. 2004, 94, 93.
N
3 R
5
Compound
X
Y
1R-N-2R
3R
4R
hUT binding (pKi)a
4
N
N
N
N
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
N
N
N
Bu-NH
Bu-NH
Bu-NH
Bu-NH
Bu-NH
(2-MeO)Et-NH
c-Pr-CH2-NH
c-Hex-CH2-NH
Bu-NH
H
H
H
H
H
H
H
H
H
8.4
7.3
7.2
5.4
7.1
6.5
7.0
6.1
7.2
7.3
7.5
6. (a) Bousette, N.; Patel, L.; Douglas, S. A.; Ohlstein, E. H.; Giaid, A. Atherosclerosis
2004, 176, 117; (b) Maguire, J. J.; Kuc, R. E.; Wiley, K. E.; Kleinz, M. J.; Davenport,
A. P. Peptides 2004, 25, 1767.
7. (a) Totsune, K.; Takahashi, K.; Arihara, Z.; Sone, M.; Satoh, F.; Ito, S.; Kimura, Y.;
Sasano, H.; Murakami, O. Lancet 2001, 358, 810; (b) Shenouda, A.; Douglas, S.
A.; Ohlstein, E. H.; Giaid, A. J. Histochem. Cytochem. 2002, 50, 885; (c) Langham,
R. G.; Gow, R.; Thomson, N. M.; Dowling, J. K.; Gilbert, R. E. Am. J. Kidney Dis.
2004, 44, 826.
11a
11b
11c
14d
14e
14f
14g
14h
14i
14j
Me
iPr
Bn
H
H
H
H
H
H
H
8. (a) Totsune, K.; Takahashi, K.; Arihara, Z.; Sone, M.; Satoh, F.; Ito, S.; Murakami,
O. Clin. Sci. 2003, 104, 1; (b) Wenyi, Z.; Suzuki, S.; Hirai, M.; Hinokio, Y.;
Tanizawa, Y.; Matsutani, A.; Satoh, J.; Oka, Y. Diabetologi 2003, 46, 972.
9. (a) Flohr, S.; Kurz, M.; Kostenis, E.; Brkovich, A.; Fournier, A.; Klabunde, T. J.
Med. Chem. 2002, 45, 1799; (b) Croston, G. E.; Olsson, R.; Currier, E. A.; Burstein,
E. S.; Weiner, D.; Nash, N.; Severance, D.; Allenmark, S. G.; Thunberg, L.; Ma, J.;
Mohell, N.; O’Dowd, B.; Brann, M. R.; Hacksell, U. J. Med. Chem. 2002, 45, 4950;
(c) Clozel, M.; Binkert, C.; Birker-Robaczewska, M.; Boukhadra, C.; Ding, S.;
Fischli, W.; Hess, P.; Mathys, B.; Morrison, K.; Muller, C.; Muller, C.; Nayler, O.;
Qiu, C.; Rey, M.; Scherz, M. W.; Velker, J.; Weller, T.; Xi, J.; Ziltener, P. J.
Pharmacol. Exp. Ther. 2004, 311, 204; (d) Jin, J.; Dhanak, D.; Knight, S. D.;
Widdowson, K.; Aiyar, N.; Naselsky, D.; Sarau, H. M.; Foley, J. J.; Schmidt, D. B.;
Bennett, C. D.; Wang, B.; Warren, G. L.; Moore, M. L.; Keenan, R. M.; Rivero, R.
A.; Douglas, S. A. Bioorg. Med. Chem. Lett. 2005, 15, 3229; (e) Douglas, S. A.;
Behm, D. J.; Aiyar, N. V.; Naselsky, D.; Disa, J.; Brooks, D. P.; Ohlstein, E. H.;
Gleason, J. G.; Sarau, H. M.; Foley, J. J.; Buckley, P. T.; Schmidt, D. B.; Wixted, W.
E.; Widdowson, K.; Riley, G.; Jin, J.; Gallagher, T. F.; Schmidt, S. J.; Ridgers, L.;
Christmann, L. T.; Keenan, R. M.; Knight, S. D.; Dhanak, D. Br. J. Pharmacol. 2005,
145, 620; (f) Lehmann, F.; Pettersen, A.; Currier, E. A.; Sherbukhin, V.; Olsson, R.;
Hacksell, U.; Luthman, K. J. Med. Chem. 2006, 49, 2232; (g) Luci, D. K.; Ghosh, S.;
8-Me
8-Cl
6-OMe
Bu-NH
Bu-NH
a
Mean of at least two determinations; pKi was calculated from Ki using formula,
pKi = ÀlogKi; for Ki determination, see Ref. 9e.
Exemplars in the series exhibited good physicochemical proper-
ties. For example, compound 4 had good aqueous solubility
(195 l
M) and artificial membrane permeability (470 nm/s).18 For
selectivity, compound 4 showed at least 100-fold selectivity vs a
number of 7TM receptors (5HT1A, 5HT1B, 5HT1D, 5HT2A, 5HT2C,
5HT3, 5H4A, 5HT6, 5HT7, Histamine H1, Histamine H3, Dopamine
D2, Dopamine D3, Adrenergic alpha 1A, Adrenergic alpha 1B,
Adrenergic beta 2, Adenosine A1, Adenosine A2a, Adenosine A2b,

Y. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4936–4939
13. Davidson, R. S.; Patel, A. M.; Safdar, A. Tetrahedron Lett. 1983, 24, 5907.
4939
Smith, C. E.; Qi, J.; Wang, Y.; Haertlein, B.; Parry, T. J.; Li, J.; Almond, H. R.; Minor,
L. K.; Damiano, B. P.; Kinney, W. A.; Maryanoff, B. E.; Lawson, E. C. Bioorg. Med.
Chem. Lett. 2007, 17, 6489; (h) Jin, J.; Wang, Y.; Wang, F.; Shi, D.; Erhard, K. F.;
Wu, Z.; Guida, B. F.; Lawrence, S. K.; Behm, D. J.; Disa, J.; Vaidya, K. S.; Evans, C.;
McMillan, L. J.; Rivero, R. A.; Neeb, M. J.; Douglas, S. A. Bioorg. Med. Chem. Lett.
2008, 18, 2860; (i) McAtee, J. J.; Dodson, J. W.; Dowdell, S. E.; Girard, G. R.;
Goodman, K. B.; Hilfiker, M. A.; Neeb, M. J.; Sehon, C. A.; Sha, D.; Wang, G.;
Wang, N.; Viet, A.; Zhang, D.; Aiyar, N.; Behm, D. J.; Carballo, L. H.; Evans, C. A.;
Fries, H. E.; Nagilla, R.; Roethke, T. J.; Xu, X.; Yuan, C. K.; Douglas, S. A. Bioorg.
Med. Chem. Lett. 2008, 18, 3500; (j) McAtee, J. J.; Dodson, J. W.; Dowdell, S. E.;
Erhard, K.; Girard, G.; Goodman, K. B.; Hilfiker, M. A.; Jin, J.; Sehon, C. A.; Sha, D.;
Shi, D.; Wang, F.; Wang, G. Z.; Wang, N.; Wang, Y.; Viet, A. Q.; Yuan, C. K.;
Zhang, D.; Aiyar, N.; Behm, D. J.; Carballo, L. H.; Evans, C. A.; Fries, H. E.; Nagilla,
R.; Roethke, T. J.; Xu, X.; Douglas, S. A.; Neeb, M. J. Bioorg. Med. Chem. Lett. 2008,
18, 3716; (k) Jin, J.; An, M.; Sapienza, A.; Aiyar, N. V.; Naselsky, D.; Sarau, H. M.;
Foley, J. J.; Salyers, K. L.; Knight, S. D.; Keenan, R. M.; Rivero, R. A.; Dhanak, D.;
Douglas, S. A. Bioorg. Med. Chem. Lett. 2008, 18, 3950.
14. (a) Stephenson, L.; Warburton, W. K. J. Chem. Soc. 1970, 1355; (b) Elks, J.; Webb,
G. B.; Gregory, G. I.; Cocker, J. D. Brit. 1972, Patent GB1268773.
15. FLIPR pA2 value determination: the experiments were performed with various
concentrations of agonist (urotensin-II) added to the cells in the presence and
absence of antagonist compounds. Eleven concentrations of each test
compounds were applied to the studies. EC50 values of the agonist were
measured for all conditions and dose-ratios calculated for each concentration
of antagonist. The antagonist potency of test compounds (pA2 value) were
calculated using Schild plot analysis using dose-ratios. See: Kenakin, T.
Pharmacologic Analysis of Drug–Receptor Interaction, 3rd ed.; Lippincott-Raven
Press, 1997.
16. For cat and rat UT receptor radioligand binding assay details, see: Ref. 9e.
17. The reason that the binding affinity was different across species for the tricyclic
series was not clear. This phenomenon was also observed for the other UT
ligand. See, Ref. 9c.
18. The artificial phospholipid membrane technique is similar to the widely used
Caco-2 cell monolayer permeation technique. In short, egg phosphatidyl
choline (1.8%) and cholesterol (1%) are dissolved in n-decane. A small amount
of the volatile mixture is applied to the bottom of the microfiltration filter
inserts. Phosphate buffer (0.05 M, pH 7.05) is quickly added to the donors and
receivers, and the lipids are allowed to form self-assembled lipid bilayers
across the small holes in the filter. Permeation experiment is initiated by
spiking the compounds of interest to the donor sides, and the experiment is
stopped at a pre-determined elapsed time. The samples are withdrawn and
transferred to appropriate vials for analysis by HPLC with UV detection
(215 nm).
10. For recent reviews, see: (a) Dhanak, D.; Neeb, M. J.; Douglas, S. A. Ann. Reports
Med. Chem. 2003, 38, 99; (b) Jin, J.; Douglas, S. A. Expert Opin. Ther. Patents 2006,
16, 467; (c) Carotenuto, A.; Grieco, P.; Rovero, P.; Novellino, E. Curr. Med. Chem.
2006, 13, 267.
11. (a) For radioligand binding and [Ca2+]i-mobilization assay details, see: Dhanak,
D.; Knight, S. D.; Jin, J.; Keenan, R. M. WO Patent 2001045711-A1, 2001; Chem.
Abstr. 2001, 135, 76785.; (b) Ref. 9e.
12. (a) Ducrocq, C.; Civier, A.; Andre-Louisfert, J.; Bisagni, E. J. Heterocycl. Chem.
1975, 12, 963; (b) Nguyen, C. H.; Bisagni, E. Tetrahedron 1987, 43, 527; (c)
Bisagni, E.; Nguyen, C. H.; Pierre, A.; Pepin, O.; De Cointet, P.; Gros, P. J. Med.
Chem. 1988, 31, 398.