Design of a new histamine H3 receptor antagonist chemotype: (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, synthesis, and structure-activity relationships

Article abstract of DOI:10.1021/jm900480x

A new histamine H₃ receptor (H₃R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural featu

Full text of DOI:10.1021/jm900480x

4640 J. Med. Chem. 2009, 52, 4640–4649
DOI: 10.1021/jm900480x
Design of a New Histamine H3 Receptor Antagonist Chemotype: (3aR,6aR)-5-Alkyl-1-aryl-
octahydropyrrolo[3,4-b]pyrroles, Synthesis, and Structure-Activity Relationships
Chen Zhao,* Minghua Sun,† Youssef L. Bennani,‡ Thomas R. Miller, David G. Witte, Timothy A. Esbenshade, Jill Wetter,
Kennan C. Marsh, Arthur A. Hancock, Jorge D. Brioni, and Marlon D. Cowart
Department of Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park,
Illinois 60064-6123. †Present address: Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080. ‡Present address: Vertex
Pharmaceuticals, 130 Waverly Street, Cambridge, MA 01239.
Received April 15, 2009
A new histamine H3 receptor (H3R) antagonist chemotype 1 was designed by combining key
pharmacophoric elements from two different precursor structural series and then simplifying and
optimizing the resulting combined structural features. First, analogues were made based on a previously
identified conessine-based H3R antagonist series. While the first analogues 11 and 15 showed no
antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound
7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too
synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify
the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series
proved to be highly potent, as exemplified by 17a having a human H3 Ki of 0.54 nM, rat H3 Ki of 4.57 nM,
and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t1/2 of 2.4 h).
Introduction
Of the two key analogues made (3a and 3b), only compound
3a retained potency, highlighting the critical basic site for H3R
ligands. The SAR identified a minimal H3 binding pharmac-
ophore as the A, B, C, and D rings of the steroid skeleton plus
the basic pyrrolidine, as depicted by the portion of the
structure encircled in compound 3a. Further SAR studies on
this pharmacophore led to compound 4,10 which had 10-25ꢀ
greater H3R potency in vitro, along with significantly reduced
off-target bindings with the exception of M1 receptor (Ki
11nM). Despiteotherwise good properties, thiscompound(4)
retained extremely slow CNS clearance (t1/2 77 h), which was
viewed as likely a detrimental profile for a drug candidate. We
hypothesized that these problems might be addressed if addit-
ional, likely extensive, changes were made through designing
new structures.
The histamine H3 receptor (H3R) was first described in
19831 and cloned in 1999.2 It is a G-protein coupled receptor
(GPCRa) predominantly expressed in the central nervous
system (CNS) and is known to modulate the release of multi-
ple neurotransmitters, including histamine, acetylcholine,
dopamine, and noradrenaline.3 Antagonists of the H3 recep-
tor are well-known to induce the release of these neurotrans-
mitters in vitro and in vivo and have been found effective in
diverse CNS behavioral animal models.4 Thus, there is ex-
tensive preclinical data supporting the notion that H3 antago-
nists offer a promising approach for the treatment of several
CNS disorders including Alzheimer’s disease,5 sleep disor-
ders,6 attention deficit hyperactivity (ADHD),7 and cognitive
dysfunctions of schizophrenia.8 We report herein the retro-
design and optimization of a new highly potent and selective
structural class of histamine H3 antagonists (1) with excellent
PK profiles and CNS penetration (Chart 1).
Results and Discussion
The earlier studies on analogues of 3 and 4 relied on the
readily available 2 to allow the semisynthesis of steroid-based
structures. However, to make yet more diverse analogues with
such a steroid skeleton would require a prohibitively demand-
ing dedication of synthetic resources to develop methods to
install and orient all the chiral centers and rings. A comprom-
ise series was thus targeted, which contained the putative C
and D rings of the steroidal lead as well as the key pyrrolidine.
Compound 5 was previously reported by Meyers11 as a syn-
thetic intermediate toward a formal total synthesis of 2. We
hypothesized that intermediate compound 5 might still retain
just enough structural similarity to the pharmacophore iden-
tified for 3a to be active as H3R antagonist and justify SAR
studies and further optimization intoa viable series. It was also
hypothesized that the aromatic ring in 5 might mimic the
saturated B ring of 2, whereas the methoxy group in 5 could act
We recently reported the discovery of 2 (conessine)9 as an
H3 antagonist in an HTS screen (Scheme 1).10 2 was potent at
H3R in vitro but possessed some significant shortcomings
including very low selectivity at adrenergic receptors, slow
CNS clearance (>60% remaining in brain 24 h after dosing in
rats), and key structural features (two dibasic amines, highly
lipophilic steroid skeleton) that have been causally associated
with the induction of phospholipidosis. SAR studies were
carried out in a first attempt to address those shortcomings.
*To whom correspondence should be addressed. Phone: (847)
938-5292. Fax: (847) 937-9195. E-mail: chen.zhao@abbott.com.
a Abbreviations: SAR, structure-activity relationships; HTS, high
throughput screening; hERG, human ether-a-go-go related gene; M1,
muscarinic acetylcholine receptor; GPCR, G-protein coupled receptor;
CNS, central nervous system; PK, pharmacokinetics.
r
pubs.acs.org/jmc
Published on Web 07/09/2009
2009 American Chemical Society

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4641
Chart 1
Scheme 1. Preparation and Binding Affinity of 2 Analogues
Figure 1. Design of hybrid series combining elements of 2 with 7.
Scheme 2. Synthetic Route for the Preparation of Benzo[4,5]
hydrindeno[1,7a-c]-1-benzylpyrrolidine Derivativesa
as a useful synthetic “handle” for new analogues (6) . As such,
the selection of the appropriate R group in the aromatic ring,
a 4-cyano and 4-acetyl were preferred, as we had already found
that these motifs conferred good drug likeness when present in
benzofurans such as 7 (ABT-239) (Figure 1).12
The key intermediate 8 was synthesized in nine steps with
27% overall yield following the previously reported method
by Meyers.11 This 3:1 mixture of isomers could be separated,
contrary to what was stated in Meyer’s paper, to yield
compounds 9 and 10. The S-isomer 9 was methylated via
reductive amination to give 11, which was then treated with
BBr3 to afford the hydroxyl analogue 12. The latter was then
converted to the reactive triflate 13, suitable for the coupling
reaction to afford the desired target compounds 14. The R-
isomeric compounds 16a-b were made from 10 by the same
reaction sequence as was used to prepare 14 from 9. The in
vitro binding data of the analogues at histamine H3 receptors
is shown in Table 1. We were disappointed to find that nei-
ther of the epimeric anisoles 11 and 15 had activity at H3R
(Ki>1000 nM). However, the addition of an extra aromatic
ring, as seen with homologated analogues 14 and 16a-b, led
to a significant boost in affinity. Of these, the S-isomeric
compound (14) was found active, although significantly less
potentthan2athuman(21-fold)andratH3R (17-fold)despite
possessing the same configuration (S) as 2. However, the new
R-isomeric compounds (16a and 16b) both displayed potent
binding affinity, only a few-fold weaker than 2 itself. This was
surprising in light of the fact that compounds 16a and 16b
have an R configuration at the benzyl-H, which is opposite to
that present in 2.
a Reagents and conditions: (i) Silica gel flash column chromatography;
10%CH3OH/CH2Cl2 þ 1%NH4OH; (ii) HCOH, NaBH3CN, CH3OH;
(iii) BBr3, CH2Cl2; (iv) Tf2O, Et3N, CH2Cl2; (v) R-B(OH)2, Pd(PPh3)4,
Na2CO3, toluene, EtOH, H2O.
synthesis (14 steps), together with the moderate potency for
H3R, could not justify additional work within the series.
Nevertheless, there were some advantages inherent in the
series: structures such as 16 are highly rigidified, and we have
previously used the principle of rigidifying structures to
improve the PK properties, selectivity, and drug-likeness of
H3R antagonists.13 Therefore, with the goal of designing a
simplifiedstructural corethatwould retain the rigidityand the
overall 3D shape of 14 and 16, yet support a more straight-
forward synthesis to facilitate SAR optimization, we pro-
posed a new structural series based on a retro-design by
combining several hypotheses.
First, the 2S-methyl substituent on the pyrrolidine moietyof
6 possibly was not absolutely necessary for H3R activity
because both 14 and 16 lack this 2S-methyl yet havesignificant
binding potency. Second, we proposed a possible structural
overlap of 6 and 7 (Figure 2), which if operative would imply
Overall, the hypothesis that structures such as 14 and 16
would be active was proven true, but the more elaborate

4642 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15
Zhao et al.
Table 1. Binding Affinities of Benzo[4,5]hydrindeno[1,7a-c]-1-benzylpyrrolidine Derivatives at Human and Rat H3Ra
compd
R group
human H3 pKi ( SEM
human H3Ki (nM)
rat H3 pKi ( SEM
rat H3Ki (nM)
2
8.27 ( 0.10
>6.00
>6.00
5.37
7.61 ( 0.08
>6.00
>6.00
24.5
11
15
14
16a
16b
7
CH3O-
CH3O-
3-AcPh-
3-AcPh-
4-CNPh-
4-CNPh-
<1000
<1000
115
<1000
<1000
417
6.94 ( 0.14
7.81 ( 0.06
7.84 ( 0.06
9.35 ( 0.04
6.38 ( 0.45
6.84 ( 0.25
7.34 ( 0.30
8.49 ( 0.04
15.5
14.5
145
45.7
0.45
3.22
a Binding potencies were assessed by displacement of 3H-N-R-methyl histamine. The human H3 values were from cloned human H3 expressed in C6
cells, while rat H3 values were from rat cortical membranes. The pKi (-log Ki) ( the standard error of the mean (SEM) are reported (n g 3).
Scheme 3. Synthetic Route for the Preparation of (3aR,6aR)-
Octahydropyrrolo[3,4-b]pyrrole Derivatives 17aa
Figure 2. Design of aryl-octahydropyrrolo[3,4-b]pyrrole series 17
based on combining elements of 6 and 7.
a Reagents and conditions: (i) HCOH, NaBH3CN, CH3OH; (ii) 3 N
HCl, CH3OH; (iii) 1,4-dibromobenzene, Pd2(dba)3, BINAP, t-BuONa,
that the two methylenes forming the cyclohexane ring of 6
could be deleted, as the highly potent 7 lacks a similarly
Ph, Toluene/i-PrOH/H2O, 70 °C.
situated substituent or ring. Third, we hypothesized that the
Toluene, 70 °C; (iv) 4-CN-Ph-B(OH)2, Pd(OAc)2, K3PO4, (Cy)2P-Ph-
benzylic carbon might be replaced with a nitrogen atom, which
would greatly simplify synthesis by imparting the benefit of
eliminating one chiral center and allowing facile formation of
the C-N bond via well-precedented cross-coupling proce-
dures. Lastly, the implementation of this plan was enabled
by the availability of the pyrrolidinylpyrrolidine intermediate
20 in optically pure form.14
was methylated with NaBH3CN and formaldehyde and then
deprotected by treatment with acid to give 20, which was then
subjected to Pd-catalyzed cross-coupling with 1,4-dibromo-
benzene to give 21. This versatile intermediate bromide was
then treated with 4-cyanobenzene boronic acid under cross-
coupling conditions to yield 17a. In addition to the first
analogue, 17a, which had an N-methyl substituent, a series
of N-alkylated analogues (17c-h) were made to probe the
SAR at this position. For these compounds, the synthetic
TherouteshowninScheme3 wasusedtosynthesize the first
targeted analogue 17a. First, the synthetic intermediate 1814
Table 2. SAR Summary of R1 Alkyls in Analogue 17a
compd
R group
Me-
H-
Et-
i-Pr-
c-Pr-CH2-
n-Pr-
i-Bu-
n-Bu-
human H3 pKi ( SEM
human H3Ki (nM)
rat H3 pKi ( SEM
rat H3Ki (nM)
17a
17b
17c
17d
17e
17f
17g
17h
9.27 ( 0.20
6.49 ( 0.04
8.18 ( 0.08
7.37 ( 0.04
7.26 ( 0.17
7.15 ( 0.03
6.64 ( 0.17
6.26 ( 0.26
0.54
324
8.34 ( 0.04
>6.00
4.57
<1000
35.5
851
6.61
42.7
55.0
70.8
229
7.45 ( 0.13
6.07 ( 0.07
6.40 ( 0.13
6.27 ( 0.07
>6.00
398
537
<1000
<1000
550
>6.00
a Binding potencies were assessed by displacement of 3H-N-R-methyl histamine. The human H3 values were from cloned human H3 expressed in C6
cells, while rat H3 values were from rat cortical membranes. The pKi (-log Ki) ( the standard error of the mean (SEM) are reported (n g 3).

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4643
Table 3. SAR Summary of Bicyclic Diamine Coresa
Table 4. SAR Summary of (3aR,6aR)-1-Aryl-5-methyl-octahydropyr-
rolo[3,4-b]pyrrole Analoguesa
a Binding potencies were assessed by displacement of 3H-N-R-methyl
histamine. The human H3 values were from cloned human H3 expressed
in C6 cells, while rat H3 values were from rat cortical membranes.
The pKi (-log Ki) ( the standard error of the mean (SEM) are reported
(n g 3).
sequence was modified in order to put the alkyl groups more
efficiently. The intermediate 18 was first protected by Cbz,
followed by Boc removal, the resulting (3aR,6aR)-hexahydro-
pyrrolo[3,4-b]pyrrole-5-carboxylic acid benzyl ester was
coupled with trifluoro-methanesulfonic acid 40-cyano-biphenyl-
4-yl ester under palladium coupling condition. The Cbz group
was finally removedtogive the N-H analogue17b, which was
alkylated under reductive amination or alkylation conditions
to give the desired N-alkyl analogues 17c-h. The in vitro
potencies on H3R of these compounds are shown in Table 2.
We were gratified to find that the first targeted analogue
(17a) was highly potent at human H3R (0.54 nM) and rat H3
(4.57 nM), which is a significant improvement compared to
the earlier series of analogues 14 and 16a-b. The SAR of the
N-alkyl substituent showed clear trends for in vitro potency.
The N-H analogue 17b had only weak activity, which was in
line with our finding that tertiary amine H3R antagonists are
significantlymorepotent thansecondary amines. Ontheother
hand, the effect of the size of alkyl groups was quite unex-
pected: asgroups grew larger thanmethyl, a rapidreductionin
potency was seen. This was a surprising finding in light of the
many reports on diverse H3R antagonists series where typi-
cally an isopropopyl or comparably sized cyclobutyl confers
higher potency than methyl substituents.15,16
a Binding potencies were assessed by displacement of 3H-N-R-methyl
histamine. The human H3 values were from cloned human H3 expressed
in C6 cells, while rat H3 values were from rat cortical membranes. The
pKi (-log Ki) ( the standard error of the mean (SEM) are reported (n g 3).
With the new finding that the (3aR,6aR)-octahydropyrrolo
[3,4-b]pyrrole ring conferred good in vitro H3 potency to the
series 17, an investigation was undertaken to understand how
broad the SAR for this bicyclic diamine moiety would be. For
this purpose, compounds 22-27 were synthesized with differ-
ent ring sizes and stereochemistries. First, with compound 22
(the opposite enantiomer of 17a), the absolute stereochemistry
was found to be criticalbecause 22 was 1440-fold lower in H3R
potency than 17a. Next, the effect of orientation of the

4644 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15
Table 5. Rat Pharmacokinetic Properties of Selected H3 Antagonistsa
Zhao et al.
purification. 1H NMR spectra were obtained on a Varian
Mercury plus 300 or Varian UNITY plus 300 MHz instrument
with chemical shifts (δ, ppm) determined using TMS as internal
standard. Abbreviations used in description of NMR spectra:
s=singlet, d=doublet, t=triplet, dd=double doublet, dt=
double triplet, m=multiplet, br=broad singlet. Mass spectra
were obtained on a Kratos MS-50 instrument, and unless
otherwise indicated, all MS instruments were operated in the
þAPCI or þDCI mode to detect positively charged ions.
Elemental analysis was performed by Quantitative Technolo-
gies, Inc. Flash column chromatography was performed with
prepacked Analogix cartridges. Thin-layer chromatography
was performed on 250 mm silica gel 60 glass-backed plates from
Merck with F254 as indicator. All target compounds possessed a
purity of at least 95% as determined by elemental analysis.
(4bS,6aS,9aR)-2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4bH-
benz[4,5]indeno[1,7a-c]pyrrole (9) and (4bR,6aS,9aR)-2-Meth-
oxy-5,6,6a,7,8,9,10,11-octahydro-4bH-benz[4,5]indeno[1,7a-c]-
pyrrole (10). 8-Benzyl-2-methoxy-6a,7,8,9,10,11-hexahydro-6H-
benzo[4,5]indeno[1,7a-c]pyrrole (prepared according to the
procedure of Meyers10) (1.0 g, 3.0 mmol) and 10% Pd/C (200
mg) were stirred in ethanol (30 mL) under hydrogen for 2 h.
The reaction mixture was filtered and concentrated under vacuum
to provide 617.8 mg (84.2%) of 2-Methoxy-5,6,6a,7,8,9,10,11-
octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrole (8) as a 3:1
mixture of R/S isomers. MS (DCI/NH3): m/z 244 (M þ H)þ.
The mixture 8 was separated by flash chromatography (silica
gel, 20:1:0.1 CH2Cl2/CH3OH/NH4OH) to provide pure 9 and 10.
9. 1H NMR (300 MHz, CDCl3): δ 6.98 (dd, 1H, J=8.7, 1.2
Hz), 6.66 (s, 1H), 6.64 (d, 1H, J=3.0 Hz), 3.76 (s, 3H), 3.16 (dd,
1H, J=11.5, 6.0 Hz), 3.00 (dd, 1H, J=19, 9.0 Hz), 2.92 (dd, 1H,
J=18.0, 9.0 Hz), 2.89 (m, 1H), 2.84 (dd, 1H, J=11.0, 2.0 Hz),
2.55 (d, 1H, J=12.0 Hz), 2.45 (d, J=12.0 Hz), 2.24 (m, 1H), 2.13
(m, 2H), 2.04 (ddd, 1H, J=12.7, 8.2, 2.5 Hz). 1.91 (m. 1H), 1.58
(m, 1H), 1.56 (m, 1H). MS (DCI/NH3): m/z 244 (M þ H)þ.
10. 1H NMR (300 MHz, CDCl3): δ 7.08 (d, 1H, J=14.0 Hz),
6.73 (dd, 1H, J=14.0, 4.5 Hz), 6.62 (d, J=4.5 Hz), 3.77 (s, 3H),
3.01 (dd, 1H, J=18.0, 12.0 Hz), 2.89 (d, 1H, J=18.0 Hz), 2.74
(dd, 1H, J=19.0, 5.5 Hz), 2.6- 2.83 (m, 2H), 2.60 (d, 1H, J=19.0
Hz), 2.13-2.21 (m, 2H), 1.79-1.98 (m, 4H), 1.50-1.68 (m, 2H),
1.33 (m, 1H). MS (DCI/NH3): m/z 244 (M þ H)þ.
1 mg/kg iv dose
1 mg/kg oral dose
compd
t 1/2
AUC
CLb
Cmax
AUC
F
17a
32
2.4
1.6
2.0
432.9
178.6
225.0
2.37
5.79
4.49
21.8
6.7
170.7
26.3
119.9
39.4
14.7
53.3
37
18.8
a 1 mg/kg dose of each compound simultaneously in each rat. Units:
t1/2 (h); Cmax (ng/mL); AUC (ng hr/ml); F (%); CLb (l/h kg); n=3.
Unable to estimate plasma elimination half-life.
3
3
pyrrolidinylpyrrolidine moiety was examined. Both 23 and 24
were much less potent than 17a, and this observation proved
that not only stereochemistry but the point of attachment to
the diamine was critical for H3R binding affinity. To further
probe the effect of the bicyclic ring size and orientation, three
different 3,6-diazabicyclo[3.2.0]heptane diamines, 25, 26, and
27, were prepared. While all of them had detectable activity at
histamine H3 receptors and 25 had quite good potency (15.9
nM at human H3), none of the diamines demonstrated affinity
comparable to the high potency seen in 17a. Overall, of diverse
diamines investigated, it was concluded that although all of
them were able to support some degree of H3 binding
when attached to the 4-cyanobiaryl moiety, the first diamine
investigated, (3aR,6aR)-octahydropyrrolo[3,4-b]pyrrole, was
superior.
We next turned our attention to a series of analogues (28-
40) with diverse aryl groups to replace the 4-cyanophenyl
moiety of 17a. These compounds were synthesized via cross
coupling reactions from the bromine intermediate 21, which
was itself active (100 nM at human H3R) but not so much as
the other analogues that were larger in size. While none of the
new analogues matched the high potency of 17a, the new
analogues 28-40 (with the exception of 29) were still highly
potent, significantly more than 21, suggesting a benefit of
most groups larger than bromine in this series.
The pharmacokinetic properties of selected compounds were
investigated in rat, with the data summarized in Table 5. The
most potent compound 17a displayed a favorable PK profile in
rats, with an oral bioavailability of 39.4% and t1/2 of 2.4 h. All
three compounds tested in this (3aR,6aR)-5-methyl-1-aryl-
octahydropyrrolo[3,4-b]pyrrole series had moderate to good
PK profiles. The drawback to this series is its high binding for
the hERG channel. The highlighted compound 17a, interacted
potently with this channel (dofetilide binding Ki =282 nM).
This is also an issue previously found for 7.
In summary, a new series of histamine H3R antagonists was
retro-designed by incorporating structural elements from two
diverse structural classes to produce the new series of H3R
antagonist (1). These novel (3aR,6aR)-5-methyl-1-aryl-oc-
tahydropyrrolo[3,4-b]pyrroles, compared with 2, its analogue
4, and the hybrid motif 6, have reduced molecular weight,
improved properties, and greatly simplified syntheses, which
increased the ability to make new analogues while retaining
the high rigidity seen in earlier series. The most potent mem-
ber 17a had subnanomolar potency (0.45 nM) at human H3
receptor and good bioavailability (good %F, low clearance
and acceptable half-life in rats). Further modification of this
novel series to reduce the interaction with hERG channels and
improve the overall drug likeness while retaining high potency
will be reported elsewhere.
(4bS,6aS,9aR)-2-Methoxy-8-methyl-5,6,6a,7,8,9,10,11-octa-
hydro-4bH-benz[4,5]indeno[1,7a-c]pyrrole (11). Compound 9
(109.0 mg, 0.45 mmol) and paraformaldehyde (403 mg, 13.4
mmol) were stirred in methanol (5 mL) at rt for 30 min.
NaBH3CN (560 mg, 9.0 mmol) was added, and stirring was con-
tinued for 60 min. The mixture was quenched with 1 N NaOH
(10 mL), extracted with CH2Cl2 (10 mL ꢀ 4). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated under vacuum to give the crude product, which
was purified by flash chromatography (silica gel, 20:1:0.1
CH2Cl2/CH3OH/NH4OH) to provide 102.0 mg (88.5%) of the
title compound (11) as a white solid. 1H NMR (300 MHz,
CDCl3): δ 7.00 (d, 1H, J=9.15 Hz, 1 H), 6.67 (s, 1 H). 6.66
(d, J = 6.44 Hz, 1 H), 3.77 (s, 3H), 2.95 (m, 2H), 2.72
(m, 2H), 2.44 (m. 1H), 2.22 (s. 3H), 2.07-1.55 (m, 9H). MS
(DCI/NH3): m/z 258 (M þ H)þ.
(4bS,6aS,9aR)-8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4bH-benz
[4,5]indeno[1,7a-c]pyrrol-2-ol (12). Compound 11 (100.0 mg,
0.39 mmol)and tetrabutylammonium iodide (158 mg, 0.43 mmol)
were dissolved in CH2Cl2 (10 mL) and cooled to -78 °C. BCl3
(0.97 mL, 1 M in CH2Cl2) was added dropwise. The mixture was
stirred at -78 °C for 30 min and 0 °C for 5 h. It was then
quenched with aq. satd. NaHCO3 (5 mL), extracted with
CH2Cl2 (10 mLꢀ3). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated under vacuum to
give the crude product, which was purified by flash chromatogr-
aphy (silica gel, 20:1:0.1 CH2Cl2/CH3OH/NH4OH) to provide
Experimental Section
1
Chemistry Methods. Unless otherwise noted, all commercially
available solvents, chemicals, and reagents were used without
26.0 mg (27.5%) of the title compound. H NMR (300 MHz,
DMSO-d6): δ 9.10 (s, 1H), 6.96 (d, 1H, J=18.5 Hz), 6.57 (dd,

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4645
1H, J=14, 3.5 Hz), 6.48 (s, 3H), 1.29-3.50 (m, 14H). MS (DCI/
NH3): m/z 244 (M þ H)þ.
compound (20.85 g, >100%) which could be used in the next step
without further purification. H NMR (300 MHz, DMSO-d6)
δ ppm 4.18 (m, 1 H) 3.47-3.59 (m, 1 H) 3.34-3.46 (m, 2 H) 2.75-
2.90 (m, 1 H) 2.71 (m, 1 H) 2.44-2.60 (m, 2 H) 2.29 (s, 3 H) 1.89-
2.06 (m, 1 H) 1.65-1.81 (m, 1 H) 1.42-1.49 (m, 9 H). MS (DCI/
NH3): m/z 226 (M þ H)þ.
1
Trifluoro-methanesulfonic Acid (4bS,6aS,9aR)-8-Methyl-
5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]
pyrrol-2-yl Ester (13). Compound 12 (25.0 mg, 0.11 mmol)
and triethylamine (21 μL, 0.12 mmol) were dissolved in
CH2Cl2 (5 mL) and cooled to -78 °C. Trifluoromethane
sulfonic anhydride (21 μL, 0.15 mmol) was added dropwise.
The mixture was stirred at 0 °C for 1 h. It was then quenched
with water (2 mL), extracted with CH2Cl2 (10 mLꢀ3). The
combined organic layers were dried over sodium sulfate,
filtered, and concentrated under vacuum to give the crude
product, which was purified by flash chromatography (silica
gel, 10:1 CH2Cl2/CH3OH) to provide 52 mg (>100%) of the
title compound as a colorless oil. MS (DCI/NH3): m/z 376
(M þ H)þ.
(3aR,6aR)-5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrole (20).
To a solution of compound 19 (20.8 g, 0.86 mol) in methanol (450
mL) was added aq 3 N HCl (300 mL). The mixture was stirred at
room temperature overnight and concentrated to dryness at 30 °C
under vacuum. The residue was treated with aq 1 N NaOH to
obtain a pH of 9-10. The mixture was concentrated to dryness
again. The residue was stirred with 200 mL of 10:1 CH2Cl2/
CH3OH overnight and then filtered. The filtrate was concentrated
and purified by flash chromatography (silica gel, 10:1:0.1 CH2Cl2/
CH3OH/NH4OH) to provide 12.4 g of the title compound as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 4.12-4.17 (m,
1 H) 3.31-3.43 (m, 1 H) 3.19-3.30 (m, 1 H) 3.12 (d, J=11.53 Hz,
1 H) 2.88-3.01 (m, 1 H) 2.69 (dd, J=9.49, 2.37 Hz, 1 H) 2.40-2.52
(m, 2 H) 2.33 (s, 3 H) 2.12-2.28 (m, 1 H) 1.82-1.95 (m, 1 H). MS
(DCI/NH3): m/z 127 (M þ H)þ.
1-[3-((4bS,6aS,9aR)-8-Methyl-5,6,6a,7,8,9,10,11-octahydro-
4bH-benz[4,5]indeno[1,7a-c]pyrrol-2-yl)-phenyl]-ethanone (14).
Compound 13 (0.1 mmol) and 3-acetylphenylboronic acid (33 mg,
0.20 mmol) were dissolved in toluene (2 mL) and ethanol (0.5 mL).
Then 0.3 mL of 1 M Na2CO3 solution was added. Nitrogen was
bubbled through the reaction mixture for 10 min. Tetrakis(triphe-
nylphosphine)palladium (12.0 mg, 0.01 mmol) was then added. The
mixture was stirred at 80 °C for 6 h. The reaction mixture was
quenched with water (2 mL), extracted with CH2Cl2 (5 mL x 4). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated under vacuum to give the crude product, which
was purified by flash chromatography (silica gel, 20:1:0.1 CH2Cl2/
CH3OH/NH4OH) to provide 5.3 mg (15.3%) of the title compound
as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 0.85-3.14 (m, 14 H)
2.47 (s, 3 H) 2.65 (s, 3 H) 7.00 (m, 2 H) 7.13 (m, 1 H) 7.48 (m, 1 H)
7.98 (m, 1 H) 8.14 (m, 1 H) 8.53 (m, 1 H). MS (DCI/NH3): m/z 346
(M þ H)þ.
3aR,6aR)-1-(4-Bromo-phenyl)-5-methyl-octahydro-pyrrolo
[3,4-b]pyrrole (21). Compound 20 (1.0 g, 7.92 mmol),
1,4-dibromobenzene (2.24 g, 9.50 mmol), tris(dibenzylideneace-
tone)dipalladium (145 mg, 0.16 mmol), racemic-2,20-bis(diphe-
nylphosphino)-1,10-binaphthyl (200 mg, 0.32 mmol) and sodium
tert-butoxide (1.14 g, 11.9 mmol) were dissolved in 10 mL of
toluene and heated to 70 °C under N2 for 5 h. The mixture was
cooled to room temperature, diluted with water, and extracted
with dichloromethane (20 mLꢀ4). The combined organic layers
were dried over sodium sulfate and filtered. The filtrate was
concentrated and purified by flash chromatography (silica gel,
40:1:0.1 CH2Cl2/CH3OH/NH4OH) to provide 1.81 g (81.2%) of
the title compound as an orange solid. 1H NMR (300 MHz,
CDCl3) δ ppm 7.25-7.30 (m, 2 H) 6.41-6.46 (m, 2 H) 4.07(m,
1 H) 3.47 (ddd, J=9.1, 7.7, 5.9 Hz, 1 H) 3.19 (dt, J=8.9, 7.3 Hz,
1 H) 2.95 (m, 1 H) 2.68 (dd, J=9.0, 3.0 Hz, 1 H) 2.55-2.60 (m,
3 H) 2.32 (s, 3 H) 2.13-2.22 (m, 1 H) 1.88-1.98 (m, 1 H). MS
(DCI/NH3): m/z 281/283 (M þ H)þ.
(4bR,6aS,9aR)-2-Methoxy-8-methyl-5,6,6a,7,8,9,10,11-octa-
hydro-4bH-benz[4,5]indeno[1,7a-c]pyrrole (15). Compound 15
(203.1 mg, 98.9%) was prepared by using the procedure for
making compound 11 except substituting Compound 10 for
Compound 9. 1H NMR (300 MHz, CDCl3): δ 7.08 (d, 1H, J=
8.4 Hz), 6.72 (dd, 1H, J=10.5, 2.1 Hz). 6.62 (s, 1H), 3.77 (s, 3H),
2.92 (m, 1H), 2.73 (m, 1H), 2.64 (m. 2H), 2.44 (m. 1H), 2.34 (s,
3H), 2.15 (m, 2H), 2.04 (m, 1H), 1.95 (m, 1H), 1.79 (m, 1H), 1.68
(m, 1H), 1.55 (m, 3H). MS (DCI/NH3): m/z 258 (M þ H)þ.
1-[3-((4bR,6aS,9aR)-8-Methyl-5,6,6a,7,8,9,10,11-octahydro-
4bH-benz[4,5]indeno[1,7a-c]pyrrol-2-yl)-phenyl]-ethanone
(16a). Compound 16a (3.9 mg, 14.1%) was prepared by using
the procedures for making compound 14, except substituting
Compound 15 for Compound 11. 1H NMR (300 MHz, CDCl3):
δ 1.53-3.05 (m, 14 H) 2.34 (s, 3 H) 2.65 (s, 3 H) 7.00 (m, 1 H) 7.34
(d, J=1.50 Hz, 1 H) 7.40 (dd, J=8.48, 1.50 Hz, 1 H) 7.51 (t, J=
7.80 Hz, 1 H) 7.77 (d, J=8.48 Hz, 1 H) 7.91 (d, J=7.80 Hz, 1 H)
8.16 (m, 1 H). MS (DCI/NH3): m/z 346 (M þ H)þ.
(3aR,6aR)-40-(5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
yl)-biphenyl-4-carbonitrile (17a). Compound 21 (30.0 mg,
0.11 mmol), 4-cyanophenylboronic acid (18.8 mg, 0.13 mmol),
palladium(II) acetate (1.2 mg, 0.005 mmol), 2-(dicyclohexylpho-
sphino)biphenyl (3.8 mg, 0.01 mmol), and potassium phosphate
(K3PO4) (75 mg, 0.35 mmol) were dissolved in 1 mL of toluene,
0.5 mL of isopropyl alcohol, and 0.5 mL of water. The mixture
was stirred at 60 °C under N2 for 5 h. The mixture was cooled to
room temperature, diluted with water, and extracted with dichlor-
omethane (5 mLꢀ5). The combined organic layers were dried over
sodium sulfate and filtered. The filtrate was concentrated and
purified by flash chromatography (silica gel, 20:1 CH2Cl2/
CH3OH) to provide 23.1 mg (71.3%) of the title compound as
4-((4bR,6aS,9aR)-8-Methyl-5,6,6a,7,8,9,10,11-octahy-
dro-4bH-benz[4,5]indeno[1,7a-c]pyrrol-2-yl)-benzonitrile
(16b). Compound 16b (6.2 mg, 30.8%) was prepared by
using the procedures for making compound 14, except
substituting Compound 15 for Compound 11 and substi-
tuting 4-cyanophenylboronic acid for 3-acetylphenylboro-
nic acid. 1H NMR (300 MHz, CDCl3): δ 7.68 (q, 4H), 7.37 (dd,
1H), 7.29-7.31 (m, 2H), 3.33-1.25 (m, 17H). MS (DCI/NH3): m/
z 329 (M þ H)þ.
1
a yellow solid. H NMR (300 MHz, CDCl3) δ ppm 7.60-7.68
(m, 4 H) 7.47-7.53 (m, 2 H) 6.61-6.68 (m, 2 H) 4.14-4.22 (m,
1 H) 3.51-3.60 (m, 1 H) 3.28-3.35 (m, 1 H) 2.93-3.01 (m, 1 H)
2.71-2.75 (m, 1 H) 2.48-2.61 (m, 3 H) 2.32 (s, 3 H) 2.14-2.25 (m,
1H)1.96(d, J=7.12Hz, 1H). MS(DCI/NH3):m/z 304 (M þ H)þ.
Anal. (C20H21N3 0.2CH3OH) C, H, N.
3
(3aR,6aR)-40-(Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphe-
nyl-4-carbonitrile (17b). Trifluoro-methanesulfonic Acid 40-
Cyano-biphenyl-4-yl Ester (SM-1 of 17b). 4-cyano-40-hydro-
xybiphenyl was dissolved in dichloromethane. Triethylamine
(2.5 equiv) was added, and the mixture was stirred at room
temperature. Triflic anhydride (1.3 equiv) was added slowly,
and the resulting solution was stirred for 2 h. The mixture was
diluted with saturated aqueous sodium bicarbonate and ex-
tracted with dichloromethane. The combined organic layers
were dried over sodium sulfate and filtered. The filtrate was
concentrated and purified by flash chromatography to pro-
vide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm
(3aR,6aR)-5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrole-1-car-
boxylic Acid tert-Butyl Ester (19). To a solution of (3aR,6aR)-
hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl es-
ter14 (18, 18.31 g, 0.86 mol) in methanol (450 mL) was added
paraformaldehyde (52 g, 1.72 mol) and the mixture was stirred at
room temperature for 1 h. Sodium cyanoborohydride was then
added, and the mixture was stirred at room temperature for 10 h,
diluted with 1 N NaOH (450 mL), and extracted with dichlor-
omethane (5ꢀ200 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated to provide the crude title

4646 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15
Zhao et al.
1
7.76 (d, J=8.82 Hz, 2 H) 7.66 (d, J=8.82 Hz, 4 H) 7.40 (d, J=
8.82 Hz, 2 H). MS (DCI/NH3): m/z 328 (M þ H)þ.
11.0 mg (46%) of the title compound. H NMR (300 MHz,
CDCl3) δ ppm 7.64 (d, J=1.36 Hz, 4 H) 7.50 (d, J=8.82 Hz, 2 H)
6.65 (d, J=8.82 Hz, 2 H) 4.14-4.23 (m, 1 H) 3.47-3.60 (m, 1 H)
3.27-3.39 (m, 1 H) 2.92-3.04 (m, 1 H) 2.70-2.81 (m, 1 H)
2.38-2.67 (m, 5 H) 2.11-2.25 (m, 1 H) 1.89-2.03 (m, 1 H) 1.08
(t, J=7.12 Hz, 3 H). MS (DCI/NH3): m/z 318 (M þ H)þ. Anal.
(3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrole-1,5-dicarboxylic
Acid 5-Benzyl Ester 1-tert-Butyl Ester (SM-2 of 17b). Comp-
ound 18 and N-(benzyloxycarbonyloxy)succinimide (3.42 g,
13.7 mmol) were mixed in 15 mL of dichloromethane. The
mixture was stirred at room temperature overnight and then
concentrated under vacuum to provide the crude product. The
residue was purified by flash chromatography (silica gel, 5:1
hexane/EtOAc) to provide 4.50 g of the title compound. 1H
NMR (300 MHz, CDCl3) δ ppm 7.29-7.43 (m, 5 H) 5.13 (s, 2 H)
4.15-4.33 (m, 1 H) 3.39-3.74 (m, 5 H) 3.20-3.37 (m, 1 H)
2.84-2.96 (m, 1 H) 1.92-2.03 (m, 1 H) 1.66-1.82 (m, 1 H) 1.46
(s, 9 H). MS (DCI/NH3): m/z 347 (M þ H)þ.
(C21H23N3 0.15CH3OH) C, H, N.
3
40-[(3aR,6aR)-5-Isopropylhexahydropyrrolo[3,4-b]pyrrol-1
(2H)-yl]-1,10-biphenyl-4-carbonitrile (17d). To a solution of
compound 17b (26 mg, 0.09 mmol) in methanol (2 mL) was
added acetone (132 μL, 1.8 mmol), and the mixture was
stirred at room temperature for 1.5 h. Sodium cyanoborohy-
dride (28 mg, 0.44 mmol) was added and the mixture stirred
overnight. The mixture was diluted with 2 mL of 1 N NaOH
and extracted with 20:1 dichloromethane/methanol (10 mLꢀ
3). The combined organic layers were dried over sodium
sulfate and filtered. The filtrate was concentrated and pur-
ified by flash chromatography (silica gel, 50:1:0.1 CH2Cl2/
CH3OH/NH4OH) to provide 17 mg (57%) of the title compound.
1H NMR (300 MHz, CDCl3) δ ppm 7.63 (d, J=3.74 Hz, 4 H)
7.50 (d, J=9.05 Hz, 2 H) 6.64 (d, J=8.73 Hz, 2 H) 4.16-4.22
(m, 1 H) 3.48-3.55 (m, 1 H) 3.31-3.38 (m, 1 H) 2.90-3.01
(m, 2 H) 2.74 (t, J=7.96 Hz, 1 H) 2.46-2.52 (m, 2 H) 2.31-
2.39 (m, 1 H) 2.10-2.20 (m, 1 H) 1.90-1.99 (m, 1 H) 1.06 (dd,
(3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic
Acid Benzyl Ester (SM-3 of 17b). Compound SM-2 of 17b
(4.5 g, 12.5 mmol) was stirred with a mixture of dichloro-
methane and trifluoroacetic acid (15 mL/15 mL) for 2 h. The
solvent was removed under reduced pressure, and the residue
was basified with saturated sodium bicarbonate and then
extracted with dichloromethane (50 mLꢀ3). The combined
organic layers were washed with brine, dried over sodium
sulfate, and filtered. The filtrate was concentrated and
purified by flash chromatography (silica gel, 15:1:0.1
CH2Cl2/CH3OH/NH4OH) to provide 1.26 g (39.4%) of the
J=6.24, 1.87 Hz, 6 H). MS (M þ H)þ=332. Anal. (C22H25N3
3
1
title compound. H NMR (300 MHz, CDCl3) δ ppm 7.28-
0.1H2O) C, H, N.
40-[(3aR,6aR)-5-(Cyclopropylmethyl)hexahydropyrrolo[3,4-b]
pyrrol-1(2H)-yl]-1,10-biphenyl-4-carbonitrile (17e). Compound
17e (19.0 mg, 61.5%) was prepared by using the procedure for
making compound 17d except substituting cyclo-propanecar-
box-aldehyde for acetone. 1H NMR (300 MHz, CDCl3) δ ppm
7.64 (d, J=2.76 Hz, 4 H), 7.50 (d, J=8.90 Hz, 2 H), 6.65 (d, J=
8.59 Hz, 2 H), 4.18-4.26 (m, 1 H), 3.51-3.59 (m, 1 H), 3.31-
3.41 (m, 1 H), 2.87-3.09 (m, 2 H), 2.73-2.83 (m, 1 H),
2.56-2.70 (m, 2 H), 2.25-2.43 (m, 2 H), 2.12-2.23 (m, 1 H),
1.93-2.05 (m, 1 H), 0.85-0.96 (m, 1 H), 0.12 (d, J=4.30 Hz, 2
H), 0.50 (d, J=7.98 Hz, 2 H). MS (DCI/NH3): m/z 344 (M þ
H)þ. Anal. (C23H25N3) C, H, N.
7.40 (m, 5 H) 5.12 (s, 2 H) 3.74-3.87 (m, 1 H) 3.53-3.71 (m, 2 H)
3.36-3.48 (m, 1 H) 3.18-3.32 (m, 1 H) 3.01-3.13 (m, 1 H)
2.88-3.01 (m, 1 H) 2.70-2.83 (m, 1 H) 1.87-2.03 (m, 1 H)
1.58-1.76 (m, 1 H). MS (DCI/NH3): m/z 247 (M þ H)þ.
(3aR,6aR)-1-(40-Cyano-biphenyl-4-yl)-hexahydro-pyrrolo
[3,4-b]pyrrole-5-carboxylic Acid Benzyl Ester (SM-4 of 17b).
Compound SM-3 of 17b (1.46 g, 5.93 mmol), compound
SM-1 of 17b (1.94 g, 5.93 mmol), palladium acetate (53 mg,
0.24 mmol), racemic-2,20-bis(diphenylphosphino)-1,10-bi-
naphthyl (BINAP, 220 mg, 0.35 mmol), and sodium tert-
butoxide (855 mg, 9.90 mmol) were mixed in 12 mL of
toluene and heated at 85 °C under N2 for 5.5 h. The mixture
was cooled to room temperature, diluted with water, and
extracted with dichloromethane (60 mLꢀ3). The combined
organic layers were dried over sodium sulfate and filtered.
The filtrate was concentrated and purified by flash chroma-
tography (silica gel, 100:1 CH2Cl2/CH3OH) to provide
0.75 g (29.9%) of the title compound. MS (DCI/NH3): m/z
424 (M þ H)þ.
40-[(3aR,6aR)-5-Propylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-
yl]-1,10-biphenyl-4-carbonitrile (17f). Compound 17f (14.0 mg,
55.5%) was prepared by using the procedure for making com-
pound 17c except substituting iodopropane for iodoethane. 1H
NMR (300 MHz, CDCl3) δ ppm 7.64 (d, J=1.70 Hz, 4 H), 7.50
(d, J=8.82 Hz, 2 H), 6.64 (d, J=8.82 Hz, 2 H), 4.12-4.22 (m, 1
H), 3.46-3.57 (m, 1 H), 3.27-3.39 (m, 1 H), 2.88-3.02 (m, 1 H),
2.61-2.74 (m, 2 H), 2.49-2.58 (m, 2 H), 2.26-2.42 (m, 2 H),
2.10-2.23 (m, 1 H), 1.86-2.04 (m, 1 H), 1.40-1.54 (m, 2 H),
0.89 (t, J = 7.29 Hz, 3 H). MS (DCI/NH3): m/z 332
(3aR,6aR)-40-(Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphe-
nyl-4-carbonitrile (17b). Compound SM-4 of 17b (750 mg,
1.77 mmol) was refluxed in 10 mL of trifluoroacetic acid for
2.5 h. The solution was concentrated and triturated with
dichloromethane. The residue was redissolved in dichloro-
methane and stirred with sodium bicarbonate powder. The
solution was loaded on a silica gel column and purified by
flash chromatography (silica gel, 20:1 CH2Cl2/CH3OH)
to provide 330 mg (64%) of the title compound. 1H NMR
(300 MHz, CDCl3) δ ppm 7.64 (d, J=2.71 Hz, 4 H) 7.51 (d, J=
8.81 Hz, 2 H) 6.66 (d, J=8.82 Hz, 2 H) 4.07-4.17 (m, 1 H)
3.50-3.65 (m, 1 H) 3.24-3.36 (m, 1 H) 2.86-3.10 (m, 5 H)
2.15-2.29 (m, 1 H) 1.74-1.93 (m, 1 H). MS (DCI/NH3): m/z
(M þ H)þ. Anal. (C22H25N3 0.1H2O) C, H, N.
3
40-((3aR,6aR)-5-Isobutyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
yl)-biphenyl-4-carbonitrile (17g). Compound 17g (34.0 mg,
100%) was prepared by using the procedure for making com-
pound 17d except substituting isobutylaldehyde for acetone. 1H
NMR (300 MHz, CDCl3) δ ppm 7.64 (d, J=1.36 Hz, 4 H), 7.50
(d, J=8.82 Hz, 2 H), 6.64 (d, J=8.82 Hz, 2 H), 4.13-4.25 (m, 1
H), 3.44-3.54 (m, 1 H), 3.29-3.41 (m, 1 H), 2.86-2.99 (m, 1 H),
2.44-2.70 (m, 4 H), 2.06-2.19 (m, 2 H), 1.86-2.02 (m, 2 H),
1.61-1.77 (m, 1 H), 0.82-0.98 (m, 6 H). MS (DCI/NH3): m/z
346 (M þ H)þ. Anal. (C23H27N3 0.9CH3OH) C, H, N.
290 (M þ H)þ. Anal. (C19H19N3 0.35CH3OH) C, H, N.
3
3
40-[(3aR,6aR)-5-Butylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-
yl]-1,10-biphenyl-4-carbonitrile (17h). Compound 17h (10.0 mg,
32%) was prepared by using the procedure for making com-
pound 17d except substituting n-butylaldehyde for acetone. 1H
NMR (300 MHz, CDCl3) δ ppm 7.64 (d, J=2.03 Hz, 4 H), 7.50
(d, J=8.81 Hz, 2 H), 6.64 (d, J=8.82 Hz, 2 H), 4.13-4.25 (m, 1
H), 3.46-3.59 (m, 1 H), 3.27-3.40 (m, 1 H), 2.87-3.04 (m, 1 H),
2.49-2.77 (m, 4 H), 2.29-2.46 (m, 2 H), 2.12-2.24 (m, 1 H),
1.86-2.03 (m, 1 H), 1.23-1.49 (m, J=44.07 Hz, 4 H), 0.89 (t, J=
7.12 Hz, 3 H). MS (DCI/NH3): m/z 346 (M þ H)þ. Anal.
(3aR,6aR)-1-(4-benzylphenyl)-5-methyloctahydropyrrolo[3,4-
b]pyrrole (17c). Compound 17b (22 mg, 0.076 mmol) was dis-
solved in 2.5 mL of anhydrous THF under nitrogen. Sodium
hydride (95%, 4 mg, 0.167 mmol) was added, and the mixture
was stirred at room temperature for 1 h. Iodoethane (18 μL,
0.225 mmol) was added, and the mixture was stirred at room
temperature overnight. The mixture was diluted with water and
extracted with dichloromethane (10 mL ꢀ 3). The combined
organic layers were dried over sodium sulfate and filtered.
The filtrate was concentrated and purified by flash chromato-
graphy (silica gel, 50:1:0.1 CH2Cl2/CH3OH/NH4OH) to provide
(C23H27N3 1.0CH3OH) C, H, N.
3

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4647
Compounds 22-27 were synthesized from corresponding
7.38-7.28 (m, 2H), 6.94 (d, J=7.7, 1H), 6.76-6.72 (m, 1H), 6.56
(dd, J=2.3, 8.1, 1H), 4.25 (dd, J=6.7, 16.5, 1H), 3.60 (dd, J=7.1,
15.0, 1H), 3.35 (dd, J=7.6, 15.0, 1H), 3.15-2.94 (m, 1H), 2.88-
2.71 (m, 2H), 2.71-2.58 (m, 1H), 2.42 (s, 3H), 2.25-2.11 (m,
1H), 2.06-1.88 (m, 1H). MS (DCI/NH3): m/z 279 (M þ H)þ.
known methyl or Boc or Cbz protected diamines using the
procedures for making compounds 17.
40-((3aS,6aS)-5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
yl)-biphenyl-4-carbonitrile (22). Prepared from (3aS,6aS)-5-
methyloctahydropyrrolo[3,4-b]pyrrole (CAS no. 876130-70-
Anal. (C19H22N2 0.9CH2Cl2) C, H, N.
3
1
0)17 (3.1 mg. 3.1%). H NMR (300 MHz, CDCl3) δ 7.63 (m,
(3aR,6aR)-1-(4-Benzyl-phenyl)-5-methyl-octahydro-pyrrolo
[3,4-b]pyrrole (30). Compound 30 was prepared by using
the procedure for making compound 21 except substituting
4-bromodiphenylmethane for 1,4-dibromobenzene. 1H NMR
(300 MHz, CDCl3) δ ppm 7.22-7.30 (m, 3 H) 7.12-7.20
(m, 2 H) 7.05 (d, J=8.48 Hz, 2 H) 6.43-6.56 (m, 2 H) 4.17-
4.25 (m, 1 H) 3.89 (s, 2 H) 3.46-3.57 (m, 1 H) 3.22-3.34
(m, 1 H) 3.01-3.15 (m, 2 H) 2.89-3.00 (m, 1 H) 2.73 (m, 2 H)
2.50 (s, 3 H) 2.08-2.24 (m, 1 H) 1.89-1.99 (m, 1 H). MS
4H), 7.51 (d, J=8.8, 2H), 6.63 (d, J=8.8, 2H), 4.35 (m, 1H), 3.63
(m, 1H), 3.42 (m, 1H), 3.20 (m, 1H), 2.85-2.40 (m, 7H), 2.22 (m,
1H), 2.03 (m, 1H). MS (DCI/NH3): m/z 304 (M þ H)þ. Anal.
(C20H21N3 0.95CH3OH) C, H, N.
3
40-((3aR,6aR)-1-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-
yl)-biphenyl-4-carbonitrile (23). Prepared from compound 18
1
(3.1 mg). H NMR (300 MHz, CDCl3) δ 7.67-7.60 (m, 4H),
7.49 (d, J=8.8, 2H), 6.69 (d, J=8.8, 2H), 3.54 (d, J=10.5, 1H),
3.43 (d, J=8.8, 1H), 3.32 (dd, J=4.9, 9.6, 1H), 3.26 (dd, J=5.3,
10.4, 1H), 3.16 (t, J=8.0, 1H), 2.99 (m, 2H), 2.42 (s, 3H), 2.38 (m,
1H), 2.25-2.10 (m, 1H), 1.87-1.71 (m, 1H). MS (DCI/NH3): m/
(DCI/NH3): m/z 293 (M þ H)þ. Anal. (C20H24N2 0.6CH2Cl2)
3
C, H, N.
(3aR,6aR)-5-Methyl-1-(4-phenoxy-phenyl)-octahydro-pyrro-
lo[3,4-b]pyrrole (31). Compound 31 (20.5 mg, 17.6%) was
prepared by using the procedure for making compound 21
except substituting 4-bromodiphenylether for 1,4-dibromo-
z 304 (M þ H)þ. Anal. (C20H21N3 0.2CH3OH) C, H, N.
3
40-((3aS,6aS)-1-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-
yl)-biphenyl-4-carbonitrile (24). Prepared from (3aS,6aS)-tert-
butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (CAS
1
benzene. H NMR (300 MHz, CDCl3) δ ppm 7.25-7.31 (m,
1
no. 370880-16-3)14,18 (20.1 mg). H NMR (300 MHz, CDCl3)
2 H) 6.87-7.05 (m, 5 H) 6.51-6.61 (m, 2 H) 4.03-4.14 (m, 1 H)
3.45-3.56 (m, 1 H) 3.15-3.26 (m, 1 H) 2.90-3.00 (m, 1 H) 2.69-
2.76 (m, 1 H) 2.50-2.63 (m, 3 H) 2.34 (s, 3 H) 2.13-2.22 (m,
1 H) 1.85-2.00 (m, 1 H). MS (DCI/NH3): m/z 295 (M þ H)þ.
δ 7.69-7.59 (m, 4H), 7.49 (d, J=8.8, 2H), 6.69 (d, J=8.8, 2H),
3.55 (m, 1H), 3.45 (t, J=9.0, 1H), 3.39-3.22 (m, 2H), 3.17 (m,
1H), 2.98 (m, 2H), 2.42 (m, 4H), 2.19 (m, 1H), 1.81 (m, 1H). MS
(DCI/NH3): m/z 304 (M þ H)þ. Anal. (C20H21N3 0.1CH2Cl2)
Anal. (C19H22N2O 0.2CH2Cl2) C, H, N.
3
3
(3aR,6aR)-1-[40-(5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-
1-yl)-biphenyl-4-yl]-ethanone (32). Compound 32 (405.6 mg,
53.2%) was prepared by using the procedure for making com-
pound 21 except substituting 4-(4-bromophenyl)acetophenone
C, H, N.
40-((1S,5R)-3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-bi-
phenyl-4-carbonitrile (25). Prepared from (1S,5R)-3,6-Diazabi-
cyclo[3.2.0]heptane-6-carboxylic acid, 1,1-dimethylethyl ester
(CAS no. 370882-66-9)14,19 (21.0 mg). 1H NMR (300 MHz,
CDCl3) δ 7.62 (q, J=8.7, 4H), 7.46 (d, J=8.6, 2H), 6.48 (d, J=
8.6, 2H), 4.72-4.57 (m, 1H), 3.97 (t, J=9.0, 1H), 3.94-3.80 (m,
1H), 3.47-3.35 (m, 1H), 3.34-3.15 (m, 2H), 2.57 (s, 3H), 2.39-
2.05 (m, 2H). MS (DCI/NH3): m/z 290 (M þ H)þ. Anal.
1
for 1,4-dibromobenzene. H NMR (300 MHz, CDCl3) δ ppm
7.96-8.00 (m, 2 H) 7.46-7.57 (m, 4 H) 6.65 (m, 2 H) 4.11-4.22
(m, 1 H) 3.49-3.62 (m, 1 H) 3.26-3.39 (m, 1 H) 2.97 (m, 1 H)
2.69-2.75 (m, 1 H) 2.61 (s, 3 H) 2.50-2.62 (m, 3 H) 2.32 (s, 3 H)
2.13-2.23 (m, 1 H) 1.91-2.01 (m, 1 H). MS (DCI/NH3): m/z
321 (M þ H)þ. Anal. (C21H24N2O 0.4CH2Cl2 0.2CH3OH)
(C19H19N3 0.2H2O) C, H, N.
3
3
3
40-((1R,5S)-3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-bi-
phenyl-4-carbonitrile (26). Prepared from (1S,5S)-benzyl 3,6-
diazabicyclo[3.2.0]heptane-3-carboxylate (CAS no. 370881-43-
C, H, N.
(3aR,6aR)-1-[40-(5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
yl)-biphenyl-3-yl]-ethanone (33). Compound 33 was prepared by
using the procedure for making compound 17a except substitut-
ing 3-acetylphenylboronic acid for 4-cyanophenylboronic acid.
1H NMR (300 MHz, CDCl3) δ ppm 8.13 (t, J=1.86 Hz, 1 H)
7.84 (d, J=7.46 Hz, 1 H) 7.74 (d, J=8.14 Hz, 1 H) 7.51 (t, J=
8.14 Hz, 2 H) 6.64 (d, J=8.48 Hz, 2 H) 4.28-4.42 (m, 1 H)
3.55-3.67 (m, 1 H) 3.34-3.49 (m, 1 H) 3.12-3.27 (m, 1 H)
2.69-2.98 (m, 4 H) 2.65 (s, 3 H) 2.57 (s, 3 H) 2.15-2.30 (m, 1 H)
1.94-2.11 (m, 1 H). MS (DCI/NH3): m/z 321 (M þ H)þ. Anal.
1
9)19a (10.0 mg). H NMR (300 MHz, CDCl3) δ 7.68-7.57 (m,
4H), 7.45 (d, J=8.7, 2H), 6.46 (d, J=8.7, 2H), 4.60 (dd, J=3.8,
6.8, 1H), 3.95 (t, J=7.8, 1H), 3.81 (dd, J=3.9, 7.5, 1H), 3.33 (d,
J=10.5, 1H), 3.22-3.10 (m, 2H), 2.48 (s, 3H), 2.22-2.10 (m,
1H), 2.05 (d, J=11.7, 1H). MS (DCI/NH3): m/z 290 (M þ H)þ.
Anal. (C19H19N3 0.2CH2Cl2) C, H, N.
3
40-((1R,5R)-6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-bi-
phenyl-4-carbonitrile (27). Prepared from (1S,5R)-3,6-Diazabi-
cyclo[3.2.0]heptane-6-carboxylic acid, 1,1-dimethylethyl ester
(CAS no. 370882-66-9)14,19 (10.0 mg). 1H NMR (300 MHz,
CDCl3) δ 7.70-7.60 (m, 4H), 7.52 (d, J=8.8, 2H), 6.80 (d, J=
8.7, 2H), 4.20-3.94 (m, 1H), 3.83-3.73 (m, 2H), 3.67-3.43 (m,
1H), 3.40-3.33 (m, 1H), 3.31-3.17 (m, 2H), 3.10-3.00 (m, 1H),
2.47 (s, 3H). MS (DCI/NH3): m/z 290 (M þ H)þ. Anal.
(C21H24N2O 0.25CH2Cl2) C, H, N.
3
(3aR,6aR)-40-(5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
yl)-biphenyl-3-carbonitrile (34). Compound 34 (26.5 mg,
48.1%) was prepared by using the procedure for making
compound 17a except substituting 3-cyanophenylboronic
acid for 4-cyanophenylboronic acid. 1H NMR (300 MHz,
CDCl3) δ ppm 7.73-7.84 (m, 2 H) 7.39-7.54 (m, 4 H) 6.62-6.69
(m, 2 H) 4.13-4.23 (m, 1 H) 3.48-3.64 (m, 1 H) 3.25-3.41 (m,
1 H) 2.91-3.04 (m, 1 H) 2.69-2.76 (m, 1 H) 2.50-2.68 (m,
3 H) 2.33 (s, 3 H) 2.11-2.25 (m, 1 H) 1.91-2.02 (m, 1 H). MS
(C19H19N3 0.15CH2Cl2) C, H, N.
3
(3aR,6aR)-1-Biphenyl-4-yl-5-methyl-octahydro-pyrrolo[3,4-
b]pyrrole (28). Compound 28 (30.0 mg, 54.4%) was prepared by
using the procedure for making compound 21 except substitut-
(DCI/NH3): m/z 304 (M þ H)þ. Anal. (C20H21N3 0.3CH3-
1
ing 4-bromobiphenyl for 1,4-dibromobenzene. H NMR (300
3
OH) C, H, N.
MHz, CDCl3) δ ppm 7.45-7.58 (m, 4 H) 7.33-7.43 (m, 3 H)
6.61-6.67 (m, 2 H) 4.15-4.27 (m, 2 H) 3.50-3.65 (m, 1 H)
3.24-3.35 (m, 1 H) 2.95-3.09 (m, 1 H) 2.59-2.82 (m, 4 H) 2.39
(s, 3 H) 2.13-2.24 (m, 1 H) 1.92-2.03 (m, 1 H). MS (DCI/NH3):
m/z 279 (M þ H)þ. Anal. (C19H22N2 1.0CH2Cl2 0.3CH3OH)
(3aR,6aR)1-(40-Fluoro-biphenyl-4-yl)-5-methyl-octahydro-
pyrrolo[3,4-b]pyrrole (35). Compound 35 (16.5 mg, 52.1%)
was prepared by using the procedure for making compound
17a except substituting 4-fluorophenylboronic acid for
4-cyanophenylboronic acid. 1H NMR (300 MHz, CDCl3)
δ ppm 7.40-7.50 (m, 4 H) 7.02-7.11 (m, 2 H) 6.58-6.67 (m, 2
H) 4.13-4.26 (m, 1 H) 3.50-3.63 (m, 1 H) 3.24-3.37 (m, 1 H)
3.01 (m, 1 H) 2.56-2.79 (m, 4 H) 2.38 (s, 3 H) 2.11-2.25 (m, 1
H) 1.91-2.01 (m, 1 H). MS (DCI/NH3): m/z 297 (M þ H)þ.
3
3
C, H, N.
(3aR,6aR)-1-Biphenyl-3-yl-5-methyl-octahydro-pyrrolo[3,4-
b]pyrrole (29). Compound 29 (26.5 mg, 48.1%) was prepared by
using the procedure for making compound 21 except substitut-
1
ing 3-bromobiphenyl for 1,4-dibromobenzene. H NMR (300
MHz, CDCl3) δ 7.58 (dd, J=1.4, 8.3, 2H), 7.46-7.38 (m, 2H),
Anal. (C20H21N3 0.1CH2Cl2) C, H, N.
3

4648 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15
Zhao et al.
(3aR,6aR)-1-(40-Bromo-biphenyl-4-yl)-5-methyl-octahydro-
pyrrolo[3,4-b]pyrrole (36). Compound 36 (340 mg, 60%) was
prepared by using the procedure for making compound 21 except
substituting 4,40-dibromobiphenyl for 1,4-dibromobenzene. 1H
NMR (300 MHz, CDCl3) δ ppm 7.38-7.51 (m, 6 H) 6.60-6.66
(m, 2 H) 4.16-4.23 (m, 1 H) 3.51-3.63 (m, 1 H) 3.27-3.34 (m, 1 H)
3.06 (m, 1 H) 2.75 (m, 2 H) 2.61 (m, 2 H) 2.38 (s, 3 H) 2.13-2.24 (m,
1 H) 1.98-2.18 (m, 1 H). MS (DCI/NH3): m/z 357, 359 (M þ H)þ.
(3aR,6aR)-1-(40-Methoxy-biphenyl-4-yl)-5-methyl-octahy-
dro-pyrrolo[3,4-b]pyrrole (37). Compound 37 (20 mg, 23.3%)
was prepared by using the procedure for making compound
21 except substituting 3-bromobiphenyl for 1,4-dibromoben-
zene. 1H NMR (300 MHz, CDCl3) δ ppm 7.47 (d, J=9.15 Hz,
2 H) 7.42 (d, J=9.15 Hz, 2 H) 6.94 (d, J=8.81 Hz, 2 H) 6.63
(d, J=8.81 Hz, 2 H) 4.11-4.19 (m, 1 H) 3.83 (s, 3 H) 3.50-
3.60 (m, 1 H) 3.22-3.33 (m, 1 H) 2.91-3.03 (m, 1 H) 2.69-
2.77 (m, 1 H) 2.52-2.62 (m, 3 H) 2.34 (s, 3 H) 2.11-2.26 (m,
1 H) 1.89-2.01 (m, 1 H). MS (DCI/NH3): m/z 309 (M þ H)þ.
(3) (a) Schlicker, E.; Malinowska, B.; Kathmann, M.; Gothert, M.
Modulation of Neurotransmitter Release via Histamine H3 Het-
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regulates histamine neurons in brain. Nature 2000, 408, 860–864.
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apeutic potential of histamine H3 receptor agonists and antago-
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attractive target for the treatment of cognitive disorders. Br. J.
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A. R.; Beresford, I. J.; Brackenborough, K.; Briggs, M. A.; Calver,
A. R.; Cilia, J.; Cluderay, J. E.; Crook, B.; Davis, J. B.; Davis, R. K.;
Davis, R. P.; Dawson, L. A.; Foley, A. G.; Gartlon, J.; Gonzalez, M. I.;
H., Teresa, H., W. D.; Jennings, C.; Jones, D. N. C.; Lacroix, L. P.;
Martyn, A.; Ociepka, S.; Ray, A.; Regan, C. M.; Roberts, J. C.;
Schogger, J.; Southam, E.; Stean, T. O.; Trail, B. K.; Upton, N.;
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Anal. (C20H24N2O 0.3CH3OH) C, H, N.
3
(3aR,6aR)-1-(6-Bromo-naphthalen-2-yl)-5-methyl-octahydro-
pyrrolo[3,4-b]pyrrole (38). Compound 38 (203.9 mg, 38.8%) was
prepared by using the procedure for making compound 21
except substituting 2,6-dibromonaphthalene for 1,4-dibromo-
1
benzene. H NMR (300 MHz, CDCl3) δ 7.83 (d, J=1.7, 1H),
7.62 (d, J=7.9, 1H), 7.50 (d, J=8.7, 1H), 7.42 (dd, J=1.9, 8.9,
1H), 6.97 (dd, J=2.4, 9.1, 1H), 6.69 (d, J=2.3, 1H), 4.55-4.31
(m, 1H), 3.76-3.59 (m, 1H), 3.56-3.43 (m, 1H), 3.36-3.16 (m,
1H), 2.89-2.47 (m, 7H), 2.36-2.19 (m, 1H), 2.11-1.93 (m, 1H).
MS (DCI/NH3): m/z 331, 333 (M þ H)þ.
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4-[6-((3aR,6aR)-5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
yl)-naphthalen-2-yl]-benzonitrile (39). Compound 39 (6.2 mg,
30.8%) was prepared by using the procedures for making
compound 17a except substituting compound 38 for compound
21. 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J=1.7, 1H), 7.81-
7.69 (m, 4H), 7.61 (dd, J=1.9, 8.6, 1H), 7.37 (m, 2H), 7.04 (dd,
J=2.5, 8.9, 1H), 6.77 (d, J=2.3, 1H), 4.41-4.28 (m, 1H), 3.67
(dd, J = 6.9, 15.9, 1H), 3.44 (dd, J = 7.7, 15.0, 1H), 3.16-3.00
(m, 1H), 2.85-2.73 (m, 2H), 2.70-2.56 (m, 2H), 2.39 (s, 3H), 2.24
(dt, J=7.8, 14.6, 1H), 2.02 (dt, J=5.9, 18.6, 1H). MS (DCI/NH3):
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5423–5430.
m/z 353 (M þ H)þ. Anal. (C24H23N3 0.1CH2Cl2) C, H, N.
3
(3aR,6aR)-1-[6-(4-Fluoro-phenyl)-naphthalen-2-yl]-5-methyl-
octahydropyrrolo[3,4-b]pyrrole (40). Compound 40 (12.8 mg,
34.9%) was prepared by using the procedures for making
compound 17a, except substituting compound 38 for com-
pound 21 and substituting 4-fluorophenylboronic acid for
4-cyanophenylboronic acid. 1H NMR (300 MHz, CDCl3) δ
7.85 (d, J=1.4, 1H), 7.76 (d, J=8.9, 1H), 7.72 7.58 (m, 4H),
7.18-7.10 (m, 2H), 6.99 (dd, J=2.4, 8.9, 1H), 6.75 (d, J=2.1,
1H), 4.62-4.35 (m, 1H), 3.83-3.62 (m, 1H), 3.60-3.44 (m, 1H),
3.40-3.17 (m, 1H), 2.95-2.44 (m, 7H), 2.35-2.18 (m, 1H),
2.17-1.92 (m, 1H). MS (DCI/NH3): m/z 347 (M þ H)þ. Anal.
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(C23H23FN2 0.1CH2Cl2) C, H, N.
3
Note Added after ASAP Publication. This manuscript was
released ASAP on July 9, 2009, with a couple of incorrect
compound numbers and without Scheme 3 due to a production
error. The correct version was posted on July 15, 2009.
(14) (a) Li, Q.; Chu, D. T. W.; Claiborne, A.; Cooper, C. S.; Lee, C. M.;
Raye, K.; Berst, K. B.; Donner, P.; Wang, W.; Hasvold, L.; Fung,
A.; Ma, Z.; Tufano, M.; Flamm, R.; Shen, L. L.; Baranowski, J.;
Nilius, A.; Alder, J.; Meulbroek, J.; Marsh, K.; Crowell, D.; Hui,
Y.; Seif, L.; Melcher, L. M.; Henry, R.; Spanton, S.; Faghih, R.;
Klein, L. L.; Tanaka, S. K.; Plattner, J. J. Synthesis and Structure-
Activity Relationships of 2-Pyridones: A Novel Series of Potent
DNA Gyrase Inhibitors as Antibacterial Agents. J. Med. Chem.
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pyrrole-1-carboxylic acid tert-butyl ester (18, CAS no. 370880-09-4)
may be prepared as described in Basha, A.; Bunnelle, W. H.; Dart,
M. J.; Gallagher, M. E.; Ji, J.; Li, T.; Pace, J. M.; Ryther, K. B.; Tietje, K. R.;
Mortell, K. H.; Nersesian, D. L.; Schrimpf, M. R. Substituted diazabicy-
cloalkane derivatives. U.S. Pat. Appl. Publ. 2005101602A1, 2005.
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as antagonists and/or inverse agonists of the histamine H3
receptor for the treatment of neurological disorders. PCT Int.
Appl. WO2004056369A1, 2004. (b) NovoNordisk Lau, J. F.;
Supporting Information Available: Combustion analysis of
compounds 17a-40. This material is available free of charge via
the Internet at http://pubs.acs.org.
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