Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity

Article abstract of DOI:10.1021/jm9608467

Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structureactivity relationships are developed at N-l, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC₅₀ of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC₅₀ of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC₅₀ values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).

Full text of DOI:10.1021/jm9608467

2196
J . Med. Chem. 1997, 40, 2196-2210
P oten t Tetr a cyclic Gu a n in e In h ibitor s of P DE1 a n d P DE5 Cyclic Gu a n osin e
Mon op h osp h a te P h osp h od iester a ses w ith Or a l An tih yp er ten sive Activity
Ho-Sam Ahn, Ana Bercovici, George Boykow, Alan Bronnenkant, Samuel Chackalamannil, J ason Chow,
Renee Cleven, J ohn Cook, Michael Czarniecki,* Carol Domalski, Ahmad Fawzi, Michael Green, Asli Gu¨ndes,
Ginny Ho, Malvina Laudicina, Neil Lindo, Ke Ma, Mahua Manna, Brian McKittrick, Bita Mirzai,
Terry Nechuta, Bernard Neustadt, Chester Puchalski, Kathryn Pula, Lisa Silverman, Elizabeth Smith,
Andrew Stamford, Richard P. Tedesco, Hsingan Tsai, Deen Tulshian, Henry Vaccaro, Robert W. Watkins,
Xiaoyu Weng, J oseph T. Witkowski, Yan Xia, and Hongtao Zhang
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New J ersey 07033
Received December 12, 1996X
Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-
hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly
active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-
activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound
31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM,
is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors
with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced
blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the
spontaneously hypertensive rat (SHR).
Ch a r t 1
In tr od u ction
Cyclic guanosine-3′,5′-monophosphate (cGMP, i; Chart
1) plays a key role in the modulation of vascular
function. Elevation of cGMP is directly correlated with
vascular smooth muscle relaxation.1,2 Therapeutic ma-
nipulation of cGMP has been exploited in the manage-
ment of angina pectoris, congestive heart failure, my-
ocardial infarction, and hypertension. The evolving
biology of cGMP and understanding of its mechanisms
of regulation are opening up new opportunities for
discovery of drugs which can produce therapeutically
desirable effects through alteration of cGMP levels. At
least two of the seven phosphodiesterase (PDE) families
of cyclic nucleotide phosphodiesterases (designated PDE1
and PDE5) participate in the hydrolysis and inactivation
of cGMP in smooth muscle. PDE1 is regulated by Ca2+
/
calmodulin and utilizes both cGMP and cAMP as
substrate, showing a preference for cGMP, while PDE5
specifically hydrolyzes cGMP. Inhibitors of these phos-
phodiesterase enzymes have the potential to offer novel
approaches toward treating cardiovascular diseases,
since PDE1 is located in vascular tissue and PDE5 is
located in vascular tissue and platelets. The field of
cyclic nucleotide PDE inhibition as a therapeutic target
has received considerable attention over the years and
been the subject of recent reviews.3,4 More recently, the
structure-activity relationships (SAR) of inhibitors of
PDE1 and PDE5, from both the published and patent
literature, have been extensively reviewed.5
The alkaloid vinpocetine (ii) is a weak but selective
inhibitor of PDE1, which does not inhibit PDE5 or the
cAMP-hydrolyzing enzyme PDE3. Zaprinast (M&B
22948, (iii) is an inhibitor of PDE5 which is selective
relative to PDE3. The xanthine 8-MeOMeMIX (iv) is
a weak inhibitor of both PDE1 and PDE5 which is also
selective relative to PDE3. When examined in a prepa-
ration of rabbit aortic slices ii, iii, and iv showed
concentration dependent elevations in cGMP but not
cAMP.6 More recently E4021 (v), a highly potent and
selective PDE5 inhibitor, has been shown to elevate
cGMP levels in and to directly relax porcine large
coronary artery.7 When iii was administered at high
doses (200 mg/kg/day po for 5 days) to the spontaneously
hypertensive rat (SHR), significant (>30 mmHg) de-
creases in mean arterial pressure were observed.8 From
this data we reasoned that a phosphodiesterase inhibi-
tor which showed good potency for both PDE1 and PDE5
as well as improved oral activity could be potentially
useful in the treatment of cardiovascular diseases.
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
S0022-2623(96)00846-1 CCC: $14.00 © 1997 American Chemical Society

Tetracyclic Guanine Inhibitors of PDE1 and PDE5
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2197
Sch em e 1a
a
Reagents: (i) CH3C(OEt)3, DMF; (ii) CH3CH2CH2CO2H, EDCl, DMAP; (iii) POCl3, DMF; (iv) amino alcohol, DIPEA, NMP; (v) SOCl2,
CH2Cl2; (vi) Pd(OH)2/C, NH4CO2H, MeOH.
Whereas both structures iii and iv have a purine or
azapurine nucleus, they are differentially substituted
from each other as well as from cGMP around the
purine nucleus. While iii is substituted at the purine
2-position, iv is substituted at positions 1, 3, and 8. With
the goal of identifying structurally novel molecules
which had both PDE1 and PDE5 inhibitory activity, we
advanced the concept that a structure such as vi might
incorporate both the features of iii and iv. We were
additionally encouraged by the fact that a search of
known ring structures indicated that a ring system such
as vi had not been previously reported. Indeed, when
we prepared one of our initial compounds with this novel
ring system (8), we were pleased to observe that it not
only retained the PDE profiles of iii and iv but also
showed oral antihypertensive activity in a rat model of
hypertension. In exploring this observation, we discov-
ered the highly potent inhibitors of PDE1 and PDE5
which are described here.
the (+)-cis-fused tetracylic guanine 7 having absolute
configuration 6aR,9aS. The diastereomeric trans-fused
[3.3.0] ring system, which would result from retention
of configuration at the displaced alcohol, was never
observed. The synthesis was completed by catalytic
hydrogenolysis of the N-3 benzyl group to give com-
pound 8.
Compounds 39-44 were prepared using the strategy
outlined in Scheme 2. Intermediate 35, which was
prepared using the general reaction conditions of Scheme
1, was formylated to give the key intermediate 36.
Reduction to the alcohol 37, chlorination (38), and
displacement of chloride led to the heteroalkyl targets
39-42. Reductive amination of the aldehyde with
pyrrolidine directly yielded target compounds 43 and
44.
Scheme 3 outlines the preparation of compounds 46
and 47 by lithiation of the C-2 position of intermediate
35 which was reacted with the protected imidazole 48
to give intermediate secondary alcohol 45. Deoxygen-
ation of the alcohol was accomplished by reduction of
its mesylate to give 46, which after hydrogenolysis of
the benzyl group under the standard conditions yielded
47.
As illustrated in Scheme 4 the arylacetylene com-
pounds 50 and 52 were prepared by phenylacetylide
anion displacement of the iodo (49) and bromo (51)
intermediates, respectively. Compounds 53-58 were
prepared by direct regioselective alkylation of the steri-
cally less hindered N-3 nitrogen using the procedures
described in the Experimental Section. For 53 dimethyl
sulfate was used to alkylate the 2-bromotetracyclic
guanine intermediate followed by 2-alkylation with
benzyl bromide of the prepared organozinc species.
Compounds 54 and 55 were prepared by alkylation
using cyclohexylmethyl bromide and 2-bromoethanol,
respectively. The catechol derivative 56 was prepared
by alkylation with 2,3-dimethoxybenzyl bromide fol-
lowed by demethylation with boron tribromide. Com-
pound 57 was prepared using 3-(chloromethyl)pyridine
as the alkylating reagent. Using 1-tosyl-2-(chlorometh-
Syn th esis
Compounds 7-34 were prepared using the general
method illustrated in Scheme 1 for compounds 7 and 8.
Starting with the known 6-amino-5-(benzylamino)-3-
methylpyrimidine-2,4(1H,3H)-dione9 (1), acylation with
either an orthoester or carboxylic acid afforded inter-
mediate 2 or 3, respectively. The choice of acylating
agent was dependent upon commercial availability, and
both types of reagent worked well. In this scheme the
orthoester leads to 7 and 8 while acylation produces the
intermediate for 9 and 10. Subsequent reactions were
identical and not dependent upon the acylation reagent
used. The intermediates 2 and 3 were treated identi-
cally with excess POCl3 to form the chloropurines 4 and
5. The third and fourth rings were added using the
sequence starting with trans-2-aminocyclopentanol for
compounds of type A or 1-amino-1-cyclopentanemetha-
nol for compounds of type B. The chiral (-)-trans-2-
aminocyclopentanol10 displaced the ring chlorine to form
intermediate 6, which upon activation with thionyl
chloride underwent stereospecific displacement to give

2198 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Ahn et al.
Sch em e 2a
a
Reagents: (i) 1. n-BuLi, THF, 2. DMF; (ii) pyrrolidine, NaBH3CN, MeOH; (iii) Pd(OH)2/C, NH4CO2H, MeOH; (iv) NaBH4, MeOH,
CH2Cl2; (v) SOCl2, CH2Cl2; (vi) NaOMe, MeOH or Me2NH, THF.
Sch em e 3a
Resu lts a n d Discu ssion
Table 1 lists the structures and PDE isozyme inhibi-
tory activity of tetracyclic guanines substituted on the
imidazole C-2 carbon and N-1, N-3, and N-5 nitrogens.
Variations included in this table at C-2 are lower alkyl
(7-14), cycloalkylmethyl (15-22), aryl (25, 26), aryl-
methyl (27-34), arylalkynyl (50, 52), heteroalkyl (39-
42), and heterocyclic (43-47). N-3 nitrogen substitu-
tions for the above compounds are limited to hydrogen
and benzyl for each of the C-2 variations. The struc-
tures are also varied with the presence of both fused,
type A or spirofused, type B cyclopentyl rings. In the
fused series (type A), the inhibitors (except for 23 and
24) are the enantiomerically pure cis (+) isomers with
the absolute configuration 6aR,9aS as illustrated in the
structural diagrams. Earlier work had suggested that
the cis (+) isomers were about 10-fold more potent as
PDE inhibitors than the cis (-) isomers.11 However,
since we did not examine each enantiomer for each
target structure, we cannot be absolutely sure that this
is true for all target compounds included in this study.
General screening protocols in this study determined
IC50 values for PDE1 and PDE5 to evaluate effective-
ness as inhibitors of cGMP hydrolysis and for PDE3 to
evaluate selectivity against the enzyme responsible for
cAMP hydrolysis in cardiac tissue. Included in Table 1
are the reference PDE inhibitors shown in Chart 1 along
with isozyme inhibition data which had been deter-
mined previously in our laboratories.6
a
Reagents: (i) LDA, 48, 60%; (ii) MsCl, Et3N, CH2Cl2; (iii)
LiBHEt3, then 3% HCl, 35% (steps ii and iii); (iv) Pd(OH)2/C,
NH4CO2H, MeOH, reflux, 100%; (v) TsCl, Et3N, 1,2-dichloro-
ethane, reflux, 90%.
yl)imidazole as the alkylating reagent, compound 58
was afforded after removal of the tosyl protection.
The N-5-modified compounds 65, 66, 67 (Scheme 5),
and 74 (Scheme 6) were prepared by building up the
guanine nucleus through imidazole intermediates 61
and 70. Cyclization to the xanthine structures 62 and
71 followed by completion of the ring system, under the
general reaction conditions illustrated in Scheme 1,
yielded the N-5-modified tetracyclic guanines.
In general the tetracyclic guanines are much more
effective inhibitors of PDE1 and PDE5 than PDE3. No
consistent differences were observed between the fused
and spirocyclopentyl series when comparable substitu-
tion patterns were present, and in general the SAR
results were qualitatively similar. Within the alkyl

Tetracyclic Guanine Inhibitors of PDE1 and PDE5
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2199
Sch em e 4a
with the active site of PDE1 exists that is not mirrored
in the active sites of the PDE3 and PDE5. Among the
heteroalkyl-substituted inhibitors (39-44), the following
trends can be observed: (i) N-3 benzyl substitution
consistently increases the potency of PDE1 inhibition;
(ii) inhibition for PDE5 is less than for PDE1 and
responds variably to N-3 benzyl substitution; (iii) all are
very weak inhibitors of PDE3. The imidazolylmethyl
analogs (46, 47) are somewhat less potent than the
arylmethyl analogs, while the phenylacetylides (50, 52)
fall in between the imidazolylmethyl analogs and the
most potent arylmethyl compounds. Although not the
most potent at any single enzyme, it should be noted
that compounds 20, 22, 30, and 50 are potent dual
inhibitors with IC50 values below 30 nM for both PDE1
and PDE5.
Table 1 also presents the activity of tetracyclic gua-
nines with modifications at other positions on the core
structure. Compounds 53-58 examine activity as a
function of N-3 nitrogen substitution and supplement
the hydrogen and benzyl examples 27-30. Methyl
substitution at nitrogen (53) resulted in significantly
reduced activity for the cGMP-hydrolyzing enzymes
when compared to the hydrogen (30) or benzyl (29)
analogs. Cyclohexylmethyl (54) showed a similar inhi-
bition pattern to the isosteric benzyl (27) suggesting that
this interaction is largely hydrophobic and not aryl
specific. Dihydroxylation of the benzyl (56) reduces
inhibition of PDE1 but has a minimal effect on PDE3
and PDE5. The polar hydroxyethyl group (55) on the
imidazole nitrogen reduced activity at all enzymes, as
did substitution with nitrogen-containing heteroaryl-
methyl groups (57, 58). These results are also consis-
tent with a significant hydrophobic interaction at this
position. The effect of groups larger than methyl on the
pyrimidone N-5 nitrogen was examined in three com-
pounds: 66, 67, and 74. A significant decrease in the
inhibition of PDE1 was observed, with a much smaller
effect on PDE3 and PDE5. Indeed, 67 and 74 are the
most selective PDE5 inhibitors discovered in the tetra-
cyclic guanine series. Finally, the effect of N-benzyla-
tion at the N-1 imidazole position was evaluated.
Compound 65 is inactive for PDE1 and PDE3 and shows
only weak activity for PDE5.
a
Reagents: (i) LDA/THF; (ii) ClCH2CH2I, 67%, two steps; (iii)
copper phenylacetylide, 120 °C; (iv) Pd(OH)2/C, NH4CO2H, MeOH,
reflux, 100%; (v) Br2, NaOAc, HOAc, 50% °C, 90%; (vi) (phenyl-
ethynyl)tributyltin, Pd(PPh3)4, NMP, 100 °C, 32%.
series (7-22) there is a trend for increasing potency
with increasing carbon count when the nitrogen sub-
stitution is hydrogen. This trend is seen across the
three enzymes. For the PDE1 enzyme benzyl substitu-
tion at N-3 increases potency for the small R2 groups
(7, 9, 15) but decreases it for the longer groups (11, 13,
21) and has little effect on the sterically intermediate
cyclopentylmethyl compounds (17, 19). The effect is
somewhat similar for PDE5 where benzyl substitution
generally decreases potency except for 7, 9, and 15. Only
the N-3-benzylated trifluoromethylated compound 23
showed good potency at PDE1 by comparison to the
desbenzyl analog 24.
Among the C-2 aryl- and arylmethyl-substituted
guanines (25-34), benzyl substitution at N-3 increased
potency against both PDE1 and PDE3 except for the
C-2 phenyl derivatives (25, 26) which are both inactive
against PDE3. The effect on PDE5 is variable within
this group. In most cases (27-34) decreases in potency
are observed except for the C-2 phenyl compounds (25,
26) where N-benzylation results in increased potency.
Compound 31, with IC50 ) 70 pM, and compound 33,
with IC50 ) 0.6 nM, are the most potent inhibitors of
PDE1. By comparison to their closest phenyl analogs
(27 and 29, respectively), the additional phenyl group
adds a 10-30-fold increase in potency for PDE1 but has
only small and mixed effects for PDE3 and PDE5. This
suggests a specific favorable interaction of the biphenyl
Nine PDE inhibitors (8, 12, 18, 20, 25, 28, 31, 33, 50)
were selected for an expanded PDE profiling, adding
PDE2 and PDE4, as well as for evaluation as antihy-
pertensive agents when administered orally to the
spontaneously hypertensive rat (SHR). As shown in
Table 2, these compounds show modest to good selectiv-
ity for the PDE1 and PDE5 enzymes relative to PDE2,
PDE3, and PDE4. The only exceptions within this
group are compounds 31 and 33, which have similar
activity for both PDE4 and PDE5 but are highly
selective for PDE1. Certain inhibitors of PDE1 and
PDE5 also demonstrate antihypertensive activity when
administered orally at 10 mg/kg in the SHR. However,
the magnitude of the maximum antihypertensive effect
is not always correlated with the specific potency of the
PDE inhibition within this limited group of compounds.
For example, 25, 31, and 50 do not show significant
blood pressure effects, while compounds 12, 20, and 28
reduced blood pressure by more than 45 mmHg. Most
strikingly compounds 31 and 33, which are among the
most potent PDE1 inhibitors and have similar profiles

2200 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Ahn et al.
Sch em e 5a
a
Reagents: (i) Na2S2O4, NaHCO3, H2O, 62%; (ii) CH3C(OEt)3, 100 °C, 71%; (iii) BnNH2, EtOH, 80 °C, 52%; (iv) RNCO, NEt3, PhH, 100
°C, then NaOMe, MeOH, reflux, 73%; (v) POCl3, 100 °C, 54%; (vi) (1R,2R)-2-aminocyclopentanol, DIPEA, NMP, 96%; (vii) MsCl, NEt3,
CH2Cl2, 57%; (viii) Pd(OH)2/C, NH4HCO2, MeOH, reflux, 78%.
Sch em e 6a
a
Reagents: (i) EtOH, HCl, 57%; (ii) ethyl 2-aminocyanoacetate; (iii) BnNH2, 49% for two steps; (iv) EtNCO, 130 °C, 41%; (v) NaOMe,
98%; (vi) POCl3, 100 °C, 55%; (vii) (-)-trans-2-aminocyclopentanol, DIPEA, 79%; (viii) MsCl, Et3N, 65%; (ix) Pd(OH)2/C, NH4HCO2, MeOH,
reflux, 60%.
against PDE2, PDE3, PDE4, and PDE5, have com-
pletely different oral activities. This result suggests
that the difference could be ascribed to the structural
differences which include the N-3 benzyl and the spiro
versus fused cyclopentane ring. It should be noted that
in our hands the potent PDE5 inhibitor E4021 (Table
C-2, with biphenylmethyl being optimum, (3) N-3 ben-
zylation tends to increase potency for PDE1 but has a
mixed effect for PDE5, and (4) increasing the steric bulk
of the alkyl group at N-5 enhances the selectivity for
PDE5 over PDE1. Compounds 31 and 33 are potent
and selective inhibitors of PDE1, with IC50 values below
1 nM. Compounds 20, 22, 30, and 50 are potent dual
PDE1/PDE5 inhibitors with IC50 values below 30 nM
for both PDE1 and PDE5. Compounds 12, 20, and 28
reduced blood pressure by >45 mmHg when adminis-
tered orally to the spontaneously hypertensive rat;
however, other potent inhibitors had poor oral activity.
2) has not shown oral antihypertensive activity.
A
recent evaluation of the biological activity of a compound
(SCH 51866), closely related to compound 28, indicated
that in vivo biological activity is well correlated with
plasma levels of PDE inhibitor.12 However, pharmaco-
kinetic/pharmacodynamic studies were not performed
on the compounds presented here, and so variability in
the absolute oral bioavailability, pharmacokinetics, and
metabolic fate of these compounds could be reflected in
the observed weak correlation between in vitro cGMP
PDE inhibition and antihypertensive activity.
Given the important roles described for cGMP in
cardiovascular regulation, it is evident that agents
which modulate cGMP through inhibition of cGMP-
hydrolyzing PDEs should have desirable effects in
cardiovascular diseases. Previously reported inhibitors
have acted predominantly on PDE5.3,5,6 The tetracyclic
guanines presented here inhibit both of the major
isoenzyme classes (PDE1 and PDE5) which hydrolyze
cGMP in vascular tissue and platelets. Furthermore,
selected members of this family have good activity when
administered orally and reduce blood pressure in hy-
pertensive animals. Thus the potential for development
of a new class of therapeutic agents is quite promising.
Con clu sion
In summary, members of a series of tetracyclic
guanines have been shown to be potent inhibitors of
PDE1 or mixed inhibitors of PDE1 and PDE5 with high
selectivity over other PDEs. General trends in the SAR
demonstrate that (1) benzylation at N-1 is poorly
tolerated, (2) a substantial enhancement of PDE1 activ-
ity is observed with hydrophobic arylmethyl groups at

Tetracyclic Guanine Inhibitors of PDE1 and PDE5
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2201
Ta ble 1. Structures and PDE1, PDE3, and PDE5 Inhibition of Tetracyclic Guanines Substituted at Positions 1, 2, 3, and 5

2202 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Ta ble 1. (Continued)
Ahn et al.

Tetracyclic Guanine Inhibitors of PDE1 and PDE5
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2203
Ta ble 1. (Continued)
a
b
From ref 6. Racemate.
according to the patent procedure.13 Several of the methods
described in this section have been previously reported in the
patent literature.14
Ta ble 2. PDE1, PDE2, PDE3, PDE4, and PDE5 Inhibiton and
Oral Antihypertensive Effects in the SHR for Selected PDE
Inhibitors
1,8-Dim eth yl-7-(p h en ylm eth yl)p u r in e-2,6-d ion e (2). A
solution of 6-amino-5-(benzylamino)-3-methylpyrimidine-2,4-
(1H,3H)-dione (1) (24.60 g, 0.1 mmol) in DMF was heated to
60 °C, and triethyl orthoacetate (73 mL, 0.4 mol) was added.
The reaction mixture was then heated at 110 °C for 5 h and
cooled in an ice bath. The precipitate thus obtained was
filtered and washed with methanol and diethyl ether to give
the title compound (24.40 g, 90%) as a white solid: mp 293-
295 °C; 1H NMR (DMSO) δ 2.35 (s, 3H, CH3), 3.15 (s, 3H,
NCH3), 5.50 (s, 2H, CH2Ph), 7.15-7.40 (m, 5H, C6H5), 11.85
(bs, 1H, NH).
N -(6-Am in o -3-m e t h y l-2,4-d io x o -5-p y r im id in y l)-N -
(p h en ylm eth yl)bu ta n a m id e (3). A mixture of 6-amino-3-
methyl-5-(benzylamino)pyrimidine-2,4-dione (1) (5.0 g, 20.33
mmol), butyric acid (1.79 g, 1.86 mL, 20.3 mmol), 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide (4.30 g, 22.4 mmol),
and 4-(N,N-dimethylamino)pyridine (0.25 g) in DMF (30 mL)
was stirred at room temperature overnight. The reaction
mixture was poured into ice-H2O, filtered, washed with water,
and dried in vacuo over P2O5 to give 3 (5.80 g, 90%): 1H NMR
(DMSO-d6) δ 0.85 (t, 3H, CH3), 1.50 (dt, 2H, CH2CH3), 2.05 (t,
2H, CH2), 3.00 (s, 3H, NCH3), 4.55 (AB, 2H, CH2Ph), 6.15 (s,
2H, NH2), 7.15-7.30 (m, 5H, C6H5),
2-Ch lor o-1,8-d im et h yl-7-(p h en ylm et h yl)p u r in -6(6H )-
on e (4). A suspension of 2 (10.0 g) in POCl3 (200 mL) was
heated at reflux for 7 h; it was then concentrated under
vacuum. The residue was partitioned between EtOAc and
ice-water and the organic layer washed with water, dried, and
concentrated. The crude product was purified by flash chro-
matography (1% MeOH/CH2Cl2) to give 4 (9.63 g, 90%) as a
white solid: mp 166-168.5 °C; 1H NMR (CDCl3) δ 2.50 (s, 3H,
CH3), 3.75 (s, 3H, NCH3), 5.60 (s, 2H, CH2Ph), 7.15-7.40 (m,
5H, C6H5); MS (EI) m/ z 290 (MH+).
IC50 (nM)
∆ mmHg
compd
PDE1
PDE2
PDE3
PDE4
5700
PDE5 @ 10 mg/kg
E4021 >100000 10900 >100000
4
-7
-35
-56
-27
-48
-10
-47
-2
8
12
18
20
25
28
31
33
50
1250 34000 >300000
82000 2400
36 12000
30 35000
14 12000
11000
30000
57000
4800
57000
5200
9000
8100
700
200
not
tested
10
34
26
11
80
305
200
4
80 35000 >300000
100
0.07
0.6
1500
2100
1800
3100
80000
3500
7000
-33
-2
21
110000
Exp er im en ta l Section
Melting points were taken on a Thomas-Hoover or Mel-
Temp II melting point apparatus and are uncorrected. The
melting points of amorphous solids are generally not reported.
Chromatography was performed over Universal Scientific or
Selecto Scientific flash silica gel 32-63 µm. 1H NMR spectra
were determined with a Varian VXR 200, Gemini 300, or
Gemini 400 MHz instrument using either Me4Si or residual
solvent signal as internal standard. IR spectra were obtained
on a Perkin Elmer 727B series IR spectrophotometer or on a
Nicolet 10 MX-FTIR. Rotations were determined on a Rudolph
Autopol III or Perkin-Elmer 243B polarimeter. Mass spectra
were obtained on a VG-ZAB-SE, Extrel-401, HP-MS Engine,
or J EOL HX-110 mass spectrometer. Elemental analyses were
determined by the Physical-Analytical Department of Scher-
ing-Plough Research Institute using either CEC 240-HA, CEC
CE-440, or Fisons EA 1108 CHNS elemental analyzers and
are within 0.4% of the theoretical value unless otherwise noted.
Fractional solvent impurities reported in the molecular com-
1
position were identified by the characteristic peaks in the H
2-Ch lor o-8-p r op yl-1-m et h yl-7-(p h en ylm et h yl)p u r in -
6(6H)-on e (5). A suspension of 3 (2.0 g) in POCl3 (50 mL)
was heated at reflux for 7 h; it was then concentrated under
NMR and were quantitated by integration of the 1H reso-
nances. The reference PDE5 inhibitor, E4021, was prepared

2204 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Ahn et al.
vacuum. The residue was partitioned between EtOAc and
ice-water and the organic layer washed with water, dried, and
concentrated. The crude product was purified by flash chro-
matography (1% MeOH/CH2Cl2) to give 5 (1.60 g, 80%): 1H
NMR (CDCl3) δ 0.95 (t, 3H, CH3), 1.55 (m, 2H), 2.55 (t, 2H,
CH2), 3.20 (s, 3H, NCH3), 5.50 (AB, 2H, CH2Ph), 7.15-7.35
(m, 5H, C6H5); MS (EI) m/ z 318 (MH+).
406.2607 (MH+), found 406.2620. Anal. (C24H31N5O) C, N;
H: calcd, 7.7; found, 7.24.
(6a R ,9a S )-2-H e xyl-5,6a ,7,8,9,9a -h e xa h yd r o-5-m e t h -
ylcyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-on e (12): 1H
NMR (CDCl3) δ 0.84 (t, 3H, J ) 6.4 Hz, CH3), 1.34 (br, 6H,
(CH2)3), 1.55 (m, 1H), 1.7-1.88 (m, 5H), 1.94 (m, 1H, CH), 2.23
(dd, 1H, J ) 13.2, 5.5 Hz, CH), 2.79 (t, 2H, J ) 7.7 Hz, CH2),
3.37 (s, 3H, NCH3), 4.72 (t, 1H, J ) 7.3 Hz, CH), 4.87 (t, 1H,
J ) 7.5 Hz, CH); MS (CI) m/ z 316 (M+). Anal. (C17H25N5O‚0.5
H2O‚0.25CH3OH) C, H, N.
2-[((1R,2R)-2-Hydr oxycyclopen tyl)am in o]-1,8-dim eth yl-
7-(p h en ylm eth yl)p u r in -6(6H)-on e (6). A mixture of 4 (6.0
g, 21 mmol), (1R,2R)-2-aminocyclopentanol10 (3.17 g, 31.4
mmol), and diisopropylethylamine (62 mmol) in N-methylpyr-
rolidone (20 mL) was heated at 130 °C until TLC indicated
the complete consumption of 4. The reaction mixture was
poured into water, extracted with EtOAc, dried (MgSO4),
filtered, and concentrated. The crude product was purified by
flash chromatography (5% MeOH/CH2Cl2) to give 6 (6.20 g,
(6a R,9a S)-2-(3-Meth ylbu tyl)-5,6a ,7,8,9,9a -h exa h yd r o-5-
m eth yl-3-(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u -
1
r in -4(3H)-on e (13): H NMR (CDCl3) δ 0.81 (d, 6H, J ) 6.5
Hz, CH(CH3)2), 1.38-2.22 (m, 9H, NCH(CH2)3CHNd, CH2-
CH2CH(CH3)2), 2.58 (m, 2H, CH2CH2CH(CH3)2), 3.33 (s, 3H,
CH3N), 4.68 (t, 1H, J ) 7.5 Hz, NCH(CH2)3CHNd), 4.81 (t,
1H, J ) 7.3 Hz, NCH(CH2)3CHNd), 5.44 (d, 2H, J ) 3.0 Hz,
CH2C6H5), 7.12 (d, 2H, J ) 7.4 Hz, ArH), 7.25 (m, 3H, ArH);
MS (CI) m/ z 392 (MH+). Anal. (C23H29N5O‚0.50H2O) C, H,
N.
85%): [R]26 +8.3° (c 1.0, EtOH); 1H NMR (CDCl3) δ 1.53-
D
2.25 (m, 6H), 3.30 (s, 3H, NCH3), 4.00 (m, 2H), 5.00 (d, 1H,
OH), 5.50 (s, 2H, CH2Ph), 6.45 (d, 1H, NH), 7.2-7.4 (m, 5H).
Anal. (C19H23N5O2‚0.5H2O) C, H, N.
(6a R ,9a S )-5,6a ,7,8,9,9a -H e xa h yd r o-2,5-d im e t h yl-3-
(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-
on e (7). To a solution of 6 (8.0 g, 23 mmol) in CH2Cl2 (150
mL) was added SOCl2 (8.1 g, 68 mmol) at 0 °C. The mixture
was warmed to room temperature and stirred for 3 h, diluted
with CH2Cl2, treated with ice, and adjusted to pH 7-8 with 1
N NaOH. The CH2Cl2 layer was separated and the aqueous
solution extracted with CH2Cl2. The combined organic solu-
tions were washed with brine, dried (MgSO4), filtered, and
concentrated. The crude product was purified by flash chro-
matography (2% MeOH/CH2Cl2) to give 7 (7.20 g, 95%) as a
(6a R,9a S)-2-(3-Meth ylbu tyl)-5,6a ,7,8,9,9a -h exa h yd r o-5-
m eth ylcyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-on e (14):
1H NMR (CDCl3) δ 0.92 (d, 6H, J ) 6.4 Hz, C(CH3)2), 1.53-
2.28 (m, 9H, NCH(CH2)3CHNd, CH2CH2CH(CH3)2), 2.82 (m,
2H, CH2CH2CH(CH3)2), 3.44 (s, 3H, CH3N), 4.76 (t, 1H, J )
7.1 Hz, NCH(CH2)3CHNd), 4.92 (t, 1H, J ) 6.9 Hz, NCH-
(CH2)3CHNd); MS (CI) m/ z 302 (MH+). Anal. (C16H23N5O‚
0.25CH2Cl2) C, H, N.
(6a R,9a S)-2-(Cyclop r op ylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h yl-3-(p h en ylm et h yl)cyclop en t [4,5]im id a zo-
[2,1-b]p u r in -4(3H)-on e (15): 1H NMR (CDCl3) δ 0.11 (q, 2H,
J ) 5.0 Hz, cyclopropyl), 0.44 (m, 2H, J ) 4.5 Hz, cyclopropyl),
0.95 (m, 1H, CH(CH2)2), 1.50-2.24 (m, 6H, NCH(CH2)3CHNd),
2.58 (t, 2H, J ) 6.3 Hz, CH2CH(CH2)2), 3.31 (s, 3H, CH3N),
4.69 (t, 1H, J ) 7.5 Hz, NCH(CH2)3CHNd), 4.83 (t, 1H, J )
7.2 Hz, NCH(CH2)3CHNd), 5.47 (AB, 2H, J ) 15.9 Hz,
CH2C6H5), 7.09 (d, 2H, J ) 7.6 Hz, ArH), 7.25 (m, 3H, ArH);
MS (CI) m/ z 376 (MH+). Anal. (C22H25N5O‚0.80H2O) C, H,
N.
(6a R,9a S)-2-(Cyclop r op ylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h ylcyclop en t [4,5]im id a zo[2,1-b]p u r in -4(3H )-
on e (16): 1H NMR (CDCl3) δ 0.30 (q, 2H, J ) 5.1 Hz,
cyclopropyl), 0.56 (m, 2H, cyclopropyl), 1.17 (m, 1H, CH(CH2)2),
1.53-2.29 (m, 6H, NCH(CH2)3CHNd), 2.73 (d, 2H, J ) 7.0
Hz, CH2CH(CH2)2), 3.40 (s, 3H, CH3N), 4.75 (t, 1H, J ) 7.5
Hz, NCH(CH2)3CHNd), 4.91 (t, 1H, J ) 7.0 Hz, NCH-
(CH2)3CHNd); MS (CI) m/ z 286 (MH+). Anal. (C15H19N5O‚
0.25CH2Cl2) C, H, N.
white solid: mp 185.5-186.5 °C (CH3CN); [R]26 +125.9° (c
D
1.0, EtOH); 1H NMR (CDCl3) δ 1.53-2.25 (m, 6H), 4.70 (t, 1H,
J ) 7.7 Hz), 4.81 (t, 1H, J ) 7.3 Hz), 5.48 (s, 2H), 7.2-7.4 (m,
5H); MS (EI) m/ z 335 (M+, 60). Anal. (C19H21N5O) C, H, N.
(6a R ,9a S )-5,6a ,7,8,9,9a -H e xa h yd r o-2,5-d im e t h ylcy-
clopen t[4,5]im idazo[2,1-b]pu r in -4(3H)-on e (8). To a stirred
suspension of 20% Pd(OH)2/C (1.5 g) in methanol was added
ammonium formate (9.5 g, 0.15 mol) followed by a solution of
7 (5.0 g, 15 mmol) in methanol. The mixture was stirred at
reflux until TLC indicated the complete consumption of 7. The
reaction mixture was filtered, washed with 10% MeOH/CH2-
Cl2, and concentrated. The residue was diluted with CH2Cl2,
washed with saturated NaHCO3 and brine, dried (MgSO4),
filtered, and concentrated. Crude product was purified by
flash chromatography (5% MeOH/CH2Cl2) to give 8 (3.30 g,
1
90%) as a white solid: [R]21 +143.7° (c 0.5, EtOH); H NMR
D
(CDCl3) δ 1.6-2.25 (m, 6H), 2.55 (s, 3H), 3.44 (s, 3H), 4.81 (t,
1H, J ) 7.1 Hz), 4.92 (t, 1H, J ) 7.1 Hz); MS (CI, CH4) m/ z
246 (MH+, 100). Anal. (C12H15N5O‚0.2H2O) C, H, N.
(6a R,9a S)-2-P r op yl-5,6a ,7,8,9,9a -h exa h yd r o-5-m eth yl-
3-(ph en ylm eth yl)cyclopen t[4,5]im idazo[2,1-b]pu r in -4(3H)-
on e (9): from compound 5 using the general methods described
above for the conversion of 4 to 7; 1H NMR (300 MHz, CDCl3)
δ 0.95 (t, 3H, J ) 7.5 Hz, CH3), 1.60-2.00 (m, 7H), 2.25 (dd,
1H, J ) 7.5, 12.5 Hz), 2.60 (dd, 2H, CH2CH2), 3.32 (s, 3H,
NCH3), 4.70 (t, 1H, J ) 7.0 Hz), 4.85 (t, 1H, J ) 7.0 Hz), 5.50
(d, 2H, J ) 12.5 Hz, NCH2Ph), 7.15 (d, 2H, ArH), 7.28-7.30
(m, 3H, ArH); MS (FAB, thioglycerol matrix) m/ z 364 (MH+).
Anal. (C21H25N5O) C, H, N.
(6a R,9a S)-2-(Cyclop en tylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h yl-3-(p h en ylm et h yl)cyclop en t [4,5]im id a zo-
[2,1-b]p u r in -4(3H)-on e (17): clear oil; [R]20 +99° (c 0.57,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.09-2.27 (m, 15H), 2.65
(d, 2H, J ) 7.4 Hz), 3.34 (s, 3H), 4.71 (t, 1H, J ) 7.6 Hz), 4.84
(t, 1H, J ) 7.2 Hz), 5.46 (d, 1H, J ) 15.6 Hz), 5.54 (d, 1H, J )
15.9 Hz), 7.14 (d, 2H, J ) 7.0 Hz), 7.26-7.35 (m, 3H); MS (CI)
m/ z 404 (MH+, 100). Anal. (C24H29N5O‚0.55CHCl3) C, H; N:
calcd, 14.93; found, 14.04.
(6a R,9a S)-2-(Cyclop en tylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h ylcyclop en t [4,5]im id a zo[2,1-b]p u r in -4(3H )-
on e (18): clear oil; [R]20D +127° (c 0.63, CHCl3); 1H NMR (400
MHz, CDCl3) δ 1.21-2.42 (m, 15H), 2.81 (d, 2H, J ) 7.6 Hz),
3.40 (s, 3H), 4.74 (t, 1H, J ) 7.4 Hz), 4.88 (t, 1H, J ) 7.2 Hz);
MS (CI) m/ z 314 (MH+, 100). Anal. (C17H23N5O‚0.75CHCl3)
C, H, N.
(6a R,9a S)-2-P r op yl-5,6a ,7,8,9,9a -h exa h yd r o-5-m et h -
ylcyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-on e (10): 1H
NMR (300 MHz, CDCl3) δ 1.00 (t, 3H, J ) 7.5 Hz, CH3), 1.60-
2.00 (m, 7H), 2.28 (dd, 1H, J ) 7.5, 12.5 Hz), 2.80 (t, 2H, J )
7.5 Hz, CH2CH2), 3.30 (s, 3H, NCH3), 4.72 (t, 1H, J ) 7.0 Hz),
4.90 (t, 1H, J ) 7.0 Hz); MS (FAB, thioglycerol matrix) m/ z
274 (MH+). Anal. (C14H19N5O) C, H, N.
5′-Meth yl-2′-(cyclop en tylm eth yl)-3′-(p h en ylm eth yl)sp i-
r o[cyclopen tan e-1,7′(8′H)-[3H]im idazo[2,1-b]pu r in ]-4(5′H)-
1
on e (19): H NMR (400 MHz, CDCl3) δ 1.10 (m, 2H), 1.40-
(6a R,9a S)-2-Hexyl-5,6a ,7,8,9,9a -h exa h yd r o-5-m eth yl-3-
(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-
1.95 (m, 14H), 2.20 (m, 1H), 2.55 (d, 2H, J ) 7.4 Hz, CH2C5H9),
3.34 (s, 3H, NCH3), 3.90 (s, 2H, CH2), 5.50 (s, 2H, CH2Ph),
7.10, 7.28 (5H, m, ArH); MS (FAB, thioglycerol matrix) m/ z
418 (MH+). Anal. (C25H31N5O) C, H, N.
1
on e (11): H NMR (CDCl3) δ 0.85 (t, 3H, J ) 6.7 Hz, CH3),
1.2 (m, 6H, (CH2)3), 1.55 (m, 3H), 1.7 (m, 1H), 1.8 (m, 2H),
1.91 (dd, 1H, J ) 12.4, 5.4 Hz, CH), 2.19 (dd, 1H, J ) 13.6,
5.3 Hz, CH), 2.60 (t, 2H, J ) 7.7 Hz, CH2), 3.3 (s, 3H, NCH3),
4.67 (t, 1H, J ) 7.4 Hz, CH), 4.80 (t, 1H, J ) 7.2 Hz, CH),
5.46 (AB, 2H, J ) 15.8 Hz, PhCH2), 7.12 (d, 2H, J ) 6.95 Hz,
ArH), 7.24-7.31 (m, 3H, ArH); HRMS FAB (C24H32N5O) calcd
5′-Met h yl-2′-(cyclop en t ylm et h yl)sp ir o[cyclop en t a n e-
1,7′(8′H)-[3H]im idazo[2,1-b]pu r in ]-4′(5′H)-on e (20): 1H NMR
(400 MHz, CDCl3) δ 1.22 (m, 2H), 1.50-1.90 (m, 14H), 2.38
(m, 1H), 2.80 (d, 2H, J ) 7.4 Hz, CH2C5H9), 3.40 (s, 3H, NCH3),

Tetracyclic Guanine Inhibitors of PDE1 and PDE5
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2205
3.92 (s, 2H, CH2); MS (FAB, thioglycerol matrix) m/ z 328
(MH+). Anal. (C18H25N5O) C, H, N.
2H), 7.50 (m, 2H), 7.55 (m, 2H); MS (CI) m/ z 488 (MH+). Anal.
(C31H29N5O‚0.33H2O) C, H, N.
(6a R,9a S)-2-(Cycloh exylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h yl-3-(p h en ylm et h yl)cyclop en t [4,5]im id a zo-
[2,1-b]p u r in -4(3H)-on e (21): white foam from silica gel
column (2% MeOH in CH2Cl2); [R]22D +99.1° (c 0.5, EtOH); 1H
NMR (CDCl3) δ 0.9-2.0 (6m, 17H), 2.54 (d, 2H, J ) 7.0 Hz),
3.34 (s, 3H), 4.72 (t, 1H, J ) 7.0 Hz), 4.85 (t, 1H, J ) 6.8 Hz),
5.35 (d, 2H, J ) 5.8 Hz), 7.14-7.36 (m, 5H); MS (CI, CH4) m/ z
418 (MH+, 100). Anal. (C25H31N5O‚0.5CH3OH) C, H, N.
(6a R,9a S)-2-(Cycloh exylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h ylcyclop en t [4,5]im id a zo[2,1-b]p u r in -4(3H )-
(6a R,9a S)-2-(Bip h en ylylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h ylcyclop en t [4,5]im id a zo[2,1-b]p u r in -4(3H )-
on e (32): white powder; mp 225-227 °C; [R]25 +114.7° (c
D
0.2, MeOH); 1H NMR (CDCl3) δ 1.55 (m, 1H, CH2), 1.68-1.92
(m, 4H, CH2), 1.96 (m, 1H, CH2), 2.27 (dd, 1H, CH2), 3.38 (s,
3H, NCH3), 4.20 (s, 2H, CH2Ar), 4.72 (t, 1H, J ) 7.6, CH-N),
4.87 (t, 1H, J ) 7.4 Hz, CH-N), 7.35 (m, 1H, ArH), 7.42 (m,
4H, ArH), 7.55 (m, 4H, ArH); MS (CI) m/ z 398 (MH+). Anal.
(C24H23N5O) C, H, N.
5′-Meth yl-2′-(bip h en ylylm eth yl)-3′-(p h en ylm eth yl)sp i-
r o[cyclopen tan e-1,7′(8′H)-[3H]im idazo[2,1-b]pu r in ]-4(5′H)-
on e (33): 1H NMR (CDCl3) δ 1.60-1.76 (m, 4H), 1.82-2.00
(m, 4H), 3.37 (s, 3H), 3.94 (s, 2H), 4.05 (s, 2H), 5.43 (s, 2H),
7.13 (d, 2H, J ) 6.2 Hz), 7.20 (d, 2H, J ) 8.0 Hz), 7.30-7.40
(m, 4H), 7.48 (dd, 2H, J ) 7.6 Hz), 7.53 (d, 2H, J ) 8.2 Hz),
7.59 (d, 2H, J ) 7.1 Hz); MS (CI) m/ z 502 (MH+). Anal.
(C32H31N5O) C, H, N.
5′-Met h yl-2′-(b ip h en ylylm et h yl)sp ir o[cyclop en t a n e-
1,7′(8′H)-[3H]im idazo[2,1-b]pu r in ]-4′(5′H)-on e (34): 1H NMR
(CDCl3) δ 1.61-1.75 (m, 4H), 1.80-1.99 (m, 4H), 3.40 (s, 3H),
3.92 (s, 2H), 4.18 (s, 2H), 7.32 (m, 1H), 7.39-7.44 (m, 4H),
7.51-7.55 (m, 4H); MS (FAB) m/ z 412.2 (MH+). Anal.
(C25H25N5O‚CH3OH) C, H, N.
on e (22): beige foam from silica gel column (5% MeOH in
1
CH2Cl2); [R]25 +127° (c 0.5 EtOH); H NMR (CDCl3) δ 1.0-
D
2.3 (6m, 17H), 2.70 (d, 2H, J ) 7.1 Hz), 3.42 (s, 3H), 4.78 (t,
1H, J ) 7.3 Hz), 4.90 (t, 1Η, J ) 7.1 Hz); MS (CI, CH4) m/ z
328 (MH+, 100). Anal. (C18H25N5O‚0.25CH3OH) C, H, N.
r a c-(6a R*,9a S*)-5,6a ,7,8,9,9a -H exa h yd r o-5-m et h yl-2-
(tr iflu or om eth yl)-3-(ph en ylm eth yl)cyclopen t[4,5]im idazo-
[2,1-b]p u r in -4(3H)-on e (23): white solid from silica gel
column (2% MeOH in CH2Cl2); 1H NMR (CDCl3) δ 1.56 (m,
1H), 1.85 (m, 4H), 2.23 (m, 4H), 3.33 (s, 3H), 4.82 (t, 1H, J )
7.5 Hz), 5.68 (s, 2H), 7.2-7.4 (m, 5Η); MS (CI, CH4) m/ z 390
(MH+, 100). Anal. (C19H18F3N5O) C, H, N.
r a c-(6a R*,9a S*)-5,6a ,7,8,9,9a -H exa h yd r o-5-m et h yl-2-
(tr iflu or om eth yl)cyclopen t[4,5]im idazo[2,1-b]pu r in -4(3H)-
on e (24): white solid; 1H NMR (400 MHz, CD3OD) δ 1.66-
2.42 (m, 6H), 3.39 (s, 3H), 4.84 (t, 1H, J ) 7.0 Hz), 5.21 (t, 1H,
J ) 7.1 Hz); MS (CI) m/ z 300 (MH+, 100). Anal. (C12H12F3N5O‚
H2O)C, H, N.
5′-Meth yl-2′-p h en yl-3′-(p h en ylm eth yl)sp ir o[cyclop en -
t a n e-1,7′(8′H)-[3H]im id a zo[2,1-b]p u r in ]-4(5′H)-on e (25):
white solid; mp 125.5-127.5 °C (from isopropyl ether); 1H
NMR (CDCl3) δ 1.67-1.95 (m, 8H), 3.36 (s, 3H), 3.95 (s, 2H),
5.59 (s, 2H), 7.03-7.56 (m, 10H); MS (CI, CH4) m/ z 412 (MH+,
100). Anal. (C25H25N5O‚0.5CH3OH) C, H, N.
5′-Meth yl-2′-p h en ylsp ir o[cyclop en ta n e-1,7′(8′H)-[3H]-
im id a zo[2,1-b]p u r in ]-4′(5′H)-on e (26): white solid; mp >300
°C (from EtOH); 1H NMR (DMSO-d6) δ 1.68-1.79 (m, 8H), 3.24
(s, 3H), 3.96 (s, 2H), 7.48 (m, 3H), 8.1 (d, 2H, J ) 6.5 Hz), 13.5
(bs, 1H); MS (CI, isob) m/ z 322 (MH+, 100). Anal. (C18H19N5O‚
0.1EtOH) C, H, N.
(6a R,9a S)-5,6a ,7,8,9,9a -H exa h yd r o-5-m et h yl-2,3-b is-
(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-
on e (27): off-white solid; [R]25D +237° (c 0.50, EtOH); 1H NMR
(400 MHz, CDCl3) δ 1.55-2.40 (m, 6H), 3.52 (s, 3H), 4.07 (s,
2H), 4.84 (t, 1H, J ) 7 Hz), 5.01 (t, 1H, J ) 7 Hz), 5.37 (s, 2H),
7.08-7.13 (m, 4H), 7.24-7.34 (m, 6H); MS (EI) m/ z 411 (M+,
48), 382 (100). Anal. (C25H25N5O) C, H, N.
(6 a R ,9 a S )-5 ,6 a ,7 ,8 ,9 ,9 a -H e x a h y d r o -5 -m e t h y l -3 -
(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-
on e (35). Intermediate 35 was prepared according to the
general methods illustrated in Scheme 1, using triethyl
orthoformate to form the imidazole ring, and recrystallized
from CH2Cl2/hexane: mp 145-146 °C; [R]26 +105.7° (c 0.5,
D
MeOH); 1H NMR (CDCl3) δ 1.50 (m, 1H, CH2), 1.61-1.92 (m,
4H, CH2), 2.14 (dd, 1H, CH2), 3.29 (s, 3H, NMe), 4.65 (t, 1H,
J ) 7 Hz, CH-N), 4.77 (t, 1H, J ) 7 Hz, CH-N), 5.35 (d, 1H, J
) 14 Hz, NCHPh), 5.40 (d, 1H, J ) 14 Hz, CHPh), 7.27-7.34
(m, 5H, ArH), 7.42 (s, 1H, C2-H); MS (EI) m/ z 321 (M+). Anal.
(C18H19N5O‚0.1H2O) C, H, N.
(6aR,9aS)-2-For m yl-cis-5,6a,7,8,9,9a-h exah ydr o-5-m eth -
yl-3-(p h en ylm et h yl)cyclop en t [4,5]im id a zo[2,1-b]p u r in -
4(3H)-on e (36). A solution of N,N-diisopropylamine (7.15 mL,
51 mmol) in THF was cooled to 0 °C and treated with n-BuLi
(2.5 M in hexanes, 20.4 mL) for 0.5 h. The reaction mixture
was then cooled to -78 °C, and compound 35 (13.70 g, 42.60
mmol) in THF (100 mL) was added. The reaction mixture was
stirred at -78 °C for 0.5 h, and DMF (5.30 mL, 68.0 mmol)
was added. The reaction mixture was allowed to warm to room
temperature over a period of 1 h and then treated with
saturated NH4Cl. The THF was removed under reduced
pressure, and the residue was extracted with CH2Cl2. The
CH2Cl2 layer was dried and evaporated. Flash chromatogra-
phy (2% MeOH/CH2Cl2) gave 36 (10.70 g, 72%): 1H NMR (400
MHz, CDCl3) δ 1.75-2.0 (m, 5H), 2.20 (m, 1H), 3.40 (s, 3H,
NCH3), 4.75, 4.85 (2bt, 2H, J ) 7.5 Hz, 2CH), 5.95 (AB, 2H,
CH2Ph), 7.20-7.30 (m, 5H, C6H5), 9.98 (s, 1H, CHO); MS (FAB,
thioglycerol matrix) m/ z 350 (MH+). Anal. (C19H19N5O2) C,
H, N.
(6a R,9a S)-2-(Hyd r oxym eth yl)-5,6a ,7,8,9,9a -h exa h yd r o-
5-m eth yl-3-(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]-
p u r in -4(3H)-on e (37). To a solution of 36 (2.60 g, 7.0 mmol)
in EtOH (100 mL) and CH2Cl2 (50 mL) was added sodium
borohydride (2.68 g, 71 mmol) in two portions over 0.5 h. The
reaction mixture was partially evaporated, and water was
added. Solids were removed by filtration, and the filtrate was
evaporated. The residue was extracted with CH2Cl2, dried
(MgSO4), and evaporated to produce 37 (2.20 g, 85%): 1H NMR
(300 MHz, DMSO-d6) δ 1.45-1.80 (m, 5H), 2.10 (m, 2H), 3.30
(s, 3H, NCH3), 4.48 (d, 2H, CH2OH), 4.55, 4.65 (2m, 2H), 5.52
(AB, 2H, J ) 14.5 Hz, CH2Ph), 7.24, 7.30 (2m, 5H, C6H5); MS
(FAB, thioglycerol matrix) m/ z 352 (MH+). Anal. (C19H21N5O2)
C, H, N.
(6a R,9a S)-2-(P h en ylm eth yl)-5,6a ,7,8,9,9a -h exa h yd r o-5-
m e t h ylc yc lop e n t [4,5]im id a zo[2,1-b]p u r in -4(3H )-on e
(28): 1H NMR (200 MHz, CDCl3 + 1 drop of CD3OD) δ 1.50
(1H, m), 1.65-2.00 (5H, m), 2.28 (dd, 1H, J ) 7.5, 12.5 Hz),
3.28 (s, 3H, NCH3), 4.18 (s, 2H, CH2Ph), 4.75 (t, 1H, J ) 7.0
Hz), 4.90 (t, 1H, J ) 7.0 Hz), 7.30 (m, 5H, ArH); MS (FAB,
thioglycerol matrix) m/ z 322 (MH+). Anal. (C18H19N5O) C,
H, N.
5′-Meth yl-2′,3′-bis(p h en ylm eth yl)sp ir o[cyclop en ta n e-
1,7′(8′H)-[3H]im idazo[2,1-b]pu r in ]-4′(5′H)-on e (29): 1H NMR
(300 MHz, DMSO-d6) δ 1.55s1.82 (m, 8H), 3.16 (s, 3H), 3.81
(s, 2H), 4.05 (s, 2H), 5.53 (s, 2H), 7.07-7.33 (m, 10H); MS (CI)
m/ z 426 (MH+). Anal. (C26H27N5O‚C2H5OH‚0.5H2O) C, H, N.
5′-Met h yl-2′-(p h en ylm et h yl)sp ir o[cyclop en t a n e-1,7′-
1
(8′H)-[3H]im id a zo[2,1-b]p u r in ]-4′(5′H)-on e (30): H NMR
(200 MHz, CDCl3 + 1 drop of CD3OD) δ 1.60-2.00 (m, 8H),
3.56 (s, 3H, NCH3), 4.18 (bs, 2H, CH2), 4.26 (s, 2H, CH2Ph),
7.30 (m, 5H, ArH); MS (FAB, thioglycerol matrix) m/ z 336
(MH+). Anal. (C19H21N5O) C, H, N.
(6a R,9a S)-2-(Bip h en ylylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h yl-3-(p h en ylm et h yl)cyclop en t [4,5]im id a zo-
[2,1-b]p u r in -4(3H)-on e (31): colorless solid; [R]25 +86.6° (c
(6a R,9a S)-2-(Ch lor om eth yl)-5,6a ,7,8,9,9a -h exa h yd r o-5-
m eth yl-3-(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u -
r in -4(3H)-on e (38). To a solution of 37 (1.90 g, 5.14 mmol)
in CH2Cl2 (60 mL) was added SOCl2 (3.70 mL, 51 mmol), and
the reaction mixture was stirred at room temperature for 4 h.
The reaction mixture was evaporated; the residue was treated
D
1
0.2, MeOH); H NMR (CDCl3) δ 1.61 (m, 1H, J ) 6 Hz, CH2),
1.72-2.02 (m, 4H, CH2), 2.30 (dd, 1H, J ) 5.2, 13.8 Hz, CH2),
3.35 (s, 3H, NCH3), 4.08 (s, 2H, CH2Ar), 4.75 (t, 1H, J ) 7.3
Hz, CH-N), 4.90 (t, 1H, J ) 7.2 Hz, CH-N), 5.40 (s, 2H, NCH2-
Ar), 7.12 (m, 2H), 7.19 (m, 2H), 7.26-7.37 (m, 4H), 7.43 (m,

2206 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Ahn et al.
with saturated NaHCO3, extracted with CH2Cl2 (3 × 100 mL),
dried (MgSO4), and evaporated to give 38 (1.70 g, 90%): 1H
NMR (300 MHz, CDCl3) δ 1.50-2.00 (m, 5H), 2.20 (m, 2H),
3.38 (s, 3H, NCH3), 4.50 (s, 2H, CH2Cl), 4.75, 4.85 (2 bt, 2H, J
) 7.5 Hz), 5.68 (2H, s, CH2Ph), 7.22, 7.35 (2m, 5H, ArH); MS
on e (44). A solution of 43 (150 mg, 0.37 mmol) in methanol
was added to a suspension of ammonium formate and Pd-
(OH)2/C in methanol at room temperature. The mixture was
heated at reflux for 15 h. The reaction mixture was poured
into 10% MeOH/CH2Cl2 (500 mL), stirred at reflux for 10 min,
filtered, and concentrated. The residue was dissolved in CH2-
Cl2 (200 mL) and washed with aqueous NaHCO3. The aqueous
solution was extracted with CH2Cl2 (3 × 100 mL). The
combined CH2Cl2 layers were dried (MgSO4), filtered, and
concentrated. Crude product was purified by flash chroma-
tography (3-20% MeOH/CH2Cl2, then 10% MeOH (saturated
with NH3)/CH2Cl2) to give 44 (40 mg, 26%): 1H NMR (CDCl3)
δ 1.51 (m, 1H), 1.60-1.80 (m, 7H), 1.81-1.95 (m, 1H), 2.18
(dd, 1H, J ) 13.0, 6.0 Hz, CH), 2.58 (s, br, 4H, 2NCH2), 3.29
(s, 3H, NCH3), 3.75 (s, 2H, CH2N), 4.65 (t, 1H, J ) 7.2 Hz,
CH), 4.79 (t, 1H, J ) 7.5 Hz, CH); HRMS (C16H23N6O) calcd
315.1933 (MH+), found 315.1926. Anal. (C16H22N6O) C, H,
N.
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-2-(1H-im id a zol-2-yl-
m eth yl)-5-m eth yl-3-(ph en ylm eth yl)cyclopen t[4,5]im idazo-
[2,1-b]p u r in -4(3H)-on e (46). A mixture of 2-imidazolecar-
boxaldehyde (2.0 g, 21 mmol), TsCl (4.8 g, 25 mmol), and Et3N
(4.3 mL, 31 mmol) was refluxed in 1,2-dichloroethane (100 mL)
for 24 h. The mixture was washed with saturated NaHCO3,
dried (MgSO4), and concentrated. Flash chromatography (20%
EtOAc/hexanes, then 30% EtOAc/hexanes) gave 48 (4.7 g, 90%)
as a pink solid: 1H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H),
7.31 (s, 1H), 7.37 (d, 2H, J ) 8 Hz), 7.84 (s, 1H), 8.00 (d, 1H,
J ) 8 Hz), 9.78 (s, 1H); MS (CI) m/ z 251 (MH+, 87), 155 (100).
Anal. (C11H10N2O3S) C, H, N.
A solution of n-BuLi in hexanes (1.6 M, 2.3 mL, 3.7 mmol)
was added to a solution of i-Pr2NH (0.63 mL, 4.5 mmol) in
dry THF (100 mL) at 0 °C under N2 and stirred for 15 min.
The solution was cooled to -78 °C, and a mixture of 35 (0.80
g, 2.5 mmol) in dry THF (40 mL) was added. The reaction
mixture was stirred at -78 °C for 40 min. The color turned
orange-red. A solution of the imidazole reagent 48 (0.94 g,
3.7 mmol) in dry THF (10 mL) was added at -78 °C, and the
reaction mixture was stirred for 40 min. The reaction was
quenched with saturated NH4Cl and extracted with CH2Cl2.
The organic extract was dried (MgSO4), filtered, and concen-
trated. Flash chromatography (3% MeOH/CH2Cl2, then 5%
MeOH/CH2Cl2) gave 0.86 g (60%) of 45 as a yellow solid: MS
(CI) m/ z 572 (MH+, 100).
MsCl (0.17 mL, 2.2 mmol) was added to a solution of 45
(0.64 g, 1.1 mmol) and Et3N (0.47 mL, 3.3 mmol) in CH2Cl2
(20 mL) at room temperature under N2 and stirred for 1 h.
The solution was diluted with CH2Cl2, washed with saturated
NaHCO3, dried (MgSO4), and concentrated to give 0.67 g of
crude product as a green solid.
A solution of LiBHEt3 in THF (1.0 M, 3.4 mL, 3.3 mmol)
was added to a solution of the above crude product (0.67 g) in
dry THF (20 mL) at 0 °C under N2 and stirred for 10 min. The
reaction mixture turned red. The reaction was quenched with
aqueous HCl (3%) and stirred at room temperature for 1 h.
The mixture was basified with saturated NaHCO3 and ex-
tracted with CH2Cl2. The organic extracts were dried (MgSO4)
and concentrated. Flash chromatography (3% MeOH/CH2Cl2,
then 5% MeOH/CH2Cl2, then 7% MeOH/CH2Cl2) gave 46 (0.157
g, 35%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.45-
2.14 (m, 6H), 3.27 (s, 3H), 4.22 (s, 2H), 4.69 (t, 1H, J ) 7.5
Hz), 4.72 (t, 1H, J ) 7.2 Hz), 5.25 (d, 1H, J ) 15.5 Hz), 5.63
(d, 1H, J ) 15.2 Hz), 7.00 (s, 2H), 7.20-7.33 (m, 5H); MS (EI)
m/ z 401 (M+, 25), 372 (36). Anal. (C22H23N7O‚0.20CH2-
Cl2‚0.90CH3OH) C, H, N.
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-2-(1H-im id a zol-2-yl-
m eth yl)-5-m eth ylcyclopen t[4,5]im idazo[2,1-b]pu r in -4(3H)-
on e (47). To a stirred suspension of 20% Pd(OH)2/C (0.16 g)
in methanol (30 mL) was added ammonium formate (0.46 g,
7.3 mmol) followed by a solution of 46 (100 mg, 0.25 mmol) in
methanol. The mixture was stirred at reflux for 20 h. The
reaction mixture was diluted with CH2Cl2 (200 mL) and
filtered. The solids were washed with 10% MeOH/CH2Cl2. The
combined filtrate and washings were concentrated to give 47
as a yellow solid (78 mg, 100%): 1H NMR (400 MHz, CD3OD)
δ 1.50-2.29 (m, 6H), 3.31 (s, 3H), 4.20 (s, ca. 1H), 4.72 (t, 1H,
(FAB, thioglycerol matrix) m/ z 370 (MH+). Anal. (C19H20
-
ClN5O) C, H, N.
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-2-(m eth oxym eth yl)-
5-m eth yl-3-(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]-
p u r in -4(3H)-on e (39). Compound 38 (0.30 g, 0.80 mmol) was
added to a freshly prepared solution of sodium methoxide (0.07
g of sodium in 10 mL of MeOH), and the reaction mixture was
refluxed for 1 h. The reaction mixture was evaporated, the
residue was suspended in water, and the pH was adjusted to
8 with 1 N HCl. The suspension was extracted with CH2Cl2
(3 × 50 mL), dried (MgSO4), and evaporated. Column chro-
matography (SiO2, 3% MeOH/CH2Cl2) gave 39 (0.20 g, 70%):
1H NMR (300 MHz, CDCl3) δ 1.50-2.00 (m, 5H), 2.20 (m, 2H),
3.35 (s, 3H, NCH3), 3.38 (s, 3H, OCH3), 4.48 (s, 2H, CH2O),
4.70, 4.82 (2bt, 2H J ) 8.0 Hz), 5.62 (2H, s, CH2Ph), 7.22, 7.32
(2m, 5H, ArH); MS (FAB, thioglycerol matrix) m/ z 366 (MH+).
Anal. (C20H23N5O2) C, H, N.
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-2-(m eth oxym eth yl)-
5-m eth ylcyclopen t[4,5]im idazo[2,1-b]pu r in -4(3H)-on e (40).
Compound 39 (0.20 g, 0.55 mmol) was reduced with am-
monium formate/Pd(OH)2, using the general procedure de-
scribed for 8, to give 40 (0.14 g, 92%): 1H NMR (300 MHz,
CDCl3) δ 1.50-2.00 (m, 5H), 2.25 (m, 2H), 3.40 (s, 3H, NCH3),
3.50 (s, 3H, OCH3), 4.60 (s, 2H, CH2O), 4.75, 4.85 (2 bt, 2H, J
) 8.0 Hz); MS (FAB, thioglycerol matrix) m/ z 276 (MH+).
Anal. (C13H17N5O2) C, H, N.
(6a R,9a S)-2-[(N,N-Dim et h yla m in o)m et h yl]-5,6a ,7,8,9,
9a -h exa h yd r o-5-m eth yl-3-(p h en ylm eth yl)cyclop en t[4,5]-
im id a zo[2,1-b]p u r in -4(3H)-on e (41). A solution of com-
pound 38 (1.0 g, 2.71 mmol) in THF and excess N,N-
dimethylamine (2 M in THF) was refluxed for 0.25 h, and the
reaction mixture was evaporated. The residue was dissolved
in CH2Cl2, washed with saturated NaHCO3, dried (MgSO4),
and evaporated. Column chromatography of the residue (SiO2,
2% MeOH/CH2Cl2) gave 41 (0.82 g, 80%): 1H NMR (300 MHz,
CDCl3) δ 1.50-2.00 (m, 5H), 2.20 (m, 2H), 2.25 (s, 6H,
N(CH3)2), 3.35 (s, 3H, NCH3), 3.45 (s, 2H, NCH2), 4.72, 4.85 (2
bt, 2H, J ) 8.0 Hz), 5.75 (AB, 2H, J ) 14.8 Hz, CH2Ph), 7.20,
7.32 (2m, 5H, ArH); MS (FAB, thioglycerol matrix) m/ z 379
(MH+). Anal. (C21H26N6O) C, H, N.
(6a R,9a S)-2-[(N,N-Dim et h yla m in o)m et h yl]-5,6a ,7,8,9,
9a -h exa h yd r o-5-m et h ylcyclop en t [4,5]im id a zo[2,1-b]p u -
r in -4(3H)-on e (42). Compound 41 was reduced with NH4-
HCO2/Pd(OH)2, using the general procedure described for 8,
to give 42: 1H NMR (300 MHz, CDCl3) δ 1.50-2.00 (m, 5H),
2.25 (m, 2H), 2.35 (s, 6H, N(CH3)2), 3.40 (s, 3H, NCH3), 3.65
(s, 2H, NCH2), 4.75, 4.85 (2 bt, 2H, J ) 8.0 Hz); MS (FAB,
thioglycerol matrix) m/ z 289 (MH+). Anal. (C14H20N6O) C,
H, N.
(6aR,9aS)-2-(1-P yr r olidin ylm eth yl)-5,6a,7,8,9,9a-h exah y-
d r o-5-m et h yl-3-(p h en ylm et h yl)cyclop en t [4,5]im id a zo-
[2,1-b]p u r in -4(3H)-on e (43). To a solution of 36 (290 mg,
0.83 mmol) and pyrrolidine (168 mg, 2.37 mmol) in methanol
was added acetic acid until pH 6-7. To the resulting red
solution was added NaBH3CN (68 mg, 1.08 mmol), and the
yellow solution stirred at room temperature for 16 h. Metha-
nol was evaporated, the residue was treated with CH2Cl2 and
1 N aqueous KOH, and the layers were separated. The
combined aqueous solution was extracted with CH2Cl2, and
the combined organic solution was dried (MgSO4), filtered, and
concentrated. The crude product was purified by flash column
chromatography (3-7% MeOH/CH2Cl2) to give 43 (160 mg,
48%): 1H NMR (CDCl3) δ 1.52 (m, 1H), 1.65-1.8 (m, 7H), 1.85
(m, 1H, CH), 2.18 (dd, 1H, J ) 13.2, 6.0 Hz, CH), 2.47 (bs, 4H,
2NCH2), 3.30 (s, 3H, NCH3), 3.60 (s, 2H, CH2N), 4.67 (t, 1H, J
) 7.3 Hz, CH), 4.80 (t, 1H, J ) 7.6 Hz, CH), 5.68 (AB, 2H, J
) 15 Hz, PhCH2), 7.17 (d, 2H, J ) 6.7 Hz, ArH), 7.29 (m, 3H,
ArH); HRMS (C23H29N6O) calcd 405.2403 (MH+), found
405.2415. Anal. (C23H28N6O) C, H, N.
(6aR,9aS)-2-(1-P yr r olidin ylm eth yl)-5,6a,7,8,9,9a-h exah y-
d r o-5-m et h ylcyclop en t [4,5]im id a zo[2,1-b]p u r in -4(3H )-

Tetracyclic Guanine Inhibitors of PDE1 and PDE5
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2207
J ) 7.2 Hz), 4.95 (t, 1H, J ) 7.4 Hz), 6.97 (s, 2H); MS (EI)
m/ z 311 (M+, 27), 282 (100). Anal. (C15H17N7O‚2.35H2CO3)
C, H, N.
reaction conditions of Scheme 1 (1H NMR (400 MHz, CDCl3)
δ 1.65-2.04 (m, 8H), 3.44 (s, 3H), 3.98 (s, 2H), 7.69 (s, 1H)).
This was directly brominated (conditions identical to prepara-
tion of 51) to give 5′-methyl-2′-bromospiro[cyclopentane-1,7′-
(8′H)-[3H]imidazo[2,1-b]purin]-4(5′H)-one (1H NMR (400 MHz,
CD3OD) δ 1.78-2.18 (m, 8H), 3.48 (s, 3H), 4.41 (s, 2H); MS
(CI) m/ z 246 (100), 324 (81), 326 (73); Anal. (C12H14BrN5O‚
HBr) C, H; N: calcd, 17.29; found: 16.03.). NaH (0.6 g, 15
mmol) was added to a solution of the brominated compound
(1.23 g 3.78 mmol) and dimethyl sulfate (1.8 mL, 19 mmol) in
DMF (50 mL) at room temperature and stirred under nitrogen
for 3 h. The mixture was poured into cold saturated NaHCO3
solution (300 mL). After several hours, the solids were filtered,
washed with H2O and ether, and air-dried to give 5′-methyl-
2′-bromo-3′-methylspiro[cyclopentane-1,7′(8′H)-[3H]imidazo-
[2,1-b]purin]-4(5′H)-one as a white solid (0.578 g, 45%): 1H
NMR (400 MHz, CDCl3) δ 1.63-2.03 (m, 8H), 3.38 (s, 3H), 3.87
(s, 2H), 3.91 (s, 3H); MS (CI) m/ z 338 (100), 340 (92). Anal.
(C13H16BrN5O‚0.15Et2O) C, H, N.
To a suspension of zinc dust (2.3 g) in dry THF (13 mL) at
room temperature under nitrogen was added 1,2-dibromo-
ethane (0.11 mL). The mixture was then stirred at 65 °C for
1 min. To this mixture at 0 °C was added dropwise a solution
of benzyl bromide (3.5 mL). The mixture was stirred at 0 °C
for 0.5 h and then at room temperature for 1.5 h. A portion of
the cloudy supernatant (1.1 mL, ca. 2.4 mmol) was heated with
the product of the previous reaction (0.162 g, 0.477 mmol), Pd-
(PPh3)4 (0.056 g, 0.048 mmol), and PPh3 (0.025 g, 0.095 mmol)
in THF (2 mL) in a sealed tube at 120 °C under argon for 20
h. The solvent was evaporated. The residue was dissolved
in CH2Cl2/MeOH (9:1), washed with saturated NaHCO3, dried
(MgSO4), and concentrated. The residue was separated by
flash chromatography (2% MeOH/CHCl3, then 3% MeOH/
CHCl3) to give 53 as a yellow solid (0.061 g, 37%): 1H NMR
(400 MHz, CDCl3) δ 1.58-1.96 (m, 8H), 3.33 (s, 3H), 3.72 (s,
3H), 3.88 (s, 2H), 4.09 (s, 2H), 7.14 (d, 2H, J ) 8.2 Hz), 7.21-
7.32 (m, 3H); MS (CI) m/ z 350 (MH+, 100). Anal. (C20H23N5O‚
0.4CH2Cl2) C, H; N: calcd, 18.27; found, 17.41.
(6a R,9a S)-5,6a ,7,8,9,9a -H exa h yd r o-5-m et h yl-2-iod o-3-
(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-
on e (49). A solution of N,N-diisopropylamine (1.54 g, 11.4
mmol) in THF (15 mL) was cooled to 0 °C and treated with
n-BuLi in hexanes (4.6 mL, 2.5 M, 11.4 mmol) for 0.5 h. The
reaction mixture was then cooled to -78 °C, and a solution of
35 (3.05 g, 9.5 mmol) in THF (50 mL) was added dropwise.
The reaction mixture was stirred at -78 °C for 0.5 h to give a
dark orange solution. To the reaction mixture was added a
precooled solution of 1-chloro-2-iodoethane (2.7 g, 14 mmol)
in THF (3 mL). The resulting yellow mixture was stirred at
-78 °C for 2 h, quenched with aqueous ammonium chloride,
and filtered. The precipitate was washed with H2O and ether
to give 49 (2.15 g, 51%) as an off-white solid. Ether and THF
were evaporated from the filtrate. The resulting aqueous
solution was extracted with 10% MeOH/CH2Cl2. The organic
solution was dried (MgSO4), filtered, and concentrated to give
a yellow solid which was washed with ether and cold CH3CN
to give additional 49 (0.66 g, 16%): 1H NMR (CDCl3) δ 1.55
(m, 1H), 1.7-1.9 (m, 3H), 1.95 (dd, 1H), 2.21 (dd, 1H), 3.35 (s,
3H, NCH3), 4.7 (t, 1H), 4.8 (t, 1H), 5.5 (s, 2H, PhCH2), 7.35
(m, 5H, ArH); MS (EI) m/ z 447 (M+), 418, 292, 91 (100).
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-5-m eth yl-2-(p h en yl-
eth yn yl)-3-(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]-
p u r in -4(3H)-on e (50). To a suspension of 49 (1.3 g, 2.9 mmol)
in pyridine (5 mL) was added copper phenylacetylide (0.58 g,
3.5 mmol). The mixture was heated to 120 °C for 1 h. The
cooled reaction mixture was partitioned with H2O and EtOAc.
The organic layer was separated and purified by silica gel flash
chromatography (5% MeOH/CH2Cl2). The highly UV active
fractions were concentrated to dryness, dissolved in EtOAc,
and treated with Chelex 100 to remove any residual Cu. After
stirring for several hours, the solution was filtered and
concentrated to give 50 as a yellow solid: mp 193-194 °C;
1
[R]25 +188° (c 0.12, EtOH); H NMR (CDCl3) δ 1.58 (m, 1H,
D
CH2), 1.72-2.10 (m, 4H, CH2), 2.30 (dd, 1H, CH2), 3.45 (s, 3H,
NCH3), 4.77 (t, J ) 7 Hz, 1H, CHN), 4.9 (t, J ) 7 Hz, 1H,
CHN), 5.62 (s, 2H, NCH2Ar), 7.30-7.48 (m, 6H, ArH), 7.52
(d, 2H, ArH), 7.58 (d, 2H, ArH); MS (CI) m/ z 422 (MH+). Anal.
(C26H23N5O‚0.33 H2O) C, H, N.
(6a R,9a S)-3-(Cycloh exylm eth yl)-5,6a ,7,8,9,9a -h exa h y-
d r o-5-m et h yl-2-(p h en ylm et h yl)cyclop en t [4,5]im id a zo-
[2,1-b]p u r in -4(3H)-on e (54). A mixture of 28 (179 mg, 0.558
mmol), cyclohexylmethyl bromide (0.39 mL, 2.8 mmol), and
K2CO3 (0.77 g, 5.6 mmol) was heated in DMF (5 mL) at 60 °C
under N2 for 20 h. The DMF was evaporated. The residue
was dissolved in CH2Cl2, washed with saturated NaHCO3
solution, dried (MgSO4), and concentrated. Flash chromatog-
(6 a R ,9 a S )-5 ,6 a ,7 ,8 ,9 ,9 a -H e x a h y d r o -5 -m e t h y l -2 -
br om ocyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-on e (51).
Compound 35 was debenzylated using the general methods
described for 8. Bromine (0.91 mL, 17.5 mmol) was added to
a solution containing desbenzyl-35 (3.38 g, 14.6 mmol) and
NaOAc (1.44 g, 17.5 mmol) in HOAc (70 mL) at room
temperature under nitrogen. The mixture was then stirred
at 50 °C for 16 h. The solid was collected, washed with CHCl3,
raphy (2% MeOH/CH2Cl2) gave 0.12 g (51%) of 54 as an off-
1
white solid: [R]23 +94° (c 0.62, EtOH); H NMR (400 MHz,
D
CDCl3) δ 0.90-2.30 (m, 17H), 3.34 (s, 3H), 3.91 (d, 2H, J )
7.4 Hz), 4.13 (s, 2H), 4.72 (t, 1H, J ) 7.2 Hz), 4.86 (t, 1H, J )
7.2 Hz), 7.15 (d, 2H, J ) 6.9 Hz), 7.21-7.33 (m, 3H); MS (EI)
m/ z 417 (M+, 62), 388 (100). Anal. (C25H31N5O‚0.39CH2Cl2)
C, H, N.
and air-dried to give 51 as a white solid (3.75 g, 83%): [R]19.8
D
+100.6° (c 0.63, MeOH); 1H NMR (400 MHz, DMSO-d6) δ
1.68-2.24 (m, 6H), 3.32 (s, 3H), 4.81 (t, 1H, J ) 7 Hz), 5.19 (t,
1H, J ) 7 Hz), 10.18 (bs, 1H); MS (CI) m/ z 312 (MH+, 25),
310 (27), 232 (100). Anal. (C11H12BrN5O‚1.02HBr) C, H, N.
(6 a R ,9 a S )-5 ,6 a ,7 ,8 ,9 ,9 a -H e x a h y d r o -5 -m e t h y l -2 -
(ph en yleth yn yl)cyclopen t[4,5]im idazo[2,1-b]pu r in -4(3H)-
on e (52). A mixture of the bromide 51 (178 mg, 0.574 mmol),
(phenylethynyl)tributyltin (0.30 mL, 0.86 mmol), Pd(PPh3)4 (66
mg, 0.057 mmol), and PPh3 (30 mg, 0.11 mmol) was heated in
N-methylpyrrolidinone (5 mL) at 100 °C under N2 for 5 h. The
solvent was evaporated under reduced pressure. The residue
was dissolved in 10% MeOH/CH2Cl2, washed with saturated
NaHCO3, dried (MgSO4), and concentrated. Preparative TLC
(5% MeOH/CH2Cl2) gave 52 (61 mg, 32%) as a light yellow
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-5-m eth yl-2-(p h en yl-
m eth yl)-3-(2-h yd r oxyeth yl)cyclop en t[4,5]im id a zo[2,1-b]-
p u r in -4(3H)-on e (55): using the general procedure described
above for 54 gave 55 as an off-white solid; 1H NMR (400 MHz,
CDCl3) δ 1.52-2.35 (m, 6H), 3.10 (bs, 1H), 3.45 (s, 3H), 3.65-
3.76 (m, 2H), 4.23 (s, 2H), 4.25-4.32 (m, 2H), 4.77 (t, 1H, J )
7 Hz), 4.96 (t, 1H, J ) 7 Hz), 7.19 (d, 2H, J ) 7.0 Hz), 7.21-
7.33 (m, 3H); MS (FAB) m/ z 366 (MH+). Anal. (C20H23N5O2‚
0.31CH2Cl2) C, H, N.
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-5-m eth yl-2-(p h en yl-
m eth yl)-3-[(2,3-d ih yd r oxyp h en yl)m eth yl]cyclop en t[4,5]-
im id a zo[2,1-b]p u r in -4(3H)-on e (56). Compound 28 was
alkylated as above with 2,3-dimethoxybenzyl bromide to give
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(phenylmethyl)-
3-[(2,3-dimethoxyphenyl)methyl]cyclopent[4,5]imidazo[2,1-b]-
purin-4(3H)-one as a white solid: 1H NMR (400 MHz, CDCl3)
δ 1.52-2.31 (m, 6H), 3.32 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H),
4.04 (s, 2H), 4.73 (t, 1H, J ) 7 Hz), 4.87 (t, 1H, J ) 7.2 Hz),
5.40 (d, 1H, J ) 15 Hz), 5.47 (d, 1H, J ) 15 Hz), 6.41 (dd, 1H,
J ) 7.7, 1.2 Hz), 6.83 (dd, 1H, J ) 8, 1.2 Hz), 6.94 (t, 1H, J )
8 Hz), 7.14 (d, 2H, J ) 7 Hz), 7.18-7.28 (m, 3H); MS (FAB)
m/ z 472 (MH+, 100).
solid: [R]24.5 +167° (c 0.56, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 1.62-2.51 (m, 6H), 3.54 (s, 3H), 4.92 (t, 1H, J ) 7.3
Hz), 5.13 (t, 1H, J ) 7.4 Hz), 7.28-7.38 (m, 3H), 7.53 (d, 2H,
J ) 8.2 Hz); MS (CI) m/ z 332 (MH+, 100); HRMS calcd for
C19H17N5O 331.1433, found 331.1440. Anal. (C19H17N5O‚
0.75H2O) C, H; N: calcd, 20.31; found, 18.36.
3,5-Dim eth yl-2′-(ph en ylm eth yl)spir o[cyclopen tan e-1,7′-
(8′H)-[3H]im id a zo[2,1-b]p u r in ]-4′(5′H)-on e (53). 5′-Meth-
yl-3′-(phenylmethyl)spiro[cyclopentane-1,7′(8′H)-[3H]imidazo-
[2,1-b]purin]-4(5′H)-one was prepared according to the general

2208 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Ahn et al.
A solution of BBr3 in CH2Cl2 (3.5 mL, 1.0 M) was added to
a solution of the product of the previous reaction (0.330 g, 0.7
mmol) in CH2Cl2 (10 mL) at -78 °C. The solution was stirred
and allowed to warm up from -78 °C to room temperature
over 18 h. The solution was then stirred with aqueous Na2-
CO3 (10%) for 10 min. The organic layer was separated, dried
(MgSO4), and concentrated. Flash chromatography on silica
gel (5% MeOH/EtOAc) gave 0.090 g (30%) of 56 as a white
solid: 1H NMR (400 MHz, CDCl3) δ 1.45-2.30 (m, 6H), 3.35
(s, 3H), 4.32 (s, 2H), 4.73 (t, 1H, J ) 7 Hz), 4.90 (t, 1H, J ) 7.2
Hz), 5.24 (d, 1H, J ) 14.7 Hz), 5.32 (d, 1H, J ) 15.3 Hz), 6.59
(dd, 1H, J ) 4.7, 2.1 Hz), 6.72 (t, 1H, J ) 7.3 Hz), 6.87 (d, 1H,
J ) 7.3 Hz), 7.21 (d, 2H, J ) 7.0 Hz), 7.24-7.33 (m, 3H); MS
(FAB) m/ z 444 (MH+). Anal. (C25H25N5O3‚H2O) C, H, N.
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-5-m eth yl-2-(p h en yl-
m eth yl)-3-(3-p yr id in ylm eth yl)cyclop en t[4,5]im id a zo[2,1-
b]p u r in -4(3H)-on e (57). Compound 28 was alkylated by
3-(chloromethyl)pyridine, using the conditions previously de-
temperature for 1 h. More Na2S2O4 (15 g) was added every 2
h until the reaction was shown to be complete by TLC (ca. 6
h). The solution was extracted with CH2Cl2. The organic
extracts were dried (MgSO4) and concentrated to give 59 (7.0
g, 62%) as an oil: 1H NMR (200 MHz, CDCl3) δ 1.36 (t, 3H, J
) 7 Hz), 2.80-3.10 (bs, 2H), 4.35 (q, 2H, J ) 7 Hz), 4.55 (s,
1H).
2-Cya n o-N-(1-et h oxyet h ylid en e)glycin e E t h yl E st er
(60). The crude 59 (7.44 g, 0.0581 mol) was heated with
triethyl orthoacetate (100 mL) at 100 °C for 16 h. The solution
was concentrated. Flash chromatography on silica gel (20%
EtOAc/hexanes) gave 60 (8.16 g, 71%) as a clear oil: 1H NMR
(300 MHz, CDCl3) δ 1.19 (t, 3H, J ) 7 Hz), 1.27 (t, 3H, J ) 7
Hz), 1.92 (s, 3H), 4.07 (q, 2H, J ) 7 Hz), 4.23 (q, 2H, J ) 7
Hz), 4.82 (s, 1H).
Eth yl 5-Am in o-2-m eth yl-1-(p h en ylm eth yl)-1H-im id a -
zole-4-ca r boxyla te (61). Compound 60 (16 g, 0.081 mol) was
heated with benzylamine (13.8 mL) in EtOH (200 mL) at 80
°C for 2 h. The solution was concentrated. The residue was
dissolved in CH2Cl2, washed with saturated NaHCO3 solution,
dried (MgSO4), and concentrated. Recrystallization from
benzene gave 61 (11 g, 52%) as a solid: 1H NMR (300 MHz,
CDCl3) δ 1.38 (t, 3H, J ) 7 Hz), 2.34 (s, 3H), 4.34 (q, 2H, J )
7 Hz), 4.69 (bs, 2H), 4.97 (s, 2H), 7.07 (d, 2H, J ) 6 Hz), 7.26-
7.41 (m, 3H).
3,9-Dih yd r o-1,8-d im eth yl-9-(p h en ylm eth yl)p u r in e-2,6-
(1H)d ion e (62). The imidazole intermediate 61 (0.62 g, 2.4
mmol) was heated with methyl isocyanate (0.7 mL, 12 mmol)
and Et3N (1.7 mL, 12 mmol) in benzene (5 mL) at 100 °C for
18 h. The solution was concentrated. The residue was heated
with NaOMe (0.65 g, 12 mmol) in refluxing MeOH for 1 h.
The solution was concentrated. The residue was triturated
with water, extracted with CH2Cl2, and adjusted to pH 6 with
10% HCl. The solids were filtered, washed with water and
ether, and dried to give 62 (0.47 g, 73%) as a white solid: 1H
NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 3.20 (s, 3H), 5.32
(s, 2H), 7.10 (d, 2H, J ) 7 Hz), 7.30-7.42 (m, 3H), 12.32 (s,
1H).
scribed for 54, to give 57 as an orange solid: [R]20 +105° (c
D
0.23, EtOH); 1H NMR (400 MHz, CDCl3) δ 1.52-2.30 (m, 6H),
3.32 (s, 3H), 4.07 (s, 2H), 4.72 (t, 1H, J ) 7.0 Hz), 4.87 (t, 1H,
J ) 7.2 Hz), 5.35 (s, 2H), 7.10 (d, 2H, J ) 6.6 Hz), 7.16-7.30
(m, 4H), 7.38 (dd, 1H, J ) 7.9, 1.6 Hz), 8.34 (d, 1H, J ) 1.8
Hz), 8.45 (dd, 1H, J ) 4.8, 1.4 Hz); MS (CI) m/ z 413 (MH+,
100). Anal. (C24H24N6O‚0.9H2O) C, H; N: calcd, 19.60; found,
18.73.
(6a R,9a S)-5,6a ,7,8,9,9a -Hexa h yd r o-3(1H-im id a zol-2-yl-
m eth yl)-5-m eth yl-2-(ph en ylm eth yl)cyclopen t[4,5]im idazo-
[2,1-b]p u r in -4(3H)-on e (58). TFA (14 mL) was added to a
solution of 48 (4.37 g, 17.5 mmol) and Et3SiH (14 mL, 88 mmol)
in CH2Cl2 (200 mL) at 0 °C. The solution was stirred at 0 °C
for 0.5 h and then at room temperature for 1.5 h. The solution
was washed with saturated NaHCO3, dried (MgSO4), and
concentrated. Flash chromatography on silica gel (40% EtOAc/
hexanes, then 60% EtOAc/hexanes) gave 1-(tolylsulfonyl)-2-
(hydroxymethyl)imidazole (3.29 g, 74%) as a white solid: 1H
NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 2.97 (bs, 1H), 4.86 (s,
2H), 7.00 (s, 1H), 7.37 (d, 2H, J ) 8 Hz), 7.40 (s, 1H), 7.83 (d,
1H, J ) 8 Hz); MS m/ z (CI) 253 (MH+, 80), 235 (100).
A solution of PPh3 (6.14 g, 23.4 mmol) in CH2Cl2 (40 mL)
was added to a solution of 1-(tolylsulfonyl)-2-(hydroxymethyl)-
imidazole (4.92 g, 19.5 mmol) and CBr4 (9.70 g, 29 mmol) in
CH2Cl2 (200 mL) at 0 °C. The solution was stirred at 0 °C for
0.5 h and then at room temperature for 1.5 h. The solution
was concentrated. Flash chromatography on silica gel (20%
EtOAc/hexanes, then 30% EtOAc/hexanes) gave 1-(tolylsulfo-
nyl)-2-(bromomethyl)imidazole (2.89 g, 47%) as a clear oil: 1H
NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 4.81 (s, 2H), 7.04 (s,
1H), 7.37 (d, 2H, J ) 8 Hz), 7.42 (s, 1H), 7.91 (d, 1H, J ) 8
Hz); MS (CI) m/ z 315 (MH+, 97), 317 (100).
Compound 28 was alkylated with 1-(tolylsulfonyl)-2-(bro-
momethyl)imidazole using the conditions described above to
give (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(phenyl-
methyl)-3-[[1-(tolylsulfonyl)imidazol-2-yl]methyl]cyclopent[4,5]-
imidazo[2,1-b]purin-4(3H)-one as a light yellow solid: 1H NMR
(400 MHz, CDCl3) δ 1.52-2.38 (m, 6H), 2.46 (s, 3H), 3.34 (s,
3H), 4.08 (s, 2H), 4.77 (t, 1H, J ) 7 Hz), 4.95 (t, 1H, J ) 7 Hz),
5.72 (s, 2H), 6.82 (s, 2H), 7.10 (d, 2H, J ) 7 Hz), 7.18-7.32
(m, 4H), 7.39 (d, 2H, J ) 8 Hz), 7.88 (d, 2H, J ) 8 Hz); MS
(FAB) m/ z 556 (MH+, 100).
2-Ch lor o-1,9-d ih yd r o-1,8-d im et h yl-9-(p h en ylm et h yl)-
p u r in -6(6H)-on e (63). Intermediate 62 (0.47 g, 1.7 mmol)
was heated with POCl3 (10 mL) at 100 °C for 25 h. The
solution was cooled and diluted with hexanes (200 mL). The
liquid layer was decanted. The residue was dissolved in CH2-
Cl2, washed with saturated NaHCO3 solution, dried (MgSO4),
and concentrated. Flash chromatography of the residue on
silica gel (1% MeOH/CH2Cl2, then 2.5% MeOH/CH2Cl2) gave
63 (0.263 g, 54%) as a white solid: 1H NMR (300 MHz, CDCl3)
δ 2.42 (s, 3H), 3.78 (s, 3H), 5.27 (s, 2H), 7.10-7.36 (m, 5H).
1,9-Dih yd r o-2-[(1R,2R)-2-h yd r oxycyclop en tyl)a m in o]-
1,8-d im eth yl-9-(p h en ylm eth yl)p u r in -6(6H)-on e (64). The
intermediate 63 (0.263 g, 0.912 mmol) was heated at 130 °C
with (1R,2R)-2-aminocyclopentanol hydrochloride (0.251 g, 1.8
mmol) and Et3N (0.63 mL, 4.5 mmol) in NMP (20 mL) under
N2 for 16 h. The solution was concentrated. The residue was
dissolved in CH2Cl2, washed with saturated NaHCO3, dried
(MgSO4), and concentrated. Flash chromatography of the
residue on silica gel (6% MeOH/CH2Cl2) gave 64 (0.310 g, 96%)
as a brown solid: 1H NMR (300 MHz, CDCl3) δ 1.45-2.45 (m,
6H), 2.36 (s, 3H), 3.48 (s, 3H), 3.95-4.05 (m, 1H), 4.22 (dd,
1H, J ) 14, 7 Hz), 4.10-4.60 (bs, 1H), 5.14 (s, 2H), 5.71 (d,
1H, J ) 4.7 Hz), 7.14 (d, 2H, J ) 7 Hz), 7.25-7.35 (m, 3H).
(6a R ,9a S )-5,6a ,7,8,9,9a -H e xa h yd r o-2,5-d im e t h yl-1-
(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(1H)-
on e (65). MsCl (0.135 mL, 1.76 mmol) was added dropwise
to a solution of 64 (0.310 g, 0.878 mmol) and Et3N (0.61 mL,
4.4 mmol) in CH2Cl2 (10 mL) at room temperature. The
solution was stirred at room temperature for 16 h, diluted with
CH2Cl2, washed with saturated NaHCO3 solution, dried (Mg-
SO4), and concentrated. Flash chromatography of the residue
on silica gel (6% MeOH/CH2Cl2) gave 65 (0.169 g, 57%) as a
The tosylimidazole product of the previous reaction (0.38
g) was stirred with excess of KOH in MeOH (15 mL) at room
temperature for 3 h. The solution was neutralized with dilute
HCl and extracted with CH2Cl2. The organic layer was washed
with saturated NaHCO3, dried (MgSO4), and concentrated.
Flash chromatography on silica gel (7% MeOH/CH2Cl2) gave
58 (0.24 g, 89%) as a light yellow solid: 1H NMR (400 MHz,
CDCl3) δ 1.48-2.28 (m, 6H), 3.48 (s, 3H), 4.40 (s, 2H), 4.76 (t,
1H, J ) 7.6 Hz), 4.91 (t, 1H, J ) 7.2 Hz), 5.28 (s, 2H), 7.02 (s,
2H), 7.25-7.35 (m, 5H); MS (FAB) m/ z 402 (MH+, 78), 154
(100). Anal. (C22H23N7O‚0.6H2O) C, H; N: calcd, 23.78; found,
22.45.
clear oil which solidified to an off-white solid: [R]23 +137° (c
D
0.05, EtOH); 1H NMR (300 MHz, CDCl3) δ 1.55-2.10 (m, 6H),
2.36 (s, 3H), 3.41 (s, 3H), 4.49 (t, 1H, J ) 7.1 Hz), 4.65 (t, 1H,
J ) 6.8 Hz), 5.21 (d, 1H, J ) 17.6 Hz), 5.30 (d, 1H, J ) 17.7
Hz), 6.94 (d, 2H, J ) 7.3 Hz), 7.32-7.43 (m, 3H); MS (FAB)
m/ z 336 (MH+, 100). Anal. (C19H21N5O‚0.50CH2Cl2) C, H, N.
2-Cya n oglycin e Eth yl Ester (59). Na2S2O4 (15 g, 0.088
mol) was added portionwise to a solution of ethyl cyano-
(hydroxyimino)acetate (12.45 g, 0.0877 mol) in saturated
NaHCO3 (80 mL) and H2O (320 mL) and stirred at room

Tetracyclic Guanine Inhibitors of PDE1 and PDE5
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2209
(6a R,9a S)-5-E t h yl-5,6a ,7,8,9,9a -h exa h yd r o-2-m et h yl-
cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(3H)-on e (66). This
compound was prepared using a procedure analogous to that
for 65 followed by hydrogenolysis of the N-1 benzyl group
under the general conditions described above to give white
layers were dried (MgSO4), filtered, and concentrated. Flash
chromatography of the residue (CH2Cl2, then 0.5% MeOH/CH2-
Cl2, then 5% MeOH/CH2Cl2) gave the chloropurine (0.522 g,
55%) as a yellow foam: 1H NMR (CDCl3) δ 1.39 (t, 3H, J )
7.1 Hz, CH2CH3), 4.04 (s, 2H, CCH2Ph), 4.41 (q, 2H, J ) 7.1
Hz, CH2CH3), 5.04 (s, 2H, NCH2Ph), 6.99 (m, 2H, ArH), 7.12
(m, 2H, ArH), 7.24-7.30 (m, 6H, ArH).
crystals: mp 101-103 °C; [R]22 +133° (c 0.44, MeOH); 1H
D
NMR (300 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.0 Hz), 1.45-2.28
(m, 6H), 2.51 (s, 3H), 4.02 (q, 2H, J ) 7.0 Hz), 4.73 (t, 1H, J )
7.6 Hz), 4.83 (t, 1H, J ) 7.2 Hz); MS (FAB) m/ z 260 (MH+,
100). Anal (C13H17N5O‚0.2CH2Cl2) C, H, N.
(6a R ,9a S )-5,6a ,7,8,9,9a -H e x a h y d r o -2-m e t h y l-5-(1-
m et h ylet h yl)cyclop en t [4,5]im id a zo[2,1-b]p u r in -4(3H )-
on e (67). This compound was prepared using a procedure
analogous to that for 65 followed by hydrogenolysis of the N-1
benzyl group under the general conditions described above to
give a white solid: [R]22D +124° (c 0.44, MeOH); 1H NMR (300
MHz, CDCl3) δ 1.45-2.28 (m, 6H), 1.54 (d, 6H, J ) 7.0 Hz),
2.54 (s, 3H), 4.73 (t, 1H, J ) 7.0 Hz), 4.83 (t, 1H, J ) 6.6 Hz),
5.10 (septet, 1H, J ) 6.9 Hz); MS (FAB) m/ z 274 (MH+, 100).
Anal. (C14H19N5O‚0.25H2O) C, H, N.
r-Eth oxyben en e Eth a n im in e Hyd r och lor id e (68). An
ice-cold solution of phenylacetonitrile (100 g, 0.85 mol) in EtOH
(55 mL) was charged with anhydrous HCl (34.5 g, 0.97 mol).
The reaction mixture was stored at 4 °C for 3 days. The solid
mass was suspended in Et2O, filtered, washed with Et2O, and
dried over P2O5 under vacuum. The imidate hydrochloride 68
(97 g, 57%) was used directly in the next step.
Eth yl 5-Am in o-1,2-bis(p h en ylm eth yl)-1H-im id a zole-4-
ca r boxyla te (69). A suspension of 68 (31.6 g, 0.16 mol) and
ethyl aminocyanoacetate (22.5 g, 0.18 mol; prepared according
to the literature procedure15) in CHCl3 (700 mL) was refluxed
under N2 for 0.5 h. The suspension was filtered through Celite.
To the filtrate was added benzylamine (20 g, 0.19 mol), and
the reaction mixture was refluxed under N2 for 16 h. The
reaction mixture was washed with 10% NaHCO3 (2 × 200 mL),
dried (MgSO4), and concentrated. Purification by flash chro-
matography (4% MeOH/CH2Cl2) followed by crystallization
from EtOAc/hexane gave imidazole 69 (21.6 g, 49%): 1H NMR
(CDCl3) δ 1.40 (t, 3H, J ) 7.1 Hz, CH3), 4.04 (s, 2H, CCH2Ph),
4.37 (q, 2H, J ) 7.1 Hz, CO2CH2CH3), 4.65 (s, 2H, NH2), 4.75
(s, 2H, NCH2Ph), 6.88 (m, 2H, ArH), 7.16-7.27 (m, 8H, ArH).
Eth yl 5-[[(Eth yla m in o)ca r bon yl]a m in o]-1,2-bis(p h en -
ylm eth yl)-1H-im id a zole-4-ca r boxyla te (70). To a mixture
of the amino ester 69 (3.0 g, 8.9 mmol) and Et3N (1.4 mL, 10.0
mmol) in toluene (20 mL) was added ethyl isocyanate (1.4 mL,
18 mmol). The mixture was heated at 130 °C in a sealed tube
under N2 for 16 h and then allowed to cool. The reaction
mixture was concentrated and the residue subjected to flash
chromatography (3% MeOH/CH2Cl2) to give the urea 70 (1.47
g, 41%): 1H NMR (CDCl3) δ 1.09 (t, 3H, J ) 7.3 Hz, CH3CH2N),
1.34 (t, 3H, J ) 7.2 Hz, CO2CH2CH3), 3.17 (m, 2H, CH3CH2N),
3.98 (s, 2H, CCH2Ph), 4.30 (q, 2H, J ) 7.2 Hz, CO2CH2CH3),
4.97 (bs, 3H, NCH2Ph + NH), 6.82 (m, 2H, ArH), 7.07 (m, 2H,
ArH), 7.15-7.26 (m, 7H, ArH + NH).
1-Eth yl-3,9-d ih yd r o-8,9-bis(p h en ylm eth yl)-1H-p u r in e-
2,6-d ion e (71). To a solution of NaOMe prepared from Na
(0.10 g, 4.3 mmol) and MeOH (20 mL) was added urea 70 (0.91
g, 2.2 mmol). The reaction mixture was refluxed for 3.5 h and
then evaporated to dryness. The residue was taken up in 1
M HCl (20 mL) and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were washed with brine, dried
(MgSO4), filtered, and evaporated to afford the xanthine 71
(0.79 g, 98%) as a white solid which was used directly in the
next step: 1H NMR (CDCl3) δ 1.09 (t, 3H, J ) 6.8 Hz, CH3-
CH2N), 3.89 (q, 2H, J ) 6.8 Hz, CH3CH2N), 4.20 (s, 2H, CCH2-
Ph), 5.35 (s, 2H, NCH2Ph), 7.02 (m, 2H, ArH), 7.17 (m, 2H,
ArH), 7.23-7.30 (m, 6H, ArH).
A mixture of the chloropurine (0.110 g, 0.29 mmol), (1R,2R)-
2-aminocyclopentanol hydrochloride (59 mg, 0.43 mmol), and
diisopropylethylamine (0.18 mL, 1.0 mmol) in NMP (0.4 mL)
was heated at 110-120 °C in a sealed tube under N2. After
14 h the reaction mixture was allowed to cool and then diluted
with H2O (20 mL). The aqueous suspension was extracted
with EtOAc (2 × 20 mL), and the combined organic extracts
were washed with H2O (5 × 20 mL), dried (MgSO4), filtered,
and evaporated. Flash chromatography of the residue (linear
gradient 1% MeOH/CH2Cl2 to 6% MeOH/CH2Cl2) gave the
product 72 (91 mg, 79%) as an off-white solid: 1H NMR
(CDCl3) δ 1.31 (t, 3H, J ) 7.3 Hz, CH2CH3), 1.50 (dd, 1H, J )
12.6, 8.2 Hz, cyclopentyl), 1.60-1.85 (m, 3H, cyclopentyl), 2.00
(m, 1H, cyclopentyl), 2.23 (m, 1H, cyclopentyl), 3.92-4.08 (m,
4H, CCH2
Ph, CHNH, CHOH), 4.11 (q, 2H, J ) 7.4 Hz, CH2-
CH3), 4.64 (bs, 1H, NH), 4.89 (d, 1H, J ) 4.3 Hz, OH), 4.92 (s,
2H, NCH2Ph), 6.98 (m, 2H, ArH), 7.13 (m, 2H, ArH), 7.19-
7.29 (m, 6H, ArH); MS (FAB) m/ z 444.0 (MH+).
(6a R ,9a S )-5-E t h y l-5,6a ,7,8,9,9a -h e x a h y d o -1,2-b is -
(p h en ylm eth yl)cyclop en t[4,5]im id a zo[2,1-b]p u r in -4(1H)-
on e (73). To a stirred suspension of alcohol 72 (169 mg, 0.38
mmol) and Et3N (0.08 mL, 0.6 mmol) in ClCH2CH2Cl (5 mL)
was added MsCl (65 mg, 0.57 mmol). The reaction mixture
was refluxed for 3 h, then diluted with CH2Cl2 (10 mL), and
washed with saturated NaHCO3 (10 mL). The organic layer
was dried (MgSO4), filtered, and evaporated. Flash chroma-
tography of the residue (2% MeOH/CH2Cl2, then 4% MeOH/
CH2Cl2) gave the tetracyclic guanine 73 (106 mg, 65%) as an
off-white solid: 1H NMR (CDCl3) δ 1.26 (t, 3H, J ) 7.6 Hz,
CH2CH3), 1.49-1.79 (m, 5H, cyclopentyl), 1.80 (m, 1H, cyclo-
pentyl), 4.00 (AB, 2H, J ) 16.2 Hz, CCH2Ph), 4.04 (m, 2H,
CH2CH3), 4.35 (dd, 1H, J ) 6.7 Hz, NCHCH2), 4.56 (dd, 1H, J
) 6.7 Hz, NCHCH2), 5.04 (AB, 2H, J ) 17.7 Hz, NCH2Ph),
6.80 (m, 2H, ArH), 7.15-7.36 (m, 8H, ArH); MS (FAB) m/ z
426.2 (MH+).
(6a R ,9a S )-5-E t h yl-5,6a ,7,8,9,9a -h e xa h yd r o-2-(p h e n -
ylm et h yl)cyclop en t [4,5]im id a zo[2,1-b]p u r in -4(3H )-on e
(74). A mixture of the N-benzyl derivative 73 (87 mg, 0.20
mmol), HCO2NH4 (193 mg, 3.06 mmol), and 20% Pd(OH)2/C
(40 mg) in MeOH (15 mL) was refluxed for 0.5 h and then
allowed to stir at room temperature overnight. The catalyst
was removed by filtration through Celite, and the filter pad
was washed with MeOH. The combined filtrate and washings
were evaporated to dryness. The residue was taken up in
EtOAc (20 mL) and washed with saturated NaHCO3
(20 mL).
The organic layer was dried (MgSO4), filtered, and evaporated
to give a foam which was crystallized from MeOH/Et2O to give
74 (40 mg, 60%): [R]22 +129.3° (c 0.23, MeOH); 1H NMR
D
(CDCl3) δ 1.24 (3H, t, J ) 7.0 Hz, CH2CH3), 1.53 (m, 1H,
cyclopentyl), 1.97 (m, 1H, cyclopentyl), 2.25 (dd, 1H, J ) 13.2,
5.7 Hz, cyclopentyl), 7.22-7.34 (m, 5H, ArH), 1.70-1.87 (m,
3H, cyclopentyl), 4.02 (m, 2H, CH2CH3), 4.15 (s, 2H, CH2Ph),
4.73 (dd, 1H, J ) 7.3 Hz, NCHCH2), 4.87 (dd, 1H, J ) 7.3 Hz,
NCHCH2); MS (FAB) m/ z 336.0 (MH+). Anal. (C19H21N5O‚
0.5H2O) C, H, N.
P DE In h ibition Assa ys. PDE assays were performed in
a reaction medium containing 50 mM Tris-HCl (pH 7.5), 2 mM
MgCl2, 0.1 mg/mL BSA, and 1 µM cGMP or cAMP, respec-
tively. Assays were carried out for 30 min at 30 °C using the
methods described by Thompson.16 Reaction mixture for assay
of PDE1 activity also contained 1 mM CaCl2 and 0.1 µM
calmodulin. The reaction mixture for assay of PDE2 contained
5 µM cGMP. [3H]cGMP was used as the substrate in the
assays for PDE1 and PDE5, while [3H]cAMP was used as the
substrate for PDE2, PDE3, and PDE4. The concentration of
compounds that produce 50% inhibition of enzyme activity
(IC50) was determined from the curve of percentage inhibition
of enzyme activity vs log molar concentration of the com-
pounds. All assays were carried out in duplicate, and reported
1-E t h yl-1,9-d ih yd r o-2-[((1R,2R)-2-h yd r oxycyclop en -
tyl)a m in o]-8-(p h en ylm eth yl)p u r in -6(6H)-on e (72). A sus-
pension of xanthine 71 (0.896 g, 2.49 mmol) in POCl3 (25 mL)
was heated to 100 °C under N2 for 18.5 h. The reaction
mixture was allowed to cool, and the POCl3 was removed by
rotary evaporation at less than 40 °C. The resulting orange
syrup was chilled in an ice bath, and saturated NaHCO3 (50
mL) was added in portions with stirring. The whole was
extracted with CH2Cl2 (2 × 50 mL), and the combined organic

2210 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Ahn et al.
(9) Fenn, M. D.; Lister, J . H. Purine Studies. XXIII Conformational
Aspects of N-(6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-
yl)formamides and Related N-Benzyl Derivatives. Aust. J . Chem.
1980, 33, 1611-1617.
(10) The (-)-trans-2-aminocyclopentanol can be prepared in >96%
ee using the method of Overman, L. E.; Sugai, S. A Convenient
Method for Obtaining trans-2-Aminocyclohexanol and trans-2-
Aminocyclopentanol in Enantiomerically Pure Form. J . Org.
Chem. 1985, 50, 4154-4155.
(11) In the early phases of this project we compared the activity of
the enantiomers of compounds closely related to the structures
disclosed in this study. In all cases examined the (+) isomer was
about 10-fold more active in a preparation of PDE1 than the
(-) isomer. Since the assay protocol used at that time was
substantially different from that reported here, those results
cannot be directly compared with the results reported in this
manuscript. These results, however, led us to continue to make
the (+) isomers in this study.
(12) Vemulapalli, S.; Watkins, R. W.; Chintala, M.; Davis, H.; Ahn,
H.-S.; Fawzi, A.; Tulshian, D.; Chiu, P.; Chatterjee, M.; Lin, C.-
C.; Sybertz, E. J . Antiplatelet and Antiproliferative Effects of
SCH 51866, a Novel Type 1 and Type 5 Phosphodiesterase
Inhibitor J . Cardiovasc. Pharmacol. 1996, 28, 862-869.
(13) Takase, Y.; Watanabe, N.; Matsui, M.; Ikuta, H.; Kimura, T.;
Saeki, T.; Adachi, H.; Tokumura, T.; Mochida, H.; Akita, Y.;
Souda, S. South African Patent 927465, 1992.
values represent the mean of the two determinations. Mea-
surements were reproducible on the average to (25%, except
for the very weakest inhibitors where solubility limits were
occasionally exceeded. PDE1, PDE2, PDE3, PDE4, and PDE5
utilized in the assays were purified from bovine aorta,6
recombinant bovine adrenal cortex,17 bovine heart,18 canine
kidney,19 and bovine lung,20 respectively. These preparations
were free of substantial contaminating phosphodiesterase
activities.
An tih yp er ten sive Activity. PDE inhibitors were evalu-
ated in the spontaneously hypertensive rat using the meth-
odology previously described by Smith et al.21 and more
recently by Vemulapalli et al.12 Reported values reflect peak
changes in mean arterial pressure in comparison to a control
group to which vehicle was administered. The compounds
were adminstered orally as aqueous solutions or suspensions
in 0.4% methylcellulose as the vehicle. In general differences
of g10 mmHg are considered statistically significant. The
drugs verapamil and nifedipine were routinely run as positive
controls in this assay. Two hours after a 30 mg/kg oral dose
of verapamil or nifedipine, reproducible falls in blood pressure
of 70 ( 4 and 58 ( 5 mmHg (mean ( SEM), respectively, were
produced.
(14) Neustadt, B.; Lindo, N.; McKittrick, B. U.S. Patent 5393755,
1995.
(15) De Meester, J . W. G.; van der Plas, H. C.; Middelhoven, W. J .
The Oxidation of 6- and 7-Aryl-4(3H)-pteridinones by Im-
mobilized Arthrobacter M-4 Cells Containing Xanthine Oxidase
J . Heterocycl. Chem. 1987, 24, 441-451.
(16) Thompson, W. J .; Brooker, G.; Appleman, M. M. Assay of Cyclic
Nucleotide Phosphodiesterases with Radioactive Substrates.
Methods Enzymol. 1974, 38, 205-212.
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