Novel selective PDE4 inhibitors. 2. Synthesis and structure-activity relationships of 4-aryl-substituted cis-tetra- and cis-hexahydrophthalazinones

Article abstract of DOI:10.1021/jm010838c

A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was synthesized. To study structure-activity relationships various substituents were introduced to the 2-, 3-, and 4-positions of the 4-phenyl ring. Substitution at the 4-position of the phenyl ring was restricted to a methoxy group, probably due to unfavorable steric interactions of larger groups with the binding site. The introduction of many alkoxy substituents including distinct ring systems and functional groups was allowed to the 3-position. It was found that in general the cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydrophthalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC₅₀ = 9.7).

Full text of DOI:10.1021/jm010838c

J . Med. Chem. 2001, 44, 2523-2535
2523
Novel Selective P DE4 In h ibitor s. 2. Syn th esis a n d Str u ctu r e-Activity
Rela tion sh ip s of 4-Ar yl-Su bstitu ted cis-Tetr a - a n d cis-Hexa h yd r op h th a la zin on es
Margaretha Van der Mey,*,†,§ Armin Hatzelmann,‡ Gerard P. M. Van Klink,§ Ivonne J . Van der Laan,§
Geert J . Sterk,§ Ulrich Thibaut,‡ Wolf R. Ulrich,‡ and Hendrik Timmerman†
Leiden/ Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Vrije
Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands; Byk Nederland, Zwanenburg, The Netherlands; and
Byk Gulden, Konstanz, Germany
Received February 7, 2001
A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-
1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was
synthesized. To study structure-activity relationships various substituents were introduced
to the 2-, 3-, and 4-positions of the 4-phenyl ring. Substitution at the 4-position of the phenyl
ring was restricted to a methoxy group, probably due to unfavorable steric interactions of larger
groups with the binding site. The introduction of many alkoxy substituents including distinct
ring systems and functional groups was allowed to the 3-position. It was found that in general
the cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydrophthalic
counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC50
) 9.7).
In tr od u ction
The cyclic nucleotide phosphodiesterases (PDEs) are
enzymes that regulate cellular levels of cyclic adenosine
monophosphate (cAMP) and cyclic guanosine mono-
phosphate (cGMP) through hydrolysis of these second
messengers. PDE isoenzyme families have been classi-
fied on the basis of their substrate specificities (cAMP
or cGMP), kinetic characteristics (Km and Vmax), and
their regulation by specific inhibitors or activators.1-7
In a wide range of immune and inflammatory cells,
including neutrophils, T-lymphocytes, macrophages, and
eosinophils, inhibition of cellular responses is associated
with elevated levels of cAMP. It has been shown that
among the classic PDE families,1 PDE4 (cAMP-specific)
is the predominant PDE isotype in such cells.8-16
Inhibition of PDE4 in inflammatory cells influences
many of the cell-specific responses including the produc-
tion and/or release of proinflammatory mediators, cy-
tokines, and active oxygen species, both in vitro and in
vivo.17-19 Chronic and acute inflammatory diseases,
such as asthma and rheumatoid arthritis, could poten-
tially be treated by the application of selective and
potent PDE4 inhibitors,20-23 because the presence and
activation of multiple types of inflammatory cells char-
acterize sites of inflammation.
F igu r e 1. Optimization of the 4-aryl moiety of the cis-
phthlalazinone lead compounds.
This paper describes the structural requirements of
the 4-aryl moiety with respect to potent PDE4 inhibi-
tion. For optimization of the hexahydrophthalazinone
series, an N-benzyl-substituted parent structure (I) was
used, whereas for the class of tetrahydrophthalazinones
the parent molecule (II) was substituted with a cyclo-
heptyl ring at the 2-position (Figure 1). After the
synthesis of hexahydrophthalazinones I, preliminary
studies showed that replacement of the benzyl group
by a cycloheptyl substituent led to an increase in PDE4
inhibitory activity; therefore, the tetrahydrophthlazi-
nones were substituted with this cycloalkyl moiety.
Subsequent investigations are planned to explore this
unexpected increase in inhibitory capacity.
The synthesis, pharmacological screening, and struc-
ture-activity relationships (SAR) of these novel 4-aryl-
substituted phthalazinones24,25,30 are presented. Fur-
thermore, the SAR of the 3,4-dialkoxyphenyl subunit
of the compounds are compared with those of other
known specific PDE4 inhibitors such as rolipram31,32
and other catechol ethers.27,28,33-35
In a previous paper we have described the discovery
of cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-
phthalazinones24,25 as interesting classes of PDE4 in-
hibitors.26 Structure-activity relationship studies on
known catechol ether containing PDE4 inhibitors have
revealed that modification of the catechol ether part can
have a dramatic effect on the activity.27-29
Ch em istr y
The synthetic procedures used for the preparation of
the 4-aryl-substituted hexahydrophthalazinones and
some of the 4a,5,8,8a-tetrahydrophthalazinones (3a -j
and 3k -o, respectively) are depicted in Scheme 1.
Condensation of γ-keto acids 1a -o with hydrazine
monohydrate yielded phthalazinones 2a -o, which were
* Address correspondence to this author at Radionuclidencentrum,
Vrije Universiteit, De Boelelaan 1085c, 1081 HV Amsterdam, The
Netherlands (telephone +31 20 4449720; fax +31 20 4449121; e-mail
mmeij@rnc.vu.nl).
† Vrije Universiteit.
§ Byk Nederland.
‡ Byk Gulden.
10.1021/jm010838c CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/04/2001

2524 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Van der Mey et al.
Sch em e 1a
a
Reagents: method A (1a ,d ,g,k ; X ) H); AlCl3, CH2Cl2; method B (1b,h -j; X ) Br); 1, BuLi, THF, -90 °C; 2, anhydride, THF, -80
°C; method C (1c,e,f,l-o; X ) Br); 1, Mg, THF, reflux; 2, anhydride, THF; (i) H2NNH2, EtOH, reflux; (ii) 1, NaH, DMF; 2, R4X.
Sch em e 2a
a
Reagents: (i) MCPBA, CH2Cl2; (ii) 2-chlorocyclopentanone, K2CO3, DMF, 60 °C; (iii) 1, KOtBu, MeP(Ph)3Br, THF; 2, 7, THF; (iv) 180
°C; (v) Amberlyst 15 ion-exchange resin, toluene, 80 °C.
deprotonated with sodium hydride and subsequently
alkylated with the selected alkyl halide to afford the
corresponding N-alkyl-4-aryl-substituted phthalazino-
nes (3a -j, R4 ) Bn; and 3k -o, R4 ) cycloheptyl). The
γ-keto acids employed were synthesized from either cis-
1,2-cyclohexanedicarboxylic or cis-1,2,3,6-tetrahydro-
phthalic anhydride and the suitable aromatic compound
using one of the following methods: Friedel-Crafts
acylation (method A), n-BuLi-mediated coupling (method
B), or Grignard reaction (method C).
The aromatic bromides used for the preparation of
γ-keto acids 1h -j and 1m -o are not commercially
available. The synthesis of bromide 10, a precursor for
γ-keto acids 1j and 1o, is shown in Scheme 2. Baeyer-
Villiger oxidation of commercially available 5-bromo-2-
methoxybenzaldehyde using m-chloroperoxybenzoic acid
(step 1)36 followed by alkylation of the resulting phenol
5 provided ketone 7. This ketone was converted into the
corresponding alkene 8 by a Wittig reaction involving
triphenylphosphonium methylide, which was prepared
in situ from (methyl)triphenylphosphonium bromide
and potassium tert-butoxide. Claisen rearrangement of
allyl ether 8 at 180 °C afforded o-allyl phenol 9.
Nucleophilic addition of the phenol oxygen to the
cyclopentenyl C1 was catalyzed by an acidic ion-
exchange resin yielding dihydrobenzofuran 10. 4-Bromo-
2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran (14, not
shown), used for the preparation of γ-keto acid 1n , was
synthesized analogously to 10 (Scheme 2), using chloro-
2-propanone as the alkylating agent.
Alkylation of phenol 5 (Scheme 2) with cyclopentyl
bromide afforded the desired catechol ether compound
(6, not shown), used for the synthesis of 1i and 1m . The
aromatic bromide employed for 1h was synthesized in
an analogous manner to 6 from 4-bromo-2-methoxy-
phenol.
Phenol 15 was obtained by hydrolysis of compound
3m using p-toluenesulfonic acid (Scheme 3).
The 4-(3-alkoxy-4-methoxyphenyl)phthalazinones
16a -r (Table 2) were prepared by alkylation of phenol
15 (method D, Scheme 3), generally followed by further
derivatization. Treatment of phenol 15 with the suitable
alkyl halides yielded phthalazinones 16a ,b and 16k .
Alkylation of phenol 15 with ethylene carbonate gave
phthalazinone 16c. Carboxylic acids 16d -f were pre-
pared by hydrolysis of the corresponding ethyl esters,
which were formed upon treatment of phenol 15 with
the appropriate ω-bromoalkyl esters. A 1:1 adduct
formed from triphenylphosphine and bromine was used
to convert alcohol 16c into a bromide, which upon
treatment with dimethylamine provided phthalazinone
16g. To synthesize the remainder (16h -j and 16l-r ),
phenol 15 was alkylated with the suitable R,ω-dibro-
moalkanes to yield the respective 4-(3-ω-bromo-n-alkoxy-
4-methoxyphenyl)phthalazinones (n ) 4 or 6), which
were then reacted with the nucleophiles of choice.
Analogues 16m and 16q were obtained by hydrolysis
of the corresponding ethyl esters. Tetrazole 16n was
prepared by a 1,3-dipolar cycloaddition of sodium azide
to nitrile 16l.

Novel Selective PDE4 Inhibitors. 2
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2525
Sch em e 3a
a
Reagents: (i) pTosOH, toluene, reflux; (ii) method D; RX, K2CO3, NMP/DMF.
Ta ble 1. 4-Aryl Substituted
Ta ble 2. 4-Aryl Substituted
4a,5,6,7,8,8a-Hexahydro-2H-phthalazin-1-ones and Their PDE4
Blocking Activities
4a,5,8,8a-Tetrahydro-2H-phthalazin-1-ones and Their PDE4
Blocking Activities
a
pIC50 ) -log IC50. Inhibition of PDE4 was investigated in the
cytosol of human neutrophils. The data are means of two inde-
pendent determinations in triplicate.
P h a r m a cology
The structures as well as the PDE3 and PDE4
inhibitory activities (pIC50 values) of the 4-aryl-substi-
tuted hexa- and 4a,5,8,8a-tetrahydrophthalazinones
under study are summarized in Tables 1 and 2, respec-
tively. The activities were determined as described
previously.26 SAR for the two series of 4-aryl-substituted
phthalazinones are discussed below.
P DE In h ibition a n d SAR
P DE3 In h ibition . The hexa- and tetrahydrophthalazi-
nones listed in Tables 1 and 2 exhibit no significant
PDE3 inhibitory activities (pIC50 < 5.5); the pIC50 values
are therefore not listed.
a
See Table 1 footnote.
P DE4 In h ibition . The effect of variations at the 2-,
3-, and 4-positions of the aromatic ring, attached to the
4-position of the phthalazinone subunit, on the PDE4
inhibitory activity is studied. The 4-(3,4-dimethoxyphe-

2526 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Van der Mey et al.
nyl)phthalazinone 3e is one of the first phthalazinones
with high PDE4 inhibitory activity synthesized by us
and was subsequently used as a lead for further
optimization of the catechol ether part (Table 1; hexa-
hydro series). Comparison of 3a -d and 3e reveals that
the 3,4-dialkoxy pattern is essential for potent enzyme
inhibition. These results agree with earlier findings of
other research groups studying catechol ether contain-
ing selective PDE4 inhibitors.27,28,33-35 In several pub-
lications it is assumed that these catechol ether oxygen
atoms are involved in hydrogen bonding.
Phthalazinones 16m , 16o, and 16r with, respectively,
a carboxy-, imidazolyl-, or carbamoylphenoxyalkoxy
substituent are 2.5-4 times more potent than analogue
3l. In the latter cases the optimum alkyl chain length
seems to be four carbon atoms (compare 16m with 16q).
The most potent compound in the current class of
tetrahydrophthalazinones is the (4-imidazol-1-yl-phen-
oxy)butoxy analogue 16o, with a pIC50 value of 9.7.
A similar change in PDE4 inhibitory capacity is
observed upon replacement of the 3-methoxy group of
the 4-aryl-substituted hexa- and tetrahydrophthalazi-
nones (3e vs 3i vs 3j and 3l vs 3m vs 3o), indicating
that such compounds may have the same binding mode.
Replacing the 3,4-dimethoxy substituents by a 3,4-
dioxymethylene group (3f) leads to a 225-fold decrease
in potency as compared to 3e. This result indicates that
one or both methyl groups are important for activity
and/or that the oxygen lone-pairs in 3,4-dioxymethylene
derivative 3f are in a position unfavorable for interac-
tion with the enzyme as was previously suggested for
rolipram analogues.29 Upon modification of the 4-meth-
oxy group to a cyclopentyloxy moiety (3h ) a complete
loss of activity is observed, which is probably caused by
unfavorable steric interactions of the large alkyl ring
with the receptor site. Comparison of 3i with 3e shows
that bulky alkoxy groups are well tolerated at the
3-position of the aromatic ring. This result is in agree-
ment with the SAR of other known selective PDE4
inhibitors; however, the activity of such compounds is
increased up to 100-fold by this modification.27,28,33,34
The 3,4-diethoxy derivative 3g is slightly less potent
than 3e, which may be due to the steric bulk of the
4-ethoxy substituent. Finally, in analogue 3j the 3-cy-
clopentyloxy group is rigidified, leading to a 4-fold
increase in activity as compared to 3i. Thus, it can be
concluded that substitution at the 2-position is allowed
and that the enhanced activity is a result of either the
reduction of the conformational freedom of the 3-cyclo-
pentyloxy group, fixing it in the bioactive conformation,
or an increase in lipophilicity.
Regr ession An a lyses
A classical QSAR method was used to establish a
possible correlation between the PDE4 inhibitory activ-
ity of tetrahydrophthalazinones 3k -m , 15, and 16a -r
(Table 2) and lipophilic (hydrophobic fragment constant
f of Rekker37 and Hansch parameter π), steric (Taft
parameter Es and multidimensional Sterimol param-
eters L, B1, and B5), and electronic parameters (Ham-
mett σ constants, σ* of Taft, and Swain and Lupton
parameters F and R). The classical physicochemical
parameters (except the Rekker constants) were taken
from Hansch.38 However, no statistically significant
correlations were found, which may have been caused
by the relatively small number of classical physicochem-
ical parameters available for the R1 substituents of
compounds 3k -m , 15, and 16a -r (Table 2) as well as
the large diversity in structure. Similarly, QSAR analy-
ses employing smaller subsets (e.g., R1 of analogues
3l,m , 15, 16a -h , and 16h -o, respectively) gave no
significant correlations.
Con clu sion
In this paper we describe a novel series of 4-aryl-
substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-
hexahydrophthalazinones with high inhibitory activity
toward PDE4 (nanomolar range). In both series the
4-(3,4-dialkoxyphenyl) pattern is essential for potent
PDE4 inhibition, suggesting a crucial role for the
catechol ether oxygen atoms in binding to the enzyme.
The catechol ether oxygen atom at the 3-position seems
to be involved in hydrogen bonding as the 3-hydroxy
derivative (15) is 50-fold less potent than compound 3l.
Furthermore, substitution at the 4-position of the phen-
yl ring is restricted to small lipophilic groups (preferably
methoxy), whereas numerous alkoxy substituents are
allowed at the 3-position. The introduction of polar
moieties close to the 4-phenyl ring is, however, unfavor-
able for PDE4 inhibition. Presumably, the substituents
at the 4-position occupy a small lipophilic pocket. In
contrast, the 3-substituents either fill a large hydro-
phobic cavity or are located near the surface of the
enzyme. In general, these findings are in accordance
with the SAR established for 3,4-dialkoxyphenyl-
substituted PDE4 inhibitors such as rolipram28,29and RP
73401.27 Nevertheless, replacement of a 3-methoxy
group by larger hydrophobic moieties usually leads to
a considerable increase in PDE4 inhibitory activity. For
example, modification of a 3-methoxy group by a 3-cy-
clopentyloxy substituent gave a 10-100-fold enhance-
ment in potency for rolipram and RP 73401, respec-
To further examine the influence of substitutions at
the 4-aromatic ring, especially at the 3-position, a large
number of 4-aryl-substituted N-cycloheptyl-4a,5,8,8a-
tetrahydrophthalazinones was prepared and tested. The
PDE4 inhibitory activities of these compounds are listed
in Table 2. Phthalazinones 3l-o and 16a ,b with 3-(cy-
clo)alkoxy moieties have excellent activities in the
nanomolar range. The various sizes and lipophilicities
of these alkoxy substituents do not seem to alter the
activity. Replacement of the 3-methoxy group in 3l by
a chlorine atom (3k ) or a hydroxy moiety (15) causes a
significant decrease in activity.
Next, the effect of alkyl chains substituted with a
functional group, aromatic ring, and/or heterocyclic ring
on enzyme inhibition was investigated. Comparison of
analogues 16c-h with 3l shows that the introduction
of hydrophilic hydroxy, carboxy or N,N-(dimethyl)amino
alkyl moieties causes a considerable reduction in activ-
ity.
Derivatives 16i-k and 16p containing an imidazolyl-,
purinyl-, phenyl-, or phenoxyalkyl moiety are ∼10-fold
less potent than 3l. Finally, changing the 3-methoxy
group (3l) to a tetrazolylphenoxybutoxy moiety (16n )
does not affect the activity, whereas substitution with
a cyano- or carboxyphenoxyalkoxy group (16l and 16q)
leads to a 2.5-3-fold reduction of the inhibitory capacity.

Novel Selective PDE4 Inhibitors. 2
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2527
(24%); mp 180-182 °C; 1H NMR (CDCl3) δ 1.20-2.39 (m, 14H,
CH2-cyclohexane, CH2CH3), 2.60-2.78 (m, 1H, H1), 3.80-3.98
tively. In the phthalazinone series a similar alteration
does not affect the activity. Because of their high activity
and easy accessibility, 4-(3,4-dimethoxyphenyl)-substi-
tuted hexa- and tetrahydrophthalazinone parent struc-
tures were used to explore the influence of N-substitu-
tion on potency as will be discussed in a future paper.
Furthermore, the resolution of various potent cis-
phthalazinone racemates will be investigated to deter-
mine the pharmacological profile of the individual
enantiomers.
3
(m, 1H, H2), 4.04-4.25 (m, 4H, OCH2), 6.86 (d, 1H, J ) 8.9
Hz, H5-arom), 7.40-7.55 (m, 2H, H2-arom, H6-arom).
cis-6-(3-Ch lor o-4-m eth oxyben zoyl)cycloh ex-3-en eca r -
boxylic a cid (1k ) was prepared via method A using cis-
1,2,3,6-tetrahydrophthalic anhydride and 2-chloroanisole: yield
18.27 g (62%); mp 207-210 °C; 1H NMR (CDCl3) δ 2.27-2.58
(m, 3H, H-cyclohexene), 2.59-2.81 (m, 1H, H-cyclohexene),
2.81-2.98 (m, 1H, H1), 3.73-3.97 (m, 4H, H6, OCH3), 5.47-
5.75 (m, 2H, HCdCH), 6.87 (d, 1H, 3J ) 8.6 Hz, H5-arom),
4
3
7.68 (dd, 1H, J ) 2.2 Hz, J ) 8.6 Hz, H6-arom), 7.78 (d, 1H,
4J ) 2.1 Hz, H2-arom).
Exp er im en ta l Section
Meth od B. Bu Li-Med ia ted Syn th esis of γ-Keto Acid s
(as for 1b). cis-2-(3-Ch lor oben zoyl)cycloh exan ecar boxylic
Acid (1b). 3-Bromochlorobenzene (14.4 g, 75.2 mmol) was
dissolved in THF (200 mL) and cooled with an ethanol/
nitrogen(l) bath to -90 °C. BuLi (1.6 M in hexane, 51.5 mL,
82.4 mmol) was added dropwise while the temperature was
kept below -80 °C. After the last addition, the mixture was
stirred for another 15 min. Under a nitrogen atmosphere the
reaction mixture was then quickly added to a cooled solution
(-90 °C) of cis-1,2-cyclohexanedicarboxylic anhydride (13.8 g,
89.5 mmol) in THF (200 mL). After 2 h at -80 °C, the reaction
was quenched with solid ammonium chloride and the mixture
was allowed to warm slowly to room temperature. Water (300
mL) was added, and after separation of the two layers, the
aqueous layer was extracted with EtOAc (200 mL). The
combined organic extract was washed with water (300 mL)
and brine (2 × 300 mL) and dried over MgSO4, and the solvent
was removed under reduced pressure. The title compound was
crystallized from diethyl ether as a white solid: yield 9.60 g
(48%); mp 117-121 °C; 1H NMR (CDCl3) δ 0.95-2.30 (m, 8H,
CH2), 2.49-2.75 (m, 1H, H1), 3.61-3.90 (m, 1H, H2), 7.11-
7.85 (m, 4H, H-arom).
cis-2-(4-Cyclop en t yloxy-3-m et h oxyb en zoyl)cycloh ex-
a n eca r boxylic a cid (1h ) was prepared in a similar way as
described for 1b using bromide 4 (16.3 g, 60.1 mmol), BuLi
(41.0 mL, 65.6 mmol), and cis-1,2-cyclohexanedicarboxylic
anhydride (11.1 g, 72.0 mmol). After workup, the remainder
was dissolved in CH2Cl2 and purified by flash column chro-
matography using petroleum ether (60-80)/ethyl acetate 1:1.
The title compound was crystallized from ethyl acetate as a
white solid: yield 5.97 g (29%); mp 168-170 °C; 1H NMR
(CDCl3) δ 1.22-2.41 (m, 16H, CH2), 2.62-2.78 (m, 1H, H1),
3.82-4.02 (m, 4H, H2, OCH3), 4.78-4.92 (m, 1H, OCH), 6.87
(d, 1H, 3J ) 8.1 Hz, H5-arom), 7.43-7.54 (m, 2H, H2-arom,
H6-arom).
(I) Ch em istr y. Gen er a l Meth od s a n d Ma ter ia ls. THF
was freshly distilled from LiAlH4 before use. DMF and NMP
were stored over 4 Å molecular sieves. All other solvents were
used as received. Starting materials were commercially avail-
able. Reactions were performed under anhydrous conditions
unless noted otherwise. Grignard reactions, BuLi-mediated
couplings, and Friedel-Crafts acylations were performed
under an N2 atmosphere. Reactions were followed by TLC
analysis on Merck TLC aluminum sheets Silicagel 60 F254.
Flash column chromatography was performed on silica gel,
30-60 µm (J . T. Baker). Melting points were measured on a
Mettler FP-5 + FP-052 apparatus equipped with a microscope
or on an Electrothermal IA9200 apparatus and are uncor-
rected. 1H NMR and 13C NMR spectra were recorded on a
Bruker AC 200 (1H NMR, δ 200.1 MHz; 13C NMR, δ 50.29
1
MHz). The H NMR chemical shifts (δ) are expressed in parts
per million values relative to CDCl3 (δ ) 7.26 ppm) or DMSO-
d6 (δ ) 2.50 ppm). 13C NMR chemical shifts (δ) are reported
in parts per million values relative to CDCl3 (δ ) 77.0 ppm)
or DMSO-d6 (δ ) 39.5 ppm). Abbreviations used in the
description of NMR spectra are as follows: s ) singlet, d )
doublet, t ) triplet, q ) quartet, dd ) double doublet, dt )
double triplet, m ) multiplet, and bs ) broad singlet. 2D NMR
(H-H, C-H) COSY techniques were frequently used to
support interpretation of 1D spectra. All phthalazinones had
an elemental analysis (C, H, and N) within (0.4% of the
theoretical value. The synthesis of phthalazinones 2l and 3e
is described in a previous paper.26
Met h od A. Gen er a l P r oced u r e for F r ied el)Cr a ft s
Acyla tion . A selected aromatic compound (100 mmol) was
slowly added to an ice-cooled suspension of anhydrous alumi-
num chloride (13.3 g, 100 mmol) in CH2Cl2 (400 mL). After
complete addition, cis-1,2-cyclohexanedicarboxylic anhydride
or cis-1,2,3,6-tetrahydrophthalic anhydride (100 mmol) was
added to the reaction mixture. The resulting solution was
refluxed until TLC showed completion of the reaction (4-16
h). The mixture was poured into ice-water, the organic layer
was dried over MgSO4, and the solvent was removed in vacuo.
The oil thus obtained was dissolved in CH2Cl2 and filtered over
silica gel to remove the dicarboxylic acid formed during
workup. The γ-keto acids obtained were crystallized from
diethyl ether as white solids. Experimental data for the
separate compounds are listed below.
cis-2-Ben zoylcycloh exa n eca r boxylic a cid (1a ) was pre-
pared via method A using cis-1,2-cyclohexanedicarboxylic
anhydride and benzene: yield 4.65 g (20%); mp 130-132 °C
(mp 138-140 °C39); 1H NMR (CDCl3) δ 1.12-2.38 (m, 8H, CH2),
2.61-2.82 (m, 2H, H1), 3.82-3.99 (m, 1H, H2), 7.33-7.62 (m,
3H, H3-arom, H4-arom, H5-arom), 7.78-7.91 (m, 2H, H2-
arom, H6-arom).
cis-2-(4-Meth oxyben zoyl)cycloh exa n eca r boxylic a cid
(1d ) was prepared via method A using anisole and cis-1,2-
cyclohexanedicarboxylic anhydride: yield 7.34 g (28%); mp
110-112 °C (mp 112-114 °C40); 1H NMR (CDCl3) δ 1.21-2.39
(m, 8H, CH2), 2.60-2.78 (dq, 1H, H1), 3.80-3.97 (m, 4H, H2,
OCH3), 6.85-6.99 (m, 2H, H3-arom, H5-arom), 7.80-7.93 (m,
2H, H2-arom, H6-arom), 10.25 (COOH).
cis-2-(3-Cyclop en t yloxy-4-m et h oxyb en zoyl)cycloh ex-
a n eca r boxylic a cid (1i) was prepared in a similar way as
described for 1b using bromide 6 (16.3 g, 60.1 mmol), BuLi
(41.0 mL, 65.6 mmol), and cis-1,2-cyclohexanedicarboxylic
anhydride (11.1 g, 72.0 mmol). After workup, the residue was
dissolved in CH2Cl2 and purified by flash column chromatog-
raphy using petroleum ether (60-80)/ethyl acetate 7:13. The
title compound was crystallized from petroleum ether (60-
80)/ethyl acetate as a white solid: yield 10.1 g (49%); mp 120-
1
121 °C; H NMR (CDCl3) δ 1.24-2.41 (m, 16H, CH2), 2.63-
2.78 (m, 1H, H1), 3.81-4.01 (m, 4H, H2, OCH3), 4.77-4.90
3
(m, 1H, OCH), 6.86 (d, 1H, J ) 8.1 Hz, H5-arom), 7.42-7.57
(m, 2H, H2-arom, H6-arom).
cis-2-(2,3-Dih yd r o-7-m eth oxyben zofu r a n -2-sp ir o-1′-cy-
clop en ta n e-4-ca r bon yl)cycloh exa n eca r boxylic a cid (1j)
was prepared in a similar way as described for 1b using
bromide 10 (20.3 g, 71.7 mmol), BuLi (49.0 mL, 78.4 mmol),
and cis-1,2-cyclohexanedicarboxylic anhydride (13.3 g, 86.3
mmol). After workup, the remainder was purified by flash
column chromatography using petroleum ether (60-80)/ethyl
acetate 1:1. The title compound was crystallized from petro-
leum ether (60-80)/ethyl acetate: yield 17.9 g (70%); mp 161-
1
163 °C; H NMR (CDCl3) δ 1.20-2.38 (m, 16H, CH2), 2.62-
cis-2-(3,4-Dieth oxyben zoyl)cycloh exan ecar boxylic acid
(1g) was prepared via method A using 1,2-diethoxybenzene
and cis-1,2-cyclohexanedicarboxylic anhydride: yield 7.69 g
2.80 (quintet, 1H, CHCO2H), 3.49 (AB, 2H, CH2-benzofuran),
3
3.72-3.99 (m, 4H, OCH3, CHCdO), 6.75 (d, 1H, J ) 8.6 Hz,
3
H-arom), 7.30 (d, 1H, J ) 8.6 Hz, H-arom).

2528 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Van der Mey et al.
Meth od C. Syn th esis of γ-Keto Acid s Usin g Gr ign a r d
Con d ition s (a s for 1c). cis-2-(3-Meth oxyben zoyl)cyclo-
h exa n eca r boxylic Acid (1c). A solution of 3-bromoanisole
(9.34 g, 49.9 mmol) in THF (30 mL) was added slowly to a
suspension of magnesium (1.45 g, 59.6 mmol) in THF (120 mL).
Subsequently, the mixture was refluxed for 4 h and stirred at
room temperature for an additional 18 h. The reaction mixture
was then added dropwise to an ice-cooled solution of cis-1,2-
cyclohexanedicarboxylic anhydride (8.00 g, 51.9 mmol) in THF
(100 mL). After the addition was complete, the resulting
mixture was stirred for another 30 min at 0 °C. The reaction
mixture was allowed to warm to room temperature overnight.
Next, the reaction was quenched by the addition of a saturated
NH4Cl solution, and the product was extracted with diethyl
ether. The combined organic extract was washed with water
and subsequently extracted with 1 N NaOH. The combined
basic extracts were acidified with concentrated HCl and
extracted with ethyl acetate. The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 and filtered over silica gel to
remove the dicarboxylic acid formed during workup. The
product was recrystallized from ethyl acetate: yield 4.00 g
(31%); mp 128-129 °C; 1H NMR (CDCl3) δ 1.22-2.40 (m,
8H, CH2), 2.66-2.80 (dq, 1H, H1), 3.77-4.02 (m, 4H, H2,
OCH3), 7.03-7.15 (m, 1H, H-arom), 7.29-7.51 (m, 3H, H-
arom).
benzofuran), 3.85-4.04 (m, 4H, H6, OCH3), 5.58-5.83 (m, 2H,
3
3
HCdCH), 6.79 (d, 1H, J ) 8.6 Hz, H5-arom), 7.32 (d, 1H, J
) 8.6 Hz, H6-arom).
Gen er a l P r oced u r e for Con d en sa tion of γ-Keto Acid s
w ith Hyd r a zin e. A mixture of γ-keto acid (7.5-60 mmol) and
hydrazine monohydrate (3 equiv) in ethanol (40-300 mL) was
refluxed for 4 h. If, upon cooling to room temperature, the
product crystallized from the reaction mixture, the crude
product was filtered off and washed with water and ethanol
to yield the pure product. Otherwise, the bulk of ethanol was
removed in vacuo and the residue was dissolved in ethyl
acetate. The solution was washed with water, 1 N HCl, and
aqueous NaHCO3 and dried over MgSO4. Evaporation of the
solvent yielded the crude product, which was purified by
crystallization or flash column chromatography and subse-
quent crystallization. Experimental data for the separate
compounds are listed below.
cis-4-P h en yl-4a ,5,6,7,8,8a -h exa h yd r o-2H-p h th a la zin -1-
on e (2a ) was prepared from γ-keto acid 1a (4.00 g, 17.2 mmol)
according to the general procedure and crystallized from
methanol: yield 3.54 g (90%); mp 170-172 °C (mp 173-174
°C42); 1H NMR (CDCl3) δ 1.22-1.93 (m, 7H, H5, H6, H7, H8),
2.45-2.69 (m, 1H, H8′), 2.70-2.84 (m, 1H, H8a), 3.07-3.26
(m, 1H, H4a), 7.32-7.50 (m, 3H, H3-arom, H4-arom, H5-arom),
7.69-7.82 (m, 2H, H2-arom, H6-arom), 8.86 (bs, 1H, NH).
cis-4-(3-Ch lor op h e n yl)-4a ,5,6,7,8,8a -h e xa h yd r o-2H -
p h th a la zin -1-on e (2b) was prepared from γ-keto acid 1b
(7.86 g, 29.5 mmol) according to the general procedure. The
title compound crystallized upon concentration of the reaction
mixture: yield 3.18 g (41%); mp 161-162 °C; 1H NMR (CDCl3)
δ 1.22-1.98 (m, 7H, H5, H6, H7, H8), 2.42-2.69 (m, 1H, H8′),
2.70-2.85 (m, 1H, H8a), 3.00-3.21 (m, 1H, H4a), 7.29-7.46
(m, 2H, H-arom), 7.56-7.70 (m, 1H, H-arom), 7.76 (s, 1H, H2-
arom), 8.71 (bs, 1H, NH).
cis-2-(Ben zo[1,3]d ioxole-5-ca r b on yl)cycloh exa n eca r -
boxylic a cid (1f) was synthesized analogously to the prepara-
tion of 1c using 4-bromo-1,2-(methylenedioxy)benzene (10.0
g, 49.7 mmol), Mg (1.34 g, 55.1 mmol), and cis-1,2-cyclohex-
anedicarboxylic anhydride (9.00 g, 58.4 mmol). The title
compound was crystallized from ethyl acetate: yield 7.98 g
(58%); mp 152-154 °C (mp 168-169 °C41); 1H NMR (CDCl3) δ
1.12-2.35 (m, 7H, 3 × CH2, CH′H), 2.58-2.93 (m, 2H, H1,
CH′H), 3.76-3.92 (m, 1H, H2), 6.04 (s, 2H, OCH2O), 6.85 (d,
cis-4-(3-Met h oxyp h en yl)-4a ,5,6,7,8,8a -h exa h yd r o-2H -
p h th a la zin -1-on e (2c) was prepared from γ-keto acid 1c (4.00
g, 15.2 mmol) according to the general procedure and crystal-
3
4
1H, J ) 8.0 Hz, H-arom), 7.34 (d, 1H, J ) 4.5 Hz, H-arom),
3
7.49 (d, 1H, J ) 8.2 Hz, H-arom).
1
cis-6-(3-Cyclop en t yloxy-4-m et h oxyben zoyl)cycloh ex-
3-en eca r boxylic a cid (1m ) was synthesized analogously to
the preparation of 1c using bromide 6 (58.4 g, 215 mmol), Mg
(5.76 g, 237 mmol), and cis-1,2,3,6-tetrahydrophthalic anhy-
dride (36.0 g, 237 mmol). The crude product was crystallized
from petroleum ether (60-80)/ethyl acetate and was recrystal-
lized from diethyl ether to yield the title compound as a white
solid: yield 36.6 g (49%); mp 114-115 °C; 1H NMR (CDCl3) δ
1.46-2.11 (m, 7H, H-cyclohexene, H-cyclopentyl), 2.26-2.71
(m, 4H, H-cyclopentyl), 2.72-3.15 (m, 2H, H-cyclohexene, H1),
3.80-4.03 (m, 4H, H6, OCH3), 4.75-4.90 (m, 1H, OCH), 5.56-
5.86 (m, 2H, HCdCH), 6.88 (d, 1H, 3J ) 8.4 Hz, H5-arom),
7.40-7.57 (m, 2H, H2-arom, H6-arom).
lized from methanol: yield 2.46 g (63%); mp 136-137 °C; H
NMR (CDCl3) δ 1.23-1.95 (m, 7H, H5, H6, H7, H8), 2.48-
2.69 (m, 1H, H8′), 2.71-2.84 (m, 1H, H8a), 3.04-3.22 (m, 1H,
H4a), 3.85 (s, 3H, OCH3), 6.90-7.02 (m, 1H, H-arom), 7.26-
7.41 (m, 3H, H-arom), 8.50 (bs, 1H, NH).
cis-4-(4-Met h oxyp h en yl)-4a ,5,6,7,8,8a -h exa h yd r o-2H -
p h th a la zin -1-on e (2d ) was prepared from γ-keto acid 1d
(2.00 g, 7.62 mmol) according to the general procedure and
crystallized from methanol: yield 1.69 g (86%); mp 158-159
°C; 1H NMR (CDCl3) δ 1.29-1.95 (m, 7H, H5, H6, H7, H8),
2.45-2.69 (m, 1H, H8′), 2.70-2.83 (m, 1H, H8a), 3.05-3.22
(m, 1H, H4a), 3.85 (s, 3H, OCH3), 6.89-7.00 (m, 2H, H3-arom,
H5-arom), 7.66-7.79 (m, 2H, H2-arom, H6-arom), 8.64 (bs, 1H,
NH).
cis-6-(2,3-Dih yd r o-2,2-d im eth yl-7-m eth oxyben zofu r a n -
4-ca r bon yl)cycloh ex-3-en eca r boxylic a cid (1n ) was syn-
thesized analogously to the preparation of 1c using bromide
14 (25.7 g, 99.9 mmol), Mg (2.92 g, 120 mmol), and cis-1,2,3,6-
tetrahydrophthalic anhydride (16.7 g, 110 mmol). The title
compound was crystallized from diethyl ether: yield 15.2 g
cis-4-Ben zo[1,3]d ioxol-5-yl-4a ,5,6,7,8,8a -h exa h yd r o-2H-
p h th a la zin -1-on e (2f) was prepared from γ-keto acid 1f (7.48
g, 27.1 mmol) according to the general procedure. The product
crystallized upon concentration of the reaction mixture in
1
vacuo: yield 6.04 g (82%); mp 140-141 °C; H NMR (CDCl3)
1
(46%); mp 127-129 °C; H NMR (CDCl3) δ 1.49 (s, 6H, CH3),
δ 1.22-1.91 (m, 7H, H5, H6, H7, H8), 2.48-2.63 (m, 1H, H8′),
2.68-2.80 (m, 1H, H8a), 3.02-3.18 (m, 1H, H4a), 6.01 (s, 2H,
2.32-2.60 (m, 3H, H-cyclohexene), 2.69-2.91 (m, 1H, H-
cyclohexene), 2.93-3.09 (m, 1H, H1), 3.34 (AB, 2H, CH2),
3.84-4.00 (m, 4H, OCH3, H6), 5.59-5.86 (m, 2H, HCdCH),
6.77 (d, 1H, 3J ) 8.6 Hz, H-arom), 7.33 (d, 1H, 3J ) 8.6 Hz,
H-arom).
3
4
OCH2O), 6.83 (d, 1H, J ) 8.2 Hz, H5-arom), 7.20 (dd, 1H, J
) 1.6 Hz, 3J ) 8.2 Hz, H6-arom), 7.33 (d, 1H, 4J ) 1.6 Hz,
H2-arom), 8.50 (bs, 1H, NH).
cis-4-(3,4-Dieth oxyp h en yl)-4a ,5,6,7,8,8a -h exa h yd r o-2H-
p h th a la zin -1-on e (2g) was prepared from γ-keto acid 1g (4.01
g, 12.5 mmol) according to the general procedure, purified by
flash column chromatography using CH2Cl2, and crystallized
from ethyl acetate: yield 3.55 g (90%); mp 156-157 °C; 1H
NMR (CDCl3) δ 1.27-1.92 (m, 13H, H5, H6, H7, H8, CH3),
2.43-2.69 (m, 1H, H8′), 2.69-2.82 (m, 1H, H8a), 3.02-3.21
cis-2-(2,3-Dih yd r o-7-m eth oxyben zofu r a n -2-sp ir o-1′-cy-
clop en t a n e-4-ca r b on yl)-1,2,3,6-t et r a h yd r ob en zoic a cid
(1o) was synthesized analogously to the preparation of 1c
using bromide 10 (35.0 g, 124 mmol), Mg (3.48 g, 143 mmol),
and cis-1,2,3,6-tetrahydrophthalic anhydride (18.8 g, 124
mmol). After workup, the remainder was purified by flash
column chromatography using petroleum ether (60-80)/ethyl
acetate/acetic acid 3:1:0.1. The title compound was crystallized
from diethyl ether: yield 22.7 g (52%); mp 132-135 °C; 1H
NMR (CDCl3) δ 1.62-2.22 (m, 8H, CH2-cyclopentane), 2.31-
2.62 (m, 3H, H-cyclohexene), 2.70-2.94 (m, 1H, H-cyclohex-
ene), 2.95-3.09 (m, 1H, H1), 3.32-3.64 (AB, 2H, CH2-
3
(m, 1H, H4a), 4.04-4.24 (m, 4H, OCH2), 6.86 (d, 1H, J ) 8.4
4
3
Hz, H5-arom), 7.19 (dd, 1H, J ) 2.0, J ) 8.4 Hz, H6-arom),
4
7.44 (d, 1H, J ) 2.0 Hz, H2-arom), 8.77 (bs, 1H, NH).
cis-4-(4-Cyclop en tyloxy-3-m eth oxyp h en yl)-4a ,5,6,7,8,-
8a-h exah ydr o-2H-ph th alazin -1-on e (2h ) was prepared from
γ-keto acid 1h (3.00 g, 8.66 mmol) according to the general

Novel Selective PDE4 Inhibitors. 2
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2529
procedure: yield 2.63 g (89%); mp 152-153 °C; 1H NMR
(CDCl3) δ 1.20-2.12 (m, 15H, H5, H6, H7, H8, CH2-cyclopen-
tyl), 2.43-2.67 (m, 1H, H8′), 2.69-2.81 (m, 1H, H8a), 3.03-
3.21 (m, 1H, H4a), 3.90 (s, 3H, OCH3), 4.73-4.90 (m, 1H,
mixture had been stirred for 3 h, the preferred alkyl halide
(1.1 equiv) was added and the reaction mixture was stirred
for another 4 h. The reaction mixture was poured into water,
and the product was extracted with ethyl acetate. The com-
bined organic extract was washed with water and brine and
dried over MgSO4. After removal of the solvent, crystallization
or flash column chromatography followed by crystallization
yielded the pure products. Experimental data for the separate
compounds are listed below.
cis-2-Be n zyl-4-p h e n yl-4a ,5,6,7,8,8a -h e xa h yd r o-2H -
p h th a la zin -1-on e (3a ) was synthesized following the general
procedure using 2a (2.00 g, 8.76 mmol) and benzyl chloride as
the alkylating agent and crystallized from methanol: yield
1.28 g (46%); mp 111 °C; 1H NMR (CDCl3) δ 1.20-1.88 (m,
7H, H5, H6, H7, H8), 2.43-2.70 (m, 1H, H8′), 2.70-2.84 (m,
1H, H8a), 3.02-3.22 (m, 1H, H4a), 5.05 (AB, 2H, CH2-Bn),
7.13-7.55 (m, 8H, H-Ph, H-Bn), 7.66-7.88 (m, 2H, H-Ph).
Anal. Calcd (C21H22N2O): C, H, N.
cis-2-Ben zyl-4-(3-ch lor oph en yl)-4a,5,6,7,8,8a-h exah ydr o-
2H-p h th a la zin -1-on e (3b) was synthesized following the
general procedure using 2b (1.50 g, 5.71 mmol) and benzyl
chloride as the alkylating agent, purified by flash column
chromatography using petroleum ether (60-80)/ethyl acetate
3:1, and crystallized from petroleum ether (60-80) and
methanol: yield 1.30 g (65%); mp 67-68 °C; 1H NMR (CDCl3)
δ 1.19-1.95 (m, 7H, H5, H6, H7, H8), 2.43-2.69 (m, 1H, H8′),
2.69-2.81 (m, 1H, H8a), 2.95-3.19 (m, 1H, H4a), 4.90-5.17
(AB, 2H, CH2-Bn), 7.18-7.44 (m, 7H, H4-arom, H5-arom,
H-Bn), 7.53-7.69 (m, 1H, H6-arom), 7.69-7.80 (m, 1H, H2-
arom). Anal. Calcd (C21H21N2OCl): C, H, N.
cis-2-Ben zyl-4-(3-m et h oxyp h en yl)-4a ,5,6,7,8,8a -h exa -
h yd r o-2H-p h th a la zin -1-on e (3c) was synthesized following
the general procedure using 2c (1.89 g, 7.32 mmol) and benzyl
chloride as the alkylating agent, purified by flash column
chromatography using CH2Cl2, and crystallized from petro-
leum ether (60-80) at 5 °C: yield 1.63 g (64%); mp 59-60 °C;
1H NMR (CDCl3) δ 1.20-1.85 (m, 7H, H5, H6, H7, H8), 2.47-
2.68 (m, 1H, H8′), 2.68-2.81 (m, 1H, H8a), 2.99-3.18 (m, 1H,
H4a), 3.83 (s, 3H, OCH3), 5.02 (AB, 2H, CH2-Bn), 6.84-7.00
(m, 1H, H-arom), 7.16-7.46 (m, 8H, H-arom). Anal. Calcd
(C22H24N2O2): C, H, N.
3
3
OCH), 6.86 (d, 1H, J ) 8.5 Hz, H6-arom), 7.18 (dd, 1H, J )
4
4
8.5 Hz, J ) 2.1 Hz, H5-arom), 7.43 (d, 1H, J ) 2.1 Hz, H2-
arom), 8.54 (bs, 1H, NH).
cis-4-(3-Cyclop en tyloxy-4-m eth oxyp h en yl)-4a ,5,6,7,8,-
8a -h exa h yd r o-2H-p h th a la zin -1-on e (2i) was prepared from
γ-keto acid 1i (2.99 g, 8.63 mmol) according to the general
procedure. When the reaction mixture cooled to room temper-
ature, compound 2i (2.42 g, 82%) crystallized. The filtrate was
concentrated to yield another 0.43 g (15%) of 2i as a white
solid. The combined solids were recrystallized from ethanol:
final yield 92%; mp 175-176 °C; 1H NMR (CDCl3) δ 1.21-
2.13 (m, 15H, H5, H6, H7, H8, CH2-cyclopentyl), 2.45-2.68
(m, 1H, H8′), 2.69-2.82 (m, 1H, H8a), 3.02-3.20 (m, 1H, H4a),
3
3.88 (s, 3H, OCH3), 4.77-4.93 (m, 1H, OCH), 6.85 (d, 1H, J
3
4
) 8.5 Hz, H5-arom), 7.20 (dd, 1H, J ) 8.5 Hz, J ) 2.1 Hz,
H6-arom), 7.43 (d, 1H, 4J ) 2.0 Hz, H2-arom), 8.58 (bs, 1H,
NH).
cis-4-(2,3-Dih yd r o-7-m e t h oxyb e n zofu r a n -2-sp ir o-1′-
cyclop e n t a n -4-yl)-4a ,5,6,7,8,8a -h e xa h yd r o-2H -p h t h a l-
a zin -1-on e (2j) was prepared from γ-keto acid 1j (5.02 g, 14.0
mmol) according to the general procedure and crystallized from
ethanol: yield 4.50 g (91%); mp 185-186 °C; 1H NMR (CDCl3)
δ 1.22-2.29 (m, 15H, H5, H6, H7, H8, CH2-cyclopentane),
2.42-2.68 (m, 1H, H8a), 2.69-2.83 (m, 1H, H8′), 3.02-3.21
(m, 1H, H4a), 3.43 (s, 1H, CH2-benzofuran), 3.90 (s, 3H, OCH3),
6.76 (d, 1H, 3J ) 8.5 Hz, H-arom), 7.00 (d, 1H, 3J ) 8.6 Hz,
H-arom), 8.46 (bs, 1H, NH).
cis-4-(3-Ch lor o-4-m eth oxyph en yl)-4a,5,8,8a-tetr ah ydr o-
2H-p h th a la zin -1-on e (2k ) was prepared from γ-keto acid 1k
(15.1 g, 51.2 mmol) according to the general procedure: yield
1
12.6 g (84%); mp 198-204 °C; H NMR (CDCl3) δ 2.07-2.34
(m, 3H, H5, H8), 2.78-3.09 (m, 2H, H8a, H8′), 3.26-3.45 (m,
1H, H4a), 3.95 (s, 3H, OCH3), 5.61-5.87 (m, 2H, HCdCH),
3
4
6.96 (d, 1H, J ) 8.7 Hz, H5-arom), 7.65 (dd, 1H, J ) 2.2 Hz,
3J ) 8.7 Hz, H6-arom), 7.83 (d, 1H, J ) 2.2 Hz, H2-arom).
4
cis-4-(3-Cyclop en t yloxy-4-m et h oxyp h en yl)-4a ,5,8,8a -
tetr a h yd r o-2H-p h th a la zin -1-on e (2m ) was prepared from
γ-keto acid 1m (20.0 g, 58.1 mmol) according to the general
procedure: yield 11.7 g (59%); mp 166-168 °C; 1H NMR
(CDCl3) δ 1.50-2.39 (m, 11H, H5, H8, CH2-cyclopentyl), 2.84
cis-2-Ben zyl-4-(4-m et h oxyp h en yl)-4a ,5,6,7,8,8a -h exa -
h yd r o-2H-p h th a la zin -1-on e (3d ) was synthesized following
the general procedure using 2d (2.00 g, 7.74 mmol) and benzyl
chloride as the alkylating agent and crystallized from diethyl
ether: yield 1.62 g (60%); mp 102-104 °C; 1H NMR (CDCl3) δ
1.16-1.92 (m, 7H, H5, H6, H7, H8), 2.44-2.68 (m, 1H, H8′),
2.68-2.79 (m, 1H, H8a), 2.96-3.18 (m, 1H, H4a), 3.83 (s, 3H,
OCH3), 5.06 (AB, 2H, CH2-Bn), 6.82-6.98 (m, 2H, H3-arom,
H5-arom), 7.19-7.47 (m, 5H, H-Bn), 7.63-7.79 (m, 2H, H2-
arom, H6-arom). Anal. Calcd (C22H24N2O2): C, H, N.
3
(t, 1H, J ) 6.0 Hz, H8a), 2.90-3.10 (m, 1H, H8′), 3.29-3.48
(m, 1H, H4a), 3.89 (s, 3H, OCH3), 4.79-4.91 (m, 1H, OCH),
5.63-5.88 (m, 2H, HCdCH), 6.86 (d, 1H, 3J ) 8.5 Hz, H5-
4
3
arom), 7.22 (dd, 1H, J ) 2.1 Hz, J ) 8.5 Hz, H6-arom), 7.45
4
(d, 1H, J ) 2.1 Hz, H2-arom), 8.59 (bs, 1H, NH).
cis-4-(7-Meth oxy-2,2-d im eth yl-2,3-d ih yd r oben zofu r a n -
4-yl)-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e (2n ) was
prepared from γ-keto acid 1n (10.0 g, 30.3 mmol) according to
the general procedure and crystallized from ethyl acetate/
diethyl ether/petroleum ether (60-80); yield 7.31 g (74%); mp
243 °C; 1H NMR (CDCl3) δ 1.51 (s, 3H, CH3), 1.53 (s, 3H, CH3),
cis-4-Ben zo[1,3]d ioxol-5-yl-2-ben zyl-4a ,5,6,7,8,8a -h exa -
h yd r o-2H-p h th a la zin -1-on e (3f) was synthesized following
the general procedure using 2f (1.93 g, 7.09 mmol) and benzyl
chloride as the alkylating agent, purified by flash column
chromatography using CH2Cl2, and crystallized from metha-
3
2.10-2.37 (m, 3H, H5, H8), 2.84 (t, 1H, J ) 5.6, H8a), 2.90-
1
3.08 (m, 1H, H8′), 3.26-3.48 (m, 3H, CH2-benzofuran, H4a),
3.91 (s, 3H, OCH3), 5.64-5.88 (m, 2H, HCdCH), 6.77 (d, 1H,
nol: yield 1.17 g (46%); mp 114-115 °C; H NMR (CDCl3) δ
1.26-1.81 (m, 7H, H5, H6, H7, H8), 2.48-2.65 (m, 1H, H8′),
2.67-2.80 (m, 1H, H8a), 2.95-3.13 (m, 1H, H4a), 5.02 (AB,
3
3J ) 8.6 Hz, H-arom), 7.04 (d, 1H, J ) 8.6 Hz, H-arom), 8.69
3
(bs, 1H, NH).
2H, CH2-Bn), 5.99 (s, 2H, OCH2O), 6.83 (d, 1H, J ) 8.2 Hz,
3
4
H5-arom), 7.17 (dd, 1H, J ) 8.1 Hz, J ) 1.8 Hz, H6-arom),
cis-4-(2,3-Dih yd r o-7-m eth oxyben zofu r a n -2-sp ir o-1′-cy-
clop en t a n -4-yl)-4a ,5,8,8a -t et r a h yd r o-2H -p h t h a la zin -1-
on e (2o) was prepared from γ-keto acid 1o (7.99 g, 22.4 mmol)
according to the general procedure and crystallized from ethyl
acetate: yield 6.87 g (87%); mp 193-194 °C; 1H NMR (CDCl3)
δ 1.62-2.32 (m, 11H, H5, H8, CH2-cyclopentane), 2.78-3.06
(m, 2H, H8′, H8a), 3.28-3.50 (m, 3H, H4a, CH2-benzofuran),
3.90 (s, 3H, OCH3), 5.63-5.87 (m, 2H, HCdCH), 6.77 (d, 1H,
3J ) 8.6 Hz, H5-arom), 7.04 (d, 1H, 3J ) 8.6 Hz, H-arom), 8.83
(bs, 1H, NH).
Gen er a l P r oced u r e for th e N-Alk yla tion of P h th a la zi-
n on es. Sodium hydride (60% dispersion in mineral oil, 1.1
equiv) was added to a suspension of the selected phthalazinone
(2.8-75 mmol) in DMF (10-750 mL). After the reaction
7.24-7.48 (m, 6H, H2-arom, H-Bn). Anal. Calcd (C22H22
-
N2O3): C, H, N.
cis-2-Ben zyl-4-(3,4-d ieth oxyp h en yl)-4a ,5,6,7,8,8a -h exa -
h yd r o-2H-p h th a la zin -1-on e (3g) was synthesized following
the general procedure using 2g (2.01 g, 6.35 mmol) and benzyl
chloride as the alkylating agent and crystallized from petro-
leum ether (60-80): yield 1.49 g (58%); mp 91-92 °C; 1H NMR
(CDCl3) δ 1.15-1.98 (m, 13H, H5, H6, H7, H8, CH3), 2.45-
2.79 (m, 2H, H8′, H8a), 2.98-3.18 (m, 1H, H4a), 4.12 (q, 4H,
3J ) 7.0 Hz, OCH2), 5.03 (AB, 2H, CH2-Bn), 6.84 (d, 1H, 3J )
4
3
8.5 Hz, H5-arom), 7.19 (dd, 1H, J ) 2.0 Hz, J ) 8.5 Hz, H6-
arom), 7.22-7.49 (m, 6H, H2-arom, H-Bn). Anal. Calcd
(C25H30N2O3): C, H, N.

2530 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Van der Mey et al.
cis-2-Ben zyl-4-(4-cyclop en t yloxy-3-m et h oxyp h en yl)-
4a,5,6,7,8,8a-h exah ydr o-2H-ph th alazin -1-on e (3h ) was syn-
thesized following the general procedure using 2h (1.00 g, 2.92
mmol) and benzyl chloride as the alkylating agent. The title
compound was crystallized from petroleum ether (60-80)/
diethyl ether as a white solid: yield 0.28 g (22%). After 1 week
at 5 °C, another 0.61 g (48%) of compound 3h had crystallized
from the filtrate: total yield 70%; mp 72-73 °C; 1H NMR
(CDCl3) δ 1.20-2.11 (m, 15H, H5, H6, H7, H8, CH2-cyclopen-
tyl), 2.48-2.65 (m, 1H, H8′), 2.65-2.81 (m, 1H, H8a), 2.99-
3.18 (m, 1H, H4a), 3.87 (s, 3H, OCH3), 4.74-4.88 (m, 1H,
agent and crystallized from petroleum ether (60-80): yield
18.0 g (56%); mp 106 °C; 1H NMR (CDCl3) δ 1.29-2.31 (m,
23H, CH2-cycloheptyl, CH2-cyclopentyl, H5, H8), 2.72 (t, 1H,
3J ) 5.7 Hz, H8a), 2.90-3.10 (m, 1H, H8′), 3.19-3.38 (m, 1H,
H4a), 3.89 (s, 3H, OCH3), 4.72-4.97 (m, 2H, NCH, OCH),
5.60-5.88 (m, 2H, HCdCH), 6.86 (d, 1H, 3J ) 8.4 Hz, H5-
3
4
arom), 7.24 (dd, 1H, J ) 8.4 Hz, J ) 2.1 Hz, H6-arom), 7.54
4
(d, 1H, J ) 2.0 Hz, H2-arom). Anal. Calcd (C27H36N2O3): C,
H, N.
cis-2-Cycloh ep tyl-4-(2,3-d ih yd r o-2,2-d im eth yl-7-m eth -
oxyben zofu r a n -4-yl)-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -
1-on e (3n ) was synthesized following the general procedure
using 2n (2.00 g, 6.13 mmol) and cycloheptyl bromide as the
alkylating agent, purified by flash column chromatography
using petroleum ether (60-80)/ethyl acetate 5:1, and crystal-
lized from petroleum ether (60-80)/ethyl acetate: yield 0.60
g (23%); mp 114-115 °C; 1H NMR (CDCl3) δ 1.37-2.32 (m,
21H, CH2-cycloheptyl, H5, H8, CH3), 2.68-2.81 (m, 1H, H8a),
2.90-3.10 (m, 1H, H8′), 3.20-3.48 (m, 3H, CH2, H4a), 3.91 (s,
3H, OCH3), 4.72-4.92 (m, 1H, NCH), 5.60-5.87 (m, 2H, HCd
3
OCH), 5.04 (AB, 2H, CH2-Bn), 6.84 (d, 1H, J ) 8.5 Hz, H5-
arom), 7.18 (dd, 1H, 3J ) 8.5 Hz, 4J ) 2.1 Hz, H6-arom), 7.24-
7.49 (m, 6H, H2-arom, H-Bn). Anal. Calcd (C27H32
N2O3): C, H, N.
-
cis-2-Ben zyl-4-(3-cyclop en t yloxy-4-m et h oxyp h en yl)-
4a ,5,6,7,8,8a -h exa h yd r o-2H-p h th a la zin -1-on e (3i) was syn-
thesized following the general procedure using 2i (1.00 g, 2.92
mmol) and benzyl chloride as the alkylating agent. After
workup, the remainder was dissolved in CH2Cl2 and purified
by flash column chromatography using petroleum ether (60-
80)/ethyl acetate 4:1. The title compound was crystallized from
petroleum ether (60-80)/ethyl acetate as a white solid: yield
0.43 g (34%); mp 91-92 °C; 1H NMR (CDCl3) δ 1.19-2.16 (m,
15H, H5, H6, H7, H8, CH2-cyclopentyl), 2.49-2.67 (m, 1H,
H8′), 2.67-2.81 (m, 1H, H8a), 2.98-3.18 (m, 1H, H4a), 3.87
(s, 3H, OCH3), 4.72-4.87 (m, 1H, OCH), 5.03 (AB, 2H, CH2-
Bn), 6.83 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.18 (dd, 1H, 3J ) 8.5
Hz, 4J ) 2.1 Hz, H6-arom), 7.23-7.49 (m, 6H, H2-arom,
H-Bn). Anal. Calcd (C27H32N2O3): C, H, N.
3
3
CH), 6.78 (d, 1H, J ) 8.5 Hz, H-arom), 7.04 (d, 1H, J ) 8.6
Hz, H-arom). Anal. Calcd (C26H34N2O3): C, H, N.
cis-2-Cycloh eptyl-4-(2,3-dih ydr o-7-m eth oxyben zofu r an -
2-sp ir o-1′-cyclop e n t a n -4-yl)-4a ,5,8,8a -t e t r a h yd r o-2H -
p h th a la zin -1-on e (3o) was synthesized following the general
procedure using 2o (1.00 g, 2.81 mmol) and cycloheptyl
bromide as the alkylating agent. Purification was by flash
column chromatography using petroleum ether (60-80)/ethyl
acetate 4:1. The title compound was crystallized from diethyl
ether/petroleum ether (60-80): yield 0.81 g (64%); mp 135 °C;
1H NMR (CDCl3) δ 1.40-2.40 (m, 23H, H5, H8, CH2-cyclopen-
tane, CH2-cycloheptyl), 2.68-2.82 (m, 1H, H8a), 2.90-3.12 (m,
1H, H8′), 3.20-3.40 (m, 1H, H4a), 3.42-3.64 (m, 2H, CH2-
benzofuran), 3.91 (s, 3H, OCH3), 4.72-4.95 (m, 1H, NCH),
5.60-5.89 (m, 2H, HCdCH), 6.77 (d, 1H, 3J ) 8.6 Hz, H6-
arom), 7.03 (d, 1H, 3J ) 8.6 Hz, H5-arom). Anal. Calcd
(C28H36N2O3): C, H, N.
4-Br om o-1-cyclop en tyloxy-2-m eth oxyben zen e (4). A
mixture of 4-bromo-2-methoxyphenol (15.0 g, 73.9 mmol),
anhydrous K2CO3 (20.4 g, 148 mmol), and cyclopentyl bromide
(19.1 g, 128 mmol) in DMF (100 mL) was stirred at 65 °C for
10 h. After cooling to room temperature, the reaction mixture
was diluted with diethyl ether, and the solution was washed
with 1 M NaOH and water. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The title compound
was obtained as a yellow oil: yield 19.5 g (97%); 1H NMR
(CDCl3) δ 1.50-2.03 (m, 8H, CH2), 3.83 (s, 3H, OCH3), 4.68-
4.80 (m, 1H, OCH), 6.73 (d, 1H, 3J ) 8.2 Hz, H6-arom), 6.93-
7.07 (m, 2H, H3-arom, H5-arom).
cis-2-Ben zyl-4-{sp ir o[cyclop en t a n e-1′,2(3H )-7-m et h -
oxybenzofurane]-4-yl}-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-
1-on e (3j) was synthesized following the general procedure
using 2j (1.00 g, 2.82 mmol) and benzyl chloride as the
alkylating agent. After workup, the residue was dissolved in
CH2Cl2 and purified by flash column chromatography using
petroleum ether (60-80)/ethyl acetate 4:1. The title compound
was crystallized from petroleum ether (60-80)/ethyl acetate:
yield 0.90 g (72%); mp 104-106 °C; 1H NMR (CDCl3) δ 1.22-
2.18 (m, 15H, H5, H6, H7, H8, CH2-cyclopentane), 2.50-2.65
(m, 1H, H8′), 2.69-2.82 (m, 1H, H8a), 2.92-3.21 (m, 3H, H4a,
CH2-benzofuran), 3.88 (s, 3H, OCH3), 5.02 (AB, 2H, CH2-Bn),
3
3
6.73 (d, 1H, J ) 8.5 Hz, H5-arom), 6.96 (d, 1H, J ) 8.6 Hz,
H6-arom), 7.14-7.41 (m, 5H, H-Bn). Anal. Calcd (C28H32
N2O3): C, H, N.
-
cis-4-(3-Ch lor o-4-m eth oxyph en yl)-2-cycloh eptyl-4a,5,8,-
8a -tetr a h yd r o-2H-p h th a la zin -1-on e (3k ) was synthesized
following the general procedure using 2k (2.00 g, 6.88 mmol)
and cycloheptyl bromide as the alkylating agent: yield 1.73 g
(65%); mp 138-141 °C; 1H NMR (CDCl3) δ 1.40-2.36 (m, 15H,
CH2-cycloheptyl, H5, H8), 2.72 (t, 1H, 3J ) 5.7 Hz, H8a), 2.90-
3.11 (m, 1H, H8′), 3.18-3.35 (m, 1H, H4a), 3.95 (s, 3H, OCH3),
4.70-4.92 (m, 1H, NCH), 5.60-5.88 (m, 2H, HCdCH), 6.96
(d, 1H, 3J ) 8.7 Hz, H5-arom), 7.67 (dd, 1H, 4J ) 2.2 Hz, 3J )
5-Br om o-2-m eth oxyp h en ol (5). A solution of 5-bromo-2-
methoxybenzaldehyde (50.0 g, 233 mmol) in CH2Cl2 (150 mL)
was cooled with an ice bath to 0 °C, and subsequently
3-chloroperoxybenzoic acid (70-75% purity) (68.1 g, 276 mmol)
in CH2Cl2 (500 mL) was added. The reaction mixture was
allowed to warm slowly to room temperature and stirred for
72 h. The white solid was filtered off, and the filtrate was
stirred for 2 h with 2 M Na2S2O3 (200 mL). The organic layer
was concentrated in vacuo, and the remainder was dissolved
in diethyl ether and washed with 1 M Na2SO3 and a half
saturated NaHCO3 solution. The organic phase was extracted
with 2 M NaOH. The combined basic extract was acidified (pH
3-4) with concentrated HCl and extracted with diethyl ether.
The combined organic extract was dried over MgSO4, and the
solvent was removed under reduced pressure to give the title
compound as a pale brown solid: yield 43.5 g (92%); mp 61-
64 °C; 1H NMR (CDCl3) δ 3.86 (s, 3H, OCH3), 5.67 (s, 1H, OH),
4
8.7 Hz, H6-arom), 7.85 (d, 1H, J ) 2.2 Hz, H2-arom). Anal.
Calcd (C22H27N2O2Cl): C, H, N.
cis-2-Cycloh ep t yl-4-(3,4-d im et h oxyp h en yl)-4a ,5,8,8a -
tetr a h yd r o-2H-p h th a la zin -1-on e (3l) was synthesized fol-
lowing the general procedure using 4-(3,4-dimethoxyphenyl)-
4a,5,8,8a-tetrahydro-2H-phthalazin-1-one26 (2.00 g, 6.98 mmol)
and cycloheptyl bromide as the alkylating agent, purified by
flash column chromatography, and crystallized from diethyl
ether/petroleum ether (60-80); yield 1.74 g (65%); mp 92-93
°C; 1H NMR (CDCl3) δ 1.41-2.32 (m, 15H, 6 × CH2-cyclohept-
yl, H5, H8), 2.68-2.81 (m, 1H, H8a), 2.91-3.13 (m, 1H, H8′),
3.21-3.40 (m, 1H, H4a), 3.93 (s, 3H, OCH3), 3.95 (s, 3H,
OCH3), 4.74-4.95 (m, 1H, NCH), 5.60-5.89 (m, 2H, HCdCH),
3
4
6.70 (d, 1H, J ) 8.6 Hz, H3-arom), 6.96 (dd, 1H, J ) 2.3 Hz,
3
4
4
6.88 (d, 1H, J ) 8.4 Hz, H5-arom), 7.27 (dd, 1H, J ) 2.0 Hz,
3J ) 8.4 Hz, H6-arom), 7.53 (d, 1H, 4J ) 2.0 Hz, H-arom). Anal.
Calcd (C23H30N2O3): C, H, N.
3J ) 8.6 Hz, H4-arom), 7.06 (d, 1H, J ) 2.3 Hz, H6-arom).
4-Br om o-2-cyclop en tyloxy-1-m eth oxyben zen e (6) was
prepared analogously to the preparation of 4 except using
phenol 5 (12.4 g, 61.1 mmol). After workup, the residue was
purified by flash column chromatography using petroleum
ether (60-80)/ethyl acetate 7:3, yielding bromide 6 as a yellow
ci s-2-C yc loh e p t y l-4-(3-c y c lo p e n t ylo xy -4-m e t h o xy-
p h en yl)-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e (3m )
was synthesized following the general procedure using 2m
(25.0 g, 73.4 mmol) and cycloheptyl bromide as the alkylating
1
oil: yield 16.3 g (99%); H NMR (DMSO-d6) δ 1.50-2.16 (m,

Novel Selective PDE4 Inhibitors. 2
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2531
8H, CH2), 3.82 (s, 3H, OCH3), 4.68-4.81 (m, 1H, OCH), 6.72
(d, 1H, 3J ) 8.7 Hz, H6-arom), 6.94-7.08 (m, 2H, H3-arom,
H5-arom).
monohydrate (10.0 g, 52.6 mmol) in toluene (250 mL) was
refluxed for 3 h. Subsequently, the toluene was evaporated
under reduced pressure, and the residue was dissolved in ethyl
acetate and washed with saturated NaHCO3. The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo.
The product was crystallized from diethyl ether: yield 12.0 g
(71%); mp 171 °C; 1H NMR (CDCl3) δ 1.39-2.30 (m, 15H, CH2-
cycloheptyl, H5, H8), 2.71 (t, 1H, 3J ) 5.7 Hz, H8a), 2.89-
3.10 (m, 1H, H8′), 3.19-3.36 (m, 1H, H4a), 3.94 (s, 3H, OCH3),
4.71-4.90 (m, 1H, NCH), 5.60-5.88 (m, 3H, HCdCH, OH),
2-(5-Br om o-2-m eth oxyp h en oxy)cyclop en ta n on e (7). A
mixture of phenol 5 (25.2 g, 124 mmol), 2-chlorocyclopentanone
(17.6 g, 148 mmol), and K2CO3 (34.3 g, 248 mmol) in DMF
(250 mL) was stirred for 2.5 h at 60 °C. The reaction mixture
was concentrated in vacuo, and the remainder was diluted
with diethyl ether and washed with 1 M NaOH and water.
The organic layer was dried over MgSO4 and concentrated in
vacuo. The remaining oil was purified by flash column chro-
matography using petroleum ether (60-80)/ethyl acetate 7:3
to yield the title compound, which crystallized after removal
of the solvent under reduced pressure: yield 24.4 g (69%); 1H
NMR (CDCl3) δ 1.78-2.60 (m, 6H, CH2), 3.83 (s, 3H, OCH3),
3
4
6.87 (d, 1H, J ) 8.5 Hz, H5-arom), 7.28 (dd, 1H, J ) 2.0 Hz,
3J ) 8.5 Hz, H6-arom), 7.48 (d, 1H, 4J ) 2.1 Hz, H2-arom).
Anal. Calcd (C22H28N2O3): C, H, N.
cis-2-Cycloh e p t yl-4-(3-d iflu or om e t h oxy-4-m e t h oxy-
p h en yl)-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e(16a ).
A solution of phenol 15 (2.00 g, 5.43 mmol), tetraethyl-
ammonium bromide (0.12 g, 0.57 mmol), and NaOH (0.65 g,
16 mmol) in water (1 mL) and dioxane (14 mL) was heated to
80 °C and saturated with chlorodifluoromethane for 30 min.
After the reaction mixture had cooled to room temperature,
the organic layer was decanted and concentrated in vacuo. The
remainder was dissolved in ethyl acetate and washed with
water. The organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The remaining oil was
purified by flash column chromatography using petroleum
ether (60-80)/ethyl acetate 4:1. The product was crystallized
from dichloromethane/petroleum ether (60-80): yield 1.45 g
(64%); mp 83 °C; 1H NMR (CDCl3) δ 1.40-2.33 (m, 15H,
H-cycloheptyl, H5, H8), 2.67-2.80 (m, 1H, H8a), 2.90-3.11
(m, 1H, H8′), 3.18-3.33 (m, 1H, H4a), 3.93 (s, 3H, OCH3),
4.71-4.91 (m, 1H, NCH), 5.58-5.88 (m, 2H, HCdCH), 6.60
(t, 1H, 2J ) 75.0 Hz, F2CHO), 6.99 (d, 1H, 3J ) 8.3 Hz, H5-
3
4.52-4.68 (m, 1H, OCH), 6.75 (d, 1H, J ) 8.8 Hz, H3-arom),
7.02-7.17 (m, 2H, H4-arom, H6-arom).
3-Br om o-2-cyclop en t -1-en ylm et h yl-6-m et h oxyp h en ol
(9). Potassium tert-butoxide (10.6 g, 94.5 mmol) was added
slowly to a solution of (methyl)triphenylphosphonium bromide
(33.7 g, 94.3 mmol) in THF (250 mL). After the reaction
mixture was stirred for 2 h, a solution of ketone 7 (22.4 g, 78.6
mmol) in THF (200 mL) was added dropwise in 45 min. The
resulting mixture was stirred for another hour, diluted with
diethyl ether, and washed with water. The organic phase was
reduced in volume under reduced pressure, dried over MgSO4,
and then fully concentrated in vacuo. Next, the residue,
containing compound 8, was heated at 180 °C for 45 min. The
remainder was purified by flash column chromatography using
petroleum ether (60-80)/ethyl acetate 8:2 to give the title
compound as a yellow oil: yield 20.3 g (91%); 1H NMR(CDCl3)
δ 1.78-1.97 (m, 2H, CH2), 2.20-2.41 (m, 4H, CH2), 3.55 (AB,
2H, CH2-Ph), 3.87 (s, 3H, OCH3), 5.13-5.24 (m, 1H, HCdC),
4
3
arom), 7.62 (dd, 1H, J ) 2.2 Hz, J ) 8.6 Hz, H6-arom), 7.68
3
4
5.79 (s, 1H, OH), 6.63 (d, 1H, J ) 8.7 Hz, H-arom), 7.06 (d,
(d, 1H, J ) 2.0 Hz, H2-arom). Anal. Calcd (C23H28N2O3F2) C,
3
1H, J ) 8.7 Hz, H-arom).
H, N.
4-Br om o-2,3-d ih yd r o-7-m eth oxyben zofu r a n -2-sp ir o-1′-
cyclop en ta n e (10). A mixture of compound 9 (20.3 g, 71.7
mmol) and Amberlyst 15 ion-exchange resin (18.8 g) in toluene
(250 mL) was heated at 80 °C for 3 h. Subsequently, the
Amberlyst 15 was filtered off and the filtrate concentrated in
cis-2-Cycloh ep t yl-4-(3-cyclop r op ylm et h oxy-4-m et h -
oxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (16b).
A mixture of phenol 15 (1.40 g, 3.80 mmol), chloromethyl-
cyclopropane (0.40 g, 4.4 mmol), potassium iodide (0.10 g, 0.60
mmol), and K2CO3 (0.60 g, 4.3 mmol) in NMP (100 mL) was
heated at 60 °C for 5 days. The reaction mixture was diluted
with diethyl ether and washed with water. The organic layer
was dried over MgSO4 and concentrated, and the residue was
purified by flash column chromatography using petroleum
ether (60-80)/ethyl acetate 4:1. The product was crystallized
from petroleum ether (60-80): yield 0.15 g (9%); mp 102-
103 °C; 1H NMR (CDCl3) δ 0.33-0.48 (m, H-cyclopropyl), 0.60-
0.75 (m, H-cyclopropyl), 1.24-2.32 (m, 16H, H-cycloheptyl, H5,
H8, CH-cyclopropyl), 2.67-2.79 (m, 1H, H8a), 2.90-3.10 (m,
1H, H8′), 3.20-3.38 (m, 1H, H4a), 3.84-4.01 (m, 5H, OCH3,
OCH2), 4.73-4.93 (m, 1H, NCH), 5.60-5.86 (m, 2H, HCdCH),
1
vacuo to give pure 10 as a yellow oil: yield 19.3 g (95%); H
NMR (CDCl3) δ 1.62-2.31 (m, 8H, CH2), 3.19 (s, 2H, CH2-
benzofuran), 3.84 (s, 3H, OCH3), 6.63 (d, 1H, 3J ) 8.6 Hz,
3
H-arom), 6.90 (d, 1H, J ) 8.6 Hz, H-arom).
1-(5-Br om o-2-m eth oxyp h en oxy)p r op a n -2-on e (11) was
synthesized analogously to the preparation of 7 using phenol
5 (50.0 g, 246 mmol), chloro-2-propanone (30.0 g, 324 mmol),
and K2CO3 (48.0 g, 347 mmol). The mixture was heated for 6
h. After workup, the remainder was purified by flash column
chromatography using petroleum ether (60-80)/ethyl acetate
3:1, yielding the title compound as a yellow oil: yield 38.9 g
1
3
4
(61%); H NMR (CDCl3) δ 2.29 (s, 3H, CH3CdO), 3.86 (s, 3H,
6.88 (d, 1H, J ) 8.4 Hz, H5-arom), 7.28 (dd, 1H, J ) 2.1 Hz,
3J ) 8.4 Hz, H6-arom), 7.51 (d, 1H, 4J ) 2.0 Hz, H2-arom).
Anal. Calcd (C26H34N2O3): C, H, N.
3
OCH3), 4.59 (s, 2H, CH2), 6.78 (d, 1H, J ) 8.6 Hz, H5-arom),
4
4
6.88 (d, 1H, J ) 2.3 Hz, H2-arom), 7.09 (dd, 1H, J ) 2.3 Hz,
3J ) 8.6 Hz, H6-arom).
ci s-2-C y c lo h e p t y l-4-[3-(2-h y d r o x y e t h o x y )-4-m e t h -
oxyph en yl]-4a,5,8,8a-tetr ah ydr o-2H-ph th alazin -1-on e (16c).
A mixture of phenol 15 (1.00 g, 2.71 mmol), ethylene carbonate
(0.50 g, 5.7 mmol), and K2CO3 (0.80 g, 5.8 mmol) in NMP (20
mL) was heated to 125 °C for 4 h. After the reaction mixture
had cooled to room temperature, water was added and the
product was extracted with diethyl ether. The combined
organic extract was dried over MgSO4 and concentrated. The
remainder was purified by flash column chromatography using
petroleum ether (60-80)/ethyl acetate 1:1. The title compound
was crystallized from diethyl ether/petroleum ether (60-80):
yield 1.01 g (90%); mp 75 °C; 1H NMR (DMSO-d6) δ 1.40-
3-Br om o-6-m eth oxy-2-(2-m eth yla llyl)p h en ol (13) was
synthesized analogously to the preparation of 9 except using
ketone 11 (38.0 g, 148 mmol). After workup, the remaining
oil was purified by flash column chromatography using
petroleum ether (60-80)/ethyl acetate 10:1. The title com-
pound was obtained as a yellow oil: yield 25.5 g (67%); NMR
spectrum not available.
4-Br om o-2,3-d ih yd r o-2,2-d im et h yl-7-m et h oxyb en zo-
fu r a n (14) was synthesized analogously to the preparation of
10 except using compound 13 (25.0 g, 97.2 mmol). After
workup, the product was purified by flash column chromatog-
raphy using petroleum ether (60-80)/ethyl acetate 30:1. The
title compound was obtained as a yellow oil: yield 16.8 (67%);
1H NMR (CDCl3) δ 1.53 (s, 6H, CH3), 3.04 (s, 2H, CH2), 3.85
3
2.30 (m, 15H, CH2-cycloheptyl, H5, H8), 2.72 (t, 1H, J ) 5.7
Hz, H8a), 2.90-3.11 (m, 1H, H8′), 3.20-3.38 (m, 1H, H4a),
3.91 (s, 3H, OCH3), 3.92-4.07 (m, 2H, CH2OH), 4.20 (t,
3
2H, 3J
) 4.1/8 Hz, OCH2), 4.72-4.91 (m, 1H, NCH),
(s, 3H, OCH3), 6.63 (d, 1H, J ) 8.6 Hz, H-arom), 6.91 (d, 1H,
3J ) 8.6 Hz, H-arom).
5.60-5.88 (m, 2H, HCdCH), 6.90 (d, 1H, 3J ) 8.5 Hz, H5-
4
3
cis-2-Cycloh e p t yl-4-(3-h yd r oxy-4-m e t h oxyp h e n yl)-
4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e (15). A mixture
of compound 3m (20.0 g, 45.8 mmol) and p-toluenesulfonic acid
arom), 7.34 (dd, 1H, J ) 2.1 Hz, J ) 8.5 Hz, H6-arom), 7.54
4
(d, 1H, J ) 2.1 Hz, H2-arom). Anal. Calcd (C24H32N2O4): C,
H, N.

2532 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Van der Mey et al.
cis-[5-(3-Cycloh ep t yl-4-oxo-3,4,4a ,5,8,8a -h exa h yd r o-
p h th a la zin -1-yl)-2-m eth oxyp h en oxy]a cetic Acid Eth yl
Ester (16.1d ). A mixture of compound 15 (1.00 g, 2.71 mmol),
ethyl bromoacetate (0.50 g, 3.0 mmol), and K2CO3 (0.40 g, 2.9
mmol) in NMP (100 mL) was heated to 60 °C for 6 h. After
the addition of water, the product was extracted with diethyl
ether. The combined organic extract was washed with satu-
rated NaHCO3 and dried over MgSO4, and the solvent was
evaporated to yield the title compound as a yellow oil: yield
1.01 g (82%); 1H NMR (CDCl3) δ 1.30 (t, 3H, 3J ) 7.1 Hz,
CH2CH3), 1.40-2.30 (m, 15H, CH2-cycloheptyl, H5, H8), 2.71
of compound 16c (10.3 g, 25.0 mmol) in dichloromethane (25
mL) was added to the reaction mixture while the temperature
was maintained at 0 °C. After the last addition, the mixture
was allowed to reach room temperature and was stirred for
another 2 h. The reaction was quenched by the addition of
aqueous NaHCO3. The organic layer was dried over MgSO4
and concentrated under reduced pressure. The title compound
was crystallized from the residue as a white solid using
methanol: yield 7.73 g (65%); mp 92-94 °C; 1H NMR (DMSO-
d6) δ 1.49-2.32 (m, 15H, CH2-cycloheptyl, H5, H8), 2.72 (t,
3
1H, J ) 5.8 Hz, H8a), 2.91-3.11 (m, 1H, H8′), 3.20-3.37 (m,
3
(t, 1H, J ) 5.9 Hz, H8a), 2.88-3.11 (m, 1H, H8′), 3.18-3.35
1H, H4a), 3.69 (t, 2H, 3J ) 6.7 Hz, CH2Br), 3.92 (s, 3H, OCH3),
4.41 (t, 2H, 3J ) 6.7 Hz, OCH2), 4.74-4.94 (m, 1H, NCH),
5.60-5.85 (m, 2H, HCdCH), 6.90 (d, 1H, 3J ) 8.5 Hz, H5-
(m, 1H, H4a), 3.93 (s, 3H, OCH3), 4.28 (q, 2H, 3J ) 7.1 Hz,
CH2CH3), 4.68-4.90 (m, 3H, NCH, CH2CdO), 5.58-5.87 (m,
2H, HCdCH), 6.91 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.33 (dd,
4
3
arom), 7.33 (dd, 1H, J ) 2.1 Hz, J ) 8.5 HZ, H6-arom), 7.55
4
3
4
4
1H, J ) 2.0 Hz, J ) 8.5 Hz, H6-arom), 7.46 (d, 1H, J ) 2.0
(d, 1H, J ) 2.0 Hz, H2-arom).
Hz, H2-arom).
cis-2-Cycloh eptyl-4-[3-(2-dim eth ylam in oeth oxy)-4-m eth -
oxyphenyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one hemi-
fu m a r a te (16g). Bromide 16.1 g (1.00 g, 2.10 mmol) was
stirred in a 30% solution of dimethylamine in ethanol (30 mL)
for 4 h. The reaction mixture was diluted with saturated
NaHCO3, and the product was extracted with diethyl ether.
The combined organic extract was dried over MgSO4 and
concentrated in vacuo. The desired product was crystallized
as the hemifumarate from ethyl acetate/diethyl ether/fumaric
acid: yield 0.99 g (95%); mp 163 °C; 1H NMR (CDCl3) δ 1.39-
2.31 (m, 15H, CH2-cycloheptyl, H5, H8), 2.65-2.84 (m, 7H,
H8a, NCH3), 2.89-3.11 (m, 1H, H8′), 3.18-3.39 (m, 3H, H4a,
NCH2), 3.89 (s, 3H, OCH3), 4.37 (t, 2H, 3J ) 5.9 Hz, OCH2),
4.71-4.90 (m, 1H, NCH), 5.60-5.86 (m, 2H, HCdCH), 6.78
cis-[5-(3-Cycloh ep t yl-4-oxo-3,4,4a ,5,8,8a -h exa h yd r o-
p h th a la zin -1-yl)-2-m eth oxyp h en oxy]a cetic a cid (16d ).
Ester 16.1d (1.00 g, 2.20 mmol) was stirred in a mixture of
THF (100 mL), MeOH (100 mL), and 2 N KOH (200 mL) for 2
h. The reaction mixture was concentrated in vacuo, the residue
was diluted with ethyl acetate, and the product was extracted
with 1 M NaOH. The combined aqueous extract was acidified
with concentrated HCl and extracted with ethyl acetate. The
combined organic extracts were dried over MgSO4, and after
removal of the solvent under reduced pressure, the title
compound was crystallized from the remainder as a white solid
1
using diethyl ether: yield 0.47 g (50%); mp 143 °C; H NMR
(CDCl3) δ 1.37-2.35 (m, 15H, CH2-cycloheptyl, H5, H8), 2.72
3
3
(t, 1H, J ) 5.7 Hz, H8a), 2.89-3.10 (m, 1H, H8′), 3.18-3.35
(s, 1H, HCdCHsfumaric acid), 6.89 (d, 1H, J ) 8.5 Hz, H5-
4
3
(m, 1H, H4a), 3.94 (s, 3H, OCH3), 4.70-4.91 (m, 3H, NCH,
arom), 7.36 (dd, 1H, J ) 2.1 Hz, J ) 8.5 Hz, H6-arom), 7.50
3
OCH2), 5.58-5.85 (m, 2H, HCdCH), 6.93 (d, 1H, J ) 8.5 Hz,
(d, 1H, 4J
N3O3.C4H4O4): C, H, N.
) 2.0 Hz, H2-arom). Anal. Calcd (C26H37-
4
3
H5-arom), 7.38 (dd, 1H, J ) 1.9 Hz, J ) 8.5 Hz, H6-arom),
7.53 (d, 1H, 4J ) 1.9 Hz, H2-arom). Anal. Calcd (C24H30N2O5):
C, H, N.
cis-4-[3-(4-Br om ob u t oxy)-4-m et h oxyp h en yl]-2-cyclo-
h ep tyl-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e (16.1h ).
cis-4-[5-(3-Cycloh ep tyl-4-oxo-3,4,4a ,5,8,8a -h exa h yd r o-
p h th a la zin -1-yl)-2-m eth oxyp h en oxy]bu tyr ic a cid (16e).
The ethyl ester of compound 16e was prepared as described
for 16.1d using ethyl 4-bromobutyrate (0.60 g, 3.1 mmol).
Hydrolysis of the ethyl ester was performed analogously to the
preparation of 16d except the reaction mixture was stirred
for 30 min. The product was crystallized from diethyl ether
as a white solid: yield 0.48 g (39%); mp 121 °C; 1H NMR
(CDCl3) δ 1.38-2.32 (m, 17H, CH2-cycloheptyl, H5, H8, H-Pr),
2.56-2.80 (m, 3H, H8a, CH2CdO), 2.90-3.11 (m, 1H, H8′),
A mixture of 15 (4.01 g, 10.9 mmol), 1,4-dibromo-
butane (7.50 g, 34.7 mmol), and K2CO3 (2.71 g, 19.6 mmol) in
NMP (100 mL) was heated to 60 °C for 4 h. Workup was
performed as described for 16.1d . The remaining oil was
purified by flash column chromatography using petroleum
ether (60-80)/ethyl acetate 4:1. The title compound was
obtained as a white solid by crystallization from petroleum
ether (60-80)/ethyl acetate: yield 3.82 g (70%); mp 101-103
1
°C; H NMR (CDCl3) δ 1.42-2.32 (m, 19H, CH2-cycloheptyl,
H5, H8, H-Bu), 2.66-2.79 (m, 1H, H8a), 2.91-3.11 (m, 1H,
3
3
3.19-3.38 (m, 1H, H4a), 3.90 (s, 3H, OCH3), 4.14 (t, 2H, J )
H8′), 3.21-3.38 (m, 1H, H4a), 3.52 (t, 2H, J ) 6.3 Hz, CH2-
6.1 Hz, OCH2), 4.72-4.93 (m, 1H, NCH), 5.59-5.85 (m, 2H,
HCdCH), 6.88 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.30 (dd, 1H, 4J
) 2.0 Hz, 3J ) 8.5 Hz, H6-arom), 7.49 (d, 1H, 4J ) 2.0 Hz,
H2-arom). Anal. Calcd (C26H34N2O5): C, H, N.
Br), 3.91 (s, 3H, OCH3), 4.13 (t, 2H, 3J ) 5.9 Hz, OCH2), 4.71-
4.93 (m, 1H, NCH), 5.60-5.87 (m, 2H, HCdCH), 6.88 (d, 1H,
3J ) 8.5 Hz, H5-arom), 7.28 (dd, 1H, 4J ) 2.0 Hz, 3J ) 8.5 Hz,
4
H6-arom), 7.50 (d, 1H, J ) 2.0 Hz, H2-arom).
cis-5-[5-(3-Cycloh ep tyl-4-oxo-3,4,4a ,5,8,8a -h exa h yd r o-
ph th alazin -1-yl)-2-m eth oxyph en oxy]pen tan oic acid (16f).
The ethyl ester of compound 16f was prepared as described
for 16.1d using ethyl 5-bromovalerate (0.60 g, 2.9 mmol) and
heating for 12 h. Hydrolysis of the ethyl ester was performed
analogously to the preparation of 16d except the reaction
mixture was stirred for 30 min. The title compound was
obtained as a white solid by crystallization from ethyl ac-
etate: yield 0.74 g (58%); mp 161 °C; 1H NMR (CDCl3) δ 1.40-
2.32 (m, 19H, CH2-cycloheptyl, H5, H8, H-pentyl), 2.48 (t, 2H,
cis-2-Cycloh eptyl-4-[3-(4-dim eth ylam in obu toxy)-4-m eth -
oxyphenyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one hemi-
fu m a r a te (16h ) was prepared from bromide 16.1h (1.00 g,
1.99 mmol) analogously to the preparation of 16g. After
workup, the title compound was crystallized as the hemifu-
marate from diethyl ether/fumaric acid: yield 0.96 g (92%);
mp 146 °C; 1H NMR (CDCl3) δ 1.40-2.32 (m, 19H, CH2-
cycloheptyl, H5, H8, H-Bu), 2.65-2.81 (m, 7H, H8a, NCH3),
2.88-3.16 (m, 3H, H8′, NCH2), 3.19-3.37 (m, 1H, H4a), 3.89
(s, 3H, OCH3), 4.04-4.19 (m, 2H, OCH2), 4.72-4.92 (m, 1H,
NCH), 5.59-5.87 (m, 2H, HCdCH), 6.78 (s, 1H, HCdCHs
fumaric acid), 6.88 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.30 (dd,
3
3J ) 6.9 Hz, CH2CdO), 2.73 (t, 1H, J ) 5.6 Hz, H8a), 2.90-
3.12 (m, 1H, H8′), 3.18-3.39 (m, 1H, H4a), 3.90 (s, 3H, OCH3),
4.11 (t, 2H, 3J ) 6.0 Hz, OCH2), 4.72-4.94 (m, 1H, NCH),
5.60-5.87 (m, 2H, HCdCH), 6.87 (d, 1H, 3J ) 8.5 Hz, H5-
4
3
4
1H, J ) 2.0 Hz, J ) 8.5 Hz, H6-arom), 7.45 (d, 1H, J ) 1.9
Hz, H2-arom), 11.07 (bs, 1H, COOH-fumaric acid). Anal.
Calcd (C28H41N3O3.C4H4O4): C, H, N.
4
3
arom), 7.28 (dd, 1H, J ) 2.0 Hz, J ) 8.5 Hz, H6-arom), 7.49
4
(d, 1H, J ) 2.0 Hz, H2-arom). Anal. Calcd (C27H36N2O5): C,
cis-2-Cycloh ep tyl-4-[3-(4-im id a zol-1-yl-bu toxy)-4-m eth -
oxyph en yl]-4a,5,8,8a-tetr ah ydr o-2H-ph th alazin -1-on e h y-
d r och lor id e (16i) was synthesized from bromide 16.1h (1.00
g, 1.99 mmol), imidazole (0.20 g, 2.9 mmol), and K2CO3 (0.50
g, 3.6 mmol) as described for 16.1d . The product was crystal-
lized as the hydrochloride from ethyl acetate/HCl: yield 0.51
g (49%); mp 73-74 °C; 1H NMR (CDCl3) δ 1.35-2.33 (m, 19H,
CH2-cycloheptyl, H5, H8, H-Bu), 2.65-2.80 (m, 1H, H8a),
H, N.
cis-4-[3-(2-Br om oet h oxy)-4-m et h oxyp h en yl]-2-cyclo-
h ep tyl-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e (16.1g).
A solution of bromine (4.00 g, 25.0 mmol) in dichloromethane
(10 mL) was added dropwise to an ice-cooled solution of
triphenylphosphine (6.56 g, 25.0 mmol) in dichloromethane (50
mL) under a nitrogen atmosphere. Subsequently, a solution

Novel Selective PDE4 Inhibitors. 2
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2533
2.90-3.12 (m, 1H, H8′), 3.21-3.39 (m, 1H, H4a), 3.96 (s, 3H,
OCH3), 4.08-4.24 (t, 2H, OCH2), 4.45-4.66 (t, 2H, NCH2),
4.70-4.92 (m, 1H, NCH), 5.58-5.87 (m, 2H, HCdCH), 6.91
(d, 1H, 3J ) 8.5 Hz, H5-arom), 7.30 (dd, 1H, 4J ) 1.9 Hz, 3J )
8.5 Hz, H6-arom), 7.41 (d, 2H, 4J ) 11.8 Hz, HCdCHs
(CDCl3) δ 1.41-2.32 (m, 19H, 6 × CH2-cycloheptyl, H5, H8, 4
× H-Bu), 2.65-2.79 (m, 1H, H8a), 2.90-3.11 (m, 1H, H8′),
3.20-3.38 (m, 1H, H4a), 3.87 (s, 3H, OCH3), 4.02-4.31 (m,
4H, OCH2), 4.74-4.96 (m, 1H, NCH), 5.61-5.89 (m, 2H,
3
3
HCdCH), 6.85 (d, 1H, J ) 8.5 Hz, H5-arom), 6.91 (d, 2H, J
4
4
3
imidazolyl), 7.47 (d, 1H, J ) 1.9 Hz, H2-arom), 9.57 (s, 1H,
) 9.0 Hz, H-benzoic), 7.26 (dd, 1H, J ) 2.0 Hz, J ) 8.5 Hz,
4 3
CH-imidazolyl), 15.13 (s, 1H, HCl). Anal. Calcd (C29H38
N4O3.HCl): C, H, N.
-
H6-arom), 7.49 (d, 1H, J ) 1.9 Hz, H2-arom), 8.03 (d, 2H, J
) 8.9 Hz, H-benzoic). Anal. Calcd (C33H40N2O6): C, H, N.
cis-2-Cycloh e p t yl-4-[4-m e t h oxy-3-(4-p u r in -7-yl-b u t -
oxy)p h en yl]-4a ,5,8,8a -t et r a h yd r o-2H -p h t h a la zin -1-on e
(16j) was synthesized from bromide 16.1h (1.00 g, 1.99 mmol)
and purine (0.27 g, 2.2 mmol) as described for 16.1d , purified
by flash column chromatography using ethyl acetate/methanol
3:1, and crystallized from methanol at -20 °C: yield 0.43 g
(40%); mp 110-111 °C; 1H NMR (CDCl3) δ 1.38-2.34 (m, 19H,
cis-2-Cycloh ep tyl-4-(4-m eth oxy-3-{4-[4-(2H-tetr a zol-5-
yl)-p h en oxy]b u t oxy}p h en yl)-4a ,5,8,8a -t et r a h yd r o-2H -
p h th a la zin -1-on e (16n ). A mixture of benzonitrile 16l (1.50
g, 2.77 mmol), NaN3 (1.81 g, 27.8 mmol), and NH4Cl (1.50 g,
28.0 mmol) in DMF (50 mL) was heated for 10 h at 120 °C.
The reaction mixture was cooled to room temperature and
concentrated, and the residue was dissolved in ethyl acetate
and washed with 1 N HCl. The organic layer was dried over
MgSO4 and concentrated in vacuo, and the remaining oil was
purified by flash column chromatography using ethyl acetate/
petroleum ether (60-80)/acetic acid 2:2:0.2. The title compound
was crystallized from ethyl acetate: yield 0.97 g (60%); mp
3
CH2-cycloheptyl, CH2-Bu, H5, H8), 2.73 (t, 1H, J ) 5.6 Hz,
H8a), 2.92-3.11 (m, 1H, H8′), 3.20-3.39 (m, 1H, H4a), 3.92
3
3
(s, 3H, OCH3), 4.16 (t, 2H, J ) 5.7 Hz, NCH2), 4.50 (t, 2H, J
) 6.9 Hz, OCH2), 4.72-4.92 (m, 1H, NCH), 5.60-5.88 (m, 2H,
HCdCH), 6.90 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.30 (dd, 1H, 4J
) 1.9 Hz, 3J ) 8.5 Hz, H6-arom), 7.49 (d, 1H, 4J ) 1.9 Hz,
H2-arom), 8.35 (s, 1H, H-purine), 8.99 (s, 1H, H-purine), 9.16
(s, 1H, H-purine). Anal. Calcd (C31H38N6O3): C, H, N.
1
153-155 °C; H NMR (DMSO-d6) δ 1.32-2.34 (m, 19H, CH2-
cycloheptyl, H5, H8, CH2-Bu), 2.71-2.87 (m, 1H, H8a), 2.91-
3.13 (m, 1H, H8′), 3.21-3.41 (m, 1H, H4a), 3.90 (s, 3H, OCH3),
4.04-4.29 (m, 4H, OCH2), 4.75-4.94 (m, 1H, NCH), 5.54-5.83
(m, 2H, HCdCH), 6.89 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.00 (d,
(5-Br om op en tyl)ben zen e (16.1k ). A solution of 5-phenyl-
pentan-1-ol (2.00 g, 12.2 mmol) and PBr3 (3.31 g, 12.2 mmol)
in diethyl ether (150 mL) was refluxed for 6 h. The reaction
was quenched with water, and the mixture was diluted with
ethyl acetate and washed with saturated NaHCO3. The organic
layer was dried over MgSO4 and concentrated in vacuo to yield
3
4
3
2H, J ) 8.8 Hz, H-arom), 7.29 (dd, 1H, J ) 1.9 Hz, J ) 8.5
Hz, H6-arom), 7.53 (d, 1H, 4J ) 1.9 Hz, H2-arom), 8.10 (d,
2H, 3J ) 8.7 Hz, H-arom). Anal. Calcd (C33H40N6O4): C, H, N.
cis-2-Cycloh eptyl-4-{3-[4-(4-im ida zol-1-yl-ph en oxy)bu t-
oxy]-4-methoxyphenyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-
1-on e h yd r och lor id e (16o) was synthesized from bromide
16.1h (1.00 g, 1.99 mmol) and 4-(imidazol-1-yl)phenol (0.35 g,
2.19 mmol) as described for 16.1d , purified by flash column
chromatography using ethyl acetate, and crystallized from
ethyl acetate/dichloromethane/HCl as the hydrochloride: yield
1
the desired bromide as an oil: yield 1.11 g (40%); H NMR-
(CDCl3) δ 1.28-1.92 (m, 6H, CH2), 2.56 (t, 2H, 3J ) 7.8 Hz,
CH2-Ph), 3.33 (t, 2H, 3J ) 6.8 Hz, CH2-Br), 7.00-7.28 (m,
5H arom).
cis-2-Cycloh ep tyl-4-[4-m eth oxy-3-(5-p h en ylp en tyloxy)-
p h en yl]-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e (16k ).
A mixture of bromide 16.1k (0.50 g, 2.2 mmol), 15 (0.82 g, 2.2
mmol), and K2CO3 (0.31 g, 2.2 mmol) in NMP (100 mL) was
heated at 60 °C for 5 h. Subsequently, the mixture was diluted
with diethyl ether and washed with water. The organic phase
was dried over MgSO4 and concentrated in vacuo, and the
remainder was purified by flash column chromatography using
petroleum ether (60-80)/ethyl acetate 4:1. The title compound
was crystallized as a white solid from diethyl ether at -20
°C: yield 0.80 g (72%); mp 59-60 °C; 1H NMR (CDCl3) δ 1.36-
2.33 (m, 21H, 6 × CH2-cycloheptyl, H5, H8, 6 × H-hexyl),
2.64-2.79 (m, 3H, H8a, CH2-Ph), 2.89-3.11 (m, 1H, H8′),
1
0.49 g (40%); mp 146-149 °C; H NMR (CDCl3) δ 1.35-2.30
(m, 19H, CH2-cycloheptyl, CH2-Bu, H5, H8), 2.68-2.80 (m,
1H, H8a), 2.91-3.11 (m, 1H, H8′), 3.22-3.39 (m, 1H, H4a),
3.91 (s, 3H, OCH3), 4.06-4.29 (m, 4H, OCH2), 4.73-4.93 (m,
3
1H, NCH), 5.60-5.88 (m, 2H, HCdCH), 6.89 (d, 1H, J ) 8.4
3
Hz, H5-arom), 7.08 (d, 2H, J ) 8.9 Hz, H-Ph), 7.29 (dd, 1H,
4J ) 1.9 Hz, 3J ) 8.4 Hz, H6-arom), 7.44 (d, 2H, 4J ) 13.2 Hz,
HCdCHsimidazole), 7.50-7.63 (m, 3H, H2-arom, H-Ph), 9.29
(s, 1H, H-imidazole). Anal. Calcd (C35H42N4O4‚HCl): C, H, N.
cis-4-[3-(6-Br om oh exyloxy)-4-m eth oxyp h en yl]-2-cyclo-
h ep tyl-4a ,5,8,8a -tetr a h yd r o-2H-p h th a la zin -1-on e (16.1p )
was prepared in a similar way as described for bromide 16.1h
except using 1,6-dibromohexane (8.47 g, 34.7 mmol). The
remaining oil was purified by flash column chromatography
using petroleum ether (60-80)/ethyl acetate 4:1. The title
compound was obtained as a white solid by crystallization from
petroleum ether (60-80)/ethyl acetate: yield 4.61 g (80%); mp
104-105 °C; 1H NMR (CDCl3) δ 1.49-2.30 (m, 23H, CH2-
cycloheptyl, CH2-hexyl, H5, H8), 2.66-2.79 (m, 1H, H8a),
2.91-3.10 (m, 1H, H8′), 3.20-3.38 (m, 1H, H4a), 3.52 (t, 2H,
3
3.18-3.37 (m, 1H, H4a), 3.88 (s, 3H, OCH3), 4.06 (t, 2H, J )
6.8 Hz, OCH2), 4.71-4.93 (m, 1H, NCH), 5.59-5.84 (m, 2H,
3
HCdCH), 6.85 (d, 1H, J ) 8.4 Hz, H5-arom), 7.05-7.40 (m,
6H, H6-arom, H-Ph), 7.49 (d, 1H, 4J ) 1.9 Hz, H2-arom). Anal.
Calcd (C33H42N2O3): C, H, N.
cis-4-{4-[5-(3-Cycloh e p t yl-4-oxo-3,4,4a ,5,8,8a -h e xa -
h ydr oph th alazin -1-yl)-2-m eth oxyph en oxy]bu toxy}ben zo-
n itr ile (16l) was synthesized from bromide 16.1h (2.00 g, 3.97
mmol) and 4-hydroxybenzonitrile (0.53 g, 4.4 mmol) as de-
scribed for 16.1d . After workup, compound 16l was crystallized
from methanol as a white solid: yield 2.13 g (99%); mp 131-
133 °C; 1H NMR (DMSO-d6) δ 1.40-2.32 (m, 19H, CH2-
cycloheptyl, H5, H8, CH2-Bu), 2.67-2.82 (m, 1H, H8a), 2.90-
3.10 (m, 1H, H8′), 3.20-3.39 (m, 1H, H4a), 3.89 (s, 3H, OCH3),
4.05-4.29 (m, 4H, OCH2), 4.73-4.93 (m, 1H, NCH), 5.60-5.88
(m, 2H, HCdCH), 6.83-7.02 (m, 3H, H5-arom, H-benzonitrile),
3
3J ) 6.3 Hz, BrCH2), 3.91 (s, 3H, OCH3), 4.13 (t, 2H, J ) 5.9
Hz, OCH2), 4.75-4.93 (m, 1H, NCH), 5.60-5.89 (m, 2H, HCd
CH), 6.88 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.28 (dd, 1H, 4J )
3
4
2.0 Hz, J ) 8.5 Hz, H6-arom), 7.50 (d, 1H, J ) 2.0 Hz, H2-
arom).
cis-2-Cycloh e p t yl-4-[4-m e t h oxy-3-(6-p h e n oxyh e xyl-
oxy)phenyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (16p).
Compound 16p was prepared in a similar way as described
for 16.1d except using bromide 16.1p (1.00 g, 1.88 mmol) and
phenol (0.20 g, 2.1 mmol) and heating for 12 h. After workup,
the product was crystallized from 2-propanol at -20 °C: yield
0.36 g (35%); mp 77-78 °C; 1H NMR (CDCl3) δ 1.40-2.33 (m,
23H, CH2-cycloheptyl, CH2-hexyl, H5, H8), 2.67-2.80 (m, 1H,
H8a), 2.91-3.10 (m, 1H, H8′), 3.20-3.39 (m, 1H, H4a), 3.90
4
3
7.28 (dd, 1H, J ) 2.0 Hz, J ) 8.4 Hz, H6-arom), 7.48-7.68
(m, 3H, H2-arom, H-benzonitrile). Anal. Calcd (C33H39N3O4):
C, H, N.
cis-4-{4-[5-(3-Cycloh e p t yl-4-oxo-3,4,4a ,5,8,8a -h e xa -
h ydr oph th alazin -1-yl)-2-m eth oxyph en oxy]bu toxy}ben zoic
a cid (16m ). The ethyl ester of compound 16m was prepared
as described for 16.1d using bromide 16.1h (1.00 g, 1.99 mmol),
ethyl 4-hydroxybenzoate (0.36 g, 2.2 mmol), and K2CO3 (0.50
g, 3.6 mmol) and heating for 5 h. Hydrolysis of the ethyl ester
was performed analogously to the preparation of 16d . The title
compound was obtained as a white solid by crystallization from
3
3
(s, 3H, OCH3), 3.97 (t, 1H, J ) 6.4 Hz, OCH2), 4.11 (t, 1H, J
) 6.7 Hz, OCH2), 4.74-4.93 (m, 1H, NCH), 5.59-5.89 (m, 2H,
HCdCH), 6.78-7.00 (m, 4H, H5-arom, H-Ph), 7.17-7.33 (m,
3H, H6-arom, H-Ph), 7.51 (d, 1H, 4J ) 1.8 Hz, H2-arom). Anal.
Calcd (C34H44N2O4): C, H, N.
1
diethyl ether: yield 0.78 g (70%); mp 142-143 °C; H NMR

2534 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Van der Mey et al.
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cis-4-{6-[5-(3-Cycloh e p t yl-4-oxo-3,4,4a ,5,8,8a -h e xa -
hydrophthalazin-1-yl)-2-methoxyphenoxy]hexyloxy}benzoic
a cid (16q) was synthesized analogously to the preparation of
16m except using bromide 16.1p (1.00 g, 1.88 mmol). The title
compound was crystallized from diethyl ether: yield 0.39 g
(35%). mp 141-142 °C; 1H NMR (CDCl3) δ 1.40-2.35 (m, 23H,
CH2-cycloheptyl, CH2-hexyl, H5, H8), 2.66-2.80 (m, 1H, H8a),
2.90-3.13 (m, 1H, H8′), 3.20-3.39 (m, 1H, H4a), 3.90 (s, 3H,
OCH3), 3.97-4.22 (m, 4H, OCH2), 4.73-4.95 (m, 1H, NCH),
5.60-5.89 (m, 2H, HCdCH), 6.80-7.01 (m, 3H, H5-arom, H3-
Ph, H5-Ph), 7.27 (dd, 1H, 4J ) 1.9 Hz, 3J ) 8.4 Hz, H6-arom),
7.52 (d, 1H, 4J ) 1.9 Hz, H2-arom), 8.05 (m, 2H, H2-Ph, H6-
Ph). Anal. Calcd (C35H44N2O6): C, H, N.
cis-4-{6-[5-(3-Cycloh e p t yl-4-oxo-3,4,4a ,5,8,8a -h e xa -
h ydr oph th alazin -1-yl)-2-m eth oxyph en oxy]h exyloxy}ben z-
a m id e (16r ) was synthesized analogously to the preparation
of 16.1d except using bromide 16.1p (1.00 g, 1.88 mmol) and
4-hydroxybenzamide (0.29 g, 2.1 mmol). The title compound
was crystallized from ethyl acetate/petroleum ether (60-80):
yield 0.44 g (40%); mp 124-125 °C; 1H NMR (DMSO-d6) δ
1.31-2.31 (m, 23H, CH2-cycloheptyl, CH2-hexyl, H5, H8),
2.67-2.78 (m, 1H, H8a), 2.91-3.10 (m, 1H, H8′), 3.20-3.38
(m, 1H, H4a), 3.90 (s, 3H, OCH3), 4.02 (t, 2H, 3J ) 6.4 Hz,
OCH2), 4.11 (t, 2H, 3J ) 6.6 Hz, OCH2), 4.73-4.93 (m, 1H,
NCH), 5.59-5.89 (6.11) (m, 2/4H, NH2, HCdCH), 6.81-6.98
4
3
(m, 3H, H6-arom, H-Ph), 7.26 (dd, 1H, J ) 1.9 Hz, J ) 8.5
Hz, H6-arom), 7.52 (d, 1H, 4J ) 1.9 Hz, H2-arom), 7.77 (d,
2H, J ) 8.8 Hz, H-Ph). Anal. Calcd (C35H45N3O5): C, H, N.
3
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