Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: A novel series of potent dual PDE3/PDE4 inhibitory agents

Article abstract of DOI:10.1021/jm030776l

In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,-8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4 inhibitory activity (pIC₅₀ = 7.0-8.7), whereas the pIC₅₀ values for inhibition of PDE3 vary from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is displayed by phthalazinones 43 and 44 showing, at a dose of 30μmol/kg po, 46% inhibition of arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral dosing.

Full text of DOI:10.1021/jm030776l

2008
J . Med. Chem. 2003, 46, 2008-2016
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of
cis-Tetr a h yd r op h th a la zin on e/P yr id a zin on e Hybr id s: A Novel Ser ies of P oten t
Du a l P DE3/P DE4 In h ibitor y Agen ts
Margaretha Van der Mey,*,†,§ Kirsten M. Bommele´,§ Hildegard Boss,‡ Armin Hatzelmann,‡
Mike Van Slingerland,§ Geert J . Sterk,§ 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 J anuary 13, 2003
In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new
series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities
are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,-
8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-
3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized
compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4
inhibitory activity (pIC50 ) 7.0-8.7), whereas the pIC50 values for inhibition of PDE3 vary
from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit
the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is
displayed by phthalazinones 43 and 44 showing, at a dose of 30 µmol/kg po, 46% inhibition of
arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro
PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral
dosing.
In tr od u ction
the bronchodilatory and antiinflammatory activities in
a dual PDE3/PDE4 inhibitor has the potential to provide
a drug that is markedly more effective in the treatment
of bronchial asthma.
Dual cGMP-inhibited phosphodiesterase (PDE3) and
cAMP-specific phosphodiesterase (PDE4) inhibitors are
being pursued as drug therapy for bronchial asthma.
Interest in these compounds stems from the potential
of elevating cAMP levels in the airway smooth muscle
and inflammatory cells involved in asthmatic response,
thereby achieving both relaxation and antiinflammatory
activity.
PDE3 and PDE4 are involved in the regulation of
airway smooth muscle tone. Consistent with the pres-
ence of large amounts of PDE3 and PDE4, studies with
human isolated bronchi have demonstrated that selec-
tive inhibitors of either isoenzyme partially reverse
spontaneous tone and elicit bronchorelaxation.1,2 PDE3
inhibitors are somewhat more potent.2 Interestingly,
either a combination of PDE3 and PDE4 inhibitors or
dual PDE3/PDE4 inhibitors produce a much larger
bronchorelaxant effect than individual isoenzyme-selec-
tive agents alone.3,4 The PDE3 and PDE4 isoenzymes
apparently act in a synergistic manner in human airway
smooth muscle. In addition, PDE4 is the prominent
isoenzyme present in the inflammatory cells, thought
to be important in asthma.5,6 Inhibitors of PDE4 are
effective in attenuating inflammatory activity.7,8
Since no selective clinical agent significantly produces
both PDE3/PDE4 pharmacological effects, combining
By far the most thoroughly studied group of PDE3
inhibitors is the 2H-pyridazin-3-ones. These agents are
especially used for the treatment of congestive heart
failure.9-13 The structures of three of these selective
PDE3 inhibitors LY264233,14 LY197055,14 and tetra-
hydrobenzimidazole II15 are shown in Figure 1. There
are only two common features of the PDE3 inhibitors
synthesized thus far: an amide (-NHCO-) functional-
ity and a near-planar topography of the molecule.9,16-19
In addition, the introduction of a small lipophilic moiety
(the size of a methyl group) at the 5-position of the
pyridazinone ring as in LY197055 has been shown to
significantly increase the PDE3 inhibitory potency in
some compounds.17
Recently we reported the synthesis and structure-
activity relationships for a novel series of hexa- and
4a,5,8,8a-tetrahydrophthalazinones as PDE4 inhibitors
(e.g., phthalazinone I, Figure 1).20-26 Numerous cis-4-
arylphthalazinones with a large variation in substitu-
ents at N2 were found to exhibit high PDE4 inhibitory
activity.25,26 Moreover, the unsaturated fused hydrocar-
bon ring of the 4a,5,8,8a-tetrahydrophthalazinones was
shown to be essential for potent in vivo antiinflamma-
tory activities in a mouse ear edema assay.24
* To whom correspondence should be addressed. Phone: +31 20
4449720. Fax: +31 20 4449121. E-mail: mmeij@rnc.vu.nl. Current
address: Vrije Universiteit, Radionuclidencentrum, De Boelelaan
1085c, 1081 HV Amsterdam, The Netherlands.
† Vrije Universiteit.
To develop mixed PDE3/PDE4 inhibitors, we com-
bined structural features of the well-known pyridazi-
none-type selective PDE3 inhibitors such as LY264233,14
LY197055,14 and tetrahydrobenzimidazole II15 with
those of tetrahydrophthalazinone I,26 a potent PDE4
§ Byk Nederland.
‡ Byk Gulden.
10.1021/jm030776l CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/12/2003

Phthalazinone/ Pyridazinone Hybrids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2009
F igu r e 1. Development of target compounds by combination of structural elements of PDE4 inhibitor phthalazinone I26 with
PDE3 blockers LY264233,14 LY197055,14 and tetrahydrobenzimidazole II.15
inhibitor, leading to target compounds with a general
structure as shown in Figure 1.27,28 In agreement with
the SAR for both the pyridazinones and phthalazinones,
the aromatic ring of the phenylpyridazinone subunit
was coupled to N2. Each of these phthalazinone/
pyridazinone hybrids possesses an overall flat topogra-
phy and an amide (-NHCO-) functionality required for
potent PDE3 inhibition9,16-19 as well as a catechol ether
moiety common to many PDE4 inhibitors.29 The present
paper describes the synthesis and in vitro and in vivo
pharmacological evaluation of these new compounds.
The synthesis of γ-keto acids 5-8 has already been
described in previous articles.20,25,26 Aniline 1 was
prepared from 6-(4-nitrophenyl)-2H-pyridazin-3-one,32
which was obtained according to literature procedures
by reduction of the nitro group with Fe in a mixture of
butanol, water, and HCl. The synthesis of aniline 2 has
also been described in the literature.30
Scheme 2 shows the general synthetic procedure for
analogues 37-41 containing an amide linker. Phthala-
zinone 926 was treated with sodium hydride and ethyl
bromoacetate to afford ester 10, which was hydrolyzed
without further purification in a mixture of 2 N KOH,
THF, and MeOH, yielding the acetic acid derivative 11.
The pentanoic acid 12 was prepared from phthalazinone
9 by alkylation with 5-bromovaleric acid using 2 equiv
of sodium hydride. Carboxylic acids 11 and 12 were
converted into the corresponding acid chlorides with
phosphorus pentachloride and subsequently coupled
with selected aniline 1, 2, or 20 (20 is only coupled with
11) to give hybrids 37-41.
The synthesis of aniline 20 is illustrated in Scheme
3. Bromination of 1-(3-nitrophenyl)propan-1-one33 in
acetic acid using bromine yielded R-bromopropan-1-one
13. This bromide was reacted with diethyl sodio-
malonate to afford ethyl ester 15, which was hydrolyzed
and decarboxylated by treatment with 6 N HCl under
reflux. Condensation of γ-keto acid 17 with hydrazine
in ethanol gave 4-(3-nitrophenyl)pyridazinone 19. Re-
duction of the nitro group of compound 19 with Fe in a
mixture of ethanol, water, and HCl provided pyridazi-
none 20.
The 4-(4-methoxyphenyl)pyridazinone 21 (Scheme 3)
was obtained in good yield following the same route as
described above for the preparation of pyridazinone 20.
Pyridazinone 21 was converted into phenol 22 by
treatment with aluminum chloride in dichloromethane.
Ch em istr y
Optimization of the target compounds (Figure 1)
involves variation of the 4-aryl substituent of the
phthalazinone subunit, modification of the molecular
nature and position of linker X, and changes in the
pyridazinone subunit. The structures of the target
compounds are listed in Table 1. The N-phenyl-
substituted phthalazinones 28,26 31, 33, and 35 were
used for pharmacological comparison.
Hybrids 29, 30, 32, 34, and 36 were synthesized as
depicted in Scheme 1. In this approach, 6-(4-amino-
phenyl)-2H-pyridazin-3-one (1, R3 ) A) and 6-(4-ami-
nophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone30 (2,
R3 ) B) were converted into the corresponding aryl-
hydrazines 3 and 4 by treatment with nitrous acid,
which was generated in situ from sodium nitrite, and
by subsequent reduction of the resulting aryldiazonium
ions with tin(II) chloride according to literature proce-
dures.31 Condensation of arylhydrazine 3 with 6-(3,4-
dimethoxybenzoyl)cyclohex-3-enecarboxylic acid (5) in
pyridine at reflux temperature provided hybrid 29 in
good yield. Analogously, compounds 30, 32, 34, and 36
were prepared from arylhydrazine 4 and the corre-
sponding γ-keto acids (5-8).

2010 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Van der Mey et al.
Ta ble 1. Pyridazinones and Their in Vitro PDE3/PDE4 Inhibitory and in Vivo Antiinflammatory Activities
% inhibition of
AA-induced mouse
ear edema (n)b
PDE3
pIC50
PDE4
pIC50
a
a
compd
R1
R2
X
position
R3
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
Me
Me
Me
Me
Me
Et
OMe
OMe
OMe
OcC5H9
OcC5H9
OEt
OEt
Cl
Cl
OMe
OMe
OMe
OMe
OMe
OMe
OEt
H
A
B
H
B
H
B
H
B
A
B
B
A
B
B
B
B
<5.0
5.4
6.7
<5.0
6.3
<5.0
6.6
<5.0
7.1
5.9
6.7
5.8
6.1
7.0
7.1
6.7
7.5
7.9
8.1
8.4
7.8
7.8
7.7
8.1
7.1
7.0
8.1
8.4
8.4
8.2
8.2
8.7
8.6
7.8
6.8
7.0
13 (1)
8 (1)
4
4
34 (2)
NDc
4
4
18 (1)
NDc
Et
42 (2)
Me
Me
Me
Me
Me
Me
Me
Me
Et
NDc
4
4
4
3
4
4
4
4
4
35 (2)
31 (1)
13 (2)
NDc
27 (1)
26 (3)
32 (1)
46 (2)
47 (2)
22
CH2CONH
CH2CONH
CH2CONH
(CH2)4CONH
(CH2)4CONH
(CH2)4O
(CH2)4O
(CH2)4O
Me
Cl
zardaverine
ariflo
6.2
<5.0
33
a
pIC50 ) -log IC50. Inhibition of PDE3 was investigated in homogenates from human platelets, and the activity against PDE4 was
determined in the cytosol of human neutrophils. The data are the mean of two independent determinations in triplicate. b Percent inhibition
of the formation of AA-induced mouse ear edema after pretreatment with the target compound (1 h before AA) at a drug concentration
of 30 µmol/kg po. c ND: not determined.
Sch em e 1a
a
Reagents: (i) (1) NaNO2, 2 N HCl, -2 to 0 °C, 30 min; (2) SnCl2, concentrated HCl, -2 to 0 °C, 1 h.
Sch em e 2a
a
Reagents: (i) (1) NaH, DMF, (2) Br(CH2)nCO2R; (ii) 2 N KOH, THF, MeOH; (iii) (1) PCl5, CH2Cl2, (2) aniline 1, 2, or 20, DMAP,
pyridine.
The synthesis of the hybrids containing an alkoxy
linker is shown in Scheme 4. Phthalazinones 25, 26, and
27 were prepared starting from phthalazinones 9, 23,
and 24,25 respectively, by successive treatment with
sodium hydride and the corresponding R,ω-dibromo-
alkane. Subsequently, alkylbromides 25-27 were used

Phthalazinone/ Pyridazinone Hybrids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2011
Sch em e 3a
a
Reagents: (i) Br2, AcOH; (ii) NaHC(CO2Et)2, DMF; (iii) 6 N HCl; (iv) H2NNH2, H2O/EtOH, reflux; (v) Fe, HCl, EtOH, H2O, reflux; (vi)
AlCl3, CH2Cl2.
Sch em e 4a
a
Reagents: (i) (1) NaH, DMF, (2) Br(CH2)nBr; (ii) phenol 22, K2CO3, KI, DMF, 60 °C.
to alkylate phenol 22 in the presence of base and a
catalytic amount of potassium iodide, yielding com-
pounds 42-44, respectively.
tion was also examined. Comparison of the individual
3,4-dimethoxyphenyl analogues 30, 38, 41, and 42, the
3,4-diethoxyphenyl derivatives 34 and 43, and the
3-chloro-4-mehoxyphenyl analogues 36 and 44 reveals
that the linker has no significant impact on PDE3 and
PDE4 inhibition.
P h a r m a cology
Table 1 summarizes the results of the pharmacologi-
cal screening of compounds 28-44. The in vitro PDE3
and PDE4 inhibitory activities and in vivo antiinflam-
matory properties using a mouse ear edema assay have
been determined as specified earlier.24,26 The dual
inhibitor zardaverine34 was tested for pharmacological
comparison.
Attachment of an acetamide linker to the meta
position instead of the para position of the pyrida-
zinonephenyl moiety results in a 10-fold reduction of
PDE3 inhibitory activity, while the ability to inhibit of
PDE4 remains unchanged (38 vs 39). Usually, the
pyridazinone-type PDE3 inhibitors contain an electron-
rich partial structure in the para position of the phenyl
ring.
Str u ctu r e-Activity Rela tion sh ip s for in Vitr o
En zym e In h ibition . Modification of the phenyl sub-
stituent for a phenylpyridazinone subunit (A or B, Table
1) connected via different linkers to N2 of the target
phthalazinones does not affect the PDE4 inhibitory
activity significantly, whereas PDE3 inhibition is strongly
influenced (compare 28 with 29 and 30, 31 with 32, 33
with 34, etc.). Inhibition of PDE3 is only observed for
compounds that contain a 5-methyl-4,5-dihydro-2H-
pyridazin-3-one (B) or 2H-pyridazin-3-one (A) moiety.
Replacement of the pyridazinone A subunit by B yields
a 6- to 20-fold increase in potency with respect to
inhibition of the PDE3 isoenzyme (37 vs 38; 29 vs 30).
This enhancement in activity is in agreement with the
known SAR of other pyridazinone-type PDE3 inhibi-
tors.9,17,18 The 5-methyl group is believed to fit into a
small lipophilic pocket located in the active site of the
PDE3 enzyme. Another explanation may be that a
better interaction of the aromatic ring with the active
site is achieved, since the methyl group disrupts the
coplanar arrangement of the aromatic and pyridazinone
rings.18,19
Subsequently, the role of the catechol moiety was
investigated. In general, 3-chloro-4-methoxyphenyl-
substituted derivatives are more potent PDE3 inhibitors
than the corresponding 3,4-dialkoxyphenyl analogues
(compare 36 with 30, 32, 34 and compare 44 with 42,
43). However, phthalazinones 36 and 44 are the least
potent PDE4 inhibitors of the present series. As was
discussed in a previous paper,25 the optimum structures
for inhibition of PDE4 contain a 3,4-dialkoxyphenyl
moiety.
In the present series, all compounds with a 5-methyl-
4,5-dihydro-2H-pyridazin-3-one (B) part at the para
position of the pyridazinonephenyl moiety are more
potent PDE3 and PDE4 inhibitors than zardaverine,
with pIC50 values of 6.3-7.5 and 7.0-8.7, respectively.
In Vivo An t iin fla m m a t or y Act ivit y a ft er Or a l
Ad m in istr a tion . Direct evidence for the potential
antiinflammatory activity of PDE4 inhibitors by inhibi-
tion of mediator release is derived from animal studies.
A much used model is the formation of arachidonic acid
(AA) induced ear edema in mice.24 In this in vivo assay,
The effect of the linker (X) connecting the phthalazi-
none and phenylpyridazinone subunits on PDE inhibi-

2012 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Van der Mey et al.
filtrate in vacuo, the title compound precipitated. The yellow
solids were collected by filtration and washed with diethyl
the suppression of the formation of arachidonic acid
(AA) induced mouse ear edema was measured after oral
administration of the drug. Two hours after oral ad-
ministration of the target compound and 1 h after
provocation and application of a solution of AA to the
mouse ear, the percentage of inhibition of edema forma-
tion was determined with respect to the provoked
nontreated control animals. The maximal possible in-
hibition of edema in this model is 80%.
Many of the final compounds prepared were tested
in this assay (Table 1). The 4-(3,4-diethoxyphenyl)-
phthalazinones 34 and 43 and 4-(3-chloro-4-meth-
oxyphenyl) derivative 44 exhibit the most effective
inhibitory activity in vivo with 42-47% inhibition of
mouse ear edema formation at a concentration of 30
µmol/kg po. Under the same conditions, the reference
compounds zardaverine and ariflo were less potent (22%
and 33% inhibition, respectively).
1
ether. Yield: 21.6 g (91%). Mp, 208 °C. H NMR (DMSO-d6):
3
δ 5.48 (bs, 2H, NH2), 6.60 (d, 2H, J ) 8.6 Hz, H-arom), 6.86
(d, 1H, 3J ) 9.9 Hz, HCdCH), 7.53 (d, 2H, 3J ) 8.6 Hz,
H-arom), 7.88 (d, 1H, 3J ) 9.9 Hz, HCdCH), 12.93 (bs, 1H,
NH).
6-(4-Hydr a zin oph en yl)-2H-p yr ida zin -3-on e Hyd r och lo-
r id e (3). Com p ou n d 3 was prepared analogously to the
synthesis of 6-(4-hydrazinophenyl)-4,5-dihydro-2H-pyridazin-
3-one hydrochloride31 from 6-(4-aminophenyl)pyridazinone 1
(11.2 g, 50.1 mmol). Yield: 9.51 g (80%). Mp, >200 °C. 1H NMR
(DMSO-d6): δ 6.96 (d, 1H, 3J ) 9.9 Hz, HCdCH), 7.05 (d, 2H,
3
3J ) 8.6 Hz, H-arom), 7.79 (d, 2H, J ) 8.6 Hz, H-arom), 8.00
(d, 1H, 3J ) 9.9 Hz, HCdCH), 10.41 (bs, 3H, NH3+), 13.10 (bs,
1H, NH).
6-(4-H yd r a zin op h en yl)-5-m et h yl-4,5-d ih yd r o-2H -p y-
r id a zin -3-on e Hyd r och lor id e (4). 6-(4-Aminophenyl)-4,5-
dihydro-5-methyl-3(2H)-pyridazinone30 (2) (10.2 g, 50.2 mmol)
was mixed with 2 N HCl (100 mL) and cooled to -2 to 0 °C.
Sodium nitrite (3.50 g, 50.1 mmol) was dissolved in water (10
mL). The solution was added dropwise while keeping the
temperature below 0 °C, and 30 min after the last addition,
tin(II) chloride dihydrate (28.0 g, 124 mmol) in concentrated
HCl (20.5 mL) was added at the same temperature. One hour
later, the solids that appeared in the reaction mixture were
filtered off and the product was extracted from the filtrate with
n-butanol. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. The crystals that were
formed upon stirring the oily remainder with dichloromethane
were filtered off to afford the title compound as an orange solid.
Single and multiple regression analyses were per-
formed to correlate the PDE3 and/or PDE4 inhibitory
activity with in vivo antiinflammatory activity; however,
no statistically significant correlations were found.
Con clu sion
Most of the investigated compounds show moderate
to high PDE3 inhibitory activity and are potent inhibi-
tors of PDE4 as well. The SAR determined for our
compounds regarding PDE inhibition is widely consis-
tent with that already observed for analogous pyridazi-
nones and phthalazinones. The in vivo data suggest that
several of these compounds are potent antiinflammatory
drugs (34, 43, and 44). No correlation was found
between the antiinflammatory activity after oral ad-
ministration and the PDE3 and/or PDE4 inhibitory
activity. Whether the combination of both PDE3 and
PDE4 inhibitory activity in one drug offers advantages
with respect to dosage, route of administration, and
pharmacokinetics over the single or combined applica-
tion of both PDE3 and PDE4 inhibitors remains to be
investigated.
1
Yield: 83%. Mp, 198 °C. H NMR (DMSO-d6): δ 1.05 (d, 3H,
2
3J ) 7.2 Hz, CH3), 2.22 (d, 1H, J ) 16.5 Hz, CHH′-pyr), 2.66
3
2
(dd, 1H, J ) 6.7 Hz, J ) 16.7 Hz, CHH′-pyr), 3.29-3.48 (m,
3
1H, CHCH3), 6.97 (d, 2H, J ) 8.6 Hz, H-arom), 7.72 (d, 2H,
3J ) 8.6 Hz, H-arom), 8.49 (bs, 1H, NH), 10.25 (bs, 3H, NH3+),
10.87 (s, 1H, NH).
cis-2-[4-(3,4-Dim eth oxyp h en yl)-1-oxo-4a ,5,8,8a -tetr a h y-
d r o-1H-p h th a la zin -2-yl]a cetic Acid (11). Sodium hydride
(60% dispersion in mineral oil, 0.92 g, 23 mmol) was added to
a suspension of cis-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahy-
dro-2H-phthalazin-1-one (9) (6.00 g, 21.0 mmol) in DMF (100
mL). After the reaction mixture was stirred for 1 h, ethyl
bromoacetate (3.84 g, 23.0 mmol) was added and the resulting
mixture was stirred for another 4 h. The reaction mixture was
poured into water, and the product was extracted with ethyl
acetate. The combined organic layers were washed with water
and brine and dried over MgSO4. Removal of the solvent in
vacuo yielded the crude ethyl ester 10, which was stirred for
3 h in a mixture of 2 N KOH (50 mL), THF (50 mL), and
methanol (50 mL). The reaction mixture was concentrated to
a volume of 50 mL, diluted with water, and acidified with
concentrated HCl. The product was extracted with ethyl
acetate, and the combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The title
compound was crystallized from diethyl ether. Yield: 5.02 g
(69%). Mp, 178-180 °C. 1H NMR (CDCl3): δ 2.08-2.50 (m,
3H, H5, H8), 2.83-3.10 (m, 2H, H8a, H8′), 3.30-3.50 (m, 1H,
H4a), 3.93 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.67 (AB, 2H,
Exp er im en ta l Section
DMF and pyridine were stored over 4 Å molecular sieves.
All the other solvents were used as received. Starting materials
were commercially available. Reactions were performed under
anhydrous conditions unless noted otherwise. Reactions were
followed by TLC analysis on Merck TLC aluminum sheets with
silica gel 60 F254. Flash column chromatography was per-
formed on silica gel, 30-60 µm (J . T. Baker). Melting points
were measured on an Electrothermal IA9200 and are uncor-
rected. 1H NMR spectra were recorded on a Bruker AC 200
(1H NMR, 200.1 MHz) spectrometer. The 1H NMR chemical
shifts (δ) are expressed in ppm values relative to CDCl3 (δ 7.26
ppm) or DMSO-d6 (δ 2.50 ppm). Abbreviations used in descrip-
tion of NMR spectra are the following: s ) singlet, d ) doublet,
t ) triplet, q ) quartet, dd ) double doublet, dt ) double
triplet, m ) multiplet, and bs ) broad singulet. All phthalazi-
nones had an elemental analysis (C, H and N) results within
(0.4% of the theoretical value.
6-(4-Am in op h en yl)-2H-p yr id a zin -3-on e Hyd r och lor id e
(1). 6-(4-Nitrophenyl)-2H-pyridazin-3-one32 (23.0 g, 106 mmol)
was dissolved in a mixture of butanol (1000 mL) and water
(250 mL) and heated to reflux temperature. Fe (80.0 g, 1.43
mol) and 2 N HCl (15 mL) were added sequentially, and the
reaction mixture was refluxed for 5 h. After the suspension
was cooled to room temperature, the solids were filtered off
and washed with hot ethanol. Upon concentration of the
3
NCH2), 5.63-5.88 (m, 2H, HCdCH), 6.87 (d, 1H, J ) 8.5 Hz,
4
3
H5-arom), 7.25 (dd, 1H, J ) 2.0 Hz, J ) 8.5 Hz, H6-arom),
4
7.44 (d, 1H, J ) 2.0 Hz, H2-arom).
cis-5-[4-(3,4-Dim et h oxyp h en yl)-1-oxo-4a ,5,8,8a -t et r a -
h yd r o-1H -p h t h a la zin -2-yl]p en t a n oic Acid (12). Com -
p ou n d 12 was prepared as described for acetic acid 11 using
5-bromopentanoic acid as the alkylating agent and 2.2 equiv
of NaH. The title compound was crystallized from diethyl
ether. Yield: 50%. Mp, 107-108 °C. 1H NMR (CDCl3/CD3-
OD): δ 1.59-1.90 (m, 4H, (CH2)2), 1.95-2.33 (m, 3H, H5, H8),
2.41 (t, 2H, 3J ) 6.9 Hz, CH2COOH), 2.72-2.86 (m, 1H, H8a),
2.90-3.10 (m, 1H, H8′), 3.24-3.43 (m, 1H, H4a), 3.70-4.10
(m, 8H, OCH3, NCH2), 5.60-5.88 (m, 2H, HCdCH), 6.87 (d,
1H, 3J ) 8.4 Hz, H5-arom), 7.25 (dd, 1H, 4J ) 2.0 Hz, 3J ) 8.4
4
Hz, H6-arom), 7.47 (d, 1H, J ) 2.0 Hz, H2-arom).

Phthalazinone/ Pyridazinone Hybrids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2013
2-Br om o-1-(4-m eth oxyp h en yl)p r op a n -1-on e (14). Bro-
mine (48.9 g, 0.31 mol) was added dropwise to a solution of
4-methoxypropiophenone (50.2 g, 0.31 mol) in acetic acid (500
mL). After the reaction mixture was decolorized, the solution
was concentrated in vacuo. The oily residue was dissolved in
ethyl acetate and washed with 2 N HCl and aqueous NaHCO3.
The organic layer was dried over MgSO4, filtered, and con-
centrated under reduced pressure. The remainder was dis-
solved in dichloromethane and filtered over silica. After
concentration of the filtrate, the title compound was obtained
as an oil. Yield: 73.3 g (99%). 1H NMR (CDCl3): δ 1.86 (d,
petroleum ether (60-80 °C) was added to the resulting solids,
which were collected by filtration. Yield: 22.1 g (89%). Mp,
62-64 °C. 1H NMR (CDCl3): δ 1.95 (d, 3H, 3J ) 6.6 Hz, CH3),
5.31 (q, 1H, 3J ) 6.6 Hz, CHBr), 7.73 (t, 1H, 3J ) 8.0 Hz,
H-arom), 8.31-8.40 (m, 1H, H-arom), 8.41-8.51 (m, 1H,
4
H-arom), 8.85 (t, 1H, J ) 1.9 Hz, H-arom).
5-Meth yl-6-(3-n itr op h en yl)-4,5-d ih yd r o-2H-p yr id a zin -
3-on e (19). Com p ou n d 19 was prepared in a similar way as
described for phthalazinone 21. 2-Bromo-1-(3-nitrophenyl)-
propan-1-one (13) (37.0 g, 143 mmol) was used as a starting
material for the synthesis of the title compound. Intermediates
have not been isolated. Condensation with hydrazine was
performed in ethanol. After the ethanol was removed in vacuo,
the title compound was crystallized from diethyl ether. The
overall yield was 14.6 g (44%). Mp, 193-195 °C. 1H NMR
3
3
3H, J ) 6.6 Hz, CH3), 3.84 (s, 3H, OCH3), 5.27 (q, 1H, J )
6.6 Hz, CHCH3), 6.88-7.00 (m, 2H, H-arom), 7.91-8.05 (m,
2H, H-arom).
E t h yl 2-E t h oxyca r b on yl-3-(4-m et h oxyb en zoyl)b u t a -
n oa te (16). Diethyl malonate (31.9 g, 199 mmol) was added
to a suspension of sodium hydride (60% dispersion in mineral
oil, 7.40 g, 185 mmol) in DMF (300 mL), keeping the temper-
ature below 30 °C. The reaction mixture was stirred overnight
at room temperature, R-bromoketone 14 (43.8 g, 180 mmol)
was added, and the reaction mixture was heated at 110 °C for
4 h. After cooling, the solution was concentrated in vacuo. The
residual oil was diluted with ethyl acetate and washed with
water. The organic layer was dried over MgSO4 and concen-
trated under reduced pressure to afford the title compound
as a yellow oil that was hydrolyzed without further purification
as described below. 1H NMR (CDCl3): δ 1.10-1.39 (m, 9H,
CH2CH3, CHCH3), 3.87 (s, 3H, OCH3), 3.93-4.38 (m, 6H,
COCHCO, CH2CH3, CHCH3), 6.89-7.02 (m, 2H, H-arom),
7.93-8.08 (m, 2H, H-arom).
3
(CDCl3/D2O): δ 1.30 (d, 3H, J ) 6.6 Hz, CH3), 2.53 (dd, 1H,
2
3
3J ) 2.5 Hz, J ) 17.0 Hz, CHH′-pyr), 2.79 (dd, 1H, J ) 6.7
Hz, 2J ) 17.0 Hz, CHH′-pyr), 3.32-3.52 (m, 1H, CHCH3), 7.62
(t, 1H, 3J ) 8.0 Hz, H-arom), 8.07-8.18 (m, 1H, H-arom), 8.20-
2
8.32 (m, 1H, H-arom), 8.60 (t, 1H, J ) 1.9 Hz, H-arom).
6-(3-Am in oph en yl)-5-m eth yl-4,5-dih ydr o-2H-pyr idazin -
3-on e (20). 4-Nitrophenyl analogue 19 (8.00 g, 34.3 mmol) was
dissolved in a mixture of ethanol (275 mL) and water (75 mL),
and the resulting mixture was heated to reflux temperature.
Fe (25.0 g, 0.45 mol) and 2 N HCl (5 mL) were added
successively, and the reaction mixture was refluxed for 2 h.
After the suspension was cooled to room temperature, the
solids were filtered off and washed with hot ethanol. The
filtrate was concentrated in vacuo, and the residual oil was
diluted with ethyl acetate and washed with 1 N HCl and
aqueous NaHCO3. The organic layer was dried over MgSO4
and concentrated under reduced pressure. The title compound
was crystallized from diethyl ether. Yield: 5.51 g (79%). Mp,
144-146 °C. 1H NMR (CDCl3): δ 1.24 (d, 3H, 3J ) 6.6 Hz,
CH3), 2.46 (dd, 1H, 3J ) 2.5 Hz, 2J ) 17.0 Hz, CHH′-pyr), 2.71
4-(4-Meth oxyp h en yl)-3-m eth yl-4-oxobu tyr ic Acid (18).
A mixture of malonic ester 16 (maximum of 180 mmol) and 6
N HCl (600 mL) was heated under reflux for 6 h. The solution
was concentrated in vacuo to a volume of 400 mL and extracted
with ethyl acetate. The combined organic extracts were dried
over MgSO4 and concentrated under reduced pressure. The
title compound was obtained as a yellow oil. Yield: 32.5 g
3
2
(dd, 1H, J ) 6.7 Hz, J ) 17.0 Hz, CHH′-pyr), 3.22-3.41 (m,
1H, CHCH3), 3.81 (bs, 2H, NH2), 6.69-6.80 (m, 1H, H-arom),
7.04-7.29 (m, 3H, H-arom), 8.93 (bs, 1H, NH).
1
3
(81%). H NMR (CDCl3): δ 1.22 (d, 3H, J ) 6 Hz, CH3), 2.47
3
2
3
(dd, 1H, J ) 4 Hz, J ) 16 Hz, CHH′-pyr), 2.98 (dd, 1H, J )
9 Hz, 2J ) 16 Hz, CHH′-pyr), 3.78-3.95 (m, 1H, CHCH3), 3.85
(s, 3H, OCH3), 6.95 (d, 2H, 3J ) 6 Hz, H-arom), 7.98 (d, 2H, 3J
) 6 Hz, H-arom).
cis-4-(3,4-Dieth oxyp h en yl)-4a ,5,8,8a -tetr a h yd r o-2H-p h -
th a la zin -1-on e (23). A mixture of 6-(3,4-diethoxybenzoyl)-
cyclohex-3-enecarboxylic acid (7) (10.0 g, 31.4 mmol) and
hydrazine monohydrate (3.20 g, 63.9 mmol) in ethanol (125
mL) was refluxed for 4 h. When the mixture cooled, the title
compound crystallized from the reaction mixture. Yield: 9.30
6-(4-M e t h o x y p h e n y l )-5 -m e t h y l -4,5-d i h y d r o -2H -
p yr id a zin -3-on e (21). A mixture of γ-keto acid 18 (33.8 g,
152 mmol) and hydrazine monohydrate (19.7 g, 394 mmol) in
water (200 mL) was refluxed for 10 h. After the mixture was
cooled to room temperature, the product was extracted with
ethyl acetate. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Subsequently the title
compound was crystallized from diethyl ether. Yield: 15.2 g
(46%). Mp, 190-192 °C. 1H NMR (CDCl3): δ 1.25 (d, 3H, 3J )
1
g (94%). Mp, 145-147 °C. H NMR (CDCl3): δ 1.39-1.58 (m,
6H, CH3), 2.10-2.37 (m, 3H, H5, H8), 2.77-2.90 (m, 1H, H8a),
2.90-3.10 (m, 1H, H8′), 3.29-3.49 (m, 1H, H4a), 4.02-4.27
(m, 4H, OCH2), 5.61-5.88 (m, 2H, HCdCH), 6.87 (d, 1H, 3J )
4
3
8.4 Hz, H5-arom), 7.22 (dd, 1H, J ) 2.1 Hz, J ) 8.4 Hz, H6-
4
arom), 7.44 (d, 1H, J ) 2.0 Hz, H2-arom), 8.58 (bs, 1H, NH).
cis-2-(4-Br om obu tyl)-4-(3,4-d im eth oxyp h en yl)-4a ,5,8,-
8a -tetr a h yd r o-2H-p h th a la zin -1-on e (25). Sodium hydride
(60% dispersion in oil, 1.54 g, 38.5 mmol) was added to a
solution of phthalazinone 9 (10.0 g, 34.9 mmol) in DMF (250
mL). After the mixture was stirred for 30 min, 1,4-dibromo-
butane (19.7 g, 91.2 mmol) was added. Another 30 min later,
the reaction mixture was poured into water and the product
was extracted with diethyl ether. The combined organic
extracts were dried over MgSO4 and concentrated in vacuo.
The remainder was purified by flash column chromatography
using dichloromethane. The title compound was crystallized
from petroleum ether (60-80 °C). Yield: 80%. Mp, 105-106
°C. 1H NMR (CDCl3): δ 1.78-2.32 (m, 7H, H5, H8, (CH2)2),
3
2
7.4 Hz, CH3), 2.46 (d, 1H, J ) 1.1 Hz, J ) 16.9 Hz, CHH′-
pyr), 2.72 (dd, 1H, 3J ) 6.7 Hz, 2J ) 16.9 Hz, CHH′-pyr), 3.25-
3.46 (m, 1H, CHCH3), 3.85 (s, 3H, OCH3), 6.88-7.00 (m, 2H,
H-arom), 7.65-7.78 (m, 2H, H-arom), 8.79 (bs, 1H, NH).
6-(4-H y d r o x y p h e n y l )-5-m e t h y l -4 ,5 -d i h y d r o -2H -
p yr id a zin -3-on e (22). Aluminum chloride (197 g, 1.48 mol)
was added to a solution of methoxyphenyl analogue 21 (15.2
g, 69.6 mmol) in dichloromethane (500 mL). The reaction
mixture was stirred overnight, the dichloromethane layer was
decanted, and the remainder was poured into ice/water and
extracted with THF. The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. Diethyl ether
was added to the crystalline residue, and the solids were
filtered off to yield the title compound as a white solid. Yield:
11.9 g (84%). Mp, 265-266 °C. 1H NMR (DMSO-d6): δ 1.05
(d, 3H, 3J ) 7.3 Hz, CH3), 2.19 (d, 1H, 2J ) 16.7 Hz, CHH′-
pyr), 2.64 (dd, 1H, 3J ) 6.7 Hz, 2J ) 16.7 Hz, CHH′-pyr), 3.22-
3
2.79 (t, 1H, J ) 5.7 Hz, H8a), 2.90-3.11 (m, 1H, H8′), 3.28-
3.55 (m, 3H, H4a, CH2Br), 3.75-4.10 (m, 5H, NCH2, OCH3),
5.62-5.89 (m, 2H, HCdCH), 6.88 (d, 1H, 3J ) 8.5 Hz, H5-
4
3
arom), 7.26 (dd, 1H, J ) 2.0 Hz, J ) 8.5 Hz, H6-arom), 7.48
4
(d, 1H, J ) 2.0 Hz, H2-arom).
3
3.48 (m, 1H, CHCH3), 6.80 (d, 2H, J ) 8.7 Hz, H-arom), 7.62
cis-2-(4-Br om obu tyl)-4-(3,4-d ieth oxyp 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 (26). Prepared as de-
scribed for bromide 25 from phthalazinone 23 (9.30 g, 29.6
mmol). The residue was purified by flash column chromatog-
raphy using ethyl acetate/petroleum ether (60-80 °C), 1:4. The
title compound was crystallized from methanol/water. Yield:
(d, 2H, 3J ) 8.7 Hz, H-arom), 9.83 (bs, 1H, NH), 10.79 (bs,
1H, OH).
2-Br om o-1-(3-n itr op h en yl)p r op a n -1-on e (13). Synthe-
sized as described for the preparation of bromide 14 from 1-(3-
nitrophenyl)propan-1-one33 (17.2 g, 96.0 mmol). After workup,

2014 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Van der Mey et al.
1
12.5 g (94%). Mp, 73-74 °C. H NMR (CDCl3): δ 1.48 (t, 3H,
yl-6-oxo-1,4,5,6-tetr a h yd r op yr id a zin -3-yl)p h en yl]-4a ,5,8,-
8a -tetr a h yd r o-2H-p h th a la zin -1-on e (32). Com p ou n d 32
was prepared according to the general procedure from γ-keto
acid 6 (1.38 g, 4.01 mmol) and arylhydrazine 4 (1.53 g, 6.01
mmol), and the mixture was refluxed for 6 h. The title
compound was crystallized from diethyl ether. Yield: 1.14 g
(68%). Mp, 121-128 °C. 1H NMR (CDCl3): δ 1.27 (d, 3H, 3J )
7.3 Hz, CH3), 1.49-2.08 (m, 8H, CH2-cyclopentyl), 2.12-2.40
3J ) 7.0 Hz, CH3), 1.49 (t, 3H, J ) 7.0 Hz, CH3), 1.77-2.33
3
3
(m, 7H, H5, H8, (CH2)2), 2.78 (t, 1H, J ) 5.8 Hz, H8a), 2.89-
3
3.11 (m, 1H, H8′), 3.22-3.41 (m, 1H, H4a), 3.47 (t, 2H, J )
6.2 Hz, CH2Br), 3.71-4.25 (m, 6H, NCH2, OCH2), 5.60-5.88
(m, 2H, HCdCH), 6.87 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.25
(dd, 1H, 4J ) 2.1 Hz, 3J ) 8.5 Hz, H6-arom), 7.46 (d, 1H, J )
4
2.0 Hz, H2-arom).
2
(m, 3H, H5, H8), 2.49 (d, 1H, J ) 16.9 Hz, CHH′-pyr), 2.74
cis-2-(4-Br om ob u t yl)-4-(3-ch lor o-4-m et h oxyp h en yl)-
4a,5,8,8a-tetr ah ydr o-2H-ph th alazin -1-on e (27). Com pou n d
27 was prepared as described for bromide 25 from 4-(3-chloro-
4-methoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (24)
(20.0 g, 68.8 mmol). Purification by flash column chromatog-
raphy using dichloromethane yielded the title compound as a
3
2
(dd, 1H, J ) 6.7 Hz, J ) 16.9 Hz, CHH′-pyr), 2.98-3.19 (m,
2H, H8a, H8′), 3.28-3.57 (m, 2H, H4a, CHCH3), 3.90 (s, 3H,
OCH3), 4.78-4.92 (m, 1H, OCH), 5.67-5.92 (m, 2H, HCdCH),
3
3
6.89 (d, 1H, J ) 8.5 Hz, H5-arom), 7.33 (dd, 1H, J ) 8.5 Hz,
4J ) 2.1 Hz, H6-arom), 7.53 (d, 1H, 4J ) 2.0 Hz, H2-arom),
7.67-7.87 (m, 4H, H-arom-pyr), 8.62 (bs, 1H, NH). Anal.
(C31H34N4O4) C, H, N.
1
colorless oil. Yield: 17.1 g (58%). H NMR (CDCl3): δ 1.74-
2.32 (m, 7H, H5, H8, (CH2)2), 2.71-2.85 (m, 1H, H8a), 2.88-
3.10 (m, 1H, H8′), 3.21-3.40 (m, 1H, H4a), 3.40-3.52 (m, 2H,
CH2Br), 3.71-4.09 (m, 5H, NCH2, OCH3), 5.59-5.87 (m, 2H,
HCdCH), 6.96 (d, 1H, 3J ) 8.7 Hz, H5-arom), 7.65 (dd, 1H, 4J
) 2.2 Hz, 3J ) 8.7 Hz, H6-arom), 7.86 (d, 1H, 4J ) 2.2 Hz,
H2-arom).
cis-4-(3,4-Diet h oxyp h en yl)-2-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 (33). Com p ou n d 33 was pre-
pared from γ-keto acid 7 (2.01 g, 6.32 mmol) and phenylhy-
drazine as described before. The title compound was purified
by flash column chromatography using ethyl acetate/petroleum
ether (60-80 °C), 1:3, and was subsequently crystallized from
methanol. Yield: 0.86 g (35%). Mp, 107-108 °C. 1H NMR
(CDCl3): δ 1.38-1.58 (m, 6H, CH3), 2.12-2.42 (m, 3H, H5,
H8), 2.94-3.18 (m, 2H, H8a, H8′), 3.34-3.51 (m, 1H, H4a),
4.02-4.22 (m, 4H, OCH2), 5.63-5.90 (m, 2H, HCdCH), 6.88
(d, 1H, 3J ) 8.4 Hz, H5-arom), 7.19-7.65 (m, 7H, H-arom).
Anal. (C24H26N2O3) C, H, N.
Gen er a l P r oced u r e for th e Con d en sa tion of γ-Keto
Acid s w ith Ar ylh yd r a zin es. A mixture of γ-keto acid (4.0
mmol) and arylhydrazine hydrochloride 3 or 4 (6.0 mmol) in
pyridine (50 mL) was refluxed for several hours until TLC
analysis showed completion of the reaction. The reaction
mixture was concentrated in vacuo, and the remainder was
dissolved in ethyl acetate and washed with 1 N HCl, aqueous
NaHCO3, and water. The organic layer was dried over MgSO4
and concentrated under reduced pressure. The isolation of the
individual products is described below.
cis-4-(3,4-Dim et h oxyp h en yl)-2-[4-(6-oxo-1,6-d ih yd r o-
pyridazin-3-yl)phenyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-
1-on e (29). Com p ou n d 29 was prepared according to the
general procedure from 6-(3,4-dimethoxybenzoyl)cyclohex-3-
enecarboxylic acid (5) (1.16 g, 4.00 mmol) and arylhydrazine
3 (1.43 g, 5.99 mmol), and the mixture was refluxed for 5 h.
The title compound was crystallized from methanol. Yield:
cis-4-(3,4-Dieth oxyp h en yl)-2-[4-(4-m eth yl-6-oxo-1,4,5,6-
tetr a h yd r op yr id a zin -3-yl)p h en yl]-4a ,5,8,8a -tetr a h yd r o-
2H-p h th a la zin -1-on e (34). Com p ou n d 34 was prepared
according to the general procedure from γ-keto acid 7 (1.27 g,
3.99 mmol) and arylhydrazine 4 (1.53 g, 6.01 mmol), and the
mixture was refluxed for 7 h. The title compound was purified
by flash column chromatography using ethyl acetate/petroleum
ether (60-80 °C), 1:1, and was subsequently crystallized from
1
diethyl ether. Yield: 1.38 g (70%). Mp, 164-165 °C. H NMR
3
(CDCl3): δ 1.27 (d, 3H, J ) 7.4 Hz, CH3), 1.41-1.59 (m, 6H,
1
2
1.68 g (71%). Mp, 279 °C. H NMR (DMSO-d6): δ 1.93-2.41
CH2CH3), 2.12-2.41 (m, 3H, H5, H8), 2.48 (d, 1H, J ) 16.9
(m, 3H, H5, H8), 2.71-2.92 (m, 1H, H8′), 3.10-3.24 (m, 1H,
H8a), 3.55-3.72 (m, 1H, H4a), 3.80 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 5.61-5.86 (m, 2H, HCdCH-phth), 6.95-7.12 (m, 2H,
H5-arom, HCdCH-pyr), 7.46-7.56 (m, 2H, H6-arom, H2-
Hz, CHH′-pyr), 2.74 (dd, 1H, 3J ) 6.7 Hz, 2J ) 16.9 Hz, CHH′-
pyr), 2.98-3.19 (m, 2H, H8a, H8′), 3.31-3.59 (m, 2H, H4a,
CHCH3), 4.07-4.25 (m, 4H, OCH2), 5.66-5.91 (m, 2H, HCd
CH), 6.90 (d, 1H, 3J ) 8.4 Hz, H5-arom), 7.33 (dd, 1H, 3J )
3
3
4
4
arom), 7.66 (d, 2H, J ) 8.6 Hz, H-arom-pyr), 7.92 (d, 2H, J
) 8.6 Hz, H-arom-pyr), 8.07 (d, 1H, 3J ) 9.9 Hz, HCdCH-
pyr), 13.23 (bs, 1H, NH). Anal. (C26H24N4O4) C, H, N.
8.4 Hz, J ) 1.9 Hz, H6-arom), 7.52 (d, 1H, J ) 1.9 Hz, H2-
arom), 7.66-7.88 (m, 4H, H-arom-pyr), 8.51 (bs, 1H, NH).
Anal. (C29H32N4O4) C, H, N.
cis-4-(3,4-Dim eth oxyph en yl)-2-[4-(4-m eth yl-6-oxo-1,4,5,6-
tetr a h yd r op yr id a zin -3-yl)p h en yl]-4a ,5,8,8a -tetr a h yd r o-
2H-p h th a la zin -1-on e (30). Com p ou n d 30 was prepared
according to the general procedure from γ-keto acid 5 (1.16 g,
4.00 mmol) and arylhydrazine 4 (1.53 g, 6.01 mmol), and the
mixture was refluxed for 5 h. The title compound was crystal-
lized from methanol. Yield: 1.41 g (65%). Mp, 192-194 °C.
1H NMR (CDCl3): δ 1.24 (d, 3H, 3J ) 7.3 Hz, CH3), 2.13-2.41
cis-4-(3-Ch lor o-4-m et h oxyp h en yl)-2-p h en yl-4a ,5,8,8a -
tetr a h yd r o-2H-p h th a la zin -1-on e (35). Com p ou n d 35 was
prepared from 6-(3-chloro-4-methoxybenzoyl)cyclohex-3-ene-
carboxylic acid (8) (1.89 g, 6.43 mmol) and phenylhydrazine
as described before. The reaction mixture was concentrated
in vacuo, and the residue was dissolved in dichloromethane
and filtered over silica. After evaporation of the solvent under
reduced pressure, the title compound was crystallized from
diethyl ether and recrystallized from ethanol. Yield: 2.00 g
(85%). Mp, 151-152 °C. 1H NMR (CDCl3): δ 2.12-2.40 (m,
3H, H5, H8), 2.95-3.17 (m, 2H, H8a, H8′), 3.32-3.50 (m, 1H,
H4a), 3.94 (s, 3H, OCH3), 5.65-5.91 (m, 2H, HCdCH), 6.95
(d, 1H, 3J ) 8.7 Hz, H5-arom), 7.20-7.32 (m, 1H, H-Ph),
7.35-7.49 (m, 2H, H-Ph), 7.51-7.63 (m, 2H, H-Ph), 7.71 (dd,
2
(m, 3H, H5, H8), 2.46 (d, 1H, J ) 16.9 Hz, CHH′-pyr), 2.71
3
2
(dd, 1H, J ) 6.7 Hz, J ) 16.9 Hz, CHH′-pyr), 2.97-3.19 (m,
2H, H8a, H8′), 3.30-3.60 (m, 2H, H4a, CHCH3), 3.90 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 5.66-5.92 (m, 2H, HCdCH), 6.87
4
(d, 1H, 3J ) 8.5 Hz, H5-arom), 7.32 (dd, 1H, 3J ) 8.5 Hz, J )
4
2.0 Hz, H6-arom), 7.50 (d, 1H, J ) 2.0 Hz, H2-arom), 7.65-
3
4
4
7.88 (m, 4H, H-arom-pyr), 8.54 (bs, 1H, NH). Anal. (C27H28N4O4)
C, H, N.
1H, J ) 8.7 Hz, J ) 2.2 Hz, H6-arom), 7.91 (d, 1H, J ) 2.2
Hz, H2-arom). Anal. (C21H19ClN2O2) C, H, N.
cis-4-(3-Cyclop en t yloxy-4-m et h oxyp h en yl)-2-p h en yl-
4a,5,8,8a-tetr ah ydr o-2H-ph th alazin -1-on e (31). Com pou n d
31 was prepared from 6-(3-cyclopentyloxy-4-methoxybenzoyl)-
cyclohex-3-enecarboxylic acid (6) (2.02 g, 5.87 mmol) and
phenylhydrazine as described before. The title compound was
crystallized from methanol. Yield: 1.59 g (65%). Mp, 134-135
cis-4-(3-Ch lor o-4-m eth oxyph en yl)-2-[4-(4-m eth yl-6-oxo-
1,4,5,6-t et r a h yd r op yr id a zin -3-yl)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 (36). Com p ou n d 36 was
prepared according to the general procedure from γ-keto acid
8 (1.18 g, 4.00 mmol) and arylhydrazine 4 (1.53 g, 6.01 mmol),
and the mixture was refluxed for 5 h. The title compound was
purified by flash column chromatography using ethyl acetate/
petroleum ether (60-80 °C), 1:1, and was subsequently
crystallized from diethyl ether. Yield: 1.20 g (71%). Mp, 198-
201 °C. 1H NMR (CDCl3): δ 1.27 (d, 3H, 3J ) 7.4 Hz, CH3),
1
°C. H NMR (CDCl3): δ 1.50-2.40 (m, 11H, CH2-cyclopentyl,
H5, H8), 2.93-3.16 (m, 2H, H8a, H8′), 3.32-3.50 (m, 1H, H4a),
3.89 (s, 3H, OCH3), 4.77-4.91 (m, 1H, OCH), 5.64-5.91 (m,
3
2H, HCdCH), 6.88 (d, 1H, J ) 8.5 Hz, H5-arom), 7.18-7.67
2
(m, 7H, H-arom). Anal. (C26H28N2O3) C, H, N.
2.17-2.42 (m, 3H, H5, H8), 2.49 (d, 1H, J ) 17.0 Hz, CHH′-
cis-4-(3-Cyclopen tyloxy-4-m eth oxyph en yl)-2-[4-(4-m eth -
pyr), 2.75 (dd, 1H, 3J ) 6.7 Hz, 2J ) 17.0 Hz, CHH′-pyr), 2.97-

Phthalazinone/ Pyridazinone Hybrids
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2015
3.19 (m, 2H, H8a, H8′), 3.30-3.55 (m, 2H, H4a, CHCH3), 3.96
d r o-1H-p h th a la zin -2-yl]p en ta n oic Acid [4-(4-Meth yl-6-
oxo-1,4,5,6-tetr a h yd r op yr id a zin -3-yl)p h en yl]a m id e (41).
Com p ou n d 41 was prepared according to the general proce-
dure from carboxylic acid 12 (0.97 g) and aniline 2 (0.51 g).
The title compound was crystallized from diethyl ether.
Yield: 63%. Mp, 154-157 °C. 1H NMR (CDCl3): δ 1.24 (d, 3H,
3J ) 7.3 Hz, CH3), 1.54-2.63 (m, 10H, (CH2)3CdO, H5, H8,
CHH′-pyr), 2.72 (dd, 1H, 3J ) 6.7 Hz, 2J ) 16.9 Hz, CHH′-
pyr), 2.80-2.92 (m, 1H, H8a), 2.93-3.14 (m, 1H, H8′), 3.27-
3.48 (m, 2H, H4a, CHCH3), 3.70-4.24 (m, 8H, OCH3, NCH2),
5.54-5.82 (m, 2H, HCdCH), 6.87 (d, 1H, 3J ) 8.5 Hz, H5-
3
(s, 3H, OCH3), 5.65-5.92 (m, 2H, HCdCH), 6.98 (d, 1H, J )
8.7 Hz, H5-arom), 7.64-7.88 (m, 5H, H-6-arom, H-arom-pyr),
4
7.92 (d, 1H, J ) 2.2 Hz, H2-arom), 8.56 (bs, 1H, NH). Anal.
(C26H25ClN4O3) C, H, N.
Gen er a l P r oced u r e for t h e Syn t h esis of Hybr id s
Lin k ed via a n Am id e Bon d . Phosphorus pentachloride (0.52
g, 2.5 mmol) was added to a solution of carboxylic acid 11 or
12 (2.5 mmol) in dichloromethane (50 mL). After the mixture
was stirred for 1 h at room temperature, the reaction mixture
was concentrated in vacuo. The acid chlorides were used
without further purification.
The selected acid chloride (maximum of 2.5 mmol) was
diluted with dichloromethane (10 mL) and added to a solution
of aniline 1, 2,30 or 20 (2.5 mmol) in pyridine (75 mL) with a
catalytic amount of 4-(dimethylamino)pyridine (DMAP).
cis-2-[4-(3,4-Dim eth oxyp h en yl)-1-oxo-4a ,5,8,8a -tetr a h y-
dr o-1H-ph th alazin -2-yl]-N-[4-(6-oxo-1,6-dih ydr opyr idazin -
3-yl)p h en yl]a ceta m id e (37). Com p ou n d 37 was prepared
according to the general procedure from carboxylic acid 11
(0.86 g) and aniline 1 (0.56 g). The title compound was
crystallized from ethyl acetate. Yield: 65%. Mp, 161-162 °C.
1H NMR (CDCl3): δ 2.18-2.45 (m, 3H, H5, H8), 2.90-3.17
(m, 2H, H8a, H8′), 3.37-3.56 (m, 1H, H4a), 3.93 (s, 6H, OCH3),
4.76 (AB, 2H, NCH2), 5.65-5.91 (m, 2H, HCdCH), 6.87 (d,
1H, 3J ) 8.5 Hz, H5-arom), 7.09 (d, 1H, 3J ) 9.7 Hz, HCd
CH-pyr), 7.27 (dd, 1H, 3J ) 8.5 Hz, 4J ) 2.0 Hz, H6-arom),
7.42-7.80 (m, 6H, H2-arom, HCdCH-pyr, H-arom-pyr), 8.62
(bs, 1H, NH). Anal. (C28H27N5O5) C, H, N.
3
4
arom), 7.26 (dd, 1H, J ) 8.5 Hz, J ) 2.0 Hz, H6-arom), 7.48
(d, 1H, 4J ) 1.9 Hz, H2-arom), 7.57-7.80 (m, 4H, H-arom-
pyr), 8.30 (bs, 1H, NH), 8.73 (bs, 1H, NH). Anal. (C32H37N5O5)
C, H, N.
Gen er a l P r oced u r e for t h e Syn t h esis of Hyb r id s
Lin k ed via Eth er Bon d s. A mixture of phenol 22 (0.51 g,
2.5 mmol), bromide 25-29 (2.5 mmol), K2CO3 (0.69 g, 5.0
mmol), and a catalytic amount of KI in DMF (50 mL) was
heated at 60 °C for 3-6 h. The reaction mixture was diluted
with water, and the product was extracted with diethyl ether.
The combined organic extracts were washed with water, dried
over MgSO4, and concentrated under reduced pressure.
cis-4-(3,4-Dim et h oxyp h en yl)-2-{4-[4-(4-m et h yl-6-oxo-
1,4,5,6-tetr a h yd r op yr id a zin -3-yl)p h en oxy]bu tyl}-4a ,5,8,-
8a -tetr a h yd r o-2H-p h th a la zin -1-on e (42). Com p ou n d 42
was synthesized following the general procedure using bromide
25 (1.05 g). The title compound was purified by flash column
chromatography using ethyl acetate/petroleum ether (60-80
°C), 1:1, and crystallized from ethyl acetate. Yield: 35%. Mp,
94-97 °C. 1H NMR (CDCl3): δ 1.21 (d, 3H, 3J ) 7.4 Hz, CH3),
cis-2-[4-(3,4-Dim eth oxyp h en yl)-1-oxo-4a ,5,8,8a -tetr a h y-
d r o-1H-p h th a la zin -2-yl]-N-[4-(4-m eth yl-6-oxo-1,4,5,6-tet-
r ah ydr opyr idazin -3-yl)ph en yl]acetam ide (38). Com pou n d
38 was prepared according to the general procedure from
carboxylic acid 11 (0.86 g) and aniline 2 (0.51 g). The title
compound was crystallized from diethyl ether. Yield: 47%. Mp,
139-141 °C. 1H NMR (CDCl3): δ 1.22 (d, 3H, 3J ) 7.3 Hz,
2
1.71-2.32 (m, 7H, (CH2)2, H5, H8), 2.42 (d, 1H, J ) 16.7 Hz,
CHH′-pyr), 2.59-2.84 (m, 2H, H8a, CHH′-pyr), 2.90-3.11 (m,
1H, H8′), 3.20-3.42 (m, 2H, H4a, CHCH3), 3.72-4.19 (m, 10H,
OCH2, OCH3, NCH2), 5.59-5.87 (m, 2H, HCdCH), 6.79-6.97
3
CH3), 2.18-2.57 (m, 4H, H5, H8, CHH′-pyr), 2.70 (dd, 1H, J
4
3
) 6.7 Hz, 2J ) 16.9 Hz, CHH′-pyr), 2.91-3.15 (m, 2H, H8a,
H8′), 3.22-3.55 (m, 2H, H4a, CHCH3), 3.93 (m, 6H, OCH3),
4.73 (AB, 2H, NCH2), 5.65-5.91 (m, 2H, HCdCH), 6.87 (d,
1H, 3J ) 8.5 Hz, H5-arom), 7.28 (dd, 1H, 3J ) 8.5 Hz, 4J ) 1.9
Hz, H6-arom), 7.43-7.73 (m, 5H, H2-arom, H-arom-pyr), 8.47
(bs, 1H, NH), 8.74 (bs, 1H, NH). Anal. (C29H31N5O5) C, H, N.
cis-2-[4-(3,4-Dim eth oxyp h en yl)-1-oxo-4a ,5,8,8a -tetr a h y-
d r o-1H-p h th a la zin -2-yl]-N-[3-(4-m eth yl-6-oxo-1,4,5,6-tet-
r ah ydr opyr idazin -3-yl)ph en yl]acetam ide (39). Com pou n d
39 was prepared according to the general procedure from
carboxylic acid 11 (0.86 g) and aniline 20 (0.51 g). The title
compound was purified by flash column chromatography using
ethyl acetate and crystallized from diethyl ether. Yield: 50%.
Mp, 136-140 °C. 1H NMR (CDCl3): δ 1.22 (d, 3H, 3J ) 7.4
(m, 3H, H5-arom, H-arom-pyr), 7.24 (dd, 1H, J ) 1.8 Hz, J
4
) 8.4 Hz, H6-arom), 7.45 (d, 1H, J ) 1.8 Hz, H2-arom), 7.64
(d, 2H, 3J ) 8.9 Hz, H-arom-pyr), 8.47 (bs, 1H, NH). Anal.
(C31H36N4O5) C, H, N.
cis-4-(3,4-Die t h oxyp h e n yl)-2-{4-[4-(4-m e t h yl-6-oxo-
1,4,5,6-tetr a h yd r op yr id a zin -3-yl)p h en oxy]bu tyl}-4a ,5,8,-
8a -tetr a h yd r o-2H-p h th a la zin -1-on e (43). Com p ou n d 43
was synthesized following the general procedure using bromide
26 (1.12 g). The title compound was purified by flash column
chromatography using ethyl acetate/petroleum ether (60-80
°C), 1:1, and crystallized from petroleum ether (60-80 °C).
1
Yield: 28%. Mp, 73-78 °C. H NMR (CDCl3): δ 1.24 (d, 3H,
3J ) 7.3 Hz, CH3), 1.39-1.57 (m, 6H, OCH2CH3), 1.72-2.32
(m, 7H, (CH2)2, H5, H8), 2.45 (d, 1H, 2J ) 16.9 Hz, CHH′-pyr),
2.61-2.87 (m, 2H, H8a, CHH′-pyr), 2.90-3.11 (m, 1H, H8′),
3.21-3.42 (m, 2H, H4a, CHCH3), 3.73-4.23 (m, 8H, OCH2,
NCH2), 5.60-5.88 (m, 2H, HCdCH), 6.81-6.98 (m, 3H, H5-
arom, H-arom-pyr), 7.25 (dd, 1H, 4J ) 1.8 Hz, 3J ) 8.4 Hz,
2
Hz, CH3), 2.17-2.39 (m, 3H, H5, H8), 2.45 (d, 1H, J ) 17.0
Hz, CHH′-pyr), 2.70 (dd, 1H, 3J ) 6.7 Hz, 2J ) 17.0 Hz, CHH′-
pyr), 2.90-3.14 (m, 2H, H8a, H8′), 3.22-3.51 (m, 2H, H4a,
CHCH3), 3.93 (m, 6H, OCH3), 4.72 (AB, 2H, NCH2), 5.63-5.91
(m, 2H, HCdCH), 6.87 (d, 1H, 3J ) 8.5 Hz, H5-arom), 7.28
(dd, 1H, 3J ) 8.5 Hz, 4J ) 2.3 Hz, H6-arom), 7.35 (d, 1H, 3J )
7.8 Hz, H-arom-pyr), 7.40-7.58 (m, 3H, H2-arom, H-arom-pyr),
7.90-8.01 (m, 1H, H-arom-pyr), 8.26 (bs, 1H, NH), 8.62 (bs,
1H, NH). Anal. (C29H31N5O5) C, H, N.
4
3
H6-arom), 7.46 (d, 1H, J ) 1.8 Hz, H2-arom), 7.66 (d, 2H, J
) 8.8 Hz, H-arom-pyr), 8.47 (bs, 1H, NH). Anal. (C33H40N4O5)
C, H, N.
cis-4-(3-Ch lor o-4-m eth oxyp h en yl)-2-{4-[4-(4-m eth yl-6-
oxo-1,4,5,6-t et r a h yd r op yr id a zin -3-yl)p h en oxy]b u t yl}-
4a,5,8,8a-tetr ah ydr o-2H-ph th alazin -1-on e (44). Com pou n d
44 was synthesized following the general procedure using
bromide 27 (1.06 g). The title compound was crystallized from
a mixture of ethyl acetate and MeOH. Yield: 21%. Mp, 105-
106 °C. 1H NMR (CDCl3): δ 1.24 (d, 3H, 3J ) 7.4 Hz, CH3),
cis-5-[4-(3,4-Dim eth oxyp h en yl)-1-oxo-4a ,5,8,8a -tetr a h y-
d r o-1H-p h th a la zin -2-yl]p en ta n oic a cid [4-(6-oxo-1,6-d i-
h yd r op yr id a zin -3-yl)p h en yl]a m id e (40). Com p ou n d 40
was prepared according to the general procedure from car-
boxylic acid 12 (0.97 g) and aniline 1 (0.56 g). The title
compound was crystallized from ethyl acetate. Yield: 59%. Mp,
1
253 °C. H NMR (DMSO-d6): δ 1.50-2.45 (m, 9H, (CH2)3Cd
2
1.71-2.32 (m, 7H, (CH2)2, H5, H8), 2.45 (d, 1H, J ) 16.9 Hz,
O, H5, H8), 2.62-2.92 (m, 2H, H8a, H8′), 3.38-3.56 (m, 1H,
H4a), 3.58-3.98 (m, 8H, OCH3, NCH2), 5.53-5.79 (m, 2H,
HCdCH), 6.89-7.04 (m, 2H, H5-arom, HCdCH), 7.29-7.47
(m, 2H, H6-arom, H2-arom), 7.61-7.86 (m, 4H, H-arom-pyr),
CHH′-pyr), 2.61-2.85 (m, 2H, H8a, CHH′-pyr), 2.90-3.10 (m,
1H, H8′), 3.20-3.41 (m, 2H, H4a, CHCH3), 3.74-4.14 (m, 7H,
OCH2, OCH3, NCH2), 5.59-5.88 (m, 2H, HCdCH), 6.84-6.99
(m, 3H, H5-arom, H-arom-pyr), 7.58-7.71 (m, 3H, H6-arom,
H-arom-pyr), 7.87 (d, 1H, 4J ) 2.2 Hz, H2-arom), 8.46 (bs, 1H,
NH). Anal. (C30H33ClN4O4) C, H, N.
3
7.99 (d, 1H, J ) 9.9 Hz, HCdCH), 10.06 (bs, 1H, NH), 13.11
(bs, 1H, NH). Anal. (C31H33N5O5) C, H, N.
cis-5-[4-(3,4-Dim eth oxyp h en yl)-1-oxo-4a ,5,8,8a -tetr a h y-

2016 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Van der Mey et al.
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