Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: Effects of lipophilicity and structure-activity relationships

Article abstract of DOI:10.1021/jm981005y

A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP- HPLC capacity factors, revealin

Full text of DOI:10.1021/jm981005y

3812
J . Med. Chem. 1998, 41, 3812-3820
In h ibition of Mon oa m in e Oxid a se-B by Con d en sed P yr id a zin es a n d
P yr im id in es: Effects of Lip op h ilicity a n d Str u ctu r e-Activity Rela tion sh ip s
Cosimo Altomare, Saverio Cellamare, Luciana Summo, Marco Catto, and Angelo Carotti*
Dipartimento Farmaco-chimico, Universita` di Bari, Via Orabona 4, I-70125 Bari, Italy
Ulrike Thull, Pierre-Alain Carrupt, and Bernard Testa
Institut de Chimie The´rapeutique, Section de Pharmacie, Universite´ de Lausanne, CH-1015 Lausanne-Dorigny, Switzerland
Helen Stoeckli-Evans
Institut de Chimie, Faculte´ de Sciences, Universite´ de Neuchaˆtel, Avenue de Bellevaux 51, CH-2000 Neuchaˆtel, Switzerland
Received February 23, 1998
A number of condensed pyridazines and pyrimidines were synthesized and tested for their
monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was
examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some
peculiar electronic and conformational effects. Further insights were obtained by X-ray
crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity
relations highlighted the main factors determining both selectivity and inhibitory potency.
Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little
or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A
inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis
of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase
MAO-B and not MAO-A inhibitory activity.
Ta ble 1. MAO Inhibition Data of Newly Synthesized
Pyridazine and Pyrimidine Derivatives
In tr od u ction
Monoamine oxidase (MAO, EC 1.4.3.4) is a FAD-
containing enzyme of the outer mitochondrial mem-
IC50 (µM) or % inhibition at µMb
compd no.
MAO-A
MAO-B
brane that catalyzes the oxidative deamination of
various neurotransmitters and dietary amines.1 MAO
exists in two enzymatic forms termed MAO-A and
MAO-B and differing by their substrate specificity,
sensitivity to inhibitors,2 and amino acid sequence.3
MAO-A and MAO-B have 70% sequence identity and
have been expressed from two genes with similar
structures. Their three-dimensional structures are not
known, but recently, relevant information about their
active site has been reported.4 In recent years, there
has been a considerable renewal of interest in MAO for
two main reasons. One was the discovery that the
neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-
dine (MPTP) causes the death of dopaminergic neurons
and induces symptoms very similar to Parkinson’s
disease in humans.5 The second reason was the obser-
vation that selective and reversible inhibitors of MAO-A
or MAO-B may be useful therapeutic agents devoid of
undesirable side-effects such as hypertensive crises and
cardiac arrhythmias caused by the alimentary intake
of tyramine.6 In humans, MAO-B inhibitors (e.g.,
deprenyl) are useful as coadjuvants in the treatment of
Parkinson’s disease and perhaps Alzheimer’s disease,7
whereas MAO-A inhibitors are valuable antidepressant
and antianxiety agents (e.g., moclobemide).8
1
2
7
26
29
30
31
32
35
36
18% at 100
97.6 ( 8.9
0% at 25
44% at 50
59.1 ( 2.7
16.4 ( 3.0
15% at 5
0% at 5
2.37 (0.11
8.39 ( 0.57
29% at 100
27.5 ( 5.1
21.0 ( 0.6
12% at 50
74.8 ( 9.7
32% at 125
12.5% at 5
0% at 5
11.6 ( 1.1
28% at 10
a
The inhibitory activity values of 5H-indeno[1,2-c]pyridazin-
5-one derivatives 2 and 7 taken from ref 11 are reported as
references. Maximum solubility.
b
activity of isoquinoline derivatives10 and condensed
pyridazines.11 Thus, we described 5H-indeno[1,2-c]-
pyridazin-5-ones, hereafter termed IPyd, some of which
were found to be reversible and competitive inhibitors
of MAO-B with little or no effect on MAO-A. A lead
optimization study by means of QSAR led to a predictive
3D-QSAR model and to the design of 3-p-CF3-phenyl-
IPyd derivatives showing submicromolar inhibition
values toward MAO-B (IC50 ) 90 nM). The influence
of lipophilicity in increasing inhibition of MAO-B (but
not MAO-A) was demonstrated by a traditional QSAR
Hansch-type analysis and by a comparative molecular
field analysis (CoMFA) including the molecular lipo-
philicity potential (MLP).12
In previous papers, we examined the MAO-mediated
toxication of MPTP analogues9 and the MAO inhibitory
To deepen our understanding of the MAO inhibitory
activity and selectivity of diazine-containing compounds,
* Corresponding author. Fax: ++39.80.5442724. E-mail: carotti@
farmchim.uniba.it.
S0022-2623(98)01005-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/04/1998

Pyridazines and Pyrimidines as MAO Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3813
Ta ble 2. Partition Coefficients and Themodynamic Parameters of RP-HPLC Retention of Pyridazine and Pyrimidine Derivatives
compd
R3
partition datab
RP-HPLC retention data
no.
R4
pIC50 (MAO-B)
CLOG P
log Poct
log Pcyh
log kf
∆H° (kJ /mol)g
[∆S°/R + ln φ]g
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
26
29
30
31
36
37
1.05
1.13
1.63
2.03
3.02
3.73
3.23
2.98
2.98
2.98
2.60
2.87
2.29
2.29
2.73
3.29
3.29
3.17
3.37
3.69
3.94
4.11
4.11
2.46
2.09
1.35
2.24
3.07
3.28
1.09
1.22
1.58
2.21
2.80
c
-0.45
-0.29
-0.04
0.70
1.40
2.16
2.34
1.05
1.66
2.34
-0.04
0.03
0.46
0.74
1.22
1.53
1.39
0.93
1.35
1.37
1.51
1.01
0.79
0.78
1.44
1.53
1.53
1.42
1.42
1.47
1.79
1.52
1.97
0.60
0.56
0.54
1.11
1.56
2.04
-3.99 (0.22)
-13.5 (0.7)
-6.27 (0.37)
-6.11 (0.33)
-14.2 (1.3)
-15.1 (1.6)
-7.1 (1.5)
-2.6 (0.2)
-3.3 (0.3)
-1.4 (0.1)
-1.3 (0.1)
-2.8 (0.5)
-2.4 (0.6)
-3.5 (0.6)
-2.1 (0.5)
-4.5 (0.7)
-4.3 (0.6)
-4.4 (0.1)
-5.4 (0.1)
-2.0 (0.2)
-5.6 (0.7)
-3.1 (0.2)
-4.1 (0.1)
-4.6 (0.1)
-2.8 (0.4)
-2.6 (0.3)
-1.2 (0.3)
-3.7 (0.4)
-2.3 (0.2)
-3.1 (0.3)
-1.5 (0.1)
-2.2 (0.1)
-4.6 (0.4)
-7.2 (0.6)
-2.8 (0.2)
-3.3 (0.4)
H
H
H
H
Ph
CH3
H
H
H
H
H
H
H
H
H
H
H
4.56
4.12
CH3
CF3
H
Ph
Ph
4.03
4.68
4.10
c
2′-NO2-C6H4
3′-NO2-C6H4
4′-NO2-C6H4
2′-OH-C6H4
4′-OH-C6H4
3′-NH2-C6H4
4′-NH2-C6H4
2′-OCH3-C6H4
3′-OCH3-C6H4
4′-OCH3-C6H4
2′-F-C6H4
2.64
c
c
d
2.88
-10.9 (1.2)
-19.3 (1.7)
-19.0 (1.6)
-20.1 (0.2)
-19.7 (0.1)
-9.80 (1.25)
-19.0 (1.4)
-16.3 (0.4)
-19.5 (0.3)
-20.8 (0.3)
-15.5 (1.2)
-15.0 (1.0)
-11.8 (1.2)
-19.9 (1.0)
-14.9 (0.6)
-19.5 (0.9)
-5.83 (0.29)
-8.83 (0.61)
-15.5 (0.9)
-24.9 (1.6)
-16.2 (0.8)
-20.5 (1.2)
(6.2)a
6.30
2.55
0.13
5.00
4.49
4.61
c
c
c
c
c
2.26
2.83
2.51
2.07
2.56
5.80
5.49
4.74
6.04
4.80
6.04
H
H
H
H
H
H
4′-F-C6H4
2′-Cl-C6H4
4′-Cl-C6H4
2′-CF3-C6H4
4′-CF3-C6H4
7.05
4.13
2.05
1.56
0.60
-2.22e
4.94
c
c
c
c
a
b
Approximated value; 42% inhibition at 0.5 µM. Partition coefficients are the means of at least 5 determinations (SD < 0.05 log
units). c log P > 3.00. log P ) 3.15 ( 0.10. e Strong dependence of log Pcyh on solute concentration; -2.22 is the log P value extrapolated
d
at infinite dilution. f Values are log of the capacity factor determined at the harmonic mean temperature (33 °C). The standard errors
g
are indicated in parentheses.
Sch em e 1a
Sch em e 2a
a
a
Reagents: (i) dioxane, reflux; (ii) NH2NH2‚H2O; (iii) air
Reagents: (i) KOH, MeOH; (ii) NH2NH2‚H2O, EtOH; (iii) DDQ,
oxidation, spontaneous.
reflux.
drastic structural modifications of the lead compound
(compound 7, Table 2) were performed, yielding the
structure-activity relationships presented here. The
lipophilicity of various derivatives was also investigated,
and new QSAR models of MAO-B inhibition were
derived.
Treatment of the intermediate 2-phenacylcyclopen-
tanone 24, obtained from the reaction of ω-bromoaceto-
phenone with 4-(1-cyclopenten-1-yl)morpholine in re-
fluxing dry dioxane, with hydrazine hydrate gave 25,
which spontaneously dehydrogenated to compound 26.
Scheme 2 illustrates the synthesis of the tetrahydro-
cynnolinone derivative 29. The intermediate product
27, prepared according to a published method,14 was
treated with hydrazine hydrate to give compound 28
which was subsequently oxidized with DDQ to afford
compound 29 in good yield.
The preparation of 3-phenyl-5,6,7,8-tetrahydro-py-
rimido[4,5-c]pyridazin-5,7-dione 30 and its 4′-CF3 con-
gener 31, hereafter called Pym-Pydones, was carried out
by a one-pot procedure11 as shown in Scheme 3. 3-Phen-
yl-5H-pyridazino[4,3-b]indole 32 was kindly made avail-
Resu lts a n d Discu ssion
Ch em istr y. By replacing the condensed indane ring
of 3-phenyl-5H-indeno[1,2-c]pyridazin-5-ones by other
less hydrophobic rings and the pyridazine ring by a
pyrimidine, novel compounds were obtained whose
syntheses are outlined in Schemes 1-4.
4-Benzoylpyridazine 1 was prepared according to
known procedures.13 The cyclopenta[c]pyridazine de-
rivative 26 was prepared as shown in Scheme 1.

3814 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Altomare et al.
Sch em e 3a
Sch em e 4a
a
Reagents: (i) HOAc, reflux; (ii) NH2NH2‚H2O.
able to us by Prof. F. Campagna (University of Bari,
Italy) and was also investigated.
a
Reagents: (i) (CH3)2NCH(OCH3)2, CHCl3; (ii) NaOH in anhy-
drous EtOH, reflux; (iii) CrO3, HOAc.
The syntheses of the indenopyrimidine derivatives 35
and 36 were accomplished in a three-step procedure as
reported in Scheme 4. First, the enaminone intermedi-
ates 33a and 33b were prepared by reacting the
appropriate indanone with N,N-dimethylformamide
dimethyl acetal at room temperature and then reacted
with benzamidine in refluxing dry ethanol to give the
indenopyrimidines 34a -b in very high yields. Finally,
oxidation of compounds 34a -b with CrO3 afforded the
desired 2-phenyl-9H-indeno[2,1-d]pyrimidin-9-one 35
and 2-phenyl-5H-indeno[1,2-d]pyrimidin-5-one 36, re-
spectively. All of the other compounds reported in Table
2 were prepared according to published procedures.11,15
Str u ctu r e-Lip op h ilicity Rela tion s. Lipophilici-
ties of the diazine MAO inhibitors were assessed by
measuring their 1-octanol/water (log Poct) and cyclohex-
ane/water (log Pcyh) partition coefficients and capacity
factors (log k) in RP-HPLC (Table 2). Due to the limited
precision of log P measurement of highly lipophilic
compounds, only experimental log P values e3 were
retained in structure-lipophilicity relationship studies.
The values of log Poct were also calculated by the
CLOGP16 algorithm. A good linear correlation was
found between experimental and calculated log Poct
values (r2 ) 0.957). However, the CLOGP program17
failed to predict some significant differences between
positional isomers, which might be of interest in ex-
plaining variations in MAO inhibitory activity.
This is exemplified by the partitioning behavior of
3-(2′-OH-Ph) IPyd, which is much more lipophilic than
3-(4′-OH-Ph) IPyd (11 and 12, respectively) in the
cyclohexane/water system. This difference is explained
by the ability of the OH group, when in the ortho
position of the phenyl group, to form an intramolecular
H-bond (-OH‚‚‚Nd) with the pyridazine N(2), as dem-
onstrated by the 1H NMR chemical shifts of phenolic
protons in CDCl3 solvent (13.50 and 5.23 ppm for the
o-OH, 11, and p-OH, 12, congeners, respectively). Com-
pletely unexpected was also the behavior of the o-NO2
derivative 8, which was markedly more hydrophilic than
both its m- 9 and p-NO2 10 congeners, the differences
F igu r e 1. Perspective view of molecule 8 showing the
numbering scheme used (thermal ellipsoids at 50% probability
level).
in log P values being in the range 0.6-1.3 log P units.
The strong increase of lipophilicity of the m- and
p-nitrophenyl congeners could partly explain their
relatively high MAO-B inhibitory activities.
The low lipophilicity of the o-nitro congener 8 could
result from both conformational and electronic effects,
all of which could be of enzymatic relevance. Indeed,
loss of coplanarity between the NO2 group and the
phenyl ring and between the phenyl and the condensed
pyridazine rings would decrease electronic conjugation
and hence lipophilicity. To validate this hypothesis, the
X-ray crystal structure of compound 8 was determined
(Figure 1). The three fused rings of the indeno[1,2-c]-
pyridazine moiety proved relatively planar. The nitro-
phenyl ring was staggered by 26.0(4)° relative to the
pyridazine ring, and the dihedral angles between the
NO2 group and the phenyl and pyridazine rings were
61.6(5)° and 56.4(6)°, respectively. These torsion angles
indicate a large deviation from planarity of the nitro
group and may indeed account for the low lipophilicity
of the compound.
As for the pyrimido[4,5-c]pyridazin-5,7-dione deriva-
tive 30, its experimental log Poct value (1.56) is very close
to that calculated for the keto tautomer (1.35) rather
than that for the enol tautomer (2.60), indicating a
predominance of the former in solution.18
To obtain a more complete set of lipophilicity param-
eters, we also measured capacity factors (log k values)

Pyridazines and Pyrimidines as MAO Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3815
F igu r e 2. Summary of the main structural factors responsible
for MAO I activity and MAO-A/B selectivity of pyridazine- and
pyrimidine-containing derivatives. Dz ) diazine ring; C )
condensed ring; R ) substituents on the diazine ring.
F igu r e 3. Enthalpy-entropy compensation plot showing
capacity ratio, ln k, vs enthalpy, ∆H° (kJ mol-1), found at the
experimental harmonic mean temperature (33 °C) for RP-18
stationary phase and methanol/water (45/55, v/v) mobile
phase: b, IPyd; 9, IPym; [, Pym-Pydone. Drawn line is the
regression line for IPyd congeners (12 and 14 omitted as
outliers).
in RP-HPLC (Table 2). The influence of temperature
on the RP-HPLC retention was also examined, leading
to the enthalpy and entropy terms to be used below as
thermodynamic parameters of lipophilicity in a QSAR
analysis of MAO-B inhibition (Table 2). The distribu-
tion constant (K) of a solute between the stationary
phase and mobile phase in a chromatographic system
is a function of the difference in free energy of the solute
in the two phases, ∆G°19
MAO In h ibition . The newly synthesized compounds
(1, 26, 29, 30-32, 35, and 36) were tested for their
inhibitory effect on MAO-A and MAO-B using a previ-
ously described method.10,11,21 The IC50 values are
reported in Table 1. The competitive, reversible MAO
inhibitor harman was used as a reference for the two
isozymes.22 Preliminary measurements showed that all
the tested compounds acted in a reversible and time-
independent manner (results not shown).
RT ln K ) -∆G° ) -(∆H° - T∆S°)
(1)
where R is the gas constant and T is the absolute
temperature. Substituting K with k/φ (φ being the
phase ratio) yields a form of the van’t Hoff equation
No novel compound described here was more active
than previously examined compounds. Nevertheless,
the inhibition data in Table 1 give helpful information
on structure-activity-selectivity relationships. For in-
stance, a comparison between compounds 1 and 2 shows
that rigidity and planarity should be favorable to
activity, since 4-benzoylpyridazine 1 is about 4 times
less active than 5H-indeno[1,2-c]pyridazin-5-one 2. Fur-
thermore, compounds 26, 29, 30-32, and 7 indicate that
the nature of the ring(s) condensed with pyridazine
influenced activity and selectivity toward MAO-A. In-
deed, replacing the indane ring with a cyclohexane or
pyrimidine ring gave compounds 29 and 30, respec-
tively, which had marked MAO-A inhibitory activity.
The pyrimido[4,5-c]pyridazine derivative 30 had the
highest MAO-A inhibitory activity among all pyridazine-
containing compounds tested so far in our laboratories.
3-Phenyl-5H-pyridazino[4,3-b]indole 32 did not show
any detectable activity up to its maximum solubility.
The effect of diazine ring activity was explored by
replacing the pyridazine with a pyrimidine ring. Inde-
nopyrimidinones, termed IPym 35 and 36, proved to be
reversible inhibitors of MAO-B almost equipotent to the
pyridazine analogue 7, but with an additional and
significant inhibitory activity toward MAO-A. 2-Phenyl-
9H-indeno[2,1-d]pyrimidin-9-one 36 was the most active
(IC50 ) 2.37 µM) and selective analogue. This suggests
that a diazine ring can influence both inhibitory potency
ln k ) -(∆H°/RT) + (∆S°/R) + ln φ
(2)
Van’t Hoff plots were constructed for each diazine
derivative by collecting retention data in 5 °C incre-
ments from 18 to 48 °C. In all cases retention decreased
with increasing temperature, indicating ∆H° to be
negative and essentially independent from temperature
in the explored range. Because the intercept includes
a constant term dependent on the phase ratio and not
known accurately, it was not possible to obtain reliable
estimates for the magnitude of the entropic forces.
Analysis can be made, however, in terms of group
contributions to ∆S° (see below). Table 2 summarizes
the data for the enthalpy and the entropy/phase ratio
[∆S°/R + ln φ] terms (eq 2).
All data in Table 2 were examined for enthalpy-
entropy compensation,20 as shown in Figure 3. Such a
compensation was found to exist for all IPyd derivatives
except for the p-OH and p-NH2 substituted congeners
of 3-Ph IPyd, which showed a deviant behavior and were
excluded from the regression. The compensation plot
indicated that a single retention mechanism and similar
solvation characteristics prevailed for most IPyd deriva-
tives. Strong H-bond donors such as the Pym-Pydones
(30 and 31) and the p-OH and p-NH2 substituted 3-Ph
IPyd were found to lie on an almost parallel line,
indicating different solvation characteristics.

3816 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Altomare et al.
Ta ble 3. Lipophilic Constants and Other Physicochemical
Parameters of Substituents on
3-(X-Phenyl)-5H-indeno[1,2-c]pyridazin-5-one Used in QSAR
Analysis of MAO-B Inhibition Data
better parameter than other lipophilicity descriptors.
Due to a high intercorrelation, τH and τS cannot be used
together in a regression equation. To improve the
equation (r2 > 0.80), the electronic σ constant and the
volume descriptor of ortho substituents (VW(2′)), taken
from standard compilations,16 also had to be included
(eqs 9-10). Thus, electronic properties and steric effects
represent additional factors modulating MAO-B inhibi-
tion. Actually, the importance of hydrophobic interac-
tions with a hydrophobic site and electronic interactions
with a nucleophilic site of the enzyme had been postu-
lated by others24 on the basis of results from univariate
regression analysis carried out on sets of various
heterocyclic MAO-B inhibitors. The results of our QSAR
study, consistent with these models, contribute to a
better definition of the nature of the forces responsible
for reversible inhibition of MAO-B and are in good
agreement with a recently published model of reversible
inhibition of MAO-B by diazo heterocyclic compounds.25
This model shows that lipophilicity is the most impor-
tant parameter governing binding to the MAO-B inhibi-
tion site, whereas minor roles are played by conforma-
tion (i.e., planar conformations are preferred) and
hydrogen bonding.
compd no.
X
π
τ
τH
τS
σ
VW(2′)
7
8
9
H
0
0
0
0
0.60
0
0.08
2′-NO2
3′-NO2
4′-NO2
4′-OH
3′-NH2
4′-NH2
3′-OCH3
4′-OCH3
2′-F
4′-F
2′-Cl
4′-Cl
4′-CF3
-0.25 -0.46 -1.06
0.80 1.20
0.71 0.08
0.78 0.08
-0.25 -0.04
-0.25 -0.02
-0.36 -0.38
0.38 -0.42
0.32 -0.34
0.44 -0.82 -0.37 0.08
0.65 -0.16 0.08
0.32 -0.93 -0.66 0.08
0.40 -0.26 0.12 0.08
0.63 -0.49 -0.27 0.08
10
12
13
14
16
17
18
19
20
21
23
-0.94 -0.60 -1.25
-0.94 -0.61
0.06
0.06
-0.06
0.14
0.46
0.71
0.88
0.14
0.14
0.03 -0.29
0.03 -0.36
0.08 -0.90
0.40
0.58
0.32
0.39
0.98
0.16 0.36
0.06 0.08
0.25 1.07
0.23 0.08
0.54 0.08
0.48 -0.08
0.40 0.18
and selectivity, and when combined with previous
results,11 leads to a broader understanding of the main
factors eliciting MAO inhibitory activity and selectivity
of condensed pyridazines and pyrimidines (Figure 2).
Thus, the diazine and condensed C ring affect both
MAO-A/B selectivity and inhibitory potency, whereas
substituents on the diazine ring affect only the latter.
QSAR An a lysis. For X-phenyl derivatives of IPyd,
a previous QSAR model11b related MAO-B inhibition
mostly to lipophilic and electronic properties of substit-
uents and to a steric negative effect of ortho substitu-
ents. A small contribution had been also noted for the
volume of para substituents. Using the RP-HPLC-
derived lipophilic substituent constants and the novel
thermodynamic parameters derived from RP-HPLC
retention offered an opportunity to examine the capacity
of these chromatographic descriptors to account for
lipophilic interactions in enzyme-inhibitor complexes.
Separate enthalpy or entropy parameters rather than
free energy parameters may improve the correlation
coefficient in some QSAR equations, e.g., blood-brain
barrier permeation.23 In this study, group contribution
toward retention, in analogy with substituent extra-
thermodynamic parameters (e.g., the Hansch π con-
stant), can be defined as
Con clu sion s
Two main conclusions emerge from the activities of
diazine derivatives as MAO inhibitors. First, structure-
activity relationships of the derivatives synthesized and
tested to date unravel the main factors affecting inhibi-
tory activity and selectivity toward MAO-A and MAO-
B. Thus, most of the condensed pyridazines are revers-
ible MAO-B inhibitors, with no or little effect on MAO-
A, whereas the condensed pyrimidines prove to be
reversible inhibitors endowed with an appreciable se-
lectivity toward MAO-A. Substituents on the diazine
nucleus modulate the inhibitory activity. In contrast,
the nature of the ring(s) condensed with diazine appear
to affect significantly the selectivity toward MAO-A and
MAO-B.
Second, the QSAR results reported in this paper bring
further evidence that lipophilicity is a property that
significantly modulates MAO-B but not MAO-A inhibi-
tion. Multiple linear regression analysis yielded QSAR
models showing the importance of lipophilic, electronic,
and steric properties of indenopyridazines in determin-
ing MAO-B inhibition. In contrast, any attempt to
derive quantitative models for MAO-A inhibition was
inconclusive, at least within the examined property
space. This is compatible with the known mechanism
of reversible inhibition of MAO-A where the formation
of the complex between the inhibitor and the FAD
cofactor appears as a crucial event.26 This implies
electrostatic interactions and charge-transfer bonding
as the major contributions to the stability of the FAD-
inhibitor complex. Work is in progress in our labora-
tory, using chromatography-based model systems and
quantum chemical calculations to find suitable electro-
static descriptors.
τ ) log kR-X - log kR-H ) -(∆(∆G°)X)/2.303RT
) -(∆(∆H°)X)/2.303RT + (∆(∆S°)X)/R
(3)
When enthalpic and entropic contributions to reten-
tion are represented as τH and τS, respectively, one
obtains
τ ) τH + τS
τH ) - (∆(∆H°)X)/2.303RT
τS ) (∆(∆S°)X)/R
(4)
(5)
(6)
Using eqs 3, 5, and 6, we calculated τ, τH, and τS for
the subset of 3-phenyl-5H-indeno[1,2-c]pyridazin-5-ones
(7-23) listed in Table 3. The QSAR results of 3-(X-Ph)
IPyd are shown in Table 4, whereas the squared
correlation matrix of variables is shown in Table 5. The
chromatographic substituent constant τ (which alone
explains about 55% of the y-variance, eq 8) is here a
Exp er im en ta l Section
Ch em istr y. Melting points were determined by the capil-
lary method on a Gallekamp MFB 595 010M electrothermal
apparatus and are uncorrected. Elemental analyses were
performed on a Carlo Erba 1106 analyzer; for C, H, and N,
the results agreed to within (0.40% of the theoretical values.

Pyridazines and Pyrimidines as MAO Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3817
Ta ble 4. QSAR of 3-(X-Phenyl)-5H-indeno[1,2-c]pyridazin-5-one MAO-B Inhibitorsa (n ) 14, Table 3) Using Lipophilicity and Other
Physical Parameters
eq no.
QSAR eqs
r2
q2
s
F
7
8
9
pIC50 ) 0.96((0.39)π + 5.43((20)
0.333
0.555
0.830
0.821
0.131
0.437
0.687
0.704
0.738
0.603
0.408
0.419
5.998
14.94
16.26
15.27
pIC50 ) 1.84((0.48)τ + 5.48((16)
pIC50 ) 0.78((0.24)π + 0.94((0.30)σ - 1.67((0.32)VW(2′) + 5.70((0.14)
pIC50 ) 1.20((0.38)τ + 0.84((0.32)σ - 1.31((0.35)VW(2′) + 5.64((0.14)
10
a
Only compounds with measurable IC50 values were included in the regression analysis (i.e., 7-10, 12-14, 16-21, and 23).
Ta ble 5. Squared Correlation Matrix of Variables Used in
QSAR Analysis
treated with CHCl3 and the solid filtered off. The chloroform
solution was evaporated to dryness, and the solid residue was
purified by crystallization to give 29 (0.35 g, 78% yield): mp
108-9 °C, from CHCl3/hexane; 1H NMR (CDCl3) δ 8.24 (s, 1H),
8.12 (dd, 2H, J ) 7.8, 1.9), 7.56-7.46 (m, 3H), 3.42 (t, 2H, J )
pIC50
1
π
τ
τH
0.333 0.555 0.374 0.049 0.152
0.863 0.064 0.086 0.157
0.206 0.013 0.139
0.696 0.020
τS
σ
Vw(2′)
pIC50
π
τ
0.258
0.012
0.031
0.436
0.394
0.137
1
6.2), 2.78 (t, 2H, J ) 6.6), 2.28 (qn, 2H, J ) 6.4); IR (cm-1
)
1
1
1700, 1405. Anal. (C14H12N2O) C, H, N.
τH
τS
σ
1
3-P h en yl-5,6,7,8-tetr a h yd r op yr im id o[4,5-c]p yr id a zin -
5,7-d ion e (30). A solution of alloxan monohydrate (0.32 g, 2
mmol) and acetophenone (0.23 mL, 2 mmol) in 4 mL of glacial
AcOH was heated at reflux for 2.5 h. The reaction mixture
was allowed to cool to room temperature, and then 0.15 mL
(3 mmol) of hydrazine hydrate (98%) was added. After stirring
overnight, the reaction mixture was filtered off, and the
solution was evaporated to dryness. The resulting yellow oil
residue was treated with ethyl acetate to give crystals of
compound 30 (0.20 g, 76% yield): mp 271-2 °C, from dioxane;
1H NMR (DMSO-d6) δ 14.30 (br, 1H), 11.46 (br, 1H), 8.65 (s,
1H), 7.99-7.94 (m, 2H), 7.81 (br, 1H), 7.68 (br, 1H), 7.60-
7.53 (m, 3H); IR (cm-1) 1690, 1570, 1375. Anal. (C12H10N4O3)
C, H, N.
1
0.151
1
Vw(2′)
IR spectra were recorded using potassium bromide disks on a
Perkin-Elmer 1600 FT-IR spectrophotometer. Only the most
significant IR absorption bands are listed. 1H NMR spectra
were recorded at 300 MHz on a Bruker 300 instrument.
Chemical shifts are expressed in δ (ppm) and the coupling
constants J in hertz (Hz). The following abbreviations are
used, s, singlet; d, doublet; t, triplet; q, quartet; qn, quintet;
m, multiplet; dd, double doublet; br, broad signal. Signals due
to OH and NH protons were located by deuterium exchange
with D2O.
4-Benzoylpyridazine (1) was synthesized according to the
procedure described by Heinisch et al.13 The synthesis of
compounds 2-23 was described by Kneubu¨hler et al.11 and
Carotti et al.15 A pure sample of 3-Phenyl-5H-pyridazino[4,3-
b]indole 32 was kindly provided by Prof. F. Campagna
(University of Bari, Italy).
3-(4′-Tr iflu or om eth ylp h en yl)-5,6,7,8-tetr a h yd r op yr im -
id o[4,5-c]p yr id a zin -5,7-d ion e (31). Compound 31 was pre-
pared in 85% yield by the same procedure described for 30:
1
mp 274-6 °C dec, from EtOH/dioxane; H NMR (acetone-d6)
δ 8.81 (s, 1H), 8.24 (d, 1H, J ) 8.0), 7.97 (br, 1H), 7.89 (d, 1H,
J ) 8.0), 6.68 (br, 1H), 7.60-7.53 (m, 2H); IR (cm-1) 1720,
1335, 1120. Anal. (C13H7F3N4O2) C, H, N.
3-P h en yl-6,7-d ih yd r o-5H-cyclop en ta [c]p yr id a zin e (26).
A mixture of ω-bromoacetophenone (4.98 g, 25 mmol) and 4-(1-
cyclopenten-1-yl)morpholine (4.2 mL, 26.25 mmol) in 50 mL
of anhydrous dioxane was heated at reflux under magnetic
stirring for 15 h. After the mixture cooled to 60 °C, 100 mL of
0.01 N HCl was added, and the solution was stirred at the
same temperature for 2 h. After the solution cooled to room
temperature, dioxane was evaporated under reduced pressure
and the solution extracted with CHCl3. The extracts were
dried over Na2SO4 and evaporated to dryness. The oil residue
was purified by column chromatography on silica gel (hexane/
ethyl acetate, 65/35 v/v, as eluent) giving pure 2-phenacyl-
pentan-1-one 24 (2.88 g, 57% yield). Analytical data are
consistent with those reported in the literature.27 Hydrazine
hydrate 98% (0.66 mL, 13.65 mmol) was added under magnetic
stirring to the solution of 24 (2.63 g, 13 mmol) in 260 mL of a
solvent mixture (CHCl3/Et2O, 4/1, v/v). After 4 h, the reaction
mixture was evaporated to dryness and the oil residue so
obtained was treated with Et2O to give the intermediate 25
(not isolated), which spontaneously dehydrogenated to 26. Pure
26 was obtained in 58% yield by column chromatography on
silica gel (CHCl3/AcOEt, 9/1 v/v, as eluent): mp 124-5 °C, from
CHCl3/hexane; 1H NMR (CDCl3) δ 8.00 (dd, 2H, J ) 7.9, 1.5),
7.65 (t, 1H, J ) 1.2), 7.52-7.44 (m, 3H), 3.25 (t, 2H, J ) 7.6),
1-(N,N-d im eth yla m in om eth ylid en )in d a n -2-on e (33a ).
To a solution of indan-2-one (2.64 g, 20 mmol) in 40 mL of
CHCl3 was added dropwise 2.65 mL (20 mmol) of N,N-
dimethylformamide dimethyl acetal under magnetic stirring
at room temperature. Then the solvent was evaporated under
reduced pressure, and the enaminone 33a was obtained as
violet solid (2.70 g, yield 72%) and used without further
purification for the subsequent reaction: mp 86-8 °C dec, from
1
CHCl3/hexane; H NMR (CDCl3) δ 7.25 (t, 1H, J ) 7.7), 7.15
(d, 1H, J ) 7.7), 7.14 (t, 1H, J ) 7.7), 6.99 (d, 1H, J ) 7.7),
6.95 (s, 1H), 3.39 (d, 1H, J ) 14.0), 3.36 (d, 1H, J ) 14.0), 3.33
(s, 3H), 3.23 (s, 3H); IR (cm-1) 1670, 1380, 755. Anal. (C12H13
NO) C, H, N.
-
2-P h en yl-9H-in d en o[2,1-d ]p yr im id in e (34a ). To a sus-
pension of sodium methoxide (0.162 g, 3 mmol) and benzami-
dine hydrochloride hydrate (0.57 g, 3 mmol) in 3 mL of
anhydrous EtOH were added dropwise under stirring 3 mL of
a solution of enaminone 33a (0.28 g, 1.5 mmol) in anhydrous
EtOH. The reaction mixture was refluxed for 1 h, and then it
was allowed to cool, filtered off, poured into 30 mL of water,
and neutralized with 1 N HCl. The aqueous solution was
extracted with CHCl3, and the extracts were dried over Na2-
SO4 and evaporated to dryness giving a violet solid residue
(0.36 g, 99% yield) of 2-Phenyl-9H-indeno[2,1-d]pyrimidine
(34a ), which was partly purified by treatment with activated
carbon and crystallized from EtOH: mp 185-6 °C, from EtOH;
1H NMR (CDCl3) δ 9.10 (s, 1H), 8.54-8.46 (m, 2H), 7.84 (dd,
1H, J ) 6.2, 2.1), 7.61 (dd, 1H, J ) 7.1, 1.1), 7.53-7.37 (m,
5H), 4.06 (s, 2H); IR (cm-1) 1550, 1385, 755, 710, 690. Anal.
(C17H12N2) C, H, N.
3.02 (td, 2H, J ) 7.6, 1.2), 2.19 (qn, 2H, J ) 7.6); IR (cm-1
)
1415, 695. Anal. (C13H12N2) C, H, N.
5,6,7,8-Tetr a h yd r ocin n olin -5-on e (29). The intermediate
triketone 27 was prepared by the reaction between cyclohexan-
1,3-dione and 2-bromoacetophenone, according to the proce-
dure described by Stetter14 and used without further purifi-
cation (mp 146-8 °C; lit. mp 158.5 °C) for the subsequent
reaction. Hydrazine hydrate 98% (0.97 mL, 2 mmol) was
added under magnetic stirring to a solution of 27 (0.46 g, 2
mmol) in 40 mL of anhydrous EtOH. After 30 min, 0.45 g (2
mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was
added, and the solution was heated at reflux for 30 min and
then evaporated to dryness to give an oil residue. The oil was
2-P h en yl-9H-in d en o[2,1-d ]p yr im id in -9-on e (35). A so-
lution of 34a (0.73 g, 0.3 mmol) and chromic anhydride (0.40
g, 0.4 mmol) in 6 mL of glacial acetic acid was heated at reflux
for 30 min. Upon cooling to room temperature, the solution
was diluted with 20 mL of water and extracted with CHCl3.
The combined extracts were washed with a saturated solution

3818 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Altomare et al.
of NaHCO3 and water and then dried (Na2SO4) and evaporated
to dryness. The oil residue obtained was purified by flash
chromatography on silica gel, using CHCl3/hexane (9/1, v/v)
as eluent, to give 0.39 g of compound 35, which was further
purified by crystallization from EtOH (50% yield): mp 228-9
where tR is the average retention time of triplicate injections
of the analyte.
The enthalpy and entropy of retention were derived from a
van’t Hoff plot. In each experimental plot the squared
correlation coefficient usually amounted to about 0.95. More-
over, thermodynamic data were examined for enthalpy-
entropy compensation effects.20 An enthalpy-entropy com-
pensation in RP-HPLC exists when the following relatioship
is verified
1
°C, from ethanol; H NMR (CDCl3) δ 9.07 (s, 1H), 8.55-8.50
(m, 2H), 7.81 (dt, 1H, J ) 7.4, 1.0), 7.67-7.59 (m, 2H), 7.52-
7.47 (m, 3H), 7.43 (td, 1H, J ) 7.1, 1.8); IR(cm-1) 1730, 1385.
Anal. (C17H10N2O) C, H, N.
2-(N,N-d im eth yla m in om eth ylid en )in d a n -1-on e (33b).
A mixture of 0.66 g (5.0 mmol) of indan-1-one and 1.25 mL
(9.4 mmol) of N,N-dimethylformamide dimethyl acetal was
heated at reflux for 3 h. Upon cooling to room temperature,
the enaminone 33b precipitated as a red orange solid and was
collected by filtration (0.92 g, yield 98%) and used without
further purification for the subsequent reaction (mp 148-50
°C; lit.28 mp 158 °C, from CHCl3/hexane).
2-P h en yl-5H-in d en o[1,2-d ]p yr im id in e (34b). With the
exception of reaction time (7h at reflux), this compound was
prepared in 52% yield following the procedure described above
for compound 34a : mp 155-6 °C, from EtOH; 1H NMR
(CDCl3) δ 8.89 (s, 1H), 8.56 (dd, 2H, J ) 8.1, 1.6), 8.26 (dd,
1H, J ) 6.3, 2.4), 7.66-7.61 (m, 1H), 7.57-7.44 (m, 5H), 3.95
(s, 2H); IR(cm-1) 1580, 1545, 1385, 745. Anal. (C17H12N2) C,
H, N.
ln kT ) -(∆H°/R)(1/T - 1/â) - ∆Gâ/Râ + ln φ (12)
where â is a compensation proportionality factor between ∆H°
and ∆S°; this factor has the dimension of absolute temperature
and is generally termed the compensation temperature. Since
in our study both enthalpy and entropy were derived from the
same equation (van’t Hoff equation), to distinguish between
artifactual and genuine chemical compensation effect, we
applied the method proposed by Krug et al.29 to the analysis
of our data. Thus, in the plot of ln k vs ∆H° at Thm (see Figure
3), from the slope of the line relative to IPyd congeners (12
and 14 omitted as outliers; n ) 22; r2 ) 0.806; s ) 0.512), we
calculated â ) 592 K with a 95% confidence interval of 495-
738 K and compared it with the harmonic mean temperature,
Thm (306 K). Since Thm did not fall within the 95% confidence
interval of the estimated value for â, we could conclude that
the observed compensation has a chemical cause.
2-P h en yl-5H-in d en o[1,2-d ]p yr im id in -5-on e (36). The
oxidation of compound 34b by CrO3 to give compound 36 was
carried out following the same procedure described for com-
pound 35 (reaction time, 4 h; 87% yield): mp 172-3 °C, from
X-r a y Cr ysta llogr a p h y of C17H9N3O3 (8). Crystal data
for C17H9N3O3: very thin orange plates from ethanol, 0.84 ×
0.42 × 0.04 mm, triclinic, space group P1 (No. 2), a ) 7.888-
(3), b ) 8.973(3), c ) 11.565 Å, R )105.08(2)°, â ) 99.57(2)°, γ
) 113.10(2)°, V ) 693.0(4) Å, Z ) 2, fw 303.27, dcalc ) 1.453
g/cm3, µ(Mo KR) ) 0.103 mm-1. Data were collected at room
temperature (293 K) on a Stoe AED2 4-circle diffractometer
using Mo KR graphite monochromated radiation (λ ) 0.710 73
Å) with ω/2θ scans in the 2θ range 5-51°. A total of 2400
independent reflections were measured, only 847 could be
observed with I > 2σ(I), limits h -9/9, k -10/10, l 0/13, and
no correction for absorption was applied. The structure was
solved by direct methods using the program SHELXS-86.30 The
refinement and all further calculations were carried out using
SHELXL-93.31 All of the H-atoms were included in calculated
positions and allowed to ride on the corresponding C atom.
The non-H atoms were refined anisotropically, using weighted
1
EtOH; H NMR (CDCl3) δ 8.94 (s, 1H), 8.60 (dd, 2H, J ) 8.0,
1.7), 8.05 (d, 1H, J ) 7.4), 7.69 (td, 1H, J ) 7.4, 1.0), 7.60 (dd,
1H, J ) 7.4, 1.0), 7.56-7.50 (m, 3H), 7.44 (t, 1H, J ) 7.4); IR
(cm-1) 1720, 1390, 740. Anal. (C17H10N2O) C, H, N.
Deter m in a tion of P a r tition Coefficien ts. Partition
coefficients were determined in 1-octanol (Poct) or cyclohexane
(Pcyh) and pH 7.4 phosphate buffer (0.05 M) at room temper-
ature by a conventional shake-flask technique. Solute con-
centrations in aqueous phase before partitioning were within
the range 1 × 10-4 to 1 × 10-3 M. To help dissolution of very
hydrophobic solutes in water, methanol or N,N-dimethylform-
amide was used in a small volume (less than 2% v/v). The
concentration of each compound in the aqueous phase before
and after partitioning was measured spectrophotometrically
(UV) or by HPLC. All of the partition coefficients are the
means of at least five determinations within the above
concentration range.
full-matrix least-squares on F2. Final R1 ) 0.0883, Rw2
)
Calculated log Poct values were obtained by the fragmental
method of Hansch and Leo16 using the MacLog P 2.0 program
(BioByte Corp., Claremont, CA).
0.1989 (observed data), goodness of fit on F2 0.920, residual
density max/min 0.256/-0.252 e Å-3. The data-to-parameter
ratio (847/209) for the observed data was only 4.1 due to the
fact that the crystal did not diffract significantly beyond 40°
in 2θ.
Th er m od yn a m ics of Reten tion in RP -HP LC. All chro-
matographic measurements were performed on a Waters
HPLC model 600 multisolvent delivery system (Waters Assoc.,
Milford, MA) equipped with a Waters 481 variable wavelength
detector. The mobile phase, which constisted of a mixture of
methanol and 0.01 M phosphate buffer, pH 5.6 (45/55, v/v),
was continually purged with helium. A 5-µm Supelcosil LC-
18 column (50 × 4.6 mm i.d.; Supelco Inc., Bellefonte, PA) was
used as the stationary phase. The mobile phase was delivered
from a glass reservoir, which was thermostated at the same
temperature as that of the column. Temperature control, (0.1
°C, was mantained by a recirculating water bath.
The chromatographic parameters were averages of at least
triplicate determinations of each solute, and detection was at
254 or 210 nm. Retention data were measured at seven
different temperatures over a temperature range 18 to 48 °C.
Before each run, the column was equilibrated with mobile
phase for at least 30 min at a flow rate of 1.0 mL/min. This
procedure was repeated each time the column temperature
was changed. The column void time, t0, was determined by
recording the first baseline perturbation. The capacity factor
k for each solute was calculated as
The bond lengths and angles are normal within experimen-
tal error. The molecular structure and crystallographic num-
bering scheme of 8 is illustrated in Figure 2, drawn using the
program Xtal GX.32 Full tables of atomic parameters and
bond lengths and angles may be obtained from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ (UK) on quoting the full journal citation.
P r ep a r a tion of Ra t Br a in Mitoch on d r ia . Rat brain
mitochondria were isolated according to the method of Clark33
modified by Walther et al.34 For further details, see Thull et
al.35 The protein content of the washed mitochondrial fraction
was determined according to the procedure of Lowry36 with
bovine serum albumin as a standard.
MAO In h ibition Assa y. The method of Weissbach21 was
modified to measure inhibitory activities. IC50 values were
calculated from a hyperbolic equation described elsewhere.35
Time dependence was tested by preincubating for 5 and 15
min at 37 °C and at a single concentration of the inhibitor.
Reversibility was demonstrated by measuring the degree of
inhibition in the presence of a higher substrate concentration
(540 µM). For details on the MAO assay, see Kneubu¨hler et
al.11
k ) (tR - t0)/t0
(11)

Pyridazines and Pyrimidines as MAO Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3819
(11) (a) Kneubu¨hler, S.; Carta, V.; Altomare, C.; Carotti, A.; Testa,
B. Synthesis and monoamine oxidase inhibitory activity of
3-substituted 5H-indeno[1,2-c]pyridazines. Helv. Chim. Acta
1993, 76, 1954-1963. (b) Kneubu¨hler, S.; Thull, U.; Altomare,
C.; Carta, V.; Gaillard, P.; Carrupt, P.-A.; Carotti, A.; Testa, B.
Inhibition of monoamine oxidase-B by 5H-indeno[1,2-c]py-
ridazines: Biological activities, quantitative structure-activity
relationships (QSARs) and 3D-QSARs. J . Med. Chem. 1995, 38,
3874-3883.
(12) Gaillard, P.; Carrupt, P.-A.; Testa, B.; Boudon, A. Molecular
lipophilicity potential, a tool in 3D QSAR: Method and applica-
tions. J . Comput.-Aided Mol. Des. 1994, 8, 83-96.
(13) Heinish, G.; J entzsch, A.; Pailer, M. C-4 Substituted pyridazines
by homolitic alkylation and acylation. Monatsh. Chem. 1974,
105, 648-652.
(14) Stetter, H.; Siehnhold, E. Zur kenntnis des kondensation-
sproduktes aus dihydroresorcin und phenacylbromid. Chem. Ber.
1955, 88, 271-274.
(15) (a) Carotti, A.; Carta, V.; Campagna, F.; Altomare, C.; Casini,
G.; An efficient route to biologically active 5H-indeno[1,2-c]-
pyridazin-5-ones. Farmaco 1993, 48, 137-141. (b) Altomare, C.;
Campagna, F.; Carta, V.; Cellamare, S.; Carotti, A.; Genchi, G.;
De Sarro, G. Farmaco 1994, 49, 313-323.
(16) (a) Hansch, C.; Leo, A. The FRAGMENT method of calculating
partition coefficients. In Substituent constants for correlation
analysis in chemistry and biology. Wiley: New York, 1979; pp
18-43. (b) Hansch, C.; Leo, A.; Hoekman, D. Exploring QSAR.
Hydrophobic, Electronic, and Steric Constants, ACS Professional
Reference Book; American Chemical Society: Washington, DC,
1995. (c) Van de Waterbeemb, H.; Testa, B. The parametrization
of lipophilicity and other structural properties in drug design.
In Advances in Drug Research; Testa, B., Ed.; Academic Press:
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Regr ession An a lysis. Multiple linear regression (MLR)
analysis was performed using the commercially available
statistical package PARVUS 1.237 running on an IBM-compat-
ible PC.
Ack n ow led gm en t. The Italian authors gratefully
acknowledge support from MURST and CNR (Rome,
Italy). B.T. and P.A.C. are indebted to the Swiss
National Science Foundation for support. The authors
wish to thank Prof. F. Campagna (University of Bari,
Italy) for the kind gift of a pure sample of 3-phenyl-5H-
pyridazino[4,3-b]indole.
Su p p or tin g In for m a tion Ava ila ble: Tables of relevant
details of the X-ray crystallographic studies and tables of final
atomic parameters, full bond lengths and angles, anisotropic
thermal parameters, hydrogen atom positions, selected torsion
angles, and various least-squares planes (7 pages). Ordering
information is given on any current masthead page.
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