Synthesis of ortho-functionalized 4-aminomethylpyridazines as substrate-like semicarbazide-sensitive amine oxidase inhibitors

Article abstract of DOI:10.1248/cpb.58.964

A series of 4-aminomethylpyridazines and -pyridazin-3(2H)-ones ( diaza-benzylamines ), bearing alkylamino side chains in ortho position relative to the CH₂NH₂ unit, was synthesized by catalytic hydrogenation of the corresponding nitriles in strongly acidic medium. N-Benzyl protecting groups either at the pyridazinone ring nitrogen or at an exocyclic nitrogen were selectively removed hydrogenolytically or by treatment with a Lewis acid. The new compounds were tested in vitro for semicarbazide-sensitive amine oxidase (SSAO) inhibitory activity and 4-(aminomethyl)-N,N-diethylpyridazine-3,5-diamine (22) was found to be the most active representative.

Full text of DOI:10.1248/cpb.58.964

964
Note
Chem. Pharm. Bull. 58(7) 964—970 (2010)
Vol. 58, No. 7
Synthesis of ortho-Functionalized 4-Aminomethylpyridazines as
Substrate-Like Semicarbazide-Sensitive Amine Oxidase Inhibitors
a
Norbert HAIDER,*,a Iris HOCHHOLDINGER,a Péter MÁTYUS,b and Andrea WOBUS
a Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna; Althanstraße 14, A-
1090 Vienna, Austria: and b Department of Organic Chemistry, Semmelweis University; Högyes E. u. 7, H-1092 Budapest,
Hungary. Received January 13, 2010; accepted April 1, 2010; published online April 12, 2010
A series of 4-aminomethylpyridazines and -pyridazin-3(2H)-ones (“diaza-benzylamines”), bearing alkyl-
amino side chains in ortho position relative to the CH2NH2 unit, was synthesized by catalytic hydrogenation of
the corresponding nitriles in strongly acidic medium. N-Benzyl protecting groups either at the pyridazinone ring
nitrogen or at an exocyclic nitrogen were selectively removed hydrogenolytically or by treatment with a Lewis
acid. The new compounds were tested in vitro for semicarbazide-sensitive amine oxidase (SSAO) inhibitory activ-
ity and 4-(aminomethyl)-N,N؅-diethylpyridazine-3,5-diamine (22) was found to be the most active representative.
Key words 4-aminomethylpyridazine; diaza-benzylamine; selective debenzylation; semicarbazide-sensitive amine oxidase/vas-
cular adhesion protein 1; semicarbazide-sensitive amine oxidase inhibitor
4-Aminomethylpyridines with one or two substituents of preliminary in-vitro biological evaluation of a series of new
the type alkyl-X- (XϭNH, O, S) at the C-3 and/or C-5 posi- 4-aminomethylpyridazine derivatives (“diaza-benzylamines”)
tion have been reported by Bertini et al.1,2) to exhibit signifi- with various alkylamino side chains located at one or both
cant inhibitory activity towards copper-containing amine oxi- positions ortho to the CH2NH2 moiety.
dases. Obviously, these compounds can mimick benzyl-
Despite the close structural similarity between the envisaged
amine, which is a prototypical substrate of these enzymes, 4-aminomethylpyridazines and the known 4-aminomethylpyri-
and thus these “aza-benzylamines” were classified as sub- dine lead compounds, we had to develop different synthetic
strate-like amine oxidase inhibitors.2) Among the copper- strategies in order to make the target compounds accessible.
containing amine oxidases, the enzyme named “semicarb- As 2-aza analogues of the 4-aminomethyl-3-alkylaminopy-
azide-sensitive amine oxidase” (SSAO), which is also known ridines,2) we first prepared the corresponding 4-aminomethyl-
as “vascular adhesion protein 1” (VAP-1) has found particu- pyridazines (3a—d) with C1—C4 alkylamino substituents at
lar attention and has been extensively investigated with re- position C-3. As the starting material, we chose 3-chloro-4-
spect to its role in various pathophysiological conditions.3—5) pyridazinecarbonitrile10) (1) which is easily accessible from
Among other implications, both for its plasma-soluble and its commercial reagents in two steps.10,11) First, the activated
tissue-bound forms, inflammatory processes and many of the chloro substituent was replaced with the requisite alkylamino
well-known late-stage complications of type-2 diabetes (such group by treatment with the appropriate amine in ethanolic
as vascular damage and retinopathy) have been associated solution at room temperature. After optimization of the reac-
with increased levels of SSAO activity.6,7) Thus, SSAO was tion times (1—4 h, depending on the alkyl chain length), the
recognized as an interesting target for new drug molecules 3-alkylamino-4-pyridazinecarbonitriles 2a—d were obtained
which could open new possibilities in the prevention and in yields between 76% and 92%. In a subsequent step, the
treatment of such diseases. Although a large number of cyano group was reduced to the desired aminomethyl group
SSAO-inhibitory agents has been identified so far, a really by catalytic hydrogenation in strongly acidic medium.
effective and selective compound fulfilling all requirements
Extending the compound library towards 4-aminomethyl-
for clinical application is still lacking, and the search for new pyridazines with heteroatom substituents both at C-3 and C-
lead structures is continuing. Among the various approaches, 5, we developed a synthesis of pyridazin-3(2H)-one deriva-
the development of 4-aminopyridines as substrate-like in- tives bearing a (cyclic) dialkylamino moiety at position C-5,
hibitors (see above) deserves attention, as these compounds next to the essential CH2NH2 group at position C-4. Starting
do not possess the frequently observed toxicity of classical from 4,5-dichloro-2-methylpyridazin-3(2H)-one12) (4), we
carbonyl reagents such as hydrazine derivatives, which are made use of the well-known regioselective nucleophilic dis-
known to irreversibly block the enzyme by forming a cova- placement of the 5-chloro function by secondary amines in
lent bond with the topaquinone subunit of SSAO.3,4) Starting aqueous medium (apolar solvents would favor substitution at
from the structural motif of Bertini’s 4aminomethylpyridines position C-4).13) Reaction of 4 with pyrrolidine or morpho-
(“aza-benzylamines”),2) we now took the aza-bioisosterism
principle one step further, as we envisaged replacement of
the pyridine ring by a pyridazine ring. It is well known that
exchange of a pyridine by a diazine (and especially by a
pyridazine) can significantly alter the physicochemical
properties of a compound (lower basicity, higher dipole
moment, increased water solubility), as demonstrated, for
instance, with some aza analogues of the pyridocarbazole
alkaloids.8,9) Here, we wish to report on the synthesis and
Chart 1
∗ To whom correspondence should be addressed. e-mail: norbert.haider@univie.ac.at
© 2010 Pharmaceutical Society of Japan

July 2010
965
Chart
2
line gave the known 4-chloro-5-cycloaminopyridazinones 5 position, we had to further modify the synthetic pathway
5a14) and 5b,13) respectively. Attempts to directly replace the described above. Starting from a 4,5-dichloropyridazin-3(2H)-
4-chloro substituent in compounds of type 5 with a cyano one precursor with a removable substituent at the pyridazine
function by palladium-catalyzed cyanation15) failed, so we N-2 atom should offer this option. Thus, the 2-benzyl com-
decided to introduce the requisite carbon side chain at posi- pound 1219) was reacted with N-ethylbenzylamine in water,
tion C-4 by an electrophilic substitution reaction, after reduc- which gave the 5-substitution product 13 along with its 4-iso-
tive removal of the halogen. Thus, catalytic transfer hydro- mer. Again, chromatographic isomer separation was success-
genation of 5a, b with ammonium formate/palladium gave fully performed after the dehalogenation step, and the result-
the known 5-cycloaminopyridazinones 6a16) and 6b,13) re- ing 4-unsubstituted intermediate 14 was formylated to give
spectively. Vilsmeier–Haack formylation of these electron- the aldehyde 15. Attempts to remove the benzyl protecting
rich pyridazinones then afforded the aldehydes 7a, b.17) group from the ring nitrogen by treatment with a Lewis acid
Treatment of the crude aldehydes with hydroxylamine hy- (AlCl3) in toluene failed, so we decided to postpone this
drochloride/sodium acetate in aqueous ethanol smoothly deprotection step. Transformation of the aldehyde 15 into the
gave the corresponding oximes (8). These new compounds nitrile 17 was achieved smoothly via the oxime 16, which
were obtained either as an E/Z mixture (in the case of 8a) or was isolated as a 4 : 1 E/Z isomer mixture. Whereas catalytic
as the pure E-configured isomer (in the case of 8b), as deter- hydrogenation of the nitrile 17 in acidic medium at 3.44 bar
1
mined by H-NMR spectroscopy (nuclear Overhauser effect effected selective debenzylation at the tertiary amino group
(NOE) between the aldehydic proton and the N-OH proton of (together with reduction of the cyano group) to yield com-
the E-oxime; see Experimental). Dehydration of the oximes pound 18, the 2-benzyl residue in 17 could be selectively
by heating in acetic anhydride led to the nitriles 9a, b, which removed with AlCl3 in toluene (in analogy to lit.20—26)),
then were reduced to the target aminomethyl compounds affording the 2-unsubstituted pyridazinone 19. When the lat-
10a, b by catalytic hydrogenation in ethanol in the presence ter was heated in phosphorus oxychloride at 110 °C, the 3-
of 2 N hydrochloric acid.
chloropyridazine 20 was obtained in good yield. Treatment
In an analogous manner, the 5-ethylamino compound 11 of this reactive intermediate with methanolic ethylamine then
was prepared, starting from 4 and N-ethylbenzylamine.18) In gave the 3-ethylamino-4-pyridazinecarbonitrile 21. In the
this case, regioselectivity of the nucleophilic substitution re- final step, the cyano group was reduced to the CH2NH2 moi-
action with the secondary amine was much lower, and the ety and the benzyl group was hydrogenolytically removed,
product (5c) was found to contain substantial amounts of the again by catalytic hydrogenation at slightly elevated pressure
4-dialkylamino-5-chloro isomer. Chromatographic separation in strongly acidic ethanol (which requires 6 N hydrochloric
turned out to be difficult, but could be achieved much more acid, in this case). Thus, the target 4-aminomethyl-N,NЈ-
conveniently after the next reaction step, i.e. reductive de- diethylpyridazine-3,5-diamine (22) was obtained in good
halogenation, thus giving the 4-unsubstituted intermediate 6c yield as the corresponding dihydrochloride.
in high purity. The remaining steps in this sequence leading
In a screening assay on recombinant human SSAO, the
to 11 are analogous to those described for the synthesis of 3,4-disubstituted pyridazines 3a—d showed only weak in-
10a, b. The benzyl protecting group is removed during the hibitory activity (between 27% and 47% at a fixed sample
final hydrogenation reaction, which requires slightly elevated concentration of 500 mM), with the methylamino compound
pressure.
3a as the most active representative (see Table 1). Among the
In order to find an access also to 4-aminomethylpyrid- pyridazin-3(2H)-one derivatives, only the morpholino-substi-
azines bearing alkylamino groups both at the C-3 and the C- tuted compound 10b was found to possess moderate activity,

966
Vol. 58, No. 7
Chart 3
Table 1. Inhibitory Activity (% Inhibition) of Compounds 3a—d, 10a, b,
11, 18 and 22 on Recombinant Human SSAO at a Fixed Sample Concentra-
tion of 500 mM
(4 ml) was added a 33% solution of methylamine in absolute ethanol
(0.60 ml, 4.8 mmol), and the mixture was stirred at room temperature for 1 h.
The volatile components were removed under reduced pressure, the residue
was taken up in 2 M aqueous Na2CO3 (15 ml) and it was extracted several
times with dichloromethane. The combined extracts were washed with
water, dried, and evaporated. The residue was purified by column chro-
matography (eluent: dichloromethane/ethyl acetate, 4 : 1) to give compound
2a (204 mg, 76%) as a pale yellow solid. Recrystallization from tert-butyl
Compound
3a
3b
3c
3d
10a 10b
93
11
18
22
% inhibition 47
29
44
27 Ͻ10
13 Ͻ10 Ͼ99
1
methyl ether afforded almost colorless crystals, mp 149—150 °C. H-NMR
(CDCl3) d: 3.23 (3H, d, Jϭ4.8 Hz, NHCH3), 5.45 (1H, br, NHCH3), 7.35
(1H, d, Jϭ4.8 Hz, 5-H), 8.69 (1H, d, Jϭ4.8 Hz, 6-H). 13C-NMR (CDCl3) d:
28.9, 97.7, 114.1, 129.2, 141.8, 156.2. IR (KBr) cmϪ1: 3392, 3261, 3137,
3059, 2225, 1589, 1505, 1387, 1296, 1137, 1036, 869, 837, 769, 599. MS
m/z (rel. int.): 135 ([Mϩ1]ϩ, 12%), 134 (Mϩ, 100), 106 (9), 91 (7), 80 (49),
79 (36), 65 (15), 64 (40), 55 (40), 52 (17). Anal. Calcd for C6H6N4: C,
53.72; H, 4.51; N, 41.77. Found: C, 54.07; H, 4.56; N, 41.57.
with an IC50 value of Ͼ200 mM (93% inhibition at 500 mM
sample concentration). The most significant SSAO inhibitory
activity was observed with the triamine 22, for which an IC50
value of 30 mM was found. The latter compound thus offers
some potential for further investigation and derivatization.
Structural modification, in this case, will be facilitated by our
flexible synthetic pathway, principally permitting also the in-
troduction of different alkylamino substituents at C-3 and C-
5 of the pyridazine nucleus. Our results also indicate that
isosteric replacement of the benzene ring of benzylamines
might lead to SSAO inhibitors.
3-(Ethylamino)pyridazine-4-carbonitrile (2b) To a solution of 3-
chloropyridazine-4-carbonitrile (1) (279 mg, 2 mmol) in absolute ethanol
(4 ml) was added a 2 M solution of ethylamine in methanol (2.2 ml,
4.4 mmol), and the mixture was stirred at room temperature for 2.5 h. Work-
up and chromatographic purification were done exactly as described for 2a,
yielding compound 2b (269 mg, 91%) as a pale yellow solid. Recrystalliza-
tion from tert-butyl methyl ether/light petroleum afforded almost colorless
crystals, mp 101—102 °C. 1H-NMR (CDCl3) d: 1.33 (3H, t, Jϭ7.2 Hz,
NHCH2CH3), 3.67—3.76 (2H, m, NHCH2CH3), 5.29 (1H, br, NHCH2CH3),
7.34 (1H, d, Jϭ4.8 Hz, 5-H), 8.67 (1H, d, Jϭ4.8 Hz, 6-H). 13C-NMR
Experimental
Melting points (uncorrected) were determined on a Kofler hot-stage
microscope (Reichert). 1H- and 13C-NMR spectra were recorded on a Varian
UnityPlus 300 spectrometer (300, 75 MHz, respectively). IR spectra were
recorded on a Perkin-Elmer 1605 FTIR or on a Perkin-Elmer Spectrum 1000
FTIR instrument. Mass spectra were recorded on a Shimadzu QP5050A
spectrometer, high-resolution mass spectra were obtained on a Finnigan
MAT 8230 instrument at the Institute of Organic Chemistry, University of
Vienna. Elemental analyses were carried out at the Microanalytical Labora-
tory, Faculty of Chemistry, University of Vienna. Column chromatography
was performed on Merck Kieselgel 60 (0.063—0.200 mm), unless stated
otherwise. For TLC, Merck aluminium sheets pre-coated with Kieselgel 60
F254 were used. Compounds 1,10) 4,12) 5a,14) 5b,13) 6a,16) 6b,13) 7a,17) 7b,17)
and 1219) were prepared by known procedures.
For determination of the SSAO inhibitory activity, the spectrophotometric
assay described by Holt et al.27) for monoamine oxidase and analogous en-
zymes was used, employing benzylamine as the substrate. Recombinant
SSAO/VAP-1 enzyme was expressed in Chinese Hamster Ovary cells
(CHO), these cells and cell cultures have been described earlier by Smith
et al.28)
(CDCl3) d: 14.4, 36.9, 97.4, 114.1, 129.1, 141.7, 155.7. IR (KBr) cmϪ1
:
3363, 3043, 2974, 2873, 2229, 1586, 1566, 1498, 1354, 1285, 1133, 1045,
858, 770, 599. MS m/z (rel. int.): 149 ([Mϩ1]ϩ, 9%), 148 (Mϩ, 78), 133
(58), 120 (100), 106 (24), 95 (21), 79 (37), 66 (66), 65 (58), 64 (89), 52 (34).
Anal. Calcd for C7H8N4: C, 56.74; H, 5.44; N, 37.81. Found: C, 57.09; H,
5.29; N, 37.61.
3-(Propylamino)pyridazine-4-carbonitrile (2c) To a solution of 3-
chloropyridazine-4-carbonitrile (1) (279 mg, 2 mmol) in absolute ethanol
(6 ml) was added freshly distilled propylamine (260 mg, 4.4 mmol), and the
mixture was stirred at room temperature for 3 h. Work-up and chromato-
graphic purification were done exactly as described for 2a, yielding com-
pound 2c (287 mg, 88%) as a yellow solid. Recrystallization from tert-butyl
methyl ether/light petroleum afforded pale yellow crystals, mp 79—80 °C.
1H-NMR (CDCl3) d: 1.01 (3H, t, Jϭ7.4 Hz, NHCH2CH2CH3), 1.67—1.80
(2H, m, NHCH2CH2CH3), 3.62—3.68 (2H, m, NHCH2CH2CH3), 5.26 (1H,
br, NHCH2CH2CH3), 7.33 (1H, d, Jϭ4.8 Hz, 5-H), 8.67 (1H, d, Jϭ4.8 Hz, 6-
H). 13C-NMR (CDCl3) d: 11.2, 22.3, 43.6, 97.4, 114.1, 129.1, 141.6, 155.8.
IR (KBr) cmϪ1: 3232, 3127, 2964, 2875, 2229, 1582, 1502, 1370, 1298,
1146, 1101, 1049, 845, 599. MS m/z (rel. int.): 163 ([Mϩ1]ϩ, 13%), 162
(Mϩ, 23), 147 (23), 135 (36), 133 (72), 120 (100), 106 (21), 92 (11), 79
3-(Methylamino)pyridazine-4-carbonitrile (2a) To a solution of 3-
chloropyridazine-4-carbonitrile (1) (279 mg, 2 mmol) in absolute ethanol

July 2010
967
(26), 66 (28), 65 (36), 64 (42), 52 (29). Anal. Calcd for C8H10N4: C, 59.24; excess of 1 M ethereal HCl to give the hydrochloride salt as almost colorless,
1
H, 6.21; N, 34.54. Found: C, 59.42; H, 6.20; N, 34.41.
very hygroscopic crystals. H-NMR (DMSO-d6) d: 0.90 (3H, t, Jϭ7.2 Hz,
3-(Butylamino)pyridazine-4-carbonitrile (2d) To a solution of 3- NHCH2CH2CH2CH3), 1.41 (2H, sext, Jϭ7.2 Hz, NHCH2CH2CH2CH3), 1.62
chloropyridazine-4-carbonitrile (1) (279 mg, 2 mmol) in absolute ethanol (2H, quint, Jϭ7.2 Hz, NHCH2CH2CH2CH3), 3.45 (2H, t, Jϭ6.9 Hz,
(6 ml) was added freshly distilled butylamine (322 mg, 4.4 mmol), and the NHCH2CH2CH2CH3), 4.17 (2H, s, ArCH2NH2), 7.96 (1H, d, Jϭ4.8 Hz, 5-
mixture was stirred at room temperature for 4 h. Work-up and chromato- H), 8.71 (1H, d, Jϭ4.8 Hz, 6-H), 8.80—9.20 (3H, br, NH). 13C-NMR
graphic purification were done exactly as described for 2a, yielding com- (DMSO-d6) d: 13.6, 19.4, 29.3, 37.0, 41.8, 130.3, 130.6, 139.6, 153.4. IR
pound 2d (326 mg, 92%) as a tan solid. Recrystallization from light petro- (KBr) cmϪ1: 3421, 3250, 2960, 2871, 2364, 2058, 1640, 1596, 1521, 1465,
1
leum afforded almost colorless crystals, mp 34—35 °C. H-NMR (CDCl3) 1374, 1199, 881, 668, 598. HR-MS m/z: 180.1372 (Calcd for C9H16N4:
d: 0.96 (3H, t, Jϭ7.5 Hz, NHCH2CH2CH2CH3), 1.40—1.50 (2H, m, 180.1375).
NHCH2CH2CH2CH3), 1.65—1.74 (2H, m, NHCH2CH2CH2CH3), 3.65—
5-[Benzyl(ethyl)amino]-2-methylpyridazin-3(2H)-one (6c) A mixture
3.72 (2H, m, NHCH2CH2CH2CH3), 5.22 (1H, br, NHCH2CH2CH2CH3), 7.33 of 4,5-dichloro-2-methylpyridazin-3(2H)-one (4) (1.79 g, 10 mmol) and
(1H, d, Jϭ4.8 Hz, 5-H), 8.67 (1H, d, Jϭ4.8 Hz, 6-H). 13C-NMR (CDCl3) d: freshly distilled N-ethylbenzylamine (3.38 g, 25 mmol) in water (50 ml) was
13.7, 20.0, 31.2, 41.7, 97.4, 114.1, 129.0, 141.6, 155.8. IR (KBr) cmϪ1
:
refluxed for 30 h. After cooling to room temperature, the mixture was made
3239, 3124, 2958, 2930, 2872, 2224, 1582, 1505, 1420, 1291, 1140, 1053, weakly acidic with 0.1 N HCl, then it was extracted with dichloromethane.
844, 599. MS m/z (rel. int.): 177 ([Mϩ1]ϩ, 8%), 176 (Mϩ, 48), 161 (10), The extract was dried and evaporated under reduced pressure to give crude
147 (50), 139 (45), 134 (71), 133 (93), 121 (31), 120 (100), 106 (19), 76 5-[benzyl(ethyl)amino]-4-chloro-2-methylpyridazin-3(2H)-one (5c) as
(92), 64 (30), 51 (22). Anal. Calcd for C9H12N4: C, 61.34; H, 6.86; N, 31.79. brown oil. This material was dissolved in methanol (60 ml). Ammonium for-
Found: C, 61.37; H, 6.80; N, 31.77. mate (5.99 g, 95 mmol) and 10% Pd on carbon (1.0 g) were added, and the
a
4-(Aminomethyl)-N-methylpyridazin-3-amine (3a) To a solution of mixture was heated to 70 °C under an argon atmosphere until TLC (eluent:
the nitrile 2a (204 mg, 1.52 mmol) in ethanol (29 ml) and 2 N HCl (2.3 ml) ethyl acetate) indicated completion of the reaction (approx. 3 h). The catalyst
was added 10% Pd on carbon (60 mg), and the mixture was hydrogenated at was filtered off and the filtrate was evaporated under reduced pressure. The
normal pressure for 3 h. The catalyst was filtered off and the filtrate was residue was taken up in water (100 ml) and it was extracted with
evaporated under reduced pressure. The solid residue was triturated with a dichloromethane. The extract was dried and evaporated, then the residue was
mixture of methanol and tetrahydrofuran (THF) (1 : 1), then it was kept in subjected to column chromatography (eluent: dichloromethane/methanol,
1
the refrigerator for 16 h. The solid material was collected by filtration, 19 : 1) to afford compound 6c (850 mg, 35%) as a yellowish oil. H-NMR
washed with THF and dried to afford the dihydrochloride-monohydrate of (DMSO-d6) d: 1.10 (3H, t, Jϭ7.1 Hz, NCH2CH3), 3.47 (3H, s, NCH3), 3.47
1
compound 3a (200 mg, 67%) as almost colorless, hygroscopic crystals. H- (2H, q, Jϭ7.1 Hz, NCH2CH3), 4.58 (2H, s, NCH2Ph), 5.55 (1H, d, Jϭ
NMR (DMSO-d6) d: 2.99 (3H, s, NHCH3), 4.17 (2H, s, ArCH2NH2), 7.95 3.0 Hz, 4-H), 7.36—7.17 (5H, m, phenyl-H), 7.76 (1H, d, Jϭ3.0 Hz, 6-H).
(1H, d, Jϭ4.8 Hz, 1H, 5-H), 8.69 (1H, d, Jϭ4.8 Hz, 6-H), 9.00—9.40 (4H, 13C-NMR (DMSO-d6) d: 12.2, 38.1, 44.7, 52.1, 97.2, 126.4, 127.0, 128.1,
br, NH). 13C-NMR (DMSO-d6) d: 29.2, 36.9, 130.4, 130.4, 140.1, 153.5. IR 128.6, 137.3, 148.0, 160.4. IR (KBr) cmϪ1: 3294, 2974, 1626, 1593, 1454,
(KBr) cmϪ1: 3445, 3234, 2994, 2840, 2602, 1630, 1597, 1480, 1440, 1384, 1358, 1242, 1180, 974, 828, 712, 608. MS m/z (rel. int.): 244 (8%), 243
1195, 1027, 856, 769, 613, 555. HR-MS m/z: 138.0907 (Calcd for C6H10N4: (Mϩ, 55), 228 (6), 214 (11), 153 (6), 136 (6), 121 (6), 91 (100), 81 (13), 69
138.0905).
(22), 65 (14). HR-MS m/z: 243.1378 (Calcd for C14H17N3O: 243.1372).
4-(Aminomethyl)-N-ethylpyridazin-3-amine (3b) To a solution of the
5-[Benzyl(ethyl)amino]-2-methyl-3-oxo-2,3-dihydropyridazine-4-car-
nitrile 2b (269 mg, 1.8 mmol) in ethanol (35 ml) and 2 N HCl (2.8 ml) was baldehyde (7c) To a solution of compound 6c (1.21 g, 5 mmol) in dry
added 10% Pd on carbon (70 mg), and the mixture was hydrogenated at nor- N,N-dimethylformamide (DMF) (25 ml) was added dropwise at 5 °C a solu-
mal pressure for 2 h. The catalyst was filtered off and the filtrate was evapo- tion of phosphorus oxychloride (1.03 ml, 11 mmol) in dry DMF (5 ml). The
rated under reduced pressure. The residue was taken up in aqueous satuarted mixture was stirred at room temperature for 15 min, then it was heated to
Na2CO3 solution (10 ml) and it was exhaustively extracted with a mixture of 70 °C for 75 min. The volatile components were removed under reduced
chloroform and 2-propanol (9 : 1; 100 ml). The combined extracts were pressure, the residue was treated with crushed ice and it was stirred for
washed with brine (10 ml) and evaporated under reduced pressure at a tem- 20 min. The mixture was made weakly alkaline (pH 8) with 40% aqueous
perature below 25 °C. The oily residue was purified by column chromatogra- NaOH, then it was extracted with ethyl acetate. The extract was washed with
phy on neutral alumina (eluent: dichloromethane/methanol/triethylamine, brine, dried, and evaporated to give the aldehyde 7c (1.08 g, 80%) as a yel-
9 : 1 : 0.1) to afford compound 3b (240 mg, 88%) as a light-brown oil. The low oil which was used for the preparation of 8c without further purification.
base was dissolved in dry toluene (10 ml) and treated with an excess of 1 M 1H-NMR (DMSO-d6) d: 1.13 (3H, t, Jϭ7.0 Hz, NCH2CH3), 3.44—3.52 (5H,
ethereal HCl to give the hydrochloride salt as almost colorless, very hygro- m, NCH2CH3, NCH3), 4.70 (2H, s, NCH2Ph), 7.12—7.16 (2H, m, phenyl-
scopic crystals. 1H-NMR (DMSO-d6) d: 1.23 (3H, t, Jϭ7.1 Hz, H), 7.22—7.35 (3H, m, phenyl-H), 8.02 (1H, d, Jϭ0.6 Hz, 6-H), 9.98 (1H, d,
NHCH2CH3), 3.48 (2H, q, unresolved, NHCH2CH3), 4.16 (2H, s, Jϭ0.6 Hz, aldehyde-H). 13C-NMR (DMSO-d6) d: 13.0, 38.2, 48.2, 55.0,
ArCH2NH2), 7.94 (1H, d, Jϭ4.5 Hz, 5-H), 8.72 (1H, d, Jϭ4.5 Hz, 6-H), 107.1, 127.3, 127.4, 128.5, 131.0, 136.0, 147.8, 161.5, 187.6. IR (KBr)
8.90—9.10 (3H, br, NH). 13C-NMR (DMSO-d6) d: 13.0, 36.9, 37.1, 130.5, cmϪ1: 2974, 2935, 2868, 1662, 1627, 1511, 1451, 1348, 1304, 1125, 705.
130.7, 139.6, 153.1. IR (KBr) cmϪ1: 3415, 3111, 2923, 2626, 1734, 1639, MS m/z (rel. int.): 272 (4%), 271 (Mϩ, 22), 242 (44), 214 (24), 180 (79), 162
1601, 1496, 1385, 1350, 1265, 1099, 851, 762, 598. HR-MS m/z: 152.1058 (19), 152 (19), 129 (6), 110 (6), 91 (100), 81 (13), 69 (18), 65 (17). HR-MS
(Calcd for C7H12N4: 152.1062).
m/z: 271.1331 (Calcd for C15H17N3O2: 271.1321).
4-(Aminomethyl)-N-propylpyridazin-3-amine (3c) To a solution of
4-[(E,Z)-(Hydroxyimino)methyl]-2-methyl-5-(pyrrolidin-1-yl)pyrid-
the nitrile 2c (287 mg, 1.77 mmol) in ethanol (34 ml) and 2 N HCl (2.7 ml) azin-3(2H)-one (8a) To a suspension of the aldehyde 7a (207 mg, 1 mmol)
was added 10% Pd on carbon (70 mg), and the mixture was hydrogenated at in ethanol (5 ml) was added hydroxylamine hydrochloride (90 mg, 1.3 mmol)
normal pressure for 2 h. Work-up and chromatographic purification were and a solution of sodium acetate (106 mg, 1.3 mmol) in water (2 ml). The
done exactly as described for 3b, yielding compound 3c (183 mg, 62%) as a mixture was refluxed and the reaction progress was monitored by TLC (elu-
light-brown oil. The base was dissolved in dry toluene (10 ml) and treated ent: ethyl acetate/methanol, 19 : 1). After completion of the reaction (approx.
with an excess of 1 M ethereal HCl to give the hydrochloride salt as almost 3 h), the solvent was removed under reduced pressure, the residue was taken
1
colorless, very hygroscopic crystals. H-NMR (DMSO-d6) d: 0.91 (3H, t, up in water (10 ml) and it was extracted with dichloromethane. The extract
Jϭ7.2 Hz, NHCH2CH2CH3), 1.64 (2H, m, NHCH2CH2CH3), 3.42 (2H, t, Jϭ was dried and evaporated, then the residue was recrystallized from ethanol to
6.1 Hz, NHCH2CH2CH3), 4.19 (2H, s, ArCH2NH2), 7.99 (1H, d, Jϭ4.8 Hz, give the oxime 8a (111 mg, 50%) as colorless crystals, mp 168—169 °C. 1H-
5-H), 8.71 (1H, d, unresolved, 6-H), 8.90—9.30 (3H, br, NH). 13C-NMR NMR (DMSO-d6), isomer ratio E : Zϭ1 : 1.16; d: 1.80—1.88, (4H, m, pyrro-
(DMSO-d6) d: 11.1, 20.5, 37.0, 43.6, 130.4, 130.6, 139.5, 153.2. IR (KBr) lidine-H). 3.20—3.29 (4H, m, pyrrolidine-H), 3.49 (3H, s, CH3, Z isomer),
cmϪ1: 3420, 3133, 2927, 2854, 2597, 2362, 1734, 1639, 1599, 1457, 1188, 3.51 (3H, s, CH3, E isomer), 7.50 (1H, s, oxime-CH, Z isomer), 7.74 (1H, s,
902, 668, 571. HR-MS m/z: 166.1222 (Calcd for C8H14N4: 166.1218).
6-H, Z isomer), 7.78 (1H, s, 6-H, E isomer), 8.11 (1H, s, oxime-CH, E iso-
4-(Aminomethyl)-N-butylpyridazin-3-amine (3d) To a solution of the mer), 10.90 (1H, s, N–OH, Z isomer), 10.97 (1H, s, N–OH, E isomer; shows
nitrile 2d (326 mg, 1.85 mmol) in ethanol (36 ml) and 2 N HCl (2.9 ml) was positive NOE on irradiation at 8.11 ppm). 13C-NMR (DMSO-d6) d: 24.9,
added 10% Pd on carbon (70 mg), and the mixture was hydrogenated at nor- 25.0, 38.3, 38.5, 48.8, 51.0, 100.0, 101.3, 129.4, 129.9, 143.5, 143.8, 144.4,
mal pressure for 2 h. Work-up and chromatographic purification were done 144.9, 159.4, 160.5. IR (KBr) cmϪ1: 3244, 2975, 2872, 1624, 1576, 1515,
exactly as described for 3b, yielding compound 3d (280 mg, 84%) as a light- 1441, 1406, 1349, 1285, 1100, 960, 850, 760, 655, 565. MS m/z (rel. int.):
brown oil. The base was dissolved in dry toluene (10 ml) and treated with an 222 (Mϩ, 4%), 205 (100), 188 (27), 176 (6), 160 (6), 149 (5), 131 (15), 120

968
Vol. 58, No. 7
(5), 104 (12), 93 (5), 68 (6). Anal. Calcd for C10H14N4O2: C, 54.04; H, 6.35; hydride (20 ml) was refluxed for 30 min. After cooling, the mixture was
N, 25.21. Found: C, 54.04; H, 6.44; N, 25.02. poured onto ice, adjusted to pH 8 with 10% aqueous NaOH, and extracted
4-[(E)-(Hydroxyimino)methyl]-2-methyl-5-(morpholin-4-yl)pyridazin- with dichloromethane. The extract was washed with water, dried, and evapo-
3(2H)-one (8b) To a suspension of the aldehyde 7b (223 mg, 1 mmol) in rated. The residue was subjected to column chromatography (eluent:
ethanol (5 ml) was added hydroxylamine hydrochloride (90 mg, 1.3 mmol) dichloromethane/methanol, 9 : 1) to afford the nitrile 9c (536 mg, 80%) as a
and a solution of sodium acetate (106 mg, 1.3 mmol) in water (2 ml). The
yellow oil.1H-NMR (DMSO-d6) d: 1.24 (3H, t, Jϭ7.0 Hz, NCH2CH3), 3.50
mixture was refluxed and the reaction progress was monitored by TLC (elu- (3H, s, NCH3), 3.73 (2H, q, Jϭ7.0 Hz, NCH2CH3), 4.94 (2H, s, NCH2Ph),
ent: ethyl acetate/methanol, 19 : 1). After completion of the reaction (approx. 7.22—7.40 (5H, m, phenyl-H), 7.79 (1H, s, 6-H). 13C-NMR (DMSO-d6) d:
3 h), the solvent was removed under reduced pressure, the residue was taken 13.6, 38.9, 46.5, 53.3, 81.8, 116.4, 126.4, 127.4, 128.3, 128.7, 136.4, 149.8,
up in water (10 ml) and it was extracted with dichloromethane. The extract 158.9. IR (KBr) cmϪ1: 2981, 2936, 2210, 1635, 1591, 1533, 1450, 1357,
was dried and evaporated, then the residue was recrystallized from ethanol to 1028, 735. MS m/z (rel. int.): 269 (10%), 268 (Mϩ, 14), 253 (4), 239 (4),
give the E-oxime 8b (155 mg, 65%) as colorless crystals, mp 179—180 °C.
1H-NMR (DMSO-d6) d: 3.22, (4H, t, Jϭ4.7 Hz, morpholine-H), 3.56 (3H, s,
CH3), 3.66 (4H, t, Jϭ4.7 Hz, morpholine-H), 7.91 (1H, s, 6-H), 8.17 (1H, s,
oxime-CH; shows positive NOE on irradiation at 11.35 ppm), 11.35 (1H, s,
N–OH). 13C-NMR (DMSO-d6) d: 39.2, 49.9, 65.8, 109.1, 131.5, 143.5,
178 (11), 106 (17), 91 (100), 65 (12). HR-MS m/z: 268.1332 (Calcd for
C15H16N4O: 268.1324).
4-(Aminomethyl)-2-methyl-5-(pyrrolidin-1-yl)pyridazin-3(2H)-one
(10a) To a suspension of the nitrile 9a (306 mg, 1.5 mmol) in ethanol
(29 ml) were added 2 N HCl (2.3 ml) and 10% Pd on carbon (60 mg). The
147.3, 159.9. IR (KBr) cmϪ1: 3260, 2866, 1635, 1616, 1575, 1394, 1256, mixture was hydrogenated for 70 h at normal pressure, then the catalyst was
1106, 964, 888, 771, 579. MS m/z (rel. int.): 239 (4%), 238 (Mϩ, 4%), 221
filtered off and the filtrate was evaporated under reduced pressure. The
(100), 176 (51), 163 (24), 150 (17), 133 (26), 105 (16), 92 (17), 65 (14), 43 residue was taken up in water (20 ml) and extracted with dichloromethane in
(19). Anal. Calcd for C10H14N4O3: C, 50.41; H, 5.92; N, 23.52. Found: C, order to remove any unreacted starting material. Then, the pH of the aque-
50.70; H, 5.95; N, 23.30.
5-[Benzyl(ethyl)amino]-4-[(E,Z)-(hydroxyimino)methyl]-2-methylpyrid
azin-3(2H)-one (8c) To a solution of the aldehyde 7c (814 mg, 3 mmol) in
ous phase was adjusted to 9 with conc. ammonia and it was extracted again
with dichloromethane. The extract was washed with brine, dried and evapo-
rated. Recrystallization of the residue from ethyl acetate/light petroleum
-
ethanol (10 ml) was added hydroxylamine hydrochloride (417 mg, 6 mmol) afforded compound 10a (187 mg, 60%) as colorless crystals, mp 111—
and a solution of sodium acetate (312 mg, 3.8 mmol) in water (3 ml). The
112 °C. 1H-NMR (DMSO-d6) d: 1.83—1.88 (4H, m, pyrrolidine-H), 3.28
mixture was heated to 65 °C for 2 h, then it was evaporated. The residue was (2H, br s, NH2), 3.52 (3H, s, CH3), 3.52—3.60 (4H, m, pyrrolidine-H), 3.63
taken up in water (20 ml) and it was extracted with dichloromethane. The (2H, s, CH2NH2), 7.64 (1H, s, 6-H). 13C-NMR (DMSO-d6) d: 25.2, 36.9,
extract was dried and evaporated and the residue was subjected to column 38.8, 50.0, 112.3, 129.9, 144.5, 161.5. IR (KBr) cmϪ1: 3415, 3301, 2963,
chromatography (eluent: dichloromethane/methanol, 19 : 1) to afford an E/Z
2872, 1603, 1528, 1437, 1408, 1303, 1165, 1017, 854, 767, 559. MS m/z
isomer mixture of the oxime 8c (643 mg, 75%) as a yellow oil. H-NMR (rel. int.): 208 (Mϩ, 2%), 191 (100), 163 (29), 162 (44), 148 (19), 120 (27),
(DMSO-d6), isomer ratio E : Zϭ1.28 : 1; d: 1.05, 1.07 (each 3H, t, Jϭ7.2 Hz, 108 (22), 80 (17), 70 (26), 66 (23). HR-MS m/z: 208.1319 (Calcd for
NCH2CH3), 3.34–3.44 (2ϫ2H, m, NCH2CH3), 3.47 (3H, s, NCH3, Z iso- C10H16N4O: 208.1324). Anal. Calcd for C10H16N4O·0.1H2O: C, 57.18; H,
1
mer), 3.48 (3H, s, NCH3, E isomer), 4.51 (2H, s, NCH2Ph, Z isomer), 4.59
(2H, s, NCH2Ph, E isomer), 7.14—7.33 (2ϫ5H, m, phenyl-H), 7.41 (1H, s,
7.77; N, 26.67. Found: C, 57.22; H, 7.82; N, 26.46.
4-(Aminomethyl)-2-methyl-5-(morpholin-4-yl)pyridazin-3(2H)-one
oxime-CH, Z isomer), 7.76 (1H, s, 6-H, Z isomer), 7.83 (1H, s, 6-H, E iso- (10b) To a suspension of the nitrile 9b (330 mg, 1.5 mmol) in ethanol
mer), 7.96 (1H, s, oxime-CH, E isomer; shows positive NOE on irradiation
at 11.25—11.27 ppm), 11.25, 11.27 (each 1H, s, N–OH). 13C-NMR
(DMSO-d6) d: 12.6, 13.0, 38.4, 38.7, 45.5, 47.1, 53.1, 53.7, 103.2, 106.8,
126.9, 127.0, 127.05, 127.1, 128.4 (2), 130.3, 131.5, 137.2, 137.6, 143.1,
(29 ml) were added 2 N HCl (2.3 ml) and 10% Pd on carbon (60 mg). The
mixture was hydrogenated for 65 h at normal pressure, then the catalyst was
filtered off and the filtrate was evaporated under reduced pressure. The
residue was taken up in water (20 ml) and extracted with dichloromethane in
144.0, 145.8, 146.3, 159.2, 160.0. IR (KBr) cmϪ1: 3262, 2977, 1593, 1437, order to remove any unreacted starting material. Then, the pH of the aque-
1348, 973, 739. MS m/z (rel. int.): 286 (Mϩ, 2%), 270 (8), 269 (43), 268 (6),
254 (4), 228 (3), 191 (7), 166 (41), 138 (6), 92 (7), 91 (100), 65 (11). HR-
MS m/z: 286.1422 (Calcd for C15H18N4O2: 286.1430).
ous phase was adjusted to 9 with conc. ammonia and it was extracted again
with dichloromethane. The extract was washed with brine, dried and evapo-
rated. Recrystallization of the residue from ethyl acetate/light petroleum
2-Methyl-3-oxo-5-(pyrrolidin-1-yl)-2,3-dihydropyridazine-4-carboni- afforded compound 10b (235 mg, 70%) as colorless crystals, mp 93—94 °C.
trile (9a) A solution of the oxime 8a (555 mg, 2.5 mmol) in acetic anhy- 1H-NMR (DMSO-d6) d: 3.19 (4H, t, Jϭ4.7 Hz, morpholine-H), 3.32 (2H,
dride (20 ml) was refluxed for 30 min. After cooling, the mixture was poured br s, NH2), 3.52 (2H, s, CH2NH2), 3.58 (3H, s, CH3), 3.68 (4H, t, Jϭ4.7 Hz,
onto ice, adjusted to pH 8 with 10% aqueous NaOH, and extracted with
dichloromethane. The extract was washed with water, dried, and evaporated. 66.2, 124.7, 131.7, 148.8, 161.3. IR (KBr) cmϪ1: 2964, 2854, 1622, 1437,
The residue was recrystallized from ethanol to afford the nitrile 9a (357 mg,
1265, 1209, 1112, 1021, 927, 897, 686, 617. MS m/z (rel. int.): 224 (Mϩ,
70%) as colorless crystals, mp 171—172 °C. 1H-NMR (DMSO-d6) d: 9%), 207 (100), 176 (17), 165 (18), 150 (33), 149 (44), 134 (23), 121 (34),
1.90—1.95 (4H, m, pyrrolidine-H), 3.55—3.80 (4H, m, pyrrolidine-H), 7.75 94 (15), 66 (20), 54 (23). Anal. Calcd for C10H16N4O2: C, 53.56; H, 7.19; N,
morpholine-H), 7.82 (1H, s, 6-H). 13C-NMR (DMSO-d6) d: 37.7, 39.2, 50.7,
(1H, s, 6-H). 13C-NMR (DMSO-d6) d: 24.6, 38.7, 49.7, 80.5, 117.1, 129.0, 24.98. Found: C, 53.57; H, 7.25; N, 24.76.
148.0, 159.0. IR (KBr) cmϪ1: 2980, 2878, 2207, 1639, 1597, 1541, 1457,
4-(Aminomethyl)-5-(ethylamino)-2-methylpyridazin-3(2H)-one (11)
1356, 1306, 1225, 1096, 919, 878, 856, 754, 577, 558. MS m/z (rel. int.): To a solution of the nitrile 9c (536 mg, 2 mmol) in ethanol (20 ml) were
205 (15%), 204 (Mϩ, 100), 176 (37), 149 (30), 133 (54), 91 (21), 77 (13), 55
added 2 N HCl (3 ml) and 10% Pd on carbon (77 mg). The mixture was
(12), 43 (21), 41 (15). Anal. Calcd for C10H12N4O: C, 58.81; H, 5.92; N, hydrogenated for 72 h in a Parr apparatus at a pressure of 3.44 bar, then the
27.43. Found: C, 59.09; H, 5.75; N, 27.39. catalyst was filtered off and the filtrate was evaporated under reduced pres-
2-Methyl-5-(morpholin-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboni- sure. The residue was taken up in water (20 ml) and extracted with
trile (9b) A solution of the oxime 8b (500 mg, 2.1 mmol) in acetic anhy- dichloromethane in order to remove any unreacted starting material. Then,
dride (18 ml) was refluxed for 30 min. After cooling, the mixture was poured the pH of the aqueous phase was adjusted to 9 with conc. ammonia and it
onto ice, adjusted to pH 8 with 10% aqueous NaOH, and extracted with
was extracted again with dichloromethane. The extract was washed with
dichloromethane. The extract was washed with water, dried, and evaporated. brine, dried and evaporated. Recrystallization of the residue from ethyl ac-
The residue was recrystallized from ethanol to afford the nitrile 9b (416 mg,
90%) as colorless crystals, mp 165—166 °C. H-NMR (DMSO-d6) d: 3.52
(3H, s, CH3), 3.69–3.73 (4H, m, morpholine-H), 3.75—3.79 (4H, m, mor-
etate afforded compound 11 (182 mg, 50%) as colorless crystals, mp 98—
99 °C. H-NMR (DMSO-d6) d: 1.12 (3H, t, Jϭ4.8 Hz, NCH2CH3), 2.50—
2.90 (2H, br s, NH2), 3.24 (2H, q, unresolved, NCH2CH3), 3.50 (3H, s,
1
1
pholine-H), 8.02 (1H, s, 6-H). 13C-NMR (DMSO-d6) d: 38.8, 48.4, 65.8, NCH3), 3.59 (2H, s, CH2NH2), 6.84 (1H, br s, NH), 7.67 (1H, s, 6-H). 13C-
84.0, 116.2, 129.4, 151.5, 158.7. IR (KBr) cmϪ1: 2868, 2209, 1635, 1585, NMR (DMSO-d6) d: 15.2, 35.2, 36.8, 38.9, 110.2, 127.3, 145.6, 160.2. IR
1527, 1411, 1318, 1274, 1110, 1035, 891, 755, 594. MS m/z (rel. int.): 221 (KBr) cmϪ1: 3378, 2973, 2940, 1618, 1456, 1349, 1268, 1177, 769. MS m/z
(17%), 220 (Mϩ, 100), 191 (9), 163 (33), 162 (32), 161 (27), 149 (20), 134 (rel. int.): 183 (9%), 182 (Mϩ, 74), 165 (100), 153 (91), 150 (72), 136 (34),
(55), 91 (31), 64 (17), 57 (19). Anal. Calcd for C10H12N4O2·0.2C2H5OH: C,
124 (51), 123 (62), 109 (24), 93 (20), 82 (28), 68 (26), 54 (31). HR-MS m/z:
54.44; H, 5.80; N, 24.42. Found: C, 54.17; H, 5.84; N, 24.29. HR-MS m/z: 182.1171 (Calcd for C8H14N4O: 182.1168).
220.0956 (Calcd for C10H12N4O2: 220.0960).
2-Benzyl-5-[benzyl(ethyl)amino]pyridazin-3(2H)-one (14) A mixture
5-[Benzyl(ethyl)amino]-2-methyl-3-oxo-2,3-dihydropyridazine-4-car- of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (12) (2.55 g, 10 mmol) and
bonitrile (9c) A solution of the oxime 8c (716 mg, 2.5 mmol) in acetic an-
N-ethylbenzylamine (3.38 g, 25 mmol) in water (50 ml) was refluxed for

July 2010
969
40 h. The mixture was made weakly acidic with 0.1 N HCl, then it was
1635, 1590, 1533, 1452, 1357, 1322, 1070, 732. MS m/z (rel. int.): 345
extracted with dichloromethane. The extract was washed with brine, dried (5%), 344 (Mϩ, 19), 253 (4), 239 (12), 224 (5), 162 (9), 121 (10), 106 (17),
and evaporated to give a brown, sticky oil (compound 13), which was dis- 92 (8), 91 (100), 65 (19). HR-MS m/z: 344.1632 (Calcd for C21H20N4O:
solved in methanol (60 ml). After addition of 10% Pd on carbon (1.0 g) and
ammonium formate (5.99 g, 95 mmol), the mixture was heated to 70 °C
344.1637).
4-(Aminomethyl)-2-benzyl-5-(ethylamino)pyridazin-3(2H)-one
(18)
under an argon atmosphere. The reaction was monitored by TLC (eluent: To a solution of the nitrile 17 (688 mg, 2 mmol) in ethanol (20 ml) were
ethyl acetate), and further portions of ammonium formate were added added 2 N HCl (3 ml) and 10% Pd on carbon (77 mg). The mixture was
as required. After completion of the reaction (approx. 3 h), the catalyst hydrogenated for 72 h in a Parr apparatus at a pressure of 3.44 bar, then the
was filtered off and the filtrate was evaporated under reduced pressure. The catalyst was filtered off and the filtrate was evaporated under reduced pres-
residue was taken up in water (50 ml) and it was extracted with
dichloromethane. The extract was washed with brine, dried and evaporated.
The residue was purified by column chromatography (eluent: dichloromethane/
sure. The residue was taken up in water (20 ml) and extracted with
dichloromethane in order to remove any unreacted starting material. Then,
the pH of the aqueous phase was adjusted to 9 with conc. ammonia and it
was extracted again with dichloromethane. The extract was washed with
1
methanol, 99 : 1) to give compound 14 (958 mg, 30%) as a yellow oil. H-
NMR (DMSO-d6) d: 1.10 (3H, t, Jϭ7.1 Hz, NCH2CH3), 3.47 (2H, q, brine, dried and evaporated. Recrystallization of the residue from ethyl
Jϭ7.1 Hz, NCH2CH3), 4.59 (2H, s, NCH2Ph), 5.09 (2H, s, NCH2Ph), 5.58 acetate afforded compound 18 (397 mg, 77%) as colorless crystals, mp
1
(1H, d, Jϭ3.0 Hz, 4-H), 7.18—7.37 (10H, m, phenyl-H), 7.82 (1H, d, 134—136 °C. H-NMR (DMSO-d6) d: 1.15 (3H, t, Jϭ6.9 Hz, NCH2CH3),
Jϭ3.0 Hz, 6-H). 13C-NMR (DMSO-d6) d: 12.2, 44.7, 52.1, 52.6, 97.2, 3.27 (2H, q, Jϭ6.9 Hz, NCH2CH3), 3.74 (2H, s, CH2NH2), 4.60—5.10 (2H,
126.4, 127.1, 127.2, 127.7, 128.3, 128.6, 137.2, 137.6, 147.9, 160.0. IR
br s, NH2), 5.14 (2H, s, NCH2Ph), 7.12 (1H, br s, NH), 7.21—7.32 (5H, m,
(KBr) cmϪ1: 3029, 2973, 1630, 1594, 1452, 1358, 1241, 822, 733. MS m/z
phenyl-H), 7.80 (1H, s, 6-H). 13C-NMR (DMSO-d6) d: 15.1, 33.9, 36.9,
(rel. int.): 320 (11%), 319 (Mϩ, 47), 214 (18), 213 (13), 199 (9), 172 (8), 53.2, 106.0, 127.2, 127.7, 128.0, 128.3, 137.6, 145.9, 160.0. IR (KBr) cmϪ1
:
137 (21), 106 (56), 91 (100), 65 (14). HR-MS m/z: 319.1680 (Calcd for
C20H21N3O: 319.1685).
3351, 3263, 3031, 2969, 1616, 1454, 1333, 1240, 946, 817, 736, 695. MS
m/z (rel. int.): 259 (4%), 258 (Mϩ, 20), 241 (13), 229 (10), 200 (7), 187 (26),
2-Benzyl-5-[benzyl(ethyl)amino]-3-oxo-2,3-dihydropyridazine-4-carb- 167 (13), 150 (12), 120 (12), 109 (17), 106 (16), 91 (100), 65 (19). HR-MS
aldehyde (15) To a solution of compound 14 (1.60 g, 5 mmol) in dry DMF
(25 ml) was added dropwise at 5 °C a solution of phosphorus oxychloride
(1.03 ml, 11 mmol) in dry DMF (5 ml). The mixture was stirred at room
temperature for 15 min, then it was heated to 70 °C for 2.5 h. The volatile
m/z: 258.1475 (Calcd for C14H18N4O: 258.1481).
5-[Benzyl(ethyl)amino]-3-oxo-2,3-dihydropyridazine-4-carbonitrile
(19) To a suspension of AlCl3 (2.13 g, 16 mmol) in dry toluene (60 ml) was
added a solution of the nitrile 17 (689 mg, 2 mmol) in dry toluene (5 ml),
components were removed under reduced pressure, the residue was treated and the mixture was heated to 80 °C for 1 h. After cooling, the solvent was
with crushed ice and it was stirred for 20 min. The mixture was made removed under reduced pressure and the residue was taken up in water (30
weakly alkaline (pH 8) with 40% aqueous NaOH, then it was extracted with ml) and extracted with dichloromethane. The extract was washed with water,
ethyl acetate. The extract was washed with brine, dried, and evaporated to dried, and evaporated. The residue was purified by column chromatography
give the aldehyde 15 (1.39 g, 80%) as a yellow oil which was used for the (eluent: toluene/ethyl acetate, 3 : 2), followed by recrystallization from ethyl
1
preparation of 16 without further purification. H-NMR (DMSO-d6) d: 1.14 acetate to give the nitrile 19 (203 mg, 40%) as colorless crystals, mp 196—
(3H, t, Jϭ7.1 Hz, NCH2CH3), 3.49 (2H, q, Jϭ7.1 Hz, NCH2CH3), 4.71 (2H, 197 °C. 1H-NMR (DMSO-d6) d: 1.24 (3H, t, Jϭ7.0 Hz, NCH2CH3), 3.73
s, NCH2Ph), 5.11 (2H, s, NCH2Ph), 7.13—7.35 (10H, m, phenyl-H), 8.08 (2H, q, Jϭ7.0 Hz, NCH2CH3), 4.94 (2H, s, NCH2Ph), 7.21—7.41 (5H, m,
(1H, d, Jϭ0.9 Hz, 6-H), 9.99 (1H, d, Jϭ0.9 Hz, aldehyde-H). 13C-NMR phenyl-H), 7.76 (1H, s, 6-H), 12.64 (1H, s, NH). 13C-NMR (DMSO-d6) d:
(DMSO-d6) d: 13.0, 48.3, 52.8, 54.9, 107.2, 127.3, 127.5, 127.7, 128.3, 13.6, 46.6, 53.4, 81.6, 116.3, 126.4, 127.4, 128.7, 129.0, 136.4, 150.1,
128.4, 128.5, 131.7, 135.8, 137.1, 147.7, 161.3, 187.7. IR (KBr) cmϪ1
:
160.2. IR (KBr) cmϪ1: 3282, 3145, 2985, 2892, 2209, 1645, 1584, 1549,
3029, 2934, 1663, 1628, 1507, 1453, 1297, 1070, 702. MS m/z (rel. int.): 1458, 1355, 1332, 1081, 858, 811, 739, 633. MS m/z (rel. int.): 255 (3%),
348 (1%), 347 (Mϩ, 2), 318 (4), 256 (6), 115 (3), 104 (4), 92 (8), 91 (100), 254 (Mϩ, 20), 252 (5), 237 (5), 163 (5), 92 (9), 91 (100), 65 (10). Anal.
89 (5), 77 (5), 65 (24). HR-MS m/z: 347.1637 (Calcd for C21H21N3O2: Calcd for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C, 66.08; H, 5.66;
347.1634).
N, 21.76.
5-[Benzyl(ethyl)amino]-3-chloropyridazine-4-carbonitrile (20) A mix
ture of compound 19 (508 mg, 2 mmol) and phosphorus oxychloride (8
2-Benzyl-5-[benzyl(ethyl)amino]-4-[(E,Z)-(hydroxyimino)methyl]pyrid-
azin-3(2H)-one (16) To a solution of the aldehyde 15 (1.04 g, 3 mmol) in
-
ethanol (10 ml) was added hydroxylamine hydrochloride (417 mg, 6 mmol) ml) was heated to 110 °C for 3 h. The volatile components were removed
and a solution of sodium acetate (312 mg, 3.8 mmol) in water (3 ml). The under reduced pressure and the residue was treated with crushed ice. The
mixture was heated to 65 °C for 2 h, then it was evaporated. The residue was mixture was made weakly alkaline with aqueous NaHCO3, then it was
taken up in water (20 ml) and it was extracted with dichloromethane. The extracted with dichloromethane. The extract was washed with water, dried,
extract was dried and evaporated to afford an E/Z isomer mixture (approx. and evaporated to afford the chloro compound 20 (457 mg, 84%) as a
1
4 : 1) of the oxime 16 (870 mg, 80%) as a yellow oil. H-NMR (DMSO-d6),
brownish oil which was used for the following transformation without any
signals of major isomer, d: 1.02—1.10 (3H, m, NCH2CH3), 3.39—3.47 (2H, further purification. 1H-NMR (DMSO-d6) d: 1.27 (3H, t, Jϭ7.0 Hz,
m, NCH2CH3), 4.61 (2H, s, NCH2Ph), 5.09 (2H, s, NCH2Ph), 7.13—7.34 NCH2CH3), 3.79 (2H, q, Jϭ7.0 Hz, NCH2CH3), 5.00 (2H, s, NCH2Ph),
(10H, m, phenyl-H), 7.90 (1H, s, 6-H), 7.94 (1H, s, oxime-CH), 11.25 (1H, 7.24—7.40 (5H, m, phenyl-H), 8.84 (1H, s, 6-H). 13C-NMR (DMSO-d6) d:
br s, N–OH); selected signals of minor isomer, d: 4.51 (2H, s, NCH2Ph), 13.1, 46.5, 53.3, 89.9, 115.1, 126.4, 127.4, 128.7, 135.6, 141.1, 146.3,
5.07 (2H, s, NCH2Ph), 7.42 (1H, s, oxime-CH), 7.83 (1H, s, 6-H), 11.27 155.2. HR-MS m/z: 272.0827 (Calcd for C14H13ClN4: 272.0829).
(1H, s, N–OH). 13C-NMR (DMSO-d6), signals of major isomer, d: 12.6,
5-[Benzyl(ethyl)amino]-3-(ethylamino)pyridazine-4-carbonitrile (21)
47.0, 53.2, 53.7, 106.4, 127.0, 127.1, 127.3, 127.7, 128.3, 128.4, 132.1, To a solution of the chloropyridazine 20 (350 mg, 1.3 mmol) in absolute
137.0, 137.2, 144.1, 145.6, 159.8. IR (KBr) cmϪ1: 3268, 3030, 2975, 1593,
1453, 1346, 1271, 1073, 949, 698. MS m/z (rel. int.): 363 (1%), 362 (Mϩ, 1),
346 (5), 345 (21), 319 (2), 267 (3), 242 (12), 106 (7), 92 (8), 91 (100), 77
(4), 65 (20), 51 (4). HR-MS m/z: 362.1747 (Calcd for C21H22N4O2:
362.1743).
ethanol (5 ml) was added a 2 M methanolic solution of ethylamine (6.6 ml,
13.2 mmol), and the mixture was stirred in a closed vessel at 50 °C for
45 h. The volatile components were removed under reduced pressure and
the residue was taken up in 2 M aqueous Na2CO3 and extracted with
dichloromethane. The extract was washed with water, dried, and evaporated.
2-Benzyl-5-[benzyl(ethyl)amino]-3-oxo-2,3-dihydropyridazine-4-car- The oily residue was subjected to column chromatography (eluent:
bonitrile (17) A solution of the oxime 16 (906 mg, 2.5 mmol) in acetic toluene/ethyl acetate, 3 : 2) to afford compound 21 (226 mg, 62%) as yellow
anhydride (15 ml) was refluxed for 30 min. After cooling, the mixture was crystals, mp 93–95 °C. 1H-NMR (DMSO-d6) d: 1.12 (3H, t, Jϭ7.2 Hz,
poured onto ice, adjusted to pH 8 with 10% aqueous NaOH, and extracted HNCH2CH3), 1.23 (3H, t, Jϭ7.0 Hz, NCH2CH3), 3.39—3.45 (2H, m,
with dichloromethane. The extract was washed with water, dried, and evapo- HNCH2CH3), 3.69 (2H, q, Jϭ7.0 Hz, NCH2CH3), 4.86 (2H, s, NCH2Ph),
rated. The residue was purified by column chromatography (eluent: 7.19—7.39 (5H, m, phenyl-H), 8.19 (1H, s, 6-H). 13C-NMR (DMSO-d6) d:
dichloromethane/methanol, 19 : 1) to afford the nitrile 17 (603 mg, 70%) as a
13.4, 14.6, 36.0, 46.0, 52.8, 74.3, 116.5, 126.3, 127.2, 128.7, 132.7, 136.8,
yellow oil. 1H-NMR (DMSO-d6) d: 1.24 (3H, t, Jϭ7.0 Hz, NCH2CH3), 3.73 145.5, 156.8. IR (KBr) cmϪ1: 3368, 2970, 2929, 2199, 1560, 1512, 1326,
(2H, q, Jϭ7.0 Hz, NCH2CH3), 4.95 (2H, s, NCH2Ph), 5.10 (2H, s, NCH2Ph), 1237, 1148, 1061, 738. MS m/z (rel. int.): 282 (2%), 281 (Mϩ, 11), 266 (17),
7.23—7.39 (10H, m, phenyl-H), 7.85 (1H, s, 6-H). 13C-NMR (DMSO-d6) d: 252 (7), 238 (9), 190 (32), 163 (7), 149 (5), 92 (12), 91 (100), 65 (24). HR-
13.5, 46.5, 53.3, 53.5, 81.8, 116.3, 126.4, 127.4, 127.5, 127.9, 128.4, 128.7, MS m/z: 281.1645 (Calcd for C16H19N5: 281.1640).
129.0, 136.3, 136.6, 149.7, 158.8. IR (KBr) cmϪ1: 3030, 2979, 2934, 2209,
4-(Aminomethyl)-N,N؅-diethylpyridazine-3,5-diamine (22) To a solu-

970
Vol. 58, No. 7
tion of the nitrile 21 (315 mg, 1.12 mmol) in ethanol (50 ml) were added 6 N
HCl (3 ml) and 10% Pd on carbon (42 mg). The mixture was hydrogenated
for 48 h in a Parr apparatus at a pressure of 3.44 bar, then the catalyst was
filtered off and the filtrate was evaporated under reduced pressure. The
residue was taken up in water (20 ml) and extracted with dichloromethane in
7) Grönvall-Nordquist J. L., Bäcklund L. B., Garpenstrand H., Ekblom J.,
Landin B., Yu P. H., Oreland L., Rosenqvist U., J. Diabetes Complica-
tions, 15, 250—256 (2001).
8) Haider N., Sotelo E., Chem. Pharm. Bull., 50, 1479—1483 (2002).
9) Haider N., Curr. Org. Chem., 10, 363—375 (2006).
order to remove any unreacted starting material. The aqueous layer was 10) Yanai M., Takeda S., Mitsuka T., Chem. Pharm. Bull., 25, 1708—1716
evaporated to dryness under reduced pressure and the crystalline residue was (1977).
dried. It was then dissolved in ethanol (3 ml) and the product was precipi- 11) Schmidt P., Druey J., Helv. Chim. Acta, 37, 134—140 (1954).
tated by addition of diethyl ether to afford the dihydrochloride-monohydrate 12) Chen S. F., Panzica R. P., J. Org. Chem., 46, 2467—2473 (1981).
of compound 22 (278 mg, 85%) as pale yellow crystals, mp Ͼ190 °C (de-
13) Takaya M., Sato M., Terashima K., Tanizawa H., Maki Y., J. Med.
Chem., 22, 53—58 (1979).
1
comp.). H-NMR (DMSO-d6) d: 1.00—1.23 (6H, m, HNCH2CH3), 3.34—
3.52 (4H, m, HNCH2CH3), 4.12 (2H, s, CH2NH2), 8.33 (1H, s, 6-H), 8.43, 14) Konecny V., Kovac S., Varkonda S., Coll. Czech. Chem. Commun., 50,
8.44 (together 5H, br, NH), 13.60—13.80 (1H, br, NH). 13C-NMR (DMSO-
d6) d: 14.0, 14.8, 31.1, 37.3, 37.7, 95.6, 133.2, 146.8, 150.7. IR (KBr) cmϪ1
3232, 3139, 3050, 2979, 1595, 1508, 1410, 1332, 1191, 1130, 872, 837.
492—502 (1985).
:
15) Weissman S. A., Zewge D., Chen C., J. Org. Chem., 70, 1508—1510
(2005).
Anal. Calcd for C9H17N5·2.10HCl·1.10H2O: C, 37.06; H, 7.36; N, 24.01; 16) Krajsovszky G., Gaal A., Haider N., Mátyus P., J. Mol. Struct., 528,
Cl, 25.53. Found: C, 36.98; H, 6.90; N, 23.93; Cl, 25.61.
13—18 (2000).
17) Mátyus P., Fuji K., Tanaka K., Heterocycles, 37, 171—174 (1994).
18) The presence of a benzyl protecting group is essential, because the
corresponding (unprotected) secondary amine fails to undergo the
Vilsmeier-Haack formylation.
Acknowledgements The authors are grateful to Biotie Therapies Corp.
(Turku, Finland) for performing the in-vitro evaluation of SSAO inhibitory
activity. We also want to thank Mr. P. Unteregger (Institute of Organic
Chemistry, University of Vienna) for measuring the high-resolution mass 19) Riedl Z., Maes B. U. W., Monsieurs K., Lemière G. L. F., Mátyus P.,
spectra. One of us, P.M., thanks the Hungarian Scientific Research Fund for
financial support (K73389).
Hajós G., Tetrahedron, 58, 5645—5650 (2002).
20) Kaji K., Nagashima H., Oda H., Chem. Pharm. Bull., 32, 1423—1432
(1984).
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