Tetrahydropyrido[d]pyridazinones - Promising scaffolds for drug discovery

Article abstract of DOI:10.1016/j.tet.2013.06.029

An approach to the synthesis of all possible tetrahydropyrido[d] pyridazinones has been developed. The method relies on the catalytic hydrogenation of the corresponding aromatic counterparts, which were obtained by cyclization of the relevant dibromomethyl-substituted pyridinecarboxylates with hydrazine. The synthetic schemes include 4-5 steps starting from commercially available materials. The tetrahydropyrido[d]pyridazinone scaffolds are combinations of a saturated heterocycle (piperidine) and a privileged aromatic heterocycle (pyridazinone); hence they are promising starting points for the design in medicinal chemistry.

Full text of DOI:10.1016/j.tet.2013.06.029

Accepted Manuscript
Tetrahydropyrido[d]pyridazinones –promising scaffolds for drug discovery
Anatoliy G. Yaremenko, Dmitriy M. Volochnyuk, Vyacheslav V. Shelyakin, Oleksandr
O. Grygorenko
PII:
S0040-4020(13)00959-9
10.1016/j.tet.2013.06.029
TET 24505
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 January 2013
Revised Date: 28 May 2013
Accepted Date: 10 June 2013
Please cite this article as: Yaremenko AG, Volochnyuk DM, Shelyakin VV, Grygorenko OO,
Tetrahydropyrido[d]pyridazinones –promising scaffolds for drug discovery, Tetrahedron (2013), doi:
10.1016/j.tet.2013.06.029.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Tetrahydropyrido[d]pyridazinones –
promising scaffolds for drug discovery
Anatoliy G. Yaremenko, Dmitriy M. Volochnyuk,
Vyacheslav V. Shelyakin,* and Oleksandr O. Grygorenko
O
O
H
N
NH HN
NH
N
N
O
O
NH
N
NH
HN
N
N
H

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Tetrahydropyrido[d]pyridazinones –promising scaffolds for drug discovery
Anatoliy G. Yaremenko,a Dmitriy M. Volochnyuk,a Vyacheslav V. Shelyakina
and Oleksandr O. Grygorenkob
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
bTaras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An approach to the synthesis of all possible tetrahydropyrido[d]pyridazinones has been
developed. The method relies on the catalytic hydrogenation of the corresponding aromatic
counterparts which were obtained by cyclization of the relevant dibromomethyl-substituted
pyridinecarboxylates with hydrazine. The synthetic schemes include 4 – 5 steps starting from
commercially available materials. The tetrahydropyrido[d]pyridazinone scaffolds are
combinations of a saturated heterocycle (piperidine) and a privileged aromatic heterocycle
(pyridazinone); hence they are promising starting points for the design in medicinal chemistry.
Available online
Keywords:
Fused heterocycles
Pyridazines
2012 Elsevier Ltd. All rights reserved.
Piperidines
Catalytic hydrogenation
Heterocyclizations
1. Introduction
There are also many examples of biologically active compounds
containing pyridazine as a part of a fused aromatic heterocyclic
system.3 Recent trends in drug discovery, however, show the
tendency of moving away from such sp2-enriched structures
towards their saturated counterparts.7,8,9,10 On the other hand, it is
widely accepted that conformational restriction is one of the
essential properties characteristic for drug molecules.11 In this
view, fusion of the piperazine ring with a saturated heterocycle
can be a valuable approach to the design of building blocks of
enhanced interest to drug discovery. For this reason, saturated
heterocyclic amines (e. g. piperidine) are especially promising as
they allow further functionalization of the molecule using well-
established methods of combinatorial chemistry.12 In the fact,
pyridazine (or pyridazinone) moiety can be also used for
selective chemical modification of the parent scaffold.
Implementation of the ideas discussed above leads to the fused
piperazines 1 – 4 as possible targets for the synthesis (Figure 1),
which is embodied in this work.
Pyridazines are a family of structures which are of top interest
to contemporary drug discovery.1,2 Several hundred papers
dealing with biologically active derivatives of this heterocycle
belonging to almost all therapeutic classes have been published
in the last decade. In a recent review by Wermuth,3 several
arguments justifying largely the status of pyridazines as
privileged structures in medicinal chemistry were given. In
particular, pyridazine is a classical bioisostere for benzene and
pyridine
rings
which
improves
significantly
both
physicochemical properties and interactions with a potential
biological target. On the other hand, it can act as a surrogate for a
number of functional groups, e. g. carboxamide. Recently,
pyridazine-based scaffolds were proposed as α-helix mimetics,4
whereas pyridazinones have attracted attention as possible
analogues of nucleobases.5, 6
To date, most of the pyridazine derivatives used in medicinal
chemistry contain aryl C-3 and/or C-6 substituent; this was
related to a higher synthetic feasibility of these compounds.
———
Corresponding author. Tel.: +380 44 292 71 50; fax: +380 44 426 40 74 ; e-mail: synthecom@bigmir.net (V.V.S.)

ACCEPTED MANUSCRIPT
2
Tetrahedron
O
O
H
H
N
NH
N
N
NH
N
N
H
O
1
3
2
4
O
O
NH
N
N
HN
HN
NH
N
NH
N
NH
HN
O
Figure 1. Tetrahydropyrido[d]pyridazinone scaffolds
Calculated values of physico-chemical properties of 1 – 4
(82–92%). Unfortunately, hydrolysis of of 25 – 28 by the action
of AgNO3 in aqueous methanol failed to produce aldehydes 13 –
16 in pure form; complex mixtures were obtained instead.
Nevertheless, dibromides 25 – 28 themselves reacted smoothly
with hydrazine and provided the pyrido[d]pyridazinones 5 – 8 in
excellent yield (95%), making isolation of free aldehydes 13 – 16
unnecessary.
(MW 151.2; Fsp3 0.43; cLogP –0.64, –1.19, –1.32 and –0.64,
respectively; TPSA 53.49 Å2)13 fit perfectly into the limits
proposed for the molecular fragments in drug discovery, e. g.
“Rule-of-three”.14 Therefore, heterocycles 1 – 4 are examples of
the bifunctional conformationally restricted scaffolds15 which can
be good starting points for the lead-oriented synthesis in drug
discovery.16
KOH
MeOH
2. Results and discussion
O
O
H2O
82%
H2SO4
85%
N
N
N
CN
One of is most obvious retrosynthetic approaches to these
compounds is from their aromatic counterparts 5 – 8 (Scheme 1).
All the compounds 5 – 8 are mentioned in the literature; their
reported syntheses relied either on the cyclization of various
precursors 9 – 12 with hydrazine (Figure 2).17, 18, 19, 20 or oxidation
of the corresponding dihydropyridopyridazines.21, 22 Looking for
a general approach to the synthesis of 5 – 8, we have turned our
attention to aldehydoesters 13 – 16 as key intermediates. The
method for the preparation of these compounds described
previously involved partial reduction of the corresponding
pyridinedicarboxylates.23, 24, 25 and was not convenient due to
selectivity problems, especially upon scale-up. In this work, we
considered bromination of the pyridinecarboxylates 17 – 20
followed by hydrolysis as an alternative approach to 13 – 16.
O
OH
17
21
29
NBS
CCl4
83%
Br
N2H4
H2, PtO2
Br
N
N
O
NH
NH
MeOH
95%
CF3COOH
97%
N
N
N
H
O
O
O
25
5
1
Scheme 2
O
O
O
NBS
H
MeOH
OH
H
O
O
O
N
OMe
OMe
CHO
O
N
N
O
N
O
N
N
Br
CCl4
88%
H2SO4
84%
N
N
N
Br
N
HN
26
22
18
1 - 4
5 - 8
13 - 16
17 - 20
N2H4
95%
MeOH
Scheme 1 Retrosynthetic analysis of 1 – 4
O
O
Ph
HO
N
Ph
HO
Cl
Cl
H
O
N
N
H2, PtO2
N
NH
N
NH
COOH
O
COONa
O
N
N
CF3COOH
96%
N
N
H
N
6
2
9
10
11
12
Scheme 3
Figure 2 Synthetic precursors of pyrido[d]pyridazinones 5 – 8 reported in
the literature
As the N–N bonds of pyridazines are susceptible to catalytic
hydrogenation, some efforts were made to find optimal
conditions for the selective reduction of the pyridine ring in 5 –
8. A number of experimentations showed that using CF3COOH
as a solvent allowed the target compounds 1 – 4 to be obtained in
96–97% yields by catalytic hydrogenation of 5 – 8 in the
presence of platinum dioxide in MeOH.
The implementation of the retrosynthetic approach discussed
above is shown in Schemes 2 – 5. Compounds 21 – 24 which are
readily available commercially were used as the starting
materials in these syntheses. They were transformed into the
esters 17 – 20 in one or two steps. To achieve selective
transformation of the methyl groups in 17 – 20 to the aldehydes,
two-step reaction sequences were used instead of the methods
based on direct oxidation. First, bromination of 17 – 20 was
performed, using N-bromosuccinimide (NBS) in CCl4; the
corresponding dibromides 25 – 28 were obtained in good yields
3. Conclusions
Recent tendencies in drug discovery show a great demand for
highly hydrophilic, low-molecular-weight molecules with a high

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3
4.2. 3-Methylpyridine-2-carboxylic acid (29)
degree of saturation which can be used as the starting points in
the search for lead compounds. Combination of a saturated
heterocycle (i. e. piperidine) and privileged aromatic
heterocycle (such as pyridazinone) into a single molecule
provides good example; the four tetrahydropyri-
3-Methylpyridine-2-carboxylic acid was prepared in 82%
yield starting from 21 according to the procedure described in the
literature.26 For spectral and physical data, ref.27.
a
a
do[d]pyridazinone scaffolds thus generated leaves much room for
the design of biologically relevant molecules. An approach to the
synthesis of these building blocks was developed starting from
the properly substituted pyridine derivatives. The methods
included 4 – 5 steps starting from commercially available
materials and were used for the multigram preparations of the
title compounds (~20 g in a single run).
4.3. 4-Methylnicotinic acid (30)
4-Methylnicotinic acid was prepared in 86% yield starting
from 23 according to the procedure described in the literature.28
For spectral and physical data, see ref. 29.
4.4. 3-Methylisonicotinic acid (31)
3-Methylisonicotinic acid was prepared in 40% yield starting
from 24 according to the procedure described in the literature.26
For spectral and physical data, ref30.
MeOH
KOH
N
O
N
O
N
H2O
86%
H2SO4
81%
CN
4.5. General procedure for the preparation of 17 – 20
O
OH
23
19
30
To a solution of carboxylic acid 22 or 29 – 31 (0.1 mol) in dry
methanol (150 mL), conc. H2SO4 (20 mL) was added. The
mixture was refluxed for 15–20 h (LC–MS control). The solvent
was removed in vacuo, and the residue was dissolved in H2O.
The solution was made alkaline with cold saturated aq K2CO3
and extracted with CH2Cl2 (4×50 mL). The combined organic
extracts were dried over Na2SO4 and evaporated in vacuo. The
residue was purified by flash chromatography (EtOAc as eluent)
or distilled in vacuo to give 17 – 20.
NBS
CCl4
83%
Br
N2H4
H2, PtO2
Br
N
N
N
O
N
NH
HN
NH
MeOH
95%
CF3COOH
97%
O
O
O
O
27
3
7
Scheme 4
4.5.1. Methyl 3-methylpyridine-2-carboxylate (17)
Yield 12.8 g (85%). For spectral and physical data, see ref.
31, 32.
O
O
SeO2
Ph2O
MeOH
H2SO4
86%
OH
4.5.2. Methyl 2-methylnicotinate (18)
N
N
N
Yield 12.7 g (84%). For spectral and physical data, see ref. 33.
120 oC
40%
24
31
20
NBS
4.5.3. Methyl 4-methylnicotinate (19)
Yield 12.8 g (81%). For spectral and physical data, see ref. 34.
CCl4 92%
4.5.4. Methyl 3-methylisonicotinate (20)
Yield 13.0 g (86%). For spectral and physical data, see ref. 32.
O
O
Br
O
O
4.6. General procedure for the preparation of 25 – 28
H2, PtO2
N2H4
Br
NH
NH
To a solution of ester 17 – 20 (13.7 g, 0.100 mol) in dry CCl4
(400 mL), N-bromosuccinimide (35.6 g, 0.200 mol) was added.
The mixture was slowly heated to reflux, then refluxed for 16 h
(monitored by LC–MS), and then cooled to rt. The succinimide
was filtered off, and the filtrate was concentrated under reduced
pressure to give gem-dibromomethyl compound 25 – 28.
Analytical samples were prepared by chromatography (hexanes –
EtOAc (1 : 9)).
HN
N
N
N
MeOH
95%
CF3COOH
97%
N
28
4
8
Scheme 5
4. Experimental part
4.1. General
4.6.1. Methyl 3-(dibromomethyl)pyridine-2-
carboxylate (25)
The solvents were purified according to standard procedures. All
the starting materials were purchased from Acros, Merck, Fluka.
Analytical TLC was performed using Polychrom SI F254 plates.
The IR spectra of all synthesed compounds were recorded on
Bruker Vertex 70/70v in KBr pellets, the frequencies are given in
cm-1. Column chromatography was performed using Kieselgel
Yield 12.5 g (83%). Colourless solid. Mp 83–84 °C (CCl4). IR
(KBr): 3413, 3075, 2949, 2844, 1934, 1716, 1580, 1563, 1449,
1427, 1315, 1264, 1197, 1172, 1133, 1080, 957, 854, 807, 718,
1
673, 652, 592, 529, 483 cm-1. H NMR (CDC13) δ 4.02 (3H, s),
1
Merck 60 (230–400 mesh) as the stationary phase. H and 13C
7.59 (1H, dd, J = 8.1 Hz and 4.6 Hz), 7.93 (1H,s), 8.49 (d, 1H,
J = 8.1 Hz), 8.64 (1H, d, J = 4.6 Hz). 13C NMR (CDC13), δ 39.6,
53.1, 120.8, 124.1, 138.9, 153.5, 157.8, 165.2. MS (m/z, APCI):
308 (MH+). Anal. Calcd for C8H7Br2NO2 C 31.10, H 2.28, Br
51.72, N 4.53. Found: C 31.15, H 2.32, Br 51.68, N 4.59.
NMR spectra were recorded on a Bruker 170 Avance 500
spectrometer (at 500 MHz for Protons and 125 MHz for Carbon-
13) and Varian Unity Plus 400 spectrometer (at 400.4 MHz for
protons, 100.7 MHz for carbon-13). Chemical shifts are reported
in ppm downfield from TMS (1H, 13C) as an internal standard.
Elemental analyses were performed at the Laboratory of Organic
Analysis, Institute of Organic Chemistry, National Academy of
Sciences of Ukraine. Mass spectra were recorded on an Agilent
1100 LCMSD SL instrument (chemical ionization (APCI)).
4.6.2. Methyl 2-(dibromomethyl)nicotinate (26)
Yield 2.71 g (88%). Colourless solid. Mp. 95–96 °C (n-
hexane). IR (KBr): 3087, 3069, 3043, 3009, 2952, 2841, 1993,
1957, 1712, 1583, 1562, 1427, 1273, 1255, 1190, 1136, 1078,
1056, 957, 858, 833, 809, 791, 737, 696, 668, 638, 599, 488 cm-1.

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4
Tetrahedron
1H NMR, δ (CDC13): 3.96 (3H, s), 7.36 (1H, dd, J = 8.1 Hz and
153.3, 159.2. MS (m/z, APCI): 146 (MH+). Anal. Calcd for
C7H5N3O C 57.14, H 3.43, N 20.56. Found: C 57.28, H 3.21, N
20.30.
4.6 Hz), 7.99 (1H, s), 8.25 (1H, dd, J = 8.1 Hz and 1.6 Hz), 8.88
(1H, dd, J = 4.6 Hz and 1.6 Hz). 13C NMR (CDC13) δ 39.6, 53.1,
124.2, 138.8, 153.4, 157.8, 165.2. MS (m/z, APCI): 308 (MH+).
Anal. Calcd. for C8H7Br2NO2.C 31.10, H 2.28, Br 51.72, N 4.53.
Found: C 31.18, H 2.34, Br 51.82, N 4.61.
4.7.4. Pyrido[3,4-d]pyridazin-1(2H)-one (8)1 7 ,
2 2
Yield 1.32 g (90%). Light yellow crystals. Mp 290–292°C
(MeOH–H2O (9 : 1)). IR(KBr): 3453, 3167, 3100, 3061, 3011,
2841, 1666, 1552, 1497, 1461, 1407, 1366, 1322, 1284, 1249,
1218, 1167, 1136, 1031, 917, 891, 848, 792, 738, 682, 611, 553,
4.6.3. Methyl 4-(dibromomethyl)nicotinate (27)35
Yield 2.56 g (83%). Colourless solid. Mp. 71–72 °C (n-
hexane). IR(KBr): 3419, 3057, 2957, 2849, 1924, 1723, 1585,
1555, 1488, 1437, 1404, 1277, 1197, 1149, 1107, 1054, 954, 846,
497, 466 cm-1 1H NMR (DMSO-d6)
δ
8.06 (1H, d, J = 5.2 Hz),
.
8.52 (1H, s), 8.98 (1H, d, J = 5.2 Hz), 9.32 (1H, s), 12.99 (1H, br.
814, 792, 726, 670, 636, 585 cm-1 1H NMR (CDC13)
δ
3.92 (3H,
s), 7.87 (1H, s), 7.94 (1H, d, J = 5.4 Hz), 8.77 (1H, d,
J = 5.4 Hz), 9.05 (1H, s). 13C NMR,
(CDC13): 35.6, 52.9,
s). 13C NMR (DMSO-d6)
δ 118.4, 124.8, 133.0, 137.0,150.6,
.
151.4,159.0. MS (m/z, APCI): 146 (MH+). Anal. Calcd for
C7H5N3O C 57.14, H 3.43, N 20.56. Found: C 56.97, H 3.55, N
20.47.
δ
119.7, 124.7, 151.1, 151.5, 153.3, 165.2. MS (m/z, APCI): 308
(MH+). Anal. Calcd for C8H7Br2NO2 C 31.10, H 2.28, Br 51.72,
N 4.53. Found: C 31.12, H 2.32, Br 51.80, N 4.60.
4.8. General procedure for the preparation of 1 – 4
Compound 5 – 8 (150 mg, 0.6 mmol) and PtO2 (30 mg) in
CF3COOH (5 mL) were stirred in a pressure vessel at rt and
50 psi of hydrogen atmosphere for 48 h. The reaction mixture
was filtered, and the filtrate was concentrated in vacuo to give
compounds 1 – 4 as trifluoroacetates. To obtain the compounds 1
2 as free bases, the trifluoroacetates were neutralized with
saturated aq K2CO3, to pH = 7 and then extracted with CH2Cl2
(3×50 mL). The combined extracts were dried over Na2SO4 and
evaporated in vacuo.
4.6.4. Methyl 3-(dibromomethyl)isonicotinate (28)
Yield 2.84 g (92%). Colourless solid. Mp 79 – 80 °C (n-
hexane). IR(KBr): 3071, 2956, 1912, 1785, 1718, 1584, 1552,
1483, 1429, 1406, 1310, 1282, 1189, 1157, 1097, 958, 854, 810,
708, 679, 679, 646, 606, 495 cm-1 1H NMR (CDC13)
δ
3.95 (3H,
.
s), 7.63 (1H, d, J = 4.8 Hz,), 7.84 (1H, s), 8.64 (1H, d,
J = 4.8 Hz,), 9.39 (1H, s). 13С NMR (CDC13)
δ 34.1, 53.2, 122.1,
131.4, 136.9, 150.6, 153.8, 165.1. MS (m/z, APCI): 308 (MH+).
Anal. Calcd. for C8H7Br2NO2 C 31.10, H 2.28, Br 51.72, N 4.53.
Found: C 31.15, H 2.30, Br 51.78, N 4.61.
4.8.1. 1,3,4,7-Tetrahydropyrido[2,3-d] pyridazin-
3 7
8(2H)-one (1)3 6 ,
4.7. General procedure for the preparation of 5 – 8
Yield 1.46 g (97%). Light grey crystals. Mp 236–238 °C
(MeOH). IR(KBr): 3320, 3105, 3023, 2956, 2864, 1766, 1633,
1562, 1439, 1366, 1334, 1274, 1239, 1186, 1133, 1096, 1052,
A solution of 25 – 28 (3.08 g, 0.01 mol) and hydrazine hydrate
(2.00 g, 0.04 mol) in methanol (50 mL) was stirred under reflux
for 5 h. The solvent was evaporated under reduced pressure, and
the residue was recrystallized from MeOH – H2O (9 : 1).
990, 887, 863, 834, 774, 698, 603, 572, 532, 497, 462, 429 cm-1
.
1H NMR (DMSO-d6)
δ
1.76 (2H, quint, J = 5.7 Hz), 2.46 (2H, t,
J = 5.7 Hz), 3.24 (2H, t, J = 5.7 Hz), 6.56 (1H, s), 7.38 (1H, s),
1 9
4.7.1. Pyrido[2,3-d]pyridazin-8(7H)-one (5)1 7 ,
12.35 (1H, br. s). 13C NMR (DMSO-d6)
δ 20.0, 22.5, 110.0,
139.7, 140.6, 156.6. MS (m/z, APCI): 150 (MH+). Anal. Calcd.
for C7H9N3O C 55.62, H 6.00, N 27.80 Found: C 55.76, H 6.13,
N 27.90.
Yield 1.37 g (95%). Light yellow crystals. Mp 285–286 °C
(MeOH–H2O (9 : 1)) (lit.17 288–290 °C). IR(KBr): 3170, 3056,
2924, 1678, 1588, 1552, 1458, 1422, 1364, 1343, 1217, 1167,
1136, 1081, 917, 899, 867, 816, 716, 679, 610, 570, 498 cm-1 1H
.
4.8.2. 2,3,4,6-Tetrahydropyrido[2,3-d] pyridazin-
NMR (DMSO-d6)
δ 7.92 (1H, dd, J = 8.1 Hz and J = 4.8 Hz),
3 7
5(1H)-one (2)3 6 ,
8.39 (1H, dd, J = 8.1 Hz and 1.6 Hz), 8.40 (1H, s), 9.07 (1H, dd,
J = 4.8 Hz and J = 1.6 Hz), 12.92 (1H, br. s). 13C NMR (DMSO-
Yield 1.44 g (96%). Light grey crystals. Mp 234–235 °C.
IR(KBr): 3232, 2957, 1676, 1605, 1561, 1410, 1379, 1351, 1316,
1287, 1194, 1138, 992, 834, 797, 749, 721, 635, 566, 513, 439
d6)
δ 127.1, 128.6, 135.8, 138.1, 144.0, 154.4, 159.5. MS (m/z,
APCI): 146 (MH+). Anal. Calcd. for C7H5N3O C 57.14, H 3.43,
N 20.56. Found: C 57.37, H 3.25, N 20.51.
cm-1 1H NMR (DMSO-d6)
δ
1.72 (2H, quint, J = 5.5 Hz), 2.34
.
(2H, t, J = 5.5 Hz), 3.18 (2H, t, J = 5.5 Hz), 7.03 (1H, br. s,), 7.41
36, 37
4.7.2. Pyrido[2,3-d]pyridazin-5(6H)-one (6)2 0 ,
(1H, s), 12.12 (1H, br. s). 13C NMR (DMSO-d6)
δ 19.3, 19.7,
105.2, 131.5, 145.8, 161.5. MS (m/z, APCI): 150 (MH+). Anal.
Calcd. for C7H9N3O C 55.62, H 6.00, N 27.80. Found: C 55.38,
H 5.74, N 27.87.
Yield 1.38 g (95%). Light yellow crystals. Mp 253–255 °C
(MeOH–H2O (9 : 1)).IR(KBr): 3178, 3118, 3062, 3012, 2956,
2871, 1667, 1602 ,1444, 1360, 1318, 1300, 1220, 1148, 1074,
921, 868, 814, 784, 713, 596, 553, 498, 471 cm-1 1H NMR
.
4.8.3. 5,6,7,8-Tetrahydropyrido[3,4-d] pyridazin-
4(3H)-one (3), trifluoroacetate
(DMSO-d6)
8.58 (1H, dd, J = 8.1 Hz and 1.2 Hz), 9.13 (1H, dd, J = 4.8 Hz
and 1.2 Hz), 12.97 (1H, br, s). 13C NMR (DMSO-d6),
124.5,
δ 7.84 (1H, dd, J = 8.1 Hz and 4.8 Hz), 8.41 (1H, s),
Yield 2.57 g (98%). White crystals. Mp 144–146°C. IR(KBr):
3417, 3195, 3049, 2807, 2647, 2538, 1677, 1620, 1568, 1479,
1422, 1372, 1330, 1281, 1189, 1129, 990, 935, 875, 838, 796,
δ
127.1, 134.5, 139.8, 146.9, 156.4, 160.3. MS (m/z, APCI): 146
(MH+). Anal. Calcd. for C7H5N3O C 57.14, H 3.43, N 28.56.
Found: C 57.40, H 3.49, N 28.77.
754, 723, 640, 597, 565, 521, 456, 422 cm-1 1H NMR (DMSO-d6)
.
δ
2.81 (2H, t, J=5.8 Hz), 3.34 (2H, d, J = 5.8 Hz), 3.97 (2H, t,
J = 5.8 Hz), 7.83 (1H, s), 9.24 (2H, br. s), 13.16 (1H, br. s). 13C
NMR (D2O) 18.6, 36.1, 36.5, 113.1 (q, J = 292 Hz) 125.6,
4.7.3. Pyrido[3,4-d]pyridazin-4(3H)-one (7)2 2
Yield 1.36 g (93%). Light yellow crystals. Mp 255–256 °C
(MeOH–H2O (9 : 1)). IR(KBr): 3167, 3101, 3062, 3025, 2846,
1664, 1594, 1554, 1496, 1461, 1408, 1366, 1323, 1285, 1247,
1220, 1168, 1135, 1032, 917, 892, 847, 792, 737, 682, 611, 554,
7.83 (1H, d, J = 5.2Hz),
8.43 (1H, s), 9.02 (1H, d, J = 5.2 Hz), 9.43 (1H, s), 13.00 (1H, br.
s). 13C NMR (DMSO-d6)
119.4, 122.1, 134.9, 137.4, 149.3,
δ
135.7, 136.8, 157.1, 159.6 (q, J = 34 Hz). MS (m/z, APCI): 150
(MH+). Anal. Calcd. for C9H10F3N3O3 C 40.76, H 3.80, N 15.85.
Found: C 40.79, H 3.94, N 15.98.
497, 468 cm-1 1H NMR (DMSO-d6)
δ
.
4.8.4. 5,6,7,8-Tetrahydropyrido[3,4-d] pyridazin-
1(2H)-one (4), trifluoroacetate
δ

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Yield 2.57 g (97%). White crystals. Mp 178–179 °C. IR
(KBr): 3478, 3144, 2982, 2841, 2675, 2500, 1677, 1623, 1566,
1482, 1455, 1425, 1375, 1302, 1208, 1179, 1115, 1040, 989, 945,
892, 836, 792, 752, 721, 640, 608, 564, 540, 517, 478, 460, 442,
30. Yuan, Y.; Elbegdorj, O.; Chen, J.; Akubathini, S. K.; Zhang, Y.;
Beletskaya, I. O.; Selley, D. E. Bioorg. Med. Chem. Lett. 2011, 21,
5625–5629.
426 cm-1 1H NMR (DMSO-d6)
δ
2.66 (2H, quint, J = 5.6 Hz),
3.36 (2H, t, J = 5.6 Hz), 4.15 (2H, t, J = 5.6 Hz), 7.79 (1H, s),
9.62 (2H, s), 13.07 (1H, br. s). 13C NMR (D2O)
16.9, 37.4,
31. Renslo, A. R.; Danheiser, R. L. J. Org. Chem. 1998, 63, 7840–
.
7850.
32. Dunn, A. D. Org. Prep. Proc. Int. 1999, 31, 120–123.
33. Lieby-Muller, F.; Allais, C.; Constantieux, T.; Rodriguez, J.
Chem. Commun. 2008, 4207–4209.
δ
38.4, 113.7 (q, J = 292 Hz), 130.2, 131.4, 134.6, 158.2, 160.2 (q,
J = 35 Hz). MS (m/z, APCI): 150 (MH+). Anal. Calcd. for
C9H10F3N3O3. C 40.76, H 3.80, N 15.85. Found: C 40.82, H 3.85,
N 15.71.
34. Comins, D. L.; Stroud, E. D.; Herric, J. J. Heterocycles 1984, 22,
151–157.
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159.
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Supporting information
Tetrahydropyrido[d]pyridazinones –promising scaffolds for drug discovery
Anatoliy G. Yaremenko,a Dmitriy M. Volochnyuk,a Vyacheslav V. Shelyakina, and Oleksandr O. Grygorenkob
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine,
Murmanska Street 5, Kyiv 02660, Ukraine
bTaras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: synthecom@bigmir.net
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Table of contents
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1. H NMR spectrum of the compound 1
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2. C NMR spectrum of the compound 1
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3. H NMR spectrum of the compound 5
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4. C NMR spectrum of the compound 5
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5. H NMR spectrum of the compound 25
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6. C NMR spectrum of the compound 25
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7. H NMR spectrum of the compound 2
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8. C NMR spectrum of the compound 2
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9. H NMR spectrum of the compound 6
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10. C NMR spectrum of the compound 6
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11. H NMR spectrum of the compound 26
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12. C NMR spectrum of the compound 26
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13. H NMR spectrum of the compound 3
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14. C NMR spectrum of the compound 3
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15. H NMR spectrum of the compound 7
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16. C NMR spectrum of the compound 7
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17. H NMR spectrum of the compound 27
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18. C NMR spectrum of the compound 27
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19. H NMR spectrum of the compound 4
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20. C NMR spectrum of the compound 4
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21. H NMR spectrum of the compound 8
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22. C NMR spectrum of the compound 8
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23. H NMR spectrum of the compound 28
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24. C NMR spectrum of the compound 28
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