Synthesis of new derivatives of 5,6,7,8-tetrahydro-1,6-naphthyridines and their pharmacological properties

Article abstract of DOI:10.1007/s11172-005-0247-y

1,5-Dicarbonyl derivatives of piperidine and tropane were studied in the heterocyclization with hydroxylamine hydrochloride. All the 5,6,7,8-tetrahydro- 1,6-naphthyridines obtained exhibit a pronounced analgesic effect.

Full text of DOI:10.1007/s11172-005-0247-y

Russian Chemical Bulletin, International Edition, Vol. 54, No. 1, pp. 257—258, January, 2005
257
Synthesis of new derivatives of 5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridines
and their pharmacological properties
a
b
b
b
a
S. Z. Vatsadze,a M. L. Kostochka, V. P. Lezina, V. G. Vinokurov, P. M. Klodt, and N. V. Zyk
ꢀ
aDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 932 8846. Eꢀmail: szv@org.chem.msu.ru
bResearch Institute of Pharmacology, Russian Academy of Medical Sciences,
8 ul. Baltiiskaya, 125315 Moscow, Russian Federation.
Fax: +7 (095) 151 1261. Eꢀmail: evaldman@mtuꢀnet.ru
1,5ꢀDicarbonyl derivatives of piperidine and tropane were studied in the heterocyclization
with hydroxylamine hydrochloride. All the 5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridines obtained
exhibit a pronounced analgesic effect.
Key words: Michael reaction, Nꢀbenzylpiperidinꢀ4ꢀone, 8ꢀmethylꢀ2ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylꢀ
propyl)ꢀ8ꢀazabicyclo[3.2.1]octanꢀ3ꢀone, 1ꢀmethylꢀ3ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)piperidinꢀ4ꢀ
one, heterocyclization of 1,5ꢀdiketones, 5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridines, opiate activꢀ
ity, agonists.
Substituted and polyfused piperidine derivatives exꢀ
hibit ganglioblocking, anticholinesterase, neuroleptic, anꢀ
tihypertensive, and analgesic activities, depending on the
type of substituents and their positions in the ring.1—7
Fused pyrazolo[4,3ꢀc]piperidines have a pronounced anꢀ
algesic effect.8 However, the pharmacological properties
of 5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridine systems with aroꢀ
matic radicals in the pyridine ring have not been docuꢀ
mented.
and 4, respectively (Scheme 1). The reactions were carꢀ
ried out in ethanol at 70 °C.
Scheme 1
The synthesis of 3ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)piꢀ
peridinꢀ4ꢀones, their heterocyclization into 5,6,7,8ꢀtetraꢀ
hydroꢀ1,6ꢀnaphthyridines, and the study of the pharmaꢀ
cological properties of the products obtained were of our
interest.
6ꢀMethylꢀ2,4ꢀdiphenylꢀ5,6,7,8ꢀtetrahydroꢀ1,6ꢀ
naphthyridine (1a) was synthesized earlier9 by the reacꢀ
tion of 4ꢀaminoꢀ1ꢀmethylꢀ1,2,5,6ꢀtetrahydropyridineꢀ3ꢀ
carbonitrile with chalcone. However, this synthesis is laꢀ
borꢀconsuming and use of chromatographic methods
complicates isolation of both reaction intermediates and
products.
For this reason, taking into account consideration that
1,5ꢀdicarbonyl compounds serve as convenient precurꢀ
sors in the preparation of the dihydropyridine and pyriꢀ
dine systems,10 we have recently11 synthesized a number
of 1,5ꢀdicarbonyl derivatives of Nꢀsubstituted piperidinꢀ
4ꢀones (2a,b) and 8ꢀmethylꢀ8ꢀazabicyclo[3.2.1]octanꢀ
3ꢀone (3).
i. NH2OH•HCl, EtOH, 70 °С.
R = Me (a), CH2Ph (b)
We found that diketones 2a,b and 3 under the action
of NH2OH•HCl in ethanol undergo heterocyclization
into 5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridine systems 1a,b
Cyclization of 1,5ꢀdicarbonyl compounds proceeds
smoothly without addition of catalytic amounts of
pꢀtoluenesulfonic acid.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 251—253, January, 2005.
1066ꢀ5285/05/5401ꢀ0257 © 2005 Springer Science+Business Media, Inc.

258
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
Vatsadze et al.
peridinꢀ4ꢀone (2b) (0.3 g, 7.5 mmol) in 10 mL of ethanol. The
reaction mixture was heated at 70 °C for 8 h and treated as
described above to give compound 1b (0.22 g, 78.5%), m.p.
143—145 °C. 1H NMR (CDCl3), δ: 2.80 (t, 2 H, H(8), J =
8.0 Hz); 3.15 (t, 2 H, H(7), J = 8.0 Hz); 3.55 (s, 2 H,
N—CH2—Ph); 3.65 (s, 2 H, H(5)); 7.20—7.45 (m, 13 H,
Ar—H+Py—H); 7.90—8.00 (m, 2 H, Ar—H). Found (%):
C, 86.45; H, 6.81; N, 7.71. C27H24N2. Calculated (%): C, 86.13;
H, 6.43; N, 7.44.
12ꢀMethylꢀ3,5ꢀdiphenylꢀ6,12ꢀdiazatricyclo[7.2.1.0.2,7]doꢀ
decaꢀ2(7),3,5ꢀtriene (4). Hydroxylamine hydrochloride (0.5 g,
7 mmol) was added to a solution of 8ꢀmethylꢀ2ꢀ(3ꢀoxoꢀ1,3ꢀ
diphenylpropyl)ꢀ8ꢀazabicyclo[3.2.1]octanꢀ3ꢀone (3) (0.5 g,
1.4 mmol) in 7 mL of ethanol. The reaction mixture was heated
at 70 °C for 8 h. Then the solvent was evaporated by two thirds
and 10% KOH (15 mL) was added. The crystals that formed were
filtered off, repeatedly washed with water, and recrystallized from
PriOH—water (1 : 0.25) to give compound 4 (0.25 g, 55%), m.p.
95—98°C. 1H NMR (CDCl3), δ: overlapping multiplets for the
protons of the tropane ring appear at 1.70—2.05 (m, 4 H,
trop.ring—H(10),H(11)); 2.37 (s, 3 H, N—CH3); 2.40 (br.d, 1 H,
H(8) J = 12.6 Hz); 2.80 (br.d, 1 H, H(8) J = 12.6 Hz); 3.10—3.70
(m, 2 H, H(1), H(9)); 7.20—7.50 (m, 9 H, Ar—H+Py—H);
7.95—8.00 (m, 2 H, Ar—H). Found (%): C, 84.98; H, 6.92;
N, 8.71. C23H22N2. Calculated (%): C, 84.63; H, 6.79; N, 8.58.
The 5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridine structure of
products 1a,b was confirmed by 1H NMR data. Their
1H NMR spectra contain singlets at δ 3.50 (1a) and
3.65 (1b) for the protons of the piperidine ring at the C(5)
atom and triplets at δ 2.85 and 3.20 (1a) and δ 2.80 and
3.15 (1b) for the protons at the C(7) and C(8) atoms,
respectively. The aromatic protons appear at δ 7.20—7.50
and 7.90—8.0. The spectrum of compound 4 is compliꢀ
cated by the presence of multiplet signals for the tropane
ring (see Experimental).
It was found that the reactions of 1,5ꢀdicarbonyl comꢀ
pounds 2 and 3 with such nucleophiles as hydrazine
hydrate, nꢀbutylamine, ethanolamine, and ethylenediꢀ
amine in ethanol or benzene in the presence of catalytic
amounts of pꢀtoluenesulfonic acid or CH3COOH yield
no dihydropyridine system. The resulting mixture of prodꢀ
ucts (TLC data) was not separated by recrystallization.
Compounds 1—4 were tested for functional activity of
opiate receptors with a model of separate organs (seminal
duct MVD). Contractions of MVD were detected with a
mechanotron and converted electrical signals were reꢀ
corded on a recorder type. Compounds 1—4 were found
to exhibit opiate activity and agonistic properties. Among
the compounds studied, compounds 1b and 2b have the
most pronounced pharmacological properties and will be
tested additionally.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 03ꢀ03ꢀ32401).
References
Experimental
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The course of the reaction was monitored and the purity of
the products was checked by TLC (Silufol UVꢀ254) and GLC
on a Tsvetꢀ152 chromatograph (L column 0.7 m × 3 mm, liquid
phase 5% SEꢀ30 on Chromaton NꢀAW (0.16—0.20 mm), nitroꢀ
gen as a carrier gas, programmed temperature rise from 75 to
325 °C at a rate of 22 deg min–1). 1H NMR spectra were reꢀ
corded on a Bruker Aꢀ250 instrument (250 MHz) in CDCl3.
Chemical shifts are given in ppm on the δ scale with reference to
HMDS as the internal standard. Melting points were deterꢀ
mined on a Boetius instrument of the Kofler system.
All solvents were purified according to common standard
procedures.12
6ꢀMethylꢀ2,4ꢀdiphenylꢀ5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridine
(1a). Hydroxylamine hydrochloride (0.25 g, 3.5 mmol) was added
to a solution of 1ꢀmethylꢀ3ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)piꢀ
peridinꢀ4ꢀone (2a) (0.3 g, 1 mmol) in 10 mL of ethanol. The
reaction mixture was heated at 70 °C for 12 h. Then the solvent
was evaporated by half and 10% NaOH (15 mL) was added. The
crystals that formed were filtered off, repeatedly washed with
water, and recrystallized from PriOH to give compound 1a
(0.18 g, 60%), m.p. 79—82 °C. 1H NMR (CDCl3), δ: 2.40 (s,
3 H, N—CH3); 2.85 (t, 2 H, H(8), J = 7.8 Hz); 3.25 (t, 2 H,
H(7), J = 7.8 Hz); 3.50 (s, 2 H, H(5)); 7.20—7.45 (m, 9 H,
Ar—H+Py—H); 7.95—8.00 (m, 2 H, Ar—H). Found (%):
C, 84.13; H, 6.82; N, 9.61. C21H20N2. Calculated (%): C, 83.96;
H, 6.71; N, 9.33.
6ꢀBenzylꢀ2,4ꢀdiphenylꢀ5,6,7,8ꢀtetrahydroꢀ1,6ꢀnaphthyridine
(1b). Hydroxylamine hydrochloride (0.25 g, 3.5 mmol) was added
to a solution of 1ꢀbenzylꢀ3ꢀ(3ꢀoxoꢀ1,3ꢀdiphenylpropyl)piꢀ
Received July 8, 2004;
in revised form September 6, 2004