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Synthesis and Muscarinic Activity of Isoxazole-substituted 1256-Tetrahydropyridines.

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Isoxazole substituted 1,2,5,6-Tetrahydropyndines
Synthesis and Muscarinic Activity of Isoxazole-substituted
1,2,5,6=Tetrahydropyridines
Synthese und muskarinische Aktivitat von isoxazolsubstituierten 1,2,5,6-Tetrahydropyridinen
Gerd Dannhardf)", Johannes Schweigera),Giinter Lambrechtb),and Ernst Mutschle?)
Institut fur Pharmazie, Johannes Gutenberg-Universitat, D-55099Mainz
Institut fiir Natunvissenschaftler, Biozentrum Niederursel, Johann Wolfgang Goethe-Universitat Frankfurt, Marie-Curie-Str. 9,
D-60439FrankfudM.
b, Pharmakologisches
Received July 14,1994
Arecoline and other arecaidine esters are semirigid derivatives of the reverse carboxy-analogue of acetylcholine
with high muscarinic potencies and intrinsic activities').
Among the arecaidine esters the propargyl derivative 1 is
more potent than arecoline and even acetylcholine'). Since
the bioisosterism of the isoxazole3) or the oxime ether
moiety 24)and the ester group was shown recently, isoxazole substituted tetrahydropyridines were part of our interest.
Scheme 2
Scheme 1
An efficient one-pot reaction of acetophenone or acetone
oxime with two equiv. of n-butyl lithium leads to the corresponding dianion which after addition of arecoline cyclizes
to the 3-substituted tetrahydropyridin derivatives 3 and 4,
respectively (Scheme 2).
The spectral data (IR, NMR, MS) agree with the expected structure:
singlets for the N-methyl protons and the vinylic proton of the isoxazole
nucleus were found at 2.48 and 6.40ppm, respectively. The vinylic proton
of the pyridine ring and the arom. protons resonate in the range of 6.67
ppm and 7.46to 7.80ppm. Three multiplets at 2.46,2.61 and 3.30 ppm are
associated with the CH2 protons of the tevahydropyridine moiety. All signals are shifted to higher field in case of the methyl derivative 1 which
shows an additional singlet of the isoxazole methyl group at 2.28 ppm
(s. Exp. Part).
The corresponding hydrochlorides of 3 and 4 were used
for the pharmacological tests.
Compounds 3 and 4 were investigated for muscarinic
properties at M1 receptors in rabbit vus deferens, at M2
receptors in guinea-pig atria and at M3 receptors in guineapig ileum5). The methyl derivative 3 was a muscarinic
antagonist at M2 and M3 receptors with pA2 values of 5.47
and 5.54, respectively, but showed no muscarinic or antimuscarinic activity at the M1 receptor in rabbit vus deferens.
Arch. Pharm. (Weinheim)327,751-752 (1994)
The corresponding phenyl derivative 4 exhibited an agonist-like negative inotropic effect in guinea-pig atria; but
this was not mediated by muscarinic receptors as it could
not be antagonized by N-methylatropine. At M1 and M3
receptors the compound displayed antimuscarinic activity
with pA2 values of 5.40 and 5.28, respectively. Thus, both
compounds were very weak and nonselective antagonists at
muscarinic receptors subtypes.
Tab. 1: Muscarinic activity of 3 and 4 (hydrochlorides). Data are means f
S.E.M. (n = 4-6)
M1
M2
4 pA2=5.40 20.12 pLl+.20+0.13*
M3
pA2=5.28+0.18
* The effect could not be antagonized by N-methyl atropine (10 nM).
Experimental Part
Melting points: Uncorrected, Biichi SMP 20 apparatus.- IR: Perkin
Elmer 299.- 'H-NMR: Bruker AC 300 MHz-spectrometer, TMS as
internal standard, CDC13, (chemical shift in 6 ppm).- Mass spectra: MAT
0 VCH Verlagsgesellschaft mbH, D-69451Weinheim, 1994 0366-6233/94/1111-0751
$5.00 + ,2510
752
212/SS 188 spectrometer, EL 90 eV.- All C, H. N analyses were within rt
0.4% of the theoretical values.
I -Me1hyl-3-(3-me1hq.liso.~a~ol-~~-~l~-l,2,5,6-te1ral1ydropq.ridine
(3)
To a solution of 13.3 mmol acetone oxime in 15 ml anhydrous THF 26.6
mniol n-BuLi are added at O°C with stirring under Nz. After I h 8.3 mmol
arecoline in 15 ml THF are added dropwise. The mixture is stirred for 18 h
slowly increasing the temp. to 2OOC. The solution is poured into a mixture
of 30 ml THF. 7 ml H 2 0 and 6 g conc. H2S04. The resulting mixture is
refluxed for 1 h and after cooling it is made alkaline. After extracting with
CH2C12the combined org. layers are dried and the solvent is distilled off.
The residue is purified by cc on A1203 (Merck 1077, activity 2) with
CH2C12KH30H (99:1).- CloH14N20
(1 78.2), pale yellow oil, yield 62%.To a solution of the base in anhydrous ethanol HCI saturated ether is added
yielding the corresponding hydrochloride, mp. 162-163°C.
The spectroscopic data are given for the base: IR: 3120; 2940; 2850;
2795; 1660 (C=C). 1585 (C=N); 1460; 1440; 1370; 1290; 1260; 1200;
1140; 1060; 1050 1020; 960,920; 860; 8 1 0 790 cm-I.- 'H-NMR: 2.28 (s,
3H. C-CH+, 2.38-2.43 (m, 2H, pyr. C-5). 2.45 (s, 3H, N-CH,), 2.48-2.58
(m,2H, CH2, pyr. C-6). 3.16-3.21 (m,2H, CH2, pyr. (2-2). 5.93 (s, IH.
vinyl-H, isox. C-4). 6.54-6.58 (m, IH. vinyl-H, pyr. C-4).- MS: m/z = 178
(M+*,95). 177 (24). 136 (60). 124 (5). 106 (24). 96 (58). 94 (51). 82 (64).
66 (100). 55 (30). 53 (30).
l-Met/i~l-3-(3-phenyliso.~a:ol-5-yl)-l,2,5,6-tetrahydropyrid~ne
(4)
Except the additional use of 5 ml HMPTA as solvent, 4 is synthesized
according to the procedure given for 3. The product was purified by cc on
Dannhardt and coworkers
A1203 (Merck
1077, activity 2) with diisopropyl ether: Cl5HlbN20(240.3).
pale yellow oil, yield 34%.- Hydrochloride: m.p. 229-230°C (dec.).
The spectroscopic data are given for the base: IR: 3060 2920; 2840
2790 1690 (C=C); 1660 (C=N): 1600; 1570; 1510; 1470; 1440; 1410,
1400; 1370; 1290; 1260; I140 1130; 1050; 1020; 950; 920; 860; 800; 760;
690 cm-'.- 'H-NMR: 2.44-2.47 (m,2H, CH2, pyr. C-5). 2.48 (s, 3H. NCH,), 2.59-2.63 (m, 2H, CH2, pyr. C-6). 3.29-3.31 (m, 2H, CHI, pyr. C-2).
6.40 (s, 1H. vinyl-H, isox. C-4). 6.65-6.69 (m,1H. vinyl-H, pyr. C-4).
7.43-7.49 (m, 3H arom.), 7.79-7.82 (m, 2H arom.).- MS: m/z= 240 (M+',
100). 198 (28), 197 (30), 196 (16). 168 (36). 144 (74). 130 (14), 116 (14j,
105 (8). 103 (2). 96 (32). 94 (16). 89 (8).81 (8). 77 (30). 66 (lo), 53 (16).
51 (12).
For details of the pharmacological tests see?).
Agonistic and antagonstic effects of compounds 3 and 4 were expressed
as pD2 and pA2 values, respectively.
References
E. Mutschler, K. Hultzsch, Arzneim.-Forsch, 1973,23, 732-737.
M. Wolf-Pflugmann, G. Lambrecht, J. Wess, E. Mutschler, Arzneim..
Forsch. 1989.39.539-544.
P. Sauerberg, J.-J. Larsen, E. Falch, P. Krogsgaard-Larsen, J . Mcd.
Chem. 1986,29,1004-1009.
E . Toja, C. Bonetti, A. Butti, P. Hunt, M. Fortin, F. Barzaghi, M.L.
Formento, A. Maggioni, A. Nencioni, G . Galliani, Eur. J. Med. Chem.
1991.26.853-868.
G. Lambrecht, R. Feifel, U. Moser, J. Aasen, M. Waelbroeck, J. Christophe, E. Mutschler. Eitr. J . Pharmacol. 1988,155, 167-170.
[ KPh632j
Arch. Pharm. (Weinheim) 327,751-752 (1994)
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synthesis, 1256, activity, muscarinic, substituted, tetrahydropyridine, isoxazole
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