31 8185 Triutene Derivatives of Cyrisine 669

Die in Tab. 1 zusammengefaflten Bindungsparameter wurden nach der Methode von Scarchard ermittelt. Die nach der Auswertuqgsmethode von Scholtan erhaltenen Ergebnisse sind hier nicht dargestellt , da sie nur geringfugig abweichen. Die gute Reproduzierbarkeit der MeBergebnisse ist aus den kleinen Standardabweichungen zu ersehen.

Experhenteller Teil Die Messung der Proteinbindung wurde wie ublich4.” durchgefiihrt. Die Konz. von Phenylbutazon im Puffer war 2.1 bis 4.5 mg/l. Die entgasten Losungen wurden mit 0.7 ml/min durch die auf 36” temperierte Ultrafiltrationskammer gepumpt. Die Extinktion wurde bei 264 nm gemessen. Es wurden sieben Versuche durchgefiihrt.

LiIeratur

+) 6. Mitt.: K. Rehse und K. Ehlert, Arch. Pharm. (Weinheim) 318, 573 (1985). * * Teil der Dissertation K. Ehlerr, FU Berlin 1984. 1 M. Orme, P. J. L. Holt, G. R. U. Hughes und C. J . Bupitt, Br. J . Clin. Pharmacol. 3, 185

(1976). 2 K. Rehse, M. Rothe und M. Kuhn, Arch. Pharm. (Weinheim) 315, 52 (1982). 3 K. Rehse und M. Rothe, Arch. Pharm. (Weinheim) 315, 259 (1981). 4 K. Rehse, M. Rothe, R. Maurer und A. Kinawi, Arch. Pharm.’(Weinheim) 314, 867 (1981). 5 P. Nickel und R. Schlerf, Pharm. Ztg. 128, 1234 (1983).

[KPh 3511

Arch. Pharm. (Weinheim) 318, 669-671 (1985)

Triazene Derivatives of Cytisine Triazen-Derivate des CytiSins

Vassil Vassilev, Svetlana Simova and Blagoy Blagoev*

Institute of Organic Chemistry, Bulgarian Academy of Sciences, Sofia 1 1 13, Bulgaria Eingegangen am 11. Marz 1985

These communication describes the preparation of cytisine derivatives containing a triazene moiety. It is known that compounds with this function possess various kinds of biological activity’).

Several new compounds 7-11 have been synthesized using an unknown coupling between cytisine (6) and the aryldiazonium salts 1-5 (see Table 1).

P2

1-5

+

’H

6

0365-6233/85/MU74669 S 02.50/0

Q VCH Verlagsgesellschaft mbH. D-6940 Weinheim. 1985

670 Vmsilev. Simova and Btanoev Arch. Pharm.

The diazotation of the aromatic amines and its interaction with 6 was carried out by the most widely used procedure for secondary amines". In the case of 4-aminopyridine only, which does not usually participate in the formation of triazene systems, diazotation was carried out under special conditions3).

All products were obtained in good yields and were easily purified. The structures of the compounds were determined by elemental analysis for N(? 0.5 %), IR spectra in CHCI, (1660,1630, 1590, 1570, 1540cm-') and NMR.

The 'H (250.1 MHz) and I3C (62.9 MHz) NMR spectra of compounds 7-11 were recorded on a Bruker WM-250 spectrometer. An essential line broadening is observed in both type of spectra at room temperature.

Table 1: (I R)-3-Arylazo-l,2,3,4,5,6-hexahydro-l ,5-methano-8H-pyrido[1,2-a][1,5]dia- zocin-&ones 7-11

Diazotited Triazene Yield I# m.p. amine Y R1 R 2 i c 0.3, CHC13 OC

1 7 C H H 53 - 530 oil

3 9 C H CH3 76 -640 oil 4 10 C CI H 84 -550 14 8 -- 155

2 8 C SO2 H 30 -775 170-176

5 I 1 4 - H 79 - 790 82-100

The detailed analysis of the spectra at various temperatures reveals that among the four likely dynamic processes, i. e. a) N = N ZIE isomerisation; b) N(I) nitrogen inversion; c) chair-boat reversal of the piperidine ring; d) rotation about the N(1)-N(I1) single bond, only the latter is observed, the molar ratio of both conformers for all studied compounds being approximately 1 : 1. The spectra of compounds 7-11 are very similar, therefore we give only the data for 11 (NMR data regarding the remaining compounds are available on request).

"C NMR (CDCI,, TMS, 228°K: 5 (ppm) = 34.30 a. 33.41 (C-1); 49.03 a. 57.84 (C-2); 58.93 a. 49.95 (C-4): 26.40 a. 27.17 (C-5); 49.37 a. 48.67 (C-6); 163.25 (C-8); 139.23 ((2-9); 117.47 a. 117.35 (C-lo); 106.07 (C-11); 147.89 a. 147.15 (C-12); 25.23 a . 25.13 (C-13); 155.44a. 155.39 (C-1'); 115.31

The coalescence temperatures (T,) were estimated to be 300°K for C-1 ( n ~ ~ ~ ~ 0 ~ = 56.5 Hz) and 293 "K for C-5 (50.3 Hz). From these values a nG:of 61.1 kJlmol(l4.6 kkal/mol) is obtained, falling well in the range of the energy of activation reported for rotational barriers of triazenes4'.

'H NMR-' (CDCI,, TMS, 223°K) b (ppm) = 3.37bs - H-1; 5.03d (J = 14.0Hz) a. 4.98 (13.0), 4.34d (12.4) a. 4.26d (13.3) - H-2.4e; 3.82bd (12.8), 3.14dd (13.0; 3.2) a. 3.12dd (14.0; 3.9) -

(C-2'): 150.34 (C-3').

* ' bs-broadened singlet; bd-broadened doublet.

318185 Buchbesprechung 671

H-2,4a;2.82bs-H-5;4.33d (16.0)a. 4.20d (15.8)-H-6e;4.00dd (15.8; 6.6) a. 3.87dd (15.7;6.3)- H-6a;6.18d(6.8)a.6.25d(6.7)-H-9;7.34dd(6.7;8.7)a. 7.41dd(6.7;8.7)-H-10;6.47d(9.0)a. 6.50d (8.5) - H-11; 2.19bs - H-13; 8.52-8.54m - H-2‘; 7.23-7.25m - H-3’.

It is interesting to note that the N(I1)-N(II1) double bond causes a strong deshielding of the equatorial (H-2,4e 2) and a strong shielding of the axial (H-2,4a Z) protons in 2-position to the N(II1) atom, whereas the influence on the corresponding protons in E-position is smaller.

The anisotropy of the N = N double bond in these compounds is therefore, very similar to the effects of a > C=O and : C=S group’). Further investigations are in progress.

Experimental Part

Preparation of the triazenes 7-10

A solution of 0.02 moles amine, diazotised at 0°C was added to a solution of 0.01 mole cytisine in 65 ml 10 % sodium carbonate’]. The mixture was kept for 24 h at 0-5 “C, then extracted with CHCI,, washed with water, dried over MgSO, and the solvent distilled under vac. Additional purification was carried out by dissolving the product in ethanol and treatment with charcoal. The triazene 11 was obtained by diazotation of 0.02 mole of 4-aminopyridine for 50-6Osec at 0°C’) and further addition of that mixture to 0.01 mole of cytisine dissolved in a cold borate buffer. After standing for 24 h at room temp. the precipitate obtained was recrystallized from acetone. Additional purification was carried out by dissolving of the precipitate in 5 % hydrochloric acid and precipitating with diluted ammonia.

References

1 a) Farbenfabriken Bayer Akt.-Ges. (H- Foerster and D. Steinhoff, inventors), S. African 6,904,895 (Jan.26, 1970); C.A. 73, 5582331 (1970). b)R. Preussmann, H. Druckrey and S. Ivankovic, Ann. N. Y. Acad. Sci. 1969,163 (Art. 2), 697. c) Agripat. S. A. (K. Gubler, inventor), Ger. Offen 2,003,333 (Oct. 08.1970); C. A. 73, 130181~ (1970).

2 Houben-Weyl, Methoden der Organischen Chemie, Band X/3, S . 702, Georg Thieme Verlag, Stuttgart 1965.

3 E. Kalatzis, J. Chem. SOC. B 1967, 273. 4 a) N. P. Marullo, C. B. Mayfield and E. H. Wagener, J . Am. Chem. SOC. 90,510, (1968); b) M. H.

Akhtar, R. S. McDaniel, M. Feser and A. C. Oehlschlager, Tetrahedron 24,3899 (1968); c) C. L. Habraken, C. Erkelens, J.R. Mellema and P. Cohen-Fernandez, J. Org. Chem. 49, 2197 (1984). a)K. Todt and H. Paulsen, Z. Anal. Chem. 235, 29 (1968); b)H. Paulsen, K. Todt and H. Ripperger, Chem. Ber. 101, 3365 (1968).

5

[KPh 3521

Buchbesprechung Lehrbuch der AnneimitlelkontroUe von L. Kny, Th. Beyrich und B. Gober, 564S. , 188Abb.,

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