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Effects of para- and meta-fluoro substitution of the 5-phenyl ring on its solution-state conformation in lactam-type 5-phenyl-14-benzodiazepines.

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32018 7
Conformation of 5-phenyl-I,I-benrodiazepines
27. Comm.: H. Oelschlager and M. M. Ellaithy, Arch. Pharm. (Weinheim) 320,80 (1987).
1 J. M. Hilbert, M. Chung, G. Maler, R. Gural, S. Symchowicz and N. Zampaglione, Clin. Pharmacol.
Ther. 36, 99 (1984).
2 E. I. Tietz, T. Roth, F. J. Zorick, P. Piccione and M. Kramer, ArznehForsch. 31, 1963 (1981).
3 J. M. Hilbert, M. Chung, E. Radwanski, R. Gural, S. Symchowicz and N. Zampaglione, Clin. Pharmacol. Ther. 36, 566 (1984).
4 J. M. Hilbert, J. M. Ning, G. Murphy, A. Jimenez and N. Zampaglione, J. Pharm. Sci. 73,516 (1984).
5 H. Oelschlager, ,,Polarographic Analysis of Psychotropic Drugs'', Bioelectrochemistry and Bioenergetics, 10,25 (1983), Section of J. Electroanal. Chem., and constituting Vol. 155 (1983).
6 S. G. Mairanovskii, J. Electroanal. Chem. 6, 77 (1963).
7 M. Jemal and A. M. Knevel, J. Electroanal. Chem. 95,201 (1979).
8 H. Oelschlager, H.-P. Oehr and G. T. Lim, Pharm. Acta Helv. 48, 662 (1973).
9 B. Breyer and H. M. Bauer in: Alternating Current Polarography and Tensammetry; Interscience Publishers, New York/London 1963.
[Ph 1921
Kur zmitteilungen
Arch. Pharm. (Weinheim) 320, 179-182 (1987)
Effects of para- and meta-fluoro substitution of the 5-phenyl ring on
its solution-stateconformation in lactam-type 5-phenyl-1,4-benzodiazepines')
Effekte der p- und m-Fluorsubstitutiondes 5-Phenylringesin Laktam-5-Phenyl-1,4-benzodiazepinenauf
ihre Konformation in Losung
Emil Finner and Horst Zeugner*
Kali-Chemie AG, Pharmaceutical Division, D-3000 Hannover
Eingegangen am 28. Juli 1986
Single-crystal X-ray diffraction studies have shown that the boat-shaped 3D structures of various 1,4benzodiazepin-2-ones are very similar to each other2). The main geometrical differences between these
molecules are in the conformation of the 5-aryl ring. In studies on topographical and electronic features in
4, we investigated the effects of o-fluoro substitution in the 5-phenyl ring on conformational equilibria. We now report on conformational effects caused by p- and m-fiuoro substitution
within the 5-phenyl ring.
We investigated these influences by means of solution-state NMR and compared the
4'-fluoro and the 3'-fluoro derivatives KC 7488 and KC 7505 with 1,3-dihydro-l-methyl-7-nitro-5 -phenyl-2H- 1,4-benzodiazepin-2-one (nimetazepam) as a reference compound.
Fig. 1 shows the 'H- and I3C-NMR spectra (aromatic region only) of nimetazepam
at room temp. and is given as an example of the known features'lof a fast rotation of
the 5-phenyl ring about the C-5-C-1' bond. The 'H and I3C signals corresponding to
0365-6233/87/0202-0179 S 02.50/0
0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1987
Finner und Zeugner
Arch. Pharm.
the 0-and m-positions of the 5-phenyl become non-equivalent at - 130". From the coalescence temp. of the H-2'- and the H-6'-resonances at - 105" the barrier of rotation
can be estimated to be about 7.4 kcal/mole. The 4'-F and the 3'-F substituents do not
appear to alter this rotational barrier considerably.
Fig. 2 shows detailed results of the low temp. 'H-NMR analyses of the three compounds and summarizes the stereochemical conclusions. While nimetazepam and KC
7488 exhibit only signals for a single rotational conformer about the C-5-C-1' bond,
KC 7505 exhibits signals of two rotational isomers A and B in a 2:3 ratio. The 5-aryl
'H shifts in their given stereochemical environment clearly confirm the shown twisted
conformation. The observed large shift differences between exchanging o-positions can
be explained by opposing shift effects: predominant shielding due to the ring-current effect of the fused benzene moiety on the A-site and deshielding caused by the mesomeric
and anisotropy effect of the C=N group on the B-site.
- 8.3
- 7.4
- 8.4
126.5 6 126.0 PPM
- 7.6
122 PPM
Fig. I : 2D-NMR 'H-"C shift correlated spectrum of the aromatic region of nimetazepam at room temp.
in CDCI, with the corresponding ID-NMR 'H and "C-/'H/ spectra shown on the axes.
KC 7488
KC 7505
in 10161
Fig. 2: 'H shifts (6 ppm) at -130" of nimetazepam, KC 7488 and KC 7505 (rotamers A and B) in
CBrCIF,/CD,Cl, v/v ratio 4:l. Values in parenthesis are shift differences A6 between exchanging positions as proved by ]H,'H magnetization transfer experiments.
Conformation of 5-phenyl-I ,I-benzodiazepines
These contributions to the o-proton shifts should be strongly dependent on the torsional angle z (C-5-C-1') and also on the angle between the planes of the 5-aryl ring and
the fused benzene moiety. Thus, the finding of very similar Ah-values within the compounds of Fig. 2 suggests that (i) the conformation of the benzodiazepine framework
and that of the 5-phenyl ring are affected only slightly upon 4'- and 3'-fluorine substitution and (ii) A and B differ in their torsional angle T (C-5-C-1') by ca. 180".
In previous studies3.4, we postulated for o-fluoro substituted 5-phenyl-benzodiazepinesan attractive
through-space interaction engendered by the halogen in 2'-position and this interaction (probably charge
transfer) was considered to contribute to the biological activity.
In KC 7505 the stability of conformer A is slightly less than that of conformer B,
most likely due to greater van der Wads crowding in A. This is contrary to the behaviour of the 2'-F compound flunitrazepam which was shown4)to exist almost exclusively in that conformation in which the fluoro atom points towards the center of the fused aromatic ring (conformer A). We interpret this difference in conformational behaviour between KC 7505 and flunitrazepam as geometrical response t o the above cited
attractive through-space interaction. The receptor binding data given in table 1 also are
in accordance with such an interpretation since the affinity of the rn-fluoro substituted
compound is somewhat less than that of the unsubstituted compound, whereas in the
o-fluoro compound the affinity is 10 times higher.
Tab. 1: Inhibition constants (Ki) from competition experiments using [ HI-diazepam
Ki (nM)
KC 7505
KC 7488
> 7 800
Regarding the I3C chemical shifts (Fig. 3) it is interesting to note that the substituent
shifts caused by the 3'-F- and the 4'-F-phenyl residues do not show striking differences
in their respective magnitudes. Therefore, the dramatical decrease in binding affinity of
KC 7488
351 10.01
KC 7505
Fig. 3: I3C shifts (6 ppm) at room temp. in CDCI, of nimetazepam, KC 7488 and KC 7505.Values in
square brackets are I3C,l9Fcoupling constants in Hz, while values in parenthesis refer to substituent chemical shifts (SCS). The assignments are proved by 2D-NMR 'H-''C shift correlation experiments. According to Fig. 1, the C-6/C-8 shift assignment for nimetazepam reported in ref.6)need to be interchanged.
Elz und Schunack
Arch. Pharm.
the 4'-F compound cannot be due to significantly altered charge densities within the
benzodiazepine part of the molecule, but has to be attributed to the electronic properties of the 5-(4'-fluorophenyl) residue itself. It appears to be associated with an electronic repulsion border rather than sterical incompatibility5).
We thank Dr. M. Tub, Duphar B. V., for the receptor binding experiments and our co-workers Mrs I.
Gehrrnann for the chemical and Mrs G . Wilkening and Mr H. Vogel for the spectroscopical work.
Experimental Part
NMR: Bruker AM 400, c = 20 mg/ml, TMS int. stand., further exp. conditions listed in the legends of the
figures. Synthesis and [3Hl-diazepambinding assay see ref.').
1 Part IX on 1,4-benzodiazepines and 1,5-benzodiazocines. Part VIII: E. Finner, H. Zeugner, and W.
Milkowski, Arch. Pharm. (Weinheim) 318, 1135 (1985).
2 T. A. Hamor and I. L. Martin in Progress in Medicinal Chemistry, G. P. Ellis and G. B. West, Eds.,
p. 157, Elsevier Science Publishers 1983.
3 E. Finner, H. Zeugner, and W. Milkowski, Arch. Pharm. (Weinheim) 317, 369 (1984).
4 E. Finner, H. Zeugner, and W. Milkowski, Arch. Pharm. (Weinheim) 31 7, 1050 (1984).
5 P. A. Borea and G. Gilli, Arzneim. Forsch. 34, 649 (1984).
6 H.-H. Paul, H. Sapper, W. Lohmann, and H. 0. Kalinowski, Org. Magn. Reson. 21, 319 (1983).
7 W. Milkowski, H. Liepmann, H. Zeugner, M. Ruhland, and M. Tulp, Eur. J . Med. Chem. Chim. Ther.
20, 345 (1985).
[KPh 4151
Arch. Pharm. (Weinheim) 320, 182-185 (1987)
Darstellung und Hz-agonistische Aktivitat alkylsubstituierter
3 4 l[midazol-4-yl)propylguanidine
Synthesis and H,-Agonistic Activity of Alkyl-3-(imidazole-4-yl)propylguanidines
Sigurd Elz' und Walter Schunack*
Institut fur Pharmazie, Johannes Gutenberg-Universitat, SaarstraBe 2 1, D-6500 Mainz und Institut fur
Pharmazie, Freie Universitat, Konigin-Luise-StraBe 2+4, D-1000 Berlin 33
Eingegangen am 24. September 1986
Derivate des 3-(Imidazol-4-yl)propylguanidinsmit einem Methyl-') oder einem 2-(Ethylthio)ethyl-Substituenten2) an der Guanidin-Gruppe weisen am H,-Rezeptor des Meerschweinchenvorhofs nur 10-20 %
der Histaminaktivitat auf. Dagegen fiihrt die Substitution mit der H,-affinen 2-[(5-Methylimidazol-4-yl)
methylthiolethyl-Gruppierung zu Impromidin3), einem hochpotenten H,-Agonisten.
0365-6233/87/0202-0182 $02.50/0
0 VCH Verlagsgesellschaft mbH, D-6940Weinheim, 1987
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meta, substitution, phenyl, ring, fluoro, state, typed, conformational, solutions, effect, para, benzodiazepine, lactam
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