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Halogenated Dimefline-type Derivatives.

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Halogenated Dimefline-likeDerivatives
+) 20. Mitt.: H. Oelschlager, F. Druckrey und F. I. Sengiin, Pharm. Acta Helv. 51, 353 (1976).
1 Mitt. der Herstellerfirma Parke, Davis & Company, Miinchen.
2 T. Chang und A.I. Glazko, Anesthesiology 36, 401 (1972).
3 H. Oelschlager, Advances in electroanalytical Methods in Topics in Pharmaceutical Sciences,
D. D. Breimer and P. Speiser, Eds., ElsevierlNorth-HollandBiomedicalPress, Amsterdam 1981.
4 D.M. Hamel und H. Oelschlager, J. Electroanal. Chem. Interfacial Electrochem. 28, 197
5 H. Lund, Acta Chem. Scand. 11, 990 (1957).
6 L. Holleck und R. Schindler, Z. Elektrochem. 62,942 (1958); R. Zahradnlk et al., Collect. Czech.
Chem. Commun. 24, 347 (1959); H. Burghardt et al., J. Electroanal. Chem. Interfacial
Electrochem. 17, 191 (1968); W. Franklin Smyth et al., Anal. Chim. Acta 78, 81 (1975).
7 Medicamentos de Actualidad, Drugs of Today, Bd. VI, S. 44,Ed. J.R.Prous, S.A., Barcelona
(Espana) 1970.
[Ph 5961
Arch. Pharm. (Weinheim) 316, 421-426 (1983)
Halogenated Dimefline-type Derivatives++)
Piero Valenti, Maurizio Recanatini, Paolo Da Re*,
Lorenzo Cima+ and Piero Giusti+)
Institute of Pharmaceutical Chemistry, University of Bologna, Via Belmeloro 6, 40126 Bologna,
Italy; +) Institute of Pharmacology, University of Padua.
Eingegangen am 7. April 1982
Some halogenated dimefline-type derivatives and their pharmacological properties are reported.
Halogenierte Dietline-W c b e Derivate
Einige halogenierte Dimefline-ahnlicheDerivate und ihre pharmakologischen Eigenschaftenwerden
The introduction of halogens, especially fluorine and to a minor extent, chlorine, in biologicallyactive
compounds in order to improve their pharmacodynamic as well as pharmacokinetic properties, is a
common trend in pharmaceutical
The successes mainly obtained in the fields of the CNS
depressants’), corticosteroid~~)
and more recently in blood substitutes4) strongly support the
importance of such strategy, also if the results not always met the expectations. The example of the
indoklon and isoindoklon pair is very indicative in this connection5).Since this method ought to allow
to resolve problems such as toxicity, specificityand duration of actionof a drug, we have tried to apply
it to a series of dimefline-type CNS stimulants. Besides the theoretical interest, this attempt might
perhaps contribute to overcome some weU known limitationsof this class of compounds, with a special
reference to a decrease of respiratory depression rather than a counterstimulation, and on outstanding
imorovement of the theraoeutic index.
Prof. Dr. Michele Amorosa with the best wishes on occasion of the 70. birthday.
0365-6233/83/0505-0421 $02.50/0
Q Verlag Chemie GmbH,Weinheim 1983
Valenti, Recanatini, DaRe, Cima and Giusti
Arch. Pharm.
With this aim we have prepared two series of derivatives of the following type, in which
fluorine and chlorine have been located in the 4' position of the 2-phenyl ring of the flavone
molecule. These derivatives were prepared by standard procedures i. e. by chloromethylation of 3-methyl-7-methoxy-4'-chloro(or 4'-fluoro) flavone and subsequent amination
of the 8-chloromethyl intermediate with selected secondary bases.
The main acute toxic effects of analeptics may be considered as result of general
hyperexcitation of CNS since these drugs cause both an increase in ventilation and in motor
activity; the animals show hyperpnea, hyperexcitability and tonic and clonic convulsions.
While clonic convulsions seem mainly an expression of cortical s t i m u l a t i ~ n ~the
? ~ ,tonic
component usually prevails in true analeptic brain-stem
Therefore in screening tests two general considerations are valuable: (i) drugs which cause clonic
convulsions without tonic extension generally exert little or no analeptic activity; (ii) the centrally
acting drugs produce a particular type of convulsive patterns which are fairly characteristic of their
analeptic properties'*.").
Since the paroxysmal excitation of CNS is usally the main cause of death and the toxic syndrome is
very acute, the reciprocal of LD, may be considered as fairly good index of stimulating activity on
CNS and is used to measure the potency ratio with respect to typical brain-stem stimulants such as
pentetrazole"). The acute toxicity was determined intraperitoneally in albino mice employing all the
compounds dissolved in saline as HCl salts. The behaviour of the animalswas observed during one day
and the LD,,, referred to the bases, was estimated following the Weil's methodI4).
CNS Stimulating Activity
Three different patterns can be outlined after overdosage of the compounds described: 1. The animals
almost suddenly loose the control of the body posture and struggle vigorously. After one or two
generalized clonic tonic attacks, the tonic component prevails and higly characteristic rigidity occurs;
the head is flexed on the chest, the forelimbs are extended and rigid, adhering to the torax and the
hindlimbs too are extended and rigid. Death usually occurs after paroxysmal convulsive excitation or,
occasionally, after a deep prostration. This pattern ist typical of brain-stem stimulants such as
pentetrazole, bemegride and di~nefline'~).
In those cases however in which the symptomatology is
delayed with maximal tonic extension occuring little before dying followed by sudden relaxation,
pattern 1 will be indicated as pattern 1a.
2. The animals maintain their posture during the first muscular twitches, but the whole body assumes
exaggerated muscular tone: they sit down on their hindlimbs which are rigid, extended and
outstretched, whereas forelimbs are lifted up (kangaroo posture). Then the animals strugglewith poor
coordination and become unable to maintain their posture, a natatory convulsive pattern is observed
associated with some gasps and a state of deep depression with respiratory failure, which leads to
death, occurs. This picture resembles that described for nicetamide and preth~amide'~).
3. The animals don't maintain their posture and tend to lie at one side or to assume a cathatonic
behaviour with a staggered gait. No clonic convulsive attacks are observed and the animals gradually
pass from tonic rigidity into a state of deep depression followed by a delayed death.
Following this classification,the tonic manifestations observed with the compounds described in these
papers fall within the type 2 (Table 1).
Halogenated Dimejline-like Derivatives
Table I: CNS stimulating activity of halogenated dimefline-type drugs
LDSOip in
mice (mglkg)
Symptoma- LDso ip in
mice (mgkg)
Symptoma- LDso ip in
mice (mg/kg) tology
3 30
> 400
> 1000
As the reference compounds la-e, all the 2a-e and 3a-e derivatives give rise to
paroxysmal seizureswhich arise 3 min after i. p. administration. However their toxicity and
activity appear to be lower, with a decreased tonic component in the neuroexcitatory
picture (type 2), so that the terminal convulsive attacks are not followed by post-mortem
sudden rigidity with ,,tin soldier" posture.
The CNS stimulating potency follows again the order of the reference series la&), as
well as of the xanthone analogues16).These results show that the decrease in toxicity in the
new derivatives is obtained at expence of changes in the action pattern which shifts from
type 1 to type 2.
At present a satisfactory interpretation of these results seems difficult to achieve, owing
to the different symptomatology from not halogenated and halogenated derivatives.
However it may be emphasized that of the two principal physical effects of the halogen,
i. e. the electronic and steric ones, the latter (obstructive halogenation) does not play a
leading role. Beside the quickness at which the stimulatingactivity rises up and then runs
out, could mean that the 4'-position of the 2-phenyl substituent may not to be directly
involved in the metabolic processes as, for instance, is claimed for p-chlorobarbitalwhich is
longer active than the parent barbital.
Finally, in both the halogenated series 2a-e and 3a-e a more direct dependence of the
CNS stimulating activity from lipophilicity is observable, since the chlorine hydrophobic
constant (n = 0.71) is higher than that of fluorine (n = 0.14).
Therefore the pharmacological results enable us to state tfiat the 4'-halogenation of the
flavone moiety causes changes of CNS stimulating picture from the leptazol and
dimefline-like to nicetamide-like pattern, probably not because of steric andor metabolic
differences, but owing to changes in lipophilicitywhich may modify pharmacokineticsand
perhaps receptor-interactions in the brain-stem.
Valenti, Recanatini, DaRe, Cima and Giusti
Arch. Pharm.
A mixture of 18g (0.1 mole) of 2-hydroxy-4-methoxypropiophenone,
36 g of p-chlorobenzoylchloride
and 54 g of sodium p-chlorobenzoate was heated in an oil bath at 180-190" for 7-8 h. The reaction
mixture was taken up in HzO, washed (NaOH dil and H,O) and extracted with CHCI,. Removal of
the solvent left a residue which from ethanol gave 18g (60% yield) of yellow solid, m. p. 147-150".
C1,HI3C1O3(300.6) Calcd.: C67.9 H4.36 C1 11.8; Found: C67.8 H4.32 C111.8.
In a similar manner from 9 g (0.05 mole) of 2-hydroxy-4-methoxy-propiophenone,18g of
p-fluorobenzoylchlorideand 27 g of sodium p-fluorobenzoate, log (70 % yield) of a yellow solid was
obtained, m.p. 176-178" (ligroin). CI7Hl3FO3 (284.1) Calcd.: C71.8 H4.61; Found: C71.7
To a solution of 3 g (0.01 mole) of 4 in 30 ml acetic acid and 15ml conc. hydrochloric acid, 0.8g of
paraformaldehyde was added and the mixture was stirred at 7CL80" for 5 h while a stream of hydrogen
chloride was introduced. The reaction was then poured into water and the separated sdid
collected, washed with water and dried. From ethanol 2.8g (80% yield) of a white product, m.p.
206-209", was obtained. Cl,H14C1203 (349.0) Calcd.: C61.9 H4.04 CI 20.3 Found: C61.9 H4.00
With the procedure outlined for the precedent compound from 2.84g (0.01 mole) of 5, 2.6g (80%
yield) of a white product, m. p. 160-163" (ethanol-water), was obtained. C1,H14CIF03 (332.6) Calcd.:
C65.0 H4.24 C1 16.7 Found: C64.8 H4.30 C1 10.5.
A solction of 3.49 g (0.01 mole) of 6 and an excess of dimethylamine in 300 ml benzene was kept at
room temp. with stirring for 2 d. The reaction mixture was washed with water and the benzene layer
dried over anhydrous sodium sulfate. Removing the solvent left a residue which was crystallized from
ligroin giving 3.2g (90% yield) of product, m.p. 157-159". C$oHmCIN03(357.6) Calcd.: C67.1
H5.64 N3.9 C19.9; Found: C67.2 H5.60 N3.9 C19.8.
With the same procedure the following compounds were prepared:
white solid, m.p. 131-133" (ligroin), 90% yield. C;,Hz,FNO3 (341.2) Calcd.: C 70.4 H 5.86 N 4.1;
Found: C 70.1 H 5.73 N 4.3.
white solid, m.p. 116-118" (ligroin), 85 % yield. C&H24FNO3 (369.2) Calcd.: C 71.5 H 6.51 N 3.8;
Found: C 71.9 H 6.58 N 4.2.
white solid, m.p. 138.140" (ligroin), 80% yield. q 2 H $ N 0 3(367.2) Calcd.: C 71.9 H 5.99 N 3.8;
Found: C 71.9 H 6.10 N 3.9.
Halogenated Dimefline-like Derivatives
white solid, m.p. 152-154" (ligroin), 85 % yield. GH,FN03 (381.2) Calcd.: C 72.4 H 6.30 N 3.5;
Found: C 72.4 H 6.26 N 3.7.
white solid, m.p. 168-170" (ligroin), 85 % yield. q2H,FN04 (383.2) Calcd.: C 68.9 H 5.75 N 3.7;
Found: C 69.1 H 5.87 N 3.5.
white solid, m.p. 138-140" (ligroin), 80 % yield. Ci,HzClN03 (385.7) Calcd.: C 68.5 H 6.27 N 3.6 C1
9.2; Found: C 68.5 H 6.30 N 3.5 C1. 9.3.
white solid, m.p. 177-179" (ligroin), 70 % yield. C&H22ClN03 (383.6) Calcd.: C 68.8 H 5.78 N 3.7 C1
9.2; Found: C 68.9 H 5.70 N 3.7 C19.3.
white solid, m.p. 180-182' (ligroin), 75 % yield. Q3H2,C1NO3 (397.7) Calcd.: C 69.4 H6.08N 3.5 CI
8.9; Found: C 69.3 H 6.00 N 3.5 C1 8.9.
white solid, m.p. 203-205" (ligroin), 80 % yield. q2H22ClN04(399.6) Calcd.: C 66.1 H 5.55 N 3.5 C1
8.9; Found: C 66.1 H 5.70 N 3.6 C1 8.8.
l a M.B. Chenowth and L.P. McCarty, Pharmacol. Rev. 15, 673 (1963).
l b Handbook of Experimental Pharmacology, Vol. XX, Part 2, p. 253, Springer Verlag, Berlin
2 Ibid. Part 1, p. 501.
3 Ibid. Part 2, p. 193.
4 J.G. Ries and M. Le Blanc, Angew. Chem. 17,621 (1978).
5 W.O. Foye, Principles of Medicinal Chemistry, p. 149, Lea& Febiger, Philadelphia 1981.
6 J. Cheymol, Actual. Pharmacol. 2, 1 (1950).
7 L.S. Goodman, M.S. Grewal, W.C. Brown and E.A. Swinyard, J. Pharmacol. 108, 168
8 A. Kreindler, E. Zuckermann, M. Steriade and D. Chimoion, J. Neurophysiol. 21, 430
9 I. Setnikar, W. Murmann and M.J. Magistretti, Arzneim. Forsch. 11, 1109 (1961).
10 T.E. Starzl, W.T. Niemer and M. Dell, J. Neuropathol. Exp. Neurol. 12, 262 (1953).
11 V.G. Longo, Electroencephalogratic Atlas for Pharmacological Research, Elsevier Publishing
Co, Amsterdam 1962.
12 I. Setnikar, W. Murmann, M.J. Magistretti, P. DaRe and L. Verlicchi, J. Med. Pharm. Chem. 3,
471 (1961).
13 I. Setnikar, Res. Progr. Org. Biol. Med.Chem. 1964,423.
14 C.S. Weil, Biometrin 8, 249 (1952).
Koch und Tscherny
Arch. Pharm.
15 P. Da Re, L. Verlicchi, I. Setnikar, W. Murmann and M.J. Magistretti, Nature (London) 184,
362 (1959).
16 P. Da Re, L. Sagramora, V. Mancini, P. Valenti and L. Cima, J. Med. Chem. 13, 527
[Ph 5971
Arch. Pharrn. (Weinheim) 316, 426-430 (1983)
Bioverfiigbarkeit von Silymarin, 3. Mitt.*)
Spaltung von Silybin-dihemisuccinat dutch Plasma- und
Heinrich Koch*)und Josef Tschemg)
Institut fur Pharmazeutische Chemie der Universitat Wien, Wahringer Str. 10, A-1090 Wien.
Eingegangen am 7. April 1982
Die Hydrolyse von Silybin-dihemisuccinat unter dem EinfluR der esterspaltenden Enzyme in
Rinderblutplasma bzw. in Rattenleberhomogenat wird untersucht. Die Plasmaesterasen zeigen
keinerlei Wirkung, die Leberesterasen hingegen hydrolysieren die Testsubstanz innerhalb 30
Minuten volistandig. Endprodukt der Reaktion ist die unveranderte Stammsubstanz Silybin. Die
Kinetik der leberenzymkatalysierten Hydrolyse wurde studiert, und die Bedeutung der Befunde fiir
die Bioverfiigbarkeit der Wirkstoffe wird diskutiert.
Bioavaihbility of Silymarin, 111: Splitting of Silybm Dihemisuccinate by Plasma and Liver
The hydrolysis of silybin dihemisuccinate by ester cleaving enzymes of bovine blood plasma and rat
liver homogenate was investigated. The compound remains unaffected by the plasma esterases,
whereas it is totally hydrolysed by the liver esterases within 30 minutes. The product of the reaction is
silybin. The kinetics of the enzyme catalyzed hydrolysis were studied, and the significance of the
findings with regard to the bioavailability of the substance is discussed.
Der Terminus ,,prodrug" hat sich eingeburgert zur Bezeichnung jener Arzneistoffe, die im
Empfangerorganismus eine chemische oder enzymatische Transformation zum aktiven Wirkstoff
durchmachen. Die gezielte Derivatisierung hat den Zweck, Wirkstoffemit ungunstigem Dissolutionsundoder Resorptionsverhalten in ihren Eigenschaften so zu modifizieren, daR sie dadurch eine
bessere Bioverfugbarkeit erlangen=) Silymann ist so ein Arzneistoff, und die Hemisuccinate der
Silymarin-Substamen') mussen demnach als gut losliche prodrugs aufgefaat werden. Unbewiesen ist
jedoch bis jetzt die riicklaufige Umwandlung dieser Derivate im Organismus zu den nativen
Nach peroraler Verabreichung und Freisetzung aus der Arzneiform sind die Wirkstoffe zunachst
dem Milieu im Magen-Darm-Trakt ausgesetzt. Wie die vorhergehende Untersuchungl) gezeigt hat,
Q Verlag Chemie GmbH, Weinheim 1983
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dimefline, typed, halogenated, derivatives
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