Addition of piperidines 15a-d to methylene lactones 8,14a gives the "gamma-lactonized" diphenylbutylpiperidine-type neuroleptics 3a,b,d,4a-d. 8 can be produced by cyclization or--as well as 14--from the corresponding alpha-carboxylactone. 1H- and 13C-nmr data give evidence for the equatorial position of the aminomethyl group in all derivatives of 3 and 4 and bisequatorial-trans-configuration in 4a-d. 3H-spiroperidole displacement at the D2 receptor in rat brain by 3,4 and the "gamma-lactonized" butyrophenone neuroleptics 1,2a-c was investigated. Some compounds show moderate up to high (3b) activity.

Considering the possibility of an in vivo equilibrium 1 + 3a, the "lactonized" neuroleptic 1 is supposed to have quite different pharmakokinetic properties compared to the analogous diphenylbutylpiperidine pimocide. 1 showed little affinity to the 5-HT*-') but high (Ki = 17 nmolj) to the dopamine D*-binding site of rat striatum'). Now we want to report on the affinity of 1, its enantiomers and its ring open derivatives 3a,b to the dopamine receptors in bovine striatum, to a number of other receptors and also on the stability of 1 under various conditions.If the in vjvo formation of the hydroxy acid 3a is assumed, its affinity should be determined as well. Alkaline hydrolysis of 1 gave 3a, treatment with pyrrolidine afforded 3b, which in contrast to 3a is not easily relactonized in acidic aqueous solution or by heating. Resolution of 1 was performed via the diastereomeric salts with (+)-and (-)-dibenzoyltartaric acid to give (+)-and (-)-1. Enantiopurity (Tab. 1) was determined by HPLC on a chiralpak AD column. Tab. 1: Affinities to dopdmine D,and D2-binding sites, K, (nmol/l) ~~_ _ _~-_ _ _ _ _ _ _ _ _~ Racem. 1 (+)-I1) (-)-l*) D2 210 1050 90 750 5490 4.3I ) ee = 85% 2, ee = 97.5% ') 5tandard butaclamol a-Aminomethyllactoneshexanolides rather than pentanolidescan eliminate amines to give cytotoxic a-methylen el act one^^). To get an impression of its stability, 1 was refluxed for 3 d in solvents of increasing boiling points (ether, ethanol, toluene) and also was stirred for 3 d at 37°C in 0.1 M HCI, 0.1 M NaOH and phosphate buffer pH 7, together with one drop of tween 80. The treatment was monitored by TLC with 4-(2-oxo-1-benzimidazolinyl)piperidine, 2, and 3a as reference compounds. No formation of these or other products was observed, so 1 proved to be more stable than other a-aminola~tones~). 9 Plmoclde F Q 2 F F 3 a : R = 0 1 1 3 b : R = 0 I Arch. Phurm (Weinhelm) 326,911-912 (1493j 0 VCH Verlagsgesellschaft mbH, D-6945 1 Weinheiin, 19930365-6233/93/111 1-091 1 $5.00 + 2510

Etngegangen am 9. Januar 1992 "*l-Lactonisierte" Neuroleptika (1,2a-c) konnen aus den a-Formyl-, a-Carboxy-und a-Methylenlactonen 5-7a,b durch Umsetzen mit den Aminen Sa-c erhalten werden. 6a und la-c fielen als &/trans-Gemische mit iiberwiegender cis-Form, 6b und 2a als &/trans-Gemische mit ubenviegender trans-Form an. Bei 2b.c wurden reine rruns-Isomere isoliert.In Fortfiihrung unserer Untersuchungen iiber lactonisierte Wirkstrukturen') setzten wir uns die Synthese lactonisierter Neuroleptika vom Butyrophenon-Typ (1,2a-c) zum Ziel.

Antagonists displaying high affinity for both dopaminergic D2-and serotonergic 5-HT2-receptors, e.g. risperidone, are potential candidates for a more effective treatment of schizophrenia and are currently undergoing clinical trials2). Some fluorophenylated a-aminomethyl-y-lactones, which can be considered as "lactonized" neuroleptics, show moderate up to high (18: pKi = 7.77) affinity at the dopamine D2-binding site'). Now we report on the synthesis of derivatives containing the two structural units (9,lO) of ketanse-rine3) in the a-position and their affinity at the serotonin 5-HT2-receptor in comparison to some "lactonized" neuroleptics. H 0 0 Ketanserin 0 Risperidone N -0

Die N -[ 1 -(Ethoxycarbonyl)-3-phenylpropyl]alanyl-Seitenkette ist in ihrer S,S-Konfiguration ein wesentlicher Bestandteil von handelsublichen (Enalapril, Ramipril, Quinapril) oder in der Entwicklung befindlichen (z.B. Moexipril) ACE-Hemmem. Die Synthese und pharmakologische Prufung von Stereoisomeren dieser S,S,S-konfigurierten ACE-Hemmer erfordert in jedem Falle die Vorabsynthese aller Stereoisomeren der Titelverbindung 4. Wir berichten hierrnit uber die Darstellung von R,S-und SR-4 und uber analytische Methoden zur Bestimmung der Diastereomerenreinheit.Urbach und Henning') beschreiben die Synthese von 4 durch Umsetzung von Sbzw. R-Alanin-benzylester mit den Triflaten von racemischen oder enantiomerenreinen 2-Hydroxy-4-phenyl-buttersaure-ethylestern, deuten in einer Patentanmeldung2) aber auch die Moglichkeit zur Umkehrung dieser Rollenverteilung an. In Anlehnung daran setzten wir R-Homophenylalanin-ethylester (R-1) mit dem Triflat von R-Milchsaure-benzylester (R-2) um. Die Reaktion verlauft unter Inversion am chiralen Zentrum in 2 und lieferte R,S-3, das zu R,S-4 debenzyliert werden konnte. Entsprechend fuhrten S-1 und S-2 zu S,R-4.Drei Methoden erwiesen sich als geeignet, die Diastereomerenreinheit von 4 zu beurteilen.