The synthesis of a series of 3-(1-substituted-4-piperidinyl)-1,2-benzisoxazoles is described. The neuroleptic activity of the series was evaluated by utilizing the climbing mice assay and inhibition of [3H]spiroperidol binding. Structure-activity relationships were studied by variation of the substituent on the benzisoxazole ring with concomitant variation of four different 1-piperidinyl substituents. Maximum neuroleptic activity was realized when there was a 6-fluoro substituent on the benzisoxazole ring. The 1-piperidinyl substituent appeared less significant, although in most cases, the (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl group imparted maximum potency. The most potent compound in both assays was 6-fluoro-3-[1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl]-4-piperidinyl]-1,2-benzisoxazole (11b).

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HR 916 K (5), the 1-(S)-(pivaloy1oxy)ethyl prodrug ester of was recycled by acidic saponification or enzymatic cleavage the cephalosporin cefdaloxime, exhibits a significantly to AMCA (7). The amine 10 was acylated with mercaptobenhigher oral bioavailability than the 1-(R) diastereomer HR zothiazole thioesters or mixed anhydrides, prepared from 916 J. An efficient'synthesis of HR 916 K was developed. The carboxylic acids 13 and 14, in almost quantitative yield. Deseparation of the diastereomers was achieved by precipita-protection of the oxime and formation of the tosylate protion of the 1-(R)-hydrochloride 9 followed by crystallization ceeded in one step. Using thioester 18, we obtained HR 916 of the 1-(S)-amine 10 (de > 96%). The 1-(R) diastereomer 9 K (5) from AMCA (7) in 42% yield.Most of the therapeutically useful third-generation cephalosporins are orally not well absorbed. Conversion of the carboxylic acid to prodrug esters, which are cleaved after absorption from the bowl, has been successfully used to obtain orally absorbable cephalosporins. Especially successful are the 1 -acyloxy-and 1 -alkoxycarbonyloxy-substituted methyl and ethyl esters, Typical examples of these types of esters are cefetamed pivoxil 1['] and cefpodoxime proxetil 2F21. In the case of the substituted ethyl esters an additional stereocenter is introduced into the molecule. Cefpodoxime proxetil 2 is on the market as a mixture of diastereomers.,OMe 1: Rf = Me, R2 = CH,OCOCMe, 2: R f = CH,OMe, R2 = CH(Me)OC02CHMe, HR 916 B (3) was selected as a candidate for clinical development, as its active metabolite cefdaloxime . shows broad antibacterial activity against Gram-positive and Gram-negative bacteria"], and the prodrug ester 3 exhibits good oral bioavailability in different animal species [4]. Formation of the toluenesulfonic acid salt increases the stability of the cephalosporin ester15]. The diastereomers could be separated by chromatography of an intermediate. HR 916 J (4) and HR 916 K (5) show comparable bioavailabilities in mice and rats, but in dogs the latter is enterally absorbed to 68%, whereas the former only to 20'Y0 [~]. Phase 1 clinical studies confirmed that HR 916 K (5) is enterally well absorbed [7]. Therefore, the pure diastereomer 5 was chosen as candidate for further clinical development.At that time HR 916 K (5) could be prepared either by separation of the diastereomers by chromatography of an intermediate or by multifold recrystallization[*l of HR 91 6 B (3). For ecological and economical reasons none of these methods was suitable for the large-scale synthesis and therefore, an efficient synthetic access to our compound 5 had to be identified. Results and DiscussionThe most elegant access to the diastereomerically pure prodrug ester would be esterification of the carboxylic acid

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The 10-formyl group in k-strophanthidine (1) reacts with (diethoxyphosphoryl)acetonitrile/ sodium hydride or ethyl (diethoxyphosphoryl)acetate/sodium hydride under non-prototropic reaction conditions via PO-activated o l e h t i o n to form the corresponding cardenolides 4 and 6, respectively, bearing two additional C-atoms in position 19, without impairing the 14@-hydroxy-17(3-butenolide system essential for cardiac activity. Under prototropic conditions, however, the butenolide ring is transformed chemically. The glycosides 12,14, and 16 are obtained by glycosidation of the 3-hydroxy group of 6 and 4 according to the KoenigsKnorr or "glycal'' process, and subsequent saponification of the sugar acetate groups. -Reaction of ethoxyethynyllithium and of methyllithium with the 10-fonnyl group of 3-0-(tetrahydro-2-pyranyl)-k-strophanthidine (17) and subsequent reactions leads to 6, and to the cardenolides 20 and 22, respectively, bearing an additional methyl group at C-19. -The glycosides 12 and 14 show the highest cardiac activity i n isolated guinea pig hearts.