Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoiminomethyl)piperidine (amidinopiperidine) as a weak, but intrinsically selective, thrombin inhibitor. Elaboration of this molecule provided compounds which inhibit thrombin with Ki's in the range of 20-50 nM and with selectivities of 1000-4000 against trypsin. These inhibitor compounds show a new and unexpected binding mode to thrombin. Modification of the central building block and then of one of the hydrophobic substituents led to the discovery of a new family of thrombin inhibitors which has reverted to the former binding mode to thrombin. This last class of compounds shows inhibitory activities in the picomolar range, low toxicity, and a short plasma half life which favors its use for an intravenous application. From this series of thrombin inhibitors, 19f(Ro 46-6240) was selected for clinical development as an antithrombotic agent for intravenous administration.

New Syntheses of 1 a,25-Dihydroxycholesterol SummaryFive convergent syntheses of 1 a,25-dihydroxycholesterol (2) essentially achieved by combining 1 a-hydroxylated C2,-and C,,-steroids with C,-or C,-sidechain building blocks, are described. The 1,3-bis(tetrahydropyranyloxy)pregnen-2 1 -01-ptoluenesulfonate (4) was used as a C,,-unit in three approaches involving sulfone 24 as a C4-, sulfone 43 and 2-propynyl ether 49 as C,-side-chain building blocks. In a further preparation, the 1,3-diacetoxypregnen-21-a15 and the phosphorane 59, a C2,-and a C,-unit, respectively, were connected. For the last one, the I ,3-bis(tetrahydropyranyloxy)pregnen-20-one (6), a C,,-unit and the C,-phosphorane building block 66 were chosen. Furthermore, new routes for the preparation of the 3-hydroxy-27-norcholestenone (29) and of 25-hydroxycholestero1(3) are described for which the ptoluenesulfonates 21 and 23 served as the steroidal units and the sulfones 24 and 43, respectively, as the side chain fragments. Finally, the 1,3-diacetoxypregnen-21-a1(5) and the C,-phosphorane unit 60 gave a novel approach to Ia-hydroxycholesterol (53).Vor kurzem konnte der vor rund 12 Jahren entdeckte, heute als Hormon betrachtete Vitamin-D,-Metabolit 1 a,25-Dihydroxycholecalciferol(l) [ 11 der Humanmedizin zugefuhrt werden'). Dies gab Anlass, nach einem ergiebigen Zugang zu der auch unter dem Namen Calcitriol ((generic name)) bekannten Verbindung zu suchen. Bereits durch die ersten Synthesen wurde gezeigt [2] [3], dass das Calcitriol nach der klassischen Methode der Vitamin-D-Gewinnung [4] aus 1 a,25-Dihydroxycholesterin (2) erhaltlich ist und letzteres somit ein wichtiges Zwischenprodukt darstellt. Im folgenden berichten wir uber Arbeiten, die gunstige Herstellungswege fur dieses Zwischenprodukt 2 zum Ziele hatten.

Synthesis of P-o-Glucopyranosides of some Hydroxylated Vitamin-D Compounds SummaryCholesta-5,7-diene-l a, 3P-diol (la) was glycosylated with 'a-acetobromoglucose' (2) as well as with 'a-acetobromocellobiose' (4) to yield the 3-(glycosides) l b and lc, respectively. Irradiation of these products with UV light followed by thermal isomerization led to the corresponding vitamin-D derivatives 3a and 3c. Direct glucosylation of vitamin D, ( 3 0 and vitamin D, (5a) with 2 gave the derivatives 3g and 5b, respectively. With 25-hydroxycholecalciferol ( = calcidiol; 6 a) as substrate, besides the 3-(glucoside) 6b small amounts of the C(25)-analog 6 c were formed. The reaction of la,25-dihydroxycholecalciferol ( = calcitriol; 6e) with 2 furnished the 3-and the 1-(glucoside) (6f and 6g, respectively) as the major components and the C(25)-analog 6h in minor quantity. From the acetylated 3-(glucosides) 3 a, 3g, 5 b, 6 b, and 6f, the free glucopyranosides 3b, 3h, 5c, 6d, and 6 4 respectively, were prepared as well as the free glucopyranosyl-glucopyranoside 3d from the acetylated disaccharide 3c.

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