Kondensation der Phosphoniumsalze (II) ‐ zugänglich aus den Aldehyden (I) ‐ mit den Formylestern (IV) bzw. (V) gibt die Retinoesäure‐Analogen (III) bzw. (VI); neben (VIc) entsteht auch das cis‐Isomere (nach 24 h Bestrahlung des Isomerengemisches in CH2Cl2 stellt sich ein 1:1‐trans/ cis‐Gleichgewicht ein).

The Metabolism of the Retinoid Ro 10‐9359. Isolation and Identification of the Major Metabolites in Human Plasma, Urine and Feces Synthesis of Three Urinary Metabolites After oral administration of therapeutic doses of the 3H‐labelled aromatic retinoic acid analog (retinoid) Ro 10‐9359 (ethyl all‐trans‐9‐(4‐methoxy‐2,3,6‐trimethyl‐phenyl)‐3,7‐dimethyl‐2,4,6,8‐nonatetraenoate) to humans 75 and 15% of the 3H‐dose were excreted within the first five days in the feces and the urine, respectively. Using chromatographic procedures including high pressure liquid chromatography 18 metabolites could be isolated from human urine. Their structures were elucidated by mass spectrometry and FT–1H‐NMR. spectroscopy. In these urinary metabolites the tetraene side chain of the parent compound Ro 10‐9359 is shortened. The radioactivity of the identified urinary metabolites accounted for about 11% of the dose. Three urinary metabolites were synthesized. The main part of the radioactivity excreted within the first five days in the feces consisted of unchanged drug (60% of the dose). A smaller (amount 15% of the dose) could not be identified. The unchanged drug and a major metabolite, the corresponding acid, were found in human plasma. In an experiment with bile‐duct cannulated rats the radioactively labelled retinoid Ro 10‐9359 was injected intravenously. About 70% of the 3H‐dose was excreted in the bile, within the first 48 hours. The whole radioactivity of the rat bile consisted of polar metabolites. No unchanged drug could be found. After enzymatic hydrolysis of the bile conjugates three metabolites were isolated. The main metabolite (49% of the i.v. dose) was a conjugate of the corresponding acid of the parent drug, already found as free compound in human plasma. The other bile metabolites (9 and 7% of the i.v. dose) had an intact side chain, too. An enterohepatic recycling of the bile metabolites was observed in the rat.

SummaryThermally induced ring formation of 2 and of its 1-alkenyl silyl ether derivative leads selectively to new bicyclic derivatives. The new retinoid 8 was synthesized and found to have potent biological activity.Ausgehend von Vitamin-A-saure (1 ; Retinsaure) ist in praparativ einfacher Weise der all-trans-9-(2-Acetyl-S, 5-dimethyl-I -cyclopentenyl)-3, 7-dimethyl-2,4,6,8-nonatetruensaure-uthylester (2) zuganglich [ 11. Dieser weist eine gegenuber der Retinsaure vergleichbare therapeutische Antipapillom-Wirkung in der Maus auf [2] und bot sich daher als Ausgangsmaterial fur weitere strukturelle Variationen an, in der Absicht, biologisch wirksame Retinoide aufzufinden.

No abstract

Aus Retinsäure ist nach einer Literaturmethode der Ester (I) zugänglich, der thermisch zu den Bicyclen (II) und (III) sowie zum Tetracyclus (IV) als Hauptprodukt cyclisiert.