Studies on the synthesis of condensed pyridazine derivatives. IV. Synthesis and anxiolytic activity of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-ones and related compound.

A series of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)- ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo. Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39--42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5,6-dihydro- (37) and 2-(4'-chlorophenyl)-5,6-dihydro-10-fluoro-(1)benzothiepino[5,4-c]+ ++pyridazin- 3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of gamma-aminobutyric acid-induced chloride current (Icl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.     

5-Fluorouracil derivatives. XX. Synthesis and antitumor activity of 5'-O-unsaturated acyl-5-fluorouridines

Various kinds of 5'-O-unsaturated acyl 5-fluorouridines were synthesized to obtain 5-fluorouridine derivatives with low toxicity and high antitumor activity. Antitumor activity of the compounds against L-1210 leukemia in mice was examined, and the 5'-O-4-pentenoyl derivative showed the highest antitumor activity.     

Organic phosphorus compounds. IV. Asymmetric 4-(benzothiazol-2-yl)benzylphosphonates as potent calcium antagonistic vasodilators

Various asymmetric or cyclic ester derivatives of the phosphonic acid moiety in the calcium antagonist fostedil (KB-944) were synthesized. The coronary vasodilator activity of these compounds was assessed by Langendorff's method. Among them, the ethyl isopropyl ester 12 showed the most potent activity, which was comparable to that of fostedil.     

A study of embolizing materials for chemo-embolization therapy of hepatocellular carcinoma: embolic effect of cisplatin albumin microspheres using chitin and chitosan in dogs, and changes of cisplatin content in blood and tissue.

Hepatic artery of dogs was embolized with cisplatin (CDDP) albumin microspheres containing chitin and chitosan to investigate the in vivo CDDP release kinetics from CDDP albumin microspheres, the CDDP cumulative characteristics in the liver, and the influence of microsphere administration on hepatic tissue. Results showed that changes in blood CDDP content were dependent on CDDP albumin microsphere type and that release kinetics were better sustained when chitin was added to the microspheres or when the microspheres were treated with chitosan. In particular, the administration of CDDP in the chitin-containing CDDP chitosan albumin microspheres showed a blood CDDP content of approximately 0.26 micrograms Pt/ml 14 d after administration. The administration of chitin-containing or chitosan treated CDDP microspheres showed a CDDP content in the hepatic tissue of 0.14 to 0.23 micrograms Pt/g 28 d after administration. They also showed better control of CDDP release than those without chitin or chitosan treatment. No CDDP influence on hepatic tissue was observed. We conclude that, even in vivo, chitin and chitosan are effective embolic materials.     

Antiviral agents of plant origin. III. Scopadulin, a novel tetracyclic diterpene from Scoparia dulcis L

The structure and stereochemistry of scopadulin, a novel aphidicolane-type diterpene isolated from Scoparia dulcis L. have been established from spectral data and single-crystal X-ray analysis of its acetone solvate.     

Electrical conducting and magnetic properties of (ethylenedithiotetrathiafulvalenothioquinone-1,3-diselenolemethide)2.FeBr4 (GaBr4) crystals with two different interlayer arrangements of donor molecules

Two donor molecules newly synthesized, dimethylthio- and ethylenedithio-tetrathiafulvalenothioquinone-1,3-diselenolemethides (1 and 2), were used to prepare their charge-transfer (CT) salts with a magnetic FeBr(4)(-) counteranion. For 1, a low electrical conducting 1:1 salt (1.FeBr(4)) was obtained, in which molecules of 1 are tightly dimerized in a one-dimensional (1D) stacking column. On the other hand, 2 gave a 2:1 salt (2(2).FeBr(4)) as two different kinds of plate crystals (I and II). Both I and II possess similar stacking structures of molecules of 2 in each 1D column with a half-cut pipelike structure along the c axis. However, for I, the stacking columns are aligned in the same direction along the a and b axes, while for II they are in the same direction along the a axis, but in the reverse direction along the b axis, resulting in the difference in the relative arrangement of molecules of 2 and FeBr(4)(-) ions between the two crystals. The room-temperature electrical conductivities of the single crystals of I and II were 13.6 and 12.7 S cm(-)(1), respectively. The electrical conducting behavior in I was metallic above 170 K but changed to be semiconducting with a very small activation energy of 7.0 meV in the temperature range 4-170 K. In contrast, II showed the semiconducting behavior in the whole temperature range 77-285 K. The corresponding nonmagnetic GaBr(4)(-) salts with almost the same crystal structure as I and II showed definitively different electrical conducting properties in the metal to semiconductor transition temperature in I as well as in the magnitude of activation energy in the semiconducting region of I and II. The interaction between the d spins of FeBr(4)(-) ions was weak and antiferromagnetic in both I and II, but the magnitude of the spin interaction was unexpectedly larger compared with that in the FeBr(4)(-) salt of the corresponding sulfur derivative of 2 with closer contact between the neighboring FeBr(4)(-) ions. These electrical conducting and magnetic results suggest a significant interaction between the conducting pi electrons and the d spins of FeBr(4)(-) ions located near the columns or layers.