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In an attempt to improve the effectiveness and duration of the action of diltiazem (1), a 1,5-benzothiazepine calcium channel blocker, its derivatives (2) with halogen substituents on the fused benzene ring were synthesized. These compounds were evaluated for their effects on vertebral and coronary blood flows and antihypertensive activity. The structure-activity relationships are discussed. The 8-chloro derivative ((+)-2b), the most potent compound in this series, was selected for clinical evaluation as a cerebral vasodilating and antihypertensive agent.

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parallels very well with the lipophilic character of the four analgeticis. Of special interest is the good agreement of the slopes of eq 9 and 11. This reflects a close parallelism between log (CbrainlCplasma) and log ( C l v e n t r l Ci,.) . This is additional support for the earlier findings that log ( C l r e n t r / C i v ) is a measure of the different capability of the analgetics to penetrate the blood-brain barrier.

Sequential permeability and chemical osmosis experiments on Wakkanai mudstones were performed to explore the relationships between the semipermeability of clayey rocks and the hydraulic and diffusion parameters as well as the pore structure characteristics. The wide ranges in osmotic efficiency (0.0004-0.046) and intrinsic permeability (8.92 × 10 À20 to 1.24 × 10 À17 m 2 ) reflect the variation in the pore size distributions of the Wakkanai mudstones. A regression analysis between osmotic efficiency and permeability shows that the osmotic efficiency is proportional to the inverse of permeability, suggesting that the permeability is indeed indicative of the degree of semipermeability. Osmotic efficiency was determined invariant with the effective diffusion coefficient for the Wakkanai mudstones (3.59-8.36 × 10 À11 m 2 /s) due to their small osmotic efficiencies (≤0.046). The wide variation in osmotic efficiencies and pore structure characteristics of Wakkanai mudstones indicates that the nanoscale pores enable semipermeability in Wakkanai mudstones. However, the pressure evolution caused by chemical osmosis is limited by the connected wide pores that are the main conduits for water, thus dissipating the osmotic pressure buildup induced by the semipermeability of nanoscale pores.