Synthesis of benzonorbornadienes: regioselective benzyne formation.

This report details the synthesis of several benzonorbornadienes by Diels--Alder cycloaddition of cyclopentadiene derivatives with substituted benzyne intermediates, which were generated by low-temperature metal--halogen exchange of halobenzenes. General conditions were developed, allowing synthesis of most benzonorbornadienes described herein at the multigram scale with isolated yields approaching 90% in some cases. Cycloaddition of the benzyne produced by substitution of a chlorodifluorobenzene for a bromodifluorobenzene in the metal--halogen exchange reaction unexpectedly gave a different benzonorbornadiene. The benzyne, which resulted by a deprotonation pathway rather than by metal-halogen exchange, formed in a highly regioselective elimination step.

Synthesis and physicochemical properties of thiadiazolo[3,2-a]pyrimidinesulfonamides and thiadiazolo[3,2-a]triazinesulfonamides as candidates for topically effective carbonic anhydrase inhibitors.

A series of bicyclic 1,3,4-thiadiazolo[3,2-a]pyrimidine- and 1,3,4-thiadiazolo[3,2-a]triazine-7-sulfonamides were synthesized from 5-amino-1,3,4-thiadiazole-2-sulfonamide and evaluated for topical efficacy as ocular hypotensive agents. The compounds were tested for the physicochemical properties of sulfonamide pKa, free acid water solubility, CHCl3/buffer partition, and transcorneal penetration (kin), as well as for activity against carbonic anhydrase (I50). A number of these compounds exhibited lower sulfonamide pKa and higher water solubility than those of acetazolamide (1) and methazolamide (2), and one, 12, brought about a small reduction in IOP in the normal rabbit eye.

Ocular pharmacology of methazolamide analogs: distribution in the eye and effects on pressure after topical application.

The authors studied the relation between physicochemical properties and lowering of intraocular pressure (IOP) after topical application to rabbit in a series of 5-acylimino- and related imino-substituted analogs of methazolamide (Compound 4). All had Ki vs. carbonic anhydrase C of about 10(-8) M. The parent, methazolamide (5-acetyl) does not lower IOP, in contrast to the 5-CF3 acetyl compound (Compound 28). The 5-propionyl compound (6) unexpectedly was 3 times more water soluble than methazolamide and had 10 times greater CHCl3-buffer partition. The in vivo transcorneal permeability constant was 6 times greater than methazolamide. One hour after 1 drop of a 2% suspension of Compound 6, anterior aqueous concentration (in micromolar) was 69 (for methazolamide, 8), posterior aqueous was 19 and ciliary process was 17. IOP dropped 2.2 mm Hg and returned to normal in 4 hr. Other compounds in the series showed varying degrees of activity, ranging from Compound 28, which elicited an IOP fall of 3.5 mm Hg, to Compound 7, (n-pentyryl), for which the fall was 1.3 mm Hg. Also studied are substitutions for CH3 on the ring N at position 4. There are multiple criteria for in vivo activity; a major factor is the balance between water and lipid solubility. The methazolamide analogs are compared with benzothiazole-2-sulfonamides, another class under investigation as topical carbonic anhydrase inhibitors designed to treat glaucoma.