PREPARATION AND IN-VITRO ACTIVITIES OF ETHERS OF [D-SERINE](8)-CYCLOSPORIN

Reactions of the [D-serine](8)-cyclosporin (2) with a series of alkylating agents under phase transfer conditions gave the alkylated products 3-6. Alkylations of with hindered esters of bromoacetate gave the crystalline esters 7 and 8. Hydrolysis under basic conditions gave the acid 10. Reduction of ester 8 led to a novel cyclosporin 11, This was transformed in two additional steps to 15. In a similar two-step sequence 17 was prepared from 15. From 2 and methyl 2-(bromomethyl)acrylate product 20 was obtained. Alkylation of 2 with 49 followed by deprotection yielded 24. The linear isomer 27 was prepared. The 3-hydroxypropyl ether 30 was prepared in two steps from 28. The 4-hydroxybutyl ether 31 was accessible from 2 and 1,4-dibromobutane. The hydroxy group of 11 was converted to the tosylate 32. Base treatment of 32 led to the bicyclic [3(R)-morpholinecarboxylic acid](8)-cyclosporin (39). The [2-ethoxy-5-morpholinecarboxylic acid](8)-cyclosporin 40 was prepared via 36. Base treatment of the bromoacetate 37 gave the morpholinone derivative 41. [4(R)-Oxazolidinecarboxylic acid](8)-cyclosporin (42) was obtained from 2 and methylene bromide. From 24 the tosylate 38 was prepared and cyclized to the hexahydrooxazepine derivative 43. [2(R)-Piperidinecarboxylic acid](8)-cyclosporin (49) was prepared from 42 and 2(R)-piperidinecarboxylic acid 45 via 46-48. The bicyclic cyclosporin 39 was found to be-about 3-4 times more active than cyclosporin A in our in vitro tests.