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 2 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.
Eberle
M K
MK
Sandoz Ltd., Basel, Switzerland.
Hiestand
P
P
Jutzi-Eme
A M
AM
Nuninger
F
F
Zihlmann
H R
HR
D000478:Alkylation; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D003524:Cyclosporins / Q000138:chemical synthesis* / Q000494:pharmacology*; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
D003524:Cyclosporins; D004987:Ethers; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C094120:cyclosporin, serine(8)-