Treatment of the required hydroxyl derivatives of cis‐3‐aminocyclopentanemethanol with 3‐ethoxyacryloyl isocyanate gave N‐(3‐ethoxyacryloyl)‐N′‐[hydroxy‐ or dihydroxy(hydroxy‐methyl)cyclopentyl]ureas. Cyclization of the ureas in dilute sulfuric acid afforded high yields of the carbocyclic analogs of uridine, 2′‐deoxyuridine, and 3′‐deoxyuridine. The uridine and 3′‐deoxyuridine analogs were also obtained in good yields by cyclizing the ureas in concentrated aqueous ammonia. None of the three analogs showed activity in tests versus KB cells in culture or L1210 leukemia in vivo.
(+/-)-(1 alpha, 2 beta, 4 alpha)-4-[(2,5-Diamino-6-chloro-4-pyrimidinyl) amino]-2-hydroxycyclopentanemethanol (9) was synthesized by beginning with 2-amino-4,6-dichloropyrimidine and (+/-)-1 alpha, 2 beta, 4 alpha)-4-amino-2-hydroxycyclopentanemethanol, preparing the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine, and reducing the azo derivative. The carbocyclic analogue of 2-amino-6-chloropurine 2'-deoxyribofuranoside (10) was prepared from 9 and triethyl orthoformate, and the analogous 8-azapurine (11) was obtained by diazotizing 9. From 10 or 11, the carbocyclic analogues of 2'-deoxyguanosine, 2'-deoxythioguanosine, 2,6-diaminopurine 2'-deoxyribofuranoside, 2'-deoxy-8-azaguanosine, and 2,6-diamino-8-azapurine 2'-deoxyribofuranoside were prepared. All of these 2'-deoxyribofuranoside analogues were active against herpes simplex virus (types 1 and 2) replicating in cells in culture; some demonstrated potent activity.
Carbocyclic analogues of 3'-deoxyuridines, 3'-deoxyuridines, and uridines with substituents at position 5 of the uracil moiety were prepared by direct halogenation (5-bromo and 5-iodo groups) and by displacement of the 5-bromo group by amino and substituted-amino groups. The analogue of 5-(hydroxymethyl)uridine was prepared via reaction of the isopropylidene derivative of the uridine analogue with paraformaldehyde. The carbocyclic analogues of thymidine and of 5-bromo-, 5-iodo-, and 5-(methylamino)-2'-deoxyuridine were highly active in vitro against herpes simplex virus, types 1 and 2. The corresponding analogues of 5-substituted 3'-deoxyuridines and of 5-substituted uridines were not active in this assay.
The carbocyclic analogs of thymidine (IXf), 1‐β‐ribofuranosylthymine (IXg), and 1‐β‐3′‐deoxyribofuranosyl‐thymine (IXe) were synthesized by incorporating modifications into the Shaw method of synthesizing 2,4‐(1H,3H)pyrimidinediones via acryloylureas. Simpler analogs of thymine nucleosides were also prepared by this method. The carbocyclic analog of thymidine displayed modest activity against Leukemia L1210 in vivo. It differs from a compound prepared previously by a Prins reaction.
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