J . Med. Chem. 1992,35,1799-1806

4f,13079851-5;4g, 139896-76-7;4h,132004-34-3;4i,139896-77-8; 4j,139896789;4k,132004-30-9;41,139896-79-0;4m,132004-354; 4n,132004-36-5;40,132004-32-1;4p,132004-33-2; 4q,139896-80-3; 4r,139896-81-4;4s, 139896-82-5;4t,139896-83-6;4u,139896-84-7; 7b, 130798-57-1; 7d, 130798-582;7f, 130829-27-5;7g,139896-86-9; 7m, 13!%96-87-0,7n,139896-881;7r,13989689-2;7~,139896-9@5; 8,101861-63-6;10,67976-94-7;11, 15733-83-2; 12,139896-91-6;

1799

13,139896-92-7;14,139896-93-8; 16b,5399582-7;178,91348-45-7; 17b, 137836-40-9;15, 139896-85-8;188, 137836-30-7;18b, 137836-28-3;198,137836-31-8;19b,137836-29-4; 20,1477-50-5; 21, 123158-59-8;m-chloroaniline, 108-42-9; 4,6-dichloroaniline, 626-43-7; 3-nitroaniline, 99-09-2; 2-carboxymethoxy-4-hydroxyquinoline, 5965-59-3;methyl acrylate, 96-33-3;ethyl 2mercaptoacetate, 623-51-8.

Synthesis and Antiviral Activity of l-Cyclobutyl-5-(2-bromovinyl)uracil Nucleoside Analogues and Related Compounds William A. Slusarchyk,* Gregory S. Bisacchi, A. Kirk Field, Deborah R. Hockstein, Glenn A. Jacobs, Bridget McGeever-Rubin, Joseph A. Tino, A. V. Tuomari, Gregory A. Yamanaka, Marian G. Young, and Robert Zahler Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000. Received June 24, 1991

A series of racemic (la(E),2~,3a)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-(2-halovinyl)uracils was synthesized and evaluated in cell culture. The bromovinyl, iodovinyl, and chlorovinyl analogues, 13, 15,and 16,respectively, are all potent inhibitors of varicella zoster virus 0 , but are leas inhibitory to the replication of human cytomegalovirus (HCMV) and herpes simplex viruses 1 and 2 (HSV-1, HSV-2).The excellent anti-VZV activities of 13,15,and 16 coupled with their virtual inability to inhibit WI-38cell growth indicate high in vitro therapeutic indices. VZV thymidine kinase readily converts these compounds to their respective monophosphates but not to their corresponding diphosphates. Compound 138,the (1'R) enantiomer of the bromovinyl analogue 13,was also synthesized, and ita potency is comparable to that of the racemate. A lower homologue 14, (la(E),2fi,3a)-l-[2-hydroxy-3-(hydroxymethyl)cyclobutyl]-5-(2-bromovinyl)uracil,waa found to be inactive against VZV, HCMV, HSV-1,and HSV-2.

Introduction We recently reported the synthesis and antiherpes activity of the 9-guanyl and 9-adenyl cyclobutyl nucleoside analogues 1-8 (ChartI).I The racemates 1 and 2, and the corresponding lower homologue racemates 3 and 4, are all potent inhibitors of a broad spectrum of herpesviruses, including herpes simplex virus 1and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), and human cytomegalovirus (1) (a) Slusarchyk, W. A.; Young, M. G.; Bisacchi, G. S.; Hockstein, D. R.; M e r , R. Synthesis of SQ-33,054,a Novel Cyclobutane Nucleoside With Potent Antiviral Activity. Tetrahedron Lett. 1989,30,6453-6456.(b) Slusarchyk, W. A.; Bisacchi, G. S.; Hockstein, D. R.; Young, M. G.; Field, A. K.; McGeever-Rubm,B.; Tuomari, A. V.; M e r , R. SQ-33,OU A Potent Member of a New Class of Nucleoside-AnalogAntivirals. 29th Znterscience Conference on Antimicrobial Agents and Chemotherapy, Houston, TX, 1989;Abstract 1330. (c) Field, A. K.; Tuomari, A. V.; McGeever-Rubin, B.; Terry, B. J.; Mazina, K. E.; Haffey, M. L.; Hagen, M. E.; Clark, J. M.; Braitman, A.; Slusarchyk, W. A.; Young, M. G.; Zahler, R. (i)-(la,2~,3a)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(*)-BHCG or SQ330541: a Potent and Selective Inhibitor of Herpesviruses. Antiviral Res. 1990,13,41-52.(d) Jacobs, G. A.; Tino, J. A.; Zahler, R. Synthesis of SQ-32,829,A New Nucleoside Antiviral Agent. Tetrahedron Lett. 1989, 30, 6955-6958. (e) Jacobs, G. A.; Slusarchyk, W. A.; Spergel, S. H.; Tino, J. A.; Field, A. K.; Tuomari, A. V.; Zahler, R. In Vitro Activity of SQ-32,829,a New Nucleoside-Analog Antiviral Agent. 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston, TX, 1989;Abstract 1328. (0 m e r , R.; Jacobs, G. A. Purinyl and Pyrimidmyl Cyclobutanes and Their Use As Antiviral Agents. U.S. Patent 4,918,075, 1990. (g) Bisacchi, G. S.; Braitman, A.; Cianci, C. W.; Clark, J. M.; Field, A. K.; Hagen, M. E.; Hockstein, D. R.; Malley, M. R.; Mitt, T.; Slusarchyk, W. A.; Sundeen, J. E.; Terry, B. H.; Tuomari, A. V.; Weaver, E. R.; Young, M. G.; Zahler, R. Synthesis and Antiviral Activity of Enantiomeric Forms of Cyclobutyl Nucleoside Analogues. J. Med. Chem. 1991, 34,

1415-1421.

Chart I

Hal+

HO A

1 2 5 6

B= B= B= B=

HO

9-guanyl (racemate) 9-adenyl (racemate) 9-guanyl (homochiral) 9-adenyl (homochiral)

3 B = 9-guanyl (racemate) 4 B = 9-adenyl (racemate)

OH

?-

H O Y " ' l S R

7 B = 9-guanyl (homochiral) 8 B = 9-adenyl (homochiral)

9 B = 9-guanyl, R = H 10 B = 9-guanyl, R = CHzOH

? 9-guanyl = c.NN