100441

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Synthesis of 5-Thiobredinin

Although pyrazofurin exhibits a high degree of aelectivity in its antiviral effects in vitro, the LD_W dose in mice is about 5 mg/kg per day, and it hae a Iow chemotherapcutic index against MLV and vaccinia yirus.^8,10,11 Like pyra-zofurin, bredinin aiso exhibits broad-spectrum antiviral activity in vitro.⁴ Bredinin i$ a potent imrauno6uppressivc agent⁴ and cytotoxic lo L5178 Y celto.¹²"¹⁶ However. it ahowed little effect on the life prolongation of mice inoc-ulated with lymphatic leukemia L1210.¹⁶ Recently in a separate in vitro and in vivo study it has been found that the aglycon of bredinin, 4'Carbamoyl-5-hydroxyimidazole, is active against 6-mercaptopurine-resistant sublines of P388 and L1210 leukemia.¹⁷¹⁸ It has been suggested that the aglycon is converted to its active nucleotide form by APRTase and this nucleotide further blocks the de novo purine synthesis of GMP by inhibiting IMP de-hydrogenase.¹⁷ Bredinin exhibits beneficial effects on experimental rheumatoid arthritis^19,20 and has been used efficiently in preventing kidney transplant rejection in doga²¹ and in human.²² The synthetic azole nucleoaide ribavirin (l-d-D-ribofuranosyl-l_t2,4-triazole-3'carbox-amide),²³ reported from our laboratories,²⁴ is a structural analogue of both pyrazofurin and bredinin. Ribavirin is a broad-spectrum antiviral agent^23,26 and is currently being investigated in human clinical triato against influenza,^ hepatitis.^{28 29} herpes,³⁰-³¹ Lassa fever,^K and respiratory

(10» Dewamps. J : De Clercq, E. "Current Chemotherapy*; $ieg* enthaler. W., Luthy, R., Eds.; American Society for Micro-biology. Washington, DC, 1978; VoL 2, p 354.

(11)    De Clercą, E.; Torrence, P. F. J. Carboh\dr. Sucleosidts Su-cleotides 1978. 5, 187-224.

(12)    Sakaguchi, K.; Tsujino. M.; Yoshizawa, M.; Mizuno, K.: Hayano, K. Cancer Re*. 1975, 35. 1643-1848.

03) Sakaguchi, K.; Tsujino, M.; Mizuno. K.; Hayar.o, K.; khida, N.

J.    Antibiot. 1973. 28, 798-803

(14)    Sakaguchi, K ; Tsujino. M.: Mizuno. K.; Hayano, K. Jpn. J. Genti. 1976. 51. 61-64.

(15)    Sakaguchi. K.: Tsujino, M.; Hayashi, M.; Kawa:. K.; Mizuno,

K. ; Hayano. K. J. Antibiot. 1976. 29. 1320-1327.

(16( Tsukagoshi. S. Concer Treatmenl Rev. 1980. 7. 215-224

(17)    Fukui. M.; lnaba. M.; Tsukagcahi. S.; Sakurai. Y. Cancer Res. 1982. 42. 1098-1102.

(18)    lnaba. M.: Fukui. M : Yoshida. N.; Tsukagoshi, S.; Sakurai, Y. Cancer Res. 1982. 42. 1103-1106.

(19)    Iwata. H.; Iwaki. H.: Musu kawa, T.; Kasamatau, S.; Okamoto, H. Eipenenlia 1977. 33. 502-503.

(20)    Ilo, H-; Nakamura. T.: Kovama, J. J. Pharmacobio-Dyn. 1979, 2, 157-163.

(21)    Uhida. H.; Yokota. K.; Aktywna, N.; Maiaki, Y.; Aso. K.; Okubo. M : Okudaira, M.. Kato. M.; Kashiwagi, N. Trans-plant. Proc. 1979. 11. 865-870.

(22)    Inou, T.; Kusaba. R ; Takahashi, I.; Sugimoto. H.: Kuzuhara, K.; Yamada. Y.: Yamauchi. J.: Otsubo, 0. Transplant. Proc. 1981. 13, 315-318.

(23)    “Rib«virin: A Broad Spectrum Antiviral Agent”: Smith, R. A., Kirkpatrick, W.. Eds.; Acadernic Press, New York, 1980.

(24)    Witkowski. <1. T.; Robins, R. K.; Sidwcll. R. W.; Simon. L. N.

J.    Sicd.. Chem. 1972, 15. 1150-1154.

(25)    For a review. see: Sidweli, R. W.; Revankar. G. R.; Robins, R.

K.    Pharmacol. Ther., in press.

(26)    Knight. V.; McCIung. H. W.; Wilson. S. Z.; Waler*. B. K.; Quar.es. J. M.; Cameron. R. W.; Greggs, S. E.; Zerw as, J. M.; Couch, R. B. Lancet 1981. 945-949.

(27)    McCIung. H. W.; Knight. V.; Gilbert. B. E.; Wilson, S. Z.; Quarla», J. M.; Divine, G. W. J. Am. Med. Astoc. 1983. 249. 2671-2674.

(28)    Galvao, P. A. A.; Castro. I. O. Ann. S.Y. Acad. Sci. 1977, 284. 278-283.

(29)    Patki. S. A.; Gupta, P. Chemotherapy 1982. 28, 298-303.

(30)    Sung. K. J.: Kim. K. J.; Cinn, Y. W.; kim. W. S.: Kim. H. S.; Lee. Y. S. Korean J. Dermatol. 1980. 18. 573-578.

(31)    Bicrman. S. M.; Kirkpatrick. W’.; Fernandez. H. Chemotherapy 1981, 27. 139-145.

(32)    McCormick. J. B.; Webb, P. A.: Johnson. K. M.. ref 23, p 213.

Journal of Medicinal Chemislry. 1985. Vol. 28, No. 9 1199

Scherae I

S    4a, R*CMj

B.R CKjCMj

syncytial³⁴'³⁴ viruse$.

In addition to bredinin. several 5-substituted imidaz-ole-4-carboxamide ribonucłeosides have aiso shown sig-nificant antivira) activity. Among these derivatives 5-fluoro-1 -d-D-ribofuranosylimidazole-4-carboxamide (Ib)³⁶ had the greatest antiviral acdvity in vitro.^r However, the antiviral potency was somewhat less than that of ribavirin in vitro.^M 5-Chloro (2)^M and 5-cyanomethyl (lc)^39,40 de-rivatives of l*/3-D-ribofuranosylimidazole-4-carboxamide, reported recently from our laboratorie6, also exhibited potent activity against several RN A viruaes in vitro. Each of the above ribonucłeosides contain a carboxamide group in the same relative position on the azole heterocyde. This suggests that ccrtain azole nucieosides containing a car-boxamide group may be of considerable importance in binding certain peptide functionalitiee of specific viral nucleic acid enzymes.⁴¹ As a part of our ongoing synthetic program directed toward the preparation of new azole-carboxamide ribonucleosides, we have now prepared 5-

(33)    Hall. C. B.; McBride. J. T.; Walsh. E. E.; Bell. D. M.; Gala, C L.; Hildrcth. S.; Eyck. L. G. T.; Hall. W J. .V Engl. J Med. 1983. 30S, 1443-1447.

(34)    Hall, C. B.: Walsh. E. E.: Hruska. J. F.: Betts. R. F.: Hall. W. J. J. Am. Med. Assoc. 1983. 249, 2666-2670

(35)    Taber. L. H.; Knight. V.. Gilbert. B. E-; McCIung. H. W._: Wilson, S. Ł; Norton, J. H.; Thurston, J. M.; Gordon, W. H : Atmar. R. L.; Schlaudt. W. R. Pediatrics, in press.

(36)    Reeproeyer. J. C.: Kirk. K. L.; Cohen, L. A- Tetrahedron Lett. 1975. 4107-4110.

(37)    De Clereą. E.; Łuczak, M.; Reepmeyer, J. C.; Kirk. K. L.; Cohen, L. A. Life Sci. 1976, 17, 187-194.

(38)    Srivastava, P. C.: Streeter, D. G.; Matthews. T. R.; Allen, L. B.; Sidweli, R. W.; Robins. R. K. J. Med. Chem. 1976. 19. 1020-1026.

(39)    Cook, P. D.; Rousseau. R. J.: Mian. A. M.; Dea. P.; Meyer. R. B„ Jr.: Robins. R. K. J. Am. Chem. Soc. 1976. 98.1492-1498.

(40)    Cook, P. D.; Allen, L. B.; Streeter. D. G.: Huffman. J. H.; Sidweli. R. W.; Robins, R. K J. Med. Chem. 1978, 21. 1212-1218-

(41)    Simon. L. N.; Sidweli. R. W.. Khare, G. P.; Streeter. D. G.; Miller. J. P.; Witkowski. J. T.; Huffman. J. H.; Robin*. R. K. “Virua Research. 2nd ICN-UCLA Sympotium on Molecul&r Biologł"; Fox, C. F., Robinson, W. S.. EdB.; Academic Press: New York. 1973: p 415.