Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-11-10
1994-11-01
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549 13, 549 28, 549417, 549419, 549420, 549423, 549424, 514460, C07D30920, A61K 3135
Patent
active
053608178
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new class of chemical compounds and to their use in medicine. In particular the invention concerns new 4-substituted-2-deoxy 2,3-didehydro derivatives of .alpha.-D-neuraminic acid, methods for their preparation, pharmaceutical formulations thereof and their use as antiviral agents.
Enzymes with the ability to cleave N-acetyl neuraminic acid (NANA), also known as sialic acid, from other sugars are present in many microorganisms. These include bacteria such as Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, and Arthrobacter sialophilus, and viruses such as influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus. Most of these viruses are of the orthomyxovirus or paramyxovirus groups, and carry a neuraminidase activity on the surface of the virus particles.
Many of the neuraminidase-possessing organisms are major pathogens of man and/or animals, and some, such as influenza virus, Newcastle disease virus, and fowl plague virus, cause diseases of enormous economic importance.
It has long been thought that inhibitors of neuraminidase activity might: prevent infection by neuraminidase-bearing viruses. Most of the known neuraminidase inhibitors are analogues of neuraminic acid, such as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and its derivatives. See, e.g., Meindl et al., Virology 1974 58 457-63. The most active of these is 2-deoxy-2,3-dehydro-N-trifluoroacetyl-neuraminic acid (FANA), which inhibits multi-cycle replication of influenza and parainfluenza viruses in vitro. See Palese et al., virology 1974 59 490-498.
A number of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid derivatives are known in the art. See for example P. Meindl et al., Virology, 58, 457-463 (1974); P. Meindl and H. Tuppy, Mh. Chem, 100 (4), 1295-1306 (1969); M. Flashner et al., Carbohydrate Research, 103, 281-285 (1982); E. Zbiral et al., Liebigs Ann Chem, 159-165 (1989); T. Ogawa and Y. Ito, Tetrahedron Letters, 28 (49), 6221-6224 (1987); T. Goto et al., Tetrahedron letters, 27 (43), 5229-5232 (1986); H. Ogura et al., Chem. Pharm. Bull, 36 (12), 4807-4813 (1988); German Offenlegungschrift P 1439249. Many of these compounds are active in vitro against neuraminidase from V. cholerae or Newcastle disease virus as well as that from influenza virus. Neuraminidase in at least some strains of influenza or parainfluenza viruses has also been reported to be inhibited in vitro by 3-aza-2,3,4-trideoxy-4-oxo-D-arabinoctonic acid .delta.-lactone and O-.alpha.-N-acetyl-D-neuraminosyl)2.fwdarw.3)-2-acetamido-2-deoxy-D-glucos e. See Zakstel'skaya et al., Vop. Virol. 1972 17 223-28.
Neuraminidase from Arthrobacter sialophilus is inhibited in vitro by the glycals 2,3-dehydro-4-epi-N-acetylneuraminic acid, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid and 5-acetamido-2,6-anhydro-2,3,5-trideoxy-D-manno-non-2-en-4-ulosonate, and by their methyl esters. See Kumar et al., Carbohydrate Res. 1981 94 123-130; Carbohydrate Res. 1982 103 281-285. The thio analogues 2-.alpha.-azido-6-thio-neuraminic acid and 2-deoxy-2,3-didehydro-6-thioneuraminic acid, Mack & Brossmer, Tetrahedron Letters 1987 28 191-194, and the fluorinated analogue N-acetyl-2,3-difluoro-.alpha.-D-neuraminic acid, Nakajima et al., Agric. Biol. Chem. 1988 52 1209-1215, were reported to inhibit neuraminidase, although the type of neuraminidase was not identified. Schmid et al., Tetrahedron Letters 1958 29 3643-3646, described the synthesis of 2-deoxy-N-acetyl-.alpha.-D-neuraminic acid, but did not report its activity or otherwise against neuraminidase.
None of the known inhibitors of neuraminidase activity in vitro has been shown to possess antiviral activity in vivo, and indeed some, such as FANA, have specifically been shown to be inactive in vivo. Thus the conventional wisdom has accordingly considered that compounds exhibiting in vitro inhibition of viral neuraminidase would not effect an in vivo blockade of virus infection.
Meindl and Tuppy, Hoppe-Seyler's Z. Physiol Chem. 1969 350 1088, d
REFERENCES:
Baumberger et al.--Helvetica Chimica Acta, 1988, 71 pp. 429-445.
Czollner et al.--Helvetica Chimica Acta, 1990, 73 pp. 1338-1357.
Flashner et al.; Arch. Biochem. Biophys., 221(1), 1983, pp. 188-196.
Mack et al., "Synthesis Of 6-Thiosialic Acids And 6-Thio-N-Acetyl-D-Neuraminic Acid", Tet. Lett., vol. 28, No. 2, 1987, pp. 191-194.
Nakamura et al., "Studies On Sialic Acids, XV. Synthesis of .alpha.- and .beta.-.alpha.-Glycosides of 3-Deoxy-D-glycero-D-galacto-2-nonulopyranosonic", Chem. Pharm. Bull. 36(12) 4807-4813 (1988).
Schreiner et al., "Synthesis Of Some 2,3-didehydro-2-deoxysialic Acids Structurally Varied At C-4 And Their Behaviour Towards Sialidase From Vibrio Cholerae", Liebigs Annalen Der Chemie, No. 2, Feb. 1991, pp. 129-134.
Danylec Basil
Jin Betty
Phan Tho V.
von Izstein Laurence M.
Wu Wen-Yang
Biota Scientific Management Pty Ltd
Hydorn Michael B.
Richter Johann
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