Dihydropyran derivatives as viral neuraminidase inhibitors

Details Dihydropyran derivatives as viral neuraminidase inhibitors Dihydropyran derivatives as viral neuraminidase inhibitors

1998-09-14

1999-07-06

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549424, A61K 3135, C07D31500

Patent

active

059198192

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a new class of chemical compounds and to their use in medicine. In particular the invention concerns novel dihydropyran derivatives, 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, 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 and Newcastle disease 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. International Application Publication No. WO91/16320 describes a number of analogues of DANA active both in vitro and in vivo against viral neuraminidase and useful in the treatment of influenza. A number of substituted guanidino derivatives were described in EP 539204. International Application Publication No: WO95/18800 describes the methanesulphonamide analogue of DANA and the trifluoroacetate analogue of DANA is described in International Application Publication No. WO95/20583.
We have now found a novel class of dihydropyran derivatives which are active against the influenza virus.
The invention therefore provides, in a first aspect, compounds of formula (I) ##STR1## wherein R.sup.1 represents NR.sup.5 R.sup.6, wherein or more of Br, Cl, F, I, CF.sub.3, NR.sup.7 R.sup.8, CO.sub.2 R.sup.9, CONR.sup.7 R.sup.8, COR.sup.9, OR.sup.10 or SR.sup.10, or a heteroaromatic group; and more of Br, Cl, F, I, CF.sub.3, NR.sup.7 R.sup.8, CO.sub.2 R.sup.9, CONR.sup.7 R.sup.8, COR.sup.9, OR.sup.10 or SR.sup.10, or a heteroaromatic group; COR.sup.9 ; halogen atoms; alkyl, amino, hydroxy, cyano or nitro;
In general, it is to be understood that when any variable occurs more than once in formula (I), that variable may be the same on each occasion, or different. In particular, when R.sup.5 and R.sup.6 each represent an optionally substituted hydrocarbon group or a heteroaromatic group they may be the same or different.
As used herein, "hydrocarbon group" includes saturated and unsaturated, straight, branched and cyclic hydrocarbon groups, including aryl groups, and combinations of such groups.
Suitable hydrocarbon groups represented by R.sup.6 and/or R.sup.5 include C.sub.1-20 alkyl, such as propyl, butyl, pentyl, hexyl, heptyl, octanyl, nonyl, decyl, undecyl and dodecyl, C.sub.5-7 cycloalkyl groups, such as cyclohexyl, phenyl and aralkyl groups such as benzyl. Suitable substituents for the hydrocarbon groups represented by R.sup.6 and/or R.sup.5 include Br, Cl, F, I, CF.sub.3, NH.sub.2, substituted amino groups such as NHCO(C.sub.4 H.sub.10), alkoxy groups such as methoxy, and hydroxy.
When R.sup.5 and/or R.sup.6 represents a heteroaromatic group, this will suitably be a pyridyl group optionally substituted by one or more of C.sub.1-6 -alkyl, Br, Cl, F, I and CF.sub.3.
Preferably R5 represents H, C.sub.1-6 -alkyl or benzyl.
Preferably R.sup.6 represents optionally substituted C.sub.1-20 alkyl or benzyl.
More preferably R.sup.5 represents H, C.sub.1-3 alkyl or benzyl and R.sup.6 represents C.sub.1-12 alkyl optionally substituted by an unsubstituted or substituted amine, or benzyl.
Preferably R.sup.2 represents COR.sup.9.
Where R.sup.3 represents C(=NR.sup.11)NR.sup.12 R.sup.13, suitably two of R.sup.11, R.sup.12 an

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