Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-12
1999-11-23
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514460, 549420, 549424, A61K 3135, C07D31500
Patent
active
059901560
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 derivatives of DANA active both in vitro and in vivo against viral neuraminidase and useful in the treatment of influenza. Further DANA derivatives are disclosed in EP 0539204, WO 95/18800 and WO 95/20583. None of these publications discloses compounds having a carboxamide group at the 6 position of the dihydropyran ring.
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) ##STR2## wherein
R.sup.1 represents OR.sup.5, SR.sup.5, NR.sup.5 R.sup.6, N(OR.sup.5)R.sup.6 or N(NR.sup.5 R.sup.6)R.sup.6 ;
X represents OH, N.sub.3, NR.sup.3 R.sup.4 or NR.sup.4 CO.sub.2 R.sup.15 ;
Y represents H or NHR.sup.2 ;
R.sup.2 represents a group SO.sub.2 R.sup.7 or COR.sup.7 ;
R.sup.3 represents H, C.sub.1-6 alkyl or C(.dbd.NR.sup.8)NR.sup.9 R.sup.10 ;
R.sup.4 represents H or C.sub.1-6 alkyl;
R.sup.5 represents H, C.sub.1-20 alkyl, C.sub.3-8 cycloalkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, CHR.sup.11 COR.sup.12 or C.sub.1-20 alkyl substituted by one or more groups selected from NR.sup.13 R.sup.14, NR.sup.13 COR.sup.14, CO.sub.2 R.sup.13, OR.sup.13, C.sub.3-8 cycloalkyl and optionally substituted aryl;
Each R.sup.6 independently represents H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-20 alkynyl, aryl, or C.sub.1-4 alkyl substituted by one or more groups selected from NR.sup.13 R.sup.14, COR.sup.13, C.sub.3-8 cycloalkyl, CN, N.sub.3, OR.sup.13 and optionally substituted aryl;
or R.sup.5 and R.sup.6 together form a C.sub.2-6 hydrocarbon chain which may optionally contain a group NR.sup.13 which chain is optionally substituted by 1, 2, 3, or 4 groups selected from oxo and C.sub.1-6 alkyl groups which groups may optionally be substituted by hydroxy or optionally substituted aryl;
R.sup.7 represents C.sub.1-6 alkyl optionally substituted by one or more halogen atoms, C.sub.3-8 cycloalkyl or optionally substituted aryl;
R.sup.8, R.sup.9 and R.sup.10 each independently represent H, C.sub.1-6 alkyl, amino, hydroxy, cyano or nitro;
R.sup.11 represents the side chain of a D- or L-amino acid;
R.sup.12 represents NR.sup.13 R.sup.14, OR.sup.13 or R.sup.13 ;
each R.sup.13 and each R.sup.14 independently represents H, C.sub.1-6 alkyl or optionally substituted arylC.sub.1-4 alkyl;
R.sup.15 represents C.sub.1-6 alkyl;
Preferably R.sup.1 represents NR.sup.5 R.sup.6 or N(OR.sup.5)R.sup.6, more preferably NR.sup.5 R.sup.6.
Suitably R.sup.5 is selected from substituted or unsubstituted C.sub.1-10 alkyl, C.sub.2-6 alkenyl or C.sub.3-8 cycloalkyl and R.sup.6 is substituted or unsubstituted C.sub.1-6 alkyl, H or
REFERENCES:
Sollis, et al., "Novel Inhibitors of Influenza Sialidase Related to GG167 Synthesis of 4-Amino abd Guanidino-4H Pyran-2-Carboxylic Acid-6-Propylamides; Selective Inhibitors of Influenza A Virus Sialidase", Bioorganic & Medicinal Chemistry Letters, pp. 8-11.
Cherry Peter
Howes Peter
Smith Paul
Sollis Stephen
Biota Scientific Management Pty Ltd.
Owens Amelia
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