Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-06
1999-09-07
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514460, 548239, 549424, 549425, A61K 3135, C07D41302
Patent
active
059488166
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to N-acetylneuraminic acid derivatives whose hydroxyl group at 7-position is replaced by fluorine, synthetic intermediates thereof and use application thereof. The derivatives are useful as a sialidase inhibitor, an antiviral agent, an immunomodulating agent, an antitumor agent and like drugs.
BACKGROUND ART
Sialic acid (1) ##STR2## exists at a terminal of glycoproteins and glycolipids, and is involved in physiological activities of glycoproteins and glycolipids. Sialic acid derivatives are actively synthesized so as to clarify functions of sialic acid at a molecular level.
In particular, research and development of sialidase inhibitors are actively conducted as an agent for prophylaxis and therapy of influenza virus. Consequently, as effective sialidase inhibitor in vitro and in vivo, 4-amino- and 4-guanidino-2-deoxy-2,3-didehydrosialic acids (2 and 3) ##STR3## are reported (M. von Itzstein et al.: Nature, 363, 418-423 (1993); M. von Itzstein et al.: Carbohydrate Research, 259, 301-305 (1994); JP-A-5-507068). It is said that no drug-resistant virus will appear at first with respect to the derivatives. However, development of highly active compounds without cross-resistance is desired, since it is well predictable that drug-resistant viruses will appear clinically.
In addition, 7-fluoro-2,7-dideoxy-2,3-didehydrosialic acid is reported (international publication WO95/32955). However, sialidase inhibiting activities thereof are not disclosed.
7-fluorosialic acid derivatives of said compound whose hydroxyl group at 4 position is substituted has not been synthesized and will be useful as a drug, since the substitution is thought to affect physiological activities thereof.
Objects of the invention relate to 4-substituted-2,7-dideoxy-7-fluoro-2,3-didehydro-sialic acids which are expected as drugs such as an antiviral agent, an immunomodulating agent and an antitumor agent, synthetic intermediates thereof and use application thereof.
DISCLOSURE OF THE INVENTION
As a result of research to synthesize sialic acid analogs which are chemically modified at side chain by fluorine, the present inventors succeeded synthesis of said analogs. Thus, the present invention has been accomplished.
The present invention relates to a compound represented by formula (I) ##STR4## wherein
A is O, CH.sub.2 or S.
R.sup.1 represents a lower alkoxy carbonyl group, COOH, PO(OH).sub.2, SO.sub.3 H or a tetrazole group.
R.sup.2 represents a hydrogen atom, OR.sup.6, F, Cl, Br, CN, NHR.sup.6 or SR.sup.6 (wherein R.sup.6 represents a hydrogen atom, an optionally substituted C.sub.1 -C.sub.6 lower alkyl group, a C.sub.1 -C.sub.4 lower acyl group or an optionally substituted aryl group.
One of R.sup.3 and R.sup.3' represents a hydrogen atom, and the other represents a hydrogen atom, a nitrile group, an optionally substituted amino group, an azido group, a lower alkylthio group, an amidino group, a formamidino(--N.dbd.CHNH.sub.2) group, a cyanoamidino group or a guanidino group.
R.sup.4 represents NHR.sup.6, N.dbd.CHR.sup.6 (wherein R is as defined above.).
R.sup.5 represents CH.sub.2 CH.sub.2 XR.sup.6 or CH(XR.sup.6)CH.sub.2 XR.sup.6 (wherein X represents an oxygen atom, a sulfur atom, a NH group, R.sup.6 is as defined above.). and salts thereof.
The invention preferably relates to a compound of formula (II) ##STR5## wherein R.sup.3 and R.sup.3' are as defined above and salts thereof.
The invention more preferably relates to a compound represented by formula (III) ##STR6## wherein
R.sup.3a represents a hydrogen atom, a nitrile group, an optionally substituted amino group, an azido group, a lower alkylthio group or a guanidino group.
R.sup.4a is NHCOR.sup.7 (wherein R.sup.7 represents a hydrogen atom, an optionally substituted C.sub.1 -C.sub.6 alkyl group or an optionally substituted aryl group,
The invention, more preferably, relates to 2,3-didehydrosialic acid derivatives represented by chemical formula (IV) and (V) ##STR7## wherein Ac represents an acetyl group.
The invention further relates
REFERENCES:
patent: 5627290 (1997-05-01), Iida et al.
Daikin Industries Ltd.
Owens Amelia
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