Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-16
2004-10-05
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S337000, C544S406000, C544S409000, C514S255060
Reexamination Certificate
active
06800629
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel pyrazine derivatives or salts thereof, a pharmaceutical composition containing the same, and production intermediates thereof.
BACKGROUND ART
As the antiviral agents clinically used today, acyclovir and vidarabine for controlling herpesvirus, ganciclovir and foscarnet for controlling cytomegalovirus, and interferon, etc. for controlling hepatitis virus can be referred to. Further, prevention by the use of vaccine is extensively adopted against influenza virus, and low molecular compounds such as amantadine hydrochloride and ribavirin are also used for this purpose. Further, zanamivir is also used lately.
On the other hand, as to the antiviral activity of nucleoside- and nucleotide-analogues having a pyrazine ring as a base, for example, it has hitherto been reported that the compounds of the following general formula:
wherein R
7
represents hydrogen atom, methyl group or C
10
H
21
, have an antiviral activity. However, this type compounds show no “Visna virus activity” [Nucleosides & Nucleotides, Vol. 15, Nos. 11 and 12, Pages 1849-1861 (1996)]. Further, nucleoside- and nucleotide-analogues having a pyrazine ring substituted with a carbamoyl group have not yet been reported so far.
As problems of amantadine, that it is not effective against B type influenza even though it is effective against A type influenza, because of its action mechanism, that its resistance virus can appear, that it causes a nerve disturbance, etc. have been mentioned. On the other hand, although ribavirin shows a polymerase-inhibitory activity and effective against A type and B type influenza, it exhibits no sufficient clinical effect when used orally.
Thus, it has been desired to develop an antiviral agent having an infection-preventive effect against various viruses and especially against influenza virus and exhibiting a therapeutic effect.
In PCT/JP99/04429 (WO00/10569), there are mentioned nitrogen-containing heterocyclic carbamoyl derivatives represented by the following general formula [22]:
wherein ring A represents a substituted or unsubstituted pyrazine, pyrimidine, pyridazine or triazine ring, R
23
represents O or OH, R
24
represents hydrogen atom, acyl group or carbamoylalkyl group, and the broken line represents a single bond or a double bond, and salts thereof, which are useful as an antiviral agent. Although mention is made in the patent application of the process for producing the compounds represented by general formula [22] and the intermediates used for the production, there is no description in the above-mentioned patent application about usefulness of the fluoropyrazine derivatives of the present patent application as a production intermediate for the compounds represented by general formula [22]. It is described there that, among the compounds of general formula [22], those in which the substituent of the pyrazine ring is a fluorine atom, namely the compounds represented by the following general formula [23]:
wherein ring A′ is a pyrazine ring, and R
23
, R
24
and the broken line have the same meanings as above, have a strong anti-influenza virus activity and are excellent as an antiviral agent.
DISCLOSURE OF THE INVENTION
With the aim of solving the problems mentioned above, the present inventors have conducted extensive studies. As a result, it has been found that a pyrazine derivative represented by the following general formula [1]:
wherein R
1
represents a hydrogen atom or a halogen atom; R
2
represents a hydrogen atom or a protected or unprotected monophosphoric, diphosphoric or triphosphoric acid group; R
3
, R
4
, R
5
and R
6
which may be the same or different represent a hydrogen atom, a halogen atom, an azido group, a substituted or unsubstituted, protected or unprotected hydroxyl or amino group or R
4
and R
6
, taken conjointly, represent a bonding unit; A represents an oxygen atom or a methylene group; n represents 0 or 1; and Y represents an oxygen atom, a sulfur atom or an NH group,
or a salt thereof has an excellent antiviral activity. Based on this finding, the present invention has been accomplished.
Further, it has also been found that a fluoropyrazine derivative represented by the following general formula [21]:
wherein R
21
represents a hydrogen atom, a methyl group, a halogenated methyl group, a methyl group substituted with a protected or unprotected mercapto group, a formyl group, a nitrile group, a halogenated carbonyl group or a protected or unprotected hydroxymethyl, aminomethyl, carbamoyl or carboxyl group; R
22
represents a hydrogen atom, a halogen atom, a protected or unprotected hydroxyl or amino group, a nitro group, an azido group or a substituted or unsubstituted phenylsulfanyl, phenylsulfinyl or phenylsulfonyl group; provided that a case that R
21
is a carbamoyl group or a carbamoyl group substituted with an acyl group and R
22
is a hydroxyl group and a case that R
21
is a hydrogen atom and R
22
is a hydrogen atom are excepted,
or a salt thereof is an excellent intermediate for the industrial production of the fluoropyrazine-carboxamide derivative which is an intermediate for production of the compound represented by general formula [1] in which R
1
is a fluorine atom. Based on this finding, the present invention has been accomplished.
Further, it has also been found that the fluoropyrazine derivative represented by general formula [21] or a salt thereof is an excellent intermediate for the industrial production of the fluoropyrazine-carboxamide derivative represented by general formula [23] having an antiviral activity. Based on these findings, the present invention has been accomplished.
Hereunder, the present invention will be detailed.
As used in this specification, meanings of the following terms are as follows, unless otherwise defined. The term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; “halogenated methyl group” means a mono-, di- or tri-substituted halogenated methyl group such as fluoromethyl, chloromethyl, bromomethyl, iodomethyl, dichloromethyl, trifluoromethyl, trichloromethyl and the like; “halogenated carbonyl group” means a fluorocarbonyl, chlorocarbonyl, bromocarbonyl or iodocarbonyl group; “lower alkyl group” means a C
1-5
alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like; “lower alkoxy group” means a C
1-5
alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and the like; “lower alkoxycarbonyl group” means a C
1-5
alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like; “lower alkylamino group” means a mono- or di-C
1-5
alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino and the like; “halogeno-lower alkyl group” means a halogeno-C
1-5
alkyl group such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, chloropropyl and the like; “lower alkenyl group” means a C
2-5
alkenyl group such as vinyl, allyl and the like; “cycloalkyl group” means a C
3-6
cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; “aryl group” means a phenyl group, a naphthyl group or the like; and “heterocyclic group” means a 4- to 6-membered or fused heterocyclic group containing at least one hetero atom selected from oxygen atom, nitrogen atom and sulfur atom, such as azetidinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,
Egawa Hiroyuki
Furuta Yousuke
Sugita Jun
Berch Mark L.
Habte Kahsay
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Toyama Chemical Co., Ltd.
LandOfFree
Pyrazine derivatives or salts thereof, pharmaceutical... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pyrazine derivatives or salts thereof, pharmaceutical..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyrazine derivatives or salts thereof, pharmaceutical... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3311391