Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1992-06-26
2001-04-03
McElwain, Elizabeth F. (Department: 1638)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S026100
Reexamination Certificate
active
06211158
ABSTRACT:
The present invention is concerned with new desazapurine-nucleoside derivatives, processes for the preparation thereof, as well as the use thereof in the sequencing of nucleic acids, and also as anti-viral agents. The compounds of the invention are characterized by enhanced stability as compared to 2′,3′-dideoxy compounds, which can easily be hydrolyzed under acidic conditions. The compounds of the invention are not so easily hydrolyzed.
The new desazapurine-nucleoside derivatives according to the present invention are compounds of the general formula:
wherein X is a nitrogen atom or a methine group, W is a nitrogen atom or a C-R
4
radical, R
1
, R
2
, R
3
and R
4
, which can be the same or different, are hydrogen or halogen atoms, hydroxyl or mercapto groups, lower alkyl, lower alkylthio, lower alkoxy, aralkyl, aralkoxy or aryloxy radicals or amino groups optionally substituted once or twice, R
5
is a hydrogen atom or a hydroxyl group and R
6
and R
7
are each hydrogen atoms or one of them is a halogen atom or a cyano or azido group or an amino group optionally substituted once or twice, whereby one of R
6
and R
7
can also be a hydroxyl group when X is a methine radical and, in addition, R
5
and R
7
can together represent a further valency bond between C-2′ and C-3′ and Y is a hydrogen atom or a mono-, di- or triphosphate group, as well as the tautomers and salts thereof and nucleic acids which contain compounds of general formula I as structural components.
The lower alkyl radicals in the definition of the substituents R
1
, R
2
, R
3
and R
4
can be saturated or unsaturated, straight-chained or branched and contain up to 7 and preferably up to 4 carbon atoms. This definition of the alkyl radicals also applies to the alkyl moieties which occur in the definitions of the lower alkylthio and lower alkoxy radicals. The methyl and ethyl radicals are quite especially preferred.
By halogen in the definition of the substituents R
1
, R
2
, R
3
, R
4
, R
6
and R
7
are to be understood fluorine, chlorine, bromine and iodine.
The aralkyl and aralkoxy radicals in the definitions of the substituents R
1
, R
2
, R
3
and R
4
contain an alkyl moiety with up to 5 and preferably with up to 3 carbon atoms which are substituted one or more times with an arylmoiety suitably of 6 to 10 carbon atoms, for example a phenyl or naphthyl radical. The aromatic radicals can, in turn, be substituted one or more times by an alkyl or alkoxy radical. The benzyl radical is especially preferred.
As aryloxy radical in the definition of R
1
, R
2
, R
3
and R
4
, the phenyloxy radical is especially preferred which can optionally be substituted one or more times by further substituents, for example nitro groups and alkyl and alkoxy radicals.
The amino group occurring in the definition of R
1
, R
2
, R
3
, R
4
, R
6
and R
7
, which can optionally be substituted once or twice, contains, as possible substituents, preferably alkyl radicals with up to 5 and preferably up to 3 carbon atoms which, in turn, can be substituted by alkoxy radicals, halogen atoms or amino groups optionally substituted once or twice. These substituents can also represent an aralkyl radical. The two nitrogen substituents can together also represent an alkylidene radical and preferably a methylidene radical which, in turn, can be substituted by alkoxy, substituted amino groups or halogen atoms. A quite especially preferred substituent of this kind is the dimethylaminomethylidene radical.
The monophosphate group is the —PO(OH)
2
group, the diphosphate group is the —P
2
O
3
(OH)
3
group and the triphosphate group is the P
3
O
5
(OH)
4
group.
As possible salts, there are especially preferred the alkali metal, alkaline earth metal and ammonium salts of the phosphate groups. The alkaline earth metal salts are especially the magnesium and calcium salts. By ammonium salts, according to the present invention there are to be understood salts which contain the ammonium ion which can be substituted up to four times by alkyl radicals containing up to 4 carbon atoms and/or by aralkyl radicals, preferably the benzyl radical. The substituents can hereby be the same or different. The salts of the phosphates can be converted in known manner into the free acids.
The compounds of general formula I can contain basic groups, especially amino groups, which can be converted into acid addition salts with appropriate acids. As acids for this purpose, there can be used, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid and methanesulphonic acid.
The compounds of general formula I are new. They can be prepared analogously to known, related compounds. For the preparation of the compounds of general formula I, a process has proved to be especially preferred in which a compound of the general formula:
in which X, W, R
1
, R
2
and R
3
have the same meanings as above, is reacted with a compound of the general formula:
in which R
5
has the above-given meaning, R
6′
and R
7′
each represent hydrogen atoms or one of these two symbols represents an azido group or a hydroxyl group protected by an oxygen protection group, R′ is an oxygen protection group and Z is a reactive group, to give a compound of the general formula:
in which X, W, R
1
, R
2
, R
3
, R
5
, R
6′
, R
7′
and R′ have the above-given meanings, and oxygen protective groups possibly present are split off and thereafter a compound thus obtained, in which R
6
or R
7
is a hydroxyl group, after selective protection of the 5′-hydroxyl group, is optionally converted with a halide, cyanide or azide in known manner into a compound of general formula I in which R
6
or R
7
is a halogen atom or a cyano or azido group or, in known manner, is deoxygenated to give a compound of general formula I, in which R
6
or R
7
is a hydrogen atom or a compound thus obtained of general formula I, in which R
6
or R
7
is an azido group, is reduced in known manner to a compound of general formula I in which R
6
or R
7
is an amino group and, if desired, a compound of general formula I, in which Y is a hydrogen atom, is converted in known manner into a mono-, di- or tri-phosphate and, if desired, a free base or acid obtained is converted into an appropriate salt or a salt obtained is converted into the corresponding free base or acid.
The compounds of general formula II are reacted with the compounds of general formula III especially advantageously under phase transfer conditions. Under the conditions of phase transfer catalysis, the bases of general formula II are converted into a corresponding anion, for example by means of a 50% aqueous solution of sodium hydroxide. The anion thus obtained is hydrophobed by a phase transfer catalyst, for example tris-[2-(2-methoxyethoxy)-ethyl]-amine, and transported into the organic phase in which it reacts with the reactive compound of general formula III.
As reactive groups Z in the compounds of general formula III, there are preferably used halogen atoms and alkoxy radicals. In the case of this reaction, the hydroxyl groups of the sugar residue are protected in the usual way by conventional oxygen protective groups, for example toluoyl, benzoyl or acetyl radicals. After completion of the reaction, the oxygen protective groups can again be split off in known manner under alkaline conditions, a 1M methanolic menthanolate solution preferably being used.
During the reaction, it is preferable to keep the radicals R
1
, R
2
, R
3
and R
4
protected by appropriate protective groups.
Another advantageous method for the preparation of compounds of general formula IV is the solid-liquid phase transfer process with the use of solid, powdered potassium hydroxide, the above-mentioned phase transfer catalyst, as well as compounds of general formulae II and III in an aprotic solvent.
Compounds of general formula I, in which R
6
or R
7
is a halogen atom or an azido group, are preferably prepared b
Batz Hans-Georg
Bourgeois Werner
Kaiser Klaus
Muhlegger Klaus
Muth Heinz-Peter
Fulbright & Jaworski LLP
McElwain Elizabeth F.
Roche Diagnostics GmbH
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