US 5,977,061 AGranted

N.sup.6 - substituted nucleotide analagues and their use

AssigneesInstitute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Rega Stichting v.z.w.

InventorsAntonin Holy, Erik Desire Alice De Clercq

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Abstract

Novel PMP, PME and HPMP and related compounds containing N-6 substituted 2,6-diaminopurine and adenine bases are provided. These compounds are useful in a variety of utilities, including as intermediates in the preparation of flame retardants, diagnostic reagents and therapeutics, including antivirals. Of particular note are compounds otherwise not known to possess anti-DNA viral activity that become potent inhibitors of DNA viruses upon substitution of the N-6 site, thereby providing a novel and unexpected and surprising use for such compounds.

Claims33

Dependent claims

A method comprising treating a subject infected by a DNA virus with a therapeutically acceptable dose of a compound having structure (1) ##STR18## wherein Y independently is, OH, --OR.sup.3, --OCH(R.sup.16)OC(O)R.sup.3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR.sup.3, or --N(R.sup.3).sub.2 ;

R.sup.3 independently is unsubstituted alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl;
alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl wherein H is substituted by halo, carboxy, hydroxyl, cyano, nitro, N-morpholino, or amino;
or alkyl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl in which a --CH.sub.2 -- moiety has been substituted by NH, S, or O;
R.sup.2 is NH.sub.2 or H;
R.sup.1 is CH.sub.3, C.tbd.CH, CH.dbd.CH.sub.2, CH.sub.2 F or azidomethyl;
R.sup.16 is H or R.sup.3 ;
and
X is --N(R.sup.10).sub.2 wherein
R.sup.10 independently is
H;
C.sub.2 -C.sub.15 alkyl, C.sub.3 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.3 -C.sub.15 alkynyl, C.sub.7 -C.sub.15 arylalkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.15 aralkyl, C.sub.6 -C.sub.15 heteroalkyl or C.sub.3 -C.sub.6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--;
C.sub.1 -C.sub.15 alkyl, C.sub.2 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.6 -C.sub.15 arylalkynyl, C.sub.2 -C.sub.15 alkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.15 aralkyl, C.sub.6 -C.sub.15 heteroaralkyl, C.sub.4 -C.sub.6 aryl, C.sub.2 -C.sub.6 heterocycloalkyl;
optionally both R.sup.10 are joined together to form a saturated or unsaturated C.sub.2 -C.sub.5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom,
or one of the foregoing R.sup.10 groups in which 1 to 3 H are substituted with halo, CN or N.sub.3,
but either one or two R.sup.10 groups are not H;
and
Z is N or CH, provided that no more than one Z varies from purine;
and the therapeutically acceptable salts thereof.

15 more elements

A compound having structure (2) wherein

Y independently is, OH, --OR.sup.3, --OCH(R.sup.16)OC(O)R.sup.3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR.sup.3, or --N(R.sup.3).sub.2 ;
X is --N(R.sup.10).sub.2 ;
Z is N or CH, provided that no more than one Z varies from purine;
R.sup.3 independently is unsubstituted alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl;
alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl wherein H is substituted by halo, carboxy, hydroxyl, cyano, nitro, N-morpholino, or amino;
or alkyl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl in which a --CH.sub.2 -- moiety has been substituted by NH, S, or O;
R.sup.2 is NH.sub.2 or H;
E is --(CH.sub.2).sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH(CH.sub.2 F)CH.sub.2 --,--CH(CH.sub.2 OH)CH.sub.2 --, --CH(CH.dbd.CH.sub.2)CH.sub.2 --, --CH(C.tbd.CH)CH.sub.2 --, --CH(CH.sub.2 N.sub.3)CH.sub.2 --, ##STR20## --CH(R.sup.6)OCH(R.sup.6')--, --CH(R.sup.9)CH.sub.2 O-- or --CH(R.sup.8)O--, wherein the right hand bond is linked to the 9 position of the purine, monoazapurine or monodeazapurine heterocycle;
the broken line represents an optional bond;
R.sup.6 and R.sup.6' are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 hydroxyalkyl, or C.sub.2 -C.sub.7 alkanoyl;
R.sup.7 independently are H, C.sub.1 -C.sub.6 alkyl, or are taken together to form --O-- or --CH.sub.2 ;
R.sup.8 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 hydroxyalkyl or C.sub.1 -C.sub.6 haloalkyl;
R.sup.9 is H, hydroxymethyl or acyloxymethyl;
and
R.sup.10 independently is
H;
C.sub.2 -C.sub.15 alkyl, C.sub.3 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.3 -C.sub.15 alkynyl, C.sub.7 -C.sub.15 arylalkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.15 aralkyl, C.sub.6 -C.sub.15 heteroalkyl or C.sub.3 -C.sub.6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--;
C.sub.2 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.6 -C.sub.15 arylalkynyl, C.sub.2 -C.sub.15 alkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.15 heteroaralkyl, or C.sub.2 -C.sub.6 heterocycloalkyl;
optionally both R.sup.10 are joined together to form a saturated or unsaturated C.sub.2 -C.sub.5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom,
or one of the foregoing R.sup.10 groups in which 1 to 3 H are substituted with halo, CN or N.sub.3
but either one or two R.sup.10 groups are not H;
and
R.sup.16 is H or R.sup.3 ;
and
the therapeutically acceptable salts thereof.

22 more elements

A method for treatment of viral infections comprising administering to a subject an antivirally effective amount of a compound having structure (2) ##STR21## wherein Y independently is, OH, --OR.sup.3, --OCH(R.sup.16)OC(O)R.sup.3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR.sup.3, or --N(R.sup.3).sub.2 ;

X is --N(R.sup.10).sub.2 ;
Z is N or CH, provided that no more than one Z varies from purine;
R.sup.3 independently is unsubstituted alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl;
alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl wherein H is substituted by halo, carboxy, hydroxyl, cyano, nitro, N-morpholino, or amino;
or alkyl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl in which a --CH.sub.2 -- moiety has been substituted by NH, S, or O;
R.sup.2 is NH.sub.2 or H;
E is --(CH.sub.2).sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH(CH.sub.2 F)CH.sub.2 --,--CH(CH.sub.2 OH)CH.sub.2 --, --CH(CH.dbd.CH.sub.2)CH.sub.2 --, --CH(C.tbd.CH)CH.sub.2 --, --CH(CH.sub.2 N.sub.3)CH.sub.2 --, ##STR22## --CH(R.sup.6)OCH(R.sup.6')--, --CH(R.sup.9)CH.sub.2 O-- or --CH(R.sup.8)O--, wherein the right hand bond is linked to the 9 position of the purine, monoazapurine or monodeazapurine heterocycle;
the broken line represents an optional bond;
R.sup.6 and R.sup.6' are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 hydroxyalkyl, or C.sub.2 -C.sub.7 alkanoyl;
R.sup.7 independently are H, C.sub.1 -C.sub.6 alkyl, or are taken together to form --O-- or --CH.sub.2 ;
R.sup.8 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 hydroxyalkyl or C.sub.1 -C.sub.6 haloalkyl;
R.sup.9 is H, hydroxymethyl or acyloxymethyl;
and
R.sup.10 independently is
H;
C.sub.2 -C.sub.15 alkyl, C.sub.3 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.3 -C.sub.15 alkynyl, C.sub.7 -C.sub.15 arylalkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.15 aralkyl, C.sub.6 -C.sub.15 heteroalkyl or C.sub.3 -C.sub.6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--;
C.sub.2 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.6 -C.sub.15 arylalkynyl, C.sub.2 -C.sub.15 alkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.15 heteroaralkyl, or C.sub.2 -C.sub.6 heterocycloalkyl;
optionally both R.sup.10 are joined together to form a saturated or unsaturated C.sub.2 -C.sub.5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom,
or one of the foregoing R.sup.10 groups in which 1 to 3 H are substituted with halo, CN or N.sub.3
but either one or two R.sup.10 groups are not H;
and
R.sup.16 is H or R.sup.3 ;
and
the therapeutically acceptable salts thereof.

21 more elements

A compound having structure (1) ##STR23## wherein Y independently is, OH, --OR.sup.3, --OCH(R.sup.16)OC(O)R.sup.3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR.sup.3, or --N(R.sup.3).sub.2 ;

R.sup.3 independently is unsubstituted alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl;
alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl wherein H is substituted by halo, carboxy, hydroxyl, cyano, nitro, N-morpholino, or amino;
or alkyl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl in which a --CH.sub.2 -- moiety has been substituted by NH, S, or O;
R.sup.2 is NH.sub.2 ;
R.sup.1 is CH.sub.3, C.tbd.CH, CH.dbd.CH.sub.2, CH.sub.2 F or azidomethyl;
R.sup.16 is H or R.sup.3 ;
and
X is -N(R.sup.10).sub.2 wherein
R.sup.10 independently is
H;
C.sub.3 -C.sub.4 cycloalkyl-substituted C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.6 -C.sub.15 arylalkynyl, C.sub.2 -C.sub.15 alkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.15 heteroaralkyl, C.sub.4 -C.sub.6 aryl, C.sub.2 -C.sub.6 heterocycloalkyl, --CH(Phe).sub.2, or C.sub.3 -C.sub.4 cycloalkyl which C.sub.3 -C.sub.4 cycloalkyl is mono-, di- or tri-substituted with C.sub.1 -C.sub.3 alkyl;
C.sub.2 -C.sub.15 branched or normal alkyl, C.sub.3 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.3 -C.sub.15 alkynyl, C.sub.7 -C.sub.15 arylalkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.15 aralkyl, C.sub.6 -C.sub.15 heteroalkyl or C.sub.3 -C.sub.6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--;
optionally both R.sup.10 are joined together to form a saturated or unsaturated C.sub.2 -C.sub.5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom,
or one of the foregoing R.sup.10 groups in which 1 to 3 H are substituted with halo, CN or N.sub.3
but either one or two R.sup.10 groups are not H;
and
Z is N or CH, provided that no more than one Z varies from purine;
and
the therapeutically acceptable salts thereof.

16 more elements

Dependencies are inferred from the claim text.

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Abstract

R.sup.3 independently is unsubstituted alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl;
alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl wherein H is substituted by halo, carboxy, hydroxyl, cyano, nitro, N-morpholino, or amino;
or alkyl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl in which a --CH.sub.2 -- moiety has been substituted by NH, S, or O;
R.sup.2 is NH.sub.2 or H;
R.sup.1 is CH.sub.3, C.tbd.CH, CH.dbd.CH.sub.2, CH.sub.2 F or azidomethyl;
R.sup.16 is H or R.sup.3 ;
and
X is --N(R.sup.10).sub.2 wherein
R.sup.10 independently is
H;
C.sub.2 -C.sub.15 alkyl, C.sub.3 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.3 -C.sub.15 alkynyl, C.sub.7 -C.sub.15 arylalkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.15 aralkyl, C.sub.6 -C.sub.15 heteroalkyl or C.sub.3 -C.sub.6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--;
C.sub.1 -C.sub.15 alkyl, C.sub.2 -C.sub.15 alkenyl, C.sub.6 -C.sub.15 arylalkenyl, C.sub.6 -C.sub.15 arylalkynyl, C.sub.2 -C.sub.15 alkynyl, C.sub.1 -C.sub.6 -alkylamino-C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.15 aralkyl, C.sub.6 -C.sub.15 heteroaralkyl, C.sub.4 -C.sub.6 aryl, C.sub.2 -C.sub.6 heterocycloalkyl;
optionally both R.sup.10 are joined together to form a saturated or unsaturated C.sub.2 -C.sub.5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom,
or one of the foregoing R.sup.10 groups in which 1 to 3 H are substituted with halo, CN or N.sub.3,
but either one or two R.sup.10 groups are not H;
and
Z is N or CH, provided that no more than one Z varies from purine;
and the therapeutically acceptable salts thereof.

15 more elements