N.sup.6 - substituted nucleotide analagues and their use
First Claim
Patent Images
1. 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, --OR3, --OCH(R16)OC(O)R3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR3, or --N(R3)2 ;
- R3 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 --CH2 -- moiety has been substituted by NH, S, or O;
R2 is NH2 or H;
R1 is CH3, C.tbd.CH, CH═
CH2, CH2 F or azidomethyl;
R16 is H or R3 ; and
X is --N(R10)2 whereinR10 independently isH;
C2 -C15 alkyl, C3 -C15 alkenyl, C6 -C15 arylalkenyl, C3 -C15 alkynyl, C7 -C15 arylalkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroalkyl or C3 -C6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--;
C1 -C15 alkyl, C2 -C15 alkenyl, C6 -C15 arylalkenyl, C6 -C15 arylalkynyl, C2 -C15 alkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroaralkyl, C4 -C6 aryl, C2 -C6 heterocycloalkyl;
optionally both R10 are joined together to form a saturated or unsaturated C2 -C5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom,or one of the foregoing R10 groups in which 1 to 3 H are substituted with halo, CN or N3,but either one or two R10 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.
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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.
214 Citations
33 Claims
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1. 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, --OR3, --OCH(R16)OC(O)R3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR3, or --N(R3)2 ;
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R3 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 --CH2 -- moiety has been substituted by NH, S, or O;R2 is NH2 or H; R1 is CH3, C.tbd.CH, CH═
CH2, CH2 F or azidomethyl;R16 is H or R3 ; and X is --N(R10)2 wherein R10 independently is H; C2 -C15 alkyl, C3 -C15 alkenyl, C6 -C15 arylalkenyl, C3 -C15 alkynyl, C7 -C15 arylalkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroalkyl or C3 -C6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--; C1 -C15 alkyl, C2 -C15 alkenyl, C6 -C15 arylalkenyl, C6 -C15 arylalkynyl, C2 -C15 alkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroaralkyl, C4 -C6 aryl, C2 -C6 heterocycloalkyl; optionally both R10 are joined together to form a saturated or unsaturated C2 -C5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom, or one of the foregoing R10 groups in which 1 to 3 H are substituted with halo, CN or N3, but either one or two R10 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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15. A compound having structure (2) wherein
Y independently is, OH, --OR3, --OCH(R16)OC(O)R3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR3, or --N(R3)2 ; -
X is --N(R10)2 ; Z is N or CH, provided that no more than one Z varies from purine; R3 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 --CH2 -- moiety has been substituted by NH, S, or O;R2 is NH2 or H; E is --(CH2)2 --, --CH(CH3)CH2 --, --CH(CH2 F)CH2 --,--CH(CH2 OH)CH2 --, --CH(CH═
CH2)CH2 --, --CH(C.tbd.CH)CH2 --, --CH(CH2 N3)CH2 --, ##STR20## --CH(R6)OCH(R6'"'"')--, --CH(R9)CH2 O-- or --CH(R8)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; R6 and R6'"'"' are independently H, C1 -C6 alkyl, C1 -C6 hydroxyalkyl, or C2 -C7 alkanoyl; R7 independently are H, C1 -C6 alkyl, or are taken together to form --O-- or --CH2 ; R8 is H, C1 -C6 alkyl, C1 -C6 hydroxyalkyl or C1 -C6 haloalkyl; R9 is H, hydroxymethyl or acyloxymethyl; and R10 independently is H; C2 -C15 alkyl, C3 -C15 alkenyl, C6 -C15 arylalkenyl, C3 -C15 alkynyl, C7 -C15 arylalkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroalkyl or C3 -C6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--; C2 -C15 alkenyl, C6 -C15 arylalkenyl, C6 -C15 arylalkynyl, C2 -C15 alkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C6 -C15 heteroaralkyl, or C2 -C6 heterocycloalkyl; optionally both R10 are joined together to form a saturated or unsaturated C2 -C5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom, or one of the foregoing R10 groups in which 1 to 3 H are substituted with halo, CN or N3 but either one or two R10 groups are not H; and R16 is H or R3 ; and the therapeutically acceptable salts thereof. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23)
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24. 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, --OR3, --OCH(R16)OC(O)R3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR3, or --N(R3)2 ;
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X is --N(R10)2 ; Z is N or CH, provided that no more than one Z varies from purine; R3 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 --CH2 -- moiety has been substituted by NH, S, or O;R2 is NH2 or H; E is --(CH2)2 --, --CH(CH3)CH2 --, --CH(CH2 F)CH2 --,--CH(CH2 OH)CH2 --, --CH(CH═
CH2)CH2 --, --CH(C.tbd.CH)CH2 --, --CH(CH2 N3)CH2 --, ##STR22## --CH(R6)OCH(R6'"'"')--, --CH(R9)CH2 O-- or --CH(R8)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; R6 and R6'"'"' are independently H, C1 -C6 alkyl, C1 -C6 hydroxyalkyl, or C2 -C7 alkanoyl; R7 independently are H, C1 -C6 alkyl, or are taken together to form --O-- or --CH2 ; R8 is H, C1 -C6 alkyl, C1 -C6 hydroxyalkyl or C1 -C6 haloalkyl; R9 is H, hydroxymethyl or acyloxymethyl; and R10 independently is H; C2 -C15 alkyl, C3 -C15 alkenyl, C6 -C15 arylalkenyl, C3 -C15 alkynyl, C7 -C15 arylalkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroalkyl or C3 -C6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--; C2 -C15 alkenyl, C6 -C15 arylalkenyl, C6 -C15 arylalkynyl, C2 -C15 alkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C6 -C15 heteroaralkyl, or C2 -C6 heterocycloalkyl; optionally both R10 are joined together to form a saturated or unsaturated C2 -C5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom, or one of the foregoing R10 groups in which 1 to 3 H are substituted with halo, CN or N3 but either one or two R10 groups are not H; and R16 is H or R3 ; and the therapeutically acceptable salts thereof. - View Dependent Claims (25, 26, 27, 28)
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29. A compound having structure (1) ##STR23## wherein Y independently is, OH, --OR3, --OCH(R16)OC(O)R3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR3, or --N(R3)2 ;
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R3 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 --CH2 -- moiety has been substituted by NH, S, or O;R2 is NH2 ; R1 is CH3, C.tbd.CH, CH═
CH2, CH2 F or azidomethyl;R16 is H or R3 ; and X is -N(R10)2 wherein R10 independently is H; C3 -C4 cycloalkyl-substituted C1 -C2 alkyl, C2 -C15 alkenyl, C6 -C15 arylalkenyl, C6 -C15 arylalkynyl, C2 -C15 alkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C6 -C15 heteroaralkyl, C4 -C6 aryl, C2 -C6 heterocycloalkyl, --CH(Phe)2, or C3 -C4 cycloalkyl which C3 -C4 cycloalkyl is mono-, di- or tri-substituted with C1 -C3 alkyl; C2 -C15 branched or normal alkyl, C3 -C15 alkenyl, C6 -C15 arylalkenyl, C3 -C15 alkynyl, C7 -C15 arylalkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroalkyl or C3 -C6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--; optionally both R10 are joined together to form a saturated or unsaturated C2 -C5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom, or one of the foregoing R10 groups in which 1 to 3 H are substituted with halo, CN or N3 but either one or two R10 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.
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30. A compound having structure (1) ##STR24## wherein Y is OH;
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R2 is H; R1 is CH3 ; X is C1 -C15 alkylamino; and Z is N or CH, provided that no more than one Z varies from purine; and the therapeutically acceptable salts thereof.
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31. A compound having structure (1) ##STR25## wherein Y is OH;
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R2 is H; R1 is CH3 ; X is ethylmethylamino, allylamino, cyclopropylamino or 2-dimethylaminoethylamino; and Z is N or CH, provided that no more than one Z varies from purine; and the therapeutically acceptable salts thereof.
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32. A compound having structure ##STR26## wherein Y independently is, OH, --OR3, --OCH(R16)OC(O)R3, a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, --NHR3, or --N(R3)2 ;
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R3 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 --CH2 -- moiety has been substituted by NH, S, or O;R2 is NH2 or H; R16 is H or R3 ; and X is --N(R10)2 wherein R10 independently is H; C2 -C15 alkyl, C3 -C15 alkenyl, C6 -C15 arylalkenyl, C3 -C15 alkynyl, C7 -C15 arylalkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroalkyl or C3 -C6 heterocycloalkyl wherein methylene in an alkyl moiety not adjacent to NH has been replaced by --O--; C1 -C15 alkyl, C2 -C15 alkenyl, C6 -C15 arylalkenyl, C6 -C15 arylalkynyl, C2 -C15 alkynyl, C1 -C6 -alkylamino-C1 -C6 alkyl, C5 -C15 aralkyl, C6 -C15 heteroaralkyl, C4 -C6 aryl, C2 -C6 heterocycloalkyl; optionally both R10 are joined together to form a saturated or unsaturated C2 -C5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom, or one of the foregoing R10 groups in which 1 to 3 H are substituted with halo, CN or N3, but either one or two R10 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.
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33. 9-(2-phosphonomethoxypropyl)-2-amino, 6-(2-dimethylamino-ethylamino)purine.
Specification
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Current AssigneeInstitute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I., REGA Stichting VZW
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Original AssigneeInstitute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I., REGA Stichting VZW
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InventorsHoly, Antonin, De Clercq, Erik Desire Alice
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Primary Examiner(s)Russel, Jeffrey E.
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Application NumberUS08/426,372Time in Patent Office1,656 DaysField of Search530/345, 530/352, 530/409, 514/7, 514/81, 544/244, 546/23US Class Current514/45CPC Class CodesA61K 31/675 having nitrogen as a ring h...A61P 31/00 Antiinfectives, i.e. antibi...A61P 31/12 AntiviralsA61P 31/20 for DNA virusesA61P 31/22 for herpes virusesC07F 9/6561 containing systems of two o...C07F 9/65616 containing the ring system ...C07H 19/16 Purine radicalsY02A 50/30 Against vector-borne diseas...
