Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
DC
First Claim
1. A method comprising contacting a cell with a compound of formula (1a) ##STR33## wherein Z is independently --OC(R2)2 OC(O)X(R)a, an ester, an amidate or --H, but at least one Z is --OC(R2)2 OC(O)X(R)a ;
- A is the residue of an antiviral phosphonomethoxy nucleotide analog;
X is N or O;
R2 independently is --H, C1 -C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR3 in which R3 is C1 -C12 alkyl, C2 -C12 alkenyl, C2 -C12 alkynyl or C5 -C12 aryl;
R independently is --H, C1 -C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkyenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, --N(R4)2 or --OR3, where R4 independently is --H or C1 -C8 alkyl, provided that at least one R is not H; and
a is 1 when X is O, or 1 or 2 when X is N;
with the proviso that when a 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be --OR3 or (c) both N-linked R groups can be --H.
1 Assignment
Litigations
1 Petition
Reexamination
Accused Products
Abstract
Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure -OC(R2)2 OC(O) X(R)a, wherein R2 independently is H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR3 in which R3 is C1 -C12 alkyl; X is N or O; R is independently H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, axido, nitro, --O--, --N═, --NR4 --, --N(R4)2 -- or OR3, R4 independently is --H or C1 -C8 alkyl, provided that at least one R is not H; and a is 1 or 2, with the proviso that when a is 2 and X is N, (a) two R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, or (b) one R additionally can be OR3. The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy or prophylaxis. Embodiments are particularly useful when administered orally.
160 Citations
1 Claim
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1. A method comprising contacting a cell with a compound of formula (1a) ##STR33## wherein Z is independently --OC(R2)2 OC(O)X(R)a, an ester, an amidate or --H, but at least one Z is --OC(R2)2 OC(O)X(R)a ;
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A is the residue of an antiviral phosphonomethoxy nucleotide analog; X is N or O; R2 independently is --H, C1 -C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR3 in which R3 is C1 -C12 alkyl, C2 -C12 alkenyl, C2 -C12 alkynyl or C5 -C12 aryl; R independently is --H, C1 -C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkyenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, --N(R4)2 or --OR3, where R4 independently is --H or C1 -C8 alkyl, provided that at least one R is not H; and a is 1 when X is O, or 1 or 2 when X is N; with the proviso that when a 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be --OR3 or (c) both N-linked R groups can be --H.
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Specification
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- Resources
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Current AssigneeGilead Sciences Inc.
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Original AssigneeGilead Sciences Inc.
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InventorsOliyai, Reza, Kim, Choung U., Arimilli, Murty N., Cundy, Kenneth C., Stella, Valentino J., Dougherty, Joseph P.
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Primary Examiner(s)Shah, Mukund J.
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Assistant Examiner(s)Sripada, Pavanaram K
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Application NumberUS09/314,606Time in Patent Office314 DaysField of Search514/81, 514/86, 544/243, 544/244US Class Current514/81CPC Class CodesC07F 9/6512 having the nitrogen atoms i...C07F 9/65616 containing the ring system ...
