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US 6,638,919 B2Granted
Antiviral purine derivatives
AssigneesUniversity College Cardiff Consultants Limited, Rega Foundation
InventorsChristopher McGuigan, Jan Balzarini
Life of this patent
Estimating the term…
Abstract
Compounds of the formula wherein Ar is aryl, R1 and R2 are hydrogen alkyl, alkyl substituted with phenyl, and aryl, O, NH, NR4 and S, R5 is hydrogen, alkyl or aryl or alkylene when taken with R1, and R3 is hydrogen, alkyl, alkyl substituted with phenyl, aryl, a heterocyclic group or a polycyclic group, are antiviral agents. A typical embodiment is (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl-(methoxy-L-alaninyl)]phosphate.
Claims19
A compound of the formula:
- wherein
- Ar is an aryl group
- each of R1 and R2 independently of the other is hydrogen, alkyl, alkyl substituted with phenyl, or aryl,
- X is O, NH, NR4 or S wherein R4 is alkyl or aryl;
- R5 when taken independently of R1 is hydrogen, alkyl or aryl, or R5 and R1 taken together are alkylene of 3 or 4 carbon atoms so as to form a 5- or 6-membered ring;
- and R3 is
- (i) hydrogen,
- (ii) alkyl,
- (iii) alkyl substituted with phenyl,
- (iv) aryl,
- (v) an unsubstituted or substituted heterocyclic group comprising (i) a saturated or unsaturated heterocyclic ring having up to 12 atoms, one or two of which atoms independently is O, S, or N, said ring being optionally bridged, or (ii) said ring fused to a benzo group or to another heterocyclic ring as herein defined;
- or
- (vi) an unsubstituted or substituted polycyclic group comprising (i) at least one saturated or unsaturated nonaromatic carbocyclic ring of up to 12 atoms and (ii) a second fused or unfused ring which is (a) a saturated or unsaturated nonaromatic carbocyclic ring as herein defined or (b) a heterocyclic group as herein defined,
- or a pharmaceutically acceptable salt, ester, or salt of said ester of said compound, which salt, ester, or salt of said ester is operable to provide in vivo either said compound or an antiviral metabolite thereof.
11 more elements
A compound of the formula:
- wherein R1 and R2 are each independently selected from the group consisting of hydrogen alkyl, alkyl substituted with phenyl, and aryl,
- X is selected from the group consisting of O, NH, NR4 and S wherein R4 is selected from the group comprising alkyl and aryl;
- R5 when taken independently of R1 is selected from the group consisting of hydrogen, alkyl and aryl, or R5 and R1 taken together are alkylene of 3 or 4 carbon atoms so as to form a 5- or 6-membered ring;
- and R3 is selected from the group consisting of
- hydrogen,
- alkyl,
- alkyl substituted with phenyl,
- aryl,
- an unsubstituted or substituted heterocyclic group comprising (i) a saturated or unsaturated ring having up to 12 atoms, one or two of which atoms consists of heteroatoms independently selected from the group consisting of O, S, and N, said ring being optionally bridged, or (ii) said ring fused to a benzo group or to another heterocyclic ring as herein defined;
- and an unsubstituted or substituted polycyclic group comprising (i) at least one saturated or unsaturated nonaromatic carbocyclic ring of up to 12 atoms and (ii) a second fused or unfused ring selected from the group consisting of (a) a saturated or unsaturated nonaromatic carbocyclic ring as herein defined and (b) a heterocyclic group as herein defined,
- or a pharmaceutically acceptable salt, ester, or salt of said ester thereof operable to provide said compound in vivo.
8 more elements
A compound selected from:
- (1S,4R)-4-[2-amino-6cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-L-alaninyl] phosphate
- (1S14R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[L-alannyl]phosphate diammonium salt
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl benzyloxy-L-alaiinyl]phosphate
- (1S,4R)-4-[2-anino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-D-alaninyl]phosphate
- (1S,4R)-4 2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-α,α-dimethylglycinyl]phosphate
- (1S,4R)-4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-L-phenylalaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene 1-methanol O-[phenyl ethoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxyglycinyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-metanol-O-[phenyl L-aspartyl dimethyl ester]phosphate,
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[4-chlorophenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-y]-2-cyclopentene-1-methanol O-[phenyl tertbutyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropyamino)-9H-purin-9-yl]-2-cyclopentene-S-metanol-O-[phenyl n-propoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[Phenyl n-butyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[Phenyl 1-propoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2cyclopentene-1-methanol O-[(p-(2″, 2″-dimethoxypropionic acid methyl ester) phenyl) methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl (2-methylpropyl)oxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene 1-methanol O-[phenyl (2,2-dimethylpropyl)oxy-L-alaninyl]phosphate
- (1S,4R)-4-amino-6-(cyclopropylamino)-9H-purin-9-yl]2-cyclopentene-1-methanol O-[phenyl 3-methylbutyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl 3-pentyloxy-L-alaninyl]phosphate
- (1S,4R)-4-2-amino-6-(cyclopropylamino)-9H-purin-9-yl],-2-cyclopentene-1-methanol O-[phenyl methoxy-L-valinyl]phosphate
- (1S,4R)-4-12-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl 3,3-dimethyl-1-butyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[Phenyl n-pentyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[Phenyl cyclohexyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[Phenyl cyclohexanemethoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[Phenyl methoxy-3-cyclohexane-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[4-bromophenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl diethoxy-L-aspartyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-L-methionyl]phosphate
- (1S,4R)-4-[2-amino6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-L-leucinyl]phosphate
- (1s,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-L-prolinyl]phosphate.
- (1S,4R)-4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methylene-[phenyl dibenzyloxy-L-aspartinyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl 4-methyl-1-pentyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-(cyclopropylamino)-9H-purin-9-yl-2-cyclopentene-1-methanol O-[phenyl cyclopentylmethoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[4-fluorophenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[4-iodophenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl dimethoxy-L-glutamyl]phosphate
- (1s,4R)-4-[2-amino6-(cyclopropylamino)-9H-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl methoxy-L-tryptophanyl]phosphate
- (1S,4R) 4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]--cyclopentene-1-methanol O-(phenyl methoxy-L-isoleucinyl]phosphate
- (1S (1S,4R)-4-[2-amino6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl cycloheptanyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl cyclobutylmethoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl cyclopropylmethoxy-L-alaninyl]phosphate
- (1S,4R)$[-amino-6cyclopropylamino)-9H-purin-9-yl]-2 cyclopentene-1-methanol O-[phenyl cyclobutyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl cyclopentyloxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-i-methanol O-[phenyl phenethoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl 3-phenyl-1-propoxy-L-alaninyl]phosphate
- (1S,4R)-4-m2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2 cyclopentene-1-methanol O-[phenyl 4-phenyl-1-butoxy-L-alaninyl]phosphate
- (1S4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl 2-cyclohexyl-1-ethoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl 3-cyclohexyl-1-propoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9yl]-2-cyclopentene-1-methanol O-[phenyl 4cyclohexyl-1-butoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-α-ethyl-L-glycinyl]phosphate
- (1S,4R)-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O[phenyl methoxy-α-phenyl(RS)glycinyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-α-propyl-L-glycinyl]phosphate)
- (1S,4R)-4-12-amino6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-([phenyl methoxy-α-butyl-L-glycinyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[p-phenoxyphenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[p-phenylphenyl methoxy-L-alaninyl)]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[4-hydroxyacetophenone methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[4-butylphenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[p-methoxyphenyl methoxy-L-alaniyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2cyclopentene-1-methanol O-[p-propoxyphenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-α,α-cyclopentylglycinyl]phosphate
- (1S,4R)-4-[2amino-6-(cyclopropylamino)-9H-purin-9-yl]-2Cyclopentene-1-methanol O-[phenyl methoxy-α,α-cylohexylglycinyl]phosphate
- (1S,4R)-[4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl methoxy-α,α-cyclopropylglycinyl)]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[phenyl (methoxycarbonyl)phenyl methoxy-L-alaninyl ]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[p-(trifluoromethylthio)phenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-&(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[p-(2-methoxyvinyl)phenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[p-(2-phenylcarbonylvinyl)phenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-64cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[p-(2,2-dicyanovinyl)phenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol O-[o-(carboxylate ethyl ester)phenyl methoxy-L-alaninyl]phosphate
- (1S,4R)-4-(2-amino-6-(cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl ethoxy-L-alaninyl) phosphate succinate salt
- (1S,4R)-4-(2-amino6-cyclopropylamino-9(H)-purin-9yl)-2-cyclopentene-1-methanol O-(phenyl methoxy-L-alaninyl) phosphate succinate salt
- (1S,4R)-4-(2-amino-6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl ethoxy-L-alaniyl) phosphate fumarate salt
- (1S,4R)-4(2-amino-6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl ethoxy-L-alaninyl) phophate glutarate salt
- (1S,4R)-4-(2-amino-6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl ethoxy-L-alaninyl) phosphate D-tartrate salt
- (1S,4R)-4-(2-amino-6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl methoxy-L-alaninyl) phophate diastereoisomers
- (1S,4R)-4-(2-amino6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl N-methylamino-L-alaninyl) phosphate sodium salt
- (1S,4R)-4-(2-amino-6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl N-cyclopropylamino-L-alaninyl) phosphate sodium salt
- (1S,4R)-4(2-amino-6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(phenyl N,N-dimethylamino-L-alaninyl) phosphate sodium salt
- (1S,4R)-4-(2-amino-6-cyclopropylamino-9(H)-purin-9-yl)-2-cyclopentene-1-methanol O-(L-alaninyl) phosphate disodium salt.
75 more elements
Dependencies are inferred from the claim text.