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US 6,444,656 B1Granted
Antiviral phosphonate nucleotides
AssigneeBioChem Pharma Inc.
InventorsNghe Nguyen-Ba, Rabindra Rej
Life of this patent
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Abstract
The present invention relates to a novel nucleotide analogue having the general formula (I) and pharmaceutically acceptable salts, esters, or salt of such esters: wherein n, X, Q U R1′, R1, Z and R2 are defined here within. The compounds object of the present invention may be a single enantiomers or as mixtures of said enantiomers, the compounds may have a αD, α-L, β-D, β-L, R or S configuration at each chiral center or mixtures thereof. This invention also relates to pharmaceutical compositions containing them, alone or in combination with other therapeutic agents, and their use as antiviral agents, particularly against HIV and/or HBV infections in mammals.
Claims49
A nucleotide analogue according to formula (I):
- or a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, or a pharmaceutically acceptable salt of an ester wherein:
- n is 0;
- X is O;
- Q is CH2;
- U is C═CH2 or CH(Ra);
- Ra is OH, CN, halogen, N3, or NH2;
- Z is (CH2)m wherein m is 1;
- R1 and R1′ are each independently selected from H, C1-6 alkyl, phosphate or diphosphate;
- and
- R2 is
- wherein
- x is oxygen or sulfur;
- y is oxygen or sulfur;
- R3 and R4 are each independently selected from hydrogen, hydroxyl, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-10 acyl, or C6-12 aryl;
- R5 and R6 are each independently selected from hydrogen, F, Cl, Br, I, hydroxyl, methyl or amino;
- R7 is H, F, Cl, I, Br, hydroxyl, amino or the formulas
- wherein:
- q is an integer selected from 1 to 4;
- R18 is selected from H, COOH, C(O)NH2, OH, SH, NH2, NO2,or C1-6 alkyl;
- R17 is H or a C1-6 alkyl;
- and
- R8 and R9 are each independently chosen from hydrogen, hydroxyl, amino, substituted amino, halogen, azido or methyl;
- provided that when R2 is adenine Ra, if present, is CN, halogen, N3, or NH2.
20 more elements
A cis nucleotide analogue according to formula (I):
- or a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, or a pharmaceutically acceptable salt of an ester wherein:
- n is 0 or 1;
- X is O;
- R1 and R1′ are each independently selected from H, phosphate or diphosphate;
- Q is CH2;
- U is C═CH2;
- Z is (CH2)m wherein m is 1;
- and
- R2 is chosen from cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, 2,6-diaminopurine, 2-amino-6-cyclopropylamino-purine;
- 2-amino-6-[1 -carboxylic acid-cyclopropylamino]-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-azetidino-purine, 2-amino-6-cyclopentylamino-purine or 5-fluoropyrimidine.
7 more elements
A cis nucleotide analogue according to formula (I):
- or a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, or a pharmaceutically acceptable salt of an ester wherein:
- n is 0 or 1;
- X is O;
- R1 and R1′ are each independently selected from H, phosphate or diphosphate;
- U and Q are both CH and are linked by a double bond;
- Ra is hydrogen, OH, CN, halogen, N3, NH2,SH, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb, NHRb, or SRb;
- Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl or C1-6 acyl, or C(O)ORc;
- Rc is C1-6 alkyl or C1-6 acyl;
- Z is (CH2)m wherein m is 1;
- and
- R2 is chosen from cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, 2,6-diaminopurine, 2-amino-6-cyclopropylamino-purine;
- 2-amino-6-[1-carboxylic acid-cyclopropylamino]-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-azetidino-purine, 2-amino-6-cyclopentylamino-purine or 5-fluoropyrimidine.
9 more elements
A nucleotide analogue chosen from:
- wherein:
- R2 is cytosine, adenine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, 2,6-diaminopurine, 2-amino-6-cyclopropylamino-purine;
- 2-amino-6-[1-carboxylic acid-cyclopropylamino]-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-azetidino-purine, 2-amino-6-cyclopentylamino-purine or 5-fluoropyrimidine and Ra is OH, F, Cl, Br, I or N3.
A nucleotide analogue selected from the group:
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-yl methyl)-(4R)-azido-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-azido-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-hydroxy-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-hydroxy-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-chloro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-chloro-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-chloro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-chloro-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2amino-6-hydroxy-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2R)-phosphonate;
- and
- pharmaceutically acceptable salts thereof.
23 more elements
A nucleotide analogue selected from the group:
- [(5R)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid;
- [(5S)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2S)-yl]-phosphonic acid;
- [(5R) -2(2-amino-6-hydroxy-purin-9-ylmethyl)-4- methylene-tetrahydro-furan(2S) -yl]-phosphonic acid;
- and
- [(5S)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid;
- and
- pharmaceutically acceptable salts thereof.
4 more elements
A nucleotide analogue selected from the group:
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-azido-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-azido-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-hydroxy-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-hydroxy-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-chloro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-chloro-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-chloro-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-chloro-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2R)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2S)-phosphonate;
- (5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2R)-phosphonate;
- and
- pharmaceutically acceptable salts thereof.
23 more elements
A nucleotide analogue selected from the group:
- [(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid;
- [(5S)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2S)-yl]-phosphonic acid;
- [(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(25)-yl]-phosphonic acid;
- [(5)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid;
- and
- pharmaceutically acceptable salts thereof.
3 more elements
A nucleotide analogue selected from the group:
- [(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2R)-yl]-phosphonic acid;
- [(5S)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2S)-yl]-phosphonic acid;
- [(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2S)-yl]-phosphonic acid;
- [(5S)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2R)-yl]-phosphonic acid;
- and
- pharmaceutically acceptable salts thereof.
3 more elements
Dependencies are inferred from the claim text.