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US 2004/0110718 A1Published application
Anti-HCV nucleoside derivatives
OwnerRene Devos, Brian William Dymock +7inventors
InventorsRene Devos, Brian William Dymock, Christopher John Hobbs, Wen-Rong Jiang, Joseph Armstrong Martin, John Herbert Merrett, Isabel Najera, Nobuo Shimma, Takuo Tsukuda
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Abstract
The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
Claims49
A method for the treatment of hepatitis C infection comprising administering a therapeutically effective amount of a compound of the formula:
- 417
- wherein
- R1 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxy, halogen, cyano, isocyano or azido;
- R2 is hydrogen, hydroxy, alkoxy, chlorine, bromine or iodine;
- R3 is hydrogen;
- or
- R2 and R3 together represent ═CH2;
- or
- R2 and R3 represent fluorine;
- X is O, S or CH2;
- and
- B is a purine base B1 which is connected through the 9-nitrogen of formula
- 418
- or B is an oxidised purine base B2 which is connected through the 9-nitrogen of formula
- 419
- or B is a purine base B3 which is connected through the 9-nitrogen of formula
- 420
- or B is a pyrimidine base B4 which is connected through the 1-nitrogen of formula
- 421
- or B is a pyrimidine base B5 which is connected through the 1-nitrogen of formula
- 422
- wherein
- R4 is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR7R8, halogen or SH;
- R5 is hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamino, halogen, NR7R8, NHOR9, NHNR7R8 or SH;
- R6 is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR7R8, halogen, SH or cyano;
- R7 and R8 are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl;
- R9 is hydrogen, alkyl or aryl;
- R10 is hydrogen, alkyl or aryl;
- Y is O, S or NR11;
- R11 is hydrogen, hydroxy, alkyl, OR9, heterocyclyl or NR7R8;
- Z is O or S;
- R12 is hydrogen, hydroxy, alkyl, alkoxy, haloalkyl, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamino, halogen, NR7R8, NHOR9, NHNR7R8 or SH;
- and
- R13 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or halogen and the hydrolyzable esters, hydrolyzable ethers and pharmaceutically acceptable salts thereof.
31 more elements
The method according to 21 wherein
- R13 is hydrogen, C1-4-alkyl or fluorine;
- R7 and R8 are independently of each other hydrogen or C1-4-alkyl.
A compound of the formula I-a
- 429
- wherein
- R1′ is hydroxy;
- R2′ is hydroxy;
- X′ is O;
- B′ is an oxidized purine base B2-a which is connected through the 9-nitrogen of formula
- 430
- wherein
- R4′ is hydrogen;
- R5′ is NHR8′;
- R6′ is hydrogen;
- R8′ is alkyl;
- and the hydrolyzable esters, hydrolyzable ethers, and pharmaceutically acceptable salts thereof.
10 more elements
A compound of the formula I-b
- 431
- wherein
- R1″ is hydroxy;
- R2″ is hydroxy;
- X″ is O;
- B″ is a purine base B3-a which is connected through the 9-nitrogen of formula
- 432
- wherein
- R4″ is hydrogen;
- R6″ is hydrogen;
- R10″ is alkyl;
- Y″ is NR11″;
- R11″ is alkyl;
- and the hydrolyzable esters, hydrolyzable ethers, and pharmaceutically acceptable salts thereof.
11 more elements
A compound of the formula I-c
- 433
- wherein
- R1′″ is hydroxy;
- R2′″ is hydroxy;
- X′″ is O;
- B′″ is a pyrimidine base B4-a which is connected through the 1-nitrogen of formula
- 434
- wherein
- R12′″ is alkylthio or heterocyclyl;
- R13′″ is hydrogen, alkyl or halogen;
- Z′″ is O;
- and the hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
9 more elements
A compound of the formula I-d
- 435
- wherein
- R1″″ is hydrogen, halogen, hydroxy, alkyl, alkoxy, cyano or azido;
- R2″″ and R3″″ represent fluorine;
- X″″ is O or CH2;
- B″″ is a pyrimidine base B4-b which is connected through the 1-nitrogen of formula
- 436
- wherein
- Z″″ is O;
- R12″″ is NR7″″R8″″;
- R13″″ is hydrogen, alkyl or halogen;
- R7″″ and R8″″ are independently of each other hydrogen or alkyl;
- and the hydrolyzable esters, hydrolyzable ethers, and pharmaceutically acceptable salts thereof.
10 more elements
A compound of the formula I-e
- 437
- wherein
- R1′″″ is alkoxy;
- R2′″″ is hydrogen;
- X′″″ is O;
- B′″″ is a pyrimidine base B5-a which is connected through the 1-nitrogen of formula
- 438
- wherein
- R10′″″ is hydrogen;
- R13′″″ is alkyl;
- Y′″″ is O;
- Z′″″ is O;
- and the hydrolyzable esters,hydrolyzable ethers, and pharmaceutically acceptable salts thereof.
10 more elements
A compound of the formula I-f
- 439
- wherein
- R1″″″ is hydroxy;
- R2″″″ is hydroxy;
- X″″″ is O;
- B″″″ is a pyrimidine base B5-b which is connected through the 1-nitrogen of formula
- 440
- wherein
- R10″″″ is hydrogen;
- R13″″″ is halogen;
- R11″″″ is hydroxy;
- Z″″″ is O;
- and the hydrolyzable esters,hydrolyzable ethers, and pharmaceutically acceptable salts thereof.
10 more elements
A compound of the formula I-g
- 441
- wherein
- R1′″″″ is hydroxy;
- R2′″″″ is hydroxy;
- B′″″″ is a pyrimidine base B5-c which is connected through the 1-nitrogen of formula
- 442
- wherein
- R10′″″″ is hydrogen;
- R13′″″″ is hydrogen;
- Y′″″″ is NR11′″″″;
- R11′″″″ is hydroxy;
- and the hydrolyzable esters, hydrolyzable ethers and pharmaceutically acceptable salts thereof.
9 more elements
A compound selected from the group consisting of:
- 6-(N-Methylpropylamino)-9-(β-D-ribofuranosyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(4-thiomorpholinyl)purine,
- 6-(N-(2-Propenyl)methylamino)-9-(β-D-ribofuranosyl)purine,
- 6-(N-Methyl-2-propynylamino)-9-(β-D-ribofuranosyl)purine,
- 6-[4-(4-Fluorophenyl)-1,2,5,6-tetrahydropyridyl]-9-(β-D-ribofuranosyl)purine,
- 6-[4-(2-Methoxyphenyl)piperazinyl]-9-(β-D-ribofuranosyl)purine,
- 6-(N-Methylphenylamino)-9-(β-D-ribofuranosyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(1,2,4,5-6-(1-tetrahydro-3H-benzazepin-3-yl)purine,
- 9-(β-D-ribofuranosyl)-6-(1,2,3,4-tetrahydro-2-isoquinolyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)purine,
- 6-[2-(4-Cyanomethylphenyl)ethylamino]-9-(β-D-ribofuranosyl)purine,
- 6-(2,3-Dihydro-1-indolyl)-9-(β-D-ribofuranosyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)purine,
- 9-(β-D-Ribofuranosyl)-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)purine,
- 6-(8-Aminosulphonyl-2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl)-9-(β-D-ribofuranosyl)purine,
- 6-(2-Isoindolinyl)-9-(β-D-ribofuranosyl)purine,
- 6-(7-Aminosulphonyl-2,3,4,5-tetrahydro-1H-benzazepin-3-yl)-9-(β-D-ribofuranosyl)purine,
- 6-(10,11-Dihydro-5H-dibenzo [a,d]cyclohepten-5-ylamino)-9-(β-D-ribofuranosyl)purine,
- 6-[N-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]-9-(β-D-ribofuranosyl)purine,
- 6-[N-(5-Aminopentyl)methylamino]-9-(β-D-ribofuranosyl)purine,
- 6-Ethylmethylamino-9-(β-D-ribofuranosyl)purine,
- 6-bis-[(3-Methyl)butylamino]-9-(β-D-ribofuranosyl)purine,
- 6-[2-Phenyl-(N-propionyl)ethylamino]-9-(β-D-ribofuranosyl)purine,
- 6-(N-Benzoyl-2-phenylethylamino)-9-(β-D-ribofuranosyl)purine,
- 1-Methyl-6-(2-phenylethylimino)-9-(β-D-ribofuranosyl)purine,
- 2-Amino-6-methylamino-9-(β-L-ribofuranosyl)purine,
- 6-[(N-Cyclohexyl)methylamino]-2-methylthio-9-(β-D-ribofuranosyl)purine,
- 6-(1-Pyrrolyl)-9-(β-D-ribofuranosyl)purin-8-(7H)-one,
- 9-(3-Deoxy-β-D-ribofuranosyl)-6-(1-pyrrolyl) purine,
- 6-(1-Pyrrolyl)-9-(β-L-ribofuranosyl)purine,
- 6-(1-Indolyl)-9-(β-D-ribofuranosyl)purine,
- 6-(1-Imidazolyl)-9-(β-D-ribofuranosyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(1,2,4-triazol-1-yl)purine,
- 6-(1-Pyrazolyl)-9-(β-D-ribofuranosyl)purine,
- 6-(2-Phenylethylamino)-9-(β-D-ribofuranosyl)purine-1-oxide,
- 8-(2-Phenylethylamino)adenosine,
- 8-(3-Phenylpropylamino)adenosine,
- 8-(4-Morpholinyl)adenosine,
- 8-(N-Methyl-2-phenylethylamino)adenosine,
- 8-(3-Pyridylmethylamino)adenosine,
- 8-(1,2,3,4-Tetrahydro-2-isoquinolyl)adenosine,
- 8-[2-(4-Morpholinyl)ethylamino]adenosine,
- 8-(2-Cyclohexylethylamino)adenosine,
- 8-(2(R,S)-Phenylpropylamino)adenosine,
- 8-[2-(4-Methylphenyl) ethylamino]adenosine,
- 8-[2-(1-methyl-2-pyrrolyl) ethylamino]adenosine,
- 8-[2-(4-Aminosulphonylphenyl) ethylamino]adenosine,
- 8-(4-Phenyl-1-piperazinyl)adenosine,
- 8-(1-Naphthylmethylamino) adenosine,
- 8-[2-(4-Hydroxyphenyl)ethylamino]adenosine,
- 8-(4-Phenylbutylamino)adenosine,
- 8-[2-(4-Chlorophenyl)ethylamino]adenosine,
- 8-[2-(2,4-Dichlorophenyl)ethylamino]adenosine,
- 8-(2-Propenylamino)adenosine,
- 8-(1(R)-Methyl-2-phenylethylamino)adenosine,
- 8-(4-Fluorobenzylamino)adenosine,
- 8-[(4-Hydroxycarbonyl)benzylamino]adenosine,
- 8-(2-propynylamino)adenosine,
- 8-[(4-trifluoromethyl)benzylamino]adenosine,
- 8-[(2,5-Dimethoxy)benzylamino]adenosine,
- 8-[2-(2-Thienyl)ethylamino]adenosine,
- 8-[2-(4-Aminophenyl)ethylamino]adenosine,
- 8-(2-Phenoxyethylamino)adenosine,
- 8-[(2-Thienyl)methylamino)adenosine,
- 8-[(4-tert-Butyl)benzylamino]adenosine,
- 8-(1(R)-Phenylethylamino)adenosine,
- 8-(1(S)-Phenylethylamino)adenosine,
- 8-(6-Phenylhexylamino)adenosine,
- 8-[2-Hydroxy-1(S)-phenyl)ethylamino]adenosine,
- 2′-Deoxy-8-(2-phenylethylamino)adenosine,
- 2′-Deoxy-8-(3-phenylpropylamino)adenosine,
- 8-Benzylamino-2′-deoxyadenosine,
- 2′-Deoxy-8-(4-phenylbutylamino)adenosine,
- 2′-Deoxy-8-(6-phenylhexylamino)adenosine,
- 8-Ethoxyadenosine,
- 9-(β-D-Ribofuranosyl)-6-(3-thienyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(1-thianthrenyl)purine,
- 6-(4-Biphenylyl)-9-(β-D-ribofuranosyl) purine,
- 6-(4-Methylthiophenyl)-9-(β-D-ribofuranosyl) purine,
- 6-(9-Phenanthrenyl)-9-(β-D-ribofuranosyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(3-trifluoromethylphenyl)purine,
- 6-(2-Phenoxyphenyl)-9-(β-D-ribofuranosyl) purine,
- 6-(4-tert-Butylphenyl)-9-(β-D-ribofuranosyl) purine,
- 9-(β-D-Ribofuranosyl)-6-(2-trifluoromethoxyphenyl)purine,
- 6-(4-Phenoxyphenyl)-9-(β-D-ribofuranosyl)purine,
- 6-(2-Naphthyl)-9-(β-D-ribofuranosyl)purine,
- 6-(3-Biphenylyl)-9-(β-D-ribofuranosyl)purine,
- 6-[4-(2-Methylpropyl)phenyl]-9-(β-D-ribofuranosyl)purine,
- 6-(3-Fluorophenyl)-9-(β-D-ribofuranosyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(4-trifluoromethylphenyl)purine,
- 6-(3-Ethoxyphenyl)-9-(β-D-ribofuranosyl)purine,
- 6-[3-(1-Methyl)ethylphenyl]-9-(β-D-ribofuranosyl)purine,
- 9-(β-D-Ribofuranosyl)-6-(4-trifluoromethoxyphenyl)purine,
- 6-(4-Ethylphenyl)-9-(β-D-ribofuranosyl)purine,
- 5-Fluoro-4-methylthio-1-(β-D-ribofuranosyl)pyrimidin-2(1H)-one,
- 5-Methyl-4-methylthio-1-(β-D-ribofuranosyl)pyrimidin-2(1H)-one,
- 2′,3′-Dideoxy-5-ethyl-3′-methoxyuridine,
- 4-(1-Pyrrolyl)-1-(β-D-ribofuranosyl)pyrimidin-2(1H)-one,
- 4-Oximino-1-(β-L-ribofuranosyl)pyrimidin-2(1H)-one,
- 5-Fluoro-4-oximino-1-(β-D-ribofuranosyl)pyrimidin-2(1H)-one;
- and
- the hydrolyzable esters, hydrolyzable ethers and pharmaceutically acceptable salts thereof.
99 more elements
Dependencies are inferred from the claim text.