Modified fluorinated nucleoside analogues
OwnerLieven J. Stuyver, Junxing Shi +1inventors
InventorsLieven J. Stuyver, Junxing Shi, Kyoichi A. Watanabe
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Abstract
The invention is a compound, composition, use for and a method of treating Flaviviridae (Hepacivirus, Flavirius, Pestivirus) infections, including BVDV and HCV, or abnormal cellular proliferation, including malignant tumors, in a host including animals, and especially humans, using a β-D or β-L nucleoside of general formula (I)-(XX), or their pharmaceutically acceptable salt or prodrug thereof.
Claims30
A β-D or β-L compound of the formula:
- 304 305 306 307 308
- or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- (a) R is H, halogen (F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH═CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH═CHCl, CH═CHBr and CH═CHI, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, CH═CHCO2R′;
- (b) X and Y are independently H, halogen, OH, OR′, OCH3, SH, SR′, SCH3, NH2, NHR′, NR′2, CH3;
- (c) each R′ is independently a hydrogen, acyl, lower alkyl of C1-C6 or lower cycloalkyl of C1-C6;
- (d) Z is O, S or CH2;
- (e) R2 is F or OH;
- (f) R3 is F or OH;
- (g) X′ is O, S, NH, NR′, CH2, or CHR′;
- with the proviso for compound II that when X is NH2 or compound XII when X is NH and R is H, then R3 is not OH.
A pharmaceutical composition for the treatment or prophylaxis of a hepatitis C virus in a host, comprising an effective amount of a β-D compound of structure:
- 311
- or its pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition for the treatment or prophylaxis of a abnormal cellular proliferation in a patient, comprising an effective amount of a β-D compound of structure:
- 312
- or its pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition for the treatment or prophylaxis of a hepatitis C virus in a host, comprising an effective amount of a β-D compound of structure:
- 313
- or its pharmaceutically acceptable salt or prodrug thereof, in combination with one or more other antivirally effective agents.
A pharmaceutical composition for the treatment or prophylaxis of a abnormal cellular proliferation in a patient, comprising an effective amount of a β-D compound of structure:
- 314
- or its pharmaceutically acceptable salt or prodrug thereof, in combination with one or more other anti-abnormal cellular proliferation agents.
A method of treatment or prophylaxis of Flaviviridae infection is a host, comprising administering an effective amount of the compound of the formula:
- 315 316 317 318 319
- or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- (a) R is H, halogen (F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH═CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH═CHCl, CH═CHBr and CH═CHI, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, CH═CHCO2R′;
- (b) X and Y are independently H, halogen, OH, OR′, OCH3, SH, SR′, SCH3, NH2, NHR′, NR′2, CH3;
- (c) each R′ is independently a hydrogen, acyl, lower alkyl of C1-C6 or lower cycloalkyl of C1-C6;
- (d) Z is O, S or CH2;
- (e) R2 is F or OH;
- (f) R3 is F or OH;
- (g) X′ is O, S, NH, NR′, CH2, or CHR′;
- with the proviso for compound II that when X is NH2 or compound XII when X is NH and R is H, then R3 is not OH.
A method of treatment or prophylaxis of abnormal cellular proliferation in a patient, comprising administering an effective amount of the compound of the formula:
- 320 321 322 323 324
- or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- (a) R is H, halogen (F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH═CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH═CHCl, CH═CHBr and CH═CHI, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, CH═CHCO2R′;
- (b) X and Y are independently H, halogen, OH, OR′, OCH3, SH, SR′, SCH3, NH2, NHR′, NR′2, CH3;
- (c) each R′ is independently a hydrogen, acyl, lower alkyl of C1-C6 or lower cycloalkyl of C1-C6;
- (d) Z is O, S or CH2;
- (e) R2 is F or OH;
- (f) R3 is F or OH;
- (g) X′ is O, S, NH, NR′, CH2, or CHR′;
- with the proviso for compound II that when X is NH2 or compound XII when X is NH and R is H, then R3 is not OH.
A method for the treatment or prophylaxis of Flaviviridae infection in a host, comprising an effective amount of a β-D compound of structure:
- 325
- or its pharmaceutically acceptable salt or prodrug thereof .
A method for the treatment or prophylaxis of abnormal cellular proliferation in a patient, comprising an effective amount of a β-D compound of structure:
- 326
- or its pharmaceutically acceptable salt or prodrug thereof.
The method of treatment or prophylaxis of Flaviviridae infection is a host, comprising administering an effective amount of the compound of the formula:
- 327 328 329 330 331
- or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- (a) R is H, halogen (F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH═CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH═CHCl, CH═CHBr and CH═CHI, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, CH═CHCO2R′;
- (b) X and Y are independently H, halogen, OH, OR′, OCH3, SH, SR′, SCH3, NH2, NHR′, NR′2, CH3;
- (c) each R′ is independently a hydrogen, acyl, lower alkyl of C1-C6 or lower cycloalkyl of C1-C6;
- (d) Z is O, S or CH2;
- (e) R2is F or OH;
- (f) R3 is F or OH;
- (g) X′ is O, S, NH, NR′, CH2, or CHR′;
- with the proviso for compound II that when X is NH2 or compound XII when X is NH and R is H, then R3 is not OH, in combination or alternation with other anti-viral agents.
The method of treatment or prophylaxis of abnormal cellular proliferation in a patient, comprising administering an effective amount of the compound of the formula:
- 332 333 334 335 336
- or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- (a) R is H, halogen (F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH═CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH═CHCl, CH═CHBr and CH═CHI, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, CH═CHCO2R′;
- (b) X and Y are independently H, halogen, OH, OR′, OCH3, SH, SR′, SCH3, NH2, NHR′, NR′2, CH3;
- (c) each R′ is independently a hydrogen, acyl, lower alkyl of C1-C6 or lower cycloalkyl of C1-C6;
- (d) Z is O, S or CH2;
- (e) R2 is F or OH;
- (f) R3 is F or OH;
- (g) X′ is O, S, NH, NR′, CH2, or CHR′;
- with the proviso for compound II that when X is NH2 or compound XII when X is NH and R is H, then R3 is not OH, in combination or alternation with other agents for the treatment of abnormal cellular proliferation.
A method for the treatment or prophylaxis of Flaviviridae infection in a host, comprising an effective amount of a β-D compound of structure:
- 337
- or its pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with other anti-viral agents.
A method for the treatment or prophylaxis of abnormal cellular proliferation in a patient, comprising an effective amount of a β-D compound of structure:
- 338
- or its pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with other anti-abnormal cellular proliferation agents.
Dependencies are inferred from the claim text.