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US 6,673,775 B2Granted
Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
AssigneeSchering Corporation
InventorsAshit K. Ganguly, Jinping McCormick, Raymond G. Lovey, Frank Bennett, Anil K. Saksena, Viyyoor M. Girijavallabhan
Life of this patent
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Abstract
Ribavirin derivatives represented by formula I wherein at least one of R2, R3 or R5 is a straight or branched chain polyalkylene oxide polymer conjugate, and pharmaceutical compositions containing them as well as their use to treat patients having susceptible viral infections, alone and in combination with a therapeutically effective amount of interferon-alpha are disclosed.
Claims38
A compound represented by formula I
- wherein at least one of R2, R3 or R5 is a straight or branched chain polyalkylene oxide polymer conjugate selected from the group consisting of R7a—OCH2CH2(OCH2CH2)q—(W)x—CO—, R7b(OCH2CH2)q—(OCH2)n—(W)x—CO—, R7a(OCH2CH2)q—O—(CH2)t—C(═NR18)—, R7a—O(CH2CH2O)q—CH2CH2—(W)x—CO—, R7a—O(CH2CH2O)q—CH2CH2—(W)x—C(═NR18)—, R7b(OCH2CH2)q—(OCH2)n—(W)x—CO—, R7bOOC—(CH2)m—[CR7a(OR7a)]n—(W)x—CO—, R7bOOC—(CH2)m—(OCHR7a)n—(W)x—CO—, R7a(OCH2CH2)q—CH2CH2—(W)x—CO—, or R7a(OCH2CH2)q—CH2CH2—(W)x—C(NR18) or is moiety selected from the group consisting of
- or a pharmaceutically acceptable salt thereof,
- and wherein at least one of the remaining of R2, R3 or R5 is H, R6—(W)x—CO—, R6—(W)x—CS—, R6—(W)x—C═NR18—, (HO)2PO—, R6—(W)x—PO(OH)— or HO—SO2— and wherein at least one of R2, R3 or R5 is not H;
- wherein R6 is H, alkyl, alkanoyl, aryl, heterocyclic, cycloalkyl, NR7aR7b, alkenyl, or alkynyl;
- or R6 is alkyl, alkanoyl, alkenyl or alkynyl substituted by halo, phenyl, cycloalkyl, NR7aR7b, hydroxy, or alkoxy;
- or R6 is aryl substituted by phenyl, halo, CN, NO2, OH, R18, CF3, SH, SR7a, SOR7a, SO2R7a;
- NR7aR7b, CO2H, CO2−, OR7a, O−M+ or S−M+ wherein M+ is an alkali metal,
- W is O, NR18 or S;
- R7a is H, alkyl, alkanoyl, or aryl;
- or R7a is alkyl, alkanoyl or aryl substituted by phenyl, halo, CN, NO2, OH, CO2H, or alkoxy;
- and R7b is H, alkyl or aryl or R7b is alkyl or aryl substituted by phenyl, halo, CN, NO2, OH, CO2H, or alkoxy;
- or R7a and R7b taken together with N and one of CHR7a, NR7a, O, S, SO or SO2 form a five-, six- or seven-membered ring;
- R17 is H, OR7a, NR7aR7b, R6—(W)x—CO—, R6—(W)x—CS—, R6—(W)x—C═NR18—, (HO)2PO—, R6—(W)x—PO(OH)— or HO—SO2—;
- R18 is H, alkanoyl or alkyl;
- and m=0 to 100;
- n=0 to 6000;
- q=1 to 5000;
- t=1 to 4;
- j and k are independently 400 to 600;
- x=0 or 1;
- or a pharmaceutically acceptable salt thereof.
18 more elements
A compound represented by formula II
- wherein at least one of R2′, R3′ or R5′ is a straight or branched chain polyalkylene oxide polymer conjugate selected from the group consisting of R7a—OCH2CH2(OCH2CH2)q—(W)x—CO—, R7b(OCH2CH2)q—(OCH2)n—(W)x—CO—, R7a(OCH2CH2)q—O—(CH2)t—C(═NR18)—, R7a—O(CH2CH2O)q—CH2CH2—(W)x—CO—, R7a—O(CH2CH2O)q—CH2CH2—(W)x—C(═NR18)—, R7b(OCH2CH2)q—(OCH2)n—(W)x—CO—, R7bOOC—(CH2)m—[CR7a(OR7a)]n—(W)x—CO—, R7bOOC—(CH2)m—(OCHR7a)n—(W)x—CO—, R7a(OCH2CH2)q—CH2CH2—(W)x—CO—, or R7a(OCH2CH2)q—CH2CH2—(W)x—C(NR18) or is moiety selected from the group consisting of
- or a pharmaceutically acceptable salt thereof,
- and wherein at least one of the remaining of R2′, R3′ or R5′ is a natural or unnatural α-amino acid residue.
A compound represented by formula III
- wherein at least one of R50, R52, R53 is a straight or branched chain polyalkylene oxide polymer conjugate selected from the group consisting of R7a—OCH2CH2(OCH2CH2)q—(W)x—CO—, R7b(OCH2CH2)q—(OCH2)n—(W)x—CO—, R7a—(OCH2CH2)q—O—(CH2)t—C(═NR18)—, R7a—O(CH2CH2O)q—CH2CH2—(W)x—CO—, R7a—O(CH2CH2O)q—CH2CH2—(W)x—C(═NR18)—, R7b(OCH2CH2)q—(OCH2)n(W)x—CO—, R7bOOC—(CH2)m—[CR7a(OR7a)]n(W)x—CO—, R7bOOC—(CH2)m(OCHR7a(n—(W)x—CO—, R7a(OCH2CH2)q—CH2CH2—(W)xCO—, or R7a(OCH2CH2)q—CH2CH2—(W)x—C(NR18) or is moiety selected from the group consisting of
- pharmaceutically acceptable salt thereof;
- wherein W is O, NR18 or S;
- R7ais H, alkyl, alkanoyl, or aryl;
- or R7a is alkyl, alkanoyl or aryl substituted by phenyl, halo, CN, NO2, OH, CO2H or alkoxy;
- and R7b is H, alkyl or aryl or R7b is alkyl or aryl or aryl substituted by phenyl, halo, CN, NO2, OH, CO2H, or alkoxy;
- or R7a and R7b taken together with N and one of CHR7a, NR7a, O, S, SO or SO2 form a five-, six- or seven-membered ring;
- R18 is H, alkanoyl or alkyl;
- and x=0 or 1;
- m=0 to 100;
- n=0 to 6000;
- q=1 to 5000;
- t=1 to 4;
- and j and k are independently 400 to 600
- and the remaining two of R50, R52, R53 are independently H or a straight or branched chain polyalkylene oxide polymer conjugate;
- or a pharmaceutically acceptable salt thereof.
13 more elements
A compound represented by the formula IV
- wherein R50′ is a straight or branched chain polyalkylene oxide polymer conjugate selected from the group consisting of R7a—OCH2CH2(OCH2CH2)q—(W)x—CO—, R7b(OCH2CH2)q—(OCH2)n—(W)x—CO, R7a(OCH2CH2)q—O—(CH2)t—C(═NR18)—, R7a—O(CH2CH2O)q—CH2CH2(W)x—CO—, R7a—O(CH2CH2O)q—CH2CH2—(W)x—C(═NR18)—, R7b(OCH2CH2)q—(OCH2)n—(W)x—CO—, R7bOOC—(CH2)m—[CR7a(OR7a)]n—(W)x—CO—, R7bOOC—(CH2)m—(OCHR7a)n—(W)x—CO—, R7a(OCH2CH2)q—CH2CH2—(W)x—CO—, or R7a(OCH2CH2)q—CH2CH2—(W)x—C(NR18) or is moiety selected from the group consisting of
- or a pharmaceutically acceptable salt thereof;
- wherein W is O, NR18 or S;
- R7a is H, alkyl, alkanoyl, or aryl;
- or R7a is alkyl, alkanoyl or aryl substituted by phenyl, halo, ON, NO2, OH, CO2H or alkoxy;
- and R7b is H, alkyl or aryl or R7b is alkyl or aryl or aryl substituted by phenyl, halo, ON, NO2, OH, CO2H, or alkoxy;
- or R7a and R7b taken together with N and one of CHR7a, NR7a, O, S, SO or SO2 form a five-, six- or seven-membered ring;
- R18 is H, alkanoyl or alkyl;
- and x=0 or 1;
- m=0 to 100;
- n=0 to 6000;
- q=1 to 5000;
- t=1 to 4;
- and j and k are independently 400 to 600;
- or a pharmaceutically acceptable salt thereof.
12 more elements
Dependencies are inferred from the claim text.