Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-04-18
2004-01-06
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S021800, C514S894000, C429S085000, C429S085000, C530S351000
Reexamination Certificate
active
06673775
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to ribavirin derivatives represented by formula I
wherein at least one of R
2
, R
3
or R
5
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.
Chronic infection with hepatitis C virus is an insidious and slow-progressing disease having a significant impact on the quality of life. It can eventually result in cirrhosis of the liver, decompensated liver disease and/or hepatocelluar carcinoma.
Combination treatment with interferon alfa-2b and ribavirin of patients with chronic hepatitis C is disclosed by Reichard et al.(The Lancet 1998; 351;83-87; and T. Poynard et al.(The Lancet 1998, Vol. 352, October 31, p 1426-1432). See also J. G. McHutchinson et al. (N. EngI. J. Med.,1998, 339:1485-1492); and G. L. Davis et al. (N. Engl. J. Med., 1998, 339:1493-1499). However, this combination therapy is not always effective due to side effects associated ribavirin such as ribavirin-related hemolysis, and anemia.
There is a definite need for more potent, safer ribavirin derivatives having fewer side effects for use as monotherapy or in combination with antiviral agents, e.g., interferon-alpha, to treat patients having suscept-ible viral infections, e.g., chronic hepatitis C infections, in a long-term, effective manner.
SUMMARY OF THE INVENTION
The present invention provides a compound represented by formula I
wherein at least one of R
2
, R
3
or R
5
is a straight or branched chain polyalkylene oxide polymer conjugate, and wherein at least one of the remaining of R
2
, R
3
or R
5
is H, R
6
—(W)
x
—CO—, R
6
—(W)
x
—CS—, R
6
—(W)
x
—C═NR
18
—, (HO)
2
PO—, R
6
—(W)
x
—PO(OH)— or HO—SO
2
— and wherein at least one of R
2
, R
3
or R
5
is not H;
wherein R
6
is H, alkyl, alkanoyl, aryl, heterocyclic, cycloalkyl, NR
7a
R
7b
, alkenyl, or alkynyl;
or R
6
is alkyl, alkanoyl, alkenyl or alkynyl substituted by halo, phenyl, cycloalkyl, NR
7a
R
7b
, hydroxy, or alkoxy;
or R
6
is aryl substituted by phenyl; halo, CN, NO
2
, OH, R
18
, CF
3
, SH, SR
7a
, SOR
7a
, SO
2
R
7a
; NR
7a
R
7b
, CO
2
H, CO
2
−
, OR
7a
, O
−
M
+
S
−
M
+
wherein M
+
is an alkali metal,
W is O, NR
18
or S;
R
7a
is H, alkyl, alkanoyl, or aryl; or R
7a
is alkyl, alkanoyl or aryl substituted by phenyl halo, CN, NO
2
, OH, CO
2
H, or alkoxy;
and R
7b
is H, alkyl or aryl or R
7b
is alkyl or aryl substituted by phenyl halo, CN, NO
2
, OH, CO
2
H, or alkoxy;
or R
7a
and R
7b
taken together with N and one of CHR
7a
, NR
7a
, O, S, SO or SO
2
form a five-, six- or seven-membered ring;
R
17
is H, OR
7a
, NR
7a
R
7b
, R
6
—(W)
x
—CO—, R
6
—(W)
x
—CS—, R
6
—(W)
x
—C═NR
18
—, (HO)
2
PO—, R
6
—(W)
x
—PO(OH)— or HO—SO
2
—;
R
18
is H, alkanoyl or alkyl;
and x=0 or 1;
or a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating patients having a susceptible viral infection, such as a chronic hepatitis C infection.
The present invention provides a method of treating patients having comprising administering a therapeutically effective amount of a ribavirin derivative of formula I and a therapeutically effective amount of interferon-alpha for a time period sufficient to eradicate detectable HCV-RNA at the end of said period of administering and to have no detectable HCV-RNA for at least 24 weeks after the end of said period of administrating, and wherein the ribavirin derivative is represented by formula I:
The present invention also provides a method of treating patients having chronic hepatitis C infection comprising administering a therapeutically effective amount of a ribavirin derivative of formula I and a therapeutically effective amount of interferon-alpha for a time period of at least 20 to 50 weeks to eradicate detectable HCV-RNA at the end of said 20 to 50 week period of administering and to have no detectable HCV-RNA for at least 24 weeks after the end of said period of administrating, and wherein the ribavirin derivative is represented by the formula I:
The present invention provides a compound represented by formula II
wherein at least one of R
2′
, R
3′
or R
5′
is a straight or branched chain polyalkylene oxide polymer conjugate, and wherein at least one of the remaining of R
2′
, R
3′
or R
5′
is a natural or unnatural &agr;-amino acid residue.
In a preferred embodiment, the natural or unnatural &agr;-amino acid residues for the compounds of formula II are represented by the formulas
Y═H, CH
3
; CH
3
CH
2
—; CH
3
CH
2
CH
2
—; Me
2
CH—; Me
2
CH
2
CH
2
—; CH
3
CH
2
CH(Me)—PhCH
2
—; HOOCCH
2
CH
2
—; HSCH
2
—; HOOCCH
2
—; MeSCH
2
CH
2
—; HOCH
2
—;
or Y is H
2
N(CH
2
)
4
— or CH
3
CH(OH)—; or a pharmaceutically acceptable salt thereof;
or Y taken together with the &agr; carbon and N form
or a phamaceutically acceptable salt thereof;
or Y taken together with the &agr; carbon and N form
or a phamaceutically acceptable salt thereof;
In another embodiment, the present invention relates to a method of treating patients having chronic hepatitis C infection comprising administering a therapeutically effective amount of a ribavirin derivative of formula II and a therapeutically effective amount of interferon-alpha for a time period sufficient to eradicate detectable HCV-RNA at the end of said period of administering and to have no detectable HCV-RNA for at least 24 weeks after the end of said period of administrating, and wherein the ribavirin derivative is represented by formula II
The present invention also provides a compound represented by formula III
wherein at least one of R
50
, R
52
, R
53
is a straight or branched chain polyalkylene oxide polymer conjugate,
and the remaining two of R
50
, R
52
, R
53
are independently H or a straight or branched chain polyalkylene oxide polymer conjugate,
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, R
52
and R
53
in the compounds of Formula III are each H.
The present invention further provides a compound represented by the formula IV
wherein R
50′
is a straight or branched chain polyalkylene oxide polymer conjugate, or a pharmaceutically acceptable salt thereof.
The present invention also provides pharmaceutical compositions for treating susceptible viral infections comprising a compound of formula IV and at least one pharmaceutically acceptable carrier.
The present invention also provides a method of treating a patient with a susceptible viral infection which comprises administering to said patient an effective amount of a compound of formula IV.
The present invention also provides a method of treating a patient infected with chronic hepatitis C which comprises administering to said patient an effective amount of a compound of formula IV in association with an effective amount of an interferon alfa for a time sufficient to eradicate detectable HCV-RNA levels.
DETAILED DESCRIPTION
The term “alkyl” as used herein means straight and branched carbon chains of one to twenty carbons, preferably one to six carbons and more preferably one to three carbons.
The term “alkenyl” as used herein means straight and branched chain alkyl groups containing at least one carbon-carbon double bond and two to twenty carbons, preferably two to eight carbons.
The term “alkynyl” as used herein means straight and branched chain alkyl groups containing at least one carbon-carbon triple bond and two to twenty carbons, and preferably two to six carbons containing at least one carbon-carbon triple bond.
The term “cycloalkyl” as used herein means carbocyclic rings of three to twelve carbons, preferably three to seven carbons and more preferably three to six carbons optionally substituted by one double bond.
The term “alkanoyl” as used herein means straight and branched chain alkanoyl groups of one to twenty carbons, preferably two to twelve, more prefer
Bennett Frank
Ganguly Ashit K.
Girijavallabhan Viyyoor M.
Lovey Raymond G.
McCormick Jinping
Hoffman Thomas D.
Lewis Patrick
Schering Corporation
Wilson James O.
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