Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-10-14
2002-06-11
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S383000, C514S894000, C530S351000, C424S085400, C424S085700, C548S266800
Reexamination Certificate
active
06403564
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods of treating patients having chronic hepatitis C infection by administering a therapeutically effective amount of a ribavirin derivative 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, as well as the ribavirin derivatives represented by formula I
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. Engl. 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 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 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:
wherein at least one of R
2
, R
3
or R
5
is H, R
6
—(W)
x
—CS—, R
6
—(W)
x
—CS—(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, cycloalkyl, heterocylic, aryl, NR
7a
R
7b
, alkenyl, or alkynyl; or is alkyl, alkanoyl, alkenyl or alkynyl substituted by halo, phenyl, cycloalkyl, NR
7a
R
7b
, hydroxy or alkoxy;
or 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
−
M
+−
, O
−
M
+
OR
7a
or S
−
M
+
;
wherein M
+
is an alkali metal cation;
or R
6
is —(CHR
7a
)
e
—(CH
2
)
1
—CO—OR
7b
, —(CHR
7a
)
e
—(CH
2
)
f
—OR
7b
, or —(CHR
7a
)
e
—(CH
2
)
f
—NR
7a
R
7b
W is O, NR
18
or S;
R
7a
is H, alkyl, alkanoyl, aryl or is alkyl, alkanoyl or aryl substituted by halo phenyl CN, NO
2
, OH, CO
2
H or alkoxy; and R
7b
is H, alkyl or aryl or is alkyl or aryl substituted by halo, CN, NO
2
, CO
2
H, OH 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—, (HO)
2
PO—, R
6
—(W)
x
—PO(OH)—, or HO—SO
2
—;
R
18
is H, alkanoyl, aryl or alkyl;
e=0 to 6, f=0 to 10, and x=0 or 1;
or a pharmaceutically acceptable salt thereof.
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:
wherein at least one of R
2
, R
3
or R
5
is H, R
6
—(W)
x
—CO—, R
6
—(W)
x
—CS—(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, cycloalkyl, aryl, heterocyclic, NR
7a
R
7b
, alkenyl, or alkynyl; or is alkyl, alkanoyl, alkenyl or alkynyl substituted by halo, phenyl, cycloalkyl, NR
7a
R
7b
, hydroxy, alkoxy;
or 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
+
or S
−
M
+
;
wherein M
+
is an alkali metal cation;
or R
6
is —(CHR
7a
)
e
—(CH
2
)
f
—CO—OR
7b
, —(CHR
7a
)
e
—(CH
2
)
f
—OR
7b
, or —(CHR
7a
)
e
—(CH
2
)
f
—NR
7a
R
7b
W is O, NR
18
or S;
R
7a
is H, alkyl, alkanoyl, or aryl is alky, alkanoyll or aryl substituted by halo, CN, NO
2
, OH, CO
2
H or alkoxy;
and R
7b
is H, alkyl or aryl or is alkyl or aryl substituted by 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—, (HO)
2
PO—, R
6
—(W)
x
—PO(OH)— or HO—SO
2
—;
R
18
is H, alkanoyl, aryl or alkyl;
e=0 to 6, f=0 to 10, and x=0 or 1;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to a compound represented by formula II
wherein at least one of R
2′
, R
3′
or R
5′
is H, R
20
—(W)
x
—CO—, R
20
—(W)
x
—CS— or R
20
—(W)
x
—PO(OH)—; and wherein at least one of R
2
, R
3
or R
5
is not H;
wherein R
20
is H, alkyl, alkanoyl, cycloalkyl, aryl, heterocyclic, NR
21
R
22
, alkenyl, or alkynyl; or is alkyl, alkanoyl alkenyl or alkynyl substituted by halogen, phenyl, cycloalkyl, NR
21
R
22
, hydroxy, alkoxy;
or is aryl substituted by halogen, phenyl, CN, NO
2
, OH, R
28
, CF
3
, SH, SR
21
SOR
21
, SO
2
R
21
; NR
21
R
22
, CO
2
−
, OR
21
, O
−
M
+
or S
−
M
+
;
wherein M
+
is an alkali metal cation;
or R
20
is —(CHR
21
)
e
—(CH
2
)
f
—CO—OR
22
, —(CHR
21
)
e
—(CH
2
)
f
—OR
22
, or —(CHR
21
)
e
—(CH
2
)
f
—NR
21
R
22
W is O, NR
28
or S;
R
21
is H, alkyl, alkanoyl, or aryl, or is alkyl, alkanoyl or aryl substituted by halo, phenyl, CN, NO
2
OH, CO
2
H or alkoxy; and R
22
is H, alkyl or aryl or is alkyl or aryl substituted by halo, phenyl, CN, NO
2
, OH, CO
2
H or alkoxy;
or R
21
and R
22
taken together with N and one of CHR
21
, NR
21
, O, S, SO or SO
2
form a five-, six- or seven- membered ring;
R
27
is H, OR
21
, NR
21
R
22
, R
20
—(W)
x
—CO—, R
20
—(W)
x
—CS—, (OH)
2
PO—, R
20
—(W)
x
—PO(OH)— or HO—SO
2
—;
R
28
is H, alkanoyl or alkyl;
e=0 to 6, f=0 to 10; and x=0 or 1;
or a pharmaceutically 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
wherein at least one of R
2′
, R
3′
or R
5′
is H, R
20
—(W)
x
—CO—, R
20
—(W)
x
—CS— or R
20
—(W)
x
—PO(OH)—; and wherein at least one of R
2
, R
3
or R
5
is not H;
wherein R
20
is H, alkyl, alkanoyl, cycloalkyl, aryl, heterocyclic, NR
21
R
22
, alkenyl, or alkynyl;
or is alkyl, alkanoyl alkenyl or alkynyl substituted by halo, phenyl, cycloalkyl, NR
21
R
22
, hydroxy, alkoxy;
or is aryl substituted by phenyl, halo, CN, NO
2
, OH, R
28
, CF
3
, SH, SR
212
, SOR
21
, SO
2
R2
1
; NR
21
R
22
CO
2
H, CO
2
−
—, OR
21
, O
−
Bennett Frank
Ganguly Ashit K.
Girijavallabhan Viyyoor M.
Lovey Raymond G.
McCormick Jinping
Hoffman Thomas D.
Low Christopher S. F.
Mohamed Abdel A.
Schering Corporation
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