Methods of Treating hepatitis virus infections with N-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy
First Claim
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1. A method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal a first amount of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:
-
wherein;
R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C1 to C20, and W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and
a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof, wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds.
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Abstract
Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antivirals agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immunostimulating agents.
88 Citations
55 Claims
-
1. A method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal a first amount of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:
-
wherein;
R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C1 to C20, and W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and
a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof, wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)
R is a straight chain alkyl having a chain length of C1 to C20, W, X, Y, and Z are each hydrogen, and said antiviral compound is a nucleoside antiviral compound. -
18. The method of claim 1, wherein
R is a straight chain alkyl having a chain length of C1 to C20, W, x, Y, and Z are each butanoyl, and said antiviral compound is a nucleoside antiviral compound. -
19. The method of claim 1, wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of:
-
N-(n-hexyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(n-heptyl-)-l,5-dideoxy-1,5-imino-D-glucitol;
N-(n-octyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(n-octyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(n-dodecyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(5-methylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(3-propylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(1-pentylpentylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(1-butylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(7-methyloctyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(8-methylnonyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(9-methyldecyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(10-methylundecyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(6-cyclohexylhexyl-)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(4-cyclohexylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(2-cyclohexylethyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(2-cyclohexylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(1-phenylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(3-(4-methyl)-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(6-phenylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;
N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(n-dodecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(5-methylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(3-propylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(1-pentylpentylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(1-butylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(7-methyloctyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(8-methylnonyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(9-methyldecyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(10-methylundecyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(6-cyclohexylhexyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(4-cyclohexylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(2-cyclohexylethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(1-cyclohexylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(1-phenylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;
N-(3-(4-methyl)-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate; and
N-(6-phenylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and said nucleoside or nucleotide antiviral compound is selected from the group consisting of;
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;
(−
)-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC);
(−
)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine (FTC);
(−
)2′
,3′
, dideoxy-3′
-thiacytidine [(−
)-SddC];
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine triphosphate (FIACTP);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5-methyluarcil (FMAU);
1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide;
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-dexocytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-cytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-cytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-cytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluorothymidine (FddThd);
2′
,3′
-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′
,3′
-dideoxy-beta-L-5-thiacytidine;
2′
,3′
-dideoxy-beta-L-5-cytidine (beta-L-ddc);
2′
,3-deoxy-3′
-thia-5-fluorocytosine;
3′
-amino-5-methyl-dexocytidine (AddMeCyt);
3′
-azido-3′
-deoxythymidine (AZT);
3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
9-(2-phosphonyl-methoxyethyl)-2′
,6′
-diaminopurine-2′
,3′
-dideoxyriboside;
9-(2-phosphonylmethoxyethyl)adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′
-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5-(2-bromovinyl)-2′
-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
stavudine;
2-deoxy-3′
-thia-5-fluorocytidine;
2′
,3′
-dideoxy-guanine; and
2′
,3′
-dideoxy-guanosine.
-
-
20. The method of claim 1, wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol and N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and said nucleoside antiviral compound is (−
- )-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC).
- )-2′
-
21. The method of claim 20, wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol and said nucleoside antiviral compound is (−
- )-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC).
- )-2′
-
22. The method of claim 1, wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 0.1 mg/kg/day to about 100 mg/kg/day.
-
23. The method of claim 22, wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 1 mg/kg/day to about 75 mg/kg/day.
-
24. The method of claim 23, wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 5 mg/kg/day to about 50 mg/kg/day.
-
25. The method of claim 1, wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 0.1 mg/person/day to about 500 mg/person/day.
-
26. The method of claim 25, wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 10 mg/person/day to about 300 mg/person/day.
-
27. The method of claim 26, wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 25 mg/person/day to about 200 mg/person/day.
-
28. The method of claim 27, wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 50 mg/person/day to about 150 mg/person/day.
-
29. The method of claim 1, wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 1 mg/person/day to about 50 mg/person/day.
-
30. The method of claim 1, wherein said hepatitis virus infection is a hepatitis B virus infection.
-
-
31. A method of treating a hepatitis B virus infection in a mammal, comprising administering to said mammal from about 0.1 mg/kg/day to about 100 mg/kg/day of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I:
-
wherein;
R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C1 to C20, and W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and
from about 0.1 mg/person/day to about 500 mg/person/day of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral, and mixtures thereof. - View Dependent Claims (32, 33)
-
-
34. A method of treating a hepatitis B virus infection in a human patient, comprising administering to said human patient from about 0.1 mg/kg/day to about 100 mg/kg/day of N-(n-nonyl-)-1,5dideoxy-1,5-imino-D-glucitol and from about 0.1 mg/person/day to about 500 mg/person/day of (−
- )-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate.
- )-2′
-
35. A method of treating a hepatits virus infection in a mammal, comprising administering to said mammal a first amount of an N-substituted,-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:
-
wherein;
R is branched or straight chain alkyl having a chain length of C6 to C12; and
W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and
a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof;
wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds. - View Dependent Claims (36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48)
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3oxathiolan-5-yl]cytosine;
(-)-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC);
(-)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5- yl]cytosine (FTC);
(-)2′
,3′
, dideoxy-3′
-thiacytidine [(-)-SddC];
1-2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine (FIAC);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine triphosphate (FIACTP);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- methyluarcil (FMAU);
1-beta-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide;
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-dexocytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-cytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-cytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-cytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluorothymidine (FddThd);
2′
,3′
-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′
,3′
-dideoxy-beta-L-5-thiacytidine;
2′
,3′
-dideoxy-beta-L-5-cytidine (beta-L-ddC);
2′
-deoxy-3′
-thia-5-fluorocytosine;
3′
-amino-5-methyl-dexocytidine (AddMeCyt);
3′
-azido-3′
-deoxythymidine (AZT);
3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
9- (2-phosphonyl-methoxyethyl)-2′
,6′
-diaminopurine-2′
,3′
- dideoxyriboside;
9- (2-phosphonylmethoxyethyl) adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′
-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5- (2-bromovinyl)-2′
-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
stavudine;
2-deoxy-3′
-thia-5-fluorocytidine;
2′
,3′
-dideoxy-guanine; and
2′
,3′
-dideoxy-guanosine.
-
-
37. The method of claim 36 wherein said nucleoside antiviral compound is (-)-2′
- -deoxy-3′
-thiocytidine-5′
- triphosphate (3TC).
- -deoxy-3′
-
38. The method of claim 35 wherein W, X, Y, and Z are each alkanoyl;
- and wherein said nucleoside or nucleotide antiviral compound is selected from the group consisting of;
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5- yl]cytosine;
(-)-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC);
(-)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine (FTC);
(-)2′
,3′
, dideoxy-3′
-thiacytidine [(-)-SddC];
1-2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine (FIAC);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine triphosphate (FIACTP);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- methyluarcil (FMAU);
1-beta-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide;
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-dexocytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-cytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-cytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-cytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluorothymidine (FddThd);
2′
,3′
-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′
,3′
-dideoxy-beta-L-5-thiacytidine;
2′
,3′
-dideoxy-beta-L-5-cytidine (beta-L-ddC);
2′
-deoxy-3′
-thia-5-fluorocytosine;
3′
-amino-5methyl-dexocytidine (AddMeCyt);
3′
-azido-3′
-deoxythymidine (AZT);
3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
9- (2-phosphonyl-methoxyethyl)-2′
,6′
-diaminopurine-2′
,3′
- dideoxyriboside;
9- (2-phosphonylmethoxyethyl) adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′
-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5- (2-bromovinyl)-2′
-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
stavudine;
2-deoxy-3′
-thia-5-fluorocytidine;
2′
,3′
-dideoxy-guanine; and
2′
,3′
-dideoxy-guanosine.
- and wherein said nucleoside or nucleotide antiviral compound is selected from the group consisting of;
-
39. The method fo claim 38 wherein said nucleoside antiviral compound is (-)-2′
- -deoxy-3′
-thiocytidine-5′
- triphosphate (3TC).
- -deoxy-3′
-
40. The method of claim 39 wherein W, X, Y, and Z are each butanoyl.
-
41. The method of claim 35, wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 0.1 mg to about 100 mg/kg/day, and wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 0.1 mg/person/day to about 500 mg/person/day.
-
42. The method fo claim 35 wherein said hepatitis virus infection is a hepatitis B virus infection.
-
43. The method of claim 42 wherein W, X, Y, and Z are each alkanoyl;
- and wherein said nucleoside or nucleotide antiviral compound is selected from the group consisting of;
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;
(-)-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC);
(-)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5- yl]cytosine (FTC);
(-)2′
,3′
, dideoxy-3′
-thiacytidine [(-)-SddC];
1-2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine (FIAC);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine triphosphate (FIACTP);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- methyluarcil (FMAU);
1-beta-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide;
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-dexocytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-cytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-cytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-cytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluorothymidine (FddThd);
2′
,3′
-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′
,3′
-dideoxy-beta-L-5-thiacytidine;
2′
,3′
-dideoxy-beta-L-5-cytidine (beta-L-ddC);
2′
-deoxy-3′
-thia-5-fluorocytosine;
3′
-amino-5methyl-dexocytidine (AddMeCyt);
3′
-azido-3′
-deoxythymidine (AZT);
3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
9- (2-phosphonyl-methoxyethyl)-2′
,6′
-diaminopurine-2′
,3′
- dideoxyriboside;
9- (2-phosphonylmethoxyethyl) adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′
-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5- (2-bromovinyl)-2′
-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
stavudine;
2-deoxy-3′
-thia-5-fluorocytidine;
2′
,3′
-dideoxy-guanine; and
2′
,3′
-dideoxy-guanosine.
- and wherein said nucleoside or nucleotide antiviral compound is selected from the group consisting of;
-
44. The method of claim 43 wherein said nucleoside antiviral compound is (-)-2′
- -deoxy-3′
-thiocytidine-5′
- triphosphate (3TC).
- -deoxy-3′
-
45. The method of claim 42 wherein W, X, Y, and Z are each alkanoyl;
- and wherein said nucleoside or nucleotide antiviral compound is selected from the group consisting of;
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;
(-)-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC);
(-)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5- yl]cytosine (FTC);
(-)2′
,3′
, dideoxy-3′
-thiacytidine [(-)-SddC];
1-2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine (FIAC);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine triphosphate (FIACTP);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- methyluarcil (FMAU);
1-beta-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide;
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-dexocytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-cytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-cytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-cytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluorothymidine (FddThd);
2′
,3′
-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′
,3′
-dideoxy-beta-L-5-thiacytidine;
2′
,3′
-dideoxy-beta-L-5-cytidine (beta-L-ddC);
2′
-deoxy-3′
-thia-5-fluorocytosine;
3′
-amino-5methyl-dexocytidine (AddMeCyt);
3′
-azido-3′
-deoxythymidine (AZT);
3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
9- (2-phosphonyl-methoxyethyl)-2′
,6′
-diaminopurine-2′
,3′
- dideoxyriboside;
9- (2-phosphonylmethoxyethyl) adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′
-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5- (2-bromovinyl)-2′
-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
stavudine;
2-deoxy-3′
-thia-5-fluorocytidine;
2′
,3′
-dideoxy-guanine; and
2′
,3′
-dideoxy-guanosine.
- and wherein said nucleoside or nucleotide antiviral compound is selected from the group consisting of;
-
46. The method of claim 45 wherein said nucleoside antiviral compound is (-)-2′
- -deoxy-3′
-thiocytidine-5′
- triphosphate (3TC).
- -deoxy-3′
-
47. The method of claim 46 wherein W, X, Y, and Z are each butanoyl.
-
48. The method of claim 42, wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 0.1 mg to about 100 mg/kg/day, and wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 0.1 mg/person/day to about 500 mg/person/day.
-
49. A method of treating a hepatits virus infection in a mammal, comprising administering to said mammal a first amount of an N-substituted,-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:
-
wherein;
R is branched or straight chain alkyl having a chain length of C6 to C12; and
W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and
a second amound of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof;
wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds. - View Dependent Claims (50, 51, 52, 53, 54, 55)
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;
(-)-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC);
(-)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine (FTC);
(-)2′
,3′
, dideoxy-3′
-thiacytidine [(-)-SddC];
1-2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine (FIAC);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine triphosphate (FIACTP);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- methyluarcil (FMAU);
1-beta-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide;
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-dexocytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-cytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-cytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-cytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluorothymidine (FddThd);
2′
,3′
-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′
,3′
-dideoxy-beta-L-5-thiacytidine;
2′
,3′
-dideoxy-beta-L-5-cytidine (beta-L-ddC);
2′
-deoxy-3′
-thia-5-fluorocytosine;
3′
-amino-5methyl-dexocytidine (AddMeCyt);
3′
-azido-3′
-deoxythymidine (AZT);
3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
9- (2-phosphonyl-methoxyethyl)-2′
,6′
-diaminopurine-2′
,3′
- dideoxyriboside;
9- (2-phosphonylmethoxyethyl) adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′
-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5- (2-bromovinyl)-2′
-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
stavudine;
2-deoxy-3′
-thia-5-fluorocytidine;
2′
,3′
-dideoxy-guanine; and
2′
,3′
-dideoxy-guanosine.
-
-
51. The method of claim 50 wherein said nucleoside antiviral compound is (-)-2′
- -deoxy-3′
-thiocytidine-5′
- triphosphate (3TC).
- -deoxy-3′
-
52. The method of claim 49, wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 0.1 mg to about 100 mg/kg/day, and wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 0.1 mg/person/day to about 500 mg/person/day.
-
53. The method of claim 52 wherein said nucleoside or nucleotied antiviral compound is selected from the group consisting of:
-
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;
(-)-2′
-deoxy-3′
-thiocytidine-5′
-triphosphate (3TC);
(-)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine (FTC);
(-)2′
,3′
, dideoxy-3′
-thiacytidine [(-)-SddC];
1-2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine (FIAC);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- iodocytosine triphosphate (FIACTP);
1-(2′
-deoxy-2′
-fluoro-beta-D-arabinofuranosyl)-5- methyluarcil (FMAU);
1-beta-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide;
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-dexocytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluoro-5-methyl-cytidine (FddMeCyt);
2′
,3′
-dideoxy-3′
-chloro-5-methyl-cytidine (ClddMeCyt);
2′
,3′
-dideoxy-3′
-amino-5-methyl-cytidine (AddMeCyt);
2′
,3′
-dideoxy-3′
-fluorothymidine (FddThd);
2′
,3′
-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′
,3′
-dideoxy-beta-L-5-thiacytidine;
2′
,3′
-dideoxy-beta-L-5-cytidine (beta-L-ddC);
2′
-deoxy-3′
-thia-5-fluorocytosine;
3′
-amino-5-methyl-dexocytidine (AddMeCyt);
3′
-azido-3′
-deoxythymidine (AZT);
3′
-chloro-5-methyl-dexocytidine (ClddMeCyt);
9-(2-phosphonyl-methoxyethyl)-2′
,6′
-diaminopurine-2′
,3′
- dideoxyriboside;
9-(2-phosphonylmethoxyethyl) adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′
-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5-(2-bromovinyl)-2′
-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
stavudine;
2-deoxy-3′
-thia-5-fluorocytidine;
2′
,3′
-dideoxy-guanine; and
2′
,3′
-dideoxy-guanosine.
-
-
54. The method of claim 49 wherein said hepatitis virus infection is a hepatitis B virus infection.
-
55. The method of claim 54 wherein said mammal is a human.
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Current AssigneeUnither Virology, LLC. (United Therapeutics Corporation)
-
Original AssigneeGD Searle LLC (Pfizer Inc.)
-
InventorsBlock, Timothy M., Dwek, Raymond A., Jacob, Gary S.
-
Primary Examiner(s)LEWIS, PATRICK T
-
Application NumberUS09/355,446Time in Patent Office1,483 DaysField of Search514/42, 514/43, 514/45, 514/46, 514/47, 514/48, 514/49, 514/50, 514/51, 514/89, 514/277US Class Current514/45CPC Class CodesA61K 2300/00 Mixtures or combinations of...A61K 31/51 Thiamines, e.g. vitamin B1A61K 31/675 having nitrogen as a ring h...A61K 31/7052 having nitrogen as a ring h...
