Methods and compositions for treating hepatitis C virus

• US 20050137161A1
• Filed: 06/20/2003
• Published: 06/23/2005
• Est. Priority Date: 05/23/2000
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Jean-Pierre Sommadossi, Paulo Lacolla
• Inventors: Sommadossi, Jean-Pierre, LaColla, Paulo
• Granted Patent: US 7,157,441 B2
• Time in Patent Office: Days
• US Class Current: 514/45
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: G03C 1/0051 Tabular grain emulsions

Abstract

A method and composition for treating a host infected with hepatitis C comprising administering an effective hepatitis C treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Claims

1-88. -88. (canceled)

89. A method for the treatment of a hepatitis C virus infection in a host, comprising administering an anti-virally effective amount of a compound of Formula XVII:

130. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an anti-virally effective amount of a compound of Formula II:

131. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an anti-virally effective amount of a compound of Formula X or XI:

132. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, wherein, in the compound of Formula XVII:

R¹⁰ is H, alkyl, chlorine, bromine or iodine;

R⁷ and R⁹ are independently hydrogen, OR², alkyl, alkenyl, alkynyl, Br-vinyl,

O-alkenyl, chlorine, bromine, iodine, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂;

R⁶ is alkyl, chlorine, bromine or iodine;

alternatively, R⁷ and R⁹, or R⁸ and R⁹ can come together to form a bond; and

X is O, S, SO₂ or CH₂.

133. The method of claim 89 wherein R¹ is hydrogen or phosphate.

134. The method of claim 89 wherein R² is hydrogen, acyl or alkyl.

135. The method of claim 89 wherein R⁶ is alkyl.

136. The method of claim 89 wherein R⁷ and R⁹ are independently hydrogen, OR², or hydroxy.

137. The method of claim 89, wherein R⁷is hydroxy.

138. The method of claim 89 wherein R⁹ is hydroxy.

139. The method of claim 89 wherein R⁷ and R⁹ are hydroxy.

140. The method of claim 89 wherein R¹⁰ is hydrogen.

141. The method of claim 89 wherein X is O.

142. The method of claim 89 wherein

R¹ is hydrogen or phosphate;

R² is hydrogen, acyl or alkyl;

R⁶ is alkyl;

R⁷ and R⁹ are independently hydrogen, OR², or hydroxy;

R¹⁰ is hydrogen; and

X is O.

143. The method of claim 89, wherein the base is a purine selected from the group consisting of N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, N 2-alkylpurines, N²-alkyl-6-thiopurines, N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.

144. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

145. The method of claim 89 for the treatment of a hepatitis c virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

148. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

149. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

150. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

151. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

152. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

153. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

154. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

155. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

156. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:

157. The method of claim 89 for the treatment of a hepatitis C virus infection in a host, wherein the purine base is selected from the group consisting of

158. The method of claim 89, wherein the method comprises administering the compound or a pharmaceutically acceptable salt or ester thereof in combination or alternation with a second anti-hepatitis C virus agent.

159. The method of claim 158, wherein the second anti-hepatitis C virus agent is selected from the group consisting of consisting of interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, and a helicase inhibitor.

160. The method of claim 159, wherein the second anti-hepatitis C virus agent is interferon.

161. The method of claim 159, wherein the second anti-hepatitis C virus agent is a protease inhibitor.

162. The method of claim 159, wherein the second anti-hepatitis C virus agent is ribavirin.

163. The method of claim 89, wherein the compound is in the form of a dosage unit.

164. The method of claim 163, wherein the dosage unit contains 50 to 1000 mg of said compound.

165. The method of claim 163, wherein said dosage unit is a tablet or capsule.

166. The method of claim 89, wherein the host is a human.

167. The method of claim 89, wherein the compound is in substantially pure form.

168. The method of claim 89, wherein the compound is at least 90% by weight of the β

-D-isomer.

169. The method of claim 89, wherein the compound is at least 95% by weight of the β

-D-isomer.

90-129. -129. (canceled)

146. The method of claim 196, wherein R is methyl, ethyl, propyl, isopropyl, or cyclopropyl.

147. The method of claim 196, wherein R is butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, or neopentyl.