4'-substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity

A compound and solvate technology, applied in the field of 4'-substituted nucleoside derivatives, can solve problems such as occurrence

Inactive Publication Date: 2007-01-31
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, another concern with this class of compounds is that patients undergoing treatment with nucleosides have developed resistant strains of HIV

Method used

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  • 4'-substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity
  • 4'-substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity
  • 4'-substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0186] Embodiment 1. Preparation of typical compounds of the present invention

[0187]

[0188] Intermediate epoxides 1.11 can be prepared as follows. Selective iodination of carbovir at the 5′-position using triphenylphosphine, iodine and pyridine or imidazole in dioxane (Maag, H. et al., J. Med. Chem., 1992, 35, 1440) 1.8 (Crimmins, M.T. et al., J.Org.Chem., 1996, 61, 4192) yielded compound 1.9. The dehydrohalogenation of 5'-halogenated nucleosides has been well described (Ueda, T.In Chemistry of Nucleosides and Nucleotides; Townsend, L.B., Ed.; Plenum Press; New York, 1988; 83). The product 1.10 was prepared using sodium methoxide. Non-stereoselective epoxidation of exocyclic olefins using m-chloroperbenzoic acid or Corey's reagent (dimethylmethylene sulfoxide) (Gololobov, Y.G. et al., Tetrahedron, 1997, 43, 12, 2609), A mixture of two diastereomeric epoxides 1.11 was obtained.

[0189] Compound 1, a typical compound of the present invention, can be prepared from ep...

Embodiment 2

[0194] Embodiment 2. Preparation of typical compounds of the present invention

[0195]

[0196] Abacavir 2.8 can be prepared from compound 1.7 as described by Crimmins, M.T. et al., J. Org Chem., 1996, 61, 4192. Selective iodination at the 5'-position using triphenylphosphine, iodine, and pyridine or imidazole in dioxane (Maag, H. et al., J. Med. Chem., 1992, 35, 1440) yields Compound 2.9. The dehydrohalogenation of 5'-halogenated nucleosides has been well described (Ueda, T. In Chemistry of Nucleosides and Nucleotides; Townsend, L.B., Ed.; Plenum Press; New York, 1988; 83). Compound 2.10 was prepared using sodium methoxide. Epoxidation of the exocyclic olefin of 2.10 produced a mixture of two diastereomers without stereoselection. Such reactions can be accomplished using m-chloroperbenzoic acid or Corey's reagent (dimethylmethylene sulfoxide) (Gololobov, Y.G. et al., Tetrahedron, 1997, 43, 12, 2609). As reported by Krause, N. et al., Chem. Ber., 1988, 121, 7, 1315, onl...

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Abstract

The application relates to compounds with activity against infectious viruses. Accordingly, in one embodiment the invention provides a compound of the invention which is a compound of Formula I: (I) wherein: B is adenine, guanine cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropuriine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosines, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil O<6> -methylguanine, N<6> -methyladenine, O<4>-methylthymine, 5,6-dihydrothymine, 5,6-dihydroucacil, 4-methylindole, triazole, or pyrazolo[3,4-d]pyrimidine; and B is optionally substituted with one or more alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy, or halo; and R<1> is alkyl, alkenyl, alkynyl, cyano, azido, or fluoromethyl; or a pharmaceutically acceptable salt or solvate thereof.

Description

[0001] priority of invention [0002] This application claims the benefit of priority to US Provisional Patent Application Serial No. 60 / 532,256, filed December 22, 2003, under 35 U.S.C. §119(e). This provisional application is incorporated herein by reference in its entirety. field of invention [0003] The present invention generally relates to 4'-substituted nucleoside derivatives having antiviral activity. Background of the invention [0004] Carbovir (EP 00,434,450 and EP 00,349,242) together with abacavir are well known anti-HIV carbocyclic nucleosides. Abacavir is the most potent nucleoside reverse transcriptase inhibitor (NRTI) developed to date. A mean reduction in viral load of more than 1.4 log10 RNA copies / ml was observed after short-term abacavir monotherapy. [0005] [0006] Kapoway Abacavir [0007] The use of dideoxynucleotides such as dideoxycytidine (ddC) and didehydrodide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/16C07D473/18A61K31/52A61K31/404A61K31/4164A61K31/4196A61K31/513A61K31/519A61K31/522
CPCC07D473/16C07D473/18C07H19/16C07H19/06A61P31/14A61P31/18A61P43/00
Inventor M·法迪斯C·U·金
Owner GILEAD SCI INC
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