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Azole nucleosides and use as inhibitors of rna and DNA varial polymerases

A technology of RNA viruses and compounds, applied in the field of azole nucleosides and as RNA and DNA virus polymerase inhibitors, can solve the problems of no better drugs

Inactive Publication Date: 2009-08-19
SOUTHERN RES INST & IP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some drugs exist for HIV, few for HBV and no better drugs for HCV

Method used

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  • Azole nucleosides and use as inhibitors of rna and DNA varial polymerases
  • Azole nucleosides and use as inhibitors of rna and DNA varial polymerases
  • Azole nucleosides and use as inhibitors of rna and DNA varial polymerases

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preparation example Construction

[0065] The preparation of such prodrug derivatives is discussed in various literature sources (example: Alexander et al , Journal of Medicinal Chemistry (J.Med.Chem.) 1988, 31, 318; Aligas-Martin (Aligas-Martin) et al , PCTWO pp / 41531, p. 30). The nitrogen functionality converted during the preparation of these derivatives is the nitrogen atom(s) of the compounds of the invention.

[0066] Prodrug forms of the carboxyl-containing compounds of the present invention include esters (-CO 2 R), wherein the R group corresponds to any alcohol which is released in vivo at pharmaceutically acceptable levels by enzymatic or hydrolytic processes. Another prodrug obtained from the carboxylic acid form of the present invention may be Bodor et al , the quaternary salt structure described in Journal of Medicinal Chemistry (J.Med.Chem.) 1980,23,469:

[0067]

[0068] Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acce...

example 1

[0177]

[0178] 2', 3', 5'-tris-(O-tert-butyldimethylsilyl)-inosine (TBS-I): at room temperature, inosine (5.36 g, 20 mmol) was dissolved in anhydrous DMF (100 mL) ) in TBS-Cl (18.1 g, 120 mmol) and imidazole (10.9 g, 160 mmol) for 48 hours. After concentration in vacuo, the mixture was washed with CH 2 Cl 2 Diluted to 200 and with water (4 washes), saturated NH 4 100 mL each of Cl (3 washes) and saturated NaCl followed by recrystallization in EtOAc gave a white crystalline solid (10.9 g, 17.8 mmol, 90%). FTIR (PTFE sheet, cm -1 )1706; 1 H NMR (400MHz, CDCl 3 -d) δ 13.0 (1H, s), 8.31 (1H, s), 8.21 (1H, s), 5.98 (1H, d, J=4.8Hz), 4.46 (1H, m), 4.26 (1H, m) , 4.09 (1H, m), 3.96 (1H, m), 3.75 (1H, m), 0.92-0.77 (27H, multiple singlets), 0.11-0.20 (18H, multiple singlets); 13 C NMR (400MHz, CDCl 3 -d) delta 159.3, 148.8, 145.3, 138.8, 124.8, 88.2, 85.2, 76.4, 71.5, 62.2, TBS - not listed.

example 2

[0180]

[0181] N 1 -(3-Fluorophenyl)-2',3',5'-tris-(O-tert-butyldimethylsilyl)-inosine (TBS-IA-3): oven dried Schlenk TBS-I (2.4 g, 4.0 mmol), 3-fluorophenylboronic acid (1.1 g, 8.0 mmol), and anhydrous Cu(OAc) were added to a Schlenk tube 2 (800.0 mg, 4.4 mmol), pyridine-N-oxide (800 mg, 4.0 mmol), triturated to 4 of molecular sieves (about 1 g) and a stir bar. The tube was then sealed with a rubber septum and evacuated and flushed with oxygen. Then add anhydrous pyridine (647 μL, 8.0 mmol) and molecular sieve dry CH 2 Cl 2 (20 mL) and the reaction was vigorously stirred at room temperature for 24 hours. followed by saturated NH in MeOH 4 The reaction was quenched with OH (0.5 mL in 5 mL individually), then diluted to 500 mL with hexane. The organics were washed with 250 mL portions of each of the following: water, saturated NH 4 Cl, 1M NaCl and saturated NaCl. Use Na 2 SO 4 Dry and concentrate in vacuo. by using CH 2 Cl 2 All compounds were purified by med...

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Abstract

Azole nucleosides represented by the formulae (I) and (II); wherein A = C or N B = C or N X = H; C1-C6 alkyl, cycloalkyl, alkenyl, cycloalkenyl, alky nyl, aryl, heterocyclo, halogen such as F, C1, Br and I; OH, NH2, NH-(C1-C6 alkyl, cycloalkyl, aryl, or heterocyclo); Z = H; C1-C6 alkyl, cycloalkyl, al kenyl, cycloalkenyl, alkynyl, aryl, heterocyclo, halogen such as F, Cl, Br, I; OH, NH2, NH-(C1-C6 alkyl, cycloalkyl, aryl, or heterocyclo; E= (CH2)HONHR 1; n is an integer from 0-6 and more typically 0-3; R1= aryl or heterocyclo; each of W, Y, R is individually selected from the group consisting of H; C1 -C6 alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclo; ha logen such as F, Cl, Br, and I; O, OH, Oalkyl, Oaryl, NH2, NH-(C1-C6 alkyl, cycloalkyl, aryl, or heterocyclo); provided that at least one of W, Y, and R is other than H and wherein both W and Y together can be =O; and each D ind ividually is OH, Oalkyl, Oaryl, Fl and H;pharmaceutically acceptable salts t hereof, prodrugs thereof and mixtures thereof are provided. Compounds of thi s disclosure are useful as inhibitors of viral RNA and DNA polymerases such as, but not limited to, Influenza, Hantaan Virus, Crimean Congo hemorrhagic fever virus, hepatitis B, hepatitis C, Polio, Coxsackie A and B, Rhino, Echo , orthopoxvirus (small pox), HIV, Ebola, and West Nile virus polymerases; an especially orthopoxvirus, HIV, and hepatitis B.

Description

technical field [0001] The present invention relates to azoles and especially diazines (such as pyrazoles and imidazoles), triazines and purines, which are useful as, but not limited to, influenza virus, Hantavirus (HTNV), Crimean - Congo Haemorrhagic Fever Virus (CCHF), Rift Valley Fever virus (RVFV), Hepatitis B virus, Hepatitis C virus, Poliovirus, Coxsackie virus A and B, Rhinovirus, Echovirus, orthopoxvirus (smallpox), HIV, Ebola virus and West Nile virus polymerase and especially influenza viruses and viruses such as Hantavirus, Crimean-Congo haemorrhagic fever virus and Rift Valley fever virus Viral RNA and DNA polymerase inhibitors of Bunyaviridae family viruses. [0002] The present invention also relates to pharmaceutical compositions comprising the above compounds, and methods of using the compounds to inhibit viral RNA and DNA polymerases and to treat patients suffering from diseases caused by various RNA and DNA viruses and various cancers. [0003] The present ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04A61K31/70C07H5/04C07H5/06C07H19/044C07H19/056
CPCC07H5/04C07H19/044C07H5/06C07H19/056A61P31/12A61P31/14A61P31/16A61P43/00A61K31/7056
Inventor 杰弗里·B·阿特伯恩科琳·B·琼森威廉·B·帕克
Owner SOUTHERN RES INST & IP
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