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Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor

a heterocyclic compound and tetracyclic technology, applied in heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of ineffective pharmaceutical agents, inability to eradicate the virus, and inability to effectively target the tumor by operation

Inactive Publication Date: 2007-03-01
JAPAN TOBACCO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Enucleation of tumor by operation does not help much, because the patient often develops recurrent hepatic cancer due to the sequela inflammation in non-cancerous parts.
However, interferon can eradicate the virus only in about one-third of the patient population.
Also, an attempt has been made to potentiate the immunocompetence of the patient with an interferon agonist, an interleukin-12 agonist and the like, thereby to eradicate the virus, but an effective pharmaceutical agent has not been found yet.
However, an effective HCV polymerase inhibitor has not been developed yet, like in other attempts to develop an anti-HCV drug based on other action mechanisms.
As the situation stands, no pharmaceutical agent can treat hepatitis C satisfactorily.

Method used

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  • Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
  • Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
  • Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0843]

wherein Q10 is, for example, O or NH, Rc1 is a leaving group such as bromine atom, iodine atom, —OTf (trifluoromethylsulfonyloxy group) and the like, —B(ORc2)(ORc3) is —B(OH)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group, ring A′ is ring A wherein G6 is carbon atom, and other symbols are as defined above.

[0844] Compound [2] can be obtained from commercially available compound [1] or compound [1] obtained by a conventional method and a boric acid ester.

[0845] As the boric acid ester, pinacolborane, bis(pinacolato)diboron and the like can be mentioned.

[0846] As a catalyst, palladium catalysts such as Pd(PPh3)4, Pd(dppb)Cl2, PdCl2(dppf)CH2Cl2, PdCl2(PPh3)2, Pd(OAc)2, PdCl2, palladium black, palladium carbon and the like can be mentioned.

[0847] As a base, strong bases such as ethylenediamine, sodium carbonate, barium hydroxide, potassium phosphate, cesium carbonate, sodium hydrogen carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, potassium acetat...

reference example 2

[0850]

wherein compound [4] is, for example, a compound wherein cycloalkyl group having 3 to 10 carbon atoms is substituted by oxo group, such as cyclopentanone, cyclohexanone and the like.

Step 1

[0851] Compound [5] can be obtained by reacting commercially available compound [3] or compound [3] obtained by a conventional method with compound [4] in the presence of a base, or under aldol reaction conditions.

[0852] As a base, preferably, sodium methoxide, sodium ethoxide, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be mentioned.

[0853] As a solvent, alcohol solvent such as methanol, ethanol and the like, THF, 1,4-dioxane, DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMA (dimethylacetamide), water and a mixed solvent thereof and the like can be mentioned.

[0854] As the reaction temperature, −20° C. to 120° C. is preferable.

[0855] In addition, for a reaction under acidic conditions, in a mixed solvent of acetic acid and pho...

reference example 3

[0857]

wherein Rc4 is carboxyl-protecting group such as methyl group, ethyl group, tert-butyl group, benzyl group and the like, Hal1 is halogen atom such as bromine atom, iodine atom and the like, and other symbols are as defined above.

Step 1

[0858] Compound [8] can be obtained by introducing a protecting group into a carboxyl group of compound [7] obtained by a conventional method or in the same manner as in Reference Example 2.

[0859] Where necessary, a protecting group may be introduced into a nitrogen atom of indole.

Step 2

[0860] Compound [9] can be obtained by halogenating compound [8] with a halogenating agent.

[0861] As the halogenating agent, bromine, N-bromosuccinimide, pyridine tribromide, dibromohydantoin, pyridinium hydrobromide perbromide, an iodide thereof and the like can be mentioned.

[0862] As a solvent, halogen solvents (dichloromethane, chloroform, carbon tetrachloride etc.), hydrocarbon solvents (toluene etc.), ether solvents (1,4-dioxane, DME (1,2-dimethoxye...

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PUM

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Abstract

The present invention relates to a tetracyclic fused heterocyclic compound represented by the following formula [I]wherein each symbol is as defined in the specification, or a pharmaceutically acceptable a salt thereof, and a hepatitis C virus (HCV) polymerase inhibitor and a therapeutic agent for hepatitis C containing this compound. The compound of the present invention shows an anti-HCV activity based on the HCV polymerase inhibitory activity, and useful as an agent for the prophylaxis or treatment of hepatitis C.

Description

TECHNICAL FIELD [0001] The present invention relates to a tetracyclic fused heterocyclic compound or a pharmaceutically acceptable salt thereof, which shows anti-hepatitis C virus (HCV) activity, particularly anti-HCV activity based on an RNA-dependent RNA polymerase inhibitory activity. In addition, the present invention relates to a hepatitis C virus polymerase inhibitor, an anti-hepatitis C virus agent and a therapeutic agent for hepatitis C containing said tetracyclic fused heterocyclic compound or a pharmaceutically acceptable salt thereof. BACKGROUND ART [0002] In 1989, a main causative virus of non-A non-B posttransfusion hepatitis was found and named hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been found besides type A, type B and type C, wherein hepatitis caused by HCV is called hepatitis C. [0003] The patients infected with HCV are considered to involve several percent of the world population, and the infection with HCV characteristically b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/02A61K31/53A61K31/519A61K31/498A61K31/503A61K31/4745
CPCA61P1/16A61P31/14C07D487/04C07D487/14C07D498/04C07D498/14C07D513/04
Inventor OKA, TAKAHIROIKEGASHIRA, KAZUTAKAHIRASHIMA, SHINTAROYAMANAKA, HIROSHINOJI, SATORUNIWA, YASUSHIMATSUMOTO, YOKOSATO, TOSHIHIROANDO, IZURUNOMURA, YUKIHIRO
Owner JAPAN TOBACCO INC
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