JP-2026076266-A - Antiviral 1,3-dioxoindene compounds

Abstract

[Problem] To provide a compound of formula (I) described herein, a pharmaceutically acceptable salt, a pharmaceutical composition containing such a compound, and a method for using these compounds, salts, and compositions to treat viral infections. [Solution] The present invention relates to a novel 1,3-dioxoindene compound that is an inhibitor of picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, and is therefore useful for treating viral infections, including polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, common cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. [Selection Diagram] None

Inventors

• ヨハン ネイツ
• キム ヘ ソ
• リ チョン－キョ
• リ サン－ホ
• ダニエル プーン
• キース ブルース フィスター
• ジュン ヨン－シク
• ハン ソ ボン
• マルパニ ヤシュワルダン アール．
• チャクラサリ プラシャント
• キム チョンセン
• シン ジン ソ

Assignees

• ノバルティス アーゲー
• カトリーケ・ユニフェルシテイト・ルーヴァン
• コーリア リサーチ インスティテュート オブ ケミカル テクノロジー

Dates

Publication Date

20260511

Application Date

20260123

Priority Date

20200420

Claims (1)

1. A viral disease.

Description

This invention relates to novel 1,3-dioxoindene compounds that are inhibitors of picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, and are therefore useful for treating viral infections, including polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, common cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. This invention provides novel tetracyclic pyridone compounds disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions in the treatment and prevention of viral diseases. Picornaviruses are non-enveloped, positive-stranded single-stranded RNA viruses with RNA genomes ranging from 7.2 to 8.5 kb in length. These viruses are very small, spherical in shape, approximately 22–30 nm in size, and were first identified a long time ago. Viruses belonging to the Picornaviridae family include rhinoviruses, polioviruses, enteroviruses (including coxsackievirus A, coxsackievirus B, and echovirus), and hepatitis A virus. Diseases caused by picornaviruses are diverse, ranging from respiratory to digestive, circulatory, and skin diseases. Examples include polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, the common cold, herpangina, and foot-and-mouth disease. However, there are currently no cures for these diseases. Most drugs under development are descathing inhibitors. Viruses belonging to the Picornaviridae family cause a variety of diseases, including the aforementioned respiratory illnesses, which pose sanitary, social, and economic problems. Picornaviruses are the main causative agents of waterborne infectious diseases. Because they are highly stable and difficult to disinfect, RNA viruses continuously cause related diseases. Human rhinovirus (hRV) has recently been associated with a large proportion of asthma exacerbations and is known to be present even in the bronchial tissue of many stable asthma patients. Comparison of bronchial mucosal biopsy samples from asthma and non-asthma patients has shown that human rhinovirus is detected at a significantly higher frequency in the lower respiratory tract of asthma patients compared to non-asthma patients. A correlation between the presence of human rhinovirus and the clinical severity of asthma has also been reported. Furthermore, rhinoviruses cause chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, and asthma. Rhinovirus is a major cause of the common cold, but enterovirus-induced diseases include meningitis and respiratory infections. Extensive efforts to provide poliovirus vaccination have significantly reduced polio incidence worldwide, although cases are still reported in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A is now controllable to some extent thanks to vaccines for the hepatitis A virus. However, vaccines for coxsackievirus, echovirus, or rhinovirus have not yet been developed. In particular, Coxsackievirus B is a major cause of myocarditis, which in severe cases can develop into idiopathic dilated cardiomyopathy requiring a heart transplant. Enviroxime derivatives are considered the most promising candidates with broad anti-enteroviral and anti-rhinoviral activity. Enviroxime interferes with positive-strand RNA synthesis by binding to viral protein 3A, which is necessary for the formation of RNA intermediates in viral replication (Heinz B A and Vance L M: J Virol, 1995, 69(7), 4189-97). However, clinical studies have observed that the compounds have little to no therapeutic effect, accompanied by poor pharmacokinetics and undesirable side effects (Miller F D et al.: Antimicrob Agents Chemother, 1985, 27(1), 102-6). The protease inhibitor AG7088 was developed based on knowledge of the ultrastructure and function of viral protease 2C. In cell cultures within the nanomolar concentration range, AG7088 is effective against 48 rhinovirus types, as well as coxsackievirus A21, B3, enterovirus 70, and echovirus 11 (Pattick A K et al.: Antimicrobila Agents Chemother, 1999, 43(10), 2444-50). The elucidation of the molecular structure of viral capsids provided the prerequisites for the intentional design of capsid blockers, known as "WIN substances" (Diana G D: Curr Med Chem 2003, 2, 1-12). These substances inhibit the adsorption and/or detachment of rhinoviruses and enteroviruses. Some WIN substances exhibit highly specific effects only against individual genera or viral types of picornaviruses. Other derivatives inhibit the replication of both rhinoviruses and enteroviruses. For example, allildone, disoxalil, a