JP2013512887A - Infectious disease treatment - Google Patents

Abstract

The present invention relates to the treatment or prevention of infectious disorders and tonaversat or an analogue of formula (1) and to a composition comprising tonaversat or an analogue of formula (1) used in said treatment.

Description

  The present invention relates to tonaversat and analogs thereof and compositions comprising tonaversat or analogs thereof for use in the treatment of infectious disorders, more particularly symptoms associated with or resulting from infections or infections with infectious agents About.

  WO 95/34545 is a member of a class of drugs called neuronal gap junction blockers, and currently studies on a range of symptoms, including migraine, epilepsy, depression and other neurological symptoms Also known as cis-6-acetyl-4- (S)-(3-chloro-4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3- ( A series of specifically named compounds have been disclosed, such as tonaversat known as S) -ol.

式中、ＹはＣ−Ｒ_１であり；
Ｒ_１はアセチルであり；
Ｒ_２は、水素、Ｃ_３−８シクロアルキル、任意選択により酸素がその間に挟まれている、またはヒドロキシで置換されているＣ_１−６アルキル、Ｃ_１−６アルコキシまたは置換アミノカルボニル、Ｃ_１−６アルキルカルボニル、Ｃ_１−６アルコキシカルボニル、Ｃ_１−６アルキルカルボニルオキシ、Ｃ_１−６アルコキシ、ニトロ、シアノ、ハロ、トリフルオロメチル、またはＣＦ_３Ｓ；またはＣＦ_３−Ａ−基（Ａは、−ＣＦ_２−、−ＣＯ−、−ＣＨ_２−、ＣＨ（ＯＨ）、ＳＯ_２、ＳＯ、ＣＨ_２−Ｏ、またはＣＯＮＨである）；またはＣＦ_２Ｈ−Ａ’−基（Ａ’は、酸素、硫黄、ＳＯ、ＳＯ_２、ＣＦ_２またはＣＦＨである）；トリフルオロメトキシ、Ｃ_１−６アルキルスルフィニル、パーフルオロＣ_２−６アルキルスルホニル、Ｃ_１−６アルキルスルホニル、Ｃ_１−６アルコキシスルフィニル、Ｃ_１−６アルコキシスルホニル、アリール、ヘテロアリール、アリールカルボニル、ヘテロアリールカルボニル、ホスホノ、アリールカルボニルオキシ、ヘテロアリールカルボニルオキシ、アリールスルフィニル、ヘテロアリールスルフィニル、アリールスルホニル、またはヘテロアリールスルホニル（いずれかの芳香族部位が任意選択により置換されている）、Ｃ_１−６アルキルカルボニルアミノ、Ｃ_１−６アルコキシカルボニルアミノ、Ｃ_１−６アルキル−チオカルボニル、Ｃ_１−６アルコキシ−チオカルボニル、Ｃ_１−６アルキル−チオカルボニルオキシ、１−メルカプトＣ_２−７アルキル、ホルミル、またはアミノスルフィニル、アミノスルホニルまたはアミノカルボニル（いずれかのアミノ部位が、１または２個のＣ_１−６アルキル基で任意選択により置換されている）、またはＣ_１−６アルキルスルフィニルアミノ、Ｃ_１−６アルキルスルホニルアミノ、Ｃ_１−６アルコキシスルフィニルアミノまたはＣ_１−６アルコキシスルホニルアミノ、またはＣ_１−６アルキルカルボニル、ニトロまたはシアノ、または−Ｃ（Ｃ_１−６アルキル）ＮＯＨまたは−Ｃ（Ｃ_１−６アルキル）ＮＮＨ_２で末端が置換されているエチレニル；または１または２個のＣ_１−６アルキルによって、またはＣ_２−７アルカノイルによって任意選択により置換されているアミノであり；Ｒ_３およびＲ_４のうちの１つが水素またはＣ_１−４アルキルであり、もう１つがＣ_１−４アルキル、ＣＦ_３またはＣＨ_２Ｘ^ａであり、フルオロ、クロロ、ブロモ、ヨードであり、Ｃ_１−４アルコキシ、ヒドロキシ、Ｃ_１−４アルキルカルボニルオキシ、−Ｓ−Ｃ_１−４アルキル、ニトロ、１または２個のアルキル基で任意選択により置換されているアミノ、シアノまたはＣ_１−４アルコキシカルボニルであり；またはＲ_３およびＲ_４は共に、Ｃ_１−４アルキルで任意選択により置換されているＣ_２−５ポリメチレンであり；
Ｒ_５は、Ｃ_１−６アルキルカルボニルオキシ、ベンゾイルオキシ、ＯＮＯ_２、ベンジルオキシ、フェニルオキシまたはＣ_１−６アルコキシであり、
Ｒ_６およびＲ_９は水素であるか、またはＲ_５はヒドロキシであり、Ｒ_６は水素またはＣ_１−２アルキルであり、Ｒ_９は水素であり；
Ｒ_７は、ヘテロアリールまたはフェニルであり、その両方が、クロロ、フルオロ、ブロモ、ヨード、ニトロ、Ｃ_１−４アルキルによって１回または２回任意選択により置換されているアミノ、シアノ、アジド、Ｃ_１−４アルコキシ、トリフルオロメトキシおよびトリフルオロメチルから選択される基または原子で独立して１回または複数回任意選択により置換されており；
Ｒ_８は、水素、Ｃ_１−６アルキル、ＯＲ_１１またはＮＨＣＯＲ_１０であり、Ｒ_１１は、水素、Ｃ_１−６アルキル、ホルミル、Ｃ_１−６アルカノイル、アロイルまたはアリールＣ_１−６アルキルであり、Ｒ_１０は、水素、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、モノまたはジＣ_１−６アルキルアミノ、アミノ、アミノＣ_１−６アルキル、ヒドロキシ−Ｃ_１−６アルキル、ハロ−Ｃ_１−６アルキル、Ｃ_１−６アシルオキシ−Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニル−Ｃ_１−６−アルキル、アリールまたはヘテロアリールであり；Ｒ_８−Ｎ−ＣＯ−Ｒ_７基はＲ_５基に対してシス位にあり；Ｘは、酸素またはＮＲ_１２であり、Ｒ_１２は水素またはＣ_１−６アルキルである。 US Pat. No. 5,948,811 (incorporated herein by reference) is used for the prevention and treatment of diseases in the central and peripheral nervous system such as migraine, psychosis, epilepsy and other neurological symptoms. A class of compounds ("analogues of formula I") that can be described is described.

Where Y is C—R ₁ ;
R ₁ is acetyl;
R ₂ is hydrogen, C _3-8 cycloalkyl, C _1-6 alkyl optionally substituted with oxygen or substituted with hydroxy, C _1-6 alkoxy or substituted aminocarbonyl, C _{1 -6} alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF ₃ S; or CF ₃ -A- group (A _{is, -CF 2 -, - CO -} , - CH 2 -, CH (OH), SO 2, SO, CH 2 -O, or CONH); or _CF 2 H-A'- group (a 'is , oxygen, sulfur, _SO, is SO 2, CF ₂ or CFH); _{trifluoromethoxy, C 1-6} alkylsulfinyl, perfluoro _{C 2-6} alkylsulfonyl C _1-6 alkylsulfonyl, C _1-6 alkoxysulfinyl sulfinyl, C _1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroaryl arylsulfinyl , Arylsulfonyl, or heteroarylsulfonyl (wherein any aromatic moiety is optionally substituted), C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino, C _1-6 alkyl-thiocarbonyl, C _1-6 alkoxy-thiocarbonyl, C _1-6 alkyl-thiocarbonyloxy, 1-mercapto C _2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or amino Nocarbonyl (any amino moiety is optionally substituted with one or two C _1-6 alkyl groups), or C _1-6 alkylsulfinylamino, C _1-6 alkylsulfonylamino, C _{1 -6} alkoxysulfinylamino or C _1-6 alkoxysulfonylamino, or C _1-6 alkylcarbonyl, nitro or cyano, or -C (C _1-6 alkyl) NOH or -C (C _1-6 alkyl) NNH ₂ Terminally substituted ethylenyl; or amino optionally substituted by 1 or 2 C _1-6 alkyl or by C _2-7 alkanoyl; one of R ₃ and R ₄ is hydrogen Or C _1-4 alkyl and the other is C _1-4 alkyl, CF ₃ or CH ₂ X ^a And is fluoro, chloro, bromo, iodo, optionally selected from C _1-4 alkoxy, hydroxy, C _1-4 alkylcarbonyloxy, —S—C _1-4 alkyl, nitro, 1 or 2 alkyl groups Amino, cyano or C _1-4 alkoxycarbonyl substituted by: or R ₃ and R ₄ are both C _2-5 polymethylene optionally substituted with C _1-4 alkyl;
R ₅ is C _1-6 alkylcarbonyloxy, benzoyloxy, ONO ₂ , benzyloxy, phenyloxy or C _1-6 alkoxy;
R ₆ and R ₉ are hydrogen, or R ₅ is hydroxy, R ₆ is hydrogen or C _1-2 alkyl, and R ₉ is hydrogen;
R ₇ is heteroaryl or phenyl, both of which are optionally substituted once or twice with chloro, fluoro, bromo, iodo, nitro, C _1-4 alkyl, amino, cyano, azide, C _Is optionally substituted one or more times independently with a group or atom selected from _1-4 alkoxy, trifluoromethoxy and trifluoromethyl;
R ₈ is hydrogen, C _1-6 alkyl, OR ₁₁ or NHCOR ₁₀ and R ₁₁ is hydrogen, C _1-6 alkyl, formyl, C _1-6 alkanoyl, aroyl or aryl C _1-6 alkyl , R ₁₀ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, mono or di C _1-6 alkylamino, amino, amino C _1-6 alkyl, hydroxy-C _1-6 alkyl, halo-C _{1 -6} alkyl, C _1-6 acyloxy-C _1-6 alkyl, C _1-6 alkoxycarbonyl-C _1-6 -alkyl, aryl or heteroaryl; the R ₈ —N—CO—R ₇ group is R ₅ In the cis position relative to the group; X is oxygen or NR ₁₂ and R ₁₂ is hydrogen or C _1-6 alkyl.

  Infectious diseases are clinically overt diseases resulting from the presence of pathogens such as pathogenic viruses, pathogenic bacteria, fungi, protozoa, multicellular parasites and abnormal proteins known as prions. Prions are infectious agents that transmit misfolded proteins. Prion-related diseases include Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) scrapie disorder, Gerstmann-Stroisler-Scheinker syndrome (GSS), lethal familial insomnia (sFI), and Koolou disease. Can be mentioned. Collectively, these diseases are known as infectious spongiform encephalopathy (TSE). Infectious disease is not synonymous with infection and may not cause significant clinical symptoms or impair host function. However, infections exhibit a diverse range of symptoms that depend on the particular infectious agent, resulting in a wide range of disorders that can occur directly or indirectly from the presence of the infectious agent or from damage caused by the infectious agent.

  In contrast to infectious diseases, infectious disorders are the presence of an infectious agent such as prion protein that can cause CJD or human immunodeficiency virus that can cause HIV neuralgia, or Streptococcus pneumoniae that can cause meningitis. From damage caused by an infectious agent such as varicella-zoster virus, which may be a disorder that arises directly from, or that occurs indirectly from a current or previous infection or infection, or that may develop postherpetic neuralgia This is a failure. Infectious disorders are often the result of an inflammatory response triggered by the presence of an infectious agent.

  There are many treatments available for infections such as antiviral, antibacterial and antifungal treatments. These therapies attack the infectious agent and in the end, and hopefully, eradicate or control the infection. However, there is a great need for safe, alternative and improved methods and compositions for treating infections.

（式中、ＹはＣ−Ｒ_１であり；
Ｒ_１はアセチルであり；
Ｒ_２は、水素、Ｃ_３−８シクロアルキル、任意選択により酸素がその間に挟まれている、またはヒドロキシで置換されているＣ_１−６アルキル、Ｃ_１−６アルコキシまたは置換アミノカルボニル、Ｃ_１−６アルキルカルボニル、Ｃ_１−６アルコキシカルボニル、Ｃ_１−６アルキルカルボニルオキシ、Ｃ_１−６アルコキシ、ニトロ、シアノ、ハロ、トリフルオロメチル、またはＣＦ_３Ｓ；またはＣＦ_３−Ａ−基（Ａは、−ＣＦ_２−、−ＣＯ−、−ＣＨ_２−、ＣＨ（ＯＨ）、ＳＯ_２、ＳＯ、ＣＨ_２−Ｏ、またはＣＯＮＨである）；またはＣＦ_２Ｈ−Ａ’−基（Ａ’は、酸素、硫黄、ＳＯ、ＳＯ_２、ＣＦ_２またはＣＦＨである）；トリフルオロメトキシ、Ｃ_１−６アルキルスルフィニル、パーフルオロＣ_２−６アルキルスルホニル、Ｃ_１−６アルキルスルホニル、Ｃ_１−６アルコキシスルフィニル、Ｃ_１−６アルコキシスルホニル、アリール、ヘテロアリール、アリールカルボニル、ヘテロアリールカルボニル、ホスホノ、アリールカルボニルオキシ、ヘテロアリールカルボニルオキシ、アリールスルフィニル、ヘテロアリールスルフィニル、アリールスルホニル、またはヘテロアリールスルホニル（いずれかの芳香族部位が任意選択により置換されている）、Ｃ_１−６アルキルカルボニルアミノ、Ｃ_１−６アルコキシカルボニルアミノ、Ｃ_１−６アルキル−チオカルボニル、Ｃ_１−６アルコキシ−チオカルボニル、Ｃ_１−６アルキル−チオカルボニルオキシ、１−メルカプトＣ_２−７アルキル、ホルミル、またはアミノスルフィニル、アミノスルホニルまたはアミノカルボニル（いずれかのアミノ部位が、１または２個のＣ_１−６アルキル基で任意選択により置換されている）、またはＣ_１−６アルキルスルフィニルアミノ、Ｃ_１−６アルキルスルホニルアミノ、Ｃ_１−６アルコキシスルフィニルアミノまたはＣ_１−６アルコキシスルホニルアミノ、またはＣ_１−６アルキルカルボニル、ニトロまたはシアノ、または−Ｃ（Ｃ_１−６アルキル）ＮＯＨまたは−Ｃ（Ｃ_１−６アルキル）ＮＮＨ_２で末端が置換されているエチレニル；または１または２個のＣ_１−６アルキルによって、またはＣ_２−７アルカノイルによって任意選択により置換されているアミノであり；Ｒ_３およびＲ_４のうちの１つが水素またはＣ_１−４アルキルであり、もう１つがＣ_１−４アルキル、ＣＦ_３またはＣＨ_２Ｘ^ａであり、フルオロ、クロロ、ブロモ、ヨードであり、Ｃ_１−４アルコキシ、ヒドロキシ、Ｃ_１−４アルキルカルボニルオキシ、−Ｓ−Ｃ_１−４アルキル、ニトロ、１または２個のアルキル基で任意選択により置換されているアミノ、シアノまたはＣ_１−４アルコキシカルボニルであり；またはＲ_３およびＲ_４は共に、Ｃ_１−４アルキルで任意選択により置換されているＣ_２−５ポリメチレンであり；
Ｒ_５は、Ｃ_１−６アルキルカルボニルオキシ、ベンゾイルオキシ、ＯＮＯ_２、ベンジルオキシ、フェニルオキシまたはＣ_１−６アルコキシであり、
Ｒ_６およびＲ_９は水素であるか、またはＲ_５はヒドロキシであり、Ｒ_６は水素またはＣ_１−２アルキルであり、Ｒ_９は水素であり；
Ｒ_７は、ヘテロアリールまたはフェニルであり、その両方が、クロロ、フルオロ、ブロモ、ヨード、ニトロ、Ｃ_１−４アルキルによって１回または２回任意選択により置換されているアミノ、シアノ、アジド、Ｃ_１−４アルコキシ、トリフルオロメトキシおよびトリフルオロメチルから選択される基または原子で独立して１回または複数回任意選択により置換されており；
Ｒ_８は、水素、Ｃ_１−６アルキル、ＯＲ_１１またはＮＨＣＯＲ_１０であり、Ｒ_１１は、水素、Ｃ_１−６アルキル、ホルミル、Ｃ_１−６アルカノイル、アロイルまたはアリールＣ_１−６アルキルであり、Ｒ_１０は、水素、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、モノまたはジＣ_１−６アルキルアミノ、アミノ、アミノＣ_１−６アルキル、ヒドロキシ−Ｃ_１−６アルキル、ハロ−Ｃ_１−６アルキル、Ｃ_１−６アシルオキシ−Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニル−Ｃ_１−６−アルキル、アリールまたはヘテロアリールであり；Ｒ_８−Ｎ−ＣＯ−Ｒ_７基はＲ_５基に対してシス位にあり；Ｘは、酸素またはＮＲ_１２であり、Ｒ_１２は水素またはＣ_１−６アルキルである）、または薬学的に許容されるその組成物を提供する。 In a first aspect, the invention relates to tonaversat, or an analogue of formula I, used in the treatment of an infection

Wherein Y is C—R ₁ ;
R ₁ is acetyl;
R ₂ is hydrogen, C _3-8 cycloalkyl, C _1-6 alkyl optionally substituted with oxygen or substituted with hydroxy, C _1-6 alkoxy or substituted aminocarbonyl, C _{1 -6} alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF ₃ S; or CF ₃ -A- group (A _{is, -CF 2 -, - CO -} , - CH 2 -, CH (OH), SO 2, SO, CH 2 -O, or CONH); or _CF 2 H-A'- group (a 'is , oxygen, sulfur, _SO, is SO 2, CF ₂ or CFH); _{trifluoromethoxy, C 1-6} alkylsulfinyl, perfluoro _{C 2-6} alkylsulfonyl C _1-6 alkylsulfonyl, C _1-6 alkoxysulfinyl sulfinyl, C _1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroaryl arylsulfinyl , Arylsulfonyl, or heteroarylsulfonyl (wherein any aromatic moiety is optionally substituted), C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino, C _1-6 alkyl-thiocarbonyl, C _1-6 alkoxy-thiocarbonyl, C _1-6 alkyl-thiocarbonyloxy, 1-mercapto C _2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or amino Nocarbonyl (any amino moiety is optionally substituted with one or two C _1-6 alkyl groups), or C _1-6 alkylsulfinylamino, C _1-6 alkylsulfonylamino, C _{1 -6} alkoxysulfinylamino or C _1-6 alkoxysulfonylamino, or C _1-6 alkylcarbonyl, nitro or cyano, or -C (C _1-6 alkyl) NOH or -C (C _1-6 alkyl) NNH ₂ Terminally substituted ethylenyl; or amino optionally substituted by 1 or 2 C _1-6 alkyl or by C _2-7 alkanoyl; one of R ₃ and R ₄ is hydrogen Or C _1-4 alkyl and the other is C _1-4 alkyl, CF ₃ or CH ₂ X ^a And is fluoro, chloro, bromo, iodo, optionally selected from C _1-4 alkoxy, hydroxy, C _1-4 alkylcarbonyloxy, —S—C _1-4 alkyl, nitro, 1 or 2 alkyl groups Amino, cyano or C _1-4 alkoxycarbonyl substituted by: or R ₃ and R ₄ are both C _2-5 polymethylene optionally substituted with C _1-4 alkyl;
R ₅ is C _1-6 alkylcarbonyloxy, benzoyloxy, ONO ₂ , benzyloxy, phenyloxy or C _1-6 alkoxy;
R ₆ and R ₉ are hydrogen, or R ₅ is hydroxy, R ₆ is hydrogen or C _1-2 alkyl, and R ₉ is hydrogen;
R ₇ is heteroaryl or phenyl, both of which are optionally substituted once or twice with chloro, fluoro, bromo, iodo, nitro, C _1-4 alkyl, amino, cyano, azide, C _Is optionally substituted one or more times independently with a group or atom selected from _1-4 alkoxy, trifluoromethoxy and trifluoromethyl;
R ₈ is hydrogen, C _1-6 alkyl, OR ₁₁ or NHCOR ₁₀ and R ₁₁ is hydrogen, C _1-6 alkyl, formyl, C _1-6 alkanoyl, aroyl or aryl C _1-6 alkyl , R ₁₀ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, mono or di C _1-6 alkylamino, amino, amino C _1-6 alkyl, hydroxy-C _1-6 alkyl, halo-C _{1 -6} alkyl, C _1-6 acyloxy-C _1-6 alkyl, C _1-6 alkoxycarbonyl-C _1-6 -alkyl, aryl or heteroaryl; the R ₈ —N—CO—R ₇ group is R ₅ There cis with respect to the base; X is oxygen or _{NR 12, R 12} is Hisage hydrogen or _{C 1-6} alkyl), or a pharmaceutically acceptable composition To.

  Preferred analogues of formula 1 are the compounds Caravelsat or (trans-(+)-6-acetyl-4- (S)-(4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H -1-Benzo [b] pyran-3Rol hemihydrate.

  For therapeutic administration according to the invention, tonaversat or an analogue of formula I is most preferably used in its free base form, but may also be used in the form of a pharmaceutically acceptable salt, preferably the hydrochloride salt. it can. Alternative salts with pharmaceutically acceptable acids for prophylactic and / or therapeutic administration, such as but not limited to hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, salicylic acid, citric acid Salts derived from acids such as oxalic acid, lactic acid, malic acid, methanesulfonic acid and p-toluenesulfonic acid can also be used.

  All references to tonaversat or analogs of formula I herein include all pharmaceutically acceptable salts thereof, and all solvates thereof.

  Polymorphs of tonaversat or analogs of formula I, solvates and radiolabeled derivatives and pharmaceutically acceptable compositions thereof are also included within the scope of the present invention. References to tonaversat or analogs of formula I include such polymorphs, solvates and radiolabeled derivatives.

  For prophylactic and / or therapeutic administration according to the present invention, tonaversat or an analogue of formula I may be administered in pure form, but preferably any suitable that brings the active ingredient to an effective level in the body. In a pharmaceutically acceptable and effective composition.

  Accordingly, the present invention provides a method for treating an infectious disorder, wherein a pharmaceutically effective amount of tonaversat or an analogue of formula I, or a pharmaceutically acceptable composition thereof is provided to a patient in need thereof. Methods of administration are provided.

  The invention also provides tonaversat, or an analogue of formula I, or a pharmaceutically acceptable composition thereof for use in the manufacture of a medicament for treating an infectious disorder.

Infectious disorders are:
i) A disease that arises directly from the presence of microbial pathogens such as viruses, bacteria, fungi, protozoa or prions. Such diseases include bacterial diseases such as meningitis from Streptococcus pneumoniae. Such diseases also include prion-related diseases such as CJD, BSE, scrapie disorder, Gerstman-Stroisler-Scheinker syndrome (GSS), lethal familial insomnia (sFI), and Kruo disease. Collectively, these diseases are known as infectious spongiform encephalopathy (TSE).
ii) refers to diseases present indirectly or indirectly from current or previous infections, such as chronic fatigue syndrome, peptic ulcers.
iii) one of herpes viruses such as varicella-zoster virus, herpes simplex, Epstein Barr virus and cytomegalovirus, which can cause postherpetic neuralgia, causing extensive damage to the nervous system and is called HIV neuralgia It refers to a disease resulting from damage caused by an infectious agent, such as HIV, which causes severe neuropathic pain. Diphtheria and leprosy are bacterial diseases characterized by a wide range of peripheral neuropathies, and Lyme disease can cause a wide range of neuropathies.

  All treatments can be acute or prophylactic treatment. For acute treatment, it is preferable to start treatment quickly, and therefore drugs that reach peak plasma concentrations shortly after administration will be most beneficial. Accordingly, compositions that provide rapid drug release and / or dissolution are preferred.

  Tonaversat or an analog of formula I may be administered alone, but generally one or more pharmaceutically acceptable selected for tonaversat or an analog of formula I and the intended route of administration Delivered in the form of a pharmaceutically acceptable composition comprising a diluent or carrier.

  Treatment with tonaversat or an analogue of formula I, or a pharmaceutically acceptable composition thereof, is a unit dose of 1-1000 mg, suitably 1-500 mg, eg active compound 2, 5, 10, 20, 30, It can be done in unit doses in amounts ranging from 2 to 400 mg, such as 40, 50, 80, 100, 200, 300 and 400 mg.

  The unit dose is usually in the range of 1 to 1000 mg, for example 1 to 500 mg for a 70 kg adult, usually about 0.01 to 15 mg / kg / day, more usually 0.1 to One or more times per day, such as 1, 2, 3, 4, 5 or 6 times per day, more generally to be in the range of 6 mg / kg / day, eg 1-6 mg / kg / day Is administered 1 to 4 times a day.

  Preferably, tonaversat or an analogue of formula I, or a pharmaceutically acceptable salt thereof, is about 0.01-15 mg / kg / day, more typically 0.1-6 mg / kg / day, such as 1 Administered to patients in a dose range of -6 mg / kg / day.

  Tonaversat or an analogue of formula I is a pharmaceutical composition, such as a composition for oral administration, including sublingual administration, intranasal administration, rectal administration, topical administration, parenteral (particularly intravenous) administration, eye drop or ear drop administration. Is preferably administered in the form of

  Those skilled in the art will readily understand pharmaceutical compositions suitable for delivery of tonaversat or analogs of formula I, and methods for their preparation. Such compositions and methods for their production are described, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

  Compositions suitable for oral administration include solid dosage forms such as tablets, capsules containing granules, solutions or powders, troches (including those filled with liquids), chewable tablets, multiparticulates and nanoparticles Examples include preparations, gels, solid solution preparations, liposome preparations, film preparations, ovule preparations, spray preparations and liquid preparations. Liquid dosage forms include suspensions, solutions, syrups and elixirs. Liquid dosage forms can also be prepared, for example, by reconstituting solids from small bags.

  Orally administrable compositions may take the form of oral solid compositions such as tablets, capsules, pastilles, pellets, pills, troches, powders and granules. The composition can be in the form of a solid that dissolves upon contact with the patient's tongue, for example in the form of a disintegrating tablet sold under the trade name ZYDIS®. Shaped oral compositions are preferred because they are more convenient for general use.

  Solid forms for oral administration are usually expressed in unit doses, adjuvants, binders, diluents, disintegrants, dispersants, excipients, fillers, tableting agents, lubricants, colorants, Contains conventional additives such as flavoring agents, drying agents, water retention agents, and wetting agents.

  Pills, pellets and tablets can be coated according to methods well known in the art. Oral solid dosage forms also include conventional sustained release dosage forms such as tablets or granules with enteric coatings.

  Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch derivatives such as starch, polyvinyl pyrrolidone and sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

  Solid oral compositions are prepared by mixing and can be produced by conventional methods such as blending, filling, tableting and the like. The blending operation can be repeated to use a large amount of filler to disperse the active agent throughout the composition. Of course, such operations are conventional in the art.

  The compositions can also take the form of oral fluid formulations including liquid formulations such as aqueous or oily blends, mixtures, suspensions, solutions, emulsions, syrups, tinctures and elixirs and gel formulations.

  The composition can also be present as a dilutable liquid concentrate or dry product, reconstitutable powder, diluted or reconstituted with water or other suitable excipients prior to use.

  Oral fluid formulations such as gels and liquid formulations include suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifiers such as lecithin, monooleic acid Sorbitan, or acacia; non-aqueous excipients (which may include edible oils) such as almond oil, coconut oil, oily esters such as glycerin, propylene glycol, or esters of ethyl alcohol: preservatives such as methyl or propyl p -Hydroxybenzoates or sorbic acid; and, if desired, conventional additives such as conventional flavoring or coloring agents.

  Oral compositions can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted and programmed release.

  Compositions suitable for parenteral administration include injectable and infusible aqueous or oily blends, mixtures, suspensions, solutions, emulsions and low viscosity gel formulations. A composition for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted and programmed release.

  The parenteral compositions used in the present invention can be prepared as long acting depot formulations. Such formulations can be administered by intramuscular injection. Thus, for example, the compositions of the present invention can be prepared with suitable polymers or hydrophobic materials (eg, as emulsions in pharmaceutically acceptable oils) or ion exchange resins, or as slightly soluble derivatives, eg, slightly soluble. It can be formulated as a salt.

  Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents are also dissolved, emulsified or suspended in the vehicle.

  Such compositions are prepared by mixing the compound with a solvent or excipient. Depending on the excipient and concentration, the compound is emulsified, suspended or dissolved. Parenteral compositions are usually prepared with the compound and a sterile excipient and / or filled in a suitable vial or ampoule and the composition is sterilized before sealing.

  To enhance stability, the composition can also exist as a dry product, a reconstitutable powder, reconstituted with water or other suitable excipients prior to use. After filling the vial, the liquid composition can be frozen and lyophilized under vacuum.

  Tonaversat or an analogue of formula I can also be administered topically to the skin or mucosa, ie dermally or transdermally. Common formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, transdermal patches, wafers, implants, sponges, Examples include fibers, bandages and microemulsions. Liposomes can also be used. Common carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated-see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

  Other means of topical administration include electroporation, iontophoresis, sonophoresis, sonophoresis and delivery by microneedle or needleless injection (eg Powderject ™, Bioject ™ etc.) .

  Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted and programmed release.

  Compositions used in surgical wounds can be prepared as long acting depot formulations. Such formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compositions of the present invention are formulated with a suitable polymer or hydrophobic material (eg, as an acceptable emulsion in oil) or ion exchange resin, or as a slightly soluble derivative, eg, as a slightly soluble salt. can do.

  Tonaversat or an analogue of formula (I) is a temporary or permanent human or other animal body opening, such as the trachea, nostril, nasal cavity, rectum, breast duct, urethra or vagina, or surgical wound, Any insertion that is inserted into such a temporary or permanent opening, such as an incision or catheter, trocar, cannula, endotracheal or other endoscopic or ostomy tube, eg tracheal ostomy or colostomy tube More preferably, it is administered in the form of a unit dose composition for administration to the device. Intranasal administration is highly preferred.

  Intranasal mucosal administrable compositions may take the form of intranasal mucosal solid compositions such as powders and granules. The composition can also take the form of intranasal liquid preparations, including liquid preparations such as aqueous or oily blends, mixtures, suspensions, liquids, emulsions and elixirs, and gel preparations. The composition can also be present as a dilutable liquid concentrate or dry product, reconstitutable powder, diluted or reconstituted with water or other suitable excipients prior to use.

  Tonaversat or analogs of formula I are generally in the form of dry powder from dry powder inhalers (alone, as a mixture, for example, in a dry blend with lactose, or mixed with phospholipids, such as phosphatidylcholine) 1,1,1,2-tetra as a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce fine mist), or an aerosol spray from a nebulizer It can be administered intranasally or by inhalation with or without the use of a suitable propellant such as fluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Solid forms for intranasal transmucosal administration are usually present in unit doses and contain conventional additives such as adjuvants, diluents, dispersants, excipients, colorants, desiccants, water retention agents, and wetting agents. To do.

  Powders and granules can be coated according to methods well known in the art. Solid dosage forms of intranasal mucosa also include conventional sustained release formulations such as powders or granules with resistant coatings.

  Suitable excipients include cellulose, mannitol, lactose, chitosan, pectin, hydroxypropylmethylcellulose, cellulose derivatives such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyoxamers such as poly (ethylene oxide), gelatin, polyvinylpyrrolidone and starch. It is done. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

  The solid composition of the intranasal mucosa can be prepared by mixing and manufactured by conventional methods such as blending. The blending operation can be repeated and the active agent can be dispersed throughout the composition using a large amount of excipients. Such operations are, of course, conventional in the art.

  Liquid formulations of intranasal mucosa, such as gels and liquid formulations, include suspending agents such as sorbitol, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; emulsifiers such as lecithin, monooleic acid Sorbitan, or acacia; non-aqueous excipients (which may include edible oils) such as almond oil, coconut oil, oily esters such as glycerin, propylene glycol, or esters of ethyl alcohol: preservatives such as methyl or propyl p -Conventional additives such as hydroxybenzoate or sorbic acid; and, if desired, conventional colorants:

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol, or suitable substitutes for dispersing, stabilizing, or extending the release of an agent, propellant as a solvent, and A solution or suspension of a compound of the present invention is included, including any surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the formulation is micronized to a size suitable for delivery by inhalation (generally less than 5 microns). This can be achieved by any suitable comminuting method such as spiral jet mill, fluid bed jet mill, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

  Capsules (eg, made from gelatin or hydroxypropylmethylcellulose), blisters and cartridges used in inhalers or infusion devices are suitable powder bases such as compounds of the invention, lactose or starch, and L-leucine, It can be formulated to contain a powder mix of performance modifiers such as mannitol or magnesium stearate. Lactose may be anhydrous or may take the form of a monohydrate, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  A suitable solution formulation used in an atomizer using electrohydrodynamics to produce a fine mist can contain 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume can be from 1 μl to It can be as varied as 100 μl. A typical formulation may comprise an analog of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  To these formulations of the invention for inhalation / intranasal administration, suitable flavoring agents such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin may be added.

  Tonaversat or an analogue of formula I can also be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas.

  Tonaversat or an analogue of formula I can also be administered directly to the eye or ear in the form of a finely divided suspension or solution drop in isotonic sterile saline, generally pH adjusted. Other formulations suitable for eye and ear administration include ointments, biodegradable (eg absorbable gelatin sponge, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses and niosomes or liposomes. Particulate or vesicular systems are mentioned. Crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or polymers of heteropolysaccharide polymers such as gellan gum can be incorporated with preservatives such as benzalkonium chloride. . Such formulations can also be delivered by iontophoresis.

  Compositions of tonaversat or analogs of formula I are described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001) and Verma RK et. al. Current Status of Drug Delivery Technologies and Future Directions, Pharmaceutical Technology On-Line, 2001, 25 (2), 1-14. Such dosage forms are also known as fast dissolving, fast dissolving, fast melting, buccal dissolution and fast disintegrating oral tablets. The composition may take the form of a solid that melts upon contact with the patient's tongue, for example in the form of a disintegrating tablet marketed under the trade name ZYDIS® (RP Scherer, UK). Instead, the composition is made up of EFVDAS (Effervescent Drug Absorption System, Elan Corporation), Fast Melt (Highly Porous Micromatrix Tablets, Elan Corporation), Flashdose (Fusz Technologies Using Shear Formation Technology, (Fuiz Technologies). , USA), Flashtab (orally dispersible multiparticulate tablet, Program, France), Multiflash (rapidly disintegrating multi-unit, multiparticulate tablet, Program), Orasolv (effervescent dispersive microcapsule tablet, Cima Labs Inc, USA), Wowtab tablets (Yamanouchi Pharma Technologies, USA), LYOC (freeze-dried rapid It can take the form of a disintegrating tablet, Farmalyoc, France) or Quicksolve (lyophilized rapid disintegrating tablet, Janssen Pharmaceuticals, USA).

  Other suitable formulation techniques include INDAS (Elan Corporation), which utilizes stabilized amorphous forms of drugs with improved solubility, generally drug nanoparticles having a particle size of less than 400 nm Non-crystalline technology (Elan Corporation) using or SoftGel (RP Scherer) using soft gelatin capsule dosage forms.

  The formulation techniques described herein can advantageously provide more rapid drug dissolution and absorption. For compositions that disintegrate in the oral cavity, such as under the tongue, the rate of absorption can be increased and the first-pass metabolic effect can be reduced.

  As with common practice, the composition will usually be accompanied by a written or printed description used in the relevant medical therapy.

  The composition used in the present invention may contain 0.1 to 99% by weight, preferably 1 to 60% by weight of the active substance depending on the administration method.

In order to illustrate the invention and assist in understanding the invention, the following are given by way of example only:
In the study at Tonabersat,
-Direct compression tablets with a tablet core weight of 250 mg 0.05, 1.0, 10 and 25 mg
-Direct compression tablets 15, 25, 40 and 80 mg with a tablet core weight of 400 mg
-20 mg directly compressed tablet with tablet core weight 400 mg
-Nanoparticulate tablets 10, 20 and 40 mg with a tablet core weight of 400 mg
Many different formulations were used, including

  Direct compression tablets use finely divided active ingredients, whereas nanoparticulate tablets were direct compression tablets with wet bed milled spray-dried nanoparticulate active ingredients. The clinical trial was conducted with round white uncoated direct compressed tablets 10, 20, 30, 40, 60 and 80 mg with a core weight of 400 mg with the following unit composition (only 20 mg tablets shown) All other strengths differ only in tonaversat and lactose content).

  Representative formulations suitable for use in the present invention are detailed in Table 1.

Experimental Method Example 1: Study of prion neuroinflammation in mice

Objective To investigate the effect of Tonaversat on two models of prion neuropathogenesis: prion-infected mice using sham-inoculated mice as controls; Pneumococcus-induced encephalitis as a model of inflammation.

Materials and Methods C57b16N mice are used as models for scrapie and BSE strain prion replication (10 ⁶ LD50 prion infectious intracerebral injection). They are compared to similar mice in sham inoculation. Acute infusion or chronic administration of tonaversat is performed at doses ranging from 0.5 mg / kg to 10 and 20 mg / kg (intraperitoneal or oral administration in saline or phosphate buffer). For EEG analysis, the group consists of 10 animals and for behavioral testing and mortality 10 animals. The analysis includes the following during the incubation period (at Phase 1, Phase 2 and Phase 3):
(A) EEG relative power analysis compared to infected and non-infected mice (EEG as the ratio of the spectral power obtained per minute in the treatment recording session to the spectral power obtained with the excipient recording treatment. Spectral power was calculated). The significance of this result is determined by the ANOVA procedure. These studies are based on drugs that modify the EEG signal or behavior of rodents with or without gap junction modifiers (tonavelat) (pharmacological doses, typically 1-32 mg / kg in NaCl or PBS). Comparison with imipramine, venlafine, diazepam, amphetamine, fluoxetine, caffeine, chlorpromazine, buspirone). This helps to assess the level of relationship between gap junctions and specific pathological neurotransmission systems, most of which are damaged during infection.
(B) Behavioral test: forced swimming test (ie Porsolt test or behavioral despair), open field test (Open Field), activity meter test (Activity Meter), tail suspension test (Tail Suspension Test), light-dark box test (Dark) Light Box). Tests are also conducted on mice injected with drugs that induce behavioral changes. The T test helps determine the significance of the results.
(C) Mortality and morbidity are assessed and significance is assessed using Kaplan-Meier estimates.
(D) Perform histological analysis (using GFAP and vimentin labeling) to assess inflammation and connexin localization.
2. Meningitis (and therefore neuroinflammation) is caused in mice using the pathogenic bacterium, Streptococcus pneumoniae, at 105 CFU (colony forming units) in the right cerebral hemisphere. Similar parameters are evaluated as parameters for prion-infected mice and compared to infected mice treated with antibiotics at pharmacological doses (antibiotics are selected among ceftriaxone, vancomycin, cefotaxime, cefdinir).
3. Mouse glial and neuronal cell lines that can be infected by the scrapie strain prion (PrPres Biochemical quantification) are used for prion sensitivity studies. Investigate the effect of Tonaberusatto represented injected before or after (6-well plate format 22L prion strain ¹ 03 in triplicate ^{at, 1 04, 1 05 LD50)} . PrPres is quantified after 3 passages. The toxicity of tonaversat in these cell models is examined before the start of the study (dose range studies from 1 nM to 100 mM are performed at this time). Other gap junction inhibitors (meclofenamic acid, glycyrrhetinic acid, flufenamic acid after dose range studies) are also tested.

Claims (15)

Tonabersat or formula 1 used in the treatment of infectious disorders

Wherein Y is C—R ₁ ;
R ₁ is acetyl;
R ₂ is hydrogen, C _3-8 cycloalkyl, C _1-6 alkyl optionally substituted with oxygen or substituted with hydroxy, C _1-6 alkoxy or substituted aminocarbonyl, C _{1 -6} alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF ₃ S; or CF ₃ -A- group (A _{is, -CF 2 -, - CO -} , - CH 2 -, CH (OH), SO 2, SO, CH 2 -O, or CONH); or _CF 2 H-A'- group (a 'is , oxygen, sulfur, _SO, is SO 2, CF ₂ or CFH); _{trifluoromethoxy, C 1-6} alkylsulfinyl, perfluoro _{C 2-6} alkylsulfonyl C _1-6 alkylsulfonyl, C _1-6 alkoxysulfinyl sulfinyl, C _1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroaryl arylsulfinyl , Arylsulfonyl, or heteroarylsulfonyl (wherein any aromatic moiety is optionally substituted), C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino, C _1-6 alkyl-thiocarbonyl, C _1-6 alkoxy-thiocarbonyl, C _1-6 alkyl-thiocarbonyloxy, 1-mercapto C _2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or amino Nocarbonyl (any amino moiety is optionally substituted with one or two C _1-6 alkyl groups), or C _1-6 alkylsulfinylamino, C _1-6 alkylsulfonylamino, C _{1 -6} alkoxysulfinylamino or C _1-6 alkoxysulfonylamino, or C _1-6 alkylcarbonyl, nitro or cyano, or -C (C _1-6 alkyl) NOH or -C (C _1-6 alkyl) NNH ₂ Terminally substituted ethylenyl; or amino optionally substituted by 1 or 2 C _1-6 alkyl or by C _2-7 alkanoyl; one of R ₃ and R ₄ is hydrogen Or C _1-4 alkyl and the other is C _1-4 alkyl, CF ₃ or CH ₂ X ^a And is fluoro, chloro, bromo, iodo, optionally selected from C _1-4 alkoxy, hydroxy, C _1-4 alkylcarbonyloxy, —S—C _1-4 alkyl, nitro, 1 or 2 alkyl groups Amino, cyano or C _1-4 alkoxycarbonyl substituted by: or R ₃ and R ₄ are both C _2-5 polymethylene optionally substituted with C _1-4 alkyl;
R ₅ is C _1-6 alkylcarbonyloxy, benzoyloxy, ONO ₂ , benzyloxy, phenyloxy or C _1-6 alkoxy, R ₆ and R ₉ are hydrogen, or R ₅ is hydroxy , R ₆ is hydrogen or C _1-2 alkyl, and R ₉ is hydrogen;
R ₇ is heteroaryl or phenyl, both of which are optionally substituted once or twice with chloro, fluoro, bromo, iodo, nitro, C _1-4 alkyl, amino, cyano, azide, C _Is optionally substituted one or more times independently with a group or atom selected from _1-4 alkoxy, trifluoromethoxy and trifluoromethyl;
R ₈ is hydrogen, C _1-6 alkyl, OR ₁₁ or NHCOR ₁₀ and R ₁₁ is hydrogen, C _1-6 alkyl, formyl, C _1-6 alkanoyl, aroyl or aryl C _1-6 alkyl , R ₁₀ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, mono or di C _1-6 alkylamino, amino, amino C _1-6 alkyl, hydroxy-C _1-6 alkyl, halo-C _{1 -6} alkyl, C _1-6 acyloxy-C _1-6 alkyl, C _1-6 alkoxycarbonyl-C _1-6 -alkyl, aryl or heteroaryl; the R ₈ —N—CO—R ₇ group is R ₅ In the cis position relative to the group; X is oxygen or NR ₁₂ and R ₁₂ is hydrogen or C _1-6 alkyl)
Or a pharmaceutically acceptable composition thereof, wherein the infectious disorder results from the presence of a bacterium, fungus, protozoan, prion or herpes virus, or tonaversat or formula 1. An analog, or a pharmaceutically acceptable composition thereof.   In the manufacture of a medicament for use in the treatment of an infectious disorder, tonaversat or an analogue of formula 1 according to claim 1, wherein the infectious disorder is a bacterium, fungus, protozoan, prion or herpes virus Tonaversat or an analogue of formula 1, characterized in that it originates from   A method of treating or preventing an infection comprising administering to a patient in need thereof a pharmaceutically effective amount of tonaversat or an analogue of formula 1 according to claim 1, wherein the infectious disorder is A method characterized in that it results from the presence of bacteria, fungi, protozoa, prions or herpes viruses.   Tonaversat or an analogue of formula 1 used as claimed in claim 1 or 2, or a method according to claim 3, wherein the infectious disorder results from the presence of bacteria, An analog or method of Formula 1.   Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2 or the method of claim 3, wherein the infectious disorder results from the presence of a herpes virus. Or an analog or method of Formula 1.   Tonaversat or an analogue of formula 1 used, or a method according to claim 5, wherein the disorder is postherpetic neuralgia.   Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2 or the method of claim 3, wherein the infectious disorder results from the presence of a prion or An analog or method of Formula 1.   Tonaversat or an analogue of formula 1 used, or a method according to claim 7, wherein the disorder is infectious spongiform encephalopathy.   Tonaversut or an analogue of formula 1 used, or a method according to claim 8, wherein the disorder is Creutzfeldt-Jakob disease.   Tonabersat or an analogue of formula 1 used according to claim 8, or a method according to claim 8, characterized in that the disorder is Gerstmann-Stroisler-Scheinker syndrome, Or the method.   Tonaversat or an analog of formula 1 used, or a method according to claim 8, wherein the disorder is lethal familial insomnia.   Tonaversat or an analogue of formula 1 used, or a method according to claim 8, characterized in that the disorder is Koolou disease.   Tonaversat or an analogue of formula 1 used as claimed in claim 1 or 2, or a method according to claim 4, characterized in that the bacterium is Streptococcus pneumoniae or An analog or method of Formula 1.   Tonaversat or an analogue of formula 1 used as claimed in claim 1 or 2 or the method of claim 4 wherein the bacteria cause diphtheria, leprosy or Lyme disease, An analog or method of Formula 1.   4. Tonaversat or an analogue of formula 1 used as claimed in claims 1 and 2, or the method of claim 3, characterized in that the infectious disorder causes chronic fatigue syndrome or peptic ulcer , Tonaversat or an analog of Formula 1 or a method.