JP2013512888A - Treatment of allodynia and hyperalgesia - Google Patents

Abstract

The present invention relates to the treatment or prevention of allodynia and / or hyperalgesia, and to a composition comprising tonaversat or an analogue of formula (1) and tonaversat or an analogue of formula (1) for use 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 and prevention of allodynia and hyperalgesia.

  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.

  Allodynia is generally defined as pain due to a stimulus that does not normally induce pain. It is usually accompanied by unpleasant, abnormal sensations or sensory deficits. There are two different types of allodynia; mechanical and thermal allodynia. Static mechanical allodynia is pain under light contact and pressure, and dynamic mechanical allodynia is pain after brushing. Thermal allodynia means pain in the affected area, usually from a mild skin temperature. Allodynia is a clinical feature of many painful symptoms and is associated with neuropathy, irritability, inflammatory symptoms, nerve compression and / or strangulation and trauma, such as postoperative trauma and phantom limb pain. Allodynia is different from the pain mentioned.

  Hyperalgesia is an overreaction and hypersensitivity to painful stimuli that can be caused by damage to nociceptors or peripheral nerves. Hyperalgesia is experienced in a localized or scattered state. Localized states are generally associated with injury and can be divided into two subtypes: primary hyperalgesia and secondary hyperalgesia. Primary hyperalgesia is described as pain sensitivity that occurs directly in damaged tissue. Secondary hyperalgesia is described as the sensitivity of pain that occurs in surrounding uninjured tissue. Hyperalgesia is induced by platelet activating factor (PAF) in patients with inflammatory or allergic symptoms. It occurs via immune cells and interacts with the peripheral nervous system and releases chemicals that produce pain. Patients receiving long-term or high-dose opioid medications for the treatment of chronic pain may experience hyperalgesia.

  Allodynia and hyperalgesia, as well as other pain associated with neuropathy, such as neuropathic pain, are selective serotonin reuptake inhibitors, tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, glucocorticoids, gabapentin or It may respond to standard treatment with various drugs such as pregabalin, NMDA antagonists or atypical opioids. Compounds that treat allodynia include lidocaine, alfentanil, adenosine, ketamine, glycine antagonists and venlafaxine. However, like other forms of pain associated with neurological dysfunction, treatment of allodynia and / or hyperalgesia is clinically difficult and not all patients respond, and therefore allodynia and / or nociception. There is a great need for safe, alternative and improved methods and compositions for treating or preventing hypersensitivity.

（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 present invention relates to tonaversat or an analogue of formula I for use in the treatment or prevention of allodynia and / or hyperalgesia

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.

  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 includes allodynia and / or comprising administering to a patient in need thereof a pharmaceutically effective amount of tonaversat or an analog of Formula I, or a pharmaceutically acceptable composition thereof. Methods of treating or preventing hyperalgesia are provided.

  In a further aspect, the invention provides tonaversat or an analogue of formula I, or a pharmaceutically acceptable thereof, for use in the treatment or prevention of neuropathy, neurosensitivity disorder and / or one or more associated symptoms. The composition is provided.

  Accordingly, the present invention relates to neuropathy, neurosensitivity comprising administering to a patient in need thereof a pharmaceutically effective amount of tonaversat or an analog of formula I, or a pharmaceutically acceptable composition thereof. Methods of treating or preventing allodynia and / or hyperalgesia associated with sexual disorders are provided.

  In a further aspect, the invention provides tonaversat or an analogue of formula I, used for the treatment or prevention of allodynia and / or hyperalgesia and / or one or more associated symptoms associated with inflammatory disorders, or The pharmaceutically acceptable composition is provided.

  In a further aspect, the present invention provides tonaversat or an analogue of formula I, or a pharmaceutically acceptable composition thereof for use in the treatment or prevention of glossodynia or mouth ablation syndrome. Mouth cauterization syndrome is a burning sensation of the tongue or mouth and may be related to gustatory and / or sensory nerve problems of the peripheral or central nervous system.

  Accordingly, the present invention is associated with inflammatory disorders comprising administering to a patient in need thereof a pharmaceutically effective amount of tonaversat or an analogue of formula I, or a pharmaceutically acceptable composition thereof. Methods of treating or preventing allodynia and / or hyperalgesia are provided.

  In a further aspect, the present invention is used for the treatment or prevention of nerve compression, nerve constriction, trauma, more particularly postoperative trauma, hyperalgesia associated with phantom limb pain and / or one or more associated symptoms. Tonaversat or an analogue of formula I, or a pharmaceutically acceptable composition thereof.

  Accordingly, the present invention is a method of treating or preventing nerve compression, nerve strangulation, trauma, more particularly postoperative trauma, allodynia and / or hyperalgesia associated with phantom limb pain, and patients in need thereof A method comprising administering a pharmaceutically effective amount of tonaversat or an analog of formula I, or a pharmaceutically acceptable composition thereof.

  The present invention further includes using tonaversat in the manufacture of a medicament for treating any one or more of the above applications.

  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 Methods Example 1: Formalin-induced hyperalgesia and inflammation objective To determine the effect of tonaversat on chronic allodynia and / or hyperalgesia model.

Method Inject 0.5% formalin into the plantar area of the right hind paw of CF1 mice (obtained from Charles River, Inc.). This leads to a unique biphasic behavior profile characterized by mice licking the affected paw. Immediately after injection, the mice lick their paws for about 10 minutes. This is the first phase (acute phase) followed by a short incubation period with little behavioral activity. It is followed by licking the foot for a longer time of about 20-30 minutes, which is the second phase (inflammatory phase).

  Each mouse is conditioned for 15 minutes in one of several 6-inch high plexiglas observation tubes (4 inches in diameter) placed in front of the mirror before administering the test drug or vehicle. . After the conditioning period, a dose of tonaversat is administered orally and the mice are returned to their home tubes. When determined to correlate with peak plasma levels (1 hour), formalin is injected subcutaneously into the sole of the right hind paw (20 ul; 27 gauge needle). Place the needle bevel face down against the skin surface. Following the injection of formalin, each animal is observed for a total of 45 minutes, the first 2 minutes of each 5 minute epoch. Measure the cumulative licking length for each period of 2 minutes. Animals that receive the requisite amount of vehicle are replaced with each mouse that received the test drug. After the experiment is complete, the animals are euthanized. In this study, 8 mice / group are used.

  GraphPad Prism Version 3.03 is used to determine the area under the curve (AUC). Calculate the total AUC for both the test and control groups for both the acute and inflammatory phases. Individual animal AUCs for each period are also calculated and converted to a percentage of the control total AUC. The average percentage and SEM for both the drug tested and the control are calculated and examined for significant differences.

Results Test data from formalin-induced pain model in Tonaversat-mice (n = 8 / group). Effect on tanning time between two phases of the study (acute phase and inflammatory phase)

Example 2: Objective of peripheral nerve sensitization induced by sciatic nerve ligation To determine the effect of tonaversat on a sciatic nerve ligation model. The sciatic nerve ligation model is an “optimal criterion” model of allodynia and / or hyperalgesia. Both gabapentin and pregabalin are active in these models.

Methods As described by Seltzer et al., Operated SD for the development of consistent mechanical allodynia (pain response to innocuous stimuli) after a 10-day postoperative period after partial ligation of the sciatic nerve. Each rat (obtained from Charles River, Inc.) is tested. Animals are placed in a bottomless Plexiglas box placed on a stainless steel platform with 1/4 inch holes. Baseline mechanical sensitivity, representing the 50% paw withdrawal threshold prior to dosing, is determined after a conditioning time of at least 30 minutes when the rat is gently placed in a cage on the platform. This procedure is performed by applying a series of graduated Von Frey monofilament fibers perpendicular to the plantar surface of each hind foot between pads or toward the heel and between the back portions. The 50% threshold for paw withdrawal is determined by using an “up-down” step method. That is, applying a weaker fiber after recording a positive response (X = paw withdrawal) until it is recorded that the paw is not retracted (O = no withdrawal). This is an estimated threshold. Once an individual rat threshold estimate is obtained, the next highest / stiffer / thicker fibers etc. are applied. This is repeated 5 stages. If the foot lifts without retraction due to the maximum diameter fiber pressure, it is considered “no response” and is recorded as> 300 grams in the data sheet.

  Following measurement of the initial response before dosing, rats are orally infused with tonaversat (n = 8 rats / dose level). The mechanical threshold is then evaluated at 1, 2, 4, 6, 8, and 24 hours after infusion to determine the duration of action and TPE of the test compound in this model of mechanical allodynia. The animal can be used again after sufficient time to wash out the drug, typically 7 days.

The withdrawal threshold for each animal determined at each time point is initially calculated using the “xoxox” step method developed by Dixon (1980). As described above, after the threshold is estimated, the fiber diameter and response pattern are recorded (the first positive response (x) followed by the first negative (o) response). According to Chaplan, the ideal reaction pattern is “xoxox”. For each animal, the pattern of response and the final fiber tested (Xf) was entered into the Excel macro, with the following formula:
50% threshold (g) = 10 ^Λ (X _f + □□) / 10,000
Is calculated.
Where □ is the tabular value of the observed pattern of positive / negative reactions (Dixon, W) where X _f is the final von Frey hair value (in log) tested. J. (1980) Ann Rev. Pharmacol Toxicol, appendix provided in Chaplan as amended from 20: 441-462), □ is the mean difference (in log) between stimuli.

Using the 50% paw withdrawal threshold determined for each animal, the mean 50% paw withdrawal threshold + standard error (SEM) is then calculated for the rats at each time point. When these individual values are divided by the mean for the pre-dose assessment, the change relative to the pre-drug average (% control value) is determined for each rat. Statistical outliers are excluded only when individual responses are found to be more than 3 standard deviations from the group mean using the Grabbs Outlier test (Graphpad Statistical Software). The% change is then averaged for the remaining groups at each time point. The data is then tested for significant differences from pre-dose values using DOS-based PCS software. If p <0.05, report 50% paw withdrawal threshold + SEM as significant ( ^* ).

Results Tonaversat-test data from a rat chronic sciatic nerve ligation model (n = 8 / group). Effect on foot withdrawal threshold (g)

Example 3: Rat model of periorbital von Frey sensitivity Objective of periorbital von Frey in rats following chronic sensitization induced by daily application of “inflammatory mediator soup” (IS) to the dura mater surface To show the effect of morning tonaversat (10 mg / kg, intraperitoneal administration) on the sensitivity threshold.

Results See the results in the attached graph (Figure 1).

It is a graph which shows the result of an Example.

Claims (11)

Tonaversut or Formula 1 used in the treatment of allodynia and / or hyperalgesia

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 an pharmaceutically acceptable composition thereof.   Tonaversat or an analogue of formula 1 according to claim 1, characterized in that it is in the manufacture of a medicament for use in the treatment of allodynia and / or hyperalgesia.   A method of treating or preventing allodynia and / or hyperalgesia, comprising administering to a patient in need thereof a pharmaceutically effective amount of tonaversat or an analogue of formula 1 according to claim 1. A method characterized by that.   4. Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2 or the method of claim 3, characterized in that the allodynia and / or hyperalgesia is associated with a neurological disorder. , Tonaversat or an analog of Formula 1 or a method.   4. Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2, or the method of claim 3, wherein the allodynia and / or hyperalgesia is an associated neurohypersensitivity disorder. Tonabersat or an analogue of formula 1 or a method characterized.   4. Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2, or the method of claim 3, wherein the allodynia and / or hyperalgesia is an associated inflammatory condition. Tonaversat or an analog of Formula 1 or a method.   4. Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2, or the method of claim 3, wherein the allodynia and / or hyperalgesia is associated with nerve compression and / or strangulation. Tonaversat or an analogue of formula 1 or a method, characterized in that   4. Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2, or the method of claim 3, wherein the allodynia and / or hyperalgesia is an associated trauma. , Tonaversat or an analog of Formula 1 or a method.   4. Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2 or the method of claim 3, wherein the allodynia and / or hyperalgesia is an associated postoperative trauma. Tonaversat or an analog of Formula 1 or a method.   4. Tonabersat or an analogue of formula 1 used as claimed in claim 1 or 2 or the method of claim 3, wherein the allodynia and / or hyperalgesia is associated phantom limb pain. Tonaversat or an analog of Formula 1 or a method.   Tonaversat or an analogue of formula 1 used as claimed in claim 1 or 2, or the method of claim 3, wherein the allodynia and / or hyperalgesia is a mouth burning sensation syndrome, Tonaversat or an analog of Formula 1 or a method.

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