JPH11503132A - New heterocyclic compounds - Google Patents

New heterocyclic compounds

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Publication number
JPH11503132A
JPH11503132A JP8529880A JP52988096A JPH11503132A JP H11503132 A JPH11503132 A JP H11503132A JP 8529880 A JP8529880 A JP 8529880A JP 52988096 A JP52988096 A JP 52988096A JP H11503132 A JPH11503132 A JP H11503132A
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Prior art keywords
ethyl
dibenzo
dihydro
yloxy
cyclohepten
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エリック アンデルセン，クヌド
バン オルセン，ウッフェ
スネ アンデルセン，ヘンリック
ホフルベグ，ロルフ
クロフ ヨーゲンセン，ティン
マドセン，ペーター
ズデネク，ポリフカ
アレクサンドラ，シルハンコバ
カレル，シンデラー
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Novo Nordisk AS
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Novo Nordisk AS
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Publication of JPH11503132A publication Critical patent/JPH11503132A/en
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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Abstract

(57)【要約】 Ｚが(ａ)，(ｂ)，(ｃ)，(ｄ)，(ｅ)，(ｆ)，(ｇ)，(ｈ)，(ｉ)，（Ｊ）及び（ｋ）より選ばれる式（Ｉ）の化合物。本発明は新規のＮ−置換化アザ複素環式カルボン酸及びそのエステルであって、置換化アルキル鎖がＮ−置換基又はその塩の一部を形成している化合物、その製造のための方法、それらを含む組成物、並びにＣ−線維が神経原性疼痛又は炎症を誘発することにより病理生理学的な役割を果している疼痛、痛覚過敏及び／又は炎症症状の臨床処置のためのその利用に関する。   (57) [Summary] An expression in which Z is selected from (a), (b), (c), (d), (e), (f), (g), (h), (i), (J) and (k) ( Compound of I). The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof, wherein the substituted alkyl chain forms part of an N-substituent or a salt thereof, and a process for the preparation thereof. And compositions comprising them, and their use for the clinical treatment of pain, hyperalgesia and / or inflammatory conditions where C-fibers play a pathophysiological role by inducing neurogenic pain or inflammation.

Description

【発明の詳細な説明】 新規の複素環化合物 発明の分野 本発明は新規のＮ−置換化アザ複素環式カルボン酸及びそのエステルであって 、置換化アルキル鎖がＮ−置換基又はその塩の一部を形成している化合物、その 製造のための方法、それらを含む組成物、並びにＣ−線維が神経原性の疼痛又は 炎症を誘発することにより病理生理学的な役割を果している疼痛、痛覚過敏及び ／又は炎症症状の臨床処置のためのその利用に関する。本発明は更に非インスリ ン依存性真性糖尿病(NIDDM)又は老化におけるインスリン抵抗性の処置のための 本化合物の利用にも関連する。本化合物はＣ線維含有ニューロペプチドを妨害し 、それ故CGRP又はアミリンの如きインスリン拮抗性ペプチドの分泌及び循環を阻 害するものと理解される。 発明の背景 神経系は炎症反応に強い効果を及ぼす。知覚神経の逆行性刺激は局在型の血管 拡張及び増大した血管浸透性をもたらし(Janecsoら、Br.J.Pharmacol．1967，31 ，138-151)、そして似たような反応が知覚神経に存在していることがわかってい るペプチドの注射を経て観察される。これら及びその他のデーターから、知覚神 経の終末から放出されるペプチドは皮膚、関節、尿路、目、髄膜、胃腸管及び気 道の如き組織における数多くの炎症反応を媒介するものと推定される。それ故、 知覚神経ペプチドの放出及び／又は活性の阻害は、例えば関節炎、皮膚炎、鼻炎 、ぜん息、膀胱炎、歯肉炎、血栓性静脈炎、緑内障、胃腸病又は片頭痛の処置に おいて有用でありうる。 更に、骨格筋グリコーゲンシンターゼ活性及び筋グルコース代謝に及ぼすCGRP の潜在的な効果は、神経興奮により神経筋肉接続部からこのペプチドが放出され ることと共に、CGRPが、ホスホリル化グルコースを、グリコーゲン貯蔵体から解 糖及び酸化経路へと誘導することによって骨格筋グルコース代謝において生理学 的役割を果たしうることを示唆する（Rossettiら、Am.J.Physiol．264，E1-E10 ，1993）。このペプチドは生理学的状況、例えば運動において往来する細胞内グ ルコースの重要な生理学的モジュレーターであり得、そしてCGRPの循環血漿レベ ルが著しく増大する NIDDM又は老化関連肥満症の如き病理生理学的症状における 低下したインスリン作用及び骨格筋グリコーゲン生合成を司りうる(Melnykら Ob esity Res．３，337-344，1995)。従って、ニューロペプチドCGRPの放出及び／ 又は活性の阻害は２型糖尿病又は老化に関連するインスリン抵抗性の処置におい て有用でありうる。 米国特許第 4,383,999号及び第 4,514,414号、並びにEP 236,342号及びEP 231 ,996号において、いくつかのＮ−（４，４−二置換化−３−ブテニル）アザ複素 環カルボン酸の誘導体がGABA取込のインヒビターとして請求されている。EP 342 ,635号及びEP 374,801号において、Ｎ−置換化アザ複素環カルボン酸であってオ キシムエーテル基及びビニルエーテル基がそれぞれＮ−置換基の一部を構成して いる化合物がGABA取込のインヒビター。 本発明の説明 本発明は次式Ｉの新規のＮ−置換化アザ複素環式カルボン酸及びそのエステル （式中、Ｒ1，Ｒ2，Ｒ3，Ｒ4，Ｒ5及びＲ6は独立して水素、ハロゲン、トリフル オロメチル、ヒドロキシ、Ｃ1-6−アルキル、Ｃ1-6−アルコキシ、−NR7R8又は −SO2NR7R8であり、ここでＲ7及びＲ8は独立して水素又はＣ1-6−アルキルであ り；そして Ｘは任意的な結合の終点、−CH2−，−CH2CH2−，−CH＝CH−，−Ｏ−，−S(O )z−（ここで、ｚは０，１又は２である）、又は−N(R9)−（ここで、Ｒ9は水素 又はＣ1-6−アルキルである）であり； Ｙは−Ｏ−，−S(O)q−（ここでｑは０，１又は２である）、又は−N(R10)− であり、ここでＲ10は水素又はＣ1-6−アルキルであり；そして ｒは１，２，３又は４であり；そして Ｚは から選ばれ、ここでｎは１又は２であり；そして Ｒ11は−(CH2)mOH又は−(CH2)tCOR12であり、ここでｍは０，１，２，３，４ ，５又は６であり、そしてｔは０又は１であり、そしてここでＲ12は−OH，−NH2 ，−NHOH又はＣ1-6−アルコキシであり；そして Ｒ13は水素、ハロゲン、トリフルオロメチル、ヒドロキシ、Ｃ1-6−アルキル 又はＣ1-6−アルコキシであり；そして Ｒ14は水素、Ｃ1-6−アルキル、Ｃ1-6−アルコキシ、又はハロゲン、トリフル オロメチル、ヒドロキシ、Ｃ1-6−アルキルもしくはＣ1-6−アルコキシにより任 意的に置換されたフェニルであり；そして Ｒ15は水素又はＣ1-6−アルキルであり；そして …は任意的に単結合又は二重結合である） 又はその薬理学的に許容される塩に関する。 式Ｉの化合物は幾何学的及び光学的異性体として存在し得、そしてその全ての 異性体及び混合物が本発明に包含される。異性体はクロマトグラフィー技術又は 適当な塩の分別結晶化の如き標準の方法により分割し得る。 好ましくは、式Ｉの化合物は個々の幾何的又は光学的異性体として存在する。 本発明に係る化合物は任意的に薬理学的に許容される酸付加塩として、又はカ ルボン酸基がエステル化されていないとき、薬理学的に許容される金属塩として 、又は任意的にアルキル化されたアンモニウム塩として存在しうる。 かかる塩の例には、無機及び有機酸付加塩、例えば塩酸塩、臭酸塩、硫酸塩、 リン酸塩、酢酸塩、フマル酸塩、マレイン酸塩、クエン酸塩、乳酸塩、酒石酸塩 、シュウ酸塩又は類似の薬理学的に許容される無機又は有機酸付加塩が含まれ、 そして引用することで本明細書に組入れる Journal of Pharmaceutical Science ，66，2(1977)に示されている薬理学的に許容される塩が含まれる。 本明細書において使用する語「Ｃ1-6−アルキル」は、単独で、又は組合さっ て、１〜６個の炭素原子を有する直鎖又は枝分れした飽和炭化水素鎖、例えばメ チル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、sec−ブチル、イソ ブチル、tert−ブチル、ｎ−ペンチル、２−メチルブチル、３−メチルブチル、 ｎ−ヘキシル、４−メチルペンチル、ネオペンチル、ｎ−ヘキシル、１，２−ジ メチルプロピル、２，２−ジメチルプロピル及び１，２，２−トリメチルプロピ ルを意味する。 本明細書において使用する語「Ｃ1-6−アルコキシ」は、単独で、又は組合さ って、エーテル酸素を介して連結したＣ1-6−アルキル基であって自由価結合が エーテル酸素に由来しており、且つ１〜６個の炭素原子を有する基を含んで成る 直鎖又は枝分れした一価の置換基、例えばメトキシ、エトキシ、プロポキシ、イ ソプロポキシ、ブトキシ、ペントキシを意味する。 「ハロゲン」なる語はフッ素、塩素、臭素又はヨウ素を意味する。 本発明により包括される化合物の具体例には以下が含まれる： １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−３−ピペリジンカルボキシアミド； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロ ヘプテン−５−イルオキシ）エチル）−４−ピペリジンカルボン酸； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−２−ピペリジンカルボン酸； （１−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン− ５−イルオキシ）エチル）ピペリジン−３−イル）メタノール； ４−（４−クロロフェニル）−１−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ 〔ａ，ｄ〕シクロヘプテン−５−イルオキシ）−エチル）−４−ピペリジノール ； ４−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−４−ピペラジンカルボン酸； （２Ｓ，４Ｒ）−１−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シ クロヘプテン−５−イルオキシ）エチル）−４−ヒドロキシ−２−ピロリジンカ ルボン酸； ４−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−２−モルホリンカルボン酸； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−２−アジリジンカルボン酸； ２−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−１，２，３，４−テトラヒドロ−４−イソキノリンカ ルボン酸； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロ ヘプテン−５−イルオキシ）エチル）−４−メチル−１，４−ジアゼパン−６− カルボン酸； ２−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−１，２，３，４−テトラヒドロ−３−イソキノリンカ ルボン酸； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−３−ピペリジンカルボン酸ヒドロキシアミド； （４−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン− ５−イルオキシ）エチル）ピペラジン−１−イル）酢酸； 又はその薬理学的に許容される塩。 本明細書において用いる語「患者」には、神経原性疼痛もしくは炎症又は NID DMにおけるインスリン抵抗性の処置により利益を被る任意の哺乳動物が含まれる 。この語は特にヒト患者を意味するが、それらに限定するつもりではない。 式Ｉの新規の化合物は知覚Ｃ線維の末梢及び中央終末からのニューロペプチド の放出に関与する神経原性炎症を阻止することが実証された。実験的に、このこ とはホルマリン誘導した疼痛又は足水腫の動物モデルにおいて実証でき(Wheeler and Cowan，Agents Actions 1991，34，264-269)、それにおいてこの式Ｉの新 規化合物は有能な阻害効果を示す。式Ｉの化合物は、Ｃ線維が神経原性の疼痛又 は炎症を誘発することにより病理生理学的な役割を果している全ての疼痛、痛覚 過敏及び／又は炎症症状、即ち： 片頭痛、術後疼痛、火傷、挫傷、後疱疹性疼痛（帯状疱疹）により例示される 急性疼痛症状、並びに急性炎症に一般に関係する疼痛；様々なタイプのニューロ パシー（糖尿病性、後外傷性、毒性）、 神経痛、リウマチ様関節炎、脊椎炎、痛風、炎症性腸炎、前立腺炎、癌痛、慢性 頭痛、せき、ぜん息、慢性膵臓炎、炎症性皮膚病、例えば乾癬及び自己免疫皮膚 病、骨粗しょう症痛により例示される慢性的な疼痛及び／又は炎症性症状、を処 置するのに利用されうる。 更に、一般式Ｉの化合物は糖尿病ob／obマウスにおけるグルコース寛容を向上 させること、及びこれが末梢神経終末からのCGRPの放出の低下に由来しうること が実証された。従って、一般式Ｉの化合物は、NIDDM及び老化関連肥満症の処置 において利用されうる。実験的には、このことは一般式Ｉの化合物による事前の 経口処置を伴う又は伴わないob／obマウスへのグルコースの皮下投与により実証 された。 式Ｉの化合物は以下の工程により調製し得る： Ｒ1，Ｒ2，Ｒ3，Ｒ4，Ｒ5，Ｒ6，Ｘ，Ｙ及びｒが前記の通りであり、そしてＷ が適当な離脱基、例えばハロゲン、ｐ−トルエンスルホネート又はメシレートで ある式IIの化合物を、Ｚが前記の通りである式IIIのアザ複素環式化合物と反応 させてよい。このアルキル化反応はアセトン、ジブチルエーテル、２−ブタノン 、メチルエチルケトン、酢酸エチル、テトラヒドロフラン(THF)又はトルエンの 如き溶媒の中で、塩基、例えば水素化ナトリウム及び触媒、例 えばアルカリ金属ヨージドの存在下で、室温から使用する溶媒にとっての還流温 度で、例えば１〜120 ｈにわたって実施してよい。もしＲ12がアルコキシである エステルを調製するなら、Ｒ12がOHである式Ｉの化合物を好ましくは室温におい て、水性アルカリ金属水酸化物とアルコール、例えばメタノール又はエタノール との混合物の中で、例えば約 0.5〜６ｈにわたってエステル基を加水分解するこ とにより調製することができる。 式II及びIIIの化合物は当業者に周知の方法により容易に調製しうる。 所定の環境のもとで、上記方法に用いる中間体、例えば式IIIの化合物を、適 当な保護基で保護することが必要でありうる。カルボン酸基は例えばエステル化 してよい。かかる基の導入及び除去は「Protective Groups in Organic Chemist ry」 J.F.W.McOrnie編（NewYork，1973）に記載されている。薬理学的方法 ホルマリン誘導型疼痛又は足水腫 本発明の化合物に関するホルマリン誘導型疼痛又は水腫の in vivo阻害につい ての値は、本質的にWheeler-Aceto and Cowan（Agents Action 1991，34，265-2 69）の方法によりマウスで評価した。 約20ｇのNMRI雌マウスに対し、20μｌの１％のホルマリンを左後足に注射した 。この動物を加熱（31℃）テーブルの上に載せ、そして疼痛反応を評点した。１ ｈ後、それらを殺し、そして出血させた。左及び右後足を切り取り、そして足間 の重量差を、ホルマリン注射を施した足の水腫反応の指標として利用した。低下したCGRPの放出 生後16週間のob／ob雌マウスにグルコース（２ｇ／kg）を皮下注射した。その 後、血液グルコースをグルコースオキシダーゼ法によ り尾静脈血液で決定した。この試験の終了時に、動物を断頭にかけ、そして胴体 血液を採取した。免疫反応CGRPをラジオイムノアッセイにより血漿において決定 した。２グループの動物を利用した。１のグループはビヒクル処理し、一方、他 のグループには試験前５日間にわたって飲料水(100mg／ｌ)を介して式Ｉの化合 物を与えた。 上記の指標に関し、用量は採用した式Ｉの化合物、投与の態様、及び所望の治 療に依存するであろう。しかしながら、一般に、満足たる結果は約 0.5mg〜約10 00mg、好ましくは約１mg〜約 500mgの用量式Ｉの化合物を、好都合には１日１〜 ５回、任意的に徐放式で与えることで得られる。通常、経口投与に適する投与形 態は、薬理担体又は希釈剤と混合した約 0.5mg〜約1000mg、好ましくは約１mg〜 約 500mgの式Ｉの化合物を含んで成る。 式Ｉの化合物は薬理学的に許容される酸付加塩形態、又は可能なら、金属又は 低級アルキルアンモニウム塩として投与されうる。かかる塩形態は遊離塩基形態 とほぼ同程度の活性を示す。 本発明は更に式Ｉの化合物又はその薬理学的に許容される塩を含んで成る薬理 組成物にも関連し、そして通常、かかる組成物は薬理担体又は希釈剤も含む。本 発明の化合物を含む組成物は慣用の技術により調製し得、そして慣用の形態、例 えばカプセル、錠剤、溶液又は懸濁物である。 採用する薬理担体は慣用の固体又は液体担体であってよい。固体担体の例はラ クトース、テラ・アルバ（terra alba）、スクロース、タルク、ゼラチン、アガ ー、ペクチン、アカシア、ステアリン酸マグネシウム及びステアリン酸である。 液体担体の例はシロップ、ピーナッツ油、オリーブ油及び水である。 同様に、担体又は希釈剤は当業界公知の任意の遅延剤、例えばグリセリルモノ ステアレート又はグリセリルジステアレートを、単独 で、又はワックスとの混合で含みうる。 もし経口投与用の固体担体を使用するなら、調製品を錠剤化する、粉末もしく はペレット状でハードゼラチンカプセルに入れる、又はトローチもしくはロゼン ジの形態にすることがよい。固体担体の量は幅広く変わるが、通常は約25mg〜約 １ｇであろう。液体担体を使用するなら、この調製品はシロップ、エマルション 、ソフトゼラチンカプセル又は無菌注射用液体の形態、例えば水性又は非水性液 体懸濁物又は溶液であってよい。 一般に、本発明の化合物は、単位投与当り、50〜200mg の活性成分を薬理学的 に許容される担体の中に、又はそれと一緒に含んで成る単位投与形態において分 配する。 本発明に係る化合物の用量は、患者、例えばヒトに薬剤として投与するとき、 １〜500mg／日、例えば１回の投与当り 100mgとする。 慣用の錠剤化技術により調製し得る典型的な錠剤は以下を含む：コア： 活性化合物（遊離化合物又はその塩） 100mg コロイド状二酸化珪素（Areosil(登録商標)） 1.5mg 微結晶セルロース（Avicel(登録商標)） 70mg 改質セルロースゴム（Ac-Di-Sol(登録商標)） 7.5mg ステアリン酸マグネシウムコーティング： HPMC 約 9mg *Mywacett（登録商標）9-40T 約 0.9mg* フィルムコーティングのための可塑剤としてアセチル化モノグリセリド使用 投与のルートは、活性化合物を適当な又は所望の作用部位に効率 的に搬送する任意のルートであってよく、例えば経口又は非経口、例えば直腸、 経皮、皮下、鼻内、筋肉内、局所、静脈内、尿道内、点眼溶液又はオイントメン トであってよく、経口ルートが好ましい。 実施例 式Ｉの化合物及びそれらを含む調製品の製造のための方法は以下の実施例に更 に例示されているが、しかしながらそれらに限定されるものではない。 以降、TLCは薄層クロマトグラフィー、CDCl3は重水素クロロホルム、そして DMSO-d6はヘキサ重水素ジメチルスルホキシドである。本化合物の構造は元素分 析又は NMRのいづれかにより確認し、ここでピークは適宜表題の化合物の中の特 徴的なプロトンの存在に起因する。1H NMRシフト（δH）は ppmで示す。M.p.は 融点であり、そして℃で表示し、そして補正していない。カラムクロマトグラフ ィーは W.C.StillらJ.Org.Chem．(1978)，43，2923-2925に記載の技術を利用し 、Merckのシリカゲル60(Art．9385)で実施した。出発材料として用いた化合物は 公知の化合物か、又は周知の方法により容易に調製し得る化合物である。 実施例１ １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）−１−エチル）−４−ピペリジンカルボン酸塩酸塩 ベンゼン(120ml)中の10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘ プテン−５−オール（10.0ｇ、0.047mol）、２−ブロモエタノール(8.6ｇ、0.06 9mol)及び濃硫酸(1.4ml)の混合物を室温で 0.5ｈ撹拌した。冷却後（氷／水）、 粗５−（２−ブロモエトキシ−10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シ クロヘプテンを濾過し、石油エーテルで洗い、そして乾かした。これは10.7ｇ（ 72％）で供され、精製せずに更なる反応に用いた。 M.p．62-70℃。 ５−（２−ブロモエトキシ）−10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕 シクロヘプテン(9.5ｇ、0.03mol)、エチル４−ピペリジンカルボキシレート(4.7 ｇ、0.03mol)、炭酸カリウム(8.1ｇ、0.06mol)及びジメチルスルホキシド(120ml )の混合物を湯浴上で40〜50℃で４ｈ撹拌した。この混合物を冷却し、濾過し、 そして固体をジメチルスルホキシド（10ml）で洗った。合わせた濾液を水で希釈 し(720ml)、そしてジエチルエーテルで抽出した(２×200ml)。エーテル抽出物を 水で洗い、乾かし(MgSO4)、そして溶媒を真空下でエバポレーションした。その 残渣を２−プロパノールに溶かし、そして２−プロパノール中の高温シュウ酸溶 液(4.0ｇ)を加えた。冷却後、エチル１−（10，11−ジヒドロ−５Ｈ−ジベンゾ 〔ａ，ｄ〕シクロヘプテン−５−イルオキシ）−１−エチル−４−ピペリジンカ ルボキシレート水素シュウ酸塩が沈殿した。これは濾過及び乾燥後に 8.3ｇ（53 ％）で供され、それを更なる反応に精製抜きで使用 した。 上記シュウ酸塩の水懸濁物(7.3ｇ、0.015mol)を25％のアンモニア溶液でアル カリ性にし、そしてジエチルエーテルで抽出した(２×100ml)。有機層を水で洗 い（２×50ml）、乾かし(MgSO4)、そして真空エバポレーションした。これは油 としての 5.7ｇ（96％）の遊離エチルエステルを供した。 上記エステル2.01ｇ（0.005mol）、2.4mlの20％の水性水酸化ナトリウム及び エタノール（15ml）の混合物を室温で４ｈ及び一夜撹拌した。ジクロロメタン(2 50ml)を加え、そして磁気撹拌及び冷却しながら（水／氷浴槽）、〜2.5Ｎの HCl をpHになるまで静かに滴下した。水層を分離させ、そして有機層を乾かし(MgSO4 )、そして真空エバポレーションした。固体残渣をアセトンで２回再エバポレー ションした。これは、エタノールとエーテルとの混合物からの結晶化を経て1.68 ｇ（83％）の表題の化合物を供した。結晶サンプルの中に存在するジクロロメタ ンを高温で真空下で除去した。 M.p．192-194℃。1 H NMR（DMSO-d6）：7.42（bd，2H）；7.19（m，6H）；5.62（s，1H）；3.83（t ，2H）；3.28（t，1H）；4.96（d，1H）；2.53（m，1H）；3.37（m，6H）；3.00 （m，4H）；1.99（m，4H）。DETAILED DESCRIPTION OF THE INVENTION New heterocyclic compounds Field of the invention   The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof. A compound wherein the substituted alkyl chain forms part of an N-substituent or a salt thereof, Methods for the manufacture, compositions containing them, and C-fibers with neurogenic pain or Pain, which plays a pathophysiological role by inducing inflammation, hyperalgesia and And / or its use for the clinical treatment of inflammatory conditions. The present invention is further For the treatment of insulin resistance in insulin-dependent diabetes mellitus (NIDDM) or aging It also relates to the use of the present compounds. The compound blocks C-fiber-containing neuropeptides Inhibits the secretion and circulation of insulin antagonist peptides such as CGRP or amylin Understood to be harmful. Background of the Invention   The nervous system has a strong effect on the inflammatory response. Retrograde stimulation of sensory nerves is a localized blood vessel Results in dilation and increased vascular permeability (Janecso et al., Br. J. Pharmacol. 1967, 31). 138-151) and a similar response is known to exist in sensory nerves. Observed via injection of certain peptides. From these and other data, Peptides released from the end of menstruation include skin, joints, urinary tract, eyes, meninges, gastrointestinal tract and air. It is presumed to mediate a number of inflammatory responses in tissues such as the tract. Therefore, Inhibition of the release and / or activity of sensory neuropeptides may include, for example, arthritis, dermatitis, rhinitis For the treatment of asthma, cystitis, gingivitis, thrombophlebitis, glaucoma, gastrointestinal disease or migraine May be useful in   Furthermore, the effect of CGRP on skeletal muscle glycogen synthase activity and muscle glucose metabolism The potential effect of nerve release is that this peptide is released from the neuromuscular junction In addition, CGRP releases phosphorylated glucose from glycogen stores. Physiology in skeletal muscle glucose metabolism by inducing sugar and oxidation pathways (Rossetti et al., Am. J. Physiol.264, E1-E10 , 1993). This peptide is useful in physiological situations, such as intracellular Can be an important physiological modulator of glucose, and circulating plasma levels of CGRP. In pathophysiological conditions such as NIDDM or aging-related obesity May be responsible for reduced insulin action and skeletal muscle glycogen biosynthesis (Melnyk et al. esity Res.3, 337-344, 1995). Therefore, the release of neuropeptide CGRP and / or Or inhibition of activity is in the treatment of insulin resistance associated with type 2 diabetes or aging Can be useful.   U.S. Pat.Nos. 4,383,999 and 4,514,414, and EP 236,342 and EP 231 No. 996, some N- (4,4-disubstituted-3-butenyl) aza complex Derivatives of cyclic carboxylic acids are claimed as inhibitors of GABA uptake. EP 342 U.S. Pat. No. 6,635 and EP 374,801 describe N-substituted azaheterocyclic carboxylic acids as The oxime ether group and the vinyl ether group each constitute part of the N-substituent The compound is an inhibitor of GABA uptake. Description of the invention   The present invention relates to novel N-substituted azaheterocyclic carboxylic acids of the formula I and their esters (Where R1, RTwo, RThree, RFour, RFiveAnd R6Is independently hydrogen, halogen, trifle Oromethyl, hydroxy, C1-6-Alkyl, C1-6-Alkoxy, -NR7R8Or −SOTwoNR7R8Where R7And R8Is independently hydrogen or C1-6-Alkyl And;   X is the optional bond endpoint, -CHTwo−, −CHTwoCHTwo-, -CH = CH-, -O-, -S (O )z-(Where z is 0, 1 or 2), or -N (R9)-(Where R9Is hydrogen Or C1-6-Is alkyl);   Y is -O-, -S (O)q-(Where q is 0, 1 or 2), or -N (RTen) − Where RTenIs hydrogen or C1-6-Alkyl; and   r is 1, 2, 3, or 4; and   Z is   Wherein n is 1 or 2; and   R11Is-(CHTwo)mOH or-(CHTwo)tCOR12Where m is 0, 1, 2, 3, 4 , 5 or 6, and t is 0 or 1, and R12Is -OH, -NHTwo , -NHOH or C1-6-Alkoxy; and   R13Is hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-Alkyl Or C1-6-Alkoxy; and   R14Is hydrogen, C1-6-Alkyl, C1-6-Alkoxy, or halogen, trifur Oromethyl, hydroxy, C1-6-Alkyl or C1-6-Appointed by alkoxy Optionally substituted phenyl; and   RFifteenIs hydrogen or C1-6-Alkyl; and   …Is optionally a single or double bond)   Or a pharmacologically acceptable salt thereof.   The compounds of formula I may exist as geometric and optical isomers and all Isomers and mixtures are included in the present invention. The isomers are chromatographic techniques or Resolution can be by standard methods such as fractional crystallization of the appropriate salt.   Preferably, the compounds of formula I exist as individual geometric or optical isomers.   The compounds according to the present invention may optionally be provided as pharmacologically acceptable acid addition salts or When the rubonic acid group is not esterified, as a pharmacologically acceptable metal salt Or optionally as an alkylated ammonium salt.   Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, bromate, sulfate, Phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate , Oxalates or similar pharmacologically acceptable inorganic or organic acid addition salts, And is incorporated herein by reference. Journal of Pharmaceutical Science ,66, 2 (1977).   As used herein, the term "C1-6-Alkyl '' alone or in combination And a straight or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, e.g. Chill, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso Butyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-di Methylpropyl, 2,2-dimethylpropyl and 1,2,2-trimethylpropyl Means le.   As used herein, the term "C1-6-Alkoxy '' alone or in combination Means that C is linked through ether oxygen1-6An alkyl group having a free valence bond Comprising groups derived from ether oxygen and having 1 to 6 carbon atoms Linear or branched monovalent substituents such as methoxy, ethoxy, propoxy, i It means sopropoxy, butoxy, pentoxy.   The term "halogen" refers to fluorine, chlorine, bromine or iodine.   Specific examples of compounds encompassed by the present invention include: 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -3-piperidinecarboxamide; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclo Hepten-5-yloxy) ethyl) -4-piperidinecarboxylic acid; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -2-piperidinecarboxylic acid; (1- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene- 5-yloxy) ethyl) piperidin-3-yl) methanol; 4- (4-chlorophenyl) -1- (2- (10,11-dihydro-5H-dibenzo [A, d] cyclohepten-5-yloxy) -ethyl) -4-piperidinol ; 4- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -4-piperazinecarboxylic acid; (2S, 4R) -1- (2- (10,11-dihydro-5H-dibenzo [a, d] cy Clohepten-5-yloxy) ethyl) -4-hydroxy-2-pyrrolidineca Rubonic acid; 4- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -2-morpholinecarboxylic acid; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -2-aziridinecarboxylic acid; 2- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -1,2,3,4-tetrahydro-4-isoquinoline linker Rubonic acid; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclo Hepten-5-yloxy) ethyl) -4-methyl-1,4-diazepan-6- carboxylic acid; 2- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -1,2,3,4-tetrahydro-3-isoquinoline linker Rubonic acid; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) ethyl) -3-piperidinecarboxylic acid hydroxyamide; (4- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene- 5-yloxy) ethyl) piperazin-1-yl) acetic acid; Or a pharmacologically acceptable salt thereof.   As used herein, the term "patient" includes neurogenic pain or inflammation or NID. Includes any mammal that would benefit from treatment of insulin resistance in DM . The term specifically refers to, but is not intended to be limited to, human patients.   The novel compounds of formula I are neuropeptides from the peripheral and central terminals of sensory C fibers Have been demonstrated to block neurogenic inflammation, which is involved in the release of. Experimentally, this Can be demonstrated in animal models of formalin-induced pain or foot edema (Wheeler  and Cowan, Agents Actions 1991, 34, 264-269), in which the new formula I The reference compound shows a potent inhibitory effect. Compounds of formula I show that C fibers have neurogenic pain or Are all pains, nociceptions that play a pathophysiological role by inducing inflammation Hypersensitivity and / or inflammatory symptoms, ie:   Exemplified by migraine, postoperative pain, burns, bruises, and herpetic pain (shingles) Acute pain symptoms, as well as pain commonly associated with acute inflammation; various types of neurons Passy (diabetic, post-traumatic, toxic), Neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic Headache, cough, asthma, chronic pancreatitis, inflammatory skin diseases such as psoriasis and autoimmune skin Disease, chronic pain and / or inflammatory conditions exemplified by osteoporosis pain. Can be used to place   Furthermore, compounds of general formula I improve glucose tolerance in diabetic ob / ob mice And that this may result from reduced CGRP release from peripheral nerve endings Has been demonstrated. Accordingly, compounds of general formula I are useful in treating NIDDM and aging-related obesity Can be used. Experimentally, this has been previously determined by compounds of general formula I Demonstrated by subcutaneous administration of glucose to ob / ob mice with or without oral treatment Was done.   Compounds of formula I can be prepared by the following steps:   R1, RTwo, RThree, RFour, RFive, R6, X, Y and r are as described above, and W Is a suitable leaving group such as halogen, p-toluenesulfonate or mesylate Reacting a compound of formula II with an azaheterocyclic compound of formula III wherein Z is as defined above You may let me. This alkylation reaction is carried out with acetone, dibutyl ether, 2-butanone. , Methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene In a solvent such as a base such as sodium hydride and a catalyst, e.g. For example, in the presence of alkali metal iodide, the reflux temperature for the solvent used from room temperature For example, over a period of 1 to 120 h. If R12Is alkoxy To prepare an ester, R12At room temperature, preferably at room temperature. An aqueous alkali metal hydroxide and an alcohol such as methanol or ethanol In a mixture with, for example, about 0.5 to 6 h. And can be prepared.   Compounds of formula II and III can be readily prepared by methods well known to those skilled in the art.   Under certain circumstances, the intermediate used in the above method, for example a compound of formula III, It may be necessary to protect with appropriate protecting groups. Carboxylic acid groups are e.g. esterified May do it. The introduction and removal of such groups is described in Protective Groups in Organic Chemist. ry ", edited by J.F.W. McOrnie (New York, 1973).Pharmacological methods Formalin-induced pain or foot edema   In vivo inhibition of formalin-induced pain or edema for compounds of the present invention Values are essentially Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-2). Evaluation was performed in mice by the method of 69).   About 20 g of NMRI female mice were injected with 20 μl of 1% formalin in the left hind paw . The animals were placed on a heated (31 ° C.) table and the pain response was scored. 1 After h, they were killed and bled. Cut off the left and right hind legs, and between the legs Was used as an indicator of the edema response of the formalin-injected paw.Reduced CGRP release   Ob / ob female mice, 16 weeks old, were injected subcutaneously with glucose (2 g / kg). That After that, blood glucose is measured by glucose oxidase method. It was determined by tail vein blood. At the end of this test, the animals are decapitated and Blood was collected. Immunoreactive CGRP determined in plasma by radioimmunoassay did. Two groups of animals were utilized. One group was vehicle treated, while the other group Group of formula I via drinking water (100 mg / l) for 5 days before the test I gave things.   For the above indications, the dosage will vary with the compound of Formula I employed, the mode of administration, and the desired treatment. Will depend on treatment. However, generally, satisfactory results are from about 0.5 mg to about 10 mg. 00 mg, preferably from about 1 mg to about 500 mg, of a dose of a compound of formula I, conveniently from 1 to It is obtained by giving 5 times, optionally in a sustained release manner. Usually a dosage form suitable for oral administration It may be present in an amount of from about 0.5 mg to about 1000 mg, preferably from about 1 mg Comprising about 500 mg of a compound of formula I.   The compounds of formula I may be in the form of a pharmaceutically acceptable acid addition salt, or where possible, a metal or It can be administered as a lower alkyl ammonium salt. Such salt forms are free base forms Shows almost the same activity.   The present invention further relates to a pharmacological composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. Also associated with the compositions, and usually such compositions also include a pharmacological carrier or diluent. Book Compositions comprising a compound of the invention may be prepared by conventional techniques, and are prepared in conventional form, e.g. For example, capsules, tablets, solutions or suspensions.   The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are Kutose, terra alba, sucrose, talc, gelatin, aga -, Pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.   Similarly, the carrier or diluent may be any retarder known in the art, such as glyceryl mono. Stearate or glyceryl distearate alone Or in admixture with wax.   If a solid carrier for oral administration is used, the preparation should be tabletted, powdered or In pellets in hard gelatin capsules, or troche or rosen It is good to be in the form of di. The amount of solid carrier will vary widely but will usually range from about 25 mg to about 25 mg. Will be 1 g. If a liquid carrier is used, this preparation may be a syrup, emulsion In the form of soft gelatin capsules or sterile injectable liquids, for example, aqueous or non-aqueous liquids It may be a body suspension or solution.   In general, the compounds of the present invention contain from 50 to 200 mg of active ingredient per unit dose. In a unit dosage form comprising, or together with, an acceptable carrier. Distribute.   The dose of the compound according to the present invention, when administered to a patient, for example a human, as a medicament, It is 1-500 mg / day, for example, 100 mg per administration.   Typical tablets that can be prepared by conventional tableting techniques include:core:   Active compound (free compound or its salt) 100mg   Colloidal silicon dioxide (Areosil®) 1.5 mg   70 mg of microcrystalline cellulose (Avicel®)   Modified cellulose rubber (Ac-Di-Sol (registered trademark)) 7.5 mg   Magnesium stearatecoating:   HPMC about 9mg   *Mywacett (registered trademark) 9-40T about 0.9mg* Use of acetylated monoglyceride as plasticizer for film coating   The route of administration will ensure that the active compound is directed to the appropriate or desired site of action. It can be by any route, eg, oral or parenteral, for example, rectal, Transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or ointment And the oral route is preferred. Example   The processes for the preparation of the compounds of the formula I and preparations containing them are further described in the examples below. However, the present invention is not limited thereto.   Since then, TLC is thin-layer chromatography, CDClThreeIs deuterated chloroform, and DMSO-d6Is hexadeuterium dimethyl sulfoxide. The structure of this compound is elemental Confirmation by either precipitation or NMR, where peaks are Due to the presence of symbolic protons.1H NMR shift (δH) Are in ppm. M.p. Melting points and are expressed in ° C. and are uncorrected. Column chromatograph See W.C. Still et al., J. Org. Chem. (1978), 43, 2923-2925 On silica gel 60 from Merck (Art. 9385). The compounds used as starting materials It is a known compound or a compound that can be easily prepared by a known method.                                 Example 1 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5 -Yloxy) -1-ethyl) -4-piperidinecarboxylic acid hydrochloride   10,11-Dihydro-5H-dibenzo [a, d] cyclohexane in benzene (120 ml) Puten-5-ol (10.0 g, 0.047 mol), 2-bromoethanol (8.6 g, 0.06 mol) 9mol) and concentrated sulfuric acid (1.4ml) were stirred at room temperature for 0.5h. After cooling (ice / water) Crude 5- (2-bromoethoxy-10,11-dihydro-5H-dibenzo [a, d] cy The cloheptene was filtered, washed with petroleum ether and dried. This is 10.7g ( 72%) and used for further reactions without purification.   M.p. 62-70 ° C.   5- (2-bromoethoxy) -10,11-dihydro-5H-dibenzo [a, d] Cycloheptene (9.5 g, 0.03 mol), ethyl 4-piperidine carboxylate (4.7 g g, 0.03 mol), potassium carbonate (8.1 g, 0.06 mol) and dimethyl sulfoxide (120 ml ) Was stirred on a water bath at 40-50 ° C. for 4 h. The mixture was cooled, filtered, The solid was washed with dimethyl sulfoxide (10 ml). Dilute the combined filtrate with water (720 ml) and extracted with diethyl ether (2 × 200 ml). Ether extract Wash with water and dry (MgSOFour), And the solvent was evaporated under vacuum. That The residue was dissolved in 2-propanol and dissolved in hot oxalic acid in 2-propanol. The liquid (4.0 g) was added. After cooling, ethyl 1- (10,11-dihydro-5H-dibenzo [A, d] cyclohepten-5-yloxy) -1-ethyl-4-piperidineca Ruboxylate hydrogen oxalate precipitated. This is 8.3 g (53 %) And use it without purification for further reactions did.   An aqueous suspension of the above oxalate (7.3 g, 0.015 mol) was added with a 25% ammonia solution. Potassium was extracted and extracted with diethyl ether (2 × 100 ml). Wash the organic layer with water (2 x 50 ml), dried (MgSOFour) And vacuum evaporation. This is oil 5.7 g (96%) of free ethyl ester were provided.   2.01 g (0.005 mol) of the above ester, 2.4 ml of 20% aqueous sodium hydroxide and A mixture of ethanol (15 ml) was stirred at room temperature for 4 h and overnight. Dichloromethane (2 50 ml) and with magnetic stirring and cooling (water / ice bath) 〜2.5 N HCl Was gently added dropwise until pH was reached. The aqueous layer was separated and the organic layer was dried (MgSOFour ) And vacuum evaporation. Re-evaporate the solid residue twice with acetone Was done. This occurs via crystallization from a mixture of ethanol and ether at 1.68. g (83%) of the title compound were provided. Dichlorometa in crystal samples Was removed under vacuum at elevated temperature. M.p. 192-194 ° C.1 H NMR (DMSO-d6): 7.42 (bd, 2H); 7.19 (m, 6H); 5.62 (s, 1H); 3.83 (t 3.28 (t, 1H); 4.96 (d, 1H); 2.53 (m, 1H); 3.37 (m, 6H); 3.00 (M, 4H); 1.99 (m, 4H).

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｋ 31/495 ＡＡＨ Ａ６１Ｋ 31/495 ＡＡＨ 31/535 ＡＤＰ 31/535 ＡＤＰ Ｃ０７Ｄ 207/16 Ｃ０７Ｄ 207/16 211/22 211/22 211/46 211/46 211/60 211/60 211/62 211/62 217/22 217/22 245/02 245/02 265/30 265/30 295/08 295/08 Ａ (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＤＥ， ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，ＩＴ，Ｌ Ｕ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ，ＣＦ ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＭＬ，ＭＲ，ＮＥ， ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＫＥ，ＬＳ，ＭＷ，ＳＤ，Ｓ Ｚ，ＵＧ)，ＵＡ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ ，ＲＵ，ＴＪ，ＴＭ)，ＡＬ，ＡＭ，ＡＴ，ＡＵ，ＡＺ ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ，ＣＺ， ＤＥ，ＤＫ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＥ，ＨＵ，Ｉ Ｓ，ＪＰ，ＫＥ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＫ，ＬＲ ，ＬＳ，ＬＴ，ＬＵ，ＬＶ，ＭＤ，ＭＧ，ＭＫ，ＭＮ， ＭＷ，ＭＸ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，ＲＵ，Ｓ Ｄ，ＳＥ，ＳＧ，ＳＩ，ＳＫ，ＴＪ，ＴＭ，ＴＲ，ＴＴ ，ＵＡ，ＵＧ，ＵＳ，ＵＺ，ＶＮ (72)発明者 アンデルセン，ヘンリック スネ デンマーク国，デーコー−2100 コペンハ ーゲン エー，カステルスバイ 24 エス テー．テーホー. (72)発明者 ホフルベグ，ロルフ デンマーク国，デーコー−3490 クビスト ガールド，ニーボバイ ６ (72)発明者 ヨーゲンセン，ティン クロフ デンマーク国，デーコー−2730 ヘーレ ブ，スタブンスビエルク アレ 80 (72)発明者 マドセン，ペーター デンマーク国，デーコー−2880 バグスバ エルト，ウルベビエルク ７ (72)発明者 ズデネク，ポリフカ チェコ国，150 00 プラハ ５，ズボロ フスカ 23 (72)発明者 アレクサンドラ，シルハンコバ チェコ国，142 00 プラハ ４，ベー スティラフ 1311／３ (72)発明者 カレル，シンデラー チェコ国，140 00 プラハ ４，オルブ ラエトバ 50────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. 6 Identification code FI A61K 31/495 AAH A61K 31/495 AAH 31/535 ADP 31/535 ADP C07D 207/16 C07D 207/16 211/22 211/22 211/46 211/46 211/60 211/60 211/62 211/62 217/22 217/22 245/02 245/02 265/30 265/30 295/08 295/08 A (81) Designated country EP ( AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ) , TM), AL, AM, AT, AU, AZ, BB, B , BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA , UG, US, UZ, VN (72) Inventors Andersen, Henriksne Denmark-2100 Copenhagen A, Castelsby 24 ST. Teho. (72) Inventor Hoflebeg, Rolf Denmark-3490 Kvist Girard, Nybabay 6 (72) Inventor Jogensen, Tinklov Denmark-2730 Hereb, Stavnsbjerg Alec 80 (72) Inventor Madsen, Peter Denmark-2880 Bagsbaerto, Urbevierk 7 (72) Inventor Zdenek, Polivka Czech Republic, 150 00 Prague 5, Zboro Huska 23 (72) Inventor Alexandra, Silhankova Czech Republic, 142 00 Prague 4, Base Stilaf 1311/3 (72) Inventor Karel, Cinderer Czech Republic, 140 00 Prague 4, Orb Laetva 50

Claims (1)

【特許請求の範囲】 １．次式Ｉの化合物 （式中、Ｒ1，Ｒ2，Ｒ3，Ｒ4，Ｒ5及びＲ6は独立して水素、ハロゲン、トリフル オロメチル、ヒドロキシ、Ｃ1ー6−アルキル、Ｃ1-6アルコキシ、−NR7R8又は−S O2NR7R8であり、ここでＲ7及びＲ8は独立して水素又はＣ1ー6−アルキルであり； そして Ｘは任意的な結合の終点、−CH2−，−CH2CH2−，−CH＝CH−，−Ｏ−，−S(O )z−（ここでｚは０，１又は２である）、又は−N（R9）−（ここでＲ9は水素又 はＣ1ー6−アルキルである）あり；そして Ｙは−Ｏ−、−S(O)q−（ここでｑは０，１又は２である）又は−N（R10）− であり、ここでＲ10は水素又はＣ1ー6−アルキルである；そして ｒは１，２，３又は４であり；そして Ｚは から選ばれ、そしてｎは１又は２であり；そして Ｒ11は−（CH2）mOH又は−（CH2）tCOR12であり、こでｍは０，１，２，３， ４，５又は６であり、そしてｔは０又は１であり、そしてここでＲ12は−OH，− NH2，−NHOH又はＣ1ー6−アルコキシであり；そして Ｒ13は水素、ハロゲン、トリフルオロメチル、ヒドロキシ、Ｃ1ー6−アルキル 又はＣ1ー6−アルコキシであり；そして Ｒ14は水素、Ｃ1ー6−アルキル、Ｃ1ー6−アルコキシ、又はハロゲン、トリフル オロメチル、ヒドロキシ、Ｃ1ー6−アルキルもしくはＣ1ー6−アルコキシにより任 意的に置換されたフェニルであり；そして Ｒ15は水素又はＣ1ー6−アルキルであり；そして …は任意的に単結合又は二重結合である） 又はその薬理学的に許容される塩。 ２．以下から選ばれる請求項１記載の化合物： １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−３−ピペリジンカルボキサミド； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−４−ピペリジンカルボン酸 ； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−２−ピペリジンカルボン酸； （１−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン− ５−イルオキシ）エチル）ピペリジン−３−イル）メタノール； ４−（４−クロロフェニル）−１−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ 〔ａ，ｄ〕シクロヘプテン−５−イルオキシ）エチル）−４−ピペリジノール； ４−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−４−ピペラジンカルボン酸； （２Ｓ，４Ｒ）−１−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シ クロヘプテン−５−イルオキシ）エチル）−４−ヒドロキシ−２−ピロリジンカ ルボン酸； ４−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−２−モルホリンカルボン酸； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−２−アジリジンカルボン酸； ２−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−１，２，３，４−テトラヒドロ−４−イソキノリンカ ルボン酸； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−４−メチル−１，４−ジア ゼパン−６−カルボン酸； ２−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−１，２，３，４−テトラヒドロ−３−イソキノリンカ ルボン酸； １−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン−５ −イルオキシ）エチル）−３−ピペリジンカルボン酸ヒドロキシアミド； （４−（２−（10，11−ジヒドロ−５Ｈ−ジベンゾ〔ａ，ｄ〕シクロヘプテン− ５−イルオキシ）エチル）ピペラジン−１−イル）酢酸； 又はその薬理学的に許容される塩。 ３．請求項１に記載の化合物の製造方法であって、 ａ）次式IIの化合物 （式中、Ｒ1，Ｒ2，Ｒ3，Ｒ4，Ｒ5，Ｒ6，Ｘ，Ｙ及びｒは前記の通りであり、そ してＷは適当な離脱基、例えばハロゲン、ｐ−トルエンスルホネート又はメシレ ートである）を次式IIIの化合物 HZ （III） （式中、Ｚは前記の通りである）と反応させて式Ｉの化合物を形成するか、又は ｂ）Ｒ12がＣ1ー6−アルコキシである式Ｉの化合物を加水分解し てＲ12がOHである式Ｉの化合物を形成する； ことを含んで成る方法。 ４．活性成分としての請求項１記載の化合物と、薬理担体又は希釈剤とを含ん で成る薬理組成物。 ５．神経原性炎症の処置に適する薬理組成物であって、有効量の請求項１記載 の化合物と、薬理学的に許容される担体又は希釈剤とを含んで成る組成物。 ６．単位投与体当り 0.5mg〜1000mgの請求項１記載の化合物を含んで成る、請 求項４又は５記載の薬理組成物。 ７．神経原性炎症の処置を必要とする被検者のかかる処置の方法であって、前 記被検者に有効な量の請求項１記載の化合物を投与することを含んで成る方法。 ８．神経原性炎症の処置を必要とする被検者のかかる処置の方法であって、前 記被検者に請求項５記載の薬理組成物を投与することを含んで成る方法。 ９．神経原性炎症の処置のための医薬品を製造するための請求項１記載の化合 物の利用。[Claims] 1. Compounds of Formula I (Wherein, R 1, R 2, R 3, R 4, hydrogen R 5 and R 6 is independently halogen, trifluoromethyl, hydroxy, C 1 -6 - alkyl, C 1-6 alkoxy, -NR 7 is R 8 or -S O 2 NR 7 R 8, wherein R 7 and R 8 are independently hydrogen or C 1 -6 and - alkyl; and X is any binding endpoint, -CH 2 - , -CH 2 CH 2 -, - CH = CH -, - O -, - S (O) z - ( wherein z is 0, 1 or 2), or -N (R 9) - (wherein R 9 is hydrogen or C 1 -6 - alkyl as) there; and Y is -O -, - S (O) q - ( wherein q is 0, 1 or 2) or -N (R 10) -, wherein R 10 is hydrogen or C 1 -6 - it is alkyl; and r is 1, 2, 3 or 4; and Z is Selected from and n is 1 or 2; and R 11 is - (CH 2) m OH or - (CH 2) t COR is 12, the m in this 0,1,2,3, 4, 5 or 6, and t is 0 or 1, and wherein R 12 is -OH, - NH 2, -NHOH or C 1 -6 - alkoxy; and R 13 is hydrogen, halogen, trifluoromethyl methyl, hydroxy, C 1 -6 - alkyl or C 1 -6 - alkoxy; and R 14 is hydrogen, C 1 -6 - alkyl, C 1 -6 - alkoxy, or halogen, trifluoromethyl, hydroxy, C 1 -6 - alkyl or C 1 -6 - alkoxy by be optionally substituted phenyl; and R 15 is hydrogen or C 1 -6 - alkyl; and ... is optionally a single bond or a double bond Or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, which is selected from the following: 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -3-piperidinecarboxamide; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -4-piperidinecarboxylic acid; 1- (2- (10,11-dihydro-5H-dibenzo [a, d]) (Cyclohepten-5-yloxy) ethyl) -2-piperidinecarboxylic acid; (1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) piperidin-3-yl) Methanol; 4- (4-chlorophenyl) -1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -4- Peridinol; 4- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -4-piperazinecarboxylic acid; (2S, 4R) -1- (2- (10 , 11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -4-hydroxy-2-pyrrolidinecarboxylic acid; 4- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -2-morpholinecarboxylic acid; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -2-aziridinecarboxylic acid Acid; 2- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -1,2,3,4-tetrahydro-4-i Quinoline carboxylic acid; 1- (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -4-methyl-1,4-diazepan-6-carboxylic acid; (2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid; 1- (2- (10 , 11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) ethyl) -3-piperidinecarboxylic acid hydroxyamide; (4- (2- (10,11-dihydro-5H-dibenzo [a, d Cyclohepten-5-yloxy) ethyl) piperazin-1-yl) acetic acid; or a pharmacologically acceptable salt thereof. 3. A process for the preparation of a compound according to claim 1, wherein: a) a compound of formula II Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y and r are as described above, and W is a suitable leaving group such as halogen, p-toluenesulfonate or Which is a mesylate) with a compound HZ (III) of the following formula III to form a compound of the formula I, or b) wherein R 12 is C 1-6- Hydrolyzing a compound of formula I which is alkoxy to form a compound of formula I wherein R 12 is OH. 4. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient and a pharmacological carrier or diluent. 5. A pharmaceutical composition suitable for treating neurogenic inflammation, comprising an effective amount of a compound according to claim 1 and a pharmacologically acceptable carrier or diluent. 6. The pharmaceutical composition according to claim 4 or 5, comprising from 0.5 mg to 1000 mg of the compound according to claim 1 per unit dose. 7. A method of treating a subject in need thereof for treating neurogenic inflammation, said method comprising administering to said subject an effective amount of a compound of claim 1. 8. A method of treating a subject in need of treatment for neurogenic inflammation, said method comprising administering to said subject a pharmacological composition according to claim 5. 9. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of neurogenic inflammation.
JP8529880A 1995-04-07 1996-04-01 New heterocyclic compounds Pending JPH11503132A (en)

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