JP2016172750A - 治療化合物 - Google Patents
治療化合物 Download PDFInfo
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- JP2016172750A JP2016172750A JP2016090584A JP2016090584A JP2016172750A JP 2016172750 A JP2016172750 A JP 2016172750A JP 2016090584 A JP2016090584 A JP 2016090584A JP 2016090584 A JP2016090584 A JP 2016090584A JP 2016172750 A JP2016172750 A JP 2016172750A
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Abstract
Description
本出願は、2009年5月5日に出願された米国仮出願第61/215,504号、2009年9月10日に出願された米国仮出願第61/241,384号、及び2009年9月24日に出願された米国仮出願第61/277,408号の恩恵を主張するPCT国際出願である。前記米国仮出願のそれぞれの全内容は、本明細書中に組み込まれる。
[連邦政府により支援された研究のもとでなされた発明に対する権利の記載]
(式中、
R1は独立してH、NH2、NH(R’)、N(R’)2であるか;
又は
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;
R2は独立して−(CH2)n−であり;
各nは独立して1又は2であり;
R3は独立してH、OH、又はハロであり;
R4は独立してH、OH、又はハロであり、
各R5は独立してアルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環式、又はアルコキシであり;
R6は独立してH又はアルキルであり;
R7は独立してH、又はN(アルキル)2であり;
各R8は独立してアリール、シクロアルキル、ヘテロアリール、又は複素環(場合によって1、2、3、若しくは4個の独立したR5で置換されている)である)
によって表されるか、又はその塩、水和物若しくは溶媒和物である。
R1は独立してH、NH2、NH(R’)、N(R’)2であるか;
又は
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;
R2は独立して−(CH2)n−であり;
各nは独立して1又は2であり;
R3は独立してH、OH、又はハロであり;
R4は独立してH、OH、又はハロであり
各R5は独立してアルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環式、又はアルコキシである)であり;
R6は独立してH又はアルキルであり;
R7は独立してH、若しくはN(アルキル)2であり;そして
各R8は独立してアリール、シクロアルキル、ヘテロアリール、若しくは複素環(場合によって1、2、3、若しくは4個の独立したR5で置換されている)である)
により表されるか、又はその塩、水和物若しくは溶媒和物である前記方法を提供する。
R1は独立してH、NH2、NH(R’)、N(R’)2であるか;
又は
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;
R2は独立して−(CH2)n−であり;
各nは独立して1又は2であり;
R3は独立してH、OH、又はハロであり;
R4は独立してH、OH、又はハロであり
各R5は独立してアルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環式、又はアルコキシであり;
R6は独立してH又はアルキルであり;
R7は独立してH、又はN(アルキル)2であり;そして
各R8は独立してアリール、シクロアルキル、ヘテロアリール、又は複素環式(場合によって1、2、3、若しくは4個の独立したR5で置換されている)である)
により表される化合物又はその塩、水和物若しくは溶媒和物を提供する。
R1は独立してH、NH2、NH(R’)、N(R’)2であるか;
又は
(式中、環Aは、O、N及びSから選択される0〜3個のさらなるヘテロ原子を含む3〜8員複素環式若しくはヘテロアリール;式中、環Aは場合によって置換されていてもよい)であり;
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;
R2は独立して−(CH2)n−であり;
各nは独立して1又は2であり;
R3は独立してH、OH、又はハロであり;
R4は独立してH、OH、又はハロであり;
各R5は独立してアルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環式、又はアルコキシであり;
R6は独立してH又はアルキルであり;
R7は独立してH、又はN(アルキル)2であり;
mは1、2又は3である)によって表されるか、又はその塩、水和物若しくは溶媒和物である。
R5は、H、メチル、エチル、プロピル、イソプロピル、ブチル、s−ブチル、t−ブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、フェニル、F、Cl、若しくはBrであり;そして
mは1、2、若しくは3である)
によって表されるか、又はその塩、水和物若しくは溶媒和物である。
(式中、
R1は独立してH、NH2、NH(R’)、N(R’)2であるか;
又は
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;
R2は独立して−(CH2)n−であり;
nは2であり;
R3は独立してH、OH、又はハロであり;
R4は独立してH、OH、又はハロであり
R5は、H、アルキル、又はハロであり;
R6は独立してH又はアルキルであり;
R7はH、又はN(アルキル)2であり;そして
mは1、2、又は3である)
によって表されるか、又はその塩、水和物若しくは溶媒和物である。
(式中、
R1は独立してH、又はN(アルキル)2であり;
R2は独立して−(CH2)n−であり;
各nは独立して1又は2であり;
R3は独立してH、OH、又はハロであり;
R4は独立してH、OH、又はハロであり
各R5は独立してアルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環式、又はアルコキシであり;
R6は独立してH又はアルキルであり;
R7は独立してH、NH2、NH(R’)、N(RM)2であるか;
又は
(式中、環Aは、O、N及びSから選択される0〜3個のさらなるヘテロ原子を含む3〜8員複素環式若しくはヘテロアリールであり;環Aは場合によって置換されていてもよい)であり;
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;そして
各R8は独立してアリール、シクロアルキル、ヘテロアリール、又は場合によって1、2、3、若しくは4個の独立したR5で置換された複素環式である)
により表される化合物、又はその塩、水和物若しくは溶媒和物を提供する。
R1は独立してH、NH2、NH(R’)、N(R’)2であるか;
又は
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;
R2は独立して−(CH2)n−であり;
各nは独立して1又は2であり;R3はH、OH、又はハロであり;
R4はH、OH、アリール、ヘテロアリール、又はハロであり;
各R5は独立してアルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキルであり;
R7はH、又はN(アルキル)2であり;そして
Zはアリール、ニトロ、アミノ、ヘテロアリール、シクロアルキルであり、そのそれぞれは場合によって1、2、3、若しくは4個の独立したR5で置換されている)によって表される化合物、又はその塩、水和物若しくは溶媒和物を提供する。
本発明のさらなる説明の前に、本発明がより容易に理解されるように、便宜のために、いくつかの用語をまず定義し、ここにまとめる。
一態様では、本発明は、5−HT及び/又はRSK結合活性を(直接的若しくは間接的に)調節(例えば阻害若しくは刺激)することができる化合物を提供する。
一実施形態では、本発明は、GPCR介在性障害に関して対象を治療するための方法であって、対象に、GPCR標的を調節(刺激、拮抗)することができる有効量の化合物を投与することによる方法を提供する。GPCR障害には、そのようなGPCRが関与する疾患及び障害が含まれる。本明細書中に記載される化合物、組成物及び方法は、たとえば、神経精神障害(例えば、肥満、中毒、コカイン中毒、アンフェタミン/メタンフェタミン中毒、不安、鬱病、統合失調症、及び睡眠障害)、神経変性障害(例えば、パーキンソン病、アルツハイマー病)、神経障害(例えば、てんかん)、心臓血管障害(例えば、5−HT2b介在性疾患、高血圧)、胃腸障害(例えば、過敏性腸症候群)、及び泌尿生殖路障害(例えば、膀胱制御)をはじめとする障害の治療又は予防に有用である。ある実施形態では、対象は、哺乳類、例えば霊長類、例えばヒトである。
本発明は、有効量の化合物及び薬剤的に許容される担体を含む医薬組成物も提供する。さらなる実施形態では、有効量は、前述のように、5−HT2C及び/又はRSK障害を治療するために有効である。
本発明の化合物を以下の合成スキームにしたがって作成することができる。
1)
スキームA:チャート1におけるN−置換PATの合成。スチレン又はハロスチレン7の[2]との反応により、4−置換−テトラレン−2−オールフェニルアセテート8を得る。8の還元により、テトラール−2−オール9を得る。トランス−(2S,4R)−N−置換PAT10は、9のトシル化とそれに続く環状アミン(ピロリジン、ピペリジン等)を用いた環状アミンSΝ2反転及びキラル固定相(CSP)−HPLCによるエナンチオマー分離によって調製される(Vincek & Booth 2009)。
スキームE:チャート3におけるテトラヒドロナフチル置換基を有するPATの合成。
容易に調製される1及び市販の2により、無水トリフルオロ酢酸(TFAA)を用いて置換フェニルテトラレン−2−オールフェニルアセテート3を得た(Vincek & Booth, 2009)。化合物3を水素化ホウ素ナトリウムにより還元して、ラセミのシス−オール4を得、これを直接トシル化し、トランス−ジメチルアミン5に変換する。CSP−HPLCを用いて、(+)−トランス−(2R,4S)−及び(−)−トランス−(2S,4R)−5を分離する。これらの新規PAT類似体を三臭化ホウ素により還元して、別のシリーズの新規化合物6にすることができた。ミツノブ反応により4を7に変換し、続いて,トシル化、アミノ化及びCSP−HPLCエナンチオマー分離を行って、(+)−及び(−)−シス−PAT8及び9を得る。
本発明を説明するが、本発明の範囲を制限しないことを意図する以下の実施例により、本発明をさらに説明する。
すべての試薬は、商業的供給元から入手し、さらに精製することなく使用した。1H及び13C NMRを対応して共振周波数400及び100MHzで、CDCl3中で集めた。化学シフトをテトラメチルシランからのppmで報告する。フラッシュカラムクロマトグラフィーを、シリカゲル60(230〜400メッシュ)を用いて実施した。融点は、水銀温度計を備えたMel−Temp装置で測定した。HPLCキラル分離は、RegisCell(商標)(5μm、25cm×10mm i.d.)カラムを備えたHPLC装置によって測定した。いくつかの1H及び13C NMRスペクトルの小さなピーク(<5%)は、位置異性体の形成が原因であった。
すべての細胞系をATCCの示唆にしたがって維持した。チャイニーズハムスター卵巣細胞(CHO−Kl、ATCC CCL−61)は10%のウシ胎仔血清、1%の重炭酸ナトリウム(Mediatech 25−035−CI)、10IU/mlのペニシリン及び10ug/mlのストレプトマイシンを追加したHamのF−12培地中、並びにヒト胚腎臓(HEK)293は、1.5g/Lの重炭酸ナトリウム、0.1mMの非必須アミノ酸、及び1.0mMのピルビン酸ナトリウム(90%)と10%ウシ胎仔血清、10IU/mlのペニシリン及び10ug/mlのストレプトマイシンを含むように調節された2mMのL−グルタミンを含む最小必須培地(イーグル)(MEM)中。細胞を、5%のCO2を含む加湿インキュベータ中37℃で増殖させる。ヒトHT2A、5−HT2B、及び5−HT2C(野生型)をコード化するcDNAを、クローン細胞の一過性トランスフェクションのためにUMR(Rolla, MO)から購入する。放射性受容体結合アッセイのために、5−HT2A、5−HT2B、及び5−HT2C受容体膜をトランスフェクトされたCHO−K1細胞から調製する。PLC/IP形成の活性を測定する機能的アッセイのために、5−HT2A及び5−HT2C受容体についてはトランスフェクトされたCHO−K1細胞を使用する。しかし、5HT2B受容体については、トランスフェクトされたHEK細胞を用いて、PLC/IPアッセイに関してさらに強力かつ一貫した結果が得られる(Setola et al., 2005)。トランスフェクションの24時間前に、細胞を、放射性受容体結合アッセイについては100mm皿中、40%コンフルエンシーで、又は機能的アッセイについては12ウェルプレート中、1ウェルあたり105細胞で蒔く。CHO−K1細胞を、放射性受容体結合アッセイについては100mm皿につき12μgのプラスミド及び32μlのリポフェクタミン(Invitrogen)で、又は機能的アッセイについてはウェルあたり0.8μgのプラスミド及び4.0μlのリポフェクタミンで、一時的にトランスフェクトする。HEK細胞を用いた5−HT2B機能的アッセイについて、24μgのプラスミドDNAを60μlのリポフェクタミン2000(Invitrogen)と混合して、10cmプレート中1〜2×106細胞をトランスフェクトする。細胞にトランスフェクトされた受容体をさらに24時間発現させる(Herrick, 1997)。
放射性受容体飽和及び競合結合アッセイを、膜ホモジネートを用い、系統学的に密接に関連するヒスタミンH1GPCRについて以前に報告されている本発明者らの方法と同様にして実施する(Booth, 2002;Moniri et al., 2004)。[3H]−ケタンセリンを用いて、5−HT2A受容体を放射標識し、[3H]−メスレルギンを5−HT2B及び5−HT2c受容体について使用する。手短に言うと、CHO細胞トランスフェクションの48時間後、細胞を収集し、0.1%のアスコルビン酸及び4.0mMのCaCl2を含むpH7.4の50mMのTris−HCl(アッセイ緩衝液)中で均質化する。ホモジネートを35,000gで25分間遠心分離し、結果として得られる膜ペレットをアッセイ緩衝液中に再懸濁させる。タンパク質濃度を、Lowryらの方法(Lowry, 1951)により測定する。飽和結合アッセイに関して、100μgのタンパク質を含む膜懸濁液を、0.1〜5.0nMの[3H]−ケタンセリン(5−HT2A受容体)又は0.1〜20nMの[3H]−メスレルギン(5−HT2B及び5−HT2c受容体)とともに250μlの合計アッセイ緩衝液体積中でインキュベートする。非特異的結合を、10μMのメチセルギド(5−HT2A受容体)又は1.0μMのミアンセリン(5−HT2B及び5−HT2c受容体)の存在下で測定する。競合結合アッセイを、1.0nMの[3H]−ケタンセリン又は[3H]−メスレルギンを用いて同様に実施する。放射性受容体結合アッセイ混合物のインキュベーションは、1.0時間37℃で、96ウェルセルハーベスター(Tomtec, Hamden, CT)を用いてWhatman GF/Bフィルターを通した急速ろ過法により終了させる。フィルターディスク上に保持される膜結合[3H]放射性リガンドを、液体シンチレーション分光測定法によって定量化する。データを、Prism 4.03(GraphPad Software Inc., San Diego, CA)のS字形曲線適合アルゴリズムを用いた非線形回帰により分析する。リガンド親和性は、IC50データを、式K0.5=/C50/I+LIKQ(式中、Lは親和性KDを有する放射性リガンドの濃度である)を用いてK0.5値に変換することによって、Ki値の近似値として表す(Cheng, 1973)。
PLCの機能的活性化を、すでに報告されているようにして、セロトニン5−HT2C受容体を一時的に発現するCHO細胞又はセロトニン5−HT2A若しくは5−HT2B受容体を一時的に発現するHEK細胞における[3H]−IP形成として測定する(Moniri et al., 2004)。手短に言うと、トランスフェクションの32時間後に、イノシトールを含まないダルベッコの修飾イーグル培地(DMEM)中の細胞を12時間1.0μCi/mlのミオ−[2−3H]−イノシトール(PLC−β基質ホスファチジルイノシトールの放射標識された前駆体)とともにインキュベートする。細胞を次いで洗浄し、10mMの塩化リチウム、10μMのパルギリン(HEK細胞について5%の透析されたウシ胎仔血清を添加)、及び種々の濃度の試験リガンドを含むDMEM中で45〜60分間37℃でインキュベートする。培地を吸引した後、50mMのギ酸とともにインキュベーション(15〜60分)することによって、ウェルを溶解させる。ギ酸を水酸化アンモニウムで中和し、各ウェルからの内容物を個々のAG1−X8 200−400ホルメート樹脂アニオン交換カラムに添加する。ギ酸アンモニウム/ギ酸(1.2M/0.1M)を用いて、液体シンチレーション分光測定法によってトリチウムを計数するために、[3H]−IPをシンチレーションバイアル中に直接溶出させる。結果として得られるデータを、Prism 4.03の非線形回帰アルゴリズムを用いて分析し、対照[3H]−IP形成の平均パーセンテージとして表し、効力は、最大基礎(構成的)[3H]−IP形成を50%±S.E.M.(n≧3)刺激(EC50)又は阻害(IC50)するために必要な濃度として表す。
PLCの機能的活性化は、本発明者らの研究室により以前に報告されているように、5−HT2A又は5−HT2C受容体を一時的に発現するCHO細胞及び5HT2B受容体を一時的に発現するHEK細胞において[3H]−IP形成として測定される(Booth, 2002;Moniri et al., 2004)。手短に言うと、トランスフェクションの32時間後、イノシトールを含まないダルベッコの修飾イーグル培地(DMEM)中の細胞を、1μCi/mlのミオ−[2−3H]−イノシトール(PLC−β基質ホスファチジルイノシトールの前駆体)で標識する。細胞を次いで洗浄し、25mMのHepes(pH7.4)、10mMのLiCl、10μMのパルギリン(HEK細胞について、5%の透析されたFBSを添加)、並びに様々な濃度の試験リガンドを含むDMEM中、45〜60分間37℃でインキュベートする。培地を吸引した後、ウェルを氷上に置き、50mMのギ酸(15〜60分)とともにインキュベーションすることによって溶解させる。ギ酸を水酸化アンモニウムで中和し、各ウェルからのすべての内容物を個々のAG1−X8 200−400ホルメート樹脂アニオン交換カラムに添加する。ギ酸アンモニウム/ギ酸(1.2M/0.1M)を使用して、液体シンチレーション分光測定法によってトリチウムを計数するために、[3H]−IPをシンチレーションバイアル中に直接溶出させる。結果として得られるデータを、Prism 4.03の非線形回帰アルゴリズムを用いて分析し、対照[3H]−IP形成の平均パーセンテージとして表し、効力を50%最大[3H]−IP形成(EC50)±S.E.M(n≧3)を得るために必要な濃度として表す。
5HT−サブタイプ受容体の放射性リガンド飽和結合分析:ヌルトランスフェクト(null−transfected)CHO及びHEK細胞から調製された膜を用いて測定可能な特異的放射性リガンド結合はない。しかし、5−HT2A、5−HT2B、又は5−HT2CcDNAで一時的にトランスフェクトされたCHO細胞から調製された膜を用いて、飽和可能な特異的放射性リガンド結合が起こる。[3H]−ケタンセリンは、5HT2A受容体の見かけ上1つの集団(Bmax=1.73±0.11pmol/mgタンパク質)と高親和性(KD=0.80±0.03nM)で結合する。同様に、[3H]−メスレルギンは、Bmax=1.13±0.39pmol/mgタンパク質及びKD=5.19±0.36nMで5HT2B受容体の1つの集団を標識する。[3H]−メスレルギンはまた、高親和性(KD=0.88±0.03nM)で5HT2c受容体の見かけ上1つの集団(Bmax=8.37±0.15pmol/mgprot)も標識する。
RSK及び他のキナーゼのキナーゼ阻害活性は、当該技術分野で公知である。RSK活性に関するアッセイは、基本的に、Jeffrey A. Smith, Celeste E. Poteet−Smith, Yaming Xu, Timothy M. Errington,, Sidney M. Hecht, and Deborah A. Lannigan Cancer Res 2005;65:(3), pp. 1027−1034. February 1, 2005で記載されているようにして実施される。
メタ置換化合物の合成及びエナンチオマーの分離
一般的合成法:本発明の化合物を合成するのに有用な関連する方法は当該技術分野で公知であり、本発明者等の合成医薬品化学刊行物(例えば、Ghoneim, O. M.;Legere, J. A.;Golbraikh, A.;Tropsha, A.;Booth, R. G. Bioorg. Med. Chem. 2006, 14, 6640;Bucholtz, E. C;Brown, R. L.;Tropsha, A.;Booth, R. G.;Wyrick, S. D. J. .Med. Chem. 1999, 42, 3041;Wyrick SD, Booth RG, Myers AM, Owens CE, KuIa NS, Baldessarini RJ, McPhail AT, and Mailman RB(1993)Synthesis and pharmacological evaluation of 1−phenyl−3−amino 1,2,3,4−tetrahydronaphthalenes as ligands for a novel receptor with sigma−like neuromedulatory activity. J Med Chem 36:2542−2551を包含する)で記載されている。インビトロの薬理学的研究は、まず、ラセミのシス及びトランス生成物を使用する。ラセミ化合物は、ジアステレオマー塩に誘導体化し、続いて分画晶出(differential crystallization)を行うことにより(+)−及び(−)−エナンチオマーに分割することができるか、又はキラル還元ステップを用いて新たに合成することができる。すでに合成された純粋なエナンチオマーと比較することにより単結晶X線結晶学又は分光測光法(NMR、旋光度)によって絶対配置を帰属させる。NMR、元素分析、質量分析、融点及び薄層クロマトグラフィーを用いて生成物を純度について特性化する(HCl塩として)。
ジイソピノカンフェニル−ボラン(DIP)類似体は、最近、スキーム2におけるケトン4と類似した構造を有するケトンについて立体選択的な還元剤として報告された(例えば、Cha et al., 2005を参照)。
結合、機能、3D QSAR、及び分子モデリング結果に基づいて、(−)−トランス−置換フェニルアミノテトラリン(PAT)C(1)ペンダントフェニル部分は、5HT2A及び5HT2B受容体の活性化なしに完全に有効な5HT2cアゴニスト活性を提供するのに重要であることが示された。
化合物を、非メチル化遊離アミンをジアステレオマー塩に誘導体化し、続いて分画晶出することにより(+)−及び(−)−エナンチオマーに分割するか、又はキラル還元ステップを用いて新たに合成した。すでに合成された純粋なエナンチオマーと比較することにより単結晶X線結晶学又は分光測光法(NMR、旋光度)によって絶対配置を帰属させた。生成物(HCl塩として)は、NMR、元素分析、質量分析、融点及び薄層クロマトグラフィーを用いて純度について特性化した。本明細書中で具体的に記載される化合物には、R2が、表7のボロン酸化合物中のホウ素原子に結合した化学基又は部分(例えば、置換若しくは非置換アルキル、アルケニル、又はアリール基)であるものが含まれる。本明細書中の化合物を調製するための別の手順は、PCT国際公開番号WO2008/156707(出願番号PCT/US2008/007458)にも記載されている。
トリフルオロアセチル混合無水物及び3−ハロスチレン(フルオロ、クロロ、及びブロモ)を、溶媒を追加することなく、4−(3−ハロフェニル)−3,4−ジヒドロナフタレン−2−イルフェニルアセテート(ブロモ、50%)に関するカスケードフリーデルクラフツ環状−アシルアルキル化、エノール化、及びO−アシル化に付した。マスクされた4−フェニルテトラール−2−オンの塩基アルコール分解により、インサイチュ不斉移動水素化のためのケト基が明らかになった。ブロモ−誘導体は、4−(ビフェン−3−イル)−3,4−ジヒドロナフタレン−2−イルフェニルアセテートを得るためにフェニルボロン酸とのスズキカップリングを受け、トランス−4−フェニル−2−アミノテトラリンへの短い有効な経路を提供した。
スキーム4:4dの(例えば、表5からの)フェニルボロン酸でのスズキカップリング(a)Wolfe, J. P.;Singer, R, A.;Yang, B. H.;Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. b)Wolfe, J. P.;Buchwald, S. L. Angew. Chem. Int. Ed. 1999, 38, 2413を参照)によりスムーズに4−(ビフェニル−3−イル)−3,4−ジヒドロ−ナフタレン−2−イルフェニル−アセテート14を得、これをスキーム3におけるようなプロトコルにしたがって所望の置換フェニルアミノテトラリンに変換した。
ベンゼンルテニウム(II)クロリド二量体(55mg、0.11ミリモル)及び(1R,2R)−(−)−N−(4−トルエンスルホニル)−1,2−ジフェニルエチレンジアミン(80mg、11ミリモル)をイソプロパノール(25mL)中で混合し、80℃で30分間加熱すると、触媒混合物が生成した。別に、4−シクロヘキシル−3,4−ジヒドロナフタレン−2−イルフェニルアセテート1a(950mg、2.8ミリモル)をイソプロパノール(25mL)中で50℃まで加熱した。窒素ガスを用いて、両頭針を通してIaを含むフラスコに触媒混合物を押し込み、直後にKOH(0.5g)のイソプロパノール(50mL)中混合物を添加した。3時間後、セライト上シリカゲルのパッドを通して反応物を濾過し、次いで減圧下で濃縮した。粗物質をカラムクロマトグラフィー(Si−ゲル)により精製して、2aを40%の収率で得た。
(2R,4R)−4−シクロヘキシル−1,2,3,4−テトラヒドロナフタレン−2−オール2a(0.23g、0.1モル)、p−トルエンスルホニルクロリド(0.20g、0.11モル)、及びピリジン(1.5mL)を溶液中で24時間、室温、不活性雰囲気(N2)下で撹拌した。溶媒を除去し、粗物質をカラムクロマトグラフィー(Si−ゲル)により精製して、3aを62%の収率で得た。HRMS m/z C23H28O3Sについての計算値 407.1651 [M+Na]+、実測値 407.1631。
ジメチルアミン(H2O中40%、6mL)及び(2R,4R)−4−シクロヘキシル1,2,3,4−テトラヒドロナフタレン−2−イル4−メチルベンゼンスルホネート3a(0.19g、0.5ミリモル)を試験管中に入れ、密封し、83℃で24時間加熱した。溶媒を除去し、粗物質をカラムクロマトグラフィー(Si−ゲル)により精製して、4a(収率70%)及び5a(30%、(R)−1−シクロヘキシル−1,2−ジヒドロナフタレン)を得た。ベンチクロマトグラフィーの後、4aを、キラル(RegisCell(商標)、EtOH(15):ヘキサン(85))HPLC技術を用いて調べて、UV波形によりeeが98%を超えることが示された。1H NMR(CDCl3);1.00−1.31(m, 5H), 1.39−1.47(m, 1H), 1.57−1.85(m, 6H), 2.48−2.52(m, 1H), 2.72−2.77(m, 1H), 2.80(s, 6H), 3.03(dd, J=9.0, 16.6 Hz, 1H), 3.34(dd, J=6.8, 16.0 Hz, 1H), 3.72−3.75(m, 1H), 7.09−7.29(m, 4H). 13CNMR(CDCl3);26.5, 26.8, 27.3, 30.2, 31.8, 32.3, 41.6, 41.9, 43.5, 56.8, 124.9, 125.7, 129.1, 129.2, 136.0, 139.7. HRMS m/z C18H27Nについての計算値258.2216 [M+H]+、実測値258.2220。薬理学的研究のために、遊離塩基をHCl塩に変換した;MP:174〜176℃。C18H27N+HCl+H2Oの元素分析計算値:C=69.32、H=9.70、N=4.49。実測値:C=69.48、H=9.98、N=4.34。
セロトニン5HT2A、5HT2B、5HT2C、及びヒスタミンH1Gタンパク質共役受容体でのCATの薬理学的活性
(−)−トランス−CAT及び(+)−トランス−CATの活性を、基本的に当該技術分野で公知のとおりであり、本明細書中に記載されるプロトコルを用いて評価した。結果を以下の表及び本明細書中の図面で示す(例えば、図1〜3)。
(−)−(2S,4R)−4−シクロヘキシル−N,N−ジメチル−1,2,3,4−テトラヒドロナフタレン−2−アミン(或いは、4−シクロヘキシル−2−ジメチルアミノテトラリン、CAT)の分子構造
化合物の5−HT2機能的活性は、PCT国際公開番号第WO2008/156707号(出願番号PCT/US2008/007458)で記載されているものをはじめとする当該技術分野で公知の方法によって評価することができる。
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Fletcher PJ, Grottick AJ, Higgins GA. Differential effects of the 5-HT(2A) receptor antagonist M 100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 2002 27:576-586.
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Claims (1)
- 対象におけるGPCR介在性障害を治療又は予防する方法であって、それを必要とすると認定された対象に式(I):
R1は独立してH、NH2、NH(R’)、N(R’)2であるか;
又は
(式中、環Aは、O、N及びSから選択される0〜3個のさらなるヘテロ原子を含む3〜8員複素環式又はヘテロアリールであり;環Aは場合によって置換されていてもよい)であり;
各R’は独立してアルキル、アルケニル、又はアルキニルであり、そのそれぞれは場合によって置換されていてもよく;
R2は独立して−(CH2)n−であり;
各nは独立して1又は2であり;
R3は独立してH、OH、又はハロであり;
R4は独立してH、OH、又はハロであり
各R5は独立してアルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環式、又はアルコキシであり;
R6は独立してH又はアルキルであり;
R7は独立してH、又はN(アルキル)2であり;そして
各R8は独立してアリール、シクロアルキル、ヘテロアリール、又は複素環式(場合によって1、2、3、若しくは4個の独立したR5で置換されている)である)の化合物又はその塩、水和物若しくは溶媒和物を投与することを含む、方法。
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US20150315127A1 (en) | 2015-11-05 |
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US9024071B2 (en) | 2015-05-05 |
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