JP5111368B2 - ヒドロイソインドリンタキキニン受容体アンタゴニスト - Google Patents
ヒドロイソインドリンタキキニン受容体アンタゴニスト Download PDFInfo
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- JP5111368B2 JP5111368B2 JP2008519428A JP2008519428A JP5111368B2 JP 5111368 B2 JP5111368 B2 JP 5111368B2 JP 2008519428 A JP2008519428 A JP 2008519428A JP 2008519428 A JP2008519428 A JP 2008519428A JP 5111368 B2 JP5111368 B2 JP 5111368B2
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Description
R1は
(1)水素、
(2)未置換であるかまたはハロゲン、ヒドロキシまたはフェニルで置換されているC1−6アルキル、
(3)未置換であるかまたはヒドロキシまたはメチルで置換されているシクロペンテノン、
(4)−(CO)−C1−6アルキル、
(5)−(CO)−NH2、
(6)−(CO)−NHC1−6アルキル、及び
(7)−(CO)−N(C1−6アルキル)(C1−6アルキル)
からなる群から選択され;
Xは独立して
(1)水素、
(2)フッ素、及び
(3)メチル
からなる群から選択される)
を有する化合物、並びにその医薬的に許容され得る塩及びその個々のエナンチオマー及びジアステレオマーに関する。
(2)メチル、
(3)2−フェニルエチル、
(4)2−ヒドロキシエチル、
(5)シクロペンタ−2−エン−1−オン、
(6)5−ヒドロキシシクロペンタ−2−エン−1−オン、
(7)4−ヒドロキシシクロペンタ−2−エン−1−オン、
(8)2−メチルシクロペンタ−2−エン−1−オン、
(9)アセチル、
(10)アセトアミド、
(11)メチル−アセトアミド、及び
(12)ジメチル−アセトアミド
からなる群から選択される化合物を含む。
COSまたはCHO細胞において発現させたヒトNK1Rの結合アッセイは、ヒトNK1Rへの結合のために非標識サブスタンスPまたは他のリガンドと競合する放射標識リガンドとして125I−サブスタンスP(マサチューセッツ州ボストンに所在のDU PONTの125I−SP)を使用することに基づいている。COSまたはCHOの単層細胞培養物を非酵素溶液(ニュージャージ州ラバレッテに所在のSPECIALTY MEDIA)により解離させ、200ulの細胞懸濁液が約10,000cpmの特異的125I−SP結合(約50,000〜200,000個の細胞)を生ずるように適当量の結合緩衝液(50mM トリス(pH7.5)、5mM MnCl2、150mM NaCl、0.04mg/ml バシトラシン、0.004mg/ml ロイペプチン、0.2mg/ml BSA、0.01mM ホスホラミドン)中に再懸濁させた。この結合アッセイでは、20ulの1.5〜2.5nM 125I−SP及び20ulの非標識サブスタンスPまたは他の試験化合物を収容しているチューブに200ulの細胞を添加した。チューブを優しく振とうしながら4℃または室温で1時間インキュベートした。結合放射能を、予め0.1% ポリエチレンイミンで湿らしたGF/Cフィルター(メリーランド州ゲーザーズバーグに所在のBRANDEL)により非結合放射能から分離した。フィルターを3mlの洗浄緩衝液(50mM トリス(pH7.5)、5mM MnCl2、150mM NaCl)で3回洗浄し、その放射能をガンマカウンターにより測定した。ホスホリパーゼCのNK1Rによる活性化もヒトNK1Rを発現するCHO細胞においてIP3の分解生成物であるイノシトールモノホスフェートの蓄積を測定することにより調べることができる。CHO細胞を12ウェルプレートに250,000細胞/ウエルで接種する。CHO培地において4日間インキュベートした後、一晩インキュベートすることにより細胞に0.025uCi/mlの3H−ミオイノシトールを充填する。リン酸緩衝食塩液で洗浄することにより細胞外放射能を除去する。LiClを場合により試験化合物の存在下で0.1mMの最終濃度でウェルに添加し、37℃で15分間インキュベートし続ける。サブスタンスPを0.3nMの最終濃度でウェルに添加して、ヒトNK1Rを活性化する。37℃で30分間インキュベートした後、培地を除去し、0.1N HClを添加する。各ウェルを4℃で音波処理し、CHCl3/メタノール(1:1)で抽出する。水性相を1mlのDowex AG 1X8イオン交換カラムにかける。カラムを0.1N ギ酸、次いで0.025M ギ酸アンモニウム−0.1N ギ酸で順次洗浄する。イノシトールモノホスフェートを0.2M ギ酸アンモニウム−0.1N ギ酸で溶離し、ベータカウンターにより定量化した。特に、本発明化合物の固有タキキニン受容体アンタゴニスト活性はこれらのアッセイにより立証され得る。下記実施例の化合物は上記アッセイにおいて0.05nM〜10μMの範囲で活性を有している。本発明化合物の活性は、Leiら,British J.Pharmacol.,105:261−262(1992)によっても立証され得る。
ステップA:2−(4−フルオロフェニル)−N−メトキシ−N−メチルアセトアミド
(4−フルオロフェニル)酢酸(16.7g,108.4ミリモル)を乾燥ジクロロメタン中に含む溶液に窒素雰囲気下でN,O−ジメチル−ヒドロキシルアミン(13.8g,141.5ミリモル)、トリエチルアミン(20mL)、4−ジメチルアミノピリジン(DMAP)(14.2g,119.3ミリモル)及びEDC(27g,140.6ミリモル)を添加した。反応混合物を室温で2時間撹拌した後、分液漏斗に移した。混合物を2N 水性HCl、ブライン、飽和水性NaHCO3及びブラインで順次洗浄した。有機層を乾燥剤を用いて乾燥し、濾過し、溶媒を真空下で蒸発させて、粗な標記化合物(21g)を得た。これを更に精製することなく使用した。1H−NMR(CDCl3)δ:7.26(2H,m),7.02(2H,m),3.77(2H,s),3.65(3H,s),3.21(3H,s)。
1.0M 臭化ビニルマグネシウム(220mL,220ミリモル)をTHF(100mL)中に含む溶液に窒素雰囲気下0℃でステップAからの2−(4−フルオロフェニル)−N−トキシ−N−メチルアセトアミド(21g,106.6ミリモル)を乾燥エーテル(〜150mL)中に含む溶液を1滴ずつ添加した。反応混合物を0℃で0.5時間撹拌した後、氷/2N 水性HCl混合物にゆっくり注いだ。生じた混合物をエーテル及びブラインで希釈し、分液漏斗に移し、有機層を分離した。有機層をブラインで洗浄し、乾燥剤を用いて乾燥し、濾過し、溶媒を真空下で蒸発させて、粗な標記化合物(14.2g)を得た。これを更に精製することなく使用した。1H−NMR(CDCl3)δ:7.19(2H,m),7.02(2H,t,J=9.5Hz),6.42(1H,dd,J1=14.2Hz,J2=11Hz),6.34(1H,d,J=14.2Hz),5.86(1H,d,J=11Hz),3.87(2H,s)。
カリウムtert−ブトキシドの1.0M THF溶液(104mL,104.0ミリモル,1.2当量)及び乾燥THF(100mL)の溶液に窒素雰囲気下−78℃でステップBからの1−(4−フルオロフェニル)ブタ−3−エン−2−オン(14.2g,86.6ミリモル,1当量)及びtert−ブチルクロロジメチルシラン(13.0g,86.6ミリモル)を乾燥THF(100mL)中に含む溶液を添加した。反応混合物を−78℃で6時間、室温で6時間撹拌した後、水(50mL)を添加することによりクエンチした。生じた混合物を室温まで加温し、ヘキサン(150mL)で希釈し、分液漏斗に移し、有機層を分離した。有機層をブライン(50mL)で洗浄し、無水硫酸マグネシウムで乾燥し、濾過し、溶媒を真空下で蒸発させて、粗な標記化合物(20.5g)を得た。これを更に精製することなく使用した。1H−NMR(CDCl3)δ:7.52(2H,m),6.98(2H,m),6.33(1H,dd,J1=13.2Hz,J2=8.5Hz),5.97(1H,s),5.52(1H,d,J=13.2Hz),5.17(1H,d,J=8.5Hz)。
ステップCからの中間体1E及び1Z tert−ブチル{[1−(4−フルオロベンジリデン)プロパ−2−エン−1−イル]オキシ}ジメチルシラン(37g,純度〜80%,133.1ミリモル,1当量)及び(2E)−ブタ−2−エンジオン酸ジエチル(17mL,18g,104.6ミリモル)をキシレン(200mL)中に含む溶液を窒素雰囲気下160℃で5時間加熱した後、室温まで冷却した。溶媒を真空下で蒸発させて、油状物を得た。これを更に精製することなく使用した。
プラスチック製反応フラスコに収容されている上記中間体をアセトニトリル(30mL)中に含む溶液に窒素雰囲気下室温でHFの2.5M アセトニトリル溶液(200mL,500ミリモル)を添加した。生じた混合物を室温で24時間撹拌した。反応混合物を5.0N 水性NaOH(125mL)と氷(100g)の混合物に添加した後、室温で5分間撹拌した。生じた混合物をエーテル(300mL)で希釈した。生じた混合物を分液漏斗に移し、有機層を分離した。水性層にNaClを飽和した後、追加量のエーテルで抽出した。合わせた有機層をブラインで洗浄し、乾燥剤を用いて乾燥し、濾過し、溶媒を真空下で蒸発させて、標記化合物(40.8g)を得た。1H−NMR(CDCl3)δ:7.10(2H,m),7.05(2H,m),4.23−4.15(2H,m),3.90−3.80(3H,m),3.32(1H,td,J1=13.0Hz,J2=4.0Hz),3.21(1H,t,J=12.9Hz),2.68(2H,m),2.55(1H,m),2.07(1H,m),1.30(3H,t,J=7.2Hz),0.85(3H,t,J=7.2Hz)。
ステップBからの中間体(40.2g,119.3ミリモル)をエタノール(150mL)中に含む溶液に窒素雰囲気下−78℃でNaBH4粉末(4.1g,108.5ミリモル)を添加した。生じた混合物を−78℃で0.5時間、次いで室温で2時間撹拌した。反応混合物を水(30mL)を添加することにより注意深くクエンチし、2N 水性HClで注意深く酸性化した。溶媒を真空下で蒸発させた。残渣をエーテル中に溶解し、分液漏斗に移し、飽和水性NaHCO3及びブラインで洗浄し、乾燥剤を用いて乾燥し、濾過し、溶媒を真空下で蒸発させて、粗な標記化合物を得た。これを次ステップにおいて精製した。1H−NMCR(CDCl3)δ:7.25(2H,m),7.05(2H,t,J=8.2Hz),4.20−4.05(2H,m),3.85−3.72(3H,m),2.85(2H,m),2.70(1H,t,J=7.8Hz),2.25(2H,m),1.70(1H,m),1.60(1H,m),1.25(3H,t,J=7.2Hz),0.85(3H,t,J=7.2Hz)。
ステップCからの(1S,2S,3R,4S)−3−(4−フルオロフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチル及び(1R,2R,3S,4R)−3−(4−フルオロフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチルのラセミ混合物(21g)をCHIRACEL ADカラムを用い、ヘプタン/i−PrOH(9/1)を溶離液とする分取キラルHPLCにより分離して、所望の最初に溶離する異性体(1S,2S,3R,4S)−3−(4−フルオロフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチル(9.09g)を得た。
(1S)−1−[3,5−ビス(トリフルオロメチル)フェニル]エタノール(25.82g,100ミリモル)を乾燥ジエチルエーテル(200mL)中に含む溶液を窒素雰囲気下で氷水浴において冷却した。反応フラスコにニートなDBU(3mL,20ミリモル,0.2当量)を添加した後、混合物を0℃で10分間撹拌した。トリクロロアセトニトリル(15mL,150ミリモル,1.5当量)をゆっくり15分間かけて1滴ずつ添加した。反応物を0℃で2時間撹拌した。この間に色は深黄色になった。揮発物を冷却浴(<35℃)を用いて真空下で除去すると、淡褐色流動性液体が生じた。これをシリカゲル(3”×10”パッド)を用い、まずヘキサン/EtOAc(9/1)、次いでヘキサン/EtOAc(4/1)を溶離液とするカラムクロマトグラフィーにより精製した。生成物画分を合わせ、溶媒を真空下で除去して、標記化合物(37.5g)を淡黄色油状物として得た。1H−NMR(CDCl3)δ:1.74(3H,d,J=6.5Hz),6.07(1H,q,J=6.5Hz),7.82(1H,s),7.86(2H,s),8.40(1H,br.s)ppm。
ステップDからの最初に溶離する異性体(1S,2S,3R,4S)−3−(4−フルオロフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチル(9.09g,26.9ミリモル)及びステップEからの(1S)−1−[3,5−ビス(トリフルオロメチル)フェニル]エチル−2,2,2−トリクロロエタンイミドエート(21.5g,53.5ミリモル)をシクロヘキサン/1,2−クロロエタン(3/1)(250mL)中に含む溶液に窒素雰囲気下−5℃で54% HBF4/エーテル(0.51mL,3.58ミリモル)を添加した。反応混合物を−5〜0℃で2時間撹拌した後、エーテルで希釈した。混合物を飽和水性NaHCO3で洗浄した。有機層を乾燥剤を用いて乾燥し、濾過し、溶媒を真空下で蒸発させた。残渣をEtOAc/ヘキサン(1/4)を溶離液とするシリカゲルフラッシュカラムクロマトグラフィーにより精製して。標記化合物(9.2g)を油状物として得た。1H−MMR(CDCl3)δ:7.70(1H,s),7.20(2H,s),7.00(2H,m),6.85(2H,t,J=8.5Hz),4.43(1H,q,J=6.0Hz),4.20−4.10(2H,m),3.80−3.73(2H,m),3.36(1H,m),2.90−2.76(2H,m),2.40(1H,m),2.28(1H,m),1.63−1.55(2H,m),1.33(3H,d,J=6.0Hz),1.25(3H,t,J=7.2Hz),0.8.2(3H,t,J=7.2Hz)。カラムにEtOAcをフラッシュすることにより未反応の出発アルコールが回収され、上記反応に再使用され得る。
ステップFからの(1S,2S,3R,4S)−4−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ}−3−(4−フルオロフェニル)シクロヘキサン−1,2−ジカルボン酸ジエチル(9.2g,15.9ミリモル)をTHF(100mL)中に含む溶液に窒素雰囲気下室温でLiBH4粉末(2g,112.4ミリモル,過剰量)を添加した。生じた混合物を68℃で2時間加熱した後、室温まで冷却した。水(30mL)を添加することにより反応混合物を注意深くクエンチした後、EtOAcで抽出した。合わせた有機抽出物を乾燥剤を用いて乾燥し、濾過し、溶媒を真空下で蒸発させて、粗な標記化合物(7.5g)を油状物として得た。これを更に精製することなく使用した。1H−NMR(CDCl3)δ:7.70(1H,s),7.20(2H,s),7.00(2H,m),6.87(2H,t,J=8.2Hz),4.20(1H,q,J=6.0Hz),3.78(1H,m),3.67(1H,m),3.52(1H,m),3.30−3.20(2H,m),2.58(1H,t,J=11.9Hz),2.32(1H,m),1.87(1H,m),1.65(1H,m),1.58−1.35(3H,m),1.30(3H,t,J=6.0Hz)。
ステップJからの中間体[(1S,2R,3R,4S)−4−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ}−3−(4−フルオロフェニル)シクロヘキサン−1,2−ジイル]ジメタノール(3.3g,6.7ミリモル)をジクロロメタン(50mL)中に含む溶液に室温でアセチルクロリド(0.52mL,7.4ミリモル)及びTEA(1.1mL,7.9ミリモル)を添加した。生じた混合物を室温で6時間撹拌した。溶媒を真空下で除去し、残渣を3:1 ヘキサン:酢酸エチルを溶離液とするシリカゲルカラムクロマトグラフィーにより分離した。TLCで極性の弱いモノアルコール(0.75g)を集めた。MS:(ME)+536.2。
オキサリルクロリド(0.22mL,2.5ミリモル)をジクロロメタン(50mL)中に含む溶液に−78℃でDMSO(0.51mL,7.2ミリモル)をゆっくり添加した。混合物を−78℃で5分間撹拌した。生じた混合物にジクロロメタン(15mL)中ステップKからの中間体モノアルコール(0.5g,1.0ミリモル)を添加した。生じた混合物を20分間撹拌した後、トリエチルアミン(1.1mL,7.9ミリモル)を添加した。冷却浴を外し、温度が約0℃に上昇するまで混合物を撹拌した。反応物を飽和水性NH4Clでクエンチし、有機層を分離し、ブラインで洗浄し、MgSO4で乾燥した。溶媒を真空下で除去し、残渣(0.56g)を直接次のステップCにおいて使用した。1H−NMR(CDCl3)δ:9.32(1H,s),7.70(1H,s),7.20(2H,s),7.00(2H,m),6.88(2H,m),4.45(1H,q,J=6.5Hz),3.98(2H,m),3.33(1H,m),3.13(1H,m),2.85(1H,t,J=11.0H),2.53(1H,m),2.37(1H,m),2.17(1H,m),2.04(3H,s),2.02(1H,m),1.55(1H,m),1.45(1H,m),1.35(1H,m),1.32(3H,d,J=6.5Hz)。
ステップLからのアルデヒド(0.56g,1.0ミリモル)、ベンジルアミン(0.15mL,1.4ミリモル)及びトリアセトキシホウ水素化ナトリウム(1.0g,4.7ミリモル)をジクロロメタン(50mL)中に含む混合物を室温で12時間撹拌した。混合物を飽和水性NaHCO3、ブラインで順次洗浄し、MgSO4で乾燥し、濾過した。溶媒を真空下で蒸発させて、油状物(0.61g)を得た。これを精製することなく次ステップにおいて使用した。MS:(MH)+624.5。
ステップMからの粗な油状物をエタノール(50mL)中に含む溶液に10% Pd(OH)2−C(0.2g,20重量%)を添加した。混合物を50Psi、室温で16時間水素化した。触媒を濾過助剤パッドを介して濾過した。濾液の溶媒を真空下で除去して、標記化合物(0.35g)を得た。1H−NMR(CDCl3)δ:7.70(1H,s),7.23(2H,m),7.21(2H,s),6.98(2H,m),4.48(1H,q,J=6.5Hz),4.15(2H,m),3.27(1H,m),2.86(2H,m),2.53(1H,d,J=11.0Hz),2.36(1H,m),2.07(3H,s),1.98(2H,m),1.75(1H,m),1.55−1.27(2H,m),1,37(3H,d,J=6.4Hz)。MS:(MH)+536.5。
ステップNからの[(1S,2R,3R,4S)−2−(アミノメチル)−4−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ}−3−(4−フルオロフェニル)シクロヘキシル]メチルアセテート(0.35g,0.65ミリモル)を乾燥トルエン(30mL)中に含む溶液にシクロペンタン−1,3−ジオン(0.064g,0.65ミリモル)及び触媒量(〜0.5mg)のPTSAを添加した。生じた混合物を1時間還流加熱した。溶媒を真空下で除去し、残渣をメタノール(30mL)中に溶解した。5N 水酸化ナトリウム(15mL)を添加し、生じた混合物を50℃で2時間撹拌した。メタノール及び若干の水を真空下で除去した。水(20mL)を添加し、水性層を酢酸エチル(3×20mL)で抽出した。合わせた抽出物をブラインで洗浄し、Na2SO4で乾燥し、溶媒を真空下で除去した。残渣を分取TLC(9:1 酢酸エチル:ヘキサン)により精製して、標記化合物(0.12g)を得た。1H−NMR(CDCl3)δ:7.70(1H,s),7.18(2H,s),6.98(2H,m),6.93(2H,m),5.18(0.5H,bs),4.67(0.5H,bs),4.22(1H,m),3.78(1H,m),3.47(1H,m),3.27(1H,m),3.07(1H,m),2.95(1H,m),2.30(1H,t),2.40−2.20(5H,m),1.90(1H,m),1.80(1H,m),1.70−1.20(3H,m),1.33(3H,d,J=6.4Hz)。MS:(MH)+574.1。
ステップOからの中間体(20mg,0.0348ミリモル)をジクロロメタン(5mL)中に含む溶液に室温でデス・マーチン・ペルヨージナン(16mg,0.038ミリモル)を添加した。混合物を室温で0.5時間撹拌した。溶媒を真空下で除去し、残渣を分取TLC(9.5:5 ジクロロメタン:2N NH3/メタノール)により精製して、標記化合物(8mg)を得た。1H−NMR(CDCl3)δ:7.71(1H,s),7.22(2H,s),7.03(2H,m),6.90(2H,m),5.30,5.20(1H,2つの二重項),5.28(1H,2つの単重項),4.45(1H,m),3.35(1H,m),3.20(1H,m),3.00(1H,m),2.84(1H,m),2.55−2.30(6H,m),2.03(1H,m),1.80−1.85(4H,m),1.33(3H,d,J=6.5Hz)。MS:(MH)+572.5。
ステップA:(1S,2S,3R,4S)−4−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ}−2−(エトキシカルボニル)−3−(4−フルオロフェニル)シクロヘキサンカルボン酸
実施例1のステップIからの中間体(1S,2S,3R,4S)−4−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ}−3−(4−フルオロフェニル)シクロヘキサン−1,2−ジカルボン酸ジエチル(3.0g,5.19ミリモル)をメタノール(50mL)中に溶解させた。5N NaOH(20mL)を室温で添加した。混合物を20時間撹拌した。溶媒のメタノール及び水を真空下で除去した。残渣を2N 水性HCl(100mL)中に溶解させた。水性層を酢酸エチル(2×100mL)で抽出した。合わせた有機抽出物をブラインで洗浄し、MgSO4で乾燥し、濾過し、溶媒を真空下で除去して、標記化合物(2.7g)を得た。1H−NMR(CDCl3)δ:7.71(1H,s),7.21(2H,s),6.98(2H,m),6.85(2H,m),4.43(1H,q,J=6.4Hz),3.75(2H,q,J=7.1Hz),3.35(1H,m),2.92−2.72(3H,m),2.38(1H,m),2.30(1H,m),1.60(2H,m),1.33(3H,d,J=6.4Hz),0.80(3H,t,J=7.1Hz)。
ステップAからの中間体カルボン酸(2.7g,4.91ミリモル)をTHF(60mL)中に含む溶液にクロロギ酸イソブチル(0.96mL,7.32ミリモル)及びトリエチルアミン(1.23mL,8.84ミリモル)を添加した。混合物を0℃で0.5時間、次いで室温で0.5時間撹拌した。白色沈澱を濾過し、固体を乾燥THFで洗浄した。濾液をNaBH4(1g)を水(3mL)中に含む懸濁液に0℃で添加した。生じた混合物を室温で16時間撹拌し、2N 水性HCl(20mL)でクエンチした後、酢酸エチル(50mL)で希釈した。有機層を分離し、水性層を酢酸エチル(2×60mL)で抽出した。合わせた有機抽出物をブラインで洗浄し、MgSO4で乾燥し、濾過し、溶媒を真空下で除去した。残渣をカラムクロマトグラフィー(2:1 ヘキサン:酢酸エチル)により精製して、標記化合物(1.8g)を得た。1H−NMR(CDCl3)δ:7.71(1H,s),7.20(2H,s),7.00(2H,m),6.85(2H,m),4.45(1H,q,J=6.4Hz),3.83(2H,m),3.55(2H,m),3.35(1H,m),2.93(1H,t,J=11.0Hz),2.47(1H,t,J=11.0Hz),2.37(1H,s),2.33(1H,m),1.97(2H,m),1.62−1.50(2H,m),1.20(1H,m),1.33(3H,d,J=6.4Hz),0.90(3H,t,J=7.1Hz)。
オキサリルクロリド(0.22mL,2.6ミリモル)をジクロロメタン(40mL)中に含む溶液に窒素下−78℃でDMSO(0.13mL,1.8ミリモル)をゆっくり添加した。混合物を同一温度で5分間撹拌した。ジクロロメタン(15mL)中のステップBから得た中間体アルコール(0.46g,8.6ミリモル)を注入により添加した。−78℃で20分間撹拌し続けた。トリエチルアミン(0.48mL,3.4ミリモル)を添加した。冷却浴を外し、温度が〜0℃に上昇するまで混合物を撹拌した。反応物を飽和水性NH4Clでクエンチした。有機層を分離し、水性層をジクロロメタン(40mL×2)で抽出した。合わせた有機抽出物をブラインで洗浄し、MgSO4で乾燥し、濾過し、溶媒を真空下で除去して、標記化合物(0.45g)を得た。これを更に精製することなく使用した。1H−NMR(CDCl3)δ:9.64(1H,s),7.71(1H,s),7.22(2H,s),7.00(2H,m),6.86(2H,m),4.43(1H,q,J=6.4Hz),3.80(2H,q,J=7.1Hz),3.34(1H,m),2.84(2H,m),2.66(1H,m),2.46(1H,m),2.32(1H,m),1.64(2H,m),1.42(1H,m),1.35(3H,d,J=6.4Hz),0.82(3H,t,J=7.1Hz)。
ステップCから得たアルデヒド(0.45g,0.84ミリモル)、ベンジルアミン(0.093mL,0.85ミリモル)、トリアセトキシホウ水素化ナトリウム(0.55g,2.6ミリモル)をジクロロメタン(30mL)中に含む溶液を室温で12時間撹拌した。反応混合物を2N 水性NaOH、ブラインで洗浄し、MgSO4で乾燥し、濾過し、溶媒を真空下で除去して、標記化合物(0.51g)を得た。これを更に精製することなく使用した。MS:(MH)+626.6。
ステップDから得た粗な油状物(0.15g,0.24ミリモル)をエタノール(40mL)中に含む溶液に10% Pd(OH)2−C(0.1g,20重量%)を添加した。混合物を50Psi、室温で16時間水素化した。触媒を濾過助剤パッドを介して濾過した。濾液の溶媒を真空下で除去して、標記化合物(0.09g)を得た。これを更に精製することなく使用した。1H−NMR(CDCl3)δ:7.71(1H,s),7.20(2H,s),7.00(2H,m),6.85(2H,m),4.45(1H,q,J=6.4Hz),3.83(2H,m),3.35(1H,m),3.00−2.86(2H,m),2.75(1H,m),2.52(1H,t,J=11.0Hz),2.40(1H,m),2.25(1H,m),1.58(1H,m),1.40(1H,m),1.33(3H,d,J=6.4Hz),0.88(3H,t,J=7.1Hz)。MS:(MH)+536.5。
ステップEからの中間体(1R,2R,3S,6S)−6−(アミノメチル)−3−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ}−2−(4−フルオロフェニル)シクロヘキサンカルボン酸エチル(0.07g,0.13ミリモル)を乾燥トルエン(30mL)中に含む溶液にシクロペンタン−1,3−ジオン(0.064g,0.65ミリモル)及び触媒量(〜0.5mg)のPTSAを添加した。生じた混合物を1時間還流加熱した。溶媒を真空下で除去した。残渣をトルエン(10mL)中に溶解し、窒素下で−78℃に冷却した。1.0M Dibal−H(2mL)を添加した。反応混合物を−78℃で16時間撹拌し、水でクエンチし、酢酸エチル(10mL)で希釈した。有機層を分離し、水性層を酢酸エチル(10mL)で抽出した。合わせた抽出物をブラインで洗浄し、MgSO4で乾燥し、濾過し、溶媒を真空下で除去した。残渣を9:1 酢酸エチル:メタノールを溶離液とする分取TLC(シリカゲル)により精製して、標記化合物(8mg)を得た。MS:(MH)+574.2。材料の残りは未反応のエステルであった。
ステップFからの中間体(8mg,0.014)をジクロロメタン(5mL)中に含む溶液に室温でデス・マーチン・ヨージナン(15mg,0.035ミリモル)を添加した。混合物を室温で0.5時間撹拌した。溶媒を除去し、残渣をアセトニトリル/01.% 水性TFA勾配を溶離液とする逆相HPLCにより精製して、標記化合物(5mg)を得た。1H−NMR(CDCl3)δ:7.71(1H,s),7.22(2H,s),7.06(2H,m),6.95(2H,m),4.95(1H,2つの単重項,1H),4.80,4.70(1H,2つの多重項),4.45(1H,m),3.75,3.65(1H,2つの多重項),3.36(1H,m),3.05−2.10(8H,m),1.80−1.50(5H,m),1.32(3H,d,J=6.4Hz)。MS:(MH)+572.5。
ステップA:2−(2−メチルフェニル)−N−メトキシ−N−メチルアセトアミド
標記化合物を2−(メチルフェニル)酢酸から実施例1のステップAの手順に従って製造した。1H−NMR(CDCl3)δ:7.23(4H,m),3.83(2H,s),3.65(3H,s),3.28(3H,s),2.36(3H,s)。
標記化合物をステップAの中間体から実施例1のステップBの手順に従って製造した。1H−NMR(CDCl3)δ:7.24−7.11(4H,m),6.42(1H,dd,J1=14.2Hz,J2=11Hz),6.34(1H,d,J=14.2Hz),5.81(1H,d,J=11Hz),3.90(2H,s)2.26(3H,s)。
標記化合物をステップBの中間体から実施例1のステップCの手順に従って製造した。1H−NMR(CDCl3):δ 7.22−7.07(4H,m),6.40(1H,dd,J1=13.2Hz,J2=8.5Hz),5.85(1H,s),5.54(1H,d,J=13.2Hz),5.19(1H,d,J=8.5Hz),2.28(3H,s)。
標記化合物をステップCの中間体から実施例1のステップDの手順に従って製造し、更に精製することなく使用した。
標記化合物をステップDの中間体から実施例1のステップEの手順に従って製造した。1H−NMR(CDCl3):δ 7.26−7.09(4H,m),4.23−4.12(2H,m),3.90−3.80(3H,m),3.32(1H,td,J1=13.0Hz,J2=4.0Hz),3.28(1H,t,J=13Hz),2.67(2H,m),2.50(1H,m),2.24(3H,s),2.09(1H,m),1.25(3H,t,J=7.2Hz),0.83(3H,t,J=7.2Hz)。
標記化合物をステップEの中間体から実施例1のステップFの手順に従って製造した。1H−NMR(CDCl3):δ 7.20−7.10(4H,m),4.15−4.07(2H,m),3.88−3.66(3H,m),3.09(1H,t),2.83(2H,m),2.30(3H,s),2.24−2.15(2H,m),1.68(1H,m),1.57(1H,m),1.25(3H,t,J=7.2Hz),0.83(3H,t,J=7.2Hz)。
ステップFからの(1S,2S,3R,4S)−3−(2−メチルフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチル及び(1R,2R,3S,4R)−3−(2−メチルフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチルのラセミ混合物をCHIRACEL ADカラムを用い、ヘプタン/i−PrOH(9/1)を溶離液とする分取キラルHPLCにより分離して、実施例1のステップGの手順に従って所望の最初に溶離する異性体(1S,2S,3R,4S)−3−(2−メチルフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチルを得た。
標記化合物をステップGからの最初に溶離する異性体(1S,2S,3R,4S)−3−(2−メチルフェニル)−4−ヒドロキシシクロヘキサン−1,2−ジカルボン酸ジエチル及び実施例1のステップHからの(1S)−1−[3,5−ビス(トリフルオロメチル)フェニル]エチル−2,2,2−トリクロロエタンイミドエートから実施例1のステップIの手順に従って製造した。1H−NMR(CDCl3):δ 7.65(1H,s),7.15(2H,s),7.08−6.92(4H,m),4.25(1H,q,J=6.0Hz),4.20−4.10(2H,m),3.85−3.66(2H,m),3.42(1H,m),3.21(1H,t),2.90−2.79(2H,m),2.35(1H,m),2.25(1H,m),2.22(3H,s),1.69−1.56(2H,m),1.30(3H,d,J=6.0Hz),1.23(3H,t,J=7.2Hz),0.77(3H,t,J=7.2Hz)。未反応の出発アルコールはカラムにEtOAcをフラッシュすることにより回収され、上記反応に再使用され得る。
標記化合物をステップHからの中間体から実施例1のステップJの手順に従って製造した。1H−NMR(CDCl3):δ 7.64(1H,s),7.16(2H,s),7.04−6.91(4H,m),4.24(1H,q,J=6.0Hz),3.74(1H,m),3.60(1H,m),3.48(1H,m),3.35−3.20(2H,m),2.90−2.70(2H,m),2.26(1H,m),2.21(3H,s),1.85(1H,m),1.62(1H,m),1.56−1.42(3H,m),1.28(3H,t,J=6.0Hz)。
標記化合物はステップIの中間体から実施例1のステップKの手順に従って製造され得る。
標記化合物はステップJの中間体から実施例1のステップLの手順に従って製造され得る。
標記化合物はステップKの中間体から実施例1のステップMの手順に従って製造され得る。
標記化合物はステップLの中間体から実施例1のステップNの手順に従って製造され得る。
標記化合物はステップMの中間体から実施例1のステップOの手順に従って製造され得る。
標記化合物はステップNの中間体から実施例1のステップPの手順に従って製造され得る。
ステップA:N−{[(1R,2R,3S,6S)−3−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ)−2−(4−フルオロフェニル)−6−(ヒドロキシメチル)シクロヘキシル]メチル}−N’−メチル尿素
実施例1のステップNからの[(1S,2R,3R,4S)−2−(アミノメチル)−4−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ}−3−(4−フルオロフェニル)シクロヘキシル]メチルアセテートを乾燥ジクロロメタン中に含む溶液に室温でメチルイソシアネート(数滴)を添加する。生じた混合物を室温で2時間攪拌する。反応混合物に2N 水性NaOH(数滴)を添加する。有機層を分離し、乾燥剤を用いて乾燥し、濾過し、溶媒を真空下で除去する。残渣をEtOAcを溶離液とする分取TLCにより精製し、主要生成物バンドを単離する。残渣をEtOAcに取り、固体を濾過する。濾液の溶媒を真空下で除去すると、標記化合物が得られ得る。
標記化合物はステップAの中間体から実施例1のステップPの手順に従って製造され得る。
Claims (8)
- 式I:
R1は
(1)水素、
(2)未置換であるかまたはハロゲン、ヒドロキシまたはフェニルで置換されているC1−6アルキル、
(3)未置換であるかまたはヒドロキシまたはメチルで置換されているシクロペンテノン、
(4)−(CO)−C1−6アルキル、
(5)−(CO)−NH2、
(6)−(CO)−NHC1−6アルキル、及び
(7)−(CO)−N(C1−6アルキル)(C1−6アルキル)
からなる群から選択され;
Xは独立して
(1)水素、
(2)フッ素、及び
(3)メチル
からなる群から選択される)
を有する化合物、並びにその医薬的に許容され得る塩及びその個々のエナンチオマー及びジアステレオマー。 - R1は(1)水素、
(2)メチル、
(3)2−フェニルエチル、
(4)2−ヒドロキシエチル、
(5)シクロペンタ−2−エン−1−オン、
(6)5−ヒドロキシシクロペンタ−2−エン−1−オン、
(7)4−ヒドロキシシクロペンタ−2−エン−1−オン、
(8)2−メチルシクロペンタ−2−エン−1−オン、
(9)アセチル、
(10)アセトアミド、
(11)メチル−アセトアミド、及び
(12)ジメチル−アセトアミド
からなる群から選択される請求項1に記載の化合物。 - Xは水素である請求項1に記載の化合物。
- Xはフッ素である請求項1に記載の化合物。
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US69448105P | 2005-06-27 | 2005-06-27 | |
US60/694,481 | 2005-06-27 | ||
PCT/US2006/024568 WO2007002457A2 (en) | 2005-06-27 | 2006-06-23 | Hydroisoindoline tachykinin receptor antagonists |
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Family
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JP2008519428A Expired - Fee Related JP5111368B2 (ja) | 2005-06-27 | 2006-06-23 | ヒドロイソインドリンタキキニン受容体アンタゴニスト |
Country Status (6)
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US (1) | US7683068B2 (ja) |
EP (1) | EP1898905A4 (ja) |
JP (1) | JP5111368B2 (ja) |
AU (1) | AU2006261930B2 (ja) |
CA (1) | CA2611550A1 (ja) |
WO (1) | WO2007002457A2 (ja) |
Families Citing this family (7)
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EP1976527A4 (en) * | 2006-01-11 | 2009-04-22 | Merck & Co Inc | CONDENSED TRIAZOL TACHYKININE RECEPTOR ANTAGONISTS |
EP2144503B9 (en) * | 2007-04-10 | 2013-09-04 | Merck Sharp & Dohme Corp. | 4-(octahydro-2H-isoindol-2-yl)-1,3-oxazol-4-one as TACHYKININ RECEPTOR ANTAGONISTS |
AU2009259493A1 (en) * | 2008-06-16 | 2009-12-23 | F. Hoffmann-La Roche Ag | Pyrrolidine derivatives as NK2 receptor antagonists |
JP2013010738A (ja) * | 2011-05-31 | 2013-01-17 | Sumitomo Chemical Co Ltd | エステル化合物の製造方法 |
DE102013211075B9 (de) | 2013-06-13 | 2017-11-02 | Technische Universität Bergakademie Freiberg | Biotechnologisches Verfahren zur Herstellung von substituierten oder unsubstituierten Phenylessigsäuren und Ketonen mit Enzymen des mikrobiellen Styrolabbaus |
US8906951B1 (en) | 2013-06-24 | 2014-12-09 | Tigercat Pharma, Inc. | Use of NK-1 receptor antagonists in pruritus |
US9198898B2 (en) | 2013-06-24 | 2015-12-01 | Tigercat Pharma, Inc. | Use of NK-1 receptor antagonists in pruritus |
Family Cites Families (5)
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GB9417956D0 (en) * | 1994-09-02 | 1994-10-26 | Merck Sharp & Dohme | Therapeutic agents |
JP2002534955A (ja) * | 1995-10-18 | 2002-10-15 | メルク エンド カンパニー インコーポレーテッド | シクロペンチルタキキニン受容体アンタゴニスト |
US5750549A (en) | 1996-10-15 | 1998-05-12 | Merck & Co., Inc. | Cycloalkyl tachykinin receptor antagonists |
CA2540061A1 (en) * | 2003-09-30 | 2005-04-14 | Merck & Co., Inc. | Phenyl pyrrolidine ether tachykinin receptor antagonists |
AR047439A1 (es) * | 2004-01-27 | 2006-01-18 | Merck & Co Inc | Antagonistas del receptor hidroisoindolina taquiquinina |
-
2006
- 2006-06-23 CA CA002611550A patent/CA2611550A1/en not_active Abandoned
- 2006-06-23 US US11/920,286 patent/US7683068B2/en not_active Expired - Fee Related
- 2006-06-23 AU AU2006261930A patent/AU2006261930B2/en not_active Ceased
- 2006-06-23 EP EP06785477A patent/EP1898905A4/en not_active Withdrawn
- 2006-06-23 WO PCT/US2006/024568 patent/WO2007002457A2/en active Application Filing
- 2006-06-23 JP JP2008519428A patent/JP5111368B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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CA2611550A1 (en) | 2007-01-04 |
AU2006261930B2 (en) | 2011-07-14 |
JP2008546838A (ja) | 2008-12-25 |
US20090054462A1 (en) | 2009-02-26 |
AU2006261930A1 (en) | 2007-01-04 |
EP1898905A2 (en) | 2008-03-19 |
WO2007002457A2 (en) | 2007-01-04 |
WO2007002457A3 (en) | 2007-07-12 |
US7683068B2 (en) | 2010-03-23 |
EP1898905A4 (en) | 2010-06-23 |
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