JP2006509022A - 好中球依存性炎症性疾患の治療におけるキラルアリールケトン - Google Patents
好中球依存性炎症性疾患の治療におけるキラルアリールケトン Download PDFInfo
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- JP2006509022A JP2006509022A JP2004558041A JP2004558041A JP2006509022A JP 2006509022 A JP2006509022 A JP 2006509022A JP 2004558041 A JP2004558041 A JP 2004558041A JP 2004558041 A JP2004558041 A JP 2004558041A JP 2006509022 A JP2006509022 A JP 2006509022A
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- phenyl
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
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- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
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Abstract
Description
より詳細には、本発明は、一般式Iのキラルアリールケトンに関する:
Arはアリール基であり;
Ra及びRbは独立して、水素、直鎖又は分岐鎖C1〜C6アルキル、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C1〜C4−アルキルフェニル、C1〜C4−アルキル(α−又はβ−ナフチル)、C1〜C4−アルキル(2,3,4−ピリジル)、シアノ(−CN)、カルボキシアミド、式CO2R”のカルボキシル又はカルボキシエステル、ここでR”は直鎖又は分岐鎖C1〜C6脂肪族アルコールの残基である、ホスホネートPO(OR”)2、ここでR”は上で定義した通りである、式ジ−X−(CH2)n−Zの基、ここでXはCO基、SO基、SO2基であり;ZはH、tert−ブチル、イソプロピル、CO2R”、CN、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C3〜C6シクロアルキル、NH−BOC、NH2であり;nは0又は1〜3の整数である、の群から選択されるか、あるいはRa及びRbはそれらが結合している炭素原子とともに式IIの環状残基4,6−ジオキソ−1,3−ジオキサニル−2,2−二置換体を形成する:
以下の化合物:
(R,S)(±)−2−ブタノン,3−[4−(2−メチルプロピル)フェニル](CAS No.64758−90−3);
(R,S)(±)−2−ブタノン,3−(3−フェノキシフェニル)(CAS No.108671−27−8);
(R,S)(±)−2−ブタノン,3−(3−ベンゾイルフェニル)(CAS No.79868−87−4);
(R,S)(±)−4−(3−ベンゾイル−フェニル)−3−オキソ−ペンタン酸エチル(CAS No.145927−45−3);
(R,S)(±)−1,3−ジオキサン−4,6−ジオン−,5−[2−(3−ベンゾイルフェニル−1−オキソプロピル)]−2,2−ジメチル(CAS No.154023−15−1);
は、2−アリールプロピオン酸[JP03024023(1991年1月2日);JP52108949(1991年12月9日);JP52083426(1977年1月7日);JP56097249(1981年5月8日);Tetr.Lett.27.4175、1986]、及びチアゾール[EP511021;(1992年10月28日);JP0528902(1993年2月11日)]を調製するためのラセミ中間体として知られている。
Arは上で定義したようなアリールであり、Yはカルボニルを活性化する残基であり、好ましくは塩素などのハロゲン、1−イミダゾリル、ピバロイル、C1〜C3−アルコキシカルボニル、スクシニルオキシ、ベンゾ−トリアゾール−1−イルオキシである、
を、式Vのカルバニオン:
− R’aがカルボキシルとマグネシウムエトキシドとの複合体の残基である場合は、R’bはCO2R”、CONH2、CN、PO(OR”)2又は−X−(CH2)n−Z’であり、ここでXは先に定義した通りである;RcはH又は−(CH2)n−Z’であり、ここでZ’はH、tert−ブチル、イソプロピル、CO2R”、CN、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C3〜C6シクロアルキル、NH−BOCである;
− R’aが水素であり、Rcは水素又は上で定義したような−(CH2)n−Z’ラジカルである場合は、R’bはホスホネートPO(OR”)2、CO2R”であるか、又はR’a及びR’bは、それらが結合している炭素原子とともに、式Vaのラジカル2,4−ジオキソ−1,3−ジオキサニルのC5炭素原子でカルバニオンを形成する:
(R)(−)−4−[(4’−イソブチル)フェニル]−3−オキソペンタン酸メチル;
(S)(+)−4−[(4’−イソブチル)フェニル]−3−オキソペンタン酸メチル;
(R,S)4−[(4’−イソブチル)フェニル]−3−オキソペンタン酸;
(R)(−)−4−[(3’−ベンゾイル)フェニル]−3−オキソペンタン酸メチル;
(R)(−)−3−[(4’−イソブチル)フェニル]ブタン−2−オン;
(S)(+)−3−[(4’−イソブチル)フェニル]ブタン−2−オン;
(R)(−)−3−[(3’−ベンゾイル)フェニル]ブタン−2−オン;
(R)(−)−3−(4−イソブチル)−2−オキソブタン−1−ホスホン酸ジメチル;
(S)(±)−3−(3’−フェノキシ−フェニル)−2−オキソ−ブチル−1−ホスホン酸ジメチル;
(R)(−)−2−(4−イソブチルフェニル)−ペンタン−3−オン;
(S)(+)−4−[(3’−ベンゾイル)フェニル]−3−オキソペンタン酸エチル;
(S)(+)−3−[(3’−ベンゾイル)フェニル]ブタン−2−オン;
(R)(−)−2−(4−イソブチルフェニル)−4−フェニル−ブタン−3−オン;
(R)(−)−2−(4−イソブチルフェニル)−5−フェニル−ペンタン−3−オン;
(R)(−)−2−(4−イソブチルフェニル)−5−(ピリド−3−イル)−ペンタン−3−オン;
(R)(−)4−[(4’−ベンゾイルオキシ)フェニル]−3−オキソペンタン酸メチル;
(R)(−)−4−[(4’−イソプロピルスルホニルオキシ)フェニル]−3−オキソペンタン酸メチル;
(R)(−)−4−{[4’−(2”−エチル)フェニルスルホニルアミノ]フェニル}−3−オキソペンタン酸メチル;
(R,S)5−(4’−イソブチルフェニル)−ヘキサン−2,4−ジオン;
(R,S)1−フェニル−5−(4’−イソブチルフェニル)−2,4−ヘキサンジオン;
(R,S)1−(ピリド−2−イル)−4−(4’−イソブチルフェニル)−1,3−ペンタジオン;
(R)(−)2−(4−イソブチルフェニル)−7−tert−ブトキシカルボニルアミノ−ヘプタン−3−オン;
(R,S)2−(4’−イソブチルフェニル)−3−オキソ−ブチル,メチル−スルホキシド;
(R,S)2−(3’−ベンゾイルフェニル)−3−オキソ−ブチル,メチル−スルホキシド;
(R,S)2−(4’−イソブチルフェニル)−3−オキソ−ブチル,メチル−スルホン;
(R,S)2−(3’−ベンゾイルフェニル)−3−オキソ−ブチル,メチル−スルホン;
(R,S)2−(3’−フェノキシフェニル)−3−オキソ−ブチル,メチル−スルホン;
(R,S)2−(4’−イソブチルフェニル)−3−オキソ−ブチル,フェニル−スルホン;
(R)(−)−4−(4’−ピリジル)−2−[(4”−イソブチル)フェニル]ブタン−3−オン;
(R)−2−[4−(1−オキソ−2−イソインドリニル)フェニル]−3−オキソ−バレルアミド;
(R)−2−[4−(1−オキソ−2−イソインドリニル)フェニル]−3−オキソ−バレロニトリル;
(R)(+)−5−[2−(4−イソブチル−フェニル)−プロピオン−1−イル]−2,2−ジメチル1,3−ジオキサン−4,6−ジオン;
(R)(−)−5−[2−(3’−ベンゾイル−フェニル)−プロピオン−1−イル]−2,2−ジメチル1,3−ジオキサン−4,6−ジオン。
走化性実験及び細胞内Ca2+イオンレベルを測定するために設計した実験では、ヒト組換えIL−8(Pepro Tech.)を刺激物質として用いた:凍結乾燥したタンパク質を100ng/mLの濃度でHBSS(ハンクス平衡塩類溶液)に溶解し、HBSSで10ng/mLの濃度に希釈後、走化性実験に用いた。[Ca2+]変化の評価には25〜50ng/mLの濃度で用いた。
細胞内[Ca2+]i変化の測定には、C.Bizzarriら(Blood、86、2388、1995)によって記載された実験モデルを採用し、1μMのFura−2 AMを添加した接着PMNを含有するスライドを用いて、[Ca2+]i変化をリアルタイムで評価した。続いて、PMNの細胞遠心分離物を5%FCS(ウシ胎仔血清)を添加したRPMI 1640培地に3×106/mLの濃度で再懸濁し、直径25mmの丸いガラススライドに蒔き、これを37℃のインキュベーターに30分間入れた。平衡化塩溶液(BSS)で連続して3回洗浄し、非接着細胞を除去した後、Fura−2 AMを添加する前に、更に接着細胞のセットについて最大4時間インキュベーションを行なった。
本発明の化合物は、「単球由来好中球活性化タンパク質」(NAP/IL−8又はより単純にはIL−8)としても知られるインターロイキン8で刺激されるヒトPMN白血球(PMN)の走化性をin vitroで阻害するその能力を特徴とする。前記阻害は用量依存性であり、IC50値(作用を50%阻害する用量)を10−7〜10−9Mの範囲で有する;阻害作用は選択的であり、IL−8で誘導される走化性刺激に対して特異的である。in vitroで他の走化因子(C5a、細菌由来又は合成由来のホルミルペプチド、例えばf−LMP)によって刺激される走化性を阻害するには1桁又は2桁高い濃度が必要とされる。本発明の化合物の特異性は、ヒトPMNにおける細胞内[Ca2+]i濃度の上昇を阻害するその能力によって更に証明され、この上昇はIL−8によるヒトPMN自体の活性化に関連する[J.H.Liuら、J.Infect.Dis.166、1089(1992)]。
実際、LPS(1μg/mL)で刺激したマウスマクロファージでは、本発明の化合物(10−5〜10−7Mの濃度範囲で評価した)は、PGE2産生の阻害を示すが、しばしば統計的有意差の限界であるにもかかわらず、決して基底値の10〜15%を超えない。
本発明の組成物は、筋肉注射で、静注経路で、ボーラスとして、外皮用製剤(クリーム、ローション、スプレー及び軟膏)で、並びにカプセル、錠剤、シロップ、放出制御製剤などの形態で経口経路により、投与することができる。
(R)(−)−イブプロフェン(2g、9.69ミリモル)を塩化チオニル(4mL)に溶解し、得られる溶液を4時間還流する。
(R)(−)−3−[(3’−ベンゾイル)フェニル]ブタン−2−オン;
実施例1の手順にしたがい、0.3g(1.33ミリモル)のS(+)−イブプロフェンを用いて、S(+)−3−[(4’−イソブチル)フェニル]ブタン−2−オンを黄白色オイルとして得る(0.13g、0.63ミリモル);[α]D=+210.5(c=1;CH3CH2OH);1H−NMR(CDCl3);δ7.10(s,4H);3.75(q,1H,J=8Hz);2.45(d,3H,J=7Hz);2.05(s,3H);1.85(m,1H);1.32(d,2H,J=8Hz);0.92(d,6H,J=7Hz)。
4−[(4’−イソブチル)フェニル]−3−オキソペンタン酸
(R)(−)−イブプロフェン(1.2g、5.8ミリモル)をジオキサン(5mL)に溶解する;塩化チオニル(2.36mL)を加え、得られる溶液を還流し、還流したまま3時間放置する。室温まで冷却後、溶媒を減圧で蒸発させ、残渣をジオキサンで2回溶解して溶媒を高真空下で除去しながら過剰量の塩化チオニルを除去する。オイル状の黄色残渣(1.3g;5.79ミリモル)を得、これを乾燥ジクロロメタン(2mL)に溶解し、不活性ガス雰囲気中、ゆっくりとしたドリッピングで、水/氷浴で前もってT=+5℃まで冷却した乾燥ジクロロメタン(5mL)中の2,2−ジメチル−1,3−ジオキサン−2,5−ジオン(メルドラム酸)(0.83g;5.79ミリモル)とピリジン(1.12mL;14ミリモル)との溶液に加える。添加終了後、混合物をこの温度で1時間放置し、更に1時間室温で放置する。ジクロロメタンで希釈した混合物を、およそ30分間の激しい撹拌下、2N HCl溶液とクラッシュ・アイスで再分離させる。相分離後、有機相を2N HCl(2×10mL)及びNaCl飽和溶液で洗浄し、Na2SO4で乾燥させる。減圧で溶媒を蒸発させた後、(R)(+)−5−[2−(4−イソブチル−フェニル)−プロピオン−1−イル]−2,2−ジメチル−1,3−ジオキサン−4,6−ジオン([α]D=+62°;c=1.1%CH2Cl2)の残渣を更に精製することなく、メタノール(14mL)に溶解する;溶液を還流温度まで3時間再加熱する。冷却して溶媒を蒸発させた後、残渣をフラッシュクロマトグラフィで精製すると(溶出液:n−ヘキサン/エチルエーテル 8:2)、純粋な(R)(−)−4−[(4’−イソブチル)フェニル]−3−オキソペンタン酸のメチルエステルが無色オイルとして生ずる(0.6g;2.28ミリモル);[α]D=−192.5°(c=1;CH3OH);1H−NMR(CDCl3):δ7.1(s,4H);3.88(q,1H,J=8Hz);3.67(s,3H);3.47−3.28(q,2H,J=8Hz);2.45(d,2H,J=8Hz);1.85(m,1H);1.40(d,3H,J=8Hz);0.95(d,6H,J=7Hz)。
1H−NMR(CDCl3):δ7.1(m,4H);3.88(q,1H,J=8Hz);3.45(m,2H);2.48(d,2H,J=8Hz);1.90(m,1H);1.45(d,3H,J=8Hz);0.90(d,6H,J=7Hz)。
R−イブプロフェンを0.74g(2.9ミリモル)のR(−)−ケトプロフェンに置き換えることにより、実施例3の方法で、0.81gの(R)(−)−5−[2−(3’−ベンゾイル−フェニル)−プロピオン−1−イル]−2,2−ジメチル−1,3−ジオキサン−4,6−ジオンを得る([α]D=−39.5°;c=1%CH2Cl2)。これをメタノール中でボイルし、フラッシュクロマトグラフィで精製後(溶出液:n−ヘキサン/酢酸エチル 8:2)、0.49g(1.56ミリモル)の純粋な(R)(−)−4−[(3’−ベンゾイル)フェニル]−3−オキソペンタン酸メチルが無色オイルとして生ずる。[α]D=−135°(c=1;CH3OH);1H−NMR(CDCl3):δ7.85−7.40(m,9H);4.0(q,1H,J=8Hz);3.70(s,3H);3.50−3.30(q,2H,J=8Hz);1.45(d,3H,J=8Hz)。
(S)(+)−3−[(3’−ベンゾイル)フェニル]ブタン−2−オン
室温で、不活性ガス雰囲気中、撹拌下、6mLの無水THF中のマグネシウムエチレート(0.57g)の懸濁液に、3mLのTHF中のマロン酸のモノエチルエステル(1.3g)の溶液を加える。試薬を完全に溶解させた後、マグネシウム−マロン酸エチルエステル複合体の混合物に、0.43gの1,1’−カルボニルジイミダゾールをS(+)2−(3−ベンゾイルフェニル)プロピオン酸(0.66g)のTHF溶液に加えることによりその場で調製した、10mLの無水THF中のS(+)2−(3−ベンゾイルフェニル)プロピオニルイミダゾリド(0.83g)の溶液を、速いドリッピングで加える。混合物を4時間撹拌し、50%AcOH水溶液(1.2mL)を添加して酸性にし、真空下で少量に濃縮し、水で希釈する。酢酸エチルで繰り返し抽出後、有機相を併せ、NaCl飽和溶液で洗浄し、硫酸ナトリウムで乾燥させ、蒸発乾固し、シリカゲルで精製後、0.82gの(S)(+)−4−[(3’−ベンゾイル)フェニル]−3−オキソペンタン酸エチルが生ずる;
[α]D=+129°(c=1;CH3OH);1H−NMR(CDCl3):δ7.82−7.45(m,9H);4.1(q,1H,J=8Hz);3.75(s,3H);3.50−3.25(q,2H,J=8Hz);1.48(d,3H,J=8Hz)。
(R)(−)4−[(4’−ベンゾイルオキシ)フェニル]−3−オキソペンタン酸メチル
1H−NMR(CDCl3):δ8.02(m,2H);7.51(m,1H);7.35(m,2H);7.27(s,1H);7.22(m,2H);3.85(m,2H);3.74(s,3H);3.42−3.37(q,2H,J=8Hz);2.78(q,2H,J=8Hz);1.25(t,3H,J=8Hz)。
[α]D=−184.2°(c=1;CH3OH);1H−NMR(CDCl3):δ7.32(d,2H,J=7Hz);7.21(d,2H,J=7Hz);4.1(q,1H,J=8Hz);3.81(m,1H);3.70(s,3H);3.50−3.30(q,2H,J=8Hz);1.75(d,6H,J=7Hz);1.45(d,3H,J=8Hz)。
[α]D=−81.3°(c=1;CH3OH);1H−NMR(CDCl3):δ7.32(d,2H,J=7Hz);7.20(m,6H);6.84(bs,1H,SO2NH);4.05(q,1H,J=8Hz);3.72(s,3H);3.55−3.35(q,2H,J=8Hz);2.75(q,2H,J=8Hz);1.45(d,3H,J=8Hz);1.22(t,3H,J=8Hz)。
(R)(−)−イブプロフェン(3.45g)のエチルエーテル溶液を5℃まで冷却し、エチルエーテル中の0.6Mジアゾメタン溶液で持続的な黄色になるまで1滴ずつ処理する。溶媒を真空下で除去する;残留オイルをフラッシュクロマトグラフィで精製すると、3.3gの(R)(−)2−(4’−イソブチルフェニル)−プロピオン酸メチルが生ずる。
3mLのメタノール中の5−tert−ブトキシカルボニルアミノ−2−エトキシカルボニル−ペンタン酸エチル(WO94/10127)(1.59g)の溶液を、水/メタノール(1:1)中の8mLの0.63N LiOH.H2O溶液に加える;混合物を室温で12時間撹拌する。混合物を10mLのリン酸1ナトリウム飽和溶液で希釈し、過剰量のメタノールを真空下で除去する。混合物を酢酸エチル(2×10mL)で抽出する;有機抽出物を併せ、硫酸ナトリウムで溶媒を蒸発させることによって乾燥させ、1.4g(4.8ミリモル)の5−tert−ブトキシカルボニルアミノ−2−エトキシカルボニル−ペンタン酸を得る。
2−カルボキシ−プロピオン酸メチル;
2−カルボキシ−2−フェニル酢酸メチル;
2−カルボキシ−3−フェニルプロピオン酸メチル;
2−カルボキシ−3(−ピリド−3−イル)プロピオン酸メチル;
2−カルボキシ−3−シクロペンチルプロピオン酸メチル、
から選択される1置換マロン酸のモノエステルを用いて、以下のβ−ケトエステル:
(R’,S’)−2−[R−2−(4−イソブチルフェニル)−プロピオニル]プロピオン酸メチル;
(R’,S’)−2−[R−2−(4−イソブチルフェニル)−プロピオニル]−2−フェニル酢酸メチル;
(R’,S’)−2−[R−2−(4−イソブチルフェニル)−プロピオニル]−3−フェニル プロピオン酸メチル;
(R’,S’)−2−[R−2−(4−イソブチルフェニル)−プロピオニル]−3−(ピリド−3−イル)プロピオン酸メチル;
(R’,S’)−2−[R−2−(4−イソブチルフェニル)−プロピオニル]−3−シクロペンチル プロピオン酸メチル、
を得、DMSO/NaCl中で脱炭酸後、以下の対応するケトンを得る:
R(−)2−(4−イソブチルフェニル)−ペンタン−3−オン
[α]D=−36°(c=1;CH3OH);1H−NMR(CDCl3);S7.20(d,2H,J=7Hz);7.10(d,2H,J=7Hz);3.70(q,1H,J=8Hz);2.47(d,2H,J=7Hz);2.40(q,2H,J=7Hz);1.82(m,1H);1.55(d,3H,J=7Hz);0.98(d,3H,J=7Hz);0.94(d,6H,J=7Hz)。
[α]D=−48.5°(c=1;CH3OH);1H−NMR(CDCl3);δ7.35−7.18(m,5H);7.15(d,2H,J=7Hz);7.05(d,2H,J=7Hz);3.72(q,1H,J=8Hz);3.65(s,2H);2.42(d,2H,J=7Hz);1.80(m,1H);1.60(d,3H,J=7Hz);0.93(d,6H,J=7Hz)。
[α]D=−40°(c=1.5;CH3OH);1H−NMR(CDCl3);δ7.37−7.20(m,5H);7.10(d,2H,J=7Hz);7.00(d,2H,J=7Hz);3.70(q,1H,J=8Hz);2.88(m,2H);2.75(m,2H);2.45(d,2H,J=7Hz);1.82(m,1H);1.63(d,3H,J=7Hz);0.95(d,6H,J=7Hz)。
[α]D=−89°(c=1;CH3OH);1H−NMR(CDCl3);δ8.62(m,2H);7.80(m,1H);7.35(m,1H);7.15(d,2H,J=7Hz);7.08(d,2H,J=7Hz);5.35(t,2H,J=8Hz);5.05(t,2H,J=8Hz);3.72(q,1H,J=8Hz);2.42(d,2H,J=7Hz);1.80(m,1H);1.63(d,3H,J=7Hz);0.94(d,6H,J=7Hz)。
1.61gのベンゾイル酢酸の溶液中の0.55gのマグネシウムエチレート懸濁液を、不活性ガス雰囲気中、室温で試薬が完全に溶解するまで撹拌する。0.6gの(R,S)−2−(4’−イソブチルフェニル)−プロピオニルイミダゾリドの溶液を加え、撹拌を室温で一晩継続する。数滴の50%AcOH水溶液を加えて混合物を中性にし、真空下で蒸発乾固させる。残渣を水と酢酸エチルで再分離させる。併せた有機相を硫酸ナトリウムで乾燥させ、蒸発乾固させる。残渣をフラッシュクロマトグラフィで精製し、0.78gの(R,S)1−フェニル−4−(4’−イソブチルフェニル)−1,3−ペンタジオンを得る。
(R,S)5−(4’−イソブチルフェニル)−ヘキサン−2,4−ジオン
1H−NMR(CDCl3);δ7.20(d,2H,J=7Hz);7.12(d,2H,J=7Hz);3.75(s,2H);3.65(q,1H,J=8Hz);2.40(d,2H,J=7Hz);2.10(s,3H);1.82(m,1H);1.62(d,3H,J=7Hz);0.94(d,6H,J=7Hz)。
1H−NMR(CDCl3);δ7.35−7.20(m,5H);7.15(d,2H,J=7Hz);7.05(d,2H,J=7Hz);3.75(s,2H);3.68(q,1H,J=8Hz);3.63(s,2H);2.41(d,2H,J=7Hz);1.80(m,1H);1.64(d,3H,J=7Hz);0.95(d,6H,J=7Hz)。
1H−NMR(CDCl3);δ8.60(m,2H);7.81(m,1H);7.37(m,1H);7.18(d,2H,J=7Hz);7.10(d,2H,J=7Hz);3.70(q,1H,J=8Hz);3.65(s,2H);2.40(d,2H,J=7Hz);1.81(m,1H);1.65(d,3H,J=7Hz);0.95(d,6H,J=7Hz)。
乾燥メチルスルホキシド(5mL)中の水素化ナトリウム(21ミリモル)の溶液を不活性ガス雰囲気中、60℃で1時間加熱する。乾燥メチルスルホキシド中の2.2g(10ミリモル)の2−(4’−イソブチルフェニル)−プロピオン酸メチルの溶液を滴下し、撹拌を60℃で2時間継続する。混合物を室温で冷却し、AcOH(0.25mL)を加えて中性にし、ジエチルエーテルで希釈する。1N HClをpH=2になるまで添加し、CH2Cl2及び水を加える。2相を分離させる;併せた有機相を硫酸ナトリウムで乾燥させ、蒸発乾固させる。残渣をフラッシュクロマトグラフィで精製し、0.350gの(R,S)2−(4’−イソブチルフェニル)−3−オキソ−ブチル,メチル−スルホキシドを得る。
(R,S)2−(3’−ベンゾイルフェニル)−3−オキソ−ブチル,メチル−スルホキシド
1H−NMR(CDCl3);δ7.85−7.60(m,4H);7.52−7.40(m,5H);3.80(m,2H);3.55(m,1H);2.62+2.55(s,3H);2.47(d,2H,J=7Hz);1.85(m,1H);1.40(d,3H,J=7Hz);0.94(d,6H,J=7Hz)。
(R,S)2−(4’−イソブチルフェニル)−3−オキソ−ブチル,メチル−スルホン
1H−NMR(CDCl3);δ7.18(s,4H);4.18(m,2H);3.90(m,1H);3.10(s,3H);2.40(d,2H,J=7Hz);1.80(m,1H);1.52(d,3H,J=7Hz);0.94(d,6H,J=7Hz)。
1H−NMR(CDCl3);δ7.85−7.60(m,4H);7.52−7.40(m,5H);4.20(m,3H);3.95(m,1H);3.18(s,3H);1.55(d,3H,J=7Hz)。
1H−NMR(CDCl3);δ7.25−7.38(m,2H);7.15−7.05(m,2H);7.02(m,2H);6.70−6.60(m,2H);6.55(s,1H);4.21(m,3H);4.15(m,1H);3.20(s,3H);1.58(d,3H,J=7Hz)。
1H−NMR(CDCl3);δ8.05(m,2H);7.75(m,1H);7.60(m,2H);7.15(s,4H);4.15(m,2H);3.95(m,1H);2.40(d,2H,J=7Hz);1.80(m,1H);1.52(d,3H,J=7Hz);0.94(d,6H,J=7Hz)。
ジイソプロピルアミン(0.17mL;1.21ミリモル)及び水素化ナトリウム(ミネラルオイル中の60%溶液、0.106mg;2.66ミリモル)を窒素雰囲気下で乾燥THF(20mL)に溶解させる;4−ピリジル酢酸(0.166g;1.21ミリモル)を混合物に少しずつ加え、混合物を15分間還流する。氷水浴を用いてT=0〜4℃で冷却後、ブチルリチウム(ヘキサン中の1.6M溶液、0.75mL;1.21ミリモル)を混合物に加え、30分後、乾燥THF(10mL)中のR(−)−2−(4’−イソブチルフェニル)プロピオニルクロリド(0.27g;1.21ミリモル)の溶液を滴下する。添加終了後、氷水浴を取り外し、溶液を室温で一晩撹拌したまま放置する。溶媒を減圧下で蒸発させ、残渣をジエチルエーテル(20mL)で希釈し、水(3×15mL)で洗浄し、Na2SO4で乾燥させ、真空下で蒸発させて、暗赤色オイルを得、これを6N HCl(5mL)に溶解させる。溶液を還流温度で2時間加熱する;室温で冷却後、真空下で溶媒を蒸発させ、残渣をフラッシュクロマトグラフィで精製し、純粋なR(−)−4−(4’−ピリジル)−2−[(4”−イソブチル)フェニル]ブタン−3−オン(0.25g;0.88ミリモル)を黄白色オイルとして得る。
カルボニルジイミダゾール(0.18g)を、無水THF(5mL)中の(S)2−(3’−フェノキシ−フェニル)−プロピオン酸(0.24g)の溶液に加え、少なくとも1時間撹拌し、対応するイミダゾリド(溶液A)を形成させる。
カルボニルジイミダゾール(1.7g)を、15mLの(無水)THF中の2.8gの(R)−インドプロフェンの溶液に加え、室温で2時間撹拌し、インドプロフェンイミダゾリド(溶液A)を形成させる。
実施例14の手順にしたがい、マロン酸のモノアミドを等分子量のシアン酢酸に置き換えて、(R)2−[4−(1−オキソ−2−イソインドリニル)フェニル]−3−オキソ−バレロニトリルを得る。
Claims (9)
- 式Iの(R,S)−1−アリールエチルケトン化合物、並びにその単一の(R)及び(S)エナンチオマー:
Arはアリール基であり;
Ra及びRbは独立して、水素、直鎖又は分岐鎖C1〜C6アルキル、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C1〜C4−アルキルフェニル、C1〜C4−アルキル(α−又はβ−ナフチル)、C1〜C4−アルキル(2,3,4−ピリジル)、シアノ(−CN)、カルボキシアミド、式CO2R”のカルボキシル又はカルボキシエステル、ここでR”は直鎖又は分岐鎖C1〜C6脂肪族アルコールの残基である、ホスホネートPO(OR”)2、ここでR”は上で定義した通りである、式ジ−X−(CH2)n−Zの基、ここで:XはCO基、SO基、SO2基であり;ZはH、tert−ブチル、イソプロピル、CO2R”、CN、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C3〜C6シクロアルキル、NH−BOC、NH2であり;nは0又は1〜3の整数である、の群から選択されるか、あるいはRa及びRbは、それらが結合している炭素原子とともに式IIの環状残基4,6−ジオキソ−1,3−ジオキサニル−2,2−二置換体を形成する:
(R,S)(±)−2−ブタノン,3−[4−(2−メチルプロピル)フェニル];
(R,S)(±)−2−ブタノン,3−(3−フェノキシフェニル);
(R,S)(±)−2−ブタノン,3−(3−ベンゾイルフェニル);
(R,S)(±)−4−(3−ベンゾイル−フェニル)−3−オキソ−ペンタン酸エチル;
(R,S)(±)−1,3−ジオキサン−4,6−ジオン−5−[2−(3−ベンゾイルフェニル)−1−オキソプロピル]−2,2−ジメチル。 - Arは、場合により1〜3の置換基で置換されているフェニルを表し、置換基は互いに同一又は異なっており、以下:
ハロゲン、C1〜C4−アルキル、C1〜C4−アルコキシ、ヒドロキシ、C1〜C4−アシルオキシ、フェノキシ、シアノ、ニトロ、アミノ、C1〜C4−アシルアミノ、ハロゲン−C1〜C3−アルキル、ハロゲンC1〜C3−アルコキシ、ベンゾイル、又は4−イソブチル−フェニル、3−ベンゾイルフェニル、5−ベンゾイル−2−アセトキシ−フェニル、3−フェノキシ−フェニル、5−ベンゾイル−2−チオフェニル、4−チエノイル−フェニル、1−オキソ−2−イソインドリニル−フェニル、3−クロロ−4−(2,5−ジヒドロ−1H−ピロル−1−イル)フェニル、6−メトキシ−β−ナフチル、1−ヒドロキシ−フェニル−1−メチルの残基、又は式IIIの残基:
から選択される、請求項1に記載の化合物。 - Arは、4−(2−メチル−プロピル)−フェニル、3−フェノキシ−フェニル、3−ベンゾイルフェニル、−2−[4−(1−オキソ−イソインドリニル)フェニル]、5−ベンゾイル−チエン−2−イル又は4−チエノイル−フェニルの残基である、請求項2に記載の化合物。
- Ar残基が結合している炭素原子の立体配置が(R)エナンチオマーに相当する、請求項1〜3のいずれか1項に記載の化合物。
- 医薬として使用するための、式Iの(R,S)−1−アリールエチルケトン化合物、並びにその単一の(R)及び(S)エナンチオマー:
Arはアリール基であり;
Ra及びRbは独立して、水素、直鎖又は分岐鎖C1〜C6アルキル、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C1〜C4−アルキルフェニル、C1〜C4−アルキル(α−又はβ−ナフチル)、C1〜C4〜アルキル(2,3,4−ピリジル)、シアノ(−CN)、カルボキシアミド、式CO2R”のカルボキシル又はカルボキシエステル、ここでR”は直鎖又は分岐鎖C1〜C6脂肪族アルコール残基である、ホスホネートPO(OR”)2、ここでR”は上で定義した通りである、式ジ−X−(CH2)n−Zの基、ここで:XはCO、SO、SO2基であり;ZはH、tert−ブチル、イソプロピル、CO2R”、CN、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C3〜C6シクロアルキル、NH−BOC、NH2であり;nは0又は1〜3の整数である、の群から選択されるか、あるいはRa及びRbは、それらが結合している炭素原子とともに式IIの環状残基4,6−ジオキソ−1,3−ジオキサニル−2,2−二置換体を形成する:
- ヒトPMNのIL−8誘導走化性阻害剤として使用するための、請求項5に記載の化合物。
- 混合物中に請求項1〜6のいずれか1項に記載の化合物をその好適な担体とともに含有する医薬組成物。
- 請求項1〜6のいずれか1項に記載の化合物の、乾癬、関節リウマチ、潰瘍性大腸炎、急性呼吸窮迫症候群(ARDS)、特発性線維症、糸球体腎炎、水疱性類天疱瘡の治療のため、並びに虚血及び再灌流によって起こる障害の予防及び治療のための医薬の製造における使用。
- 請求項1〜6のいずれか1項に記載の化合物の製造方法であって、式(IV)の活性化2−アリールプロピオン酸:
Arはアリール基であり、Yは、ハロゲン、1−イミダゾリル、ピバロイル、C1〜C3−アルコキシカルボニル、スクシニルオキシ、ベンゾ−トリアゾール−1−イルオキシなどのカルボニルを活性化する残基である、
と、式Vのカルバニオン:
− R’aが、カルボキシルとマグネシウムエトキシドとの複合体の残基である場合は、R’bはCO2R”、CONH2、CN、PO(OR”)2又は−X−(CH2)n−Z’であり、ここでXは先に定義した通りである;RcはH又は−(CH2)n−Z’であり、ここでZ’はH、tert−ブチル、イソプロピル、CO2R”、CN、フェニル、α−又はβ−ナフチル、2,3,4−ピリジル、C3−C6シクロアルキル、NH−BOCである;
− R’aが水素であり、Rcが水素又は上で定義したような−(CH2)n−Z’ラジカルである場合は、R’bはホスホネートPO(OR”)2、CO2R”であるか、あるいはR’a及びR’bは、それらが結合している炭素原子とともに式Vaの2,4−ジオキソ−1,3−ジオキサニルのカルバニオンを形成する:
との反応を含む、前記方法。
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JP2003522750A (ja) * | 2000-02-11 | 2003-07-29 | ドムペ・ソチエタ・ペル・アツィオーニ | 好中球のil−8誘発走化性の阻害に有用なアミド |
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