JP2009514797A - 4−((フェノキシアルキル)チオ)−フェノキシ酢酸誘導体の新規なリシン塩 - Google Patents
4−((フェノキシアルキル)チオ)−フェノキシ酢酸誘導体の新規なリシン塩 Download PDFInfo
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- JP2009514797A JP2009514797A JP2008531264A JP2008531264A JP2009514797A JP 2009514797 A JP2009514797 A JP 2009514797A JP 2008531264 A JP2008531264 A JP 2008531264A JP 2008531264 A JP2008531264 A JP 2008531264A JP 2009514797 A JP2009514797 A JP 2009514797A
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- compound
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- lysine
- alkoxy
- alkyl
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Abstract
Description
本発明は、新規なリシン塩、それらを含有する製薬学的組成物ならびにPPARデルタにより調節される障害及び状態の処置におけるそれらの使用を目的とする。さらに特定的に、本発明の化合物は脂質低下薬、血圧降下薬又は両方として有用である。さらに化合物は、PPARデルタにより直接又は間接的に媒介される状態の処置、予防又はその進行の妨害において有用である。該状態には糖尿病、心臓血管病、代謝性Xシンドローム、高コレステロール血症、低−HDL−コレステロール血症、高−LDL−コレステロール血症、異脂肪血症、アテローム性動脈硬化症及び肥満が含まれるが、これらに限られない。本発明はさらに、該リシン塩の製造のための新規な方法を目的とする。
引用することによりそれらの記載事項全体が本明細書の内容となる2003年9月19日に申請された特許文献1及び2004年9月16日に申請された特許文献2は、PPARデルタにより直接又は間接的に媒介される状態の処置、予防及び/又はその進行の妨害のために有用な式(I)の化合物及びその製薬学的に許容され得る塩を開示している。しかしながら、2003年9月19日に申請された特許文献1及び2004年9月16日に申請された特許文献2は、式(I)の化合物の結晶性の塩も、式(I)の化合物のリシン塩も開示していない。
本発明は、式(I)
Xは共有結合、S又はOから選ばれ;
YはS又はOであり;
-----W-----は=CH−、−CH=、−CH2−、−CH2−CH2−、=CH−CH2−、−CH2−CH=、=CH−CH=及び−CH=CH−から選ばれる基を示し;
ZはO、CH及びCH2から選ばれ;但しYがOである場合、ZはOであり;
nは1又は2であり;
R1及びR2はそれぞれ独立してH、C1−3アルキル、C1−3アルコキシ、ハロ及びNRaRbから選ばれ;ここでRa及びRbはそれぞれ独立してH又はC1−3アルキルであり;
R3及びR4はそれぞれ独立してH、ハロ、シアノ、ヒドロキシ、アセチル、C1−5アルキル、C1−4アルコキシ及びNRcRdから選ばれ;ここでRc及びRdはそれぞれ独立してH又はC1−3アルキルであり;但しR3及びR4は両方がHであることはなく;
R5はハロ、フェニル、フェノキシ、(フェニル)C1−5アルコキシ、(フェニル)C1−5アルキル、C2−5ヘテロアリールオキシ、C2−5ヘテロアリールC1−5アルコキシ、C2−5ヘテロシクリルオキシ、C1−9アルキル、C1−8アルコキシ、C2−9アルケニル、C2−9アルケニルオキシ、C2−9アルキニル、C2−9アルキニルオキシ、C3−7シクロアルキル、C3−7シクロアルコキシ、C3−7シクロアルキル−C1−7アルキル、C3−7シクロアルキル−C1−7アルコキシ、C3−7シクロアルキルオキシ−C1−6アルキル、C1−6アルコキシ−C1−6アルキル、C1−5アルコキシ−C1−5アルコキシ又はC3−7シクロアルキルオキシ−C1−7アルコキシから選ばれ;
そして-----W-----が−CH=、−CH2−、−CH2−CH2−、−CH2−CH=及び−CH=CH−から選ばれる基を示す場合には、R6はHであるか;
あるいは-----W-----が=CH−、=CH−CH2−及び=CH−CH=から選ばれる基を示す場合には、R6は存在しない]
の化合物のリシン塩を目的とする。
図1は、本明細書記載される通りに測定される式(Ia)の化合物の非水和物L−リシン塩に関するXRDパターンを示す。
図2は、本明細書記載される通りに測定される式(Ia)の化合物の二水和物L−リシン塩に関するXRDパターンを示す。
図3は、本明細書に記載される通りに測定される式(Ia)の化合物のL−リシン塩に関する、0−90%RHを循環するDVS等温図(isotherm)を示す。
本発明は、式(I)
の化合物のリシン塩及びそれらの製造方法を目的とする。式(I)の化合物はPPARデルタアゴニスト、好ましくは選択的PPARデルタアゴニストである。
ロメチル、2−ブロモエチル、トリフルオロメチル及び3−ヨードシクロペンチル)、ヒドロキシアルキル(例えばヒドロキシメチル、ヒドロキシエチル、2−ヒドロキシプロピル)、アミノアルキル(例えばアミノメチル、2−アミノエチル、3−アミノプロピル及び2−アミノプロピル)、アルコキシアルキル、ニトロアルキル、アルキルアルキル、シアノアルキル、フェニルアルキル、ヘテロアリールアルキル、ヘテロシクリルアルキル、フェノキシアルキル、ヘテロアリールオキシアルキル(例えば2−ピリジルオキシアルキル)、ヘテロシクリルオキシ−アルキル(例えば2−テトラヒドロピラノキシ−アルキル)、チオアルキルアルキル(例えばMeS−アルキル)、チオフェニルアルキル(例えばPhS−アルキル)、カルボキシアルキルなどを含む。ジ(C1−3アルキル)アミノ基は、ジメチルアミノ又はジエチルアミノのように2個の同じアルキル基を有するジアルキルアミノ基の他に、独立して選ばれるアルキル基を含み、例えばメチルプロピルアミノ及びイソプロピルメチルアミノを形成する。
単環式もしくは二環式芳香族環系を示す。ヘテロアリール基は、安定な構造の形成を生ずるいずれのヘテロ原子又は炭素原子において結合することもできる。ヘテロアリール基の例にはベンズイミダゾリル、ベンズイソオキサゾリル、ベンゾフラニル、ベンゾピラゾリル、ベンゾチアジアゾリル、ベンゾチアゾリル、ベンゾチエニル、ベンゾトリアゾリル、ベンズオキサゾリル、フラニル、フラザニル、フリル、イミダソリル、インダゾリル、インドリジニル、インドリニル、インドリル、イソベンゾフラニル、イソインドリル、イソチアゾリル、イソオキサゾリル、オキサゾリル、プリニル、ピラジニル、ピラゾリル、ピリダジニル、ピリジニル、ピリミジニル、ピロリル、キノリニル、キノリル、チアジアゾリル、チアゾリル、チオフェニル又はトリアゾリルが含まれるが、これらに限られない。ヘテロアリール基が置換されている場合、ヘテロアリール基は、C1−C8アルキル、ハロゲン及びアリールを含むがこれらに限られない1〜3個の置換基を有することができる。
ここで式(Ia)の化合物、L−リシン及び有機溶媒と水を含んでなる混合物を加熱して式(Ia)の化合物を溶解し、好ましくは、式(Ia)の化合物、リシン及び有機溶媒と水を含んでなる混合物を加熱還流し、次いで冷却して対応する式(Ia)の化合物のL−リシン塩を二水和物として沈殿させる。
より好ましくはエタノール、イソプロパノール、メタノール及び水を含んでなる混合物中;
より好ましくはC1−4アルコール、水及び酢酸エチルを含んでなる混合物中、より好ましくはメタノール、水及び酢酸エチルの混合物中、より好ましくはメタノール:水:酢酸エチルの比率が約20:1:5〜約20:1:30の範囲内であるメタノール、水及び酢酸エチルの混合物中、より好ましくはメタノール:水:酢酸エチルの比率が約20:1:20であるメタノール、水及び酢酸エチルの混合物中で;式(Ia)の化合物をL−リシンと反応させることにより製造することができ;
ここで式(Ia)の化合物、L−リシン及び有機溶媒と水を含んでなる混合物を加熱して式(Ia)の化合物を溶解し、好ましくは、式(Ia)の化合物、リシン及び有機溶媒と水を含んでなる混合物を加熱還流し、次いで冷却して対応する式(Ia)の化合物のL−リシン塩を非水和物として沈殿させる。
dosing)を用いることができる。
、無菌非経口用溶液もしくは懸濁剤、計量エアゾールもしくは液体スプレー、滴剤、アンプル、自動注入装置又は座薬のような単位投薬形態にある。あるいはまた、週に1回又は月に1回の投与に適した形態で組成物を与えることができ;例えばデカン酸塩のような活性化合物の不溶性塩を適応させて筋肉内注入のためのデポ剤を与えることができる。錠剤のような固体組成物の調製のために、主な活性成分を製薬学的担体、例えばコーンスターチ、ラクトース、スクロース、ソルビトール、タルク、ステアリン酸、ステアリン酸マグネシウム、リン酸二カルシウム又はゴムのような通常の錠剤化成分ならびに他の製薬学的希釈剤、例えば水と混合し、本発明の化合物又は製薬学的に許容され得るその塩の均一な混合物を含有する固体の予備調製組成物を形成する。これらの予備調製組成物を均一と言及する場合、活性成分が組成物全体に均一に分散し、組成物を錠剤、丸薬及びカプセルのような等しく有効な投薬形態物に容易に細分できることを意味する。この固体の予備調製組成物を次いで0.1〜約1000mgの本発明の活性成分を含有する上記の型の単位投薬形態物に細分する。新規な組成物の錠剤又は丸薬をコーティングするか、又は他の方法で配合し、長期間の作用の利点を与える投薬形態物を与えることができる。例えば錠剤又は丸薬は内部投薬及び外部投薬成分を含むことができ、後者は前者を覆う外被の形態にある。2つの成分は腸溶層により隔てられていることができ、それは胃における崩壊に抵抗して内部成分が十二指腸中に無損傷で通過するか又はその放出を遅らせることを可能にするように働く。そのような腸溶層又はコーティングのために多様な材料を用いることができ、そのような材料にはシェラック、アセチルアルコール及び酢酸セルロースのような材料とともに複数の高分子酸が含まれる。
合わせることができる。さらに、望ましいかもしくは必要な場合、適した結合剤;滑沢剤、崩壊剤及び着色剤も混合物中に導入することができる。適した結合剤にはデンプン、ゼラチン、天然糖類、例えばグルコース又はベータ−ラクトース、コーン甘味剤、天然及び合成ゴム、例えばアラビアゴム、トラガカントゴム又はオレイン酸ナトリウム、ステアリン酸ナトリウム、ステアリン酸マグネシウム、安息香酸ナトリウム、酢酸ナトリウム、塩化ナトリウムなどが含まれるが、制限ではない。崩壊剤にはデンプン、メチルセルロース、寒天、ベントナイト、キサンタンゴムなどが含まれるが、制限ではない。
れると治療的−未満又は予防的−未満であるが一緒に投与されると治療的又は予防的である量で投与される。
(1)ロシグリタゾン(rosiglitazone)(2,4−チアゾリジンジオン,5−((4−(2−(メチル−2−ピリジニルアミノ)エトキシ)フェニル)メチル)−,(Z)−2−ブテン二酸塩(1:1)又は5−((4−(2−(メチル−2−ピリジニルアミノ)エトキシ)フェニル)メチル)−2,4−チアゾリジンジオン,AVANDIAとして既知;BRL 49653、BRL 49653C、BRL 49653c、SB 210232又はロシグリタゾンマレートとしても既知);
(2)ピオグリタゾン(pioglitazone)(2,4−チアゾリジンジオン,5−((4−(2−(5−エチル−2−ピリジニル)エトキシ)フェニル)メチル)−,一塩酸塩,(+−)−又は5−((4−(2−(5−エチル−2−ピリジル)エトキシ)フェニル)メチル)−2,4−チアゾリジンジオン、ACTOS、ZACTOS又はGLUSTINとして既知;AD 4833、U 72107、U 72107A、U72107E、ピオグリタゾン塩酸塩(USAN)としても既知);
(3)トログリタゾン(troglitazone)(5−((4−((3,4−ジヒドロ−6−ヒドロキシ−2,5,7,8−テトラメチル−2H−1−ベンゾピラン−2−イル)メトキシ)フェニル)メチル)−2,4−チアゾリジンジオン,NOSCAL、REZULIN、ROMOZIN又はPRELAYとして既知;CI 991、CS 045、GR 92132、GR 92132Xとしても既知);
(4)イサグリタゾン(isaglitazone)((+)−5−[[6−[(2−フルオロフェニル)メトキシ]−2−ナフタレニル]メチル]−2,4−チアゾリジンジオン又は5−((6−((2−フルオロフェニル)メトキシ)−2−ナフタレニル)メチル−2,4−チアゾリジンジオン又は5−(6−(2−フルオロベンジルオキシ)ナフタレン−2−イルメチル)チアゾリジン−2,4−ジオン,MCC−555又はネオグリタゾン(neoglitazone)としても既知);ならびに
(5)5−BTZD
である。
(1)JT−501(JTT 501、PNU−1827、PNU−716−MET−0096又はPNU 182716:イソオキサゾリジン−3,5−ジオン,4−((4−(2−フェニル−5−メチル)−1,3−オキサゾリル)エチルフェニル−4)メチル−);
(2)KRP−297(5−(2,4−ジオキソチアゾリジン−5−イルメチル)−2−メトキシ−N−(4−(トリフルオロメチル)ベンジル)ベンズアミド又は5−((2,4−ジオキソ−5−チアゾリジニル)メチル)−2−メトキシ−N−((4−(トリフルオロメチル)フェニル)メチル)ベンズアミド);ならびに
(3)ファルグリタザル(Farglitazar)(L−チロシン,N−(2−ベンゾイルフェニル)−o−(2−(5−メチル−2−フェニル−4−オキサゾリル)エチル)−又はN−(2−ベンゾイルフェニル)−O−(2−(5−メチル−2−フェニル−4−オキサゾリル)エチル)−L−チロシン又はGW2570もしくはGI−262570
)
が含まれるが、これらに限られない。
(1)AD 5075;
(2)R 119702((+−)−5−(4−(5−メトキシ−1H−ベンズイミダゾール−2−イルメトキシ)ベンジル)チアゾリン−2,4−ジオン塩酸塩又はCI 1037もしくはCS 011);
(3)CLX−0940(ペルオキシソームプロリフェレーター−活性化受容体アルファアゴニスト/ペルオキシソームプロリフェレーター−活性化受容体ガンマアゴニスト);
(4)LR−90(2,5,5−トリス(4−クロロフェニル)−1,3−ジオキサン−2−カルボン酸、PPARデルタ/γアゴニスト);
(5)チュラリク(Tularik)(PPARγアゴニスト);
(6)CLX−0921(PPARγアゴニスト);
(7)CGP−52608(PPARアゴニスト);
(8)GW−409890(PPARアゴニスト);
(9)GW−7845(PPARアゴニスト);
(10)L−764406(PPARアゴニスト);
(11)LG−101280(PPARアゴニスト);
(12)LM−4156(PPARアゴニスト);
(13)リサレスタット(Risarestat)(CT−112);
(14)YM 440(PPARアゴニスト);
(15)AR−H049020(PPARアゴニスト);
(16)GW 0072(4−(4−((2S,5S)−5−(2−(ビス(フェニルメチル)アミノ)−2−オキソエチル)−2−ヘプチル−4−オキソ−3−チアゾリジニル)ブチル)安息香酸);
(17)GW 409544(GW−544又はGW−409544);
(18)NN 2344(DRF 2593);
(19)NN 622(DRF 2725);
(20)AR−H039242(AZ−242);
(21)GW 9820(フィブレート);
(22)GW 1929(N−(2−ベンゾイルフェニル)−O−(2−(メチル−2−ピリジニルアミノ)エチル)−L−チロシン、GW 2331として既知,PPARアルファ/γアゴニスト);
(23)SB 219994((S)−4−(2−(2−ベンズオキサゾリルメチルアミノ)エトキシ)−アルファ−(2,2,2−トリフルオロエトキシ)ベンゼンプロパン酸又は3−(4−(2−(N−(2−ベンズオキサゾリル)−N−メチルアミノ)エトキシ)フェニル)−2(S)−(2,2,2−トリフルオロエトキシ)プロパン酸又はベンゼンプロパン酸,4−(2−(2−ベンズオキサゾリルメチルアミノ)エトキシ)−アルファ−(2,2,2−トリフルオロエトキシ)−,(アルファS)−、PPARアルファ/γアゴニスト);
(24)L−796449(PPARアルファ/γアゴニスト);
(25)フェノフィブレート(Fenofibrate)(プロパン酸,2−[4−(4−クロロベンゾイル)フェノキシ]−2−メチル−,1−メチルエチルエステル、TRICOR、LIPCOR、LIPANTIL、LIPIDIL、MICROとして既知、PPARアルファアゴニスト);
(26)GW−9578(PPARアルファアゴニスト);
(27)GW−2433(PPARアルファ/γアゴニスト);
(28)GW−0207(PPARγアゴニスト);
(29)LG−100641(PPARγアゴニスト);
(30)LY−300512(PPARγアゴニスト);
(31)NID525−209(NID−525);
(32)VDO−52(VDO−52);
(33)LG 100754(ペルオキシソームプロリフェレーター−活性化受容体アゴニスト);
(34)LY−510929(ペルオキシソームプロリフェレーター−活性化受容体アゴニスト);
(35)ベキサロテン(bexarotene)(4−(1−(3,5,5,8,8−ペンタメチル−5,6,7,8−テトラヒドロ−2−ナフタレニル)エテニル)安息香酸、TARGRETIN、TARGRETYN、TARGREXINとして既知;LGD 1069、LG 100069、LG 1069、LDG 1069、LG 69、RO
264455としても既知);ならびに
(36)GW−1536(PPARアルファ/γアゴニスト)。
(1)INS−1(D−キロイノシトール又はD−1,2,3,4,5,6−ヘキサヒドロキシシクロヘキサン);
(2)タンパク質チロシンホスファターゼ1B(PTP−1B)阻害剤;
(3)グリコゲンシンターゼキナーゼ−3(GSK3)阻害剤;
(4)ベータ3アドレナリン受容体アゴニスト、例えばZD 2079((R)−N−(2−(4−(カルボキシメチル)フェノキシ)エチル)−N−(2−ヒドロキシ−2−フェネチル)アンモニウムクロリド、ICI D 2079としても既知)又はAZ 40140;
(5)グリコゲンホスホリラーゼ阻害剤;
(6)フルクトース−1,6−ビスホスファターゼ阻害剤;
(7)ピコリン酸第二クロム,バナジルサルフェート(バナジウムオキシサルフェート);
(8)KP 102(有機−バナジウム化合物);
(9)ポリニコチン酸第二クロム;
(10)カリウムチャンネルアゴニスト NN 414;
(11)YM 268(5,5’−メチレン−ビス(1,4−フェニレン)ビスメチレンビス(チアゾリジン−2,4−ジオン);
(12)TS 971;
(13)T 174((+−)−5−(2,4−ジオキソチアゾリジン−5−イルメチル)−2−(2−ナフチルメチル)ベンズオキサゾール);
(14)SDZ PGU 693((+)−トランス−2(S−((4−クロロフェノキシ)メチル)−7アルファ−(3,4−ジクロロフェニル)テトラヒドロピロロ(2,1−b)オキサゾール−5(6H)−オン);
(15)S 15261((−)−4−(2−((9H−フルオレン−9−イルアセチル)アミノ)エチル)安息香酸2−((2−メトキシ−2−(3−(トリフルオロメチル)フェニル)エチル)アミノ)エチルエステル);
(16)AZM 134(アリザイム(Alizyme));
(17)ARIAD;
(18)R 102380;
(19)PNU 140975(1−(ヒドラジノイミノメチル)ヒドラジノ)酢酸;
(20)PNU 106817(2−(ヒドラジノイミノメチル)ヒドラジノ)酢酸;
(21)NC 2100(5−((7−(フェニルメトキシ)−3−キノリニル)メチ
ル)−2,4−チアゾリジンジオン;
(22)MXC 3255;
(23)MBX 102;
(24)ALT 4037;
(25)AM 454;
(26)JTP 20993(2−(4−(2−(5−メチル−2−フェニル−4−オキサゾリル)エトキシ)ベンジル)−マロン酸ジメチルジエステル);
(27)デクスリポタム(Dexlipotam)(5(R)−(1,2−ジチオラン−3−イル)ペンタン酸、(R)−アルファリポ酸又は(R)−チオクト酸としても既知);
(28)BM 170744(2,2−ジクロロ−12−(p−クロロフェニル)ドデカン酸);
(29)BM 152054(5−(4−(2−(5−メチル−2−(2−チエニル)オキサゾール−4−イル)エトキシ)ベンゾチエン−7−イルメチル)チアゾリジン−2,4−ジオン);
(30)BM 131258(5−(4−(2−(5−メチル−2−フェニルオキサゾール−4−イル)エトキシ)ベンゾチエン−7−イルメチル)チアゾリジン−2,4−ジオン);
(31)CRE 16336(EML 16336);
(32)HQL 975(3−(4−(2−(5−メチル−2−フェニルオキサゾール−4−イル)エトキシ)フェニル)−2(S)−(プロピルアミノ)プロピオン酸);
(33)DRF 2189(5−((4−(2−(1−インドリル)エトキシ)フェニル)メチル)チアゾリジン−2,4−ジオン);
(34)DRF 554158;
(35)DRF−NPCC;
(36)CLX 0100、CLX 0101、CLX 0900又はCLX 0901;
(37)IカッパBキナーゼ(IKK B)阻害剤
(38)マイトジェン−活性化タンパク質キナーゼ(MAPK)阻害剤 p38 MAPK 刺激物質
(39)ホスファチジル−イノシチド三リン酸
(40)インスリン循環受容体阻害剤
(41)グルコース輸送物質4調節物質
(42)TNF−αアンタゴニスト
(43)プラズマ細胞分化抗原−1(PC−1)アンタゴニスト
(44)脂肪細胞脂質−結合タンパク質(ALBP/aP2)阻害剤
(45)ホスホグリカン
(46)ガルパラン(Galparan);
(47)レセプトロン(Receptron);
(48)島細胞(islet cell)成熟因子;
(49)インスリン増強因子(IPF又はインスリン増強因子−1);
(50)結合タンパク質とカップリングしたソマトメジン C(somatomedin C)(IGF−BP3、IGF−BP3、ソマトカイン(SomatoKine)としても既知);
(51)Biotech Holdings Ltd.又はVolque Pharmaceuticalにより生産されるディアブ II(Diab II)(V−411としても既知)又はグルカニン(Glucanin);
(52)グルコース−6ホスファターゼ阻害剤;
(53)脂肪酸グルコース輸送タンパク質;
(54)グルココルチコイド受容体アンタゴニスト;ならびに
(55)グルタミン:フルクトース−6−ホスフェートアミドトランスフェラーゼ(GFAT)調節物質
が含まれるが、これらに限られない。
(1)1,1−ジメチルビグアニド(例えばメツフォルミン−DepoMed、メツフォルミン−Biovail Corporation又はMETFORMIN GR(メツフォルミン胃貯留ポリマー(metformin gastric retention polymer);及び
(2)メツフォルミン塩酸塩(N,N−ジメチルイミドジカルボンイミド酸ジアミド一塩酸塩、LA 6023、BMS 207150、GLUCOPHAGE又はGLUCOPHAGE XRとしても既知)
が含まれる。
(1)アカルボース(acarbose)(D−グルコース,O−4,6−ジデオキシ−4−(((1S−(1アルファ,4アルファ,5ベータ,6アルフア))−4,5,6−トリヒドロキシ−3−(ヒドロキシメチル)−2−シクロヘキセン−1−イル)アミノ)−アルファ−D−グルコピラノシル−(1−4)−O−アルフア−D−グルコピラノシル−(1−4)−、AG−5421、Bay−g−542、BAY−g−542、GLUCOBAY、PRECOSE、GLUCOR、PRANDASE、GLUMIDA又はASCAROSEとしても既知);
(2)ミグリトール(Miglitol)(3,4,5−ピペリジントリオール,1−(2−ヒドロキシエチル)−2−(ヒドロキシメチル)−,(2R(2アルフア,3ベータ,4アルファ,5ベータ))−又は(2R,3R,4R,5S)−1−(2−ヒドロキシエチル)−2−(ヒドロキシメチル−3,4,5−ピペリジントリオール)、BAY 1099、BAY M 1099、BAY−m−1099、BAYGLITOL、DIASTABOL、GLYSET、MIGLIBAY、MITOLBAY、PLUMAROLとしても既知);
(3)CKD−711(O−4−デオキシ−4−((2,3−エポキシ−3−ヒドロキシメチル−4,5,6−トリヒドロキシシクロヘキサン−1−イル)アミノ)−アルフア−b−グルコピラノシル−(1−4)−アルファ−D−グルコピラノシル−(1−4)−D−グルコピラノース);
(4)エミグリテート(emiglitate)(4−(2−((2R,3R,4R,5S)−3,4,5−トリヒドロキシ−2−(ヒドロキシメチル)−1−ピペリジニル)エトキシ)安息香酸エチルエステル、BAY o 1248又はMKC 542としても既知);
(5)MOR 14(3,4,5−ピペリジントリオール,2−(ヒドロキシメチル)−1−メチル−,(2R−(2アルファ,3ベータ,4アルファ,5ベータ))−、N−メチルデオキシノジリマイシン(N−methyldeoxynojirimycin)又はN−メチルモラノリン(N−methylmoranoline)としても既知);ならびに
(6)ボグリボース(Voglibose)(3,4−ジデオキシ−4−((2−ヒドロキシ−1−(ヒドロキシメチル)エチル)アミノ)−2−C−(ヒドロキシメチル)−D−エピ−イノシトール又はD−エピ−イノシトール,3,4−ジデオキシ−4−((2−ヒドロキシ−1−(ヒドロキシメチル)エチル)アミノ)−2−C−(ヒドロキシメチ
ル)−、A 71100、AO 128、BASEN、GLUSTAT、VOGLISTATとしても既知)
が含まれるが、これらに限られない。
(1)ビオタ(Biota);
(2)LP 100;
(3)(SP−5−21)−オキソビス(1−ピロリジンカルボジチオエート−S,S’)バナジウム、
(4)インスリンアスパルト(insulin aspart)(ヒトインスリン(28B−L−アスパラギン酸)又はB28−Asp−インスリン、インスリン X14、INA−X14、NOVORAPID、NOVOMIX又はNOVOLOGとしても既知);
(5)インスリンデテミル(insulin detemir)(Human 29B−(N6−(1−オキソテトラデシル)−L−リシン)−(1A−21A),(1B−29B)−インスリン又はNN 304);
(6)インスリンリスプロ(insulin lispro)(“28B−L−リシン−29B−L−プロリンヒトインスリン又はLys(B28)、Pro(B29)ヒトインスリン類似物、lys−proインスリン、LY 275585、HUMALOG、HUMALOG MIX 75/25又はHUMALOG MIX 50/50としても既知);
(7)インスリングラルギン(insulin glargine)(ヒト(A21−グリシン,B31−アルギニン,B32−アルギニン)インスリン HOE 901、LANTUS、OPTISULINとしても既知);
(8)インリスン亜鉛懸濁剤,広範囲(extended)(ウルトラレンテ(Ultralente))、HUMULIN U又はULTRALENTEとしても既知;
(9)インスリン亜鉛懸濁剤(レンテ(Lente)),70%結晶性及び30%非晶質インスリン懸濁剤、LENTE ILETIN II、HUMULIN L又はNOVOLIN Lとしても既知;
(10)HUMULIN 50/50(50%イソフェンインスリン及び50%インスリン注射);
(11)HUMULIN 70/30(70%イソフェンインスリン NPH及び30%インスリン注射)、NOVOLIN 70/30、NOVOLIN 70/30 PenFill、NOVOLIN 70/30 Prefilledとしても既知;
(12)インスリンイソフェン懸濁剤、例えばNPH ILETIN II、NOVOLIN N、NOVOLIN N PenFill、NOVOLIN N Prefilled、HUMULIN N;
(13)正規のインスリン注射、例えばILETIN II Regular、NOVOLIN R、VELOSULIN BR、NOVOLIN R PenFill、NOVOLIN R Prefilled、HUMULIN R又はRegular U−500(濃);
(14)ARIAD;
(15)LY 197535;
(16)L−783281;及び
(17)TE−17411
が含まれるが、これらに限られない。
(1)グルカゴン−様ペプチド−1(GLP−1)及びそのミメティックス;
(2)グルコース−インスリン向性ペプチド(GIP)及びそのミメティックス;
(3)エキセンジン及びそのミメティックス;
(4)ジペプチルプロテアーゼ(DPP又はDPPIV)阻害剤、例えば
(4a)DPP−728又はLAF 237(2−ピロリジンカルボニトリル,1−(((2−((5−シアノ−2−ピリジニル)アミノ)エチル)アミノ)アセチル)、NVP−DPP−728、DPP−728A、LAF−237としても既知);
(4b)P 3298又はP32/98(ジ−(3N−((2S,3S)−2−アミノ−3−メチル−ペンタノイル)−1,3−チアゾリジン)フマレート);
(4c)TSL 225(トリプトフィル−1,2,3,4−テトラヒドロイソキノリン−3−カルボン酸);
(4d)バリンピロリジン(バルピル(valpyr));
(4e)1−アミノアルキルイソキノリノン−4−カルボキシレート及びその類似物質;
(4f)SDZ 272−070(1−(L−バリル)ピロリジン);
(4g)TMC−2A、TMC−2B又はTMC−2C;
(4h)ジペプチドニトリル(2−シアノピロロジド);
(4i)CD26阻害剤;及び
(4j)SDZ 274−444;
(5)グルカゴンアンタゴニスト、例えばAY−279955;ならびに
(6)プラムリンチド(pramlintide)を含むがこれに限られないアミリンアゴニスト(AC−137、Symlin、トリプロ−アミリン又はプラムリンチドアセテート)。
release forms)、例えばADX−159(延長放出ロバスタチン(lovastatin))ならびにコレスチド(Colestid)、ロコレスト(Locholest)、クエストラン(Questran)、アトロミド(Atromid)、ロピド(Lopid)及びトリコル(Tricor)が含まれる。
sc)、バソテク(Vasotec)及びゼストリル(Zestril))、アドレナリン作動性ブロッカー(例えばカルドゥラ(Cardura)、ジベンジリン(Dibenzyline)、ヒロレル(Hylorel)、ヒトリン(Hytrin)、ミニプレス(Minipress)及びミニジド(Minizide))、アルファ/ベータアドレナリン作動性ブロッカー(例えばコレグ(Coreg)、ノルモジン(normodyne)及びトランデート(Trandate))、カルシウムチャンネルブロッカー(例えばアダラト(Adalat)、カラン(Calan)、カルデン(Cardene)、カルジゼム(Cardizem)、コベラ−HS(Covera−HS)、ジラコル(Dilacor)、ジナシルク(DynaCirc)、イソプチン(Isoptin)、ニモトプ(Nimotop)、ノルベイス(Norvace)、プレンジル(Plendil)、プロカルジア(Procardia)、プロカルジア XL、スラ(Sula)、チアザク(Tiazac)、バスコル(Vascor)及びベレラン(Verelan))、利尿薬、アンギオテンシン II受容体アンタゴニスト(例えばアタカンド(Atacand)、アバプロ(Avapro)、コザアル(Cozaar)及びジオバン(Diovan))、ベータアドレナリン作動性ブロッカー(例えばベタペイス(Betapace)、ブロカドレン(Blocadren)、ブロビブロク(Brevibloc)、カルトロル(Cartrol)、インデラル(Inderal)、ケルロン(Kerlone)、ラバトル(Lavatol)、ロプレソル(Lopressor)、セクトラル(Sectral)、テノルミン(Tenormin)、トプロル−XL(Toprol−XL)及びゼベタ(Zebeta))、血管拡張薬(例えばデポニト(Deponit)、ジラトレート(Dilatrate)、SR、イムドゥル(Imdur)、イスモ(Ismo)、イソルジル(Isordil)、イソルジル チトラドース(Isordil
Titradose)、モノケト(Monoket)、ニトロ−ビド(Nitro−Bid)、ニトロ−ドゥル(Nitro−Dur)、ニトロリンガルスプレー(Nitrolingual Spray)、ニトロスタト(Nitrostat)及びソルビトレート(Sorbitrate))ならびにそれらに組み合わせ(例えばレクセル(Lexxel)、ロトレル(Lotrel)、タルカ(Tarka)、テクゼム(Teczem)、ロテンシン HCT(Lotensin HCT)、プリンジド(Prinzide)、ユニレチク(Uniretic)、バセレチク(Vaseretic)、ゼストレチク(Zestoretic))が含まれる。
て開示されている式(I)の化合物は、当該技術分野における熟練者にわかる通り、(a)てんかん及び関連障害;(b)糖尿病、シンドロームX、経口的耐糖能障害(impaired oral glucose tolerance)及び他の代謝障害;(c)高血圧;(d)高い脂質レベル;(e)肥満及び体重過剰状態を含むがこれらに限られない種々の障害及び疾患の処置、予防及び/又はその進行の妨害において有用である。
1H NMRδ(300MHz,DMSO−d6)7.64(2H,d,J=8.8Hz),7.21−7.14(2H,m),7.12(2H,d,J=8.8Hz),6.65(1H,d,J=8.1Hz),4.23−4.08(4H,m),3.76−3.66(1H,m),3.54(2H,dt,J=7.1Hz,J=7.1Hz),3.27−3.19(1H,m),3.15−3.06(2H,m),2.73(2H,dd,J=7.1Hz,J=7.1Hz),2.12(3H,s),1.80−1.24(6H,m),1.07(3H,t,J=7.1Hz)。
ガラス皿に移した。皿を密閉された系中の皿乾燥機中に置いた。適した量の水(5.5〜6.5重量%)が取得されるまで固体を監視し、二水和物材料を与えた。
Claims (44)
- 式(I)
Xは共有結合、S又はOから選ばれ;
YはS又はOであり;
-----W-----は=CH−、−CH=、−CH2−、−CH2−CH2−、=CH−CH2−、−CH2−CH=、=CH−CH=及び−CH=CH−から選ばれる基を示し;
ZはO、CH及びCH2から選ばれ;但しYがOである場合、ZはOであり;
nは1又は2であり;
R1及びR2はそれぞれ独立してH、C1−3アルキル、C1−3アルコキシ、ハロ及びNRaRbから選ばれ;ここでRa及びRbはそれぞれ独立してH又はC1−3アルキルであり;
R3及びR4はそれぞれ独立してH、ハロ、シアノ、ヒドロキシ、アセチル、C1−5アルキル、C1−4アルコキシ及びNRcRdから選ばれ;ここでRc及びRdはそれぞれ独立してH又はC1−3アルキルであり;但しR3及びR4は両方がHであることはなく;
R5はハロ、フェニル、フェノキシ、(フェニル)C1−5アルコキシ、(フェニル)C1−5アルキル、C2−5ヘテロアリールオキシ、C2−5ヘテロアリールC1−5アルコキシ、C2−5ヘテロシクリルオキシ、C1−9アルキル、C1−8アルコキシ、C2−9アルケニル、C2−9アルケニルオキシ、C2−9アルキニル、C2−9アルキニルオキシ、C3−7シクロアルキル、C3−7シクロアルコキシ、C3−7シクロアルキル−C1−7アルキル、C3−7シクロアルキル−C1−7アルコキシ、C3−7シクロアルキルオキシ−C1−6アルキル、C1−6アルコキシ−C1−6アルキル、C1−5アルコキシ−C1−5アルコキシ又はC3−7シクロアルキルオキシ−C1−7アルコキシから選ばれ;
そして-----W-----が−CH=、−CH2−、−CH2−CH2−、−CH2−CH=及び−CH=CH−から選ばれる基を示す場合には、R6はHであるか;
あるいは-----W-----が=CH−、=CH−CH2−及び=CH−CH=から選ばれる基を示す場合には、R6は存在しない]
の化合物のリシン塩。 - 塩が結晶性である請求項1のリシン塩。
- リシンがL−リシンである請求項2のリシン塩。
- 塩が結晶性である請求項4のリシン塩。
- リシンがL−リシンである請求項5のリシン塩。
- 塩が非水和物である請求項6のリシン塩。
- 塩が二水和物である請求項6のリシン塩。
- 製薬学的に許容され得る担体及び請求項1の化合物を含んでなる製薬学的組成物。
- 請求項1の化合物及び製薬学的に許容され得る担体を混合することにより調製される製薬学的組成物。
- 請求項1の化合物及び製薬学的に許容され得る担体を混合することを含んでなる製薬学的組成物の調製方法。
- 必要のある患者に請求項1の化合物の治療的に有効な量を投与することを含んでなる、PPARデルタ受容体により媒介される障害の処置方法。
- PPARデルタ受容体により媒介される障害がI相高脂血症(phase I hyperlipidemia)、前臨床的高脂血症、II相高脂血症(phase II hyperlipidemia)、高血圧、冠動脈疾患、冠動脈性心疾患、高トリグリセリド血症、低密度リポタンパク質(LDL)の高い血清レベル、中密度リポタンパク質(IDL)の高い血清レベル、小密度(small−density)LDLの高い血清レベル、高い空腹時血漿グルコース(fasting plasma glucose)(FPG)/HbA1c、高い血圧、II型糖尿病、代謝性シンドロームX、異脂肪血症(dylpipidemia)、アテローム性動脈硬化症及び肥満より成る群から選ばれる請求項16に記載の方法。
- 必要のある患者に請求項1に記載の化合物の治療的に有効な量を投与することを含んでなる、I相高脂血症、前臨床的高脂血症、II相高脂血症、高血圧、冠動脈疾患、冠動脈性心疾患、高トリグリセリド血症、低密度リポタンパク質(LDL)の高い血清レベル、中密度リポタンパク質(IDL)の高い血清レベル、小密度LDLの高い血清レベル、高い空腹時血漿グルコース(FPG)/HbA1c、高い血圧、II型糖尿病、代謝性シンドロームX、異脂肪血症、アテローム性動脈硬化症及び肥満より成る群から選ばれる障害の処置方法。
- 製薬学的に許容され得る担体及び請求項4の化合物を含んでなる製薬学的組成物。
- 請求項4の化合物及び製薬学的に許容され得る担体を混合することにより調製される製薬学的組成物。
- 請求項4の化合物及び製薬学的に許容され得る担体を混合することを含んでなる製薬学的組成物の調製方法。
- 必要のある患者に請求項4の化合物の治療的に有効な量を投与することを含んでなる、PPARデルタ受容体により媒介される障害の処置方法。
- PPARデルタ受容体により媒介される障害がI相高脂血症、前臨床的高脂血症、II相高脂血症、高血圧、冠動脈疾患、冠動脈性心疾患、高トリグリセリド血症、低密度リポタンパク質(LDL)の高い血清レベル、中密度リポタンパク質(IDL)の高い血清レベル、小密度LDLの高い血清レベル、高い空腹時血漿グルコース(FPG)/HbA1c、高い血圧、II型糖尿病、代謝性シンドロームX、異脂肪血症、アテローム性動脈硬化症及び肥満より成る群から選ばれる請求項22に記載の方法。
- 必要のある患者に請求項4に記載の化合物の治療的に有効な量を投与することを含んでなる、I相高脂血症、前臨床的高脂血症、II相高脂血症、高血圧、冠動脈疾患、冠動脈性心疾患、高トリグリセリド血症、低密度リポタンパク質(LDL)の高い血清レベル、中密度リポタンパク質(IDL)の高い血清レベル、小密度LDLの高い血清レベル、高い空腹時血漿グルコース(FPG)/HbA1c、高い血圧、II型糖尿病、代謝性シン
ドロームX、異脂肪血症、アテローム性動脈硬化症及び肥満より成る群から選ばれる障害の処置方法。 - 製薬学的に許容され得る担体及び請求項8の化合物を含んでなる製薬学的組成物。
- 請求項8の化合物及び製薬学的に許容され得る担体を混合することにより調製される製薬学的組成物。
- 請求項8の化合物及び製薬学的に許容され得る担体を混合することを含んでなる製薬学的組成物の調製方法。
- 必要のある患者に請求項8の化合物の治療的に有効な量を投与することを含んでなるPPARデルタ受容体により媒介される障害の処置方法。
- PPARデルタ受容体により媒介される障害がI相高脂血症、前臨床的高脂血症、II相高脂血症、高血圧、冠動脈疾患、冠動脈性心疾患、高トリグリセリド血症、低密度リポタンパク質(LDL)の高い血清レベル、中密度リポタンパク質(IDL)の高い血清レベル、小密度LDLの高い血清レベル、高い空腹時血漿グルコース(FPG)/HbA1c、高い血圧、II型糖尿病、代謝性シンドロームX、異脂肪血症、アテローム性動脈硬化症及び肥満より成る群から選ばれる請求項28に記載の方法。
- 必要のある患者に請求項8に記載の化合物の治療的に有効な量を投与することを含んでなる、I相高脂血症、前臨床的高脂血症、II相高脂血症、高血圧、冠動脈疾患、冠動脈性心疾患、高トリグリセリド血症、低密度リポタンパク質(LDL)の高い血清レベル、中密度リポタンパク質(IDL)の高い血清レベル、小密度LDLの高い血清レベル、高い空腹時血漿グルコース(FPG)/HbA1c、高い血圧、II型糖尿病、代謝性シンドロームX、異脂肪血症、アテローム性動脈硬化症及び肥満より成る群から選ばれる障害の処置方法。
- 式(I)
Xは共有結合、S又はOから選ばれ;
YはS又はOであり;
-----W-----は=CH−、−CH=、−CH2−、−CH2−CH2−、=CH−CH2−、−CH2−CH=、=CH−CH=及び−CH=CH−から選ばれる基を示し;
ZはO、CH及びCH2から選ばれ;但しYがOである場合、ZはOであり;
nは1又は2であり;
R1及びR2はそれぞれ独立してH、C1−3アルキル、C1−3アルコキシ、ハロ及びNRaRbから選ばれ;ここでRa及びRbはそれぞれ独立してH又はC1−3アルキルであり;
R3及びR4はそれぞれ独立してH、ハロ、シアノ、ヒドロキシ、アセチル、C1−5ア
ルキル、C1−4アルコキシ及びNRcRdから選ばれ;ここでRc及びRdはそれぞれ独立してH又はC1−3アルキルであり;但しR3及びR4は両方がHであることはなく;
R5はハロ、フェニル、フェノキシ、(フェニル)C1−5アルコキシ、(フェニル)C1−5アルキル、C2−5ヘテロアリールオキシ、C2−5ヘテロアリールC1−5アルコキシ、C2−5ヘテロシクリルオキシ、C1−9アルキル、C1−8アルコキシ、C2−9アルケニル、C2−9アルケニルオキシ、C2−9アルキニル、C2−9アルキニルオキシ、C3−7シクロアルキル、C3−7シクロアルコキシ、C3−7シクロアルキル−C1−7アルキル、C3−7シクロアルキル−C1−7アルコキシ、C3−7シクロアルキルオキシ−C1−6アルキル、C1−6アルコキシ−C1−6アルキル、C1−5アルコキシ−C1−5アルコキシ又はC3−7シクロアルキルオキシ−C1−7アルコキシから選ばれ;
そして-----W-----が−CH=、−CH2−、−CH2−CH2−、−CH2−CH=及び−CH=CH−から選ばれる基を示す場合には、R6はHであるか;
あるいは-----W-----が=CH−、=CH−CH2−及び=CH−CH=から選ばれる基を示す場合には、R6は存在しない]
の化合物の結晶性リシン塩の製造方法であって、1種もしくはそれより多い有機溶媒及び水を含んでなる混合物中で式(I)の化合物をリシンと反応させ、対応する式(I)の化合物のリシン塩を与えることを含んでなる方法。 - C1−4アルコールがメタノールである請求項32に記載の方法。
- 水が約2モル当量より多いかもしくはそれに等しい量で存在する請求項33に記載の方法。
- 水が約2〜約3モル当量の範囲内の量で存在する請求項34に記載の方法。
- 式(Ia)の化合物、L−リシン及びC1−4アルコールと水を含んでなる混合物を加熱して式(Ia)の化合物を溶解し、次いで冷却して対応する式(Ia)の化合物のL−リシン塩を沈殿させる請求項35に記載の方法。
- 該混合物がさらに酢酸エチルを含んでなる請求項33に記載の方法。
- メタノール:水:酢酸エチルの比率が約20:1:20である請求項37に記載の方法。
- 式(Ia)の化合物、L−リシンならびにメタノール、水及び酢酸エチルを含んでなる混合物を加熱して式(Ia)の化合物を溶解し、次いで冷却して対応する式(Ia)の化合物のL−リシン塩を沈殿させる請求項37に記載の方法。
- 式(Ia)の化合物、L−リシンならびにエタノール、イソプロパノール、メタノール及び水を含んでなる混合物を加熱して式(Ia)の化合物を溶解し、次いで冷却して対応する式(Ia)の化合物のL−リシン塩を沈殿させる請求項40に記載の方法。
- 請求項31の方法に従って製造される生成物。
- 請求項32の方法に従って製造される生成物。
- 請求項40の方法に従って製造される生成物。
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