JP2012528884A - リゾリン脂質受容体の多環式アンタゴニスト - Google Patents
リゾリン脂質受容体の多環式アンタゴニスト Download PDFInfo
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- JP2012528884A JP2012528884A JP2012514144A JP2012514144A JP2012528884A JP 2012528884 A JP2012528884 A JP 2012528884A JP 2012514144 A JP2012514144 A JP 2012514144A JP 2012514144 A JP2012514144 A JP 2012514144A JP 2012528884 A JP2012528884 A JP 2012528884A
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- Prior art keywords
- phenyl
- compound
- methyl
- isoxazol
- biphenyl
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- 108010027749 Lysophospholipid Receptors Proteins 0.000 title 1
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- 238000000034 method Methods 0.000 claims abstract description 185
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- -1 oxadiazol-3-yl Chemical group 0.000 claims description 124
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 77
- 241000124008 Mammalia Species 0.000 claims description 74
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- 229910052794 bromium Inorganic materials 0.000 claims description 19
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- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
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- SNMIPBWRYZGYRK-HXUWFJFHSA-N 1-[4-[4-[3-methyl-4-[[(1r)-1-(4-methylphenyl)ethoxy]carbonylamino]-1,2-oxazol-5-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound O([C@H](C)C=1C=CC(C)=CC=1)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C(C=C1)=CC=C1C1(C(O)=O)CC1 SNMIPBWRYZGYRK-HXUWFJFHSA-N 0.000 claims description 5
- PJFQXHGEFFTYLX-MRXNPFEDSA-N 1-[4-[4-[4-[[(1r)-1-cyclopropylethoxy]carbonylamino]-3-methyl-1,2-oxazol-5-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound O([C@H](C)C1CC1)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C(C=C1)=CC=C1C1(C(O)=O)CC1 PJFQXHGEFFTYLX-MRXNPFEDSA-N 0.000 claims description 5
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 5
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- NLIODHRUFXCONO-HXUWFJFHSA-N [(1r)-1-phenylethyl] n-[5-[4-[4-(1-cyanocyclopropyl)phenyl]phenyl]-3-methyl-1,2-oxazol-4-yl]carbamate Chemical compound O([C@H](C)C=1C=CC=CC=1)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C(C=C1)=CC=C1C1(C#N)CC1 NLIODHRUFXCONO-HXUWFJFHSA-N 0.000 claims description 4
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Abstract
Description
本願は米国仮出願番号第61/183,785号、名称「リゾホスファチジン酸受容体アンタゴニスト」(2009年6月3日出願)の優先権による利益を主張し、引用によって本明細書中に取り込む。
R1は−CO2H、−CO2RD、−CN、−C(=O)N(R9)2、−C(=O)NHCH2CH2SO3H、または−C(=O)NHSO2R10、テトラゾリル、または5−オキソ−2,5−ジヒドロ−[1,2,4]オキサジアゾール−3−イルであり;RDはHまたはC1−C4アルキルであり;
R3はH、C1−C4アルキル、C3−C6シクロアルキル、またはC1−C4フルオロアルキルであり;
R4は−NR7C(=O)OCH(R8)−CYであり;
R7はHまたはC1−C4アルキルであり;
R8はH、C1−C4アルキル、またはC1−C4フルオロアルキルであり;
CYは置換もしくは非置換のC3−C6シクロアルキルまたは置換もしくは非置換のフェニルであり(ここで、CYが置換される場合、CYは1または2個のRCで置換される);
R9はH、C1−C6アルキル、C1−C6フルオロアルキル、C3−C6シクロアルキル、または置換もしくは非置換のフェニルであり;
R10はC1−C6アルキル、C1−C6フルオロアルキル、C3−C6シクロアルキル、または置換もしくは非置換のフェニルであり;
各RA、RB、およびRCは独立して、F、Cl、Br、I、−CN、−OH、C1−C4アルキル、C1−C4フルオロアルキル、C1−C4フルオロアルコキシ、C1−C4アルコキシ、およびC1−C4ヘテロアルキルから選択され;
mは0、1、または2であり;nは1、2、3または4であり;pは0、1、または2である]
の化合物、またはその医薬的に許容される塩を提供する。
リゾリン脂質(リゾホスファチジン酸(LPA)など)は、細胞の基礎的な機能、例えば、細胞増殖、分化、生存、遊走、接着、浸潤、および形態形成などに影響する。これらの機能は、多くの生物学的プロセス、例えば、神経発生、血管新生、創傷治癒、免疫、および発癌に影響を及ぼす。
R1は−CO2H、−CO2RD、−CN、−C(=O)N(R9)2、−C(=O)NHCH2CH2SO3H、または−C(=O)NHSO2R10、テトラゾリル、または5−オキソ−2,5−ジヒドロ−[1,2,4]オキサジアゾール−3−イルであり;RDはHまたはC1−C4アルキルであり;
R3はH、C1−C4アルキル、C3−C6シクロアルキル、またはC1−C4フルオロアルキルであり;
R4は−NR7C(=O)OCH(R8)−CYであり;
R7はHまたはC1−C4アルキルであり;
R8はH、C1−C4アルキル、またはC1−C4フルオロアルキルであり;
CYは置換もしくは非置換のC3−C6シクロアルキルまたは置換もしくは非置換のフェニルであり、ここで、CYが置換される場合、CYは1または2個のRCで置換され;
R9はH、C1−C6アルキル、C1−C6フルオロアルキル、C3−C6シクロアルキル、または置換もしくは非置換のフェニルであり;
R10はC1−C6アルキル、C1−C6フルオロアルキル、C3−C6シクロアルキル、または置換もしくは非置換のフェニルであり;
各RA、RB、およびRCは独立して、F、Cl、Br、I、−CN、−OH、C1−C4アルキル、C1−C4フルオロアルキル、C1−C4フルオロアルコキシ、C1−C4アルコキシ、およびC1−C4ヘテロアルキルから選択され;
mは0、1、または2であり;nは1、2、3または4であり;pは0、1、または2である]
の構造を有する化合物、またはその医薬的に許容される塩が提供される。
本発明で開示される式(I)の化合物は、標準的な合成技法または当業者に周知の方法を本明細書中に記載される方法と共に用いて製造される。さらに、本明細書中に提示される溶媒、温度および他の反応条件は変更されてもよい。
態様の1つにおいて、式(I)の化合物は1つまたはそれ以上の立体中心を有し、各立体中心はRまたはSの配置において独立して存在する。本発明で開示される化合物は全てのジアステレオマー、およびエナンチオマーの形態を包含する。立体異性体は、必要な場合、立体選択的合成および/またはキラルクロマトグラフィカラムによる分離といった方法により得られる。
特に断らない限り、本願(明細書および請求項を含む)で用いられる以下の用語は以下に提供される定義を有する。本明細書中および付属の請求項で用いられるように、文脈から明確に指示されない限り、単数形「a」、「an」および「the」が複数形を含むことは記しておかなければならない。特に指定がない限り、質量分析、NMR、HPLC、タンパク質化学、生化学、組み換えDNA技法および薬理学の一般的な方法が用いられた。本願において、特に断らない限り、「または」または「および」の使用は「および/または」を意味する。さらに、用語「含んでいる」、ならびに他の形態、例えば、「含む」および「含まれる」の使用は限定されない。本明細書中で用いられる段落の表題は構成に関する目的でのみ使用され、記載対象の限定を意図するものではない。
いくつかの実施態様において、本発明で開示される化合物は医薬組成物に製剤化される。医薬組成物は、活性化合物の医薬的に使用可能な製剤への加工を容易にする1つまたはそれ以上の医薬的に許容される不活性な成分を用い、一般的な方法で製剤化される。適当な製剤は選択される投与経路に依存する。本発明に記載される医薬組成物の概要は、例えば、Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.:Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999)に記載されており、引用により本明細書中に取り込む。
態様の1つにおいて、式(I)の化合物はLPA依存性またはLPA介在性の疾患または病状の治療のための薬物の製造に用いられる。さらに、治療が必要な対象における本発明で提示されるいずれの疾患または病状の治療方法は、少なくとも1つの式(I)の化合物またはその医薬的に許容される塩、活性な代謝物、プロドラッグもしくは溶媒和物を含む医薬組成物を該対象に治療上有効量において投与することに関連する。
LPA介在性の疾患または病状の予防または治療に関連する前記のいずれの態様のさらなる実施態様は、LPA受容体遺伝子におけるSNPのスクリーニングによる患者の同定を特徴とする。患者はさらに、対象の組織におけるLPA受容体の発現上昇に基づいて選別することができる。LPA受容体の発現は、例えば、限定されないが、ノーザンブロッティング、ウェスタンブロッティング、定量的PCR(qPCR)、フローサイトメトリー、オートラジオグラフィ(低分子量放射標識リガンドまたはPETリガンドを用いる)などの方法により決定される。いくつかの実施態様において、患者は血清または組織におけるLPA濃度(質量分析により測定)に基づき選択される。いくつかの実施態様において、患者は上記のマーカー(LPA濃度の上昇およびLPA受容体発現量の上昇)の組み合わせに基づき選択される。
いくつかの例において、少なくとも1つの式(I)の化合物を別の治療薬と組み合わせて投与することが適当である。
これらの実施例は例示することのみが目的であり、本明細書中で提供される請求項の範囲を限定するものではない。
(R)−2’−クロロ−アルファ−メチルベンジルアルコール
Meierらの方法(Tetrahedron, 1996, 52, 589;方法3)を用い、2’−クロロアセトフェノン(Aldrich)を還元して(R)−2’−クロロ−アルファ−メチルベンジルアルコールを得た(%e.e.は、99:1 ヘキサン:エタノールで溶出するChiralcel ODを用いたアセテート誘導体(塩化メチレン中におけるベンジルアルコールとアセチルクロリドおよびトリエチルアミンの反応により製造)のHPLC分析により決定した。R異性体の保持時間は4.3分であった)。
Meierらの方法(Tetrahedron, 1996, 52, 589;方法3)を用い、2’−クロロアセトフェノン(Aldrich)を還元して(S)−2’−クロロ−アルファ−メチルベンジルアルコールを得た(%e.e.は、99:1 ヘキサン:エタノールで溶出するChiralcel ODを用いたアセテート誘導体(塩化メチレン中におけるベンジルアルコールとアセチルクロリドおよびトリエチルアミンの反応により製造)のHPLC分析により決定した。S異性体の保持時間は5.3分であった)。
Meierらの方法(Tetrahedron, 1996, 52, 589;方法3)を用い、2’−フルオロアセトフェノン(Aldrich)を還元して(R)−2’−フルオロ−アルファ−メチルベンジルアルコールを得た(%e.e.は、99.8:0.2 ヘキサン:エタノールで溶出するChiralcel ODを用いたアセテート誘導体(塩化メチレン中におけるベンジルアルコールとアセチルクロリドおよびトリエチルアミンの反応により製造)のHPLC分析により決定した。R異性体の保持時間は5.9分であった)。
Meierらの方法(Tetrahedron, 1996, 52, 589;方法3)を用い、2’−フルオロアセトフェノン(Aldrich)を還元して(S)−2’−フルオロ−アルファ−メチルベンジルアルコールを得た(%e.e.は、99.8:0.2 ヘキサン:エタノールで溶出するChiralcel ODを用いたアセテート誘導体(塩化メチレン中におけるベンジルアルコールとアセチルクロリドおよびトリエチルアミンの反応により製造)のHPLC分析により決定した。S異性体の保持時間は6.7分であった)。
工程1:3−メチルアミノ−ブタ−2−エン酸メチルエステル:メチルアセトアセテート(29.4g、253mmol)のMeOH(30mL)溶液にメチルアミン(33wt%/EtOH;48mL、385mmol)を室温で滴下して加えた。反応液を1時間撹拌し、濃縮し、乾燥し、表題化合物を白色の結晶性固形物として得た。
工程1:1−(ビフェニル−4−イル)シクロプロパンカルボニトリル:4−フェニル−フェニルアセトニトリル(VWR scientific、55.7g、289mmol)を、KOH(161.6g、2890mmol)の水(170mL)およびトルエン(550mL)溶液に室温で加えた。テトラブチルアンモニウムブロミド(9.2g、29mmol)、次いで1,2−ジブロモメタン(64.9g、347mmol)を加え、該溶液を65℃で終夜加熱した。反応の完了はTLC(10% EtOAc/ヘキサン)で確認した。有機層を2回、希塩酸で抽出し、乾燥し、エバポレートし、63gの1−(ビフェニル−4−イル)シクロプロパンカルボニトリルを得た。
工程1:1−(ビフェニル−4−イル)シクロプロパンカルボン酸イソプロピルエステル:1−(ビフェニル−4−イル)シクロプロパンカルボン酸(10g、42mmol)、イソプロパノール(100mL)、塩化チオニル(6.8mL、92mmol)を65℃で4時間加熱した。硫酸(20mL)を加え、65℃で終夜加熱した。生成物をCH2Cl2および水(2x)で抽出し、乾燥し、エバポレートし、10.8gの表題化合物を得た。
工程1:1−(4−ブロモ−フェニル)−シクロプロパンカルボニトリル:水酸化カリウム(14.3g、255mmol)をH2O(5mL)およびトルエン(40mL)に溶解した。4−ブロモフェニルアセトニトリル(5.0g、25.5mmol)およびテトラブチルアンモニウムブロミド(0.41g、1.3mmol)を加え、次いで1,2−ジブロモエタン(3.25mL、38mmol)を10分間かけて滴下して加えた。反応物を室温で2時間撹拌し、ワークアップを行い、表題化合物を得た。
実施例3a:(R)−1−{4’−[4−(1−シクロプロピル−エトキシカルボニルアミノ)−3−メチル−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物6)の合成
工程1:[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸1−シクロプロピル−エチルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸およびアルファ−メチルシクロプロパンメタノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:(R)−アルファ−メチルシクロプロパンメタノール:Meierらの方法(Tetrahedron, 1996, 52, 589;方法3)と類似の方法を用い、シクロプロピルメチルケトン(Aldrich)を還元して(R)−アルファ−メチルシクロプロパンメタノールを得た。
工程1:[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸(R)−1−(2−クロロ−フェニル)−エチルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸および(R)−1−(2−クロロ−フェニル)−エタノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:(R)−1−(2−トリフルオロメチル−フェニル)−エタノール:2’−(トリフルオロメチル)アセトフェノンを用い、実施例2、工程5に記載の方法により製造した。
工程1:1−(4−ブロモ−フェニル)−シクロペンタンカルボン酸エチルエステル:0℃のエチル4−ブロモフェニルアセテート(2g、8.2mmol)のDMF(20mL)溶液に水素化ナトリウム(60%/ミネラル油;0.72g、18.1mmol)を加え、該混合物を10分間撹拌した。1,4−ジブロモブタン(1.07mL、9.0mmol)を加え、該混合物を室温で30分間撹拌した。分析TLCにより出発物質が検出されなくなると、該混合物をEtOAcおよび10%HCl水溶液でワークアップし、粗物質をシリカゲルクロマトグラフィで精製し、表題化合物を得た。
工程1:1−(4−ブロモ−フェニル)−シクロブタンカルボン酸エチルエステル:エチル4−ブロモフェニルアセテートおよび1,3−ジブロモプロパンを用い、実施例6、工程1に記載の方法により製造した。
工程1:[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸1−シクロヘキシル−エチルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸および1−シクロヘキシルエタノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸ベンジルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸およびベンジルアルコールを用い、実施例1、工程5に記載の方法を用いて製造した。
実施例3a、工程2のエナンチオマーA(1−{4’−[4−(1−シクロプロピル−エトキシカルボニルアミノ)−3−メチル−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸エチルエステル)を用い、実施例2、工程8に記載の方法により製造した。
工程1:[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸シクロプロピルメチルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸およびシクロプロピルカルビノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸1−(2−メトキシ−フェニル)−エチルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸および1−(2−メトキシフェニル)エタノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸1−(4−トリフルオロメチル−フェニル)−エチルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸および1−[4−(トリフルオロメチル)フェニル]エタノールを用い、実施例1、工程5に記載の方法により製造した。
実施例13、工程2のエナンチオマーB(1−(4’−{3−メチル−4−[1−(4−トリフルオロメチル−フェニル)−エトキシカルボニルアミノ]−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸エチルエステル)を用い、実施例6、工程4に記載の方法により製造した。
工程1:3−(1−ヒドロキシ−エチル)−ベンゾニトリル:室温の3−アセチルベンゾニトリル(1当量)/メタノールにナトリウムボロヒドリド(約1.67当量)を加え、反応物を約20分間撹拌した。水性のワークアップを行い、表題化合物を得た。
工程1:(R)−1−p−トリル−エタノール:4’−メチルアセトフェノンを用い、実施例2、工程5に記載の方法により製造した。
工程1:(R)−1−m−トリル−エタノール:3’−メチルアセトフェノンを用い、実施例2、工程5に記載の方法により製造した。
工程1:4−((R)−1−ヒドロキシ−エチル)−ベンゾニトリル:4−アセチルベンゾニトリルを用い、実施例2、工程5に記載の方法により製造した。
工程1:2−((R)−1−ヒドロキシ−エチル)−ベンゾニトリル:2−アセチルベンゼンカルボニトリルを用い、実施例2、工程5に記載の方法により製造した。
工程1:(R)−1−シクロブチル−エタノール:シクロブチルメチルケトンを用い、実施例2、工程5に記載の方法により製造した。
工程1:2−クロロ−シクロヘキサ−1−エンカルボアルデヒド:室温のシクロヘキサノン(1.34g、13.6mmol)のトルエン溶液にDMF(1.58mL、20.5mmol)およびオキシ塩化リン(1.88mL、20.5mmol)を加えた。該反応物を室温で終夜撹拌し、次いでH2Oで希釈し、30分間撹拌した。4N NaOH水溶液(10mL)を加え、該混合物をEtOAcで抽出した。有機層を合わせ、飽和NH4Cl水溶液で洗浄し、MgSO4で乾燥し、濾過し、濃縮し、表題化合物を得た。
工程1:(R)−1−(3−トリフルオロメチル−フェニル)−エタノール:3’−(トリフルオロメチル)アセトフェノンを用い、実施例2、工程5に記載の方法により製造した。
工程1:(R)−1−(3−メトキシ−フェニル)−エタノール:3’−メトキシアセトフェノンを用い、実施例2、工程5に記載の方法により製造した。
工程1:(R)−1−(4−メトキシ−フェニル)−エタノール:4’−メトキシアセトフェノンを用い、実施例2、工程5に記載の方法により製造した。
工程1:1−(4’−{4−[1−(3−ブロモ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸エチルエステル:5−[4’−(1−エトキシカルボニル−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−カルボン酸および3−ブロモ−アルファ−メチルベンジルアルコールを用い、実施例1、工程5に記載の方法により製造した。
工程1:1−(4’−{4−[1−(3−クロロ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸エチルエステル:5−[4’−(1−エトキシカルボニル−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−カルボン酸および1−(3−クロロフェニル)エタノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:(S)−[5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸1−フェニル−エチルエステル:5−(4−ブロモ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸および(S)−1−フェニルエタノール(市販、または本明細書中もしくはE.J. Corey et al. J. Am. Chem. 1987, 109, 5551−5553などの文献に記載の方法により製造される)を用い、実施例1、工程5に記載の方法により製造した。
工程1:1−[3−(tert−ブチル−ジメチル−シラニルオキシ)−フェニル]−エタノン:3’−ヒドロキシアセトフェノン(0.500g、3.67mmol)およびイミダゾール(0.500g、7.34mmol)のCH2Cl2(5mL)溶液にtert−ブチルジメチルシリルクロリド(0.609g、4.04mmol)を加え、反応物を室温で1時間撹拌した。混合物をCH2Cl2およびH2Oで分液処理し、水層を分離し、CH2Cl2で抽出した。有機層を合わせ、MgSO4で乾燥し、濾過し、濃縮し、表題化合物を得た。
工程1:2−(4−ブロモ−ベンゾイル)−3−オキソ−ペンタン酸メチルエステル:4−ブロモベンゾイルクロリドおよび3−オキソ吉草酸メチルを用い、実施例1、工程2に記載の方法により製造した;ナトリウムtert−ブトキシドをピリジンの代わりに用いた。
工程6:1−{4’−[3−エチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸:1−{4’−[3−エチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸エチルエステルを用い、実施例2、工程8に記載の方法により製造した。
工程1:[5−(4−ブロモ−フェニル)−3−エチル−イソオキサゾール−4−イル]−カルバミン酸(R)−1−(3−トリフルオロメチル−フェニル)−エチルエステル:5−(4−ブロモ−フェニル)−3−エチル−イソオキサゾール−4−カルボン酸および(R)−1−(3−トリフルオロメチル−フェニル)−エタノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:1−{4’−[3−メチル−4−((1−フェニル−エトキシ−d9)−カルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸エチルエステル:5−[4’−(1−エトキシカルボニル−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−カルボン酸および1−フェニルエタノール−d9(Carbocoreから購入した1−フェニルエタノールを重水素化したもの)を用い、実施例1、工程5に記載の方法により製造した。
工程1:4−ブロモ−2−メトキシ−ベンゾイルクロリド:4−ブロモ−2−メトキシ安息香酸(2.5g、11.04mmol)のCHCl3(20mL)溶液にDMF(触媒)および塩化チオニル(1.6mL、22.08mmol)を加えた。反応物を55℃で1時間撹拌し、次いで濃縮乾燥し、表題化合物を得た。
工程1:1−(3,5−ジブロモ−フェニル)−エタノン:3,5−ジブロモ安息香酸(2.5g、8.9mmol)のEt2O(30mL)溶液(0℃)にメチルリチウム(1.6M/Et2O;12.3mL、19.6mmol)を滴下して加えた。反応物を0℃で2時間撹拌し、次いで、EtOAcおよび10% HCl水溶液によるワークアップを行った。粗物質をシリカゲルクロマトグラフィで精製し、表題化合物を得た。
1−{4’−[3−メチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(0.1g、0.2mmol)、メタンスルホンアミド(0.08g、0.8mmol)、およびN,N’−カルボニルジイミダゾール(0.15g、0.6mmol)をTHF(4mL)中で混合した。ジイソプロピルエチルアミン(0.5mL)を加え、反応物を65℃で終夜撹拌した。混合物を酸性化し、CH2Cl2で抽出した。粗物質をシリカゲルクロマトグラフィ(0−50% EtOAc/ヘキサン)で抽出し、表題化合物を得た。
1−{4’−[3−メチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸およびベンゼンスルホンアミドを用い、実施例34、工程1に記載の方法により製造した。
工程1:1−[4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−フェニル]−シクロプロパンカルボニトリル:1−(4−ブロモ−フェニル)−シクロプロパンカルボニトリルおよびビス(ピナコレート)ジボロンを用い、実施例2、工程4に記載の方法により製造した。
工程1:(5−{4’−[1−(N−ヒドロキシカルバムイミドイル)−シクロプロピル]−ビフェニル−4−イル}−3−メチル−イソオキサゾール−4−イル)−カルバミン酸(R)−1−フェニル−エチルエステル:{5−[4’−(1−シアノ−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−イル}−カルバミン酸(R)−1−フェニル−エチルエステル(0.307g、0.66mmol)、ヒドロキシルアミン塩酸塩(0.046g、0.67mmol)、およびトリエチルアミン(0.097mL、0.67mmol)をEtOH(7mL)中で混合し、反応物を50℃で終夜撹拌した。さらなるヒドロキシルアミン塩酸塩(0.100g、1.45mmol)およびトリエチルアミン(0.30mL、2.15mmol)を加え、反応物を終夜撹拌した。次いで、混合物を濃縮し、表題化合物を得た。
{5−[4’−(1−シアノ−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−イル}−カルバミン酸(R)−1−フェニル−エチルエステル(0.385g、0.83mmol)およびN,N−ジメチルエタノールアミン(0.101mL、1.0mmol)をジグリム(ジエチレングリコールジメチルエーテル;2mL)中で混合した。塩酸(4M/1,4−ジオキサン;4.2mL)を加え、反応物を15分間撹拌した。さらにN,N−ジメチルエタノールアミン(0.221mL、2.2mmol)、次いでアジ化ナトリウム(0.098g、1.5mmol)を加え、反応物を120℃で24時間撹拌した。室温に冷却後、混合物をCH2Cl2(20mL)およびH2O(10mL)で希釈した。有機層をMgSO4で乾燥し、濾過し、濃縮し、残渣をシリカゲルクロマトグラフィで精製し、表題化合物を得た。
工程1:N−[1−(4−ブロモ−フェニル)−シクロプロパンカルボニル]−メタンスルホンアミド:1−(4−ブロモ−フェニル)−シクロプロパンカルボン酸(5.0g、20.7mmol)のトルエン(30mL)溶液に塩化チオニル(17.7mL、243mmol)をゆっくりと加え、反応物を4時間還流した。混合物を濃縮し、粗物質をトルエン(50mL)に溶解した。メタンスルホンアミド(11.41g、120mmol)、次いでトリエチルアミン(15mL)を加え、反応物を3時間還流した。室温に冷却後、混合物をCH2Cl2(200mL)に注ぎ、H2O(150mL)で洗浄した。有機層をMgSO4で乾燥し、濾過し、濃縮し、粗物質をシリカゲルクロマトグラフィで精製し、表題化合物を得た。
工程1:[5−(4−ブロモ−2−メトキシ−フェニル)−3−メチル−イソオキサゾール−4−イル]−カルバミン酸(R)−1−(3−トリフルオロメチル−フェニル)−エチルエステル:5−(4−ブロモ−2−メトキシ−フェニル)−3−メチル−イソオキサゾール−4−カルボン酸および(R)−1−(3−トリフルオロメチル−フェニル)−エタノールを用い、実施例1、工程5に記載の方法により製造した。
工程1:5−(4−ブロモ−フェニル)−イソオキサゾール−4−カルボン酸エチルエステル:エチル(4−ブロモベンゾイル)アセテート(1.19g、4.39mmol)のN,N−ジメチルホルムアミドジメチルアセタール(10mL)溶液を100℃で1時間撹拌した。混合物を濃縮し、残渣をEtOH(10mL)に溶解した。ヒドロキシルアミン塩酸塩(0.454g、6.57mmol)を加え、反応物を100℃で1時間撹拌した。室温に冷却後、混合物をEtOAcおよびH2Oで分液処理し、有機層を分離し、MgSO4で乾燥し、濾過し、濃縮した。粗物質をシリカゲルクロマトグラフィで精製し、表題化合物を得た。
ラセミ体の1−フェニルエチルアルコールを(R)−(+)−1−フェニルエチルアルコールの代わりに用い、実施例1、化合物1に記載の方法により製造した。
ヒトLPA1受容体をコードする1.1kbのcDNAをヒトの肺からクローニングした。RETROscript kit(Ambion, Inc.)を用いてヒト肺RNA(Clontech Laboratories, Inc. USA)の逆転写反応を行い、逆転写反応産物のPCRによりヒトLPA1の全長cDNAを得た。クローニングしたヒトLPA1の塩基配列はシークエンス反応により決定し、文献におけるヒトLPA1配列(An et al. Biochem. Biophys. Res. Commun. 231:619 (1997))と同一であることを確認した。cDNAをpCDNA5/FRT発現プラスミドに組み込み、lipofectamine 2000(Invitrogen Corp., USA)を用いてCHO細胞にトランスフェクションした。ハイグロマイシンを用いてヒトLPA1を安定的に発現するクローンを選別し、LPAに応答してCa流入を示す細胞として同定した。
ヒトLPA2受容体のcDNAを含むベクターをMissouri S&T cDNA Resource Center(www.cdna.org)から購入した。このベクターのPCRにより、ヒトLPA2の全長cDNA断片を得た。得られたヒトLPA2のcDNAの塩基配列はシークエンス反応により決定し、文献のヒトLPA2配列(NCBI accession number NM_004720)と同一であることを確認した。該cDNAをpCDNA3.1発現プラスミドに組み込み、B103細胞(Invitrogen Corp., USA)にトランスフェクションした(トランスフェクションは、細胞を96ウェルのポリ−D−リジンコートされたプレートに30,000−35,000個/ウェルの濃度で、0.2μlのlipofectamine 2000および0.2μgのLPA2発現ベクターと共に播種することにより行った)。LPA誘発性Ca流入のアッセイを行う前に、細胞を完全培地中で終夜培養した。
ヒトLPA3受容体cDNAを含むベクターをMissouri S&T cDNA Resource Center(www.cdna.org)から購入した。このベクターのPCRにより、ヒトLPA3の全長cDNA断片を得た。得られたヒトLPA3のcDNAの塩基配列はシークエンス反応により決定し、文献のヒトLPA3配列(NCBI accession number NM_012152)と同一であることを確認した。該cDNAをpCDNA5/FRT発現プラスミドに組み込み、lipofectamine 2000(Invitrogen Corp., USA)を用いてCHO細胞にトランスフェクションした。ヒトLPA3を安定的に発現するクローンをハイグロマイシンにより選別し、LPAに応答してCa流入を示す細胞として同定した。
アッセイの1または2日前、ヒトLPA1またはLPA3を発現するCHO細胞を、96ウェルのポリ−D−リジンコートされたプレートに20,000−45,000個/ウェルの濃度で播種した。アッセイ前に、細胞をPBSで1回洗浄し、血清不含培地中で終夜培養した。アッセイ当日、カルシウム指示薬色素(Calcium 4、Molecular Devices)/アッセイバッファー(Ca2+およびMg2+含有HBSS、20mM Hepesおよび0.3%脂肪酸不含ヒト血清アルブミンを含む)を各ウェルに加え、37℃で1時間インキュベートを続けた。10μlの試験化合物/2.5% DMSOを加え、室温で30分間インキュベートした。10nm LPAを加えて細胞を刺激し、細胞内Ca2+をFlexstation 3(Molecular Devices)を用いて測定した。薬剤の滴定曲線をGraphpad prismにより分析し、IC50を決定した。
BT−20ヒト乳癌細胞を25,000−35,000個/ウェルの濃度で、150μlの完全培地を用い、ポリ−D−リジンでコートしたblack−wall clear−bottomプレートに播種した。終夜培養後、細胞をPBSで1回洗浄し、次いで、アッセイ前の4−6時間、血清を欠乏させた。アッセイ当日、カルシウム指示薬色素(Calcium 5、Molecular Devices)/アッセイバッファー(Ca2+およびMg2+含有HBSS、20mM Hepesおよび0.3%脂肪酸不含ヒト血清アルブミンを含む)を各ウェルに加え、37℃で15分間、インキュベートを続けた。25μlの試験化合物/2.5% DMSOを細胞に加え、37℃で15分間インキュベートした。100nM LPAを加えて細胞を刺激し、細胞内Ca2+をFlexstation 3(Molecular Devices)を用いて測定した。薬剤の滴定曲線をSymyx Assay Explorerで分析し、IC50を決定した。
化合物のGTPのLPA1への結合阻害能は、膜GTPγSアッセイにより評価した。組み換えヒトLPA1受容体を安定的に発現するCHO細胞を10mM Hepes(pH7.4、1mM DTTを含む)に再懸濁し、溶解し、75,000xgで遠心して膜を沈殿させた。膜画分を10mM Hepes(pH7.4、1mM DTTおよび10%グリセロール含有)に再懸濁した。96ウェルプレート中で、膜画分(〜25μg/ウェル)を0.1nM [35S]−GTPγS、900nM LPA、5μM GDP、および試験化合物/アッセイバッファー(50mM Hepes、pH7.4、100mM NaCl、10mM MgCl2、50μg/mlサポニンおよび0.2%脂肪酸不含ヒト血清アルブミン)と共に30℃で30分間インキュベートした。Whatman GF/Bガラス繊維濾紙プレートに通す急速濾過により反応を終了させた。該濾紙プレートを1ml冷洗浄バッファー(50mM Hepes、pH7.5、100mM NaClおよび10mM MgCl2)で3回洗浄し、乾燥した。次いで、シンチラントをプレートに加え、濾紙上に保持された放射活性をPackard TopCount(Perkin Elmer)で測定した。特異的な結合は、総放射活性から非特異的結合(リガンド(900nM LPA)がない状態)を差し引いて決定した。薬剤の滴定曲線をGraphpad prismで分析し、IC50を決定した。
A2058ヒト黒色腫細胞の走化性を、Neuroprobe ChemoTx(登録商標) Systemプレート(孔径8μm、直径5.7mm)を用いて測定した。フィルター部位を0.001%フィブロネクチン(Sigma)/20mM Hepes、pH7.4でコートし、乾燥した。A2058細胞を24時間、血清を欠乏させ、Cell Stripperで回収し、DMEM(0.1%脂肪酸不含ウシ血清アルブミン(BSA)含有)で1x106/mlの濃度に再懸濁した。細胞を等量(2x)の試験化合物/DMEM(0.1%脂肪酸不含BSA含有)と混合し、37℃で15分間インキュベートした。LPA(100nM/0.1%脂肪酸不含BSA含有DMEM)またはベヒクルを各ウェルの下部チャンバーに加え、50μlの細胞懸濁液/試験化合物混合物をChemoTxプレートの上部チャンバーに加えた。プレートを37℃で3時間インキュベートし、次いで、PBSによる洗浄および剥離により上部から細胞を除去した。フィルターを乾燥し、HEMA 3 Staining System(Fisher Scientific)で染色した。590nmにおけるフィルターの吸光度を測定し、Symyx Assay ExplorerによりIC50を決定した。
メスC57Bl/6マウス(Harlan、25−30g)を4匹/ケージで飼料および水を自由に摂取させて飼育し、試験開始前に少なくとも7日間馴化を行った。馴化フェーズ後、イソフルラン(5%/100% O2)でマウスを軽度に麻酔し、硫酸ブレオマイシン(0.01−5U/kg、Henry Schein)を気管内注入により投与した(Cuzzocrea S et al. Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1095−104. Epub 2007 Jan 12.)。マウスをケージに戻し、実験期間中毎日モニターした。試験化合物またはベヒクルを、毎日経口、腹腔内または皮下から投与した。投与経路および投与頻度は先に決定した薬物動態学的性質に基づく。ブレオマイシン注入から3、7、14、21または28日後に全ての動物をイソフルラン吸入により屠殺した。屠殺後、マウスに1mlシリンジを装着した20ゲージの血管カテーテルを挿管した。肺をPBSで灌流して気管支肺胞洗浄液(BALF)を得、次いで肺を除去し、後で行う病理組織学的分析用に10%中性緩衝ホルマリンで固定した。BALFは800xgで10分間遠心して細胞を沈殿させ、細胞上清を除去し、後で行うタンパク質分析(DC protein assay kit (Biorad, Hercules, CA.)を用いる)および可溶性コラーゲン分析用(Sircol (Biocolor Ltd, UK)を用いる)に−80℃で凍結した。市販のELISAを用いて、BALFにおける炎症性、向線維症性および組織損傷性のバイオマーカー(例えばトランスフォーミング増殖因子β1、ヒアルロン酸、組織メタロプロテアーゼ阻害物質1、マトリックスメタロプロテアーゼ−7、結合組織増殖因子)濃度および乳酸脱水素酵素活性を分析した。細胞ペレットをPBSで再懸濁した。次いで、全細胞数をHemavet hematology system(Drew Scientific, Wayne, PA.)を用いて求め、分画細胞成分をShandon cytospin(Thermo Scientific, Waltham, MA.)を用いて求めた。肺組織をヘマトキシリンおよびエオシン(H&E)ならびにトリクロームで染色し、肺線維症を、光学顕微鏡(倍率10x)を用いた半定量的病理組織学的スコアリング(Ashcroft T. et al. J. Clin. Path. 1988;41;4, 467−470)および光学顕微鏡を用いた肺組織切片コラーゲンの定量的コンピューター支援デンシトメトリーにより決定した。データをGraphpad prismによりプロットし、群間の統計的有意差を決定した。
メスC57BL/6マウス(Harlan、20−25g)を4匹/ケージで水および飼料を自由に摂取させて飼育し、試験開始前に少なくとも7日間馴化を行った。馴化フェーズ後、マウスにCCl4(1.0 ml/kg体重)をトウモロコシ油媒体(100μL)で希釈したものを週2回、8週間腹腔内投与した(Higazi, A. A. et al., Clin Exp Immunol. 2008 Apr;152(1):163−73. Epub 2008 Feb 14.)。コントロールマウスには等量のトウモロコシ油媒体のみを投与した。試験化合物またはベヒクルは、経口、腹腔内または皮下経路により毎日投与した。実験終了時(CCl4の最初の腹腔内注射から8週間後)、マウスをイソフルラン吸入により屠殺し、後で行うALT/AST量の分析用に血液を心穿刺により採取した。肝臓を回収し、半分を−80℃で凍結、残り半分を光学顕微鏡(倍率10x)で行う肝線維症の病理組織学的評価用に10%中性緩衝ホルマリンで固定した。肝組織のホモジネートにおけるコラーゲン量をSircol(Biocolor Ltd, UK)を用いて分析した。固定した肝組織はヘマトキシリンおよびエオシン(H&E)ならびにトリクロームで染色し、光学顕微鏡を用いた肝組織切片のコラーゲンの定量的コンピューター支援デンシトメトリーにより肝線維症を決定した。市販のELISAを用いて、血漿および肝組織溶解液中の炎症性、向線維症性および組織損傷性のバイオマーカー(例えばトランスフォーミング増殖因子β1、ヒアルロン酸、組織メタロプロテアーゼ阻害物質1、マトリックスメタロプロテアーゼ−7、結合組織増殖因子)濃度および乳酸脱水素酵素活性を分析した。得られたデータをGraphpad prismによりプロットし、群間の統計学的有意差を決定した。
マウスのLPA静脈内投与誘発性ヒスタミン放出モデルを、LPA1およびLPA3受容体アンタゴニストのインビボにおける効力の決定に用いた。メスCD−1マウス(体重25−35グラム)に、LPA静脈内投与(マウス1匹当たり300μg/0.1%FAF BSA)の30分から24時間前に、化合物を10ml/kgの体積において投与した(腹腔内、皮下、または経口)。LPA投与直後にマウスを密閉したPlexiglas chamberに入れ、2分間イソフルランに曝した。マウスを取り出し、断頭し、EDTAを含んだチューブに体血を採取した。次いで、血液を4℃、10,000xgで10分間遠心した。血漿中のヒスタミン濃度をEIAにより求めた。血漿中の薬物濃度は質量分析により求めた。血中ヒスタミン放出の50%阻害が得られる投与量を非線形回帰(Graphpad Prism)により算出し、ED50としてプロットした。この投与量に相関する血漿中濃度をEC50としてプロットした。
実験開始2週間前、メスBALB/cマウス(Harlan、体重20−25グラム)に一般的なマウス飼料および水を自由に摂取させ、馴化を行った。化合物1を水媒体で3mg/mlに調製し、30mg/kgの投与量となるよう10ml/kgの体積で強制経口投与した。投与から3時間後、マウスを拘束具で拘束し、エバンスブルー色素を尾静脈投与した(0.5%の溶液を0.2ml)。次いで、マウスを3%イソフルランで麻酔し、LPAを皮内注射した(30μg/20μl(0.1%脂肪酸不含BSA))。LPA注射から30分後、マウスをCO2吸入により屠殺し、投与部位から皮膚を剥ぎ、2mlホルムアミド中に終夜置き、エバンスブルー色素を抽出した。
メスC57BL/6マウス(Harlan、20−25g)を4匹/ケージで飼料および水を自由に摂取させて飼育し、試験開始前に少なくとも7日間馴化を行った。馴化フェーズ後、一側尿管結紮(UUO)手術または偽手術をマウスの左腎に施術した。簡潔に述べると、左上部切開を行い、左腎を露出した。腎動脈が位置しており、6/0絹糸を動脈と尿管の間に通した。その絹糸を尿管の周りに巻き、3回結んで尿管を完全に結紮した。左腎を腹部に戻し、腹筋を縫合し、皮膚をステープルで止めた。マウスをケージに戻し、実験期間中毎日モニターした。試験化合物またはベヒクルは、毎日経口、腹腔内または皮下経路で投与した。投与経路および投与頻度は、先に求めた薬物動態学的性質に基づく。UUO手術から4、8または14日後に全ての動物をイソフルラン吸入により屠殺した。屠殺後、心穿刺により脱血し、腎臓を採取し、半分を−80℃で凍結し、残りの半分は光学顕微鏡(倍率10x)を用いた腎線維症の病理組織学的評価用に10%中性緩衝ホルムアミドで固定した。腎組織ホモジネートにおけるコラーゲン量をSircol(Biocolor Ltd、UK)により分析した。固定した腎組織をヘマトキシリンおよびエオシン(H&E)ならびにトリクロームで染色し、光学顕微鏡を用いた腎組織切片のコラーゲンの定量的コンピューター支援デンシトメトリーおよび腎臓溶解液中のコラーゲン量から腎線維症を決定した。市販のELISAを用いて、血漿および腎組織溶解液中の炎症性、向線維症性および組織損傷性のバイオマーカー(例えばトランスフォーミング増殖因子β1、ヒアルロン酸、組織メタロプロテアーゼ阻害物質1、マトリックスメタロプロテアーゼ−7、結合組織増殖因子)濃度および乳酸脱水素酵素活性を分析した。得られたデータをGraphpad prismによりプロットし、群間の統計学的有意差を決定した。
目的
本治験の目的は、特発性肺線維症(IPF)患者における式(I)の化合物による治療効果をプラセボと比較して評価し、IPF患者における式(I)の化合物による治療の安全性をプラセボと比較して評価することである。
本治験に適格な患者は、例えば、以下の組み入れ基準を満たす患者である:IPFと診断されること;年齢40から80歳;FVC≧50%(推定値);DLco≧35%(推定値);FVCまたはDLco≦90%(推定値);過去に改善が認められないこと;6L/分を超えない酸素供給量で6分以内に150メートル歩行可能であり、酸素飽和度≧83%を維持できること。
注射による投与(皮下、静脈内など)に適した非経口医薬組成物の製造では、式(I)の化合物の100mgの水溶性の塩を滅菌水に溶解し、10mLの0.9%滅菌生理食塩水と混合する。混合物は、注射による投与に適した単位投与剤形に組み込まれる。
経口投与のための医薬組成物の製造では、100mgの式(I)の化合物を750mgのデンプンと混合する。該混合物は経口投与単位、例えば経口投与に適した硬ゼラチンカプセルに組み込まれる。
頬側送達のための医薬組成物(硬質ロゼンジ剤など)の製造では、100mgの式(I)の化合物を、1.6mLのライトコーンシロップ、2.4mLの蒸留水、および0.42mLのミントエキスと混合した420mgの粉砂糖と混合する。混合物を緩やかにブレンドし、頬側投与に適したロゼンジ剤を形成するための鋳型に注ぐ。
速崩壊性舌下錠は、48.5重量%の式(I)の化合物、44.5重量%の結晶セルロース(KG−802)、5重量%の低置換度ヒドロキシプロピルセルロース(50μm)、および2重量%のステアリン酸マグネシウムを混合することにより製造される。錠剤は、直接打錠(AAPS PharmSciTech. 2006;7(2):E41)により製造される。圧縮錠の総重量は150mgに維持される。該製剤は、所定量の式(I)の化合物を所定量全量の結晶セルロース(MCC)および所定の3分の2の量の低置換度ヒドロキシプロピルセルロース(L−HPC)を、3次元マニュアルミキサー(lnversina(登録商標)、Bioengineering AG, Switzerland)を用いて4.5分間混合する。ステアリン酸マグネシウム(MS)全量およびL−HPCの残り3分の1を混合終了の30秒前に加える。
吸入送達のための医薬組成物の製造では、20mgの式(I)の化合物を50mgの無水クエン酸および100mLの0.9%塩化ナトリウム溶液と混合する。次いで、混合物をネブライザーなどの吸入投与に適した吸入送達単位に組み込む。
直腸送達のための医薬組成物の製造では、100mgの式(I)の化合物を2.5gのメチルセルロース(1500mPa)、100mgのメチルパラペン、5gのグリセリンおよび100mLの精製水と混合する。得られたゲル混合物を、次いで、直腸投与に適したシリンジなどの直腸送達単位に組み込む。
局所ゲル医薬組成物の製造では、100mgの式(I)の化合物を1.75gのヒドロキシプロピルセルロース、10mLのプロピレングリコール、10mLのミリスチン酸イソプロピルおよび100mLの精製アルコール(USP)を混合する。得られたゲル混合物を、次いで、チューブなどの局所投与に適した容器に組み込む。
眼科用溶液医薬組成物の製造では、100mgの式(I)の化合物を0.9gのNaCl/100mL精製水と混合し、0.2ミクロンのナイロンフィルターに通して濾過する。得られた等張の溶液を、次いで、眼球投与に適した点眼容器などの眼球送達単位に組み込む。
経鼻噴霧用液の製造では、10gの式(I)の化合物を30mLの0.05Mリン酸緩衝溶液(pH4.4)と混合する。該溶液を、1回の適用につき100μlを送達するようデザインされた経鼻投与用容器に入れる。
Claims (18)
- 式(I):
R1は−CO2H、−CO2RD、−CN、−C(=O)N(R9)2、−C(=O)NHCH2CH2SO3H、−C(=O)NHSO2R10、テトラゾリル、または5−オキソ−2,5−ジヒドロ−[1,2,4]オキサジアゾール−3−イルであり;RDはHまたはC1−C4アルキルであり;
R3はH、C1−C4アルキル、C3−C6シクロアルキル、またはC1−C4フルオロアルキルであり;
R4は−NR7C(=O)OCH(R8)−CYであり;
R7はHまたはC1−C4アルキルであり;
R8はH、C1−C4アルキル、またはC1−C4フルオロアルキルであり;
CYは置換もしくは非置換のC3−C6シクロアルキルまたは置換もしくは非置換のフェニルであり(ここで、CYが置換される場合、CYは1または2個のRCで置換される);
R9はH、C1−C6アルキル、C1−C6フルオロアルキル、C3−C6シクロアルキル、または置換もしくは非置換のフェニルであり;
R10はC1−C6アルキル、C1−C6フルオロアルキル、C3−C6シクロアルキル、または置換もしくは非置換のフェニルであり;
各RA、RB、およびRCは独立して、F、Cl、Br、I、−CN、−OH、C1−C4アルキル、C1−C4フルオロアルキル、C1−C4フルオロアルコキシ、C1−C4アルコキシ、およびC1−C4ヘテロアルキルから選択され;
mは0、1、または2であり;
nは1、2、3または4であり;
pは0、1、または2である]
の構造を有する化合物、またはその医薬的に許容される塩。 - R1が−CO2H、−CO2RD、−C(=O)NHSO2R10またはテトラゾリルであり;
R3がHまたはC1−C4アルキルであり;
R7がHであり;
R8がH、−CH3または−CF3であり;
R10がC1−C6アルキルまたは置換もしくは非置換のフェニルであり;
各RAが独立して、F、Cl、Br、I、−OH、−CH3、−CF3、−OCF3、および−OCH3から選択され;
各RBが独立して、F、Cl、Br、I、−OH、−CH3、−CF3、−OCF3、および−OCH3から選択され;
各RCがF、Cl、Br、I、−OH、−CH3、−CF3、−OCF3、および−OCH3から選択され;
mが0または1であり;
nが1、2、または3であり;
pが0または1である、
請求項1に記載の化合物。 - R1が−CO2Hまたは−CO2RDであり;RDがH、−CH3、または−CH2CH3であり;
R3がH、−CH3または−CH2CH3であり;
R4が−NHC(=O)OCH(R8)−CYであり;
R8がH、または−CH3であり;
CYが置換または非置換のフェニルである(ここで、CYが置換されたフェニルの場合、該フェニルは1または2個のRCで置換される)、
請求項2に記載の化合物。 - R1が−C(=O)NHSO2R10であり;
R3がH、−CH3または−CH2CH3であり;
R8がH、または−CH3であり;
R10が−CH3、または−CH2CH3である、
請求項2に記載の化合物。 - R4が−NHC(=O)OCH(CH3)−(置換または非置換のフェニル)であり;ここで、該フェニルが置換されるときはRCで置換され;
RCがF、Cl、−CH3、またはCF3であり;
nが1である、
請求項1−5のいずれか一項に記載の化合物。 - CYがフェニル、2−フルオロフェニル、3−フルオロフェニル、2−クロロフェニル、3−クロロフェニル、2−メチルフェニル、3−メチルフェニル、2−トリフルオロメチルフェニル、または3−トリフルオロメチルフェニルである、請求項7に記載の化合物。
- R1が−CO2Hであり;
CYがフェニル、2−フルオロフェニル、3−フルオロフェニル、2−クロロフェニル、3−クロロフェニル、2−メチルフェニル、3−メチルフェニル、2−トリフルオロメチルフェニル、または3−トリフルオロメチルフェニルである、
請求項9に記載の化合物。 - R1が−CO2H、−CO2RD、−C(=O)NHSO2R10、テトラゾリル、または5−オキソ−2,5−ジヒドロ−[1,2,4]オキサジアゾール−3−イルであり;
R3がHまたはC1−C4アルキルであり;
R7がHであり;
R8がH、または−CH3であり;
R10がC1−C6アルキルまたは置換もしくは非置換のフェニルであり;
CYがシクロプロピル、シクロブチル、シクロペンチル、シクロペンタ−1−エニル、2−クロロシクロペンタ−1−エニル、シクロヘキシル、シクロヘキサ−1−エニル、2−クロロシクロヘキサ−1−エニル、フェニル、2−フルオロフェニル、2,3−ジフルオロフェニル、2,4−ジフルオロフェニル、2,5−ジフルオロフェニル、2,6−ジフルオロフェニル、2−クロロフェニル、2,6−ジクロロフェニル、2−ブロモフェニル、3−ブロモフェニル、2,4−ジクロロフェニル、2−ヒドロキシフェニル、3−ヒドロキシフェニル、4−ヒドロキシフェニル、2−メトキシフェニル、3−メトキシフェニル、4−メトキシフェニル、2−トリフルオロメチルフェニル、3−トリフルオロメチルフェニル、4−トリフルオロメチルフェニル、2−フルオロ−4−メトキシフェニル、2−メチルフェニル、3−メチルフェニル、4−メチルフェニル、2−シアノフェニル、3−シアノフェニル、または4−シアノフェニルである、
請求項1に記載の化合物。 - 各RAが独立して、F、Cl、−CH3、−CF3、−OH、−OCF3、および−OCH3から選択され;
各RBが独立して、F、Cl、−CH3、−CF3、−OH、−OCF3、および−OCH3から選択され;
mが0または1であり;
nが1であり;
pが0または1である、
請求項11に記載の化合物。 - 1−{4’−[3−メチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物1);
1−{4’−[4−(1−シクロヘキシル−エトキシカルボニルアミノ)−3−メチル−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物2);
1−{4’−[3−メチル−4−((R)−1−o−トリル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物3);
1−[4’−(4−ベンジルオキシカルボニルアミノ−3−メチル−イソオキサゾール−5−イル)−ビフェニル−4−イル]−シクロプロパンカルボン酸(化合物4);
(S)−1−{4’−[4−(1−シクロプロピル−エトキシカルボニルアミノ)−3−メチル−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物5);
(R)−1−{4’−[4−(1−シクロプロピル−エトキシカルボニルアミノ)−3−メチル−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物6);
1−[4’−(4−シクロプロピルメトキシカルボニルアミノ−3−メチル−イソオキサゾール−5−イル)−ビフェニル−4−イル]−シクロプロパンカルボン酸(化合物7);
1−(4’−{4−[(R)−1−(2−クロロ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物8);
1−(4’−{3−メチル−4−[(R)−1−(2−トリフルオロメチル−フェニル)−エトキシカルボニルアミノ]−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物9);
1−{4’−[3−メチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロブタンカルボン酸(化合物10);
1−{4’−[3−メチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロペンタンカルボン酸(化合物11);
1−(4’−{4−[1−(2−メトキシ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物12);
1−(4’−{3−メチル−4−[1−(4−トリフルオロメチル−フェニル)−エトキシカルボニルアミノ]−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物13);
1−(4’−{3−メチル−4−[1−(4−トリフルオロメチル−フェニル)−エトキシカルボニルアミノ]−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物14);
1−(4’−{4−[1−(3−シアノ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物15);
1−{4’−[3−メチル−4−((R)−1−p−トリル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物16);
1−{4’−[3−メチル−4−((R)−1−m−トリル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物17);
1−(4’−{4−[(R)−1−(4−シアノ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物18);
1−(4’−{4−[(R)−1−(2−シアノ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物19);
1−{4’−[4−((R)−1−シクロブチル−エトキシカルボニルアミノ)−3−メチル−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物20);
1−(4’−{4−[1−(2−クロロ−シクロヘキサ−1−エニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物21);
1−(4’−{3−メチル−4−[(R)−1−(3−トリフルオロメチル−フェニル)−エトキシカルボニルアミノ]−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物22);
1−(4’−{4−[(R)−1−(3−メトキシ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物23);
1−(4’−{4−[(R)−1−(4−メトキシ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物24);
1−(4’−{4−[1−(3−ブロモ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物25);
1−(4’−{4−[1−(3−クロロ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物26);
1−{4’−[3−メチル−4−((S)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物27);
1−(4’−{4−[1−(3−ヒドロキシ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物28);
1−{4’−[3−エチル−4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物29);
1−(4’−{3−エチル−4−[(R)−1−(3−トリフルオロメチル−フェニル)−エトキシカルボニルアミノ]−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物30);
1−(3’−メトキシ−4’−{3−メチル−4−[(R)−1−(3−トリフルオロメチル−フェニル)−エトキシカルボニルアミノ]−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物31);
1−(4’−{4−[(R)−1−(3,5−ジブロモ−フェニル)−エトキシカルボニルアミノ]−3−メチル−イソオキサゾール−5−イル}−ビフェニル−4−イル)−シクロプロパンカルボン酸(化合物32);
1−{4’−[4−((R)−1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物33);
1−{4’−[3−メチル−4−(1−フェニル−エトキシカルボニルアミノ)−イソオキサゾール−5−イル]−ビフェニル−4−イル}−シクロプロパンカルボン酸(化合物34);
{5−[4’−(1−メタンスルホニルアミノカルボニル−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−イル}−カルバミン酸(R)−1−フェニル−エチルエステル(化合物35);
{5−[4’−(1−ベンゼンスルホニルアミノカルボニル−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−イル}−カルバミン酸(R)−1−フェニル−エチルエステル(化合物36);
{5−[4’−(1−シアノ−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−イル}−カルバミン酸(R)−1−フェニル−エチルエステル(化合物37);
(3−メチル−5−{4’−[1−(5−オキソ−2,5−ジヒドロ−[1,2,4]オキサジアゾール−3−イル)−シクロプロピル]−ビフェニル−4−イル}−イソオキサゾール−4−イル)−カルバミン酸(R)−1−フェニル−エチルエステル(化合物38);
(3−メチル−5−{4’−[1−(1H−テトラゾール−5−イル)−シクロプロピル]−ビフェニル−4−イル}−イソオキサゾール−4−イル)−カルバミン酸(R)−1−フェニル−エチルエステル(化合物39);
{5−[4’−(1−メタンスルホニルアミノカルボニル−シクロプロピル)−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−イル}−カルバミン酸(R)−1−(3−トリフルオロメチル−フェニル)−エチルエステル(化合物40);
{5−[4’−(1−メタンスルホニルアミノカルボニル−シクロプロピル)−3−メトキシ−ビフェニル−4−イル]−3−メチル−イソオキサゾール−4−イル}−カルバミン酸(R)−1−(3−トリフルオロメチル−フェニル)−エチルエステル(化合物41);
から選択される請求項1に記載の化合物、またはその医薬的に許容される塩。 - 治療上有効量の請求項1−13のいずれか一項に記載の化合物またはその医薬的に許容される塩を含む医薬組成物。
- (a)静脈内注射、皮下注射、経口投与、吸入、経鼻投与、局所投与、眼球投与または耳内投与のために製剤化された医薬組成物;または
(b)錠剤、丸剤、カプセル剤、液剤、吸入剤、経鼻噴霧液、坐剤、懸濁液、ジェル剤、コロイド、分散系、懸濁液、溶液、エマルジョン、軟膏、ローション、点眼薬または点耳薬である医薬組成物
である、請求項14に記載の医薬組成物。 - 哺乳類における癌の治療方法であって、治療上有効量の請求項1−13のいずれか一項に記載の化合物またはその医薬的に許容される塩を治療が必要な哺乳類に投与することを特徴とする方法。
- 哺乳類における線維症の治療方法または予防方法であって、治療上有効量の請求項1−13の化合物またはその医薬的に許容される塩を治療が必要な哺乳類に投与することを特徴とする方法。
- 哺乳類における肺線維症、喘息、慢性閉塞性肺疾患(COPD)、腎線維症、急性腎障害、慢性腎臓病、肝線維症、皮膚線維症、腸線維症、乳癌、膵癌、卵巣癌、前立腺癌、膠芽腫、骨癌、大腸癌、腸癌、頭頚部癌、黒色腫、多発性骨髄腫、慢性リンパ性白血病、癌性疼痛、腫瘍転移、移植臓器拒絶、強皮症、眼線維症、加齢黄斑変性(AMD)、糖尿病網膜症、膠原病性脈管疾患、アテローム動脈硬化症、レイノー現象、または神経障害性疼痛の予防方法または治療方法であって、治療上有効量の請求項1−13のいずれか一項に記載の化合物またはその医薬的に許容される塩を治療が必要な哺乳類に投与することを特徴とする方法。
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JP2021529733A (ja) * | 2018-06-18 | 2021-11-04 | エピゲン バイオサイエンシズ, インコーポレイテッドEpigen Biosciences, Inc. | 疾患の治療に有用な複素環化合物 |
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JP7422788B2 (ja) | 2019-06-18 | 2024-01-26 | ブリストル-マイヤーズ スクイブ カンパニー | Lpaアンタゴニストとしてのイソキサゾールカルボン酸 |
JP7465898B2 (ja) | 2019-06-18 | 2024-04-11 | ブリストル-マイヤーズ スクイブ カンパニー | Lpaアンタゴニストとしてのトリアゾールカルボン酸 |
JP7465899B2 (ja) | 2019-06-18 | 2024-04-11 | ブリストル-マイヤーズ スクイブ カンパニー | Lpaアンタゴニストとしてのシクロブチルカルボン酸 |
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