JP5870111B2 - mGluR2/3アンタゴニストとしての4−置換−3−ベンジルオキシ−ビシクロ[3.1.0]ヘキサン化合物 - Google Patents
mGluR2/3アンタゴニストとしての4−置換−3−ベンジルオキシ−ビシクロ[3.1.0]ヘキサン化合物 Download PDFInfo
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- JP5870111B2 JP5870111B2 JP2013539932A JP2013539932A JP5870111B2 JP 5870111 B2 JP5870111 B2 JP 5870111B2 JP 2013539932 A JP2013539932 A JP 2013539932A JP 2013539932 A JP2013539932 A JP 2013539932A JP 5870111 B2 JP5870111 B2 JP 5870111B2
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Description
R3は、独立して各存在において、メチル、フルオロまたはクロロであり;
R4は、ヒドロキシル、メチルカルボニルアミノ、ヒドロキシメチルカルボニルアミノ、メトキシカルボニルアミノ、イミダゾール−2−イルスルファニル、チアゾール−2−イルスルファニル、1,2,4−トリアゾール−3−イルスルファニル、1−メチル−1,2,4−トリアゾール−3−イルスルファニル、または1−メチル−1,2,4−トリアゾール−5−イルスルファニルであり;
nは、1または2である]
またはその薬学的に許容可能な塩を提供する。
1)R1およびR2の両方が、水素である;
2)R1もしくはR2またはその両方が、水素以外である;
3)R1およびR2の両方が、水素以外である;
4)R1およびR2が、同じであり、かつ水素以外である;
5)R1およびR2が各々、イソプロポキシカルボニルオキシメチルである;
6)nが、2である;
7)nが、2であり、両方のR3基がクロロであり、かつクロロ基がフェニル3位および4位にある;
8)R4が、ヒドロキシルである、
化合物である。
9)nが2であり、両方のR3基がクロロであり、かつクロロ基がフェニル3位および4位にある(パラグラフ7)、パラグラフ1〜5のいずれか1つの好ましい化合物(R1およびR2についての好ましい選択);
10)R4がヒドロキシルである(パラグラフ8)、パラグラフ1〜5のいずれか1つの好ましい化合物(R1およびR2についての好ましい選択);
11)nが2であり、両方のR3基がクロロであり、かつクロロ基がフェニル3位および4位にあり(パラグラフ7)、R4がヒドロキシルである(パラグラフ8)、パラグラフ1〜5のいずれか1つの好ましい化合物(R1およびR2についての好ましい選択)。
(1S,2R,3S,4S,5R,6R)−2−アミノ−3−[(3,4−ジクロロベンジル)オキシ]−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸またはその薬学的に許容可能な塩;および
ビス(イソプロポキシカルボニルオキシメチル)(1R,2S,3S,4R,5S,6R)−4−アミノ−3−[(3,4−ジクロロフェニル)メトキシ]−2−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボキシレートまたはその薬学的に許容可能な塩(すなわち、実施例1、10および15の化合物ならびにそれらの代替の薬学的に許容可能な塩)である。
「BSA」は、ウシ血清アルブミンを意味する。
「DCG IV」は、(2S,2’R,3’R)−2−(2’,3’−ジカルボキシシクロプロピル)グリシンを意味する。
「DMEM」は、ダルベッコ最小イーグル培地を意味する。
「DMSO」は、ジメチルスルホキシドを意味する。
「DPBS」は、ダルベッコリン酸緩衝食塩水を意味する。
「EDTA」は、エチレンジアミン四酢酸を意味する。
「GTP」は、グアノシン三リン酸を意味する。
「HBSS」は、ハンクス緩衝塩溶液を意味する。
「HEPES」は、4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸を意味する。
「HPLC」は、高圧液体クロマトグラフィーを意味する。
「IBMX」は、3−イソブチル−1−メチルキサンチンを意味する。
「IC50」は、最大阻害の50%が達成される濃度を意味する。
「i.v.」は、静脈内のまたは静脈内にを意味する。
「i.p.」は、腹腔内を意味する。
「L−AP−4」は、L−(+)−2−アミノ−4−ホスホノ酪酸を意味する。
「LC/MS」は、液体クロマトグラフィーに続く質量分析を意味する。
「mFST」は、マウス強制水泳試験;抗うつ活性に対する動物モデルを意味する。
「MS」は、質量分析を意味する。
「MS(ES+)」は、エレクトロスプレーイオン化を用いた質量分析を意味する。
「NMR」は、核磁気共鳴を意味する。
「p.o.」は、口による経口的を意味する。
「tBu」は、第三級ブチル部分を意味する。
本発明の化合物は、当該分野において周知であり認められている方法による以下の合成スキームに従って調製され得る。これらのスキームの工程に適した反応条件は、当該分野で周知であり、溶媒および補助試薬(co−reagents)の適切な置換は、当該分野の技術範囲内である。同様に、合成中間体が、必要に応じまたは所望であれば、様々な周知の手法によって単離され得るおよび/または精製され得ること、ならびにしばしば、様々な中間体をほとんどまたは全く精製せずに直接その後の合成工程において使用することが可能であり得ることも当業者に認識されるだろう。さらに、当業者は、いくつかの状況では、部分が導入される順序が重大な意味を持たないことを認識するだろう。本発明の化合物を生成するために必要な特定の工程の順序は、合成される特定の化合物、出発化合物、および熟練の化学者が十分に認識しているような、置換部分の相対的な傾向に依存する。別段示されない限り、すべての置換基が、先に定義されたとおりであり、すべての試薬が、当該分野において周知でありかつ認識されているものである。
アンタゴニスト活性は、ヒトmGlu2またはmGlu3受容体およびラットグルタミン酸トランスポーターEAAT1(興奮性アミノ酸トランスポーター1)を安定的に発現する組換えAV12細胞においてアッセイされる。その細胞株は、5%透析ウシ胎児血清(FBS)、1mMピルビン酸ナトリウム、1mM HEPESおよび1mM L−グルタミンが補充された、高グルコースおよび塩酸ピリドキシンを含むDMEM中で培養することによって維持される;ジェネテシンおよびハイグロマイシンBが、選択抗生物質として使用される。コンフルエントな培養物を、6.5%CO2を含む雰囲気中、37℃で生育し、2週間に1回継代する。0.25%トリプシンを用いて細胞を回収し、凍結培地(10%DMSOを含むFBS)に107細胞/mlで懸濁し、アリコートを液体窒素中で凍結する。アッセイの24時間前に、細胞を、組織培養処理済96ウェルハーフエリア黒色プレート(Costar3875)において、5%透析FBS、1mMピルビン酸ナトリウム、1mM HEPES、100μg/mlアンピシリンおよび250μM(mGlu2)または125μM(mGlu3)のL−グルタミンが補充された高グルコースおよび塩酸ピリドキシンを含む50μlのDMEM中、8,000〜10,000細胞/ウェルの密度でプレーティングする。
他のヒトmGlu受容体に対する本発明の化合物の相対的なアンタゴニスト効力は、cAMPアッセイまたは蛍光定量的なカルシウム反応アッセイを用いて評価され得る(例えば、Fellら、JPET(印刷中)を参照のこと)。簡潔には、ラットEAAT1グルタミン酸トランスポーターを含み、かつヒトmGlu1、2、3、4、5、6および8受容体を安定的に発現する個別のAV12細胞株が、本研究のために使用される。mGlu1および5受容体は、Gq共役型であるので、それらは、天然には、ホスホリパーゼCを介してシグナル伝達し、Fluorometric Imaging Plate Reader(FLIPR,Molecular Devices)を用いて受容体の活性化を測定するために使用され得るカルシウム流動反応を生じる。mGlu2、3、4および8受容体を発現する細胞株は、Gα15サブユニットを発現するように設計され、これらのGi共役型受容体は、mGlu1および5受容体を発現する細胞株と同様のカルシウム流動反応をもたらすことになる。mGlu6受容体は、上記のmGlu2およびmGlu3に対して開発された方法と類似の方法を用いて、cAMP形式で試験される。これらの細胞株は、L−グルタミンの量および選択薬剤(ジェネテシン、ハイグロマイシンB、ゼオシンおよびブラストサイジン)が細胞株に応じて変化し得ることを除いて、先に記載されたように維持される。コンフルエントな培養物が、2週間に1回継代される。
mFSTは、抗うつ活性に対して確立されたインビボアッセイである(Li et al.J Pharmacol Exp Ther.319(1):254−9,2006.)。公知の臨床的に有効な抗うつ薬(選択的セロトニン再取り込み阻害薬および/または三環系抗うつ薬)で処置されたマウスは、水槽に入れられた後に、不動で過ごす行動(絶望状態に関連する行動)の時間の短縮を示す。本質的には以前に公開された方法(例えば、Li et al.J Pharmacol Exp Ther.319(1):254−9,2006を参照のこと)に記載されているように、新規mGlu2/3アンタゴニストの潜在的な抗うつ様活性を評価するためにmFSTを使用した。簡潔には、体重が25〜30gの雄NIH−Swissマウス(Harlan Sprague−Dawley,Indianapolis,IN)を使用する。群で収容されている動物を、動物飼育施設から取り出して、それ専用のケージ内の試験エリアに移し、試験の前に少なくとも1時間、新しい環境に適応させる。R1およびR2の両方が水素である化合物を、溶解のために最小量のNaOHが加えられた水に溶解し、i.p.投与する。R1および/またはR2が水素以外である化合物は、使用当日に、2.0〜2.5%N−メチル−ピロリジノン中に調製され、次いで、1%HEC、0.25%Tween80および0.05%Dow消泡剤に懸濁し、経口的に投与される。マウスを、6cmの水(22〜25℃)で満たされた筒(直径:10cm;高さ:25cm)に6分間入れる。その試験時間の6分間のうちの最後の4分間における不動の時間をスコア付けした。マウスは、動かずに浮いているかまたは頭部を水より上で維持するのに必要な動きだけをするとき、不動と記録される。
(i)反跳性傾眠過剰は、有効な処置が施された後の8〜19時間における覚醒状態のレベルの低下として判定され得る。生物学的に有意な低下は、最初の7時間における50パーセントを超える累積的増加と定義される。したがって、覚醒状態が、最初の7時間において100分増加した場合、ビヒクルコントロールと比べて処置後の8〜19時間において累積覚醒状態が50分以上減少することが、生物学的に有意であると見なされる。表2に示される群平均値の変化は、反跳性傾眠過剰が無いことを示す。
(ii)運動活性の増大は、ビヒクルコントロールと比べたとき、有効性閾値用量においてEEGによって定義される覚醒状態の1分あたり5回のLMAを超え、かつその作用が用量関連性である、平均値の増加と定義される。表2における群平均値の増加はすべて、覚醒状態1分あたり5回を下回り、用量依存的でない。
Claims (8)
- 以下の式の化合物
R3は、独立して各存在において、メチル、フルオロまたはクロロであり;
R4は、ヒドロキシル、メチルカルボニルアミノ、ヒドロキシメチルカルボニルアミノ、メトキシカルボニルアミノ、イミダゾール−2−イルスルファニル、チアゾール−2−イルスルファニル、1,2,4−トリアゾリルスルファニル、1−メチル−1,2,4−トリアゾール−3−イルスルファニル、または1−メチル−1,2,4−トリアゾール−5−イルスルファニルであり;
nは、1または2である]
またはその薬学的に許容可能な塩。 - R1およびR2が各々、水素である、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- R1およびR2が同じであり、かつ水素以外である、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- R1およびR2が各々、イソプロピルオキシカルボニルオキシメチルである、請求項3に記載の化合物。
- (1S,2R,3S,4S,5R,6R)−2−アミノ−3−[(3,4−ジクロロベンジル)オキシ]−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸である、請求項1に記載の化合物またはその薬学的に許容可能な塩。
- ビス({[(1−メチルエトキシ)カルボニル]オキシ}メチル)(1S,2R,3S,4S,5R,6R)−2−アミノ−3−[(3,4−ジクロロベンジル)オキシ]−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボキシレートである、請求項1に記載の化合物またはその薬学的に許容可能な塩。
- 請求項1〜6のいずれか1項に記載の化合物、またはその薬学的に許容可能な塩と、薬学的に許容可能な担体、賦形剤または希釈剤とを含む、医薬組成物。
- 請求項1〜6のいずれか1項に記載の化合物またはその薬学的に許容可能な塩を含む、うつ病性障害を処置するための医薬組成物。
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US41511310P | 2010-11-18 | 2010-11-18 | |
US61/415,113 | 2010-11-18 | ||
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JP2014505663A5 JP2014505663A5 (ja) | 2014-11-20 |
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EP (1) | EP2640687B1 (ja) |
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CN (1) | CN103209954B (ja) |
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CA (1) | CA2818118C (ja) |
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JO2978B1 (en) * | 2009-12-21 | 2016-03-15 | ايلي ليلي اند كومباني | MGLU2 aids |
EP3000814A1 (en) | 2014-09-26 | 2016-03-30 | Domain Therapeutics | Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors |
MX2018012442A (es) * | 2016-04-18 | 2019-02-21 | Taisho Pharmaceutical Co Ltd | Profarmaco de derivado de aminoacido. |
KR102549584B1 (ko) * | 2018-03-27 | 2023-06-30 | 삼성전자주식회사 | 메모리 모듈을 포함하는 메모리 시스템, 메모리 모듈, 그리고 메모리 모듈의 동작 방법 |
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JPH0669928B2 (ja) | 1987-10-06 | 1994-09-07 | 宇部興産株式会社 | 光重合性歯科材料 |
JP2589812B2 (ja) | 1989-07-05 | 1997-03-12 | 松下電器産業株式会社 | スチームアイロン |
ZA969485B (en) | 1995-11-16 | 1998-05-12 | Lilly Co Eli | Excitatory amino acid receptor antagonists. |
CN1202103A (zh) * | 1995-11-16 | 1998-12-16 | 伊莱利利公司 | 兴奋性的氨基酸受体拮抗剂 |
ZA983930B (en) * | 1997-05-14 | 1999-11-08 | Lilly Co Eli | Excitatory amino acid receptor modulators. |
US6136861A (en) | 1998-03-17 | 2000-10-24 | Pfizer Inc | Bicyclo[2.2.1]heptanes and related compounds |
GB9815542D0 (en) | 1998-07-17 | 1998-09-16 | Lilly Co Eli | Bicyclohexane derivatives |
CH694053A5 (de) | 1998-09-03 | 2004-06-30 | Hoffmann La Roche | Verfahren zur Herstellung von 2-Amino-bicyclo[3.1.0]hexan-2,6-dicarbonsäure-Derivaten. |
WO2002068380A1 (en) * | 2001-02-22 | 2002-09-06 | Eli Lilly And Company | Synthetic excitatory amino acids |
NZ533699A (en) | 2001-12-27 | 2006-05-26 | Taisho Pharmaceutical Co Ltd | 6-fluorobicyclo[3.1.0]hexane derivatives |
NZ536459A (en) | 2002-06-11 | 2008-03-28 | Lilly Co Eli | Prodrugs of excitatory amino acids |
KR101071507B1 (ko) * | 2003-06-26 | 2011-10-10 | 다이쇼 세이야꾸 가부시끼가이샤 | 2-아미노바이시클로〔3.1.0〕헥산-2,6-디카르복실산 에스테르 유도체 |
CN100582087C (zh) * | 2003-06-26 | 2010-01-20 | 大正制药株式会社 | 2-氨基-双环[3.1.0]己烷-2,6-二甲酸酯衍生物 |
JP2007063129A (ja) * | 2003-06-26 | 2007-03-15 | Taisho Pharmaceut Co Ltd | 2−アミノ−3−アルコキシビシクロ[3.1.0]ヘキサン誘導体 |
WO2005000790A1 (ja) | 2003-06-26 | 2005-01-06 | Taisho Pharmaceutical Co., Ltd. | 2-アミノビシクロ[3.1.0]ヘキサン-2,6-ジカルボン酸誘導体 |
JP5485492B2 (ja) * | 2004-12-15 | 2014-05-07 | 大正製薬株式会社 | うつ病の予防・治療薬 |
JO2978B1 (en) * | 2009-12-21 | 2016-03-15 | ايلي ليلي اند كومباني | MGLU2 aids |
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EP2640687B1 (en) | 2018-06-27 |
KR20130080858A (ko) | 2013-07-15 |
AU2011329136A1 (en) | 2013-05-02 |
AU2011329136B2 (en) | 2014-11-06 |
US20130237573A1 (en) | 2013-09-12 |
EA201390568A1 (ru) | 2013-09-30 |
BR112013012384A2 (pt) | 2019-09-24 |
WO2012068041A1 (en) | 2012-05-24 |
MX2013005623A (es) | 2013-07-05 |
JP2014505663A (ja) | 2014-03-06 |
CA2818118C (en) | 2016-03-29 |
KR101554793B1 (ko) | 2015-09-21 |
US9056844B2 (en) | 2015-06-16 |
CN103209954A (zh) | 2013-07-17 |
EA022196B1 (ru) | 2015-11-30 |
EP2640687A1 (en) | 2013-09-25 |
CA2818118A1 (en) | 2012-05-24 |
ES2682959T3 (es) | 2018-09-24 |
CN103209954B (zh) | 2015-09-02 |
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