JP4767973B2 - Nk1アンタゴニスト - Google Patents
Nk1アンタゴニスト Download PDFInfo
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- JP4767973B2 JP4767973B2 JP2007556522A JP2007556522A JP4767973B2 JP 4767973 B2 JP4767973 B2 JP 4767973B2 JP 2007556522 A JP2007556522 A JP 2007556522A JP 2007556522 A JP2007556522 A JP 2007556522A JP 4767973 B2 JP4767973 B2 JP 4767973B2
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- 0 CC(*)(*c(c(C1=CC=CCC2C1(C)C2)c1)cnc1N1CCN(C)CC1)c1cc(*)cc(C(F)(F)F)c1 Chemical compound CC(*)(*c(c(C1=CC=CCC2C1(C)C2)c1)cnc1N1CCN(C)CC1)c1cc(*)cc(C(F)(F)F)c1 0.000 description 4
- YZJPHCKYNCZTHL-UHFFFAOYSA-N CC(C)(C)C(N(c1ccc(N2CCN(C)CC2)nc1)N)=O Chemical compound CC(C)(C)C(N(c1ccc(N2CCN(C)CC2)nc1)N)=O YZJPHCKYNCZTHL-UHFFFAOYSA-N 0.000 description 1
- NZTCEWZBMOTKCJ-UHFFFAOYSA-N CN(CC1)CCN1c(nc1)ccc1N Chemical compound CN(CC1)CCN1c(nc1)ccc1N NZTCEWZBMOTKCJ-UHFFFAOYSA-N 0.000 description 1
- KQJDENNFFKXTGT-UHFFFAOYSA-N Cc(nccc1)c1-c(cc(nc1)Cl)c1C(O)=O Chemical compound Cc(nccc1)c1-c(cc(nc1)Cl)c1C(O)=O KQJDENNFFKXTGT-UHFFFAOYSA-N 0.000 description 1
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- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Description
R1/R1′は、水素又はメチルであり;
Xは、−C(O)N(CH3)−又は−N(CH3)C(O)−である]
で示される化合物及びその薬学的に許容される酸付加塩に関する。
2−メチル−6′−(4−メチル−ピペラジン−1−イル)−[3,4′]ビピリジニル−3′−カルボン酸(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミド及び
2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−[2−メチル−6′−(4−メチル−ピペラジン−1−イル)−[3,4′]ビピリジニル−3′−イル]−イソブチルアミド。
更に、US 5,972,938は、NK−1レセプターアンタゴニストなどのタキキニンレセプターの投与による精神免疫障害又は心身症の処置の方法を記載している。
a)式(II−1):
b)式(II−2):
所望であれば、得られた化合物を薬学的に許容される酸付加塩に変換することを含む。
dppf [1,1′−ビス(ジフェニルホスフィノ)フェロセン]
DMF N,N−ジメチルホルムアミド
DMAP 4−(N,N−ジメチルアミノ)ピリジン
DPPA ジフェニルホスホリルアジド
THF テトラヒドロフラン
PivCl ピバロイルクロリド
THF テトラヒドロフラン
TMEDA N,N,N′,N′−テトラメチルエチレンジアミン
DIPEA N−エチルジイソプロピル−アミン
KHMDS ヘキサメチルジシラジドカリウム
N,N−ジメチルホルムアミド中のトリフルオロ−メタンスルホン酸2−メチル−ピリジン−3−イルエステル、ビス(ピナコラート)ジボロン、酢酸カリウムとジクロロ[1,1′−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロロメタン付加物の混合物を、アルゴン下、約80℃で一晩加熱する。室温に冷却した後、5−ブロモ−2−クロロ−4−ヨード−ピリジン、別の部分のジクロロ[1,1′−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロロメタン付加物及び脱酸素化した炭酸ナトリウム水溶液を加える。反応混合物を約80℃で4.5時間加熱する。室温に冷却した後、混合物を濃縮し、乾燥し、従来の手法により精製する。
テトラヒドロフラン中の5′−ブロモ−2′−クロロ−2−メチル−[3,4′]ビピリジニルの溶液に、ヘキサン中のn−ブチルリチウムの溶液を、アルゴン下、約−100℃で滴下する。出発物質を完全に消費した後、二酸化炭素ガスを反応混合物にゆっくりとバブリングする。約15分後、混合物をゆっくりと0℃に温め、この温度で約1時間撹拌する。水で希釈し、水酸化ナトリウム水溶液を加えてpH9まで塩基性にする。tert−ブチルメチルエーテルで洗浄した後、水層に塩酸水溶液を加えてpH3まで酸性にし、濃縮し、乾燥し、従来の手法により精製する。
ジクロロメタン中の6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−カルボン酸(VI)の懸濁液に、オキサリルクロリド及びDMF 1滴を、アルゴン下、約0℃で加える。反応混合物を、ゆっくりと室温に温める。約1時間後、混合物を減圧下で濃縮し、ジクロロメタンに再溶解する。この溶液を、ジクロロメタン中の(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミンとN,N−ジイソプロピルエチルアミンの混合物に、0℃で滴下する。約30分後、反応混合物を酢酸エチルで希釈し、水酸化ナトリウム水溶液で洗浄して、式(II−1)で示される6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−カルボン酸(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミドを得る。
6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−カルボン酸(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミドと1−メチルピペラジンの混合物を、約120℃で2時間加熱する。室温に冷却した後、混合物をジクロロメタンで希釈し、水で洗浄する。水層を従来の手法により処理して、式(I−1)で示される化合物である2−メチル−6′−(4−メチル−ピペラジン−1−イル)−[3,4′]ビピリジニル−3′−カルボン酸(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミドを得る。
tert−ブタノール中の6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−カルボン酸(VI)、トリエチルアミン及びジフェニルホスホリルアジドの溶液を、アルゴン下、約90℃で1.5時間撹拌する。室温に冷却した後、溶媒を蒸発させる。残渣を酢酸エチルで希釈し、炭酸水素ナトリウム水溶液及びブラインで洗浄する。有機層を濃縮し、精製して、式(VIII)の化合物である(6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−イル)−カルバミン酸tert−ブチルエステルを得る。
NK−1レセプターに対する試験化合物の親和性を、ヒトNK−1レセプターを感染させ(セムリキウイルス発現系を用いる)、および[3H]サブスタンスP(最終濃度0.6nM)で放射線標識した、CHO細胞中のヒトNK−1レセプターで評価した。結合アッセイは、BSA(0.04%)ロイペプチン(8μg/ml)、MnCl2(3mM)およびホスホラミドン(2μM)を含有するHEPES緩衝液(50mM、pH7.4)中で行った。結合アッセイは、250μlの膜懸濁液(細胞1.25×105個/アッセイ用試験管)、0.125μlの置換剤の緩衝液及び125μlの[3H]サブスタンスPから成った。置換曲線は、化合物の少なくとも7つの濃度を用いて決定した。アッセイ用試験管を60分間、室温でインキュベートし、その後、60分間PEI(0.3%)に前もって浸漬したGF/Cフィルタを通して真空下で試験管の内容物を迅速に濾過し、HEPES緩衝液(50mM、pH7.4)で2ml×2回洗浄した。フィルタ上に保持された放射能をシンチレーションカウンティングによって測定した。すべてのアッセイは、少なくとも2回の別の実験で3回ずつ行った。
方法の説明:平衡溶解度
平衡溶解度値は、pH4.2(0.15M クエン酸−緩衝液)で決定した。公知量の薬剤を、通常1〜2mg、緩衝液(ガラスチューブ)250μlに加え、得られた懸濁液を5分間超音波処理した後、2時間(21℃)撹拌した。溶液のpHの値を調べ、必要であれば調整し(pHの調整に際しては、溶液を再度振とうし、平衡させた)、24時間後、懸濁液を0.65μmフィルタを通して濾過した。次に濾過した溶液をHPLCにより分析して薬剤濃度を決定した。薬剤が完全に緩衝液に溶解した場合には、平衡溶解度値はHPLCにより決定された値より高いとみなされ、そのように報告した。DMSO中の保存溶液(〜1mg/ml)を、関連する緩衝液中におけるHPLC分析を用いた検量線の作成に使用した。
5′−ブロモ−2′−クロロ−2−メチル−[3,4′]ビピリジニル
MS m/e(%):285(M+H+、100)
6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−カルボン酸
MS m/e(%):247(M−H+、100)
2−メチル−6′−(4−メチル−ピペラジン−1−イル)−[3,4′]ビピリジニル−3′−カルボン酸(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミド
a)6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−カルボン酸(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミド
MS m/e(%):488(M+H+、100)
MS m/e(%):552(M+H+、100)
2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−[2−メチル−6′−(4−メチル−ピペラジン−1−イル)−[3,4′]ビピリジニル−3′−イル]−イソブチルアミド
a)(6′−クロロ−2−メチル−[3,4′]ビピリジニル−3′−イル)−カルバミン酸tert−ブチルエステル
MS m/e(%):320(M+H+、100)
MS m/e(%):334(M+H+、100)
MS m/e(%):234(M+H+、100)
MS m/e(%):516(M+H+、100)
MS m/e(%):580(M+H+、100)
以下の組成の錠剤を通常の手法により製造した:
mg/錠
活性物質 5
乳糖 45
トウモロコシデンプン 15
微晶質セルロース 34
ステアリン酸マグネシウム 1
錠剤重量 100
以下の組成のカプセル剤を製造した:
mg/カプセル
活性物質 10
乳糖 155
トウモロコシデンプン 30
タルク 5
充填カプセル重量 200
した。混合物をミキサーに戻し、タルクをそこに添加して、充分に混合した。混合物を硬ゼラチンカプセルに機械によって充填した。
以下の組成の坐剤を製造した:
mg/坐剤
活性物質 15
坐剤用錬剤 1285
合計 1300
Claims (8)
- 2−メチル−6′−(4−メチル−ピペラジン−1−イル)−[3,4′]ビピリジニル−3′−カルボン酸(3,5−ビス−トリフルオロメチル−ベンジル)−メチル−アミドである、請求項1記載の化合物。
- 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−[2−メチル−6′−(4−メチル−ピペラジン−1−イル)−[3,4′]ビピリジニル−3′−イル]−イソブチルアミドである、請求項1記載の化合物。
- 請求項1〜3のいずれか一項記載の一種又はそれ以上の化合物及び薬学的に許容される賦形剤を含む医薬。
- 数々の炎症性状態、偏頭痛、関節リュウマチ、喘息、炎症性腸疾患、嘔吐反射、パーキンソン病、不安、うつ、精神病、乗り物酔い、誘発嘔吐、疼痛、頭痛、アルツハイマー病、多発性硬化症、モルヒネ禁断の減弱、浮腫、慢性炎症性疾患、気管支過敏症、アレルギー性鼻炎、潰瘍性大腸炎及びクローン病を含む腸の炎症疾患、眼球の外傷及び眼球の炎症疾患、外傷性脳損傷、乗り物酔い、嘔吐、又は精神免疫障害若しくは心身症の処置のための請求項4記載の医薬。
- 請求項6記載の工程により製造される、請求項1〜3のいずれか1項記載の化合物。
- 数々の炎症性状態、偏頭痛、関節リュウマチ、喘息、炎症性腸疾患、嘔吐反射、パーキンソン病、不安、うつ、精神病、乗り物酔い、誘発嘔吐、疼痛、頭痛、アルツハイマー病、多発性硬化症、モルヒネ禁断の減弱、浮腫、慢性炎症性疾患、気管支過敏症、アレルギー性鼻炎、潰瘍性大腸炎及びクローン病を含む腸の炎症疾患、眼球の外傷及び眼球の炎症疾患、外傷性脳損傷、乗り物酔い、嘔吐、又は精神免疫障害若しくは心身症の処置用の、式(I)で示される化合物を一種又はそれ以上含む医薬の製造のための請求項1〜3のいずれか一項記載の化合物の使用。
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EP05101324 | 2005-02-22 | ||
PCT/EP2006/001310 WO2006089658A2 (en) | 2005-02-22 | 2006-02-14 | Nk1 antagonists |
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EP (1) | EP1856052B1 (ja) |
JP (1) | JP4767973B2 (ja) |
KR (1) | KR100902425B1 (ja) |
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AU (1) | AU2006218179B2 (ja) |
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CA (1) | CA2601935C (ja) |
DE (1) | DE602006008900D1 (ja) |
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CA2695331A1 (en) * | 2007-08-03 | 2009-02-12 | F. Hoffmann-La Roche Ag | Pyridinecarboxamide and benzamide derivatives as taar1 ligands |
EP4371613A3 (en) * | 2018-02-26 | 2024-07-24 | Ospedale San Raffaele S.r.l. | Compounds for use in the treatment of ocular pain |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1035115A1 (en) * | 1999-02-24 | 2000-09-13 | F. Hoffmann-La Roche Ag | 4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists |
JP2003500478A (ja) * | 1999-05-31 | 2003-01-07 | エフ.ホフマン−ラ ロシュ アーゲー | 4−フェニル−ピリミジン誘導体 |
JP2004536119A (ja) * | 2001-07-10 | 2004-12-02 | エフ.ホフマン−ラ ロシュ アーゲー | 脳、脊髄又は神経損傷の処置のためのnk−1レセプターアンタゴニストの使用 |
JP2005500354A (ja) * | 2001-07-31 | 2005-01-06 | エフ.ホフマン−ラ ロシュ アーゲー | 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−〔6−(1,1−ジオキソ−1λ6−チオモルホリン−4−イル)−4−(2−メチル又は4−フルオロ−2−メチル置換)フェニル−ピリジン−3−イル〕−N−メチル−イソブチルアミド |
WO2005002577A1 (en) * | 2003-07-03 | 2005-01-13 | F. Hoffmann-La Roche Ag | Dual nk1/nk3 antagonists for treating schizophrenia |
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IL111960A (en) | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
SG52217A1 (en) | 1993-12-29 | 1998-09-28 | Merck Sharp & Dohme | Substituted morpholine derivatives and their use as therapeutic agents |
IL112778A0 (en) | 1994-03-04 | 1995-05-26 | Merck & Co Inc | Substituted heterocycles, their preparation and pharmaceutical compositions containing them |
US5972938A (en) * | 1997-12-01 | 1999-10-26 | Merck & Co., Inc. | Method for treating or preventing psychoimmunological disorders |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1035115A1 (en) * | 1999-02-24 | 2000-09-13 | F. Hoffmann-La Roche Ag | 4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists |
JP2003500478A (ja) * | 1999-05-31 | 2003-01-07 | エフ.ホフマン−ラ ロシュ アーゲー | 4−フェニル−ピリミジン誘導体 |
JP2004536119A (ja) * | 2001-07-10 | 2004-12-02 | エフ.ホフマン−ラ ロシュ アーゲー | 脳、脊髄又は神経損傷の処置のためのnk−1レセプターアンタゴニストの使用 |
JP2005500354A (ja) * | 2001-07-31 | 2005-01-06 | エフ.ホフマン−ラ ロシュ アーゲー | 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−〔6−(1,1−ジオキソ−1λ6−チオモルホリン−4−イル)−4−(2−メチル又は4−フルオロ−2−メチル置換)フェニル−ピリジン−3−イル〕−N−メチル−イソブチルアミド |
WO2005002577A1 (en) * | 2003-07-03 | 2005-01-13 | F. Hoffmann-La Roche Ag | Dual nk1/nk3 antagonists for treating schizophrenia |
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CN101128429A (zh) | 2008-02-20 |
ES2329827T3 (es) | 2009-12-01 |
MX2007010034A (es) | 2007-10-04 |
EP1856052B1 (en) | 2009-09-02 |
WO2006089658A3 (en) | 2006-12-21 |
BRPI0606843A2 (pt) | 2009-07-21 |
US20060189626A1 (en) | 2006-08-24 |
IL185010A0 (en) | 2007-12-03 |
AU2006218179A1 (en) | 2006-08-31 |
WO2006089658A2 (en) | 2006-08-31 |
DE602006008900D1 (de) | 2009-10-15 |
CN101128429B (zh) | 2012-03-21 |
EP1856052A2 (en) | 2007-11-21 |
CA2601935A1 (en) | 2006-08-31 |
AU2006218179B2 (en) | 2010-12-23 |
ATE441633T1 (de) | 2009-09-15 |
JP2008531507A (ja) | 2008-08-14 |
KR20070098933A (ko) | 2007-10-05 |
KR100902425B1 (ko) | 2009-06-11 |
US7176205B2 (en) | 2007-02-13 |
IL185010A (en) | 2012-10-31 |
CA2601935C (en) | 2013-04-09 |
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