JP2008169224A - TAFIa阻害剤としての置換されたイミダゾール - Google Patents
TAFIa阻害剤としての置換されたイミダゾール Download PDFInfo
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- JP2008169224A JP2008169224A JP2008045382A JP2008045382A JP2008169224A JP 2008169224 A JP2008169224 A JP 2008169224A JP 2008045382 A JP2008045382 A JP 2008045382A JP 2008045382 A JP2008045382 A JP 2008045382A JP 2008169224 A JP2008169224 A JP 2008169224A
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
【解決手段】(2S)-5-アミノ-2-[(1-n-プロピル-1H-イミダゾール-4-イル)メチル]ペンタン酸またはその薬理学的に許容可能な塩による医薬品及びそれらを調製した方法。
【選択図】なし
Description
ル環の任意の位置に結合させることができる。
11、NR11SO2R12、アリールのいずれかで置換されている)である。 それ以上に好ましいR1は、C1-6アルキル(場合によっては、C3-4シクロアルキルまたはアリールで置換されている)である。 最も好ましいR1は、C1-3アルキルである。
記酸素保護基を除去した後に、この窒素保護基を除去する必要があろう。適切な窒素保護基と、その窒素保護基を除去するのに適した条件は、当業者には周知である。
a)の化合物をステップ(i)の条件下で反応させること(アミノ基をジアゾ基に変換した後、適切なハロゲン化物と一般にその場で反応させる操作を含むジアゾ化/ハロゲン化反応)によって調製することができる。適切な条件は、濃塩酸:水(30:5)の中で-5℃にて1当量のアミンを3.3当量のNaNO2で処理した後、17時間にわたって室温で処理するというものである。
法ならびに以下の実施例と調製例を参照されたい。
ュベーションが終わると、10μlのPPACK(D-フェニルアラニン-プロリン-アルギニン・クロロメチルケトン)(100nM)を用いてトロンビンを中和した。TAFIa溶液は、氷上に5分間保持し、最終的に175μlのHEPES緩衝液で希釈した。
の形態にして、加圧容器、ポンプ、スプレー、霧吹き、噴霧器から供給すると便利である。その際、適切な推進剤を用いても用いなくてもよい。推進剤としては、例えば、ジクロロジフルオロメタン、トリクロロフルオロメタン、ジクロロテトラフルオロエタン、ヒドロフルオロアルカン(例えば、1,1,1,2-テトラフルオロエタン(HFA 134A(登録商標))、1,1,1,2,3,3,3-ヘプタフルオロプロパン(HFA 227EA(登録商標)))、二酸化炭素その他の適切なガスが挙げられる。加圧エーロゾルの場合には、投与単位は、所定量を供給するバルブを取り付けることによって決定することができる。加圧容器、ポンプ、スプレー、霧吹き、噴霧器は、例えばエタノールと推進剤の混合物を溶媒とした活性成分の溶液または懸濁液を含むことができる。この中には、光沢剤(例えばトリオレイン酸ソルビタン)がさらに含まれていてもよい。吸入器または散布器で用いられるカプセルとカートリッジ(例えばゼラチン製)は、一般式(I)の化合物と、ベースになる適切な粉末(ラクトースやデンプンなど)の粉末混合物を含むようにすることができる。
水酸化ナトリウム水溶液を用いてpH10に調節し、ジクロロメタン(1×40ml、2×20ml)を用いてこの混合物を抽出した。5Nの塩酸を用いて残った懸濁液のpHを0.5にし、この溶液を室温にて18時間にわたって撹拌した。この溶液を、勾配溶離液(水:0.88アンモニア=100:0〜97:3)を用いてダウェックス(登録商標)HCR-Sイオン交換樹脂カラム(40g)で精製した。得られた泡をアセトン(20ml)でスラリー化し、固形物を濾過し、真空中で40℃にて乾燥させたところ、表題の化合物が白色の固形物として4.6g(収率68%)得られた。
らの生成物(200mg、0.8ミリモル)を脱イオン水(20ml)に溶かした溶液を撹拌している中に、水酸化ナトリウム水溶液(1.7ml、5N)を一滴ずつ添加し、この溶液を室温にて一晩撹拌した。次に、この溶液を、勾配溶離液(脱イオン水:0.88アンモニア=95:5)を用いてイオン交換クロマトグラフィ(ダウェックス(登録商標)50WX8-200)で精製したところ、表題の化合物がピンク色の泡として90mg(収率50%)得られた。
ラフィで精製したところ、表題の化合物が120mg(収率35%)得られた。
メチル}-1H-イミダゾール-4-イル)メチル]-5-(トリチルアミノ)ペンタノエート
酸中に45%、5ml)に4-ヒドロキシ安息香酸(0.22g、1.5ミリモル)を分散させた0℃の懸濁液に添加し、室温にて72時間にわたって撹拌した。脱イオン水(20ml)を添加したところ懸濁液が得られたので、それを酢酸エチルを用いて抽出した(3×20ml)。次に、残留水溶液を減圧下で抽出した。得られたオレンジ色の泡をメタノール:酢酸エチルから結晶化させたところ、表題の化合物である三臭化水素酸塩が無色の固形物として82mg(54%)得られた。融点は211〜213℃である。
せ、減圧下で濃縮したところ、表題の化合物が固形物として58.0g(収率88%)得られた。
4ミリモル)を添加し、この反応物を還流させながら18時間にわたって加熱した。この反応物を冷却し、塩化アンモニウム水溶液を添加して反応を停止させ、この混合物を酢酸エチルで抽出した(2回)。合わせた有機抽出液を乾燥させ(Na2SO4)、濾過し、減圧下で濃縮した。粗生成物を、溶離液(酢酸塩:ペンタン=95:5)を用いてシリカゲル上のカラム・クロマトグラフィで精製したところ、表題の化合物が透明な油として6.1g(収率47%)得られた。
せ(MgSO4)、濾過し、減圧下で濃縮した。粗生成物を、勾配溶離液(酢酸エチル:メタノール=100:0〜90:10)を用いてシリカゲル上のカラム・クロマトグラフィで精製したところ、表題の化合物が無色の油として300mg(収率32%)得られた。
添加し、この反応物を室温にて18時間にわたって撹拌した。この混合物を減圧下で濃縮してテトラヒドロフランを除去し、残った水溶液を酢酸を用いてpH=5に調節した。得られた沈殿物を氷浴の中で1時間にわたって粉末化した後、濾過し、水で洗浄し、真空中で乾燥させた。この固形物をイソプロパノールと水から再結晶させると、表題の化合物が白色の固形物として304g(収率63%)で得られた。
Claims (6)
- (2S)-5-アミノ-2-[(1-n-プロピル-1H-イミダゾール-4-イル)メチル]ペンタン酸またはその薬理学的に許容可能な塩。
- (2S)-5-アミノ-2-[(1-n-プロピル-1H-イミダゾール-4-イル)メチル]ペンタン酸またはその薬理学的に許容可能な塩を含む医薬組成物。
- 血栓症、癒着、皮膚の傷、線維疾患および炎症疾患から選択される症状を治療または予防するための請求項2に記載の医薬組成物。
- 上記症状が、心筋梗塞、深静脈血栓症、脳卒中、若年性脳卒中、脳梗塞、脳血栓、脳塞栓症、末梢血管疾患、アンギナ、他の形態の急性冠状動脈症候群、播種性血管内凝固症候群、敗血症、肺塞栓症、心臓不整脈から派生する塞栓症、外科的血管再形成後又は外科手術後の心臓血管疾患の中から選択した血栓症状である、請求項3に記載の医薬組成物。
- 上記症状が、嚢胞性線維症、肺性線維症、慢性閉塞性肺疾患(COPD)、成人呼吸促迫症候群(ARDS)、線維筋異形成、線維性肺疾患、目の手術中に起こる眼内フィブリン堆積、関節炎の中から選択された線維疾患である、請求項3に記載の医薬組成物。
- 上記症状が、喘息、子宮内膜症、炎症性腸疾患、乾癬、アトピー性皮膚炎、及び神経変性疾患、アルツハイマー病及びパーキンソン病の中から選択された炎症性疾患である、請求項3に記載の医薬組成物。
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JP2008045382A Expired - Fee Related JP4778531B2 (ja) | 2000-08-17 | 2008-02-27 | TAFIa阻害剤としての置換されたイミダゾール |
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SE0103272D0 (sv) | 2001-09-28 | 2001-09-28 | Astrazeneca Ab | Chemical compounds |
MXPA04005940A (es) * | 2002-01-22 | 2004-09-13 | Pfizer | Acidos 3-(imidazolil)-2-aminopropanoicos. |
US6713496B2 (en) | 2002-01-22 | 2004-03-30 | Pfizer Inc | 3-(imidazolyl)-2-alkoxypropanoic acids |
JP2005520811A (ja) * | 2002-01-22 | 2005-07-14 | ファイザー・インク | TAFIaインヒビターとしての3−(イミダゾリル)−2−アルコキシプロパン酸 |
JP4866233B2 (ja) | 2003-04-29 | 2012-02-01 | ウニヴェルジテート・チューリッヒ | fac配位により高効率で[M(OH2)3(CO)3]+標識化するために生体分子にカップリングさせるための、Nεおよび/またはNαで誘導体化され、金属および有機保護されたL−ヒスチジン |
SE0302853D0 (sv) * | 2003-10-29 | 2003-10-29 | Astrazeneca Ab | Chemical compounds |
US20050137142A1 (en) * | 2003-11-03 | 2005-06-23 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
WO2005051384A1 (en) * | 2003-11-25 | 2005-06-09 | Pfizer Limited | Stabilised pharmaceutical compositions |
EP1874322A1 (en) * | 2005-04-18 | 2008-01-09 | Bayer Schering Pharma Aktiengesellschaft | Use of tafi inhibitors for enhanced myocardial reperfusion and facilitated pci |
DE102005049385A1 (de) | 2005-10-15 | 2007-04-19 | Sanofi-Aventis Deutschland Gmbh | Imidazolderivate als Inhibitoren von TAFIa |
BRPI0720241A2 (pt) * | 2006-12-06 | 2013-12-31 | Sanofi Aventis | Derivados de ureia e sulfamida como inibidores de tafia |
WO2009103432A2 (en) * | 2008-02-21 | 2009-08-27 | Sanofi-Aventis | Covalently binding imaging probes |
JPWO2010050525A1 (ja) * | 2008-10-29 | 2012-03-29 | 大正製薬株式会社 | TAFIa阻害活性を有する化合物 |
FR2947266B1 (fr) * | 2009-06-26 | 2011-06-17 | Servier Lab | Nouveaux derives d'acide 2-mercaptocyclopentanecarboxylique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
ES2608779T3 (es) | 2010-03-18 | 2017-04-17 | Daiichi Sankyo Company, Limited | Derivado de ácido ciclopropanocarboxílico |
SG182767A1 (en) * | 2010-03-18 | 2012-08-30 | Daiichi Sankyo Co Ltd | Cycloalkyl-substituted imidazole derivative |
KR20140074259A (ko) * | 2011-05-17 | 2014-06-17 | 조인트 스톡 컴퍼니 “파르마신세즈” | 화합물, 약학 조성물 및 부착 과정의 예방과 치료를 위한 방법 |
ES2665093T3 (es) * | 2011-07-22 | 2018-04-24 | Cambrex Karlskoga Ab | Nuevos procedimiento de preparación de imidazoles 4-sustituidos |
WO2013039202A1 (ja) * | 2011-09-15 | 2013-03-21 | 第一三共株式会社 | 新規アクリル酸誘導体 |
JP6461113B2 (ja) | 2013-06-10 | 2019-01-30 | サノフイSanofi | TAFIaの阻害剤としての大環状尿素誘導体、それらの製造および医薬としての使用 |
CN108349904B (zh) | 2015-10-07 | 2021-08-31 | 米托布里奇公司 | Ppar激动剂、化合物、药物组合物及其使用方法 |
FR3046793B1 (fr) * | 2016-01-14 | 2018-01-05 | Les Laboratoires Servier | Nouveaux derives de phosphinanes et azaphosphinanes, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
CN108883094A (zh) * | 2016-03-29 | 2018-11-23 | 第三共株式会社 | 炎症性肠病治疗剂 |
ES2861503T3 (es) * | 2016-04-13 | 2021-10-06 | Mitobridge Inc | Agonistas de PPAR, compuestos, composiciones farmacéuticas y métodos de uso de los mismos |
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US5993815A (en) * | 1996-11-08 | 1999-11-30 | University Of Vermont | Methods and compositions for inhibiting the activation of thrombin-activatable fibrinolysis inhibitor (TAFI) |
SE9901572D0 (sv) * | 1999-05-03 | 1999-05-03 | Astra Ab | New compounds |
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