JP2019089761A - デュアルヒスタミンh1及びヒスタミンh4受容体リガンドとしての新規ベンゾイミダゾール誘導体 - Google Patents
デュアルヒスタミンh1及びヒスタミンh4受容体リガンドとしての新規ベンゾイミダゾール誘導体 Download PDFInfo
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- JP2019089761A JP2019089761A JP2018214452A JP2018214452A JP2019089761A JP 2019089761 A JP2019089761 A JP 2019089761A JP 2018214452 A JP2018214452 A JP 2018214452A JP 2018214452 A JP2018214452 A JP 2018214452A JP 2019089761 A JP2019089761 A JP 2019089761A
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- methyl
- yloxy
- methylpiperidin
- benzoimidazol
- phenol
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Description
*が規定された立体化学、典型的には(S)の立体化学を示す不斉炭素を表し、
XがH又はFを表し、
同じであるか又は異なるR1、R2、R3、及びR4がH、ハロゲン、アルキル又はアルコキシを独立に表し、
X、R1、R2、R3、及びR4の1つはHを表さない一般式(II)、
並びにそれらの薬学的に許容される塩、互変異性体、水和物及び溶媒和物である。
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩,一水和物
2-[(5-クロロ-4-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーB
2-[(4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーB
2-[(5-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーB
2-[(4-クロロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーB
2-[(5-クロロ-4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーB
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,(R)-パラ-メチルマンデレート、
及び特に
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩,一水和物
(S)-2-[(5-クロロ-4-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(5-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(4-クロロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(5-クロロ-4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,(R)-パラ-メチルマンデレート,
からなる群から選択される化合物、
並びにそれらのエナンチオマー、ジアステレオマー、これらの混合物及び薬学的に許容される塩、遊離型、互変異性体、水和物及び溶媒和物を提供する。
トランスミッションモード
2°から50°の間の記録値
でPANALYTICAL X'PERT PRO MPD回折計装置を用いて測定される、以下の粉末X線回折ピークを含む。
トランスミッションモード
2°から50°の間の記録値
でPANALYTICAL X'PERT PRO MPD回折計装置を用いて測定される、以下の粉末X線回折ピークを含む。
の化合物を、下記式(IV):
の化合物のメチル化によって調製することができる。
・ ヒスタミンH1、H2、H3、又はH4受容体アンタゴニスト、
・ ロイコトリエンアンタゴニスト、
・ 5-リポキシゲナーゼ(5-LO)阻害剤又は5-リポキシゲナーゼ活性化タンパク質(FLAP)アンタゴニスト
・ 鬱血除去用途のCX1-及びα2-アドレナリン作動性受容体アゴニスト、血管収縮性交感神経興奮薬
・ テオフィリン及びアミノフィリン等のキサンチン
・ クロモグリク酸ナトリウム及びネドクロミルナトリウム等の非ステロイド性抗炎症薬
・ ケトティフェン
・ COX-1阻害剤(NSAID)及びCOX-2選択的阻害剤
・ 免疫抑制薬
・ 粘液溶解薬又は鎮咳薬
から選択される1つ又は複数の治療剤(複数可)と本発明の化合物(II)の組合せ物に関する。
ラセミ2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノールの合成は特許出願WO2012041860(実施例581)中に記載されている。
アセトン(100mL)中に溶かした(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール(7.82g)の溶液を、室温において1当量の37%塩酸で処理した。3時間強く攪拌した後、固体を濾過し、アセトンですすぎ、減圧下で乾燥させて以下のNMRスペクトルを示す白色粉末として2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩,一水和物を得た。1H NMR (MeOD): 7.55 (m,2H), 7.23 (m,2H), 7.10 (m,1H), 7.08 (m,1H), 6.83 (m,1H), 6.28 (s,1H), 3.89 (m,1H), 3.43-3.20 (ms,4H), 2.84 (s,3H), 2.20-1.90 (ms,4H)。交換可能なプロトンは報告していない。
XRPD(主要ピーク、°単位の2θ): 13.6、15.1、15.6、16.4、18.1、20.3、22.2、27.6、29.0
2-[(5-クロロ-4-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを、実施例1に従い、ラセミ2-[(5-クロロ-4-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール及び(1R)-クロロギ酸メチルを用いた誘導体化から調製した。分取HPLC中、最初に溶出したジアステレオマーを回収し、次いで水酸化カリウム処理により脱保護して、以下のNMRスペクトルを示す白色粉末として2-[(5-クロロ-4-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを得た。1H NMR (MeOD): 7.34 (m,1H), 7.27 (m,1H), 7.22 (m,1H), 7.11 (m,1H), 6.83 (m,1H), 6.79 (m,1H), 6.20 (s,1H), 3.57 (m,1H), 2.71 (m,2H), 2.22 (s,3H), 2.18 (m,2H), 1.93 (m,2H), 1.75 (m,2H)。交換可能なプロトンは報告していない。
テトラヒドロフラン(30mL)中に溶かした5-クロロ-4-フルオロ-1-(ピロリジン-1-イルメチル)-1H-ベンゾイミダゾール(5.50g)の溶液に、リチウムジイソプロピルアミドの2M溶液(19.4mL)を-78℃で添加し、この温度で2時間攪拌した。テトラヒドロフラン(30mL)中のサリチルアルデヒド(4.58g)とリチウムジイソプロピルアミドの2M溶液(20mL)の冷却混合物を次いで添加した。混合物は-78℃で50分間攪拌し、15分かけて-10℃まで温めた。飽和塩化アンモニウム水溶液での加水分解及び濃塩酸での6付近へのpH調節後、有機相を塩水で洗浄し、硫酸マグネシウム上で乾燥させ、減圧下で濃縮した。残渣は15分間ジクロロメタン中での還流によって精製した。冷却後、固体を濾過して2-[(5-クロロ-4-フルオロ-1H-ベンゾイミダゾール-2-イル)ヒドロキシメチル]フェノールを得た。
エタノール(100mL)中に溶かした5-クロロ-4-フルオロ-1H-ベンゾイミダゾール(10.7g)、ピロリジン(4.68g)、及びホルムアルデヒド(水中37%、5.85g)の溶液を100分間還流させた。減圧下での濃縮後、残渣をジクロロメタンで希釈し、硫酸マグネシウム上で乾燥させ、減圧下で濃縮して5-クロロ-4-フルオロ-1-(ピロリジン-1-イルメチル)-1H-ベンゾイミダゾールを得た。
4-クロロ-3-フルオロベンゼン-1,2-ジアミン(13.9g)及びギ酸(6.84g)の混合物を35分間95℃で攪拌した。冷却後、混合物を水と酢酸エチルで希釈し、pH1〜2へ酸性化した。濾過後、水性相を酢酸エチルで洗浄し、水酸化ナトリウムを用いてpH9〜10まで塩基性化して、酢酸エチルで抽出した。貯めた抽出物は硫酸マグネシウム上で乾燥させ、減圧下で濃縮した。残渣はジクロロメタン中での再結晶により精製して5-クロロ-4-フルオロ-1H-ベンゾイミダゾールを得た。
2-[(4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを、実施例1に従い、ラセミ2-[(4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール及び(1S)-クロロギ酸メチルを用いた誘導体化から調製した。分取HPLC中、二番目に溶出したジアステレオマーを回収し、次いで水酸化カリウム処理により脱保護して、以下のNMRスペクトルを示す白色粉末として2-[(4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを得た。1H NMR (MeOD): 7.33 (m,2H), 7.13 (m,1H), 7.09 (m,1H), 6.96 (m,1H), 6.81 (m,1H), 6.79 (m,1H), 6.21 (s,1H), 3.56 (m,1H), 2.70 (m,2H), 2.53 (s,3H), 2.21 (s,3H), 2.17 (m,2H), 1.92 (m,2H), 1.74 (m,2H).交換可能なプロトンは報告していない。
ラセミ2-[(4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールを、2,3-ジアミノトルエンから出発して手順3B、3C、3D、及び3Eと同様にして調製した。
2-[(5-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを、実施例1にしたがい、ラセミ2-[(5-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール及び(1S)-クロロギ酸メチルを用いた誘導体化から調製した。分取HPLC中、二番目に溶出したジアステレオマーを集め、次に水酸化カリウム処理により脱保護して、以下のNMRスペクトルを示す白色粉末として2-[(5-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを得た。1H NMR (MeOD): 7.46 (m,1H), 7.32 (d,1H), 7.20 (m,1H), 7.12 (m,1H), 6.96 (m,1H), 6.80 (m,2H), 6.19 (s,1H), 3.56 (m,1H), 2.73 (m,2H), 2.23 (s,3H), 2.20 (m,2H), 1.93 (m,2H), 1.75 (m,2H)。交換可能なプロトンは報告していない。
ラセミ2-[(5-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールを、1,2-ジアミノ-4-フルオロベンゼンから出発して、手順3B、3C、3D、及び3Eと同様にして調製した。
2-[(4-クロロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを、実施例1に従い、ラセミ2-[(4-クロロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール、及び(1S)-クロロギ酸メチルを用いた誘導体化から調製した。分取HPLC中、二番目に溶出したジアステレオマーを集め、次いで水酸化カリウム処理により脱保護して、以下のNMRスペクトルを示す白色粉末として2-[(4-クロロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを得た。1H NMR (MeOD): 7.43 (d,1H), 7.34 (d,1H), 7.21-7.10 (ms,3H), 6.85-6.78 (ms,2H), 6.22 (s,1H), 3.59 (m,1H), 2.74 (m,2H), 2.24 (s,3H), 2.22 (m,2H), 1.93 (m,2H), 1.76 (m,2H)。交換可能なプロトンは報告していない。
ラセミ2-[(4-クロロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールを、2,3-ジアミノクロロベンゼンから出発して、手順3B、3C、3D、及び3Eと同様にして調製した。
2-[(5-クロロ-4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを、実施例1に従い、ラセミ2-[(5-クロロ-4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール、及び(1R)-クロロギ酸メチルを用いた誘導体化から調製した。分取HPLC中、最初に溶出したジアステレオマーを集め、次いで水酸化カリウム処理により脱保護して、以下のNMRスペクトルを示す白色粉末として2-[(5-クロロ-4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールエナンチオマーBを得た。1H NMR (MeOD): 7.33 (d,1H), 7.30 (d,1H), 7.18 (d,1H), 7.12 (m,1H), 6.83-6.78 (ms,2H), 6.21 (s,1H), 3.56 (m,1H), 2.72 (m,2H), 2.56 (s,3H), 2.22 (s,3H), 2.17 (m,2H), 1.92 (m,2H), 1.76 (m,2H)。交換可能なプロトンは報告していない。
ラセミ2-[(5-クロロ-4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノールを、6-クロロ-2,3-ジアミノトルエンから出発して、手順3B、3C、3D、及び3Eと同様にして調製した。
約2900mlのアセトン及び112gの(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール(塩基)を反応容器に投入した。混合物を約40℃まで温め、出発物質が溶けるまで攪拌し、溶液を濾過して不溶粒子/外来粒子を除去した。濾液の温度を約30℃に調節し、約47.5gのHCl/MeOH(アッセイ26.4%、1.1当量)を32〜34℃で15〜25分のあいだに添加した。混合物を1〜2時間攪拌し、25〜30℃で濾過し、約1000mlのアセトンで洗浄した。約1時間、1750mlのアセトンとともに室温でそれらを攪拌することによって、5つのバッチを最終的に混合した。生成物を濾過し、250mlのアセトンで洗浄した。最後に、45℃において減圧下で生成物を乾燥させた。
(実施例1と同様に)キラルHPLCにより測定したエナンチオマー純度: 99.8%
滴定によるアッセイ: 99.3%
GCヘッドスペースによるアセトン含有率: 0.3%
XRPD(主要ピーク、°単位の2θ): 8.6、12.4、13.1、15.9、16.8、19.9、20.4、21.3、23.4、25.0、25.7、26.3、26.9、28.4、30.1
メタノール(450mL)中のラセミ2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール(64.7g)の懸濁液を温めて還流させ、次いでメタノール(150mL)中に溶かした(R)-p-マンデル酸メチル(18.1g)の溶液で処理した。2時間の還流後、混合物を室温まで冷却して白色固体を濾過した。数回の再結晶を実施して、以下のNMRスペクトルを示す光学的に純粋な(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,(R)-p-メチルマンデレートを得た。1H NMR (DMSO-d6): 12.45 (大きなs,1H), 7.50 (m,2H), 7.25 (d,2H), 7.20 (d,1H), 7.14 (m,2H), 7.12-7.06 (ms,3H), 6.82 (m,1H), 6.11 (s,1H), 4.77 (s,1H), 2.75 (m,2H), 2.32-2.20 (ms,8H), 1.87 (m,2H), 1.63 (m,2H)。交換可能なプロトンは報告していない。
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,(R)-p-メチルマンデレート(36.7g)を水及び水酸化ナトリウム水溶液中で希釈した。次いで酢酸エチルを添加し、約8.5にpHを調節した。酢酸エチルで水性相を(5回)抽出した後、貯めた抽出物を硫酸マグネシウム上で乾燥させ、減圧下で濃縮し灰白色の固体として(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノールを得た。アセトン(330mL)及び濃塩酸(1当量)で処理し3時間激しく攪拌した後、形成された固体を濾過し、アセトンですすぎ、減圧下で乾燥させて、以下のNMRスペクトルを示す白色固体として(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩,一水和物を得た。1H NMR (MeOD): 7.55 (m,2H), 7.23 (m,2H), 7.10 (m,1H), 7.08 (m,1H), 6.83 (m,1H), 6.28 (s,1H), 3.89 (m,1H), 3.43-3.20 (ms,4H), 2.84 (s,3H), 2.20-1.90 (ms,4H)。.交換可能なプロトンは報告していない。
XRPD(主要ピーク、°単位の2θ): 6.3、11.0、13.7、15.1、15.7、16.4、18.1、20.3、22.1、24.4、27.6、及び29.1
IR及びVCDスペクトルを、3000スキャンコレクション、4cm-1解像度、1050〜1700cm-1領域で、FVS-6000VCD分光計において記録した。実施例1(400μLのCD2Cl2中20.8mg)及び実施例1(300μLのCD2Cl2中14.06mg)のディストマーの試料を、BaF2ウインドウを有する200μmパス長のセル中に入れた。2つのエナンチオマーについて観察したIRスペクトルのオーバーレイを図1に示す。それらは、より高濃度のため、実施例1のディストマーについてわずかに高い強度をもつ同一IRピークを示す。図2中には、溶媒を差し引いた、実施例1の2つのエナンチオマー及び実施例1のディストマーについての実験VCDスペクトルを示す。ベースラインの勾配にもかかわらず、VCDスペクトルは予想された鏡像関係を示す。考えられる人工産物及びVCDベースラインの勾配を排除するため、図1に示したように、2つのVCDスペクトルは全体の半分を差し引かれている。
理論計算をGaussian09ソフトウエアで実施した。振動円偏光二色性スペクトルは、B3LYP機能性及び6-311G(d,p)ベースセットを使用してTD-DFTによって得た。
実施例1のエナンチオマー試料ディストマーの実験VCDスペクトルと、その最も多い(96%)コンフォーマーA2中のRエナンチオマーの計算したVCDスペクトルの比較によって得た非常に充分な合致によって、実施例1のディストマーに関する絶対配置R及び実施例1のSを、高い信頼度で決定することができる。更に、このVCD試験によって、CD2Cl2溶液において、分子がそのA2コンフォメーションのみで存在する事実を確認する。
多くの相(フェーズ)及び多形体が、(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール塩酸塩について発見されている。より安定したフェーズは、無水塩酸塩に相当するフェーズIと、塩酸塩一水和物に相当するフェーズIIである。
スキャン範囲2°〜50°
ステップサイズ0.026°
取得時間20.4秒
スキャン数20
フェーズIのXRPD (特徴的ピーク、°単位の2θ): 8.6、12.4、13.1、15.9、16.8、18.8、19.9、20.4、21.3、23.4、25.0、25.7、26.3、26.9、28.4、及び30.1
フェーズIIのXRPD (特徴的ピーク、°単位の2θ): 6.3、13.7、15.1、15.7、16.4、20.3、22.1、24.4、及び29.1
実施例13a: H1-H4結合
ユートマー(eutomer)が両受容体を認識するという上述した性質を以下の表中に示す。ヒトH1受容体における活性は、組換え受容体における放射性GTP-γ-S結合のアゴニスト誘導型刺激の阻害によって測定する。この活性は定数Kbとして報告され、最小値が最も効力が高い。ヒトH4受容体に関するアフィニティーは結合競合によって測定する。このアフィニティーはKiで報告され、最小値が最も効力が高い。
ヒトH1受容体におけるアンタゴニスト又はインバースアゴニストである化合物はhERGチャネルと結合し、突然の心停止につながり得る不整脈をもたらすことがしばしば発見されている。このためクリニックから数種の薬が回収された。したがって、本出願の化合物に関してこのパラメーターを評価した。
脳の曝露:
ヒスタミンH1受容体に対するアンタゴニスト又はインバースアゴニストとして作用する化合物は脳に進入し得ない。これは、鎮静状態及び体重増加等の望ましくない副作用をもたらし得る。脳内への進入に関する効率は、マウスに化合物を経口投与し、脳中及び血漿中での8時間の曝露を測定することによって評価することができる。結果は、血漿中でのそれに対する脳内の曝露の比によって表すことができる。
更に、本発明の化合物は、マウスに経口投与したとき生物学的に利用可能であることが分かった。肺中の濃度は、興味深いことに高いことが分かった。下の表中に報告したように、薬物動態調査の累積曝露及び曲線下面積として、これを示すことができる。
Claims (12)
- 式(II)のエナンチオマー:
*は規定された立体化学を示す不斉炭素を表し;
Xは、H又はFを表し;
R1、R2、R3、及びR4は同じであるか又は異なり、独立に、H、ハロゲン、アルキル又はアルコキシを表し;
X、R1、R2、R3、及びR4の1つはHを表さず;
並びにその薬学的に許容される塩、互変異性体、水和物、及び溶媒和物。 - XがFを表し;
R1、R2、R3、及びR4は同じであるか又は異なり、独立に、H、ハロゲン、アルキル又はアルコキシ表す、
請求項1に記載のエナンチオマー。 - (S)エナンチオマーである、請求項1又は2に記載の化合物。
- (S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩,一水和物
(S)-2-[(5-クロロ-4-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(5-フルオロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(4-クロロ-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(5-クロロ-4-メチル-1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]フェノール
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,塩酸塩
(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノール,(R)-パラ-メチルマンデレート
からなる群から選択される、請求項1から3のいずれか一項に記載の化合物。 - 対応するラセミ混合物のエナンチオマー分離の工程を含む、請求項1から4のいずれか一項に記載の式(II)の化合物の製造方法。
- 前記ラセミ混合物を、
- 式(III) :
の化合物の、式(IV) :
又は
- 式(V):
の化合物のメチル化
のいずれかによって製造する、請求項5に記載の製造方法。 - 炎症障害の治療及び/又は予防に使用するための、請求項1〜4のいずれか一項に記載の化合物。
- 炎症障害が、アナフィラキシーショック、呼吸器炎症疾患及びアレルギー疾患、成人型呼吸窮迫症候群、急性呼吸窮迫症候群、呼吸器感染症、気管支炎、慢性気管支炎、慢性閉塞性肺疾患、嚢胞性線維症、喘息、気腫、鼻炎、鼻漏、副鼻腔炎、慢性蓄膿症、アレルギー、アレルギー誘導型気道反応、アレルギー性鼻炎、ウイルス性鼻炎、非アレルギー性鼻炎、非季節性及び季節性鼻炎、結膜炎、アレルギー性結膜炎、耳炎、鼻ポリープ、咳、眼部掻痒、慢性蕁麻疹、湿疹、痒疹、皮膚掻痒、多形滲出性紅斑、鼻充血、アレルギー性充血、尿生殖管の障害、女性及び男性性機能障害、過活動膀胱状態、尿失禁、膀胱過活動、良性前立腺肥大及び下部尿路症状等、皮膚疾患、皮膚炎、アトピー性皮膚炎、並びに乾癬及び皮膚掻痒等、掻痒症、術後疼痛の皮膚切開モデル、アレルギー性皮膚疾患/掻痒及び炎症、アレルギー性接触皮膚炎、肝臓又は腎臓不全と関連した掻痒、血栓塞栓症、アテローム性動脈硬化症、心筋梗塞、狭心症、心筋虚血、不整脈、末梢閉塞性動脈疾患、肺動脈閉塞症、深部静脈血栓症、低血圧、肺高血圧、血管性浮腫、悪性高血圧、心不全、心又は腎不全、脳血管発作及び腎機能不全を含めた心臓血管系の疾患、炎症性腸疾患、クローン病、潰瘍性大腸炎、腸管アナフィラキシーを含めた胃腸管の疾患、食物アレルギー、炎症後過敏性腸症候群、腹膜炎、リウマチ様関節炎、多発性硬化症、ループス、骨関節炎、関節痛、全身性炎症を含めた自己免疫疾患、がん、疼痛、神経障害性疼痛、慢性好酸球増加症、マスト細胞増殖と関連した慢性疾患、リンパ増殖性疾患から選択される、請求項7に記載の使用のための化合物。
- 請求項1〜4のいずれか一項に記載の化合物及び薬学的に許容される賦形剤を含む医薬組成物。
- 請求項1〜4のいずれか一項に記載の化合物とH1Rアンタゴニストを含む組合せ物。
- 以下の粉末X線回折ピーク:(特徴的ピーク、°単位の2θ):8.6、12.4、13.1、15.9、16.8、18.8、19.9、20.4、21.3、23.4、25.0、25.7、26.3、26.9、28.4、及び30.1によって特徴付けられる(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノールの塩酸塩無水物(I型)である、請求項1〜4のいずれか一項に記載の化合物。
- 以下の粉末X線回折ピーク:(特徴的ピーク、°単位の2θ):6.3、13.7、15.1、15.7、16.4、20.3、22.1、24.4、及び29.1によって特徴付けられる(S)-2-[(1H-ベンゾイミダゾール-2-イル)(1-メチルピペリジン-4-イルオキシ)メチル]-6-フルオロフェノールの塩酸塩一水和物(II型)である、請求項1〜4のいずれか一項に記載の化合物。
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