JP6486358B2 - (−)−(2r,3s)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(l)−(+)酒石酸塩、その製造方法及び使用 - Google Patents
(−)−(2r,3s)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(l)−(+)酒石酸塩、その製造方法及び使用 Download PDFInfo
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- JP6486358B2 JP6486358B2 JP2016534827A JP2016534827A JP6486358B2 JP 6486358 B2 JP6486358 B2 JP 6486358B2 JP 2016534827 A JP2016534827 A JP 2016534827A JP 2016534827 A JP2016534827 A JP 2016534827A JP 6486358 B2 JP6486358 B2 JP 6486358B2
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- hydroxy
- amino
- pyridin
- tartrate
- pyrrolidin
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Description
本出願は、2013年8月15日に提出された米国仮出願番号61/866,155号の利益を主張するものであり、該仮出願の全体を本明細書の一部として援用する。
本発明は、(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩(即ち、モノ酒石酸塩)、その合成、並びに疼痛の治療における鎮痛剤としての使用、または認知障害の治療におけるその使用に関する。
もう一つの実施形態において、この塩は、下記のおおよその角度(2θ)で表される特性ピークを有する粉末X線回折スペクトルを示す:
(a)イソシアノ酢酸エチルをピロリジンと反応させて中間体1を生成させ、次いで、中間体1を4―ピリジンカルボキシアルデヒドと反応させて中間体2を生成させ、ここでの前記中間体2は(+/−)−DL−スレオ−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン二塩酸塩に加水分解される。
(b)上記(+/−)−DL−スレオ−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン二塩酸塩を、ジ−p−トルオイル−L−酒石酸の存在下で分割して、(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・ジ−p−トルオイル−L−酒石酸塩を生成させる。
(c)上記(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・ジ−p−トルオイル−L−酒石酸塩を、L−酒石酸の存在下で、粗製の(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩に変換する。
(d)上記粗製の(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩を、適切な溶媒の存在下で結晶化して、精製された(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩を生成する。
最初の塩スクリーニング試験をラセミ混合物に対して行った。以下の対イオンを使用した:硫酸、グルタミン酸、塩酸、リン酸、マレイン酸、アスパラギン酸、ナフタレン−2−スルホン酸、ナフタレン−1,5−ジスルホン酸、ベンゼンスルホン酸、エタン−1,2−ジスルホン酸、エタンスルホン酸、メタンスルホン酸、p−トルエンスルホン酸、パモ酸、ジクロロ酢酸、及び(+)−カンファ−10−スルホン酸。これらのなかで、p−トルエンスルホン酸塩及びマレイン酸塩で最も良好な結果が見出された。しかしながら、これらの塩は何れも許容されないことが判明した。強力な催奇形物質であるスルホン酸エステルが存在する可能性があるので、スルホン酸塩は回避することが勧められる。またマレイン酸エステルは、特に高い投与量において腎臓の問題を引き起こす可能性がある。
この塩は、商業的に入手可能な出発物質から4ステップで造られる。最初のステップは、ラセミ体の塩酸塩、即ち、(+/−)−DL−スレオ−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン二塩酸塩の合成であり、それを以下に概略的に示す。
T=18〜22℃の温度を維持して、19Kgの粗製(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・L−酒石酸塩(ON−ピラミドL酒石酸塩)、9.5KgのH2O、15Kg(19Lt)のMeOHを反応器に充填する。完全に溶解するまで、約0.5時間、T=18〜22℃で撹拌下に維持し、確認する。T=18〜22℃において、60Kg(76Lt)のMeOHを攪拌しながら徐々に加える。約15分間、撹拌下で同じ温度に維持し、次いで、0.01kgの純粋な/精製された(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・L−酒石酸塩(ON−ピラミドL酒石酸塩)を種付けする。
選択された塩である、(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩を、多型試験に付した。非晶質形態の外に2つの結晶形が得られた。評価に際し、結晶形態の一つは、分解産物を伴うモノ酒石酸塩の混合物であることが決定された。最も安定な結晶形態は、単一の無溶媒の結晶形態(形態A)であり、単離および特徴付けされ、スケールアップされた。ボールミルでの粉砕は、結晶形Aを非晶質形態に変換する。非晶質形態は、MeOH/H2Oから凍結乾燥することにより調製され、FTラマン(図12)、PXRD(粉末X線回折;図13)、1H−NMR(図14)、TG−FTIR(熱重量分析−フーリエ変換−赤外分光法;図15)、DSC(図16)、及びDVS(図17)により特徴付けされた。
Claims (20)
- (−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩。
- 結晶性である、請求項1に記載の塩。
- 下記の角度(2θ)で表される特性ピークを有する粉末X線回折スペクトルを示す、請求項2に記載の塩:
- 結晶性であり、下記の角度(2θ):7.61、7.89、12.97、13.50、15.13、15.19、15.38、16.23、16.71、16.83、17.05、19.76、20.14、20.43、20.76、21.00、22.77、22.86、23.07、23.66、24.58、24.90、25.11、25.35、25.63、25.83、26.33、27.09、28.08、30.71、31.02、31.72、33.00及び34.15
で表されるピークを有する粉末X線回折スペクトルを示す、請求項1に記載の塩。 - 請求項1の酒石酸塩を含み、少なくとも1つの医薬的に許容可能な担体を任意に含んでいてもよい、医薬組成物。
- 哺乳動物における疼痛を治療する為の請求項5に記載の組成物。
- 前記疼痛が慢性疼痛である、請求項6に記載の組成物。
- 哺乳動物における認知障害を治療する為の請求項5に記載の組成物。
- 前記認知障害が、失認症、健忘症、失語症、失行、せん妄、痴呆及び学習障害からなる群から選択される、請求項8に記載の組成物。
- 前記認知障害がAIDS痴呆合併症、ビンスワンガー病、レヴィ小体型認知症、前頭側頭型認知症、軽度認知機能障害、多発梗塞性認知症、ピック病、意味認知症、老人性認知症、及び血管性認知症からなる群より選択される、請求項8に記載の組成物。
- 前記学習障害が、アスペルガー症候群、注意欠陥障害、注意欠陥多動性障害、自閉症、小児期崩壊性障害、及びレット症候群からなる群から選択される、請求項9に記載の組成物。
- 前記失語症が、進行性非流暢失語症である、請求項9に記載の組成物。
- 前記認知障害が、神経変性疾患、脳に対する損傷、精神障害、または慢性疼痛に関連している、請求項8に記載の組成物。
- 前記神経変性疾患が、アルツハイマー病、大脳皮質基底核変性症、クロイツフェルト・ヤコブ病、前頭側頭葉変性症、ハンチントン病、多発性硬化症、正常圧水、有機慢性脳症候群、パーキンソン病、ピック病、進行性核上性麻痺、及び老人性痴呆(アルツハイマー型)からなる群から選択される、請求項13に記載の組成物。
- 前記脳への損傷が、慢性硬膜下血腫、脳震とう、脳内出血、脳炎、髄膜炎、敗血症、薬物中毒、及び薬物乱用からなる群から選択される、請求項13に記載の組成物。
- 前記精神障害が、不安障害、解離性障害、気分障害、統合失調症、身体表現性障害及び虚偽性障害からなる群から選択される、請求項13に記載の組成物。
- (−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル −1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩を調製するためのプロセスであって、
(a)イソシアノ酢酸エチルをピロリジンと反応させて中間体1を生成させ、次いで、中間体1を4―ピリジンカルボキシアルデヒドと反応させて中間体2を生成させ、ここでの前記中間体2は(+/−)−DL−スレオ−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン二塩酸塩に加水分解されることと、
(b)前記(+/−)−DL−スレオ−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン二塩酸塩を、ジ−p−トルオイル−L−酒石酸の存在下で分割して、(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・ジ−p−トルオイル−L−酒石酸塩を生成させることと、
(c)前記(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・ジ−p−トルオイル−L−酒石酸塩を、L−酒石酸の存在下で、粗製の(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩に変換することと、
(d)前記粗製の(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩を、適切な溶媒の存在下で結晶化して、精製された(−)−(2R,3S)−2−アミノ−3−ヒドロキシ−3−ピリジン−4−イル−1−ピロリジン−1−イル−プロパン−1−オン・(L)−(+)酒石酸塩を生成させることを含んでなる前記プロセス。 - ステップ(a)において、中間体1は単離されず、下記の構造:
- ステップ(a)において、中間体2は単離されず、下記の構造:
- ステップ(d)において、前記適切な溶媒はメタノールを含む、請求項17に記載のプロセス。
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