JP2008514627A - N−(4−フルオロベンジル)−n−(1−メチルピペリジン−4−イル)−n’−(4−(2−メチルプロピルオキシ)フェニルメチル)カルバミドの塩及びその調製 - Google Patents
N−(4−フルオロベンジル)−n−(1−メチルピペリジン−4−イル)−n’−(4−(2−メチルプロピルオキシ)フェニルメチル)カルバミドの塩及びその調製 Download PDFInfo
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- JP2008514627A JP2008514627A JP2007533699A JP2007533699A JP2008514627A JP 2008514627 A JP2008514627 A JP 2008514627A JP 2007533699 A JP2007533699 A JP 2007533699A JP 2007533699 A JP2007533699 A JP 2007533699A JP 2008514627 A JP2008514627 A JP 2008514627A
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
本発明は医学及び化学の分野に関する。より詳細には、本発明は、N−(4−フルオロベンジル)−N−(1−メチルピペリジン−4−イル)−N’−(4−(2−メチルプロピルオキシ)−フェニルメチル)カルバミド、その塩、並びにそれらの合成及び使用に関する。
国際公開第01/66521号は、N−アザシクロアルキル−N−アラルキルカルバミド及びカルボン酸アミドを記載しており、これらは、5−HT2Aサブクラスのセロトニン受容体を含むモノアミン受容体の活性を阻害するのに効果的な新種の化合物を構成する。当該化合物が使用される病状の例としては、統合失調症及び関連特発性精神病等の神経精神病;うつ病;不安神経症;睡眠障害;食欲不振;大うつ病、双極性障害、精神病性特徴を伴ううつ病及びツレット症候群等の情動障害が挙げられるが、これらに限定されない。他の有益な治療は、薬物性精神病及びパーキンソン病の副作用;並びにアルツハイマー病又はハンチントン病等の神経変性障害、高血圧、偏頭痛、血管痙攣、虚血に続発する精神病;並びに、様々な血栓状態(心筋梗塞、血栓発作又は虚血発作、特発性血小板減少性紫斑病及び血栓性血小板減少性紫斑病、並びに抹消血管疾患を含む)の一次治療及び二次予防であり得る。
マレイン酸、リンゴ酸、リン酸、コハク酸、硫酸、及びエジシル酸から成る群より選択される。一実施形態では、アニオンが、クエン酸、マレイン酸、リンゴ酸、リン酸、コハク酸、及び硫酸から成る群より選択される場合、化学量論は1:1であり、アニオンが、エジシル酸及びフマル酸から成る群より選択される場合、化学量論は2:1である。一実施形態では、上記塩が式IVのクエン酸塩である。
a)有機溶媒中の式Iの化合物の溶液を形成する工程;
b)クエン酸、フマル酸、マレイン酸、L−(−)−リンゴ酸、リン酸、コハク酸、硫酸又は1,2−エタンジスルホン酸から成る群より選択される酸を上記溶液に添加する工程;及び
c)上記塩を単離すること
を含む、方法を含む。一実施形態では、上記単離することは、工程b)の後に形成される懸濁液から上記塩を分離することを含む。別の実施形態では、上記単離することは、工程b)の後に形成される溶液から当該塩を、冷却、溶媒除去又は非溶媒の添加のうちの1つ以上によって析出させることを含む。
b)クエン酸、フマル酸、マレイン酸、L−(−)−リンゴ酸、リン酸、コハク酸、硫酸又は1,2−エタンジスルホン酸から成る群より選択される酸を上記溶液に添加する工程;及び
c)上記塩を単離すること
を含むプロセスによって生成される、塩。
;精神運動遅延;動作緩慢;及び神経障害疼痛から成る群より選択される。
1つの有用なN−アザシクロアルキル−N−アラルキルカルバミドは、式IのN−(4−フルオロベンジル)−N−(1−メチルピペリジン−4−イル)−N’−(4−(2−メチルプロピルオキシ)フェニルメチル)カルバミドである。
一実施形態では、式IIの化合物((4−フルオロベンジル)−(1−メチルピペリジン−4−イル)アミン)と、式IIIの化合物(4−(2−メチルプロピルオキシ)フェニルメチル−イソシアネート)とを反応させることを含む、式(I)の化合物を合成する方法である。
離は、溶媒の部分除去により濃度を上げ、不純物を濾過し、さらなる濃縮又は非溶媒(例えば脂肪族炭化水素(例えば、ペンタン、ヘキサン、ヘプタン、オクタン、シクロヘキサン、メチルシクロヘキサン又は水))の添加のいずれかにより式Iの固体化合物を析出させ、この固体を濾過し、乾燥させることによっても可能である。単離された式Iの化合物は、蒸留法又はクロマトグラフ法等の既知の方法によって精製できる。
幾つかの実施形態では、リン酸、硫酸、硝酸、二リン酸、重炭酸、炭酸、クラブラン酸、イソチオン酸、ホウ酸、ハライド、硝酸、酢酸、コハク酸、乳酸、ラクトビオン酸、ラ
ウリン酸、マンデル酸、リンゴ酸、クエン酸、フマル酸、マレイン酸、オレイン酸、シュウ酸、アスコルビン酸、ニコチン酸、安息香酸、メシル酸、サリチル酸、ステアリン酸、タンニン酸、トシル酸、吉草酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、2−エタンジスルホン酸、又はナフタレンスルホン酸から成る群より選択されるアニオンを含む、N−(4−フルオロベンジル)−N−(1−メチルピペリジン−4−イル)−N’−(4−(2−メチルプロピルオキシ)フェニルメチル)カルバミドの塩である。
。様々な実施形態では、結晶性のマレイン酸塩が少なくとも約50%、約70%、約80%、約90%、約95%、又は約98%の量で存在し、残りは、式Iの化合物の他の塩又は結晶形態(水和物及び溶媒和物を含む)及び/若しくはアモルファスである。
4.29(vs)、4.17(s)、4.00(s)、3.97(m)、3.87(s)、3.83(s)、3.61(m)。任意の特定の理論にとらわれることなく、式VIIのリンゴ酸塩のこの結晶形態はセスキ水和物であってもよい。様々な実施形態では、結晶性リンゴ酸塩が少なくとも約50%、約70%、約80%、約90%、約95%、又は約98%の量で存在し、残りは、式Iの化合物の他の塩又は結晶形態(水和物及び溶媒和物を含む)及び/若しくはアモルファスである。
.6(w)、7.6(m)、6.4(w)、5.51(s)、5.27(w)、5.19(m)、4.79(m)、4.42(w)、4.32(m)、4.16(s)、4.05(s)、3.91(m)、3.69(w)、3.31(w)、3.27(w)、3.14(w)、2.97(w)、2.76(w)。様々な実施形態では、結晶性コハク酸塩が少なくとも約50%、約70%、約80%、約90%、約95%、又は約98%の量で存在し、残りは、式Iの化合物の他の塩又は結晶形態(水和物及び溶媒和物を含む)及び/若しくはアモルファスである。
末X線回折パターンを示し、以下、結晶性エジシル酸塩と称される。具体的には、粉末X線回折パターンは、d値(Å)で表わされる以下の特性ピークを示す。12.1(m)、10.0(s)、9.3(m)、8.1(m)、6.6(m)、6.05(vs)、5.31(s)、5.18(m)、4.97(vs)、4.81(w)、4.68(s)、4.57(m)、4.46(m)、4.35(m)、4.26(s)、4.12(s)、3.96(m)、3.88(w)、3.75(m)、3.62(m)、3.53(w)、3.48(m)、3.42(w)、3.31(m)、3.15(w)、3.07(w)。様々な実施形態では、結晶性エジシル酸塩が少なくとも約50%、約70%、約80%、約90%、約95%、又は約98%の量で存在し、残りは、式Iの化合物の他の塩又は結晶形態(水和物及び溶媒和物を含む)及び/若しくはアモルファスである。
a)有機溶媒中の式Iの化合物の溶液を形成する工程;
b)適当な有機酸又は無機酸を上記溶液に添加する工程;及び
c)式Iの化合物の塩を、得られた懸濁液から単離する工程、又は塩を、冷却、溶媒除去、非溶媒の添加若しくはこれらの方法の組合せによって析出させる工程
を含む。
いて、結晶化合物を形成及び単離し得る。希釈溶液又は飽和溶液は、適当な核剤による種添加を伴って、又は伴わずに結晶化に使用され得る。得られた結晶固体は、当該技術分野でよく知られた結晶化手法によって精製し得る。溶液を形成するのに100℃までの温度を適用してもよい。
ニルピロリドン;並びにキトサン等の天然ポリマーである。
又は粉剤として製剤化され得る。
式IV、V、VI、VII、VIII、IX、X、又はXIの化合物より選択される塩を対象者に投与することを含む。
実験手順
粉末X線回折(PXRD):CuKα照射線を用いたPhilips1710粉末X線回折装置によりPXRDを実施した。1.54060Åの波長を用いた2θ値からd間隔を計算した。一般的に、2θ値は±0.1〜0.2°の誤差の範囲内であった。このため、d間隔の値の実験的な誤差はピーク位置によって決定された。
で有機相から73〜127℃で蒸留した。この段階で、残渣を、本方法に従って調製される第2の未処理のバッチと混合した。次に、混合生成物を139〜140℃/20mbarで蒸留し、11.2kg(>82%)の生成物を得た。
工程fによる式Iの化合物の酢酸イソプロピル(96L)溶液に、事前に調製した酒石酸(1.7kg)の水(1.7L)溶液、及びテトラヒドロフラン(23L)を23℃で添加した。残留懸濁液を2.5日間、22℃で攪拌した。酒石酸塩の粗生成物を遠心分離し、ケークを4回に分けて酢酸イソプロピル(4×23L)で洗浄した。合計107kgの母液を、酒石酸塩を得る際の以後の使用のために取っておいた。湿潤ケークを約40℃で乾燥させて、8.3kg(50%)の生成物を得た。
工程g)の酒石酸塩の粗生成物(8.1kg)を脱塩水(41L)に22℃で溶解した。酢酸イソプロピル(40L)、30%水性水酸化ナトリウム(4.3kg)及び塩化ナトリウム(2kg)を添加した。pHを調べ(>12)、この溶液を15分間攪拌した。溶液を15分かけてデカントし、水性相を分離した。水性相を酢酸イソプロピル(12L)で再抽出した。脱塩水(20L)及び塩化ナトリウム(2.0kg)を、混合有機相に添加し、この溶液を15分間攪拌し、15分間かけてデカントし、水性相を廃棄した。チャコール(0.4kg)を添加してこの混合物を20分間攪拌し、濾過した。ラインを酢酸イソプロピル(12L)で洗浄した後、溶媒を減圧下、20〜25℃で除去した。ヘプタン(49L)を添加し、この懸濁液を15分間40℃で攪拌した。その後、8Lの溶媒を、減圧下、38〜41℃の蒸留により除去した。このスラリーを20℃に冷却し、1時間攪拌した。生成物を遠心分離し、ケークをヘプタン(5L)で洗浄した。湿潤した式Iの化合物(5.5kg)を45℃のエタノール(28L)に溶解した。酒石酸(0.72kg)のエタノール(11L)溶液を45℃で添加し、ラインをエタノール(9L)で洗浄した。この溶液を43℃に冷却し、式Iの化合物の酒石酸塩を種添加した後、スラリーを30分間のうちに35℃に冷却し、この温度で1時間攪拌し、−5℃に冷却した。14時間後、この温度で生成物を遠心分離し、2回に分けてエタノール(2×6L)で洗浄した。湿潤ケークを約45℃で76時間乾燥させると、4kgの半酒石酸塩が得られた。
h)で得られた150.0gの半酒石酸塩を、65℃で攪拌下112mlの無水エタノールに溶解し、次いで、攪拌下で48℃まで1℃/分の冷却速度で冷却した。数分後、この温度で結晶化が始まり、懸濁液が1時間以内に粘稠なペーストになった。懸濁液を、60℃まで再度加熱し、次いで、48℃まで1℃/分の速度で冷却した。得られた懸濁液を攪拌し、15℃まで3℃/時間の冷却速度で冷却した。結晶性の析出物を濾過によって分離し、5℃に冷却した無水エタノール10mlでボトルを洗浄した。結晶性残渣を40℃で50時間、真空乾燥して146gの結晶性で純粋な半酒石酸塩を得た。
工程i)で調製した酒石酸塩15.78gを130mlの水に溶解した。500mlのTBMEを添加し、2N NaOH溶液の添加によってpHを9.8に調整した。白色固形物の析出後、水相を500mlのTBMEによって5回抽出した。有機相を、残りが約400mlの容量となるまで濃縮した。この溶液を6℃で保存した。析出物を濾過し、TBMEで洗浄し、最後に5時間真空乾燥した。収量:8.24gの白色粉末。母液を4分の1まで濃縮し、6℃で保存した。析出物を濾過し、18時間真空乾燥した。収量:1.6gの白色粉末。
a)実施例1の生成物90mg及びフマル酸24.3mgを5.0mlの酢酸エチルに懸濁した。懸濁液を60℃で15分間攪拌し、次いで75分間23±2℃で保存した。光学顕微鏡検査により結晶性物質が示された。懸濁液を濾過し、t−ブチルメチルエーテル(TBME)で洗浄した。収量:83mgの白色粉末。PXRD及びラマン分光分析は、アモルファス部分を含む結晶形態Aを示す。
に対して96.7%であった)。結晶性粉末は、フマル酸塩と半フマル酸塩の混合物であると考えられ得る。
a)実施例1の生成物181mg及びマレイン酸48.2mgを10.0mlの酢酸エチ
ルに溶解した。溶液を60℃で15分間、次いで20分間23±2℃で攪拌した。この時点後、白色固形物の析出が始まった。懸濁液を5℃で48時間保存し、次いで溶媒の容量を窒素流によって4分の1に減少させた。5℃での保存を72時間継続した。白色固形物を濾別し、113mgの結晶性粉末を得た。PXRD及びラマン分光分析は結晶形態を示す。TG−FTIRは、60〜160℃の間で約7.2%の質量損失を示し、これは、吸収された水及び酢酸エチルによるものであった。約160℃で分解が始まる。
、1:1の化学量論に適合する。水中における溶解度は>500mg/mlであった。
実施例1の生成物181mg及びL−(−)−リンゴ酸56.0mgを10.0mlの酢酸エチルに懸濁した。懸濁液を60℃で30分間攪拌して透明な溶液を形成した。溶液を5℃で1日保存した。固形物を、形成された懸濁液から濾別し、155mgの結晶性白色粉末を得た。PXRD及びラマン分光分析は結晶形態Aを示す。TG−FTIRは、50〜160℃の間で約5.5%の質量損失を示す。これは、水及びCO2によるものであった。約160℃で分解が始まった。元素分析及び1H−NMRは、1:1の化学量論に適合する。水中における溶解度は>500mg/mlであった。
実施例1の生成物181mgを3mlの2−プロパノールに溶解した。842μlのリン酸(0.5モル)を添加し、透明な溶液を形成した。試料を5℃で1日保存した。析出物を濾別し、15時間真空乾燥した。収量は60mgの白色結晶性粉末であった。PXR
D及びラマン分光分析は、結晶形態Aを示す。TG−FTIRは、80〜160℃の間で約3.9%の質量損失を示し、これは、2−プロパノールによるものであった。約170℃で分解が始まった。1H−NMRは、1:1の化学量論に適合する。水中における溶解度は>250mg/mlであった。
0℃の間で約18.8%の質量損失を示し、これは、大部分はCO2及び水によるものであり、元素分析は、二水和物の形成を示す。1H−NMRは、1:1の化学量論に適合する。水中における溶解度は>500mg/mlであった。
−(4−(2−メチルプロピルオキシ)フェニルメチル)カルバミド硫酸塩の調製
実施例1の生成物180mgを5mlのエタノールに溶解した。842μlの硫酸(0
.5モル)を添加し、形成された透明な溶液を5℃で48時間で保存した。溶媒を窒素流によって蒸発させた。固形物残渣を3mlのTBME及び0.1mlのエタノールに懸濁し、懸濁液を17時間23±2℃で攪拌した。濾過により、80mgの結晶性白色粉末が得られた。PXRD及びラマン分光分析は結晶形態を示す。
実施例1の生成物180mgを2mlのジオキサンに溶解し、次いで、48mgの1,
2−エタンジスルホン酸二水和物を4mlのジオキサン中に含む溶液を添加した。溶液を8℃10日間保存した。析出した固形物を濾別し、206mgの結晶性白色粉末を得た。PXRD及びラマン分光分析は結晶形態を示す。TG−FTIRは、60〜160℃の間で、約1.2%の質量損失を示し、これは、ジオキサンによるものであった。約170℃で分解が始まる。元素分析は、2:1の化学量論(式Iの化合物:1,2−エタンジスルホン酸)を示す。1H−NMRは、2:1又は1:1の両方の化学量論に適合する。水中における溶解度は4mg/mlであった。結晶性粉末は、1週間60℃及び約75%相対湿度で密閉容器内に保存したとき、白色粉末のままであった(HPLC面積は、参照値96.8%に対して97.4%であった)。密閉アンプル内に100℃で1週間の保存では、結晶性生成物は分解されず、白色粉末は実質的に未変化のままである(HPLC面積97.4%)。
Claims (34)
- 式IのN−(4−フルオロベンジル)−N−(1−メチルピペリジン−4−イル)−N’−(4−(2−メチルプロピルオキシ)フェニルメチル)カルバミドの塩であって、
- 前記アニオンが、クエン酸、フマル酸、マレイン酸、リンゴ酸、リン酸、コハク酸、硫酸、及びエジシル酸から成る群より選択される、請求項1に記載の塩。
- 前記アニオンが、クエン酸、マレイン酸、リンゴ酸、リン酸、コハク酸、及び硫酸から成る群より選択される場合、化学量論は1:1であり、前記アニオンが、エジシル酸及びフマル酸から成る群より選択される場合、化学量論は2:1である、請求項2に記載の塩。
- 約31.8、約15.9、約7.9、約6.3、約5.96、約5.23、及び約4.68のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請
求項4に記載の塩。 - 約21.7、約18.3、約15.7、約14.5、約12.6、約12.3、約10.9、約5.52、約4.72、及び約4.47のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項6に記載の塩。
- 約18.4、約15.7、約12.6、約9.2、約5.50、約4.93、約4.70、約4.51、約4.17、及び約4.06のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項6に記載の塩。
- 約13.0、約5.71、約5.24、約4.77、約4.37、及び約4.19のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項9に記載の塩。
- 約13.1、約12.0、約5.35、約5.05、約4.83、約4.75、約4.71、約4.37、約4.29、約4.17、約4.00、約3.87、及び約3.83のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項11に記載の塩。
- 約17.3、約5.91、約4.80、約4.27、約4.14、及び約3.86のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項13に記載の塩。
- 約12.8、約7.6、約5.51、約5.19、約4.79、約4.16、及び約4.05のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項15に記載の塩。
- 約17.0、約9.6、約5.49、約4.79、約4.65、約4.53、約4.30、約4.15、約4.04、及び約3.89のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項17に記載の塩。
- 約10.0、約6.05、約5.31、約4.97、約4.68、約4.26、及び約4.12のd値(オングストローム)を有するピークを含む粉末X線回折パターンを示す、請求項19に記載の塩。
- a)有機溶媒中の式Iの化合物の溶液を形成する工程;
b)クエン酸、フマル酸、マレイン酸、L−(−)−リンゴ酸、リン酸、コハク酸、硫酸又は1,2−エタンジスルホン酸から成る群より選択される酸を前記溶液に添加する工程;及び
c)前記塩を単離する工程
を含む、請求項1に記載の塩を製造する方法。 - 前記単離する工程が、工程b)の後に形成される懸濁液から前記塩を分離する工程を含む、請求項21に記載の方法。
- 前記単離する工程が、工程b)の後に形成される溶液から前記塩を、冷却、溶媒除去又は非溶媒の添加のうちの1つ以上によって析出させる工程を含む、請求項21に記載の方法。
- 請求項1に記載の塩の1種類以上と、薬学的に許容可能な担体とを含む、医薬組成物。
- モノアミン受容体の活性を阻害する方法であって、請求項1に記載の少なくとも1種の塩を対象者に投与することを含む、方法。
- 神経精神病を治療する方法であって、請求項1に記載の少なくとも1種の塩を対象者に投与することを含む、方法。
- 前記神経精神病が、精神病;統合失調症;分裂情動障害;躁病;精神病性うつ病;情動障害;認知症;不安神経症;睡眠障害;食欲不振;双極性障害;高血圧、偏頭痛、血管痙攣及び虚血に続発する精神病;運動性チック;振せん;精神運動遅延;動作緩慢;及び神経障害疼痛から成る群より選択される、請求項27に記載の方法。
- 神経変性疾患を治療する方法であって、請求項1に記載の少なくとも1種の塩を対象者に投与することを含む、方法。
- 前記神経変性疾患が、パーキンソン病、ハンチントン病、アルツハイマー病、脊髄小脳萎縮症、ツレット症候群、フリードライヒ運動失調症、マシャド・ジョセフ病、レービー小体型認知症、ジストニア、進行性核上麻痺及び前頭側頭型認知症から成る群より選択される、請求項29に記載の方法。
- ドーパミン作動性療法に関連するジスキネジアを治療する方法であって、請求項1に記載の少なくとも1種の塩を対象者に投与することを含む、方法。
- ドーパミン作動性療法に関連するジストニア、ミオクローヌス又は振せんを治療する方法であって、請求項1に記載の少なくとも1種の塩を対象者に投与することを含む、方法。
- 血栓状態を治療する方法であって、請求項1に記載の少なくとも1種の塩を対象者に投与することを含む、方法。
- 前記血栓状態が、心筋梗塞、血栓発作又は虚血発作、特発性血小板減少性紫斑病及び血栓性血小板減少性紫斑病、抹消血管疾患、並びにレイノー病から成る群より選択される、請求項33に記載の方法。
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