JP4708024B2 - (2s,5z)−2−アミノ−7−(エタンイミドイルアミノ)−2−メチルヘプタ−5−エン酸の結晶性固体型 - Google Patents
(2s,5z)−2−アミノ−7−(エタンイミドイルアミノ)−2−メチルヘプタ−5−エン酸の結晶性固体型 Download PDFInfo
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- JP4708024B2 JP4708024B2 JP2004529853A JP2004529853A JP4708024B2 JP 4708024 B2 JP4708024 B2 JP 4708024B2 JP 2004529853 A JP2004529853 A JP 2004529853A JP 2004529853 A JP2004529853 A JP 2004529853A JP 4708024 B2 JP4708024 B2 JP 4708024B2
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- amino
- ethanimidylamino
- enoic acid
- methylhept
- hcl
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Description
ずれか1種によって産生される生物学的に活性な遊離ラジカルの気体である。後にNOとして同定されたこの物質の生理学的活性は、1980年代の初期に、アセチルコリンにより惹起される血管弛緩が血管内皮の存在に依存することが見出されたときに、始めて発見された。このような血管弛緩を仲介する内皮由来因子はその後、内皮由来弛緩因子(EDRF)と呼ばれ、現在ではNOSのアイソフォームの1種により血管内皮に産生されるNOであることが知られている。血管拡張剤としてのNOの活性は100年以上にわたって周知であった。さらにNOは亜硝酸アミルおよび硝酸グリセリルを含めた既知のニトロ血管拡張剤に由来する活性種である。一酸化窒素はまた可溶性グアニル酸サイクラーゼ(cGMP)の内因性刺激物質であり、したがってcGMPの産生を刺激することになる。N-モノメチルアルギニン(L-NMMA)によってNOSを阻害するとcGMPの形成は完全に防止される。内皮依存性の弛緩に加えて、NOは多くの生物学的活性たとえば食細胞の細胞毒性および中枢神経系における細胞−細胞間連絡に関与することが知られている。
(i)受容体または物理学的刺激に応答してNOを放出する、脳に局在する構成的なCa++/カルモジュリン依存性酵素、
(ii)血管平滑筋、マクロファージ、内皮細胞および他の数多くの細胞のエンドトキシンおよびサイトカインによる活性化後に誘導される130 kD蛋白質のCa++非依存性酵素、ならびに
(iii)受容体または物理学的刺激に応答してNOを放出する、内皮に局在する構成的なCa++/カルモジュリン依存性酵素
である。
ら, J. Exp. Med. 184: 1519, 1996参照)、炎症性腸疾患(たとえば、Lundberg J. O. N.ら, Lancet 344: 1673, 1994)および喘息(たとえば、Hamid Q.ら, Lancet 342: 1510, 1993)において増大し、iNOSはこれらの慢性的炎症性疾患における主要な病因因子と考えられている。
ミドイルアミノ)-2-メチルヘプタ-5-エン酸は、2001年9月15日に同一出願人により出願された国際特許出願PCT/US 0128673の公報である、2002年3月21日公開の国際公開番号WO 02/22562に記載されている。その化合物は、しかしながら、無定形の固体である。したがって、iNOS阻害剤、たとえば(2S,5Z)-2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸の結晶固体の提供が望まれる。
塩酸塩の新規な結晶性塩、医薬組成物、新規な塩化合物を製造するための方法、医薬組成物を製造するための方法、ならびに一酸化窒素合成の阻害または調節のために、このような阻害または調節を必要とする対象に、一酸化窒素シンターゼの構成的アイソフォームよりも、一酸化窒素シンターゼの誘導性アイソフォームを優先的に阻害または調節する化合物の塩を投与することによる上記の新規な塩化合物および組成物の使用方法を意図するものである。本発明の塩化合物は有用な一酸化窒素シンターゼ阻害活性を有し、一酸化窒素の合成または過剰合成が一因となる疾患または状態の処置または予防における有用性が期待される。
トル)の一部または全部によって特徴づけられる。
に使用できる。
の免疫抑制に対するアジュバントとしての使用が包含される。
迫症候群(ARDS)、オキシダント誘発肺損傷、たとえば癌患者におけるIL-2療法、悪液質、移植療法における免疫抑制、胃腸の運動性障害、日焼け、湿疹、乾癬、歯肉炎、膵炎、感染によって生じる胃腸管の傷害、嚢胞性線維症の処置、免疫系の機能不全に対する処置たとえば臓器移植療法における短期間の免疫抑制に対するアジュバント、分娩の誘発、腺種様ポリープ、腫瘍の増殖制御、化学療法、化学療法的予防および気管支炎に有用である。
図2は、本発明の2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸 1.5 HClの示差走査熱量測定のグラフである。
図3は、2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸 1.5 HClの
粉末X−線パターンである。
図4は、2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸 1.5 HClの
粉末X−線パターンに重ねた単一結晶構造から計算された粉末X−線パターンである。
図5は、本発明の2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸 1.5 HClの熱重量分析結果のプロットである。
図6は、本発明の(2S,5Z)-2-アミノ-7-(エタンイミドイルアミノ)- 2-メチルヘプタ-5-エン酸の1.5 HCl塩のラマンスペクトルである。
「処置する」、「処置すること」および「処置」の語は、本明細書において、予防、待機的療法または回復的処置を含めて使用される。
に数回に分割して投与することができる。
ACNまたはCH3CNはアセトニトリルである。
AcOHは酢酸である。
CH2Clはメチルクロリドである。
DIBALはジイソブチルアルミニウムヒドリドである。
DMFはジメチルホルムアミドである。
Et3Nはトリエチルアミンである。
EtOAcは酢酸エチルである。
KHMDSはカリウムヘキサメチルジシラジドである。
KOHは水酸化カリウムである。
MeIはヨウ化メチルである。
MSはマススペクトルである。
MsClはメシルクロリドである。
NaHCO3は炭酸水素ナトリウム(重炭酸ナトリウム)である。
Na2SO4は硫酸ナトリウムである。
THFはテトラヒドロフランである。
与量において投与することができる。
塩はまた、経皮デバイスによって投与することもできる。好ましくは、局所投与は、リザーバおよび多孔性膜型または固体マトリックス型いずれかのパッチを使用して達成される。いずれの場合も、活性剤はリザーバまたはマイクロカプセルから膜を通って、活性剤が透過できる接着層に送達され、この層は受容者の皮膚または粘膜と接触する。活性剤が皮膚を通して吸収されると、制御され予め定められた流量の活性剤が受容者に投与される。マイクロカプセルの場合は封入剤も膜として機能する。
アルコール、ミリスチルアルコール、グリセリルモノステアレート、およびラウリル硫酸ナトリウムが包含される。
を0.5〜20%、有利には0.5〜10%、とくに約1.5%w/wを存在させることが好ましい。
(2S,5Z)-2-アミノ-2-メチル-7-[(1-イミノエチル)アミノ]-5-ヘプテン酸二塩酸塩の製造:
(Z)-5-t-ブチルジメチルシリルオキシ-2-ペンテン-1-オール(EX-1A)を5,5-ジヒドロ-2-ピロン(Aldrich)から、Harold, Mohr & Tamm, Helvetica Chimica Acta 66, 2, 1983, 744-754の方法によって製造した。
EX-1A(720 mg, 3.3ミリモル)のCH2Cl2(25 mL)中溶液にEt3N(525 mg, 5.3ミリモル)およびメタンスルホニルクロリド(561 mg, 4.90ミリモル)を加えた。反応混合物を0℃で15分、ついで室温で16時間攪拌した。CH2Cl2をさらに加え、溶液をNaHCO3、食塩水で抽出し、乾燥すると790 mgの黄色油状物が生成した。油状物をDMF(20 mL)に溶解し、3-メチル-1,2,4-オキサジアゾリン-5-オン カリウム塩(513 mg, 3.7ミリモル)を加えた。得られた溶液を50℃で16時間攪拌した。溶媒を真空中で除去し、残留物をEtOAcと食塩水に分配した。有機層を乾燥(Na2SO4)し、濃縮すると油状物が得られ、これをシリカゲル上フラッシュカラムクロマトグラフィーに付し、エーテル:ヘキサン(1:1)で溶出させて精製すると、所望の保護されたZ-アリル環状アミジン生成物780 mg(79%)が澄明な油状物として得られ、これは1HNMRによれば所望のZ-アイソマーのみを含有した。
酢酸(1 mL)、THF(3 mL)および水(1 mL)の混合物中の、EX-1B(100 mg, 0.34ミリモル)の溶液を室温で16時間攪拌した。得られた溶液を真空中で油状物に濃縮し、これをEtOAcに溶解した。有機層を飽和NaHCO3で洗浄し、乾燥(Na2SO4)し、ろ過して蒸発させ
ると、所望のアルコール生成物80 mg(定量的)が無色澄明な油状物として得られた。
EX-1C(80 mg, 0.43ミリモル)のCH2Cl2(3 mL)溶液にEt3N(44 mg)およびトリフリ
ック酸無水物(146 mg, 0.52ミリモル)を0℃で加え、混合物を0℃で1.5時間攪拌した
。この溶液を真空中で濃縮し、得られた黄色のスラリーにEX-2D(0.15 g, 0.74ミリモル
)のCH2Cl2(1.5 mL)の溶液を加えた。粗製の材料をシリカゲル上フラッシュカラムクロマトグラフィーに付し、EtOAc:ヘキサン(1:1)で溶出させて精製すると、所望のトリフレート生成物62 mg(44%)が澄明な油状物として得られた。
(2S,4S)-3ベンゾイル-2-t-ブチル-4-メチル-1,3-オキサゾリジン-5-オン(参考)(532
mg, 2.04ミリモル)のTHF(10 mL)溶液に−78℃でKHMDS(4.48 mL, 2.2ミリモル, THF
中0.5 M)を加えた。得られた橙色の溶液を15分間攪拌し、ついでEX-1D(580 mg, 1.8ミリモル)を加えた。得られた溶液を室温に放置して加温し、ついでKHSO4(10%, 1.5 mL)、食塩水およびEtOAcを加えた。有機層を分離し、乾燥し、真空中で濃縮すると黄色の油状物960 mgが生成した。粗製の材料をシリカゲル上フラッシュカラムクロマトグラフィーに付し、EtOAc:ヘキサン(1:1)で溶出させて精製すると、所望のアルキル化生成物138 mg(18%)が澄明な油状物として得られた。
EX-1E(138 mg, 0.32ミリモル)のメタノール(10 mL)溶液に、リンドラー触媒(260 mg)を加えた。スラリーを攪拌しながら2時間還流し、ついで室温に冷却した。 セライトを通してろ過して触媒を除去し、ろ液を蒸発させると所望の脱保護されたアミジン生成物が淡黄色の油状物として得られた。HCl(6 N, 10 mL)中の黄色油状物の溶液を1.75時間
還流した。溶媒を真空中で除去し、得られた泡状物を逆相HPLCに付し、0〜40% CH3CN/H2O(0.25%酢酸)の30分勾配で溶出して精製した。生成物を含む分画を合わせて濃縮し、泡状物を得た。生成物を1 N HClに溶解し、溶媒を真空中で除去(2×)すると、所望の(2S,5Z)-2-アミノ-2-メチル-7-[(1-イミノエチル)アミノ-5-ヘプテン酸二塩酸塩生成物34 mg(20%)が得られた。MS C10H19N3O2としての計算値:m/z=214 [M+H]+, 分析値:214. (100%)。1H NMR (D2O)δ1.40 (s, 3H), 1.5-2.0 (m, 4H), 1.90 (s, 3H), 3.55 (m, 2H), 5.15-5.25 (m, ビニル, 1H), 5.30-5.45 (m, ビニル, 1H).
(2S,5Z)-2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸の結晶型の製
造
結晶化
無定形(2S,5Z)-2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸は過
剰の塩酸塩とともに、水、メタノールおよびエタノールに自由に溶解し、イソプロパノールおよび水を含む各種の溶媒、たとえばTHF中10%の水、水飽和酢酸エチル、アセトニト
リル中10%の水および水を含む高級アルコールに可溶である。無定形物質は試験した乾燥溶媒たとえばアセトン、MEK、メチルイソブチルケトン、THF、酢酸エチル、クロロホルム、塩化メチレン、ヘキサン、シクロヘキサン、ジイソプロピルエーテル、アセトニトリルおよびトルエンには、有意に1 mg/mL未満しか溶解しない。
がHPLC等級の水10 mlに溶解した。クロライド型をヒドロキシ型に変換するAmberlite IRA
400イオン交換樹脂を用いて、(2S,5Z)-2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸の溶液をpH 10.7に滴定した。クロライド選択的電極が指示するクロライドは200 ppmに低下した。この溶液を、Millipore 5μm LS膜を通してろ過し、溶液を凍結乾燥した。凍結乾燥した固体の元素分析(表II)が指示するクロライドは0.25当量に低下し、イオン選択性電極の読み200 ppmに一致した。
、水、各種低級アルコール、THF-水、アセトニトリル-水および水飽和酢酸エチルに溶解
し、濃厚溶液を得た。上に掲げた逆溶媒を用いて溶液から塩を形成させた。液−液相晶出、エマルジョンおよびガラス状の沈殿がすべての場合について得られた。蒸気拡散セルも数種の系と同様に設けたがもっぱらエマルジョン相の産生が認められた。
〜6週間換気フード中に放置した。このサンプルは自動的に変化し始めた。偏光顕微鏡を
使用すると、結晶化が起こったことがわかった。サンプルのほぼ半容量は脱色して決して結晶化しなかったが、ほぼ半量は結晶化した。様々な溶媒による多くの結晶化実験では、種晶としてこの物質の一部を用いて(2S,5Z)-2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸塩酸塩からさらに結晶物質が得られた。結晶化が起こったとしても
きわめてわずかであり、きわめてゆっくりとしか進行しない。各ロットからの結晶形を偏光顕微鏡で検査して多形の証拠とした。結晶の習性および光学的性質は1つの形に対して一貫していた。各ロットからの結晶は二軸性で、高い複屈折面と低い複屈折面n1−n2<0.006を示し、低い複屈折面から光学軸が発生した。
β=73.472, γ=86.086であった。2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸の絶対配置は“S”であることが確認された。
種晶添加する」と、記載の条件において核生成が開始または増大し得ることを理解すべきである。結晶はPharmacia Corporation, 4901 Searle Parkway, Skokie, Illinois, USA,
60077から入手される。
チルヘプタ-5-エン酸数百ミリグラムを、前回の実験における凍結乾燥材料とほぼ同濃度
でイソプロパノールに溶解した。塩酸塩の濃度は調整しなかった。この系に種晶添加し、周囲温度で攪拌した。結晶化は認められなかった。次の実験では溶液のpHを濃水酸化ナトリウムで約pH 3に調整して種晶添加した。結晶生成物がいくらか得られたが、収率は約30〜40%にすぎなかった。エーテルを加えると収率は90%近くに上昇した。
(2S,5Z)-2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸結晶性塩の特
徴決定
固体2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸 1.5 HClは偏光
顕微鏡により結晶であり、結晶子サイズは1μmのオーダーであった。凝集した粒子は球晶であった。2-アミノ-7-(エタンイミドイルアミノ)-2-メチルヘプタ-5-エン酸 1.5 HClの
元素分析は物理的方法により与えられ、溶媒和のない1.5 HCl塩の理論値にきわめてよく
一致した(表III参照)。電量カール・フィッシャー水分析による2回の測定の平均から
、0.6%水(0.09等量)であることがわかった。
偏光顕微鏡法により、屈折率nd α1.508, β約1.59, γ1.608, 陰性光学的サイン(negative optic sign)および2Vほぼ37度であった。光学軸の強い分散が干渉像中にはっきりと見られた。
末x−線パターンを示す。
5 HClの粉末x−線パターンと重複させた単一結晶構造から計算したx−線粉末パターン
は、温度差についての許容範囲内でよく一致した。単一結晶のデータは120°Kで、粉末
x−線データは周囲温度で収集した。
湿度70%およびそれ未満で非吸湿性である。DVS水分バランスによる、2-アミノ-7-(エタ
ンイミドイルアミノ)-2-メチルヘプタ-5-エン酸 1.5 HClの25℃における水分の吸収は、相対湿度(R.H.)70%において水分増加0.91%を示した。R.H. 80%において18.5%の増
加、R.H. 90%において76.8%の増加を示した。装置を低相対湿度に逆回転させ、ついで
サンプルを取出し、偏光顕微鏡で検査した。サンプルは水分バランスから取出したのちは完全に結晶質であったが、結晶のサイズは増大した。PLMにより容易に観察される光学的
性質は、結晶型には変化は起こらなかったが、少なくとも一部のサンプルは潮解し、乾燥時に再結晶されることが示唆された。表IVはDVS水分バランスからのデータの詳細を示す
。この塩形態1.5 HClは、溶媒和を有しなかった。
MP 253
H-NMR, HR-MS, CHN >99.0
白色結晶性固体
MP 229.33
H-NMR, HR-MS, CHN >99.0
Claims (1)
- 図3に示すx−線粉末回折パターン、図6に示すラマンスペクトル、224℃の融点および147ジュール・グラム-1の融解熱によって特徴づけられる(2S,5Z)−2−アミノ−7−(エタンイミドイルアミノ)−2−メチルヘプタ−5−エン酸1.5塩酸塩の結晶型。
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US40552602P | 2002-08-23 | 2002-08-23 | |
US60/405,526 | 2002-08-23 | ||
PCT/US2003/026347 WO2004018412A1 (en) | 2002-08-23 | 2003-08-22 | Crystalline solid form of (2s-5z)-2-amino-7-(ethanimidoylamino)-2-methylhept-5-enoic acid |
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CA (1) | CA2494583C (ja) |
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HK (1) | HK1078562A1 (ja) |
IL (2) | IL166599A0 (ja) |
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Citations (2)
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WO2002022562A1 (en) * | 2000-09-15 | 2002-03-21 | Pharmacia Corporation | 2-amino-2-alkyl-5 heptenoic and heptynoic acid derivatives useful as nitric oxide synthase inhibitors |
WO2002050021A1 (en) * | 2000-12-21 | 2002-06-27 | Glaxo Group Limited | Nitric oxide synthase inhibitor phosphate salt |
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DK0751930T3 (da) | 1994-03-24 | 2000-04-17 | Searle & Co | Amidinoderivater anvendelige som nitrogenoxid-synthase-inhibitorer |
US5684008A (en) | 1994-11-09 | 1997-11-04 | G. D. Searle & Co. | Aminotetrazole derivatives useful as nitric oxide synthase inhibitors |
US5945408A (en) | 1996-03-06 | 1999-08-31 | G.D. Searle & Co. | Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors |
US7012098B2 (en) * | 2001-03-23 | 2006-03-14 | Pharmacia Corporation | Inhibitors of inducible nitric oxide synthase for chemoprevention and treatment of cancers |
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WO2002050021A1 (en) * | 2000-12-21 | 2002-06-27 | Glaxo Group Limited | Nitric oxide synthase inhibitor phosphate salt |
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RU2005104954A (ru) | 2005-07-20 |
AR041038A1 (es) | 2005-04-27 |
AU2003258327A1 (en) | 2004-03-11 |
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WO2004018412A1 (en) | 2004-03-04 |
US6998503B2 (en) | 2006-02-14 |
EP1534668A1 (en) | 2005-06-01 |
TW200413291A (en) | 2004-08-01 |
CA2494583A1 (en) | 2004-03-04 |
CN1678572A (zh) | 2005-10-05 |
ZA200501134B (en) | 2006-10-25 |
KR100893647B1 (ko) | 2009-04-17 |
US20040132822A1 (en) | 2004-07-08 |
MXPA05001708A (es) | 2005-04-19 |
PL375557A1 (en) | 2005-11-28 |
CA2494583C (en) | 2010-02-02 |
RU2314290C2 (ru) | 2008-01-10 |
BR0313752A (pt) | 2005-06-21 |
EP1534668B1 (en) | 2012-05-02 |
NZ538184A (en) | 2008-02-29 |
JP2005536541A (ja) | 2005-12-02 |
NO20050609L (no) | 2005-03-21 |
AU2003258327B2 (en) | 2009-05-21 |
KR20050058443A (ko) | 2005-06-16 |
TWI340133B (en) | 2011-04-11 |
ATE556047T1 (de) | 2012-05-15 |
ES2384969T3 (es) | 2012-07-16 |
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