JP5416408B2 - 5−クロロ−n−({(5s)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミドの新規多形および無定形 - Google Patents
5−クロロ−n−({(5s)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミドの新規多形および無定形 Download PDFInfo
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/28—Halogen atoms
Description
・脂質低下剤、特にHMG−CoA(3−ヒドロキシ−3−メチルグルタリル−補酵素A)リダクターゼ阻害剤;
・冠血管治療剤/血管拡張剤、特にACE(アンジオテンシン変換酵素)阻害剤;AII(アンジオテンシンII)受容体アンタゴニスト;β−アドレナリン受容体アンタゴニスト;アルファ−1−アドレナリン受容体アンタゴニスト;利尿剤;カルシウムチャネル遮断剤;環状グアノシン一リン酸(cGMP)の増加をもたらす物質、例えば、可溶性グアニル酸シクラーゼの刺激剤;
・プラスミノーゲン活性化剤(血栓溶解剤/線維素溶解剤)および血栓溶解/線維素溶解を高める化合物、例えば、プラスミノーゲン活性化因子阻害因子の阻害剤(PAI阻害剤)またはトロンビン活性型繊維素溶解阻害因子の阻害剤(TAFI阻害剤);
・抗凝血活性を有する物質(抗凝血剤);
・血小板凝集を阻害する物質(血小板凝集阻害剤、栓球凝集阻害剤);
・およびフィブリノーゲン受容体アンタゴニスト(糖タンパク質IIb/IIIaアンタゴニスト)。
これらの投与経路のために、本発明による化合物を適する投与形で投与できる。
経口または非経腸投与、特に経口投与が好ましい。
Perkin-Elmer の DSC 7 または Pyris-1 示差走査熱量計および TGA 7 熱重量分析計を使用して、サーモグラムを得た。Stoe 透過型回折装置でX線回折図を記録した。Bruker の IFS 66v Fourier IR(IR、FIR)、IFS 28/N(NIR)および RFS 100 (ラマン) 分光計を使用して、IR、FIR、NIRおよびラマンスペクトルを記録した。
表題化合物の変態Iの製造は、WO01/47919およびWO2004/060887に記載されている。
実施例2.1
クロロチオフェンカルボン酸208gを、トルエン1100mlに懸濁し、75ないし80℃に加熱した。塩化チオニル112mlを、この温度で2時間かけて滴下して添加した。得られた反応溶液をさらに2時間、ガスの発生が終了するまで撹拌した。この間に、内部温度を5°ずつ100−110℃まで上昇させた。混合物を冷却し、酸塩化物の溶液をロータリーエバポレーターで濃縮した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約200mgを、高温でテトラヒドロフラン約80mlに溶解した。溶液を濾過し、半分に分けた。2分の1を、室温で、n−へプタンにより、活性物質が沈殿するまで処理した。残渣を濾過し、室温で乾燥させた。それをX線回折法により調べた。それは、変態IIの表題化合物に相当した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約200mgを、高温で1−ペンタノール約40mlに溶解した。溶液を濾過し、半分に分けた。2分の1をn−へプタンで活性物質が沈殿するまで処理した。残渣を濾過し、室温で乾燥させた。それをX線回折法により調べた。それは、変態IIの表題化合物に相当した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約200mgを、高温で1,4−ジオキサン約40mlに溶解した。溶液を濾過し、半分に分けた。2分の1を、50℃で、乾燥オーブン中、溶媒が蒸発するまで保存した。残渣をX線回折法により調べた。それは、変態IIの表題化合物に相当した。
Kofler 加熱ベンチ上、約240℃で溶融し、続いて室温に衝撃冷却することにより製造した無定形の5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約50mgを、エタノール約2mlに懸濁し、25℃で0.5時間撹拌した。晶出物を単離し、乾燥した。残渣をX線回折法により調べた。それは、変態IIの表題化合物に相当した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約100mgを、高温でアセトン約50mlに溶解した。溶液を濾過し、n−へプタンで、氷浴中、活性物質が沈殿するまで処理した。残渣を濾過し、室温で乾燥させた。それをX線回折法により調べた。それは、変態IIの表題化合物に相当した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約120mgを、高温でアセトン約50mlに溶解した。溶液を濾過し、水約50mlで処理し、溶媒が蒸発するまで室温で静置した。残渣を熱分析的に調べた。それは、変態IIIの表題化合物に相当した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約400mgを、高温でエタノール:水(1:1)約60mlに溶解し、濾過した。溶液の一部を、冷凍庫中、約−20℃の温度で、溶媒が蒸発するまで保存した。残渣は表題化合物の水和物に相当した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約3.5gを、1−メチル−2−ピロリドン10mlに懸濁し、室温で撹拌した。数時間後、NMP約20mlをさらに添加した。2日後、懸濁液を吸引濾過し、残渣を室温で乾燥させた。残渣を熱分析的に調べた。それは、NMP含量18.5重量パーセントを有する表題化合物のNMP溶媒和物に相当した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約400mgを、高温でテトラヒドロフラン約50mlに溶解し、濾過した。溶液の一部を室温で溶媒が蒸発するまで保存した。残渣を熱分析的に調べた。それは、表題化合物のTHFとの包接化合物に相当した。
実施例7.1
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約50mgを、Kofler 加熱ベンチ上、約240℃で溶融し、続いて衝撃冷却により室温にした。活性物質をX線回折法により調べた。それは、無定形で存在した。
変態Iの5−クロロ−N−({(5S)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミド約3gを、乾燥オーブン中、約250℃で溶融し、続いて衝撃冷却により室温にした。活性化合物をX線回折により調べた。それは、無定形で存在した。
ガラス転移温度:約83℃
Claims (11)
- NIRスペクトルにおいて4082、4142、4170、4228、4299、4376、4429、4479、4633、4791、4877、4907、5081、5760、5885、6002、6441、6564、8473および8833cm−1で最大ピークを示す変態Iの請求項1に記載の式(I)の化合物の結晶を、メタノール、エタノール、n−プロパノール、イソプロパノール、n−ブタノール、sec−ブタノール、イソブタノール、1−ペンタノール、ケトン、アルカン、テトラヒドロフラン、アセトニトリル、トルエン、酢酸エチルまたは1,4−ジオキサン、または、上述の溶媒の混合物、または、上述の溶媒の水との混合物に溶解し、n−へプタン、シクロヘキサンまたはトルエンの添加により化合物を沈殿させることを特徴とする、NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶の製造方法。
- NIRスペクトルにおいて4082、4142、4170、4228、4299、4376、4429、4479、4633、4791、4877、4907、5081、5760、5885、6002、6441、6564、8473および8833cm−1で最大ピークを示す変態Iの請求項1に記載の式(I)の化合物の結晶を、メタノール、エタノール、n−プロパノール、イソプロパノール、n−ブタノール、sec−ブタノール、イソブタノール、1−ペンタノール、ケトン、アルカン、テトラヒドロフラン、アセトニトリル、トルエン、酢酸エチルまたは1,4−ジオキサン、または、上述の溶媒の混合物、または、上述の溶媒の水との混合物に溶解し、溶媒の蒸発が完了するまで溶液を30℃から溶媒の還流温度までの温度で保存することを特徴とする、NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶の製造方法。
- 無定形の請求項1に記載の式(I)の化合物をn−へプタン、シクロヘキサンまたはトルエンに懸濁し、変態IIへの定量的転換まで懸濁液を撹拌または振盪することを特徴とする、NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶の製造方法。
- 疾患の処置および/または予防のための、NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶。
- 血栓塞栓性疾患の処置および/または予防用の医薬を製造するための、NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶の使用。
- インビトロで血液凝固を防止するための医薬を製造するための、NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶の使用。
- NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶を、不活性、非毒性の医薬的に適する補助剤と組み合わせて含む医薬。
- NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶を、さらなる活性物質と組み合わせて含む医薬。
- 血栓塞栓性疾患の処置および/または予防のための、請求項8または請求項9に記載の医薬。
- 抗凝血活性を有する量の、NIRスペクトルにおいて4086、4228、4418、4457、4634、4905、5846、5911、6026、6081および6582cm−1で最大ピークを示す変態IIの請求項1に記載の式(I)の化合物の結晶を添加することを特徴とする、インビトロで血液凝固を防止する方法。
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DE102005047563.9 | 2005-10-04 | ||
DE102005047564A DE102005047564A1 (de) | 2005-10-04 | 2005-10-04 | Amorphe Form von 5-Chlor-N-({(5S)2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl)-methyl)-2-thiophencarboxamid |
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DE102005047564.7 | 2005-10-04 | ||
PCT/EP2006/009202 WO2007039132A1 (de) | 2005-10-04 | 2006-09-22 | Neue polymorphe form und die amorphe form von 5-chlor-n- ( { ( 5s ) -2-0x0-3-[4-( 3-oxo-4-morpholinyl) - phenyl] -1,3-oxazolidin-5-yl} -methyl) -2- thiophencarboxamid |
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DE102005047558A1 (de) | 2005-10-04 | 2008-02-07 | Bayer Healthcare Ag | Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen |
DE102005047561A1 (de) | 2005-10-04 | 2007-04-05 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung |
DE102005048824A1 (de) | 2005-10-10 | 2007-04-12 | Bayer Healthcare Ag | Behandlung und Prophylaxe von Mikroangiopathien |
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