JP4516962B2 - カルボスチリル誘導体アミン塩 - Google Patents
カルボスチリル誘導体アミン塩 Download PDFInfo
- Publication number
- JP4516962B2 JP4516962B2 JP2006520510A JP2006520510A JP4516962B2 JP 4516962 B2 JP4516962 B2 JP 4516962B2 JP 2006520510 A JP2006520510 A JP 2006520510A JP 2006520510 A JP2006520510 A JP 2006520510A JP 4516962 B2 JP4516962 B2 JP 4516962B2
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- JP
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- Prior art keywords
- amine
- carbostyril derivative
- preparation
- acid
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001412 amines Chemical class 0.000 claims description 49
- 238000002360 preparation method Methods 0.000 claims description 44
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- 239000000825 pharmaceutical preparation Substances 0.000 claims description 22
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 22
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 15
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 claims description 12
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 11
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 10
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- 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
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Toxicology (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Quinoline Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
上記一般式(1)で示されるカルボスチリル誘導体及びその製法は特許文献1に記載されている。また該カルボスチリル誘導体がビスマスと塩を形成すること及びカルボン酸ビスマス錯体及びジアミン誘導体又はピペラジン誘導体の塩を形成することも知られている(特許文献2及び3)。しかし、これらの塩も水への溶解性が低い。
1.式(1)
カルボスチリル誘導体自体の解離を防止するために反応系内に塩酸等の酸を添加してもよい。
また、該カルボスチリル誘導体アミン塩は、塩として単離することなく、カルボスチリル誘導体の水溶性溶媒中の溶液にアミンを添加して、水溶性溶媒の溶液状態の製剤を製造するときに形成させてもよい。
炎症性疾患としては、炎症性角化症(乾癬など)、アトピー性皮膚炎、接触性皮膚炎等の炎症性皮膚疾患、慢性関節リウマチ、全身性エリトマトーテス(SLE)、ベーチェット病等の慢性炎症性疾患である自己免疫疾患、B型肝炎、C型肝炎、アルコール性肝炎、薬物アレルギー性肝炎等の炎症性肝疾患、腎炎、糸球体腎炎等の炎症性腎疾患、気管支炎等の炎症性呼吸器疾患、口内炎、喉頭炎、声帯炎、音声障害、人工臓器・人工血管使用時に起こる炎症、非ステロイド性消炎剤による消化管粘膜障害、腸粘膜障害などが挙げられるが、これらに限定されるものではない。
上記腸粘膜障害としては、単純性原発性小腸潰瘍、非特異性結腸潰瘍、非特異性炎症による潰瘍性大腸炎、クローン(Crohn)病等の原因不明のもの等があり、さらに感染、循環障害、膠原病、放射線、薬剤等が原因で起こる障害等を挙げることができる。
該ウレアーゼ阻害作用に基づき、本発明の化合物は、種々の細菌の増殖によりウレアーゼ活性が上昇し、アンモニアが産生することにより起こると考えられる疾患の予防、治療に有用であり、例えば、H.ピロリーの増殖によりアンモニアが産生して起こると考えられている胃粘膜障害等の予防、治療に利用され得る。また、腸管内のアンモニアの産生を抑制することにより高アンモニア血症および高アンモニア血症に伴う症状の改善、治療、具体的には肝炎、肝硬変等の肝疾患で起こる肝性脳症、精神神経障害、脳波異常、手指振戦の予防、治療に利用できる。
本発明の水性溶液製剤は、該カルボスチリル誘導体アミン塩を水、生理食塩水などの水性溶媒中に添加して調製される。また、用時調製用医薬製剤では、該カルボスチリル誘導体とアミンからなり、用時水性溶媒を添加して製剤中でカルボスチリル誘導体アミンを形成させて水性溶液製剤とすることができる。
本発明の医薬製剤の調製には、通常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤、香料、風味料、甘味料、着色料などの添加剤あるいは賦形剤を用いることもできる。また、樹脂などに配合して徐放性を高めて使用することもできる。本発明の製剤を眼疾患治療剤として用いる場合には、その適応症に応じて、眼適用製剤、例えば点眼剤、眼軟膏剤等の形に調製するのが特に好ましい。
なお、この場合等張性の注射溶液を調製するに充分な量の食塩、ブドウ糖あるいはD−マンニトール等を該治療剤中に含有せしめてもよく、また通常のポリソルベート80等の溶解補助剤、クエン酸、クエン酸ナトリウム、リン酸、乳酸等の緩衝剤、グリセリン等の無痛化剤などを、更に必要に応じて着色剤、保存剤、香料、風味剤、甘味剤などや他の医薬品を該治療剤中に含有せしめてもよい。
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・L−アルギニン塩
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(3.88g,10.5mmol)、L−アルギニン(2.00g,11.5mmol)のエタノール(200mL)懸濁液を30分間還流させた。水(20mL)を加えて還流を継続すると一時的に完全に溶解した。その後、還流下で析出物が生じた。加熱をやめて室温まで冷却後、さらに氷水で冷却した。析出物をヌッチェを用いてろ取し、それをヌッチェ上にてエタノールで洗浄した。50℃で20時間送風乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・L−アルギニン塩(5.38g,95%収率)を得た。
1H NMR (DMSO-d6) δ= 1.43 - 1.92 (4H, m), 2.95 - 3.85 (5H, m), 4.41 - 4.58 (1H, m), 6.42 (1H, s), 7.20 (1H, dd, J = 8.1, 7.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.47 (1H, dd, J = 8.2, 7.6 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.81 (2H, d, J = 8.4 Hz), 7.96 (1H, d, J = 8.1 Hz), 8.34 ppm (1H, d, J = 8.2 Hz).
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・L−リジン塩
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(1.94g,5.23mmol)、L−リジン(0.84g,5.76mmol)のエタノール(100mL)懸濁液を30分間還流させた。水(25mL)を加えて還流を継続すると反応生成物は完全に溶解した。その後、還流下で析出物が生じた。加熱をやめて室温まで冷却後、さらに氷水で冷却した。析出物をヌッチェを用いてろ取し、それをヌッチェ上にてエタノールで洗浄した。60℃で終夜送風乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・L−リジン塩(1.46g,54%収率)を得た。
1H NMR (DMSO-d6) δ= 1.18 - 1.80 (6H, m), 2.74 (2H, br.d, J = 6.7 Hz), 3.08 (1H, br.dd, J = 13.6, 9.8 Hz), 3.29 (1H, br.t, J = 5.8 Hz), 3.43 - 3.59 (1H, m), 4.48 (1H, br.ddd, J = 9.8, 8.0, 3.6 Hz), 6.44 (1H, s), 7.18 (1H, dd, J = 8.1, 7.5 Hz), 7.31 (1H, d, J = 7.9 Hz), 7.45 (1H, dd, J = 7.9, 7.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.81 (2H, d, J = 8.5 Hz), 7.96 (1H, d, J = 8.1 Hz), 8.40 ppm (1H, d, J = 8.0 Hz)
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・1/2エチレンジアミン塩
(A):2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(2.00g,5.39mmol)、エチレンジアミン(0.18mL,2.69mmol)のエタノール(100mL)懸濁液を30分間還流させた。水を5mLずつ溶解するまで加えた。全部で35mLの水を加えた時点で完全に溶解した。その後、加熱をやめて室温まで冷却すると結晶が析出した。反応混合物をさらに氷水で冷却後、析出物をヌッチェを用いてろ取し、60℃で送風乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・1/2エチレンジアミン塩(1.92g,89%収率)を得た。
(B):2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(2.00g,5.39mmol)、エチレンジアミン(0.40mL,5.98mmol)のエタノール(100mL)懸濁液を30分間還流させた。水を5mLずつ反応生成物が溶解するまで加えた。全部で25mLの水を加えた時点で、反応生成物は完全に溶解した。その後、加熱をやめて室温まで冷却したが結晶が析出しなかったため溶媒を減圧で留去した。残渣にエタノール(50mL)を加えて還流下で分散洗浄後、室温まで冷却した。結晶をヌッチェを用いてろ取し、60℃で送風乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・1/2エチレンジアミン塩(1.96g,91%収率)を得た。
1H NMR (DMSO-d6) δ= 2.87 (2H, s), 3.11 (1H, br.dd, J = 13.9, 9.8 Hz), 3.52 (1H, br.dd, J = 13.9, 3.5 Hz), 4.50 - 4.57 (1H, m), 6.41 (1H, s), 7.20 (1H, dd, J = 8.0, 7.6 Hz), 7.30 (1H, d, J = 7.5 Hz), 7.48 (1H, dd, J = 8.0, 7.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.80 (2H, d, J = 8.5 Hz), 7.93 (1H, d, J = 7.6 Hz), 8.40 ppm (1H, d, J = 8.0 Hz).
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・トリス(ヒドロキシメチル)アミノメタン塩
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(2.00g,5.39mmol)、トリス(ヒドロキシメチル)アミノメタン(0.72g,5.94mmol)のエタノール(100mL)懸濁液を30分間還流させた。水を5〜10mLずつ反応生成物が溶解するまで加えた。全部で40mLの水を加えた時点で、反応生成物は完全に溶解した。その後、加熱をやめて室温まで冷却、さらに氷水で冷却したものの結晶が析出しなかったため溶媒を減圧で留去した。残渣にエタノールを加え、該混合物を減圧濃縮した。残渣にエタノール(50mL)を加えて室温下撹拌した。析出物をヌッチェを用いてろ取し、60℃で送風乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・トリス(ヒドロキシメチル)アミノメタン塩(2.58g,97%収率)を得た。
1H NMR (DMSO-d6) δ= 3.07 (1H, br.dd, J = 13.8, 10.1 Hz), 3.47 (6H, s), 3.54 (1H, br.dd, J = 13.9, 3.3 Hz), 4.49 - 4.56 (1H, m), 6.41 (1H, s), 7.21 (1H, dd, J = 8.1, 7.7 Hz), 7.31 (1H, d, J = 7.5 Hz), 7.45 (1H, dd, J = 8.1, 7.5 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.81 (2H, d, J = 8.5 Hz), 7.94 (1H, d, J = 7.7 Hz), 8.38 ppm (1H, d, J = 8.3 Hz).
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・ジエタノールアミン塩
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(2.00g,5.39mmol)、ジエタノールアミン(0.62g,5.90mmol)のエタノール(100mL)懸濁液を30分間還流させた。水を加えなくても反応生成物は完全に溶解した。その後、加熱をやめて該混合物を室温まで冷却、さらに氷水で冷却した。生じた析出物をヌッチェを用いてろ取し、60℃で送風乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・ジエタノールアミン塩(1.95g,76%収率)を得た。
1H NMR (DMSO-d6) δ= 2.89 (4H, t, J = 5.4 Hz), 3.10 (1H, br.dd, J = 13.9, 9.9 Hz), 3.52 (1H, br.dd, J = 13.9, 3.6 Hz), 3.61 (4H, t, J = 5.4 Hz), 4.50 - 4.56 (1H, m), 6.41 (1H, s), 7.21 (1H, dd, J = 8.1, 7.6 Hz), 7.31 (1H, d, J = 7.5 Hz), 7.48 (1H, dd, J = 8.1, 7.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.81 (2H, d, J = 8.5 Hz), 7.94 (1H, d, J = 7.6 Hz), 8.44 ppm (1H, d, J = 8.2 Hz).
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・ジイソプロパノールアミン塩
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(2.00g,5.39mmol)、ジイソプロパノールアミン(0.79g,5.93mmol)のエタノール(100mL)懸濁液を30分間還流させた。水を加えなくても完全に溶解した。その後、加熱をやめて室温まで冷却、さらに氷水で冷却した。析出物をヌッチェを用いてろ取し、60℃で送風乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・ジイソプロパノールアミン塩(1.66g,61%収率)を得た。
1H NMR (DMSO-d6) δ= 1.07 (3H, d, J = 6.2 Hz), 1.13 (3H, d, J = 6.2 Hz), 2.54 - 2.68 (2H, m), 2.77 (2H, dd, J = 12.2, 3.5 Hz), 3.08 - 3.18 (1H, m), 3.43 - 3.56 (1H, m), 3.75 - 3.92 (2H, m), 4.47 - 4.60 (1H, m), 6.41 (1H, s), 7.21 (1H, dd, J = 8.0, 7.7 Hz), 7.30 (1H, d, J = 7.5 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.81 (2H, d, J = 8.6 Hz), 7.93 (1H, d, J = 7.7 Hz), 8.48 ppm (1H, d, J = 8.1 Hz).
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・メグルミン塩
2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸(3.7g,10mmol)に1mol/Lメグルミン水溶液(10mL,10mmol)を加え、50℃で加熱溶解させた。これにメグルミンと塩酸の等モル混合水溶液(0.5mol/L;20mL)を添加した後に冷却した。析出物をろ取し、水洗後に室温で減圧乾燥して、白色晶として2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸・メグルミン塩(0.9g,16%収率)を得た。
1H NMR (DMSO-d6) δ= 2.82 - 3.14 (3H, m), 3.37 - 3.73 (6H, m), 3.82 - 3.94 (1H, m), 4.52 (1H, ddd, J = 9.6, 8.2, 3.5 Hz), 6.41 (1H, s), 7.20 (1H, dd, J = 8.0, 7.2 Hz), 7.30 (1H, d, J = 7.8 Hz), 7.48 (1H, dd, J = 7.8, 7.2 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.80 (2H, d, J = 8.5 Hz), 7.94 (1H, d, J = 8.0 Hz), 8.37 ppm (1H, d, J = 8.2 Hz).
25℃水に対する溶解度試験
化合物A:2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸
<試料溶液の調製>
上記実施例1〜7で得られた塩0.5gを50mL遠沈管にとり、水5mLを加え、25℃の恒温槽中、振とう機で3時間振とうした(メグルミン塩については、5日間)。振とう後、該混合物を0.45μm(メグルミン塩については、0.2μm)のメンブランフィルターで濾過した。ろ液1mLを正確にとり、50%DMFを加えて正確に50mLとした。この液2mLを正確にとり、50%DMFを加えて正確に20mLとし、試料溶液とした。
<標準溶液の調製>
化合物A0.01gにジメチルホルムアミド(DMF)5mLを加えて溶かし、50%DMFを加えて正確に100mLとし、標準溶液(1)とした。標準溶液(1)5mLを正確にとり、50%DMFを加えて正確に10mLとし、標準溶液(2)とした。標準溶液(1)1mLを正確にとり、50%DMFを加えて正確に10mLとし、標準溶液(3)とした。標準溶液(3)1mLを正確にとり、50%DMFを加えて正確に10mLとし、標準溶液(4)とした。
<クロマトグラフィ>
試料溶液及び標準溶液10μLにつき、次の試験条件により、液体クロマトグラフ法により試験を行った。標準溶液(1)〜(4)より得られた化合物Aのピーク面積と化合物Aの濃度で検量線を作成し、この検量線を用いて、試料溶液の化合物Aのピーク面積より試料溶液の化合物A濃度を算出し、希釈倍率で補正して、各種塩の溶解度(%)をもとめた。
塩を取りだすことなく用時調製での25℃に対する溶解度試験
化合物Aに各アミンを等モル加え、全溶解しない範囲で水を添加し、25℃の恒温槽中で7日間振とうした。その後アルギニン添加試料については懸濁液を0.2μmのメンブランフィルターでろ過した。リジン、ジイソプロパノールアミン、メグルミン、モノエタノールアミンおよびジエタノールアミンが加えられた試料については、溶液部分が固化してろ過できなかったため、ろ過が可能になるまでさらに水を加えた後0.2μmのメンブランフィルターでろ過した。実施例8と同様にしてHPLCを用いて各種塩の溶解度(%)をもとめた。
本発明化合物、アビセル、コーンスターチおよびステアリン酸マグネシウムを混合粉砕後、糖衣R10mmの杵で打錠した。得られた錠剤をヒドロキシプロピルメチルセルロース、ポリエチレングリコール−6000、ヒマシ油およびメタノールからなるフィルムコーティング剤で被覆を行ないフィルムコーティング錠を製造した。
Claims (19)
- 2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸と、
L−アルギニン、L−リジン、エチレンジアミン、トリス(ヒドロキシメチル)アミノメタン、モノエタノールアミン、ジエタノールアミン、ジイソプロパノールアミンおよびメグルミンからなる群から選ばれるアミンから形成されるカルボスチリル誘導体アミン塩。 - 該アミンが、L−アルギニンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 該アミンが、L−リジンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 該アミンが、エチレンジアミンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 該アミンが、トリス(ヒドロキシメチル)アミノメタンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 該アミンが、モノエタノールアミンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 該アミンが、ジエタノールアミンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 該アミンが、ジイソプロパノールアミンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 該アミンが、メグルミンである請求項1に記載のカルボスチリル誘導体アミン塩。
- 請求項1〜9のいずれか1つに記載のカルボスチリル誘導体アミン塩を有効成分とする医薬製剤。
- 2−(4−クロロベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸と、
L−アルギニン、L−リジン、エチレンジアミン、トリス(ヒドロキシメチル)アミノメタン、モノエタノールアミン、ジエタノールアミン、ジイソプロパノールアミンおよびメグルミンからなる群から選ばれるアミンからなり、用時水性溶媒を添加して水性溶液製剤とする用時調製用医薬製剤。 - 該アミンが、L−アルギニンである請求項11に記載の用時調製用医薬製剤。
- 該アミンが、L−リジンである請求項11に記載の用時調製用医薬製剤。
- 該アミンが、エチレンジアミンである請求項11に記載の用時調製用医薬製剤。
- 該アミンが、トリス(ヒドロキシメチル)アミノメタンである請求項11に記載の用時調製用医薬製剤。
- 該アミンが、モノエタノールアミンである請求項11に記載の用時調製用医薬製剤。
- 該アミンが、ジエタノールアミンである請求項11に記載の用時調製用医薬製剤。
- 該アミンが、ジイソプロパノールアミンである請求項11に記載の用時調製用医薬製剤。
- 該アミンが、メグルミンである請求項11に記載の用時調製用医薬製剤。
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JP2004013402 | 2004-01-21 | ||
PCT/JP2005/001034 WO2005070892A1 (en) | 2004-01-21 | 2005-01-20 | Amine salt of carbostyril derivative |
Publications (2)
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JP2007514641A JP2007514641A (ja) | 2007-06-07 |
JP4516962B2 true JP4516962B2 (ja) | 2010-08-04 |
Family
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JP2006520510A Active JP4516962B2 (ja) | 2004-01-21 | 2005-01-20 | カルボスチリル誘導体アミン塩 |
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US (2) | US7732611B2 (ja) |
EP (2) | EP2253619B1 (ja) |
JP (1) | JP4516962B2 (ja) |
KR (1) | KR100844762B1 (ja) |
CN (1) | CN1934086B (ja) |
AR (1) | AR047438A1 (ja) |
AT (1) | ATE549318T1 (ja) |
AU (1) | AU2005206430B2 (ja) |
BR (1) | BRPI0506982A (ja) |
CA (1) | CA2553231C (ja) |
CY (2) | CY1112723T1 (ja) |
DK (2) | DK1706383T3 (ja) |
ES (2) | ES2544327T3 (ja) |
HK (2) | HK1101327A1 (ja) |
HU (1) | HUE027990T2 (ja) |
MY (1) | MY148416A (ja) |
PL (2) | PL1706383T3 (ja) |
PT (2) | PT1706383E (ja) |
RU (1) | RU2372336C2 (ja) |
SG (1) | SG149854A1 (ja) |
SI (2) | SI2253619T1 (ja) |
TW (1) | TWI340650B (ja) |
WO (1) | WO2005070892A1 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US6187197B1 (en) * | 1998-10-28 | 2001-02-13 | Marvin Haddock | Multi-stage engine coolant recycling process |
TWI340650B (en) * | 2004-01-21 | 2011-04-21 | Otsuka Pharma Co Ltd | Amine saly of carbostyril derivative |
KR101551506B1 (ko) * | 2007-08-10 | 2015-09-08 | 오츠카 세이야쿠 가부시키가이샤 | 레바미피드를 함유하는 의약 조성물 |
US9486418B2 (en) * | 2008-04-08 | 2016-11-08 | Dynamis Pharmaceuticals, Inc. | Method for treating or preventing dry eye disorders using alkylamino-polyhydroxyalkanes |
PL2285413T3 (pl) * | 2008-06-19 | 2013-01-31 | Otsuka Pharma Co Ltd | Kompozycja farmaceutyczna |
WO2012114317A1 (en) * | 2011-02-25 | 2012-08-30 | Nuformix Limited | Novel rebamipide complexes and cocrystals |
Family Cites Families (16)
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JPS517614Y2 (ja) | 1971-02-12 | 1976-03-01 | ||
JPS597168A (ja) | 1982-07-05 | 1984-01-14 | Otsuka Pharmaceut Co Ltd | カルボスチリル誘導体 |
US4578381A (en) * | 1982-07-05 | 1986-03-25 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
KR0180248B1 (ko) * | 1991-06-07 | 1999-03-20 | 오오쓰까 아끼히꼬 | 항당뇨병약품 |
TW227558B (ja) * | 1992-05-14 | 1994-08-01 | Otsuka Pharma Co Ltd | |
US5415872A (en) * | 1992-06-22 | 1995-05-16 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing salts of bile acids |
JP2872546B2 (ja) * | 1992-11-26 | 1999-03-17 | 大塚製薬株式会社 | 腸粘膜障害保護剤 |
JP2839847B2 (ja) * | 1993-10-21 | 1998-12-16 | 大塚製薬株式会社 | インターロイキン−8産生抑制剤 |
WO1995012579A1 (en) | 1993-11-05 | 1995-05-11 | Otsuka Pharmaceutical Company, Limited | Bismuth salt of carbostyril derivatives for the treatment of peptic ulcers |
JP3621463B2 (ja) | 1995-04-26 | 2005-02-16 | 大塚製薬株式会社 | カルボスチリル誘導体ビスマス塩 |
AR004214A1 (es) * | 1995-10-12 | 1998-11-04 | Otsuka Pharma Co Ltd | Una preparación de gotas oftálmicas para la cura de enfermedades oftálmicas |
GB9613455D0 (en) | 1996-06-27 | 1996-08-28 | Aston Molecules Ltd | Analogues or derivatives of quercetin |
AU2003214112A1 (en) | 2002-03-11 | 2003-09-22 | Novartis Ag | Salts of nateglinide |
KR20040104020A (ko) | 2003-06-02 | 2004-12-10 | 진양제약주식회사 | 신규 레바미피드 리지네이트와 레바미피드 아르기니네이트및 이 신규 레바미피드 리지네이트와 레바미피드아르기니네이트를 유효성분으로 함유하는 약학적 제제 |
TWI340650B (en) * | 2004-01-21 | 2011-04-21 | Otsuka Pharma Co Ltd | Amine saly of carbostyril derivative |
JP4719917B2 (ja) | 2007-03-30 | 2011-07-06 | 国立大学法人 岡山大学 | アズキ加工食品のアズキ原料品種判定方法 |
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