JP2006151977A - (r)−3−[[(4−フルオロフェニル)スルホニル]アミノ]−1,2,3,4−テトラヒドロ−9h−カルバゾール−9−プロパン酸(ラマトロバン)の熱力学的に安定な形態の結晶の製造方法 - Google Patents
(r)−3−[[(4−フルオロフェニル)スルホニル]アミノ]−1,2,3,4−テトラヒドロ−9h−カルバゾール−9−プロパン酸(ラマトロバン)の熱力学的に安定な形態の結晶の製造方法 Download PDFInfo
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- JP2006151977A JP2006151977A JP2005340586A JP2005340586A JP2006151977A JP 2006151977 A JP2006151977 A JP 2006151977A JP 2005340586 A JP2005340586 A JP 2005340586A JP 2005340586 A JP2005340586 A JP 2005340586A JP 2006151977 A JP2006151977 A JP 2006151977A
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- Prior art keywords
- ramatroban
- modification
- thermodynamically stable
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/06—Antiasthmatics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/08—Antiallergic agents
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- 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
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
【解決手段】 ラマトロバンの熱力学的に安定な形態の結晶は、ラマトロバンを融解させ、続いて再結晶するか、或いははラマトロバンの溶液又はラマトロバンの準安定な形態の結晶の懸濁液に熱力学的に安定な形態の種晶を種晶添加することにより製造される。
【選択図】 なし
Description
518において開示されている。
融解物からの種晶の製造
約300mgの変態IIのラマトロバンを十分に融解させ、急速に室温に冷却する。非晶質物質を5mlのエタノール/水(1:1)中に懸濁させ、懸濁液を室温で24時間撹拌する。撹拌時間の最後に懸濁液を濾過し、残留物を室温で真空中において乾燥することにより、融点が151℃のラマトロバンの種晶が得られる。
種晶添加法
130gのラマトロバン(変態II)を650gの酢酸n−ブチル及び15gの水中に約40℃で溶解する。175gの溶媒を真空中において40〜45℃で蒸留する。次いで溶液に1gのラマトロバン(変態I)を種晶添加し、さらに300gの溶媒を真空中において40〜45℃で蒸留する。得られる結晶懸濁液を室温に冷却し、数時間撹拌する。それを吸引濾過し、酢酸n−ブチル及びメチルtert−ブチルエーテルで洗浄し、真空中において50℃で乾燥する。約100gのラマトロバンが得られる(変態I)。
沈殿法
75gのラマトロバン(変態II)を温めながら135gの酢酸エチル中に溶解する。85gの石油エーテル(35/60)を約40℃で滴下し、バッチに1gのラマトロバン(変態I)を種晶添加する。混合物を40℃において約2〜3時間撹拌し、次いで室温に冷却する。さらに130gの石油エーテル(35/60)を懸濁液に加え、それをさらに室温で約5時間撹拌する。それを吸引濾過し、100gの石油エーテル(35/60)で洗浄し、50℃において真空中で乾燥する。約65gのラマトロバン(変態I)が得られる。
懸濁液における転換1
50gのラマトロバン(変態II)を75gの酢酸n−ブチル中に懸濁させ、0.5gのラマトロバン(変態I)と混合する。混合物を室温で約100時間撹拌する。次いでそれを吸引濾過し、メチルtert−ブチルエーテルで洗浄し、50℃において真空中で乾燥する。約40gのラマトロバン(変態I)が得られる。
懸濁液における転換2
約0.5gの変態I及びII(混合比は約1:1)を8mlのn−ヘプタン中に懸濁させ、約80℃において還流させる。1週間後に懸濁液を濾過し、残留物を真空中で室温において1日間乾燥する。
錠剤の製造
4590gの変態Iの極微細ラマトロバンをホモジナイザーにおいて9180gの水性HPC−L(367g)を用いて分散させ、次いで355imのメッシュ幅を有する篩を介して濾過する。顆粒化液をグラニュレーターにおいて、3162gのラクトース、4860gのHPC−L及び540gのHPC−Mを含む13,500gの予備混合され且つ予備加熱された水溶液と反応させ、顆粒を形成する。得られる顆粒を65℃において乾燥する。次いで回転式プレスにおいて加圧成形を行い、9.0mmの直径を有する錠剤を得る。
Claims (2)
- ラマトロバンを融解及び急速な冷却によりその非晶質形に転換し、次いでこれを不活性溶媒中において撹拌することにより熱力学的に安定な形態の結晶に転換することを特徴とする、151℃の融点(DSC、2K分−1)を有するラマトロバンの熱力学的に安定な形態の種晶の製造方法。
- ラマトロバンの熱力学的に準安定な形態の結晶を水又は不活性有機溶媒中に懸濁させ、熱力学的に安定な形態の結晶を種晶添加し、所望の程度の転換が達成されるまで転換を行うことを特徴とする、151℃の融点(DSC、2K分−1)を有するラマトロバンの熱力学的に安定な形態の結晶の製造方法。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19757983A DE19757983A1 (de) | 1997-12-24 | 1997-12-24 | Thermodynamisch stabile Form von (r)-3[[(4-Fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-0-propansäure (Ramatroban) |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000526487A Division JP3817668B2 (ja) | 1997-12-24 | 1998-12-24 | (r)−3−[[(4−フルオロフェニル)スルホニル]アミノ]−1,2,3,4−テトラヒドロ−9h−カルバゾール−9−プロパン酸(ラマトロバン)の熱力学的に安定な形態 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2006151977A true JP2006151977A (ja) | 2006-06-15 |
JP4411269B2 JP4411269B2 (ja) | 2010-02-10 |
Family
ID=7853457
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000526487A Expired - Lifetime JP3817668B2 (ja) | 1997-12-24 | 1998-12-24 | (r)−3−[[(4−フルオロフェニル)スルホニル]アミノ]−1,2,3,4−テトラヒドロ−9h−カルバゾール−9−プロパン酸(ラマトロバン)の熱力学的に安定な形態 |
JP2005340586A Expired - Lifetime JP4411269B2 (ja) | 1997-12-24 | 2005-11-25 | (r)−3−[[(4−フルオロフェニル)スルホニル]アミノ]−1,2,3,4−テトラヒドロ−9h−カルバゾール−9−プロパン酸(ラマトロバン)の熱力学的に安定な形態の結晶の製造方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000526487A Expired - Lifetime JP3817668B2 (ja) | 1997-12-24 | 1998-12-24 | (r)−3−[[(4−フルオロフェニル)スルホニル]アミノ]−1,2,3,4−テトラヒドロ−9h−カルバゾール−9−プロパン酸(ラマトロバン)の熱力学的に安定な形態 |
Country Status (37)
Country | Link |
---|---|
US (1) | US6362214B1 (ja) |
EP (1) | EP1051398B1 (ja) |
JP (2) | JP3817668B2 (ja) |
KR (1) | KR100586350B1 (ja) |
CN (1) | CN1140510C (ja) |
AR (1) | AR013803A1 (ja) |
AT (1) | ATE263152T1 (ja) |
AU (1) | AU744242B2 (ja) |
BG (1) | BG65024B1 (ja) |
BR (1) | BR9814496A (ja) |
CA (1) | CA2313230A1 (ja) |
CO (1) | CO4970800A1 (ja) |
DE (2) | DE19757983A1 (ja) |
DK (1) | DK1051398T3 (ja) |
ES (1) | ES2218874T3 (ja) |
GT (1) | GT199800198A (ja) |
HK (1) | HK1034517A1 (ja) |
HN (1) | HN1998000186A (ja) |
HU (1) | HUP0004432A3 (ja) |
ID (1) | ID25446A (ja) |
IL (1) | IL136278A (ja) |
IN (1) | IN192932B (ja) |
MY (1) | MY116312A (ja) |
NO (1) | NO316618B1 (ja) |
NZ (1) | NZ504741A (ja) |
PE (1) | PE20000115A1 (ja) |
PL (1) | PL341359A1 (ja) |
PT (1) | PT1051398E (ja) |
RU (1) | RU2220137C2 (ja) |
SI (1) | SI1051398T1 (ja) |
SK (1) | SK285109B6 (ja) |
TR (1) | TR200001936T2 (ja) |
TW (1) | TW552258B (ja) |
UA (1) | UA66832C2 (ja) |
UY (2) | UY25324A1 (ja) |
WO (1) | WO1999033803A1 (ja) |
ZA (1) | ZA9811817B (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE543501T1 (de) * | 2006-12-20 | 2012-02-15 | Cardoz Ab | Kombination von pemirolast und ramatroban zur verwendung bei der behandlung von entzündlichen erkrankungen |
EP2104534A1 (en) * | 2007-01-16 | 2009-09-30 | Cardoz AB | New combination for use in the treatment of inflammatory disorders |
WO2009007674A2 (en) * | 2007-07-11 | 2009-01-15 | Cardoz Ab | Combination for use in the treatment of atherosclerosis comprising a mast cell inhibitor and ramatroban or seratrodast |
CN101434571B (zh) * | 2007-11-13 | 2012-05-30 | 杭州容立医药科技有限公司 | 环烷并[1,2-b]吲哚磺酰胺、其异构体或其盐的合成方法 |
WO2011115069A1 (ja) * | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | 結晶の網羅的探索 |
CN103054857A (zh) * | 2012-12-30 | 2013-04-24 | 北京阜康仁生物制药科技有限公司 | 一种以雷马曲班为活性成分的固体制剂 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3631824A1 (de) | 1986-02-21 | 1988-03-31 | Bayer Ag | Cycloalkano(1.2-b)indol-sulfonamide |
CN1015711B (zh) * | 1986-02-21 | 1992-03-04 | 拜尔公司 | 制备环烷并[1,2-b]吲哚-磺酰胺类化合物的方法 |
DE19506739A1 (de) | 1995-02-27 | 1996-08-29 | Bayer Ag | [3-Amino]-tetrahydrocarbazol-propansäureester |
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- 1997-12-24 DE DE19757983A patent/DE19757983A1/de not_active Withdrawn
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- 1998-12-09 HN HN1998000186A patent/HN1998000186A/es unknown
- 1998-12-11 AR ARP980106318A patent/AR013803A1/es unknown
- 1998-12-15 GT GT199800198A patent/GT199800198A/es unknown
- 1998-12-22 PE PE1998001272A patent/PE20000115A1/es not_active Application Discontinuation
- 1998-12-22 MY MYPI98005837A patent/MY116312A/en unknown
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- 1998-12-23 CO CO98076459A patent/CO4970800A1/es unknown
- 1998-12-23 ZA ZA9811817A patent/ZA9811817B/xx unknown
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- 1998-12-24 RU RU2000119741/04A patent/RU2220137C2/ru not_active IP Right Cessation
- 1998-12-24 ES ES98961506T patent/ES2218874T3/es not_active Expired - Lifetime
- 1998-12-24 DE DE69822882T patent/DE69822882T2/de not_active Expired - Fee Related
- 1998-12-24 SI SI9830656T patent/SI1051398T1/xx unknown
- 1998-12-24 AT AT98961506T patent/ATE263152T1/de not_active IP Right Cessation
- 1998-12-24 IN IN43MU2000 patent/IN192932B/en unknown
- 1998-12-24 TR TR2000/01936T patent/TR200001936T2/xx unknown
- 1998-12-24 BR BR9814496-0A patent/BR9814496A/pt not_active Application Discontinuation
- 1998-12-24 AU AU16874/99A patent/AU744242B2/en not_active Ceased
- 1998-12-24 KR KR1020007007031A patent/KR100586350B1/ko not_active IP Right Cessation
- 1998-12-24 WO PCT/JP1998/005844 patent/WO1999033803A1/en not_active Application Discontinuation
- 1998-12-24 EP EP98961506A patent/EP1051398B1/en not_active Expired - Lifetime
- 1998-12-24 JP JP2000526487A patent/JP3817668B2/ja not_active Expired - Lifetime
- 1998-12-24 CN CNB98812405XA patent/CN1140510C/zh not_active Expired - Fee Related
- 1998-12-24 SK SK975-2000A patent/SK285109B6/sk unknown
- 1998-12-24 DK DK98961506T patent/DK1051398T3/da active
- 1998-12-24 US US09/582,250 patent/US6362214B1/en not_active Expired - Fee Related
- 1998-12-24 CA CA002313230A patent/CA2313230A1/en not_active Abandoned
- 1998-12-24 NZ NZ504741A patent/NZ504741A/xx unknown
- 1998-12-24 HU HU0004432A patent/HUP0004432A3/hu unknown
- 1998-12-24 IL IL13627898A patent/IL136278A/xx not_active IP Right Cessation
- 1998-12-24 PL PL98341359A patent/PL341359A1/xx not_active Application Discontinuation
- 1998-12-24 ID IDW20001226A patent/ID25446A/id unknown
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1999
- 1999-06-18 UY UY25575A patent/UY25575A1/es unknown
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2000
- 2000-06-21 NO NO20003217A patent/NO316618B1/no unknown
- 2000-06-23 BG BG104554A patent/BG65024B1/bg unknown
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2001
- 2001-07-27 HK HK01105260A patent/HK1034517A1/xx not_active IP Right Cessation
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- 2005-11-25 JP JP2005340586A patent/JP4411269B2/ja not_active Expired - Lifetime
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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EXPY | Cancellation because of completion of term |