JP5336509B2 - (r)−3−フルオロフェニル−3,4,5−トリフルオロベンジルカルバミン酸1−アザビシクロ[2.2.2]オクト−3−イルエステルの安定な結晶性塩 - Google Patents
(r)−3−フルオロフェニル−3,4,5−トリフルオロベンジルカルバミン酸1−アザビシクロ[2.2.2]オクト−3−イルエステルの安定な結晶性塩 Download PDFInfo
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- JP5336509B2 JP5336509B2 JP2010535281A JP2010535281A JP5336509B2 JP 5336509 B2 JP5336509 B2 JP 5336509B2 JP 2010535281 A JP2010535281 A JP 2010535281A JP 2010535281 A JP2010535281 A JP 2010535281A JP 5336509 B2 JP5336509 B2 JP 5336509B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- 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
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
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- Engineering & Computer Science (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明は、(R)−3−フルオロフェニル−3,4,5−トリフルオロベンジルカルバミン酸1−アザビシクロ[2.2.2]オクト−3−イルエステルの安定な結晶性塩、および特に、切迫尿失禁、または尿生殖器障害を伴うその他の疾患の治療を含む医療用の、この塩の医薬処方物に関する。
WO0200652号公報は、下記式(I)を有する化合物I((R)−3−フルオロフェニル−3,4,5−トリフルオロベンジルカルバミン酸1−アザビシクロ[2.2.2]オクト−3−イルエステル)を開示している。
1H−NMRおよび13C−NMRスペクトルはBruker ARX 400装置にて、それぞれ400MHおよび100.61MHで記録した。ジメチルスルホキシド(99.8%D)を溶媒として用い、テトラメチルシラン(TMS)を内部参照標準として用いた。
実施例1:(R)−3−フルオロフェニル−3,4,5−トリフルオロベンジルカルバミン酸1−アザビシクロ[2.2.2]オクト−3−イルエステル(化合物I)の合成
中間体2:(R)−イミダゾール−1−カルボン酸1−アザビシクロ[2.2.2]オクト−3−イルエステル
IR(KBr,cm-1):1746
1H-NMR: 1.33-1.43 (m, 1 H); 1.47-1.57 (m, 1 H); 1.58-1.70 (m, 1 H); 1.75-1.87 (m, 1 H); 2.07-2.12 (m, 1 H); 2.56-2.90 (m, 5H); 3.18 (ddd, J=14.5, J=8, J=2, 1 H); 4.95-5.00 (m, 1 H); 7.07 (s, 1 H); 7.61 (s, 1 H); 8.29 (s, 1 H).
13C-NMR: 18.9; 23.7; 24.9; 45.7; 46.6; 54.1; 75.7; 117.3; 130.1 ; 137.1 ; 147.9.
1H-NMR: 4.29 (s, 2H); 4.33 (br, 1 H), 6.28 (dtd, J=11 , J=2.5 ; J= 1 , 1 H), 6.40 (ddd, J=8.5 ; J=2, J=1 , 1 H), 6.46 (tdt, J=8,5 ; J=2,5, J=1 ); 7.24 (dd, J=8 ; J=7, 2H); 7.14 (tdd, J= 8 ; J=6.5, J=1).
13C-NMR: 47.1 ; 99.9 (d, J= 25.5); 104.8 (d, J= 21); 109.1 (d, J= 2); 111.0 (d, J= 10.5); 111.0 (d, J= 21.5); 149.4 (dd, J= 1 1 , J=1 ); 136.0 (tdd, J=6, J=4, J=2); 139.0 (dt, J= 248, J=5); 151.6 (ddd, J= 248, J=10, J=4); 164.3 (d, J=241).
−10℃に冷却した17LのTHF中、2.72Kgの中間体(1)の溶液に、不活性雰囲気下でゆっくり(2時間)3Kgのヘキシルリチウム(ヘキサン中33%)を加え、得られた混合物を−10℃で1時間攪拌した。次に、−10℃で、23LのTHF中、2.41Kgの中間体2をゆっくり加えた(75分)。得られた混合物を2時間攪拌し、室温まで上げた後に水を加え、溶液をメチルtertブチルエーテルで抽出した。有機相を無水硫酸ナトリウムで乾燥させ、溶媒を減圧下で除去し、3.6kgの標題化合物を橙色油状物として得た。
60℃にて、エタノール(3L)中、3Kgの(R)−3−フルオロフェニル−3,4,5−トリフルオロベンジルカルバミン酸1−アザビシクロ[2.2.2]オクト−3−イルエステル(化合物I)の溶液に、60℃に温めた30Lのエタノール中、1.1KgのD−酒石酸を加え、得られた混合物1時間攪拌した後、室温より低い温度まで冷却し、この温度で1時間維持した。沈殿を濾去し、濾過ケーキをエタノール(8L)で洗浄した。この濾過ケーキをほとんどの溶媒が無くなるまで吸引し、生成物を16時間45℃で乾燥させた。3.5kgの標題化合物を白色結晶性固体として得た。
1H-NMR: 1.45-1.49 (m, 2H) 1.65-1.75 (m, 2H)1 2.05 (m, 1 H); 2.87-3.01 (m, 3H); 3.07-3.1 1 (m, 1 H); 3.08-3.11 (d, J=14, 1 H); 3.39-3.45 (ddd, J=M, J=8, 5 J=2, 1 H); 4.00 (s, 2H); 4.83-4.89 (m, 1 H); 4.84-4.89 (d, J=16.5, 1 H); 4.93^.97 (d, J=16.5, 1 H); 7.05 (td, J=8.5 ; J=2, 1 H); 7.21 (dd, J=8 ; J=1.5, 1 H); 7.24 (dd, J=8.5 ; J=7, 2H), 7.33-7.38 (m, 2H).
13C-NMR: 17.1 ; 20.4; 24.0; 44.5; 45.1 ; 51.6; 52.7; 69.5 ; 72.1 ; 111.8 (d, J= 19.5); 10 113.4 (d, J= 20.5); 114.1 (d, J= 22); 122.6; 130.3 (d, J= 9); 135.1 ; 137.8 (dt, J= 246, J= 16); 142.6 (d, J= 9); 150.2 (ddd, J= 246, J= 9.5, J= 3.5); 154.0; 161.9 (d, J=242); 174.7
元素分析 C25H26F4N2O8の理論値:C,53.77;H,4.69;N,5.02。測定値:C,53.63;H,4.73;N,5.01
形態I(実施例I)をDSCにて以下のように処理した:蓋無しパン(STGF)、0.0295g、25〜143.5℃、2℃/分、130℃までスキャンダウン、15分間等温保持、25℃まで冷却。
0.49gの形態Iを1mLの水に懸濁させた後、10分間(溶解するまで)20℃で振盪したところ、2時間後、サンプルは粘稠となった。
0.522gの形態Iを1mLの無水EtOHに懸濁させた後、60℃で振盪したところ、1日後に懸濁液が無くなり、容器の壁面に粘着している溶媒の上に新たな白色結晶塊が形成していた。
Claims (7)
- 無水結晶性塩である、請求項1に記載の塩。
- 請求項1および2のいずれか一項に記載の塩を含んでなる、医薬組成物。
- 少なくとも一種類の薬学上許容される担体または賦形剤を更に含んでなる、請求項3に記載の医薬組成物。
- 尿生殖器障害を伴う疾患または症状の治療のための、請求項3または4に記載の医薬組成物。
- 前記尿生殖器障害を伴う疾患が尿失禁である、請求項5に記載の医薬組成物。
- 前記尿生殖器障害を伴う疾患が過活動膀胱である、請求項5に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07384038.1 | 2007-11-28 | ||
EP07384038A EP2065385A1 (en) | 2007-11-28 | 2007-11-28 | Stable crystalline salt of (R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid 1-azabiciyclo [2.2.2]oct-3-yl ester |
PCT/EP2008/010012 WO2009068253A2 (en) | 2007-11-28 | 2008-11-26 | Stable crystalline salt of (r)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid 1-azabicyclo [2.2.2]oct-yl ester |
Publications (3)
Publication Number | Publication Date |
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JP2011504890A JP2011504890A (ja) | 2011-02-17 |
JP2011504890A5 JP2011504890A5 (ja) | 2011-09-01 |
JP5336509B2 true JP5336509B2 (ja) | 2013-11-06 |
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JP2010535281A Expired - Fee Related JP5336509B2 (ja) | 2007-11-28 | 2008-11-26 | (r)−3−フルオロフェニル−3,4,5−トリフルオロベンジルカルバミン酸1−アザビシクロ[2.2.2]オクト−3−イルエステルの安定な結晶性塩 |
Country Status (19)
Country | Link |
---|---|
US (2) | US8492402B2 (ja) |
EP (2) | EP2065385A1 (ja) |
JP (1) | JP5336509B2 (ja) |
KR (1) | KR101557832B1 (ja) |
CN (1) | CN101925600B (ja) |
AU (1) | AU2008329181B2 (ja) |
BR (1) | BRPI0819607A2 (ja) |
CA (1) | CA2706565C (ja) |
DK (1) | DK2220082T3 (ja) |
EA (1) | EA017483B1 (ja) |
ES (1) | ES2498819T3 (ja) |
HK (1) | HK1144192A1 (ja) |
IL (1) | IL206032A (ja) |
MX (1) | MX2010005850A (ja) |
NZ (1) | NZ585833A (ja) |
PL (1) | PL2220082T3 (ja) |
UA (1) | UA102083C2 (ja) |
WO (1) | WO2009068253A2 (ja) |
ZA (1) | ZA201003718B (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA03005583A (es) | 2000-12-22 | 2004-05-05 | Almirall Prodesfarma Ag | Derivados de carbamato de quinuclidina y su uso como antagonistas m3. |
RU2570198C2 (ru) † | 2010-02-12 | 2015-12-10 | Пфайзер Инк. | СОЛИ И ПОЛИМОРФЫ 8-ФТОР-2-{4-[(МЕТИЛАМИНО)МЕТИЛ]ФЕНИЛ}-1,3,4,5-ТЕТРАГИДРО-6Н-АЗЕПИНО[5,4,3-cd]ИНДОЛ-6-ОНА |
KR101978364B1 (ko) | 2017-06-15 | 2019-05-14 | 크리스탈지노믹스(주) | 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 또는 그 유도체의 약학적으로 허용 가능한 염 및 그 제조방법 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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SE510305C2 (sv) * | 1997-05-30 | 1999-05-10 | Astra Ab | Nytt salt |
BR0112297A (pt) | 2000-06-27 | 2003-05-06 | S A L V A T Lab Sa | Compostos carbamatos derivados de arilalquilaminas |
MXPA03005583A (es) * | 2000-12-22 | 2004-05-05 | Almirall Prodesfarma Ag | Derivados de carbamato de quinuclidina y su uso como antagonistas m3. |
EA006505B1 (ru) | 2001-12-20 | 2005-12-29 | Лабораториос С.А.Л.В.А.Т.,С.А. | Производные карбамата 1-алкил-1-азониабицикло[2.2.2]октана и их применение в качестве антагонистов мускаринового рецептора |
ES2203327B1 (es) * | 2002-06-21 | 2005-06-16 | Almirall Prodesfarma, S.A. | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. |
ES2246170B1 (es) * | 2004-07-29 | 2007-04-01 | Almirall Prodesfarma, S.A. | Nuevo procedimiento para preparar derivados de carbamato de quinuclidinio. |
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2007
- 2007-11-28 EP EP07384038A patent/EP2065385A1/en not_active Withdrawn
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2008
- 2008-11-26 CN CN2008801254506A patent/CN101925600B/zh not_active Expired - Fee Related
- 2008-11-26 ES ES08854867.2T patent/ES2498819T3/es active Active
- 2008-11-26 DK DK08854867.2T patent/DK2220082T3/da active
- 2008-11-26 EA EA201070651A patent/EA017483B1/ru not_active IP Right Cessation
- 2008-11-26 NZ NZ585833A patent/NZ585833A/en not_active IP Right Cessation
- 2008-11-26 WO PCT/EP2008/010012 patent/WO2009068253A2/en active Application Filing
- 2008-11-26 AU AU2008329181A patent/AU2008329181B2/en not_active Ceased
- 2008-11-26 MX MX2010005850A patent/MX2010005850A/es active IP Right Grant
- 2008-11-26 CA CA2706565A patent/CA2706565C/en not_active Expired - Fee Related
- 2008-11-26 EP EP08854867.2A patent/EP2220082B1/en not_active Not-in-force
- 2008-11-26 PL PL08854867T patent/PL2220082T3/pl unknown
- 2008-11-26 JP JP2010535281A patent/JP5336509B2/ja not_active Expired - Fee Related
- 2008-11-26 BR BRPI0819607A patent/BRPI0819607A2/pt not_active IP Right Cessation
- 2008-11-26 UA UAA201007997A patent/UA102083C2/uk unknown
- 2008-11-26 US US12/744,493 patent/US8492402B2/en not_active Expired - Fee Related
- 2008-11-28 KR KR1020107013939A patent/KR101557832B1/ko not_active IP Right Cessation
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2010
- 2010-05-25 ZA ZA2010/03718A patent/ZA201003718B/en unknown
- 2010-05-27 IL IL206032A patent/IL206032A/en not_active IP Right Cessation
- 2010-11-04 HK HK10110355.6A patent/HK1144192A1/xx not_active IP Right Cessation
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2013
- 2013-02-08 US US13/763,063 patent/US8871787B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JP2011504890A (ja) | 2011-02-17 |
NZ585833A (en) | 2011-05-27 |
HK1144192A1 (en) | 2011-02-02 |
CA2706565A1 (en) | 2009-06-04 |
US8492402B2 (en) | 2013-07-23 |
UA102083C2 (uk) | 2013-06-10 |
US20140051721A1 (en) | 2014-02-20 |
CN101925600B (zh) | 2013-01-09 |
EA201070651A1 (ru) | 2010-12-30 |
WO2009068253A2 (en) | 2009-06-04 |
BRPI0819607A2 (pt) | 2015-10-13 |
ZA201003718B (en) | 2011-08-31 |
CA2706565C (en) | 2015-04-28 |
IL206032A0 (en) | 2010-11-30 |
PL2220082T3 (pl) | 2014-12-31 |
US8871787B2 (en) | 2014-10-28 |
EP2220082B1 (en) | 2014-06-25 |
CN101925600A (zh) | 2010-12-22 |
EP2220082A2 (en) | 2010-08-25 |
ES2498819T3 (es) | 2014-09-25 |
US20110207769A1 (en) | 2011-08-25 |
AU2008329181A1 (en) | 2009-06-04 |
AU2008329181B2 (en) | 2012-03-29 |
KR20100103532A (ko) | 2010-09-27 |
WO2009068253A3 (en) | 2009-08-13 |
KR101557832B1 (ko) | 2015-10-06 |
EA017483B1 (ru) | 2012-12-28 |
IL206032A (en) | 2014-07-31 |
MX2010005850A (es) | 2010-09-03 |
DK2220082T3 (da) | 2014-10-06 |
EP2065385A1 (en) | 2009-06-03 |
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