JP2011511064A - (r),(r)−2,2’−ビス−メチルナルトレキソンの製造及び用途 - Google Patents
(r),(r)−2,2’−ビス−メチルナルトレキソンの製造及び用途 Download PDFInfo
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- JP2011511064A JP2011511064A JP2010545835A JP2010545835A JP2011511064A JP 2011511064 A JP2011511064 A JP 2011511064A JP 2010545835 A JP2010545835 A JP 2010545835A JP 2010545835 A JP2010545835 A JP 2010545835A JP 2011511064 A JP2011511064 A JP 2011511064A
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- compound
- purity
- methylnaltrexone
- isolated
- mntx
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/24—Automatic injection systems
Abstract
Description
(R),(R)-2,2’-ビス-MNTXは、式(I):
(R)-MNTX(8.5 g, 0.0195 mol)の水:メタノール:トリフルオロ酢酸(94.9:5:0.1) 40mL及び臭化第二鉄(0.57 g, 1.95 mmol)の溶液を氷浴で冷却した。過酸化水素水(0.66 g, 0.0195 mol)10mLを当該溶液に、30分以上かけて滴下した。氷浴中で30分間攪拌後、溶液はHPLC分析で、(R)-MNTXを74%及び(R),(R)-2,2’-ビス-MNTXを16%含有した。溶液から氷浴を取り外し、室温まで昇温した。30分後HPLC分析により、溶液は(R)-MNTXを44%、(R),(R)-2,2’-ビス-MNTXを27%、及びより長い保持時間のところに不純物を2%含有した。さらに1時間後、HPLC分析では、溶液は、(R)-MNTXを27%、(R),(R)-2,2’-ビス-MNTXを35%、及び不純物を6.2%含み、さらなる不純物が含まれていることが示唆された。
反応混合物を、プレパラティブ逆相カラム(Biotage 40M C18)に直接アプライし、一定両のTFAを含む、水:メタノール2.4Lの直線的溶媒勾配(12mL、水:メタノール=95:5ないし82.5:17.5の割合)で溶出した。フラクションはHPLCで分析し、同様の組成のフラクションは純度により2つのロットに分けて集めた。34℃以下に浴槽を保ち、溶媒をアスピレーター圧力下、続いて高真空下、回転蒸発器で除去した。
カラム: フェノメネックス・インターシル(Phenomonex Intersil) ODS-3カラム(C18, 5μ, 150×4.6 mm)
流速: 1.5mL/分
カラム温度: 50℃
検出器: ダイオードアレイ検出器で280nmにおけるモニタリング
溶出: 直線的勾配
A = メタノール
B = 水
C = 水:メタノール:TFA (49.5:49.5:1)
HPLC法Bは「HPLC法II」として、米国特許出願公開第2007-0099946 A1公報(米国特許出願番号11/441,395)に記載されている。
Claims (69)
- Xがそれぞれ独立して、同一又は異なるカウンターイオンである、又はXがそれぞれ、他のXと共有結合することができるものである請求項1に記載の化合物。
- X又はYが、ハロゲン化物、硫酸塩、リン酸塩、スルホン酸塩、硝酸塩、カルボン酸塩、又は有機種である請求項1に記載の化合物。
- Xが臭化物である請求項1に記載の化合物。
- 該化合物は少なくとも0.5%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも1%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも5%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも10%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも15%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも25%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも50%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも75%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも95%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物が少なくとも97%の純度で単離されるものである請求項1に記載の化合物。
- 該化合物は固体である、請求項1ないし14記載の化合物。
- 密封ボトルに溶液として充填されている請求項1に記載の化合物。
- セプタムを含む密封ボトルに溶液として充填されている請求項1に記載の化合物。
- Xがそれぞれ独立して、同一又は異なるカウンターイオンであり得、又はそれぞれXが他のXと共有結合することができる請求項18に記載のキット。
- X又はYが、ハロゲン化物、硫酸塩、リン酸塩、スルホン酸塩、硝酸塩、カルボン酸塩、又は有機種である請求項18に記載のキット。
- Xが臭化物である請求項18に記載のキット。
- 該印が化合物の純度を示す請求項18に記載のキット。
- 該印が化学式又は構造式を提示することにより化合物の化学構造を示す請求項18に記載のキット。
- Xがそれぞれ独立して、同一又は異なるカウンターイオンであり、又は、それぞれのXが他の共有結合することができる請求項24に記載の方法。
- X又はYが、ハロゲン化物、硫酸塩、リン酸塩、スルホン酸塩、硝酸塩、カルボン酸塩、又は有機種である請求項24に記載の方法。
- Xが臭化物である請求項24に記載の方法。
- (R)-メチルナルトレキソンの第1分子の量と対比して、触媒が25モル%以下である請求項24に記載の方法。
- (R)-メチルナルトレキソンの第1分子の量と対比して、触媒が10モル%以下である請求項24に記載の方法。
- (R)-メチルナルトレキソンの第1分子の量と対比して、触媒が化学量論量である請求項24に記載の方法。
- 触媒が臭化第二鉄である請求項24に記載の方法。
- 酸化剤が過酸化水素である請求項24に記載の方法。
- さらに化合物を固体で単離することを含む請求項24に記載の方法。
- 該化合物が少なくとも0.5%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも1%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも5%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも10%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも15%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも25%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも50%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも75%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも95%の純度で単離されるものである請求項33記載の方法。
- 該化合物が少なくとも97%の純度で単離されるものである請求項33記載の方法。
- Xがそれぞれ独立して、同一又は異なるカウンターイオンであり、又はXがそれぞれ他のXと共有結合している請求項44記載の方法。
- X又はYが、ハロゲン化物、硫酸塩、リン酸塩、スルホン酸塩、硝酸塩、カルボン酸塩、又は有機種である請求項44記載の方法。
- Xが臭化物である請求項44記載の方法。
- 該決定が、第1と第2のHPLCクロマトグラムのピークの保持時間を比べることを含む、試料溶液中における化合物の存在を決定するための請求項44記載の方法。
- 該決定が、HPLCクロマトグラムにおいて試料溶液におけるピーク面積及び試料溶液中のピーク面積を定量し、及びこれらから試料溶液中の化合物の量を計算すること含む請求項44記載の方法。
- 試料溶液が、(R)-メチルナルトレキソン及び/又は(S)-メチルナルトレキソンを含む請求項44記載の方法。
- 試料溶液が、(R)-メチルナルトレキソン及び(S)-メチルナルトレキソンの混合物を含む請求項44記載の方法。
- HPLCカラムが、逆相カラムであり、該カラムが水、メタノール、トリフルオロ酢酸、又はそれらの混合物を含む移動相を用いて溶出される請求項44記載の方法。
- さらに、不純物としての化合物の化学的特定名及び量を文書に記載することを含む請求項44記載の方法。
- Xがそれぞれ独立して、同一又は異なるカウンターイオンであり得、又は、Xがそれぞれ独立して他のXに共有結合することができる請求項54記載の方法。
- X又はYが、ハロゲン化物、硫酸塩、リン酸塩、スルホン酸塩、硝酸塩、カルボン酸塩、又は有機種である請求項54記載の方法。
- Xが臭化物である請求項54記載の方法。
- 試料溶液が、(R)-メチルナルトレキソンを含む請求項54記載の方法。
- 試料溶液が、(R)-メチルナルトレキソン及び(S)-メチルナルトレキソンの混合物を含む請求項54記載の方法。
- HPLCカラムは逆相カラムであり、該カラムが水、メタノール、トリフルオロ酢酸又はそれらの混合物を含む移動相を用いて溶出されるカラムである請求項54記載の方法。
- さらに、不純物としての化合物の化学的特定名及び量を文書に記載することを含む請求項54記載の方法。
- 化合物中の該物質の量が、(i)コントロール・クロマトグラムにおいて対応するピークをクロマトグラムにおいて同定する、(ii)式(I)の構造式を有すると知られている化合物の、相対保持時間に対応するクロマトグラムのピークを同定する、及び/又は(iii)式(I)の構造を有すると知られている目的化合物の既知量に対応するピークをクロマトグラムにおいて同定することにより決定される請求項62記載の方法。
- Xがそれぞれ独立して、同一又は異なるカウンターイオンであり得、又はXがそれぞれ他のXと共有結合することができる請求項62記載の方法。
- X又はYが、ハロゲン化物、硫酸塩、リン酸塩、スルホン酸塩、硝酸塩、カルボン酸塩、又は有機種である請求項62記載の方法。
- Xが臭化物である請求項62記載の方法。
- 試料溶液が、(R)-メチルナルトレキソンを含む請求項62記載の方法。
- 試料溶液が、(R)-メチルナルトレキソン及び(S)-メチルナルトレキソンの混合物を含む請求項62記載の方法。
- HPLCカラムが逆相カラムであり、該カラムが水、メタノール、トリフルオロ酢酸、又はそれらの混合物を含む移動相を用いて溶出される請求項62記載の方法。
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PCT/US2008/001660 WO2009099411A1 (en) | 2008-02-06 | 2008-02-06 | Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone |
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JP2011511064A true JP2011511064A (ja) | 2011-04-07 |
JP2011511064A5 JP2011511064A5 (ja) | 2012-03-29 |
JP5358587B2 JP5358587B2 (ja) | 2013-12-04 |
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US (2) | US8471022B2 (ja) |
EP (2) | EP2730578A1 (ja) |
JP (1) | JP5358587B2 (ja) |
KR (1) | KR101581480B1 (ja) |
CN (1) | CN101959892B (ja) |
AU (1) | AU2008349873B2 (ja) |
CA (1) | CA2713568C (ja) |
WO (1) | WO2009099411A1 (ja) |
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CN101959892B (zh) | 2008-02-06 | 2014-01-08 | 普罗热尼奇制药公司 | (r),(r)-2,2’-二-甲基纳曲酮的制备和用途 |
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WO2016014864A1 (en) * | 2014-07-23 | 2016-01-28 | Salix Pharmaceuticals, Inc. | Hydroxy-(r)-2,2'-bismethylnal trexones and uses thereof |
WO2020012245A1 (en) | 2018-07-13 | 2020-01-16 | Alkermes Pharma Ireland Limited | Thienothiophene-naltrexone prodrugs for long-acting injectable compositions |
WO2020012248A1 (en) | 2018-07-13 | 2020-01-16 | Alkermes Pharma Ireland Limited | Novel naphthylenyl compounds for long-acting injectable compositions and related methods |
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KR20100110387A (ko) | 2010-10-12 |
EP2240489A1 (en) | 2010-10-20 |
AU2008349873B2 (en) | 2014-02-13 |
US8916706B2 (en) | 2014-12-23 |
US8471022B2 (en) | 2013-06-25 |
CN101959892A (zh) | 2011-01-26 |
JP5358587B2 (ja) | 2013-12-04 |
CN101959892B (zh) | 2014-01-08 |
EP2730578A1 (en) | 2014-05-14 |
US20130296570A1 (en) | 2013-11-07 |
AU2008349873A1 (en) | 2009-08-13 |
CA2713568A1 (en) | 2009-08-13 |
WO2009099411A1 (en) | 2009-08-13 |
KR101581480B1 (ko) | 2015-12-30 |
CA2713568C (en) | 2016-09-20 |
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