JP5899214B2 - 4−[−2−[[5−メチル−1−(2−ナフタレニル)−1h−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩の固体形態 - Google Patents
4−[−2−[[5−メチル−1−(2−ナフタレニル)−1h−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩の固体形態 Download PDFInfo
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- JP5899214B2 JP5899214B2 JP2013523580A JP2013523580A JP5899214B2 JP 5899214 B2 JP5899214 B2 JP 5899214B2 JP 2013523580 A JP2013523580 A JP 2013523580A JP 2013523580 A JP2013523580 A JP 2013523580A JP 5899214 B2 JP5899214 B2 JP 5899214B2
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- methyl
- water
- naphthalenyl
- pyrazol
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- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
-
- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
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- Biomedical Technology (AREA)
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- Medicinal Preparation (AREA)
Description
− 溶媒蒸発;
− 貧溶媒添加;または
− 熱飽和溶液からの結晶化
によりポリマーの結晶化を誘導することで得ることもできる。
% 結晶度=100×C/(A+C)
C=回折図におけるピークからの面積(「結晶面積」)、
A=ピークとバックグラウンドとの間の面積(「非晶質面積」)
− 室温で2種類の速度での溶媒蒸発
− 異なる温度(−21℃、4℃および60℃)での溶媒蒸発
− 2種類の冷却速度での熱飽和溶液からの結晶化
− 水和物の調製を目的とする結晶化
− 貧溶媒の添加による結晶化
− 貧溶媒の拡散による結晶化
− 粉砕実験
− 加圧実験
− スラリー実験
− 室温での溶媒蒸発
− 貧溶媒添加による結晶化
− 熱飽和溶液からの結晶化
− 粉砕実験
a)粉末X線回折分析(PXRD)
約20mgの未処理サンプルを2枚のポリアセテート箔を用いて標準サンプルホルダーに準備した。
プロトン核磁気共鳴分析は、ATM付きz−勾配5mmBBO(ブロードバンド観察)プローブおよび自動BACS−120オートサンプラーを備えた、Bruker Avance 400ウルトラシールドNMR分光計にて重水素化クロロホルム(CDCl3)中で記録した。0.6mLの重水素化溶媒中に2〜10mgのサンプルを溶解させてスペクトルを得た。
標準DSC分析は、Mettler Toledo DSC822eにて記録した。1〜2mgのサンプルを、ピンホール蓋付きの40μLアルミニウムるつぼ中に秤量し、窒素下(50mL/分)、10℃/分で、30℃から300℃まで昇温した。データ収集および評価はソフトウェアSTAReを用いて行った。
熱重量分析は、Mettler Toledo SDTA851eにて記録した。3〜4mgのサンプルを、ピンホール蓋付きの開口40μLアルミニウムるつぼ中に秤量し(マイクロスケールMX5(Mettler)を用いて)、窒素下(80mL/分)、10℃/分で、30℃から500℃の間で昇温した。データ収集および評価はソフトウェアSTAReを用いて行った。
FTIRペクトルは、MKII金ゲート単一反射ATRシステム、励起源として中間赤外線源、およびDTGS検出器を備えた、Bruker Tensor27を用いて記録した。スペクトルは4cm−1の解像度にて32回のスキャンで得た。分析を行うのにサンプル調製は必要なかった。
P027の非晶質形態の調製および特性決定
0.2gの化合物P027を室温で4.8mLの水に溶解した。得られた溶液を60℃でペトリ皿中に放置して蒸発させた。得られた凝固油および得られた固体を、PXRD、1H NMR、DSC、TGA、FTIRおよびKFによって分析した。
− アセトニトリル/H2Oが75/25で、1か月間;
− イソプロパノール/H2Oが25/75で、1か月間;および
− メタノール/H2Oが50/50および25/75で、1か月間。
得られたP027の非晶質形態の安定性評価
非晶質相の安定性を試験し、その安定性を調べるために、非晶質相の種々の部分を様々な温度で4時間乾燥させた(表5)。サンプルが乾燥したところで、固体をPXRDによって分析した。最大60℃までの温度で4時間行った乾燥実験において、非晶質相を回収した。60℃を超える温度では、非晶質相はわすかに結晶相に変換し、明確には同定されなかった。100℃よりも高い温度で4時間乾燥後、非晶質相は明確に相Iに変換した。
非晶質形態を得るための触媒量のポリマーを用いる結晶化スクリーニング
ポリマーの選択
P027の新規結晶形態の形成を誘導する目的で、触媒量のポリマーを結晶化実験に添加した。用いたポリマーを表3に列挙する。
P027のサンプル(20〜25mg)を室温で最小量の対応する溶媒に溶解し、少量のポリマー(4〜5mg)を対応する溶液に添加した(表7および8)。得られた溶液または懸濁液を室温で開口バイアル中に放置して蒸発させた。すべての固体サンプルをPXRDによって分析した。
ジイソプロピルエーテル(DIE)を貧溶媒の添加による結晶化実験のための貧溶媒として選択した。P027(20〜25mg)のサンプルおよび対応するポリマー(5〜6mg)を最小量の溶解溶媒中に室温で溶解し、激しく攪拌しながら貧溶媒を添加した(表9)。貧溶媒添加後に固体が得られた場合、これらの固体を遠心分離によって分離した。固体が得られなければ、溶液を室温に放置して蒸発させた。得られた固体をPXRDによって分析した。
P027(20〜30mg)のサンプルおよび対応するポリマー(4〜5mg)を最小量の対応する溶媒中に高温で溶解し、飽和溶液を得て、室温までゆっくり冷却した(表10)。室温で冷却後に固体が得られた場合、これらの固体を遠心分離によって分離した。固体が得られなければ、溶液を室温に放置して乾燥するまで蒸発させた。得られたすべての固体をPXRDによって分析した。
Claims (9)
- 30%未満の結晶化度を有する、4−[2−[[5−メチル−1−(2−ナフタレニル)−1H−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩の固体形態物。
- 非晶質である、請求項1に記載の固体形態物。
- 特性ピークを示すFTIRスペクトルを3421、3137、3054、2959、2859、2540、2447、1632、1600、1557、1509、1487、1442、1372、1305、1290、1256、1236、1199、1169、1130、1100、1046、1013、982、933、917、861、819および748cm−1に有する、請求項2に記載の固体形態物。
- 請求項1〜3のいずれか一項に記載の固体形態物の調製方法であって:
a)4−[2−[[5−メチル−1−(2−ナフタレニル)−1H−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩を適切な溶媒または溶媒混合物中に溶解する工程と、
b)溶媒または溶媒混合物を蒸発させる工程とを含んでなり、
前記溶媒または溶媒混合物が、水、アセトニトリル、イソプロパノール、メタノール、アセトニトリル−水、イソプロパノール−水、およびメタノール−水からなる群から選択されるものである、方法。 - 4−[2−[[5−メチル−1−(2−ナフタレニル)−1H−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩を室温から120℃の範囲の温度で溶解させる、請求項4に記載の方法。
- 溶媒を室温乃至60℃で蒸発させる、請求項4に記載の方法。
- 請求項1〜3のいずれか一項に記載の固体形態物の調製方法であって:
− a)4−[2−[[5−メチル−1−(2−ナフタレニル)−1H−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩を、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリ(アクリル酸)、ポリ(スチレン−コ−ジビニルベンゼン)、ポリ塩化ビニル、ポリアクリルアミド、ポリスルホンからなる群から選択される触媒量のポリマーの存在下で、適切な溶媒または溶媒混合物中に溶解する工程;およびb)溶媒または溶媒混合物を蒸発させる工程;
− a)4−[2−[[5−メチル−1−(2−ナフタレニル)−1H−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩を、ポリ(アクリル酸)、ポリ(スチレン−コ−ジビニルベンゼン)、ポリ塩化ビニル、ポリ(ビニルアルコール)およびポリアクリルアミドからなる群から選択される触媒量のポリマーの存在下で、適切な溶媒または溶媒混合物中に溶解する工程;およびb)貧溶媒としてジイソプロピルエーテルを添加する工程;または
− ヒドロキシプロピルメチルセルロース、ナイロン6/6、ポリ(スチレン−コ−ジビニルベンゼン)、ポリ塩化ビニル、ポリ(酢酸ビニル)、ポリ(ビニルアルコール)、ポリアクリルアミド(Polyacrilamide)、ポリスルホンまたはポリ(メタクリル酸メチル)からなる群から選択される触媒量のポリマーの存在下で、適切な溶媒または溶媒混合物の熱飽和溶液からの結晶化工程を含んでなり、
前記溶媒または溶媒混合物が、水、アセトニトリル、イソプロパノール、メタノール、アセトニトリル−水、イソプロパノール−水、およびメタノール−水からなる群から選択されるものである方法。 - 4−[2−[[5−メチル−1−(2−ナフタレニル)−1H−ピラゾール−3−イル]オキシ]エチル]モルホリン塩酸塩の多形体の一つを調製するための、請求項1〜3のいずれか一項に記載の固体形態物の使用。
- 請求項1〜3のいずれか一項に記載の固体形態を含んでなる医薬組成物。
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EP10382225A EP2426111A1 (en) | 2010-08-09 | 2010-08-09 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride amorphous solid forms |
PCT/EP2011/063583 WO2012019984A1 (en) | 2010-08-09 | 2011-08-08 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride amorphous solid forms |
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EP2353591A1 (en) | 2010-02-04 | 2011-08-10 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof |
EP2353598A1 (en) | 2010-02-04 | 2011-08-10 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for use in the prevention and/or treatment of postoperative pain |
EP2388005A1 (en) | 2010-05-21 | 2011-11-23 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
EP2415471A1 (en) | 2010-08-03 | 2012-02-08 | Laboratorios Del. Dr. Esteve, S.A. | Use of sigma ligands in opioid-induced hyperalgesia |
EP2524694A1 (en) | 2011-05-19 | 2012-11-21 | Laboratorios Del. Dr. Esteve, S.A. | Use of sigma ligands in diabetes type-2 associated pain |
EP2792352A1 (en) | 2013-04-16 | 2014-10-22 | Laboratorios Del. Dr. Esteve, S.A. | Alpha-2 adrenoreceptor and sigma receptor ligand combinations |
JP2016540771A (ja) | 2013-12-17 | 2016-12-28 | ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ | セロトニン−ノルアドレナリン再取り込み阻害薬(snri)およびシグマ受容体リガンドの組み合わせ |
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