JP6140151B2 - 統合失調症の処置において4−((1r,3s)−6−クロロ−3−フェニル−インダン−1−イル)−1,2,2−トリメチル−ピペラジンおよびその塩を投与する方法 - Google Patents
統合失調症の処置において4−((1r,3s)−6−クロロ−3−フェニル−インダン−1−イル)−1,2,2−トリメチル−ピペラジンおよびその塩を投与する方法 Download PDFInfo
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Description
本発明は、化合物(I)の塩も含み、典型的には、薬学的に許容される塩である。そのような塩には、薬学的に許容される酸付加塩が挙げられる。酸付加塩は、無機酸および有機酸の塩を含む。
本発明は、治療有効量の本発明の化合物(I)および薬学的に許容される担体または賦形剤を含む医薬組成物をさらに提供する。
長く作用する抗精神病性化合物、長く作用する調製物、および抗精神病性化合物の長く作用する調製物は、体外から投与される化合物の医薬的活性水準を、1週間など1日超にわたって維持して、化合物を毎日与えずに、週2回、週1回、または隔週1回でさえ済むようにする、化合物および化合物の調製物を指す。
結合アッセイ
ヒトD 2 結合アッセイの説明
本アッセイは、NaCl120mM、KCl5mM、MgCl24mM、CaCl21.5mM、EDTA1mMを含有する、pH7.4のアッセイバッファであるトリス50mM中で、SPAに基づく競合結合として実行できる。
本アッセイは、NaCl120mM、KCl5mM、MgCl24mM、CaCl21.5mM、EDTA1mMを含有する、pH7.4のアッセイバッファであるトリス50mM中で、SPAに基づく競合結合として実行される。均一化したヒトD1受容体膜調製物2.5マイクロg、およびSPAビーズ(WGA RPNQ0001、Amersham)0.25mgを加える前に、3H−SCH23390(Perkin Elmer、NET930)およそ1nMを、試験化合物と総量60マイクロLに混合する。
Cerep Contract Laboratories(カタログ参照#471)にて実験を行う。
Andersenら(Eur J Pharmacol、(1987)144:1-6ページ)と、少しの改変(Kapur S.ら、J Pharm Exp Ther、2003、305、625-631ページ)に従って、in vivo結合を行う。簡潔には、ラット6匹(雄のWistar種、180〜200g)を、尾静脈を経由して[3H]−ラクロプライド9.4ミクロCiを静脈内に投与する30分前に、皮下に20mg/kgの試験化合物を用いて処置する。
化合物(I)の結合親和性
予め行ったin vivo結合の研究により、化合物(I)はD1、D2および5−HT2Aの受容体と、以下の親和性で結合することが示された。
ヒトD1結合:Ki=19nM
ヒト5−HT2A結合:Ki=4.2nM
脳におけるD2受容体へのin vivo結合:ED50=4.1mg/kg
(実施例2)
研究デザイン
化合物(I)のコハク酸水素塩の形態で投与される、化合物(I)の週1回投薬の実現可能性を評価するために行われた研究デザインを、図1にまとめる。本研究は、統合失調症患者における化合物(I)の1日1回投薬対週1回投薬の安全性、耐性およびPKの、無作為化、二重盲検、並行群予備研究である。
(実施例3)
PANSS総得点のランダム化に由来する変化
研究を、実施例2に記載の研究デザインを用いて行った。
また、本願は、特許請求の範囲に記載の発明に関するものであるが、他の態様として以下も包含し得る。
(1)化合物(I)の遊離塩基として計算される、20mg/週から50mg/週の間に相当する用量で、週2回、週1回または隔週1回投与されることを特徴とする、中枢神経系における疾患を処置するための化合物(I)。
(3)化合物(I)の遊離塩基として計算される、約30mg/用量から約45mg/用量の間の用量で、週1回投与される、上記(1)または(2)に記載の化合物(I)。
(4)化合物(I)の遊離塩基として計算される、約30mg/用量の用量で、週1回投与される、上記(1)、(2)または(3)に記載の化合物(I)。
(5)化合物(I)の遊離塩基として計算される、約45mg/用量の用量で、週1回投与される、上記(1)、(2)または(3)に記載の化合物(I)。
(6)疾患が、精神病、特に統合失調症、または精神病の症状に関連する他の疾患、例えば統合失調症、統合失調症様障害、統合失調感情障害(分裂感情障害)、妄想性障害、短期精神障害、共有精神病性障害、ならびに精神病の症状、例えば双極性障害における躁病を呈する他の精神障害もしくは疾患、例えば双極性障害、からなる疾患群から選択される、上記(1)に記載の処置のための化合物(I)であって、パーキンソン氏病における精神病を処置するための化合物(I)。
(7)精神病、特に統合失調症、または精神病の症状に関連する他の疾患、例えば統合失調症様障害、統合失調感情障害(分裂感情障害)、妄想性障害、短期精神障害、共有精神病性障害、ならびに精神病の症状、例えば双極性障害における躁病を呈する他の精神障害もしくは疾患、例えば双極性障害、を処置し、パーキンソン氏病における精神病を処置するための薬剤を製造するための、化合物(I)の使用であって、化合物(I)が、化合物(I)の遊離塩基として計算される、20mg/週から50mg/週。の間に相当する用量で、週2回、週1回または隔週1回投与される、化合物(I)の使用。
(8)精神病、特に統合失調症、または、精神病の症状に関連する他の疾患、例えば統合失調症様障害、統合失調感情障害(分裂感情障害)、妄想性障害、短期精神障害、共有精神病性障害、ならびに精神病の症状、例えば双極性障害における躁病を呈する他の精神障害もしくは疾患、例えば双極性障害、を処置し、パーキンソン氏病における精神病を処置するための薬剤を調製する、セルチンドール、オランザピン、リスペリドン、クエチアピン、アリピプラゾール、ハロペリドール、クロザピン、ジプラシドン、およびオサネタントからなる群から選択されるさらなる化合物を含む、上記(1)に記載の化合物(I)または上記(7)に記載の化合物(I)の使用であって、化合物(I)の遊離塩基として計算される、20mg/週から50mg/週。の間に相当する用量で、週2回、週1回または隔週1回投与される、化合物(I)または化合物(I)の使用。
(9)精神病、特に統合失調症、または、精神病の症状に関連する他の疾患、例えば統合失調症様障害、統合失調感情障害(分裂感情障害)、妄想性障害、短期精神障害、共有精神病性障害、ならびに精神病の症状、例えば双極性障害における躁病を呈する他の精神障害もしくは疾患、例えば双極性障害、に罹患している患者を処置し、パーキンソン氏病における精神病を処置する方法であって;有効量の化合物(I)を単独で、またはセルチンドール、オランザピン、リスペリドン、クエチアピン、アリピプラゾール、ハロペリドール、クロザピン、ジプラシドン、およびオサネタントから選択される1つもしくは複数の神経遮断剤と組み合わせて、患者に投与することを含み、化合物(I)が、化合物(I)の遊離塩基として計算される、20mg/週から50mg/週。の間に相当する用量で、週2回、週1回または隔週1回投与される、方法。
(10)中枢神経系の疾患、特に統合失調症などの精神病を処置するための化合物(I)または化合物(I)の塩、ならびに1つまたは複数の薬学的に許容される担体、賦形剤および添加剤を含む医薬組成物であって、化合物(I)を含む医薬組成物が、週2回、週1回または隔週1回投与されることを特徴とする、医薬組成物。
(11)セルチンドール、オランザピン、リスペリドン、クエチアピン、アリピプラゾール、ハロペリドール、クロザピン、ジプラシドン、およびオサネタントから選択される1つまたは複数の神経遮断剤をさらに含む、上記(10)に記載の医薬組成物。
Claims (8)
- 化合物(I)の遊離塩基として計算される、20mg/週から50mg/週の間に相当する用量で、週2回、または週1回、経口投与用の即放性製剤(IR−製剤)、徐放性製剤、制御放出製剤、または遅延放出製剤において投与されることを特徴とする、統合失調症、統合失調症様障害、または統合失調感情障害(分裂感情障害)を処置するための下記式の化合物(I)を含む医薬組成物。
- 化合物(I)が、塩基化合物(I)の遊離したものとして計算される、20mg/用量から50mg/用量の間の用量で、週1回投与される、請求項1に記載の医薬組成物。
- 化合物(I)が、化合物(I)の遊離塩基として計算される、約30mg/用量から約45mg/用量の間の用量で、週1回投与される、請求項1または2に記載の医薬組成物。
- 化合物(I)が、化合物(I)の遊離塩基として計算される、約30mg/用量の用量で、週1回投与される、請求項1、2または3に記載の医薬組成物。
- 化合物(I)が、化合物(I)の遊離塩基として計算される、約45mg/用量の用量で、週1回投与される、請求項1、2または3に記載の医薬組成物。
- 統合失調症、統合失調症様障害、または統合失調感情障害(分裂感情障害)を処置するための薬剤を製造するための、下記式の化合物(I)の使用であって、化合物(I)が、化合物(I)の遊離塩基として計算される、20mg/週から50mg/週の間に相当する用量で、週2回、または週1回、経口投与用の即放性製剤(IR−製剤)、徐放性製剤、制御放出製剤、または遅延放出製剤において投与される、化合物(I)の使用。
- 請求項1に記載の医薬組成物であって、セルチンドール、オランザピン、リスペリドン、クエチアピン、アリピプラゾール、ハロペリドール、クロザピン、ジプラシドン、およびオサネタントからなる群から選択される化合物をさらに含み、統合失調症、統合失調症様障害、または統合失調感情障害(分裂感情障害)を処置するための薬剤を調製するための医薬組成物。
- 統合失調症、統合失調症様障害、または統合失調感情障害(分裂感情障害)に罹患している患者を処置するための医薬組成物であって;有効量の下記式の化合物(I)を単独で、またはセルチンドール、オランザピン、リスペリドン、クエチアピン、アリピプラゾール、ハロペリドール、クロザピン、ジプラシドン、およびオサネタントから選択される1つもしくは複数の神経遮断剤とともに含み、化合物(I)が、化合物(I)の遊離塩基として計算される、20mg/週から50mg/週の間に相当する用量で、週2回、または週1回、経口投与用の即放性製剤(IR−製剤)、徐放性製剤、制御放出製剤、または遅延放出製剤において投与される、医薬組成物。
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KR20190095355A (ko) | 2016-12-15 | 2019-08-14 | 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 | 암의 치료를 위한 조성물 및 방법 |
US11555031B2 (en) | 2017-03-20 | 2023-01-17 | The Broad Institute, Inc. | Compounds and methods for regulating insulin secretion |
US20210395751A1 (en) | 2018-10-31 | 2021-12-23 | The University Of Sydney | Compositions and methods for treating viral infections |
US11325978B2 (en) | 2018-11-06 | 2022-05-10 | The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Compositions and methods for treating beta-globinopathies |
WO2023081167A2 (en) | 2021-11-02 | 2023-05-11 | The Regents Of The University Of California | P-selectin mutants and modulation of integrin-mediated signaling |
WO2023146807A1 (en) | 2022-01-25 | 2023-08-03 | The Regents Of The University Of California | Vegf mutants and modulation of integrin-mediated signaling |
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AU2006269927B2 (en) * | 2004-01-12 | 2013-05-16 | The Trustees Of The University Of Pennsylvania | Drug-containing implants and methods of use thereof |
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CA2838055C (en) | 2021-01-26 |
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TW201306840A (zh) | 2013-02-16 |
KR20140033419A (ko) | 2014-03-18 |
EP2720698A1 (en) | 2014-04-23 |
DK2720698T3 (en) | 2018-11-26 |
CA2838055A1 (en) | 2012-12-27 |
JO3421B1 (ar) | 2019-10-20 |
ZA201309617B (en) | 2015-04-29 |
JP2014517050A (ja) | 2014-07-17 |
US9610287B2 (en) | 2017-04-04 |
PL2720698T3 (pl) | 2019-01-31 |
AU2012274150A1 (en) | 2014-01-09 |
MX2013014978A (es) | 2014-04-10 |
BR112013032178A2 (pt) | 2016-12-20 |
US20140194409A1 (en) | 2014-07-10 |
MX349754B (es) | 2017-08-11 |
RU2613177C2 (ru) | 2017-03-15 |
TWI552751B (zh) | 2016-10-11 |
RU2014101482A (ru) | 2015-07-27 |
WO2012175531A1 (en) | 2012-12-27 |
AU2012274150B2 (en) | 2016-10-06 |
LT2720698T (lt) | 2018-11-12 |
SI2720698T1 (sl) | 2018-12-31 |
EP2720698B1 (en) | 2018-10-03 |
HRP20181684T1 (hr) | 2018-12-14 |
ES2694298T3 (es) | 2018-12-19 |
CN103608015A (zh) | 2014-02-26 |
KR101900989B1 (ko) | 2018-09-20 |
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