JP7332841B2 - 疼痛を治療するための薬用組成物 - Google Patents
疼痛を治療するための薬用組成物 Download PDFInfo
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Description
さらに、オピオイドと、AC1阻害剤NB001である5-((2-(6-アミノ-9H-プリン-9-イル)エチル)アミノ)ペンタン-1-オール、AC1&8混合阻害剤NB010である6-アミノ-9-(2-パラトリルオキシ-エチル)-9H-プリン-8-チオール及びNB011である4-(9H-プリン-6-イル)モルホリンの少なくとも1種を組み合わせた使用に関する。
(Minら、1994; Nestler 、1997; Leeら、2003)。中枢神経系において、AC1及びAC8は、ニューロンにおけるCREBを調節するために、上流の重要なシグナルタンパク質に作用することが知られている(Weiら、2002; Zhuo、2012)。AC1及びAC8シングルノックアウト(KO)マウス及びDKOマウスを使用することにより、AC1又はAC8遺伝子シングルノックアウトマウス、又はDKOマウス及び野生型マウスに対して、短時間ではモルヒネの鎮痛効果には差が生じないことが報告されている(Liら、2006)。AC1&8DKOマウス及びAC8シングルノックアウトマウスは、モルヒネ(10mg/kg体重)注射を毎日行うことにより、耐性の低下が継続的に誘発された。モルヒネで継続的に治療されたDKOマウスは、禁断挙動が顕著に減少した(Li ら、2006)。AC1阻害剤ST034037を用いた最近の研究により、AC1活性がMOR慢性的な活性化によって誘発されたAC感作を必要とすることが発見された。それは、AC1阻害が慢性的なモルヒネの使用により誘発された耐性及び他の反応を克服するのに有益であることを示唆している(Brustら、2017)。
(1)オピオイド系薬物と、
NB001、NB010、及びNB011からなる群から選択される少なくとも1種と、を含む疼痛を治療するための薬用組成物であって、
上記NB001は、5-((2-(6-アミノ-9H-プリン-9-イル)エチル)アミノ)ペンタン-1-オールであり、
上記NB010は、6-アミノ-9-(2-パラトリルオキシ-エチル)-9H-プリン-8-チオールであり、
上記NB011は、4-(9H-プリン-6-イル)モルホリン(6-モルホリン-4-イル-7H-プリンとも称する)である、ことを特徴とする薬用組成物である。
(4)疼痛を治療する薬物の調製のための薬用組成物の使用であって、上記薬用組成物は、
オピオイド系薬物と、
NB001、NB010、及びNB011からなる群から選択される少なくとも1種と、を含み、
上記NB001は、5-((2-(6-アミノ-9H-プリン-9-イル)エチル)アミノ)ペンタン-1-オールであり、以下の構造を有し、
上記NB010は、6-アミノ-9-(2-パラトリルオキシ-エチル)-9H-プリン-8-チオールであり、
上記NB011は、4-(9H-プリン-6-イル)モルホリン(6-モルホリン-4-イル-7H-プリンとも称する)であることを特徴とする使用である。
(7)オピオイド系薬物の使用に基づいて疼痛を治療する方法であって、NB001、NB010、及びNB011のうちの少なくとの1種と、それら化合物に製薬上許容される塩又は溶媒和物からなる群から選択される少なくとも1種を併用し、
上記NB001は、5-((2-(6-アミノ-9H-プリン-9-イル)エチル)アミノ)ペンタン-1-オールであり、上記NB010は、6-アミノ-9-(2-パラトリルオキシ-エチル)-9H-プリン-8-チオールであり、
上記NB011は、4-(9H-プリン-6-イル)モルホリン(6-モルホリン-4-イル-7H-プリンとも称する)である、ことを特徴とする。
(9)神経因性疼痛による不安及び他の疾患に関連する不安や憂鬱を治療する薬用組成物であって、上記薬用組成物は、NB001、NB010、及びNB011ののうちの少なくとも1種を含む薬用組成物である。
(11)慢性内臓痛及びそれに関連する不安や憂鬱を治療する薬用組成物であって、上記薬用組成物は、NB001、NB010、及びNB011のうちの少なくとも1種を含む、ことを特徴とする薬用組成物。
本発明の活性化合物又はその医薬用組成物の治療上有効な用量が、所望する効果により変化することは、当業者には明白である。そして、投与される最適な用量が容易に決定される。その用量は、使用される特定の化合物、投与形態、製剤の強さ、及び疾患の進行により変化する。さらに、患者の年齢、体重、飲食物、及び投与時間等、治療される特定の患者に関連する因子に応じて、適切な治療レベルの用量への調節が必要となる。したがって、本明細書に記載される用量は一般的な例である。当然のことながら、個々の状況に応じ、より多い又は少ない用量としてもよく、それは、本発明の技術的範囲に含まれる。
市販品としては、アシネックス(Asinex LTD)社のBAS03384号が挙げられる。
市販品としては、メイブリッジ(Maybridge)社のJFD02793号が挙げられる。
〈実施例1〉AC1&8混合阻害剤のスクリーニング
〈実施例2〉不安関連皮質LTPに対するNB010及びNB011の影響評価
〈実施例3〉モルヒネ耐性に対するAC1及びAC1&8阻害剤の行動影響
〈実施例4〉モルヒネの条件付け場所嗜好性試験(Conditioned Place Preference,CPP)
〈実施例5〉不安行動試験
実験方法については、Koga, K., et al., Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain. Neuron, 2015. 85(2): p. 377-389を参照した。
掻痒の反応
試験動物
AC8及びAC1の新規阻害剤の生化学的スクリーニング試験
CREルシフェラーゼレポーター遺伝子アッセイ
全細胞パッチクランプ記録
条件付け場所嗜好性試験
神経因性疼痛モデル
機械的異痛の試験
Claims (2)
- AC1阻害剤である5-((2-(6-アミノ-9H-プリン-9-イル)エチル)アミノ)ペンタン-1-オール(NB001)、又はNB001の製薬上許容される塩若しくは溶媒和物の、オピオイド系薬物耐性を低下させるための薬剤の製造における使用。
- 前記オピオイド系薬物はモルヒネである、ことを特徴とする請求項1に記載の使用。
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017100431A JP7332841B2 (ja) | 2017-05-20 | 2017-05-20 | 疼痛を治療するための薬用組成物 |
TW107116441A TWI729290B (zh) | 2017-05-20 | 2018-05-15 | 治療疼痛的藥物組合物 |
IL259442A IL259442A (en) | 2017-05-20 | 2018-05-16 | Medicinal preparations for the treatment of pain |
AU2018203501A AU2018203501B2 (en) | 2017-05-20 | 2018-05-17 | Pharmaceutical compositions for treating pain |
EP18000462.4A EP3403674B1 (en) | 2017-05-20 | 2018-05-17 | Pharmaceutical compositions for treating pain |
DK18000462.4T DK3403674T3 (da) | 2017-05-20 | 2018-05-17 | Farmaceutiske sammensætninger til behandling af smerte |
ES18000462T ES2886855T3 (es) | 2017-05-20 | 2018-05-17 | Composiciones farmacéuticas para tratar el dolor |
ZA2018/03320A ZA201803320B (en) | 2017-05-20 | 2018-05-18 | Pharmaceutical compositions for treating pain |
CN201810482871.XA CN108743589B (zh) | 2017-05-20 | 2018-05-18 | 治疗疼痛的药物组合物 |
CA3005375A CA3005375C (en) | 2017-05-20 | 2018-05-18 | Pharmaceutical compositions for treating pain |
KR1020180057362A KR102096557B1 (ko) | 2017-05-20 | 2018-05-18 | 통증 치료용 약학 조성물 |
US15/984,410 US20180333420A1 (en) | 2017-05-20 | 2018-05-20 | Pharmaceutical compositions for treating pain |
US16/871,628 US11541060B2 (en) | 2017-05-20 | 2020-05-11 | Pharmaceutical compositions for treating pain |
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JP2017100431A JP7332841B2 (ja) | 2017-05-20 | 2017-05-20 | 疼痛を治療するための薬用組成物 |
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JP2019052094A JP2019052094A (ja) | 2019-04-04 |
JP2019052094A5 JP2019052094A5 (ja) | 2020-06-25 |
JP7332841B2 true JP7332841B2 (ja) | 2023-08-24 |
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US (2) | US20180333420A1 (ja) |
EP (1) | EP3403674B1 (ja) |
JP (1) | JP7332841B2 (ja) |
KR (1) | KR102096557B1 (ja) |
CN (1) | CN108743589B (ja) |
AU (1) | AU2018203501B2 (ja) |
CA (1) | CA3005375C (ja) |
DK (1) | DK3403674T3 (ja) |
ES (1) | ES2886855T3 (ja) |
IL (1) | IL259442A (ja) |
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CN114984020A (zh) * | 2022-01-20 | 2022-09-02 | 永展控股有限公司 | 腺苷酸环化酶抑制剂在制备用于治疗癫痫及其相关疾病的药物中的用途 |
CN114931561B (zh) * | 2022-05-25 | 2024-02-02 | 青岛永展医药科技有限公司 | 一种治疗慢性痛的胶囊组合物及其制备方法 |
CN115998745B (zh) * | 2023-02-17 | 2024-05-14 | 永展控股有限公司 | 腺苷酸环化酶抑制剂nb001在制备治疗帕金森氏病疼痛和焦虑药物中的用途 |
CN115990167A (zh) * | 2023-02-17 | 2023-04-21 | 永展控股有限公司 | 腺苷酸环化酶抑制剂nb001在制备治疗偏头痛和焦虑药物中的用途 |
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JP2009511508A (ja) | 2005-10-14 | 2009-03-19 | チュオ ミン | 神経および非神経痛を治療する方法 |
US20110098295A1 (en) | 2009-10-22 | 2011-04-28 | Min Zhuo | Methods of treating anxiety, itching and psychiatric disorders |
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JP6902336B2 (ja) * | 2016-08-01 | 2021-07-14 | 永展国際有限公司Forever Cheer International Limited | 5−[2−[(6−アミノ)−9h−プリン−9−イル]エチルアミノ]−1−ペンタノール多結晶体 |
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JP2009511508A (ja) | 2005-10-14 | 2009-03-19 | チュオ ミン | 神経および非神経痛を治療する方法 |
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CN108743589B (zh) | 2021-05-14 |
AU2018203501A1 (en) | 2018-12-06 |
EP3403674B1 (en) | 2021-06-30 |
US11541060B2 (en) | 2023-01-03 |
TWI729290B (zh) | 2021-06-01 |
DK3403674T3 (da) | 2021-08-30 |
KR20180127248A (ko) | 2018-11-28 |
JP2019052094A (ja) | 2019-04-04 |
IL259442A (en) | 2018-06-28 |
US20200268766A1 (en) | 2020-08-27 |
CA3005375A1 (en) | 2018-11-20 |
TW201900173A (zh) | 2019-01-01 |
AU2018203501B2 (en) | 2019-11-21 |
ES2886855T3 (es) | 2021-12-21 |
KR102096557B1 (ko) | 2020-04-03 |
EP3403674A1 (en) | 2018-11-21 |
CN108743589A (zh) | 2018-11-06 |
CA3005375C (en) | 2020-12-08 |
ZA201803320B (en) | 2019-04-24 |
US20180333420A1 (en) | 2018-11-22 |
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