JP2022540275A - テトラメチルピラジンニトロンの結晶形、製造方法及び使用 - Google Patents
テトラメチルピラジンニトロンの結晶形、製造方法及び使用 Download PDFInfo
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- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims abstract description 203
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 239000013078 crystal Substances 0.000 title claims abstract description 31
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- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
Description
工程(1):テトラメチルピラジンニトロン粗体を有機溶媒と混合し、水浴にて60~80℃まで加熱し、撹拌して濾過し、濾液を冷却して結晶化させ、結晶性固形分を得、
工程(2):工程(1)で得られた結晶性固形分をn-ヘプタンと混合し、加熱して溶解させ、冷却して結晶化させ、テトラメチルピラジンニトロンの結晶形Aを得る。
(1)本発明に記載されたテトラメチルピラジンニトロンの結晶形A及びテトラメチルピラジンニトロンの二水和物は、製造方法が簡単であり、大規模な工業生産が容易である。
1、溶媒のテトラメチルピラジンニトロン最終生成物の収率及び品質への影響について調査した結果を表2に示す。
1、安定性の調査
1.1 懸濁による結晶転位試験
(1)テトラメチルピラジンニトロンの結晶形Aを石油エーテル(1.0mL)中に室温条件で7日間懸濁してスラリー化した後、懸濁液を遠心分離し、固体サンプルを収集し、XRPD特性評価を行った。
(2)テトラメチルピラジンニトロンの結晶形A及びテトラメチルピラジンニトロンの二水和物をそれぞれ10分間研磨し、処理後のサンプルをXRPDにより分析した。
(3)結晶形A及びテトラメチルピラジンニトロンの二水和物を、圧力2トンで2分間打錠処理し、錠状に加圧した後にXRPDにより分析した。
(4)結晶形Aを-55℃まで冷却してから、25℃まで昇温させた。その結果、図15及び16に示すように、結晶形Aは変化しなかった。
結晶形Aを40℃、RH=75%の環境で7日間加速させた。XRPD特性評価の結果、図21に示すように、結晶形Aであった。
カニクイザルの脳卒中動物モデルの薬力学研究を行うと同時に、カニクイザルの脳脊髄液におけるテトラメチルピラジンニトロンの結晶形Aの薬物動態研究も行った。2回目投与(30mg/kgで1回目静脈内投与してから6時間後に、30mg/kgで投与する)してから10分、30分、60分、120分後にそれぞれ0.5mlの脳脊髄液を採取し、薬物動態試験を行った。
SDラットに静脈内注射によりテトラメチルピラジンニトロンの結晶形Aを30mg/kgの用量で投与し、各組織におけるテトラメチルピラジンニトロンの結晶形Aの分布状況を調査した。
Claims (10)
- XRPDスペクトルが10.60±0.2、11.03±0.2、15.31±0.2、15.55±0.2、17.14±0.2、17.93±0.2、23.81±0.2の2θ角度位置において特徴的な回折ピークを示し、好ましくは、XRPDスペクトルが10.60±0.2、11.03±0.2、13.51±0.2、15.31±0.2、15.55±0.2、17.14±0.2、17.93±0.2、21.22±0.2、23.81±0.2、25.23±0.2、27.08±0.2の2θ角度位置に特徴的な回折ピークを示すことを特徴とする、テトラメチルピラジンニトロンの結晶形A。
- 図1と基本的に同じXRPDスペクトルを有することを特徴とする、請求項1に記載の結晶形A。
- 融点が76℃~78℃であることを特徴とする、請求項1に記載の結晶形A。
- DSCスペクトルが図3に示されるものと基本的に同じであり、TGAスペクトルが図7に示されるものと基本的に同じであり、赤外線スペクトルが図9に示されるものと基本的に同じであることを特徴とする、請求項1に記載の結晶形A。
- 請求項1~4のいずれか一項に記載の結晶形Aの製造方法であって、以下の工程を含むことを特徴とする製造方法。
工程(1):テトラメチルピラジンニトロン粗体を有機溶媒と混合し、水浴にて60~80℃まで加熱し、撹拌して濾過し、濾液を冷却して結晶化させ、結晶性固形分を得、
工程(2):工程(1)で得られた結晶性固形分をn-ヘプタンと混合し、加熱して溶解させ、冷却して結晶化させ、テトラメチルピラジンニトロンの結晶形Aを得る。 - 工程(1)における前記有機溶媒は酢酸エチル、n-ヘキサン、n-ヘプタン及びシクロヘキサンから選択される一種又は複数種であり、更に好ましくは、有機溶媒はn-ヘキサン又はn-ヘプタンである、又は、前記有機溶媒は、n-ヘキサンと酢酸エチルとの混合溶媒であり、工程(1)においてテトラメチルピラジンニトロン粗体と有機溶媒との重量体積比は1:5~20であり、好ましくは1:8~12であり、工程(1)において冷却して結晶化させる温度は2~12℃から選択され、より好ましくは3~10℃であり、最も好ましくは3~5℃であり、工程(2)においてテトラメチルピラジンニトロン粗体とn-ヘプタンとの重量体積比は好ましくは1:1~5であり、最も好ましくは1:1~3であり、工程(2)において結晶性固形分をn-ヘプタンと混合して加熱する温度は60~80℃であり、好ましくは65~75℃であり、冷却して結晶化させる温度は2~12℃から選択され、より好ましくは4~10℃である、ことを特徴とする、請求項5に記載の製造方法。
- XRPDスペクトルが8.91±0.2、11.46±0.2、14.29±0.2、17.60±0.2、21.19±0.2、22.02±0.2、23.19±0.2、24.30±0.2、24.92±0.2、29.20±0.2、31.41±0.2の2θ角度位置に特徴的な回折ピークを示し、好ましくは、XRPDスペクトルが8.91±0.2、11.46±0.2、12.00±0.2、14.29±0.2、17.60±0.2、19.50±0.2、21.19±0.2、22.02±0.2、23.19±0.2、24.30±0.2、24.92±0.2、26.70±0.2、29.20±0.2、31.41±0.2、36.20±0.2の2θ角度位置に特徴的な回折ピークを示すことを特徴とする、テトラメチルピラジンニトロンの二水和物。
- 融点が37~40℃であることを特徴とする、請求項7に記載の二水和物。
- 請求項1~4のいずれか一項に記載の結晶形A又は請求項7~8のいずれか一項に記載の二水和物を含む、薬物組成物。
- 神経系疾患、心血管・脳血管疾患及び変性老化疾患の治療用の薬物の製造における、請求項1~4のいずれか一項に記載の結晶形A又は請求項7~8のいずれか一項に記載の二水和物の使用。
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PCT/CN2019/098724 WO2020199440A1 (zh) | 2019-04-01 | 2019-07-31 | 硝酮嗪晶型、制备方法及应用 |
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US (1) | US20220153707A1 (ja) |
EP (1) | EP3950679A4 (ja) |
JP (1) | JP2022540275A (ja) |
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WO2020199440A1 (zh) | 2020-10-08 |
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AU2019439986A1 (en) | 2021-11-18 |
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