WO2018221551A1 - ピラゾロキノリン誘導体を含有するレビー小体病治療剤 - Google Patents
ピラゾロキノリン誘導体を含有するレビー小体病治療剤 Download PDFInfo
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- WO2018221551A1 WO2018221551A1 PCT/JP2018/020650 JP2018020650W WO2018221551A1 WO 2018221551 A1 WO2018221551 A1 WO 2018221551A1 JP 2018020650 W JP2018020650 W JP 2018020650W WO 2018221551 A1 WO2018221551 A1 WO 2018221551A1
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- lewy body
- dementia
- disease
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- parkinson
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Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a therapeutic agent for Lewy body dementia and Parkinson's disease associated with dementia, comprising a pyrazoloquinoline derivative having phosphodiesterase 9 (PDE9) inhibitory activity or a pharmaceutically acceptable salt thereof as an active ingredient. is there.
- PDE9 phosphodiesterase 9
- Lewy body dementia (DLB; Dementia with Lewy bodies), Parkinson's disease (PD), an abnormal inclusion body (Lewy body) mainly composed of ⁇ -synuclein appears in nerve cells. It is a progressive neurodegenerative disease that causes degeneration and shedding. When Lewy bodies are distributed in large amounts in the cerebral cortex, cognitive dysfunction develops, and when they are distributed in large numbers in the brain stem, Parkinsonism develops. Other symptoms include hallucinations, hallucinations, delusions, mental symptoms such as depressive symptoms, sleep disorders, and autonomic symptoms.
- DLB Dementia with Lewy bodies
- PD Parkinson's disease
- Lewy body an abnormal inclusion body mainly composed of ⁇ -synuclein appears in nerve cells. It is a progressive neurodegenerative disease that causes degeneration and shedding.
- Lewy bodies When Lewy bodies are distributed in large amounts in the cerebral cortex, cognitive dysfunction develops, and when they are distributed in large numbers in the brain stem, Parkinsonism develops
- Lewy body dementia is diagnosed when dementia develops before or within 1 year of onset of Parkinsonism, but Parkinson's disease with dementia occurs when Parkinsonism has existed more than 1 year before the onset of dementia Diagnosed as (PDD; Parkinson disease with dementia).
- PDD Parkinson disease with dementia
- the diagnosis is different from Lewy body dementia, Parkinson's disease with dementia, and Parkinson's disease. These are considered to be the same disease and are collectively referred to as Lewy body disease (LBD).
- LBD Lewy body disease
- brain SPECT and FDG PET in addition to the posterior cingulate gyrus and parietotemporal cortex associated with Alzheimer's disease, decreased blood flow and abnormal glucose metabolism are seen in the occipital lobe including the visual region.
- DAT dopamine transporter
- Non-Patent Documents 5, 6, 7, and 8 there is no fundamental treatment that modifies the progress of brain lesions in Lewy body dementia and Parkinson's disease.
- Parkinson's symptoms dopamine adjuvant therapy such as L-DOPA or surgery is performed.
- the only approved indications for cognitive impairment are donepezil for dementia with Lewy bodies and rivastigmine for Parkinson's disease with dementia, including changes in cognitive function, psychiatric symptoms (hall hallucinations, delusions, apathy, depression) (Symptoms, behavioral symptoms) are also effective (see Non-Patent Documents 5, 6, 7, and 8).
- Non-Patent Document 9 acetylcholinesterase inhibitors worsen Parkinson's symptoms
- Pimavanserin a 5-HT 2A inverse agonist
- atypical antipsychotics such as olanzapine, quetiapine, and risperidone
- black box warnings that the risk of death increases when used to treat psychiatric symptoms of dementia in the elderly.
- scopolamine is a muscarinic receptor inhibitor that blocks transmission in the acetylcholine nervous system.
- the acetylcholine nervous system is involved in memory, attention, etc., healthy people and animals receiving scopolamine show dementia-like amnesia, and are attenuated by drugs used to treat cognitive impairment in Lewy body disease (See Non-Patent Documents 11 and 12).
- 6-OHDA is a neurotoxin that selectively denatures dopaminergic and noradrenergic nerves.
- a compound represented by formula (I) (hereinafter referred to as compound (I)) or a pharmaceutically acceptable salt thereof exhibits a PDE9 inhibitory action and is expected to be effective against Alzheimer's dementia (patent) Reference 1).
- a PDE9 inhibitor showed a cognitive function improving effect in a novel object recognition test using scopolamine-induced cognitive impairment rats (see Non-Patent Document 14), a pyrazoloquinoline derivative that showed a cognitive function improving effect was unknown.
- An object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof that exhibits an anti-dementia effect in an animal model and has the potential to be used as a therapeutic agent for Lewy body disease.
- the present inventors have found that a pyrazoloquinoline derivative represented by the formula (I) or a pharmacologically thereof. It has been found that acceptable salts have the effect of suppressing cognitive dysfunction induced by scopolamine. In addition, the present inventors have found that the effect of improving cognitive function against Lewy body disease can be confirmed by evaluating using a 6-OHDA model.
- the present invention relates to ⁇ 1> to ⁇ 4> below.
- a therapeutic agent for Parkinson's disease associated with Lewy body dementia or dementia comprising a pharmaceutically acceptable salt thereof.
- the pyrazoloquinoline derivative of the present invention or a pharmaceutically acceptable salt thereof exhibits an effect of suppressing cognitive dysfunction induced by scopolamine in a rat model of scopolamine-induced cognitive impairment, which is an animal model of Lewy body disease.
- the pyrazoloquinoline derivative of the present invention or a pharmaceutically acceptable salt thereof is expected to show an effect of suppressing cognitive dysfunction in a 6-OHDA model that is an animal model of Lewy body disease. Therefore, the compound according to the present invention or a pharmaceutically acceptable salt thereof has applicability as a therapeutic agent for Lewy body disease.
- the “pharmaceutically acceptable salt” in the present specification is not particularly limited as long as it forms a salt with the compound according to the present invention, and specifically, for example, an inorganic acid salt or an organic acid salt. Or acid addition salts, such as acidic amino acid salt, are mentioned.
- the “pharmaceutically acceptable salt” means that an acid for one molecule of the compound is formed in the formed salt as long as the salt is formed in an appropriate ratio.
- the number of molecules is not particularly limited, but in one embodiment, the acid is about 0.1 to about 5 molecules per molecule of the compound, and in another embodiment, the acid is about 0.001 molecule per molecule of the compound. In another embodiment, the acid is about 0.5, about 1, or about 2 molecules per molecule of the compound.
- the inorganic acid salt include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like.
- Specific examples of the organic acid salt include, for example, acetate. Succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, etc. It is done.
- acidic amino acid salts include aspartate and glutamate.
- the pharmaceutical composition according to the present invention can be produced by mixing a pharmaceutically acceptable additive with compound (I) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition according to the present invention can be produced in accordance with a known method such as the method described in the General Formulation of the 16th revised Japanese Pharmacopoeia.
- the pharmaceutical composition according to the present invention can be appropriately administered to a patient according to its dosage form.
- the dose of Compound (I) or a pharmaceutically acceptable salt thereof varies depending on the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, etc. In the case of an adult, about 30 ⁇ g to 10 g orally per day, 100 ⁇ g to 5 g in one embodiment, 100 ⁇ g to 1 g in another embodiment, about 30 ⁇ g to 1 g by injection administration, 100 ⁇ g to 500 mg in one embodiment, In another embodiment, 100 ⁇ g to 300 mg is administered once or divided into several times.
- Compound (I) can be produced, for example, by the method described in Patent Document 1.
- Scopolamine (Wako Pure Chemical Industries) was administered at a dose of 0.7 mg / kg subcutaneously in saline as a medium 30 minutes before T1.
- T1 the rats were habituated to an empty test apparatus for 3 minutes and then placed in the waiting room.
- T2 a retention trial
- T1 familiar object
- new object the object not used in T1
- T1 and T2 rat behavior was photographed with a digital video camera, and the total search time for each object was manually measured using a stopwatch. The behavior in which the rat approached the nose within 2 cm of the object and the nose was directed toward the object was defined as the search behavior.
- the new object search rate of T2 is regarded as an amnestic index that reflects discrimination between a known object and a new object.
- the difference between the disease state control group and the drug-only treatment group was analyzed using Dunnett's multiple comparison test (significant difference: #). p ⁇ 0.05 was judged as a statistically significant difference. Statistical analysis was performed using GraphPad Prism version 5.04 or 6.02.
- the rats in the pathological condition control group showed a significant decrease in the new object search rate compared with the rats in the normal control group. This means that scopolamine induced memory impairment in rats.
- Compound (I) showed a significant improvement effect of the new object search rate at 3.3 mg / kg and 10 mg / kg.
- 6-OHDA model Male SD rats are used to create the 6-OHDA model. The rat is fixed to a stereotaxic apparatus under anesthesia, and after exposing the skull, a cannula is inserted into the brain. 6-OHDA dissolved in ascorbic acid-added physiological saline is infused over several minutes using a microinjection pump. In order to protect the noradrenaline nerve, desipramine is administered before 6-OHDA injection. 6-OHDA untreated rats are created by cannulating the same site in the brain. A few days after surgery, a new object recognition test or object position recognition test is performed. A new object recognition test is described in Ennacer etc.
- the test method described in 47-51 is partially modified.
- the object position recognition test was conducted in accordance with Dix Behavior Brain Research 99 (1999) pp.
- the test method described in 191-200 is partially modified.
- the object position recognition test is a cognitive function evaluation test system based on the voluntary behavioral characteristics of rodents that the search behavior increases when the environment where the object is placed changes even if it is a familiar object . In all tests, habituation to the experimental procedure is performed before the test date. In the running-in operation, the vehicle is administered with a medium, and an empty test apparatus (40 cm ⁇ 30 cm ⁇ 45 cm in height) is freely searched for a fixed time (several minutes to several tens of minutes).
- T1 On the day of the test, Compound (I) is orally administered prior to the acquisition trial (T1).
- T1 two identical objects installed in the test apparatus are freely searched for a predetermined time (several minutes). Rats are returned to their home cages and then a holding trial (T2) is performed.
- T2 of the new object recognition test an object used in T1 (“familiar” object) and an object not used in T1 (“new” object) are installed one by one in the test apparatus, and these objects are set for a certain period of time (several minutes). ) Search freely.
- T2 of the object position recognition test one of the two identical objects presented in T1 is changed to a new position and installed in the test apparatus.
- the object is wiped with wet tissue containing ethanol after each experiment so that no clues of odor remain.
- the behavior of rats at T1 and T2 is photographed with a digital video camera, and the total search time for each object is manually measured using a stopwatch.
- the behavior in which the rat brings the nose close to within 2 cm of the object and the nose is directed toward the object is defined as a search behavior.
- the new object search ratio of T2 is regarded as an amnestic index that reflects discrimination between a known object and a new object.
- the new position search ratio of T2 is regarded as an amnestic index that reflects discrimination between a known position and a new position.
- the new object search ratio and the new position object search ratio are calculated by the following formulas.
- New object search ratio (%) No / (No + Fo) ⁇ 100
- Fo Known object search time
- New position object search ratio (%) Nl / (Nl + Fl) ⁇ 100
- Fl Known position object search time
- the new object search ratio or the new position object search ratio is compared between groups to confirm the effect of the compound (I).
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Abstract
Description
<1>(S)-7-(2-メトキシ-3,5-ジメチルピリジン-4-イル)-1-(テトラヒドロフラン-3-イル)-1H-ピラゾロ[4,3-c]キノリン-4(5H)-オン
<2>(S)-7-(2-メトキシ-3,5-ジメチルピリジン-4-イル)-1-(テトラヒドロフラン-3-イル)-1H-ピラゾロ[4,3-c]キノリン-4(5H)-オン
<3>レビー小体型認知症または認知症を伴うパーキンソン病の治療に使用される、(S)-7-(2-メトキシ-3,5-ジメチルピリジン-4-イル)-1-(テトラヒドロフラン-3-イル)-1H-ピラゾロ[4,3-c]キノリン-4(5H)-オン
<4>レビー小体型認知症または認知症を伴うパーキンソン病治療剤の製造のための、(S)-7-(2-メトキシ-3,5-ジメチルピリジン-4-イル)-1-(テトラヒドロフラン-3-イル)-1H-ピラゾロ[4,3-c]キノリン-4(5H)-オン
本発明に係る医薬組成物は、薬剤学的に許容される添加物を化合物(I)またはその薬剤学的に許容される塩と混和することにより製造することができる。本発明に係る医薬組成物は、例えば第十六改正日本薬局方の製剤総則に記載の方法など既知の方法に従って製造することができる。
本発明に係る医薬組成物は、その剤形に応じて適切に患者に投与することができる。
本発明者らは、レビー小体病に対する認知機能改善効果を確認するために以下の試験を行った、または行うことができる。
アセチルコリン神経系障害によって誘発される認知機能障害に対する改善効果を確認する為、スコポラミン誘発認知機能障害ラットを用いた新規物体認識試験を実施した。新規物体認識試験は、見慣れた物体よりも新規の物体をより多く探索するというげっ歯類の自発的な行動特性に基づいた認知機能評価試験系である。Ennacer etc. Behavioural Brain Research,31(1988)pp.47-51に記載された試験方法を一部修正して実施した。
6週齢の雄性Long Evansラット(一般財団法人動物繁殖研究所)を試験に供した。試験前2日間にわたり、実験手順への慣らし操作を1日1回行った。慣らし操作では、ラットに媒体投与を行い、その後、空の試験装置(40cm×30cm×高さ45cm)にラットを入れて3分間探索させ、控室(13cm×30cm×高さ45cm)に1分程度入れたのち、再び空の試験装置にラットを戻し5分間置いた。
試験日当日、獲得試行(T1)を行った。化合物(I)はT1の2時間前に、0.5%メチルセルロースの0.01M塩酸溶液を媒体に経口投与した。スコポラミン(和光純薬工業)は0.7mg/kg用量でT1の30分前に、生理食塩水を媒体に皮下投与した。T1では、ラットを3分間、空の試験装置に慣らした後、控室に入れた。試験装置に2つの同一の物体を設置した後、再びラットを試験装置に戻し、2つの同一の物体を5分間自由に探索させた。その後、ラットは飼育ケージに戻した。2時間後、保持試行(T2)を行った。ラットを空の試験装置に3分間入れて慣らした後、控室に移した。T1で使った物体(“familiar”物体)とT1で使っていない物体(“新規”物体)を1つずつ試験装置に設置した後、再びラットを試験装置に戻し、これら物体を3分間自由に探索させた。匂いの手がかりが残らないよう、物体は実験のたびにエタノールを含んだウエットティシュでふき取った。T1とT2のラットの行動はデジタルビデオカメラで撮影し、各物体の総探索時間をストップウォッチを用いてマニュアルで計測した。ラットが鼻を物体の2cm以内に近づけ、鼻を物体に向けている行動を、探索行動と定義した。
新規物体認識試験ではT2の新規物体探索割合を既知物体と新規物体の弁別を反映する健忘指標とみなす。新規物体探索割合は以下の計算式で算出した。
新規物体探索割合(%)=N/(N+F)×100
F:既知物体探索時間
N:新規物体探索時間
T1ないしはT2において物体の総探索時間が10秒以下のラット、または、T1においていずれかの物体に対する探索時間の割合が総探索時間の70%以上ないしは30%以下のラットはデータ解析から除外した。
結果は平均値±標準誤差で表した。スコポラミン非処置の正常対照群とスコポラミン処置の病態対照群間の差は対応のないt検定で解析した(有意差あり:*)。病態対照群と薬剤単独処置群との差はDunnett型多重比較検定を用いて解析した(有意差あり:#)。p<0.05を統計学的有意差として判断した。統計解析はGraphPad Prism version 5.04 または6.02を用いて行った。
T2において、病態対照群のラットは正常対照群のラットに比べて新規物体探索割合の有意な低下を示した。これは、スコポラミンによってラットの記憶障害が誘発されたことを意味するものである。化合物(I)は3.3mg/kgおよび10mg/kgで新規物体探索割合の有意な改善効果を示した
レビー小体病の前臨床病態モデルとしては、レビー小体病関連遺伝子を改変またはレビー小体病関連物質を導入して作成した細胞モデルや動物モデル(αシヌクレイントランスジェニック、AAVベクターを用いたαシヌクレイン過剰発現、Parkinノックアウト、DJ-1ノックアウト、αシヌクレイン凝集体注入モデルなど)、レビー小体病患者で確認されている神経系障害を反映した薬剤投与モデル(6-OHDA、MPTP、パラコート、ロテノン、LPS、サポリン毒素などの神経毒投与モデル、スコポラミンなどの神経遮断薬投与モデルなど)、患者iPS細胞由来の神経細胞モデルなどがあり、レビー小体病に対する薬剤の効果はこれら前臨床モデルで確認することができる。
ここでは6-OHDAモデルを用いてレビー小体病の治療効果を確認できることを示す。
6-OHDAモデル作成には雄性SDラットを用いる。ラットは麻酔下にて脳定位保定装置に固定し、頭蓋骨を露出させたのちカニューレを脳内に挿入する。アスコルビン酸添加生理食塩水に溶解させた6-OHDAをマイクロインジェクションポンプを用いて数分かけて注入する。ノルアドレナリン神経を保護する為、6-OHDA注入前にデシプラミンを投与する。6-OHDA無処置ラットは、脳内の同部位にカニューレを挿入し作成する。手術の数日後、新規物体認識試験または物体位置認識試験を行う。新規物体認識試験はEnnacer etc. Behavioural Brain Research,31(1988)pp.47-51に記載された試験方法を一部修正して行う。物体位置認識試験は、Dix Behavioural Brain Research 99(1999)pp.191-200に記載された試験方法を一部修正して行う。物体位置認識試験は、見慣れた物体であっても、物体の置かれた環境が変化した場合に探索行動が増加するというげっ歯類の自発的な行動特性に基づいた認知機能評価試験系である。
いずれの試験も、試験日以前に実験手順への慣らし操作を行う。慣らし操作では、ラットに媒体投与を行い、空の試験装置(40cm×30cm×高さ45cm)を一定時間(数分間~数十分間)自由に探索させる。
試験日当日、化合物(I)を獲得試行(T1)の前に経口投与する。いずれの試験でもT1では試験装置に設置した2つの同一の物体を一定時間(数分間)自由に探索させる。ラットを飼育ケージに戻し、その後保持試行(T2)を行う。新規物体認識試験のT2では、試験装置にT1で使った物体(“familiar”物体)とT1で使っていない物体(“新規”物体)を1つずつ設置し、これら物体を一定時間(数分間)自由に探索させる。物体位置認識試験のT2では、T1で提示した2つの同一の物体のうち1つを新規位置にかえて、試験装置に設置する。これら物体を一定時間(数分間)自由に探索させる。いずれの試験においても、匂いの手がかりが残らないよう、物体は実験のたびにエタノールを含んだウエットティシュでふき取る。T1とT2のラットの行動はデジタルビデオカメラで撮影し、各物体の総探索時間をストップウォッチを用いてマニュアルで計測する。ラットが鼻を物体の2cm以内に近づけ、鼻を物体に向けている行動を、探索行動と定義する。
新規物体認識試験では、T2の新規物体探索割合を既知物体と新規物体の弁別を反映する健忘指標とみなす。物体位置認識試験では、T2の新規位置探索割合を既知位置と新規位置の弁別を反映する健忘指標とみなす。新規物体探索割合および新規位置物体探索割合は以下の計算式で算出する。
新規物体探索割合(%)=No/(No+Fo)×100
Fo:既知物体探索時間
No:新規物体探索時間
新規位置物体探索割合(%)=Nl/(Nl+Fl)×100
Fl:既知位置物体探索時間
Nl:新規位置物体探索時間
新規物体探索割合または新規位置物体探索割合を群間比較し、化合物(I)の効果を確認する。
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AU2018276568A1 (en) | 2017-06-01 | 2019-11-07 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and memantine |
MX2019013198A (es) | 2017-06-01 | 2020-01-20 | Eisai R&D Man Co Ltd | Composicion farmaceutica que comprende un inhibidor de (s)-7-(2metoxi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)- 1h-pirazolo[4,3-c]quinolin-4(5h)-ona (pde9). |
SG10202113198TA (en) | 2017-06-01 | 2021-12-30 | Eisai R&D Man Co Ltd | Dementia therapeutic agent combining pyrazoloquinoline derivative and donepezil |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013051639A1 (ja) * | 2011-10-07 | 2013-04-11 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピラゾロキノリン誘導体 |
WO2014163147A1 (ja) * | 2013-04-05 | 2014-10-09 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピラゾロキノリン誘導体の塩およびその結晶 |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5318759A (en) | 1976-08-02 | 1978-02-21 | Nisshin Oil Mills Ltd | Method of making fried beancurd |
JPH05132484A (ja) | 1991-04-26 | 1993-05-28 | Otsuka Pharmaceut Factory Inc | ピラゾロキノリン及びピラゾロナフチリジン誘導体 |
JP2828506B2 (ja) | 1994-05-24 | 1998-11-25 | エフ・ホフマン−ラ ロシュ アーゲー | 三環式ジカルボニル誘導体 |
DE19642591A1 (de) | 1996-10-15 | 1998-04-16 | Basf Ag | Neue Piperidin-Ketocarbonsäure-Derivate, deren Herstellung und Anwendung |
HN2002000317A (es) | 2001-11-02 | 2003-05-21 | Pfizer | Inhibidores de pde9 para tratamiento de trastornos cardiovasculares |
AU2003250539A1 (en) | 2002-08-07 | 2004-02-25 | Mitsubishi Pharma Corporation | Dihydropyrazolopyridine compounds |
DE10238722A1 (de) * | 2002-08-23 | 2004-03-11 | Bayer Ag | Selektive Phosphodiesterase 9A-Inhibitoren als Arzneimittel zur Verbesserung kognitiver Prozesse |
DE102004004142A1 (de) | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | 6-Cyclylmethyl- und 6-Alkylmethyl-substituierte Pyrazolopyrimidine |
RU2426734C2 (ru) | 2003-10-03 | 2011-08-20 | Зм Инновейтив Пропертиз Компани | Пиразолопиридины и их аналоги |
WO2005118583A1 (en) | 2004-05-28 | 2005-12-15 | Millennium Pharmaceuticals, Inc. | 2, 5-dihydro-pyrazolo`4, 3-c!quinolin-4-ones as chk-1 inhibitors |
JP2006045118A (ja) | 2004-08-04 | 2006-02-16 | Mochida Pharmaceut Co Ltd | 新規ピラゾロキノロン誘導体 |
CN101268073B (zh) | 2005-09-15 | 2011-10-19 | Aska制药株式会社 | 杂环化合物、制备方法及其用途 |
ES2536906T3 (es) | 2006-12-13 | 2015-05-29 | Aska Pharmaceutical Co., Ltd. | Derivado de quinoxalina |
CA2672591A1 (en) | 2006-12-13 | 2008-06-19 | Aska Pharmaceutical Co., Ltd. | Treating agent of uropathy |
NZ580904A (en) | 2007-05-11 | 2012-02-24 | Pfizer | Amino-heterocyclic compounds for inhibiting pde9 |
UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
PE20110383A1 (es) | 2008-09-08 | 2011-07-15 | Boehringer Ingelheim Int | Pirazolopirimidinonas como inhibidores de la fosfodiesterasa 9a (pde9a) |
TWI404721B (zh) | 2009-01-26 | 2013-08-11 | Pfizer | 胺基-雜環化合物 |
CN102341399A (zh) | 2009-03-05 | 2012-02-01 | 安斯泰来制药株式会社 | 喹喔啉化合物 |
JP5542196B2 (ja) | 2009-03-31 | 2014-07-09 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1−複素環−1,5−ジヒドロ−ピラゾロ[3,4−d]ピリミジン−4−オン誘導体及びpde9aモジュレーターとしてのそれらの使用 |
US8880976B2 (en) | 2009-09-25 | 2014-11-04 | Stmicroelectronics, Inc. | Method and apparatus for encoding LBA information into the parity of a LDPC system |
PL2603511T3 (pl) | 2010-08-12 | 2017-08-31 | Boehringer Ingelheim Int | Pochodne 6-cykloalkilo-1,5-dihydropirazolo[3,4-d]pirymidyn-4-onu i ich zastosowanie jako inhibitorów PDE9A |
ES2583528T3 (es) | 2010-09-07 | 2016-09-21 | Astellas Pharma Inc. | Compuesto de pirazoloquinolina |
US20130040971A1 (en) | 2011-02-14 | 2013-02-14 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of cns disorders |
JP6042060B2 (ja) | 2011-09-26 | 2016-12-14 | サノフイ | ピラゾロキノリノン誘導体、その調製および治療上の使用 |
PT2573073E (pt) | 2011-09-26 | 2015-02-05 | Sanofi Sa | Derivados de pirazoloquinolinona, sua preparação e sua utilização terapêutica |
PE20151718A1 (es) | 2013-04-05 | 2015-11-22 | Eisai Randd Man Co Ltd | Compuestos piridinilpirazoloquinolina |
AU2018276568A1 (en) | 2017-06-01 | 2019-11-07 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and memantine |
SG10202113198TA (en) | 2017-06-01 | 2021-12-30 | Eisai R&D Man Co Ltd | Dementia therapeutic agent combining pyrazoloquinoline derivative and donepezil |
MX2019013198A (es) | 2017-06-01 | 2020-01-20 | Eisai R&D Man Co Ltd | Composicion farmaceutica que comprende un inhibidor de (s)-7-(2metoxi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)- 1h-pirazolo[4,3-c]quinolin-4(5h)-ona (pde9). |
-
2018
- 2018-05-30 KR KR1020197033124A patent/KR20200010220A/ko not_active Application Discontinuation
- 2018-05-30 CN CN201880030146.7A patent/CN110612102A/zh active Pending
- 2018-05-30 BR BR112019023552-3A patent/BR112019023552A2/pt unknown
- 2018-05-30 CA CA3061884A patent/CA3061884A1/en active Pending
- 2018-05-30 US US16/611,374 patent/US11311530B2/en active Active
- 2018-05-30 EP EP18810202.4A patent/EP3632438B1/en active Active
- 2018-05-30 TW TW107118423A patent/TWI784006B/zh active
- 2018-05-30 IL IL270357A patent/IL270357B2/en unknown
- 2018-05-30 ES ES18810202T patent/ES2961554T3/es active Active
- 2018-05-30 AU AU2018278422A patent/AU2018278422B2/en active Active
- 2018-05-30 WO PCT/JP2018/020650 patent/WO2018221551A1/ja active Application Filing
- 2018-05-30 MX MX2019013397A patent/MX2019013397A/es unknown
- 2018-05-30 JP JP2019521251A patent/JP7269875B2/ja active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013051639A1 (ja) * | 2011-10-07 | 2013-04-11 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピラゾロキノリン誘導体 |
US8563565B2 (en) | 2011-10-07 | 2013-10-22 | Eisai R&D Management Co., Ltd. | Pyrazoloquinoline derivatives |
WO2014163147A1 (ja) * | 2013-04-05 | 2014-10-09 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピラゾロキノリン誘導体の塩およびその結晶 |
Non-Patent Citations (18)
Title |
---|
"(non-official translation) "materials in reporter meeting"", 9 March 2017 (2017-03-09), Japan (internet), XP055636315, Retrieved from the Internet <URL:https://www.eisai.co.jp/ir/library/presentations/pdf/4523_170309.pdf> [retrieved on 20191028] * |
"(non-official translation) Chapter 7: Dementia with Lewy bodies (included Parkinson's disease)", DEMENTIA DISEASE TREATMENT GUIDELINES 2010, JAPANESE SOCIETY OF NEUROLOGY, 2010, pages 300 - 302, XP055636341, Retrieved from the Internet <URL:http://www.neurology-jp.org/guidlinem/degl/sinkei_degl_2010_08.pdf> * |
"Dix Behavioural Brain Research", vol. 99, 1999, pages: 191 - 200 |
"General Rules for Preparations of the Japanese Pharmacopoeia", vol. 31, 1988, pages: 47 - 51 |
BERGMAN ET AL., CLIN. NEUROPHARMACOL., vol. 25, 2002, pages 107 - 110 |
BOURKE ET AL., ANN. PHARMACOTHER., vol. 32, 1998, pages 610 - 611 |
CUMMINGS ET AL., LANCET, vol. 383, 2014, pages 533 - 540 |
DUBOIS ET AL., MOVEMENT DISORDERS, vol. 27, 2012, pages 1230 - 1238 |
HUTSON ET AL., NEUROPHARMACOLOGY, vol. 61, 2011, pages 665 - 676 |
KADOWAKI ET AL., PSYCHOPHARMACOLOGY, vol. 230, 2013, pages 345 - 352 |
MCKEITH ET AL., LANCET, vol. 356, 2000, pages 2031 - 2036 |
MCKEITH ET AL., NEUROLOGY, vol. 65, 2005, pages 1863 - 1872 |
MORI ET AL., ANN. NEUROL, VOL., vol. 72, 2012, pages 41 - 52 |
PERRY, NEUROREPORT, vol. 5, 1994, pages 747 - 749 |
SAMBETH ET AL., EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 572, 2007, pages 151 - 159 |
SHIMADA ET AL., NEUROLOGY, vol. 73, 2009, pages 273 - 278 |
SNYDER ET AL., ALZHEIMER'S & DEMENTIA, vol. 1, 2005, pages 126 - 135 |
TIRABOSCHI ET AL., NEUROLOGY, vol. 54, 2000, pages 407 - 411 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
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BR112019023552A2 (pt) | 2020-06-02 |
JPWO2018221551A1 (ja) | 2020-04-02 |
ES2961554T3 (es) | 2024-03-12 |
EP3632438A4 (en) | 2020-12-23 |
EP3632438A1 (en) | 2020-04-08 |
US20200155541A1 (en) | 2020-05-21 |
TWI784006B (zh) | 2022-11-21 |
IL270357A (ja) | 2020-02-27 |
CA3061884A1 (en) | 2019-10-29 |
AU2018278422B2 (en) | 2022-03-17 |
AU2018278422A1 (en) | 2019-11-21 |
JP7269875B2 (ja) | 2023-05-09 |
CN110612102A (zh) | 2019-12-24 |
EP3632438B1 (en) | 2023-08-23 |
IL270357B1 (en) | 2023-10-01 |
RU2019135690A3 (ja) | 2021-08-25 |
MX2019013397A (es) | 2020-02-07 |
TW201902479A (zh) | 2019-01-16 |
RU2019135690A (ru) | 2021-07-13 |
US11311530B2 (en) | 2022-04-26 |
IL270357B2 (en) | 2024-02-01 |
KR20200010220A (ko) | 2020-01-30 |
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