JP2002338467A - Adenylate cyclase type 5 inhibitor - Google Patents
Adenylate cyclase type 5 inhibitorInfo
- Publication number
- JP2002338467A JP2002338467A JP2001153954A JP2001153954A JP2002338467A JP 2002338467 A JP2002338467 A JP 2002338467A JP 2001153954 A JP2001153954 A JP 2001153954A JP 2001153954 A JP2001153954 A JP 2001153954A JP 2002338467 A JP2002338467 A JP 2002338467A
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- acceptable salt
- pharmacologically acceptable
- active ingredient
- adenylate cyclase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、７，８−ジヒドロ
−５（６Ｈ）−キナゾリノン誘導体のアデニル酸シクラ
ーゼ５型阻害剤としての用途に関する。TECHNICAL FIELD The present invention relates to the use of a 7,8-dihydro-5 (6H) -quinazolinone derivative as an adenylate cyclase type 5 inhibitor.
【０００２】[0002]
【従来の技術】アドレナリンβ１受容体を遮断する薬剤
は、循環器疾患の治療薬として世界的に広く認知されて
いる薬剤である。その作用機序はβ１受容体を介して間
接的にアデニル酸シクラーゼを制御し、細胞内ｃＡＭＰ
量を調節することによる。その優れた臨床効果から積極
的使用が推奨されているものの、低い受容体の組織特異
性に基づく副作用により、その使用頻度や使用継続性
（服薬コンプライアンス）は他の循環器作用薬に比べて
低い（Ｃｌｉｎｉｃａｌ Ｔｈｅｒａｐｅｕｔｉｃｓ、
２０巻、６７１項（１９９８年））。例えば、気管支喘
息を併発している患者には禁忌であり、肺への作用がな
いβ１遮断作用を有する化合物の開発が大きな課題とな
っている。2. Description of the Related Art Drugs that block the adrenergic β1 receptor are widely recognized worldwide as therapeutic agents for cardiovascular diseases. Its mechanism of action regulates adenylate cyclase indirectly via the β1 receptor, and intracellular cAMP
By adjusting the amount. Active use is recommended for its excellent clinical efficacy, but its frequency of use and continuity of use (drug compliance) are lower than other cardiovascular drugs due to side effects based on the low tissue specificity of the receptor. (Clinical Therapeutics,
20, 671 (1998)). For example, it is contraindicated for patients with bronchial asthma, and the development of a compound having a β1-blocking action that has no effect on the lungs has been a major issue.
【０００３】アデニル酸シクラーゼは、主にβ受容体か
らの刺激により活性化され、ATPを基質としてcAMPを産
生する酵素である。１９８９年に初めてクローニングさ
れて以来、９種類のサブタイプが見いだされているが、
サブタイプの組織分布が著明に異なることが最近明らか
になった。例えば、心臓にはアデニル酸シクラーゼ５型
の分布が多く他の末梢臓器、例えば肺にはほとんどアデ
ニル酸シクラーゼ５型は発現していないことが明らかに
されている（Ｃｉｒｃｕｌａｔｉｏｎ Ｒｅｓｅａｒｃ
ｈ、８０巻、２９７項（１９９７年））。このことか
ら、アデニル酸シクラーゼ５型阻害薬を創製することに
より、β１受容体の組織特異性が低いことによるβ１受
容体遮断薬の副作用が改善でき、高い心臓選択性を持つ
循環器作用剤（高血圧症、心不全、狭心症、不整脈治療
薬）を医療現場に供給することが出来る。[0003] Adenylate cyclase is an enzyme that is activated mainly by stimulation from a β receptor and produces cAMP using ATP as a substrate. Since its first cloning in 1989, nine subtypes have been discovered.
It has recently been found that the tissue distribution of subtypes is significantly different. For example, it has been shown that adenylate cyclase type 5 is highly distributed in the heart, and almost no adenylate cyclase type 5 is expressed in other peripheral organs, for example, the lungs (Circulation Research).
h, 80, 297 (1997)). From this, by creating an adenylate cyclase type 5 inhibitor, the side effect of the β1 receptor blocker due to the low tissue specificity of the β1 receptor can be improved, and a cardiovascular agent having high cardiac selectivity ( Medicine for treating hypertension, heart failure, angina pectoris, and arrhythmia).
【０００４】アデニル酸シクラーゼの阻害剤はいくつか
報告されている。ＳＱ２２５３６はアデノシン誘導体で
あり、アデニル酸シクラーゼ阻害薬として、例えばカル
ビオケム社から販売されている。また、ジョンソンらに
よる、同様のヌクレオシド誘導体、あるいはヌクレオチ
ド誘導体によるアデニル酸シクラーゼ阻害の報告がある
（Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．、２７４巻、３４７４２項
（１９９９年）、Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．、２７２
巻、８９６２項（１９９７年））。しかし、これらのヌ
クレオシド誘導体、あるいはヌクレオチド誘導体は生体
成分類似物であり副作用が懸念され、さらにその物性か
らアデニル酸シクラーゼの存在する細胞膜内に到達しに
くいと考えられ、医薬品としては適していない。またそ
の他にもいくつか非核酸系の化合物の報告もあるが、阻
害に要する濃度が非常に高く、活性として満足のいくも
のはない。このような状況ではあるが、医療上の有用性
が高いアデニル酸シクラーゼ５型を阻害する薬剤の提供
は強く望まれている。一方、７，８−ジヒドロ−５（６
Ｈ）−キナゾリノン誘導体は、その合成法が既に報告さ
れているが、生理活性については記載がない（Ｊ．Ｈｅ
ｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｓｔｒｙ、２０巻、６
４９項（１９８３））。Several inhibitors of adenylate cyclase have been reported. SQ22536 is an adenosine derivative and is sold as an adenylate cyclase inhibitor, for example, by Calbiochem. In addition, Johnson et al. Have reported the inhibition of adenylate cyclase by similar nucleoside derivatives or nucleotide derivatives (J. Biol. Chem., 274, 34742 (1999), J. Biol. Chem., 272).
Vol., 8962 (1997)). However, these nucleoside derivatives or nucleotide derivatives are analogous to biological components, and there are concerns about side effects. Further, their physical properties are considered to make it difficult to reach the cell membrane where adenylate cyclase is present, and are not suitable as pharmaceuticals. Some other non-nucleic acid compounds have been reported, but the concentration required for inhibition is very high, and none of them has satisfactory activity. Under such circumstances, it is strongly desired to provide a drug that inhibits adenylate cyclase type 5 which has high medical utility. On the other hand, 7,8-dihydro-5 (6
Although a method for synthesizing the (H) -quinazolinone derivative has already been reported, no description is given of its physiological activity (J. He).
terocyclic Chemstry, Volume 20, 6
49 (1983)).
【０００５】[0005]
【発明が解決しようとする課題】本発明は、アデニル酸
シクラーゼ５型阻害活性を有する薬剤を提供するもので
ある。DISCLOSURE OF THE INVENTION The present invention provides a drug having an adenylate cyclase type 5 inhibitory activity.
【０００６】[0006]
【課題を解決するための手段】本発明者は鋭意研究を重
ねた結果、７，８−ジヒドロ−５（６Ｈ）−キナゾリノ
ン誘導体またはその薬理学的に許容されうる塩がアデニ
ル酸シクラーゼ５型を阻害することを見いだし、本発明
を完成した。すなわち、本発明は以下の(１)から（７）
に関するものである。The present inventors have made intensive studies and as a result, have found that a 7,8-dihydro-5 (6H) -quinazolinone derivative or a pharmacologically acceptable salt thereof is adenylate cyclase type 5 Inhibition was found, and the present invention was completed. That is, the present invention provides the following (1) to (7)
It is about.
【０００７】（１）下記一般式［１］(1) The following general formula [1]
【化３】 Embedded image
【０００８】［式中、Ａは酸素原子または硫黄原子を示
す］、または下記一般式［２］Wherein A represents an oxygen atom or a sulfur atom, or the following general formula [2]
【化４】 ［式中、Ｂは水素原子、メトキシ基またはハロゲン原子
を示す］で表される７，８−ジヒドロ−５（６Ｈ）−キ
ナゾリノン誘導体またはその薬理学的に許容される塩を
有効成分とするアデニル酸シクラーゼ５型阻害剤。Embedded image [Wherein B represents a hydrogen atom, a methoxy group or a halogen atom], an adenyl containing a 7,8-dihydro-5 (6H) -quinazolinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient Acid cyclase type 5 inhibitors.
【０００９】（２）１項記載の７，８−ジヒドロ−５
（６Ｈ）−キナゾリノン誘導体またはその薬理学的に許
容される塩を有効成分とする循環器作用薬。 （３）１項記載の７，８−ジヒドロ−５（６Ｈ）−キナ
ゾリノン誘導体またはその薬理学的に許容される塩を有
効成分とする高血圧治療薬。 （４）１項記載の７，８−ジヒドロ−５（６Ｈ）−キナ
ゾリノン誘導体またはその薬理学的に許容される塩を有
効成分とする心不全治療薬。 （５）１項記載の７，８−ジヒドロ−５（６Ｈ）−キナ
ゾリノン誘導体またはその薬理学的に許容される塩を有
効成分とする狭心症治療薬。 （６）１項記載の７，８−ジヒドロ−５（６Ｈ）−キナ
ゾリノン誘導体またはその薬理学的に許容される塩を有
効成分とする不整脈治療薬。 （７）１項記載の７，８−ジヒドロ−５（６Ｈ）−キナ
ゾリノン誘導体またはその薬理学的に許容される塩を有
効成分とする医薬。(2) 7,8-dihydro-5 as described in (1) above
A (6H) -quinazolinone derivative or a pharmacologically acceptable salt thereof as a circulatory agent comprising an active ingredient. (3) A therapeutic agent for hypertension comprising the 7,8-dihydro-5 (6H) -quinazolinone derivative or the pharmaceutically acceptable salt thereof according to the above item 1, as an active ingredient. (4) A therapeutic agent for heart failure comprising the 7,8-dihydro-5 (6H) -quinazolinone derivative or the pharmaceutically acceptable salt thereof according to the above item (1) as an active ingredient. (5) A therapeutic agent for angina pectoris, comprising the 7,8-dihydro-5 (6H) -quinazolinone derivative or the pharmacologically acceptable salt thereof according to the above item 1, as an active ingredient. (6) A therapeutic agent for arrhythmia comprising the 7,8-dihydro-5 (6H) -quinazolinone derivative or the pharmacologically acceptable salt thereof according to item 1 as an active ingredient. (7) A medicament comprising, as an active ingredient, the 7,8-dihydro-5 (6H) -quinazolinone derivative or the pharmaceutically acceptable salt thereof described in (1).
【００１０】[0010]
【発明の実施の形態】本発明において、一般式［１］に
示されたＡとは酸素原子、硫黄原子を示す。好ましいＡ
としては、酸素原子が挙げられる。また、一般式［２］
に示されたＢは水素原子、メトキシ基、またはハロゲン
原子を示す。ハロゲン原子としては、フッ素原子、塩素
原子、臭素原子が挙げられる。好ましいハロゲン原子と
しては塩素原子である。BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, A in the general formula [1] represents an oxygen atom or a sulfur atom. Preferred A
Examples include an oxygen atom. Also, the general formula [2]
Represents a hydrogen atom, a methoxy group, or a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Preferred halogen atoms are chlorine atoms.
【００１１】一般式［１］または一般式［２］で表され
る化合物としては、以下のような化合物が挙げられる。 １．２−アミノ−７−（４−クロロフェニル）−７、８
−ジヒドロ−５（６Ｈ）−キナゾリノン ２．２−アミノ−７−（４−メトキシフェニル）−７、
８−ジヒドロ−５（６Ｈ）−キナゾリノン ３．２−アミノ−７−フェニル−７、８−ジヒドロ−５
（６Ｈ）−キナゾリノン ４．２−アミノ−７−（２−フラニル）−７、８−ジヒ
ドロ−５（６Ｈ）−キナゾリノン ５．２−アミノ−７−（２−チエニル）−７、８−ジヒ
ドロ−５（６Ｈ）−キナゾリノンThe compound represented by the general formula [1] or [2] includes the following compounds. 1.2-amino-7- (4-chlorophenyl) -7,8
-Dihydro-5 (6H) -quinazolinone 2.2-amino-7- (4-methoxyphenyl) -7,
8-dihydro-5 (6H) -quinazolinone 3.2-amino-7-phenyl-7,8-dihydro-5
(6H) -quinazolinone 4.2-amino-7- (2-furanyl) -7,8-dihydro-5 (6H) -quinazolinone 5.2-amino-7- (2-thienyl) -7,8-dihydro -5 (6H) -quinazolinone
【００１２】本発明の化合物には立体異性体が存在する
が、本発明はこれらの異性体すべてを包含する。例え
ば、光学活性体及びラセミ体等はすべて本発明に含まれ
る。The compounds of the present invention exist in stereoisomers, and the present invention includes all these isomers. For example, optically active forms, racemic forms and the like are all included in the present invention.
【００１３】次に本発明の入手方法について説明する。
本発明記載の化合物は、例えばＣｈｅｍＳｔａｒ社（ロ
シア）から購入することができる。また、７，８−ジヒ
ドロ−５（６Ｈ）−キナゾリノン誘導体は一般的に、
Ｊ．ＨｅｔｅｒｏｃｙｃｌｉｃＣｈｅｍｓｔｒｙ（２０
巻、６４９項（１９８３））に記載の方法で製造するこ
とが出来る。Next, a method for obtaining the present invention will be described.
The compounds according to the invention can be purchased, for example, from ChemStar (Russia). Also, 7,8-dihydro-5 (6H) -quinazolinone derivatives are generally
J. Heterocyclic Chemstry (20
649 (1983)).
【００１４】本発明における薬理学的に許容しうる塩と
しては、塩酸塩、硫酸塩、リン酸塩等の無機塩、ｐ−ト
ルエンスルホン酸塩、クエン酸塩、フマル酸塩、マレイ
ン酸塩、コハク酸塩、シュウ酸塩、酒石酸塩、酢酸塩等
の有機酸塩が挙げられる。The pharmacologically acceptable salts in the present invention include inorganic salts such as hydrochloride, sulfate and phosphate, p-toluenesulfonate, citrate, fumarate, maleate, and the like. Organic acid salts such as succinate, oxalate, tartrate, acetate and the like can be mentioned.
【００１５】本発明においては、アデニル酸シクラーゼ
５型阻害薬を創製することにより、β１受容体の組織特
異性が低いことによるβ１受容体遮断薬の副作用が改善
でき、高い心臓選択性を持つ循環器作用剤（高血圧症、
心不全、狭心症、不整脈治療薬）を医療現場に供給する
ことが出来る。本発明の化合物またはその薬理学的に許
容される塩が医薬として用いられる場合には、単独また
は担体、賦形剤、希釈剤、溶解補助剤、安定化剤等の製
薬上許容し得る添加剤と混合して用いることができる。
賦形剤の種類は特に制限はないが、例えば、ショ糖、乳
糖、マンニトール及びソルビトールのような糖類、セル
ロース類、またはリン酸カルシウムのような充填剤が使
用できる。In the present invention, by creating an adenylate cyclase type 5 inhibitor, the side effect of the β1 receptor blocker due to the low tissue specificity of the β1 receptor can be improved, and circulating with high cardiac selectivity can be achieved. Drugs (hypertension,
Heart failure, angina, and arrhythmia). When the compound of the present invention or a pharmacologically acceptable salt thereof is used as a medicament, it may be used alone or as a pharmaceutically acceptable additive such as a carrier, an excipient, a diluent, a solubilizing agent, and a stabilizer. Can be used as a mixture.
The type of the excipient is not particularly limited, and for example, a saccharide such as sucrose, lactose, mannitol and sorbitol, a cellulose, or a filler such as calcium phosphate can be used.
【００１６】本発明の剤形としては、経口剤または非経
口剤が挙げられる。非経口剤としては、注射剤、吸入
剤、点鼻剤、クリーム剤、軟膏剤等が挙げられるが、好
ましい剤形としては錠剤、カプセル剤等の経口剤であ
る。The dosage form of the present invention includes an oral preparation or a parenteral preparation. Parenteral preparations include injections, inhalants, nasal drops, creams, ointments and the like. Preferred dosage forms are oral preparations such as tablets and capsules.
【００１７】製剤中の本発明化合物またはその薬理学的
に許容される塩の含量は製剤により異なるが、通常０．
１〜１００重量％であることが好ましい。投与量は患者
の年令、性別、体重、症状、治療目的等により決定され
るが、投与量は一般に０．００１〜５０００ｍｇ／ｋｇ
／日程度である。The content of the compound of the present invention or a pharmacologically acceptable salt thereof in the preparation varies depending on the preparation.
Preferably it is 1 to 100% by weight. The dose is determined depending on the age, sex, body weight, symptoms, treatment purpose, etc. of the patient, and the dose is generally 0.001 to 5000 mg / kg.
/ Day.
【００１８】次に、本発明について実施例を以下に示す
が、本発明はこれらに限定されるものではない。Next, examples of the present invention will be described below, but the present invention is not limited thereto.
【実施例】実施例１ 試験化合物のアデニル酸シクラー
ゼ阻害活性 ５型アデニル酸シクラーゼ阻害活性測定は以下のように
行った。まず、酵素を含む膜たんぱく質の調製を行っ
た。ラット心臓及び肺はＴｒｉｓ／ＨＣｌ（ｐＨ８．
０、５０ｍｍｏｌ／Ｌ）、ＥＧＴＡ（１ｍｍｏｌ／
Ｌ）、ＥＤＴＡ（１ｍｍｏｌ／Ｌ）、ジチオスレイトー
ル（１ｍｍｏｌ／Ｌ）、シュークロース（２００ｍｍｏ
ｌ／Ｌ）、及びタンパク質分解酵素阻害剤混液（Ｌ−１
−トシルアミド−２−フェニルエチル クロロメチルケ
トン（２０μｇ／ｍｌ）、ロイペプチン（１０μｇ／ｍ
ｌ）、フェニルメチルスルフォニルフルオリド（１ｍｍ
ｏｌ／Ｌ）、卵白トリプシンインヒビター（５０Ｕ／ｍ
ｌ）、及びアプロチニン（２μｇ／ｍｌ））を含む緩衝
液中で細切した。これらの組織をポリトロンで１０秒間
ずつ３回ホモジナイズし、次いで５００×Ｇ、４度で１
０分間遠心分離した。上澄みを採取し、さらに１００，
０００×Ｇ、４度で４０分間遠心分離した。得られた沈
殿物を、先述の緩衝液（但しＥＤＴＡを除く）に再び懸
濁して粗膜標品とし、使用するまで−８０度で保存し
た。Example 1 Adenylate cyclase inhibitory activity of test compounds The type 5 adenylate cyclase inhibitory activity was measured as follows. First, a membrane protein containing an enzyme was prepared. Rat heart and lung were Tris / HCl (pH 8.
0, 50 mmol / L), EGTA (1 mmol / L
L), EDTA (1 mmol / L), dithiothreitol (1 mmol / L), sucrose (200 mmol / L)
1 / L) and a mixture of proteolytic enzyme inhibitors (L-1
-Tosylamide-2-phenylethyl chloromethylketone (20 μg / ml), leupeptin (10 μg / m
l), phenylmethylsulfonyl fluoride (1 mm
ol / L), egg white trypsin inhibitor (50 U / m
l) and aprotinin (2 μg / ml)). These tissues were homogenized three times for 10 seconds each with a Polytron, and then 500 × G, 1 × at 4 ° C.
Centrifuged for 0 minutes. Collect the supernatant and add 100,
Centrifugation was performed at 000 × G and 4 degrees for 40 minutes. The obtained precipitate was resuspended in the above-mentioned buffer solution (excluding EDTA) to obtain a crude membrane sample, and stored at -80 ° C until use.
【００１９】酵素活性測定は、以前に報告された方法
（Ｍｅｔｈ．Ｅｎｚｙｍｏｌ．、２３８巻、３１項（１
９９４年））を一部変更して以下の方法で行った。ＨＥ
ＰＥＳ（ｐＨ８．０、２０ｍＭ）、ＥＤＴＡ（０．５ｍ
Ｍ）、ＡＴＰ（３２Ｐで標識されたＡＴＰを１，００
０,０００ｃｐｍ含む、０．１ｍＭ）、ｃＡＭＰ（０．
１ｍＭ）、クレアチンリン酸（１ｍＭ）、クレアチンホ
スホキナーゼ（８Ｕ／ｍｌ）、フォルスコリン（１００
μＭ）、膜たんぱく質（８μｇ）、及び試験化合物４
［２−アミノ−７−（２−フラニル）−７、８−ジヒド
ロ−５（６Ｈ）−キナゾリノン］を１０−５Ｍまたは１
０−４．５Ｍを用い、最終容量が１００μｌとなるよう
に調製した。また、コントロールとして試験化合物を添
加しない上記組成のものを調製した。反応は３０度の条
件下２０分間行い、１０μｌの氷冷した２．２Ｎ−ＨＣ
ｌを加え反応を停止した。反応中に生成した３２Ｐで標
識されたｃＡＭＰは、酸性アルミナカラムを用いて分離
し、放射線強度はシンチレーションカウンターで測定し
た。活性測定の結果を図１に記した。試験化合物４は心
臓由来（５型）及び肺由来のアデニル酸シクラーゼ阻害
活性を示した。The enzyme activity was measured by the method reported previously (Meth. Enzymol., 238, 31 (1)
994)) was modified in the following manner. HE
PES (pH 8.0, 20 mM), EDTA (0.5 m
M), ATP (ATP labeled with 32 P
0.1 mM containing 000 cpm, cAMP (0.
1 mM), creatine phosphate (1 mM), creatine phosphokinase (8 U / ml), forskolin (100
μM), membrane protein (8 μg), and test compound 4
[2-amino-7- (2-furanyl) -7,8-dihydro-5 (6H) -quinazolinone] at 10-5 M or 1
Using 0-4.5 M, the final volume was adjusted to 100 μl. In addition, a control having the above composition without the test compound was prepared as a control. The reaction was carried out at 30 ° C. for 20 minutes, and 10 μl of ice-cooled 2.2N-HC
1 was added to stop the reaction. The cAMP labeled with 32 P generated during the reaction was separated using an acidic alumina column, and the radiation intensity was measured with a scintillation counter. The results of the activity measurement are shown in FIG. Test compound 4 showed inhibitory activity on adenylate cyclase derived from heart (type 5) and lung.
【００２０】[0020]
【発明の効果】本発明により得られた７，８−ジヒドロ
−５（６Ｈ）−キナゾリノン誘導体またはその薬理学的
に許容しうる塩が、アデニル酸シクラーゼ５型阻害剤で
あることを見いだした。よって、本発明記載の化合物ま
たはその薬理学的に許容しうる塩を有効成分として含有
する薬剤組成物は循環器作用薬として有用であり、医薬
としての用途が示された。The 7,8-dihydro-5 (6H) -quinazolinone derivative or a pharmaceutically acceptable salt thereof obtained by the present invention has been found to be an adenylate cyclase type 5 inhibitor. Therefore, a pharmaceutical composition containing the compound according to the present invention or a pharmacologically acceptable salt thereof as an active ingredient is useful as a circulatory agent and has been shown to be used as a medicament.
【図１】試験化合物４の心臓由来（５型）及び肺由来の
アデニル酸シクラーゼ阻害活性を図１に示す。FIG. 1 shows the inhibitory activity of test compound 4 on adenylate cyclase derived from heart (type 5) and lung.
フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｐ 9/12 Ａ６１Ｐ 9/12 43/00 １１１ 43/00 １１１ // Ｃ０７Ｄ 239/84 Ｃ０７Ｄ 239/84 407/04 407/04 409/04 409/04 Ｆターム(参考） 4C063 AA01 BB01 CC75 CC92 DD31 EE01 4C086 AA01 AA02 BC46 GA02 GA03 GA07 NA14 ZA36 ZA37 ZA39 ZA40 ZA42 ZC20 Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat II (reference) A61P 9/12 A61P 9/12 43/00 111 43/00 111 // C07D 239/84 C07D 239/84 407/04 407 / 04 409/04 409/04 F term (reference) 4C063 AA01 BB01 CC75 CC92 DD31 EE01 4C086 AA01 AA02 BC46 GA02 GA03 GA07 NA14 ZA36 ZA37 ZA39 ZA40 ZA42 ZC20
Claims (7)
下記一般式［２］ 【化２】 ［式中、Ｂは水素原子、メトキシ基またはハロゲン原子
を示す］で表される７，８−ジヒドロ−５（６Ｈ）−キ
ナゾリノン誘導体またはその薬理学的に許容される塩を
有効成分とするアデニル酸シクラーゼ５型阻害剤。1. A compound represented by the following general formula [1] [In the formula, A represents an oxygen atom or a sulfur atom], or the following general formula [2] [Wherein B represents a hydrogen atom, a methoxy group or a halogen atom], an adenyl containing a 7,8-dihydro-5 (6H) -quinazolinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient Acid cyclase type 5 inhibitors.
Ｈ）−キナゾリノン誘導体またはその薬理学的に許容さ
れる塩を有効成分とする循環器作用薬。2. The 7,8-dihydro-5 (6) according to claim 1,
H) -A circulatory agent containing a quinazolinone derivative or a pharmacologically acceptable salt thereof as an active ingredient.
Ｈ）−キナゾリノン誘導体またはその薬理学的に許容さ
れる塩を有効成分とする高血圧治療薬。3. The 7,8-dihydro-5 (6) according to claim 1,
H) -A drug for treating hypertension comprising a quinazolinone derivative or a pharmacologically acceptable salt thereof as an active ingredient.
Ｈ）−キナゾリノン誘導体またはその薬理学的に許容さ
れる塩を有効成分とする心不全治療薬。4. The 7,8-dihydro-5 (6) according to claim 1,
H) -A quinazolinone derivative or a pharmacologically acceptable salt thereof as a therapeutic agent for heart failure.
Ｈ）−キナゾリノン誘導体またはその薬理学的に許容さ
れる塩を有効成分とする狭心症治療薬。5. The 7,8-dihydro-5 (6) according to claim 1,
H) -A quinazolinone derivative or a pharmacologically acceptable salt thereof as a therapeutic agent for angina pectoris.
Ｈ）−キナゾリノン誘導体またはその薬理学的に許容さ
れる塩を有効成分とする不整脈治療薬。6. The 7,8-dihydro-5 (6) according to claim 1,
H) -A therapeutic agent for arrhythmia comprising a quinazolinone derivative or a pharmacologically acceptable salt thereof as an active ingredient.
Ｈ）−キナゾリノン誘導体またはその薬理学的に許容さ
れる塩を有効成分とする医薬。7. The 7,8-dihydro-5 (6) according to claim 1,
A medicament comprising an H) -quinazolinone derivative or a pharmacologically acceptable salt thereof as an active ingredient.
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| JP2001153954A JP4723115B2 (en) | 2001-05-23 | 2001-05-23 | Adenylate cyclase type 5 inhibitor |
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|---|---|---|---|
| JP2001153954A JP4723115B2 (en) | 2001-05-23 | 2001-05-23 | Adenylate cyclase type 5 inhibitor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008536867A (en) * | 2005-04-14 | 2008-09-11 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス， インコーポレイテッド | 2-Amino-quinazolin-5-one as an HSP90 inhibitor useful in treating proliferative diseases |
| WO2013051330A1 (en) * | 2011-10-07 | 2013-04-11 | 公立大学法人横浜市立大学 | Treatment of atrial fibrillation by means of vidarabine |
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| US3757017A (en) * | 1967-01-25 | 1973-09-04 | J Mathieu | 4,5 polymethylene pyrimidine derivatives |
| US3915976A (en) * | 1972-09-01 | 1975-10-28 | Sandoz Ag | Substituted-4-phenyl-5h-cycloalkano(d)pyrimidines |
| JPH02289551A (en) * | 1989-02-21 | 1990-11-29 | Dainippon Pharmaceut Co Ltd | Ameliorant containing pyrimidine derivative as active ingredient for cerebral function |
| WO1998029397A1 (en) * | 1996-12-27 | 1998-07-09 | Yoshitomi Pharmaceutical Industries, Ltd. | Fused pyrimidine compounds and medicinal use thereof |
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2001
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3757017A (en) * | 1967-01-25 | 1973-09-04 | J Mathieu | 4,5 polymethylene pyrimidine derivatives |
| US3915976A (en) * | 1972-09-01 | 1975-10-28 | Sandoz Ag | Substituted-4-phenyl-5h-cycloalkano(d)pyrimidines |
| JPH02289551A (en) * | 1989-02-21 | 1990-11-29 | Dainippon Pharmaceut Co Ltd | Ameliorant containing pyrimidine derivative as active ingredient for cerebral function |
| WO1998029397A1 (en) * | 1996-12-27 | 1998-07-09 | Yoshitomi Pharmaceutical Industries, Ltd. | Fused pyrimidine compounds and medicinal use thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008536867A (en) * | 2005-04-14 | 2008-09-11 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス， インコーポレイテッド | 2-Amino-quinazolin-5-one as an HSP90 inhibitor useful in treating proliferative diseases |
| WO2013051330A1 (en) * | 2011-10-07 | 2013-04-11 | 公立大学法人横浜市立大学 | Treatment of atrial fibrillation by means of vidarabine |
| JPWO2013051330A1 (en) * | 2011-10-07 | 2015-03-30 | 公立大学法人横浜市立大学 | Treatment of atrial fibrillation with vidarabine |
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| JP4723115B2 (en) | 2011-07-13 |
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