JPH0480911B2 - - Google Patents
Info
- Publication number
- JPH0480911B2 JPH0480911B2 JP19580783A JP19580783A JPH0480911B2 JP H0480911 B2 JPH0480911 B2 JP H0480911B2 JP 19580783 A JP19580783 A JP 19580783A JP 19580783 A JP19580783 A JP 19580783A JP H0480911 B2 JPH0480911 B2 JP H0480911B2
- Authority
- JP
- Japan
- Prior art keywords
- pyridazinone
- compound
- dihydro
- acid
- methyl
- 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.)
- Expired - Lifetime
Links
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- -1 3-dihydropyridyl Chemical group 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000496 cardiotonic agent Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 125000003047 N-acetyl group Chemical group 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 210000003540 papillary muscle Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- NWSBNVVOFKKFNV-UHFFFAOYSA-N chloroform;oxolane Chemical compound ClC(Cl)Cl.C1CCOC1 NWSBNVVOFKKFNV-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 2
- MGCGJBXTNWUHQE-UHFFFAOYSA-N quinoline-4-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CC=NC2=C1 MGCGJBXTNWUHQE-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- GPWNWKWQOLEVEQ-UHFFFAOYSA-N 2,4-diaminopyrimidine-5-carbaldehyde Chemical compound NC1=NC=C(C=O)C(N)=N1 GPWNWKWQOLEVEQ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- XMTUHSIIBGFSTQ-UHFFFAOYSA-N 3-(4-aminophenyl)-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(N)=CC=C1C1=NNC(=O)CC1 XMTUHSIIBGFSTQ-UHFFFAOYSA-N 0.000 description 1
- FXEZKEQKFKTXAK-UHFFFAOYSA-N 3-[4-(quinolin-4-ylmethylamino)phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound N1C(=O)CCC(C=2C=CC(NCC=3C4=CC=CC=C4N=CC=3)=CC=2)=N1 FXEZKEQKFKTXAK-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 239000004041 inotropic agent Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は強心剤として有用な新規なピリダジノ
ン誘導体またはその塩類に関する。
強心剤は心臓に直接作用してその収縮力を強め
る作用を有し、従来種々の薬剤が心不全の治療に
利用されている。
しかしながら、これらの強心剤は安全域が極度
に狭く不整脈の原因となつたりあるいはその強心
作用が一過性でかつ経口投与に適さないといつた
不都合を有するものが多い。
本発明者らは強心剤として活性が高くかつ効果
の持続性が十分発揮できる化合物の探索を行ない
本発明に到達した。
すなわち本発明の要旨は、下記一般式（）：
（上記式中で、Ｒは炭素数１〜６のアルキル基
を表わし、Ａは、ピリジル基、ピロリル基あるい
はキノリル基を表わし、Ａはその環上に炭素数１
〜６のアルキル基、を有していてもよい。ｎは１
〜４の整数を表わし、点線は、一重結合または二
重結合を表わす。）
で示されるピリダジノン誘導体またはその塩類に
存する。
以下、本発明を詳細に説明する。
上記一般式（）において、Ｒの具体例として
は、メチル、エチル、ｎ−プロピル、１−プロピ
ル、ｎ−ブチル、ｔ−ブチル、ぺンチル、ヘキシ
ル等の炭素数１〜６（好ましくは１〜４）のアル
キル基が挙げられる。
Ａの具体例としては、例えば、２−ピリジル、
３−ピリジル、４−ピリジル、３−ジヒドロピリ
ジル、２−ピロリル、３−ピロリル、４−キノリ
ル等が挙げられ、該環上に少なくとも１つの置換
基を有していてもよい。該置換基としては、メチ
ル、エチル、プロピル、ブチル、ペンチル、ヘキ
シル等の炭素数１〜６のアルキル基が挙げられる
が、特に、メチル、エチル等の炭素数１〜４のア
ルキル基が好ましい。
一般式（）で示されるピリダジノン誘導体の
具体例としては、例えば下記のものが挙げられ
る。
また、上記化合物の薬剤的に許容され得る塩類
も本発明の範囲に包含される。上記の塩類として
はリン酸、塩酸、硫酸等の無機酸塩およびシユウ
酸、乳酸等の有機酸塩が挙げられる。
次に本発明化合物の製造法について説明する。
本発明におけるピリダジノン誘導体は、たとえ
ば、次の様な経路で合成できる。
（上記式中で、Ｘはハロゲン原子を表わし、
Ａ，ｎおよびＲは一般式（）で定義したとおり
である。）
化合物（）と化合物（）との反応は、ｐ−
トルエンスルホン酸などの触媒の存在下、Ｎ，Ｎ
−ジメチルホルムアミド、ベンゼン、トルエンな
どの溶媒またはこれらの混合溶媒中で還流しなが
ら行われる。反応時間は0.5〜５時間で、好まし
くは、生成する水を共沸によつて系外に除去しな
がら行うのがよい。使用される化合物（）およ
び（）の量は、ほぼ等モルである。
次に、得られた化合物（）を接触水素添加法
などによつて還元することにより化合物（）が
得られる。
接触水素添加は、Ｎ，Ｎ−ジメチルホルムアミ
ドなどの溶媒中、０℃〜100℃で、常圧または加
圧下、パラジウム−ブラツク、パラジウム−炭素
などの触媒の存在下行われる。反応時間は0.5〜
10時間である。
得られた化合物（）を酸塩化物（）または
酸無水物（）と反応させてアシル化することに
より、目的物であるピリダジノン誘導体（）と
得ることができる。
該アシル化反応は、ベンゼン、Ｎ，Ｎ−ジメチ
ルホルムアミド、ピリジン、２，４，６−コリジ
ンなどの溶媒またはこれらの混合溶媒中、−20〜
180℃で行われる。反応時間は、0.5〜５時間であ
り、酸塩化物（）または酸無水物（）の使用
量は、化合物（）１モルに対して１〜４モルで
ある。
また、得られたピリダジノン誘導体（）をリ
ン酸、塩酸、硫酸等の無機酸またはシユウ酸、乳
酸等の有機酸と反応させると、薬剤的に許容され
得る塩が得られる。
このようにして得られたピリダジノン誘導体
（）またはその塩類は、カラムクロマト処理等
の通常の方法により精製することができる。
本発明に係る化合物を強心剤として用いる場合
は、経口、非経口の適当な投与方法により投与す
ることができる。
この場合、提供される形態としては、経口投与
用には例えば散剤、顆粒、錠剤、糖衣錠、ピル、
カプセル、液剤等、非経口投与用には例えば座
剤、懸濁液、液剤、乳剤、アンプルおよび注射液
等が挙げられる。勿論これらを組み合わせた形態
でも提供しうる。
製剤化に際しては、この分野における常法によ
ることができる。
また、本発明化合物を強心薬として投与する量
は、年令、性別、体重、感受性差、投与方法、投
与の時期・間隔、病状の程度、体調、医薬製剤の
性質・調剤・種類、有効成分の種類などを考慮し
て、医師により決定される。
例えば、経口投与の場合、１日当り、0.1〜10
mg／Kg体重程度の投与量が選ばれるが、もちろん
これに制限されない。
以下、実施例および参考例により本発明をさら
に具体的に説明するが、本発明は、その要旨を超
えない限り、以下の実施例に限定されない。
実施例 １
（６−〔４−（Ｎ−（４−ピリジル）メチル−
Ｎ−アセチル）アミノフエニル〕−４，５−ジ
ヒドロ−３（2H）−ピリダジノン）の製造
(a) ６−（ｐ−アミノフエニル）−４，５−ジヒド
ロ−３（2H）−ピリダジノン18.8g、イソニコチ
ンアルデヒド10ml、ｐ−トルエンスルホン酸50
mg、トルエン150mlおよびＮ，Ｎ−ジメチルホ
ルムアミド70mlの混合物を150°〜160℃で３時
間反応させ（反応中、共沸脱水により生成する
水を系外に除去する。）、反応液を冷却後、エチ
ルエーテル300mlを添加し、析出している結晶
を取した。乾燥後、６−（４−（４−ピリジ
ル）メチリデンアミノフエニル）−４，５−ジ
ヒドロ−３（2H）−ピリダジノン23.25gを得た。
(b) (a)で得られた化合物23.25gをトリエチルアミ
ン２mlおよびＮ，Ｎ−ジメチルホルムアミド
200mlの溶液に懸濁させ、更に５％パラジウム
−炭素2.9gを加え、常温にて常圧下接触水添し
た。理論量の水素を吸収させた後、触媒を去
し、液を氷水700mlに注ぎ、析出した結晶を
取した。乾燥後の収量は18.4gであつた。こ
の粗結晶をカラムクロマトにより精製して（シ
リカゲル、溶媒：クロロホルム−THF）、純品
の６−〔４−（４−ピリジル）メチルアミノフエ
ニル〕−４，５−ジヒドロ−３（2H）−ピリダジ
ノン12.2gを得た。
(c) (b)で得られた化合物1.13g、２，４，６−コ
リジン２mlおよび無水酢酸0.5mlの混合物を150
℃で３時間反応させ、反応液をそのままカラム
クロマト処理して（シリカゲル、溶媒：クロロ
ホルム−THF），目的物である６−〔４−（Ｎ−
（４−ピリジル）メチル−Ｎ−アセチル）アミ
ノフエニル〕−４，５−ジヒドロ−３（2H）−ピ
リダジノン0.44gを得た。
IR（KBr）：1655cm-1
実施例 ２
（６−〔４−（Ｎ−（２−（１−メチル）ピロリ
ル）メチル−Ｎ−アセチル）アミノフエニル〕
−４，５−ジヒドロ−３（2H）−ピリダジノン）
の製造
(a) 実施例１の(a)と同様の条件で、イソニコチン
アルデヒドの代りに、１−メチルピロール−２
−カルバルデヒド5.22gを使用し、６−〔４−
（２−（１−メチル）ピロリル）メチリデンアミ
ノフエニル〕−４，５−ジヒドロ−３（2H）−ピ
リダジノン7.56gを得た。
(b) (a)で得られた化合物7gを実施例１の(b)と同
様の条件で接触水添し、６−〔４−（２−（１−
メチル）ピロリル）メチルアミノフエニル〕−
４，５−ジヒドロ−３（2H）−ピリダジノン
6.6gを得た。
(c) (b)で得られた化合物1.14gを、実施例１の(c)
と同様の条件でアセチル化を行い、目的とする
６−〔４−（Ｎ−（２−（１−メチル）ピロリル）
メチル−Ｎ−アセチル）アミノフエニル〕−４，
５−ジヒドロ−３（2H）−ピリダジノン0.94gを
得た。
IR（KBr）：1645、1675cm-1
実施例 ３
（６−〔４−（Ｎ−（４−キノリル）メチル−
Ｎ−アセチル）アミノフエニル〕−４，５−ジ
ヒドロ−３（2H）−ピリダジノン）の製造
(a) 実施例１の(a)と同様の条件で、イソニコチン
アルデヒドの代りに、４−キノリンカルバルデ
ヒド8.10gを使用し、６−〔４−（４−キノリル）
メチリデンアミノフエニル〕−４，５−ジヒド
ロ−３（2H）−ピリダジノン14.60gを得た。
(b) (a)で得られた化合物13.70gを、実施例１の(b)
と同様の条件で接触水添し、６−〔４−（４−キ
ノリル）メチルアミノフエニル〕−４，５−ジ
ヒドロ−３（2H）−ピリダジノン12.90gを得た。
(c) (b)で得られた化合物1.15gを、実施例１の(c)
と同様の条件でアセチル化を行い、目的とす
る、６−〔４−（Ｎ−（４−キノリル）メチル−
Ｎ−アセチル）アミノフエニル〕−４，５−ジ
ヒドロ−３（2H）−ピリダジノン0.39gを得た。
IR（KBr）：1660cm-1
参考例 １
本発明におけるピリダジノン誘導体の強心剤の
しての有用性を、犬摘出乳頭筋交叉かん流標本を
用いる方法により試験した。
犬摘出乳頭筋交叉かん流標本は遠藤と橋本の方
法〔アメリカン・ジヤーナル・オブ・フイジオロ
ジー（American J.Physiol.）218巻、1459−
1463頁、1970年参照〕に従い作成した。
実施例１〜３で得られた化合物を溶媒に溶解
し、これらを標本に近接動注し、乳頭筋の収縮力
に対する作用を記録した。結果を第１表に示す。
The present invention relates to novel pyridazinone derivatives or salts thereof useful as cardiotonic agents. Cardiac inotropes have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used to treat heart failure. However, many of these inotropic agents have disadvantages such as extremely narrow safety margins, causing arrhythmia, or their inotropic effects being transient and unsuitable for oral administration. The present inventors have searched for a compound that is highly active as a cardiotonic agent and has a sufficiently long-lasting effect, and has thus arrived at the present invention. That is, the gist of the present invention is the following general formula (): (In the above formula, R represents an alkyl group having 1 to 6 carbon atoms, A represents a pyridyl group, pyrrolyl group, or quinolyl group, and A has 1 to 1 carbon atoms on the ring.
to 6 alkyl groups. n is 1
It represents an integer of ~4, and the dotted line represents a single or double bond. ) Pyridazinone derivatives or salts thereof. The present invention will be explained in detail below. In the above general formula (), specific examples of R include methyl, ethyl, n-propyl, 1-propyl, n-butyl, t-butyl, pentyl, hexyl, etc. having 1 to 6 carbon atoms (preferably 1 to 6 carbon atoms). Examples include the alkyl group of 4). Specific examples of A include 2-pyridyl,
Examples include 3-pyridyl, 4-pyridyl, 3-dihydropyridyl, 2-pyrrolyl, 3-pyrrolyl, 4-quinolyl, and the like, which may have at least one substituent on the ring. Examples of the substituent include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, and hexyl, and particularly preferred are alkyl groups having 1 to 4 carbon atoms such as methyl and ethyl. Specific examples of the pyridazinone derivative represented by the general formula () include the following. Also included within the scope of the present invention are pharmaceutically acceptable salts of the above compounds. Examples of the above salts include inorganic acid salts such as phosphoric acid, hydrochloric acid, and sulfuric acid, and organic acid salts such as oxalic acid and lactic acid. Next, a method for producing the compound of the present invention will be explained. The pyridazinone derivative in the present invention can be synthesized, for example, by the following route. (In the above formula, X represents a halogen atom,
A, n and R are as defined in the general formula (). ) The reaction between compound () and compound () is p-
In the presence of a catalyst such as toluenesulfonic acid, N,N
- It is carried out in a solvent such as dimethylformamide, benzene, toluene or a mixed solvent thereof under reflux. The reaction time is 0.5 to 5 hours, and it is preferable to carry out the reaction while removing produced water from the system by azeotropy. The amounts of compounds () and () used are approximately equimolar. Next, the compound () is obtained by reducing the obtained compound () by a catalytic hydrogenation method or the like. The catalytic hydrogenation is carried out in a solvent such as N,N-dimethylformamide at 0°C to 100°C under normal or elevated pressure in the presence of a catalyst such as palladium-black or palladium-carbon. Reaction time is 0.5~
It is 10 hours. By reacting the obtained compound () with an acid chloride () or an acid anhydride () to acylate it, the desired pyridazinone derivative () can be obtained. The acylation reaction is carried out in a solvent such as benzene, N,N-dimethylformamide, pyridine, 2,4,6-collidine, or a mixed solvent thereof.
Performed at 180℃. The reaction time is 0.5 to 5 hours, and the amount of acid chloride () or acid anhydride () used is 1 to 4 mol per 1 mol of compound (). Moreover, when the obtained pyridazinone derivative () is reacted with an inorganic acid such as phosphoric acid, hydrochloric acid, or sulfuric acid or an organic acid such as oxalic acid or lactic acid, a pharmaceutically acceptable salt can be obtained. The pyridazinone derivative () or salt thereof thus obtained can be purified by a conventional method such as column chromatography. When the compound according to the present invention is used as a cardiotonic agent, it can be administered by an appropriate oral or parenteral administration method. In this case, the forms provided include, for example, powders, granules, tablets, sugar-coated tablets, pills,
Examples of parenteral administration such as capsules and liquid preparations include suppositories, suspensions, solutions, emulsions, ampoules, and injection solutions. Of course, a combination of these can also be provided. For formulation, conventional methods in this field can be used. In addition, the amount of the compound of the present invention to be administered as a cardiotonic drug should be determined based on age, sex, body weight, sensitivity differences, administration method, administration timing/interval, severity of disease, physical condition, nature/preparation/type of pharmaceutical preparation, and active ingredients. It is determined by the doctor, taking into account the type of For example, in the case of oral administration, 0.1 to 10
The dosage is selected to be approximately mg/Kg body weight, but is of course not limited to this. Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof. Example 1 (6-[4-(N-(4-pyridyl)methyl-
Production of N-acetyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone) (a) 18.8 g of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, isonicotine Aldehyde 10ml, p-toluenesulfonic acid 50ml
150 ml of toluene and 70 ml of N,N-dimethylformamide are reacted at 150° to 160°C for 3 hours (during the reaction, water generated by azeotropic dehydration is removed from the system), and after cooling the reaction solution. , 300 ml of ethyl ether was added, and the precipitated crystals were collected. After drying, 23.25 g of 6-(4-(4-pyridyl)methylideneaminophenyl)-4,5-dihydro-3(2H)-pyridazinone was obtained. (b) 23.25 g of the compound obtained in (a) was mixed with 2 ml of triethylamine and N,N-dimethylformamide.
The suspension was suspended in 200 ml of solution, 2.9 g of 5% palladium-carbon was added, and catalytic hydrogenation was carried out at room temperature and pressure. After absorbing the theoretical amount of hydrogen, the catalyst was removed and the liquid was poured into 700 ml of ice water to collect the precipitated crystals. The yield after drying was 18.4g. The crude crystals were purified by column chromatography (silica gel, solvent: chloroform-THF) to obtain pure 6-[4-(4-pyridyl)methylaminophenyl]-4,5-dihydro-3(2H)- 12.2 g of pyridazinone was obtained. (c) A mixture of 1.13 g of the compound obtained in (b), 2 ml of 2,4,6-collidine and 0.5 ml of acetic anhydride was added to
The reaction was allowed to proceed at ℃ for 3 hours, and the reaction solution was directly subjected to column chromatography (silica gel, solvent: chloroform-THF) to obtain the target product 6-[4-(N-
0.44 g of (4-pyridyl)methyl-N-acetyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone was obtained. IR (KBr): 1655cm -1 Example 2 (6-[4-(N-(2-(1-methyl)pyrrolyl)methyl-N-acetyl)aminophenyl]
-4,5-dihydro-3(2H)-pyridazinone)
(a) Under the same conditions as in Example 1 (a), 1-methylpyrrole-2 was used instead of isonicotinaldehyde.
- Using 5.22g of carbaldehyde, 6-[4-
7.56 g of (2-(1-methyl)pyrrolyl)methylideneaminophenyl]-4,5-dihydro-3(2H)-pyridazinone was obtained. (b) 7 g of the compound obtained in (a) was subjected to catalytic hydrogenation under the same conditions as in Example 1 (b), and 6-[4-(2-(1-
methyl)pyrrolyl)methylaminophenyl]-
4,5-dihydro-3(2H)-pyridazinone
Obtained 6.6g. (c) 1.14g of the compound obtained in (b) was added to (c) in Example 1.
Acetylation was carried out under the same conditions as for the desired 6-[4-(N-(2-(1-methyl)pyrrolyl)
Methyl-N-acetyl)aminophenyl]-4,
0.94 g of 5-dihydro-3(2H)-pyridazinone was obtained. IR (KBr): 1645, 1675cm -1 Example 3 (6-[4-(N-(4-quinolyl)methyl-
Preparation of N-acetyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone) (a) Under the same conditions as in Example 1 (a), 4-quinolinecarbaldehyde was used instead of isonicotinaldehyde. Using 8.10g, 6-[4-(4-quinolyl)
14.60 g of methylideneaminophenyl]-4,5-dihydro-3(2H)-pyridazinone was obtained. (b) 13.70g of the compound obtained in (a) was added to (b) in Example 1.
Catalytic hydrogenation was carried out under the same conditions as above to obtain 12.90 g of 6-[4-(4-quinolyl)methylaminophenyl]-4,5-dihydro-3(2H)-pyridazinone. (c) 1.15g of the compound obtained in (b) was added to (c) in Example 1.
Acetylation was carried out under the same conditions as for the desired 6-[4-(N-(4-quinolyl)methyl-
0.39 g of N-acetyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone was obtained. IR (KBr): 1660 cm -1 Reference Example 1 The usefulness of the pyridazinone derivative of the present invention as a cardiotonic agent was tested by a method using a canine isolated papillary muscle cross-perfusion specimen. Canine isolated papillary muscle cross-perfusion specimens were prepared using the method of Endo and Hashimoto [American Journal of Physiol., Vol. 218, 1459-
p. 1463, 1970]. The compounds obtained in Examples 1 to 3 were dissolved in a solvent and injected proximately into the specimen, and the effect on the contractile force of papillary muscles was recorded. The results are shown in Table 1.
【表】【table】
Claims (1)
を表わし、Ａはピリジル基、ピロリル基あるいは
キノリル基を表わし、Ａはその環上に炭素数１〜
６のアルキル基を有していてもよい。ｎは１〜４
の整数を表わし、点線は、一重結合または二重結
合を表わす。） で示されるピリダジノン誘導体またはその種類。[Claims] 1. The following general formula (): (In the above formula, R represents an alkyl group having 1 to 6 carbon atoms, A represents a pyridyl group, pyrrolyl group, or quinolyl group, and A has 1 to 6 carbon atoms on the ring.
It may have 6 alkyl groups. n is 1 to 4
The dotted lines represent single or double bonds. ) Pyridazinone derivatives or their types.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19580783A JPS6087283A (en) | 1983-10-19 | 1983-10-19 | Pyridazinone derivative and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19580783A JPS6087283A (en) | 1983-10-19 | 1983-10-19 | Pyridazinone derivative and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6087283A JPS6087283A (en) | 1985-05-16 |
| JPH0480911B2 true JPH0480911B2 (en) | 1992-12-21 |
Family
ID=16347304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19580783A Granted JPS6087283A (en) | 1983-10-19 | 1983-10-19 | Pyridazinone derivative and its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6087283A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW309520B (en) * | 1994-04-26 | 1997-07-01 | Mitsubishi Chem Corp | |
| MX2009000884A (en) * | 2006-07-25 | 2009-06-05 | Cephalon Inc | Pyridizinone derivatives. |
-
1983
- 1983-10-19 JP JP19580783A patent/JPS6087283A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6087283A (en) | 1985-05-16 |
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