JPS6242900B2 - - Google Patents
Info
- Publication number
- JPS6242900B2 JPS6242900B2 JP15899679A JP15899679A JPS6242900B2 JP S6242900 B2 JPS6242900 B2 JP S6242900B2 JP 15899679 A JP15899679 A JP 15899679A JP 15899679 A JP15899679 A JP 15899679A JP S6242900 B2 JPS6242900 B2 JP S6242900B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- general formula
- mol
- phenyl
- represented
- 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
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- 150000001875 compounds Chemical class 0.000 claims description 11
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000013078 crystal Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- WDTNTQRNRCZODV-UHFFFAOYSA-N 1-cyano-2-methyl-3-[3-(6-oxo-3-phenylpyridazin-1-yl)propyl]guanidine Chemical compound C1=CC(=O)N(CCCN\C(=N/C)NC#N)N=C1C1=CC=CC=C1 WDTNTQRNRCZODV-UHFFFAOYSA-N 0.000 description 1
- WLCLKMPRHUHLMF-UHFFFAOYSA-N 2-(2-aminoethylsulfanylmethyl)-6-phenylpyridazin-3-one Chemical compound C1=CC(=O)N(CSCCN)N=C1C1=CC=CC=C1 WLCLKMPRHUHLMF-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010020601 Hyperchlorhydria Diseases 0.000 description 1
- -1 N-cyano-S-methyl-N′-[4-(3- oxo-6-phenyl-2-pyridazinyl) Butyl]isothiourea 2-(4-aminobutyl)-6-phenyl-3 (2H) pyridazinone Chemical compound 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- UHGKYJXJYJWDAM-UHFFFAOYSA-N Propylthiourea Chemical compound CCCNC(N)=S UHGKYJXJYJWDAM-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 150000002541 isothioureas Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- PVJKVIFOHYMVQP-UHFFFAOYSA-N methyl n-cyano-n'-[2-[(6-oxo-3-phenylpyridazin-1-yl)methylsulfanyl]ethyl]carbamimidothioate Chemical compound C1=CC(=O)N(CSCCN=C(NC#N)SC)N=C1C1=CC=CC=C1 PVJKVIFOHYMVQP-UHFFFAOYSA-N 0.000 description 1
- PFCBISFUCBFZMU-UHFFFAOYSA-N methyl n-cyano-n'-[3-(6-oxo-3-phenylpyridazin-1-yl)propyl]carbamimidothioate Chemical compound C1=CC(=O)N(CCCN=C(NC#N)SC)N=C1C1=CC=CC=C1 PFCBISFUCBFZMU-UHFFFAOYSA-N 0.000 description 1
- QWSHZFSGAVKJDX-UHFFFAOYSA-N methyl n-cyano-n'-[5-(6-oxo-3-phenylpyridazin-1-yl)pentyl]carbamimidothioate Chemical compound C1=CC(=O)N(CCCCCN=C(NC#N)SC)N=C1C1=CC=CC=C1 QWSHZFSGAVKJDX-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は一般式
〔式中、R1は低級アルキル基；Ｚは硫黄また
はメチレン；Ｘは硫黄またはNH；ｍは１〜３の
整数およびｎは０，１または２を表わす〕で示さ
れる新規なピリダジノン誘導体〔〕に関する。
上記一般式〔〕で示される本発明のピリダジ
ノン誘導体は新規化合物で、消化性潰瘍の治療お
よび予防薬として有用な医薬品として使用されう
る。すなわちラツト等で胃液分泌を抑制する作用
を示し、アスピリン、ストレス、シエイ等の実験
的潰瘍の発生を抑制し、その作用は持続的であ
る。一方毒性は弱く、耐薬性もすぐれている。し
たがつて胃酸過多、胃潰瘍、十二指腸潰瘍の治療
および予防に極めて有効である。
本発明の新規化合物〔〕は種々の方法により
製造することができる。例えばＸが硫黄の目的化
合物は、
一般式
〔式中、Ｚ、ｍおよびｎは前記と同じものを表
わす〕で示されるアミン誘導体〔〕と一般式
〔式中、R1は前記と同じもの、R2は低級アル
キル基を表わす〕で示される化合物〔〕を反応
対応量作用させることにより得られる。反応に際
しては無溶媒かエタノール、アセトニトリル、ク
ロロホルム等の不活性溶媒が適当であり、反応は
室温あるいは冷却下で行なわれるが、溶媒を使用
して還流下で行なうことができる。
またＸがNHである目的化合物を製造するに
は、上記製造法で得られる一般式
〔式中、R2、Ｚ、ｍおよびｎは前記と同じも
のを表わす〕で示されるイソチオ尿素誘導体
〔〕と一般式 R1―NH2 〔〕
〔式中、R1は前記と同じものを表わす〕で示
されるアミン誘導体〔〕を無溶媒あるいはエタ
ノール、アセトニトリル、ベンゼン等の不活性溶
媒中にて数時間、室温ないし加熱反応することに
より容易に高収率で得ることができる。
つぎに実施例を挙げて本発明を説明する。
実施例 １
Ｎ―シアノ―Ｓ―メチル―N′―〔３―（３―
オキソ―６―フエニル―２―ピリダジニイル）
プロピル〕イソチオ尿素
２―（３―アミノプロピル）―６―フエニル―
３（2H）ピリダジノン13.8ｇ（0.06モル）をエタ
ノール50mlに溶解し、この溶液を室温でジメチル
シアノジチオイミドカルボネート8.8ｇ（0.06モ
ル）をエタノール50mlに溶解した溶液に除々に加
える。淡黄色結晶が除々に析出し、そのまま約８
時間撹拌すると反応は終了する。析出した結晶を
エタノールとイソプロピルエーテルから再結する
と融点159〜160℃を示す淡黄色粉末晶16.1ｇ（収
率82％）を得る。
赤外吸収スペクトル（Nujol法）、cm-1：3200
（NH）、2185（CN）、1660（CO）
核磁気共鳴スペクトル（DMSO―d6）、δ：
2.10（2H、ｍ、−CH2―CH2―CH2）
2.62（3H、ｓ、―SCH3）
3.44（2H、ｔ、Ｊ＝６、Hz、NH―CH2）
4.22（2H、ｔ、Ｊ＝６Hz、Ｎ―CH2）
6.0（1H、ｂ、NH）
7.10（1H、ｄ、Ｊ＝10Hz、C4―Ｈ）
7.5および7.9（5H、ｍ、芳香環のＨ）
8.08（1H、ｄ、Ｊ＝10Hz、C5−Ｈ）
質量スペクトルｍ／ｅ：327
元素分析値（C16H17N5OSとして）
理論値（％）：Ｃ、58.69；Ｈ、5.23；
Ｎ、21.39
実測値（％）：Ｃ、58.96；Ｈ、5.34；
Ｎ、21.56
実施例 ２
Ｎ―シアノ―Ｓ―メチル―N′―〔４―（３―
オキソ―６―フエニル―２―ピリダジニイル）
ブチル〕イソチオ尿素
２―（４―アミノブチル）―６―フエニル―３
（2H）ピリダジノン14.6ｇ（0.06モル）とジメチ
ルシアノジチオイミドカルボネート8.8ｇ（0.06
モル）を用いて実施例１に準拠して反応および後
処理を行なうと融点171〜172℃を示す淡黄色粉末
晶17.8ｇ（87％収率）を得る。
赤外吸収スペクトル（Nujol法）cm-1：3280
（NH）、2170（CN）、1670（CO）
核磁気共鳴スペクトル（DMSO―d6）δ：
1.7（4H、ｍ、―NH―CH2CH2CH2N）
2.58（3H、ｓ、―SCH3）
3.38（2H、ｔ、Ｊ＝７Hz、―NHCH2）
4.19（2H、ｔ、Ｊ＝７Hz、―Ｎ―CH2）
7.06（1H、ｄ、Ｊ＝10Hz、C4―Ｈ）
7.5および7.9（5H、ｍ、芳香環のＨ）
8.06（1H、ｄ、Ｊ＝10Hz、C5―Ｈ）
8.3（1H、ｂ、NH）
質量スペクトルｍ／ｅ：341
元素分析値（C17H19N5OSとして）
理論値（％）：Ｃ、59.79；Ｈ、5.62；
Ｎ、20.51
実測値（％）：Ｃ、59.81；Ｈ、5.89；
Ｎ、20.46
実施例 ３
Ｎ―シアノ―Ｓ―メチル―N′―〔５―（３―
オキソ―６―フエニル―２―ピリダジニイル）
ペンチル〕イソチオ尿素
２―（５―アミノペンチル）―６―フエニル―
３（2H）ピリダジノン15.4ｇ（0.06モル）とジメ
チルシアノジチオイミドカルボネート8.8ｇ
（0.06モル）を用いて実施例１に準拠して反応お
よび後処理を行なうと融点103〜105℃を示す淡黄
色粉末晶16.2ｇ（76％収率）を得る。
赤外吸収スペクトル（Nujol法）cm-1：3280
（NH）、2180（CN）、1660（CO）
核磁気共鳴スペクトル（DMSO―d6）δ：
1.6（6H、ｍ、―Ｎ―CH2―（CH2）3―CH2
―NH）
2.60（3H、ｓ、―SCH3）
3.34（2H、ｄ、Ｊ＝７Hz、NH―CH2）
3.5（1H、ｂ、NH）
4.18（2H、ｄ、Ｊ＝７Hz、Ｎ―CH2）
7.08（1H、ｄ、Ｊ＝10Hz、C4―Ｈ）
7.5および7.9（5H、ｍ、芙香環のＨ）
8.06（1H、ｄ、Ｊ＝10Hz、C5―Ｈ）
質量スペクトルｍ／ｅ：355
元素分析値（C18H21N5OSとして）
理論値（％）：Ｃ、60.81；Ｈ、5.97；
Ｎ、19.70
実測値（％）：Ｃ、60.90；Ｈ、5.84；
Ｎ、19.98
実施例 ４
Ｎ―シアノ―Ｓ―メチル―N′―｛２―〔（３―
オキソ―６―フエニル―２―ピリダジニイル）
メチルチオ〕エチル｝イソチオ尿素
(a) 金属ナトリウム3.5ｇ（0.15モル）を含むエ
タノール溶液100mlにシステアミン塩酸塩8.5ｇ
（0.075モル）を加え70℃で30分間撹拌する。つ
いでこれに２―クロルメチル―６―フエニル―
３（2H）ピリダジノン11ｇ（0.05モル）のエ
タノール溶液100mlを加え５時間加熱還流す
る。冷却後溶媒を留去し、その残渣をクロロホ
ルム抽出し充分水洗いする。乾燥、クロロホル
ム留去後、エタノール中で活性炭処理し、溶媒
を留去すると褐色油状物として２―〔（２―ア
ミノエチル）チオメチル〕―６―フエニル―３
（2H）ピリダジノン10ｇ（77％収率）を得る。
赤外吸収スペクトル（Neat）cm-1：3350
（NH）、1670（CO）
核磁気共鳴スペクトル（DMSO―d6）δ：
2.53（2H、ｓ、NH2）
2.86（4H、ｓ、Ｓ―CH2CH2―Ｎ）
5.28（2H、ｓ、Ｎ―CH2―Ｓ）
7.12（1H、ｄ、Ｊ＝10Hz、C4―Ｈ）
7.5および7.9（5H、ｍ、芳香環のＨ）
8.08（1H、ｄ、Ｊ＝10Hz、C5―Ｈ）
(b) ２―〔（２―アミノエチル）チオメチル〕―
６―フエニル―３（2H）ピリダジノン9.7ｇ
（0.037モル）とジメチルシアノジチオイミドカ
ルボネート5.4ｇ（0.037モル）を用いて実施例
１に準拠して反応および後処理を行なうと融点
136〜138℃を示す淡黄色結晶9.7ｇ（73％収
率）を得る。
赤外吸収スペクトル（Nujol法）cm-1：3240
（NH）、2180（CN）、1670（CO）
核磁気共鳴スペクトル（DMSO―d6）δ：
2.62（3H、ｓ、Ｓ―CH3）
3.03（2H、ｔ、Ｊ＝６Hz、Ｓ―CH2CH2―
Ｎ）
3.68（2H、ｔ、Ｊ＝６Hz、Ｓ―CH2CH2―
Ｎ）
5.36（2H、ｓ、Ｎ―CH2―Ｓ）
7.20（1H、ｄ、Ｊ＝10Hz、C4―Ｈ）
7.6および8.0（5H、ｍ、芳香環のＨ）
8.22（1H、ｄ、Ｊ＝10Hz、C5―Ｈ）
8.6（1H、ｂ、NH）
質量スペクトルｍ／ｅ：359
元素分析値（C16H17N5OS2として）
理論値（％）：Ｃ、53.45；Ｈ、4.78；
Ｎ、19.48
実測値（％）：Ｃ、53.21；Ｈ、4.59；
Ｎ、19.60
実施例 ５
Ｎ―シアノ―N′―メチル―N″―〔３―（３―
オキソ―６―フエニル―２―ピリダジニイル）
プロピル〕グアニジン
Ｎ―シアノ―Ｓ―メチル―N′―〔３―（３―
オキソ―６―フエニル―２―ピリダジニイル）プ
ロピル〕イソチオ尿素2.5ｇ（0.0073モル）を30
％メチルアミンメタノール溶液20mlに溶解し、８
時間加熱（約60℃）すると反応は終了する。その
後溶媒を留去し、残渣をクロロホルム―メタノー
ル混液（15：１）を展開溶媒とするシリカゲルカ
ラムクロマトグラフイーで精製して得た結晶をエ
タノール―イソプロピルエーテルから再結すると
融点185〜186℃を示す無色塊状晶2.0ｇ（84％収
率）を得る。
赤外吸収スペクトル（Nujol法）cm-1：3320、
3240（NH）、2160（CN）、1655（CO）
核磁気共鳴スペクトル（DMSO―d6）δ：
2.04（2H、qui、Ｊ＝６Hz、Ｎ―
CH2CH2CH2NH）
2.72（3H、ｄ、Ｊ＝４Hz、NHCH3）
3.28（2H、ｔ、Ｊ＝６Hz、NH―CH2）
4.22（2H、ｔ、Ｊ＝６Hz、Ｎ―CH2）
7.0（2H、ｂ、NH）
7.10（1H、ｄ、Ｊ＝10Hz、C4―Ｈ）
7.5および7.9（5H、ｍ、芳香環のＨ）
8.06（1H、ｄ、Ｊ＝10Hz、C5―Ｈ）
質量スペクトルｍ／ｅ：310
実施例 ６〜15
相当するイソチオウレア誘導体を原料とし、実
施例５に準拠して反応および後処理を行なうこと
により第１表に記載したピリダジノン誘導体を得
る。
The present invention is based on the general formula [In the formula, R 1 is a lower alkyl group; Z is sulfur or methylene; X is sulfur or NH; m is an integer of 1 to 3 and n represents 0, 1 or 2]. Regarding. The pyridazinone derivative of the present invention represented by the above general formula [] is a new compound and can be used as a pharmaceutical useful as a therapeutic and preventive agent for peptic ulcers. That is, it exhibits the effect of suppressing gastric juice secretion in rats, etc., and suppresses the occurrence of experimental ulcers caused by aspirin, stress, and acne, and its effect is continuous. On the other hand, it has low toxicity and excellent chemical resistance. Therefore, it is extremely effective in treating and preventing gastric acid hyperacidity, gastric ulcer, and duodenal ulcer. The novel compound of the present invention [ ] can be produced by various methods. For example, the target compound where X is sulfur has the general formula [In the formula, Z, m and n represent the same as above] and the general formula It can be obtained by reacting a reaction-equivalent amount of a compound represented by the formula [wherein R 1 is the same as above and R 2 represents a lower alkyl group]. In the reaction, it is appropriate to use no solvent or an inert solvent such as ethanol, acetonitrile, chloroform, etc., and the reaction is carried out at room temperature or under cooling, but it can be carried out under reflux using a solvent. In addition, to produce the target compound where X is NH, the general formula obtained by the above production method is [In the formula, R 2 , Z, m and n are the same as above] and the general formula R 1 -NH 2 [] [In the formula, R 1 is the same as above] The amine derivative [] represented by the following formula can be easily obtained in high yield by reacting without a solvent or in an inert solvent such as ethanol, acetonitrile, benzene, etc. for several hours at room temperature or with heating. Next, the present invention will be explained with reference to Examples. Example 1 N-cyano-S-methyl-N′-[3-(3-
oxo-6-phenyl-2-pyridazinyl)
Propyl]isothiourea 2-(3-aminopropyl)-6-phenyl-
13.8 g (0.06 mol) of 3(2H) pyridazinone is dissolved in 50 ml of ethanol, and this solution is gradually added at room temperature to a solution of 8.8 g (0.06 mol) of dimethylcyanodithioimide carbonate dissolved in 50 ml of ethanol. Pale yellow crystals gradually precipitate and remain as they are for about 8
After stirring for an hour, the reaction is complete. The precipitated crystals were recrystallized from ethanol and isopropyl ether to obtain 16.1 g (yield: 82%) of pale yellow powder crystals having a melting point of 159-160°C. Infrared absorption spectrum (Nujol method), cm -1 : 3200
(NH), 2185 (CN), 1660 (CO) Nuclear magnetic resonance spectrum (DMSO-d 6 ), δ: 2.10 (2H, m, -CH 2 -CH 2 -CH 2 ) 2.62 (3H, s, -SCH 3 ) 3.44 (2H, t, J=6, Hz, NH-CH 2 ) 4.22 (2H, t, J=6Hz, N-CH 2 ) 6.0 (1H, b, NH) 7.10 (1H, d, J= 10Hz, C 4 -H) 7.5 and 7.9 (5H, m, H of aromatic ring) 8.08 (1H, d, J = 10Hz, C 5 -H) Mass spectrum m/e: 327 Elemental analysis value (C 16 H 17 N 5 OS) Theoretical value (%): C, 58.69; H, 5.23;
N, 21.39 Actual value (%): C, 58.96; H, 5.34;
N, 21.56 Example 2 N-cyano-S-methyl-N′-[4-(3-
oxo-6-phenyl-2-pyridazinyl)
Butyl]isothiourea 2-(4-aminobutyl)-6-phenyl-3
(2H) pyridazinone 14.6 g (0.06 mol) and dimethylcyanodithioimide carbonate 8.8 g (0.06 mol)
When the reaction and work-up are carried out according to Example 1 using mol), 17.8 g (87% yield) of pale yellow powder crystals having a melting point of 171 DEG -172 DEG C. are obtained. Infrared absorption spectrum (Nujol method) cm -1 : 3280
(NH), 2170 (CN), 1670 (CO) Nuclear magnetic resonance spectrum (DMSO-d 6 ) δ: 1.7 (4H, m, -NH-CH 2 CH 2 CH 2 N) 2.58 (3H, s, -SCH 3 ) 3.38 (2H, t, J=7Hz, -NHCH 2 ) 4.19 (2H, t, J=7Hz, -N-CH 2 ) 7.06 (1H, d, J=10Hz, C 4 -H) 7.5 and 7.9 (5H, m, H in aromatic ring) 8.06 (1H, d, J=10Hz, C 5 -H) 8.3 (1H, b, NH) Mass spectrum m/e: 341 Elemental analysis value (C 17 H 19 N 5 (as OS) Theoretical value (%): C, 59.79; H, 5.62;
N, 20.51 Actual value (%): C, 59.81; H, 5.89;
N, 20.46 Example 3 N-cyano-S-methyl-N′-[5-(3-
oxo-6-phenyl-2-pyridazinyl)
Pentyl]isothiourea 2-(5-aminopentyl)-6-phenyl-
15.4 g (0.06 mol) of 3(2H) pyridazinone and 8.8 g of dimethylcyanodithioimide carbonate
(0.06 mol) was used in the reaction and work-up according to Example 1 to obtain 16.2 g (76% yield) of pale yellow powder crystals having a melting point of 103-105°C. Infrared absorption spectrum (Nujol method) cm -1 : 3280
(NH), 2180 (CN), 1660 (CO) Nuclear magnetic resonance spectrum (DMSO-d 6 ) δ: 1.6 (6H, m, -N-CH 2 -(CH 2 ) 3 -CH 2
-NH) 2.60 (3H, s, -SCH 3 ) 3.34 (2H, d, J=7Hz, NH-CH 2 ) 3.5 (1H, b, NH) 4.18 (2H, d, J=7Hz, N-CH 2 ) 7.08 (1H, d, J = 10Hz, C 4 -H) 7.5 and 7.9 (5H, m, H of Fukan ring) 8.06 (1H, d, J = 10Hz, C 5 -H) Mass spectrum m/e :355 Elemental analysis value (as C 18 H 21 N 5 OS) Theoretical value (%): C, 60.81; H, 5.97;
N, 19.70 Actual value (%): C, 60.90; H, 5.84;
N, 19.98 Example 4 N-cyano-S-methyl-N'-{2-[(3-
oxo-6-phenyl-2-pyridazinyl)
Methylthio]ethyl}isothiourea (a) 8.5 g of cysteamine hydrochloride in 100 ml of an ethanol solution containing 3.5 g (0.15 mol) of sodium metal.
(0.075 mol) and stirred at 70°C for 30 minutes. Next, add 2-chloromethyl-6-phenyl to this.
Add 100 ml of an ethanol solution containing 11 g (0.05 mol) of 3(2H) pyridazinone, and heat under reflux for 5 hours. After cooling, the solvent is distilled off, and the residue is extracted with chloroform and thoroughly washed with water. After drying and distilling off chloroform, it was treated with activated carbon in ethanol, and when the solvent was distilled off, 2-[(2-aminoethyl)thiomethyl]-6-phenyl-3 was obtained as a brown oil.
Obtain 10 g (77% yield) of (2H) pyridazinone. Infrared absorption spectrum (Neat) cm -1 : 3350
(NH), 1670 (CO) Nuclear magnetic resonance spectrum (DMSO-d 6 ) δ: 2.53 (2H, s, NH 2 ) 2.86 (4H, s, S-CH 2 CH 2 -N) 5.28 (2H, s, N-CH 2 -S) 7.12 (1H, d, J = 10Hz, C 4 -H) 7.5 and 7.9 (5H, m, H of aromatic ring) 8.08 (1H, d, J = 10Hz, C 5 -H) (b) 2-[(2-aminoethyl)thiomethyl]-
6-phenyl-3(2H)pyridazinone 9.7g
(0.037 mol) and 5.4 g (0.037 mol) of dimethylcyanodithioimide carbonate were reacted and worked up in accordance with Example 1.
9.7 g (73% yield) of pale yellow crystals are obtained, exhibiting a temperature of 136-138°C. Infrared absorption spectrum (Nujol method) cm -1 : 3240
(NH), 2180 (CN), 1670 (CO) Nuclear magnetic resonance spectrum (DMSO-d 6 ) δ: 2.62 (3H, s, S-CH 3 ) 3.03 (2H, t, J=6Hz, S-CH 2 CH 2 -
N) 3.68 (2H, t, J=6Hz, S-CH 2 CH 2 -
N) 5.36 (2H, s, N-CH 2 -S) 7.20 (1H, d, J=10Hz, C 4 -H) 7.6 and 8.0 (5H, m, H in aromatic ring) 8.22 (1H, d, J = 10Hz, C 5 - H) 8.6 (1H, b, NH) Mass spectrum m/e: 359 Elemental analysis value (as C 16 H 17 N 5 OS 2 ) Theoretical value (%): C, 53.45; H, 4.78 ;
N, 19.48 Actual value (%): C, 53.21; H, 4.59;
N, 19.60 Example 5 N-cyano-N′-methyl-N″-[3-(3-
oxo-6-phenyl-2-pyridazinyl)
propyl]guanidine N-cyano-S-methyl-N'-[3-(3-
Oxo-6-phenyl-2-pyridazinyl)propyl isothiourea 2.5 g (0.0073 mol) in 30
8% methylamine dissolved in 20ml of methanol solution.
The reaction is completed after heating for a period of time (approximately 60°C). Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography using a chloroform-methanol mixture (15:1) as the developing solvent. The crystals obtained were re-crystallized from ethanol-isopropyl ether, with a melting point of 185-186°C. 2.0 g (84% yield) of colorless bulk crystals are obtained. Infrared absorption spectrum (Nujol method) cm -1 : 3320,
3240 (NH), 2160 (CN), 1655 (CO) Nuclear magnetic resonance spectrum (DMSO- d6 ) δ: 2.04 (2H, qui, J=6Hz, N-
CH 2 CH 2 CH 2 NH) 2.72 (3H, d, J=4Hz, NHCH 3 ) 3.28 (2H, t, J=6Hz, NH-CH 2 ) 4.22 (2H, t, J=6Hz, N-CH 2 ) 7.0 (2H, b, NH) 7.10 (1H, d, J = 10Hz, C 4 - H) 7.5 and 7.9 (5H, m, H of aromatic ring) 8.06 (1H, d, J = 10Hz, C 5 - H) Mass spectrum m/e: 310 Examples 6 to 15 Using the corresponding isothiourea derivatives as raw materials, the pyridazinone derivatives listed in Table 1 are obtained by carrying out the reaction and post-treatment according to Example 5.
【表】【table】
Claims (1)
はメチレン；Ｘは硫黄またはNH；ｍは１〜３の
整数およびｈは０，１または２を表わす〕で示さ
れるピリダジノン誘導体。 ２ 一般式 〔式中、R1、Ｘ、ｍ、およびｎは前記と同じ
ものを表わす〕で示される特許請求の範囲第１項
記載の化合物。 ３ 一般式 〔式中、R1、ｍおよびｎは前記と同じものを
表わす〕で示される特許請求の範囲第２項記載の
化合物。 ４ 一般式 〔式中、R1、ｍおよびｎは前記と同じものを
表わす〕で示される特許請求の範囲第２項記載の
化合物。 ５ 一般式 〔式中、R1、Ｘ、ｍおよびｎは前記と同じも
のを表わす〕で示される特許請求の範囲第１項記
載の化合物。 ６ 一般式 〔式中、R1、ｍおよびｎは前記と同じものを
表わす〕で示される特許請求の範囲第５項記載の
化合物。 ７ 一般式 〔式中、R1、ｍおよびｎは前記と同じものを
表わす〕で示される特許請求の範囲第５項記載の
化合物。[Claims] 1. General formula A pyridazinone derivative represented by the following formula: [wherein R 1 is a lower alkyl group; z is sulfur or methylene; 2 General formula The compound according to claim 1, represented by the formula: [wherein R 1 , X, m, and n are the same as defined above]. 3 General formula The compound according to claim 2, represented by the formula: [wherein R 1 , m and n are the same as defined above]. 4 General formula The compound according to claim 2, represented by the formula: [wherein R 1 , m and n are the same as defined above]. 5 General formula The compound according to claim 1, represented by the formula: [wherein R 1 , X, m and n are the same as defined above]. 6 General formula The compound according to claim 5, represented by the formula: [wherein R 1 , m and n are the same as defined above]. 7 General formula The compound according to claim 5, represented by the formula: [wherein R 1 , m and n are the same as defined above].
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15899679A JPS5681568A (en) | 1979-12-05 | 1979-12-05 | Pyridazinone derivative |
| ZA00807209A ZA807209B (en) | 1979-12-05 | 1980-11-19 | Derivatives of 2-substituted-6-phenyl-3(2h)-pyridazinone |
| EP19800304409 EP0030835B1 (en) | 1979-12-05 | 1980-12-05 | Derivatives of 2-substituted-6-phenyl-3(2h)pyridazinone, their production and pharmaceutical compositions containing them |
| AT80304409T ATE3288T1 (en) | 1979-12-05 | 1980-12-05 | 2-SUBSTITUTED-6-PHENYL-3(2H)-PYRIDAZINONE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| ES498263A ES8201553A1 (en) | 1979-12-05 | 1980-12-05 | Procedure for the preparation of derivatives of 6-fenil-3 (2H) -piridacinona 2-substitute. (Machine-translation by Google Translate, not legally binding) |
| DE8080304409T DE3063196D1 (en) | 1979-12-05 | 1980-12-05 | Derivatives of 2-substituted-6-phenyl-3(2h)pyridazinone, their production and pharmaceutical compositions containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15899679A JPS5681568A (en) | 1979-12-05 | 1979-12-05 | Pyridazinone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5681568A JPS5681568A (en) | 1981-07-03 |
| JPS6242900B2 true JPS6242900B2 (en) | 1987-09-10 |
Family
ID=15683939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15899679A Granted JPS5681568A (en) | 1979-12-05 | 1979-12-05 | Pyridazinone derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS5681568A (en) |
| ZA (1) | ZA807209B (en) |
-
1979
- 1979-12-05 JP JP15899679A patent/JPS5681568A/en active Granted
-
1980
- 1980-11-19 ZA ZA00807209A patent/ZA807209B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA807209B (en) | 1981-11-25 |
| JPS5681568A (en) | 1981-07-03 |
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