JPS6257626B2 - - Google Patents
Info
- Publication number
- JPS6257626B2 JPS6257626B2 JP3861478A JP3861478A JPS6257626B2 JP S6257626 B2 JPS6257626 B2 JP S6257626B2 JP 3861478 A JP3861478 A JP 3861478A JP 3861478 A JP3861478 A JP 3861478A JP S6257626 B2 JPS6257626 B2 JP S6257626B2
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- hydrogen
- general formula
- methyl
- melting point
- 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
Links
- -1 pyridylalkyl Chemical group 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 150000004892 pyridazines Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000000354 decomposition reaction Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VYSYZMNJHYOXGN-UHFFFAOYSA-N ethyl n-aminocarbamate Chemical compound CCOC(=O)NN VYSYZMNJHYOXGN-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Description
この発明は、循環器系用薬剤として有用な、一
般式
〔式中R1は水素、低級アルキル、アシルを、R2は
水素、低級アルキルを、R3、R4は同一または異
つて水素、低級アルキル、ジ低級アルキルアミノ
アルキル、ピリジルアルキル、アラルキル、アミ
ノ、低級アルコキシカルボニルアミノを示すか、
R3、R4は隣接する窒素原子とともに４位に低級
アルキルまたはアラルケニルを有した１−ピペラ
ジニルを形成する基を示す。ｎは１、２を、Ｘは
Ｏ、H2を示す。〕
で表わされる新規なピリダジン誘導体およびその
製造法に関する。
上記の各記号の定義をさらに具体的に説明する
と、低級アルキルとはメチル、エチル、プロピ
ル、イソプロピル、ブチル、イソブチル、第三級
ブチルなどの炭素数１〜４個の直鎖又は分枝アル
キルを、アシルとはアセチル、プロピオニルなど
を、ジ低級アルキルアミノアルキルとはジメチル
アミノエチル、ジエチルアミノエチル、ジメチル
アミノプロピル、ジエチルアミノプロピルなど
を、ピリジルアルキルとは３−ピリジルメチル、
２−ピリジルエチルなどを、アラルキルとは低級
アルキル、低級アルコキシ、ハロゲンなどの置換
基を有していてもよいベンジル、フエネチルなど
を、低級アルコキシカルボニルアミノとはメトキ
シカルボニルアミノ、エトキシカルボニルアミ
ノ、プロポキシカルボニルアミノなどを、アラル
ケニルとはシンナミルなどである。
一般式（）の化合物は、たとえば以下の方法
１、２により製造することができる。
方法１
一般式
〔式中各記号は前記と同義である。〕
で表わされる化合物と、一般式
〔式中各記号は前記と同義である。〕
で表わされる化合物とを反応させる方法。
方法２
一般式
〔式中各記号は前記と同義である。〕
で表わされる化合物とヒドラジン（１水和物の形
で用いる）とを反応させる方法。この方法は一般
式（）において、
This invention provides a general formula useful as a drug for the circulatory system. [In the formula, R 1 is hydrogen, lower alkyl, acyl, R 2 is hydrogen, lower alkyl, R 3 and R 4 are the same or different and hydrogen, lower alkyl, di-lower alkylaminoalkyl, pyridylalkyl, aralkyl, amino , represents lower alkoxycarbonylamino,
R 3 and R 4 represent a group that together with the adjacent nitrogen atom forms 1-piperazinyl having lower alkyl or aralkenyl at the 4-position. n represents 1 or 2; X represents O or H 2 ; ] This invention relates to a novel pyridazine derivative represented by the following and a method for producing the same. To explain the definitions of each of the above symbols more specifically, lower alkyl refers to straight chain or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. , acyl refers to acetyl, propionyl, etc., di-lower alkylaminoalkyl refers to dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, etc., and pyridylalkyl refers to 3-pyridylmethyl,
2-pyridylethyl, etc., aralkyl refers to lower alkyl, lower alkoxy, benzyl, phenethyl, etc. which may have a substituent such as halogen, lower alkoxycarbonylamino refers to methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonyl, etc. Amino etc., and aralkenyl such as cinnamyl. The compound of general formula () can be produced, for example, by methods 1 and 2 below. Method 1 General formula [Each symbol in the formula has the same meaning as above. ] The compound represented by and the general formula [Each symbol in the formula has the same meaning as above. ] A method of reacting with a compound represented by Method 2 General formula [Each symbol in the formula has the same meaning as above. ] A method of reacting a compound represented by these with hydrazine (used in the form of monohydrate). In this method, in the general formula (),
【式】が−NHNH2化合
物に適用される。
上記の方法１、２の反応は、無溶媒または適当
な溶媒中、室温ないし加熱下に行われる。溶媒と
しては、これら反応を妨げないものであればいか
なるものでもよく、たとえば水、メタノール、エ
タノール、プロパノール、イソプロパノール、テ
トラヒドロフラン、ジオキサン、アセトン、メチ
ルエチルケトン、ベンゼン、トルエン、メチレン
クロライド、クロロホルム、ジメチルホルムアミ
ド、またはこれらの混合溶媒が挙げられる。
一般式（）および一般式（）の原料化合物
は新規化合物であり、たとえば以下に示すように
それ自体は公知の方法で調製できる。
〔式中Ｘはハロゲン（塩素、臭素など）を、他の
各記号は前記と同義である。〕
上記の方法で調製される原料化合物を例示する
と例えば次の通りである。
(1) ６−（１・２・３・４−テトラヒドロキノリ
ン−６−イル）−４・５−ジヒドロ−５−メチ
ル−３（2H）−ピリダジンチオン、融点177〜
180℃
(2) ６−（１−アセチルインドリン−５−イル）−
４・５−ジヒドロ−５−メチル−３（2H）−ピ
リダジンチオン、融点234〜237℃
(3) ６−（１−アセチルインドリン−５−イル）−
３−ベンジルチオ−４・５−ジヒドロ−５−メ
チルピリダジン、融点92〜93℃
(4) ６−（１−メチル−２−オキソ−１・２・
３・４−テトラヒドロキノリン−６−イル）−
４・５−ジヒドロ−５−メチル−３（2H）−ピ
リダジンチオン、融点185〜187℃
(5) ６−（１−メチル−２−オキソ−１・２・
３・４−テトラヒドロキノリン−６−イル）−
３−ベンジルチオ−４・５−ジヒドロ−５−メ
チルピリダジン、融点134〜136℃
一般式〔〕の化合物は所望により、無機酸
（塩酸、臭化水素酸、硝酸、硫酸、リン酸など）、
あるいは有機酸（シユウ酸、マレイン酸、フマー
ル酸、クエン酸、酒石酸、メタンスルホン酸、ベ
ンゼンスルホン酸、パラトルエンスルホン酸な
ど）と処理することにより酸付加塩となしうる。
本発明の一般式（）の化合物およびその酸付
加塩は、降圧、血管拡張、脳血流増大、血小板凝
集抑制などの薬理作用を有し、循環器系用薬剤と
して有用である。
本発明の化合物を前記の医薬として用いる場
合、適宜の薬理的に許容される担体、賦形剤、希
釈剤などと混合し、散剤、顆粒剤、錠剤、カプセ
ル剤、注射剤などの形態で経口的または非経口的
に投与できる。投与量は対象疾患、症状、化合物
などによつても異なるが、経口的投与する場合、
通常成人１日あたり１mg〜1000mg程度である。
以下実施例により本発明をより一層具体的に説
明する。
実施例 １
３−ベンジルチオ−６−（１−メチル−２−オ
キソ−１・２・３・４−テトラヒドロキノリン−
６−イル）−４・５−ジヒドロ−５−メチルピリ
ダジン５ｇ、エトキシカルボニルヒドラジン２
ｇ、エタノール80mlの混合物を３時間加熱還流す
る。冷後溶媒を減圧留去し、残査にイソプロピル
エーテルを加え、析出する結晶を取し、エタノ
ールより再結晶すれば、融点161〜163℃（分解）
の３−エトキシカルボニルヒドラジノ−６−（１
−メチル−２−オキソ−１・２・３・４−テトラ
ヒドロキノリン−６−イル）−４・５−ジヒドロ
−５−メチルピリダジン3.5ｇが得られる。
実施例 ２
３−ベンジルチオ−６−（１−メチル−２−オ
キソ−１・２・３・４−テトラヒドロキノリン−
６−イル）−４・５−ジヒドロピリダジン5.5ｇ、
３・４−ジメトキシフエネチルアミン3.3ｇ、エ
タノール80mlの混合物を５時間加熱還流する。冷
後溶媒を減圧留去し、残査をエタノールにとか
し、イソプロパノール−塩酸を加え、析出する結
晶を取し、メタノールより再結晶すれば、融点
249〜252℃（分解）の３−（３・４−ジメトキシ
フエネチルアミノ）−６−（１−メチル−２−オキ
ソ−１・２・３・４−テトラヒドロキノリン−６
−イル）−４・５−ジヒドロピリダジン・塩酸塩
3.7ｇが得られる。
実施例 ３
６−（５−インドリニル）−４・５−ジヒドロ−
５−メチルピリダジン−３−チオン6.6ｇ、ヒド
ラジンヒドラート10ml、メタノール100mlの混合
物を１時間加熱還流する。冷後溶媒を減圧留去
し、残査を酢酸エチルにとかし、水洗、硫酸マグ
ネシウムで乾燥後、減圧留去する。残査をエタノ
ールにとかし、イソプロパノール−塩酸を加え、
析出する結晶を取し、エタノールより再結晶す
れば、融点161〜163℃（分解）の６−（５−イン
ドリニル）−３−ヒドラジノ−４・５−ジヒドロ
−５−メチルピリダジン・２塩酸塩・１水和物
2.8ｇが得られる。
上記実施例と同様にして、さらにたとえば次の
化合物が製造される。
◎３−ヒドラジノ−６−（１・２・３・４−テト
ラヒドロキノリン−６−イル）−４・５−ジヒ
ドロ−５−メチルピリダジン、２塩酸塩の融点
222〜224℃（分解）
◎３−ヒドラジノ−６−（１−メチル−２−オキ
ソ−１・２・３・４−テトラヒドロキノリン−
６−イル）−４・５−ジヒドロ−５−メチルピ
リダジン、塩酸塩の融点250〜252℃（分解）
◎６−（１−アセチルインドリン−５−イル）−３
−ヒドラジノ−４・５−ジヒドロ−５−メチル
ピリダジン、融点208〜210℃（分解）
◎６−（１−アセチルインドリン−５−イル）−３
−エトキシカルボニルヒドラジノ−４・５−ジ
ヒドロ−５−メチルピリダジン、融点204〜205
℃（分解）
◎３−（３・３−ジフエニルプロピルアミノ）−６
−（１−メチル−２−オキソ−１・２・３・４
−テトラヒドロキノリン−６−イル）−４・５
−ジヒドロピリダジン、塩酸塩の融点259〜262
℃（分解）
◎３−（３−ジメチルアミノプロピルアミノ）−６
−（１−メチル−２−オキソ−１・２・３・４
−テトラヒドロキノリン−６−イル）−４・５
−ジヒドロピリダジン、２塩酸塩・2.5水和物
の融点157〜160℃（分解）
◎３−（４−シンナミル−１−ピペラジニル）−６
−（１−メチル−２−オキソ−１・２・３・４
−テトラヒドロキノリン−６−イル）−４・５
−ジヒドロピリダジン、２塩酸塩・0.5水和物
の融点284〜286℃（分解）
◎３−〔Ｎ−メチル−Ｎ−〔２−（２−ピリジル）
エチルアミノ〕−６−（１−メチル−２−オキソ
−１・２・３・４−テトラヒドロキノリン−６
−イル）−４・５−ジヒドロピリダジン、２塩
酸塩・３水和物の融点226〜228℃（分解）
◎３−（４−メチル−１−ピペラジニル）−６−
（１−メチル−２−オキソ−１・２・３・４−
テトラヒドロキノリン−６−イル）−４・５−
ジヒドロピリダジン、２塩酸塩・１水和物の融
点255〜260℃（分解）
◎３−ｎ−ブチルアミノ−６−（１−メチル−２
−オキソ−１・２・３・４−テトラヒドロキノ
リン−６−イル）−４・５−ジヒドロ−５−メ
チルピリダジン、塩酸塩の融点247〜249℃（分
解）
◎３−〔２−（２−ピリジル）エチルアミノ〕−６
−（１−メチル−２−オキソ−１・２・３・４
−テトラヒドロキノリン−６−イル）−４・５
−ジヒドロ−５−メチルピリダジン、２塩酸
塩・0.5水和物の融点249℃（分解）The formula applies to the -NHNH2 compound. The reactions in Methods 1 and 2 above are carried out without a solvent or in a suitable solvent at room temperature or under heating. Any solvent may be used as long as it does not interfere with these reactions, such as water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, benzene, toluene, methylene chloride, chloroform, dimethylformamide, or A mixed solvent of these may be mentioned. The starting compounds of general formula () and general formula () are new compounds, and can be prepared by methods known per se, for example, as shown below. [In the formula, X represents halogen (chlorine, bromine, etc.), and the other symbols have the same meanings as above. ] Examples of raw material compounds prepared by the above method are as follows. (1) 6-(1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro-5-methyl-3(2H)-pyridazinethione, melting point 177~
180℃ (2) 6-(1-acetylindolin-5-yl)-
4,5-dihydro-5-methyl-3(2H)-pyridazinethione, melting point 234-237°C (3) 6-(1-acetylindolin-5-yl)-
3-benzylthio-4,5-dihydro-5-methylpyridazine, melting point 92-93℃ (4) 6-(1-methyl-2-oxo-1,2,
3,4-tetrahydroquinolin-6-yl)-
4,5-dihydro-5-methyl-3(2H)-pyridazinethione, melting point 185-187℃ (5) 6-(1-methyl-2-oxo-1,2.
3,4-tetrahydroquinolin-6-yl)-
3-benzylthio-4,5-dihydro-5-methylpyridazine, melting point 134-136℃ The compound of general formula [] may be optionally inorganic acid (hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.),
Alternatively, it can be made into an acid addition salt by treatment with an organic acid (oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). The compound of general formula () and its acid addition salt of the present invention have pharmacological effects such as lowering blood pressure, dilating blood vessels, increasing cerebral blood flow, and inhibiting platelet aggregation, and are useful as drugs for the cardiovascular system. When the compound of the present invention is used as the above-mentioned medicine, it is mixed with an appropriate pharmacologically acceptable carrier, excipient, diluent, etc., and administered orally in the form of a powder, granule, tablet, capsule, injection, etc. It can be administered intravenously or parenterally. The dosage varies depending on the target disease, symptoms, compound, etc., but when administered orally,
It is usually about 1 mg to 1000 mg per day for adults. The present invention will be explained in more detail below using Examples. Example 1 3-benzylthio-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-
6-yl)-4,5-dihydro-5-methylpyridazine 5g, ethoxycarbonylhydrazine 2
A mixture of g and 80 ml of ethanol is heated under reflux for 3 hours. After cooling, the solvent is distilled off under reduced pressure, isopropyl ether is added to the residue, the precipitated crystals are collected, and recrystallized from ethanol, resulting in a melting point of 161-163°C (decomposition).
3-ethoxycarbonylhydrazino-6-(1
3.5 g of -methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro-5-methylpyridazine are obtained. Example 2 3-benzylthio-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-
5.5 g of 6-yl)-4,5-dihydropyridazine,
A mixture of 3.3 g of 3,4-dimethoxyphenethylamine and 80 ml of ethanol is heated under reflux for 5 hours. After cooling, the solvent is distilled off under reduced pressure, the residue is dissolved in ethanol, isopropanol-hydrochloric acid is added, the precipitated crystals are collected, and recrystallized from methanol, the melting point is
3-(3,4-dimethoxyphenethylamino)-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6 at 249-252°C (decomposition)
-yl)-4,5-dihydropyridazine hydrochloride
3.7g is obtained. Example 3 6-(5-indolinyl)-4,5-dihydro-
A mixture of 6.6 g of 5-methylpyridazine-3-thione, 10 ml of hydrazine hydrate, and 100 ml of methanol is heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and then distilled off under reduced pressure. Dissolve the residue in ethanol, add isopropanol-hydrochloric acid,
If the precipitated crystals are collected and recrystallized from ethanol, 6-(5-indolinyl)-3-hydrazino-4,5-dihydro-5-methylpyridazine dihydrochloride with a melting point of 161-163°C (decomposition) is obtained. monohydrate
2.8g is obtained. For example, the following compounds are further produced in the same manner as in the above examples. ◎Melting point of 3-hydrazino-6-(1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro-5-methylpyridazine, dihydrochloride
222-224℃ (decomposition) ◎3-hydrazino-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-
6-yl)-4,5-dihydro-5-methylpyridazine, hydrochloride melting point 250-252℃ (decomposition) ◎6-(1-acetylindolin-5-yl)-3
-Hydrazino-4,5-dihydro-5-methylpyridazine, melting point 208-210℃ (decomposition) ◎6-(1-acetylindolin-5-yl)-3
-Ethoxycarbonylhydrazino-4,5-dihydro-5-methylpyridazine, melting point 204-205
°C (decomposition) ◎3-(3,3-diphenylpropylamino)-6
-(1-methyl-2-oxo-1,2,3,4
-tetrahydroquinolin-6-yl)-4・5
-Dihydropyridazine, hydrochloride melting point 259-262
°C (decomposition) ◎3-(3-dimethylaminopropylamino)-6
-(1-methyl-2-oxo-1,2,3,4
-tetrahydroquinolin-6-yl)-4・5
-Dihydropyridazine, dihydrochloride/2.5 hydrate melting point 157-160℃ (decomposition) ◎3-(4-cinnamyl-1-piperazinyl)-6
-(1-methyl-2-oxo-1,2,3,4
-tetrahydroquinolin-6-yl)-4・5
-Dihydropyridazine, dihydrochloride/0.5 hydrate melting point 284-286℃ (decomposition) ◎3-[N-Methyl-N-[2-(2-pyridyl)]
ethylamino]-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6
3-(4-methyl-1-piperazinyl)-6-
(1-methyl-2-oxo-1,2,3,4-
Tetrahydroquinolin-6-yl)-4,5-
Dihydropyridazine, dihydrochloride/monohydrate melting point 255-260℃ (decomposition) ◎3-n-butylamino-6-(1-methyl-2
Melting point of oxo-1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro-5-methylpyridazine, hydrochloride 247-249℃ (decomposition) ◎3-[2-(2- pyridyl)ethylamino]-6
-(1-methyl-2-oxo-1,2,3,4
-tetrahydroquinolin-6-yl)-4・5
-Dihydro-5-methylpyridazine, dihydrochloride/0.5 hydrate Melting point 249℃ (decomposition)
Claims (1)
水素、低級アルキルを、R3、R4は同一または異
つて水素、低級アルキル、ジ低級アルキルアミノ
アルキル、ピリジルアルキル、アラルキル、アミ
ノ、低級アルコキシカルボニルアミノを示すか、
R3、R4は隣接する窒素原子とともに４位に低級
アルキルまたはアラルケニルを有した１−ピペラ
ジニルを形成する基を示す。ｎは１、２を、Ｘは
Ｏ、H2を示す。〕 で表わされるピリダジン誘導体。 ２ 一般式 で表わされる化合物と、一般式 で表わされる化合物を反応させることを特徴とす
る、一般式 で表わされるピリダジン誘導体の製造法。 〔式中R1は水素、低級アルキル、アシルを、R2は
水素、低級アルキルを、R3、R4は同一または異
つて水素、低級アルキル、ジ低級アルキルアミノ
アルキル、ピリジルアルキル、アラルキル、アミ
ノ、低級アルコキシカルボニルアミノを示すか、
R3、R4は隣接する窒素原子とともに４位に低級
アルキルまたはアラルケニルを有していてもよい
１−ピペラジニルを形成する基を示す。ｎは１、
２を、ＸはＯ、H2を示す。〕 ３ 一般式 で表わされる化合物とヒドラジンとを反応させる
ことを特徴とする、一般式 で表わされるピリダジン誘導体の製造法。 〔式中R1は水素、低級アルキル、アシルを、R2は
水素、低級アルキルを、ｎは１、２を、ＸはＯ、
H2を示す。〕[Claims] 1. General formula [In the formula, R 1 is hydrogen, lower alkyl, acyl, R 2 is hydrogen, lower alkyl, R 3 and R 4 are the same or different and hydrogen, lower alkyl, di-lower alkylaminoalkyl, pyridylalkyl, aralkyl, amino , represents lower alkoxycarbonylamino,
R 3 and R 4 represent a group that together with the adjacent nitrogen atom forms 1-piperazinyl having lower alkyl or aralkenyl at the 4-position. n represents 1 or 2; X represents O or H 2 ; ] A pyridazine derivative represented by. 2 General formula Compounds represented by and general formula A general formula characterized by reacting a compound represented by A method for producing a pyridazine derivative represented by [In the formula, R 1 is hydrogen, lower alkyl, acyl, R 2 is hydrogen, lower alkyl, R 3 and R 4 are the same or different and hydrogen, lower alkyl, di-lower alkylaminoalkyl, pyridylalkyl, aralkyl, amino , represents lower alkoxycarbonylamino,
R 3 and R 4 represent a group that together with the adjacent nitrogen atom forms 1-piperazinyl which may have lower alkyl or aralkenyl at the 4-position. n is 1,
2, and X represents O or H2 . ] 3 General formula A general formula characterized by reacting a compound represented by with hydrazine A method for producing a pyridazine derivative represented by [In the formula, R 1 is hydrogen, lower alkyl or acyl, R 2 is hydrogen or lower alkyl, n is 1 or 2, X is O,
Indicates H2 . ]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3861478A JPS54130589A (en) | 1978-03-31 | 1978-03-31 | Pyridazine derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3861478A JPS54130589A (en) | 1978-03-31 | 1978-03-31 | Pyridazine derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS54130589A JPS54130589A (en) | 1979-10-09 |
| JPS6257626B2 true JPS6257626B2 (en) | 1987-12-02 |
Family
ID=12530123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3861478A Granted JPS54130589A (en) | 1978-03-31 | 1978-03-31 | Pyridazine derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS54130589A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0518904Y2 (en) * | 1988-04-19 | 1993-05-19 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5777676A (en) * | 1980-10-31 | 1982-05-15 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
-
1978
- 1978-03-31 JP JP3861478A patent/JPS54130589A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0518904Y2 (en) * | 1988-04-19 | 1993-05-19 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54130589A (en) | 1979-10-09 |
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