JPS63145272A - 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative - Google Patents
4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivativeInfo
- Publication number
- JPS63145272A JPS63145272A JP29457586A JP29457586A JPS63145272A JP S63145272 A JPS63145272 A JP S63145272A JP 29457586 A JP29457586 A JP 29457586A JP 29457586 A JP29457586 A JP 29457586A JP S63145272 A JPS63145272 A JP S63145272A
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- JP
- Japan
- Prior art keywords
- group
- formula
- dihydro
- general formula
- integer
- 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.)
- Pending
Links
- -1 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone Chemical class 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims abstract description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 206010008088 Cerebral artery embolism Diseases 0.000 abstract description 2
- 206010008132 Cerebral thrombosis Diseases 0.000 abstract description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 abstract description 2
- 206010058990 Venous occlusion Diseases 0.000 abstract description 2
- 201000010849 intracranial embolism Diseases 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 230000004520 agglutination Effects 0.000 abstract 1
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000002093 peripheral effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
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- 239000003814 drug Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
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- 229940079593 drug Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 201000010099 disease Diseases 0.000 description 3
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- 238000000921 elemental analysis Methods 0.000 description 3
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- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
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- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 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
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
- 150000005303 alkyl halide derivatives Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- 238000003776 cleavage reaction Methods 0.000 description 1
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- 230000001186 cumulative effect Effects 0.000 description 1
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、抗血栓薬として有用な新規４．５−ジヒドロ
−６−（４−置換フェニル）−３（２Ｈ）−ピリダジノ
ン誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to novel 4,5-dihydro-6-(4-substituted phenyl)-3(2H)-pyridazinone derivatives useful as antithrombotic agents.
特開昭５０−９３９８４．特開昭５８−８０１５及び特
開昭６１−４０２７０に本発明化合物と構造類似の４．
５ジヒドロ−３（２Ｈ）−ピリダジノン誘導体が開示さ
れている。Japanese Patent Publication No. 50-93984. 4. JP-A-58-8015 and JP-A-61-40270 have structural similarities to the compounds of the present invention.
5dihydro-3(2H)-pyridazinone derivatives are disclosed.
しかし、前記のいずれの公報にも本発明化合物ないしそ
の抗血栓作用について何ら示唆するところはない。However, none of the above-mentioned publications suggests anything about the compound of the present invention or its antithrombotic effect.
近年、高齢イし社会が進むにつれて血栓症をはじめとす
る成人病の増加がクローズアップされてきており、特に
これらの疾患を抗血小板剤を用いて予防或いは治療しよ
うとする試みが注目されている。抗血小板剤としては、
その作用機序から種々の薬剤が知られているが実際に臨
床に応用されている薬剤は数少なく、必ずしも満足でき
るものではない。In recent years, as the population ages and society progresses, the increase in adult diseases such as thrombosis has come into focus, and efforts to prevent or treat these diseases using antiplatelet agents have been attracting particular attention. . As an antiplatelet agent,
Various drugs are known based on their mechanisms of action, but only a few have actually been used clinically, and they are not always satisfactory.
本発明者らは１種々の血栓症の予防或いは治療剤として
安全性の高い優れた薬効を示す化合物を得ることを目的
に鋭意研究を重ねた。その結果。The present inventors have conducted extensive research with the aim of obtaining a compound that is highly safe and exhibits excellent medicinal efficacy as a prophylactic or therapeutic agent for various thromboses. the result.
４．５−ジヒドロ−６−（４−置換フェニル）−３（２
Ｈ）−ピリダジノン誘導体のなかに所期の目的を達成す
る優れた化合物を見い出し１本発明を完成した。4.5-dihydro-6-(4-substituted phenyl)-3(2
The present invention was completed by discovering an excellent compound that achieves the desired objective among H)-pyridazinone derivatives.
［問題点を解決するための手段〕
本発明の４．５−ジヒドロ−６−（４−置換フェニル）
−３（２Ｈ）−ピリダジノン誘導体は。[Means for solving the problems] 4,5-dihydro-6-(4-substituted phenyl) of the present invention
-3(2H)-pyridazinone derivatives.
一般式ＣＩ） 〔式中、Ｒは水素原子又は低級アルキル基を示す。General formula CI) [In the formula, R represents a hydrogen atom or a lower alkyl group.
Ａは水酸基、ハロゲン原子、シアン基、アミノ基。A is a hydroxyl group, a halogen atom, a cyan group, an amino group.
ジメチルアミノ基、ジエチルアミノ基、アセチル基、ヘ
ンジイル基、Ｐ−メトキシカルボニルフェニル基、フタ
ルイシド−１−イルＬ ３−フェニルピリダジン−６−
イル基、３−アニリノピリダジン−６−イル基、４−フ
ェニル−１−オキソイソキノリン−２−イル基、テトラ
ゾール−５−イル基、２−オキソベンズイミダゾール−
１−イル基、２−オキソベンズチアゾール−１−イル基
。Dimethylamino group, diethylamino group, acetyl group, hendiyl group, P-methoxycarbonylphenyl group, phthalicid-1-yl L 3-phenylpyridazine-6-
yl group, 3-anilinopyridazin-6-yl group, 4-phenyl-1-oxoisoquinolin-2-yl group, tetrazol-5-yl group, 2-oxobenzimidazole-
1-yl group, 2-oxobenzthiazol-1-yl group.
２−ｎ−オクチルチオベンズイミダゾール−１−イル基
、１−メチルヒダントイン−１−イル基又は３−オキソ
フタラジン−２−イル基を示し、ｎは０から１２の整数
を示す。〕で表わされる。 、一般式〔Ｉ〕において、
Ｒの低級アルキル基としては、メチル基、エチル基等が
例示できるｏｎは好ましくは２から６の整数があげられ
る。It represents a 2-n-octylthiobenzimidazol-1-yl group, a 1-methylhydantoin-1-yl group, or a 3-oxophthalazin-2-yl group, and n represents an integer from 0 to 12. ]. , in general formula [I],
Examples of the lower alkyl group for R include a methyl group and an ethyl group, and on is preferably an integer from 2 to 6.
本発明の化合物ＣＩ’ｌは、下記反応式で示す方法によ
り容易に製造できる。Compound CI'l of the present invention can be easily produced by the method shown in the reaction formula below.
すなわち、目的の化合物（１）は、アニソールと対応す
るジカルボン酸無水物とのフリーデル・クラフト反応１
次いで臭化水素酸によるエーテル結合の開裂、更にヒド
ラジンとの藺環反応によって得られる化合物（ＩＩ）と
ハロゲン化アルキルキル誘導体（ＩＩ［）とを反応させ
て得ることができる（Ａ法）、。That is, the target compound (1) can be obtained by Friedel-Crafts reaction 1 between anisole and the corresponding dicarboxylic acid anhydride.
It can then be obtained by reacting the compound (II) obtained by cleavage of the ether bond with hydrobromic acid and further ring reaction with hydrazine with the alkyl halide derivative (II[) (method A).
また、一般式（１）において八が窒素原子を含む前記例
示のような複素環残基である化合物（１〕は、へ法によ
って得られる化合物ＣＩ：Ａ＝Ｘ〕と、それぞれ対応す
る複素環化合物ＨＡとの反応によっても製造できる（Ｂ
法）。Compound (1) in which 8 in general formula (1) is a heterocyclic residue as exemplified above containing a nitrogen atom is a compound CI:A=X] obtained by the hexamethod, and the corresponding heterocyclic ring It can also be produced by reaction with compound HA (B
law).
これらの脱ハロゲン化水素反応は、塩基性化合物を脱ハ
ロゲン化剤として用いて行なわれる。例えば、水酸化ナ
トリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリ
ウム、炭酸水素ナトリウム。These dehydrohalogenation reactions are carried out using a basic compound as a dehalogenation agent. For example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate.
炭酸水素カリウムなどの無機塩基、トリエチルアミン、
ピリジン、ジメチルアニリンなどの有機塩基があげられ
る。反応に用いられる溶媒としては。Inorganic bases such as potassium bicarbonate, triethylamine,
Examples include organic bases such as pyridine and dimethylaniline. As a solvent used in the reaction.
例えばメタノール、エタノール、プロパツール。For example, methanol, ethanol, propatool.
ブタノール等のアルコール類、テトラヒドロフラン、ジ
オキサン、エチレングリコールジメチルニーｆル等のエ
ーテル類、アセトン、メチルエチルケトン等のケトン類
、ベンゼン、トルエン、キンレン等の芳香族炭化水素類
、Ｎ、Ｎ−ジメチルホルムアミド、ジメチルスルフオキ
シド等の非プロトン性溶媒などがあげられる。反応温度
は、通常室温〜２００℃、好ましくは５０〜１５０℃で
行なわれ１反応時間は１〜３０時間であるが、好ましく
は１−１５時間である。化合物ｃＩＩ！とハロゲン化ア
ルキル誘導体〔■〕、及び化合物〔■：Δ＝Ｘ）と複素
環化合物ＨＡの使用割合は、特に限定されず広い範囲内
で選択されるが１通常は前者に対して後者を等モル−５
倍モル使用され、好適には等モル−２倍モル使用するの
が有利である。Alcohols such as butanol, ethers such as tetrahydrofuran, dioxane, and ethylene glycol dimethyl nitrogen, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, and quinolene, N,N-dimethylformamide, and dimethyl Examples include aprotic solvents such as sulfoxide. The reaction temperature is usually room temperature to 200°C, preferably 50 to 150°C, and one reaction time is 1 to 30 hours, preferably 1 to 15 hours. Compound cII! The proportions of the halogenated alkyl derivative [■], the compound [■:Δ=X), and the heterocyclic compound HA are not particularly limited and are selected within a wide range; however, the latter is usually equal to the former. Mol-5
It is advantageous to use double moles, preferably equimolar to twice moles.
本発明化合物（Ｔ）を医薬として使用する場合。When using the compound (T) of the present invention as a medicine.
経口的にも非経口的にも投与することができる。It can be administered either orally or parenterally.
化合物ＣＩ〕の投与量は患者の年齢１体重、或いは疾患
の程度などにより異なるが１通常１日当りの投与量は５
〜２０００ｍｇ、好ましくは１０〜５００ｍｇである。The dosage of Compound CI] varies depending on the patient's age, body weight, degree of disease, etc., but the usual dosage per day is 5.
-2000 mg, preferably 10-500 mg.
更に本発明の化合物〔■〕は、通常の経口又は非経口投
与に適した賦形剤との混合物の形で用いることもできる
。このような賦形剤としては１例えば乳糖、シヨ糖、カ
オリン、結晶セルロース。Furthermore, the compound [■] of the present invention can also be used in the form of a mixture with excipients suitable for conventional oral or parenteral administration. Such excipients include, for example, lactose, sucrose, kaolin, and crystalline cellulose.
コーンスターチ、ステアリン酸マグネシウム、グルコー
ス、タルク、塩化ナトリウム、レシチン。Cornstarch, magnesium stearate, glucose, talc, sodium chloride, lecithin.
ゼラチン、ペクチン、植物油などをあげることができる
。また１種々の剤型をとることができ１錠剤、散剤、頚
粒剤、カプセル剤、丸刑などの固形剤とすることができ
、安定剤、湿潤化剤、乳化剤等の補助剤を含むものであ
ってもよい。Examples include gelatin, pectin, and vegetable oil. In addition, it can take a variety of dosage forms, such as solid dosage forms such as tablets, powders, granules, capsules, and pills, and may contain auxiliary agents such as stabilizers, wetting agents, and emulsifiers. It may be.
次に本発明を実施例をあげて説明する。Next, the present invention will be explained by giving examples.
〔実施例１〕
４．５−ジヒドロ−６−Ｃ４−（３−クロルプロポキシ
）フェニル）−３（２Ｈ）−ピリダジノン
４．５−ジヒドロ−６−（４−ヒドロキシフェニル）−
３（２Ｈ）−ピリダジノン（Ｗ、Ｖ、Ｃｕｒｒａｎ。[Example 1] 4.5-dihydro-6-C4-(3-chloropropoxy)phenyl)-3(2H)-pyridazinone 4.5-dihydro-6-(4-hydroxyphenyl)-
3(2H)-pyridazinone (W, V, Curran.
＾、Ｒｏｓｓ、 Ｊ、 Ｍｅｄ、 Ｃｈｅｍｏ、 １
７ Ｄ）、 ２７３ （１９７４））１９ｇと１−ブロ
ム−３−クロルプロパン１９ｇ及び水酸化カリウム１２
ｇ をインプロパツール５６０ｍ１と水７０ｍ１の混
液に加え４時間還流した。減圧下に溶媒を留去して残渣
をクロロホルムに溶解し、ＩＮ水酸化す） ＩＪウム溶
液、ＩＮ塩酸。^, Ross, J., Med, Chemo, 1
7 D), 273 (1974)), 19 g of 1-bromo-3-chloropropane, and 12 g of potassium hydroxide.
g was added to a mixed solution of 560 ml of Improper Tool and 70 ml of water, and the mixture was refluxed for 4 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform and IN hydroxide) IJum solution, IN hydrochloric acid.
水で順次洗浄後、無水硫酸ナトリウムで乾燥、溶媒留去
し、残渣をエタノール−エーテルから再結晶して融点１
２０℃の黄色針状晶１５．５ｇ（収率５８．１％）を得
た。After successively washing with water, drying over anhydrous sodium sulfate, evaporating the solvent, and recrystallizing the residue from ethanol-ether to give a melting point of 1.
15.5 g (yield 58.1%) of yellow needle crystals at 20° C. were obtained.
元素分析 Ｃｌ ３ ＨＯ４Ｎ ａ Ｏ２Ｃｌとして
理論値（％） ： Ｃ，５８，５４； Ｈ，５，６３
； ’Ｉ、 １０．５１゜実測値（％） ： Ｃ，５
８，３６： Ｈ，５，５４： Ｎ、 １０．６３゜ＩＲ
νｍａｎ ｃｍ 、 １６８０ （ｃｍｏ）Ｎ
ＭＲ（ＤＭＳＯｄ＋、）δ：２．１８（２Ｈ。Elemental analysis Cl3HO4Na Theoretical value (%) as O2Cl: C, 58,54; H, 5,63
'I, 10.51゜Actual value (%): C, 5
8,36: H, 5,54: N, 10.63°IR
νman cm, 1680 (cmo)N
MR (DMSOd+,) δ: 2.18 (2H.
ｇ、Ｊ＝６Ｈｚ 、−ＣＨ，ＣＨ２ＣＨ，−）、２゜４
２ （２Ｈ，ｔ、 Ｊ＝７Ｈｚ 、 Ｃ−Ｈ） 、 ２
．９０ （２Ｈ，ｔ、 Ｊ＝７Ｈ，、Ｃ，−Ｈ） 、
３．７８（２Ｈ，ｔ、Ｊ＝６Ｈｚ、−ＣＨ２Ｃ１）、４
．１２（２Ｈ，ｔ、Ｊ＝６８．、−０ＣＨ２−）、６．
９５（２日、 ａ、 Ｊ＝８８．、Ａ、 −Ｈ） 、
７．６５ （２Ｈ，ｄ、Ｊ＝８ｚ、Ａｒ Ｈ）、１０．
７４ （ＩＨ。g, J=6Hz, -CH,CH2CH,-), 2゜4
2 (2H, t, J=7Hz, C-H), 2
．． 90 (2H, t, J=7H,,C,-H),
3.78 (2H, t, J=6Hz, -CH2C1), 4
．． 12 (2H, t, J=68., -0CH2-), 6.
95 (2 days, a, J=88., A, -H),
7.65 (2H, d, J=8z, Ar H), 10.
74 (IH.
Ｓ、 ＮＨ＞ 、 Ｍａｓｓ （ｍ／Ｚ） ： ２６
６ （Ｍ＋） 。S, NH>, Mass (m/Z): 26
6 (M+).
〔実施例２〕
４．５−ジヒドロ−６−（４−シアノメトキシフェニル
）−３（２Ｈ）−ピリダジノン４．５−ジヒドロ−６（
４−ヒドロキシフェニル）−３（２Ｈ）−ピリダジノン
３．８ ｇ 、クロルアセトニトリル１．５ ｇ 、炭
酸カリウム３ｇをジメチルホルムアミド５９ｍ１に加え
、１００℃、４時間加熱攪拌した。以後実施例１と同様
にして融点１７４〜１７６℃の淡黄色針状晶１．２ｇ（
収率２６．２％）を得た。[Example 2] 4.5-dihydro-6-(4-cyanomethoxyphenyl)-3(2H)-pyridazinone 4.5-dihydro-6(
3.8 g of 4-hydroxyphenyl)-3(2H)-pyridazinone, 1.5 g of chloroacetonitrile, and 3 g of potassium carbonate were added to 59 ml of dimethylformamide, and the mixture was heated and stirred at 100° C. for 4 hours. Thereafter, in the same manner as in Example 1, 1.2 g of pale yellow needle crystals with a melting point of 174 to 176°C (
A yield of 26.2%) was obtained.
元素分析 ＣＩ ２８ ＋ 、Ｎ ｓ Ｏ２理論値（
％） ’： Ｃ，６２，８８、Ｈ，４，８０、Ｎ、
１８．３４実測値（％） ： Ｃ，６２，６９； Ｈ
，４，９５、Ｎ、 １８．６６＋’ ｕ Ｊ ＃ Ｌ
１ １１Ｒνｖ、ａｘ Ｃ１−−１６６５（
Ｃ・０）Ｎ Ｍ Ｒ（Ｄ Ｍ Ｓ Ｏ−ｄ ｓ ）δ：
２．４４（２Ｈ。Elemental analysis CI 28 +, N s O2 theoretical value (
%) ': C, 62, 88, H, 4, 80, N,
18.34 Actual value (%): C, 62, 69; H
,4,95,N, 18.66+' u J # L
1 11Rνv, ax C1--1665(
C・0)NMR(DMSO-ds)δ:
2.44 (2H.
ｔ、Ｊ＝８Ｈｚ 、Ｃ，−Ｈ）、２．９４ （２Ｈ，ｔ
。t, J=8Hz, C, -H), 2.94 (2H, t
.
Ｊ＝８Ｈ２、Ｃｓ −Ｈ） 、 ５．１７ （２Ｈ，Ｓ
、−ＣＨ２） 、 ７．０８ （２Ｈ，ｄ、 Ｊ＝８Ｈ
ｚ、Ａｒ−Ｈ）、７．７４ （２Ｈ，ｄ、Ｊ＝８Ｈｚ、
Ａｒ−Ｈ）、１０．８３ （ＬＨ，Ｓ、ＮＨ）。J=8H2, Cs-H), 5.17 (2H,S
, -CH2) , 7.08 (2H,d, J=8H
z, Ar-H), 7.74 (2H, d, J=8Hz,
Ar-H), 10.83 (LH, S, NH).
実施例２に従い、実施例３〜１９の化合物を合成した。According to Example 2, the compounds of Examples 3 to 19 were synthesized.
得られた化合物及びその分析データを一括して第１表に
記載する。なお、第１表中の実施例２０，２１．２２．
２３．２４のノヒ合物は、実施例１５，１６．１７．１
８．１９の化合物を。The obtained compounds and their analytical data are listed in Table 1. In addition, Examples 20, 21, 22. in Table 1.
Nohi compound of 23.24 is Example 15, 16.17.1
8.19 compounds.
それぞれガブリエル法に従ってヒドラジンヒトラード処
理して得た。Each was obtained by treatment with hydrazine hydride according to the Gabriel method.
第１表 Ａ−（ＣＨ２）、つ（）吾）す〔実施例２
５〕
４．５−ジヒドロ−６−Ｃ４−（３−（２−オキ゛ソベ
ンズオキサゾールー１−イル）プロポキシ）フェニル）
−３（２Ｈ）−ピリダジノン４．５−ジヒドロ−６−Ｃ
４−（３−（３−クロルブロホキシ）フェニルＥ−３（
２Ｈ）−ピリダジノン２．７ｇ、２−ベンズオキサシリ
ノン１．５ｇ、炭酸カリウム１．７ｇをＤＭＦ５０ｍｌ
ｌ：加え。Table 1 A-(CH2), Tsu()go) [Example 2
5] 4.5-dihydro-6-C4-(3-(2-oxobenzobenzoxazol-1-yl)propoxy)phenyl)
-3(2H)-pyridazinone 4,5-dihydro-6-C
4-(3-(3-chlorobrofoxy)phenyl E-3(
2.7 g of 2H)-pyridazinone, 1.5 g of 2-benzoxacylinone, and 1.7 g of potassium carbonate in 50 ml of DMF.
l: Add.
３時間加熱攪拌した。冷後、不溶物を炉去、溶媒を留去
し、残渣をクロロホルムに溶解、ＩＮ水酸化ナトリウム
溶液、ＩＮ塩酸、水で順次洗浄した後、無水硫酸す）
ＩＪウムで乾燥した。溶媒を留去し残渣をエタノールよ
り再結晶して融点１７８〜１８０℃の無色針状晶１．８
ｇ（収率５０％）を得た。The mixture was heated and stirred for 3 hours. After cooling, insoluble matter was removed from the oven, the solvent was distilled off, the residue was dissolved in chloroform, and washed with IN sodium hydroxide solution, IN hydrochloric acid, and water in sequence, and then dissolved in anhydrous sulfuric acid.
It was dried with IJum. The solvent was distilled off and the residue was recrystallized from ethanol to give colorless needle crystals with a melting point of 178-180°C.
g (yield 50%) was obtained.
元素分析 Ｃ２０Ｈ１ｓ Ｎ ｓ Ｏ−として理論値
（％） ： Ｃ，６５，７５； ｉｔ、 ５．２１ ：
Ｎ、１１．５１゜実測値（％） ： Ｃ，６５，９１
； Ｈ，５，１６； Ｎ、１１．３４゜ｒ Ｒシ二謬
＠Ｌ Ｃｍ−’ ： １７８０ （Ｃｍ０）、
１６８０ （Ｃｍ０）ＮＭＲ（ＤＭＳＯ−’ｄｓ ）
δ：２．２０（２Ｈ。Elemental analysis Theoretical value (%) as C20H1sNsO-: C, 65,75; it, 5.21:
N, 11.51° Actual value (%): C, 65,91
; H, 5, 16; N, 11.34゜r R error @L Cm-': 1780 (Cm0),
1680 (Cm0) NMR (DMSO-'ds)
δ: 2.20 (2H.
ｑ、Ｊ＝６Ｈ２，−ＣＨ２ＣＨ２ＣＨ２−）、２゜４４
（２Ｈ，ｔ、Ｊ＝７Ｈｚ、Ｃ＜ Ｈ） 、２．８
８（２Ｈ，ｔ、Ｊ＝７Ｈｚ、Ｃ５Ｈ）、４．００ （２
Ｈ，ｔ、Ｊ＝６Ｈｚ、−ＣＨ，Ｏ−）、４．０４ （２
Ｈ，ｔ、 Ｊ＝６Ｈ２，ＣＨ２Ｎ ） 、６．８０
（２Ｈ，ｄ、Ｊ＝８８．、 Ａｒ−Ｈ）、７．０〜７
．３（４Ｈ，ｍ、Ａ、−Ｈ）、７．５６ （２Ｈ，ｄ、
Ｊ＝８Ｈｚ、Ａｒ−Ｈ）、１０．７２ （ＩＨ，Ｓ、Ｎ
Ｈ）
Ｍａｓｓ （ｍ／ｚ）；３６５ （Ｍ゛ ）実施例２５
に従い、実施例２６〜３８の化合物を合成した。得られ
た化合物及びその分析データを一括して第２表に記載す
る。q, J=6H2, -CH2CH2CH2-), 2゜44
(2H, t, J=7Hz, C<H), 2.8
8 (2H, t, J=7Hz, C5H), 4.00 (2
H, t, J=6Hz, -CH,O-), 4.04 (2
H, t, J=6H2,CH2N), 6.80
(2H, d, J=88., Ar-H), 7.0-7
．． 3 (4H, m, A, -H), 7.56 (2H, d,
J=8Hz, Ar-H), 10.72 (IH, S, N
H) Mass (m/z); 365 (M゛) Example 25
Compounds of Examples 26 to 38 were synthesized according to the following. The obtained compounds and their analytical data are listed in Table 2.
〔製剤例１〕
有効物質 ５０ｍｇ結晶セルロー
ス ４０ｍｇコーンスターチ
４０ｍｇ乳糖 １
５０ｍｇステアリン酸マグネシウム ２．５ ｍ
ｇ上記混合物を通常の方法により打錠し、１錠中主薬
５０ｍｇを含有する錠剤を作製する。[Formulation Example 1] Active substance 50mg crystalline cellulose 40mg cornstarch
40mg lactose 1
50mg magnesium stearate 2.5 m
g The above mixture is compressed into tablets by a conventional method to prepare tablets containing 50 mg of the active ingredient per tablet.
〔製剤例２〕
有効物ｊｌｉｊ ５０ｍｇ乳＠
１００ｍｇバレーショデン
プン ５０ｍｇタルク
２０ｍｇステアリン酸マグネシウム ５ｍ
ｇ上記混合物を常法に従って造粒し、顆粒剤とする。[Formulation Example 2] Active substance jlij 50mg milk @
100mg Vallecho starch 50mg Talc
20mg magnesium stearate 5m
g The above mixture is granulated according to a conventional method to obtain granules.
〔製剤例３〕
有効物質 ５ｍｇメタンスルホ
ン酸 ２ｍｇ塩化ナトリウム
３ｍｇ注射用蒸留水 １ｍ
ｌｍｌ上記音常法に従って混合して１ｍｌアンプルを調
整する。[Formulation Example 3] Active substance 5mg methanesulfonic acid 2mg sodium chloride
3mg distilled water for injection 1m
Prepare a 1 ml ampoule by mixing according to the standard method above.
薬理実験
〔Ｉ〕血小板凝集抑制作用
本発明化合物の血小板凝集抑制作用をポーンの方法ＣＧ
、Ｖ、Ｒ，Ｂｏｒｎ、Ｎａｔｕｒｅ、９２７−９２９頁
（１９６２年）〕により測定した。Pharmacological experiment [I] Platelet aggregation inhibitory effect Method CG to demonstrate the platelet aggregation inhibitory effect of the compound of the present invention
, V.R., Born, Nature, pp. 927-929 (1962)].
すなわち、クエン酸加ウサギ血液を採取し、遠心分離操
作により血小板濃度の高い血漿（ＰＰＰ）および血小板
濃度の低い血漿（ＰＰＰ）を得た。That is, citrated rabbit blood was collected and centrifuged to obtain plasma with a high platelet concentration (PPP) and plasma with a low platelet concentration (PPP).
ついで、ジメチルスルフオキシドに溶解した被検化合物
１．５μｌをＰＲＰ２７０μｍに加え３７℃で１分間イ
ンキュベーションした後、コラ−ケン又はΔＤＰを加え
凝集を若起した。血小板凝集はＮＫＫヘマトレーサーで
測定し、被検化合物の５０％抑制濃度（ＩＣ，。μＭ〉
は濃度抑制率曲線から求めた。なお、対照薬としてアス
ピリンを用いた。代表例の結果を第３表に示す。Next, 1.5 .mu.l of the test compound dissolved in dimethyl sulfoxide was added to 270 .mu.m of PRP and incubated at 37.degree. C. for 1 minute, followed by addition of Kolaken or .DELTA.DP to induce aggregation. Platelet aggregation was measured with NKK hematotracer, and the 50% inhibitory concentration (IC, μM) of the test compound was measured.
was determined from the concentration inhibition rate curve. Note that aspirin was used as a control drug. Table 3 shows the results of representative examples.
第３表
〔２〕急性毒性実験
被検薬を０．５％カルボキシメチルセルロース溶液に懸
濁し１体重２０〜２５ｇのＤＤＹ系雄性マウス（１群ｌ
Ｏ匹）に経口投与して、投与後７日間の累積死亡率から
５０％致死量（ＬＤ、。）を算出した。代表例の結果を
第４表に示す。対照薬として用いたアスピリンの結果に
ついても併記する。Table 3 [2] Acute toxicity test drug was suspended in 0.5% carboxymethyl cellulose solution and DDY male mice weighing 20-25 g (1 group)
The 50% lethal dose (LD, ) was calculated from the cumulative mortality rate for 7 days after administration. Table 4 shows the results of representative examples. The results of aspirin, which was used as a control drug, are also listed.
第４表
〔発明の効果〕
本発明化合物［１）はマウスを用いた毒性実験において
極めて毒性が低く、またその薬理作用は。Table 4 [Effects of the Invention] The compound [1] of the present invention has extremely low toxicity in toxicity experiments using mice, and its pharmacological effects are as follows.
ｉｎ ＶｉｔｒＯにおいて優れた血小板凝集抑制作用
を示し、抗血栓薬として１例えば脳血栓症。Shows excellent platelet aggregation inhibitory effect in VitrO, and is used as an antithrombotic agent, for example, for cerebral thrombosis.
脳塞栓症、末梢勤・静脈閉塞症等の予防及び治療に優れ
た効果を特徴するCharacterized by excellent effects on the prevention and treatment of cerebral embolism, peripheral occlusion and venous occlusion, etc.
Claims (6)
チルアミノ基、ジエチルアミノ基、アセチル基、ベンゾ
イル基、ｐ−メトキシカルボニルフェニル基、フタルイ
ミド−１−イル基、３−フェニルピリダジン−６−イル
基、３−アニリノピリダジン−６−イル基、４−フェニ
ル−１−オキソイソキノリン−２−イル基、テトラゾー
ル−５−イル基、２−オキソベンズイミダゾール−１−
イル基、２−オキソベンズオキサゾール−１−イル基２
−オキソベンズチアゾール−１−イル基、２−ｎ−オク
チルチオベンズイミダゾール−１−イル基、１−メチル
ヒダントイン−１−イル基又は３−オキソフタラジン−
２−イル基を示し、ｎは０から１２の整数を示す。〕で
表わされる４，５−ジヒドロ−６−（４−置換フェニル
）−３（２Ｈ）−ピリダジノン誘導体。(1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R represents a hydrogen atom or a lower alkyl group. A is a hydroxyl group, a halogen atom, a cyano group, an amino group, a dimethylamino group, a diethylamino group, an acetyl group, a benzoyl group, a p-methoxycarbonylphenyl group, a phthalimid-1-yl group, a 3-phenylpyridazin-6-yl group, 3-anilinopyridazin-6-yl group, 4-phenyl-1-oxoisoquinolin-2-yl group, tetrazol-5-yl group, 2-oxobenzimidazole-1-
yl group, 2-oxobenzoxazol-1-yl group 2
-Oxobenzthiazol-1-yl group, 2-n-octylthiobenzimidazol-1-yl group, 1-methylhydantoin-1-yl group or 3-oxophthalazine-
It represents a 2-yl group, and n represents an integer from 0 to 12. ] A 4,5-dihydro-6-(4-substituted phenyl)-3(2H)-pyridazinone derivative.
ｎが２から６の整数で表わされる特許請求の範囲第１項
記載の化合物。(2) In the general formula [I], R is a hydrogen atom,
The compound according to claim 1, wherein n is an integer from 2 to 6.
ミノ基であり、ｎが３から６の整数で表わされる特許請
求の範囲第１項記載の化合物。(3) The compound according to claim 1, wherein in the general formula [I], R is a hydrogen atom, A is an amino group, and n is an integer from 3 to 6.
ミノ基であり、ｎが４の整数で表わされる特許請求の範
囲第３項記載の化合物。(4) The compound according to claim 3, wherein in the general formula [I], R is a hydrogen atom, A is an amino group, and n is an integer of 4.
−オキソベンズオキサゾール−１−イル基を示し、ｎが
２又は３の整数で表わされる特許請求の範囲第１項記載
の化合物。(5) In the general formula [I], R is a hydrogen atom, and A is 2
-oxobenzoxazol-1-yl group, and n is an integer of 2 or 3.
の範囲第４項記載の化合物。(6) The compound according to claim 4, which is in the form of a pharmacologically acceptable salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29457586A JPS63145272A (en) | 1986-12-09 | 1986-12-09 | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29457586A JPS63145272A (en) | 1986-12-09 | 1986-12-09 | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63145272A true JPS63145272A (en) | 1988-06-17 |
Family
ID=17809554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29457586A Pending JPS63145272A (en) | 1986-12-09 | 1986-12-09 | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63145272A (en) |
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|---|---|---|---|---|
| US5698554A (en) * | 1995-06-27 | 1997-12-16 | Tanabe Seiyaku Co., Ltd. | Pyridazinone derivatives and processes for preparing the same |
| WO2001019818A1 (en) * | 1999-09-14 | 2001-03-22 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Phthalazinone derivatives as pd3/4 inhibitors |
| US6410536B1 (en) | 1998-03-31 | 2002-06-25 | Warner-Lambert Company | Quinoxalinones as serine protease inhibitors such as factor XA and thrombin |
| US7652009B2 (en) | 2004-11-30 | 2010-01-26 | Amgem Inc. | Substituted heterocycles and methods of use |
| US7858623B2 (en) | 2005-04-27 | 2010-12-28 | Amgen Inc. | Substituted amide derivatives and methods of use |
| US8207168B2 (en) | 2006-07-25 | 2012-06-26 | Cephalon, Inc. | Pyridazinone derivatives |
| US20160200711A1 (en) * | 2014-04-25 | 2016-07-14 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine d1 ligands |
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-
1986
- 1986-12-09 JP JP29457586A patent/JPS63145272A/en active Pending
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5698554A (en) * | 1995-06-27 | 1997-12-16 | Tanabe Seiyaku Co., Ltd. | Pyridazinone derivatives and processes for preparing the same |
| US5808065A (en) * | 1995-06-27 | 1998-09-15 | Tanabe Seiyaku Co., Ltd. | Pyridazinone derivatives and processes for preparing the same |
| US6410536B1 (en) | 1998-03-31 | 2002-06-25 | Warner-Lambert Company | Quinoxalinones as serine protease inhibitors such as factor XA and thrombin |
| US6916805B2 (en) | 1998-03-31 | 2005-07-12 | Warner-Lambert Company Llc | Quinoxalinones as serine protease inhibitors |
| WO2001019818A1 (en) * | 1999-09-14 | 2001-03-22 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Phthalazinone derivatives as pd3/4 inhibitors |
| US7652009B2 (en) | 2004-11-30 | 2010-01-26 | Amgem Inc. | Substituted heterocycles and methods of use |
| US8685983B2 (en) | 2005-04-27 | 2014-04-01 | Amgen Inc. | Method of treating cancer with substituted amide derivatives |
| US8088794B2 (en) | 2005-04-27 | 2012-01-03 | Amgen Inc. | Substituted amide derivatives and methods of use |
| US7858623B2 (en) | 2005-04-27 | 2010-12-28 | Amgen Inc. | Substituted amide derivatives and methods of use |
| US8207168B2 (en) | 2006-07-25 | 2012-06-26 | Cephalon, Inc. | Pyridazinone derivatives |
| US8247414B2 (en) | 2006-07-25 | 2012-08-21 | Cephalon, Inc. | Pyridizinone derivatives and the use thereof as H3 inhibitors |
| US8586588B2 (en) | 2006-07-25 | 2013-11-19 | Cephalon, Inc. | Aryl pyridazinone derivatives and their use as H3 receptor ligands |
| US8673916B2 (en) | 2006-07-25 | 2014-03-18 | Cephalon, Inc. | Methods of treating disorders mediated by histamine H3 receptors using pyridazinone derivatives |
| US20160200711A1 (en) * | 2014-04-25 | 2016-07-14 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine d1 ligands |
| US9850232B2 (en) * | 2014-04-25 | 2017-12-26 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| KR20180118717A (en) * | 2016-03-04 | 2018-10-31 | 오츠카 세이야쿠 가부시키가이샤 | 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3- |
| JP2019506432A (en) * | 2016-03-04 | 2019-03-07 | 大塚製薬株式会社 | 5-Methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one derivative |
| US10611731B2 (en) | 2016-03-04 | 2020-04-07 | Otsuka Pharmaceutical Co., Ltd. | 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one derivative |
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