JP2008088107A - New pyridazine derivative - Google Patents
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Abstract
Description
本発明は、キサンチンオキシダーゼ阻害活性を有する新規なピリダジン誘導体、又はその医薬上許容される塩、若しくはそれらの水和物であり、これらを有効成分とする高尿酸血症及び痛風、又は活性酸素の発生に関与するとされる疾患の治療薬に関する。 The present invention is a novel pyridazine derivative having xanthine oxidase inhibitory activity, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and hyperuricemia and gout containing these as active ingredients, or active oxygen The present invention relates to a therapeutic agent for diseases that are considered to be involved in development.
痛風の要因である尿酸は、細胞内の核酸および体内のエネルギー源であるＡＴＰ(アデノシン三リン酸)の分解により生じるプリン体が代謝されて生じる。尿酸は通常尿中に***されるが、体内の尿酸が増えると血液中に蓄積され、高尿酸血症となる。 Uric acid, which is a cause of gout, is produced by the metabolism of purines produced by the degradation of intracellular nucleic acids and ATP (adenosine triphosphate), which is an internal energy source. Uric acid is usually excreted in the urine, but when uric acid in the body increases, it accumulates in the blood, resulting in hyperuricemia.
一般に高尿酸血症の状態が長く続く場合、尿酸塩となって結晶が血中及び尿中で析出し、血中で析出した場合には関節に沈着して、痛風関節炎及び痛風結節等を発症させ、尿中で析出した場合には尿路結石等の腎障害などを引き起こす。更に、高尿酸血症では、肥満、高脂血症、耐糖能異常、高血圧症などの生活習慣病が高率に合併し、こうした合併症が虚血性心疾患や脳血管障害などの発症率を高くしている事が知られている。 In general, when hyperuricemia persists for a long time, it becomes urate and crystals precipitate in the blood and urine. If it precipitates in the blood, it deposits on the joint, causing gouty arthritis and gout nodules. If it is deposited in urine, it may cause kidney damage such as urinary calculi. Moreover, in hyperuricemia, lifestyle-related diseases such as obesity, hyperlipidemia, impaired glucose tolerance, and hypertension are associated with a high rate, and these complications increase the incidence of ischemic heart disease and cerebrovascular disorders. It is known that it is high.
痛風治療では、一般的に痛風発作の前兆期にはコルヒチンが使用され、痛風発作時にはステロイド系、あるいはインドメタシン、ナプロキセン等の非ステロイド性の抗炎症剤が使用される。発作沈静化後は高尿酸血症を是正するため生活習慣改善指導が行われるが、痛風関節炎を繰り返す症例や痛風結節を認める症例など、症状に改善が認められない場合、尿酸***低下型の疾患に対しては尿酸***促進剤、尿酸産生亢進型の疾患に対しては尿酸合成阻害剤による薬物療法が適用される。
尿酸***促進剤としてはプロベネシド及びベンズブロマロンが使用されているが、プロベネシドには消化管障害や他の薬剤との相互作用がみられ，ベンズブロマロンには重篤な肝障害が報告されており（例えば、非特許文献１参照。）、尿酸***低下型であっても尿酸合成阻害剤を選択する場合も多い。また、尿酸***促進剤は尿酸結石の形成を促進する危険性があるので、尿酸結石を有する患者または尿酸結石の罹患歴を有する患者に対しても尿酸合成阻害剤が処方される。
In the treatment of gout, colchicine is generally used in the precursor phase of gout attacks, and steroids or nonsteroidal anti-inflammatory agents such as indomethacin and naproxen are used in gout attacks. After the seizure subsides, lifestyle improvement guidance is given to correct hyperuricemia, but if symptoms do not improve, such as cases with repeated gout arthritis or cases with gout nodules, a uric acid excretion-type disease For this, uric acid excretion promoters are used, and for uric acid production-promoting diseases, drug therapy with uric acid synthesis inhibitors is applied.
Probenecid and benzbromarone are used as uric acid excretion promoters, but probenecid has gastrointestinal disorders and interactions with other drugs, and benzbromarone has been reported to cause severe liver damage. In many cases, a uric acid synthesis inhibitor is selected even if it is a uric acid excretion-reducing type. Moreover, since a uric acid excretion promoter has a risk of promoting the formation of uric acid stones, uric acid synthesis inhibitors are prescribed for patients with uric acid stones or patients with a history of uric acid stones.
尿酸合成阻害剤としてはヒポキサンチンの誘導体であるアロプリノールが唯一の治療薬として使用されており、キサンチンオキシダーゼを阻害することによりヒポキサンチン及びキサンチンからの尿酸産生を抑制し、血清尿酸値を低下させることが知られている。 Allopurinol, a hypoxanthine derivative, is used as the only therapeutic agent as a uric acid synthesis inhibitor. By inhibiting xanthine oxidase, it suppresses uric acid production from hypoxanthine and xanthine and lowers serum uric acid levels. It has been known.
他方、キサンチンオキシダーゼは、活性酸素の産生にも関わる事が報告されており（例えば、非特許文献２参照。）、キサンチンオキシダーゼ阻害剤は活性酸素が関与するとされている炎症性疾患(例えば、非特許文献３参照。）、うっ血性心不全（例えば、非特許文献４参照。）、虚血‐再灌流障害（例えば、非特許文献５、６参照。）、癌（例えば、特許文献１、非特許文献７、８参照。）、神経疾患（例えば、非特許文献９、１０参照。）等に対しても有用であると考えられている。 On the other hand, xanthine oxidase has been reported to be involved in the production of active oxygen (see, for example, Non-Patent Document 2), and xanthine oxidase inhibitor is an inflammatory disease in which active oxygen is considered to be involved (for example, non-patent document 2). Patent Document 3), congestive heart failure (for example, see Non-Patent Document 4), ischemia-reperfusion injury (for example, see Non-Patent Documents 5 and 6), cancer (for example, Patent Document 1 and Non-patent) It is considered useful for neurological diseases (see, for example, Non-Patent Documents 9 and 10) and the like.
しかしながら、アロプリノールでは副作用として腎および肝機能障害、アロプリノールの代謝産物であるオキシプリノールに起因するとされる発疹等の過敏症等が報告されており、これら副作用の少ない、優れたキサンチンオキシダーゼ阻害効果を持つ、高尿酸血症および痛風ならびに活性酸素が関与する各種疾患の治療薬および／または予防薬が望まれている。 However, allopurinol has been reported as a side effect such as renal and liver dysfunction, hypersensitivity such as rash caused by oxypurinol, a metabolite of allopurinol, and has excellent xanthine oxidase inhibitory effects with few of these side effects. A therapeutic and / or prophylactic agent for various diseases involving hyperuricemia and gout and active oxygen is desired.
キサンチンオキシダーゼ阻害作用を有する化合物の研究は、これまでキサンチン誘導体を中心に広く行われてきたが（例えば、非特許文献１１、１２参照。）、現在のところ、臨床的に薬効と安全性の面から満足すべき薬物はなく、唯一アロプリノールのみが臨床適用されている。 Research on compounds having an inhibitory action on xanthine oxidase has been extensively conducted mainly on xanthine derivatives so far (see, for example, Non-Patent Documents 11 and 12), but at present, clinically effective and safe aspects. There is no satisfactory drug, and only allopurinol is clinically applied.
近年、アロプリノールの副作用を軽減し、より強い血清尿酸低下作用を持つ、キサンチンオキシダーゼ阻害作用を有する新規構造の研究が進められている。例えば、特許文献２，３，４には１，２，４‐トリアゾール誘導体が開示されている。また、最近、１‐フェニルピラゾール誘導体（例えば、特許文献５参照。）、２‐アリールチアゾール誘導体（例えば、特許文献６参照。）、新規１，２，４−トリアゾール系化合物（例えば、特許文献７参照。）が開発されているが、いずれも現在、臨床的に使用されていない。 In recent years, research on a novel structure having an action of inhibiting xanthine oxidase, which has a side effect of allopurinol and has a stronger serum uric acid lowering action, has been promoted. For example, Patent Documents 2, 3, and 4 disclose 1,2,4-triazole derivatives. Recently, 1-phenylpyrazole derivatives (for example, see Patent Document 5), 2-arylthiazole derivatives (for example, see Patent Document 6), novel 1,2,4-triazole compounds (for example, Patent Document 7). Have been developed, but none are currently in clinical use.
そこで、本発明の目的は、新規構造を持ち、かつキサンチンオキシダーゼ阻害作用による強力で持続的な血清尿酸低下作用をもつ化合物を提供することである。 Therefore, an object of the present invention is to provide a compound having a novel structure and having a strong and continuous serum uric acid lowering action by inhibiting xanthine oxidase.
本発明者らは、キサンチンオキシダーゼ阻害による強い血清尿酸低下作用を有する新規構造化合物の探求をすべく鋭意研究を行った結果、これまでにない強力で持続的な血清尿酸低下作用をもつ、新規ピリダジン誘導体を見出し、本発明の完成に至った。 As a result of intensive research aimed at searching for a novel structural compound having a strong serum uric acid lowering action by inhibiting xanthine oxidase, the present inventors have found that a novel pyridazine having an unprecedented powerful and sustained serum uric acid lowering action. A derivative was found and the present invention was completed.
即ち、本発明は下記一般式（I）で示されるキサンチンオキシダーゼ阻害作用を有する新規なピリダジン誘導体、又はその医薬上許容される塩、若しくはそれらの水和物を含んでなる医薬組成物に関する。 That is, the present invention relates to a novel pyridazine derivative having a xanthine oxidase inhibitory activity represented by the following general formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a hydrate thereof.
から選ばれる基であり、
A group selected from
R１、R2およびR3のうち少なくとも１つの基で置換されたフェニル基若しくはピリジル基を示す。R１は、シアノ基、ニトロ基、ハロゲン原子若しくはトリフルオロメチル基を示す。R2およびR3は、独立して選ばれる各種置換基であり、ハロゲン原子、ニトロ基、シアノ基、ヒドロキシ基、低級アルキル基、低級環状アルキル基、ハロアルキル基、アルコキシアルキル基、低級アルキルカルボニル基、アリール基、アルキルカルボニル基、アリールカルボニル基、低級アルコキシカルボニル基、カルボキシル基、無置換あるいは置換された低級アルコキシ基、ハロアルコキシ基、低級環状アルコキシ基、無置換あるいは置換された低級アルキルスルファニル基、アミノ基、低級アルキル置換（モノ若しくはジ置換）アミノ基、低級アルキル置換（モノ若しくはジ置換）アミド基、低級アルキル基置換若しくは非置換ピペラジル基、モルホリル基を表す。 A phenyl group or a pyridyl group substituted with at least one group of R 1 , R 2 and R 3 is shown. R 1 represents a cyano group, a nitro group, a halogen atom or a trifluoromethyl group. R 2 and R 3 are each independently selected various substituents, such as halogen atom, nitro group, cyano group, hydroxy group, lower alkyl group, lower cyclic alkyl group, haloalkyl group, alkoxyalkyl group, lower alkylcarbonyl group Aryl group, alkylcarbonyl group, arylcarbonyl group, lower alkoxycarbonyl group, carboxyl group, unsubstituted or substituted lower alkoxy group, haloalkoxy group, lower cyclic alkoxy group, unsubstituted or substituted lower alkylsulfanyl group, An amino group, a lower alkyl substituted (mono or disubstituted) amino group, a lower alkyl substituted (mono or disubstituted) amide group, a lower alkyl group substituted or unsubstituted piperazyl group, and a morpholyl group are represented.
即ち、上記式中、Ｘは、
R１、R2およびR3のうち少なくとも１つの基で置換されたフェニル基を示す。R１は、シアノ基、ニトロ基、ハロゲン原子若しくはトリフルオロメチル基を示す。R2およびR3は、独立して選ばれる各種置換基であり、ハロゲン原子、ニトロ基、シアノ基、ヒドロキシ基、低級アルキル基、低級環状アルキル基、ハロアルキル基、アルコキシアルキル基、低級アルキルカルボニル基、アリール基、アルキルカルボニル基、アリールカルボニル基、低級アルコキシカルボニル基、カルボキシル基、無置換あるいは置換された低級アルコキシ基、ハロアルコキシ基、低級環状アルコキシ基、無置換あるいは置換された低級アルキルスルファニル基、アミノ基、低級アルキル置換（モノ若しくはジ置換）アミノ基、低級アルキル置換（モノ若しくはジ置換）アミド基、低級アルキル基置換若しくは非置換ピペラジル基、モルホリル基を表す。
That is, in the above formula, X is
A phenyl group substituted with at least one group of R 1 , R 2 and R 3 is shown. R 1 represents a cyano group, a nitro group, a halogen atom or a trifluoromethyl group. R 2 and R 3 are each independently selected various substituents, such as halogen atom, nitro group, cyano group, hydroxy group, lower alkyl group, lower cyclic alkyl group, haloalkyl group, alkoxyalkyl group, lower alkylcarbonyl group Aryl group, alkylcarbonyl group, arylcarbonyl group, lower alkoxycarbonyl group, carboxyl group, unsubstituted or substituted lower alkoxy group, haloalkoxy group, lower cyclic alkoxy group, unsubstituted or substituted lower alkylsulfanyl group, An amino group, a lower alkyl substituted (mono or disubstituted) amino group, a lower alkyl substituted (mono or disubstituted) amide group, a lower alkyl group substituted or unsubstituted piperazyl group, and a morpholyl group are represented.
又、上記式中、Ｘは、
R１、R2およびR3のうち少なくとも１つの基で置換されたピリジル基を示す。R１は、シアノ基、ニトロ基、ハロゲン原子若しくはトリフルオロメチル基を示す。R2およびR3は、独立して選ばれる各種置換基であり、ハロゲン原子、ニトロ基、シアノ基、ヒドロキシ基、低級アルキル基、低級環状アルキル基、ハロアルキル基、アルコキシアルキル基、低級アルキルカルボニル基、アリール基、アルキルカルボニル基、アリールカルボニル基、低級アルコキシカルボニル基、カルボキシル基、無置換あるいは置換された低級アルコキシ基、ハロアルコキシ基、低級環状アルコキシ基、無置換あるいは置換された低級アルキルスルファニル基、アミノ基、低級アルキル置換（モノ若しくはジ置換）アミノ基、低級アルキル置換（モノ若しくはジ置換）アミド基、低級アルキル基置換若しくは非置換ピペラジル基、モルホリル基を表す。
In the above formula, X is
A pyridyl group substituted with at least one group of R 1 , R 2 and R 3 is shown. R 1 represents a cyano group, a nitro group, a halogen atom or a trifluoromethyl group. R 2 and R 3 are each independently selected various substituents, such as halogen atom, nitro group, cyano group, hydroxy group, lower alkyl group, lower cyclic alkyl group, haloalkyl group, alkoxyalkyl group, lower alkylcarbonyl group Aryl group, alkylcarbonyl group, arylcarbonyl group, lower alkoxycarbonyl group, carboxyl group, unsubstituted or substituted lower alkoxy group, haloalkoxy group, lower cyclic alkoxy group, unsubstituted or substituted lower alkylsulfanyl group, An amino group, a lower alkyl substituted (mono or disubstituted) amino group, a lower alkyl substituted (mono or disubstituted) amide group, a lower alkyl group substituted or unsubstituted piperazyl group, and a morpholyl group are represented.
本発明の新規ピリダジン誘導体、又はその医薬上許容される塩、若しくはそれらの水和物は、優れたキサンチンオキシダーゼ阻害による強力で持続的な血清尿酸低下作用を有することにより、高尿酸血症、痛風、炎症性疾患、うっ血性心不全、虚血‐再灌流障害、癌、神経疾患等の予防薬および／または治療薬として有用である。 The novel pyridazine derivative of the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate thereof has a strong and sustained serum uric acid lowering action by excellent xanthine oxidase inhibition, thereby causing hyperuricemia, gout. It is useful as a prophylactic and / or therapeutic agent for inflammatory diseases, congestive heart failure, ischemia-reperfusion injury, cancer, neurological diseases and the like.
以下、本発明を具体的に説明する。 Hereinafter, the present invention will be specifically described.
一般式（II）および（III）の各種置換基において、ハロゲン原子としては、フッ素、塩素、臭素若しくはヨウ素が挙げられる。低級アルキル基としては、炭素数１〜６の直鎖または分岐鎖のメチル基、エチル基、ｎ‐プロピル基、イソプロピル基、ｎ‐ブチル基、イソブチル基、s‐ブチル基、t‐ブチル基、ｎ−ペンチル基、ｎ‐ヘキシル基等が挙げられる。低級環状アルキル基としては例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。ハロアルキル基としては例えばモノクロロメチル基、トリフルオロメチル基等が挙げられる。アルコキシアルキル基としては、メトキシメチル基、エトキシメチル基、２，２，２−トリフルオロエトキシメチル基等が挙げられる。低級アルキルカルボニル基としては例えばアセチル基等が挙げられる。アリール基としては例えばフェニル基等が挙げられる。アリールカルボニル基としては例えばベンゾイル基等が挙げられる。低級アルコキシカルボニル基としては例えばメトキシカルボニル基、エトキシカルボニル基等が挙げられる。無置換あるいは置換された低級アルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、イソブトキシ基、ｔ−ブトキシ基、メトキシメトキシ基、２−メトキシエトキシ基、３−メトキシプロポキシ基、エトキシエトキシ基、２−メトキシエトキシメトキシ基、２−メトキシエトキシエトキシ基、（３−メトキシ−３，３−ジメチル）プロポキシ基、２−シクロプロポキシエトキシ基、２−シクロプロポキシエトキシエトキシ基、２−（２−メトキシエチルスルファニル）エトキシ基、２−（２−メチルスルファニルエトキシ）エトキシ基等が挙げられる。ハロアルコキシ基としては、トリクロロメトキシ基、トリフルオロメトキシ基、２，２，２−トリフルオロエトキシ基等が挙げられる。低級環状アルコキシ基としては例えばシクロプロポキシ基、シクロブチロキシ基、シクロペンチロキシ基、シクロヘキシロキシ基等が挙げられる。無置換あるいは置換された低級アルキルスルファニル基としては、メチルスルファニル基、エチルスルファニル基、プロピルスルファニル基、メトキシエトキシスルファニル基等が挙げられる。低級アルキル置換（モノ若しくはジ置換）アミノ基としては、メチルアミノ基、エチルアミノ基、ジメチルアミノ基、ジエチルアミノ基等が挙げられる。低級アルキル置換アミド基としては、N-エチルアセトアミド基等が挙げられる。また、好ましい置換基としては、R1はシアノ基、トリフルオロメチル基を挙げることができ、R2およびR3は、ハロアルキル基、ハロアルコキシ基を挙げることができる。 In the various substituents of the general formulas (II) and (III), the halogen atom includes fluorine, chlorine, bromine or iodine. As the lower alkyl group, a straight chain or branched chain methyl group having 1 to 6 carbon atoms, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, An n-pentyl group, an n-hexyl group, etc. are mentioned. Examples of the lower cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the haloalkyl group include a monochloromethyl group and a trifluoromethyl group. Examples of the alkoxyalkyl group include a methoxymethyl group, an ethoxymethyl group, and a 2,2,2-trifluoroethoxymethyl group. Examples of the lower alkylcarbonyl group include an acetyl group. Examples of the aryl group include a phenyl group. Examples of the arylcarbonyl group include a benzoyl group. Examples of the lower alkoxycarbonyl group include a methoxycarbonyl group and an ethoxycarbonyl group. Examples of the unsubstituted or substituted lower alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, t-butoxy group, methoxymethoxy group, 2-methoxyethoxy group, 3- Methoxypropoxy group, ethoxyethoxy group, 2-methoxyethoxymethoxy group, 2-methoxyethoxyethoxy group, (3-methoxy-3,3-dimethyl) propoxy group, 2-cyclopropoxyethoxy group, 2-cyclopropoxyethoxyethoxy group , 2- (2-methoxyethylsulfanyl) ethoxy group, 2- (2-methylsulfanylethoxy) ethoxy group, and the like. Examples of the haloalkoxy group include a trichloromethoxy group, a trifluoromethoxy group, and a 2,2,2-trifluoroethoxy group. Examples of the lower cyclic alkoxy group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like. Examples of the unsubstituted or substituted lower alkylsulfanyl group include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, and a methoxyethoxysulfanyl group. Examples of the lower alkyl-substituted (mono- or di-substituted) amino group include a methylamino group, an ethylamino group, a dimethylamino group, and a diethylamino group. Examples of the lower alkyl-substituted amide group include an N-ethylacetamide group. Preferred examples of the substituent, R 1 is can be a cyano group, a trifluoromethyl group, R 2 and R 3 can be exemplified haloalkyl groups, haloalkoxy groups.
さらに好ましくは、R1はシアノ基、R2およびR3はトリフルオロメチル基、トリフルオロメトキシ基を挙げることができる。また、（II）の場合、R1及びR2もしくはR3のふたつの置換が好ましい。これらの置換基の置換位置としてはXが（II）である場合にはトリアゾール環の置換位置からパラ位およびメタ位が、またXが（III）の場合には2位が好ましい。 More preferably, R 1 may be a cyano group, and R 2 and R 3 may be a trifluoromethyl group or a trifluoromethoxy group. In the case of (II), two substitutions of R 1 and R 2 or R 3 are preferred. The substitution positions of these substituents are preferably the para-position and the meta-position from the substitution position of the triazole ring when X is (II), and the 2-position when X is (III).
本発明の化合物は、１，２，４−トリアゾール核を有し、以下のような互変異性形として存在しうる。本発明化合物の１，２，４−トリアゾール核は、これら全ての互変異性を包含する。 The compounds of the present invention have a 1,2,4-triazole nucleus and can exist in the following tautomeric forms. The 1,2,4-triazole nucleus of the compound of the present invention includes all these tautomers.
本発明の新規ピリダジン誘導体、又はその医薬上許容される塩、若しくはそれらの水和物は、次の反応式に従って製造できる。
かかる溶媒としてはN，N−ジメチルホルムアミド、N，N−ジメチルアセトアミド、Ｎ−メチルピロリドン、テトラヒドロフラン、１，２−ジメトキシエタン、メタノール、エタノール等が挙げられ、好ましくはメタノールおよびエタノールが挙げられる。また、塩基としてはナトリウムメトキシド、ナトリウムエトキシドなどが挙げられる。反応温度は室温〜溶媒の還流温度が好ましい。反応時間は温度との兼ね合いにもよるが通常３０分〜数時間行えばよい。また、（IVａ）又は（IVｂ）を、例えば塩基としてナトリウムメトキシドをあらかじめ作用させ、中間体であるイミド酸エステルを単離した後、ピリダジンカルボン酸ヒドラジド（V）と反応させても良い。 Examples of such a solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol and the like, preferably methanol and ethanol. Examples of the base include sodium methoxide and sodium ethoxide. The reaction temperature is preferably room temperature to the reflux temperature of the solvent. The reaction time is usually 30 minutes to several hours although it depends on the temperature. Alternatively, (IVa) or (IVb) may be reacted with pyridazinecarboxylic acid hydrazide (V) after preliminarily reacting, for example, sodium methoxide as a base to isolate an imidic acid ester as an intermediate.
目的化合物（VIIａ、VIIｂ）の製造は、下式によっても製造可能である。
尚、上記化６、化７の製造方法において、R1、R2、R3の置換基は、あらかじめ導入しておく必要はなく、トリアゾール環の形成後に、保護されたものを脱保護することや、通常の化学変換によりR1、R2、R3とすることができる。 In the production methods of Chemical Formulas 6 and 7, it is not necessary to introduce the substituents R 1 , R 2 , and R 3 in advance, and the protected one should be deprotected after the formation of the triazole ring. Alternatively, R 1 , R 2 , and R 3 can be obtained by ordinary chemical conversion.
一般式（I）の化合物は、塩として用いる場合、塩の種類は医学上許容される塩であれば特に限定されないが、例えば、塩酸、硫酸、硝酸、臭化水素酸、酢酸、シュウ酸、フマール酸、マレイン酸、クエン酸、コハク酸、酒石酸、安息香酸、メタンスルホン酸、トシル酸、乳酸、酪酸、アミノ酸、炭酸水素ナトリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、メグルミン、トロメタミンと処理をすることにより、塩とすることができる。 When the compound of the general formula (I) is used as a salt, the type of salt is not particularly limited as long as it is a medically acceptable salt. For example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, acetic acid, oxalic acid, Fumaric acid, maleic acid, citric acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, tosylic acid, lactic acid, butyric acid, amino acid, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, meglumine, tromethamine By processing, it can be converted into a salt.
一般式（I）の化合物の医薬上許容しうる水和物としては、１／２水和物、１水和物、２水和物などが例として挙げられる。また、一般式（I）の化合物は溶媒和物として存在することもあるので、溶媒和物も包含される。 Examples of the pharmaceutically acceptable hydrate of the compound of the general formula (I) include 1/2 hydrate, monohydrate, dihydrate and the like. Moreover, since the compound of general formula (I) may exist as a solvate, a solvate is also included.
一般式（I）で示される化合物、又はその医薬上許容される塩、若しくはそれらの水和物を含んでなる医薬組成物は、そのまま用いても良いが、製剤用添加物の1種又は2種以上を用いた製剤として使用しても良い。該医薬組成物は、如何なる剤形で用いても良く、錠剤、丸剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、懸濁剤、シロップ剤、注射剤、外用剤、坐剤等として適用することが出来る。 A pharmaceutical composition comprising a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be used as it is. You may use as a formulation using more than a seed. The pharmaceutical composition may be used in any dosage form, such as tablets, pills, capsules, powders, fine granules, granules, solutions, suspensions, syrups, injections, external preparations, suppositories, etc. It can be applied as
一般式（I）で示される化合物、又はその医薬上許容される塩、若しくはそれらの水和物を含んでなる医薬組成物を前記医薬製剤として用いる場合、製剤用添加物の種類は特に限定されないが、基剤、賦形剤、滑沢剤、コーティング剤、糖衣剤、湿潤剤、結合剤、崩壊剤、溶剤、可溶化剤、溶解剤、溶解補助剤、懸濁化剤、分散剤、乳化剤、界面活性剤、等張化剤、緩衝剤、ｐH調節剤、無痛化剤、防腐剤、保存剤、安定化剤、抗酸化剤、着色剤、甘味剤等単独で又は適宜組み合わせて用いることが出来る。 When a pharmaceutical composition comprising a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate thereof is used as the pharmaceutical preparation, the type of additive for preparation is not particularly limited. But base, excipient, lubricant, coating agent, sugar coating, wetting agent, binder, disintegrant, solvent, solubilizer, solubilizer, solubilizer, suspending agent, dispersant, emulsifier , Surfactants, tonicity agents, buffers, pH regulators, soothing agents, preservatives, preservatives, stabilizers, antioxidants, colorants, sweeteners, etc., alone or in appropriate combination. I can do it.
基剤としては、例えばカオリン、カカオ脂、トウモロコシデンプン、乾燥水酸化アルミニウムゲル、結晶セルロース、メチルセルロース、ヒドロキシプロピルセルロース、マクロゴール等が挙げられる。賦形剤としては、例えば乳糖、白糖、デンプン、Ｄ−マンニトール、トウモロコシデンプン、結晶セルロース、セルロース誘導体（ヒドロキシプロピルセルロース、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース等）、軽質無水ケイ酸、リン酸水素カルシウム等が挙げられる。滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、酸化チタン等が挙げられる。コーティング剤としては、例えばカルメロースカルシウム、酸化チタン、ステアリン酸アルミニウム、タルク等が挙げられる。糖衣剤としては、例えば白糖、乳糖、ゼラチン、パラフィン、結晶セルロース等が挙げられる。湿潤剤としては、例えばグリセリン、尿素、マクロゴール等が挙げられる。結合剤としては、例えば結晶セルロース、白糖、アラビアゴム末、アルギン酸ナトリウム、カルボキシメチルエチルセルロース、デンプン、ショ糖、精製ゼラチン、デキストリン、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、カルボキシメチルエチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、プルラン、ポリビニルアルコール、ポリビニルピロリドン等が挙げられる。崩壊剤としては、例えば白糖、乳糖、デンプン、カンテン末、クロスポピドン、カルボキシメチルセルロース、カルボキシメチルスターチナトリウム、カルメロース、ヒドロキシプロピルメチルセルロース、無水クエン酸、ラウリル硫酸ナトリウム、リン酸二水素カルシウム等が挙げられる。溶剤としては、例えば精製水、注射用水、エタノール、グリセリン、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、塩酸、酢酸等が挙げられる。可溶化剤としては、グリセリン、ステアリン酸ポリオキシル、ポリソルベート、マクロゴール等が挙げられる。溶解剤としては、前記記載の溶剤として使用されるものの他に、水酸化ナトリウム、炭酸ナトリウム、メグルミン等が挙げられる。溶解補助剤としては、例えば塩酸、酢酸、クエン酸、クエン酸ナトリウム、アスパラギン酸、水酸化ナトリウム、エタノール、プロピレングリコール、Ｄ−マンニトール、安息香酸ナトリウム、安息香酸ベンジル、尿素、トリエタノールアミン、ポリソルベート、ポリビニルピロリドン、マクロゴール等が挙げられる。懸濁化剤としては、例えばアラビアゴム、塩化ベンザルコニウム、カオリン、カルメロース、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、モノステアリン酸グリセリン、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等が挙げられる。分散剤としては、例えばクエン酸ナトリウム、軽質酸化アルミニウム、酸化チタン、ステアリン酸亜鉛、ポリソルベート、マクロゴール、デキストリン、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルセルロース等が挙げられる。乳化剤としては、例えば塩化ベンザルコニウム、グリセリン、プロピレングリコール、セタノール、レシチン、ラノリン、ラウリル硫酸ナトリウム等が挙げられる。界面活性剤としては、例えばスクワラン、セタノール、ポリオキシエチレンセチルエーテル、ラウロマクロゴール等が挙げられる。等張化剤としては、例えばブドウ糖、D−ソルビトール、塩化ナトリウム、グリセリン、Ｄ−マンニトール等が挙げられる。緩衝剤としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液等が挙げられる。pH調節剤としては、例えば塩酸、リン酸等の無機酸およびその塩、酢酸、クエン酸、乳酸等の有機酸およびその塩等が挙げられる。無痛化剤としては、例えばクレアチニン、ベンジルアルコール等が挙げられる。防腐剤としては、例えばパラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。保存剤としては、例えば安息香酸、パラオキシ安息香酸エステル類、ソルビン酸等が挙げられる。安定化剤としては、例えばタウリン、アミノ酸、パラオキシ安息香酸エステル類、ベンジルアルコール、結晶セルロース、マクロゴール等が挙げられる。抗酸化剤としては、例えば亜硫酸塩、アスコルビン酸等が挙げられる。着色剤としては、食用色素、β−カロチン、リボフラビン等が挙げられる。甘味剤としては、アスパルテーム、白糖、D−ソルビトール、マルトース等が挙げられる。香料としては、ビターエッセンス、ビターベース等が挙げられる。 Examples of the base include kaolin, cacao butter, corn starch, dry aluminum hydroxide gel, crystalline cellulose, methylcellulose, hydroxypropylcellulose, macrogol and the like. Examples of excipients include lactose, sucrose, starch, D-mannitol, corn starch, crystalline cellulose, cellulose derivatives (hydroxypropylcellulose, carmellose calcium, low-substituted hydroxypropylcellulose, etc.), light anhydrous silicic acid, phosphoric acid Examples thereof include calcium hydrogen. Examples of the lubricant include magnesium stearate, calcium stearate, talc, titanium oxide and the like. Examples of the coating agent include carmellose calcium, titanium oxide, aluminum stearate, talc and the like. Examples of the sugar coating agent include sucrose, lactose, gelatin, paraffin, crystalline cellulose and the like. Examples of the wetting agent include glycerin, urea, macrogol and the like. Examples of the binder include crystalline cellulose, sucrose, gum arabic powder, sodium alginate, carboxymethyl ethyl cellulose, starch, sucrose, purified gelatin, dextrin, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl. Examples thereof include cellulose, hydroxypropylmethylcellulose, pullulan, polyvinyl alcohol, and polyvinylpyrrolidone. Examples of the disintegrant include sucrose, lactose, starch, agar powder, crospovidone, carboxymethylcellulose, carboxymethyl starch sodium, carmellose, hydroxypropylmethylcellulose, anhydrous citric acid, sodium lauryl sulfate, and calcium dihydrogen phosphate. Examples of the solvent include purified water, water for injection, ethanol, glycerin, propylene glycol, macrogol, sesame oil, corn oil, hydrochloric acid, acetic acid and the like. Examples of the solubilizer include glycerin, polyoxyl stearate, polysorbate, macrogol and the like. Examples of the solubilizer include sodium hydroxide, sodium carbonate, meglumine and the like in addition to those used as the above-mentioned solvents. Examples of the solubilizer include hydrochloric acid, acetic acid, citric acid, sodium citrate, aspartic acid, sodium hydroxide, ethanol, propylene glycol, D-mannitol, sodium benzoate, benzyl benzoate, urea, triethanolamine, polysorbate, Examples include polyvinyl pyrrolidone and macrogol. Examples of the suspending agent include gum arabic, benzalkonium chloride, kaolin, carmellose, sodium lauryl sulfate, laurylaminopropionic acid, glyceryl monostearate, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxy Examples include ethyl cellulose and hydroxypropyl cellulose. Examples of the dispersant include sodium citrate, light aluminum oxide, titanium oxide, zinc stearate, polysorbate, macrogol, dextrin, low-substituted hydroxypropylcellulose, hydroxypropylcellulose and the like. Examples of the emulsifier include benzalkonium chloride, glycerin, propylene glycol, cetanol, lecithin, lanolin, sodium lauryl sulfate, and the like. Examples of the surfactant include squalane, cetanol, polyoxyethylene cetyl ether, lauromacrogol and the like. Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Examples of the pH adjuster include inorganic acids such as hydrochloric acid and phosphoric acid and salts thereof, organic acids such as acetic acid, citric acid and lactic acid and salts thereof. Examples of soothing agents include creatinine and benzyl alcohol. Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the preservative include benzoic acid, paraoxybenzoic acid esters, sorbic acid and the like. Examples of the stabilizer include taurine, amino acids, paraoxybenzoates, benzyl alcohol, crystalline cellulose, macrogol and the like. Examples of the antioxidant include sulfite and ascorbic acid. Examples of the colorant include food dyes, β-carotene, riboflavin and the like. Examples of the sweetening agent include aspartame, sucrose, D-sorbitol, maltose and the like. Examples of the fragrances include bitter essence and bitter base.
本発明の新規ピリダジン誘導体は、薬理試験において優れたキサンチンオキシダーゼ阻害を有する為、高尿酸血症および高尿酸血症による痛風などの疾患に対し有用である。また、本発明の化合物は活性酸素が関与する、炎症性疾患、うっ血性心不全、虚血‐再灌流障害、癌、神経疾患等の疾患の治療及び／または予防のための医薬として有用である。具体的には、心筋梗塞、不整脈、血管攣縮、虚血再循環障害、セレン欠乏症、動脈硬化、肺炎、感染症、SIRS（全身性炎症反応症候群。敗血症を含む）、ARDS（急性呼吸窮迫症候群）、肺気腫、高酸素療法、インフルエンザ、脳浮腫、脳梗塞、脳出血、てんかん、脳血管攣縮、パーキンソン病、ALS（筋萎縮性側索硬化症）、自律神経障害(Reilly 現象)、遅発性神経障害、脊髄損傷、神経原性肺浮腫、急性胃粘膜障害、胃潰瘍、潰瘍性大腸炎、クローン病、ベーチェット病、肝炎、肝硬変、薬物性肝障害、肝移植病態、各種の黄疸病態、膵炎、慢性肉芽腫症、白血病、AIDS（後天性免疫不全症候群）、異常ヘモグロビン症（メトヘモグロビン、サラセミア、鎌状赤血球）、ヘモクロマトーシス、プリマキン過敏症、夜間発作性血色素尿症、薬物性貧血、アカタラセミア、アルファ１−酸性糖蛋白の傷害、高脂血症、DIC（播種性血管内凝固症候群）、血小板異常症、出血性ショック、糖尿病、副腎代謝障害、ストレス反応、糸球体腎炎、溶血性腎障害、薬物性腎障害、ファンコニー症候群、やけど、日光皮膚炎、アトピー性皮膚炎、皮膚潰瘍、未熟児網膜症、網膜変成、白内障、癌、放射線障害と放射線療法、関節リウマチ、自己免疫疾患、膠原病、薬物障害、制癌剤の副作用(白血球減少症、ブレオマイシン肺繊維症、アドリアマイシン心筋症、シスプラチン腎障害等)、光線療法(光増感剤) による障害、重金属障害、水俣病、シリコーシス、喘息、排気ガス性肺障害、アラキドン酸代謝病態、食中毒、壊血病、臓器移植等の手術／処置にともなう予後の悪化等が挙げられる。 Since the novel pyridazine derivatives of the present invention have excellent xanthine oxidase inhibition in pharmacological tests, they are useful for diseases such as hyperuricemia and gout due to hyperuricemia. In addition, the compounds of the present invention are useful as medicaments for the treatment and / or prevention of diseases involving active oxygen, such as inflammatory diseases, congestive heart failure, ischemia-reperfusion injury, cancer, and neurological diseases. Specifically, myocardial infarction, arrhythmia, vasospasm, ischemia recirculation disorder, selenium deficiency, arteriosclerosis, pneumonia, infection, SIRS (systemic inflammatory response syndrome, including sepsis), ARDS (acute respiratory distress syndrome) , Emphysema, hyperoxia, influenza, cerebral edema, cerebral infarction, cerebral hemorrhage, epilepsy, cerebral vasospasm, Parkinson's disease, ALS (amyotrophic lateral sclerosis), autonomic disorder (Reilly phenomenon), delayed neuropathy Spinal cord injury, neurogenic pulmonary edema, acute gastric mucosal disorder, gastric ulcer, ulcerative colitis, Crohn's disease, Behcet's disease, hepatitis, cirrhosis, drug-induced liver injury, liver transplantation condition, various jaundice conditions, pancreatitis, chronic granulation Tumor, leukemia, AIDS (acquired immune deficiency syndrome), abnormal hemoglobinosis (methemoglobin, thalassemia, sickle cell), hemochromatosis, primaquine hypersensitivity, nocturnal hemoglobinuria, drug anemia Acataracemia, alpha 1-acid glycoprotein injury, hyperlipidemia, DIC (disseminated intravascular coagulation syndrome), thrombosis, hemorrhagic shock, diabetes, adrenal metabolic disorders, stress reaction, glomerulonephritis, hemolytic kidney Disorder, drug-induced nephropathy, Fancony syndrome, burns, sun dermatitis, atopic dermatitis, skin ulcer, retinopathy of prematurity, retinal degeneration, cataract, cancer, radiation disorder and radiation therapy, rheumatoid arthritis, autoimmune disease, Collagen disease, drug disorders, side effects of anticancer drugs (leukopenia, bleomycin pulmonary fibrosis, adriamycin cardiomyopathy, cisplatin nephropathy, etc.), phototherapy (photosensitizer) damage, heavy metal disorders, Minamata disease, silicosis, asthma, Examples include exhaustive lung disorder, arachidonic acid metabolic pathology, food poisoning, scurvy, worsening prognosis associated with surgery / treatment such as organ transplantation.
本発明の化合物又は該化合物を含有する医薬組成物の投与量及び投与回数は症状、年齢、性別、剤形、併用薬剤の種類などによって適時選択できるが、通常０．１〜１０００ｍｇ／ｄａｙ／人、好ましくは１〜５００ｍｇ／ｄａｙ／人の範囲で、１日１回あるいは数回に分けて投与することができる。また、本発明の医薬組成物は、単独投与のみならず、同じ薬効を有する他の医薬及び／又は別の薬効を有する他の医薬と併用してもよい。 The dose and frequency of administration of the compound of the present invention or the pharmaceutical composition containing the compound can be appropriately selected according to symptoms, age, sex, dosage form, type of concomitant drug, etc., but usually 0.1 to 1000 mg / day / person The dose can be administered once or several times a day, preferably in the range of 1 to 500 mg / day / person. In addition, the pharmaceutical composition of the present invention may be used not only alone but also in combination with other drugs having the same drug effect and / or other drugs having another drug effect.
以下、実施例、試験例によって本発明を詳述するが、本発明はこれらの例により、何ら限定されるものではない。 EXAMPLES Hereinafter, although this invention is explained in full detail according to an Example and a test example, this invention is not limited at all by these examples.
実施例記載の略語は以下のとおりである。ＭｅＯＨ；メタノール、ＤＭＦ；N，N−ジメチルホルムアミド、ＣＨ２Ｃｌ２；塩化メチレン、ＣＨＣｌ３；クロロホルム、ＴＨＦ：テトラヒドロフラン、ＮａＣｌ；塩化ナトリウム、ＮａＯＭｅ；ナトリウムメトキシド、ＩＰＡ；イソプロピルアルコール、ＤＭＳＯ；ジメチルスルホキシド、ＤＭＳＯ−ｄ６；重ジメチルスルホキシド 、ＣＤＣｌ３；重クロロホルム，ＣＤ３ＯＤ：重メタノール。 Abbreviations described in the examples are as follows. MeOH; methanol, DMF; N, N- dimethylformamide, CH 2 Cl 2; methylene chloride, CHCl 3; chloroform, THF: tetrahydrofuran, NaCl; sodium chloride, NaOMe; sodium methoxide, IPA; isopropyl alcohol, DMSO; dimethyl sulfoxide , DMSO-d 6; deuterated dimethyl sulfoxide, CDCl 3; deuterochloroform, CD3 OD: deuterated methanol.
ＮＭＲは２７０ＭＨｚ核磁気共鳴スペクトルを示し、内部標準物質としてＴＭＳ（テトラメチルシラン）を用いた。ＭＳは質量分析を示し、イオン化法がＥＳＩ（エレクトロスプレーイオン化法）である測定機器を用いた。 NMR showed a 270 MHz nuclear magnetic resonance spectrum, and TMS (tetramethylsilane) was used as an internal standard substance. MS indicates mass spectrometry, and a measuring instrument whose ionization method is ESI (electrospray ionization method) was used.
実施例1 ４−{５−[３−シアノ−４−（２−メトキシ）エトキシフェニル]−１，２，４−トリアゾール−３−イル}ピリダジン Example 1 4- {5- [3-Cyano-4- (2-methoxy) ethoxyphenyl] -1,2,4-triazol-3-yl} pyridazine
（１）３−シアノ−４−（２−メトキシ）エトキシベンゾニトリル (1) 3-Cyano-4- (2-methoxy) ethoxybenzonitrile
４−ニトロベンゾニトリルとシアン化カリウムの混合物をDMSO中加熱攪拌下反応して得た２，４−ジシアノフェノレートカリウムのDMSO溶液に、２−ブロモエチルメチルエーテルを加え、室温にて反応後、通常の後処理およびカラム精製により目的とする化合物を得た。 2-Bromoethyl methyl ether was added to a DMSO solution of potassium 2,4-dicyanophenolate obtained by reacting a mixture of 4-nitrobenzonitrile and potassium cyanide in DMSO with heating and stirring. The target compound was obtained by post-treatment and column purification.
（２）４−{５−[３−シアノ−４−（２−メトキシ）エトキシフェニル]−１，２，４−トリアゾール−３−イル}ピリダジン (2) 4- {5- [3-Cyano-4- (2-methoxy) ethoxyphenyl] -1,2,4-triazol-3-yl} pyridazine
（１）で得た３−シアノ−４−（２−メトキシ）エトキシベンゾニトリル（５０６ｍｇ）のＭｅＯＨ溶液（１３ｍＬ）に、ナトリウムメトキシド（６８ｍｇ）を加え、室温下１８時間攪拌した。続いてピリダジン−４−カルボン酸ヒドラジド（３４５ｍｇ）を加え、加熱還流下１９時間攪拌した。反応終了後、溶媒を留去し、残渣に水を加え、クロロホルムで抽出した。水層にＮａＣｌを加え塩析後、ＴＨＦで抽出し、有機層を混合し無水硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をカラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝９／１）で精製し、目的物（２９０ｍｇ）を得た。 Sodium methoxide (68 mg) was added to a MeOH solution (13 mL) of 3-cyano-4- (2-methoxy) ethoxybenzonitrile (506 mg) obtained in (1) and stirred at room temperature for 18 hours. Subsequently, pyridazine-4-carboxylic acid hydrazide (345 mg) was added, and the mixture was stirred for 19 hours with heating under reflux. After completion of the reaction, the solvent was distilled off, water was added to the residue, and the mixture was extracted with chloroform. NaCl was added to the aqueous layer for salting out, followed by extraction with THF. The organic layer was mixed and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (CHCl 3 / MeOH = 9/1) to obtain the desired product (290 mg).
1H−NMR(DMSO‐d6)δppm:3.36 ( 3H, s ) , 3.75 ( 2H, t, J=4.45Hz ) , 4.39 ( 2H, t, J=4.5Hz ) , 7.51 ( 1H, d, J=8.9Hz ) , 8.20 ( 1H, dd, J=5.4 & 2.1Hz ) , 8.31−8.38 ( 2H, m ) , 9.39 ( 1H, d, J=5.4Hz ) , 9.81( 1H, dd, J=2.1 & 1.3Hz ) , 15.03 ( 1H, br s ).
MS m/z : 321 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 3.36 (3H, s), 3.75 (2H, t, J = 4.45 Hz), 4.39 (2H, t, J = 4.5 Hz), 7.51 (1H, d, J = 8.9Hz), 8.20 (1H, dd, J = 5.4 & 2.1Hz), 8.31-8.38 (2H, m), 9.39 (1H, d, J = 5.4Hz), 9.81 (1H, dd, J = 2.1 & 1.3Hz), 15.03 (1H, br s).
MS m / z: 321 [M−H] − .
以下、相当する臭化アルキルを用いて実施例1と同様に行い、実施例２〜実施例１１の化合物を得た。 Thereafter, the same procedure as in Example 1 was carried out using the corresponding alkyl bromide to obtain the compounds of Examples 2 to 11.
実施例２ ４−[５−（３−シアノ−４−イソプロポキシフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 2 4- [5- (3-Cyano-4-isopropoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:1.04 ( 6H, d, J=6.60Hz ) , 2.03−2.19 ( 1H, m ) , 4.02 ( 2H, d, J=6.4Hz ) , 7.48 ( 1H, d, J=8.9Hz ) , 8.19 ( 1H, dd, J=5.3 & 2.3Hz ) , 8.31−8.37 ( 2H, m ) , 9.39 ( 1H, dd, J=5.3 & 1.2Hz ) , 9.81( 1H, dd, J=2.3 & 1.2Hz ) , 15.01 ( 1H, br s ) . 1 H-NMR (DMSO-d 6 ) δppm: 1.04 (6H, d, J = 6.60 Hz), 2.03−2.19 (1H, m), 4.02 (2H, d, J = 6.4 Hz), 7.48 (1H, d , J = 8.9Hz), 8.19 (1H, dd, J = 5.3 & 2.3 Hz), 8.31-8.37 (2H, m), 9.39 (1H, dd, J = 5.3 & 1.2 Hz), 9.81 (1H, dd, J = 2.3 & 1.2Hz), 15.01 (1H, br s).
実施例３ ４−｛５−[３−シアノ−４−（２−メトキシ）エトキシエトキシフェニル]−１，２，４−トリアゾール−３−イル｝ピリダジン Example 3 4- {5- [3-Cyano-4- (2-methoxy) ethoxyethoxyphenyl] -1,2,4-triazol-3-yl} pyridazine
1H−NMR(DMSO‐d6)δppm:3.25 ( 3H, s ) , 3.48 ( 2H, t, J=4.7Hz ) , 3.65 ( 2H, t, J=4.7Hz ) , 3.83 ( 2H, t, J=4.5Hz ) , 4.38 ( 2H, t, J=4.5Hz ) , 7.51 ( 1H, d, J=9.1Hz ) , 8.19 ( 1H, dd, J=5.3 & 2.3Hz ) , 8.31−8.38 ( 2H, m ) , 9.39 ( 1H, dd, J=5.3 & 1.3Hz ) , 9.81( 1H, dd, J=2.3 & 1.3Hz ) , 15.02 ( 1H ,br s ) . 1 H-NMR (DMSO-d 6 ) δppm: 3.25 (3H, s), 3.48 (2H, t, J = 4.7 Hz), 3.65 (2H, t, J = 4.7 Hz), 3.83 (2H, t, J = 4.5Hz), 4.38 (2H, t, J = 4.5Hz), 7.51 (1H, d, J = 9.1Hz), 8.19 (1H, dd, J = 5.3 & 2.3Hz), 8.31-8.38 (2H, m ), 9.39 (1H, dd, J = 5.3 & 1.3 Hz), 9.81 (1H, dd, J = 2.3 & 1.3 Hz), 15.02 (1H, br s).
実施例４ ４−[５−（３−シアノ−４−プロポキシフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 4 4- [5- (3-Cyano-4-propoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:1.03 ( 3H, t, J=7.3Hz ) , 1.75−1.88 ( 2H, m ) , 4.20 ( 2H, t, J=6.4Hz ) , 7.49 ( 1H, d, J=8.7Hz ) , 8.19 ( 1H, dd, J=5.4 & 2.3Hz ) , 8.31−8.37 ( 2H, m ) , 9.39 ( 1H, d, J=5.4Hz ) , 9.81( 1H, dd, J=2.3 & 1.2Hz ) , 15.01 ( 1H, br s ).
MS m/z : 305 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 1.03 (3H, t, J = 7.3 Hz), 1.75-1.88 (2H, m), 4.20 (2H, t, J = 6.4 Hz), 7.49 (1H, d , J = 8.7Hz), 8.19 (1H, dd, J = 5.4 & 2.3 Hz), 8.31−8.37 (2H, m), 9.39 (1H, d, J = 5.4 Hz), 9.81 (1H, dd, J = 2.3 & 1.2Hz), 15.01 (1H, br s).
MS m / z: 305 [M−H] − .
実施例５ ４−{５−[３−シアノ−４−（３−メトキシ−３，３−ジメチル）プロポキシフェニル]−１，２，４−トリアゾール−３−イル}ピリダジン Example 5 4- {5- [3-Cyano-4- (3-methoxy-3,3-dimethyl) propoxyphenyl] -1,2,4-triazol-3-yl} pyridazine
1H−NMR(CDCl3)δppm:1.30 ( 6H, s ) , 2.14 ( 2H, t, 6.9Hz ) , 3.26 ( 3H, s ) , 4.31 ( 2H, t, J=6.9Hz ) , 7.19 ( 1H, d, J=8.9Hz ) , 8.27−8.37 ( 2H, m ) , 8.42 ( 1H, s ) , 9.38 ( 1H, d, J=5.3 Hz ) , 10.07 ( 1H, s ).
MS m/z : 363 [M−H]−.
1 H-NMR (CDCl 3 ) δppm: 1.30 (6H, s), 2.14 (2H, t, 6.9 Hz), 3.26 (3H, s), 4.31 (2H, t, J = 6.9 Hz), 7.19 (1H, d, J = 8.9Hz), 8.27-8.37 (2H, m), 8.42 (1H, s), 9.38 (1H, d, J = 5.3Hz), 10.07 (1H, s).
MS m / z: 363 [M−H] − .
実施例６ ４−{５−[３−シアノ−４−（２−メトキシ）エトキシメトキシフェニル]−１，２，４−トリアゾール−３−イル}ピリダジン Example 6 4- {5- [3-Cyano-4- (2-methoxy) ethoxymethoxyphenyl] -1,2,4-triazol-3-yl} pyridazine
1H−NMR(DMSO‐d6)δppm:3.21 ( 3H, s ) , 3.49 ( 2H, t, J=4.6Hz ) , 3.82 ( 2H, t, J=4.6Hz ) , 5.53 ( 2H, s ) , 7.56 ( 1H, d, J=8.9Hz ) , 8.20 ( 1H, dd, J=5.4 & 2.3Hz ) , 8.32−8.40 ( 2H, m ) , 9.39 ( 1H , d, J=5.4Hz ) , 9.81( 1H, dd, J=2.3 & 1.3Hz ) , 15.04 ( 1H, s ). 1 H-NMR (DMSO-d 6 ) δppm: 3.21 (3H, s), 3.49 (2H, t, J = 4.6 Hz), 3.82 (2H, t, J = 4.6 Hz), 5.53 (2H, s), 7.56 (1H, d, J = 8.9Hz), 8.20 (1H, dd, J = 5.4 & 2.3Hz), 8.32−8.40 (2H, m), 9.39 (1H, d, J = 5.4Hz), 9.81 (1H , dd, J = 2.3 & 1.3Hz), 15.04 (1H, s).
実施例７ ４−｛５−［３−シアノ−４−（３−メトキシ）プロポキシフェニル］−１，２，４−トリアゾール−３−イル｝ピリダジン Example 7 4- {5- [3-Cyano-4- (3-methoxy) propoxyphenyl] -1,2,4-triazol-3-yl} pyridazine
1H−NMR(DMSO‐d6)δppm:1.98−2.08 ( 2H, m ) , 3.31 ( 3H, s ) , 3.53 ( 2H, t, J=6.2z ) , 4.29 ( 2H, t, J=6.4Hz ), 7.50 ( 1H, d, J=8.9Hz ) , 8.19 ( 1H, d , J=5.4 & 2.3Hz ) , 8.31−8.37 ( 2H, m ) , 9.39 ( 1H, d, J=5.4Hz ) , 9.80( 1H, d, J=2.3Hz ) , 15.00 ( 1H, s ).
MS m/z : 335 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 1.98-2.08 (2H, m), 3.31 (3H, s), 3.53 (2H, t, J = 6.2z), 4.29 (2H, t, J = 6.4 Hz ), 7.50 (1H, d, J = 8.9Hz), 8.19 (1H, d, J = 5.4 & 2.3Hz), 8.31-8.37 (2H, m), 9.39 (1H, d, J = 5.4Hz), 9.80 (1H, d, J = 2.3Hz), 15.00 (1H, s).
MS m / z: 335 [M−H] − .
実施例８ ４−[５−(３−シアノ−４−シクロプロポキシエトキシフェニル)−１，２，４−トリアゾール−３−イル]ピリダジン Example 8 4- [5- (3-Cyano-4-cyclopropoxyethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:0.46−0.52 ( 4H, m ) , 3.40−3.47 ( 1H, m ) , 3.85 ( 2H, t, J=4.3Hz ) , 4.37 ( 2H, t, J=4.3Hz ) , 7.49 ( 1H, d, J=8.9Hz ) , 8.19 ( 1H, dd, J=5.4 & 2.1Hz ) , 8.31−8.37 ( 2H, m ) , 9.39 ( 1H, d, J=5.3Hz ) , 9.81( 1H, s ) , 15.02 ( 1H, s ).
MS m/z : 347 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 0.46−0.52 (4H, m), 3.40−3.47 (1H, m), 3.85 (2H, t, J = 4.3 Hz), 4.37 (2H, t, J = 4.3Hz), 7.49 (1H, d, J = 8.9Hz), 8.19 (1H, dd, J = 5.4 & 2.1Hz), 8.31-8.37 (2H, m), 9.39 (1H, d, J = 5.3Hz) , 9.81 (1H, s), 15.02 (1H, s).
MS m / z: 347 [M−H] − .
実施例９ ４−（５−｛４−シアノ−３−[２−（２−メトキシエトキシ）エトキシ]フェニル｝−１，２，４−トリアゾール−３−イル）ピリダジン Example 9 4- (5- {4-Cyano-3- [2- (2-methoxyethoxy) ethoxy] phenyl} -1,2,4-triazol-3-yl) pyridazine
1H−NMR(DMSO‐d6)δppm:3.25 ( 3H, s ) , 3.48 ( 2H, t, J=4.7Hz ) , 3.66 ( 2H, t, J=4.7Hz ) , 3.86 ( 2H, t, J=4.5Hz ) , 4.41 ( 2H, t, J=4.5Hz ) , 7.80 ( 1H, d, J=8.1Hz ) , 7.91−7.97 ( 2H, m ) , 8.22 ( 1H, dd, J=5.4 & 2.3Hz ), 9.41 ( 1H, d, J=5.4Hz ), 9.83( 1H, d, J=2.3Hz ). 1 H-NMR (DMSO-d 6 ) δppm: 3.25 (3H, s), 3.48 (2H, t, J = 4.7 Hz), 3.66 (2H, t, J = 4.7 Hz), 3.86 (2H, t, J = 4.5Hz), 4.41 (2H, t, J = 4.5Hz), 7.80 (1H, d, J = 8.1Hz), 7.91−7.97 (2H, m), 8.22 (1H, dd, J = 5.4 & 2.3Hz ), 9.41 (1H, d, J = 5.4Hz), 9.83 (1H, d, J = 2.3Hz).
実施例１０ ４−｛５−［４−シアノ−３−（３−メトキシ−３−メチル）ブトキシフェニル］−１，２，４−トリアゾール−３−イル｝ピリダジン Example 10 4- {5- [4-Cyano-3- (3-methoxy-3-methyl) butoxyphenyl] -1,2,4-triazol-3-yl} pyridazine
1H−NMR(DMSO‐d6)δppm:1.24 ( 6H, s ) , 2.04 ( 2H, t, J=6.8Hz ) , 3.16 ( 3H, s ) , 4.32 ( 2H, t, J=6.8Hz ) , 7.77−7.98 ( 3H, m ), 8.22 ( 1H, dd, J=5.3 & 2.15Hz ), 9.40 ( 1H, s ), 9.83 ( 1H, d, J=2.2Hz ). 1 H-NMR (DMSO-d 6 ) δppm: 1.24 (6H, s), 2.04 (2H, t, J = 6.8 Hz), 3.16 (3H, s), 4.32 (2H, t, J = 6.8 Hz), 7.77-7.98 (3H, m), 8.22 (1H, dd, J = 5.3 & 2.15Hz), 9.40 (1H, s), 9.83 (1H, d, J = 2.2Hz).
実施例１１ ４−（５−｛３−シアノ−４−[２−（２−シクロプロポキシエトキシ）エトキシ]フェニル｝−１，２，４−トリアゾール−３−イル）ピリダジン Example 11 4- (5- {3-Cyano-4- [2- (2-cyclopropoxyethoxy) ethoxy] phenyl} -1,2,4-triazol-3-yl) pyridazine
1H−NMR(DMSO‐d6)δppm:0.38−0.48 ( 4H , m ) , 3.55−3.66 ( 5H , m ) , 3.82 ( 2H , t , J=4.5Hz ) , 4.38 ( 2H , t , J=4.5Hz ) , 7.51 ( 1H , d , J=8.9Hz ) , 8.19 ( 1H , dd , J=5.4 & 2.3Hz ) , 8.31−8.38 ( 2H , m ) , 9.39 ( 1H , dd , J=5.4 & 1.2Hz ) , 9.81( 1H , dd , J=2.3 & 1.2Hz ) , 15.02 ( 1H , br s ).
MS m/z : 391 [M−1]−.
1 H-NMR (DMSO-d 6 ) δppm: 0.38-0.48 (4H, m), 3.55-3.66 (5H, m), 3.82 (2H, t, J = 4.5 Hz), 4.38 (2H, t, J = 4.5Hz), 7.51 (1H, d, J = 8.9Hz), 8.19 (1H, dd, J = 5.4 & 2.3Hz), 8.31-8.38 (2H, m), 9.39 (1H, dd, J = 5.4 & 1.2 Hz), 9.81 (1H, dd, J = 2.3 & 1.2Hz), 15.02 (1H, br s).
MS m / z: 391 [M−1] − .
実施例１２ ４−[５−（3−シアノ−４−エトキシメチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 12 4- [5- (3-Cyano-4-ethoxymethylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）4−アセトキシメチル−3−ブロモベンゾニトリル (1) 4-Acetoxymethyl-3-bromobenzonitrile
4−ヒドロキシメチルベンゾニトリル（５．５６ｇ）、ピリジン（６．７６ｍＬ）のＣＨＣｌ３溶液（５０ｍＬ）に、無水酢酸（４．７ｍＬ）及び4−ジメチルアミノピリジン（触媒量）を加え、５０℃下一晩攪拌した。反応終了後、水を加えＣＨＣｌ３で抽出した。有機層を１０％クエン酸水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去後、4−アセトキシメチルベンゾニトリル（６．９４ｇ）を得た。これをトリフルオロ酢酸（５０ｍＬ）に溶かし、ブロモイソシアヌル酸一ナトリウム１３．７ｇを加え７０℃で攪拌した。反応終了後、反応液を氷水に注ぎＣＨＣｌ３で抽出した。有機層を水、チオ硫酸ナトリウム水溶液、飽和食塩水で順じ洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル=４／１）で精製し、目的物（４．５２ｇ）を得た。 Acetic anhydride (4.7 mL) and 4-dimethylaminopyridine (catalytic amount) were added to a solution of 4-hydroxymethylbenzonitrile (5.56 g) and pyridine (6.76 mL) in CHCl 3 (50 mL) at 50 ° C. Stir overnight. After completion of the reaction, water was added and extracted with CHCl 3 . The organic layer was washed with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, 4-acetoxymethylbenzonitrile (6.94 g) was obtained. This was dissolved in trifluoroacetic acid (50 mL), 13.7 g of monosodium bromoisocyanurate was added, and the mixture was stirred at 70 ° C. After completion of the reaction, the reaction solution was poured into ice water and extracted with CHCl 3 . The organic layer was washed successively with water, aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain the desired product (4.52 g).
1H−NMR (CDCl3)δppm:
2.18 ( 3H, s ), 5.22 ( 2H, s ), 7.52 ( 1H, d, J=8.1Hz ), 7.63 ( 1H, d, J=8.1Hz ), 7.87 ( 1H, s).
1 H-NMR (CDCl 3 ) δppm:
2.18 (3H, s), 5.22 (2H, s), 7.52 (1H, d, J = 8.1Hz), 7.63 (1H, d, J = 8.1Hz), 7.87 (1H, s).
（２）３−ブロモ−4−メタンスルホニルオキシメチルベンゾニトリル (2) 3-Bromo-4-methanesulfonyloxymethylbenzonitrile
炭酸カリウム（２．７ｇ）のＴＨＦ／ＭｅＯＨ（５／１、２４ｍＬ）懸濁液に、０℃下（１）で得た4−アセトキシメチル−３−ブロモベンゾニトリル（４．５２ｇ）のＴＨＦ溶液（１０ｍＬ）を滴下し、室温下攪拌した。反応終了後、水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去し、3−ブロモ−4−ヒドロキシメチルベンゾニトリル（３．７３ｇ）を得た。これをＣＨ２Ｃｌ２（３０ｍＬ）に溶かし、トリエチルアミン（３．２ｍＬ）を加え、−５０℃で攪拌下、メタンスルホニルクロライド（２．７ｇ）のＣＨ２Ｃｌ２（５ｍＬ）溶液を滴下し、−３０℃下攪拌した。反応終了後、氷水に反応液を注ぎＣＨ２Ｃｌ２で抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムにて乾燥後、溶媒を留去し、目的物（５．１４ｇ）を得た。 To a suspension of potassium carbonate (2.7 g) in THF / MeOH (5/1, 24 mL), a solution of 4-acetoxymethyl-3-bromobenzonitrile (4.52 g) obtained at 0 ° C. (1) in THF. (10 mL) was added dropwise and stirred at room temperature. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 3-bromo-4-hydroxymethylbenzonitrile (3.73 g). This was dissolved in CH 2 Cl 2 (30 mL), triethylamine (3.2 mL) was added, and a solution of methanesulfonyl chloride (2.7 g) in CH 2 Cl 2 (5 mL) was added dropwise with stirring at −50 ° C. − The mixture was stirred at 30 ° C. After completion of the reaction, the reaction solution was poured into ice water and extracted with CH 2 Cl 2 . The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the desired product (5.14 g).
1H−NMR (CDCl3)δppm:
3.12 ( 3H, s ), 5.34 ( 2H, s ), 7.64 ( 1H, d, J=8.1Hz ), 7.69 ( 1H, dd, J=8.1 & 1.４Hz ), 7.90 ( 1H, d, J=1.４Hz ).
1 H-NMR (CDCl 3 ) δppm:
3.12 (3H, s), 5.34 (2H, s), 7.64 (1H, d, J = 8.1 Hz), 7.69 (1H, dd, J = 8.1 & 1.4 Hz), 7.90 (1H, d, J = 1 .4Hz).
（３）３−シアノ−４−エトキシメチルベンゾニトリル (3) 3-Cyano-4-ethoxymethylbenzonitrile
（２）で得た３−ブロモ−４−メタンスルホニルオキシメチルベンゾニトリル（１．５ｇ）とジイソプロピルエチルアミン（５．３ｍＬ）のＥｔＯＨ（２０ｍＬ）溶液を加熱還流下攪拌した。反応終了後、溶媒を留去し、水を加えＣＨＣｌ３で抽出、有機層を２０％クエン酸水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後した。溶媒を留去し、３−ブロモ−４−エトキシメチルベンゾニトリル（１．３２ｇ）を得た。これをN−メチルピロリドン（２０ｍＬ）に溶解し、シアン化銅（５４２ｍｇ）を加え１８０℃で４時間攪拌した。室温に冷却後、反応液に希塩酸を加え、酢酸エチルで抽出した。有機層を水、飽和炭酸ナトリウム水溶液、飽和食塩水で順じ洗浄し、無水硫酸マグネシウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトフィー（ヘキサン／酢酸エチル＝４／１）で精製し、目的物（７００ｍｇ）を得た。 A solution of 3-bromo-4-methanesulfonyloxymethylbenzonitrile (1.5 g) obtained in (2) and diisopropylethylamine (5.3 mL) in EtOH (20 mL) was stirred with heating under reflux. After completion of the reaction, the solvent was distilled off, water was added and the mixture was extracted with CHCl 3. The organic layer was washed with 20% aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 3-bromo-4-ethoxymethylbenzonitrile (1.32 g). This was dissolved in N-methylpyrrolidone (20 mL), copper cyanide (542 mg) was added, and the mixture was stirred at 180 ° C. for 4 hr. After cooling to room temperature, dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain the desired product (700 mg).
1H−NMR (CDCl3)δppm:
1.31 ( 3H, t, J=7.0Hz ), 3.68 ( 2H, q, J=7.0Hz ), 4.75 (2H, s ), 7.80 ( 1H, d, J=8.1Hz ), 7.89 ( 1H, dd, J=8.1 & 1.6Hz ), 7.93 ( 1H, d, J=1.6Hz ).
1 H-NMR (CDCl 3 ) δppm:
1.31 (3H, t, J = 7.0Hz), 3.68 (2H, q, J = 7.0Hz), 4.75 (2H, s), 7.80 (1H, d, J = 8.1Hz), 7.89 (1H, dd, J = 8.1 & 1.6Hz), 7.93 (1H, d, J = 1.6Hz).
（４）４−[５−（３−シアノ−４−エトキシメチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン (4) 4- [5- (3-Cyano-4-ethoxymethylphenyl) -1,2,4-triazol-3-yl] pyridazine
（３）で得た３−シアノ−４−エトキシメチルベンゾニトリルを用い実施例１（２）と同様に行い、目的物を得た。 Using 3-cyano-4-ethoxymethylbenzonitrile obtained in (3), the same procedure as in Example 1 (2) was performed to obtain the desired product.
1H−NMR(CDCl3‐d6)．ppm:1.33 ( 3H, t, J=7.3Hz ), 3.71 ( 2H, q, J=7.3Hz ), 4.77 ( 2H, s ), 7.78 ( 1H, d, J=8.1Hz ), 8.26 ( 1H, dd, J=5.4 & 2.2Hz ), 8.34 ( 1H, dd, J=8.1 & 1.6Hz ), 8.41 ( 1H, d, J=1.6Hz ), 9.30 ( 1H, dd, J=5.4 & 1.4Hz ), 9.89 ( 1H, dd, J=2.2 & 1.4Hz ).
MS m/z : 305 [M−H]−.
1 H-NMR (CDCl 3 -d 6 ). ppm: 1.33 (3H, t, J = 7.3Hz), 3.71 (2H, q, J = 7.3Hz), 4.77 (2H, s), 7.78 (1H, d, J = 8.1Hz), 8.26 (1H, dd , J = 5.4 & 2.2Hz), 8.34 (1H, dd, J = 8.1 & 1.6Hz), 8.41 (1H, d, J = 1.6 Hz), 9.30 (1H, dd, J = 5.4 & 1.4 Hz), 9.89 (1H, dd, J = 2.2 & 1.4Hz).
MS m / z: 305 [M−H] − .
実施例１３ ４−{５−[３−シアノ−４−（２，２，２−トリフルオロエトキシ）メチルフェニル]−１，２，４−トリアゾール−３−イル}ピリダジン Example 13 4- {5- [3-Cyano-4- (2,2,2-trifluoroethoxy) methylphenyl] -1,2,4-triazol-3-yl} pyridazine
実施例１２（２）で得た3−ブロモ−4−メタンスルホニルオキシメチルベンゾニトリルと２，２，２−トリフルオロエタノールより、実施例１２（３）、（４）と同様に行い、目的物を得た。 Using 3-bromo-4-methanesulfonyloxymethylbenzonitrile obtained in Example 12 (2) and 2,2,2-trifluoroethanol in the same manner as in Examples 12 (3) and (4), the desired product Got.
1H−NMR(DMSO‐d6)δppm:4.28 ( 2H, q, J=9.2 Hz ), 4.93 ( 2H, s ), 7.84 ( 1H, d, J=8.4Hz ), 8.22 ( 1H, dd, J=5.4 & 2.2Hz ), 8.41 ( 1H, dd, J=8.4 & 1.9Hz ), 8.50 ( 1H, d, J=1.9Hz ), 9.41 ( 1H, dd, J=5.4 & 1.1Hz), 9.83 ( 1H, dd, J=2.2 & 1.1Hz). 1 H-NMR (DMSO-d 6 ) δppm: 4.28 (2H, q, J = 9.2 Hz), 4.93 (2H, s), 7.84 (1H, d, J = 8.4 Hz), 8.22 (1H, dd, J = 5.4 & 2.2Hz), 8.41 (1H, dd, J = 8.4 & 1.9Hz), 8.50 (1H, d, J = 1.9Hz), 9.41 (1H, dd, J = 5.4 & 1.1Hz), 9.83 (1H , dd, J = 2.2 & 1.1Hz).
実施例１４ ４−[５−（３−シアノ−４−メトキシメチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 14 4- [5- (3-Cyano-4-methoxymethylphenyl) -1,2,4-triazol-3-yl] pyridazine
実施例１２（２）で得た３−ブロモ−４−メタンスルホニルオキシメチルベンゾニトリルとメタノールより、実施例１２（３）、（４）と同様に行い、目的物を得た。 Using 3-bromo-4-methanesulfonyloxymethylbenzonitrile obtained in Example 12 (2) and methanol in the same manner as in Examples 12 (3) and (4), the desired product was obtained.
1H−NMR(CDCl3‐d6)δppm:3.54 ( 3H, s ), 4.72 ( 2H, s ), 7.76 ( 1H, d, J=8.1Hz ), 8.24 ( 1H, dd, J=5.4 & 2.2Hz ), 8.34 ( 1H, dd, J=8.1 & 2.2Hz ), 8.41 ( 1H, d, J=2.2Hz ), 9.30 ( 1H, dd, J=5.4 & 1.4Hz ), 9.88 ( 1H, dd, J=2.2 & 1.4Hz).
MS m/z : 291 [M−H]−.
1 H-NMR (CDCl 3 -d 6 ) δppm: 3.54 (3H, s), 4.72 (2H, s), 7.76 (1H, d, J = 8.1 Hz), 8.24 (1H, dd, J = 5.4 & 2.2 Hz), 8.34 (1H, dd, J = 8.1 & 2.2 Hz), 8.41 (1H, d, J = 2.2 Hz), 9.30 (1H, dd, J = 5.4 & 1.4 Hz), 9.88 (1H, dd, J = 2.2 & 1.4Hz).
MS m / z: 291 [M−H] − .
実施例１５ ４−[５−（３−シアノ−４−メチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 15 4- [5- (3-Cyano-4-methylphenyl) -1,2,4-triazol-3-yl] pyridazine
４−メチルイソフタロニトリルを用い、実施例１（２）と同様に行い、目的物を得た。 4-Methylisophthalonitrile was used in the same manner as in Example 1 (2) to obtain the desired product.
1H−NMR(DMSO‐d6) δ(ppm): 2.50 (3H, s), 7.69(1H, d, J=8.1Hz), 8.20(1H, dd, J=5.4 & 2.2Hz), 8.27(1H, dd, J=8.1 & 1.9Hz), 8.40(1H, d, J=1.9Hz), 9.40(1H, dd, J=5.4 & 1.1Hz), 9.81(1H, dd, J=2.2 & 1.1Hz).
MS m/z : 263 [M＋H]＋, 261 [M−H]−.
1 H-NMR (DMSO-d 6 ) δ (ppm): 2.50 (3H, s), 7.69 (1H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 5.4 & 2.2 Hz), 8.27 ( 1H, dd, J = 8.1 & 1.9Hz), 8.40 (1H, d, J = 1.9Hz), 9.40 (1H, dd, J = 5.4 & 1.1Hz), 9.81 (1H, dd, J = 2.2 & 1.1Hz ).
MS m / z: 263 [M + H] + , 261 [M−H] − .
実施例１６ ４−[５−（４−ブロモフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 16 4- [5- (4-Bromophenyl) -1,2,4-triazol-3-yl] pyridazine
４−ブロモベンゾニトリル（３９５ｍｇ）をＭｅＯＨ（３０ｍＬ）に溶解させNaOMe（３５ｍｇ）を加え、室温下終夜撹拌した。ピリダジン−４−カルボン酸ヒドラジド（３００ｍｇ）を加え終夜加熱還流させた。溶媒を留去しDMF１５ｍＬに溶解し１７０℃で終夜撹拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させた。溶媒を留去しシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝５／１）で精製し、目的物（７０ｍｇ）を得た。 4-Bromobenzonitrile (395 mg) was dissolved in MeOH (30 mL), NaOMe (35 mg) was added, and the mixture was stirred overnight at room temperature. Pyridazine-4-carboxylic acid hydrazide (300 mg) was added and heated to reflux overnight. The solvent was distilled off, dissolved in 15 mL of DMF, and stirred at 170 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 5/1) to obtain the desired product (70 mg).
1H−NMR(DMSO‐d6)δppm:7.80 ( 2H , d , J=8.4Hz ) , 8.04 ( 2H , d , J=8.4Hz ) , 8.19 ( 1H , dd , J=5.1 & 2.2Hz ) , 9.38 ( 1H , dd , J=5.1 & 1.4Hz ) , 9.80 ( 1H , dd , J=2.2 & 1.4Hz ).
MS m/z : 301 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.80 (2H, d, J = 8.4 Hz), 8.04 (2H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 5.1 & 2.2 Hz), 9.38 (1H, dd, J = 5.1 & 1.4 Hz), 9.80 (1H, dd, J = 2.2 & 1.4 Hz).
MS m / z: 301 [M−H] − .
以下、相当するベンゾニトリルを用いて実施例１６と同様にし、実施例１７〜実施例２０を得た。 Hereinafter, Example 17 to Example 20 were obtained in the same manner as Example 16 using the corresponding benzonitrile.
実施例１７ ４−[５−（３，５−ジフルオロフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 17 4- [5- (3,5-Difluorophenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:7.43-7.54 ( 1H , m ) , 7.71-7.82 ( 2H , m ) , 8.21 ( 1H , dd , J=5.4 & 2.4Hz ) , 9.41 ( 1H , dd , J=5.4 & 1.35Hz ) , 9.82 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 258 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.43-7.54 (1H, m), 7.71-7.82 (2H, m), 8.21 (1H, dd, J = 5.4 & 2.4 Hz), 9.41 (1H, dd, J = 5.4 & 1.35Hz), 9.82 (1H, dd, J = 2.4 & 1.4 Hz).
MS m / z: 258 [M−H] − .
実施例１８ ４−[５−（４−ニトロフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 18 4- [5- (4-Nitrophenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:8.23 ( 1H , dd , J=5.1 & 2.2Hz ) , 8.36 ( 2H , d , J=8.4Hz ) , 8.45 ( 2H , d , J=8.4Hz ) , 9.43 ( 1H , d , J=5.1Hz ) , 9.83 ( 1H , dd , J=2.2 & 1.1Hz ).
MS m/z : 267 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 8.23 (1H, dd, J = 5.1 & 2.2 Hz), 8.36 (2H, d, J = 8.4 Hz), 8.45 (2H, d, J = 8.4 Hz), 9.43 (1H, d, J = 5.1Hz), 9.83 (1H, dd, J = 2.2 & 1.1Hz).
MS m / z: 267 [M−H] − .
実施例１９ ４−[５−（４−クロロフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 19 4- [5- (4-Chlorophenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:7.67 ( 2H , d , J=8.4Hz ) , 8.11 ( 2H , d , J=8.4Hz ) , 8.20 ( 1H , dd , J=5.4 & 2.2Hz ) , 9.39 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.81 ( 1H , dd , J=2.2 & 1.4Hz ).
MS m/z : 256 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.67 (2H, d, J = 8.4 Hz), 8.11 (2H, d, J = 8.4 Hz), 8.20 (1H, dd, J = 5.4 & 2.2 Hz), 9.39 (1H, dd, J = 5.4 & 1.4 Hz), 9.81 (1H, dd, J = 2.2 & 1.4 Hz).
MS m / z: 256 [M−H] − .
実施例２０ ４−[５−（３−シアノフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 20 4- [5- (3-Cyanophenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:7.80 ( 1H , t , J=7.83Hz ) , 8.01 ( 1H , d , J=7.8Hz ) , 8.20 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.39 ( 1H , d , J=7.8Hz ) , 8.46 ( 1H , s ) , 9.39 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.81 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 247 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.80 (1H, t, J = 7.83 Hz), 8.01 (1H, d, J = 7.8 Hz), 8.20 (1H, dd, J = 5.4 & 2.4 Hz), 8.39 (1H, d, J = 7.8Hz), 8.46 (1H, s), 9.39 (1H, dd, J = 5.4 & 1.4 Hz), 9.81 (1H, dd, J = 2.4 & 1.4 Hz).
MS m / z: 247 [M−H] − .
実施例２１ ４−（５−｛３−シアノ−４−[２−（２−メチルスルファニルエトキシ）エトキシ]フェニル｝−１，２，４−トリアゾール−３−イル）ピリダジン Example 21 4- (5- {3-Cyano-4- [2- (2-methylsulfanylethoxy) ethoxy] phenyl} -1,2,4-triazol-3-yl) pyridazine
（１）４−[２−（２−メチルスルファニルエトキシ）エトキシ]イソフタロニトリル (1) 4- [2- (2-Methylsulfanylethoxy) ethoxy] isophthalonitrile
４−ヒドロキシイソフタロニトリル（１ｇ）をＴＨＦ（３０ｍＬ）に溶解させ、２−（２−メチルスルファニルエトキシ）エタノ−ル（１．４ｇ）及びジイソプロピルアゾジカルボキシレート（２ｍＬ）トリフェニルホスフィン（２．７ｇ）を加え室温下終夜撹拌した。反応終了後５％クエン酸水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させた。溶媒を留去し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝２／１）で精製し、１，２−ジイソプロポキシカルボニルヒドラジンの混合物として目的物（３．３３ｇ）を得た。 4-Hydroxyisophthalonitrile (1 g) was dissolved in THF (30 mL) and 2- (2-methylsulfanylethoxy) ethanol (1.4 g) and diisopropyl azodicarboxylate (2 mL) triphenylphosphine (2. 7 g) was added and stirred overnight at room temperature. After completion of the reaction, 5% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1) to obtain the desired product (3.33 g) as a mixture of 1,2-diisopropoxycarbonylhydrazine.
1H−NMR(CDCl3)δppm:
2.15 ( 3H , s ) , 2.71 ( 2H , t , J=6.5Hz ) , 3.77 ( 2H , t , J=6.5Hz ) , 3.89−3.97 ( 2H , m ) , 4.30−4.38 ( 2H , m ) , 7.15 ( 1H , d , J=8.6Hz ) , 7.81 ( 1H , dd , J=8.6 & 1.9Hz ) , 7.86 ( 1H , d , J=1.9Hz ).
1 H-NMR (CDCl 3 ) δ ppm:
2.15 (3H, s), 2.71 (2H, t, J = 6.5Hz), 3.77 (2H, t, J = 6.5Hz), 3.89−3.97 (2H, m), 4.30−4.38 (2H, m), 7.15 (1H, d, J = 8.6Hz), 7.81 (1H, dd, J = 8.6 & 1.9 Hz), 7.86 (1H, d, J = 1.9 Hz).
（２）４−（５−｛３−シアノ−４−[２−（２−メチルスルファニルエトキシ）エトキシ]フェニル｝−１，２，４−トリアゾール−３−イル）ピリダジンの合成 (2) Synthesis of 4- (5- {3-cyano-4- [2- (2-methylsulfanylethoxy) ethoxy] phenyl} -1,2,4-triazol-3-yl) pyridazine
（１）で得た４−[２−（２−メチルスルファニルエトキシ）エトキシ]イソフタロニトリルを用い、実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as Example 16 using 4- [2- (2-methylsulfanylethoxy) ethoxy] isophthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:2.09 ( 3H , s ) , 2.66 ( 2H , t , J=6.8Hz ) , 3.70 ( 2H , t , J=6.8Hz ) , 3.80-3.89 ( 2H , m ) , 4.32-4.42 ( 2H , m ) , 7.52 ( 1H , d , J=8.9Hz ) , 8.20 ( 1H , dd , J=5.4 & 2.2Hz ) , 8.28-8.41 ( 2H , m ) , 9.39 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.81 ( 1H , dd , J=2.2 & 1.4Hz ).
MS m/z : 381 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 2.09 (3H, s), 2.66 (2H, t, J = 6.8 Hz), 3.70 (2H, t, J = 6.8 Hz), 3.80-3.89 (2H, m ), 4.32-4.42 (2H, m), 7.52 (1H, d, J = 8.9Hz), 8.20 (1H, dd, J = 5.4 & 2.2 Hz), 8.28-8.41 (2H, m), 9.39 (1H, dd, J = 5.4 & 1.4Hz), 9.81 (1H, dd, J = 2.2 & 1.4 Hz).
MS m / z: 381 [M−H] − .
実施例２２ ４−（５−｛３−シアノ−4−[２−（２−メトキシエチルスルファニル）エトキシ]フェニル｝−１，２，４−トリアゾール−３−イル）ピリダジン Example 22 4- (5- {3-Cyano-4- [2- (2-methoxyethylsulfanyl) ethoxy] phenyl} -1,2,4-triazol-3-yl) pyridazine
２−（２−メトキシエチルスルファニル）エタノ−ルを用いて実施例２１と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 21 using 2- (2-methoxyethylsulfanyl) ethanol.
1H−NMR(DMSO‐d6)δppm:2.84 ( 2H , t , J=6.4Hz ) , 3.00 ( 2H , t , J=6.5Hz ) , 3.26 ( 3H , s ) , 3.54 ( 2H , t , J=6.4Hz ) , 4.41 ( 2H , t , J=6.5Hz ) , 7.52 ( 1H , d , J=8.9Hz ) , 8.20 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.31-8.40 ( 2H , m ) , 9.40 ( 1H , dd , J=5.4 & 1.1Hz ) , 9.81 ( 1H , dd , J=2.4 & 1.1Hz ).
MS m/z : 381 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 2.84 (2H, t, J = 6.4 Hz), 3.00 (2H, t, J = 6.5 Hz), 3.26 (3H, s), 3.54 (2H, t, J = 6.4Hz), 4.41 (2H, t, J = 6.5Hz), 7.52 (1H, d, J = 8.9Hz), 8.20 (1H, dd, J = 5.4 & 2.4Hz), 8.31-8.40 (2H, m ), 9.40 (1H, dd, J = 5.4 & 1.1 Hz), 9.81 (1H, dd, J = 2.4 & 1.1 Hz).
MS m / z: 381 [M−H] − .
相当する置換ベンゾニトリルを用い、実施例１６と同様にして実施例２３〜２５の化合物を得た。 The compounds of Examples 23 to 25 were obtained in the same manner as Example 16 using the corresponding substituted benzonitrile.
実施例２３ ４−[５−（４−シアノフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 23 4- [5- (4-Cyanophenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:8.07 ( 2H , d , J=8.1Hz ) , 8.21 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.27 ( 2H , d , J=8.1Hz ) , 9.42 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.82 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 247 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 8.07 (2H, d, J = 8.1 Hz), 8.21 (1H, dd, J = 5.4 & 2.4 Hz), 8.27 (2H, d, J = 8.1 Hz), 9.42 (1H, dd, J = 5.4 & 1.4 Hz), 9.82 (1H, dd, J = 2.4 & 1.4 Hz).
MS m / z: 247 [M−H] − .
実施例２４ ４−[５−（３，４−ジフルオロフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 24 4- [5- (3,4-Difluorophenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:7.62-7.75 ( 1H , m ) , 7.93-8.00 ( 1H , m ) , 8.04-8.13 ( 1H , m ) , 8.19 ( 1H , dd , J=5.4 & 2.4Hz ) , 9.39 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.81 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 258 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.62-7.75 (1H, m), 7.93-8.00 (1H, m), 8.04-8.13 (1H, m), 8.19 (1H, dd, J = 5.4 & 2.4 Hz), 9.39 (1H, dd, J = 5.4 & 1.4Hz), 9.81 (1H, dd, J = 2.4 & 1.4Hz).
MS m / z: 258 [M−H] − .
実施例２５ ４−[５−（３−クロロフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 25 4- [5- (3-Chlorophenyl) -1,2,4-triazol-3-yl] pyridazine
1H−NMR(DMSO‐d6)δppm:7.60-7.64 ( 2H , m ) , 8.02-8.10 ( 1H , m ) , 8.12-8.16 ( 1H , m ) , 8.21 ( 1H , dd , J=5.4 & 2.2Hz ) , 9.40 ( 1H , dd , J=5.4 & 1.1Hz ) , 9.82 ( 1H , dd , J=2.2 & 1.1Hz ).
MS m/z : 256 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.60-7.64 (2H, m), 8.02-8.10 (1H, m), 8.12-8.16 (1H, m), 8.21 (1H, dd, J = 5.4 & 2.2 Hz), 9.40 (1H, dd, J = 5.4 & 1.1Hz), 9.82 (1H, dd, J = 2.2 & 1.1Hz).
MS m / z: 256 [M−H] − .
実施例２６ ４−（５−｛３−シアノ−4−[２−（２−メトキシエトキシ）エチルスルファニル]フェニル｝−１，２，４−トリアゾール−３−イル）ピリダジン Example 26 4- (5- {3-Cyano-4- [2- (2-methoxyethoxy) ethylsulfanyl] phenyl} -1,2,4-triazol-3-yl) pyridazine
（１）４−[２−（２−メトキシエトキシ）エチルスルファニル]イソフタロニトリル (1) 4- [2- (2-methoxyethoxy) ethylsulfanyl] isophthalonitrile
トリフルオロメタンスルホン酸−２，４−ジシアノフェニルエステルを（１．４４ｇ）ＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（１．０８ｇ）、２−（２−メトキシエトキシ）エタンチオ−ル（７８１ｍｇ）を加え、７０℃にて終夜撹拌した。反応終了後、水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させた。溶媒を留去しシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／１）で精製し、更にジイソプロピルエーテルで洗浄して、目的物（５４０ｍｇ）を得た。 Trifluoromethanesulfonic acid-2,4-dicyanophenyl ester is dissolved in (1.44 g) DMF (20 mL), and potassium carbonate (1.08 g) and 2- (2-methoxyethoxy) ethanethiol (781 mg) are added. And stirred at 70 ° C. overnight. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) and further washed with diisopropyl ether to obtain the desired product (540 mg).
1H−NMR(CDCl3)δppm:3.31 ( 2H , t , J=6.5Hz ) , 3.38 ( 3H , s ) , 3.50−3.55 ( 2H , m ) , 3.62−3.67 ( 2H , m ) , 3.80 ( 2H , t , J=6.5Hz ) , 7.55 ( 1H , d , J=8.4Hz ) , 7.72 ( 1H , dd , J=8.4 & 1.6Hz ) , 7.84 ( 1H , d , J=1.6Hz ). 1 H-NMR (CDCl 3 ) δppm: 3.31 (2H, t, J = 6.5 Hz), 3.38 (3H, s), 3.50−3.55 (2H, m), 3.62−3.67 (2H, m), 3.80 (2H , t, J = 6.5Hz), 7.55 (1H, d, J = 8.4 Hz), 7.72 (1H, dd, J = 8.4 & 1.6 Hz), 7.84 (1H, d, J = 1.6 Hz).
（２）４−（５−｛３−シアノ−4−[２−（２−メトキシエトキシ）エチルスルファニル]フェニル｝−１，２，４−トリアゾール−3−イル）ピリダジン (2) 4- (5- {3-Cyano-4- [2- (2-methoxyethoxy) ethylsulfanyl] phenyl} -1,2,4-triazol-3-yl) pyridazine
（１）で得た４−[２−（２−メトキシエトキシ）エチルスルファニル]イソフタロニトリルを用い実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as Example 16 using 4- [2- (2-methoxyethoxy) ethylsulfanyl] isophthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:3.24 ( 3H , s ) , 3.38-3.47 ( 4H , m ) , 3.54-3.59 ( 2H , m ) , 3.69-3.75 ( 2H , m ) , 7.83 ( 1H , d , J=8.6Hz ) , 8.20 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.29 ( 1H , dd , J=8.6 & 1.9Hz ) , 8.41 ( 1H , d , J=1.9Hz ) , 9.40 ( 1H , dd , J=5.4 & 1.1Hz ) , 9.81 ( 1H , dd , J=2.4 & 1.1Hz ).
MS m/z : 381 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 3.24 (3H, s), 3.38-3.47 (4H, m), 3.54-3.59 (2H, m), 3.69-3.75 (2H, m), 7.83 (1H, d, J = 8.6Hz), 8.20 (1H, dd, J = 5.4 & 2.4 Hz), 8.29 (1H, dd, J = 8.6 & 1.9 Hz), 8.41 (1H, d, J = 1.9 Hz), 9.40 ( 1H, dd, J = 5.4 & 1.1Hz), 9.81 (1H, dd, J = 2.4 & 1.1 Hz).
MS m / z: 381 [M−H] − .
実施例２７ ４−[５−（４−トリフルオロメチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン
４−トリフルオロメチルベンゾニトリルを用い、実施例１６と同様にして目的物を得た。
Example 27 4- [5- (4-trifluoromethylphenyl) -1,2,4-triazol-3-yl] pyridazine Using 4-trifluoromethylbenzonitrile, the target product was obtained in the same manner as in Example 16. Obtained.
1H−NMR(DMSO‐d6)δppm:7.97 ( 2H , d , J=8.6Hz ) , 8.22 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.32 ( 2H , d , J=8.6Hz ) , 9.41 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.83 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 290 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.97 (2H, d, J = 8.6 Hz), 8.22 (1H, dd, J = 5.4 & 2.4 Hz), 8.32 (2H, d, J = 8.6 Hz), 9.41 (1H, dd, J = 5.4 & 1.4 Hz), 9.83 (1H, dd, J = 2.4 & 1.4 Hz).
MS m / z: 290 [M−H] − .
実施例２８ ４−［５−（３−シアノ−4−メトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 28 4- [5- (3-Cyano-4-methoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）４−メトキシイソフタロニトリル
４−ヒドロキシイソフタロニトリル（５００ｍｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（７１９ｍｇ）、ヨウ化メチル（０．３２４ｍＬ）を加え、室温下終夜反応させた。反応終了後水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させた。溶媒を留去し、残渣をジイソプロピルエーテルで洗浄し、目的物（４１２ｍｇ）得た。
(1) 4-methoxyisophthalonitrile 4-hydroxyisophthalonitrile (500 mg) was dissolved in DMF (20 mL), potassium carbonate (719 mg) and methyl iodide (0.324 mL) were added, and the mixture was reacted at room temperature overnight. . After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was washed with diisopropyl ether to obtain the desired product (412 mg).
1H−NMR(CDCl3)δppm:4.03 ( 3H , s ) , 7.08 ( 1H , d , J=8.6Hz ) , 7.84 ( 1H , dd , J=8.6& 1.9Hz ) , 7.86−7.88 ( 1H , m ). 1 H-NMR (CDCl 3 ) δppm: 4.03 (3H, s), 7.08 (1H, d, J = 8.6 Hz), 7.84 (1H, dd, J = 8.6 & 1.9 Hz), 7.86−7.88 (1H, m ).
（２）４−［５−（３−シアノ−4−メトキシフェニル）−１，２，４−トリアゾール−3−イル］ピリダジン (2) 4- [5- (3-Cyano-4-methoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）で得た４−メトキシイソフタロニトリルを用い実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 4-methoxyisophthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:4.02 ( 3H , s ) , 7.50 ( 1H , d , J=8.4Hz ) , 8.20-8.28 ( 1H , m ) , 8.41-8.51 ( 2H , m ) , 9.37-9.44 ( 1H , m ) , 9.81-9.87 ( 1H , m ).
MS m/z : 277 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 4.02 (3H, s), 7.50 (1H, d, J = 8.4 Hz), 8.20-8.28 (1H, m), 8.41-8.51 (2H, m), 9.37 -9.44 (1H, m), 9.81-9.87 (1H, m).
MS m / z: 277 [M−H] − .
実施例２９ ４−［５−（３−シアノ−4−エトキシフェニル）−１，２，４−トリアゾール−3−イル］ピリダジン Example 29 4- [5- (3-Cyano-4-ethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
ヨウ化エチルを用い実施例２８と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 28 using ethyl iodide.
1H−NMR(DMSO‐d6)δppm:1.42 ( 3H , t , J=7.0Hz ) , 4.31 ( 2H , q , J=7.0Hz ) , 7.48 ( 1H , d , J=8.9Hz ) , 8.21 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.31-8.40 ( 2H , m ) , 9.39 ( 1H , d , J=5.4Hz ) , 9.81 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 291 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 1.42 (3H, t, J = 7.0 Hz), 4.31 (2H, q, J = 7.0 Hz), 7.48 (1H, d, J = 8.9 Hz), 8.21 ( 1H, dd, J = 5.4 & 2.4Hz), 8.31-8.40 (2H, m), 9.39 (1H, d, J = 5.4 Hz), 9.81 (1H, dd, J = 2.4 & 1.4 Hz).
MS m / z: 291 [M−H] − .
実施例３０ ４−［５−（３−メチル−4−ニトロフェニル）−１，２，４−トリアゾール−3−イル］ピリダジン Example 30 4- [5- (3-Methyl-4-nitrophenyl) -1,2,4-triazol-3-yl] pyridazine
４−ニトロ−３−メチルベンゾニトリルを用い、実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 4-nitro-3-methylbenzonitrile.
1H−NMR(DMSO‐d6)δppm:2.63 ( 3H , s ) , 8.10-8.27 ( 4H , m ) , 9.36-9.50 ( 1H , m ) , 9.83 ( 1H , dd , J=2.2 & 1.4Hz ).
MS m/z : 281 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 2.63 (3H, s), 8.10-8.27 (4H, m), 9.36-9.50 (1H, m), 9.83 (1H, dd, J = 2.2 & 1.4 Hz) .
MS m / z: 281 [M−H] − .
実施例３１ ４−｛５−［３−シアノ−４−（２，２，２−トリフルオロエトキシ）フェニル］−１，２，４−トリアゾール−３−イル｝ピリダジン Example 31 4- {5- [3-Cyano-4- (2,2,2-trifluoroethoxy) phenyl] -1,2,4-triazol-3-yl} pyridazine
（１） ４−（２，２，２−トリフルオロエトキシ）イソフタロニトリル (1) 4- (2,2,2-trifluoroethoxy) isophthalonitrile
トリフルオロメタンスルホン酸−２，４−ジシアノフェニルエステルを（１．００ｇ）ＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（７５０ｍｇ）、２，２，２−トリフルオロエタノール（２．６ｍＬ）を加え、室温で３時間撹拌した。反応終了後、水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を留去し目的物（１３０ｍｇ）を得た。 Trifluoromethanesulfonic acid-2,4-dicyanophenyl ester is dissolved in (1.00 g) DMF (10 mL), potassium carbonate (750 mg), 2,2,2-trifluoroethanol (2.6 mL) are added, and room temperature is added. For 3 hours. After completion of the reaction, water was added, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the desired product (130 mg).
1H−NMR(CDCl3)δppm:4.58 ( 2H , q , J=7.6Hz ) , 7.11 ( 1H , d , J=8.6Hz ) , 7.88 ( 1H , dd , J=8.6 & 1.9Hz ) , 7.95 ( 1H , d , J=1.9Hz ). 1 H-NMR (CDCl 3 ) δppm: 4.58 (2H, q, J = 7.6 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.88 (1H, dd, J = 8.6 & 1.9 Hz), 7.95 ( 1H, d, J = 1.9Hz).
（２）４−｛５−［３−シアノ−４−（２，２，２−トリフルオロエトキシ）フェニル］−１，２，４−トリアゾール−３−イル｝ピリダジン (2) 4- {5- [3-Cyano-4- (2,2,2-trifluoroethoxy) phenyl] -1,2,4-triazol-3-yl} pyridazine
（１）で得た４−（２，２，２−トリフルオロエトキシ）イソフタロニトリルを用い実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 4- (2,2,2-trifluoroethoxy) isophthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:5.11 ( 2H , q , J=8.6Hz ) , 7.63 ( 1H , d , J=8.6Hz ) , 8.26 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.39-8.50 ( 2H , m ) , 9.43 ( 1H , d , J=5.4Hz ) , 9.82-9.87 ( 1H , m ).
MS m/z : 345 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 5.11 (2H, q, J = 8.6 Hz), 7.63 (1H, d, J = 8.6 Hz), 8.26 (1H, dd, J = 5.4 & 2.4 Hz), 8.39-8.50 (2H, m), 9.43 (1H, d, J = 5.4Hz), 9.82-9.87 (1H, m).
MS m / z: 345 [M−H] − .
実施例３２ ４−［５−（３−シアノ−４−トリフルオロメトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 32 4- [5- (3-Cyano-4-trifluoromethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）３−ヨ−ド−４−（トリフルオロメトキシ）ベンズアルデヒドの合成
トリフルオロメタンスルホン酸（２３．３ｍＬ）を、窒素置換下、氷冷しながらＮ−ヨ−ドスクシイミド（１１．８ｇ）を加えた。その混合物に４−（トリフルオロメトキシ）ベンズアルデヒド（５ｇ）を滴下した。氷冷下1時間撹拌し、室温で４時間撹拌した。反応混合物を氷水に注ぎ、塩化メチレンで抽出し、抽出液を１０％チオ硫酸ナトリウム水溶液、１０％炭酸カリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧濃縮して、目的物（６．８９ｇ）を得た。
(1) Synthesis of 3-iodo-4- (trifluoromethoxy) benzaldehyde N-iodosuccinimide (11.8 g) was added to trifluoromethanesulfonic acid (23.3 mL) while cooling with ice under nitrogen substitution. It was. 4- (Trifluoromethoxy) benzaldehyde (5 g) was added dropwise to the mixture. The mixture was stirred for 1 hour under ice-cooling and stirred at room temperature for 4 hours. The reaction mixture is poured into ice water and extracted with methylene chloride. The extract is washed with 10% aqueous sodium thiosulfate solution, 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (6.89 g) was obtained.
（２）３−シアノ−４−（トリフルオロメトキシ）ベンズアルデヒド (2) 3-Cyano-4- (trifluoromethoxy) benzaldehyde
ＤＭＦ（４０ｍＬ）に（１）で得た３−ヨ−ド−４−（トリフルオロメトキシ）ベンズアルデヒド（６．８９ｇ）及びシアン化亜鉛（４．１ｇ）を加え、室温下、懸濁させた。この混合物に、テトラキス（トリフェニルホスフィン）パラジウム（３．０ｇ）を少しずつ加えた後、１００℃で８時間加熱した。反応混合物に１０％炭酸カリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、酢酸エチルを減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５）で精製し、目的物（３．１４ｇ）を得た。 3-iodo-4- (trifluoromethoxy) benzaldehyde (6.89 g) and zinc cyanide (4.1 g) obtained in (1) were added to DMF (40 mL) and suspended at room temperature. Tetrakis (triphenylphosphine) palladium (3.0 g) was added little by little to this mixture, and then heated at 100 ° C. for 8 hours. To the reaction mixture was added 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/5) to obtain the desired product (3.14 g).
（３）４−トリフルオロメトキシイソフタロニトリル (3) 4-trifluoromethoxyisophthalonitrile
酢酸ナトリウム（９．５ｇ）を氷酢酸（１００ｍＬ）に溶解させ、（２）で得た３−シアノ−４−（トリフルオロメトキシ）ベンズアルデヒド（１２．５１ｇ）及びヒドロキシルアミン塩酸塩（４．４４ｇ）を加え１４０℃で終夜加熱撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）で精製し、目的物（５．７４ｇ）を得た。 Sodium acetate (9.5 g) was dissolved in glacial acetic acid (100 mL), and 3-cyano-4- (trifluoromethoxy) benzaldehyde (12.51 g) and hydroxylamine hydrochloride (4.44 g) obtained in (2) were obtained. And heated and stirred at 140 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain the desired product (5.74 g).
1H−NMR(CDCl3)δppm:7.51−7.58 ( 1H , m ) , 7.96 ( 1H , dd , J=8.9 & 2.2Hz ) , 8.04 ( 1H , d , J=2.2Hz ). 1 H-NMR (CDCl 3 ) δ ppm: 7.51-7.58 (1H, m), 7.96 (1H, dd, J = 8.9 & 2.2 Hz), 8.04 (1H, d, J = 2.2 Hz).
（４）４−［５−（３−シアノ−４−トリフルオロメトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン (4) 4- [5- (3-Cyano-4-trifluoromethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（３）で得た４−トリフルオロメトキシイソフタロニトリルを用い、実施例１６と同様にして目的物を得た。 Using 4-trifluoromethoxyisophthalonitrile obtained in (3), the target product was obtained in the same manner as in Example 16.
1H−NMR(DMSO‐d6)δppm:7.89-7.97 ( 1H , m ), 8.21 ( 1H , dd , J=5.1 & 2.2Hz ) , 8.52 ( 1H , dd , J=8.9 & 2.4Hz ) , 8.65 ( 1H , d , J=2.4Hz ) , 9.43 ( 1H , dd , J=5.1 & 1.1Hz ) , 9.82 ( 1H , dd , 2.2 & 1.1Hz ).
MS m/z : 331 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 7.89-7.97 (1H, m), 8.21 (1H, dd, J = 5.1 & 2.2 Hz), 8.52 (1H, dd, J = 8.9 & 2.4 Hz), 8.65 (1H, d, J = 2.4Hz), 9.43 (1H, dd, J = 5.1 & 1.1 Hz), 9.82 (1H, dd, 2.2 & 1.1 Hz).
MS m / z: 331 [M−H] − .
実施例３３ ４−［５−（４−シアノ−３−メチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 33 4- [5- (4-Cyano-3-methylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）２−フルオロテレフタロニトリル (1) 2-Fluoroterephthalonitrile
４−ブロモ−２−フルオロベンゾニトリルを（１０ｇ）Ｎ−メチルピロリドンに溶解し、シアン化銅（４．９ｇ）を加え１９０℃で６時間加熱した。反応終了後、アンモニア水を加え、酢酸エチルで抽出し飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を留去し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）で精製し目的物（５．７１ｇ）を得た。 4-Bromo-2-fluorobenzonitrile (10 g) was dissolved in N-methylpyrrolidone, copper cyanide (4.9 g) was added, and the mixture was heated at 190 ° C. for 6 hours. After completion of the reaction, aqueous ammonia was added, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain the desired product (5.71 g).
1H−NMR(CDCl3)δppm:7.53−7.63 ( 2H , m ) , 7.76−7.83 ( 1H , m ). 1 H-NMR (CDCl 3 ) δ ppm: 7.53-7.63 (2H, m), 7.76-7.83 (1H, m).
（２）２−メチルスルファニルテレフタロニトリル (2) 2-methylsulfanyl terephthalonitrile
（１）で得た２−フルオロテレフタロニトリル（１ｇ）をＤＭＦ（３０ｍＬ）に溶解させ、ナトリウムチオメトキシド（５２８ｍｇ）を加え、アルゴン置換下室温で終夜撹拌した。反応終了後水を加え、濾取し１００℃で減圧乾燥させ、目的物（１．１３ｇ）を得た。 2-Fluoroterephthalonitrile (1 g) obtained in (1) was dissolved in DMF (30 mL), sodium thiomethoxide (528 mg) was added, and the mixture was stirred overnight at room temperature under argon substitution. After completion of the reaction, water was added, filtered and dried under reduced pressure at 100 ° C. to obtain the desired product (1.13 g).
1H−NMR(CDCl3)δppm:2.61 ( 3H , s ) , 7.47 ( 1H , dd , J=7.8 & 1.4Hz ) , 7.49−7.51 ( 1H , m ) 7.69 ( 1H , d , J=7.8Hz ) 1 H-NMR (CDCl 3 ) δppm: 2.61 (3H, s), 7.47 (1H, dd, J = 7.8 & 1.4 Hz), 7.49-7.51 (1H, m) 7.69 (1H, d, J = 7.8 Hz)
（３）４−［５−（４−シアノ−３−メチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン (3) 4- [5- (4-Cyano-3-methylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（２）で得た２−メチルスルファニルテレフタロニトリルを用い、実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 2-methylsulfanyl terephthalonitrile obtained in (2).
1H−NMR(DMSO‐d6)δppm:2.67 ( 3H , s ) , 7.86-8.00 ( 2H , m ) , 8.08-8.11 ( 1H , m ) , 8.13 ( 1H , dd , J=5.4 & 2.4Hz ) , 9.27 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.80 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 293 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 2.67 (3H, s), 7.86-8.00 (2H, m), 8.08-8.11 (1H, m), 8.13 (1H, dd, J = 5.4 & 2.4 Hz) , 9.27 (1H, dd, J = 5.4 & 1.4 Hz), 9.80 (1H, dd, J = 2.4 & 1.4 Hz).
MS m / z: 293 [M−H] − .
実施例３４ ４−［５−（４−シアノ−３−メトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 34 4- [5- (4-Cyano-3-methoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）２−ヒドロキシテレフタロニトリル (1) 2-hydroxyterephthalonitrile
ＤＭＳＯ（５ｍＬ）に水素化ナトリウム（６０％ ｉｎ ｏｉｌ）（１６４ｍｇ）を加え、７０℃で３０分加温した。ベンズアルドオキシム（４９７ｍｇ）をＤＭＳＯ（２ｍＬ）に溶解させ滴下し、７０℃で３０分加温した。２−フルオロテレフタロニトリル（３００ｍｇ）をＤＭＳＯ（５ｍＬ）に溶解させ滴下し、室温で２日間撹拌した。反応終了後、１０％炭酸カリウム水溶液を加え、酢酸エチルで洗浄した。水層を１０％塩酸水溶液で酸性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を留去し、ｎ−ヘキサンで洗浄し目的物（２７５ｍｇ）を得た。 Sodium hydride (60% in oil) (164 mg) was added to DMSO (5 mL), and the mixture was heated at 70 ° C. for 30 minutes. Benzaldoxime (497 mg) was dissolved in DMSO (2 mL) and added dropwise, and the mixture was heated at 70 ° C. for 30 minutes. 2-Fluoroterephthalonitrile (300 mg) was dissolved in DMSO (5 mL) and added dropwise, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, 10% aqueous potassium carbonate solution was added, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and washed with n-hexane to obtain the desired product (275 mg).
1H−NMR(DMSO‐d6)δppm:7.33−7.43 ( 2H , m ) , 7.87 ( 1H , d , J=8.1Hz ). 1 H-NMR (DMSO-d 6 ) δ ppm: 7.33-7.43 (2H, m), 7.87 (1H, d, J = 8.1 Hz).
（２）２−メトキシテレフタロニトリル (2) 2-Methoxyterephthalonitrile
（１）で得た２−ヒドロキシテレフタロニトリルをＤＭＦ（２０ｍＬ）に溶解させ炭酸カリウム（７２８ｍｇ）ヨウ化メチル（０．３２８ｍＬ）を加え、室温下終夜撹拌した。反応終了後、水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させた。溶媒を留去し、目的物（４１０ｍｇ）を得た。 The 2-hydroxyterephthalonitrile obtained in (1) was dissolved in DMF (20 mL), potassium carbonate (728 mg) and methyl iodide (0.328 mL) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the desired product (410 mg).
1H−NMR(CDCl3)δppm:
4.00 ( 3H , s ) , 7.22 ( 1H , d , J=1.4Hz ) , 7.32 ( 1H , dd , J=7.8 & 1.4Hz ) , 7.68 ( 1H , d , J=7.8Hz ).
1 H-NMR (CDCl 3 ) δ ppm:
4.00 (3H, s), 7.22 (1H, d, J = 1.4Hz), 7.32 (1H, dd, J = 7.8 & 1.4Hz), 7.68 (1H, d, J = 7.8Hz).
（３）４−［５−（４−シアノ−３−メトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン (3) 4- [5- (4-Cyano-3-methoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（２）で得た２−メトキシテレフタロニトリルを用いて、実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 2-methoxyterephthalonitrile obtained in (2).
1H−NMR(DMSO‐d6)δppm:4.06 ( 3H , s ) , 7.82 ( 1H , dd , J=7.8 & 1.4Hz ) , 7.90-8.00 ( 2H , m ) , 8.25 ( 1H , dd , J=5.4 & 2.4Hz ) , 9.43 ( 1H , dd , J=5.4 & 1.1Hz ) , 9.85 ( 1H , dd , J=2.4 & 1.1Hz ).
MS m/z : 277 [M−H]−.
1 H-NMR (DMSO-d 6 ) δ ppm: 4.06 (3H, s), 7.82 (1H, dd, J = 7.8 & 1.4 Hz), 7.90-8.00 (2H, m), 8.25 (1H, dd, J = 5.4 & 2.4Hz), 9.43 (1H, dd, J = 5.4 & 1.1Hz), 9.85 (1H, dd, J = 2.4 & 1.1Hz).
MS m / z: 277 [M−H] − .
実施例３５ ４−［５−（４−シアノ−３−エチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 35 4- [5- (4-Cyano-3-ethylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）２−エチルスルファニルテレフタロニトリル (1) 2-ethylsulfanyl terephthalonitrile
ナトリウムエタンチオレ−トを用い実施例３３（２）と同様にして目的物を得た。 The desired product was obtained in the same manner as in Example 33 (2) using sodium ethanethiolate.
1H−NMR(CDCl3)δppm:1.42 ( 3H , t , J=7.3Hz ) , 3.10 ( 2H , q , J=7.3Hz ) , 7.49 ( 1H , dd , J=8.1 & 1.4Hz ) , 7.57−7.60 ( 1H , m ) , 7.70 ( 1H , dd , J=8.1 & 0.5Hz ). 1 H-NMR (CDCl 3 ) δppm: 1.42 (3H, t, J = 7.3 Hz), 3.10 (2H, q, J = 7.3 Hz), 7.49 (1H, dd, J = 8.1 & 1.4 Hz), 7.57− 7.60 (1H, m), 7.70 (1H, dd, J = 8.1 & 0.5Hz).
（２）４−［５−（４−シアノ−３−エチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン (2) 4- [5- (4-Cyano-3-ethylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）で得た２−エチルスルファニルテレフタロニトリルを用い、実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as Example 16 using 2-ethylsulfanyl terephthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:1.36 ( 3H , t , J=7.4Hz ) , 3.26 ( 2H , q , J=7.4Hz ) , 7.99-8.08 ( 2H , m ) , 8.15-8.20 ( 1H , m ) , 8.22 ( 1H , dd , J=5.4 & 1.9Hz ) , 9.35-9.45 ( 1H , m ) , 9.80-9.97 ( 1H , m ).
MS m/z : 307 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 1.36 (3H, t, J = 7.4 Hz), 3.26 (2H, q, J = 7.4 Hz), 7.99-8.08 (2H, m), 8.15-8.20 (1H , m), 8.22 (1H, dd, J = 5.4 & 1.9 Hz), 9.35-9.45 (1H, m), 9.80-9.97 (1H, m).
MS m / z: 307 [M−H] − .
実施例３６ ４−［５−（４−シアノ−３−エトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 36 4- [5- (4-Cyano-3-ethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）２−エトキシテレフタロニトリル
ヨウ化エチルを用いて実施例３４（２）と同様にして目的物を得た。
(1) The target product was obtained in the same manner as in Example 34 (2) using 2-ethoxyterephthalonitrile ethyl iodide.
1H−NMR(CDCl3)δppm:1.53 ( 3H , t , J=6.8Hz ) , 4.20 ( 2H , q , J=6.8Hz ) , 7.19−7.21 ( 1H , m ) , 7.30 ( 1H , dd , J=7.8 & 1.4Hz ) , 7.67 ( 1H , dd , J=7.8 & 0.5Hz ). 1 H-NMR (CDCl 3 ) δppm: 1.53 (3H, t, J = 6.8 Hz), 4.20 (2H, q, J = 6.8 Hz), 7.19−7.21 (1H, m), 7.30 (1H, dd, J = 7.8 & 1.4Hz), 7.67 (1H, dd, J = 7.8 & 0.5Hz).
（２）４−［５−（４−シアノ−３−エトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン (2) 4- [5- (4-Cyano-3-ethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）で得た２−エトキシテレフタロニトリルを用い、実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 2-ethoxyterephthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:1.45 ( 3H , t , J=6.9Hz ) , 4.33 ( 2H , q , J=6.9Hz ) , 7.79 ( 1H , d , J=7.8Hz ) , 7.86 ( 1H , s ) , 7.90-8.01 ( 1H , m ) , 8.22 ( 1H , dd , J=5.4 & 2.4Hz ) , 9.34-9.47 ( 1H , m ) , 9.80-9.85 ( 1H , m ).
MS m/z : 291 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 1.45 (3H, t, J = 6.9 Hz), 4.33 (2H, q, J = 6.9 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.86 ( 1H, s), 7.90-8.01 (1H, m), 8.22 (1H, dd, J = 5.4 & 2.4 Hz), 9.34-9.47 (1H, m), 9.80-9.85 (1H, m).
MS m / z: 291 [M−H] − .
実施例３７ ４−［５−（４−シアノ−３−トリフルオロメトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 37 4- [5- (4-Cyano-3-trifluoromethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine
２−トリフルオロメトキシテレフタロニトリル（アヅマックス社）を用い、実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 2-trifluoromethoxyterephthalonitrile (Amax Co.).
1H−NMR(DMSO‐d6)δppm:8.23 ( 1H , dd , J=5.4 & 2.4Hz ) , 8.25-8.31 ( 3H , m ) , 9.44 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.83 ( 1H , dd , J=2.4 & 1.4Hz ).
MS m/z : 331 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 8.23 (1H, dd, J = 5.4 & 2.4 Hz), 8.25-8.31 (3H, m), 9.44 (1H, dd, J = 5.4 & 1.4 Hz), 9.83 (1H, dd, J = 2.4 & 1.4Hz).
MS m / z: 331 [M−H] − .
実施例３８ ４−［５−（３−シアノ−４−メチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 38 4- [5- (3-Cyano-4-methylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）４−メチルスルファニルイソフタロニトリル (1) 4-methylsulfanylisophthalonitrile
４−フルオロイソフタロニトリル（５００ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、ナトリウムチオメトキシド（３１２ｍｇ）を加え、アルゴン置換下室温で終夜撹拌した。反応終了後、水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させた。溶媒を留去し、目的物（５２０ｍｇ）を得た。 4-Fluoroisophthalonitrile (500 mg) was dissolved in DMF (15 mL), sodium thiomethoxide (312 mg) was added, and the mixture was stirred overnight at room temperature under argon substitution. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the desired product (520 mg).
1H−NMR(CDCl3)δppm:2.62 ( 3H , s ) , 7.35 ( 1H , d , J=8.4Hz ) , 7.76 ( 1H , d , J=8.4Hz ) , 7.84 ( 1H , s ). 1 H-NMR (CDCl 3 ) δ ppm: 2.62 (3H, s), 7.35 (1H, d, J = 8.4 Hz), 7.76 (1H, d, J = 8.4 Hz), 7.84 (1H, s).
（２）４−［５−（３−シアノ−４−メチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン (2) 4- [5- (3-Cyano-4-methylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）で得た４−メチルスルファニルイソフタロニトリルを用いて実施例１６と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 16 using 4-methylsulfanylisophthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:2.68 ( 3H , s ) , 7.69 ( 1H , d , J=8.4Hz ) , 8.25 ( 1H , dd , J=5.4 & 2.2Hz ) , 8.33 ( 1H , dd, J=8.4 & 1.9Hz ) , 8.42 ( 1H , d , J=1.9Hz ) , 9.42 ( 1H , dd , J=5.4 & 1.6Hz ) , 9.84 ( 1H , dd , J=2.2 & 1.6Hz ).
MS m/z : 293 [M−H]−.
1 H-NMR (DMSO-d 6 ) δ ppm: 2.68 (3H, s), 7.69 (1H, d, J = 8.4 Hz), 8.25 (1H, dd, J = 5.4 & 2.2 Hz), 8.33 (1H, dd , J = 8.4 & 1.9Hz), 8.42 (1H, d, J = 1.9Hz), 9.42 (1H, dd, J = 5.4 & 1.6Hz), 9.84 (1H, dd, J = 2.2 & 1.6Hz).
MS m / z: 293 [M−H] − .
実施例３９ ４−［５−（３−シアノ−４−エチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン Example 39 4- [5- (3-Cyano-4-ethylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）４−エチルスルファニルイソフタロニトリルの合成 (1) Synthesis of 4-ethylsulfanylisophthalonitrile
ナトリウムエタンチオレ−トを用いて、実施例３８（１）と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 38 (1) using sodium ethanethiolate.
1H−NMR(CDCl3)δppm:1.44 ( 3H , t , J=7.6Hz ) , 3.12 ( 2H , q , J=7.6Hz ) , 7.39 ( 1H , d , J=8.6Hz ) , 7.73 ( 1H , dd , J=8.6 & 1.9Hz ) , 7.84 ( 1H , d , J=1.9Hz ). 1 H-NMR (CDCl 3 ) δppm: 1.44 (3H, t, J = 7.6 Hz), 3.12 (2H, q, J = 7.6 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.73 (1H, dd, J = 8.6 & 1.9Hz), 7.84 (1H, d, J = 1.9Hz).
（２）４−［５−（３−シアノ−４−エチルスルファニルフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン (2) 4- [5- (3-Cyano-4-ethylsulfanylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）で得た４−エチルスルファニルイソフタロニトリルを用いて実施例１６と同様にして目的化合物を得た。 The target compound was obtained in the same manner as in Example 16 using 4-ethylsulfanylisophthalonitrile obtained in (1).
1H−NMR(DMSO‐d6)δppm:1.34 ( 3H , t , J=7.3Hz ) , 3.23 ( 2H , q , J=7.3Hz ) , 7.77 ( 1H , d , J=8.4Hz ) , 8.24 ( 1H , dd , J=5.4 & 2.2Hz ) , 8.32 ( 1H , dd, J=8.4 & 1.9Hz ) , 8.44 ( 1H , d , J=1.9Hz ) , 9.42 ( 1H , dd , J=5.4 & 1.4Hz ) , 9.83 ( 1H , dd , J=2.2 & 1.4Hz ).
MS m/z : 307 [M−H]−.
1 H-NMR (DMSO-d 6 ) δppm: 1.34 (3H, t, J = 7.3 Hz), 3.23 (2H, q, J = 7.3 Hz), 7.77 (1H, d, J = 8.4 Hz), 8.24 ( 1H, dd, J = 5.4 & 2.2 Hz), 8.32 (1H, dd, J = 8.4 & 1.9 Hz), 8.44 (1H, d, J = 1.9 Hz), 9.42 (1H, dd, J = 5.4 & 1.4 Hz ), 9.83 (1H, dd, J = 2.2 & 1.4Hz).
MS m / z: 307 [M−H] − .
実施例４０ ４−[５−（３，５−ジブロモ−４−ヒドロキシフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン ｐ−トルエンスルホン酸塩 Example 40 4- [5- (3,5-Dibromo-4-hydroxyphenyl) -1,2,4-triazol-3-yl] pyridazine p-toluenesulfonate
炭酸カリウム（１．１ｇ）のＤＭＦ（２０ｍＬ）溶液に、室温下3，5−ジブロモ−4−ヒドロキシベンゾニトリル（２．０ｇ）を加え、室温下攪拌した。続いてp-メトキシベンジルクロライド（１．０８ｇ）を加え、６０℃下一晩攪拌した。反応終了後、水を加え、析出した不溶物を濾取し、３，５−ジブロモ−4−（4−メトキシベンジルオキシ）ベンゾニトリル（２．３ｇ）を得た。３，５−ジブロモ−4−（4−メトキシベンジルオキシ）ベンゾニトリル７９４ｍｇのＭｅＯＨ／ＣＨＣｌ３（１／１、８ｍＬ）溶液に、ＮａＯＭｅ（５４ｍｇ）を加え、室温下攪拌した。続いてピリダジン-4-カルボン酸ヒドラジド（２００ｍｇ）を加え、加熱還流下一晩攪拌した。反応終了後、溶媒を留去し、残渣にＭｅＯＨを加え、析出した不溶物を濾取し、４−{５−[３，５−ジブロモ−４−（４−メトキシベンジル）フェニル]−１，２，４−トリアゾール−３−イル}ピリダジン（２５０ｍｇ）を得た。これをイソプロピルアルコール/テトラヒドロフラン溶液（１／１、１０ｍＬ）に溶かし、p-トルエンスルホン酸一水和物（４１０ｍｇ）を加え、加熱還流下一晩攪拌した。反応終了後、溶媒を留去し、残渣にクロロホルムを加え、析出した不溶物を濾取し、目的物（２２０ｍｇ）を得た。 To a solution of potassium carbonate (1.1 g) in DMF (20 mL) was added 3,5-dibromo-4-hydroxybenzonitrile (2.0 g) at room temperature, and the mixture was stirred at room temperature. Subsequently, p-methoxybenzyl chloride (1.08 g) was added, and the mixture was stirred at 60 ° C. overnight. After completion of the reaction, water was added, and the insoluble precipitate was collected by filtration to obtain 3,5-dibromo-4- (4-methoxybenzyloxy) benzonitrile (2.3 g). NaOMe (54 mg) was added to a solution of 794 mg of 3,5-dibromo-4- (4-methoxybenzyloxy) benzonitrile in MeOH / CHCl 3 (1/1, 8 mL), and the mixture was stirred at room temperature. Subsequently, pyridazine-4-carboxylic acid hydrazide (200 mg) was added, and the mixture was stirred overnight with heating under reflux. After completion of the reaction, the solvent was distilled off, MeOH was added to the residue, the precipitated insoluble matter was collected by filtration, and 4- {5- [3,5-dibromo-4- (4-methoxybenzyl) phenyl] -1, 2,4-Triazol-3-yl} pyridazine (250 mg) was obtained. This was dissolved in isopropyl alcohol / tetrahydrofuran solution (1/1, 10 mL), p-toluenesulfonic acid monohydrate (410 mg) was added, and the mixture was stirred overnight with heating under reflux. After completion of the reaction, the solvent was distilled off, chloroform was added to the residue, and the precipitated insoluble material was collected by filtration to obtain the desired product (220 mg).
1H−NMR(DMSO‐d6)δppm:7.12 ( 2H, d, J=8.1Hz ), 7.48 ( 2H, d, J=8.1Hz ), 8.26−8.31 ( 3H, m ), 9.41 ( 1H, d, J=5.4Hz ), 9.83 ( 1H, s ). 1 H-NMR (DMSO-d 6 ) δppm: 7.12 (2H, d, J = 8.1 Hz), 7.48 (2H, d, J = 8.1 Hz), 8.26-8.31 (3H, m), 9.41 (1H, d , J = 5.4Hz), 9.83 (1H, s).
実施例４１ ４−[５−（３−シアノ−４−メトキシカルボニルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 41 4- [5- (3-Cyano-4-methoxycarbonylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）４−[５−（３−ヨ−ド−４−メトキシカルボニルフェニル）−１，２，４−テトラゾ−ル−３−イル]ピリダジン (1) 4- [5- (3-Iodo-4-methoxycarbonylphenyl) -1,2,4-tetrazol-3-yl] pyridazine
４−シアノ−２−ヨード安息香酸メチルを用いて実施例１（２）と同様にして、目的物を得た。 The target product was obtained in the same manner as in Example 1 (2) using methyl 4-cyano-2-iodobenzoate.
1H−NMR(DMSO−d6) δ(ppm):3.90(3H, s), 7.92(1H, d, J=8.1Hz), 8.19−8.24(2H, m), 8.71(1H, d, J= 1.4Hz), 9.41(1H, dd, J=5.4 & 0.8Hz), 9.82(1H, dd, J=1.5 & 0.8Hz). 1 H-NMR (DMSO-d 6 ) δ (ppm): 3.90 (3H, s), 7.92 (1H, d, J = 8.1 Hz), 8.19-8.24 (2H, m), 8.71 (1H, d, J = 1.4Hz), 9.41 (1H, dd, J = 5.4 & 0.8Hz), 9.82 (1H, dd, J = 1.5 & 0.8Hz).
（２）４−[５−（３−シアノ−４−メトキシカルボニルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン (2) 4- [5- (3-Cyano-4-methoxycarbonylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）で得た４−[５−（３−ヨード−４−メトキシカルボニルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジンのDMF溶液（２ｍＬ）に、シアン化亜鉛(II)（０．０３ｇ）とテトラキストリフェニルホスフィンパラジウム（０．０２ｇ）を加え、外温８０℃−１１０℃で終夜撹拌した。反応終了後水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去し、残渣を薄層シリカゲルプレート(メルク社、１０５７４４、展開溶媒；ＣＨＣｌ３／ＭｅＯＨ＝１０／１)で分取し、目的物（０．０２ｇ）を得た。 To a DMF solution (2 mL) of 4- [5- (3-iodo-4-methoxycarbonylphenyl) -1,2,4-triazol-3-yl] pyridazine obtained in (1), zinc (II) cyanide was added. (0.03 g) and tetrakistriphenylphosphine palladium (0.02 g) were added, and the mixture was stirred overnight at an external temperature of 80 ° C. to 110 ° C. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was fractionated with a thin layer silica gel plate (Merck, 105744, developing solvent; CHCl 3 / MeOH = 10/1) to obtain the desired product (0.02 g).
1H−NMR(DMSO‐d6) δ(ppm):3.96(3H, s), 8.22(1H, dd, J=5.4 & 2.2Hz), 8.31(1H, d, J=8.4Hz), 8.50(1H, dd, J=8.4 & 1.6Hz), 8.60(1H, d, J=1.6Hz), 9.42(1H, dd, J=5.4 & 0.8Hz), 9.83(1H, dd, J=2.2 & 0.8Hz).
MS m/z : 307[M＋H]＋, 305 [M−H]−.
1 H-NMR (DMSO-d 6 ) δ (ppm): 3.96 (3H, s), 8.22 (1H, dd, J = 5.4 & 2.2 Hz), 8.31 (1H, d, J = 8.4 Hz), 8.50 ( 1H, dd, J = 8.4 & 1.6Hz), 8.60 (1H, d, J = 1.6Hz), 9.42 (1H, dd, J = 5.4 & 0.8Hz), 9.83 (1H, dd, J = 2.2 & 0.8Hz ).
MS m / z: 307 [M + H] + , 305 [M−H] − .
実施例４２ ４−[５−（３−シアノ−４−トリフルオロメチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 42 4- [5- (3-Cyano-4-trifluoromethylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）３−シアノ−４−トリフルオロメチルベンズイミン酸メチルエステル (1) 3-cyano-4-trifluoromethylbenziminic acid methyl ester
４−トリフルオロメチルイソフタロニトリル（１．７６ｇ）のメタノ−ル溶液（１８ｍＬ）にナトリウムメトキシド（０．２４ｇ）を加え室温で５０分間撹拌した。反応終了後水を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を留去し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）で精製し、目的物（１．４８ｇ）を得た。 Sodium methoxide (0.24 g) was added to a methanol solution (18 mL) of 4-trifluoromethylisophthalonitrile (1.76 g), and the mixture was stirred at room temperature for 50 minutes. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain the desired product (1.48 g).
1H−NMR(CD3OD) δ(ppm):3.95(3H, s), 8.01(1H, d, J=8.5Hz), 8.27(1H, d, J=8.5Hz), 8.44(1H, s). 1 H-NMR (CD 3 OD) δ (ppm): 3.95 (3H, s), 8.01 (1H, d, J = 8.5Hz), 8.27 (1H, d, J = 8.5Hz), 8.44 (1H, s ).
（２）４−[５−（3−シアノ−４−トリフルオロメチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン (2) 4- [5- (3-Cyano-4-trifluoromethylphenyl) -1,2,4-triazol-3-yl] pyridazine
（１）で得た３−シアノ−４−トリフルオロメチルベンズイミン酸メチルエステル（１．４８ｇ）の２−ブタノール溶液（１５ｍＬ）に、ピリダジン−４−カルボン酸ヒドラジド（０．９０ｇ）を加え、外温１００℃で終夜撹拌した。析出した結晶を濾取し、ＭｅＯＨで洗浄後、減圧乾燥により、目的物（１．３２ｇ）を得た。 Pyridazine-4-carboxylic acid hydrazide (0.90 g) was added to a 2-butanol solution (15 mL) of 3-cyano-4-trifluoromethylbenziminic acid methyl ester (1.48 g) obtained in (1), The mixture was stirred overnight at an external temperature of 100 ° C. The precipitated crystals were collected by filtration, washed with MeOH, and then dried under reduced pressure to obtain the desired product (1.32 g).
1H−NMR(DMSO‐d6) δ(ppm):8.18-8.24(2H, m), 8.55(1H, dd, J=8.24 & 0.81Hz), 8.71(1H, br s), 9.43(1H, dd, J=5.3 & 1.4Hz), 9.82(1H, dd, J=2.4, 1.4Hz).
MS m/z : 317 [M＋H]＋, 315 [M−H]−.
1 H-NMR (DMSO-d 6 ) δ (ppm): 8.18-8.24 (2H, m), 8.55 (1H, dd, J = 8.24 & 0.81Hz), 8.71 (1H, br s), 9.43 (1H, dd, J = 5.3 & 1.4Hz), 9.82 (1H, dd, J = 2.4, 1.4Hz).
MS m / z: 317 [M + H] + , 315 [M−H] − .
実施例４３ ４−[５−（４−ブロモ−３−シアノフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 43 4- [5- (4-Bromo-3-cyanophenyl) -1,2,4-triazol-3-yl] pyridazine
４−ブロモイソフタロニトリルを用いて実施例４２と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 42 using 4-bromoisophthalonitrile.
1H−NMR(DMSO−d6) δ(ppm):8.11(1H, d, J=8.5Hz), 8.20(1H, dd, J=5.3 & 2.2Hz), 8.29(1H, dd, J=8.5 & 1.9Hz), 8.53(1H, d, J=1.9Hz), 9.42(1H, dd, J=5.3 & 1.1Hz), 9.82(1H, dd, J=2.2 & 1.1Hz). MS m/z : 327 [M＋H]＋, 329 [(M＋2)＋ H]＋, 325 [M−H]−, 327 [(M＋2)−H]−. 1 H-NMR (DMSO-d 6 ) δ (ppm): 8.11 (1H, d, J = 8.5 Hz), 8.20 (1H, dd, J = 5.3 & 2.2 Hz), 8.29 (1H, dd, J = 8.5 & 1.9Hz), 8.53 (1H, d, J = 1.9Hz), 9.42 (1H, dd, J = 5.3 & 1.1Hz), 9.82 (1H, dd, J = 2.2 & 1.1Hz) .MS m / z: 327 [M + H] + , 329 [(M + 2) + H] + , 325 [M−H] − , 327 [(M + 2) −H] − .
実施例４４ ４−[５−（３，４−ジシアノフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 44 4- [5- (3,4-Dicyanophenyl) -1,2,4-triazol-3-yl] pyridazine
ベンゼン−１，２，４−トリカルボニトリルを用いて実施例４２と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 42 using benzene-1,2,4-tricarbonitrile.
1H−NMR(DMSO−d6) δ(ppm):8.20(1H, dd, J=5.4 & 2.4Hz), 8.32(1H, d, J=8.4Hz), 8.52(1H, dd, J=8.4 & 1.6Hz), 8.69(1H, d, J=1.6Hz), 9.43(1H, dd, J=5.4 & 1.4Hz), 9.82(1H, dd, J=2.4 & 1.4Hz). MS m/z : 274 [M+H]＋, 272 [M−H]−. 1 H-NMR (DMSO-d 6 ) δ (ppm): 8.20 (1H, dd, J = 5.4 & 2.4 Hz), 8.32 (1H, d, J = 8.4 Hz), 8.52 (1H, dd, J = 8.4 & 1.6Hz), 8.69 (1H, d, J = 1.6Hz), 9.43 (1H, dd, J = 5.4 & 1.4Hz), 9.82 (1H, dd, J = 2.4 & 1.4Hz) .MS m / z: 274 [M + H] + , 272 [M−H] − .
実施例４５ ４−[５−（４−シアノ−３−トリフルオロメチルフェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 45 4- [5- (4-Cyano-3-trifluoromethylphenyl) -1,2,4-triazol-3-yl] pyridazine
３−トリフルオロメチルテレフタロニトリルを用いて実施例４２と同様にして目的物を得た。 The target product was obtained in the same manner as in Example 42 using 3-trifluoromethylterephthalonitrile.
1H−NMR(DMSO−d6) δ(ppm):8.22(1H, dd, J=5.3 & 2.2Hz), 8.37(1H, d, J=8.4Hz), 8.53(1H, d, J=8.4Hz), 8.57(1H, s), 9.43(1H, dd, J=5.3 & 1.4Hz), 9.82(1H, dd, J=2.2 & 1.4Hz).
MS m/z : 317 [M＋H]＋, 315 [M−H]−.
1 H-NMR (DMSO-d 6 ) δ (ppm): 8.22 (1H, dd, J = 5.3 & 2.2 Hz), 8.37 (1H, d, J = 8.4 Hz), 8.53 (1H, d, J = 8.4 Hz), 8.57 (1H, s), 9.43 (1H, dd, J = 5.3 & 1.4Hz), 9.82 (1H, dd, J = 2.2 & 1.4Hz).
MS m / z: 317 [M + H] + , 315 [M−H] − .
実施例４６ ４−{５−[３−シアノ−４−（N−アセチルエチルアミノ）フェニル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 46 4- {5- [3-Cyano-4- (N-acetylethylamino) phenyl) -1,2,4-triazol-3-yl] pyridazine
（１）３−ブロモ−４−エチルアミノ安息香酸メチルエステル (1) 3-bromo-4-ethylaminobenzoic acid methyl ester
３−ブロモ−４−アセチルアミノ安息香酸メチルエステル（１．２０ｇ）テトラヒドロフラン溶液（１２ｍＬ）に、氷冷下、1Mボラン・テトラヒドロフラン錯体テトラヒドロフラン溶液（９．７ｍＬ）を加え、滴下後室温で撹拌した。反応終了後水を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。溶媒を留去し、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／１）より精製し、目的物（０．６１ｇ）を得た。 To a solution of 3-bromo-4-acetylaminobenzoic acid methyl ester (1.20 g) in tetrahydrofuran (12 mL) was added 1M borane / tetrahydrofuran complex tetrahydrofuran solution (9.7 mL) under ice cooling, and the mixture was added dropwise and stirred at room temperature. After completion of the reaction, water was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain the desired product (0.61 g).
1H−NMR(CDCl3) δ(ppm):1.33(3H, t, J=7.29Hz), 3.27(2H, dq, J=7.29 & 5.13Hz), 3.86(3H, s), 4.70(1H, brs), 6.58(1H, d, J=8.91Hz), 7.86(1H, dd, J=8.91 & 2.16Hz), 8.11(1H, d, J=2.16Hz). 1 H-NMR (CDCl 3 ) δ (ppm): 1.33 (3H, t, J = 7.29Hz), 3.27 (2H, dq, J = 7.29 & 5.13Hz), 3.86 (3H, s), 4.70 (1H, brs), 6.58 (1H, d, J = 8.91Hz), 7.86 (1H, dd, J = 8.91 & 2.16Hz), 8.11 (1H, d, J = 2.16Hz).
（２） ３−シアノ−４−（N−アセチルエチルアミノ）安息香酸メチルエステル (2) 3-cyano-4- (N-acetylethylamino) benzoic acid methyl ester
（１）で得た３−ブロモ−４−エチルアミノ安息香酸メチルエステル（０．８６ｇ）のピリジン溶液に無水酢酸（３．８３ｍＬ）加え、外温８０℃〜１１０℃で終夜撹拌した。反応終了後１N塩酸水溶液を加え、酢酸エチルで抽出し、有機層を１N塩酸水溶液で洗浄で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）より精製し、３−ブロモ−４−（N−アセチルエチルアミノ）安息香酸メチルエステル（０．７２ｇ）を得た。これをＤＭＦ（７．２ｍＬ）に溶解し、テトラキストリフェニルホスフィンパラジウム錯体（０．３３ｇ）、シアン化亜鉛（０．２０ｇ）を加え、外温１００℃で１日撹拌した。反応終了後飽和炭酸水素ナトリウム水溶液を加え、減圧濾過した。濾液を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥した。溶媒を留去し、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）より精製し、目的物（０．２６ｇ）を得た。 Acetic anhydride (3.83 mL) was added to a pyridine solution of 3-bromo-4-ethylaminobenzoic acid methyl ester (0.86 g) obtained in (1), and the mixture was stirred at an external temperature of 80 ° C. to 110 ° C. overnight. After completion of the reaction, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to give 3-bromo-4- (N-acetylethylamino) benzoic acid methyl ester (0.72 g). Obtained. This was dissolved in DMF (7.2 mL), tetrakistriphenylphosphine palladium complex (0.33 g) and zinc cyanide (0.20 g) were added, and the mixture was stirred at an external temperature of 100 ° C. for 1 day. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was filtered under reduced pressure. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain the desired product (0.26 g).
1H−NMR(CDCl3) δ(ppm):1.16(3H, t, J=6.8Hz), 1.87 & 2.35(3H, s), 3.85(2H, brq), 3.99(3H, s), 7.41(1H, d, J=8.4Hz), 8.33(1H, d, J=8.4Hz), 8.43(1H, s). 1 H-NMR (CDCl 3 ) δ (ppm): 1.16 (3H, t, J = 6.8Hz), 1.87 & 2.35 (3H, s), 3.85 (2H, brq), 3.99 (3H, s), 7.41 ( 1H, d, J = 8.4Hz), 8.33 (1H, d, J = 8.4Hz), 8.43 (1H, s).
（３）３−シアノ−４−（N−アセチルエチルアミノ）フェニルヒドラジド (3) 3-cyano-4- (N-acetylethylamino) phenylhydrazide
（２）で得た３−シアノ−４−（N−アセチルエチルアミノ）安息香酸メチルエステル（０．２６ｇ）のメタノ−ル溶液（２．６ｍL）に、無水ヒドラジン（０．３０ｍL）を加え、室温で３時間撹拌した。反応終了後溶媒を留去し、目的物（０．２４ｇ）を得た。 Anhydrous hydrazine (0.30 mL) was added to a methanol solution (2.6 mL) of 3-cyano-4- (N-acetylethylamino) benzoic acid methyl ester (0.26 g) obtained in (2), Stir at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off to obtain the desired product (0.24 g).
1H−NMR(CDCl3) δ(ppm):1.15(3H, t, J=6.5Hz), 1.87 & 2.39(3H, s), 3.66-3.96(2H, m), 7.43(1H, d, J=7.6Hz), 8.13(1H, d, J=7.6Hz), 8.24(1H, s). 1 H-NMR (CDCl 3 ) δ (ppm): 1.15 (3H, t, J = 6.5 Hz), 1.87 & 2.39 (3H, s), 3.66-3.96 (2H, m), 7.43 (1H, d, J = 7.6Hz), 8.13 (1H, d, J = 7.6Hz), 8.24 (1H, s).
（４） N−{２−シアノ−４−[N'−(イミノピリダジン−４−イルメチル)ヒドラジノカルボニル]フェニル}−N−エチルアセトアミド (4) N- {2-cyano-4- [N '-(iminopyridazin-4-ylmethyl) hydrazinocarbonyl] phenyl} -N-ethylacetamide
４−シアノピリダジン（０．２０ｇ）メタノ−ル溶液にＮａＯＭｅ（０．０５ｇ）を加え、室温で２時間撹拌した。反応終了後水を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。溶媒を留去し、イミデ−ト（０．２４ｇ）を得た。その内の０．１５ｇをメタノ−ル（２４ｍＬ）に溶かし、（３）で得た３−シアノ−４−（N−アセチルエチルアミノ）フェニル−４−ヒドラジド（０．２４ｇ）加え、終夜還流撹拌後、２−ブタノ−ルを加え、外温１１５℃で終夜撹拌した。析出した結晶を濾取し、目的物（０．１２ｇ）を得た。 To the 4-cyanopyridazine (0.20 g) methanol solution was added NaOMe (0.05 g), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain an imidate (0.24 g). 0.15 g of this was dissolved in methanol (24 mL), 3-cyano-4- (N-acetylethylamino) phenyl-4-hydrazide (0.24 g) obtained in (3) was added, and the mixture was stirred at reflux overnight. Thereafter, 2-butanol was added and stirred overnight at an external temperature of 115 ° C. The precipitated crystals were collected by filtration to obtain the desired product (0.12 g).
1H−NMR(DMSO−d6) δ(ppm):1.05(3H, t, J=7.0Hz), 1.78 & 2.28(3H, s), 3.60-3.90(2H, m), 7.19(2H, s), 7.77(1H, d, J=7.8Hz), 8.03(1H, dd, J=5.4 & 2.2Hz), 8.28(1H, d, J= 7.8Hz), 8.52(1H, s), 9.37(1H, d, J=5.4Hz), 9.63(1H, s), 10.48(1H, s). 1 H-NMR (DMSO-d 6 ) δ (ppm): 1.05 (3H, t, J = 7.0 Hz), 1.78 & 2.28 (3H, s), 3.60-3.90 (2H, m), 7.19 (2H, s ), 7.77 (1H, d, J = 7.8Hz), 8.03 (1H, dd, J = 5.4 & 2.2Hz), 8.28 (1H, d, J = 7.8Hz), 8.52 (1H, s), 9.37 (1H , d, J = 5.4Hz), 9.63 (1H, s), 10.48 (1H, s).
（５）４−｛５−［３−シアノ−４−（N−アセチルエチルアミノ）フェニル］−１，２，４−トリアゾール−３−イル｝ピリダジン (5) 4- {5- [3-Cyano-4- (N-acetylethylamino) phenyl] -1,2,4-triazol-3-yl} pyridazine
（４）で得たN−{２−シアノ−４−[N'−(イミノピリダジン−４−イルメチル)ヒドラジノカルボニル]フェニル}−N−エチルアセトアミドの２−ブタノール溶液を５日間還流撹拌した後、室温とし、析出した結晶を濾取し、目的物（０．０８ｇ）を得た。 After the 2-butanol solution of N- {2-cyano-4- [N ′-(iminopyridazin-4-ylmethyl) hydrazinocarbonyl] phenyl} -N-ethylacetamide obtained in (4) was stirred at reflux for 5 days The resulting crystals were collected by filtration to obtain the desired product (0.08 g).
1H−NMR(DMSO−d6) δ(ppm):1.07(3H, t, J=6.75Hz), 1.81 & 2.28(3H, s), 3.60-3.90(2H, m), 7.84(1H, d, J=8.37Hz), 8.22(1H, dd, J=5.40 & 1.89Hz), 8.47(1H, d, J=8.37Hz), 8.60(1H, s), 9.43(1H, d, J=5.40Hz), 9.83(1H, br s).
MS m/z : 334 [M+H]＋, 332 [M−H]−.
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.07 (3H, t, J = 6.75Hz), 1.81 & 2.28 (3H, s), 3.60-3.90 (2H, m), 7.84 (1H, d , J = 8.37Hz), 8.22 (1H, dd, J = 5.40 & 1.89Hz), 8.47 (1H, d, J = 8.37Hz), 8.60 (1H, s), 9.43 (1H, d, J = 5.40Hz ), 9.83 (1H, br s).
MS m / z: 334 [M + H] + , 332 [M−H] − .
実施例４７ ４−[５−（２−シアノピリジン−４−イル）−１，２，４−トリアゾール−３−イル]ピリダジン Example 47 4- [5- (2-Cyanopyridin-4-yl) -1,2,4-triazol-3-yl] pyridazine
４−シアノピリダジン（５７０ｍｇ）のＭｅＯＨ溶液（１４．５ｍＬ）にＮａＯＭｅ（４４０ｍｇ）を加え、室温下1時間攪拌した。これに２−シアノイソニコチン酸ヒドラジド・３／２p−トルエンスルホン酸塩（２．２８ｇ）を加え、加熱還流下１７時間攪拌した。析出した結晶を濾取した後、ＭｅＯＨで洗浄し、２−シアノイソニコチン酸N’−（イミノ−ピリダジン−４−イル−メチル）ヒドラジド（７２０ｍｇ）を得た。これをＤＭＦ（１１ｍＬ）に溶かし、１４０℃下１８時間攪拌した。続いて室温にまで冷却し、ＭｅＯＨ（１１ｍＬ）を加え、１時間攪拌した。析出した不溶物を濾取し、ＭｅＯＨで洗浄後、目的物（３７０ｍｇ）を得た。 NaOMe (440 mg) was added to a MeOH solution (14.5 mL) of 4-cyanopyridazine (570 mg), and the mixture was stirred at room temperature for 1 hour. To this was added 2-cyanoisonicotinic acid hydrazide.3 / 2p-toluenesulfonate (2.28 g), and the mixture was stirred for 17 hours while heating under reflux. The precipitated crystals were collected by filtration and washed with MeOH to obtain 2-cyanoisonicotinic acid N ′-(imino-pyridazin-4-yl-methyl) hydrazide (720 mg). This was dissolved in DMF (11 mL) and stirred at 140 ° C. for 18 hours. Subsequently, the mixture was cooled to room temperature, MeOH (11 mL) was added, and the mixture was stirred for 1 hour. The precipitated insoluble material was collected by filtration and washed with MeOH to obtain the desired product (370 mg).
1H−NMR(DMSO−d6)δppm:8.22 ( 1H, dd, J=5.4 & 2.3Hz ) , 8.32 ( 1H, dd, J=5.1 & 1.7Hz ) , 8.56 ( 1H, dd, J=1.7 & 0.8Hz ) , 8.95 ( 1H, dd, J=5.1 & 0.8Hz ) , 9.46 ( 1H, dd, J=5.4 & 1.3Hz ) , 9.83 ( 1H, dd, J=2.3 & 1.3Hz ). 1 H-NMR (DMSO-d 6 ) δppm: 8.22 (1H, dd, J = 5.4 & 2.3 Hz), 8.32 (1H, dd, J = 5.1 & 1.7 Hz), 8.56 (1H, dd, J = 1.7 & 0.8Hz), 8.95 (1H, dd, J = 5.1 & 0.8Hz), 9.46 (1H, dd, J = 5.4 & 1.3Hz), 9.83 (1H, dd, J = 2.3 & 1.3Hz).
実施例４８ ４−［５−（３−シアノ−４−トリフルオロメトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジンナトリウム塩 Example 48 4- [5- (3-Cyano-4-trifluoromethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine sodium salt
実施例３２の化合物（１００ｍｇ）にエタノール（１５ｍL）を加え、６０℃に加温し溶解させた。この溶液に炭酸水素ナトリウム（２５．３ｍｇ）の水溶液（５ｍL）を加え、室温とした後、溶媒を減圧留去し、目的物（１０６ｍｇ）を得た。 Ethanol (15 mL) was added to the compound of Example 32 (100 mg) and heated to 60 ° C. to dissolve. To this solution was added an aqueous solution (5 mL) of sodium hydrogen carbonate (25.3 mg), and the mixture was brought to room temperature, and the solvent was evaporated under reduced pressure to obtain the desired product (106 mg).
1H−NMR(DMSO-ｄ６)δppm:7.68 (1H, dq, J=9.5 & 1.4Hz), 8.01 (1H, dd, J=5.4 & 2.2Hz), 8.42-8.49 (2H, m), 9.10 (1H, dd, J =5.4 & 1.4Hz), 9.74 (1H, dd, J =2.2 & 1.4Hz). 1 H-NMR (DMSO-d 6 ) δ ppm: 7.68 (1H, dq, J = 9.5 & 1.4 Hz), 8.01 (1H, dd, J = 5.4 & 2.2 Hz), 8.42-8.49 (2H, m), 9.10 (1H, dd, J = 5.4 & 1.4Hz), 9.74 (1H, dd, J = 2.2 & 1.4Hz).
実施例４９ ４−［５−（３−シアノ−４−トリフルオロメトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジン塩酸塩 Example 49 4- [5- (3-Cyano-4-trifluoromethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine hydrochloride
実施例３２の化合物（１００ｍｇ）にエタノール（２５ｍL）を加え、６０℃に加温し溶解させた。この溶液に１．０mol/L塩酸を（０．３ｍL）加え、室温とした後、溶媒を減圧留去し、目的物（１１０ｍｇ）を得た。 Ethanol (25 mL) was added to the compound of Example 32 (100 mg) and heated to 60 ° C. to dissolve. 1.0 mol / L hydrochloric acid (0.3 mL) was added to this solution to bring it to room temperature, and then the solvent was distilled off under reduced pressure to obtain the desired product (110 mg).
1H−NMR(DMSO-ｄ６)δppm:7.89-7.97 (1H, m), 8.28 (1H, dd, J=5.7 & 2.4Hz), 8.55 (1H, dd, J =8.9 & 1.9Hz), 8.69 (1H, d, J =1.9Hz), 9.45 (1H, dd, J =5.7 & 1.4Hz), 9.86 (1H, dd, J =2.4 & 1.4Hz). 1 H-NMR (DMSO-d 6 ) δ ppm: 7.89-7.97 (1H, m), 8.28 (1H, dd, J = 5.7 & 2.4 Hz), 8.55 (1H, dd, J = 8.9 & 1.9 Hz), 8.69 (1H, d, J = 1.9Hz), 9.45 (1H, dd, J = 5.7 & 1.4Hz), 9.86 (1H, dd, J = 2.4 & 1.4Hz).
実施例５０ ４−［５−（３−シアノ−４−トリフルオロメトキシフェニル）−１，２，４−トリアゾール−３−イル］ピリダジンメグルミン塩 Example 50 4- [5- (3-Cyano-4-trifluoromethoxyphenyl) -1,2,4-triazol-3-yl] pyridazine meglumine salt
実施例３２の化合物（１００ｍｇ）にエタノール（２５ｍＬ）を加え、６０℃に加温し溶解させた。この溶液にメグルミン（５８．８ｍｇ）を加え、室温とした後、溶媒を減圧留去し、目的物（１５８ｍｇ）を得た。 Ethanol (25 mL) was added to the compound of Example 32 (100 mg), and the mixture was heated to 60 ° C. and dissolved. Meglumine (58.8 mg) was added to this solution, and the mixture was brought to room temperature, and the solvent was evaporated under reduced pressure to obtain the desired product (158 mg).
1H−NMR(CD3OD)δppm:2.67 (3H, s), 3.11 (2H, d, J =6.2Hz), 3.60-3.85 (5H, m), 4.01 (1H, q, J =5.9Hz), 7.61-7.69 (1H , m) , 8.26 (1H , dd , J=5.4 & 2.4Hz), 8.47 (1H, dd, J =8.9 & 2.2Hz), 8.51 (1H, d, J =2.2Hz), 9.21 (1H, d, J =5.4Hz), 9.85 (1H, d, J =2.4Hz). 1 H-NMR (CD 3 OD) δppm: 2.67 (3H, s), 3.11 (2H, d, J = 6.2Hz), 3.60-3.85 (5H, m), 4.01 (1H, q, J = 5.9Hz) , 7.61-7.69 (1H, m), 8.26 (1H, dd, J = 5.4 & 2.4Hz), 8.47 (1H, dd, J = 8.9 & 2.2Hz), 8.51 (1H, d, J = 2.2Hz), 9.21 (1H, d, J = 5.4Hz), 9.85 (1H, d, J = 2.4Hz).
各実施例の構造式を下記に示す。
処方例１（錠剤）
実施例３２ １０．０ｍｇ
乳糖 ６３．２ｍｇ（又は適量）
トウモロコシデンプン ２４．０ｍｇ
結晶セルロース １８．０ｍｇ
ヒドロキシプロピルセルロース ３．６ｍｇ
ステアリン酸マグネシウム １．２ｍｇ
合 計 １２０．０ｍｇ
Formulation Example 1 (tablet)
Example 32 10.0 mg
Lactose 63.2mg (or appropriate amount)
Corn starch 24.0mg
Crystalline cellulose 18.0mg
Hydroxypropylcellulose 3.6mg
Magnesium stearate 1.2mg
Total 120.0mg
上記成分を処方の比に量り、湿式造粒法により打錠用粉末を製する。この粉末を1錠中実施例３２を１０ｍｇ含有するように打錠し、錠剤を得た。 The above ingredients are weighed to the prescription ratio, and a tableting powder is produced by a wet granulation method. This powder was tableted so as to contain 10 mg of Example 32 in 1 tablet to obtain a tablet.
処方例２（注射剤）
実施例３２ １．０ｍｇ
塩酸 適量
水酸化ナトリウム 適量
塩化ナトリウム ４５．０ｍｇ
注射用水
合 計 １ｍｇ／５ｍｌ
Formulation Example 2 (Injection)
Example 32 1.0 mg
Hydrochloric acid Suitable amount Sodium hydroxide Suitable amount Sodium chloride 45.0mg
Water for injection
Total 1mg / 5ml
実施例３２を注射用水及び塩酸を加えて溶かし、水酸化ナトリウムでｐH調製し、等張化剤として塩化ナトリウムを加えて５ｍL中実施例３２を１ｍｇ含有するように調製し、注射剤を得た。 Example 32 was dissolved by adding water for injection and hydrochloric acid, adjusted to pH with sodium hydroxide, and sodium chloride was added as an isotonic agent to prepare 1 mg of Example 32 in 5 mL to obtain an injection. .
試験例１［キサンチンオキシダーゼ阻害作用の測定法］ Test Example 1 [Measurement method of xanthine oxidase inhibitory action]
ウシミルクキサンチンオキシダーゼを５０ｍＭリン酸緩衝液（ｐＨ７．４）中で１５μＭキサンチンとともに２５℃でインキュベートした。反応開始直後から２９２ｎｍにおける吸光度を１５０秒間測定し、吸光度の変化量を反応の指標とした。キサンチンオキシダーゼ活性の阻害率は下記の式より算出し、プロビット法により５０％阻害濃度（ＩＣ５０）を求めた。 Bovine milk xanthine oxidase was incubated at 25 ° C. with 15 μM xanthine in 50 mM phosphate buffer (pH 7.4). Immediately after the start of the reaction, the absorbance at 292 nm was measured for 150 seconds, and the amount of change in absorbance was used as an indicator of the reaction. The inhibition rate of xanthine oxidase activity was calculated from the following formula, and the 50% inhibitory concentration (IC 50 ) was determined by the probit method.
阻害率（％）＝(１−被験物質添加時の吸光度変化量／溶媒（ジメチルスルフォキシド）添加時の吸光度変化量)×１００ Inhibition rate (%) = (1−Amount of change in absorbance when test substance is added / Amount of change in absorbance when solvent (dimethyl sulfoxide) is added) × 100
試験例２ [血漿尿酸低下作用の測定法] Test Example 2 [Method for measuring plasma uric acid lowering effect]
１群３〜４匹の雄性ＩＣＲマウスに０．５％メチルセルロース溶液に懸濁した所定用量の被験物質を１ｍｇ／ｋｇの用量で経口投与し、２時間後にペントバルビタール(採血の１０分前に７５ｍｇ／ｋｇを腹腔内投与)による麻酔下でヘパリン処理したシリンジを用いて腹大動脈から全採血した。オキソネートカリウム２５０ｍｇ／ｋｇを採血の０．５時間前に皮下投与した。血液を遠心分離して血漿を得、血漿中尿酸濃度をリンタングステン酸法により測定し、血漿中尿酸濃度の低下率は下記の式より算出した。 A predetermined dose of the test substance suspended in 0.5% methylcellulose solution was orally administered to 3-4 male ICR mice per group at a dose of 1 mg / kg. Pentobarbital (75 mg 10 minutes before blood collection) Blood was collected from the abdominal aorta using a syringe that had been heparinized under anesthesia under the following conditions: Oxonate potassium 250 mg / kg was administered subcutaneously 0.5 hours before blood collection. The blood was centrifuged to obtain plasma, the plasma uric acid concentration was measured by the phosphotungstic acid method, and the decrease rate of the plasma uric acid concentration was calculated from the following equation.
低下率（％）＝(１−被験物質投与群の平均血漿中尿酸濃度／対照群の平均血漿中尿酸濃度)×１００ Decrease rate (%) = (1−average plasma uric acid concentration in test substance administration group / average plasma uric acid concentration in control group) × 100
比較例１：WO92/09279、 実施例７７
比較例２：WO98/18765、 実施例１２
比較例３：WO03/064410、実施例１２
比較例４：US4011218、 実施例１３
比較例５：Allopurinol
Comparative Example 1: WO92 / 09279, Example 77
Comparative Example 2: WO98 / 18765, Example 12
Comparative Example 3: WO03 / 064410, Example 12
Comparative Example 4: US4011218, Example 13
Comparative Example 5: Allopurinol
試験例１及び２から、例えば実施例１１の化合物の血漿尿酸低下率は83%と、比較例に比べ２倍以上の低下率を示していることがわかる。また他の実施例も比較例より高い効果を示している。このような効果は比較例からは全く予期できない高い効果である。 From Test Examples 1 and 2, it can be seen that, for example, the plasma uric acid reduction rate of the compound of Example 11 is 83%, which is 2 times or more that of the Comparative Example. Other examples also show higher effects than the comparative example. Such an effect is a high effect which is completely unexpected from the comparative example.
試験例3
［尿酸低下作用持続性の測定法］
7週齢の雄性ウィスター系ラット（1群4匹）に0.5％メチルセルロース溶液に懸濁した所定用量の被験物質を経口投与し、その2および12時間後にエーテルによる軽麻酔下で眼底採血した。オキソネートカリウム（250mg/kgを皮下投与）は被験物質投与1時間前に1回目を投与し、その後4時間ごとに3回投与した。血液は室温で1時間放置した後遠心分離して血清を得た。血清中尿酸濃度をリンタングステン酸法により測定した。血清中尿酸濃度の低下率は下記の式より算出し、プロビット法によりED50値（血清中尿酸濃度を50％低下させる用量）を求めた。
Test example 3
[Method for measuring duration of uric acid lowering effect]
A predetermined dose of the test substance suspended in 0.5% methylcellulose solution was orally administered to 7-week-old male Wistar rats (4 animals per group), and blood was collected under light anesthesia with ether 2 and 12 hours later. Potassium oxonate (250 mg / kg administered subcutaneously) was administered for the first time 1 hour before administration of the test substance, and then 3 times every 4 hours. The blood was left at room temperature for 1 hour and then centrifuged to obtain serum. Serum uric acid concentration was measured by the phosphotungstic acid method. The rate of decrease in serum uric acid concentration was calculated from the following formula, and the ED 50 value (dose that decreases serum uric acid concentration by 50%) was determined by the probit method.
数１
低下率＝（1-被験物質投与群の平均血清中尿酸濃度／対照群の平均血清中尿酸濃度）×１００（％）
Number 1
Decrease rate = (1−average serum uric acid concentration in test substance administration group / average serum uric acid concentration in control group) × 100 (%)
オキソネートカリウム高尿酸血症ラットにおける尿酸低下作用の持続性の比較（投与2および12時間後のED50値）
上記試験例３より、本願の実施例化合物の血漿尿酸低下作用は従来の化合物に比べはるかに持続性が高いことが示された。このような効果は比較例からは全く予期できない高い効果である。 From the above Test Example 3, it was shown that the plasma uric acid lowering action of the Example compound of the present application is much longer than that of the conventional compound. Such an effect is a high effect which is completely unexpected from the comparative example.
即ち、本発明である新規なピリダジン誘導体、又はその医薬上許容される塩、若しくはそれらの水和物は、in vitro試験においてキサンチンオキシダーゼに対し強い阻害活性を有し、又in vivo試験においても極めて強力で持続的な血漿尿酸低下作用を示すことより、高尿酸血症および痛風、活性酸素が関与するとされる炎症性疾患、うっ血性心不全、虚血‐再灌流障害、癌、神経疾患等の各種疾患の治療薬および／または予防薬として有用である。更に、本発明の化合物は顕著な作用の持続性を有しており、上記疾患における１日１回投与による治療が期待される。 That is, the novel pyridazine derivative of the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate thereof has a strong inhibitory activity against xanthine oxidase in an in vitro test, and is extremely effective in an in vivo test. Due to its strong and sustained plasma uric acid lowering action, various hyperuricemia and gout, inflammatory diseases in which active oxygen is involved, congestive heart failure, ischemia-reperfusion injury, cancer, neurological diseases, etc. It is useful as a therapeutic and / or prophylactic agent for diseases. Furthermore, the compound of the present invention has a remarkable long-lasting action and is expected to be treated once a day in the above diseases.
Claims (7)
ここでＲ１は、シアノ基、ニトロ基、ハロゲン原子若しくはトリフルオロメチル基を示す。Ｒ２およびＲ３は、独立して選ばれる各種置換基であり、ハロゲン原子、ニトロ基、シアノ基、ヒドロキシ基、低級アルキル基、低級環状アルキル基、ハロアルキル基、アルコキシアルキル基、低級アルキルカルボニル基、アリール基、アルキルカルボニル基、アリールカルボニル基、低級アルコキシカルボニル基、カルボキシ基、無置換あるいは置換された低級アルコキシ基、ハロアルコキシ基、低級環状アルコキシ基、低級アルキルスルファニル基、アミノ基、低級アルキル置換（モノ若しくはジ置換）アミノ基、低級アルキル置換（モノ若しくはジ置換）アミド基、低級アルキル基置換若しくは非置換ピペラジル基、モルホリル基を表す。 A pyridazine derivative represented by the following general formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
Here, R 1 represents a cyano group, a nitro group, a halogen atom or a trifluoromethyl group. R 2 and R 3 are various substituents independently selected, and are a halogen atom, nitro group, cyano group, hydroxy group, lower alkyl group, lower cyclic alkyl group, haloalkyl group, alkoxyalkyl group, lower alkylcarbonyl group. , Aryl group, alkylcarbonyl group, arylcarbonyl group, lower alkoxycarbonyl group, carboxy group, unsubstituted or substituted lower alkoxy group, haloalkoxy group, lower cyclic alkoxy group, lower alkylsulfanyl group, amino group, lower alkyl substituted (Mono- or di-substituted) represents an amino group, a lower alkyl-substituted (mono- or di-substituted) amide group, a lower alkyl group-substituted or unsubstituted piperazyl group, or a morpholyl group.
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