JP2010180183A

JP2010180183A - New compound having pyrimidin-4(3h)-one structure and medicine containing the same

Info

Publication number: JP2010180183A
Application number: JP2009026781A
Authority: JP
Inventors: Toru Miura; 徹三浦; Kazuhiro Onoki; 和弘小野木; Seiichi Sato; 精一佐藤; Ryohei Sekimoto; 亮平堰本; Tadaaki Ogiya; 忠明扇谷; Mitsuhiro Yoshimatsu; 三博吉松
Original assignee: Kowa Co Ltd
Current assignee: Kowa Co Ltd
Priority date: 2009-02-06
Filing date: 2009-02-06
Publication date: 2010-08-19

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound which has angiotensin II receptor antagonistic action and PPARγ activating action and is useful as a drug for preventing and/or treating hypertension, cardiac diseases, angina, cerebrovascular diseases, cerebral circulatory diseases, ischemic peripheral circulatory disorders, renal diseases, arteriosclerosis, inflammatory diseases, type 2 diabetes, etc. <P>SOLUTION: The compound is a pyrimidin-4(3H)-one derivative represented by formula (I), a salt thereof or a solvate thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

本発明は、アンジオテンシンII拮抗作用及びＰＰＡＲγ活性化作用を有する新規なピリミジン−４（３Ｈ）−オン構造を有する化合物及びこれを含有する医薬に関する。 The present invention relates to a compound having a novel pyrimidin-4 (3H) -one structure having an angiotensin II antagonistic action and PPARγ activating action, and a pharmaceutical containing the same.

近年、生活水準向上に伴うライフ・スタイルの変化、即ち、高カロリー、高コレステロール食の摂取、肥満、運動不足、高齢化等により、糖尿病、高血圧、脂質異常症、肥満等の、動脈硬化性疾患の危険因子となり得る疾患が急増している。これらの疾患は互いに独立した危険因子ではあるが、これらの重複により動脈硬化性疾患の、より高頻度の発症や重症化を引き起こすことが明らかにされてきた。そこで、複数の動脈硬化性疾患の危険因子を合併する病態をメタボリックシンドロームという概念でとらえ、その原因の解明と治療法の開発を目指した努力がなされている。 In recent years, lifestyle changes accompanying the improvement of living standards, ie, intake of high calorie, high cholesterol diet, obesity, lack of exercise, aging, etc., diabetes, hypertension, dyslipidemia, obesity, etc., arteriosclerotic diseases The number of diseases that can be risk factors is increasing rapidly. Although these diseases are independent risk factors, their duplication has been shown to cause more frequent onset and aggravation of arteriosclerotic diseases. Therefore, efforts are being made to understand the pathology that combines risk factors of multiple arteriosclerotic diseases with the concept of metabolic syndrome, and to elucidate the cause and develop treatments.

アンジオテンシンII（ＡII）は、レニン−アンジオテンシン系（ＲＡ系）により産生される内因性の昇圧物質として発見されたペプチドである。薬理学的なＡIIの作用抑制は、高血圧等の循環器系疾患の治療又は予防につながると考えられ、ＲＡ系の抑制薬として、アンジオテンシンI（ＡＩ）からＡIIへの変換酵素を阻害するAngiotensin Converting Enzyme（ＡＣＥ）阻害薬が臨床的に用いられている。また、その後経口投与可能なＡII受容体拮抗剤（Angiotensin Receptor Blocker：ＡＲＢ）が開発され、既にロサルタン、カンデサルタン、テルミサルタン、バルサルタン、オルメサルタン、イルベサルタン等が降圧剤として臨床的に用いられている。更に、ＡＲＢは単に降圧作用のみならず、抗炎症作用、内皮機能改善作用、心血管リモデリング抑制作用、酸化ストレス抑制作用、増殖因子抑制作用、インスリン抵抗性改善作用等の様々な作用により、心血管疾患、腎疾患、動脈硬化等にも有用であることが、臨床もしくは基礎試験において多数報告されている（非特許文献１、２）。特に近年では、降圧作用に依存しないＡＲＢの腎保護作用について報告されている（非特許文献３）。 Angiotensin II (AII) is a peptide discovered as an endogenous vasopressor produced by the renin-angiotensin system (RA system). Pharmacological inhibition of AII action is thought to lead to treatment or prevention of cardiovascular diseases such as hypertension, and angiotensin converting enzyme that inhibits angiotensin I (AI) -to-AII converting enzyme as an inhibitor of RA. Enzyme (ACE) inhibitors are used clinically. Further, an AII receptor antagonist (Angiotensin Receptor Blocker: ARB) that can be administered orally thereafter has been developed, and losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan, and the like have been clinically used as antihypertensive agents. Furthermore, ARB is not only an antihypertensive effect, but also has various effects such as an anti-inflammatory effect, an endothelial function improving effect, a cardiovascular remodeling suppressing effect, an oxidative stress suppressing effect, a growth factor suppressing effect, and an insulin resistance improving effect. Numerous reports have been reported in clinical or basic tests that are useful for vascular diseases, renal diseases, arteriosclerosis, and the like (Non-patent Documents 1 and 2). In particular, in recent years, the renal protective effect of ARB independent of the antihypertensive effect has been reported (Non-patent Document 3).

一方、核内受容体スーパーファミリーに属するペルオキシソーム増殖因子活性化受容体（Peroxisome Proliferator-Activated Receprors：ＰＰＡＲｓ）は、現在までにα、γ及びδの３種アイソフォームが同定されている。中でもＰＰＡＲγは、脂肪組織中で最も大量に発現するアイソフォームであり、脂肪細胞の分化や糖脂質代謝に重要な役割を果たしている。現在、ピオグリタゾンやロシグリタゾン等のチアゾリジンジオン誘導体（ＴＺＤ）がＰＰＡＲγ活性化作用を有する糖尿病治療薬として臨床的に用いられており、インスリン抵抗性、耐糖能、脂質代謝の改善作用等を示す事が知られている。更に近年、ＴＺＤはＰＰＡＲγの活性化により、降圧作用、抗炎症作用、内皮機能改善作用、増殖因子抑制作用、ＲＡ系との干渉作用等の多様な作用を示すことが報告されている。これら多面的な作用により、特に糖尿病性腎症においてＴＺＤは血糖コントロールに依存しない腎保護作用を示すことが報告されている（非特許文献４、５、６、７、８）。しかしながら、その一方でＴＺＤはＰＰＡＲγ作動で誘発される体液貯留、体重増加、末梢浮腫、肺浮腫等の副作用が危惧されている（非特許文献９、１０）。 On the other hand, peroxisome proliferator-activated receptors (PPARs) belonging to the nuclear receptor superfamily have been identified so far as three isoforms of α, γ and δ. Among them, PPARγ is an isoform that is most expressed in adipose tissue and plays an important role in adipocyte differentiation and glycolipid metabolism. Currently, thiazolidinedione derivatives (TZD) such as pioglitazone and rosiglitazone are clinically used as anti-diabetic drugs having PPARγ activation activity, and may show insulin resistance, glucose tolerance, lipid metabolism improving action, etc. Are known. In recent years, it has been reported that TZD exhibits various actions such as an antihypertensive action, an anti-inflammatory action, an endothelial function improving action, a growth factor suppressing action, and an interference action with the RA system by the activation of PPARγ. Due to these multifaceted actions, it has been reported that TZD exhibits a renal protective action independent of blood glucose control, particularly in diabetic nephropathy (Non-Patent Documents 4, 5, 6, 7, and 8). However, on the other hand, TZD is feared for side effects such as fluid retention, weight gain, peripheral edema, and pulmonary edema induced by PPARγ operation (Non-Patent Documents 9 and 10).

近年、テルミサルタンにＰＰＡＲγ活性化作用があることが報告された（非特許文献１１）。また、イルベサルタンについても同様の作用があることが報告されている（非特許文献１２）。これらの化合物は、ＲＡ系抑制及びＰＰＡＲγ活性化作用を併せ持つことにより、ＴＺＤで懸念される体液貯留、体重増加、末梢浮腫、肺浮腫又はうっ血性心不全のリスクを高めることなく循環器系疾患（高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患等）や糖尿病関連疾患（２型糖尿病、糖尿病性合併症、インスリン抵抗性症候群、メタボリックシンドローム、高インスリン血症等）の統合的な予防及び／又は治療剤として期待されている（特許文献１）。中でも糖尿病性腎症においては、ＲＡ系抑制及びＰＰＡＲγ活性化作用による複合的な腎保護作用により、相乗的な予防及び／又は治療効果が期待できる。 Recently, it has been reported that telmisartan has a PPARγ activation effect (Non-patent Document 11). It has also been reported that irbesartan has a similar effect (Non-patent Document 12). These compounds combine the effects of RA system inhibition and PPARγ activation, so that they do not increase the risk of fluid retention, weight gain, peripheral edema, pulmonary edema, or congestive heart failure, which is a concern in TZD. ), Heart disease, angina pectoris, cerebrovascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, kidney disease, etc.) and diabetes related diseases (type 2 diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, high It is expected as an integrated preventive and / or therapeutic agent for insulinemia and the like (Patent Document 1). Among them, in diabetic nephropathy, a synergistic preventive and / or therapeutic effect can be expected by a combined renal protective action by RA system inhibition and PPARγ activation action.

このような作用を有する化合物として、ピリミジン及びトリアジン誘導体（特許文献１）、イミダゾピリジン誘導体（特許文献２）、インドール誘導体（特許文献３）、イミダゾール誘導体（特許文献４）の報告がある。このうち、前記特許文献１には、ビフェニル環上にオキサジアゾリジノン環やチアジアゾリジノン環を有することを特徴とする化合物群が記載されており、この中で下式（Ａ）： As compounds having such actions, there are reports of pyrimidine and triazine derivatives (Patent Document 1), imidazopyridine derivatives (Patent Document 2), indole derivatives (Patent Document 3), and imidazole derivatives (Patent Document 4). Among these, Patent Document 1 describes a compound group characterized by having an oxadiazolidinone ring or a thiadiazolidinone ring on a biphenyl ring, in which the following formula (A):

のような、同じピリミジノン骨格を有する化合物も記載されている（特許文献１の実施例２８５参照）。しかしながら、特許文献１に記載されている化合物群は、ビフェニル環上にテトラゾリル基を有するものではない。 A compound having the same pyrimidinone skeleton as described above is also described (see Example 285 of Patent Document 1). However, the compound group described in Patent Document 1 does not have a tetrazolyl group on the biphenyl ring.

また、ＡII拮抗作用を有し、高血圧症、冠状、心臓、腎臓又は肺機能不全ならびに緑内障の治療に有用であるピリミジノン骨格を有する化合物が報告されている（特許文献５）。この刊行物には、ビフェニル環上にカルボキシル基、１Ｈ−テトラゾール−５−イル基、アミド基、スルホンアミド基などを有するピリミジノン骨格の化合物が開示されており、その具体例として、下式（Ｂ）、（Ｃ）、（Ｄ）： In addition, a compound having an AII antagonistic activity and having a pyrimidinone skeleton useful for the treatment of hypertension, coronary, heart, kidney or lung dysfunction and glaucoma has been reported (Patent Document 5). This publication discloses a compound having a pyrimidinone skeleton having a carboxyl group, 1H-tetrazol-5-yl group, amide group, sulfonamide group and the like on the biphenyl ring. Specific examples thereof include the following formula (B ), (C), (D):

で示される化合物も記載されている（特許文献５の化合物５５、５６、６３参照）が、薬理活性についての詳細は具体的に記載されていない。また、特許文献５には、薬理活性としてＰＰＡＲγ活性化作用や糖尿病、肥満又はメタボリックシンドロームの治療に関する記載や示唆もない。 Are also described (see compounds 55, 56, and 63 of Patent Document 5), but details of pharmacological activity are not specifically described. In addition, Patent Document 5 has no description or suggestion regarding PPARγ activation action or treatment of diabetes, obesity or metabolic syndrome as pharmacological activity.

国際公開第２００８/０６２９０５号パンフレットInternational Publication No. 2008/062905 Pamphlet 国際公開第２００８/０８４３０３号パンフレットInternational Publication No. 2008/084303 Pamphlet 国際公開第２００８/０９６８２０号パンフレットInternational Publication No. 2008/096820 Pamphlet 国際公開第２００８/０９６８２９号パンフレットInternational Publication No. 2008/096829 Pamphlet 特開平０４-３４６９８０号公報Japanese Patent Laid-Open No. 04-346980

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本発明の目的は、循環器系の疾患である高血圧症及び代謝性疾患である糖尿病等の予防及び／又は治療に供する医薬として有用な新規化合物を提供することにある。 An object of the present invention is to provide a novel compound useful as a medicament for use in the prevention and / or treatment of hypertension, which is a circulatory disease, and diabetes, which is a metabolic disease.

本発明者らは、上記目的を達成するため鋭意研究を続けた結果、下記一般式（１）で表されるピリミジン−４（３Ｈ）−オン誘導体が、優れたＡII拮抗作用とＰＰＡＲγ活性化作用とを併せ持つ化合物であることを見出し、本発明に至った。 As a result of continual studies to achieve the above object, the present inventors have found that a pyrimidine-4 (3H) -one derivative represented by the following general formula (1) has an excellent AII antagonistic action and PPARγ activation action. And the present invention has been achieved.

すなわち、本発明は、以下に示す発明に関する。
［１］次の一般式（Ｉ）： That is, this invention relates to the invention shown below.
[1] The following general formula (I):

［式中、Ｑは次式： [Where Q is the following formula:

から選ばれるいずれか一つの複素環基を示し、
Ｒ^１、Ｒ^２は同一又は異なってもよく、水素原子；Ｃ_１−６アルキル基；又はハロゲン原子で置換してもよいフェニル基；を示し、
Ｒ^３は、Ｃ_１−６アルキル基又はハロＣ_１−６アルキル基を示し、
ｎは、０〜２の整数を示す］
で表されるピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物。
［２］一般式（Ｉ）における−Ｑ（Ｒ^１）（Ｒ^２）基が、次の一般式： Any one heterocyclic group selected from
R ¹ and R ² may be the same or different and each represents a hydrogen atom; a C _1-6 alkyl group; or a phenyl group that may be substituted with a halogen atom;
R ³ represents a C _1-6 alkyl group or a halo C _1-6 alkyl group,
n represents an integer of 0 to 2]
The pyrimidine-4 (3H) -one derivative represented by these, its salt, or those solvates.
[2] ^-Q in general formula (I) (R 1) ( R 2) group has the following general formula:

［式中、Ｒ^１、Ｒ^２は同一又は異なってもよく、Ｃ_１−６アルキル基；又はハロゲン原子で置換してもよいフェニル基；を示す。］
で表される基である前記［１］に記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物。
［３］一般式（Ｉ）で表される化合物が、
６−ブチル−２−［２−(ピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［２−(５−エチルピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
２−［２−(５−エチルピリジン−２−イル)エチル］−６−プロピル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−２−イル)エチル］ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−３−イル)エチル］ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−６−（トリフルオロメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［（ピリジン−２−イル）メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イルメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−３−イルメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［(５−メチル−２−フェニルオキサゾール−４−イル)メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−｛［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イル］メチル｝−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリジン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリダジン−３−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリミジン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（フラン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−３−イル）ピリミジン−４（３Ｈ）−オン、
及び６−ブチル−２−（２−メチルチアゾール−４−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン
からなる群から選ばれる化合物である、前記［１］記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物。
［４］一般式（Ｉ）で表される化合物が、
６−ブチル−２−［２−(５−エチルピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−３−イル)エチル］ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［（ピリジン−２−イル）メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イルメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［(５−メチル−２−フェニルオキサゾール−４−イル)メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリダジン−３−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
及び６−ブチル−２−（２−メチルチアゾール−４−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン
からなる群から選ばれる化合物である、前記［１］記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物。 [Wherein R ¹ and R ² may be the same or different and each represents a C _1-6 alkyl group; or a phenyl group which may be substituted with a halogen atom]. ]
The pyrimidin-4 (3H) -one derivative according to the above [1], a salt thereof, or a solvate thereof.
[3] The compound represented by the general formula (I) is:
6-Butyl-2- [2- (pyridin-2-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 (3H)- on,
6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
2- [2- (5-Ethylpyridin-2-yl) ethyl] -6-propyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-2-yl) ethyl] pyrimidine-4 (3H)- on,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-3-yl) ethyl] pyrimidine-4 (3H)- on,
6-butyl-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} Pyrimidine-4 (3H) -one,
2- [2- (5-Methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -6- ( Trifluoromethyl) pyrimidin-4 (3H) -one,
6-butyl-2-[(pyridin-2-yl) methyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-ylmethyl) pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-ylmethyl) pyrimidin-4 (3H) -one,
6-Butyl-2-[(5-methyl-2-phenyloxazol-4-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine- 4 (3H) -on,
6-butyl-2-{[2- (4-chlorophenyl) -5-methyloxazol-4-yl] methyl} -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] Methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyridin-2-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyridazin-3-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyrimidin-2-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (furan-2-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-yl) pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-yl) pyrimidin-4 (3H) -one,
And 6-butyl-2- (2-methylthiazol-4-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one The pyrimidin-4 (3H) -one derivative according to the above [1], a salt thereof, or a solvate thereof, which is a compound selected from the group consisting of:
[4] The compound represented by the general formula (I) is:
6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-3-yl) ethyl] pyrimidine-4 (3H)- on,
6-butyl-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} Pyrimidine-4 (3H) -one,
6-butyl-2-[(pyridin-2-yl) methyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-ylmethyl) pyrimidin-4 (3H) -one,
6-Butyl-2-[(5-methyl-2-phenyloxazol-4-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine- 4 (3H) -on,
6-butyl-2- (pyridazin-3-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
And 6-butyl-2- (2-methylthiazol-4-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one The pyrimidin-4 (3H) -one derivative according to the above [1], a salt thereof, or a solvate thereof, which is a compound selected from the group consisting of:

［５］前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物、及び製薬上許容される担体を含有してなる医薬組成物。
［６］前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物を有効成分とする、アンジオテンシンII受容体拮抗作用及びＰＰＡＲγ活性化作用を併せ持つ医薬組成物。
［７］前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする循環器系疾患の予防及び／又は治療剤。
［８］循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症である前記［７］に記載の予防及び／又は治療剤。
［９］前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする代謝性疾患の予防及び／又は治療剤。
［１０］代謝性疾患が、２型糖尿病、糖尿病性合併症（糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症）、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である前記［９］に記載の予防及び／又は治療剤。
［１１］治療を必要としている患者に、前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物の有効量を投与することを特徴とする循環器系疾患の予防及び／又は治療方法。
［１２］治療を必要としている患者に、前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物の有効量を投与することを特徴とする代謝性疾患の予防及び／又は治療方法。
［１３］循環器系疾患の予防及び／又は治療のための製剤を製造するための、前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物の使用。
［１４］代謝性疾患の予防及び／又は治療のための製剤を製造するための、前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物の使用。
［１５］アンジオテンシンII受容体拮抗作用及びＰＰＡＲγ活性化作用の両方の作用を併せ持つ前記［１］〜［４］のいずれかに記載のピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩、又はそれらの溶媒和物。 [5] A pharmaceutical comprising the pyrimidin-4 (3H) -one derivative according to any one of [1] to [4], or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. Composition.
[6] Angiotensin II receptor antagonistic action and PPARγ comprising the pyrimidin-4 (3H) -one derivative according to any one of [1] to [4], a salt thereof, or a solvate thereof as an active ingredient A pharmaceutical composition having an activating action.
[7] Prevention and / or prevention of cardiovascular diseases comprising the pyrimidin-4 (3H) -one derivative according to any one of [1] to [4], or a salt thereof, or a solvate thereof as an active ingredient Or a therapeutic agent.
[8] The prevention and prevention according to [7] above, wherein the circulatory system disease is hypertension, heart disease, angina pectoris, cerebrovascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, renal disease or arteriosclerosis. / Or therapeutic agent.
[9] Prevention and / or prevention of metabolic diseases comprising as an active ingredient the pyrimidin-4 (3H) -one derivative according to any one of [1] to [4], or a salt thereof, or a solvate thereof. Therapeutic agent.
[10] Said metabolic disease is type 2 diabetes, diabetic complications (diabetic retinopathy, diabetic neuropathy or diabetic nephropathy), insulin resistance syndrome, metabolic syndrome or hyperinsulinemia [9] The preventive and / or therapeutic agent according to 1.
[11] An effective amount of the pyrimidin-4 (3H) -one derivative according to any one of [1] to [4], a salt thereof, or a solvate thereof is administered to a patient in need of treatment. A method for preventing and / or treating a circulatory system disease.
[12] An effective amount of the pyrimidin-4 (3H) -one derivative according to any one of [1] to [4], a salt thereof, or a solvate thereof is administered to a patient in need of treatment. A method for preventing and / or treating a metabolic disease characterized by the above.
[13] The pyrimidin-4 (3H) -one derivative according to any one of [1] to [4] or a salt thereof for producing a preparation for the prevention and / or treatment of cardiovascular disease Or the use of solvates thereof.
[14] The pyrimidin-4 (3H) -one derivative according to any one of the above [1] to [4] or a salt thereof for producing a preparation for the prevention and / or treatment of a metabolic disease Use of those solvates.
[15] The pyrimidin-4 (3H) -one derivative according to any one of the above [1] to [4], which has both an angiotensin II receptor antagonistic action and a PPARγ activation action, or a salt thereof, or Solvates.

本発明の一般式（Ｉ）で表されるピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物は、アンジオテンシンII受容体に対し強い拮抗作用を示し、アンジオテンシンIIの関与する疾患、例えば、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患、動脈硬化症等の疾患の予防及び／又は治療剤の有効成分として好適に使用できる。 The pyrimidin-4 (3H) -one derivative represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof exhibits a strong antagonistic action on the angiotensin II receptor, and angiotensin II is involved. Suitable as an active ingredient of a preventive and / or therapeutic agent for diseases such as hypertension, heart disease, angina pectoris, cerebrovascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, renal disease, arteriosclerosis Can be used.

また、本発明の一般式（Ｉ）で表されるピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物は、ＰＰＡＲγ活性化作用を示し、ＰＰＡＲγの関与する疾患、例えば、動脈硬化症、２型糖尿病、糖尿病性合併症（糖尿病網膜症、糖尿病性神経障害、糖尿病性腎症）、インスリン抵抗性症候群、シンドロームＸ、メタボリックシンドローム、高インスリン血症等の疾患の予防及び／又は治療剤の有効成分として好適に使用できる。 In addition, the pyrimidin-4 (3H) -one derivative represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof exhibits a PPARγ activation action, for example, a disease involving PPARγ, for example, Prevention and / or prevention of diseases such as arteriosclerosis, type 2 diabetes, diabetic complications (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), insulin resistance syndrome, syndrome X, metabolic syndrome, hyperinsulinemia, etc. Or it can use suitably as an active ingredient of a therapeutic agent.

さらに、本発明の一般式（Ｉ）で表されるピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物は、アンジオテンシンII受容体拮抗作用とＰＰＡＲγ活性化作用とを併せ持ち、アンジオテンシンIIとＰＰＡＲγの両方が関与する疾患、例えば、動脈硬化症、糖尿病性腎症、インスリン抵抗性症候群、シンドロームＸ、メタボリックシンドロームの疾患の予防及び／又は治療剤の有効成分として好適に使用できる。 Furthermore, the pyrimidin-4 (3H) -one derivative represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof has both an angiotensin II receptor antagonistic action and a PPARγ activation action, It can be suitably used as an active ingredient of a prophylactic and / or therapeutic agent for diseases involving both angiotensin II and PPARγ, such as arteriosclerosis, diabetic nephropathy, insulin resistance syndrome, syndrome X, and metabolic syndrome.

本明細書中で使用するとき、「Ｃ_１−６アルキル基」とは、直鎖又は分岐鎖の炭素数１〜６の炭化水素基を示し、例えば、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、ｔ−ブチル基、ｎ−ペンチル基、２−メチルブチル基、２，２−ジメチルプロピル基、ｎ−ヘキシル基等が挙げられる。 As used herein, the “C _1-6 alkyl group” refers to a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, or an n-propyl group. Isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group and the like.

本明細書中で使用するとき、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子又はヨウ素原子等が挙げられる。従って「ハロゲン原子で置換してもよいフェニル基」とは、無置換のフェニル基に加え、環状に１〜５個の上記ハロゲン原子が置換したフェニル基を意味する。環状に複数個のハロゲン原子が置換する場合は、ハロゲン原子は同一であっても異なってもよい。このようなハロゲン原子が置換したフェニル基としては、例えば、２−フルオロフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、２−クロロフェニル基、３−クロロフェニル基、４−クロロフェニル基、２−ブロモフェニル基、３−ブロモフェニル基、４−ブロモフェニル基、２−ヨードフェニル基、３−ヨードフェニル基、４−ヨードフェニル基、２，３−ジフルオロフェニル基、２，３−ジクロロフェニル基、３，４，５−トリクロロフェニル基、２−クロロ−４−ブロモフェニル基等が挙げられる。 As used herein, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Therefore, the “phenyl group which may be substituted with a halogen atom” means a phenyl group in which 1 to 5 of the above halogen atoms are cyclically substituted in addition to an unsubstituted phenyl group. When a plurality of halogen atoms are substituted in a ring, the halogen atoms may be the same or different. Examples of such a phenyl group substituted with a halogen atom include a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, and 2- Bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 3 , 4,5-trichlorophenyl group, 2-chloro-4-bromophenyl group, and the like.

本明細書中で使用するとき、「ハロ_Ｃ１−６アルキル基」とは、同一若しくは異なった１個〜置換可能な最大数のハロゲン原子で置換されているアルキル基を意味し、例えば、モノフルオロメチル基、トリフルオロメチル基、モノクロロメチル基、モノブロモメチル基、モノヨードメチル基又は２，２，２−トリフルオロエチル基等が挙げられる。 As used herein, “halo _{C 1-6} alkyl group” means an alkyl group substituted with the same or different one to the maximum number of substitutable halogen atoms, for example, monofluoro Examples thereof include a methyl group, a trifluoromethyl group, a monochloromethyl group, a monobromomethyl group, a monoiodomethyl group, and a 2,2,2-trifluoroethyl group.

本発明の好ましい様態として、以下のものをあげることができる。 Preferred embodiments of the present invention include the following.

一般式（Ｉ）中、Ｑにおける複素環基としては、次式： In general formula (I), the heterocyclic group in Q is represented by the following formula:

から選ばれるいずれか一つの複素環基が好ましく、次式： Preferred is any one heterocyclic group selected from:

から選ばれるいずれか一つの複素環基がより好ましく、次式： More preferred is any one heterocyclic group selected from:

の複素環基が特に好ましい。これらの複素環基は置換基を有していなくてもよいが、好ましくは置換基を有する複素環基が挙げられる。複素環基が置換基を有する場合であって、複素環状基Ｑがピリジル基、チアゾリル基又はオキサゾリル基の場合の置換基Ｒ^１及びＲ^２の置換位置としては、次式： The heterocyclic group is particularly preferred. These heterocyclic groups may not have a substituent, but preferably include a heterocyclic group having a substituent. In the case where the heterocyclic group has a substituent and the heterocyclic group Q is a pyridyl group, a thiazolyl group or an oxazolyl group, the substitution positions of the substituents R ¹ and R ² are as follows:

の場合がより好ましい。本発明の好ましい−Ｑ（Ｒ^１）（Ｒ^２）基としては、前記した式で示される置換ピリジル基、置換チアゾリル基又は置換オキサゾリル基が挙げられる。この場合のＲ^１としてはＣ_１−６アルキル基；又はハロゲン原子で置換してもよいフェニル基；が挙げられるが、Ｃ_１−６アルキル基が好ましい。また、この場合のＲ^２としては、Ｃ_１−６アルキル基；又はハロゲン原子で置換してもよいフェニル基；が挙げられるが、ハロゲン原子で置換してもよいフェニル基が好ましい。 Is more preferable. Preferred -Q (R ¹ ) (R ² ) group of the present invention includes a substituted pyridyl group, a substituted thiazolyl group or a substituted oxazolyl group represented by the above formula. As the R ¹ when C _1-6 alkyl group; or a phenyl group which may be substituted with a halogen atom; but the like, C _1-6 alkyl groups are preferred. In addition, as R ² in this case, a C _1-6 alkyl group; or a phenyl group which may be substituted with a halogen atom may be mentioned, and a phenyl group which may be substituted with a halogen atom is preferable.

一般式（Ｉ）中、Ｒ^１、Ｒ^２におけるＣ_１−６アルキル基としては、Ｃ_１−４アルキル基が好ましく、メチル基、エチル基がより好ましい。 In the general formula (I), the C _1-6 alkyl group in R ¹ and R ² is preferably a C _1-4 alkyl group, and more preferably a methyl group or an ethyl group.

一般式（Ｉ）中、Ｒ^１、Ｒ^２におけるハロゲン原子で置換してもよいフェニル基としては、塩素原子で置換してもよいフェニル基が好ましく、フェニル基又は４−クロロフェニル基がより好ましい。 In general formula (I), the phenyl group which may be substituted with a halogen atom in R ¹ and R ² is preferably a phenyl group which may be substituted with a chlorine atom, and more preferably a phenyl group or a 4-chlorophenyl group.

一般式（Ｉ）中、Ｒ^３におけるＣ_１−６アルキル基としては、Ｃ_１−４アルキル基が好ましく、ｎ−プロピル基又はｎ−ブチル基がより好ましく、ｎ−ブチル基が特に好ましい。 In the general formula (I), the C _1-6 alkyl group in R ³ is preferably a C _1-4 alkyl group, more preferably an n-propyl group or an n-butyl group, and particularly preferably an n-butyl group.

一般式（Ｉ）中、Ｒ^３におけるハロＣ_１−６アルキル基としては、ハロＣ_１−４アルキル基が好ましく、トリフルオロメチル基がより好ましい。 In general formula (I), the halo C _1-6 alkyl group in R ³ is preferably a halo C _1-4 alkyl group, more preferably a trifluoromethyl group.

一般式（Ｉ）中、ｎは０、１、及び２のいずれの整数でもよいが、ｎが整数１又は２の場合が好ましく、ｎが整数２の場合がさらに好ましい。 In general formula (I), n may be any integer of 0, 1, and 2. However, n is preferably an integer 1 or 2, and n is more preferably an integer 2.

一般式（Ｉ）で表されるピリミジン−４（３Ｈ）−オン誘導体のより好ましい化合物としては、
６−ブチル−２−［２−(ピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［２−(５−エチルピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
２−［２−(５−エチルピリジン−２−イル)エチル］−６−プロピル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−２−イル)エチル］ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−３−イル)エチル］ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−６−（トリフルオロメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［（ピリジン−２−イル）メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イルメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−３−イルメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［(５−メチル−２−フェニルオキサゾール−４−イル)メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−｛［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イル］メチル｝−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリジン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリダジン−３−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリミジン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（フラン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−３−イル）ピリミジン−４（３Ｈ）−オン、又は、
６−ブチル−２−（２−メチルチアゾール−４−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン
を挙げることができる。 As a more preferable compound of the pyrimidine-4 (3H) -one derivative represented by the general formula (I),
6-Butyl-2- [2- (pyridin-2-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 (3H)- on,
6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
2- [2- (5-Ethylpyridin-2-yl) ethyl] -6-propyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-2-yl) ethyl] pyrimidine-4 (3H)- on,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-3-yl) ethyl] pyrimidine-4 (3H)- on,
6-butyl-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} Pyrimidine-4 (3H) -one,
2- [2- (5-Methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -6- ( Trifluoromethyl) pyrimidin-4 (3H) -one,
6-butyl-2-[(pyridin-2-yl) methyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-ylmethyl) pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-ylmethyl) pyrimidin-4 (3H) -one,
6-Butyl-2-[(5-methyl-2-phenyloxazol-4-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine- 4 (3H) -on,
6-butyl-2-{[2- (4-chlorophenyl) -5-methyloxazol-4-yl] methyl} -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] Methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyridin-2-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyridazin-3-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyrimidin-2-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (furan-2-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-yl) pyrimidin-4 (3H) -one,
6-butyl-5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-yl) pyrimidin-4 (3H) -one, or
6-butyl-2- (2-methylthiazol-4-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one Can be mentioned.

一般式（Ｉ）で表されるピリミジン−４（３Ｈ）−オン誘導体のさらに好ましい化合物としては、
６−ブチル−２−［２−(５−エチルピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−３−イル)エチル］ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［（ピリジン−２−イル）メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イルメチル）ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−［(５−メチル−２−フェニルオキサゾール−４−イル)メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
６−ブチル−２−（ピリダジン−３−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、又は、
６−ブチル−２−（２−メチルチアゾール−４−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン
を挙げることができる。 As a more preferable compound of the pyrimidine-4 (3H) -one derivative represented by the general formula (I),
6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-3-yl) ethyl] pyrimidine-4 (3H)- on,
6-butyl-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} Pyrimidine-4 (3H) -one,
6-butyl-2-[(pyridin-2-yl) methyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-ylmethyl) pyrimidin-4 (3H) -one,
6-Butyl-2-[(5-methyl-2-phenyloxazol-4-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine- 4 (3H) -on,
6-butyl-2- (pyridazin-3-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one, or
6-butyl-2- (2-methylthiazol-4-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one Can be mentioned.

一般式（Ｉ）で表されるピリミジン−４（３Ｈ）−オン誘導体の特に好ましい化合物としては、
６−ブチル−２−［２−(５−エチルピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オン、
を挙げることができる。 As a particularly preferable compound of the pyrimidin-4 (3H) -one derivative represented by the general formula (I),
6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
Can be mentioned.

本化合物に幾何異性体又は光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。 When geometric isomers or optical isomers are present in the present compound, these isomers are also included in the scope of the present invention.

一般式（Ｉ）で表される化合物の塩としては、薬学上許容される塩であれば特に制限されない。化合物を酸性化合物として扱う場合は、例えば、ナトリウム、カリウム、マグネシウム、カルシウム等の金属塩；トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、Ｎ−メチルピロリジン、Ｎ−メチルヒペリジン、Ｎ−メチルモルホリン等の有機塩基との塩等が挙げられる。化合物を塩基性化合物として扱う場合には、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩のような鉱酸の酸付加塩；安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ−トルエンスルホン酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、酢酸塩等の有機酸の酸付加塩等が挙げられる。 The salt of the compound represented by the general formula (I) is not particularly limited as long as it is a pharmaceutically acceptable salt. When treating the compound as an acidic compound, for example, metal salts such as sodium, potassium, magnesium, calcium; organic bases such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylhyperidine, N-methylmorpholine Examples include salts. When treating a compound as a basic compound, for example, acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, Examples include acid addition salts of organic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. It is done.

一般式（Ｉ）で表される化合物、又はその塩の溶媒和物としては、例えば、水和物等が挙げられるが、これに限定されるものではない。 Examples of the solvate of the compound represented by the general formula (I) or a salt thereof include, but are not limited to, hydrates and the like.

なお、生体内において代謝されて一般式（Ｉ）で表される化合物に変換される化合物、いわゆるプロドラッグもすべて本発明に包含される。本発明化合物のプロドラッグを形成する基としては、「プログレス・イン・メディシン（Progress in Medicine）」、ライフサイエンス・メディカ社、１９８５年、５巻、２１５７−２１６１ページに記載されている基や、廣川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３−１９８ページに記載されている基が挙げられる。 It should be noted that all compounds that are metabolized in vivo and converted into the compound represented by the general formula (I), so-called prodrugs, are also included in the present invention. Examples of the group that forms a prodrug of the compound of the present invention include “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161, Examples include the groups described in Yodogawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163-198.

上記一般式（Ｉ）で表される化合物、若しくはその塩、又はそれらの溶媒和物は種々の公知の方法で製造することができ、特に制限されるものではなく、例えば、次の反応工程に従い製造することができる。また、下記反応を行う際において、反応部位以外の官能基については必要に応じてあらかじめ保護しておき、適当な段階においてこれを脱保護してもよい。さらに、各工程において、反応は通常行われる方法で行えばよく、単離精製は結晶化、再結晶化、クロマトグラフィー等の慣用される方法を適宜選択し、又は組み合わせて行えばよい。 The compound represented by the above general formula (I), or a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited. For example, according to the following reaction step Can be manufactured. Moreover, when performing the following reaction, functional groups other than the reaction site may be protected in advance if necessary, and may be deprotected at an appropriate stage. Further, in each step, the reaction may be carried out by a commonly performed method, and isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, chromatography and the like.

一般式（Ｉ）で表される化合物、若しくはその塩、又はそれらの溶媒和物の製造方法
本発明の一般式（Ｉ）表される化合物は、下記の方法により製造することが可能である。すなわち、下記反応経路図１に記載の通り、一般式（II）で表されるオキソカルボン酸エステルに一般式（III）で表されるアミジン誘導体を反応させると、一般式（IV）で表されるピリミジノン誘導体が得られる。一般式（IV）で表されるピリミジノン誘導体にアジド化合物を反応させると、本発明の一般式（Ｉ）で表される化合物を製造することができる。この反応経路を化学反応式で示すと次の通りである。
反応経路図１ Method for Producing Compound Represented by General Formula (I), or a Salt thereof, or a Solvate thereof The compound represented by general formula (I) of the present invention can be produced by the following method. That is, as shown in the following reaction route diagram 1, when an amidine derivative represented by general formula (III) is reacted with an oxocarboxylic acid ester represented by general formula (II), it is represented by general formula (IV). The pyrimidinone derivative is obtained. When an azide compound is reacted with a pyrimidinone derivative represented by the general formula (IV), a compound represented by the general formula (I) of the present invention can be produced. This reaction path is represented by the chemical reaction formula as follows.
Reaction path 1

（式中、Ｑ、Ｒ^１、Ｒ^２、Ｒ^３、ｎは、前記と同じものを示し、Ｒ^４は、Ｃ_１−６アルキル基を示す。）
［工程１］オキソカルボン酸エステル（II）とアミジン誘導体（III）の反応は溶媒中、塩基の存在下により行うことができる。溶媒としては、特に制限は無いが、例えば、メタノール、エタノール、イソプロパノール、酢酸エチル、酢酸イソプロピル、トルエン、ベンゼン、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等を単独又は組み合わせて使用することができる。塩基としては、特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムメトキシド、カリウムメトキシド、ナトリウムｔ−ブトキシド、カリウムｔ−ブトキシド、ｎ−ブチルリチウム、ｓ−ブチルリチウム、ｔ−ブチルリチウム等を使用することができる。反応条件は、使用する原料によって異なるが、一般に０〜１８０℃、好ましくは５０〜１２０℃にて、１分〜２４時間、より好ましくは５分〜１２時間反応させることによってピリミジノン誘導体（IV）が得られる。 (In the formula, Q, R ¹ , R ² , R ³ , and n are the same as described above, and R ⁴ is a C _1-6 alkyl group.)
[Step 1] The reaction of oxocarboxylic acid ester (II) and amidine derivative (III) can be carried out in a solvent in the presence of a base. The solvent is not particularly limited. For example, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, toluene, benzene, dioxane, tetrahydrofuran, acetonitrile, propionitrile, N, N-dimethylformamide, N-methylpyrrolidone, Dimethyl sulfoxide or the like can be used alone or in combination. The base is not particularly limited, and examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as metal lithium, metal sodium and metal potassium, lithium hydroxide, water Alkali metal hydroxides such as sodium oxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide Sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium methoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide, n-butyllithium, s-butyllithium, t-butyllithi It is possible to use a beam or the like. The reaction conditions vary depending on the raw materials used, but generally the pyrimidinone derivative (IV) is reacted by reacting at 0 to 180 ° C, preferably 50 to 120 ° C for 1 minute to 24 hours, more preferably 5 minutes to 12 hours. can get.

［工程２］上記方法で得られたピリミジノン誘導体（IV）とアジド化合物の反応は溶媒中により行うことができる。アジド化合物としては、トリメチルスズアジド、トリブチルスズアジド、トリフェニルスズアジド、アジ化ナトリウム、アジ化水素酸等を使用することができる。また、酸化ジブチルスズの存在下、トリメチルシリルアジドを用いても良い。溶媒としては、特に制限は無いが、メタノール、エタノール、イソプロパノール、酢酸エチル、酢酸イソプロピル、トルエン、ベンゼン、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等を単独又は組み合わせて使用することができる。反応条件は、使用する原料によって異なるが、一般に０〜１８０℃、好ましくは５０〜１２０℃にて、１分〜２週間、好ましくは１時間〜３日間反応させることによって目的物が得られる。 [Step 2] The reaction of the pyrimidinone derivative (IV) obtained by the above method and the azide compound can be carried out in a solvent. As the azide compound, trimethyltin azide, tributyltin azide, triphenyltin azide, sodium azide, hydrazoic acid or the like can be used. Trimethylsilyl azide may be used in the presence of dibutyltin oxide. The solvent is not particularly limited, but methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, toluene, benzene, dioxane, tetrahydrofuran, acetonitrile, propionitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide Etc. can be used alone or in combination. The reaction conditions vary depending on the raw materials used, but the desired product is generally obtained by reacting at 0 to 180 ° C., preferably 50 to 120 ° C. for 1 minute to 2 weeks, preferably 1 hour to 3 days.

前記の各反応で得られた中間体及び目的物は、有機合成化学で常用されている精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して必要に応じて単離、精製することができる。また、中間体においては、特に精製することなく次反応に供することもできる。 Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

さらに、各種の異性体は異性体間の物理化学的性質の差を利用した常法を適用して単離できる。ラセミ混合物は、例えば酒石酸等の一般的な光学活性酸とのジアステレオマー塩に導き光学分割する方法又は光学活性カラムクロマトグラフィーを用いた方法等の一般的ラセミ分割法により、光学的に純粋な異性体に導くことができる。また、ジアステレオマー混合物は、例えば分別結晶化又は各種クロマトグラフィー等により分割できる。また、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。 Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between the isomers. The racemic mixture is optically pure by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to isomers. Moreover, a diastereomeric mixture can be divided | segmented by fractional crystallization or various chromatography, for example. An optically active compound can also be produced by using an appropriate optically active raw material.

得られた化合物（Ｉ）は通常の方法で塩にすることができる。また、反応溶媒、再結晶溶媒等の溶媒の溶媒和物や水和物とすることもできる。 The obtained compound (I) can be converted into a salt by a usual method. Moreover, it can also be set as the solvate and hydrate of solvents, such as a reaction solvent and a recrystallization solvent.

本発明の化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とする医薬の投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤等による経口投与又は静脈内注射剤、筋肉注射剤、坐剤、吸入剤、経皮吸収剤、点眼剤、点鼻剤等による非経口投与が挙げられる。また、このような種々の剤型の医薬製剤を調製するには、この有効成分を単独で、又は他の製薬上許容される担体、すなわち、賦形剤、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、保存剤、矯味剤、香料、被膜剤、希釈剤等を適宜組み合わせて医薬組成物として調製できる。 Examples of the administration form of a pharmaceutical comprising the compound of the present invention, or a salt thereof, or a solvate thereof as an active ingredient include, for example, oral administration or intravenous injection by tablets, capsules, granules, powders, syrups, etc. Parenteral administration by intramuscular injection, suppository, inhalation, transdermal absorption agent, eye drop, nasal drop and the like. In order to prepare pharmaceutical preparations of such various dosage forms, this active ingredient can be used alone or in other pharmaceutically acceptable carriers, that is, excipients, binders, extenders, disintegrants, Surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, diluents and the like can be appropriately combined to prepare a pharmaceutical composition.

本発明の医薬の投与量は、患者の体重、年齢、性別、症状等によって異なるが、通常成人の場合、一般式（Ｉ）で表わされる化合物として、１日０．１〜１０００ｍｇ、特に１〜３００ｍｇを、一回又は数回に分けて経口投与又は非経口投与することができる。 The dose of the medicament of the present invention varies depending on the patient's weight, age, sex, symptoms, etc., but in the case of a normal adult, it is 0.1 to 1000 mg per day as the compound represented by the general formula (I), particularly 1 ˜300 mg can be administered orally or parenterally in one or several divided doses.

次に、実施例及び試験例を挙げて本発明をさらに説明するが、本発明はこれらに限定されるものではない。なお、下記実施例中で用いられている略号は下記の意味を示す。
ｓ：シングレット（singlet）
ｄ：ダブレット（doublet）
ｔ：トリプレット（triplet）
ｑ：クアルテット（quartet）
ｍ：マルチプレット（multiplet）
ｂｒ：ブロード（broad）
Ｊ：カップリング定数（coupling constant）
Ｈｚ：ヘルツ（Hertz）
ＣＤＣｌ_３：重クロロホルム
ＤＭＳＯ−ｄ_６：重ジメチルスルホキシド
^１Ｈ-ＮＭＲ：プロトン核磁気共鳴
ＩＲ：赤外線吸収スペクトル EXAMPLES Next, although an Example and a test example are given and this invention is further demonstrated, this invention is not limited to these. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: Doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl _3: deuterated chloroform _{DMSO-d 6:} deuterated dimethyl sulfoxide
¹ H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum

実施例１６−ブチル−２−［２−(ピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 1 6-Butyl-2- [2- (pyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -ON production

工程１：４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの製造
２−［（２’−シアノビフェニル−４−イル）メチル］−３−オキソヘプタン酸メチル（１．７８ｇ，５．１ｍｍｏｌ）と３−（ピリジン−２−イル）プロパンイミダミド（２．２６ｇ，１５．２ｍｍｏｌ）のメタノール（８０ｍＬ）溶液にナトリウムメトキシド（１．１０ｇ，２０ｍｍｏｌ）を加えて、８時間加熱還流した。反応液に水を加え、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にて乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝６０：１）にて分離精製し、表題化合物（１．０５ｇ，４６％）を無色針状晶として得た。 Step 1: 4 ′-{{4-Butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Manufacturing of
Methyl 2-[(2′-cyanobiphenyl-4-yl) methyl] -3-oxoheptanoate (1.78 g, 5.1 mmol) and 3- (pyridin-2-yl) propanimidamide (2.26 g, Sodium methoxide (1.10 g, 20 mmol) was added to a methanol (80 mL) solution of 15.2 mmol), and the mixture was heated to reflux for 8 hours. 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 resulting residue was separated and purified by silica gel column chromatography (chloroform: methanol = 60: 1) to give the title compound (1 .05 g, 46%) was obtained as colorless needles.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３） δ:
0.90 (3H, t, J=7 Hz), 1.35 (2H, sextet, J=7 Hz),
1.55 (2H, quintet, J=7 Hz), 2.60 (2H, t, J=8 Hz),
3.12 (2H, d, J=8 Hz), 3.26 (2H, d, J=6 Hz), 3.96 (2H, s),
7.12-7.25 (2H, m), 7.32-7.40 (6H, m), 7.56-7.67 (2H, m),
7.73 (1H, d, J=6 Hz), 8.61 (1H, d, J=5 Hz), 13.1 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.90 (3H, t, J = 7 Hz), 1.35 (2H, sextet, J = 7 Hz),
1.55 (2H, quintet, J = 7 Hz), 2.60 (2H, t, J = 8 Hz),
3.12 (2H, d, J = 8 Hz), 3.26 (2H, d, J = 6 Hz), 3.96 (2H, s),
7.12-7.25 (2H, m), 7.32-7.40 (6H, m), 7.56-7.67 (2H, m),
7.73 (1H, d, J = 6 Hz), 8.61 (1H, d, J = 5 Hz), 13.1 (1H, brs).

工程２：６−ブチル−２−［２−(ピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造
４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリル（３００ｍｇ，０．６７ｍｍｏｌ）のトルエン（４ｍＬ）溶液にトリメチルシリルアジド（２．３０ｇ，２０ｍｍｏｌ）と酸化ジブチルスズ（５００ｍｇ，２ｍｍｏｌ）を加え、アルゴン雰囲気下で８時間加熱還流した。反応溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝２０：１）にて分離精製し、表題化合物（１３０ｍｇ，４０％）を白色結晶性粉末として得た。 Step 2: 6-Butyl-2- [2- (pyridin-2-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -one preparation 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2 -Trimethylsilyl azide (2.30 g, 20 mmol) and dibutyltin oxide (500 mg, 2 mmol) were added to a toluene (4 mL) solution of carbonitrile (300 mg, 0.67 mmol), and the mixture was heated to reflux for 8 hours under an argon atmosphere. The residue obtained by evaporating the reaction solvent was separated and purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title compound (130 mg, 40%) as a white crystalline powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６） δ:
0.79 (3H, t, J=7 Hz), 1.19 (2H, sextet, J=7 Hz),
1.35 (2H, quintet, J=7 Hz), 2.40 (2H, t, J=8 Hz),
2.94 (2H, t, J=7 Hz), 3.13 (2H, t, J=7 Hz), 3.74 (2H, s),
6.97 (2H, d, J=8 Hz), 7.09 (2H, d, J=8 Hz), 7.18-7.23 (1H, m),
7.26 (1H, d, J=8 Hz), 7.50-7.60 (2H, m), 7.60-7.73 (3H, m),
8.47 (1H, d, J=1Hz), 12.4 (1H, brs). ¹ H-NMR (DMSO-d ₆ ) δ:
0.79 (3H, t, J = 7 Hz), 1.19 (2H, sextet, J = 7 Hz),
1.35 (2H, quintet, J = 7 Hz), 2.40 (2H, t, J = 8 Hz),
2.94 (2H, t, J = 7 Hz), 3.13 (2H, t, J = 7 Hz), 3.74 (2H, s),
6.97 (2H, d, J = 8 Hz), 7.09 (2H, d, J = 8 Hz), 7.18-7.23 (1H, m),
7.26 (1H, d, J = 8 Hz), 7.50-7.60 (2H, m), 7.60-7.73 (3H, m),
8.47 (1H, d, J = 1Hz), 12.4 (1H, brs).

実施例２６−ブチル−２−［２−(５−エチルピリジン−２−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 2 6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine Of -4 (3H) -one

アルゴン雰囲気下、２−（５−エチルピリジン−２−イル）エタノール（８．７６ｇ，５８ｍｍｏｌ）及びトリフェニルホスフィン（１５．２ｇ，５８ｍｍｏｌ）のテトラヒドロフラン（５０ｍＬ）溶液にアセトンシアノヒドリン（７．４０ｇ，８７ｍｍｏｌ）を加え、引き続きアゾジカルボン酸ジエチル（２．２Ｍトルエン溶液，２６．８ｍＬ，５９ｍｍｏｌ）を滴下した。室温で４時間攪拌後、反応溶媒を留去した。残渣をクロロホルム（１５０ｍＬ）に溶解し、２Ｍ塩酸で抽出した。水層をクロロホルムで洗浄後、水酸化カリウム水溶液で塩基性にし、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムにて乾燥後、減圧濃縮して３−（５−エチルピリジン−２−イル）プロピオニトリル（９．１１ｇ，９８％）を濃赤色油状物として得た。 Acetone cyanohydrin (7.40 g, 87 mmol) was added to a solution of 2- (5-ethylpyridin-2-yl) ethanol (8.76 g, 58 mmol) and triphenylphosphine (15.2 g, 58 mmol) in tetrahydrofuran (50 mL) under an argon atmosphere. Then, diethyl azodicarboxylate (2.2 M in toluene, 26.8 mL, 59 mmol) was added dropwise. After stirring at room temperature for 4 hours, the reaction solvent was distilled off. The residue was dissolved in chloroform (150 mL) and extracted with 2M hydrochloric acid. The aqueous layer was washed with chloroform, basified with an aqueous potassium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3- (5-ethylpyridin-2-yl) propionitrile (9.11 g, 98%) as a dark red oil. Got as.

３−（５−エチルピリジン−２−イル）プロピオニトリル（３．８０ｇ，２３．８ｍｍｏｌ）のエタノール（３０ｍＬ）溶液に氷冷下でアセチルクロリド（３０ｍＬ）を滴下した。室温で１時間攪拌後、反応溶媒を留去した。得られた残渣をメタノール（４０ｍＬ）に溶解し、飽和アンモニア−メタノール溶液（４０ｍＬ）へ滴下した。室温で１２時間攪拌後、反応溶媒を留去した。得られた残渣に水及び水酸化カリウム水溶液を加え、クロロホルム−メタノール混合溶媒（２：１）で抽出した。有機層を無水硫酸マグネシウムにて乾燥後、減圧濃縮して、３−（５−エチルピリジン−２−イル）プロパンイミダミド（２．９４ｇ，７０％）を黄色固体として得た。
３−（ピリジン−２−イル）プロパンイミダミドの代わりに３−（５−エチルピリジン−２−イル）プロパンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（５−エチルピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリル（１２０ｍｇ，１８％）を得た。 Acetyl chloride (30 mL) was added dropwise to an ethanol (30 mL) solution of 3- (5-ethylpyridin-2-yl) propionitrile (3.80 g, 23.8 mmol) under ice cooling. After stirring at room temperature for 1 hour, the reaction solvent was distilled off. The obtained residue was dissolved in methanol (40 mL) and added dropwise to a saturated ammonia-methanol solution (40 mL). After stirring at room temperature for 12 hours, the reaction solvent was distilled off. Water and aqueous potassium hydroxide solution were added to the resulting residue, and the mixture was extracted with a chloroform-methanol mixed solvent (2: 1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3- (5-ethylpyridin-2-yl) propaneimidamide (2.94 g, 70%) as a yellow solid.
Using 3- (5-ethylpyridin-2-yl) propaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the reaction and treatment were conducted in the same manner as in Step 1 of Example 1, and 4′- {{4-Butyl-1,6-dihydro-2- [2- (5-ethylpyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile (120 mg, 18%).

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.88 (3H, t, J=8 Hz), 1.21 (3H, t, J=8 Hz), 1.25-1.39 (2H, m),
1.51-1.59 (2H, m), 2.03-2.63 (4H, m), 3.11 (2H, t, J=7 Hz),
3.24 (2H, t, J=7 Hz), 3.97 (2H, s), 7.11 (1H, d, J=8 Hz),
7.29-7.44 (8H, m), 7.57-7.61 (1H, m), 7.71 (1H, d, J=7 Hz), 8.40 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.88 (3H, t, J = 8 Hz), 1.21 (3H, t, J = 8 Hz), 1.25-1.39 (2H, m),
1.51-1.59 (2H, m), 2.03-2.63 (4H, m), 3.11 (2H, t, J = 7 Hz),
3.24 (2H, t, J = 7 Hz), 3.97 (2H, s), 7.11 (1H, d, J = 8 Hz),
7.29-7.44 (8H, m), 7.57-7.61 (1H, m), 7.71 (1H, d, J = 7 Hz), 8.40 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（５−エチルピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物（４０ｍｇ，３９％）を白色結晶性粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile 4 ′-{{4-Butyl-1,6-dihydro-2- [2- (5-ethylpyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Was used in the same manner as in Step 2 of Example 1 to obtain the title compound (40 mg, 39%) as a white crystalline powder.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.85 (3H, t, J=7 Hz), 1.17 (3H, t, J=7 Hz), 1.29-1.32 (4H, m),
1.52-1.53 (2H, m), 2.51-2.62 (4H, m), 2.99 (2H, t, J=7 Hz),
3.17 (2H, t, J=7 Hz), 3.80 (2H, s), 6.84 (2H, d, J=8 Hz),
6.94 (2H, d, J=8 Hz), 7.17 (1H, d, J=8 Hz), 7.27-7.59 (5H, m),
7.84 (1H, d, J=8 Hz), 7.90 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.85 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz), 1.29-1.32 (4H, m),
1.52-1.53 (2H, m), 2.51-2.62 (4H, m), 2.99 (2H, t, J = 7 Hz),
3.17 (2H, t, J = 7 Hz), 3.80 (2H, s), 6.84 (2H, d, J = 8 Hz),
6.94 (2H, d, J = 8 Hz), 7.17 (1H, d, J = 8 Hz), 7.27-7.59 (5H, m),
7.84 (1H, d, J = 8 Hz), 7.90 (1H, brs).

実施例３２−［２−(５−エチルピリジン−２−イル)エチル］−６−プロピル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 3 2- [2- (5-Ethylpyridin-2-yl) ethyl] -6-propyl-5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine Of -4 (3H) -one

２−［（２’−シアノビフェニル−４−イル）メチル］−３−オキソヘプタン酸メチルの代わりに２−［（２’−シアノビフェニル−４−イル）メチル］−３−オキソヘキサン酸メチルを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛１，６−ジヒドロ−２−［２−（５−エチルピリジン−２−イル）エチル］−６−オキソ−４−プロピルピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを得た。 Instead of methyl 2-[(2′-cyanobiphenyl-4-yl) methyl] -3-oxoheptanoate, methyl 2-[(2′-cyanobiphenyl-4-yl) methyl] -3-oxohexanoate And treated in the same manner as in Step 1 of Example 1, and 4 ′-{{1,6-dihydro-2- [2- (5-ethylpyridin-2-yl) ethyl] -6-oxo-4. -Propylpyrimidin-5-yl} methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.94 (3H, t, J=7 Hz), 1.23 (3H, t, J=7 Hz), 1.62 (2H, sextet, J=8 Hz),
2.61 (4H, quintet, J=7 Hz), 3.10 (2H, t, J=8 Hz), 3.22 (2H, t, J=8 Hz),
3.97 (2H, s), 7.11 (1H, d, J=8 Hz), 7.33-7.55 (7H, m),
7.60 (1H, td, J=8, 2 Hz), 7.72 (1H, t, J=2 Hz), 8.45 (1H, d, J=2 Hz),
13.3 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.94 (3H, t, J = 7 Hz), 1.23 (3H, t, J = 7 Hz), 1.62 (2H, sextet, J = 8 Hz),
2.61 (4H, quintet, J = 7 Hz), 3.10 (2H, t, J = 8 Hz), 3.22 (2H, t, J = 8 Hz),
3.97 (2H, s), 7.11 (1H, d, J = 8 Hz), 7.33-7.55 (7H, m),
7.60 (1H, td, J = 8, 2 Hz), 7.72 (1H, t, J = 2 Hz), 8.45 (1H, d, J = 2 Hz),
13.3 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛１，６−ジヒドロ−２−［２−（５−エチルピリジン−２−イル）エチル］−６−オキソ−４−プロピルピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物（３１０ｍｇ，５６％）を白色結晶性粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile 4 ′-{{1,6-dihydro-2- [2- (5-ethylpyridin-2-yl) ethyl] -6-oxo-4-propylpyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Was used in the same manner as in Step 2 of Example 1 to obtain the title compound (310 mg, 56%) as a white crystalline powder.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.92 (3H, t, J=7 Hz), 1.15 (3H, t, J=7 Hz), 1.65 (2H, sextet, J=8 Hz),
2.46-2.60 (4H, m), 2.98 (2H, t, J=8 Hz), 3.17 (2H, t, J=8 Hz),
3.83 (2H, s), 5.36 (1H, brs), 6.85 (2H, d, J=8 Hz), 6.97 (2H, d, J=8 Hz),
7.16 (1H, d, J=8 Hz), 7.44 (1H, d, J=7 Hz), 7.47-7.56 (2H, m),
7.62 (1H, t, J=6 Hz), 7.72 (1H, s), 7.89 (1H, d, J=8 Hz). ¹ H-NMR (CDCl ₃ ) δ:
0.92 (3H, t, J = 7 Hz), 1.15 (3H, t, J = 7 Hz), 1.65 (2H, sextet, J = 8 Hz),
2.46-2.60 (4H, m), 2.98 (2H, t, J = 8 Hz), 3.17 (2H, t, J = 8 Hz),
3.83 (2H, s), 5.36 (1H, brs), 6.85 (2H, d, J = 8 Hz), 6.97 (2H, d, J = 8 Hz),
7.16 (1H, d, J = 8 Hz), 7.44 (1H, d, J = 7 Hz), 7.47-7.56 (2H, m),
7.62 (1H, t, J = 6 Hz), 7.72 (1H, s), 7.89 (1H, d, J = 8 Hz).

実施例４６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−２−イル)エチル］ピリミジン−４（３Ｈ）−オンの製造 Example 4 6-Butyl-5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-2-yl) ethyl] pyrimidine-4 ( 3H) -ON production

３−（ピリジン−２−イル）プロパンイミダミドの代わりに３−（チオフェン−２−イル）プロパンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛４−ブチル−１，６−ジヒドロ−６−オキソ−２−［２−(チオフェン−２−イル)エチル］ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを得た。 Using 3- (thiophen-2-yl) propaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the same reaction and treatment as in Step 1 of Example 1 was carried out, and 4 ′-{{4 -Butyl-1,6-dihydro-6-oxo-2- [2- (thiophen-2-yl) ethyl] pyrimidin-5-yl} methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.91 (3H, t, J=8 Hz), 1.31-1.40 (2H, m), 1.54-1.62 (2H, m),
2.64 (2H, t, J=8 Hz), 3.00 (2H, t, J=8 Hz), 3.33 (2H, t, J=8 Hz),
3.98 (2H, s), 6.79 (1H, d, J=3 Hz), 6.83 (1H, dd, J=5, 3 Hz),
7.06 (1H, dd, J=5, 1 Hz), 7.35 (2H, d, J=8 Hz), 7.38-7.43 (4H, m),
7.58-7.62 (1H, m), 7.73 (1H, dd, J=8, 1 Hz). ¹ H-NMR (CDCl ₃ ) δ:
0.91 (3H, t, J = 8 Hz), 1.31-1.40 (2H, m), 1.54-1.62 (2H, m),
2.64 (2H, t, J = 8 Hz), 3.00 (2H, t, J = 8 Hz), 3.33 (2H, t, J = 8 Hz),
3.98 (2H, s), 6.79 (1H, d, J = 3 Hz), 6.83 (1H, dd, J = 5, 3 Hz),
7.06 (1H, dd, J = 5, 1 Hz), 7.35 (2H, d, J = 8 Hz), 7.38-7.43 (4H, m),
7.58-7.62 (1H, m), 7.73 (1H, dd, J = 8, 1 Hz).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛４−ブチル−１，６−ジヒドロ−６−オキソ−２−［２−(チオフェン−２−イル)エチル］ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Using 4 ′-{{4-butyl-1,6-dihydro-6-oxo-2- [2- (thiophen-2-yl) ethyl] pyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Reaction and treatment were conducted in the same manner as in Step 2 of Example 1 to obtain the title compound.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.91 (3H, t, J=8 Hz), 1.31-1.40 (2H, m), 1.54-1.62 (2H, m),
2.64 (2H, t, J=8 Hz), 3.00 (2H, t, J=8 Hz), 3.33 (2H, t, J=8 Hz),
3.98 (2H, s), 6.79 (1H, d, J=3 Hz), 6.83 (1H, dd, J=3 and 5 Hz),
7.06 (1H, dd, J=1 and 5 Hz), 7.35 (2H, d, J=8 Hz), 7.38-7.43 (4H, m),
7.58-7.62 (1H, m), 7.73 (1H, dd, J=1 and 8 Hz). ¹ H-NMR (CDCl ₃ ) δ:
0.91 (3H, t, J = 8 Hz), 1.31-1.40 (2H, m), 1.54-1.62 (2H, m),
2.64 (2H, t, J = 8 Hz), 3.00 (2H, t, J = 8 Hz), 3.33 (2H, t, J = 8 Hz),
3.98 (2H, s), 6.79 (1H, d, J = 3 Hz), 6.83 (1H, dd, J = 3 and 5 Hz),
7.06 (1H, dd, J = 1 and 5 Hz), 7.35 (2H, d, J = 8 Hz), 7.38-7.43 (4H, m),
7.58-7.62 (1H, m), 7.73 (1H, dd, J = 1 and 8 Hz).

実施例５６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−［２−(チオフェン−３−イル)エチル］ピリミジン−４（３Ｈ）−オンの製造 Example 5 6-Butyl-5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-3-yl) ethyl] pyrimidine-4 ( 3H) -ON production

３−（ピリジン−２−イル）プロパンイミダミドの代わりに３−（チオフェン−３−イル）プロパンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛４−ブチル−１，６−ジヒドロ−６−オキソ−２−［２−(チオフェン−３−イル)エチル］ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを得た。 Using 3- (thiophen-3-yl) propaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the reaction and treatment were conducted in the same manner as in Step 1 of Example 1, and 4 ′-{{4 -Butyl-1,6-dihydro-6-oxo-2- [2- (thiophen-3-yl) ethyl] pyrimidin-5-yl} methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.96 (3H, t, J=7 Hz), 1.34-1.37 (2H, m), 1.56-1.59 (2H, m),
2.64 (2H, t, J=8 Hz), 2.94 (2H, t, J=8 Hz), 3.12 (2H, t, J=8 Hz),
3.98 (2H, s), 6.91-6.92 (2H, m), 7.12 (1H, dd, J=4, 3 Hz),
7.34 (2H, d, J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.42 (2H, d, J=8 Hz),
7.59 (1H, t, J=8 Hz), 7.73 (1H, d, J=8 Hz). ¹ H-NMR (CDCl ₃ ) δ:
0.96 (3H, t, J = 7 Hz), 1.34-1.37 (2H, m), 1.56-1.59 (2H, m),
2.64 (2H, t, J = 8 Hz), 2.94 (2H, t, J = 8 Hz), 3.12 (2H, t, J = 8 Hz),
3.98 (2H, s), 6.91-6.92 (2H, m), 7.12 (1H, dd, J = 4, 3 Hz),
7.34 (2H, d, J = 8 Hz), 7.38 (1H, d, J = 8 Hz), 7.42 (2H, d, J = 8 Hz),
7.59 (1H, t, J = 8 Hz), 7.73 (1H, d, J = 8 Hz).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛４−ブチル−１，６−ジヒドロ−６−オキソ−２−［２−(チオフェン−３−イル)エチル］ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile With 4 ′-{{4-butyl-1,6-dihydro-6-oxo-2- [2- (thiophen-3-yl) ethyl] pyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Reaction and treatment were conducted in the same manner as in Step 2 of Example 1 to obtain the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ：
0.88 (3H, t, J=7 Hz), 1.28-1.32 (2H, m), 1.42-1.46 (2H, m),
2.52 (2H, brt, J=8 Hz), 2.90 (2H, t, J=8 Hz), 3.08 (2H, t, J=8 Hz),
3.87 (2H, s), 6.93 (1H, d, J=5 Hz), 7.01-7.04 (2H, m),
7.11 (2H, d, J=8 Hz), 7.30-7.31 (1H, m), 7.53 (2H, d, J=8 Hz),
7.64 (2H, d, J=8 Hz), 7.89 (1H, s). ¹ H-NMR (CD ₃ OD) δ:
0.88 (3H, t, J = 7 Hz), 1.28-1.32 (2H, m), 1.42-1.46 (2H, m),
2.52 (2H, brt, J = 8 Hz), 2.90 (2H, t, J = 8 Hz), 3.08 (2H, t, J = 8 Hz),
3.87 (2H, s), 6.93 (1H, d, J = 5 Hz), 7.01-7.04 (2H, m),
7.11 (2H, d, J = 8 Hz), 7.30-7.31 (1H, m), 7.53 (2H, d, J = 8 Hz),
7.64 (2H, d, J = 8 Hz), 7.89 (1H, s).

実施例６６−ブチル−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 6 6-Butyl-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl Production of methyl} pyrimidin-4 (3H) -one

３−（５−エチルピリジン−２−イル）プロピオニトリルの代わりに３−（５−メチル−２−フェニルオキサゾール−４−イル）プロピオニトリルを用いて、実施例２と同様に反応・処理し、３−（５−メチル−２−フェニルオキサゾール−４−イル）プロパンイミダミドを得た。 Reaction and treatment in the same manner as in Example 2 except that 3- (5-methyl-2-phenyloxazol-4-yl) propionitrile was used instead of 3- (5-ethylpyridin-2-yl) propionitrile. 3- (5-methyl-2-phenyloxazol-4-yl) propaneimidamide was obtained.

３−（ピリジン−２−イル）プロパンイミダミドの代わりに３−（５−メチル−２−フェニルオキサゾール−４−イル）プロパンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを得た。 The reaction and treatment were conducted in the same manner as in Step 1 of Example 1 using 3- (5-methyl-2-phenyloxazol-4-yl) propaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide. 4 ′-{{4-Butyl-1,6-dihydro-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl -2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.88 (3H, t, J=7 Hz), 1.31-1.38 (2H, m), 1.50-1.57 (2H, m),
2.27 (3H, s), 2.59 (2H, t, J=8 Hz), 2.92-3.01 (4H, m), 3.91 (2H, s),
7.36-7.44 (8H, m), 7.46-7.59 (1H, m), 7.71 (1H, d, J=8 Hz),
7.99 (2H, d, J=8 Hz). ¹ H-NMR (CDCl ₃ ) δ:
0.88 (3H, t, J = 7 Hz), 1.31-1.38 (2H, m), 1.50-1.57 (2H, m),
2.27 (3H, s), 2.59 (2H, t, J = 8 Hz), 2.92-3.01 (4H, m), 3.91 (2H, s),
7.36-7.44 (8H, m), 7.46-7.59 (1H, m), 7.71 (1H, d, J = 8 Hz),
7.99 (2H, d, J = 8 Hz).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile 4 ′-{{4-Butyl-1,6-dihydro-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl- The reaction and treatment were conducted in a similar manner to process 2 of example 1 using 2-carbonitrile to give the title compound.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.85 (3H, t, J=8 Hz), 1.29-1.31 (2H, m), 1.54 (2H, brs), 2.31 (3H, s),
2.51 (2H, brt, J=8 Hz), 2.87 (2H, brt, J=8 Hz), 2.95 (2H, t, J=7 Hz),
3.84 (2H, s), 6.91 (2H, d, J=8 Hz), 7.02 (2H, d, J=8 Hz),
7.27-7.51 (7H, m), 7.82 (2H, d, J=7 Hz), 7.90 (1H, d, J=7 Hz). ¹ H-NMR (CDCl ₃ ) δ:
0.85 (3H, t, J = 8 Hz), 1.29-1.31 (2H, m), 1.54 (2H, brs), 2.31 (3H, s),
2.51 (2H, brt, J = 8 Hz), 2.87 (2H, brt, J = 8 Hz), 2.95 (2H, t, J = 7 Hz),
3.84 (2H, s), 6.91 (2H, d, J = 8 Hz), 7.02 (2H, d, J = 8 Hz),
7.27-7.51 (7H, m), 7.82 (2H, d, J = 7 Hz), 7.90 (1H, d, J = 7 Hz).

実施例７２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−６−（トリフルオロメチル）ピリミジン−４（３Ｈ）−オンの製造 Example 7 2- [2- (5-Methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl}- Preparation of 6- (trifluoromethyl) pyrimidin-4 (3H) -one

トリフルオロアセト酢酸メチル（３．６８ｇ，２０．０ｍｍｏｌ）のＤＭＦ（２０ｍＬ）溶液に水素化ナトリウム（０．９６ｇ，２４ｍｍｏｌ）を加えて、室温で３０分間攪拌した。氷冷下、４’−ブロモメチルビフェニル−２−カルボニトリル（５．４４ｇ，２０．０ｍｍｏｌ）のＤＭＦ（２０ｍＬ）溶液を滴下した。室温で６時間攪拌後、７０℃で６時間攪拌した。冷却後、反応液に水を加え、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にて乾燥後、減圧濃縮して得られ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＝１０：１）にて分離精製し、２−［（２’−シアノビフェニル−４−イル）メチル］−４，４，４，−トリフルオロアセト酢酸メチル（４．２０ｇ，５８％）を得た。 Sodium hydride (0.96 g, 24 mmol) was added to a solution of methyl trifluoroacetoacetate (3.68 g, 20.0 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, a solution of 4'-bromomethylbiphenyl-2-carbonitrile (5.44 g, 20.0 mmol) in DMF (20 mL) was added dropwise. After stirring at room temperature for 6 hours, the mixture was stirred at 70 ° C. for 6 hours. After cooling, 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 resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and 2- [ (2′-Cyanobiphenyl-4-yl) methyl] -4,4,4, -trifluoroacetoacetate methyl (4.20 g, 58%) was obtained.

３−（ピリジン−２−イル）プロパンイミダミドの代わりに３−（５−メチル−２−フェニルオキサゾール−４−イル）プロパンイミダミドを用い、２−［（２’−シアノビフェニル−４−イル）メチル］−３−オキソヘプタン酸メチルの代わりに２−［（２’−シアノビフェニル−４−イル）メチル］−４，４，４，−トリフルオロアセト酢酸メチルを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛１，６−ジヒドロ−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−６−オキソ−４−（トリフルオロメチル）ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを得た。 Instead of 3- (pyridin-2-yl) propaneimidamide, 3- (5-methyl-2-phenyloxazol-4-yl) propaneimidamide was used and 2-[(2′-cyanobiphenyl-4-yl) was used. Steps of Example 1 using methyl 2-[(2′-cyanobiphenyl-4-yl) methyl] -4,4,4, -trifluoroacetoacetate instead of methyl] -3-oxoheptanoate The reaction and treatment were carried out in the same manner as in 1, and 4 ′-{{1,6-dihydro-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -6-oxo-4- (tri Fluoromethyl) pyrimidin-5-yl} methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
2.31 (3H, s), 2.90-2.95 (2H, m), 3.06-3.09 (2H, m), 4.11 (2H, s),
7.36-7.43 (9H, m), 7.56-7.60 (1H, m), 7.71 (1H, brd, J=8 Hz),
7.98-8.00 (2H, m). ¹ H-NMR (CDCl ₃ ) δ:
2.31 (3H, s), 2.90-2.95 (2H, m), 3.06-3.09 (2H, m), 4.11 (2H, s),
7.36-7.43 (9H, m), 7.56-7.60 (1H, m), 7.71 (1H, brd, J = 8 Hz),
7.98-8.00 (2H, m).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛１，６−ジヒドロ−２−［２−(５−メチル−２−フェニルオキサゾール−４−イル)エチル］−６−オキソ−４−（トリフルオロメチル）ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を橙色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile 4 ′-{{1,6-dihydro-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -6-oxo-4- (trifluoromethyl) pyrimidin-5-yl} Methyl} biphenyl-2-carbonitrile was used for the reaction and treatment in the same manner as in Step 2 of Example 1 to obtain the title compound as an orange powder.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
2.32 (3H, s), 2.93 (2H, brs), 3.05 (2H, brs), 3.95 (2H, brs),
6.91 (2H, brs), 7.04 (2H, brs), 7.26-7.50 (7H, m), 7.81(2H, d, J=7 Hz),
7.86 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
2.32 (3H, s), 2.93 (2H, brs), 3.05 (2H, brs), 3.95 (2H, brs),
6.91 (2H, brs), 7.04 (2H, brs), 7.26-7.50 (7H, m), 7.81 (2H, d, J = 7 Hz),
7.86 (1H, brs).

実施例８６−ブチル−２−［（ピリジン−２−イル）メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 8 6-Butyl-2-[(pyridin-2-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 (3H) -Production of ON

３−（ピリジン−２−イル）プロパンイミダミドの代わりに（ピリジン−２−イル）エタンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛４−ブチル−１，６−ジヒドロ−６−オキソ−２−［（ピリジン−２−イル）メチル］ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを得た。 Using (pyridin-2-yl) ethaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the same reaction and treatment as in Step 1 of Example 1 was carried out to give 4 ′-{{4-butyl-1 , 6-Dihydro-6-oxo-2-[(pyridin-2-yl) methyl] pyrimidin-5-yl} methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.90 (3H, t, J=7 Hz), 1.36 (2H, sextet, J=8 Hz),
1.55 (2H, quintet, J=8 Hz), 2.60 (2H, t, J=8 Hz), 3.95 (2H, s),
4.10 (2H, s), 7.30-7.52 (8H, m), 7.62 (1H, t, J=8 Hz), 7.68-7.77 (2H, m),
8.63 (1H, d, J=5 Hz), 11.6 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.90 (3H, t, J = 7 Hz), 1.36 (2H, sextet, J = 8 Hz),
1.55 (2H, quintet, J = 8 Hz), 2.60 (2H, t, J = 8 Hz), 3.95 (2H, s),
4.10 (2H, s), 7.30-7.52 (8H, m), 7.62 (1H, t, J = 8 Hz), 7.68-7.77 (2H, m),
8.63 (1H, d, J = 5 Hz), 11.6 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛４−ブチル−１，６−ジヒドロ−６−オキソ−２−［（ピリジン−２−イル）メチル］ピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を黄色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Example using 4 ′-{{4-butyl-1,6-dihydro-6-oxo-2-[(pyridin-2-yl) methyl] pyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The reaction and treatment were conducted in the same manner as in Step 2 of 1 to give the title compound as a yellow powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.76 (3H, t, J=7 Hz), 1.18 (2H, sextet, J=7 Hz),
1.33 (2H, quintet, J=7 Hz), 2.40 (2H, t, J=7 Hz), 3.75 (2H, s),
4.03 (2H, s), 6.96 (2H, d, J=8 Hz), 7.11 (2H, d, J=8 Hz),
7.22-7.29 (1H, m), 7.34 (1H, d, J=8 Hz), 7.47-7.56 (2H, m),
7.57-7.70 (2H, m), 7.71-7.79 (1H, m), 8.47 (1H, d, J=5 Hz), 12.5 (1H, brs). ¹ H-NMR (DMSO-d ₆ ) δ:
0.76 (3H, t, J = 7 Hz), 1.18 (2H, sextet, J = 7 Hz),
1.33 (2H, quintet, J = 7 Hz), 2.40 (2H, t, J = 7 Hz), 3.75 (2H, s),
4.03 (2H, s), 6.96 (2H, d, J = 8 Hz), 7.11 (2H, d, J = 8 Hz),
7.22-7.29 (1H, m), 7.34 (1H, d, J = 8 Hz), 7.47-7.56 (2H, m),
7.57-7.70 (2H, m), 7.71-7.79 (1H, m), 8.47 (1H, d, J = 5 Hz), 12.5 (1H, brs).

実施例９６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イルメチル）ピリミジン−４（３Ｈ）−オンの製造 Example 9 6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-ylmethyl) pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりに（チオフェン−２−イル）エタンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−２−イルメチル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using (thiophen-2-yl) ethaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the reaction and treatment were conducted in the same manner as in Step 1 of Example 1, and 4 '-{[4-butyl-1 , 6-Dihydro-6-oxo-2- (thiophen-2-ylmethyl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.91 (3H, t, J=7 Hz), 1.37 (2H, sextet, J=7 Hz),
1.58 (2H, quintet, J=7 Hz), 2.64 (2H, t, J=8 Hz), 3.97 (2H, s),
4.17 (2H, s), 6.88-6.94 (1H, m), 7.03 (1H, d, J=3 Hz),
7.19-7.23 (1H, m), 7.32-7.51 (6H, m), 7.74 (1H, t, J=6 Hz),
7.75 (1H, d, J=2 Hz), 11.7 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.91 (3H, t, J = 7 Hz), 1.37 (2H, sextet, J = 7 Hz),
1.58 (2H, quintet, J = 7 Hz), 2.64 (2H, t, J = 8 Hz), 3.97 (2H, s),
4.17 (2H, s), 6.88-6.94 (1H, m), 7.03 (1H, d, J = 3 Hz),
7.19-7.23 (1H, m), 7.32-7.51 (6H, m), 7.74 (1H, t, J = 6 Hz),
7.75 (1H, d, J = 2 Hz), 11.7 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−２−イルメチル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 '-{[4-butyl-1,6-dihydro-6-oxo-2- (thiophen-2-ylmethyl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment were conducted in the same manner as in 2 to give the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.80 (3H, t, J=7 Hz), 1.24 (2H, sextet, J=7 Hz),
1.42 (2H, quintet, J=7 Hz), 2.45 (2H, t, J=8 Hz), 3.74 (1H, s),
4.02 (2H, s), 6.98-7.03 (4H, m), 7.09 (2H, d, J=8 Hz),
7.38 (1H, d, J=5 Hz), 7.48-7.57 (2H, m), 7.57-7.70 (2H, m), 12.6 (1H, brs). ¹ H-NMR (DMSO-d ₆ ) δ:
0.80 (3H, t, J = 7 Hz), 1.24 (2H, sextet, J = 7 Hz),
1.42 (2H, quintet, J = 7 Hz), 2.45 (2H, t, J = 8 Hz), 3.74 (1H, s),
4.02 (2H, s), 6.98-7.03 (4H, m), 7.09 (2H, d, J = 8 Hz),
7.38 (1H, d, J = 5 Hz), 7.48-7.57 (2H, m), 7.57-7.70 (2H, m), 12.6 (1H, brs).

実施例１０６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−３−イルメチル）ピリミジン−４（３Ｈ）−オンの製造 Example 10 6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-ylmethyl) pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりに（チオフェン−３−イル）エタンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−３−イルメチル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using (thiophen-3-yl) ethaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the reaction and treatment were carried out in the same manner as in Step 1 of Example 1, and 4 ′-{[4-butyl-1 , 6-Dihydro-6-oxo-2- (thiophen-3-ylmethyl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.91 (3H, t, J=7 Hz), 1.37 (2H, sextet, J=7 Hz),
1.60 (2H, quintet, J=7 Hz), 2.64 (2H, t, J=7 Hz), 3.96 (2H, s),
3.98 (2H, s), 7.09 (1H, d, J=2 Hz), 7.10 (1H, d, J=2 Hz),
7.30-7.55 (7H, m), 7.63 (1H, t, J=1 Hz), 7.75 (1H, d, J=8 Hz),
12.8 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.91 (3H, t, J = 7 Hz), 1.37 (2H, sextet, J = 7 Hz),
1.60 (2H, quintet, J = 7 Hz), 2.64 (2H, t, J = 7 Hz), 3.96 (2H, s),
3.98 (2H, s), 7.09 (1H, d, J = 2 Hz), 7.10 (1H, d, J = 2 Hz),
7.30-7.55 (7H, m), 7.63 (1H, t, J = 1 Hz), 7.75 (1H, d, J = 8 Hz),
12.8 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−３−イルメチル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 ′-{[4-butyl-1,6-dihydro-6-oxo-2- (thiophen-3-ylmethyl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment were conducted in the same manner as in 2 to give the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.79 (3H, t, J=7 Hz), 1.21 (2H, sextet, J=7 Hz),
1.39 (2H, quintet, J=7 Hz), 2.45 (2H, t, J=7 Hz), 3.74 (2H, s),
3.81 (2H, s), 6.95 (2H, d, J=8 Hz), 7.05 (1H, d, J=7 Hz),
7.09 (2H, d, J=8 Hz), 7.30 (1H, d, J=3 Hz), 7.43-7.69 (5H, m),
12.5 (1H, brs). ¹ H-NMR (DMSO-d ₆ ) δ:
0.79 (3H, t, J = 7 Hz), 1.21 (2H, sextet, J = 7 Hz),
1.39 (2H, quintet, J = 7 Hz), 2.45 (2H, t, J = 7 Hz), 3.74 (2H, s),
3.81 (2H, s), 6.95 (2H, d, J = 8 Hz), 7.05 (1H, d, J = 7 Hz),
7.09 (2H, d, J = 8 Hz), 7.30 (1H, d, J = 3 Hz), 7.43-7.69 (5H, m),
12.5 (1H, brs).

実施例１１６−ブチル−２−［(５−メチル−２−フェニルオキサゾール−４−イル)メチル］−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 11 6-Butyl-2-[(5-methyl-2-phenyloxazol-4-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl } Production of Pyrimidin-4 (3H) -one

３−（５−エチルピリジン−２−イル）プロピオニトリルの代わりに（５−メチル−２−フェニルオキサゾール−４−イル）アセトニトリルを用いて、実施例２と同様に反応・処理し、（５−メチル−２−フェニルオキサゾール−４−イル）エタンイミダミドを得た。 Using (5-methyl-2-phenyloxazol-4-yl) acetonitrile instead of 3- (5-ethylpyridin-2-yl) propionitrile, the reaction and treatment were carried out in the same manner as in Example 2, and (5 -Methyl-2-phenyloxazol-4-yl) ethaneimidamide was obtained.

３−（ピリジン−２−イル）プロパンイミダミドの代わりに（５−メチル−２−フェニルオキサゾール−４−イル）エタンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−２−（５−メチル−２−フェニルオキサゾール−４−イルメチル）−６−オキソピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using (5-methyl-2-phenyloxazol-4-yl) ethaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the reaction and treatment were conducted in the same manner as in Step 1 of Example 1, and 4′- {[4-Butyl-1,6-dihydro-2- (5-methyl-2-phenyloxazol-4-ylmethyl) -6-oxopyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.92 (3H, t, J=7 Hz), 1.35-1.41 (2H, m), 1.55-1.62 (2H, m),
2.40 (3H, s), 2.61 (2H, t, J=8 Hz), 3.87 (2H, s), 3.95 (2H, s),
7.35-7.48 (8H, m), 7.59-7.60 (2H, m), 7.72 (1H, d, J=7 Hz),
7.81 (1H, d, J=7 Hz), 8.01-8.03 (2H, m), 10.88 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.92 (3H, t, J = 7 Hz), 1.35-1.41 (2H, m), 1.55-1.62 (2H, m),
2.40 (3H, s), 2.61 (2H, t, J = 8 Hz), 3.87 (2H, s), 3.95 (2H, s),
7.35-7.48 (8H, m), 7.59-7.60 (2H, m), 7.72 (1H, d, J = 7 Hz),
7.81 (1H, d, J = 7 Hz), 8.01-8.03 (2H, m), 10.88 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−２−（５−メチル−２−フェニルオキサゾール−４−イルメチル）−６−オキソピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile 4 ′-{[4-butyl-1,6-dihydro-2- (5-methyl-2-phenyloxazol-4-ylmethyl) -6-oxopyrimidin-5-yl] methyl} biphenyl-2-carbonitrile Was used and reacted in the same manner as in Step 2 of Example 1 to obtain the title compound.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.86 (3H, t, J=7 Hz), 1.30-1.34 (2H, m), 1.52-1.56 (2H, m),
2.37 (3H, s), 2.56 (2H, t, J=7 Hz), 3.81 (2H, s), 3.83 (2H, s),
7.00 (2H, d, J=7 Hz), 7.13 (2H, d, J=7 Hz), 7.36-7.42 (4H, m),
7.44-7.53 (2H, m), 7.88 (2H, d, J=7 Hz), 7.96 (1H, brd, J=7 Hz),
11.60 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.86 (3H, t, J = 7 Hz), 1.30-1.34 (2H, m), 1.52-1.56 (2H, m),
2.37 (3H, s), 2.56 (2H, t, J = 7 Hz), 3.81 (2H, s), 3.83 (2H, s),
7.00 (2H, d, J = 7 Hz), 7.13 (2H, d, J = 7 Hz), 7.36-7.42 (4H, m),
7.44-7.53 (2H, m), 7.88 (2H, d, J = 7 Hz), 7.96 (1H, brd, J = 7 Hz),
11.60 (1H, brs).

実施例１２６−ブチル−２−｛［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イル］メチル｝−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 12 6-Butyl-2-{[2- (4-chlorophenyl) -5-methyloxazol-4-yl] methyl} -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4 -Il] methyl} pyrimidin-4 (3H) -one

３−（５−エチルピリジン−２−イル）プロピオニトリルの代わりに［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イル］アセトニトリルを用いて、実施例２と同様に反応・処理し、［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イル］エタンイミダミドを得た。 Reaction and treatment in the same manner as in Example 2 except that [2- (4-chlorophenyl) -5-methyloxazol-4-yl] acetonitrile was used instead of 3- (5-ethylpyridin-2-yl) propionitrile. [2- (4-chlorophenyl) -5-methyloxazol-4-yl] ethaneimidamide was obtained.

３−（ピリジン−２−イル）プロパンイミダミドの代わりに［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イル］エタンイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛｛４−ブチル−２−［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イルメチル］−１，６−ジヒドロ−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを得た。 Using [2- (4-chlorophenyl) -5-methyloxazol-4-yl] ethaneimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the reaction and treatment were carried out in the same manner as in Step 1 of Example 1. 4 ′-{{4-butyl-2- [2- (4-chlorophenyl) -5-methyloxazol-4-ylmethyl] -1,6-dihydro-6-oxopyrimidin-5-yl} methyl} biphenyl- 2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.90 (3H, t, J=6 Hz), 1.33-1.39 (2H, m), 1.52-1.58 (2H, m),
2.37 (3H, s), 2.60 (2H, t, J=8 Hz), 3.86 (2H, s), 3.94 (2H, s),
7.35-7.45 (8H, m), 7.58-7.61 (1H, m), 7.71-7.73 (1H, m),
7.88 (2H, d, J=9 Hz), 11.49 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.90 (3H, t, J = 6 Hz), 1.33-1.39 (2H, m), 1.52-1.58 (2H, m),
2.37 (3H, s), 2.60 (2H, t, J = 8 Hz), 3.86 (2H, s), 3.94 (2H, s),
7.35-7.45 (8H, m), 7.58-7.61 (1H, m), 7.71-7.73 (1H, m),
7.88 (2H, d, J = 9 Hz), 11.49 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛｛４−ブチル−２−［２−（４−クロロフェニル）−５−メチルオキサゾール−４−イルメチル］−１，６−ジヒドロ−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile 4 '-{{4-butyl-2- [2- (4-chlorophenyl) -5-methyloxazol-4-ylmethyl] -1,6-dihydro-6-oxopyrimidin-5-yl} methyl} biphenyl-2 Reaction was carried out in the same manner as in Step 2 of Example 1 using carbonitrile to obtain the title compound.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.86 (3H, t, J=7 Hz), 1.30-1.34 (2H, m), 1.53-1.56 (2H, m),
2.38 (3H, s), 2.56 (2H, t, J=8 Hz), 3.82 (4H, brs),
6.99 (2H, brd, J=8 Hz), 7.10 (2H, brd, J=8 Hz), 7.33-7.37 (3H, m),
7.45-7.48 (1H, m), 7.52-7.54 (1H, m), 7.81 (2H, d, J=9 Hz),
7.95 (1H, d, J=7 Hz). ¹ H-NMR (CDCl ₃ ) δ:
0.86 (3H, t, J = 7 Hz), 1.30-1.34 (2H, m), 1.53-1.56 (2H, m),
2.38 (3H, s), 2.56 (2H, t, J = 8 Hz), 3.82 (4H, brs),
6.99 (2H, brd, J = 8 Hz), 7.10 (2H, brd, J = 8 Hz), 7.33-7.37 (3H, m),
7.45-7.48 (1H, m), 7.52-7.54 (1H, m), 7.81 (2H, d, J = 9 Hz),
7.95 (1H, d, J = 7 Hz).

実施例１３６−ブチル−２−（ピリジン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 13 6-butyl-2- (pyridin-2-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりにピリジンカルボキシイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（ピリジン−２−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using pyridinecarboxyimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the same reaction and treatment as in Step 1 of Example 1 was carried out, and 4 ′-{[4-butyl-1,6-dihydro -6-Oxo-2- (pyridin-2-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.94 (3H, t, J=7 Hz), 1.40 (2H, sextet, J=7 Hz),
1.69 (2H, quintet, J=7 Hz), 2.71 (2H, t, J=7 Hz), 4.06 (2H, s),
7.32-7.55 (7H, m), 7.61 (1H, t, J=7 Hz), 7.73 (1H, d, J=7 Hz),
7.86 (1H, t, J=6Hz), 8.45 (1H, d, J=8 Hz), 8.64 (1H, d, J=4 Hz),
11.0 (1H, s). ¹ H-NMR (CDCl ₃ ) δ:
0.94 (3H, t, J = 7 Hz), 1.40 (2H, sextet, J = 7 Hz),
1.69 (2H, quintet, J = 7 Hz), 2.71 (2H, t, J = 7 Hz), 4.06 (2H, s),
7.32-7.55 (7H, m), 7.61 (1H, t, J = 7 Hz), 7.73 (1H, d, J = 7 Hz),
7.86 (1H, t, J = 6Hz), 8.45 (1H, d, J = 8 Hz), 8.64 (1H, d, J = 4 Hz),
11.0 (1H, s).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（ピリジン−２−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を無色プリズム晶として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 ′-{[4-butyl-1,6-dihydro-6-oxo-2- (pyridin-2-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment in the same manner as in 2 gave the title compound as colorless prism crystals.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.84 (3H, t, J=7Hz), 1.28 (2H, sextet, J=7 Hz),
1.53 (2H, quintet, J=7 Hz), 2.58 (2H, t, J=7 Hz), 3.86 (2H, s),
6.99 (2H, d, J=7 Hz), 7.15 (2H, d, J=8 Hz), 7.46-7.72 (5H, m),
8.03 (1H, t, J=8 Hz), 8.39 (1H, d, J=8 Hz), 8.71 (1H, d, J=5 Hz),
12.0 (1H, s). ¹ H-NMR (DMSO-d ₆ ) δ:
0.84 (3H, t, J = 7Hz), 1.28 (2H, sextet, J = 7 Hz),
1.53 (2H, quintet, J = 7 Hz), 2.58 (2H, t, J = 7 Hz), 3.86 (2H, s),
6.99 (2H, d, J = 7 Hz), 7.15 (2H, d, J = 8 Hz), 7.46-7.72 (5H, m),
8.03 (1H, t, J = 8 Hz), 8.39 (1H, d, J = 8 Hz), 8.71 (1H, d, J = 5 Hz),
12.0 (1H, s).

実施例１４６−ブチル−２−（ピリダジン−３−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 14 6-butyl-2- (pyridazin-3-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりに３−ピリダジンカルボキシイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（ピリダジン−３−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using 3-pyridazine carboxyimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the reaction and treatment were conducted in the same manner as in Step 1 of Example 1, and 4 ′-{[4-butyl-1,6 -Dihydro-6-oxo-2- (pyridazin-3-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.85 (3H, t, J=7 Hz), 1.32 (2H, sextet, J=7 Hz),
1.54 (2H, quintet, J=7 Hz), 2.60 (2H, t, J=7 Hz), 3.87 (2H, s),
6.98 (2H, d, J=8 Hz), 7.15 (2H, d, J=8 Hz), 7.47-7.57 (2H, m),
7.57-7.67 (2H, m), 8.78 (1H, s), 8.84 (1H, d, J=2 Hz), 9.40 (1H, s),
12.5 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.85 (3H, t, J = 7 Hz), 1.32 (2H, sextet, J = 7 Hz),
1.54 (2H, quintet, J = 7 Hz), 2.60 (2H, t, J = 7 Hz), 3.87 (2H, s),
6.98 (2H, d, J = 8 Hz), 7.15 (2H, d, J = 8 Hz), 7.47-7.57 (2H, m),
7.57-7.67 (2H, m), 8.78 (1H, s), 8.84 (1H, d, J = 2 Hz), 9.40 (1H, s),
12.5 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（ピリダジン−３−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 ′-{[4-butyl-1,6-dihydro-6-oxo-2- (pyridazin-3-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment were conducted in the same manner as in 2 to give the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.85 (3H, t, J=7 Hz), 1.32 (2H, sextet, J=7 Hz),
1.54 (2H, quintet, J=7 Hz), 2.60 (2H, t, J=7 Hz), 3.87 (2H, s),
6.98 (2H, d, J=2 Hz), 7.15 (2H, d, J=8 Hz), 7.47-7.57 (2H, m),
7.57-7.67 (2H, m), 8.78 (1H, s), 8.84 (1H, d, J=2 Hz), 9.40 (1H, s),
12.5 (1H, brs). ¹ H-NMR (DMSO-d ₆ ) δ:
0.85 (3H, t, J = 7 Hz), 1.32 (2H, sextet, J = 7 Hz),
1.54 (2H, quintet, J = 7 Hz), 2.60 (2H, t, J = 7 Hz), 3.87 (2H, s),
6.98 (2H, d, J = 2 Hz), 7.15 (2H, d, J = 8 Hz), 7.47-7.57 (2H, m),
7.57-7.67 (2H, m), 8.78 (1H, s), 8.84 (1H, d, J = 2 Hz), 9.40 (1H, s),
12.5 (1H, brs).

実施例１５６−ブチル−２−（ピリミジン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 15 6-butyl-2- (pyrimidin-2-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりに２−ピリミジンカルボキシイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（ピリミジン−２−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using 2-pyrimidinecarboxyimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the same reaction and treatment as in Step 1 of Example 1 was carried out, and 4 ′-{[4-butyl-1,6 -Dihydro-6-oxo-2- (pyrimidin-2-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.91 (3H, t, J=7 Hz), 1.39-1.43 (2H, m), 1.63-1.67 (2H, m),
2.81-2.84 (2H, m), 4.09 (2H, s), 7.39-7.42 (3H, m), 7.47-7.49 (4H, m),
7.60-7.63 (1H, m), 7.74 (1H, d, J=7 Hz), 8.97 (2H, d, J=5 Hz),
11.07 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.91 (3H, t, J = 7 Hz), 1.39-1.43 (2H, m), 1.63-1.67 (2H, m),
2.81-2.84 (2H, m), 4.09 (2H, s), 7.39-7.42 (3H, m), 7.47-7.49 (4H, m),
7.60-7.63 (1H, m), 7.74 (1H, d, J = 7 Hz), 8.97 (2H, d, J = 5 Hz),
11.07 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（ピリミジン−２−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 '-{[4-butyl-1,6-dihydro-6-oxo-2- (pyrimidin-2-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment in the same manner as in 2 gave the title compound as a pale yellow solid.

^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ：
0.92 (3H, t, J=7 Hz), 1.37-1.42 (2H, m), 1.58-1.61 (2H, m),
2.73 (2H, t, J=7 Hz), 3.62 (2H, t, J=7 Hz), 4.01 (2H, s),
7.05 (2H, brd, J=8 Hz), 7.20 (2H, brd, J=8 Hz), 7.51-7.53 (2H, m),
7.63-7.68 (3H, m), 7.74 (1H, brs), 9.02 (2H, s). ¹ H-NMR (CD ₃ OD) δ:
0.92 (3H, t, J = 7 Hz), 1.37-1.42 (2H, m), 1.58-1.61 (2H, m),
2.73 (2H, t, J = 7 Hz), 3.62 (2H, t, J = 7 Hz), 4.01 (2H, s),
7.05 (2H, brd, J = 8 Hz), 7.20 (2H, brd, J = 8 Hz), 7.51-7.53 (2H, m),
7.63-7.68 (3H, m), 7.74 (1H, brs), 9.02 (2H, s).

実施例１６６−ブチル−２−（フラン−２−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 16 6-butyl-2- (furan-2-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりに２−フランカルボキシイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−２−（フラン−２−イル）−６−オキソピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using 2-furancarboxyimidamide instead of 3- (pyridin-2-yl) propaneimidamide, the same reaction and treatment as in Step 1 of Example 1 was carried out, and 4 ′-{[4-butyl-1,6 -Dihydro-2- (furan-2-yl) -6-oxopyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.93 (3H, t, J=7 Hz), 1.39 (2H, sextet, J=7 Hz),
1.65 (2H, quintet, J=7 Hz), 2.70 (2H, t, J=8 Hz), 4.04 (2H, s),
7.12 (1H, d, J=2 Hz), 7.35-7.55 (7H, m), 7.62 (1H, t, J=2 Hz),
7.74 (1H, d, J=6 Hz), 8.41 (1H, s), 13.6 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.93 (3H, t, J = 7 Hz), 1.39 (2H, sextet, J = 7 Hz),
1.65 (2H, quintet, J = 7 Hz), 2.70 (2H, t, J = 8 Hz), 4.04 (2H, s),
7.12 (1H, d, J = 2 Hz), 7.35-7.55 (7H, m), 7.62 (1H, t, J = 2 Hz),
7.74 (1H, d, J = 6 Hz), 8.41 (1H, s), 13.6 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−２−（フラン−２−イル）−６−オキソピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 ′-{[4-butyl-1,6-dihydro-2- (furan-2-yl) -6-oxopyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment were conducted in the same manner as in 2 to give the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.82 (3H, t, J=7 Hz), 1.27 (2H, sextet, J=7 Hz),
1.47 (2H, quintet, J=7 Hz), 2.47 (2H, t, J=7 Hz), 3.81 (2H, s),
6.97 (2H, d, J=8 Hz), 7.06 (1H, s), 7.12 (2H, d, J=8 Hz),
7.47-7.58 (2H, m), 7.58-7.69 (2H, m), 7.80 (1H, s), 8.49 (1H, s),
12.6 (1H, s). ¹ H-NMR (DMSO-d ₆ ) δ:
0.82 (3H, t, J = 7 Hz), 1.27 (2H, sextet, J = 7 Hz),
1.47 (2H, quintet, J = 7 Hz), 2.47 (2H, t, J = 7 Hz), 3.81 (2H, s),
6.97 (2H, d, J = 8 Hz), 7.06 (1H, s), 7.12 (2H, d, J = 8 Hz),
7.47-7.58 (2H, m), 7.58-7.69 (2H, m), 7.80 (1H, s), 8.49 (1H, s),
12.6 (1H, s).

実施例１７６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−２−イル）ピリミジン−４（３Ｈ）−オンの製造 Example 17 6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-yl) pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりに２−チオフェンカルボキシイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−２−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using 2-thiophenecarboximidamide instead of 3- (pyridin-2-yl) propaneimidamide, the same reaction and treatment as in Step 1 of Example 1 was carried out to give 4 ′-{[4-butyl-1,6 -Dihydro-6-oxo-2- (thiophen-2-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.81 (3H, t, J=7 Hz), 1.28 (2H, sextet, J=7 Hz),
1.49 (2H, quintet, J=7 Hz), 2.54 (2H, t, J=7 Hz), 3.91 (2H, s),
7.19 (1H, d, J=5 Hz), 7.35 (2H, d, J=8 Hz), 7.47 (2H, d, J=8 Hz),
7.52-7.62 (2H, m), 7.73-7.84 (2H, m), 7.91 (1H, d, J=8 Hz), 8.13 (1H, s). ¹ H-NMR (DMSO-d ₆ ) δ:
0.81 (3H, t, J = 7 Hz), 1.28 (2H, sextet, J = 7 Hz),
1.49 (2H, quintet, J = 7 Hz), 2.54 (2H, t, J = 7 Hz), 3.91 (2H, s),
7.19 (1H, d, J = 5 Hz), 7.35 (2H, d, J = 8 Hz), 7.47 (2H, d, J = 8 Hz),
7.52-7.62 (2H, m), 7.73-7.84 (2H, m), 7.91 (1H, d, J = 8 Hz), 8.13 (1H, s).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−２−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 ′-{[4-butyl-1,6-dihydro-6-oxo-2- (thiophen-2-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment were conducted in the same manner as in 2 to give the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.82 (3H, t, J=7 Hz), 1.27 (2H, sextet, J=7 Hz),
1.47 (2H, quintet, J=7 Hz), 2.49 (2H, br), 3.82 (2H, s),
6.98 (2H, d, J=8 Hz), 7.13 (2H, d, J=8 Hz), 7.20 (1H, t, J=3 Hz),
7.46-7.57 (2H, m), 7.57-7.68 (2H, m), 7.80 (1H, d, J=5 Hz),
8.12 (1H, s), 12.8 (1H, s). ¹ H-NMR (DMSO-d ₆ ) δ:
0.82 (3H, t, J = 7 Hz), 1.27 (2H, sextet, J = 7 Hz),
1.47 (2H, quintet, J = 7 Hz), 2.49 (2H, br), 3.82 (2H, s),
6.98 (2H, d, J = 8 Hz), 7.13 (2H, d, J = 8 Hz), 7.20 (1H, t, J = 3 Hz),
7.46-7.57 (2H, m), 7.57-7.68 (2H, m), 7.80 (1H, d, J = 5 Hz),
8.12 (1H, s), 12.8 (1H, s).

実施例１８６−ブチル−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝−２−（チオフェン−３−イル）ピリミジン−４（３Ｈ）−オンの製造 Example 18 6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-yl) pyrimidin-4 (3H) -one Manufacturing

３−（ピリジン−２−イル）プロパンイミダミドの代わりに３−チオフェンカルボキシイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−３−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 Using 3-thiophenecarboximidamide instead of 3- (pyridin-2-yl) propaneimidamide, the same reaction and treatment as in Step 1 of Example 1 was carried out to give 4 ′-{[4-butyl-1,6 -Dihydro-6-oxo-2- (thiophen-3-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.93 (3H, t, J=7 Hz), 1.40 (2H, sextet, J=7 Hz),
1.69 (2H, quintet, J=7 Hz), 2.73 (2H, t, J=7 Hz), 4.06 (2H, s),
7.31 (1H, d, J=3 Hz), 7.36-7.52 (6H, m), 7.56-7.64 (1H, m),
7.73 (1H, d, J=8 Hz), 7.90 (1H, dd, J=5, 1 Hz), 8.46 (1H, dd, J=3, 1 Hz),
13.7 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.93 (3H, t, J = 7 Hz), 1.40 (2H, sextet, J = 7 Hz),
1.69 (2H, quintet, J = 7 Hz), 2.73 (2H, t, J = 7 Hz), 4.06 (2H, s),
7.31 (1H, d, J = 3 Hz), 7.36-7.52 (6H, m), 7.56-7.64 (1H, m),
7.73 (1H, d, J = 8 Hz), 7.90 (1H, dd, J = 5, 1 Hz), 8.46 (1H, dd, J = 3, 1 Hz),
13.7 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−６−オキソ−２−（チオフェン−３−イル）ピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile The process of Example 1 using 4 ′-{[4-butyl-1,6-dihydro-6-oxo-2- (thiophen-3-yl) pyrimidin-5-yl] methyl} biphenyl-2-carbonitrile. Reaction and treatment were conducted in the same manner as in 2 to give the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.83 (3H, t, J=7 Hz), 1.27 (2H, sextet, J=7 Hz),
1.49 (2H, quintet, J=7 Hz), 2.49 (2H, t, J=7 Hz), 3.82 (2H, s),
6.97 (2H, d, J=8 Hz), 7.13 (2H, d, J=8 Hz), 7.52 (2H, q, J=7 Hz),
7.58-7.70 (3H, m), 7.75 (1H, d, J=4 Hz), 8.47 (1H, s), 12.6 (1H, brs). ¹ H-NMR (DMSO-d ₆ ) δ:
0.83 (3H, t, J = 7 Hz), 1.27 (2H, sextet, J = 7 Hz),
1.49 (2H, quintet, J = 7 Hz), 2.49 (2H, t, J = 7 Hz), 3.82 (2H, s),
6.97 (2H, d, J = 8 Hz), 7.13 (2H, d, J = 8 Hz), 7.52 (2H, q, J = 7 Hz),
7.58-7.70 (3H, m), 7.75 (1H, d, J = 4 Hz), 8.47 (1H, s), 12.6 (1H, brs).

実施例１９６−ブチル−２−（２−メチルチアゾール−４−イル）−５−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝ピリミジン−４（３Ｈ）−オンの製造 Example 19 6-Butyl-2- (2-methylthiazol-4-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 (3H) -Production of ON

３−（ピリジン−２−イル）プロパンイミダミドの代わりに（２−メチルチアゾール−４−イル）カルボキシイミダミドを用いて実施例１の工程１と同様に反応・処理し、４’−｛［４−ブチル−１，６−ジヒドロ−２−（２−メチルチアゾール−４−イル）−６−オキソピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを得た。 The reaction and treatment were conducted in the same manner as in Step 1 of Example 1 using (2-methylthiazol-4-yl) carboxyimidamide instead of 3- (pyridin-2-yl) propaneimidamide, and 4 ′-{[ 4-Butyl-1,6-dihydro-2- (2-methylthiazol-4-yl) -6-oxopyrimidin-5-yl] methyl} biphenyl-2-carbonitrile was obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：
0.92 (3H, t, J=7 Hz), 1.38 (2H, sextet, J=7 Hz),
1.64 (2H, quintet, J=7 Hz), 2.65 (2H, t, J=8 Hz), 2.75 (3H, s),
4.03 (2H, s), 7.33-7.42 (3H, m), 7.42-7.50 (3H, m),
7.61 (1H, td, J=8, 1 Hz), 7.73 (1H, dd, J=8, 1 Hz), 8.12 (1H, s),
10.4 (1H, brs). ¹ H-NMR (CDCl ₃ ) δ:
0.92 (3H, t, J = 7 Hz), 1.38 (2H, sextet, J = 7 Hz),
1.64 (2H, quintet, J = 7 Hz), 2.65 (2H, t, J = 8 Hz), 2.75 (3H, s),
4.03 (2H, s), 7.33-7.42 (3H, m), 7.42-7.50 (3H, m),
7.61 (1H, td, J = 8, 1 Hz), 7.73 (1H, dd, J = 8, 1 Hz), 8.12 (1H, s),
10.4 (1H, brs).

４’−｛｛４−ブチル−１，６−ジヒドロ−２−［２−（ピリジン−２−イル）エチル］−６−オキソピリミジン−５−イル｝メチル｝ビフェニル−２−カルボニトリルの代わりに４’−｛［４−ブチル−１，６−ジヒドロ−２−（２−メチルチアゾール−４−イル）−６−オキソピリミジン−５−イル］メチル｝ビフェニル−２−カルボニトリルを用いて実施例１の工程２と同様に反応・処理し、表題化合物を白色粉末として得た。 Instead of 4 '-{{4-butyl-1,6-dihydro-2- [2- (pyridin-2-yl) ethyl] -6-oxopyrimidin-5-yl} methyl} biphenyl-2-carbonitrile Example using 4 ′-{[4-butyl-1,6-dihydro-2- (2-methylthiazol-4-yl) -6-oxopyrimidin-5-yl] methyl} biphenyl-2-carbonitrile The reaction and treatment were conducted in the same manner as in Step 2 of 1 to give the title compound as a white powder.

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：
0.82 (3H, t, J=7 Hz), 1.27 (2H, sextet, J=7 Hz), 1.47 (2H, br),
2.52 (2H, br), 2.73 (3H, s), 3.82 (2H, s), 6.97 (2H, d, J=8 Hz),
7.13 (2H, d, J=8 Hz), 7.46-7.58 (2H, m), 7.58-7.70 (2H, m),
8.32 (1H, s), 12.1 (1H, brs). ¹ H-NMR (DMSO-d ₆ ) δ:
0.82 (3H, t, J = 7 Hz), 1.27 (2H, sextet, J = 7 Hz), 1.47 (2H, br),
2.52 (2H, br), 2.73 (3H, s), 3.82 (2H, s), 6.97 (2H, d, J = 8 Hz),
7.13 (2H, d, J = 8 Hz), 7.46-7.58 (2H, m), 7.58-7.70 (2H, m),
8.32 (1H, s), 12.1 (1H, brs).

試験例１：ウサギ摘出血管におけるアンジオテンシンII拮抗作用
本発明化合物のアンジオテンシンIIタイプ１受容体に対する拮抗作用は、ウサギ摘出血管標本を用いてＡIIによる血管収縮反応に対する用量−反応曲線により算出した。すなわち、ウサギ（New Zealand White：雄性，２．４〜３．０ｋｇ）の胸部大動脈リング標本をKrebs-Henseleite液（組成：１１８ｍＭＮａＣｌ，４．７ｍＭＫＣｌ，２．５５ｍＭＣａＣｌ_２，１．１８ｍＭＭｇＳＯ_４，１．１８ｍＭＫＨ_２ＰＯ_４，２４．８８ｍＭＮａＨＣＯ_３，１１．１ｍＭ D-glucose）で充填したマグヌス槽に懸垂し、各実施例化合物存在下（０．０１〜１０μｍｏｌ／Ｌ）のＡII（１０ｎＭ）収縮反応を得た。測定中はマグヌス槽内を３７℃に保温し、十分な混合ガス（９５％Ｏ_２，５％ＣＯ_２）で連続的に通気した。ＡII収縮反応は、各実施例化合物非存在下のＡII（１０ｎＭ）収縮に対する相対値（％）に換算し、得られた濃度−反応曲線より統計解析プログラム、ＳＡＳ前臨床パッケージＶｅｒ５．０（SAS institute Japan Co., 東京）を用いて５０％阻害濃度（ＩＣ_５０値）を算出した。 Test Example 1: Angiotensin II antagonistic action in isolated rabbit blood vessels The antagonistic action of the compound of the present invention on angiotensin II type 1 receptor was calculated from a dose-response curve for the vasoconstriction response by AII using a rabbit isolated blood vessel specimen. That is, a thoracic aortic ring specimen of a rabbit (New Zealand White: male, 2.4-3.0 kg) was prepared from a Krebs-Henseleite solution (composition: 118 mM NaCl, 4.7 mM KCl, 2.55 mM CaCl ₂ , 1.18 mM MgSO _4). , 1.18 mM KH ₂ PO ₄ , 24.88 mM NaHCO ₃ , 11.1 mM D-glucose), suspended in a Magnus tank, and AII (10 nM) in the presence of each Example compound (0.01 to 10 μmol / L). ) A shrinkage reaction was obtained. During the measurement, the inside of the Magnus tank was kept at 37 ° C. and continuously vented with a sufficient mixed gas (95% O ₂ , 5% CO ₂ ). The AII contraction reaction was converted into a relative value (%) with respect to AII (10 nM) contraction in the absence of each Example compound, and the statistical analysis program, SAS preclinical package Ver 5.0 (SAS institute) was obtained from the obtained concentration-response curve. japan Co., was calculated 50% inhibition concentration using Tokyo) _{(IC 50} values).

この結果、実施例に記載した各化合物は、１０μＭの濃度でアンジオテンシンII阻害活性を有していることが確認された。好ましい結果を示した化合物の結果を表１に示す。表１からわかるように、本発明の化合物は強力なアンジオテンシンII拮抗作用を有することが確認された。特に、実施例２、５、８の化合物はＩＣ_５０の値が０．１μＭ未満であり、テルミサルタンと同程度の強いアンジオテンシンII拮抗作用を有していた。 As a result, it was confirmed that each compound described in the Examples has angiotensin II inhibitory activity at a concentration of 10 μM. The results of the compounds that showed favorable results are shown in Table 1. As can be seen from Table 1, it was confirmed that the compound of the present invention has a strong angiotensin II antagonism. In particular, the compounds of Examples 2, 5 and 8 is the _{IC 50} values are less than 0.1 [mu] M, had a strong angiotensin II antagonistic activity of the same degree and telmisartan.

試験例２：ＰＰＡＲγ活性化作用
本発明化合物のＰＰＡＲγに対するアゴニスト活性は、アフリカミドリザルの腎由来細胞株であるＣＯＳ７細胞（ＤＳファーマバイオメディカル、大阪）を用いたトランスフェクションアッセイ法により測定した。ＣＯＳ７細胞の培養は５％のＣＯ_２濃度で行い、培養液には１０％のウシ胎児血清、グルタミン酸及び抗生物質を含有するＤＭＥＭ培地を用いた。
発現ベクターとしては、酵母の転写因子であるＧａｌ４のＤＮＡ結合領域と、ヒトＰＰＡＲγ２のリガンド結合領域を融合したキメラ体、すなわち、Ｇａｌ４転写因子の１から１４７番目のアミノ酸及びヒトＰＰＡＲγ２の１８２から５０５番目のアミノ酸を融合したものを用いた。また、レポーターベクターとして、プロモーター領域に５個のＧａｌ４認識配列が含まれているホタルルシフェラーゼを用いた。細胞へのプラスミドのトランスフェクションはｊｅｔＰＥＩ(フナコシ、東京)を用いた方法により行った。更にβ−ガラクトシダーゼの発現ベクターを内部標準として用いた。
細胞へのトランスフェクションの後、化合物を添加したＤＭＥＭ培地(１％血清含有)に交換し，更に１６時間の培養を行った。その後、細胞溶解液中のルシフェラーゼ活性及びβ−ガラクトシダーゼ活性を測定した。
なお、本実験では被検化合物の溶解・希釈にはジメチルスルホキシド（ＤＭＳＯ）を用い、細胞への処理の際はＤＭＥＭ培地（１％血清含有）中のＤＭＳＯ濃度が０．１％になるように調整した。陽性化合物としてロシグリタゾン（ALEXIS Corporation、Switzerland）を用い、ロシグリタゾン(３−１０mｍｏｌ／Ｌ)のルシフェラーゼ活性を１００％、被検化合物非添加時のルシフェラーゼ活性を０％とした時の各被検化合物（１−３０mｍｏｌ／Ｌ）のルシフェラーゼ活性から百分率（％）を算出した。各被検化合物の５０％効果濃度(ＥＣ_５０、50% effect concentration)は統計解析プログラム、ＳＡＳ前臨床パッケージＶｅｒ５．０（SAS institute Japan Co.,東京）を用いて算出した。 Test Example 2: PPARγ Activating Activity The agonist activity of the compound of the present invention for PPARγ was measured by a transfection assay using COS7 cells (DS Pharma Biomedical, Osaka), which is an African green monkey kidney-derived cell line. COS7 cells in culture was performed in a CO ₂ concentration of 5% in the culture solution using a DMEM medium containing 10% fetal bovine serum, glutamic acid and antibiotics.
The expression vector is a chimera in which the DNA binding region of Gal4, a yeast transcription factor, and the ligand binding region of human PPARγ2, ie, amino acids 1 to 147 of Gal4 transcription factor and 182 to 505 of human PPARγ2. A fusion of these amino acids was used. As a reporter vector, firefly luciferase containing 5 Gal4 recognition sequences in the promoter region was used. Plasmid transfection into cells was performed by a method using jetPEI (Funakoshi, Tokyo). Furthermore, an expression vector for β-galactosidase was used as an internal standard.
After transfection into the cells, the medium was replaced with a DMEM medium (containing 1% serum) supplemented with the compound, and further cultured for 16 hours. Thereafter, luciferase activity and β-galactosidase activity in the cell lysate were measured.
In this experiment, dimethyl sulfoxide (DMSO) is used to dissolve and dilute the test compound, and the DMSO concentration in the DMEM medium (containing 1% serum) is 0.1% when the cells are treated. It was adjusted. Each test compound when rosiglitazone (ALEXIS Corporation, Switzerland) is used as a positive compound, luciferase activity of rosiglitazone (3-10 mmol / L) is 100%, and luciferase activity when no test compound is added is 0% The percentage (%) was calculated from the luciferase activity of (1-30 mmol / L). The 50% effect concentration (EC ₅₀ , 50% effect concentration) of each test compound was calculated using a statistical analysis program, SAS preclinical package Ver 5.0 (SAS institute Japan Co., Tokyo).

この結果、実施例に記載した各化合物は、３０μＭの濃度でＰＰＡＲγ活性化作用を有していることが確認された。好ましい結果を示した化合物の結果を表２に示す。表２からわかるように、本発明の化合物は強力なＰＰＡＲγ活性化作用を有することが確認された。特に、実施例２、９、１０、１１などの化合物はＥＣ_５０の値が３μＭ未満であり、テルミサルタンと同程度のＰＰＡＲγ活性化作用を有していた。 As a result, it was confirmed that each compound described in the Examples has a PPARγ activation action at a concentration of 30 μM. The results of the compounds that showed favorable results are shown in Table 2. As can be seen from Table 2, it was confirmed that the compound of the present invention has a strong PPARγ activation action. In particular, the compounds of Examples 2, 9, 10, 11 and the like had EC ₅₀ values of less than 3 μM, and had PPARγ activation effects comparable to telmisartan.

以上の結果より、一般式（Ｉ）で表される化合物は強力なアンジオテンシンII受容体拮抗作用及びＰＰＡＲγ活性化作用を併せ持つことが確認された。中でも化合物２は、アンジオテンシンII拮抗作用におけるＩＣ_５０の値が０．０４３μＭであり、ＰＰＡＲγ活性化作用のＥＣ_５０の値が０．４８μＭであり、テルミサルタンと同程度のアンジオテンシンII受容体拮抗作用及びＰＰＡＲγ活性化作用の両方を有していた。従って、本発明の化合物（Ｉ）ならびにその薬学的に許容される塩は、アンジオテンシンIIとＰＰＡＲγの関与する疾患、例えば、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患、動脈硬化症、炎症性疾患、２型糖尿病、糖尿病性合併症、インスリン抵抗性症候群、シンドロームＸ、メタボリックシンドローム、高インスリン血症、等の疾患の予防及び／又は治療剤有効成分として好適に使用できる。 From the above results, it was confirmed that the compound represented by the general formula (I) has both a strong angiotensin II receptor antagonistic action and a PPARγ activation action. Among them, Compound 2 has an IC ₅₀ value of 0.043 μM in angiotensin II antagonism, an EC ₅₀ value of PPARγ activation of 0.48 μM, angiotensin II receptor antagonism and PPARγ comparable to telmisartan. It had both activation effects. Therefore, the compound (I) of the present invention and pharmaceutically acceptable salts thereof are diseases involving angiotensin II and PPARγ, such as hypertension, heart disease, angina pectoris, cerebrovascular disorder, cerebral circulation disorder, imaginary disorder. Prevention and / or treatment of diseases such as blood peripheral circulatory disorder, renal disease, arteriosclerosis, inflammatory disease, type 2 diabetes, diabetic complications, insulin resistance syndrome, syndrome X, metabolic syndrome, hyperinsulinemia It can be suitably used as an agent active ingredient.

本発明は、本発明の一般式（Ｉ）で表されるピリミジン−４（３Ｈ）−オン誘導体、若しくはその塩又はそれらの溶媒和物は、アンジオテンシンII受容体拮抗作用とＰＰＡＲγ活性化作用とを併せ持つ新規化合物を提供するものである。アンジオテンシンIIとＰＰＡＲγの関与する疾患、例えば、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患、動脈硬化症、炎症性疾患、２型糖尿病、糖尿病性合併症、インスリン抵抗性症候群、シンドロームＸ、メタボリックシンドローム、高インスリン血症、等の疾患の予防及び／又は治療剤として有用な新規な医薬品の有効成分となり、産業上の利用可能性を有している。 In the present invention, the pyrimidin-4 (3H) -one derivative represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof has an angiotensin II receptor antagonistic action and a PPARγ activation action. The present invention provides a novel compound that has both. Diseases involving angiotensin II and PPARγ, such as hypertension, heart disease, angina pectoris, cerebrovascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, renal disease, arteriosclerosis, inflammatory disease, type 2 diabetes, It becomes an active ingredient of a novel drug useful as a preventive and / or therapeutic agent for diseases such as diabetic complications, insulin resistance syndrome, syndrome X, metabolic syndrome, hyperinsulinemia, etc., and has industrial applicability. is doing.

Claims

The following general formula (I):
[Where Q is the following formula:
Any one heterocyclic group selected from
R ¹ and R ² may be the same or different and each represents a hydrogen atom; a C _1-6 alkyl group; or a phenyl group that may be substituted with a halogen atom;
R ³ represents a C _1-6 alkyl group or a halo C _1-6 alkyl group,
n represents an integer of 0 to 2]
The pyrimidine-4 (3H) -one derivative represented by these, its salt, or those solvates.

In the general formula (I), a -Q (R ¹ ) (R ² ) group has the following general formula:
[Wherein R ¹ and R ² may be the same or different and each represents a C _1-6 alkyl group; or a phenyl group which may be substituted with a halogen atom]. ]
The pyrimidin-4 (3H) -one derivative according to claim 1, or a salt thereof, or a solvate thereof.

The compound represented by the general formula (I) is:
6-Butyl-2- [2- (pyridin-2-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 (3H)- on,
6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
2- [2- (5-Ethylpyridin-2-yl) ethyl] -6-propyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-2-yl) ethyl] pyrimidine-4 (3H)- on,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-3-yl) ethyl] pyrimidine-4 (3H)- on,
6-butyl-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} Pyrimidine-4 (3H) -one,
2- [2- (5-Methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -6- ( Trifluoromethyl) pyrimidin-4 (3H) -one,
6-butyl-2-[(pyridin-2-yl) methyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-ylmethyl) pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-ylmethyl) pyrimidin-4 (3H) -one,
6-Butyl-2-[(5-methyl-2-phenyloxazol-4-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine- 4 (3H) -on,
6-butyl-2-{[2- (4-chlorophenyl) -5-methyloxazol-4-yl] methyl} -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] Methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyridin-2-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyridazin-3-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (pyrimidin-2-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-2- (furan-2-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-yl) pyrimidin-4 (3H) -one,
6-butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-3-yl) pyrimidin-4 (3H) -one,
And 6-butyl-2- (2-methylthiazol-4-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one The pyrimidin-4 (3H) -one derivative according to claim 1, or a salt thereof, or a solvate thereof, which is a compound selected from the group consisting of:

The compound represented by the general formula (I) is:
6-Butyl-2- [2- (5-ethylpyridin-2-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 ( 3H) -On,
6-Butyl-5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- [2- (thiophen-3-yl) ethyl] pyrimidine-4 (3H)- on,
6-butyl-2- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} Pyrimidine-4 (3H) -one,
6-butyl-2-[(pyridin-2-yl) methyl] -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
6-Butyl-5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -2- (thiophen-2-ylmethyl) pyrimidin-4 (3H) -one 6-butyl- 2-[(5-Methyl-2-phenyloxazol-4-yl) methyl] -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidine-4 (3H) -On,
6-butyl-2- (pyridazin-3-yl) -5-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one,
And 6-butyl-2- (2-methylthiazol-4-yl) -5-{[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} pyrimidin-4 (3H) -one The pyrimidin-4 (3H) -one derivative according to claim 1, or a salt thereof, or a solvate thereof, which is a compound selected from the group consisting of:

A pharmaceutical composition comprising the pyrimidin-4 (3H) -one derivative according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition having both an angiotensin II receptor antagonistic action and a PPARγ activating action comprising the pyrimidin-4 (3H) -one derivative according to any one of claims 1 to 4 or a salt thereof or a solvate thereof as active ingredients object.

The preventive and / or therapeutic agent of the circulatory system disease which uses the pyrimidine-4 (3H) -one derivative in any one of Claims 1-4, its salt, or those solvates as an active ingredient.

The prophylactic and / or therapeutic agent according to claim 7, wherein the circulatory system disease is hypertension, heart disease, angina pectoris, cerebrovascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, renal disease or arteriosclerosis.

A preventive and / or therapeutic agent for a metabolic disease comprising the pyrimidin-4 (3H) -one derivative according to any one of claims 1 to 4 or a salt thereof, or a solvate thereof as an active ingredient.

The prophylactic and / or therapeutic agent according to claim 9, wherein the metabolic disease is type 2 diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance syndrome, metabolic syndrome or hyperinsulinemia. .

Circulation characterized by administering an effective amount of the pyrimidin-4 (3H) -one derivative according to any one of claims 1 to 4 or a salt thereof or a solvate thereof to a patient in need of treatment. A method for preventing and / or treating systemic diseases.

The method for prevention and / or treatment according to claim 11, wherein the cardiovascular disease is hypertension, heart disease, angina pectoris, cerebrovascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, renal disease or arteriosclerosis.

A metabolism comprising administering to a patient in need of treatment an effective amount of the pyrimidin-4 (3H) -one derivative according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof. For the prevention and / or treatment of sexually transmitted diseases.

The method for prevention and / or treatment according to claim 13, wherein the metabolic disease is type 2 diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance syndrome, metabolic syndrome or hyperinsulinemia. .

The pyrimidin-4 (3H) -one derivative according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof, for producing a preparation for the prevention and / or treatment of cardiovascular disease Use of.

The use according to claim 15, wherein the circulatory system disease is hypertension, heart disease, angina pectoris, cerebrovascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, renal disease or arteriosclerosis.

A pyrimidin-4 (3H) -one derivative according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof, for producing a preparation for the prevention and / or treatment of metabolic diseases use.

18. Use according to claim 17, wherein the metabolic disease is type 2 diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance syndrome, metabolic syndrome or hyperinsulinemia.