明 細 書 Specification
ピラゾール誘導体 Pyrazole derivative
技術分野 Technical field
[0001] 本発明は、糖尿病の予防 '治療薬に関する。より具体的には、ペルォキシソーム増 殖薬活性化受容体 aハァゴ-スト(PPAR / y agonist: Peroxisome proliferator -activated a / y receptor agonist)に関する。 [0001] The present invention relates to a preventive / therapeutic agent for diabetes. More specifically, the present invention relates to a peroxisome proliferator-activated receptor a ligand (PPAR / y agonist: Peroxisome proliferator-activated a / y receptor agonist).
背景技術 Background art
[0002] 糖尿病は、虚血性心疾患や脳血管障害などを始めとして急性あるいは慢性の種々 の合併症を発症 '進展させて日常生活に著しい障害をもたらす疾患である。したがつ て、早期発見と厳格な血糖コントロールにより、それらの合併症の発症や進展を阻止 する必要がある。 [0002] Diabetes mellitus is a disease that develops and develops various acute and chronic complications such as ischemic heart disease and cerebrovascular disorder, and causes a significant impairment in daily life. Therefore, it is necessary to prevent the onset and progression of these complications through early detection and strict glycemic control.
糖尿病は、血糖をコントロールするインシュリンの産生 ·分泌が障害されて!、る 1型 糖尿病と、インシュリンの産生'分泌は正常範囲から高レベルにあるがインシュリンの 標的臓器や組織にぉ ヽて感受性が低下して ヽる (すなわち、インシュリン抵抗性が高 まっている) 2型糖尿病に分類される。 Diabetes is impaired in the production and secretion of insulin to control blood sugar! Type 1 diabetes and the production of insulin 'secretion is at a high level from the normal range, but it is very sensitive to the target organ and tissue of insulin. It is classified as type 2 diabetes that is reduced (ie, increased insulin resistance).
インシュリンの主要な標的臓器や組織は、筋、脂肪組織および肝であり、筋におい てはグルコースの取り込みやグリコーゲン合成を促進し、脂肪組織にぉ ヽてはダルコ ースの取り込みや利用を促進し、肝においては糖新生を抑制するとともにグリコーゲ ン合成を促進する。また、インシュリンは、上記のような糖代謝をコントロールするばか りではなぐ脂肪組織において脂肪代謝 (脂肪の合成促進や分解抑制)にも関与して いる。 The main target organs and tissues of insulin are muscle, adipose tissue, and liver, which promotes glucose uptake and glycogen synthesis in muscle, and promotes uptake and utilization of dulose in adipose tissue. In the liver, it suppresses gluconeogenesis and promotes glycogen synthesis. Insulin is also involved in fat metabolism (facilitation of fat synthesis and inhibition of degradation) in adipose tissue that is not just for controlling sugar metabolism as described above.
近年、インシュリン抵抗性を改善する薬剤として、ピオグリタゾン (pioglitazone)等の チアゾリジンジオン誘導体 (非特許文献 1)が開発され、 2型糖尿病患者、特に肥満を 伴う 2型糖尿病患者の治療に広く使われて、る。 In recent years, thiazolidinedione derivatives such as pioglitazone (pioglitazone) (Non-Patent Document 1) have been developed as drugs that improve insulin resistance, and are widely used for the treatment of type 2 diabetics, especially type 2 diabetics with obesity. RU
[0003] [化 1]
[0003] [Chemical 1]
Pi ogl i tazone Pi ogl i tazone
[0004] これらのチアゾリジンジオン誘導体は、ペルォキシソーム増殖薬活性化受容体 γ ( PPAR y )のァゴ-ストであることが明らかにされて!、る(非特許文献 2)。 PPAR yァ ゴニストがインシュリン抵抗性を改善するメカニズムは充分には解明されていないが、 インシュリン抵抗性を惹起する遊離脂肪酸などを産生'分泌する肥大脂肪細胞のァ ポトーシス促進や前駆脂肪細胞から脂肪細胞への分化促進による遊離脂肪酸の取 り込み ·貯蔵促進が有力な説として挙げられている。 [0004] These thiazolidinedione derivatives have been shown to be pergosomes of peroxisome proliferator-activated receptor γ (PPAR y)! (Non-patent Document 2). The mechanism by which PPAR yagonists improve insulin resistance has not been fully elucidated, but it promotes apoptosis of hypertrophic adipocytes that produce and secrete free fatty acids that cause insulin resistance, and from preadipocytes to adipocytes Incorporation of free fatty acids by promoting differentiation into plants · Promoting storage is cited as a promising theory.
[0005] PPAR γァゴニストであるピオグリタゾンは、特に肥満を伴う 2型糖尿病患者に投与 されて高!、治療効果を上げて 、るが、その一方で体重増加や体液貯留がー部の患 者で見られて!/ヽる (非特許文献 3)。前述のように糖尿病は虚血性心疾患や脳血管障 害などの合併症を発症 ·進展させることから、このような体重増加や体液貯留は好ま しいことではない。最近では、 PPAR γァゴ-ストに PPAR αァゴ-スト作用を付カロし た PPAR a / yァゴ-ストの研究が活発であり、動物モデルにぉ 、て PPAR γァゴ 二ストよりも優れた糖尿病治療薬としての性質を示すことが示唆されて 、る。例えば、 db/dbマウスを用いた試験において、 PPAR a / γァゴ-スト KRP— 297がピオグ リタゾンと比較して有意に体重の増加を抑制することが示されている (非特許文献 4) 。また、 PPAR a / yァゴ-スト LY465608が用量依存的に高比重リポタンパク(H DL)を増カロさせるとともに、血漿トリグリセリドを低下させ、虚血性心疾患のリスクを低 減することが示されて 、る (非特許文献 5)。 [0005] PPAR γ-agonist, pioglitazone, is especially high when administered to type 2 diabetic patients with obesity and has improved therapeutic effects, while weight gain and fluid retention are in Watched! / Speak (Non-Patent Document 3). As mentioned above, diabetes causes and develops complications such as ischemic heart disease and cerebrovascular disorder, so such weight gain and fluid retention are not desirable. Recently, there has been active research on PPAR a / y agonists in which PPAR γ agonists have been subjected to PPAR α agonist action. It has also been suggested that it exhibits properties as an excellent anti-diabetic drug. For example, in a test using db / db mice, it has been shown that PPAR a / γagost KRP-297 significantly suppresses body weight gain compared to pioglitazone (Non-patent Document 4). . PPAR a / yagost LY465608 has been shown to increase high-density lipoprotein (HDL) in a dose-dependent manner and lower plasma triglycerides, reducing the risk of ischemic heart disease. (Non-Patent Document 5).
代表的な PPAR a / yァゴニストとしては、下記の化合物が挙げられる(非特許文 献 6〜7および特許文献 1〜2)。 Typical PPAR a / y agonists include the following compounds (Non-patent Documents 6 to 7 and Patent Documents 1 and 2).
[0006] [化 2]
[0006] [Chemical 2]
[0007] 非特許文献 l:Chem. Pharm. Bull, 39, 1440-1445 (1991) [0007] Non-patent literature l: Chem. Pharm. Bull, 39, 1440-1445 (1991)
非特許文献 2: J. Biol. Chem., 270, 12953-12956 (1995) Non-Patent Document 2: J. Biol. Chem., 270, 12953-12956 (1995)
非特許文献 3: Am. J. Med., 115 (8A), 111S- 115S (2003) Non-Patent Document 3: Am. J. Med., 115 (8A), 111S- 115S (2003)
非特許文献 4: Am. J. Physiol, 284, E966-E971 (2003) Non-Patent Document 4: Am. J. Physiol, 284, E966-E971 (2003)
非特許文献 5: Diabetes, 51, 1083-1087 (2002) Non-Patent Document 5: Diabetes, 51, 1083-1087 (2002)
非特許文献 6:Bioorg. Med. Chem. Lett., 9, 533-538 (1999) Non-Patent Document 6: Bioorg. Med. Chem. Lett., 9, 533-538 (1999)
非特許文献 7: Chem. Pharm. Bull, 51, 138-151 (2003) Non-Patent Document 7: Chem. Pharm. Bull, 51, 138-151 (2003)
特許文献 l:WO2001— 021602号公報 Patent Literature l: WO2001-021602
特許文献 2:WO2004— 000785号公報 Patent Document 2: WO2004—000785
発明の開示 Disclosure of the invention
発明が解決しょうとする課題 Problems to be solved by the invention
[0008] 本発明の目的は、前記の公知 PPAR a/yァゴ-ストとは化学構造が異なり、優 れた PPAR a/yァゴ-スト作用を有し、医薬品として望ま 、性質を有する化合物 を提供することにある。 [0008] The object of the present invention is to have a chemical structure that is different from the above-mentioned known PPAR a / y agonist, has an excellent PPAR a / y agonist action, and has desirable properties as a pharmaceutical product. Is to provide a compound.
課題を解決するための手段 Means for solving the problem
[0009] そこで本発明者は、種々検討した結果、下記一般式 (I)で表される化合物が、優れ た PPAR a/yァゴニスト作用を示し、糖尿病の予防 '治療薬として有用であることを 見出し、本発明を完成した。
すなわち、一般式 (I) [0009] Thus, as a result of various studies, the present inventor has shown that the compound represented by the following general formula (I) exhibits an excellent PPAR a / y agonist action and is useful as a prophylactic or therapeutic agent for diabetes. The headline and the present invention were completed. That is, the general formula (I)
[0010] [化 3] [0010] [Chemical 3]
RR
0 0
[0011] (上記式中、下記の部分構造式は、 5員の芳香族複素環を示し、 (In the above formula, the following partial structural formula represents a 5-membered aromatic heterocyclic ring,
[0012] [化 4] [0012] [Chemical 4]
[0013] (上記構造において、 X、 Y、および Ζは、各々独立に窒素原子または炭素原子を示 す。) [In the above structure, X, Y, and 各 々 each independently represent a nitrogen atom or a carbon atom.]
mは、 0〜3の整数を示し、 m represents an integer of 0 to 3,
nは、 1〜3の整数を示し、 n represents an integer of 1 to 3,
Qは、水酸基、ハロゲン原子、低級アルケニル基、低級アルコキシ基、置換もしくは 非置換の低級アルキル基、および置換もしくは非置換のァミノ基の中力 選ばれる 1 または 2個の基で置換されてもよ!、ベンゼン環を示し、 Q may be substituted with one or two groups selected from among hydroxyl group, halogen atom, lower alkenyl group, lower alkoxy group, substituted or unsubstituted lower alkyl group, and substituted or unsubstituted amino group. !, Indicates a benzene ring,
R1は、水酸基、ハロゲン原子、低級アルケニル基、置換もしくは非置換の低級アル コキシ基、置換もしくは非置換のフエノキシ基、置換もしくは非置換のフエ二ル基、置 換もしくは非置換の低級アルキル基、および置換もしくは非置換のアミノ基力 選ば れる 1または 2個の基で置換されてもよい、フエ-ル基、ナフチル基、または 5もしくは 6員の芳香族複素環基を示し、 R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group. And a substituted or unsubstituted amino group, a phenyl group, a naphthyl group, or a 5- or 6-membered aromatic heterocyclic group, which may be substituted with 1 or 2 groups selected,
R2は、置換もしくは非置換の低級アルキル基、置換もしくは非置換の力ルバモイル 基、置換もしくは非置換のフエニル基、または置換もしくは非置換の 5もしくは 6員の 芳香族複素環基を示し、 R 2 represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted force rubamoyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group,
R3および R4は、各々独立に水素原子または低級アルキル基を示し、
R5は、水素原子、低級アルキル基、または置換もしくは非置換のベンジル基を示し R 3 and R 4 each independently represent a hydrogen atom or a lower alkyl group, R 5 represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted benzyl group.
R6は、水素原子、水酸基、ハロゲン原子、低級アルケニル基、低級アルコキシ基、 置換もしくは非置換のフエノキシ基、置換もしくは非置換のフエ二ル基、置換もしくは 非置換の低級アルキル基、または置換もしくは非置換のアミノ基を示す (ただし、 mが 2以上のとき、 2つ以上の R6はそれぞれ同じでも異なってもよい。)で表される化合物 、その塩、およびそれらの溶媒和物を提供するものである。 R 6 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted Provided is a compound represented by an unsubstituted amino group (provided that when m is 2 or more, two or more R 6 s may be the same or different from each other), a salt thereof, and a solvate thereof To do.
[0014] また本発明は、上記一般式 (I)で表される化合物、その塩またはそれらの溶媒和物 を有効成分とする医薬を提供するものである。 [0014] The present invention also provides a pharmaceutical comprising the compound represented by the above general formula (I), a salt thereof or a solvate thereof as an active ingredient.
また本発明は、上記一般式 (I)で表される化合物、その塩またはそれらの溶媒和物 及び薬学的に許容し得る担体を含有する医薬組成物を提供するものである。 The present invention also provides a pharmaceutical composition comprising a compound represented by the above general formula (I), a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier.
さらに本発明は、上記一般式 (I)で表される化合物、その塩またはそれらの溶媒和 物の、医薬製造のための使用を提供するものである。 Furthermore, the present invention provides use of a compound represented by the above general formula (I), a salt thereof or a solvate thereof for the production of a medicament.
さらにまた、本発明は、上記一般式 (I)で表される化合物、その塩、またはそれらの 溶媒和物の有効量を投与することを特徴とするインシュリン抵抗性に起因する疾患の 処置方法を提供するものである。 Furthermore, the present invention provides a method for treating a disease caused by insulin resistance, which comprises administering an effective amount of a compound represented by the above general formula (I), a salt thereof, or a solvate thereof. It is to provide.
発明の効果 The invention's effect
[0015] 本発明の一般式 (I)で表される化合物は、優れた PPAR a Z yァゴ-スト作用を示 し、糖尿病の予防 ·治療薬として有用である。 The compound represented by the general formula (I) of the present invention exhibits an excellent PPAR a Zyagost action and is useful as a prophylactic / therapeutic agent for diabetes.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
[0016] 以下に、置換基について説明する。 [0016] The substituent will be described below.
ノ、ロゲン原子とは、フッ素原子、塩素原子、臭素原子または沃素原子を意味する。 ハロゲン原子としては、フッ素原子または塩素原子が好ましい。 The hydrogen atom and the rogen atom mean a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. As the halogen atom, a fluorine atom or a chlorine atom is preferable.
非置換の低級アルキル基とは、炭素数 1〜6の直鎖状、分枝状および環状のアル キル基を意味し、メチル基、ェチル基、プロピル基、ブチル基、ペンチル基、へキシ ル基、イソプロピル基、イソブチル基、 sec—ブチル基、 tert—ブチル基、 tert—ペン チル基、 1, 2—ジメチルプロピル基、ネオペンチル基、 sec—ペンチル基、 2—メチル ブチル基、イソペンチル基、 tert—へキシル基、 1, 2—ジメチルブチル基、 1, 3—ジ
メチルブチル基、ネオへキシル基、 2, 3—ジメチルブチル基、 3, 3—ジメチルブチル 基、 sec—へキシル基、 2—メチルペンチル基、 3—メチルペンチル基、イソへキシル 基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基、シクロ プロピルメチル基、シクロブチルメチル基、およびシクロペンチルメチル基を代表例と して挙げることができ、メチル基、ェチル基およびプロピル基が好ましい。 An unsubstituted lower alkyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, tert-pentyl group, 1,2-dimethylpropyl group, neopentyl group, sec-pentyl group, 2-methylbutyl group, isopentyl group, tert —Hexyl group, 1,2-dimethylbutyl group, 1,3-di Methylbutyl group, neohexyl group, 2, 3-dimethylbutyl group, 3,3-dimethylbutyl group, sec-hexyl group, 2-methylpentyl group, 3-methylpentyl group, isohexyl group, cyclopropyl group , Cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclobutylmethyl group, and cyclopentylmethyl group can be given as representative examples, and a methyl group, an ethyl group, and a propyl group are preferable.
[0017] 低級ァルケ-ル基とは、炭素数 2〜6の直鎖状および分枝状のアルケニル基を意 味し、ビュル基、ァリル基、およびブテニル基を代表例として挙げることができる。 非置換の低級アルコキシ基とは、炭素数 1〜6の直鎖状、分枝状および環状の低 級アルキル基を有するアルコキシ基を意味し、メトキシ基、エトキシ基、プロポキシ基、 イソプロポキシ基、ブトキシ基、イソブトキシ基、ペントキシ基、およびシクロペンチル ォキシ基を代表例として挙げることができる。これらの中で、メトキシ基およびエトキシ 基が好ましぐメトキシ基がより好ましい。 [0017] The lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, and a buyl group, an allyl group, and a butenyl group can be given as typical examples. An unsubstituted lower alkoxy group means an alkoxy group having a linear, branched and cyclic lower alkyl group having 1 to 6 carbon atoms, and includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Typical examples include butoxy, isobutoxy, pentoxy, and cyclopentyloxy. Of these, a methoxy group is preferred, with a methoxy group and an ethoxy group being preferred.
[0018] 置換低級アルコキシ基としては、水酸基、ハロゲン原子、および低級アルコキシ基 の中力 選ばれる 1〜3個の基が置換した低級アルコキシ基が挙げられる。具体的に は、トリフルォロメトキシ基、 2, 2, 2—トリフルォロエトキシ基、 2—ヒドロキシエトキシ基 、 3—ヒドロキシプロポキシ基、 2—フルォロエトキシ基、 2—クロ口エトキシ基、 3—フル ォロプロポキシ基、メトキシメトキシ基、 2—メトキシェトキシ基、および 3—メトキシプロ ポキシ基を代表例として挙げることができ、トリフルォロメトキシ基、 2, 2, 2—トリフル ォロエトキシ基、 2—ヒドロキシエトキシ基、 2—フルォロエトキシ基、 2—クロ口エトキシ 基、メトキシメトキシ基、および 2—メトキシェトキシ基が好ましぐトリフルォロメトキシ基 、 2, 2, 2—トリフルォロエトキシ基、 2—ヒドロキシエトキシ基、 2—フルォロエトキシ基 、メトキシメトキシ基、および 2—メトキシエトキシ基がより好ましぐトリフルォロメトキシ 基、 2, 2, 2—トリフルォロエトキシ基、 2—フルォロエトキシ基、および 2—メトキシエト キシ基が特に好ましい。 [0018] Examples of the substituted lower alkoxy group include a lower alkoxy group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, a halogen atom, and a lower alkoxy group. Specific examples include trifluoromethoxy group, 2, 2, 2-trifluoroethoxy group, 2-hydroxyethoxy group, 3-hydroxypropoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 3-fluoro group. Typical examples include fluoropropoxy, methoxymethoxy, 2-methoxyethoxy, and 3-methoxypropoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy. Groups, 2-fluoroethoxy group, 2-chloroethoxy group, methoxymethoxy group, and 2-methoxyethoxy group are preferred trifluoromethoxy group, 2, 2, 2-trifluoroethoxy group, 2-hydroxy group Trifluoromethoxy is more preferred, with ethoxy, 2-fluoroethoxy, methoxymethoxy, and 2-methoxyethoxy. Group, 2, 2, 2-triflate Ruo b ethoxy group, 2-Furuoroetokishi group, and 2-Metokishieto alkoxy group is particularly preferred.
[0019] 置換低級アルキル基としては、水酸基、ハロゲン原子、アミノ基、低級アルキルアミ ノ基、ジ低級アルキルアミノ基、低級アルコキシ基、カルボキシ基、低級アルコキシ力 ルボニル基、力ルバモイル基、低級アルキル力ルバモイル基、ジ低級アルキルカル バモイル基、力ルバモイルァミノ基、低級アルキル力ルバモイルァミノ基、ジ低級アル
キル力ルバモイルァミノ基、低級アルキルスルホ -ルァミノ基、低級アルコキシカルボ[0019] The substituted lower alkyl group includes a hydroxyl group, a halogen atom, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a carboxy group, a lower alkoxy group, a rubamoyl group, and a lower alkyl group rubamoyl. Group, di-lower alkylcarbamoyl group, force ruberamoylamino group, lower alkyl force ruberamoylamino group, di-lower alkyl Kill power ruberamoylamino group, lower alkyl sulfo-ramino group, lower alkoxycarbo
-ルァミノ基、および低級アルカノィルァミノ基の中力 選ばれる 1〜3個の基が置換 した低級アルキル基が挙げられる。ここで、低級アルカノィルァミノ基とは、炭素数 2 〜6のアルカノィル基によって置換されたアミノ基を意味し、具体的には、ァセチルァ ミノ基、プロピオ-ルァミノ基、ブチリルァミノ基、イソブチリルアミノ基、およびバレリル アミノ基を挙げることができる。置換低級アルキル基の具体例として、トリフルォロメチ ル基、 2, 2, 2—トリフルォロェチル基、ヒドロキシメチル基、 2—ヒドロキシェチル基、 3—ヒドロキシプロピル基、 2—フルォロェチル基、 2—クロ口ェチル基、 3—フルォロ プロピル基、アミノメチル基、 2—アミノエチル基、 3—ァミノプロピル基、メチルアミノメ チル基、 2—メチルアミノエチル基、 3—メチルァミノプロピル基、ジメチルァミノメチル 基、 2—ジメチルアミノエチル基、 3—ジメチルァミノプロピル基、メトキシメチル基、 2 ーメトキシェチル基、 3—メトキシプロピル基、カルボキシメチル基、 2—カルボキシェ チル基、 3—カルボキシプロピル基、メトキシカルボ-ルメチル基、 2—メトキシカルボ -ルェチル基、 3—メトキシカルボ-ルプロピル基、力ルバモイルメチル基、 2—カル バモイルェチル基、 3—力ルバモイルプロピル基、メチルカルバモイルメチル基、 2— メチルカルバモイルェチル基、 3—メチルカルバモイルプロピル基、ェチルカルバモ ィルメチル基、 2—ェチルカルバモイルェチル基、 3—ェチルカルバモイルプロピル 基、ジメチルカルバモイルメチル基、 2—ジメチルカルバモイルェチル基、 3—ジメチ ルカルバモイルプロピル基、ジェチルカルバモイルメチル基、 2—ジェチルカルバモ ィルェチル基、 3—ジェチルカルバモイルプロピル基、力ルバモイルァミノメチル基、 2—力ルバモイルアミノエチル基、 3—力ルバモイルァミノプロピル基、メチルカルバモ ィルァミノメチル基、 2—メチルカルバモイルアミノエチル基、 3—メチルカルバモイル ァミノプロピル基、ェチルカルバモイルァミノメチル基、 2—ェチルカルバモイルァミノ ェチル基、 3—ェチルカルバモイルァミノプロピル基、ジメチルカルバモイルアミノメチ ル基、 2—ジメチルカルバモイルアミノエチル基、 3—ジメチルカルバモイルァミノプロ ピル基、ジェチルカルバモイルァミノメチル基、 2—ジェチルカルバモイルアミノエチ ル基、 3—ジェチルカルバモイルァミノプロピル基、メチルスルホ -ルァミノメチル基、 2—メチルスルホ -ルアミノエチル基、 3—メチルスルホ -ルァミノプロピル基、メトキシ
カルボ-ルァミノメチル基、 2—メトキシカルボ-ルアミノエチル基、 3—メトキシカルボ -ルァミノプロピル基、エトキシカルボ-ルァミノメチル基、 2—エトキシカルボ-ルアミ ノエチル基、 3—エトキシカルボ-ルァミノプロピル基、ァセチルァミノメチル基、 2— ァセチルアミノエチル基、および 3—ァセチルァミノプロピル基を代表例として挙げる ことができ、トリフルォロメチル基、 2, 2, 2—トリフルォロェチル基、ヒドロキシメチル基 、 2—ヒドロキシェチル基、 2—フルォロェチル基、 2—クロ口ェチル基、アミノメチル基 、 2—アミノエチル基、メチルァミノメチル基、 2—メチルアミノエチル基、ジメチルァミノ メチル基、 2—ジメチルアミノエチル基、メトキシメチル基、 2—メトキシェチル基、カル ボキシメチル基、 2—カルボキシェチル基、メトキシカルボ-ルメチル基、 2—メトキシ カルボ-ルェチル基、力ルバモイルメチル基、 2—力ルバモイルェチル基、メチルカ ルバモイルメチル基、 2—メチルカルバモイルェチル基、ェチルカルバモイルメチル 基、 2—ェチルカルバモイルェチル基、ジメチルカルバモイルメチル基、 2—ジメチル 力ルバモイルェチル基、ジェチルカルバモイルメチル基、 2—ジェチルカルバモイル ェチル基、力ルバモイルァミノメチル基、 2—力ルバモイルアミノエチル基、メチルカル バモイルァミノメチル基、 2—メチルカルバモイルアミノエチル基、ェチルカルバモイ ルァミノメチル基、 2—ェチルカルバモイルアミノエチル基、ジメチルカルバモイルアミ ノメチル基、 2—ジメチルカルバモイルアミノエチル基、ジェチルカルバモイルアミノメ チル基、 2—ジェチルカルバモイルアミノエチル基、メチルスルホ -ルァミノメチル基 、 2—メチルスルホ -ルアミノエチル基、メトキシカルボ-ルァミノメチル基、 2—メトキ シカルボ-ルアミノエチル基、エトキシカルボ-ルァミノメチル基、 2—エトキシカルボ -ルアミノエチル基、ァセチルァミノメチル基、および 2—ァセチルアミノエチル基が 好ましぐトリフルォロメチル基、 2, 2, 2—トリフルォロェチル基、ヒドロキシメチル基、 2—ヒドロキシェチル基、 2—フルォロェチル基、アミノメチル基、 2—アミノエチル基、 メチルァミノメチル基、 2—メチルアミノエチル基、ジメチルァミノメチル基、 2—ジメチ ルアミノエチル基、メトキシメチル基、 2—メトキシェチル基、力ルバモイルメチル基、 2 一力ルバモイルェチル基、メチルカルバモイルメチル基、 2—メチルカルバモイルェ チル基、ジメチルカルバモイルメチル基、 2—ジメチルカルバモイルェチル基、ジェ チルカルバモイルメチル基、力ルバモイルァミノメチル基、メチルカルバモイルアミノメ
チル基、ェチルカルバモイルァミノメチル基、ジメチルカルバモイルァミノメチル基、ジ ェチルカルバモイルァミノメチル基、およびメチルスルホ -ルァミノメチル基がより好ま しぐトリフルォロメチル基、 2, 2, 2—トリフルォロェチル基、ヒドロキシメチル基、 2— メトキシェチル基および 2—フルォロェチル基が特に好まし 、。 -Lumino group and lower alkyl group substituted with 1 to 3 groups selected from the medium strength of lower alkanoylamino group. Here, the lower alkanoylamino group means an amino group substituted by an alkanoyl group having 2 to 6 carbon atoms, and specifically includes an acetylamino group, a propio-lamino group, a butyrylamino group, an isobutyryl group. Mention may be made of amino groups and valeryl amino groups. Specific examples of the substituted lower alkyl group include trifluoromethyl group, 2, 2, 2-trifluoroethyl group, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-fluoroethyl group, 2-chloro group. Oral ethyl group, 3-fluoropropyl group, aminomethyl group, 2-aminoethyl group, 3-aminoamino group, methylaminomethyl group, 2-methylaminoethyl group, 3-methylaminopropyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, 3-dimethylaminopropyl group, methoxymethyl group, 2-methoxyethyl group, 3-methoxypropyl group, carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, methoxycarboromethyl group , 2-methoxycarbo-ruethyl group, 3-methoxycarbopropyl group, rubamoyl A methyl group, a 2-carbamoylethyl group, a 3-carbamoylpropyl group, a methylcarbamoylmethyl group, a 2-methylcarbamoylethyl group, a 3-methylcarbamoylpropyl group, an ethylcarbamoylmethyl group, a 2-ethylcarbamoylethyl group, 3-Ethylcarbamoylpropyl group, Dimethylcarbamoylmethyl group, 2-Dimethylcarbamoylethyl group, 3-Dimethylcarbamoylpropyl group, Detylcarbamoylmethyl group, 2-Detylcarbamoylpropyl group, 3-Dethylcarbamoylpropyl group, Power Luba Molyaminomethyl group, 2-force rubamoylaminoethyl group, 3-force rubamoylaminopropyl group, methylcarbamoylaminomethyl group, 2-methylcarbamoylaminoethyl group, 3-methylcarbamoylaminopropyl group, ethylcarba Iraminomethyl group, 2-ethylcarbamoylaminoethyl group, 3-ethylcarbamoylaminopropyl group, dimethylcarbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, 3-dimethylcarbamoylaminopropyl group, jeti Rucarbamoylaminomethyl group, 2-Dethylcarbamoylaminoethyl group, 3-Dethylcarbamoylaminopropyl group, Methylsulfo-luminomethyl group, 2-Methylsulfoaminoamino group, 3-Methylsulfo-laminopropyl group, Methoxy Carbo-aminoamino group, 2-methoxycarboaminoamino group, 3-methoxycarbo-aminoamino group, ethoxycarboaminomethyl group, 2-ethoxycarboaminoethyl group, 3-ethoxycarboaminopropyl group, acetylaminoamino group , 2-acetylaminoethyl group, and 3-acetylaminopropyl group can be given as representative examples, such as trifluoromethyl group, 2,2,2-trifluoroethyl group, hydroxymethyl group, 2 —Hydroxyethyl group, 2-fluoroethyl group, 2-chloroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl group, 2-methylaminoethyl group, dimethylaminomethyl group, 2-dimethylaminoethyl Group, methoxymethyl group, 2-methoxyethyl group, carboxymethyl group, 2-carbo Shetyl group, methoxycarbolmethyl group, 2-methoxycarboleethyl group, strong rubamoylmethyl group, 2-strong rubamoylethyl group, methylcarbamoylmethyl group, 2-methylcarbamoylethyl group, ethylcarbamoylmethyl group, 2-ethylcarbamoyl group Ethyl group, Dimethylcarbamoylmethyl group, 2-Dimethyl strong rubamoylethyl group, Jetylcarbamoylmethyl group, 2-Dethylcarbamoylethyl group, Strong rubamoylaminomethyl group, 2-Strong rubamoylaminoethyl group, Methylcarbamoyl Aminomethyl group, 2-methylcarbamoylaminoethyl group, ethylcarbamoylaminomethyl group, 2-ethylcarbamoylaminoethyl group, dimethylcarbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, jetylcarbamoyla Minomethyl group, 2-Dethylcarbamoylaminoethyl group, Methylsulfolaminomethyl group, 2-Methylsulfolaminoethyl group, Methoxycarboaminomethyl group, 2-Methoxycarbolaminoethyl group, Ethoxycarboaminoamino group, 2-Ethoxycarbo- Triaminomethyl group, 2,2,2-trifluoroethyl group, hydroxymethyl group, 2-hydroxyethyl group are preferred, which is preferably aminoethyl group, acetylaminoamino group, and 2-acetylaminoamino group. 2-fluoroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl group, 2-methylaminoethyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxymethyl group, 2-methoxyethyl group, Rubamoylmethyl group, 2 rubamoylethyl group, Carbamoylmethyl group, 2-methylcarbamoyl E methyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoyl E methyl group, Jefferies Chi carbamoylmethyl group, a force Luba Moyle § amino methyl, methylcarbamoylamino main A trifluoromethyl group, 2, 2, 2-triflul, more preferably a til group, an ethylcarbamoylaminomethyl group, a dimethylcarbamoylaminomethyl group, a dimethylcarbamoylaminomethyl group, and a methylsulfo-luminaminomethyl group Particularly preferred are oloethyl, hydroxymethyl, 2-methoxyethyl and 2-fluorethyl groups.
[0020] 置換フエノキシ基としては、水酸基、ハロゲン原子、低級アルコキシ基、置換もしくは 非置換の低級アルキル基、および置換もしくは非置換のァミノ基の中力 選ばれる 1 または 2個の基が置換したフエノキシ基が挙げられ、フルオロフエノキシ基、クロ口フエ ノキシ基、ブロモフエノキシ基、メトキシフエノキシ基、エトキシフエノキシ基、メチルフエ ノキシ基、ェチルフエノキシ基、トリフルォロメチルフエノキシ基、ジメチルフエノキシ基 、フルオローメチルフエノキシ基、クロローメチルフエノキシ基、ジフルオロフエノキシ基 、ジクロロフエノキシ基、クロ口一フルオロフエノキシ基等を代表例として挙げることが できる。これらの中で、フルオロフエノキシ基、クロロフエノキシ基、ブロモフエノキシ基 、メチルフエノキシ基、トリフルォロメチルフエノキシ基が好ましい。 [0020] The substituted phenoxy group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a phenoxy substituted with 1 or 2 groups selected from the central forces of a substituted or unsubstituted amino group. Groups such as fluorophenoxy, chlorophenoxy, bromophenoxy, methoxyphenoxy, ethoxyphenoxy, methylphenoxy, ethylphenoxy, trifluoromethylphenoxy, dimethylphenol Representative examples include an enoxy group, a fluoromethylphenoxy group, a chloromethylphenoxy group, a difluorophenoxy group, a dichlorophenoxy group, and a black chlorophenoxy group. Of these, a fluorophenoxy group, a chlorophenoxy group, a bromophenoxy group, a methylphenoxy group, and a trifluoromethylphenoxy group are preferable.
[0021] 置換フエ-ル基としては、水酸基、ハロゲン原子、低級アルコキシ基、低級ァルケ- ル基、メチルスルホ -ルォキシ基、置換もしくは非置換の低級アルキル基、および置 換もしくは非置換のァミノ基の中力 選ばれる 1または 2個の基が置換したフエニル基 が挙げられ、ヒドロキシフエ-ル基、フルオロフェ-ル基、クロ口フエ-ル基、ブロモフ ェ-ル基、メトキシフエ-ル基、エトキシフエ-ル基、ビュルフエ-ル基、メチルスルホ -ルォキシフエ-ル基、メチルフエ-ル基、ェチルフエ-ル基、 tert—ブチルフエ-ル 基、トリフルォロメチルフエ-ル基、ァミノフエ-ル基、メチルァミノフエ-ル基、ェチル ァミノフエ-ル基、ジメチルァミノフエ-ル基、ジェチルァミノフエ-ル基、およびメチル スルホ -ルァミノフエ-ル基をモノ置換フエ-ル基の代表例として挙げることができ、 ジメチルフエ-ル基、メチルートリフルォロメチルフエ-ル基、フルオローメチルフエ- ル基、クロローメチルフエ-ル基、フルオローヒドロキシフエ-ル基、クロローヒドロキシ フエ-ル基、ジフルオロフェ-ル基、ジクロロフエ-ル基、クロ口一フルオロフェ-ル基 、アミノーフルオロフェ-ル基、アミノークロ口フエ-ル基、フルオローメチルァミノフエ -ル基、クロローメチルァミノフエ-ル基、ジメチルアミノーフルオロフェ-ル基、ジメチ ルァミノークロ口フエ-ル基、ジェチルアミノーフルオロフェ-ル基、クロロージェチル
ァミノフエ-ル基、フルオローメトキシフエ-ル基、クロローメトキシフエ-ル基、ェチレ ンジォキシフエニル基等をジ置換フエニル基の代表例として挙げることができる。これ らの中で、ヒドロキシフエ-ル基、クロ口フエ-ル基、フルオロフェ-ル基、ブロモフエ- ル基、メトキシフエ-ル基、メチルフエ-ル基、トリフルォロメチルフエ-ル基、メチルス ルホ-ルォキシフエ-ル基、およびメチルスルホ -ルァミノフエ-ル基が好まし 、。 [0021] The substituted phenol group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group. Examples include phenyl groups substituted with 1 or 2 groups selected, such as hydroxyphenyl group, fluorophenol group, black-opened phenyl group, bromophenol group, methoxyphenyl group, and ethoxyphenol group. Group, butylphenol group, methylsulfophenyl group, methylphenol group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group Typical examples of mono-substituted phenyl groups are ethylaminophenol, dimethylaminophenol, dimethylaminophenol, and methylsulfophenol. Dimethylphenol group, methyl-trifluoromethylphenol group, fluoromethylphenyl group, chloromethylphenol group, fluorohydroxyphenyl group, chlorohydroxyphenyl group Group, difluorophenol group, dichlorophenol group, black-and-fluorophenol group, amino-fluorophenol group, amino-chlorophenol group, fluoromethylaminophenol group and chloromethyl Aminophenol group, dimethylamino-fluorophenol group, dimethylaminochlorophenol group, jetylamino-fluorophenol group, chloro-jetyl Aminophenyl group, fluoromethoxyphenyl group, chloromethoxyphenyl group, ethylenediphenyl group and the like can be given as typical examples of disubstituted phenyl groups. Among them, hydroxyphenyl group, black-faced phenyl group, fluorophenol group, bromophenol group, methoxyphenyl group, methylphenol group, trifluoromethylphenol group, methylsulfur group. -Luxoxyphenyl groups and methylsulfo-aminophenol groups are preferred.
[0022] 置換アミノ基としては、低級アルキルアミノ基、ジ低級アルキルアミノ基、低級アルコ キシカルボ-ルァミノ基、力ルバモイルァミノ基、低級アルキル力ルバモイルァミノ基、 ジ低級アルキル力ルバモイルァミノ基、低級アルキルスルホ -ルァミノ基、および低 級アルカノィルァミノ基が挙げられ、メチルァミノ基、ェチルァミノ基、プロピルアミノ基 、ブチルァミノ基、ペンチルァミノ基、へキシルァミノ基、イソプロピルアミノ基、 tert— ブチルァミノ基、 sec—ブチルァミノ基、ジメチルァミノ基、ジェチルァミノ基、ジプロピ ルァミノ基、ジブチルァミノ基、ジペンチルァミノ基、ジへキシルァミノ基、ジイソプロピ ルァミノ基、メチルェチルァミノ基、メトキシカルボ-ルァミノ基、エトキシカルボ-ルァ ミノ基、力ルバモイルァミノ基、メチルカルバモイルァミノ基、ェチルカルバモイルアミ ノ基、ジメチルカルバモイルァミノ基、ジェチルカルバモイルァミノ基、メチルスルホ- ルァミノ基、ェチルスルホ -ルァミノ基、ァセチルァミノ基、およびプロピオ-ルァミノ 基を代表例として挙げることができ、メチルァミノ基、ェチルァミノ基、イソプロピルアミ ノ基、ジメチルァミノ基、ジェチルァミノ基、ジプロピルアミノ基、メチルェチルァミノ基 、メトキシカルボ-ルァミノ基、エトキシカルボ-ルァミノ基、力ルバモイルァミノ基、メ チルカルバモイルァミノ基、ェチルカルバモイルァミノ基、ジメチルカルバモイルァミノ 基、ジェチルカルバモイルァミノ基、メチルスルホ -ルァミノ基、ェチルスルホ -ルアミ ノ基、ァセチルァミノ基が好ましい。 [0022] The substituted amino group includes a lower alkylamino group, a di-lower alkylamino group, a lower alkoxycarbolamino group, a strong ruberamoylamino group, a lower alkyl force ruberamoylamino group, a di-lower alkyl force ruberamoylamino group, and a lower alkylsulfo-amino group. , And lower alkanoylamino groups, such as methylamino group, ethylamino group, propylamino group, butyramino group, pentylamino group, hexylamino group, isopropylamino group, tert-butylamino group, sec-butylamino group, dimethylamino group, Jetylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, diisopropylamino group, methylethylamino group, methoxycarbolamino group, ethoxycarboamino group, force rubamoi Typical examples are amino group, methylcarbamoylamino group, ethylcarbamoylamino group, dimethylcarbamoylamino group, jetylcarbamoylamino group, methylsulfolumino group, ethylsulfo-lumino group, acetylamino group, and propio-ramino group. Methylamino group, ethylamino group, isopropylamino group, dimethylamino group, jetylamino group, dipropylamino group, methylethylamino group, methoxycarbolamamino group, ethoxycarbolamamino group, strong ruberamoylamino group. A methylcarbamoylamino group, an ethylcarbamoylamino group, a dimethylcarbamoylamino group, a jetylcarbamoylamino group, a methylsulfo-lumino group, an ethylsulfo-amino group, and an acetylamino group are preferred.
[0023] 以下に、 Qについて説明する。 [0023] Hereinafter, Q will be described.
Qは、水酸基、ハロゲン原子、低級アルケニル基、低級アルコキシ基、置換もしくは 非置換の低級アルキル基、および置換もしくは非置換のァミノ基の中力 選ばれる 1 または 2個の基で置換されてもよいベンゼン環を示し、ハロゲン原子、低級ァルケ- ル基、低級アルコキシ基、および置換もしくは非置換の低級アルキル基の中力ゝら選 ばれる 1または 2個の基で置換されてもょ 、ベンゼン環が好ましぐ低級アルコキシ基
および置換もしくは非置換の低級アルキル基の中カゝら選ばれる 1または 2個の基で置 換されてもょ 、ベンゼン環がより好ま 、。 Q may be substituted with one or two groups selected from the group consisting of a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group. A benzene ring, which may be substituted with one or two groups selected from among halogen atoms, lower alkenyl groups, lower alkoxy groups, and substituted or unsubstituted lower alkyl groups; Preferred lower alkoxy group And a benzene ring is more preferred, when substituted with one or two groups selected from among a substituted or unsubstituted lower alkyl group.
[0024] 具体的には、ヒドロキシベンゼン環、フルォロベンゼン環、クロ口ベンゼン環、ブロモ ベンゼン環、ビュルベンゼン環、ァリルベンゼン環、メトキシベンゼン環、エトキシベン ゼン環、メチルベンゼン環、ェチルベンゼン環、 tert—ブチルベンゼン環、トリフルォ ロメチルベンゼン環、ァミノベンゼン環、メチルァミノベンゼン環、ェチルァミノべンゼ ン環、ジメチルァミノベンゼン環、ジェチルァミノベンゼン環をモノ置換ベンゼン環の 代表例として挙げることができ、ジメチルベンゼン環、メチル一トリフルォロメチルベン ゼン環、フルオローメチルベンゼン環、クロローメチルベンゼン環、フルオローヒドロキ シベンゼン環、クロ口一ヒドロキシベンゼン環、ジフルォロベンゼン環、ジクロロべンゼ ン環、クロローフルォロベンゼン環、アミノーフルォロベンゼン環、アミノークロ口ベン ゼン環、フルオローメチルァミノベンゼン環、クロローメチルァミノベンゼン環、ジメチ ルァミノーフルォロベンゼン環、ジメチルアミノークロ口ベンゼン環、ジェチルアミノー フルォロベンゼン環、クロロージェチルァミノベンゼン環、フルオローメトキシベンゼン 環、クロローメトキシベンゼン環、エチレンジォキシベンゼン環等をジ置換ベンゼン環 の代表例として挙げることができる。それらの中では、メチルベンゼン環、ジメチルべ ンゼン環、メトキシベンゼン環、フルォロベンゼン環、トリフルォロメチルベンゼン環、 およびァリルベンゼン環が好ましぐメチルベンゼン環、ジメチルベンゼン環、および メトキシベンゼン環がより好ましい。 [0024] Specifically, a hydroxybenzene ring, a fluorobenzene ring, a black benzene ring, a bromobenzene ring, a butylbenzene ring, an arylbenzene, a methoxybenzene ring, an ethoxybenzene ring, a methylbenzene ring, an ethylbenzene ring, and tert-butylbenzene The ring, trifluoromethylbenzene ring, aminobenzene ring, methylaminobenzene ring, ethylaminobenzene ring, dimethylaminobenzene ring, and jetylaminobenzene ring can be listed as typical examples of mono-substituted benzene rings. Benzene ring, methyl-trifluoromethylbenzene ring, fluoro-methylbenzene ring, chloro-methylbenzene ring, fluoro-hydroxybenzene ring, black-hydroxybenzene ring, difluorobenzene ring, dichlorobenzene ring, Chlorofluoro Ring, amino-fluorobenzene ring, amino-chlorobenzene ring, fluoro-methylaminominobenzene ring, chloromethylaminoaminobenzene ring, dimethylaminofluorobenzene ring, dimethylamino-chlorobenzene ring, Typical examples of the di-substituted benzene ring include a jetylamino-fluorobenzene ring, a chloro-jetylaminobenzene ring, a fluoro-methoxybenzene ring, a chloro-methoxybenzene ring, and an ethylenedioxybenzene ring. Among them, a methylbenzene ring, a dimethylbenzene ring, and a methoxybenzene ring are more preferable, with a methylbenzene ring, a dimethylbenzene ring, a methoxybenzene ring, a fluorobenzene ring, a trifluoromethylbenzene ring, and an arylbenzene ring being preferred. .
[0025] 以下に R1について説明する。 [0025] R 1 will be described below.
R1が、水酸基、ハロゲン原子、低級アルケニル基、置換もしくは非置換の低級アル コキシ基、置換もしくは非置換のフエノキシ基、置換もしくは非置換のフエ二ル基、置 換もしくは非置換の低級アルキル基、および置換もしくは非置換のアミノ基力 選ば れる 1または 2個の基で置換されてもよいフエ-ル基である場合には、非置換のフエ -ル基に加えて、ヒドロキシフヱ-ル基、フルオロフヱ-ル基、クロロフヱ-ル基、ブロ モフエ-ル基、ビュルフエ-ル基、メトキシフエ-ル基、エトキシフエ-ル基、 2—メトキ シエトキシフエ-ル基、フエノキシフエ-ル基、フルオロフエノキシフエ-ル基、クロロフ エノキシフヱ-ル基、ビフヱ-ル基、フルオロフヱ-ルーフヱ-ル基、メチルフエ-ル
基、ェチルフエ-ル基、 tert—ブチルフエ-ル基、トリフルォロメチルフヱ-ル基、アミ ノフエ-ル基、メチルァミノフエ-ル基、ェチルァミノフエ-ル基、ジメチルァミノフエ- ル基、ジェチルァミノフエ二ル基をモノ置換フエ-ル基の代表例として挙げることがで き、ジメチルフエ-ル基、メチルートリフルォロメチルフエ-ル基、フルオローメチルフ ェ-ル基、クロ口一メチルフエ-ル基、フルォロ一ヒドロキシフエ-ル基、クロ口一ヒドロ キシフエ-ル基、ジフルオロフェ-ル基、ジクロロフエ-ル基、クロ口一フルオロフェ- ル基、アミノーフルオロフェ-ル基、アミノークロ口フエ-ル基、フルオローメチルァミノ フエ-ル基、クロローメチルァミノフエ-ル基、ジメチルアミノーフルオロフェ-ル基、ジ メチルアミノークロ口フエ-ル基、ジェチルアミノーフルオロフェ-ル基、クロロージェ チルァミノフエ-ル基、フルオローメトキシフエ-ル基、クロローメトキシフエ-ル基、ェ チレンジォキシフエニル基等をジ置換フエ-ル基の代表例として挙げることができる。 これらの中で、フヱ -ル基、フルオロフヱ-ル基、クロロフヱ-ル基、ブロモフヱ-ル基 、メトキシフエ-ル基、メチルフエ-ル基、トリフルォロメチルフエ-ル基、ジメチルフエ -ル基、および 2—メトキシェトキシフエ-ル基が好ましぐフエ-ル基、クロ口フエニル 基、フルオロフヱ-ル基、メトキシフヱ-ル基、メチルフヱ-ル基、ジメチルフヱ-ル基 、および 2—メトキシェトキシフエ-ル基がより好ましい。 R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group. And a substituted or unsubstituted amino group, in the case of a phenyl group which may be substituted with one or two selected groups, in addition to the unsubstituted phenol group, a hydroxyphenol group, Fluorophenol group, Chlorophenol group, Bromophenol group, Buhlphenol group, Methoxyphenol group, Ethoxyphenyl group, 2-Methoxyethoxyphenyl group, Phenoxyphenyl group, Fluorophenyl group Group, chlorophenol group, biphenyl group, fluoro-furol group, methylphenol Group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group, ethylaminophenol group, dimethylaminophenol group, jetyl The aminophenyl group can be cited as a typical example of a mono-substituted phenyl group, such as a dimethylphenol group, a methyl-trifluoromethylphenol group, a fluoromethylphenol group, a black mouth. 1-methylphenol group, fluoro-hydroxyphenyl group, black-hydroxyl group, difluorophenol group, dichloro-phenol group, black-fluorophenol group, amino-fluorophenol group, Amino-black mouth phenyl group, fluoro-methylamino phenol group, chloro-methyl amino-phenol group, dimethylamino-fluorophenol group, dimethylamino-chlorophenol group, jetylamino Fluorophenol group, chloro-diethylaminophenol group, fluoro-methoxyphenyl group, chloro-methoxyphenyl group, ethylenediphenyl group, etc. can be mentioned as typical examples of disubstituted phenol groups. it can. Among these, a phenol group, a fluorophenol group, a chlorophenol group, a bromophenol group, a methoxyphenol group, a methylphenol group, a trifluoromethylphenol group, a dimethylphenol group, And 2-methoxyphenyl groups are preferred, chlorophenyl, fluorophenyl, methoxyphenol, methylphenol, dimethylphenol, and 2-methoxyethoxy. A phenol group is more preferred.
R1が、水酸基、ハロゲン原子、低級アルケニル基、置換もしくは非置換の低級アル コキシ基、置換もしくは非置換のフエノキシ基、置換もしくは非置換のフエ二ル基、置 換もしくは非置換の低級アルキル基、および置換もしくは非置換のアミノ基力 選ば れる 1または 2個の基で置換されてもよいナフチル基である場合は、非置換のナフチ ル基にカロえて、ヒドロキシナフチル基、フルォロナフチル基、クロロナフチル基、ブロ モナフチル基、ビニルナフチル基、メトキシナフチル基、エトキシナフチル基、メチル ナフチル基、ェチルナフチル基、 tert—ブチルナフチル基、トリフルォロメチルナフ チル基、ァミノナフチル基、メチルァミノナフチル基、ェチルァミノナフチル基、ジメチ ルァミノナフチル基、ジェチルァミノナフチル基をモノ置換ナフチル基の代表例として 挙げることができ、ジメチルナフチル基、メチル一トリフルォロメチルナフチル基、フル オローメチルナフチル基、クロローメチルナフチル基、フルオローヒドロキシナフチル 基、クロローヒドロキシナフチル基、ジフルォロナフチル基、ジクロロナフチル基、クロ
ローフルォロナフチル基、アミノーフルォロナフチル基、アミノークロロナフチル基、フ ルオローメチルァミノナフチル基、クロローメチルァミノナフチル基、ジメチルアミノー フルォロナフチル基、ジメチルアミノークロロナフチル基、ジェチルアミノーフルォロナ フチル基、クロロージェチルァミノナフチル基、フルオローメトキシナフチル基、およ びクロローメトキシナフチル基をジ置換ナフチル基の代表例として挙げることができる 。これらの中で、ナフチル基、フルォロナフチル基、クロロナフチル基、ブロモナフチ ル基、トリフルォロナフチル基が好ましぐナフチル基、クロロナフチル基、およびトリ フルォロナフチル基がより好まし 、。 R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group. In the case of a naphthyl group that may be substituted with one or two selected groups, hydroxy naphthyl group, fluoronaphthyl group, chloronaphthyl Group, bromonaphthyl group, vinyl naphthyl group, methoxy naphthyl group, ethoxy naphthyl group, methyl naphthyl group, ethyl naphthyl group, tert-butyl naphthyl group, trifluoromethyl naphthyl group, amino naphthyl group, methylamino naphthyl group, ethyl Aminonaphthyl group, dimethylaminonaphthyl group, jetylaminonaphthyl group Typical examples of the non-substituted naphthyl group include dimethyl naphthyl group, methyl monotrifluoromethyl naphthyl group, fluoromethyl naphthyl group, chloro-methyl naphthyl group, fluoro-hydroxy naphthyl group, chloro-hydroxy naphthyl group, Difluoronaphthyl group, dichloronaphthyl group, chloro Low fluoronaphthyl, amino-fluoronaphthyl, amino-chloronaphthyl, fluoromethylaminonaphthyl, chloromethylaminonaphthyl, dimethylamino-fluoronaphthyl, dimethylamino-chloronaphthyl, A typical example of a disubstituted naphthyl group is a jetylamino-fluoronaphthyl group, a chloro-jetylaminonaphthyl group, a fluoro-methoxynaphthyl group, or a chloro-methoxynaphthyl group. Of these, naphthyl, chloronaphthyl, chloronaphthyl, bromonaphthyl, trifluoronaphthyl, naphthyl, chloronaphthyl, and trifluoronaphthyl are more preferred.
[0027] R1が、水酸基、ハロゲン原子、低級アルケニル基、置換もしくは非置換の低級アル コキシ基、置換もしくは非置換のフエノキシ基、置換もしくは非置換のフエ二ル基、置 換もしくは非置換の低級アルキル基、および置換もしくは非置換のアミノ基力 選ば れる 1または 2個の基で置換されてもよい 5または 6員の芳香族複素環基である場合 について説明する。 [0027] R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted group. The case of a lower alkyl group and a 5- or 6-membered aromatic heterocyclic group which may be substituted with 1 or 2 groups selected from substituted or unsubstituted amino groups will be described.
5または 6員の芳香族複素環とは、環構造の構成要素として 1つ以上の窒素原子、 酸素原子または硫黄原子を含む 5または 6員の芳香環を意味する。具体例としては、 ピリジン環、ピリミジン環、ピリダジン環、ピラジン環、チォフェン環、フラン環、ピロ一 ル環、イミダゾール環、ピラゾール環、チアゾール環、イソチアゾール環、ォキサゾー ル環、イソォキサゾール環、ォキサジァゾール環、トリァゾール環、およびチアジアゾ 一ル環を挙げることができる。それらの中で、ピリジン環、ピリミジン環、フラン環、チア ゾール環、およびォキサゾール環が好ましぐピリジン環、フラン環、チアゾール環、 およびォキサゾール環がより好ま U、。 A 5- or 6-membered aromatic heterocycle means a 5- or 6-membered aromatic ring containing one or more nitrogen, oxygen or sulfur atoms as a constituent of the ring structure. Specific examples include pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, thiophene ring, furan ring, pyrrole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, oxadiazole ring. , Triazole rings, and thiadiazol rings. Among them, a pyridine ring, a furan ring, a thiazole ring, and an oxazole ring are preferred, and a pyridine ring, a pyrimidine ring, a furan ring, a thiazole ring, and an oxazole ring are preferred.
[0028] 以下に具体的な例について説明する。 [0028] A specific example will be described below.
芳香族複素環がピリジン環である場合、 R1は、ピリジル基、フルォロピリジル基、クロ 口ピリジル基、ブロモピリジル基、トリフルォロメチルピリジル基、フエ-ルビリジル基、 およびメトキシピリジル基が好ましぐピリジル基、クロ口ピリジル基、トリフルォロメチル ピリジル基、およびメトキシピリジル基がより好まし 、。 When the aromatic heterocycle is a pyridine ring, R 1 is preferably a pyridyl group, a fluoropyridyl group, a cyclopyridyl group, a bromopyridyl group, a trifluoromethylpyridyl group, a ferrobiridyl group, or a methoxypyridyl group. Pyridyl group, black-and-white pyridyl group, trifluoromethyl pyridyl group, and methoxypyridyl group are more preferred.
芳香族複素環がピリミジン環である場合、 R1は、ピリミジ -ル基、フルォロピリミジ- ル基、クロ口ピリミジ -ル基、ブロモピリミジ -ル基、トリフルォロメチルピリミジ -ル基、
フエニルピリミジニル基、およびメトキシピリミジニル基が好ましぐピリミジ -ル基、クロ 口ピリミジ -ル基、トリフルォロメチルピリミジ -ル基、およびメトキシピリミジ-ル基がよ り好ましい。 When the aromatic heterocycle is a pyrimidine ring, R 1 represents a pyrimidyl group, a fluoropyrimidyl group, a black-opened pyrimidyl group, a bromopyrimidyl group, a trifluoromethylpyrimidyl group, Pyrimidyl, chloropyrimidyl, trifluoromethylpyrimidyl, and methoxypyrimidyl groups are more preferred, as are phenylpyrimidinyl and methoxypyrimidinyl groups.
[0029] 芳香族複素環がピリダジン環である場合、 R1は、ピリダジ -ル基、フルォロピリダジ -ル基、クロロピリダジ-ル基、ブロモピリダジ-ル基、トリフルォロメチルピリダジ-ル 基、およびメトキシピリダジニル基が好ましぐピリダジニル基、クロロピリダジニル基、 トリフルォロメチルピリダジ-ル基、およびメトキシピリダジ-ル基がより好まし 、。 芳香族複素環がピラジン環である場合、 R1は、ビラジニル基、フルォロビラジニル基 、クロロビラジ-ル基、ブロモピラジュル基、トリフルォロメチルピラジュル基、およびメ トキシピラジニル基が好ましぐピラジュル基、クロロビラジ-ル基、トリフルォロメチル ピラジュル基、およびメトキシピラジュル基がより好まし 、。 [0029] When the aromatic heterocycle is a pyridazine ring, R 1 represents a pyridazyl group, a fluoropyridazil group, a chloropyridazyl group, a bromopyridazyl group, a trifluoromethylpyridazil group, and A methoxypyridazinyl group is preferred, a pyridazinyl group, a chloropyridazinyl group, a trifluoromethylpyridazyl group, and a methoxypyridazyl group are more preferred. When the aromatic heterocyclic ring is a pyrazine ring, R 1 is preferably a birazinyl group, a fluorobirazinyl group, a chlorobirazyl group, a bromopyrazuryl group, a trifluoromethylpyrazuryl group, or a methoxypyrazinyl group. More preferred are a pyrajur group, a chlorovirazyl group, a trifluoromethyl pyrajur group, and a methoxypyradur group.
[0030] 芳香族複素環がチォフェン環である場合、 R1は、チェ-ル基、フルォロチェ-ル基 、クロ口チェ-ル基、ブロモチェ-ル基、トリフルォロメチルチェ-ル基、およびメトキ シチェ-ル基が好ましぐチェ-ル基、クロ口チェ-ル基、トリフルォロメチルチェ-ル 基、およびメトキシチェニル基がより好ましい。 [0030] When the aromatic heterocycle is a thiophene ring, R 1 represents a chael group, a fluorchael group, a black-eye chaer group, a bromochael group, a trifluoromethyl chaer group, and More preferred are a methoxy group, a chloro group, a trifluoromethyl group, and a methoxy group.
芳香族複素環がフラン環である場合、 R1は、フリル基、フルオロフリル基、クロロフリ ル基、ブロモフリル基、トリフルォロメチルフリル基、およびメトキシフリル基が好ましく 、フリル基、クロ口フリル基、トリフルォロメチルフリル基、およびメトキシフリル基がより 好ましい。 When the aromatic heterocycle is a furan ring, R 1 is preferably a furyl group, a fluorofuryl group, a chlorofuryl group, a bromofuryl group, a trifluoromethylfuryl group, or a methoxyfuryl group, and a furyl group, a chlorofuryl group , Trifluoromethylfuryl group, and methoxyfuryl group are more preferred.
芳香族複素環がピロール環である場合、 R1は、ピロリル基、フルォロピロリル基、ク ロロピロリル基、ブロモピロリル基、トリフルォロメチルピロリル基、およびメトキシピロリ ル基が好ましぐピロリル基、クロ口ピロリル基、トリフルォロメチルピロリル基、およびメ トキシピロリル基がより好まし 、。 When the aromatic heterocyclic ring is a pyrrole ring, R 1 is a pyrrolyl group, a chloropyrrolyl group, a chloropyrrolyl group, a bromopyrrolyl group, a trifluoromethylpyrrolyl group, or a methoxypyrrolyl group, and a chloropyrrole group. Pyrrolyl, trifluoromethylpyrrolyl, and methoxypyrrolyl groups are more preferred.
[0031] 芳香族複素環力 Sイミダゾール環である場合、 R1は、イミダゾリル基、フルォロイミダゾ リル基、クロロイミダゾリル基、ブロモイミダゾリル基、トリフルォロメチルイミダゾリル基、 およびメトキシイミダゾリル基が好ましぐイミダゾリル基、クロロイミダゾリル基、トリフル ォロメチルイミダゾリル基、およびメトキシイミダゾリル基がより好まし 、。 [0031] Aromatic heterocyclic ring In the case of an S imidazole ring, R 1 is preferably an imidazolyl group, a fluorloyimidazolyl group, a chloroimidazolyl group, a bromoimidazolyl group, a trifluoromethylimidazolyl group, or a methoxyimidazolyl group. More preferred are groups, chloroimidazolyl, trifluoromethylimidazolyl, and methoxyimidazolyl.
芳香族複素環がピラゾール環である場合、 R1は、ピラゾリル基、フルォロビラゾリル
基、クロロビラゾリル基、ブロモピラゾリル基、トリフルォロメチルピラゾリル基、およびメ トキシピラゾリル基が好ましぐピラゾリル基、クロロビラゾリル基、トリフルォロメチルピ ラゾリル基、およびメトキシピラゾリル基がより好まし 、。 When the aromatic heterocycle is a pyrazole ring, R 1 is a pyrazolyl group, fluorovirazolyl Groups, chlorovirazolyl, bromopyrazolyl, trifluoromethylpyrazolyl, and methoxypyrazolyl are preferred, pyrazolyl, chlorovirazolyl, trifluoromethylpyrazolyl, and methoxypyrazolyl are more preferred.
芳香族複素環がチアゾール環である場合、 R1は、チアゾリル基、フルォロチアゾリ ル基、クロ口チアゾリル基、ブロモチアゾリル基、トリフルォロメチルチアゾリル基、およ びメトキシチアゾリル基が好ましぐチアゾリル基、クロ口チアゾリル基、トリフルォロメチ ルチアゾリル基、およびメトキシチアゾリル基がより好まし!/、。 When the aromatic heterocyclic ring is a thiazole ring, R 1 is preferably a thiazolyl group, a fluorothiazolyl group, a black thiazolyl group, a bromothiazolyl group, a trifluoromethylthiazolyl group, or a methoxythiazolyl group. More preferred are thiazolyl, black thiazolyl, trifluoromethylthiazolyl, and methoxythiazolyl! / ,.
[0032] 芳香族複素環力 Sイソチアゾール環である場合、 R1は、イソチアゾリル基、フルォロイ ソチアゾリル基、クロ口イソチアゾリル基、ブロモイソチアゾリル基、トリフルォロメチルイ ソチアゾリル基、およびメトキシイソチアゾリル基が好ましぐイソチアゾリル基、クロロイ ソチアゾリル基、トリフルォロメチルイソチアゾリル基、およびメトキシイソチアゾリル基 力 り好ましい。 [0032] In the case of an aromatic heterocyclic force S isothiazole ring, R 1 is an isothiazolyl group, a fluoroloy thiazolyl group, a black isothiazolyl group, a bromoisothiazolyl group, a trifluoromethylisothiazolyl group, and a methoxyisothiazolyl An isothiazolyl group, a chloroisothiazolyl group, a trifluoromethylisothiazolyl group, and a methoxyisothiazolyl group, which are preferable to a ryl group, are more preferable.
芳香族複素環がォキサゾール環である場合、 R1は、ォキサゾリル基、フルォロォキ サゾリル基、クロロォキサゾリル基、ブロモォキサゾリル基、トリフルォロメチルォキサゾ リル基、およびメトキシォキサゾリル基が好ましぐォキサゾリル基、クロロォキサゾリル 基、トリフルォロメチルォキサゾリル基、およびメトキシォキサゾリル基がより好ましい。 芳香族複素環力 Sイソォキサゾール環である場合、 R1は、イソォキサゾリル基、フルォ ロイソォキサゾリル基、クロロイソォキサゾリル基、ブロモイソォキサゾリル基、トリフル ォロメチルイソォキサゾリル基、およびメトキシイソォキサゾリル基が好ましぐイソォキ サゾリル基、クロロイソォキサゾリル基、トリフルォロメチルイソォキサゾリル基、および メトキシイソォキサゾリル基がより好ま 、。 When the aromatic heterocycle is an oxazole ring, R 1 represents an oxazolyl group, a fluoroxazolyl group, a chlorooxazolyl group, a bromooxazolyl group, a trifluoromethyloxazolyl group, and a methoxyoxaxyl group. Of these, oxazolyl, chlorooxazolyl, trifluoromethyloxazolyl, and methoxyoxazolyl are preferred. Aromatic heterocyclic force In the case of S isoxazole ring, R 1 is an isoxazolyl group, a fluoroisoxazolyl group, a chloroisoxazolyl group, a bromoisoxazolyl group, a trifluoromethylisooxazol group. Izoxazolyl, chloroisoxazolyl, trifluoromethylisoxazolyl, and methoxyisoxazolyl are more preferred than zolyl and methoxyisoxazolyl ,.
[0033] 芳香族複素環がォキサジァゾール環である場合、 R1は、ォキサジァゾリル基、フル ォロォキサジァゾリル基、クロ口ォキサジァゾリル基、ブロモォキサジァゾリル基、メチ ルォキサジァゾリル基、ェチルォキサジァゾリル基、トリフルォロメチルォキサジァゾリ ル基、およびメトキシォキサジァゾリル基が好ましぐォキサジァゾリル基、クロロォキ サジァゾリル基、メチルォキサジァゾリル基、ェチルォキサジァゾリル基、トリフルォロ メチルォキサジァゾリル基、およびメトキシォキサジァゾリル基がより好ま U、。 [0033] When the aromatic heterocyclic ring is an oxadiazole ring, R 1 represents an oxadiazolyl group, a fluoroxadiazolyl group, a clooxadiazolyl group, a bromooxadiazolyl group, a methyloxazia Zolyl, ethyloxadiazolyl, trifluoromethyloxadiazolyl, and methoxyoxadiazolyl are preferred. Oxadiazolyl, chloroxadiazolyl, methyloxadi U, more preferred are azolyl, ethyloxadiazolyl, trifluoromethyloxadiazolyl, and methoxyoxadiazolyl.
芳香族複素環がトリァゾール環である場合、 R1は、トリァゾリル基、フルォロトリアゾリ
ル基、クロロトリアゾリル基、ブロモトリアゾリル基、トリフルォロメチルトリァゾリル基、お よびメトキシトリァゾリル基が好ましぐトリァゾリル基、クロロトリアゾリル基、トリフルォロ メチルトリァゾリル基、およびメトキシトリアゾリル基がより好まし!/、。 When the aromatic heterocycle is a triazole ring, R 1 is a triazolyl group, a fluorotriazolyl. Group, chlorotriazolyl group, bromotriazolyl group, trifluoromethyltriazolyl group, and methoxytriazolyl group are preferred triazolyl group, chlorotriazolyl group, trifluoromethyltriazolyl group , And methoxytriazolyl groups are more preferred!
以上 R1について述べた中で、フエ-ル基、クロ口フエ-ル基、フルオロフェ-ル基、 メトキシフエ-ル基、メチルフエ-ル基、およびジメチルフエ-ル基が特に好ましい。 In the above description of R 1 , a phenyl group, a black-opened phenyl group, a fluorophenol group, a methoxyphenyl group, a methylphenol group, and a dimethylphenol group are particularly preferable.
[0034] 以下に R2について説明する。 [0034] R 2 will be described below.
置換もしくは非置換の低級アルキル基は、前述のアルキル基を意味し、特に好まし い例としては、トリフルォロメチル基、 2, 2, 2—トリフルォロェチル基、メトキシメチル 基、および 2—メトキシェチル基を挙げることができる。 The substituted or unsubstituted lower alkyl group means the above-mentioned alkyl group, and particularly preferable examples include trifluoromethyl group, 2, 2, 2-trifluoroethyl group, methoxymethyl group, and 2 -Methoxyethyl group can be mentioned.
置換もしくは非置換の力ルバモイル基としては、 1または 2個の低級アルキル基で置 換されてもよい力ルバモイル基が挙げられ、具体例として、力ルバモイル基、メチルカ ルバモイル基、ジメチルカルバモイル基、ェチルカルバモイル基、ジェチルカルバモ ィル基、プロピル力ルバモイル基、イソプロピル力ルバモイル基、ブチルカルバモイル 基、ペンチルカルバモイル基を挙げることができ、力ルバモイル基、メチルカルバモイ ル基、ジメチルカルバモイル基、ェチルカルバモイル基、およびジェチルカルバモイ ル基が好ましい。 Examples of the substituted or unsubstituted force rubamoyl group include force rubamoyl groups which may be substituted with one or two lower alkyl groups. Specific examples include force rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, Examples include butyl carbamoyl group, jetyl carbamoyl group, propyl carbamoyl group, isopropyl carbamoyl group, butyl carbamoyl group, pentyl carbamoyl group, carbamoyl group, methyl carbamoyl group, dimethyl carbamoyl group, ethyl carbamoyl group. And a jetylcarbamoyl group are preferred.
[0035] 置換もしくは非置換のフエニル基としては、水酸基、ハロゲン原子、低級アルコキシ 基、低級アルケニル基、メチルスルホ -ルォキシ基、置換もしくは非置換の低級アル キル基、置換もしくは非置換のアミノ基、置換もしくは非置換のフヱ-ル基、置換もし くは非置換のフエノキシ基、および置換もしくは非置換のピリジル基力 選ばれる 1ま たは 2個の基で置換されてもよいフエ-ル基が挙げられる。具体例として、ヒドロキシ フエ-ル基、フルオロフェ-ル基、クロ口フエ-ル基、ブロモフエ-ル基、メトキシフエ- ル基、エトキシフエ-ル基、ビュルフエ-ル基、ァリルフエ-ル基、メチルスルホ -ルォ キシフエ-ル基、メチルフエ-ル基、ェチルフエ-ル基、 tert—ブチルフエ-ル基、ト リフルォロメチルフエ-ル基、ァミノフエ-ル基、メチルアミノフヱ-ル基、ェチルァミノ フエ-ル基、ジメチルアミノフヱ-ル基、ジェチルアミノフヱ-ル基、メチルスルホ -ル ァミノフエ-ル基、フエノキシフエ-ル基、フルオロフエノキシフエ-ル基、クロロフエノ キシフエ-ル基、ビフエ-ル基、およびフルオロフェ-ルーフエ-ル基をモノ置換フエ
-ル基の代表例として挙げることができ、ジメチルフエ-ル基、メチル一トリフルォロメ チルフエ-ル基、フルオローメチルフエ-ル基、クロローメチルフエ-ル基、フルォロ —ヒドロキシフエ-ル基、クロ口一ヒドロキシフエ-ル基、ジフルオロフェ-ル基、ジクロ 口フエ-ル基、クロ口一フルオロフェ-ル基、アミノーフルオロフェ-ル基、アミノークロ 口フエ-ル基、フルオローメチルァミノフエ-ル基、クロローメチルァミノフエ-ル基、ジ メチルアミノーフルオロフェ-ル基、ジメチルアミノークロ口フエ-ル基、ジェチルァミノ フルオロフェ-ル基、クロロージェチルァミノフエ-ル基、フルオローメトキシフエ- ル基、クロローメトキシフエ-ル基、エチレンジォキシフエ-ル基等をジ置換フエ-ル 基の代表例として挙げることができる。これらの中で、ヒドロキシフエ-ル基、クロ口フエ -ル基、フルオロフェ-ル基、ブロモフエ-ル基、メトキシフエ-ル基、メチルフエ-ル 基、トリフルォロメチルフエ-ル基、メチルスルホ -ルォキシフエ-ル基、およびメチル スルホ-ルアミノフヱ-ル基が好まし 、。 [0035] The substituted or unsubstituted phenyl group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, and a substituted group. Alternatively, an unsubstituted phenyl group, a substituted or unsubstituted phenoxy group, and a substituted or unsubstituted pyridyl group may be substituted with one or two selected phenyl groups. Can be mentioned. Specific examples include hydroxyphenol groups, fluorophenol groups, black-and-white phenyl groups, bromophenol groups, methoxyphenol groups, ethoxyphenol groups, butylphenol groups, arylphenol groups, and methylsulfol groups. Xylophyl group, methylphenol group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group, ethylaminophenol group, dimethylamino Phenyl group, jetylaminophenyl group, methylsulfoaminophenol group, phenoxyphenyl group, fluorophenol group, chlorophenol group, biphenyl group, and fluorophenol -Mono-substituted fue Typical examples of the benzene group include: dimethylphenol group, methyl trifluoromethyl group, fluoromethylphenol group, chloromethylphenol group, fluoro-hydroxyphenol group, Mouth hydroxyphenol group, difluorophenol group, diclonal phenyl group, black monofluorophenol group, amino-fluorophenol group, amino-chlorophenol group, fluoromethylaminophenol -Group, chloromethylaminophenol group, dimethylamino-fluorophenol group, dimethylamino-chlorophenol group, jetylaminofluorophenol group, chloro-demethylaminophenol group, Fluoromethoxyphenyl group, chloromethoxyphenyl group, ethylenedioxyphenyl group and the like can be mentioned as typical examples of disubstituted phenol groups. Among these, hydroxyphenyl group, black-faced phenol group, fluorophenol group, bromophenol group, methoxyphenol group, methylphenol group, trifluoromethylphenol group, methylsulfoxyphenyl group. -Methyl group, and methylsulfolaminophenol group are preferred.
[0036] 置換もしくは非置換の 5または 6員の芳香族複素環基としては、水酸基、ハロゲン原 子、低級アルコキシ基、低級アルケニル基、メチルスルホ -ルォキシ基、置換もしくは 非置換の低級アルキル基、置換もしくは非置換のアミノ基、置換もしくは非置換のフ ェニル基、置換もしくは非置換のフエノキシ基、および置換もしくは非置換のピリジル 基力も選ばれる 1または 2個の基で置換されてもよい 5または 6員の芳香族複素環基 が挙げられる。ここで、 5または 6員の芳香族複素環は、 R1で説明した 5または 6員の 芳香族複素環と同一であり、好ましい例も同様であるが、それらの中でも 5員の芳香 族複素環が好ましぐ特にフラン環、チアゾール環、ォキサゾール環、イソォキサゾー ル環、およびォキサジァゾール環が好ましい。具体的な置換基としては、フリル基、 チアゾリル基、ォキサゾリル基、イソォキサゾリル基、およびメチルォキサジァゾリル基 が特に好ましい。 [0036] The substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfo-oxy group, a substituted or unsubstituted lower alkyl group, and a substituted group. Alternatively, an unsubstituted amino group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenoxy group, and a substituted or unsubstituted pyridyl group may also be substituted with one or two groups that are also selected 5 or 6 Member aromatic heterocyclic group. Here, the 5- or 6-membered aromatic heterocycle is the same as the 5- or 6-membered aromatic heterocycle described in R 1 , and preferred examples are the same, but among them, the 5-membered aromatic heterocycle is the same. Rings are preferred, and a furan ring, a thiazole ring, an oxazole ring, an isoxazole ring, and an oxaziazole ring are particularly preferred. As specific substituents, a furyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, and a methyloxazazolyl group are particularly preferable.
以上 R2について述べた中で、特に好ましい基としては、力ルバモイル基、メチルカ ルバモイル基、ジメチルカルバモイル基、メトキシメチル基、 2—メトキシェチル基、ォ キサゾリル基、およびメチルォキサジァゾリル基が挙げられる。 Among the groups described above for R 2 , particularly preferred groups include rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, methoxymethyl group, 2-methoxyethyl group, oxazolyl group, and methyloxadiazolyl group. Can be mentioned.
[0037] 以下に R3〜R5について説明する。 [0037] R 3 to R 5 will be described below.
R3および R4が低級アルキル基である場合は、前述のアルキル基を意味し、具体的
には、メチル基、ェチル基、プロピル基、ブチル基、ペンチル基、へキシル基を代表 例として挙げることができ、各々独立に、メチル基、ェチル基が好ましぐメチル基がよ り好ましい。 When R 3 and R 4 are a lower alkyl group, it means the aforementioned alkyl group, specifically The methyl group, ethyl group, propyl group, butyl group, pentyl group and hexyl group can be mentioned as representative examples, and each independently preferred is a methyl group in which a methyl group or an ethyl group is preferred.
[0038] R5が低級アルキル基である場合には、前述のアルキル基を意味し、メチル基、ェチ ル基、プロピル基、 tert—ブチル基を好ましい例として挙げることができる。 [0038] When R 5 is a lower alkyl group means an alkyl group described above include a methyl group, E Ji group, a propyl group, a tert- butyl group Preferred examples.
R5が置換もしくは非置換のベンジル基である場合は、水酸基、ハロゲン原子、低級 アルコキシ基、低級アルケニル基、ニトロ基、置換もしくは非置換の低級アルキル基、 および置換もしくは非置換のアミノ基力 選ばれる 1または 2個の基で置換されてもよ いべンジル基が挙げられる。具体例として、ベンジル基、ヒドロキシベンジル基、フル ォ口べンジル基、クロ口べンジル基、ブロモベンジル基、メトキシベンジル基、エトキシ ベンジル基、ビュルべンジル基、ァリルべンジル基、ニトロべンジル基、メチルベンジ ル基、ェチルベンジル基、 tert—ブチルベンジル基、トリフルォロメチルベンジル基、 ァミノべンジル基、メチルァミノべンジル基、ェチルァミノべンジル基、ジメチルァミノ ベンジル基、ジェチルァミノべンジル基、およびメチルスルホ -ルァミノベンジル基を モノ置換べンジル基の代表例として挙げることができ、ジメチルベンジル基、メチルー トリフルォロメチルベンジル基、フルオローメチルベンジル基、クロローメチルベンジ ル基、フルオローヒドロキシベンジル基、クロ口一ヒドロキシベンジル基、ジフルォ口べ ンジル基、ジクロロべンジル基、クロローフルォ口べンジル基、アミノーフルォロベンジ ル基、アミノークロ口べンジル基、フルオローメチルァミノべンジル基、クロローメチル ァミノべンジル基、ジメチルアミノーフルォ口べンジル基、ジメチルアミノークロ口ベン ジル基、ジェチルアミノーフルォ口べンジル基、クロロージェチルァミノべンジル基、 フルオローメトキシベンジル基、クロローメトキシベンジル基、エチレンジォキシベンジ ル基等をジ置換べンジル基の代表例として挙げることができる。これらの中で、ベン ジル基、ヒドロキシベンジル基、クロ口べンジル基、フルォロベンジル基、ブロモベン ジル基、メトキシベンジル基、メチルベンジル基、トリフルォロメチルベンジル基、およ び-トロベンジル基が好まし 、。 When R 5 is a substituted or unsubstituted benzyl group, a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a nitro group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group are selected. Examples thereof include a benzyl group which may be substituted with 1 or 2 groups. Specific examples include a benzyl group, a hydroxybenzyl group, a fluorbenzyl group, a black benzyl group, a bromobenzyl group, a methoxybenzyl group, an ethoxybenzyl group, a burbenzil group, a arrylbenzyl group, and a nitrobenzyl group. , Methyl benzyl group, ethyl benzyl group, tert-butyl benzyl group, trifluoromethyl benzyl group, amamino benzyl group, methylamino benzyl group, ethylamino benzyl group, dimethylamino benzyl group, jetylamino benzyl group, and methyl sulfo-laminobenzyl group As typical examples of mono-substituted benzyl groups, dimethylbenzyl group, methyl-trifluoromethylbenzyl group, fluoro-methylbenzyl group, chloromethylbenzyl group, fluoro-hydroxybenzyl group, black-and-hydroxy group Ben Group, difluorine benzyl group, dichlorobenzil group, chlorofluorine benzyl group, amino-fluorobenzil group, amino-chloro benzyl group, fluoro-methylaminobenzil group, chloromethylaminobenzyl group, Dimethylamino-fluoro-benzyl group, dimethylamino-chloro-benzyl group, jetylamino-fluoro-benzyl group, chloro-jetylaminobenzyl group, fluoro-methoxybenzyl group, chloro-methoxybenzyl group An ethylenedioxybenzyl group can be given as a typical example of a di-substituted benzyl group. Of these, benzyl, hydroxybenzyl, black benzyl, fluorbenzyl, bromobenzyl, methoxybenzyl, methylbenzyl, trifluoromethylbenzyl, and -trobenzyl are preferred. ,.
[0039] R5としては、水素原子、メチル基、ェチル基、プロピル基、 tert—ブチル基、ベンジ ル基、 4—メトキシベンジル基、または 4— -トロベンジル基等を好ましい例として挙げ
ることがでさる。 [0039] Preferred examples of R 5 include a hydrogen atom, a methyl group, an ethyl group, a propyl group, a tert-butyl group, a benzyl group, a 4-methoxybenzyl group, or a 4-trobenzyl group. It can be done.
[0040] 以下に R6について説明する。 [0040] R 6 will be described below.
R6は、水素原子、水酸基、ハロゲン原子、低級アルケニル基、低級アルコキシ基、 置換もしくは非置換のフエノキシ基、置換もしくは非置換のフエ二ル基、置換もしくは 非置換の低級アルキル基、または置換もしくは非置換のアミノ基であるが、それぞれ それらの置換基は、前述の説明と同様である。それらの中で、水素原子、フッ素原子 、塩素原子、メチル基、ェチル基、イソプロピル基、トリフルォロメチル基、メトキシ基、 およびエトキシ基が好ましぐ水素原子、塩素原子、メチル基、ェチル基、イソプロピ ル基、トリフルォロメチル基、およびメトキシ基がより好ましい。 R 6 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted Although it is an unsubstituted amino group, each of those substituents is the same as described above. Among them, a hydrogen atom, a chlorine atom, a methyl group, or an ethyl group, preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methoxy group, or an ethoxy group. An isopropyl group, a trifluoromethyl group, and a methoxy group are more preferable.
mは 0〜3の整数であり、 1または 2が好ましい。 m is an integer of 0 to 3, preferably 1 or 2.
nは 1〜3の整数であり、 1または 2が好ましい。 n is an integer of 1 to 3, preferably 1 or 2.
以下に下記の 5員の芳香族複素環について説明する。 The following 5-membered aromatic heterocycle is described below.
[0041] [化 5] [0041] [Chemical 5]
[0042] (上記式中、 X、 Yおよび Zは各々独立に窒素原子または炭素原子を示し、 mは 0〜3 の整数を示し、 R6は水素原子、水酸基、ハロゲン原子、低級アルケニル基、低級アル コキシ基、置換もしくは非置換のフエノキシ基、置換もしくは非置換のフエ二ル基、置 換もしくは非置換の低級アルキル基、または置換もしくは非置換のアミノ基を示す (た だし、 mが 2以上のとき、 2つ以上の R6はそれぞれ同じでも異なってもよい。 ) (In the above formula, X, Y and Z each independently represent a nitrogen atom or a carbon atom, m represents an integer of 0 to 3, R 6 represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, A lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted amino group (where m is 2 In these cases, two or more R 6 s may be the same or different.
[0043] 上記の 5員の芳香族複素環としては、ピロール環、ピラゾール環、イミダゾール環、ト リアゾール環、およびテトラゾール環を具体例として挙げることができる。 [0043] Specific examples of the 5-membered aromatic heterocycle include a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, and a tetrazole ring.
上記の 5員の芳香族複素環に置換する R6としては、ハロゲン原子、低級アルケニル 基、低級アルコキシ基、置換もしくは非置換の低級アルキル基、および置換アミノ基 が好ましぐ 1または 2個の R6が置換した当該 5員芳香族複素環としては、メチルピロ ール環、トリフルォロメチルピロール環、メチルビラゾール環、トリフルォロメチルピラゾ
ール環、メチルイミダゾール環、トリフルォロメチルイミダゾール環、メチルトリアゾール 環、トリフルォロメチルトリアゾール環、フルオロフェ-ルビラゾール環、ジメチルビロー ル環、ジメチルビラゾール環、およびジメチルイミダゾ一ル環を好ましい例として挙げ ることがでさる。 R 6 substituted on the 5-membered aromatic heterocyclic ring is preferably a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted amino group, preferably 1 or 2 The 5-membered aromatic heterocycle substituted with R 6 includes methylpyrrole ring, trifluoromethylpyrrole ring, methylbiazole ring, trifluoromethylpyrazo ring. Preferable examples are a diol ring, a methyl imidazole ring, a trifluoromethyl imidazole ring, a methyl triazole ring, a trifluoromethyl triazole ring, a fluoro ferrobiazole ring, a dimethyl pyrrole ring, a dimethyl virazole ring, and a dimethyl imidazole ring. It can be mentioned as.
[0044] 本発明の一般式 (I)で示される化合物には、立体異性体あるいは不斉炭素原子に 由来する光学異性体が存在することもあるが、これらの立体異性体、光学異性体及 びこれらの混合物の 、ずれも本発明に含まれる。 The compound represented by the general formula (I) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms. These stereoisomers, optical isomers and Deviations of these and mixtures thereof are also included in the present invention.
[0045] 本発明の一般式 (I)で示される化合物の塩としては、医薬的に許容し得る塩であれ ば特に限定されないが、具体的には、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、お よび硫酸塩等の鉱酸塩類メタンスルホン酸塩、 2—ヒドロキシエタンスルホン酸塩およ び p―トルエンスルホン酸塩等の有機スルホン酸塩類等を挙げることができる。 [0045] The salt of the compound represented by the general formula (I) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloride, hydrobromide, iodine Examples thereof include hydrous acid salts and mineral acid salts such as sulfates, methanesulfonic acid salts, and organic sulfonic acid salts such as 2-hydroxyethanesulfonic acid salts and p-toluenesulfonic acid salts.
[0046] また、一般式 (I)で示される化合物が酸性基を有する場合には、ナトリウム、カリウム 等のアルカリ金属、マグネシウム、カルシウム等のアルカリ土類金属、またはメチルァ ミン、ジメチルァミン、トリメチルァミン、ェチルァミン、ジェチルァミン、トリェチルァミン 、イソプロピルァミン、ジイソプロピルァミン、ブチルァミン、イソブチルァミン、 sec—ブ チルァミン、 tert—ブチルァミン等の有機塩基の塩となってもよい。溶媒和物としては 、医薬的に許容し得るものであれば特に限定されないが、具体的には、水和物、エタ ノール和物等を挙げることができる。 [0046] When the compound represented by the general formula (I) has an acidic group, an alkali metal such as sodium or potassium, an alkaline earth metal such as magnesium or calcium, or methylamine, dimethylamine, or trimethylamine. It may be a salt of an organic base such as ethylamine, jetylamine, triethylamine, isopropylamine, diisopropylamine, butylamine, isobutylamine, sec-butylamine, tert-butylamine. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.
[0047] 以下に、本発明の化合物の代表的な合成方法について説明する。 [0047] A typical synthesis method of the compound of the present invention will be described below.
先ず、本発明の一般式 (I)で示される化合物 (以下、化合物 (I)と称する。ここで、 R5 が水素原子以外の基を示す場合を化合物 (la)、 R5が水素原子を示す場合を化合物 (lb)とする)の合成方法につ!、て説明する。 First, a compound represented by general formula (I) of the present invention (hereinafter referred to as compound (I). Here, when R 5 represents a group other than a hydrogen atom, compound (la), R 5 represents a hydrogen atom. The method of synthesizing the compound (lb) is described below.
[0048] [化 6]
合成法 1一 1 [0048] [Chemical 6] Synthesis method 1 1 1
(上記式中、 1〜!^ 6、 Q、 X、 Y、 Ζ、 m、および ηは、前記のものを示し、 H a 1は、 塩素原子、 臭素原子または沃素原子を示す。) 化合物(3)は、アルデヒド(1)とァミン(2)を還元剤の存在下に反応させることにより 合成することができる。酢酸等の酸の存在下または非存在下に、アルデヒド(1)とアミ ン(2)からシッフ塩基を生成させた後に還元剤を作用させて化合物(3)を得る。この 場合、アルデヒド(1)とァミン(2)を溶媒に溶解し、シッフ塩基の生成を確認することな く還元剤を作用させることによつても、化合物(3)を合成することができる。通常、アル デヒド(1)に対して 1当量ないし過剰量のアミン(2)を用いる。還元剤としては水素化 ホウ素ナトリウム、シァノ水素化ホウ素ナトリウム、トリァセトキシ水素化ホウ素ナトリウム 等の水素化金属錯体が挙げられ、アルデヒド(1)に対して 1当量ないし過剰量の、好 ましくは 1〜5当量の還元剤を用いる。反応溶媒としては、メタノールやエタノール等 のアルコール類、テトラヒドロフラン等のエーテル系溶媒、ジクロロメタン、クロ口ホルム 等のハロゲンィ匕アルカンを挙げることができる。反応温度は、 20°C力も用いる溶媒 の沸点まで、好ましくは 0〜50°Cであり、反応時間は 15分〜 24時間、好ましくは 30
分〜 10時間程度である。 (In the above formula, 1 to! ^ 6 , Q, X, Y, Ζ, m, and η represent the above, and H a 1 represents a chlorine atom, a bromine atom, or an iodine atom.) Compound ( 3) can be synthesized by reacting aldehyde (1) and amine (2) in the presence of a reducing agent. Compound (3) is obtained by producing a Schiff base from aldehyde (1) and amine (2) in the presence or absence of an acid such as acetic acid and then reacting with a reducing agent. In this case, compound (3) can also be synthesized by dissolving aldehyde (1) and amine (2) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, 1 equivalent to an excess of amine (2) is used with respect to aldehyde (1). Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Use 5 equivalents of reducing agent. Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogen alkanes such as dichloromethane and chloroform. The reaction temperature is up to the boiling point of the solvent that also uses 20 ° C force, preferably 0-50 ° C, and the reaction time is 15 minutes-24 hours, preferably 30 About minutes to 10 hours.
[0050] 化合物(3)から化合物 (la)の合成は、化合物(3)に対して化合物 (4)を作用させる ことによって行うことができる。化合物(3)に対して、 1当量ないし過剰量の、好ましく は 1〜2当量の化合物 (4)を塩基の存在下に作用させ、必要によりヨウ化テトラプチ ルアンモ-ゥム、ヨウ化カリウム等の反応促進剤を用いることができる。塩基としては、 1当量ないし過剰量のトリェチルァミン等の三級アミン類ゃ炭酸カリウム、炭酸セシゥ ム等の炭酸塩を用いる。溶媒としてはメタノール、エタノール等のアルコール類、テト ラヒドロフラン等のエーテル系溶媒、 N, N—ジメチルホルムアミド、ァセトニトリル等の 溶媒が挙げられる。反応温度は 20°C力 用いる溶媒の沸点まで、好ましくは室温か ら 100°Cであり、反応時間は 1時間から 7日間、好ましくは 1〜48時間程度である。 [0050] Synthesis of compound (la) from compound (3) can be carried out by allowing compound (4) to act on compound (3). 1 equivalent to excess, preferably 1 to 2 equivalents, of compound (4) is allowed to act on compound (3) in the presence of a base, and if necessary, such as tetrabutylammonium iodide and potassium iodide. A reaction accelerator can be used. As the base, 1 equivalent to an excess amount of tertiary amine such as triethylamine, potassium carbonate, carbonate such as cesium carbonate, or the like is used. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and solvents such as N, N-dimethylformamide and acetonitrile. The reaction temperature is from 20 ° C to the boiling point of the solvent used, preferably from room temperature to 100 ° C, and the reaction time is from 1 hour to 7 days, preferably from about 1 to 48 hours.
[0051] 化合物 (la)から化合物 (lb)の合成は、エステルの種類によって異なるが、文献記 載の方法 [プロテクティブ ·グループス ·イン ·オーガニック ·シンセシス (Protective Gro ups in Organic Synthesis)、第 2版、 T. W.グリーン(T. W. Green)、 P. G. M.ウッツ (P. G. M. Wuts)著、 John Wiley & Son社(1991年)を参照]またはそれに準ずる方 法に従って行うことができる。酸または塩基を用いる加水分解反応、パラジウム 炭 素等の触媒の存在下に行う水素化反応、トリフルォロ酢酸を用いて行う方法が挙げら れる。例えば、塩基を用いる加水分解反応では、化合物 (la)に対して 1当量ないし過 剰量の水酸化リチウム、水酸化ナトリウム等の水酸化金属塩や炭酸ナトリウム、炭酸 カリウム等の炭酸塩を作用させることにより行う。溶媒としてはメタノール、エタノール 等のアルコール類、テトラヒドロフラン等のエーテル系溶媒、または水、およびそれら の混合溶媒が挙げられる。反応温度は 0〜100°C、好ましくは 0〜60°Cである。反応 時間は、エステルの種類によって異なる力 通常 1〜72時間、好ましくは 1〜24時間 程度である。化合物(la)の R5力 tert ブチル基の場合、トリフルォロ酢酸、塩酸等の 酸を作用させる方法により行うことができる。トリフルォロ酢酸、塩酸は過剰量を用い る。溶媒としてはジクロロメタン、ジォキサン等の溶媒が挙げられ、反応温度は 0°Cか ら用いる溶媒の沸点まで、好ましくは 0〜30°Cであり、反応時間は 1〜48時間、好ま しくは 1〜24時間である。 [0051] The synthesis of compound (lb) from compound (la) differs depending on the type of ester, but the method described in the literature [Protective Groups in Organic Synthesis, 2nd] Edition, TW Green, by PGM Wuts, John Wiley & Son (1991)] or similar methods. Examples thereof include a hydrolysis reaction using an acid or a base, a hydrogenation reaction performed in the presence of a catalyst such as palladium carbon, and a method using trifluoroacetic acid. For example, in a hydrolysis reaction using a base, 1 equivalent to an excess amount of a metal hydroxide salt such as lithium hydroxide or sodium hydroxide or a carbonate salt such as sodium carbonate or potassium carbonate is allowed to act on the compound (la). By doing. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and a mixed solvent thereof. The reaction temperature is 0 to 100 ° C, preferably 0 to 60 ° C. The reaction time varies depending on the type of ester, usually 1 to 72 hours, preferably about 1 to 24 hours. In the case of the R 5 force tert butyl group of the compound (la), it can be carried out by a method of reacting an acid such as trifluoroacetic acid or hydrochloric acid. Use excess amounts of trifluoroacetic acid and hydrochloric acid. Examples of the solvent include solvents such as dichloromethane and dioxane. The reaction temperature is from 0 ° C to the boiling point of the solvent used, preferably 0 to 30 ° C, and the reaction time is 1 to 48 hours, preferably 1 to 24 hours.
[0052] 上記合成法 1 1に記載の化合物 (la)は、下記合成法 1 2に示すように化合物(
3)と化合物(5)との反応によっても製造することが可能である。 [0052] The compound (la) described in the above synthesis method 11 is a compound (la) as shown in the following synthesis method 12 It can also be produced by reaction of 3) with compound (5).
[0053] [化 7] [0053] [Chemical 7]
合成法 1一 2 Synthesis method 1 1 2
(上記式中、 1〜!^ 6、 Q、 X、 Y、 Z、 m、 および nは、 前記のものを示す。) (In the above formula, 1 to! ^ 6 , Q, X, Y, Z, m, and n represent the above-mentioned ones.)
[0054] 化合物 (la)は、ァミン(3)とアルデヒド(5)を還元剤の存在下に反応させることにより 合成することができる。酢酸等の酸の存在下または非存在下に、ァミン(3)とアルデヒ ド(5)からシッフ塩基を生成させた後に還元剤を作用させて化合物 (la)を得る。この 場合、ァミン(3)とアルデヒド(5)を溶媒に溶解し、シッフ塩基の生成を確認することな く還元剤を作用させることによつても、化合物 (la)を合成することができる。通常、アミ ン(3)に対してアルデヒド(5)を 1当量ないし過剰量を用いる。還元剤としては水素化 ホウ素ナトリウム、シァノ水素化ホウ素ナトリウム、トリァセトキシ水素化ホウ素ナトリウム 等の水素化金属錯体が挙げられ、中でもトリァセトキシ水素化ホウ素ナトリウムが好ま しぐアルデヒド(5)に対して通常 1当量ないし過剰量の、好ましくは 1 5当量の還元 剤を用いる。反応溶媒としては、メタノールやエタノール等のアルコール類、テトラヒド 口フラン等のエーテル系溶媒、ジクロロメタン、クロ口ホルム等のハロゲン化アルカンを 挙げることができる。反応温度は、 20°C力も用いる溶媒の沸点まで、好ましくは 0 50°Cであり、反応時間は 15分〜 24時間、好ましくは 30分〜 10時間程度である。 [0054] Compound (la) can be synthesized by reacting amine (3) with aldehyde (5) in the presence of a reducing agent. In the presence or absence of an acid such as acetic acid, a Schiff base is formed from amine (3) and aldehyde (5), and then a reducing agent is allowed to act to give compound (la). In this case, compound (la) can also be synthesized by dissolving ammine (3) and aldehyde (5) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, 1 equivalent to excess of aldehyde (5) is used with respect to amine (3). Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. Among them, 1 equivalent is usually equivalent to aldehyde (5) in which sodium triacetoxyborohydride is preferred. An excess of, preferably 15 equivalents of reducing agent is used. Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogenated alkanes such as dichloromethane and chloroform. The reaction temperature is up to the boiling point of the solvent which also uses 20 ° C force, preferably 050 ° C, and the reaction time is about 15 minutes to 24 hours, preferably about 30 minutes to 10 hours.
[0055] 上記合成法 1 1に記載の化合物 (la)は、下記に示すように化合物(7)を経由する 合成法 2によっても合成可能である。 [0055] The compound (la) described in the synthesis method 11 can also be synthesized by the synthesis method 2 via the compound (7) as shown below.
[0056] [化 8]
合成法 2 [0056] [Chemical 8] Synthesis method 2
(上記式中、 尺1〜!^ 6、 Q、 X、 Y、 Ζ、 m、 および ηは、 前記のものを示す。) (In the above formula, the scales 1 to! ^ 6 , Q, X, Y, Ζ, m, and η are as described above.)
[0057] 化合物(1)と化合物(6)から化合物(7)の合成は、合成法 1—1における化合物(1 )と化合物(2)から化合物(3)を合成する場合と同様の方法により行うことができる。 また、化合物(7)と化合物(8)から化合物 (la)の合成は、合成法 1— 2におけるィ匕 合物(3)と化合物(5)から化合物 (la)を合成する場合と同様の方法により行うことが できる。 Compound (7) is synthesized from compound (1) and compound (6) in the same manner as compound (3) is synthesized from compound (1) and compound (2) in Synthesis Method 1-1. It can be carried out. The synthesis of compound (la) from compound (7) and compound (8) is the same as the synthesis of compound (la) from compound (3) and compound (5) in synthesis method 1-2. It can be done by the method.
[0058] 上記合成法 1 1に記載の化合物 (la)は、下記に示すように化合物(9)を経由する 合成法 3 - 1によっても合成することが可能である。 [0058] The compound (la) described in the above synthesis method 11 can also be synthesized by the synthesis method 3-1 via the compound (9) as shown below.
[0059] [化 9]
[0059] [Chemical 9]
合成法 3 1 Synthesis method 3 1
(l a) (l a)
(上記式中、 !^〜尺6、 Q、 X、 Y、 Ζ、 m、 および ηは、 前記のものを示す。) (In the above formula,! ^ To Shaku 6 , Q, X, Y, Ζ, m, and η represent the aforementioned ones.)
[0060] 化合物(5)と化合物(2)から化合物(9)の合成および化合物(6)と化合物(8)から 化合物(9)の合成は、合成法 1 1における化合物(1)と化合物(2)から化合物(3) を合成する場合と同様の方法により行うことができる。 [0060] The synthesis of compound (9) from compound (5) and compound (2) and the synthesis of compound (9) from compound (6) and compound (8) are carried out by using compound (1) and compound ( It can be carried out by the same method as in the synthesis of compound (3) from 2).
また、化合物(9)と化合物(1)から化合物 (la)の合成は、合成法 1—2におけるィ匕 合物(3)と化合物(5)から化合物 (la)を合成する場合と同様の方法により行うことが できる。 The synthesis of compound (la) from compound (9) and compound (1) is the same as the synthesis of compound (la) from compound (3) and compound (5) in synthesis method 1-2. It can be done by the method.
[0061] 上記合成法 3— 1に記載の化合物(9)は、下記に示す合成法 3— 2によっても合成 することが可能である。 [0061] Compound (9) described in Synthesis Method 3-1 can also be synthesized by Synthesis Method 3-2 shown below.
[0062] [化 10]
合成法 3— 2 [0062] [Chemical 10] Synthesis Method 3— 2
(11) (11)
(上記式中、 R R 2、 R 6、 X、 Y、 Z、 m、 および nは、 前記のものを示し、 R 3 0は 水素原子またはニトロ基を示し、 L Gは水酸基、 ハロゲン原子、 アルキルスルホ二ルォキ シ基またはァリ一ルスルホニルォキシ基を示す。) (In the above formula, RR 2 , R 6 , X, Y, Z, m, and n represent the above, R 30 represents a hydrogen atom or a nitro group, LG represents a hydroxyl group, a halogen atom, an alkylsulfo group. It represents a diloxy group or an arylsulfonyloxy group.)
[0063] 化合物(9)は化合物(2)と化合物(12)を用いて、文献記載の方法 [福山ら (T. Fuk uyama et al)、テトラへドロン レターズ (Tetrahedron Letters),第 36卷、第 36号、 637 3— 6374頁、 1995年]に準じて合成することが可能である。 [0063] Compound (9) was prepared by the method described in the literature using compound (2) and compound (12) [T. Fuk uyama et al, Tetrahedron Letters, 36th, No. 36, 637 3-6374, 1995].
化合物(2)から化合物(11)の合成は、化合物(2)に 2当量の化合物(10)を塩基 存在下に作用させて合成する。塩基としてはトリエチルァミン等の三級アミン類、ピリ ジン、または炭酸水素ナトリウム等の炭酸塩を用いる。溶媒としてはジクロロメタン等 のハロゲン化アルカン、ジェチルエーテル等のエーテル系溶媒、 N, N—ジメチルホ ルムアミド、ァセトニトリル、水などの溶媒もしくはそれらの混合溶媒が挙げられる。反 応は 0°C力も用いる溶媒の沸点まで、好ましくは 0〜30°C程度であり、反応時間は 30 分〜 24時間、好ましくは 30分〜 5時間程度である。 Compound (11) is synthesized from compound (2) by reacting compound (2) with 2 equivalents of compound (10) in the presence of a base. As the base, tertiary amines such as triethylamine, pyridine, or carbonates such as sodium hydrogen carbonate are used. Examples of the solvent include halogenated alkanes such as dichloromethane, ether solvents such as jetyl ether, N, N-dimethylformamide, acetonitrile, water and the like, or a mixed solvent thereof. The reaction is up to the boiling point of the solvent that also uses 0 ° C. force, preferably about 0 to 30 ° C., and the reaction time is 30 minutes to 24 hours, preferably about 30 minutes to 5 hours.
[0064] 化合物(11)と化合物(12)力 化合物(13)の合成は、下記のように化合物(12)の 置換基 LGの種類によって異なる。
置換基 LGが水酸基の場合は、化合物(11)と化合物(12)にァゾジカルボン酸ジェ ステルおよびトリフ -ルホスフィンを作用させる文献記載の方法 [光延 (0. Mitsunob u)、シンセシス (Synthesis)、 1頁、 1981年]、いわゆる光延反応によって合成すること ができる。例えば、化合物(11)と化合物(12)にァゾジカルボン酸ジエステルおよび トリフエニルホスフィンを 1当量ないし過剰量、好ましくは 1〜2当量を作用させる。溶 媒としてはジクロロメタン等のハロゲン化アルカン、ジェチルエーテル、テトラヒドロフラ ン等のエーテル系溶媒、 N, N—ジメチルホルムアミド、トルエン、ベンゼン等の溶媒 もしくはそれらの混合溶媒が挙げられる。反応は 0°Cから用いる溶媒の沸点まで、好 ましくは 0〜30°C程度であり、反応時間は通常 10分〜 48時間、好ましくは 20分〜 1 0時間程度である。 [0064] Compound (11) and Compound (12) Strength The synthesis of compound (13) varies depending on the type of substituent LG of compound (12) as described below. When the substituent LG is a hydroxyl group, a method described in the literature in which an azodicarboxylate ester and triphenylphosphine are allowed to act on the compound (11) and the compound (12) [Mitsunobu (0. Mitsunobu), Synthesis, 1 Page, 1981], can be synthesized by the so-called Mitsunobu reaction. For example, compound (11) and compound (12) are allowed to act on azodicarboxylic acid diester and triphenylphosphine in an amount of 1 equivalent to excess, preferably 1 to 2 equivalents. Examples of the solvent include halogenated alkanes such as dichloromethane, ether solvents such as jetyl ether and tetrahydrofuran, solvents such as N, N-dimethylformamide, toluene and benzene, or a mixed solvent thereof. The reaction is carried out from 0 ° C. to the boiling point of the solvent used, preferably about 0 to 30 ° C., and the reaction time is usually 10 minutes to 48 hours, preferably about 20 minutes to 10 hours.
[0065] 置換基 LGがハロゲン原子の場合は、ハロゲン原子として塩素原子、臭素原子、沃 素原子が好ましぐ化合物(11)に 1当量ないし過剰量の化合物(12)を過剰量の塩 基存在下に反応させて合成することができる。塩基としては炭酸カリウム等の炭酸塩 が挙げられ、溶媒としては N, N—ジメチルホルムアミド、ァセトニトリル、ジクロロメタン 等が挙げられる。反応温度は 0°C力も用いる溶媒の沸点まで、好ましくは 0〜30°C程 度であり、反応時間は通常 10分〜 24時間、好ましくは 30分〜 8時間程度である。 置換基 LGが、アルキルスルホ-ルォキシ基およびァリールスルホ-ルォキシ基の 場合は、置換基 LGがハロゲン原子の場合と同様な反応条件で、化合物(13)を製造 可能である。アルキルスルホ-ルォキシ基としては、メタンスルホ -ルォキシ基を代表 例として挙げることができ、ァリールスルホ-ルォキシ基としては、ベンゼンスルホ- ルォキシ基、 p -トルエンスルホニルォキシ基を代表例として挙げることができる。 [0065] When the substituent LG is a halogen atom, 1 equivalent to an excess amount of the compound (12) is added to an excess amount of the chloride group (11) in which a chlorine atom, a bromine atom or an iodine atom is preferred as the halogen atom. It can be synthesized by reacting in the presence. Examples of the base include carbonates such as potassium carbonate, and examples of the solvent include N, N-dimethylformamide, acetonitrile, and dichloromethane. The reaction temperature is up to the boiling point of the solvent that also uses 0 ° C force, preferably about 0 to 30 ° C, and the reaction time is usually about 10 minutes to 24 hours, preferably about 30 minutes to 8 hours. When the substituent LG is an alkylsulfo-loxy group or an arylsulfo-loxy group, the compound (13) can be produced under the same reaction conditions as when the substituent LG is a halogen atom. A typical example of the alkylsulfo-oxy group is a methanesulfo-oxy group, and examples of the aryl sulfo-oxy group include a benzene sulfo-oxy group and a p-toluenesulfonyloxy group.
[0066] 化合物(13)力も化合物(9)の合成は、化合物(13)に過剰量の炭酸カリウム、炭酸 セシウム等の炭酸塩もしくはトリェチルァミン等の三級アミンまたは水酸化リチウム等 の塩基の存在下に、チォフエノールもしくはチォグリコール酸を作用させることにより 合成することができる。中でもトリエチルァミンとチォグリコール酸の組み合わせが好 ましい。溶媒としてはジクロロメタン等のハロゲン化アルキル、 N, N—ジメチルホルム アミド等が挙げられる。反応温度は 0°C力 用いる溶媒の沸点まで、好ましくは 0〜30 °C程度であり、反応時間は通常 30分〜 24時間、好ましくは 30分〜 8時間程度である
[0067] 上記合成法 3— 2に記載の化合物(13)は、合成法 3— 2において述べた合成方法 またはそれに準ずる合成方法により、下記に示す合成法 3— 3によっても合成するこ とが可能である。 [0066] Compound (13) and compound (9) were synthesized in the presence of an excess amount of potassium carbonate, a carbonate such as cesium carbonate, a tertiary amine such as triethylamine, or a base such as lithium hydroxide. It can be synthesized by reacting thiophenol or thioglycolic acid. Of these, the combination of triethylamine and thioglycolic acid is preferred. Examples of the solvent include alkyl halides such as dichloromethane, N, N-dimethylformamide and the like. The reaction temperature is 0 ° C force, up to the boiling point of the solvent used, preferably about 0 to 30 ° C, and the reaction time is usually 30 minutes to 24 hours, preferably about 30 minutes to 8 hours. [0067] The compound (13) described in the above synthesis method 3-2 can also be synthesized by the synthesis method 3-3 shown below by the synthesis method described in the synthesis method 3-2 or a synthesis method analogous thereto. Is possible.
[0068] [化 11] 合成法 3— 3 [0068] [Chemical Formula 11] Synthesis Method 3— 3
(上記式中、 R 1 R 2、 R 6、 X、 Y、 Z、 m、 および ηは、 前記のものを示し、 R 3 0は 水素原子またはニトロ基を示し、 L Gは水酸基、 ハロゲン原子、 アルキルスルホ二ルォキ シ基、 またはァリールスルホニルォキシ基を示す。) (In the above formula, R 1 R 2 , R 6 , X, Y, Z, m, and η represent the above, R 30 represents a hydrogen atom or a nitro group, LG represents a hydroxyl group, a halogen atom, Represents an alkylsulfonoxy group or an arylsulfonyloxy group.)
[0069] 化合物(6)から化合物(14)の合成は、合成法 3— 2における化合物(2)から化合 物(11)の合成方法に準じて行うことが可能である。また、化合物(14)から化合物(1 3)の合成は、合成法 3— 2における化合物(11)から化合物(13)の合成方法に準じ て行うことが可能である。 [0069] The compound (14) can be synthesized from the compound (6) according to the synthesis method of the compound (11) from the compound (2) in Synthesis Method 3-2. In addition, the synthesis of compound (13) from compound (14) can be performed according to the synthesis method of compound (13) from compound (11) in synthesis method 3-2.
[0070] 上記合成法 1 1に記載の化合物 (la)は、下記合成法 4に示すように化合物(17) を経由する合成経路によっても合成することが可能である。 [0070] The compound (la) described in the above synthesis method 11 can also be synthesized by a synthesis route via the compound (17) as shown in the following synthesis method 4.
[0071] [化 12]
合成法 4 [0071] [Chemical 12] Synthesis method 4
(上記式中、 !^〜 6、 Q、 X、 Y、 Ζ、 m、および ηは、 前記のものを示し、 H a 1は、 塩素原子、 臭素原子または沃素原子を示す。) 化合物(3)と化合物(16)から化合物(17)の合成は、合成法 1 2における化合物 (3)と化合物(5)から化合物 (la)を合成する場合と同様の方法により行うことができる 化合物(17)力 化合物 (la)の合成は、文献記載の方法、例えば、ウールマン反応 (Ullman reaction)またはゴールドバーグ カップリング反応 [H—J.クリストら(H-J. Cr istau et al)、ョ一口ピアン'ジャーナル'ォブ 'オーガニック 'ケミストリー (European Jour nal of Organic Chemistry), 695— 709頁、 2004年]、もしくはそれに準じた方法によ り行うことができる。化合物(17)と化合物(18)を塩基の存在下にヨウ化銅もしくは酸 ィ匕銅を作用させることにより行う。化合物(18)のハロゲン原子としては臭素原子もしく は沃素原子が好ましぐ通常、化合物(17)に対して化合物(18)を 1当量ないし過剰 量を用いる。ヨウ化銅もしくは酸化銅は 0. 01〜1当量、好ましくは 0. 01〜0. 1当量 を用い、ヨウ化銅もしくは酸化銅の代りにテトラキス(トリフエ-ルホスフィン)パラジウム 等のパラジウム錯体を用いることができる。塩基としては、 2当量ないし過剰量の炭酸 セシウム、炭酸カリウム等の炭酸金属塩、りん酸三カリウム等のりん酸金属塩、ナトリウ ム tert ブトキシド等の金属アルコキシドを用いる。溶媒としては、ジォキサン、トル ェン、ァセトニトリル、ピリジン、 N, N ジメチルホルムアミド、テトラヒドロフラン等の不 活性溶媒を用い、反応温度は 10°C力も用いる溶媒の沸点まで、また反応時間は 30
分〜 48時間、好ましくは 2〜24時間である。さらに、反応促進剤として 1, 2—ジァミノ シクロへキサン等のジァミン類、サリチルアルドキシムゃジメチルダリオキシム等のォ キシム類. X X(In the above formula,! ^ To 6 , Q, X, Y, Ζ, m, and η represent the above, and H a 1 represents a chlorine atom, a bromine atom, or an iodine atom.) Compound (3 ) And compound (16) can be synthesized from compound (17) by a method similar to that for synthesizing compound (la) from compound (3) and compound (5) in synthesis method 12. ) Force Compound (la) can be synthesized by methods described in the literature, such as the Ullman reaction or the Goldberg coupling reaction [HJ. Crisau et al. 'Ob' Organic 'Chemistry (European Journal of Organic Chemistry), 695-709, 2004], or a similar method. Compound (17) and compound (18) are reacted with copper iodide or acid copper salt in the presence of a base. The halogen atom of compound (18) is preferably a bromine atom or an iodine atom. Usually, compound (18) is used in an amount of 1 equivalent to an excess amount relative to compound (17). Copper iodide or copper oxide is 0.01 to 1 equivalent, preferably 0.01 to 0.1 equivalent, and a palladium complex such as tetrakis (triphosphine) palladium is used instead of copper iodide or copper oxide. be able to. As the base, 2 equivalent to excess amounts of metal carbonates such as cesium carbonate and potassium carbonate, metal phosphates such as tripotassium phosphate, and metal alkoxides such as sodium tert butoxide are used. As the solvent, an inert solvent such as dioxane, toluene, acetonitrile, pyridine, N, N dimethylformamide, tetrahydrofuran, etc. is used, the reaction temperature is up to the boiling point of the solvent using 10 ° C force, and the reaction time is 30. Min to 48 hours, preferably 2 to 24 hours. Furthermore, diamines such as 1,2-diaminocyclohexane and oximes such as salicylaldoxime dimethyldarioxime as reaction accelerators. XX
¾を 6添加することができ、 0. 01-0. 5当量程度、好ましくは 0. 1当量程度で ある。 6 can be added, and it is about 0.01 to 0.5 equivalent, preferably about 0.1 equivalent.
[0073] 上記の合成において用いたィ匕合物(4)、(5)、(6)および(12)は、 nの数によりメチ レン鎖の長さが異なるが、それらは慣用の合成法により容易に合成することができる。 5員のへテロ環の種類および所望のメチレン鎖などにより用いる合成方法はそれぞれ 異なるが、例えば、下記の合成法 5のように容易にメチレン鎖を伸長することができる [0073] The compounds (4), (5), (6), and (12) used in the above synthesis differ in the length of the methylene chain depending on the number of n. Can be easily synthesized. Although the synthesis method used varies depending on the type of 5-membered heterocycle and the desired methylene chain, for example, the methylene chain can be easily extended as shown in Synthesis Method 5 below.
X ¾士 X ¾ 士
6) 6)
S 6 S 6
[0074] [化 13] [0074] [Chemical 13]
合成法 5 Synthesis method 5
NaCN 還 兀 NaCN 還
'Ha l 、レ Γ CN'Ha l, Les Γ CN
(18) (19) (20) 加水 還 兀 (18) (19) (20) Hydrolysis
、レ Γ 02H, Les Γ 0 2 H
(21 ) (22) (24) (21) (22) (24)
酸化 Oxidation
、1 - CH0 , 1-CH0
(23) (twenty three)
(上記式中、 R 6、 X、 Y、 Ζ、 および mは、 前記のものを示し、 H a 1は、 塩素原子、 臭素原子または沃素原子を示す。) (In the above formula, R 6 , X, Y, Ζ, and m represent the above, and H a 1 represents a chlorine atom, a bromine atom, or an iodine atom.)
[0075] 化合物 (4)に含まれる化合物(18)とシアンィ匕ナトリウムもしくはシアンィ匕カリウムを 反応させることによりシァノ誘導体(19)を合成し、続く還元反応によりメチレン鎖が一 つ伸長したァミン(20)を合成することができる。一方、シァノ誘導体(19)を酸または
アルカリ加水分解することによりカルボン酸(21)とし、続く還元反応によりヒドロキシ 誘導体(22)を得ることができる。ヒドロキシ誘導体(22)を酸ィ匕することによりメチレン 鎖が一つ伸長したアルデヒド(23)を得ることができる。また、ヒドロキシ誘導体(22)を ハロゲンィ匕して化合物(24)に導き、更に上記と同様に炭素鎖の伸長を行えば、更に メチレン鎖の長い化合物を得ることができる。また、上記の方法以外にも、例えばアル デヒド(23)力 ウィティッヒ反応により炭素伸長を行 、、メチレン鎖を 1つ伸長させた 化合物を合成することができる。 [0075] A cyano derivative (19) was synthesized by reacting the compound (18) contained in the compound (4) with cyanide sodium or cyanate potassium, followed by a reduction reaction in which an amine (20) ) Can be synthesized. On the other hand, the cyano derivative (19) is acid or Carboxylic acid (21) can be obtained by alkaline hydrolysis, and hydroxy derivative (22) can be obtained by subsequent reduction reaction. By acidifying the hydroxy derivative (22), an aldehyde (23) having one extended methylene chain can be obtained. Further, a compound having a longer methylene chain can be obtained by halogenating the hydroxy derivative (22) to lead to the compound (24) and further extending the carbon chain in the same manner as described above. In addition to the above method, for example, a compound in which carbon is extended by an aldehyde (23) force Wittig reaction to extend one methylene chain can be synthesized.
[0076] 化合物(18)からシァノ誘導体(19)の合成は、化合物(18)に対して、シアン化ナト リウムもしくはシアンィ匕カリウムを 1当量ないし過剰量、好ましくは 1〜2当量を作用さ せる。 N, N—ジメチルホルムアミド等の不活性溶媒中、通常 0°C力も反応に用いる溶 媒の沸点まで、好ましくは 0〜80°C程度にて行う。反応時間は通常 1〜16時間、好ま しくは 1〜5時間程度であり、化合物(18)において、 Halが塩素原子や臭素原子の 場合には、必要によりヨウ化ナトリウムもしくはヨウ化カリウム等を用いて反応を促進さ せることができる。 [0076] In the synthesis of the cyano derivative (19) from the compound (18), 1 equivalent to excess, preferably 1 to 2 equivalents, of sodium cyanide or potassium cyanide is allowed to act on the compound (18). . In an inert solvent such as N, N-dimethylformamide, the reaction is usually performed at a temperature of 0 ° C up to the boiling point of the solvent used for the reaction, preferably about 0 to 80 ° C. The reaction time is usually 1 to 16 hours, preferably 1 to 5 hours. In the compound (18), when Hal is a chlorine atom or a bromine atom, sodium iodide or potassium iodide is used if necessary. Reaction can be promoted.
[0077] ァミン (20)は、化合物(19)をパラジウム—炭素等の触媒の存在下に接触還元する 力 ある 、は水素化リチウムアルミニウム等を用いて還元することにより合成すること ができる。接触還元では、触媒としてパラジウム—炭素以外に、水酸化パラジウム、 酸ィ匕白金等を用いてもよい。溶媒としては、水、エタノール等のアルコール系溶媒、 ジェチルエーテル等のエーテル系溶媒、酢酸ェチル等が挙げられる。反応時間は、 通常 3時間〜 5日間、好ましくは 10時間〜 2日間程度である。また、水素化リチウムァ ルミ-ゥムによる還元の場合には、化合物(19)に対して水素化リチウムアルミニウム を通常 1〜5当量、好ましくは 1〜3当量程度を用いる。溶媒としては、ジェチルエー テル、テトラヒドロフラン等のエーテル系溶媒を用いる。反応時間は、通常 1〜10時間 、好ましくは 1〜3時間程度、反応温度は通常 0°C力 用いる溶媒の沸点まで、好まし くは 0〜60°C程度である。 Amine (20) is capable of catalytic reduction of compound (19) in the presence of a catalyst such as palladium-carbon or can be synthesized by reduction using lithium aluminum hydride or the like. In catalytic reduction, palladium hydroxide, platinum oxide, etc. may be used in addition to palladium-carbon as a catalyst. Examples of the solvent include water, alcohol solvents such as ethanol, ether solvents such as jetyl ether, and ethyl acetate. The reaction time is usually about 3 hours to 5 days, preferably about 10 hours to 2 days. In the case of reduction with lithium aluminum hydride, lithium aluminum hydride is usually used in an amount of 1 to 5 equivalents, preferably about 1 to 3 equivalents, relative to compound (19). As the solvent, ether solvents such as jetyl ether and tetrahydrofuran are used. The reaction time is usually about 1 to 10 hours, preferably about 1 to 3 hours, and the reaction temperature is usually about 0 ° C to the boiling point of the solvent used, preferably about 0 to 60 ° C.
[0078] シァノ誘導体(19)力 カルボン酸(21)への加水分解は、硫酸、塩酸等の酸、また は水酸ィ匕ナトリウム、水酸ィ匕カリウム、水酸化リチウム等のアルカリを用いる。シァノ誘 導体(19)に対して酸を過剰量、また、アルカリの場合は通常 3〜20当量、好ましくは
3〜15当量を用いる。溶媒としては、水、エタノール等のアルコール系溶媒、テトラヒ ドロフラン、ジォキサン、 N, N—ジメチルホルムアミド等またはそれらの混合溶媒を用 いる。反応時間は、通常 1〜24時間、好ましくは 1〜8時間程度、反応温度は通常 50 °Cから用いる溶媒の沸点まで、好ましくは 50〜 100°C程度である。 [0078] Cyan derivative (19) force Hydrolysis to carboxylic acid (21) uses an acid such as sulfuric acid or hydrochloric acid, or an alkali such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. An excess of acid relative to the Cyan derivative (19), and usually 3 to 20 equivalents in the case of alkali, preferably 3-15 equivalents are used. As the solvent, water, an alcohol solvent such as ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide, or a mixed solvent thereof is used. The reaction time is usually 1 to 24 hours, preferably about 1 to 8 hours, and the reaction temperature is usually from 50 ° C to the boiling point of the solvent used, preferably about 50 to 100 ° C.
[0079] カルボン酸(21)力 化合物(22)への還元反応では、カルボン酸(21)に水素化リ チウムアルミニウムもしくはボラン一ジメチルスルフイド錯体等のボラン錯体を用いるこ とにより行うことができる。カルボン酸(21)に対して、水素化リチウムアルミニウムもしく はボラン錯体を通常過剰量、好ましくは 2〜3当量程度を用いる。溶媒としては、テト ラヒドロフラン等のエーテル系溶媒を用いる。反応時間は、通常 1〜24時間、好ましく は 1〜8時間程度であり、反応温度は通常 0°C力 用いる溶媒の沸点まで、好ましく は 30〜80°C程度である。 [0079] Carboxylic acid (21) force The reduction reaction to the compound (22) can be carried out by using a borane complex such as lithium aluminum hydride or a borane-dimethylsulfide complex for the carboxylic acid (21). it can. The lithium aluminum hydride or borane complex is usually used in an excess amount, preferably about 2 to 3 equivalents, relative to the carboxylic acid (21). As the solvent, an ether solvent such as tetrahydrofuran is used. The reaction time is usually 1 to 24 hours, preferably about 1 to 8 hours, and the reaction temperature is usually 0 ° C. to the boiling point of the solvent used, preferably about 30 to 80 ° C.
[0080] 化合物(22)力もアルデヒド(23)の合成にぉ 、ては、通常の酸ィ匕反応を用いること ができる。例えば、塩化ォキサリルとジメチルスルホキシドを用いる Swern酸化 (S. L. Huang, K. Omura and D. Swern, Tetrahedron, 34, 1651 (1978))、デス一マーチン ペルョージナンを用いる酸化反応(D. B. Dess and J. C. Martin, Journal of America n Chemical Society, 113, 7277 (1991))、テトラ— n—プロピルアンモ-ゥム過ルテ- ゥム酸塩と 4—メチルモルホリン— 4—ォキシドを用いる酸化反応(W.P. Griffith, S. L. Ley, u. P. Whitcombe, and A. D. White, Journal Chemical Society Chemicalし omm unication, 1625 (1987》等の文献記載の方法によって行うことができる。 [0080] For the synthesis of the aldehyde (23), the compound (22) force can be used in the usual acid-acid reaction. For example, Swern oxidation using oxalyl chloride and dimethyl sulfoxide (SL Huang, K. Omura and D. Swern, Tetrahedron, 34, 1651 (1978)), oxidation reaction using Dess-Martin periodinane (DB Dess and JC Martin, Journal of America n Chemical Society, 113, 7277 (1991)), oxidation reaction using tetra-n-propylammonium perruthemate and 4-methylmorpholine-4-oxide (WP Griffith, SL Ley, u P. Whitcombe, and AD White, Journal Chemical Society Chemical, omm unication, 1625 (1987).
[0081] 化合物(22)からハロゲン誘導体(24)の合成は、通常のハロゲンィヒ反応により行う ことができる。例えば、塩ィ匕チォニルによる塩素化、三臭化ホウ素、ジブ口モトリフエ- ルホスフィンもしくは N—ブロモスクシンイミドとトリフエ-ルホスフィンを用いる臭素化、 ヨウ化ナトリウムとトリメチルクロロシランを用いるヨウ素化等が挙げられる。 [0081] The synthesis of the halogen derivative (24) from the compound (22) can be carried out by a normal halogen reaction. For example, chlorination with sodium chloride, bromination using boron tribromide, dibuccyl trifluorophosphine or N-bromosuccinimide and triphenylphosphine, iodination using sodium iodide and trimethylchlorosilane, etc. .
なお、上記の合成法における化合物(18)は、ヘテロサイクルズ(Heterocycles) , 6 0卷, 167— 175頁、 2003年に記載の方法、または参考例に記載の方法、あるいは それらに準じた方法により、製造することができる。 The compound (18) in the above synthesis method is the method described in Heterocycles, 60s, pp. 167-175, 2003, the method described in Reference Examples, or a method according to them. Can be manufactured.
[0082] また、本発明の一般式 (I)で表される化合物のうち、 R2が置換もしくは非置換のカル バモイル基である化合物(ここで、 R2が置換もしくは非置換の力ルバモイル基であり、
R5が水素原子以外である場合をィ匕合物 (Ic)、 R2が置換もしくは非置換の力ルバモイ ル基であり、 R5が水素原子である場合をィ匕合物 (Id)とする。 )は、下記の方法でも合 成することも可能である。 [0082] Among the compounds represented by the general formula (I) of the present invention, a compound in which R 2 is a substituted or unsubstituted carbamoyl group (where R 2 is a substituted or unsubstituted force rubamoyl group) And When R 5 is other than a hydrogen atom (Ic), when R 2 is a substituted or unsubstituted force rubermoyl group and R 5 is a hydrogen atom, the compound (Id) To do. ) Can also be synthesized by the following method.
[0083] [化 14] 合成法 6 [0083] [Chemical 14] Synthesis method 6
[0084] (上記式中、
R3〜R6、 Q、 X、 Y、 Z、 mおよび nは、前記のものを示し、 R7および R8 は、各々独立に水素原子または低級アルキル基を示す。 ) [0084] (In the above formula, R 3 to R 6 , Q, X, Y, Z, m and n represent the above, and R 7 and R 8 each independently represent a hydrogen atom or a lower alkyl group. )
[0085] 化合物(7)から化合物(26)の合成は、化合物(7)とダリオキシル酸(25)にトリァセ トキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム、シァノ水素化ホウ素ナトリウム 等の水素化金属錯体、好ましくはトリァセトキシ水素化ホウ素ナトリウムを作用させるこ とにより行う。通常、化合物(7)に対してダリオキシル酸(25)を 1当量あるいは過剰量 を用いる。水素化金属錯体は化合物(7)に対して通常 1当量あるいは過剰量、好ま しくは 2〜3当量程度用いる。反応溶媒としてはテトラヒドロフラン、ジクロロメタン、クロ 口ホルム等の不活性溶媒が挙げられ、反応温度は 0°C力 40°Cまで、好ましくは 0〜 30°C程度であり、反応時間は 1〜48時間、好ましくは 1〜10時間程度である。 [0085] The compound (26) is synthesized from the compound (7) by compounding a metal hydride complex such as sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, etc. into the compound (7) and darioxylic acid (25). Preferably, it is carried out by the action of sodium triacetoxyborohydride. Usually, 1 equivalent or excess of darioxylic acid (25) is used relative to compound (7). The metal hydride complex is usually used in an amount of 1 equivalent or excess, preferably 2 to 3 equivalents, relative to compound (7). Examples of the reaction solvent include inert solvents such as tetrahydrofuran, dichloromethane, chloroform, etc., the reaction temperature is 0 ° C. force up to 40 ° C., preferably about 0 to 30 ° C., and the reaction time is 1 to 48 hours. It is preferably about 1 to 10 hours.
[0086] 化合物(26)から化合物 (Ic)の合成は、一般的なアミド結合形成反応によって行う ことが可能であり、例えば、化合物(26)にァミン(27)を縮合剤の存在下に作用させ て行うことができる。例えば、化合物(26)に対してァミン(27)を 1当量ないし過剰量
を不活性溶媒中で— 50°Cな 、し反応に用いる溶媒の沸点まで、好ましくは 0〜30°C において縮合剤の存在下に作用させることにより行われる。反応時間は 10分力も 48 時間、好ましくは 30分から 12時間程度である。縮合剤としては、 N, N'—ジシクロへ キシルカルボジイミド、 1—ェチル 3— (3 ジメチルァミノプロピル)カルボジイミド、 シァノリン酸ジェチル、ベンゾトリアゾリルォキシ—トリス [ピロリジノ]—ホスホ -ゥム へキサフルォロホスフェート、 2— (1H ベンゾトリアゾール 1—ィル) 1, 1, 3, 3 ーテトラメチルゥロニゥム テトラフルォロボレート等を挙げることができ、化合物(26) に対して 1当量ないし過剰量、好ましくは 1〜5当量を用いる。不活性溶媒としては、 ジクロロメタン、 N, N ジメチルホルムアミド、テトラヒドロフラン、酢酸ェチル等の溶 媒、またはそれらの混合物が挙げられる。また、必要によりトリェチルァミン、ジィソプ 口ピルェチルァミン、 N—メチルモルホリンや 4ージメチルァミノピリジン等の塩基の存 在下に行うことができる。さらに、 1—ヒドロキシベンゾトリァゾール、 N—ヒドロキシスク シンイミド、 N -ヒドロキシフタルイミド等の N -ヒドロキシ化合物もしくは 4—ニトロフエ ノール、 2, 4 ジニトロフエノール、 2, 4, 5 トリクロ口フエノール、ペンタクロロフエノ ール等のフエノールイ匕合物を反応促進剤として添加することができる。 [0086] Synthesis of compound (Ic) from compound (26) can be carried out by a general amide bond forming reaction. For example, compound (26) is reacted with ammine (27) in the presence of a condensing agent. Can be done. For example, 1 equivalent or excess of ammine (27) to compound (26) Is carried out in an inert solvent at −50 ° C. until the boiling point of the solvent used in the reaction, preferably 0 to 30 ° C., in the presence of a condensing agent. The reaction time is 10 minutes at 48 hours, preferably 30 minutes to 12 hours. Condensation agents include N, N'-dicyclohexylcarbodiimide, 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide, cyanoethyl ethylate, benzotriazolyloxy-tris [pyrrolidino] -phospho-um hexa Fluorophosphate, 2- (1H benzotriazole 1-yl) 1, 1, 3, 3-tetramethyluronium tetrafluoroborate, etc. An equivalent to excess amount, preferably 1 to 5 equivalents is used. Examples of the inert solvent include solvents such as dichloromethane, N, N dimethylformamide, tetrahydrofuran, and ethyl acetate, or mixtures thereof. If necessary, it can be carried out in the presence of a base such as triethylamine, di-sodium pyrethylamine, N-methylmorpholine or 4-dimethylaminopyridine. In addition, N-hydroxy compounds such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, 4-nitrophenol, 2,4 dinitrophenol, 2,4,5 triclonal phenol, pentachlorophenol Phenolic compounds such as ru can be added as a reaction accelerator.
[0087] 化合物 (Ic)から化合物 (Id)の合成は、合成法 1 1における化合物 (la)から化合 物 (lb)の合成の場合と同様の方法により行うことができる。 [0087] The compound (Id) can be synthesized from the compound (Ic) by the same method as in the synthesis of the compound (lb) from the compound (la) in Synthesis Method 11.
[0088] また、本発明の一般式 (I)で表される化合物のうち、 R2が置換もしくは非置換の 1, 3 , 4—ォキサジァゾリル基である化合物(ここで、 R2が置換もしくは非置換の 1, 3, 4— ォキサジァゾリル基であり、 R5が水素原子以外である場合をィ匕合物 (Ie)、 R2が置換も しくは非置換の 1, 3, 4 ォキサジァゾリル基であり、 R5が水素原子である場合をィ匕 合物 (If)とする。)は、下記の方法でも合成することができる。 [0088] Further, among the compounds represented by the general formula (I) of the present invention, a compound in which R 2 is a substituted or unsubstituted 1,3,4-oxadiazolyl group (wherein R 2 is substituted or unsubstituted A substituted 1, 3, 4-oxadiazolyl group, wherein R 5 is other than a hydrogen atom (Ie), R 2 is a substituted or unsubstituted 1, 3, 4 oxadiazolyl group The case where R 5 is a hydrogen atom is referred to as a compound (If)) can also be synthesized by the following method.
[0089] [化 15]
合成法 7 [0089] [Chemical 15] Synthesis method 7
[0090] (上記式中、
R3〜R6、 Q、 X、 Y、 Ζ、 mおよび ηは、前記のものを示し、 R ま水素 原子、置換もしくは非置換の低級アルキル基、または置換もしくは非置換のフエニル 基を示す。 ) [0090] (In the above formula, R 3 to R 6 , Q, X, Y, Ζ, m and η are as defined above, and R, a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted phenyl group. )
[0091] 化合物(26)と化合物(28)から化合物(29)の合成は、合成法 6における化合物(2 6)から化合物 (Ic)の合成の場合と同様の方法により行うことができる。 [0091] Compound (29) can be synthesized from compound (26) and compound (28) by the same method as in the synthesis of compound (Ic) from compound (26) in synthesis method 6.
[0092] 化合物(29)力 化合物 (Ie)の合成は、慣用の方法、例えば、ポリりん酸、もしくは ォキシ塩化りんの存在下に熱処理する方法のほか、トリェチルァミン等の塩基の存在 下にトリフエ-ルホルフィンと四塩ィ匕炭素をジクロロメタン中で作用させる方法 [例えば 、米国特許公開公報 2004019215号]などの既知の方法によって行うことができる。 Compound (29) Strength Compound (Ie) can be synthesized by a conventional method, for example, a heat treatment in the presence of polyphosphoric acid or phosphorus oxychloride, or triphenylamine in the presence of a base such as triethylamine. It can be carried out by a known method such as a method in which ruphorphine and tetrasalt carbon are reacted in dichloromethane [for example, US Patent Publication No. 2004019215].
[0093] 化合物 (Ie)から化合物 (If)の合成は、合成法 1 1における化合物 (la)から化合物 [0093] Synthesis of compound (If) from compound (Ie) is carried out by compound from compound (la) in synthesis method 11
(lb)の合成の場合と同様の方法により行うことができる。 It can be carried out by the same method as in the synthesis of (lb).
[0094] さらに、一般式 (I)で表される本発明の化合物 (I)のうち、 R2が置換もしくは非置換 の、ピラゾール環、チアゾール環、ォキサゾール環、イソォキサゾール環、 1, 2, 4— ォキサジァゾール環、または 1, 2, 4ートリアゾール環である化合物は、上記化合物( 26)のカルボキシ基を文献 [例えば、 W. Roger Tullyら、 Journal of Medicinal Chemist ry, 34, 2060-2067, (1991)などが挙げられる。 ]に記載の方法に準じて、 5員の複素環 に変換することにより合成することが可能である。
[0095] 本発明の化合物 (I)は、種々の製剤を用いて経口投与可能である。その製剤に用 いられる本発明の化合物 (I)は、遊離体、塩またはそれらの水和物もしくは溶媒和物 のいずれでもよい。本発明の化合物 (I)を含有する経口用製剤としては、錠剤、細粒 剤、散剤、顆粒剤、およびカプセル剤を挙げることができ、錠剤およびカプセル剤が 好ましい。これらの経口用製剤は、製剤学上許容される添加物を含み、例えば充填 剤類、増量剤類、結合剤類、崩壊剤類、溶解促進剤類、湿潤剤類、潤滑剤類等を必 要に応じて選択して使用することができる。 [0094] Further, among the compounds (I) of the present invention represented by the general formula (I), R 2 is a substituted or unsubstituted pyrazole ring, thiazole ring, oxazole ring, isoxazole ring, 1, 2, 4 — A compound having an oxaziazole ring or a 1,2,4-triazole ring may be obtained by referring to the carboxy group of the above compound (26) in the literature [for example, W. Roger Tully et al., Journal of Medicinal Chemistry, 34, 2060-2067, (1991 ) And the like. Can be synthesized by converting to a 5-membered heterocyclic ring. [0095] Compound (I) of the present invention can be administered orally using various preparations. The compound (I) of the present invention used for the preparation may be any of a free form, a salt, and a hydrate or solvate thereof. Examples of the oral preparation containing the compound (I) of the present invention include tablets, fine granules, powders, granules, and capsules, and tablets and capsules are preferred. These oral preparations contain pharmaceutically acceptable additives such as fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants and the like. It can be selected and used as needed.
[0096] また、投与量については、一人当たり一日に 0. lmg〜1500mgが好ましぐ特に 1 mg〜500mg力 子ましい。この投与量は、 1日 1回でもよく、 2〜3回に分けてもよい。 実施例 [0096] The dosage is preferably 0.1 mg to 1500 mg per person per day, particularly 1 mg to 500 mg. This dose may be once a day or divided into 2 to 3 times. Example
[0097] 以下に実施例を示して本発明を説明する。 [0097] The present invention will be described below with reference to examples.
[0098] [参考例 1] [0098] [Reference Example 1]
4 クロロメチル一 1— (4 クロ口フエニル) 3—メチル 1H ピラゾール 4 Chloromethyl 1- (4-chlorophenyl) 3-methyl 1H pyrazole
[0099] [化 16]
[0099] [Chemical 16]
[0100] 1— (4 クロ口フエ-ル)一 3—メチル 1H ピラゾール(1. 25g)を 4規定塩酸一 ジォキサン溶液(10ml)に溶解し、パラホルムアルデヒド(292mg)をカ卩えて 80°Cで 1 0時間攪拌した。反応液を室温に戻し、炭酸水素ナトリウム水溶液を加え、酢酸ェチ ルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減 圧下に濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1 : 9)で精製し、標題化合物(1. 30g)を淡黄色固体として得た。 [0100] 1- (4 Black Mole) 1-Methyl 1H Pyrazole (1.25 g) is dissolved in 4N hydrochloric acid-dioxane solution (10 ml), and paraformaldehyde (292 mg) is added at 80 ° C. And stirred for 10 hours. The reaction mixture was allowed to return to room temperature, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound (1.30 g) as a pale yellow solid.
'H-NMR (400MHz, CDC1 ) δ : 2. 38 (3Η, s) , 4. 60 (2Η, s) , 7. 39 (2H, d 'H-NMR (400MHz, CDC1) δ: 2.38 (3Η, s), 4.60 (2Η, s), 7.39 (2H, d
3 Three
, J = 8. 8Hz) , 7. 57 (2H, d, J = 8. 8Hz) , 7. 84 (1H, s) . , J = 8.8Hz), 7.57 (2H, d, J = 8.8Hz), 7.84 (1H, s).
[0101] [参考例 2] [0101] [Reference Example 2]
( 1) 2—(4 ホルミルフエノキシ) 2 メチルプロピオン酸 ェチル エステル (1) 2— (4 Formylphenoxy) 2 Methylpropionic acid ethyl ester
[0102] [化 17]
[0102] [Chemical 17]
[0103] 4—ヒドロキシベンズアルデヒド(lOg)と 2 ブロモ 2—メチルプロピオン酸 ェチ ル エステル(18ml)を N, N ジメチルホルムアミド(50ml)に溶解し、炭酸セシウム (53g)を加え、 80°Cにて 4日間攪拌した。反応液を酢酸ェチルで希釈し、水、飽和 食塩水の順に洗浄した後、無水硫酸ナトリウムで乾燥して減圧下に濃縮乾固した。 残渣をシリカゲルカラムクロマトグラフィー(へキサン:酢酸ェチル =4: 1)にて精製し 、標題化合物(8. 91g)を淡黄色油状物として得た。 [0103] 4-Hydroxybenzaldehyde (lOg) and 2-bromo-2-methylpropionic acid ethyl ester (18 ml) were dissolved in N, N dimethylformamide (50 ml), cesium carbonate (53 g) was added, and the mixture was heated to 80 ° C. And stirred for 4 days. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (8.91 g) as a pale yellow oil.
'H-NMR (400MHz, CDC1) δ :1. 21 (3Η, t, J = 7. 1Hz), 1. 67 (6H, s), 4 'H-NMR (400MHz, CDC1) δ: 1.21 (3Η, t, J = 7.1 Hz), 1.67 (6H, s), 4
3 Three
. 23 (2H, q, J = 7. 1Hz) , 6. 90 (2H, d, J = 8. 8Hz) , 7. 79 (2H, d, J = 8. 8Hz ), 9. 88(1H, s). 23 (2H, q, J = 7.1 Hz), 6. 90 (2H, d, J = 8.8 Hz), 7. 79 (2H, d, J = 8.8 Hz), 9. 88 (1H, s).
[0104] (2) 2— [4— [[(フラン一 2—ィルメチル)ァミノ]メチル]フエノキシ ]—2—メチルプロ ピオン酸 ェチル エステル [0104] (2) 2— [4— [[(Furan-2-ylmethyl) amino] methyl] phenoxy] —2-methylpropionic acid ethyl ester
[0105] [化 18] [0105] [Chemical 18]
[0106] 参考例 2— (1)で得たィ匕合物(10g)とフルフリルァミン (4. 1ml)をテトラヒドロフラン Reference Example 2—The compound (10 g) obtained in (1) and furfurylamine (4.1 ml) were added to tetrahydrofuran.
(100ml)に溶解し、 5時間加熱還流した。反応液を室温まで冷却し、減圧下に濃縮 乾固した後、残渣をメタノール(100ml)に溶解し、水素化ホウ素ナトリウム(2.4g)を 加え、 0°Cで 2時間攪拌した。反応液に炭酸水素ナトリウム水溶液を加え、酢酸ェチ ルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減 圧下に濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール = 96:4)で精製し、標題化合物(12. 9g)を黄色油状物として得た。 (100 ml) and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, the residue was dissolved in methanol (100 ml), sodium borohydride (2.4 g) was added, and the mixture was stirred at 0 ° C. for 2 hr. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 96: 4) to give the title compound (12.9 g) as a yellow oil.
iH—NMR (400MHz, CDC1 ) δ :1. 25 (3Η, t, J = 7.4Hz),
1.58 (6H, s), 3.71 (2H, s), 3.79 (2H, s), 4.23 (2H, q, J = 7.4Hz), 6.1iH—NMR (400MHz, CDC1) δ: 1.25 (3Η, t, J = 7.4Hz), 1.58 (6H, s), 3.71 (2H, s), 3.79 (2H, s), 4.23 (2H, q, J = 7.4Hz), 6.1
7(1H, d, J = 2.9Hz), 6.31 (1H, dd, J = 2.0, 2.9Hz), 6.80 (2H, d, J = 8.7 (1H, d, J = 2.9Hz), 6.31 (1H, dd, J = 2.0, 2.9Hz), 6.80 (2H, d, J = 8.
8Hz), 7.19 (2H, d, J = 8.8Hz), 7.37(1H, d, J = 2. OHz) . 8Hz), 7.19 (2H, d, J = 8.8Hz), 7.37 (1H, d, J = 2. OHz).
MS m/z:318(M+H)+. MS m / z: 318 (M + H) +.
[0107] [参考例 3] [0107] [Reference Example 3]
(1)3—メチルー 1一(4 トリフルォロメチルフエ-ル) 1H ピラゾール (1) 3-Methyl-1 (4 trifluoromethyl phenol) 1H pyrazole
[0108] [化 19]
[0108] [Chemical 19]
[0109] (4 トリフルォロメチルフエ-ル)ヒドラジン(2. Og)をエタノール(15ml)、水(15ml )の混合溶媒に溶解し、 1, 1—ジメトキシ一 3 ブタノン(1.5ml)をカロえ、 100°Cで 1 4時間加熱した。反応液を室温まで冷却し、炭酸水素ナトリウム水溶液を加え、酢酸 ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後 、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1:19)で精製し、標題化合物 (718mg)を黄色固体として得た。 [0109] (4 Trifluoromethylphenol) hydrazine (2. Og) was dissolved in a mixed solvent of ethanol (15 ml) and water (15 ml), and 1,1-dimethoxy-1-butanone (1.5 ml) was dissolved in It was heated at 100 ° C for 14 hours. The reaction mixture was cooled to room temperature, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19) to give the title compound (718 mg) as a yellow solid.
'H-NMR (400MHz, CDC1) δ :2.38 (3Η, s), 6.29(1Η, d, J = 2.5Hz), 7 'H-NMR (400MHz, CDC1) δ: 2.38 (3Η, s), 6.29 (1Η, d, J = 2.5Hz), 7
3 Three
.68 (2H, d, J = 8.6Hz), 7.78 (2H, d, J = 8.6Hz), 7.87(1H, d, J = 2.5Hz ). .68 (2H, d, J = 8.6Hz), 7.78 (2H, d, J = 8.6Hz), 7.87 (1H, d, J = 2.5Hz).
MS m/z:227(M+H)+. MS m / z: 227 (M + H) + .
[0110] (2)4 クロロメチル一 1— (4 トリフルォロメチルフエ-ル) 3—メチル 1H—ビラ ゾーノレ [0110] (2) 4 Chloromethyl mono 1— (4 trifluoromethyl phenol) 3-Methyl 1H—Villa Zonole
[0111] [化 20]
参考例 1と同様にして、参考例 3— (1)で得たィ匕合物(715mg)とパラホルムアルデ ヒド(142mg)力も標題ィ匕合物(597mg)を黄色油状物として得た。
Ή-NMR (400MHz, CDC1 ) δ : 2. 39 (3H, s) , 4. 57 (2H, s) , 7. 69 (2H, d [0111] [Chemical 20] In the same manner as in Reference Example 1, the compound (715 mg) obtained in Reference Example 3- (1) and paraformaldehyde (142 mg) also gave the title compound (597 mg) as a yellow oil. NMR-NMR (400MHz, CDC1) δ: 2.39 (3H, s), 4.57 (2H, s), 7.69 (2H, d
3 Three
, J = 8. 6Hz) , 7. 76 (2H, d, J = 8. 6Hz) , 7. 94 (1H, s) . , J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz), 7.94 (1H, s).
[0113] [参考例 4] [0113] [Reference Example 4]
4—クロロメチル 3 メチル 1 フエニル 1 H ピラゾール 4-chloromethyl 3 methyl 1 phenyl 1 H pyrazole
[0114] [化 21]
[0114] [Chemical 21]
[0115] 参考例 1と同様にして、 3—メチルー 1 フエ-ルー 1H ピラゾール(7. 87g)とパ ラホルムアルデヒド(2. Og)力も標題ィ匕合物(3. 04g)を得た。 [0115] In the same manner as in Reference Example 1, the title compound (3.04 g) was also obtained in terms of 3-methyl-1phenol 1H pyrazole (7.87 g) and paraformaldehyde (2. Og).
'H-NMR (400MHz, CDC1 ) δ : 2. 39 (3Η, s) , 4. 59 (2Η, s) , 7. 25 (1H, t, 'H-NMR (400MHz, CDC1) δ: 2.39 (3Η, s), 4.59 (2Η, s), 7.25 (1H, t,
3 Three
J = 8. 6Hz) , 7. 43 (2H, t, J = 8. 6Hz) , 7. 62 (2H, d, J = 8. 6Hz) , 7. 87 (1H , s) . J = 8.6Hz), 7.43 (2H, t, J = 8.6Hz), 7.62 (2H, d, J = 8.6Hz), 7.87 (1H, s).
[0116] [参考例 5] [0116] [Reference Example 5]
(1) 2— (4—ホルミルー2—メトキシフエノキシ)ー2—メチルプロピオン酸 ェチル ェ ステル (1) 2- (4-Formyl-2-methoxyphenoxy) -2-ethyl propionate
[0117] [化 22] [0117] [Chemical 22]
[0118] 4 ヒドロキシ一 3—メトキシベンズアルデヒド(5. Og)を N, N ジメチルホルムアミ ド(20ml)に溶解し、炭酸セシウム(10g)、 2 ブロモ—2—メチルプロピオン酸 ェチ ル エステル(10ml)をカ卩ぇ 80°Cにて 12時間攪拌した。室温に戻した後、酢酸ェチ ル(200ml)、水 (40ml)を加え分液した。有機層を分取し、飽和食塩水にて洗浄後 、無水硫酸ナトリウムにて乾燥した。減圧下に濃縮し、残渣をシリカゲルカラムクロマト グラフィー(酢酸ェチル:へキサン = 1: 3)で精製し標題化合物(6. 3g)を固体として 得た。
Ή-NMR (400MHz, CDC1 ): 1.23 (3H, t, J = 7. 1Hz), 1.66 (6H, s), 3. [0118] 4 Hydroxy-3-methoxybenzaldehyde (5. Og) was dissolved in N, N dimethylformamide (20 ml), cesium carbonate (10 g), 2 bromo-2-methylpropionic acid ethyl ester (10 ml) ) Was stirred at 80 ° C for 12 hours. After returning to room temperature, ethyl acetate (200 ml) and water (40 ml) were added for liquid separation. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (6.3 g) as a solid. Ή-NMR (400MHz, CDC1): 1.23 (3H, t, J = 7.1 Hz), 1.66 (6H, s), 3.
3 Three
90 (3H, s), 4.24 (2H, q, J = 7.1Hz) , 6.85(1H, d, J = 8.3Hz), 7.35(1H , dd, J = 8.3, 1.9Hz), 7.42(1H, d, J=l.9Hz), 9.85(1H, s) . 90 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.85 (1H, d, J = 8.3Hz), 7.35 (1H, dd, J = 8.3, 1.9Hz), 7.42 (1H, d , J = l.9Hz), 9.85 (1H, s).
[0119] (2) 2— [4 [[(フラン一 2—ィルメチル)ァミノ]メチル ]—2—メトキシフエノキシ]—2 メチルプロピオン酸 ェチル エステル [0119] (2) 2- [4 [[(Furan-2-ylmethyl) amino] methyl] -2-methoxyphenoxy] -2 methyl propionic acid ethyl ester
[0120] [化 23] [0120] [Chemical 23]
[0121] 参考例 2と同様にして、参考例 5— (1)で得たィ匕合物(850mg)とフルフリルアミン( 310 1)力も標題ィ匕合物(1.1 lg)を無色油状物として得た。 [0121] In the same manner as in Reference Example 2, the compound (850 mg) obtained in (5) (1) and the furfurylamine (310 1) strength were also obtained from the title compound (1.1 lg) as a colorless oil. Obtained.
iH—NMR (400MHz, CDC1 ) δ :1.28 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 3 iH—NMR (400MHz, CDC1) δ: 1.28 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 3
3 Three
.72 (2H, s), 3.78 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.32(1H, dd, J = 2.0, 3.2Hz), 6.74(1H, dd, J = 2. 0, 8.1Hz), 6.82(1H, d, J = 8.1Hz), 6.88 (1H, d, J = 2. OHz), 7.37(1H , d, J = 2. OHz). .72 (2H, s), 3.78 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = 2.0, 3.2Hz), 6.74 (1H, dd, J = 2.0, 8.1Hz), 6.82 (1H, d, J = 8.1Hz), 6.88 (1H, d, J = 2. OHz) , 7.37 (1H, d, J = 2. OHz).
MS m/z:348(M+H)+. MS m / z: 348 (M + H) +.
[0122] [参考例 6] [0122] [Reference Example 6]
(1)2— (4 ホルミルフエノキシ) 2 メチルプロピオン酸 tert ブチル エステル [0123] [化 24] (1) 2- (4 Formylphenoxy) 2 Methylpropionic acid tert butyl ester [0123] [Chemical formula 24]
参考例 2—(1)と同様にして、 4ーヒドロキシベンズアルデヒド(20g)と 2 ブロモー 2 メチルプロピオン酸 tert ブチル エステル(40ml)から標題化合物(15.4g)を 淡黄色油状物として得た。
Ή-NMR (400MHz, CDC1 ) δ : 1. 41 (9H, s) , 1. 64 (6H, s) , 6. 91 (2H, d In the same manner as in Reference Example 2- (1), the title compound (15.4 g) was obtained as a pale yellow oil from 4-hydroxybenzaldehyde (20 g) and 2 bromo-2-methylpropionic acid tert butyl ester (40 ml). NMR-NMR (400MHz, CDC1) δ: 1.41 (9H, s), 1.64 (6H, s), 6. 91 (2H, d
3 Three
, J = 8. 82Hz) , 7. 78 (2H, d, J = 8. 82Hz) , 9. 88 (1H, s) . , J = 8. 82Hz), 7. 78 (2H, d, J = 8. 82Hz), 9. 88 (1H, s).
[0125] (2)アジドメチル一 1— (4 クロ口フエ-ル) 3—メチル 1H ピラゾール [0125] (2) Azidomethyl mono 1— (4 black mouth) 3-methyl 1H pyrazole
[0126] [化 25] [0126] [Chemical 25]
[0127] 4 クロロメチル一 1— (4 クロ口フエ-ル) 3—メチル 1H ピラゾール(634m g)を N, N ジメチルホルムアミド(8ml)に溶解し、アジ化ナトリウム(205mg)をカロえ て 70°Cで 2時間攪拌した。反応液を室温まで冷却し、溶媒を減圧下に留去した後、 飽和炭酸水素ナトリウム水溶液を加え、酢酸ェチルで 3回抽出した。有機層を飽和食 塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下に濃縮した。残渣をシリカゲル カラムクロマトグラフィー(酢酸ェチル:へキサン = 1:15)で精製し、標題化合物(576 mg)を無色油状物として得た。 [0127] 4 Chloromethyl mono 1- (4 black mouth phenol) 3-Methyl 1H Pyrazole (634 mg) was dissolved in N, N dimethylformamide (8 ml), and sodium azide (205 mg) was added to prepare 70 The mixture was stirred at ° C for 2 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 15) to give the title compound (576 mg) as a colorless oil.
'H-NMR (400MHz, CDC1 ) δ : 2. 36 (3Η, s) , 4. 27 (2Η, s) , 7. 40 (2H, d 'H-NMR (400MHz, CDC1) δ: 2.36 (3Η, s), 4.27 (2Η, s), 7.40 (2H, d
3 Three
, J = 8. 8Hz) , 7. 59 (2H, d, J = 8. 8Hz) , 7. 83 (1H, s) . , J = 8.8Hz), 7.59 (2H, d, J = 8.8Hz), 7.83 (1H, s).
[0128] (3) [1— (4 クロ口フエ-ル)—3—メチル—1H ピラゾールー 4—ィルメチル]カル バミン酸 tert—ブチノレ エステノレ [0128] (3) [1— (4 Black Mole) —3-Methyl-1H-pyrazole-4-ylmethyl] carbamic acid tert-Butinole Estenole
[0129] [化 26] [0129] [Chemical 26]
参考例 6— (2)で得たィ匕合物(570mg)とトリフ -ルホスフィン(785mg)をテトラヒ ドロフラン(10ml)に溶解し、水(0. 5ml)を氷浴下でカ卩えて、徐々に室温まで昇温し な力 Sら 1日攪拌した。溶媒を減圧下に留去し、残渣に飽和炭酸水素ナトリウム水溶液 を加えて酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリ
ゥムで乾燥後、減圧濃縮した。残渣をジクロロメタン (8ml)に溶解し、ジ tert—プチ ルジカルボネート(581 1)を加えて、室温で 15時間攪拌した。反応液に炭酸水素 ナトリウム水溶液を加え、ジクロロメタンで 3回抽出した。有機層を飽和食塩水で洗浄 し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトダラ フィー(酢酸ェチル:へキサン = 1 :4)で精製し、標題化合物(689mg)を無色固体と して得た。 Reference Example 6— The compound (570 mg) obtained in (2) and trif-phosphine (785 mg) were dissolved in tetrahydrofuran (10 ml), and water (0.5 ml) was added in an ice bath. The mixture was gradually warmed to room temperature and stirred for 1 day. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and anhydrous sodium sulfate. After drying with hum, concentrated under reduced pressure. The residue was dissolved in dichloromethane (8 ml), ditert-butyl dicarbonate (5811) was added, and the mixture was stirred at room temperature for 15 hours. To the reaction solution was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (689 mg) as a colorless solid.
'H-NMR (400MHz, CDC1 ) δ : 1. 46 (9Η, s) , 2. 32 (3Η, s) , 4. 20 (2H, d 'H-NMR (400MHz, CDC1) δ: 1.46 (9Η, s), 2.32 (3Η, s), 4.20 (2H, d
3 Three
, J = 5. 7Hz) , 4. 67 (1H, brs) , 7. 38 (2H, d, J = 9. 0Hz) , 7. 56 (2H, d, J = 9 , J = 5.7Hz), 4.67 (1H, brs), 7.38 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9
. 0Hz) , 7. 76 (1H, s) . 0Hz), 7.76 (1H, s).
MS m/z : 322 (M+H)+. MS m / z: 322 (M + H) + .
[0131] (4) 2— [4— [ [ [1一(4 クロ口フエ-ル) 3 メチル 1 H ピラゾール 4ーィル メチル]ァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 tert—ブチル エステル [0132] [化 27] [0131] (4) 2— [4— [[[1 (4-Chromium) 3 Methyl 1 H Pyrazole 4-Methyl] amino] Methyl] phenoxy] -2-Methylpropionic acid tert-butyl ester [ 0132] [Chemical 27]
[0133] 参考例 6— (3)で得たィ匕合物(322mg)をジクロロメタン (4ml)に溶解し、トリフルォ 口酢酸(lml)を加えて、室温で 1時間攪拌した。反応液を減圧濃縮し、残渣に飽和 炭酸水素ナトリウム水溶液を加えて、ジクロロメタンで 3回抽出した。有機層を飽和食 塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をテトラヒドロフラン (6ml)に溶解し、参考例 6— (1)で得たィ匕合物(317mg)をカ卩えて 70°Cで 3. 5時間 攪拌した。反応液を室温まで冷却し、溶媒を減圧下に留去した後、残渣をメタノール (8ml)に溶かし、水素化ホウ素ナトリウム(57mg)をカ卩えて、室温で 20時間攪拌した 。反応液を減圧濃縮した後、残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸ェ チルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、 減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール = 97: 3)で精製し、標題化合物 (428mg)を淡褐色油状物として得た。
Ή-NMR (400MHz, CDC1 ) δ :1.44 (9H, s), 1.56 (6H, s), 2.28 (3H, s) Reference Example 6— The compound (322 mg) obtained in (3) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (lml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 ml), and the compound (317 mg) obtained in Reference Example 6- (1) was collected and stirred at 70 ° C. for 3.5 hours. The reaction solution was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (8 ml), sodium borohydride (57 mg) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 97: 3) to give the title compound (428 mg) as a pale brown oil. NMR-NMR (400MHz, CDC1) δ: 1.44 (9H, s), 1.56 (6H, s), 2.28 (3H, s)
3 Three
, 3.68 (2H, s), 3.78 (2H, s), 6.85 (2H, d, J = 8.8Hz), 7.23 (2H, d, J = 8 .8Hz), 7.37 (2H, d, J = 9. 1Hz), 7.56 (2H, d, J= 9.1Hz), 7.78 (1H, s ). , 3.68 (2H, s), 3.78 (2H, s), 6.85 (2H, d, J = 8.8Hz), 7.23 (2H, d, J = 8.8Hz), 7.37 (2H, d, J = 9. 1Hz), 7.56 (2H, d, J = 9.1Hz), 7.78 (1H, s).
[0134] [参考例 7] [0134] [Reference Example 7]
(1)N—フラン一 2—ィルメチル一 2, 4—ジ-トロベンゼンスルホンアミド (1) N-furan-2-ylmethyl-1,2,4-di-trobenzenesulfonamide
[0135] [化 28] [0135] [Chemical 28]
[0136] フルフリルァミン(3ml)、 2, 4—ジニトロベンゼンスルホユルクロリド(8.65g)をジク ロロメタン(50ml)に溶解し、トリェチルァミン(5.4ml)をカ卩えて、室温で 2時間攪拌し た。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで 3回抽出した。 有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣 にジェチルエーテルを加えて不溶物をろ取し、標題化合物(8.49g)を得た。 [0136] Furfurylamine (3 ml) and 2,4-dinitrobenzenesulfuryl chloride (8.65 g) were dissolved in dichloromethane (50 ml), triethylamine (5.4 ml) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Jetyl ether was added to the residue and the insoluble material was collected by filtration to give the title compound (8.49 g).
'H-NMR (400MHz, CDC1) δ :4.43 (2Η, d, J = 6.1Hz), 5.98 (1H, t, J = 'H-NMR (400MHz, CDC1) δ: 4.43 (2Η, d, J = 6.1Hz), 5.98 (1H, t, J =
3 Three
6. 1Hz), 6.13 (1H, dd, J = 2.0, 3.2Hz), 6.15 (1H, d, J = 3.2Hz), 7.02 6.1Hz), 6.13 (1H, dd, J = 2.0, 3.2Hz), 6.15 (1H, d, J = 3.2Hz), 7.02
(1H, d, J = 2.0Hz), 8.19(1H, d, J = 8.8Hz), 8.42(1H, dd, J = 2.2, 8.8(1H, d, J = 2.0Hz), 8.19 (1H, d, J = 8.8Hz), 8.42 (1H, dd, J = 2.2, 8.8
Hz), 8.64(1H, d, J = 2.2Hz) . Hz), 8.64 (1H, d, J = 2.2Hz).
[0137] (2)4—メチル—1— (4—トリフルォロメチルフエ-ル)— 1H—ピロール— 3—カルボ ン酸 ェチノレ エステノレ [0137] (2) 4-Methyl—1— (4-Trifluoromethylphenol) — 1H—Pyrrole— 3-Carbonic acid Ethenole Estenole
[0138] [化 29] [0138] [Chemical 29]
[0139] 3—メチルー 1H—ピロ一ルー 4一力ルボン酸ェチル(lg)、 4 トリフルォロメチルョ ードベンゼン(1. 06ml)、ヨウィ匕銅(124mg)、リン酸カリウム(2. 77g)、トランス一シ クロへキサンジァミン(75mg)をジォキサン(30ml)に溶解し、 120°Cで 4時間攪拌し た。反応液を室温まで冷却し、反応液に水を加え、酢酸ェチルで 3回抽出した。有機 層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリ 力ゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1 : 19)で精製し、標題化合 物(1. 75g)を得た。 [0139] 3-Methyl- 1H-Pyrro-Lu 4 Strong Eruvyl Ethyl Bonate (lg), 4 Trifluoromethyl Benzene (1.06 ml), Yowi Copper (124 mg), Potassium Phosphate (2. 77 g), Trans-cyclohexanediamine (75 mg) was dissolved in dioxane (30 ml) and stirred at 120 ° C. for 4 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 19) to give the title compound (1.75 g).
'H-NMR (400MHz, CDC1 ) δ : 1. 37 (3Η, t, J = 7. 1Hz) , 2. 34 (3H, s) , 4 'H-NMR (400MHz, CDC1) δ: 1.37 (3Η, t, J = 7.1 Hz), 2.34 (3H, s), 4
3 Three
. 31 (2H, q, J = 7. 1Hz) , 6. 87 (1H, d, J = 2. 5Hz) , 7. 49 (2H, d, J = 8. 3Hz 31 (2H, q, J = 7.1 Hz), 6. 87 (1H, d, J = 2.5 Hz), 7. 49 (2H, d, J = 8.3 Hz)
) , 7. 68 (1H, s) , 7. 70 (2H, d, J = 8. 3Hz) . ), 7.68 (1H, s), 7.70 (2H, d, J = 8.3Hz).
MS m/z : 297 (M+H)+. MS m / z: 297 (M + H) + .
[0140] ( 3) N—フラン 2 ィルメチル N— [4 メチル 1 4 トリフルォロメチルフェ[0140] (3) N—Furan 2-methylmethyl N— [4 Methyl 1 4 Trifluoromethylphenol
-ル)—1H ピロール— 3—ィルメチル]—2, 4 ジ-トロベンゼンスルホンアミド [0141] [化 30] -L) —1H pyrrole—3-ylmethyl] —2, 4 di-trobenzenesulfonamide [0141] [Chemical 30]
[0142] 参考例 7— (2)で得たィ匕合物(500mg)を無水テトラヒドロフラン(7ml)に溶解し、氷 水冷却下水素化リチウムアルミニウム(96mg)を加え、同温で 2時間攪拌した。反応 液に水を加えてセライトろ過し、ろ液を酢酸ェチルで 3回抽出した。有機層を飽和食 塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、 [4ーメチルー 1一(4 トリ フルォロメチルフエ-ル)一 1H ピロ一ルー 3—ィル]メタノールを得た。このものをテ トラヒドロフラン(15ml)に溶解し、参考例 7— (1)で得た化合物(550mg)、トリフエ- ノレホスフィン(529mg)、ァゾジ力ノレボン酸 ジイソプロピノレ エステノレ (397 μ 1)をカロ え、室温で 15時間攪拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマ トグラフィー(酢酸ェチル:へキサン = 1: 9〜1: 5)で精製し、標題化合物(603mg)を
黄色固体として得た。 [0142] Reference Example 7— Dissolving the compound (500 mg) obtained in (2) in anhydrous tetrahydrofuran (7 ml), adding lithium aluminum hydride (96 mg) with cooling with ice water and stirring at the same temperature for 2 hours. did. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted three times with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [4-methyl-1- (4-trifluoromethyl) -1- 1H-pyrrole-1-yl] methanol. It was. This compound was dissolved in tetrahydrofuran (15 ml), and the compound obtained in Reference Example 7- (1) (550 mg), triphenol-norephosphine (529 mg), azodi force norlevonic acid diisopropinole esterol (397 μ 1) And stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 5) to give the title compound (603 mg). Obtained as a yellow solid.
'H-NMR (400MHz, CDC1) δ :2.05 (3Η, s), 4.49 (2Η, s), 4.52 (2H, s) 'H-NMR (400MHz, CDC1) δ: 2.05 (3Η, s), 4.49 (2Η, s), 4.52 (2H, s)
3 Three
, 6.17(1H, d, J = 3.2Hz), 6.25(1H, dd, J = 2.0, 3.2Hz), 6.85(1H, d, J = 2.5Hz), 7.03 (1H, d, J = 2.5Hz), 7.21 (1H, d, J = 2.0Hz), 7.39 (2H , d, J = 8.3Hz), 7.67 (2H, d, J=8.3Hz), 8.05(1H, d, J = 8.6Hz), 8.32 (1H, dd, J = 2.2, 8.6Hz), 8.44 (1H, d, J = 2.2Hz) . , 6.17 (1H, d, J = 3.2Hz), 6.25 (1H, dd, J = 2.0, 3.2Hz), 6.85 (1H, d, J = 2.5Hz), 7.03 (1H, d, J = 2.5Hz) , 7.21 (1H, d, J = 2.0Hz), 7.39 (2H, d, J = 8.3Hz), 7.67 (2H, d, J = 8.3Hz), 8.05 (1H, d, J = 8.6Hz), 8.32 (1H, dd, J = 2.2, 8.6Hz), 8.44 (1H, d, J = 2.2Hz).
MS m/z:565(M+H)+. MS m / z: 565 (M + H) +.
[0143] (4)フラン 2—ィルメチルー [4ーメチルー 1 4 トリフルォロメチルフエ-ル) 1 H ピロ—ル— 3—ィルメチルァミン [0143] (4) Furan 2-ylmethyl- [4-methyl-1 4 trifluoromethylphenol) 1 H pyrrole-3-ylmethylamine
[0144] [化 31] [0144] [Chemical 31]
[0145] 参考例 7— (3)で得たィ匕合物(600mg)をジクロロメタン (8ml)に溶解し、氷浴下トリ ェチルァミン (442 1)、チオダリコール酸(222 1)を順に加え、室温まで徐々に昇 温しながら 1.5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジク ロロメタンで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥 後、減圧乾固し、標題化合物を油状物として得た。このものを精製することなぐ次の 反応に用いた。 [0145] Reference Example 7— The compound (600 mg) obtained in (3) was dissolved in dichloromethane (8 ml), and tritylamine (442 1) and thiodaricholic acid (222 1) were added in this order in an ice bath, The mixture was stirred for 1.5 hours while gradually raising the temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to give the title compound as an oil. This was used in the next reaction without purification.
[0146] [参考例 8] [0146] [Reference Example 8]
2- [4— [[フラン— 2—ィルメチル—(1H—イミダゾールー 4—ィルメチル)ァミノ]メ チル]フエノキシ ] 2—メチルプロピオン酸 ェチル エステル 2- [4 -— [[Furan-2-ylmethyl- (1H-imidazole-4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid ethyl ester
[0147] [化 32] [0147] [Chemical 32]
[0148] 実施例 7— (1)と同様にして、 1H—イミダゾールー 3—カルバルデヒド(215mg)と 参考例 2—(2)で得たィ匕合物(677mg)から、標題化合物(771mg)を無色油状物と して得た。 Example 7— In the same manner as in (1), from the compound (677 mg) obtained in 1H-imidazole-3-carbaldehyde (215 mg) and Reference Example 2- (2), the title compound (771 mg) Was obtained as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 3 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 3
3 Three
.54 (2H, s), 3.61 (2H, s), 3.63 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.33(1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6 Hz), 6.95(1H, s), 7.20 (2H, d, J = 8.6Hz), 7.40(1H, d, J = 2. OHz), 7 .58 (1H, s). .54 (2H, s), 3.61 (2H, s), 3.63 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6 Hz), 6.95 (1H, s), 7.20 (2H, d, J = 8.6Hz), 7.40 (1H, d, J = 2 OHz), 7 .58 (1H, s).
MS m/z:398(M+H)+. MS m / z: 398 (M + H) +.
[0149] [参考例 9] [0149] [Reference Example 9]
(1)4 アジドメチル 3 メチル 1 フエニル 1 H ピラゾール (1) 4 Azidomethyl 3 Methyl 1 Phenyl 1 H Pyrazole
[0150] [化 33]
[0150] [Chemical 33]
[0151] 参考例 6— (2)と同様にして参考例 4で得た化合物 (6. lg)から、標題化合物 (6.0 7g)を無色油状物として得た。 Reference Example 6—The title compound (6.0 7 g) was obtained as a colorless oil from the compound (6. lg) obtained in Reference Example 4 in the same manner as (2).
'H-NMR (400MHz, CDC1) δ :2.37(3Η, s), 4.27 (2Η, s), 7.25— 7.29 'H-NMR (400MHz, CDC1) δ: 2.37 (3Η, s), 4.27 (2Η, s), 7.25— 7.29
3 Three
(1Η, m), 7.40-7.46 (2H, m), 7.63— 7.65 (2H, m), 7.86 (1H, s) . (1Η, m), 7.40-7.46 (2H, m), 7.63—7.65 (2H, m), 7.86 (1H, s).
MS m/z:214(M+H)+. MS m / z: 214 (M + H) + .
[0152] (2) (3—メチル—1—フエ-ルー 1H ピラゾールー 4—ィルメチル)力ルバミン酸 te rt—ブチル エステル [0152] (2) (3-Methyl-1-phenol-H 1H pyrazole-4-ylmethyl) rubamic acid te rt-butyl ester
[0153] [化 34] [0153] [Chemical 34]
[0154] 参考例 6— (3)と同様にして参考例 9— (1)で得たィ匕合物(6. Og)から、標記化合
物(5.85g)を無色固体として得た。 [0154] Reference Example 6— In the same manner as in (3), from the compound (6. Og) obtained in Reference Example 9— (1), the title compound (5.85 g) was obtained as a colorless solid.
'H-NMR (400MHz, CDC1) δ :1.47 (9Η, s), 2.33 (3Η, s), 3.49 (2H, s) 'H-NMR (400MHz, CDC1) δ: 1.47 (9Η, s), 2.33 (3Η, s), 3.49 (2H, s)
3 Three
, 4.21 (2H, d, J = 5.6Hz), 4.67(1H, br s), 7.22— 7.26 (1H, m), 7.42 , 4.21 (2H, d, J = 5.6Hz), 4.67 (1H, br s), 7.22— 7.26 (1H, m), 7.42
(2H, t, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz), 7.79(1H, s) . (2H, t, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz), 7.79 (1H, s).
MS m/z:288(M+H)+. MS m / z: 288 (M + H) +.
[0155] (3) 2— [2—メトキシ一 4— [[ (3—メチル 1 フエ-ル一 1H ピラゾール一 4—ィ ルメチル)ァミノ]メチル]フエノキシ ]ー2—メチルプロピオン酸 ェチル エステル [0156] [化 35] [0155] (3) 2- [2-Methoxy-1-4-[[(3-Methyl 1-phenol-1 1H Pyrazole-1-4-methyl) amino] methyl] phenoxy] -2-Methylpropionic acid ethyl ester [0156] ] [Chemical 35]
[0157] 参考例 6— (4)と同様にして参考例 9— (2)で得たィ匕合物(1. Og)と参考例 5— (1) で得た化合物(1.18g)から標題ィ匕合物(1.43g)を無色油状物として得た。 [0157] Reference Example 6— In the same manner as (4), Reference Example 9— From the compound (1. Og) obtained in (2) and Reference Example 5- (1) from the compound (1.18 g) The title compound (1.43 g) was obtained as a colorless oil.
MS m/z:438(M+H)+. MS m / z: 438 (M + H) +.
[0158] [参考例 10] [0158] [Reference Example 10]
(1) 1 フエ-ルー 3 トリフルォロメチルー 1H ピラゾールー 4一力ルボン酸 ェチ ノレ エステル (1) 1 Ferru 3 Trifluoromethyl 1H Pyrazole 4 Strenuous rubonic acid ester
[0159] [化 36] [0159] [Chemical 36]
[0160] 3 トリフルォロメチル— 1H ピラゾール— 4—カルボン酸 ェチル エステル(1. [0160] 3 Trifluoromethyl— 1H pyrazole — 4-carboxylic acid ethyl ester (1.
Og)、ヨウ化ベンゼン(803 μ 1)、サリチルアルドキシム(132mg)、酸化第一銅(34m g)、炭酸セシウム(3. 13g)をァセトニトリル(6ml)に懸濁させて、 80°Cでー晚攪拌し た。反応液を室温まで冷却し、炭酸水素ナトリウム水溶液を加えて酢酸ェチルで 3回 抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し
た。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 9)で精製 し、標題化合物(1. 5 lg)を無色個体として得た。 Og), benzene iodide (803 μ 1), salicylaldoxime (132 mg), cuprous oxide (34 mg) and cesium carbonate (3.13 g) were suspended in acetonitrile (6 ml) at 80 ° C. -Stirred. The reaction mixture was cooled to room temperature, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. It was. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound (1.5 lg) as a colorless solid.
MS m/z : 285 (M+H)+. MS m / z: 285 (M + H) +.
[0161] (2) (1—フエ-ル一 3 トリフルォロメチル一 1H ピラゾール一 4—ィル)メタノール [0162] [化 37]
[0161] (2) (1—Ferule 3 Trifluoromethyl 1 1H Pyrazole 1-yl) Methanol [0162] [Chemical Formula 37]
[0163] 参考例 10— (1)で得たィ匕合物(1. 5g)を無水テトラヒドロフラン(15ml)に溶解し、 水素化リチウムアルミニウム(200mg)をカ卩えて 0°Cで 30分攪拌した。反応液に水と 酢酸ェチルを加え、セライトで濾過し、母液に炭酸水素ナトリウム水溶液を加え、酢酸 ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後 、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 1)で精製し、標題化合物 (603mg)を無色油状物として得た。[0163] Reference Example 10— The compound (1.5 g) obtained in (1) was dissolved in anhydrous tetrahydrofuran (15 ml) and lithium aluminum hydride (200 mg) was added and stirred at 0 ° C for 30 minutes. did. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. To the mother liquor was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (603 mg) as a colorless oil.
— NMR(400 MHz, CDC1 ) δ : 1. 83 (1Η, t, J = 5. 9Hz) , 4. 77 (2Η, d, J — NMR (400 MHz, CDC1) δ: 1. 83 (1Η, t, J = 5. 9Hz), 4. 77 (2Η, d, J
3 Three
= 5. 9Hz) , 7. 34— 7. 38 (1H, m) , 7. 45— 7. 50 (2H, m) , 7. 67— 7. 70 (2H = 5. 9Hz), 7. 34— 7. 38 (1H, m), 7. 45— 7. 50 (2H, m), 7. 67— 7. 70 (2H
, m) , 8. 00 (1H, s) . , m), 8.00 (1H, s).
MS m/z : 243 (M+H)+. MS m / z: 243 (M + H) + .
[0164] (3) N フラン一 2—ィルメチル一 2, 4 ジニトロ一 N— (1—フエ-ルー 3 トリフル ォロメチルー 1H ピラゾールー 4 ィルメチル)ベンゼンスルホンアミド [0164] (3) N furan-2-ylmethyl-1,2,4 dinitro-N— (1-Ferru 3 trifluoromethyl-1H pyrazole-4-ylmethyl) benzenesulfonamide
[0165] [化 38] [0165] [Chemical 38]
[0166] 参考例 7— (3)と同様にして、参考例 10— (2)で得たィ匕合物(242mg)、参考例 7 Reference Example 7—In the same manner as (3), Reference Example 10—Compound (242 mg) obtained in (2), Reference Example 7
- (1)で得た化合物(327mg)力も標題ィ匕合物(586mg)を黄色油状物として得た。
Ή- NMR (400MHz, CDCl) δ :4.54 (2H, s), 4.61 (2H, s), 6.24— 6.25 -The compound (327 mg) obtained in (1) also gave the title compound (586 mg) as a yellow oil. NMR-NMR (400MHz, CDCl) δ: 4.54 (2H, s), 4.61 (2H, s), 6.24— 6.25
3 Three
(2H, m), 7.19(1H, d, J=l.7Hz), 7.37— 7.41 (1H, m), 7.47— 7.52(2 (2H, m), 7.19 (1H, d, J = l.7Hz), 7.37—7.41 (1H, m), 7.47—7.52 (2
H, m), 7.65-7.69 (2H, m), 8.05(1H, s), 8.12(1H, d, J = 8.8Hz), 8.H, m), 7.65-7.69 (2H, m), 8.05 (1H, s), 8.12 (1H, d, J = 8.8Hz), 8.
42(1H, dd, J = 2.2, 8.8Hz), 8.50(1H, d, J = 2.2Hz) . 42 (1H, dd, J = 2.2, 8.8Hz), 8.50 (1H, d, J = 2.2Hz).
MS m/z:551(M+H)+. MS m / z: 551 (M + H) +.
[0167] [参考例 11] [0167] [Reference Example 11]
(1)2— (2, 6 ジメチルフエノキシ) 2 メチルプロピオン酸 ェチル エステル [0168] [化 39] (1) 2- (2, 6 dimethylphenoxy) 2-methylpropionic acid ethyl ester [0168] [Chemical 39]
[0169] 参考例 5—(1)と同様にして 3, 5 ジメチルー 4ーヒドロキシベンズアルデヒド(5.0 g)と 2—ブロモ—2—メチルプロピオン酸 ェチル エステル(10ml)力 標題化合物 (6.2g)を固体として得た。 [0169] In the same manner as in Reference Example 5— (1), 3,5 dimethyl-4-hydroxybenzaldehyde (5.0 g) and 2-bromo-2-methylpropionic acid ethyl ester (10 ml) force the title compound (6.2 g) as a solid Got as.
iH—NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.2Hz), 1.50 (6H, s), 2 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.50 (6H, s), 2
3 Three
.31 (6H, s), 4.30 (2H, q, J = 7.2Hz) , 7.52 (2H, s) , 9.85(1H, s) . .31 (6H, s), 4.30 (2H, q, J = 7.2Hz), 7.52 (2H, s), 9.85 (1H, s).
[0170] (2)2— [4— [[(フラン一 2—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ] [0170] (2) 2— [4— [[(Furan-2-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy]
2—メチルプロピオン酸 ェチル エステル 2-Methylpropionic acid ethyl ester
[0171] [化 40] [0171] [Chemical 40]
参考例 5— (2)と同様にして参考例 11— (1)で得たィ匕合物(2. Og)とフルフリルアミ ン(700 μ 1)力も標題ィ匕合物(2.13g)を無色油状物として得た。 Reference Example 5— In the same manner as in (2), the compound (2. Og) and furfurylamine (700 μ 1) force obtained in Reference Example 11 (1) were also applied to the title compound (2.13 g) in a colorless manner. Obtained as an oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 18 (6H, s), 3.66 (2H, s), 3.79 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.32(1H, dd, J=l.7, 3.2Hz), 6.92 (2H, s), 7.37(
1H, d, J=l.7Hz). 18 (6H, s), 3.66 (2H, s), 3.79 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = l.7, 3.2Hz), 6.92 (2H, s), 7.37 ( (1H, d, J = l.7Hz).
MS m/z:346(M+H)+. MS m / z: 346 (M + H) +.
[0173] [参考例 12] [0173] [Reference Example 12]
(5—メチル 2 フエ-ルー 2H— [1, 2, 3]トリァゾールー 4—ィル)メタノール (5-Methyl-2-Ferru 2H- [1, 2, 3] Triazol-4-yl) methanol
[0174] [化 41]
[0174] [Chemical 41]
[0175] (5—メチルー 2—フエ-ルー 2H—[1, 2, 3]トリァゾールー 4 ィル)カルボン酸(3 OOmg)を無水テトラヒドロフラン(5ml)に溶かし、ボラン一ジメチルスルフイド錯体(28 0 1)を加え、室温で一晩攪拌後、 60°Cで 4時間攪拌した。反応液に水を加え、酢酸 ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し。無水硫酸ナトリウムで乾燥後 、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 2)で精製し、標題化合物(259mg)を無色固体として得た。 [0175] (5-Methyl-2-phenol-2H— [1, 2, 3] triazole-4-yl) carboxylic acid (3 OOmg) was dissolved in anhydrous tetrahydrofuran (5ml) to give a borane-dimethylsulfide complex (28 0 1) was added, and the mixture was stirred overnight at room temperature and then stirred at 60 ° C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (259 mg) as a colorless solid.
'H-NMR (400MHz, CDC1) δ :1.85 (1Η, t, J = 6.1Hz), 2.42 (3H, s), 4 'H-NMR (400MHz, CDC1) δ: 1.85 (1Η, t, J = 6.1Hz), 2.42 (3H, s), 4
3 Three
.81 (2H, d, J = 6.1Hz), 7.29— 7.33(1H, m), 7.46 (2H, t, J = 8.6Hz)7 .81 (2H, d, J = 6.1Hz), 7.29— 7.33 (1H, m), 7.46 (2H, t, J = 8.6Hz) 7
.99 (2H, d, J = 8.6Hz). .99 (2H, d, J = 8.6Hz).
MS m/z:190(M+H)+. MS m / z: 190 (M + H) +.
[0176] [参考例 13] [0176] [Reference Example 13]
(1) (3-メチル 1 フエ-ル 1 H ピラゾール 4 ィル)ァセトニトリル (1) (3-Methyl 1-phenol 1 H-pyrazole 4-yl) acetonitrile
[0177] [化 42]
[0177] [Chemical 42]
[0178] 参考例 4で得た化合物(1. Og)を N, N ジメチルホルムアミド(10ml)に溶解し、シ アンィ匕ナトリウム(237mg)を加え、 80°Cで 4時間攪拌した。反応液を減圧濃縮し、残 渣に炭酸水素ナトリウム水溶液を加えて、酢酸ェチルで 3回抽出した。有機層を飽和 食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲル力
ラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 6)で精製し、標題化合物(931mg[0178] The compound (1. Og) obtained in Reference Example 4 was dissolved in N, N dimethylformamide (10 ml), cyano sodium (237 mg) was added, and the mixture was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel force on the residue Purification by ram chromatography (ethyl acetate: hexane = 1: 6) gave the title compound (931 mg
)を無色油状物として得た。 ) Was obtained as a colorless oil.
[0179] (2)2- (3—メチル 1—フエ-ルー 1H ピラゾールー 4—ィル)エタノール [0179] (2) 2- (3-Methyl 1-Ferru 1H pyrazole-4-yl) ethanol
[0180] [化 43] [0180] [Chemical 43]
[0181] 参考例 13— (1)で得たィ匕合物(93 lmg)を濃塩酸(20ml)に溶解し、 80°Cで 1.5 時間攪拌した。反応液を室温まで冷却し、水を加え、酢酸ェチルで 3回抽出した。有 機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣を無 水テトラヒドロフラン(10ml)に溶解し、氷浴下ボラン一ジメチルスルフイド錯体(885 1)を加えて、 1.5時間攪拌した。反応液に 10%クェン酸水溶液を加えて 10分間 攪拌後、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリ ゥムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル :へキサン = 1: 1)で精製し、標題化合物 (481mg)を無色油状物として得た。 Reference Example 13— The compound (93 lmg) obtained in (1) was dissolved in concentrated hydrochloric acid (20 ml) and stirred at 80 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 ml), and borane-dimethylsulfide complex (885 1) was added in an ice bath and stirred for 1.5 hours. A 10% aqueous citrate solution was added to the reaction mixture, and the mixture was stirred for 10 minutes, and then extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (481 mg) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :2.32(3Η, s), 2.74 (2Η, t, J = 6.6Hz), 3 'H-NMR (400MHz, CDC1) δ: 2.32 (3Η, s), 2.74 (2Η, t, J = 6.6Hz), 3
3 Three
.82 (2H, br s), 7.20— 7.24 (1H, m), 7.40— 7.44 (2H, m), 7.61— 7.6 .82 (2H, br s), 7.20— 7.24 (1H, m), 7.40— 7.44 (2H, m), 7.61— 7.6
4(2H, m), 7.74 (1H, s) . 4 (2H, m), 7.74 (1H, s).
MS m/z:203(M+H)+. MS m / z: 203 (M + H) + .
[0182] (3)N フラン一 2—ィルメチル一 N— [2— (3—メチル 1—フエ-ル一 1H ピラゾ 一ルー 4—ィル)ェチル ]—2, 4 ジニトロベンゼンスルホンアミド [0182] (3) N furan-2-ylmethyl-1-N- [2- (3-methyl-1-phenyl-1H pyrazo-lru 4-yl) ethyl] -2, 4 dinitrobenzenesulfonamide
[0183] [化 44] [0183] [Chemical 44]
[0184] 参考例 7— (3)と同様にして、参考例 13— (2)で得たィ匕合物 (470mg)と参考例 7 - (1)で得たィ匕合物(761mg)から、標題化合物(1.19g)を黄色固体として得た。 'H-NMR (400MHz, CDCl) δ :2.25 (3Η, s), 2.74 (2Η, t, J = 6.9Hz), 3 Reference Example 7—In the same manner as (3), Reference Example 13—The compound (470 mg) obtained in (2) and Reference Example 7-Compound (761 mg) obtained in (1). Gave the title compound (1.19 g) as a yellow solid. 'H-NMR (400MHz, CDCl) δ: 2.25 (3Η, s), 2.74 (2Η, t, J = 6.9Hz), 3
3 Three
.51 (2H, t, J = 6.9Hz), 4.63 (2H, s), 6.30— 6.34 (2H, m), 7.21— 7.2 5(1H, m), 7.33(1H, d, J=l.7Hz), 7.37— 7.42 (2H, m), 7.49— 7.52( 2H, m), 7.63(1H, s), 8.01 (1H, d, J = 8.6Hz), 8.24 (1H, d, J = 2.2Hz) , 8.32(1H, dd, J = 2.2, 8.6Hz) . .51 (2H, t, J = 6.9Hz), 4.63 (2H, s), 6.30—6.34 (2H, m), 7.21—7.2 5 (1H, m), 7.33 (1H, d, J = l.7Hz ), 7.37—7.42 (2H, m), 7.49—7.52 (2H, m), 7.63 (1H, s), 8.01 (1H, d, J = 8.6Hz), 8.24 (1H, d, J = 2.2Hz) , 8.32 (1H, dd, J = 2.2, 8.6Hz).
MS m/z:512(M+H)+. MS m / z: 512 (M + H) + .
[0185] [参考例 14] [0185] [Reference Example 14]
(1)N— [3— (4 フルオロフェ-ル)—1—フエ-ルー 1H ピラゾールー 4—ィルメ チル]—N フラン一 2—ィルメチル一 2, 4 ジニトロベンゼンスルホンアミド (1) N— [3— (4 Fluorophenol) —1—Fueru 1H Pyrazole-4-ylmethyl] —N Furan-2-ylmethyl-1,2,4 dinitrobenzenesulfonamide
[0186] [化 45] [0186] [Chemical 45]
[0187] 参考例 7—(3)と同様にして、 [3— (4 フルオロフェ-ル) 1 フエ-ルー 1H— ピラゾール— 4—ィル]メタノール(lOOmg)と参考例 7— (1)で得たィ匕合物から、標題 化合物(207mg)を黄色固体として得た。 [0187] In the same manner as in Reference Example 7- (3), in [3— (4 Fluoro-Fel) 1 Ferru 1H-pyrazole-4-yl] methanol (lOOmg) and Reference Example 7- (1) The title compound (207 mg) was obtained as a yellow solid from the obtained compound.
MS m/z:578(M+H)+. MS m / z: 578 (M + H) + .
[0188] (2) [3— (4 フルオロフェ-ル)—1—フエ-ルー 1H ピラゾールー 4—ィルメチル[0188] (2) [3— (4 Fluorophenol) —1—Fueru 1H Pyrazole-4-ylmethyl
]フラン一 2—ィルメチルァミン ] Fran 1-ylmethylamine
[0189] [化 46]
[0189] [Chem 46]
[0190] 参考例 7— (4)と同様にして、参考例 14— (1)で得たィ匕合物(200mg)から標題ィ匕 合物を油状物として得、精製することなく次の反応に用いた。 Reference Example 7—In the same manner as in (4), the title compound was obtained as an oil from the compound (200 mg) obtained in Reference Example 14- (1). Used for reaction.
[0191] [参考例 15] [0191] [Reference Example 15]
(1) 4ーブロモメチルー 5—メチルー 2—フエ-ルー 2H—[1, 2, 3]トリァゾール (1) 4-Bromomethyl-5-methyl-2-ferro- 2H— [1, 2, 3] triazole
[0192] [化 47]
[0192] [Chemical 47]
[0193] 参考例 12で得たィ匕合物 (4. 2g)をジクロロメタン (60ml)に溶解し、氷水冷却下、 三臭化りん(2. 3ml)をカ卩えて、同温で 1時間攪拌した。反応液に水を加え、ジクロロ メタンで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキ サン = 1 : 19)で精製し、標題化合物(5. 2g)を無色固体として得た。 [0193] The compound (4.2 g) obtained in Reference Example 12 was dissolved in dichloromethane (60 ml), and after cooling with ice water, phosphorus tribromide (2.3 ml) was added and kept at the same temperature for 1 hour. Stir. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19) to give the title compound (5.2 g) as a colorless solid.
'H-NMR (400MHz, CDCl ) δ : 2. 42 (3Η, s) , 4. 58 (2Η, s) , 7. 32 (IH, t, 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 4.58 (2Η, s), 7.32 (IH, t,
3 Three
J = 7. 4Hz) , 7. 45 (2H, t, J = 7. 8Hz) , 7. 98 (2H, d, J = 8. 6Hz) . J = 7.4Hz), 7.45 (2H, t, J = 7.8Hz), 7.98 (2H, d, J = 8.6Hz).
[0194] (2) 4—アジドメチルー 5—メチルー 2—フエ-ルー 2H—[1, 2, 3]トリァゾール [0194] (2) 4-Azidomethyl-5-methyl-2-ferro- 2H— [1, 2, 3] triazole
[0195] [化 48]
参考例 6— (2)と同様にして、参考例 15— (1)で得たィ匕合物(3. 5g)とアジィ匕ナトリ ゥム(0. 993g)力も標題ィ匕合物(2. 86g)を無色油状物として得た。 [0195] [Chemical 48] Reference Example 6—Similar to (2), the compound (3.5 g) obtained in Reference Example 15- (1) and the aziana sodium (0.993 g) force were also applied to the title compound (2 86 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl ) δ : 2. 42 (3Η, s) , 4. 46 (2Η, s) , 7. 33 (IH, t,
J = 7.4Hz), 7.47 (2H, t, J = 8.6Hz), 8.01 (2H, d, J = 8.6Hz) . 'H-NMR (400MHz, CDCl) δ: 2. 42 (3Η, s), 4. 46 (2Η, s), 7. 33 (IH, t, J = 7.4Hz), 7.47 (2H, t, J = 8.6Hz), 8.01 (2H, d, J = 8.6Hz).
[0197] (3) (5—メチル 2 フエ-ルー 2H— [1, 2, 3]トリァゾールー 4—ィルメチル)カル バミン酸 tert—ブチノレ エステノレ [0197] (3) (5-Methyl-2-Fel-Lo 2H- [1, 2, 3] Triazol-4-ylmethyl) carbamic acid tert-Butinole Estenole
[0198] [化 49] [0198] [Chemical 49]
[0199] 参考例 6— (3)と同様にして、参考例 15— (2)で得た化合物(2.85g)から標題ィ匕 合物(3.06g)を無色固体として得た。 Reference Example 6- In the same manner as in (3), the title compound (3.06 g) was obtained as a colorless solid from the compound (2.85 g) obtained in Reference Example 15- (2).
'H-NMR (400MHz, CDCl) δ :1.47 (9Η, s), 2.38 (3Η, s), 4.44 (2H, d 'H-NMR (400MHz, CDCl) δ: 1.47 (9Η, s), 2.38 (3Η, s), 4.44 (2H, d
3 Three
, J = 5.6Hz), 5.00(1H, br s), 7.30(1H, t, J = 7.4Hz), 7.45 (2H, t, J = , J = 5.6Hz), 5.00 (1H, br s), 7.30 (1H, t, J = 7.4Hz), 7.45 (2H, t, J =
7.6Hz), 7.97 (2H, d, J = 7.6Hz) . 7.6Hz), 7.97 (2H, d, J = 7.6Hz).
[0200] (4)2— [2, 6 ジメチルー 4— [[(5—メチル—2 フエ-ルー 2H—[1, 2, 3]トリア ゾールー 4 ィルメチル)ァミノ]メチル]フエノキシ ]ー2 メチルプロピオン酸 ェチル エステル [0200] (4) 2— [2, 6 Dimethyl 4-— [[(5-Methyl-2 Ferrule 2H— [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] -2 Methylpropion Acid ethyl ester
[0201] [化 50] [0201] [Chemical 50]
[0202] 参考例 6— (4)と同様にして、参考例 15— (3)で得た化合物(2. Og)および参考例 11— (1)で得たィ匕合物(1.83g)から標題ィ匕合物(3.03g)を淡黄色油状物として得 た。 Reference Example 6—In the same manner as (4), Reference Example 15—Compound (2. Og) obtained in (3) and Reference Example 11—Compound obtained in (1) (1.83 g) To give the title compound (3.03 g) as a pale yellow oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 19 (6H, s), 2.34 (3H, s), 3.74 (2H, s), 3.88 (2H, s), 4.29 (2H, q, J = 7. 1Hz), 6.95 (2H, s), 7.29 (1H, t, J = 7.4Hz), 7.43 (2H, t, J = 7.8Hz) , 7.99 (2H, d, J = 8.6Hz) . 19 (6H, s), 2.34 (3H, s), 3.74 (2H, s), 3.88 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.95 (2H, s), 7.29 (1H, t, J = 7.4Hz), 7.43 (2H, t, J = 7.8Hz), 7.99 (2H, d, J = 8.6Hz).
[0203] [参考例 16]
(1) 2— (4—ホルミル— 2, 6 ジメチルフエノキシ)—2—メチルプロピオン酸 tert— ブチル エステル [0203] [Reference Example 16] (1) 2— (4-Formyl-2,6 dimethylphenoxy) -2-methylpropionic acid tert-butyl ester
[0204] [化 51] [0204] [Chemical 51]
[0205] 炭酸セシウムの代りに炭酸カリウムを用いる以外は参考例 6— (1)と同様にして、 3, 5 ジメチルー 4 ヒドロキシベンズアルデヒド(15. Og)と 2 ブロモ 2—メチルプロ ピオン酸 tert ブチル エステル(56ml)を炭酸カリウム(55. 3g)の存在下に処理 することにより標題ィ匕合物 (4. 47g)を淡黄色油状物として得た。 [0205] In the same manner as Reference Example 6- (1) except that potassium carbonate was used in place of cesium carbonate, 3, 5 dimethyl-4-hydroxybenzaldehyde (15. Og) and 2 bromo-2-methylpropionic acid tert butyl ester ( 56 ml) was treated in the presence of potassium carbonate (55.3 g) to give the title compound (4.47 g) as a pale yellow oil.
'H-NMR (400MHz, CDC1 ) δ : 1. 41 (6Η, s) , 1. 47 (9Η, s) , 2. 25 (6H, s) 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.47 (9Η, s), 2.25 (6H, s)
3 Three
, 7. 48 (2H, s) , 9. 83 (1H, s) . , 7. 48 (2H, s), 9. 83 (1H, s).
[0206] (2) 2- [2, 6 ジメチルー 4 [ (メチルカルバモイルメチルァミノ)メチル]フエノキシ[0206] (2) 2- [2, 6 Dimethyl-4 [(Methylcarbamoylmethylamino) methyl] phenoxy
]—2—メチルプロピオン酸 tert—ブチル エステル ] —2-Methylpropionic acid tert-butyl ester
[0207] [化 52] [0207] [Chemical 52]
[0208] 参考例 16— (1)で得たィ匕合物(2. 92g)と 2 ァミノ一 N—メチルァセタミド塩酸塩([0208] Reference Example 16- Compound (2.92g) obtained in (1) and 2-amino-1-N-methylacetamide hydrochloride (
2. 49g)をメタノール(200ml)に溶かし、氷水冷却下にシァノ水素化ホウ素ナトリウム (1規定テトラヒドロフラン溶液、 15ml)を加えた。室温に戻し一晩攪拌した後、溶媒を 減圧下に留去し、残渣〖こジクロロメタン、 1規定水酸化ナトリウム水溶液を加えて分液 した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下に留去し、残渣をシリカゲ ルカラムクロマトグラフィー(ジクロロメタン:メタノール = 9 : 1)で精製し、標題化合物(2. 49 g) was dissolved in methanol (200 ml), and sodium cyanoborohydride (1N tetrahydrofuran solution, 15 ml) was added under ice water cooling. After returning to room temperature and stirring overnight, the solvent was distilled off under reduced pressure, and the residue was diluted with dichloromethane and 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to give the title compound (
3. 6 lg)を黄色油状物として得た。
Ή-NMR (400MHz, CDC1 ) δ :1.42 (3H, s), 1.52 (9H, s), 2.22 (6H, s) 3.6 lg) was obtained as a yellow oil. NMR-NMR (400MHz, CDC1) δ: 1.42 (3H, s), 1.52 (9H, s), 2.22 (6H, s)
3 Three
, 2.83 (3H, d, J = 5.1Hz), 3.31 (2H, s), 3.66 (2H, s), 6.89 (2H, s), 7. 23 (1H, br s) . , 2.83 (3H, d, J = 5.1Hz), 3.31 (2H, s), 3.66 (2H, s), 6.89 (2H, s), 7.23 (1H, br s).
MS m/z:364(M+H)+. MS m / z: 364 (M + H) + .
[0209] [参考例 17] [0209] [Reference Example 17]
(1) 2— [4 [ (tert ブトキシカルボ-ルメチルァミノ)メチル ]—2, 6 ジメチルフエ ノキシ ] 2—メチルプロピオン酸 ェチル エステル (1) 2- [4 [(tert-Butoxycarboromethylamino) methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0210] [化 53] [0210] [Chemical 53]
[0211] 参考例 11— (1)で得たィ匕合物(15.8g)をテトラヒドロフラン(300ml)に溶解し、グ リシン tert ブチル エステル(9ml)と硫酸マグネシウム(50g)加えて 4時間加熱 還流した。反応液を室温に戻し、セライトを通してろ過後、ろ液を減圧留去した。残渣 をメタノール(100ml)に溶解し、氷水冷却下に水素化ホウ素ナトリウム(2.3g)をカロ え、室温で 4時間攪拌した。反応液に水を加えて、減圧濃縮後、酢酸ェチルにて抽 出し、飽和重曹水、飽和食塩水の順に洗浄した。無水硫酸ナトリウムで乾燥後、溶媒 を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(クロ口ホルム:メタノール = 19:1)にて精製し、標題化合物 (21.6g)を淡黄色油状物として得た。 [0211] Reference Example 11— The compound (15.8 g) obtained in (1) was dissolved in tetrahydrofuran (300 ml), glycine tert butyl ester (9 ml) and magnesium sulfate (50 g) were added, and the mixture was heated to reflux for 4 hours. did. The reaction solution was returned to room temperature, filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (100 ml), sodium borohydride (2.3 g) was added while cooling with ice water, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure, extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 19: 1) to give the title compound (21.6 g) as a pale yellow oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.48 (9H, s), 2.18 (6H, s), 3.30 (2H, s), 3.65 (2H, s), 4.29 (2H, q, J = 7. 1Hz), 6.93 (2H, s) . .48 (9H, s), 2.18 (6H, s), 3.30 (2H, s), 3.65 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.93 (2H, s).
MS m/z:380(M+H)+. MS m / z: 380 (M + H) +.
[0212] (2) 2— [4 [[tert ブトキシカルバモイルメチルー(5—メチルー 2 フエ-ルー 2 H— [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキ
シ ] 2—メチルプロピオン酸 ェチル エステル [0212] (2) 2— [4 [[tert Butoxycarbamoylmethyl- (5-methyl-2-phenol 2 H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 Enoki 2] 2-Methylpropionic acid ethyl ester
[0213] [化 54] [0213] [Chemical 54]
[0214] 参考例 17— (1)で得たィ匕合物 (0.301g)と参考例 15— (1)で得たィ匕合物 (0.20 g)を N, N ジメチルホルムアミド(5ml)に溶解し、炭酸カリウム(0. 132g)をカ卩えて 、 80°Cで 3日間攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶液 を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリ ゥムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢 酸ェチル:へキサン =1:4)で精製し、標題化合物(0.42 lg)を無色油状物として得 た。 [0214] Reference Example 17— Combine the compound (0.301 g) obtained in (1) with the compound (0.20 g) obtained in Reference Example 15 (1) into N, N dimethylformamide (5 ml). After dissolution, potassium carbonate (0.132 g) was added and stirred at 80 ° C. for 3 days. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (0.42 lg) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.47 (9H, s), 2.18 (6H, s), 2.31 (3H, s), 3.24 (2H, s), 3.69 (2H, s), 3. 87 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 6.98 (2H, s), 7.28 (1H, t, J=7.6H z), 7.44 (2H, t, J = 7.6Hz), 7.99 (2H, d, J = 7.6Hz) . .47 (9H, s), 2.18 (6H, s), 2.31 (3H, s), 3.24 (2H, s), 3.69 (2H, s), 3.87 (2H, s), 4.28 (2H, q , J = 7.1Hz), 6.98 (2H, s), 7.28 (1H, t, J = 7.6H z), 7.44 (2H, t, J = 7.6Hz), 7.99 (2H, d, J = 7.6Hz) .
MS m/z:551(M+H)+. MS m / z: 551 (M + H) +.
[0215] (3)2— [4— [[カルボキシメチル—(5—メチル—2 フエ-ル— 2H—[1, 2, 3]トリ ァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチル プロピオン酸 ェチノレ エステノレ [0215] (3) 2— [4 — [[Carboxymethyl— (5-methyl-2 phenol—2H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2,6 dimethyl Phenoxy] —2-methyl propionate ethenore estenore
[0216] [化 55] [0216] [Chemical 55]
[0217] 参考例 17— (2)で得た化合物(0.437g)をジクロロメタン(2ml)に溶解し、トリフル
ォロ酢酸(lml)を加えて、室温で一晩攪拌した。反応液を減圧下濃縮し、残渣をシリ 力ゲルカラムクロマトグラフィー(クロ口ホルム:メタノール = 94: 6)で精製し、標題化合 物(0.236g)を無色油状物として得た。 Reference Example 17— Dissolving the compound (0.437 g) obtained in (2) in dichloromethane (2 ml) Oroacetic acid (lml) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (black form: methanol = 94: 6) to give the title compound (0.236 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 19 (6H, s), 2.25 (3H, s), 3.43 (2H, s), 3.72 (2H, s), 3.85 (2H, s), 4. 29 (2H, q, J = 7.1Hz) , 6.94 (2H, s) , 7.32(1H, t, J = 7.8Hz), 7.46 (2H, t, J = 7.8Hz), 7.99 (2H, d, J = 7.8Hz) . 19 (6H, s), 2.25 (3H, s), 3.43 (2H, s), 3.72 (2H, s), 3.85 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.94 (2H, s), 7.32 (1H, t, J = 7.8Hz), 7.46 (2H, t, J = 7.8Hz), 7.99 (2H, d, J = 7.8Hz).
MS m/z:509(M+H)+. MS m / z: 509 (M + H) +.
[0218] [参考例 18] [0218] [Reference Example 18]
2-[4-[[[2-(Ν'ーァセチルヒドラジノ) 2—ォキソェチル]一(5—メチルー 2— フエ-ルー 2Η—[1, 2, 3]トリァゾールー 4 ィルメチル)ァミノ]メチル ] 2, 6 ジメ チルフエノキシ ] 2—メチルプロピオン酸 ェチル エステル 2- [4-[[[2- (Ν'-acetyl-hydrazino) 2-oxoethyl]-(5-methyl-2-phenol-2Η- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] 2, 6-dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0219] [化 56] [0219] [Chem 56]
[0220] 参考例 17— (3)で得たィ匕合物(0.230g)、ァセトヒドラジド (0.038g)、 1—ェチル — 3— (3 ジメチルァミノプロピル)カルボジイミド塩酸塩 (0. 107g)、 1 -ヒドロキシ ベンゾトリアゾール水和物(0.085g)を N, N ジメチルホルムアミド(4ml)に溶解し 、室温で一晩攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶液を 加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウ ムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢 酸ェチル)で精製し、標題化合物 (0.163g)を無色油状物として得た。 [0220] Reference Example 17—Compound obtained in (3) (0.230 g), acetohydrazide (0.038 g), 1-ethyl — 3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.107 g) ), 1-hydroxybenzotriazole hydrate (0.085 g) was dissolved in N, N dimethylformamide (4 ml) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.163 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
.05 (3H, s), 2.21 (6H, s), 2.24 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3.
77 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 7.02 (2H, s) , 7.30(1H, t, J=7.6H z), 7.45 (2H, t, J = 7.6Hz), 8.00 (2H, d, J = 7.6Hz), 8.12(1H, br s),.05 (3H, s), 2.21 (6H, s), 2.24 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3. 77 (2H, s), 4.29 (2H, q, J = 7.1Hz), 7.02 (2H, s), 7.30 (1H, t, J = 7.6H z), 7.45 (2H, t, J = 7.6Hz) , 8.00 (2H, d, J = 7.6Hz), 8.12 (1H, br s),
9.56 (1H, br s) . 9.56 (1H, br s).
MS m/z:551(M+H)+. MS m / z: 551 (M + H) +.
[0221] [参考例 19] [0221] [Reference Example 19]
2- [4— [(3—メトキシプロピルァミノ)メチル ]—2, 6—ジメチルフエノキシ]—2—メ チルプロピオン酸 ェチル エステル 2- [4 -— [(3-Methoxypropylamino) methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester
[0222] [化 57] [0222] [Chemical 57]
[0223] 参考例 2— (2)と同様にして、参考例 11— (1)で得たィ匕合物(0.800g)と 3—メトキ シプロピルアミン (0.339ml)力も標題ィ匕合物(1.02g)を無色油状物として得た。 'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 [0223] Reference Example 2—In the same manner as (2), the compound (0.800 g) obtained in Reference Example 11- (1) and 3-methoxypropylamine (0.339 ml) were also used in the title compound. (1.02 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.79 (2H, quint, J = 6.4Hz), 2. 18 (6H, s), 2.72 (2H, t, J = 6.9Hz), 3.33 .79 (2H, quint, J = 6.4Hz), 2. 18 (6H, s), 2.72 (2H, t, J = 6.9Hz), 3.33
(3H, s), 3.45 (2H, t, J = 6.4Hz), 3.66 (2H, s), 4.28 (2H, q, J = 7. 1Hz)(3H, s), 3.45 (2H, t, J = 6.4Hz), 3.66 (2H, s), 4.28 (2H, q, J = 7.1 Hz)
, 6.91 (2H, s). , 6.91 (2H, s).
MS m/z:437(M+H)+. MS m / z: 437 (M + H) + .
[0224] [参考例 20] [0224] [Reference Example 20]
2- [4— [(2—メトキシェチルァミノ)メチル ]—2, 6 ジメチルフエノキシ ] 2—メチ ルプロピオン酸 tert ブチル エステル 2- [4 -— [(2-Methoxyethylamino) methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid tert butyl ester
[0225] [化 58] [0225] [Chemical 58]
[0226] 参考例 16— (1)で得たィ匕合物(3. lg)、 2—メトキシェチルァミン(1. Olml)をエタ
ノール(30ml)に溶解し、 80°Cで 2時間攪拌した。反応液を氷水にて冷却し、水素化 ホウ素ナトリウム (0.40g)を加えて、徐々に室温まで昇温しながら一晩攪拌した。反 応液に飽和食塩水を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄 し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムク 口マトグラフィー(クロ口ホルム:メタノール =97 :3)で精製し、標題化合物(3.73g)を 無色油状物として得た。 [0226] Reference Example 16— The compound (3. lg) obtained in (1) and 2-methoxyethylamine (1. The product was dissolved in anol (30 ml) and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled with ice water, sodium borohydride (0.40 g) was added, and the mixture was stirred overnight while gradually warming to room temperature. Saturated saline was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 97: 3) to obtain the title compound (3.73 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s) 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s)
3 Three
, 2.80 (2H, t, J = 5.1Hz), 3.35 (3H, s), 3.51 (2H, t, J = 5.1Hz), 3.68 ( 2H, s), 6.91 (2H, s) . , 2.80 (2H, t, J = 5.1Hz), 3.35 (3H, s), 3.51 (2H, t, J = 5.1Hz), 3.68 (2H, s), 6.91 (2H, s).
MS m/z:352(M+H)+. MS m / z: 352 (M + H) + .
[0227] [参考例 21] [0227] [Reference Example 21]
参考例 21—(3)の化合物を文献記載の方法(E. Klingsberg, Synthesis, 475 —477(1972))に従って合成した。 The compound of Reference Example 21- (3) was synthesized according to a method described in the literature (E. Klingsberg, Synthesis, 475-477 (1972)).
(1)2- (ヒドロキシィミノ) 3—ォキソ N フエ-ルブチラミド (1) 2- (Hydroxyimino) 3-oxo-N-butylbutyramide
[0228] [化 59] [0228] [Chemical 59]
[0229] ァセトキシァセトァ -リド(10g)を酢酸(100ml)に溶解し、氷水冷却下に亜硝酸ナ トリウム (4.67g)の水溶液(50ml)を滴下した。同温で 2時間攪拌後、反応液を減圧 下濃縮した。残渣に炭酸水素ナトリウム水溶液を加え、酢酸ェチルで 3回抽出した。 有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し た。残渣にジェチルエーテルを加え、不溶物をろ取した。母液を減圧下濃縮し、残渣 にジェチルエーテル一へキサンを加えて、不溶物をろ取し、合わせて標題ィ匕合物(1 0.9g)を黄色固体として得た。 Acetoxyacetolide (10 g) was dissolved in acetic acid (100 ml), and an aqueous solution (50 ml) of sodium nitrite (4.67 g) was added dropwise with cooling with ice water. After stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Jetyl ether was added to the residue, and insolubles were collected by filtration. The mother liquor was concentrated under reduced pressure, to the residue was added diethyl ether monohexane, and the insoluble material was collected by filtration to give the title compound (1 0.9 g) as a yellow solid.
[0230] (2)2- (ヒドロキシィミノ) N フエ-ルー 3— (p トリルヒドラゾノ)ブチラミド [0230] (2) 2- (Hydroxyimino) N Hue-Lou 3— (p-tolylhydrazono) butyramide
[0231] [化 60]
[0231] [Chemical 60]
[0232] 参考例 21— (1)で得たィ匕合物(1. 16g)をエタノール(20ml)に溶解し、塩酸 p—ト リノレヒドラジン(0. 985g)とトリエチノレアミン(0. 865ml)をカロ免て、 80。Cで 30分携枠 した。反応液を室温まで冷却して、溶媒を減圧下留去した。残渣に炭酸水素ナトリウ ム水溶液を加えて、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無 水硫酸ナトリウムで乾燥後、減圧下濃縮し、標題ィ匕合物の粗生成物(1. 75g)を得た Reference Example 21— The compound (1.16 g) obtained in (1) was dissolved in ethanol (20 ml), and p-trinolehydrazine hydrochloride (0.985 g) and triethinoreamine (0 865ml) free from calo, 80. I carried it with C for 30 minutes. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the title compound (1.75 g).
MS m/z : 311 (M+H)+. MS m / z: 311 (M + H) +.
[0233] (3) 5—メチル— 2— p—トリル— 2H— [1, 2, 3]トリァゾール— 4—カルボン酸 [0233] (3) 5-Methyl-2-p-tolyl-2H— [1, 2, 3] triazole-4-carboxylic acid
[0234] [化 61] [0234] [Chemical 61]
[0235] 参考例 21— (2)で得たィ匕合物(1. 75g)をメトキシエタノール(15ml)に溶解し、水 酸ィ匕カリウム(3. 4g)を加えて、 140°Cで一晩攪拌した。反応液を濃塩酸—氷に注ぎ 、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで 乾燥後、減圧下溶媒を留去し、標題化合物の粗生成物を得た。 [0235] Reference Example 21— The compound (1.75 g) obtained in (2) was dissolved in methoxyethanol (15 ml), and potassium hydroxide (3.4 g) was added at 140 ° C. Stir overnight. The reaction mixture was poured into concentrated hydrochloric acid-ice and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of the title compound.
[0236] (4) (5—メチル— 2— p—トリル— 2H— [1, 2, 3]トリァゾール— 4—ィル)メタノール [0236] (4) (5-Methyl-2-p-tolyl-2H— [1, 2, 3] triazole-4-yl) methanol
[0237] [化 62] [0237] [Chemical 62]
[0238] 参考例 21— (3)で得たィ匕合物(1. 22g)をテトラヒドロフラン(10ml)に溶解し、ボラ
ン—ジメチルスルフイド錯体(1. 08ml)を加え、 60°Cで 45分間攪拌した。反応液に 水を加え、 10分間 60°Cで攪拌した。反応液を飽和食塩水に注ぎ、酢酸ェチルで 3 回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下 溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 3)で精製し、標題化合物 (0. 80g)を無色個体として得た。 [0238] Reference Example 21— The compound (1.22 g) obtained in (3) was dissolved in tetrahydrofuran (10 ml). N-dimethylsulfide complex (1.08 ml) was added and stirred at 60 ° C for 45 minutes. Water was added to the reaction solution, and the mixture was stirred at 60 ° C for 10 minutes. The reaction mixture was poured into saturated brine and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (0.80 g) as a colorless solid.
'H-NMR (400MHz, CDCl ) δ : 2. 39 (3Η, s) , 2. 41 (3Η, s) , 4. 80 (2H, s) 'H-NMR (400MHz, CDCl) δ: 2.39 (3Η, s), 2.41 (3Η, s), 4.80 (2H, s)
3 Three
, 7. 25 (2H, d, J = 8. 6Hz) , 7. 86 (2H, d, J = 8. 6Hz) . , 7. 25 (2H, d, J = 8.6 Hz), 7. 86 (2H, d, J = 8.6 Hz).
MS m/z : 204 (M+H)+. MS m / z: 204 (M + H) + .
[0239] (5) 4—ブロモメチル— 5—メチル— 2— p—トリル— 2H— [1, 2, 3]トリァゾール [0239] (5) 4-Bromomethyl-5-methyl-2-p-tolyl-2H- [1, 2, 3] triazole
[0240] [化 63]
[0240] [Chemical 63]
[0241] 参考例 15— (1)と同様にして、参考例 21— (4)で得た化合物 (0. 80g)から標題 化合物(0. 65g)を無色固体として得た。 [0241] In the same manner as in Reference Example 15- (1), the title compound (0.665 g) was obtained as a colorless solid from the compound (0.80 g) obtained in Reference Example 21- (4).
'H-NMR (400MHz, CDCl ) δ : 2. 39 (3Η, s) , 2. 41 (3Η, s) , 4. 58 (2H, s) 'H-NMR (400MHz, CDCl) δ: 2.39 (3Η, s), 2.41 (3Η, s), 4.58 (2H, s)
3 Three
, 7. 25 (2H, d, J = 8. 6Hz) , 7. 86 (2H, d, J = 8. 6Hz) . , 7. 25 (2H, d, J = 8.6 Hz), 7. 86 (2H, d, J = 8.6 Hz).
[0242] [参考例 22] [0242] [Reference Example 22]
(1) 2— [4— [ [tert—ブトキシカルボ-ルメチルー(9H—フルオレン— 9—ィルメトキ シカルボ-ル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチルプロピオン酸 ェチノレ エステル (1) 2- [4 -— [[tert-Butoxycarboromethyl- (9H-fluorene-9-ylmethoxy) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethinore ester
[0243] [化 64] [0243] [Chemical 64]
[0244] 参考例 17— (1)で得たィ匕合物(3.5g)をァセトニトリル(30ml)に溶解し、氷水冷 却下に N— (9—フルォレ -ルメトキシカルボ-ルォキシ)スクシンイミド(3.74g)を加 えて、室温で 4時間攪拌した。減圧下溶媒を留去し、残渣を酢酸ェチルで抽出し、有 機層を水、飽和重曹水、クェン酸水溶液、飽和食塩水の順で洗浄した。無水硫酸ナ トリウムで乾燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー( 酢酸ェチル:へキサン = 1: 1)で精製することにより標題ィ匕合物(5.24g)を淡黄色油 状物として得た。 [0244] Reference Example 17— The compound (3.5 g) obtained in (1) was dissolved in acetonitrile (30 ml), and N— (9-fluoromethoxycarbo-loxy) succinimide (3.74) was cooled with ice water. g) was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium bicarbonate, aqueous citrate solution and saturated brine in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (5.24 g) as pale yellow Obtained as an oil.
'H-NMR (400MHz, CDC1) δ :1.34—1.38 (3Η, m), 1.43— 1.54(15Η 'H-NMR (400MHz, CDC1) δ: 1.34—1.38 (3Η, m), 1.43—1.54 (15Η)
3 Three
, m), 2.17(3Η, s), 2.18 (3Η, s), 3.78 (1Η, s), 3.84(1H, s), 4.26—4. , m), 2.17 (3Η, s), 2.18 (3Η, s), 3.78 (1Η, s), 3.84 (1H, s), 4.26-4.
30 (3H, m), 4.44—4.49 (4H, m), 6.77(1H, s), 6.85(1H, s), 7.25— 730 (3H, m), 4.44—4.49 (4H, m), 6.77 (1H, s), 6.85 (1H, s), 7.25— 7
.31 (2H, m), 7.35— 7.41 (2H, m), 7.53(1H, d, J = 7.4Hz), 7.59(1H, d, J = 7.4Hz), 7.73(1H, d, J = 7.6Hz), 7.76 (1H, d, J = 7.6Hz) . .31 (2H, m), 7.35—7.41 (2H, m), 7.53 (1H, d, J = 7.4Hz), 7.59 (1H, d, J = 7.4Hz), 7.73 (1H, d, J = 7.6 Hz), 7.76 (1H, d, J = 7.6Hz).
MS m/z:624(M+Na)+. MS m / z: 624 (M + Na) + .
[0245] (2) 2— [4 [[カルボキシメチルー(9H—フルオレンー9 ィルメトキシカルボ-ル) ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピオン酸 ェチル エス テノレ [0245] (2) 2— [4 [[Carboxymethyl- (9H-fluorene-9-ylmethoxycarbol) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionate Ethyl ester
[0246] [化 65] [0246] [Chemical 65]
[0247] 参考例 22— (1)で得たィ匕合物(5.24g)をジクロロメタン (60ml)に溶解し、氷水冷 却下にトリフルォロ酢酸(20ml)をカ卩えて、室温で 16時間攪拌した。減圧留去し、残 渣を酢酸ェチルで抽出し、有機層を水、飽和食塩水の順で洗浄した。無水硫酸ナト リウムで乾燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー (メ タノール:クロ口ホルム = 1: 9)で精製することにより標題ィ匕合物(5.70g)を淡黄色油
状物として得た。 Reference Example 22— The compound (5.24 g) obtained in (1) was dissolved in dichloromethane (60 ml), and trifluoroacetic acid (20 ml) was added while cooling with ice water, followed by stirring at room temperature for 16 hours. . The residue was extracted with ethyl acetate, and the organic layer was washed with water and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (5.70 g) Yellow oil Obtained as a product.
'H-NMR (400MHz, CDC1) δ :1.33— 1.38 (3Η, m), 1.45 (3Η, s), 1.4 'H-NMR (400MHz, CDC1) δ: 1.33— 1.38 (3Η, m), 1.45 (3Η, s), 1.4
3 Three
6(3H, s), 2. 17(6H, s), 3.77(1H, s), 3.98(1H, s), 4.25—4.32 (3H, m ), 4.44 (2H, s), 4.52-4.55 (2H, m), 6.75(1H, s), 6.82(1H, s), 7.23 -7.31 (2H, m), 7.38 (2H, t, J = 7.4Hz), 7.56— 7.53 (2H, m), 7.74(2 H, d, J=7.3Hz). 6 (3H, s), 2.17 (6H, s), 3.77 (1H, s), 3.98 (1H, s), 4.25—4.32 (3H, m), 4.44 (2H, s), 4.52-4.55 ( 2H, m), 6.75 (1H, s), 6.82 (1H, s), 7.23 -7.31 (2H, m), 7.38 (2H, t, J = 7.4Hz), 7.56-7.53 (2H, m), 7.74 (2 H, d, J = 7.3 Hz).
MS m/z:568(M+H)+. MS m / z: 568 (M + H) +.
[0248] (3) 2— [4— [[[2—(N,ーァセチルヒドラジノ) 2—ォキソェチル]一(9H—フルォ レン— 9—ィルメトキシカルボ-ル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2— メチルプロピオン酸 ェチル エステル [0248] (3) 2— [4— [[[2- (N, -Acetylhydrazino) 2-oxoethyl] (9H-fluorene-9-ylmethoxycarbol) amino] methyl] — 2,6 Dimethylphenoxy] —2-Methylpropionic acid ethyl ester
[0249] [0249]
[0250] 参考例 18と同様にして、参考例 22— (2)で得たィ匕合物(1.5g)とァセトヒドラジド( 0.31g)から標題ィ匕合物(1. lg)を無色固体として得た。 [0250] In the same manner as in Reference Example 18, the title compound (1. lg) was colorless from the compound (1.5 g) obtained in Reference Example 22- (2) and acetohydrazide (0.31 g). Obtained as a solid.
MS m/z:602(M+H)+. MS m / z: 602 (M + H) + .
[0251] (4) 2— [4— [[(9H フルオレン— 9—ィルメトキシカルボ-ル)一(5—メチルー [1, 3, 4]ォキサジァゾ—ルー 2—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ ]一 2—メチルプロピオン酸 ェチル エステル [0251] (4) 2— [4— [[(9H Fluorene-9-ylmethoxycarbol) mono (5-methyl- [1, 3, 4] oxadiazo-ru 2-ylmethyl) amino] methyl] — 2, 6-Dimethylphenoxy] 1 2-methylpropionic acid ethyl ester
[0252] [化 67]
[0252] [Chemical 67]
[0253] 実施例 26— (1)と同様にして、参考例 22— (3)で得たィ匕合物(1. lg)から標題ィ匕 合物(1. Og)を無色固体として得た。 In the same manner as in Example 26- (1), the title compound (1. Og) was obtained as a colorless solid from the compound (1. lg) obtained in Reference Example 22- (3). It was.
'H-NMR (400MHz, CDC1) δ :1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 16 (6H, s), 2.46, 2.49 (3H, each s), 4.26—4.31 (3H, m), 4.39—4. 16 (6H, s), 2.46, 2.49 (3H, each s), 4.26—4.31 (3H, m), 4.39—4.
44 (3H, m), 4.55—4.59 (3H, m), 6.73, 6.85 (2H, each s), 7.36— 7.44 (3H, m), 4.55—4.59 (3H, m), 6.73, 6.85 (2H, each s), 7.36— 7.
40 (2H, m), 7.46— 7.49(1H, m), 7.53— 7.57 (3H, m), 7.65— 7.70(140 (2H, m), 7.46— 7.49 (1H, m), 7.53— 7.57 (3H, m), 7.65— 7.70 (1
H, m), 7.75-7.73 (2H, m) . H, m), 7.75-7.73 (2H, m).
MS m/z:584(M+H)+. MS m / z: 584 (M + H) + .
[0254] (5)2— [2, 6 ジメチル一 4— [[(5—メチル [1, 3, 4]ォキサジァゾ一ル一 2—ィ ルメチル)ァミノ]メチル]フエノキシ ]ー2—メチルプロピオン酸 ェチル エステル [0255] [化 68] [0254] (5) 2- [2,6 Dimethyl 4-[[((5-Methyl [1, 3, 4] oxadiazol 2-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid Ethyl ester [0255] [Chemical formula 68]
[0256] 参考例 22— (4)で得たィ匕合物(1. Og)をテトラヒドロフラン(50ml)に溶解し、氷水 冷却下に 1, 8 ジァザビシクロ [5.4.0]ゥンデー7 セン(2%テトラヒドロフラン溶 液、 42.2ml)を加えて、室温で 2時間攪拌後、減圧下溶媒を留去した。残渣を酢酸
ェチルで抽出し、飽和重曹水、飽和食塩水の順に洗浄した。無水硫酸ナトリウムで乾 燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー (メタノール:ク ロロホルム = 1: 9)で精製することにより標題ィ匕合物(0.54g)を黄色油状物として得 た。 [0256] Reference Example 22— The compound (1. Og) obtained in (4) was dissolved in tetrahydrofuran (50 ml) and 1,8 diazabicyclo [5.4.0] undane 7 sen (2%) was cooled with ice water. Tetrahydrofuran solution (42.2 ml) was added, and the mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. Acetic acid residue The mixture was extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (0.54 g) as a yellow oil. Got as.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (7H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (7H, s), 2
3 Three
. 19 (6H, s), 2.53 (3H, s), 3.73 (2H, s), 3.98 (2H, s), 4.29 (2H, q, J = 7. 1Hz), 6.92 (2H, s) . 19 (6H, s), 2.53 (3H, s), 3.73 (2H, s), 3.98 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.92 (2H, s).
MS m/z:362(M+H)+. MS m / z: 362 (M + H) + .
[0257] [参考例 23] [0257] [Reference Example 23]
(1) (5—メチル— 2— m—トリル— 2H— [1, 2, 3]トリァゾールー 4—ィル)メタノール [0258] [化 69] (1) (5-Methyl-2- m-tolyl-2H- [1, 2, 3] triazol-4-yl) methanol [0258] [Chemical 69]
[0259] 参考例 21— (2)から (4)と同様にして、塩酸 m—トリルヒドラジン (0.846g)カも標 題化合物(0.944g)を淡黄色固体として得た。 Reference Example 21 In the same manner as (2) to (4), m-tolylhydrazine hydrochloride (0.846 g) was also obtained as the title compound (0.944 g) as a pale yellow solid.
'H-NMR (400MHz, CDC1) δ :2.41 (3Η, s), 2.42 (3Η, s), 4.80 (2H, s) 'H-NMR (400MHz, CDC1) δ: 2.41 (3Η, s), 2.42 (3Η, s), 4.80 (2H, s)
3 Three
, 7.12(1H, d, J = 8.1Hz), 7.33(1H, t, J = 8.1Hz), 7.78 (1H, d, J = 8. 1 , 7.12 (1H, d, J = 8.1Hz), 7.33 (1H, t, J = 8.1Hz), 7.78 (1H, d, J = 8.1)
Hz), 7.82(1H, s). Hz), 7.82 (1H, s).
MS m/z:204(M+H)+. MS m / z: 204 (M + H) + .
[0260] (2)4—ブロモメチル— 5—メチル— 2— m—トリル— 2H— [1, 2, 3]トリァゾール [0261] [化 70] [0260] (2) 4-Bromomethyl-5-methyl-2-m-tolyl-2H— [1, 2, 3] triazole [0261] [Chemical 70]
[0262] 参考例 15— (1)と同様にして、参考例 23— (1)で得たィ匕合物 (0.940g)から標題 化合物(0.805g)を無色固体として得た。 [0262] In the same manner as in Reference Example 15- (1), the title compound (0.805 g) was obtained as a colorless solid from the compound (0.940 g) obtained in Reference Example 23- (1).
'H-NMR (400MHz, CDCl) δ :2.42 (3Η, s), 2.43 (3Η, s), 4.58 (2H, s) 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 2.43 (3Η, s), 4.58 (2H, s)
3 Three
, 7.13(1H, d, J = 8.1Hz), 7.33(1H, t, J = 8.1Hz), 7.80(1H, d, J = 8. 1 Hz), 7.82 (1H, s). , 7.13 (1H, d, J = 8.1Hz), 7.33 (1H, t, J = 8.1Hz), 7.80 (1H, d, J = 8.1 Hz), 7.82 (1H, s).
[0263] [参考例 24] [0263] [Reference Example 24]
( 1 ) 2— [4— [ [tert -ブトキシカルボ-ルメチル ( 5 メチル 2— m トリル— 2H — [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキ シ ] 2—メチルプロピオン酸 ェチル エステル (1) 2— [4— [[tert-Butoxycarboromethyl (5 methyl 2-m tolyl-2H — [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 dimethylphenol ] 2-Methylpropionic acid ethyl ester
[0264] [化 71] [0264] [Chemical 71]
[0265] 参考例 17— (2)と同様にして、参考例 23— (2)で得た化合物(0.210g)と参考例 17— (1)で得たィ匕合物(0.299g)力も標題ィ匕合物(0.398g)を無色油状物として 得た。 In the same manner as Reference Example 17- (2), the compound (0.210 g) obtained in Reference Example 23- (2) and the compound (0.299 g) obtained in Reference Example 17- (1) were also used. The title compound (0.398 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.47 (9H, s), 2.18 (6H, s), 2.31 (3H, s), 2.42 (3H, s), 3.23 (2H, s), 3. 69 (2H, s), 3.86 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.10( 1H, d, J = 7.8Hz), 7.32(1H, t, J = 7.8Hz), 7.79(1H, d, J = 7.8Hz), 7. 83 (1H, s). .47 (9H, s), 2.18 (6H, s), 2.31 (3H, s), 2.42 (3H, s), 3.23 (2H, s), 3.69 (2H, s), 3.86 (2H, s ), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.10 (1H, d, J = 7.8Hz), 7.32 (1H, t, J = 7.8Hz), 7.79 (1H, d , J = 7.8Hz), 7. 83 (1H, s).
MS m/z:565(M+H)+. MS m / z: 565 (M + H) +.
[0266] (2)2— [4— [[カルボキシメチル—(5—メチル—2— m—トリル— 2H—[1, 2, 3]トリ ァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチル プロピオン酸 ェチノレ エステノレ
[0267] [化 72] [0266] (2) 2— [4 — [[Carboxymethyl— (5-methyl-2-m-tolyl-2H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 Dimethylphenoxy] -2-ethyl propionate [0267] [Chemical 72]
[0268] 参考例 17— (3)と同様にして、参考例 24— (1)で得たィ匕合物 (0.446g)力も標題 化合物(0.235g)を無色油状物として得た。 Reference Example 17- In the same manner as in (3), the compound (0.446 g) force obtained in Reference Example 24- (1) was also used to give the title compound (0.235 g) as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
.20 (6H, s), 2.24 (3H, s), 2.44 (3H, s), 3.44 (2H, s), 3.72 (2H, s), 3. 85 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 6.94 (2H, s), 7.14(1H, d, J = 7.8 Hz), 7.34(1H, t, J=7.8Hz), 7.79(1H, d, J = 7.8Hz), 7.82(1H, s) . MS m/z:509(M+H)+. .20 (6H, s), 2.24 (3H, s), 2.44 (3H, s), 3.44 (2H, s), 3.72 (2H, s), 3.85 (2H, s), 4.29 (2H, q , J = 7.1Hz), 6.94 (2H, s), 7.14 (1H, d, J = 7.8 Hz), 7.34 (1H, t, J = 7.8Hz), 7.79 (1H, d, J = 7.8Hz), 7.82 (1H, s) .MS m / z: 509 (M + H) +.
[0269] (3) 2— [4— [[[2—(N,ーァセチルヒドラジノ) 2—ォキソェチル]一(5—メチルー 2— m—トリル— 2H— [1, 2, 3]トリァゾール— 4—ィルメチル)ァミノ]メチル ]—2, 6 ージメチルフエノキシ ] 2—メチルプロピオン酸 ェチル エステル [0269] (3) 2— [4— [[[2— (N, -acetyl-hydrazino) 2-oxoethyl]-(5-methyl-2-m-tolyl— 2H— [1, 2, 3] triazole — 4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0270] [化 73] [0270] [Chemical 73]
参考例 18と同様にして、参考例 24— (2)で得たィ匕合物(0.230g)とァセトヒドラジ ド (0.037g)力も標題ィ匕合物(0.196g)を無色油状物として得た。 In the same manner as in Reference Example 18, the compound (0.230 g) obtained in Reference Example 24- (2) and acetohydrazide (0.037 g) also gave the title compound (0.196 g) as a colorless oil. .
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
.21 (6H, s), 2.23 (3H, s), 2.43 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3. 76 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 7.02 (2H, s) , 7.12(1H, d, J = 7.6
Hz), 7.33(1H, t, J=8.1Hz), 7.79(1H, d, J = 8. 1Hz), 7.83(1H, s), 8. 16 (1H, br s), 9.56 (1H, br s) . .21 (6H, s), 2.23 (3H, s), 2.43 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3.76 (2H, s), 4.29 (2H, q , J = 7.1Hz), 7.02 (2H, s), 7.12 (1H, d, J = 7.6 Hz), 7.33 (1H, t, J = 8.1Hz), 7.79 (1H, d, J = 8.1 Hz), 7.83 (1H, s), 8. 16 (1H, br s), 9.56 (1H, br s).
MS m/z:565(M+H)+. MS m / z: 565 (M + H) +.
[0272] [参考例 25] [0272] [Reference Example 25]
(1)[2— (4 クロロフヱ-ル)一 5—メチル 2H— [1, 2, 3]トリァゾールー 4 ィル] メタノーノレ (1) [2— (4 Chlorophenyl) 1-5-methyl 2H— [1, 2, 3] triazole- 4 yl] methanol
[0273] [化 74] [0273] [Chemical 74]
[0274] 参考例 21— (2)から(4)と同様にして、塩酸 (4 クロ口フエ-ル)ヒドラジン(0.955 g)力も標題ィ匕合物(0.926g)を無色固体として得た。 Reference Example 21 In the same manner as in (2) to (4), the title compound (0.926 g) was obtained as a colorless solid in the same manner as in (4), with the strength of hydrochloric acid (4 black mouth) hydrazine (0.955 g).
'H-NMR (400MHz, CDCl) δ :2.42 (3Η, s), 4.80 (2Η, s), 7.42 (2H, d 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 4.80 (2Η, s), 7.42 (2H, d
3 Three
, J = 8.8Hz), 7.94 (2H, d, J = 8.8Hz) . , J = 8.8Hz), 7.94 (2H, d, J = 8.8Hz).
MS m/z:224(M+H)+. MS m / z: 224 (M + H) + .
[0275] (2)4 ブロモメチル 2— (4 クロ口フエ-ル)一 5—メチル 2H—[1, 2, 3]トリア ゾーノレ [0275] (2) 4 Bromomethyl 2— (4 Black Mole) 1-Methyl 2H— [1, 2, 3] Tria Zonole
[0276] [化 75] [0276] [Chemical 75]
[0277] 参考例 15— (1)と同様にして、参考例 25— (1)で得たィ匕合物 (0.920g)力も標題 化合物(0.772g)を無色固体として得た。 Reference Example 15—In the same manner as in (1), the compound (0.920 g) force obtained in Reference Example 25- (1) also gave the title compound (0.772 g) as a colorless solid.
'H-NMR (400MHz, CDCl) δ :2.41 (3Η, s), 4.57 (2Η, s), 7.42 (2H, d 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 4.57 (2Η, s), 7.42 (2H, d
3 Three
, J = 8.8Hz), 7.94 (2H, d, J = 8.8Hz) . , J = 8.8Hz), 7.94 (2H, d, J = 8.8Hz).
[0278] [参考例 26]
(1) 2— [4— [[tert—ブトキシカルボ-ルメチルー [2— (4 クロ口フエ- チルー 2H—[1, 2, 3]トリァゾールー 4 ィルメチル]ァミノ]メチル ]—2, ルフエノキシ ] 2—メチルプロピオン酸 ェチル エステル [0278] [Reference Example 26] (1) 2— [4— [[tert-Butoxycarbolmethyl- [2— (4 Chlorophthalyl-tilu 2H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, Ruphenoxy] 2— Methyl propionic acid ethyl ester
[0279] [化 76] [0279] [Chem 76]
[0280] 参考例 17— (2)と同様にして、参考例 25— (2)で得た化合物 (0.130g)と参考例 17— (1)で得たィ匕合物(0.172g)力も標題ィ匕合物(0.21 lg)を無色油状物として 得た。 [0280] In the same manner as Reference Example 17- (2), the compound (0.130 g) obtained in Reference Example 25- (2) and the compound (0.172 g) force obtained in Reference Example 17- (1) were also used. The title compound (0.21 lg) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.47 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 3.23 (2H, s), 3.68 (2H, s), 3. 86 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 6.96 (2H, s), 7.40 (2H, d, J = 9.1 Hz), 7.94 (2H, d, J = 9.1Hz) . .47 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 3.23 (2H, s), 3.68 (2H, s), 3.86 (2H, s), 4.28 (2H, q , J = 7.1Hz), 6.96 (2H, s), 7.40 (2H, d, J = 9.1 Hz), 7.94 (2H, d, J = 9.1Hz).
[0281] (2) 2— [4 [[カルボキシメチル— [2— (4 クロロフヱ-ル) 5—メチル 2H— [ 1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジメチルフエノキシ] 2—メチルプロピオン酸 ェチル エステル [0281] (2) 2— [4 [[Carboxymethyl— [2— (4 Chlorophenyl) 5-Methyl 2H— [1, 2, 3] Triazol-4-ylmethyl] amino] methyl] —2, 6 Dimethyl Phenoxy] 2-methylpropionic acid ethyl ester
[0282] [化 77] [0282] [Chemical 77]
[0283] 参考例 17— (3)と同様にして、参考例 26— (1)で得たィ匕合物 (0.205g)力も標題 化合物(0. 185g)を無色固体として得た。 Reference Example 17—In the same manner as in (3), the compound (0.205 g) force obtained in Reference Example 26- (1) was also used to give the title compound (0.185 g) as a colorless solid.
MS m/z:529(M+H)+.
[0284] (3)2-[4-[[[2- (N,ーァセチルヒドラジノ) 2—ォキソェチル] [2—(4 クロ 口フエ-ル)— 5—メチル 2H— [1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチ ル ]ー 2, 6 ジメチルフエノキシ ] 2 メチルプロピオン酸 ェチル エステル MS m / z: 529 (M + H) +. [0284] (3) 2- [4-[[[2- (N, -acetyl-hydrazino) 2-oxoethyl] [2 -— (4-cylinder)-5-methyl 2H— [1, 2 , 3] Triazol-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0285] [化 78] [0285] [Chemical 78]
[0286] 参考例 18と同様にして、参考例 26— (2)で得たィ匕合物(0.185g)とァセトヒドラジ ド (0.03 lg)力も標題ィ匕合物(0.183g)を無色油状物として得た。 [0286] In the same manner as in Reference Example 18, the compound (0.185 g) obtained in Reference Example 26- (2) and the acetohydrazide (0.03 lg) force were also obtained from the title compound (0.183 g) as a colorless oil. Got as.
'H-NMR (400MHz, CDC1) δ :1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
.05 (3H, s), 2.20 (6H, s), 2.23 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3. 76 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 7.01 (2H, s) , 7.42 (2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.8Hz), 8.08 (1H, br s), 9.55 (1H, br s) . .05 (3H, s), 2.20 (6H, s), 2.23 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3.76 (2H, s), 4.29 (2H, q , J = 7.1Hz), 7.01 (2H, s), 7.42 (2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.8Hz), 8.08 (1H, br s), 9.55 (1H, br s).
MS m/z:584(M+H)+. MS m / z: 584 (M + H) + .
[0287] [参考例 27] [0287] [Reference Example 27]
(1)[2— (3 クロ口フエ-ル)一 5—メチル 2H— [1, 2, 3]トリァゾールー 4 ィル] メタノーノレ (1) [2— (3 black mouth) 1-5-methyl 2H— [1, 2, 3] triazole- 4 yl] methanol
[0288] [化 79] [0288] [Chemical 79]
参考例 21— (2)から (4)と同様にして、塩酸(3 クロ口フエ-ル)ヒドラジン (0.955 g)力も標題ィ匕合物 (0.815g)を無色固体として得た。
Ή- NMR (400MHz, CDCl) δ :2.42 (3H, s), 4.81 (2H, s), 7.26— 7.29 Reference Example 21—In the same manner as (2) to (4), the title compound (0.815 g) was also obtained as a colorless solid with the strength of hydrochloric acid (3 black mouth) hydrazine (0.955 g). NMR-NMR (400MHz, CDCl) δ: 2.42 (3H, s), 4.81 (2H, s), 7.26— 7.29
3 Three
(1H, m), 7.38(1H, t, J=8.1Hz), 7.90(1H, d, J = 8. 1Hz), 8.04 (1H, t (1H, m), 7.38 (1H, t, J = 8.1Hz), 7.90 (1H, d, J = 8.1 Hz), 8.04 (1H, t
, J = 2.0Hz). , J = 2.0Hz).
MS m/z:224(M+H)+. MS m / z: 224 (M + H) + .
[0290] (2)4 ブロモメチル 2— (3 クロ口フエ-ル)一 5—メチル 2H—[1, 2, 3]トリア ゾーノレ [0290] (2) 4 Bromomethyl 2— (3 Black Mole) 1-Methyl 2H— [1, 2, 3] Tria Zonole
[0292] 参考例 15— (1)と同様にして、参考例 27— (1)で得たィ匕合物 (0.810g)力も標題 化合物(0.761g)を無色固体として得た。 Reference Example 15—In the same manner as in (1), the compound (0.810 g) force obtained in Reference Example 27- (1) was also used to obtain the title compound (0.761 g) as a colorless solid.
'H-NMR (400MHz, CDCl) δ :2.42 (3Η, s), 4.56 (2Η, s), 7.28 (1H, d 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 4.56 (2Η, s), 7.28 (1H, d
3 Three
, J = 2. OHz), 7.38(1H, t, J = 8.1Hz), 7.88— 7.91 (1H, m), 8.04 (1H, t , J = 2. OHz). , J = 2. OHz), 7.38 (1H, t, J = 8.1Hz), 7.88— 7.91 (1H, m), 8.04 (1H, t, J = 2. OHz).
[0293] [参考例 28] [0293] [Reference Example 28]
(1) 2— [4— [[tert—ブトキシカルボ-ルメチルー [2— (3—クロ口フエ-ル)—5—メ チルー 2H—[1, 2, 3]トリァゾールー 4 ィルメチル]ァミノ]メチル ]—2, 6 ジメチ ルフエノキシ ] 2—メチルプロピオン酸 ェチル エステル (1) 2— [4— [[tert-Butoxycarboromethyl] [2— (3—Black mouth phenyl) -5-methyl-2H— [1, 2, 3] triazole-4-ylmethyl] amino] methyl] —2, 6-dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0294] [化 81] [0294] [Chemical 81]
[0295] 参考例 17—(2)と同様にして、参考例 27—(2)で得た化合物(0.130g)と参考例
17— (1)で得たィ匕合物(0.172g)力 標題ィ匕合物(0.265g)を無色油状物として 得た。 [0295] In the same manner as in Reference Example 17- (2), the compound (0.130 g) obtained in Reference Example 27- (2) and Reference Example 17- Compound (0.172 g) force obtained in (1) The title compound (0.265 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.48 (9H, s), 2.18 (6H, s), 2.30 (3H, s), 3.23 (2H, s), 3.68 (2H, s), 3. 86 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 6.97 (2H, s), 7.24— 7.26 (1H, m) , 7.36(1H, d, J = 7.8Hz), 7.88— 7.90(1H, m), 8.04 (1H, d, J = 2. OHz ). .48 (9H, s), 2.18 (6H, s), 2.30 (3H, s), 3.23 (2H, s), 3.68 (2H, s), 3.86 (2H, s), 4.29 (2H, q , J = 7.1Hz), 6.97 (2H, s), 7.24— 7.26 (1H, m), 7.36 (1H, d, J = 7.8Hz), 7.88— 7.90 (1H, m), 8.04 (1H, d, J = 2.OHz).
[0296] (2) 2— [4— [[カルボキシメチル一 [2— (3 クロ口フエ-ル) 5—メチル 2H— [ 1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジメチルフエノキシ] 2—メチルプロピオン酸 ェチル エステル [0296] (2) 2— [4— [[Carboxymethyl mono [2— (3 throat) phenol] 5-Methyl 2H— [1, 2, 3] Triazol-4-ylmethyl] amino] methyl] —2 , 6 Dimethylphenoxy] 2-Methylpropionic acid ethyl ester
[0297] [化 82] [0297] [Chemical 82]
[0298] 参考例 17— (3)と同様にして、参考例 28— (1)で得たィ匕合物 (0.260g)力も標題 化合物(0.235g)を無色固体として得た。 Reference Example 17—In the same manner as in (3), the compound (0.260 g) force obtained in Reference Example 28- (1) was also used to give the title compound (0.235 g) as a colorless solid.
MS m/z:529(M+H)+. MS m / z: 529 (M + H) +.
[0299] (3)2-[4-[[[2-(Ν'ーァセチルヒドラジノ) 2—ォキソェチル] [2— (3 クロ 口フエ-ル)— 5—メチル 2Η— [1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチ ル ]ー 2, 6 ジメチルフエノキシ ] 2 メチルプロピオン酸 ェチル エステル [0299] (3) 2- [4-[[[2- (Ν'-Acetylhydrazino) 2-oxoethyl] [2-— (3-Circle Phenyl) — 5-Methyl 2Η— [1, 2 , 3] Triazol-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0300] [化 83]
[0300] [Chemical 83]
[0301] 参考例 18と同様にして、参考例 28— (2)で得た化合物(0.233g)とァセトヒドラジ ド (0.039g)力も標題ィ匕合物(0.206g)を無色油状物として得た。 [0301] In the same manner as in Reference Example 18, the compound (0.233 g) obtained in Reference Example 28- (2) and acetohydrazide (0.039 g) were also used to obtain the title compound (0.206 g) as a colorless oil. .
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
.05 (3H, s), 2.20 (6H, s), 2.23 (3H, s), 3.37 (2H, s), 3.63 (2H, s), 3. .05 (3H, s), 2.20 (6H, s), 2.23 (3H, s), 3.37 (2H, s), 3.63 (2H, s), 3.
76 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 7.01 (2H, s) , 7.26— 7.28 (1H, m)76 (2H, s), 4.28 (2H, q, J = 7.1Hz), 7.01 (2H, s), 7.26— 7.28 (1H, m)
, 7.38(1H, d, J = 8.1Hz), 7.89— 7.92(1H, m), 8.02(1H, d, J = 2. OHz, 7.38 (1H, d, J = 8.1Hz), 7.89— 7.92 (1H, m), 8.02 (1H, d, J = 2. OHz
), 8.27(1H, br s), 9.57(1H, br s) . ), 8.27 (1H, br s), 9.57 (1H, br s).
MS m/z:585(M+H)+. MS m / z: 585 (M + H) +.
[0302] [参考例 29] [0302] [Reference Example 29]
(1)[2— (4—メトキシフエ-ル)— 5—メチル 2H— [1, 2, 3]トリァゾール— 4—ィ ル]メタノール (1) [2— (4-Methoxyphenol) —5-Methyl 2H— [1, 2, 3] Triazole—4-yl] methanol
[0303] [化 84]
[0303] [Chemical 84]
[0304] 参考例 21— (2)から (4)と同様にして、塩酸 (4—メトキシフエ-ル)ヒドラジン (0.9 32g)力も標題ィ匕合物(0.468g)を黄色固体として得た。 Reference Example 21 In the same manner as in (2) to (4), the title compound (0.468 g) was obtained as a yellow solid in the same manner as in (4), with the strength of hydrochloric acid (4-methoxyphenol) hydrazine (0.9 32 g).
'H-NMR (400MHz, CDCl) δ :2.41 (3Η, s), 3.85 (3Η, s), 4.80 (2H, s) 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 3.85 (3Η, s), 4.80 (2H, s)
3 Three
, 6.97 (2H, d, J = 9.1Hz), 7.89 (2H, d, J = 9.1Hz) . , 6.97 (2H, d, J = 9.1Hz), 7.89 (2H, d, J = 9.1Hz).
MS m/z:220(M+H)+. MS m / z: 220 (M + H) + .
[0305] (2)4 ブロモメチル 2— (4—メトキシフエ-ル)一 5—メチル 2H—[1, 2, 3]トリ
ァゾール [0305] (2) 4 Bromomethyl 2- (4-methoxyphenyl) 1 5-methyl 2H— [1, 2, 3] tri Azol
[0306] [化 85]
[0306] [Chemical 85]
[0307] 参考例 15— (1)と同様にして、参考例 29— (1)で得たィ匕合物 (0.460g)力も標題 化合物(0.458g)を無色固体として得た。 Reference Example 15 In the same manner as in (1), the compound (0.460 g) force obtained in Reference Example 29- (1) also gave the title compound (0.458 g) as a colorless solid.
'H-NMR (400MHz, CDCl) δ :2.41 (3Η, s), 3.85 (3Η, s), 4.58 (2H, s) 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 3.85 (3Η, s), 4.58 (2H, s)
3 Three
, 6.96 (2H, d, J = 9.1Hz), 7.90 (2H, d, J = 9.1Hz) . , 6.96 (2H, d, J = 9.1Hz), 7.90 (2H, d, J = 9.1Hz).
MS m/z:282(M+H)+. MS m / z: 282 (M + H) + .
[0308] [参考例 30] [0308] [Reference Example 30]
(1) 2— [4 [[tert ブトキシカルボ-ルメチルー [2—(4ーメトキシフエ-ル)ー5— メチル 2H— [1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジメ チルフエノキシ ] 2—メチルプロピオン酸 ェチル エステル (1) 2- [4 [[tert Butoxycarboromethyl- [2- (4-methoxyphenyl) -5-methyl 2H- [1, 2, 3] triazol-4-ylmethyl] amino] methyl] -2, 6 dimethyl Tylphenoxy] 2-methylpropionic acid ethyl ester
[0309] [化 86] [0309] [Chemical 86]
参考例 17— (2)と同様にして、参考例 29— (2)で得た化合物 (0.190g)と参考例 17— (1)で得たィ匕合物(0.256g)力 標題ィ匕合物(0.391g)を無色油状物として 得た。 Reference Example 17—In the same manner as (2), the compound (0.190 g) obtained in Reference Example 29— (2) and the compound (0.256 g) obtained in Reference Example 17— (1) The compound (0.391 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.47 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 3.23 (2H, s), 3.57 (2H, s), 3. 68 (2H, s), 3.84 (3H, s), 3.85 (2H, s), 4.28 (2H, q, J = 7. 1Hz), 6.95( 2H, d, J = 9.1Hz), 6.97 (2H, s), 7.90 (2H, d, J = 9.1Hz) .
MS m/z:581(M+H)+. .47 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 3.23 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 3.84 (3H, s ), 3.85 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.95 (2H, d, J = 9.1Hz), 6.97 (2H, s), 7.90 (2H, d, J = 9.1 Hz). MS m / z: 581 (M + H) +.
[0311] (2) 2— [4 [[カルボキシメチル一 [2— (4—メトキシフエ-ル) 5—メチル 2H— [0311] (2) 2— [4 [[Carboxymethyl mono [2— (4-methoxyphenyl) 5-methyl 2H—
[1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジメチルフエノキシ] 2—メチルプロピオン酸 ェチル エステル [1, 2, 3] triazol-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0312] [化 87] [0312] [Chemical 87]
[0313] 参考例 17— (3)と同様にして、参考例 30— (1)で得たィ匕合物 (0.391g)から標題 化合物(0.318g)を無色固体として得た。 Reference Example 17— In the same manner as in (3), the title compound (0.318 g) was obtained as a colorless solid from the compound (0.391 g) obtained in Reference Example 30— (1).
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 19 (6H, s), 2.26 (3H, s), 3.60 (2H, s), 3.85 (3H, s), 3.99 (2H, s), 4. 19 (6H, s), 2.26 (3H, s), 3.60 (2H, s), 3.85 (3H, s), 3.99 (2H, s), 4.
11 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 6.97 (2H, d, J = 9.1Hz), 7.04 (2H11 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.97 (2H, d, J = 9.1Hz), 7.04 (2H
, s), 7.91 (2H, d, J = 9.1Hz) . , s), 7.91 (2H, d, J = 9.1Hz).
MS m/z:525(M+H)+. MS m / z: 525 (M + H) + .
[0314] (3)2-[4-[[[2- (N,一ァセトヒドラジノ)ー2—ォキソェチル] [2—(4ーメトキシ ェチル)ー5—メチルー 2H—[1, 2, 3]トリァゾールー 4 ィルメチル]ァミノ]メチル][0314] (3) 2- [4-[[[2- (N, acetohydrazino) -2-oxoethyl] [2- (4-methoxyethyl) -5-methyl-2-H- [1, 2, 3] triazole 4 [Ilmethyl] amino] methyl]
—2, 6 ジメチルフエノキシ ] 2 メチルプロピオン酸 ェチル エステル —2, 6-Dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0315] [化 88] [0315] [Chemical 88]
[0316] 参考例 18と同様にして、参考例 30— (2)で得た化合物(0.150g)とァセトヒドラジ
ド (0.023g)力も標題ィ匕合物(0.145g)を無色油状物として得た。 [0316] Reference Example 30—Compound (0.150 g) obtained in (2) and acetohydrazine in the same manner as Reference Example 18. The title compound (0.145 g) was also obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
.05 (3H, s), 2.21 (6H, s), 2.23 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3. 75 (2H, s), 3.85 (3H, s), 4.29 (2H, q, J = 7.1Hz), 6.96 (2H, d, J = 9.1 Hz), 7.02 (2H, s), 7.91 (2H, d, J = 9. 1Hz), 8.09(1H, br s), 9.58(1H , br s) . .05 (3H, s), 2.21 (6H, s), 2.23 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3.75 (2H, s), 3.85 (3H, s ), 4.29 (2H, q, J = 7.1Hz), 6.96 (2H, d, J = 9.1 Hz), 7.02 (2H, s), 7.91 (2H, d, J = 9.1 Hz), 8.09 (1H, br s), 9.58 (1H, br s).
MS m/z:581(M+H)+. MS m / z: 581 (M + H) +.
[0317] [参考例 31] [0317] [Reference Example 31]
(l)[2-(3, 4ージメチルフエ-ル)ー5—メチルー 2H—[1, 2, 3]トリァゾールー 4 ィル]メタノール (l) [2- (3,4-dimethylphenol) -5-methyl-2H— [1,2,3] triazole-4-yl] methanol
[0318] [化 89] [0318] [Chemical 89]
[0319] 参考例 21— (2)から (4)と同様にして、塩酸(3, 4 ジメチルフエ-ル)ヒドラジン (0 .392g)力も標題ィ匕合物 (0. 195g)を淡黄色固体として得た。 [0319] Reference Example 21—Similarly to (2) to (4), the strength of hydrochloric acid (3,4 dimethylphenol) hydrazine (0.392 g) was reduced to the title compound (0.195 g) as a pale yellow solid. Obtained.
'H-NMR (400MHz, CDCl) δ :2.29 (3Η, s), 2.33 (3Η, s), 2.42 (3H, s) 'H-NMR (400MHz, CDCl) δ: 2.29 (3Η, s), 2.33 (3Η, s), 2.42 (3H, s)
3 Three
, 4.80 (2H, s), 7.20(1H, d, J = 8. 1Hz), 7.68(1H, dd, J = 2.2, 8.1Hz) , 4.80 (2H, s), 7.20 (1H, d, J = 8.1 Hz), 7.68 (1H, dd, J = 2.2, 8.1 Hz)
, 7.77(1H, d, J = 2.2Hz). , 7.77 (1H, d, J = 2.2Hz).
MS m/z:218(M+H)+. MS m / z: 218 (M + H) + .
[0320] (2)4 ブロモメチル—2— (3, 4 ジメチルフエ-ル)— 5—メチル—2H— [1, 2, 3[0320] (2) 4 Bromomethyl-2- (3,4 dimethylphenol)-5-methyl-2H- [1, 2, 3
]トリアゾール ] Triazole
[0321] [化 90] [0321] [Chemical 90]
[0322] 参考例 15— (1)と同様にして、参考例 31— (1)で得たィ匕合物 (0.190g)力も標題
化合物(0. 177g)を無色固体として得た。 [0322] Reference Example 15—Similar to (1), Reference Example 31—Compound (0.190 g) force obtained in (1) The compound (0.177 g) was obtained as a colorless solid.
'H-NMR (400MHz, CDCl) δ :2.29 (3Η, s), 2.33 (3Η, s), 2.41 (3H, s) 'H-NMR (400MHz, CDCl) δ: 2.29 (3Η, s), 2.33 (3Η, s), 2.41 (3H, s)
3 Three
, 4.58 (2H, s), 7.19(1H, d, J = 8. 1Hz), 7.69(1H, dd, J = 2.2, 8.1Hz) , 4.58 (2H, s), 7.19 (1H, d, J = 8.1 Hz), 7.69 (1H, dd, J = 2.2, 8.1 Hz)
, 7.77(1H, d, J = 2.2Hz). , 7.77 (1H, d, J = 2.2Hz).
MS m/z:280(M+H)+. MS m / z: 280 (M + H) +.
[0323] [参考例 32] [0323] [Reference Example 32]
(1)3— [(4—フルオロフヱ-ル)ヒドラゾノ]—2— (ヒドロキシィミノ) N—フエ-ル一 ブチラミド (1) 3 — [(4-Fluorophenyl) hydrazono] —2— (Hydroxyimino) N-phenol butyramide
[0324] [化 91] [0324] [Chemical 91]
[0325] 参考例 21— (2)と同様にして、参考例 21— (1)で得たィ匕合物(0.958g)と塩酸 (p —フルオロフェ -ル)ヒドラジン (0.83 lg)力も標題ィ匕合物の粗生成物を得た。 [0325] In the same manner as in Reference Example 21- (2), the compound (0.958 g) obtained in Reference Example 21- (1) and hydrochloric acid (p-fluorophenyl) hydrazine (0.83 lg) force were also measured. A crude crude product was obtained.
[0326] (2)2—[4ー(2—メトキシェトキシ)フェ-ル]ー5—メチルー211—[1, 2, 3]トリァゾ 一ルー 4一力ルボン酸 [0326] (2) 2- [4- (2-Methoxyethoxy) phenol] -5-Methyl-211— [1, 2, 3] triazo
[0327] [化 92] [0327] [Chem 92]
参考例 21— (3)と同様にして、参考例 32— (1)で得たィ匕合物をメトキシエタノール (15ml)中で水酸ィ匕カリウム(2. Og)を加えて処理し、標題ィ匕合物の粗生成物を得た
[0329] (3)[2—[4ー(2—メトキシェトキシ)フェ-ル]ー5—メチルー211—[1, 2, 3]トリァゾ ール 4—ィル]メタノール Reference Example 21—In the same manner as (3), the compound obtained in Reference Example 32— (1) was treated with methoxyethanol (15 ml) by adding potassium hydroxide (2. Og), A crude product of the title compound was obtained. [0329] (3) [2- [4- (2-Methoxyethoxy) phenol] -5-methyl-211— [1, 2, 3] triazole 4-yl] methanol
[0330] [化 93] [0330] [Chemical 93]
[0331] 参考例 21— (4)と同様にして、参考例 32— (2)で得たィ匕合物力も標題ィ匕合物 (0. [0331] In the same manner as in Reference Example 21- (4), the compound strength obtained in Reference Example 32- (2) was also the same as that of the title compound (0.
928g)を褐色固体として得た。 928 g) was obtained as a brown solid.
'H-NMR (400MHz, CDCl) δ :2.41 (3Η, s), 3.47 (3Η, s), 3.77 (2H, t, 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 3.47 (3Η, s), 3.77 (2H, t,
3 Three
J=4.7Hz), 4.16 (2H, t, J=4.7Hz), 4.79 (2H, s), 7.00 (2H, d, J = 8.8 J = 4.7Hz), 4.16 (2H, t, J = 4.7Hz), 4.79 (2H, s), 7.00 (2H, d, J = 8.8
Hz), 7.88 (2H, d, J = 8.8Hz) . Hz), 7.88 (2H, d, J = 8.8Hz).
MS m/z:264(M+H)+. MS m / z: 264 (M + H) + .
[0332] (4) 4ーブロモメチルー 2— [4一(2—メトキシエトキシ)フエ-ル ]ー5—メチルー 2H [0332] (4) 4-Bromomethyl-2- [4 (2-methoxyethoxy) phenol] -5-Methyl-2H
[1, 2, 3]トリァゾール [1, 2, 3] triazole
[0333] [化 94] [0333] [Chemical 94]
[0334] 参考例 15— (1)と同様にして、参考例 32— (3)で得たィ匕合物 (0.924g)力も標題 化合物(0.558 g)を無色固体として得た。 Reference Example 15—In the same manner as in (1), the compound (0.924 g) force obtained in Reference Example 32- (3) also gave the title compound (0.558 g) as a colorless solid.
'H-NMR (400MHz, CDCl) δ :2.40 (3Η, s), 3.47 (3Η, s), 3.76— 3.79 'H-NMR (400MHz, CDCl) δ: 2.40 (3Η, s), 3.47 (3Η, s), 3.76— 3.79
3 Three
(2H, m), 4.15-4.17(2H, m), 4.57 (2H, s), 7.00 (2H, d, J = 9. 1Hz), 7.89 (2H, d, J = 9.1Hz) . (2H, m), 4.15-4.17 (2H, m), 4.57 (2H, s), 7.00 (2H, d, J = 9.1Hz), 7.89 (2H, d, J = 9.1Hz).
MS m/z:326(M+H)+. MS m / z: 326 (M + H) + .
[0335] [参考例 33] [0335] [Reference Example 33]
(1)4— (2 アジドエチル)—5—メチル—2 フエ-ル— 2H—[1, 2, 3]トリァゾー
ル (1) 4- (2 Azidoethyl) -5-Methyl-2 Phenol-2H— [1, 2, 3] Triazol Le
[0336] [化 95] [0336] [Chemical 95]
[0337] 2— (5—メチル 2—フエ-ルー 2H— [1, 2, 3]トリァゾールー 4—ィル)エタノー ル(1. 02g)をァセトニトリル(10ml)に溶解し、氷水冷却下にトリェチルァミン(1. 05 ml)と塩化メタンスルホ-ル (0. 47ml)を加えて室温で 2時間攪拌した。減圧下溶媒 を留去し、残渣を酢酸ェチルで抽出後、水で洗浄し、無水硫酸ナトリウムで乾燥した 。減圧下溶媒を留去して、油状の残渣を N, N ジメチルホルムアミド(6ml)に溶解 した。アジィ匕ナトリウム (0. 39g)を加えて、室温で 18時間攪拌した。反応液を氷水約 200mlに注ぎ、酢酸ェチルで抽出し、飽和重曹水で 2回、次いで飽和食塩水で 1回 洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去し、残渣をシリカゲルカラ ムクロマトグラフィー(5%酢酸ェチル—へキサン)にて精製し、標題化合物(0. 58g) を無色油状物として得た。 [0337] 2— (5-Methyl-2-phenol-2H— [1, 2, 3] triazol-4-yl) ethanol (1.02 g) was dissolved in acetonitrile (10 ml) and cooled with ice water to triethylamine. (1.05 ml) and methanesulfonyl chloride (0.47 ml) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the oily residue was dissolved in N, N dimethylformamide (6 ml). Azimuth sodium (0.39 g) was added and stirred at room temperature for 18 hours. The reaction mixture was poured into about 200 ml of ice water, extracted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, and then once with saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate-hexane) to obtain the title compound (0.58 g) as a colorless oil. .
'H-NMR (400MHz, CDC1 ) δ : 2. 36 (3Η, s) , 2. 96 (2Η, t, J = 7. 1Hz) , 3 'H-NMR (400MHz, CDC1) δ: 2.36 (3Η, s), 2.96 (2Η, t, J = 7.1 Hz), 3
3 Three
. 67 (2H, t, J = 7. 1Hz) , 7. 27— 7. 31 (1H, m) , 7. 41— 7. 46 (2H, m) , 7. 9 6- 7. 99 (2H, m) . 67 (2H, t, J = 7.1 Hz), 7. 27— 7. 31 (1H, m), 7. 41— 7. 46 (2H, m), 7. 9 6- 7. 99 (2H , m).
[0338] (2) [2— (5—メチル 2 フエ-ルー 2H— [1, 2, 3]トリァゾールー 4—ィル)ェチ ル]力ルバミン酸 tert ブチル エステル [0338] (2) [2— (5-Methyl-2-Ferrule 2H— [1, 2, 3] Triazol-4-yl) ethyl] strength rubamic acid tert butyl ester
[0339] [化 96] [0339] [Chemical 96]
[0340] 参考例 33— (1)で得たィ匕合物(0. 58g)を酢酸ェチル(15ml)に溶解し、 10%パ
ラジウム一炭素(0. 10g)とジ一 tert—ブチル ジカルボネート(0. 997g)を加え、水 素雰囲気下で 24時間攪拌した。 10%パラジウム—炭素をろ別し、酢酸ェチルで洗 浄した。ろ液と洗液を併せて減圧下溶媒を留去した。残渣をへキサンより結晶化して 、標題化合物(0. 6 lg)を無色固体として得た。 [0340] Reference Example 33— The compound (0.58 g) obtained in (1) was dissolved in ethyl acetate (15 ml), and 10% Radium monocarbon (0.10 g) and di-tert-butyl dicarbonate (0.999 g) were added, and the mixture was stirred under a hydrogen atmosphere for 24 hours. 10% palladium-carbon was filtered off and washed with ethyl acetate. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to give the title compound (0.6 lg) as a colorless solid.
'H-NMR (400MHz, CDC1 ) δ : 1. 44 (9Η, s) , 2. 34 (3Η, s) , 2. 87 (2H, t, 'H-NMR (400MHz, CDC1) δ: 1.44 (9Η, s), 2.34 (3Η, s), 2.87 (2H, t,
3 Three
J = 6. 4Hz) , 3. 50- 3. 54 (2H, m) , 4. 91 (1H, br) , 7. 27— 7. 30 (1H, m) , J = 6.4Hz), 3.50-3.54 (2H, m), 4.91 (1H, br), 7.27—7.30 (1H, m),
7. 42- 7. 46 (2H, m) , 7. 97 (2H, d, J = 7. 6Hz) 7. 42- 7. 46 (2H, m), 7. 97 (2H, d, J = 7.6 Hz)
[0341] (3) 2— [2, 6 ジメチルー 4— [ [2— (5—メチル—2 フエ-ルー 2H—[1, 2, 3]ト リアゾールー 4 ィル)ェチルァミノ]メチル]フエノキシ ] 2 メチルプロピオン酸 te rt—ブチル エステル [0341] (3) 2— [2, 6 Dimethyl 4-— [[2— (5-Methyl-2 Fe-Lu 2H— [1, 2, 3] Triazol-4-yl) ethylamino] methyl] phenoxy] 2 Methylpropionic acid te rt-butyl ester
[0342] [化 97] [0342] [Chemical 97]
[0343] 参考例 33— (2)で得た化合物(0. 60g)をジクロロメタン (2ml)に溶解し、 4規定塩 酸—ジォキサン溶液(10ml)を加えて、室温で 3日間攪拌した。減圧下溶媒を溜去し 、残渣に 0. 1規定水酸ィ匕ナトリウム水溶液(20ml)を加えて、ジクロロメタンで抽出し た。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、 2- (5—メチルー 2 フエ- ルー 2H— [1, 2, 3]トリァゾールー 4 ィル)ェチルァミン(0. 38g)を黄色油状物と して得た。このものをエタノール(10ml)に溶解し、参考例 16— (1)で得たィ匕合物(0 . 55g)を加えて 85°Cにて 2時間攪拌した。冷後、氷水冷却下に水素化ホウ素ナトリウ ム(0. 092g)をカ卩えて、室温で 1時間攪拌した。ジクロロメタンで希釈し、飽和重曹水 と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣 をシリカゲルカラムクロマトグラフィー (4%メタノール一ジクロロメタン)にて精製し、標 題化合物(0. 66g)を淡黄色油状物として得た。
Ή-NMR (400MHz, CDC1 ) δ :1.41 (6H, s), 1.51 (9H, s), 2.20 (6H, s) Reference Example 33— The compound (0.60 g) obtained in (2) was dissolved in dichloromethane (2 ml), 4N hydrochloric acid-dioxane solution (10 ml) was added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and 0.1N sodium hydroxide aqueous solution (20 ml) was added to the residue, followed by extraction with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 2- (5-methyl-2phenol-2H— [1, 2, 3] triazol-4-yl) ethylamine (0.38 g) was dissolved as a yellow oil. I got it. This was dissolved in ethanol (10 ml), the compound (0.55 g) obtained in Reference Example 16- (1) was added, and the mixture was stirred at 85 ° C. for 2 hours. After cooling, sodium borohydride (0.092 g) was collected under cooling with ice water and stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (4% methanol / dichloromethane) to obtain the title compound (0.66 g) as a pale yellow oil. NMR-NMR (400MHz, CDC1) δ: 1.41 (6H, s), 1.51 (9H, s), 2.20 (6H, s)
3 Three
, 2.32 (3H, s), 2.87-2.91 (2H, m), 2.97— 3.01 (2H, m), 3.72 (2H, s ), 6.91 (2H, s), 7.27-7.29(1H, m), 7.41-7.48 (2H, m), 7.95— 7.9 7(2H, m). , 2.32 (3H, s), 2.87-2.91 (2H, m), 2.97—3.01 (2H, m), 3.72 (2H, s), 6.91 (2H, s), 7.27-7.29 (1H, m), 7.41 -7.48 (2H, m), 7.95—7.9 7 (2H, m).
[0344] (4) 2— [4— [[カルボキシメチルー [2— (5—メチルー 2—フエ-ルー 2H—[1, 2, 3 ]トリァゾールー 4 ィル)—ェチル]ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2 メチルプロピオン酸 tert ブチル エステル [0344] (4) 2— [4— [[Carboxymethyl- [2— (5-Methyl-2-Ferrule 2H— [1, 2, 3] Triazol-4-yl) -ethyl] amino] methyl] — 2, 6-Dimethylphenoxy] —2 Methylpropionic acid tert butyl ester
[0345] [化 98] [0345] [Chemical 98]
[0346] 参考例 33—(3)で得たィ匕合物(0.66g)をテトラヒドロフラン(3ml)とメタノール(3m 1)の混合液に溶解し、ダリオキシル酸 (0.254g)とトリァセトキシ水素化ホウ素ナトリウ ム(0.585g)をカ卩えて、室温で 15時間攪拌した。ジクロロメタンで希釈し、飽和重曹 水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去 後、残渣をシリカゲルカラムクロマトグラフィー (メタノール:クロ口ホルム =3 :7)にて精 製し、標題ィ匕合物 (0.64g)を無色油状物として得た。 [0346] Reference Example 33—The compound (0.66 g) obtained in (3) was dissolved in a mixture of tetrahydrofuran (3 ml) and methanol (3 ml), and darioxylic acid (0.254 g) and triacetoxyborohydride. Sodium (0.585 g) was added and stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol: chloroform = 3: 7) to give the title compound (0.64 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.36 (6Η, s), 1.49 (9Η, s), 2.05 (6H, s) 'H-NMR (400MHz, CDC1) δ: 1.36 (6Η, s), 1.49 (9Η, s), 2.05 (6H, s)
3 Three
, 2.19 (3H, s), 2.86-2.91 (4H, m), 3.38 (2H, s), 3, 67 (2H, s), 6.71( 2H, s), 7.29(1H, d, J = 7.5Hz), 7.44 (2H, t, J = 7.8Hz), 7.98 (2H, d, J =8. 1Hz). , 2.19 (3H, s), 2.86-2.91 (4H, m), 3.38 (2H, s), 3, 67 (2H, s), 6.71 (2H, s), 7.29 (1H, d, J = 7.5Hz ), 7.44 (2H, t, J = 7.8Hz), 7.98 (2H, d, J = 8.1 Hz).
MS m/z:537(M+H)+. MS m / z: 537 (M + H) + .
[0347] [参考例 34] [0347] [Reference Example 34]
2-[4-[[[2-(Ν'ーァセチルヒドラジノ) 2—ォキソェチル] [2—(5 メチル — 2 フエ-ルー 2Η— [1, 2, 3]トリァゾールー 4—ィル)ェチル]ァミノ]メチル ]—2
, 6—ジメチルフエノキシ]—2—メチルプロピオン酸 tert—ブチル エステル 2- [4-[[[2- (Ν'-Acetylhydrazino) 2-oxoethyl] [2- (5 Methyl — 2 -Fu-Lu 2Η— [1, 2, 3] Triazol-4-yl) ethyl ] Amino] methyl] —2 , 6-Dimethylphenoxy] -2-methylpropionic acid tert-butyl ester
[0348] [化 99] [0348] [Chemical 99]
[0349] 参考例 18と同様にして、参考例 33— (4)で得たィ匕合物 (0.24g)から標題ィ匕合物 ( 0.29g)を無色油状物として得た。 In the same manner as in Reference Example 18, the title compound (0.29 g) was obtained as a colorless oil from the compound (0.24 g) obtained in Reference Example 33- (4).
'H-NMR (400MHz, CDC1) δ :1.39 (6Η, s), 1.51 (9Η, s), 1.91 (3H, s) 'H-NMR (400MHz, CDC1) δ: 1.39 (6Η, s), 1.51 (9Η, s), 1.91 (3H, s)
3 Three
, 2.14 (6H, s), 2.17(3H, s), 2.85 (4H, s), 3.31 (2H, s), 3.56 (2H, s), 6.82 (2H, s), 7.27-7.30(1H, m), 7.43 (2H, dd, J = 8.3, 7.5Hz), 7.9 6(2H, d, J = 7.5Hz), 8.04 (1H, br s), 9.60(1H, br) . , 2.14 (6H, s), 2.17 (3H, s), 2.85 (4H, s), 3.31 (2H, s), 3.56 (2H, s), 6.82 (2H, s), 7.27-7.30 (1H, m ), 7.43 (2H, dd, J = 8.3, 7.5Hz), 7.9 6 (2H, d, J = 7.5Hz), 8.04 (1H, br s), 9.60 (1H, br).
[0350] [参考例 35] [0350] [Reference Example 35]
2— [ 2 , 6 ジメチル 4— [ [ ( 3 メチル 1H ピラゾール 4 ィルメチル)ァミノ ]メチル]フエノキシ ]ー2—メチルプロピオン酸 tert ブチル エステル 2- [2,6dimethyl 4-[[((3-methyl 1H pyrazole 4-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid tert butyl ester
[0351] [化 100] [0351] [Chemical 100]
[0352] 参考例 9— (2)で得たィ匕合物(1.6g)をジクロロメタン(15ml)に溶解し、トリフルォ 口酢酸(3ml)を加えて、室温で一晩攪拌した。反応液を減圧下濃縮し、残渣に 1規 定水酸化ナトリウム水溶液を加え、酢酸ェチルで 3回抽出した。有機層を水、飽和食 塩水で順に洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣をェ
タノール(20ml)に溶解し、参考例 16— (1)で得たィ匕合物(1.63g)を加えて、 80°C で 6時間攪拌した。反応液を氷水で冷却し、水素化ホウ素ナトリウム (0.316g)をカロ えて、 4.5時間攪拌した。反応液に食塩水を加え、酢酸ヱチルで 3回抽出した。有機 層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシ リカゲルカラムクロマトグラフィー(クロ口ホルム:メタノール = 97: 3)で精製し、標題ィ匕 合物(2. 16g)を無色油状物として得た。 Reference Example 9— The compound (1.6 g) obtained in (2) was dissolved in dichloromethane (15 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Residue The compound (1.63 g) obtained in Reference Example 16- (1) was added to the residue dissolved in ethanol (20 ml), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was cooled with ice water, sodium borohydride (0.316 g) was added, and the mixture was stirred for 4.5 hours. Brine was added to the reaction solution, and the mixture was extracted 3 times with acetyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 97: 3) to give the title compound (2.16 g) as a colorless oil.
[0353] 'H-NMR (400MHz, CDC1 ) δ :1.42 (6Η, s), 1.52 (9Η, s), 2.22 (6H, s) [0353] 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.22 (6H, s)
3 Three
, 2.30 (3H, s), 3.68 (2H, s), 3.72 (2H, s), 6.93 (2H, s), 7.22(1H, t, J =8.3Hz), 7.41 (2H, t, J = 8.3Hz), 7.63 (2H, d, J = 8.3Hz), 7.81 (1H, s). , 2.30 (3H, s), 3.68 (2H, s), 3.72 (2H, s), 6.93 (2H, s), 7.22 (1H, t, J = 8.3Hz), 7.41 (2H, t, J = 8.3 Hz), 7.63 (2H, d, J = 8.3Hz), 7.81 (1H, s).
MS m/z:464(M+H)+. MS m / z: 464 (M + H) + .
[0354] [参考例 36] [0354] [Reference Example 36]
(1) 2— [4— [[tert—ブトキシカルボ-ルメチルー(3—メチルー 1—フエ-ルー 1H (1) 2— [4 — [[tert-Butoxycarboromethyl- (3-Methyl-1-Ferru 1H
—ピラゾール一 4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メ チルプロピオン酸 ェチル エステル —Pyrazol-4-ylmethyl) amino] methyl] —2, 6-dimethylphenoxy] —2-methylpropionic acid ethyl ester
[0355] [化 101] [0355] [Chemical 101]
参考例 17— (2)と同様にして、参考例 17— (1)で得たィ匕合物 (0.759g)と参考例 4で得た化合物(0.455g)力も標題ィ匕合物(0.770g)を無色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (9H, s), 1 In the same manner as in Reference Example 17- (2), the compound (0.759 g) obtained in Reference Example 17- (1) and the compound (0.455 g) obtained in Reference Example 4 were also treated with the title compound (0.770 g). g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (9H, s), 1
3 Three
.47 (9H, s), 2.19 (6H, s), 2.28 (3H, s), 3. 17(2H, s), 3.66 (2H, s), 3 .68 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 6.96 (2H, s), 7.20— 7.24 (1H, m ), 7.39-7.43 (2H, m), 7.61— 7.64 (2H, m), 7.79(1H, s) .
MS m/z : 550 (M+H)+. .47 (9H, s), 2.19 (6H, s), 2.28 (3H, s), 3.17 (2H, s), 3.66 (2H, s), 3.68 (2H, s), 4.28 (2H , q, J = 7.1Hz), 6.96 (2H, s), 7.20— 7.24 (1H, m), 7.39-7.43 (2H, m), 7.61— 7.64 (2H, m), 7.79 (1H, s). MS m / z: 550 (M + H) +.
[0357] (2) 2— [4 [ [カルボキシメチルー(3—メチルー 1 フエ-ルー 1H ピラゾールー[0357] (2) 2— [4 [[Carboxymethyl- (3-methyl-1-phenol 1H pyrazole-
4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピオン 酸 ェチノレ エステル 4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionate ethinole ester
[0358] [化 102] [0358] [Chemical 102]
[0359] 参考例 17— (3)と同様にして、参考例 36— (1)で得たィ匕合物 (0. 765g)力も標題 化合物(0. 690g)の粗生成物を得た。 Reference Example 17- In the same manner as in (3), the compound (0.765 g) force obtained in Reference Example 36- (1) also gave a crude product of the title compound (0.690 g).
[0360] [参考例 37] [0360] [Reference Example 37]
( 1 )イソキサゾール 5 カルボン酸 ( 3 -メチル 1 フエニル - 1H-ピラゾール 4—ィルメチル)アミド (1) Isoxazole 5 carboxylic acid (3-methyl 1-phenyl-1H-pyrazole 4-ylmethyl) amide
[0361] [化 103] [0361] [Chemical 103]
[0362] 参考例 9— (2)で得た化合物(0. 710g)をジクロロメタン(5ml)に溶解し、トリフル ォロ酢酸(2ml)を加えて、室温で 3時間攪拌した。反応液を減圧下濃縮し、残渣に 炭酸水素ナトリウム水溶液を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水 で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣を N, N—ジメ チルホルムアミド(10ml)に溶解し、イソキサゾール— 5—カルボン酸(0. 279g)、 1 —ェチルー 3— (3 ジメチルァミノプロピル)カルボジイミド塩酸塩(0. 568g)と 1ーヒ ドロキシベンゾトリアゾール水和物(0. 454g)をカ卩えて、室温でー晚攪拌した。反応
液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶液を加え、酢酸ェチルで 3回抽出 した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留 去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 3: 2)で 精製し、標題化合物 (0.573g)を無色固体として得た。 Reference Example 9— The compound (0.710 g) obtained in (2) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (10 ml), and isoxazole-5-carboxylic acid (0. 279 g), 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.568 g) and 1 -Hydroxybenzotriazole hydrate (0.454 g) was added and stirred at room temperature. reaction The solution was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (0.573 g) as a colorless solid.
[0363] 'H-NMR (400MHz, CDC1 ) δ :2.37(3Η, s), 4.54 (2Η, d, J = 5.6Hz), 6 [0363] 'H-NMR (400MHz, CDC1) δ: 2.37 (3Η, s), 4.54 (2Η, d, J = 5.6Hz), 6
3 Three
.78 (1H, br s), 6.95(1H, d, J=l.7Hz), 7.24— 7.28 (1H, m), 7.40— 7 .45 (2H, m), 7.61— 7.64 (2H, m), 7.89(1H, s), 8.34(1H, d, J=l.7H z). .78 (1H, br s), 6.95 (1H, d, J = l.7Hz), 7.24— 7.28 (1H, m), 7.40— 7.45 (2H, m), 7.61— 7.64 (2H, m) , 7.89 (1H, s), 8.34 (1H, d, J = l.7H z).
MS m/z:283(M+H)+. MS m / z: 283 (M + H) + .
[0364] (2)イソキサゾ一ルー 5—ィルメチルー(3—メチルー 1 フエ-ルー 1H ピラゾール[0364] (2) Isoxazo One-Lou 5-ylmethyl- (3-Methyl-1 Hueru 1H Pyrazole
—4—ィルメチル)ァミン —4—Ilmethyl) amine
[0365] [化 104] [0365] [Chemical 104]
[0366] 参考例 37— (1)で得たィ匕合物(0.276g)をテトラヒドロフラン(7ml)に溶解し、ボラ ン—ジメチルスルフイド錯体 (0.278ml)を加えて、 50°Cで 3時間攪拌した。反応液 に水を加え、 60°Cで 2時間攪拌後、反応液に炭酸水素ナトリウム水溶液を加え、酢 酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥 後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル: メタノール =99:1)で精製し、標題化合物(0.068g)を無色油状物として得た。 'H-NMR (400MHz, CDC1) δ :2.33 (3Η, s), 3.73 (2Η, s), 4.00 (2H, s) [0366] Reference Example 37— The compound (0.276 g) obtained in (1) was dissolved in tetrahydrofuran (7 ml), and borane-dimethylsulfide complex (0.278 ml) was added thereto at 50 ° C. Stir for 3 hours. Water was added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 99: 1) to give the title compound (0.068 g) as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 2.33 (3Η, s), 3.73 (2Η, s), 4.00 (2H, s)
3 Three
, 6.19(1H, d, J=l.7Hz), 7.24 (1H, d, J = 7.6Hz), 7.42 (2H, t, J = 7.6 Hz), 7.63 (2H, d, J = 7.6Hz), 7.81 (1H, s), 8.21 (1H, d, J=l.7Hz) . MS m/z:269(M+H)+. , 6.19 (1H, d, J = l.7Hz), 7.24 (1H, d, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.63 (2H, d, J = 7.6Hz), 7.81 (1H, s), 8.21 (1H, d, J = l.7Hz) .MS m / z: 269 (M + H) +.
[0367] [参考例 38] [0367] [Reference Example 38]
2— [2, 6 ジメチルー 4 [ (メチルカルバモイルメチルァミノ)メチル]フエノキシ]
2—メチルプロピオン酸 ェチル エステル 2— [2, 6 Dimethyl-4 [(Methylcarbamoylmethylamino) methyl] phenoxy] 2-Methylpropionic acid ethyl ester
[0368] [化 105] [0368] [Chemical 105]
[0369] 参考例 16— (2)と同様にして、 2 ァミノ— N—メチルァセタミド塩酸塩(1.12g)、 トリェチルァミン(1.5ml)と参考例 11— (1)で得たィ匕合物(2.38g)から標題ィ匕合物 (1.89g)を無色油状物として得た。 Reference Example 16—In the same manner as (2), 2-amino-N-methylacetamide hydrochloride (1.12 g) and triethylamine (1.5 ml) were combined with the compound (2.38) obtained in Reference Example 11- (1). The title compound (1.89 g) was obtained as a colorless oil from g).
MS m/z:337(M+H)+. MS m / z: 337 (M + H) + .
[0370] [参考例 39] [0370] [Reference Example 39]
(1) 2— [4 [[tert ブトキシカルボ-ルメチルー [2— (3, 4 ジメチルフエ-ル) 5—メチル 2H— [1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジ メチルフエノキシ ] 2—メチルプロピオン酸 ェチル エステル (1) 2— [4 [[tert Butoxycarboromethyl] [2— (3, 4 Dimethylphenol) 5—Methyl 2H— [1, 2, 3] Triazol 4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0371] [化 106] [0371] [Chem 106]
[0372] 参考例 17— (2)と同様にして、参考例 31— (2)で得たィ匕合物 (0.207g)と参考例 17— (1)で得たィ匕合物(0.280g)から標題ィ匕合物(0.359g)を無色油状物として 得た。 [0372] In the same manner as Reference Example 17- (2), the compound (0.207 g) obtained in Reference Example 31- (2) and the compound obtained in Reference Example 17- (1) (0.280 g) The title compound (0.359 g) was obtained as a colorless oil from g).
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.47 (9H, s), 2.18 (6H, s), 2.28 (3H, s), 2.30 (3H, s), 2.32 (3H, s), 3. 23 (2H, s), 3.68 (2H, s), 3.86 (2H, s), 4.28 (2H, q, J = 7. 1Hz), 6.98 (
2H, s), 7. 18(1H, d, J = 8.3Hz), 7.69(1H, dd, J = 2.2, 8.3Hz), 7.77 (.47 (9H, s), 2.18 (6H, s), 2.28 (3H, s), 2.30 (3H, s), 2.32 (3H, s), 3. 23 (2H, s), 3.68 (2H, s ), 3.86 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.98 ( 2H, s), 7.18 (1H, d, J = 8.3Hz), 7.69 (1H, dd, J = 2.2, 8.3Hz), 7.77 (
1H, d, J = 2.2Hz). (1H, d, J = 2.2Hz).
MS m/z:579(M+H)+. MS m / z: 579 (M + H) + .
[0373] (2) 2— [4 [[カルボキシメチルー [2— (3, 4ージメチルフエ-ル)ー5—メチルー 2[0373] (2) 2— [4 [[Carboxymethyl- [2— (3,4-dimethylphenol) -5-Methyl-2
H— [1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジメチルフエノキ シ ] 2—メチルプロピオン酸 ェチル エステル H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0374] [化 107] [0374] [Chemical 107]
[0375] 参考例 17— (3)と同様にして、参考例 39— (1)で得たィ匕合物 (0.352g)力も標題 化合物(0.359g)を無色固体として得た。 Reference Example 17 In the same manner as in (3), the compound (0.352 g) force obtained in Reference Example 39- (1) was also used to give the title compound (0.359 g) as a colorless solid.
[0376] (3) 2— [4— [[[2—(N,ーァセチルヒドラジノ) 2—ォキソェチル] [2— (3, 4 ジメチルフエ-ル)ー5—メチルー 2H—[1, 2, 3]トリァゾールー 4 ィルメチル]アミ ノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピオン酸 ェチル エステル [0376] (3) 2— [4— [[[2— (N, -Acetylhydrazino) 2-oxoethyl] [2— (3,4 Dimethylphenol) -5-methyl-2H— [1, 2 , 3] Triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] —2-methylpropionic acid ethyl ester
[0377] [化 108] [0377] [Chemical 108]
[0378] 参考例 18と同様にして、参考例 39— (2)で得たィ匕合物(0.318g)とァセトヒドラジ ド (0.054g)力も標題ィ匕合物(0.262g)を無色油状物として得た。 [0378] In the same manner as in Reference Example 18, the compound (0.318 g) obtained in Reference Example 39- (2) and acetohydrazide (0.054 g) were also mixed with the title compound (0.262 g) as a colorless oil. Got as.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
.05 (6H, s), 2.21 (3H, s), 2.23 (3H, s), 2.29 (3H, s), 2.33 (3H, s), 3.
38 (2H, s), 3.63 (2H, s), 3.76 (2H, s), 4.29 (2H, q, J = 7. 1Hz), 7.02 ( 2H, s), 7. 19 (1H, d, J = 8.3Hz), 7.69 (1H, dd, J = 2.2, 8.3Hz), 7.78 ( 1H, d, J = 2.2Hz), 8.13(1H, br s), 9.57(1H, br s) . .05 (6H, s), 2.21 (3H, s), 2.23 (3H, s), 2.29 (3H, s), 2.33 (3H, s), 3. 38 (2H, s), 3.63 (2H, s), 3.76 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 7.02 (2H, s), 7.19 (1H, d, J = 8.3Hz), 7.69 (1H, dd, J = 2.2, 8.3Hz), 7.78 (1H, d, J = 2.2Hz), 8.13 (1H, br s), 9.57 (1H, br s).
MS m/z:579(M+H)+. MS m / z: 579 (M + H) + .
[0379] [参考例 40] [0379] [Reference Example 40]
2- [4— [(2—メトキシェチルァミノ)メチル ]—2, 6 ジメチルフエノキシ ] 2—メチ ルプロピオン酸 ェチル エステル 2- [4 -— [(2-Methoxyethylamino) methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0380] [化 109] [0380] [Chem 109]
[0381] 参考例 20と同様にして、参考例 11— (1)で得たィ匕合物(2. Og)と 2—メトキシェチ ルァミン (0.568g)力も標題ィ匕合物(2.53g)を無色油状物として得た。 [0381] In the same manner as in Reference Example 20, the compound (2. Og) obtained in Reference Example 11- (1) (2-Og) and 2-methoxyethylamine (0.568 g) also had the same force as the title compound (2.53 g). Obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 18 (6H, s), 2.81 (2H, t, J=4.9Hz), 3.35 (3H, s), 3.52 (2H, t, J=4.9 18 (6H, s), 2.81 (2H, t, J = 4.9Hz), 3.35 (3H, s), 3.52 (2H, t, J = 4.9
Hz), 3.69 (2H, s), 4.28 (2H, q, J = 7. 1Hz) , 6.93 (2H, s) . Hz), 3.69 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.93 (2H, s).
MS m/z:324(M+H)+. MS m / z: 324 (M + H) + .
[0382] [参考例 41] [0382] [Reference Example 41]
2- [4— [(2 ヒドロキシェチルァミノ)メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 tert ブチル エステル 2- [4 — [(2 Hydroxyethylamino) methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid tert butyl ester
[0383] [化 110] [0383] [Chem 110]
[0384] 参考例 20と同様にして、参考例 16— (1)で得たィ匕合物(1.02g)とエタノールアミ ン (0.230ml)力 標題ィ匕合物(1.08g)を黄色油状物として得た。 [0384] In the same manner as in Reference Example 20, the compound (1.02 g) obtained in Reference Example 16- (1) and ethanolamine (0.230 ml) were mixed with the title compound (1.08 g) as a yellow oil. Obtained as a thing.
'H-NMR (400MHz, CDC1) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s) 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)
3 Three
, 2.82 (2H, t, J = 5.1Hz), 3.69 (2H, t, J = 5.1Hz), 3.73 (2H, s), 6.95( 2H, s) . , 2.82 (2H, t, J = 5.1Hz), 3.69 (2H, t, J = 5.1Hz), 3.73 (2H, s), 6.95 (2H, s).
MS m/z:338(M+H)+. MS m / z: 338 (M + H) +.
[0385] [参考例 42] [0385] [Reference Example 42]
(1) (1— p—トリル— 1H— [1, 2, 3]トリァゾールー 4—ィル)メタノール (1) (1— p-Tolyl— 1H— [1, 2, 3] triazol-4-yl) methanol
[0386] [化 111] [0386] [Chem 111]
[0387] 1— p—トリル— 1H— [1, 2, 3]トリァゾールー 4—カルボン酸 ェチル エステル(0 .575g)をテトラヒドロフラン(7ml)に溶解し、氷水冷却下に水素化リチウムアルミ-ゥ ム(0.094g)を加えて、 1.5時間攪拌した。反応液に水を加えて、セライトを用いて ろ過した。ろ液を酢酸ェチルで 3回抽出し、飽和食塩水で洗浄した。無水硫酸ナトリ ゥムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで 精製 (酢酸ェチル:へキサン =1:4〜酢酸ェチル)し、標題化合物(0.404g)を淡黄 色固体として得た。 [0387] 1—p-Tolyl— 1H— [1, 2, 3] triazole-4-carboxylic acid ethyl ester (0.575 g) was dissolved in tetrahydrofuran (7 ml), and lithium aluminum hydride was cooled with ice water. (0.094 g) was added and stirred for 1.5 hours. Water was added to the reaction solution and filtered using Celite. The filtrate was extracted 3 times with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to ethyl acetate) to give the title compound (0.404 g) as a pale yellow solid.
[0388] 'H-NMR (400MHz, CDC1 ) δ :2.43 (3Η, s), 4.89 (2Η, s), 7.32 (2H, d [0388] 'H-NMR (400MHz, CDC1) δ: 2.43 (3Η, s), 4.89 (2Η, s), 7.32 (2H, d
3 Three
, J = 8.6Hz), 7.60 (2H, d, J = 8.6Hz), 7.94(1H, s) . , J = 8.6Hz), 7.60 (2H, d, J = 8.6Hz), 7.94 (1H, s).
MS m/z:190(M+H)+. MS m / z: 190 (M + H) +.
[0389] (2)4—ブロモメチル— 1— p—トリル— 1H— [1, 2, 3]トリァゾール [0389] (2) 4-Bromomethyl- 1- p-tolyl- 1H- [1, 2, 3] triazole
[0390] [化 112]
[0390] [Chem 112]
[0391] 参考例 15— (1)と同様にして、参考例 42— (1)で得たィ匕合物 (0.400g)力も標題 化合物 (0.205g)を淡黄色固体として得た。 Reference Example 15—In the same manner as in (1), the compound (0.400 g) force obtained in Reference Example 42— (1) was also used to obtain the title compound (0.205 g) as a pale yellow solid.
'H-NMR (400MHz, CDCl) δ :2.43 (3Η, s), 4.65 (2Η, s), 7.32 (2H, d 'H-NMR (400MHz, CDCl) δ: 2.43 (3Η, s), 4.65 (2Η, s), 7.32 (2H, d
3 Three
, J = 8.6Hz), 7.60 (2H, d, J = 8.6Hz), 7.98(1H, s) . , J = 8.6Hz), 7.60 (2H, d, J = 8.6Hz), 7.98 (1H, s).
[0392] [参考例 43] [0392] [Reference Example 43]
(1)2— [4— [[tert—ブトキシカルボ-ルメチル—(1— p—トリル— 1H— [1, 2, 3]ト リアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチル プロピオン酸 ェチノレ エステノレ (1) 2- [4 -— [[tert-Butoxycarboromethyl- (1-p-tolyl-1H- [1,2,3] triazole-4-ylmethyl) amino] methyl] -2,6-dimethyl Phenoxy] —2-methyl propionate ethenore estenore
[0393] [化 113] [0393] [Chem 113]
[0394] 参考例 17— (2)と同様にして、参考例 42— (2)で得た化合物 (0. lOOg)と参考例 17— (1)で得たィ匕合物(0.166g)力も標題ィ匕合物(0.240g)を無色油状物として 得た。 Reference Example 17—In the same manner as (2), Reference Example 42—Compound (0. lOOg) obtained in (2) and Reference Example 17—Compound obtained in (1) (0.166 g) The title compound (0.240 g) was also obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1
3 Three
.47 (9H, s), 2.19 (6H, s), 2.42 (3H, s), 3.26 (2H, s), 3.72 (2H, s), 4. 00 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 7.00 (2H, s) , 7.31 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.6Hz), 7.89 (1H, br s) . .47 (9H, s), 2.19 (6H, s), 2.42 (3H, s), 3.26 (2H, s), 3.72 (2H, s), 4.00 (2H, s), 4.28 (2H, q , J = 7.1Hz), 7.00 (2H, s), 7.31 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.6Hz), 7.89 (1H, br s).
MS m/z:551(M+H)+. MS m / z: 551 (M + H) +.
[0395] (2)2— [4— [[カルボキシメチル—(1— p—トリル— 1H— [1, 2, 3]トリァゾールー 4
—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチルプロピオン酸 ェチノレ エステル [0395] (2) 2— [4— [[Carboxymethyl— (1— p-tolyl— 1H— [1, 2, 3] triazole 4 —Ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethynole ester
[0396] [化 114] [0396] [Chemical 114]
[0397] 参考例 17— (3)と同様にして、参考例 43— (1)で得たィ匕合物 (0.218g)から不純 を含む標題ィ匕合物(0.240g)を無色油状物として得た。 [0397] In the same manner as Reference Example 17- (3), the title compound (0.240g) containing impurities was removed from the compound (0.218g) obtained in Reference Example 43- (1) as a colorless oil. Got as.
[0398] (3)2-[4-[[[2-(Ν'—ァセチルヒドラジノ)—2—ォキソェチル]― (1— ρ トリル — 1H— [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフ エノキシ ] 2—メチルプロピオン酸 ェチル エステル [0398] (3) 2- [4-[[[2- (Ν'—Acetylhydrazino) —2-Oxoethyl] — (1— ρ Tolyl — 1H— [1, 2, 3] triazol-4-ylmethyl ) Amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0399] [化 115] [0399] [Chemical 115]
[0400] 参考例 18と同様にして、参考例 43— (2)で得たィ匕合物(0.196g)とァセトヒドラジ ド (0.059g)力も標題ィ匕合物(0.202g)を無色油状物として得た。 [0400] In the same manner as in Reference Example 18, the compound (0.196 g) obtained in Reference Example 43- (2) and acetohydrazide (0.059 g) were also mixed with the title compound (0.202 g) as a colorless oil. Got as.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
.06 (3H, s), 2.19 (6H, s), 2.42 (3H, s), 3.31 (2H, s), 3.69 (2H, s), 3. 94 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 6.97 (2H, s), 7.32 (2H, d, J = 8.3 Hz), 7.65 (2H, d, J = 8.3Hz), 8.14(1H, s), 8.26 (1H, br s), 9.60(1H , br s) . .06 (3H, s), 2.19 (6H, s), 2.42 (3H, s), 3.31 (2H, s), 3.69 (2H, s), 3.94 (2H, s), 4.28 (2H, q , J = 7.1Hz), 6.97 (2H, s), 7.32 (2H, d, J = 8.3 Hz), 7.65 (2H, d, J = 8.3Hz), 8.14 (1H, s), 8.26 (1H, br s), 9.60 (1H, br s).
MS m/z:551(M+H)+.
[0401] [参考例 44] MS m / z: 551 (M + H) +. [0401] [Reference Example 44]
(1)2, 2 ジフルォロ— N— (5—メチル 2 フエ-ル— 2H— [1, 2, 3]トリァゾー ルー 4—ィルメチル)ァセタミド (1) 2, 2 Difluoro-N— (5-Methyl 2 phenol— 2H— [1, 2, 3] triazol 4-ylmethyl) acetamide
[0402] [化 116] [0402] [Chem 116]
[0403] 参考例 15— (3)で得たィ匕合物(0.250g)をジクロロメタン (4ml)に溶解し、 4規定 塩酸—ジォキサン溶液(2ml)を加えて、室温で 15時間攪拌した。減圧下濃縮し、残 渣を N, N ジメチルホルムアミド(6ml)に溶解し、ジフルォロ酢酸(0.083ml)、 1 ェチルー 3—(3 ジメチルァミノプロピル)カルボジイミド塩酸塩(0.199g)、 1ーヒド ロキシベンゾトリアゾール水和物(0. 159g)と N—メチルモルホリン(0.286ml)をカロ えて、室温で 22時間攪拌した。減圧下溶媒を留去し、残渣に炭酸水素ナトリウム水を カロえて、酢酸ェチルで 3回抽出した。飽和食塩水で洗浄後、無水硫酸ナトリウムで乾 燥し、減圧下に溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチ ル:へキサン=1:4〜4:1)で精製し、標題化合物(0.128g)を無色固体として得た Reference Example 15— The compound (0.250 g) obtained in (3) was dissolved in dichloromethane (4 ml), 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was stirred at room temperature for 15 hours. Concentrate under reduced pressure, dissolve the residue in N, N dimethylformamide (6 ml), difluoroacetic acid (0.083 ml), 1 ethyl 3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.199 g), 1-hydroxybenzo Triazole hydrate (0.159 g) and N-methylmorpholine (0.286 ml) were added and stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, and the residue was charged with aqueous sodium hydrogen carbonate and extracted three times with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4-4: 1) to give the title compound (0.128 g) as a colorless solid.
[0404] 'H-NMR (400MHz, CDC1 ) δ :2.39 (3Η, s), 4.64 (2Η, d, J = 5.4Hz), 5 [0404] 'H-NMR (400MHz, CDC1) δ: 2.39 (3Η, s), 4.64 (2Η, d, J = 5.4Hz), 5
3 Three
.96(1H, t, J = 54.2Hz), 6.82(1H, br s), 7.33(1H, t, J=7.8Hz), 7.4 .96 (1H, t, J = 54.2Hz), 6.82 (1H, br s), 7.33 (1H, t, J = 7.8Hz), 7.4
7(2H, t, J = 7.8Hz), 7.98 (2H, d, J = 7.8Hz) . 7 (2H, t, J = 7.8Hz), 7.98 (2H, d, J = 7.8Hz).
MS m/z:267(M+H)+. MS m / z: 267 (M + H) + .
[0405] (2) (2, 2 ジフルォロェチル)一(5—メチルー 2 フエ-ルー 2H—[1, 2, 3]トリア ゾール 4 ィルメチル)ァミン [0405] (2) (2, 2 Difluoroethyl) mono (5-methyl-2 ferrue 2H— [1, 2, 3] triazole 4-ylmethyl) amine
[0406] [化 117]
[0406] [Chemical 117]
[0407] 参考例 44— (1)で得た化合物(0. 124g)をテトラヒドロフラン (4ml)に溶解し、ボラ ン—ジメチルスルフイド錯体 (0. 133ml)を加えて、 50°Cにて 23時間攪拌した。反応 液に水をカ卩えて 60°Cにて 1時間攪拌後、飽和食塩水を加えて、酢酸ェチルで 3回抽 出した。更に、参考例 44— (1)で得たィ匕合物(0. 066g)を上記と同様に反応および 処理して、酢酸ェチルにて抽出した。得られた二つの有機層を併せて、飽和食塩水 で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣をシリカゲル カラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 9〜1: 1)で精製し、標題化合物 (0. 113g)を茶色固体として得た。 [0407] Reference Example 44— The compound (0.124 g) obtained in (1) was dissolved in tetrahydrofuran (4 ml), and borane-dimethylsulfide complex (0.133 ml) was added thereto at 50 ° C. Stir for 23 hours. Water was added to the reaction mixture, and the mixture was stirred at 60 ° C for 1 hour, saturated brine was added, and the mixture was extracted 3 times with ethyl acetate. Further, the compound (0.066 g) obtained in Reference Example 44- (1) was reacted and treated in the same manner as above and extracted with ethyl acetate. The obtained two organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 1) to obtain the title compound (0.113 g) as a brown solid.
[0408] 'H-NMR (400MHz, CDC1 ) δ : 2. 39 (3Η, s) , 3. 06 (2Η, dt, J=4. 2, 15. [0408] 'H-NMR (400MHz, CDC1) δ: 2.39 (3Η, s), 3.06 (2Η, dt, J = 4, 2, 15.
3 Three
OHz) , 3. 98 (2H, s) , 5. 90 (1H, tt, J=4. 2, 56. 4Hz) , 7. 30 (1H, t, J = 7. 6Hz) , 7. 45 (2H, t, J = 7. 6Hz) , 7. 98— 8. 00 (2H, m) . OHz), 3.98 (2H, s), 5.90 (1H, tt, J = 4, 2, 56.4Hz), 7.30 (1H, t, J = 7.6Hz), 7.45 ( 2H, t, J = 7.6Hz), 7.98—8.00 (2H, m).
MS m/z : 253 (M+H)+. MS m / z: 253 (M + H) + .
[0409] [実施例 1] [0409] [Example 1]
(1) 2— [4— [ [ [1— (4 クロ口フエ-ル)一 3—メチル 1H ピラゾール一 4—ィル メチル]フラン一 2—ィルメチルァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 ェチノレ エステル (1) 2— [4— [[[1— (4 Black Mole) 1-Methyl 1H Pyrazole 1-yl Methyl] furan 2-ylmethylamino] Methyl] phenoxy] —2-Methylpropionic acid Echinore Esther
[0410] [化 118] [0410] [Chemical 118]
[0411] 参考例 1で得た化合物(362mg)と参考例 2— (2)で得た化合物(317mg)を N, N —ジメチルホルムアミド(8ml)に溶解し、炭酸セシウム (489mg)、ヨウ化カリウム (触 媒量)を加えて 80°Cで 15時間攪拌した。反応液を室温まで冷却し、溶媒を減圧留去
した後、炭酸水素ナトリウム水溶液を加えて、酢酸ェチルで 3回抽出した。有機層を 飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲ ルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 6)で精製し、標題化合物(39 7mg)を無色油状物として得た。 [0411] The compound (362 mg) obtained in Reference Example 1 and the compound (317 mg) obtained in Reference Example 2- (2) were dissolved in N, N-dimethylformamide (8 ml), and cesium carbonate (489 mg) was added. Potassium (catalyst amount) was added, and the mixture was stirred at 80 ° C for 15 hours. Cool the reaction solution to room temperature and evaporate the solvent After adding an aqueous sodium hydrogen carbonate solution, the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to give the title compound (39 7 mg) as a colorless oil.
iH—NMR (400MHz, CDC1 ) δ :1. 24 (3Η, t, J = 7. 3Hz), 1. 58 (6H, s), 2 iH—NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.3Hz), 1.58 (6H, s), 2
3 Three
. 26 (3H, s), 3.46 (2H, s), 3. 54 (2H, s), 3.61 (2H, s), 4. 22 (2H, q, J = 7. 3Hz), 6. 16(1H, d, J = 2. 9Hz), 6. 34(1H, dd, J = 2.0, 2. 9Hz), 6.80 (2H, d, J = 8. 3Hz), 7. 22 (2H, d, J = 8. 3Hz), 7. 37 (2H, d, J=8.8Hz), 7 .40(1H, d, J = 2.0Hz), 7. 57 (2H, d, J = 8.8Hz), 7. 77(1H, s) . 26 (3H, s), 3.46 (2H, s), 3.54 (2H, s), 3.61 (2H, s), 4.22 (2H, q, J = 7.3 Hz), 6.16 ( 1H, d, J = 2.9Hz), 6.34 (1H, dd, J = 2.0, 2.9Hz), 6.80 (2H, d, J = 8.3Hz), 7.22 (2H, d, J = 8. 3Hz), 7.37 (2H, d, J = 8.8Hz), 7.40 (1H, d, J = 2.0Hz), 7.57 (2H, d, J = 8.8Hz), 7. 77 (1H, s).
MS m/z:522(M+H)+. MS m / z: 522 (M + H) + .
[0412] ( 2) 2— [4 [ [ [ 1一(4 クロ口フエ-ル) 3 メチル 1H ピラゾール 4ーィル メチル]フラン一 2—ィルメチルァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 [0412] (2) 2— [4 [[[1- (4-Chromium-Fuel) 3 Methyl 1H Pyrazole 4-yl Methyl] furan 2-ylmethylamino] methyl] phenoxy] —2-Methylpropionic acid
[0413] [化 119] [0413] [Chemical 119]
[0414] 実施例 1— (1)で得た化合物(394mg)をテトラヒドロフラン (4ml)、エタノール (4ml )の混合溶媒に溶解し、 5規定水酸化ナトリウム水溶液 (453 μ 1)を加えて室温で 20 時間攪拌した。反応液に濃塩酸 (0. 3ml)を加えて中和し、減圧濃縮した。残渣をシ リカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール = 95: 5)で精製した後、さ らに分取用薄相クロマトグラフィー(20x20xlmm、ジクロロメタン:メタノール =96 :4 で展開)で再度精製し、標題化合物 (269mg)を無色固体として得た。 [0414] Example 1— The compound (394 mg) obtained in (1) was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and ethanol (4 ml), and 5N aqueous sodium hydroxide solution (453 μ 1) was added at room temperature. Stir for 20 hours. The reaction mixture was neutralized with concentrated hydrochloric acid (0.3 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 95: 5) and then purified again by preparative thin phase chromatography (20x20xlmm, developed in dichloromethane: methanol = 96: 4). Compound (269 mg) was obtained as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.46 (6Η, s), 2. 13 (3Η, s), 3.40(2 'H-NMR (400MHz, DMSO-d) δ: 1.46 (6Η, s), 2.13 (3Η, s), 3.40 (2
6 6
H, s), 3.47 (2H, s), 3. 55 (2H, s), 6. 34(1H, d, J = 2. 9Hz), 6.42(1H, d d, J=l. 7, 2. 9Hz), 6. 79 (2H, d, J = 8.6Hz), 7. 21 (2H, d, J = 8.6Hz), 7 .49 (2H, d, J = 9. 1Hz), 7. 62(1H, d, J=l. 7Hz), 7. 81 (2H, d, J = 9. 1Hz ), 8. 34(1H, s).
MS m/z:494(M+H)+. H, s), 3.47 (2H, s), 3.55 (2H, s), 6.34 (1H, d, J = 2.9Hz), 6.42 (1H, dd, J = l. 7, 2. 9Hz), 6.79 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz), 7.49 (2H, d, J = 9.1Hz), 7.62 ( 1H, d, J = l. 7Hz), 7. 81 (2H, d, J = 9.1Hz), 8. 34 (1H, s). MS m / z: 494 (M + H) + .
元素分析値 C H C1N O · 1/2H Oとして Elemental analysis value C H C1N O · 1 / 2H O
27 28 3 4 2 27 28 3 4 2
計算値: C, 64.47;H, 5.81;C1, 7.05;N, 8.35. Calculated values: C, 64.47; H, 5.81; C1, 7.05; N, 8.35.
測定値:。, 64.46;H, 5.62; CI, 7.43;N, 8.28. measured value:. 64.46; H, 5.62; CI, 7.43; N, 8.28.
[0415] [実施例 2] [0415] [Example 2]
(1) 2— [4 [[フラン一 2—ィルメチルァミノ一 [3—メチル 1— (4 トリフルォロメチ ルフエ-ル)一 1H ピラゾールー 4 ィルメチル]ァミノ]メチル]フエノキシ ]— 2 メ チルプロピオン酸 ェチル エステル (1) 2— [4 [[Furan-2-ylmethylamino] [3-Methyl 1- (4 Trifluoromethyl)-1H Pyrazole-4-ylmethyl] amino] methyl] phenoxy] — 2 Methylpropionic acid ethyl ester
[0416] [化 120] [0416] [Chemical 120]
[0417] 実施例 1— (1)と同様にして、参考例 3— (2)で得たィ匕合物(275 mg)と参考例 2 [0417] Example 1— In the same manner as (1), Reference Example 3—The compound obtained in (2) (275 mg) and Reference Example 2
- (2)で得た化合物(317mg)力も標題ィ匕合物(503mg)を無色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2 -The compound (317 mg) obtained in (2) also gave the title compound (503 mg) as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2
3 Three
.27 (3H, s), 3.47 (2H, s), 3.55 (2H, s), 3.62 (2H, s), 4.23 (2H, q, J = 7. 1Hz), 6.17(1H, d, J = 3.2Hz), 6.34(1H, dd, J =1.7, 3.2Hz), 6.8 1(2H, d, J = 8.8Hz), 7.22 (2H, d, J = 8.8Hz), 7.40 (1H, d, J=l.7Hz), 7.67 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz), 7.85(1H, s) . .27 (3H, s), 3.47 (2H, s), 3.55 (2H, s), 3.62 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 6.17 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = 1.7, 3.2Hz), 6.8 1 (2H, d, J = 8.8Hz), 7.22 (2H, d, J = 8.8Hz), 7.40 (1H, d, J = l.7Hz), 7.67 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz), 7.85 (1H, s).
MS m/z:556(M+H)+. MS m / z: 556 (M + H) +.
[0418] (2) 2— [4— [[フラン一 2—ィルメチルァミノ一 [3—メチル 1— (4 トリフルォロメチ ルフエ-ル)一 1H ピラゾールー 4 ィルメチル]ァミノ]メチル]フエノキシ ]— 2 メ チルプロピオン酸 [0418] (2) 2— [4 — [[Furan-2-ylmethylamino] [3-Methyl 1- (4 trifluoromethyl)-1H pyrazole-4-ylmethyl] amino] methyl] phenoxy] — 2 methylpropionic acid
[0419] [化 121] [0419] [Chemical 121]
[0420] 実施例 2— (1)で得た化合物(500mg)をテトラヒドロフラン (4ml)、メタノール (4ml )の混合溶媒に溶解し、 5規定水酸化ナトリウム水溶液 (360 μ 1)を加えて室温で 14 時間攪拌した。反応液に濃塩酸 (0. 15ml)を加えて中和し、減圧濃縮した。残渣を シリカゲルカラムクロマトグラフィー (塩化メチレン:メタノール = 94: 6)で精製した後、 水一エタノール力も結晶化し、標題ィ匕合物(158mg)を無色固体として得た。 [0420] Example 2— The compound obtained in (1) (500 mg) was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and methanol (4 ml), and 5N aqueous sodium hydroxide solution (360 μ1) was added at room temperature. Stir for 14 hours. The reaction mixture was neutralized with concentrated hydrochloric acid (0.15 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 94: 6), and then the aqueous ethanol was crystallized to obtain the title compound (158 mg) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.48 (6Η, s), 2. 15 (3Η, s), 3.42(2 'H-NMR (400MHz, DMSO-d) δ: 1.48 (6Η, s), 2.15 (3Η, s), 3.42 (2
6 6
H, s), 3.48 (2H, s), 3.56 (2H, s), 6.35 (1H, d, J = 3.2Hz), 6.43 (1H, d d, J = 2.0, 3.2Hz), 6.79 (2H, d, J = 8.6Hz), 7.23 (2H, d, J = 8.6Hz), 7 H, s), 3.48 (2H, s), 3.56 (2H, s), 6.35 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz), 6.79 (2H, d , J = 8.6Hz), 7.23 (2H, d, J = 8.6Hz), 7
.63 (1H, d, J = 2.0Hz), 7.81 (2H, d, J = 8.6Hz), 8.01 (2H, d, J = 8.6Hz.63 (1H, d, J = 2.0Hz), 7.81 (2H, d, J = 8.6Hz), 8.01 (2H, d, J = 8.6Hz)
), 8.47(1H, s). ), 8.47 (1H, s).
MS m/z:528(M+H)+. MS m / z: 528 (M + H) + .
元素分析値 C H FNO · 1/4H Oとして Elemental analysis value C H FNO 1 / 4H O
27 28 3 3 4 2 27 28 3 3 4 2
計算値: C, 63.21;H, 5.40 ;F, 10.71;N, 7.90. Calculated values: C, 63.21; H, 5.40; F, 10.71; N, 7.90.
測定値:。, 63.21;H, 5.50;F, 10.42;N, 7.93. measured value:. 63.21; H, 5.50; F, 10.42; N, 7.93.
[0421] [実施例 3] [0421] [Example 3]
(1)2— [4— [[フラン一 2—ィルメチル一( 3 メチル 1 フエ-ル 1 H ピラゾー ルー 4—ィルメチル)ァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 ェチル ェ ステル (1) 2- [4 -— [[Furan-2-ylmethyl-((3-methyl-l-phenyl) 1 H-pyrazole-l-ylmethyl) amino] methyl] phenoxy] —2-methylpropionate
[0422] [化 122] [0422] [Chemical 122]
実施例 1— (1)と同様にして、参考例 4で得たィ匕合物(207mg)と参考例 2— (2)で 得た化合物(317mg)力も標題ィ匕合物 (424mg)を無色油状物として得た。 In the same manner as in Example 1- (1), the compound (207 mg) obtained in Reference Example 4 and the compound (317 mg) obtained in Reference Example 2- (2) were also mixed with the title compound (424 mg). Obtained as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2
3 Three
.27 (3H, s), 3.47 (2H, s), 3.54 (2H, s), 3.61 (2H, s), 4.22 (2H, q, J = 7. 1Hz), 6.16(1H, d, J = 3.2Hz), 6.34(1H, dd, J=l.7, 3.2Hz), 6.81
(2H, d, J = 8.3Hz), 7.20— 7.26 (3H, m), 7.39— 7.43 (3H, m), 7.63(2.27 (3H, s), 3.47 (2H, s), 3.54 (2H, s), 3.61 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.16 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = l.7, 3.2Hz), 6.81 (2H, d, J = 8.3Hz), 7.20— 7.26 (3H, m), 7.39— 7.43 (3H, m), 7.63 (2
H, d, J=7.6Hz), 7.81 (IH, s) . H, d, J = 7.6Hz), 7.81 (IH, s).
MS m/z:488(M+H)+. MS m / z: 488 (M + H) +.
[0424] (2)2— [4— [[フラン一 2—ィルメチル一( 3 メチル 1 フエ-ル 1 H ピラゾー ルー 4 ィルメチル)ァミノ]メチル]フエノキシ] 2—メチルプロピオン酸 [0424] (2) 2— [4— [[Furan-2-ylmethyl- (3 methyl 1-phenol 1 H-pyrazol 4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid
[0425] [化 123] [0425] [Chemical 123]
[0426] 実施例 2— (2)と同様にして、実施例 3— (1)で得たィ匕合物 (420mg)から標題ィ匕 合物(335mg)を無色固体として得た。 In the same manner as in Example 2- (2), the title compound (335 mg) was obtained as a colorless solid from the compound (420 mg) obtained in Example 3- (1).
'H-NMR (400MHz, DMSO-d) δ :1.48 (6Η, s), 2. 14 (3Η, s), 3.41(2 'H-NMR (400MHz, DMSO-d) δ: 1.48 (6Η, s), 2.14 (3Η, s), 3.41 (2
6 6
H, s), 3.47 (2H, s), 3.55 (2H, s), 6.34(1H, d, J = 3.2Hz), 6.43(1H, d d, J = 2.0, 3.2Hz), 6.79 (2H, d, J = 8.6Hz), 7.23 (IH, s), 7.23 (2H, d H, s), 3.47 (2H, s), 3.55 (2H, s), 6.34 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz), 6.79 (2H, d , J = 8.6Hz), 7.23 (IH, s), 7.23 (2H, d
, J = 8.6Hz), 7.42-7.46 (2H, m), 7.63(1H, d, J=2.0Hz), 7.76— 7.7, J = 8.6Hz), 7.42-7.46 (2H, m), 7.63 (1H, d, J = 2.0Hz), 7.76—7.7
9(2H, m), 8.31 (IH, s) . 9 (2H, m), 8.31 (IH, s).
MS m/z:458(M— H)+. MS m / z: 458 (M-H) +.
元素分析値 C H NO '1Z4HOとして Elemental analysis value as C H NO '1Z4HO
27 29 3 4 2 27 29 3 4 2
計算値: C, 69.88;H, 6.41;N, 9.06. Calculated value: C, 69.88; H, 6.41; N, 9.06.
測定値:。, 70.13;H, 6.38;N, 9.04. measured value:. 70.13; H, 6.38; N, 9.04.
[0427] [実施例 4] [0427] [Example 4]
(1)2— [4— [[フラン一 2—ィルメチル一( 3 メチル 1 フエ-ル 1 H ピラゾー ルー 4—ィルメチル)ァミノ]メチル ]—2—メトキシフエノキシ]—2—メチルプロピオン 酸 ェチノレ エステル (1) 2- [4-[[Furan-2-ylmethyl-((3-methyl-1-phenol) 1 H-pyrazole-l-ylmethyl) amino] methyl] -2-methoxyphenoxy] -2-methylpropionate Ester
[0428] [化 124]
[0428] [Chemical 124]
[0429] 実施例 1— (1)と同様にして、参考例 4で得たィ匕合物(207mg)と参考例 5— (2)で 得た化合物(347mg)力も標題ィ匕合物(182mg)を無色油状物として得た。 In the same manner as in Example 1- (1), the compound (207 mg) obtained in Reference Example 4 and the compound (347 mg) obtained in Reference Example 5- (2) were also treated with the title compound (347 mg). 182 mg) was obtained as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2
3 Three
.28 (3H, s), 3.49 (2H, s), 3.55 (2H, s), 3.63 (2H, s), 3.81 (3H, s), 4. 24 (2H, q, J = 7.1Hz) , 6.17(1H, d, J = 3.2Hz), 6.34(1H, dd, J = 2.0, 3 .2Hz), 6.79(1H, ABq, J = 8.3Hz) , 6.82(1H, ABq, J = 8.3Hz) , 6.95(1 H, s), 7.24 (1H, t, J = 7.4Hz), 7.39— 7.43 (3H, m), 7.63 (2H, d, J = 8 .3Hz), 7.81 (1H, s). .28 (3H, s), 3.49 (2H, s), 3.55 (2H, s), 3.63 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = 2.0, 3.2Hz), 6.79 (1H, ABq, J = 8.3Hz), 6.82 (1H, ABq, J = 8.3Hz) , 6.95 (1 H, s), 7.24 (1H, t, J = 7.4Hz), 7.39—7.43 (3H, m), 7.63 (2H, d, J = 8.3Hz), 7.81 (1H, s).
MS m/z:518(M+H)+. MS m / z: 518 (M + H) +.
[0430] (2)2— [4— [[フラン一 2—ィルメチル一(3—メチル 1—フエ-ル一 1H ピラゾー ルー 4—ィルメチル)ァミノ]メチル ]—2—メトキシフエノキシ]—2—メチルプロピオン 酸 [0430] (2) 2— [4— [[Furan-2-ylmethyl-1- (3-methyl-1-phenol-1H 1-pyrazolu 4-ylmethyl) amino] methyl] -2-methoxyphenoxy] -2 —Methylpropionic acid
[0431] [化 125] [0431] [Chemical 125]
[0432] 実施例 2— (2)と同様にして、実施例 4— (1)で得たィ匕合物(178mg)から標題ィ匕 合物(125mg)を無色固体として得た。 Example 2- In the same manner as in (2), the title compound (125 mg) was obtained as a colorless solid from the compound (178 mg) obtained in Example 4- (1).
'H-NMR (400MHz, DMSO-d) δ :1.41 (6Η, s), 2. 15 (3Η, s), 3.43(2 'H-NMR (400MHz, DMSO-d) δ: 1.41 (6Η, s), 2.15 (3Η, s), 3.43 (2
6 6
H, s), 3.49 (2H, s), 3.58 (2H, s), 3.73 (3H, s), 6.35 (1H, d, J = 2.9Hz ), 6.43(1H, dd, J=l.7, 2.9Hz), 6.79 (2H, s), 6.95(1H, s), 7.44 (1H , t, J = 8.6Hz), 7.63(1H, d, J=l.7Hz), 7.77 (2H, d, J = 8.8Hz), 8.31(
1H, s). H, s), 3.49 (2H, s), 3.58 (2H, s), 3.73 (3H, s), 6.35 (1H, d, J = 2.9Hz), 6.43 (1H, dd, J = l.7, 2.9Hz), 6.79 (2H, s), 6.95 (1H, s), 7.44 (1H, t, J = 8.6Hz), 7.63 (1H, d, J = l.7Hz), 7.77 (2H, d, J = 8.8Hz), 8.31 ( 1H, s).
MS m/z:488(M— H)+. MS m / z: 488 (M-H) +.
元素分析値 C H NO '1Z4HOとして Elemental analysis value as C H NO '1Z4HO
28 31 3 5 2 28 31 3 5 2
計算値: C, 68.07;H, 6.43;N, 8.50. Calculated values: C, 68.07; H, 6.43; N, 8.50.
測定値:。, 67.90;H, 6.44 ;N, 8.33. measured value:. 67.90; H, 6.44; N, 8.33.
[0433] [実施例 5] [0433] [Example 5]
(1) 2— [4— [[[1— (4 クロ口フエ-ル)一 3—メチル 1H ピラゾール一 4—ィル メチル]フラン一 2—ィルメチルァミノ]メチル ]—2—メトキシフエノキシ]—2—メチルプ ロピオン酸 ェチノレ エステノレ (1) 2— [4— [[[1— (4 Phylogen) 1-Methyl 1H Pyrazole 1-yl Methyl] Furan 2-ylmethylamino] Methyl] -2-Methoxyphenoxy] —2—Methylpropionate Ethenole Estenore
[0434] [化 126] [0434] [Chemical 126]
[0435] 実施例 1— (1)と同様にして、参考例 1で得たィ匕合物(241mg)と参考例 5— (2)で 得た化合物(347mg)力も標題ィ匕合物(255mg)を無色油状物として得た。 In the same manner as in Example 1- (1), the compound (241 mg) obtained in Reference Example 1 and the compound (347 mg) obtained in Reference Example 5- (2) were also used in the title compound ( 255 mg) was obtained as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2
3 Three
.27 (3H, s), 3.48 (2H, s), 3.54 (2H, s), 3.62 (2H, s), 3.90 (3H, s), 4. .27 (3H, s), 3.48 (2H, s), 3.54 (2H, s), 3.62 (2H, s), 3.90 (3H, s), 4.
25 (2H, q, J = 7.1Hz) , 6.17(1H, d, J = 2.9Hz), 6.34(1H, dd, J=l.7, 225 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 2.9Hz), 6.34 (1H, dd, J = l.7, 2
.9Hz), 6.79(1H, ABq, J = 8.6Hz) , 6.82(1H, ABq, J = 8.6Hz) , 6.94(1.9Hz), 6.79 (1H, ABq, J = 8.6Hz), 6.82 (1H, ABq, J = 8.6Hz), 6.94 (1
H, s), 7.37 (2H, d, J = 8.8Hz), 7.41 (1H, d, J=l.7Hz), 7.57 (2H, d, JH, s), 7.37 (2H, d, J = 8.8Hz), 7.41 (1H, d, J = l.7Hz), 7.57 (2H, d, J
=8.8Hz), 7.76 (1H, s) . = 8.8Hz), 7.76 (1H, s).
MS m/z:551(M+H)+. MS m / z: 551 (M + H) +.
[0436] ( 2) 2— [4— [ [ [ 1— (4—クロ口フエ-ル) 3 メチル 1H ピラゾール 4—ィル メチル]フラン一 2—ィルメチルァミノ]メチル ]—2—メトキシフエノキシ]—2—メチルプ ロピオン酸 [0436] (2) 2— [4— [[[1- (4-Cylphlophthal) 3 methyl 1H pyrazole 4-yl methyl] furan 2-ylmethylamino] methyl] —2-methoxyphenoxy ] —2-Methylpropionic acid
[0437] [化 127]
[0437] [Chemical 127]
[0438] 実施例 2— (2)と同様にして、実施例 5— (1)で得たィ匕合物(250mg)から標題ィ匕 合物(151mg)を無色固体として得た。 In the same manner as in Example 2- (2), the title compound (151 mg) was obtained as a colorless solid from the compound (250 mg) obtained in Example 5- (1).
'H-NMR (400MHz, DMSO-d) δ :1.41 (6Η, s), 2. 14 (3Η, s), 3.42(2 'H-NMR (400MHz, DMSO-d) δ: 1.41 (6Η, s), 2.14 (3Η, s), 3.42 (2
6 6
H, s), 3.49 (2H, s), 3.58 (2H, s), 3.72 (3H, s), 6.35(1H, d, J = 3.2Hz ), 6.43(1H, dd, J = 2.0, 3.2Hz), 6.79 (2H, s), 6.95(1H, s), 7.50 (2H , d, J = 9.1Hz), 7.63(1H, d, J=2.0Hz), 7.80 (2H, d, J = 9.1Hz), 8.35 (1H, s). H, s), 3.49 (2H, s), 3.58 (2H, s), 3.72 (3H, s), 6.35 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz ), 6.79 (2H, s), 6.95 (1H, s), 7.50 (2H, d, J = 9.1Hz), 7.63 (1H, d, J = 2.0Hz), 7.80 (2H, d, J = 9.1Hz) ), 8.35 (1H, s).
MS m/z:522(M-H)+. MS m / z: 522 (MH) + .
元素分析値 C H C1N O · 1/4H Oとして Elemental analysis value C H C1N O · 1 / 4H O
28 30 3 5 2 28 30 3 5 2
計算値: C, 63.63;H, 5.82; CI, 6.71;N, 7.95. Calculated values: C, 63.63; H, 5.82; CI, 6.71; N, 7.95.
測定値:。, 63.53;H, 5.90; CI, 6.53;N, 7.70. measured value:. 63.53; H, 5.90; CI, 6.53; N, 7.70.
[0439] [実施例 6] [0439] [Example 6]
(1)2— [4— [[(3, 5 ジメチル 1 フエ-ル -1H-ピラゾール 4 ィルメチル) フラン— 2—ィルメチルァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 ェチル エステル (1) 2- [4 -— [[(3,5 Dimethyl 1-phenol-1H-pyrazole 4-methyl) furan-2-ylmethylamino] methyl] phenoxy] -2-methylpropionic acid ethyl ester
[0440] [化 128] [0440] [Chemical 128]
3, 5 ジメチル 1 フエ-ル -1H-ピラゾール 4 カルバルデヒド( 173mg) と参考例 2— (2)で得たィ匕合物(250mg)をジクロロメタン(5ml)に溶解し、トリァセト キシ水素化ホウ素ナトリウム(334mg)を加えて室温で 15時間攪拌した。反応液に飽
和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで 3回抽出した。有機層を飽和食 塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラム クロマトグラフィー(酢酸ェチル:へキサン = 3: 7)で精製し、標題化合物(323mg)を 無色油状物として得た。 3, 5 Dimethyl 1-phenol -1H-pyrazole 4 Carbaldehyde (173 mg) and Reference Example 2-—Compound obtained in (2) (250 mg) was dissolved in dichloromethane (5 ml) and triacetoxyborohydride Sodium (334 mg) was added and stirred at room temperature for 15 hours. Saturated with reaction solution An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3 : 7) to give the title compound (323 mg) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2
3 Three
.23 (3H, s), 3.26 (3H, s), 3.42 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 4. .23 (3H, s), 3.26 (3H, s), 3.42 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 4.
23 (2H, q, J = 7.1Hz) , 6.15 (1H, d, J = 3.2Hz), 6.32(1H, dd, J = 2.0, 323 (2H, q, J = 7.1Hz), 6.15 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = 2.0, 3
.2Hz), 6.79 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz), 7.30— 7.34 (.2Hz), 6.79 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz), 7.30—7.34 (
1H, m), 7.38-7.45 (5H, m) . 1H, m), 7.38-7.45 (5H, m).
MS m/z:502(M+H)+. MS m / z: 502 (M + H) + .
[0442] (2)2-[4-[[(3, 5—ジメチルー 1—フエ-ルー 1H—ピラゾールー 4—ィルメチル) フラン一 2—ィルメチルァミノ]メチル]フエノキシ]— 2—メチルプロピオン酸 [0442] (2) 2- [4-[[(3,5-Dimethyl-1-phenol- 1H-pyrazole-4-ylmethyl) furan 2-ylmethylamino] methyl] phenoxy] —2-methylpropionic acid
[0443] [化 129] [0443] [Chemical 129]
[0444] 実施例 2— (2)と同様にして、実施例 6— (1)で得たィ匕合物(320mg)から標題ィ匕 合物(206mg)を無色固体として得た。 Example 2- In the same manner as (2), the title compound (206 mg) was obtained as a colorless solid from the compound (320 mg) obtained in Example 6- (1).
'H-NMR (400MHz, DMSO-d) δ :1.45 (6Η, s), 2. 11 (3Η, s), 2.20(3 'H-NMR (400MHz, DMSO-d) δ: 1.45 (6Η, s), 2. 11 (3Η, s), 2.20 (3
6 6
H, s), 3.35 (2H, s), 3.42 (2H, s), 3.51 (2H, s), 6.28 (1H, d, J = 2.9Hz ), 6.40(1H, dd, J=l.7, 2.9Hz), 6.77 (2H, d, J = 8.6Hz), 7.18 (2H, d , J = 8.6Hz), 7.32-7.36(1H, m), 7.43— 7.48 (4H, m), 7.60(1H, s) . MS m/z:472(M-H)+. H, s), 3.35 (2H, s), 3.42 (2H, s), 3.51 (2H, s), 6.28 (1H, d, J = 2.9Hz), 6.40 (1H, dd, J = l.7, 2.9Hz), 6.77 (2H, d, J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz), 7.32-7.36 (1H, m), 7.43— 7.48 (4H, m), 7.60 (1H, s) .MS m / z: 472 (MH) + .
元素分析値 C H NO '1Z4HOとして Elemental analysis value as C H NO '1Z4HO
28 31 3 4 2 28 31 3 4 2
計算値: C, 70.35;H, 6.64 ;N, 8.79. Calculated values: C, 70.35; H, 6.64; N, 8.79.
測定値:。, 70.13;H, 6.69;N, 8.51. measured value:. , 70.13; H, 6.69; N, 8.51.
[0445] [実施例 7]
(1)2— [4— [[(3, 5 ジメチル 1 フエ-ル -1H-ピラゾール 4 ィルメチル) フラン一 2—ィルメチルァミノ]メチル ]—2—メトキシフエノキシ]—2—メチルプロピオ ン酸 ェチノレ エステノレ [0445] [Example 7] (1) 2- [4 -— [[(3,5 Dimethyl 1-phenol-1H-pyrazole 4-methyl) furan-2-ylmethylamino] methyl] -2-methoxyphenoxy] -2-methylpropionate Ethenole Estenole
[0446] [化 130] [0446] [Chemical 130]
[0447] 実施例 6—(1)と同様にして、 3, 5 ジメチルー 1 フエ-ルー 1H ピラゾールー 4—カルバルデヒド(252mg)と参考例 5 - (2)で得た化合物 (437mg)から標題化合 物(304mg)を無色油状物として得た。 [0447] In the same manner as in Example 6- (1), the title compound was prepared from 3,5 dimethyl-1 ferlue 1H pyrazole-4-carbaldehyde (252 mg) and the compound obtained in Reference Example 5-(2) (437 mg). (304 mg) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2
3 Three
.24 (3H, s), 2.27 (3H, s), 3.44 (2H, s), 3.50 (2H, s), 3.58 (2H, s), 3. 80 (3H, s), 4.24 (2H, q, J = 7.1Hz) , 6. 15(1H, d, J = 2.9Hz), 6.33(1H , dd, J = 2.0, 2.9Hz), 6.76— 6.82 (2H, m), 6.95 (1H, s), 7.30— 7.34 ( 1H, m), 7.38-7.45 (5H, m) . .24 (3H, s), 2.27 (3H, s), 3.44 (2H, s), 3.50 (2H, s), 3.58 (2H, s), 3.80 (3H, s), 4.24 (2H, q , J = 7.1Hz), 6. 15 (1H, d, J = 2.9Hz), 6.33 (1H, dd, J = 2.0, 2.9Hz), 6.76— 6.82 (2H, m), 6.95 (1H, s) , 7.30- 7.34 (1H, m), 7.38-7.45 (5H, m).
MS m/z:532(M+H)+. MS m / z: 532 (M + H) +.
[0448] ( 2) 2— [4— [ [ ( 3 , 5 ジメチル 1 フエ-ル 1H ピラゾール 4 ィルメチル) フラン一 2—ィルメチルァミノ]メチル ]—2—メトキシフエノキシ]—2—メチルプロピオ ン酸 [0448] (2) 2— [4— [[(3, 5 Dimethyl 1-Fell 1H Pyrazole 4-Yrmethyl) Furan-2-ylmethylamino] Methyl] -2-Methoxyphenoxy] -2-Methylpropionic acid
[0449] [化 131] [0449] [Chemical 131]
[0450] 実施例 2— (2)と同様にして、実施例 7— (1)で得たィ匕合物(300mg)から、標題ィ匕 合物(238mg)を無色固体として得た。 Example 2- In the same manner as (2), the title compound (238 mg) was obtained as a colorless solid from the compound (300 mg) obtained in Example 7- (1).
'H-NMR (400MHz, DMSO-d) δ :1.40 (6Η, s), 2. 12(3Η, s), 2.20(3
H, s), 3.37 (2H, s), 3.44 (2H, s), 3.54 (2H, s), 3.71 (3H, s), 6.29 (1H , d, J = 3.2Hz), 6.41 (1H, dd, J = 2.0, 3.2Hz), 6.76 (2H, s), 6.93 (2H , s), 7.32-7.36(1H, m), 7.42— 7.48 (4H, m), 7.61(1H, d, J = 2. OHz ). 'H-NMR (400MHz, DMSO-d) δ: 1.40 (6Η, s), 2.12 (3Η, s), 2.20 (3 H, s), 3.37 (2H, s), 3.44 (2H, s), 3.54 (2H, s), 3.71 (3H, s), 6.29 (1H, d, J = 3.2Hz), 6.41 (1H, dd , J = 2.0, 3.2Hz), 6.76 (2H, s), 6.93 (2H, s), 7.32-7.36 (1H, m), 7.42— 7.48 (4H, m), 7.61 (1H, d, J = 2 OHz).
MS m/z:502(M-H)+. MS m / z: 502 (MH) + .
元素分析値 C H NO '1Z4HOとして Elemental analysis value as C H NO '1Z4HO
29 33 3 4 2 29 33 3 4 2
計算値: C, 68.55;H, 6.65;N, 8.27. Calculated values: C, 68.55; H, 6.65; N, 8.27.
測定値:。, 68.35;H, 6.74 ;N, 7.93. measured value:. 68.35; H, 6.74; N, 7.93.
[0451] [実施例 8] [0451] [Example 8]
(1) 2— [4— [[[1— (4 クロ口フエ-ル)一 3—メチル 1H ピラゾール一 4—ィル メチル]チアゾールー 2—ィルメチルァミノ]メチル]フエノキシ ]ー2—メチルプロピオン 酸 tert ブチル エステル (1) 2— [4 — [[[1— (4 Black Mole) 1-Methyl 1H Pyrazole 1-yl Methyl] thiazole-2-ylmethylamino] methyl] phenoxy] -2-Methylpropionic acid tert Butyl ester
[0452] [化 132] [0452] [Chemical 132]
[0453] 参考例 6 - (4)で得た化合物(420mg)をジクロロメタン (8ml)に溶解し、 2 -ホルミ ルチアゾール(93 1)、トリァセトキシ水素化ホウ素ナトリウム(379mg)をカ卩えて、室 温で 1.5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメ タンで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、 減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 2)で精製し、標題化合物(363mg)を無色油状物として得た。 [0453] Reference Example 6-The compound (420 mg) obtained in (4) was dissolved in dichloromethane (8 ml), and 2-formylthiazole (931) and sodium triacetoxyborohydride (379 mg) were added to the room temperature. And stirred for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (363 mg) as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.45 (9Η, s), 1.56 (6Η, s), 2.27 (3H, s) 'H-NMR (400MHz, CDCl) δ: 1.45 (9Η, s), 1.56 (6Η, s), 2.27 (3H, s)
3 Three
, 3.53 (2H, s), 3.62 (2H, s), 3.92 (2H, s), 6.86 (2H, d, J = 8.8Hz), 7. 24 (2H, d, J = 8.8Hz), 7.27(1H, d, J = 3.4Hz), 7.37 (2H, d, J = 9.1Hz) , 7.56 (2H, d, J = 9.1Hz), 7.68(1H, d, J = 3.4Hz), 7.80(1H, s) . , 3.53 (2H, s), 3.62 (2H, s), 3.92 (2H, s), 6.86 (2H, d, J = 8.8Hz), 7. 24 (2H, d, J = 8.8Hz), 7.27 ( 1H, d, J = 3.4Hz), 7.37 (2H, d, J = 9.1Hz), 7.56 (2H, d, J = 9.1Hz), 7.68 (1H, d, J = 3.4Hz), 7.80 (1H, s).
MS m/z:567(M+H)+.
( 2) 2— [4— [ [ [ 1— (4 クロ口フエ-ル) 3 メチル 1H ピラゾール 4 ィル メチル]チアゾールー 2—ィルメチルァミノ]メチル]フエノキシ ]ー2—メチルプロピオン MS m / z: 567 (M + H) + . (2) 2— [4— [[[1- (4 Chlorophthalate) 3 Methyl 1H Pyrazole 4 Yil Methyl] thiazole-2-yl Methylamino] Methyl] phenoxy] -2-Methylpropion
[0456] 実施例 8— (1)で得たィ匕合物(360mg)をジクロロメタン(5ml)に溶解し、トリフルォ 口酢酸(lml)を加えて室温で 4時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲ ルカラムクロマトグラフィー(ジクロロメタン:メタノール = 95: 5)で精製した後、エタノー ル—エーテルカゝら結晶化させ、標題化合物のトリフルォロ酢酸塩( 15 lmg)を無色固 体として得た。 Example 8— The compound (360 mg) obtained in (1) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (lml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 95: 5) and crystallized from ethanol-ether carbonate to give the title compound trifluoroacetate (15 lmg) as colorless. Obtained as a solid.
'H-NMR (400MHz, DMSO-d ) δ : 1. 50 (6Η, s) , 2. 14 (3Η, s) , 6. 83 (2 'H-NMR (400MHz, DMSO-d) δ: 1.50 (6Η, s), 2.14 (3Η, s), 6.83 (2
6 6
H, d, J=8. 8Hz) , 7. 36 (2H, d, J = 8. 3Hz) , 7. 53 (2H, d, J = 8. 8Hz) , 7. 7 8- 7. 81 (4H, m) , 8. 45 (1H, br s) . H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.3 Hz), 7. 53 (2H, d, J = 8.8 Hz), 7. 7 8- 7. 81 ( 4H, m), 8.45 (1H, br s).
MS m/z : 511 (M+H)+. MS m / z: 511 (M + H) +.
[0457] [実施例 9] [Example 9]
(1) 2— [4 [ [フラン 2—ィルメチルー [4ーメチルー 1一(4 トリフルォロメチルフ ェ-ル)— 1H ピロール— 3—ィルメチル]ァミノ]メチル]フエノキシ ]—2—メチルプ ロピオン酸 ェチノレ エステノレ (1) 2— [4 [[Furan 2-ylmethyl- [4-methyl-11] (1 trifluoromethyl-3-aminomethyl] amino] methyl] phenoxy] -2-methylpropionic acid ethynole Estenore
[0458] [化 134] [0458] [Chemical 134]
参考例 7— (4)で得たィ匕合物をジクロロメタン (8ml)に溶解し、参考例 2— (1)で得 た化合物(250mg)とトリァセトキシ水素化ホウ素ナトリウム (449mg)を加え、室温で
19時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで 3 回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃 縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 19〜1 : 6)で精製し、標題化合物 (494mg)を黄色油状物として得た。 Reference Example 7— Dissolve the compound obtained in (4) in dichloromethane (8 ml), add the compound (250 mg) obtained in Reference Example 2- (1) and sodium triacetoxyborohydride (449 mg), and add room temperature. so Stir for 19 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19-1: 6) to give the title compound (494 mg) as a yellow oil.
'H-NMR (400MHz, CDC1) δ :1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2
3 Three
.06 (3H, s), 3.46 (2H, s), 3.55 (2H, s), 3.62 (2H, s), 4.23 (2H, q, J = 7. 1Hz), 6.17(1H, d, J = 3.2Hz), 6.33(1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6Hz), 6.87(1H, s), 7.04 (1H, d, J = 2.0Hz), 7.24 (2H, d , J = 8.6Hz), 7.40 (2H, d, J = 8.6Hz), 7.40(1H, s), 7.63 (2H, d, J = 8. 6Hz). .06 (3H, s), 3.46 (2H, s), 3.55 (2H, s), 3.62 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 6.17 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6Hz), 6.87 (1H, s), 7.04 (1H, d, J = 2.0Hz), 7.24 (2H, d, J = 8.6Hz), 7.40 (2H, d, J = 8.6Hz), 7.40 (1H, s), 7.63 (2H, d, J = 8.6Hz).
MS m/z:554(M+H)+. MS m / z: 554 (M + H) + .
[0460] (2) 2— [4 [[フラン 2—ィルメチルー [4ーメチルー 1一(4 トリフルォロメチルフ ェ-ル)— 1H ピロール— 3—ィルメチル]ァミノ]メチル]フエノキシ ]—2—メチルプ ロピオン酸 [0460] (2) 2— [4 [[Furan 2-ylmethyl- [4-methyl-11] (1 trifluoromethyl-3-ylmethyl] amino] methyl] phenoxy] —2-methylpropyl Lopionic acid
[0461] [化 135] [0461] [Chemical 135]
[0462] 実施例 2— (2)と同様にして、実施例 9— (1)で得たィ匕合物 (490mg)から標題ィ匕 合物(362mg)を黄色固体として得た。 Example 2- In the same manner as (2), the title compound (362 mg) was obtained as a yellow solid from the compound (490 mg) obtained in Example 9- (1).
'H-NMR (400MHz, DMSO-d) δ :1.45 (6Η, s), 1.97 (3Η, s), 3.37(2 'H-NMR (400MHz, DMSO-d) δ: 1.45 (6Η, s), 1.97 (3Η, s), 3.37 (2
6 6
H, s), 3.46 (2H, s), 3.55 (2H, s), 6.32(1H, d, J = 3.2Hz), 6.42(1H, d d, J = 2.0, 3.2Hz), 6.78 (2H, d, J = 8.6Hz), 7.20 (2H, d, J = 8.6Hz), 7 .25(1H, s), 7.38(1H, d, J = 2.5Hz), 7.62(1H, d, J = 2.0Hz), 7.74(4 H, s). H, s), 3.46 (2H, s), 3.55 (2H, s), 6.32 (1H, d, J = 3.2Hz), 6.42 (1H, dd, J = 2.0, 3.2Hz), 6.78 (2H, d , J = 8.6Hz), 7.20 (2H, d, J = 8.6Hz), 7.25 (1H, s), 7.38 (1H, d, J = 2.5Hz), 7.62 (1H, d, J = 2.0Hz ), 7.74 (4 H, s).
MS m/z:525(M-H)+. MS m / z: 525 (MH) + .
元素分析値 C H FNO · 1/4H Oとして
計算値: C, 65. 59;H, 5. 60;N, 5. 28. Elemental analysis value CH FNO · 1 / 4H O Calculated values: C, 65. 59; H, 5. 60; N, 5. 28.
測定値:。, 65.44 ;H, 5.45;N, 5.02. measured value:. , 65.44; H, 5.45; N, 5.02.
[0463] [実施例 10] [Example 10]
(1) 2— [4— [[フラン一 2—ィルメチル一 [1— (4 トリフルォロメチルフエ-ル)一 1H イミダゾールー 4 ィルメチル]ァミノ]メチル]フエノキシ ]ー2 メチルプロピオン酸 ェチノレ エステル (1) 2— [4 -— [[Furan-2-ylmethyl mono [1— (4 trifluoromethyl phenol) -mono 1H imidazole-4-ylmethyl] amino] methyl] phenoxy] -2 methyl propionic acid ethinole ester
[0464] [化 136] [0464] [Chemical 136]
[0465] 参考例 7— (2)と同様にして、 4 トリフルォロメチルョードベンゼン(109 μ 1)と参考 例 8で得たィ匕合物(267mg)力も標題ィ匕合物(113mg)を黄色油状物として得た。 MS m/z:542(M+H)+. [0465] Reference Example 7—In the same manner as (2), the force of 4 trifluoromethyl iodide benzene (109 μ 1) and the compound (267 mg) obtained in Reference Example 8 was also the same as that of the title compound ( 113 mg) was obtained as a yellow oil. MS m / z: 542 (M + H) + .
[0466] (2) 2— [4— [[フラン— 2—ィルメチル— [1— (4 トリフルォロメチルフエ-ル)— 1H イミダゾールー 4 ィルメチル]ァミノ]メチル]フエノキシ ]ー2 メチルプロピオン酸 [0466] (2) 2— [4— [[Furan-2-ylmethyl] [1— (4 trifluoromethylphenol) — 1H imidazole-4-ylmethyl] amino] methyl] phenoxy] -2 methylpropionic acid
[0467] [化 137] [0467] [Chemical 137]
実施例 2— (2)と同様にして、実施例 10— (1)で得たィ匕合物(llOmg)から、標題 化合物(31mg)を無色固体として得た。 Example 2- In the same manner as (2), the title compound (31 mg) was obtained as a colorless solid from the compound (llOmg) obtained in Example 10- (1).
iH—NMR (400MHz, DMSO d) δ :1.44 (6H, s), 3. 51 (4H, s), 3.60(2 iH—NMR (400MHz, DMSO d) δ: 1.44 (6H, s), 3.51 (4H, s), 3.60 (2
6 6
H, s), 6. 34(1H, d, J = 3. 2Hz), 6. 39(1H, dd, J = 2.0, 3. 2Hz), 6. 75(2 H, d, J=8.6Hz), 7. 23 (2H, d, J = 8.6Hz), 7. 58 (1H, d, J = 2.0Hz), 7. 7 2(1H, s), 7. 85 (2H, d, J = 8.6Hz), 7. 90 (2H, d, J = 8.6Hz), 8. 34(1H, s
MS m/z:514(M+H)+. H, s), 6.34 (1H, d, J = 3.2 Hz), 6.39 (1H, dd, J = 2.0, 3.2 Hz), 6.75 (2 H, d, J = 8.6 Hz ), 7.23 (2H, d, J = 8.6Hz), 7.58 (1H, d, J = 2.0Hz), 7. 7 2 (1H, s), 7. 85 (2H, d, J = 8.6Hz), 7.90 (2H, d, J = 8.6Hz), 8. 34 (1H, s MS m / z: 514 (M + H) + .
元素分析値 C H FNO · 1/2H Oとして Elemental analysis value C H FNO 1 / 2H O
27 26 3 3 4 2 27 26 3 3 4 2
計算値: C, 62.06;H, 5.21;F, 10.91;N, 8.04. Calculated values: C, 62.06; H, 5.21; F, 10.91; N, 8.04.
測定値:。, 62.21;H, 5. 16;F, 10.77;N, 7.83. measured value:. 62.21; H, 5. 16; F, 10.77; N, 7.83.
[0469] [実施例 11] [Example 11]
(1)2— [2—メトキシ一 4— [[(3—メチノレ一 1—フエ-ノレ一 1H ピラゾーノレ一 4—ィ ルメチル)ォキサゾール— 2—ィルメチルァミノ]メチル]フエノキシ]— 2—メチルプロ ピオン酸 ェチル エステル (1) 2- [2-Methoxy-1-4-[[((3-Methylenol 1-Phenol-1-H1Pyrazonole 4-Hydrmethyl) oxazole- 2-ylmethylamino] methyl] phenoxy]-2-methylpropionic acid ethyl Ester
[0470] [化 138] [0470] [Chemical 138]
[0471] 実施例 8— (1)と同様にして参考例 9 (3)で得た化合物(335mg)とォキサゾール — 2—カルバルデヒド (85mg)カゝら標題ィ匕合物(64mg)を褐色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2 Example 8— Similar to (1), the compound (335 mg) obtained in Reference Example 9 (3) and oxazole-2-carbaldehyde (85 mg) were combined with the title compound (64 mg) in brown color. Obtained as an oil. 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2
3 Three
.28 (3H, s), 3.56 (2H, s), 3.64 (2H, s), 3.78 (2H, s), 3.81 (3H, s), 4. 24 (2H, q, J = 7.1Hz) , 6.82 (2H, s) , 6.96 (1H, s) , 7.09 (1H, s), 7.20— 7.24 (1H, m), 7.39— 7.44 (2H, m), 7.61— 7.64 (3H, m), 7.86(1H, s) .28 (3H, s), 3.56 (2H, s), 3.64 (2H, s), 3.78 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.82 (2H, s), 6.96 (1H, s), 7.09 (1H, s), 7.20— 7.24 (1H, m), 7.39— 7.44 (2H, m), 7.61— 7.64 (3H, m), 7.86 ( 1H, s)
MS m/z:519(M+H)+. MS m / z: 519 (M + H) +.
[0472] (2) 2— [2—メトキシ一 4— [[ (3—メチル 1 フエ-ル一 1H ピラゾール一 4—ィ ルメチル)ォキサゾール— 2—ィルメチルァミノ]メチル]フエノキシ]— 2—メチルプロ ピオン酸 [0472] (2) 2- [2-Methoxy-1-4-[[(3-Methyl-1-Phenol-1H-Pyrazole-1-4-Methyl) oxazole-2-ylmethylamino] methyl] phenoxy]-2-Methylpropionic acid
[0473] [化 139]
[0473] [Chemical 139]
[0474] 実施例 2— (2)と同様にして、実施例 11— (1)で得たィ匕合物 (62mg)から標題ィ匕 合物(56mg)を無色固体として得た。 In the same manner as in Example 2- (2), the title compound (56 mg) was obtained as a colorless solid from the compound (62 mg) obtained in Example 11- (1).
'H-NMR (400MHz, CDCl) δ :1.40 (6Η, s), 2. 16 (3Η, s), 3.51 (2H, s) 'H-NMR (400MHz, CDCl) δ: 1.40 (6Η, s), 2.16 (3Η, s), 3.51 (2H, s)
3 Three
, 3.56 (2H, s), 3.70 (2H, s), 3.71 (3H, s), 6.75— 6.81 (2H, m), 6.94 ( 1H, s), 7. 19-7.24 (2H, m), 7.43 (2H, t, J = 8.6Hz), 7.74 (2H, d, J = 8 .6Hz), 8.08 (1H, s), 8.29(1H, s) . , 3.56 (2H, s), 3.70 (2H, s), 3.71 (3H, s), 6.75— 6.81 (2H, m), 6.94 (1H, s), 7. 19-7.24 (2H, m), 7.43 (2H, t, J = 8.6Hz), 7.74 (2H, d, J = 8.6Hz), 8.08 (1H, s), 8.29 (1H, s).
MS m/z:491(M+H)+. MS m / z: 491 (M + H) +.
[0475] [実施例 12] [0475] [Example 12]
(1)2— [4— [[フラン一 2—ィルメチル一( 1 フエ-ル 3 トリフルォロメチル -1H —ピラゾールー 4—ィルメチル)ァミノ]メチル ]—2—メトキシフエノキシ]—2—メチル プロピオン酸 ェチノレ エステノレ (1) 2- [4 -— [[furan-2-ylmethyl-1- (1-phenol 3 trifluoromethyl-1H —pyrazole-4-ylmethyl) amino] methyl] —2-methoxyphenoxy] -2-methyl Propionate Etenore Estenore
[0476] [化 140] [0476] [Chemical 140]
参考例 7— (4)と同様に参考例 10— (3)で得たィ匕合物(551mg)からフラン— 2— ィルメチル一( 1—フエ-ル 3 トリフルォロメチル -1H-ピラゾール 4 ィルメ チル)ァミンの粗精製物を得た。このものと参考例 5—(1)で得た化合物(268mg)か ら実施例 7— (1)と同様にして標題ィ匕合物 (603mg)を黄色油状物として得た。 Reference Example 7—Similar to (4), from the compound (551 mg) obtained in Reference Example 10 (3), furan-2-ylmethyl mono (1-phenol 3 trifluoromethyl-1H-pyrazole 4 A crude product of ilmethyl) amine was obtained. From this and the compound (268 mg) obtained in Reference Example 5- (1), the title compound (603 mg) was obtained as a yellow oil in the same manner as in Example 7- (1).
iH—NMR (400MHz, CDCl) δ :1.26 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 3 iH—NMR (400MHz, CDCl) δ: 1.26 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 3
3 Three
.59 (2H, s), 3.65 (2H, s), 3.67 (2H, s), 3.81 (3H, s), 4.23 (2H, q, J =
7. 1Hz), 6.17(1H, d, J = 3.2Hz), 6.33(1H, dd, J = 2.0, 3.2Hz), 6.80 -6.81 (2H, m), 6.97(1H, s), 7.34— 7.37(1H, m), 7.40— 7.42(1H, m), 7.46-7.50 (2H, m), 7.67— 7.70 (2H, m), 7.99(1H, s) . .59 (2H, s), 3.65 (2H, s), 3.67 (2H, s), 3.81 (3H, s), 4.23 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0, 3.2Hz), 6.80 -6.81 (2H, m), 6.97 (1H, s), 7.34— 7.37 (1H, m), 7.40- 7.42 (1H, m), 7.46-7.50 (2H, m), 7.67-7.70 (2H, m), 7.99 (1H, s).
MS:m/z:572(M+H)+. MS: m / z: 572 (M + H) + .
[0478] (2)2— [4— [[フラン一 2—ィルメチル一 ( 1 フエ-ル一 3 トリフルォロメチル一 1H —ピラゾールー 4—ィルメチル)ァミノ]メチル ]—2—メトキシフエノキシ]—2—メチル プロピオン酸 [0478] (2) 2— [4— [[Furan-2-ylmethyl-1- (1-phenol-3 Trifluoromethyl-1- 1H-pyrazole-4-ylmethyl) amino] methyl] -2-methoxyphenoxy] —2—Methyl propionic acid
[0479] [化 141] [0479] [Chemical 141]
[0480] 実施例 2— (2)と同様にして、実施例 12— (1)で得たィ匕合物(571mg)から標題ィ匕 合物 (449mg)を黄色固体として得た。 Example 2— In the same manner as in (2), the title compound (449 mg) was obtained as a yellow solid from the compound (571 mg) obtained in Example 12 (1).
'H-NMR (400MHz, CDCl) δ :1.39 (6Η, s), 3.51 (2Η, s), 3.59 (2H, s) 'H-NMR (400MHz, CDCl) δ: 1.39 (6Η, s), 3.51 (2Η, s), 3.59 (2H, s)
3 Three
, 3.61 (2H, s), 3.71 (3H, s), 6.32(1H, d, J = 3.2Hz), 6.41 (1H, dd, J = , 3.61 (2H, s), 3.71 (3H, s), 6.32 (1H, d, J = 3.2Hz), 6.41 (1H, dd, J =
2.0, 3.2Hz), 6.75(1H, d, J = 8.1Hz), 6.80(1H, d, J = 8.1Hz), 6.96 (2.0, 3.2Hz), 6.75 (1H, d, J = 8.1Hz), 6.80 (1H, d, J = 8.1Hz), 6.96 (
1H, s), 7.39 (1H, t, J = 7.4Hz), 7.53 (2H, t, J = 7.4Hz), 7.61 (1H, d, J1H, s), 7.39 (1H, t, J = 7.4Hz), 7.53 (2H, t, J = 7.4Hz), 7.61 (1H, d, J
=2. OHz), 7.85 (2H, d, J = 7.4Hz), 8.64(1H, s) . = 2.OHz), 7.85 (2H, d, J = 7.4Hz), 8.64 (1H, s).
MS m/z:544(M+H)+. MS m / z: 544 (M + H) + .
元素分析値 C H FNO · 1/2H Oとして Elemental analysis value C H FNO 1 / 2H O
28 28 3 3 5 2 28 28 3 3 5 2
計算値 C:60.86, H:5.29, N:7.60, F:10.31. Calculated C: 60.86, H: 5.29, N: 7.60, F: 10.31.
実測値 C:60.78, H:5.22, N:7.61, F:10.21. Actual value C: 60.78, H: 5.22, N: 7.61, F: 10.21.
[0481] [実施例 13] [0481] [Example 13]
(1)2— [4— [[フラン一 2—ィルメチル一( 3 メチル 1 フエ-ル 1 H ピラゾー ルー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピ オン酸 ェチノレ エステノレ
[0482] [化 142] (1) 2- [4 -— [[Furan-2-ylmethyl mono (3 methyl 1-phenol 1 H pyrazol 4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] -2-methylpropionic acid Echinore Estenore [0482] [Chemical 142]
[0483] 実施例 1— (1)と同様にして参考例 11— (2)で得たィ匕合物(345mg)と参考例 4で 得た化合物(207mg)から、標題化合物(312mg)を無色油状物として得た。 [0483] In the same manner as in Example 1- (1), the title compound (312mg) was obtained from the compound (345mg) obtained in Reference Example 11- (2) and the compound (207mg) obtained in Reference Example 4. Obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 19 (6H, s), 2.26 (3H, s), 3.45 (2H, s), 3.50 (2H, s), 3.63 (2H, s), 4. 19 (6H, s), 2.26 (3H, s), 3.45 (2H, s), 3.50 (2H, s), 3.63 (2H, s), 4.
28 (2H, q, J = 7.1Hz) , 6.17(1H, d, J = 3.2Hz), 6.34(1H, dd, J = 2.0,28 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = 2.0,
3.2Hz), 6.96 (2H, s), 7.22(1H, t, J = 7.6Hz), 7.38— 7.43 (3H, m), 73.2Hz), 6.96 (2H, s), 7.22 (1H, t, J = 7.6Hz), 7.38—7.43 (3H, m), 7
.63 (2H, d, J = 8.6Hz), 7.82(1H, s) . .63 (2H, d, J = 8.6Hz), 7.82 (1H, s).
MS m/z:516(M+H)+. MS m / z: 516 (M + H) +.
[0484] (2)2— [4— [[フラン一 2—ィルメチル一( 3 メチル 1 フエ-ル 1 H ピラゾー ルー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピ オン酸 [0484] (2) 2— [4— [[Furan-2-ylmethyl- (3 methyl 1-phenol 1 H-pyrazole-l-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] —2— Methyl propionic acid
[0485] [化 143] [0485] [Chemical 143]
実施例 2— (2)と同様にして、実施例 13— (1)で得たィ匕合物(310mg)から、標題 化合物(224mg)を無色固体として得た。 Example 2- In the same manner as (2), the title compound (224 mg) was obtained as a colorless solid from the compound (310 mg) obtained in Example 13- (1).
'H-NMR (400MHz, CDCl) δ :1.33 (6Η, s), 2. 12(3Η, s), 2.15 (6Η, s) 'H-NMR (400MHz, CDCl) δ: 1.33 (6Η, s), 2.12 (3Η, s), 2.15 (6Η, s)
3 Three
, 3.39 (2H, s), 3.43 (2H, s), 3.57 (2H, s), 6.34(1H, d, J = 3.2Hz), 6. 43 (1H, dd, J = 2.0, 3.2Hz), 6.95 (2H, s), 7.23 (1H, t, J = 7.4Hz), 7. 44 (2H, t, J = 7.4Hz), 7.63(1H, d, J = 2. OHz), 7.77 (2H, d, J = 8.6Hz)
, 8.31 (1H, s). , 3.39 (2H, s), 3.43 (2H, s), 3.57 (2H, s), 6.34 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz), 6.95 (2H, s), 7.23 (1H, t, J = 7.4Hz), 7.44 (2H, t, J = 7.4Hz), 7.63 (1H, d, J = 2. OHz), 7.77 (2H, d, J = 8.6Hz) , 8.31 (1H, s).
MS m/z:488(M+H)+. MS m / z: 488 (M + H) +.
元素分析値 C H NO · 1/2H Oとして Elemental analysis value as C H NO 1/2 H O
29 33 3 4 2 29 33 3 4 2
計算値 C:70.14, H:6.90, N:8.46. Calculated C: 70.14, H: 6.90, N: 8.46.
実測値 C:70.34, H:6.84, N:8.56. Found C: 70.34, H: 6.84, N: 8.56.
[0487] [実施例 14] [Example 14]
(1)2— [4— [[フラン一 2—ィルメチル一(5—メチル 2 フエ-ル一 2H—[1, 2, 3 ]トリアゾール 4—ィルメチル)ァミノ]メチル ]—2—メトキシフエノキシ]—2—メチル プロピオン酸 ェチノレ エステノレ (1) 2- [4-[[Furan-2-ylmethyl-1- (5-methyl-2-phenol-1H- [1, 2, 3] triazole 4-ylmethyl) amino] methyl] -2-Methoxyphenoxy ] —2-Methyl propionate Estenole Estenore
[0488] [化 144] [0488] [Chemical 144]
[0489] 参考例 12で得たィ匕合物(125mg)をジクロロメタン (4ml)に溶解し、トリェチルアミ ン(110 1)、メタンスルホユルクロリド(56 μ 1)を加え、氷浴下 3時間攪拌した。反応 液に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで 3回抽出した。有機層を飽和 食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣を Ν, Ν ジメチ ルホルムアミド (4ml)に溶解し、参考例 5— (2)の化合物(230mg)、炭酸セシウム(2 58mg)を加え、 70°Cで一晩攪拌した。反応液を減圧濃縮し、残渣に炭酸水素ナトリ ゥム水溶液を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無 水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (酢酸ェチル:へキサン = 1: 6)で精製し、標題ィ匕合物(149mg)を無色油状物として 得た。 [0489] The compound (125 mg) obtained in Reference Example 12 was dissolved in dichloromethane (4 ml), triethylamine (110 1) and methanesulfuryl chloride (56 μ 1) were added, and the mixture was stirred for 3 hours in an ice bath. did. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Ν, Ν dimethylformamide (4 ml), the compound of Reference Example 5- (2) (230 mg) and cesium carbonate (258 mg) were added, and the mixture was stirred at 70 ° C overnight. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to give the title compound (149 mg) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2
3 Three
.30 (3H, s), 3.58 (2H, s), 3.67 (2H, s), 3.72 (2H, s), 3.81 (3H, s), 4. 24 (2H, q, J = 7.1Hz) , 6.26 (1H, d, J = 3.2Hz), 6.35 (1H, dd, J = 2.0, 3
[9fl^ [ 6 0] エ ^エ 邈べ ci l /^ —
[ ^ [ ^ ( ^ / — — /— 、 (H[ ε 'ζ 'ΐ]— HS— / ェ — ^ — s)— ^ / — ベ έ ]]— ]— .30 (3H, s), 3.58 (2H, s), 3.67 (2H, s), 3.72 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.26 (1H, d, J = 3.2Hz), 6.35 (1H, dd, J = 2.0, 3 [9fl ^ [6 0] d ^ d ci ci l / ^ — [^ [^ (^ / — — / —, (H [ε 'ζ' ΐ] — HS— / é — ^ — s) — ^ / — Be έ]] —] —
•+(H+PV)I6^:Z/RA SPV • + (H + PV) I6 ^: Z / RA SPV
•(ZHS '8 = Γ • (ZHS '8 = Γ
'Ρ 'HS)S6 ' L '(ΖΗ0 ·2 = Γ'Ρ 'Ηΐ) 9 ' L '(ZHS ·8=Γ 'HS)S9 ' L '(^ 'HI 'Ρ' HS) S6 'L' ( Ζ Η0 2 = Γ'Ρ 'Ηΐ) 9' L '( Z HS 8 = Γ' HS) S9 'L' (^ 'HI
)ζε ·ζ-εε ' L '(S 'ΗΙ)96 ·9 '(s 'HS)8 ·9 '(zHS Έ 'Ο ·2=Γ'ΡΡ ¾ΐ)ε ) ζε ζ-εε 'L' ( S 'ΗΙ) 96 9' ( s ' HS) 8 9 '( z HS Έ' Ο 2 = Γ'ΡΡ ¾ΐ) ε
•9 '(ΖΗ2 Έ = Γ'Ρ 'HI)9S ·9 '(s 'U£)ZL Έ '(s 'Η2)89 Έ '(s ΉΖ)£9 Έ '• 9 '( Ζ Η2 Έ = Γ'Ρ' HI) 9S 9 '( s ' U £) ZL Έ '( s ' Η2) 89 Έ '( s ΉΖ) £ 9 Έ'
(S 'Η2)ε9 ·ε '(s ¾ε) ζ 'ζ '(s ¾9)ΐ ·ΐ: 9 (\οαο 'ZH OO^)H N-HT ( S 'Η2) ε9 · ε' ( s ¾ε) ζ 'ζ' ( s ¾9) ΐ · ΐ: 9 (\ οαο 'ZH OO ^) H NH T
。 ェつ; : (SraiOI)i¾J^ . : (SraiOI) i¾J ^
[ ^ [i6 o] 邈べ ΰ 1 ^ — S—
S— [ ^ [ ^ ( ^ / — — /— 、 (H[ S 'Ζ 'ΐ]— HS— / ェ — ^ — S)— ^ / — ベ έ ]]— ]— [06W)][^ [i6 o] 邈 ΰ 1 ^ — S— S— [^ [^ (^ / — — / —, (H [S 'Ζ' ΐ] — HS— / é — ^ — S) — ^ / — Be έ]] —] — [06W)]
•+(H+PV)6I9:z/ra SPV •(ZHS ·8 = ΓΡ 'Η2)66 ' L '(ZHS ·8 = Γ 'UZ) ' L '(ΖΗ0 'Ζ = ί 'Ρ 'ΗΙ) • + (H + PV) 6I9: z / ra SPV • (ZHS · 8 = ΓΡ 'Η2) 66' L '( Z HS · 8 = Γ' UZ) 'L' ( Ζ Η0 'Ζ = ί' Ρ ' ΗΙ)
0 ' L ' ^ 'ΗΙ)θε Ί- Ζ ' L '(s 'ΗΙ)96 ·9 '(^ 'HS)S8 '9-8Ζ ·9 '(ΖΗ2 · 0 'L' ^ 'ΗΙ) θε Ί- Ζ' L '( s ' ΗΙ) 96 9 '(^' HS) S8 '9-8Ζ 9' ( Ζ Η2
ZCCM0/S00Zdf/X3d ε 6C6CT0/900Z OAV
ZCCM0 / S00Zdf / X3d ε 6C6CT0 / 900Z OAV
[0495] 実施例 14一(1)と同様にして参考例 12で得たィ匕合物(125mg)と参考例 11— (2) で得た化合物(230mg)から、標題化合物(236mg)を無色油状物として得た。 'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 In the same manner as in Example 14-1 (1), the title compound (236 mg) was obtained from the compound (125 mg) obtained in Reference Example 12 and the compound (230 mg) obtained in Reference Example 11- (2). Obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 18 (6H, s), 2.26 (3H, s), 3.52 (2H, s), 3.68 (2H, s), 3.69 (2H, s), 4. 18 (6H, s), 2.26 (3H, s), 3.52 (2H, s), 3.68 (2H, s), 3.69 (2H, s), 4.
28 (2H, q, J = 7.1Hz) , 6.26 (1H, d, J = 3.2Hz), 6.35 (1H, dd, J = 2.0,28 (2H, q, J = 7.1Hz), 6.26 (1H, d, J = 3.2Hz), 6.35 (1H, dd, J = 2.0,
3.2Hz), 6.96 (2H, s), 7.29 (1H, t, J = 8.3Hz), 7.41— 7.46 (3H, m), 73.2Hz), 6.96 (2H, s), 7.29 (1H, t, J = 8.3Hz), 7.41— 7.46 (3H, m), 7
.99 (2H, d, J = 8.3Hz). .99 (2H, d, J = 8.3Hz).
MS m/z:517(M+H)+. MS m / z: 517 (M + H) + .
[0496] (2)2— [4— [[フラン— 2—ィルメチル—(5—メチル—2—フエ-ル— 2H—[1, 2, 3[0496] (2) 2— [4— [[Furan-2-ylmethyl- (5-methyl-2-phenyl) 2H— [1, 2, 3
]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メ チルプロピオン酸 ] Triazole-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid
[0497] [化 147] [0497] [Chemical 147]
実施例 2— (2)と同様にして、実施例 15— (1)で得たィ匕合物(230mg)から、標題 化合物(192mg)を無色固体として得た。 Example 2- In the same manner as (2), the title compound (192 mg) was obtained as a colorless solid from the compound (230 mg) obtained in Example 15- (1).
'H-NMR (400MHz, CDCl) δ :1.32 (6Η, s), 2. 12(6Η, s), 2.19 (3Η, s) 'H-NMR (400MHz, CDCl) δ: 1.32 (6 Η, s), 2. 12 (6 Η, s), 2.19 (3 Η, s)
3 Three
, 3.48 (2H, s), 3.645 (2H, s), 3.652(2H, s), 6.36(1H, d, J = 2.9Hz), 6.44 (1H, dd, J=l.7.2.9Hz), 6.92 (2H, s), 6.96(1H, s), 7.33— 7.3 7(1H, m), 7.52 (2H, t, J = 8.3Hz), 7.64(1H, d, J=l.7Hz), 7.93 (2H, d, J = 8.3Hz).
MS m/z:489(M+H)+. , 3.48 (2H, s), 3.645 (2H, s), 3.652 (2H, s), 6.36 (1H, d, J = 2.9Hz), 6.44 (1H, dd, J = l.7.2.9Hz), 6.92 (2H, s), 6.96 (1H, s), 7.33—7.3 7 (1H, m), 7.52 (2H, t, J = 8.3Hz), 7.64 (1H, d, J = l.7Hz), 7.93 ( (2H, d, J = 8.3Hz). MS m / z: 489 (M + H) +.
[0499] [実施例 16] [0499] [Example 16]
(1) 2— [4— [[フラン一 2—ィルメチル一 [2— (3—メチル 1—フエ-ル一 1H—ビラ ゾールー 4 ィル)ェチル]ァミノ]メチル ]—2, 6 ジメチルフエノキシ ] 2 メチル プロピオン酸 ェチノレ エステノレ (1) 2— [4 — [[Furan-2-ylmethyl-1- [2- (3-Methyl-1-phenyl-1H-virazol-4-yl) ethyl] amino] methyl] -2,6 dimethylphenol 2] 2 methyl propionate ethenore estenore
[0500] [化 148] [0500] [Chemical 148]
[0501] 実施例 12— (1)と同様にして参考例 13— (3)で得たィ匕合物(593mg)と参考例 11 [0501] Example 12- Reference Example 13- Compound (593mg) obtained in (3) in the same manner as (1) and Reference Example 11
- (1)で得た化合物(264mg)から、標題化合物(516mg)を黄色油状物として得た -The title compound (516 mg) was obtained as a yellow oil from the compound (264 mg) obtained in (1).
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 16 (6H, s), 2.20 (3H, s), 2.64 (4H, s), 3.54 (2H, s), 3.71 (2H, s), 4. 16 (6H, s), 2.20 (3H, s), 2.64 (4H, s), 3.54 (2H, s), 3.71 (2H, s), 4.
28 (2H, q, J = 7.1Hz) , 6.18(1H, d, J = 3.2Hz), 6.33(1H, dd, J = 2.0,28 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0,
3.2Hz), 6.92 (2H, s), 7.20 (1H, t, J = 7.4Hz), 7.38— 7.42 (3H, m), 73.2Hz), 6.92 (2H, s), 7.20 (1H, t, J = 7.4Hz), 7.38—7.42 (3H, m), 7
.60 (2H, d, J = 8.8Hz), 7.65(1H, s) . .60 (2H, d, J = 8.8Hz), 7.65 (1H, s).
MS m/z:529(M+H)+. MS m / z: 529 (M + H) + .
[0502] (2) 2— [4 [[フラン一 2—ィルメチル一 [2— (3—メチル 1—フエ-ル一 1H—ビラ ゾールー 4 ィル)ェチル]ァミノ]メチル ]—2, 6 ジメチルフエノキシ ] 2 メチル プロピオン酸 [0502] (2) 2— [4 [[furan-2-ylmethyl-1- [2- (3-methyl-1-phenyl-1H-virazol-4-yl) ethyl] amino] methyl] —2, 6 dimethyl Phenoxy] 2-methyl propionic acid
[0503] [化 149]
[0503] [Chemical 149]
[0504] 実施例 2— (2)と同様にして、実施例 16— (1)で得たィ匕合物(510mg)から、標題 化合物 (441mg)を淡黄色固体として得た。 Example 2- In the same manner as in (2), the title compound (441 mg) was obtained as a pale yellow solid from the compound (510 mg) obtained in Example 16- (1).
'H-NMR (400MHz, CDCl) δ :1.32 (6Η, s), 2.07 (3Η, s), 2.10 (6H, s) 'H-NMR (400MHz, CDCl) δ: 1.32 (6 Η, s), 2.07 (3 Η, s), 2.10 (6H, s)
3 Three
, 2.53-2.58 (4H, m), 3.50 (2H, s), 3.70 (2H, s), 6.32(1H, d, J = 3.2 Hz), 6.42(1H, dd, J=l.7, 3.2Hz), 6.89 (2H, s), 7.21 (IH, t, J = 7.4 Hz), 7.41-7.45 (2H, m), 7.62(1H, d, J=l.7Hz), 7.70 (2H, d, J = 8. 6Hz), 8.11 (IH, s). , 2.53-2.58 (4H, m), 3.50 (2H, s), 3.70 (2H, s), 6.32 (1H, d, J = 3.2 Hz), 6.42 (1H, dd, J = l.7, 3.2Hz ), 6.89 (2H, s), 7.21 (IH, t, J = 7.4 Hz), 7.41-7.45 (2H, m), 7.62 (1H, d, J = l.7Hz), 7.70 (2H, d, J = 8. 6Hz), 8.11 (IH, s).
MS m/z:504(M+H)+. MS m / z: 504 (M + H) + .
[0505] [実施例 17] [0505] [Example 17]
(1) 2— [4— [[フラン一 2—ィルメチル一 [2— (3—メチル 1—フエ-ル一 1H—ビラ ゾールー 4 ィル)ェチル]ァミノ]メチル ] 2—メトキシフエノキシ ] 2 メチルプロ ピオン酸 ェチル エステル (1) 2- [4 -— [[Furan-2-ylmethyl-1- [2- (3-Methyl-1-phenyl-1H-virazol-4-yl) ethyl] amino] methyl] 2-methoxyphenoxy] 2 Methylpropionic acid ethyl ester
[0506] [化 150] [0506] [Chemical 150]
実施例 12— (1)と同様にして参考例 13— (3)で得たィ匕合物(593mg)と参考例 5 - (1)で得た化合物(264mg)から、標題化合物(617mg)を黄色油状物として得た Example 12- Reference Example 13- In the same manner as (1), the title compound (617 mg) was obtained from the compound (593 mg) obtained in (3) and the compound (264 mg) obtained in Reference Example 5- (1). Was obtained as a yellow oil.
'H-NMR (400MHz, CDCl) δ :1.23 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.23 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2
3 Three
.22 (3H, s), 2.65-2.68 (4H, m), 3.60 (2H, s), 3.71 (2H, s), 3.72(3
[23ΐ^ ] [2 ISO].22 (3H, s), 2.65-2.68 (4H, m), 3.60 (2H, s), 3.71 (2H, s), 3.72 (3 [23ΐ ^] [2 ISO]
/ ェ ^エ 邈べ — — /— ½ — Ηΐ— / ェ — ΐ— ^ — ε)]]— — ^^ — S]— / É ^ e 邈 be — — / — ½ — Ηΐ— / é— ΐ— ^ — ε)]] — — ^^ — S] —
ismm ^ [π so] ismm ^ [π so]
•+(H + V)SOS:zZra SPV •(s ΉΙ)ΖΙ ·8 '(ΖΗ9 '8 = Γ 'Ρ ΉΖ)69 ' L '(ΖΗΖ ·Ι=Γ'Ρ 'ΗΙ)29 ' L ' ΉΖ) ^ ' L-\V ' L '(ΖΗ Ί = • + (H + V) SOS: z Z ra SPV • ( s ΉΙ) ΖΙ · 8 '( Ζ Η9' 8 = Γ 'Ρ ΉΖ) 69' L '( Ζ ΗΖ · Ι = Γ'Ρ' ΗΙ) 29 'L' ΉΖ) ^ 'L- \ V' L '( Ζ Η Ί =
Γ 'ΐ ΉΙ)ΙΖ ' L '(s 'ΗΙ)Ι6 ·9 '(s 'Η2)9Ζ ·9 '(ΖΗ6 'Ζ Ί ·ΐ=ΓΡΡ Ήΐ)Ζ^ Γ 'ΐ ΉΙ) ΙΖ' L '( s ' ΗΙ) Ι6 9 '( s ' Η2) 9Ζ9 '( Ζ Η6' Ζ ΊΊ = ΓΡΡ Ήΐ) Ζ ^
•9 '(ΖΗ6 'Ζ = ΓΡ ΉΙ)Ζ£ ·9 '(s 'UZ)OL Έ '(s ¾ε) 9 Έ '(s 'UZ)L Έ ' (s 'Η^)69 'Ζ '(s ¾ε)60 'Ζ '(s 'Η9)ΐ ·ΐ: 9 (\θαθ 'ZH 00^)H N-HT • 9 '( Ζ Η6' Ζ = ΓΡ ΉΙ) Ζ £ 9 '( s ' UZ) OL Έ' ( s ¾ε) 9 Έ '( s ' UZ) L Έ' ( s ' Η ^) 69 'Ζ' ( s ¾ε) 60 'Ζ' ( s 'Η9) ΐ · ΐ: 9 (\ θαθ' ZH 00 ^) H NH T
。 ェつ; : {^ i ) . : (^ I)
[ΐ3ΐ¾] [60S0] 邈べ [ΐ3ΐ¾] [60S0]
ΰ l ^ [ ^:,ェ ^ ー S—[ ^ [ ^ [ ^エ( / — 一 /— 、 6c¾-HI— / ェ — ΐ / —ε) -Ζ - /^ ^-Ζ- ^Δ^-^-Ζ(Ζ) [80S0] ΰ l ^ [^ :, é ^ ー S— [^ [^ [^ é (/ — one / —, 6c¾-HI— / é — ΐ / —ε) -Ζ-/ ^ ^ -Ζ- ^ Δ ^ -^-Ζ (Ζ) [80S0]
(U + W)Z£9-Z/^ SPV (U + W) Z £ 9- Z / ^ SPV
•(s 'HI) • ( s ' HI)
99 ' L '(ΖΗ9 ·8 = ΓΡ 'HS)69 ' L '(^ 'U£)Z 'LS£ ' L '(ΖΗ ·Ζ = Γ 'HI 99 'L' ( Ζ Η9 8 = ΓΡ 'HS) 69' L '(^' U £) Z 'LS £' L '( Ζ Η · Ζ = Γ' HI
)02 ' L '(ΖΗΖ ·Ι=Γ'Ρ 'ΗΙ)06 ·9 '(^ 'Η2)Ι8 '9-9Ζ ·9 '(ΖΗ6 'Ζ Ί Ί = ) 02 'L' ( Ζ ΗΖ · Ι = Γ'Ρ 'ΗΙ) 06 9' (^ 'Η2) Ι8' 9-9Ζ 9 '( Ζ Η6' Ζ Ί Ί =
Γ 'ΡΡ 'ΗΙ)εε ·9 '(ΖΗ6 'Ζ = ΓΡ 'ΗΙ)ΖΙ ·9 '(ΖΗΙ · = Γ '¾ ΉΖ)£Ζ ' '(S 'Η Γ 'ΡΡ' ΗΙ) εε 9 '( Ζ Η6' Ζ = ΓΡ 'ΗΙ) ΖΙ 9' ( Ζ ΗΙ · = Γ '¾ ΉΖ) £ Ζ''( S ' Η
ZCCM0/S00Zdf/X3d III 6C6CT0/900Z OAV
ZCCM0 / S00Zdf / X3d III 6C6CT0 / 900Z OAV
[0513] 実施例 8— (1)と同様にして、参考例 9— (3)で得たィ匕合物(250mg)と 2— (トリフ ルォロメチル)ベンズアルデヒド(83 μ 1)力 標題ィ匕合物(167mg)を無色油状物とし て得た。 [0513] In the same manner as in Example 8- (1), the compound (250 mg) obtained in Reference Example 9- (3) and 2- (trifluoromethyl) benzaldehyde (83 μ 1) force were combined. (167 mg) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.25 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.25 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2
3 Three
.26 (3H, s), 3.46 (2H, s), 3.51 (2H, s), 3.74 (2H, s), 3.80 (3H, s), 4. .26 (3H, s), 3.46 (2H, s), 3.51 (2H, s), 3.74 (2H, s), 3.80 (3H, s), 4.
23 (2H, q, J = 7.1Hz) , 6.82 (2H, s) , 6.89(1H, s) , 7.22(1H, t, J=7.4H z), 7.31 (IH, t, J = 7.6Hz), 7.41 (2H, t, J = 7.4Hz), 7.52(1H, t, J = 7.23 (2H, q, J = 7.1Hz), 6.82 (2H, s), 6.89 (1H, s), 7.22 (1H, t, J = 7.4H z), 7.31 (IH, t, J = 7.6Hz) , 7.41 (2H, t, J = 7.4Hz), 7.52 (1H, t, J = 7.
4Hz), 7.58-7.66 (3H, m), 7.76 (IH, s), 7.90(1H, d, J = 7.6Hz) .4Hz), 7.58-7.66 (3H, m), 7.76 (IH, s), 7.90 (1H, d, J = 7.6Hz).
MS m/z:596(M+H)+. MS m / z: 596 (M + H) +.
[0514] (2)2— [2—メトキシ一 4— [[(3—メチル 1—フエ-ル一 IH ピラゾール一 4—ィ ルメチル) - (2—トリフルォロメチルベンジル)ァミノ]メチル]フエノキシ ]—2—メチル プロピオン酸 [0514] (2) 2 -— [2-Methoxy-1-4-[[(3-Methyl-1-phenol-1 IH-Pyrazole-1-4-methyl)-(2-trifluoromethylbenzyl) amino] methyl] phenoxy ] —2-Methylpropionic acid
[0515] [化 153] [0515] [Chemical 153]
実施例 2— (2)と同様にして、実施例 18— (1)で得たィ匕合物(163mg)から、標題 化合物(63mg)を無色固体として得た。 Example 2- In the same manner as in (2), the title compound (63 mg) was obtained as a colorless solid from the compound (163 mg) obtained in Example 18- (1).
'H-NMR (400MHz, DMSO-d) δ :1.39 (6Η, s), 2. 13 (3Η, s), 3.43(2 'H-NMR (400MHz, DMSO-d) δ: 1.39 (6Η, s), 2.13 (3Η, s), 3.43 (2
6 6
H, s), 3.47 (2H, s), 3.68 (2H, s), 3.71 (3H, s), 6.78 (IH, d, J = 8.3Hz
), 6.83(1H, d, J = 8.3Hz), 6.92(1H, s), 7.22(1H, t, J = 7.6Hz), 7.41H, s), 3.47 (2H, s), 3.68 (2H, s), 3.71 (3H, s), 6.78 (IH, d, J = 8.3Hz ), 6.83 (1H, d, J = 8.3Hz), 6.92 (1H, s), 7.22 (1H, t, J = 7.6Hz), 7.41
-7.45 (3H, m), 7.65— 7.70 (2H, m), 7.74 (2H, dd, J=l.2, 8.8Hz), 7-7.45 (3H, m), 7.65— 7.70 (2H, m), 7.74 (2H, dd, J = l.2, 8.8Hz), 7
.96(1H, d, J = 7.6Hz), 8.35(1H, s) . .96 (1H, d, J = 7.6Hz), 8.35 (1H, s).
MS m/z:568(M+H)+. MS m / z: 568 (M + H) +.
元素分析値 C H FNO · 1/4H Oとして Elemental analysis value C H FNO 1 / 4H O
31 32 3 3 4 2 31 32 3 3 4 2
計算値: C, 65.08;H, 5.73;N, 7.34. Calculated values: C, 65.08; H, 5.73; N, 7.34.
実測値: C, 64.97;H, 5.75;N, 7.10. Found: C, 64.97; H, 5.75; N, 7.10.
[0517] [実施例 19] [0517] [Example 19]
(1)2— [2—メトキシ一 4— [[(2—メトキシベンジル)一(3—メチル 1—フエ-ル一 (1) 2- [2-Methoxy-1-4-[[(2-Methoxybenzyl)-(3-methyl-1-phenyl-
1H ピラゾール 4 ィルメチル)ァミノ]メチル]フエノキシ] 2 メチルプロピオン 酸 ェチノレ エステル 1H Pyrazole 4-methyl) amino] methyl] phenoxy] 2 methylpropionate ethinole ester
[0518] [化 154] [0518] [Chemical 154]
[0519] 実施例 8— (1)と同様にして、参考例 9— (3)で得たィ匕合物(250mg)と o ァニス アルデヒド (83 1)力 、標題ィ匕合物(109mg)を無色油状物として得た。 [0519] In the same manner as in Example 8- (1), the compound (250 mg) obtained in Reference Example 9- (3) and o-anisaldehyde (83 1) force, title compound (109 mg) Was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.26 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.26 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2
3 Three
.24 (3H, s), 3.47 (2H, s), 3.53 (2H, s), 3.61 (2H, s), 3.79 (3H, s), 3. 87 (3H, s), 4.23 (2H, q, J = 7.1Hz) , 6.79— 7.28 (7H, m), 7.40 (2H, t, J = 7.6Hz), 7.49 (1H, d, J= 7.4Hz), 7.61 (2H, d, J = 7.6Hz), 7.78(1 H, s). .24 (3H, s), 3.47 (2H, s), 3.53 (2H, s), 3.61 (2H, s), 3.79 (3H, s), 3. 87 (3H, s), 4.23 (2H, q , J = 7.1Hz), 6.79— 7.28 (7H, m), 7.40 (2H, t, J = 7.6Hz), 7.49 (1H, d, J = 7.4Hz), 7.61 (2H, d, J = 7.6Hz ), 7.78 (1 H, s).
MS m/z:558(M+H)+. MS m / z: 558 (M + H) +.
[0520] (2)2— [2—メトキシ一4— [[(2—メトキシベンジル)一 (3—メチルー 1一フエ-ルー 1H ピラゾール 4 ィルメチル)ァミノ]メチル]フエノキシ] 2 メチルプロピオン 酸 [0520] (2) 2- [2-Methoxy-1-4-[[(2-Methoxybenzyl)-((3-Methyl-11-Ferru 1H-Pyrazole-4-ylmethyl) amino] methyl] phenoxy] 2 Methylpropionic acid
[0521] [化 155]
[0521] [Chemical 155]
[0522] 実施例 2— (2)と同様にして、実施例 19— (1)で得たィ匕合物(105mg)から、標題 化合物(59mg)を無色油状物として得た。 Example 2- In the same manner as in (2), the title compound (59 mg) was obtained as a colorless oil from the compound (105 mg) obtained in Example 19- (1).
'H-NMR (400MHz, DMSO-d) δ :1.39 (6Η, s), 2. 12(3Η, s), 3.41(2 'H-NMR (400MHz, DMSO-d) δ: 1.39 (6Η, s), 2.12 (3Η, s), 3.41 (2
6 6
Η, s), 3.46 (2Η, s), 3.51 (2H, s), 3.70 (3H, s), 3.73 (3H, s), 6.77(1H , d, J = 8.1Hz), 6.82(1H, d, J=8.1Hz), 6.92— 6.95 (3H, m), 7.21(1 H, t, J = 7.6Hz), 7.41-7.48 (3H, m), 7.74 (2H, d, J = 7.8Hz), 8.31( 1H, s). Η, s), 3.46 (2Η, s), 3.51 (2H, s), 3.70 (3H, s), 3.73 (3H, s), 6.77 (1H, d, J = 8.1Hz), 6.82 (1H, d , J = 8.1Hz), 6.92— 6.95 (3H, m), 7.21 (1 H, t, J = 7.6Hz), 7.41-7.48 (3H, m), 7.74 (2H, d, J = 7.8Hz), 8.31 (1H, s).
MS m/z:530(M+H)+. MS m / z: 530 (M + H) +.
元素分析値 C H NO -3/4HO として Elemental analysis value as C H NO -3 / 4HO
31 35 3 5 2 31 35 3 5 2
計算値: C, 68.55;H, 6.77;N, 7.74. Calculated values: C, 68.55; H, 6.77; N, 7.74.
実測値: C, 68.59;H, 6.70 ;N, 7.53. Found: C, 68.59; H, 6.70; N, 7.53.
[0523] [実施例 20] [0523] [Example 20]
(1)2— [4— [[(5 クロ口一 3—メチノレ一 1—フエ-ノレ一 1H ピラゾーノレ一 4—ィノレ メチル)フラン一 2—ィルメチルァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 ェチノレ エステル (1) 2— [4 — [[(5 Black Mouth 3—Metinole 1—Phenol 1 1H Pyrazolone 1—4-Inole Methyl) Furan 2—Yylmethylamino] Methyl] Phenoxy] —2-Methylpropionic acid Ester
[0524] [化 156] [0524] [Chemical 156]
[0525] 実施例 6— (1)と同様にして、参考例 2— (2)で得たィ匕合物(250mg)と 5 クロ口— 3 メチル 1 フエ-ル 1H ピラゾール 4 カルバルデヒド( 174mg)から、標
題化合物(371mg)を無色油状物として得た。 [0525] Example 6— In the same manner as (1), the compound (250 mg) obtained in Reference Example 2 (2) and 5 × 3 methyl 1-phenol 1H pyrazole 4 carbaldehyde (174 mg) ) The title compound (371 mg) was obtained as a colorless oil.
iH—NMR (400MHz, DMSO d) δ :1.24 (3H, t, J = 7.1Hz), 1.58 (6H, iH—NMR (400MHz, DMSO d) δ: 1.24 (3H, t, J = 7.1Hz), 1.58 (6H,
6 6
s), 2.27 (3H, s), 3.47 (2H, s), 3.50 (2H, s), 3.59 (2H, s), 4.23 (2H, q , J = 7.1Hz), 6.19(1H, d, J = 3.2Hz), 6.32(1H, dd, J = 2.0, 3.2Hz), 6 .80 (2H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.6Hz), 7.34— 7.46 (4H, m), 7.50-7.53 (2H, m) . s), 2.27 (3H, s), 3.47 (2H, s), 3.50 (2H, s), 3.59 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.19 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.6Hz), 7.34— 7.46 (4H , m), 7.50-7.53 (2H, m).
MS m/z:521(M+H)+. MS m / z: 521 (M + H) + .
[0526] (2)2— [4— [[(5 クロ口一 3—メチル 1—フエ-ル一 1H ピラゾール一 4—ィル メチル)フラン一 2—ィルメチルァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 [0526] (2) 2— [4 — [[(5 Mouth 3-Methyl 1-Fel 1H 1 Pyrazole 1-Fil Methyl) Furan 2-ylmethylamino] Methyl] Phenoxy] —2-Methyl Propionic acid
[0527] [化 157] [0527] [Chemical 157]
[0528] 実施例 2— (2)と同様にして、実施例 20— (1)で得たィ匕合物(365mg)から、標題 化合物(268mg)を無色固体として得た。 Example 2- In the same manner as in (2), the title compound (268 mg) was obtained as a colorless solid from the compound (365 mg) obtained in Example 20- (1).
'H-NMR (400MHz, DMSO-d) δ :1.46 (6Η, s), 2. 16 (3Η, s), 3.42(2 'H-NMR (400MHz, DMSO-d) δ: 1.46 (6Η, s), 2.16 (3Η, s), 3.42 (2
6 6
H, s), 3.45 (2H, s), 3.55 (2H, s), 6.31 (1H, d, J = 3.2Hz), 6.40(1H, d d, J = 2.0, 3.2Hz), 6.77 (2H, d, J = 8.6Hz), 7. 19 (2H, d, J = 8.6Hz), 7 .40-7.45(1H, m), 7.48— 7.53 (4H, m), 7.61(1H, d, J = 2.0Hz) . MS m/z:494(M+H)+. H, s), 3.45 (2H, s), 3.55 (2H, s), 6.31 (1H, d, J = 3.2Hz), 6.40 (1H, dd, J = 2.0, 3.2Hz), 6.77 (2H, d , J = 8.6Hz), 7.19 (2H, d, J = 8.6Hz), 7.40-7.45 (1H, m), 7.48—7.53 (4H, m), 7.61 (1H, d, J = 2.0 Hz) .MS m / z: 494 (M + H) + .
元素分析値 C H C1N O · 1/4H Oとして Elemental analysis value C H C1N O · 1 / 4H O
27 28 3 4 2 27 28 3 4 2
計算値: C, 65.06;H, 5.76; CI, 7.11 ;N, 8.43. Calculated values: C, 65.06; H, 5.76; CI, 7.11; N, 8.43.
実測値: C, 64.86;H, 5.69; CI, 7.10;N, 8.21. Found: C, 64.86; H, 5.69; CI, 7.10; N, 8.21.
[0529] [実施例 21] [0529] [Example 21]
(1)2— [2—メトキシ一 4— [[(3—メチル 1—フエ-ル一 1H ピラゾール一 4—ィ ルメチル)一(3, 3, 3 トリフルォロプロピル)ァミノ]メチル]フエノキシ ]—2—メチル プロピオン酸 ェチノレ エステノレ
[0530] [化 158](1) 2- [2-Methoxy-1-4-[[((3-Methyl-1-phenol-1 1H-pyrazole-1-4-methyl)] ((3, 3, 3 trifluoropropyl) amino] methyl] phenoxy] —2—Methyl propionate [0530] [Chemical 158]
[0531] 実施例 8— (1)と同様にして、参考例 9— (3)で得たィ匕合物(120mg)と 3, 3, 3 ト リフルォロプロピオンアルデヒド(34mg)から、標題化合物(80mg)を無色油状物とし て得た。 [0531] In the same manner as in Example 8- (1), from the compound (120 mg) obtained in Reference Example 9- (3) and 3, 3, 3 trifluoropropionaldehyde (34 mg), the title was obtained. Compound (80 mg) was obtained as a colorless oil.
iH—NMR (400MHz, CDCl) δ :1.26 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2 iH—NMR (400MHz, CDCl) δ: 1.26 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2
3 Three
.22-2.28 (2H, m), 2.29 (3H, s), 2.73 (2H, t, J = 7.4Hz), 3.47 (2H, s ), 3.52 (2H, s), 3.80 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.75(1H, dd, J =2.0, 8.1Hz), 6.82(1H, d, J = 8.1Hz), 6.88(1H, d, J = 2. OHz), 7.23 (1H, t, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.60— 7.63 (2H, m), 7.75 (1H, s). .22-2.28 (2H, m), 2.29 (3H, s), 2.73 (2H, t, J = 7.4Hz), 3.47 (2H, s), 3.52 (2H, s), 3.80 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.75 (1H, dd, J = 2.0, 8.1Hz), 6.82 (1H, d, J = 8.1Hz), 6.88 (1H, d, J = 2. OHz) , 7.23 (1H, t, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.60—7.63 (2H, m), 7.75 (1H, s).
MS m/z:534(M+H)+. MS m / z: 534 (M + H) + .
[0532] (2) 2— [2—メトキシ一 4— [[ (3—メチル 1 フエ-ル一 1H ピラゾール一 4—ィ ルメチル)一(3, 3, 3 トリフルォロプロピル)ァミノ]メチル]フエノキシ ]—2—メチル プロピオン酸 [0532] (2) 2— [2-Methoxy-1-4- [[(3-Methyl 1-phenol 1H 1-Pyrazole 4- 4-methyl)] (3, 3, 3 trifluoropropyl) amino] methyl] Phenoxy] -2-methylpropionic acid
[0533] [化 159] [0533] [Chemical 159]
実施例 2— (2)と同様にして、実施例 21— (1)で得たィ匕合物(75mg)から、標題ィ匕 合物 (45mg)を無色固体として得た。 Example 2- In the same manner as (2), the title compound (45 mg) was obtained as a colorless solid from the compound (75 mg) obtained in Example 21- (1).
H-NMR (400MHz, DMSO d) δ :1.41 (6Η, s), 2. 19 (3H, s), 2.49—
2.54 (2H, m), 2.56— 2.67 (2H, m), 3.46 (2H, s), 3.51 (2H, s), 3.72 ( 3H, s), 6.79 (2H, s), 6.95(1H, s), 7.21— 7.25 (1H, m), 7.45 (2H, t, J =8.6Hz), 7.75 (2H, d, J = 8.6Hz), 8.33 (1H, s) . H-NMR (400MHz, DMSO d) δ: 1.41 (6Η, s), 2. 19 (3H, s), 2.49— 2.54 (2H, m), 2.56— 2.67 (2H, m), 3.46 (2H, s), 3.51 (2H, s), 3.72 (3H, s), 6.79 (2H, s), 6.95 (1H, s) , 7.21— 7.25 (1H, m), 7.45 (2H, t, J = 8.6Hz), 7.75 (2H, d, J = 8.6Hz), 8.33 (1H, s).
MS m/z:506(M+H)+. MS m / z: 506 (M + H) +.
[0535] [実施例 22] [0535] [Example 22]
(l)2-[4-[[[3-(4-フルオロフヱ-ル) 1 フエ-ル 1H ピラゾール 4 ィルメチル]フラン一 2—ィルメチルァミノ]メチル ]—2—メトキシフエノキシ]—2—メチ ルプロピオン酸 ェチル エステル (l) 2- [4-[[[3- (4-Fluorophenyl) 1 Phyl 1H Pyrazole 4-ylmethyl] furan-2-ylmethylamino] methyl] —2-methoxyphenoxy] —2-methyl Propionic acid ethyl ester
[0536] [化 160] [0536] [Chemical 160]
[0537] 実施例 9— (1)と同様にして、参考例 14— (2)で得た化合物と参考例 5— (1)で得 た化合物(92mg)から、標題化合物(207mg)を黄色油状物として得た。 In the same manner as in Example 9- (1), the title compound (207 mg) was obtained from the compound obtained in Reference Example 14- (2) and the compound obtained in Reference Example 5- (1) (92 mg) from yellow. Obtained as an oil.
MS m/z:598(M+H)+. MS m / z: 598 (M + H) +.
[0538] (2) 2— [4 [[ [3—(4 フルオロフェ -ル) 1 フエ-ル 1H ピラゾール 4 ィルメチル]フラン一 2—ィルメチルァミノ]メチル ]—2—メトキシフエノキシ]—2—メチ ルプロピオン酸 [0538] (2) 2— [4 [[[3- (4 Fluorophenol) 1 Phenol 1H Pyrazole 4-ylmethyl] furan 2-ylmethylamino] methyl] -2-Methoxyphenoxy] -2-Meth Lupropionic acid
[0539] [化 161] [0539] [Chemical 161]
[0540] 実施例 2— (2)と同様にして、実施例 22— (1)で得た化合物(204mg)から、標題 化合物(164mg)を淡黄色固体として得た。 Example 2- In the same manner as in (2), the title compound (164 mg) was obtained as a pale yellow solid from the compound (204 mg) obtained in Example 22- (1).
iH—NMR (400MHz, DMSO— d) δ :1.39 (6H, s), 3.53 (2H, s), 3.59(3 iH—NMR (400MHz, DMSO—d) δ: 1.39 (6H, s), 3.53 (2H, s), 3.59 (3
6 6
H, s), 3.61 (2H, s), 3.63 (2H, s), 6.33(1H, d, J = 2.9Hz), 6.42(1H, d d, J=l.7, 2.9Hz), 6.73 (2H, s), 6.83(1H, s), 7.20 (2H, t, J = 8.8Hz) , 7.31 (1H, t, J = 7.6Hz), 7.51 (2H, d, J = 7.6Hz), 7.69(1H, d, J=l.7 Hz), 7.88 (2H, d, J = 8.8Hz), 7.95— 7.99 (2H, m), 8.56 (1H, s) . H, s), 3.61 (2H, s), 3.63 (2H, s), 6.33 (1H, d, J = 2.9Hz), 6.42 (1H, dd, J = l.7, 2.9Hz), 6.73 (2H , s), 6.83 (1H, s), 7.20 (2H, t, J = 8.8Hz), 7.31 (1H, t, J = 7.6Hz), 7.51 (2H, d, J = 7.6Hz), 7.69 (1H , d, J = l.7 Hz), 7.88 (2H, d, J = 8.8Hz), 7.95—7.99 (2H, m), 8.56 (1H, s).
MS m/z:570(M+H)+. MS m / z: 570 (M + H) + .
元素分析値 C H FNO '3Z4HOとして Elemental analysis value as C H FNO '3Z4HO
33 32 3 5 2 33 32 3 5 2
計算値: C, 67.97;H, 5.79;N, 7.21. Calculated values: C, 67.97; H, 5.79; N, 7.21.
実測値: C, 68.14;H, 5.70 ;N, 7.19. Found: C, 68.14; H, 5.70; N, 7.19.
[0541] [実施例 23] [0541] [Example 23]
(1) 2— [4— [[力ルバモイルメチルー(5—メチルー 2—フエ-ルー 2H—[1, 2, 3]ト リアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチル プロピオン酸 ェチノレ エステノレ (1) 2— [4 — [[Strengthened rubermoylmethyl- (5-methyl-2-ferro- 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2,6-dimethyl Phenoxy] —2-methyl propionate ethenore estenore
[0542] [化 162] [0542] [Chemical 162]
[0543] 参考例 15—(4)で得た化合物(0.20g)と 2—ブロモアセタミド(0.095g)を N, N —ジメチルホルムアミド(5ml)に溶解し、炭酸カリウム(0.095g)をカ卩えて、 70°Cにて 一晩攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶液を加え、酢 酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥 後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(クロ口ホルム: メタノール =97 :3)で精製し、標題化合物(0.226g)を淡黄色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
. 19 (6H, s), 2.24 (3H, s), 3.26 (2H, s), 3.60 (2H, s), 3.72 (2H, s), 4. 29 (2H, q, J = 7.1Hz) , 5.42(1H, br s), 6.93 (2H, s), 7.14(1H, br s), 7.31 (1H, t, J = 7.4Hz), 7.46 (2H, t, J = 7.4Hz), 7.99 (2H, t, J = 7.6H z). [0543] Reference Example 15—Dissolve the compound (0.20 g) obtained in (4) and 2-bromoacetamide (0.095 g) in N, N —dimethylformamide (5 ml), and add potassium carbonate (0.095 g). And stirred at 70 ° C overnight. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 97: 3) to give the title compound (0.226 g) as a pale yellow oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 19 (6H, s), 2.24 (3H, s), 3.26 (2H, s), 3.60 (2H, s), 3.72 (2H, s), 4.29 (2H, q, J = 7.1Hz), 5.42 (1H, br s), 6.93 (2H, s), 7.14 (1H, br s), 7.31 (1H, t, J = 7.4Hz), 7.46 (2H, t, J = 7.4Hz), 7.99 (2H , t, J = 7.6H z).
MS m/z:494(M+H)+. MS m / z: 494 (M + H) + .
[0544] (2)2— [4— [[力ルバモイルメチル—(5—メチル—2—フエ-ル— 2H—[1, 2, 3]ト リアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチル プロピオン酸 [0544] (2) 2— [4— [[Strengthened rubermoylmethyl- (5-methyl-2-phenol—2H— [1, 2, 3] triazole-4-ylmethyl) amino] methyl] —2, 6-Dimethylphenoxy] —2-methylpropionic acid
[0545] [化 163] [0545] [Chemical 163]
[0546] 実施例 1— (2)と同様にして、実施例 23— (1)で得たィ匕合物 (0.226g)力も標題 化合物(0. 143g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.226 g) force obtained in Example 23- (1) was also used to give the title compound (0.143 g) as a colorless solid.
iH—NMR (400MHz, DMSO d) δ :1.32 (6H, s), 2. 13 (6H, s), 2.22(3 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 13 (6H, s), 2.22 (3
6 6
H, s), 3.06 (2H, s), 3.57 (2H, s), 3.73 (2H, s), 6.99 (2H, s), 7.09 (1H , br s), 7.16 (1H, br s), 7.36 (1H, t, J = 7.4Hz), 7.53 (2H, t, J = 7.8H z), 7.93 (2H, t, J = 7.8Hz). H, s), 3.06 (2H, s), 3.57 (2H, s), 3.73 (2H, s), 6.99 (2H, s), 7.09 (1H, br s), 7.16 (1H, br s), 7.36 (1H, t, J = 7.4Hz), 7.53 (2H, t, J = 7.8Hz), 7.93 (2H, t, J = 7.8Hz).
MS m/z:466(M+H)+. MS m / z: 466 (M + H) +.
[0547] [実施例 24] [0547] [Example 24]
(1)2— [2, 6 ジメチルー 4 [[メチルカルバモイルメチルー(5—メチルー 2 フエ -ル— 2H— [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル]フエノキシ ]—2 メチルプロピオン酸 ェチル エステル (1) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-phenol-2H- [1,2,3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 methylpropion Acid ethyl ester
[0548] [化 164]
[0548] [Chemical 164]
[0549] 参考例 12で得たィ匕合物(0.13g)をジクロロメタン (4ml)に溶解し、氷水冷却下にト リエチノレアミン(0. 124ml)と塩ィ匕メタンスノレホニノレ(0.064ml)をカロえて、 1.5時間 攪拌した。反応液に水を加え、ジクロロメタンで 3回抽出した。有機層を飽和食塩水で 洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣を N, N ジメチ ルホルムアミド (4ml)に溶解し、参考例 16— (2)で得た化合物(0.175g)と炭酸カリ ゥム(0.095g)を加えて、 70°Cで一晩攪拌した。反応液を減圧下濃縮し、残渣に炭 酸水素ナトリウム水溶液を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で 洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラ ムクロマトグラフィー(酢酸ェチル:へキサン =3 :2)で精製し、標題化合物(0.262g )を無色油状物として得た。 [0549] The compound (0.13 g) obtained in Reference Example 12 was dissolved in dichloromethane (4 ml). Stir for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the residue in N, N-dimethylformamide (4 ml), add the compound (0.175 g) obtained in Reference Example 16- (2) and potassium carbonate (0.095 g), and stir at 70 ° C overnight. did. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (0.262 g) as a colorless oil.
[0550] 'H-NMR (400MHz, CDC1 ) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s) [0550] 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)
3 Three
, 2.24 (3H, s), 2.80 (3H, d, J = 5. 1Hz), 3.25 (2H, s), 3.58 (2H, s), 3. , 2.24 (3H, s), 2.80 (3H, d, J = 5.1 Hz), 3.25 (2H, s), 3.58 (2H, s), 3.
69 (2H, s), 6.90 (2H, s), 7.23— 7.26 (1H, m), 7.31 (1H, t, J = 7.6Hz)69 (2H, s), 6.90 (2H, s), 7.23— 7.26 (1H, m), 7.31 (1H, t, J = 7.6Hz)
, 7.46 (2H, t, J = 7.6Hz), 7.99 (2H, d, J = 7.6Hz) . , 7.46 (2H, t, J = 7.6Hz), 7.99 (2H, d, J = 7.6Hz).
MS m/z:536(M+H)+. MS m / z: 536 (M + H) +.
[0551] (2)2— [2, 6 ジメチルー 4 [[メチルカルバモイルメチルー(5—メチルー 2 フエ[0551] (2) 2— [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-phenol
-ル— 2H— [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル]フエノキシ ]—2 メチルプロピオン酸 -Lu-2H— [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] —2 methylpropionic acid
[0552] [化 165]
[0552] [Chemical 165]
[0553] 実施例 24— (1)で得たィ匕合物(0.257g)をジクロロメタン(3ml)に溶解し、 4規定 塩酸—ジォキサン溶液(2ml)を加えて、室温で 4日間攪拌した。反応液を減圧下濃 縮し、残渣をシリカゲルカラムクロマトグラフィー(クロ口ホルム:メタノール = 92: 8)で 精製し、標題化合物 (0.186g)を無色固体として得た。 Example 24— The compound (0.257 g) obtained in (1) was dissolved in dichloromethane (3 ml), 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 92: 8) to give the title compound (0.186 g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.31 (6Η, s), 2. 13 (6Η, s), 2.21(3 'H-NMR (400MHz, DMSO-d) δ: 1.31 (6Η, s), 2.13 (6Η, s), 2.21 (3
6 6
H, s), 2.57 (3H, d, J=4.7Hz), 3.08 (2H, s), 3.56 (2H, s), 3.70 (2H, s H, s), 2.57 (3H, d, J = 4.7Hz), 3.08 (2H, s), 3.56 (2H, s), 3.70 (2H, s
), 6.99 (2H, s), 7.35(1H, t, J = 7.6Hz), 7.52 (2H, t, J = 7.6Hz), 7.58), 6.99 (2H, s), 7.35 (1H, t, J = 7.6Hz), 7.52 (2H, t, J = 7.6Hz), 7.58
(1H, q, J = 4.7Hz), 7.92 (2H, t, J = 7.6Hz) . (1H, q, J = 4.7Hz), 7.92 (2H, t, J = 7.6Hz).
MS m/z:480(M+H)+. MS m / z: 480 (M + H) + .
[0554] [実施例 25] [0554] [Example 25]
(1) 2— [4— [[ジメチルカルバモイルメチルー(5—メチルー 2—フエ-ルー 2H— [1 (1) 2— [4 — [[Dimethylcarbamoylmethyl- (5-methyl-2-phenol-2H— [1
, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—, 2, 3] triazol-4-ylmethyl) amino] methyl] —2,6-dimethylphenoxy] —
2—メチルプロピオン酸 ェチル エステル 2-Methylpropionic acid ethyl ester
[0555] [化 166] [0555] [Chemical 166]
参考例 17— (3)で得たィ匕合物(0.250g)、ジメチルァミン塩酸塩 (0.062g)、 1— ェチルー 3—(3—ジメチルァミノプロピル)カルボジイミド塩酸塩(0.116g)、 1ーヒド ロキシベンゾトリアゾール水和物(0.093g)と N—メチルモルホリン(0.083ml)を N
, N—ジメチルホルムアミド (4ml)に溶解し、室温で 3日間攪拌した。反応液を減圧下 濃縮し、残渣に炭酸水素ナトリウム水溶液を加え、酢酸ェチルで 3回抽出した。有機 層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残 渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 3: 2)で精製し、標 題化合物(0.202g)を無色油状物として得た。 Reference Example 17—Compound obtained in (3) (0.250 g), dimethylamine hydrochloride (0.062 g), 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.116 g), 1-hydride Roxybenzotriazole hydrate (0.093g) and N-methylmorpholine (0.083ml) , N-dimethylformamide (4 ml) and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (0.202 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 18 (6H, s), 2.25 (3H, s), 2.82 (3H, s), 2.91 (3H, s), 3.33 (2H, s), 3. 18 (6H, s), 2.25 (3H, s), 2.82 (3H, s), 2.91 (3H, s), 3.33 (2H, s), 3.
62 (3H, s), 3.80 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.94 (2H, s), 7.29 (62 (3H, s), 3.80 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.94 (2H, s), 7.29 (
1H, t, J = 7.5Hz), 7.45 (2H, t, J = 7.5Hz), 7.99 (2H, d, J = 7.5Hz) .1H, t, J = 7.5Hz), 7.45 (2H, t, J = 7.5Hz), 7.99 (2H, d, J = 7.5Hz).
MS m/z:522(M+H)+. MS m / z: 522 (M + H) + .
[0557] (2) 2— [4— [[ジメチルカルバモイルメチルー(5—メチルー 2—フエ-ルー 2H—[1[0557] (2) 2— [4— [[Dimethylcarbamoylmethyl- (5-methyl-2-phenol-2H— [1
, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—, 2, 3] triazol-4-ylmethyl) amino] methyl] —2,6-dimethylphenoxy] —
2—メチルプロピオン酸 2-Methylpropionic acid
[0558] [化 167] [0558] [Chemical 167]
[0559] 実施例 1— (2)と同様にして、実施例 25— (1)で得たィ匕合物 (0.197g)力も標題 化合物(0. 167g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.197 g) force obtained in Example 25- (1) was also used to give the title compound (0.167 g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.32 (6Η, s), 2. 11 (6Η, s), 2.19(3 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6 Η, s), 2. 11 (6 Η, s), 2.19 (3
6 6
H, s), 2.79 (3H, s), 2.83 (3H, s), 3.32 (2H, s), 3.58 (3H, s), 3.77 (2H , s), 6.90 (2H, s), 7.35(1H, t, J = 7.6Hz), 7.52 (2H, d, J = 7.6Hz), 7. 92 (2H, d, J = 7.6Hz). H, s), 2.79 (3H, s), 2.83 (3H, s), 3.32 (2H, s), 3.58 (3H, s), 3.77 (2H, s), 6.90 (2H, s), 7.35 (1H , t, J = 7.6Hz), 7.52 (2H, d, J = 7.6Hz), 7. 92 (2H, d, J = 7.6Hz).
MS m/z:494(M+H)+. MS m / z: 494 (M + H) + .
[0560] [実施例 26] [0560] [Example 26]
(1)2— [2, 6—ジメチルー 4— [[[5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ
ルメチル]— (5—メチル— 2—フエ-ルー 2H— [1, 2, 3]トリァゾールー 4—ィルメチ ル)ァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 ェチル エステル (1) 2— [2, 6-Dimethyl- 4 -— [[[5-Methyl- [1, 3, 4] Oxadiazo 2-L Rumethyl] — (5-Methyl-2-Fe-Lu 2H— [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] —2-methylpropionic acid ethyl ester
[0561] [化 168] [0561] [Chemical 168]
[0562] トリフエ-ルホスフィン(0.244g)をテトラヒドロフラン(5ml)に溶解し、氷水冷却下 にへキサクロロェタン (0.186g)を加えて 15分攪拌した。ここにトリェチルァミン (0.2 59ml)と参考例 18で得た化合物(0.160g)を加え、室温で一晩攪拌した。反応液 に飽和食塩水を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、 無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマ トグラフィー(酢酸ェチル:へキサン =3 :2)で精製し、標題化合物(0.141g)を無色 油状物として得た。 Triphenylphosphine (0.244 g) was dissolved in tetrahydrofuran (5 ml), and hexachloroethane (0.186 g) was added with cooling with ice water, followed by stirring for 15 minutes. To this, triethylamine (0.259 ml) and the compound obtained in Reference Example 18 (0.160 g) were added, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (0.141 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 18 (6H, s), 2.28 (3H, s), 2.52 (3H, s), 3.64 (2H, s), 3.82 (2H, s), 3. 18 (6H, s), 2.28 (3H, s), 2.52 (3H, s), 3.64 (2H, s), 3.82 (2H, s), 3.
93 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 6.95 (2H, s), 7.29 (1H, t, J=7.6H z), 7.45 (2H, t, J = 7.6Hz), 7.99 (2H, d, J = 7.6Hz) . 93 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.95 (2H, s), 7.29 (1H, t, J = 7.6H z), 7.45 (2H, t, J = 7.6Hz) , 7.99 (2H, d, J = 7.6Hz).
MS m/z:533(M+H)+. MS m / z: 533 (M + H) +.
[0563] (2) 2- [2, 6—ジメチルー 4— [[[5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ ルメチル]— (5—メチル— 2—フエ-ルー 2H— [1, 2, 3]トリァゾールー 4—ィルメチ ル)ァミノ]メチル]フエノキシ ]ー2—メチルプロピオン酸 [0563] (2) 2- [2, 6-Dimethyl-4-[[[[5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl]-(5-Methyl-2-Fe-Lu 2H- [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid
[0564] [化 169]
[0564] [Chemical 169]
[0565] 実施例 1— (2)と同様にして、実施例 26— (1)で得たィ匕合物(0.135g)力も標題 化合物(0. 112g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.135 g) force obtained in Example 26- (1) also gave the title compound (0.112 g) as a colorless solid.
iH—NMR (400MHz, DMSO d) δ :1.32 (6H, s), 2. 12(6H, s), 2.22(3 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3
6 6
H, s), 2.45 (3H, s), 3.60 (2H, s), 3.80 (2H, s), 3.90 (2H, s), 6.93 (2H , s), 7.36(1H, t, J = 7.6Hz), 7.53 (2H, t, J=7.6Hz), 7.92 (2H, d, J = 7 .6Hz) . H, s), 2.45 (3H, s), 3.60 (2H, s), 3.80 (2H, s), 3.90 (2H, s), 6.93 (2H, s), 7.36 (1H, t, J = 7.6Hz ), 7.53 (2H, t, J = 7.6Hz), 7.92 (2H, d, J = 7.6Hz).
MS m/z:505(M+H)+. MS m / z: 505 (M + H) +.
[0566] [実施例 27] [0566] [Example 27]
(1)2— [4— [[(3—メトキシプロピル)一(5—メチル 2—フエ-ル一 2H—[1, 2, 3 ]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 ェチル エステル (1) 2- [4-[[(3-Methoxypropyl) mono (5-methyl-2-phenyl) 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 Dimethylphenoxy] -2-methylpropionic acid ethyl ester
[0567] [化 170] [0567] [Chemical 170]
参考例 15— ( 1)で得た化合物(0.10g)と参考例 19で得た化合物(0.134g)を N , N—ジメチルホルムアミド(4ml)に溶解し、炭酸カリウム(0.066g)を加えて、 70°C で 3.5時間攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶液を 加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウ
ムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢 酸ェチル:へキサン =1:4)で精製し、標題化合物(0.202g)を無色油状物として得 た。 Reference Example 15— The compound (0.10 g) obtained in (1) and the compound (0.134 g) obtained in Reference Example 19 were dissolved in N 2, N-dimethylformamide (4 ml), and potassium carbonate (0.066 g) was added. The mixture was stirred at 70 ° C for 3.5 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated saline and anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (0.202 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1
3 Three
.79 (2H, quint, J = 6.9Hz), 2. 17(6H, s), 2.26 (3H, s), 2.56 (2H, t, J = 6.9Hz), 3.25 (3H, s), 3.36 (2H, t, J = 6.6Hz), 3.48 (2H, s), 3.64(2 .79 (2H, quint, J = 6.9Hz), 2.17 (6H, s), 2.26 (3H, s), 2.56 (2H, t, J = 6.9Hz), 3.25 (3H, s), 3.36 ( 2H, t, J = 6.6Hz), 3.48 (2H, s), 3.64 (2
H, s), 4.28 (2H, q, J = 7.1Hz) , 6.92 (2H, s) , 7.27(1H, t, J = 6.4Hz), 7H, s), 4.28 (2H, q, J = 7.1Hz), 6.92 (2H, s), 7.27 (1H, t, J = 6.4Hz), 7
.44 (2H, t, J = 7.6Hz), 7.98 (2H, t, J = 7.6Hz) . .44 (2H, t, J = 7.6Hz), 7.98 (2H, t, J = 7.6Hz).
MS m/z:509(M+H)+. MS m / z: 509 (M + H) +.
[0569] (2)2— [4— [[(3—メトキシプロピル)一(5—メチル 2 フエ-ル一 2H—[1, 2, 3[0569] (2) 2— [4— [[(3-Methoxypropyl) -one (5-methyl-2-phenyl) 2H— [1, 2, 3
]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 ] Triazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid
[0570] [化 171] [0570] [Chemical 171]
実施例 1— (2)と同様にして、実施例 27— (1)で得たィ匕合物 (0.202g)力も標題 化合物(0. 114g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.202 g) force obtained in Example 27- (1) also gave the title compound (0.114 g) as a colorless solid.
iH—NMR (400MHz, DMSO d) δ :1.31 (6H, s), 1.70 (2H, quint, J = 6 iH—NMR (400MHz, DMSO d) δ: 1.31 (6H, s), 1.70 (2H, quint, J = 6
6 6
. 1Hz), 2.12(6H, s), 2.23 (3H, s), 2.47 (2H, t, J = 6.1Hz), 3.11 (3H, s), 3.29 (2H, t, J = 6.1Hz), 3.44 (2H, s), 3.62 (2H, s), 6.91 (2H, s), 7 .35(1H, t, J = 7.4Hz), 7.52 (2H, t, J = 7.6Hz), 7.92 (2H, t, J = 7.6Hz) 元素分析値 C H NO '1Z4HOとして 1Hz), 2.12 (6H, s), 2.23 (3H, s), 2.47 (2H, t, J = 6.1Hz), 3.11 (3H, s), 3.29 (2H, t, J = 6.1Hz), 3.44 (2H, s), 3.62 (2H, s), 6.91 (2H, s), 7.35 (1H, t, J = 7.4Hz), 7.52 (2H, t, J = 7.6Hz), 7.92 (2H, t, J = 7.6Hz) Elemental analysis CH NO '1Z4HO
27 36 4 4 2 27 36 4 4 2
計算値: C, 66.85;H, 7.58;N, 11.55.
実測値: C, 66.77;H, 7.63;N, 11.32. Calculated value: C, 66.85; H, 7.58; N, 11.55. Found: C, 66.77; H, 7.63; N, 11.32.
[0572] [実施例 28] [0572] [Example 28]
(1)2—[4ー[[(2—メトキシェチル)ー(5—メチルー2—フヱ-ルー211—[1, 2, 3] トリァゾール— 4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチ ルプロピオン酸 tert—ブチル エステル (1) 2- [4-[[(2-Methoxyethyl)-(5-Methyl-2-Flu-Lu 211- [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] -2, 6- Dimethylphenoxy] -2-methylpropionic acid tert-butyl ester
[0573] [化 172] [0573] [Chemical 172]
[0574] 参考例 12で得たィ匕合物(0.130g)をジクロロメタン (4ml)に溶解し、氷水冷却下ト リエチノレアミン(0. 124ml)と塩ィ匕メタンスノレホニノレ(0.064ml)をカロえて、 1.5時間 攪拌した。反応液に水を加え、ジクロロメタンで 3回抽出した。有機層を飽和食塩水で 洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣を N, N—ジメチ ルホルムアミド (4ml)に溶解し、参考例 20で得た化合物(0.169g)と炭酸カリウム (0 .095g)を加えて、 70°Cで一晩攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素 ナトリウム水溶液を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し 、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロ マトグラフィー(酢酸ェチル:へキサン =1:4)で精製し、標題化合物(0.263g)を無 色油状物として得た。 [0574] The compound (0.130 g) obtained in Reference Example 12 was dissolved in dichloromethane (4 ml). Stir for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (4 ml), the compound (0.169 g) obtained in Reference Example 20 and potassium carbonate (0.095 g) were added, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (0.263 g) as a colorless oil.
[0575] 'H-NMR (400MHz, CDC1 ) δ :1.41 (6Η, s) , 1.51 (9Η, s), 2.20 (6Η, s) [0575] 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.20 (6Η, s)
3 Three
, 2.29 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (2H, s), 3.50 (3H, t, J = 5 .9Hz), 3.56 (2H, s), 3.74 (2H, s), 6.93 (2H, s), 7.26— 7.29(1H, m), 7.44 (2H, t, J = 8.6Hz), 7.99 (2H, d, J = 8. Hz). , 2.29 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (2H, s), 3.50 (3H, t, J = 5.9Hz), 3.56 (2H, s), 3.74 (2H , s), 6.93 (2H, s), 7.26— 7.29 (1H, m), 7.44 (2H, t, J = 8.6Hz), 7.99 (2H, d, J = 8. Hz).
MS m/z:522(M+H)+. MS m / z: 522 (M + H) + .
[0576] (2) 2— [4— [[(2—メトキシェチル)一(5—メチルー 2—フエ-ルー 2H—[1, 2, 3] トリァゾール— 4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチ
ルプロピオン酸 [0576] (2) 2— [4— [[(2-Methoxyethyl) mono (5-methyl-2-phenol-2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6-dimethylphenoxy] -2-methyl Lupropionic acid
[0577] [化 173] [0577] [Chemical 173]
[0578] 実施例 24— (2)と同様にして、実施例 28— (1)で得たィ匕合物(0.258g)力も標題 化合物(0. 175g)を無色固体として得た。 Example 24-—In the same manner as (2), the compound (0.258 g) force obtained in Example 28- (1) was also used to give the title compound (0.175 g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.30 (6Η, s), 2. 11 (6Η, s), 2.23(3 'H-NMR (400MHz, DMSO-d) δ: 1.30 (6Η, s), 2. 11 (6Η, s), 2.23 (3
6 6
H, s), 2.62 (2H, t, J = 5.9Hz), 3.18 (3H, s), 3.44 (2H, t, J = 5.9Hz), 3 .49 (2H, s), 3.69 (2H, s), 6.91 (2H, s), 7.34(1H, t, J = 7.6Hz), 7.51( 2H, t, J = 7.6Hz), 7.91 (2H, t, J = 7.6Hz) . H, s), 2.62 (2H, t, J = 5.9Hz), 3.18 (3H, s), 3.44 (2H, t, J = 5.9Hz), 3.49 (2H, s), 3.69 (2H, s ), 6.91 (2H, s), 7.34 (1H, t, J = 7.6Hz), 7.51 (2H, t, J = 7.6Hz), 7.91 (2H, t, J = 7.6Hz).
元素分析値 C H NO '1Z4HOとして Elemental analysis value as C H NO '1Z4HO
26 34 4 4 2 26 34 4 4 2
計算値: C, 66.29;H, 7.38;N, 11.89. Calculated value: C, 66.29; H, 7.38; N, 11.89.
実測値: C, 66.37;H, 7.44 ;N, 11.45. Found: C, 66.37; H, 7.44; N, 11.45.
[0579] [実施例 29] [0579] [Example 29]
(1)2— [4— [[(2—メトキシメチル)—(5—メチル—2— p—トリル— 2H—[1, 2, 3] トリァゾール— 4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチ ルプロピオン酸 tert—ブチル エステル (1) 2- [4 -— [[(2-Methoxymethyl)-(5-methyl-2-p-tolyl-2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2 6-Dimethylphenoxy] -2-methylpropionic acid tert-butyl ester
[0580] [化 174] [0580] [Chemical 174]
参考例 21— (5)で得たィ匕合物(0.12g)と参考例 20で得たィ匕合物(0.174g)を N , N—ジメチルホルムアミド (4ml)に溶解し、炭酸カリウム(0.075g)をカ卩えて、 70°C
で 3日間攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶液を加え 、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで 乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェ チル:へキサン =1:6)で精製し、標題化合物(0.242g)を無色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.41 (6Η, s), 1.51 (9Η, s), 2.20 (6H, s) Reference Example 21— The compound (0.12 g) obtained in (5) and the compound (0.174 g) obtained in Reference Example 20 were dissolved in N 2, N-dimethylformamide (4 ml), and potassium carbonate ( 0.075g), 70 ° C For 3 days. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to give the title compound (0.242 g) as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.20 (6H, s)
3 Three
, 2.29 (3H, s), 2.38 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.29 (3H, s), 3. , 2.29 (3H, s), 2.38 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.29 (3H, s), 3.
50 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.73 (2H, s), 6.93 (2H, s), 7.23(250 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.73 (2H, s), 6.93 (2H, s), 7.23 (2
H, d, J=8.6Hz), 7.86 (2H, d, J = 8.6Hz) . H, d, J = 8.6Hz), 7.86 (2H, d, J = 8.6Hz).
MS m/z:537(M+H)+. MS m / z: 537 (M + H) + .
[0582] (2)2— [4— [[(2—メトキシメチル)—(5—メチル—2— p トリル— 2H—[1, 2, 3] トリァゾール— 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチ ルプロピオン酸 [0582] (2) 2 -— [4 -— [[(2-Methoxymethyl)-(5-methyl-2-p-tolyl-2H— [1, 2, 3] triazole-4-ylmethyl) amino] methyl] — 2, 6-Dimethylphenoxy] —2-methylpropionic acid
[0583] [化 175] [0583] [Chemical 175]
[0584] 実施例 24— (2)と同様にして、実施例 29— (1)で得た化合物(0.242g)力も標題 化合物 (0.217g)を淡褐色固体として得た。 Example 24—In the same manner as in (2), the compound (0.242 g) strength obtained in Example 29- (1) was also used to obtain the title compound (0.217 g) as a light brown solid.
iH—NMR (400MHz, DMSO d) δ :1.32 (6H, s), 2. 12(6H, s), 2.22(3 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3
6 6
H, s), 2.34 (3H, s), 2.63 (2H, t, J = 5.9Hz), 3.19 (3H, s), 3.45 (2H, t , J = 5.9Hz), 3.50 (2H, s), 3.68 (2H, s), 6.92 (2H, s), 7.32 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz) . H, s), 2.34 (3H, s), 2.63 (2H, t, J = 5.9Hz), 3.19 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3.50 (2H, s), 3.68 (2H, s), 6.92 (2H, s), 7.32 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz).
MS m/z:481(M+H)+. MS m / z: 481 (M + H) +.
[0585] [実施例 30] [0585] [Example 30]
( 1 ) 2— [ 2, 6 ジメチル 4 [ [メチルカルバモイルメチル ( 5 メチル 2— p— トリル—2H—[1, 2, 3]トリァゾールー 4 ィルメチル)ァミノ]メチル]フエノキシ ]ー2
メチルプロピオン酸 tert ブチル エステル (1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl (5 Methyl 2- p-Tolyl-2H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 Methylpropionic acid tert butyl ester
[0586] [化 176] [0586] [Chemical 176]
[0587] 参考例 21— (5)で得た化合物(0.120g)と参考例 16— (2)で得た化合物(0.18 lg)を N, N ジメチルホルムアミド(4ml)に溶解し、炭酸カリウム(0.075g)をカロえ て、 70°Cで 3日間攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶 液を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナ トリウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸ェチル:へキサン =3 :2)で精製し、標題化合物(0.248g)を無色油状物とし て得た。 [0587] Reference Example 21- Compound (0.120 g) obtained in (5) and Reference Example 16- (2) (0.18 lg) were dissolved in N, N dimethylformamide (4 ml), and potassium carbonate ( 0.075 g) was added and stirred at 70 ° C for 3 days. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (0.248 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s) 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)
3 Three
, 2.24 (3H, s), 2.39 (3H, s), 2.80 (3H, d, J = 5.1Hz), 3.25 (3H, s), 3. , 2.24 (3H, s), 2.39 (3H, s), 2.80 (3H, d, J = 5.1Hz), 3.25 (3H, s), 3.
57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.26 (2H, d, J = 8.3Hz), 7.87 (57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.26 (2H, d, J = 8.3Hz), 7.87 (
2H, d, J = 8.3Hz). (2H, d, J = 8.3Hz).
MS m/z:550(M+H)+. MS m / z: 550 (M + H) +.
[0588] (2)2— [2, 6 ジメチルー 4 [[メチルカルバモイルメチルー(5—メチルー 2— p— トリル—2H—[1, 2, 3]トリァゾールー 4 ィルメチル)ァミノ]メチル]フエノキシ ]ー2 メチルプロピオン酸 [0588] (2) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-p-tolyl-2H- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] phenoxy]- 2 Methylpropionic acid
[0589] [化 177] [0589] [Chemical 177]
[0590] 実施例 24— (2)と同様にして、実施例 30— (1)で得た化合物(0.248g)カゝら標題 化合物(0.209g)を無色固体として得た。 Example 24—In the same manner as in (2), the title compound (0.209 g) was obtained as a colorless solid from the compound (0.248 g) obtained in Example 30- (1).
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 14 (6Η, s), 2.21(3 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.21 (3
6 6
H, s), 2.35 (3H, s), 2.58 (3H, d, J=4.7Hz), 3.08 (3H, s), 3.56 (2H, s ), 3.57 (2H, s), 3.69 (2H, s), 7.00 (2H, s), 7.33 (2H, d, J = 8.3Hz), 7 .58 (1H, q, J=4.7Hz) , 7.81 (2H, d, J = 8.3Hz) . H, s), 2.35 (3H, s), 2.58 (3H, d, J = 4.7Hz), 3.08 (3H, s), 3.56 (2H, s), 3.57 (2H, s), 3.69 (2H, s ), 7.00 (2H, s), 7.33 (2H, d, J = 8.3Hz), 7.58 (1H, q, J = 4.7Hz), 7.81 (2H, d, J = 8.3Hz).
MS m/z:494(M+H)+. MS m / z: 494 (M + H) + .
[0591] [実施例 31] [0591] [Example 31]
(1)2— [2, 6—ジメチルー 4— [[(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ ルメチル)—(5—メチル— 2— p—トリル— 2H— [1, 2, 3]トリァゾール— 4—ィルメチ ル)ァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 ェチル エステル (1) 2— [2, 6-Dimethyl-4-[[((5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(5-Methyl-2-p-tolyl-2H- [1 , 2, 3] triazole—4-methyl) amino] methyl] phenoxy] —2-methylpropionic acid ethyl ester
[0592] [化 178] [0592] [Chemical 178]
[0593] 参考例 21— (5)で得た化合物(0.120g)と参考例 22— (5)で得た化合物(0.12 0g)を N, N—ジメチルホルムアミド(4ml)に溶解し、炭酸カリウム(0.055g)をカロえ て、 70°Cで一晩攪拌した。反応液を減圧下濃縮し、残渣に炭酸水素ナトリウム水溶 液を加え、酢酸ェチルで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナ トリウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸ェチル:へキサン =2 :3)で精製し、標題化合物(0.149g)を無色油状物とし て得た。 [0593] Reference Example 21— Compound (0.120 g) obtained in (5) and Reference Example 22— Compound (0.120 g) obtained in (5) were dissolved in N, N-dimethylformamide (4 ml), and potassium carbonate was dissolved. (0.055 g) was added and stirred at 70 ° C overnight. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to give the title compound (0.149 g) as a colorless oil.
[0594] 'H-NMR (400MHz, CDC1 ) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 [0594] 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 18 (6H, s), 2.27 (3H, s), 2.38 (3H, s), 2.52 (3H, s), 3.65 (2H, s), 3. 82 (2H, s), 3.93 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.96 (2H, s), 7.24 (
2H, d, J = 8.6Hz), 7.86 (2H, d, J = 8.6Hz) . 18 (6H, s), 2.27 (3H, s), 2.38 (3H, s), 2.52 (3H, s), 3.65 (2H, s), 3.82 (2H, s), 3.93 (2H, s ), 4.29 (2H, q, J = 7.1Hz), 6.96 (2H, s), 7.24 ( 2H, d, J = 8.6Hz), 7.86 (2H, d, J = 8.6Hz).
MS m/z:547(M+H)+. MS m / z: 547 (M + H) + .
[0595] (2) 2- [2, 6 ジメチルー 4— [[(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ ルメチル)—(5—メチル 2— p トリル— 2H— [1, 2, 3]トリァゾール— 4—ィルメチ ル)ァミノ]メチル]フエノキシ ]ー2—メチルプロピオン酸 [0595] (2) 2- [2, 6 Dimethyl 4 -— [[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(5-Methyl-2-p-tolyl-2H- [1 , 2, 3] triazole-4-methyl) amino] methyl] phenoxy] -2-methylpropionic acid
[0596] [化 179] [0596] [Chemical 179]
[0597] 実施例 1— (2)と同様にして、実施例 31— (1)で得たィ匕合物 (0.145g)力も標題 化合物(0. 134g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.145 g) force obtained in Example 31- (1) was also used to obtain the title compound (0.134 g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.32 (6Η, s), 2. 13 (6Η, s), 2.21(3 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.13 (6Η, s), 2.21 (3
6 6
H, s), 2.35 (3H, s), 2.45 (3H, s), 3.59 (2H, s), 3.78 (2H, s), 3.89 (2H , s), 6.93 (2H, s), 7.32 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz) . MS m/z:519(M+H)+. H, s), 2.35 (3H, s), 2.45 (3H, s), 3.59 (2H, s), 3.78 (2H, s), 3.89 (2H, s), 6.93 (2H, s), 7.32 (2H , d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz) .MS m / z: 519 (M + H) +.
[0598] [実施例 32] [0598] [Example 32]
(1)2— [4— [[(3—メトキシプロピル)一(5—メチル 2— p トリル一 2H—[1, 2, 3 ]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 ェチル エステル (1) 2- [4-[[(3-Methoxypropyl) mono (5-methyl-2-p-tolyl 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 dimethyl Phenoxy] -2-methylpropionic acid ethyl ester
[0599] [化 180] [0599] [Chemical 180]
[0600] 実施例 27— (1)と同様にして、参考例 21— (5)で得たィ匕合物 (0.138g)と参考例 19で得たィ匕合物(0.176g)力も標題ィ匕合物(0.218g)を無色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1 Example 27— In the same manner as (1), the force of the compound (0.138 g) obtained in Reference Example 21- (5) and the compound (0.176 g) obtained in Reference Example 19 Compound (0.218 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1
3 Three
.79 (2H, quint, J = 6.9Hz), 2. 18 (6H, s), 2.26 (3H, s), 2.38 (3H, s), 2 .79 (2H, quint, J = 6.9Hz), 2. 18 (6H, s), 2.26 (3H, s), 2.38 (3H, s), 2
.55 (2H, t, J = 6.9Hz), 3.25 (3H, s), 3.35 (2H, t, J = 6.9Hz), 3.47 (2H.55 (2H, t, J = 6.9Hz), 3.25 (3H, s), 3.35 (2H, t, J = 6.9Hz), 3.47 (2H
, s), 3.63 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 6.92 (2H, s), 7.23 (2H, d, J, s), 3.63 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.92 (2H, s), 7.23 (2H, d, J
=8.6Hz), 7.85 (2H, d, J = 8.6Hz) . = 8.6Hz), 7.85 (2H, d, J = 8.6Hz).
MS m/z:523(M+H)+. MS m / z: 523 (M + H) + .
[0601] (2)2— [4— [[(3—メトキシプロピル)一(5—メチル 2— p トリル一 2H—[1, 2, 3[0601] (2) 2— [4— [[(3-Methoxypropyl) mono (5-methyl-2-p-tolyl) 2H— [1, 2, 3
]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 ] Triazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid
[0602] [化 181] [0602] [Chemical 181]
[0603] 実施例 1— (2)と同様にして、実施例 32— (1)で得たィ匕合物(0.213g)から標題 化合物(0. 163g)を無色固体として得た。このものを 4規定塩酸—ジォキサン溶液に 溶解し、減圧下濃縮乾固することにより標題ィ匕合物の塩酸塩を無色固体として得た。 'H-NMR (400MHz, DMSO-d) δ :1.36 (6Η, s), 2. 17(6Η, s), 2.28(3 [0603] In the same manner as in Example 1- (2), the title compound (0.163 g) was obtained as a colorless solid from the compound (0.213 g) obtained in Example 32- (1). This was dissolved in 4N hydrochloric acid-dioxane solution and concentrated to dryness under reduced pressure to obtain the hydrochloride of the title compound as a colorless solid. 'H-NMR (400MHz, DMSO-d) δ: 1.36 (6Η, s), 2.17 (6Η, s), 2.28 (3
6 6
Η, s), 2.37 (3Η, s), 3.10— 3.21 (5H, m), 3.35— 3.40 (6H, m), 4.30— 4.34 (2H, m), 4.40—4.44 (2H, m), 7.25 (2H, s), 7.39 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6Hz) . Η, s), 2.37 (3Η, s), 3.10—3.21 (5H, m), 3.35—3.40 (6H, m), 4.30—4.34 (2H, m), 4.40—4.44 (2H, m), 7.25 ( 2H, s), 7.39 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6 Hz).
元素分析値 C H NO 'HC1'3/4H Oとして Elemental analysis value as C H NO 'HC1'3 / 4H O
28 38 4 4 2 28 38 4 4 2
計算値: C, 61.75;H, 7.50; CI, 6.51;N, 10.29. Calculated values: C, 61.75; H, 7.50; CI, 6.51; N, 10.29.
実測値: C, 61.96;H, 7.57; CI, 6.29;N, 10.09. Found: C, 61.96; H, 7.57; CI, 6.29; N, 10.09.
MS m/z:495(M+H)+.
[0604] [実施例 33] MS m / z: 495 (M + H) +. [0604] [Example 33]
(1)2— [4— [[(2—メトキシェチル)—(5—メチル—2— m—トリル— 2H—[1, 2, 3 ]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 tert ブチル エステル (1) 2- [4-[[(2-Methoxyethyl)-(5-methyl-2-m-tolyl-2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 Dimethylphenoxy] -2-methylpropionic acid tert butyl ester
[0605] [化 182] [0605] [Chemical 182]
[0606] 実施例 29—(1)と同様にして、参考例 23—(2)で得た化合物(0. lOOg)と参考例 20で得たィ匕合物(0.132g)力も標題ィ匕合物(0.116g)を無色油状物として得た。 'H-NMR (400MHz, CDCl) δ :1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s) [0606] In the same manner as in Example 29- (1), the compound (0.1Og) obtained in Reference Example 23- (2) and the compound (0.132g) obtained in Reference Example 20 were also subjected to the same effect. The compound (0.116 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s)
3 Three
, 2.33 (3H, s), 2.42 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3. 50 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.74 (2H, s), 6.93 (2H, s), 7.09(1 H, d, J=8.1Hz), 7.31 (1H, t, J = 8.1Hz), 7.78 (1H, d, J = 8.1Hz), 7.8 2(1H, s). , 2.33 (3H, s), 2.42 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 (2H, t, J = 5.9Hz), 3.55 ( 2H, s), 3.74 (2H, s), 6.93 (2H, s), 7.09 (1 H, d, J = 8.1Hz), 7.31 (1H, t, J = 8.1Hz), 7.78 (1H, d, J = 8.1Hz), 7.8 2 (1H, s).
MS m/z:537(M+H)+. MS m / z: 537 (M + H) + .
[0607] (2)2— [4— [[(2—メトキシェチル)一(5—メチル 2— m—トリル一 2H—[1, 2, 3[0607] (2) 2— [4 — [[(2-Methoxyethyl) mono (5-methyl-2-m-tolyl) 2H— [1, 2, 3
]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 ] Triazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid
[0608] [化 183] [0608] [Chemical 183]
[0609] 実施例 24— (2)と同様にして、実施例 33— (1)で得たィ匕合物(0. llOg)力も標題
化合物(0.071g)を無色固体として得た。このものを 4規定塩酸—ジォキサン溶液に 溶解し、減圧下濃縮乾固することにより標題ィ匕合物の塩酸塩を無色固体として得た。 元素分析値 C H NO 'HC1'5/4H Oとして Example 24—Similar to (2), Example 33—Compound (0. llOg) force obtained in (1) The compound (0.071 g) was obtained as a colorless solid. This was dissolved in 4N hydrochloric acid-dioxane solution and concentrated to dryness under reduced pressure to obtain the hydrochloride of the title compound as a colorless solid. Elemental analysis value as CH NO 'HC1'5 / 4H O
27 36 4 4 2 27 36 4 4 2
計算値: C, 59.42;H, 7. 19;C1, 6.75;N, 10.66. Calculated values: C, 59.42; H, 7. 19; C1, 6.75; N, 10.66.
実測値: C, 59.59;H, 7.09; CI, 6.92;N, 10.39. Found: C, 59.59; H, 7.09; CI, 6.92; N, 10.39.
MS m/z:537(M+H)+. MS m / z: 537 (M + H) + .
[0610] [実施例 34] [0610] [Example 34]
(1)2— [2, 6 ジメチルー 4 [[メチルカルバモイルメチルー(5—メチルー 2 m— トリル—2H—[1, 2, 3]トリァゾールー 4 ィルメチル)ァミノ]メチル]フエノキシ ]ー2 メチルプロピオン酸 tert ブチル エステル (1) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2m-tolyl-2H- [1,2,3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 methylpropionic acid tert butyl ester
[0611] [化 184] [0611] [Chemical 184]
[0612] 実施例 30— (1)と同様にして、参考例 23— (2)で得た化合物 (0.100g)と参考例 16— (2)で得た化合物(0.137g)力も標題ィ匕合物(0.180g)を無色油状物として 得た。 [0612] In the same manner as in Example 30- (1), the compound (0.100g) obtained in Reference Example 23- (2) and the compound (0.137g) obtained in Reference Example 16- (2) were also subjected to the same effect. The compound (0.180 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s) 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)
3 Three
, 2.24 (3H, s), 2.43 (3H, s), 2.80 (3H, d, J=4.9Hz), 3.25 (3H, s), 3. 57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.13(1H, d, J = 8. 1Hz), 7.22 ( 1H, d, J=4.9Hz), 7.34(1H, t, J = 8.1Hz), 7.79(1H, d, J = 8.1Hz), 7. 82 (1H, s). , 2.24 (3H, s), 2.43 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.25 (3H, s), 3.57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.13 (1H, d, J = 8.1 Hz), 7.22 (1H, d, J = 4.9 Hz), 7.34 (1H, t, J = 8.1 Hz), 7.79 (1H, d, J = 8.1Hz), 7.82 (1H, s).
MS m/z:550(M+H)+. MS m / z: 550 (M + H) +.
[0613] (2)2— [2, 6 ジメチルー 4 [[メチルカルバモイルメチルー(5—メチルー 2 m— トリル—2H—[1, 2, 3]トリァゾールー 4 ィルメチル)ァミノ]メチル]フエノキシ ]ー2 メチルプロピオン酸
[0614] [化 185] [0613] (2) 2— [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2 m-tolyl-2H- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 Methyl propionic acid [0614] [Chemical 185]
[0615] 実施例 24— (2)と同様にして、実施例 34—(1)で得たィ匕合物(0.175g)力も標題 化合物(0. 132g)を無色固体として得た。 Example 24—In the same manner as in (2), the compound (0.175 g) force obtained in Example 34- (1) was also used to give the title compound (0.132 g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 14 (6Η, s), 2.21(3 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.21 (3
6 6
H, s), 2.40 (3H, s), 2.58 (3H, d, J=4.7Hz), 3.09 (2H, s), 3.56 (2H, s ), 3.70 (2H, s), 7.00 (2H, s), 7.17(1H, d, J = 7.8Hz), 7.40(1H, t, J = 7.8Hz), 7.60(1H, q, J= 4.7Hz) , 7.72(1H, d, J = 7.8Hz), 7.76 (IH, s). H, s), 2.40 (3H, s), 2.58 (3H, d, J = 4.7Hz), 3.09 (2H, s), 3.56 (2H, s), 3.70 (2H, s), 7.00 (2H, s ), 7.17 (1H, d, J = 7.8Hz), 7.40 (1H, t, J = 7.8Hz), 7.60 (1H, q, J = 4.7Hz), 7.72 (1H, d, J = 7.8Hz), 7.76 (IH, s).
MS m/z:494(M+H)+. MS m / z: 494 (M + H) + .
[0616] [実施例 35] [0616] [Example 35]
(1)2— [2, 6 ジメチルー 4— [[[5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ ルメチル]— (5—メチル 2— m—トリル— 2H— [1, 2, 3]トリァゾールー 4 ィルメ チル)ァミノ]メチル]フエノキシ ]ー2—メチルプロピオン酸 ェチル エステル (1) 2— [2, 6 Dimethyl 4 -— [[[5-Methyl- [1, 3, 4] Oxadiazo 2-ylmethyl] — (5-Methyl 2- m-Tolyl— 2H— [1, 2 , 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester
[0617] [化 186] [0617] [Chemical 186]
実施例 26— (1)と同様にして、参考例 24— (3)で得たィ匕合物 (0.192g)から標題 化合物(0. 173g)を無色油状物として得た。 Example 26- In the same manner as in (1), the title compound (0.173 g) was obtained as a colorless oil from the compound (0.192 g) obtained in Reference Example 24- (3).
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
[88ΐ^ ] [S290] エ ^エ 邈べ ci l /^ ー [ ^:,ェ ^ — 9 's— [ ^ [ ^ ( ^ ^— — /— 、 (Η[ε 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 [88ΐ ^] [S290] d ^ d ci ci ci l / ^ ー [^ :, — ^ — 9 's— [^ [^ (^ ^ — — / —, (Η [ε
'Ζ Ί]-Η2- ίί4-^-2- ^-9)-( ^ΰ0^ ^:4^-ε)]]-^]-2(Ι) 'Ζ Ί] -Η2- ίί4-^-2- ^ -9)-(^ ΰ 0 ^ ^: 4 ^ -ε)]]-^]-2 (Ι)
[9S圏第] [2290] •+(H+PV)8I9:z/ra SPV •(s 'ΗΙ)9Ζ ' L '(ΖΗ8 'Ζ = Γ 'Ρ 'ΗΙ)ΙΖ [9S zone number] [2290] • + (H + PV) 8I9: z / ra SPV • ( s 'ΗΙ) 9Ζ' L '( Ζ Η8' Ζ = Γ 'Ρ' ΗΙ) ΙΖ
' L '(ΖΗ8 · = Γ'ΐ 'Ηΐ)0 Ί '(ΖΗ8 ·Ζ = ΓΡ 'ΗΙ)ΖΙ ' L '(s 'HS)S6 ·9 '(s ' HS)06 Έ '(s 'Η2)6Ζ Έ '(s 'Η2)69 Έ '(s 'HS)S 'Ζ '(s 'HS)6S 'Ζ '(s 'Η 'L' ( Ζ Η8 · = Γ'ΐ 'Ηΐ) 0 Ί' ( Ζ Η8 · Ζ = ΓΡ 'ΗΙ) ΖΙ' L '( s ' HS) S6 9' ( s ' HS) 06 Έ '( s 'Η2) 6Ζ Έ' ( s ' Η2) 69 Έ '( s ' HS) S' Ζ '( s ' HS) 6S' Ζ '( s ' Η
£)ΙΖ 'Ζ '(s 'Η9)2Ι 'Ζ '(s 'H9)SS ·ΐ: 9 (P-OSWa 'zH OO^)H N-HT £) ΙΖ 'Ζ' ( s ' Η9) 2Ι 'Ζ' ( s ' H9) SS · ΐ: 9 (P-OSWa 'zH OO ^) H NH T
o-M ^ m^ ^ (§χοχ Ό)呦 oM ^ m ^ ^ ( § χοχ Ό) 呦
[Ζ8ΐ^ ] [0290] 邈べ ー S [ ^:,ェ [ ^ [ ^ ( ^[Ζ8ΐ ^] [0290] 邈 S [^ :, ye [^ [^ (^
/ — — /— 、 ίΗ[ε 'z 'x]-HS- fi4-ra-2- ^-g)-[ ^ / — — / —, ΊΗ [ε 'z' x] -HS- fi4-ra-2- ^ -g)-[^
S— /— 、
[6Ϊ90]S— / —, [6Ϊ90]
•+(H + S:zZra SPV • + (H + S: z Z ra SPV
•(s 'HI)S8 • (s' HI) S8
' L '(ZHI ·8 = ΓΡ 'ΗΙ)8Ζ ' L '(ΖΗΙ ·8 = Γ 'HI)SS ' L '(ΖΗΙ ·8 = ΓΡ 'HI 'L' ( Z HI 8 = ΓΡ 'ΗΙ) 8 Ζ ' L '( Ζ ΗΙ 8 = Γ' HI) SS 'L' ( Ζ ΗΙ 8 = ΓΡ 'HI
)11 ' L '(s 'HS)96 ·9 '(ΖΗΙ ·Ζ = Γ¾ 'HS)6S '(s 'HS) 6 Έ '(s 'HS)S8 ) 11 'L' ( s ' HS) 96 9 '( Ζ ΗΙ · Ζ = Γ¾' HS) 6S '( s ' HS) 6 Έ' ( s ' HS) S8
Έ '(s 'HS)99 Έ '(s 'HS)S9 '(s 'HS)S '(s 'HS)8S '(s 'H9)8I · Έ '( s ' HS) 99 Έ '( s ' HS) S9 '( s ' HS) S '( s ' HS) 8S '( s ' H9) 8I
ZCCM0/S00Zdf/X3d 6C6CT0/900Z OAV
ZCCM0 / S00Zdf / X3d 6C6CT0 / 900Z OAV
[0624] 実施例 27— (1)と同様にして、参考例 23— (2)で得た化合物 (0.138g)と参考例 19で得たィ匕合物(0.176g)力も標題ィ匕合物(0.239g)を無色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1 [0624] In the same manner as in Example 27- (1), the compound (0.138 g) obtained in Reference Example 23- (2) and the compound (0.176 g) obtained in Reference Example 19 were also combined with the title compound. Product (0.239 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1
3 Three
.79 (2H, quint, J = 6.6Hz), 2. 17(6H, s), 2.26 (3H, s), 2.42 (3H, s), 2 .55 (2H, t, J = 6.6Hz), 3.25 (3H, s), 3.36 (2H, t, J = 6.6Hz), 3.47 (2H , s), 3.63 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 6.92 (2H, s), 7.09(1H, d, J =7.8Hz), 7.31 (1H, d, J = 7.8Hz), 7.78 (1H, d, J = 7.8Hz), 7.81(1H , s). .79 (2H, quint, J = 6.6Hz), 2.17 (6H, s), 2.26 (3H, s), 2.42 (3H, s), 2.55 (2H, t, J = 6.6Hz), 3.25 (3H, s), 3.36 (2H, t, J = 6.6Hz), 3.47 (2H, s), 3.63 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.92 (2H, s ), 7.09 (1H, d, J = 7.8Hz), 7.31 (1H, d, J = 7.8Hz), 7.78 (1H, d, J = 7.8Hz), 7.81 (1H, s).
MS m/z:523(M+H)+. MS m / z: 523 (M + H) + .
[0625] (2)2— [4— [[(3—メトキシプロピル)一(5—メチル 2— m—トリル一 2H—[1, 2,[0625] (2) 2 -— [4 -— [[(3-Methoxypropyl) -one (5-methyl-2-m-tolyl-one 2H— [1, 2,
3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 3] Triazol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid
[0626] [化 189] [0626] [Chemical 189]
実施例 1— (2)と同様にして、実施例 36— (1)で得たィ匕合物 (0.234g)力も標題 化合物(0.20 lg)を無色固体として得た。このものを 4規定塩酸—ジォキサン溶液 溶解し、減圧下濃縮乾固することにより標題ィ匕合物の塩酸塩を無色固体として得た。
Ή- NMR (400MHz, DMSO d) δ :1.36 (6H, s), 2. 17(6H, s), 2.29(3 In the same manner as in Example 1- (2), the compound (0.234 g) force obtained in Example 36- (1) also gave the title compound (0.20 lg) as a colorless solid. This was dissolved in 4N hydrochloric acid-dioxane solution and concentrated to dryness under reduced pressure to obtain the hydrochloride of the title compound as a colorless solid. NMR-NMR (400MHz, DMSO d) δ: 1.36 (6H, s), 2.17 (6H, s), 2.29 (3
6 6
H, s), 2.42 (3H, s), 3.15— 3.23 (5H, m), 3.35— 3.41 (6H, m), 4.32( 2H, br s), 4.43 (2H, d, J = 3.9Hz), 7.26 (2H, s), 7.26(1H, d, J = 7.8 Hz), 7.47(1H, t, J=7.8Hz), 7.79(1H, d, J = 7.8Hz), 7.83(1H, s) . 元素分析値 C H NO 'HC1'3/4H Oとして H, s), 2.42 (3H, s), 3.15—3.23 (5H, m), 3.35—3.41 (6H, m), 4.32 (2H, br s), 4.43 (2H, d, J = 3.9Hz), 7.26 (2H, s), 7.26 (1H, d, J = 7.8 Hz), 7.47 (1H, t, J = 7.8Hz), 7.79 (1H, d, J = 7.8Hz), 7.83 (1H, s). Elemental analysis value as CH NO 'HC1'3 / 4H O
28 38 4 4 2 28 38 4 4 2
計算値: C, 61.75;H, 7.50; CI, 6.51;N, 10.29. Calculated values: C, 61.75; H, 7.50; CI, 6.51; N, 10.29.
実測値: C, 61.90;H, 7.59; CI, 6.40;N, 10.13. Found: C, 61.90; H, 7.59; CI, 6.40; N, 10.13.
MS m/z:495(M+H)+. MS m / z: 495 (M + H) +.
[0628] [実施例 37] [0628] [Example 37]
(1)2— [4— [[[2— (4 クロロフヱ-ル)一 5—メチル 2H—[1, 2, 3]トリァゾール —4—ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6 ジメチルフエノキ シ]— 2—メチルプロピオン酸 tert—ブチル エステル (1) 2— [4— [[[2— (4 Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole —4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy] — 2-Methylpropionic acid tert-butyl ester
[0629] [化 190] [0629] [Chemical 190]
[0630] 実施例 30—(1)と同様にして、参考例 25—(2)で得た化合物(0.120g)と参考例 16— (2)で得た化合物(0.153g)力も標題ィ匕合物(0.151g)を無色油状物として 得た。 [0630] In the same manner as in Example 30- (1), the compound (0.120 g) obtained in Reference Example 25- (2) and the compound (0.153 g) obtained in Reference Example 16- (2) were also subjected to the same effect. The compound (0.151 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.42 (6Η, s), 1.52 (9Η, s), 2.22 (6H, s) 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.22 (6H, s)
3 Three
, 2.23 (3H, s), 2.80 (3H, d, J = 5. 1Hz), 3.25 (2H, s), 3.57 (2H, s), 3. 68 (2H, s), 6.89 (2H, s), 7.18 (1H, br s), 7.43 (2H, d, J = 8.8Hz), 7.9 4(2H, d, J = 8.8Hz). , 2.23 (3H, s), 2.80 (3H, d, J = 5.1 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 6.89 (2H, s) , 7.18 (1H, br s), 7.43 (2H, d, J = 8.8Hz), 7.9 4 (2H, d, J = 8.8Hz).
MS m/z:570(M+H)+. MS m / z: 570 (M + H) + .
[0631] (2) 2— [4— [[[2— (4 クロロフヱ-ル)ー5—メチルー 2H—[1, 2, 3]トリァゾール —4—ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6 ジメチルフエノキ
シ] 2—メチルプロピオン酸 [0631] (2) 2— [4— [[[2— (4 Chlorophenyl) -5-methyl-2H— [1, 2, 3] triazole —4-ylmethyl] methylcarbamoylmethylamino] methyl] — 2, 6 Dimethylphenol 2] 2-Methylpropionic acid
[0632] [化 191] [0632] [Chemical 191]
[0633] 実施例 24— (2)と同様にして、実施例 37— (1)で得たィ匕合物(0.145g)から標題 化合物(0. llOg)を無色固体として得た。 Example 24— In the same manner as (2), the title compound (0. llOg) was obtained as a colorless solid from the compound (0.145 g) obtained in Example 37 (1).
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 13 (6Η, s), 2.21(3 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.13 (6Η, s), 2.21 (3
6 6
H, s), 2.58 (3H, d, J = 5.1Hz), 3.09 (2H, s), 3.57 (2H, s), 3.71 (2H, s ), 6.99 (2H, s), 7.58-7.59(1H, m), 7.59 (2H, d, J = 8.8Hz), 7.93(2 H, d, J=8.8Hz). H, s), 2.58 (3H, d, J = 5.1Hz), 3.09 (2H, s), 3.57 (2H, s), 3.71 (2H, s), 6.99 (2H, s), 7.58-7.59 (1H , m), 7.59 (2H, d, J = 8.8Hz), 7.93 (2 H, d, J = 8.8Hz).
MS m/z:514(M+H)+. MS m / z: 514 (M + H) + .
[0634] [実施例 38] [0634] [Example 38]
(1)2— [4— [[[2— (4 クロロフヱ-ル)一 5—メチル 2H—[1, 2, 3]トリァゾール 4ーィルメチル ]一(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2 ィルメチル)アミ ノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピオン酸 ェチル エステル [0635] [化 192] (1) 2— [4 — [[[2— (4 Chlorophenol) 1 5-methyl 2H— [1, 2, 3] triazole 4-ylmethyl] 1 (5-methyl- [1, 3, 4] oxazolazo 1 Ru-2-ylmethyl) amino] methyl] —2,6 dimethylphenoxy] —2-methylpropionic acid ethyl ester [0635] [Chemical 192]
実施例 26— (1)と同様にして、参考例 26— (3)で得たィ匕合物 (0.180g)力も標題 化合物(0. 142g)を無色油状物として得た。 Example 26- In the same manner as in (1), the compound (0.180 g) strength obtained in Reference Example 26- (3) also gave the title compound (0.142 g) as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
. 18 (6H, s), 2. 27 (3H, s), 2. 52 (3H, s), 3.65 (2H, s), 3. 81 (2H, s), 3.'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 18 (6H, s), 2.27 (3H, s), 2.52 (3H, s), 3.65 (2H, s), 3.81 (2H, s), 3.
93 (2H, s), 4. 29 (2H, q, J = 7. 1Hz) , 6. 95 (2H, s), 7.41 (2H, d, J = 8.893 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6. 95 (2H, s), 7.41 (2H, d, J = 8.8
Hz), 7. 93 (2H, d, J = 8.8Hz) . Hz), 7.93 (2H, d, J = 8.8Hz).
MS m/z:567(M+H)+. MS m / z: 567 (M + H) + .
[0637] (2) 2— [4— [[[2— (4 クロロフヱ-ル)ー5—メチルー 2H—[1, 2, 3]トリァゾール[0637] (2) 2— [4— [[[2— (4 Chlorophenyl) -5-methyl-2H— [1, 2, 3] triazole
4ーィルメチル ]一(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2 ィルメチル)アミ ノ]メチル] 2, 6 ジメチルフエノキシ]—2—メチルプロピオン酸 4-methyl] mono (5-methyl- [1, 3, 4] oxadiazo 2-ylmethyl) amino] methyl] 2,6 dimethylphenoxy] -2-methylpropionic acid
[0638] [化 193] [0638] [Chemical 193]
[0639] 実施例 1— (2)と同様にして、実施例 38— (1)で得たィ匕合物(0. 138g)力も標題 化合物(0. 118g)を無色固体として得た。 [0639] In the same manner as in Example 1- (2), the compound (0.138 g) force obtained in Example 38- (1) was also obtained as the title compound (0.118 g) as a colorless solid.
iH—NMR (400MHz, DMSO d) δ :1. 32 (6H, s), 2. 12(6H, s), 2. 22(3 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3
6 6
H, s), 2.45 (3H, s), 3.60 (2H, s), 3.80 (2H, s), 3. 91 (2H, s), 6. 92 (2H , s), 7. 59 (2H, d, J = 8.8Hz), 7. 92 (2H, d, J = 8.8Hz) . H, s), 2.45 (3H, s), 3.60 (2H, s), 3.80 (2H, s), 3. 91 (2H, s), 6. 92 (2H, s), 7. 59 (2H, d, J = 8.8Hz), 7. 92 (2H, d, J = 8.8Hz).
MS m/z:539(M+H)+. MS m / z: 539 (M + H) +.
[0640] [実施例 39] [0640] [Example 39]
(1)2— [4— [[[2— (3 クロロフヱ-ル)一 5—メチル 2H—[1, 2, 3]トリァゾール —4—ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6 ジメチルフエノキ シ]— 2—メチルプロピオン酸 tert—ブチル エステル (1) 2— [4— [[[2— (3 Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole —4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy] — 2-Methylpropionic acid tert-butyl ester
[0641] [化 194]
[0641] [Chemical 194]
[0642] 実施例 30— (1)と同様にして、参考例 27— (2)で得た化合物 (0.120g)と参考例 16— (2)で得た化合物(0.153g)力も標題ィ匕合物(0.151g)を無色油状物として 得た。 Example 30— Reference Example 27—Compound (0.120 g) obtained in (2) and Reference Example 16— (2)) (0.153 g) The compound (0.151 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.42 (6Η, s), 1.52 (9Η, s), 2.23 (6H, s) 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.23 (6H, s)
3 Three
, 2.24 (3H, s), 2.81 (3H, d, J=4.9Hz), 3.25 (2H, s), 3.57 (2H, s), 3. 68 (2H, s), 6.89 (2H, s), 7.20(1H, q, J=4.9Hz) , 7.26— 7.30(1H, m) , 7.39(1H, t, J = 8.1Hz), 7.89(1H, dd, J = 2.0, 8.1Hz), 8.03 (1H, t, J =2. OHz). , 2.24 (3H, s), 2.81 (3H, d, J = 4.9Hz), 3.25 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.20 (1H, q, J = 4.9Hz), 7.26— 7.30 (1H, m), 7.39 (1H, t, J = 8.1Hz), 7.89 (1H, dd, J = 2.0, 8.1Hz), 8.03 (1H , t, J = 2. OHz).
MS m/z:570(M+H)+. MS m / z: 570 (M + H) + .
[0643] (2)2— [4— [[[2— (3 クロロフヱ-ル)一 5—メチル 2H—[1, 2, 3]トリァゾール[0643] (2) 2— [4— [[[2— (3 Chlorophenol)] 5-Methyl 2H— [1, 2, 3] triazole
—4—ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6 ジメチルフエノキ シ] 2—メチルプロピオン酸 —4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid
[0644] [化 195] [0644] [Chemical 195]
実施例 24— (2)と同様にして、実施例 39— (1)で得たィ匕合物 (0.155g)から標題 化合物(0. 115g)を無色固体として得た。 Example 24- In the same manner as in (2), the title compound (0.115 g) was obtained as a colorless solid from the compound (0.155 g) obtained in Example 39- (1).
iH—NMR (400MHz, DMSO d) δ :1.33 (6H, s), 2. 13 (6H, s), 2.22(3 iH—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2. 13 (6H, s), 2.22 (3
6 6
H, s), 2.58 (3H, d, J=4.7Hz), 3.10 (2H, s), 3.57 (2H, s), 3.72 (2H, s
), 7.00 (2H, s), 7.42-7.45(1H, m), 7.56(1H, t, J = 8.1Hz), 7.61(1 H, q, J=4.7Hz), 7.88— 7.90(1H, m) , 7.92(1H, t, J = 2.0Hz) . H, s), 2.58 (3H, d, J = 4.7Hz), 3.10 (2H, s), 3.57 (2H, s), 3.72 (2H, s ), 7.00 (2H, s), 7.42-7.45 (1H, m), 7.56 (1H, t, J = 8.1Hz), 7.61 (1 H, q, J = 4.7Hz), 7.88—7.90 (1H, m ), 7.92 (1H, t, J = 2.0Hz).
元素分析値 C H NO '1Z2HOとして Elemental analysis value as C H NO '1Z2HO
27 35 5 4 2 27 35 5 4 2
計算値: C, 59.71;H, 6.36; CI, 6.78;N, 13.39. Calculated values: C, 59.71; H, 6.36; CI, 6.78; N, 13.39.
実測値: C, 59.71;H, 6.43; CI, 6.92;N, 12.98. Found: C, 59.71; H, 6.43; CI, 6.92; N, 12.98.
MS m/z:514(M+H)+. MS m / z: 514 (M + H) + .
[0646] [実施例 40] [0646] [Example 40]
(1)2— [4— [[[2— (3 クロロフヱ-ル)一 5—メチル 2H—[1, 2, 3]トリァゾール 4ーィルメチル ]一(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2 ィルメチル)アミ ノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピオン酸 ェチル エステル [0647] [化 196] (1) 2- [4 -— [[[[2- (3 Chlorophenol)] 5-Methyl 2H— [1, 2, 3] triazole 4-ylmethyl] -one (5-Methyl- [1, 3, 4] oxazodiazo [Ru-2-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] —2-methylpropionic acid ethyl ester [0647] [Chemical 196]
[0648] 実施例 26— (1)と同様にして、参考例 28— (3)で得たィ匕合物(0.200g)から標題 化合物(0. 194g)を無色油状物として得た。 In the same manner as in Example 26- (1), the title compound (0.194 g) was obtained as a colorless oil from the compound (0.200 g) obtained in Reference Example 28- (3).
'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 19 (6H, s), 2.27 (3H, s), 2.53 (3H, s), 3.65 (2H, s), 3.81 (2H, s), 3. 93 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 6.95 (2H, s), 7.25— 7.26 (1H, m) , 7.37(1H, d, J = 8.3Hz), 7.89(1H, dd, J = 2.0, 8.3Hz), 8.03(1H, t, J =2.0Hz). 19 (6H, s), 2.27 (3H, s), 2.53 (3H, s), 3.65 (2H, s), 3.81 (2H, s), 3.93 (2H, s), 4.29 (2H, q , J = 7.1Hz), 6.95 (2H, s), 7.25— 7.26 (1H, m), 7.37 (1H, d, J = 8.3Hz), 7.89 (1H, dd, J = 2.0, 8.3Hz), 8.03 (1H, t, J = 2.0Hz).
MS m/z:567(M+H)+. MS m / z: 567 (M + H) + .
[0649] (2)2— [4— [[[2— (3 クロロフヱ-ル)一 5—メチル 2H—[1, 2, 3]トリァゾール [0649] (2) 2— [4— [[[2— (3 Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole
4ーィルメチル ]一(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2 ィルメチル)アミ ノ]メチル] 2, 6—ジメチルフエノキシ]—2—メチルプロピオン酸 4-ylmethyl] mono (5-methyl- [1, 3, 4] oxadiazo 2-ylmethyl) amino] methyl] 2,6-dimethylphenoxy] -2-methylpropionic acid
[0650] [化 197]
HS)96 ·9 '(ZHS ·6 = ΓΡ ΉΖ) 6 ·9 '(ΖΗΙ ·Ζ = Γ¾ ΉΖ)6Ζ ' '(s 'HS)S6 [0650] [Chemical 197] HS) 96 9 '( Z HS 6 = ΓΡ ΉΖ) 6 9' ( Ζ ΗΙ ΗΙ Ζ = Γ¾ ΉΖ) 6 Ζ '' ( s ' HS) S6
Έ '(s 'Η2)98 Έ '(s 'HS)9 Έ '(s 'HS)S9 'Ζ '(s 'U£)LZ 'Z '(s 'H9)8I · z '(S ¾9)9 ·χ '(ΖΗΙ · =Γ'^ 'Ηε)9ε ·χ: 9 (\οαο 'ZH OO^)H N-HT Έ '( s ' Η2) 98 Έ' ( s ' HS) 9 Έ '( s ' HS) S9' Ζ '( s ' U £) LZ' Z '( s ' H9) 8I z' ( S ¾9) 9 · χ '( Ζ ΗΙ · = Γ' ^ 'Ηε) 9ε · χ: 9 (\ οαο' ZH OO ^) H NH T
[86ΐ^ ] [SS90] エ ^エ
[86ΐ ^] [SS90] D ^ D
[ ^ ( ^ ^ー s— /— 、 fH [ 'ε ' I ] - - 9 ) - →-Λ( [^ (^ ^ ー s— / —, fH ['ε' I]--9)-→ -Λ (
— 、 (Η[ε 'Ζ Ί] ( /-^Δ^^→) - 2]]] - ¾ -2 (I) —, (Η [ε 'Ζ Ί] (/-^ Δ ^^ →)-2]]]-¾ -2 (I)
[lH}«] [2S90] •+(H + PV)6S9:z/ra SPV [lH} «] [2S90] • + (H + PV) 6S9: z / ra SPV
·( · (
^ ΉΖ)16 ·Ζ— 98 ' L '(ΖΗΙ ·8 = Γ 'ΗΙ)99 ' L ' 'Ηΐ) ' L-ZV ' L '(s ' ^ ΉΖ) 16 · Ζ— 98 'L' ( Ζ ΗΙ · 8 = Γ 'ΗΙ) 99' L '' Ηΐ) 'L-ZV' L '( s '
HS)S6 ·9 '(s 'HS)S6 Έ '(s 'Η2)08 Έ '(s 'Η2)09 Έ '(s ¾ε)9 'Ζ '(s 'Η HS) S6 9 '( s ' HS) S6 Έ '( s ' Η2) 08 Έ '( s ' Η2) 09 Έ '( s ¾ε) 9' Ζ '( s ' Η
£)ΖΖ 'Ζ '(s 'Η9)2Ι 'Ζ '(s 'H9)SS ·ΐ: 9 (P-OSWa 'ZH 00^)H N-HT £) ΖΖ 'Ζ' ( s ' Η9) 2Ι 'Ζ' ( s ' H9) SS · ΐ: 9 (P-OSWa 'ZH 00 ^) H NH T
o-M ^ m^ ^ (§s9i Ό)呦 oM ^ m ^ ^ ( § s9i Ό) 呦
ZCCM0/S00Zdf/X3d 6 6C6CT0/900Z OAV
, s), 7.89 (2H, d, J = 9.3Hz) . ZCCM0 / S00Zdf / X3d 6 6C6CT0 / 900Z OAV , s), 7.89 (2H, d, J = 9.3Hz).
MS m/z:563(M+H)+. MS m / z: 563 (M + H) +.
[0655] (2) 2— [4— [[[2— (4—メトキシフエ-ル) 5—メチルー 2H—[1, 2, 3]トリァゾー ルー 4ーィルメチル ]一(5—メチルー [1, 3, 4]トリァゾールー 2 ィルメチル)ァミノ] メチル] 2, 6 ジメチルフエノキシ] 2 メチルプロピオン酸 [0655] (2) 2— [4— [[[2— (4-Methoxyphenol) 5-methyl-2H— [1, 2, 3] triazol 4-ylmethyl] one (5-methyl- [1, 3, 4] Triazol-2-ylmethyl) amino] methyl] 2, 6 dimethylphenoxy] 2 methylpropionic acid
[0656] [化 199] [0656] [Chemical 199]
[0657] 実施例 1— (2)と同様にして、実施例 41— (1)で得たィ匕合物 (0.130g)力も標題 化合物(0. 105g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.130 g) force obtained in Example 41- (1) was also used to obtain the title compound (0.105 g) as a colorless solid.
iH—NMR (400MHz, DMSO d) δ :1.33 (6H, s), 2. 13 (6H, s), 2.20(3 iH—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2. 13 (6H, s), 2.20 (3
6 6
H, s), 2.45 (3H, s), 3.59 (2H, s), 3.77 (2H, s), 3.80 (3H, s), 3.89 (2H , s), 6.93 (2H, s), 7.07 (2H, d, J = 9.1Hz), 7.83 (2H, d, J = 9.1Hz) . MS m/z:535(M+H)+. H, s), 2.45 (3H, s), 3.59 (2H, s), 3.77 (2H, s), 3.80 (3H, s), 3.89 (2H, s), 6.93 (2H, s), 7.07 (2H , d, J = 9.1Hz), 7.83 (2H, d, J = 9.1Hz) .MS m / z: 535 (M + H) +.
[0658] [実施例 42] [0658] [Example 42]
(1) 2— [4— [[[2— (4—メトキシフヱ-ル) 5—メチルー 2H—[1, 2, 3]トリァゾー ルー 4—ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6 ジメチルフエノ キシ ] 2—メチルプロピオン酸 ェチル エステル (1) 2— [4 — [[[2— (4-Methoxyphenyl) 5-methyl-2H— [1, 2, 3] triazol 4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0659] [化 200] [0659] [Chemical 200]
[0660] 実施例 25— (1)と同様にして、参考例 30— (2)で得た化合物(0.160g)とメチル ァミン塩酸塩 (0.023g)力も標題ィ匕合物(0.096g)を無色油状物として得た。 Example 25—In the same manner as in (1), the compound (0.160 g) obtained in Reference Example 30— (2) and methylamine hydrochloride (0.023 g) were also mixed with the title compound (0.096 g). Obtained as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 'H-NMR (400MHz, CDC1) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2
3 Three
. 19 (6H, s), 2.23 (3H, s), 2.80 (3H, d, J=4.9Hz), 3.25 (2H, s), 3.57 (2H, s), 3.67 (2H, s), 3.86 (3H, s), 4.29 (2H, q, J = 7. 1Hz), 6.90 (2H , s), 6.97 (2H, d, J = 9.1Hz), 7.23— 7.26 (1H, m), 7.90 (2H, d, J = 9.1 Hz). 19 (6H, s), 2.23 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.25 (2H, s), 3.57 (2H, s), 3.67 (2H, s), 3.86 ( 3H, s), 4.29 (2H, q, J = 7.1 Hz), 6.90 (2H, s), 6.97 (2H, d, J = 9.1Hz), 7.23— 7.26 (1H, m), 7.90 (2H, d, J = 9.1 Hz).
MS m/z:538(M+H)+. MS m / z: 538 (M + H) +.
[0661] (2) 2— [4— [[[2— (4—メトキシフエ-ル) 5—メチルー 2H—[1, 2, 3]トリァゾー ルー 4—ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6 ジメチルフエノ キシ ] 2—メチルプロピオン酸 [0661] (2) 2— [4— [[[2— (4-Methoxyphenol) 5-methyl-2H— [1, 2, 3] triazol 4-ylmethyl] methylcarbamoylmethylamino] methyl] — 2, 6-Dimethylphenoxy] 2-methylpropionic acid
[0662] [化 201] [0662] [Chemical 201]
[0663] 実施例 1— (2)と同様にして、実施例 42— (1)で得た化合物(0.090g)カゝら標題 化合物(0.076g)を無色固体として得た。 Example 1— In the same manner as in (2), the title compound (0.076 g) was obtained as a colorless solid from the compound (0.090 g) obtained in Example 42 (1).
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 14 (6Η, s), 2.20(3 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.20 (3
6 6
H, s), 2.58 (3H, d, J= 4.7Hz), 3.08 (2H, s), 3.56 (2H, s), 3.67 (2H, s), 3.80 (3H, s), 7.00 (2H, s), 7.07 (2H, d, J = 9.1Hz), 7.59(1H, q, J =4.7Hz), 7.84 (2H, d, J = 9. 1Hz) . H, s), 2.58 (3H, d, J = 4.7Hz), 3.08 (2H, s), 3.56 (2H, s), 3.67 (2H, s), 3.80 (3H, s), 7.00 (2H, s ), 7.07 (2H, d, J = 9.1Hz), 7.59 (1H, q, J = 4.7Hz), 7.84 (2H, d, J = 9.1Hz).
MS m/z:510(M+H)+. MS m / z: 510 (M + H) + .
[0664] [実施例 43] [0664] [Example 43]
(l)2-[4-[[[2-(3, 4ージメチルフヱ-ル)ー5—メチルー 2H—[1, 2, 3]トリア ゾールー 4 ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6—ジメチル フエノキシ ]—2—メチルプロピオン酸 tert ブチル エステル
[0665] [化 202] (l) 2- [4-[[[2- (3,4-Dimethylphenol) -5-methyl-2H- [1, 2, 3] triazol-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2, 6-Dimethylphenoxy] -2-methylpropionic acid tert butyl ester [0665] [Chemical 202]
[0666] 実施例 30— (1)と同様にして、参考例 31— (2)で得た化合物(0.090g)と参考例 16— (2)で得た化合物(0.117g)力も標題ィ匕合物(0.117g)を無色油状物として 得た。 Example 30— Reference Example 31—Compound (0.090 g) obtained in (2) and Reference Example 16—Compound (0.117 g) obtained in (2) in the same manner as (1). The compound (0.117 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s) 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)
3 Three
, 2.24 (3H, s), 2.30 (3H, s), 2.34 (3H, s), 2.80 (3H, d, J = 5.1Hz), 3. , 2.24 (3H, s), 2.30 (3H, s), 2.34 (3H, s), 2.80 (3H, d, J = 5.1Hz), 3.
25 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 6.90 (2H, s), 7.20 (1H, d, J = 825 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 6.90 (2H, s), 7.20 (1H, d, J = 8
. 1Hz), 7.23-7.26(1H, m), 7.69(1H, dd, J = 2.2, 8.1Hz), 7.77(1H1Hz), 7.23-7.26 (1H, m), 7.69 (1H, dd, J = 2.2, 8.1Hz), 7.77 (1H
, d, J = 2.2Hz). , d, J = 2.2Hz).
MS m/z:564(M+H)+. MS m / z: 564 (M + H) + .
[0667] (2)2-[4-[[[2-(3, 4ージメチルフエ-ル)ー5—メチルー 2H— [1, 2, 3]トリア ゾールー 4 ィルメチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6—ジメチル フエノキシ ] 2—メチルプロピオン酸 [0667] (2) 2- [4-[[[2- (3,4-Dimethylphenol) -5-methyl-2H- [1, 2, 3] triazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6-dimethylphenoxy] 2-methylpropionic acid
[0668] [化 203] [0668] [Chemical 203]
実施例 24— (2)と同様にして、実施例 43— (1)で得たィ匕合物 (0.112g)から標題 化合物(0.031g)を無色固体として得た。 Example 24- In the same manner as in (2), the title compound (0.031 g) was obtained as a colorless solid from the compound (0.112 g) obtained in Example 43- (1).
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 14 (6Η, s), 2.21(3 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.21 (3
6 6
H, s), 2.25 (3H, s), 2.30 (3H, s), 2.58 (3H, d, J=4.7Hz), 3.08 (2H, s
), 3.56 (2H, s), 3.69 (2H, s), 7.00 (2H, s), 7.27(1H, d, J = 8.3Hz), 7 .58-7.64 (2H, m), 7.72(1H, d, J = 2.0Hz) . H, s), 2.25 (3H, s), 2.30 (3H, s), 2.58 (3H, d, J = 4.7Hz), 3.08 (2H, s ), 3.56 (2H, s), 3.69 (2H, s), 7.00 (2H, s), 7.27 (1H, d, J = 8.3Hz), 7.58-7.64 (2H, m), 7.72 (1H, d, J = 2.0Hz).
MS m/z:508(M+H)+. MS m / z: 508 (M + H) +.
[0670] [実施例 44] [0670] [Example 44]
(l)2-[4-[[[2- [4一(2—メトキシエトキシ)フエ-ル ] 5—メチルー 2H— [1, 2 , 3]トリァゾールー 4 ィルメチル]メチルカルバモイルメチルァミノ]メチル ] 2, 6— ジメチルフエノキシ ] 2—メチルプロピオン酸 tert ブチル エステル (l) 2- [4-[[[2- [4 (2-Methoxyethoxy) phenol] 5-Methyl-2H- [1,2,3] Triazol-4-ylmethyl] methylcarbamoylmethylamino] methyl] 2, 6-dimethylphenoxy] 2-methylpropionic acid tert butyl ester
[0671] [化 204] [0671] [Chemical 204]
[0672] 実施例 30— (1)と同様にして、参考例 32— (4)で得たィ匕合物 (0.120g)と参考例 16— (2)で得た化合物(0.134g)力も標題ィ匕合物(0.147g)を無色油状物として 得た。 Example 30— In the same manner as in (1), the compound (0.120 g) obtained in Reference Example 32— (4) and the compound (0.134 g) obtained in Reference Example 16— (2) were also used. The title compound (0.147 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s) 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)
3 Three
, 2.23 (3H, s), 2.80 (3H, d, J=4.9Hz), 3.24 (2H, s), 3.47 (3H, s), 3. 57 (2H, s), 3.78 (2H, t, J=4.9Hz), 4.16 (2H, t, J=4.9Hz), 6.89 (2H, s), 7.20 (2H, d, J = 9.1Hz), 7.22(1H, q, J=4.9Hz), 7.89 (2H, d, J=9 . 1Hz). , 2.23 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.24 (2H, s), 3.47 (3H, s), 3.57 (2H, s), 3.78 (2H, t, J = 4.9Hz), 4.16 (2H, t, J = 4.9Hz), 6.89 (2H, s), 7.20 (2H, d, J = 9.1Hz), 7.22 (1H, q, J = 4.9Hz), 7.89 ( 2H, d, J = 9.1 Hz).
MS m/z:610(M+H)+. MS m / z: 610 (M + H) + .
[0673] (2) 2— [4— [[[2— [4— (2—メトキシエトキシ)フエ-ル ]ー5—メチルー 2H—[1, 2[0673] (2) 2— [4— [[[2— [4— (2-Methoxyethoxy) phenol] -5-methyl-2-H— [1, 2
, 3]トリァゾールー 4 ィルメチル]メチルカルバモイルメチルァミノ]メチル ] 2, 6— ジメチルフエノキシ ] 2—メチルプロピオン酸 , 3] Triazol-4-ylmethyl] methylcarbamoylmethylamino] methyl] 2,6-dimethylphenoxy] 2-methylpropionic acid
[0674] [化 205]
[0674] [Chemical 205]
[0675] 実施例 24— (2)と同様にして、実施例 44— (1)で得た化合物(0.142g)力も標題 化合物(0.091g)を無色固体として得た。 Example 24—In the same manner as in (2), the compound (0.142 g) force obtained in Example 44 (1) was also used to obtain the title compound (0.091 g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 14 (6Η, s), 2.20(3 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.20 (3
6 6
H, s), 2.58 (3H, d, J=4.9Hz), 3.08 (2H, s), 3.57 (2H, s), 3.67 (2H, s H, s), 2.58 (3H, d, J = 4.9Hz), 3.08 (2H, s), 3.57 (2H, s), 3.67 (2H, s
), 4.14 (2H, dd, J = 2.9, 6. 1Hz), 7.00 (2H, s), 7.08 (2H, d, J = 9.3Hz)), 4.14 (2H, dd, J = 2.9, 6.1 Hz), 7.00 (2H, s), 7.08 (2H, d, J = 9.3 Hz)
, 7.59(1H, q, J=4.9Hz) , 7.82 (2H, d, J = 9.3Hz) . , 7.59 (1H, q, J = 4.9Hz), 7.82 (2H, d, J = 9.3Hz).
MS m/z:554(M+H)+. MS m / z: 554 (M + H) + .
[0676] [実施例 45] [0676] [Example 45]
( 1 ) 2— [ 2, 6 ジメチル 4 [ [メチルカルバモイルメチル [ 2—( 5 メチル 2 (1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl [2— (5 Methyl 2
—フエ-ルー 2H—[1, 2, 3]トリァゾールー 4—ィル)ェチル]ァミノ]メチル]フエノキ シ]— 2—メチルプロピオン酸 tert—ブチル エステル —Fe-Lu 2H— [1, 2, 3] triazol-4-yl) ethyl] amino] methyl] phenoxy] — 2-methylpropionic acid tert-butyl ester
[0677] [化 206] [0677] [Chemical 206]
実施例 25— (1)と同様にして、参考例 33— (4)で得たィ匕合物 (0.20g)とメチルァ ミン(2M—テトラヒドロフラン溶液)を用いて標題ィ匕合物(0.064g)を無色油状物とし て得た。 Example 25—In the same manner as (1), the title compound (0.064 g) was prepared using the compound (0.20 g) obtained in Reference Example 33- (4) and methylamine (2M-tetrahydrofuran solution). ) Was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.40 (6Η, s), 1.51 (9Η, s), 2.13 (6H, s)
[802^ ] [S890]'H-NMR (400MHz, CDCl) δ: 1.40 (6Η, s), 1.51 (9Η, s), 2.13 (6H, s) [802 ^] [S890]
/ エ 邈べ ^ / D
ζ -
[ ^ [ ^ [ ^エ( ^— — /— 、 (Η[ε ' ζ- [^ [^ [^ D (^ — — / —, (Η [ε '
Ζ Ί]-Η2- / ェ -Ζ- -9)-2]- ^ / ¾ ] ]-^]-2(1) Ζ Ί] -Η2- / Ζ -Ζ- -9) -2]-^ / ¾]]-^]-2 (1)
[9,圏第] [2890] •+(H+ V) 6 :zZra SPV •(ra 'UZ)Z ·8— 66 ' L '(m 'HS)6 · ' L '(m 'ΗΙ)εε Ί-6Ζ ' L '(s 'UZ)LL ·9 '(s 'HS)S9 Έ '(s 'HS)9I · S '(m 'HS)88 'Z→ 'Z '(m 'UZ)Z 'Z-LL 'Ζ '(ΖΗ6 · =ΓΡ 'HS)S9 'Z ' (s 'U£)IZ 'Z '(s 'H9)SI 'Ζ '(s 'Η9)8 ·ΐ: 9 (\θαθ 'zH OO^)H N-HT [9, No. 2] [2890] • + (H + V) 6: z Z ra SPV • (ra 'UZ) Z · 8— 66' L '(m' HS) 6 · 'L' (m 'ΗΙ) εε Ί-6Ζ 'L' ( s 'UZ) LL 9' ( s 'HS) S 9 Έ' ( s 'HS) 9 IS S (m' HS) 88 'Z →' Z '(m' UZ) Z 'Z-LL' Ζ '( Ζ Η6 · = ΓΡ' HS) S9 'Z' ( s ' U £) IZ 'Z' ( s ' H9) SI 'Ζ' ( s ' Η9) 8 · ΐ: 9 (\ θαθ 'zH OO ^) H NH T
[0890] 邈べ l ^ S [ 、 [0890] l l ^ S [,
^P,ェ [ ^ [ ^ [ ^エ( ^— — /— 、 (Η[ε 'ζ 'ΐ]— — /-ェ — ^ P, e [^ [^ [^ e (^ — — / —, (Η [ε 'ζ' ΐ] — — / -e —
-Ζ — ^ / ¾ ^ ]]— — ^ — 9 'Ζ -Ζ{Ζ) [6 90] -Ζ — ^ / ¾ ^]] — — ^ — 9 'Ζ -Ζ {Ζ) [6 90]
•+(H + V)OSS:zZra SPV • + (H + V) OSS: z Z ra SPV
·( · (
^ 'HS)SO ·8— 66 ' L '(m 'HS)8 ' L→ ' L '(^ 'HI)SS Ί-6Ζ ' L '(^ 'H l)£Z Ί- Ζ ' L '(s 'UZ) L ·9 '(s 'HS)S9 Έ '(s 'UZ) l Έ '(^ 'HS)98 · Z-£S 'Z '(m 'HS)6Z 'Z-9L 'Ζ '(ΖΗΙ ·9 = ΓΡ 'HS)S9 '(s 'HS)IS ' ^ 'HS) SO 8—66' L '(m' HS) 8 'L →' L '(^' HI) SS Ί-6Ζ 'L' (^ 'H l) £ Z Ί- Ζ' L ' ( s 'UZ) L 9' ( s 'HS) S 9 Έ' ( s 'UZ) l Έ' (^ 'HS) 98 · Z- £ S' Z '(m' HS) 6Z 'Z-9L' Ζ '( Ζ ΗΙ 9 = ΓΡ' HS) S9 '( s ' HS) IS'
ZCCM0/S00Zdf/X3d 991- 6C6CT0/900Z OAV
ZCCM0 / S00Zdf / X3d 991- 6C6CT0 / 900Z OAV
[0684] 参考例 33— (4)で得た化合物(0.20g)をジクロロメタン (5ml)に溶解し、氷水冷 却下に 1—ェチル—3— (3 ァミノプロピル)カルボジイミド塩酸塩(0.075g)、トリエ チルァミン(0.055ml)と 1—ヒドロキシベンゾトリアゾール水和物(0.060g)を加えて 、室温で 15分攪拌した。塩化アンモ-ゥム(0.060g)とトリェチルァミン(0.156ml) を加えて更に室温で 21時間攪拌した。反応液を減圧下濃縮し、残渣に水を加えて 酢酸ェチルで抽出し、飽和重曹水、飽和食塩水で洗浄した。無水硫酸ナトリウムで 乾燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーにて精製(1 %メタノール一クロ口ホルム)することにより標題ィ匕合物(0.156g)を無色油状物とし て得た。 [0684] Reference Example 33— The compound (0.20 g) obtained in (4) was dissolved in dichloromethane (5 ml), and 1-ethyl-3- (3 aminopropyl) carbodiimide hydrochloride (0.075 g), trie Tyramine (0.055 ml) and 1-hydroxybenzotriazole hydrate (0.060 g) were added, and the mixture was stirred at room temperature for 15 minutes. Ammonium chloride (0.060 g) and triethylamine (0.156 ml) were added, and the mixture was further stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (1% methanol / chloroform form) to give the title compound (0.156 g) as a colorless oil. I got it.
[0685] 'H-NMR (400MHz, CDC1 ) δ :1.40 (6Η, s), 1.51 (9Η, s), 2.12(6H, s) [0685] 'H-NMR (400MHz, CDC1) δ: 1.40 (6Η, s), 1.51 (9Η, s), 2.12 (6H, s)
3 Three
, 2.19 (3H, s), 2.75-2.88 (4H, m), 3.17(2H, s), 3.53 (2H, s), 5.27 ( , 2.19 (3H, s), 2.75-2.88 (4H, m), 3.17 (2H, s), 3.53 (2H, s), 5.27 (
1H, br), 6.72 (2H, s), 7.26— 7.30(1H, m), 7.43— 7.47 (2H, m), 7.91H, br), 6.72 (2H, s), 7.26— 7.30 (1H, m), 7.43— 7.47 (2H, m), 7.9
5-7.98 (2H, m). 5-7.98 (2H, m).
MS m/z:536(M+H)+. MS m / z: 536 (M + H) +.
[0686] (2) 2— [4 [[力ルバモイルメチルー [2— (5—メチルー 2 フエ-ルー 2H—[1, 2[0686] (2) 2— [4 [[Strengthened Lubamoylmethyl- [2— (5-Methyl-2 Ferro-Lu 2H— [1, 2
, 3]トリァゾールー 4—ィル)ェチル]ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2 メチルプロピオン酸 , 3] Triazol-4-yl) ethyl] amino] methyl] -2, 6 dimethylphenoxy] -2 methylpropionic acid
[0687] [化 209]
[0687] [Chemical 209]
[0688] 実施例 24— (2)と同様にして、実施例 46— (1)で得たィ匕合物(0. 153g)から標題 化合物(0. 104g)を無色固体として得た。 Example 24-—In the same manner as in (2), the title compound (0.104 g) was obtained as a colorless solid from the compound (0.153 g) obtained in Example 46- (1).
iH—NMR (400MHz, CD OD) δ :1. 39 (6H, s), 2.08 (6H, s), 2. 16 (3H, s iH—NMR (400MHz, CD OD) δ: 1.39 (6H, s), 2.08 (6H, s), 2. 16 (3H, s
3 Three
), 2. 79-2.82 (2H, m), 2.86— 2. 91 (2H, m), 3. 18 (2H, s), 3. 54 (2H, s), 6. 78 (2H, s), 7. 29— 7. 34(1H, m), 7.45— 7. 50 (2H, m), 7. 94— 7. 97 (2H, m). ), 2. 79-2.82 (2H, m), 2.86— 2. 91 (2H, m), 3. 18 (2H, s), 3. 54 (2H, s), 6. 78 (2H, s) , 7. 29— 7. 34 (1H, m), 7.45— 7. 50 (2H, m), 7. 94— 7. 97 (2H, m).
MS m/z:480(M+H)+. MS m / z: 480 (M + H) + .
[0689] [実施例 47] [0689] [Example 47]
(1)2— [2, 6 ジメチルー 4— [[(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ ルメチル) [2— (5—メチルー 2 フエ-ルー 2H—[1, 2, 3]トリァゾールー 4ーィ ル)ェチル]ァミノ]メチル]フエノキシ ]—2—メチルプロピオン酸 tert—ブチル エス テノレ (1) 2— [2, 6 Dimethyl 4 -— [[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl) [2-— (5-Methyl-2-Ferru 2H— [1, 2 , 3] Triazol-4-yl) ethyl] amino] methyl] phenoxy] —2-methylpropionic acid tert-butyl ester
[0690] [化 210] [0690] [Chemical 210]
[0691] 実施例 26— (1)と同様にして、参考例 34で得たィ匕合物 (0. 29g)から標題ィ匕合物 (
[ZIZ^ [9690] エ Λ(-^ -^^ 邈べ[0691] In the same manner as in Example 26- (1), from the compound (0.29 g) obtained in Reference Example 34, the title compound ( [ZIZ ^ [9690] d Λ (-^-^^
^ / — —
]] - ¾ -2 (I) ^ / — — ]]-¾ -2 (I)
[8H}«] [S690] •+(H+PV)6I9:z/ra SPV •(ra ΉΖ)96 Ί-£6 ' L '(^ 'HS)S ' L-\V ' L '(^ 'HI)OS 'L-LZ ' L [8H} «] [S690] • + (H + PV) 6I9: z / ra SPV • (ra ΉΖ) 96 Ί- £ 6 'L' (^ 'HS) S' L- \ V 'L' (^ 'HI) OS' L-LZ 'L
'(s 'HS)06 ·9 '(s 'HS)S6 Έ '(s 'HS)99 Έ '(s 'Η )ΐ6 '(s 'HS)09 'Z ' (s 'HS)9S 'Z '(s 'H9)9I 'Z '(s 'Η9)8 Ί- 9 (\OaO 'zH OO^)H N-HT '( s ' HS) 06 9 '( s ' HS) S6 Έ '( s ' HS) 99 Έ '( s ' Η) ΐ6 '( s ' HS) 09 'Z' ( s 'HS) 9S' Z '( s ' H9) 9I 'Z' ( s 'Η9) 8 Ί-9 (\ OaO' zH OO ^) H NH T
0-M ^ Ww^ (§990 -o) ^ 0 -M ^ Ww ^ ( § 990 -o) ^
[ΠΖ^ [S690] ? , ^Λί^-Ζ - i^ -^ [ ^ [ "^ェ( — 一 /— 、 (Η[ε 'Ζ ' I ] - HS - -Ζ- - 9 ) - S ] - ( /^ / y-Z- — ^ 'ε 'ΐ]— /^ ー S)]]— — ^ ー 9 'Ζ -Ζ{Ζ) [S690][ΠΖ ^ [S690]? , ^ Λί ^ -Ζ-i ^-^ [^ ["^ é (— One / —, (Η [ε 'Ζ' I]-HS--Ζ--9)-S]-(/ ^ / yZ -— ^ 'Ε' ΐ] — / ^ ー S)]] — — ^ ー 9 'Ζ -Ζ {Ζ) [S690]
•+(H+PV)9Z9:z/ra SPV • + (H + PV) 9Z9: z / ra SPV
)Z6 'Z-96 ' L '(m 'HS)S Ί-I ' L '(^ 'HI)6S ' L '(s 'HS)88 ·9 ) Z6 'Z-96' L '(m' HS) S Ί-I 'L' (^ 'HI) 6S' L '( s ' HS) 88 9
'(s 'HS)S6 Έ '(s 'HS)99 Έ '(s 'H )06 'Z '(s ¾ε)8 'Ζ '(s 'U£) Z 'Z ' (s 'H9)8I 'Z '(s 'H6)I9 Ί '(s 'Η9)Ι^ Ί- 9 (\OaO 'zH OO^)H N-HT '( s ' HS) S6 Έ '( s ' HS) 99 Έ '( s ' H) 06 'Z' ( s ¾ε) 8 'Ζ' ( s 'U £) Z' Z '( s ' H9) 8I 'Z' ( s 'H6) I9 Ί' ( s 'Η9) Ι ^ Ί- 9 (\ OaO' zH OO ^) H NH T
ZCCM0/S00Zdf/X3d 891- 6C6CT0/900Z OAV
ZCCM0 / S00Zdf / X3d 891- 6C6CT0 / 900Z OAV
[0697] 参考例 35で得たィ匕合物(0.463g)をジクロロメタン (7ml)に溶解し、メトキシァセト アルデヒド (0.170g)とトリァセトキシ水素化ホウ素ナトリウム(0.424g)をカ卩えて、室 温で一晩攪拌した。反応液に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで 3回 抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶 媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 2)で精製し、標題化合物 (0.390g)を無色油状物として得た。 [0697] The compound (0.463 g) obtained in Reference Example 35 was dissolved in dichloromethane (7 ml), and methoxyacetaldehyde (0.170 g) and sodium triacetoxyborohydride (0.424 g) were added at room temperature. Stir overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (0.390 g) as a colorless oil.
[0698] 'H-NMR (400MHz, CDC1 ) δ :1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s) [0698] 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s)
3 Three
, 2.27 (3H, s), 2.66 (2H, t, J = 6.1Hz), 3.29 (3H, s), 3.47 (2H, t, J = 6 . 1Hz), 3.50 (2H, s), 3.51 (2H, s), 6.92 (2H, s), 7.22(1H, t, J = 7.6H z), 7.41 (2H, t, J = 7.6Hz), 7.63 (2H, d, J = 7.6Hz), 7.78 (1H, s) . MS m/z:522(M+H)+. , 2.27 (3H, s), 2.66 (2H, t, J = 6.1Hz), 3.29 (3H, s), 3.47 (2H, t, J = 6.1 Hz), 3.50 (2H, s), 3.51 (2H , s), 6.92 (2H, s), 7.22 (1H, t, J = 7.6H z), 7.41 (2H, t, J = 7.6Hz), 7.63 (2H, d, J = 7.6Hz), 7.78 ( 1H, s) .MS m / z: 522 (M + H) + .
[0699] (2)2— [4— [[(2—メトキシェチル)一(3—メチルー 1一フエ-ルー 1H ピラゾール —4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチルプロピオ ン酸 [0699] (2) 2— [4— [[(2-Methoxyethyl) mono (3-methyl-11-phenol 1H pyrazole-4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] -2 —Methylpropionic acid
[0700] [化 213] [0700] [Chemical 213]
実施例 48— (1)で得たィ匕合物(0.385g)をジクロロメタン(5ml)に溶解し、 4規定 塩酸 ジォキサン溶液(lml)を加えて、室温で一晩攪拌した。反応液を減圧下濃縮
し、残渣をシリカゲルカラムクロマトグラフィー(クロ口ホルム:メタノール = 93: 7)で精 製し、標題ィ匕合物 (0.334g)を無色固体として得た。 Example 48— The compound (0.385 g) obtained in (1) was dissolved in dichloromethane (5 ml), 4N hydrochloric acid dioxane solution (l ml) was added, and the mixture was stirred overnight at room temperature. Concentrate the reaction under reduced pressure The residue was purified by silica gel column chromatography (chloroform: methanol = 93: 7) to give the title compound (0.334 g) as a colorless solid.
[0702] 'H-NMR (400MHz, DMSO— d) δ :1.32 (6H, s), 2. 14 (6H, s), 2.16(3 [0702] 'H-NMR (400MHz, DMSO— d) δ: 1.32 (6H, s), 2. 14 (6H, s), 2.16 (3
6 6
H, s), 2.56 (2H, t, J = 6.1Hz), 3.18 (3H, s), 3.41— 3.46 (6H, m), 6.9 H, s), 2.56 (2H, t, J = 6.1Hz), 3.18 (3H, s), 3.41—3.46 (6H, m), 6.9
4(2H, s), 7.22(1H, t, J = 7.6Hz), 7.44 (2H, t, J = 8.6Hz), 7.76 (2H, d4 (2H, s), 7.22 (1H, t, J = 7.6Hz), 7.44 (2H, t, J = 8.6Hz), 7.76 (2H, d
, J = 8.6Hz), 8.29(1H, s) . , J = 8.6Hz), 8.29 (1H, s).
MS m/z:466(M+H)+. MS m / z: 466 (M + H) +.
[0703] [実施例 49] [0703] [Example 49]
(1)2— [2, 6—ジメチルー 4— [[(3—メチル—1—フエ-ルー 1H—ピラゾールー 4 (1) 2- [2, 6-Dimethyl- 4-[[(3-Methyl-1-Fuelue 1H-pyrazole- 4
—ィルメチル)一(3, 3, 3—トリフルォロプロピル)ァミノ]メチル]フエノキシ ]—2—メ チルプロピオン酸 tert—ブチル エステル —Ylmethyl) mono (3,3,3-trifluoropropyl) amino] methyl] phenoxy] —2-methylpropionic acid tert-butyl ester
[0704] [化 214] [0704] [Chemical 214]
[0705] 実施例 48— (1)と同様にして、参考例 35で得たィ匕合物(0.463g)と 3, 3, 3—トリ フルォロプロピオンアルデヒド (0.224g)力も標題ィ匕合物(0.432g)を無色油状物と して得た。 Example 48—Similarly to (1), the compound (0.463 g) obtained in Reference Example 35 and 3, 3, 3-trifluoropropionaldehyde (0.224 g) force were The compound (0.432 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s) 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)
3 Three
, 2.24-2.28 (2H, m), 2.26 (3H, s), 2.71 (2H, t, J = 7.8Hz), 3.44 (2H , s), 3.47 (2H, s), 6.91 (2H, s), 7.23(1H, t, J = 7.8Hz), 7.42 (2H, t, J =7.8Hz), 7.62 (2H, d, J = 7.8Hz), 7.75(1H, s) . , 2.24-2.28 (2H, m), 2.26 (3H, s), 2.71 (2H, t, J = 7.8Hz), 3.44 (2H, s), 3.47 (2H, s), 6.91 (2H, s), 7.23 (1H, t, J = 7.8Hz), 7.42 (2H, t, J = 7.8Hz), 7.62 (2H, d, J = 7.8Hz), 7.75 (1H, s).
MS m/z:560(M+H)+. MS m / z: 560 (M + H) +.
[0706] (2)2— [2, 6—ジメチルー 4— [[(3—メチル—1—フエ-ルー 1H—ピラゾールー 4 —ィルメチル)一(3, 3, 3—トリフルォロプロピル)ァミノ]メチル]フエノキシ ]—2—メ チルプロピオン酸
[0707] [化 215] [0706] (2) 2— [2, 6-Dimethyl-4-] [[(3-Methyl-1-Ferru 1H-Pyrazole-4-Ilmethyl) (3,3,3-Trifluoropropyl) amino] Methyl] phenoxy] -2-methylpropionic acid [0707] [Chemical 215]
[0708] 実施例 48— (2)と同様にして、実施例 49— (1)で得たィ匕合物(0.425g)から、標 題化合物(0.379g)を無色固体として得た。これをジクロロメタン(2ml)に溶解し、 4 規定塩酸 ジォキサン溶液 (0.376ml)を加えて減圧下に溶媒を留去して塩酸塩と した。 Example 48— In the same manner as (2), the title compound (0.379 g) was obtained as a colorless solid from the compound (0.425 g) obtained in Example 49 (1). This was dissolved in dichloromethane (2 ml), 4N hydrochloric acid dioxane solution (0.376 ml) was added, and the solvent was distilled off under reduced pressure to obtain hydrochloride.
'H-NMR (400MHz, DMSO-d) δ :1.35 (6Η, s), 2. 17(6Η, s), 2.19(3 'H-NMR (400MHz, DMSO-d) δ: 1.35 (6Η, s), 2.17 (6Η, s), 2.19 (3
6 6
Η, s), 2.95-3.12(2Η, m), 3.60— 3.80 (4Η, m), 4.18—4.29 (2H, m) Η, s), 2.95-3.12 (2Η, m), 3.60—3.80 (4Η, m), 4.18—4.29 (2H, m)
, 7.32-7.34 (3H, m), 7.52 (2H, t, J = 7.6Hz), 7.76 (2H, d, J = 7.6Hz, 7.32-7.34 (3H, m), 7.52 (2H, t, J = 7.6Hz), 7.76 (2H, d, J = 7.6Hz
), 8.74 (1H, s). ), 8.74 (1H, s).
MS m/z:504(M+H)+. MS m / z: 504 (M + H) + .
[0709] [実施例 50] [0709] [Example 50]
( 1 ) 2— [ 2, 6 ジメチル 4 [ [メチルカルバモイルメチル ( 3 メチル 1 フエ (1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl (3 Methyl 1 Hue
-ル 1H ピラゾール 4 ィルメチル)ァミノ]メチル]フエノキシ] -2-メチルプロ ピオン酸 ェチル エステル -Le 1H pyrazole 4-methyl) amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester
[0710] [化 216] [0710] [Chemical 216]
[0711] 実施例 25— (1)と同様にして、参考例 36— (2)で得た化合物(0.345g)とメチル ァミン(2Mテトラヒドロフラン溶液、 1ml)を用いて、標題ィ匕合物(0.341g)を無色油 状物として得た。 Example 25— In the same manner as in (1), using the compound (0.345 g) obtained in Reference Example 36- (2) and methylamine (2M tetrahydrofuran solution, 1 ml), the title compound ( 0.341 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (9H, s), 2
. 17(6H, s), 2.23 (3H, s), 2.76 (3H, d, J=4.9Hz), 3.24 (2H, s), 3.62'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (9H, s), 2 17 (6H, s), 2.23 (3H, s), 2.76 (3H, d, J = 4.9Hz), 3.24 (2H, s), 3.62
(2H, s), 3.64 (2H, s), 4.29 (2H, q, J = 7.1Hz) , 6.90 (2H, s), 7.21— 7.(2H, s), 3.64 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.90 (2H, s), 7.21— 7.
24 (1H, m), 7.33(1H, d, J = 7.6Hz), 7.40 (2H, t, J = 7.6Hz), 7.58 (2H24 (1H, m), 7.33 (1H, d, J = 7.6Hz), 7.40 (2H, t, J = 7.6Hz), 7.58 (2H
, d, J = 7.6Hz), 7.80(1H, s) . , d, J = 7.6Hz), 7.80 (1H, s).
MS m/z:507(M+H)+. MS m / z: 507 (M + H) + .
[0712] (2)2— [2, 6 ジメチルー 4 [[メチルカルバモイルメチルー(3—メチルー 1 フエ[0712] (2) 2— [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (3-methyl-1-phenol
-ル 1H ピラゾール 4 ィルメチル)ァミノ]メチル]フエノキシ] -2-メチルプロ ピオン酸 -Le 1H pyrazole 4-methyl) amino] methyl] phenoxy] -2-methylpropionic acid
[0713] [化 217] [0713] [Chemical 217]
[0714] 実施例 1— (2)と同様にして、実施例 50— (1)で得たィ匕合物 (0.335g)力も標題 化合物(0.266g)を無色固体として得た。 [0714] In the same manner as in Example 1- (2), the compound (0.335g) force obtained in Example 50- (1) also gave the title compound (0.266g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 14 (3Η, s), 2.16(6 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (3Η, s), 2.16 (6
6 6
H, s), 2.59 (3H, d, J=4.7Hz), 2.97 (2H, s), 3.43 (2H, s), 3.50 (2H, s ), 7.01 (2H, s), 7.24 (1H, t, J = 7.8Hz), 7.46 (2H, d, J = 7.8Hz), 7.55 (1H, q, J=4.7Hz), 7.76 (2H, d, J = 7.8Hz), 8.37(1H, s) . H, s), 2.59 (3H, d, J = 4.7Hz), 2.97 (2H, s), 3.43 (2H, s), 3.50 (2H, s), 7.01 (2H, s), 7.24 (1H, t , J = 7.8Hz), 7.46 (2H, d, J = 7.8Hz), 7.55 (1H, q, J = 4.7Hz), 7.76 (2H, d, J = 7.8Hz), 8.37 (1H, s).
元素分析値 C H NO ·Η Oとして Elemental analysis value as C H NO · Η O
27 34 4 4 2 27 34 4 4 2
計算値: C, 65.30;H, 7.31;N, 11.28. Calculated value: C, 65.30; H, 7.31; N, 11.28.
実測値: C, 65.45;H, 7.22;N, 10.92. Found: C, 65.45; H, 7.22; N, 10.92.
MS m/z:479(M+H)+. MS m / z: 479 (M + H) + .
[0715] [実施例 51] [0715] [Example 51]
(1) 2— [4 [[ジメチルカルバモイルメチルー(3—メチルー 1 フエ-ルー 1H ピ ラゾールー 4 ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ ] 2 メチル
プロピオン酸 ェチノレ エステノレ (1) 2- [4 [[Dimethylcarbamoylmethyl- (3-methyl-1 phenol- 1H pyrazole-4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] 2 methyl Propionate Etenore Estenore
[0716] [化 218] [0716] [Chemical 218]
[0717] 実施例 25— (1)と同様にして、参考例 36— (2)で得た化合物 (0.345g)とジメチ ルァミン(2Mテトラヒドロフラン溶液、 1ml)を用いて、標題ィ匕合物(0.195g)を無色 油状物として得た。 Example 25— In the same manner as in (1), using the compound (0.345 g) obtained in Reference Example 36- (2) and dimethylamine (2M tetrahydrofuran solution, 1 ml), the title compound ( 0.195 g) was obtained as a colorless oil.
'H-NMR (400MHz, CDCl) δ :1.36 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 'H-NMR (400MHz, CDCl) δ: 1.36 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 18 (6H, s), 2.25 (3H, s), 2.81 (3H, s), 2.87 (3H, s), 3.22 (2H, s), 3. 55 (2H, s), 3.61 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.92 (2H, s), 7.23 ( 1H, t, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.64 (2H, d, J = 7.6Hz), 7. 83 (1H, s). 18 (6H, s), 2.25 (3H, s), 2.81 (3H, s), 2.87 (3H, s), 3.22 (2H, s), 3.55 (2H, s), 3.61 (2H, s ), 4.29 (2H, q, J = 7.1Hz), 6.92 (2H, s), 7.23 (1H, t, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.64 (2H, d , J = 7.6Hz), 7. 83 (1H, s).
MS m/z:521(M+H)+. MS m / z: 521 (M + H) + .
[0718] (2) 2— [4 [[ジメチルカルバモイルメチルー(3—メチルー 1 フエ-ルー 1H ピ ラゾールー 4 ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ ] 2 メチル プロピオン酸 [0718] (2) 2— [4 [[Dimethylcarbamoylmethyl- (3-methyl-1 phenol- 1H pyrazole-4-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] 2 methyl propionic acid
[0719] [化 219] [0719] [Chemical 219]
[0720] 実施例 1— (2)と同様にして、実施例 51— (1)で得たィ匕合物 (0.190g)力も標題 化合物(0.087g)を無色固体として得た。
Ή-NMR (400MHz, DMSO— d) δ :1.32 (6H, s), 2. 11 (3H, s), 2.14(6 In the same manner as in Example 1- (2), the compound (0.190 g) force obtained in Example 51- (1) was also used to obtain the title compound (0.087 g) as a colorless solid. NMR-NMR (400MHz, DMSO— d) δ: 1.32 (6H, s), 2.11 (3H, s), 2.14 (6
6 6
H, s), 2.75 (3H, s), 2.79 (3H, s), 3.18 (2H, s), 3.49 (2H, s), 3.50 (2H , s), 6.92 (2H, s), 7.23(1H, t, J = 7.6Hz), 7.44 (2H, t, J = 7.6Hz), 7. 75 (2H, d, J = 7.6Hz), 8.29 (1H, s) . H, s), 2.75 (3H, s), 2.79 (3H, s), 3.18 (2H, s), 3.49 (2H, s), 3.50 (2H, s), 6.92 (2H, s), 7.23 (1H , t, J = 7.6Hz), 7.44 (2H, t, J = 7.6Hz), 7.75 (2H, d, J = 7.6Hz), 8.29 (1H, s).
元素分析値 C H NO ·3Ζ4ΗΟとして Elemental analysis value as C H NO 3Ζ4ΗΟ
28 36 4 4 2 28 36 4 4 2
計算値: C, 66.45;H, 7.47;N, 11.07. Calculated values: C, 66.45; H, 7.47; N, 11.07.
実測値: C, 66.33;H, 7.41;N, 10.74. Found: C, 66.33; H, 7.41; N, 10.74.
MS m/z:493(M+H)+. MS m / z: 493 (M + H) +.
[0721] [実施例 52] [0721] [Example 52]
( 1 ) 2— [4— [ [イソキサゾール— 5—ィルメチル—( 3—メチル— 1—フエ-ル— 1 H— ピラゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチ ルプロピオン酸 tert—ブチル エステル (1) 2— [4— [[Isoxazole-5-ylmethyl- (3-methyl-1-phenol- 1 H-pyrazole-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] — 2-Methylpropionic acid tert-butyl ester
[0722] [化 220] [0722] [Chemical 220]
[0723] 参考例 37— (2)で得た化合物(0.073g)、参考例 16— (1)で得た化合物(0.08 8g)をジクロロメタン (4ml)に溶解し、トリァセトキシ水素化ホウ素ナトリウム(0.086g) を加えて、室温で一晩攪拌した。反応液に炭酸水素ナトリウム水溶液を加え、ジクロ ロメタンで 3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥 後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル: へキサン =1:4)で精製し、標題化合物(0.110g)を無色油状物として得た。 Reference Example 37— Compound (0.073 g) obtained in (2) and Reference Example 16— Compound (0.08 8 g) obtained in (1) were dissolved in dichloromethane (4 ml), and sodium triacetoxyborohydride (0.086 g) was added and stirred at room temperature overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (0.110 g) as a colorless oil.
'H-NMR (400MHz, CDC1) δ :1.42 (6Η, s), 1.51 (9Η, s), 2.23 (6H, s) 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.23 (6H, s)
3 Three
, 2.28 (3H, s), 3.50 (2H, s), 3.53 (2H, s), 3.78 (2H, s), 6.12(1H, d, J =1.7Hz), 6.96 (2H, s), 7.23 (1H, d, J = 7.4Hz), 7.42 (2H, t, J = 8.6H z), 7.64 (2H, d, J = 8.6Hz), 7.83(1H, s), 8.21 (1H, d, J=l.7Hz) .
MS m/z:545(M+H)+. , 2.28 (3H, s), 3.50 (2H, s), 3.53 (2H, s), 3.78 (2H, s), 6.12 (1H, d, J = 1.7Hz), 6.96 (2H, s), 7.23 ( 1H, d, J = 7.4Hz), 7.42 (2H, t, J = 8.6H z), 7.64 (2H, d, J = 8.6Hz), 7.83 (1H, s), 8.21 (1H, d, J = l.7Hz) MS m / z: 545 (M + H) +.
[0724] ( 2) 2— [4 [ [イソキサゾール 5 ィルメチル ( 3 メチル 1 フエ-ル -1H- ピラゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メチ ルプロピオン酸 [0724] (2) 2— [4 [[Isoxazole 5ylmethyl (3methyl-1phenol-1H-pyrazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid
[0725] [化 221] [0725] [Chem 221]
[0726] 実施例 24— (2)と同様にして、実施例 52— (1)で得たィ匕合物(0.105g)から、標 題化合物(0.081g)を無色固体として得た。 Example 24-—In the same manner as (2), the title compound (0.081 g) was obtained as a colorless solid from the compound (0.105 g) obtained in Example 52- (1).
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 13 (3Η, s), 2.15(6 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.13 (3Η, s), 2.15 (6
6 6
H, s), 3.43 (2H, s), 3.47 (2H, s), 3.77 (2H, s), 6.46 (1H, d, J=l.7Hz ), 6.97 (2H, s), 7.23(1H, d, J = 7.6Hz), 7.45 (2H, t, J = 7.6Hz), 7.77 (2H, d, J = 7.6Hz), 8.34(1H, s), 8.52(1H, d, J=l.7Hz) . H, s), 3.43 (2H, s), 3.47 (2H, s), 3.77 (2H, s), 6.46 (1H, d, J = l.7Hz), 6.97 (2H, s), 7.23 (1H, d, J = 7.6Hz), 7.45 (2H, t, J = 7.6Hz), 7.77 (2H, d, J = 7.6Hz), 8.34 (1H, s), 8.52 (1H, d, J = l.7Hz ).
MS m/z:545(M+H)+. MS m / z: 545 (M + H) +.
[0727] [実施例 53] [0727] [Example 53]
(1) 2— [4— [[[1— (4 クロ口フエ-ル)一 3—メチル 1H ピラゾール一 4—ィル メチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2— メチルプロピオン酸 ェチル エステル (1) 2— [4— [[[1— (4 Black Mouth Phenol) 1 3-Methyl 1H Pyrazole 1- 4-Methyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy ] —2— Methylpropionic acid ethyl ester
[0728] [化 222] [0728] [Chemical 222]
[0729] 実施例 30— (1)と同様にして、参考例 1で得た化合物 (0.143g)と参考例 38で得
た化合物(0.200g)から標題ィ匕合物(0.305g)を無色油状物として得た。 Example 30— In the same manner as (1), the compound (0.143 g) obtained in Reference Example 1 and Reference Example 38 were obtained. The title compound (0.305 g) was obtained as a colorless oil from the compound (0.200 g).
MS m/z:540(M+H)+. MS m / z: 540 (M + H) + .
[0730] (2) 2— [4— [[[ 1— (4 クロ口フエ-ル) 3 メチル 1H ピラゾール 4 ィル メチル]メチルカルバモイルメチルァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2— メチルプロピオン酸 [0730] (2) 2— [4— [[[1— (4 Black Mouth Phenol) 3 Methyl 1H Pyrazole 4 Methyl] Methylcarbamoylmethylamino] Methyl] -2, 6-Dimethylphenoxy ] —2— Methylpropionic acid
[0731] [化 223] [0731] [Chemical 223]
[0732] 実施例 1— (2)と同様にして、実施例 53— (1)で得たィ匕合物(0.300g)から標題 化合物(0.091g)を無色固体として得た。 [0732] In the same manner as in Example 1- (2), the title compound (0.091g) was obtained as a colorless solid from the compound (0.300g) obtained in Example 53- (1).
'H-NMR (400MHz, DMSO-d) δ :1.33 (6Η, s), 2. 13 (3Η, s), 2.16(6 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.13 (3Η, s), 2.16 (6
6 6
H, s), 2.58 (3H, d, J=4.9Hz), 2.97 (2H, s), 3.42 (2H, s), 3.50 (2H, s ), 7.00 (2H, s), 7.50-7.55 (3H, m), 7.79 (2H, t, J = 8.8Hz), 8.39(1 H, s). H, s), 2.58 (3H, d, J = 4.9Hz), 2.97 (2H, s), 3.42 (2H, s), 3.50 (2H, s), 7.00 (2H, s), 7.50-7.55 (3H , m), 7.79 (2H, t, J = 8.8Hz), 8.39 (1 H, s).
MS m/z:512(M+H)+. MS m / z: 512 (M + H) + .
[0733] [実施例 54] [0733] [Example 54]
(l)2-[4-[[[2-(3, 4ージメチルフヱ-ル)ー5—メチルー 2H—[1, 2, 3]トリア ゾール 4 ィルメチル] ( 5 メチル—[1, 3, 4]ォキサジァゾール 2 ィルメチ ル)ァミノ]メチル] 2, 6 ジメチルフエノキシ ] 2 メチルプロピオン酸 ェチル エステル (l) 2- [4-[[[2- (3,4-Dimethylphenol) -5-methyl-2H— [1, 2, 3] triazole 4-methylmethyl] (5 Methyl— [1, 3, 4] Oxadiazole 2-dimethyl) amino] methyl] 2,6 dimethylphenoxy] 2 methyl propionic acid ethyl ester
[0734] [化 224]
PP ΉΙ)Ζ9 ' L '(ΖΗ9 ·8 = ΓΡ 'ΗΙ)92 ' L '(S 'HS)S6 ·9 '(S 'HS)68 Έ '(S ' UZ)SL Έ '(S 'HS)69 Έ '(S 'HS)S 'Z '(S 'HS)OS 'Z '(S 'HS)9S 'Z '(S 'H [0734] [Chemical 224] PP ΉΙ) Ζ 9 'L' ( Ζ · 9 8 = Γ Ρ 'ΗΙ) 92' L '( S ' HS) S6 9 '( S ' HS) 68 Έ '( S ' UZ) SL Έ '( S ' HS ) 69 Έ '( S ' HS) S 'Z' ( S 'HS) OS' Z '( S ' HS) 9S 'Z' ( S 'H
£)IZ 'Z '(S 'H9)SI 'Ζ '(S 'H9)SS Ί- 9 (P-OSWa 'ZH 00^)H N-HT £) IZ 'Z' ( S 'H9) SI' Ζ '( S ' H9) SS Ί-9 (P-OSWa 'ZH 00 ^) H NH T
^m ^ ^ ^ ^ (§oox -o) ^ ^ m ^ ^ ^ ^ ( § oox -o) ^
-Z- /— 、 ; ^ ^ 'ε 'χ]- -9) - →- /— 、 (Η[ε 'Ζ Ί]-Η2- -έ^-9- ( /—^Δ /^^→ 'ε) -2]]]-¾-2(2) [9SZ0] -Z- / —,; ^ ^ 'ε' χ]--9)-→-/ —, (Η [ε 'Ζ Ί] -Η2- -έ ^ -9- (/ — ^ Δ / ^^ → 'ε) -2]]]-¾-2 (2) [9SZ0]
•+(H + PV)I99:Z/RA SPV • + (H + PV) I99: Z / RA SPV
•(ZHS '2 = Γ 'Ρ 'ΗΙ • (ZHS '2 = Γ' Ρ 'ΗΙ
)91 Ί '(ζΗε ·8 'Ζ 'Ζ = ί'νν 'ΗΙ)69 ' L '(ZHS ·8 = ΓΡ 'ΗΙ)6Ι ' L '(s 'ΗΖ ) 91 Ί '( ζ Ηε 8' Ζ 'Ζ = ί'νν' ΗΙ) 69 'L' ( Z HS 8 = ΓΡ 'ΗΙ) 6 Ι L' ( s ' ΗΖ
)96 ·9 '(ΖΗΙ · = Γ '¾ 'Η2)62 '(S 'HS) 6 Έ '(S 'HS)S8 Έ '(S 'HS)99) 96 · 9 '( Ζ ΗΙ · = Γ' ¾ 'Η2) 62' ( S 'HS) 6 Έ' ( S 'HS) S8 Έ' ( S 'HS) 99
•ε '(s Ή£)Ζ 'ζ '(s Ήε)εε 'ζ '(S 'HS)8S 'Ζ '(S Ή£)ιζ 'Ζ '(S 'Η9)8Ι · z '(S ¾9)9 ·χ '(ΖΗΙ · =Γ'^ 'Ηε)9ε ·χ: 9 ('ιοαο 'ZH OO^)H N-HT Ε '( s Ή £) Ζ' ζ '( s Ήε) εε' ζ '( S ' HS) 8S 'Ζ' ( S Ή £) ιζ 'Ζ' ( S 'Η9) 8 Ι z' ( S ¾9 ) 9 χ '( Ζ ΗΙ · = Γ' ^ 'Ηε) 9ε χ: 9 (' ιοαο 'ZH OO ^) H NH T
ZCCM0/S00Zdf/X3d 19 V 6C6CT0/900Z OAV
, J = 2.2, 8.6Hz), 7.70(1H, d, J = 2.2Hz) . ZCCM0 / S00Zdf / X3d 19 V 6C6CT0 / 900Z OAV , J = 2.2, 8.6Hz), 7.70 (1H, d, J = 2.2Hz).
MS m/z:533(M+H)+. MS m / z: 533 (M + H) +.
[0739] [実施例 55] [0739] [Example 55]
(1)2— [4— [[[2— (4 クロロフヱ-ル)一 5—メチル 2H—[1, 2, 3]トリァゾール 4 ィルメチル] - (2—メトキシェチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ] 2—メチルプロピオン酸 ェチル エステル (1) 2- [4 -— [[[2- (4-Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole 4-methyl]-(2-methoxyethyl) amino] methyl] —2, 6 Dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0740] [化 226] [0740] [Chemical 226]
[0741] 実施例 29— (1)と同様にして、参考例 25— (2)で得た化合物 (0.113g)と参考例 40で得たィ匕合物(0.141g)力も標題ィ匕合物(0.226g)を無色油状物として得た。 'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 [0741] In the same manner as in Example 29- (1), the compound (0.113g) obtained in Reference Example 25- (2) and the compound (0.141g) obtained in Reference Example 40 were also combined with the title compound. Product (0.226 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 17(6H, s), 2.27 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 ( 2H, t, J = 5.9Hz), 3.55 (2H, s), 3.72 (2H, s), 4.29 (2H, q, J = 7. 1Hz), 6.93 (2H, s), 7.40 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.8Hz) . 17 (6H, s), 2.27 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.72 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.93 (2H, s), 7.40 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.8Hz).
MS m/z:529(M+H)+. MS m / z: 529 (M + H) +.
[0742] (2) 2— [4— [[[2— (4 クロロフヱ-ル)ー5—メチルー 2H—[1, 2, 3]トリァゾール [0742] (2) 2— [4— [[[2— (4 Chlorophenyl) -5-methyl-2H— [1, 2, 3] triazole
4 ィルメチル] - (2—メトキシェチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ] 2—メチルプロピオン酸 4-ylmethyl]-(2-methoxyethyl) amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid
[0743] [化 227] [0743] [Chemical 227]
[0744] 実施例 1— (2)と同様にして、実施例 55— (1)で得たィ匕合物 (0.210g)力も標題 化合物(0.200g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.210 g) force obtained in Example 55- (1) was also used to obtain the title compound (0.200 g) as a colorless solid.
'H-NMR (400MHz, DMSO-d) δ :1.31 (6Η, s), 2. 11 (6Η, s), 2.23(3 'H-NMR (400MHz, DMSO-d) δ: 1.31 (6Η, s), 2.11 (6Η, s), 2.23 (3
6 6
H, s), 2.63 (2H, t, J = 5.9Hz), 3.20 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3 .50 (2H, s), 3.70 (2H, s), 6.91 (2H, s), 7.58 (2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.8Hz). H, s), 2.63 (2H, t, J = 5.9Hz), 3.20 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3.50 (2H, s), 3.70 (2H, s ), 6.91 (2H, s), 7.58 (2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.8Hz).
元素分析値 C H C1NO ·0.25HOとして Elemental analysis value C H C1NO · 0.25HO
26 33 4 4 2 26 33 4 4 2
計算値: C, 61.77;H, 6.68; CI, 7.01;N, 11.08. Calculated values: C, 61.77; H, 6.68; CI, 7.01; N, 11.08.
実測値: C, 61.52;H, 6.67; CI, 6.73;N, 10.94. Found: C, 61.52; H, 6.67; CI, 6.73; N, 10.94.
[0745] [実施例 56] [0745] [Example 56]
(1) 2— [4 [[(2—メトキシェチル) [2—(4ーメトキシフヱ-ル) 5—メチルー 2 (1) 2— [4 [[((2-Methoxyethyl) [2- (4-methoxyphenyl) 5-methyl-2]
H— [1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジメチルフエノキ シ ] 2—メチルプロピオン酸 ェチル エステル H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid ethyl ester
[0746] [化 228] [0746] [Chemical 228]
[0747] 実施例 29— (1)と同様にして、参考例 29— (2)で得た化合物 (0.120g)と参考例 40で得たィ匕合物(0.138g)力も標題ィ匕合物(0.130g)を無色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 [0747] In the same manner as in Example 29- (1), the compound (0.120g) obtained in Reference Example 29- (2) and the compound (0.138g) obtained in Reference Example 40 had the same strength. Product (0.130 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 18 (6H, s), 2.28 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 ( 2H, t, J = 5.9Hz), 3.55 (2H, s), 3.72 (2H, s), 3.84 (3H, s), 4.29 (2H, q, J = 7. 1Hz), 6.94 (2H, s) , 6.95 (2H, d, J = 9.1Hz), 7.89 (2H, d, J=9 . 1Hz). 18 (6H, s), 2.28 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.72 (2H, s), 3.84 (3H, s), 4.29 (2H, q, J = 7.1 Hz), 6.94 (2H, s), 6.95 (2H, d, J = 9.1 Hz), 7.89 (2H, d, J = 9.1 Hz).
MS m/z:525(M+H)+. MS m / z: 525 (M + H) +.
[0748] (2) 2— [4— [[(2—メトキシェチル) [2—(4ーメトキシフエ-ル) 5—メチルー 2
H— [1, 2, 3]トリァゾールー 4—ィルメチル]ァミノ]メチル ]—2, 6 ジメチルフエノキ シ] 2—メチルプロピオン酸 [0748] (2) 2— [4— [[(2-Methoxyethyl) [2- (4-methoxyphenyl) 5-methyl-2] H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid
[化 229] [Chemical 229]
[0750] 実施例 1— (2)と同様にして、実施例 56— (1)で得たィ匕合物(0.125g)力も標題 化合物(0. 117g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.125 g) force obtained in Example 56- (1) was also used to obtain the title compound (0.117 g) as a colorless solid.
iH—NMR (400MHz, DMSO d) δ :1.32 (6H, s), 2. 12(6H, s), 2.22(3 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3
6 6
H, s), 2.62 (2H, t, J = 5.9Hz), 3.19 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3 .49 (2H, s), 3.68 (2H, s), 3.80 (3H, s), 6.92 (2H, s), 7.07 (2H, d, J = 9. 1Hz), 7.83 (2H, d, J = 9. 1Hz) . H, s), 2.62 (2H, t, J = 5.9Hz), 3.19 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3.49 (2H, s), 3.68 (2H, s ), 3.80 (3H, s), 6.92 (2H, s), 7.07 (2H, d, J = 9.1Hz), 7.83 (2H, d, J = 9.1Hz).
元素分析値 C H NO ·0.25HOとして Elemental analysis value as C H NO · 0.25HO
27 36 4 5 2 27 36 4 5 2
計算値: C, 64.72;H, 7.34 ;N, 11.18. Calculated value: C, 64.72; H, 7.34; N, 11.18.
実測値: C, 64.51;H, 7.38;N, 11.06. Found: C, 64.51; H, 7.38; N, 11.06.
[0751] [実施例 57] [0751] [Example 57]
(1) 2— [4— [[(2 ヒドロキシェチル)一(5—メチルー 2 フヱ-ルー 2H—[1, 2, 3 ]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2—メ チルプロピオン酸 tert ブチル エステル (1) 2- [4 -— [[(2 Hydroxyethyl) mono (5-methyl-2 furo-lu 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 dimethyl Phenoxy] -2-methylpropionic acid tert butyl ester
[0752] [化 230] [0752] [Chemical 230]
[0753] 実施例 29— (1)と同様にして、参考例 15— (1)で得たィ匕合物 (0.108g)と参考例
41で得たィ匕合物(0.145g)から標題ィ匕合物(0.228g)を無色油状物として得た。 'H-NMR (400MHz, CDCl) δ :1.42 (6Η, s), 1.52 (9Η, s), 2.21 (6H, s) [0753] Example 29—In the same manner as (1), Reference Example 15—Compound (0.108 g) obtained in (1) and Reference Example The title compound (0.228 g) was obtained as a colorless oil from the compound (0.145 g) obtained in 41. 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.21 (6H, s)
3 Three
, 2.22 (3H, s), 2.79 (2H, br s), 3.59 (2H, br s), 3.65 (2H, br s), 3.7 , 2.22 (3H, s), 2.79 (2H, br s), 3.59 (2H, br s), 3.65 (2H, br s), 3.7
3(2H, br s), 6.93 (2H, s), 7.30(1H, t, J = 7.6Hz), 7.45 (2H, t, J = 7.63 (2H, br s), 6.93 (2H, s), 7.30 (1H, t, J = 7.6Hz), 7.45 (2H, t, J = 7.6
Hz), 7.99 (2H, d, J = 7.6Hz) . Hz), 7.99 (2H, d, J = 7.6Hz).
MS m/z:509(M+H)+. MS m / z: 509 (M + H) +.
[0754] (2) 2— [4— [[(2—ヒドロキシェチル)一(5—メチルー 2—フエ-ルー 2H—[1, 2, 3[0754] (2) 2— [4— [[(2-Hydroxyethyl) mono (5-methyl-2-ferrue) 2H— [1, 2, 3
]トリアゾール—4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メ チルプロピオン酸 ] Triazole-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid
[0755] [化 231] [0755] [Chemical 231]
[0756] 実施例 24— (2)と同様にして、実施例 57— (1)で得たィ匕合物(0.219g)から標題 化合物(0. 184g)を無色固体として得た。 Example 24- In the same manner as in (2), the title compound (0.184 g) was obtained as a colorless solid from the compound (0.219 g) obtained in Example 57- (1).
'H-NMR (400MHz, DMSO-d) δ :1.32 (6Η, s), 2. 12(6Η, s, ), 2.24( 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.12 (6Η, s,), 2.24 (
6 6
3Η, s), 2.55 (2Η, t, J = 6.4Hz), 3.51 (2H, s), 3.52 (2H, t, J = 6.4Hz), 3.68 (2H, s), 4.39 (1H, br s), 6.93 (2H, s), 7.35 (1H, t, J = 7.6Hz), 7 .52 (2H, t, J = 7.6Hz), 7.92 (2H, d, J = 7.6Hz) . 3Η, s), 2.55 (2Η, t, J = 6.4Hz), 3.51 (2H, s), 3.52 (2H, t, J = 6.4Hz), 3.68 (2H, s), 4.39 (1H, br s) , 6.93 (2H, s), 7.35 (1H, t, J = 7.6Hz), 7.52 (2H, t, J = 7.6Hz), 7.92 (2H, d, J = 7.6Hz).
元素分析値 C H NO ·0.25HOとして Elemental analysis value as C H NO · 0.25HO
25 32 4 4 2 25 32 4 4 2
計算値: C, 65.70;H, 7. 17;N, 12.26. Calculated values: C, 65.70; H, 7. 17; N, 12.26.
実測値: C, 65.81;H, 7.25;N, 12.04. Found: C, 65.81; H, 7.25; N, 12.04.
[0757] [実施例 58] [0757] [Example 58]
(1)2— [4— [[(2—メトキシェチル)—(1— p—トリル— 1H— [1, 2, 3]トリァゾール —4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチルプロピオ ン酸 ェチノレ エステノレ
[0758] [化 232] (1) 2- [4-[[(2-Methoxyethyl)-(1-p-tolyl- 1H- [1, 2, 3] triazole —4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy 2] -Methylpropioate Ethenole Estenole [0758] [Chemical 232]
[0759] 実施例 29— (1)と同様にして、参考例 42— (2)で得た化合物 (0. lOOg)と参考例 40で得たィ匕合物(0.128g)力も標題ィ匕合物(0.182g)を無色油状物として得た。 'H-NMR (400MHz, CDCl) δ :1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2 Example 29— In the same manner as (1), Reference Example 42—Compound (0. lOOg) obtained in (2) and the compound (0.128 g) force obtained in Reference Example 40 were The compound (0.182g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2
3 Three
. 19 (6H, s), 2.42 (3H, s), 2.73 (2H, t, J = 5.4Hz), 3.31 (3H, s), 3.53( 2H, t, J = 5.4Hz), 3.60 (2H, s), 3.92 (2H, s), 4.28 (2H, q, J = 7. 1Hz), 6.97 (2H, s), 7.31 (2H, d, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz), 7.87(1 H, s). 19 (6H, s), 2.42 (3H, s), 2.73 (2H, t, J = 5.4Hz), 3.31 (3H, s), 3.53 (2H, t, J = 5.4Hz), 3.60 (2H, s), 3.92 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.97 (2H, s), 7.31 (2H, d, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz), 7.87 (1 H, s).
MS m/z:495(M+H)+. MS m / z: 495 (M + H) +.
[0760] (2)2— [4— [[(2—メトキシェチル)—(1— p—トリル— 1H— [1, 2, 3]トリァゾール[0760] (2) 2— [4 — [[(2-Methoxyethyl) — (1—p-tolyl—1H— [1, 2, 3] triazole
—4—ィルメチル)ァミノ]メチル ]—2, 6—ジメチルフエノキシ]—2—メチルプロピオ ン酸 —4-ylmethyl) amino] methyl] —2,6-dimethylphenoxy] —2-methylpropionic acid
[0761] [化 233] [0761] [Chemical 233]
実施例 1— (2)と同様にして、実施例 58— (1)で得たィ匕合物 (0.178g)力も標題 化合物(0. 164g)を無色固体として得た。 In the same manner as in Example 1- (2), the compound (0.178 g) force obtained in Example 58- (1) was also used to obtain the title compound (0.164 g) as a colorless solid.
iH—NMR (400MHz, DMSO— d) δ :1.33 (6H, s), 2. 15 (6H, s), 2.38(3 iH-NMR (400MHz, DMSO- d) δ: 1.33 (6H, s), 2. 15 (6H, s), 2.38 (3
6 6
H, s), 2.59 (2H, t, J = 6.1Hz), 3.20 (3H, s), 3.45 (2H, t, J = 6.1Hz), 3 .52 (2H, s), 3.78 (2H, s), 6.99 (2H, s), 7.40 (2H, d, J = 8.6Hz), 7.80
(2H, d, J = 8.6Hz), 8.64 (1H, s) . H, s), 2.59 (2H, t, J = 6.1Hz), 3.20 (3H, s), 3.45 (2H, t, J = 6.1Hz), 3.52 (2H, s), 3.78 (2H, s ), 6.99 (2H, s), 7.40 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz), 8.64 (1H, s).
元素分析値 C H NO ·0.5HOとして Elemental analysis value as C H NO 0.5 HO
26 34 4 4 2 26 34 4 4 2
計算値: C, 65.66;H, 7.42;N, 11.78. Calculated values: C, 65.66; H, 7.42; N, 11.78.
実測値: C, 65.95;H, 7.41;N, 11.86. Found: C, 65.95; H, 7.41; N, 11.86.
[0763] [実施例 59] [0763] [Example 59]
(1)2— [2, 6 ジメチルー 4— [[(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ ルメチル)—(1— p トリル— 1H— [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メ チル]フエノキシ ] 2—メチルプロピオン酸 ェチル エステル (1) 2- [2, 6 Dimethyl-4-[[((5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(1-p-tolyl- 1H- [1, 2, 3] triazole- 4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid ethyl ester
[0764] [化 234] [0764] [Chemical 234]
[0765] 実施例 26— (1)と同様にして、参考例 43— (3)で得たィ匕合物(0.200g)からトリフ ェニルホスフィンォキシドを含む標題ィ匕合物(0.467g)を無色固体として得た。Example 26—In the same manner as (1), the title compound (0.467 g) containing triphenylphosphine oxide was obtained from the compound (0.200 g) obtained in Reference Example 43- (3). Was obtained as a colorless solid.
MS m/z:533(M+H)+. MS m / z: 533 (M + H) +.
[0766] (2)2— [2, 6 ジメチルー 4 [[(5—メチルー [1, 3, 4]ォキサジァゾ一ルー 2—ィ ルメチル)—(1— p トリル— 1H— [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メ チル]フエノキシ ] 2—メチルプロピオン酸 [0766] (2) 2— [2, 6 Dimethyl-4 [[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(1-p-tolyl- 1H— [1, 2, 3 ] Triazol-4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid
[0767] [化 235] [0767] [Chemical 235]
[0768] 実施例 1— (2)と同様にして、実施例 59— (1)で得た混合物 (0.467g)力も標題 化合物(0. 124g)を無色固体として得た。 In the same manner as in Example 1- (2), the mixture (0.467 g) obtained in Example 59- (1) also gave the title compound (0.124 g) as a colorless solid.
iH—NMR (400MHz, DMSO d) δ :1.33 (6H, s), 2. 15 (6H, s), 2.39(3 iH—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2. 15 (6H, s), 2.39 (3
6 6
H, s), 2.46 (3H, s), 3.61 (2H, s), 3.86 (4H, s), 6.98 (2H, s), 7.40 (2H , d, J = 8.6Hz), 7.79 (2H, d, J=8.6Hz), 8.65 (1H, s) . H, s), 2.46 (3H, s), 3.61 (2H, s), 3.86 (4H, s), 6.98 (2H, s), 7.40 (2H, d, J = 8.6Hz), 7.79 (2H, d , J = 8.6Hz), 8.65 (1H, s).
元素分析値 C H NO ·0.5HOとして Elemental analysis value as C H NO 0.5 HO
27 32 6 4 2 27 32 6 4 2
計算値: C, 63.14;H, 6.48;N, 16.36. Calculated values: C, 63.14; H, 6.48; N, 16.36.
実測値: C, 63.16;H, 6.47;N, 15.99. Found: C, 63.16; H, 6.47; N, 15.99.
[0769] [実施例 60] [0769] [Example 60]
(l)2-[4-[[(2, 2 ジフルォロェチル)一(5—メチルー 2 フエ-ルー 2H—[1, (l) 2- [4-[[(2, 2 Difluoroethyl) mono (5-methyl-2-ferule 2H- [1,
2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2 メチルプロピオン酸 ェチル エステル 2,3] Triazol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2 methyl propionate ethyl ester
[0770] [化 236] [0770] [Chemical 236]
[0771] 参考例 44— (2)で得たィ匕合物(0.105g)と参考例 11— (1)で得たィ匕合物(0.11 Og)をジクロロメタン(5ml)に溶解し、トリァセトキシ水素化ホウ素ナトリウム(0.106g) を加えて、室温で 21時間攪拌した。炭酸水素ナトリウム水をカ卩えて、ジクロロメタンで 3回抽出した。飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留 去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸ェチル:へキサン = 1: 4)で 精製し、参考例 11— (1)の化合物と標題ィ匕合物の混合物 (0.105g)を無色油状物 として得た。 [0771] Reference Example 44— The compound (0.105 g) obtained in (2) and the reference compound 11- (1) (1) were dissolved in dichloromethane (5 ml) and triacetoxy was added. Sodium borohydride (0.106 g) was added and stirred at room temperature for 21 hours. Aqueous sodium hydrogen carbonate was added and extracted three times with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give a mixture (0.105 g) of the compound of Reference Example 11— (1) and the title compound as a colorless oil.
MS m/z:501(M+H)+. MS m / z: 501 (M + H) +.
[0772] (2)2— [4— [[(2, 2 ジフルォロェチル)一(5—メチルー 2 フエ-ルー 2H— [1, 2, 3]トリァゾールー 4—ィルメチル)ァミノ]メチル ]—2, 6 ジメチルフエノキシ]—2
メチルプロピオン酸 [0772] (2) 2— [4— [[(2, 2 Difluoroethyl)-(5-methyl-2 ferro- 2H- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 Dimethylphenoxy] —2 Methyl propionic acid
[0773] [化 237] [0773] [Chemical 237]
[0774] 実施例 60— (1)で得た混合物を、実施例 1— (2)と同様に処理後、薄層シリカゲル クロマトグラフィー(7%メタノール—クロ口ホルム)で精製して標題ィ匕合物を得た。この ものに 4規定塩酸—ジォキサン溶液 (0.063ml)をカ卩えて、減圧下濃縮乾固すること により標題ィ匕合物の塩酸塩 (0.060g)を無色固体として得た。 Example 60— After treating the mixture obtained in (1) in the same manner as in Example 1— (2), the mixture was purified by thin layer silica gel chromatography ( 7 % methanol-chloroform form). A compound was obtained. To this was added a 4N hydrochloric acid-dioxane solution (0.063 ml), and the mixture was concentrated to dryness under reduced pressure to give the title compound hydrochloride (0.060 g) as a colorless solid.
[0775] 'H-NMR (400MHz, DMSO d) δ :1. 31 (6H, s) , 2. 12(6H, s), 2. 21(3 [0775] 'H-NMR (400MHz, DMSO d) δ: 1.31 (6H, s), 2. 12 (6H, s), 2. 21 (3
6 6
H, s), 2. 92 (2H, dt, J=4. 2, 15.4Hz), 3.60 (2H, s), 3. 79 (2H, s), 6. 1 0(1H, tt, J=4. 2, 55. 9Hz), 6. 93 (2H, s), 7. 36(1H, t, J = 7.6Hz), 7. 5 3(2H, t, J = 7.6Hz), 7. 93 (2H, d, J = 7.6Hz) . H, s), 2. 92 (2H, dt, J = 4, 2, 15.4Hz), 3.60 (2H, s), 3. 79 (2H, s), 6. 1 0 (1H, tt, J = 4. 2, 55.9Hz), 6.93 (2H, s), 7.36 (1H, t, J = 7.6Hz), 7.5 3 (2H, t, J = 7.6Hz), 7.93 (2H, d, J = 7.6Hz).
元素分析値 C H FNO ·0. 6HC1-0. 75H Oとして Elemental analysis value C H FNO · 0.6HC1-0.75H O
25 30 2 4 3 2 25 30 2 4 3 2
計算値: C, 59. 12;H, 6. 37; CI, 4. 19;F, 7.48;N, 11.03. Calculated values: C, 59. 12; H, 6. 37; CI, 4. 19; F, 7.48; N, 11.03.
実測値: C, 59. 30;H, 6. 36;C1;4. 39;F, 7.41;N, 10.87. Found: C, 59. 30; H, 6. 36; C1; 4. 39; F, 7.41; N, 10.87.
[0776] [試験例 1] [0776] [Test Example 1]
GAL4— hPPAR トランスァクチべーシヨンアツセィ GAL4— hPPAR transactivation assembly
(a)プラスミド (a) Plasmid
GAL4 DNA結合領域 PPARリガンド結合領域の融合蛋白発現プラスミド pFA -hPPAR a /GAL4および pFA— hPPAR y /GAL4は、それぞれ hPPAR aお よび hPPARyの LBD cDNAを、 CMVプロモーター下に酵母の GAL4 DNA結 合領域(GAL4 DBD)を持つ市販の発現ベクター(pFA trans -Activator pla smids, STRATAGENE社)に組み込むことで得た。レポーター蛋白発現プラスミド は、分泌型アルカリフォスファターゼ(SEAP)の cDNA上流に GAL4応答領域(GA L4 UAS)を持つ市販のプラスミド(pFR— SEAP, STRATAGENE社)を使用し
た。 GAL4 DNA binding region PPAR ligand binding region fusion protein expression plasmids pFA -hPPAR a / GAL4 and pFA— hPPAR y / GAL4 are the hPPAR a and hPPARy LBD cDNAs respectively, and the yeast GAL4 DNA binding region under the CMV promoter (GAL4 DBD) was obtained by incorporating into a commercially available expression vector (pFA trans-Activator plasmids, STRATAGENE). As a reporter protein expression plasmid, a commercially available plasmid (pFR—SEAP, STRATAGENE) having a GAL4 response region (GA L4 UAS) upstream of the secretory alkaline phosphatase (SEAP) cDNA is used. It was.
[0777] (b)細胞培養およびトランスァクチべーシヨンアツセィ [0777] (b) Cell culture and transactivation assembly
10%ゥシ胎仔血清(Hyclone社)、 100単位 ZmLペニシリン Gおよび lOOmgZm L硫酸ストレプトマイシンを含む高グルコースのダルベッコの調整イーグル培地(DM EM)に HEK293T細胞を懸濁し、 24ゥエル細胞培養プレートに 8 X 104個 Zゥェル の密度で播種した。 5%COの加湿雰囲気下に 37°Cで 24時間培養後、製造業者の Suspend HEK293T cells in high glucose Dulbecco's conditioned Eagle's medium (DM EM) containing 10% urine fetal serum (Hyclone), 100 units ZmL penicillin G and lOOmgZm L streptomycin sulfate, and add 8 X 10 4 seeded at a density of Zwell. After 24 hours of incubation at 37 ° C in a humidified atmosphere of 5% CO, the manufacturer's
2 2
説明に従ってリポフエクトァミン(Lipofectamine, Invitrogen社)およびプラス試薬 ( Plus Reagent, Invitrogen社)を用いて無血清条件下でトランスフエクシヨンを行つ た。すなわち、リポフエクトァミン 0. 48 μ L、 pFA—PPAR/GAL4発現プラスミド 0. 030 μ g、 pFR- SEAPO. 13 μ gを含む 225 μ Lのトランスフエクシヨン用培地 (OPT I— MEM, Invitrogen社)中、 5%CO雰囲気下に 37°Cで、細胞を 5時間インキュべ According to the description, transfection was performed under serum-free conditions using Lipofectamine (Lipofectamine, Invitrogen) and Plus Reagent (Invitrogen). In other words, 0.48 μL of lipofectamine, 030 μg of pFA—PPAR / GAL4 expression plasmid, 0.030 μg, and pFR-SEAPO. 13 μg (OPT I—MEM, Invitrogen Incubate the cells for 5 hours at 37 ° C in a 5% CO atmosphere.
2 2
ートした。次に、 10%ゥシ胎仔血清、 100単位 ZmLペニシリン Gおよび lOOmgZm L硫酸ストレプトマイシンおよび指定の 2倍濃度の被験化合物を含む新鮮な高ダルコ ース DMEMを等容量添加し、細胞を約 48時間インキュベートした。化合物を DMS O中で可溶ィ匕したことから、同等濃度の DMSOとともに対照細胞のインキュベーショ ンを行った。なお、最終 DMSO濃度は 0. 1 %以下であり、その濃度はトランスァクチ ベーシヨン活性には影響しないことが明らかになつている。インキュベーション終了後 、培養上清を回収し、キット(Reporter assay kit— SEAP, TOYOBO社)を用い て製造業者の説明に従って SEAP活性を測定した。すなわち、培養上清 5 Lに等 量の内在性アルカリフォスファターゼ阻害液をカ卩えて 37°Cで 30分間インキュベートし 、次に化学発光基質(Lumiphos PLUS, Lumigen)を 100 L添カ卩して 37°Cで 1 5分間インキュベートした後、発光をマルチラベルカウンター(ARVOsx, PerkinEl mer)を用いて測定した。上記操作により得られた値と被験化合物の濃度との関係を プロットし、 EC 値を求めた。 I started. Next, add an equal volume of 10% urine fetal serum, 100 units ZmL penicillin G and lOOmgZm L streptomycin sulfate and the specified 2X concentration of test compound, and incubate the cells for approximately 48 hours. did. Since the compounds were soluble in DMS O, control cells were incubated with an equivalent concentration of DMSO. The final DMSO concentration is 0.1% or less, and it has been revealed that the concentration does not affect the transactivation activity. After completion of the incubation, the culture supernatant was collected, and SEAP activity was measured using a kit (Reporter assay kit—SEAP, TOYOBO) according to the manufacturer's instructions. That is, 5 L of the culture supernatant was mixed with an equal volume of endogenous alkaline phosphatase inhibitor, incubated at 37 ° C for 30 minutes, and then added with 100 L of chemiluminescent substrate (Lumiphos PLUS, Lumigen). After incubation for 15 minutes at ° C, luminescence was measured using a multilabel counter (ARVOsx, PerkinElmer). The EC value was obtained by plotting the relationship between the value obtained by the above operation and the concentration of the test compound.
50 50
[0778] <試験結果 > [0778] <Test results>
下表に示すように、本発明の化合物は、強力な GAL4— hPPAR トランスァクチべ ーシヨン活性を示した。 As shown in the table below, the compounds of the present invention showed potent GAL4-hPPAR transactivation activity.
[0779] [表 1]
G A I.4 - h P P AR 卜ランスァクチべーシヨン活'性 (μ Μ) 実施例番号 [0779] [Table 1] GA I.4-h PP AR 卜 Lance activation activity (μ Μ) Example number
P PAR a P PAR γ P PAR a P PAR γ
実施例 2— ( 2) 0. O i l 0. 3 2 実施^ 5— ( 2) 0. O i l 0. 2 3 実施例 1 5— (2) 0. 00 2 8 0. 00 8 9 実施例 4 8— (2) 0. 0 8 0 0. 06 9 実施例 5 2— (2) 0. 0 0 7 1 0. 0 1 5 Example 2— (2) 0. O il 0. 3 2 Example ^ 5— (2) 0. Oil 0. 2 3 Example 1 5— (2) 0.00 2 8 0. 00 8 9 Example 4 8— (2) 0. 0 8 0 0. 06 9 Example 5 2— (2) 0. 0 0 7 1 0. 0 1 5
[0780] 本発明を詳細にまた特定の実施態様を参照して説明したが、本発明の精神と範囲 を逸脱することなぐ様々な変更や修正を加えることができることは当業者にとって明 らかである。 [0780] Although the present invention has been described in detail and with reference to certain embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. is there.
本出願は、 2004年 8月 5日出願の日本特許出願 (特願 2004— 229445)に基づくもの であり、その内容はここに参照として取り込まれる。 This application is based on a Japanese patent application filed on August 5, 2004 (Japanese Patent Application No. 2004-229445), the contents of which are incorporated herein by reference.
産業上の利用可能性 Industrial applicability
[0781] 本発明の一般式 (I)で表される化合物は、糖尿病の予防.治療薬として有用である
[0781] The compound represented by the general formula (I) of the present invention is useful as a preventive or therapeutic agent for diabetes.